Practical Issues in Geriatrics

Series Editor: Stefania Maggi

Antonio Cherubini
Arduino A. Mangoni
Denis O’Mahony
Mirko Petrovic Editors

Optimizing
Pharmacotherapy
in Older Patients
An Interdisciplinary Approach
Practical Issues in Geriatrics

Series Editor
Stefania Maggi, Aging Branch, CNR-Neuroscience Institute
Padua, Italy
This practically oriented series presents state of the art knowledge on the principal
diseases encountered in older persons and addresses all aspects of management,
including current multidisciplinary diagnostic and therapeutic approaches. It is
intended as an educational tool that will enhance the everyday clinical practice of
both young geriatricians and residents and also assist other specialists who deal
with aged patients. Each volume is designed to provide comprehensive information
on the topic that it covers, and whenever appropriate the text is complemented by
additional material of high educational and practical value, including informative
video-clips, standardized diagnostic flow charts and descriptive clinical cases.
Practical Issues in Geriatrics will be of value to the scientific and professional
community worldwide, improving understanding of the many clinical and social
issues in Geriatrics and assisting in the delivery of optimal clinical care.
Antonio Cherubini • Arduino A. Mangoni
Denis O’Mahony • Mirko Petrovic
Editors

Optimizing
Pharmacotherapy in Older
Patients
An Interdisciplinary Approach
Editors
Antonio Cherubini Arduino A. Mangoni
Geriatric Discipline of Clinical Pharmacology
Geriatric Admissions and Aging Research College of Medicine and Public Health,
Center, IRCCS INRCA Flinders University
Ancona, Italy Bedford Park, SA, Australia

Denis O’Mahony Mirko Petrovic

Department of Medicine, and Department Section of Geriatrics, Department of
of Geriatric Medicine Internal Medicine and Paediatrics
Cork University Hospital Ghent University
Cork, Ireland Gent, Belgium

ISSN 2509-6060     ISSN 2509-6079 (electronic)

Practical Issues in Geriatrics
ISBN 978-3-031-28060-3    ISBN 978-3-031-28061-0 (eBook)
https://doi.org/10.1007/978-3-031-28061-0

© Springer Nature Switzerland AG 2023

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Foreword

Aging seems to be a longer lasting pandemic than COVID. Older people enjoy liv-
ing happily despite a rapidly increasing disease burden, and this has to do with the
robust and expanding achievements of hygiene and medicine. This may or may not
include the most important option for treatment in almost all therapeutic areas,
which is the prescription of drugs. Medication can positively contribute to disease
prevention and mitigation, but due to inevitable side effects it could also be limiting
the enjoyment of life or even end it.
This topic of medication in older people thus is of paramount importance for this
steadily growing population part of our industrial societies. The new book on
Optimizing pharmacotherapy in older patients is one of the very few attempts to
condense our knowledge on this issue and comprehensively detail the dimensions,
implications, and technical accommodations for coping with this challenging aspect
of medicine. In its 29 chapters, the book deals with the epidemiology of “polyphar-
macy” (a widely used, but incorrect term which should rather be multimedication),
the detrimental impact of some pharmacodynamic and pharmacokinetic features of
the aging body on therapeutic outcomes and on instruments, practices, and tools to
optimize medication use in older people. Catchwords like “deprescribing” or
“potentially inappropriate medications” (PIM) are defined and discussed in the cur-
rent scientific context. Drug–drug, drug–nutrient, and drug–disease interactions are
being exemplified, issues of adherence and the roles of potential networking part-
ners such as pharmacists addressed in chapters by outstanding researchers in
the area.
The content of this first section on general issues is applied to geriatric syn-
dromes such as frailty or falls, and to special aspects of medications for frequent
diseases in older people (e.g., hypertension or heart failure) in the second main part
of the book.
It thus does not only provide the theoretical background but also practical,
disease-­oriented solutions to medication-related problems in older people.
In its comprehensive approach, this book provides all relevant information for
enabling a better and more appropriate medication process in the geriatric popula-
tion. The book, thus, addresses physicians both in ambulatory and clinical care,
pharmacists, nursing staff, and all care providers involved in the complex process of
individualized medication in older people. Only few similar books have been

v
vi Foreword

published on this important issue to date, but none is comparably actual and
comprehensive.
We are convinced that this new book is instructive, helpful, and protective in this
context by not only showing the risks, but also the opportunities by the correct
application of drugs in older people. It clearly conveys that drugs may harm, but
also successfully treat older people if chosen correctly. The current FORTA-list con-
tains 41% of positively labelled drugs. Thus, the right drug for the right patient is
still a very good option for older people to live longer and/or better.
In the name of all those patients benefitting from the book, we sincerely thank
the editors and authors for the creation of this important work.

Co-leader EuGMS Special Interest Group on Pharmacology Rob van Marum

Amsterdam, The Netherlands
Department of General Practice and Elderly Care Medicine
Amsterdam Public Health Research Institute
Amsterdam UMC, VUmc
Amsterdam, The Netherlands
Departments of Clinical Pharmacology and Geriatrics
Jeroen Bosch Hospital
‘s-Hertogenbosch, The Netherlands

Co-leader EuGMS Special Interest Group on Pharmacology Martin Wehling

Mannheim, Germany
Institut für Experimentelle und Klinische Pharmakologie
und Toxikologie Klinische Pharmakologie Mannheim
Medizinische Fakultät Mannheim der Universität
Heidelberg, Germany
December 2022
Contents

Part I General Issues

1
The Impact of Ageing on Pharmacokinetics��������������������������������������������   3
Arduino A. Mangoni and Elzbieta A. Jarmuzewska
2
Polypharmacy: Definition, Epidemiology, Consequences
and Solutions���������������������������������������������������������������������������������������������� 15
Donal Fitzpatrick and Paul F. Gallagher
3
Drug–Drug and Drug–Nutrients Interactions:
From Theory to Clinical Relevance���������������������������������������������������������� 33
Eline M. de Koning, Jeannine Huisbrink, and Wilma Knol
4
Inappropriate Prescription of Medicines������������������������������������������������ 47
Denis O’Mahony
5 Prescribing Cascades �������������������������������������������������������������������������������� 59
Shelley A. Sternberg, Jerry H. Gurwitz, and Paula A. Rochon
6
Adverse Drug Reactions in Older People: A Twenty-First
Century View���������������������������������������������������������������������������������������������� 69
Mary Randles and Denis O’Mahony
7
Adherence: How to Measure and Improve It������������������������������������������ 81
Alessandra Marengoni and Laura J. Sahm
8
Medication Reconciliation and Review: Theory, Practice
and Evidence���������������������������������������������������������������������������������������������� 91
Tamasine Grimes and Cristin Ryan
9
The Role of Pharmacists in Optimising Drug Therapy�������������������������� 105
Anne Spinewine, Stephen Byrne, and Olivia Dalleur

vii
viii Contents

10
Deprescribing: Evidence Base and Implementation������������������������������ 119
Denis Curtin and Denis O’Mahony

Part II Geriatric Syndromes and Common Chronic Conditions

11
General Principles of Management of Patients with
Multimorbidity and Frailty���������������������������������������������������������������������� 131
Camilla Cocchi, Graziano Onder, and Maria Beatrice Zazzara
12 Frailty and Drug Therapy������������������������������������������������������������������������ 143
Annette Eidam, Matteo Cesari, and Jürgen M. Bauer
13
Falls and Impaired Mobility �������������������������������������������������������������������� 161
Lotta Seppala and Nathalie van der Velde
14
Optimizing Pharmacotherapy in Older Patients: Delirium������������������ 173
Giuseppe Bellelli and Alessandro Morandi
15 Optimizing Pharmacotherapy in Older Adults:
Urinary Incontinence�������������������������������������������������������������������������������� 185
Antoine Vella and Claudio Pedone
16 Constipation����������������������������������������������������������������������������������������������� 199
Giammarco Fava
17 Pain�������������������������������������������������������������������������������������������������������������� 217
Sophie Pautex, Monica Escher, and Petra Vayne-Bossert
18 Hypertension���������������������������������������������������������������������������������������������� 229
Timo E. Strandberg, Mirko Petrovic, and Athanase Benetos
19 Heart Failure���������������������������������������������������������������������������������������������� 239
T. L. De Backer and A. A. Mangoni
20
Pharmacological Treatment of Cognitive and Behavioral
Disorders in Dementia ������������������������������������������������������������������������������ 269
F. Trotta, L. Biscetti, and A. Cherubini
21
Pharmacological Treatment of Osteoporosis in Older Patients������������ 289
Marian Dejaeger, Jolan Dupont, Michaël R. Laurent,
and Evelien Gielen
22
Chronic Respiratory Disease: COPD, IPF���������������������������������������������� 311
Raffaele Antonelli Incalzi and Filippo Luca Fimognari
23 Diabetes Mellitus���������������������������������������������������������������������������������������� 331
Edoardo Mannucci and Daniele Scoccimarro
24
Stroke Therapeutics in the Care of Older Persons �������������������������������� 349
A. Bahk, F. A. Kirkham, Y. T. Ng, and Chakravarthi Rajkumar
Contents ix

25
Optimizing Pharmacotherapy in Older Patients
with Depression or Anxiety ���������������������������������������������������������������������� 369
Sylvie Bonin-Guillaume
26
Nutritional Deficiency and Malnutrition ������������������������������������������������ 381
Eva Kiesswetter and Cornel C. Sieber
27
Pharmacotherapy of Insomnia in Older Adults�������������������������������������� 391
Mirko Petrovic
28
Optimizing Pharmacotherapy in Older Patients:
An Interdisciplinary Approach: Chronic Kidney Disease �������������������� 405
Andrea Corsonello, Antonello Rocca, Carmela Lo Russo,
and Luca Soraci
29
Palliation at End of Life���������������������������������������������������������������������������� 427
Joanne Droney, Phoebe Wright, and Dola Awoyemi
Index�������������������������������������������������������������������������������������������������������������������� 441
Part I
General Issues
The Impact of Ageing
on Pharmacokinetics 1
Arduino A. Mangoni and Elzbieta A. Jarmuzewska

1.1 Introduction

The age-associated accumulation and coexistence of disease states and the increas-
ingly proactive approach towards disease management by healthcare professionals
have led to an increased medication use in the older patient population [1, 2].
However, a concomitant increasing exposure to drugs that are potentially inappro-
priate has also been extensively reported, with the consequent risk of toxicity and its
clinical sequelae, for example, falls, cognitive impairment, hospitalisation and death
[3–8]. The predisposition of older people to the unintended effects of drug exposure
is largely due to specific alterations in body composition, organ function and homeo-
static capacity, both at the cellular and the system level, that may influence the
pharmacokinetics of several drugs [9]. Such alterations, in turn, lead to excessive
drug accumulation and an increased risk of drug–drug and drug–disease interac-
tions, particularly in the context of inappropriate prescribing and polypharmacy [9].
A better understanding of the main pharmacokinetic changes associated with
advancing age might play an important role in minimising the burden of inappropri-
ate polypharmacy. This burden is particularly high in frail patients, an ever-growing
subgroup characterised by reduced functional capacity and marked vulnerability to
adverse health outcomes [10].

A. A. Mangoni (*)
Discipline of Clinical Pharmacology, College of Medicine and Public Health,
Flinders University and Flinders Medical Centre, Adelaide, SA, Australia
Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local
Health Network, Adelaide, Australia
e-mail: [email protected]
E. A. Jarmuzewska
Department of Internal Medicine, Polyclinic IRCCS, Ospedale Maggiore, University of
Milan, Milan, Italy
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 3

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_1
4 A. A. Mangoni and E. A. Jarmuzewska

This chapter describes the main physiological and pathophysiological changes in

organ function and homoeostatic capacity occurring with human ageing and the
current knowledge on the effects of advancing age on the four pillars of pharmaco-
kinetics, that is, absorption, distribution, metabolism and elimination. A critical
appraisal of the available evidence and the potential use of pharmacokinetic data in
the routine care of older patients are also discussed. In particular, the development
of robust, yet relatively simple, pharmacokinetic-based prescribing tools that assist
with therapeutic decisions are likely to augment therapeutic efficacy and minimise
toxicity in this highly heterogeneous patient group.

1.2 Age-Associated Changes in Organs and Systems

A critical determinant of the pharmacokinetic changes observed with advancing age

is the occurrence of structural and/or functional alterations in the body overall, that
is, body composition as well as specific organs and systems, that is, cardiovascular
system, kidney and gastrointestinal system (Table 1.1).

1.2.1 Body Composition

Under physiological circumstances, the fat mass, body mass index (BMI) and per-
centage of body fat progressively increase from age 20 and tend to level off at
approximately 80 years in men. By contrast, the fat-free mass increases slightly
from age 20 to 47 and then declines with advancing age [11]. Similar observations
have been reported in other studies, although women have been shown to have
higher percentage body mass values than men across different age groups [12].
Furthermore, the actual age-related increase in fat mass and decrease in lean mass
appear to be somewhat attenuated in women [13]. The possible implications of
gender-­associated differences in body composition trajectories across age groups,
both in terms of pharmacokinetics and clinical effects, require further studies.

1.2.2 Cardiovascular System

Left ventricular ejection fraction and cardiac output at rest are both preserved in
healthy older adults. However, the increase in left ventricular ejection fraction that
is normally observed during exercise is blunted in old age, mainly due to a reduction

Table 1.1 Main age-associated structural and functional changes in organs and systems
 • Relative increase in body fat and reduction in lean mass
 • Blunted cardiac output and heart rate response during exercise
 • Reduction in kidney volume and glomerular filtration rate
 • Reduction in liver volume and hepatic blood flow
1 The Impact of Ageing on Pharmacokinetics 5

in ejection fraction reserve [14]. Similarly, although the resting heart rate is not
significantly different compared to younger cohorts, a significant reduction in the
maximal, exercise-induced heart rate is observed with advancing age [14]. The lat-
ter is primarily responsible for the age-associated reduction in maximal cardiac out-
put, in the presence of a preserved stroke volume [14]. Therefore, physiological
ageing is not associated with significant changes in cardiac function under resting
conditions. Rather, it is characterised by a diminished overall cardiac reserve and
cardiac output during stress, which might adversely affect the perfusion to critical
organs, for example, the liver and the kidney, involved in drug metabolism and
elimination. The prevalence of heart failure, particularly the subtype with left ven-
tricular dysfunction and reduced ejection fraction, increases significantly with
advancing age [15]. In these patients, the reduced peripheral organ perfusion and
increased venous pressure, with or without concomitant kidney and/or liver disease,
might exert significant effects on pharmacokinetics [16, 17].

1.2.3 Kidney

A progressive volume loss of the kidneys, primarily affecting the cortex, is typically
observed after the age of 50 [18]. There is also a concomitant reduction in glomeru-
lar filtration rate (GFR), approximately 1 mL/min per year, after the age of 40 [19].
These processes can be accelerated by conditions such as hypertension and diabe-
tes, the main causes of chronic kidney disease (CKD) worldwide [20]. Additionally,
age-­associated alterations in tubular structure and function can impair the capacity
to reabsorb sodium and secrete hydrogen and potassium, increasing the risk of fluid,
electrolyte and acid–base abnormalities in older adults [21].

1.2.4 Gastrointestinal System

There is no convincing evidence that advancing age per se is associated with signifi-
cant changes in gastric emptying, intestinal transit or absorptive capacity of the
small intestine and the colon, despite a reduced gastric secretion of hydrochloride
acid and the presence of morphological changes in enterocytes [22–24]. By con-
trast, a significant age-related reduction, between 20 and 50%, in liver mass and
hepatic blood flow has been reported [25].

1.3 Age-Associated Changes in Pharmacokinetics

1.3.1 Absorption

The absorption process for drugs administered orally predominantly occurs in the
small intestine through passive diffusion or active transport [26]. With advancing
age, drug absorption via passive diffusion across the gastrointestinal epithelium
6 A. A. Mangoni and E. A. Jarmuzewska

seems to be relatively preserved [27], whilst a reduction in the active transport of

iron, calcium and vitamin B12 has been reported [28]. Similarly, the function and the
expression of p-glycoprotein, the main intestinal efflux transporter, seems to be pre-
served in older age [29]. Whilst more research is required to investigate the effects
of ageing, with or without concomitant disease states, on intestinal absorption, the
reported age-related reduction in gastric acid production might affect the dissolu-
tion of drugs in the stomach [30]. This effect is likely augmented by the common,
albeit often inappropriate, use of proton pump inhibitors in the older population [5,
31]. The consequent increase in gastric pH may facilitate the absorption of weakly
acidic drugs, a result of increased dissolution, and reduce the absorption of weakly
basic drugs, due to decreased dissolution. By contrast, gastric emptying does not
seem to be significantly altered in older adults, in absence of comorbidities such as
diabetes and Parkinson’s disease [27]. For drugs that are administered via non-oral
routes, there is virtually no information available regarding possible age-related
alterations in absorption. Therefore, research is warranted to investigate the effects
of advancing age, if any, on the extent and the rate of non-oral drug absorption.

1.3.2 Distribution

In line with the previously described age-related changes in body composition, that
is, relative reduction in total body water and lean muscle mass and concomitant
increase in body fat, the volume of distribution of highly lipophilic drugs, for exam-
ple, benzodiazepines, significantly increases in older adults [32]. As a result, there
is a prolongation in the elimination half-life, in absence of significant changes in
clearance (see formula below), with the risk of drug accumulation and toxicity [33]:
0.693 ´ Vd
t½ = ,
CL
where t½ is the half-life, Vd is the volume of distribution and CL is the clearance.
For example, in a study in healthy subjects divided in two age groups (young
adults, n = 7, age 28 ± 4 years; older adults, n = 8, age 69 ± 6 years), the half-life of
diazepam in older adults was nearly three times that of younger participants (86 ± 36
vs. 31 ± 12 h, p < 0.005) [34]. By contrast, the volume of distribution of highly
hydrophilic medications, for example, digoxin, tends to decrease in the older patient
population. In a pharmacokinetic study, the volume of distribution of digoxin in older
and younger participants was 4.1 ± 0.9 L/kg and 5.3 ± 0.6 L/kg, respectively [35].
A progressive reduction in the serum concentrations of the drug-binding protein
albumin has been reported with advancing age [36, 37]. Such changes may theoreti-
cally affect the active, unbound, portion of highly protein-bound drugs, for example,
warfarin and phenytoin. However, the rapid equilibrium occurring through drug elimi-
nation significantly limits this phenomenon’s biological and clinical significance,
therefore, minimising fluctuations in the concentrations of the unbound fraction [38].
1 The Impact of Ageing on Pharmacokinetics 7

1.3.3 Metabolism

The process of drug metabolism occurs primarily in the liver and involves the
biotransformation of active drugs into more soluble inactive or active metabolites
that subsequently undergo renal elimination [39]. These reactions include Phase I
functionalisation (i.e. oxidation, reduction and hydrolysis, mediated by the cyto-
chrome P450 enzyme superfamily) and Phase II conjugation (i.e. acetylation,
glucuronidation and sulphation, mediated by transferases) [40]. Phase I and II
reactions have also been described in the intestine, lung and kidney. However, the
biological and clinical significance of these extra-hepatic reactions are not fully
established [41].

1.3.3.1 Hepatic Blood Flow

The previously described age-related decrease in liver mass and hepatic blood flow
can potentially reduce the metabolism, particularly first-pass, of drugs with high
(>0.7) extraction ratio, defined as the ratio between hepatic clearance and hepatic
blood flow. The reduction in metabolism is likely to be clinically significant (>50%)
with amitriptyline and fentanyl [42]. Consequently, both the loading and the main-
tenance dose of such drugs should be decreased in older age [43]. By contrast, drugs
with relatively low extraction ratio are not significantly affected by alterations in
hepatic blood flow; however, they can be affected by modifications in the intrinsic
metabolising capacity of the liver (see below).

1.3.3.2 Phase I–II Metabolism

Studies have shown a 30–50% reduction in the clearance of several drugs undergo-
ing Phase I metabolism; however, it is unclear whether this is due to a reduction in
the expression and/or activity of specific cytochrome P450 isoforms, hepatic blood
flow or a combination of both [44–47]. This issue notwithstanding, caution is rec-
ommended when prescribing high- and low-extraction drugs undergoing significant
Phase I metabolism in older patients. Examples of such drugs include clozapine
(metabolised by CYP1A2), citalopram (metabolised by CYP2C19) and carbamaze-
pine (metabolised by CYP3A4).
In contrast to Phase I metabolism, there is no clear evidence that advancing age
affects Phase II metabolism in healthy individuals [48–51]. However, a reduction in
Phase II metabolism of paracetamol, metoclopramide and aspirin has been reported
in frail older patients when compared to fit age-matched and younger healthy con-
trols [52–54]. The effect of frailty on Phase II metabolism might have additional
adverse clinical consequences that are independent of reduced drug elimination. For
example, the reduced Phase II conjugation of paracetamol results in the synthesis of
N-acetyl-p-benzoquinone imine, a highly toxic metabolite. The impaired detoxifica-
tion of N-acetyl-p-benzoquinone imine in frail subjects, secondary to the reduced
production of the antioxidant glutathione, might significantly increase the risk of
paracetamol-induced hepatotoxicity [55, 56].
8 A. A. Mangoni and E. A. Jarmuzewska

1.3.4 Drug Elimination

The kidneys are the main site of elimination of soluble drugs and their metabolites.
Renal clearance is considered to be the net result of glomerular filtration, tubular
excretion and tubular reabsorption [57]. The previously reported decline in GFR
with advancing age inevitably leads to impaired drug elimination and consequent
accumulation. This is particularly relevant for drugs that have a narrow therapeutic
index, for example, digoxin, lithium and gentamicin [58]. The dose of such drugs
should be reduced proportionally to the reduction in renal clearance and regularly
monitored [59].
The direct calculation of the GFR by measuring the renal clearance of inulin has
been replaced by formulae that estimate either the creatinine clearance or the GFR
(eGFR), the Cockcroft–Gault formula, the Modification of Diet in Renal Disease
formula and the CKD Epidemiology Collaboration formula [60–62]. However, the
available evidence regarding dose adjustment according to renal function is still
largely based on the Cockcroft–Gault formula.
There is increasing evidence that an impairment in renal function can also influ-
ence absorption, distribution and non-renal elimination. The accumulation of ure-
mic toxins in CKD can inhibit the expression and/or activity of CYP3A4, CYP1A2,
CYP2B6, CYP2C9 and CYP2D6 [63, 64]. Examples of drugs with reduced extra-­
renal clearance include carvedilol (CYP3A4, CYP2C9 and CYP2D6), ciprofloxacin
(CYP1A), cyclophosphamide (CYP2B6, CYP2C9 and CYP3A4), duloxetine
(CYP1A and CYP2D6), erythromycin (CYP3A4), solifenacin (CYP3A4) and
tadalafil (CYP3A4) [64]. In some cases, for example, intravenous midazolam
(CYP3A4), the increase in exposure, expressed as area under the concentration
curve, can be as high as sixfold in patients with renal failure when compared with
healthy controls [65].

1.4 General Considerations

The available evidence regarding the impact of ageing on pharmacokinetics, albeit

useful, needs to be interpreted with some caution (Table 1.2). Studies addressing
this issue have generally been conducted in relatively healthy older participants.
However, the age-related pharmacokinetic changes observed in clinical practice are
likely to be the result of complex organ–organ and/or drug–disease interactions in
patients with extensive medication exposure and comorbidity. This requires the con-
duct of studies in cohorts that are better representative of patients that are routinely
managed in clinical practice. Furthermore, most pharmacokinetic studies have
investigated relatively old drugs that are rarely prescribed in current medical prac-
tice [9, 16, 33, 66]. Therefore, additional research is warranted to investigate the
potential pharmacokinetic alterations of newer drugs, particularly cardiovascular,
anti-cancer and immunomodulating agents. Finally, there is emerging evidence that
frailty can affect Phase II metabolism, as previously discussed, and drug elimina-
tion, although other studies have reported negative results [53, 67–69]. The poten-
tial influence of frailty on drug metabolism and elimination further justifies the need
1 The Impact of Ageing on Pharmacokinetics 9

Table 1.2 Key changes in drug metabolism and elimination in older adults
 • Reduction in phase I metabolism, with consequent reduction in first-pass metabolism and
clearance
 • Reduction in phase II metabolism, with consequent reduction in clearance, in frail
subjects
 • Reduction in the clearance of renally excreted drugs
 • Reduction in non-renal drug elimination, through impaired phase I metabolism, in
patients with renal disease

Table 1.3 Areas requiring further pharmacokinetic studies in older age

 • Impact of frailty
 • Role of pharmacogenomics and ethnicity
 • Study of subjects >80 years
 • Impact of renal disease on extra-renal metabolism
 • Assessment of drugs prescribed in current practice

for pre- and/or post-marketing studies that also include frail older participants
(Table 1.3) [70, 69].

1.5 Pharmacokinetic Data for Personalised Prescribing

The incorporation of pharmacokinetic parameters, particularly those pertaining to

drug metabolism and elimination, into electronic tools can potentially assist with the
practice of personalised prescribing in a highly complex and heterogeneous patient
population. The difficulties in routinely assessing hepatic blood flow and the impact
of advancing age on Phase I and Phase II metabolism currently prevent the use of
these parameters for optimal selection of drugs and dose regimens in individual
patients. By contrast, an increasing contribution of the eGFR, an easily measurable
and robust marker of renal drug elimination, in personalised prescribing decisions is
anticipated. eGFR-based decisions are likely to assist not only with the selection of
specific treatments but also with dose adjustments over time. The increasing evidence
of a significant association between CKD and impairment in Phase I metabolism sug-
gests that eGFR-based prescribing decisions might not only be limited to the use of
renally cleared drugs but also include those undergoing significant Phase I metabo-
lism. However, any new prescribing tool that incorporates pharmacokinetic parame-
ters will require robust evidence of superiority versus standard of care or existing
tools, in terms of practicality, accessibility, risk of adverse drug reactions and clinical
and patient-centred outcomes [71], in adequately designed intervention trials.

1.6 Conclusions

The available evidence suggests that human ageing is characterised by several phar-
macokinetic changes, particularly an increased volume of distribution for highly
lipophilic drugs, a reduction in Phase I metabolism, a reduction in Phase II
10 A. A. Mangoni and E. A. Jarmuzewska

metabolism in the presence of frailty and a reduction in the clearance of renally

excreted drugs. Another potentially relevant age-related effect is the impaired Phase
I metabolism in older patient with chronic kidney disease. Whilst the routine use of
this information may, in principle, improve the quality and safety of drug prescrib-
ing, more research is warranted to investigate the specific impact of frailty, pharma-
cogenomics and drug–drug, drug–disease and organ–organ interactions. The results
of these studies will further assist with the development of personalised prescribing
tools that are likely to improve the quality of life and clinical outcomes in this ever-­
expanding patient population.

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6.1100074.
Polypharmacy: Definition,
Epidemiology, Consequences 2
and Solutions

Donal Fitzpatrick and Paul F. Gallagher

Sample Case Scenario

Ms. PP is an 82-year-old woman with the following past medical history and regular
medications:

Past medical history Current medications

 • Epilepsy 1. Valproate (slow release) 400 mg od
 • Ischaemic heart disease 2. Amlodipine 5 mg od
 • Hypertension 3. Amitriptyline 10 mg od
 • Mild cognitive impairment 4. Clopidogrel 75 mg od
 • Cervical spondylosis 5. Omeprazole 20 mg od

She attends her general practitioner (GP) for a routine visit and is noted to be
hypertensive. Amlodipine is prescribed. A few weeks later, she returns to her GP
with bilateral lower limb swelling. The GP prescribes furosemide. She then devel-
ops urinary frequency and is prescribed fesoterodine. She becomes delirious and is
admitted to the hospital. She becomes agitated and is prescribed haloperidol. She
develops constipation, urinary retention and a urinary tract infection. She has sev-
eral non-convulsive vacant episodes which are diagnosed as partial seizures. Her
medications are reviewed, and potentially inappropriate medications are depre-
scribed. Her delirium slowly resolves, and after a short period of rehabilitation, she
is discharged home.
Questions
1. What drug–disease interaction is illustrated in this case?
2. What drug–drug interactions (DDIs) are illustrated in this case?
3. Can you identify the prescribing cascade in this case?

D. Fitzpatrick
Department of Geriatric Medicine, Cork University Hospital, Cork, Ireland
P. F. Gallagher (*)
Department of Geriatric Medicine, Bon Secours Hospital, Cork, Ireland

© Springer Nature Switzerland AG 2023 15

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_2
16 D. Fitzpatrick and P. F. Gallagher

2.1 Introduction

The increasing age profile and consequent rising prevalence of multimorbidity

means that older people are taking more medications than ever before [1, 2]. The
concurrent use of multiple medications is referred to as polypharmacy, multimor-
bidity being the principal cause. Complex combinations of drugs are often hazard-
ous in older adults. Pharmacodynamic and pharmacokinetic changes in older adults
increases the risk of adverse drug interactions and adverse drug events [3–5].
In many cases, polypharmacy is justified. For example, after a myocardial infarc-
tion, a patient may require multiple medications for acute treatment and for second-
ary prevention [6]. It is therefore important to differentiate between appropriate and
inappropriate polypharmacy (Box 2.1).

Box 2.1 Definitions

Appropriate polypharmacy
Appropriate polypharmacy is present, when (a) all medicines are pre-
scribed for the purpose of achieving specific therapeutic objectives; (b) thera-
peutic objectives are actually being achieved or there is a high probability that
they will be achieved in the future; (c) medication therapy has been optimised
to minimise the risk of adverse drug reactions (ADRs) and adverse drug
events (ADEs); and (d) the patient is motivated and able to take all medicines
as intended [7].
Inappropriate polypharmacy
Inappropriate polypharmacy is defined as the prescribing of multiple medi-
cines inappropriately, or where the intended benefit of the medication is not
realised. It pertains to the prescription of drugs that:
• have no indication or an incorrect indication
• have a high risk of ADRs and ADEs
• are unnecessarily expensive
• are used for inappropriate duration (for too short or too long a time period)

2.2 Epidemiology of Polypharmacy

The prevalence of polypharmacy in older adults has uniformly increased across

Europe and in the United States over the last two decades [8–16]. This is intrinsi-
cally associated with rising prevalence of multimorbidity. Two-thirds of the
European older adult population have two or more chronic diseases [17]. A cross-­
sectional analysis of the Survey of Health, Ageing and Retirement in Europe
(SHARE) database found 20% of people aged 70–74 years were prescribed 10 or
more medicines [11], often referred to as ‘hyperpolypharmacy’.
Despite multimorbidity being the rule rather than the exception in older people,
clinical guidelines often follow a single disease approach with each comorbidity
generating prescription of additional medications without consideration of other
2 Polypharmacy: Definition, Epidemiology, Consequences and Solutions 17

health conditions or medications. Certain chronic conditions are particularly associ-

ated with polypharmacy including chronic obstructive pulmonary disease, atrial
fibrillation, hypertension, ischaemic heart disease, obesity and depression [9].
Inappropriate polypharmacy is associated with significant morbidity through
drug–drug interactions, drug–disease interactions, adverse clinical events and non-­
adherence. Up to 11% of all unplanned hospital admissions are attributable to
medicine-­related harm [18].

2.3 Age-Related Changes in Pharmacokinetics

and Pharmacodynamics

Ageing is associated with physiological changes which affect drug pharmacokinet-

ics (what the body does to the drug i.e. absorption, distribution, metabolism and
excretion) and pharmacodynamics (the effect of the drug on the body) [19]. There
is significant variability in the ageing process amongst individuals. This variability
is accentuated by the presence of chronic disease and the use of other medications.
Biochemical processes and organ function can often vary substantially between
individuals of the same age. This heterogeneity extends to drug pharmacokinetics
and pharmacodynamics, meaning that the clinical effects and adverse event profile
of medications are less predictable in older adults [5].

2.3.1 Pharmacokinetics

2.3.1.1 Absorption and Bioavailability

Normal ageing has minimal impact on drug absorption, which takes place predomi-
nantly in the small bowel. Prokinetic drugs such as domperidone and erythromycin
increase gastric emptying, potentially increasing the rate at which a drug is absorbed
after ingestion. Anticholinergic drugs can decrease saliva production, reducing the
rate but not necessarily the extent of drug absorption through the buccal mucosa, for
example, glyceryl trinitrate and midazolam.
The bioavailability of most drugs is not affected by normal ageing. However,
drugs such as morphine, buprenorphine, midazolam, propranolol, nitrates, vera-
pamil and tricyclic antidepressants undergo substantial first-pass hepatic metabo-
lism. Age-related reductions in liver volume and blood flow result in reduced
first-pass hepatic extraction leading to higher systemic bioavailability. For example,
the greater bioavailability of nitrates and verapamil in older patients can lead to
significant first-dose hypotension. Initial doses of these drugs should therefore be
reduced in older patients (“start low and go slow”).

2.3.2 Distribution

Ageing is associated with an increased volume of distribution (Vd) of lipid soluble

drugs. Older people generally have reduced lean muscle mass and therefore a
18 D. Fitzpatrick and P. F. Gallagher

relative increase in total body fat. This larger Vd results in longer elimination half-
lives and a tendency to accumulation of lipid soluble drugs such as morphine, ben-
zodiazepines, antipsychotics and amitriptyline. This increases the risk of toxicity
and adverse events such as falls and oversedation from these drugs. Smaller doses
and a slower up-titration should therefore be used in older people.
Conversely, the lower lean body mass in older patients means that for water-­
soluble drugs, the Vd is smaller than in younger adults leading to higher plasma
concentrations, and therefore, lower doses are necessary. For example, Vd of digoxin
falls with age, and the loading dose should be reduced in older adults [4]. Other
examples of this reduced Vd phenomenon include lithium, theophylline and
gentamicin.
Most drugs are inactive when they are bound to circulating plasma proteins (e.g.
albumin and α-1 glycoprotein). Serum albumin concentration decreases slightly in
older age [20]. More significant reductions in albumin are found in chronic disease
states, which can lead to higher concentrations of unbound (active) drug. This can
result in clinically significant effects for drugs, which are heavily protein bound, for
example, benzodiazepines, antipsychotics, non-steroidal anti-inflammatory drugs
(NSAIDs), warfarin and phenytoin. These drugs have a higher Vd in patients with
hypoalbuminaemia leading to longer half-lives and higher potential for toxicity [19].

2.3.2.1 Metabolism
Liver enzyme activity is preserved in ageing. However, many drug interactions of
patients affected by polypharmacy are mediated through inhibition and induction of
hepatic cytochrome p450 metabolising enzymes. Cytochrome p450 enzyme inhibi-
tion can cause a significant reduction in drug metabolism leading to toxic accumula-
tion. For example, haloperidol inhibits cytochrome p450 2D6, which is responsible
for the metabolism of amitriptyline. Therefore, haloperidol can exacerbate the
potential for anticholinergic side effects of amitriptyline by increasing its active
drug concentration. Similarly, clarithromycin can inhibit the metabolism of statins
leading to statin toxicity, including myositis and hepatitis.
Conversely, drugs such as carbamazepine and phenytoin can induce cytochrome
p450 enzymes, which can accelerate the metabolism and clearance of other drugs.
Clinically relevant examples of cytochrome p450 enzyme inhibitors include antimi-
crobials, antiarrhythmics and some anticoagulants (see Table 2.1) [19].

Table 2.1 Cytochrome p450 inducers and inhibitors

Enzyme Inducers Inhibitors
CYP1A2 Phenytoin, rifampin Ciprofloxacin, fluvoxamine
CYP2C9 Carbamazepine, Fluconazole
rifampin
CYP2D6 Bupropion, fluoxetine, paroxetine
CYP3A Carbamazepine, Macrolides (e.g. erythromycin, clarithromycin), azole
phenytoin, rifampicin, antifungals (e.g. voriconazole, itraconazole, ketoconazole,
St John’s wort fluconazole), protease inhibitors (e.g. indinavir, ritonavir,
saquinavir), cimetidine, grapefruit juice
2 Polypharmacy: Definition, Epidemiology, Consequences and Solutions 19

2.3.2.2 Elimination
The kidneys are primarily responsible for the removal of drugs and their metabolites
from the body. Ageing is associated with reduced renal size, perfusion and urine
concentrating capability, and even in healthy ageing, glomerular filtration rate
(GFR) begins to decline progressively from the age of 30 years onwards [21].
Chronic diseases such as hypertension and diabetes mellitus and the use of nephro-
toxic medications such as NSAIDs accelerate this decline in GFR.
Serum creatinine concentration should not be used as the sole measure to esti-
mate renal function in older adults, because production of creatinine is related to
muscle mass which, as discussed earlier, is significantly reduced in older adults.
Approximately 50% of older patients have a normal serum creatinine level but a
reduced creatinine clearance estimate. The Cockcroft–Gault formula [22], based on
serum creatinine, age, weight and sex, has been the most common method of esti-
mating GFR. This formula underestimates GFR in older adults and newer formulas
such as the CKD Epidemiology Collaboration (CKD-EPI, based on serum creati-
nine, age and sex) [23], are likely more accurate in older individuals. However,
many dosing recommendations are based on the Cockcroft–Gault formula.
Older adults frequently develop acute kidney injury (AKI) in the context of acute
illness and premorbid chronic kidney disease (CKD). Precipitating factors include
hypotension, dehydration, sepsis, cardiorenal syndrome and cardiac failure. Drugs
often mediate or exacerbate AKI in older adults especially NSAIDs, diuretics, ACE
inhibitors and angiotensin receptor blockers. These drugs often need to be stopped
temporarily in patients with an AKI or those at high risk of an AKI. Other drugs may
need to be reduced or stopped because of the risk of toxic accumulation during an
AKI or in the context of CKD, for example, lithium and metformin.

2.3.3 Pharmacodynamics

Pharmacodynamics is the study of the physiologic effect of drugs on the body.

Drugs mediate their effects by binding to receptors and target molecules within the
body. Ageing is associated with changes in receptor expression, activity and affinity
resulting in altered (usually increased) pharmacodynamic effects of commonly pre-
scribed drugs (Table 2.2). In practice, this means that older patients are more sensi-
tive to medications (obtain clinical effects and experience adverse effects) at doses
that produce a therapeutic effect and are normally used in younger patients, for
example, the anticoagulant response to warfarin is proportionately more potent in
older patients resulting in a greater risk of bleeding than in younger patients receiv-
ing the same dose.
Similarly, older patients are often more susceptible to the effects of drugs acting
on the central nervous system than younger patients. Reduced integrity of the blood
brain barrier and reduced cholinergic neurotransmission make older adults more
sensitive to the effects of anticholinergic drugs, benzodiazepines, opioids, antide-
pressants and antipsychotics.
20 D. Fitzpatrick and P. F. Gallagher

Table 2.2 Medications with altered pharmacodynamics in older patients

Age-related
pharmacodynamic Recommendation for
Drug change Clinical consequences use
Antipsychotics Increased sensitivity Typical Limit use if possible
Typical: to antipsychotics,  • Impaired mobility and review need for
Haloperidol, reduced dopamine and balance, gait ongoing prescription
chlorpromazine reserve, loss of disorders: regularly
Atypical: integrity of blood extrapyramidal Use smallest possible
Quetiapine, brain barrier effects: Parkinsonism dose and titrate up
risperidone, (tremor, rigidity, slowly
olanzapine bradykinesia) Avoid co-prescription
dystonia, akathisia— of anticholinergic
more commonly with medications and
typical than atypical sedative medications
drugs
Atypical
 • Orthostatic
hypotension
 • Sedation and
cognitive impairment
 • Weight gain
 • Incontinence
 • Anticholinergic
Benzodiazepines Greater sensitivity of  • Sedation and Avoid use if possible.
older patients to the cognitive impairment Use for shortest
effects of  • Mobility and balance duration possible
benzodiazepines impairment with
increased falls risk
 • Drug dependence
 • Impaired
consciousness and
respiratory
depression in toxicity
Calcium channel Reduced  • Greater hypotensive ‘Start low, go slow’
blockers baroreceptor effect—especially with dose
response to low first dose Apply caution if using
blood pressure  • Bradycardia concurrently with other
Greater sinoatrial antihypertensives or
suppressive effect heart rate-lowering
(verapamil, medications
diltiazem)
Diuretics Reduced diuretic  • Reduced efficacy at May need higher doses.
response due to conventional doses. Need to use cautiously
reduced tubular Increased risk of as more susceptible to
secretion of drug and hypokalaemia, hypotensive effects and
reduced GFR hypomagnesaemia dehydration. Use
cautiously with other
antihypertensives, ACE
inhibitors, NSAID’s
(continued)
2 Polypharmacy: Definition, Epidemiology, Consequences and Solutions 21

Table 2.2 (continued)

Age-related
pharmacodynamic Recommendation for
Drug change Clinical consequences use
Opioids Greater sensitivity to  • Sedation, cognitive Use lower doses and
opioids, more prone impairment, titrate up cautiously
to accumulation and hallucinations according to effect and
toxicity  • Nausea, vomiting, tolerability
constipation
 • Mobility and balance
impairment with
increased falls risk
 • Respiratory
depression in toxicity
 • Drug dependence
 • Orthostatic
hypotension
especially with
tramadol

Antihypertensive medications can be more challenging to use in older adults.

Altered autonomic regulation including reduced baroreceptor sensitivity to changes
in posture, combined with loss of elasticity in large arteries, means that older
patients are more likely to experience orthostatic hypotension, which is associated
with falls, injuries and reduced mobility. Alpha-1 adrenergic receptor antagonists,
such as doxazosin, are especially likely to induce orthostatic hypotension as they
counteract the reflex vasoconstriction that occurs normally when a person stands up.
Other drugs with anticholinergic properties such as tricyclic antidepressants and
first-generation antihistamines may also exacerbate orthostatic hypotension.
In general, in older patients, it is wise to commence a new drug at a low dose and
titrate the dose upward with caution, that is, ‘start low and go slow’.

2.3.4 Consequences of Polypharmacy

Clearly, some instances of polypharmacy are appropriate and justified. However

inappropriate polypharmacy leads to a range of potentially harmful consequences.
Each additional drug prescribed adds to the potential adverse effects he/she may
experience. The interplay of multiple drugs and comorbidities in an older person
with altered pharmacokinetics and pharmacodynamics often leads to drug–drug
interactions and drug–disease interactions with increased risk of adverse outcomes.

2.3.4.1 Drug–Drug Interactions

The potential for drug–drug interactions rises almost exponentially with the number
of prescribed medications [24]. The drugs most frequently involved with DDIs are
diuretics, antihypertensive drugs, anticoagulants, cardiac glycoside drugs and
22 D. Fitzpatrick and P. F. Gallagher

antithrombotic agents. Clinically significant drug–drug interactions are found in

80–90% of older patients hospitalised in geriatric units [25].
Drug–drug interactions can be pharmacokinetic where one drug affects the
absorption, distribution, metabolism or excretion of another drug or pharmacody-
namic, where a drug directly influences the effect of another drug on its receptor or
target molecule. Many of the common and significant drug–drug interactions are
pharmacokinetic, mediated through the cytochrome p450 system. Table 2.3 illus-
trates frequently encountered important drug–drug interactions.

Table 2.3 Examples of common and important drug–drug interactions

Drug interaction Mechanism Clinical significance
Lithium plus NSAIDs NSAIDs reduce NSAIDs increase the potential for
prostaglandin synthesis lithium toxicity
leading to vasoconstriction of
the afferent arteriole of the
glomerulus reducing GFR
Nitrates plus Increased cyclic guanosine Concurrent use is contraindicated, risk
phosphodiesterase monophosphate (GMP) in of severe hypotension
type-5 inhibitors (e.g. smooth muscle. Combined
sildenafil, tadalafil) effect leads to excessive
vasodilation
Potassium sparing Both drugs increase serum Combined effect leads to dangerous
diuretics plus ACE potassium levels hyperkalaemia
inhibitor
Tamoxifen plus Tamoxifen is a prodrug Paroxetine reduces the level of active
Paroxetine metabolised to its active tamoxifen reducing its clinical effect
form by CYP2D6.
Paroxetine inhibits CYP2D6
Olanzapine plus Using multiple drugs with May cause confusion, urinary retention,
tricyclic anticholinergic properties dry mouth, and constipation. Many
antidepressants increases the risk of medications have anticholinergic side
anticholinergic toxicity properties. The cumulative clinical
effect of taking more than one of these
medications is referred to as
anticholinergic burden
Haloperidol plus Both drugs prolong the QT Use of multiple QT prolonging drugs
macrolide antibiotic interval increases the risk of arrhythmias and
e.g. clarithromycin sudden cardiac death
Phenytoin plus Both drugs are inducers of Both drugs reduce the plasma
carbamazepine cytochrome p450 concentrations of each other and if used
in combination, increased risk of
seizures such that more therapeutic
monitoring is needed
Allopurinol plus Allopurinol is a xanthine Toxic levels of 6-mercaptopurine lead
azathioprine oxidase inhibitor which to bone marrow suppression. These two
breaks down drugs should not be used together
6-mercaptopurine, the active
metabolite of azathioprine
Valproate plus Carbapenems inhibit Carbapenems substantially reduce the
carbapenems acylpeptide hydrolase, an therapeutic efficacy of valproate and
enzyme that converts inactive co-administration of these two drugs
valproate-­glucuronide to should be avoided if possible
active valproate
2 Polypharmacy: Definition, Epidemiology, Consequences and Solutions 23

Table 2.4 Clinically significant drug–disease interactions in older patients

Drug Disease or condition Drug–disease interaction
Benzodiazepines Falls Increased risk of falls, gait
Antipsychotics instability
Antihypertensives
Anticholinergics
Benzodiazepines Cognitive Increased confusion, delirium
Anticholinergics impairment/dementia
Antipsychotics
Corticosteroids
Opioids
Diuretics Orthostatic hypotension Syncope, falls, hip fracture
Anticholinergics
Peripheral vasodilators
Nitrates
Levodopa
Corticosteroids Osteopenia/osteoporosis Fragility facture
Antiepileptics such as
carbamazepine, valproate and
Phenytoin
Proton pump inhibitors
Aromatase inhibitors
SSRI’s
NSAIDs Heart failure Cause sodium retention (NSAIDs),
Dihydropyridine calcium and increased incidence of heart
channel blockers failure
Anticholinergics Benign prostate Urinary retention
Alpha agonists Hyperplasia
NSAIDS Renal failure Particularly in combination with
other drugs harmful to the kidney
Metoclopramide Parkinsonism Extrapyramidal side effects
Prochlorperazine
Antipsychotics

2.3.4.2 Drug–Disease Interactions

Drug–disease interactions are present when a drug prescribed for one disease exac-
erbates a concomitant disease. Drug–disease interactions in older adults have been
associated with increased risk of functional decline, health services use and adverse
drug events [25, 26]. Potentially inappropriate medications should be minimised,
and safer alternatives should be prescribed instead if possible. Drug–disease inter-
actions are more common in frailer older adults who have reduced physiologic
reserve. The major geriatric syndromes of dementia, delirium, incontinence and
falls can frequently be caused or exacerbated by medications (Table 2.4).

2.3.4.3 Prescribing Cascades

A prescribing cascade occurs when a medication generates an adverse drug reac-
tion, and instead of the culpable medication being stopped, a new medication is
added to manage the symptoms of the adverse drug reaction. In this way, the patient
continues to be exposed to further potential adverse drug reactions, which may in
turn be managed by further medications. (See Fig. 3 in the case answers at the end
24 D. Fitzpatrick and P. F. Gallagher

of the chapter for an example of a prescribing cascade). Prescribing cascades are

discussed and illustrated in detail in Chap. 5.

2.3.4.4 Falls, Immobility and Fractures

Falls and subsequent fractures have been linked to polypharmacy in numerous stud-
ies [27–29]. Amongst the most common culprits are antihypertensives, which are
often used in combination. Whilst having therapeutic and mortality benefits for
many, older patients are more likely to experience orthostatic hypotension and falls.
Other drugs such as psychotropics, anticholinergics, benzodiazepines and opioids
can cause sedation and cognitive impairment, increasing falls risk.
As people age, bone mineral density reduces. Osteoporosis is highly prevalent in
older people and is associated with a much higher incidence of fractures after rela-
tively low impact trauma [30]. Several medications, including corticosteroids, anti-
epileptic drugs, selective serotonin receptor inhibitors and proton pump inhibitors
can accelerate osteoporosis.

2.3.4.5 Cognitive Impairment

Polypharmacy is often associated with impaired cognitive function and dementia
[31, 32]. Drugs with anticholinergic properties are associated with cognitive impair-
ment in older patients [33]. Drugs with anticholinergic properties are used to treat a
wide variety of common chronic diseases including depression, psychosis, overac-
tive bladder, Parkinson’s disease and COPD. It is common for older patients to be
prescribed more than one anticholinergic drug. Various anticholinergic burden
scales have been developed to quantify the cumulative effect of multiple anticholin-
ergic medications [34]. Benzodiazepines and antipsychotics also cause cognitive
impairment and should be avoided if possible [35]. These drugs, especially benzo-
diazepines, often need to be reduced very gradually to avoid withdrawal reactions.

2.3.4.6 Frailty, Physical Function, and Disability

Polypharmacy is associated with impaired physical function in older patients with
reductions in gait speed and grip strength [3]. Older patients with polypharmacy are
more likely to be frail and to have functional impairments. It is inherently difficult
to prove a causal relationship between polypharmacy and these variables as patients
who are frail and have functional and physical impairments are more likely to have
higher levels of multimorbidity and be taking multiple medications.

2.3.4.7 Medication Errors

The greater the number of medications a patient takes the higher the potential for
medication errors [36]. Transitions of care, such as admission to and discharge from
hospital are particularly hazardous for patients with polypharmacy such that metic-
ulous medication reconciliation is vital at points of care transition.

2.3.4.8 Economic Cost of Polypharmacy

Adverse drug events (ADEs) and unnecessary prescriptions resulting from inappro-
priate polypharmacy represents an enormous public health cost. It is estimated that
2 Polypharmacy: Definition, Epidemiology, Consequences and Solutions 25

Polypharmacy

Drug-drug Drug-disease Medication Prescribing

Non-adherence
interactions interactions errors cascades

Adverse drug events

Cognitive Frailty and

Falls and Immobility Physical disability
impairment sarcopenia

Hospitalisation
Reduced Quality of Life
Mortality

Fig. 2.1 Consequences of polypharmacy in older people

18 billion US dollars, 0.3% of the global total health expenditure, could be saved by
avoidance of inappropriate prescribing [37]. Avoiding ADEs would not only
improve safety outcomes for patients but would also reduce costs in terms of fewer
hospital admissions, readmissions and shorter length of stay. National campaigns
promoting appropriate prescribing and reducing inappropriate polypharmacy have
demonstrated significant cost savings and economic benefits in Sweden [38] and
Scotland [39] (Fig. 2.1).

2.3.5 Optimising Medications in Patients with Polypharmacy

Addressing polypharmacy has the potential to reduce an older person’s risk of

ADEs, improve treatment of their underlying comorbidities, reduce medication bur-
den and substantially reduce costs for both the patient and the healthcare system in
general. These are summarised in Table 2.5.

2.3.5.1 Use of Nonpharmacological Options

When making treatment decisions, doctors frequently underuse nonpharmacologi-
cal options. For example, cognitive behavioural therapy reduces the need for antide-
pressants and anxiolytics in many cases. Implementing good sleep hygiene practices
is more effective that sedative medications. Diet and exercise can reduce the need
for diabetes medications [40].

2.3.5.2 Medication Reconciliation

The first step in optimising a patient’s medications is drawing up an accurate list of
the medications a patient is actually taking—a process known as medication
26 D. Fitzpatrick and P. F. Gallagher

Table 2.5 Summary of recommendations for prescribing in older adults

1. Prioritise nonpharmacological treatment when possible
2. Use shared decision-making with the patient (and carer if appropriate)
3. Ensure each medication has an appropriate indication, clear therapeutic goal, clear duration
of treatment and consideration is given to the patient’s individual goals of care and life
expectancy. Prescribing tools such as STOPP/START criteria are useful when evaluating
prescribing appropriateness
4. ‘START low, go slow’, that is, initiate medications at the lowest dose and titrate up slowly
according to response and tolerability
5. Use the simplest possible dosing regimen (e.g. once a day is preferable to three times a day)
and the most appropriate formulation; use a pre-prepared blister pack if available
6. Provide the patient with clear instructions on indication, time and route of administration
and potential adverse effects of each medication
7. Maintain an up-to-date list of all medications being taken by the patient, including
over-the-­counter and complementary/alternative medicines
8. Review a patient’s medications regularly in the context of coexisting disease states, drug
interactions, functional and cognitive status, and goals of care
9. Be aware that newly presenting symptoms may be due to an existing medication, drug–drug
interaction or drug–disease interaction (avoid prescribing cascades)
10. When stopping a medication, check that it can be stopped immediately or whether it needs
to be reduced gradually, for example, long-term steroids, benzodiazepines

reconciliation. This is all the more likely in older patients who may be on many dif-
ferent medications and are not able to reliably discuss their medication regimens.
Transitions in care represent an opportunity for medication errors with potentially
serious adverse outcomes to occur [41, 42]. Careful medication reconciliation is
vital to reduce these errors. Medication reconciliation is dealt with in more detail in
Chap. 8.

2.3.5.3 Adherence
Non-adherence with prescribed medication is a major public health issue and is
closely associated with polypharmacy [17]. It is estimated that between 50 and 80%
of patients with chronic conditions are non-adherent with their medications. Non-­
adherence has been estimated to contribute to 48% of asthma deaths, an 80%
increased risk of death in diabetes and a 3.8-fold increased mortality following
myocardial infarction [43]. It is estimated that non-adherence to medicines costs the
European Union 125 billion euros per year [17].
Adherence may be intentional or nonintentional. Barriers to non-adherence
should be addressed. For example, a patient with cognitive impairment may simply
forget to take their medications or make mistakes in their administration. Medication
blister packs or reminder alarms are simple ways to overcome some to these barriers
(Fig. 2.2).

2.3.5.4 Medication Review

Medication review is an integral component of comprehensive geriatric assessment
in which a holistic multidisciplinary systematic approach should be used. It is
important to ascertain the patient’s goals and expectations regarding their
2 Polypharmacy: Definition, Epidemiology, Consequences and Solutions 27

Fig. 2.2 Example of blister packed medications

medications and to individualise treatment accordingly. Shared decision-making is

likely to improve adherence. It is important to educate patients about the medica-
tions they are taking, the purpose of each medication and associated common poten-
tial adverse side-effects. The indication, efficacy, safety and the cost of each drug
should be assessed during each review. The medications should then be assessed for
potential drug–drug interactions and drug–disease interactions.

2.3.5.5 Medication Review Tools

Recognition of the impact of polypharmacy on older individuals and on public
health at large has led to the development of multiple medication review tools.
Beers criteria, originally drafted in 1991 and more recently modified in 2019,
comprises a list of medications that are considered potentially inappropriate and a
list of medications to avoid in certain conditions. STOPP/START criteria, initially
published in 2008 [44] and revised in 2015 [45], appraise an older patient’s medica-
tions in the context of their clinical conditions. The tool is organised by physiologi-
cal system. STOPP criteria describe specific contexts where medications would be
potentially inappropriate to prescribe for an older person, so-called potentially
28 D. Fitzpatrick and P. F. Gallagher

inappropriate medications or PIMs. START criteria identify potential prescribing

omissions (PPOs), that is, where evidence-based medications likely to provide ben-
efit to older patients for specific indications should be initiated rather than withheld
for irrational or ageist reasons. This tool has been demonstrated to improve medica-
tion appropriateness and reduce adverse drug reactions [46]. Inappropriate prescrib-
ing is described in greater detail in Chap. 4.

2.3.6 Polypharmacy in the Frailest Adults

Frailty and polypharmacy are clearly linked in a bidirectional way, that is, frailty
reflects multimorbidity, which generates polypharmacy, whilst polypharmacy
engenders PIMs and ADRs/ADEs which often exacerbate frailty. The severely frail
older person cohort is especially vulnerable to the adverse effects of polypharmacy
[47]. The goals of medication in this group are often directed toward symptomatic
benefit rather than prolonging life and long-term disease prevention. Despite this,
the SHELTER study reported rates of polypharmacy (defined as 5–9 long-term
drugs daily) and excessive polypharmacy (≥10 drugs) in nursing home residents to
be 48.7% and 24.3%, respectively [44].
In patients with frailty and limited life expectancy, medication review should
focus on reducing medication burden and optimising symptom management, rather
than long-term preventative strategies. The STOPPFrail criteria provide a list of
medications that should be discontinued or withdrawn in certain settings for older
people who meet all the following criteria: ‘end stage irreversible pathology, poor
1-year survival prognosis, severe functional impairment or severe cognitive impair-
ment or both, [in whom] symptom control is the priority rather than prevention of
disease progression’ [48, 49].
Whilst medication review tools are helpful in this group, it is important to recog-
nise that this is a heterogeneous group and prescribing decisions should be individu-
alised, and the patient (and carer when appropriate) should be involved as much as
possible.

Sample Case Answers

Question 1: What drug–disease interaction is illustrated in this case?
Answer: Ciprofloxacin lowers the seizure threshold, and an alternative antibiotic
should be used for patients in epilepsy. Fluoroquinolones would usually not be first
line for uncomplicated cystitis due to significant adverse effects including clostrid-
ium difficile infection, tendinopathy, neuropathy and QT prolongation. Haloperidol
also lowers the seizure threshold.
Question 2: What drug–drug interactions are illustrated in this case?
Answer: Omeprazole and clopidogrel: see Table 2.4. There is also no clear indi-
cation for a proton pump inhibitor. Amitriptyline, festerodine and haloperidol have
anticholinergic properties. Combining anticholinergics increases the likelihood of
anticholinergic side effects such as delirium, constipation, urinary retention, and dry
mouth. She is also taking multiple QT prolonging agents which when combined
2 Polypharmacy: Definition, Epidemiology, Consequences and Solutions 29

increase the risk of dangerous arrhythmias: ciprofloxacin, haloperidol and

amitriptyline.
Question 3: Can you identify the prescribing cascade in this case?
Amlodipine causes lower limb swelling, which is inappropriately managed with
diuretics. The diuretic causes urinary frequency, which is mismanaged with an anti-
cholinergic medication which causes delirium, constipation and urinary retention
and leads the patient to be admitted to hospital with exposure to multiple other
drugs and drug interactions.

Author Declaration The above chapter is, in its entirety, the work of the listed authors. It does
not contain any third party material or any material under copyright.

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Drug–Drug and Drug–Nutrients
Interactions: From Theory to Clinical 3
Relevance

Eline M. de Koning, Jeannine Huisbrink, and Wilma Knol

3.1 Introduction

The ageing of the population is accompanied by the development of a growing

number of chronic diseases. This multimorbidity increases the prevalence of poly-
pharmacy, which is often defined as using five or more medications daily [1]. An
expanding number of prescribed drugs is one of the most important risk factors for
drug–drug interactions (DDIs) [2, 3]. A drug–drug interaction is defined as an inter-
action between two or more drugs on a pharmacokinetic and/or a pharmacodynamic
level, with the risk of increasing the toxicity or reducing the intended effect of one
or more of the involved drugs [4, 5]. Not only multimorbidity and polypharmacy
increase the susceptibility to DDI’s, but also age-related changes in pharmacokinet-
ics and pharmacodynamics are involved.
DDIs are associated with an elevated risk of adverse drug reactions, worsening
of functional status, mortality and are responsible for approximately 5% of hospital
admissions in older patients [6–11].

E. M. de Koning
Department of Hospital Pharmacy, Medisch Spectrum Twente, Enschede, The Netherlands
e-mail: [email protected]
J. Huisbrink
Department of Hospital Pharmacy, Franciscus Gasthuis en Vlietland,
Schiedam/Rotterdam, The Netherlands
e-mail: [email protected]
W. Knol (*)
Department of Geriatric Medicine and Expertise Centre Pharmacotherapy in Old Persons,
University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 33

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_3
34 E. M. de Koning et al.

Not only interactions between drugs are prevalent. Drugs can also interfere with
certain foods or enteral feeding (drug–nutrition interactions or DNIs), herbs or flu-
ids like alcohol. Drug–nutrition interactions are defined as modifications of pharma-
cokinetics or pharmacodynamics of a drug because of nutrients or a modification in
nutritional status because of the addition of a drug [12].
This chapter will focus on drug–drug interactions and drug–nutrition interactions.

3.2 Theory

Drugs may interact on a pharmaceutical, pharmacokinetic or pharmacodynamic

basis. Pharmaceutical interactions emerge when two drugs are mixed in IV fluids or
syringes and chemically react, which may affect the safety, efficacy and stability of
the drug. This could also occur with the combination of a drug and a nutrient, for
example, in an enteral feeding tube. For instance sucralfate, when given simultane-
ously with enteral nutrition, binds to proteins within the enteral feed, leading to a
change in consistency and possibly tube blockage.
Enteral feeding could be applied in cases of malnourishment or when swallow-
ing is no longer possible or recommended. If given continuously or over large parts
of the day, problems may arise when medication needs to be administered. This
chapter will address pharmacokinetic (PK) and pharmacodynamic (PD)
interactions.

3.2.1 Pharmacokinetic Interactions

Pharmacokinetic interactions are defined as interactions where a drug or nutrient

affects the absorption, distribution, metabolism or excretion of another drug. These
interactions can lead to changes in serum drug concentrations, which might alter
clinical response. We will discuss the most important elements of
pharmacokinetics.

3.2.1.1 Absorption
Absorption defines the uptake of a substance into the systemic circulation. Several
factors influence the degree of absorption, such as physiochemical properties (e.g.
drug solubility, lipophilicity of the drug), drug formulation, route of administration
and patient factors (e.g. gastrointestinal pH). Additionally, the presence of food
could affect drug absorption, for example, by decreasing gastric emptying, chang-
ing the pH of the stomach and decreasing gut motility [13–15].
An active substance can become unsuitable for absorption due to chemical reac-
tion with another active substance within the gastrointestinal tract. This happens for
example when iron is given simultaneously with quinolones, such as ciprofloxacin.
The latter drugs form an insoluble complex, which reduces the bioavailability of
ciprofloxacin. This interaction could be avoided by prolonging the interval of
3 Drug–Drug and Drug–Nutrients Interactions: From Theory to Clinical Relevance 35

administration. Furthermore, calcium ions in milk or other dairy products could

form insoluble complexes with ciprofloxacin and also with bisphosphonates, which
should, therefore, be taken on an empty stomach. Ciprofloxacin absorption is also
significantly decreased when combined with enteral feed [16]. Another example is
the combination of phenytoin with enteral formulations. Phenytoin is known to bind
certain components of the enteral formulations, particularly proteins and calcium
salts, reducing drug absorption. Given that it is not always possible to have intermit-
tent feeding, the doctor could consult a pharmacist to provide advice about an alter-
native drug or feeding regimen.
Another type of interaction could emerge when one drug or nutrient causes a
change in pH of the stomach. Some drugs, such as itraconazole, require an acidic
environment in order for the drug to be converted to a soluble salt form. Drugs that
increase the pH of the stomach, such as proton pump inhibitors, diminish the absorp-
tion of those drugs. It is, therefore, recommended to administer drugs such as itra-
conazole with an acidic substance to decrease the pH. Drugs that have an enteric
coating could dissolve too early when acidity is changed. This coating normally
protects the drug from early degradation or protects the stomach from damaging
effects of the drug itself.
The rate of absorption could also be influenced by agents that alter the rate of
gastric emptying. The intestinal motility could be altered by anticholinergic drugs,
opioids or metoclopramide, thus leading to delayed absorption. This might enhance
the emergence of DDIs and DNIs.

3.2.1.2 Distribution
The absorbed drug will be distributed after entering the general circulation. Drugs
can bind to several proteins in the bloodstream or diffuse to tissues located outside
the bloodstream. Many drugs are highly bound to plasma proteins, such as albumin
or alpha-1-acid glycoprotein. An interaction may emerge if one agent displaces
another agent from its plasma binding site. By displacement, more unbound drug
becomes available. Such protein binding interactions hardly ever lead to clinically
significant changes in efficacy, since there will be further distribution or elimination
of the drug. In theory, the interaction could become relevant if one agent has a small
volume of distribution, a narrow therapeutic index and high plasma protein binding
properties.

3.2.1.3 Metabolism
The cytochrome P450 (CYP) enzyme family plays a very important role in catalys-
ing the biotransformation of certain drugs and other xenobiotic agents. Approximately
half of the 200 most commonly used drugs undergo CYP-mediated metabolism
[17]. CYP3A4/5, CYP2D6, CYP2C9, CYP2B6 and CYP2C19 are mostly involved
in this metabolism [18].
Drug metabolism occurs mainly within the liver and kidney, but could also take
place inside the lungs or gastro-intestinal tract, where CYP3A4 is present in the
gut wall.
36 E. M. de Koning et al.

Hepatic metabolism incorporates two types of biochemical reactions to create

more water-soluble compounds, phase I and phase II reactions. Phase I reactions
include minor molecular modifications, where hydrophilic groups are added to the
drug molecule. Phase II reactions cover conjugation reactions.
Many pharmacokinetic-based interactions emerge through the altered function
of drug-metabolising enzymes (e.g. phase I CYP enzymes) and transporters [e.g.
P-glycoprotein (P-gp)].
The risk of a clinical relevant interaction increases if the substrate (= the agent
whose metabolism is affected) has only one metabolism pathway, and the corre-
sponding enzyme is strongly inhibited or induced by another substance.
For example, grapefruit juice is well known for inhibiting intestinal CYP3A4,
thereby reducing the metabolism of CYP3A4 substrates, such as simvastatin.
CYP1A2 is involved in the metabolism of clozapine. Smoking has an inducing
effect on CYP1A2. When a patient is using drugs that are metabolised by
CYP1A2, quitting smoking could have a considerable inducing effect on their
metabolism.
Inhibition of CYP enzymes occurs rapidly and is generally reversible. After dis-
continuation, the inhibitory effect is mainly dependent on the (elimination) half-life
of the inhibitor. By inducing CYP enzymes, more additional enzymes will be
formed. Hence, the inducing effect sets in more gradually (over days to weeks).
Following withdrawal of the enzyme-inducing agent, the disappearance of the
inducing effect depends on the (elimination) half-life of the inducer and on the deg-
radation of enzymes additionally produced by the induction. The inducing effect
will, therefore, diminish gradually (usually in a few weeks).

3.2.1.4 Elimination
Elimination is a process of clearance of the drug, mostly by the kidney or via bile.
There are also other routes of elimination, such as pulmonary or dermal
elimination.
Drug-induced changes in hepatic blood flow could affect certain drugs that have
high hepatic extraction ratios, such as propranolol. Drugs that increase hepatic
blood flow, such as glucagon and verapamil, accelerate elimination of drugs like
propranolol. This, however, has an unknown clinical relevance.
Renal elimination of drugs may be diminished by agents that decrease glomerular
filtration rate, such as aminoglycoside antibiotics or angiotensin-converting enzyme
(ACE)-inhibitors. Drug-­induced renal impairment may be aggravated by concomi-
tantly prescribing drugs that enhance renal impairment. A combination of non-steroi-
dal anti-inflammatory drugs (NSAIDs) and ACE-inhibitors could lead to renal failure.
A third mechanism that could lead to interactions is competition for tubular
active transport. One substance could disrupt renal excretion of another agent, pos-
sibly leading to accumulation and toxicity. For example, the body recognizes lith-
ium as sodium and is, therefore, processed in similar ways. Drugs that induce
reabsorption of sodium could also provoke reabsorption of lithium, resulting in
toxicity.
3 Drug–Drug and Drug–Nutrients Interactions: From Theory to Clinical Relevance 37

3.2.2 Pharmacodynamic Interactions

Pharmacodynamic interactions include interactions of drugs acting on the same

receptors, site of action or physiological systems. These interactions could result in
additive, synergistic or antagonistic effects. Interactions at the receptor site arise
when one agent has a higher affinity for the receptor than the other agent, leading to
competition. This could occur at opioid receptors when combining a partial opioid
agonist and a full opioid agonist or at beta-adrenoceptors with non-selective beta-­
antagonists such as propranolol together with beta-agonists such as salbutamol.
Furthermore, a diet or enteral feed rich of vitamin K antagonizes the therapeutic
effect of vitamin K antagonists, such as warfarin.
Moreover, some drugs can change the pharmacodynamic effects of another drug
by altering receptor sensitivity. Drugs can also influence PD by acting on another
receptor resulting in synergistic or antagonistic effects within that cell or at another
downstream site. For example, opioids enhance the sedative response to
benzodiazepines.
Additionally, drugs that act on the same physiological system may enhance their
mutual effect. The combination of an angiotensin receptor blocker with an ACE-­
inhibitor potentiates a stronger lowering of blood pressure, but can also lead to a
reduction in kidney function. Both drugs act on the renin–angiotensin–aldosterone
system (RAAS), but through a different mechanism. Furthermore, prescribing two
different drugs effecting the central nervous system causes more sedation.
Changes in fluid and electrolyte balance may alter the effects of drug action on
the kidney, myocardium and on neuromuscular transmission. For example, if a
patient is using digoxin and becomes hypokalaemic, which could be induced by
diuretics, the action of digoxin is altered. Digoxin inhibits the exchange of sodium
and potassium by acting on the sodium–potassium pump (Na-K-ATP-ase). This
increases the concentration of intracellular sodium ions and decreases the concen-
tration of intracellular potassium ions. Potassium and digoxin compete for bind-
ing on the Na-K-ATP-ase pump. Hypokalaemia, therefore, results in increased
binding of digoxin, increasing its therapeutic effect and possibly enhancing
toxicity.

3.3 Age-Related Changes in Pharmacokinetics

There are minor changes regarding absorption in the older patient. The absorption
is slightly slowed, but total drug absorption does not change. There is a higher avail-
ability for drugs with very large first pass effect. The gastric pH is higher, which
could lead to a variable absorption of tablets requiring low pH. However, most of
these changes do not lead to clinically relevant alterations in drug levels.
Older patients hold more fat, less muscle tissue and less body water. Hydrophilic
drugs with a high volume of distribution (e.g. digoxin) have a smaller volume of
distribution due to less fluid and muscle tissue. Thus, a lower loading dose of
38 E. M. de Koning et al.

digoxin should be given to avoid toxicity. On the contrary, lipophilic drugs have a
larger volume of distribution. Therefore, accumulation of lipophilic drugs (e.g.
diazepam) could occur, and such drugs may cause prolongation of action and
adverse effects.
Phase I metabolism is reduced in older people (approximately 30%), especially
regarding CYP1A2 and CYP3A4. Phase II metabolism remains intact. Clinical con-
sequences regarding altered phase I metabolism remain unknown.
The age-related changes concerning elimination are of highest relevance. Kidney
function decreases with age but is also affected by comorbidities such as hyperten-
sion or diabetes. In case of renal insufficiency, dose adjustments are frequently nec-
essary for drugs that are cleared renally.

3.4 Clinically Relevant PK Interactions

PK interactions that could become clinically relevant are mostly due to CYP-related
metabolism. For example, the use of ciprofloxacin (CYP1A2 inhibitor) in older
patients treated with clozapine (CYP1A2 substrate) leads to a decreased metabo-
lism of clozapine. Moreover, phase I metabolism by CYP1A2 is shown to be
reduced by aging. Additionally, CYP1A2 activity is known to be reduced during
infection. These combined effects may further enhance the therapeutic effects or
even toxicity of clozapine.
Another example is the combination of simvastatin or atorvastatin and CYP3A4
inhibitors. Increased statin exposure due to the inhibition of CYP3A4-mediated
metabolism by, for example, verapamil and grapefruit juice could lead to severe
myopathy and rhabdomyolysis, which, in turn, may lead to acute renal failure. On
the contrary, prescribing simvastatin with CYP3A4 inducers such as carbamazepine
(70–80% reduction of plasma concentration) or St John’s wort (60% reduction)
could lead to higher cholesterol concentrations [19, 20].
A third example is the combination of lithium with an ACE-inhibitor or
diuretic. Diuretics or ACE-inhibitors enhance sodium loss. Because of this, there
will be a compensatory distal reabsorption of sodium and lithium, leading to lith-
ium toxicity.

3.5 Age-Related Changes in Pharmacodynamics

Older patients have an increased vulnerability because of a decline in physiological

reserve [less functional homoeostatic mechanisms (e.g. reduced sense of thirst with
a risk of dehydration)] and a decline across multiple organ systems (reduced ability
to excrete free water). Furthermore, older patients are known to have a lower recep-
tor responsiveness (e.g. beta-adrenoceptor), which could lead to an altered sensitiv-
ity to drugs [21–25].
3 Drug–Drug and Drug–Nutrients Interactions: From Theory to Clinical Relevance 39

Older people are more sensitive to adverse effects of psychotherapeutic drugs. A

decline of central receptors (e.g. dopamine D2) with age and a greater affinity, for
example, for antipsychotics may account for this increased risk.

3.6 Clinically Relevant PD Interactions

The most clinically relevant changes in pharmacodynamics are increased suscepti-

bility to certain drugs, for example, central acting drugs. Research has shown that
most clinically relevant interactions are of pharmacodynamic origin [26–29]. These
interactions concern drugs that are often used by older patients to treat age-related
conditions, as cardiovascular or neurological conditions. For example, prescribing a
combination of psychotropic medication may enhance sedation, apathy or falls.
Multiple agents that act on haemostasis, such as oral anticoagulants in combination
with antiplatelet drugs potentially increase the risk of bleeding. The risk of (mainly
gastrointestinal) bleeding also increases with concomitant use of NSAIDs with a
serotonin-selective reuptake inhibitor (SSRI) or serotonin–noradrenalin reuptake
inhibitor (SNRI), by additive effects on platelet inhibition.
Combining two drugs with potassium sparing effects (e.g. triamterene, spirono-
lactone, ACE-inhibitors, cotrimoxazole) may enhance additive potassium retention
leading to hyperkalaemia.
Combining drugs that reduce potassium (e.g. beta 2-agonists, thiazides, loop
diuretics, corticosteroids) could, however, also be potentially dangerous, especially
if a patient is also on digoxin.
Furthermore, if an older patient is using a diuretic agent or inhibitor of the RAAS
system and is prescribed an NSAID, the patient is at risk of renal failure. NSAIDs
negatively influence the compensatory mechanism that is activated to maintain ade-
quate renal blood flow, when renal perfusion seems to decrease.
A clinically relevant pharmacodynamic DNI could occur if a patient is prescribed
paroxetine whilst using St John’s wort. When St John’s wort is used in conjunction
with paroxetine, an additive serotonergic effect may occur, which could lead to
serotonin syndrome.
Table 3.1 provides an overview of DDIs and DNIs that are commonly clinically
relevant in older adults.
Table 3.1 Most common drug–drug and drug–nutrient interactions in older people
40

Type of
Drug class Drug/nutrient Drug/nutrient Impact/mechanism IA
Cardiovascular ACE-inhibitors Potassium supplements/ Elevated serum potassium PD
aldosterone antagonists/
potassium sparing diuretics
ACE-inhibitor ARB Risk of renal failure by additive or synergistic effects on PD
renal blood flow and blood pressure
Digoxin Amiodarone Digoxin toxicity due to p-gp inhibition; both drugs PK + PD
suppress the SA node, resulting in bradycardia
Digoxin Verapamil PK: Verapamil inhibits both renal tubular secretion and PK + PD
non-renal excretion of digoxin. Diltiazem decreases the
clearance and/or volume of distribution of digoxin
PD: The slowing effects of verapamil or diltiazem and
digoxin on atrioventricular conduction may be additive
Verapamil/diltiazem CYP3A4 substrates (e.g. Inhibition metabolism of substrates, therefore higher PK
carbamazepine, simvastatin, concentrations
midazolam)
Dabigatran/edoxaban P-gp inhibitor Higher risk of bleeding PK
Rivaroxaban/apixaban P-gp inhibitor or CYP3A4 Higher risk of bleeding PK
inhibitor
Oral anticoagulant Antiplatelet drug Higher risk of bleeding PD
Antiplatelet drugs Ginkgo biloba Increased risk of bleeding. Mechanism remains unknown PD
Beta-blocker Verapamil/diltiazem Increased effect on AV nodal conduction, heart rate or PD
cardiac contractility, resulting in bradycardia, AV block
and hypotension
Beta-blocker Beta2-agonist Beta-blockers may diminish the bronchodilatory effect of PD
beta2-agonists. Of particular concern with non-selective
beta-blockers or higher doses of the beta1 selective
beta-blockers
E. M. de Koning et al.
Type of
Drug class Drug/nutrient Drug/nutrient Impact/mechanism IA
3

Diuretics RAAS-inhibitors Volume depletion induced by diuretic therapy, combined PD

with the peripheral vasodilation and initial decrease in renal
blood flow produced by the RAAS-inhibitor, leading to
exaggerated hypotensive response and possible renal injury
Vitamin K antagonists Vitamin K-rich foods/vitamin Vitamin K antagonists interfere with the ability of the PD
K supplements/vitamin K-rich body to effectively use vitamin K in the production of
enteral nutrition formulations certain clotting factors (II, VII, IX, X). This interference
can be overcome by administering adequate quantities of
exogenous vitamin K
Warfarin Enteral nutrition formulations Warfarin could bind to proteins in enteral nutrition PK
formulations, reducing bioavailability
Simvastatin/atorvastatin/ Grapefruit juice Inhibition of CYP3A4-mediated metabolism, resulting in PK
nifedipine an increased bioavailability and AUC
Central nervous Lithium Thiazide diuretic Thiazide diuretics enhance proximal tubular reabsorption PK
system of lithium, leading to elevated lithium serum
concentrations
Lithium ACE-inhibitor/ARB Lowered levels of angiotensin II lead to lower circulating PK
levels of aldosterone. Subsequently, sodium and water
excretion increase possibly causing greater renal retention
of the lithium ion
Lithium NSAID NSAIDs inhibit the synthesis of prostaglandins (PGE2) in PK
the kidneys. As a result, the blood flow to the kidneys is
inhibited, and thus, lithium excretion is reduced. This will
cause the lithium concentration to rise
Levodopa High-protein diet High-protein diets have the potential to impair levodopa PK
absorption; levodopa competes with certain amino acids
for transport across the gut wall or across the BBB
Levodopa Iron Reduced absorption due to complexation PK
Levodopa Metoclopramide Diminished effect levodopa due to D2 blockage PD
Drug–Drug and Drug–Nutrients Interactions: From Theory to Clinical Relevance

(continued)
41
Table 3.1 (continued)
42

Type of
Drug class Drug/nutrient Drug/nutrient Impact/mechanism IA
MAO-inhibitors SSRI/opioid Serotonin syndrome or opioid toxicity by enhancing the PD
serotonergic effect of MAO inhibitors
MAO-inhibitors Tyramine-rich foods Severe hypertensive episodes by inhibiting tyramine PK
metabolism, leading to increased biosynthesis of
catecholamines
Phenytoin Enteral nutrition formulations Phenytoin binds proteins and calcium salts in enteral PK
nutrition formulations, leading to reduced absorption
Paroxetine/fluoxetine Metoprolol Increase in metoprolol concentrations due to CYP2D6 PK
inhibition, possibly resulting in bradycardia
Fluoxetine Tricyclic antidepressant Risk of serotonin syndrome by additive serotonergic PK + PD
effects or tricyclic antidepressant toxicity due to
fluoxetine-mediated inhibition of CYP2D6 and/or
CYP2C19, enzymes responsible for the metabolism of
tricyclic antidepressants
Paroxetine/fluoxetine St John’s wort St John’s wort may enhance the serotonergic effect of PD
paroxetine or fluoxetine, which could result in serotonin
syndrome
Concomitant use of ≥3 centrally acting drugs (e.g. opioids, Increased risk of falling, possibly leading to fractures and PD
antipsychotics, benzodiazepines, antidepressants or impaired cognition
antiepileptics)
Clozapine CYP1A2 inducers/inhibitors Influences on clozapine concentrations due to induction or PK
(e.g. carbamazepine/ inhibition of CYP1A2, leading to loss of effect or toxicity
ciprofloxacin)
Anti-infective agents Fluoroquinolones/doxycyclin Calcium/dairy products/iron/ Reduced absorption due to complexation PK
cations in enteral nutrition
Antifungal agents e.g. Warfarin/acenocoumarol/ Increased serum concentrations of vitamin K antagonists PK
miconazole fenprocoumon by inhibition of CYP2C9 enzymes
E. M. de Koning et al.
Type of
Drug class Drug/nutrient Drug/nutrient Impact/mechanism IA
3

Itraconazole Proton pump inhibitors Decreased bioavailability because of increased gastric pH PK

Endocrine Metformin Proton pump inhibitors Malabsorption of vitamin B12, possibly leading to vitamin PK
B12 deficiency
Most probably, metformin may interfere with the active
calcium dependent absorption of the vitamin B12-intrinsic
factor complex
Levothyroxine Calcium/dairy products/iron/ Reduced absorption due to complexation PK
cations in enteral nutrition
Pain medication Oxycodone CYP3A4 inhibitors (e.g. Increase in serum concentration of oxycodone. Serum PK
voriconazole) concentrations of the active metabolite oxymorphone may
also be increased
Opioid agonist Mixed opioid agonist/ Reduced effects of pure opioid agonists via competition/ PD
antagonist (e.g. antagonism at opioid receptor sites. This could precipitate
buprenorphine) withdrawal symptoms, necessitate unusually high doses,
or lead to therapeutic failure
NSAID SSRI/SNRI Increased risk of gastrointestinal bleeding by additive PD
inhibitory effects on platelet aggregation
NSAID ACE-inhibitor/ARB Significant decrease in renal function and risk of renal PD
failure due to the ability of NSAIDs to reduce the
synthesis of vasodilating renal prostaglandins. This would
affect vascular tone and fluid homoeostasis
Immunosuppressive Methotrexate Trimethoprim/cotrimoxazole Methotrexate toxicity (e.g. bone marrow suppression). PD
agents Both drugs contribute to folate deficiency (via suppression
of dihydrofolate reductase)
Respiratory Theophylline Ciprofloxacin (or other Theophyllin toxicity due to inhibition of CYP1A2-­ PK
moderate to strong CYP1A2 mediated metabolism of theophylline
inhibitors)
(continued)
Drug–Drug and Drug–Nutrients Interactions: From Theory to Clinical Relevance
43
Table 3.1 (continued)
44

Type of
Drug class Drug/nutrient Drug/nutrient Impact/mechanism IA
Gastro-intestinal Proton pump inhibitor Vitamin B12 Malabsorption of vitamin B12 due to inhibition of PK
intrinsic factor
Sucralfate Enteral nutrition formulations Sucralfate binds proteins within the enteral feed, leading PC
to a change in consistency and possible feeding tube
blockage
Other Bisphosphonate Calcium/dairy products/iron/ Reduced absorption due to complexation PK
cations in enteral nutrition
St John’s wort CYP3A4 substrate (e.g. Reduced efficacy due to induction of CYP3A4 PK
verapamil)
ACE angiotensin-converting enzyme, ARB angiotensin II receptor blocker, AV atrioventricular, AUC area under the curve, BBB blood–brain barrier, CYP cyto-
chrome P450, D2 dopamine 2 receptor, IA interaction, MAO monoamine oxidase, NSAID non-steroidal anti-inflammatory drug, PC pharmaceutical, PD phar-
macodynamic, P-gp P-glycoprotein, PK pharmacokinetic, RAAS renin–angiotensin–aldosterone-system, SA sinoatrial, SNRI serotonin and noradrenalin
reuptake inhibitor, SSRI selective serotonin reuptake inhibitor
E. M. de Koning et al.
3 Drug–Drug and Drug–Nutrients Interactions: From Theory to Clinical Relevance 45

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Inappropriate Prescription of Medicines
4
Denis O’Mahony

4.1 Introduction

Inappropriate prescribing (IP) of medication to patients of any age refers to any one
or more of the following patterns:

1. Prescribing that increases the risk of adverse drug–drug interactions to an unac-

ceptably high level.
2. Prescribing that increases the risk of adverse drug–disease interactions to an
unacceptably high level.
3. Prescribing of medications at too high a dose.
4. Prescribing of medications for too long or too short a duration.
5. Prescribing of medications that are too expensive when cheaper alternatives exist.
6. Failure to prescribe appropriate medications for irrational or ageist reasons when
they are clearly indicated.

Instances of IP that fall into categories (1)–(5) are generally referred to as ‘poten-
tially inappropriate medications’ or PIMs; instances of category (6) are termed
‘potential prescribing omissions’ or PPOs.
PIMs and PPOs are important in older people because they are associated with
significant adversity, that is, increased risk of adverse drug reactions (ADRs) and
adverse drug events (ADEs), greater levels of unscheduled hospitalization, more
healthcare utilization (mostly through primary care physician consultation), poorer
quality of life and increased mortality. It is estimated that more than half of all
instances of PIMs and PPOs are avoidable; this has highly significant economic, as

D. O’Mahony (*)
Department of Medicine, University College Cork, Cork, Ireland
Department of Geriatric Medicine, Cork University Hospital, Cork, Ireland
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 47

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_4
48 D. O’Mahony

well as individual patient, implications in the context of rapidly ageing populations

in most countries globally.
There are a number of important risk factors for IP which every prescriber should
be aware of, principally polypharmacy (i.e. where patients take ≥5 long-term daily
medications), age-related changes in pharmacokinetics and pharmacodynamics,
cognitive impairment, reduced functional capacity and higher levels of overall
frailty. In addition, certain classes of drugs carry inherently higher risks of medica-
tion-related morbidity in older people, such as non-steroidal anti-­inflammatory
drugs, anticoagulants, insulin and other hypoglycaemic agents, antipsychotic drugs,
benzodiazepines and loop diuretics.
In this chapter, we will examine the challenge of IP in general, important
instances of PIMs and PPOs in particular and how IP can be systematically
detected and addressed during routine medication review of older people. There
will be specific focus on the multimorbid older person because multimorbidity
is the rule rather than the exception amongst people aged over 70 years and
because polypharmacy occurs as a result of multimorbidity. The central aim in
detecting PIMs and PPOs is for the prescriber to consider the following issues
carefully:

1. Which medications are essential for symptom control?

2. Which medications are essential for short-term and long-term prevention?
3. Which medications are safest in individual patients?
4. Which medications address the issues that matter most to the patient?
5. Which combination of medications is most acceptable and manageable for the
patient?

4.2 Inappropriate Prescribing Criteria

There are several sets of criteria for defining IP in older people in the literature.
These are broadly classified as ‘implicit criteria’ and ‘explicit criteria’.
Implicit IP criteria are usually based on decision algorithms without specific
reference to any one drug or drug class; well-cited examples include ACOVE crite-
ria and the Medication Appropriateness Index (MAI) [1, 2]. In general, implicit IP
criteria have remained in the research domain and have not been deployed in routine
clinical practice to any significant extent.
Explicit IP criteria, in contrast, have had much greater application in the clinical
arena. The first of the explicit IP criteria sets was published in 1991 by Mark Beers
and colleagues [3]. This first iteration of Beers criteria provided for the first time a
list of drugs and drug doses that should be avoided in older nursing home residents
in all circumstances and certain drugs that should be avoided in certain disease
groups. Since the first iteration of Beers criteria, there have been five subsequent
updated versions; the most recent of which was published in 2019 [4]. Beers crite-
ria, as the longest established explicit IP criteria, are the most widely cited in the
literature. One limitation of Beers criteria is that they do not include instances of
4 Inappropriate Prescription of Medicines 49

PPOs. In contrast, STOPP/START criteria deal both with PIMs and PPOs arranged
by physiological system, as one finds in drug formularies. STOPP/START criteria
were first published in 2008 [5] revised in 2015 [6] and again in 2023 [in press].
There are over 30 other explicit PIM criteria sets in the literature, which describe
a variety of approaches to PIM detection [7]. FORTA criteria, PRISCUS criteria,
French Consensus criteria and NORGEP criteria have all gained significant atten-
tion in the literature. However, Beers criteria and STOPP/START criteria are the
most cited in mainstream online bibliographies. They have also had the most trac-
tion in terms of clinical application in routine practice.

4.3 Clinical Relevance of PIMs and PPOs

There would be little point in looking for PIMs and PPOs if they were not clinically
relevant or avoidable. However, the literature demonstrates clearly that PIMs and
PPOs are both associated with significant adversity for older people and for the
most part readily detectable and, therefore, preventable. In a prospective study of
600 unselected older patients presenting to hospital with acute illness, Hamilton
et al. showed that ADEs occurred significantly more often in those who were pre-
scribed STOPP criteria-defined PIMs; in contrast, patients taking Beers version 3
criteria-­defined PIMs had no significant increase in ADEs [8]. Previous studies had
shown a lack of association between Beers criteria and ADEs [9–11].
The increased risk of ADRs and ADEs arising from PIMs are associated with
several related adverse outcomes for older people, including increased incidence of
acute hospitalization, increased physician consultation, increased healthcare costs
and diminished quality of life [12–14]. Risk factors for PIMs include polypharmacy,
poor functional status and depression [15].

4.4 Clinical Trials of STOPP/START Criteria

as an Intervention

Given the significantly increased risk of ADEs (approximately 85%) when STOPP-­
defined PIMs were prescribed to multimorbid older people [8], a series of single-­
centre intervention clinical trials were undertaken to test the clinical efficacy of
STOPP/START criteria. These trials are summarized in Table 4.1. They demon-
strated that STOPP/START criteria as an intervention had the following benefits
compared to standard pharmaceutical care:

1. Reduced prevalence of PIMs and PPOs.

2. Reduced polypharmacy.
3. Improved medication appropriateness.
4. Reduced incident ADRs.
5. Reduced monthly medication costs.
6. Reduced incident falls.
50 D. O’Mahony

Table 4.1 Single-centre clinical trials in which STOPP/START criteria were used as an interven-
tion in multimorbid older people with polypharmacy
Target patient
population Impact of intervention compared to usual
Trial authors, year of (number of patients pharmaceutical care (control) group that was
publication randomized) statistically significant
Gallagher et al. [16] Acutely ill Unnecessary polypharmacy, the use of drugs at
hospitalized incorrect doses and potential drug–drug and
multimorbid, aged drug–disease interactions were less frequent in the
(400) intervention group at discharge (absolute risk
reduction 35.7%); underutilization of clinically
indicated medications was also reduced (absolute
risk reduction 21.2%)
Dalleur et al. [17] Hospitalized ‘frail’ Approximately twice as many PIMs removed at
(146) discharge in the intervention group compared to
the control group
Frankenthal et al. [18] Chronic care Fewer drugs, lower care costs and reduced
geriatric facility incidence of falls
residents (359)
O’Connor et al. [19] Acutely ill Reduced ADR incidence in hospital; reduced
hospitalized median monthly medication cost (physician-
multimorbid (732) delivered intervention)
O’Sullivan et al. [20] Acutely ill Reduced ADR incidence (pharmacist-delivered
hospitalized intervention)
multimorbid (737)

These benefits were demonstrated from single-centre, unblinded clinical trials.

However, two subsequent multi-centre, partially blinded clinical trials (SENATOR
[21] and OPERAM [22]) have not shown significant benefit from STOPP/START
application in multimorbid older patients exposed to polypharmacy. The primary
endpoint in the SENATOR trial was incident ADRs within 14 days of randomization
to STOPP/START criteria application (with drug–drug and drug–disease interaction
screening) and feedback to attending clinicians or standard pharmaceutical care. A
total of 1537 patients were randomized in a 1:1 ratio in SENATOR. Incident ADRs
within 14 days of randomization occurred in 24.5% of intervention patients and in
24.8% of control patients; however, the overall uptake of STOPP/START recommen-
dations by attending clinician prescribers was poor, that is, approximately 15%.
The OPERAM trial was designed to maximize the uptake of STOPP/START rec-
ommendations by attending clinicians of older multimorbid patients in hospital. The
intervention with details of the prescribing changes was further supported following
discharge through contact with patients’ primary care physicians and community phar-
macists as well as follow-up with the patients and their carers. In all, 2008 patients were
cluster randomized in OPERAM in a 1:1 ratio. With these additional features in the
OPERAM intervention, the adherence with one or more proposed medication changes
was approximately 62%. The primary endpoint in OPERAM was drug-related admis-
sions (DRAs) within 12 months of randomization to STOPP/START intervention or
standard pharmaceutical care; DRAs occurred in 21.9% of intervention patients and in
22.4% of control patients, that is, despite greater adherence with STOPP/START pre-
scribing recommendations, there was no significant reduction in DRAs.
4 Inappropriate Prescription of Medicines 51

4.5 Other Clinical Trials of PIM Criteria as an Intervention

Another set of PIM criteria called FORTA (Fit fOR The Aged) criteria devised and
validated by Wehling and colleagues in Germany have also been assessed by clini-
cal trial. FORTA criteria are divided into four categories: A (indispensable), B (ben-
eficial), C (questionable) or D (avoid). In the VALFORTA clinical trial [23], 409
multimorbid patients (cared for in two specialist geriatric medicine units in
Mannheim and Essen) were randomized to a control unit with standard pharmaceu-
tical care or to an intervention unit where a FORTA team instructed attending physi-
cians on FORTA assessment of each prescribed medication. The primary endpoint,
that is, the FORTA score was the sum of medication errors, defined as over-, under-,
or incorrect treatment with prescribed medication. Enrolled patients were random-
ized to intervention or control trial arms in a 1:1 ratio. They had a mean age of
81.5 years; 64% were female, and the mean hospital length of stay was 17.4 days.
The trial results showed a greater reduction of medication errors in the intervention
group versus the control group, with a mean (± SD) FORTA score difference
between admission and discharge in the intervention group of 2.7 (± 2.25) versus
1.0 (± 1.8) in the control group, which was highly significant (p < 0.0001). In addi-
tion, ADRs (not a pre-specified endpoint) were significantly reduced in the interven-
tion group compared to the control group; the absolute risk reduction for incident
ADRs was 19.8%, equating to a number needed to treat of 5 which was once again
statistically significant (p < 0.05). These results are certainly interesting and of
potential clinical importance; however, the VALFORTA trial was a validation trial,
treatment groups not blinded and, to date, results have not been replicated.

4.6 Clinical Trials Using Pharmacist-Driven Interventions

to Optimize Medication in Multimorbid Older People

A number of other interventions have been designed to minimize IP in multimorbid

older people that are not based on the application of IP criteria. Principally, these
involve structured medication review and feedback to attending physician prescrib-
ers. There is evidence that medication review by an appropriately trained pharma-
cist with feedback to the attending physician can minimize medication errors and
improve medication appropriateness [24]. However, evidence of clear clinical ben-
efit to older multimorbid patients from pharmacist-driven structured medication
review and feedback is lacking [25].
The OPTIMIST trial [26], carried out in four Danish hospitals, addressed these
issues where 1467 patients (median age 72 years) were randomized to one of three
trial arms: (1) standard pharmaceutical care (control), (2) limited pharmacist-driven
medication optimization or (3) extended pharmacist-driven medication optimiza-
tion. The trial endpoints were (i) readmission within 30 days, (ii) readmission within
180 days and (iii) number of emergency department (ED) visits within 180 days; the
composite primary endpoint was hospital readmission or ED visit within 180 days.
Readmissions at 30 days and at 180 days were significantly reduced in the extended
52 D. O’Mahony

intervention group, but not in the basic intervention group, compared to controls.
For the primary composite endpoint, once again patients in the extended interven-
tion group but not those in the basic intervention group experienced a significant
benefit compared to control patients. The hazard ratio (95% CI) for experiencing the
composite primary endpoint was 0.77 (0.64–0.93) representing a number needed to
treat with the extended intervention of 12, that is, a clinically relevant intervention.
The basic pharmacist intervention included structured detailed medication review
with particular focus on aspirin, diuretics, anticoagulants and NSAIDs followed by
a structured report placed in electronic medical record with medication adjustment
recommendations and one-to-one contact with the attending physician. The
extended intervention in the OPTIMIST trial included the basic intervention with
the following elements added:

• Medication reconciliation on discharge.

• A 30-min interview with the patient (“motivational approach”).
• A comprehensive summary of changes in medication during hospitalization.
• A report with details of all recommended medication changes implemented or
not sent to the patient’s primary care physician post-discharge.
• A follow-up telephone contact with (1) the patient’s primary care physician, (2)
the patient’s principal carer and (3) the community pharmacist at 72 hours
post-discharge.
• A follow-up motivational interview with the patient’s primary care physician,
caregiver and community pharmacist at 1 week and 6 months post-discharge.

The extended intervention that yielded significant benefit to the patients in

OPTIMIST in terms of unscheduled hospital readmissions and ED attendances was
complex, multifaceted and challenging to implement, with uncertain cost-­
effectiveness. Very likely, elements of the pharmacist intervention are clinically rel-
evant. However, the transferability of the extended intervention in OPTIMIST to
routine clinical practice for the purpose of minimizing IP in older people is, there-
fore, uncertain.

4.7 Clinical Manifestations of IP in Older People

Inappropriate prescribing in older people is commonplace but avoidable. It is clini-

cally and economically important to minimize IP, as IP is intimately associated with
medication-related morbidity which, in turn, is the primary reason for admission in
approximately 10% of unselected older people who are hospitalized with acute ill-
ness. A recent systematic review and meta-analysis provides important clarity on
IP-related ADRs in older people in the hospital setting [27]. The study showed that
approximately one in six older people will experience a non-trivial ADR during
hospitalization for acute illness.
The most commonly reported ADRs in older people and their presentations are
listed in Table 4.2. As can be seen, many of these ADR presentations mimic
4 Inappropriate Prescription of Medicines 53

Table 4.2 Common adverse drug reaction (ADR) presentations in older people in order of fre-
quency (after Jennings et al. [27])
ADR type Frequency Clinical or laboratory manifestation
Fluid and electrolyte 17.3% Hypokalaemia, hyperkalaemia, hyponatraemia,
derangement hypernatraemia, fluid volume overload, fluid volume
depletion
Gastrointestinal motility 14.8% Constipation, diarrhoea
disorders
Renal function 8.2% Acute kidney injury, renal failure complications
impairment
Blood pressure 5.5% Hypotension, orthostatic symptoms
derangement
Delirium 4.1% New onset confusion
Injuries 3.8% Falls
Cardiac arrhythmias 3.7% Bradycardia, atrioventricular block, tachycardia
Other cardiovascular 3.4% Various
disorders
Coagulopathy/bleeding 3.0% Increased INRa, increased APTTb, increased prothrombin
time
Other gastrointestinal 2.8% Various
disorders
Vascular haemorrhagic 2.7% Overt bleeding, haematoma
disorders
Gastrointestinal 2.6% Overt bleeding, malaena
haemorrhage
Neurological disorder 2.5% Various
(unspecified)
Glucose derangement 2.3% Hypoglycaemia, hyperglycaemia
Skin disorder 2.2% Rash, exanthems and other eruptions
Other gastrointestinal 2.2% Nausea/vomiting, dyspepsia, abdominal pain
disorders
a
INR international normalized ratio
b
APTT activated partial thromboplastin time

common symptom presentations in older people; consequently, prescribers must

always consider the possibility of medication being the basis for symptoms such as
constipation, diarrhoea, hypotension, acute confusion and so forth.
This analysis of ADR presentations in older people has formed the basis of an
ADR ‘Trigger List’, which can be helpful in clinical practice based on the fact that
approximately 90% of all ADRs result from 16 medication classes, that is, occur-
rence of any of the clinical manifestations of ADRs summarized in Table 4.2 should
make prescribers consider the possibility of an underlying ADR.

