Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

Oral pharmacotherapy for overactive bladder

in older patients: mirabegron as a potential
alternative to antimuscarinics

Adrian Wagg, Victor W. Nitti, Con Kelleher, David Castro-Diaz, Emad Siddiqui
& Todd Berner

To cite this article: Adrian Wagg, Victor W. Nitti, Con Kelleher, David Castro-Diaz, Emad
Siddiqui & Todd Berner (2016) Oral pharmacotherapy for overactive bladder in older patients:
mirabegron as a potential alternative to antimuscarinics, Current Medical Research and
Opinion, 32:4, 621-638, DOI: 10.1185/03007995.2016.1149806

To link to this article: http://dx.doi.org/10.1185/03007995.2016.1149806

Accepted author version posted online: 01

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Published online: 17 Feb 2016.

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 CURRENT MEDICAL RESEARCH AND OPINION, 2016
VOL. 32, NO. 4, 621–638
http://dx.doi.org/10.1185/03007995.2016.1149806
Article RT-0512.R1/1149806
All rights reserved: reproduction in whole or part not permitted

BRIEF REVIEW

Oral pharmacotherapy for overactive bladder in older patients: mirabegron as a

potential alternative to antimuscarinics
Adrian Wagga, Victor W. Nittib, Con Kelleherc, David Castro-Diazd, Emad Siddiquie and Todd Bernerf
a
University of Alberta, Edmonton, Canada; bNew York University, USA; cGuy’s and St Thomas’ NHS Foundation Trust, UK; dUniversity Hospital
of the Canary Islands, Spain; eAstellas Pharma Europe Ltd, Chertsey, Surrey, UK; fFormerly of Astellas Scientific and Medical Affairs,
Northbrook, IL, USA

ABSTRACT ARTICLE HISTORY

Objective Overactive bladder (OAB) is a particular challenge to treat in older adults with co-morbid Received 23 November 2015
conditions taking multiple medications. Antimuscarinics (e.g., solifenacin, fesoterodine) and b3-adrener- Revised 28 January 2016
Accepted 29 January 2016
gic receptor agonists (mirabegron) are similarly efficacious; however, antimuscarinics may be associated Published online 16 February
with side effects that result in poor persistence and contribute to anticholinergic burden, particularly in 2016
those taking other medications with anticholinergic properties. With a mechanism of action distinct
from antimuscarinics, mirabegron has a different tolerability profile and does not contribute to anti- KEYWORDS
cholinergic burden. The objective of this review was to compare and contrast the tolerability profiles of Antimuscarinic; b3-
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antimuscarinics and mirabegron in older patients to inform practice. adrenoceptors; Older;

Methods Prospective trials or retrospective subgroup analyses of antimuscarinics for the treatment Overactive bladder;
of OAB in older patients were identified through a search of PubMed. Tolerability data and results of Tolerability
subgroup analyses of mirabegron in patients aged 65 and 75 years from a pooled analysis of three
trials each of 12 weeks and a 1 year trial are described.
Results Anticholinergic adverse events (AEs) including dry mouth and constipation were more frequent
with antimuscarinics versus mirabegron. In patients aged 65 years, dry mouth occurred with a six-fold
higher incidence with tolterodine extended-release (ER) 4 mg than with mirabegron 25 mg or 50 mg
over 12 weeks, and a three-fold higher incidence with tolterodine ER than mirabegron 50 mg over
1 year. Mirabegron had a low incidence of central nervous system effects. A systematic review of the
cardiovascular safety profile of mirabegron has not identified any clinically significant effects on blood
pressure or pulse rate at therapeutic doses amongst patients aged 65 years.
Conclusions Mirabegron has a more favorable tolerability profile than antimuscarinics amongst older
patients and may provide an improved benefit-to-risk ratio and therefore be considered as an alterna-
tive to antimuscarinics for older patients.

The burden of overactive bladder in older patients
Overactive bladder (OAB) is a symptom complex comprising
urinary urgency, usually accompanied by frequency and noc-
turia, with or without urgency incontinence, in the absence of
residents, nocturia, which is often associated with OAB, is the
most frequent cause of disturbed sleep, affecting 71% of cog-
nitively intact nursing home residents at least three times per
week8. In the elderly, nocturia is associated with poor sleep
9–11

patterns and tiredness as well as a fear of falling with

urinary tract infection (UTI) or other obvious pathology1. The
prevalence of OAB increases with age, as do declining general
health and cognitive function2. OAB affects up to 41% of
men and 31% of women aged >75 years3, although the
actual prevalence may be higher as many symptomatic
patients do not consult their doctor4. Of adults aged >65
years in residential care in the United States, 30% to 50% are
estimated to have OAB5.
OAB is a particular burden for older patients due to the
increased prevalence of chronic comorbidities, cognitive or
functional impairment, or frailty6. In addition, OAB can lead to
further adverse consequences including UTI, incontinence-
related dermatitis, fear of incontinence, low self-esteem,
depression7 and sleep disturbance8. Among nursing home
associated trauma, morbidity and mortality, which can cause
older people to restrict daily activities12 or lead to isolation,
with further negative outcomes.
All older persons are not alike: this population encom-
passes robust community-dwelling individuals with no or few
comorbidities, individuals with multiple long-term conditions
and/or cognitive and functional impairment, and those with
obvious frailty. The latter are particularly vulnerable and char-
acterized by their risk of significant functional decline or
death. The requirements for treatment and care of an elderly
patient with OAB are therefore highly variable and must
account for the dual challenges of multimorbidity and
polypharmacy13,14.

CONTACT Adrian Wagg, MB, FRCP (Lond), FRCP (Edin) adrian.wagg@ualberta.ca FHEA, Division of Geriatric Medicine, Department of Medicine, University of
Alberta, 1-116, Clinical Sciences Building, 11350-83 Avenue, Edmonton, Alberta, Canada
2016 Taylor & Francis
www.cmrojournal.com
 622 A. WAGG ET AL.
The two major classes of drugs for treating symptoms of
OAB are muscarinic receptor antagonists (antimuscarinics)
and b3-adrenoceptor agonists. Antimuscarinics are the main-
stay of oral pharmacotherapy, and include agents with differ-
ent tolerability profiles partially dictated by their selectivity
for muscarinic receptor subtypes. Antimuscarinics are associ-
ated with a number of side effects that can result in poor
persistence (12% to 39% of patients are still taking their
medication after 1 year)15. Anticholinergic burden, taking mul-
tiple medications with anticholinergic properties, is associated
with adverse outcomes in older patients16.
Antimuscarinic agents
The five muscarinic receptor subtypes (M1 to M5) have differ-
ing roles in various tissues throughout the body17,18. Of those
expressed in the bladder, 80% are M2, but normal human
detrusor contraction is mediated by M3; however in patho-
logical states the M2 receptor may contribute to abnormal
detrusor pathology18. Antimuscarinic agents alleviate the
symptoms of OAB through inhibition of muscarinic receptors
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in the urothelium and detrusor muscle, reducing detrusor
contraction and sensations associated with urgency19.
Depending on their relative binding affinity for each muscar-
inic receptor subtype (Table 1)20, antimuscarinics may be
associated with a range of side effects, including dry mouth
and constipation21. Newer antimuscarinics generally have
greater selectivity and stronger affinity for M2 and M3 versus
M1 receptors (Table 1), a characteristic that may improve tol-
erability; however, M3 selectivity may be associated with
higher rates of other adverse events (AEs) such as
constipation22.
All five muscarinic receptor subtypes are expressed in the
brain23 and, in mice, have been shown to play a pivotal role
in learning, memory, control of movement, pain reception
and circadian cycle regulation24. Antagonism of M1 is
expected to have the greatest impact on cognitive function,
although M2 and M4 receptors in the central nervous system
(CNS) may also play a role24,25. CNS side effects such as som-
nolence, fatigue, confusion, delirium and cognitive impair-
ment can result when antimuscarinics cross the blood–brain
barrier (BBB)26; penetration is dependent on the structural
and chemical properties of the drug and its permeability
across the BBB. Active transport across the BBB is mediated
by protein transporter systems, such as the permeability-
glycoprotein (P-gp). The antimuscarinics darifenacin, fesotero-
dine and trospium chloride are substrates for P-gp and are
actively transported from the brain. Genetic polymorphisms
of P-gp, and inhibition by commonly used drugs or foods,
can attenuate active transport of the drug out of the CNS27.
The BBB becomes more permeable in older people28,29, exa-
cerbated by cerebrovascular disease or other comorbid-
ities30–33, while polypharmacy and age-related reductions in
muscarinic receptor density in the brain and in drug metabol-
ism also increase the risk of CNS AEs.
It has been suggested that the total burden of anticholin-
ergic drugs determines the incidence of CNS AEs, rather than
the use of any single agent34. Anticholinergic burden is
negatively associated with global parameters of physical func-
tion, as measured using the Barthel Index, and can predict in-
hospital mortality in the presence of hyponatremia in older
patients35. It is also independently associated with length of
stay among older hospitalized patients35, increased morbidity,
hospitalization and mortality36. In acutely hospitalized, frail
older people, a group at high risk of serious AEs, higher anti-
cholinergic burden is independently associated with poorer
functional ability and institutionalization37,38 and an increased
risk of dementia16,39. Mild cognitive impairment occurs in up
to 20% of people aged 80 years, and is associated with an
increased risk of progression to dementia40. Thus, persons
with mild cognitive impairment may be especially vulnerable
to the impact of antimuscarinics on cognition. The American
Geriatric Society’s updated Beer’s Criteria41 for potentially
inappropriate medication use in older adults cites oral anti-
muscarinics as ‘‘potentially inappropriate medications and
classes to avoid in older adults’’.
The M2 receptor appears to have a functional role in medi-
ating heart rate42 while the M3 receptor mediates vasodila-
tion43. Hence there is the potential for cardiovascular (CV)
side effects with antimuscarinics including increased blood
pressure, increased heart rate, QT prolongation and induction
of polymorphic ventricular tachycardia (torsade de pointes)42.
In clinical practice, the potential effects on heart rate and
blood pressure seldom appear to be of clinical significance.
Antimuscarinics are highly effective for people of all ages
with OAB21. Their efficacy has been demonstrated in older
patients (generally defined as >65 or >75 years) in prospect-
ive studies and retrospective subgroup analyses44–57. These
agents provide similar clinical efficacy in older patients but
differ in tolerability due to individual chemical characteristics
and selectivity for muscarinic receptor subtypes (Table 1).
Mirabegron, the first commercially available b3-adrenocep-
tor agonist for the treatment of OAB, has a mechanism of
action and side-effect profile distinct from that of antimuscar-
inics58. In older patients, when switching between antimuscar-
inic drugs fails to improve efficacy and/or tolerability, or
where there is already an existing anticholinergic burden, mir-
abegron may be preferred. This paper reviews the tolerability
profiles and effects on quality of life (QoL) of these two
classes of agent in older patients.
Methods
Prospective trials or prospective/retrospective subgroup analy-
ses of antimuscarinics in the treatment of OAB in older
patients were identified through a search of PubMed. The
majority of studies were prospective, randomized, double-
blind, placebo-controlled with/without active control, for
durations ranging from 2 to 12 weeks and conducted in
patients aged >60 years with/without cognitive impairment.
Other studies included retrospective post-hoc analyses of 12
week pooled data and open-label extension studies for up to
2 years.
Tolerability data from these studies were described,
along with results of subgroup analyses of mirabegron in
patients aged 65 and 75 years from a pooled analysis of

