LOWER URINARY TRACT SYMPTOMS
13
The overactive bladder:
where are we in 2016?
NADIR OSMAN AND CHRISTOPHER CHAPPLE
In this article the authors
discuss some of the issues
and controversies generated
by the development of
the overactive bladder
symptom complex, the
challenges in its clinical
application and the current
state of play with regards
to pharmacotherapeutic
management.
S
ince its inception two decades ago, the
symptom complex of the overactive
bladder (OAB) has continued to generate
a great deal of interest and controversy.
Several large epidemiological studies have
confirmed the frequency of its occurrence
(approximately 10–20% in both sexes),
as well as its considerable impact on
quality of life. The economic costs
related to the care and treatment of
patients with urinary incontinence are
significant, in addition to costs related to
lost productivity in those of working age.
Debate continues as to the accuracy and
reliability of the definition of OAB, the
most recent of which was introduced in
the 2002 standardisation document of the
International Continence Society (ICS) as
‘urinary urgency with or without urgency
incontinence usually accompanied by
frequency and nocturia’.1 The sine qua non
of OAB is urinary urgency, described as ‘a
sudden and compelling desire to void that
is difficult to defer’.1 Voiding frequency of
more than eight times a day is regarded as
abnormal, although limited evidence was
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Figure 1. Urodynamic trace showing detrusor overactivity on
bladder filling
put forward to substantiate this criterion
when it was introduced.
DEFINITION AND DIAGNOSIS
The OAB symptom complex was
introduced by Paul Abrams and Alan
Wein in 1996. Prior to this, terminology
in lower urinary tract dysfunction was
largely related to pathophysiology and
the urodynamic finding of non-voluntary
detrusor contractions during bladder
filling (Figure 1). This was referred to as
‘detrusor instability’ in idiopathic cases
and ‘detrusor hyper-reflexia’ where
there was a documented neurological
problem.1 These terms were later
superseded by idiopathic or neurogenic
detrusor overactivity (DO) respectively.
The introduction of a symptom complex
was driven in part by the observation that
in many patients, in particular up to 60%
of women complaining of bothersome
lower urinary tract storage symptoms,
there is no urodynamic evidence of DO.
SEPTEMBER/OCTOBER 2016
Nadir Osman, Specialist Registrar in
Urology; Christopher Chapple, Consultant
Urologist, Department of Urology, Royal
Hallamshire Hospital, Sheffield
www.trendsinmenshealth.com
LOWER URINARY TRACT SYMPTOMS
14
Drug therapy was found to be beneficial
in some of these patients, hence the need
for an invasive urodynamic study prior to
instigating conservative treatment became
questionable.2
OAB was proposed as the descriptive term
for the complex of symptoms thought to
be associated with DO and was particularly
attractive due to its simplicity and clarity,
especially in relation to patient education
and public health measures. Subsequently,
OAB became widely accepted within
healthcare and the pharmaceutical
industry, and by the regulatory authorities.
This undoubtedly led to a rise in the
awareness of the importance of the
storage component of lower urinary
tract symptoms amongst the public, as
well as an increase in basic and clinical
research, leading to the development
and introduction of a number of new
pharmacotherapeutic agents.
Despite the clear benefits that have arisen
as a consequence of the concept of OAB,
the current definition lacks universal
endorsement. Some have suggested that
inclusion of terms such as ‘with or without’
and ‘usually’ introduce a lack of specificity.3
This is compounded by the lack of an
evidence base to support the suggested
thresholds relating to what can be
considered significant urinary frequency,
nocturia and incontinence. There has been
concern, therefore, that many individuals
who have very mild symptoms or who
are perhaps on the spectrum of normality
are encompassed by the definition. The
inference is that some individuals may
be overtreated and that the scale of
the problem has been overestimated,
particularly in light of the fact that most of
the epidemiological data are derived from
internet- and telephone-based surveys.
The definition of urinary urgency has
also been a point of some contention,
as arguably a ‘compelling desire to void’
is also felt by individuals with normal
urinary function if the bladder is overfull
www.trendsinmenshealth.com
and hence is not necessarily pathological.
