Keywords overactive bladder - systematic review - botulinum toxin - randomized controlled trials
Palavras-chave bexiga hiperativa - revisão sistemática - incontinência urinária - toxina botulínica
- estudos randomizados controlados
Introduction
The International Continence Society defines overactive bladder as a syndrome characterized
by urinary urgency, with or without urgency urinary incontinence, usually accompanied
by nocturia and an increase in urinary frequency, in the absence of infection, metabolic
or local factors.[1 ]
Different population studies concluded that overactive bladder is highly prevalent
both in males and females, with relevant negative impact on the patients' quality
of life (social, physical, psychological, sexual, personal relationships, work, and
domestic domains); moreover, it has a considerable financial impact on patients themselves
and thus on the health care system.[2 ]
[3 ]
[4 ]
[5 ]
Patients who do not satisfactorily respond to behavioral and/or pharmacological treatment
are diagnosed with refractory overactive bladder. This group includes patients with
contraindications and intolerable side effects to medication.[6 ]
While both the European Association of Urology (EAU) and the American Urological Association
(AUA) recommend intravesical injection of botulinum toxin A in refractory overactive
bladder cases, a vast majority of articles discusses only neurogenic cases of this
dysfunction.[7 ]
[8 ]
Our systematic review followed by meta-analysis included only non-neurogenic overactive
bladder patients who were treated with 100 units of onabotulinumtoxinA.
Methods
Our study was registered in the PROSPERO database in 2016, under the reference number
CRD42016035815.
Prospective randomized placebo-controlled studies featuring Jadad scale methodological
quality ≥ 3 were selected.[9 ] The study populations should necessarily include patients aged 18 years or older
with a diagnosis of non-neurogenic overactive bladder syndrome treated with 100 units
of onabotulinumtoxinA, at least in one of the arms of the study.
Patients with mixed urinary incontinence and a clear prevalence of overactive bladder
complaints were also included. Performance of urodynamic study was not considered
a prerequisite for inclusion in our analysis, since overactive bladder diagnosis is
clinically suspected and detrusor overactivity may or may not be present. The exclusion
criteria comprised use of a dose other than 100 units of onabotulinum toxin A, use
of botulinum toxin other than onabotulinumtoxinA, neurogenic cases and literature
or systematic reviews.
Primary Outcomes
The primary outcome of our study was to evaluate the clinical effectiveness with regard
to the following variables: urgency (complaint of a sudden compelling desire to pass
urine that is difficult to defer),[1 ] urinary frequency (complaint by the patient who considers that he/she voids too
often by day),[1 ] nocturia (complaint that the individual has to wake up at night one or more times
to void),[1 ] and incontinence episodes (complaint of any involuntary leakage of urine).[1 ]
Secondary Outcomes
The secondary outcome was to evaluate all adverse effects reported in the studies
included in the meta-analysis.
Study Search and Selection
We performed a search for randomized clinical trials (RCTs) in the following electronic
databases: Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE.
The MEDLINE search included the following terms: “overactive bladder,” “detrusor overactivity,”
“bladder overactivity,” “botulinum toxin,” “onabotulinumtoxinA” and “botox.”
Only studies in English were selected, and the search was done from the inception
of the database, given that the use of botulinum toxin in the treatment of non-neurogenic
overactive bladder is relatively recent. Two authors (R. M. A. and C. C. T.) independently
reviewed all the abstracts and titles to select the papers that were relevant for
review, later analyzing the full text of the selected studies to determine eligibility.
The last online search was performed on June 20th , 2015. A spreadsheet for data collection was created to extract the data of interest
in each article, which were then retyped in a single database to avoid loss of data
or mistyping of any kind. Any disagreements were resolved by consulting a third author
(R. A. C.). Outcomes verified in two articles or more were grouped for meta-analysis.
Statistical Analysis
We summarized binary outcomes based on the number of events using Peto odds ratio
in situations with zero number of events in one of the groups, or the Mantel-Haenszel
method in situations of a very low event rate. Furthermore, we summarized continuous
outcomes (incontinence, urgency, frequency and nocturia) using the mean difference
(MD), calculated by the inverse variance method. Precision of estimates appear as
95% confidence intervals (95CIs).
Heterogeneity across studies was evaluated using Cochran Q statistic and Higgins I2.[10 ] We quantified statistical heterogeneity using I2, informing its value together with
the estimates. We considered I2 elevated whenever it was higher than 60%. However,
a fixed-effect model was considered when a very small number of studies were included.[10 ]
In addition to the heterogeneity analyses described above, sensitivity analyses excluding
one study at a time were performed to evaluate the influence of individual studies
on the overall result. We used the RevMan 5.3 statistical package (Nordic Cochrane
Center, Copenhagen, Denmark) to perform the analysis.