4.8 Medication Review Aimed at Minimizing IP and Its

Consequences: A Practical Approach

In the current literature, there are numerous described methods for identifying or
minimizing IP. In a recent review by Rochon et al. [28], a practical method for per-
forming medication review in a way that is designed to minimize IP and its
54 D. O’Mahony

Table 4.3 DRUGS guide to minimizing IP and optimizing medication safety for older adults
(after Rochon et al. [28])
Discuss goals of care and what matters most to the patient
Include patients and caregivers in deprescribing discussions to ensure decisions focus on goals
of care
Review medications
 • Encourage patients to bring all prescribed and over-the-counter medications to their
appointment
 • Review medications on an ongoing basis and when clinical conditions or goals of care
change
 • Discontinue potentially unnecessary drugs
 • Consider drug side effects as a potential cause for a new symptom
 • Consider non-pharmacological options
 • Change for safer alternatives
 • Lower the dose
 • To identify possible prescribing cascades, determine when the medication was started and
why
Use tools and frameworks
 • Identify drugs from the inappropriate prescribing tools, including Beers criteria or STOPP
criteria
 • Use the STOPPFrail list when the individual is extremely frail and approaching the end of
life
 • Consider whether the new or existing medical condition could be the result of a
prescribing cascadea and ask:
   – Is a new drug being prescribed to manage a side effect from another prescribed drug?
   – Could the initial drug be replaced with a safer drug or could the dose be reduced?
   – Does the patient need the first drug or could this drug be stopped?
   – Pay attention to older people who are receiving so-called good drugs with narrow
therapeutic windows that might no longer be needed or for whom dose reduction might be
beneficial
Geriatric medicine approach
Geriatricians carefully consider how multiple medical problems, frailty, cognitive impairment
and limited life expectancy reduce medication benefit, increase adverse events or interfere with
medication adherence
STOP the medications
Consider the algorithm created by Scott [29] or the Good Palliative–Geriatric Practice
algorithm to guide deprescribing [30]
a
‘Prescribing cascades’ refer to inappropriate prescription of drugs for symptoms arising from
side-effects of medications that are misinterpreted as new conditions

consequences has been described. This approach is usefully summarized under the
acronym DRUGS, that is, (1) Discuss goals of care and what matters most to the
patient, (2) Review medications, (3) Use tools and frameworks, (4) Geriatric medi-
cine approach and (5) Stop the medications. More specific details of this approach
are shown in Table 4.3.
Rochon et al. also stressed the importance of patient sex and gender consider-
ations when reviewing and optimizing older people’s medications. Some of these
considerations include the following:

• Older women consume more non-prescription (“over-the-counter”) medications

than older men.
• Older women receive more psychotropic prescriptions than older men.
4 Inappropriate Prescription of Medicines 55

• Older men receive more preventive medication than older women.

• Older women tend to experience higher levels of chronic multimorbidity, greater
degrees of frailty and more ADEs than older men.
• Older men are less likely to discuss deprescribing with their physicians than
older women.
• Older men are more likely to have their chronic medical conditions managed
more aggressively than older women, for example, ischaemic heart disease, uri-
nary incontinence and osteoarthritis.

A constant awareness of sex-determined differences in pharmacokinetics and

pharmacodynamics is necessary in the selection of well-balanced and safer poly-
pharmacy for older multimorbid patients. These differences are discussed in Chap. 1.

4.9 Minimizing IP in Older People with Marked Frailty

Approaching End-of-Life

With the rapid growth of the frail older person population aged over 80 years (pre-
dominantly female) in most countries, physicians encounter the challenge of medi-
cation optimization in those older people with a poor 1-year survival prognosis.
These older patients usually have complex multimorbid illness, often have major
impairment of physiological homoeostatic reserve in more than one physiological
system and are usually exposed to high-level polypharmacy. In one study, the asso-
ciation between the extent of chronic multimorbid illness (measured by the
Cumulative Index Rating Scale—Geriatric, CIRS-G) and number of daily prescrip-
tion drugs was a linear one with a high correlation R value of 0.726 [31], i.e. cause-
and-effect is manifest.
Deprescribing in these frailer older people is generally considered desirable in
order to minimize risk of adverse drug–drug and drug–disease interactions as well
as to lessen medication burden for the patients and their carers. Various approaches
to deprescribing have been tried, from implicit criteria algorithms to explicit criteria
for deprescribing of several medication classes, mostly prescribed initially for long-­
term disease prevention, in end-of-life situations. In small-scale clinical trials, both
approaches been shown to be both feasible and effective in reducing polypharmacy
and medication burden in multimorbid frailer older people [32–34]. The impact of
deprescribing interventions on clinical outcomes, like incident ADEs, rehospitaliza-
tion and quality of life, however, remains unclear. Approaches to structured depre-
scribing are discussed in greater detail in Chap. 10.

4.10 Inappropriate Medication Avoidance: Summary

and Practical Points

PIMs and PPOs are highly prevalent in older people in all clinical settings. Because
they have clear cut and often serious negative consequences for older people, PIMs
and PPOs should be looked for using appropriate explicit criteria screening tools
56 D. O’Mahony

during routine medication review particularly in multimorbid older people with

polypharmacy. Whilst large scale multi-centre trials do not show significant patient
outcome benefit from application of STOPP/START criteria in hospitalized older
people with multimorbidity and polypharmacy in terms of ADR incidence or rehos-
pitalization, there are nevertheless good reasons to minimize PIMs and PPOs in
these at-risk patients. Consideration of older frailer patients’ life expectancy is criti-
cally important in decision-making relating to medication. Patients who are unlikely
to survive beyond 12 months should have their long-term preventive medications
reviewed carefully and possibly deprescribed, and their overall medication list ratio-
nalized with a focus on symptom management. Explicit STOPPFrail criteria can
assist prescribers with choosing which medications to discontinue in frailer older
people with very limited life expectancy.
In addition to the patients themselves and their principal carers, involvement of
all relevant healthcare professionals involved in prescribing, dispensing and moni-
toring older people’s medication is important for medication optimization and
achieving therapeutic targets, that is, patients’ primary care physicians, community
pharmacists and community nurses.
It is likely that in the future as the information technology support for medication
prescribing, dispensing and monitoring becomes more sophisticated, PIM and PPO
detection software will become more user friendly and effective in terms of enhanc-
ing patient safety. However, this is also contingent on health service providers
investing meaningfully in the software systems necessary to deploy and support
PIM/PPO detection criteria. Systematic review evidence indicates that computer-
ized prescribing systems can significantly reduce PIMs; however, evidence is lack-
ing for PPO prevention because PPO prevalence is not currently defined as an
outcome measure [35]. Future studies will need to address this deficiency in the
literature, since the presence of two or more START criteria PPOs predicts hospital-
ization at least as effectively as the presence of PIMs [36].

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Prescribing Cascades
5
Shelley A. Sternberg, Jerry H. Gurwitz,
and Paula A. Rochon

5.1 Introduction

Prescribing cascades are important contributors to drug-related harm in older adults.

A prescribing cascade occurs when a healthcare provider misinterprets the side
effect of a drug as a new medical condition and prescribes a second, potentially
unnecessary drug therapy to address the side effect [1–3]. Many prescribing cas-
cades have been described in the literature [4–6]. The ageing of the population with
its associated multimorbidity and polypharmacy highlights the importance of con-
sidering prescribing cascades and their impact on the health of older people at an
international level [7]. As a result, many countries have addressed the need to
decrease the risk of drug-related harm in older adults specifically targeting prescrib-
ing cascades [8, 9].

S. A. Sternberg
Department of Geriatric Medicine, Maccabi Healthcare Services, Modiin, Israel
J. H. Gurwitz
Division of Geriatric Medicine and Meyers Primary Care Institute, University of
Massachusetts Medical School, Worcester, MA, USA
e-mail: [email protected]
P. A. Rochon (*)
Women’s Age Lab, Women’s College Hospital, Toronto, ON, Canada
Department of Medicine, University of Toronto, Toronto, ON, Canada
Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health,
University of Toronto, Toronto, ON, Canada
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 59

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_5
60 S. A. Sternberg et al.

Providers can prevent prescribing cascades by asking a few simple questions at

the time of prescribing [10]. In addition, the identification of prescribing cascades
during medication review, especially in older women, can provide an opportunity to
deprescribe and to optimize drug therapy [11]. These interventions to prevent and
interrupt prescribing cascades can lead to improved quality of care and patient
safety in older adults.

5.2 Definition of Prescribing Cascades

Prescribing cascades were described by Rochon and Gurwitz in the 1990s [1, 2].
One typical example of a prescribing cascade is a non-steroidal anti-inflamma-
tory drug (NSAID) leading to hypertension and subsequently leading to the ini-
tiation of a new anti-hypertensive medication prescription [2]. This definition
was expanded in 2017 [3] to include the prescribing of potentially unnecessary
over-the-counter drug therapies and medical devices such as permanent pace-
maker devices to counteract severe bradyarrhythmias unrecognized as being
caused by cardiovascular drugs like beta-blockers, digoxin and verapamil.
Prescribing cascades must, by definition, reflect inappropriate prescribing
(Fig. 5.1).

Fig. 5.1 Expanded prescribing cascade definition

5 Prescribing Cascades 61

5.3 Why Prescribing Cascades are Important

for Older Adults

Older adults are particularly at risk for prescribing cascades and drug-related harm
due to the high prevalence of multimorbidity and associated polypharmacy. Most
older adults have multiple medical conditions and drug therapies that are used to
treat these conditions [11]. Polypharmacy is also extremely common in older adults,
especially in the long-term care setting [12]. In the United States, the use of five or
more medications by older adults over age 65 has increased from 13% in 1988 to
39% in 2010 [13]. The prevalence of polypharmacy in European older adults ranged
from 26% in Switzerland to 40% in the Czech Republic, as reported by the Survey
of Health, Ageing and Retirement in Europe (SHARE) based on 2015 data from 17
countries [14]. Among older adults living in long-term care in Europe and Israel,
almost half used between five and nine daily drug therapies, and almost a quarter
used ten or more drugs [15]. For older adults living in long-term care homes in
Canada, where almost 70% of residents are women [16], almost 50% were pre-
scribed medications from ten or more drug classes [12]. This high rate of hyperpoly-
pharmacy (i.e. ten or more daily drugs) is related not only to multimorbidity but is
also a consequence of multiple prescribers caring for older people without adequate
communication between the prescribers. In addition, clinical guidelines tend to
focus on single diseases without taking into consideration that two-thirds of adults
over the age of 65 have multiple chronic conditions requiring the use of numerous
medications [11]. Finally, current prescribing guidelines do not routinely take into
consideration an older adult’s goals of care or their remaining life expectancy [17].
Important factors such as a person’s cognitive and frailty status are insufficiently
considered when assessing the potential risks and benefits of a medication [18]. The
combination of these factors increases the risk of prescribing cascades occurring in
older adults.
Among older adults, prescribing cascades may disproportionately impact
older women. Older women have the most chronic conditions and often use the
greatest number of drug therapies [19]. In addition, sex (female biology) and
gender (sociocultural construct), in combination, contribute to this increased risk
of prescribing cascades. The pharmacokinetic and pharmacodynamic changes
associated with the female sex and older age contribute to the increased preva-
lence of adverse drug events in women compared to men [20–23]. Furthermore,
it was found that older European women were more likely than men to have
multimorbidity and as a result were more likely to be prescribed multiple
62 S. A. Sternberg et al.

medications [24]. In summary, differences in pharmacokinetics and pharmaco-

dynamics as well as patterns of multimorbidity put older women at higher risk
for prescribing cascades.
Gender (sociocultural factors) impacts both the patients and the prescribers and
contributes to the risk of prescribing cascades. On the patients’ side, women are
more likely than men to seek medical care and to follow recommendations from
their providers [25]. Older women are less likely than older men to have pensions or
drug benefit plans because they were less likely to have been part of the formal work
force [26] and, therefore, may have less ability to pay for medications. On the pre-
scribers’ side, there is evidence that physicians may treat female patients differently
from male patients [27]. For example, women are more likely to be prescribed psy-
chotropic medications, whereas men are more likely to receive drug therapy for
physical disorders, particularly cardiovascular conditions [28]. These sex and gen-
der factors all contribute to placing older women at increased risk for prescribing
cascades.

5.4 Original Investigations to Identify Prescribing Cascades

In 1997, three initial prescribing cascades were described [2]. The original exam-
ples were: NSAIDs leading to a prostaglandin-mediated rise in blood pressure with
the subsequent prescription of antihypertensive therapy in older people; thiazide
diuretics prescribed to treat hypertension leading to hyperuricemia and the subse-
quent prescription of colchicine for gout; and the initiation of antipsychotic drug
therapy followed by the development of Parkinsonism, which was misinterpreted as
Parkinson’s disease and treated with levodopa/carbidopa. As awareness has
increased, so have the number of prescribing cascades. In 2017 [3], there were 20
examples of prescribing cascades, and recently, more than 100 prescribing cascades
have been identified as part of an international project [7]. Examples of prescribing
cascades can be seen in Table 5.1.
One notable example of a prescribing cascade is a cholinesterase inhibitor (e.g.
donepezil) prescribed to manage the symptoms of dementia leading to the develop-
ment of urinary incontinence with the subsequent initiation of a urinary anticholin-
ergic drug to treat the incontinence [6]. The concern about starting a urinary
anticholinergic agent is that this therapy can lead to additional side effects, includ-
ing dry mouth, constipation and confusion. Another example of a prescribing cas-
cade is a calcium channel blocker (CCB) leading to ankle oedema and the subsequent
prescribing of loop diuretics [4]. This cascade was described in a large population-­
based cohort study that included 41,000 adults over age 65 (59% women) who were
newly prescribed a CCB. After adjustment, individuals who were newly dispensed
a CCB had significantly increased relative rates of being dispensed a loop diuretic
compared with individuals who were newly dispensed an angiotensin-converting
enzyme inhibitor or angiotensin II receptor blocker. Given that calcium channel
blockers are among the top ten prescribed medications, and that 2–25% of CCBs
5 Prescribing Cascades 63

Table 5.1 Examples of prescribing cascades commonly encountered in clinical practice

Adverse event misinterpreted as a New drug therapy
Initial drug therapy prescribed new medical condition prescribed
Prescribing cascades: drug classes
ACE inhibitor [33, 34] Cough Antibiotic
Anticholinergic [35] Lowered oesophageal sphincter Proton pump
pressure (GERD) inhibitors
Antiepileptic [33] Nausea Metoclopramide
Antipsychotica [33, 36–38] Parkinsonism Anti-Parkinsonian
agents
Beta-blocker [36] Depression Antidepressant
Calciuma channel blocker [4, Edema Diuretics
39–41]
Cholinesterasea inhibitor [6, 33, 36] Urinary incontinence Urinary
anticholinergics
NSAID [2, 33, 36] Hypertension Antihypertensive
Sodiuma glucose cotransporter 2 Genital mycotic infection Antifungals
inhibitors (SGLT-2) [29] Urinary tract infection Antibiotics
Thiazide and thiazide-like diuretics Gout Anti-gout
[2, 33]
Prescribing cascades: individual drug therapy
Amitriptyline [36] Decreased cognition Donepezil
Amlodipine [36] Oedema Furosemide
Bupropion [36] Insomnia Mirtazapine
Ciprofloxacin [36] Delirium Risperidone
Gabapentina [5, 36] Oedema Furosemide
Metoclopramide [2, 33, 36, 42] Parkinsonism Levodopa/carbidopa
Diarrhoea Loperamide
Omeprazole [36] Low B12 B12 supplement
This table is an expansion of a table which appeared in our recent Commentary in The Lancet
ACE inhibitor angiotensin converting enzyme inhibitor, NSAID non-steroidal anti-­
inflammatory drug
a
Prescribing cascades supported by large population-based studies

cause peripheral oedema, this prescribing cascade has the potential to cause impor-
tant drug-related harm to older adults.
Another population-based study investigated the prescribing cascade of sodium
glucose cotransporter 2 inhibitor (SGLT2) medications leading to genital fungal
infection and the subsequent initiation of an anti-fungal medication to treat this
SGLT2 side effect [29]. It compared 21,444 new users of SGLT2 inhibitors to
22,463 incident users of dipeptidyl-peptidase-4 (DPP4) inhibitors. After adjusting
for propensity score, age, sex and recent urinary tract infection, there was a 2.47-­
fold increased risk of genital fungal infection (determined by the use of antimycotic
medication) with incident use of SGLT2 inhibitors within 30 days compared to
incident use of DPP4 inhibitors. This prescribing cascade should be an important
consideration when using SGLT2 medications for older adults with diabetes and
cardiovascular disease.
In the expanded version of the prescribing cascade definition, over-the-counter
(OTC) drugs and medical devices were also included (Table 5.2). One case study
64 S. A. Sternberg et al.

Table 5.2 Examples of the expanded definition of prescribing cascades involving over-the-­
counter therapies and medical devices
Over-the-counter therapy
Initial drug therapy Adverse event misinterpreted as a Subsequent over-the-counter
prescribed new medical condition drug therapy
Cholinesterase inhibitor Gastrointestinal symptoms Bismuth subsalicylate
[30]
Cholinesterase inhibitor Rhinorrhoea Diphenhydramine
[43]
Enalapril [36] Cough Dextromethorphan
Bupropion [44] Insomnia Sleep medication
Ramipril [44] Cough Cough syrup
Medical device
Initial drug therapy Adverse event misinterpreted as a Medical device
prescribed new medical condition
Cholinesterase Bradycardia Pacemaker device
inhibitorsa [45]
a
The article did not mention the term prescribing cascade in the text, but described the concept of
a prescribing cascade

[30] example involved an acetylcholinesterase that was prescribed for dementia and
subsequently led to abdominal discomfort. The patient self-medicated with large
quantities of bismuth salicylate causing him to suffer from salicylate toxicity and
bismuth neurotoxicity, leading to a fall and hospitalization for subdural haemor-
rhage and bilateral frontal contusions. This case illustrates that prescribing cascades
can occur with OTC drugs and with prescription medications. In addition, prescrib-
ing cascades can increase the risk of serious consequences such as morbidity and
hospitalization.

5.5 The Application of Prescribing Cascades to Inform

Better Clinical Care and Deprescribing Initiatives

Identifying and preventing prescribing cascades can inform better clinical care.
Many tools and frameworks have been described to identify inappropriate prescrib-
ing [11] including the prescribing cascade framework. Providing a detailed medica-
tion history, particularly when a medication was started, would help clinicians
determine the drug prescribing sequence and facilitate the early recognition of a
prescribing cascade. One such tool includes four simple questions to help physi-
cians identify and interrupt prescribing cascades [10]. These questions were devel-
oped to raise awareness of prescribing cascades each time a new drug is prescribed.
Providers need to think of prescribing cascades and be adept at identifying when
they occur, in order to prevent them (Box 5.1).
5 Prescribing Cascades 65

Box 5.1 Questions to help identify and prevent prescribing cascades

Questions to help identify and prevent prescribing cascades
1. Is the patient reporting a symptom that could represent a drug side effect?
2. Is a new drug being prescribed to address an adverse event from a previously
prescribed drug therapy?
3. Could the initial drug be substituted for a safer alternative, or could the dose be
reduced, potentially eliminating the need for the subsequent drug therapy?
4. Does the patient really need the initial drug therapy, so could it be stopped?

Physicians are often confronted with prescribing cascades in their clinical prac-
tice. For example, enalapril is prescribed for hypertension leading to a persistent dry
cough and an antibiotic such as levofloxocin is prescribed for suspected underlying
respiratory infection. Atenolol, a beta-blocker, is prescribed after a cardiac event,
leading to depression, and escitalopram is prescribed to treat the depression.
Table 5.1 presents examples of drug classes and specific examples of prescribing
cascades reported by physicians in clinical practice, and Table 5.2 provides some
examples of prescribing cascades involving OTC medications and medical devices,
as described in the expanded definition (see Fig. 5.1). Prescribing cascades have
also been incorporated into many deprescribing protocols [11]. Deprescribing is the
process of tapering or stopping medications that may not be indicated, in accor-
dance with the patients’ preferences, to minimize polypharmacy and improve
patient outcomes [31]. Most deprescribing protocols review all medications and
indications for use, consider each drugs risk/benefit profile and then develop a pri-
oritized plan for deprescribing. The medication review stage provides an opportu-
nity to identify prescribing cascades and then determine their potential for
deprescribing. Process mapping is another tool that can be used by clinicians to
identify prescribing cascades in their patients [32]. A clinical process map is a tool
designed to graphically illustrate a patient’s presentation, symptoms, medications,
possible side effects and interventions. This is generated quickly at the bedside by
the clinician to help visualize the sequence of events leading to the development of
the prescribing cascade and to understand its consequences.

5.6 Conclusions

Prescribing cascades are well documented in the literature and are an important
cause of drug-related harm in older adults. Older women are at higher risk for drug-­
related harm than older men. Prescribing cascades can be prevented by implement-
ing interventions at each stage of drug prescription and use. At the time of
prescribing, the provider should be aware of potential prescribing cascades that may
arise from the drug being initiated and carefully document the date that each new
drug was started. At regular follow-up, providers should question whether a new
complaint could be a medication side effect and whether a new prescription is really
necessary. At medication review, validated tools and frameworks should be applied
66 S. A. Sternberg et al.

to identify inappropriate prescribing and to recognize opportunities for deprescrib-

ing. Preventing, detecting and reversing prescribing cascades provide an opportu-
nity to improve quality of care for older adults and reduce drug-related harm.

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Adverse Drug Reactions in Older People:
A Twenty-First Century View 6
Mary Randles and Denis O’Mahony

6.1 Introduction

The unprecedented number of adults living beyond 65 years is one of the great suc-
cess stories of modern civilisation and modern medicine. Over the past century, the
proportion of older adults in the United States of America has increased threefold,
similar to like western Europe and most developed countries globally, leading to an
increase in life expectancy that has not yet reached a plateau [1, 2]. The proportion
of adults over 65 years in the United States was recently calculated at 20.3%, repre-
senting an increase of 2.9% over the 10 years to 2019. While these increases in
longevity represent progress in relation to societal health in general, they also pose
many challenges currently and in the future in terms of growing levels of comorbid-
ity and frailty accompanied by higher prevalence of polypharmacy and adverse drug
reactions in the population of any country observing societal ageing.
The success of medical management and pharmacotherapy in this population is
not straightforward. It is generally accepted that medical interventions have facili-
tated older people to increase their longevity and maintain generally better health.
However, greater exposure to polypharmacy has resulted in an ever-increasing
potential for adverse drug reactions (ADRs), adverse drug events (ADEs) and
adverse drug withdrawal events (ADWEs).

M. Randles · D. O’Mahony (*)

Department of Medicine (Geriatrics), University College Cork, Cork, Ireland
Department of Geriatric Medicine, Cork University Hospital, Cork, Ireland
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2023 69

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_6
70 M. Randles and D. O’Mahony

6.2 Definition of Adverse Drug Reactions

An adverse drug reaction was originally defined by the World Health Organisation
(WHO) over 50 years ago as: “A response to a drug that is noxious and unintended
and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy
of disease, or for the modification of physiological function” [3]. This WHO defini-
tion was developed with the aim of monitoring ADRs, particularly in drug develop-
ment trials and soon after approval of drugs for marketing for general use. Edwards
and Aronson further defined an ADR as: “An appreciably harmful or unpleasant
reaction, resulting from an intervention related to the use of a medicinal product,
which predicts hazard from future administration and warrants prevention or spe-
cific treatment, or the alteration of the dosage regimen, or withdrawal of the prod-
uct” [4]. They further point out that while an adverse drug effect and adverse drug
reaction are often used interchangeably, an adverse drug effect is seen from the
point of view of the drug, whereas the adverse drug reaction is seen from the point
of view of the patient [4]. Edwards and Aronson’s definition was further expanded
in 2010 to include reactions occurring as a result of error, misuse or abuse and to
suspected reactions to medicines that are unlicensed or used off label in addition to
the authorised use of a medicinal product in normal doses [5].
When discussing ADRs, some experts emphasise the need to differentiate
between ADRs and ADEs. The difference depends essentially on the adverse effect.
While we can define an ADE as an adverse outcome that occurs while a patient is
taking a drug, it is not necessarily directly attributable to the drug [4], such as the
increased incidence of falls and fractures when older people are taking
benzodiazepines.

6.3 Prevalence and Cost of ADRs in Older Adults

While historically there has been little interest in the specific effect of ADRs in
older adults, over the past two decades, there has been increasing focus on the prev-
alence, incidence, clinical effect and cost of ADRs in older adults. In the general
adult hospitalised population, ADRs account for approximately 6% of all admis-
sions [6]. Furthermore, prospective analysis of inpatient episodes demonstrated that
14.7% (95% CI, 13.6–15.9%) of patients experienced at least one incident ADR [6,
7]. Given the increased complexity of comorbid diseases and polypharmacy in older
people, it is unsurprising that a systematic review and meta-­analysis [8] found the
prevalence of ADRs in older adults in acute care settings was greater than in the
general adult population. The overall mean prevalence of ADRs in the same review
was 11.0% (95% CI: 5.1–16.8) with 11.5% occurring during hospitalisation. This
meta-analysis demonstrated a wide variation of overall ADR prevalence across the
included studies, that is, from 5.8% [8] to 46.3% [9]. The authors note that prospec-
tive studies and larger scale studies generally found higher ADR prevalence rates
[10] in studies of ADRs in ‘old old’ adults (i.e. over 80 years), reporting an average
in-hospital ADR incidence of 13%. Although the large variance in the prevalence of
6 Adverse Drug Reactions in Older People: A Twenty-First Century View 71

ADRs observed in older hospitalised adults has been attributed to the difference in
sample sizes and different admission settings within hospitals (general unselected
medical acute admissions versus dedicated geriatric medicine unit admissions) [11],
it remains very clear that ADRs are a common problem faced by all clinicians treat-
ing older adults.
Highly variable prevalence rates of ADRs have been reported in community-­
dwelling older adults also, varying from 6.5% in one prospective study [6] to 78%
in a retrospective cohort of older adults where the ADRs were self-reported by
patients and corroborated by clinician review [12]; the latter study also included
drug events that may not have resulted in the index hospitalisation. Older adults in
long-term care settings were found to have an ADR prevalence of 14% with other
studies reporting an ADR incidence in long-term care older patients between 1.19
and 7.26 per 100 resident-months [12]. It is estimated that older adults are approxi-
mately seven times more likely to experience an ADR requiring hospital admission,
and when hospitalised they are substantially more likely to experience ADRs during
their hospital admission than younger patients [13, 14].
ADRs in older adults result in excess economic costs during hospital admissions,
increased length of stay, additional cost of care and increased mortality. A French
study evaluating the cost of ADRs with the aim of assessing the additional financial
resource utilisation arising from ADRs found that the ADR incidence increased
with age and that half of the ADRs led to additional investigations and increased
median length of stay, that is, 11 days versus 7 days in those patients who did not
experience ADRs. This increase in length of stay resulted in a mean cost of approxi-
mately €1800 per ADR [15], similar to the cost of €2128 per ADR-related hospitali-
sation calculated by Beijer and Blaey [16]. ADRs have a significant impact on
hospital running costs accounting for 5% of overall hospital running costs in the
USA, estimated at between $3.5 billion and $30 billion per annum [13–15, 17]. The
fatality rate from ADRs has been reported as 0.15% in a larger scale, retrospective,
population-based study and 0.44% in older adults in one meta-analysis [6, 18].

6.4 Why Do ADRs Occur More Commonly in Older People?

As discussed in previous chapters, old age results in diminished ability to maintain

homoeostasis with a concomitant decrease in the functional capacity of multiple
organ systems leading to changes in absorption, distribution, metabolism and excre-
tion of some drugs [19]. Older age is associated with delayed gastric emptying,
decreased splanchnic blood flow and reduced surface area for absorption, coupled
with increased gastric pH. Older people often have a greater body fat to lean body
mass ratio with an overall reduction in body total water and serum albumin concen-
tration. This leads to a relative increase of the volume of distribution such that the
half-life for lipophilic drugs such as benzodiazepines is prolonged; there is an
increased concentration of water-soluble drugs like lithium and an increased pro-
portion of free unbound highly protein-bound drugs like Ibuprofen and phenyt-
oin [19].
72 M. Randles and D. O’Mahony

Metabolism of drugs may be altered with ageing also due to reductions in hepatic
volume, renal and hepatic perfusion, and protein binding. Older people who experi-
ence polypharmacy are more likely to take drugs that cause inhibition or activation
of the CYP pathway [11, 20]. Normal physiological ageing and common disorders
such as cardiovascular disease, diabetes, heart failure and hypertension can all lead
to reduced renal clearance and excretion of drugs [20].
Multimorbidity, the co-occurrence of two or more coinciding medical conditions
was shown to affect up to 95.1% of patients aged over 65 in the primary care setting
in a systematic review of 39 studies [21]. Older people are at considerably higher risk
of experiencing polypharmacy due to a much higher burden of multimorbidity than is
encountered in younger people. Polypharmacy, as the principal risk factor for ADRs,
may be engendered and exacerbated by older people attending multiple specialists for
individual diseases or conditions, leading to more evidence-based drug therapies.
In one study [22], researchers found that taking five or more daily medications
was associated with an odds ratio for ADEs of 1.88 (95% CI, 1.58–2.25) compared
to patients taking zero to four daily medications). Over the last 20 years, there has
been a notable increase in treatment guidelines for many common conditions, par-
ticularly in cardiovascular disease and diabetes where treatment guidelines recom-
mend multiple drugs for secondary prevention and ongoing management of these
conditions. Worryingly, studies demonstrate that polypharmacy has increased in the
last decade, particularly after hospital admissions [23, 24]. Higher levels of poly-
pharmacy increase the risk of both drug–disease interactions and drug–drug interac-
tions [25].
Although older patients experience most of the burden of multimorbidity and poly-
pharmacy and are the largest group of patients receiving evidence-based pharmaco-
therapies, paradoxically, they are often excluded from clinical drug trials because of
their multimorbidity. An example of this discrepancy can be seen in cancer drug trials.
While people over 65 years represent over 60% of new cancer cases in Europe and the
US annually, they only account for 22% of patients recruited into cancer trials; this
proportion drops to 8–13% in those aged over 70 years [26]. This degree of older
patient exclusion from clinical trials is further illustrated in a review of 440 trials of
drugs for type 2 diabetes [27]. Despite being the most common long-term metabolic
condition experienced by older adults, only six trials were specifically designed to
study older adults; 289 trials excluded individuals based on an arbitrary age cut-off
and a further 76.8% of trials excluded people with comorbidities.

6.5 Types of ADRs

Historically, ADRs were classified as Type A and Type B reactions. In Rawlins and
Thompson’s classification, Type A reactions were typically associated with drug
doses and were predictable from the pharmacological properties and physiological
actions of the drug. Type B or “Bizarre” reactions were not seen as dose related,
such as idiosyncratic hypersensitivity reactions [28]. Over time, these categorical
ADR types were expanded to include further four categories; (Table 6.1) Type C
6

Table 6.1 Classifications of adverse drug reactions

Reaction
type Type of effect Common Characteristics Example Management
A Augmented Yes Dose related  • Side effects: orthostatic  • Dose reduction
 • Related to the hypotension with  • Withdrawal of drug if
pharmacological action of the anti-­hypertensives necessary
drug  • Toxic effects: serotonin  • Review for drug–drug
 • Predictable syndrome with SSRIs, digoxin interactions
 • Low mortality toxicity
B Bizarre No Non-dose related  • Immunological reactions:  • Immediate withdrawal of drug
 • Not related to anaphylaxis to penicillin and avoidance in the future
pharmacological action of the  • Idiosyncratic reactions:
drug malignant hyperthermia with
 • Unpredictable anaesthetics, acute porphyria
 • High mortality
C Chronic No Dose-related and time-related  • Hypothalamic–pituitary–  • Dose reduction
 • Related to cumulative dose of adrenal axis suppression by  • Withdrawal, if necessary,
the drug corticosteroids often over a prolonged period
of time
D Delayed No Time related  • Traditive dyskinesia  • Often non-treatable
 • Often also dose related  • Carcinogenesis
 • Occurs some time after the  • Teratogenesis
use of the drug
E End-of-use No Withdrawal  • Withdrawal syndrome after  • Reintroduction of drug
 • Occurs soon after withdrawal discontinuation of opiates or  • Slow withdrawal
Adverse Drug Reactions in Older People: A Twenty-First Century View

of drug benzodiazepines
 • Myocardial ischemia after
withdrawal of beta-blockers
F Failure Yes Unexpected failure of therapy  • Inadequate anticoagulation  • Increase in dosage
 • Dose related effect from warfarin with  • Review of effects of
 • Drug interaction related carbamazipine concomitant therapy
(Adapted from Edwards & Aronson, 2000)
73
74 M. Randles and D. O’Mahony

[dose- and time-dependent (chronic) reactions], Type D (delayed reactions), Type E

(withdrawal reactions) and Type F (failure of therapy) [4].
Aronson and Ferner proposed the DoTS (Dose-related/Time-­
related/Susceptibility-related) system of classification to incorporate the temporal
relationship and susceptibility of the individual to the reaction [29]. They argue that
the Type A–F classification is defined only by the properties of the drug and its
known pharmacology and dose-dependent effects. They proposed a classification
system that takes account of the time course and severity of a reaction and the
genetic, pathological and biological differences of the individual, which may make
them more susceptible to an adverse reaction.
In the DoTS classification, dose relatedness divides ADRs into reactions that
occur at supratherapeutic doses (toxic effects), ADRs that occur at standard thera-
peutic doses (collateral effects) and ADRs that occur at subtherapeutic doses in
sensitive individuals, that is, hyper-susceptibility reactions. They distinguish two
distinct patterns of time course for ADRs, i.e. one that is dependent on the time
exposed to the drug and one that is time independent, occurring at any time during
drug treatment. Time-dependent reactions range from rapid to delayed and can be
seen in greater detail in Table 6.2.
This classification also acknowledges that different individuals will have differ-
ent levels of susceptibility to particular ADRs based on their genetics, age, sex,
disease profile and drug or food interactions, for example, older women are consid-
ered to be more susceptible to ADRs from hypnotics than younger adults. The three
elements of dose, time and susceptibility can be combined to give greater informa-
tion about an ADR and also guide future prescribing to prevent further ADRs.

Table 6.2 Types of time-dependent drug reactions based of Aronson and Ferner ADR classifica-
tion [29]
Time-dependant reactions
Type of
reaction Features Example
Rapid reactions Occur only when a drug is administered Vancomycin → red man syndrome
too quickly
First dose Occur after the first dose of a certain Ace inhibitor-hypotension
reactions treatment. May or may not occur again Type I hypersensitivity reaction to
penicillin
Early reactions Occur early in treatment but abate as Acetylcholinesterase inhibitors →
treatment progresses gastrointestinal disturbance or
nausea
Intermediate Occur after some delay, however if a Type II–IV hypersensitivity
reactions reaction hasn’t occurred after a certain reactions
time, the population risk falls
Late reactions Risk increases with repeated exposure Dopamine receptor antagonists →
Also includes withdrawal reactions tardive dyskinesias
Corticosteroids → osteoporosis
Delayed Effects are observed at some time after Carcinogens
reactions exposure, even if the drug has been
withdrawn
6 Adverse Drug Reactions in Older People: A Twenty-First Century View 75

6.6 Recognising ADRs in Older Adults

Recognising ADRs in older adults can present a particular challenge to clinicians.

ADRs have been described as one of the great mimics in healthcare due to their
propensity to present in a similar manner to other common age-related disorders,
often with non-specific symptoms [30]. Acute kidney injury, electrolyte distur-
bance, falls, orthostatic hypotension, symptomatic bradycardia, gastrointestinal
upset and bleeding are familiar presentations of acute illness to clinicians caring for
older people. However, these presentations were also found to be the most common
presentations of ADRs in a study of 513 older adults during their hospital stay for
acute illness [31]. Medications that were associated with these common clinical
problems included diuretics, benzodiazepines, opioids, antihypertensives, antiplate-
let/anticoagulants, antidiabetic drugs and NSAIDs [31–33], that is, medications that
are commonly utilised in the care of older adults. Recognising non-specific symp-
toms such as fatigue, cognitive decline, new onset of falls and constipation as poten-
tial ADRs is important to prevent potential prescribing cascades (see Chap. 5).
Reliably defining and classifying ADRs in practice can be challenging in due to
heterogeneity of ADR risk assessment and causality tools [34]. Despite the high
prevalence of ADRs in older adults, none of the most frequently used ADR assess-
ment tools was developed specifically with older patients in mind. The WHO–UMC
assessment matrix (Table 6.3) relies on expert judgement, knowledge of the medical
conditions, understanding of comorbid illness and laboratory results. It considers
drug–drug interactions, which is advantageous when assessing causality in comor-
bid older adults. Algorithm or probability-based methods such as the Naranjo ADR
probability [35] algorithm are less reliant on expert judgement; however, they use
some criteria such as response to placebo and drug rechallenge to confirm suspected
ADRs, which could pose practical and ethical difficulties in the management of
older adults in routine clinical practice.
Once the causality of an ADR has been established, a severity rating can be
applied such as that proposed by Hartwig and Siegal (1992). This scale assigns
severity of ADRs into seven categories depending on the clinical consequences to
the patient (Table 6.4). The Hallas ADR avoidability criteria are also illustrated in
Table 6.4.
While the tools discussed in this section may be of benefit in assessing ADRs at
a population level, they may not be practical for routine clinical use. Nevertheless,

Table 6.3 Adverse drug reactions (ADR) causality matrix adapted from World Health
Organisation–Upsala Monitoring Centre (WHO–UMC) ADR causality criteria [36]
Categories of Time sequence Other drugs/ Dechallenge Rechallenge
ADR consistent with diseases ruled response, that is, response, that is,
attribution ADR out as causative clinical improvement clinical relapse
Certain Yes Yes Yes Yes
Probable Yes Yes Yes No
Possible Yes No No No
Unlikely No No No No
76 M. Randles and D. O’Mahony

Table 6.4 Hartwig adverse drug reactions (ADR) severity scale and Hallas ADR avoidability
criteria
Hartwig ADR severity grade (Hartwig Hallas ADR avoidability criteria (Hallas et al. 1990)
et al. 1992) [37] [38]
1 An ADR occurred but no Definitely The drug event was due to a drug
change in treatment with avoidable treatment procedure inconsistent with
suspected drug present-day knowledge of good
medical practice or was clearly
unrealistic, taking the known
circumstances into account
2 The ADR required that Possibly The prescription was not erroneous,
treatment with the suspected avoidable but the drug event could have been
drug be held, discontinued or avoided by an effort exceeding the
otherwise changed (no antidote obligatory demands
required and no increase in
length of stay)
3 The ADR required that Unavoidable The drug event could not have been
treatment with the suspected avoided by any reasonable means, or
drug be held, discontinued or it was an unpredictable event in the
otherwise changed or and an course of a treatment fully in
antidote or other treatment was accordance with good medical
required practice
4 Any level 3 ADR which Unclassifiable The data for rating could not be
resulted in admission or obtained or the evidence was
increased length of stay by at conflicting
least 1 day
5 Any level 4 ADR which
required intensive medical care
6 Any ADR causing permanent
harm to the patient
7a The ADR indirectly linked to
death in the patient
7b The ADR was directly linked to
death in the patient

clinicians caring for older patients need to maintain a heightened vigilance for
detection of possible ADRs and to carefully examine all presentations to ensure that
ADRs are not overlooked as a diagnosis.

6.7 Preventing ADRs in Older People

ADRs are a potentially preventable form of iatrogenic harm. In the past decade,
interest in developing new clinical tools designed to reduce and prevent ADRs in
older people has grown. Given the association between inappropriate prescribing
(IP) and ADRs, explicit IP assessment tools such as STOPP/START criteria and
Beers criteria, although developed to identify and reduce IP, may have potential to
reduce ADRs. In one single-centre, single-blinded study, application of STOPP/
START criteria (version 1) to the medication lists of acutely hospitalised older
6 Adverse Drug Reactions in Older People: A Twenty-First Century View 77

adults was associated with a 9.3% absolute risk reduction in hospital-acquired

ADRs compared to standard pharmaceutical care [39]. In contrast, the larger scale,
multi-centre OPERAM trial examining the impact of application of STOPP/START
criteria (version 2) on drug-related admissions (DRAs) in older hospitalised patients
compared with standard pharmaceutical care did not show any significant beneficial
impact on DRAs in the 12 months post-intervention [40].
ADR risk assessment tools designed specifically for use in older people have
appeared in the literature in recent years, such as the GerontoNet ADR risk score [41]
the BADRI score [42] and the ADRROP score [43]. In each model, researchers have
attempted to prioritise and quantify the main risk factors for ADRs in multimorbid
older people leading to an ADR risk score that might be applicable in routine clinical
practice. However, none of these ADR risk scores has through prospective validation
assessment been sufficiently robust to recommend their routine use.
More recently, Jennings et al. (2019) have identified the need for an ADR risk
prediction tool that looks beyond the individual patient factors and suggest a shift in
focus to the drugs that carry higher risk for ADRs in older people [44]. In a recent
systematic review and meta-analysis [44], the same group has identified those drug
classes that are most associated with ADRs in older people in hospital [43]; these
higher risk drug classes are listed in Table 6.5. Given the doubt about benefit from
applying ADR risk tools, clinician awareness and vigilance remain fundamental to
ADR detection and avoidance. By applying knowledge of the physiological changes
associated with ageing and remaining vigilant to the risks of inappropriate prescrib-
ing and drug–drug and drug–disease interactions, clinicians can reduce the risk of
ADRs. Increased awareness of common ADRs and a high index of suspicion when

Table 6.5 The ten most common drug classes causing adverse drug reactions (ADRs) in hospital-
ised older patients [43]
Drug class (in rank order of Proportion of total Most commonly reported
frequency) reported ADRs pharmacological subgroup
Diuretics 19.83% Loop (high ceiling) diuretics
Antibacterials (systemic 14.84% Beta-lactams (penicillins,
use) cephalosporins), macrolides, quinolones
Antithrombotics 12.24% VKAsa, heparin and heparinoids,
antiplatelet agents
Analgesics 10.90% Opioids
Drugs for obstructive 4.74% Beta-2 adrenergic agonists, xanthines
airways disease (e.g. theophylline)
Renin–angiotensin system 4.11% ACE inhibitors, angiotensin-II receptor
antagonists blockers
Psychotropics 3.86% Benzodiazepines, antipsychotics
Corticosteroids (systemic 3.23% Glucocorticoids
use)
Cardiac drugs 2.98% Cardiac glycosides, vasodilators, class I
and III antiarrhythmics
Antidiabetic drugs 2.56% Insulin and insulin analogues, oral
antidiabetics
Vitamin K antagonists, for example, warfarin
a
78 M. Randles and D. O’Mahony

new symptoms develop in an older person, particularly after commencing or chang-

ing medications, could help reduce ADR risk.
Advanced (electronic) medication reconciliation at points of transition care can
also reduce medication errors and ADEs by identifying prescribing errors or dis-
crepancies or dose errors in patients’ prescriptions [45]. Deprescribing of unneces-
sary or inappropriate medications with particular focus on attainable therapeutic
goals coupled with incorporating the wishes of the patient could reduce the number
of drugs prescribed, particularly those drugs with minimal benefit to the patient that
are repeatedly prescribed.
Routine review of regular medications for appropriateness, drug–drug and drug–
disease interactions is recommended, incorporating specific enquiry about over-the-­
counter (OTC) medication use and medication adherence.

6.8 Conclusion

As multimorbidity and polypharmacy become more prevalent in tandem with soci-

etal ageing, risk of ADRs in older people increases. Clinicians must seek to achieve
a balance between potentially beneficial medications and risk of ADRs.
Acknowledging that older people are a heterogeneous group with varying degrees
of physiological and physical function, prescribers should be vigilant in order to
minimise risk of iatrogenic harm. It is imperative that clinicians caring for older
adults are aware of ADRs, the main risk factors for ADRs and the often-non-specific
clinical presentations of ADRs in order to reduce ADR risk while maintaining ben-
eficial medications. Careful assessment of the individual older patient, his/her goals
and expectations from pharmacotherapy and careful review of medications at each
healthcare encounter, with a focus on potentially inappropriate medications helps to
minimise ADR risk in older adults.

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Adherence: How to Measure
and Improve It 7
Alessandra Marengoni and Laura J. Sahm

7.1 State of the Art

Older adults are typically affected by multimorbidity, the co-occurrence of multiple

diseases, which makes their care complex, and the use of medications, a challenging
task [1]. More than 90% of older adults receive drug prescriptions according to
guidelines for specific diseases; it has been shown that around 50% of older adults
chronically receive polypharmacy (≥5 drugs) and about 10% excessive polyphar-
macy (≥10 drugs) [2]. The mean number of prescribed medications progressively
rises from the age group with less than 65 years to the 80–84-year age group [3] and
is higher among patients affected by dementia [4].
Polypharmacy is one of the main determinants of poor adherence to treatment in
older patients. The World Health Organization defines adherence as the extent to
which a person’s behavior—taking medication, following a diet and/or executing
lifestyle changes—corresponds with agreed recommendations from a healthcare
provider [5]. When limiting to medication adherence, the latter is usually defined as
the proportion of days covered of more than 80%. Adherence can be split into three
phases: initiation (taking the first dose of prescribed drug), implementation (taking
the prescribed dosing regimen from the initiation on) and persistence (time between
initiation and the last dose); each of them presents specific issues and challenges.
Non-adherence may be intentional (when the patient decides not to take treatment
or to take it in a way that differs from the one suggested by the care provider) or
unintentional (when the patient is willing to take his/her treatment but cannot due to

A. Marengoni (*)
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
e-mail: [email protected]
L. J. Sahm
School of Pharmacy, University College Cork, Cork, Ireland
Department of Pharmacy, Mercy University Hospital, Cork, Ireland
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 81

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_7
82 A. Marengoni and L. J. Sahm

Table 7.1 Determinants of non-adherence

Health-­
Patient-­ Therapy-­ Condition-­ system Social and
related related related related economical
Forgetfulness x x
Lack of information x x
Length of treatment x x
Number of drugs x x
Previous adverse drug x x x
reactions
Therapeutic failures x x
Poor education x x x
Reimbursement x x x
system
Cultural beliefs x x

limitations in mental or physical capacity or resources). In older persons, uninten-

tional adherence is very often due to cognitive and psychological problems, visual
and motor impairments and inadequate caregivers or social support [6].
Overall, a number of studies have found that, in developed countries, adherence
among older patients suffering chronic diseases averages only 50% [7], and it is
even less in developing countries.
According to the World Health Organization (WHO), determinants of non-­
adherence can be aggregated into five dimensions: patient-related, therapy-related,
condition-related, health system-related, and socio-economic [8] (Table 7.1).
Several initiatives have been taken worldwide in order to better understand factors
of non-adherence and possible interventions to improve it, especially in older
persons. For instance, the European Innovation Partnership on Active and Healthy
Ageing Action Group A1 focused on “Adherence to prescriptions” bringing
together partners representing multi-stakeholder commitments from national,
regional and local authorities, academic and non-academic research centres,
industries and enterprises across the European Union. As a general aim, the Action
Group A1 has to contribute to the improvement of adherence to medical plans and
medication at European level [9]. Still, at present, poor adherence is the main fac-
tor underlying the failure of patients and healthcare systems to achieve treatment
outcomes.

7.2 How to Assess Adherence

Measuring medication adherence is important to clinicians and researchers, and

there is no “one size fits all” approach. The methods used should be tailored to the
question being asked and in the specific population and should consider the severity
of the consequences of non-adherence. There are many ways to measure medication
adherence, and they usually fall into direct or indirect methods. The World Health
Organization (WHO) delineates these into subjective and objective measures [8].
We know from listening to our patients that whilst they may not have taken the
7 Adherence: How to Measure and Improve It 83

medication, they would also not like to admit this as it may cause some embarrass-
ment or perhaps a fear of disappointing the prescriber. In addition, we know that the
more medications a patient needs, due to multimorbidity and/or older adult with
polypharmacy, the more likely that medication adherence will be suboptimal [10].

7.2.1 Let Us Look First at the Direct Methods

There can be the direct measurement of the amount of drug in the patient at a par-
ticular point in time, for example, by taking a blood sample. This is commonly used
when dealing with narrow therapeutic index drugs, for example, digoxin or theoph-
ylline, and there is a need to establish the therapeutic drug concentration, to avoid
sub- or supra- therapeutic doses. This can also be used to measure adherence but is
not done routinely in practice due to its cumbersome and costly nature, in addition
to the fact that parameters such as the absorption, distribution, metabolism and
elimination of the drug (or indeed its metabolites) may have individual variation.
Also, bearing in mind that the patient may have taken this drug with food or other
drugs, there may well be drug–drug or drug–food or indeed drug–herbal interac-
tions. These interactions may result in the faster/slower elimination of the drug and,
therefore, muddy the water.
At best these drug levels provide a snapshot of what is happening in the body at
the time and do not offer a view as to the long-term medication adherence. This is
analogous to the doctor who relies on a fasting blood glucose to indicate the adher-
ence of a patient to their antidiabetic agents rather than seeking to review the glyco-
sylated haemoglobin. This method may be appropriate for the measurement of
adherence to single drug therapy but does little to offer explanations as to why the
patient may not be adhering to therapy or any indication of whether this non-­
adherence is a single event or indicative of someone who is persistently non-­
adherent. The simplistic nature of this result, that is, plasma level of drug detected,
also fails to consider the myriad factors that go into the patient’s intentional or
unintentional non-adherence to the prescribed regimen.
I remember a specific instance when I was monitoring warfarin (vitamin K
antagonist) for a patient, and this is commonly done with the aid of an automated
decision-making tool to aid dose adjustment. The patient had a target Internationalized
Normalized Ratio (INR) of 2.5 with a range of 2–3. On this occasion, the patient
said that he was wondering whether he could consume alcohol. I answered with my
usual “warfarin loves everything but change” and that a moderate amount of alcohol
(less than two units per day) should be fine. The following week, the patient pre-
sented with an INR of 4.5. I asked whether there had been any variations in diet/
coprescribed medications/taking too many tablets and of course alcohol consump-
tion. The patient told me that he had stuck with the guidance and that he had saved
up his two units of alcohol per day and had consumed 14 units of alcohol the night
before; this was a big lesson for me and one that helps to illustrate the importance
of clear communication with our patients. Needless to say, I modified this message
going forward!
84 A. Marengoni and L. J. Sahm

Another method of directly measuring adherence is Directly Observed Therapy

(DOT). As the name implies, the healthcare worker (HCW) (doctor, nurse, pharma-
cist) observes the patient ingesting (or simulating ingestion) the medicine. This is
seen when patients have to follow complex regimens, for example, those with tuber-
culosis, and according to the Centre for Disease Control this is an effective strategy
to ensure adherence [11]. Again, here the question remains as to whether this is a
measure of adherence or whether it may promote adherence at a certain time. This
is true of drug rounds in hospitals where patients may be asked to take their medica-
tion as soon as they receive it from the HCW, and the HCW documents this as hav-
ing successfully administered the medication, but there have been instances whereby
patients have simulated this medication-taking behaviour but not swallowed the
medication.

7.2.2 Indirect Measures

These tend to be more widely used research and include the use of electronic health
records (EHR) electronic monitoring devices, pill count and self-reported measures.
From an adherence point of view, we talk about primary and secondary non-­
adherence. Primary non-adherence would be the patient who visits their physician
and receives a prescription for medication but does not take this to be dispensed. In
other words, the non-adherence is clear from the first point in the sequence.
Secondary non-adherence is whereby this patient does go to the pharmacy and gets
the medication order filled, but having brought the medications home, the medica-
tion is not taken at all or not taken as directed.
If we look at the data available from pharmacy claims databases, we can estimate
what is often termed the Medication Possession Ration (MPR). The MPR has been
defined as the proportion (or percentage) of days’ supply obtained during a speci-
fied time or over a period of refill intervals [4]. Another method, the Proportion of
Days Covered (PDC) is the number of days when the medication was available
divided by the number of days in the study period. A cut-off point is commonly
advised (e.g. at least 80% adherent), and this allows the group to be divided into
adherent and non-adherent [12]. For both the MPR and the PDC, it is important to
be clear on how the calculation is performed as this can vary between studies. These
measures of adherence may be useful for seeing trends in a particular population,
but as we know just because a patient has collected the medicine, it does not mean
that it will be taken. The MPR and PDC determine the maximum adherence possi-
ble; in other words, if a patient has only collected 30 days of medication in the last
60 days, they are unable to be more than 50% adherent. Conversely, if pharmacists
were to interrogate their own data, they would be able to find individual patients
who may benefit from a medicine use review (MUR).
A MUR is a planned face-to-face consultation between a pharmacist and a patient
to discuss their medicines, both prescribed and non-prescribed. The review is medi-
cation adherence-centred and aims to help increase patients’ knowledge and under-
standing of their medicines, including how and why they should be taken. It also
7 Adherence: How to Measure and Improve It 85

provides an opportunity to highlight any medication adherence questions, side

effects or other medicine-related problems from the patient’s perspective and pro-
pose solutions where appropriate [13]. It should be noted, however, that whilst it is
relatively common, in some jurisdictions, for pharmacists to perform MUR, other
healthcare professionals, for example, nurses, also have a crucial role to play. A
recent systematic review by Mardani and colleagues in 2020 highlights the role that
nurses play in the medication management process at transitions of care, including,
but not limited to, medication reconciliation and monitoring of adverse effects. This
review included ten studies conducted between 2014 and 2020, seven studies from
the USA, one from Canada, one from Oman and one from Australia. They discuss
the role of communication within the multidisciplinary team in the optimization of
medication and, thus, better outcomes for patients [14].
There are also electronic monitoring (EM) devices, such as Medication Event
Monitoring System (MEMS). The most often used EM device consists of a medica-
tion vial cap that has the same appearance as regular medication bottle caps but
electronically records the date and time of bottle opening [15]. This has proven use-
ful for those with mental health disorders with one study finding that the greater
mean EM adherence was significantly related to lower mean symptom severity in
their study population of patients with schizophrenia or schizoaffective disor-
der [16].
Newer developments in this space include the Ingestible event marker also
termed digital health feedback systems. One of the first to be marketed and approved
by the Food and Drug Administration (FDA) in 2012 was the Proteus ingestible sen-
sor [17]. These sensors are formulated within the medication and give real-time,
data-driven healthcare. The sensor communicates this information regarding inges-
tion time and other variables (e.g. heart rate) to a patch on the skin which is then
communicated to an external electronic device such as mobile phone. Whilst the
advantage of having this information accessible to the prescriber is clear, what is not
so clear is whether this technology would suit all patient groups.
Pill count is a straightforward process that literally requires the counting of tab-
lets from one appointment to the next. If a patient was due to take one tablet in the
morning and one in the evening for 30 days, then the patient receives 60 tablets. If
the researcher/clinician wants to check, after 10 days, for example, then they know
that there should be 40 tablets remaining and compare this to actual number thereby
calculating an adherence ratio. Whilst this is a simple method and one that can be
used for different formulations, for example, a pill count can also be used with
inhalers to assess the remaining actuations left, nonetheless it also is associated with
certain assumptions. There is an assumption that if the tablet is missing that it has
been ingested and that this occurred at the correct time.

7.2.3 Subjective Measures

These measures include written questionnaires, semi-structured interviews or per-

haps online assessments, and there are over 40 available. I refer the reader to the
86 A. Marengoni and L. J. Sahm

review article by Nguyen et al. in which the authors have summarized the main
measures as well as their advantages and disadvantages for different cohorts [18].
Many of these questionnaires require the patient to self-complete introducing more
variability and challenges. If we consider those who are (1) non-native speakers, (2)
have low health literacy and/or specifically in the older adult, practicalities such as
being able to read the font size and/or ability to accurately recall when and how
many medications were taken in the last day(s), we can see that likelihood of having
any meaningful data is quite low. Certainly, these measures may be useful in clinical
practice by providing an opportunity to discuss any obstacles to medication adher-
ence; however, they would likely lead to inaccuracies and probable overestimation
of medication adherence due to the challenges mentioned above and social desir-
ability reporting bias. In addition, not all these questionnaires are free from restric-
tions regarding their use even for research purposes, so readers should consult the
copyright and licensing rules prior to any inclusion in a protocol.
In summary, it is likely that a multi-modal approach encompassing objective and
subjective measures will likely yield the most accurate estimate of adherence.

7.3 How to Improve Adherence

The benefits of proper adherence to treatment are several, including preventing dis-
eases, improvement of health, better quality of life and a more cost-effective use of
healthcare resources [19]. To date, no single intervention strategy has proven effec-
tiveness in enhancing adherence across all patients, clinical conditions and settings.
Unfortunately, a number of knowledge gaps still exist and limit previous clinical
trials aiming to improve adherence as well as adherence in the real world popula-
tion; for instance, poor understanding of the interplay between adherence, multi-
morbidity and polypharmacy, fragmentation of care and poor communication
among care players, the lack of definition of a specific target population, absence of
validated information on new technologies and lack of standardized information
systems [6].
In a Cochrane review including randomized clinical trials of interventions to
improve adherence, measuring both medication adherence and clinical outcome,
with at least 80% follow-up of each group studied and at least 6 months’ follow-up
for studies with positive findings at earlier time points, only few randomized clinical
studies showed a low risk of bias and among them only five improved both adher-
ence and clinical outcome [20]. A narrative review focused on the most frequent
interventions employed to improve medication adherence and the outcomes
achieved, with a special eye on factors associated with ageing and with cognitive
impairment or dementia [21]. The authors underlined that older persons have been
systematically excluded from randomized clinical trials especially if affected by
multimorbidity and prescribed with polypharmacy. As a consequence, the onset of
unknown adverse drug reactions during the marketing of the drugs limit adherence
in this group of patients. Regarding cognition and drug consumption, a systematic
evidence-based review showed the importance of relational aspects in improving
7 Adherence: How to Measure and Improve It 87

adherence in patients with dementia, which may benefit more from human commu-
nication as reminder than technology [22]. Indeed, in the same review, only three
studies met inclusion criteria of interventional, two evaluated reminder systems and
showed no benefit, whereas one study improved adherence through telephone and
televideo reminders at each dosing interval. Another reason of poor adherence in
older persons living in countries without welfare is the limitation to medications
access, the so-called cost-related non-adherence. The Medicare Current Beneficiary
Survey showed that in 2016, 34.5% of enrollees under 65 years with disability and
14.4% of those 65 years and older did not take their medications as prescribed due
to high costs [23]. Three indicators of worse health (general health status, functional
limits and count of conditions) were all independently associated with higher risk of
cost-related non-adherence. Strategies that effectively improve adherence could
produce financial benefits by attenuating the effect of risk factors and preventing
disease progression in a wide number of patients and different settings [24].
A few years ago, a group of professionals with expertise in geriatrics, pharmacol-
ogy, epidemiology and public health reached a consensus on the possible best inter-
ventions to improve adherence in older individuals. Seven strategies were identified
and classified based on their target (patient, therapy and public health/society)
(Table 7.2): (1) Comprehensive Geriatric Assessment (CGA)—CGA should be
administered to all older adults participating in a program aimed at improving medi-
cation adherence because it identifies their needs and priorities; (2) patient and care-
giver education—educational programs should account for health literacy level and
include lifestyle recommendations in order to improve patient empowerment; (3)
optimization of treatment—optimized treatment should be reached through clinical
decision, use of criteria for appropriate prescription and computerized prescription
support systems; (4) use of adherence aids—electronic support devices for patients,
particularly alerting non-adherence systems, web-based software tools and wear-
able units need to be implemented; (5) physicians and other healthcare profession-
als should be trained by educational professionals through a cascade model and
regular meetings focused on improving both medication knowledge and communi-
cation skills; (6) adherence assessment—adherence assessment should be mostly
objective (e.g. drug refill, clinical assays) and continuous; (7) facilitating access to
medicine by service integration by medication delivery and general practitioner–
pharmacist bidirectional consultation [6]. The authors suggested that the reasons of
non-adherence are so multifactorial that interventions to improve it should be
patient-centred, involving multiple stakeholders, with the different players provid-
ing different services, but integrated with one another. Further, in the near future,
information and communication technology (ICT) systems may become particu-
larly relevant for improving adherence, through the use of Tele-Medicine and
Internet-linked clinical support models, wireless sensor networks and so forth. ICT
technologies may provide self-management utilities for patients and caregivers;
education modules for patients, caregivers, and health professionals; and informa-
tion integration for patient care by physicians and nurses.
At present, another important issue that may limit adherence improvement at
population level is the wide variability in methodology used to evaluate adherence
Table 7.2 Interventions to improve adherence [6]
88

Health professional
Definition Target population involved How Time
Intervention 1 Comprehensive geriatric All older adults GP + healthcare assistant InterRai + tools to assess Program entry and then
Assessment (including adherence (i.e. MARS) every year or if change in
adherence behaviour) health status occurs
Intervention 2 Patient (and caregiver if Patients and caregivers or GP + healthcare assistant, Health beliefs model, Continuously
needed) education to all older and willing to pharmacist, healthcare training, multilevel
improve patient receive the intervention system, patients interventions
empowerment associations
Intervention 3 Optimization of treatment All older adults GP + healthcare assistantSoftware (i.e. Program entry and then
(reduction of CDSS) + clinical every year or if change in
polypharmacy) judgement health status occurs
Intervention 4 Use of adherence aids Older adults with Pharmacist, ICT company, Pillboxes, reminders, Continuously
cognitive impairment; pharma company blistering by the pharmacy
disability; social isolation;
polypharmacy; unintended
non-adherence
Intervention 5 Physician and other Physician and other Educational professional Cascade model; circle Continuously
healthcare professional healthcare professional and professional meetings (both focused on
education associations improved medication
knowledge and
communication skill)
Intervention 6 Adherence assessment All older adults GP + healthcare assistant; Objective (drug refill; Continuously
pharmacist drug count; clinical
assays) and subjective (i.e.
MARS/communication)
evaluation
Intervention 7 Facilitating access to All older adults GP and pharmacists ICT, medication delivery, Continuously
medicine by service GP-pharmacist
integration bidirectional consultation
A. Marengoni and L. J. Sahm
7 Adherence: How to Measure and Improve It 89

and poor reporting of findings from research on this topic. An international panel of
experts elaborated guidelines to improve the quality of drug adherence research
reporting, the ESPACOM Medication Adherence Reporting Guidelines (EMERGE)
[25], where ESPACOM is the European Society for Patient Adherence (www.espa-
com.eu). EMERGE provides guidance on reporting observational and interven-
tional studies on medication adherence useful for different stakeholders, such as
investigators, authors, journal editors and health policy decision makers.
Finally, a relevant question to be answered is whether higher adherence to medi-
cal prescription would produce better outcomes in older subjects, not only in term
of length of life, symptoms control and healthcare utilization [26], but also as ben-
eficial on functional outcomes, such as falls and cognitive decline. In a study of
community-dwelling older people presenting a prescription for antihypertensive
medication to 106 community pharmacies in Ireland, with no evidence of cognitive
impairment, taking antihypertensive medication for ≥1 year (n = 938), each 5-day
gap in antihypertensive refill adherence increased the risk of self-reported injurious
falls by 18% [27].

7.4 Conclusions

Despite being a major cause of morbidity, medication non-adherence in older per-

sons is not well described in the literature, and thus, it is difficult to draw final con-
clusions on potential barriers and improvements. Future research should focus on
standardizing medication adherence measurements and better scientific reporting as
well as on clinical trials based on multifactorial interventions.

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Medication Reconciliation and Review:
Theory, Practice and Evidence 8
Tamasine Grimes and Cristin Ryan

8.1 Introduction

As older people age, the complexity of their medication use often increases as does
the frequency of healthcare utilisation. The onset of additional age-related morbidity,
destabilisation of chronic conditions and increase in frequency of hospitalisation and
healthcare utilisation can add to the older person’s medication complexity. Previous
research shows that at least 10% of hospital admissions in older people are due to
adverse drug reactions and that medication error occurs in 50% of cases following
hospital discharge [1, 2]. Therefore, strategies are needed to prevent, recognise and
manage medication-related problems prevalent in older patients at points of care tran-
sition and throughout the clinical care journey. Medication review and medication
reconciliation are processes within an overall medication management strategy that
address these issues and collectively aim to improve the older person’s transitional
medication safety (Fig. 8.1). This chapter describes these processes individually and

Medication optimisation
A series of processes to support people to get the most out of their medication

Medication reconciliation Medication review

A process of creating the most accurate list possible of all
A critical examination of a person’s medicines with
medications a patient is taking and comparing that list against
the objective of reaching an agreement with the
the prescriber's orders. In addition, the patient's allergies,
person about treatment, optimising the impact of
history of side effects from medications and medication aids
medicines, minimising the number of medication-
are listed with the goal of providing correct medication to the
related problems and reducing waste
patient at all transition points within the health care system

Fig. 8.1 Overview of medication optimisation [3, 4]

T. Grimes (*) · C. Ryan

School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2023 91

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_8
92 T. Grimes and C. Ryan

collectively within a medication optimisation strategy. It also summarises the evi-

dence regarding effectiveness and implementation and proposes action points for the
senior clinician seeking to improve transitional medication safety for older people.

8.2 Medication Reconciliation

8.2.1 Theory

Medication reconciliation is a process intended to increase the integrity of informa-

tion about a person’s medication use that is shared between care providers and set-
tings and across a transition of care, hereon referred to as ‘MedRec’. The Delphi
consensus definition is presented in Fig. 8.1 [1]. A transition of care is a period in the
patient’s care when s/he moves from one care setting to another, for example, hospi-
tal admission or discharge, or between care providers, for example, transition from
one family physician to another. In theory, if a MedRec process is undertaken at a
care transition, then information continuity should be achieved, and the likelihood of
the patient experiencing medication error or miscommunication should be reduced.

8.2.2 Practice

The MedRec process should ideally be applied at each point of care transition. For
example, it should be applied at hospital admission, at internal transfers and then
again at hospital discharge (Fig. 8.2). MedRec by itself is quite a transactional pro-
cess, composed of three steps: (1) collect and create, (2) check by comparing and
(3) document and communicate [5].

Step 1: Collect and Create Collect information and create the person’s Best Possible
Medication History (BPMH). This involves building a comprehensive list of the med-
ications that the person was using immediately prior to the care transition, for exam-
ple, pre-admission. This is usually created by discussion with the patient or their
representative and by obtaining information from other sources, for example, the per-
son’s community pharmacist or general practitioner, or an electronic medication
record. At least two reference sources should be consulted to build a complete list, one
of which is the patient/proxy representative. Importantly, this step should create a list
of the medication that the person was actually taking, which can differ from what was
prescribed for or dispensed to them. This may uncover potential medication non-
adherence; the reader should cross refer to Chap. 7 for information about how to
improve adherence.

Step 2: Check by Comparing This is the reconciliation step; it involves either a proac-
tive or a reactive MedRec process (Fig. 8.2). The proactive process sees the BPMH built
before the admission orders are made and the retroactive process sees the BPMH built
after the admission orders are made. In both cases, the BPMH and the post-transition
8 Medication Reconciliation and Review: Theory, Practice and Evidence 93

Fig. 8.2 An overview of medication optimisation across care transition. BPMH best possible
medication history, MO medication order

medication orders should be compared to enable identification and resolution of any

differences (otherwise called discrepancies) between the two lists. The types of medica-
tion discrepancies that are typically identified during MedRec are described below.
94 T. Grimes and C. Ryan

A. For use at hospital admission

Healthcare facility identity details Patient identity details
Allergy or intolerance information Vaccination history
BPMH details (Medication name, dose, frequency, route) Medication orders
Include all prescribed, over-the-counter, herbal Time/date Continue Comments

Discrepancy

Resolved
Intended
and supplement products of last or stop
dose

No preadmission medication

B. For use at hospital discharge

Healthcare facility identity details Patient identity details
Allergy or intolerance information Vaccination history
List of medication to take after discharge (Medication name, Medication reconciliation
dose, frequency, route, duration) Compare discharge list to BPMH and explain any differences
Include all prescribed, over-the-counter, herbal and supplement Reason for change or addition of medication

Unchanged

New
Changed
products

Pre-admission medication stopped in hospital and not to Reason for stopping

continue after discharge

C. For use post-discharge (readmission to the community)

Pre-admission medication list Hospital discharge medication list Discrepancy Intended Resolved Comment
(BPMH) (Medication name, dose, frequency,
(Medication name, dose, route, duration)
frequency, route)

Fig. 8.3 Sample medication reconciliation forms

Step 3: Document and Communicate This step is intended to support complete

and clear communication about the medication list, and any changes made across
the care transition, to the patient, their representative and the healthcare practitio-
ners contributing to the patient’s care following the transition. Sample forms to
facilitate adequate communication at several transition points are displayed
(Fig. 8.3). It is important that these documents are accessible and readable by lay
people (patients/family).

8.2.2.1 Medication Discrepancies

During the MedRec “Check by comparing” step, differences may be identified
between the pre-transition and the post-transition medication lists. These differ-
ences are termed discrepancies and fall into two broad sub-categories: intentional
discrepancies and unintentional discrepancies.
An example of an intentional discrepancy is the omission of a non-steroidal
anti-­inflammatory drug in a patient presenting to hospital with haematemesis.
There is a clear clinical rationale for withholding the medication. Ideally, all peo-
ple contributing to the person’s medication management are aware of that decision,
which is typically achieved by documenting in the healthcare record. Studies have
identified that undocumented intentional discrepancies can lead to medication
error, and therefore, it is helpful to maintain a clear record of prescribing decisions
and their rationale. Intentional discrepancies between the pre-transition and post-
transition lists are typically the outcome of a medication review and demonstrate
the interaction between the two processes to support transitional medication safety.
Unintentional discrepancies are differences between the person’s medication
list pre-transition and post-transition, which do not have a clinical rationale and are
a medication error. For example, omission of long-standing glaucoma eyedrops
8 Medication Reconciliation and Review: Theory, Practice and Evidence 95

and respiratory inhalers for a patient admitted with a transient ischaemic attack.
The causes of unintentional discrepancies are multi-fold and may relate to the
patient, the healthcare professionals, the environment or the organisational
care issues.
Medication discrepancies are also categorised by the nature of the difference, the
most common being omission of medication, followed by differences in the dosage,
frequency, formulation or route of administration, and finally commission of medi-
cation, meaning the prescribing or ordering of a medication which the patient is not
actually using. Medication discrepancies are a necessary part of medication optimi-
sation and are often a clinically appropriate response to a comprehensive medica-
tion review (Fig. 8.2). They become problematic if they are errors (unintentional
discrepancies) or if intentional but not documented/communicated (Step 3).
Previous studies identified that both unintentional discrepancies and undocumented
intentional discrepancies persist across care transitions into the next care setting or
episode, potentially exposing the patient to medication-related harm due to incor-
rect administration or omission of medication.

8.2.3 Evidence

Several systematic reviews have explored the impact of undertaking the MedRec
process, few of which have focussed exclusively on older people [6–12]. Most
reviews have focussed on the hospital admission and discharge transitions and less
on MedRec following hospital discharge or transition to other care settings. Most
have investigated the benefit of MedRec as a stand-alone intervention whilst a
minority have investigated the benefit of complex transitional care interventions that
include MedRec as a component. MedRec interventions have been delivered by a
variety of healthcare personnel, most commonly pharmacy, often working interpro-
fessionally, and some studies have investigated electronic solutions.
Medication discrepancy, a process measure, is the most reported outcome in
MedRec studies. The available evidence identifies that MedRec alone may reduce
the presence of any and sum of medication discrepancies at care transition. However,
the certainty of this evidence is low because of the generally poor quality of the
available studies. The evidence of a direct benefit of MedRec on clinical outcomes,
such as adverse events or healthcare utilisation, is less clear, as is the effect on
humanistic outcomes such as quality of life. One systematic review which explored
interventions that included activities focussed on medication continuity delivered
during hospital stay or following discharge identified that MedRec reduced hospital
readmissions [12]. Interventions found to best support older patients’ medication
continuity and to have the greatest impact on reducing hospital readmission are
those that bridge transitions and include patient self-management, telephone fol-
low-­up and MedRec activities.
Qualitative research studies, however, enable a broader understanding of the out-
comes affected by MedRec at care transitions, for example, the patient’s or informal
carer’s experience, activation, involvement in decision-making, workload around
managing medication and knowledge and confidence in medication use at periods
around care transitions [13].
96 T. Grimes and C. Ryan

8.2.3.1 Optimising Limited Resources

Few studies have undertaken economic analysis of transitional medication safety
interventions, providing scant evidence to support investment in scaling up these
activities. The MedRec process has been reported to take up to 45 min per patient
to complete. Therefore, organisations may not have adequate resources to deliver
MedRec to each patient or at each care transition. Decisions may be required
about how best to allocate scarce MedRec resources. Risk factors for potentially
harmful unintentional medication discrepancy in pre-admission medication have
been identified across three domains and may be incorporated into clinical deci-
sion support or algorithms to prioritise patients for MedRec at hospital admis-
sion [14]:

• Medication-related
–– Increasing number of pre-admission drugs
–– Increasing number of high-risk drugsa
–– Class of medication: intake of four of the following classes, gout medication,
muscle relaxants, lipid lowering agents, antidepressants and respiratory
medication
• Patient-related
–– Age 65+ years is associated with discrepancy compared to younger people,
but amongst extremely older (>85) people, advancing age is associated with
fewer discrepancies
–– Use of multiple outpatient pharmacies
• Setting-related
–– Lack of availability of a medication list
–– Family member or caregiver consulted as an information source

As defined on the Institute for Safe Medication Practices high-alert or the North
a

Carolina Narrow Therapeutic Index lists

8.2.3.2 Electronic Supports

Studies have explored the benefit of automating all or parts of the MedRec process
[10]. Several countries have made national databases of patient’s personal medica-
tion prescription or dispensing records available for clinical use at care transitions
and developed solutions to integrate this information across care settings. Many
organisations use electronic medication prescribing and administration systems;
some of which include functionality to support the MedRec process. Previous stud-
ies have identified a positive benefit of technology-assisted MedRec on medication
discrepancies but have also identified challenges with implementing technology at
scale and managing human–computer interaction in clinical practice. One review
developed a list of ten theories to explain how, why, when, where and for whom
personal electronic records of medications (PERMs) are designed, implemented or
used in practice at care transitions that impacts on MedRec: (1) Engage stakehold-
ers; (2) Use inclusive design; (3) PERMs should complement existing good prac-
tices; (4) Build trust; (5) Tailor training to learners’ needs; (6) provide support and
8 Medication Reconciliation and Review: Theory, Practice and Evidence 97

deliver on-demand training throughout; (7) Optimise interoperability; (8) Resource

investment; (9) Support by legislation or governance to enhance engagement with
PERMs; (10) Support patients as users of PERMs [15].

8.2.3.3 The Role of Patients, Family and Informal Carers

Patient and family members contribute meaningfully to the older person’s transi-
tional medication safety [13]. For example, they provide critical detail about the
patient’s medication-taking activities at crucial times, such as patients experiencing
acute cognitive changes; they identify and alert the healthcare team to potential
medication errors or adverse effects; they participate in decision-making about
medication management, and they act as a safety net to mitigate and manage the
effects of transitional medication error. Evidence-based opportunities to enhance
patient and family involvement in transitional medication optimisation, using the
acronym LISTEN, are presented in Table 8.1.

8.2.3.4 Organisational Complexity and Management

Although it appears to be a straightforward process, MedRec has proven to be chal-
lenging to implement because it is time consuming and resource intensive. The job
of collecting and checking a patient’s medication information often spans multiple
interpersonal, organisational and temporal boundaries. For example, an older per-
son may be prescribed medication by their family physician and multiple specialist
prescribers, s/he may collect medication from one or more community pharmacy(s)
and obtain over-the-counter/supplemental medications from multiple retailers. The
patient’s medication use pattern might change over time, for example, they might be
adherent to medication at one moment in time and become non-adherent at another.
Therefore, organisations need to invest resources to support MedRec and use those
resources efficiently.

Table 8.1 Various ways to engage patients/families in transitional medication safety

L Listen actively To patients and families to comprehensively understand the individual
patient’s complexity, rather than a focus on a single medical condition, to
elicit the patient’s preferences and aspects of their home situation that
may impact on their medication-related needs
I Involve early Patients/family early in transition planning and provide opportunity to
consider the practical work involved in managing medicines at home,
considering who will administer medication; equipment, devices and
workforce needed to support this, for example, medication administered
via an enteral feeding tube
S Structure To enable patients and families to be actively involved in conversations
opportunity and decision-making about medication use
T Timely meetings Avoid scheduling patient/family meetings at times when patients/family
may not be able to engage, for example, the day of discharge
E Explicit Changes made to a patient’s BPMH and the reasoning for them so
communication patients/family can understand and implement these changes when they
return to their regular care setting
N Normalise Using patients and families during transitions to obtain reliable
information about routine medication use
98 T. Grimes and C. Ryan

MedRec may be performed by multiple personnel, for example, medical, nursing

or pharmacy staff. Studies have examined how accurately different professional
groups build the BPMH (the collect and create step), favourably identifying pharmacy
and nursing staff, although fewer studies have explored professional roles and respon-
sibilities for the ‘check by comparing’ and ‘document and communicate’ steps. In
reality, each organisation should assign tasks based on the personnel and resources
available to them and ideally should avoid duplication of work, for example, having
multiple professionals build a patient’s BPMH. All personnel should work to the top
of their license, meaning for example, that a pharmacy technician or physician assis-
tant could be tasked with collecting, whilst a pharmacist or physician might be tasked
with checking and communicating. Good interprofessional working (teamwork, coor-
dination, collaboration and networking) is essential to MedRec. Opportunities for
senior clinicians to support organisational management of MedRec are:

• Assign responsibility for collecting the BPMH to dedicated personnel.

• Employ well-designed forms to support documentation and communication of
medication information. This may be electronic or hard-copy.
• Advocate for adequate medical, nursing and pharmacy resource to deliver the
MedRec process.
• Measure and monitor MedRec activity and engage in regular audit to assess
MedRec performance.
• Encourage training and facilitate competence assessment to support MedRec
activities.
• Foster a culture of positive interprofessional working.
• Engineer opportunity to engage and involve patients/family in transitional medi-
cation safety activities.

8.3 Medication Review

8.3.1 Theory

A structured clinical medication review is defined as ‘a critical examination of a

person’s medicines with the objective of reaching an agreement with the person
about treatment, optimising the impact of medicines, minimising the number of
medication-related problems and reducing waste’, by the National Institute for
Health and Care Excellence in the United Kingdom [3]. The term ‘clinical medica-
tion review’ and linked definition is synonymous with other programmes globally,
such as the medication therapy management programme in the United States and
the Home Medicines Review in Australia (Table 8.2). The Pharmaceutical Care
Network Europe identify that medication review is a step in the pharmaceutical care
strategy, that is, it is a component process within a wider medication optimisation
system (Figs. 8.1 and 8.2) [16].
Medication reviews, whilst most commonly undertaken by pharmacists, can be
undertaken by any healthcare professional in any healthcare setting and are often an
8 Medication Reconciliation and Review: Theory, Practice and Evidence 99

Table 8.2 ‘Medicines review’ and international equivalent terms used defined
Organisation, country Term used Definition
Pharmaceutical care ‘Medication ‘A structured evaluation of a patient’s medicines
network Europe, review’ with the aim of optimising medicines use and
European-wide improving health outcomes. This entails detecting
drug related problems and recommending
interventions’
Pharmaceutical Society ‘Home ‘Systematic assessment of a consumer’s
of Australia’s (PSA), medicines medications and the management of those
Australia review’ medications, with the aim of optimising consumer
health outcomes and identifying potential
medication-related issues within the framework of
the quality use of medicines’
National Institute for ‘Medication ‘A structured, critical examination of a patient’s
Health and Care review’ medicines with the objective of reaching an
Excellence (NICE, UK), agreement with the patient about treatment,
United Kingdom optimising the impact of medicines, minimising
the number of medication related problems and
reducing waste’
United States ‘Medication ‘A distinct service or group of services that
therapy optimise therapeutic outcomes for individual
management’ patients’

interprofessional exercise. When undertaking a medication review, all medicines taken

by the patient, that is, prescribed medications and over-the-counter (OTC) medicines,
complementary and alternative medicines and supplements should be considered.
The overall aim of undertaking a medication review is to form a partnership with
patients to optimise patients’ medication regimens and to prevent medication-­
related problems. Additional aims of a medication review include:

• To enhance patients’ knowledge and understanding of their medicines and medi-

cal conditions.
• To identify and address any problems that patients’ have in adhering to pre-
scribed treatments.
• To identify side effects to prescribed medicines.
• To identify potentially inappropriate prescribing of medicines, including pre-
scribing cascades, drug interactions, therapeutic duplication, suboptimal dosing
[i.e. (under and over) and untreated conditions].
• To identify monitoring requirements, for example, cholesterol and undertake
appropriate clinical assessments, for example, blood pressure.
• To communicate issues raised during the medication review with the prescriber
(if another healthcare professional is undertaking the review).

8.3.2 Practice

A structured medication review should be a collaborative process with the patient/

family, facilitating dialogue and shared decision-making, based on the patient’s
100 T. Grimes and C. Ryan

elicited preferences. Skilled questioning is essential to optimise the review by iden-

tifying information about preferences, symptoms or signs of adverse effects,
achievement of therapeutic goals or evidence of therapeutic failure. There is no
single best way to perform a medication review, although tools are available to
guide the process, including the Scottish NHS ‘seven-step’ model and the NO
TEARS tool (Table 8.3) [17, 18]. Regardless of the particular approach employed,
the review should provide a structured, stepwise approach to developing individual-
ised, patient-centred management plans.
Implementing structured medication review is challenging due to the complexity
and consultation time required to manage older patients experiencing
(hyper)polypharmacy and multimorbidity. Several tools are available to streamline
steps within the medication review process. For example, the ‘Stop, sorted, special’
approach can help to focus the review by rapidly identifying the medications that
should be ‘stopped’, for example, the condition has resolved or the patient chosen
to stop, and those that have already been ‘sorted’, for example, recently reviewed or
no current concerns, thereby maximising the time available to tend to the shortened
list of ‘special’ medications [17]. Additionally, several guidelines and tools exist to
support prescribing decisions, including explicit or implicit criteria and mixed or
other approaches. The reader is guided to Chaps. 4 and 10 for further detail on this.
A medication-related problem (MRP), also known as a drug-related problem
(DRP), is an event or circumstance involving drug therapy that actually or poten-
tially interferes with desired health outcomes. The Pharmaceutical Care Network
Europe classifies a DRP as a (potential) problem with (1) treatment effectiveness,
(2) treatment safety or (3) other [19]. The (possible) causes for (potential) problems
have been categorised (Table 8.3). MRPs have also been classified from the patient
perspective into four categories: (1) obtaining medications; (2) taking medications;
(3) medication effects, including side effects and concerns over lack of effectiveness
and (4) communication and care coordination [14]. The MRPs identified in a

Table 8.3 Sample structured medication review tools and aids

PCNE DRP
The seven steps medication review The NO TEARS tool causes
Step 1: (Aim) what matters to the patient Need and indication Drug selection
Step 2: (Need) identify essential drug therapy Open questions Drug form
Step 3: (Need) does the patient take unnecessary Tests and monitoring Dose selection
drug therapy? Evidence and Treatment
guidelines duration
Step 4: (Effectiveness) are therapeutic objectives Adverse events Dispensing
being achieved? Risk reduction or Drug use process
prevention
Step 5: (Safety) is the patient at risk of ADRs or Simplification and Patient
suffers actual ADRs? switches transfer-related
Other
Step 6: (Efficiency) is drug therapy cost-effective?
Step 7: (Patient-centred) is the patient willing and
able to take drug therapy as intended?
ADR adverse drug reaction, DRP drug-related problem, PCNE Pharmaceutical Care Network Europe
8 Medication Reconciliation and Review: Theory, Practice and Evidence 101

medication review may warrant further intervention at the drug, patient or prescriber
level. Such intervention may trigger the need for an additional process such as the
management of an interaction (Chap. 3), an inappropriate medication (Chap. 4), a
prescribing cascade (Chap. 5), an adverse effect (Chap. 6), adherence (Chap. 7) or
deprescribing (Chap. 10), and the reader should consult these chapters for fur-
ther detail.

8.3.3 Evidence

8.3.3.1 Effectiveness of Medication Review

Systematic reviews have reported the effects of medication review undertaken in
multiple settings, including primary care, hospital care and long-term care facilities;
some of which included interventions delivered to older people [20–25]. A variety
of medication review interventions has been described, including those led by gen-
eral practice-based pharmacists, hospital pharmacists and pharmacist delivering
care to residents of aged care facilities, working independently or collaboratively
with prescribers. The findings in general suggest that performing medication review
enhances appropriate polypharmacy, supports deprescribing and reduces medication-­
regimen complexity although the evidence is less clear regarding patient outcomes.
Medication review may enhance patient medication adherence, and for certain
groups of patients, it may reduce the likelihood of healthcare utilisation (e.g. emer-
gency department visits, hospital (re)admission), patient outcomes (e.g. mortality,
adverse drug events, disability), and improve the patient’s understanding of and
adherence to medication treatment.

8.3.3.2 Optimising Limited Resources

Structured medication review is challenging to implement because it is time con-
suming and complex. Prioritising medication review for certain patient cohorts of
older people using certain classes of medication may enable more efficient use of
scarce resources (Table 8.4) [26]. Adverse drug reactions may cause or contribute to
hospital admission or may occur during hospital admission. Therefore, medication
reviews in secondary care should be targeted at those at risk for or manifesting
medication-related harm. There are a number of tools and algorithms available to
support this, for example, AT-HARM10 and the DRA Adjudication Guide, and the
reader is guided to these and to Chap. 6 to extend learning about this [27, 28].

Table 8.4 Risk patients and risk medications to target for medication review in primary care
Risk medication Risk patients
Medication increasing risk of falls Frail patients
Anticoagulant medication Patients recently discharged from hospital
Blood pressure lowering medication Patients with multimorbidity
Antidiabetic medication
Medication for Parkinson’s disease
102 T. Grimes and C. Ryan

8.4 Summary

MedRec, a process to create, check and communicate accurate information about

medication use across care settings, should be applied at every care transition
including admission to, discharge from and an internal transfer within a healthcare
facility. Medication review is a process of critically examining a person’s medicines
with the objective of reaching an agreement with the person about treatment, opti-
mising the impact of medicines, minimising the number of medication-related prob-
lems and reducing waste.
MedRec and medication review may be delivered by medical, nursing or phar-
macy staff and often requires patient-centred interprofessional working between
these groups. A robust communication infrastructure, electronic or otherwise, is
necessary to support both processes, as is workforce planning. MedRec reduces the
prevalence and burden of unintentional medication discrepancies and may prevent
hospitalisation. Medication review has a positive effect on enhancing the quality of
medication use and several patient outcomes, including adherence, the frequency of
healthcare utilisation and experiencing medication-related harm.
Patients/family should be facilitated to be actively involved in both MedRec and
medication review, and the healthcare professional’s interpersonal and interprofes-
sional skills combined with therapeutics expertise are critical to support positive
outcomes.

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The Role of Pharmacists in Optimising
Drug Therapy 9
Anne Spinewine, Stephen Byrne, and Olivia Dalleur

9.1 Pharmaceutical Care at Patient Level

9.1.1 Medication Review

Following a consensus consultative process undertaken in 2018 defined a medica-

tion review (MR) “as a structured evaluation of a patient’s medicines with the aim
of optimising medicines use and improving health outcomes. This entails detecting
drug-related problems and recommending interventions” [1]. The extensive consul-
tative process included consultation amongst over 200 healthcare professionals
(HCPs) across 35 countries and resulted also in a medication review classification,
which also took into consideration the available sources of information.
The overarching aim of an MR is to improve the quality, safety and appropriate
use of medicines. Such a review can be conducted by multiple HCPs themselves or
in collaboration with the prescribing physician [2], and there is a growing body of
evidence in the literature that medication reviews result in improved prescribing
outcomes such as reduced polypharmacy, inappropriate prescribing and adverse
drug effects for patients [3].
The complexity of the medication review is determined by the nature of the
patient, their concurrent illnesses and their co-prescribed medications. The depth of
the review is also influenced by the level of detailed information available to the

A. Spinewine · O. Dalleur
Université catholique de Louvain, Louvain Drug Research Institute and Faculty of Pharmacy
and Biomedical Sciences, Brussels, Belgium
e-mail: [email protected]; [email protected];
[email protected]; [email protected]
S. Byrne (*)
Pharmaceutical Care Research Group, School of Pharmacy, University College Cork,
Cork, Ireland
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 105

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_9
106 A. Spinewine et al.

HCP at the time of the review. The Pharmaceutical Care Network European (PCNE)
group in 2018 also agreed through their consensus process on four subtypes of
medication reviews, ranging from those conducted in a community pharmacy, to
more comprehensive reviews, which require full access to patient’s medical record
(e.g. access to medical notes in hospital, long-term care or general practice set-
tings). The subclassification of a medication review is as follows:

• “PCNE Type 1: Simple MR: A simple medication review is based on the avail-
able medication history in the pharmacy; this type of review occurs routinely
during the medication supply/dispensing process, for example, drug–drug inter-
actions, reviewing the appropriateness of a particular medication dosages, poten-
tial side effects and medication adherence issues.”
• “PCNE Type 2A: Intermediate MR: An intermediate medication review can be
performed when the patient can be approached for information. Such a review is
based on medication history and patient information.” Which builds upon a Type
1 review and expands the review to include issues such as drug–food interac-
tions, issues with over-the-counter (OTC) medication and medication effective-
ness issues.
• “PCNE Type 2B: Intermediate MR: An intermediate medication review can be
performed if information from the general practitioner is also available. Such a
review is based on medication history and medical information.” This type of
review builds upon Type 2A by including the identification of potential medi-
cines without a current clinical indication.
• “PCNE Type 3: Advanced MR: An advanced medication review is based on
medication history, patient information and clinical information. This type of
review is the most comprehensive and in-depth review and results in all of the
above being addressed with the addition of the identification of an indication
without a potential medication being prescribed for its treatment [1].

In addition to strong clinical and technical skills, interprofessional communica-

tion and collaboration are central to the effective implementation of medication
review services for patients [4].

9.1.2 Continuity of Supply and Care

Continuity of medication supply and continuity of care is essential whenever

patients’ transition from one setting to another or from one HCP to another takes
place. Principles ensuring continuity of care in medication management include: (a)
developing processes of care and responsibilities across the caregivers to coordinate
the medication discharge plan as early as possible after admission; (b) obtaining an
accurate medication history upon admission; (c) evaluating the current medication
list as compared to the medication history in order to detect and reconcile discrepan-
cies, to perform medication review and to establish a treatment plan, on admission
as well as at discharge; (d) involving the patient in the treatment plan decisions; (e)
9 The Role of Pharmacists in Optimising Drug Therapy 107

ensuring the patient has been educated about the discharge treatment plan; (f) dis-
pensing an adequate amount of medication at discharge and (g) communicating to
follow-up healthcare [5]. A core concept that is closely related to these principles is
medication reconciliation (MedRec) (see Chap. 8). MedRec has been defined as
“the process of identifying the most accurate list of all medications a patient is
taking—including name, dosage, frequency, and route—and using this list to pro-
vide correct medications for patients anywhere within the health care system” [6].
MedRec is a safety strategy adopted by most guidelines and health organisations
that should be performed at each transition, ideally within 24 h.
MedRec prevents transcribing errors, improves monitoring of prescriptions, facili-
tates switch from medication taken at home towards formulary medicines upon
admission [7]. By improving communication between HCPs and with the patient,
MedRec reduces medication discrepancies and potentially harmful medication errors.
In older patients specifically, pharmacist-led MedRec reduces medication errors [8].
However, evidence on patient-related clinical outcomes is inconclusive. Nevertheless,
a meta-analysis focusing on the effectiveness of pharmacist-led MedRec on patient-
related clinical outcomes during the transition to and from hospital settings showed a
reduction in drug-related hospital revisits, emergency department visits and in hospi-
tal readmissions [9]. Additionally, there is evidence that pharmacist-led MedRec at
discharge could be a cost-effective intervention by reducing readmissions [10].
Many pharmaceutical societies provide guidelines, practical tools and educa-
tional support for MedRec implementation. Strategies for implementing MedRec
include the use of standardised forms, electronic reconciliation tools, collaborative
models and patient engagement.
After discharge, many patients might have difficulties with medication manage-
ment, including delays in filling their medications. Therefore, at discharge, addi-
tional pharmacists’ interventions complement MedRec to improve continuity of
care, often evaluated in the literature in combination: supplying of medications,
medication counselling of patients, provision of verbal and written information to
the patient, communication between primary and secondary care providers, follow-
­up phone calls with the patient or the community pharmacist and home visits. These
interventions are particularly recommended in older patients and can be performed
by both the hospital pharmacist and the community pharmacist.
The written report that all patients and subsequent HCPs receive at discharge, also
called discharge plan, contains a detailed list of all medications the patient is currently
taking (name and respective indications, strength, form, timing, frequency, duration,
date and time of the last dose), identification and explanation about medicines that
have been started/stopped, any known adverse reactions and known allergies. This
report is in a format suitable and adapted to the patient’s and/or carer’s health literacy.

9.1.3 Patient Education and Shared Decision-Making

Medication adherence has been defined as “the process by which patients take their
medications as prescribed” [11]. Several factors influence adherence such as
108 A. Spinewine et al.

knowledge and skills in managing medications, previous side effects, health liter-
acy, beliefs about the medication and lack of involvement in the treatment decision-­
making process.
Patient education is a common intervention to improve medication adherence.
Pharmacists-led education can be provided in several settings and formats: meet-
ing during hospital stay, consultations, including in community pharmacies, provi-
sion of written information, home visits, phone calls and motivational interviewing
[12]. Rather than just presenting information about medications, pharmacist dis-
cusses it and assesses non-adherence and beliefs about medication. Education to
tackle non-­adherence should include tailored practical suggestion (e.g. to the type
of medicines or regimen, monitoring, use of a pill-box or reminders). Pharmacists
also implement patient self-management plans, to support people with chronic
conditions who want to be involved in managing of their own medicines. Patient
education can be general or specifically focused on oncology medications, antico-
agulation, antihypertensive drugs, analgesics, potentially inappropriate medica-
tions, fall-risk medications and so forth. Health literacy tools can help pharmacists
adapt education and counselling.
Although evidence of pharmacists-led education in older patients on adherence
and clinical outcomes is inconsistent, some studies have shown promising results on
optimisation of medication in terms of deprescribing of inappropriate medications
and benzodiazepines in ambulatory and hospital setting [13, 14].
Most patients, including the older ones, wish to be involved in making decisions
about their own medicines. Shared decision-making (SDM) is “an approach where
healthcare professionals and patients share the best available evidence when faced
with making decisions regarding healthcare, and where patients are supported to
consider options to achieve informed preferences” [15]. In older patients, SDM and
patient involvement are important to reduce inappropriate polypharmacy. Moreover,
SDM results in older patient to choose more conservative options (medication
reduction or cessation, less initiation of new drugs), which support deprescribing
and decrease of treatment burden [16, 17]. Pharmacists should integrate shared
decision-making (SDM) with the patient in their medication review and treatment
optimisation process. They can also help develop medication decision tools, which
will support discussion but not replace it.

9.2 Pharmacists’ Role in the Education and Training

of Other Healthcare Professionals

Pharmacy teams internationally have played a pivotal role in the education and
training of fellow HCPs in both the acute and non-acute settings over several
decades. Such education and training sessions take place both in formal, for exam-
ple, lecture, and/or informal, for example, ward rounds settings, but one thing is
clear, if our desire is to improve prescribing amongst older patients, then constant
and up-to-date education of all prescribers including non-medical prescribers (e.g.
nurse and other HCP prescribers) is crucial. There have been numerous educational
9 The Role of Pharmacists in Optimising Drug Therapy 109

interventions published in the literature, which aim to enhance prescribing appro-

priateness [18, 19].
Several different approaches have been used to deliver these education sessions
from traditional lecture sessions with pre-printed materials to more innovative
approaches such as massive open online course (MOOC) and academic detailing
[20–22]. Interestingly, the majority of reported educational interventions published
in the literature examine the impact of an intervention on a single agent of a single
drug class, for example, antibiotics [21] and hypnotics [19]. Relatively few educa-
tional studies have examined the broader issue of prescribing in an older population.
The benefits of such single drug/drug class education interventions are that the pre-
scriber’s knowledge of that particular medicine/drug class is enhanced substantially,
although broader educational issues, for example, pharmacokinetic and pharmaco-
dynamic alteration in older patients, may be required by the prescriber to prepare
them for the complex issues which are routinely present in this population.
In recent years, pharmacists have become increasingly involved in the delivery
of educational materials via academic detailing [20]. Academic detailing is a means
of delivering continuing education to HCPs by another trained HCP such as a phar-
macist, nurse or doctor. The trainer visits the trainee, that is, the prescriber in their
practice setting and provides evidence-based information on a selected topic [23].
These outreach educational sessions are interactive in nature and can be tailored to
the needs of the trainee. They also facilitate discussion and feedback during the
session.
Likewise, pharmacists have embraced the use of online educational platforms.
These platforms have facilitated the delivery of materials simultaneous to large
audiences via MOOC or E-learning platforms. These online modes of delivery have
enabled broader topics such as altered pharmacokinetic and pharmacodynamic
principles of an older population to be discussed and delivered to the audience [24,
25]. Both online delivery methods have their advantages and disadvantages, but a
key advantage is the ability to deliver tailored materials to large numbers of pre-
scribers simultaneously.