A ‘fear of leakage’ is probably what truly
defines patients with urinary urgency.4
Another deficiency lies in the lack of detail
as to whether the sensation of urgency
can be considered to be discrete or on a
spectrum of intensity, analogised to a light
switch and dimmer switch respectively. A
further important issue is that the word
‘urgency’ is not differentiated from urge
in many languages, thus hampering the
universal application of the definition.
Should the patient fail to reach the toilet
in time, urgency urinary incontinence
(UUI) results. Patients who suffer this are
further described as having OAB-wet as
opposed to OAB-dry. The distinction is
important due to the increased anxiety
that incontinence produces, coupled with
the fact that OAB-wet is more strongly
correlated with underlying DO in both
men and women. This was clearly shown
by Hashim and Abrams, where 69% and
90% of men with OAB-dry and OAB-wet
have DO respectively, whilst in women
the proportion is 44% and 58%.5 Several
other studies have supported these
findings.6,7 Work undertaken in Sheffield
demonstrated that ambulatory urodynamic
studies have a higher sensitivity for the
detection of DO, suggesting that DO
could be simply missed in a proportion of
patients with OAB.8
PHARMACOTHERAPY FOR OAB
Over the past two decades, a large
number of agents have been developed
to treat OAB. Antimuscarinics are the
traditional option and a great multitude
of placebo-controlled, randomised trials
have been published establishing their
safety and efficacy. A systematic review
and meta-analysis conducted by our group
demonstrated a reduction in micturition
episodes of 0.5 to 1.3 per day and a
reduction in incontinence episodes of 0.4
to 1.1 per day.9 As only a few studies have
included direct comparisons of different
antimuscarinics, a direct meta-analysis was
not possible. Nevertheless, it is generally
accepted that there is very little difference
in efficacy between different agents. The
main drawback of antimuscarinic therapy
is the incidence of side-effects, particularly
with increasing dosages, including dry
mouth, heartburn and constipation and
cognitive impairment in vulnerable risk
groups (eg frail elderly). There is very little
high-quality evidence of a difference
between agents in terms of these sideeffects, with only oxybutynin 10mg
conferring a significantly increased risk.10
An analysis of UK prescription data found
that the proportion of patients still on their
originally prescribed agent at 12 months
ranged from 14–35% for different agents
in common use.11 This poor persistence rate
is due to a combination of side-effects and
lack of perceived efficacy.
For many years, antimuscarinic agents
were avoided in men for fear of
precipitating urinary retention. Over the
past decade, a strong body of evidence
has emerged to support the safety of
antimuscarinic use in men with postvoiding residuals of 200ml or less, with
rates of retention similar to placebo.12
In addition, when prostate size was
measured, it was towards the lower end
of the spectrum. Moreover, most studies
span three months in duration, which
may not be sufficiently long to assess the
risk of retention accurately. Consequently,
most guidelines do not recommend
antimuscarinic use in men with large
residuals, large prostates or a previous
history of retention.
Mirabegron
Mirabegron has been introduced into
practice relatively recently. It is a
beta3-receptor agonist and stimulates
beta3-receptors in the detrusor muscle,
causing relaxation. Mirabegron improves
bladder storage without impacting on
voiding contraction. The drug has been
studied in over 10 000 subjects. Pooled
analysis of the pivotal phase 3 studies
shows significant reduction in mean
incontinence episodes for mirabegron
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SEPTEMBER/OCTOBER 2016
LOWER URINARY TRACT SYMPTOMS
15
50mg (recommended dose) compared
to placebo, –1.48 and –1.10 respectively
(p<0.05).13 The mean number of micturition
episodes also decreased significantly with
mirabegron 50mg compared to placebo,
–1.75 versus –1.20 respectively (p<0.05).
The safety profile of mirabegron appears
to be acceptable. The pooled analysis
demonstrated the main treatmentrelated adverse events of nasopharyngitis,
hypertension and urinary tract infection
occurring at a similar rate to placebo.