Table 1. Physicochemical properties and relative selectivity of antimuscarinic
agents at the M3 versus M1 and M2 receptors20,79.
Molecular Relative M3 versus M3 versus
weight (kDa) lipophilicity M1
Darifenacin 507.5 Highly lipophilic High
Fesoterodine 527.66 Very slightly lipophilic* None
Oxybutynin 393.9 (oral) Lipophilic None
357 (transdermal) Lipophilic
Propiverine 403.9† NA None
Solifenacin 480.55 Lipophilic Moderate
Tolterodine 475.6 Slightly lipophilic None
Trospium 427.97 Not lipophilic None
*Active metabolite 5-hydroxymethyl tolterodine.
†Value in g/mol as molecular weight in kDa units unavailable.
NA ¼ not available.
three 12 week double-blind, placebo-controlled trials and a 1
year active-controlled trial.
Tolerability of antimuscarinics in older patients
The mode of action of antimuscarinics is based on antagon-
ism of the M2 and M3 receptors of the detrusor and urothe-
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lium. Dry mouth, UTI, constipation and nausea are a
consequence of non-selective and selective antagonism of
muscarinic receptor subtypes including the M3 receptor. In a
meta-analysis of 73 clinical trials encompassing seven anti-
muscarinic agents (darifenacin, fesoterodine, oxybutynin, pro-
piverine, solifenacin, tolterodine and trospium) dry mouth
(29.6% of patients) and pruritus (15.4% of patients [treated
with transdermal oxybutynin]) were the most commonly
reported AEs in adults aged 18 years21. Constipation, head-
ache and UTI were seen in 7.7%, 5.9% and 5.0% of patients,
respectively21. A network meta-analysis of 90 trials enrolling
39,919 patients reported that gastrointestinal AEs were the
most commonly explored and reported, followed by neuro-
logical, ocular and renal/genitourinary AEs59.
Studies that specifically evaluated antimuscarinics for the
treatment of OAB in older patients (prospectively or retro-
spectively) are summarized in Table 244–51,53,55,57,60–70. The
incidence of any AEs across these analyses was high, ranging
from 26% of the >75 year old patient subgroup treated with
fesoterodine (4 or 8 mg once daily [QD]) in a 12 week, open-
label extension of the SOFIA trial50 to 97% of patients aged
65 years treated with oxybutynin 15 mg immediate-release
(IR) in the VECTOR study67. The observation that oxybutynin
is associated with more systemic AEs than other antimuscar-
inics is consistent with the fact that it is one of the least
selective muscarinic receptor antagonists71, and is able to
penetrate the BBB72. Transdermal oxybutynin is generally bet-
ter tolerated than other antimuscarinics, but has a higher rate
of dermatological AEs73; however, transdermal oxybutynin has
not been specifically investigated in older patients. In add-
ition, the use of extended-release (ER) formulations (e.g. oxy-
butynin and tolterodine) has been associated with improved
tolerability compared with IR formulations74; however, the
relative benefit of using ER vs IR formulations has not been
evaluated in older patients.
Dry mouth was the most common AE in almost every ana-
lysis of antimuscarinics (Table 2). In general, most AEs were
mild or moderate in intensity, rarely serious and infrequently
led to treatment discontinuation. When AEs were severe in
MIRABEGRON VS ANTIMUSCARINICS IN OLDER PATIENTS WITH OAB 623
intensity or led to discontinuation in older patients, the AE
responsible was generally dry mouth. The highest incidence
M2 of dry mouth was observed with oxybutynin: 93% of patients
aged 70 years enrolled in a 6 week prospective, double-
High
None blind, parallel-group study69 and 80% of patients aged 65
Moderate years in a post-hoc analysis of the VECTOR study67. However,
None pre-existing dry mouth is common in the older population,
Moderate affecting up to 30% of people aged 65 years75, or dry
None mouth may be caused by the concomitant use of additional
None
medications in older patients with OAB. Future trials could
potentially explore the extent to which antimuscarinics con-
tribute to dry mouth in older patients with OAB.
Constipation is another common side effect that arises
from M3 antagonism. It is already common in older people76,
and is often a burdensome and bothersome side effect of
antimuscarinics21 that may even aggravate OAB symptoms77.
The incidence of constipation varies by antimuscarinic agent
but there is a clear dose-related increase with rates as high as
24% reported with darifenacin 15 mg QD in patients aged
65 years44 (Table 2). Hence, there is the possibility of exac-
erbating existing constipation when treating older OAB
patients with antimuscarinics.
Central nervous system side effects are a potential concern
with antimuscarinics. Darifenacin is a substrate for the P-gp
drug efflux transporter present in the BBB, and has a rela-
tively large molecular size compared with other antimuscar-
inics (Table 1)78,79, which may limit its penetration into brain
and ocular tissue and reduce its side-effect potential80.
Darifenacin is associated with a low incidence of CNS side
effects in older patients (2% of patients receiving both 7.5 mg
and 15 mg doses of darifenacin QD in a pooled subgroup
analysis of patients aged 65 years enrolled in three phase
III, 12 week, double-blind trials)44. Darifenacin was not associ-
ated with significant cognitive impairment, or significant
changes in self-rated alertness, contentment and calmness
relative to placebo in 129 elderly volunteers62 at three differ-
ent doses (3.75 mg, 7.5 mg, and 15 mg QD or 5 mg TID) for 12
days. There was also no significant difference between darife-
nacin and placebo on delayed recall in healthy subjects aged
60 years after 3 weeks of treatment60.
Fesoterodine has demonstrated favorable CNS tolerability
among antimuscarinics, presumably as a result of having the
lowest penetration across the BBB81. Fesoterodine is a pro-
drug that is rapidly metabolized to 5-hydroxymethyl toltero-
dine, which is a substrate for P-gp with limited penetration
into the brain82. In a 12 week study in individuals aged 65
years, no change in Mini Mental State Examination (MMSE)
score (a measure of cognition) was seen, although 3/392
patients in the fesoterodine group discontinued due to cogni-
tive function-related AEs of which only one was judged to be
related to study drug49. Vulnerable elderly subjects treated
with fesoterodine also demonstrated no deterioration in
mean MMSE score but subjective memory impairment was
seen in 2/281 fesoterodine-treated subjects, and another
withdrew from the study after exhibiting mild confusion that
resolved after the last dose of medication63.
A small single-center, randomized, double-blind, placebo-
controlled study in 12 healthy elderly volunteers found no
evidence that a single dose of 10 mg solifenacin impaired
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624
Table 2. Summary of prospective or retrospective studies or subanalyses of antimuscarinic agents in older patients.
Study design Treatment arms Adverse events Reference