9.3 Models of Pharmacy Practice in Different Settings

of Care and Countries

Clinical pharmacy services with a focus on older people (also called “geriatric phar-
macy practice”) emerged in the mid-1970s, and since then a substantial body of
published literature has accumulated, demonstrating patient safety and economic
benefits of clinical pharmacy services for older people, including evidence from
randomised controlled trials [26]. Clinical pharmacy services have been shown to
improve prescribing, prevent adverse drug reactions and medication errors, improve
patients’ medication knowledge and adherence and, in some populations, reduce the
risk of medication-related hospital admissions [26].
This movement of pharmacists’ involvement in direct patient care away from the
traditional medication-dispensing/supply functions is widespread globally, although
110 A. Spinewine et al.

there is major inter- and intra-country variability in the practice models and their
level of implementation [27, 28]. Below we describe and discuss these models of
practice in each type of setting of care.

9.3.1 Ambulatory Care

The availability of MR services provided by pharmacists in ambulatory care is

increasing worldwide, although it is varying in content, scope, implementation and
level of interprofessional collaboration across countries.
European data show that at least one type of MR service is implemented in com-
munity pharmacy in more than half of European countries, either as a project or as
an implemented service [29, 30]. Type 2A MR is the more widespread, because it is
more convenient to implement in the community pharmacy setting [29]. Four coun-
tries (Switzerland, England, The Netherlands and Northern Ireland) had a reim-
bursed, fully implemented MR (type 2B or type 3) service in the community
pharmacy [30]. Such pharmaceutical care service is also available in non-EU coun-
tries such as Australia, New Zealand and the United States of America. In Canada,
the service is organised on a province level with variability in eligibility criteria and
reimbursement of MR services. There is funding for providing specific recommen-
dations to prescribers on various types of drug-related problems. Such pharmaceuti-
cal opinions, coupled to sending patients an educational deprescribing brochure,
have shown to be effective in discontinuation of inappropriate prescriptions in older
people [14].
MR services in the community pharmacy offer significant opportunities to sup-
port patients with managing comorbidities and complex medicine regimens,
although many challenges remain to be overcome, ranging from poor public aware-
ness and acceptance, organisational constraints, and issues over interprofessional
collaboration [31]. As an example, a study of Bulajeva found that only half of inter-
mediate MR services available in Europe incorporated reporting to the physician
and a third included multidisciplinary case conferences during the review.
In a few countries, type 3 MR is performed by pharmacists outside the commu-
nity pharmacy. In England, for example, since 2015, clinical pharmacists can be
hired in general practitioner practices and perform, amongst other tasks, MR and
medication reconciliation [32]. Evidence from published evaluations suggests that
pharmacists in general practice can have a positive impact on clinical outcomes,
may reduce medication-related hospitalisations. This model may provide advan-
tages over a community pharmacy service, including (co-)location, access to medi-
cal records to inform the quality and appropriateness of recommendations, the
potential for formal and informal communication and discussion of the pharmacist’s
recommendations and reduced fragmentation of care. In Australia, the Home
Medicines Review program started in 2001 [4]. This Commonwealth-funded pro-
gram aims to maximise patient benefit from medicines and prevent drug-related
problems through a collaborative process involving both general practitioners and
accredited pharmacists. It includes the following steps: the general practitioner
9 The Role of Pharmacists in Optimising Drug Therapy 111

identifies and refers the patient for MR; an accredited pharmacist visits the patient
at home and obtains a comprehensive medication history, then documents its medi-
cation review findings and recommendations in a report for the general practitioner
(GP); then based on this, the GP and patient formulate a medication plan [4]. The
positive impact has been demonstrated on medication use measures mainly [4].

9.3.2 Acute Care

Drug-related admissions, adverse drug events during hospital stay and after dis-
charge are all frequent in older people with multimorbidity and polypharmacy. The
involvement of clinical pharmacists to optimise drug therapy in older inpatients is,
therefore, appealing. Various practices for pharmacists’ involvement in the care of
inpatients exist, ranging from single approaches such as simple or intermediate MR
during hospital stay to more comprehensive, multifaceted and collaborative
approaches implemented from admission to discharge or even post-discharge.
Current evidence to date shows that medication reconciliation, patient education,
HCP education and transitional care are essential elements that need to be imple-
mented in addition to medication review to reach an effect on hospital readmissions
[33–35]. Even though there has been some progress over the last decade, such com-
prehensive model of care is not yet widely implemented in hospitals in Europe and
beyond. The role of the “ward-based clinical pharmacist,” whilst well established in
some countries, is still a rarity in others. Lack of capacity, capability and support
from managers are the commonly cited reasons for this [36, 37].
In the case of limited resources, pharmacists and hospital managers may decide
to have a comprehensive model of practice implemented for a restricted number of
older people at highest risk of drug-related problems, or to have a less comprehen-
sive and more diluted approach implemented for a larger population. The former
approach is probably preferable, although there are no strong direct comparison
data available to date to confirm this.

9.3.3 Long-Term Care

Polypharmacy, together with other factors such as frailty and complexity of the
medication use process, makes the safe use of medications for nursing home resi-
dents highly challenging, and pharmacists have been involved in many initiatives
aiming to optimise the use of medicines in that setting. Pharmacists’ contribution to
optimise medicines use in the nursing home setting includes (a) practices directed
at nursing home residents, often in the form of medication reviews, which can be
uni- or multiprofessional, and aimed at specific drugs or the whole regimen and (b)
practices directed at HCPs—often educational approaches directed at prescribers
[19, 38]. These practices are described further below. Even though most activities
performed to date by pharmacists focus on the prescription component, there is
wide room for pharmacists’ input towards improving administration
112 A. Spinewine et al.

process—although only limited data are available on the practice models and evi-
dence of effect [38].
In several countries such as the United Kingdom, Australia and the United
States, comprehensive MR programs in nursing homes are funded. MRs are gener-
ally conducted collaboratively by the resident’s general practitioner and a pharma-
cist who is accredited to conduct MRs (also referred to as consultant pharmacists).
As an example, Australian guidelines recommend that a MR (called Residential
Medication Management Review—similar to the Home Medicines Review pro-
gram funded in ambulatory care) is provided as soon as possible after an individual
first enters permanent residential care and when clinical circumstances change [4,
39]. Each review identifies an average of 2.7–3.9 medication-related problems per
resident receiving the service, with general practitioners accepting 45–84% of
pharmacists’ recommendations [40]. Targeted MRs for people taking psychotropic
drugs is also recommended and encouraged in several countries. There is evidence
that such programs lead to more appropriate prescriptions and lower use of seda-
tive and anticholinergics drug use, although certainty of the evidence was found to
be low in a Cochrane review [19]. Some recent clinical trials showed positive
results of collaborative and innovative approaches towards MR in the nursing
home setting, for example, by involving nursing home residents and/or nurses in
the process [41, 42]. Wider scale implementation of these approaches has yet
to occur.
Pharmacists also contribute to optimised medication use in nursing homes
through educational approaches, case conferencing, audit and feedback directed at
other HCPs (or sometimes at nursing home residents and their families) [18, 28].
Such practices are less resource intensive—and may, therefore, be encouraged in
countries where there is no government-funded MR program. They may contribute
to better use of medicines, although probably with lower effect than comprehensive
MR. As an example, in Switzerland there is funding for regular meetings (also
called quality circles) between pharmacists, physicians and nurses active in a nurs-
ing home, with the goal of producing local prescribing consensus to improve drug
use [43]. This approach led, in particular, to a reduction in drug costs and improved
antibiotics stewardship.

9.3.4 Interprofessional Practice is Desirable But Challenging

to Implement

Pharmacists have distinct expertise that can contribute to team knowledge and com-
petence in managing older patients with polypharmacy and multiple chronic condi-
tions. Importantly, evidence shows that globally, interventions developed by a
pharmacist within a multidisciplinary team seem to provide greater benefits in terms
of clinical outcomes and economic results than those carried out by individual phar-
macists [34].
Pharmacists can be members of geriatric evaluation and management (GEM)
teams. Such teams provide comprehensive geriatric assessment, which is by nature
9 The Role of Pharmacists in Optimising Drug Therapy 113

interdisciplinary. Studies have shown that pharmacists working in geriatric evalua-

tion and management teams have favourable effects on therapeutic, safety, hospi-
talisation, and adherence outcomes in older adults [27]. This is most easily
implemented in the acute care setting with clinical pharmacists.
Interprofessional collaboration in the primary care setting is critical for sustain-
ing high-quality care in the context of the increasing burden on primary healthcare
services [44]. Several studies have shown positive effects of working as a team,
including better care continuity and coordination, beneficial changes in patient
behaviour, improvement of patient symptoms and satisfaction through better
response to their needs [45]. However, health providers in primary health care set-
tings—and pharmacists are no exception to this—face enormous ideological, organ-
isational, structural and relational challenges whilst promoting teamwork and
interprofessional collaboration [46]. A better understanding of barriers and enablers
for effective interprofessional collaboration are essential for adapting services and
context, whenever possible. For example, collaboration between general practitio-
ners and community pharmacists is mostly facilitated by an environment with suf-
ficient resources and a close distance between the two professions, clear and regular
communication, experience with collaboration and understanding each other’s
capabilities and roles towards delivering patient care [44]. Although this takes time
to evolve, progress is being made in the right direction.

9.3.5 The Prescribing Pharmacist

Traditionally the prescribing role has being a key domain of the medical practitio-
ner, although globally numerous healthcare systems have broadened this authority
to other HCPs, for example, nurses, pharmacist, physiotherapist, in the form of
supplementary or independent prescribing [47]. The expansion of such authority
has demonstrated several benefits in terms of increased patient satisfaction, cost
effectiveness [37], concordance with therapeutic regimens [48], increasing continu-
ity of care and increased medication access [49, 50]. This broadening of roles for
other HCPs has been in response to changing service needs and increased specialist
roles within these professionals [47].
Key drivers resulting in the expansion of prescription authority have been a
desire by medical providers to reduce costs whilst simultaneously enhancing patient
services, whereas a key barrier for many healthcare professions to take on such roles
in the past has been the lack of access to patient’s clinical data and medical notes.
Without access to such data, it is hard for any professionals to provide clinically
appropriate advice pertaining to either prescribing or indeed appropriate advice in
relation to deprescribing [25, 47].
The impact of non-medical prescribing upon professional boundaries and rela-
tionships is often dependent upon whether supplementary or independent prescrib-
ing is legislated. In the former, continued medical authority/responsibility is retained
by the physician with supplementary prescribing authority given to the pharmacist
by the doctor after they have undertaken the clinical assessment and made the initial
114 A. Spinewine et al.

diagnosis. This typically involves an agreed clinical management plan/protocol in

advance for a given cohort of patient, for example, diabetic treatment plans [47, 51,
52], whereas the independent prescribing model is more self-governing/autono-
mous allowing the non-medical prescriber to diagnose and prescribe without direct
involvement from a medical practitioner [47].
Within the countries where pharmacists have prescribing authorisation either as
independent or supplemental prescribers, their scope of practice may vary consider-
ably depending on whether formularies or agreed protocols are in existence [47].
The development of such protocols and formularies in collaboration with medical
staff could potentially lead to restrictions being placed upon non-medical prescrib-
ers’ scope of practice [53].
Generally, the literature has reported that in practice, non-medical prescribing
increases effectiveness and independence of the HCP, but it also raises issues con-
cerning confidence, workload and the need for continued specialist training in the
form of CPD (continued professional development) [54]. Non-medical prescribers
tend also to be aware of their limitations and are known to regularly consult with
medical colleagues on complex cases [47].
The role of the pharmacist prescribing continues to grow in various healthcare
setting internationally, although differences in legislative procedures/practices by
professional bodies and governments has resulted in the implementation of several
models of pharmacist prescribing worldwide [47, 54]. Nonetheless, prescribing
pharmacists internationally continue to publicise that extending prescribing rights
has allowed them to utilise their therapeutics knowledge, gain increased profes-
sional recognition and demonstrate enhanced patient care [47].

9.4 Conclusions and Perspectives

Pharmacists have specific knowledge and skills that are essential to optimising med-
ication use in older people. At the patient individual level, pharmacists’ activities
most frequently encompass medication review, medication reconciliation and
patient education. Several models of care have been implemented in different set-
tings of care (ambulatory, acute and long-term care) in many countries, although
there remains a large variability in the existence and implementation for such ser-
vices worldwide. More comprehensive, patient-centred and interprofessional
approaches seem to provide greater benefit, although there are more challenges to
implementing these approaches, especially in the ambulatory setting. Standardisation
and enhanced coverage/implementation of geriatric pharmacist practice are impor-
tant challenges for the future.
Pharmacists also make an important contribution to optimising medication use in
older people by educating other HCPs. This can happen through different approaches,
from traditional lecture sessions to more innovative approaches such as massive
open online course and academic detailing.
Finally, and even though this was not specifically addressed in the current chap-
ter, the role of pharmacists as researchers—to measure the quality of medication
9 The Role of Pharmacists in Optimising Drug Therapy 115

use, understand the barriers and enablers, and design and evaluate the effect of opti-
misation approaches—is also an important contribution towards optimising phar-
macotherapy in older patients.

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Deprescribing: Evidence Base
and Implementation 10
Denis Curtin and Denis O’Mahony

10.1 Introduction

Older people in their final years are commonly prescribed multiple medications to
manage their chronic diseases. These medications may ameliorate symptoms, pre-
vent future adverse health events and extend life. However, the use of multiple med-
ications is also associated with an increased risk of adverse side effects, drug
interactions and medication adherence problems. Furthermore, as older people
become increasingly frail, the use of multiple medications may be considered bur-
densome or even futile. For frailer older patients taking multiple medications, when
does the balance shift from net benefit to net harm? If declining health and death are
unavoidable, it follows logically that there must come a point in time when patients
no longer benefit from certain chronic disease drug therapies.
Chapter 4 discussed the process of deprescribing in the context of potentially
inappropriate medication (PIM) use where the goal is to minimize the adverse con-
sequences of inappropriate prescribing that is, adverse drug reactions (ADRs) and
adverse drug events (ADEs). The present chapter will focus on older people with
more advanced degrees of frailty and the discontinuation of medications that may,
ordinarily, be therapeutically useful and appropriate but of less clinical value or pos-
sibly futile in the patient who is likely to be approaching end-of-life. In this context,
the key question for the clinician is how to separate essential medications from
those that are non-essential.

D. Curtin · D. O’Mahony (*)

Department of Medicine (Geriatrics), University College Cork, Cork, Ireland
Department of Geriatric Medicine, Cork University Hospital, Cork, Ireland
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 119

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_10
120 D. Curtin and D. O’Mahony

10.2 Definition of Deprescribing

The term ‘deprescribing’ is a relatively new term and first appeared in the English
language literature in 2003 [1]. In the first review of the subject, Woodward outlined
the principals of deprescribing. These included:

(a) Reviewing all current medications.

(b) Identifying medications to be discontinued, substituted or reduced.
(c) Planning a deprescribing regimen in partnership with the patient.
(d) Frequently reviewing and supporting the patient [1].

Since then, several new definitions have been proposed [2–4]. A 2015 system-
atic review of the literature by Reeve et al. was conducted to determine whether
a standardized definition of deprescribing could be reached to inform future
research on the subject [5]. The most common characteristics of the various defi-
nitions were used by the authors to develop a new definition: ‘Deprescribing is
the process of withdrawal of an inappropriate medication, supervised by a health
care professional with the goal of managing polypharmacy and improving
outcomes’.

10.2.1 Evidence Base for Deprescribing

Several recent systematic reviews have examined the impact of deprescribing

interventions on prescribing and clinical outcomes [6–8]. Thillainadesan et al.
[6] focused on older hospitalized patients (i.e. ≥65 years); Dills et al. [7] included
adult patients aged ≥18 years in outpatient, assisted living, nursing home and
acute care settings; while Shrestha et al. [8] specifically examined the impact of
deprescribing interventions on older patients with life-limiting illnesses and
reduced life expectancy. In Thillainadesan’s and Dills’ reviews, only randomized
controlled trials (RCTs) were included, whereas Shrestha included both random-
ized and non-­randomized studies. Heterogeneity in design and outcome mea-
surement as well as small sample sizes in included studies were limitations
reported by authors in each review. All three reviews concluded that deprescrib-
ing interventions can reduce potentially inappropriate prescribing, but evidence
of a positive impact on important clinical outcomes such as ADRs, falls, re-hos-
pitalization, quality of life and mortality was currently weak or of low quality.
Nevertheless, it is generally agreed among specialists in geriatric medicine and
clinical pharmacology that discontinuation of excessive or unnecessary medica-
tion in frailer older people is generally desirable.
10 Deprescribing: Evidence Base and Implementation 121

10.3 Operationalizing Deprescribing for Older People

Approaching End-of-Life

10.3.1 Prognostication of Survival

An assessment of survival prognosis is central to the decision to discontinue an

otherwise appropriate medication in a frail older person. Prognostic estimates may
be formulated subjectively (i.e. clinician prediction) or objectively (i.e. using prog-
nostic models). Clinician prediction has the advantage of being instantaneous and
convenient, and while it may incorporate known prognostic factors in its determina-
tion, accuracy will undoubtedly vary depending on the knowledge, experience and
insight into the particular case on the part of the clinician. Most studies have found
that clinicians generally give optimistic estimations of life expectancy [9–11].
Christakis and Lamont described clinicians’ prognostic accuracy in terminally ill
patients [10]. In their study, 343 doctors provided survival estimates for 468 termi-
nally ill patients at the time of hospice referral. Only 20% of survival predictions
were accurate (i.e. predicted survival rate within ±33% of actual survival), and over-
all, doctors overestimated survival by an average factor of 5.3 times that of actual
survival. The most experienced clinicians tended to be most accurate, whereas the
longer the duration of the doctor–patient relationship, the greater the likelihood of
an inaccurate prediction [10].
Prognostic models synthesize clinical and demographic data to produce a mor-
tality risk estimate for a specified time period. In a similar manner, frailty scales
utilize clinical data to predict risk of a range of adverse health outcomes (e.g. falls,
dependency, institutionalization, complications related to invasive procedures etc.)
in addition to death. The clinical data included are generally taken at a fixed time-­
point, and therefore, the predicted risk may vary depending on whether the patient
is in the acute or recovery phase of illness. Multiple prognostic models and frailty
scales have been developed in the last two decades but lack the support of validation
and impact studies to be recommended for use as mortality prediction tools [12, 13].
Predication models, even when very accurate, indicate the likely outcome in an
average patient with a given set of risk factors under average conditions. Therefore,
while prediction models and frailty scales may be useful to identify groups of
patients with shared characteristics who may benefit from a particular care pathway,
it is questionable whether they should influence important decisions about individ-
ual patient care.
For now, prognostic certainty seems unattainable and clinical judgement is likely
to be the physician’s best tool. Clinical judgement may be improved by posing the
prognostic question slightly differently: rather than asking ‘How long is this patient
likely to live?’ which is associated with overly optimistic predictions, the clinician
could ask, ‘Would I be surprised if this patient were to die within the next 12
months?’ [14]. The answer to the ‘surprise question’ is binary (yes or no) and essen-
tially functions as a method of separating those with an intermediate-to-high prob-
ability of dying (the clinician answers that he/she would not be surprised if the
patient died within the specified time period i.e. surprise question positive [SQ+])
122 D. Curtin and D. O’Mahony

from those with a low probability of dying (the clinician would be surprised, i.e.
surprise question negative [SQ−]). Recent systematic reviews of the ‘surprise ques-
tion’ indicate that while it leads to the detection of many false positives, the method
appears to be very effective at excluding patients with longer survival times (nega-
tive predictive value >90% in both reviews) [15, 16]. Clinical judgement may also
be improved by considering the illness and disability trajectory of the patient. Most
older people experience loss of functional capabilities in the last year of life and
very often this decline coincides with acute illness requiring hospitalization [15,
16]. One large Scottish study indicates that more than one in four patients aged
≥65 years admitted to hospital will be deceased in the prospective 12 months [17].
An acute hospital admission, therefore, is often a sentinel event for an older person,
especially if associated with new or additional disability, and may be an appropriate
trigger for discussions around goals of care medication rationalization.

10.3.2 Identifying Medications to be Deprescribed

A logical approach to deprescribing would involve examining the likelihood of a

drug-conferring benefit within the remaining life expectancy of the patient. Holmes
et al. have suggested that number needed to treat (NNT), time to benefit (TTB) and
time to harm (TTH; see Table 10.1 for definitions) data from drug trials could be
balanced against an estimate of remaining life expectancy in order to determine an
accurate evaluation of net benefit (or net harm) of a particular drug [18]. This
approach has problems however: first, drug data are derived from trials that gener-
ally exclude older patients approaching end-of-life and therefore may have limited
applicability [19]; second, as discussed, estimates of remaining life expectancy are
commonly inaccurate [9–11]; third, the approach is likely to be time-consuming
and, therefore, impractical in a routine clinical setting.
Approaches to deprescribing through multidisciplinary team consensus and
pharmacist- and physician-led interventions have been described in the literature.
The reproducibility of these methods is uncertain. Several tools have been devel-
oped in recent years to support clinicians to make systematic deprescribing deci-
sions in older people approaching end-of-life. Many of these tools were examined
in a recent systematic review by Thompson et al. [20] This chapter focuses

Table 10.1 Definitions of number needed to treat (NNT), time to benefit (TTB) and time to
harm (TTH)
Definition
Number needed The number of patients that need to be treated for one patient to benefit
to treat (NNT)
Time to benefit The time taken for a statistically significant benefit to be observed in trials
(TTB) of people receiving a particular medication or therapy compared to the
control group
Time to harm The time period until a statistically significant adverse effect is observed in
(TTH) a trial within the treatment group compared to the control group
10 Deprescribing: Evidence Base and Implementation 123

primarily on the two most widely used deprescribing tools that have been tested as
interventions in well-designed clinical trials, that is, Scott’s deprescribing algorithm
and STOPPFrail criteria.
The algorithm proposed by Scott et al. (Fig. 10.1) requires the user to answer a
series of questions about each individual medication in the patient’s regimen [21].
Although comprehensive and patient-centred, the outcome is likely to depend on
the knowledge, experience and attitudes of the user. Nuanced clinical judgement is

STOPPFrail is a list of potentially inappropriate prescribing indicators designed to assist physicians with deprescribing decisions.
It is intended for older people with limited life expectancy for whom the goal of care is to optimize quality of life and minimize the risk
of drug-related morbidity. Goals of care should be clearly defined and, where possible, medication changes should be discussed and
agreed with patient and/or family. Appropriate candidates for STOPPFrail-guided deprescribing typically meet ALL of the
following criteria:
1. ADL dependency (i.e. assistance with dressing, washing, transferring, walking) and/or severe chronic disease and/or terminal illness
2. Severe irreversible frailty i.e. high risk of acute medical complications and clinical deterioration
3. Physician overseeing care of patient would not be surprised if the patient died in the next 12 months

Section A: i. Any drug that the patient persistently fails to take or tolerate despite adequate education and consideration of all
General appropriate formulations.
ii. Any drug without a clear clinical indication
iii. Any drug for symptoms which have now resolved (e.g. pain, nausea, vertigo, pruritis)

Section B: i. Lipid lowering therapies (statins, ezetimibe, bile acid sequestrants, fibrates, nicotinic acid, lomitapide, andacipimox)
Cardiology ii. Antihypertensive therapies: Carefully reduce or discontinue these drugs in patients with systolic blood pressure (SBP)
system persistently <130mmHg. An appropriate SBP target in frail older people is 130 -160mmHg. Before stopping, consider
whether the drug is treating additional conditions (e.g. beta-blocker for rate control in atrial fibrillation, diuretics for
ymptomatic heart failure)
iii. Anti-anginal therapy (specifically: nitrates, nicorandil, ranolazine): None of these anti-anginal drugs havebeen
proven to reduce cardiovascular mortality or the rate of myocardial infarction. Aim to carefully reduce and discontinue
these drugs in patients who have had no reported anginal symptoms in the previous 12 months AND who have no
proven or objective evidence of coronary artery disease.

Section C: i. Anti-platelets: No evidence of benefit forprimary (as distinct from secondary) cardiovascular prevention.
Coagulation ii. Aspirin for stroke prevention in atrial fibrillation: Aspirin has little or no role for stroke prevention in frail older
system people who are not candidates for anticoagulation therapy and may significantly increase bleeding risk.

Section D: i. Neuroleptic antipsychotics in patients with dementia: Aim to reduce dose and discontinue these drugs in patients taking them
Central for longer than 12 weeks if there are no current clinical features of behavioural and psychiatric symptoms of dementia (BPSD).
Nervous ii. Memantine: Discontinue and monitor in patients with moderate to severe dementia, unless memantine has clearly
System improved BPSD
Section E: i. Proton Pump Inhibitors: Reduce dose of Proton Pump Inhibitors when used at full therapeutic dose ≥ 8 weeks, unless
Gastrointestinal persistent dyspeptic symptoms at lower maintenance dose.
System
ii. H2 receptor antagonist: Reduce dose of H2 receptor antagonists when used at full therapeutic dose for ≥
8 weeks, unless persistent dyspeptic symptoms at lower maintenance dose.
Section F: i. Theophylline and aminophylline: These drugs have a narrow therapeutic index,have doubtful therapeutic benefit andrequire
Respiratory monitoring of serum levels and interact with other commonly prescribed drugs putting patients at an increased risk of ADEs.
System ii. Leukotriene antagonists (Montelukast, Zafirlukast): These drugs have no proven role in COPD, they are indicated only in
asthma.
Section G: i. Calcium supplements: Unlikely to be of any benefitin short-termunless proven, symptomatic hypocalcaemia.
Musculoskeletal ii. Vitamin D (ergocalciferol and colecalciferol): Lack of clearevidence to support the use of vitamin D to prevent falls and
System fractures, cardiovascular events, or cancer.
iii. Anti-resorptive/bone anabolic drugsFOR OSTEOPOROSIS (bisphosphonates, strontium, teriparatide, denosumab)
iv. Long-term oral NSAIDs: Increased risk of side effects (e.g. peptic ulcer disease, bleeding, worsening heart failure) when
taken regularly for ≥ 2 months.
v. Long-term oral corticosteroids: Increased risk of major side effects (e.g. fragility fractures, proximal myopathy, peptic
ulcer disease) when taken regularly for ≥ 2 months. Consider careful dose reduction and discontinuation.

Section H: i. Drugs for benign prostatic hyperplasia (5-alpha reductase inhibitors and alpha-blockers) in catheterized male
Urogenital patients: No benefit with longtermbladder catheterisation.
System ii. Drugs for overactive bladder (muscarinic antagonists and mirabegron): No benefit in patients with persistent, irreversible
urinary incontinenceunless clear history ofpainful detrusor hyperactivity.

Section I: i. Anti-diabetic drugs: De-intensify therapy. Avoid HbA1c targets (HbA1C <7.5% [58 mmol/mol] associated with net harm in
Endocrine this population). Goal of care is to minimize symptoms related to hyperglycaemia(e.g. excessive thirst, polyuria).
System

Section J: i. Multi-vitamin combination supplements: Discontinue when prescribed for prophylaxis rather than treatmentof hypovitaminosis.
Miscellaneous ii. Folic acid: Discontinue when treatment course completed. Usual treatment duration 1-4 months unless malabsorption,
malnutrition or concomitant methotrexate use.
iii. Nutritional supplements:Discontinue when prescribed for prophylaxis rather than treatment of malnutrition.

Fig. 10.1 STOPPFrail version 2 deprescribing criteria [24]

124 D. Curtin and D. O’Mahony

required, the user is not provided with resources or decision aids to estimate treat-
ment benefit–harm trade-offs in individual patients. The use of implicit medication
assessment tools is, in general, time-consuming and is likely to result in variations
in practice between physicians, and for these reasons, integration into routine clini-
cal practice has been limited [22]. Serial considerations for deprescribing according
to the CEASE algorithm of Scott et al. [21] comes in the form of four key questions
relating to any medication that the patient is taking. If the answer to these four ques-
tions in series is ‘No’, the drug may be continued. If there is a ‘Yes’ answer to any
of the four questions, deprescribing should be considered. The four questions are as
follows:

1. Does a drug provide no current patient benefit?

2. Does a drug present greater harm than benefit?
3. Are disease symptoms stable or non-existent?
4. If a drug is prescribed for disease prevention, is the patient’s life expectancy too
short to realize benefit from that drug?

STOPPFrail (Screening Tool of Older Persons Prescriptions in Frail adults with

limited life expectancy; Fig. 10.1) Criteria were first published in 2017 and updated
in 2020 [23, 24]. The updated criteria include a method for identifying patients
approaching end-of-life and comprise 25 predominantly explicit indicators to assist
physicians with deprescribing decisions [24]. The criteria were created following a
literature appraisal and Delphi validation process involving clinicians with expertise
geriatric medicine, clinical pharmacology, palliative medicine, general practice and
psychiatry. Substantial inter-rater reliability has been demonstrated between users
of different clinical disciplines and STOPPFrail-guiding deprescribing recommen-
dations have been shown to generally align with gold-standard deprescribing deci-
sions [25, 26].
Scott’s deprescribing algorithm and STOPPFrail have been evaluated individu-
ally as interventions in randomized controlled trials involving older people with
advanced frailty. These trials are summarized in Table 10.2. While both methods
resulted in reduced numbers of prescribed medications compared with usual phar-
maceutical care, neither trial was sufficiently powered to detect significant changes
in secondary patient-related end points.
Table 10.2 Randomized controlled trials using Scott’s algorithm and STOPPFrail
Study Intervention Design Population Outcomes measured Results
Potter et al. Scott’s algorithm RCT Nursing home residents Primary: change in number of Mean change in number of
(2016) [27] Follow-up: 1 year 95 patients (47 medications medications −1.9 ± 4.1 in
intervention patients; 48 Secondary: mortality, falls, intervention group compared
control patients) fractures, unplanned hospital with +0.1 ± 3.5 in control group
Mean age (SD): 84.3 (6.9) presentations, cognitive status, (p = 0.04).
functional status, QOL, sleep No statistically significant
differences between groups for
secondary outcomes.
Curtin et al. STOPPFrail RCT Hospitalized patients with Primary: change in number of Mean change in number of
(2020) [28] version 1 Follow-up: advanced frailty medications medications −2.6 ± 2.73 in
3 months undergoing transition to Secondary: mortality, acute intervention group compared
10 Deprescribing: Evidence Base and Implementation

nursing home care. hospital presentations, with −0.36 ± 2.60 in control

130 patients (65 unscheduled medical reviews, group (p < 0.001).
intervention patients and falls, non-vertebral fractures, Reduction in medication costs
65 control patients) medication costs, QOL, 28% in intervention group vs 5%
Mean age (SD): 85.1 (5.7) prescription of antipsychotic in control group (p < 0.02).
medications No statistically significant
differences between groups for
other secondary outcomes.
125
126 D. Curtin and D. O’Mahony

10.4 Shared Decision-Making

Patient involvement in healthcare decisions is a key component of patient-centred care

[29]. Qualitative studies indicate that clinicians are often reluctant to initiate discus-
sions about deprescribing with older people, believing that they would resist having
their medications discontinued or that they would interpret deprescribing as with-
drawal of care or ‘giving up’ on active treatment [30, 31]. These perceptions, however,
have not been borne out in patient-focussed research [32, 33]. Reeve et al. recently
examined attitudes of older people towards deprescribing in a nationally representa-
tive sample of Medicare beneficiaries in the United States [32]. In that study, 92% of
people indicated a willingness to discontinue one or more of their medications if their
physician said it was possible, and 66% reported a desire to reduce the number of
medications that they were taking. The greatest predictor of willingness to deprescribe
was the consumption of six or more daily medications [32]. The results are important
and suggest that physicians can be reassured that broaching the topic of deprescribing
with their older patients is generally acceptable to them.
Decisions about medications represent just one aspect of many considerations
that patients and their physicians face when they discuss goals of care, and some-
times other aspects of the discussion may take priority. For this reason, a focus on
the patient’s values, such as whether the patient favours a primary focus on extend-
ing life or on symptom palliation, may be more worthwhile than concentrating on
the merits of individual therapies. Once a shared understanding of the patient’s val-
ues is established, prescribed medications can be aligned with the goals of care.
Some patients may desire more detailed information, and, in general, the discussion
should be adapted to the patient’s information preferences. Although withdrawal of
certain treatments may be recommended, commitment to supporting patients
through their illness should be re-emphasized.

10.5 Conclusion

Larger, multi-centre, randomized trials with extended follow-up times are required
to provide further clarification on the impact of deprescribing interventions on
patient-related outcomes such as hospital admissions, quality of life and mortality.
Expectation that deprescribing interventions will improve these outcomes may be
overreaching. Deprescribing involves the withdrawal of a medical intervention,
and, therefore, demonstrating that patient’s symptoms do not subsequently deterio-
rate and that quality of life is maintained may be enough to justify the process.
The goal of deprescribing is to minimize drug-related morbidity and medication
burden for older people approaching end-of-life. Central to this goal is the recogni-
tion that clinicians have prescribing responsibilities beyond the restoration and
maintenance of health. Increasing dependency and, ultimately, death do not neces-
sarily represent a failure of medical care but are natural processes for which science
has no ultimate remedy. In this context, clinicians need to support their older frailer
10 Deprescribing: Evidence Base and Implementation 127

patients approaching end of life with personalized care that prioritizes symptom
control rather than survival extension.
Finally, deprescribing is generally acceptable to older patients and their carers
[33]. Recent evidence also indicates that deprescribing in older people is cost-­
effective [34].

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Part II
Geriatric Syndromes and Common Chronic
Conditions
General Principles of Management
of Patients with Multimorbidity 11
and Frailty

Camilla Cocchi, Graziano Onder,

and Maria Beatrice Zazzara

11.1 Multimorbidity, Frailty and Their Interconnection

The progressive ageing of the population has led to a new health scenario, where
frailty and multimorbidity are extremely common. Although both are strongly asso-
ciated with poor quality of life, increased risk of disability, hospitalization, institu-
tionalization and higher mortality, multimorbidity and frailty should be considered
as different entities.

11.1.1 Multimorbidity

Multimorbidity is usually described as the coexistence of two or more chronic dis-

eases in the same individual. This condition should be considered as an entity by
itself and not just the co-occurrence of multiple diseases. It is in fact a synergy of
different clinical conditions associated with worse health outcomes and a more
complex clinical management.
In high-income countries, 20% of the population before the age of 40, and almost
70% of those above 60, have two or more chronic diseases, making multimorbidity
itself ‘the most common chronic condition’. Low- and middle-income countries are
expected to present similar figures in few decades. Onset and severity of multimor-
bidity are influenced by behavioural, clinical and social factors and lifestyle during
the entire lifespan. The clinical picture of multimorbidity is heterogeneous across
individuals, and it is characterized by a great complexity, which impacts on quality

C. Cocchi (*)
Università Cattolica del Sacro Cuore, Rome, Italy
Fondazione Universitaria Policlinico Gemelli, IRCCS, Rome, Italy
e-mail: [email protected]
G. Onder · M. B. Zazzara
Fondazione Universitaria Policlinico Gemelli, IRCCS, Rome, Italy

© Springer Nature Switzerland AG 2023 131

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_11
132 C. Cocchi et al.

of life, frequency of healthcare use, level of required assistance and survival, with a
consequent challenging medical and care management.
Multimorbidity should not be confused with comorbidity, which refers to the
presence of one or more additional conditions co-occurring with a primary condi-
tion. The difference between the two is important, because it implies a different
clinical approach. In fact, whereas multimorbidity suggests a holistic assessment
that takes into consideration the individual’s clinical complexity, equally weighting
all diseases, comorbidity implies the presence of a prevailing clinical condition
requiring attention. To put it simple, multimorbidity refers to a patient-centred
vision, while comorbidity is more disease-centred.
Even though multimorbidity as a concept is now well known and established, it
is not free from limitations. In particular, multimorbidity suggests that diseases are
equally weighted, whereas the impact on the individual’s health is greater than the
mere sum of the singular clinical effects of every disease [1, 2].

11.1.2 Polypharmacy

One of the most problematic consequences of multimorbidity is polypharmacy,

which is defined as the concurrent use of multiple drugs in the same individual. This
phenomenon is greatly spread in the older population, and its prevalence varies
between 10 and 90% depending on the country or setting. The simultaneous use of
a large number of drugs in the context of an ageing organism, characterized by
reduced kidney and liver function and an altered volume of drug distribution,
increases the likelihood of adverse drug reactions, including drug–drug interactions
and drug–disease interactions. Polypharmacy has been associated with a high num-
ber of adverse outcomes, including adverse drug reactions, hospitalizations related
to adverse drug events, an increased risk of falling, a higher incidence of disability
and increased mortality. To date, there is agreement on considering the correct man-
agement of polypharmacy as one of the key strategies for treating patients with
multimorbidity [3].

11.1.3 Frailty

Frailty is a condition of extreme vulnerability of the individual to endogenous and

exogenous stressors. It is determined by the age-related exhaustion of the body’s
homeostatic reserves and involves an increased risk of adverse events. Even minor
stressors can lead to rapid changes in health status. Frailty is common in older
adults, with a prevalence between 8 and 16% in community-dwelling older adults
and up to 85% among nursing home residents. Frailty is associated with shorter
survival, poor quality of life and increased risk of disability, hospitalization, and
institutionalization.
Chronic diseases play a crucial role in the onset of frailty. According to the
widely used frailty phenotype construct proposed by Fried et al., the presence of
11 General Principles of Management of Patients with Multimorbidity and Frailty 133

chronic diseases has a central role in initiating or worsening frailty. In addition, the
frailty index proposed by Rockwood et al., which is based on a combination of dif-
ferent deficits, primarily includes chronic diseases as a criterion [4, 5]. In a recent
meta-analysis, the prevalence of multimorbidity in frail individuals was 72%, and
the prevalence of frailty among multimorbid individuals was 16%. This means that
most frail individuals are also multimorbid, whereas very few people with multi-
morbidity are also frail. In the general adult population, only 6% are both frail and
multimorbid [1].
As chronic diseases and multimorbidity have such a strong role in determining
frailty, it could be hypothesized that treating these conditions may counteract the
development of frailty, eventually reducing any associated negative consequences.
However, the hypothesis that intensive treatment of chronic diseases might reduce
the progression of frailty is poorly supported by existing studies. In contrast, some
evidence suggests that intensive treatment of chronic diseases may increase nega-
tive health outcomes in frail older adults. For example, polypharmacy, anticholiner-
gic and psychotropic medications have been associated with incident frailty and
pre-frailty over 2 to 5-year follow-up periods [6].
The clinical picture of patients with chronic diseases is strongly influenced by
the presence of frailty features (see Table 11.1): presence of chronic disease might
represent a limited part of the complexity of frail patients that usually present with
multiple impairments in systems and organs, and this complexity might influence
the approach to pharmacological treatment.

Table 11.1 Clinical picture of frail and non-frail patients with chronic conditionsa
Characteristic/
Domain Non-frail Frail
Chronic Diabetes, hypertension Diabetes, hypertension
diseases
Symptoms None Present (i.e. pain, dyspnoea, dizziness)
Functional Physically active Slow walking speed
status Independent in instrumental activities Need help in instrumental activities of
of daily, including managing finances daily living, including managing
and/or medications, use of finances and/or medications, use of
transportation, housework, shopping, transportation, housework, shopping,
walking outside alone, preparing walking outside alone, preparing
meals meals
Cognition Not impaired Mild to moderate impairment
Social function Availability social support (i.e. lives Poor social support (i.e. lives alone,
with spouse or relatives) limited support available from
relatives or friends)
Continence Continent Urinary incontinence
Nutrition Normal nutritional status Obesity or malnutrition, recent weight
loss
Mood Normal Depressive symptoms, sad or
depressed
a
Tables 1 and 2 inspired by Onder G. (coauthor of this work), Vetrano DL et al. “Accounting for
frailty when treating chronic diseases”. Consent obtained by other coauthors via email
134 C. Cocchi et al.

Whereas multimorbidity offers a nosological risk profile, frailty studies focus on

the individual in a more exhaustive manner through a comprehensive assessment
that also consider social determinants of health (i.e. environment, social entourage
etc.), thus facilitating the implementation of tailored interventions. With this regard,
frailty might be used to identify multimorbid patients who need a comprehensive
and integrated intervention, instead of a traditional disease-oriented approach
[1, 7, 8].

11.2 Management of Multimorbidity

With increasing multimorbidity and frailty, the world of healthcare must reinvent
itself to find effective ways of dealing with complexity. As of today, medicine is still
single-disease oriented, an approach that appears obsolete when confronted with
today’s reality.
One of the main problems for multimorbid patients is represented by the frag-
mentation of care. Patients are often subjected to a large number of specialist visits
and treated with a large number of drugs. The models of care must be modified
to cope with this new type of patient. A new clinical approach is needed, and it
must be multidisciplinary-centred and focused on promoting individual’s
independence.
The complexity and heterogeneity of patients with multimorbidity and poly-
pharmacy make traditional guidelines often inadequate and not supportive in
decision-­making. An increasing number of studies have pointed out that disease-
specific guidelines are difficult to apply in multimorbid patients. This difficulty
arises primarily from how these guidelines are developed. Indeed, disease-specific
guidelines are developed on data collected with randomized clinical trials that
exclude fragile individuals a priori, to avoid confounding factors. Second, these
guidelines often do not account for other coexisting chronic diseases: drug–drug or
drug–disease interactions may easily occur in persons suffering from multiple
chronic conditions.
New guidelines have recently been developed (i.e. Ariadne principles, NICE,
JA-CHRODIS) for the management of the multimorbid patient. The first purpose
of these guidelines is to maximize the quality of life, focusing not on the symp-
tom nor the disease but on the individual as a whole. Those guidelines present
several commonalities. First, they try to identify a target population that can
benefit from the application of these principles (e.g. fragile individuals). In addi-
tion, they support the flexible use of existing guidelines on individual diseases,
focusing on treatment burden. Moreover, they theorize the importance of coordi-
nating all the different specialists involved in patient care, often via the special-
ized figure of the case manager, who acts as facilitator. Those guidelines also
focus on a shared decision-­making with the patient, in order to agree on an indi-
vidualized care plan. Lastly, they emphasize on patient and caregivers’ education
to improve self-management and self-efficacy. Below, we will analyze in more
detail the main points of the recent guidelines on the management of the multi-
morbid patient [6, 9].
11 General Principles of Management of Patients with Multimorbidity and Frailty 135

11.2.1 Target Population

Patients with multimorbidity are heterogeneous, and their global health status and
risk of negative outcomes may vary largely. Furthermore, the consequences of mul-
timorbidity cannot be linearly estimated on the basis of the number of clinical con-
ditions. In order to develop the best care plan for each individual patient, it is
important to be able to identify different care needs. Indeed, there are older adults
who, despite the presence of multiple coexisting chronic conditions, are in good
health and have a good life expectancy, so they must receive the standard level of
assistance, including preventive programs and appropriate diagnostic-therapeutic
interventions. On the other hand, there are patients who are more at risk of develop-
ing negative events and who, therefore, need specific treatment plans.
In the population with multimorbidity, stratification strategies carried out on the
basis of patterns of different diseases, presence of symptoms, and physical, cogni-
tive, and socio-economic status help to identify the most demanding and complex-­
to-­treat groups—those that might benefit most from individualized and integrated
healthcare plans. In this context, the assessment of frailty with appropriate instru-
ments (i.e. Frailty index, Clinical Frailty Scale, physical performance measures) can
be used to identify the most care-demanding groups that might benefit most from
individualized and integrated approaches. Both guidelines from the National
Institute for Health and Care Excellence on multimorbidity and Italian Guidelines
on Multimorbidity and Polypharmacy suggest to assess frailty status to identify
people with multimorbidity who are susceptible and at risk of negative health out-
comes, thus more likely to benefit from a patient-centred approach [3, 10, 11].

11.2.2 Assessing of Interacting Conditions and Treatments

The therapeutic management of the multimorbid patient can be extremely complex

and requires a holistic approach, which considers the individual in his/her entirety.
In multimorbid patients, who naturally take multiple prescriptions, various interac-
tions between disease and therapies can occur, which can lead to the onset of numer-
ous adverse events, including worsening of clinical conditions and the onset of new
symptoms that can complicate the patient’s therapeutic management. In this con-
text, the so-called cascades-effect—when additional medications are prescribed to
counteract side effects of other drugs—can take place and increase the burden of
pharmacological treatment.
Therefore, once the target population has been identified, it would be advisable
to make a multidimensional assessment of the patient, studying different aspects of
the patient’s life, including clinical conditions, adherence to medication, social con-
text and psychological status. In particular, the following aspects seem important to
develop an individualized approach to multimorbidity:

–– Diseases and health problems, including clinical and functional status, cognition,
geriatric syndromes, life expectancy, presence of any symptoms, their severity
and their impact on quality of life
136 C. Cocchi et al.

–– Psychosocial context
–– Treatment burden (pharmacological and nonpharmacological): evaluating poten-
tial interactions or adverse effect, adherence or underuse and treatment burden

All of these elements should be reviewed regularly, with special attention for
signs and symptoms of cognitive impairment and psychological or social problems,
since they could modify our intervention [3, 6, 10–13].

11.2.3 Incorporate Patient Preferences and Goal Setting

Since the management of the multimorbid patient is complex and challenging, the
identification of health priorities, shared between patients and care provider, repre-
sents a relevant step to provide individualized, patient-centred care. Decisions about
the patient’s health must be made in full agreement with patient and caregivers. It is
necessary to explain the purpose of the therapeutic approach and the realistically
achievable goals so that the patient can express his/her preferences based on per-
sonal values and priorities. When suggesting a treatment, the person’s prognosis
should always be taken into consideration, as well as the patient’s attitude towards
the treatment, his expectations and objectives. Monitoring and re-­discussing priori-
ties is fundamental, as they can change overtime [3, 6, 10, 11].

11.2.4 Individualized Management

After performing a comprehensive assessment and identifying shared and achiev-

able goals together, it is necessary to develop an individualized treatment plan with
the patient and the caregiver. Once a care plan has been discussed, it is necessary to
choose therapies that optimize benefits, minimize potential harms and enhance
quality of life. It is also important to consider treatment burden and all possible
interaction, considering not only other medications but also food and food supple-
ments as well.
Finding balance between the treatment of chronic disease and drug-related
harm is a key goal of drug prescribing but has proven difficult to achieve in clinical
practice. In fact, multimorbidity can modify the patient’s risks, harms or even the
potential treatment benefit. In addition, complex medications regimens are difficult
to comply with, so when planning a treatment, it is advisable to consider also the
patient’s/caregiver’s ability to adhere to it. The prescribing process should be indi-
vidualized and flexible, and it should be based upon using effective drugs, at the
minimum effective dose, with the lowest number of dosage units per day and daily
administrations. These interventions must be targeted health priorities identified
with the patient during the multidimensional assessment. The use of IT support
tools for the prescription can provide a valuable support to evaluate cumulative
drug toxicity, risk of interactions and adverse drug reactions and risk of fall [3, 6,
10, 11].
11 General Principles of Management of Patients with Multimorbidity and Frailty 137

11.2.5 Self-management

Multimorbid patients are the major users of healthcare resources, and their involve-
ment in disease management is a goal to be pursued. Self-management of chronic
diseases is a treatment process characterized by the responsible and proactive par-
ticipation of the patient himself, allowing the patient to be aware of his own health
condition and empowering his/her involvement in the therapeutic decision-making
process. Self-management represents a fundamental lever for the effectiveness and
efficiency of the health system. On the assumption that knowledgeable and expert
patients are able to manage their quality of life to the fullest of their potential, edu-
cational programs are useful to enable patients to acquire a central role in the man-
agement of his own health. Many patients who have lived with chronic diseases for
years can be trained to manage the disease and take active responsibility of both non
pharmaceutical (i.e. diet, physical exercises) and pharmaceutical (i.e. use of medi-
cations) management [3, 6, 10, 11].

11.2.6 Monitoring and Follow-Up

Patients with multimorbidity often receive disjointed care, which leads to ineffi-
cient, ineffective and possibly harmful clinical interventions. Ideally, care for
patients with multimorbidity should involve numerous healthcare professionals,
include various dimensions (clinical, functional and social), and be based on solid
evidence. A careful coordination by a case manager of the various healthcare pro-
fessionals is therefore essential.
Care plans for multimorbid patients are not static, but they can often change due
to a change in the patient’s priorities, to the onset of new problems or as a result of
co-occurring events. This is why it is important to re-evaluate the patient, especially
after hospitalizations or the prescription of new drugs [3, 6, 10, 11].

11.3 Treatment of Chronic Diseases and Multimoridity

in Frail Patients

As mentioned earlier, the identification of frailty is a key step to stratify the popula-
tion with multimorbidity and to identify patients that need an individualized care
approach. In particular, the use of symptomatic and preventive drugs in persons with
frailty should be evaluated carefully based on several considerations.

11.3.1 Symptomatic Treatment of Diseases in Frailty

Symptoms related to chronic diseases might have a relevant role in the onset or
worsening of frailty status, and the treatment of these symptoms might potentially
reverse frailty. For example, pain is a strong determinant of frailty in patients with
138 C. Cocchi et al.

osteoarthritis and it could be considered as a component of the frailty phenotype.

Pain impacts on walking ability, speed, and strength and consequently cause a
reduction in physical activity levels. These parameters are all criteria used to assess
Fried’s phenotype and can contribute to the development of frailty. In addition, pain
increases the risk of falls, causes depression, reducing the individual’s quality of life
and consequently precipitating the onset of frailty. Therefore, the pharmacological
treatment of pain could virtually reverse the frailty status.
Similarly, Parkinson’s disease is often associated with frailty, and its symptom-
atic treatment (e.g. levodopa) might have an impact on frailty status. Medications
used for symptomatic treatment of Parkinson’s disease impact on the motor symp-
toms, improving walking ability and speed and potentially reducing the risk of
exhaustion and falls, with great benefit in persons with frailty.
Another example is dyspnoea. This condition could lead to physical inactivity,
loss of skeletal muscle strength, mobility problems (including walking deficits) and
ultimately frailty. For this reason, an optimized treatment of dyspnoea might reduce
frailty progression.
Despite a beneficial effect of treatment of pain, motor symptoms of Parkinson’s
disease and dyspnoea on frailty seem clinically obvious, studies providing evidence
on this association are currently lacking [14].

11.3.2 Preventive Treatment of Diseases in Frailty

Treatment of chronic diseases might have an impact on the onset of frailty by pre-
venting the occurrence of negative health events. For example, it would be reason-
able to hypothesize that pharmacological treatment of frail persons who experienced
a bone fracture may prevent the onset of new fractures and reduce the risk of frailty
and disability. However, evidence has suggested lack of benefit from treatment with
bisphosphonates on fractures and mortality in frail women in nursing home.
Similarly, possible benefits related to preventive pharmacological treatment of
hypertension on frailty onset are still being discussed. In observational studies,
hypertension does not seem to have an impact on frailty, and the negative effects of
antihypertensive treatment seem to be more pronounced in patients with frailty. In
addition, the negative effects of hypertension on health outcomes might be reduced
in the presence of frailty, suggesting a reverse epidemiology phenomenon in patients
with frailty.
The example of hypertension could also apply to other chronic diseases, where
the pros and the cons of intensive pharmacological treatment in frailty are still
debated, and any possible positive effects might be counterbalanced by an increased
risk of negative effects. Indeed, treatment of chronic diseases in frail individuals
may raise several concerns that might alter the risk/benefit ratio of a given treatment
(Table 11.2).
11 General Principles of Management of Patients with Multimorbidity and Frailty 139

Table 11.2 Factors challenging pharmacological treatment of chronic diseases in the presence of
frailtya
Problem Consequences Potential solutions
Exclusion of frail Uncertainties about the Inclusion of frail patients in RCTs;
persons from studies efficacy and safety of Evidence from observational studies
treatment in frail persons
Reduced life expectancy Reduced/absent Assess life expectancy;
in frail persons beneficial effects Evaluate risk-benefit ratio of treatments
Increased susceptibility Higher rate of adverse Periodic therapeutic review and
to iatrogenic events due drug events reconciliation;
to intensive treatment Evaluate risk-benefit ratio of treatments;
Focus treatment on specific goals
Functional deficits Poor medication Assess the capacity of patients to
associated with frailty adherence; self-manage their medication regimen;
Medication errors Focus treatment on health priorities;
Adjust communication strategies;
Use of tools to improve adherence;
Reduce number medications and
medication regimen complexity
(frequency of medication
administrations, use of appropriate dose
forms)
a
Tables 1 and 2 inspired by Onder G. (coauthor of this work), Vetrano DL et al. “Accounting for
frailty when treating chronic diseases”. Consent obtained by other coauthors via email

Exclusion from studies. Frail older people are often excluded from randomized
clinical trials assessing the effects of treatments for chronic diseases. Practical limi-
tation—difficulties in reaching the research centre—or and higher mortality rates
that prevent having appropriate follow-up times may in part justify this exclusion.
However, this limits the generalizability of clinical trial findings and estimation of
the efficacy and safety of treatments for chronic diseases in persons with frailty.
Limited life expectancy. Frailty is associated with limited life expectancy; esti-
mates from the SHARE study suggests that life expectancy for frail individuals at
age of 70 years ranges between 0.1 and 1.8 years in men and between 0.4 and
5.5 years in women. This suggests that several preventive treatments for chronic
disease might have limited benefits in persons with frailty, given that the time-until-­
benefit might exceed the actual life expectancy in frail individuals. In frail popula-
tions, it is essential to assess life expectancy, evaluate the risk/benefit ratio of
treatments and consider discontinuing medications aimed at prolonging life or pre-
venting adverse clinical events if the time needed to obtain the expected benefits is
longer than the estimated life expectancy and when they do not offer symptomatic
benefits.
Increased risk of negative outcomes from intensive treatment. Frailty is associ-
ated with an increased risk of negative events associated with pharmacological
treatments. Some of the current guidelines for the treatment of chronic diseases
140 C. Cocchi et al.

acknowledge this increased risk of negative events. For example, guidelines for
treatment of type II diabetes supports the adoption of less strict blood glucose tar-
gets in frail patients, given the increased risk of hypoglycaemia without accruing
meaningful benefit for frail older adults.
Ability to adhere. Functional deficits related to frailty might be associated with
unintentional non-adherence through reduced ability to manage pill containers,
open child-resistant containers and/or split tablets. Functional impairment may
reduce the ability to adhere to a complex medication regimen and in case of poly-
pharmacy, increase the risk of medication errors and limit the capacity to self-report
adverse drug events. Treatment of chronic diseases in frailty should be simplified
and focused on clinical priorities, established by the patient and his/her physician.
Communication strategies should be implemented to empower and educate frail
patients and their caregivers on how to properly take a medication, discussing with
patients and caregivers about the importance of medication adherence, providing
information about health and associated treatments and suggesting the use of aids
(i.e. pill boxes) to improve adherence. Medication regimen complexity can often be
reduced through consolidating the number of dose times and using long-acting for-
mulations where appropriate [14].

11.4 Treatment of Multimorbidity and Frailty in the Precision

Medicine Era

Precision medicine, as suggested by the Precision Medicine Initiative, is an innova-

tive approach to provide personalized care focused on individual characteristics and
deliver the most appropriate one by taking into consideration individual variability in
genes, environment and lifestyle. This is opposed to the more common “one-size-
fits-all” approach, whereby treatment and prevention strategies are developed for an
average person. The precision medicine approach could represent an epochal change
in the field of chronic diseases and a breakthrough in research and clinical trials per-
formed in the last 30 years that assess the average effect of a given treatment with
little consideration for individual differences. However, so far this approach has been
poorly implemented in the multimorbidity field for several reasons.
First, precision medicine approach has been successfully applied in the treatment
of mono-factorial diseases, in which it is easier to identify a single, potentially tar-
getable, predictor of the disease. This may explain the wide application of precision
medicine for the treatment of some diseases, especially cancer, and possible diffi-
culties in implementing this approach to the care of multifactorial conditions, such
as multimorbidity. Second, there is lack of a clear understanding of risk factors
contributing to the onset and evolution of multimorbidity. A personalized approach
to multimorbidity prevention and treatment would require the presence of reliable
biomarkers and a systematic investigation of potential risk factors. Third, precision
medicine is mainly focused on understanding genetic aspects of diseases, under-
mining other characteristics that are important to define profiles of frail multimorbid
individuals. Such clinical and non-clinical characteristics (i.e. function and living
11 General Principles of Management of Patients with Multimorbidity and Frailty 141

environment, education and social capital, lifestyle) represent key elements of care
in the approach to multimorbidity and can influence treatment adherence and suc-
cess. This approach focuses on identifying multiple targetable risk factors of multi-
morbidity and individual pathways that could drive effective interventions and
tailored management of the persons with multimorbidity, in line with the principles
of precision medicine.
At the same time, however, numerous different individual pathways may lead to
the development of different multimorbidity phenotypes, characterized by several
combinations of individual factors. A clear understanding interplay and interaction
between these factors might be extremely complex, making the definition of indi-
vidual and personalized interventions challenging. Given multimorbidity heteroge-
neity, a possible solution to simplify the application of precision medicine to this
condition is to reduce the dimensionality of its complexity and to find homogeneous
patterns that may work as effective targets of preventive and therapeutic strategies.
Focusing on clusters of chronic diseases could represent a useful strategy aiming to
identify diseases that co-occur in the same person beyond chance. Diseases tend to
cluster together because they share common risk factors and pathophysiological
mechanisms or because one disease is the direct cause of another. Knowing how and
why diseases cluster together can lead to the development of preventive and thera-
peutic strategies targeting specific but common pathways. At the time of writing,
applying precision medicine to specific clusters of diseases remains a work in prog-
ress that requires further research including the analyses of large epidemiological
and biological datasets investigating the interplay between genetic disease predis-
position and personal and environmental determinants of multimorbidity such as
gender, social and living factors, performance status, education and lifestyles. More
information is needed to identify specific factor or combination of factors that need
to be systematically assessed in individuals with specific clusters of diseases and
understand how these factors also interact at an individual level. This approach
could help define interventions that might comprehensively target multimorbid-
ity [15].

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Frailty and Drug Therapy
12
Annette Eidam, Matteo Cesari, and Jürgen M. Bauer

12.1 The Concept of Frailty

Frailty is a complex, multidimensional geriatric syndrome [1]. The theoretical con-

cept of frailty was formally defined in 2013 by an international group of experts as
“A medical syndrome with multiple causes and contributors that is characterized by
diminished strength, endurance, and reduced physiologic function that increases an
individual’s vulnerability for developing increased dependency and/or death” [2].
This theoretical framework embraces different operational models that have been
proposed over the years, especially since the beginning of this century. These mod-
els try to determine the main characteristics of the frailty condition, paving the way
for its assessment in the clinical and research settings through the development of
ad hoc instruments. The most widely known and adopted models of frailty are [3]:

–– The physical phenotype model. Proposed in 2001 by Fried and colleagues [4],
this model is based on the evaluation of five signs/symptoms (i.e., exhaustion,
slowness, muscle weakness, involuntary weight loss, sedentary behavior) pheno-
typically describing the frail individual. Older adults who are negative for all
these criteria are considered robust, those who are positive for one or two are
considered prefrail, and those who are positive for three or more are consid-
ered frail.
–– The accumulation of health deficit model. This model was proposed by Mitnitski
and colleagues in 2001 [5]. It stems from the observation that the aging process

A. Eidam (*) · J. M. Bauer

Center for Geriatric Medicine, Heidelberg University Hospital, Agaplesion
Bethanien Hospital, Heidelberg, Germany
e-mail: [email protected]
M. Cesari
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

© Springer Nature Switzerland AG 2023 143

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_12
144 A. Eidam et al.

is associated with an accumulation of health deficits (i.e., signs, symptoms, dis-

eases, disabilities, laboratory abnormalities). The so-called Frailty Index is quan-
titatively computed by the ratio between the deficits the person presents and the
number of potential deficits evaluated during a comprehensive assessment. It
estimates the biological age and the proximity of death (due to the unsustain-
ability of the deficits accumulation with life).

However, there is still an ongoing discussion on the best method for diagnosing
frailty, in clinical practice and in research as well [6]. Besides the physical pheno-
type and the Frailty Index, a large number of other instruments to assess frailty have
been developed and are used, with the exception of the Clinical Frailty Scale mostly
in research settings. Examples include the Edmonton Frail Scale and the Groningen
Frailty Indicator [7].
Independently of the preferred model for its operationalization, frailty has been
acknowledged by the scientific community not only as a clinically relevant condi-
tion associated with major adverse health outcomes (e.g., hospitalization, institu-
tionalization, disability, falls, death [8]) but also as a valuable approach that can
improve the care of older persons [9]. In fact, it has become evident that chronologi-
cal age does not adequately capture the heterogeneity of the biological, clinical, and
social background of older persons [10]. Furthermore, a preference of chronological
age over biological age in the clinical decisional process may increase ageism in
medicine by excluding older persons from preventive and therapeutic options. In
other words, frailty may represent an alternative approach for measuring the indi-
vidual’s biological age.
The detection of frailty and the exploration of its underlying causes are critical
for the proper management of the older person. It means understanding whether the
individual, regardless of his/her age, is biologically fit to sustain and benefit from
standard interventions or whether an adapted approach with potentially different
treatment strategies and objectives should be put in place. The adapted approach
may include the design of a personalized plan aimed at solving potentially revers-
ible barriers to restore (at least, partially) robustness to allocate the highest stan-
dards of care. Such an adapted approach should also acknowledge the particular
vulnerabilities of the frail older patient.
In this context, the evaluation and management of frailty play an important
role in the drugs prescription. The holistic approach needed to identify the under-
lying causes of frailty (i.e., the comprehensive geriatric assessment) allows to
measure the priorities, needs, and resources of the individual [8]. This approach
supports the clinician in the therapeutical choice by allowing a more informed
evaluation of the risk–benefit profile of their frail patient. However, it cannot be
overlooked that frail older persons are often excluded from randomized con-
trolled trials given their complexity [11]. For this reason, the conduction of evi-
dence-based medicine and prescribing in this population are frequently
challenging. Frailty may, thus, become a condition to weigh the endogenous and
exogenous factors potentially interfering with the “one-fits-all” approach typical
12 Frailty and Drug Therapy 145

of traditional medicine, supporting the delivery of a person-centered model of

care and pharmacotherapy.

12.2 Influence of Frailty on Pharmacokinetics

As outlined above, frailty may be regarded as a proxy estimate of individual biologi-

cal age [12]. Therefore, age-related changes in pharmacokinetics (Chap. 1) are
likely to be more distinct in frail than in robust older adults [13], which may put frail
older patients at a higher risk for inappropriate dosing and adverse drug reactions
[14]. However, evidence from studies that compared pharmacokinetics in robust
and frail older adults is still sparse [15].
Pathophysiological changes associated with frailty may affect pharmacokinetic
processes, including the absorption, distribution, metabolism, and elimination of
drugs [13]. Physical frailty has a pronounced overlap with sarcopenia (Chap. 13)
[16]. Sarcopenia has been defined as a geriatric syndrome characterized by low
muscle strength in combination with low quantity and quality of skeletal muscle
[16]. In addition, it may be associated with an increase in fat mass [17]. These
changes in body composition may alter the volume of distribution of both lipophilic
and hydrophilic drugs. In this context, the volume of distribution of lipophilic drugs
would be expected to increase, whereas the volume of distribution of hydrophilic
drugs would be expected to decrease [13]. However, empirical data describing the
pharmacokinetics of hydrophilic drugs in frailty have been inconsistent. Using the
Reported Edmonton Frail Scale to define frailty, Hilmer and colleagues reported
that the volume of distribution of gentamicin did not differ between frail and non-­
frail older participants [18]. On the other hand, Bendayan and colleagues found that
lower appendicular lean mass was associated with supratherapeutic apixaban or
rivaroxaban peak and trough concentrations in older adults. The authors attributed
this increase in plasma concentrations to a decreased volume of distribution of the
hydrophilic direct oral anticoagulants in frail individuals with reduced skeletal mus-
cle mass [19].
Age-related physiological changes that could affect hepatic metabolism, such as
the reduction in liver size and hepatic blood flow, might be more pronounced in
frailty [13]. In addition, frailty is associated with a state of chronic inflammation
[20]. Because inflammatory markers such as interleukin-6 may reduce the expres-
sion of certain cytochrome P450 (CYP) enzymes [21], phase I drug metabolism via
these enzymes could be inhibited in frailty. However, two studies examining the
activity of CYP3A and CYP2D6 in frail versus robust older adults failed to demon-
strate a reduced CYP activity in their frail participants [22, 23]. On the other hand,
Hubbard and colleagues found that the activity of different drug metabolizing
plasma esterases was reduced in individuals with frailty, probably because of the
underlying chronic inflammatory state [24].
Renal failure is highly prevalent in frail older persons [25]. Because of the accel-
erated decrease in muscle mass in frail persons, estimations of glomerular filtration
rate (GFR) based on creatinine are likely to underestimate the degree of renal failure
146 A. Eidam et al.

in this population compared to estimations based on cystatin C [25, 26]. There has
been emerging evidence that the difference between estimated GFR based on cys-
tatin C and estimated GFR based on creatinine might suggest the presence of frailty
[27, 28]. Given the high number of renally eliminated drugs used by frail older
patients, careful dose adaptation appears to be particularly relevant in this popula-
tion [13, 25].
To date, only a limited number of pharmacokinetic studies have used validated
frailty assessments to characterize their study populations [15]. So far, Fried and
colleagues’ physical phenotype of frailty [22–24] and variants of the Edmonton
Frail Scale [18, 26, 29, 30] remain the most frequently used assessment instruments
in this context. A small number of studies have used disease-specific assessments
(International Myeloma Working Group Frailty Score [31]) or functional parame-
ters (grip strength [26]) to evaluate the presence of frailty. Applying a standardized
assessment to measure frailty would be essential for future pharmacokinetic studies,
as this approach would facilitate the comparison across studies [15]. At present,
many instruments are used to diagnose frailty, which differ significantly in their
components and consecutively in the populations that are interpreted as being frail
[7, 32]. It remains to be identified which frailty criteria would be particularly rele-
vant to pharmacokinetics in older persons and could support optimized dosing
schemes in this patient group.

12.3 Frail Populations in Clinical Trials

Age-sensitive eligibility criteria often exclude older adults from clinical drug trials
[33]. A recent evaluation found that almost 80 % of adults with elevated blood pres-
sure aged ≥ 80 years met at least one exclusion criterion of two major clinical trials
that informed guideline recommendations for arterial hypertension [34]. Frail older
adults are particularly underrepresented in clinical trials [35]. Moreover, trials that
include a relevant number of older adults usually do not assess and report on the
participants’ frailty status [35]. As frailty is associated with both mortality [36] and
adverse drug reactions [14], the therapeutic outcome and especially the risk–benefit
ratio of drug therapy might differ significantly in frail compared to robust older
persons. Therefore, it is essential to include older adults in clinical drug trials and
characterize older study populations regarding their functionality, including frailty.
In the absence of standardized baseline frailty assessments of clinical trial popu-
lations, several research groups have attempted to identify frail study participants
retrospectively. By including a 26-item frailty index in a pooled analysis of 14 mul-
ticenter trials of primarily cardiovascular medicines, Farooqi and colleagues found
that frail participants had a higher risk of cardiovascular events, cardiovascular mor-
tality, and all-cause mortality than non-frail participants [37]. Using a 40-item
frailty index, Hanlon and colleagues reported that mild to moderate frailty was
unexpectedly common in phase 3/4 trials of drug therapies for rheumatoid arthritis,
type 2 diabetes mellitus, and chronic obstructive pulmonary disease [38]. Brefka
and colleagues proposed a categorization for the retrospective identification of older
12 Frailty and Drug Therapy 147

study participants with functional impairments [39]. Including 51 assessments of

physical frailty and functionality in their analysis, the authors defined specific cut-
offs for four levels of functional impairment, which were designated as “indepen-
dent,” “slightly impaired,” “significantly impaired,” and “severely impaired/
disabled/dependent” [39]. The application of this retrospective categorization may
help compare treatment evidence between studies that used different instruments to
assess frailty and functional status in general [39].
Applying the classification by Brefka and colleagues, two systematic reviews
revealed evidence gaps in the pharmacological treatment of two common chronic
diseases in frail older persons: hypertension and type 2 diabetes mellitus [40, 41].
The authors could not identify a single randomized clinical trial (RCT) that had
assessed the effectiveness and safety of antihyperglycemic drug therapy in frail
older adults [41]. Concerning antihypertensive treatment, they identified two RCTs
that assessed functional status and two RCTs that applied validated frailty assess-
ments [40]. Warwick and colleagues reported that the positive effects of antihyper-
tensive treatment with indapamide ± perindopril on the risk of stroke, cardiovascular
events, and total mortality were preserved in a separate analysis of frail individuals
that participated in the “HYpertension in the Very Elderly Trial” (HYVET) study
[42]. In an exploratory secondary analysis in participants aged ≥ 75 years of the
“Systolic Blood Pressure Intervention Trial” (SPRINT), absolute event rates of car-
diovascular and mortality outcomes were lower in the intensive treatment group in
both slow and normal walkers and all frailty index groups compared with the stan-
dard treatment group [43].
There are emerging efforts from regulatory agencies to provide guidance on how
to address frailty in clinical trials. For example, in 2018, the European Medicines
Agency (EMA) published a “Reflection paper on physical frailty” [44]. In this
paper, EMA recommended the “Short Physical Performance Battery” (SPPB) for
baseline characterization of older adults in clinical trials or other clinical investiga-
tions [44]. The SPPB takes 10–15 min when applied in an older individual, and it
measures lower extremity performance with three subtests: standing balance, gait
speed, and chair rise test [45]. If the complete SPPB is not feasible, EMA encour-
ages the isolated use of gait speed as an alternative to assess baseline physical func-
tion [44].
Up to now, the assessment of frailty is still uncommon in ongoing clinical drug
trials, and if it is included, different assessment instruments might be chosen,
thereby complicating the comparison of results. The “PRagmatic EValuation of
evENTs And Benefits of Lipid-lowering in oldEr Adults” (PREVENTABLE) trial
(https://clinicaltrials.gov/ct2/show/NCT04262206) examines the benefit of atorvas-
tatin 40 mg for reducing the risk of dementia and chronic disability in community-­
dwelling adults aged ≥ 75 years. In this trial, the SPPB is applied for baseline
characterization of the study population. The “Switching anticoagulant manage-
ment from a VKA to a NOAC-based treatment strategy in frail elderly patients with
atrial fibrillation” (FRAIL-AF) study (https://www.clinicaltrialsregister.eu/ctr-­
search/trial/2017-­000393-­11/NL) assesses the safety of switching from a vitamin K
antagonist to a direct oral anticoagulant in adults aged ≥ 75 years with atrial
148 A. Eidam et al.

fibrillation and a score ≥ 3 on the Groningen Frailty Indicator [46]. Few studies
focus on frailty as an outcome parameter of drug therapy. The phase 2 trial
“Metformin for Preventing Frailty in High-risk Older Adults” (https://clinicaltrials.
gov/ct2/show/NCT02570672) investigates whether regular intake of metformin
could prevent the progression of frailty status in robust and prefrail older adults with
prediabetes [47]. In this trial, Fried and colleagues’ physical phenotype is used.

12.4 Measuring Frailty in Healthcare Databases

In the absence of sufficient evidence from randomized controlled trials, researchers

have turned to routine healthcare databases, for example, administrative claims
data, to analyze outcomes of drug therapy in frail older patients. Routine healthcare
databases offer real-world longitudinal data from large populations that include
individuals with frailty [48]. However, as clinicians in most countries do not rou-
tinely assess and encode frailty, surrogate measures are needed to identify frailty in
healthcare databases [48]. Several research groups have developed frailty indicators
that each include a set of proxy variables for frailty, such as codes for frailty-related
diagnoses and procedures and demographic variables such as age [48]. The Johns
Hopkins claims-based frailty indicator was validated against the physical phenotype
of frailty. It predicts adverse outcomes such as death and nursing home admission
[49]. The claims-based frailty index by Kim and colleagues is based on the deficit-­
accumulation concept of frailty [50]. It has been validated in a Medicare data sam-
ple against physical performance measures (grip strength, gait speed) and several
adverse health outcomes [50]. The electronic frailty index is also based on the frailty
model of deficit accumulation. It has been developed and validated using two large
primary care databases in the United Kingdom [51]. Since 2017, the National Health
Service England has mandated that general practitioner’s offices screen patients for
frailty via the application of the electronic frailty index or other validated frailty
measures [52] with the final aim of allocating ad hoc preventive strategies (includ-
ing medication reviews and possible deprescribing).
Direct oral anticoagulants (DOAC) may serve as an example that illustrates how
analyses of healthcare databases provide relevant evidence on outcomes of drug
therapy in frail older patients. Both the Johns Hopkins claims-based frailty indicator
and the claims-based frailty index have been used to generate data on the effective-
ness and safety of treatment with direct oral anticoagulants in older patients with
frailty and atrial fibrillation [53–56]. In a large 1:1 propensity score-matched analy-
sis in Medicare beneficiaries aged ≥ 65 years, Kim and colleagues found that frailty
levels affected the association of DOAC versus warfarin therapy with the composite
primary endpoint (death, ischemic stroke, or major bleeding) [56]. Whereas hazard
ratios in the dabigatran and rivaroxaban groups were lower compared to warfarin in
the non-frail but not in the prefrail and frail older patients, therapy with apixaban
showed consistent relative reductions across all three frailty levels [56].
12 Frailty and Drug Therapy 149

12.5 The Complex Relationship of Frailty and Polypharmacy

Polypharmacy is highly prevalent in prefrail and frail older individuals [57].

Although there has been no universally accepted definition of polypharmacy, it is
most commonly defined as the chronic intake of five or more medicines [58]. Some
authors use the added term hyperpolypharmacy, usually defined as the regular intake
of 10 or more medicines [58]. Polypharmacy has been linked to several adverse
outcomes in older patients, including hospitalization and inappropriate prescribing
[59]. There is an ongoing debate whether polypharmacy might also contribute to the
development of frailty. While there is a strong association between frailty and poly-
pharmacy in cross-sectional analyses, only a limited number of longitudinal studies
have examined the relationship of polypharmacy with incident frailty [57]. In a
cohort of community-dwelling adults, participants with polypharmacy or hyper-
polypharmacy at baseline were at a higher risk of developing frailty within 3 years
[60]. This finding was independent of the number and the severity of the partici-
pants’ comorbidities [60]. In a meta-analysis of three longitudinal studies that used
identical criteria for defining frailty (Fried physical phenotype) and polypharmacy
(≥ 5 drugs), robust individuals with baseline polypharmacy had a significantly
higher risk of prefrailty at follow-up [57].
Considering the limited evidence resulting from longitudinal studies, the causal
relationship between frailty and polypharmacy may still be regarded as undeter-
mined. It has also been described as a “chicken and egg” scenario [61]. Most authors
have assumed a bidirectional relationship between both entities [57, 61–63]. Frail
older individuals are more likely to suffer from multiple chronic conditions than
their robust counterparts [64], and multimorbidity itself may lead to polypharmacy
[65]. Yet, there are several mechanisms through which medicines and polypharmacy
may interfere with the pathogenesis of frailty. Polypharmacy and specific drug
classes might cause malnutrition and weight loss [66]. Certain drugs increase the
risk of experiencing a fall [67], and falls and fall-related injuries could precipitate a
decline in functionality and overall physical activity in older adults [68]. Several
drug classes, for example, anticholinergics and benzodiazepines, could negatively
affect cognitive performance in older adults [69, 70], while cognitive impairment
may be considered an element of the frailty concept [71].
However, the positive association between frailty and polypharmacy or hyper-
polyharmacy may not apply to every setting. Cross-sectional studies found that
polypharmacy was less common in frail older nursing home residents than in non-­
frail residents [72], or they failed to find an association between both variables in
this population [73]. This observation may reflect both inappropriate underprescrip-
tion and an appropriate shift of focus from preventive to primarily symptomatic
drug prescribing in this population [72, 73].
150 A. Eidam et al.

12.6 Adverse Drug Reactions and the Development of Frailty

As indicated in the previous paragraph, polypharmacy is associated with inappro-

priate prescribing [59], and adverse drug reactions due to low-quality prescribing
might contribute to the development of frailty in patients with polypharmacy.
Several drug classes have been implicated in the development of frailty. Most
research in this area has focused on medicines with potentially unfavorable adverse
effects in older adults, the so-called “Potentially Inappropriate Medications”, such
as anticholinergics and sedatives.
In a cross-sectional analysis in older community-dwelling veterans, frailty was
associated with both past and current exposure to strong anticholinergic drugs as
defined by the Anticholinergic Cognitive Burden Scale [74]. In a cross-sectional
analysis of the Australian Longitudinal Study of Aging, users of anticholinergics
and sedatives had higher odds for frailty and components of frailty such as slower
walking speed [75]. After adjusting for polypharmacy, the prescription of anticho-
linergics was found to be the only potentially inappropriate medication significantly
associated with frailty in a French cross-sectional analysis [76].
Longitudinal data focusing on a possible causal relationship between certain
medicines and frailty are again limited. In an Australian cohort study in community-­
dwelling men aged ≥ 70 years, the Drug Burden Index was used to measure expo-
sure to medicines with anticholinergic and sedative properties. Drug Burden Index
exposure at baseline increased the risk of developing frailty within 2 years. Every
unit increase in the Drug Burden Index was associated with an increased risk of
transitioning from the robust state to prefrailty [77, 78]. In a prospective population-­
based cohort study in community-dwelling older adults from Germany, use of spe-
cific drug classes from the 2015 Beers criteria (anticholinergics, benzodiazepines,
z-substances, and antipsychotics) was significantly associated with prevalent frailty
and showed a nonsignificant association with incident frailty [79]. In a French lon-
gitudinal study in community-dwelling older adults, prescription drug use to man-
age pain and insomnia was associated with incident frailty [80].
Trials on the effect of deprescribing might further examine the relationship
between frailty and high risk prescribing and polypharmacy [60, 78]. Deprescribing
is the supervised withdrawal of an inappropriate medication to manage polyphar-
macy and improve outcomes [81]. Mach and colleagues realized an interesting pre-
clinical study that may contribute to the current discussion on frailty and drug
therapy, examining deprescribing in a mouse model of polypharmacy [82]. The
authors found that in male mice, polypharmacy significantly increased frailty only
in combination with a high Drug Burden Index exposure. With deprescribing, the
authors observed a significant reduction in the animals’ frailty score compared to
continued treatment [82].
12 Frailty and Drug Therapy 151

12.7 Frailty and Medication Management

12.7.1 Deprescribing

There has been a growing interest in the concept of deprescribing and in withdraw-
ing potentially harmful and/or unnecessary medicines in older adults, particularly in
those with frailty. Current research focuses on the question, whether deprescribing
might be feasible without causing a negative impact on favorable health outcomes
and whether it might reduce adverse drug reactions that contribute to frailty.
Several instruments have been developed to address deprescribing in frail older
adults [83]. Such instruments may offer a framework for targeting deprescribing, a
deprescribing approach for the patient’s entire medication list, or guidance on
deprescribing specific medications [83]. Some deprescribing instruments have been
developed for a particular subgroup within the frail population. For example, in
2017, Lavan and colleagues published the Screening Tool of Older Persons
Prescriptions in Frail adults with limited life expectancy (STOPPFrail) [84]. They
later provided an updated version of this tool [85]. STOPPFrail has been designed
to support physicians with deprescribing medications in older patients living with
severe frailty who approach the end of their lives. This tool, therefore, only applies
to this specific group of frail individuals. It does not apply to all frail patients and
especially not to prefrail individuals. The tool was validated using the Delphi con-
sensus methodology [84, 85], and currently includes 25 deprescribing criteria [85].
The evidence from empirical studies examining the practicality and the benefits
and harms of deprescribing in older patients with frailty is still limited, and com-
parison of deprescribing studies in frail older individuals is complicated due to het-
erogeneity in interventions, outcome measures, and frailty criteria [86]. Nevertheless,
though still incomplete, existing research indicates that deprescribing in this patient
group might be both feasible and safe as well as beneficial [86].

12.7.2 Medication Underuse

Frailty is not only associated with polypharmacy and the prescription of potentially
harmful medicines but also with potential prescribing omissions and underprescrip-
tion of potentially beneficial medicines. The individual frailty status may affect the
decision whether to start or to withhold anticoagulation therapy in older adults with
atrial fibrillation [87, 88]. A retrospective cohort study found that between 2009 and
2018, the prescription of anticoagulants had increased in patients with nonvalvular
atrial fibrillation who met guideline indications for anticoagulation [89]. However,
this increase was less pronounced in the frail population [89]. Initiation of statin
treatment after acute coronary syndrome was inversely correlated to the degree of
frailty in older patients [90]. In a prospective population-based cohort study in older
adults, underuse of preventive cardiovascular medicines was significantly associ-
ated with frailty [91].
152 A. Eidam et al.

Medication underuse in frail older individuals could reflect a degree of ageism

and indicate true undertreatment [73]. On the other hand, underuse might also be
rational and result from a patient-centered prescribing process that considers
expected time-to-benefit, individual risk profiles, and a shift in therapeutic goals [73].

12.7.3 Medication Optimization

In the absence of robust evidence on the impact of medication optimization on

frailty and favorable health outcomes in frail older adults [92, 93], there is currently
no standardized approach to optimal medication management for this group of
patients. Under these circumstances, recommendations derived from expert group
discussions may serve as guiding principles. The Optimizing Geriatric
Pharmacotherapy through Pharmacoepidemiology Network published a list of
international consensus principles for medication management in frail older adults
[94]. Key recommendations for medication management in clinical practice call on
providers to (1) reconcile the patient’s medications, resulting possibly from dif-
ferent prescribers, and to keep an up-to-date medication list, (2) consider the
patient’s capacity for self-management of their medication, and (3) guarantee
appropriate prescribing and deprescribing [94]. Medication regimen complexity
is known to increase with the degree of frailty [95], and clinicians should (4) con-
sider simplifying a frail patient’s medication regimen [94]. Because common
symptoms in older adults could be drug-related, healthcare professionals should (5)
pay vigilance to the contribution of medicines in the development of geriatric
syndromes, such as delirium and incontinence [94].
Given the lack of evidence from randomized controlled trials and because of
potential trade-offs between competing health outcomes, individuals with multiple
chronic conditions, polypharmacy, and frailty usually face several preference-­
sensitive decisions concerning their medication. Although data specifically focusing
on older patients with frailty are lacking, evidence from studies in older adults with
multiple chronic conditions and/or polypharmacy suggests that preference-based
prescribing could reduce treatment burden and the number of health complaints
affecting daily life as well as improve health-related quality of life [96, 97].
Clinicians are asked to (6) regularly repeat medication reviews and adapt the
patients’ medication to their changing goals of care, and (7) promote multidisci-
plinary communication and include patients, caregivers, and other healthcare pro-
fessionals in the medication management process [94].

12.8 Knowledge Gaps

Although frailty is a highly relevant geriatric syndrome, evidence on drug therapy

in frail older adults is still limited. In addition to providing critical recommenda-
tions for practical medication management in individuals with frailty (Sect. 12.7.3),
the Optimizing Geriatric Pharmacotherapy through Pharmacoepidemiology
12 Frailty and Drug Therapy 153

Network has named international consensus principles for research activities in this
context. The authors emphasize the need to include frail older adults in randomized
controlled trials and identify strategies that would improve recruitment and reduce
dropout rates in this population [94]. Research studies should include outcome mea-
sures that reflect the priorities of frail older patients by focusing both on physical
health and on social well-being, such as physical and cognitive function as well as
functional independence [94]. Moreover, the authors encourage research in the
nursing home setting, which has been particularly underrepresented in clinical stud-
ies despite the fact that nursing home residents carry a notably high medication
burden [94].
Frailty might be a better predictor of an individual’s response to drug therapy than
chronological age, and frailty is likely to modify the effect and risk–benefit profile of
medicines [94, 98]. However, reflecting the lack of an international consensus on the
diagnostic criteria of frailty, it is still unclear which frailty assessment could be best
suited for application in drug trials and for evaluating the effects of polypharmacy in
the older population. Although different frailty measures correlate significantly with
each other, different frail populations are identified by the various assessment tools
[99, 100]. However, the best choice might differ between study settings, as the physi-
cal, cognitive, emotional, or social domains of the frailty construct are likely to be of
varying relevance to pharmacokinetic studies, randomized controlled drug trials, or
studies examining medication management strategies. Furthermore, the choice of the
instrument for the detection of frailty should also be made considering the interven-
tion and resources that will be allocated if the screening result is positive.
Frail older adults carry an exceptionally high medication burden. Without com-
prehensive evidence on the benefits and the risks of drug therapy in this patient
group, prescribing in frail older individuals is likely to be inadequate and potentially
harmful. Academic researchers and regulatory authorities are called upon to design
feasible strategies to recruit and characterize frail older individuals in pharmaco-
logical research, and all clinicians involved in the medical care of older patients
need to acknowledge the demands of this important population during the prescrib-
ing process.

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Falls and Impaired Mobility
13
Lotta Seppala and Nathalie van der Velde

13.1 Impact of Falls

Falls are a significant and rapidly growing global public health problem. A third of
people aged 65 years and older fall at least once per year [1]. In long-term care, falls
are even more common. Approximately, half of the nursing home residents will
experience one or more falls yearly [2]. Furthermore, in adult inpatients, falls are
the most frequently reported safety incident [3]. For example, the rate of falls has
been estimated to range from 3.3 to 11.5 falls per 1000 patient days in US hospitals
[4]. Falls have substantial impact on both mortality and morbidity. More than
684,000 people die as the result of a fall every year globally [5]. Older people are at
highest risk of dying as a result of a fall and this risk grows with advancing age [5].
Falls can have both physical and mental consequences. Over 60% of those who
experienced a fall in the past year report being injured [6]. It has been estimated that
annually, 172 million are left with short or long-term disability globally [5]. The
main physical consequences in older persons include hip fracture, other fractures,
traumatic brain injury, damage to intrathoracic and intra-abdominal organs, spinal
and nerve injuries, joint distortion and dislocation, soft-tissue damage, and bruises
and cuts [5]. Fear of falling (FOF) is common among older fallers, and FOF is
linked to impaired mobility and decreased functional status [1]. Negative mental
health effects in older persons include social withdrawal, symptom of anxiety and
depression [1]. Also, due to all negative health-related effects, falls place a

L. Seppala (*) · N. van der Velde

Internal Medicine, Section of Geriatric Medicine, Amsterdam UMC Location University of
Amsterdam, Amsterdam, The Netherlands
Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2023 161

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_13
162 L. Seppala and N. van der Velde

significant burden on healthcare expenditure. Around 0.85–1.5% of the total health-

care expenditure are fall-related costs in Western countries [7].

13.2 Risk Factors for Falls

Mostly falls result from several interacting risk factors [8], of which medication use
and mobility, both modifiable key risk factors, will be discussed in detail in this
chapter. Fall risk factors have been intensively studied during the past decades. In
general, fall risk factors can be classified into intrinsic (such as medical conditions)
and extrinsic risk factors (such as home hazards) [8]. Perhaps the most important
risk factors in terms of predictive power are older age and history of past falls [5].
Some of the other key risk factors are first of all as earlier mentioned the use of
certain medications and mobility disorders as well as poor balance, visual impair-
ment, cognitive impairment and Parkinson’s disease, arthritis, and/or depression
[5]. The risk factors for falls in long-term care or in hospital differ somewhat from
the risk factors among community-dwellers [5].

13.3 Mobility and Risk of Falling

Impaired mobility is a key risk factor for falls and includes impairments in muscle
strength, balance and/or gait [5]. In a systematic review by Deandrea et al., gait
problems doubled the odds of falling [9]. Also, quantitative performance measures
of gait including gait variability and gait speed have been shown to be robust predic-
tors of fall risk [10]. Gait disorders are believed to occur among a third of older
adults aged 70 years or older [11]. The origins of gait disorders include orthopedic
problems (e.g., osteoarthritis and skeletal deformities), neurological conditions
(e.g., sensory or motor impairments), and medical conditions (e.g., respiratory
insufficiency, heart failure, peripheral arterial occlusive disease, and obesity) [12],
and also certain medication use is linked to reduced gait speed [13]. With advancing
age, gait disorders usually have multiple origins [12]. Also, balance disorders are
one of the most significant reasons resulting in falls [5]. Sensory, motor, and central
processing mediate balance activity, and impairment in any of these three systems
can lead to a deficit in balance control [14]. Sensory inputs are integrated by the
central nervous system, and the central nervous system created the motor com-
mands [14]. The impairments can be due to the progressive decline of function in
the course of normal aging or due to specific pathology including use of certain
medications [14]. The prevalence of balance impairment has been estimated to vary
between 20 and 50% [14]. Last, muscle weakness (in particular lower extremity
weakness) is a major risk factor for falls [15]. Muscle strength is an essential com-
ponent of preserved mobility. The rate of muscle loss has been estimated to vary
from 1 to 2% past the age of 50 years [16]. Aging and inactivity or disuse is associ-
ated with a decline in strength, muscle mass, and structure [16]. Use of certain
medications can negatively affect either muscle strength or mass or both.
13 Falls and Impaired Mobility 163

13.4 Falls and Impaired Mobility, Common Adverse

Drug Events

In general, several medication classes belonging to cardiovascular and psychotropic

medication groups have been considered to increase fall risk. FRIDs are commonly
prescribed to older people. According to recent literature review, the use of FRIDs is
ranging from 65 to 93% in older adults with a fall-related injury [17]. In addition,
almost 90% of older adults visiting their general practitioner due to dizziness are
using at least one FRID [18]. The prescriptions of the FRIDs in general have been
increasing in the past decades [19]. Shaver et al. found that the percentage of older
persons who were prescribed a FRID increased to 94% in 2017, a significant leap
from 57% in 1999 [19]. Antihypertensives were the most often prescribed FRIDs
[19]. However, there was also a major rise in the prescriptions of antidepressants from
1999 to 2017 as the amount prescriptions was more than fourfold [19]. Data on FRIDs
is mostly based on observational studies, as regrettably fall incidents are not stan-
dardly assessed as adverse events in drug trials to date [20]. Data on observational
studies have been summarized in several systematic reviews and meta-­analyses dur-
ing past decades. For example, in the meta-analyses by the European Geriatric
Medicine Society (EuGMS) Task and Finish Group on FRIDs, a significant associa-
tion for falls was found for the following medication classes: antidepressants [selec-
tive serotonin reuptake inhibitors, tricyclic antidepressants], antipsychotics,
benzodiazepines, loop diuretics, antiepileptics, opioids, and polypharmacy (four or
more medications) [21–23]. Furthermore, it was concluded that digitalis may increase
fall risk [21]. In addition, inconsistent associations were observed for antiarrhythmics,
antihypertensives, diuretics, anticholinergics, NSAIDs, analgesics, antiplatelets, and
laxatives [21, 22]. However, these kinds of systematic reviews and meta-analysis are
confined to evaluation of commonly prescribed medication classes and to addressing
the average risk in the older population instead of individual risk [24]. To overcome
these shortcomings, the STOPPFall (Screening Tool of Older Persons Prescriptions in
older adults with high fall risk) was developed and published in 2020 [24].This is the
first European expert consensus FRID list of 14 medication groups [24]. The European
consensus list of FRIDs is presented in Table 13.1 [24]. In addition to STOPPFall, in
other general (de)prescribing tools, several medication classes are listed as potentially
inappropriate among fallers. The medication classes included in the STOPP/START
version 2 and 2019 updated Beers Criteria are presented in Table 13.2 [41, 42]. FRIDs
can induce fall risk through different mechanisms (cardiovascular, central nervous
system, or motoric) including, for example, orthostatic hypotension, sedation, dizzi-
ness, and muscle weakness [24]. The possible pathways leading to falls of STOPPFall
medication classes are shown in Table 13.1. Most of these adverse effects are revers-
ible after deprescribing [43, 44]. One of the key pathways to increased fall risk due to
FRID use is motoric mechanisms. Drugs with sedative properties have been consis-
tently associated with reduced gait speed [13]. In contrast, statin use has not been
consistently associated with reduced gait speed [13]. In addition, the evidence for
other drug classes is mixed, and other quantitative gait parameters have not been suf-
ficiently investigated [13]. Most of the research regarding FRIDs and falls have
164 L. Seppala and N. van der Velde

Table 13.1 Fall risk-increasing drugs according to Delphi consensus effort [24] and their possi-
ble mechanisms leading to falls
• Benzodiazepines and benzodiazepine-related drugs
 – Muscular weakness, ataxia, sedation, extrapyramidal symptoms, imbalance and/or
dizziness, visual disorders, delirium, possibly orthostatic hypotension [25, 26]
• Antipsychotics
 – Sedation, drowsiness or somnolence, dizziness or vertigo, orthostatic hypotension,
extrapyramidal side effects, cardiac effects (QTc prolongation and tachycardia),
anticholinergic effects (e.g., blurred vision), delirium, confusion, hyponatremia [27, 28]
• Antidepressants
 – Sedation, impaired balance/reaction time, orthostatic hypotension, cardiac conduction
and rhythm disorders, visual impairment, hyponatremia, delirium, and drug-induced
movement disorders [29]
• Diuretics
 – Orthostatic hypotension, hypotension, electrolyte disturbances [30]
• Alpha-blockers used as antihypertensives
 – Orthostatic hypotension, hypotension, dizziness, asthenia, and syncope [31]
• Centrally acting antihypertensives
 – Orthostatic hypotension, hypotension, weakness and sedation [32]
• Vasodilators used in cardiac diseases
 – Hypotension, orthostatic hypotension, dizziness, syncope [33]
• Opioids
 – Orthostatic hypotension, drowsiness, sedation, confusion, delirium, eye disorders, muscle
problems (e.g., rigidity) [34]
• Antiepileptics
 – Drowsiness, fatigue, dizziness, unsteadiness, vertigo, imbalance, ataxia, diplopia,
cognitive impairment, and hyponatraemia [35]
• Anticholinergics
 – Effects on central nervous system (sedation, confusion, delirium, dizziness, cognitive
impairment, impaired concentration) and blurred vision, tachycardia [36]
• Alpha-blockers used for prostate hyperplasia
 – Orthostatic hypotension, hypotension, dizziness, somnolence, visual impairment, and
syncope [37, 38]
• Overactive bladder and incontinence medications
 – Dizziness or vertigo, somnolence, delirium, visual impairment [38, 39]
• Antihistamines
 – Central nervous system side effects (e.g., sedation, drowsiness, somnolence, fatigue,
cognitive decline), anticholinergic effects, cardiovascular toxicities (e.g., arrhythmias,
prolongation of the QT interval, and postural hypotension) [40]

focused on commonly prescribed overarching medication classes (such as beta-block-

ers), and little is known regarding the differences of fall risk-increasing properties
between pharmacological subclasses (such as selective versus nonselective beta-
blockers). In STOPPFall, these differences between subclasses were explored based
on expert opinion [24]. The differences between subclasses that reached consensus
are presented in Table 13.3. In addition to risk differences within pharmacological
groups, there are other medication-related issues such as initiation or duration of use
and dosage, which all appear to play a role in medication-related falls. Higher dosages
of psychotropics have been associated with increased fall risk [23]. The higher blood
and tissue concentrations related to higher dosages might explain this dose-dependent
relationship. In addition, the fall risk related to certain medication use appears to be
highest when starting the medication use. For example, the risk of
13 Falls and Impaired Mobility 165

Table 13.2 Fall-related potentially inappropriate medication in older persons: STOPP/START

version 2 and Beers Criteria
STOPP/START Version 2: Drugs That Increase the Risk of Falls in Older People [41]
 • Benzodiazepines
 • Neuroleptic drugs
 • Vasodilator drugs with persistent postural hypotension, i.e., recurrent drop in systolic
blood pressure ≥ 20 mmHg
 • Hypnotic Z-drugs
2019 Updated AGS Beers Criteria®: Potentially Inappropriate Medication Use in Case of
History of Falls or Fractures [42]
 • Antiepileptics
 • Antipsychotics
 • Benzodiazepines
 • Hypnotic Z-drugs
 • Antidepressants
 • Opioids

Table 13.3 The differences of fall risk-increasing properties between pharmacological subclasses
according to STOPPFall
Antipsychotics: agents with strong (1) sedative, (2) anticholinergic, and (3) alpha-receptor
properties
Opioids: strong opioidsa
Antidepressants: tricyclic antidepressants (TCAs), agents with strong (1) sedative effects, (2)
propensity to cause orthostatic hypotension, and (3) anticholinergic activity
Anticholinergics: agents high anticholinergic activity
Antiepileptics: older generation antiepileptics, agents with strong sedative effects
Diuretics: loop diuretics
Alpha-blockers for benign prostatic hyperplasia: nonselective alpha-blockers
Antihistamines: first-generation antihistamines, agents with strong (1) sedative effects and (2)
anticholinergic activity
Medications for overactive bladder and urge incontinence: agents with strong
anticholinergic activity
Oral hypoglycemics: agents that can cause hypoglycemia
a
A low dose of a more potent opioid, e.g., morphine, may be better tolerated than weak opioids at
a higher dose

benzodiazepine-related falls has been found to be highest after starting the therapy
[45, 46], and the association between thiazide prescription and falls was found to be
strongest in the 3 weeks after prescription [47]. The role of drug-drug interactions in
medication-related falls is still unclear [20]. But potentially, drug-drug interactions
can cause additive pharmacological effects and lead to cytochrome P-450 interactions
possibly resulting in increased drug efficacy and toxicity [48]. Furthermore, some
patient characteristics appear to be of importance when defining the medication-
related fall risk of an individual. Tinetti et al. reported that antihypertensive use was
associated with an increased risk of serious fall injuries especially among those with
history of injurious falls, which could be a marker, for example, for multimorbidity or
frailty [49]. Ham et al. showed that individuals using benzodiazepines and having
reduced CYP2C9 enzyme activity, on the basis of their genotype, had an increased fall
risk [50]. Nevertheless in general the majority of studies have focused on general risk
related to medication use instead of personalized medication optimization.
166 L. Seppala and N. van der Velde

13.5 Prevention of (Medication-Related) Falls: Background

and Evidence

The new world guidelines for fall prevention and management exist to guide profes-
sionals regarding fall prevention in clinical practice [51]. According to the guide-
lines, all older adults should be advised on fall prevention and physical activity [51],
and those considered at high risk should be offered a comprehensive multifactorial
fall risk assessment with a view to codesign and implement personalized multido-
main interventions [51]. One of the standard domains to be included in the interven-
tion is medication review [51]. This is supported by among others the recent network
meta-analysis showing that basic fall risk assessment including a medication review
is one the effective components of multifactorial fall prevention intervention [52].
There is however uncertainty regarding the effectiveness of deprescribing as a
single intervention in fall prevention in the literature. The meta-analysis by Lee et al.
showed no effect of pure FRID deprescribing on any of the fall outcomes as a single
intervention [53]. In addition, Cameron et al. reported that a medication review, as a
single intervention, may make little or no difference to risk of falling or rate of falls
in long-term care facilities [54]. Nevertheless, in a meta-analysis of the FRID work-
ing group of the “World Falls Guidelines for the Prevention and Management of Falls
in Older Adults” investigating the effect of medication reviews, a trend for a lower
number of fallers in long-term care was seen [55]. This suggests that in a frailer sub-
group of older adults (e.g., in case of severe frailty, advanced dementia, long-term
care residents), deprescribing might be effective also as a single intervention. Thus,
as recommended by the World Falls Guidelines Task Force, in long-term care resi-
dents, the fall prevention strategy should always include rational deprescribing of fall
risk-increasing drugs [51]. However, given the multifactorial nature of falls, depre-
scribing interventions are recommended to be implemented as a part of multimodal
strategy rather than a stand-alone strategy [55], and multifactorial fall prevention
intervention has consistently shown to reduce falls rate [56]. Common components
of multiple interventions significantly associated with a reduction in number of fall-
ers and falls rate are exercise, assistive technology, quality improvement strategies,
environmental assessment and modifications, and basic fall risk assessment (includ-
ing a medication review) as mentioned above [52]. Nevertheless, in current clinical
practice, deprescribing FRIDs after a fall incident is not frequently conducted.
According to a recent review, FRID use was not reduced at 1 and 6 months following
the fall-related healthcare contact in observational studies [17]. In addition, when
implementing fall preventive strategies among primary care providers, majority of
patients with high fall risk received most of recommended interventions and assess-
ments, except medication modification. The reluctance can be partly explained by
the general overestimation of the benefits of the medication and underestimation of
the potential harms by both physicians and patients [20]. In additions, many physi-
cians perceive the uncertainty related to the consequences of withdrawing FRIDs as
uncomfortable and challenging [20]. Nevertheless, in general, deprescribing of
FRIDs can be conducted safely [57]. Few adverse withdrawal effects occur, and if
symptoms reoccur, they can be treated safely by reintroducing the stopped medica-
tion or if possible a safer alternative [57]. To increase the implementation uptake of
13 Falls and Impaired Mobility 167

a complex intervention such as medication review, education and engagement of

both healthcare professionals and patients are essential [58]. Given the complexity of
the intervention, supporting structured tools accompanied with appropriate training
are warranted [24, 59]. In addition, allocation of sufficient time and resources is nec-
essary to optimize the uptake and effectiveness.

