Keywords
overactive bladder - urge incontinence - urinary frequency and antimuscarinics
Palavras chaves
bexiga hiperativa - incontinência de urgência - frequência urinária e antimuscarínicos
Introduction
Overactive bladder (OAB) is defined by the International Continence Society as the
presence of urinary urgency, usually accompanied by frequency and nocturia, with or
without urge urinary incontinence (UUI), in the absence of a urinary tract infection
or another obvious pathology.[1] Overactive bladder is a highly prevalent disease in both men and women, affecting
12–17% of the adult population. This condition has a significant negative impact on
the quality of life of patients, affecting emotional, physical, social, occupational,
and domestic functions.[2]
[3]
[4]
Overactive bladder symptoms are thought to develop as a result of inappropriate contractions
of the bladder detrusor during the filling phase of the micturition cycle. Normal
and abnormal bladder contractions occur via cholinergic activation of the muscarinic
receptors. As is the case in other chronic conditions, OAB typically requires long-term
persistence and adherence to therapy.[5] Behavior modification, which includes education about the disorder, lifestyle changes
(, such as avoiding caffeinated beverages, for example), as well as pelvic floor muscle
training and bladder retraining, represent the first-line therapy options for this
condition. However, when these approaches are insufficient, second-line therapy involves
pharmacological treatment, and antimuscarinic agents are the treatment of choice.[6]
[7]
[8]
Although anticholinergic medications have been shown to improve patients' symptoms,
they create a widespread blockade of cholinergic activity that often results in side
effects such as dry mouth, cognitive changes, constipation, urinary retention, blurred
vision, and dyspepsia.[9] These problems can be difficult to manage, and may contribute to poor patient adherence
to treatment.[10]
The objective of this systematic review and meta-analysis was to examine the currently
available evidence from randomized clinical trials (RCTs) about the outcomes of the
pharmacological management of OAB, and to summarize the comparative effectiveness
of the drugs available in Brazil. Only antimuscarinic agents commercialized in Brazil
were included in the analysis, since this meta-analysis is the basis for the development
of Brazilian urogynecology guidelines.[11]
Methods
This study was exempt from institutional review board approval, given that it was
a systematic review and meta-analysis; it did not involve the use of any interventions
on humans. To report the results of this meta-analysis, we utilized the Preferred
Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement.[12]
Search Strategy
An exhaustive electronic search was performed using the MEDLINE database, as well
as the Cochrane Central Register of Controlled Trials, with the dates of the included
articles spanning from the inception of these databases through to September 2015.
We also searched the references of the identified articles and restricted the search
to articles published in English. The search combined relevant terms and descriptors
related to OAB, anticholinergic drugs, oxybutynin, darifenacin, tolterodine, solifenacin,
and RCTs.
Eligibility Criteria and Data Extraction
The review only included RCTs featuring adult male and female patients diagnosed with
OAB or with a diagnosis of detrusor over activity, and who were also submitted to
any of the anticholinergic treatments available in Brazil. The selection criteria
are described in [Table 1]. In a first screening, two independent authors (AMRMF and MVCM) assessed all of
the abstracts retrieved from the search; they then obtained the full manuscripts of
the citations that met the inclusion criteria. These authors evaluated the studies'
eligibility and quality, and extracted the data subsequently. Any discrepancies were
solved by agreement, and, if needed, the authors reached a consensus with a third
author (MR). The meta-analysis included studies that provided accurate data related
to those primary outcomes that could be analyzed. Thus, only studies that provided
the mean, sample size, and standard deviation (SD) values of the primary outcomes
were included in the analysis. Otherwise, when the available data were expressed as
the median, it was necessary that the study provided the range values (lowest and
highest values) to extrapolate the mean. If only the ranges of continuous variables
were reported, we would estimate the SD by dividing the range by four. Dose escalation
and crossover studies were excluded, as it was not possible to abstract the data related
to our primary outcomes.