A. WAGG ET AL.
Cohort 60 years of age
Three-week, multicenter, double-blind, Darifenacin 7.5 mg QD in weeks Darifenacin Oxybutynin Placebo Kay et al., 200660
double-dummy, parallel-group study in 1 and 2; then 15 mg QD Total AEs ¼ 55.1% Total AEs ¼ 52.0% Total AEs ¼ 45.1%
150 participants aged 60 years (mean (n ¼ 49) Most common TEAEs: Most common TEAEs: Most common TEAEs:
age 66.4, 68.0 and 67.4 years in darife- Oxybutynin ER 10 mg QD Dry mouth ¼ 26.5% Dry mouth ¼ 40.0% Dry mouth ¼ 11.8%
nacin, oxybutynin and placebo groups, increasing to 20 mg QD Constipation ¼ 20.4% Constipation ¼ 4.0%
respectively) by week 3 (n ¼ 50) Dyspepsia ¼ 6.1% Dyspepsia ¼ 4.0%
Placebo (n ¼ 51)
Cohort 65 years of age
Multicenter, 12 week, double-blind, Darifenacin 7.5 or 15 mg Darifenacin Placebo Chapple et al., 200761
randomized, placebo-controlled, paral- (n ¼ 266)
Total AEs ¼ 56.0% Total AEs ¼ 45.1%
lel-group study in patients aged 65 (voluntary up-titration to 15 mg
Most common TEAEs: Most common TEAEs:
years (mean age 72 years) after 2 weeks)
Placebo (n ¼ 133) Dry mouth ¼ 22.2% Dry mouth ¼ 3.8%
Constipation ¼ 15.4% Constipation ¼ 8.3%
Post-hoc analysis of data from patients Darifenacin 7.5 mg Darifenacin 7.5 mg Darifenacin 15 mg Placebo Foote et al., 200544
aged 65 years from pooled analysis (n ¼ 97)
Total AEs ¼ 53.6% Total AEs ¼ 69.1% Total AEs ¼ 50.9%
of three randomized, double-blind, pla- Darifenacin 15 mg
Most common TEAEs: Most common TEAEs: Most common TEAEs:
cebo-controlled 12 week studies (n ¼ 110)
Placebo (n ¼ 110) Dry mouth ¼ 21% Dry mouth ¼ 31% Dry mouth ¼ 5%
Constipation ¼ 19% Constipation ¼ 24% Constipation ¼ 6%
CV system ¼ 3% Dyspepsia ¼ 7%
Post-hoc analysis of data from patients Darifenacin 7.5 or 15 mg Darifenacin 7.5 or 15 mg Hill et al., 200745
aged 65 years enrolled in a 2 year (n ¼ 214)
Most common TEAEs:
extension study of a 12 week, double- Dry mouth ¼ 23.4%
blind study Constipation ¼ 22.4%
CNS ¼ 3.3%
Double-blind, three-period crossover study Darifenacin controlled-release Darifenacin (3.75/7.5/15 mg Placebo Lipton et al., 200562
in volunteers aged 65 years with no/ (3.75, 7.5 or 15 mg QD) or QD or 5 mg IR TID)
darifenacin IR (5 mg TID) Treatment-related AEs ¼ 14.5%
mild cognitive impairment Treatment-related AEs ¼
(n ¼ 72, 74, 65 and 71, 20.8%, 14.9%, 18.5% Most common TEAEs:
respectively) for 3.75, 7.5, and 15 mg Constipation ¼ 8.7%
Placebo (n ¼ 69) doses, respectively Dry mouth ¼ 2.9%
Most common TEAEs:
Constipation ¼ 8.1% to
12.7%
Dry mouth ¼ 4.2% to 12.7%

Fesoterodine 4 or 8 mg Fesoterodine
Prospective, 12 week, randomized, double- Placebo DuBeau et al., 201463
blind, flexible-dose, placebo-controlled (n ¼ 281) Total AEs ¼ 56.2%
Placebo (n ¼ 281) Most common TEAEs: Total AEs ¼ 42.7%
study in community-dwelling, vulner- Most common TEAEs:
able participants aged 65 years Dry mouth ¼ 23.5%
Constipation ¼ 11.1% Dry mouth ¼ 6.0%
Constipation ¼ 4.3%

Urinary retention ¼ 3.2%

(continued )
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Table 2. Continued
Study design Treatment arms Adverse events Reference
Four-week, randomized, double-blind, pla- Oxybutynin 5 mg daily extended- Oxybutynin Placebo Lackner et al., 200864
cebo-controlled trial in women aged release (n ¼ 26) Total AEs ¼ 30.8% Total AEs ¼ 37.5%
65 years with urge incontinence and Placebo (n ¼ 24)
Most common TEAEs: Most common TEAEs:
cognitive impairment in 12 skilled nurs- Cough ¼ 11.5% Cough ¼ 12.5%
ing homes Constipation ¼ 7.7% Fall ¼ 8.3%
Abdominal pain/nausea/vom- Dry mouth ¼ 4.2%
iting, fall,
dry mouth/urine retention/dry
nasal or
sinus membranes/headache/
skin rash ¼ 3.8%

Prespecified subanalyses of data stratified Oxybutynin 15 mg controlled Oxybutynin Aaron et al., 201265
by age from 4 week, open-label study release (n ¼ 111) Most common TEAEs:
(STOP) in patients aged 18 years Dry mouth ¼ 36%
Pharyngitis ¼ 11%
Dizziness ¼ 9%
Constipation ¼ 7%
Asthenia ¼ 7%
Headache ¼ 5%
Dyspepsia ¼ 5%
Abdominal pain ¼ 5%

14 day, randomized, placebo-controlled, Oxybutynin 2.5/5 mg TID Oxybutynin Placebo Ouslander et al., 199566

double-blind, dose-adjusted crossover Placebo

study in 75 nursing home residents Most common TEAEs: Most common TEAEs:

MIRABEGRON VS ANTIMUSCARINICS IN OLDER PATIENTS WITH OAB

with predominantly urge incontinence Dry mouth ¼ 42%
whose incontinence did not respond Constipation ¼ 30%
well to a trial of prompted voiding Incomplete bladder emptying
¼ 25%
Trouble sleeping ¼ 22%
Headache ¼ 20%
Joint pain ¼ 20%
Hesitancy ¼ 15%
Blurry vision ¼ 13%
Straining ¼ 13%
Reflux/heartburn ¼ 9%
Tremor ¼ 4%
Other ¼ 4%
Dry mouth ¼ 35%
Incomplete bladder emptying ¼ 31%
Constipation ¼ 25%
Headache ¼ 20%
Reflux/heartburn ¼ 20%
Straining ¼ 18%
Joint pain ¼ 16%
Trouble sleeping ¼ 15%
Hesitancy ¼ 13%
Blurry vision ¼ 13%

Retrospective analysis of pooled data from Solifenacin 5 mg (n ¼ 192) Solifenacin 5 mg Solifenacin 10 mg Placebo Wagg et al., 200653
patients aged 65 years in four dou- Solifenacin 10 mg (n ¼ 431) Most common TEAEs: Most common TEAEs: Most common TEAEs:
ble-blind, randomized, 12 week studies Placebo (n ¼ 422)
Dry mouth ¼ 13.5% Dry mouth ¼ 31.6% Dry mouth ¼ 4.7%
Constipation ¼ 9.4% Constipation ¼ 18.1% Constipation ¼ 4.3%
UTI ¼ 3.6% UTI ¼ 7.0% UTI ¼ 3.1%
Retrospective analysis of data from Solifenacin 5 mg Solifenacin 5 mg Solifenacin 10 mg
patients aged 65 years in a 40 week, (n ¼ 509)
Most common TEAEs: Most common TEAEs:
open-label extension study of two of Solifenacin 10 mg
the four double-blind studies (n ¼ 330) Dry mouth ¼ 13.6% Dry mouth ¼ 21.5%
Constipation ¼ 6.1% Constipation ¼ 11.5%
UTI ¼ 5.7% UTI ¼ 7.0%
(continued )