13.6 Effect of Deprescribing of FRIDs on Impaired Mobility

and Other Adverse Effects

As described above, FRIDs have mostly cardiovascular, motoric, and central nervous
system related adverse effects which can lead to falls, and most of these adverse effects
are reversible after deprescribing [43, 44]. In terms of mobility outcomes, van der Velde
et al. found that withdrawal of FRIDs among geriatric outpatients improved Timed Up
and Go Test and the walking time on the 10-m walking test in a follow-up (mean,
6.7 months) and reduced occurrence of orthostatic hypotension [43, 44]. In addition,
Tsunoda et al. found that benzodiazepine withdrawal improved the stability of the body
and a recovery of cognitive functions [60]. In a study by Nurminen et al., benzodiaze-
pine withdrawal was found to improve muscle strength and balance rapidly [61].

13.7 How to Perform Medication Management of FRIDs

The first step in reducing the risk of falls caused by FRIDs is to prevent their inap-
propriate use in the older population (primary prevention) [20]. Therefore, as rec-
ommended by the World Falls Guideline Task Force, a history of falls and risk of
falling should be checked before prescribing FRIDs, and the risks and benefits
should be weighted for older persons [51]. In addition, possible safer alternatives
should be considered. Furthermore, medication review (including FRIDs review)
should be performed regularly (at least annually in older persons). In frail older
adults, a medication review should be done minimally every 6 months [62–64]. In a
medication review of risks for developing adverse drug events (ADEs), the safety
and effectiveness of each drug and compliance are assessed, and views of patients
and carers are being considered [65]. FRID review is an essential part of the regular
medication review as falls are important ADEs. The regularity of these reviews will
help to keep the exposure to FRIDs as short as possible and potentially reduce asso-
ciated fall risk. It is recommended to use a validated, structured screening and
assessment tool (such as STOPPFall) to identify FRIDs when performing medica-
tion review [51]. As described earlier, studies have shown that the effect of FRIDs
on fall risk appears to be dependent on characteristics [49]. Thus, these characteris-
tics, including polypharmacy, frailty status, comorbidities, patient’s preferences,
and other geriatric syndromes, should be taken into account when performing a
medication review [65]. To succeed in this, the medication review is optimally
embedded in a holistic assessment to enable personalized medication strategy.
Furthermore, it is important to realize that in practice, when deprescribing of FRIDs
is initiated, compliance is notoriously poor, especially for psychotropic medications
168 L. Seppala and N. van der Velde

[66]. Thus, a single one-time advice does not suffice. For the long-term success of
deprescribing provision of support, monitoring, and documentation are essential
[67]. Monitoring should be arranged on individual basis [24]. Finally, about 10–15%
of falls result in fractures, and therefore, in the medication review, the known drugs
to affect skeletal fragility should also be considered [20].
The generic steps of medication management of older fallers are shown in
Fig. 13.1 [20]. Further practical guidance regarding deprescribing of FRIDs is

Fig. 13.1 Generic steps of medication management in older fallers [20]

13 Falls and Impaired Mobility 169

provided in the STOPPFall deprescribing tool [24]. The tool is a freely available
online decision support tool which works in a stepwise manner containing all the
steps of the decision tree of the Fig. 13.1 separately for each STOPPFall medication
class [68]. For example, for antidepressants, it states that at least in the following
cases deprescribing should be considered: (1) hyponatremia, orthostatic hypoten-
sion, dizziness, sedative symptoms, or tachycardia/arrhythmia; (2) if given for sleep
disorder; and (3) if given for depression, but this is dependent on symptom-free time
and history of symptoms [24]. Furthermore, the tool indicates that stepwise depre-
scribing is needed and after deprescribing at least the following symptoms should
be monitored: recurrence of depression, anxiety, irritability, and insomnia [24]. Also
a paper version is available in the Appendix of the publication [24].

13.8 Conclusion

Falls have a major impact on both individual and societal level. Mostly falls tend to
occur due to several interacting risk factors in an individual. Some of the key risk
factors are older age, past falls, mobility, and certain medication use (fall risk-­
increasing drugs). Several psychotropic medications (benzodiazepines and related
drugs, antidepressants, antipsychotics), anticholinergics (such as overactive bladder
and incontinence medications and antihistamines), opioids, alpha-blockers, and
other cardiovascular medications (diuretics and centrally acting antihypertensives)
are considered to induce increased fall risk. FRIDs have cardiovascular, motoric,
and central nervous system related adverse effects which can lead to falls. Medication
review with the aim of FRID deprescribing as a part of multifactorial fall prevention
strategy is effective in fall prevention. This medication review should be a holistic
assessment including the evaluation of characteristics such as frailty and patient
goals to produce a personalized medication optimization plan. Regular medication
reviews will help to keep the exposure to FRIDs as short as possible. Structured
tools (such as STOPPFall) can aid with FRID deprescribing.

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Optimizing Pharmacotherapy in Older
Patients: Delirium 14
Giuseppe Bellelli and Alessandro Morandi

14.1 Introduction

Delirium is a complex neuropsychiatric syndrome characterized by acute onset of

fluctuating inattention, altered arousal, cognitive, and behavioral disorders [1]. It is
common in older people across various settings of care, but mainly in acute hospi-
talized patients [2].
Delirium can be regarded as a healthcare priority since it is associated with sev-
eral negative outcomes, including patient’s increased risk of mortality, institutional-
ization, cognitive and functional worsening [3–7], as well as increased patients’ and
caregiver’s emotional burden [8, 9]. Furthermore, delirium is associated with
increased healthcare expenditure [10].
Historically, a relatively short list of medications, such as barbiturates, analgesic,
and alkaloids of the morphine groups [11], has been associated with delirium in the
older people. However, in the recent years, it has become clear that almost all drugs
are causal or contributing factors for delirium if used in individuals vulnerable, such
as those with dementia and/or frailty. Knowing the potential danger of these drugs
in terms of delirium development is key, given the impact of delirium on healthcare
outcomes.
This article provides an approach for clinicians to recognize delirium potentially
induced by drugs and reviews the current evidence regarding the mechanisms of
drug-induced delirium, the existing tools to evaluate the contribution of drugs to

G. Bellelli (*)
School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
IRCCS San Gerardo Hospital Monza, Acute Geriatrics Unit, Monza, Italy
e-mail: [email protected]
A. Morandi
REFiT Barcelona Research Group, Parc Sanitari Pere Virgili and Vall d’Hebron Institut de
Recerca (VHIR), Barcelona, Spain

© Springer Nature Switzerland AG 2023 173

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_14
174 G. Bellelli and A. Morandi

delirium development, and the prevention and treatment of delirium using the phar-
macological approaches in older patients outside of intensive care settings.

14.2 Mechanisms of Medications-Induced Delirium

There is general agreement that delirium represents an altered reaction of the central
nervous system (CNS) to the effect of one or more precipitating factors that inter-
play with one or more predisposing factors of delirium [12]. Drugs, in this context,
may represent either a precipitating or a predisposing factor (or both).
The exact mechanisms of drug-induced delirium are yet to be completely under-
stood. However, neurotransmitter imbalances involving acetylcholine, dopamine,
and gamma aminobutyric acid (GABA) traversing the cortical and subcortical ner-
vous system pathways have been observed in drug-induced delirium [13]. It is
hypothesized that delirium may develop as the result of an alteration of function of
the ascending arousal system directly provoked by an effect of GABAergic seda-
tives, anesthetics, and antihistamine drugs [14]. GABA acting at GABA-A recep-
tors inhibits the release of dopamine GABA antagonist [15], or a sudden withdrawal
from a GABA agonist may increase the risk of a hyperdopaminergic state, which in
turn facilitates the action of glutamate at N-methyl-D-aspartate (NMDA) receptors
[16]. This can explain why an abrupt benzodiazepine withdrawal may precipitate
delirium. In addition, this can explain why an imbalance of the brain cholinergic
and dopaminergic activity, which can be induced by a broad list of drugs with mus-
carinic antagonist activity, is also involved in delirium onset [14, 17–19]. Indeed,
drugs acting on GABA and NMDA receptors or with dopaminergic activity, such as
digoxin, quinolone antibiotics, morphine, and histamine (H2) receptor blockers, are
well-known causes of delirium [20].
Importantly, the receptor distribution of cholinergic and dopaminergic neu-
rotransmitters among layers of prefrontal cortex and temporal lobe indirectly sug-
gests that neurons of these areas could interact with each other during delirium [18].
It follows that a drug prescribed, for instance, to calm an agitated patient may lead
to a completely different effect in specific circumstances and patients, depending on
the receptor subtype which is more prevalent in those cortical areas. Older adults are
particularly sensitive to anticholinergic medication adverse effects because of
increased permeability of the blood-brain barrier, heightened sensitivity of cholin-
ergic receptors, deficient drug metabolism/elimination, and deficits in central cho-
linergic transmission. Anticholinergic activity has also been associated with an
increased severity of delirium [21].
The incidence of drug-induced delirium is particularly high even among older
individuals with multimorbidity and polypharmacy. Multimorbidity refers to a
coexistence of two or more chronic conditions in the same individual, and polyphar-
macy is commonly defined as the chronic use of five or more prescribed drugs [22,
23]. Patients with multimorbidity have an increased odd of assuming multiple medi-
cations and are thus at risk of polypharmacy prescription [24]. In addition, they
commonly have other co-occurring conditions, such as malnutrition, muscle mass
14 Optimizing Pharmacotherapy in Older Patients: Delirium 175

reduction, and low albumin serum levels, which leads to alterations in distribution,
with water-soluble drugs having a reduced volume of distribution and lipophilic
drugs having increased volume of distribution [25].
Aloisi and colleagues evaluated the association between polypharmacy and
delirium in a cohort of 4133 older inpatients, of which 23.4% had delirium [26]. The
authors found that polypharmacy was higher in patients with delirium, but the asso-
ciation was statistically significant only in surgical but not medical units. A possible
explanation was that in surgical settings, where the healthcare professionals were
not trained in geriatric care, older individuals were relatively overtreated with psy-
choactive drugs. Indeed, patients with delirium in these units had higher prescrip-
tion of benzodiazepines and antipsychotics [26]. However, another study including
410 consecutive patients admitted to an acute geriatric ward, of whom 25% devel-
oped delirium, found that polypharmacy was an independent risk factor for delir-
ium, after adjusting for covariates [27].
In addition to polypharmacy, Catic identified the following risk factors that
placed elders at increased risk of delirium: >9 chronic medications, >12 doses of
medication per day, >6 concurrent chronic diagnoses, prior adverse drug reaction,
low body weight, estimated creatinine clearance <50 mL/min, and age
>85 years [20].

14.3 Scales to Assess Patient’s Drug Burden of Delirium

The observation that neurotransmitter dysfunctions are implicated in delirium

pathophysiology gave the impulse to the development of scales to assess the contri-
bution of this dysfunction on the onset of delirium. One of the obvious targets was
the anticholinergic drug load. A recent systematic literature search reviewed the
existing scales that are commonly used to evaluate the anticholinergic drug burden
(ADB) and are potentially associated with delirium [28]. In the 16 studies included
in the qualitative analysis of this systematic review, ADB was measured with 6 dif-
ferent scales, namely, the Anticholinergic Risk Scale (ARS) [29, 30], the
Anticholinergic Cognitive Burden Scale (ACB) [19, 31, 32], the list of Chew [33],
the Anticholinergic Drug Scale (ADS) [21, 34, 35], a modified version of the ARS
[36], and a modified version of the ACB [37]. The ARS is a tool for estimating the
extent to which a patient may be at risk of anticholinergic adverse effects leading to
cognitive dysfunction and delirium. The ARS ranks a list of 500 drugs for anticho-
linergic potential on a three-point scale (0, no or low risk; 3, high anticholinergic
potential), and the ARS score is given by the sum of points for the patient’s number
of medications [30]. The ACB was developed by Boustani [38] and includes a list of
88 drugs with known anticholinergic activities. A multidisciplinary panel assessed
individual drugs to have none, possible, or definite anticholinergic properties with a
score ranging from 0 to 3. The ADS was developed by Carnahan et al., based on
expert consensus, and ranks medicines with anticholinergic properties in an ordinal
fashion from 0 to 3, with 0 indicating no known anticholinergic activity and 3 indi-
cating definite/high anticholinergic activity [39].
176 G. Bellelli and A. Morandi

Overall, the systematic review found that ARS was the only scale which was
consistently associated with delirium and thus supports its use. On the contrary,
when ADB was assessed with other scales, the findings were inconclusive.
However, delirium can be precipitated also by drugs which have not relevant
anticholinergic properties, such as opioids, steroids, and sedatives [4]. Therefore,
other researchers have developed other scales to assess a patient’s drug burden of
delirium. The Delirium Drug Scale (DDS) is a tool evaluation scale developed to
this aim [40, 41]. A rank of 1 or 2 is attributed to each member of the DDS drug list,
and to calculate the DDS score, the patient’s medication list is compared to the
DDS. The rank attributed to the drug is multiplied by the dosage factor to give a
weighted rank. The dosage factor is the result of the administered daily dose taken
divided by the sum of the administered daily dose and the minimal daily geriatric
dose (as reported by the Geriatric Dosage Handbook). The DDS score is the sum of
all weighted rank present in the patient’s drug list [40]. In an observational retro-
spective study on 1205 older individuals, Nguyen and colleagues found that the
DDS was associated with an increased risk of delirium incidence [41]. Importantly,
the risk of delirium increased as the DDS score rises from low to high exposure,
independently of risk and precipitating factors for delirium. The authors concluded
that the DDS could act as a decision tool for physicians when a new medication is
added to a patient’s drug therapy [41]. However, further research is required to con-
firm their results.
In addition, it is also important to highlight those other causal mechanisms, unre-
lated to drugs, can interfere with neurotransmission. For instance, during a sepsis, a
brain neuroinflammatory response triggered by inflammatory cytokines is com-
monly seen, leading to endothelial damage, disruption of the blood-brain barrier,
impaired blood flow, and neuronal apoptosis. Neuroinflammation can lead to
microglial overactivation, resulting in a neurotoxic response with further neuronal
injury. In these conditions, weighting the contribution of a specific drug to delirium
development might not always be possible, since the different inflammatory factors
and neurotransmitters are closely intertwined [42].

14.4 The Recommendations of the Scientific Societies

on the Medications with Potential Impact on Delirium

The American Geriatrics Society (AGS) Beers Criteria are an explicit list of poten-
tially inappropriate medications that, under specific situations, should be avoided in
older adults. The AGS Beers Criteria are updated on a 3-year cycle by an interdisci-
plinary expert panel that periodically reviews the evidence published since the last
update and then releases their recommendations [43, 44]. In the last update (i.e.,
2019), the list of drugs that should be avoided in people with delirium includes the
H2-receptor antagonists, the benzodiazepine (short, intermediate, and long acting),
the benzodiazepine receptor agonist hypnotics (i.e., the “Z drugs”: zolpidem, eszop-
iclone, and zaleplon), first (conventional) and second (atypical) generation antipsy-
chotics, and some pain medications, such as meperidine. In addition, the AGS Beers
14 Optimizing Pharmacotherapy in Older Patients: Delirium 177

Criteria recommend that all drugs acting on the central nervous system should be
avoided in older adults at high risk of delirium because of their potential to precipi-
tate delirium. In general, it is recommended that antipsychotics should not be pre-
scribed for behavioral problems of dementia and/or delirium unless
nonpharmacological options have failed or are not possible and the older adult is
threatening substantial harm to self or others [45].
The STOPP/START (Screening Tool of Older People’s Prescriptions and
Screening Tool to Alert to Right Treatment) criteria include a list of both potential
inappropriate medications and potential prescribing omissions in older people [46,
47], which was developed by a panel of European experts. There are not explicit
recommendations to avoid the use of medications for preventing delirium; however,
it is recommended to avoid tricyclic antidepressants in individuals with dementia,
the long-term use of long-acting benzodiazepines (e.g., chlordiazepoxide, fluraze-
pam, nitrazepam, chlorazepate, and diazepam), and the long-term use of neurolep-
tics as hypnotics, especially in those with parkinsonism, as well as anticholinergics
to treat extrapyramidal side effects of neuroleptic medications.

14.5 Medication Candidates for Delirium Prevention

In 1999, Inouye and colleagues proposed firstly the Hospital Elder Life Program
(HELP), a model of care tailored for older patients and specifically oriented to pre-
vent delirium during the hospital stay, including cognitive stimulation, sleep
enhancement, promotion of mobility, and avoidance of dehydration and sensory
impairments (i.e., visual and hearing impairments) [48]. Since then, several studies,
systematic reviews, and meta-analysis have confirmed the effectiveness of non-­
pharmacological, multicomponent, and multidisciplinary interventions in delirium
prevention [49, 50]. The most recently updated delirium guidelines support such
approach as the first step for delirium prevention [51], leading to a reduction of
delirium incidence by almost 43%.
On the contrary, there is insufficient evidence to recommend the use of specific
medications for delirium prevention [52]. Fok and colleagues reported a possible
role on the use of antipsychotics to reduce the incidence of postoperative delirium,
mainly in orthopedic settings and in those patients at higher risk of delirium [53].
However, a subsequent systematic review investigating the possible effect of halo-
peridol vs. placebo in adult patients reported a limited evidence of a small dose of
haloperidol in delirium reduction among surgical patients [54]. Therefore, guide-
lines suggest that the pharmacological risk reduction should occur only by acting on
three specific areas of intervention: (a) medication reconciliation with a thorough
review of medication including over-the-counter and herbal medications; (b) the
physiological changes related to aging and their effects on medication metabolism;
and (c) considering the risk of delirium related to the introduction of a new drug [52].
Recent studies have claimed potential applications for some medications. For
example, there is emerging evidence that dexmedetomidine—a highly selective
α2-adrenergic agonist—alone or in combination with other sedatives may reduce
178 G. Bellelli and A. Morandi

postoperative delirium [55]. This type of medication has been widely studied in
critically ill patients admitted to intensive care units (ICU) [56], and its potential use
outside the ICU needs to be further investigated.
Given that sleep-cycle alterations are often present in patients with delirium and
especially in delirium superimposed on dementia, there has been an increasing interest
on the effect of melatonin and melatonin receptor agonist (i.e., ramelteon) for delirium
prevention. A recent meta-analysis showed that both melatonin and ramelteon are
effective in reducing delirium incidence in hospitalized patients, but this effect was
found significant in surgical patients and not in medical patients [57]. Furthermore, in
a recent multicenter randomized placebo-controlled trial, Hatta et al. showed that
suvorexant (an orexin inhibitor used in the treatment of insomnia) significantly reduced
the occurrence of delirium compared to the administration of placebo [58]. A meta-
analysis that included seven studies conducted in patients undergoing this treatment
compared with controls showed that delirium incidence could be reduced in the treat-
ment groups compared to controls [59]. However, further larger studies are required.

14.6 Medications to Treat Delirium

As for the prevention of delirium, even for delirium treatment, it is important to

provide a timely non-pharmacological approach and identify and treat the underly-
ing causes of delirium52. Different acronyms are available to help clinicians system-
atically reminding the possible causes of delirium [60].
Several studies investigated the possibility to treat delirious patients with anti-
psychotics. However, one meta-analysis showed that antipsychotic medications are
not effective to reduce delirium duration or severity in adult surgical and medical
patients [61]. Two Cochrane reviews confirmed these findings both in non-ICU
patients and ICU patients [62], and two other systematic reviews found that the
routine use of haloperidol or second-generation antipsychotics is not useful to treat
delirium in adult inpatients [63, 64].
It is also interesting to report that a relatively recent large randomized clinical
trial found that palliative care patients treated with haloperidol or risperidone com-
pared with placebo had worse delirium symptom scores [65]. However, one study
on patients affected by advanced cancer in the last weeks or days of their life showed
a reduction in agitated behavior by adding a single 3 mg dose of lorazepam intrave-
nously to haloperidol, when compared with placebo [66].
Other medications have been investigated for their possible role in delirium treat-
ment. One systematic review found no efficacy of acetylcholinesterase inhibitors
(i.e., donepezil or rivastigmine) compared to placebo on delirium duration and
severity [67], and one trial investigating the effect of the adjunct of rivastigmine to
usual care based on haloperidol on delirium duration in critically ill patients was
halted because of increased mortality in the rivastigmine group compared to pla-
cebo [68]. Finally, a systematic review, including only two studies outside the ICU,
reported that there is not enough evidence to determine whether benzodiazepines
are effective when used to treat patients with delirium [69].
14 Optimizing Pharmacotherapy in Older Patients: Delirium 179

According to the current evidence, antipsychotics should therefore be prescribed

only in patients with disturbing psychotic symptoms (e.g., delusions, hallucina-
tions) and when the patients’ safety or the safety of those around them was compro-
mised [52]. The prescription and dosages should be reviewed on a daily basis for the
medication tapering and discontinuation.

14.7 Conclusions

Drug-induced delirium is often encountered in clinical practice, especially in older

people who are frail or have dementia. It is therefore important that all clinicians
should be aware of the impact of specific medications in inducing delirium, to avoid
their use and/or rapidly detect them as a potential cause of delirium. A conceptual
framework and an algorithm to guide clinicians in managing medications to prevent
and treat delirium are provided in Fig. 14.1. The first step includes drug reconcilia-
tion, keeping in mind the physiological changes related to aging and their effects on
metabolism. Adjusting drug doses considering the pharmacokinetic changes and the
potential interactions between drugs will reduce the risk of drug-induced delirium.
Furthermore, before initiating a new medication, it is appropriate to consider all the
factors that placed elders at increased risk of delirium, including dementia, multi-
morbidity, frailty, polypharmacy, prior adverse drug reaction, malnutrition, and
chronic renal failure. Then, it should be chosen the tool to measure the anticholiner-
gic drug burden. There are several scales that can be used to this aim. Finally, spe-
cific drugs can be used to prevent (i.e., drugs acting on the sleep-wake rhythm) or to
treat delirium. It’s important to recognize that the use of antipsychotics is allowed
only when patients are suffering psychotic symptoms (e.g., delusions, hallucina-
tions) or when the safety around them is compromised. Heightening the awareness
of drug-induced delirium among clinicians will encourage them to use more conser-
vatively and closely monitor the drugs at highest risk.

Fig. 14.1 Medication management and delirium

180 G. Bellelli and A. Morandi

This is a very important area of research that promises to provide exciting news
for clinicians and opportunities for the patients.

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Optimizing Pharmacotherapy in Older
Adults: Urinary Incontinence 15
Antoine Vella and Claudio Pedone

15.1 Introduction

Urinary incontinence (UI) in older persons is common and increases with age,
affecting around 70% of older persons over 85 years of age. It can have a major
adverse impact on their quality of life and is one of the reasons why older persons
end up in long-term care. Unfortunately, it is frequently underdiagnosed and often
not treated even though it is potentially reversible.
Management of patients suffering from UI requires not only a focused history,
examination, and investigations for an accurate diagnosis to be made but also a
comprehensive geriatric assessment that usually requires the involvement of a mul-
tidisciplinary team. Treatment options usually include lifestyle changes, behavioral
interventions, often pharmacotherapy, and less commonly surgical interventions
besides the use of appropriate devices and absorbent aids.
Pharmacotherapy in the incontinence setting must have a two-pronged approach.
Before considering specific pharmacotherapy targeting the incontinence, a compre-
hensive review of all ongoing medications, including those over-the-counter, must
be undertaken. This is because there are several drugs that, directly or indirectly, can

A. Vella (*)
Department of Geriatric Medicine, St. Vincent De Paul Hospital, Luqa, Malta
e-mail: [email protected]
C. Pedone
Department of Medicine and Surgery, Research Unit of Geriatrics, Università Campus
Bio-Medico di Roma, Rome, Italy
Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 185

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_15
186 A. Vella and C. Pedone

impact negatively on the patient’s continence status. This shall be discussed sepa-
rately below. The second aspect of the pharmacotherapeutic management can then
be directed more specifically at the patient’s continence problem.
Pharmacotherapy for incontinence should form part of a holistic approach and
must take the patients’ comorbidities, desires, and quality of life into account.
Treatment must be carefully monitored with special vigilance for side effects of
medications. The value of team management, preferably with a continence outreach
service, cannot be overstressed.
The mode of actions and effects that medications have on micturition, whether
they are medications that the patient is on or pharmacotherapy for incontinence, can
only be understood when the basis of the complex micturition process is
comprehended.
The lower urinary tract consists essentially of two units: the bladder which acts
as a reservoir and the outlet unit which consists of the bladder neck, the urethra, and
the external urethral sphincter (EUS). The bladder and bladder neck, including the
internal urethral sphincter (IUS), consist of smooth muscle, while the EUS consists
of striated muscle. The bladder has two modes of action—storage and elimina-
tion—and works in a switch on/off pattern which is under voluntary control. The
mechanisms that underlie the control of micturition consist of complex neural path-
ways that function at the levels of the brain, spinal cord, and peripheral nerves that
are mediated via multiple neurotransmitters at all levels. A complex description of
this is beyond the scope of the chapter, but a very simplified version of the efferent
neural pathways and neurotransmitter mechanisms that regulate the lower urinary
tract (LUT) will be summarized in Fig. 15.1.
The LUT has three main nerve supplies: the sympathetic, parasympathetic, and
somatic systems [1].
The sympathetic system via the hypogastric nerve is inhibitory to the detrusor
muscle and motor to the IUS. Sympathetic postganglionic neurons release nor-
adrenaline (NA) which activates the following:

Parasympathetic Pelvic Nerves Sympathetic (Hypogastric) Nerve

Ach (+) Bladder

S2 Pelvic Ganglion contraction NA (-) Inferior mesenteric ganglion T12
M3 (M2) b3 (b2)
S3 L1
Bladder
S4
Bladder relaxation L2

L3

NO (-) NA (+)

IUS relaxation IUSU a1 IUS contraction Somatic (Pudendal) Nerve

r
e
S2
t Ach (+)
EUS h NR S3

r EUS contraction S4
a

IUS - internal urethral sphincter α - alpha receptors ACh - acetylcholine

EUS - external urethral sphincter NR - nicotine receptors M - muscarinic receptors
NA - noradrenaline β - beta receptors NO - nitric oxide

Fig. 15.1 Lower urinary tract: efferent innervation and neurotransmitter–receptor mechanisms
15 Optimizing Pharmacotherapy in Older Adults: Urinary Incontinence 187

–– Beta adrenergic inhibitory (−ve) receptors in the detrusor muscle resulting in

bladder relaxation
–– Alpha-adrenergic excitatory (+ve) receptors in the bladder neck and urethra
resulting in contraction

The parasympathetic system via the pelvic nerve plexus is motor to the detrusor
muscle and inhibitory to the IUS. When the bladder fills to beyond 300 mL, stretch
mechanoreceptors in the bladder wall relay via pelvic splanchnic nerves to the spi-
nal cord. Efferent parasympathetic nerves synapse with postganglionic nerves in the
bladder wall and IUS via acetylcholine (ACh) acting on muscarinic receptors (M).
This results in the following:

–– Bladder contraction
–– Relaxation of the IUS

The somatic system via the pudendal nerve is motor to the EUS which is under
voluntary control and is always contracted except during micturition when the EUS
is inhibited. The somatic axons release acetylcholine which via nicotinic receptors
(NR) result in the following:

–– EUS contraction

The majority of the pharmacotherapeutic agents used to manage incontinence act

on one or more of the above systems (Fig. 15.2); however, the control of micturition
is far more complex than as described above and includes spinal, pontine, and corti-
cal centers. The spinal center results in reflex incomplete bladder evacuation, the

Antimuscarinic
(Bladder relaxation)
b receptor agonist
Parasympathetic Pelvic Nerves (Bladder relaxation) Sympathetic (Hypogastric) Nerve

S2 Ach (+) T12

M3 (M2)
S3
b3 (b2) L1
NA (-)
S4 Bladder wall L2
neurotransmitters
- receptors L3
(-)
(-)

U a1 a receptor blockers
IUS (IUS relaxation) Somatic (Pudendal) Nerve
BoNT/A r
Bladder relaxation e
S2
t Ach (+)
EUS h NR S3

r duloxetine S4
a (increase in EUS tone during
storage phase of micturition)

IUS - internal urethral sphincter α - alpha receptors ACh - acetylcholine

EUS - external urethral sphincter NR - nicotine receptors M - muscarinic receptors
NA - noradrenaline β - beta receptors BoNT / A - botulinum toxin A

Fig. 15.2 Mechanisms of action of therapeutic agents on the lower urinary tract
188 A. Vella and C. Pedone

pontine center synchronizes and maintains sustained bladder contractions, and the
cortical center inhibits the pontine center until a suitable time and place for micturi-
tion is available. These centers are regulated by several neurotransmitters which can
be affected by disease processes a well as medications that the patients are taking.

15.2 Medications Review

An important part of the comprehensive geriatric assessment (CGA) in the manage-

ment of UI is a careful evaluation of the medications that the patient is on. There are
several medications (Table 15.1) that could precipitate or worsen LUTS through a
direct or an indirect effect on the LUT. Sometimes even a simple over-the-counter
medication such as a pseudoephedrine-containing common cold preparation can
give rise to obstructive symptoms in men with consequent urinary retention with
overflow incontinence.
This list is not exhaustive, and a possible medication-induced effect on the lower
urinary tract (LUT) should be suspected if the symptoms of UI develop soon after
the introduction of a new agent. Lower urinary tract symptoms (LUTS) secondary
to medications are particularly common in patients with polypharmacy, those who
have been recently hospitalized and the frail. If possible, when one or more medica-
tions are suspected to be the cause of incontinence/LUTS, the particular medication
should be changed to that of another class, e.g., using an ARB instead of an ACEI;
the dose or time of administration adjusted (e.g., in the case of diuretics) or the

Table 15.1 Medications as causative or predisposing factors for UI [2]

Medication Effects on lower urinary tract
ACE inhibitors Cough, stress urinary incontinence
Calcium channel Frequency, nocturia, and obstructive symptoms (especially in
inhibitors males)
Diuretics Polyuria
Lithium Polyuria
Alpha-adrenergic agonists Stimulate the IUS, urinary retention
Antihistamines Retention of urine, delirium
Acetylcholinesterase Increased detrusor contractility, urge incontinence
inhibitors
Opiates Urinary retention, constipation with overflow incontinence
Alpha-adrenergic Reduction in urethral/IUS tone, stress urinary incontinence
inhibitors
Benzodiazepines Delirium, stress urinary incontinence (relaxation of EUS),
impaired mobility (functional incontinence)
Gabapentin Nocturnal polyuria, delirium
NSAIDs Nocturnal polyuria
SSRIs Increased detrusor contractility (cholinergic effect), urge
incontinence
Anticholinergic Retention of urine with overflow incontinence, delirium
medications
Antipsychotics Anticholinergic effects, sedation, immobility, delirium
15 Optimizing Pharmacotherapy in Older Adults: Urinary Incontinence 189

suspected medication should be stopped, e.g., in the case of an acetylcholinesterase

inhibitor.

15.3 Evaluation of Bowel Function

Attention to bowel care is an integral part of a workup for urinary incontinence

since constipation can have a profound effect on bladder function particularly in the
frail older person and severe constipation can result in retention of urine with over-
flow incontinence. This is especially common in hospitalized patients where all too
often bowel and bladder care is not given due importance. Older persons with mod-
erate to severe dementia and patients who are recovering from surgery, e.g., fracture
of the neck of femur (often on opiates), are particularly prone to constipation and its
consequences on the LUT. Their treatment must be reviewed and accurate stool
charting encouraged.

15.4 Pharmacological Treatment for Urinary Incontinence

Pharmacological treatment for UI is usually commenced after a trial of conservative

treatment (Table 15.2) has not proven to be adequately effective. However, the con-
servative measures should still be pursued after the initiation of pharmacological
treatment since they have a complementary effect.
Most pharmacological interventions for UI are for use in urge UI and bladder
outflow obstruction (BOO), while a few agents have been used in stress UI (SUI).
The agents used for urge UI and SUI have a moderate efficacy when used for the
correct indication but unfortunately are not without adverse effects to a greater or
lesser extent. These factors result in a relatively poor perseverance and a high dropout

Table 15.2 Conservative management of urinary incontinence [2]

Lifestyle interventions
No specific data in the frail elderly
Weight reduction May be inappropriate in the frail older patient
Fluid intake Only modify if excessive; avoid caffeine and carbonated
beverages
Constipation Chronic constipation should be addressed
Smoking Smoking cessation is recommended
Behavioural interventions
Continuous incorporation into daily routine is essential
Motivation of patient and/or caregiver is required
Timed voiding Applicable in older patients with or without cognitive impairment
Prompted voiding Gold standard in care dependent older patients in nursing homes
Pelvic floor muscle training Advised in stress incontinence
Could be implemented to decrease bladder contractions in OAB
Must be continued to maintain beneficial effect
Bladder training Can be applied for any type of UI
Sufficient motivation is required
190 A. Vella and C. Pedone

rate from treatment. Adverse effects can be short term, e.g., nausea with duloxetine for
SUI, but can also be long term, e.g., worsening of cognitive impairment with antimus-
carinic agents in predisposed older patients. Treatment for BOO is usually better toler-
ated, but long-term adverse effects such as erectile dysfunction can be a problem.
One must therefore carefully weigh the risk of adverse effects, taking into con-
sideration the particular patient’s comorbidities, quality of life, and wishes, before
embarking on treatment. Evidence of efficacy of these medications in the frail older
person is scant, and patients that started on these medications should be monitored
vigilantly for adverse effects.

15.5 Drug Management of Overactive Bladder/

Urge Incontinence

15.5.1 Antimuscarinic Drugs

Antimuscarinic drugs are the mainstay of the drug therapy for overactive bladder
(OAB), with or without urinary urge incontinence (UUI). These drugs seem to be
effective in the short term, while data on long-term efficacy are scant [3]. Overall,
the effect on incontinence itself is limited (about 20% reduction of incontinence
episodes), but the effect on quality of life seems to be more substantial. Evidence
pertaining to efficacy in older and frail people is limited. Side effects due to sys-
temic anticholinergic action are common and frequently lead to therapy discontinu-
ation. In older people, negative effects on cognition are of some concern, and these
drugs should be avoided in patients with cognitive impairment.

15.5.1.1 Mechanism of Action

All anticholinergic drugs used for OAB and UUI exert their action by blocking the
M2 and M3 muscarinic receptor that are expressed in several tissues including the
detrusor muscle. The M3 receptor is primarily involved in detrusor contraction,
while the M2 receptor stimulation induces an increase in detrusor muscle tone. The
selectivity of antimuscarinic drugs for these receptors varies: only solifenacin and
darifenacin are selective for the M3 receptor, while all other compounds bind also
to other antimuscarinic receptor, including M1 that is abundantly expressed in the
central nervous system. The propensity of nonselective antimuscarinic drugs to
cause cognitive side effects (e.g., confusion) is a function not only of their receptor
affinity but also of their lipophilicity and capacity of penetrating the blood-brain
barrier. Oxybutynin is a nonselective antimuscarinic, and being small and highly
lipophilic can easily cross the blood-brain barrier, and consequently it is the drug
with the highest risk for cognitive side effects. Other nonselective antimuscarinics
are much larger and in normal conditions do not cross the blood-brain barrier, with
lower risk for cognitive side effects. It must be kept in mind, however, that several
conditions such as diabetes or neurodegenerative disorders (Alzheimer’s disease,
Parkinson’s disease) can disrupt the integrity of the blood-brain barrier, increasing
the risk of central side effects even for drugs that normally do not enter the central
nervous system.
15 Optimizing Pharmacotherapy in Older Adults: Urinary Incontinence 191

15.5.1.2 Evidence
In older people, antimuscarinic drugs improve the severity of urinary incontinence,
although the effect size is generally small and no data are available on their long-­
term efficacy. No evidence is available, however, in older people with multiple mor-
bidities and polypharmacotherapy. Side effects are common and related to systemic
anticholinergic activity: dry mouth, constipation, blurred vision, and dizziness.
These side effects have a sizable impact on persistence on treatment: about 40% of
patients discontinue these drugs within 3 months of therapy.

15.5.1.3 Clinical Use

Oxybutynin is currently not frequently used because of the less favorable risk/ben-
efit ratio compared to other available agents, and extended-release formulations are
preferred. With respect to other available drugs (tolterodine, solifenacin, darifena-
cin, propiverine, trospium), there is no clear-cut indication that one drug may be
preferable over another in older people. Given the high prevalence of polypharmacy
in older people, attention to possible drug-drug interaction is warranted. Most of
these drugs are metabolized by CYP3A4 and must be used with caution in patients
taking potent inhibitors of this enzyme.
Inherent to the mechanism of action of these drugs is the risk for urinary reten-
tion that is especially high in men with severe prostatic hyperplasia: in this situation,
antimuscarinic drugs may be contraindicated.

15.5.2 β3 Receptor Agonists

β3 receptor agonists (mirabegron and vibegron) are generally considered safe, but
data specific for older people is scant. In particular, their effect on the QT interval in
people also taking drugs known to cause QT prolongation is unknown.

15.5.2.1 Mechanism of Action

These drugs cause an increase of cAMP concentration in bladder smooth muscle
cells with muscle relaxation and consequent improvement in filling capacity. It does
not impair voiding pressure because the activation of M2 muscarinic receptor that
triggers muscular contraction also inhibits the cAMP signaling.

15.5.2.2 Evidence
A meta-analysis of head-to-head studies has shown that mirabegron is as effective
as solifenacin in reducing the burden of OAB/UUI, with comparable rates of adverse
events [4].

15.5.2.3 Clinical Use

They are recommended as a stand-alone or add-on pharmacological therapy in
patients with UUI. In people taking a combination of β3 receptor agonists and anti-
muscarinic drugs, special attention must be paid to the risk of urinary retention.
These drugs are metabolized by CYP3A, and dose adjustment may be required in
patients with renal or liver function impairment also taking potent inhibitors of this
192 A. Vella and C. Pedone

cytochrome. Furthermore, they should not be used in patients with poorly controlled
arterial hypertension.

15.5.3 Botulinum Toxin

Botulinum toxin A (BoNT/A) could be offered to patients with UUI who are refrac-
tory to treatment with antimuscarinics or beta 3 receptor agonists. This therapy is
not without side effects, and patients need to be counseled before embarking on this
treatment. Evidence in frail older persons is limited.

15.5.3.1 Mechanism of Action

BoNT/A seems to have an effect on three neural pathways [5]. Firstly, it inhibits the
fusion of neurosecretory vesicles and blocks acetylcholine release from the presyn-
aptic nerve terminals. This affects both the afferent suburothelial and the efferent
(motor) nerve endings, thereby inhibiting bladder contraction in response to increase
in the intravesical pressure. Secondly BoNT/A exerts complex inhibitory effects on
bladder neurotransmitters, neuropeptides, and receptors involved with neurotrans-
mission. It was shown that patients with detrusor overactivity had an increased
expression of capsaicin and purinergic receptors, and intravesical infiltration of
BoNT/A resulted in a decrease of these sensory receptors. Thirdly, evidence sug-
gests that this agent could act centrally by an effect on the lumbosacral cord causing
peripheral desensitization as well.

15.5.3.2 Evidence
BoNT/A infiltration for UUI has been shown to decrease the number of micturitions
and episodes of UI per day and increase bladder filling capacity and the volume of
urine per voiding episode. In a meta-analysis comparing BoNT/A treatment to pla-
cebo, 30% of the patients were cured against 7% in the placebo arm. Quality of life
at 6 months was higher in the treatment group. A study comparing BoNT/A to anti-
muscarinics showed similar rates of improvement in the first 6 months, but the cure
rate was higher in the BoNT/A arm [6]. However, there were higher rates of urinary
tract infections (UTIs) and retention of urine than with the antimuscarinics. These
side effects as well as the need for this treatment to be repeated at 5–9-month inter-
vals result in a high dropout rate from treatment which has been shown to be 60%
at 5-year follow-up [7].

15.5.3.3 Clinical Use

Onabotulinum toxin A has been licensed for use to treat OAB or treatment refrac-
tory UUI in Europe. The intravesical injection can be performed under both local
and general anesthesia, and the trigone area is usually spared to reduce the potential
complication of vesicoureteral reflux.
Although side effects are mainly limited to the urinary tract, patients should be
counseled before starting therapy about the need for repeated treatment sessions
and the possible side effects of retention of urine (5%) requiring clean intermittent
15 Optimizing Pharmacotherapy in Older Adults: Urinary Incontinence 193

catheterization (CIC) as well as UTIs (30%). Risk factors for adverse effects
include age over 61 years as well as a low maximal flow rate, low voiding effi-
ciency, and a high PVR baseline prior to starting treatment. Evidence for use in the
frail older person is limited, and CIC in this patient group can prove difficult to
perform safely.

15.6 Pharmacotherapeutic Management of Stress

Urinary Incontinence

15.6.1 Duloxetine

Duloxetine is the main pharmacotherapeutic agent available for the management of

stress urinary incontinence (SUI) in both females and males. It is not a cure for UI
but provides temporary relief of symptoms. It is usually commenced after a trial of
conservative treatment with pelvic floor muscle training (PFMT) has not proven to
be adequately effective. However, PMFT should be anyway continued when start-
ing duloxetine since it has been shown that clinical improvement as well as improve-
ment in quality of life (QoL) is more significant when duloxetine is combined with
PFMT. Unfortunately, this treatment is associated with a high withdrawal rate
because of side effects. There is very scant data on its efficacy in the older and frail
older persons.

15.6.1.1 Mechanism of Action

Duloxetine is a dual norepinephrine (NE) and serotonin (5HT) reuptake inhibitor.
NE and 5HT receptors are abundantly present in the sacral areas of the spinal cord
particularly in the region of Onuf’s nucleus [8]. NE and 5HT stimulate the motor
neurons (via the pudendal nerve) that results in increased resting tone and contrac-
tion of the external urethral sphincter (EUS). However, this effect depends on a
descending neurotransmitter from the brain (thought to be glutamate) that acts as an
on-off switch for micturition to occur. In the presence of glutamate, in the storage
phase of micturition, NE and 5HT enhance EUS contraction but in the voiding
phase, in the absence of glutamate, this enhancing effect is lost [9]. Duloxetine
therefore preferentially works during the storage phase with no significant effect on
the voiding phase, in this way not affecting voiding function and not resulting in
retention of urine.

15.6.1.2 Evidence
Duloxetine improves SUI, mixed urinary incontinence (MUI), and to a lesser extent
UUI in women. It can improve SUI in males and has also been shown to decrease
post-prostatectomy leakage [6].
It is more effective than PFMT alone in reducing leakage although a trial of
PFMT is usually recommended prior to commencing the medication. However,
PFMT works synergistically with duloxetine, and the effect of the latter on quality
of life (QoL) is better when combined with PFMT.
194 A. Vella and C. Pedone

Unfortunately, duloxetine is associated with a high patient withdrawal rate of 20–40%

in the short term and up to 90% in the long term. Side effects include poor appetite, dry
mouth, nausea and vomiting, constipation, headache, dizziness, falls, sleep disturbance,
tremor, palpitations, and sexual dysfunction. The option of effective minimally invasive
surgical procedures in the younger elderly women, which offers a more definitive form
of treatment, could be a contributing factor to the high withdrawal rate in the long term.
There is no clear data in older persons regarding the duration of usage and
whether the efficacy of duloxetine is sustainable in the long term.

15.6.1.3 Clinical Use

Duloxetine can be used in patients suffering from SUI, MUI, and in women
UUI. Ideally it should be combined with PFMT and bladder training. It should be
explained to the patient that this treatment will not result in a permanent cure for the
UI but can provide temporary relief of their symptoms.
In older persons, it should ideally be started at 20 mg twice daily for 2 weeks and
then increased to 40 mg twice daily which is the recommended therapeutic dose
[10]. Patients should be assessed for benefit and tolerability after 2–4 weeks on the
therapeutic dose.
Duloxetine is eliminated primarily in the urine (one-half life of 12 h) after exten-
sive hepatic metabolism. It can cause some inhibition of CYP2D6 and should not be
used in combination with CYP1A2 inhibitors or nonselective irreversible mono-
amine oxidase inhibitors. Caution must be taken for interactions including possible
serotonergic effects with several antidepressants. Ciprofloxacin inhibits metabolism
of duloxetine and should therefore be avoided. Also, duloxetine could inhibit
metabolism of tamoxifen to its active metabolites.
Because of its side effects and paucity of evidence in the frail older person, in
certain situations such as a high level of dependence and advanced cognitive impair-
ment, the use of appropriate absorbent aids could be a valuable alternative.

15.6.2 Desmopressin

Desmopressin, a synthetic analog of vasopressin (antidiuretic hormone), is primar-

ily used in the treatment of diabetes insipidus but has also been used to treat noctu-
ria. However, it is not licensed for the treatment of UI and is associated with
hyponatraemia.

15.6.2.1 Mechanism of Action

Desmopressin acts as a selective agonist on receptors present throughout the col-
lecting ducts and distal convoluted tubules of the kidneys, and it increases the
amount of solute-free water that is reabsorbed into the circulation from the filtrate
in this way concentrating the urine and decreasing its volume.

15.6.2.2 Evidence
Although it has been shown to be beneficial in the treatment of nocturia, there is no
evidence to support its use in UI. Two RCTs have shown some decrease in daytime
15 Optimizing Pharmacotherapy in Older Adults: Urinary Incontinence 195

incontinence in the 4-h period following its administration; however, this effect
was not sustained thereafter. Its long-term use does not improve UI in men
and women.

15.6.2.3 Clinical Use

Desmopressin should not be used to manage UI in older patients. Hyponatremia is
a relatively common and serious risk when using this medication, and, in several
cases, patients required hospitalization [11]. This risk increases with age and with a
baseline hyponatremia.

15.7 Topical Estrogen Therapy

Vaginal estrogen therapy can be used to treat incontinence in postmenopausal

women. It has been shown to improve quality of life and can improve continence
especially UUI, but there is no consistent data of its effect on SUI.

15.7.1 Mechanism of Action

Estrogen receptors have been found in the pelvic floor muscles, urogenital liga-
ments, the epithelial tissue of the bladder, urethra and trigone, detrusor muscle,
and vagina.
Estrogens produce a trophic effect on the epithelial mucosa in the vagina, ure-
thra, and bladder in this way enhancing the “mucosal sphincter” effect as well as
increasing the periurethral vascularization which is important in regulating the ure-
thral closing pressure [12]. They also increase the ratio of alpha to beta adrenergic
receptors favoring increased urethral tonicity. Some of the perceived improvement
in lower urinary tract symptoms might be because of their estrogenic effect of
decreasing vaginal discomfort associated with vaginal atrophy.
The effects of estrogens on incontinence comes about from the fact that estrogen
receptors are ubiquitous in the LUT and therefore maintain a stable balance between
tissues that confers improvement in postmenopausal UI.

15.7.2 Evidence

Vaginal estrogen therapy improves UI in postmenopausal women particularly those

with symptoms of vulvovaginal atrophy. It is most effective in urge urinary inconti-
nence. There is no consistent evidence on its effect in SUI, but in some studies, it
has been shown to improve symptoms and quality of life. Evidence on their use in
frail older patients is mainly related to prophylaxis of urinary tract infections rather
than for UI.
Oral or any other non-vaginal routes of administration do not improve UI and
can actually worsen it [13].
196 A. Vella and C. Pedone

15.7.3 Clinical Use

Vaginal estrogen therapy can be administered as estradiol, estriol, or conjugated

equine estrogen in various forms that include creams, vaginal pessaries, and impreg-
nated vaginal rings. There is no significant difference between these modes of deliv-
ery, and this might have to be adapted to the patient’s ability to apply these
preparations. Commoner side effects include abdominal pain, vaginal hemorrhage,
and vulvovaginal disorders.
It has been shown that there is a degree of systemic absorption of these topical
preparations, and one should anyway be vigilant for side effects. The ideal duration
of treatment and the long-term side effects in older persons are uncertain, and this
treatment should be used at the smallest effective dose to minimize systemic effects.
Patients should be reviewed at least annually with special considerations given to
any symptoms of endometrial hyperplasia.
They are contraindicated in patients with breast cancer taking aromatase inhibi-
tors since they could counteract the therapeutic benefit of the chemotherapy.

15.8 Drugs for Benign Prostatic Hypertrophy (BPH)

In men, one of the most common causes of overactive bladder and urge incontinence is
benign prostatic hypertrophy (BPH). In people with this condition, the association of
drugs for BPH and antimuscarinic/mirabegron may be used, although the latter must be
avoided in the presence of severe obstruction. Among drugs used for BPH, both
5-alpha-reductase inhibitors (including Serenoa repens) and alpha-­adrenergic antago-
nists are effective in reducing overactive bladder symptoms. In the older people, how-
ever, alpha-adrenergic antagonists are associated with increased risk of hypotension
and falls, and while the risk is smaller with prostate-specific drugs, it is still significant.
Serenoa repens is also used to treat symptoms. Phosphodiesterase inhibitors such as
tadalafil may also be used as adjuvant therapy in selected subset of patients.

15.8.1 Mechanism of Action

5-Alpha-reductase inhibitors block the conversion of testosterone to 5-alpha-­

dihydrotestosterone (DIT) that has higher affinity for the androgen receptor and
therefore reduce the androgen stimulation on the prostate. Alpha-adrenergic block-
ers act by relaxing smooth muscle both within the prostatic gland and the bladder
neck; phosphodiesterase inhibitors also act on prostatic smooth muscle cells.
However, the effects of these drugs are at least in part independent on their effects
on bladder outlet obstruction.

15.8.2 Evidence

5-Alpha-reductase inhibitors, even in monotherapy, can reduce lower urinary tract

symptoms, although the effect of alpha-blockers is more evident [14]. These drugs,
15 Optimizing Pharmacotherapy in Older Adults: Urinary Incontinence 197

however, may be less tolerated by older patients because of the risk of orthostatic
hypotension. Evidence on the effect of Serenoa repens are conflicting.

15.8.3 Clinical Use

5-Alpha-reductase inhibitors are the first-line medical therapy in the treatment of

BPH. They are generally well tolerated but may mask an increase of prostate-­
specific antigen (PSA) in people with prostate cancer. It is recommended to obtain
the PSA serum concentration before starting the therapy with these drugs and then
to repeat the assessment after the beginning of the therapy to have a baseline for
prostate cancer screening (when indicated). Alpha-receptor blockers may be used
when rapid symptom control is desired, but the risk for falls due to orthostatic hypo-
tension must be weighed against the potential benefits.

15.9 Conclusions

Drug therapy is to be considered a second-line option in the management of UI in

older people. Currently, options are available especially for overactive bladder/urge
incontinence. These drugs seem to be effective, especially in the short term, and the
risk for serious drug-related adverse events is low. Nonetheless, evidence on very
old and frail people is scant, and the very low rate of persistence on drug therapy
indicates that the overall benefit may not offset the untoward effects of these drugs.
Currently, new drug targets are being investigated, and a selective norepinephrine
reuptake inhibitor has shown promising results in a phase II clinical trial.
In conclusion, drug therapy may be an option in the treatment of UI, but patients’
expectations and risk profile (e.g., low cognitive reserve) must be weighed against a
realistic evaluation of efficacy.

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Constipation
16
Giammarco Fava

Constipation is a common clinical manifestation in older adults. The prevalence of

constipation increases with age and differs among settings with ranges in the elderly
from 24 to 50% [1–7]. The correct etiology of constipation in the elderly is required
to establish the best management. In fact, constipation may be chronic functional or
secondary to other etiologic factors [8]. Primary colorectal dysfunction consists of
three overlapping subtypes: slow transit constipation, dyssynergic defecation, and
irritable bowel syndrome with constipation. Secondary causes of constipation
should be excluded by history, physical examination, and medical history followed
by diagnostic testing [8]. The treatment of secondary constipation is beyond the aim
of this chapter. The first step for the treatment of chronic functional constipation is
modification of lifestyle and diet behavior.

16.1 Lifestyle

General measures such as increased fluid intake and exercise are suggested to man-
age constipation (Fig. 16.1). Even if poor evidences support this advice [9], it is
suggested increasing water intake to 1.5–2 L daily to enhance the effects of fiber in
constipated patients [10] (Fig. 16.1). Patients with a normal bowel transit usually
empty stools at approximately the same time daily [11, 12], and defecation is par-
tially a conditioned reflex. Colonic motor activity is more active after waking and
after a meal [13]; thus, the optimal time for defecation is usually within the first 2 h
after waking and after breakfast. For this reason, there is a rationale in educating
patients to attempt a bowel movement at least twice a day, usually 30 min after
meals, and to strain for no more than 5 min [14].

G. Fava (*)
Gastroenterology and Digestive Endoscopy Unit, Italian National Research Center on Aging
(IRCCS-INRCA), Ancona, Italy
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 199

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_16
200 G. Fava

Constipation (primary)

Increase physical exercise

Increase fluid intake
Increase fiber intake

no response response
continue

Bulking forming laxatives

no response response
continue

Osmotic laxatives
PAMORAs
In opioid-induced response
no response
constipation continue, adjusting dosage
Stimulant laxatives (temporary)
no response response
reducing dosage
Loosing
Colonic secretagogues
response
5HT4 receptor agonists

no response response
continue, adjusting dosage
Reassess diagnosis
Surgery

Fig. 16.1 Algorithm for the choice of laxative

16.2 Diet and Fiber

Fiber increases stool bulk, which causes colonic distention and promotes stool pro-
pulsion. Fiber is obtained primarily from grains and bran cereals [12]. There is a
weak evidence for the effectiveness of fiber consumption as treatment of constipa-
tion in older people. One study demonstrates that higher fiber intake was associated
with lower laxative use among older women [15], but another work shows that
higher intake of bran was associated with no reduction in constipation symptoms
and greater fecal loading in the colon [5]. In practical terms, a daily fiber intake of
20–30 g/day is generally recommended to improve bowel transit (Fig. 16.1). The
effects of fiber on bowel movements may take several weeks. Bloating, flatulence,
and cramps are a common problem with increased fiber intake, especially bran
fiber [16].
16 Constipation 201

16.3 Pharmacologic Treatment

Laxatives are prescribed in patients with constipation not responding to lifestyle and
dietary modification. Many studies comparing laxative effects in older people are of
poor quality and limited by unclear definitions for constipation, inconsistent out-
come measurement, and underreporting of potential confounding factors during the
trial period (e.g., fiber intake) [17–26]. Laxatives are used daily by 10–18% of com-
munity dwelling older adults and 74% of nursing home residents [4, 27, 28]. These
data suggest that sometimes these drugs are empirically prescribed to older patients
[29, 30]. However, osmotic salts, sugars and sugar alcohols, polyethylene glycol
(PEG), anthraquinones, diphenolic laxatives, and diphenylmethanes generally have
been shown efficacy and safety [17, 29, 30].

16.4 Bulk Forming Laxatives

Bulk forming laxatives include psyllium husk, methylcellulose, calcium polycarbo-

phil, and wheat dextrin. They are natural, synthetic polysaccharides or cellulose
derivatives that primarily exert their laxative effect by absorbing water and swelling
in the small and large intestine to form soft and bulky stool [17]. These drugs
increase the frequency and reduce the consistency of stool with a minimum of
adverse effects. They may be used alone or in combination with an increase in
dietary fiber and require an adequate amount of fluid intake (Fig. 16.1); otherwise,
they may worsen constipation [17]. Despite anecdotal clinical experience indicating
benefit for bulk forming laxatives, clear evidence regarding the effectiveness is
inconsistent. A systematic review found evidence that psyllium increases stool fre-
quency in patients with chronic constipation but found insufficient evidence for
benefit of other forms of fiber including calcium polycarbophil, methylcellulose,
and bran [18]. On the contrary, another review shows efficacy and safety of calcium
polycarbophil instead of psyllium and methylcellulose [19]. No statistically signifi-
cant differences in adverse events were identified between any bulking agent and an
active comparator or placebo. Task force members noted that large quantities of
psyllium may be associated with bloating. Also, mechanical obstruction of the
esophagus and colon has been rarely reported with bulking agents, and anaphylactic
reactions have been reported with psyllium [18].

16.5 Osmotic Laxatives

Osmotic laxatives should be used in patients not responding to bulk forming laxa-
tives [20] (Fig. 16.1). Osmotic laxatives increase fecal volume and reduce stool
consistency by creating an intraluminal osmotic gradient that leads to secretion of
202 G. Fava

water and electrolytes into the intestinal lumen [17]. They are divided into three
categories: poorly absorbed ions, nonabsorbable carbohydrates, and polyethyl-
ene glycol.

16.5.1 Poorly Absorbed Ions

Magnesium, sulfate, and phosphate ions are partly absorbed by the intestine, thus
creating a hyperosmolar intraluminal environment. This leads to an osmotic mecha-
nism, even if they have other possible effects with unclear consequences, such as
increase of prostaglandin concentrations in the stool [21]. Magnesium hydroxide
typically induces a bowel movement within 6 h (Table 16.1). Moreover, magnesium
sulfate is a potent laxative that produces a large volume of liquid stool and often
leads to abdominal distention and sudden passage of a foul-smelling liquid stool.
However, the assumption of magnesium, particularly in older adults, needs to be
limited since it could cause adverse effects such as flatulence, abdominal cramps,
and volume overload. A small amount of magnesium is actively absorbed in the
small intestine, while the remainder draws water into the intestine by an osmotic
gradient [22]. Hypermagnesemia can develop particularly in patients with kidney
diseases and in children, and hypermagnesemia-induced paralytic ileus was
described as a rare complication [23]. Absorption of magnesium can cause electro-
lyte and volume overload in patients with kidney failure or cardiac dysfunction.
Also, in case of dehydration, excessive use of magnesium based laxatives can
develop these complications even in healthy patients.
Phosphate is mostly absorbed by the small intestine; thus, a large quantity needs
to be ingested to produce an osmotic laxative effect, and this is not ideal for routine
use [17]. Rare but serious reports of acute phosphate nephropathy have been
described in patients treated with oral sodium phosphate products for colon cleans-
ing prior to colonoscopy. Some patients have resulted in permanent damage of renal
function and required long-term dialysis. While some cases have occurred in
patients with normal baseline renal function, risk factors of acute phosphate
nephropathy include advanced age, hypovolemia, increased bowel transit time (such
as bowel obstruction), active colitis, kidney disease, and use of medicines that affect
renal perfusion or function such as diuretics, angiotensin-converting enzyme [ACE]
inhibitors, angiotensin receptor blockers, and possibly nonsteroidal anti-­
inflammatory drugs [NSAIDs]. Patients should be advised to split dosage regimen
and warning about the importance of adequate hydration before, during, and after
use of oral sodium phosphate products. Additional sodium phosphate-based purga-
tive or enema products should be avoided [24].

16.5.2 Nonabsorbable Carbohydrates

Lactulose. Lactulose is a nonabsorbable synthetic disaccharide constituted by galac-

tose and fructose linked by a bond resistant to lactase. Lactulose is not absorbed by
16 Constipation

Table 16.1 Summary of more common laxatives

Osmotic laxatives
Nonabsorbable Metabolically Stool
Poorly absorbed ions carbohydrates inert Stimulant laxatives Colonic secretagogues Serotoninergics softener Enemas Suppositories
Drugs (generic Bulking agents Magnesium Sodium Lactulose PEG Senna Bisacodyl Lubiprostone Linaclotide Prucalopride Docusate Phosphate enema Bisacodyl Bisacodyl Glycerin
name) (psyllium, hydroxide phosphate sodium
methylcellulose,
polycarbophil)
Recommended 4–20 g 15–30 mL once 20 mL once 15–30 mL 17–34 g once 5–20 mL 10–30 mg 24 μg twice 290 μg 2 mg once 100 mg 120 mL once 10 mg 10 mg 60 g
dose (daily) or twice once or twice or twice once; once once twice once once once
7.5–
15 mg
once
Side effects Bloating, Bloating, Acute Bloating, Bloating, Cramps, Cramps, Headache, Diarrhea, Nausea, Efficacy Rectal mucosa Rectal Rectal Rectal
intestinal abdominal phosphate diarrhea, cramps, diarrhea, nausea, nausea, bloating headache, not well injury, mucosa mucosa mucosa
obstruction, cramps, volume nephropathy nausea, flatulence, nausea, electrolyte diarrhea diarrhea defined hyperphosphatemia irritation irritation irritation
allergic overload (in pts. (during hyperglycemia electrolyte vomiting, imbalance,
reactions (rare) with kidney bowel in diabetics imbalance, melanosis vomiting
disease or cardiac preparation) allergic coli
dysfunction), reaction,
hypermagnesemia Mallory
Weiss tears
(rare, during
bowel prep)
203
204 G. Fava

the small intestine and is transformed in the colon to yield short-chain fatty acids,
hydrogen, and carbon dioxide, with consequent pulling water out from the body and
into the colon and lowering of the fecal pH. If lactulose is administered at dosage of
20 g (30 mL) daily, the sugar is not detectable in the stool. Indeed, in larger doses,
some drug passes through the colon unchanged; thus, it should be used with caution
in diabetic patients because of the risk of increasing glycemia. The recommended
dose of lactulose in adults is 15–30 mL once or twice daily. The time to onset of
action is longer than that of other osmotic laxatives since 2 or 3 days are required
for lactulose to achieve an effect. Some patients report that lactulose is effective
initially but then gradually loses its effect, possibly due to alteration in the intestinal
flora in response to the medication [25]. Side effects related to lactulose include
abdominal distention or discomfort, presumably as a result of colonic gas produc-
tion, diarrhea, and nausea. Cases of lactulose-induced megacolon have been also
reported [25].
The osmotic laxatives are consistently better than placebo for improving the
symptoms of constipation [26, 31]. Four studies compared osmotic laxative with
placebo, and three studies compared two osmotic laxatives. In two RCTs, lactulose
significantly increased the defecation frequency in respect with placebo and signifi-
cantly decreased the need for laxative use [32, 33]. Lactitol also significantly
increased the number of defecations, improved stool consistency, and decreased
laxative use compared with placebo [34].
Sorbitol and Mannitol. Sorbitol is widely used in the food industry as an artificial
sweetener but is rarely used in clinical practice. Ingestion of 5 g sorbitol causes a
rise in breath hydrogen, and 20 g produces diarrhea in about half of normal subjects
[35]. Sorbitol is as effective as lactulose and less expensive. A randomized double-­
blind crossover trial of lactulose (20 g/day) and sorbitol (21 g/day) in ambulatory
older men with chronic constipation showed no difference between the two com-
pounds with regard to frequency or normality of bowel movements or patient pref-
erence [36]. The frequency of side effects was similar except for nausea, which was
more common with lactulose. Mannitol is another sugar alcohol that can be used as
a laxative. Like sorbitol, it is rarely used for clinical management of constipation.

16.5.3 Polyethylene Glycol

Polyethylene glycol (PEG) is an isosmotic and metabolically inert laxative able to

bind water molecules, thereby increasing intraluminal water retention [37]. PEG is
not metabolized by colonic bacteria and is excreted mostly unaltered into the feces
leading to an increase in stool volume and softer stools, which may become liquid
depending to the volume of PEG ingested. Electrolytes are added to PEG solutions
used for colonic preparation before colonoscopy to avoid the potential adverse
effects associated with diarrhea, such as dehydration and electrolyte imbalance.
PEG-3350 without electrolytes is available as an over-the-counter powder and is
mixed in smaller doses with water for regular use to treat constipation. The most
common adverse events of PEG, especially if used at high dosage (34 g/day),
16 Constipation 205

include abdominal bloating, cramps, and flatulence [37, 38] (Table 16.1). In addi-
tion, the most commonly reported side effects of PEG used for colonoscopy prepa-
ration include electrolyte imbalances, allergic reactions, and Mallory-Weiss tears
[39] (Table 16.1). Cases of fulminant pulmonary edema have been reported after
administration of PEG solution by nasogastric tube, with one fatality [40, 41]. In
each case, the patient had emesis, suggesting aspiration of PEG. PEG also may
delay gastric emptying [42]. The strongest evidence for clinical benefit exists for
PEG, which has been evaluated in 19 trials, mostly compared to placebo, followed
by lactulose and tegaserod [31, 43]. In the largest study (304 patients treated for
6 months), patients given PEG had more bowel movements per week than patients
of placebo group [44]. In a retrospective series study, its efficacy was maintained for
up to 24 months [44, 45]. Patients prefer PEG preparations without electrolyte sup-
plements [46], which are necessary when a large volume is required [47].

16.6 Stimulant Laxatives

Stimulant laxatives are generally used as a rescue in case of no response to osmotic

laxatives (Fig. 16.1), especially if patients have not defecated for 2–3 days [48].
These compounds accelerate intestinal motility and secretion of water, electrolytes,
and prostaglandin into the lumen of colon [49], thus accelerating transit [50]. Their
effect starts within hours after assumption, and it is often accompanied by abdomi-
nal cramps. Stimulant laxatives include anthraquinone derivatives (e.g., cascara,
aloe, senna) and diphenylmethane derivatives (e.g., bisacodyl, sodium picosulfate,
phenolphthalein). Castor oil is used less commonly because of its side-effect pro-
file. The effect of these stimulant laxatives is dose dependent. Low doses prevent
absorption of water and sodium, whereas high doses stimulate secretion of sodium,
followed by water, into the colonic lumen [17]. Stimulant laxatives are sometimes
abused, especially in patients with an eating disorder even though at high doses they
have only a modest effect on calorie absorption [51]. Stimulant laxatives can pro-
duce normal, soft, formed stools in some patients but are often associated with
abdominal cramps and diarrhea even in standard doses (Table 16.1). They act rap-
idly and are particularly suitable for use in a single dose for temporary constipation
[17]. Most clinicians are cautious about recommending daily dosing of stimulant
laxatives indefinitely for chronic constipation. Stimulant laxatives vary widely in
clinical effectiveness, and some patients with severe constipation are nonre-
sponder [17].

16.6.1 Anthraquinone Derivatives

Anthraquinones (e.g., cascara, senna, aloe, frangula) are obtained by a variety of

plants [17]. They are constituted by inactive glycosides which pass unabsorbed and
unchanged through the small intestine. These drugs are hydrolyzed into the colon
by bacterial glycosidases to active metabolites able to increase the transport of
206 G. Fava

electrolytes into the lumen and stimulate myenteric plexuses to induce intestinal
motility. The anthraquinones typically permit defecation 6–8 h after ingestion [51]
(Table 16.1). Senna has been shown to soften stools [52] and increase stool fre-
quency and weight. Anthraquinones cause apoptosis of colonic epithelial cells,
which are then phagocytosed by macrophages and appear as a lipofuscin-like pig-
ment that darkens the colonic mucosa, a condition termed Melanosis coli [53]
(Table 16.1). Moreover, these laxatives don’t induce significant adverse functional
or structural changes in the intestine. Animal studies have shown neither damage to
the myenteric plexus after long-term administration of sennosides [54] nor a func-
tional defect in motility [55].

16.6.2 Diphenylmethane Derivatives

Diphenylmethane compounds include bisacodyl and sodium picosulfate. After oral

ingestion, bisacodyl and sodium picosulfate are hydrolyzed to the same active
metabolite, but the mode of hydrolysis differs since the first is hydrolyzed by intes-
tinal enzymes, thus acting in the small and large intestines, and the second is hydro-
lyzed by colonic bacteria [17]. Like anthraquinones, the action of sodium picosulfate
is confined to the colon, and its activity depends by the bacterial flora. The effects
of bisacodyl, and presumably sodium picosulfate, on the colon are similar to those
of the anthraquinone laxatives [17]. When applied to the colonic mucosa, bisacodyl
induces an almost immediate, powerful, propulsive motor activity in healthy and
constipated subjects, although the effect is sometimes reduced in the latter [56].
These laxatives also stimulate colonic secretion. Similarly to the anthraquinone
laxatives, bisacodyl leads to apoptosis of colonic epithelial cells, the remnants of
which accumulate in phagocytic macrophages, but these cellular remnants are not
pigmented [57]. Bisacodyl is a useful and predictable laxative, especially suitable
for single-dose use in patients with temporary constipation. Bisacodyl was evalu-
ated in a randomized, double-blind, placebo-controlled, parallel-group study in
which patients were randomized to bisacodyl (10 mg) or placebo for 4 weeks. The
mean number of complete spontaneous bowel movements (CSBMs) per week, the
number of spontaneous bowel movements (SBMs), constipation-associated symp-
toms, and quality of life were significantly improved in the bisacodyl group com-
pared to placebo [58]. Treatment with bisacodyl was also well tolerated (Table 16.1).
However, the long-term safety of stimulant laxatives has not been established.
Sodium picosulfate is available as part of a colonoscopy preparation. In a ran-
domized, double-blind, placebo-controlled study conducted in Germany, 233
patients with chronic constipation were randomized to sodium picosulfate (10 mg
drops) or placebo once daily for 4 weeks. Patients of the sodium picosulfate group
reported a greater number of CSBM per week during the treatment period compared
with those in the placebo group (0.9 ± 0.1 at baseline increased to 3.4 ± 0.2 in the
sodium picosulfate group and 1.1 ± 0.1 at baseline increased to 1.7 ± 0.1 in the
placebo group). Patients who received sodium picosulfate reported improvement in
straining, incomplete evacuation, a feeling of anal obstruction, and improvement in
16 Constipation 207

stool form and had increased quality-of-life scores compared with those who
received placebo. Diarrhea was reported by 32% of patients who received the
sodium picosulfate [59] (Table 16.1).
A systematic review and meta-analysis of pharmacotherapies for chronic consti-
pation showed that bisacodyl and sodium picosulfate met the primary endpoints of
responder analysis with greater than or equal to 3 CSBM per week and an increase
over baseline of greater than or equal to 1 CSBM per week [60]. However, bisacodyl
may be superior to other prescription drugs in secondary endpoints, including an
increase from baseline in the number of spontaneous bowel movements (SBM) per
week and in the number of CSBM per week [17]. No studies have compared bisaco-
dyl to placebo in elderly patients with constipation [26].

16.6.3 Castor Oil

Castor oil is obtained from the castor bean. After oral ingestion, it is hydrolyzed by
lipase in the small intestine to ricinoleic acid, which inhibits intestinal water absorp-
tion and stimulates intestinal motor function by damaging mucosal cells and releas-
ing neurotransmitters [61]. Cramping is frequent, and consequently castor oil is not
commonly used in clinical practice.

16.7 Other Therapies for Chronic Constipation

Several agents have been studied or are undergoing further studies for the treatment
of chronic constipation. These include colonic secretagogues, opioid antagonists,
and 5HT4 receptor agonists (Fig. 16.1 and Table 16.1).

16.8 Colonic Secretagogues

Lubiprostone is an oral bicyclic fatty acid that activates the type 2 chloride channels
on the intestinal epithelial cells, thus secreting chloride and water into the intestinal
lumen [14]. In two phase III studies of 4 weeks’ duration, lubiprostone 24 μg twice
daily significantly enhanced bowel movement frequency and relieved other
constipation-­related symptoms compared with placebo [62]. In a subgroup analysis,
lubiprostone also demonstrated efficacy in older patients. It is best reserved for
patients with severe constipation in whom other approaches have been unsuccessful
[8]. Nausea was the most common reported adverse event, occurring in up to 31.7%
of patients and leading to discontinuation in 5% [63] (Table 16.1). Lubiprostone is
also approved in the USA for the treatment of opioid-induced constipation as well
as for women with IBS with constipation at a dose of 8 μg twice daily [17].
Linaclotide and plecanatide are guanylate cyclase C receptor (GCC) agonists
that stimulate intestinal fluid secretion and transit [64]. Linaclotide is a minimally
absorbed 14-amino-acid peptide that activates the guanylate cyclase C receptor on
208 G. Fava

the luminal surface of the intestinal epithelium, resulting in increased levels of

cyclic guanosine monophosphate and increased secretion of chloride and bicarbon-
ate into the intestinal lumen. In animal models, cyclic guanosine monophosphate
also appears to reduce firing of afferent nerves in the bowel [65].
In two large phase III trials of patients with chronic constipation, the linaclotide-­
treated groups (both 145 μg and 290 μg) had significantly higher rates of three or
more complete spontaneous bowel movements (CSBM) per week and an increase
in one or more CSBMs from baseline during at least 9 out of 12 weeks as compared
with placebo (145 μg: 21 and 16%; 290 μg: 19 and 21%; placebo: 3 and 6%) [66].
Linaclotide also increased stool frequency, improved stool consistency, and reduced
straining, abdominal bloating, and discomfort as compared with placebo [66]. The
most common dose-related adverse event was diarrhea that led to discontinuation of
treatment in 4% of patients in both linaclotide-treated groups [66].

16.9 Opioid Antagonists

Opioids are a drug family largely used to manage chronic pain in clinical practice.
Opioid-induced constipation (OIC) results from the agonist actions of opioid medi-
cations at μ-opioid receptors, which are abundant throughout the gastrointestinal
tract. This adverse event is often underrecognized and undertreated in the elderly
[67]. In elderly patients with OIC and chronic pain who do not respond to lifestyle
interventions or laxatives, treatment of symptoms of constipation may be obtained
using peripherally acting μ-opioid receptor antagonists (PAMORAs), such as alvi-
mopan, methylnaltrexone, naloxegol, naldemedine, or alvimopan for paralytic ileus
[68]. These opioid receptor antagonists act peripherally and do not cross the blood-­
brain barrier, thus decreasing the constipating effects of opioids without impairing
their analgesic effects [69]. The availability of the new pharmacologic agents meth-
ylnaltrexone, naloxegol, and lubiprostone may offer more specific and effective
treatment options for elderly patients with OIC and noncancer pain. Moreover,
healthcare providers should consider that methylnaltrexone [70] and naloxegol [71],
because of their peripheral mechanism of action, do not interfere with opioid-­
induced, centrally mediated analgesia when administered to patients with noncan-
cer pain and OIC [67]. The complex multifactorial nature of constipation and its
potentially negative impact in elderly patients with OIC and chronic pain, coupled
with the availability of newer pharmacologic agents that target the underlying
mechanisms of constipation (i.e., PAMORAs), and the locally acting secretagogue
lubiprostone, provide an opportunity for healthcare providers to better manage their
elderly patients with OIC and chronic pain without change in pain medications [67].

16.10 Serotonergic Laxatives

Serotonin (5HT) is a key regulator of gastrointestinal motility. Stimulation of the

5-HT4 receptor on afferent nerves in the wall of the GI tract stimulates peristaltic
contraction of the intestine. Several 5-HT4 agonists have been tested for treating
16 Constipation 209

constipation. Among them, cisapride, was widely used and clinically effective [72]
but was withdrawn from the commercial market in July 2000 for inducing poten-
tially lethal cardiac dysrhythmias. Similarly, tegaserod, another partial 5-HT4 ago-
nist, was also withdrawn in 2007 because of its potential cardiovascular effects.
Prucalopride, a selective high affinity 5HT4 receptor agonist, is a benzofuran
derivative that accelerates colonic transit in healthy humans and patients with
chronic constipation [73]. In a dose of 1 and 4 mg once daily, prucalopride has been
shown to be superior to placebo in 4- and 12-week trials and safe and well tolerated
in patients aged 65 years or older [74, 75]. In clinical trials, prucalopride 2 mg pro-
vided comparable efficacy to 4 mg, and it is therefore the widely used dosage in
clinical practice. The dose of prucalopride can be titrated up based on clinical
response [8]. The most frequent adverse effects were headaches, nausea, and diar-
rhea (Table 16.1). No cardiovascular side effects have been observed to date with
prucalopride, nor any electrocardiographic abnormalities been reported. In addition,
in a study of elderly constipated patients in nursing homes, no differences in vital
signs, electrocardiograph parameters, or Holter-monitoring results were found in
patients receiving prucalopride and placebo. Approximately 88% of the patients had
a history of cardiovascular disease [76].

16.11 Enemas and Suppositories

Enemas and suppositories should be used only as needed for constipation in the
older adult, i.e., after several days of constipation, in order to prevent fecal impac-
tion. Both stimulate evacuation by distention or chemical action toward the rectal
walls, or soften hard stools, or both [17]. Enemas, in particular, need to be used with
caution since the extravasation of the solution into the submucosa can induce seri-
ous damage to the rectal wall [17].

16.11.1 Phosphate Enemas

Hypertonic sodium phosphate enemas cause distention and stimulation of the rec-
tum. Meisel et al. showed that in normal subjects, a single hypertonic phosphate
enema caused disruption of the surface epithelium in 17 of 21 biopsy specimens
[77]. The damage was evident by scanning electron microscopy, showing patchy
denudation of the surface epithelium, exposure of the lamina propria, and absence
of goblet cells. In every case, the mucosa was endoscopically pathological but
returned to normal within 1 week [77]. Phosphate enemas are widely used, although
studies documenting their efficacy are lacking. The use of sodium phosphate ene-
mas for the treatment of constipation in older adults is contraindicated. In a retro-
spective series, the use of sodium phosphate enemas in this setting of patients (mean
age, 80 years) was followed by complications including hypotension and volume
depletion, hyperphosphatemia, hypo- or hyperkalemia, metabolic acidosis, severe
hypocalcemia, renal failure, and electrocardiogram changes (prolonged QT inter-
val) [78]. In January 2014, the US Food and Drug Administration (FDA) issued a
210 G. Fava

safety warning regarding electrolyte abnormalities and severe dehydration caused

by a single dose of over-the-counter sodium phosphate that was larger than recom-
mended or with more than one dose in 24 h [79]. The FDA stated that individuals at
higher risk for potential adverse effects when the recommended dose is exceeded
include individuals older than 55 years; patients with dehydration, bowel obstruc-
tion, or inflammation; and patients with kidney disease or on medication that may
affect renal function [80].

16.11.2 Saline, Tap Water, and Soapsuds Enemas

Saline, tap water, or soapsuds enemas exert their action by distending the rectum
and softening feces. Stool evacuation typically occurs 2–5 min following adminis-
tration. If utilized with small volume, they usually don’t induce damage; however,
large volumes can be accompanied by serious effects such as water intoxication
hyperphosphatemia and other electrolyte disturbances in case of enema retention.
Soapsuds enemas can cause rectal mucosal damage and necrosis [17] (Table 16.1).

16.11.3 Stimulant Suppositories and Enemas

Glycerin or bisacodyl suppositories can be used in institutionalized older adults

with dyssynergic defecation to favor evacuation by stimulating the rectum through
an osmotic effect. The effect of glycerin on the rectal mucosa is unknown, while
bisacodyl 10 mg acts topically by stimulating enteric neurons [81] (Table 16.1). A
study showed that in normal subjects, a single bisacodyl suppository or an enema
containing 19 mg of bisacodyl in 100 or 200 mL of water produced marked changes
in 23 of 25 rectal mucosal biopsy specimens. The epithelium of the surface and
within the crypts was altered; with use of the enema, the surface epithelium was
absent [77]. Regular use of bisacodyl suppositories, therefore, is contraindicated.

16.11.4 Dioctyl Sulfosuccinate (Docusate)

Dioctyl sulfosuccinate, commonly named docusate (calcium or sodium), is a stool

softener acting as an anionic surfactant able to stimulate fluid secretion in the small
and large intestines [82, 83]. Findings from systematic reviews involving hospital-
ized patients indicate that docusate does not prevent or improve symptoms of con-
stipation [19] and was less effective than psyllium for treating chronic idiopathic
constipation [84]. The clinical practice guideline in the diagnosis, assessment, and
management of constipation in advanced cancer from the European Society for
Medical Oncology lists docusate as a medication not recommended in the treatment
of constipation in patients with advanced malignancies [82]. Thus, for older adults
and patients at risk for constipation, the adverse effects of inappropriate prescribing
of docusate are of concern. A recent investigation suggests to remove docusate from
all standardized order sets and/or hospital [85].
16 Constipation 211

16.12 Mineral Oils

Mineral oils alter the stool by undergoing emulsification into the stool mass and
facilitating lubrication for stool passage. Long-term use can cause intestinal malab-
sorption of fat-soluble vitamins, anal seepage, and lipoid pneumonia in patients
predisposed to aspiration of liquids [17].

16.13 Probiotics

A recent review of the literature showed that probiotic supplementation decreases

intestinal time, thus significantly improving constipation and increasing defecation
frequency in elderly individuals by 10–40% compared to placebo controls. The
strain of bacteria most commonly tested was Bifidobacterium longum [86]. In addi-
tion, a more recent Japanese observational study [87] demonstrated that almost
daily consumption of Lactobacillus casei strain Shirota (LcS)-containing fermented
milk products could benefit older people who tend to be constipated by increasing
the intestinal population of beneficial microbes (Lactobacillus species) and raising
the intestinal level of metabolites of microbial fermentation (lactic acids), thus stim-
ulating intestinal peristalsis/motility [88, 89]. However, caution is needed when
interpreting these reports because of the heterogeneity of the original study designs,
populations, and the risk of bias. Therefore, further placebo-controlled trials are
necessary to determine the most efficient strains, doses, and the optimal treatment
duration.

16.14 Conclusion

In older adults, constipation is a very common clinical problem with challenging

treatment. Laxative prescription should be individualized according to the patient’s
history (cardiac and kidney diseases), drug interactions, cost, side effects, and other
considerations (e.g., chewing/swallowing disorders). Although laxatives are a first-
line treatment option and considered generally well tolerated, sometimes evidence
is lacking to support their effectiveness. Healthcare providers should take a stepwise
approach (Fig. 16.1) when considering the various treatment options for constipa-
tion in the elderly.

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Pain
17
Sophie Pautex, Monica Escher, and Petra Vayne-Bossert

17.1 Introduction

The International Association for the Study of Pain (IASP) definition states that
pain is an unpleasant sensory and emotional experience associated with actual or
potential tissue damage or described in terms of such damage. Although aging and
especially neurocognitive disorders are associated with structural, biochemical, and
functional changes in the nervous system, there are no arguments that these changes
have a clear and important influence on the perception of pain in the older patient
population [1]. Chronic pain, i.e. pain present for more than 3–6 months, affects
25–76% of home-dwelling people over 65 years and up to 93% of older people in
nursing homes [2, 3]. Most common causes are musculoskeletal pain (up to 83% of
patients) such as joint pain and low back pain due to osteoarthritis, pain from previ-
ous fractures, and peripheral neuropathies. Older adults have often multiple pain-­
associated conditions that likely reflect multiple physiological mechanisms for pain.
Linking pain qualities with other associated pain characteristics serve to develop a
multidimensional approach to geriatric pain assessment [4]. In most studies, about
60% of pain is of pure nociceptive origin resulting from an actual or threatened
damage to nonneural tissue and is due to the activation of nociceptors located in
somatic (e.g., skin, musculoskeletal tissues) or visceral tissues. Secondly, pain can
be caused by a lesion or disease of the nervous system which is called neuropathic
pain. Pure neuropathic pain is present in about 10% of the older population, while
combined nociceptive and neuropathic pain is found in about 1 out of 3 older per-
sons. Persistent pain has a significant impact on all levels of functioning and on
quality of life. Inadequate treatment is associated with various adverse outcomes in
older people, including functional impairment, falls, slow rehabilitation, mood

S. Pautex (*) · M. Escher · P. Vayne-Bossert

Palliative Medicine Division, University Hospital Geneva and University of Geneva,
Geneva, Switzerland
e-mail: [email protected]; [email protected]; [email protected]

© Springer Nature Switzerland AG 2023 217

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_17
218 S. Pautex et al.

changes (depression and anxiety), decreased socialization, sleep and appetite distur-
bance, and greater healthcare use and costs [5, 6]. The management of this persis-
tent pain should be more multidimensional than for acute pain, in particular in this
population.
Pain management includes nonpharmacologic and pharmacologic approaches,
and shared decision making is essential to balance their benefits and burdens. Pain
management goals should be determined with patients before the initiation of any
treatment, and there must be ongoing monitoring of treatment efficacy and adverse
effects over time. Interventions should generally be targeted at improvements in
pain-related disability rather than pain intensity, because improvements in disability
are more tangible outcomes among persons with persistent pain [7, 8].

17.2 Practical Recommendations for the Use of Analgesics

in Older Patients

17.2.1 Paracetamol

Paracetamol is indicated for the management of mild to moderate pain. It is often

considered as the first-line therapy for acute and chronic pain in the older popula-
tion, and regular use has been shown to increase over the years among community-­
dwelling older persons, from 2% in 1999 to 11% in 2019 [9]. Paracetamol does not
exhibit significant anti-inflammatory or antiplatelet effects because it does not
inhibit thromboxane. Taken at recommended doses, it is considered safe although
decreased clearance is observed in frail older people, which might change its safety
in this population [10]. Malnutrition, a common finding in older people, and an
acute fasting state such that which occurs after surgery, may expose older patients
to an increased risk of liver toxicity, notably because of diminished stores of gluta-
thione, an antioxidant that neutralizes N-acetyl-p-benzoquinone-imine (NAPQI), a
toxic metabolite of paracetamol [11]. Furthermore, acute liver toxicity due to inad-
vertent overdose can happen when patients unknowingly consume multiple
paracetamol-containing products simultaneously [12]. One meta-analysis of seven
randomized controlled trials showed superior efficacy of paracetamol compared to
placebo in reducing moderate pain but inferior to NSAIDs for both pain reduction
and physical functioning [13].

17.2.2 Nonsteroidal Anti-inflammatory Drugs

NSAIDs are particularly helpful in treating an inflammatory type of pain where

paracetamol has limited efficacy. However, the American Geriatric Society recom-
mends great caution while using NSAID therapy in older patients due to its estab-
lished gastrointestinal, renal, and cardiovascular side effects and recommends
giving NSAIDs preferably for only short periods of time during episodic flares. A
study on drug reactions leading to hospitalizations in the older population showed
17 Pain 219

NSAID-related side effects as the cause for hospitalization in 23.5% of patients [14,
15]. Gastrointestinal toxicity due to NSAIDs is dose dependent, increases with age
and the concomitant use of cardioprotective doses of aspirin, which is a common
medication in this group. Use of NSAIDs can also lead to renal impairment through
sodium and water retention, electrolyte imbalances, prerenal azotemia, and reduced
blood flow to the kidneys. The concomitant use of NSAIDS and several medications
commonly prescribed in older adults (i.e., anticoagulants, aspirin, and selective
serotonin reuptake inhibitors) increases the risk of bleeding.
Topical NSAIDs are often used for knee or hand osteoarthritis (OA)-related pain.
Evidence from a recent randomized controlled trial showed the comparable efficacy
of topical diclofenac sodium and oral NSAIDs in the treatment of knee osteoarthri-
tis with fewer adverse effects [16]. The mechanism is thought to be an increased
delivery of the drug to the adjacent synovium without significant systemic
absorption.

17.2.3 Opioids

Opioid analgesics are considered for managing severe pain or failed response to
other treatments in older patients. Although the short-term efficacy of opioid anal-
gesics in chronic pain in this group is established, limited evidence is available
regarding the long-term efficacy because of the discontinuation of opioid therapy
due to various poorly tolerated side effects. A prerequisite before initiation of opioid
therapy is the evaluation of risk versus benefit. While taking into account the adverse
outcomes, mandatory efforts should be made to reduce the risks. Administration of
opioids in the older patient is done on a trial basis to titrate the effective dose reach-
ing the therapeutic goal with minimal adverse effects, starting with the lowest pos-
sible dose and continuing with gradual titration. Patients with moderate to severe
pain and diminished pain-related quality of life should be considered for opioid
therapy (low quality of evidence, strong recommendation) [17]. Studies comparing
the efficacy and tolerability of opioids, such as transdermal fentanyl, oral morphine,
and sublingual or transdermal buprenorphine in the older population and other pop-
ulations have shown that older people respond to opioid treatment as well as, or
even better than, younger age groups [18–20]. The “start low and go slow” approach
is essential when dosing opioids. Patients who report severe pain or those who have
experienced uncontrolled pain for prolonged periods of time will likely require
ongoing titration of opioid therapy to balance pain relief with adverse effects.
Opioids should be started at 25–50% of the recommended dose for younger
adults [21].
The decreased volume of distribution that occurs owing to decreased total body
water with aging may also result in increased plasma levels of more hydrophilic
opioids (e.g., morphine) compared with levels observed in younger persons. In gen-
eral, oral bioavailability does not seem to be affected by age, and although first-pass
metabolism may be affected, dosage adjustments are not routinely necessary beyond
the 25–50% dose reduction recommended at opioid initiation [22, 23]. Decrements
220 S. Pautex et al.

in renal function may decrease the excretion of some neurotoxic opioid-related

metabolites. This caution is particularly true for codeine, morphine, hydromor-
phone, and oxycodone, and dose adjustments with even low doses of these agents
should be made accordingly, along with close monitoring for toxicity (e.g., myoclo-
nus [24, 25]).

17.2.3.1 Side Effects of Opioids

Nausea develops in about one-third of patients initiated on opioids and occurs
because these agents slow down the motility of the gastrointestinal (GI) tract, stimu-
late the chemoreceptor trigger zone, and sensitize the vestibular apparatus. If severe
nausea occurs, low-dose haloperidol (0.5 mg), metoclopramide (10 mg), or ondan-
setron (4 mg) scheduled or “as needed” typically manage nausea until it resolves
over the first week of therapy.
Constipation is common in older persons with serious illnesses and nearly uni-
versal in patients taking an opioid. It is often cited by older adults as a reason to
refuse opioid therapy. Constipation results from binding to the mu-receptors in the
GI tract, resulting in slower transit time and subsequent increased water resorption.
Prevention is the cornerstone of constipation management with a bowel stimulant of
senna or bisacodyl scheduled daily at initiation and increased to twice daily if
needed [26]. Osmotic agents, such as polyethylene glycol or milk of magnesia, as
monotherapy generally lack sufficient action to counteract opioid GI effects but can
be helpful in conjunction with stimulant laxatives when needed. Bulk-forming
agents such as psyllium are ineffective and can worsen symptoms if patients do not
ingest an adequate amount of fluid.
Falls: The relationship between pain, falls, and opioids is complex and not com-
pletely understood. Cohort studies support that pain interference is associated with
an increased risk of falls among community-dwelling older adults. The use of opi-
oids in older patients with arthritis may increase the likelihood of falls compared
with patients treated with an NSAID. The risk seems to be higher with short-acting
opioids and at treatment initiation or shortly after [27, 28]. A limitation of published
studies examining the relationship between analgesic use and falls is the lack of
adjustment for the starting opioid dose. Older patients with multiple comorbidities
are more likely to be prescribed opioids for pain. This confounder was addressed in
a study determining the safety of various classes of analgesics in older patients.
Opioids were found to be significantly associated with an increased risk of fracture
compared with NSAIDS and highly selective cox-2 inhibitors (coxibs) [29].
Cognition impairment: The relationship among pain, cognition, and opioids
also remains inconclusive. Undertreated pain may predispose to an increased risk of
confusion, particularly in the hospital. For example, a study of hospitalized hip
fracture patients found that patients taking higher opioid doses had a lower delirium
risk compared with patients taking low-dose or no opioid [30].
Recommendations from The European Association of Palliative Care (EAPC)
Research Network for management of opioid side effects include the following: dose
reduction, symptomatic management of the adverse effects using drugs targeting the
symptoms, opioid rotation, and switching the route of administration [31, 32].
17 Pain 221

Misuse or abuse: In recent years, the abuse or misuse of opioids has steadily
gone up, especially in the USA [33]. The older population is also concerned although
much less than the younger adults. Nevertheless, clinicians must remain vigilant
about the possibility of misuse or abuse of opioid agents in older adults and apply
the abovementioned precautions while prescribing and initiating these agents in
patients with non-cancer pain [34].
Respiratory depression is more frequent (although still rare) in patients who are
opioid naive, receive the agent intravenously, and have increased their doses rapidly.
Furthermore, patients receiving drugs with variable pharmacokinetics such as meth-
adone, patients with concomitant use of central nervous system depressing drugs
such as benzodiazepines or barbiturates, or patients who develop sudden acute kid-
ney failure are more at risk for this adverse event.

17.2.3.2 Examples of Opioids Frequently Used for Pain

Management (See Table 17.1)

Tramadol
Tramadol, a weak mu-opioid agonist with additional serotonin and norepinephrine
reuptake inhibition, is not routinely recommended for older adults with moderate to
severe pain but is commonly used. Importantly, its mu-opioid receptor activity
results in a similar side effect profile as other opioids and requires similar cautions
described herein. Nausea, dizziness, and tiredness seem particularly common [35].
In addition, tramadol increases seizure risk, particularly at doses higher than
300 mg/day, the maximum daily dose recommended in an older adult. Lastly, the
development of serotonin syndrome may occur with the use of tramadol, particu-
larly with concomitant use of serotonergic drugs. Tramadol is activated to its opioid
metabolite by CYP2D6. Patients should be closely monitored to detect a potential
clinical impact—either decreased efficacy or increased side effects—due to drug-­
drug interactions or to modified metabolism in ultrarapid and poor metabolizers.
Tramadol should be initiated at 25 mg three or four times daily and increased in
25 mg increments every 2–3 days to an initial goal of 100 mg–200 mg/day.

Tapentadol
Tapentadol is a weak opioid that acts on the mu receptor and on neuronal reuptake
of noradrenaline. Unlike tramadol, it has only weak effects on serotonin reuptake. It
has no active metabolites and does not need to be activated to exert its analgesic
opioid effect [36]. There are no sufficient data to support the use of newer drug
tapentadol over other opioids.

Morphine
Morphine has been used to treat malignant pain for many years and has been the
subject of a large number of trials, generally involving small numbers of patients.
Morphine is metabolized in the liver by glucuronidation. Morphine-6-glucuronide
(M6G) is a potent analgesic, and morphine-3-glucuronide (M3G) may cause neuro-
excitatory effects [37]. Renal excretion accounts for about 90% of the elimination
222 S. Pautex et al.

Table 17.1 Opioids commonly used in older patients

Onset
Route of of Duration Recommended and
Medication admin action of action maximal doses Comments
Tramadol p.o immediate IR: 75 mg Often in
release 25–50 mg every 6 h association with
p.o. extended every 150 mg paracetamol
release 6–8 h every Reduces the
s.c., i.m. ER: 12 h seizure threshold
i.v. 50–100 mg Risk of
every 12 h serotoninergic
syndrome in
combination
with other
serotoninergic
drugs
Drug-drug
interaction (in
particular
CYP2D6)
Tapentadol p.o. immediate IR: 25 mg 150 mg Low potential
release every every 6 h for drug
p.o. extended 4–6 h 300 mg interactions
release ER: 50 mg every Because of a
every 12 h 12 h lack of evidence,
not
recommended in
frail older
people
Morphine p.o. immediate 30– 4h IR: NA M6G contributes
release 60 min 8–12 h 2.5–5 mg to the overall
p.o. extended 3h 4h every analgesic effect;
release 15 min 4h 4–6 h M3G passes the
s.c., i.m. 15 min ER: 10 mg blood-brain
i.v. every 12 h barrier and may
cause neurotoxic
effects.
Decreased
glomerular
filtration rate
causes
accumulation of
those
metabolites
causing even
more severe side
effects
17 Pain 223

Table 17.1 (continued)

Onset
Route of of Duration Recommended and
Medication admin action of action maximal doses Comments
Oxycodone p.o. immediate 15– 4h IR: 2.5 mg See Daily maximal
release 30 min 12 h every comment dose for
p.o. extended 3–4 h 4–6 h extended release
release ER: oxycodone
5–10 mg combined with
every 12 h naloxone:
160 mg/80 mg
Active opioid
metabolite
(CYP2D6)
Fentanyl i.v., 5 min 30– 12 mcg/h NA Avoid starting in
s.cut. 30 min 60 min patch every opioid naïve
Transdermic 12– 6–12 h 72 h patients
14 h 72 h No dose
2–3 h adaptations
necessary in
renal failure
patients
Buprenorphine Sublingual 45– 6–8 h 17.5 mcg/h NA No dose
i.v., s. cut. 60 min 6–8 h patch every adaptations
Transdermic** 20– 72 h 72–96 h necessary in
40 min renal failure
12– patients
24 h
Hydromorphone p.o. immediate 30– 4h IR: 1 mg NA
release 60 min 12 h every
p.o. extended 3 h 4h 4–6 h
release 15 min 4h ER: 4 mg
s.c. 15 min every 12 h
i.v.

of morphine and its metabolites. Therefore, accumulation of the metabolites in

patients with renal impairment can occur and cause side effects requiring dose
adjustment or switching to an alternative opioid [38]. Older adults are more sensi-
tive to the analgesic and side effects of morphine than younger subjects, which war-
rants low starting doses and careful monitoring.

