World Journal of Urology

https://doi.org/10.1007/s00345-020-03425-3

ORIGINAL ARTICLE

Efficacy and safety of mirabegron versus solifenacin as additional

therapy for persistent OAB symptoms after tamsulosin monotherapy
in men with probable BPO
Mohamed G. Soliman1   · Shawky A. El‑Abd1 · Ahmed M. Tawfik1 · Mohamed H. Radwan1 · Ahmed S. El‑Abd1

Received: 6 January 2020 / Accepted: 24 August 2020

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Purpose  To investigate the efficacy and safety of mirabegron versus solifenacin as add-on for persistent OAB symptoms
after tamsulosin monotherapy in men with probable BPO.
Patients and methods  This prospective randomized single-blind study was conducted on patients with persistent OAB
symptoms after at least 12 weeks of tamsulosin 0.4 mg. The patients were randomized into group A in which mirabegron
(50 mg once daily) was added and group B in which solifenacin (5 mg once daily) was added. Before and 12 weeks after
addition of either drugs, we assessed the efficacy of the treatment using the OABSS, IPSS, Q max, MVV/mic and PVR.
Results  Ninety two men were included in this study (46 patients in each group). All the study parameters were significantly
improved after the 12-week treatment period in both groups except mean PVR which showed non-significant change in
group A and a significant change in group B despite of being clinically irrelevant with only one case of acute urine retention.
Overall, no significant difference has been observed between both groups after 12 weeks of treatment regarding all studied
parameters except PVR. The incidence of side effects in group A was 10.9% versus 26.1% in group B. Main side effects
included dry mouth in 2.2% and 8.7% and constipation in 2.2% and 6.5% in group A and B, respectively.
Conclusion  Our results indicate that the addition of either mirabegron or solifenacin to patients with persistent OAB symp-
toms after tamsulosin monotherapy has significant efficacy in controlling these symptoms. The adequate balance between
efficacy and tolerability reported in this study with mirabegron may result in better QOL and overall patient satisfaction if
compared with antimuscarinics.

Keywords  Mirabegron · Solifenacin · Tamsulosin · BPO-related LUTS

Introduction have been proved to be more bothersome and embarrassing

Overactive bladder (OAB) symptoms are commonly
observed in men with lower urinary tract symptoms (LUTS)
suggestive of benign prostatic obstruction (BPO). OAB
is characterized by the presence of urinary urgency, with
or without urge urinary incontinence (UUI), usually with
increased daytime frequency and nocturia that is not caused
by an infection or other obvious pathology [1–3].
While LUTS related to voiding are typically more pre-
dominant, the urinary storage symptoms related to OAB
* Mohamed G. Soliman
Mohagab2006@yahoo.com
1
Urology Department, Faculty of Medicine, Tanta University,
Tanta, Egypt
for the patients [4].
Several studies evaluated the efficacy and safety of the
combination treatment of α1-adrenoceptor antagonist and
antimuscarinic agent and recommend this combination for
patients with coexisting OAB symptoms [5].
However, the use of antimuscarinic agents in men with
a BPO is associated with several side effects as dry mouth
and constipation that commonly happen especially in elderly
patients. Therefore, a new drug without these side effects has
been desired [6].
Mirabegron is a selective beta-3 agonist that acts specifi-
cally on beta-3 receptors, the stimulation of which leads to
active relaxation of detrusor muscle during storage phase
with subsequent increase in bladder capacity without affect-
ing bladder contractility during voiding phase [7].