Table 1
Selection criteria of included studies (PICOs)
|
Included
|
Excluded
|
|
Population
|
Symptomatic diagnosis of overactive bladder (OAB) or a urodynamic diagnosis of detrusor
over activity
|
OAB as consequence of surgery
|
|
Intervention
|
Anticholinergic drugs available in Brazil (oxybutynin 5 mg and 10 mg; darifenacin
7.5 mg and 15 mg; tolterodine 1 mg, 2 mg, and 4 mg; solifenacin 5 mg and 10 mg)
|
Anticholinergic drugs not available in Brazil or with different doses or routes of
administration that are not available in Brazil
|
|
Comparison
|
Placebo, comparison between different drugs, or comparison between different doses
of the same drug
|
|
|
Outcomes
|
Primary outcomes
• Mean decrease in urge urinary incontinence (UUI) episodes per day
• Mean decrease in the number of micturitions per day
Secondary outcomes
• Mean decrease in total incontinence episodes (related or not to urgency)
• Dry mouth
• Constipation
• Withdrawals resulting from drug-related adverse effects
|
|
|
Study type
|
Randomized controlled trials (RCTs)
|
Non RCTs
|
Abbreviation: PICOs, population, intervention, comparison and outcomes.
Outcome Measures
The primary outcomes of interest for this systematic review and meta-analysis were
the mean decrease in the number of UUI episodes per day and the mean decrease in the
number of micturitions per day. The secondary outcomes included the mean decrease
in total incontinence episodes (either related or not to urgency), dry mouth, constipation,
and withdrawals resulting from drug-related adverse effects. We tried to perform meta-analytic
comparisons between each drug (and their different dosages) versus placebo, comparisons
between different drugs, and comparisons between different dosages of the same drug.
Risk of Bias Assessment
We followed the guidance suggested by the Cochrane Collaboration[13] to assess the risk of bias from the included studies. We evaluated sequence generation,
allocation concealment, blinding, and incomplete outcome data for each trial included
in the review. A low risk of bias was considered when a judgment of “yes” for all
domains was obtained, whereas a high risk of bias was considered when a judgment of
“no” for one or more domains was obtained. An unclear risk of bias was defined when
an “unclear” judgment in any domain was considered. The quality assessment of the
included trials is shown in [Table 2].
Table 2
Quality assessment of included trials
|
Study
|
Sequence generation
|
Allocation concealed
|
Blinding
|
Incomplete outcome data
|
|
Appell et al.[15]
|
Unclear
|
Yes
|
Yes
|
Yes
|
|
Drutz et al.[16]
|
Unclear
|
Yes
|
Yes
|
Yes
|
|
Lee et al.[17]
|
Yes
|
Yes
|
Yes
|
Yes
|
|
Malone-Lee et al.[18]
|
Unclear
|
Unclear
|
Yes
|
Yes
|
|
Chapple et al.[19]
|
Unclear
|
Yes
|
Unclear
|
Yes
|
|
Jacquetin et al.[20]
|
Unclear
|
Yes
|
Unclear
|
Yes
|
|
Khullar et al.[21]
|
Yes
|
Yes
|
Yes
|
Yes
|
|
Millard et al.[22]
|
Unclear
|
Unclear
|
Unclear
|
Yes
|
|
Swift et al.[23]
|
Yes
|
Yes
|
Yes
|
Yes
|
|
Van Kerrebroeck et al.[24]
|
Unclear
|
Unclear
|
Unclear
|
Yes
|
|
Van Kerrebroeck et al.[25]
|
Yes
|
Yes
|
Yes
|
Yes
|
|
Zinner et al.[26]
|
Yes
|
Yes
|
Yes
|
Yes
|
|
Cardozo et al.[27]
|
Unclear
|
Unclear
|
Unclear
|
Yes
|
|
Karram et al.[28]
|
Unclear
|
Unclear
|
Unclear
|
Yes
|
|
But et al.[29]
|
Yes
|
Unclear
|
Unclear
|
Yes
|
Analysis
We pooled the data of the continuous outcomes from the original studies to obtain
the mean difference (MD) for the occurrence of an outcome event, and presented their
corresponding 95% confidence intervals (CIs). Data for dichotomous outcomes from the
original studies were pooled to obtain the relative ratio (RR), and the corresponding
95% CIs were calculated. Statistical significance was set at a p-value of < 0.05. In order to quantify the statistical heterogeneity, we used the
I2 statistic to describe the variations across trials that were due to heterogeneity
and not to sampling error. We pooled the outcome data from each study using a Mantel–Haenszel
model, and applied the fixed-effects model. When the heterogeneity was greater than
50% (I2 > 50%), we applied the random-effects model.[14] We used the software Review Manager (RevMan, Version 5.3; Copenhagen) to conduct
the meta-analysis.