Fentanyl
Fentanyl, a phenylpiperidine derivative, is chemically related to pethidine. It is a
pure fat-soluble μ-opioid agonist. Its volume of distribution increases in older
patients because of the increased fat-to-lean body mass ratio that accompanies
224 S. Pautex et al.

aging, hence prolonging its effective half-life. Fentanyl can be used in renal failure.
It makes it an interesting alternative to morphine as renal function is altered with
age and older patients are more likely to experiment acute renal failure in case of
dehydration or nephrotoxic drugs use.

Buprenorphine
Buprenorphine is a semisynthetic, partial μ-opioid agonist. It also weakly binds as
an antagonist at kappa and delta receptors. It has high affinity for μ-receptors and is
not readily reversed by naloxone. Buprenorphine is excreted primarily in the feces
unchanged and is considered safe in persons with renal impairment [39]. Because of
significant first-pass effect, it is available in sublingual form or transdermal patch.
The sublingual formulation is of limited utility in patients with cognitive impair-
ment or dry mouth since the tablet must be kept under the tongue until it is dissolved
completely.

Methadone
Methadone is a synthetic lipophilic opioid analgesic. It is extensively metabolized
by CYP450 enzymes (CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6) into
inactive metabolites, and it is considered safe for use in persons with renal impair-
ment. However, equianalgesic ratios between morphine and methadone are dose
dependent, the half-life is highly variable, and numerous drug interactions must be
considered. Therefore, methadone should be used only by practitioners experienced
with this agent [40].

17.2.4 Adjuvant Drugs and Treatment of Neuropathic Pain

Neuropathic pain: Co-analgesics such as antidepressants and anticonvulsants are

often recommended and especially beneficial for neuropathic pain in older people.
If acute rescue therapy is needed, the addition of a weak (tramadol) or a strong opi-
oid can be considered [41].
The two anticonvulsants most commonly used for neuropathic pain, gabapentin
and pregabalin, both presynaptically bind to the a2d subunit on voltage-dependent
calcium channels, modulating calcium influx and reducing overall excitatory neu-
rotransmitter release. The difference between the agents is that pregabalin has
increased binding affinity to the subunit and has predictable linear absorption com-
pared to gabapentin. Both medications have few drug interactions [42]. They are
excreted renally as unchanged drug, and dose reduction with renal insufficiency is
necessary. Dizziness, sedation, and peripheral edema are the most common side
effects and are more common in older adults. Anticonvulsants, including gabapentin
and pregabalin, have been associated with increased rates of falls in several studies
of older patients in the community and in nursing homes. Additionally, inhibition of
serotonin reuptake in platelets may lead to a reduction in serotonin-induced platelet
aggregation. Evidence for the efficacy of other anticonvulsants in neuropathic pain
is either lacking (e.g., clonazepam) or negative (e.g., lamotrigine, oxcarbazepine,
17 Pain 225

topiramate). Benzodiazepines, which have muscle relaxant effects, are associated

with sedation and increased risk of falls. Furthermore, when a benzodiazepine is
combined with an opioid, the risk for potentially fatal opioid-induced respiratory
depression increases [43].
Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine
and duloxetine can be used for neuropathic pain in older adults. SNRIs are generally
well tolerated. Side effects include hyponatremia, giddiness, nausea, and abdominal
pain. Venlafaxine is given at a daily starting dose of 37.5 mg, which can be increased
up to 300 mg particularly in patients with associated depression. Its use in the older
patient population is still debated and may be limited by the occurrence of hyperten-
sive episodes. Duloxetine has no cardiovascular effects, and it showed a 50% reduc-
tion in diabetic neuropathic pain compared to placebo [44]. Although tricyclic
antidepressants may be useful in treating neuropathic pain, anticholinergic and car-
diovascular side effects limit their use in older patients [45, 46].

17.2.5 Cannabinoids

The efficacy and safety profile of cannabinoids are not established in this popula-
tion. Common side effects include euphoria, anxiety, psychosis, sedation, dizziness,
cognitive effects, tachycardia, palpitations, and postural hypotension. Due to a nar-
row therapeutic index, older patients are at higher risk of dysphoric effects of can-
nabinoids [47].
In conclusion, as the quality of research is weak, and few older patients have
been enrolled in cannabinoid studies, dedicated research is needed to determine the
efficiency and safety of cannabinoids in older patients.

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Hypertension
18
Timo E. Strandberg, Mirko Petrovic, and Athanase Benetos

Hypertension is a leading cause of disability and major risk factor for cardiovascu-
lar diseases (CVD), which are common among older people, such as stroke, heart
failure, and coronary heart disease. Hypertension is also an important risk factor for
cognitive decline. In modern societies, systolic blood pressure generally starts to
rise after 50 years of age, and consequently systolic hypertension and antihyperten-
sive treatment are very prevalent among older people.
The most recent meta-analysis of randomized controlled trials (RCT) of pharma-
cotherapy clearly demonstrates that antihypertensive treatment is effective in the
prevention of CVD irrespective of older age and blood pressure level at randomiza-
tion [1]. However, evidence from age 85 and older is weaker, probably because of a
relatively small number of oldest-old participants in trials. Besides prevention of
CVD, it is noteworthy that according to systematic reviews of RCTs, medical treat-
ment of hypertension is actually the only method proven to prevent adjudicated
incident dementia—not only cognitive decline [2–4].
Results from RCTs also show that besides chronological age, strict blood pres-
sure goals are irrelevant [1] and the benefit from treatment depends on the overall
risk of the patient. Because “physiologically” normal blood pressure is as low as

T. E. Strandberg (*)
University of Helsinki and Helsinki University Hospital, Helsinki, Finland
University of Oulu, Oulu, Finland
e-mail: [email protected]
M. Petrovic
Section of Geriatrics, Department of Internal Medicine and Paediatrics, Ghent University,
Ghent, Belgium
e-mail: [email protected]
A. Benetos
Department of Geriatrics, University Hospital of Nancy, FHU-CARTAGE Profiles and
INSERM DCAC, Université de Lorraine, Vandeoeuvre-les-Nancy, France
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 229

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_18
230 T. E. Strandberg et al.

<115/75 mmHg—a finding dating back long before the development of antihyper-
tensive drugs [5]—this would make practically all older people candidates for anti-
hypertensive treatment. On the other hand, a repeating finding in unselected
epidemiological cohorts is that low blood pressure is often associated with worse
prognosis [6–10]. Interestingly, this negative association between SBP and morbid-
ity/mortality was observed mainly in very frail subjects receiving antihypertensive
treatment and not in subjects without blood pressure lowering drugs [11–14]. How
should all this information be taken into account when assessing treatment of blood
pressure in an older patient?

18.1 Hypertension Is Multifaceted in an Older Patient

Observational studies cannot confirm cause and effect and may even involve reverse
causality. In other words, frailty, subclinical disease, and low cardiac output may
lower blood pressure and simultaneously worsen prognosis leading to a biased rela-
tionship between high blood pressure and better prognosis. Therefore, it is urgent to
include in future therapeutic trials very frail older patients, i.e., those who usually
have been excluded from clinical trials in the past. Presently, we have evidence for
the relatively robust older patients (i.e., those with the “HYVET or SPRINT pro-
file”) in which our strategy should be very close to that proposed for the “younger-­
old” subjects, i.e., 65–75 years old community-dwelling subjects. European
guidelines propose targeting BP levels <140/90 in these populations though for very
old frail subjects, such targets should be individualized. A treatment algorithm and
goals in various situations are presented in Fig. 18.1.
More generally, when antihypertensive treatment has been started earlier in life
and continuing without problems, the common sense indicates that the treatment
must not be modified or stopped due to age alone. As a whole, antihypertensive
treatment should be started clearly earlier, i.e., in midlife, to reach the full benefit of
treatment during the life course [15]. Good adherence and sufficient control of
blood pressure are essential also in an older patient, and prudent lifestyle advice
about diet and physical activity are useful. If problems, such as orthostatic

Preserved autonomy and function Preserved activities of daily living (ADL) but Loss of function and loss of
status Clinical Frailty Scale(CFS 1-3) reduced function (CFS4-6) autonomy for ADL; possibly with
limited life expectancy (CFS7-9)

Treatment outline and goal similar to Complete geriatric assessment in order to Consider antihypertensive treatment
younger adults individualize antihypertensive treatment from a holistic perspective
-If treated, start with one drug and
-Systolic blood pressure < 120-140 mm Only moderately altered Significantly altered proceed cautiously with systolic blood
Hg function: function: pressure goal < 150 mm Hg
-Start low and go slow to meet goal proceed according to proceed according to -Avoid using more than 3
-Always check supine and standing left panel right panel antihypertensive drugs, if possible
blood pressure to identify orthostatic
-Consider deprescribing
reaction
-Optimizeglobal cardiovascular -Identify other factors/drugs affecting
prevention blood pressure

Fig. 18.1 A treatment algorithm and goals in various situations of older patients with hypertension
18 Hypertension 231

hypotension, electrolyte disturbances, or kidney dysfunction emerge, drug treat-

ment must be adequately revised.
Orthostatic hypotension (OH) is common among older people and may cause
problems for effective treatment of hypertension. It is defined as a reduction of
blood pressure more than 20/10 mmHg (with or without symptoms) after 1–3 min
of standing from 5 min in supine position. Although several drugs may increase
risk of OH, the most common etiology of OH is aging-related arterial stiffness
and declined intrinsic capacity to resist abrupt blood pressure drop. In fact,
appropriate control of high blood pressure may paradoxically reduce OH predis-
position [16, 17]. In the SPRINT trial, intensive control of blood pressure, as
compared to standard treatment, was not associated with increased tendency for
OH [18]. Therefore, reducing antihypertensive treatment in a patient with OH
must be carefully considered, and also other medications (such as alpha-block-
ers) with hypotensive effects must be taken into account. Furthermore, it is
important to advice a patient with OH to stand up gradually, have adequate
hydration, and possible use of support stockings. Nevertheless, orthostatic test is
indicated before treatment is started and when treatment changes are made, and
this is emphasized in a patient with frailty.
At end of life, with development of frailty and comorbidities, it is appropriate to
consider deprescribing, i.e., reducing or even stopping antihypertensive drugs [19].
However, deprescribing is not an end itself but must be based on a careful and com-
plete geriatric assessment. It is also important to consider the drug to be depre-
scribed, e.g., low-dose beta-blocker may be more feasible to remove than a
calcium-channel blocker [20]. Trials on this topic have been short and equivocal,
and before more information from randomized trials, it is vital that discontinuation
does not harm the patient [21].
Starting antihypertensive treatment in old age, >80 years of age, also requires
careful consideration. The general fears of antihypertensive treatment in older
patients—prevents CVD but increases total mortality due to falls and hypoten-
sion—were put to rest especially by the HYVET and SPRINT trials. They showed
that total mortality was decreased when antihypertensive drug treatment was com-
pared to placebo (HYVET, start of treatment >80 years of age [22] or when inten-
sive blood pressure control was compared to standard treatment (SPRINT, 75+
[23–25]).
However, people aged 75 years and older are a very heterogenous group from
fully functional to individuals with frailty and multimorbidity, and these are impor-
tant to take into account when assessing treatment [26, 27]. Although in the HYVET
[28] and SPRINT [25] cohorts benefits were seen irrespective of the frailty status,
the trials did not include the frailest and most multimorbid patients [29]. While
intensive treatment reduced mortality in SPRINT, it was nevertheless associated
with more hypotension and electrolyte and kidney adverse effects, which are obvi-
ously accentuated in the frailest patients.
An unsettled question is effects of low diastolic pressure, i.e., <60 mmHg [30,
31]. There is no consensus of potential harms for coronary circulation if diastolic
pressure is too low. Because systolic pressure is simultaneously also lowered, the
232 T. E. Strandberg et al.

burden for the heart is reduced. Too low diastolic may be harmful for brain circula-
tion [32, 33] and vulnerable patients must be carefully monitored.

18.2 Diagnostic Procedures

It is important to exclude secondary hypertension also in the older patient, and the
diagnostic procedures are similar to those in younger patients. Especially in an older
patient, it is mandatory to measure blood pressure in both supine and standing posi-
tion in order to detect OH predisposing to falls. It is recommended that a 3-min
orthostatic test is always performed before medication changes. Isolated office
(“white coat”) hypertension is relatively common in an older patient, and its detec-
tion may require ambulatory measurement. On the other hand, office and its coun-
terpart isolated masked (home) hypertension are not innocuous phenomena [34] and
may indicate treatment, or at least careful follow-up. Pseudohypertension refers to
a situation when brachial blood pressure measurement gives a high reading due to
the pronounced arteriosclerosis. However, pseudohypertension is not so common,
and one should pose this diagnosis very carefully in order to avoid underestimation
of the importance of very elevated SBP levels in high-risk populations such as
patients with diabetes or severe renal failure. The condition may be a reason for
“resistant” hypertension and should be remembered, although confirmation may be
difficult without direct arterial measurement.

18.3 Treatment Modalities

18.3.1 Lifestyle

There are surrogate data of the effects of lifestyle modification and hypertension in
old age. Prudent advice on a healthy diet, especially salt intake, and exercise are
recommended. Substituting ordinary salt to mineral salt is beneficial [35]. For
obese, weight reduction could lower blood pressure [36], but trial evidence is non-
existent for people 75 years and older, and malnutrition and development of sarco-
penia are possible hazards. Physical activity adjusted to clinical condition is always
recommended to sustain general health and functional capacity, but again without
specific trial evidence for the treatment of hypertension in an older patient. In gen-
eral, when treatment for hypertension is indicated, lifestyle modification alone is
seldom sufficient.
18 Hypertension 233

18.3.2 Drug Treatment

There are no specific differences in the selection of drug treatment between younger
and older patients, although it is often best to start low and go slow [26]. The main
drug classes of antihypertensives, i.e., diuretics, angiotensin-converting enzyme
inhibitors, angiotensin II receptor blockers, and calcium channel blockers, can be
used and with doses ultimately adjusted individually to reach appropriate targets. As
in younger patients, beta blockers are not recommended as first-line treatment with-
out specific indications. An interesting new possibility are the SGLT2-inhibitors,
which were initially developed as antidiabetic drugs. They lower blood pressure,
prevented CVD endpoints in RCTs, and are effective for heart failure (both systolic
and diastolic) even in nondiabetic patients [37, 38]. Experience of SGLT2-inhibitors
is accumulating also in older patients. Other drugs affecting blood pressure like
nitrates, alpha-blockers, and various psychotropic drugs must be remembered, espe-
cially as they may be prescribed by other specialists than general practitioners or
geriatricians. Although psychotropic drugs may not directly affect blood pressure,
they can nevertheless make a frail patient more susceptible to falls.
The general principle should be to start with monotherapy when treating older
patients especially frail patients over 80 years old. However, in most subjects, one
single BP-lowering drug is not enough to control BP, and therefore, patients and
their caregivers should be informed from the beginning about the possible adapta-
tion after the initiation of the treatment. Combining low doses of drugs with differ-
ent mode of action is usually better than increasing the dose of a single drug.
Dividing doses for morning and evening may be indicated, and there is ongoing
debate about the potential benefits of evening dosing [39]. Although maximum of
three drugs are sometimes recommended, this cannot be absolute, and treatment
must be individualized also for this.
Potential adverse effects and special considerations when using antihyperten-
sives for older patients are listed in Table 18.1.
A special case, not uncommon in an older patient with hypertension, is the acute
or subacute rise of blood pressure to very high levels (“hypertensive crisis”) [40,
41]. It is defined as systolic and diastolic blood pressure of >200 mmHg and
>130 mmHg, respectively, and divided to an emergency (signs of end-organ dam-
age) or urgency state without specific symptoms except blood pressure rise.
Emergency requires immediate treatment in a hospital setting and intensive care
unit, whereas urgency state can usually be treated ambulatory by enhancing oral
antihypertensive treatment with close follow-up. In both states, it is important to
avoid exaggerated treatment and reduce blood pressure safely.
234 T. E. Strandberg et al.

Table 18.1 Adverse effects and precautions of antihypertensives in older patients

Drug type Potential adverse effects Special considerations in older patients
Calcium channel Signs related to sympathetic LLO, which is relatively frequent with
blockers (CCB) activation (flushing, these drugs, can be erroneously
Dihydropyridine headache, tachycardia) are interpreted as a clinical sign of heart
CCB less frequent than in youngerfailure. In addition, LLO can contribute to
Non-­ subjects the decrease in social and physical
dihydropyridine Lower limb edema (LLO) activities for practical reasons (difficulties
CCB Bradycardia, AV block, in walking with shoes)
worsening heart failure, Second-line selection, diltiazem can also
constipation (verapamil), cause LLO
fatigue, dyspnea With verapamil, LLO is unusual, but
constipation may be a major problem in
very old individuals, as it can lead to fecal
impaction, with nausea, anorexia,
delirium, and functional decline
Never combine verapamil with β-blockers
Diuretics Hyponatremia, hypokalemia, Diuretic should be titrated according to
Thiazides, loop hyperuricemia and gout the patient’s volemic status. Creatinine
diuretics (not attacks, hypotension, and electrolyte monitoring is warranted
usually for dehydration after each dose change
hypertension) Association with SSRI antidepressants
increases the risk of severe hyponatremia
Risk of aggravation of urine incontinence.
Small doses (up to 25 mg of
hydrochlorothiazide or equivalent) are
safe and well tolerated
Loop diuretics are not indicated for
hypertension unless there is severe renal
insufficiency (estimated creatinine
clearance <30 mL/[min·1.73 m2]), or
indicated for heart failure
Thiazide-like indapamide has been tested
in the only RCT specific for subjects aged
80 years and older
Angiotensin-­ Dry cough, hyperkalemia, Angiotensin-converting enzyme inhibitors
converting enzyme rash, angioedema, dizziness, have been tested in the only randomized
inhibitors fatigue, acute renal failure placebo-controlled
Specific for patients aged 80 years and
over
Avoid if you suspect dehydration, do not
simultaneously increase diuretics to avoid
a worsening in renal function
Regular control of creatinine and
potassium levels
Angiotensin II Hyperkalemia, rash, The same as for angiotensin-converting
receptor blockers dizziness, fatigue, acute enzyme inhibitors: Do not combine
renal failure angiotensin receptor blockers with
angiotensin-converting enzyme inhibitors
or renin inhibitor. Be cautious with
aldosterone antagonist because of
increased risk of hyperkalemia
18 Hypertension 235

Table 18.1 (continued)

Drug type Potential adverse effects Special considerations in older patients
Beta-blockers Bradycardia, cardiac Fatigue can be accentuated. Sleep
decompensation, peripheral disturbances, depression, and confusion
vasoconstriction, may be present especially for the
bronchospasm, fatigue, beta-blockers crossing the blood brain
depression, dizziness, barrier
confusion, hypoglycemia Cardiac conduction problems can also be
aggravated
Caution when used in combination with
acetylcholinesterase inhibitors (for
memory disorders): risk of major
bradycardia
Aldosterone Hyperkalemia, Aldosterone antagonist should not be
antagonists hyponatremia, and given in instances of severe renal
gastrointestinal disturbances, insufficiency, estimated creatinine
including cramps and clearance <30 mL/(min·1.73 m2) or
diarrhea, gynecomastia hyperkalemia. Creatinine and electrolyte
monitoring is warranted after each dose
change
α-adrenoreceptor Dizziness, fatigue, nausea, Usually not indicated
antagonists urinary incontinence, Risk of hypotension (orthostatic,
(α-blockers) orthostatic hypotension, postprandial) and syncope
syncope
Central Drowsiness, dry mouth, High risk of delirium
α-adrenoreceptor dizziness, constipation, Depression can be aggravated
agonists depression, anxiety, fatigue,
urinary problems, orthostatic
hypotension, confusion, and
delirium
CCB calcium channel blockers, LLO lower limb edema

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Heart Failure
19
T. L. De Backer and A. A. Mangoni

19.1 Introduction

Older people represent an ever-growing population with a variety of health states

ranging from healthy to multimorbid and frail, and in whom biological as well as
chronological age should be considered. This heterogeneity makes a careful indi-
vidualised management plan necessary.
In general, increased age comes with increased morbidity and mortality. Heart
failure (HF) is a typical example of an increasingly prevalent disease in the older
population.
Many older patients with heart failure show multimorbidity often leading to
polypharmacy with overprescribing as well as underprescribing, frailty, sarcopenia,
and cognitive decline. All these factors have to be considered when initiating a treat-
ment plan [1, 2]. These patients are excluded in most randomised clinical trials. One
has to ask if the treatment goal is improving prognosis and/or improving symptoms
and so quality of life. This should be discussed within a multidisciplinary team

T. L. De Backer (*)
Cardiovascular Department, Ghent University Hospital, Ghent, Belgium
Clinical Pharmacology, Ghent University, Ghent, Belgium
e-mail: [email protected]
A. A. Mangoni
Discipline of Clinical Pharmacology, Flinders University and Flinders Medical Centre,
Adelaide, South Australia
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 239

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_19
240 T. L. De Backer and A. A. Mangoni

including primary and secondary healthcare staff as well as with the patient and/or
her/his caregivers (Figs. 19.1 and 19.2).
Optimising pharmacotherapy in older patients with heart failure is discussed.
Device-based treatments (cardiac resynchronisation therapy, implantable cardio-
verter defibrillator, assist devices) and heart transplantation considered for selected
advanced heart failure patients do not fall within this scope.

Caregivers at home
or nursing home

Multidiscipinary team
GP, geriatrician, Patient
cardiologist, surgeon, Old & Relatives, Friends,
nurse, pharmacologist, Heart failure Neighbours
social worker,
physiotherapist,
psychologist, dietician

Health care
system

Fig. 19.1 Parties involved in the care of the old heart failure patient
19 Heart Failure 241

Heart failure & Old

Age, Sex, Hypertension, Smoking, Dyslipidemia

PK & PD changes,
Alcohol, Substance abuse, Obesity, Sedentarism,
Drug-Drug & Drug-Food interactions, Adherence,
Psychosocial stress, Personal & Family history,
Adverse effects, Overprescribing, Underprescribing
Race/ethnicity

Risk Factors
Polypharmacy
Patient Risk Modifiers

Diabetes Mellitus, Coronary artery disease,

Cerebrovascular disease, Aorta & Peripheral Vascular Resting Tachycardia, Uric acid, Metabolic Syndrome,
Disease, Arrhythmia, Valvular heart disease, Chronic Earlier Pregnancy Complications, EarlyMenopause,
Kidney Disease, Bone-Joint-Muscular Diseases, Iron Deficiency, Anemia, Chronic pain, Malnutrition
Respiratory diseases, Cancer, Infections,Constipation, & Deficiencies, Frailty, Sarcopenia, Cognitive
Urinary & Fecal Incontinence Impairment, Dementia, Delirium

Physical & Mental

Comorbidities

Fig. 19.2 Holistic approach of the old heart failure patient

19.2 Definition of Heart Failure

Heart failure is defined as a clinical syndrome consisting of cardinal symptoms (e.g.

breathlessness, ankle swelling, fatigue) that may be accompanied by signs (e.g.
elevated jugular venous pressure, pulmonary crackles, peripheral oedema).
Underlying structural and/or functional abnormalities of the heart result in elevated
242 T. L. De Backer and A. A. Mangoni

intracardiac pressures and/or inadequate cardiac output at rest and/or during exer-
cise [3].
Although definitions and interpretations may vary and may be somewhat artifi-
cial, the definition of left ventricular HF currently includes three phenotypes based
on left ventricular ejection fraction: heart failure with preserved ejection fraction
(HFpEF, LVEF ≥50%, with evidence of structural and/or functional cardiac abnor-
malities and/or raised natriuretic peptides (NPs)), mildly reduced (HFmrEF, LVEF
41–49%, mildly reduced LV systolic function), and reduced ejection fraction
(HFrEF, LVEF <40%, significant reduction in LV systolic function) [3]. Heart fail-
ure can also be due to right ventricular dysfunction assessed by RV function mea-
surements. Right ventricular heart failure is a syndrome by its own, however often
due to and in association with LV heart failure.
There are many potential causes of heart failure having an ischaemic and/or non-­
ischaemic origin. Of note, in the ageing population, an increased prevalence and
incidence of senile cardiac amyloidosis or wild-type transthyretin amyloidosis
(ATTRwt) often in combination with aortic valve stenosis are noted.

19.3 Epidemiology and Natural History of Heart Failure

In the general population, the prevalence of HF in adults is around 1–2%, increasing

with age from around 1% in ages 45–55 years to >10% in ages 70 years and older.
In 2022, the incidence of HF in Europe is about 3/1000 person-years (all age-­
groups) or about 5/1000 person-years in adults, and over 50% of the HF patients are
women. Although the age-adjusted incidence of HF may be falling, presumably
related to better CVD management, the overall incidence of HF is increasing due to
increasing age. In a general primary care practice, 1 out of 6 patients >65 years
presenting with exertional dyspnoea are diagnosed with heart failure [3, 4]. Of the
population affected by heart failure, the majority, up to 75% are 75 years or older [5].
Mainly based on studies in hospitalised patients, it is assumed that of all cases
with HF, about 50% have HFrEF and about 50% have FpEF/HFmrEF [6–9].
In an ambulatory setting, the ESC Long-Term (ESC-HF-LT) Registry found 60%
having HFrEF, 24% having HFmrEF, and only 16% having HFpEF. This latter rela-
tively low number might be due to the inclusion of a younger, predominantly male
population and the strict inclusion of patients from cardiology departments or spe-
cialised HF units caring mostly for HFrEF patients, while HFpEF patients rather
present with worsening non-cardiac comorbidities and, therefore, are more likely to
be admitted and followed in internal medicine or geriatric wards. One of the conclu-
sions from this ESC-HF-LT Registry is that chronic HF patients stratified by catego-
ries of EF (i.e., <40%, 40–49%, ≥50%) represent different phenotypes in terms of
demography, clinical presentation, aetiology, mechanical and electrical remodel-
ling, and pharmacotherapies. Outcomes at 1 year showed that HFrEF patients had a
significantly higher mortality rate than HFpEF patients, all-cause mortality in
HFmrEF did not differ significantly from mortality in HFrEF or in HFpEF, while
non-cardiovascular mortality was higher in patients with HFmrEF and HFpEF com-
pared to HFrEF [10].
19 Heart Failure 243

Although prognosis of patients with HF, mainly HFrEF, has improved since the
publication and emergence on the market of successful HF treatment trials, progno-
sis remains poor, and quality of life (QOL) markedly reduced.
Mortality rates are higher in observational studies than in clinical trials [11]. In
the Olmsted County cohort, 1-year and 5-year mortality rates after diagnosis, for all
types of HF patients, were 20% and 53% [12]. In a report combining results of the
Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts,
mortality rate within 5 years following diagnosis was 67% [13].
A better overall survival in HFmrEF and HfpEF compared to HfrEF was consid-
ered. The MAGGIC meta-analysis concluded that the adjusted mortality risk in
patients with HfpEF was lower than in patients with HfrEF. However, most obser-
vational studies show that this difference is negligible [12, 13]. In the Olmsted
county cohort of hospitalised patients, it was shown that the prevalence of HFpEF
over 15 years increased together with an increase in hypertension, atrial fibrillation,
and diabetes and that the death rate remained unchanged (29% at 1 years and 65%
at 5 years) which was minimally lower than the death rate for HFrEF (32% and
68%, respectively) [14].
The various and evolving definitions and categorisations of the heart failure syn-
drome over time together with heterogeneity in patient characteristics and the evo-
lution in prevention and treatment also may contribute to the varying numbers in
epidemiological data. Data from GWTG-HF (Get With The Guidelines–Heart
Failure) linked to Medicare data looking at 5-year outcomes and median survival in
patients hospitalised for heart failure showed a median survival of 2.1 years and a
similar high 5-year mortality, 75%, in HFrEF, HFbEF(borderline, =mrEF), and
HFpEF. Also, the composite of mortality and rehospitalisation was similar for all
subgroups, with cardiovascular and HF readmission rates being higher in HFrEF
and HFbEF compared to HFpEF. Conclusion was that patients with HF across all
ages and EF groups had a markedly lower median survival compared to the overall
population [15, 16].
Age by itself is an independent risk factor for mortality. Patients >75 years have
significantly higher in-hospital mortality rates than patients <75 years (11.2% vs
4.4%) (www.nicor.org.uk). Two nationwide cohorts of patients hospitalised for
new-onset heart failure based on linkage of the Dutch Hospital Discharge Registry
and the National Cause of Death registry assessed overall and cause-specific mortal-
ity rates over time stratified by age and sex. Mortality rates at 1 year were high and
increased considerably with age similarly in men and women, from 10.5% in
women aged 25–54 years to 46.1% in women aged >85 years and from 9.8% in men
aged 25–54 years to 53.4% in men >85 years, although the overall 1-year absolute
risk of death across all ages declined by 4.0% in men and 3.2% in women [17]. The
Cardiovascular Health Study, a longitudinal cohort study of community-dwelling
older adults >65 years in the USA, reported 1-, 5-, and 10-year mortality rates of
19%, 56%, and 83%, respectively, following the onset of HF [13]. The Canadian
Chronic Disease Surveillance System data confirmed that once HF develops, mor-
tality increases exponentially with age [18]. Hospital admissions and readmissions
are frequent in heart failure patients for cardiac as well as non-cardiac reasons and
negatively impact prognosis. The proportion of hospitalisations related to
244 T. L. De Backer and A. A. Mangoni

decompensated HF sharply increases after the age of 65 years, with 1 in 7 HF hos-

pitalisations occurring in patients ≥80 years of age [19].

19.4 Pharmacological Management of HF

The aim of treatment of heart failure is to improve survival, to prevent (repeated)

hospitalisations due to heart failure, to reduce symptoms, and to improve functional
capacity and quality of life. Together with non-pharmacological measures, pharma-
cotherapy is the cornerstone of treatment of heart failure.
Optimising drug therapy in older patients is a complex process because of the
presence of physical and mental comorbidities, age-related changes in pharmacoki-
netics and pharmacodynamics, polypharmacy, under- and overprescribing, and
issues with adherence [2, 20]. Management of HF patients should be planned in a
multidisciplinary setting with a cardiogeriatrics team involving primary and
secondary-­tertiary care, and the patients and their caregivers should be educated
about the HF syndrome and self-management [21] (Figs. 19.1, 19.2, and 19.3).

Comprehensive
Geriatric Assessment

Mainstay Pharmacotherapy
ARNI or ACEI (ARB)

b-blocker

MRA

SGLT-2inhibitor

Loop Diuretics
Cardiac rehabilitation,
Consider
Education &
Self-management, Digoxin
Weight, Fluid & Food Hydralazine/ISSDN Devices,
intake, Medication Ivabradine percutaneous
Reviews, intervention,
Iron iv
Telemonitoring, surgery
Life Care Plan

Fig. 19.3 Management of the old patient with heart failure

19 Heart Failure 245

19.5 Pharmacological Treatment of Heart Failure in Older

Persons (Fig. 19.3)

The ageing population is growing, heart failure increases with age, and age is an
independent predictor of morbidity and mortality. With a few exceptions, hard evi-
dence on the best treatment for heart failure specifically in older persons is lacking
since they were largely excluded from major HF trials [22]. In the earlier studies
over the past 40 years, the upper limit of age was often put at patients of 65 up to
70–75 years old and with little or no comorbidities. The more recent trials also
allowed patients >75 years old, being appropriate and logical given the growing
older population. However, evidence in the very old and/or multimorbid and/or frail
older person is virtually non-existent.
Most drug trials until now provided evidence for a positive benefit-risk effect on
morbidity and mortality mainly in HFrEF, while almost none could prove signifi-
cant benefit on hard outcomes as mortality in HFpEF. Few trials demonstrated
symptomatic benefit and reduced hospitalisations in HFpEF.
The recent EMPEROR-preserved and DELIVER trials showed a significant
reduction by empagliflozin and dapagliflozin in the combined endpoint of CV death
and HF hospitalisations, driven by a reduction in hospitalisation [23]. Treatment of
HFpEF is quite individualised and mainly involves treatment of risk factors (such as
hypertension) and comorbidities (such as atrial fibrillation, coronary artery disease,
diabetes, renal insufficiency, pulmonary hypertension, thyroid disorder, etc.) and
control of symptoms (fluid balance).
To deal with age, most trials specified subgroup analyses looking at different age
ranges or at older versus younger participants, often defined as <65 years and
>65 years old. This was done for most trials with ACE inhibitors (ACE-I), beta-­
blockers (BB), angiotensin receptor blockers (ARB), digoxin, hydralazine/ISDN,
aldosterone antagonists/mineralocorticoid receptor antagonist (MRA), ivabradine,
angiotensin receptor-neprilysin inhibitors (ARNI), and sodium-glucose cotrans-
porter 2 inhibitors (SGLT2i).
An increasing number of post hoc analyses of the effectiveness of HF treatment
in a broader range of older patients are performed.
A BIOSTAT-CHF analysis assessing the association between up-titration of
angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers
(ARB), and beta-blockers and outcome across the age spectrum in HFrEF patients
showed that achieving higher doses of ACEI/ARB was associated with improved
outcome regardless of age, while achieving higher doses of beta-blockers was asso-
ciated with improved outcome only in younger but not in older patients. The incon-
sistent association between beta-blocker dosage and heart rate in older patients is
hypothesised to be due to a decreased cardiovascular responsiveness to beta-­
adrenergic stimulation, already acting as an intrinsic beta-blockade, as reflected by
the lower resting heart rate in older patients [24]. Heart rate reduction might be
more important than the achieved beta-blocker dose in HFrEF. For example, in
CIBIS-ELD, the achieved heart rate target rather than beta-blocker dose (carvedilol
or bisoprolol) was significantly associated with outcome (see further, [25, 26]).
246 T. L. De Backer and A. A. Mangoni

Also, the higher prevalence of atrial fibrillation in older patients might lower the
beneficial effects of beta-blockers.
One systematic review and meta-analysis of the efficacy (mortality and hospitali-
sations for cardiovascular causes) and safety of MRA treatment in older HF patients
≥65 years reported overall benefit from MRA therapy with no significant treatment
interaction for age in patients with HFrEF, while no significant effect on any effi-
cacy outcome in patients with HFpEF. In a subanalysis in patients ≥75 years with
HErEF, the effect of MRA treatment on overall mortality seemed uncertain, mainly
due to heterogeneity [25].
In an IPD meta-analysis of RALES, EMPHASIS-HF, and TOPCAT in patients
≥75 years versus <75 years of age, the primary outcome (composite of death from
cardiovascular causes or hospitalisation for HF), cardiovascular death, and all-cause
death were reduced by MRAs without significant between-trial or age (younger vs.
older) heterogeneity. Worsening renal function (without more hyperkalaemia) was
found more frequently in older patients. The reduction in morbidity and mortality
was more marked in patients with HFrEF however overall homogenous across
HFrEF and HFpEF (in HFpEF lower events, but not statistically significant). The
authors pleaded for measures to increase MRA treatment in the older popula-
tion [26].
A cohort study using US Medicare fee-for-service claims data (2014–2017) in
patients >65 years with HFrEF evaluating the effectiveness of angiotensin receptor-­
neprilysin inhibitor (ARNI) versus renin-angiotensin system inhibition (RAS)
found that ARNI treatment was associated with lower risk of the composite effec-
tiveness endpoint (worsening HF or all-cause mortality) compared with RAS block-
ade alone [27].
In the PARADIGM-HF trial (LCZ696 vs. enalapril), efficacy (CV death or heart
failure hospitalisation) and safety according to age (<55 years (n = 1624),
55–64 years (n = 2655), 65–74 years (n = 2557), and ≥75 years (n = 1563)) were
consistent across all age categories with LCZ696 having a favourable benefit–risk
profile in all age groups [28].
A meta-analysis of the effects of the SGLT2 inhibitors dapagliflozin (DAPA-HF)
and empagliflozin (EMPEROR-reduced) on cardiovascular outcomes in patients
with HFrEF with or without diabetes showed a significant reduction in all-cause
death (−13%), cardiovascular death (−14%), combined endpoint of cardiovascular
death or first hospitalisation for heart failure (−24%), composite endpoint of recur-
rent hospitalisations for heart failure or cardiovascular death (−25%), and compos-
ite endpoint of renal events (−38%). Analysis based on age groups, < and >65 years,
showed a persistent 25% reduction in the composite endpoint of cardiovascular
death or hospitalisation for heart failure [29].
Empagliflozin in patients with HFpEF (in the EMPEROR-Preserved trial defined
as EF >40%) and with or without diabetes lowered the composite of cardiovascular
death or hospitalisation for heart failure by 21%, mainly due to lower risk of hospi-
talisation for heart failure (29% reduction). Based on age, the endpoint reduction in
patients <70 years was −12% (0.88, 0.70–1.11), while it was −25% (0.75, 0.64–0.87)
in patients >70 years. If confirmed in other trials (confirmed for dapagliflozin in
19 Heart Failure 247

DELIVER trial) and in real-world data, SGLT2 inhibitors are the first class showing
significant beneficial effect in HFpEF (subgroup analysis showed significance in EF
>40 to <50% and >50% to <60%, in EF >60% NS) [23].
Pooled data on the safety (12 studies) and efficacy (9 studies; outcome: HbA1c
reduction) of the SGLT2 inhibitor dapagliflozin 10 mg/day monotherapy or com-
bined with oral antidiabetic drugs or with insulin in older patients >65 years (20%
of the studied populations) with type 2 diabetes showed HbA1c reductions across
age subgroups (<65 years and >65 years) with greater reductions in HbA1c in
patients aged <65 years than in patients aged >65 years. Hypoglycaemia, volume
depletion, and renal AEs (predefined serum creatinine thresholds) occurred more
often in patients aged >65 years, reflecting the lower eGFR in the older persons.
Orthostatic hypotension occurred in <0.1% in both age groups. Urinary tract and
genital infections were similar for both DAPA-treated age groups. It was concluded
that DAPA’s efficacy and safety observations indicate a practical, new approach to
the treatment of T2DM patients aged >65 years [30].
Very few trials investigated the efficacy and safety of drug therapy specifically in
an older population.
The PEP-CHF trial in patients >70 years of age and with evidence of diastolic
dysfunction, comparing placebo with perindopril 4 mg/day, showed a clear trend
towards reduction in the primary endpoint of combined all-cause mortality and
heart failure hospitalisation (HR 0.692: 95% CI 0.474–1.010; P = 0.055), however
not reaching statistical significance due to insufficient power. A significant reduc-
tion in hospitalisation for heart failure and a significant improvement in functional
class and 6-min walking distance at 1 year were observed in patients receiving per-
indopril [31].
The SENIORS trial assessed the effect of nebivolol, a beta-blocker with vasodi-
lating properties, on mortality and cardiovascular hospital admission in older
patients >70 years with heart failure, regardless of ejection fraction, compared to
placebo. The primary outcome, a composite of all-cause mortality or cardiovascular
hospital admission, was reduced by 34%(HR, 0.86; 95% CI, 0.74–0.99; P = 0.039),
with no significant influence of age, gender, or ejection fraction on the effect of
nebivolol on the primary outcome. For all-cause mortality HR was 0.88 (95% CI,
0.71–1.08; P = 0.21). Nebivolol was considered an effective and well-tolerated
treatment for heart failure in the older population [32].
As part of the larger CIBIS trial, the CIBIS–ELD trial was a tolerability superior-
ity study of bisoprolol versus carvedilol comparing the tolerability and clinical
effects of the two beta-blockers in older patients with heart failure with reduced or
preserved left ventricular ejection fraction. The primary endpoint tolerability,
defined as reaching and maintaining guideline-recommended target doses after
12 weeks treatment, was comparable, 24% versus 25%. Bisoprolol treatment
resulted in greater reduction of heart rate (adjusted mean difference, 2.1 bpm; 95%
CI, 0.5–3.6; P = 0.008) and more, dose-limiting, bradycardic adverse events (16 vs.
11%; P = 0.02), while carvedilol intake resulted in a reduction of forced expiratory
volume (adjusted mean difference, 50 mL; 95% CI, 4–95; P = 0.03) and more, non-­
dose-­limiting, pulmonary adverse events (10 vs. 4%; P = 0.001). It was concluded
248 T. L. De Backer and A. A. Mangoni

that overall tolerability to target doses was comparable, while the pattern of intoler-
ance was different with bradycardia occurring more often in the bisoprolol group,
whereas pulmonary adverse events occurring more often in the carvedilol group [33].
A 4-year follow-up study of the CIBIS-ELD trial investigated the prognostic
value of achieved heart rate after beta-blocker optimisation on long-term mortality.
Heart rate increases by 10 bpm following beta-blocker up-titration which was asso-
ciated with a subsequent mortality hazard ratio of 1.19 (95% CI, 1.02–1.38;
P = 0.023). The heart rate range with the lowest mortality and the fewest treatment-­
related adverse events was 55–64 bpm. The achieved beta-blocker dose was not
associated with mortality risk. It was concluded that the achieved heart rate after
up-titration, but not the beta-blocker dose, predicted all-cause mortality risk in older
patients with chronic
heart failure and that titration should aim for resting heart rates between 55 and
64 bpm [34].
Several smaller, mainly Japanese, studies looked at real-world data on the effec-
tiveness and safety of SGLT2 inhibition in older persons.
The STELLA-ELDER study was a post-marketing surveillance (PMS) study inves-
tigating real-world evidence on the safety of ipragliflozin in older (>65 years) Japanese
patients with type 2 diabetes mellitus. Of all patients, 16.91% experienced 1880 adverse
drug reactions (ADR), of which 165 ADRs were considered serious in 1.49% of the
patients. The most common ADRs were skin and subcutaneous tissue disorders (3.25%),
renal and urinary disorders (2.74%), and infections (2.23%). Of special interest were
skin complications, volume depletion, polyuria/pollakisuria, genital and urinary tract
infection, renal disorders, hypoglycaemia, cerebrovascular disease, cardiovascular dis-
ease, malignant tumour, fracture, and ketone body-related events. Risk factors identified
for hypoglycaemia were BMI (<18.5 kg/m2 vs. ≥22.0 to <25.0 kg/m2; OR, 9.356) and
concomitant insulin use (vs. no; OR, 4.946), and risk factors identified for volume
depletion were age (≥75 years vs. <75 years; OR, 1.737) and concomitant loop diuretic
use (vs. no; OR, 2.105). Overall, there were no safety concerns that were not previously
observed in pre-marketing trials. The conclusion was that this PMS revealed probable
ADRs in older Japanese patients with T2DM taking ipragliflozin with no new safety
concerns and that PMS should help physicians to identify possible treatment-emergent
ADRs in ipragliflozin-treated patients in real-world settings [35].
Another Japanese study assessing the use of sodium-glucose cotransporter 2
inhibitors in older patients (mean age 73.7 ± 10 years) with type 2 diabetes mellitus
did not report events associated with oral administration of SGLT-2 inhibitors after
a mean follow-up period of 289.3 days. Fasting blood glucose and glycosylated
haemoglobin levels at 6 months were significantly lowered without signs of intra-
vascular collapse or changes in creatinine, blood urea nitrogen/creatinine ratio, or
estimated glomerular filtration rate. Treatment with SGLT-2 inhibitors did signifi-
cantly increase haemoglobin and haematocrit levels. In a small subgroup with a
brain natriuretic peptide level exceeding the normal upper limit before treatment
with SGLT-2 inhibitors, the brain natriuretic peptide levels significantly decreased
after 6 months of treatment. SGLT-2 inhibitors at 6 months exerted a favourable
hypoglycaemic effect and no signs of dehydration were observed [36].
19 Heart Failure 249

A small Spanish study of real-world safety and efficacy of SGLT-2 inhibitors in

older patients with DM also concluded that these drugs are safe and effective in not
well-controlled elderly (>65 years, however mean age being (only) 67 years) DM2
patients and that effect on systolic BP should be considered and so the antihyperten-
sive treatment be reviewed [37].
Because of concerns on muscle wasting with the use of SGLT-2 inhibitors mainly
in the older population, a highly represented population in Japan, Japanese investi-
gators launched the EMPA-ELDERLY trial (ClinicalTrials.gov NCT04531462), a
randomised, double-blind, placebo-controlled trial to assess the efficacy and safety
of the sodium-glucose cotransporter-2 inhibitor empagliflozin 10 mg in patients
>65 years of age with type 2 diabetes (with BMI > 22). The primary endpoint is the
change in HbA1c level from baseline to week 52. Secondary endpoints include
changes from baseline to week 52 in body composition, including muscle mass and
body fat, skeletal muscle index, grip strength, and time in the five-time chair stand
test. Other endpoints include changes in patient-reported outcomes (including qual-
ity of life), cognitive function, and safety (hypoglycaemia, hepatic injury, diabetic
ketoacidosis, decreased renal function and lower-limb amputation) (ClinicalTrials.
gov Identifier: NCT04531462; Recruitment Status: Active, not recruiting) [38].
Finally, a systematic review and meta-analysis (11 studies; 93,502 patients) of
GLP-1 receptor agonists and SGLT2 inhibitors for older people with type 2 diabetes
assessed the cardiovascular effects of glucagon-like peptide-1 receptor agonists
(GLP-1 RAs) and sodium-glucose co-transporter-2 (SGLT2) inhibitors in older
people (>65 years) with type 2 diabetes. Comparable to the overall population,
GLP-1 RAs significantly reduced major adverse cardiovascular events (MACE) and
all its subcomponents (hazard ratio [HR], 0.86; 95% CI, 0.80–0.92) in the patients
≥65 years. SGLT2 inhibitors reduced MACE (HR, 0.90; 95% CI, 0.83–0.98) (how-
ever, neutral effect on its subcomponents), reduced heart failure hospitalisation
(HR, 0.62; 95% CI, 0.51–0.76), and the composite renal endpoint (HR, 0.57; 95%
CI, 0.43–0.77). Similar results were obtained in patients ≥75 years. From this sys-
tematic review and meta-analysis, it was concluded that in older adults with diabe-
tes, GLP-1 RAs reduced MACE and its components and that SGLT2 inhibitors
reduced MACE, heart failure, and renal outcomes [39].
Summarising the results, overall, in heart failure, ACE-I reduced all-cause mor-
tality around 20%, while ARBs did not significantly reduce all-cause mortality;
however, around 18% reduction in CV death or HF hospitalisation was shown, an
outcome more and more used as primary endpoint in heart failure RCTs. Beta-­
blockers showed an all-cause mortality reduction around 20–30%. MRA showed a
15% (eplerenone) to 30% (spironolactone) all-cause mortality reduction, with
eplerenone also showing reduction of CV death or HF hospitalisation by 37%.
Digoxin did not significantly reduce all-cause mortality but did reduce HF hospitali-
sations by 28%. Ivabradine did not show effect on all-cause mortality, however
reduced CV deaths or HF hospitalisation by 18%. Sacubitril-Valsartan reduced CV
deaths or HF hospitalisation by 20%. The SGLT2 inhibitors (empagliflozin and
dapagliflozin) gave a 13% reduction in all-cause death, 14% reduction in cardiovas-
cular death, 26% reduction in the combined risk of cardiovascular death or first
250 T. L. De Backer and A. A. Mangoni

hospitalisation for heart failure, and 25% reduction in the composite of cardiovas-
cular death or recurrent hospitalisations for heart failure. For patients with HFpEF
with or without diabetes, empagliflozin reduced the composite of cardiovascular
death or hospitalisation for heart failure by 21% in the overall population and 25%
in patients >70 years. If confirmed in other trials and in real-world data, SGLT 2
inhibitors are the first class showing beneficial effect in HFpEF. As a comparison, in
earlier trials, the ARB candesartan, MRA spironolactone, and Sacubitril-Valsartan
also showed some modest effect on CV death and HF hospitalisation (up to 15%
risk reduction) in HfpEF patients, however mainly in the groups with an EF 40–49%
considered as mildly reduced EF [23].
Overall, it can be assumed that older patients also benefit from these evidence-­
based pharmacological treatments and that guideline recommended HF treatment
aiming at improving the quality of patient care should also be applied in older peo-
ple. A guideline gives an advice, not an order, and a benefit-risk balance should be
made for each individual patient.
Current mainstay drug therapy recommended for all heart failure patients are
ARNI or ACE-I if ARNI not tolerated (ARB only if ARNI and ACE-I not tolerated),
beta-blockers, MRA, and SGLT2i as they improve prognosis by reduction of mor-
bidity and mortality. Dosage should be started low and slow and then progressively
increased based on tolerance. Symptomatic treatment with loop diuretics and acet-
azolamide in certain cases (ADVOR trial) is given in case of congestion to improve
symptoms, exercise tolerance, and reduce HF hospitalisations.
The following drugs should or might be considered in specific conditions.
Ivabradine, an If channel blocker, should be considered in case of EF <35%, sinus
rhythm with a heart rate >70 bpm in patients on mainstay HF therapy (with or with-
out a beta-blocker). Digoxin might be considered for symptomatic patients on base-
line HF therapy. Hydralazine/isosorbide dinitrate might be considered in
symptomatic patients not tolerating any of the baseline therapies.
Some other drug classes for use in HF are being investigated; however, current
evidence is limited. The soluble guanylate cyclase stimulator vericiguat might be
considered in patients with HFrEF, on top of standard therapy to further reduce the
risk of CV mortality and hospitalisations for HF (VICTORIA study) [40]. The car-
diac myosin activator omecamtiv mecarbil might be considered for HFrEF patients
on top of standard therapy to reduce the risk of CV mortality and HF hospitalisation
(GALACTIC-HF study) [41–44].
Besides optimal HF drug therapy, other cardiovascular and non-CV therapies,
including non-pharmacological strategies, should be applied in the setting of cardio-
vascular and non-cardiovascular risk factors and comorbidities, which may play a
role in initiating and worsening of heart failure directly and/or indirectly (Fig. 19.3).

19.6 Risk Factors and Comorbidities

In older patients, heart failure seldom comes alone. Several factors may play a role
in the initiation and/or worsening of heart failure, may compromise or hamper opti-
mal therapy, and may as such influence prognosis. The list of risk factors and
19 Heart Failure 251

comorbidities is inexhaustive. Some risk factors and comorbidities, important in the

setting of ageing and heart failure, are shortly discussed. Guideline-based therapies
proven to prevent or stabilise cardiovascular diseases have to be weighed by an
overall benefit-risk balance. Many conditions to be taken into account and to be
taken care of in clinical practice (impact of ageing on PK, polypharmacy, drug-­
drug-­food interactions, adverse drug reactions, inappropriate prescribing, geriatric
syndromes & chronic conditions, multimorbidity & frailty, COPD, Diabetes,
chronic kidney disease, sarcopenia, falls, pain, sleep disorders, dementia, delirium,
constipation, incontinence) are discussed in detail in the other book chapters.

19.6.1 Risk Factors

Prevention of cardiovascular disease and early recognition and treatment of disease

might increase survival and/or improve quality of life [3, 45].
Smoking is a strong and independent risk factor for cardiovascular and respira-
tory diseases and cancer. Patients should be encouraged to stop smoking to prevent
cardiovascular, respiratory and cancer diseases or the worsening of it. After 1 year
of smoking cessation, the risk for a myocardial infarction is reduced by 50%, and
the risk for stroke becomes similar as for a non-smoker. After 5 years of smoking
cessation, the risk of lung cancer is reduced by 50%.
Sedentary lifestyle should be avoided and physical activity increased to reduce
morbidity and all-cause and CV mortality. Exercise-based cardiac rehabilitation is
recommended in HF patients to improve functional capacity and quality of life and
to reduce hospitalisations. Especially in the older people, this should also prevent
further muscle wasting, frailty, and osteoporosis. For all adults of all ages at least
150–300 min a week of moderate intensity and/or 75–150 min a week of vigorous
intensity aerobic physical activity are recommended. People who cannot perform
150 min of moderate-intensity physical activity a week should stay as active as their
abilities and health condition allow. Anyhow at least some light activity throughout
the day is recommended. Along with this, obesity prevention and weight control can
be supported through a balanced food intake and energy expenditure.
Alcohol intake should not exceed 100 g a week, and binge drinking should be
avoided. In alcoholic cardiomyopathy, alcohol should be forbidden. Also, other sub-
stance abuse should be checked and handled appropriately. While for some older
patients an occasional drink might be part of social contact, excessive alcohol might
harm physical and mental health. In patients taking (multiple) medications, drug-­
alcohol interactions as well as alcohol by itself might cause adverse reactions and
influence adherence [46].
Fluid and salt intake. In HF patients, excessive fluid and salt intake should be
avoided and are often restricted to a maximum of 1.5–2 l a day and to <5 g a day,
respectively. Intake of fluid and salt should be modified following the hydration
status. For example, in case of vomiting, diarrhoea, and prolonged heath, dehydra-
tion and electrolyte disturbances must be avoided by temporarily increasing fluid
intake. A healthy varied diet should help risk factor control and prevent malnutri-
tion. Nutrition should be more flexible in the old patient than in the young patient.
252 T. L. De Backer and A. A. Mangoni

Especially older patients with HF have increased risk for malnutrition and deficien-
cies, which should be checked for and treated accordingly [47]. In the OPTIMIZE-HF
study, low sodium serum levels was a predictor of in-hospital mortality [48].
Psychosocial stress (mental, financial, familial, loneliness, anxiety, etc.) increases
cardiovascular risk and should be assessed (e.g., via Patient Health Questionnaire),
and psychosocial support should be given when necessary. Increased attention and
support in patients with mental disorders and cardiovascular disease is recom-
mended to help improve adherence to lifestyle changes and medication.
Blood pressure should be regularly measured, and hypertension, an important
risk factor in heart failure, should be prevented and/or efficiently treated with life-
style interventions (no smoking, salt intake <5 g/day, physical exercise, weight con-
trol, stress reduction) and antihypertensive drugs (main classes: RAS inhibitors,
diuretics, calcium channel blockers, beta-blockers). Blood pressure should also be
measured in the standing position and/or after a meal to detect orthostatic and/or
postprandial hypotension, especially in older persons. A blood pressure target of
<140/90 mmHg with ranges of SBP <140 to 130 and DBP <80 to 70 mmHg are
recommended, if tolerated. In older persons >80 years with good functionality, an
antihypertensive treatment as given to younger adults should be considered. In the
older persons with a moderate functional limitation and preserved autonomy for the
activities of daily living, a geriatric risk assessment might be performed to decide on
the individual treatment approach. Patients with few comorbidities and only very
limited loss of autonomy can be considered to receive the same antihypertensive
regimen as the older persons with good functionality. In older persons with severe
functional limitations and loss of autonomy and/or very reduced life expectancy,
quality of life and symptom control is the main aim, and treatment should be regu-
larly reviewed and discussed in a multidisciplinary context. Because of safety rea-
sons, treatment might be reduced or stopped [49–52].
Hypercholesterolemia should be treated with lifestyle measures (physical activ-
ity, healthy diet) and lipid-lowering drugs (mainly statins). The targets depend on
the overall cardiovascular risk and tolerance. In calculating cardiovascular risk in
older persons, often important non-CVD risk has to be taken into account, and
therefore the Older Person SCORE and LIFE-CVD scores are more appropriate.
Guidelines recommend statins in older people (>65 years) with atherosclerotic car-
diovascular disease in the same way as in younger people. In primary prevention,
according to level of risk, statins are recommended in older people <75 years. In
people >75 years, initiation of statins may be considered if at high risk. In older
patients, one should be alert for myopathy. Although there is less direct evidence of
benefits in the primary prevention setting among patients older than 75 years, results
from RCTs support the use of statins in older patients at high or very high risk of
ASCVD. The results from the STAREE (Statin Therapy for Reducing Events in the
Elderly; NCT02099123), from the SITE/SAGA (Statins In The Elderly;
NCT02547883), and PREVENTABLE (Pragmatic Evaluation of Events and
Benefits of Lipid-Lowering in Older Adults; NCT04262206) trials will be of help to
elucidate some of the questions that remain unanswered. Shared decision-making
on statin therapy in 75+-year-old people in primary prevention should be based on
19 Heart Failure 253

good clinical judgment, comorbidities, frailty, patient preferences, and life expec-
tancy [53].
Diabetes mellitus, considered more as a comorbidity, should be as much as pos-
sible prevented by lifestyle measures (weight control, physical activity). Once DM
is established, pharmacological treatment should be installed taking into account
age, risk factors, and comorbidities. SGLT2 inhibitors are the preferred choice in the
setting of CV disease and heart failure. Overall, in diabetes patients, an HbA1c
target of <7% is recommended. Based on personal physical and mental health sta-
tus, less rigorous HbA1c and glucose targets should be considered in older patients,
ranging from <7.5% in healthy older persons up to <8.5–9% in very complex older
patients with a poor overall health status [54, 55].

19.6.2 Cardiovascular Comorbidities

19.6.2.1 Atrial Fibrillation and Conduction Abnormalities

Atrial Fibrillation
The incidence and prevalence of atrial fibrillation (AF), the most frequent cardiac
arrhythmia worldwide, typically increases with age and with HF severity [56].
AF and HF frequently coexist and can cause or exacerbate each other through
several mechanisms such as structural cardiac remodelling, activation of neurohor-
monal systems, and heart rate-related LV impairment [57–60]. However, if AF is the
cause of HF (called tachycardiomyopathy), the clinical course may be more favour-
able than with other causes of HF [61]. On the contrary, if AF develops in patients
with chronic HF, prognosis seems worse, with increased stroke and increased mor-
tality [62, 63].
The management of patients with concomitant HF and AF includes identification
and treatment of potential causes and/or triggers of AF, management of HF, preven-
tion of thromboembolic events, rate control, and/or rhythm control.
Potential causes or precipitating factors, such as thyroid disorders, electrolyte
disturbances, infections, uncontrolled hypertension, and valve disease, should be
checked and corrected. Heart failure should be optimally managed with the main-
stay therapy, and increased congestion due to AF should be managed with diuretics.
Oral anticoagulants (OACs) are the cornerstone of treatment of AF to reduce the
risk for stroke/systemic thromboembolism, and—unless contraindicated—long-­
term oral anticoagulant therapy is recommended in all patients with HF and parox-
ysmal, persistent, or permanent AF and CHA2DS2-VASc score >2 in men and >3 in
women. Four large randomised controlled trials (RCTs) have shown that non-­
vitamin K antagonist oral anticoagulants (NOACs) also called direct oral anticoagu-
lants (DOACs) are non-inferior to vitamin K antagonists (VKAs) in preventing
stroke and systemic embolism, as well as regarding their risk for major bleeding.
Direct-acting oral anticoagulants (DOACs) are preferred for the prevention of
thromboembolic events in patients with AF—except in patients with moderate or
severe mitral valve stenosis and mechanical prosthetic heart valves—as they have
254 T. L. De Backer and A. A. Mangoni

similar efficacy to vitamin K antagonists (VKAs) and a lower risk of intracranial

haemorrhage [64]. Vulnerable geriatric patients with AF were underrepresented in
trials, making the choice of the right anticoagulant in real-life patients particularly
challenging. In these vulnerable patients, NOACs tend to be underused and/or
underdosed due to concerns of fall-related intracranial bleeding, cognitive impair-
ment, drug-drug interactions, low body weight, or impaired renal function. The
SAFIR trial was the first large-scale prospective study assessing bleeding risk in
geriatric patients aged ≥80 years with AF newly treated with rivaroxaban compared
to patients treated with VKA. While ischemic stroke and all-cause mortality rates
were similar, major bleeding rates were significantly lower with rivaroxaban than
with VKAs (hazard ratio of 0.67 (95% CI, 0.45–0.99)) and with a lower intracranial
bleeding rate (HR = 0.52; 0.21–1.28) [65]. An individual benefit-risk assessment
and shared decision-making are key elements in the decision on whether to antico-
agulate in the vulnerable geriatric patient with AF at high thromboembolic as well
as high bleeding risk. A comprehensive geriatric assessment (CGA) in hospitalised
older patients with AF may help guide clinicians in this individual benefit-risk
assessment [66].
In patients with HF and AF who have a contraindication to oral anticoagulation
left atrial appendage closure can be considered, although trials did not include
patients with contraindications to oral anticoagulants [67, 68].
The debate and research on rate control versus rhythm control is ongoing, and no
clear benefit of one strategy over the other has been shown in patients with AF and
HF (except for symptomatic improvement with catheter ablation). Overall, higher
heart rates are associated with worse outcomes in observational studies [69, 70].
The ESC Atrial Fibrillation Guidelines [56] advice beta-blockers for rate control
in patients with HFrEF, HFmrEF, and HFpEF because of their proven safety in these
patients. Digoxin can be considered when the ventricular rate remains high, despite
beta-blockers, or when beta-blockers are contraindicated or not tolerated.
AV node ablation can be considered in patients with poor ventricular rate control
despite medical treatment not eligible for rhythm control by catheter ablation or in
patients with biventricular pacing.
Urgent electrical cardioversion is recommended in the setting of acute worsen-
ing HF in patients presenting with rapid ventricular rates and haemodynamic
instability, after consideration of the thromboembolic risk. Electrical cardiover-
sion may also be considered to improve symptoms in patients with persistent and
symptomatic AF, despite optimal pharmacological management. In case of phar-
macological cardioversion, amiodarone is the preferred drug as other antiarrhyth-
mic drugs (flecainide, propafenone, dronedarone) are associated with worse
outcomes in HFrEF. Amiodarone also can help maintain sinus rhythm after
cardioversion.
Catheter ablation should be considered for the prevention or treatment of AF if
there is a clear association between paroxysmal or persistent AF and worsening of
HF symptoms, which persist despite medical therapy [56].
19 Heart Failure 255

Symptomatic Conduction Abnormalities

Due to the ageing process degeneration of the conduction system can occur involv-
ing the sinus node, atria, AV node, His bundle, and the Purkinje system. The use of
pacemakers is growing worldwide as people live longer. In older people, although
the periprocedural risk is mildly increased, the implantation of a pacemaker is rela-
tively safe. In patients with HF, the indications for pacemaker therapy do not differ
from patients with other CV diseases.
Long-term RV pacing is associated with potential adverse effect on LV systolic
function leading to HF (pacemaker-induced cardiomyopathy) [71]. In older patients
with sinus node disease, DDD pacing programmed to minimal ventricular pacing is
advised, while in the very old patients with intermittent atrioventricular block, VVI
pacing may be preferred. In patients with HF and in need of frequent ventricular
pacing, implantation of a CRT pacemaker should be considered (BLOCK-HF trial)
[72]. More physiological pacing methods are developed and increasingly implanted.
His bundle pacing, compared to RV pacing, showed less HF hospitalisation and a
trend in reduced mortality [73]. In patients with a higher pacing burden (>40%), His
bundle pacing showed a lower risk of new-onset atrial fibrillation compared to RV
pacing [74].
Leadless pacemakers avoiding complications of access site and at the pulse gen-
erator are increasingly used instead of the classic VVIR pacemakers.
When deciding about device implantation in an older patient, general physical
and mental status, risk factors and comorbidities, and physiological age rather than
chronological age should be decisive for device implantation selection for survival
and quality of life [75].

Valve Disease
The prevalence of valve disease is increasing with age, with more than 10% of
people aged 75 years and older having moderate or severe valve disease.
Improved surgical techniques and percutaneous valve interventions increase the
treatment options for older patients with or without comorbidities.
Aortic valve stenosis and mitral valve and tricuspid valve regurgitation are com-
mon in older people. Aortic valve stenosis and mitral valve regurgitation are the two
most prevalent left-sided valve pathologies observed in older people.

Aortic Valve Stenosis (AS)

Degenerative or calcific aortic valve disease is common in older patients with vary-
ing numbers of prevalence reported with a prevalence of severe aortic stenosis going
from 1 to 2% in people aged 75 years to 6–18% in people aged 85 years and further
increasing in people over 90 years old. A systematic review and meta-analysis of
population-based studies found a prevalence of 12.4% for AS and 3.4% for severe
AS among the elderly [76–78].
Isolated aortic valve regurgitation is uncommon in older adults; however, aortic
valve stenosis might be accompanied by aortic valve regurgitation.
256 T. L. De Backer and A. A. Mangoni

Risk factors associated with the development of AS in older adults may be simi-
lar to those for atherosclerosis. In the Cardiovascular Health Study evaluating 5201
persons aged ≥65 years old, the overall incidence of aortic sclerosis and AS was
26% and 2% increasing up to 37% and 2.6% in the 75 years old. Major independent
clinical risk factors for degenerative aortic valve disease were age with a twofold
increased risk for each 10-year increase in age, male sex with a twofold excess risk,
current cigarette smoking with a 35% increased risk, and hypertension with a 20%
increased risk. High serum concentrations of lipoprotein(a) and low-density lipo-
protein cholesterol were also significant risk factors [77]. Aortic valve stenosis may
cause or worsen HF by increasing LV afterload with consequent LV hypertrophy
and remodelling [79].
Once heart failure symptoms (angina, dyspnoea, syncope) occur in patients with
severe aortic valve stenosis, the prognosis is very poor. There are no pharmacologi-
cal therapies specifically for improving outcomes of AS. However, HF patients with
symptomatic aortic valve stenosis should receive standard HF therapy, paying extra
attention to the risk of hypotension.
Aortic valve intervention is recommended in patients with HF symptoms and
severe, high-gradient aortic valve stenosis (valve area <1 cm2, mean gradient
>40 mmHg), regardless of LVEF and with a life expectancy of >1 year.
In low-gradient aortic valve stenosis, haemodynamic assessment (with dobuta-
mine) might be necessary to determine further management [80].
Older patients have higher in-hospital mortality than younger patients, due to a
poorer preoperative general status, more extensive age-related valve calcifications,
and fragile connective tissues, and if CABG, aneurysm repair, and mitral valve sur-
gery are concomitantly performed. Death after 30 days is more likely (up to 70%)
due to non-cardiac causes as pneumonia, stroke, and malignancy. However, older
patients who do survive the perioperative period, mostly do well with a functional
and quality of life improvement. In older patients referred for cardiac surgery, a
global assessment integrating frailty, disability, and risk scores should characterise
elderly patients better and identify those at increased risk [81].
Transcatheter aortic valve implantation (TAVI) is non-inferior to surgical aor-
tic valve replacement (SAVR) in reducing clinical events and mortality and dis-
abling stroke in patients at high and intermediate risk for surgery [82–84]. In
low-risk patients, SAVR is recommended in patients <75 years and at low surgical
risk (STS-­PROM score or EurCORE II <4%), whereas TAVI is recommended in
patients >75 years or at high surgical risk (STS-PROM score or EuroSCORE II
>8%). In specific cases, balloon aortic valvuloplasty may be considered as in
highly symptomatic patients with acute heart failure and shock as a bridge to
TAVI or SAVR [80].
A multidisciplinary team (cardiologists, cardiac surgeons, geriatricians, nurses)
should make the benefit risk balance of TAVI and SAVR according to the patients
age, medical history, clinical features, anatomical aspects, life expectancy, and
patient preference.
19 Heart Failure 257

Mitral Regurgitation
Mitral regurgitation is a common valve abnormality in older adults with an esti-
mated odds ratio of 1.3 per 10-year increase in age.
Mitral regurgitation can be caused by organic or primary mitral regurgitation and
functional or secondary ischemic or non-ischaemic mitral regurgitation.
Organic or primary mitral regurgitation is due to intrinsic disease of the mitral
leaflets or subvalvular apparatus such as calcific degeneration, mitral valve pro-
lapse, flail mitral leaflet, and ruptured chordae tendineae. Surgery, preferably repair,
is recommended in patients with severe primary MR and HF symptoms.
Functional or secondary mitral regurgitation is mainly a disease of the left ven-
tricle. Functional or secondary ischemic mitral regurgitation is due to ischaemia or
papillary muscle infarction, with or without rupture, associated with an acute myo-
cardial infarction. Functional secondary non-ischaemic mitral regurgitation is due
to apical displacement of the papillary muscles associated with annular dilatation
and left atrial dilatation caused by left ventricular dilatation of any origin. Secondary
mitral regurgitation is a dynamic condition, and echocardiographic quantification
during exercise may be helpful in patients with moderate regurgitation at rest and
developing symptoms during physical activity [80, 85].
In older patients, the most common causes of mitral regurgitation referred for
mitral valve surgery are prolapse due to myxomatous degeneration and ischaemic
heart disease. Moderate or severe mitral regurgitation is associated with a poor
prognosis in patients with HF [86, 87]. Follow-up by a multidisciplinary heart team
is recommended. Optimal medical therapy, including cardiac resynchronisation
therapy, should be considered. In patients with severe mitral regurgitation and
HFrEF requiring revascularisation, mitral valve surgery and CABG should be con-
sidered. Isolated mitral valve surgery may be considered in symptomatic patients
with severe mitral regurgitation despite optimal therapy and at low surgical risk [80].
Chronic mitral regurgitation is the second most common reason for valve surgery
in older adults, after aortic valve surgery. While in younger asymptomatic patients
with early evidence of left ventricular dysfunction, surgery is recommended, in
patients over 80 years old, surgery might be considered only when symptoms are
present since postoperative outcomes are less favourable in this group. The risk
associated with the intervention, repair as well as with replacement, increases with
the presence of ischaemic heart disease, extent of calcification, and concomitant
interventions. Outcome after surgery in older patients varies with age and disease
severity and is better after mitral valve repair than replacement. However, late sur-
gery might contribute more than age to worse outcome in mitral valve surgery in
older adults <80 years.
Mitral valve repair, if feasible, is the surgical treatment of choice for mitral regur-
gitation and HF symptoms, also in older patients, as well as in primary MR and
secondary MR. If surgery is contraindicated or considered at high risk, then percu-
taneous repair may be considered [80, 88–90].
258 T. L. De Backer and A. A. Mangoni

Various percutaneous edge-to-edge mitral valve repair techniques are currently

being evaluated and showed very different results (Mitra-FR and COAPT). The
procedure may be considered to improve symptoms in patients with severe heart
failure, severe mitral regurgitation, and severe symptoms and not eligible for sur-
gery [91].
Other percutaneous mitral valve repair systems, such as transcatheter indirect
annuloplasty, are available for treatment of secondary mitral regurgitation. IPD
meta-analysis showed trends towards improvement in mean 6MWT distance and
symptoms and reduction in HF hospitalisations [92–95]. Transcatheter mitral valve
replacement is a possible alternative option [96, 97].
Mitral valve interventions are not recommended in patients with a life expec-
tancy of <1 year due to extracardiac conditions. A personal care plan including pal-
liative care should be discussed with the patient [80].

19.6.3 Non-cardiovascular Comorbidities

19.6.3.1 Cancer
As heart failure increases with age, so does cancer. The incidence rates for cancer
overall go from fewer than 25 cases per 100,000 people in age groups under
20 years, to about 350 per 100,000 people in ages 45–49 years, to more than 1000
per 100,000 people in ages 60 years and older.
On the one hand, the risk of heart failure is increased in cancer patients deter-
mined by the cancer itself, cancer treatments, age, and underlying existing cardio-
vascular risk factors and comorbidities. Older people compared to younger people
seem more susceptible to cardiotoxicity related to cancer therapies. The cardiotoxic
effects of cancer therapies may be directly through cardiomyocyte damage or indi-
rectly through ischaemia, myocarditis, systemic arterial hypertension, pulmonary
hypertension, valvular heart disease, and arrhythmia.
On the other hand, the risk of worse cancer outcome in HF patients is increased
due to not starting or withdrawing anticancer therapies [98].
Management of HF in cancer patients should be done in a multidisciplinary
approach by preference in a cardio-oncology service and according to the stan-
dard guidelines of heart failure. Baseline cv risk assessment and a HFA-ICOS risk
assessment to define the risk for cardiotoxicity are advised [99]. Close clinical
and echocardiographic follow-up from the start, during, and after cancer treat-
ment is advised. An absolute drop of >10% in LVEF to <50% indicates cardiac
dysfunction. Global longitudinal strain is more sensitive to detect cardiac dys-
function at earlier stages. Monitoring of biomarkers such as (pro-NT)BNPs and
troponin is also advised, especially in patients on immunotherapy with immune
checkpoint inhibitors being at increased risk of myocarditis [100]. People who
survived cancer should remain monitored in the long term as HF may develop
several years after cancer treatment.
19 Heart Failure 259

Fear for increased cardiotoxicity often leads to undertreatment of cancer in older

people, and in clinical oncology trials, older people are underrepresented. A careful
benefit risk assessment where quality of life might be more important than pro-
longed survival should be performed within a multidisciplinary team (family physi-
cian, cardiologist, oncologist, geriatrician) and in a shared decision with the patient.

19.6.3.2 Iron Deficiency and Anaemia

Iron deficiency and anaemia are prevalent in patients with heart failure (up to 55%
in chronic HF and up to 80% in acute HF) and are independently associated with
reduced exercise capacity, recurrent HF hospitalisations, and high CV and all-cause
mortality. Anaemia in older people is highly prevalent due to chronic kidney dis-
ease, chronic inflammatory diseases, and iron deficiency.
In older HF patients with anaemia, the rate of death is doubled over 3 years with
patients with low haematocrit being more likely to die from worsening heart fail-
ure [101].
Prevalence of iron deficiency in heart failure patients aged 75 years or older was
found to be very high in very old patients with heart failure (73.8%; 95% CI: 65.7–80.8%),
irrespective of type of heart failure, however more in those with HF with mid-range EF
(78.4% (95% CI: 61.8–90.2%)) or HF with preserved EF(86.5% (95% CI:
74.2%–94.4%)) compared to HF with reduced EF 57.7% (95% CI: 43.2–71.3%) [102].
In patients with HF, iron deficiency is defined as either a serum ferritin concen-
tration of <100 ng/mL or 100–299 ng/mL with transferrin saturation (TSAT) of
<20%. The cause of iron deficiency in heart failure may be increased loss, reduced
intake or absorption, and/or impaired iron metabolism related to the chronic inflam-
matory activation of HF, although the exact cause of iron deficiency in HF is not
fully clear [103].
Iron deficiency by itself may impair functional capacity and skeletal muscle
function and precipitate circulatory decompensation. It is associated with frailty,
irrespective of anaemia [104]. It is recommended that all patients with HF are regu-
larly screened for anaemia and iron deficiency with full blood count, serum ferritin
concentration, and TSAT. In case of anaemia and/or iron deficiency, appropriate
investigations should define their cause.
Based on RCTs and meta-analyses, iron supplementation with iv ferric carboxy-
maltose should be considered for the improvement of symptoms, exercise capacity,
and QOL in patients with HF and LVEF <45% and should also be considered for the
reduction of HF rehospitalisations in patients with LVEF <50% recently hospital-
ised for worsening HF (Ferric HF, FAIR HF, AFFIRM AHF). Similar benefits were
seen in older and younger ages [105].
Oral iron therapy is not effective in iron repletion and in improvement of exercise
capacity in patients with HFrEF and iron deficiency; therefore, it is not recom-
mended for the treatment of iron deficiency in patients with HF. Erythropoietin-­
stimulating agents are not indicated for the treatment of anaemia in HF due to
negative benefit-risk.
260 T. L. De Backer and A. A. Mangoni

19.6.3.3 Infections
Infections, viral or bacterial, may trigger acute heart failure and may worsen chronic
HF. Due to diminished activity of the immune system and underlying chronic disor-
ders such as COPD, older persons are more susceptible for infections. On top of
that, in the older patient, infection may lead to severe physical and mental dysregu-
lation and rapid global deterioration. Sepsis can cause myocardial damage and
depression leading to severe heart failure, with higher risk in people with pre-­
existing heart failure.
Older people and people with cardiovascular morbidity have a higher risk for all
types of pneumonia (community acquired, healthcare related, and aspiration pneu-
monia) with increased risk for a severe course leading to respiratory and cardiac
failure. An observational retrospective study identified clinical characteristics and
risk factors of pulmonary infection in older patients with heart failure and found that
age ≥70 years, diabetes, NYHA III, LVEF <55%, and CRP ≥10 mg/L are higher
risks of pulmonary infections. Preventive measures targeting these risk factors
might reduce pulmonary infections [106]. Influenza and coronavirus disease 2019
(COVID-19 (SARS-COV-2)) are major causes of morbidity and mortality, includ-
ing heart failure. Course of the disease and case fatality rates are highest at older
ages [107–109]. The multicentre, multinational PCHF-COVICAV registry assessed
the outcome of hospitalised COVID-19 patients with heart failure (HF) compared
with patients with other cardiovascular disease and/or risk factors (arterial hyperten-
sion, diabetes, or dyslipidaemia). Hospitalised COVID-19 patients with HF were at
1.5-fold increased risk for in-hospital death. In-hospital worsening of HF or acute
HF de novo was common and associated with a further increase in in-hospital
mortality(threefold increased likelihood) [110]. In observational studies and retro-
spective analyses, influenza vaccination is associated with a reduced risk of all-­
cause death in patients with HF [111]. Influenza, COVID-19 vaccination, and
pneumococcal vaccination should be considered in patients with HF.

19.7 Considerations

As life expectancy continues to rise worldwide, the number of geriatric patients

substantially increases.
Given the complexity of the older patient as well as of heart failure, the manage-
ment requires a multidisciplinary team involving general practitioners, geriatri-
cians, cardiologists, liaison nurses, pharmacists, physiotherapists, dieticians,
psychologists, social workers, surgeons, and other healthcare workers.
Regular patient follow-up with global assessment of general status, mental and
physical functional status, nutritional status, and full clinical exam should be per-
formed, accompanied each time by a medication review, checking appropriate and
inappropriate drugs and medication adherence. Educational support to the patient
and family/caregivers should be given. Optimal care should translate in reduced
hospital admissions.
If feasible, remote monitoring and/or teleconsultations might be provided.
19 Heart Failure 261

An increase in resource utilisation and economic costs are expected in the grow-
ing older population with multiple comorbidities and with broad discrepancies in
outcomes. Implementation of prospective databases, quality checks, and cost-­
efficiency of treatment plans is essential [112].
The ESC 2021 cardiovascular disease prevention guidelines are a major step
forward by considering age more appropriately in the risk estimation scores
(SCORE2-OP) and in risk factor management (lifetime benefit estimation of treat-
ment), taking into account comorbidities and patient preferences.
Future guidelines should focus more on the ageing population, an ever-growing
yet highly heterogeneous population which makes a tailored holistic personal
approach more than necessary.

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Pharmacological Treatment of Cognitive
and Behavioral Disorders in Dementia 20
F. Trotta, L. Biscetti, and A. Cherubini

20.1 Introduction

Dementia (now called major neurocognitive disorder according to the DSM-5) is a

syndrome, characterized by a decline in one or more cognitive domains (learning
and memory, language, executive function, complex attention, perceptual-motor,
social cognition) that interferes with independence in everyday activities. These
cognitive deficits do not occur exclusively in the context of delirium, and they are
not better explained by another mental disorder (e.g., major depressive disorder,
schizophrenia). The major neurocognitive disorder differs from mild cognitive
impairment (MCI) due to the presence of functional impairment that is related to the
cognitive deficits [1, 2].
The incidence of dementia increases exponentially with increasing age [3].
Dementia and cognitive impairment are the leading chronic disease contributors to
disability and dependence among older people worldwide. The need for support
from a caregiver often starts early in the dementia course, intensifies as the illness
progresses over time, and continues until death. Furthermore, behavioral distur-
bances are common in people with major neurocognitive disorder and cause signifi-
cant impairment in quality of life and healthcare outcomes. Therefore, care and
assistance to people with dementia requires a significant practical, psychological,
and economic burden for families and society. Based on the etiology, there are sev-
eral subtypes of dementia.

F. Trotta · A. Cherubini (*)

Geriatria, Accettazione geriatrica e Centro di ricerca per l’invecchiamento, IRCCS INRCA,
Ancona, Italy
e-mail: [email protected]; [email protected]
L. Biscetti
Neurologia, IRCCS INRCA, Ancona, Italy
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 269

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_20
270 F. Trotta et al.

20.1.1 Alzheimer’s Disease (AD)

The most common (60–80% of all dementia cases) is Alzheimer’s disease (AD).
AD has a complex etiology, and our understanding of the relationships between the
numerous pathways involved in the development of AD and subsequent neurode-
generation is still incomplete. AD is characterized by extracellular amyloid plaques,
intracellular neurofibrillary tangles, and nerve cell death [4–6]. The typical form of
Alzheimer’s disease is characterized by a progressive episodic memory loss, subse-
quently accompanied by cognitive deficits involving non-amnestic domains, e.g.,
language and executive functions.

20.1.2 Vascular Dementia (VaD)

Vascular dementia (VaD) is considered the second most common cause of dementia
in the elderly. VaD is defined as any form of dementia caused by cerebrovascular
disease or impaired blood flow. VaD can develop after stroke and can have a step-
wise progression; otherwise, it can develop in individuals without clinical strokes
and can have a gradual progression [7].

20.1.3 Dementia with Lewy Bodies (DLB)

Dementia with Lewy bodies (DLB) is a neurodegenerative dementia with distinc-

tive clinical features including fluctuations of cognitive ability, early and persistent
visual hallucinations, parkinsonism, and sleep disorders. Lewy bodies are spherical,
eosinophilic neuronal cytoplasmic inclusions composed of aggregates of alpha-­
synuclein, a synaptic protein. Between 3 and 7% of patients with dementia were
found to meet the criteria for DLB [8].

20.1.4 Frontotemporal Dementia (FTD)

Frontotemporal dementia (FTD) is a disorder characterized by focal degeneration of

the frontal and/or temporal lobes [9]. Age of onset is typically in the late 50s or early
60s. About half of frontotemporal dementias are genetically inherited: most of the
mutations involve chromosome 17q21–22 and cause abnormalities in the
microtubule-­ associated protein tau. The primary initial clinical manifestations
include changes in personality and social behavior or language, while there is less
memory impairment than in Alzheimer’s disease; then, the disease progresses over
time to a more global dementia affecting other cognitive domains. Symptoms of
extrapyramidal or motor neuron involvement, including generalized muscle wast-
ing, weakness, fasciculations, bulbar symptoms (e.g., dysphagia, dysphonia), and
increased risk of aspiration pneumonia and premature death, may also occur in a
subset of patients. FTD accounts for 2.5% of the dementias across all age groups
20 Pharmacological Treatment of Cognitive and Behavioral Disorders in Dementia 271

and 10.2% in those aged <65 [10–12]. There are different types of frontotemporal
dementia, depending on which part of the brain is affected: behavioral variant (fron-
tal) and primary progressive aphasia.

20.1.5 Other Neurocognitive Disorders

Other subtypes are neurocognitive disorder due to Parkinson’s disease, Huntington’s

disease, traumatic brain injury, HIV infection, and prion disease [2]. In very old
patients, mixed dementia is quite common.

20.2 Pharmacologic Management of Cognitive Impairment

Currently, in the management of dementia, the main goals are to treat symptoms
related to cognitive decline and to reduce the burden of the disease on caregivers.
The recommended treatment strategy includes symptomatic pharmacological ther-
apy of cognitive deficits, cognitive rehabilitation, environmental adaptations to
reduce the impact of cognitive deficits and behavioral symptoms, nonpharmacologi-
cal and pharmacological treatment of behavioral symptoms, and prevention and
treatment of complications (e.g., falls, malnutrition, incontinence, bed rest; plan-
ning of care and family support; education and support of caregivers).
First of all, it is necessary to evaluate the medical history: The presence of
drugs with anticholinergic effect can induce a worsening of cognitive functions.
An increased risk for dementia was seen in people with higher use of anticho-
linergics (e.g., antihistamines, gastrointestinal tract antispasmodics, antivertigo
agents/antiemetic, antidepressants, bladder antimuscarinics, skeletal muscle
relaxant, antipsychotics, antiarrhythmic, antiparkinsonians). Therefore, pre-
scribers should be aware of this potential association, and alternative drugs
should be considered when possible. If no therapeutic alternative exists, pre-
scribers should use the lowest effective dose and discontinue therapy if ineffec-
tive [13]. Some tools have been developed to quantify the cumulative
anticholinergic effect of the drugs and their impact on cognitive functions and
activities of life: Anticholinergic Drug Scale (ADS), the Anticholinergic Burden
Scale (ACS), the Anticholinergic Risk Scale (ARS), and the Drug Burden Index
(DBI) [14–17]. In the advanced stages of dementia, the worsening of the impair-
ment of cognitive functions makes it impossible to carry out the activities of
daily living. This leads to an increased risk of malnutrition, pneumonia, and
pressure sores. As the disease progresses, treatment should be aimed to preserve
the patient’s well-being, rather than trying to prolong life. Provision of pallia-
tive care was empirically recognized as a care step in the management of demen-
tia. However, as several studies have shown, the palliative care pathway for
patients with dementia is still far from being accepted, shared, and applied [18–
20]. Holmes criteria have been developed for the appropriateness of prescribing
drugs in advanced dementia [21].
272 F. Trotta et al.

Dementia severity can be categorized by different instruments. Mini Mental

State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are
screening tools only evaluating the global cognitive functioning. Clinical
Dementia Rating (CDR) and FAST Scale evaluate both the patient’s cognitive and
functional performance. Both nonpharmacological [22] and pharmacological
approaches are used for dementia management, but in this chapter, only the latter
will be presented [12]. There are no disease-modifying therapies approved for
dementia; therefore, management is currently based on the treatment of neuro-
logical and neuropsychiatric symptoms in order to improve the quality of life of
patients and their caregivers. Treatment for major cognitive impairment differs
according to the etiologic subtype.
Until now, the only pharmacological treatments approved for dementia can be
used on label in AD field. The use of the same drugs in other forms of dementia is
off-label.

20.2.1 Acetylcholinesterase Inhibitors

The acetylcholinesterase inhibitors inhibit the brain acetylcholinesterase enzyme,

responsible for the breakdown of the neurotransmitter acetylcholine, enhancing
cholinergic neurotransmission in the brain by relative increase in acetylcholine at
the synaptic cleft. They are considered symptomatic therapies and are not believed
to be neuroprotective or to alter the underlying disease progression.
Cochrane reviews found that all three acetylcholinesterase inhibitors improve
global and cognitive symptoms in people with mild to moderate AD. They all dem-
onstrated efficacy compared with placebo, and a limited number of direct compari-
sons do not suggest major differences in efficacy or tolerability among the three
drugs [23–27]. In a metanalysis review of 13 randomized, double-blinded, placebo-­
controlled trials, they were associated with slower decline [28]; however, the mag-
nitude of the clinically relevant benefits is uncertain. Modest improvements were
observed in activities of daily living and behaviors. Real-life studies found that
treatment with these drugs reduced the rate of cognitive decline and increased sur-
vival during a follow-up lasting up to 8 years [29, 30].
Therefore, for patients with newly diagnosed mild to moderate AD dementia, a
cholinesterase inhibitor therapy should be introduced. For patients with severe
dementia, the efficacy of anticholinesterase inhibitors may be less clinically impor-
tant, and fewer studies have been performed. Not all patients have a clinical benefit
from these drugs. Studies have tried to investigate whether gene alterations can
affect the clinical response to AChEI: the most relevant genes influencing AChEI
efficacy and safety are APOE and CYPs [31].
Most of the studies of cholinesterase inhibitors have been performed in patients
with a clinical diagnosis of AD, and data are more limited and less consistent for
other forms of dementia. Evidence of mixed pathology at the time of autopsy is
common, especially the combination of Alzheimer’s disease and vascular
20 Pharmacological Treatment of Cognitive and Behavioral Disorders in Dementia 273

pathology. Therefore, many experts find it reasonable to offer a trial of a cholines-

terase inhibitor in patients with a clinical diagnosis of other types of dementia,
including vascular dementia and Parkinson’s disease dementia [32, 33].
Cholinesterase inhibitors are also suggested in most patients with DLB and may
have comparatively greater symptomatic benefits (cognition, fluctuations, psychotic
symptoms, activities of daily living, and reduced caregiver burden) than those
observed in patients with AD. In some instances, the response is dramatic but tem-
porary. A meta-analysis [34] concludes that donepezil and rivastigmine improved
cognitive function and visual hallucinations in patients with DLB, but rivastigmine
appears to induce more side effects than placebo. Evidence for galantamine in DLB
remains sparse, limited to only open-label trials.
Conversely, the available data do not support the use of cholinesterase inhibitors
in FTD except when there is uncertainty about whether the patient has FTD or AD
[35–39].
Each drug is available for use orally, tablet or other formulations useful in dys-
phagia patients (donepezil as disintegrating sublingual tablet or transdermal
patch, galantamine as oral solution, rivastigmine as transdermal patch or oral
solution). A slow titration dosing regimen over 4–8 weeks is recommended to
reach the target dose and minimize adverse effects. Selection of an agent is based
largely upon ease of use, individual patient tolerability, cost, and clinician and
patient preference. In a pragmatic, open-label trial, patients were randomly
assigned to donepezil, galantamine, or rivastigmine using dosing and formula-
tions at the discretion of the treating clinician. At 18 weeks, rates of discontinua-
tion for any reason were similar for the three drugs; side-effect rates and profiles
were largely similar among groups [26].
Cholinesterase inhibitors should be avoided in patients with baseline bradycardia
or known cardiac conduction system disease (e.g., sick sinus syndrome, incomplete
heart block) related to cholinergic toxicity and consequently risk of syncope, falls,
and fractures. They should be used with caution in combination with drugs that
induce bradycardia or alter nodal conduction [40, 41]. Other relative contraindica-
tions are asthma and peptic ulcer disease. The main features of cholinesterase inhib-
itors are summarized in Tables 20.1 and 20.2 [26, 42–46].

20.2.1.1 Treatment Monitoring

Dementia patients taking AChEI should be periodically reevaluated concerning
cognition, function, neuropsychiatric and behavioral symptoms, and medication
reconciliation [47–50].
After the introduction of anticholinesterase inhibitor, patients should be seen for
follow-up at 3 and 6 months to assess drug tolerance and response. Patients on a
stable dose of drug are then seen every 6–12 months thereafter. During treatment
with anticholinesterase inhibitor, cardiac rate should be monitored and a drug dis-
continuation should be considered in the presence of bradycardia. Caregiver impres-
sion of change, behavioral symptoms, sleep, and other neuropsychiatric symptoms
should also be assessed at each visit.
274 F. Trotta et al.

Table 20.1 Acetylcholinesterase inhibitors

AChE
inhibitors Formulation Dose Dose adjustments
Donepezil – Once-daily Starting dose: None
tablet  – 5 mg once daily
– Once-daily Increasing to 10 mg per day
disintegrating after 4–6 weeksa
sublingual tablet
– Once-weekly
patch formulation
(not in Europe)
Galantamine – Once-daily Starting dose: Moderate renal (creatinine
extended-release  – 8 mg daily clearance 9–59 mL/min) or
capsule Increasing to 16 mg daily hepatic impairment:
– Twice-daily after 4 weeks maximum dose 16 mg daily
tablet Target maintenance dose: End-stage kidney disease
– Twice-daily 24 mg daily after four more (eGFR <9 mL/min) or
solutionb weeksc severe hepatic impairment
(Child-Pugh >9):
contraindicated
Rivastigmine – Oral capsule Transdermal patch starting Body weight <50 kg and
– Oral solution dose: mild to moderate hepatic
– Daily  – 4.6 mg/24 htitrated impairment: 4.6 mg/24 h
transdermal upwards every 4 weeks Severe hepatic impairment:
patchd until 13.3 mg/24 h the patch has not been
Oral capsule or solution studied
starting dose:
 – 1.5 mg twice daily
Increasing to 1.5 mg
twice-daily in 2- to 4-week
intervalse
a
Withdrawal and adverse events were higher the higher the dose [42]
b
Given with meals to decrease the risk of nausea
c
Galantamine improves global and cognitive symptoms at doses of 16 mg/day or greater, in people
with mild to moderate AD, for at least 6 months [43]
d
The patch is preferred due to superior pharmacokinetics and tolerability (less nausea, vomiting,
weight loss, dizziness) with similar efficacy [44]
e
One trial found that side effects of oral rivastigmine may be ameliorated and higher daily doses
achieved when it is given three times a day, rather than twice daily [44]

There is not a universal consensus on how long to continue cholinesterase inhibi-

tors in patients who are tolerating therapy. Therapy should not be continued in
patients who do not appear to be benefiting or who have significant side effects: in
the absence of subjective or objective improvement after a 6-month trial, some clini-
cians, patients, and families may choose to stop treatment. An alternative cholines-
terase inhibitor is not typically used in this setting, while another drug approved in
AD field, memantine, can be added or substituted in patients with moderate to
severe dementia, or it can be used as a single agent among patients who do not toler-
ate cholinesterase inhibitors.
20 Pharmacological Treatment of Cognitive and Behavioral Disorders in Dementia 275

Table 20.2 Cholinesterase inhibitors: Side effects

Side effects Drugs Actions
Gastrointestinal upset [26, Donepezil seems to be • Switching to donepezil may be
45, 46] (upset stomach, less likely to cause reasonable in patients who do not
nausea, diarrhea, gastrointestinal upset than
tolerate galantamine or rivastigmine
anorexia) the other two drugs even if they are taken with meals
Weight loss, anorexia • Nutritional counseling
• If comorbid depression exist,
mirtazapine is a good choice of
antidepressant because it can augment
appetite
Bradycardia, Hypotension • If no other modifiable cause is
identified, cholinergic therapy should
be discontinued in patients who
develop symptomatic bradycardia and/
or hypotension
Sleep disturbances More common with • Recognize and treat, as they are a
(insomnia, vivid dreams, donepezil major contributor to caregiver distress
nightmares, and other and are associated with an increased
sleep disturbances) likelihood of institutionalization
Others Donepezil → rare cases of rhabdomyolysis and/or neuroleptic
malignant syndrome in post-marketing surveillance
Rivastigmine transdermal patch → skin irritation: application sites
should be rotated

20.2.2 Memantine

Memantine is a moderate affinity uncompetitive N-methyl-D-aspartate (NMDA)

receptor antagonist licensed for use in moderate and severe AD. Glutamate is the
principal excitatory amino acid neurotransmitter in cortical and hippocampal neu-
rons. One of the receptors activated by glutamate is the NMDA receptor, which is
involved in learning and memory. Excessive NMDA stimulation can be induced by
ischemia and lead to excitotoxicity.
A Cochrane review found a small clinical benefit for cognitive function and for
behavior and mood of memantine in people with moderate to severe AD regardless
the concomitant acetylcholinesterase inhibitor assumption, but no benefit in people
with mild AD [51]. Memantine does not appear to have significant side effects: diz-
ziness, headache, and constipation are the most common ones, while confusion and
hallucinations are infrequent, but increased agitation and delusional behaviors may
occur in some patients with AD. The dosage of memantine is 10–20 mg, which
should be slowly titrated (an increase of 5 mg each week, starting from a dosage of
5 mg). The standard dosage is 20 mg, with the exception of patients with moderate-­
severe renal failure (glomerular filtration rate 5–29 mL/min), for which the maxi-
mum dosage is 10 mg per day. A fixed-dose combination with donepezil and
memantine was approved for moderate to severe AD who are on stable donepezil
therapy [52].
276 F. Trotta et al.

In DLB, whether memantine should be used as monotherapy or together with

cholinesterase inhibitors remains unclear and requires further study.

20.2.3 Aducanumab

Aducanumab is a recombinant monoclonal antibody directed against amyloid beta.

The US Food and Drug Administration (FDA) has approved aducanumab for the
treatment of mild AD using the accelerated approval pathway, based on the positive
results of one of the two pivotal phase III trials (the results in the other were nega-
tive) and aducanumab’s effect on a surrogate endpoint of reducing amyloid beta
plaques in the brain [53].
The approval of aducanumab has caused on ongoing controversy in the scientific
community as it is not still clear whether the reduction of beta amyloid plaques
induced by the drug leads to clinical benefits. In fact, faced to a robust effect of
aducanumab with respect to reduction in brain amyloid levels, observed benefits on
clinical endpoints have been small and inconsistent and therefore uncertain [54].
To date, aducanumab has been administered primarily in research settings in the
USA limited to the following patients [55]:

• Mild cognitive impairment or mild AD (MMSE ≥21, MoCA ≥17, or CDR 0.5–1)
• Documented amyloid pathology: Clinicians should limit use of aducanumab to
those patients proven to be amyloid positive (by amyloid positron emission
tomography [PET] scan or lumbar puncture)

Contraindications Cases where aducanumab therapy should not be offered:

• Cognitive decline attributed to non-AD pathologies

• AD in the setting of Down syndrome
• High risk of hemorrhagic side effects (hemorrhagic findings on brain MRI
including >4 microhemorrhages, any areas of superficial siderosis, prior macro-
hemorrhage, and underlying brain lesion or vascular malformation; anticoagu-
lant or antiplatelet use other than aspirin 81 mg daily, bleeding disorders, or any
other condition leading to increased risk of central nervous system hemorrhage)
• Unstable medical/ psychiatric conditions
• Pregnancy or breastfeeding

Furthermore, patients with an apolipoprotein E epsilon allele have a greater risk

of side effects.
Adverse effects Adverse effects observed with aducanumab include the follow-
ing [56]:

• Amyloid-related imaging abnormalities (ARIA), especially in APOE ε4 carriers

• Hypersensitivity, including angioedema and urticaria
• Headache, falls, diarrhea, and confusion (except for diarrhea, these may reflect
symptoms of ARIA)
20 Pharmacological Treatment of Cognitive and Behavioral Disorders in Dementia 277

In addition, up to 0.6% of patients in the clinical trials developed aducanumab

antibodies, and no determination was made as to whether such antibodies are
neutralizing.
In Europe, Biogen withdrew its application for a marketing authorization of
Aducanumab for the treatment of Alzheimer’s disease on April 20, 2022.
Other monoclonal antibodies against beta-amyloid, such as gantenerumab, cren-
ezumab, and lecanemab, are being tested in clinical trials enrolling patients with
mild AD and individuals with early cognitive impairment. Furthermore, gan-
tenerumab and solanezumab are also being studied in preclinical patients with auto-
somal dominant AD mutations, but without cognitive symptoms. So far, none of
these drugs has been approved by regulatory agencies in the USA and Europe for
clinical use.

20.2.4 Vascular Risk Modifications

Patients with cognitive impairment and clinical or radiological evidence of cerebro-

vascular disease must undergo screening and treatment for vascular risk factors: this
intervention is essential in the prevention of dementia since stroke is associated with
a greater risk of cognitive intervention and post-stroke dementia is associated with
higher mortality [57–59].
Treatment of cardiovascular risk factors is based on antihypertensive therapy
[60, 61], diabetes management, statins [62–64], and antithrombotic therapy [64].

20.2.5 Other Therapies

Other agents have been studied for VaD, but the trials have mostly been small and
without conclusive results [65]: nimodipine, ergot alkaloids (hydergine, nicergo-
line), cerebrolysin, vitamin E, ginkgo biloba, xanthine derivatives (propentofylline,
pentoxifylline, and denbufylline), cytidinediphosphocholine, and piracetam. None
of these therapies are recommended at this time.