Importantly, the rate of dry mouth, a
common issue with antimuscarinics,
was also at placebo level, as were
rates of retention. With any agonist
working on the sympathetic system
there is some theoretical concern over
cardiovascular effects. Mirabegron was
found to be associated with negligible
rises in pulse rate (<1bpm) and blood
pressure (<1mmHg).
It is important to note that in the pooled
dataset around half of the patients had
had prior treatment with an antimuscarinic
that was stopped due to lack of efficacy
or because of side-effects. Mirabegron
was similarly effective in both groups. It
remains to be seen whether this efficacy,
together with a lower rate of dry mouth, will
translate to better long-term persistence
rates in real-life clinical practice.
Botulinum toxin A
When oral pharmacotherapy fails, the next
step in OAB treatment is often intravesical
injection of botulinum toxin A (BTX-A)
(Figure 2). Botox is the BTX-A product
licensed for OAB in the UK. In a systematic
review, including a total of 1380 subjects,
BTX-A gave a reduction in mean changes
in number of micturitions/24 hour of 29%
and incontinence episodes of 59%.14 In
terms of urodynamic effects, maximum
cystometric capacity increased by 32%,
while maximal detrusor pressure declined
by 31%. When the two doses of BTX-A
(100 and 200 units) were compared, the
higher dose was associated with greater
TRENDS IN UROLOGY & MEN’S HEALTH
Dome
Injection sites
BTX-A injector
Figure 2. Diagram showing the technique used to inject botulinum toxin A into the smooth
muscle of the bladder wall
improvements in symptoms, but also a
greater risk of urinary tract infection and
higher self-catheterisation rates. A starting
dose of 100 units has therefore been
recommended for OAB.
method of delivery of BTX-A may change
in the future, with developments such as
electromotive drug administration and
liposome instillation having recently been
reported in the literature.
Other formulations of BTX-A are produced
by different manufacturing processes and
should not be considered as equivalents.15
The efficacy of BTX-A persists for six
to nine months and injections can be
repeated as needed. The development
of antibodies to BTX-A over time has
been observed and has been mooted
as a possible cause of loss of efficacy;16
however, investigators have shown that,
with time, further injections have resulted
in good outcomes.17 Biopsies in patients
undergoing repeated injections have failed
to demonstrate a significant association
with inflammation or dysplasia.18 Although
experience with BTX-A has accumulated,
questions remain around the optimal
volume and number of injections, and the
place of trigonal injections.
CONCLUSIONS
OAB is firmly established as a bothersome
and treatable symptom complex. It is
unlikely that a significant change to its
definition will occur in the foreseeable
future, although it would certainly
benefit from further refinement in terms
of the definition of urinary urgency
and clarification as to what constitutes
significant urinary frequency and nocturia.
The advent of mirabegron has provided
a further option in pharmacotherapeutic
management, while BTX-A continues
to be a highly efficacious option in
those patients not responding to oral
treatment. Sacral neuromodulation is
a well-established alternative therapy,
albeit with a high initial cost.
Finally, the results of a direct comparison
of BTX-A with sacral neuromodulation
(ROSETTA trial) should shed much-needed
light on which option is superior in terms
of efficacy, adverse effects and cost. The
SEPTEMBER/OCTOBER 2016
Declaration of interests
Nadir Osman has received speaker fees
and an educational grant from Astellas.
Christopher Chapple is a researcher and
speaker for Astellas, Pfizer, Recordati, Lilly
and Allergan.
www.trendsinmenshealth.com
LOWER URINARY TRACT SYMPTOMS
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KEY POINTS
• Overactive bladder (OAB) is a complex of symptoms, not a disease
• It is common in both men and women and increases in prevalence with ageing
• OAB is variably correlated to underlying detrusor overactivity, more so in men
than in women
• Antimuscarinic agents remain the mainstay of pharmacological treatment,
but are associated with poor adherence and persistence due to side-effects
and/or perceived lack of efficacy
• Mirabegron has emerged as an efficacious alternative to antimuscarinics that
is not associated with dry mouth
• Intravesical botulinum toxin A is a good option when oral pharmacotherapy
has failed to improve symptoms, but carries a risk of urinary retention
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