13
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Mirabegron has been accepted worldwide in the treat-
ment of OAB due to its efficacy, good safety and tolerability
profile with lower incidence of adverse events observed with
antimuscarinic [8, 9].
Other researchers have focused on its role as add-on
treatment combined with α1-adrenoceptor antagonist and
showed high efficacy in improvement of storage symptoms
and demonstrated urodynamic safety on voiding parameters
and concluded that this combination can be considered as a
reasonable treatment regimen [10–12].
To the best of our knowledge, this study is the first one
to prospectively compare the add-on effect of mirabegron
versus solifenacin as one of the most commonly used anti-
muscarinics for patients with probable BPO and persistent
OAB symptoms after tamsulosin 0.4 mg monotherapy.
Patients and methods
Between September 2018 and September 2019, 95 male
patients aged 50  years or older who reported that they
were bothered by persistent OAB symptoms after at least
12 weeks of regular dose of tamsulosin 0.4 mg for the treat-
ment of previously diagnosed BPO-related LUTS (based
on US assessment of prostate size, PVR and uroflowmetry)
were candidates for this randomized prospective single-blind
study. Three patients were lost during the follow-up and so,
excluded from the study.
OAB has been diagnosed using the Overactive Bladder
Symptom Score (OABSS), and persistent OAB symptoms
were defined as a total OABSS of 3 or more points with uri-
nary urgency at least once per week [13]. The ethical com-
mittee of our institute has approved the study protocol with
the informed consent signed by all our included patients.
Exclusion criteria were a significant post-void residual
urine volume (PVR) of more than 100 ml, history of urinary
retention, severe hypertension, renal or liver impairment,
glaucoma, urological malignancy or patients taking any anti-
muscarinic drugs.
The patients were randomized into two groups. Mirabe-
gron (50 mg once daily) was added to tamsulosin in group A
and solifenacin (5 mg) in group B. Before and 12 weeks after
addition of either drugs, we assessed the subjective param-
eters using OABSS and IPSS, and we used the uroflowme-
try and transabdominal ultrasound to assess mean voided
volume (MVV)/micturition, Q max and PVR respectively.
Moreover, before addition of both drugs, prostate volume
(PV) was assessed with transabdominal ultrasound. These
subjective and objective parameters were compared between
two groups. Adverse events were recorded throughout the
study period.
The primary endpoint was the change in total OABSS.
The secondary endpoints were the change in the subscale
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World Journal of Urology
scores of the OABSS, total IPSS, each subscale score of the
IPSS and IPSS-QOL, MVV, Q max, and PVR.
Statistical analysis
Data were analyzed by SPSS ver. 20.0., Chi-square test was
used for categorical variables and t test to compare differ-
ence among groups for continuous variables. P value less
than 0.05 was considered to be statistically significant.
Results
Ninety two men were finally included in this series (46
patients in each group) after exclusion of three cases who
were lost for follow-up (Fig.  1). The mean patient age
was 55.7 ± 5.7 years, while the mean prostate volume was
41.9 ± 8.3 ml. All patients had taken tamsulosin for at least
12 weeks before the study.
At baseline, there was no significant difference between
both groups as regard age (56.2 ± 5.8 in group A versus
55.2 ± 5.7 in group B), prostate volume (43.4 ± 8.6 in group
A versus 40.4 ± 7.9 in group B), OABSS, IPSS, quality of
life score, Q max, MVV and PVR (Table 1).
The OABSS and its all subscores, the IPSS total score,
QOL index, MVV and Q max were significantly improved
after the 12-week treatment period in both groups. (Table 1).
Although a statistically significant improvement has been
observed in the IPSS-related storage symptoms score, there
were no significant changes observed in voiding symptom
score, Q max before and 12 weeks after treatment in either
groups (Table 1).
Mean PVR before and after the addition of mirabegron in
group A showed non-significant change; while in group B,
mean PVR increases with a significant difference.
Overall, no significant difference has been observed
between both groups after 12 weeks of treatment regarding
all studied parameters except PVR. Despite the statistically
significant difference between both groups regarding PVR,
it was not considered clinically meaningful.
Acute retention was not observed in any patient in group
A. The incidence of side effects in group A was 10.9%,
among which dry mouth was 2.2%, tachycardia in 2.2%,
constipation was 2.2% and hypertension in 4.3%. In group
B, there was one case of acute retention that required cath-
eter insertion and the incidence of side effects was 26.1%,
among which dry mouth was 8.7%, dizziness in 2.2%,
blurred vision in 2.2%, tachycardia in 2.2%, constipation in
6.5% and hypertension in 2.2% (Table 2). All cases with the
exception of the patient with acute retention were grade 1
according to common terminology criteria for adverse events
(CTCAE) ver. 4.0.
World Journal of Urology

95 paents met the

inclusion criteria and were
randomized into

(A) Tamsulosin 0.4mg + Mirabegron 50 mg (n=47) (B) Tamsulosin 0.4mg + Solefenacin 5mg (n=48)

Excluded (n=2)
Excluded (n=1)
Lost for follow up
Lost for follow up

Completed Completed

(n=46) (n=46)

Fig. 1  Flow diagram

Table 1  Comparison between Group A (mirabegron add-on) Group B (solifenacin 5 mg add-on)