20.2.6 Other Considerations

There is no specific therapy for frontotemporal dementias. Treatment is generally

supportive: The environment should be bright, cheerful, and familiar and should be
designed to reinforce orientation (e.g., placing large clocks and calendars in the
room). Symptoms are treated as needed: behavioral disturbances and parkinsonism
(patients with FTD who have parkinsonism typically do not respond to dopaminer-
gic medications).
In DLB also, there are currently no treatments with evidence of disease-­modifying
effects, and treatment is primarily symptomatic and targeted toward specific disease
manifestations: cognition and neuropsychiatric symptoms, parkinsonian symptoms,
REM sleep behavior disorder, orthostatic hypotension, and urinary symptoms.
278 F. Trotta et al.

20.3 Behavioral and Psychological Symptoms

In 1996, a definition of behavioral and psychological symptoms in dementia (BPSD)

was proposed as a heterogeneous group of clinical manifestations observed in
patients with dementia and characterized by alterations in perception, thought con-
tent, mood, and behavior, including agitation, aggression, delusions, hallucinations,
paranoia, wandering, depression, apathy, disinhibition, and sleep disturbances (IPA
Consensus conference; 1996).
Most patients with dementia develop one or more BPSD [66]. BPSD can have
serious consequences: they are associated with worsening cognition and progres-
sion to more severe stages of dementia and lead to individual suffering and impact
the caregiver burden; they increase the risk for secondary complications such as
falls and fractures leading to emergency room admissions, and ultimately institu-
tionalization and result in higher costs of therapy and caregiving.
The pathophysiology of BPSD is complex and multifactorial [67]. Considering
that BPSD tend to occur in clusters, often co-present, a multiple neurotransmitter
dysregulation maybe involved (monoamine 5-hydroxytryptamine, serotonin, dopa-
minergic system, and histamine) [68, 69].
In order to measure treatment effects, frequency and severity of BPSD should be
quantified at baseline, possibly using a validity scale, such as the Neuropsychiatric
Inventory (NPI) and Behavioral Pathology in Alzheimer’s Disease Rating Scale
(BEHAVE-AD) [69].
First, Garre-Olmo identified four clusters of symptoms [70]:

1. “psychotic” cluster (“delusions” and/or “hallucinations” items)

2. “emotional” cluster (“agitation/aggression” and/or “depression/dysphoria” and/
or “anxiety” and/or “irritability” items)
3. “behavioral” cluster (“euphoria/elation” and/or “apathy” and/or “disinhibition”
and/or “aberrant motor behavior” items)
4. “sleep and night-time behavior disorders” and “appetite and eating disorders”

Apathy, depression, anxiety, and agitation were found to be the most frequent
forms of BPSD. However, a recent systematic review revealed substantial variation
in the reported prevalence, incidence, and longitudinal course among different stud-
ies. In an individual patient, the type and severity of BPSD tend to change over time,
but some forms such as wandering seem to be more persistent. Overall, the “natural
course” of BPSD over time is still largely unknown [70].
The treatment of BPSD is often highly challenging. BPSD management requires
both a patient-centered and caregiver-centered focus. Treating concomitant somatic
diseases can reduce BPSD. Effective pain management is part of successful BPSD
treatment. It is important to always consider medication toxicity, such as anticholin-
ergic side effects, or abrupt discontinuation of chronic therapies. Pharmacotherapy
for BPSD is frequently provided, but it carries the risk of serious side effects.
Therefore, nonpharmacological therapies are the first choice, and they should be
continued also when pharmacotherapy is necessary.
20 Pharmacological Treatment of Cognitive and Behavioral Disorders in Dementia 279

The topic of depression is treated in a separate chapter, so below we will only

deal with the management of hyperactivity/agitation.

20.3.1 Treatment of Hyperactivity-Impulsivity-Irritiability-­Dis

inhibition-Aggression-­Agitation (HIDA) Domain

The hyperactivity-impulsivity-irritability-disinhibition-aggression-agitation
(HIDA) domain represents one of the most difficult sets of symptoms to manage
and accounts for much of the burden for caregivers and hospital staff. These symp-
toms can arise from a variety of underlying causes in patients with dementia, and
identifying the genesis of the abnormal behavior is critical to effective management
(e.g., delirium, depression, sleep disorders, misperception). Many studies suggest
non-pharmacological treatments for HIDA domain symptoms as first line, for
instance, music therapy, sensory interventions, and person-centered communication
skill for caregivers [71].
When non-pharmacological intervention fails and neuropsychiatric symptoms
produced severe distress or safety issues, acute pharmacologic therapy with an anti-
psychotic drug is often necessary [72]. NICE Guidelines recommend (1) to use the
lowest effective dose for the shortest possible time, (2) to reassess the patients at
least every 6 weeks, (3) to check whether they still need medication, and (4) to stop
treatment with antipsychotics if the person with dementia is not getting a clear
ongoing benefit from taking these drugs (after discussion with the person taking
them and their family members or careers when appropriate). To this regard, it
should be acknowledged that many of these drugs may increase mortality, and most
of them are not approved for treatment of behavioral disorders in patients with
dementia by FDA. Despite the warnings issued by the FDA, the EMA and the UK
Medicines and Healthcare Products Regulatory Agency mainly related to increased
risk of death, cerebrovascular adverse events (CVAEs), parkinsonism, sedation, gait
disturbance, cognitive decline, and pneumonia, antipsychotics are often used in
individuals with dementia for sustained periods (≥6 months). It is noteworthy that
the drug-related mortality risk remains elevated for at least 2 years, with a risk of
death that is greater than the longer duration of use [69].
Benzodiazepines are not recommended for the management of neuropsychiatric
symptoms in elderly patients with dementia because they can induce worsening of
gait and balance, potential paradoxical agitation, and physical dependence [73].

20.3.1.1 Antipsychotic Drugs

Antipsychotic drugs, also known as neuroleptics, are a class of psychotropic medi-
cation primarily used to manage psychosis (including delusions, hallucinations,
paranoia, or disordered thought), principally in schizophrenia but also in a range of
other psychotic disorders. They have a complex mechanism of action, interacting
with several different class of receptors, mainly dopaminergic and serotoninergic.
Specifically, all antipsychotic drugs block dopaminergic D2 receptors with different
grade of affinity, and some of them show also a significant interaction with
280 F. Trotta et al.

serotoninergic 5HT2A receptors. Based on their potency as dopamine D2 receptor

antagonists and their actions on serotonin 5-HT2A receptors, antipsychotics are
commonly classed as either typical or atypical, with the latter showing a more effec-
tive modulation of 5HT2A receptors.

Typical (or First-Generation) Antipsychotics

Typical antipsychotics have significant potential to cause extrapyramidal side
effects (i.e., drug-related parkinsonism) and tardive dyskinesia due to their strong
block of D2 receptors. This propensity to cause movement disorders is the pri-
mary difference between typical and atypical antipsychotics. The main mecha-
nism of action of all typical antipsychotics indeed appears to be postsynaptic
blockade of brain dopamine D2 receptors [74]. Evidence supporting this mecha-
nism includes strong antagonism of D2 receptors in both cortical and striatal
areas, a high correlation between D2 receptor binding and clinical potency, and a
consistent requirement of about 65% D2 receptor occupancy for antipsychotic
efficacy in functional imaging studies. Aside from their common activity as D2
antagonists, each typical antipsychotic drug has distinct effects on neuronal
5-HT2a, alpha-1, histaminic, and muscarinic receptors, which generally corre-
spond to their individual side effect profiles.
Based on their chemical structures, they are grouped into several classes: (1)
phenothiazines (e.g., chlorpromazine and fluphenazine), (2) butyrophenones (e.g.,
haloperidol), (3) benzamides (e.g., sulpiride and tiapride).
The pharmacologic differences are the basis for the classification of typical anti-
psychotics as either high- or low-potency drugs. The high-potency typical antipsy-
chotics (fluphenazine, haloperidol, loxapine, perphenazine, pimozide, thiothixene,
and trifluoperazine) have low activity on histaminic and muscarinic receptors. They
are associated with relatively small risk of sedation and weight gain but a high risk
for extrapyramidal side effects.
The low-potency typical antipsychotics (chlorpromazine and thioridazine),
instead, have high histaminic and muscarinic activity with a corresponding increased
prevalence of sedation and anticholinergic effects but lower risk of extrapyramidal
side effects compared to high-potency antipsychotics.
All these drugs can be administered in oral and/or i.m. and/or i.v. formulation,
and all of these can cause QTc prolongation (in particular, haloperidol, for which
QTc prolongation is an absolute contraindication).
Nowadays, a long-acting injectable formulation of some antipsychotic medica-
tions, for instance, haloperidol, is also available. However, the American Psychiatric
Association (APA) recommends that in individuals with dementia complicated by
agitation or psychosis, a long-acting injectable antipsychotic medication should not
be utilized unless it is otherwise indicated for a co-occurring chronic psychotic ill-
ness [72] (Recommendation 1B). From a general point of view, the use of all typical
antipsychotic medications is off-label in dementia context, due to a non-clear evi-
dence of a favorable risk/benefit profile.
20 Pharmacological Treatment of Cognitive and Behavioral Disorders in Dementia 281

Atypical (or Second-Generation) Antipsychotics

Atypical antipsychotic drugs (AAPs), also known as nonconventional, are more
active on serotoninergic receptors (mainly on 5HT2A) and less active on dopami-
nergic receptors than typical antipsychotics. Based on this pharmacodynamic pro-
file, unconventional antipsychotics, compared to conventional antipsychotics, may
cause less cognitive impairment, induce significantly fewer extrapyramidal symp-
toms and a lower risk of tardive dyskinesia, and have few or no effects on prolactin
production (with exception of risperidone, which increases prolactin as conven-
tional antipsychotics). On the other hand, most of these drugs can generate a meta-
bolic syndrome, with insulin resistance, weight gain, and hypertension. Very
relevant are also the risk of falls and fractures and of QTc prolongation.
In general, adverse events with the use of these drugs in patients with dementia
are dose related.
The atypical antipsychotics are very similar to each other in efficacy but differ in
adverse effects, so the selection of a specific drugs should be based on consideration
of side effects and individual patient characteristics: For instance, olanzapine, which
has a relatively high rate of sedation, may be prescribed for patients with agitation
or insomnia; furthermore, it could be useful in patients with loss of appetite because
weight gain is a frequent side effect of this drug.
Among AAPs, only risperidone is indicated for the short-term management of
persisting and severe aggression in individuals with AD, even if, in clinical practice,
also other antipsychotic therapies are used off-label.

Typical Vs Atypical Antipsychotics

Many clinical studies have systematically compared atypical with typical antipsy-
chotics in terms of efficacy, quality of life, tolerability, dropout, and side effects, and
most of them demonstrated a better outcome with atypical ones in several aspects.
From a general point of view, even if not all atypical antipsychotics drugs have
achieved the same results, AAPs have been shown to have an improved pharmaco-
logical profile in the treatment of positive and negative symptoms compared to the
prototypical typical haloperidol, with clozapine being probably the most effective
[75]. To this regard, it is noteworthy the uniqueness of clozapine’s clinical effect
based on its ideal activity on dopamine and serotonin receptors, strongly in favor of
the second, and also on other targets, i.e., muscarinic and noradrenergic receptors,
glycine transporter, and BDNF. Conversely, risperidone’s activity is mostly based
on a similar antagonism at dopamine and serotonin receptors, making it the least
atypical in the family of atypical antipsychotics. For these reasons, some authors
proposed a continuum spectrum of atypia that ranges from risperidone, the least
atypical, to clozapine, the most atypical. On the continuum spectrum of atypia,
there are three levels of atypicality, based on the molecular profiles, wherein risperi-
done is the least atypical (level I) and clozapine is the most atypical (level III), while
all others (aripiprazole, amisulpride, luraseride, ziprasidone, asenapine, quetiap-
ine, olanzapine) fall within these two extremes of the spectrum (level II) [76].
282 F. Trotta et al.

Anyway, it is important to underline that although clozapine has a good efficacy

and a low risk of extrapyramidal side effects, its use requires regular blood monitor-
ing due to a risk of agranulocytosis. Therefore, clozapine should be used with cau-
tion, and generally, it should be introduced only if other drugs are ineffective
(however, in some cases, for instance, for the treatment of Parkinson’s disease
patients with psychosis, clozapine represents the first-choice drug).

Risperidone
Risperidone, at low dosages (1–2 mg per day), shows higher affinity for 5-HT 2A
than for D2, while at high dosages (3–6 mg per day), the affinity for D2 overcomes
that for 5-HT2A. Risperidone has shown good efficacy in treating positive symp-
toms. However, the strong binding to 5-HT 2C, α1, and H1 is responsible for the
side effects, such as weight gain, sedation, orthostatic hypotension, and
parkinsonism.

Aripiprazole
Together with amisulpride, aripiprazole represents an exception among AAPs,
given the relatively low affinity to 5HT2A receptor. It is associated to a low risk of
extrapyramidal side effects, and it is efficacious against both positive and negative
symptoms. Aripiprazole causes minimal weight gain and sedation and does not pro-
duce elevation in serum prolactin levels; most importantly, unlike other neurolep-
tics, it does not significantly lengthen QTc interval. However, based on randomized
controlled trial performed to test efficacy and safety of aripiprazole in the context of
Alzheimer’s dementia [77], faced to a small but statistically significant efficacy in
controlling BPSD in AD patients, aripiprazole resulted to be associated to higher
mortality and higher risk of stroke compared to placebo. Although a real causal role
of the drug in inducing these severe side effects is still controversial, the prevalent
expert opinion suggests that aripiprazole should be used with caution in AD
patients [78].

Olanzapine
Olanzapine can be started at a dose of 2.5 mg daily and titrated up to a maximum of
5 mg twice a day (the incidence of extrapyramidal symptoms is quite low at doses
of 5 mg per day). It appears to be quite effective for treating neuropsychiatric symp-
toms in Alzheimer’s disease or vascular dementia [79]. Metabolic side effects
(weight gain, diabetes, and hypercholesterolemia) are more common compared to
other antipsychotic drugs.

Quetiapine
Quetiapine generally is used at a dose of 25 mg at bedtime and titrating up a maxi-
mum of 75 mg twice a day. It has different effects based on the dose administrated:
antipsychotic effect with 600 mg per day, antidepressant with 300 mg per day, hyp-
notic effect with 50 mg per day. Because of its effects on the cardiac repolarization,
it is necessary to check the QTc before the prescription.
20 Pharmacological Treatment of Cognitive and Behavioral Disorders in Dementia 283

In conclusion, it must be highlighted that only three drugs are licensed for BPSD
treatment in dementia: pimavanserin (only in the USA) and clozapine for hallucina-
tions and delusions associated with Parkinson’s disease (PD) psychosis and risperi-
done for short-term treatment of persistent aggression in moderate-to-severe
Alzheimer’s disease (AD). In the remaining cases, the use of antipsychotics is off-­
label and guided by the physician’s judgment.
Risperidone, aripiprazole, and olanzapine have been evaluated in multiple stud-
ies and show improvement in symptoms like severe agitation, aggression, and psy-
chosis (such as delusions and hallucinations) in patients with dementia.
Maximal duration of antipsychotic treatment should be limited according to 3Ts
(target symptom, titration, time) whereby the duration of the treatment should not
exceed 3 months due to an increased risk of mortality, and regular reassessment is
necessary.
Antipsychotics are generally to be avoided when diagnosing dementia with
Lewy bodies due to particular sensitivity of these patients to extrapyramidal side
effects. A use with caution of quetiapine and clozapine is possible [80, 81].

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Pharmacological Treatment
of Osteoporosis in Older Patients 21
Marian Dejaeger, Jolan Dupont, Michaël R. Laurent,
and Evelien Gielen

21.1 Epidemiology of Osteoporosis and Osteoporotic

Fractures in Old Age

Osteoporosis is a systemic bone disease, characterized by low bone mass and dis-
ruptions in the micro-architectural structure of bone tissue, resulting in an increase
in bone fragility and fracture risk [1]. The incidence of osteoporotic fractures
increases with age, and osteoporosis at advanced age is a challenge because of coex-
isting comorbidities and the major post-fracture implications in terms of morbidity,
loss of mobility, and mortality. Currently, the cumulative incidence of hip and ver-
tebral fractures in women at the age of 80 years is close to 30% and more than 40%,
respectively. Women over the age of 80 represent more than 30% of all osteoporotic
fractures and even more than 60% of all non-vertebral fractures [2–4]. Age is also
one of the main determinants of the type of osteoporotic fracture. Between the ages
of 55 and 75, the risk of vertebral fractures peaks in women, whereas beyond the
age of 75, women become increasingly at risk of non-vertebral fractures, e.g., hip
fractures [5]. The burden of osteoporosis will only increase further because of the
aging society.

M. Dejaeger · J. Dupont · E. Gielen (*)

Geriatrics & Gerontology, Department of Public Health and Primary Care, KU Leuven,
Leuven, Belgium
Department of Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium
Centre for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium
e-mail: [email protected]; [email protected];
[email protected]
M. R. Laurent
Centre for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium
Geriatrics Department, Imelda Hospital, Bonheiden, Belgium
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 289

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_21
290 M. Dejaeger et al.

21.2 Older Persons with Osteoporotic Fractures Are Frail

Osteoporosis and osteoporotic fractures tend to occur in a part of the older popula-
tion already suffering from frailty [6]. Indeed, older persons with osteoporotic frac-
tures are not “average” older persons but frail individuals with a high prevalence of
underlying comorbidities and at risk of disabilities [7]. This frailty is reflected in the
poor post-fracture outcomes of these patients. For example, 1 year post-fracture,
40% of the patients are still unable to walk independently, 33% are institutionalized
or totally dependent, and 20% are deceased [8, 9]. These poor outcomes are not
restricted to hip fractures alone, as similar observations have been made in older
persons with other types of non-vertebral fractures and even vertebral fractures [10].
Moreover, the excess mortality is not only observed within the first year after the
fracture but persists in the years thereafter due to the underlying comorbidities of
these frail older persons [11, 12].

21.3 Diagnosis of Osteoporosis and Intervention Thresholds

in Old Age

Despite the high prevalence and significant burden of osteoporosis, this condition
remains to be underdiagnosed and undertreated. This is most prominent in women
aged ≥80 years [13]. To illustrate, according to a study in more than 700,000 per-
sons aged ≥75 years in Sweden, 16.1% of women and 3.4% of men used osteopo-
rosis medication, lower than the estimated prevalence of osteoporosis in that
country. In particular in persons ≥90 years, osteoporosis was largely under-
treated [14].
Yet, the operational definition of osteoporosis also applies to older persons. The
World Health Organization (WHO) defines osteoporosis as a bone mineral density
(BMD) value at the lumbar spine or the proximal femur of at least −2.5 standard
deviations (SD) below the peak bone mass of a young healthy individual [15].
However, sensitivity of dual-energy X-ray absorptiometry (DXA) for fracture is
low, as the majority of fractures occurs in persons with a T-score above −2.5. This
implies that factors other than BMD contribute to fracture risk [16]. More specifi-
cally, an existing osteoporotic fracture is the most significant predictor of future
fracture risk, resulting in a doubling of fracture risk compared to persons without
previous fractures. Also, increasing age itself is an important risk factor for fractures
as over a 4 SD interval of BMD (+1 to −3 SD), a 14-fold increase in hip fracture risk
is seen at the age of 50, but a 145-fold increase at the age of 80 [17, 18]. Therefore,
fracture risk assessment tools based on age and other clinical risk factors are increas-
ingly being used to target osteoporosis therapy. Among these is the FRAX algo-
rithm, which includes the weight of various clinical risk factors for fractures, with
or without femoral neck BMD, to estimate the 10-year probability of hip fracture
and major osteoporotic fractures (clinical spine, forearm, hip, or shoulder fractures)
[19]. The main goal of FRAX is to identify individuals at higher fracture risk who
qualify for osteoporosis treatment. Three approaches can be distinguished, which,
21 Pharmacological Treatment of Osteoporosis in Older Patients 291

especially in older persons, differ in the threshold above which treatment is recom-
mended: fixed, age-dependent, and hybrid thresholds.
First, according to the fixed model of the USA National Osteoporosis Foundation
(NOF), treatment should be initiated when the 10-year fracture risk of a person
exceeds the 10-year fracture probability at which treatment becomes cost-effective
[20, 21]. Second, the age-dependent model of the UK National Osteoporosis
Guideline Group (NOGG) indicates that treatment should be considered when the
fracture probability of an individual exceeds the FRAX intervention threshold,
defined as the age-specific fracture probability of a man or woman with a previous
fragility fracture, no other risk factors, an average BMI (24 kg/m2), and without
knowledge of BMD [22, 23]. The rationale is that in general, a person with a previ-
ous fragility fracture is considered to qualify for treatment. Third, as the previous
model induces inequalities in access to therapy especially at older age, an alterna-
tive threshold using a hybrid model has been proposed by the NOGG. According to
this model, the intervention threshold rises with age but remains constant from the
age of 70, being at 20% for a major osteoporotic fracture and 5.4% for a hip fracture
[23, 24].

21.4 Treatment of Osteoporosis in Older Persons

In this section, we will discuss the efficacy and safety of the pharmacological treat-
ment options for osteoporosis in older persons. Osteoporosis treatment for older
persons should be proven to be effective in this cohort, not only against vertebral
fractures but even more so against non-vertebral fractures, as these account for the
majority of negative outcomes (e.g., morbidity, mortality). Treatment should also be
safe in frail older adults, with underlying comorbidities and at increased risk of
adverse events.

21.4.1 Calcium and Vitamin D Supplementation in Old Age

One of the main determinants of bone loss and fracture risk in old age is calcium
and vitamin D deficiency. Therefore, combined supplementation of calcium and
vitamin D has become one of the main treatment strategies for reducing bone loss
and fracture risk in old age. Low vitamin D status and insufficient dietary calcium
intake can lead to secretion of parathyroid hormone (age-related hyperparathyroid-
ism), stimulating bone resorption and increasing the fracture risk.
Despite a high degree of consensus on the essential role of vitamin D for bone
health and other extra-skeletal effects, there remains some lack of consensus regard-
ing the optimal concentration of total 25-hydroxyvitamin D (25(OH)D). Yet, it is
clear that vitamin D insufficiency occurs in all age groups. In fact, a gradual decline
in 25(OH)D levels from healthy adults over independent older adults to institution-
alized individuals and hip fracture patients can be observed [25]. Severe vitamin D
deficiency (<10 μg/L) is seen in almost 4 out of 5 institutionalized people [25]. The
292 M. Dejaeger et al.

intestinal absorption of vitamin D is adequate, even at very advanced ages [25].

However, the vitamin D status deteriorates with aging above 70 years due to a very
low dietary intake, decreased sun exposure, and a reduced capacity to produce vita-
min D in the skin with aging [25, 26].
There has been some debate whether calcium and vitamin D supplementation
has an influence on fracture prevention. A meta-analysis of Bolland et al., for exam-
ple, found that vitamin D co-administered with calcium reduced hip fracture risk in
institutionalized but not in community-dwelling older persons [27]. This and other
meta-analyses and individual RCTs may have failed to demonstrate a reduction in
fracture risk with calcium and vitamin D because of an insufficient dose, therapeutic
incompliance, or lack of targeting of supplementation to persons at risk of vitamin
D deficiency or a negative calcium balance [28–31]. Calcium and vitamin D supple-
mentation indeed need to be directed to persons with documented or at risk of cal-
cium and/or vitamin D deficiency, which is, as mentioned before, highly prevalent
in osteoporosis patients, home-bound frail persons, and institutionalized persons
[25]. A recent systematic review and meta-analysis of the effectiveness of calcium
and vitamin D showed a significant reduction in the risk of total fractures and hip
fractures and concluded that the minimum effective dose of calcium is 1200 mg
while vitamin D should not be below 800 IU [32].
In addition to the effect on bone loss, a daily intake of 800 IU to 1000 IU vitamin
D lowers the risk of falling by 20% in older adults, independent of calcium intake
[33]. Efficacy of doses higher than 1000 IU/day has not been observed in RCTs. On
the contrary, intermittent supplementation with very high doses, such as a single
oral dose of 500,000 IU, even increases the risk of falls, especially in the first months
after intake when serum 25(OH)D levels are >45 ng/mL [34]. Also, an increased
risk of falls was seen at a monthly intake of 60,000 IU vitamin D compared to
24,000 IU [35]. Therefore, an intake of >1000 IU of vitamin D per day is not recom-
mended to prevent falls in all older adults [31]. Both the International Osteoporosis
Foundation as the American Geriatrics Society recommend 800–1000 IU of vitamin
D per day in community-dwelling and institutionalized older adults [33, 36].
To conclude, the combination of calcium and vitamin D has become an essential
part in fracture risk prevention in the aged population. A daily intake of 1200 mg
calcium per day (but not more than 2000 mg/day) is recommended in older adults at
risk of fracture. As some cardiovascular safety issues have been raised about the use
of calcium supplements (that, however, were not confirmed in other studies), the
preferable source of calcium is by food intake of dairy products [27]. When the
daily recommended intake cannot be achieved by food intake, oral supplements
should be considered.

21.4.2 Pharmacological Osteoporosis Treatment in Old Age

Besides optimizing calcium and vitamin D intake, osteoporosis treatment should be

in added in older persons with osteoporosis and osteoporotic fractures. Currently
available osteoporosis medications are classified as antiresorptive
21 Pharmacological Treatment of Osteoporosis in Older Patients 293

(bisphosphonates, denosumab, and selective estrogen receptor modulators) and ana-

bolic (teriparatide, abaloparatide, romosozumab) drugs.
When considering drug therapy for osteoporosis in older persons, one should
bear in mind that these older adults often have a reduced intestinal absorption,
metabolism, and excretion of drugs as well as polypharmacy, therapeutic incompli-
ance, and concomitant disorders [37]. Aging is, for example, associated with a
reduced kidney function. Since about 50% of the bisphosphonates are excreted by
the kidneys, reduced kidney function may result in an accumulation of these drugs,
which potentially affects efficacy and safety [38]. In the following paragraphs, evi-
dence in older persons about the efficacy (Table 21.1) and safety of the available
osteoporosis medications will be elucidated. The evidence is mostly based on sub-
group analyses of the landmark osteoporosis trials in postmenopausal women.

21.4.2.1 Antiresorptive Treatment for Osteoporosis

Alendronate
The efficacy of alendronate in postmenopausal women was demonstrated by the
Fracture Intervention Trial (FIT). The FIT Vertebral Fracture Arm (FIT I) included
women who suffered from vertebral fracture(s), while the FIT Clinical Fracture
Arm (FIT II) included women with a T-score of ≤−1.6 at the femoral neck (mean
age 70.8 years and 67.7 years, respectively) [39, 40].
Two sub-analyses of the FIT trials have been undertaken to determine the anti-­
fracture efficacy and safety of alendronate in older persons. A post hoc analysis of
FIT I has focused on the efficacy of alendronate in postmenopausal women with the
highest fracture risk, including a subgroup of women aged ≥75 years (range
75–82 years) [41]. In order to prevent one new vertebral fracture, eight women aged
≥75 years (RR = 0.62; 95% CI, 0.41–0.94) needed to be treated for 3 years with
alendronate compared with nine women aged <75 years (RR = 0.49; 95% CI,
0.35–0.68). Another analysis, based on pooled data from both FIT arms, aimed to
calculate age-specific fracture rates by treatment group (55 to <65 years, 65 to
<70 years, 70 to <75 years, and 75–85 years) [42]. Relative risk reductions were
comparable among age groups for hip (RR = 0.47; 95% CI, 0.27–0.81; p < 0.01) and
vertebral (RR = 0.55; 95% CI, 0.37–0.83; p < 0.01) fractures, revealing an even
greater absolute risk reduction as age increases, which can be explained by the age-­
related increase in fracture risk in the placebo group [42]. A study on older patients
(range 71–92 years) with a previous fracture showed also a significant reduction in
hip fracture risk (hazard ratio (HR) = 0.72; 95% CI, 0.61–0.85, p < 0.001), which
was maintained across all age quartiles [43]. Finally, using a national database of
men and women undergoing a fall risk assessment at a Swedish healthcare facility,
the efficacy of alendronate treatment was investigated in patients aged ≥80 years
(mean age of 85.7+/− 3.9 years) and history of fracture [43]. Alendronate was asso-
ciated with a lower hip fracture risk (HR = 0.66; 95% CI, 0.51–0.86; P < 0.01).
The post hoc analysis of FIT I and the pooled analysis from both FIT arms did
not report safety data in older persons [41, 42]. The Swedish study reported a
reduced mortality risk in patients treated with alendronate (HR = 0.88; 95% CI,
Table 21.1 Relative risk (95% CI) of new vertebral, hip and non-vertebral fractures compared with placebo in older women receiving currently available
294

osteoporosis treatments
Mean age
RCT Included participants N (years) Vertebral fractures Hip fractures Non-vertebral fractures
Alendronate Post hoc analysis Women aged 539 Not RR = 0.62; – –
FIT I (3 years) 75–82 y specified 95% CI 0.41–0.94.
(Ensrud 1997) p < 0.05
pinteract < 75 & ≥75 y NS
Pooled analysis Women aged 3658 RR = 0.55; RR = 0.47; –
FIT I and FIT II 55–80 y 95% CI 0.37–0.83 95% CI 0.27–0.81
(3–4 years)  55–<65 y (constant RR) (constant RR)
(Hochberg 2005)  65–<70 y
 70–<75 y
 75–85 y
Axelsson et al. Women aged 110.190 82.4 y – HR = 0.72; –
(5 years) 71.1–92.3 y with a 95% CI: 0.61–0.85;
(Axelsson 2016) prior fracture p < 0.001
Risedronate HIP - arm 2 Women aged ≥80 y 3886 83 y – RR = 0.8; 10.8% (Risedronate) vs
(3 years) with at least one 95% CI 0.6–1.2; 11.9% (placebo);
(McClung 2001) non-skeletal risk p = 0.35 p = 0.43
factor for hip
fracture
or T-score at
FN < −4 or
<−3 + hip axis
length of ≥11.1 cm
Post hoc pooled Women aged ≥80 y 1392 83 y HR = 0.56; – 14.0% (Risedronate) vs
analysis VERT-NA, with T-score <−2.5 95% CI 0.39–0.81; 16.2% (placebo);
VERT-MN and HIP at FN or at least one p = 0.003 p = 0.66
(3 years) prevalent vertebral pinteract < 80 & ≥85 y NS
(Boonen 2004b) fracture
M. Dejaeger et al.
Mean age
RCT Included participants N (years) Vertebral fractures Hip fractures Non-vertebral fractures
21

Zoledronic Post hoc analysis Women aged ≥75 y 3888 79.4 y HR = 0.34; HR = 0.82; HR = 0.73;
acid HORIZON-PFT with T-score ≤−2.5 95% CI 0.21–0.55; 95% CI 0.56–1.2; 95% CI 0.60–0.90;
and RFT (3 years) at FN or ≥1 vertebral p < 0.001 p = 0.297 p = 0.002
(Boonen 2010) or hip fracture pinteract < 75 & ≥75 y NS pinteract < 70 & ≥75 y SS pinteract < 70 & ≥75 y NS
Denosumab Post hoc analysis Women aged ≥75 y 2471 78.2 y – 0.9% (Denosumab) –
FREEDOM vs 2.3% (placebo);
(3 years) (Boonen p < 0.01; ARR 1.4%
2011) pinteract < 75 & ≥75 y NS
Preplanned analysis Women aged ≥75 y 2471 78.2 y 3.1% (Denosumab) vs – 7.9% (Denosumab) vs
FREEDOM 8.6% (placebo); 9.0% (placebo);
(3 years) (McClung RR = 0.36; RR = 0.84;
2012) 95% CI 0.25–0.53 95% CI 0.63–1.12
pinteract < 75 & ≥75 y NS pinteract < 75 & ≥75 y NS
FREEEDOM Women aged ≥75 y 662 78 y 3.6% (Denosumab) 1.0% (Denosumab) 5.4% (Denosumab)
Extension (6 years) (no placebo group) (no placebo group) (no placebo group)
(Papapoulos 2012)
Teriparatide Prespecified Women aged ≥75 y 244 78.3 y RR = 0.35, – RR = 0.75; p = 0.661
subgroup analysis p < 0.05 (not powered)
FPT (19 months) pinteract < 75 & ≥75 y NS pinteract < 75 & ≥75 y NS
(Boonen 2006a)
Abalopratide Posthoc analysis Women aged ≥80 y 94 81.7 0 fractures 1 fracture
ACTIVE (Aboloparatide) vs 2 (Abaloparatide) vs 2
(18 months) fractures (placebo) fractures (placebo)
Pharmacological Treatment of Osteoporosis in Older Patients

McClung 2018
Posthoc analysis Women aged ≥75 y 303 NA <65 y, 65–75 y, ≥75 y: <65 y, 65–75 y, ≥75 y:
ACTIVE consistent fracture risk consistent fracture risk
(18 months) reduction reduction
Cosman 2017
(continued)
295
Table 21.1 (continued)
296

Mean age
RCT Included participants N (years) Vertebral fractures Hip fractures Non-vertebral fractures
Romosozumab FRAME (2 years) Women 55–90 y 7180 70.9 y 12 months (Romo vs 12 months (Romo vs 12 months (Romo vs
Cosman 2016 placebo): RR = 0.27; placebo): HR = 0.54; placebo): HR = 0.75;
95% CI 0.16–0.47 95% CI 0.22–1.35 95% CI 0.53–1.05
24 months (Romo/ 24 months (Romo/ 24 months (Romo/
Dmab vs placebo/ Dmab vs placebo/ Dmab vs placebo/
Dmab): RR = 0.25; Dmab): HR = 0.50; Dmab): HR = 0.75;
95% CI 0.16–0.40 95% CI 0.24–1.04 95% CI 0.57–0.97
ARCH (2 years) Women 55–90 y 4093 74.3 y 12 months (Romo vs 12 months (Romo vs 12 months (Romo vs
Saag 2017 ALN): RR = 0.63; ALN): HR = 0.64; ALN): HR = 0.74;
95% CI 0.47–0.85 95% 0.33–1.26 95% CI 0.54–1.01
24 months (Romo/ Primary analysis Primary analysis
ALN vs ALN/ALN): (Romo/ALN vs ALN/ (Romo/ALN vs ALN/
RR = 0.52; 95% CI ALN): HR = 0.62; ALN): HR = 0.81;
0.40–0.66 95% CI 0.42–0.92 95% CI 0.66–0.99
FN Femoral neck, LS Lumbar spine, y Years, ITT Intention to treat, NS Not significant, RR Risk ratio, HR Hazard ratio, Romo Romosozumab, Dmab Denosumab,
ALN Alendronate. Results in bold indicate significant results
Table adapted from: Vandenbroucke A et al. Pharmacological treatment of osteoporosis in the oldest old. Clinical Interventions in Aging 2017:12; 1065–1077.
Dove Medical Press Limited
M. Dejaeger et al.
21 Pharmacological Treatment of Osteoporosis in Older Patients 297

0.82–0.95) as well as an increased risk of mild upper gastrointestinal symptoms

(UGI) (HR = 1.58; 95% CI, 1.12–2.24). The association between alendronate and
mild UGI, however, did not change with age. Furthermore, the Number Needed to
Harm (NNH) was 91, as compared to the Number Needed to Treat (NNT) of 26 for
hip fracture, which is considered as a favorable risk-benefit ratio [43]. Together,
these data illustrate that alendronate is safe in older persons, with reduced vertebral
and hip fracture risk, and suggest that older persons, who intrinsically have a higher
baseline fracture risk, benefit more from osteoporosis treatment than younger
persons.

Risedronate
The Vertebral Efficacy with Risedronate Therapy North America (VERT-NA) and
Multinational (VERT-MN) studies showed both that risedronate can efficiently
reduce vertebral and non-vertebral fractures rates [44, 45] in postmenopausal
women with one or more vertebral fractures (mean age +/− 70 years) [44, 45]. In
addition, the HIP trial has studied the effect of risedronate on hip fracture risk in two
different arms, of which the first arm included postmenopausal women with a mean
age of 74 years [46]. To determine the efficacy of risedronate in older persons, the
second arm of the HIP trial included 3886 women, aged ≥80 years (mean age
83 years). These older women were included based on having a low BMD at the
femoral neck or at least one nonskeletal risk factor for hip fracture (e.g., poor gait or
a propensity to fall) [46]. After 3 years of risedronate use, no significant reduction
in the risk of hip fractures was observed (RR = 0.8; 95% CI, 0.6–1.2; p = 0.35).
Only in the subgroup of women (16%) included based on low BMD, a significant
reduction in hip fracture rate was seen. However, most of the participants (58%)
were included on the basis of a nonskeletal risk factor. A second analysis on pooled
data from these three studies (VERT-NA, VERT-MN, and HIP trials) focused on
older individuals [47]. This analysis included 1392 women aged ≥80 years (mean
age 83 years) with osteoporosis (T-score <−2.5 or at least one vertebral fracture).
After 1 year, the vertebral fracture risk decreased by 81% (HR = 0.19; 95% CI,
0.09–0.40; P < 0.001) and after 3 years by 44% (HR = 0.56; 95% CI, 0.39–0.81;
p = 0.003). Regarding non-vertebral fractures, the incidence did not differ signifi-
cantly between the treatment group and the placebo group (p = 0.66).
This gap in benefit for vertebral vs non-vertebral fractures in both analyses in
older persons might be explained by the knowledge that bisphosphonates impact
on BMD, demonstrated by the significant reduction of vertebral fractures [46, 47].
In spite of this, bisphosphonates do not intervene with the nonskeletal risk factors
of fractures such as gait disturbances, impaired balance, and fall risk. These non-
skeletal factors play a major role in the occurrence of non-vertebral fractures,
such as hip fractures, in older persons, who are more at risk of falling [48]. On the
contrary, vertebral fractures are often spontaneous or atraumatic, thus less influ-
enced by these nonskeletal risk factors. Furthermore, the discrepancy between the
older and younger population in preventing non-vertebral fractures might be
explained, at least partly, due to insufficient statistical power in the older age
group [47].
298 M. Dejaeger et al.

Older women (aged ≥80 years) in the HIP trial had a marginally higher inci-
dence of death, other serious adverse events, and discontinuation due to adverse
events than younger women [46]. However, the overall occurrence and types of
adverse events, including those involving the upper gastrointestinal tract, were com-
parable in the risedronate and placebo group, aside from age. Additionally, in
women aged ≥80 years in the pooled analysis of the VERT-NA, VERT-MN, and
HIP trials, adverse events were similar in the risedronate and placebo group [47].
Even in older persons with active gastrointestinal tract disease at baseline or on
aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or proton pump inhibitors
(PPIs), the incidence of adverse events was similar in both treatment groups.
Thus, safety data of oral bisphosphonates confirm that they are well tolerated in
older persons and not associated with an increased risk of adverse events as com-
pared to placebo. Nonetheless, in clinical practice, treatment with oral bisphospho-
nates may be challenging, as the rather demanding intake instructions (e.g., to stay
upright for at least 30 min after the intake) may be difficult for physically or cogni-
tively impaired persons. Inappropriate administration, however, increases the risk of
adverse events and potentially further decreases the already low oral bioavailability
(around 1%–2%) [38, 49, 50]. Furthermore, oral osteoporosis medication rises the
pill burden in older persons, which contributes to low compliance. Indeed, almost
50% of those who have been prescribed an oral bisphosphonate have discontinued
treatment after 1 year [51].

Zoledronic Acid
Usage of an intravenous bisphosphonate, such as zoledronic acid, might provide an
alternative in older persons that cannot tolerate or adhere to oral bisphosphonates
[52]. The Health Outcomes and Reduced Incidence with Zoledronic Acid Once
Yearly Pivotal Fracture Trial (HORIZON-PFT) demonstrated that once-yearly infu-
sion of zoledronic acid significantly reduces the risk of vertebral, hip, and non-­
vertebral fractures in postmenopausal women with osteoporosis (mean age 73 years)
[53]. In a second analysis in participants with surgical repair of a low-trauma hip
fracture (mean age 74.4 years), the HORIZON-Recurrent Fracture Trial (HORIZON-­
RFT), zoledronic acid significantly lowers the risk of new vertebral and new non-­
vertebral fractures [54].
Additional post hoc pooled analysis of the HORIZON-PFT and HORIZON-RFT
was performed, focusing on older persons, by including postmenopausal women
aged ≥75 years (mean age 79.4 years) with osteoporosis (T-score ≤−2.5 at the
femoral neck or ≥1 prevalent vertebral or hip fracture) [52]. After 3 years of treat-
ment, incidence of any clinical vertebral (1.1% vs 3.7%) and non-vertebral fracture
(9.9% vs 13.7%) was significantly lower in the zoledronic acid group compared to
the placebo group (HR = 0.34; 95% CI 0.21–0.55; p < 0.001 and HR = 0.73; 95%
CI 0.6–0.9; p = 0.002 respectively). This benefit was similar to the relative risk
reduction in subjects younger than 75 years in the HORIZON-PFT and HORIZON-­
RFT. Hence, zoledronic acid is an efficient treatment option for the prevention of
vertebral and non-vertebral fractures in older persons. However, in patients aged
≥75 years, the incidence of hip fractures decreased with zoledronic acid, but this did
21 Pharmacological Treatment of Osteoporosis in Older Patients 299

not reach statistical significance (HR = 0.82; 95% CI 0.56–1.2; P = 0.297).

Presumably, the sample size was not statistically powered to observe a reduction of
hip fracture risk in this older age group. An alternative explanation is the large influ-
ence of nonskeletal risk factors for hip fractures with ageing [47, 52].
In the post hoc analysis of the HORIZON-PFT and RFT trial in women aged
≥75 years, incidence of adverse events and post-administration symptoms occur-
ring within 3 days of the infusion (pyrexia, myalgia, and influenza-like illness) was
higher with zoledronic acid than with placebo [52]. The incidence of renal events,
serious adverse events, and death was similar in the two treatment arms. An
increased risk of atrial fibrillation, suggested in the HORIZON-PFT, which could be
a concern in older persons, was not observed in the post hoc analysis evaluating
older persons on zoledronic acid [52].

Denosumab
Denosumab is a human monoclonal antibody that acts on RANKL, a mediator of
bone resorption. In the Fracture Reduction Evaluation of Denosumab in
Osteoporosis Every 6 months (FREEDOM) trial, 7800 women between 60 and
90 years (mean age 72.3 years) with a BMD T-score of <−2.5 but not <−4.0 at the
lumbar spine or total hip received denosumab or placebo for 3 years. Denosumab
was linked with a significant reduction in the risk of vertebral, hip, and non-verte-
bral fractures [55].
An additional post hoc analysis of the FREEDOM trial focused on the effect of
denosumab in populations at high risk of fractures, among which women aged
≥75 years [56]. In this age group (mean age 78.2 years), denosumab lowered the
risk of hip fractures by 62% (2.3% placebo vs 0.9% denosumab; p < 0.01). This risk
reduction in older patients is similar with the risk reduction in the overall study
population of the FREEDOM trial. One more analysis of the FREEDOM trial con-
firmed that denosumab lowers the risk of vertebral fractures to the same extent in
subjects aged ≥75 years (RR = 0.36; 95% CI, 0.25–0.53) as in subjects <75 years
(RR = 0.30; 95% CI, 0.22–0.41; interaction p-value, 0.482) [57]. Moreover, the
effect on non-vertebral fractures in persons older than 75 years (RR = 0.84; 95% CI,
0.63–1.12) was comparable to younger persons (RR = 0.78; 95% CI, 0.63–0.96;
interaction p-value, 0.642). Also, the FREEDOM Extension trial demonstrated that
also in women aged ≥75 years, denosumab for up to 6 years was associated with a
persistently low incidence of new vertebral, hip, and non-vertebral fractures, with a
fracture incidence similar to that observed after 3 years [58].
Hence, denosumab is effective in preventing vertebral and hip fractures in older
persons [56, 57]. In contrast, as indicated, no significant reduction in hip fracture
risk was shown for the bisphosphonates risedronate and zoledronic acid in older
persons, although, as mentioned, this might be explained by lack of statistical power
[41, 42, 52]. However, it is tempting to speculate that this observation of hip fracture
reduction with denosumab is due to the mechanism of action of denosumab, differ-
ent from that of bisphosphonates, with distinct effects on cortical bone [59]. Cortical
porosity is indeed one of the main determinants of non-vertebral fracture risk,
including hip fracture risk.
300 M. Dejaeger et al.

Denosumab was well tolerated in postmenopausal women in the FREEDOM

trial [55]. In the post hoc analysis of women aged ≥75 years, no significant differ-
ences were noted regarding safety between placebo- and denosumab-treated sub-
jects, and the incidence of adverse events was similar to those in the overall
FREEDOM population [56]. Importantly, the efficacy of denosumab is not influ-
enced by kidney function, so older persons with renal impairment will profit the
same anti-fracture efficacy as patients with normal kidney function [60]. However,
since the use of denosumab is associated with a high rate of severe hypocalcemia in
patients with advanced chronic kidney disease, close monitoring and replacement of
calcium and vitamin D is required to avoid hypocalcemia in these patients.
Finally, denosumab, like the bisphosphonates, may be associated with very rare
but severe adverse events, such as atypical femoral fractures and osteonecrosis of
the jaw. In particular for denosumab, treatment interval should be respected, and
discontinuation without alternative treatment should be avoided, in order to avoid
rebound phenomena. Denosumab has a washout period of 6 months, following the
6-month dosing interval, and there is no persistent effect on BMD and BTM (bone
turnover makers) after discontinuation, in contrast to long-acting bisphosphonates
[61]. In case of discontinuation, BTM rise to levels above the pre-treatment baseline
levels [62]. Subsequently, several case reports and a post hoc analysis of the
FREEDOM trial confirmed that vertebral fracture rate increased after denosumab
discontinuation to a level comparable with untreated patients [63–66]. These
rebound phenomena might be counteracted by using a potent bisphosphonate (e.g.,
zoledronic acid or alendronate) as alternative treatment upon discontinuation [67].
However, clinical studies have not yet determined the optimal approach for prevent-
ing the effects of denosumab discontinuation [68]. These findings highlight the
importance of respecting dosage intervals and avoiding noncompliance in persons
treated with denosumab, even in older adults. To our knowledge, there is no evi-
dence that these events are independently associated with age [69]. Since there are
no guidelines about the optimal duration of denosumab and no definitive answers
yet about the sequential treatment with a bisphosphonate after stopping denosumab,
a lifelong treatment with denosumab may be the preferred approach, especially in
older patients [70].

Selective Estrogen Receptor Modulators (SERM)

Raloxifene and bazedoxifene are approved for osteoporosis treatment, but like the
bisphosphonate ibandronate, SERMS have only a proven preventive effect on verte-
bral fractures. As such, these drugs are reserved for young postmenopausal women
that are at low risk of hip fractures.

21.4.2.2 Anabolic Treatment for Osteoporosis

Currently available anabolic drugs for osteoporosis are teriparatide, abaloparatide,
and romosozumab. Teriparatide and abaloparatide are parathyroid hormone ana-
logues administered in a once-daily injection inducing an anabolic effect on bone
formation. Romosozumab is a human monoclonal antibody, administered once-­
monthly, that binds to and inhibits sclerostin. Romosozumab has a dual mode of
21 Pharmacological Treatment of Osteoporosis in Older Patients 301

action, by increasing bone formation and decreasing bone resorption. In patients

that have received a course with anabolic treatment (which lasts 1 to 2 years), it is
recommended to continue with antiresorptive therapy to maintain the gain in bone
mass (sequential therapy).

Teriparatide
In the Fracture Prevention Trial (FPT), teriparatide lowered the risk of vertebral
fractures by 65% (HR = 0.35; 95% CI, 0.22–0.55; P < 0.001) and the risk of non-
vertebral fractures by 53% (HR = 0.47; 95% CI, 0.25–0.88; P = 0.04) in postmeno-
pausal women with a prior vertebral fracture (mean age 69.5 years) [71]. In a
subgroup analysis on the FPT study, Boonen et al. investigated the effect of teripa-
ratide in persons aged ≥75 years after 19 months of treatment (mean age 78.3 years)
[72]. About 5.2% of the older persons in the teriparatide group and 15.1% in the
placebo group suffered a new vertebral fracture (RR = 0.35, P < 0.05). Hip fracture
incidence was not a primary endpoint in this trial. Treatment-by-age interaction was
not significant (p = 0.99), indicating that there was no significant difference in the
effect of teriparatide in younger vs older patients. Also in the older subgroup, 3.2%
of the women in the teriparatide group and 4.2% in the placebo group had a new
non-vertebral fracture (RR = 0.75; p = 0.661). Again, the treatment-by-age interac-
tion was not significant (p = 0.42). The nonsignificant effect on non-vertebral frac-
ture risk in older persons can be justified by the small number of non-vertebral
fractures in the older subgroup, resulting in a lack of power for this aspect [72]. In
conclusion, teriparatide has a significant effect on vertebral and non-vertebral frac-
ture risk in young as well as in older fracture patients.
In the post hoc analysis of the FPT trial in women aged ≥75 years, there was no
rise in adverse events in women treated with teriparatide compared to placebo [72].
On the contrary, back pain, cataract, and pruritus were significantly less present in
those treated with teriparatide. Treatment-by-age interaction (≥75 vs <75 years)
was not significant for the major adverse events. Cataract, deafness, pruritus, and
weight loss were reported to be less frequent in the older compared to the younger
age group, whereas only diarrhea was reported to be more frequent. Thus, in older
persons, the safety profile of teriparatide is comparable to placebo. In clinical prac-
tice, the major disadvantages of teriparatide are the cost and the daily subcutaneous
administration which may be a hamper for older patients.

Abaloparatide
The pivotal phase 3 trial ACTIVE (Abaloparatide Comparator Trial In Vertebral
Endpoints) and its extension (ACTIVExtend) showed that 18 months of abalopara-
tide, a 34-amino acid PTH-related peptide (PTHrP), followed by sequential treat-
ment with alendronate for an additional 24 months, significantly reduced the risk of
vertebral, non-vertebral, clinical, and major osteoporotic fractures in postmeno-
pausal women with osteoporosis (mean age of 68.8 years) [73].
Two post hoc analyses, by McClung et al. and Cosman et al., investigated the
efficacy and safety of abaloparatide in women aged ≥80 years [74] and ≥75 years
[75], respectively. In the analysis of McClung et al., abaloparatide was associated
302 M. Dejaeger et al.

with numerical, but not statistically significant reductions in the risk of vertebral
and non-vertebral fractures (two vertebral and two non-vertebral fractures in the
placebo group vs. zero and one fracture, respectively, in the abaloparatide group)
[74]. These numerical reductions in fracture risk are consistent with the effective-
ness of abaloparatide in the overall ACTIVE population, but the difference is not
statistically significant, which may be explained by the very small number of frac-
tures in the older age group [74]. In the analysis by Cosman et al., the effect of
abaloparatide on vertebral and non-vertebral fracture risk reduction was consistent
across different age groups (<65 vs. 65 to <75 vs. ≥75 years) [75]. In these separate
age groups, vertebral and non-vertebral fracture risk reduction was not significant,
which may be explained by the small number of participants and events in these
subgroups.
Regarding tolerability and safety, the proportion of women reporting adverse
events was similar in the older age group (≥80 years) and the overall ACTIVE
population [74]. However, the older patients reported more serious adverse events
than the overall ACTIVE population. This may not be unexpected for an older popu-
lation but, more importantly, did not differ between abaloparatide and placebo [74].

Romosozumab
In the FRAME (Fracture Study in Postmenopausal Women with Osteoporosis)
study in postmenopausal women aged 55–90 years with osteoporosis, romoso-
zumab was associated with a lower risk of vertebral fractures than placebo at
12 months and, after the transition to denosumab, at 24 and 36 months [76, 77].
At 12 months, the risk of clinical fracture was also significantly lower with romo-
sozumab than with placebo. The ARCH study (Active-Controlled Fracture Study
in Postmenopausal Women with Osteoporosis at High Risk) showed that in post-
menopausal women aged 55 to 90 years at high risk of fracture, 12 months of
romosozumab followed by alendronate resulted in a significantly lower risk of
clinical, vertebral, non-vertebral, and hip fractures compared to alendronate
alone [78].
No post hoc analyses have been performed regarding the efficacy of romoso-
zumab in older persons, but the mean age in FRAME and ARCH was 71 years and
74.3 years, respectively, with 31.2% and 52% of included women being ≥75 years.

21.4.2.3 Osteoporosis Treatment in Men

There is little evidence from studies in men, but it is recommended that 1000 mg of
calcium and 800 IU of vitamin D should be taken, similar as in women [79]. Medical
agencies such as the US Food and Drug Administration (FDA) and European
Medicines Agency (EMA) state that it is not necessary to demonstrate antifracture
efficacy in men for drugs that already have shown antifracture efficacy in postmeno-
pausal osteoporosis. Hence, majority of clinical trials in men only have effects on
BMD and BTM as outcome parameters.
In a meta-analysis, bisphosphonates (alendronate and risedronate) significantly
reduced vertebral fracture risk and possibly also non-vertebral fracture risk in men
[80]. There is only one study in men evaluating zoledronic acid that has been
21 Pharmacological Treatment of Osteoporosis in Older Patients 303

sufficiently powered for vertebral fracture. This study showed that men treated with
zoledronic acid had fewer vertebral fractures than those on placebo [81]. The effect
of denosumab was investigated in the ADAMO trial in 242 men, showing a signifi-
cant increase of BMD at the spine and hip after 12 months of treatment vs placebo
[82]. The study was not powered for fractures. Teriparatide significantly increases
BMD in men with osteoporosis and is licensed by the FDA and EMA as treatment
for osteoporosis in men [83]. Romosozumab for 12 months increased BMD at the
spine and hip in men in the BRIDGE study, yet fracture endpoints were not included.
According to the authors, based on the observed BMD gains and similar fracture
risk, the fracture reduction observed in the FRAME study in postmenopausal
women can be extrapolated to men [84]. While in some countries (Japan, Australia,
etc.) romosozumab is approved for men at high risk of fractures, this is not the case
in Europe. Finally, testosterone replacement results in a small increase in BMD but
not as large as osteoporosis treatments and no data are available on fracture risk.
Thus, testosterone (taking also the potential side effects into account) is not consid-
ered as an adequate treatment option for osteoporosis in men.
Hence, we conclude that men seem to respond to the available osteoporosis treat-
ments in the same way as women, and therefore, the treatment approach, for the
most part, is similar in both genders.

21.4.2.4 Effectiveness of Osteoporosis Treatment in Older Persons

in the Clinical Setting
Older persons in clinical practice may differ from the persons included in trials,
both in terms of patient characteristics and comorbidities. Patients in clinical prac-
tice may also be less compliant or take the medication for a longer or shorter time
period than recommended. These aspects may impact the effectiveness of medica-
tion. Therefore, the real-word effectiveness of osteoporosis treatments was com-
pared between persons aged ≥80 years and younger women (60–79 years) using the
Swedish health register data [85]. The results showed that osteoporosis medication
is effective in women older than 80 years, with an effect size similar to that in
younger women and to that reported in RCTs [85].

21.4.2.5 Lag Time to Benefit from Osteoporosis Treatment

In clinical practice, physicians may have doubts about starting osteoporosis treat-
ment in very old patients with a rather short life expectancy. However, in the land-
mark osteoporosis trials, most pharmacological therapies for osteoporosis obtained
a significant reduction in fracture risk within 12 months of treatment, at least for
vertebral fractures. A recent meta-analysis about the time to benefit of bisphospho-
nate therapy found that 12.4 months were needed to avoid one non-vertebral frac-
ture per 100 postmenopausal women receiving bisphosphonate therapy. In addition,
200 postmenopausal women would need to be treated with a bisphosphonate for
12.1 months and 20.3 months to avoid one clinical vertebral fracture and one hip
fracture, respectively [86]. These results suggest that starting osteoporosis treatment
is appropriate for persons with a life expectancy greater than 1 year [70, 87]. In
2015, the average life expectancy at 80 years in the EU was 9.2 years [88].
304 M. Dejaeger et al.

21.5 Conclusion

Osteoporosis is one of the most common age-associated conditions causing

increased bone fragility and risk of fractures. In old age, osteoporosis and osteopo-
rotic fractures tend to occur in a subset of frail people. Treatment of osteoporosis is
of particular concern in older persons because of the substantial impact of osteopo-
rotic fractures on morbidity, mortality, and economic cost. Moreover, as the risk of
a subsequent fracture is the highest in the year following a fragility fracture, inter-
national guidelines and scientific bodies highly recommend focus on secondary
fracture prevention.
The treatment window for osteoporosis is never closed, not even in older patients
with the most severe degree of osteoporosis and not even in those who have already
suffered an osteoporotic fracture. Calcium and vitamin D supplementation is a cru-
cial component but not sufficient in the management of osteoporosis in old age.
Adding osteoporosis treatment significantly lowers the risk of fractures, at least for
vertebral fractures and possibly also for hip fractures. In frail older persons with
documented osteoporosis, osteoporosis treatment may even be more effective than
in younger patients, with more fractures avoided and decreased numbers needed
to treat.
Data in older persons clearly indicate that the existing osteoporosis therapies are
relatively safe, with no significant differences in the incidence of most adverse
events in the treated group compared to that in the placebo group. Also, the inci-
dence of adverse events in older persons is not higher than reported in the general
population. In the clinical setting, specific issues such as comorbidity and polyphar-
macy should be taken into account in older persons and may influence the choice of
therapy. However, real-word data confirmed that osteoporosis medication is safe
and effective in older persons. All together, these data in older persons indicate that
age in itself is no reason to withhold osteoporosis treatment in old persons with
osteoporosis or at high fracture risk.

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Chronic Respiratory Disease: COPD, IPF
22
Raffaele Antonelli Incalzi and Filippo Luca Fimognari

22.1 Introduction

Chronic obstructive pulmonary disease (COPD) may be considered an age-related

condition for biological and epidemiological reasons. Indeed, pathogenetic mecha-
nisms largely mimic aging-associated changes in bronchial tree and alveoli, and a
distinctive phenotype of aging lung, the secretory one, may be considered a proxy
of the bronchitic type of COPD [1]. On the other hand, age itself does not account
for emphysematous changes, but the longer the exposure to pollutants, not only to
smoke, the greater the possibility that emphysematous and bronchitic changes, in
variable proportion, occur. This explains why COPD prevalence dramatically
increases with age, though the earliest pathological expressions of the disease date
back to the young adulthood. Similarly, severity of COPD increases with age so that
chronic respiratory failure complicates COPD mainly in the geriatric population:
the main age of people under long-term oxygen therapy, the vast majority of whom
suffers from COPD, is well over 70 years [2].
Treatment of COPD has been the object of international guidelines, the Global
Initiative for Lung Disease (GOLD), which are updated yearly. The last GOLD
release dates 2022 (2022 GOLD Reports—Global Initiative for Chronic Obstructive
Lung Disease, https://goldcopd.org). These guidelines are a framework for the
approach to COPD in older adults. However, they only to some extent take into

R. A. Incalzi (*)
Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy
e-mail: [email protected]; [email protected]
F. L. Fimognari
Department of Medicine and Unit of Geriatrics, Azienda Ospedaliera “Annunziata, Mariano
Santo, S. Barbara”, Cosenza, Italy

© Springer Nature Switzerland AG 2023 311

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_22
312 R. A. Incalzi and F. L. Fimognari

consideration selected distinctive features of COPD in the elderly, especially in the

oldest old. First, rating COPD severity is troublesome because coexisting morbidi-
ties co-determinate symptoms and frequently COPD is not the main disease,
although it largely accounts for health status impairment. Thus, the therapeutic
approach should be decided in the perspective of multimorbidity including COPD
rather than of COPD and comorbid diseases. Second, spirometry, a key diagnostic
exam, requires cognitive and physical function which is frequently defective in the
elderly [3]. Thus, tailoring the therapy on symptoms and respiratory function may
be impossible or difficult. Furthermore, polypharmacy, a typical trait of the elderly
multimorbid patient, requires a judicious choice of topical anti-inflammatory and
bronchodilating drugs: acting locally, they are variably absorbed, have systemic
effects, and the potential for important pharmacokinetic interactions. In addition,
impaired praxic abilities could limit the quality of the inhaling maneuver. Finally,
measuring the effects of the therapy requires that different outcomes be pursued
and measured according to individual conditions. This implies that a multidimen-
sional geriatric assessment guides the choice and the ensuing tailoring of the
therapy.

22.2 Therapy of COPD: An Overview

It is difficult to image a disease requiring such an articulate and comprehensive

therapy as COPD in the elderly (Table 22.1). The pharmacological component of
the therapy may be poorly effective in patients requiring mainly educational and

Table 22.1 Components of the therapy of COPD in the elderly

Intervention Comment
Smoking cessation Highly effective at any age
Education Proved to decrease the frequency and to improve the
management of exacerbations. It also reduces the risk of
adverse drug reactions
Rehabilitation It improves personal capabilities and health status besides
decreasing the risk of exacerbations and contrasting depression
Telerehabilitation Proposed as an alternative to traditional approaches, it has
been promoted during the COVID-19 pandemic
Vaccines Flu, pneumococcus, pertussis, zoster
Mucus clearance devices Important in the bronchitic (secretory) form of COPD
Sleep hygiene If sleep problems are present, exclude comorbid OSAS or
night time hypoxia
Nutrition Selected interventions tailored to the individual needs can
improve nutritional status and independence
Cognitive training Overall ineffective, should not be further recommended
Topically acting Effective at any age, should be carefully chosen according to
bronchodilators the individual conditions
22 Chronic Respiratory Disease: COPD, IPF 313

Table 22.1 (continued)

Intervention Comment
Topically acting steroids Able to prevent the desensitization and to promote the
expression of the beta receptor, are a key measure at any age
Theophylline and related Though they are no further recommended (GOLD 2020), they
compounds maintain efficacy in carefully selected patients, mainly to
sustain the nocturnal respiratory drive. Due to their low cost,
they may be considered as an alternative to topical drugs in
low-income countries as well as in patients with major praxic
problems
Roflumilast In difficult to control bronchitic forms of severe COPD
Mucolytics (erdosteine, Likely decrease the frequency of exacerbations in the
carbocysteine, NAC) bronchitic type
Long-term oxygen therapy For SpO2 < 93% at rest or during sleep or exercise
Noninvasive ventilation To contrast dyspnea in end-stage COPD or to prevent muscle
exhaustion in cachectic patients. Of primary importance in
severe acute exacerbations
Endoscopic therapeutic Giant bullectomy, lung sealants, large airway stenting, coil,
procedures thermal vapor ablation
Lung volume reduction Upper lobe emphysema and low exercise capacity
surgery
Remote monitoring Effective if performed according to a standardized model and
tailored to the individual patient
Palliative care It might be started before the patient enters the end stage of
COPD because it can largely improve the quality of life,
mainly by relieving dyspnea
Pharmacological assessment A comprehensive revision of the pharmacological therapy for
any problem allows to identify drugs having the potential for
worsening the respiratory status

rehabilitation measures. Thus, therapy may be considered as a mix of integrated

measures aimed at optimizing the health status. However, important caveats should
be considered because coexisting diseases and social, cognitive, and functional
problems have the potential for waning the effects of the therapy. Some problems
potentially affecting the diagnosis of exacerbation or limiting the efficacy of the
therapy of COPD in the elderly are reported in Table 22.2. Thus, a preliminary com-
prehensive geriatric assessment is needed to optimize the cost/effectiveness of the
therapeutic approach. Interestingly, the approach to COPD changes as a function of
the specialty of the caring physician [4]. Thus, efforts should be made to promote
the awareness of the complex clinical picture and related needs of the older COPD
patient in different specialists.
For obvious reasons, we will present individual components of the therapy, but
we will do it in a relational and dynamic perspective. Missing the network of thera-
peutic measures, i.e., considering each of them as an isolated intervention, would
negatively affect the cumulative effect of the therapy.
314 R. A. Incalzi and F. L. Fimognari

Table 22.2 Main problems affecting the diagnosis of exacerbation or limiting the efficacy of
therapy of COPD in the elderly
Coexistent OSASs Frequently it manifests with nocturia due to brisk changes in abdominal
pressure and, then, is misinterpreted as a prostatic symptom
Cognitive Attention should be paid to tailor the therapeutic plan to the individual
impairment/linguistic capabilities and to provide a follow-up
barriers
Impaired dexterity As above
Coexisting CHF Nt-proBNP should be measured and, if high, cardiological work-up
performed
Malnutrition MNA might be used as a screening test
Anorexia Pharyngeal or esophageal mycosis is a frequently missed cause of
anorexia with or without dysphagia
Atypical exacerbation Delirium, gait problems, lethargy, CHF-like presentation, no or mild
dyspnea, thoracic pain may confound the examiner
Arrhythmias Atrial fibrillation, flutter, atrial chaotic tachycardia could account for
hemodynamic instability and require urgent dedicated intervention
besides the correction of the blood gas derangement
Concealed chronic An important cause of fluid retention and a risk factor for drug toxicity
kidney disease
Frequently defective Mainly in patients with diabetes or hyposmia it could make the patient
enteroception unaware of her/his true health status

22.3 Therapy of COPD: The Main Individual Components

22.3.1 Education

Making the patient aware of her/his disease, able to recognize significant changes
and to disregard minor ones, and able to adopt pertinent behaviors are a primary
therapeutic objective. Indeed, empowerment and promotion of the enteroception
have been associated with decreased frequency and more timely treatment of exac-
erbations as well as with better disease-related health status [5]. Furthermore, edu-
cation decreases the risk of adverse drug reactions and the use, mainly the improper
use, of healthcare services. To pursue this objective, either individual education or
group programs proved effective. Furthermore, a well-informed patient is able to
appreciate the individual and cumulative values of each therapeutic measure, which
promotes the adherence to maintenance rehabilitation, periodical control visits, and
so on. Finally, an important objective of education is a periodical check of adher-
ence to and retraining the correct use of inhaler devices. Indeed, it has been demon-
strated that even mild cognitive impairment, as reflected by a MMSE < 24 or a
defective performance in the copy of the two pentagons test, identifies people who
will have difficulty with inhalers [6].

22.3.2 Rehabilitation

Once considered a typical post-acute therapeutic measure, rehabilitation is pres-

ently recognized as a leading therapeutic tool all over the course of COPD at any
22 Chronic Respiratory Disease: COPD, IPF 315

age and for any stage of COPD severity [7]. Rehabilitation is effective also during
the acute exacerbations, but it plays a primary role as a continuous aid, “mainte-
nance rehabilitation,” with positive effects on both physical and affective domains
[8]. Also patients with disabling COPD benefit from rehabilitation, else more than
patients with mild to moderate COPD [9]. Besides the classical respiratory rehabili-
tation, worthy of attention are general rehabilitation; upper limb exercise, mainly
for the emphysematous patient; and occupational therapy. If possible, rehabilitation
should be tailored to the individual needs by taking into account the mainly hyper-
secretive or dyspneic trait of COPD, exercise-related fatigue, ability to retain the
inherent information, and mood. Thus, a comprehensive assessment is functional to
plan the best rehabilitation for the individual patient. However, if such an approach
is unavailable, it is well proved that also simple exercise such as walking is effective
at improving exercise tolerance and health status [10]. Finally, selected forms of
rehabilitation, such as rehabilitation of swallowing [11], may be of benefit on indi-
vidual bases.

22.3.3 Devices Promoting Airways Mucus Clearance

The mucus changes physical status, from more to less dense, by absorbing kinetic
energy (thixotropism). Thus, exercise itself is the primary promoter of mucus clear-
ance. However, mainly in sarcopenic or disabled hypersecretive patients, some
mechanical aids may improve mucus clearance. Among these is the flutter, which,
by delivering kinetic energy, loosens the mucus from the airway walls and increases
airways patency. A comparable effect is obtained by the oscillating positive expira-
tory pressure devices. Other devices produce a negative pressure in the mouth and,
thus, a favorable gradient for mucus clearance; however, their use should be limited
to patient with an efficient cough reflex. Finally, high-frequency and low-frequency
chest compression devices are simple and totally passive mucus clearance promot-
ers [12]. These tools should not be regarded as an alternative to rehabilitation, but
they have the potential for complementing and speeding it in the hypersecretive
phenotype of COPD, mainly in patients whom early fatigability makes unable to
take the full benefit from rehabilitation.

22.3.4 Vaccinations

Vaccination is a key measure of care for older COPD patients [13]. Annual influenza
vaccination prevents exacerbations and is associated with decreased mortality [14].
Pneumococcal 13-valent polysaccharide vaccine (PPSV13), to be repeated every
5 years, has been proved to prevent acute exacerbations and bacteremia from pneu-
mococcus in the elderly. Current CDC recommendations bend toward PPSV23,
which has been proved to decrease pneumonia in COPD patients under 65 years or
FEV1 <40% or comorbidities. Given that pertussis or whooping cough is a primary
cause and a severity factor of COPD exacerbations, a dTaP/dTPa vaccination is
recommended for patients who were not vaccinated in adolescence. However,
316 R. A. Incalzi and F. L. Fimognari

immunity wanes in a few years and a booster dose should be provided after 10 years
and should be repeated every 10 years. Vaccination anti-herpes zoster is also indi-
cated in people over 65 years. COPD patients are at special risk of immunodepres-
sion to malnutrition, steroid use, and chronic inflammation. The adjuvant zoster
vaccine is safe and effective also in immunocompromised patients. Finally,
COVID-19 vaccine is strongly advocated for COPD patients, given that COPD
qualifies as a severity factor for COVID-19 disease [15].

22.3.5 Sleep Hygiene

Sleep is essential to life, but it is frequently impaired in elderly and diseased

patients. COPD is a major cause of sleep troubles [16], but unrecognized obstruc-
tive sleep apnea frequently contributes to disrupt the sleep architecture.
Interestingly, nocturia, commonly considered a clue to urologic problems, may be
an effect of OSAS [17]. Furthermore, defective tailoring of oxygen supplementa-
tion to changing needs at night may account for hypoxia and related sleep troubles
in COPD patients under long-term oxygen therapy. Thus, any COPD patient
should undergo at least one nocturnal oximetry in standard conditions, i.e., the
ones characterizing her/his usual health status, to exclude or, if present, to correct
nocturnal hypoxia, e.g., by increasing O2 delivery or providing nocturnal ventila-
tion as needed. Furthermore, a careful scrutiny of pharmacological therapy,
including over-the-counter drugs and nutritional supplementations, is mandatory
to identify possible pharmacological-related sleep troubles. For instance, antide-
pressants are associated with a variety of sleep disturbances besides carrying
some risk respiratory depression [18]. Thus, a thorough pharmacological revision
is needed to disentangle the potential effects of COPD, comorbidity, and drugs on
the quality of sleep.

22.3.6 Nutrition

Obesity and, mainly, undernutrition are traditionally considered severity factors of

COPD, and the emphysematous cachexia the hallmark of malnutrition. While these
problems maintain importance, both sarcopenia, also in the presence of normal or
increased body mass index (sarcopenic obesity), and more subtle nutritional deficits
are gaining importance as an expression of malnutrition. Worthy of interest are defi-
cits of folate, D vitamin, iron, and B12 vitamin [19]. Even if isolated, these deficits
have important health implications; thus, they should be object of screening and, if
demonstrated, correction (Table 22.3). Several definitions of sarcopenia do exist
[20]; an universal consensus lacking the one by Crutz Jentoft seems the most con-
venient [21]; the ultrasound might help to rate sarcopenia [22]. Overall, the screen-
ing of malnutrition may rely upon the Mini Nutritional Assessment, freely available
online. More sophisticated questionnaires, such as the EPIC, are used only for a
point estimate of nutrient intake.
22 Chronic Respiratory Disease: COPD, IPF 317

Table 22.3 Main nutritional deficits in COPD

Deficit Screening Clinical meaning Correction
Overall Mini nutritional Worsened heath status Tailored dietetic intervention
malnutrition assessment and respiratory
conditions, severity
factor in the event of
exacerbation
Vitamin D Serum level <30 pg/mL Increased risk of Oral supplementation.
fracture and infection Provide 1alpha25
dihydrotachysterol if eGFR
<30 mL/1.72 m2/min
Iron Ferritin <100 mcg/L or Muscle weakness, Per os or iv
ferritin <300 mcg/L, anemia, worsened (Fe-carboxymaltose)
but transferrin dyspnea, and correction as for clinical
saturation <20% respiratory failure judgment
B12 vitamin Serum cyanocobalamin Anemia, postural I. B12 supplementation
<200 pg/mL instability, neuropathic
pain
Folate Serum level <3.4 Depression, cognitive Per os folate supplementation
ng/mL or 5 mg/dL impairment (e.g., 5 mg daily)
Sarcopenia See Ref. [19] Fatigability, worsened Both exercise and nutrient
dyspnea, and supplementation are needed
respiratory failure
Iv Intravenous, Im Intramuscular

Age does not decrease the nutrient needs. Thus, the elderly COPD patient
should receive a balanced and complete diet, not differently from an adult one.
Dietary supplementation shown to improve muscle strength is branched amino
acids and PUFA, though the strength of the evidence is only moderate [23, 24].
In hypercatabolic status characterizing selected patients, a greater caloric and
protein intake should be provided, but several obstacles, like digestive problems
(early satiety, epigastric burn) and sarcopenia (mastication, exhaustion, etc.),
make such an objective difficult to reach. Furthermore, dysphagia is highly
prevalent, though unreported, in severe, mainly emphysematous, COPD, and
can manifest either as malnutrition or as chronic cough and/or ab ingestis
pneumonia.

22.3.7 Pharmacological Therapy

Overall, it should conform to GOLD guidelines. However, selected factors should

be considered to tailor the therapy to the older patient:

1. Polypharmacy is very common in the elderly multimorbid patient. Thus, phar-

macokinetic interactions should be prevented by choosing drugs having the least
potential for interactions. Among LABA, salmeterol serum levels may increase
for coadministration of inhibitors of the CYP3A4, like antifungal azoles and
clarithromycin. While the available data are inconclusive for olodaterol,
318 R. A. Incalzi and F. L. Fimognari

vilanterol, and indacaterol, formoterol is known to undergo direct metaboliza-

tion with only a marginal role of CYP3A4, and, thus, it is less exposed to impor-
tant serum level fluctuations. Furthermore, formoterol has an early onset of
action and, thus, can promptly relieve dyspnea. It is worth considering that, even
if inhaled, LABA are variably absorbed, and their non-respiratory side effects,
like tremor, anxiety, and arrhythmias, prove it.
2. Beta2 receptor desensitization occurs more easily in the elderly. Thus, promot-
ing the alpha to beta receptor conversion through a steroid seems of special inter-
est for the elderly. Accordingly, besides being first choice in the bronchitic type
of COPD, the ICS-LABA may be tried every time the suspicion of defective
response to LABA arises.
3. Side effects of ICS are of special interest in the elderly; while the risk of pneu-
monia is well recognized, attention should be paid to oral or esophageal candi-
diasis, which may manifest simply with dysphagia or anorexia or dysphonia or
low-grade fever.
4. LAMA are usually well tolerated in the elderly, but they carry some risk of acute
urinary retention. It is likely that aclidinium bromide, being metabolized be
endothelial esterase and not by the kidney, is safer in patients with depressed
renal function.
5. The 2023 GOLD update suggests a LAMA-LABA combination as the preferred
therapy for patients not amenable or unresponsive to a single drug treatment and,
in the event of poor effectiveness, a triple therapy (LAMA+LABA+ICS) rather
than a trial with ICS + LABA.
6. Loss of dexterity and cognitive abilities makes the elderly patient at risk of mis-
using inhalers. Accordingly, a trial of use should be performed rather than merely
prescribing a given drug, and the most reliable technical solution should be iden-
tified. The use of distancers enables many disabled or sarcopenic patients to
benefit from topical therapy. Only in severely impaired patients aerosol therapy
should be considered a therapeutic option, although it is less effective than topi-
cal long-acting drugs.
7. Theophylline: once largely prescribed, it is actually considered a second-line
drug with an unfavorable cost/benefit ratio. However, it is also accredited of
biologically interesting actions such as immunostimulance, which are evident
for low and safe doses, and may represent a therapeutic option for elderly patients
with nocturnal slowing of the respiratory drive.
8. The possibility that bronchiectases complicate the COPD lung increases with
age and carries some risk of selecting Gram negative bacteria, mainly the
Pseudomonas aeruginosa, and of hemoptysis. Thus, in the event of exacerba-
tions, an antibiotic therapy active on Gram- bacteria may be required.
9. In patients with highly symptomatic bronchitic type of COPD, especially if
bronchiectases coexist, a long-term (6–12 months) therapy with low-dose
azithromycin (250 mg every other day or 500 mg three times a week) may ben-
efit due to the immunostimulant action of macrolides. Thus, the direct antimicro-
bial effect is unlikely to account for clinical benefit. In the older adult, attention
should be paid to the risk of pharmacokinetic interactions.
22 Chronic Respiratory Disease: COPD, IPF 319

22.3.8 Oxygen Therapy

Oxygen should be prescribed like a drug, i.e., at the correct dosage, not more and not
less. Indeed, excess oxygen may depress the respiratory drive, causing hypercarbia until
carbonarcosis, but in the elderly, it carries an important additional risk, the one of coro-
nary or cerebral vasoconstriction [25]. Thus, efforts should be made to obtain and main-
tain an arterial oxygen saturation (SaO2) of 90–95%; higher values might be associated
with adverse effects. Importantly, percutaneous oxygen saturation (SpO2) is frequently
unreliable in the elderly due to hypotension, fever, tremor, chills, atrial fibrillation, and
other causes. Thus, SpO2 >90% should not deter from performing an arterial blood gas
analysis if one or more of these confounding conditions occur and/or if the inherent
information may be of value to assess the metabolic status, e.g., in patients on high-dose
diuretics or renal failure. Attention should be paid to modulate the inspired fraction of
oxygen according to potentially changing needs with sleep and exercise.
High-flow oxygen therapy is safe and effective in elderly patients who are
severely hypoxemic while on Ventimask, but moderate to severe hypercarbia carries
an important risk of ineffectiveness or respiratory depression. Thus, its effects
should be checked timely and, then, monitored to prevent adverse events. Finally,
for people using oxygen concentrators, it is important to know that the provided
fraction of oxygen varies with the respiratory rate and, for selected models, dramati-
cally declines for increasing respiratory rate [26].

22.3.9 Noninvasive Ventilation (NIV)

Besides being a vital support in severe acute exacerbation, NIV plays an important role
in the chronic care of elderly COPD patients either as a component of palliative care,
to relieve dyspnea, or as an intermittent aid to patient experiencing fatigue and respira-
tory muscle exhaustion. Thus, it should not be considered a measure dedicated to acute
care; else its use is gaining importance in the chronic patient. There are no age-related
changes in the operating rules; else NIV is highly efficacious in the elderly [27, 28].
However, extra caution is needed to prevent pneumothorax or pneumomediastinum
and CHF worsening due to increased intrathoracic barrage, both of which are more
likely to occur in the elderly. In patients experiencing frequent lung atelectases due to
either hypoexpansion or defective mucus clearance, NIV has the potential for prevent-
ing atelectases. Finally, NIV may be of value to assist the patient proved or likely to
undergo nocturnal depression of the respiratory drive which cannot be compensated by
changing the inspired fraction of oxygen. However, the individual needs should be
carefully scrutinized; in the event of coexisting OSAS, C-PAP should be preferred.

22.3.10 Remote Monitoring

It has been proved to prevent exacerbations and improve the quality of life, but only
few studies reach high-quality standards. Nevertheless, there is evidence that a
320 R. A. Incalzi and F. L. Fimognari

well-­organized telemonitoring system is highly cost-effective and has positive indi-

rect effects by improving empowerment and confidence in the caregivers [29].

22.3.11 Palliative Care

Dyspnea and, to a lesser extent, pain are the two symptoms which characterize end
stage COPD. Being deeply generated and phylogenetically ancient sensations, they
are perceived also in end-stage COPD. Thirst and hunger also are “hard” sensation.
Thus, the end-stage COPD patients should be the object of a comprehensive care
aimed at relieving these untoward sensations through a properly tailored strategy.
However, the principles and practice of palliative care should not be the patrimony
of preterminal care. It has been proved that even in patients with severe COPD,
mainly of the emphysematous type, but not in preterminal stage, using these prin-
ciples and practice can significantly improve the health status. For instance, low-­
dose morphine has the potential for relieving dyspnea without causing major
respiratory depression. Furthermore, it can improve the amount and quality
of sleep.

22.4 Therapy of Acute COPD Exacerbations

GOLD recommendations apply to patients of any age. However, selected points are
worthy of comment for elderly COPD patients:

1. Concurrent conditions like acutely decompensated heart failure or pulmonary

embolism frequently underlie the sudden worsening of the health status in these
patients. Thus, exacerbation of COPD should not be invariably considered as
the cause of acute respiratory distress.
2. Older age does not affect the response to NIV. Thus, NIV should be provided at
any age if indicated on clinical and pathophysiological ground.
3. In frequent exacerbators, sputum cultures are desirable to redirect the antibiotic
therapy, if needed. Fungi could also sustain the exacerbation.
4. Delirium is a common presentation of acute exacerbation in the elderly.
5. Dyspnea may play a marginal role in the clinical picture of an exacerbation of
the elderly.
6. Arrhythmias, mainly atrial fibrillation or atrial chaotic rhythm, frequently com-
plicate the exacerbation. They may subside after reverting the acute respiratory
failure and decreasing the adrenergic drive but frequently must be timely
reversed because of severe hemodynamic effects.
7. Anorexia, besides being common in advanced COPD, is highly prevalent dur-
ing the acute exacerbation. The nutrient intake should be monitored and inte-
grated, if needed.
8. Fluid retention is frequently due to hypoxia and hypercarbia related renal func-
tion impairment and, thus, revert with blood gases normalization. However,
diuretic therapy is frequently needed and should be adopted on an individual basis.
22 Chronic Respiratory Disease: COPD, IPF 321

9. Hypoxia, malnutrition, and immobility make the older patient at special risk of
developing pressure ulcers. Thus, preventative measures are highly
recommended.
10. A severely hypoxic and normo- or hypocarbic exacerbation should raise the
suspicion of pulmonary embolism or heart failure.
11. Once a worsening of the lung problem and a cardiac complication has been
excluded, a sudden increase or worsening of hypercarbia likely reflects muscle
exhaustion.
12. In older COPD patients hospitalized for severe exacerbations, any effort should
be made to guarantee family and social contacts and to provide a supportive
environment as a strategy preventing delirium.

22.5 Idiopathic Pulmonary Fibrosis and Other Interstitial

Lung Diseases in the Elderly

22.5.1 An Overview

The interstitial lung diseases (ILDs) constitute a group of parenchymal lung dis-
eases that affect the interstitial space with different grades of inflammation and
fibrosis (Table 22.4). Some ILDs are secondary to known etiologies, including drug

Table 22.4 Classification of interstitial lung diseases

Idiopathic interstitial pneumonias
 Chronic fibrosing idiopathic interstitial pneumonias
 • Idiopathic pulmonary fibrosis
 • Idiopathic nonspecific interstitial pneumonia
 Smoking-related idiopathic interstitial pneumonias
 • Respiratory bronchiolitis-interstitial lung disease
 • Desquamative interstitial pneumonia
 Acute/subacute idiopathic interstitial pneumonias
 • Cryptogenic organizing pneumonia
 • Acute interstitial pneumonia
 Rare idiopathic interstitial pneumonias
 • Lymphocytic interstitial pneumonia
 • Idiopathic pleuroparenchymal fibroelastosis
 Unclassifiable idiopathic interstitial pneumonias
ILD of known association
 • Connective tissues diseases
 • Drugs (amiodarone, nitrofurantoin, methotrexate)
 • Occupational or environmental exposure (asbestosis and silicosis)
Sarcoidosis (granulomatous interstitial lung disease)
Hypersensitivity pneumonitis
Miscellaneous interstitial lung diseases
 • Lymphangioleiomyomatosis
 • Pulmonary Langerhans’ cell histiocytosis/histiocytosis X
 • Eosinophilic pneumonia
From references [30–32], and, with changes
322 R. A. Incalzi and F. L. Fimognari

toxicity, exposure to occupational or environmental factors (e.g., asbestosis and sili-

cosis), allergens like mold, animal dander, and others (hypersensitivity pneumoni-
tis), or represent the lung manifestation of sarcoidosis and connective tissue diseases
(CTDs) such as systemic sclerosis (SSc) and rheumatoid arthritis (RA) [30].
The “idiopathic” ILDs encompass a composite family of ILDs without any rec-
ognizable origin [31, 32]. Idiopathic pulmonary fibrosis (IPF), the most common
(about 50% of all idiopathic ILDs), is characterized by histopathologic and high-­
resolution computed tomography (HRTC) pattern of usual interstitial pneumonia
(UIP). IPF is a highly severe illness and is usually diagnosed in men older than
60 years, although it may rarely occur in younger adults. Smoking is a risk factor.
Thus, IPF is typical of older patients and may also initially manifest with an “acute
exacerbation,” that is featured by acute respiratory failure, dyspnea, and ground-­
glass infiltrates. Later on, acute exacerbations will punctuate the natural history of
IPF, along with progressive lung deterioration [31, 32]. HRTC hallmarks of typical
UIP pattern include basilar and subpleural predominant reticulation and honey-
combing, with frequently present traction bronchiectasis and traction bronchiolec-
tasis [33]. This HRTC phenotype, but without honeycombing, qualifies the
“probable” UIP pattern. The typical UIP pattern in a typical patient, together with
the exclusion of other known causes of ILD, may authorize the diagnosis of IPF
without resorting to cellular analysis of bronchoalveolar lavage (BAL) or to surgical
lung biopsy (SLB). When clinical suspicion is associated with “probable,” “indeter-
minate,” or “alternative diagnosis” HRTC patterns, BAL or even SLB may be rec-
ommended to obtain a diagnosis [33]. Transbronchial lung cryobiopsy (TLC) is a
less invasive alternative to SLB but is burdened by not negligible complications
[33]. Many frail older patients, however, present with advanced disease and multi-
ple comorbidities and are not suitable to SLB or TLC, owing to the unfavorable risk/
benefit ratio.
Nonspecific interstitial pneumonia (NSIP) is the second idiopathic ILD for fre-
quency (25% of all idiopathic ILDs; median age of onset 40–50 years; no associa-
tion with smoking). NSIP has a more favorable prognosis compared to IPF and
exhibits some response to corticosteroids, but evolution to end-stage fibrosis and
death may occur, causing death 5 years after diagnosis in 20% of patients [34].
HRTC pattern includes extensive, prevalently basal, ground-glass opacities, retic-
ular lines, traction bronchiectasis, and subpleural preservation [34]. Smoking-
related idiopathic ILDs encompass respiratory bronchiolitis-interstitial lung
disease (RB-ILD) and desquamative interstitial pneumonia (DIP). The first is
more frequent and can be diagnosed in middle-aged current smokers showing at
HRTC patchy ground-glass opacities and centrilobular nodules mainly in the
upper field. The outcome of RB-ILD is good, and the majority of patients improve
after smoking cessation and/or treatment with corticosteroids. DIP is considered
to represent the end of the spectrum of RB-ILD and may progress to respiratory
failure, but the overall survival is about 70% after 10 years [31, 32]. The acute/
subacute idiopathic ILDs are cryptogenic organizing pneumonia (COP) and acute
interstitial pneumonia (AIP) [31, 32]. Organizing pneumonia (OP) is a nonspe-
cific response to lung injuries secondary to infections, drugs, aspiration, CTDs,
22 Chronic Respiratory Disease: COPD, IPF 323

acute exacerbation of IPF, and other conditions. When OP occurs without a spe-
cific cause, COP is diagnosed. There is no association with smoking, and patients
have a mean age of 55 years. The HRTC pattern is represented by peripheral
bilateral (but also unilateral) and diffuse ground-glass opacities or alveolar con-
solidations with air bronchograms, which are often migratory, spare the subpleu-
ral space, more frequently involve the lower lobes, and can spontaneously
disappear. COP is known for its excellent response to corticosteroids, although
relapse is common with corticosteroid tapering or discontinuation [35]. AIP is
similar to the acute respiratory distress syndrome (ARDS), but while ARDS is
provoked by identifiable associated conditions, AIP is idiopathic. Mean age of
patients is 50 years, and there is no relation with smoking. AIP develops as a
severe form of diffuse alveolar damage (DAD), and mortality is around 50%.
Management relies on supportive care, even though steroid therapy is often tried,
without any demonstrated benefit. HRTC pattern is characterized by bilateral,
basal, ground-glass attenuation or consolidation in the dependent areas, in the late
phase followed by architectural distortion, traction bronchiectasis, and honey-
combing in the nondependent areas [31, 32]. Very rare idiopathic ILDs are lym-
phoid interstitial pneumonia (LIP: ground-glass opacities at HRTC and polyclonal
lymphocytes in BAL, good response to corticosteroids) and idiopathic pleuropa-
renchymal fibroelastosis (PPFE, death in 40% of patients). A category of unclas-
sifiable idiopathic interstitial pneumonias [31, 32] completes the idiopathic ILDs
classification (Table 22.4).
Idiopathic ILDs are rare, but their histopathologic and HRTC patterns (UIP,
NSIP, OP, LIP, DAD, and others) represent “prototypes” recurring in more frequent
ILDs, including those associated with CTDs, drugs, vasculitis, and in the hypersen-
sitivity pneumonitis (HP). NSIP is common in most CTDs, particularly SSc, but in
RA and vasculitis, the UIP pattern predominates [36]. HP is an immune-mediated
inflammatory and fibrotic pulmonary response to the inhalation of several antigens
(mainly organic, including avian and microbial agents). HP has been recently cate-
gorized as non-fibrotic HP (ground-glass opacities and mosaic attenuation, associ-
ated with centrilobular nodules on inspiratory images or air trapping in expiratory
images) and fibrotic HP. The fibrotic phenotype is clinically more severe, and
patients are often older [37].

22.5.2 Therapeutic Approach

22.5.2.1 Antifibrotic Therapy in IPF: Implications in Elderly Patients

In 2012, the PANTHER-IPF trial (prednisone, azathioprine, and n-acetyl cysteine
for pulmonary fibrosis) conclusively showed that immunosuppression, previously
the “gold standard” of IPF therapy, is ineffective and associated with increased risk
of hospitalization and death compared to placebo [38].
Two antifibrotic agents, nintedanib and pirfenidone, have been recently
approved for the treatment of IPF, ushering in a new era. Nintedanib, an oral tyro-
sine kinase inhibitor, at a dosage of 150 mg twice daily reduced the rate of decline
324 R. A. Incalzi and F. L. Fimognari

of forced vital capacity (FVC) in IPF patients by about 50%, without affecting the
time to the first IPF acute exacerbation [39–41]. The mean age of patients enrolled
in the INPULSIS 1 and INPULSIS 2 trials was around 67 years, and eligibility
criteria included age ≥40 years, FVC ≥50%, and diffusing capacity of the lung for
carbon monoxide (DLCO) ≥30% [39]. An analysis of prespecified subgroups from
the INPULSIS trials demonstrated a similar benefit of nintedanib in older
(≥65 years) compared to younger (<65 years) patients [42]. Diarrhea was the
most common adverse effect but caused drug discontinuation in less than 5% of
study patients [39]. Nintedanib is a substrate of P-glycoprotein (P-gp) and
CYP3A4, and concurrent use of P-gp and CYP3A4 inhibitors (e.g., ketoconazole)
or inducers (e.g., carbamazepine) may, respectively, reduce or increase nintedanib
exposure [43].
Pirfenidone, an orally administered pyridine, regulates the expression of TGF-β
and inhibits collagen synthesis, exerting anti-inflammatory, antioxidant, and anti-­
fibrotic actions. The recommended dosage of 801 mg 3 times per day is reached
after a 2-week dose titration starting from 267 mg 3 times daily on the first day [43].
In the ASCEND trial, pirfenidone treatment was associated—compared to pla-
cebo—with a reduced rate of FVC decline (by about 45%), a lower proportion of
patients who reported a decreased distance at the 6-min walk test, and with an
increased progression-free survival (neither disease progression nor death) [44].
Pooled data from ASCEND and CAPACITY [45] trials demonstrated lower overall
and IPF-related mortality in the pirfenidone group [44]. The two trial-enrolled
patients aged between 40 and 80 years (mean age was about 67 years), who had
baseline FVC ≥50%, together with DLCO ≥30% in ASCEND and ≥35% in
CAPACITY. However, a recent post hoc analysis from ASCEND and CAPACITY
trials that included a small sample of patients who had more impaired respiratory
function (FVC <50% and/or DLCO <35%) and a mean age of 70 years confirmed
pirfenidone-related clinical benefits, including lower FVC decline and decreased
all-cause mortality [46]. Possible adverse effects are gastrointestinal symptoms
(nausea, dyspepsia), photosensitivity rash, and elevation in aminotransferase level;
these side effects led to discontinuation of study drug in less than 3% of patients
enrolled in the ASCEND trial. Pirfenidone is metabolized by CYP1A2, and the
concurrent use of CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) should war-
rant dosage reduction [43].
Nintedanib and pirfenidone provide similar benefits in terms of reduction of
FVC decline: the choice of administering one agent or the other should be individu-
alized according to patient’s preference, age, and possible side effects. Since the
eligibility criteria of clinical trials (FVC >50%; DLCO >30–35%; age less than
80 years for pirfenidone) were translated into clinical practice as clinical conditions
required for authorizing treatment, these agents are prescribed only to patients with
mild to moderate IPF, and very elderly patients with advanced disease, comorbidi-
ties, and respiratory failure are always excluded from such treatments. In addition,
possible drug-drug interactions are an obvious concern in frail patients affected by
several illnesses and treated with multiple drugs [30].
22 Chronic Respiratory Disease: COPD, IPF 325

22.5.2.2 Corticosteroids and Immunosuppressive Cytotoxic

Therapy in Non-IPF ILDs
Therapy may not be indicated when ILD is mild and asymptomatic. In symptomatic
ILDs, however, corticosteroids and/or cytotoxic immunosuppressive drugs are usu-
ally prescribed, even though this therapeutic approach is not supported by random-
ized controlled trials, except for SSc-ILD. NSIP, the most frequent idiopathic ILD
after IPF, is currently treated with corticosteroids (starting from 0.5–1 mg/kg/day or
40–60 mg of prednisone, followed by gradual tapering until maintenance dose).
One cytotoxic drug, mainly cyclophosphamide (CYC), but also azathioprine (AZA)
or mycophenolate mofetil (MMF), can be added to implement or replace corticoste-
roid treatment in more severe NSIP cases. There is no agreement about the length of
treatment that should be individualized [34]. The dramatic response to corticoste-
roids (in general beginning with prednisone 0.75 mg/kg/day) is a clinical distinctive
characteristic of COP [35].
The efficacy of CYC in SSc-ILD was proven by two randomized controlled trials
versus placebo [47, 48]. In another randomized trial, oral MMF was as effective as
oral CYC in improving FVC in SSc-ILD and caused fewer adverse effects [49].
These three trials included elderly patients, but the mean age of enrolled patients did
not exceed 55 years. MMF (first line) or CYC (second line) are thus recommended
as induction therapy in SSc-ILD. Based on uncontrolled studies, MMF and CYC are
also recommended in RA-ILD, together with corticosteroids [50].
Corticosteroids (prednisone 0.5 mg/kg/day followed by gradual tapering to reach
maintenance dose of 10 mg/day) are used to treat HP, together with MMF or AZA
as steroid-sparing agents in patients with disease progression or in whom it is
impossible to avoid exposure to the inciting antigen [37].
Sarcoidosis, the most common ILD (28–38% of all ILDs), can remit spontane-
ously, and the first challenge is to identify patients deserving treatment due to pro-
gressive organ involvement and quality of life impairment. The first line of treatment
relies on corticosteroids (prednisone 0.5 mg/kg/day for 4–8 weeks, followed by
gradual tapering to maintenance dose). Second-line and steroid-sparing agents
include methotrexate or, less commonly, AZA. Antitumor necrosis factor (TNF) α
agents (especially infliximab) represent the third line, and the three lines of therapy
can be administered concomitantly [51].

22.5.2.3 Antifibrotic Treatment in Progressive Fibrosing

Non-IPF ILDs
Some non-IPF ILDs—including idiopathic NSIP, CTDs-ILD, fibrotic-HP, unclas-
sifiable ILDs, exposure-related IPF (asbestosis and silicosis), and sarcoidosis—at a
certain time of their natural history may develop progressive fibrosis, worsening
clinical course, and more accelerated FVC decline, despite standard therapy with
corticosteroids and immunosuppressive agents. The umbrella terminology of “non-­
IPF progressive fibrosing ILDs” (non-IPF PF-ILDs) is used to indicate this pheno-
type of non-IPF ILDs with progressive fibrosis [52]. Because IPF, the prototype of
fibrotic ILD, responds to antifibrotic agents, it is hypothesized that such drugs could
326 R. A. Incalzi and F. L. Fimognari

exert a similar benefit also in non-IPF PF-ILDs. There is no agreement on a precise

clinical definition of PF-ILD, but rapid FVC decline (e.g., ≥10% in 24 months),
worsening of respiratory symptoms directly attributable to the ILD, and growing
extent of fibrosis and honeycombing on HRTC are all useful signals to establish
fibrotic disease progression [52]. Recent randomized controlled trials proved the
efficacy of nintedanib versus placebo in decreasing the rate of FVC decline in a
mixed group of patients with PF-ILDs (26% with HP, 26% CTDs-ILDs, and 19%
NSIP) [53] and in SSc-ILD [54]. Similar results were obtained for pirfenidone in
patients with unclassifiable ILDs [55] and in a mixed PF-ILDs group [56]. Since the
conventional therapeutic approach to non-IPF ILDs of corticosteroids and immuno-
suppressive agents offers uncertain benefits and could be harmful, particularly
among older frail patients, the possibility to treat non-IPF-ILDs with antifibrotic
agents may have promising implications. The proportion of older patients enrolled
in non-IPF PF-ILDs trials, however, was low.