625
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Table 2. Continued

626
Study design Treatment arms Adverse events Reference
Post-hoc analysis of data from patients Solifenacin 5 or 10 mg Solifenacin 5 or 10 mg Capo et al., 201151
aged 65 years from the 12 week, (n ¼ 892)

A. WAGG ET AL.
Total AEs ¼ 59%
open-label, flexible dosing VOLT study Most common TEAEs:
Dry mouth ¼ 23%
Constipation ¼ 16%
UTI ¼ 4%
Blurred vision, headache, upper
respiratory tract infection ¼ 3%
Post-hoc analysis of data from patients Solifenacin 5 or 10 mg Solifenacin 5 or 10 mg
aged 65 years from the 12 week, (n ¼ 194)
Total AEs ¼ 62%
open-label, flexible dosing VERSUS Most common TEAEs:
study Dry mouth ¼ 19%
Constipation ¼ 12%
UTI ¼ 6%
Dry eye ¼ 4% Upper
respiratory tract
infection ¼ 3%

Post-hoc subgroup analysis of patients Solifenacin 5 mg (n ¼ 27) Solifenacin 5 mg Oxybutynin 15 mg Herschorn et al., 201167
aged 65 years from 12 week, double- Oxybutynin 15 mg IR (n ¼ 30) Total AEs ¼ 70% Total AEs ¼ 97%
blind, double-dummy VECTOR study Most common TEAEs: Most common TEAEs:
comparing solifenacin and oxybutynin Dry mouth ¼ 37% Dry mouth ¼ 80%
Constipation ¼ 19% Nasal dryness ¼ 17%
Fatigue ¼ 15% Dizziness ¼ 13%
Dyspepsia ¼ 11% Constipation ¼ 10%
UTI ¼ 7% Dysphagia ¼ 10%
Dysphonia ¼ 4% Fatigue, cough, dry eye,
Cough ¼ 4% nasopharyngitis ¼ 7%
Somnolence ¼ 4% Headache, UTI,
Dysgeusia ¼ 4% somnolence, confusion,
abdominal pain ¼ 3%
Prospectively designed, randomized, dou- Tolterodine 1 mg BID (n ¼ 61) Tolterodine 1 mg Tolterodine 2 mg Placebo Malone-Lee et al., 200155
ble-blind, placebo-controlled, study in Tolterodine 2 mg BID (n ¼ 73)
Total AEs ¼ 70% Total AEs ¼ 73% Total AEs ¼ 63%
patients aged 65 years Placebo (n ¼ 43)
Most common TEAEs: Most common TEAEs: Most common TEAEs:
Dry mouth ¼ 30% Dry mouth ¼ 48% Dry mouth ¼ 9%
Diarrhea ¼ 8% Headache ¼ 7% Dyspepsia ¼ 9%
Dizziness ¼ 5% Dyspepsia ¼ 6% Dizziness ¼ 7%
Constipation ¼ 5% Abdominal pain ¼ 6% Diarrhea ¼ 5%
Headache ¼ 5% Diarrhea ¼ 4% Abdominal pain ¼ 5%
Abdominal pain ¼ 3% Dizziness ¼ 4%
Nausea ¼ 3%
Abnormal

accommodation ¼ 3%
(continued)
 Downloaded by [Reprints Desk Inc] at 15:14 28 July 2016
Table 2. Continued
Study design Treatment arms
Mixed cohort 65–75 years and >75 years of age
Post-hoc analysis of pooled data from two Fesoterodine 8 mg Fesoterodine (65–75 cohort)
placebo- and active (tolterodine)-con- (n ¼ 546)
Total AEs ¼ 57.3%
trolled, randomized, 12 week trials
Most common TEAEs:
Dry mouth ¼ 31.9%
Constipation ¼ 5.8%
Headache ¼ 4.0%
Tolterodine ER 4 mg Tolterodine (65–75 cohort)
(n ¼ 586)
Total AEs ¼ 37.6%
Most common TEAEs:
Dry mouth ¼ 13.3%
Constipation ¼ 5.1%
Placebo (n ¼ 306) Placebo (65–75 cohort)
Total AEs ¼ 31.7%
Most common TEAEs:
Dry mouth ¼ 6.0%
Post-hoc analysis of data from two Fesoterodine 4 mg Fesoterodine 4 mg
randomized, placebo-controlled, 12 week (n ¼ 184) (65–75 cohort)
studies pooled and stratified by age: 65 Most common TEAEs:
to <75 and 75 years Dry mouth ¼ 17%
UTI ¼ 5%
Nasopharyngitis ¼ 3%
Dyspepsia ¼ 3%
Dizziness ¼ 3%
Fesoterodine 8 mg Fesoterodine 8 mg (65–75
(n ¼ 186) cohort)
Most common TEAEs:
Dry mouth ¼ 35%
Constipation ¼ 11%
UTI ¼ 5%
Dry throat ¼ 4%
Urinary retention ¼ 4%
Dry eye ¼ 3%
Placebo (n ¼ 178) Placebo (65–75 cohort)
Most common TEAEs:
Dry mouth ¼ 7%
UTI ¼ 4% Sinusitis
¼ 4% Constipation
¼ 3% Diarrhea ¼
3%
Adverse events Reference
Fesoterodine (>75 cohort) DuBeau et al., 201247
Total AEs ¼ 49.1%
Most common TEAEs:
Dry mouth ¼ 29.9%
Constipation ¼ 9.6%
Tolterodine (> 75 cohort)
Total AEs ¼ 45.4%
Most common TEAEs:
Dry mouth ¼ 17.8%
Constipation ¼ 6.9%
Diarrhea ¼ 4.6%
Placebo (> 75 cohort)
Total AEs ¼ 35.5%
Most common TEAEs:
Dry mouth ¼ 5.6%
Fesoterodine 4 mg Kraus et al., 201048
(>75 cohort)
Most common TEAEs:
Dry mouth ¼ 17%
Constipation ¼ 10%
UTI ¼ 3%
MIRABEGRON VS ANTIMUSCARINICS IN OLDER PATIENTS WITH OAB
Nasopharyngitis ¼ 3%
Toothache ¼ 3%
Fesoterodine 8 mg (>75 cohort)
Most common TEAEs:
Dry mouth ¼ 46%
Constipation ¼ 15%
UTI ¼ 13%
Dyspepsia ¼ 7%
Dizziness ¼ 6%
Upper RTI ¼ 4%
Balance disorder ¼ 4%
Placebo (>75 cohort)
Most common TEAEs:
Dry mouth ¼ 9%
UTI ¼ 7%
Headache ¼ 5%
Diarrhea ¼ 5%
Influenza ¼ 5%
Dizziness ¼ 3%
Nausea ¼ 3%
Epistaxis ¼ 3%
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627
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Table 2. Continued
Study design Treatment arms
Prospective, 12 week, double-blind, Fesoterodine 4 or 8 mg Fesoterodine (65–75 cohort)
randomized, placebo-controlled trial (n ¼ 392)
Total AEs ¼ 64.8% Most
(SOFIA) in patients aged 65 years common TEAEs: Dry
mouth ¼ 38.3%
Constipation ¼ 9.5%
Nasopharyngitis ¼ 3.8%
Headache ¼ 3.8%
Dizziness ¼ 3.0%
Fatigue ¼ 3.0%
Placebo (n ¼ 393) Placebo (65–75 cohort)
Total AEs ¼ 34.1%
Most common TEAEs:
Dry mouth ¼ 4.5%
Fatigue ¼ 3.7%
Prospective, 12 week, open-label extension Fesoterodine Placebo þ open label
of SOFIA trials (see above). Patients who 4 or 8 mg fesoterodine (65–75 cohort)
had received double-blind placebo started Double-blind placebo þ open- Total AEs ¼ 45.1%
the open-label phase on fesoterodine label fesoterodine (n ¼ 341) Most common TEAEs:
4 mg with option to increase to 8 mg dose Dry mouth ¼ 27.0%
after 4 or 8 weeks. Patients who had Constipation ¼ 6.4%
received double-blind fesoterodine contin- Headache ¼ 3.0%
ued on the same dose Double-blind fesoterodi- Fesoterodine þ open label
ne þ open-label fesoterodine fesoterodine (65–75 cohort)
(n ¼ 313)
Total AEs ¼ 32.9%
Most common TEAEs:
Dry mouth ¼ 7.5%
UTI ¼ 3.8%
Retrospective analysis of pooled data from Tolterodine 4 mg ER QD Tolterodine (65–74 cohort)
five randomized, double-blind, placebo- (n ¼ 867)
Most common TEAEs:
controlled trials of 8–12 weeks’ duration, Dry mouth ¼ 16%†
stratified by age, 65–74 years and 75 Constipation ¼ 4.2%
years Headache ¼ 3.5%
Placebo (n ¼ 765) Placebo (65–74 cohort)
Dry mouth ¼ 5%†
Post-hoc analyses of data from 12 week, Tolterodine 4 mg ER QD Tolterodine (65–74 cohort)
double-blind, placebo-controlled study; (n ¼ 214) Total AEs ¼ 54.2%
results stratified by age, <65 years and Placebo (n ¼ 222) Most common TEAEs:
65 years Dry mouth ¼ 24.3%
Constipation ¼ 6.1%
Headache ¼ 3.7%
UTI ¼ 3.7%
628
Adverse events Reference
Fesoterodine (>75 cohort) Wagg et al., 201349
A. WAGG ET AL.
Total AEs ¼ 57.0%
Most common TEAEs:
Dry mouth ¼ 25.0%
Constipation ¼ 7.8%
Dizziness ¼ 4.7%
UTI ¼ 3.9%
Diarrhea ¼ 3.9%
Nausea ¼ 3.1%
Placebo (>75 cohort)
Total AEs ¼ 40.5% Most
common TEAEs: Dry
mouth ¼ 7.1%
Constipation ¼ 4.0%
Nasopharyngitis ¼ 4.0%
Diarrhea ¼ 3.2%
Placebo þ open label Wagg et al., 201450
fesoterodine (>75 cohort)
Total AEs ¼ 54.6%
Most common TEAEs:
Dry mouth ¼ 29.6%
Constipation ¼ 5.6%
Fesoterodine þ open label
fesoterodine (>75 cohort)
Total AEs ¼ 26.0%
Most common TEAEs:
UTI ¼ 6.0%
Dry mouth ¼ 5.0%
Tolterodine ( 75 cohort) Griebling et al., 200968
Most common TEAEs:
Dry mouth ¼ 15%†
Constipation ¼ 4%
Placebo ( 75 cohort)
Dry mouth ¼ 3%†
Constipation¼ 3%
Placebo (65–74 cohort) Zinner et al., 200257
Total AEs ¼ 46.0%
Most common TEAEs:
Dry mouth ¼ 7.2%
Constipation ¼ 4.5%
Headache ¼ 3.2%
UTI ¼ 3.2%
(continued )
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Table 2. Continued
Study design Treatment arms Adverse events Reference
Cohort 70 years of age
Prospective, 6 week, double-blind, parallel- Oxybutynin 2.5 mg BID (n ¼ 30) Oxybutynin Placebo Szonyi et al., 199569
group study in which elderly patients Placebo (n ¼ 30) Most common TEAEs: Most common TEAEs:
aged 70 years living in the commu-
Dry mouth ¼ 93% Dry mouth ¼ 86%
nity received bladder training and drug
Blurred vision ¼ 50% Blurred vision ¼ 59%
or placebo
Heartburn ¼ 57% Heartburn ¼ 45%
Constipation ¼ 50% Constipation ¼ 45%
Dry skin ¼ 50% Dry skin ¼ 59%
Cohort 75 years of age
Prospective, randomized, double-blind, tri- Solifenacin 5 mg QD (n ¼ 23) Solifenacin Oxybutynin Placebo Wagg et al., 201370
ple-crossover trial in participants aged Oxybutynin 5 mg BID (n ¼ 25)
Total AEs ¼ 60.9% Total AEs ¼ 84.0% Total AEs ¼ 50.0%
75 years with mild cognitive Placebo (n ¼ 22)
Most common TEAEs: Most common TEAEs: Most common TEAEs:
impairment Dry mouth, oropharyngeal
Dry mouth ¼ 17.4% Dry mouth ¼ 52.0%
Eye disorders ¼ 8.7% Dyspepsia ¼ 16.0% pain, pruritus, micturition
Balance disorder ¼ 8.7% Eye disorders ¼ 12.0% disorder ¼ 9.1%
Constipation, nausea, dys- Pain in extremity ¼ 8.0% Constipation, diarrhea,
pnea, pruritus, pollakiuria, Diarrhea, nausea, naso- nasopharyngitis ¼ 4.5%
back pain, vision blurred ¼ pharyngitis, oropharyngeal
4.3% pain, dyspnea, pollakiuria,
No other AEs reported back pain, memory impair-
ment, vision blurred ¼
4.0%
Subgroup analysis of pooled data from Trospium chloride 60 mg Trospium Placebo Sand et al., 201146
patients aged 75 years from two ER (n ¼ 85) Total AEs ¼ 49.4% Total AEs ¼ 50%