Quality Assessment
The quality of studies included in the analysis was independently assessed by two
authors (R. M. A. and C. C. T.) using the Jadad scale for RCTs classification.[9 ] Studies scoring ≥ 3 were considered eligible for inclusion. Any disagreements were
resolved by consulting a third author (R. A. C.).
The Jadad scale assesses the quality of published clinical trials based on methods
relevant to random assignment, double blinding, and patient flow. There are seven
items, but points may be deducted in the last two, which means that the range of possible
scores is 0 (bad) to 5 (good).[9 ] The bias risk was assessed by the use of a Cochrane collaboration tool.[1 ]
Results
Description of Studies
[Fig. 1 ] describes the flow chart for this review. Five hundred and thirty-two articles were
retrieved after research on the Cochrane and Medline databases, using the keywords
“overactive bladder” OR, “detrusor overactivity” OR “bladder overactivity” AND “botulinum
toxin” OR “onabotulinumtoxinA” OR “botox.”
Fig. 1 Flow diagram of article selection.
Out of those, 333 articles were selected after reading the title and abstract, whereas
271 were excluded since they did not meet selection criteria. Therefore, 62 articles
were considered eligible and read in full by two authors. After this initial reading,
53 articles were excluded for using onabotulinumtoxinB and/or for including patients
with neurogenic overactive bladder. Eventually, 9 studies met all the inclusion criteria
and were selected for this meta-analysis ([Fig. 1 ] and [Table 1 ])
Table 1
Articles included in the meta-analysis
References
Study design
Jadad scale
N placebo/toxin
Weeks follow-up
Chapple et al.[11 ]
Multicenter, randomized, double-blind
5
271/277
12
Denys et al.[12 ]
Multicenter, randomized, double-blind
5
29/70
24
Dmochowski et al.[13 ]
Multicenter, randomized, double-blind
5
43/268
36
Dowson et al.[14 ]
Single-center, randomized, double-blind
5
11/10
24
Flynn et al.[15 ]
Single-center, randomized, double-blind
5
7/15
6
Nitti et al.[16 ]
Multicenter, randomized, double-blind
5
44/54
36
Rovner et al.[17 ]
Multicenter, randomized, double-blind
5
44/269
36
Two studies could be included for analysis of urinary urgency, urinary frequency,
nocturia, and incontinence episodes. There was no evidence of heterogeneity among
the articles, except for urinary incontinence. However, because the number of articles
is very small, the fixed-effect model was considered.
It can be observed in [Fig. 2 ] that there was significant reduction in urinary urgency episodes in the toxin group
(experimental group) in comparison with the placebo group (control group) (MD = -2.07,
95CI = [-2.55; -1.58]; p < 0.0001).
Fig. 2 Forest plot of change in urgency after onabotulinumtoxinA (experimental) and placebo
(control) injections.
[Fig. 3 ] shows that there was significant reduction in urinary frequency in the toxin group
(experimental group) when compared with the placebo group (control group) (MD = -1.64,
95CI = [-2.10; -1.18]; p < 0.0001).
Fig. 3 Forest plot of change in frequency after onabotulinumtoxinA (experimental) and placebo
(control) injections.
A similar result was observed in analyzing nocturia episodes ([Fig. 4 ]). There was significant reduction in nocturia in the toxin group (experimental group)
in relation to the placebo group (control group) (MD = -0.25, 95CI = [-0.39; -0.11];
p < 0.0001).
Fig. 4 Forest plot of change in nocturia episodes after onabotulinumtoxinA (experimental)
and placebo (control) injections.
In [Fig. 5 ] we further confirmed that there was significant reduction in the number of urinary
incontinence episodes in the toxin group (experimental group) in relation to the placebo
group (control group) (MD = -2.06, 95CI = [-2.60; -1.52]; p < 0.0001).
Fig. 5 Forest plot of change in urinary incontinence episodes after onabotulinumtoxinA (experimental)
and placebo (control) injections.
Secondary Purposes
Adverse Effects of Catheterization
For analysis of vesical catheterization occurrence, it was possible to include five
studies. According to the data ([Fig. 6 ]), it is possible to verify that the need for catheterization was significantly higher
in the toxin group (experimental group) when compared with the placebo group (control
group), with no heterogeneity in this analysis.
Fig. 6 Forest plot of change of pulmonary vascular resistance-related catheterization after
100 units of onabotulinumtoxinA (experimental) and placebo (control) injections.