22.5.2.4 Practical Considerations on the Therapeutic Management

of IPF and Other ILDs in the Elderly
The diagnostic and therapeutic management of IPF and other ILDs in older patients
poses relevant challenges (Table 22.5) [30]. The restrictive spirometric pattern of
ILD can be observed in about 15% of older subjects without ILDs [57]. Indeed,
restriction is the ventilator epiphenomenon of frequent age-related chronic non-­
respiratory disorders, such as diabetes, metabolic syndrome, congestive heart fail-
ure, obesity, sarcopenia, or rib cage deformity, and is associated with increased
mortality [58]. Thus, while taking decisions on ILD treatment in elderly patients,
the accelerated FVC decline should be carefully interpreted in the context of other

Table 22.5 Practical considerations on therapeutic management of ILDs older patients

 • Differential diagnosis should be accurate: the treatment of IPF (nintedanib or pirfenidone)
is different from that of non-IPF ILDs (corticosteroids and/or immunosuppressive agents)
 • In older patients, a typical HRTC pattern of UIP may be sufficient to diagnose IPF
 • Before starting treatment, overall patient’s prognosis should be estimated by the
comprehensive geriatric assessment
 • The efficacy of corticosteroids and/or immunosuppressive agents in non-IPF ILDs is not
proved by controlled trials, and expected benefits should be weighed against possible
harmful effects
 • Management of comorbid conditions should be optimized.
 • If IPF is diagnosed, therapy with nintedanib or pirfenidone should be initiated in eligible
older patients with mild-to-moderate IPF
 • Older IPF patients treated with nintedanib or pirfenidone should undergo careful
monitoring of adverse drug effects and drug-drug interactions
 • Consideration of treatment with antiacid therapy is recommended in all IPF older patients
 • Pulmonary rehabilitation improves the capacity of exercise and should be offered to all
suitable older IPF patients
 • High-flow nasal cannula oxygen therapy is useful as end-of-life treatment in patients
requiring high flows of oxygen and can facilitate the transition from hospital to home
Abbreviations: ILDs Interstitial lung diseases, IPF Idiopathic pulmonary fibrosis, HRTC High-­
resolution computed tomography, UIP Usual interstitial pneumonia
22 Chronic Respiratory Disease: COPD, IPF 327

comorbidities and not hastily attributed to progressive lung fibrosis. IPF is prevalent
in the elderly, but also CTD-ILDs and occupational or environmental ILDs tend to
manifest clinically with advancing age. Differential diagnosis should be accurate,
because the standard treatment of IPF (nintedanib or pirfenidone) is different from
that of non-IPF ILDs (immunosuppression). HRTC is a crucial diagnostic tool, but
the current gold standard for ILD diagnosis is a multidisciplinary discussion [33].
Once a diagnosis of non-IPF ILD is obtained in elderly patients, the expected ben-
efits of corticosteroids and/or immunosuppressive agents should be weighed against
possible drug-related complications, comorbidities, overall prognosis estimated by
the comprehensive geriatric assessment, and patient’s expectations. If a confident
diagnosis of IPF is ascertained, nintedanib or pirfenidone should not be denied to
eligible older patients with mild to moderate IPF, accompanied by a strict monitor-
ing of possible drug-related side effects and drug-drug interactions. The gastro-
esophageal reflux disease is highly prevalent in IPF, and episodes of reflux with
microaspiration are believed to contribute to IPF pathogenesis and to the onset of
acute exacerbations. Since a survival benefit was suggested in patients treated with
antiacid agents [59], this treatment should be considered in all IPF patients.
Pulmonary rehabilitation is a crucial intervention in the symptom-centered manage-
ment of IPF and improves the capacity of exercise [60]. High-flow nasal cannula
oxygen therapy is gaining a role as end-of-life palliative treatment of patients requir-
ing very high flow of oxygen that cannot be guaranteed by conventional oxygen
therapy [61] and may facilitate the transition from hospital to home in frail end-­
stage ILD patients.

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Diabetes Mellitus
23
Edoardo Mannucci and Daniele Scoccimarro

Diabetes mellitus is a heterogeneous metabolic disorder characterized by the pres-

ence of hyperglycemia. In the most frequent form of diabetes, i.e., type 2 diabetes,
hyperglycemia is due to the impairment of insulin secretion, associated with differ-
ent degrees of defective insulin action. Chronic hyperglycemia is associated with
relatively specific long-term microvascular complications affecting eyes, kidneys,
and nerves, as well as with an increased risk of cardiovascular disease (CVD).
An increasing number of newly diagnosed older adults with diabetes, together
with increasing life expectancy, have led to an increase in the prevalence of diabetes
in the geriatric age group [1]: it is estimated that 19.3% of people aged 65–99 years
have diabetes. It is projected that the worldwide number of people older than
65 years with diabetes will reach 195.2 million by 2030 and 276.2 million by
2045 [2].
Although type 2 diabetes is the most common form of diabetes in advanced age,
there are also more older adults than ever with long-standing type 1 diabetes. Older
patients have unique and different needs and challenges, which should be consid-
ered when developing a treatment plan. The approach to the management of diabe-
tes in older adults must be individualized and adapted over time, considering
comorbidities, risk of hypoglycemia, social support, and patient’s preferences.

E. Mannucci (*)
University of Florence, Florence, Italy
Diabetology and Metabolic Diseases, Careggi Hospital, Florence, Italy
e-mail: [email protected]
D. Scoccimarro
Diabetology and Metabolic Diseases, Careggi Hospital, Florence, Italy

© Springer Nature Switzerland AG 2023 331

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_23
332 E. Mannucci and D. Scoccimarro

23.1 Therapeutic Targets in the Elderly

The aims of treatment of diabetes are the elimination of symptoms (polyuria,

polydipsia, dehydration) and the prevention of long-term diabetic complications.
The elimination of symptoms can be achieved even with glucose levels well above
the normal range, whereas the prevention of chronic complications requires a
stricter glycemic control [3, 4]. Since the risk of developing chronic complica-
tions depends on the length of exposure to hyperglycemia, and not only on the
degree of hyperglycemia, the potential benefits of accurate glucose control are
inversely related to life expectancy. Thus, older patients have smaller advantages
from strict glycemic control in the long term than younger individuals. In addi-
tion, the risk of some adverse events associated with pharmacological treatment
(e.g., severe hypoglycemia) is increased in older patients, particularly with comor-
bidities. Hospital admissions for hypoglycemia are more frequent than those for
hyperglycemia, and the older population is at particularly high risk: the age-
related impairment of renal function and adrenergic counter-regulatory mecha-
nisms lead to an increased risk of hypoglycemia [5, 6]. In patients with long
duration of diabetes, recurrent hypoglycemic episodes and autonomic neuropathy
can determine hypoglycemia unawareness, further increasing the risk of severe
hypoglycemia [6]. On the other hand, hypoglycemia in older patients could be
associated with a higher risk of cognitive impairment [7] and cardiovascular mor-
bidity [8, 9]. In addition, hypoglycemia in advanced age is a major risk factor for
falls and fractures [10].
The identification of appropriate glycemic targets is based on the assessment of
the ratio between clinical benefits and potential risks, such as hypoglycemia and
other drug-related adverse events. Most guidelines provide recommendations for
desired HbA1c levels, indicating either 53 or 48 mmol/mol as a target [11–14].
Some guidelines suggest different HbA1c targets depending on current pharmaco-
logical treatments [12, 14], discriminating between patients treated or not treated
with hypoglycemia-inducing drugs [12, 14]. In fact, in subjects receiving treatment
with insulin or sulfonylureas, the incidence of severe hypoglycemia is markedly
increased when glucose and HbA1c levels are close to the normal range [15]. As a
consequence, higher HbA1c targets are recommended when patients receive
hypoglycemia-­inducing treatments [12, 14], sometimes indicating minimum HbA1c
thresholds below which the risk-benefit ratio is no longer favorable [14].
Unfortunately, trials exploring the longer-term effects of the improvement of
glycemic control in diabetes usually do not include patients aged more than 75 years
[14, 16]. Results obtained in younger age groups cannot be automatically extended
to older patients, since both beneficial and detrimental effects of diabetes treatment
are moderated by age.
Furthermore, the complexity of treatment, in terms of need of subcutaneous
injections, multiple administrations, and frequent glucose monitoring, can influence
the adherence to therapy, as patients develop medical conditions that may impair
their ability to follow prescribed therapies. Psychological factors, with an increased
inertia, and a reduced willingness to change habits and try new medications, should
23 Diabetes Mellitus 333

also be considered. In addition, the close availability of family members or caregiv-

ers is often crucial to support self-management of T2DM in older persons.
In summary, a reasonable target for patients aged over 75 years could be that of
maintaining HbA1c below 58 mmol/mol in individual treated with drugs that do not
induce hypoglycemia, and between 53 and 64 mmol/mol in those treated with insu-
lin. Higher HbA1c levels can be acceptable only in frail patients with very limited
life expectancy.

23.2 Insulin Therapy in the Elderly

Basal-bolus insulin therapy is the only adequate treatment of type 1 diabetes, irre-
spective of age. The management of such treatment in older adults is more problem-
atic: cognitive impairment, visual loss, and reduced ability to perform complex
manual tasks can all increase the risk of inappropriate insulin administration; renal
impairment, hypoglycemia unawareness, and irregularities in food intake increase
the risk of severe hypoglycemia, and frailty further increases the risk of
hypoglycemia-­induced falls. Ability to self-manage cannot be readily passed onto
family members, and older adults with type 1 diabetes are increasingly reliant on
care from the community and outpatient structures.
When basal insulin is needed, long-acting analogs (glargine, detemir, and
degludec insulin) are preferable to NPH human insulin, since they guarantee lower
glucose variability and less hypoglycemia [17], thus allowing a more accurate dose
titration [18]. Insulin glargine U-300 and degludec are ultra-long-acting analogs
with a higher half-life and a lower risk for nocturnal hypoglycemia than glargine
U-100, even in people aged ≥75 years [19, 20]. In addition, their longer duration of
action warrants a greater flexibility in the timing of administration, which can be
advantageous for patients needing third-party assistance for drug administra-
tion [21].
For the management of postprandial glycemia, short-acting analogs (lispro,
aspart, glulisine) should be preferred to human regular insulin, since they allow a
better control of early postprandial hyperglycemia with lower risk for late postpran-
dial hypoglycemia [22, 23]. In addition, short-acting analogs can also be adminis-
tered immediately before or even after, meals, instead of 20–30 min in advance. In
older patients with irregular food intake, the administration of insulin at the end of
the meal allows for the regulation of insulin dose on the basis of the amount of food
actually eaten.
In patients with type 2 diabetes, insulin should be considered when glycemic
control cannot be achieved otherwise. Insulin therapy schemes should be individu-
alized, based on the patient’s actual needs, as determined by the results of glucose
monitoring. Thus, basal insulin should be prescribed when needed for the control of
fasting glucose and prandial insulin for the management of postprandial glucose
excursions. Once-daily basal insulin facilitates compliance to therapy, particularly
in patients requiring caregiver assistance, and it is therefore often considered the
strategy of choice. On the other hand, the age-related reduction in insulin secretion
334 E. Mannucci and D. Scoccimarro

[24] often requires the use of rapid insulin for postprandial glucose control [25, 26],
which cannot be achieved otherwise. The attempt at reducing the postprandial
increase of blood glucose with of basal insulin would be scarcely effective, and it
would imply a high risk of inter-prandial hypoglycemia.
An adequate education of patients and/or caregivers is an integral part of insulin
therapy, particularly in older adults. Such education should include the technique of
insulin injection, the recognition and treatment of hypoglycemia, and the manage-
ment of insulin therapy in relation to food intake and concurrent acute conditions.
All those skills should be periodically verified [27]. In addition, capillary blood
glucose monitoring—which could be problematic in some elderly patients with
reduction in visual acuity, cognitive dysfunction, or limited motor skills—is needed
in all individuals on insulin therapy.
In older patients, the complexity of the insulin treatment induces to consider
insulin only when an acceptable glucose control cannot be achieved otherwise.
Although insulin is still a precious therapeutic option for many elderly patients, it is
associated with a relevant risk for hypoglycemia, falls, and fractures.

23.3 Non-insulin Therapy in Older Patients

Many drugs other than insulin are currently available for the treatment of type 2
diabetes. Some of those agents provide health benefits (e.g., reduction of cardiovas-
cular risk, nephroprotection, etc.) which outreach the favorable effects of improved
glucose control. However, most of available data on the effects of drugs for type 2
diabetes have been collected in adult non-geriatric populations; the risks and bene-
fits associated with some classes of drugs could be partly different in the elderly.

23.3.1 Biguanides

The biguanide metformin exerts its glucose-lowering effect primarily by decreasing

hepatic glucose production and increasing peripheral insulin sensitivity [28].
Additionally, metformin may improve glucose homeostasis by interacting with the
incretin axis through the action of glucagon-like peptide 1 (GLP-1) [29]. Metformin
is effective, inexpensive, and well tolerated; it does not induce hypoglycemia or
weight gain; and it may reduce cardiovascular events and mortality [30–32],
although specific data on cardiovascular and overall mortality in the older popula-
tion from randomized controlled trials are lacking. For these reasons, most guide-
lines recommend metformin as first-line therapy in all people with type 2 diabetes,
including older adults, if tolerated and not contraindicated [14, 33, 34].
The principal side effect of metformin is diarrhea, which can be mitigated by a
gradual dose titration and by the use of extended-release formulations [35]. Severe
renal failure, 3rd/4thNYHA class heart failure, liver insufficiency, and hypoxemic
respiratory failure contraindicate metformin therapy because of the increased risk
for lactic acidosis. In particular, the Food and Drug Administration (FDA)
23 Diabetes Mellitus 335

recommends against the use of metformin with serum creatinine above 1.5 mg/dL
(114.4 mmol/L) in men and above 1.4 mg/dL (106.8 mmol/L) in women, respec-
tively, whereas according to the European Society of Cardiology (ESC) and the
European Association for the Study of Diabetes (EASD), metformin is contraindi-
cated in patient with estimated glomerular filtration ratio (eGFR) below 30 mL/min,
recommending caution and dosage reduction when eGFR is between 30 and 60
mL/min [27, 36]. Notably, creatinine levels do not always adequately reflect renal
function in older patients due to sarcopenia. Moreover, older individuals are at
higher risk for dehydration and acute kidney failure. For these reasons, it is advis-
able not to exceed a daily metformin dose of 1500 mg in patients aged more than
75 years. In addition, patients and caregivers should be instructed to suspend met-
formin in case of prolonged fever, vomiting, and diarrhea.
An additional concern is the development of vitamin B12 deficiency in chronic
metformin users [37, 38], which could contribute to anemia, cognitive dysfunc-
tion [37], and symptomatic peripheral neuropathy [39]. Although there are no
available randomized trials on the topic, some guidelines suggest that vitamin
B12 levels should be monitored yearly in older patients in therapy with metfor-
min [34].

23.3.2 Glucagon-Like Peptide 1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) released from enteroendocrine cells controls

meal-related glycemic excursions through a glucose-dependent stimulation of insu-
lin release and inhibition of glucagon secretion. Thus, GLP-1 receptor agonists
(GLP-1Ras) reduce hyperglycemia in type 2 diabetes without inducing hypoglyce-
mia. GLP-1 also inhibits food intake, determining weight loss [40].
GLP-1 RAs can be classified according to their half-life as short-acting (exena-
tide, lixisenatide), with a duration of action of 2–3 h, and long-acting (exenatide
q.w., liraglutide, dulaglutide, semaglutide), which, administered once daily or once
weekly, warrant drug circulating levels within the therapeutic range for the whole
day [41]. Short-acting GLP-1 RAs are more effective than longer-acting agents on
postprandial glucose increments, whereas long-acting compounds have a wider
effect on fasting glucose and HbA1c [42].
In head-to-head trials, GLP1-RAs reduce HbA1c to a greater extent than other
glucose-lowering agents, including aggressively titrated basal insulin [43, 44].
Although all drugs of the class induce weight loss, the weight-reducing action is
different across molecules, mainly depending on their ability to cross the blood-­
brain barrier [45]. In addition, long-acting GLP-1Ras prevent cardiovascular dis-
ease in high-risk patients [46, 47], including those aged ≥65 years [46]. However,
specific data on cardiovascular outcomes in patients older than 75 years are not
available.
Results from clinical and preclinical studies suggest a protective effect of
GLP-1RAs on cognitive decline [10]. An analysis of the REWIND study shows that
long-term therapy with dulaglutide could prevent cognitive impairment in people
336 E. Mannucci and D. Scoccimarro

with type 2 diabetes, including those aged ≥70 years [48], but further purposely
designed studies are needed to confirm these data.
GLP-1RAs, with the only exception of oral semaglutide, are administered with
subcutaneous injections, requiring adequate visual, motor, and cognitive skills. On
the other hand, the possibility of once-weekly administration facilitates drug man-
agement by patients and caregivers.
The most frequent side effects of GLP-1RAs are gastrointestinal symptoms, such
as nausea and, less frequently, vomiting, and diarrhea [36]. These effects usually
appear in the first weeks of treatment and decrease over the time with the prosecu-
tion of therapy; an initial dose titration is needed with some molecules of the class
in order to minimize side effects. Data from randomized clinical trials seem to show
similar efficacy and safety across ages, with no significant differences across age
classes, even if there was a trend toward higher rates of discontinuation for adverse
events with increasing age [49, 50].
Since weight loss and reduced appetite are usually associated with GLP1-RAs,
these drugs should not be used in malnourished or cachexic elderly patients [33]. In
addition, even if obesity is associated with frailty [51], weight loss is not always
desirable in the elderly because of an increased risk of sarcopenia, falls, and frac-
tures. For this reason, although GLP1-RAs are a very interesting option for the
treatment of type 2 diabetes, their use in older patients is limited by weight loss;
caution is recommended in nonobese elderly patients.

23.3.3 Sodium-Glucose Transporter 2 Inhibitors

The primary action of sodium-glucose transporter 2 inhibitors (SGLT-2i) is the inhi-

bition of glucose reabsorption in the kidney, thus inducing glycosuria and reducing
both postprandial and fasting hyperglycemia. This primary renal effect of SGLT2is
is independent of insulin, limiting the risk of hypoglycemia [52].
SGLT2i-induced glycosuria is associated with transient sodium excretion and
osmotic diuresis, resulting in a reduction of blood pressure [53]. The risk of sus-
tained reductions in plasma volume with SGLT2is is controversial [54, 55]. In addi-
tion, SGLT-2i induce a moderate weight loss due to the calorie loss determined by
glycosuria [56].
In large-scale trials, SGLT2i reduce the incidence of cardiovascular events, hos-
pitalization for heart failure, and progression of kidney disease in high-risk patients
with type 2 diabetes [57–61]. Protection from hospitalization for heart failure and
renal failure has also been shown in nondiabetic patients with heart failure and
chronic kidney disease, respectively [60, 62]; however, data on patients older than
75 years are not available [58, 61].
A post hoc pooled analysis of patient-level data from clinical trials showed that
the efficacy of SGLT2i on HbA1c, body weight, and blood pressure in patients aged
over 60 years is not different from that observed in younger individuals [63].
However, specific RCTs assessing the efficacy and safety of SGLT2i in the patients
aged >75 years are still lacking, and only very limited data have been published
23 Diabetes Mellitus 337

from observational studies. The theoretical risk of volume depletion suggests cau-
tion in prescribing SGLT2is in very old patients. SGLT2is can be an interesting
option in selected healthy elderly patients with T2DM, particularly if overweight or
with uncontrolled hypertension; on the other hand, these medications are not the
treatment of choice in frail patients, especially when treated with loop diuretics (due
to the increased risk of dehydration and orthostatic hypotension) [52]. Dose adjust-
ments for diuretics and insulin are generally required at the initiation of SGLT2i
treatment [36].
Mycotic genital infection is the most frequent adverse event with SGLT2i.
Treatment with SGLT2 inhibitors has also been associated with a modest increase
in the risk of urinary tract infections [64]. Genitourinary infections are more fre-
quent in women, particularly those with a history of recurrent genital infections
[65], and in current or former smokers [66]. In clinical trials, events were gener-
ally mild to moderate in intensity and rarely lead to discontinuation of treat-
ment [67].

23.3.4 Dipeptidyl Peptidase 4-Inhibitors

The inhibition of dipeptidyl peptidase 4 (DPP-4), which is the principal enzyme

responsible for the inactivation of endogenous GLP-1, increases the concentration
of both active incretin hormones GLP-1 and glucose-dependent insulinotropic poly-
peptide (GIP) [68]. Since these hormones are mostly released by the enteroendo-
crine L and K cells in response to meals, DPP-4 inhibitors (DPP-4i) exert their
glucose-lowering effects mainly acting on postprandial glycemia.
DPP4-I are effective and well tolerated in patients aged ≥65 years, with minimal
risk of hypoglycemia [69]. Pooled analysis from phase 2 and 3 studies showed no
differences across age groups in terms of safety and efficacy [70], and this was con-
firmed in clinical trials specifically performed in elderly patients [71, 72]. However,
it should be considered that β-cells function declines with the duration of diabetes
[73], and a preserved pancreatic function is required for the therapeutic action of
DPP4i: in fact, the glucose-lowering effect of this class can be blunted or absent in
patients with very low residual insulin secretion.
Despite increases in active GLP-1 concentrations, there are no effects of these
compounds on directly measured gastric emptying and satiation [74]. For these rea-
sons, DPP-4 inhibitors are not usually associated with typical GLP-1RAs gastroin-
testinal side effects, and they are neutral on body weight [75].
In cardiovascular outcome trials, DPP4 inhibitors were generally safe, without
increasing, nor reducing, the risk of major cardiovascular events [76]. An increase
of hospitalizations for heart failure was shown in patients treated with saxagliptin
[77], but not with other molecules of the class; a possible detrimental effect on heart
failure has also been suggested for alogliptin [78] and vildagliptin [79], but not with
sitagliptin [80] and linagliptin [81, 82].
Experimental data suggest that DPP-4i could have neuroprotective effects, delay-
ing cognitive decline in a glucose-independent way in animal models of Alzheimer’s
338 E. Mannucci and D. Scoccimarro

and Parkinson’s disease [83], but to date, there is no available clinical evidence in
humans supporting this hypothesis.
Efficacy, tolerability, and safety of DPP-4i in older patients with impaired kidney
function have been confirmed by randomized controlled trials [71, 72], so that this
class can represent a useful option in patients with declined eGFR.
Side effects are uncommon with DPP-4 inhibitors, which are a very considerable
advantage in the elderly. The possibility of an increased risk of pancreatitis associ-
ated with DPP-4i is controversial [84], but it is advisable not to use these drugs in
patients with a history of pancreatitis. Data from observational and randomized con-
trolled trials also show an increased risk for bullous pemphigoid, in particular for
linagliptin and vildagliptin, but the absolute risk is low [85].
DPP4 inhibitors are probably the most extensively studied class of glucose-­
lowering drugs in elderly patients. Available evidences show that they are safe in
older individuals, with low risk of hypoglycemia and neutral effect on body weight.
In addition, they are administered orally once daily, facilitating adherence and man-
agement of therapy. Therefore, despite their limited efficacy on glucose control and
the lack of specific cardiovascular actions, they are an interesting treatment option
in elderly, particularly in non-overweight patients with mainly postprandial hyper-
glycemia, as add-on to metformin, or when metformin is not tolerated or
contraindicated.

23.3.5 Thiazolidinediones

Thiazolidinediones, or glitazones, enhance insulin sensitivity through the activation

of nuclear PPARγ receptors, which modulate the expression of several genes, pro-
moting differentiation of adipocytes and lipogenesis in peripheral adipocytes,
increasing glucose uptake in skeletal muscle, and suppressing hepatic gluconeogen-
esis [86]. In patients with type 2 diabetes, glitazones reduce fasting glycemia and
HbA1c, without inducing hypoglycemia. Pioglitazone is the only thiazolidinedione
(TZD) available at present in Europe, while rosiglitazone is available in the USA
with limited indications.
Pioglitazone is effective and potentially well tolerated in the elderly, with no risk
of hypoglycemia, unless it is associated with insulin. The most frequent adverse
event is fluid retention, with peripheral edema, which contributes to pioglitazone-­
associated weight gain. In patients with left ventricular dysfunction, fluid retention
can precipitate symptoms of heart failure; for this reason, glitazones are associated
with an increased risk of hospitalization for heart failure despite the lack of detri-
mental effects on myocardial contractility. Fluid retention, which develops predom-
inantly within the first months of treatment, seems to be more frequent in the elderly
[87, 88], particularly when glitazones are associated with insulin [88]. This suggests
caution in using these drugs in advanced age, unless an undetected impairment of
cardiac function can be reasonably excluded.
In addition, TZDs stimulate the differentiation of bone marrow mesenchymal
stem cells into adipocytes, reducing the differentiation of osteoblasts and therefore
23 Diabetes Mellitus 339

inducing a reduction of bone mass [89]. In postmenopausal women, the use of gli-
tazones is associated with accelerated osteoporosis [90] and increased risk of frac-
tures [91]. This phenomenon is not observed in men, since androgens antagonize
the inhibitory effect of TZDs on osteoblastogenesis [89]. As a consequence, gli-
tazones are not among the drugs of choice in postmenopausal women. Finally, pio-
glitazone has been associated with an increased risk of bladder cancer [92],
prompting a relative contraindication in patients with a familiar or personal history
of bladder cancer.
Pioglitazone should be considered as a second-/third-line therapy in elderly
patients due to its effect on bone and heart failure. It could be an effective option in
selected patients, in particular male patients, provided that ventricular function is
preserved.

23.3.6 Alpha-Glucosidase Inhibitors

α-Glucosidase inhibitors are competitive inhibitors of the intestinal enzymes

responsible for terminal carbohydrate digestion, thereby delaying carbohydrate
absorption. They need to be administered 10 min before meals, and they reduce the
postprandial increment of glycemia, with a moderate efficacy on HbA1c and no
relevant action on body weight. Specific trials on cardiovascular outcomes are not
available.
The most common side effects are gastrointestinal adverse events, such as flatu-
lence and diarrhea, with a relatively high rate of nonadherence and/or withdrawal [8].
α-Glucosidase inhibitors are not associated with hypoglycemia, unless they are
combined with insulin or sulfonylureas. In this latter case, the drug-induced delay
in digestion and absorption of disaccharides (i.e., sugar) commonly used for the
self-treatment of hypoglycemia interferes with the efficacy of treatment of non-­
severe hypoglycemia. Insulin-treated patients who receive a prescription of
α-glucosidase inhibitors should be instructed to use glucose, instead of sucrose, for
the correction of hypoglycemia.
The only drug of this class widely available in Europe is acarbose (miglitol is
authorized in very few countries), which can be considered a therapeutic option in
elderly non-insulin-treated patients with type 2 diabetes with moderate postprandial
hyperglycemia.

23.3.7 Sulfonylureas and Glinides

Sulfonylureas and glinides promote insulin release by blocking β-cell K-ATP chan-
nels, thus inducing membrane hyperpolarization, which triggers insulin secretion.
Sulfonylureas stimulate insulin secretion irrespective of glucose levels [92], poten-
tially leading to hypoglycemia. In epidemiological studies, the incidence of severe
hypoglycemia with sulfonylureas is not dissimilar from that observed with insulin
in type 2 diabetes [93]. This risk is even greater in elderly patients, in whom the
340 E. Mannucci and D. Scoccimarro

impairment of renal function can alter the pharmacokinetic of many drugs of the
class, and the recognition and early treatment of mild hypoglycemia are often com-
promised. Furthermore, in both randomized clinical trials and observational studies,
sulfonylureas are associated with an increased risk of overall and cardiovascular
mortality [94, 95]. The explanation of this phenomenon is still controversial; it is
possible that the blockade of myocardial and cerebral K-ATP channels similar to
those expressed in β-cells reduces the ability of adapting to ischemia [96, 97]. For
all these reasons, sulfonylureas are excluded by some guidelines [14] and consid-
ered third-line treatment by many others [11–13]. An even greater caution should be
taken in elderly patients, considering the greater risk of hypoglycemia and conse-
quent falls and fractures.

23.4 Conclusion

Individuals aged more than 75 years represent a growing fraction of patients with
type 2 diabetes. Despite the epidemiological relevance of this population, most inter-
vention studies enroll only younger individuals, thus limiting available specific evi-
dence. Clinical reasoning suggests that less ambitious glycemic goals should be
chosen for older patients, in the attempt of limiting undesired side effects of pharma-
cological therapy. In addition, the choice of drugs requires caution, considering exist-
ing comorbidities and other factors (such as social support) possibly affecting the
incidence of drug-related adverse events (Table 23.1). Most guidelines [11, 12, 14]

Table 23.1 Strengths and weaknesses of different drug classes

Strength General side effects Warnings in elderly
Biguanides Effective on HbA1c Diarrhea Accumulation due to
No hypoglycemia Lactic acidosisa higher risk of acute
Weight loss (modest) renal insufficiency
Overall/cardiovascular Vitamin B12
mortality reduction deficiency
GLP-1 receptor Very effective on HbA1c Nausea/vomiting/ Visual and motor
agonists No hypoglycemia diarrhea skills required for
Weight loss administration
Protection from cognitive Risk of excessive
impairment weight loss
Protection from major
cardiovascular eventsb
Once weekly
administrationc
SGLT2 inhibitors Effective on HbA1c Genital infections Interaction with
No hypoglycemia Plasma volume diuretics and
Weight loss depletion dehydration
Nephroprotection
Protection from
hospitalization for heart
failure and major
cardiovascular eventsb
23 Diabetes Mellitus 341

Table 23.1 (continued)

Strength General side effects Warnings in elderly
DPP4 inhibitors No hypoglycemia Bullous Low effectiveness on
Safe and very well pemphigoid HbA1c when reduced
tolerated (uncommon) β-cells function
Thiazolidinediones No hypoglycemia Fluid retention and Increased risk of heart
heart failure failure
Weight gain Increased risk of
Bone loss and pathologic bone
fractures (women) fracture (women)
α-Glucosidase No hypoglycemia Flatulence and Gastrointestinal
inhibitors diarrhea tolerability
Sulfonylureas and Hypoglycemia Higher risk for falls
glinides Weight gain and fractures
Mild increase of Frequent self-­
overall/ monitoring of blood
cardiovascular glucose required
mortality
Insulin Effective on HbA1c Hypoglycemia Higher risk for falls
Adjustable dosage Weight gain and fractures
Cognitive, visual, and
motor skills required
for administration
Frequent self-­
monitoring of blood
glucose required
a
In predisposing conditions
b
In high risk patients
c
For dulaglutide, semaglutide, exenatide LAR

recommend metformin as the first-line pharmacological treatment irrespective of

age; this position is reasonable, provided that contraindications are observed, and
higher doses are avoided. The choice of the second drug, when needed, is more prob-
lematic. The majority of current guidelines supports a wide use of SGLT2 inhibitors
and/or GLP1 receptor agonists, at least in patients at high cardiovascular and/or renal
risk [11, 13, 14]; however, the safety of those classes could be less satisfactory in
very old patients. On the other hand, other classes, such as DPP4 inhibitors, do not
show relevant safety issues in the elderly, but they do not provide additional health
advantages beyond the reduction of hyperglycemia. The choice of treatment should
therefore be individualized, considering specific goals and concurrent conditions.

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Stroke Therapeutics in the Care of Older
Persons 24
A. Bahk, F. A. Kirkham, Y. T. Ng, and Chakravarthi Rajkumar

24.1 Background and Epidemiology

Stroke is defined as ‘rapidly developing clinical signs of focal (or global) distur-
bance of cerebral function, with symptoms lasting 24 h or longer or leading to
death, with no apparent cause other than of vascular origin’ [1]. It accounts for
approximately 11% of deaths worldwide [2], and over 116 million years of healthy
life lost are due to stroke-related conditions. In Europe, stroke mortality has declined
in recent years due to improvements in diagnosis and treatment [3], but with chang-
ing demographics and population structure, the projected number of stroke survi-
vors in Europe is expected to increase 27% by 2047 [4].
While 87% of strokes are ischaemic compared to only 13% that are haemor-
rhagic [5], the World Stroke Organisation reports that 51% of all deaths from stroke
occur from haemorrhages [6], defined as intracerebral or subarachnoid haemor-
rhages in the absence of trauma [7]. An estimated 30% of strokes occur in those over
80 years, with this group experiencing a threefold higher 30-day case fatality rate
compared to their younger counterparts [8]. Older adults often present with higher
NIHSS (National Institute of Health Stroke Scale) score which translates to more
severe strokes, increased levels of risk factors [9] and have delayed time to throm-
bolysis administration, when given [10], making this patient group a particularly
important focus when it comes to stroke management.

A. Bahk · F. A. Kirkham · Y. T. Ng
University Hospitals Sussex NHS Foundation Trust, Brighton, East Sussex, UK
e-mail: [email protected]; [email protected]; [email protected]
C. Rajkumar (*)
University Hospitals Sussex NHS Foundation Trust, Brighton, East Sussex, UK
Department of Medicine, Brighton and Sussex Medical School, University of Sussex,
Brighton, UK
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2023 349

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_24
350 A. Bahk et al.

Transient ischaemic attack (TIA) is an episode of neurological dysfunction

caused by focal brain, spinal cord, or retinal ischaemia, without acute infarction,
lasting less than 24 h [11]. It is estimated that 4.7% of TIA patients will go on to
have a stroke in the subsequent 90 days [12].

24.2 Ischaemic Stroke Classification

A number of different classification systems have been proposed. The most com-
monly used system is the TOAST criteria (trial of ORG 10172 in acute stroke treat-
ment), focusing on the likely causative event to divide strokes predominately into
large artery atherosclerotic, cardioembolic or small vessel occlusion [13] while
allowing for undetermined or other causes. Approximately 45% of ischaemic
strokes are due to thrombosis [14] in a large or small vessel, while one fifth are
thought to derive from cardiac emboli [15].
Alternatively, Bamford classification (Table 24.1) relies on clinical findings to
determine the brain territory affected, defining strokes as lacunar (LAC), total (TAC)
or partial anterior (PAC), or posterior (POC) and assigning a letter following CT
imaging (I for infarct, H for haemorrhage or S for syndrome) [16]. The oldest old
are more likely to have large vessel (TAC/PAC) occlusion than small vessel (POC/
LAC) occlusion compared to those under 80 years [17].

Table 24.1 Bamford classification of ischaemic stroke

Stroke type Clinical findings
Lacunar (LAC) Any of:
Pure motor
Pure sensory
Sensorimotor
Ataxic hemiparesis
Dysarthria-clumsy hand syndrome
Without higher cortical dysfunction.
Total anterior circulation All of:
(TAC) Higher cortical dysfunction
Homonymous visual field deficit
Unilateral motor and/or sensory loss affecting 2 out of 3 regions
(face, upper limb, lower limb).
Partial anterior 2 out of 3:
circulation (PAC) Higher cortical dysfunction
Homonymous visual field deficit
Unilateral motor and/or sensory loss affecting 2 out of 3 regions
(face, upper limb, lower limb).
Posterior circulation Any of:
(POC) Cerebellar syndrome
Homonymous visual field deficit
Ipsilateral cranial nerve impairment with contralateral motor and/or
sensory loss
Bilateral motor and/or sensory loss.
24 Stroke Therapeutics in the Care of Older Persons 351

Additionally, there are numerous ‘brainstem syndromes’ describing specific

groups of symptoms occurring in rarer stroke subtypes, often with eponymous
names and defined by their vascular supply. Examples include Wallenberg syn-
drome (lateral medullary syndrome) and Millard-Gubler syndrome (ventral pontine
syndrome). In general, brainstem strokes are characterised by ipsilateral cranial
nerve palsy and contralateral hemiparesis and/or hemisensory loss.

24.3 Pathophysiology

Hypertension is implicated in many of the changes to cerebral blood vessels associ-

ated with both ischaemic and haemorrhagic stroke. Over time, exposure to high
pressure causes arterial remodelling, changes in elastic and muscular constituents of
vessels and endothelial dysfunction, as well as promoting atherosclerotic plaque
formation [18]. Precursors to stroke include microaneurysms and microbleeds,
white matter changes [19] and subclinical infarcts.
Inflammation plays a significant role in the pathophysiology of ischaemic stroke,
with increases in reactive oxidant species and endothelial dysfunction contributing
to atherosclerosis, platelet aggregation and plaque rupture [20]. Impaired microvas-
cular function secondary to chronic hypertension and age-induced vascular stiffness
interacts with a systemic inflammatory state to predispose fragile vessels to bleed-
ing and thrombosis. Further changes with age such as reduced cerebral perfusion
and deposition of β-amyloid are associated with degeneration of vascular func-
tion [21].
Embolic strokes can originate from thrombosis (formed in a blood vessel, car-
diac chamber or heart valve), atherosclerotic material or non-thrombotic material
such as tumour, infectious vegetations, air or fat [22].

24.4 Risk Factors

The Framingham Stroke Risk Profile (FSRP) is the most commonly used tool for
evaluating stroke risk [23] and has been validated for predicting cerebrovascular
events in older patient groups. It incorporates the following established risk factors:

• Sex
• Age
• Smoking
• Blood pressure (treatment for hypertension or raised SBP)
• Diabetes
• Cardiovascular disease
• Atrial fibrillation

In high-income countries, almost half of global stroke mortality could be

accounted for by modifiable risk factors. Additional to those included in the
352 A. Bahk et al.

FSRP, hyperlipidaemia, alcohol use, obesity, air pollution and dietary choices
have been shown to contribute to increased risk of stroke [24], while higher lev-
els of physical activity have also been shown to be inversely related to stroke
risk [25].
Additional risk factors have been investigated in recent years. There is some
evidence to suggest that serum biomarkers including advanced glycation end prod-
ucts, CRP and total homocysteine are independently associated with increased risk
of stroke [26]. The role of measurable sex hormones and adipokines has been sug-
gested; however, thus far results are inconclusive. Genetic elements have also been
proposed as tools for identifying those at higher risk of stroke, and the APOEε2
allele has been shown to be protective against ischaemic stroke in those aged
71–79 years, but not in people over 80 years [27]. Psychosocial factors shown to
increase stroke risk include depressive symptoms [28], low psychological well-­
being and reduced cognitive function [29]. Finally, low socioeconomic status not
only increases the risk of having a stroke but is also associated with reduced access
to care and poorer outcomes [30].

24.5 Presentation

Stroke in older patients does not always present with typical features, and the term
‘stroke chameleon’ has been used to describe unusual presentations. The oldest
old are more likely to present with falls or reduced mobility and less likely to have
sensory symptoms [31]. Other potential presentations include neuropsychiatric
symptoms (such as confusion, memory loss or reduced GCS), abnormal move-
ments, dizziness or headache [32]. The reasons for such divergent presentations
are manifold, as symptoms may still be evolving with subtly different brain
regions involved, alongside practical difficulties in performing comprehensive
examinations in frail older people and the possibility that dual pathologies may
exist simultaneously in multimorbid adults [33]. Full assessment, however, is
paramount to avoid misdiagnosis or attribution of symptoms to another coinciden-
tal illness (e.g. urinary tract infection or pre-existing mobility issues). The most
common misdiagnoses are delirium, syncope, hypertensive emergencies or sys-
temic infection [34].

24.6 Assessment

The Recognition Of Stroke In the Emergency Room (ROSIER) scale is designed for
use in emergency departments to aid in the diagnosis of stroke [35]. However, as
older patients may present with atypical symptoms, and ‘time is brain’ [36], it is
generally recommended to prioritise brain imaging in the form of CT for all poten-
tial strokes. Table 24.2 outlines the recommended investigations for all stroke
patients being assessed in the acute setting.
24 Stroke Therapeutics in the Care of Older Persons 353

Table 24.2 Investigations for older people presenting with acute stroke
Bedside investigations Blood tests Imaging
History and clinical examination Full blood count CT brain within 1 h of presentation
including NIHSS score
Functional assessment Urea and Chest X-ray
electrolytes
Blood pressure Clotting Consider CT angiography or diffusion-­
weighted MRI
12-lead ECG Inflammatory Consider echocardiography and 24-h
markers ambulatory ECG to identify cause
Bedside glucose Lipid profile Consider carotid doppler US
Swallow assessment HbA1c
NIHSS National Institutes of Health Stroke Scale

24.7 Functional Assessment

It has been shown that in older adults, frailty score is a better predictor of stroke
outcome than other measures [37]. Equally, pre-stroke cognitive function is an
important determinant of cognitive recovery [38]. Therefore, it is of particular sig-
nificance to assess pre-morbid frailty and cognition in this patient group.
The most widely used tools for frailty assessment include the Rockwood Clinical
Frailty Scale [39] which relies on the judgement of an experienced clinician; the
Fried Frailty Index [40] which focuses on independently measurable variables such
as BMI and handgrip strength; or the Barthel Index [41] which looks at self-reported
ability to perform activities of daily living.
The modified Rankin Scale (mRS) has been applied within stroke research and
in clinical settings as a measure of disability and dependence after stroke. The scale
ranges from 0 (no symptoms) to 6 (death). It can be used to evaluate pre-stroke dis-
ability with validity in prognostication.
Although it is not possible to measure pre-morbid cognitive function on presen-
tation, it is widely accepted that cognitive assessment should be performed prior to
discharge [42]. Many tools have been validated for use in older adults; however,
there is limited evidence for their use in acute stroke [43]. The Montreal Cognitive
Assessment (MoCA) has been suggested as the most useful for identifying cogni-
tive impairment after stroke [44], offering a validated evaluation that is also feasible
to perform regularly in clinical practice.

24.8 Hyperacute Management of Acute Stroke

The hyperacute management of stroke is largely dependent on the stroke subtype.

With loss of neurons every second, rapid treatment is crucial to reduce the sequelae
of further neuronal death. Stroke patients treated in a specialist stroke unit are more
likely to achieve a favourable outcome, taking into account different stroke types,
severity and age [45].
354 A. Bahk et al.

24.8.1 Ischaemic Stroke

The immediate treatment of acute ischaemic strokes targets the occluded cerebral
artery to enable revascularisation and re-establish cerebral blood flow. The use of
thrombolytic agents and mechanical thrombectomy is now widely adopted as stan-
dard practice owing to the overall net benefit in reducing disability and mortality.
Numerous studies have shown thrombolysis treatment with intravenous recom-
binant tissue-plasminogen activator (rt-PA), when delivered within 4.5 h, achieved
significant reduction in disability [46, 47]. This was despite symptomatic intracere-
bral haemorrhage (sICH) of 7.7% and fatal intracerebral haemorrhage of 3.6%
within the first 7 days [48].
The exclusion of patients aged ≥80 from these initial trials has led to uncertainty
of potential benefits in this cohort. A major concern was the theoretically greater
bleeding risk in older patients. The Third International Stroke Trial (IST-3) provided
valuable safety and efficacy data in patients aged ≥80, and subsequent trials indi-
cate that the overall benefit of treatment is comparable to younger patients [49].
While sICH rates are similar across age groups, delay in treatment time, larger
strokes, hyperglycaemia and hypertension is implicated in higher bleeding risk and
considered to be contraindications for thrombolysis. The presence of leukoaraiosis
on brain imaging, which is more commonly seen in older patients, is also linked to
increased risk of thrombolysis-related sICH [50]. However, in general, increasing
age is a predictor of adverse outcome and mortality due to non-haemorrhagic com-
plications, often associated with the ageing process. Multi-morbidity and pre-stroke
frailty are also linked to poor prognosis [51]. Treatment decisions therefore require
careful consideration, balancing the overall benefit and risk on an individual basis.
Research continues in the use of magnetic resonance imaging (MRI) and com-
puted tomography perfusion (CTP) to support thrombolysis in patients with stroke
of unknown time of onset or symptoms beyond 4.5 h [52]. This could potentially
widen the treatment time window.
The efficacy of endovascular therapy in the hyperacute treatment of ischaemic
stroke with anterior proximal large vessel occlusion is well established. Mechanical
devices are deployed to remove the clot and open up the occluded cerebral artery
thereby restoring blood flow (Figs. 24.1 and 24.2). The development of newer gen-
eration mechanical devices and advances in technique has led to lower mortality
rates and a substantial reduction in disability at 90 days [53]. These findings have
also been observed in patients aged ≥80 when compared to those given standard
care [53, 54]. Where possible, it is considered to be the treatment of choice for isch-
aemic strokes with a proximal large vessel occlusion for several reasons. Patients
who would otherwise not be eligible for thrombolysis can be offered treatment
without the bleeding risks associated. These include patients with underlying bleed-
ing tendencies and those on anticoagulation treatment. It can also be performed in
conjunction with thrombolysis to achieve higher rates of recanalisation than throm-
bolysis alone [53]. However, the overall recanalisation rates are lower in older
patients [54] with associated higher rates of adverse outcome and mortality [55].
24 Stroke Therapeutics in the Care of Older Persons 355

Fig. 24.1 Angiography of right middle cerebral artery occlusion

Poorer neurological reserve and higher risk of post-stroke complication are sug-
gested to be contributing factors.
Current evidence supports the use of intravenous thrombolysis and mechanical
thrombectomy in the treatment of ischaemic strokes, regardless of age. However,
the utilisation of these treatments remains less in older patients [53, 56]. These deci-
sions are likely to be based on various factors including pre-existing comorbidities
and frailty, perceived risk of complications and the overall benefit. Therefore, deci-
sion to treat should be based on the individual patient to avoid potentially harmful
intervention in patients who are unlikely to achieve a favourable outcome.

24.8.2 Intracerebral Haemorrhage

The management of intracerebral haemorrhage (ICH) involves measures to reduce

haematoma expansion and thereby prevent further neurological deterioration.
Compared to acute ischaemic strokes, patients with ICH are more likely to be com-
menced on end-of-life care within the first 72 h with less patients receiving higher
level care, independent of premorbid mRS, age, comorbidities and level of con-
sciousness [57]. In doing so, this could impose limitations in acute treatment and
thus impact recovery and outcome [58]. Coordinated specialist stroke units and
356 A. Bahk et al.

Fig. 24.2 Angiography of reperfusion in the right middle cerebral artery after mechanical
thrombectomy

neurocritical care are associated with improved mortality and level of independence
in patients with ICH [45].
Elevated blood pressure in the acute phase is a common physiological response in
ICH. Resultant haematoma enlargement and cerebral oedema are feared complica-
tions and predictors of poor outcome [59]. Initiating intensive blood pressure lowering
has shown to be safe in reducing haematoma size without added risk of neurological
deterioration or recurrent stroke events. While this did not translate to significant
reduction in mortality or major disability at 3 months, improved functional outcome
was observed in ordinal shift analysis of mRS in the INTERACT trials with rapid
lowering of blood pressure to a target systolic of 140 mmHg in the first 6 h [60]. Thus,
other factors are likely to contribute to clinical outcome including time frame from
symptom onset to first brain imaging, the volume of haematoma at presentation and
effects of blood pressure variability in the acute phase [61, 62]. Furthermore, extrapo-
lation of data in the oldest old population should be interpreted with caution in view
of uncertainties in the blood pressure physiology of this age group.
The use of vitamin K antagonists (VKA) such as warfarin at presentation results
in larger haematoma size at baseline with greater risk of haematoma expansion and
24 Stroke Therapeutics in the Care of Older Persons 357

mortality compared to those not on anticoagulation [63]. In comparison, haema-

toma size tends to be smaller with less severe stroke in patients on direct oral anti-
coagulant (DOAC) although with comparable case fatality rates [64]. Due to the
correlation of haematoma expansion and poor outcome, rapid reversal of anticoagu-
lants to attenuate haematoma enlargement has been widely adopted. The use of
prothrombin complex concentrate (PCC) and other targeted reversal agents for
DOACs has shown to be effective [65]. Currently, there is no licensed reversal agent
for patients on antiplatelet therapy.
Earlier trials evaluating the clinical outcome of neurosurgery in patients with
ICH concluded no overall benefit in mortality or favourable outcome [66]. There is
now emerging evidence that targeted therapy using minimally invasive surgery
(MIS) in select patients improves mortality and, potentially, functional outcome
[67, 68]. Due to small sample size, variability in timing of surgery and haematoma
size, as well as the exclusion of older patients in these studies, further research is
required to appreciate the role of surgery in the treatment of ICH in older patients.

24.8.3 Transient Ischaemic Attack

Stroke prevention is central to the management of transient ischaemic attacks (TIA).

Currently, guidelines for TIA management involve prompt assessment by a stroke
specialist, ideally within 24 h [69]. Detailed history and clinical examination are
key to confirm diagnosis and exclude mimics which can account for up to 60% of
patients seen in the TIA clinic [70]. This can be particularly challenging when
assessing older patients as recollection of symptoms may be vague; however, brain
imaging can be helpful. Urgent investigations are performed to identify modifiable
risk factors, including atrial fibrillation, carotid disease and hypertension. Immediate
treatment with the combination of antithrombotic agents, blood pressure and lipid
lowering strategies has been shown to reduce stroke risk by up to 80% [71].
Addressing the precipitating cause and risk factors for TIA, such as initiating anti-
coagulation in atrial fibrillation and surgical intervention for significant carotid ste-
nosis, is important to secondary prevention [69]. Opportunities should be taken to
promote non-pharmacological measures such as dietary adjustments, exercise and
smoking cessation.

24.9 Secondary Prevention of Stroke and TIA

The success of stroke prevention with decline in stroke incidence has been offset by
the rapidly ageing population. The exclusion of older patients in numerous land-
mark clinical trials on stroke prevention has led to a paucity of evidence in the
benefits of secondary prevention measures in this cohort. However, with increasing
life expectancy, even patients aged 80 of average health would benefit from second-
ary stroke prevention [72].
358 A. Bahk et al.

24.9.1 Antiplatelets

Antiplatelet agents are a key component in secondary prevention following a non-­

cardioembolic acute ischaemic stroke or TIA [73]. Thus far, aspirin is the only anti-
platelet agent shown to significantly reduce recurrent ischaemic stroke risk in the
acute phase [74]. Patients presenting with TIAs or minor strokes observe greater
benefit with aspirin, with a risk reduction for recurrent ischaemic stroke of 60% and
disabling or fatal ischaemic stroke of 70% [74]. It is therefore vital that patients
suspected of a TIA or stroke (after haemorrhage has been excluded) are immedi-
ately administered aspirin. After the acute phase, clopidogrel has been shown to be
a superior long-term monotherapy compared to aspirin in reducing the combined
risk of ischaemic stroke, myocardial infarction or vascular death [75]. Dual anti-
platelet therapy (DAPT), with aspirin and a P2Y12 inhibitor, such as clopidogrel or
ticagrelor, can be used in select patients with acute minor ischaemic strokes or high-
risk TIAs. By initiating early treatment and duration of up to 90 days, stroke recur-
rence is reduced by 24% with a small absolute increased risk of haemorrhage.
Exclusion of very elderly patients in the trials with DAPT (mean age in these trials
62–68) may implicate bias in clinical practice [76].

24.9.2 Antihypertensives

Hypertension is the single most important modifiable risk factor for both ischaemic
and haemorrhagic stroke, and reduction in blood pressure correlates with lower
stroke risk [77].
In the hyperacute phase, blood pressure can be elevated as normal cerebral auto-
regulation is impaired. Lowering blood pressure may be beneficial in the manage-
ment of ICH; however, in acute ischaemic stroke, elevated blood pressure is
considered to have a neuroprotective effect to improve cerebral perfusion to the
ischaemic areas. Optimum timing to initiate antihypertensive treatment remains
uncertain, and recommendations vary from days to weeks [78]. In TIAs, antihyper-
tensive treatment can be commenced once the diagnosis of hypertension is estab-
lished [79], and there are no specific contraindications.
Comparison data between patients aged ≥65 versus <65 showed comparable risk
reduction [80]. Patients aged ≥80 were underrepresented in this study; however, the
Hypertension in the Very Elderly Trial (HYVET) showed that antihypertensive ther-
apy reduced stroke risk by 30% and all-cause mortality by 21% [81]. Adverse effects
of intensive blood pressure lowering in older patients include cerebral hypoperfusion
and orthostatic hypotension. However, slightly higher blood pressure targets of
150/80 mmHg as seen in the HYVET trial could still achieve satisfactory outcome.

24.9.3 Lipid-Lowering Agents

Hyperlipidaemia is a common modifiable risk factor for ischaemic stroke in older

patients, observed in over 50% of those aged ≥65 [82]. Reducing low-density
24 Stroke Therapeutics in the Care of Older Persons 359

lipoprotein (LDL) cholesterol levels to less than 70 mg/dL (1.8 mmol/L) following
ischaemic stroke or TIA could lower risk of subsequent cardiovascular events [83].
Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also
known as statins, have proven to have protective benefits in reducing stroke risk by
lowering LDL cholesterol [84]. These benefits have also been reflected in further
studies examining older patients for both primary and secondary prevention and with
high level of tolerability [85]. However, these findings have not been consistently
replicated and only seen to be effective in patients with carotid disease [86].
Furthermore, the use of statins should be guided by the life expectancy of the patient
as its benefits are observed over several years. Newer lipid-lowering agents such as
PCSK9 inhibitors have been utilised in patients who are intolerant to statins. With
higher rates of statin intolerance in the older patient, alternative agents may be con-
sidered, although the evidence of its role in the older population is yet to be evaluated.

24.9.4 Diabetes Treatment

Diabetes mellitus is a recognised risk factor for ischaemic stroke and is associated
with a fourfold increase in stroke risk. The prevalence of type 2 diabetes increases
with age, and these patients have a higher propensity for strokes and cardiovascular
disease compared to those with type 1 diabetes [87]. Pre-existing diabetes is associ-
ated with recurrent ischaemic stroke and poorer prognosis [88]. However, intensive
glycaemic control has not been shown to reduce cardiovascular events including
stroke and can lead to adverse outcome [89]. This emphasises the need for an indi-
vidualised approach to glycaemic targets and optimisation of coexisting vascular
risk factors, including hypertension and hyperlipidaemia. The extent of glycaemic
control should be balanced with the risk of major hypoglycaemic events. The cur-
rent recommendation is to aim for a target HbA1c of 48 mmol/mol (6.5%) in type 2
diabetes [90].

24.9.4.1 Atrial Fibrillation

Atrial fibrillation (AF) accounts for up to one in three ischaemic strokes, and the
incidence increases with age. It is associated with worse prognosis; however, it can
be preventable [91]. The benefits of anticoagulation therapy are well established and
accordingly recommended in guidelines [69, 79, 92]. The superiority of vitamin K
antagonists, such as warfarin, over aspirin in stroke prevention is also widely recog-
nised, even in older patients [93]. However, with effectiveness dependent on ‘time
in therapeutic range’ (TTR) and the challenges of monitoring the international nor-
malised ratio (INR), this can be particularly problematic in older patients [94].
Direct oral anticoagulants (DOAC) have been shown to be non-inferior to warfarin
in stroke reduction with potentially better safety profile. Importantly, these results
were also evident in those aged ≥75 years [95]. However, in clinical practice, older
patients are often denied anticoagulation due to age and perceived risks of bleeding
and falls [96].
While there may be valid reasons not to commence older patients on anticoagu-
lation, individual risk assessment is vital to ensure that appropriate treatment is
360 A. Bahk et al.

offered to eligible patients. A comprehensive assessment should be carried out to

determine the suitability of commencing anticoagulation using risk stratification
tools. The Outcome Registry for Better Informed Treatment of Atrial Fibrillation
(ORBIT) score has been shown to be superior in assessing bleeding risk when com-
pared to the HASBLED score. Stroke recurrence risk in AF can be estimated using
the CHA2DS2VASc score. There is always a debate around avoiding anticoagulation
in elderly patients due to the risk of falls. Current guidelines in the management of
AF emphasise that falls alone should not be treated as a contraindication to antico-
agulation [92]. The various factors which affect the patient and the benefit of anti-
coagulation versus not anticoagulating should be taken into account before deciding
treatment. Discussions with the patient and the family on the risks and benefits of
treatment are beneficial.

24.9.5 Carotid Endarterectomy

Atherosclerotic carotid stenosis is associated with 10–15% of ischaemic strokes and

TIAs, with prevalence increasing with age [97]. Carotid revascularization is
achieved by carotid endarterectomy (CEA) or carotid artery stenting (CAS).
The benefits of CEA are based on two landmark trials. The European Carotid
Surgery Trial (ESCT) and the North American Symptomatic Carotid
Endarterectomy Trial (NASCET) [98, 99]. Currently, CEA is performed for sec-
ondary stroke prevention in the context of symptomatic significant internal
carotid artery stenosis in TIAs and non-disabling strokes [100]. Symptomatic
carotid disease is defined as diameter reduction of ≥50% using the NASCET
method [99]. The risk of recurrent stroke is highest in the first 7–14 days, and the
benefits of CEA diminish beyond this period; therefore, there is emphasis on
performing surgery soon after the index event (within 2 weeks). The number
needed to treat (NNT) is significantly reduced when stenosis is >70%, hence the
need to refer for surgical intervention early in the presence of high-grade carotid
stenosis [98]. Reassuringly, advancing age was not associated with increased risk
of 30-day stroke or mortality rates and conversely patients aged ≥75 years
observed greater benefits following carotid surgery [101]. The short- and long-
term stroke complications are not insignificant and particularly more common in
patients aged ≥70 [102]. Given that the absolute risk reduction is calculated over
5 years, the decision to proceed with surgical treatment should be based on the
overall prognosis.
The risks of peri-procedural stroke and mortality following CAS are higher when
compared to CEA and particularly in patients aged ≥70. It is therefore currently not
recommended as first-line treatment for symptomatic carotid disease. However,
there is a role for CAS in patients aged ≤70 who are unable to undergo CEA in the
treatment of symptomatic carotid stenosis [103].
Guidelines recommend CEA in asymptomatic carotid artery stenosis in high-risk
patients despite best medical therapy. Patients aged ≥75 years with expected sur-
vival of at least 5 years may be considered following careful multidisciplinary
24 Stroke Therapeutics in the Care of Older Persons 361

assessment. CAS is, however, not routinely recommended in asymptomatic carotid

stenosis owing to limited evidence [103].

24.9.5.1 Post-Stroke Sequelae in the Older Person

Studies estimate that up to 85% of stroke patients encounter a medical complication
during hospital admission [104]. These conditions are common in older patients and
can occur early or late in the stroke recovery phase, limiting the rehabilitation pro-
cess. Often these conditions are preventable and treatable, emphasising the impor-
tance of organised stroke care in a hyperacute stroke unit in reducing stroke mortality
and improving functional outcome [45].
Malignant middle cerebral artery (MCA) syndrome is a potentially fatal compli-
cation of middle cerebral artery ischaemic stroke. Decompressive hemicraniectomy
is proven to be a life-saving treatment without increasing the risk of severe disabil-
ity among patients aged 60 years or younger [105]. However, its benefits in older
patients remain controversial, and further research is needed.
Seizures are common complication following a stroke and can occur early
(within the first 7 days) or late (after 7 days). Seizures occurring after 7 days are
diagnostic for post-stroke epilepsy and carry a risk of seizure recurrence of up to
71.5% at 10 years [106]. Anti-epileptic agents should be initiated; however, assess-
ment is advised to determine the need for long-term treatment.
Infections are frequently seen in stroke patients, and early detection and treat-
ment are crucial. Stroke-associated pneumonia is one of the most common forms of
infection. Dysphagia, severe strokes and increasing age are independent predictors.
Urinary tract infections are also seen in patients following a stroke and are often
related to urinary catheterisation.
Prolonged immobility can lead to thromboembolism such as deep vein thrombo-
sis (DVT) and pulmonary embolism (PE). The use of intermittent pneumatic com-
pression devices has been proven to reduce rates of thromboembolic events [107].
Pressure ulcers, spasticity and contractures are also common complications related
to impaired mobility. Involvement of multidisciplinary team to support early mobil-
isation and pressure-relieving strategies is vital for prevention. The use of botuli-
num toxin and neuropathic analgesia can reduce the severity of spasticity.
Post-stroke neuropsychological complications can occur in patients of all ages.
Anxiety and depression can significantly limit recovery and can last for many years
after stroke. Both non-pharmacological and pharmacological treatment with antide-
pressants can help. Post-stroke fatigue is a common problem and closely associated
with mood. There is inconsistent evidence of age as a risk factor for developing
post-stroke fatigue. Thus far, there is no specific treatment proven to be effective
[108]. Early neuropsychological assessment and therapy are components in its
management.
The incidence of dementia can be up to 50 times greater following a stroke or
TIA compared to the general population. Vascular dementia is closely associated
with stroke, and treatment of reversible causes will help reduce progression of the
disease. Stroke burden and severity, age and premorbid dependency are risk factors
for developing dementia in stroke survivors [109].
362 A. Bahk et al.

24.10 Conclusion

Stroke remains common in older patient groups, and while mortality has declined in
recent years, it is a significant cause of morbidity and impaired function. In older
people, presenting symptoms may be atypical, and time to treatment is often
delayed, potentially resulting in poorer outcomes. With advances in imaging and
novel therapeutic approaches, it is imperative for geriatricians to stay informed of
up-to-date evidence and guidelines on stroke management to maximise opportuni-
ties for intervention both in the acute setting and as secondary prevention.
Management within a hyperacute stroke unit by a multidisciplinary team has been
shown to improve outcomes and encourage holistic care. In the future, targeted
molecular therapies and nanotechnology may enable even greater reductions in
mortality and enable faster detection, more effective reperfusion and prevent the
complications still associated with this important condition.

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Optimizing Pharmacotherapy in Older
Patients with Depression or Anxiety 25
Sylvie Bonin-Guillaume

25.1 Depression

Depression occurs up to 11% in the ageing population [1] with numerous atypical
presentations; only 12% of depressed older persons meet the DSM major depressive
criteria [2]. This prevalence reaches 40% in long-term care and nursing homes [3].
Thus, depression in older patient is often underdiagnosed and undertreated,
although it is associated with a poor prognosis (suicide [4], relapse, chronicity [5]).
Depression is also independently associated with frailty [6], malnutrition [7], func-
tional decline [8] and morbidity.

25.1.1 Pharmacological Treatment of Depression

Antidepressants are the first-line treatment for depression in older adults.

25.1.1.1 Antidepressants Efficacy

In a large meta-analysis that included 51 randomized control trials comprising of
old patients with depressive disorders, all classes of antidepressant (tricyclic agents
(TCAs), selective serotonin reuptake inhibitors (SSRIs) and other antidepressants)
were more effective than placebo in achieving response and remission. No differ-
ences were found in remission or response rates between classes of antidepressants.
The numbers needed to treat (NNT) were 14.4 (95% CI 8.3–50) for one additional
remission to antidepressants compared with placebo and 6.7 (95% CI 4.8–10) for
response [9], which is similar to the rates observed in younger adults [10].

S. Bonin-Guillaume (*)
Internal Medicine and Geriatric Department, Aix Marseille University, University Hospital of
Marseille, Hôpital de Sainte Marguerite, Marseille, France
e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2023 369

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_25
370 S. Bonin-Guillaume

Lower treatment response in elderly might be due to a vascular component in

late-onset depression, executive dysfunctions and longer current depressive episode
[11, 12].
Tricyclics are also very effective treatments, but they should be reserved for spe-
cific types of depression (e.g. depression with pain) or for depression that is resistant
to other therapeutic classes. Indeed, their anticholinergic effects (aggravation of cog-
nitive disorders, risk of falling, confusion) are the cause of significant adverse effects
in elderly subjects, especially when there are associated cognitive disorders [13].
More recently, vortioxetine has been studied in people over 65 years of age, and
the results showed its efficacy versus placebo at a dose of 5 mg/d. Preliminary data
suggest that vortioxetine has promising effects in improving cognition in older
adults with depressive symptoms (processing speed, as well as learning and mem-
ory [14, 15]. A recent review showed that vortioxetine had no difference in response
or remission comparing with SSRIs or the serotonin noradrenaline reuptake inhibi-
tors (SNRIs) [16]. Although well tolerated, caution should be exercised when treat-
ing patients 65 years of age and older with dosages greater than 10 mg of vortioxetine
once daily.
Anyhow, old patients with depression are poorly represented in randomized con-
trol trials, and those with significant medical comorbidities are commonly excluded
[17]. Moreover, antidepressant response involved defined small sample sizes popu-
lations (i.e. mostly major depressive disorders according to the DSMV [18]) and is
short lasting (about 8 weeks). Then, the results reported are difficult to generalize to
the real world of clinically depressed elderly patients. At last, there is a lack of effi-
cacy studies examining relapse prevention.

25.1.1.2 Antidepressant Management

Thus, to determine the best pharmacological treatment options for individual
patients, careful considerations are required (see Table 25.1): (1) ascertain depres-
sion and the type of mood disorders by trained health professionals; (2) assessing
concurrent medical problem and drug therapy; and (3) looking for previous response
to treatment if history of depression is known.
According to current recommendations, SSRIs are the first-line choice treatment
for old patients because they are effective for treating depression with fewer side
effects than other classes (see Table 25.2) [13, 19, 20].
One or two doses escalation steps are required to achieve the final daily dose and
avoid side effect. The final daily dose is for most cases the same as for younger
[10, 22].
In a dimensional approach and according to their action on brain monoaminergic
systems, antidepressants might be selected for their expected behavioural effects.
For example, psychomotor retardation and loss of energy may be linked to a reduced
dopaminergic activity. Anhedonia, lack of motivation and arousal and loss of con-
centration are linked to noradrenergic activity, while irritability, pessimism, sadness
or dysphoria are mediated by serotoninergic system [21, 23].
25 Optimizing Pharmacotherapy in Older Patients with Depression or Anxiety 371

Table 25.1 Recommendations for a better antidepressant treatment efficiency (from [13, 19–21])
1. Discuss the choice of antidepressant with the patient
 • First choice: SSRI (selective serotonin reuptake inhibitors)
 • Efficiency and tolerability of any antidepressants previously taken
2. Inform the patient about the following:
 • Gradual development of the full antidepressant effect
 • Importance of taking medication as prescribed and the need to continue beyond remission
 • Potential side effects and drug interactions
3. Monitor AD response regularly and side effects carefully
 • Do not prescribe sub-therapeutic doses of antidepressants
 • Evaluate improvement or remission (a delayed response up to 12 weeks is usual in older
patients)
 • Monitor carefully for side effects
4. Check treatment duration and adherence
 • >6 months after complete remission for the first episode (optimally 1 year after complete
remission), longer if past history of depression episode
 • A step-by-step withdrawal (at least 1 month, optimally 3 months)
5. Avoid psychotropic drugs co-prescription unless:
 • Congruent psychosis symptoms present (antipsychotic should be proposed)
 • Severe anxiety (benzodiazepines might be associated with 12 weeks maximum)

Table 25.2 Antidepressant drugs [22, 23]

Drug class Contraindication Common side effects Comments
Selective serotoninergic Association with Nausea Hyponatremia, First choice
reuptake inhibitors other serotoninergic parkinsonism, tremor, Monitor drug-­
drugs (i.e. tramadol) insomnia, serotonin drugs interactions
syndrome
Changes in QT interval
Selective serotonin Association with Hypotension Second choice
noradrenaline other serotoninergic Nausea, vomiting, Monitor drugs-­
(norepinephrine) drugs Anticholinergic effects drugs interaction
reuptake inhibitor for some drugs
(SNRI)
Selective inhibitors of Hypertension, Other Hypertension or Only occasionally
monoamine oxidase A IMO and hypotension, tremor, Need specific diet
antidepressants dry mouth Monitor hepatic
enzymes
Conventional tricyclic Glaucoma, Anticholinergic effects Not a first choice
agents Enlarged prostate Urinary retention Monitor carefully
Heart failure Visual disturbance side effects avoid
Association to tachycardia, when cognitive
monoamine oxidase Constipation, impairments
inhibitors Dry mouth
delusion+++
Sedative effects, etc.
Other antidepressants According to the drug Different types of side Not a first choice
Mianserine, mirtazapine, effects according to the Use with caution in
tianeptine, drug old patients
Agomelatine
372 S. Bonin-Guillaume

The final step in the choice of antidepressant is to provide a sedative or anxiolytic

action of the antidepressant. This often avoids co-prescription of anxiolytics or sed-
atives, the systematic use of which is no longer recommended.
Particular attention must be paid to the monitoring of adverse effects at the
beginning of treatment, which are always likely to discourage a patient if they are
not managed, and clear information must be given to the patient and his or her fam-
ily on the usefulness of the prescription, the time required to respond to the treat-
ment and the expected results, taking into account comorbidities and associated
treatments (possible drug-drug interactions) [19]. Yet, although SSRIs appear to be
safer, they also cause many adverse effects. For example, with SSRIs, there is an
increased risk of gastrointestinal bleeding, especially in combination with antico-
agulants and risk of developing serotonin syndrome if combining with certain opi-
oid analgesics (e.g. tramadol). These potential adverse effects necessitate controls
of ECG and lab tests including blood count, electrolytes, serum creatinine and
transaminases on a regular basis [22]. Finally, many drug interactions must be taken
into account because of the action of SRIs on cytochrome P450.

25.1.1.3 Duration of Treatment

Complete remission should be the goal of antidepressant treatment and should
continue. The risk of recurrence or relapse is mainly due to the premature antide-
pressant discontinuation [24]. The current consensus is to propose a 1-year treat-
ment for a first episode, a 2-year treatment for a second episode and a 3-year
treatment or more from the third episode [10]. If the episode was particularly
severe or if minimal depressive symptoms persist, it is advisable to continue anti-
depressant treatment for a longer period [21]. Treatment discontinuation should be
prepared with a gradual decrease steps over several weeks to avoid withdrawal
effects.

25.1.1.4 Antidepressant Adherence

Poor adherence to antidepressant is common in old depressed patients. In a cohort
study with more than 90,000 veteran antidepressant users, 50% of the prevalent
users discontinued their treatment within 6 months and 61% within 12 months [25].
In a recent population-based study conducted on 27,865 older patients, 26.9% of the
incident antidepressant users were fully adherent as recommended by guidelines
(i.e. duration of treatment and daily doses) [26].
Moreover, compared with non-depressed persons, depressed medical patients
are three times more likely to be non-adherents with other medication regimes or
medical care [27].
Factors of poor adherence to treatment are misperceptions about mental illness
and its treatment, the stigma associated with depression, the lack of family support,
cognitive impairment, adverse events and drug side effects, cost of treatments and
poor physician-patient communication or relationship. The choice of drug is an
important factor influencing compliance. Patients and family education must be
given priority, and a caring enthusiastic attitude from the caring team promotes
compliance [10, 13].
25 Optimizing Pharmacotherapy in Older Patients with Depression or Anxiety 373

25.1.1.5 Antidepressant Resistance

Treatment resistance is defined as failure to respond to two different evidence-based
antidepressant treatments of adequate duration and dosage. Only 50% of elderly
patients respond (generally defined as a 50% decrease in scores on depression
scales) to first-line treatment and less than 40% reach remission (the patient experi-
ences few, if any, symptoms of depression as measured on a depression scale) [10].
If depressive symptoms persist after the second treatment approach, patients
should be referred to a specialist (geriatric psychiatrist), and change of antidepres-
sant or adding a second substance should be considered with a possible improve-
ment up to 50% [22].

25.1.1.6 Antidepressant, Depression and Neurocognitive Disorders

Efficiency of antidepressants for depression in cognitively impaired adults is con-
troversial. Antidepressants are frequently prescribed in subjects with dementia:
from 39% in the general population with dementia [28] to 69% in patients followed
in memory consultations [29]. Yet the use of antidepressants in cognitive impaired
patients is more often related to the control of psychobehavioural symptoms of
dementia than to the treatment of identified depressive disorders.
A clinical trial comparing with three groups (two antidepressants and a pla-
cebo groups) including 326 patients with an Alzheimer’s disease and a depres-
sion status according to the Cornell’s scale [30] showed no superiority of
antidepressants over placebo after 39 weeks of treatment [31]. This has been
confirmed by a recent Cochrane review showing limited efficiency of antidepres-
sants, regardless of the class evaluated, in old subjects with documented demen-
tia and depression [32]. Moreover antidepressants did not affect the ability to
manage daily activities and probably had little or no effect on a test of cognitive
function.
Main limitations of these trials are the short duration of the trials (6–12 weeks),
different depression scales used and small samples included.
Neurocognitive disorders and depression often coexist, from 30 to 50% [33].
One of the difficulties in treating depression in people with dementia is the lack of
reliable diagnostic criteria for depression in this population [12, 34]. Usually, the
diagnosis is based on depression scales. In addition, the depressive symptomatology
changes with the progression of the disease. Finally, apathetic behaviour makes dif-
ferential diagnosis complex, as it can be present in both depression and Alzheimer’s
disease [35]. Antidepressants are not indicated for apathy [36] especially since
some, in particular SSRIs, can induce apathy [37].
Thus, the existence of documented depression in a person with Alzheimer’s dis-
ease justifies antidepressant treatment. However, close monitoring and reassessment
are essential to limit ineffective prolonged treatments that may aggravate psychobe-
havioural disorders of the dementia.

25.1.1.7 Mood Stabilizer

Lithium is the gold-standard treatment for old age bipolar disorders and the most
studied in geriatric samples, although there are few older adults being often excluded
374 S. Bonin-Guillaume

from clinical trials. However, it has shown to be effective both in treating manic
symptoms and in reducing depressive symptoms.
Although there can be adverse effects with lithium, it is generally well tolerated
in older adults. Regular monitoring of renal function and lithium levels
(0.4–0.8 mmol/L) as well as drug-drug interactions (as diuretics, angiotensin-­
converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and
non-steroidal anti-inflammatory drugs (NSAIDs) is necessary to prevent side effects
[38]. Some studies have described a positive effect of continuous lithium treatment
in reducing the risk of neurocognitive disorders in older adults [39].

25.1.2 Non-pharmacological Treatment of Depression

25.1.2.1 Psychological Approach

Psychotherapy is recommended for patients with mild to moderate severity of
depression [10, 20]. Evidence shows that cognitive behavioural therapy (CBT) is
the most widely available structured psychotherapy for depression. A large random-
ized control trial provided robust evidence that CBT given as an adjunct to usual
care that includes antidepressant medication is effective in reducing depressive
symptoms and improving quality of life. The treatment response was maintained at
the 12-month follow-up after the CBT treatment had ended [40].
However, access to this treatment is scarce in old depressed patients, and there is
a lack of trained therapists skilled enough to interact with vulnerable, multimorbid
and/or dependent populations.

25.1.2.2 Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is considered to be the most effective treatment in
severe or treatment-resistant depression in older populations (up to 75% of remis-
sion). For patients who cannot tolerate or respond poorly to medications and who
are at a high risk for drug-induced toxicity or toxic drug interactions, ECT is the
safest treatment option [41].
The principal adverse effects associated with ECT are confusion and memory
loss. Memory impairment is usually transient and undetectable 6 months later. ECT
decreases the risk of relapse when associated with antidepressant.
Clinical predictors of a good response to ECT are age, depression with melan-
cholic features, psychotic depression, a high severity of suicide behaviour and speed
of response. On the other side, the longer the duration of the depressive episode, the
lower the response to ECT [42].
The strong negative attitude towards ECT that still prevails among both profes-
sionals and old patients and caregivers remains the highest limitation to its use [43].

25.1.2.3 Repetitive Transcranial Magnetic Stimulation

During the past 20 years, therapeutic effects of repetitive transcranial magnetic
stimulation (rTMS) have been studied in psychiatric diseases, particularly in the
treatment of depressive disorders with data suggesting its efficiency in the
25 Optimizing Pharmacotherapy in Older Patients with Depression or Anxiety 375

treatment of depression in older patients. The r-TMS is a non-invasive method of

brain stimulation for the treatment of patients with no need of analgesia or induc-
tion seizure.
Literature data globally confirm that rTMS is safe and does not produce cogni-
tive deficits, even among highly vulnerable patients. Poorer responsiveness to rTMS
may be related to several patient factors, including older age and smaller frontal
grey matter volumes [44].
A review comparing ECT and r-TMS concluded that ECT was superior to high-­
frequency rTMS in terms of response (64.4% vs. 48.7%, RR = 1.41, p = 0.03) and
remission (52.9% vs. 33.6%, RR = 1.38, p = 0.006), particularly for psychotic depres-
sion [45]. However, ECI is less tolerated, whereas unilateral right prefrontal -rTMS is
better, and bilateral-rTMS appears to have the most favourable balance between effi-
cacy and acceptability [46].

25.2 Anxiety

The prevalence of anxiety disorders (generalized anxiety disorders, phobic disor-

ders, panic attacks, and obsessive compulsive disorders) decreases with ageing and
is estimated to be 13.5%. However, anxiety is frequently associated with other psy-
chiatric disorders (coexisting with 30% of depressive disorders) or chronic condi-
tions (heart failure, Parkinson’s disease, stroke, diabetes, hyperthyroidism), or drugs
side effect (corticoids, calcium channel blockers) and cognitive impairment [47].

25.2.1 Pharmacological Treatment of Anxiety

Benzodiazepines are the first-line treatment for anxiety attacks episodes but are
overused in older populations. Recent studies showed that 60% of older persons on
benzodiazepines are chronic users (over 5 consecutive months) [28], especially
those living in nursing homes [48] or having neurocognitive disorders [29].
Guidelines recommend that benzodiazepines should not be prescribed for more than
12 weeks for acute anxiety that impacts on daily life, and no more than 4 weeks for
sleep disorders [49]. Principles of benzodiazepines prescription are summarized in
Table 25.3.

Table 25.3 Optimizing benzodiazepines prescription in anxiety disorders (from [21, 50])
1. Check the indication (anxiety/insomnia)
2. Inform patients of the treatment effect and treatment duration
3. Inform patient of the drug side effects
4. Prescribe for a maximum of 12 weeks for anxiety including the withdrawal
5. Ensure patient understanding and compliance to the treatment
6. Start with a low dose and keep the lowest dose
7. Choose a short-lasting effect product
8. In case of a long users, propose a step-by-step withdrawal in a specific consultation
376 S. Bonin-Guillaume

It is well known that benzodiazepine has numerous side effects, injurious falls,
fractures, drowsiness, delirium and agitation [50]. Recently, several pharmacologi-
cal studies demonstrated an association between BZD users and the risk of develop-
ing neurocognitive disorders, particularly for chronic users (over 6 months) and for
long-acting BZD users [51]. This risk decreases, but several months after, benzodi-
azepines withdrawal [52].
To avoid benzodiazepine prescription, some non-benzodiazepine drugs may be
used to treat anxiety. They are considered to have fewer side effects because of dif-
ferent pharmacological action. However, no clinical trials have been conducted in old
populations. Buspirone and etifoxine are not commonly used in this population.
Hydroxyzine is more often prescribed for agitation and/or anxiety in older patients.
However, because of a high anticholinergic score and the risk of a QT lengthening
[53], the use of this drug is no more recommended for patients aged 75 years and over.
Benzodiazepine reduction in older patients is effective even in general practice
with low risk of withdrawal symptoms [54]. This should be attempted in chronic
users during a dedicated consultation with a progressive reduction regimen [49].

25.2.2 Non-pharmacological Treatment of Anxiety

Non-pharmacological treatment should be the first line for anxiety disorders

management.
However, there are very few studies showing psychological approach efficiency
in anxiety disorders in older adults. Most studies have tested cognitive behavioural
therapies showing that CBT has more helpful than having no treatment for GAD in
later life. Nevertheless, whether CBT shows long-term durability, or is superior to
other commonly available treatments (such as supportive psychotherapy), remains
to be tested [55]. Psychological interventions cognitive behavioural therapy and
mindfulness showed better benefit in the presence of co-occurring anxiety and
mood disorders in older adults, but with moderate effect sizes and few information
about follow-up [56].

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Nutritional Deficiency and Malnutrition
26
Eva Kiesswetter and Cornel C. Sieber

26.1 Introduction

A balanced nutrition providing sufficient energy and nutrients is considered an

important factor contributing to health and well-being throughout life. However,
with older age, several physiological, disease-related, functional, mental, and social
changes occur making older people more prone to nutritional deficiencies and mal-
nutrition (Box 26.1).

Box 26.1 Definitions of nutritional deficiency and malnutrition

Nutritional deficiencies occur due to an imbalance between energy or nutri-
ent needs and actual intake (needs > intake). This can be due to increased
needs, reduced absorption, and/or reduced intake.
Malnutrition is defined as “a state of energy, protein or nutrient deficiency
which produces a measurable change in body function, and is associated with
a worse outcome from illness as well as being specifically reversible by nutri-
tional support” [1]. This chapter mainly refers to energy-protein malnutrition.

E. Kiesswetter (*)
Institute for Biomedicine of Aging, Friedrich-Alexander-Universität Erlangen Nürnberg,
Nürnberg, Germany
e-mail: [email protected]
C. C. Sieber
Institute for Biomedicine of Aging, Friedrich-Alexander-Universität Erlangen Nürnberg,
Nürnberg, Germany
Department of Medicine, Kantonsspital Winterthur, Winterthur, Switzerland
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 381

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_26
382 E. Kiesswetter and C. C. Sieber

In particular, in older people in need of care, with insufficient social support, or

with acute medical conditions obtaining an adequate diet is challenging, and insuf-
ficient intakes of energy and nutrients are frequently reported [2, 3]. Energy needs
are usually reduced in older adults due to changes in body composition and reduced
physical activity levels, while nutrient requirements do not decline accordingly
making a more nutrient-dense diet necessary [4]. Studies in older adults demon-
strate that nutrients such as protein, fiber, vitamin D, B1, B2, B12, folate, calcium,
magnesium, and selenium become deficient more readily due to low intakes or sub-
optimal levels in the body [5–7]. Compared to community-dwelling older adults,
older hospitalized patients and nursing home residents experience low intakes of
energy and nutrients more frequently [3, 8]. This likely can be attributed to impaired
health and function in these populations but also situational or structural aspects
related to the settings.
In a recently published meta-analysis of 240 studies which included 113,967
older adults, the prevalence of malnutrition according to the Mini Nutritional
Assessment (MNA) was 3% in community-dwelling older adults, 6% in older out-
patients, 9% in older adults receiving home care, 18% in nursing home residents,
22% in geriatric inpatients, and 29% in geriatric rehabilitation inpatients [9].
Furthermore, in all settings, high proportions of older persons were identified as
being at nutritional risk (27%–55%) [9]. Based on these data, it can be summarized
that malnutrition prevalence increases in groups with deteriorated health and func-
tional status. However, based on sampling strategies and diagnostic criteria, differ-
ences in prevalence need to be considered.
If nutritional deficiencies and malnutrition are left untreated, numerous negative
clinical consequences are more likely, including increased rates of infections and
pressure ulcers, longer hospital stays, increased in-hospital complications, increased
duration of convalescence after acute illness, and increased all-cause mortality [10–
12]. In addition, malnutrition is linked to the common geriatric syndromes of frailty
and sarcopenia [13, 14], mainly due to the malnutrition-associated loss of muscle
mass and is a risk factor for functional impairment [15, 16] and reduced quality of
life [17]. Consequently, malnutrition poses a major burden for the individual and
healthcare systems [11].

26.2 Causes of Malnutrition in Older People

At younger ages, the origin of nutritional deficiency and malnutrition is mainly

disease-related, while in older people, the causes are commonly multifactorial
(Fig. 26.1). Potential causes are:

• Age-related physiological changes (e.g., chemosensory decline, changes in the

regulation of hunger and satiety (anorexia of aging))
• Disease-related factors (e.g., dysphagia, multimorbidity, adverse effects of medi-
cation, polypharmacy)
• Psychological factors (e.g., depression, impaired cognition, anxiety)
26 Nutritional Deficiency and Malnutrition 383

Fig. 26.1 The DoMAP schematic model illustrating the various factors contributing to malnutri-
tion in older people. Level 1 in dark green represents the core etiological mechanisms that lead to
malnutrition. Level 2 in light green consists of the factors that lead directly to one or more of the
core etiological mechanisms that cause malnutrition. Level 3 in yellow lists the various common
conditions that indirectly contribute to malnutrition [18]

• Functional aspects (e.g., oral function, loss of dentition, mobility limitations,

eating dependency)
• Socioeconomic factors (e.g., poverty, missing social support)
• Lifestyle factors

Even though there is broad consensus by experts on the multiple causes of mal-
nutrition in older adults, evidence for many of these determinants is low or conflict-
ing [19, 20]. This is mainly due to a different operationalization of determinants and
malnutrition among studies, inappropriate confounder control, and lack of longitu-
dinal or randomized trials.

26.3 Screening of Malnutrition

Screening is regarded as a first step in identifying persons at risk of malnutrition

or with overt malnutrition. It is recommended to routinely screen older people
for their malnutrition risk independent of diagnoses and the presence of over-
weight and obesity using a validated screening tool [21]. In institutional care
384 E. Kiesswetter and C. C. Sieber

settings, screening should be conducted at admission and afterward at regular

intervals. In the long-­term care setting, intervals of 3 months are recommended,
while in the acute care setting, much shorter intervals between screenings are
necessary. In the outpatient setting, malnutrition screening in older persons
should be conducted by general practitioners or ambulatory nursing staff at least
once a year.
For screening purposes, standardized short questionnaires are commonly used
focusing on the following core aspects:

• Current nutritional status (usually assessed by body mass index)

• Prehistory (usually assessed by enquiring about unintentional weight loss within
the past 3 months)
• Further development of nutritional status (assessed by acute stress/diseases and/
or reduced dietary intake as both aspects can be reasons for not meeting the
energy requirements and consequently for future weight loss)

The European Society for Clinical Nutrition and Metabolism (ESPEN) recom-
mends the Mini Nutritional Assessment (MNA) as screening tool for malnutrition
in older people [22] as the MNA was specifically developed for older people and
can be used in the outpatient and institutional settings [23]. Its short form has six
items comprising the core aspects of reduced food intake, weight loss, acute
stress, and BMI. In addition, there are questions on mobility limitations and neu-
ropsychological problems—two important risk factors for malnutrition in older
people. A further feature is the option to exchange the BMI item with calf circum-
ference if BMI assessment is not possible, e.g., due to immobility. According to a
sum score ranging from 0 to 14 points, patients are categorized as well-nourished
(12–14 points), at risk of malnutrition (8–11 points), or malnourished (<7
points) [24].
A screening alternative in the hospital setting is the Nutritional Risk Screening
tool (NRS) [25], specifically developed for the acute care setting and which can
be used also in younger patients. The NRS is designed to identify patients who
might benefit from nutrition interventions. It is composed of a prescreening with
four questions on the core aspects low BMI, recent weight loss, reduced dietary
intake, and severe disease. In case of a positive prescreening, the above core ele-
ments are quantified during the main screening. The age of patients (≥70 years) is
considered as a further risk factor. Three or more points on the NRS indicate
nutritional risk.
There are several other screening tools available that are less often used in clinical
practice. In a systematic review on the validity of malnutrition screening instruments
in older people, 34 different tools that have been used in older people were identified,
of which 23 were specifically developed for this age group [26]. The usage of a spe-
cific tool often depends on the health policies and guidelines of the respective
countries.
26 Nutritional Deficiency and Malnutrition 385

26.4 Assessment of Nutritional Status

Following a positive screening result, the nutritional status of an older person needs
to be further assessed to form the basis for targeted interventions aiming to improve
nutritional status, the overall clinical course of the presenting illness, and the quality
of life [21].

26.4.1 Diagnosis of Malnutrition

Both, in research and clinical practice, different criteria and cutoff values are used
for the diagnosis of malnutrition. To align the diagnosis of malnutrition, a coalition
of several international medical nutrition societies mostly from Europe, the USA,
and Asia—the so-called Global Leadership Initiative on Malnutrition (GLIM)—
compiled consensus-based criteria for malnutrition [27]. The concept proposes that
after a positive screening, the phenotypic criteria “unintentional weight loss,” “low
BMI,” and “low muscle mass” as well as the etiologic criteria “reduced food intake
or assimilation” and “inflammation” should be assessed (Table 26.1). If at least one
phenotypic and one etiological criterion apply, malnutrition can be assumed. The
severity of malnutrition can be further evaluated based on the expression of the
phenotypic criteria [27].
In clinical trials, muscle mass or lean body mass and fat-free mass as its proxies
are usually assessed by bioelectrical impedance analysis (BIA) or dual-energy

Table 26.1 Phenotypic and etiological criteria to diagnose malnutrition (based on Global
Leadership Initiative [27])
Phenotypic criteria
Weight loss >5% within past 6 months
or
>10% beyond 6 months
Low body mass index <20 kg/m2, if <70 years
or
<22 kg/m2, if ≥70 years
Reduced muscle mass Depends on the measuring technique,
e.g., BIA: FFMI <17 (m), <15 (f) kg/m2,
BIA, DXA: ASMI <7 (m), <6 (f) kg/m2
Etiologic criteria
Reduced food intake or ≤50% of energy needs >1 week
assimilation or
any reduction for >2 weeks
or
any chronic gastrointestinal condition adversely affecting food
assimilation or absorption, e.g., short bowel syndrome or chronic
diarrhea
Inflammation Acute disease/injury, e.g., infections, burns, trauma
Chronic diseases, e.g., cancer, chronic obstructive pulmonary disease
BIA Bio-electrical impedance analysis, DXA Dual-energy X-ray absorptiometry, FFMI Fat free
mass index, ASMI Appendicular skeletal muscle mass index, m male, f female
386 E. Kiesswetter and C. C. Sieber

X-ray absorptiometry (DXA). As these methods are often not available in routine
clinical practice or are too expensive, calf circumference is often used as an indica-
tor of muscle mass (cutoff <31 cm for both sexes).

26.4.2 Quantification of Energy and Nutrient Deficiency

By quantifying the nutritional deficits, the necessity for and the amount of nutri-
tional interventions can be determined. The fundamental metrics for the determina-
tion are the individual’s energy and protein intake and the corresponding
requirements.
As in routine clinical practice, measurement of energy requirements is usually
not possible, formulae to estimate resting energy expenditure, e.g., by Mueller [28]
or Harris-and Benedict [29], are used. For this purpose, details of age, sex, and body
weight are needed. In combination with the physical activity level (PAL), total
energy expenditure can be calculated. A PAL between 1.2 and 1.3 represents a low
energy expenditure in frail, immobile, or bedridden older people. For older people,
a guiding value for energy intake of 30 kcal/kg body weight (BW)/day is proposed,
which needs to be adjusted according to nutritional status, physical activity level,
disease status, and tolerance [21].
Protein requirements of older people are currently the subject of the much scientific
debate, and reference values differ by country. While the European Food Safety
Authority recommends an intake of 0.8 g/kg BW/day for young and older adults [30],
expert groups suggest a higher optimal protein intake in older people to prevent decline
in muscle mass (1–1.2 g/kg BW/day) [31]. Higher amounts might be needed to com-
pensate for increased metabolic demands due to inflammation, sepsis, or wounds.
Intake can be assessed by dietary records of at least 3 days, where all consumed
foods and their quantities are described in detail. An approximate measure of the
amount eaten is plate diagrams where the intake is estimated by quarters of the
offered amount [nothing, ¼, ½, ¾, all].

26.4.3 Identification of Potential Causes of Malnutrition

The elimination of causes of malnutrition is an important element of nutritional

therapy. Therefore, potential causes should be systematically clarified within the
assessment, e.g., during interviews with older people and, if necessary, supported by
interviewing relatives or care persons of the older person. Summary lists of possible
causes can give guidance. An example is the so-called DoMap, a theoretical model
on determinants of malnutrition in aged persons, which was developed by experts in
the field of geriatric nutrition based on a Delphi validation process [18]. The DoMap
displays beside the central etiologic mechanisms of malnutrition, factors directly or
indirectly affecting these mechanisms (Fig. 26.1).
26 Nutritional Deficiency and Malnutrition 387

26.5 Nutritional Therapy

Based on the nutritional assessment, realistic and individualized goals for nutri-
tional therapy need to be established, considering potential risks, contraindications,
benefits as well as resources, needs, and preferences of the older patient. Nutritional
interventions generally incorporate the following options:

• Nutritional counseling by a dietitian (provision individualized recommendations

to optimize dietary intake)
• Food modification, e.g., by texture modification, energy-dense meals, energy and
nutrient (e.g., protein) fortification, additional snacks, or finger food
• Oral nutritional supplements (usually provided if oral intake is insufficient;
availability of different products, e.g., low volume or protein-rich)
• Tube feeding (used if oral nutrition is impossible or insufficient for >3 days, hav-
ing a good overall prognosis for recovery to a degree that allows resumption of
sufficient nutritional intake)
• Parenteral feeding (used if oral and enteral nutrition are impossible/insufficient
for >3 days, having an overall good prognosis for recovery to a degree that allows
resumption of sufficient nutritional intake)

For tube feeding (and parenteral nutrition), end-of-life situations or severe

dementia are considered contraindications [21].
Nutritional care goes far beyond simple nutritional interventions, also covering
nursing support (e.g., mealtime assistance (verbal prompting or eating support),
provision of adequate tools like ergonomic cutlery), the adaption of environmental
factors (e.g., avoiding disturbances during mealtimes, pleasant meal ambience), and
the treatment of underlying causes [21].
In clinical practice, combinations of different intervention strategies are often
needed. Consequently, multidisciplinary contributions of dietitians, nursing and
kitchen staff, medical doctors, and therapists (speech, occupational, physio) are
vitally important factors for successful nutrition interventions [21]. Detailed
evidence-­based recommendations for clinical nutrition and hydration in geriatrics
can be found in the ESPEN guidelines [21].

26.6 Conclusions

Nutritional deficiency and malnutrition are common in older people in all care set-
tings and are commonly multifactorial. Early detection by a routine screening, a
thorough comprehensive nutritional assessment, and an individualized and multi-
disciplinary therapy regimen can improve nutritional status, related clinical out-
comes, and overall prognosis in older people with malnutrition.
388 E. Kiesswetter and C. C. Sieber

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Pharmacotherapy of Insomnia in Older
Adults 27
Mirko Petrovic

27.1 Insomnia as the Most Common Sleep Disorder

Separately from age-related changes, sleep problems affect 10–15% of the general
population and increase with older age as well [1, 2]. Sleep disturbances include
insomnia, as the most common sleep disorder and therefore the most researched
one, dyssomnia (restless legs, periodic limb movement, sleep apnoea, narcolepsy)
and parasomnia (REM sleep behaviour disorder, night terrors, sleepwalking).
Insomnia is often identified as the subjective complaint of problems with initiating
or maintaining sleep, or non-restorative sleep, causing significant daytime symp-
toms such as concentration problems and mood disturbances. The overall preva-
lence of insomnia symptoms ranges from 30% to 48% among older adults [3–6],
while the prevalence of insomnia disorder ranges from 12% to 20% [7]. Insomnia is
usually categorised by the predominant symptom of either difficulty in sleep onset
or sleep maintenance. Sleep maintenance symptoms are most prevalent among
adults complaining of insomnia (50–70%), followed by difficulty in initiating sleep
(35–60%) and non-restorative sleep (20–25%). An incidence rate for insomnia
symptoms of 5% per year, with a yearly incidence of 8% at 1-year follow-up, has
been observed among older adults [8, 9].

27.2 Treatment

Treatment options for insomnia can be categorised into non-pharmacological, fore-

most cognitive behavioural therapy, and pharmacological options [3, 10–12]. There
is large evidence to support the effectiveness and sustainability of non-­pharmacologic

M. Petrovic (*)
Section of Geriatrics, Department of Internal Medicine and Paediatrics, Ghent University,
Ghent, Belgium
e-mail: [email protected]

© Springer Nature Switzerland AG 2023 391

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_27
392 M. Petrovic

interventions for insomnia in adults of all ages. For the purpose of this chapter,
however, only the pharmacological options have been discussed here in detail.

27.3 Pharmacological Treatment

Pharmacological treatments are principally categorised as benzodiazepines (BZDs)

and non-benzodiazepine receptor agonists (so-called Z-drugs), as the most com-
monly used drug classes and alternatives including antidepressants, melatonin
receptor agonists and orexin receptor antagonists. Recently published clinical prac-
tice guidelines of the American Academy of Sleep Medicine for the pharmacologi-
cal treatment of chronic insomnia represent an evidence-based review of each class
of drug commonly used in the treatment of insomnia [13].

27.4 Benzodiazepines and Non-benzodiazepine

Receptor Agonists

BZDs and Z-drugs are the most commonly used symptomatic treatment for insom-
nia. The term benzodiazepine has been related to the portion of the structure com-
posed of a benzene ring fused to a seven-membered diazepine ring. Since almost all
BZDs contain a 5-aryl substituent and a 1,4 diazepine ring, the term actually denotes
the 5-aryl-1,4-benzodiazepines. Although variations in the structure of the ring sys-
tems yield different chemical compounds, pharmacological activity remains similar
[29, 30]. Three non-benzodiazepine receptor agonists are now available: zaleplon (a
pyrazolopyrimidine), zolpidem (an imidazopyridine) and zopiclone (a cyclopyrro-
lone). Although termed non-BZD, Z-drugs interact with BZD receptors [14–16].
Almost all the effects of the BZDs result from actions on the central nervous
system (CNS).
Molecular targets for BZD actions in the CNS are inhibitory neurotransmitter
receptors directly activated by the amino acid gamma-aminobutyric acid (GABA)
[14, 15].
Two central BZD receptor subtypes (BZ1, and BZ2,) and one peripheral BZD
receptor have been categorised. BZ1, (also called omega 1) receptors are located in
the cerebellum. Hypnosedative and anxiolytic actions are mediated mainly through
the BZ1 receptor subtype. BZ2, (omega 2) receptors, on the other hand, are located
predominantly in the spinal cord and striatum. These receptors may be involved in
mediating the muscle relaxant actions of BZDs [17]. Most BZDs interact non-­
selectively with both receptor subtypes, which result in a variety of inhibitory cen-
tral nervous system effects [18]. The peripheral BZD receptor is located in the
kidney. Its role in anxiolytic and hypnosedative actions remains unclear [17].
There are obvious differences in potency between different BZDs. The equiva-
lent dose may differ as much as 20-fold [19, 20]. We should keep this in mind when
substituting one BZD by another. These differences in potency relate to differences
in affinity for various receptor subtypes.
27 Pharmacotherapy of Insomnia in Older Adults 393

Almost all of the BZDs are completely absorbed; some of them reach the sys-
temic circulation only in the form of active metabolites. As a result, three categories
BZDs are identified based on the elimination half-lives (t1/2): short-acting agents (t1/2
2–5 h), intermediate acting agents (t1/2 6–24 h) and long-acting agents (t1/2 more than
24 h) [15].
The BZDs and their metabolites have a high affinity for binding to plasma pro-
teins. The degree of binding correlates with lipid solubility and varies from 70 to 99
%. Most BZDs have a large volume of distribution due to their high lipid solubility.
The concentration in cerebrospinal fluid is practically the same as the concentration
of free drug in plasma [21].
BZDs are metabolised in the liver primarily by oxidation, nitroreduction and
glucuronidation [15, 22]. Most of them can be classified as low clearance drugs.
Alterations in BZD pharmacokinetics have been observed in older adults. A pro-
longation of the half-life of the oxidised drugs has been reported in this age group,
but the clearance or half-life of the glucuronised drugs is less affected. Consequently,
the BZDs metabolised by oxidation (e.g. flurazepam and diazepam) should not be
prescribed to older adults, since higher plasma concentrations for a given drug dos-
age and consequently enhanced clinical effects are expected [21, 23].
Other significant and often seen age-related changes that may alter BZD metabo-
lism include decreased liver blood flow, plasma albumin and lean body mass.
Reduced hepatic blood flow can change the plasma concentration-time profile and
increase peak concentrations. Decrease in plasma albumin levels may affect protein-­
binding capacity as well. Distribution volume may increase as a consequence of
decreased lean body mass and increased proportion of fat. This results in an
increased elimination half-time, prolonged effects after administration and accumu-
lation of active metabolites [24, 25].
Changes in pharmacodynamics may also occur, as a result of altered affinity of
the receptors, which implies a greater effect for a given plasma concentration. Older
adults are more vulnerable to the effects of BZDs on cognitive function, especially
at higher dosages. Different researchers report that older adults require both a lower
dose and a lower plasma concentration to cause a constant level of sedation [26, 27].
Memory loss, altered balance and high risk of falls and fractures have been reported
after short-term administration of BZDs [28, 29].

