1Department of Neuro-Urology, Rheinisch Friedrich-Wilhelms University, Germany
2Department of Urology, The first people’s hospital of Changde, Changde China
Submission: August 04, 2017; Published: September 11, 2017
*Corresponding author: Wei Sheng, University Clinic, Rheinisch Friedrich-Wilhelms University, Clinic of Urology/Neuro-Urology Bonn, Germany, Tel: 04915776513089; Email: email@example.com
How to cite this article: Wei S, Hongwei Z, Kirschner H R. Mirabegron Combined with Solifenacin Versus solifenacin Monotherapy for Overactive
002 Bladder: A Systematic Review and Meta-Analysis. JOJ
uro & nephron. 2017; 4(1): 555628. DOI: 10.19080/JOJUN.2017.04.555628
Objective: To evaluate the efficacy and safety of mirabegron and solifenacin combined therapy compared with solifenacin monotherapy for overactive bladder.
Methods: We searched the Cochrane Central Register of Controlled Trials, PubMed and EMBASE from inception until March 2017 to identify all eligible studies that compared mirabegron and solifenacin combined therapy with solifenacin monotherapy for overactive bladder.
Results: Five articles were identified as eligible for this meta-analysis, with a total of 2614 participants. Synthetic data showed combined therapy had significant increase in mean volume voided per micturition (mean difference [MD]=9.02; 95% confidence interval [CI] 3.87 to 14.16, P =0.0006), statistically significant improvement in HRQoL (heath related quality of life) total score (mean difference [MD]=3.87; 95% CI 1.30 to 6.45, P=0.003) and decrease of OAB-q symptom bother score (mean difference [MD]=-3.33; 95% CI -4.90 to -1.76, P<0.0001), without significant differences on drug-related adverse effects (AEs),except that it showed combined therapy had a significant low rate of dry mouth than monotherapy therapy in our study (RR=0.57; 95% CI 0.43 to 0.77, P=0.0002).
Conclusion: Mirabegron and solifenacin combined therapy showed a superiority over solifenacin monotherapy, no matter in effectiveness or safety and maybe an alternative for those who experience resistance to solifenacin monotherapy or discontinuation because of severe adverse effects.
Overactive bladder (OAB) is a very common syndrome in elderly people, especially for women, which is defined as urgency with or without urinary in continence, usually associated with frequency and nocturia by the International Continence Society (ICS) . OAB has a great impact on quality of life (QoL), with higher rates reported for depression, psychological and emotional distress, and social isolation, particularly for those who have experienced the incontinence . That’s the reason why we often call it a “social disease”, not too lethal but really troublesome. Currently, we have several methods for treatment of OAB anti-muscarinic agents are the pharmacological mainstay at present [3,4]. Solifenacin as a first-line drug for OAB has been wildly used in recent years, and it functions well at the beginning
. However, the symptom control is often insufficient over time, leading to increase of dosage. That often aggravates anti-
cholinergic adverse events (AEs), which can cause treatment discontinuation [6,7].
Mirabegron, a selective β3-adrenoceptor (AR) agonist, is a first in class drug for the treatment of OAB . It has a totally different mechanism
for the treatment of OAB from anti-muscarinic drugs. Comparing to the main blockage of M3 receptor from anti-muscarinic drugs, mirabegron mediate human detrusor relaxation through activation of ARs. Whereas, β3-ARs account for more than 95% of all β-AR mRNA in the human bladder [8,9], it suggests mirabegron as an effective and well-tolerated drug in treating OAB. The goal of our study is to evaluate the efficacy and safety of mirabegron and solifenacin combined therapy in comparison with solifenac in mono therapy.
To identify relevant studies until March 2017 according to
PRISMA, we searched PubMed, EMBASE and Cochrane Library
database. All RCTs were retrieved in which patients were
randomly selected to receive either solifenacin or solifenacin
combined with mirabegron for the treatment OAB. Searches
included combinations of the following terms: solifenacin,
mirabegron, α-blocker oradrenergic α1- receptor, muscarinic
antagonist or anti-muscarinic or anti-cholinergic, overactive
bladder or OAB, randomised trial. We also reviewed the
references of the included studies to identify potential relevant
studies and tried to contact all corresponding authors when data
were found missing. There was no restriction regarding to the
language of the publications.
Publications had to meet the following inclusion criteria 
the investigation was performed in patients associated with OAB
 the patients were treated with mirabegron and solifenacin
combined therapy versus solifenacicn monotherapy  the
study reported at least one of the following end points: mean
volume voided per micturition, episodes of incontinence per day,
episodes of micturition per day, episodes of urgency per day, OAB
related questionnaire, adverse effects. The exclusion criteria
were as follow  the studies reported on OAB associated
with other pathological neurological diseases  patients had
a history of surgery that affected the function of bladder 
patients had an active urinary tract infection.