MIRABEGRON VS ANTIMUSCARINICS IN OLDER PATIENTS WITH OAB

randomized, double-blind, 12 week Placebo (n ¼ 58) Most common TEAEs: Most common TEAEs:
studies Constipation* ¼ 10.6% Diarrhea ¼ 5.2%
Dry mouth*¼ 10.6% Dry mouth ¼ 3.4%
Dizziness ¼ 3.4%
Subgroup analysis of pooled data from Trospium chloride 60 mg Total AEs ¼ 65.2%
patients aged 75 years from 9 month ER (n ¼ 112) Most common TEAEs:
extension studies of the two random- Constipation* ¼ 8.0%
ized, double-blind, 12 week studies Dry mouth* ¼ 8.0%
above

The incidence of AEs of any cause is provided where available, along with the incidence of the most common AEs. 65 and 75 year age cut-offs were typically used in the age stratification of the data. Note that data for the
older but not the younger cohort (whether aged <65 years or <75 years) are shown. Those AEs that occurred with an incidence of 3% are shown, where data are available44–51,53,55,57,60–70.
AE: adverse event; BID: twice daily; CV: cardiovascular; ER: extended-release; IR: immediate-release; QD: once daily; TEAE: treatment-emergent adverse event; TID: three times daily; UTI: urinary tract infection.
*AEs considered at least possibly related to study medication.
†Percentages are approximated from Figure 1 of Griebling et al., 200968 as actual data are not provided in the paper.

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630
A. WAGG ET AL.
Table 3. Treatment-emergent adverse events by preferred term; 12 week and 1 year analyses (SAF)121.
12 week analysis

Age category 65 years 75 years

Placebo* Mirabegron Tolterodine ER 4 mg Placebo* Mirabegron Tolterodine ER 4 mg
(n = 521) 25 mg (n = 154) 50 mg (n = 514) (n = 192) (n = 157) 25 mg (n = 32) 50 mg (n = 154) (n = 37)
Studies 046, 047, 074 074 046, 047, 074 046 046, 047, 074 074 046, 047, 074 046
Any TEAE, n (%) 254 (48.8) 84 (54.5) 258 (50.2) 95 (49.5) 77 (49.0) 20 (62.5) 77 (50.0) 22 (59.5)
TEAEs reported by 3% of patients in any treatment group in the 65 year subgroup (by preferred term), n (%)
Hypertension† 44 (8.4) 21 (13.6) 51 (9.9) 23 (12.0) 15 (9.6) 6 (18.8) 21 (13.6) 8 (21.6)
Nasopharyngitis 13 (2.5) 7 (4.5) 21 (4.1) 7 (3.6) 2 (1.3) 0 4 (2.6) 2 (5.4)
Urinary tract infection 15 (2.9) 10 (6.5) 16 (3.1) 3 (1.6) 3 (1.9) 5 (15.6) 3 (1.9) 0
Headache 9 (1.7) 4 (2.6) 14 (2.7) 9 (4.7) 0 2 (6.3) 4 (2.6) 1 (2.7)
Dry mouth 8 (1.5) 3 (1.9) 9 (1.8) 21 (10.9) 0 0 4 (2.6) 4 (10.8)
Dizziness 8 (1.5) 7 (4.5) 9 (1.8) 3 (1.6) 1 (0.6) 1 (3.1) 2 (1.3) 0
Constipation 8 (1.5) 4 (2.6) 7 (1.4) 6 (3.1) 5 (3.2) 1 (3.1) 2 (1.3) 1 (2.7)
Pain in extremity 8 (1.5) 5 (3.2) 7 (1.4) 0 1 (0.6) 1 (3.1) 4 (2.6) 0
Any TEAE leading to discontinuation, n (%) 26 (5.0) 7 (4.5) 29 (5.6) 14 (7.3) 6 (3.8) 1 (3.1) 12 (7.8) 6 (16.2)
Any SAE, n (%) 15 (2.9) 2 (1.3) 14 (2.7) 8 (4.2) 3 (1.9) 0 5 (3.2) 4 (10.8)
1 year study
(n = 289) (n = 303) (n = 75) (n = 83)
Any TEAE, n (%) 188 (65.1) 195 (64.4) 51 (68.0) 53 (63.9)
TEAEs reported by 3% of patients in any treatment group in the 65 year subgroup (by preferred term), n (%)
Hypertension† 30 (10.4) 39 (12.9) 7 (9.3) 12 (14.5)
Urinary tract infection 23 (8.0) 25 (8.3) 7 (9.3) 9 (10.8)
Dizziness 14 (4.8) 11 (3.6) 2 (2.7) 5 (6.0)
Constipation 12 (4.2) 10 (3.3) 3 (4.0) 5 (6.0)
Influenza 12 (4.2) 7 (2.3) 5 (6.7) 2 (2.4)
Back pain 10 (3.5) 5 (1.7) 4 (5.3) 1 (1.2)
Nasopharyngitis 9 (3.1) 6 (2.0) 2 (2.7) 1 (1.2)
Dry mouth 9 (3.1) 31 (10.2) 0 8 (9.6)
Bronchitis 9 (3.1) 10 (3.3) 1 (1.3) 2 (2.4)
Diarrhea 8 (2.8) 9 (3.0) 3 (4.0) 4 (4.8)
Cystitis 8 (2.8) 14 (4.6) 2 (2.7) 4 (4.8)
Fatigue 5 (1.7) 9 (3.0) 1 (1.3) 3 (3.6)
Headache 4 (1.4) 9 (3.0) 2 (2.7) 2 (2.4)
Any TEAE leading to discontinuation, n (%) 20 (6.9) 23 (7.6) 6 (8.0) 6 (7.2)
Any SAE, n (%) 18 (6.2) 22 (7.3) 9 (12.0) 8 (9.6)
AE: adverse event; SAE: serious adverse event; SAF: safety analysis set; TEAE: treatment-emergent adverse event.
*Tolerability data for the placebo groups of Study 046 and Study 074 are not shown separately as these placebo groups are included in the pooled placebo group shown; tolerability data for individual placebo groups were
similar to that shown here for the pooled placebo group.
†Hypertension was reported as an AE if average systolic blood pressure (SBP) was 140 mmHg and/or average diastolic blood pressure (DBP) 90 mmHg at two consecutive post-baseline visits for normotensive patients at
baseline; average SBP increased 20 mmHg and/or average DBP increased 10 mmHg at two consecutive post-baseline visits for patients with hypertension at baseline; initiation or increase in antihypertensive medication;
or according to clinical assessment by the investigator.