Results
Our electronic search retrieved 468 articles. After screening the titles and abstracts,
we ended up with 37 articles that were considered eligible for inclusion in this review
by one or both reviewers, and the full texts were subsequently assessed. The complete
article selection process is presented in [Fig. 1].
Fig. 1 Flowchart for the trial identification and selection process.
Description of Included Studies
Fifteen RCTs assessing the pharmacological management (drugs and dosages available
in Brazil) of OAB met the inclusion criteria and provided data to perform the meta-analysis.
With the available data of the included studies,[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29] it was only possible to perform comparisons between tolterodine (and its different
dosages) versus placebo, solifenacin versus placebo, and oxybutynin versus tolterodine.
Excluded Studies
Twenty-two articles were excluded because they either did not meet the inclusion criteria[30]
[31]
[32]
[33]
[34]
[35] or they did not provide adequate data to be included in the meta-analysis.[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
Primary Outcomes
For this outcome, it was only possible to perform a comparison between oxybutynin
and tolterodine. The MD in the mean decrease in UUI episodes per day was higher for
patients that used oxybutynin than for those that used tolterodine (MD = –0.49; 95%
CI: –1.00, 0.03; I2 = 0; p = 0.07); however, this difference was not significant ([Fig. 2]).
Fig. 2 Forest plot – mean difference in decrease in urge urinary incontinence (UUI) episodes
per day.
We were able to perform the following comparisons: oxybutynin versus tolterodine;
tolterodine (and its different doses) versus placebo; different doses of tolterodine;
and solifenacin versus placebo. We found significant differences that favored tolterodine
1 mg when compared with placebo (MD = –0.55; 95% CI: –1.08, –0.02; I2 = 0; p = 0.04); tolterodine 2 mg versus placebo (MD = –0.57; 95% CI: –0.82, –0.32; I2 = 0;
p < 0.001); and tolterodine 4 mg versus placebo (MD = –0.66; 95% CI: –0.85, –0.47;
I2 = 0; p < 0.001). Moreover, significant differences favored the use of solifenacin when compared
with placebo (MD = –0.77; 95% CI: –1.09, –0.45; I2 = 0; p < 0.001) ([Fig. 3]). All of these outcome data were pooled from each study using a Mantel–Haenszel
model, and a fixed-effects model was applied, as there was no heterogeneity (I2 = 0)
among the studies. For all other available comparisons for this outcome (oxybutynin
versus tolterodine; tolterodine 2 mg versus tolterodine 1 mg; and tolterodine 4 mg
versus tolterodine 2 mg), the MD was not significant, as presented in [Fig. 3].
Fig. 3 Forest plot – mean difference in decrease in the number of micturitions per day.