For each study, information was carefully collected from all
eligible publications, including first author, year of publication,
countries, main outcomes, inclusion details, intervention of the
trial groups, For studies including different doses of combined
therapy and monotherapy, we chose the mirabegron (50mg)
and solifenacin (5mg) as the combined therapy and solifenacin
(10mg) as the monotherapy. If more than one paper with
the same study was found, we included all the studies with
available data. If the data for meta-analysis were missing or only
expressed graphically, we tried to contact authors to inquire for
further information or calculated by ourselves if available. The
methodological quality of RCTs was assessed independently
using the Cochrane Handbook for Systematic Reviews of
Interventions. Two investigators independently evaluated the
methodological quality of the included articles. Disagreements
were resolved through consensus or discussed with another
We used the weighted mean difference (WMD) for continuous
data (e.g. changes in MVV) and risk ratio (RR) for dichotomous
data (e.g. AEs) as the estimated effect measures, and both were
reported with 95% confidence intervals. Mean and standard
deviation (SD) were calculated for the continuous pooled
results. Four articles expressed the data as mean and standard
error (SE) [10,11], so we transformed the standard error of the
mean into SD by the following formula:
For the assessment of change of urgency episodes, we used
the values which were calculated from adjusted difference
versus solifenacin 5mg. In an article  they didn’t calculate
the change value of solifenacin (10mg) adjusted from solifenacin
5mg. The mean value was the subtraction from solifenacin
(10mg) by solifenacin (5mg). The standard error (SE) was
calculated from the following formula.
For all statistical comparisons, differences with a P<0.05
were considered significant. Heterogeneity between studies
was assessed using the I2 test (I2 value: <50% was considered
low heterogeneity; 50% to 75% means moderate heterogeneity;
75% indicates high heterogeneity . When heterogeneity
was present (I2>50%), the data was analyzed using the randomeffects
model, otherwise, the fixed-effects model was applied
when heterogeneity was low. All statistical analyses were
performed with Review Manager 5.3 software (The Cochrane
Collaboration, Oxford, UK).
Database searches revealed 537 publications up to March
2017. Of these, 245 were immediately because of duplicated
series. A further 283 papers were excluded owing to unrelated
abstracts, reviews, comments. 11 papers were selected for
intensive reading. 2 papers were excluded because of lack of
useful data, and another 4 papers were ruled out because the comparison were only between monotherapy or combined
therapy (Figure 1). Finally, 3 RCT studies (5 papers) involving
a total of 2676 patients were included in the meta-analysis
[10,11,13-15] (Table 1).
AEs: Adverse Effects; MVV: Mean Volume Voided per Micturition; EI: Episodes of Incontinence; EM: Episodes of Micturition; EU: Episodes of
Urgency; MCC: Maximum Cystometric Capacity; HRQoL total score: Heath Related Quality of Life Total Score
We utilized the criteria recommended by Cochrane
Handbook for Systematic Reviews to assess the risk of bias in
the 3 RCTs included. All the studied had a randomization and
described the method of random sequences generation. An
adequate concealment of allocation procedure was also used in
each study. Non-selective reporting was found in the three trials.
Therefore, all of the included trials were considered to have a
low risk of bias. The methodological quality of each study was
summarized in Table 2.
Mean volume voided per micturition (MVV) and urgency
episodes per day: MVV was reported in only two studies and
were pooled in our meta-analysis. The result revealed that
mirabegron and solifenacin combined therapy was associated
with dramatically greater increase in MVV compared with
solifenacin monotherapy (mean difference WMD=9.02; 95%
confidence interval [CI] 3.87 to 14.16, P=0.0006). There was
no significant difference between combined therapy and
monotherapy over the change of urgency episodes per day.
(WMD=-0.37; 95% confidence interval [CI] -0.75 to 0.01, P
=0.05) (Figure 2).
HRQoL (heath related quality of life) and OAB-q symptom
bother score: HRQoL (heath related quality of life) total score
showed statistically significant improvement in combined
therapy over monotherapy (mean difference WMD=3.87; 95%
CI 1.30 to 6.45, P =0.003) and decreased OAB-q symptom bother
score in combined therapy group (mean difference WMD=-3.33;
95% CI -4.90 to -1.76, P<0.0001) (Figure 3).
Dry mouth, constipation and drug-related treatmentemergent
adverse events (TEAEs): Dry mouth and constipation
were discussed in all papers and TEAEs were discussed in
two papers. Our results showed that there were no significant
differences between the combined therapy group and the
monotherapy group in terms of constipation (RR=0.64; 95% CI
0.19 to 2.13, P=0.46) and drug-related TEAEs (RR=0.67; 95%
CI 0.39 to 1.16, P=0.15)., However, a statistically significant
difference could be observed in the evaluation of Dry mouth, and
monotherapy group had a higher rate.(RR=0.57; 95% CI 0.43 to
0.77, P=0.0002) ( Figure 4).