cognition or self-ratings of mood and alertness compared
with placebo83, and at a chronic dose of 5 mg it had no effect
on cognitive function in 23 participants with mild cognitive
impairment70. In a prospective, non-interventional, multicen-
ter study in 917 patients aged 70 years (mean age 77 years)
flexible-dose solifenacin was well tolerated with no clinically
relevant impact on cognitive status, as measured by the
MMSE, over a 12 week period84.
Clinical case reports have associated tolterodine, solifena-
cin and oxybutynin with impaired cognitive functioning,
which may be related to lipophilicity, anticholinergic potential
and/or molecular size. Oxybutynin is a relatively small tertiary
amine with the highest lipophilicity among antimuscarinics
(Table 1)79, enabling it to penetrate the BBB72 and, more than
any other antimuscarinic, is associated with an increased risk
of cognitive impairment83,85. Oxybutynin demonstrated sig-
nificant effects on quantitative topographical electroencephal-
ography activity, perhaps implying a higher risk of CNS side
effects72. It also precipitated acute confusional states in an
elderly patient with Parkinson’s disease who was cognitively
impaired86, and produced memory impairment as measured
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using the Name–Face Association Test compared with pla-
cebo after 3 weeks in healthy subjects aged 60 years60.
However, one study reported that oral oxybutynin ER 5 mg
daily for 4 weeks was not associated with delirium or short-
term decline in cognition in older female nursing home resi-
dents with urgency urinary incontinence and mild-to-severe
cognitive impairment64. As they are less lipophilic, tolterodine
and solifenacin are less likely to cross the BBB than oxybuty-
nin87; although there have been reports of night terrors, hal-
lucinations and forgetfulness in two older women (aged 73
and 80 years) and one younger woman (aged 46 years) tak-
ing tolterodine88–90 and an 80 year old male treated with
solifenacin91.
Trospium ER is a nonselective and hydrophilic quaternary
amine that is unlikely to cross the BBB92. Trospium chloride
levels were undetectable at steady state in the cerebrospinal
fluid of 12 cognitively intact older adults with OAB who
received trospium chloride ER 60 mg QD over a 10 day
period93. These participants demonstrated no significant net
drug effect on learning or recall as measured using the
Hopkins Verbal Learning Test–Revised and Brief Visuospatial
Memory Test93. Trospium has demonstrated a lack of effect
on central nervous electrical activity in healthy adult volun-
teers72,94. However, there is little data from trials which have
specifically reported on its effects in older persons.
Propiverine, which displays both antimuscarinic and cal-
cium channel blocking properties, is not associated with
impaired cognitive functioning, as measured by the MMSE
score. Following 12 weeks’ treatment with propiverine 30 mg
ER in 201 patients aged 70 years with OAB, there was no
significant change in MMSE score including those patients
(n ¼ 66) who had mild-to-moderate cognitive impairment at
baseline95.
A recent review of the literature on the CV effects of anti-
muscarinics in OAB patients concluded that while the CV
safety profile of antimuscarinics is acceptable, there is insuffi-
cient evidence to exclude the possibility of an increase in
heart rate, QT prolongation or an increase in CV risk in older
MIRABEGRON VS ANTIMUSCARINICS IN OLDER PATIENTS WITH OAB 631
patients with comorbidities taking multiple medications.
Clinical and electrocardiogram monitoring is therefore war-
ranted in older patients who may be predisposed to a higher
CV risk96.
A number of studies of antimuscarinics in older patients
with OAB have included validated assessments of health-
related QoL. In a 12 week, multicenter, double-blind, random-
ized, placebo-controlled, parallel-group study of darifenacin in
patients aged 65 years61, significant improvements relative
to placebo were seen on total OAB questionnaire (OAB-q)
scores; its individual domains of symptom bother, coping,
concern and sleep; the Patient Perception of Bladder
Condition (PPBC); and patient and physician assessment of
treatment benefit at weeks 6 and 1221. In two 12 week, multi-
center, randomized, double-blind, placebo-controlled studies
of flexible-dose fesoterodine in patients aged >65 years
(SOFIA trial)49 and in vulnerable elderly subjects (>65 years)
with urgency incontinence63, fesoterodine was associated
with statistically significant improvements relative to placebo
in patient-reported outcomes, including OAB-q scores and
PPBC; these improvements were maintained in the 12 week,
open-label extension of the SOFIA trial50. In a post-hoc ana-
lysis of pooled data from two double-blind, placebo-con-
trolled, 12 week trials, fesoterodine resulted in statistically
significant improvements relative to placebo in symptom
bother, total health-related QoL (HRQoL) and its domains of
coping, concern, sleep and social interaction in patients aged
75 years and in all of these endpoints except social inter-
action in patients aged 65 to 74 years47. Subgroup analysis of
a 12 week, multicenter, prospective, open-label, flexible-dos-
ing study of solifenacin in patients aged 65 years found sig-
nificant improvement in symptom bother, HRQoL, work
productivity and activity participation as well as reduced
medical care resource utilization97. In the only other study to
evaluate effects on HRQoL, trospium did not improve HRQoL
as measured using the King’s Health Questionnaire46.
Despite the potential for anticholinergic side effects with
antimuscarinics, the American Urological Association guide-
lines recognize that these can often be prevented or avoided
by proactively monitoring and managing side effects through
dose modification or switching to an alternative antimuscar-
inic. Measures to prevent constipation include patient educa-
tion on the potential anticholinergic effects on bowel
function and recommendations such as adequate dietary
fiber, fluid intake and regular exercise. To avoid dry mouth,
patients are advised to use oral lubricants, alcohol-free
mouthwashes, and to consume small sips of water, sugar-free
hard sweets and chew sugar-free gum98. In the only trial to
formally assess such measures, the use of oral salivary stimu-
lant pastilles in addition to oxybutynin had no impact on
adherence or symptom relief99; therefore, it is unclear
whether these interventions are effective.
The b3-adrenoceptor agonist mirabegron
An introduction to mirabegron
Adherence is a common problem in chronic conditions
requiring long-term therapy such as diabetes, glaucoma,
 632 A. WAGG ET AL.
hypertension and OAB. Treatment factors responsible for
medication nonadherence include poor tolerability, inad-
equate efficacy, and, for some, the cost of medication.
Suboptimal use of well tolerated medications is also common
and probably related to poor patient education and expecta-
tions from treatment100. Effective treatment of any chronic
condition is predicated on long-term adherence. Therefore,
OAB medications with potentially less burdensome anticholin-
ergic side effects, such as the b3-adrenoceptor agonists, may
result in improved adherence and treatment outcomes in
older patients. Early experience in Canada with mirabegron
indicates significantly improved 6 month persistence rates
compared with antimuscarinics, with a median medication
possession ratio (i.e., the percentage of time a patient has
access to medication) of 77% vs 32%–49% in OAB patients
treated with mirabegron and antimuscarinics, respectively.
Furthermore, patients aged 65 years were on average 38%
less likely to discontinue treatment than those aged <46
years of age101. A retrospective analysis of a large United
States medical claims database (Optum) showed that adult
patients persisted with mirabegron for a significantly longer
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period compared with those receiving tolterodine, and treat-
ment with mirabegron led to a reduction in overall costs and
resource utilization; age 65 years was a significant factor
associated with increased persistence with mirabegron102.
The b3-adrenoceptor, along with the b1- and b2-adreno-
ceptors, is located in the bladder detrusor muscle and urothe-
lium103,104. In the human bladder, the b3-adrenoceptor
accounts for 97% of total b-adrenoceptor messenger RNA105
and is thought to be the main subtype mediating relaxation
of detrusor smooth muscle during the storage phase in
humans106. Stimulation of b3-adrenoceptors elicits direct
relaxation of detrusor smooth muscle, and is associated with
increased bladder capacity without a change in micturition
pressure, post-void residual (PVR) volume or voiding contrac-
tion107–109. Because b3-adrenoceptors are only sparsely dis-
tributed in the human body, it might be reasonable to expect
binding at this receptor to be associated with fewer AEs and
a more favorable tolerability profile than antimuscarinics. All
of the b-adrenergic receptor subtypes are important regula-
tors of human cardiac function so there is the potential for
CV side effects.
Mirabegron is the first b3-adrenoceptor agonist to enter
clinical practice, although others including solabegron110, rito-
begron111,112 and TRK-380113 are currently under develop-
ment. In vitro, the affinity of mirabegron for b3-adrenoceptors
is 150- and 33-fold higher than for b1- and b2-adrenoceptors,
respectively114. Mirabegron has been shown to improve the
storage capacity of the bladder without impairing bladder
contraction during voiding109. In three pivotal, large-scale, 12
week, multicenter, parallel-group, phase III trials in patients
with OAB aged 18 years (Studies 046115, 047116 and 074117),
mirabegron, at doses of 25 mg, 50 mg and 100 mg QD (the
100 mg dose is not an approved dose), demonstrated signifi-
cant efficacy relative to placebo in treating the symptoms of
OAB, including micturition frequency, urinary incontinence
and urgency118. Furthermore, the incidence of hypertension
and effects on vital signs were similar between mirabegron
(50 mg and 100 mg), tolterodine (active control) and
placebo118,119.
Efficacy and tolerability of mirabegron in older patients
A prospectively designed phase IV study to evaluate the effi-
cacy, safety and tolerability of mirabegron in adults with OAB
aged 65 years (NCT02216214) is currently recruiting partici-
pants. In the interim, insights into the efficacy and tolerability
of mirabegron in older patients have been derived from pre-
specified subanalyses of: mirabegron 25 mg data from one 12
week study (Study 074)117; mirabegron 50 mg data pooled
from three phase III 12 week trials115–117; and of mirabegron
50 mg from a 1 year, randomized, phase III trial120. In the
pooled subanalyses, 12 weeks of once daily treatment with
mirabegron 50 mg reduced the mean numbers of incontin-
ence episodes per 24 hours from baseline to final visit by 0.66
and 0.65, and micturitions per 24 hours by 0.62 and 0.59 in
the subgroups of patients aged 65 and 75 years, respect-
ively121. Improvements of a similar magnitude in incontinence
and micturition frequency were evident with mirabegron
25 mg after 12 weeks of treatment in patients aged 65 and
75 years121. Moreover, it was well tolerated in both sub-
groups over 12 weeks: the incidence of serious AEs and treat-
ment-emergent AEs that led to discontinuation of mirabegron
was low and comparable across the mirabegron 25 mg, mira-
begron 50 mg and placebo groups in patients aged 65
years (Table 3). Over 1 year, the incidence of serious AEs and
treatment-emergent AEs that led to discontinuation of mira-
begron 50 mg in patients aged 65 years was lower than
with tolterodine ER (Table 3). The incorporation of tolterodine
ER 4 mg as an active control arm in one of the pivotal 12
week studies, and the 1 year study, enabled assessment of
mirabegron and a commonly used antimuscarinic in the same
trial population and allowed their tolerability profiles to be
contrasted. Whereas dry mouth (10.9%) and hypertension
(12.0%) were the two most common AEs seen in patients
aged 65 years treated with tolterodine, the most common
AEs seen in patients treated with mirabegron 50 mg were
hypertension (9.9%) and nasopharyngitis (4.1%); hypertension
was defined according to three prespecified criteria (Table 3).
Dry mouth was seldom reported in association with mirabe-
gron in both 12 week and 1 year studies115–117,120. With dry
mouth often causing discontinuation of treatment with anti-
muscarinics122, this is an important difference that underlines
the different mechanisms of action of these two drug classes.
There are few if any b3-adrenoceptors in the human
CNS123 which may explain the low incidence of adverse CNS
effects reported in the clinical trial program for mirabegron,
encompassing more than 13,600 participants on monotherapy
cumulatively over more than 10 years. Mirabegron is also a
substrate for the P-gp active efflux system. However, all three
b-adrenoceptor subtypes are expressed in the CV system,
with b1-mediated effects increasing heart rate and force of
contraction; b2-adrenoceptors mediating vasodilation in the
vascular smooth muscle124; and b3-adrenoceptors triggering
positive inotropic effects in human atrial tissue and negative
inotropic effects in ventricular tissue125. As a consequence,