Secondary Outcomes
Significant differences were found that favored tolterodine 2 mg when compared with
placebo (MD = –0.45; 95% CI: –0.76, –0.14; I2 = 0; p = 0.005); tolterodine 4 mg versus placebo (MD = –0.46; 95% CI: –0.83, –0.08; I2 = 0;
p = 0.02); and solifenacin versus placebo (MD = –0.77; 95% CI: –1.09, –0.45; I2 = 0;
p < 0.001) ([Fig. 4]). All of these outcome data were pooled from each study using a Mantel–Haenszel
model, and a fixed-effects model was applied, as there was no heterogeneity (I2 = 0)
among the studies. We did not find significant differences across any of the other
available comparisons (oxybutynin versus tolterodine; tolterodine 1 mg versus placebo;
tolterodine 2 mg versus tolterodine 1 mg; and tolterodine 4 mg versus tolterodine
2 mg).
Fig. 4 Forest plot – mean difference in decrease of total incontinence episodes per day.
There were significant differences and higher RRs in patients treated with oxybutynin
when compared with tolterodine (RR = 1.49; 95% CI: 1.06, 2.10; I2 = 84%; p = 0.02); tolterodine 1 mg versus placebo (RR = 2.33; 95% CI: 1.26, 4.29; I2 = 84%;
p = 0.02); tolterodine 2 mg versus placebo (RR = 3.72; 95% CI: 3.05, 4.54; I2 = 0%;
p < 0.001); tolterodine 4 mg versus placebo (RR = 2.88; 95% CI: 2.40, 3.45; I2 = 0%;
p < 0.001); tolterodine 2 mg versus tolterodine 1 mg (RR =1.69; 95% CI: 1.26, 2.28;
I2 = 0%; p < 0.001), and solifenacin versus placebo (RR =3.73; 95% CI: 1.80, 7.77; I2 =0%; p < 0.001). The group of patients that used tolterodine 4 mg exhibited a lower risk
(RR = 0.79; 95% CI: 0.68, 0.92; I2 = 0%; p = 0.02) when compared with tolterodine 2 mg. All of these results are presented in
[Fig. 5].
Fig. 5 Forest plot – Risk Ratio (RR) of dry mouth.
The findings indicated that there was a significant difference and a higher RR in
patients treated with tolterodine 2 mg versus those treated with placebo (RR = 1.61;
95% CI: 1.11, 2.32; I2 = 0%; p = 0.01), and those treated with tolterodine 4 mg versus placebo (RR = 1.52; 95% CI:
1.11, 2.09; I2 =0%; p = 0.009). We did not find significant differences across any of the other available
comparisons (oxybutynin versus tolterodine; solifenacin versus placebo). All of these
results are presented in [Fig. 6].
Fig. 6 Forest plot – Risk Ratio (RR) of constipation.
We did not find statistical differences in any of the available comparisons (oxybutynin
versus tolterodine, p = 0.18; tolterodine 1 mg versus placebo, p = 0.47; tolterodine 2 mg versus placebo, p = 0.32; tolterodine 4 mg versus placebo, p = 0.13; tolterodine 2 mg versus tolterodine 1 mg, p = 0.59; tolterodine 4 mg versus tolterodine 2 mg, p = 0.92; and solifenacin versus placebo, p = 0.67) when evaluating the risk of withdrawals due to drug-related adverse effects.
Discussion
To our knowledge, this is the first comprehensive review featuring a pooled analysis
that has addressed the question of efficacy and the main adverse effects of all antimuscarinic
drugs available in Brazil for the treatment of OAB.
This systematic review showed that there is no significant difference in the mean
decrease in UUI episodes per day between oxybutynin and tolterodine. Although there
was a trend of a higher reduction in UUI episodes with the use of oxybutynin, the
difference was not statistically significant. It was not possible to perform comparisons
between oxybutynin versus solifenacin, oxybutynin versus darifenacin, tolterodine
versus solifenacin, tolterodine versus darifenacin, and solifenacin versus darifenacin
due to limitations in data reporting (that is, studies without a measure of variation)
and the lack of similarity in measures.