High blood pressure, Tachycardia and Urinary tract infection
(UTI): In the consideration of cardiovascular effects and UTI,
our analysis suggested that there were no significant differences
between the combined therapy group and the monotherapy
group regarding to high blood pressure (RR=1.05; 95% CI 0.64
to 1.71, P=0.84), tachycardia (RR=1.01; 95% CI 0.41 to 2.53,
P=0.85), UTI (RR=1.18; 95% CI 0.40 to 1.26, P=0.24) (Figure 5).
To date, there are a variety of methods available in treating
OAB, including bladder and behavioral training, biofeedback
procedures, pharmacotherapy, botulinum toxin, electrical
or magnetic stimulation, surgery. The pharmacotherapeutic
treatment is always the first priority. Because of its effectiveness
in alleviating OAB symptoms, while the other treatments such
as biofeedback procedures, electrical stimulation or botulinum
toxin are either less effective or invasive. There are several
muscarinic receptor antagonists that used in clinical practice,
for instance solifenacin, tolterodine, fesoterodine, which are the
current first-line drugs. Especially for solifenacin, which is a high
selective M3 receptor blocker. However, OAB patients may have
a suboptimal response or find that anti-muscarinic therapy is
limited by associated AEs [16,17].
Mirabegron, a high selective β3-AR agonist, is the first in a
new class of agents developed for the treatment OAB, which
mediates relaxation of the detrusor during the storage phase
of the micturition cycle, improving bladder storage capacity
without hindering bladder voiding, and no muscarinic side
effects such as dry mouth and constipation . It provides
us another effective alternative drug for OAB. Nevertheless, in
a phase 3B noninferiority trial in OAB patients refractory to
previous anti-muscarinic therapy, mirabegron 50mg did not
demonstrate superiority versus solifenacin 5mg  That’s why
we think mirabegron cannot replace solifenacin completely, the
combined therapy maybe a proper option for those who suffer
from severe OAB symptoms and muscarinic side effects.
As far as we know, we are the first meta-analysis to evaluate
the efficacy and safety of mirabegron and solifenacin combined
therapy compared with solifenacin monotherapy for OAB, which
is based on RCTs. The most eminent finding in our study is
that we observed that combined therapy (mirabegron 50mg+
solifinacin 5mg) was associated with more significant increase
in MVV, HRQoL total score and decrease of OAB-q symptom
bother score than monotherapy (solifenacin 10mg). It also
showed no inferiority for combined therapy over the change
of urgency episodes per day (WMD=-0.37; 95% confidence
interval [CI] -0.75 to 0.01, P=0.05). No significant difference was
found between combined therapy and solifenacin monotherapy
concerning drug-related AEs, except the dry mouth rates, which
showed monotherapy group had a higher rate of getting dry
Concerning AEs, the primary side effects of solifenacin are dry
mouth and constipation, especially the dry mouth, which is the
most common reason for majority of discontinuation . From
our results, it suggests the combined therapy is a good option
if patients suffer from dry mouth severely. Another worrying
adverse effect is the cardiovascular effect for mirabegron.
However, no significant differences were found between the
two groups concerning the high blood pressure, tachycardia.
In a study of systematic review and meta-analysis of phase
III trials in efficacy and safety of mirabegron in treating OAB,
the rates of getting hypertension, cardiac arrhythmia TEAEs,
urinary retention didn’t exceed placebo . That suggests
mirabegron is a well-tolerated drug for clinical use. Probably,
the combined therapy should not be worried too much about
the cardiovascular effect in treating OAB. However, because
lack of data of patients with poorly controlled hypertension,
arrhythmia, or cardiac heart failure, periodic blood pressure and
heart rate measurements are recommended for patients with
significant cardiovascular risk factors, such as coronary heart
disease and cardiomyopathy, and those aged >80 yr [21-23].
Some limitations of this meta-analysis should be
acknowledged. First of all, the number of included studies is
not too much, but we believe they are all high quality studies and included enough patients in each research, particularly the
two cross-boundary studies, it is robust to draw a conclusion.
Secondly, in one study from Kosilov etc., They used the
mirabegron 50mg and solifenacin 10mg as combined group,
which was different from the other two studies. However,
no primary outcomes were included from that study when
performing the meta-analysis. What’s more, theoretically, the
larger dosage of solifenacin, the more adverse events it will get.
In reality, the AEs would be less in the combined group in our
study. Because of the relative small number of included patients.
It would have a little impact on the results. Thirdly, the longer
term safety, efficacy cannot be extrapolated from this article.
More high-quality long term trials should be proposed to learn
more about the comparison between the combined therapy and
Mirabegron and solifenacin combined therapy showed
a superiority over solifenacin monotherapy, no matter in
effectiveness or safety and may be an alternative for those
who experience resistance to solifenacin monotherapy or
discontinuation because of severe adverse effects.