the CV safety of mirabegron (including QTc prolongation,
hypertension, cardiac arrhythmia [including atrial fibrillation
and tachycardia] and vital signs) has been monitored
closely in the clinical trial program. Over one third of the OAB
population exposed to mirabegron in clinical studies had
hypertension at baseline and approximately one in 10 had
diabetes mellitus at baseline119,126.
In spite of these risk factors and its mechanism of action,
the CV safety profile of mirabegron has been found to be
acceptable at therapeutic doses. While mirabegron 50 mg was
associated with a mean (6 standard error [SE]) increase of 0.6
(6 0.35) and 0.4 (6 0.22) mmHg in morning systolic and dia-
stolic blood pressure, respectively, and 1 (6 0.24) bpm
increase in pulse rate compared with placebo in a prospective
analysis of pooled data from three phase III 12 week trials127,
these increases were reversible upon treatment discontinu-
ation and did not result in more CV-related AEs than in
patients treated with placebo or tolterodine127,128. In the total
patient population enrolled in the 1 year phase III study,
reports of increased heart rate were lower with mirabegron
50 mg compared with tolterodine120. There were no cases of
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increased heart rate with mirabegron in patients aged 65
and 75 years in the three phase III 12 week trials. Using a
consistent definition, the incidence of hypertension in the
oldest patients ( 75 years) was higher with tolterodine
(14.5%) than mirabegron 50 mg (9.3%) over a 1 year period
(Table 3). Hence, the risk of CV AEs may be the same as or
even lower with mirabegron than with tolterodine. Despite
the absence of CV AEs, mirabegron is not recommended
in patients with severe uncontrolled hypertension (systolic
blood pressure 180 mmHg and/or diastolic blood pressure
110 mmHg)129. Periodic blood pressure and heart rate moni-
toring is recommended in patients aged >80 years given the
lack of data on patients with significant CV risk factors in the
phase III trials119.
Bladder emptying and voiding efficiency may deteriorate
with age, contributing to higher rates of urinary retention in
older patients with OAB. PVR volumes >500 mL appear to be
predictive of acute urinary retention in men with benign pros-
tatic hyperplasia (BPH)/bladder outlet obstruction130, although
the AUA guidelines recommend avoiding antimuscarinics in
men with BPH and PVR volumes that exceed 250–300 mL131;
monitoring of PVR volume in older men with OAB and a
raised PVR volume may help to minimize the risk of acute
urinary retention during treatment. In men with moderate-to-
severe lower urinary tract symptoms (LUTS; American
Urological Association symptom index score >7), the 5 year
cumulative incidence of acute urinary retention rises from
2.1% (3.0/1000 person-years) in men aged 40 to 49 years, to
13.8% (34.7/1000 person-years) in men aged 70 to 79
years132. In another study in men with no or mild LUTS, the
incidence of acute urinary retention increased from 0.4/1000
person-years for those aged 45 to 49 years, to 7.9/1000
person-years for those aged 70 to 83 years. In men with
moderate or severe LUTS rates increased from 3.3/1000 per-
son-years for those aged 45 to 49 years, to 11.3/1000 person-
years for those aged 70 to 83 years133. Although the risk of
MIRABEGRON VS ANTIMUSCARINICS IN OLDER PATIENTS WITH OAB 633
association between antimuscarinic use and acute urinary
retention has been seen in a community-based population135.
Mirabegron increases bladder capacity without a change in
micturition pressure, PVR volume or voiding contraction107–109
and (at doses of 50 mg and 100 mg QD) did not adversely
affect urodynamic voiding parameters (maximum urinary flow
and detrusor pressure at maximum urinary flow) compared
with placebo in a 12 week phase II study in men with LUTS
and bladder outlet obstruction136. In the clinical trial program,
the incidence of urinary retention was not increased in
patients randomized to mirabegron. In older men with benign
prostatic hyperplasia and OAB (voiding and storage symp-
toms) with PVR volumes >500 mL or with a history of urinary
retention, treatment with mirabegron may be preferred over
antimuscarinics to avoid exacerbating the risk of acute urinary
retention. In cases where the PVR volume is not excessive,
and a history of urinary retention is absent, antimuscarinics or
mirabegron may be considered.
The incidence of glaucoma increases with age, and OAB
and glaucoma are known to frequently coexist in older peo-
ple137,138. Antimuscarinics are not recommended for patients
with uncontrolled narrow-angle glaucoma, which is less com-
mon than open-angle glaucoma but considered the more ser-
ious form of the disease139. Although there are no data in
older persons, in an 8 week, randomized, double-blind, pla-
cebo-controlled study in adults aged 18 years with normal
intraocular pressure, mirabegron 100 mg QD did not increase
intraocular pressure compared with placebo; no AEs of glau-
coma were reported and the incidence of ocular AEs was
low140.
Effect of mirabegron on QoL
Consistent with its favorable efficacy and tolerability profile in
121
older patients mirabegron 25 mg and 50 mg QD improved
measures of HRQoL in OAB patients aged 65 years as meas-
ured using the OAB-q141, PPBC142 and the treatment satisfac-
143
tion–visual analog scale (TS-VAS) . Patients’ perceived
acute urinary retention in male patients with LUTS treated
with antimuscarinics is low ( 3%) in clinical trials134, an
improvements in QoL measures with mirabegron to be clinic-
ally meaningful: the minimally important difference (defined
as a 10 point change in total HRQoL, its subscales and the
symptom bother score and a 1 point change in PPBC) was
reached on all outcomes with mirabegron 25 mg and 50 mg,
except PPBC and the social subscale of HRQoL. In a post-hoc
analysis of pooled patient-reported outcome data from two
12 week phase III trials (Studies 047 and 074), patients aged
65 years showed more improvement than those receiving
placebo on the PPBC, TS-VAS and the OAB-q total HRQoL
score, reaching statistical significance on all but one compo-
nent of the OAB-q144. These improvements in subjectively
assessed symptoms and QoL are important indicators of long-
term persistence and overall treatment success.