In [Fig. 7 ] we present the forest plot graph for the data referring to urinary tract infection
occurrence. We note in the plot forest graph that the Peto odds ratio meta-analytical
value (OR = 2.69, IC (95%) = [1.83; 3.97]; p value < 0.0001) is located fully to the right of the vertical line. Such result demonstrates
higher probability of urinary infection in the toxin group (experimental) when compared
with the placebo group (control). Homogeneity among studies was confirmed by Q (Chi)
in the Cochran test (p value = 0.25).
Fig. 7 Forest plot of change of urinary tract infection after 100 units of onabotulinumtoxinA
(experimental) and placebo (control) injections.
Regarding the quality of life evaluation, it was not possible to perform the meta-analysis,
since the authors used different questionnaires, which made it impossible to evaluate
this item.
Discussion
Our results demonstrated that the onabotulinumtoxinA had greater efficiency when compared
with the placebo in relation to the all the symptoms analyzed (urinary frequency,
nocturia, and urinary incontinence episodes). Such results are also in agreement with
other systematic reviews and meta-analyses in respect to the subject.[18 ]
[19 ]
There was significant reduction in the number of urinary urgency episodes in the group
treated with toxin in comparison with the placebo group. However, none of the studies
evaluated urgency intensity, probably because it is a subjective symptom, and it is
very difficult to be characterized.
The last Cochrane review (2011)[19 ] on this topic included 19 studies, mostly with neurogenic patients. In our study,
we were interested in demonstrating the efficacy of onabotulinumtoxinA in the treatment
of non-neurogenic overactive bladder, which is usually followed by the gynecologist.
We chose to include only articles in which the toxin used was onabotulinumtoxinA because
it is the toxin most frequently indicated in Brazil, and it is available to treat
overactive bladder in both private and public health services.
Although most studies included analyzed the patients' quality of life, unfortunately
it was not possible to perform a systematic review of this variable given that the
authors used different tools for this evaluation. Nevertheless, different studies
have concluded that botulinum toxin significantly improves patient symptoms and quality
of life.[11 ]
[20 ]
In the articles included in our study, the only side effects significantly higher
in the toxin group in comparison with the placebo were urinary tract infection and
urinary retention. Such side effects were both more frequent in the 100 units dose.
Furthermore, other possible side effects are dry mouth, hematuria, respiratory depression,
and general muscular weakness.[21 ]
Urinary retention was the main complication reported in the studies. According to
the literature data, its incidence ranges from 0–72%, depending on the toxin dose
used and the definition of urinary retention with or without need for catheterization
(which is extremely variable among the authors).[19 ]
[20 ] Most articles included in this meta-analysis considered as urinary retention the
presence of post-urination residue ≥ 200 mL.[11 ]
[12 ]
[13 ]
[17 ]
The need for intermittent catheterization at the 100 units dose, which is the most
frequently used dosage in non-neurogenic cases, ranged from 6.9[11 ]–30%.[14 ]
It should be noted, however, that the indication of catheterization was varied among
the studies. The lowest rate was in Chapple et al,[11 ] which only indicated it in asymptomatic cases if post-urination residue was ≥ 350
mL. In turn, Brubaker et al (2008)[21 ] indicated intermittent catheterization in cases with post-urination residue > 200
mL after 4 weeks from the injection, regardless of the symptoms. Such differences
between the definitions for urinary retention and the need for catheterization render
comparison among studies difficult. In addition, possible clinical consequences of
asymptomatic urinary retention are not clear. Regardless, such retention is transitory
and dose-dependent.[11 ]
[20 ]
[22 ]
The primary strength of this systematic review was to only include prospective, randomized,
placebo-controlled articles featuring Jadad scale methodological quality ≥ than 3.[9 ] The fact that we have only included patients treated with 100 units of onabotulinumtoxinA
and non-neurogenic cases also contributed to facilitate the interpretation of results.
The limitations refer mainly to the differences between injection application techniques,
the follow-up time, and the evaluation of quality of life, which undoubtedly renders
greater generalization of results.
Conclusion
In comparison with the placebo, onabotulinumtoxinA promotes significant improvement
of urinary urgency, urinary frequency, nocturia, and incontinence symptoms. There
is higher incidence of urinary retention and urinary tract infection among patients
in the toxin group in relation with the placebo group. It was not possible to evaluate
the effects on quality of life. This systematic review is endorsed by the Urogynecology
Committee of the Federação das Associações Brasileiras de Ginecologia e Obstetrícia
(Brazilian Federation of the Societies of Gynecology and Obstetrics, [FEBRASGO, in
the Portuguese acronym]) and suggests that the dose of 100 units of onabotulinumtoxinA
is effective in the treatment of non-neurogenic refractory overactive bladder.