27.5 Clinical Effects of BZDs

All BZDs are characterised by, in somewhat altering degrees, five major effects:
hypnosedative, anxiolytic, anticonvulsant, muscular relaxant and amnesic. In the
short term, BZDs may be used safely in certain clinical conditions. With long-term
use, tolerance, dependence and withdrawal effects may become major drawbacks
[30, 31].
As to hypnotic effects, BZDs accelerate sleep onset, decrease nocturnal arousals
and increase total sleep time [23]. However, they change the normal sleep pattern:
light sleep is prolonged, while the duration of restorative slow wave sleep and rapid
394 M. Petrovic

eye movement sleep is reduced. The onset of the first rapid eye movement sleep
episode may be delayed [20]. Although some long-term users of BZDs are self-­
assured that sleep quality and duration are bettered as a result of the treatment, the
findings of polysomnographic studies illustrate that the sleep pattern remains clearly
different from normal sleep [32]. The aberrant sleep profile possibly results from
unselective depression of both arousal and sleep mechanisms in the brainstem
[33, 34].
Anxiolytic effects are induced by doses that cause minimal sedation, although the
hypnotic, muscular relaxant and amnesic actions may all provide relief of associ-
ated tension and insomnia [35]. The effect on anxiety is presumably related to sup-
pressive activity in limbic and other brain areas involved in the development of
anxiety. The principal clinical characteristic of BZDs prescribed for anxiety is the
rapid onset of action, usually noticeable after a single dose. BZDs provide only
symptomatic treatment for anxiety. However, they might be indicated in the initial
management of distressing anxiety while awaiting enduring clinical effects from
more specific non-pharmacological treatments [17].
As to anticonvulsant effects, BZDs are effective in the treatment of status epilep-
ticus and convulsions due to drug poisoning and, however, can only be used in
emergency situations and are not indicated for the long-term treatment of epilepsy
because of the development of tolerance in the majority of patients [36, 37].
Muscular relaxant effects of BZDs can sometimes be used in case of different
motor disorders (i.e. dystonias and involuntary movements, myoclonus, restless
limbs syndrome and muscle spasm associated with pain) [38].
As to amnesic effects, BZDs also cause dose-related anterograde amnesia. These
amnesic effects may be clinically significant, particularly in older adults and in
those with coexisting medical problems [23, 39].

27.6 Susceptibility of Older Adults to BZDs

Older adults in particular are vulnerable to adverse effects of BZDs. These patients
are more sensitive to CNS depression, states of confusion and ataxia that can result
in falls and fractures [29, 40]. They are also prone to respiratory depression,
decreased ventilatory response, hypercapnia and increased hypopnoeic episodes
during sleep [40].

27.7 Side Effects of BZDs

In addition to tolerance to the hypnotic and anxiolytic effects, ageing increases the
susceptibility to the side effects of BZDs. The atrophy of neurons and the increased
sensitivity of the CNS, together with pharmacokinetic changes, which lead to BZD/
Z-drug accumulation, increase the possibility of confusion and CNS side effects,
hangover effects and subsequent risk of falling [41–43]. Often falls have no major
consequences, but in frail older adults, they can cause injuries and fractures, leading
27 Pharmacotherapy of Insomnia in Older Adults 395

to hospitalisation and serious disability [44]. It has been questioned whether there is
an independent association between BZD/Z-drug use and increased fall risk. Not
only have falls a multifactorial aetiology but other psychotropic drugs are also asso-
ciated with a 30–70% increased risk of falls [45–47].
Even though BZDs at first induce and prolong sleep, tolerance develops shortly.
Sleep latency and duration regress to pre-treatment levels after a few weeks of con-
tinued treatment. Sleep quality, on the other hand, does not improve, since deep
NREM sleep and REM sleep stages are partially replaced by stage 2 light NREM
sleep [23, 48]. Tolerance to the anxiolytic properties of BZDs develops more gradu-
ally than to the hypnotic effects.
Rebound insomnia refers to an increase in the initial symptom beyond the base
level after withdrawal from BZDs. Population surveys and results from large treat-
ment effectiveness studies show rebound insomnia in 14–20% of patients treated
with BZDs, a rate indistinguishable from that seen with over-the-counter drugs or
placebo [49].

27.8 Rationale for Prescribing BZDs

If cognitive-behavioural therapy alone is not sufficient in alleviating insomnia,

beginning of pharmacotherapy might be considered. The decision should be based
on the severity of symptoms and on the patient’s quality of life [50]. BZDs in low
doses for 1 or 2 weeks only may be indicated for short-term insomnia due to tempo-
rary stress. Treatment of chronic insomnia secondary to physical, psychological or
psychiatric conditions with hypnotics is rarely indicated [23].
Before choosing a hypnotic agent, the types of sleep problems reported by the
patient should be taken into consideration and matched to the properties of different
available medications. An ideal hypnotic agent should have a rapid onset of action,
a duration of action that lasts through the night with no residual and no adverse
effects [51]. The most worrying side effects of BZDs in older adults are residual
sedation, psychomotor impairment and cognitive impairment, all of which revoke
any benefit from obtaining a better night sleep [50]. Another concern with older
patients using BZDs is the effect of respiratory depressants on sleep apnoea [52]
and the risk of nocturnal falls [29].
BZDs and Z-drugs are effective for short-term treatment of insomnia [53].
Systematic reviews showed that time to fall asleep is decreased and total sleep dura-
tion enhanced [54–57]. Polysomnographic research showed also a changed sleep
structure, with an increase in NREM, a decrease in deep sleep (SWS) and a pro-
longed REM latency. A meta-analysis in older adults with insomnia [58] showed an
improvement in sleep quality, an increased total sleep time (mean 25 min) and a
decreased number of night-time awakenings when using BZDs and/or Z-drugs
compared to placebo. Although the effect sizes are statistically significant, their
extent is small. Moreover, a meta-analysis indicated that the polysomnographic
findings show small improvement in sleep latency and sleep duration, while the
patient’s reported subjective sleep latency (assessed with sleep diaries or
396 M. Petrovic

questionnaires) was more optimistic [55]. This indicates that there may be an over-
estimation of the BZD’s effects on sleep outcome parameters. Moreover, the selec-
tive reporting and publishing of positive studies and results also indicate that there
is an overestimation favouring the BZD/Z-drugs’ effects [56, 59]. In addition to the
possible overestimation of the BZD/Z-drug’s effects, several meta-analyses showed
that placebo treatment also improves the sleep significantly [60, 61]. Because
BZDs/Z-drugs are not free of side effects, the overall risk/benefit balance must be
taken into account. Moreover, all these studies investigated the effect of a short-term
treatment. The maximum study duration for BZDs is 8 weeks [62], and for Z-drugs,
it is 1 year [63, 64]. Although the majority of BZD/Z-drug users are chronic users,
research on long-term BZD or Z-drug use is lacking.
So far, there is a lack of a sound evidence base for the long-term efficacy of
BZD/Z-drug use. Because of practical barriers but also because the fact that long-­
term BZD/Z therapy is not concordant with the guidelines, it is difficult to initiate
randomised controlled trials with incident users and follow the sleep longitudinal.
The studies that tried to evaluate long-term effectiveness found a worse sleep qual-
ity in long-term users [65–67]. After taking into consideration both the short-term
and long-term risks of BZD/Z-drug use, and in the light of questionable effect of
these drugs on insomnia in the long term, guidelines discourage chronic BZD/Z-­-
drug use.

27.9 Guidance for Withdrawal

This age group, with a higher risk of abovementioned side effects, needs tailored
prescribing which also includes deprescribing [68]. Discontinuation of BZDs/Z-­
drugs is widely advised but has not reached global acceptance among prescribers,
caregivers and patients.
There is a general agreement on the notion that most patients who take BZDs
regularly should try and discontinue treatment [69, 70]. Many patients who have
taken BZDs for years can have these drugs withdrawn successfully. Men under the
age of 50 without personality disturbance show particularly good response after
withdrawal from BZDs. On the contrary, older women with anxious symptoms and
personality disturbance respond less successfully to withdrawing [71].
The factors presumed to affect withdrawal are personality profile, dose and half-­
life of BZDs, duration of treatment and mode of withdrawal [71, 72]. On the con-
trary, there are reports suggesting that with the exception of age, withdrawal
outcome is not related to any particular variable [72].
Withdrawal symptoms, if any, occur most often after 3 months of habitual use.
They may include anxiety, restlessness, sleep disturbance, headache, muscle
cramps, nausea, delirium or convulsions.
The treatment of BZD withdrawal symptoms includes appropriate psychological
support together with a gradual dosage tapering. The level of psychological support
may range from simple encouragement to anxiety management or behavioural ther-
apy. Chronic insomnia can be effectively treated in older subjects with structured
27 Pharmacotherapy of Insomnia in Older Adults 397

and sleep-focused interventions designed to change poor sleep habits [73]. In most
of the cases, sleep symptoms progressively improve after withdrawal. It has been
demonstrated that older adults tolerate withdrawal as well as if not better than young
individuals [74].
There are no unanimous recommendations in the literature with regard to the
optimal duration of the withdrawal process. Therefore, a variable withdrawal period
ranging from 2 to 12 weeks may be allowed. The size of the stepwise lowering in
dosage that should be applied is arguable as well. Some researchers propose a fixed
tapering schedule, while others claim that the reduction rate should be titrated
against the patient’s withdrawal symptoms [75].
In a systematic review of interventions to deprescribe BZDs among older adults,
seven studies of benzodiazepines and Z-drug withdrawal were identified.
Benzodiazepine discontinuation rates were 64.3% in one study that applied pharma-
cological substitution with melatonin and 65.0% in a study that applied general
practitioner-targeted intervention. Mixed interventions including patient education
and tapering (n = 2), pharmacological substitution with psychological support
(n = 1) and tapering with psychological support (n = 1) yielded discontinuation rates
between 27.0 and 80.0%. Five studies measured clinical outcomes following benzo-
diazepine discontinuation. Most of the studies (n = 4) observed no difference in
prevalence of withdrawal symptoms or sleep quality, while one study reported
decline in quality of life in those who continued taking benzodiazepine vs. those
who discontinued over 8 months [76].
Most older BZD/Z users for the indication insomnia are low-dose users. Although
there is not much research done on which BZD/Z-drug is more resistant to with-
drawal, generally, short-acting BZD/Z-drugs are more likely to cause withdrawal
symptoms upon discontinuation than long-acting BZDs. Therefore, substitution
with a long-acting BZD (diazepam) can lessen (and delay) withdrawal symptoms
[77]. However, it is not appropriate to use long-acting BZDs/Z-drugs in older adults
(in concordance with all explicit criteria). The long half-life can result in accumula-
tion. Therefore, substitution with an intermediate working BZD/Z-drug (lorazepam/
lormetazepam) or simply stay with the same product when discontinuing is advised.
Psychological interventions which support withdrawal, such as cognitive behav-
ioural therapy (CBT), have shown to be effective, also in older adults [78, 79].
These psychological techniques are intended to facilitate withdrawal and motivate
patients to maintain abstinent over time (relapse prevention).
A meta-analysis focusing on older adults showed that the best strategy for dis-
continuing BZDs/Z-drugs in older adults residing in the nursing home setting was
the combination of supervised withdrawal with psychotherapy [80]. Supervising the
withdrawal in a setting with supporting care personnel is possible, but delivering
psychotherapy seems more difficult to implement. A promising strategy for reduc-
ing BZDs/Z-drugs in the nursing home setting was the implementation of a pharma-
cist medication review [81, 82]. Often, the pharmacists gave recommendations or
feedback to the nursing staff and delivered “an educational message”. Also, a pro-
gramme led by a psychologist which educated prescribers and caregivers, offered
health education and relaxation training to the residents, reduced the overall
398 M. Petrovic

prevalence of BZD/Z-drug use (from 70% to 35%) in this setting [83]. The educa-
tional tools used in long-term care facilities varied from prescribing algorithms and
bulletins to staff meetings and lectures [84]. However, educational interventions
alone cannot be expected to change behaviour when healthcare providers do not
perceive it to be important, or when the change is complex and dependent on the
interaction of too many stakeholders.
Several studies have investigated BZD/Z-drug withdrawal in the nursing home
setting and focused on the success rate (focus on residents already willing to discon-
tinue) [83, 85, 86]. However, health policy-makers should have an idea of the extent
of the target population and the overall feasibility, including the willingness towards
discontinuation in this setting. Therefore, general practitioner, nurse and, more
importantly, the patient have to be susceptible towards change. Moreover, a lack of
knowledge on non-pharmacological treatments and a lack of their availability and/
or time to administer make it difficult for health providers to offer alternatives when
withdrawal or rebound symptoms emerge. Some studies show that patients are sus-
ceptible towards change. Therefore, it is advised to routinely raise the issue of dis-
continuation and negotiate dose reduction [87, 88]. Current evidence shows that
benzodiazepine withdrawal is feasible in older population, but withdrawal rates
vary according to the type of intervention. As the benefits and sustainability of these
interventions are unclear, further studies should be conducted to assess this.

27.10 Alternatives to BZDs

There are several pharmacotherapeutic alternatives that are used as alternative for
BZDs including antidepressants, melatonin receptor agonists and orexin receptor
antagonists. Different antidepressants, including trazodone, tricyclic antidepres-
sants (doxepin) and serotonergic antidepressant (mirtazapine), have sedating prop-
erties and are often used for the treatment of insomnia [3].
However, despite the fact that these alternatives have been shown to be more
effective than placebo at bettering short-term sleep outcomes, the size of effect is
variable; most trials have been industry sponsored, posing questions about publica-
tion bias, and the overall estimation of risk-to-benefit ratio is low [13]. The potential
benefits of pharmacotherapy on sleep quality and daytime function should always be
balanced against the risk of side effects and physical and psychological dependence
with long-term use.Trazodone is often prescribed for insomnia in doses of 25–100 mg.
A study on trazodone comparing its effect with zolpidem in 21- to 65-year-olds
showed a similar efficacy for sleep latency and sleep efficiency; however, both effects
decrease after the first week [89]. Adverse effects such as cardiac arrhythmias, ortho-
static hypotension, dizziness and potential priapism are well documented and can be
important in older population [90]. There is lack of evidence about pharmacotherapy
of sleep disorders in older adults with dementia. Several small trials showed certain
beneficial effects on sleep outcomes from trazodone, although larger trials are needed
to allow more sound conclusions. Systematic assessment of adverse effects in future
studies is essential [91]. However, clinical practice guidelines from the American
27 Pharmacotherapy of Insomnia in Older Adults 399

Academy of Sleep Medicine suggest that trazodone should not be used for treatment
of insomnia because its harms prevail over its benefits [13].
Doxepin is the only antidepressant approved by the Food and Drug Administration
(FDA) for insomnia at doses of 3–6 mg. Studies of adults aged 65 years and older
have shown, based on patient reports, that doxepin in doses of 1 mg and 3 mg,
respectively, improved measures of sleep onset, sleep duration, sleep quality and
global treatment outcomes over the 12-week study period [92].
Mirtazapine, a serotonergic antidepressant, might also improve insomnia. In a
study of adults with mean age of 40.9 years, the mirtazapine group showed improve-
ment in sleep latency, sleep efficiency and awakenings after sleep onset after
2 weeks of treatment. However, because of conflicting evidence and tolerance to its
sedative effects, it should not be used to treat insomnia in the absence of depres-
sion [93].
Ramelteon is a melatonin receptor agonist. It is approved by the FDA for treat-
ment of insomnia. In a study of older adults, ramelteon reduced patient reports of
sleep latency over 5 weeks of treatment with no significant rebound insomnia or
withdrawal effects [94, 95].
Melatonin at a dose of 2 mg has been approved by the European Medicines
Agency (EMA) for the short-term treatment of primary insomnia in patients aged
55 years and older. However, formal recommendations for the use of melatonin in
the treatment of insomnia still require further research [13, 96, 97].
Suvorexant is an orexin receptor antagonist. It is the first FDA-approved dual
orexin receptor antagonist and may be prescribed up to a 20-mg dose. It targets
wakefulness-promoting neuropeptides that regulate the sleep-wake cycle. It has
shown to be effective in decreasing sleep latency and in increasing total sleep time.
Suvorexant has been studied in both older (age 65 years or older) and younger (age
18–64 years) patients, showing no significant differences efficacy or safety between
these two groups. Long-term data are still lacking [98–100].

27.11 Conclusions

A profound discriminatory history should identify a real cause of insomnia among

diverse somatic, psychological and situational factors in order to line up a problem-­
oriented treatment strategy in older adults.
Despite the fact that pharmacological treatments these alternatives have been
shown to be more effective than placebo at bettering short-term sleep outcomes, the
size of effect is variable, and the overall benefit-to-risk ratio is low. The potential
benefits of pharmacotherapy on sleep quality and daytime function in older adults
should always be balanced against the risk of side effects and physical and psycho-
logical dependence with long-term use. As to future perspectives, trials should focus
on advising and motivating patients already using hypnotic drugs to discontinue
these medications, while effective non-pharmacological programs should be given
a priority in respect of avoiding the use of hypnotics. Psychological support and
follow-up of the patient make herein an important task for caregivers.
400 M. Petrovic

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Optimizing Pharmacotherapy in Older
Patients: An Interdisciplinary Approach: 28
Chronic Kidney Disease

Andrea Corsonello, Antonello Rocca, Carmela Lo Russo,

and Luca Soraci

28.1 Epidemiology and Staging Issues

Chronic kidney disease (CKD) is defined as the occurrence of abnormalities of kid-

ney structure or function, present for more than 3 months, with implications for
health. Such a definition is accompanied by a staging system based on GFR (G1
≥90, G2 89–60, G3a 59–45, G3b 44–30, G4 29–15, and G5 <15 mL/min/1.73 m2)
and albumin-to-creatinine ratio (ACR) (A1 <30, A2 30–300, A3 >300 mg/g).
Different combinations of reduced GFR and increased ACR are able to stratify
prognosis and to identify patients carrying high risk of negative outcomes
(Fig. 28.1) [1].
Older adults over 65 years encompass the most rapidly growing subset of the
end-stage renal disease (ESRD) population. While there has been a significant
increase in the prevalence of CKD from 10.3% to 13.1% of the population, the
greatest percentage increase was observed in those older than 70 years of age, rising
from a prevalence of 37–47% [2, 3]. Additionally, CKD and its complications may
significantly impact functional status and health-related quality of life among older
people, and geriatric syndromes (including cognitive status, depression, disability,
frailty, and sarcopenia) are more and more considered in the assessment of older
people with CKD [3, 4].
Accordingly, recognizing CKD is of paramount relevance in order to imple-
ment interventions aimed at preventing or delaying disease progression and the
development of CKD complications and end-stage renal disease (ESRD), as well
as reducing the risk of adverse drug reactions (ADRs) and/or nephrotoxicity.
However, several reasons make the diagnosis of CKD in the older population

A. Corsonello · A. Rocca · C. L. Russo · L. Soraci (*)

Unit of Geriatric Medicine and Laboratory of Geriatric Pharmacoepidemiology, Italian
National Research Center on Aging (IRCCS-INRCA), Cosenza, Italy
e-mail: [email protected]; [email protected]; [email protected]; [email protected]

© Springer Nature Switzerland AG 2023 405

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_28
406 A. Corsonello et al.

PATIENT-RELATED FACTORS DRUG-RELATED FACTORS DANGEROUS INTERACTIONS

Age, CKD, Diabetes, Sepsis, Volume Intrinsic nephrotoxic potential, Dosage, Avoid specific drug combinations
depletion, Sodium depletion, Multiple Frequency of administrations, Duration NSAIDs and ACEI/ARB (and/or
myeloma, Acid-base disturbances, of treatment, Timing of administration, diuretics)
Hypoalbuminemia, Polypharmacy. Route of administration, Pharmaceutical Cephalosporins and
Careful assessment of: formulation. aminoglycosides
Age-related diseases (renovascular Careful assessment of: Vancomycin and aminoglycosides
disease, heart failure) Nephrotoxic potential
Cephalosporins and acyclovir
CKD, diabetes and sepsis Dose-dependent effect (mainly for
(increased risk of nephrotoxic AKI) drugs causing crystal deposition,
Volume depletion (NSAID-induced tubular toxicity, and hemodynamic
and ACEI/ARB-induced toxicity)
nephrotoxicity) Frequency of administrations
Volume and sodium depletion (aminoglycosides)
(diuretics-induced nephrotoxicity) Route of administration (intra-
Hypoalbuminemia (cisplatin- and arterial administration of contrast)
aminoglycosides-induced Pharmaceutical formulation
nephrotoxicity) (nephrotoxicity is lower with
Polypharmacy (exposure to multiple liposomal amphotericin than for
nephrotoxic drugs) amphotericin lipid complex)

Fig. 28.1 Factors to be considered for preventing nephrotoxic AKI among older patients

cumbersome. Distinguishing age-related decline in kidney function from true

CKD may be difficult, and many people with CKD are asymptomatic or have
nonspecific symptoms; thus, clinical and laboratory clues are to be searched for to
make a diagnosis before symptoms become severe or complications develop.
Staging issues should be also taken into consideration. While there is substantial
agreement in considering GFR <60 mL/min/1.73 m2 as a clinically and prognosti-
cally relevant reduction of kidney function in the general population, not all older
patients with an eGFR <60 mL/min/1.73 m2 should be labeled as having kidney
disease, since this may be part of physiological aging. Indeed, age adaptation of
CKD definition is still matter of debate. The lack of an age calibration for CKD
diagnosis has been considered as an inherent and potentially serious weakness
that might lead to substantial overdiagnosis of CKD in otherwise healthy popula-
tions of older subjects [5]. The most common CKD category observed in commu-
nity-based programs is stage 3A (i.e., GFR of 45–59 mL/min/1.73 m2), which
predominantly affects older persons and is seldom progressive in the absence of
significant proteinuria [5]. An age-adjusted definition of CKD based on eGFR less
than 45 mL/min/1.73m2 has been proposed for older patients, but it would only be
applicable to those who do not have any other corroborating signs of kidney dis-
ease such as proteinuria [6]. However, the KDIGO guidelines do not support the
use of age-dependent thresholds for CKD diagnosis [1]. Finally, even older
patients with stage 3a CKD need to be always assessed for appropriate use of
28 Optimizing Pharmacotherapy in Older Patients: An Interdisciplinary Approach… 407

treatments slowing kidney function decline, correct dosing of kidney cleared

drugs, and limited use of nephrotoxic medications.

28.2 Multimorbidity and Polypharmacy

CKD usually coexists with other chronic diseases due to a pathogenetic link, e.g.,
diabetes and atherosclerosis as the cause of CKD, and to the sharing of risk factors
(e.g., age and smoking habits) and pathophysiological pathways described above.
Recurrent and highly prevalent clusters of diseases including CKD are the rule
according to the multimorbidity approach, which defines the main associations
between and among diseases without any hierarchical assumption. According to
such approach, Formiga et al. [7] reported that CKD contributes to a multimorbidity
cluster including coronary artery disease, hypertension, stroke, and diabetes.
Zemedikun et al. [8] showed that the multimorbidity cluster including CKD may be
wider than that previously observed, being composed by 26 conditions, among
which cardiovascular, liver, neurologic, psychiatric, respiratory, endocrine, and
muscle-skeletal diseases. More recently, cluster analysis showed that CKD may
cluster with hypertension and sensory impairments, but physical performance as
assessed by SPPB may be associated with not negligible changes in multimorbidity
clusters. These findings strengthen the need of assessing physical performance and
investigating interventions targeting physical function among complex multimorbid
patients in an attempt to improve outcomes and reduce costs associated with multi-
morbidity. Finally, CKD severity may significantly affect patterns of multimorbid-
ity, which should be also taken into account in clinical approach to multimorbid
patients [9]. In such a complex scenario, the clinical presentation of CKD may be
concealed by coexistent diseases. Thus, fatigue, sarcopenia, dyspnea, and anorexia
may be expression of several conditions. As a consequence, CKD may remain
unrecognized until blood exams performed for unrelated reasons allow detect it.
Furthermore, multimorbidity accounts for polypharmacy which, in turn, is fre-
quently nephrotoxic. The kinetics of many drugs is variously compromised in CKD,
and recognizing CKD is mandatory to tailor the doses to actual eGFR values. Thus,
renal function should systematically be screened for in the aged and multimorbid
patients. Furthermore, sarcopenia and hypoalbuminemia may decrease the distribu-
tion volume and the bound fraction of water-soluble drugs and reduce serum creati-
nine out of proportion to the true eGFR, which defines the condition of concealed
renal failure, which may further increase the risk of ADRs [10]. Indeed, diabetes
mellitus, musculoskeletal diseases, and COPD are commonly associated with this
condition [11]. Not unfrequently, acute kidney injury due to contrast medium unrav-
els CKD [12–14]. Indeed, the inherent risk starts increasing from eGFR <60 mL/
min/1.73 m2 and further increases in patients given metformin or other potentially
nephrotoxic drugs as well as in those having anemia, diabetes mellitus, CHF, and
hypotension, which are well-known age-related diseases [15].
408 A. Corsonello et al.

28.3 Guideline-Based Recommendations and CKD Treatment

Among Older Patients

Evidence-based guidelines for managing CKD do not include specific recommen-

dations for older patients. Nevertheless, geriatric issues, such as frailty, quality of
life, life expectancy, end of life, and iatrogenic risk, usually challenge physicians
and need to be addressed when managing CKD in the older population. In this sec-
tion, we provide an overview of the impact of these issues on the pharmacological
treatment for CKD and its complications.

28.3.1 Hypertension

Hypertension is present in up to 80–85% of CKD patients and can be both a cause

and a consequence of CKD. Several mechanisms including sodium retention, fluid
overload, and increased activities of sympathetic and renin-angiotensin systems
concur to its pathogenesis [16]. Blood pressure control in CKD has shown to be
useful to slow progressive renal function loss [17]; however, many of the key studies
supporting guideline-based recommendations did not include participants older
than 70 [18] which reduces their generalizability [16]. For this reason, individual-
ized antihypertensive approaches are generally advised in older patients with CKD,
depending upon concurrent comorbidities and renal function [19]:

• Target BP levels should be 130/70 mmHg (and not below) for older people of
65 years or more; in older patients over 80 years or in all frail older patients, a
smaller reduction of SBP is advised according to the benefit/risk ratio of treat-
ment. These target thresholds are higher compared with those suggested from
clinical practice guidelines [20] and are derived from independent studies show-
ing how a more intensive BP treatment may worsen prognosis in such popula-
tions [21]. Diastolic blood pressure levels <70 mmHg were in fact associated
with increased cardiovascular risk [21] and accelerated decline in kidney func-
tion in patients aged 85 years or more [22]; similarly, systolic blood pressure
<130 mmHg was associated with increased mortality in CKD patients aged
75 years or more [23].
• Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor
antagonists (ARBs) are still considered first-line agents for patients with diabetic
CKD (defined as an eGFR <60 mL/min per 1.73 m2 or micro- or macroalbumin-
uria) and nondiabetic proteinuric CKD [24], even in the absence of hypertension
[25, 26]. Usage of renin angiotensin system (RAS) blockers is important to slow
progression of CKD, thanks to their antiproteinuric effects. However, potential
iatrogenic risks related to ACE-I or ARBs should be taken into account. Indeed,
prescription of ACE-I and ARBs in older patients with CKD mandates careful
monitoring for acute renal failure and hyperkalemia; the occurrence of symp-
tomatic hypotension or eGFR <15 mL/min/1.73 m2 suggests discontinuation of
treatment, whereas reduction of drug doses is indicated for milder renal function
28 Optimizing Pharmacotherapy in Older Patients: An Interdisciplinary Approach… 409

deteriorations; increase in serum potassium levels requires dietary modification

and chronic administration of ion-exchange resins and can also limit the use of
other medications raising serum potassium (e.g., spironolactone) [24]. Thus, the
presence of proteinuria in the context of a clearly progressive CKD, the occur-
rence of other health concerns or priorities that might make another antihyper-
tensive agent preferable, as well as the patient’s acceptance of the additional
burden that these agents may impose should always be considered when pre-
scribing an ACE-I or ARB to slow the progression of CKD [24].
• Diuretics should be added to RAS blockers in older CKD patients with fluid
overload/edema; additionally, they may be considered the first-line medication in
nondiabetic nonproteinuric CKD with fluid retention; loop diuretics are pre-
ferred over thiazides when antiproteinuric effects of RAS blockers need to be
enhanced; torasemide, which has a longer duration of action than furosemide,
may be preferred. Administration of diuretics in older patients needs strict moni-
toring of serum electrolytes, body weight, and renal function because of increased
risk of electrolyte abnormalities and dehydration; additionally, despite thiazides
are usually not recommended when eGFR falls below 30 mL/min/1.73 m2 [24],
a recent RCT showed that adding chlortalidone to either ACEi, ARBs, or beta-­
blockers may improve 24-h systolic blood pressure control in patients with CKD
stage 4 and poorly controlled hypertension; indeed, patients receiving chlortali-
done underwent a significant reduction of 10.5 mmHg of systolic blood pressure
at 3 months, as well as a significant decrease in NT-proBNP, body weight, and
albuminuria [27].
• Calcium channel blockers (CCBs) are the second-line medications in BP control
in CKD patients. The non-dihydropyridine CCBs, such as diltiazem and vera-
pamil, have significant antiproteinuric effects and are then preferred in older
patients with proteinuria; amlodipine is generally preferred in nondiabetic non-
proteinuric CKD. However, administration of these drugs in older patients should
be carefully monitored as they are associated with several side effects (hypoten-
sion, tachycardia, peripheral edema for dihydropyridine CCBs; bradycardia for
non-dihydropyridine CCBs) [24].
• Mineralocorticoid receptor antagonists (MRA) can be used in patients with resis-
tant hypertension despite combination therapy; careful monitoring of renal func-
tion is suggested; the risk of MRA-related adverse effects, including hyperkalemia
and worsening renal function, is amplified in individuals with eGFR <30 mL/
min/1.73 m2 [24].

28.3.2 Diabetes

Glycemic control in diabetic patients also represents an important intervention to

reduce the burden of CKD and to slow its progression. Older diabetic patients with
stages 3–4 CKD have particular needs that differ from those of younger patients
with the same conditions, mainly due to frailty and reduced life expectancy [28].
Therapeutic options for older diabetic patients and CKD are limited because reduced
410 A. Corsonello et al.

kidney function may result in the accumulation of several drugs and/or their
metabolites.

• HbA1c target levels should be individualized: a target from 6.5% to 8.0% in

patients with diabetes and CKD not treated with dialysis should be considered;
for patients with multiple comorbidities and decreased life expectancy, higher
HbA1c targets might be more appropriate [29, 30].
• Metformin is the first-line therapeutic option in older patients with diabetic kid-
ney disease; it should be cautiously used in patients with mild to moderate
chronic kidney disease, with appropriate dosage reductions and careful follow-
­up of kidney function [30, 31].
• Conventional oral hypoglycemic agents, such as sulfonylureas (SUs), are not
suitable due to the risk of prolonged hypoglycemia [28, 30]. However, in selected
older patients with CKD and adequate hypoglycemia awareness, low-dose glipi-
zide, gliclazide, or glimepiride can be considered [32].
• Glinides are rapid- and short-acting insulinotropic SU receptor ligands, but simi-
lar to the Sus, the main concern with repaglinide and nateglinide use in patients
with CKD is a potentially increased risk of hypoglycemia [30, 33]. Thus, lower
initial doses of these agents are recommended in this population.
• α-glucosidase inhibitors, acarbose and miglitol, are minimally absorbed from the
gastrointestinal tract, yet plasma levels can increase in CKD; therefore, caution
is advised for the use of these agents in diabetic patients with low eGFR (<30 mL/
min/1.73 m2) [30, 33].
• Thiazolidinediones are known to increase insulin sensitivity and HDL levels in
diabetic patients; some of them, namely, rosiglitazone and pioglitazone, are
metabolized by the liver and could be preferred in CKD patients; however, these
drugs are not generally recommended in CKD because of increased risk of fluid
overload, which mandates a close body weight monitoring and checking of fluid
retention signs [32]. Additionally, according to a recent metanalysis, the effects
on cardiovascular outcomes and hypoglycemia are uncertain [34]. These medi-
cations are also contraindicated in all individuals with osteoporosis and NYHA
III-IV heart failure, which are frequently associated with CKD in older
patients [32].
• Incretin mimetics and dipeptidyl peptidase-4 (DPP-4) inhibitors are changing the
paradigm of antidiabetic treatment, especially for older diabetic patients with
CKD. Incretin-mimetics are currently the glucose-lowering drugs with the stron-
gest evidence of benefit on cardiovascular and kidney outcomes in patients with
preexisting cardiovascular or kidney disease [35]. They are then indicated in
patients with type 2 diabetes and CKD who have not achieved glycemic control
despite first-line therapy (with metformin and eventually SGLT2 inhibitors) [32].
However, incretin mimetics have important limitations in older patients. Despite
recent studies have decreased the eGFR threshold for GLP-1 discontinuation to
up to 15 mL/min/1.73 m2 for liraglutide, semaglutide, and dulaglutide [30],
administration of these drugs in older adults needs to take into account the ben-
efit/risk ratio, as several (severe weight loss, vomiting, nausea) may lead to kid-
ney function worsening and AKI development, if not appropriately counteracted
28 Optimizing Pharmacotherapy in Older Patients: An Interdisciplinary Approach… 411

[30]. Conversely, DPP-4 inhibitors are potentially advantageous for older dia-
betic patients with CKD because they are associated with a lower risk of hypo-
glycemia compared to other antidiabetic medications [30]. All currently available
DPP-4 inhibitors can be used in CKD, but dosage of sitagliptin, saxagliptin, and
alogliptin needs to be reduced in patients with GFR <50 mL/min/1.73 m2 [30,
36]. Linagliptin is not cleared by the kidney and does not require any dosage
adjustment in patients with CKD [30, 37].
–– Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) significantly and
consistently improve glycemic control with a marginal risk of hypoglycemia,
especially when in monotherapy [30]. Furthermore, they have recently
emerged as a disease-modifying treatment to counteract the progression of
chronic renal disease in patients with or without diabetes [38]. No dose adjust-
ment is required in mild CKD, but current evidence suggests being very cau-
tious in moderate-severe stages of the disease. Indeed, findings from
DECLARE-TIMI 58 [39, 40], CREDENCE [41], DAPA-CKD [42], and
EMPA-KIDNEY trials have shown that these drugs can be safely prescribed
after dose adjustment in patients with eGFR ≥20–30 mL/min/1.73 m2; con-
versely, their use in patients with lower eGFR is not recommended. Within
this family, canagliflozin has good safety profile in older diabetic patients
with macroalbuminuria [43], whereas dapagliflozin can be safely prescribed
to decrease the risk of CKD progression irrespective of albuminuria [44];
previous evidence of an increased risk of lower limb amputations in patients
taking canagliflozin [35] has not been confirmed by recent RCTs, while con-
cerns of genital mycotic infections and euglycemic diabetic ketoacidosis were
confirmed for canagliflozin only [41, 42].
• Insulin remains the mainstay of treatment in diabetic patients with secondary
failure and moderate to advanced CKD, especially those undergoing dialysis
[30]. About one third of exogenous insulin is cleared by the kidney. Sixty percent
of the renal clearance is due to glomerular filtration, while the remaining 40% is
secreted after uptake from peritubular vessels. The available long- and short-­
acting insulin analogues have similar pharmacokinetics in patients with CKD
[30]. To reduce the risk of hypoglycemia, insulin dosage reduction of 25% has
been recommended in patients with GFR = 10–50 mL/min. However, when the
long-acting insulins glargine or detemir are used, it may be wise to start treat-
ment with 50% of the usual initial dosage of 0.1 IU/kg, titrating the dosage until
target fasting glucose concentrations are reached [45]. The pharmacokinetics of
the ultralong-acting insulin degludec does not change in patients with different
degrees of kidney dysfunction [32, 46], thus suggesting that dose adjustments in
patients with mild to severe renal impairment should not be required.

28.3.3 Albuminuria

Evidence have clearly shown that renin-angiotensin system blockade by ACE-I or

ARBs is associated with a significant decrease in proteinuria and a slower decline in
renal function in hypertensive adults. Lowering urinary albumin excretion may slow
412 A. Corsonello et al.

the progression of diabetic kidney disease and improve clinical outcomes even in
the absence of hypertension [47]. Guidelines recommend that normotensive people
with diabetes and macroalbuminuria should be treated with ACE-I or ARBs [19].
However, treatment with ACE-I or ARBs was found beneficial even in microalbu-
minuric normotensive patients, where benefits were more pronounced in diabetic
compared to nondiabetic patients and in patients with more severe proteinuria
(>3 g/24 h) compared to those with less severe proteinuria (<1 g/24 h) [19, 48].
Evidence from subgroup analysis of older patients from proteinuria-lowering trials
suggests a reduced risk of cardiovascular outcomes even in this group of patients
compared with that seen in younger subjects [49].
However, concerns related to treatment outcomes in older patients already
described above (see paragraph dealing with hypertension) also apply to the use of
these medications in normotensive patients. Additionally, combined therapy with
ACE-I and ARBs was proposed to treat proteinuria, but the ONTARGET study
clearly showed that combining ACE-I and ARBs was associated with faster decline
in renal function, more side effects, and worse overall outcome [50, 51]. These find-
ings are of particular concerns for older complex patients who are much more vul-
nerable to iatrogenic injury.

28.3.4 Hyperlipidemia

Lipid metabolism abnormalities are commonly associated with CKD and contribute
to cardiovascular morbidity and mortality in CKD patients.

• Primary prevention: according to current knowledge, statin treatment should not

be used for primary prevention in older patients with CKD. A recent metanalysis
concerning the efficacy and safety of statin in older people has shown no signifi-
cant benefit of statins for primary prevention among older individuals of 75 years
of age [52].
• Secondary prevention: although secondary prevention trials using LDL-lowering
therapies have shown beneficial effects on both cardiac events and all-cause mor-
tality, limited data are available in older subjects. Statin trials in the general pop-
ulation included a variable proportion of older participants [53], but the
percentage of older patients in CKD treatment statin trials ranged between 28
and 32% [54–56]. Currently, moderate-intensity statin or statin/ezetimibe treat-
ment is recommended in adults aged 50 years or older, and dose adjustment is
necessary with GFR <30 mL/min for statins other than atorvastatin and fluvas-
tatin [57]. Evidence from subgroup analysis of older patients from lipid-lowering
trials suggests a similar evidence in terms of reductions in all-cause mortality,
major cardiovascular events, and outcomes of revascularization procedures in
older compared to younger patients [58]. However, the benefits of treatment need
to be weighed carefully against potential risks in older patients. With the excep-
tion of non-CYP3A4 substrates pravastatin, rosuvastatin, and fluvastatin, several
statins are metabolized by cytochrome P450-CYP3A4 and therefore can interact
28 Optimizing Pharmacotherapy in Older Patients: An Interdisciplinary Approach… 413

with commonly used medications such as amiodarone, macrolides, calcium

channel blockers, fibric acid derivatives, and cyclosporine, thus resulting in
increased risk of hepatotoxicity and myopathy [59, 60]. Thus, the choice of statin
to treat older CKD patients should take into account the additional risk of poten-
tially dangerous drug interactions.

28.3.5 Bone Metabolism

CKD-related mineral bone disorder (CKD-MBD) is characterized by derangements

in bone and mineral metabolism leading to abnormal regulation of calcium, phos-
phorous, vitamin D, and PTH [61]. Whether medications used for osteoporosis in
general population should be also used to treat older patients with CKD is not
always clear. According to current guidelines, serial assessment of calcium, phos-
phate, vitamin D, and parathyroid hormone (PTH) levels provides indications for
treatment [62].

• Hyperphosphatemia (phosphate serum levels >5.5 mg/dL) develops early in

CKD because of decreased filtering of phosphate load, even if overt excess of
serum phosphates starts when eGFR falls below 40 mL/min/1.73 m2 [63]. Low-­
phosphate diet (<900 mg/day) is the first-line treatment for hyperphosphatemia
aiming at maintaining a serum concentration of <4.5 mg/dL [64]; administration
of phosphate binders should be reserved to persistent hyperphosphatemia despite
lifestyle modifications or severe hyperphosphatemia (>6 mg(dL); non-calcium
phosphate binders (sevelamer, lanthanum) are the first-line medications.
Calcium-­containing binders (calcium carbonate and calcium acetate) may lead
several side effects (e.g., hypercalcemia, adynamic bone disease, vascular calci-
fication) [64].
• Vitamin D deficiency: a large proportion of patients with CKD exhibit vitamin D
deficiency (plasma 25-OH vitamin D <25–30 nmol/L) [65]. Additionally, older
patients with CKD are particularly prone to vitamin D deficiency, as resulting
from multiple mechanisms including reduced synthesis, inadequate intake,
dietary restrictions, and inactive lifestyle in dialysis patients [66]. 25(OH) vita-
min D deficiency may lead to CKD-MBD via increase in iPTH levels, reduced
bone mineral density (BMD), and increased rate of hip fractures [65]. For this
reason, clinical practice guidelines recommend maintaining 25(OH)vitamin D
levels above 30 ng/mL by supplementation with ergocalciferol in moderate-to-­
severe CKD [61]; caution should be taken in older patients with overt manifesta-
tions of CKD-MBD (e.g., hypercalcemia and hyperphosphatemia) [65]. In older
patients, vitamin D supplementation should be tailored on the basis of several
factors, including food intake, sun exposure, physical activity, and skin pigmen-
tation. Furthermore, vitamin D dose should be increased according to serum
25(OH) vitamin D in patients taking selected medications (e.g., cholestyramine
bind vitamin D in the gut, while phenytoin and phenobarbital accelerate the
breakdown of vitamin D by inducing the cytochrome P450 pathway) [67]. In
414 A. Corsonello et al.

patients with persistently high PTH levels (>2.3–3 times the normal values),
despite treatment of hyperphosphatemia and vitamin D deficiency, calcitriol
should be administered with a regimen of 0.25 mcg three times a week [64].
• Hypercalcemia: in CKD stages 3 to 5, total elemental calcium intake including
dietary and supplements should not exceed 2000 mg/d. The National Osteoporosis
Foundation recommends a daily calcium intake of 1200 mg and vitamin D intake
of 800–1000 IU/d for adults 50 and older [64, 68]. However, an only modestly
increased risk of cardiovascular events in postmenopausal women undergoing
calcium supplementation with or without vitamin D was reported in some stud-
ies [69, 70], thus suggesting the need to weigh the clinical significance of cardio-
vascular risks related to calcium supplements against the risks related to
osteoporosis and its complications.
• Osteoporosis in CKD patients:
–– Use of bisphosphonates in CKD older patients with osteoporosis is controver-
sial, as it was found associated with progressive renal disease, acute renal
failure, and nephrotic syndrome [71]. This finding was not confirmed in other
studies showing that even in older, frail, osteoporotic patients with renal
impairment, intravenous bisphosphonate therapy did not result in long-term
renal function decline [72]. However, it is worth reminding that bisphospho-
nates are not indicated in adynamic or osteomalacic bone disease. Additionally,
calcium-phosphorous alterations, vitamin D deficiency, and hyperparathy-
roidism should always be addressed before starting bisphosphonates. Finally,
there is no evidence that using bisphosphonates for short periods of time
(2–3 years) in the CKD population will result in a significantly reduced inci-
dence of fractures [71, 73].
–– The anti-RANKL monoclonal antibody denosumab decreases bone reabsorp-
tion, is useful for osteoporosis treatment and prevention of fractures, and is
not cleared by the kidney. The efficacy and renal safety of denosumab have
been demonstrated in elderly women [74]. However, by inhibiting bone
resorption, it may lead to hypocalcemia. For this reason, patients with creati-
nine clearance <30 mL/min and/or other conditions predisposing to hypocal-
cemia should be strictly monitored during denosumab treatment [75, 76].
–– The use of selective estrogen receptor modulators (SERM) raloxifene was
found associated with increased spine BMD, reduced incidence of vertebral
fractures, and no effect on non-vertebral fractures compared with placebo in
postmenopausal women with osteoporosis. No safety risk related to raloxi-
fene in patients with mild to moderate CKD over the 2- to 3-year observation
period [64, 77]. However, SERMs may increase the risk of deep venous
thrombosis (DVT), pulmonary embolism, and fatal stroke in postmenopausal
women with coronary heart disease, which raise the need for further investi-
gations about their long-term safety in older patients already carrying
increased risk of cardiovascular events [64].
–– Strontium ranelate is able to rebalance bone remodeling without a strong inhi-
bition of bone reabsorption, which could reduce the risk of hypocalcemia
during treatment. However, it is cleared by the kidney and is contraindicated
in patients with GFR <30 mL/min. Additionally, an increased cardiovascular
28 Optimizing Pharmacotherapy in Older Patients: An Interdisciplinary Approach… 415

risk was observed in a pooled analysis of strontium RCTs [78, 79], which
makes this drug less appealing for use in older patients with CKD.

28.3.6 Acidosis

Metabolic acidosis is a common complication associated with progressive loss of

kidney function and leading to other complications, including uremic bone disease,
muscle catabolism, bone derangement, and increased mortality [80].
Recommendations to treat chronic metabolic acidosis in patients with CKD include
the following:

• Start oral alkali therapy with sodium bicarbonate (or citrate) when serum bicar-
bonate <22 mmol/L [81].
• Therapy should be given to maintain the normal range (23–29 mmol/L) [82],
since small clinical trials have reported that treatment within this range may
delay CKD progression [83, 84], improve nutrition status [85], increase insulin
sensitivity [86], and decrease atherogenic lipid levels [87]. Conversely, the effect
on bone health was not fully documented [88]. However, especially in older
patients, overcorrection should be avoided because of potentially harmful effects,
mainly resulting from the U-shaped relationship between serum bicarbonate lev-
els and mortality [89]. Whether the sodium load that accompanies alkali therapy
could cause volume overload and hypertension remains to be determined.
Additionally, alkali therapy may lead to hypokalemia, ionized hypocalcemia,
and QTc prolongation. The above evidence supports a judicious use of alkali
treatment as well as a careful monitoring of serum bicarbonates, electrolytes, and
ECG in older patients with acidosis.

28.3.7 Anemia

The association between CKD and anemia is related to several mechanisms such as
impaired production of erythropoietin, iron deficiency, and inflammation with
increased hepcidin levels [90]. Despite its prevalence increases with decline of
eGFR, in some older patients, e.g., those with diabetic kidney disease, impaired
production of erythropoietin usually precedes the decline of eGFR, and even mildly
depressed eGFR may then be associated with significant anemia of renal origin
[91]. Recommendations for treatment of CKD-related anemia are mainly based on
clinical practice guidelines, although most studies did not include geriatric popula-
tions [92]:

• Consider treating anemia when hemoglobin <10.0 g/dL or symptoms attribut-

able to anemia develop with Hb between 10 and 12–13 g/dL [93].
• Determine individual iron’s status and potential responsiveness to iron supple-
mentation by checking the percent hypochromic red cells (%HRC) and reticulo-
cyte hemoglobin content (CHr) to estimate the Hb content in RBCs [92]. Whether
416 A. Corsonello et al.

%HRC and CHr are not available or the patient has thalassaemia/thalassaemia
trait, check transferrin saturation (TSAT), and ferritin serum levels.
• Start iron supplementation before erythropoiesis stimulating factors (ESAs) in
patients with iron responsiveness, defined as having %HRC >6% and CHR
>29 pg (or TSAT <20% and ferritin <100 μg/L). Oral iron (ferrous sulfate, fuma-
rate, or gluconate) is the preferred starting treatment, at a daily regimen of
200 mg in up to three divided doses. Target iron status is defined as a %HRC
<6% (unless ferritin >800 μg/L) and CHr >29 pg (or TSAT >20% and ferritin
>100 μg/L) when above tests are not available or patient has thalassaemia/thal-
assaemia trait; serum ferritin levels should be checked every 1–3 months to
check for potential iron overload.
• Start ESA for patients who are likely to benefit in quality of life and physical
function, only after correcting iron status (patients with %HRC >6% and CHr
>29 pg). Although patients of 75 years or more were excluded from studies
assessing ESA efficacy in the treatment of CKD-related anemia [90], guidelines
clearly suggest that age alone should not be a determinant for treating or not
treating anemia in CKD [90]. However, long-term treatment with ESA has been
associated with increased blood pressure and seizures [94], as well as polyglobu-
lia and increased thrombotic risk. For this reason, older patients should always
be closely monitored, and ESAs should be given at the lowest dose capable of (a)
maintaining stable Hb between 10.0 and 12.0 g/dL and (b) keeping rate of Hb
increase between 1.0 and 2.0 g/dL/month. Caution should be taken in some cat-
egories, including patients with previous cancer or previous/current stroke (risk
of recurrence) and older patients with increased thrombotic risk, bedridden
patients, and individuals with very limited functional capacity (in whom risks
clearly outweigh the benefits of treatment).

Among older CKD patients, ESA administration may be not sufficient to coun-
teract anemia due to the coexistence of systemic inflammatory processes blunting
response to erythropoietin, and inflammation-induced increased hepcidin produc-
tion reducing iron absorption and utilization [90], which further strengthen the need
for studies in older patients with multimorbidity.

28.4 Nephrotoxicity

Medications can impair any of the kidney functions, including renal arterial blood
flow, glomerular filtration, tubular fluid formation, and urine output. While many
drugs have a single mechanism of injury, some medications may affect kidney func-
tion by multiple pathways. Main mechanisms of nephrotoxicity are summarized in
Table 28.1 [95, 96].
Overall, nephrotoxic medications contribute to up to 66% of all acute kidney
injuries (AKIs) in older hospitalized patients [97]. Older age is an independent pre-
dictor of AKI in several different study populations [98–105]. In particular, the rela-
tive risk of developing AKI after myocardial revascularization with or without
28 Optimizing Pharmacotherapy in Older Patients: An Interdisciplinary Approach… 417

Table 28.1 Mechanisms of drug-induced nephrotoxicity [95, 96]

Mechanism Pathophysiology Example medication(s)
Hemodynamically Reduced hydrostatic ACE-I, ARBs
mediated damage pressure in glomerular
capillaries
Imbalance between NSAIDs, cyclosporine, tacrolimus
vasoconstriction/
vasodilation
Tubular epithelial cell Acute tubular necrosis Aminoglycosides, radiocontrast media,
damage platinum compounds, amphotericin B
Osmotic nephrosis Mannitol, LMW-dextran, radiocontrast
media, sucrose, propylene glycol
Tubulointerstitial Acute allergic interstitial β-Lactams, NSAIDs
disease nephritis
Chronic interstitial Lithium, cyclosporine, aristolochic acid
nephritis
Nephrocalcinosis Oral sodium phosphate solutions
Papillary necrosis Analgesics
Glomerular disease Minimal change NSAIDs
glomerular injury
Focal segmental Heroine abuse, HIV infection
glomerulosclerosis
Membranous nephropathy Gold, penicillamine, NSAIDs
Vascular disease Renal vasculitis and Hydralazine, propylthiouracil,
thrombosis allopurinol, penicillamine, minocycline
Mitomycin C, contraceptive agents,
cyclosporin, tacrolimus, antineoplastic
agents, interferon, ticlopidine, clopidogrel
Obstructive Intratubular obstruction Rhabdomyolysis from statins,
nephropathy
Nephrolithiasis Sulfonamides, antiviral agents,
ciprofloxacin, nitrofurantoin

concurrent valvular surgery increases from 1.6 (95% CI, 1.1–2.3) among patients
aged 70–79 years to 3.5 (95%CI, 1.9–6.3) among patients aged 80–95 years com-
pared to those aged less than 70 [106]. The risk of developing AKI was 50% higher
in patients admitted to intensive care units aged 65 or more compared to younger
ones [102]. Nevertheless, only few studies were devoted to address nephrotoxic
AKI among older patients. In a single-center Japanese study of hospitalized patients
aged 80 or more, the use of nephrotoxic medications (with antibiotics being the
most common culprit medications) was among major causes of AKI, together with
hypovolemia, cardiac dysfunction, and respiratory failure [107]. In other studies,
the relationship between age and risk of nephrotoxic AKI was no longer significant
after adjusting for confounders [108, 109]. However, it should be considered that
older patients are frequently affected by multiple chronic diseases which need to be
treated with complex polypharmacy regimens. In this scenario, both multimorbidity
per se and the use of multiple nephrotoxic medications may contribute to increase
the risk of AKI [96, 108–110]. Older age is also associated with increased risk of
nephrotoxic AKI-related death [96]. More recently, glycopeptide antibiotics, drugs
418 A. Corsonello et al.

for anti-heart failure, ICU transfer, multi-organ dysfunction, and cardiopulmonary

resuscitation were found to be independent risk factors for mortality among people
aged 65 or more affected by community-acquired AKI receiving dialysis [111].
Finally, consequences of nephrotoxic AKI among older patients are not limited to
negative effects in terms of mortality or risk of developing progressive CKD. Indeed,
patients surviving to AKI often experience worsening quality of life and disability,
with physical pain, sleep disorders, depression, and loss of mobility and energy
reported as the most frequently complaints [96, 112–114]. Additionally, negative
effects of AKI in terms of disability are supported by data showing an increased risk
of stroke among AKI survivors [115].

28.4.1 Suggestions to Prevent Nephrotoxic AKI

Preventing AKI first involves recognizing the increased vulnerability of the aging
kidney to injury due to age-related structural and functional changes. Indeed, age
>75 years is a recognized risk factor for nephrotoxicity [110]. However, vulnerabil-
ity to nephrotoxic injury may be further increased by multiple chronic diseases
accumulated over the life span, and especially CKD. Thus, identifying CKD patients
may help to individuate patients at greater risk of nephrotoxicity. Other diseases
associated with increased risk of developing AKI are diabetes, heart failure, liver
disease, peripheral arterial disease, hypotension, hypovolemia, and acid-base disor-
ders [116]. Physicians should be aware of such an increased risk when prescribing
a potentially nephrotoxic medication for patients carrying one or more of these
conditions.
General rules to reduce the risk of nephrotoxic AKI include assessing baseline
renal function and consider patient’s renal function when prescribing a new drug,
adjusting medication dosages to renal function, avoiding dangerous nephrotoxic
combinations (e.g., the triple whammy, cephalosporins plus aminoglycosides, van-
comycin plus aminoglycosides, cephalosporins plus acyclovir), and correcting,
when possible, risk factors for nephrotoxicity before the initiation of drug therapy.
Adequate attention should be also devoted to ensure valid hydration before and dur-
ing therapy with potential nephrotoxins, use equally effective non-nephrotoxic
drugs whenever possible, monitoring drug levels to use the correct dose [117].
Improving overall quality of prescriptions may also contribute to reducing risks. In
a study of hospitalized patients with a minimum 0.5 mg/dL change in serum creati-
nine who were prescribed a nephrotoxic or renal eliminated medication, failure to
adjust dosing for kidney function (63%) and the use of nephrotoxic medications
during AKI accounted for 63% and 28% of all recorded adverse drug events [118].
Thus, reducing inappropriate prescribing is very likely to represent a good strategy
for reducing the risk of nephrotoxicity, and studies using available explicit criteria
to target inappropriate medications in older patients [119, 120] are highly desirable.
A summary of useful strategies is suggested in Fig. 28.1.
Specific recommendations exist for preventing radiocontrast-induced AKI
(CI-AKI), which is among the most common cause of hospital-acquired AKI. Prior
28 Optimizing Pharmacotherapy in Older Patients: An Interdisciplinary Approach… 419

to contrast media exposure, serum creatinine must be measured and GFR calcu-
lated. Patients with GFR less than 60 mL/min/1.73 m2 should be considered at risk.
Volume expansion with either isotonic sodium chloride or sodium bicarbonate solu-
tions may be useful to prevent CI-AKI in patients with reduced volemia. The use of
established nephrotoxic drugs (e.g., cyclosporine, aminoglycoside, NSAIDs,
COX-2 inhibitors) should be stopped for at least 2 days. Diabetic patients with pre-
existing renal impairment should withhold metformin for 48 h because lactic acido-
sis may occur once CI-AKI develops [121]. Finally, GFR should always be estimated
48–72 h after receiving contrast media in order to ensure timely CI-AKI detection.
Preventing strategies include isotonic fluid administration, N-acetylcysteine,
alkalization of the urine with IV or oral agents, and statins. Volume expansion with
either isotonic sodium chloride or sodium bicarbonate solutions may be useful to
prevent CI-AKI in patients with reduced volemia. While no specific benefits have
been observed when using sodium bicarbonate vs. isotonic saline likely because
target urine alkalization was not always reached [122, 123], the combination of oral
sodium/potassium citrate and volume expansion with isotonic saline was found to
significantly reduce the risk of CI-AKI [124]. Volume expansion often raises the
concern related to the risk of fluid overload in patients with impaired renal function
or heart failure. Using left ventricular end-diastolic pressure (LVEDP) to guide vol-
ume expansion was found to reduce the risk of CI-AKI but not that of stopping fluid
administration because of the occurrence of dyspnea [125]. The Prevention of
Radiocontrast Induced Nephropathy Clinical Evaluation (PRINCE) trial showed
that forcing diuresis with loop diuretics with urinary flow rate >150 mL/h may pro-
tect against CI-AKI, even if the risk of volume depletion needs to be taken into
account [126]. However, forced diuresis in combination with saline infusion to
match the input and maintain iso-volemia was found to lower the risk of
CI-AKI [127].
N-acetylcysteine did not show any significant benefit in terms of reduction of
CI-AKI risk in both low-risk or high-risk populations [128, 129], while rosuvastatin
was found to reduce the likelihood of CI-AKI [130, 131].

28.5 Conclusions

Optimizing pharmacological treatments among older people with chronic kidney

disease (CKD) may be very difficult. Main issues faced in clinical practice are
related to the observation that CKD is usually observed in the context of complex
multimorbidity profiles which may conceal its clinical presentation, delay diagno-
sis, and make use of kidney-cleared and/or potentially nephrotoxic medications
which are a really challenging task. Guidelines not always provide age-specific rec-
ommendations for treating CKD and related disorders, and there is substantial evi-
dence suggesting that target of treatments should be carefully adapted to the older
population. Taking into account patient- and drug-related factors as well as avoiding
potentially dangerous interactions and reducing inappropriate prescribing may be
useful to prevent nephrotoxicity.
420 A. Corsonello et al.

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Palliation at End of Life
29
Joanne Droney, Phoebe Wright, and Dola Awoyemi

29.1 Introduction: Palliative Care for Older Patients

Palliative care is a multidisciplinary approach that improves the quality of life of

patients and their families when faced with complex chronic or acute, life-­threatening
illness or life-limiting health conditions. It involves early identification, assessment
and management of pain and other symptoms and provision of emotional, spiritual,
psychological and social support [1, 2]. All healthcare and social care providers, with
some basic training, should be able to provide palliative care. Specialist multi-­
professional palliative care teams focus mainly on complex cases. The role of geriatri-
cians in the provision of palliative and end of life care is well described, and there is
an increased recognition of the benefits of collaboration with specialist palliative care
teams [3, 4]. Specialist palliative care complements geriatric medicine in several
ways, principally:

• It can be provided in any healthcare setting and also in extended care facilities
and patients’ own homes [1, 2] with integration between services and settings
leading to improved quality of life [5].
• Palliative care can be beneficial for patients with a wide range of serious ill-
nesses, including cancer, chronic organ failure [6], dementia and progressive
neurological disorders. Palliative care has traditionally focused on patients who

J. Droney (*) · P. Wright · D. Awoyemi

Symptom Control and Palliative Care Team, Royal Marsden NHS Foundation Trust,
London, UK
e-mail: [email protected]; [email protected]; [email protected]

© Springer Nature Switzerland AG 2023 427

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0_29
428 J. Droney et al.

are imminently dying. However, palliative care is also increasingly recognised as

adding value at any stage of illness and is applicable early in the course of illness,
alongside other life prolonging therapies [1].
• Early involvement of palliative care for patients improves patient experience and
quality of life, supports communication and promotes patient choice and
decision-­making [7, 8]. Early palliative care has also been shown to reduce the
use of unplanned acute hospital admissions and emergency department atten-
dances [9].

There have been several recent initiatives specifically designed to enhance pallia-
tive care provision for older patients. These include the following:

• Palliative care as a core component of care for older patients with cancer [10]
• Integrated community-based palliative care for older patients with chronic non-­
cancer diagnoses [11]
• Palliative care in long-term care facilities and nursing homes [12–16]

In many countries, there is an aging population, and older people are living lon-
ger with a high burden of serious health-related suffering [1, 17, 18]. Palliative care
is particularly relevant for patients with multi-morbidities, chronic illnesses with
fluctuant and unpredictable disease trajectories [19] and patients with complex clin-
ical conditions manifested in severe physical and psychosocial needs [20].
Over the next two to three decades, with major demographic changes expected in
most countries, there is likely to be a significant increase in the need for palliative
and end-of-life care for older patients, especially for those being cared for and dying
at home and in care homes [17, 21].

29.2 Approach to Prescribing Medications to Palliate

Symptoms at End of Life in Older Patients

Palliative care is considered “an essential component of comprehensive care” [1].

Core principles of palliative care include communication, advance care planning
and setting goals of treatment, provision of care that is centred around the needs and
priorities of the individual patient and careful and judicious use of medications to
alleviate symptoms [7]. Unmanaged symptoms are common in older people as they
approach the end of life. Patients with advanced dementia have a similar symptom
burden to those with advanced cancer [22]. Pain and breathlessness are most preva-
lent in this population, and other common symptoms include nausea, respiratory
secretions and agitated delirium. Impeccable assessment of symptoms and response
to medication is the mainstay of palliative care. To support this, validated pain
assessment tools can be used to quantify the severity of pain [23] and are available
for assessing pain in patients with dementia [24]. Ongoing assessment is required to
ensure pain remains controlled, and adverse effects are managed.
29 Palliation at End of Life 429

In addition to its being a physical symptom, pain is an outcome of a person’s

psychological, social, spiritual and cultural circumstances, a concept sometimes
known as “Total Pain” [25]. Holistic assessment and management of all potential
areas of suffering is required.
Studies of pharmacological agents have mostly excluded older patients with
multi-morbidity [4]. There are little specific data about the pharmacological man-
agement of symptoms at end of life in older people, and much of the information
available is extrapolated from studies of and experience with younger patients.
When using medications to manage symptoms in older patients, especially those
who are dying, there is a need for regular review of drugs and doses against symp-
toms, adverse effects and individualised goals of treatment.
There are a number of specialist pharmacotherapy resources available for refer-
ence when prescribing in palliative care; the reader is referred to these for greater
detail [26, 27].

29.3 Route and Mode of Administration of Medications at

End of Life

The paradigm for treating pain—by mouth, by the clock (on a regular basis), indi-
vidualised and with attention to detail [28]—holds true for most medications used
for symptom control. Patients suffering from pain, nausea, agitation, constipation or
respiratory secretions should have medications administered regularly to prevent
rather than to merely alleviate symptoms, with “when required” doses available.
This is particularly relevant in the frail elderly population: it has been demonstrated
that medications prescribed “when required” in residential homes are not given as
often as clinicians anticipate [29].
The preferred route for medication administration in palliative care is by mouth
[30]. However, if absorption is compromised, for example, by vomiting or intestinal
obstruction, or when swallowing is difficult in the last days of life, an alternative
route may be more appropriate, e.g. the subcutaneous route. The daily dose of medi-
cation can be given as a continuous subcutaneous infusion over 24 hours, and “when
required” medication as subcutaneous injections. A number of the medications used
frequently at the end of life can be combined within one infusion to ensure symp-
toms are managed effectively. For most medications, this route of administration is
off licence. Syringe driver compatibility charts are available to guide drug
choice [26].

29.4 Managing Symptoms in Last Days of Life

This section presents a concise guide to the use of some key medications in the
management of specific symptoms in the last days of life, including pain, dyspnoea,
nausea, anxiety and agitation.
430 J. Droney et al.

29.4.1 The Use of Opioids for Pain Management at End of Life

Pain is common in the elderly, with around half of care home residents experiencing
pain which often remains under detected and undertreated especially in those with
dementia [29]. There is an association between pain and behavioural and psycho-
logical symptoms of dementia including agitation and anxiety [31].

29.4.2 Starting Opioids in a Patient Who Is Approaching

End of Life

For patients who are in moderate-severe pain and who have not been prescribed a
regular opioid previously, a low-dose strong opioid such as morphine should be
initiated and up-titrated, based on response, until a balance is achieved between
acceptable pain control and medication side effects. It is generally accepted that
there is little or no pharmacological indication for weak opioids in cancer pain, as
low-dose morphine (or other strong opioids) often provides better pain relief with a
lower adverse effect burden [26].
Opioids should generally be administered at regular intervals, with “as required”
doses also available for breakthrough pain. If appropriate, the oral route is prefer-
able for initial up-titration of opioids, for example, 2.5–5 mg immediate release
morphine 4 hourly by mouth. For frail older patients, it is recommended that the
starting dose is reduced by 30–50% [32] and that a more cautious approach is taken
in up-­titration. For morphine, an appropriate “as required” dose is usually 1/6th of
the total 24-h morphine dose. Once the opioid has been up-titrated to a point where
good pain relief is achieved, this may be converted to either a modified release
formulation (which is administered less frequently) or, if a non-oral route is pre-
ferred, to a transdermal patch, such as a buprenorphine or fentanyl patch [33]. If
the patient is imminently dying, a subcutaneous syringe driver may be more
appropriate.

29.4.3 Morphine and Alternative Opioids for Dying Patients

On a population level, there is no difference between any of the strong opioids in

terms of effectiveness or tolerability [34]. For moderate to severe cancer pain, mor-
phine is often the initial opioid of choice [23, 33], a decision commonly based on
cost, availability and familiarity.
However, there is marked inter-individual variation in response to opioids for
pain. This inter-individual variability means that there is no predetermined dose to
manage a particular patient’s pain and individualised titration according to medica-
tion effect is required [35]. Most patients respond well to whichever opioid they are
started on, that is, they achieve adequate analgesia without significant side effects.
However, some patients experience either inadequate analgesia despite upward dose
29 Palliation at End of Life 431

titration and/or intolerable side effects. In these cases, switching to an alternative

opioid can be beneficial to improve analgesia and minimise adverse effects [36].
Alternative strong opioids include oxycodone, fentanyl, buprenorphine and
methadone, to mention more commonly prescribed drugs in this category. These
drugs have different potencies and bioavailability compared to morphine, which
must be taken into consideration when switching between opioids. For example,
oral oxycodone is considered 1.5–2 times more potent, milligram for milligram,
than oral morphine [26]. Therefore 60 mg of oral morphine is the equivalent of
30–40 mg of oral oxycodone. Transdermal fentanyl (as in fentanyl patches) is
100–150 times more potent than oral morphine. A fentanyl patch 25 mcg/h is
roughly equivalent to 60–90 mg oral morphine in 24 h [27]. A buprenorphine patch
5 mcg/h is roughly equivalent to 12 mg oral morphine in 24 h (based on dose con-
version ratio of oral morphine to transdermal buprenorphine of 100:1) [26].
Opioids also differ in their side effects and how they are metabolised. Methadone
is associated with QT prolongation and has a long plasma half-life, making it more
likely to accumulate in frailer older people [44]. Oxycodone, unlike morphine, is
metabolised via the Cytochrome P450 system with potential for multiple drug inter-
actions, especially in patients with multi-morbidity and polypharmacy [37].
Differences in the pharmacodynamic and pharmacokinetic properties of opioids and
the phenomenon of incomplete cross tolerance make switching between opioids
sometimes challenging and unpredictable, requiring careful supervision, regular
review and cautious dose titration.
Published opioid “equianalgesic” conversion ratios are merely guidelines to the
relative potencies of different opioids and are often taken from single-dose studies
that cannot be fully extrapolated into clinical practice. Importantly, these guides do
not take into account individual patient factors which may contribute to effect, such
as genetic variation, pharmacokinetics, previous opioid therapy, opioid tolerance,
concomitant medication and disease status [38].
When switching between opioids, it is recommended that the equivalent opioid
dose is reduced by 33–50% before the second opioid is initiated, especially in
patients who are older and frailer, and titrated according to desired effect [35, 39].
Opioid switching should be carried out with caution and in challenging cases, with
advice and supervision from a specialist palliative care team.

29.4.4 Subcutaneous Opioids for Dying Patients Who Are No

Longer Able to Take Oral Medications

Patients who are no longer able to take oral medications can be given morphine (and
certain other strong opioids) administered as a continuous 24-h subcutaneous
syringe driver infusion. The bioavailability of subcutaneous opioids is often much
higher than oral opioids, and therefore the total 24-h subcutaneous dose will differ
from the oral equivalent. For example, 60 mg of oral morphine in a 24-h period is
approximately equivalent to 30 mg of subcutaneous morphine administered by con-
tinuous infusion over 24 h [26]. Opioids can often be combined with other
432 J. Droney et al.

necessary medications, e.g. anti-emetics, anti-secretory agents in a single syringe

driver delivery system.

29.4.5 The Use of Transdermal Opioid Patches in a Patient Who Is

Imminently Dying

Transdermal opioids (e.g. transdermal fentanyl or buprenorphine) are not suitable

for rapid titration in a patient with acute or severe pain or for whom prognosis is
very short. Effective systemic analgesic concentrations of fentanyl are generally
not reached until approximately 12 h after dose change and steady-state plasma
concentrations of fentanyl are not achieved for at least 36–48 h. Substantial plasma
concentrations of fentanyl can persist for at least 24 h after removal of the transder-
mal patch.
Due to the high potency and risk of overdose, transdermal fentanyl is usually not
recommended pharmacotherapy in opioid naïve patients. Drug absorption from
transdermal opioid patches can be increased by heat (e.g. electric blanket, hot water
bottles), resulting in an increased risk of opioid adverse effects, toxicity and
overdose.
In dying patients who are already on a stable fentanyl or buprenorphine patch, if
pain is controlled, it is sensible to continue the transdermal patch and provide addi-
tional subcutaneous (SC) morphine on an “as required” basis. The appropriate SC
morphine dose can be calculated based on one-sixth of the total oral morphine
equivalent dose of the fentanyl patch. In this circumstance, careful and regular
review of the patient is required, and specialist palliative care advice is
recommended.

29.4.6 Opioid Adverse Effects

The majority of patients taking morphine for cancer pain achieve good analgesia
with minimal adverse effects. Common and predictable adverse effects include con-
stipation and dry mouth, the former being largely avoidable with co-prescription of
laxatives. Other adverse effects such as nausea and vomiting are usually temporary,
following initiation of the opioid, and can be managed with a suitable antiemetic.
This may need to be added to the syringe driver if the patient is no longer able to
take oral medications. Central adverse effects, such as severe drowsiness, confu-
sion, myoclonus or hallucinations, are more concerning and suggestive of opioid
toxicity. Prompt assessment of the patient is necessary to determine the dose reduc-
tion that is required and assessment of potential precipitants, e.g. renal impairment,
infection or interacting medicines. Respiratory depression is rare if strong opioids
are titrated carefully according to individual patient response. If this occurs, the
opioid should be stopped, and the use of naloxone considered; however, this must
be judged carefully in the palliative patient population due to the risk of opioid
withdrawal syndrome and severe pain.
29 Palliation at End of Life 433

Renal and hepatic impairment is more prevalent in the older patient population
and can increase the risk of opioid toxicity. This risk varies between opioids; thus,
caution is required, and an alternate formulation or dose adjustment will often be
required [26]. Some alternate strong opioids may be indicated in specific circum-
stances, for example, fentanyl and alfentanil are safer than morphine in patients
with renal failure.
Non-opioids and adjuvants can be used to better target pain with an opioid spar-
ing intent; this is discussed in more detail elsewhere in this book.

29.4.7 Medications for Nausea and Vomiting at End of Life

Reversible causes of nausea and vomiting, such as hypercalcaemia, should be cor-

rected with specific treatments. The most appropriate antiemetic can be selected
based on the likely cause of the nausea and the mechanism of action of the drug [40,
41]; see Table 29.1. If the initial antiemetic is not successful then a second, more
broadly active choice (e.g. levomepromazine) may be used. A combination of anti-­
emetics with different mechanisms of action may be useful for persistent nausea.

Table 29.1 Commonly used antiemetics at end of life: mechanisms of action, indications and
cautions
Starting
“as
required”
Principle dose for
mechanism of Cautions and frail
Antiemetic action Main indication contraindications elderly
Haloperidol [42] D2 antagonist. Chemical causes of Parkinson’s disease; 0.5 mg
Acts in the nausea, e.g. renal dementia; epilepsy;
chemoreceptor failure, renal and liver
trigger zone hypercalcaemia, impairment; cardiac
medication-induced disease
Cyclizine [43] H1 and muscarinic Raised intracranial Severe heart failure; 50 mg
receptor pressure or liver disease
antagonist vestibular
symptoms
Metoclopramide D2 antagonist. Gastritis, gastric Heart disease; 10 mg
[44, 45] Acts as stasis, functional bowel obstruction;
prokinetic, also bowel obstruction Parkinson’s disease.
5HT3 receptor Avoid long-term
antagonist and treatment in older
5HT4 agonist people
Can cause acute
dystonia in older
patients
Levomepromazine D2, H1, 5HT2 and Second-line or for Parkinson’s disease; 3.125 mg
[46] muscarinic nausea of unclear dementia. Can be
antagonist aetiology sedating
D2 Dopamine type 2, H1 Histamine type 1, 5HT 5′hydroxytryptamine (serotonin)
434 J. Droney et al.

The listed antiemetics can be given orally, subcutaneously or via syringe driver
in equivalent dose (although in some specialist centres, it is advised to dose reduce
levomepromazine by 50% when converting from oral to subcutaneous).
The choice and dose of antiemetic might be influenced by several factors in older
patients. Firstly, physiological changes in the frail elderly can lead to a potential
need for dose reduction [47]. In addition, comorbidities and concurrent use of medi-
cations that might influence antiemetic choice are more common in older people.
For example, medications with dopamine antagonist activity such as metoclo-
pramide and haloperidol should be avoided in Parkinson’s disease patients and used
with caution in frail older people due to increased risk of extra-pyramidal adverse
effects [48]. In heart failure, cyclizine should be avoided. Those with pre-existing
risk factors for ventricular arrhythmia should be prescribed with caution antiemetics
that prolong the QT interval (e.g. domperidone, ondansetron or haloperidol).
Furthermore, co-prescription of some antiemetics should be avoided, for example,
cyclizine with metoclopramide, where cyclizine can be expected to block the proki-
netic action of metoclopramide.

29.4.8 Management of Respiratory Secretions at End of Life

Respiratory secretions at end of life, sometimes called the “death rattle”, are thought
to be due to an accumulation of secretions in the airways and are common in the last
hours of life, usually when the patient has become unconscious. Prior to commenc-
ing medications, non-pharmacological interventions such as repositioning can be
useful. While it is unclear if clinically assisted hydration worsens respiratory secre-
tions [49], the need for this should be regularly reviewed. In addition, it is important
to address any concerns and to provide reassurance to family members and others
present that the noisy breathing is generally not thought to be distressing to the
patient [50].
Anticholinergic medications are commonly used to reduce secretions [50]. As
older people are at increased risk, monitoring for adverse effects such as severe
xerostomia (dry mouth) and urinary retention is necessary.
Commonly used non-sedating medications include glycopyrronium and hyoscine
butylbromide. Neither is known to be more efficacious than the other [50]. Both have
poor bioavailability and therefore are given subcutaneously, either “as required” or in
a syringe driver over 24 h. The usual “as required” dose for glycopyrronium is
200–400 micrograms, with a maximum recommended dose of 1.2 mg over 24 h; for
hyoscine butylbromide, this is 20 mg with a maximum recommended dose of
60–120 mg over 24 h [51] (some specialist centres use higher maximum doses).
Hyoscine hydrobromide crosses the blood brain barrier and can cause central
adverse effects including sedation and delirium, especially in patients with renal
and liver failure. This drug can be administered subcutaneously. It is also available
as a transdermal patch, which is changed every 3 days. This may be useful in set-
tings such as nursing homes, where access to syringe drivers may be more of a chal-
lenge [52]. For patients with fluid overload secondary to heart failure, this can
29 Palliation at End of Life 435

contribute to respiratory symptoms so can be managed with furosemide, which can

be given subcutaneously in the community setting [53].

29.4.9 Management of Dyspnoea at End of Life

Breathlessness is a common symptom in the last week of life. As with other symp-
toms, careful assessment is required to understand the most likely aetiology and to
ensure that any reversible causes are treated, including using supplemental oxygen
in hypoxia. Simple, instant non-pharmacological interventions can be trialled, such
as handheld or electric fans. If these are not effective, then pharmacological mea-
sures include low-dose morphine should be applied. For patients who are not immi-
nently dying, the published evidence demonstrates improvement with regular
low-dose morphine, e.g. modified release morphine, starting at 5 mg twice a day,
which can be up-titrated weekly to a maximum of 15 mg twice a day. Within these
doses, there is no evidence of excess hospital admissions or mortality [54]. The oral
route is preferred, but if a patient is thought to be in the final days of life, low-dose
morphine can be given subcutaneously for breathlessness, e.g. 5–10 mg over 24 h
via syringe driver.
Benzodiazepines are used to relieve the sensation of breathlessness especially
where there is associated anxiety [55], most commonly sublingual lorazepam or
subcutaneous midazolam. However there is no evidence in the literature to support
this approach [56].

29.4.10 The Use of Medications to Relieve Agitation at

End of Life

Sometimes patients can become agitated and restless when they are imminently
dying. This is called “terminal agitation” and may be a feature of delirium at end of
life. It can also be due to uncontrolled physical symptoms or psychological or spiri-
tual distress. Reversible causes of agitation should be investigated and treated where
appropriate and when possible, e.g. hypercalcaemia and urinary retention.
The main types of medications that are used to relieve terminal agitation are
benzodiazepines and antipsychotics. It is generally not appropriate to use opioids
for this purpose [57].
Benzodiazepines, such as midazolam, can be used if anxiety is a predominant
symptom. If refractory symptoms of delirium including confusion and hallucina-
tions are predominant, then antipsychotics such as haloperidol or levomepromazine
are preferable treatment options [58]. There has been a recent move away from the
use of neuroleptics in older patients and in palliative care patients with delirium due
to a lack of high-quality evidence [59]. However, if a patient is thought to be immi-
nently dying and is exhibiting severe distress and agitation, then drug treatment can
be considered with the aim of relieving symptoms [60]. Ideally, this should be car-
ried out with specialist palliative care support.
436 J. Droney et al.

Patients who are sufficiently distressed and agitated to require medications to

manage their symptoms are often not able to take oral medications. In such cases,
medications may be administered by intermittent subcutaneous bolus or by continu-
ous subcutaneous infusion.
Refractory agitation in a dying patient should be treated with a low dose of medi-
cation, which should be reviewed regularly and titrated as necessary. In frail older
patients, the starting dose should be reduced, with cautious up-titration, aiming to
relieve symptoms. For example, a starting single dose of haloperidol would be
0.5 mg subcutaneously and levomepromazine 6.25 mg subcutaneously [61, 62].
Usually, low doses of medications are sufficient to relieve symptoms. A national
audit of the care of dying patients in UK hospitals found that the final median dose
of midazolam prescribed prior to death was 10 mg subcutaneously over 24 h, (inter-
quartile range of 5–15 mg) [63].
Many of the medications used to treat terminal agitation can be sedating.
Palliative sedation is the monitored use of medications intended to induce a state of
decreased or absent awareness (unconsciousness) in order to relieve intractable and
intolerable symptoms or distress in a patient close to death [58, 64], usually in the
last hours and days of life. Palliative sedation should be carried out with support
from the specialist palliative care team.
The aim of palliative sedation is patient comfort at end of life, not to hasten
death. When used appropriately, palliative sedation does not appear to have any
detrimental effect on survival of patients with terminal cancer. Palliative sedation
differs from euthanasia in its intentions, procedures and results [57]. The level of
sedation should be proportional, i.e. the lowest necessary to provide adequate relief
of suffering [65–67]. Good symptom relief may be attainable with light sedation,
where the patient is still able to communicate. Continuous sedation should only be
considered if the patient is in the very terminal stages of their illness with an
expected prognosis of hours, or a short number of days at most.
The decision to use medications to sedate a patient at end of life should be made in
conjunction with the multidisciplinary team involved in the care of that patient includ-
ing senior clinicians, ward staff and, if possible, the patient and his/her close family
members [64]. Where possible and appropriate, clinicians should have a pre-­emptive
discussion of the potential role of sedation with the patient and his/her family particu-
larly for patients at risk of catastrophic end-of-life events such as major bleeding [67].
Patients requiring sedation need ongoing regular review and assessment to ensure that
the level of sedation is adequately controlling their symptoms. The need for continued
palliative sedation should be re-evaluated regularly. Management of pain and other
symptoms should be continued. The need for and appropriateness of artificial hydra-
tion should be considered in each individual case [67].
Delirium is a neurocognitive syndrome that commonly occurs in older popula-
tions and people with cancer, particularly in those with advanced disease and in the
last hours or days of life [68]. Up to 88% of patients suffer from delirium in their
final weeks of life [69]. As cognitive impairment, comorbidity and increased age are
independent risk factors for delirium, an understanding of this condition is particu-
larly important for the older patient population. Management of agitated delirium in
29 Palliation at End of Life 437

palliative care involves optimising patient environment; treating causes such as

infection, constipation and urinary retention and pain [70]; and careful explanatory
communication with patients and their families [60]. Sedation should only be used
for patients with delirium who are imminently dying and whose distress and suffer-
ing cannot be alleviated by any other means.

29.5 Using Medications for Palliation at End

of Life: Summary

Medications may be used to relieve symptoms for patients who are approaching the
end of life. Careful assessment of cause, regular review of effect and a clear under-
standing of pharmacokinetics and pharmacodynamics of individual drugs can guide
rational and effective prescribing.

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Index

A Assessment, 9, 51, 75–78, 85, 87, 88, 98, 99,

Abaloparatide, 293, 300–302 113, 121, 124, 132, 135, 136, 143, 144,
Adherence, 17, 26, 27, 50, 54, 78, 81–89, 92, 146, 147, 153, 166, 167, 169, 197, 210,
101, 102, 106–109, 113, 119, 135, 136, 217, 231, 252, 254, 256, 258–260, 290,
139–141, 230, 244, 251, 252, 260, 314, 293, 312, 313, 317, 332, 352–353, 357,
332, 338, 371, 372 359, 361, 387, 398, 405, 413, 427–429,
Adverse drug events (ADEs), 16, 23, 24, 47, 432, 435, 437
61, 101, 111, 119, 132, 139, 140,
163–167, 418
Adverse drug reactions (ADRs), 9, 16, 23, 28, B
33, 47, 49–53, 56, 69, 70, 82, 86, 91, 100, Balance, 20, 21, 37, 78, 136, 147, 162, 164,
101, 109, 119, 120, 132, 136, 145, 146, 167, 195, 218, 219, 245, 297, 375,
149–150, 175, 179, 248, 251, 312, 393, 430
314, 405 Beers criteria, 27, 48, 49, 54, 76, 150, 163,
Aged, 16, 48, 50, 51, 55, 72, 101, 120, 122, 165, 176–177
146–148, 150, 161, 162, 231, 234, 243, Behavioral disorders, 173, 269–283
247, 259, 271, 290, 292, 297–299, 301, Benefit-risk, 245, 246, 250, 251, 254,
303, 331–333, 335–337, 340, 352, 354, 256, 259
358–361, 376, 399, 407, 408, 412, 417 Benign prostatic hypertrophy (BPH),
Ageing, 4–6, 8, 9, 16–19, 33, 48, 61, 69, 78, 196–197
82, 131, 132, 177, 179, 217, 231, 242, 251, Benzodiazepines, 6, 18–20, 23, 24, 26, 37,
289, 292, 293, 299, 357, 369, 375, 394 48, 70, 71, 73, 75, 77, 108, 149, 150,
Alendronate, 293–297, 300–302 163–165, 167, 169, 174–178, 188, 221,
Analgesics, 77, 108, 163, 173, 208, 218–224, 225, 279, 371, 375, 376, 392–393, 397,
372, 417, 432 398, 435
Anticholinergic drug burden (ADB), 175, 179 Beta 3 receptor agonists, 191–192
Antidepressants, 17, 19, 21, 22, 25, 63, 96, Botulinum A toxin, 192
163–165, 169, 177, 194, 224, 225, 234, Breathlessness, 241, 428, 435
271, 282, 316, 361, 369–374, 392,
398, 399
Anti-emetics, 271, 432–434 C
Antihypertensive therapy, 62, 277, 358 Calcium, 6, 20, 23, 35, 63, 188, 201, 210, 224,
Antipsychotic drugs, 48, 62, 279–283 231, 233–235, 252, 291–292, 300, 302,
Anxiety, 161, 169, 218, 225, 235, 252, 278, 304, 375, 382, 409, 413, 414
361, 369, 371, 375, 382, 394, 396, Cardiogeriatrics, 244
430, 435 Cardiovascular disease (CVD), 63, 72, 209,
Appropriateness, 26, 28, 48, 49, 51, 78, 106, 229, 248, 251, 252, 260, 261, 331, 335,
109, 110, 271 351, 359

© Springer Nature Switzerland AG 2023 441

A. Cherubini et al. (eds.), Optimizing Pharmacotherapy in Older Patients,
Practical Issues in Geriatrics, https://doi.org/10.1007/978-3-031-28061-0
442 Index

Cholinesterase inhibitors, 62–64, E

272–274, 276 Elderly, 147, 189, 194, 199, 207–209, 211,
Chronic kidney disease (CKD), 19, 405–416, 249, 252, 255, 256, 270, 279, 312–327,
418, 419 332–334, 336–341, 358, 360, 370, 373,
Chronic obstructive pulmonary disease 414, 429, 430, 433, 434
(COPD), 24, 251, 260, 311–321, 407 Electroconvulsive therapy (ECT), 374
CKD, see Chronic kidney disease
(CKD)
Co-morbidities, 72, 167, 186, 242, 245, 253, F
258–260, 355 Fall-risk-increasing drugs (FRIDs),
Comprehensive assessment, 134, 136, 163, 166–169
315, 360 Falls, 3, 18, 20, 21, 23, 24, 39, 49, 50, 53, 70,
Comprehensive geriatric assessment (CGA), 74, 75, 89, 101, 120, 121, 125, 138, 144,
26, 87, 88, 112, 144, 185, 188, 254, 313, 149, 161–167, 169, 194, 196, 197, 217,
326, 327 220, 224, 225, 231–233, 251, 271, 273,
Conservative treatment, 189, 193 276, 278, 281, 292, 332–334, 340, 341,
Constipation, 15, 21, 22, 28, 29, 53, 352, 360, 376, 393–395, 409, 413
62, 75, 188, 189, 191, 194, 199, Fractures, 23, 24, 70, 125, 138, 161, 165, 168,
220, 234, 235, 251, 275, 371, 429, 189, 217, 220, 248, 273, 278, 281,
432, 437 289–293, 297–304, 317, 332, 334, 336,
Continuity of care, 92, 95, 106, 107, 113 339–341, 376, 393, 394, 414
COPD, see Chronic obstructive pulmonary Frail older adults, 133, 140, 145–147,
disease (COPD) 150–153, 167, 291, 394
Frailty, 7–10, 24, 28, 48, 54, 55, 61, 69, 111,
119, 121, 124, 125, 131–135, 137–140,
D 143–152, 165–167, 169, 173, 179, 230,
Defecation, 199, 204, 206, 210, 211 231, 239, 251, 253, 256, 259, 290, 333,
Delirium, 15, 23, 28, 29, 53, 63, 152, 164, 336, 353–355, 369, 382, 405, 408, 409
173–179, 188, 220, 234, 235, 251, 269,
279, 314, 320, 352, 376, 396,
428, 434–436 G
Dementia, 23, 24, 62, 64, 81, 86, 87, 166, 173, Gait, 20, 23, 24, 147, 148, 162, 163, 279,
177–179, 189, 229, 251, 361, 373, 398, 297, 314
427, 428, 430, 433 Geriatric syndromes, 23, 135, 143, 145, 152,
Denosumab, 293, 299–300, 302, 303, 414 167, 251, 382, 405
Deprescribing, 54, 55, 64–66, 78, 101, 108,
110, 113, 119–127, 148, 150–152, 163,
166–169, 231 H
Depression, 17, 20, 21, 24, 49, 63, 65, 138, Heart failure (HF), 5, 23, 72, 162, 229, 233,
161, 162, 169, 218, 221, 225, 235, 260, 234, 239–250, 252, 253, 256, 258–260,
278, 279, 312, 316, 317, 319, 320, 361, 320, 321, 326, 334, 336–341, 371, 375,
369, 371, 374–375, 394, 399, 405, 410, 418, 419, 433, 434
418, 432 Heart failure with mildly reduced or midrange
Drug interactions, 16, 18, 22, 26, 29, ejection fraction (HFmrEF), 242, 243, 254
73, 99, 119 Heart failure with preserved ejection fraction
Drug–drug interactions (DDIs), 15, 17, (HFpEF), 242, 243, 245, 246, 250, 254
21–23, 26–28, 33, 40–44, 47, 72, Heart failure with reduced ejection fraction
73, 75, 106, 132, 165, 191, 221, (HFrEF), 242, 243, 245, 246, 250, 254,
222, 254, 326, 327, 372, 374 257, 259
Drug–nutrition interactions, 34, 40–44 Holistic medicine, 140
Drugs, 19, 21, 22, 34–37, 77, 163, 165, Hypertension, 5, 17, 19, 38, 60, 62, 63, 65, 72,
174, 196–197, 218–219, 221, 224–225, 133, 138, 146, 147, 192, 234, 243, 245,
230, 321 252, 253, 256, 258, 260, 281, 337, 351,
Duloxetine, 8, 190, 193–194, 225 371, 407, 408, 412, 415
Index 443

I N
Iatrogenic injury, 76, 78, 408, 412 Neuropsychiatric symptoms, 272, 273, 277,
Inappropriate medications, 55–56, 78, 101, 279, 282, 352
119, 120, 150, 165, 418 New York Heart Association (NYHA) class,
Inappropriate prescribing (IP), 3, 25, 264, 334
28, 47–49, 52, 54, 60, 64, 66, 76, Non pharmacologic therapy, 279
77, 99, 105, 119, 120, 149, 210, 251, Non-pharmacological treatment, 26, 376
418, 419 Nutritional deficiency, 381, 382, 387
Insomnia, 63, 64, 150, 169, 178, 281, Nutritional therapy, 386, 387
371, 375

O
L Older
Laxatives, 163, 200–209, 211, 220, 432 adults, 4–6, 9, 16–19, 21, 23, 26, 39,
59–63, 65, 66, 69–72, 75–76,
78, 81, 83, 86–88, 113, 132,
M 133, 135, 140, 143, 145–153, 162,
Major neurocognitive disorder, 269 163, 166, 167, 174, 176, 177,
Malnutrition, 133, 149, 174, 179, 218, 232, 185–197, 199, 201, 202, 209–211,
251, 252, 271, 314, 316, 317, 321, 217, 219–221, 223–225, 243, 249,
369, 381–387 252, 255, 257, 291–293, 300, 311,
Mechanical thrombectomy, 354, 355 318, 331, 333, 334, 349, 353, 369,
Medication 370, 373, 374, 376, 382, 383, 386,
discrepancy, 95, 96 388, 391, 393–395, 397–399,
error, 91, 92, 94, 97 405, 410
optimisation, 91–93, 95, 97 patients, 3, 6, 7, 10, 17–24, 26–28, 37–39,
reconciliation (MedRec), 24–26, 52, 78, 47, 49, 50, 55, 71, 72, 75–78, 81,
85, 91–98, 107, 110, 111, 114, 273 82, 91, 95, 100, 107–109, 112, 115,
review, 26–28, 48, 51–56, 60, 65, 91, 94, 120, 122, 126, 127, 144, 145, 148,
95, 98–102, 105–106, 108, 110, 149, 151–153, 174, 177, 189, 190,
111, 114, 166–169, 260, 397 195, 197, 201, 207, 217–225,
review tool, 27–28, 100 230–235, 239, 244–257, 260,
safety, 54, 91, 92, 94, 96–98 289–304, 317, 321, 322, 326, 327,
Medicines review, 98, 99, 110, 112 331–340, 351, 352, 354, 355,
Melatonin receptor agonists orexin receptor 357–359, 361, 362, 369, 371, 375,
antagonists, 392, 398 376, 387, 395, 406, 408–418,
Mobility, 20, 21, 138, 161–167, 169, 177, 188, 427–430, 433–436
289, 352, 361, 383, 384, 418 Older (cont.)
Models of pharmaceutical care people, 3, 16, 17, 24, 25, 28, 38–40, 47–56,
Mood stabilizer, 373–374 59, 61, 62, 69–78, 89, 91, 92, 95,
Morphine, 17, 18, 165, 173, 174, 219–221, 101, 109–111, 114, 119–126, 139,
223, 224, 320, 430–433, 435 161, 163, 165, 173, 177, 179, 190,
Multidisciplinary, 26, 85, 110, 112, 122, 134, 191, 196, 197, 200, 201, 211,
152, 177, 239, 244, 252, 256–260, 327, 217–219, 222, 224, 229–231, 239,
361, 362, 387 249–252, 255, 259, 260, 269, 352,
Multimorbidity, 16, 24, 28, 33, 48, 55, 353, 362, 381–384, 386, 387, 405,
56, 59, 61, 62, 72, 78, 81, 83, 86, 408, 412, 419, 429, 431, 433, 434
100, 101, 111, 131–137, 140, 141, persons, 82, 86, 87, 89, 124, 144–146, 151,
149, 165, 174, 179, 231, 239, 251, 161, 163, 165, 167, 185, 189,
312, 382, 407, 416, 417, 419 192–194, 196, 217, 218, 220,
Muscle strength, 138, 145, 162, 167, 317 245–250, 252, 253, 260, 290–304,
Muscle strength medication discrepancy 333, 369, 375, 382, 384, 406
444 Index

Oldest old, 229, 312, 350, 352, 356 R

Opioids, 19, 21, 23, 24, 37, 75, 77, 163–165, Risedronate, 297–299, 302
169, 176, 208, 219–224, 430–433, 435 Risk factors for stroke, 251, 253, 282, 349,
Organ function, 3, 4, 17 351, 352, 357–359, 361
Orthostatic hypotension, 20, 21, 23, 24, 73, Romosozumab, 293, 300, 302
75, 163–165, 167, 169, 197, 230–231, 235,
247, 277, 282, 337, 358, 398
Osteoporosis, 23, 24, 74, 251, 289–304, 339, S
410, 413, 414 Safety, 10, 25, 27, 34, 97, 100, 105, 107, 113,
139, 147, 148, 161, 167, 179, 201, 206,
210, 218, 220, 225, 246–249, 252, 254,
P 272, 279, 282, 291–293, 298, 300–302,
Pain, 133, 137, 138, 150, 176, 217–225, 251, 336–338, 341, 354, 359, 386, 399, 411,
278, 314, 317, 320, 370, 394, 418, 412, 414
427–430, 432, 433, 436, 437 Screening, 50, 55, 124, 151, 153, 163, 167,
Palliative care, 178, 258, 271, 313, 319, 320, 177, 197, 272, 277, 314, 316, 317,
427–429, 431, 432, 435–437 383, 384
Patient safety, 56, 60, 109 Secretions, 428, 429, 434–435
Personalized care, 127, 140 Sedation, 20, 21, 24, 37, 39, 163, 164, 188,
Pharmacists role in education and train- 224, 225, 279–282, 393–395, 434,
ing, 108–109 436, 437
Pharmacodynamics, 17–29, 33, 34, 38–39, 48, Shared-decision making (SDM), 26, 27, 99,
55, 62, 244, 393, 437 107–108, 126, 134, 218, 252
Pharmacokinetics, 3–8, 17–29, 33, 34, 37–38, STOPP/START criteria, 26, 27, 49–50,
48, 55, 62, 145–146, 221, 244, 393, 411, 56, 76, 77
431, 437 Stroke in the elderly, 358, 361
Pharmacotherapy, 311, 369, 391, 395, 398, Survival prognosis, 28, 55, 121
399, 429, 432 Symptom control, 28, 48, 127, 429
Polypharmacy, 3, 16–18, 21–28, 33, 48–50, Symptom control secretions, 429
55, 56, 59, 61, 65, 69, 70, 72, 78, 81, 83, Symptom control stroke in the elderly
86, 88, 100, 101, 105, 108, 111, 112,
132–134, 140, 148–153, 163, 167, 174,
175, 179, 188, 191, 239, 244, 251, 293, T
304, 382, 407, 417, 431 Teriparatide, 293, 300, 301, 303
Polytherapy Thrombolysis, 349, 354, 355
Potential prescribing omissions (PPOs), 28, Topical oestrogen therapy, 195–196
47, 151, 177 Transient ischaemic attack, 95, 350, 357
Potentially inappropriate medications, 15, 23, Transitions of care, 24, 85
27–28, 47, 78, 108, 149, 176 Treatment, 16, 51, 70, 81, 106, 108, 114, 122,
Precision medicine, 140, 141 144, 229–233, 239, 240, 243–255,
Prefrailty, 149, 150 257–259, 261, 271–274, 276–283,
Prescribing cascade, 15, 23, 24, 29, 54, 290–304, 311, 314, 318, 322–326,
59–66, 101 331–334, 336–341, 349–351, 353–355,
Prescribing tools, 4, 10, 26, 54, 163 357–362, 370–376, 387, 391–392,
Prevention, 16, 28, 48, 55, 56, 70, 72, 100, 394–396, 398, 399, 407–416, 419, 428,
124, 140, 166–167, 169, 174, 177–178, 429, 433, 435
220, 229, 243, 251–254, 261, 271, 277,
292, 298, 332, 357, 359, 361, 370, 397,
414, 419 U
Pulmonary fibrosis, 321–327 Underprescription, 149, 151
Index 445

V Z
Vitamin D, 291, 292, 300, 302, 304, 317, 382, Z-drugs, 165, 392, 395–397
413, 414 Zoledronic acid, 298–300, 302, 303

W
Wasting, 251