The case of the frail older patient

While the healthy, robust older person is phenotypically and
physiologically similar to someone in ‘middle age’, and should
receive a similar range of treatment options145, the frail older
 634 A. WAGG ET AL.
person poses a greater treatment challenge. The 5th
International Consultation on Incontinence 145 defines the frail
elderly as ‘‘over the age of 65 with a clinical presentation or
phenotype combining impairments in physical activity, mobil-
ity, balance, muscle strength, motor processing, cognition,
nutrition and endurance including feelings of fatigue and
exhaustion’’. In these patients, multiple risk factors and mul-
tiple organ systems may be involved in a single outcome,
such as incontinence, rendering identification of underlying
causes difficult. In these vulnerable, frail older patients, mul-
tiple etiological factors contribute to interacting pathogenic
pathways, resulting in a single, unified manifestation – the
geriatric syndrome146 – for which the precipitating risk factor
may not be located in the genitourinary tract146. It is possible
that treatment may not only improve urinary incontinence
with a concomitant improvement in QoL, but also improve
domains other than urinary incontinence145, although this has
yet to be investigated in clinical trials.
A recent systematic review of pharmacological treatment
for urinary incontinence147 identified two studies, both with
oxybutynin, in nursing home residents (taken as a proxy for
Downloaded by [Reprints Desk Inc] at 15:14 28 July 2016
frailty) with urinary incontinence64,66,148, and found no effect
of oxybutynin on urinary leakage and no difference in AE pro-
file between oxybutynin and placebo. More recently, DuBeau
et al.63 reported that flexible-dose fesoterodine significantly
improved urgency urinary incontinence and other outcomes
compared with placebo in a population of vulnerable (a score
of 3 on the Vulnerable Elders Survey [VES]), community-
dwelling adults, and improvements relative to placebo in
PPBC; OAB-q symptom bother score and total HRQoL; greater
satisfaction with symptom improvement and medication; and
a reduction in absorbent product use. However, when consid-
ering the results of these studies, it should be noted that the
relationship between frailty and the VES score is not clear.
Regarding other antimuscarinics, the 5th International
Consultation on Incontinence concluded that there is insuffi-
cient evidence to determine their efficacy, tolerability and
safety in the frail elderly145.
Given its improved tolerability profile and lack of contribu-
tion to the patient’s anticholinergic burden, mirabegron may
be a suitable treatment option in these complex patients.
However, current recommendations for the management of
these patients are restricted to lifestyle interventions and
behavioral therapies with the cautious addition of
antimuscarinics13,145.
Limitations of the review
There are several limitations that need to be considered in
this review. For instance, there were few mirabegron studies
available for inclusion, a number of studies were of a very
short duration (<12 weeks) with wide variations in the size of
the study population, and there was a mix of prospective and
retrospective study designs. The overall lack of evidence with
mirabegron and antimuscarinics in older patients is exempli-
fied by the FORTA (Fit fOR The Aged) LUTS classification,
designed to identify appropriate oral pharmacotherapies to
treat LUTS for people >65 years (FORTA-A ¼ indispensable;
B ¼ beneficial; C ¼ questionable; D ¼ avoid), which rated all
antimuscarinics (with the exception of fesoterodine [FORTA-
B]) and mirabegron as FORTA-C (questionable)149.
Conclusions
OAB is a widespread problem with potentially far-reaching
adverse consequences, particularly in older patients, and even
more so in frail or vulnerable older patients. However, older
OAB patients can and should be treated. The successful treat-
ment of OAB is dependent on medication adherence, which
is affected by inadequate efficacy, bothersome side effects
and cost of treatment. Antimuscarinics and the b3-adrenocep-
tor agonist, mirabegron, are efficacious in the treatment of
older OAB patients. However, antimuscarinics are associated
with low persistence rates due to bothersome AEs including
dry mouth and constipation; mirabegron has a low incidence
of these particular AEs. In addition, studies report a low inci-
dence of CNS effects with mirabegron, a particular benefit in
older patients at risk of cognitive decline. No evidence for an
excess of CV events at therapeutic doses has been demon-
strated with mirabegron or antimuscarinics; however, regular
blood pressure monitoring is advised in older patients where
CV risk may be cumulative due to comorbidities or comedica-
tion. Compared with antimuscarinics, mirabegron may provide
an improved benefit-to-risk ratio in older patients.
Transparency
Declaration of funding
Editorial assistance was funded by Astellas Pharma.
Declaration of financial/other relationships
A.W. has disclosed that he has received personal or institutional fees
from Astellas, Pfizer and SCA for research, and for speaker and consult-
ancy roles. V.W.N. has disclosed that he has participated in advisory
boards for Allergan, Medtronic, Ipsen, Uroplasty and Astellas and has
acted as an investigator for Allergan and Astellas. C.K. has disclosed that
he has received consulting fees or honoraria and support for travel to
meetings from Astellas and payment for lectures including service on
speakers’ bureaus (honoraria and travel assistance) from Astellas, Allergan
and Ethicon. D.C-D. has disclosed that he has received personal fees from
Astellas, AMS, Allergan and Lilly for providing services as investigator,
consultant and speaker. E.S. has disclosed that he is an employee of
Astellas. T.B. has disclosed that he was formerly an employee of Astellas.
CMRO peer reviewer 1 has disclosed that he has received grants and
is a consultant to Astellas, Pfizer, and Allergan; he is also a consultant to
Ferring, and is on the speakers’ bureau of Astellas, Pfizer and Ferring.
CMRO peer reviewer 2 has disclosed that she is a consultant to Allergan,
Astellas, Pfizer and Ferring and is on the speakers’ bureau of Astellas,
Allergan, Pfizer and Laborie. CMRO peer reviewers 3 and 4 have no rele-
vant financial or other relationships to disclose.
Acknowledgments
The authors thank Aideen Young PhD and Stuart Murray MSc of Envision
Scientific Solutions for editorial assistance and Mary Beth Blauwet of
Astellas Pharma Global Development for data checking.

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