Regarding the decrease in the number of micturitions per day, which was another important
primary outcome, the results favored tolterodine in its various dosages and solifenacin
when compared with placebo. The comparison between oxybutynin and tolterodine showed
no significant difference in treatment efficacy across any of the outcomes; the same
was found for the comparisons of tolterodine in its various dosages. As result of
the relative paucity of data that qualified for inclusion in the meta-analysis – and
that directly compared pharmacological agents –, it is impossible to report definitively
whether any specific agent is superior to another in terms of efficacy.
Antimuscarinic agents may be associated with adverse effects. The human bladder tissue
contains M2 and M3 muscarinic receptors. The M3 subtype has been identified as the
primary mediator of detrusor contraction in response to cholinergic activation.[52]
[53] Different subtypes of muscarinic receptors are widely distributed in the body. M1
receptors in the brain and salivary glands are involved in cognition and in the production
of mucous saliva;[54]
[55] M2 receptors in the cardiovascular system play a role in mediating heart rate and
cardiac output;[56] and M5 receptors in the eye are involved in ciliary muscle contraction.[57]
[58]
[59] As a result, antimuscarinic agents, which bind to some or all of these receptors,
are effective in treating OAB symptoms, but they may also be associated with adverse
effects such as dry mouth, constipation, cognitive impairment, tachycardia, and blurred
vision.[57] This systematic review showed that oxybutynin was associated with significantly
higher rates of dry mouth when compared with tolterodine. When compared with placebo,
tolterodine, in its various dosages, and solifenacin were associated with significantly
higher rates of dry mouth. The group of patients that used tolterodine 4 mg presented
lower risk when compared with the group treated with tolterodine 2 mg. This can be
explained by the fact that tolterodine 4 mg is an extended-release (ER) presentation.
Compared with the immediate-release drug, tolterodine ER releases the drug in a steady
and constant manner, thus lowering peaks. This translates into more constant serum
concentrations and theoretically improves patient tolerability.[60] Concerning constipation, differences were not found between oxybutynin and tolterodine.
Significantly high rates of constipation were found in patients treated with tolterodine
2 mg and 4 mg when compared with placebo.
The current data demonstrate that a substantial proportion of patients discontinue
anticholinergic drugs, with 75–90% of patients discontinuing therapy within 12 months.
Among those studies that provided information about the reasons for the discontinuation
of the therapy, the most frequently cited reasons were that the medication did not
work as expected, and that the medication's side effects were not desirable.[7] We did not find a statistical difference associated with withdrawals resulting from
drug-related adverse effects.
New drugs for the treatment of OAB are emerging, such as imidafenacin and tarafenacin,
but they are not available in Brazil yet. Mirabegron, a β3-adrenoreceptor agonist,
has just recently been released into the Brazilian market with some promising results,
especially when associated with regular antimuscarinic drugs.[61]
[62]
The quality of the available evidence that supports these results is moderate. The
main limitation of the available evidence concerning OAB treatment is that although
there is a large amount of RCTs, it is not possible to combine all of the data in
a meta-analysis due to their heterogeneity. If the goal of a meta-analysis is to estimate
the MD between two treatments, then the means, sample sizes, and a measure of variation
(standard deviation, standard error, or a confidence interval) are required. Thus,
many of the available RCTs on OAB treatment did not contribute to the meta-analysis,
and were excluded from our study. Unfortunately, we discovered a lack of high-quality
evidence pertaining to the available drugs and dosages for the treatment of OAB in
Brazil that can inform clinical decision making for patients and care providers.
In summary, the results of this meta-analysis suggest that there is a moderate to
high quality of evidence supporting the benefits of using anticholinergic drugs in
alleviating OAB symptoms when compared with placebo. Despite its lower improvement
in primary and secondary outcomes when compared with anticholinergics, the use of
placebo contributed to many of the improvements in OAB symptoms. It is still not clear
if any one specific drug available in Brazil has any advantage over the others. The
use of these drugs is associated with adverse effects (mainly dry mouth and constipation),
although the use of these agents is not related to an increase in the number of withdrawals.