the 2 groups regarding
subjective and objective 0 W 12 W P value 0 W 12 W P value
parameters
OABSS
 Q1 Daytime frequency 1.4 ± 0.5 0.8 ± 0.4 < 0.001 1.3 ± 0.5 0.7 ± 0.5 < 0.001
 Q2 Nighttime frequency 2.1 ± 0.6 1.4 ± 0.5 < 0.001 2.2 ± 0.5 1.5 ± 0.5 < 0.001
 Q3 Urgency 2.7 ± 0.8 1.6 ± 0.7 < 0.001 2.5 ± 0.8 1.5 ± 0.7 < 0.001
 Q4 Urgency incontinence 1.7 ± 0.7 1.1 ± 0.3 < 0.001 1.5 ± 0.5 1.0 ± 0.2 < 0.001
 Total score 7.8 ± 1.6 5.0 ± 1.2 < 0.001 7.6 ± 1.2 4.8 ± 1.1 < 0.001
IPSS
 Q1 Incomplete emptying 1.2 ± 0.4 1.3 ± 0.5 = 0.16 1.4 ± 0.5 1.5 ± 0.5 = 0.08
 Q2 Frequency 3.3 ± 0.8 2.2 ± 0.7 < 0.001 3.1 ± 1.1 1.9 ± 0.9 < 0.001
 Q3 Intermittency 1.2 ± 1.1 1.1 ± 1.2 = 0.551 1.6 ± 1.7 1.4 ± 1.3 = 0.516
 Q4 Urgency 2.8 ± 0.9 1.7 ± 0.9 < 0.001 2.6 ± 1.2 1.6 ± 0.9 < 0.001
 Q5 Weak stream 2.2 ± 1.0 2.1 ± 1.1 = 0.301 2.3 ± 1.7 1.9 ± 1.5 = 0.066
 Q6 Straining 1.6 ± 1.2 1.5 ± 1.1 = 0.421 0.9 ± 1.2 0.9 ± 1.2 = 0.644
 Q7 Nocturia 2.9 ± 0.9 1.9 ± 1.1 < 0.001 2.8 ± 1.0 2.0 ± 1.1 < 0.001
 Storage symptoms 8.9 ± 1.9 4.9 ± 2.1 < 0.001 8.6 ± 2.8 4.8 ± 2.5 < 0.001
 Voiding symptoms 6.2 ± 3.4 6.1 ± 0.6 = 0.562 4.7 ± 3.7 4.2 ± 3.2 = 0.253
 Total score 15.1 ± 4.2 11.8 ± 4.6 < 0.001 15.1 ± 5.9 11.2 ± 5.1 < 0.001
 QOL score 3.6 ± 1.1 2.6 ± 0.8 < 0.001 3.8 ± 0.9 2.7 ± 0.8 < 0.001
Urodynamic study
 MVV (ml)/micturition 138.1 ± 62.3 180.4 ± 90.3 < 0.001 140.3 ± 65.4 172.3 ± 82.2 < 0.001
 Q max (ml/s) 9.7 ± 1.3 11.6 ± 1.3 < 0.01 9.8 ± 1.2 11.9 ± 1.3 < 0.001
 PVR (ml) 28.7 ± 12.9 32 ± 19.1 = 0.07 29.5 ± 13.3 35.2 ± 20.2 < 0.001

13

Table 2  Comparison between the 2 groups regarding adverse events
Group A Group B
Dry mouth 1 patient (2.2%) 4 patients (8.7%)
Constipation 1 Patient (2.2%) 3 patients (6.5%)
Acute retention – 1 Patient (2.2%)
Dizziness – 1 Patient (2.2%)
Blurring of vision – 1 Patient (2.2%)
Tachycardia 1 Patient (2.2%) 1 Patient (2.2%)
Hypertension 2 Patients (4.3%) 1 Patient (2.2%)
Total 10.9% 26.1%
Discussion
In elderly patients with BPO, about 50% of patients have
OAB [14]. Therefore, treatment of BPO with standard
α1-adrenergic receptor antagonist can significantly improve
voiding symptoms but unfortunately may leave a population
of patients with bothersome OAB symptoms such as urgency
and frequency.
For this population, several well-designed prospective
placebo-controlled trials investigated the use of either anti-
muscarinic or beta-3 adrenergic agonist in combination with
various α1-adrenergic receptor antagonist as add-on treat-
ment [15, 16].
However, to our knowledge, no study in the literature
investigated the comparison between antimuscarinic versus
beta-3 agonist as add-on treatment for this aforementioned
population and therefore, this was the aim of this study.
Most of the studies revealed significant improvement of
the remaining OAB symptoms, QOL index, the IPSS stor-
age symptoms without deterioration of voiding symptoms
by add-on of antimuscarinic agents [3, 17] which is similar
to the finding reported in our study.
Mirabegron, a β3-adrenergic receptor agonist, acts to
improve the bladder storage capacity with no interference
with its voiding function and, hence, its worldwide accept-
ance as a good therapeutic option for OAB symptoms [18].
It has been reported in several randomized trials that it sig-
nificantly improves the OABSS with its all subscores and
the IPSS storage symptoms, QOL index when used as add-
on treatment after tamsulosin monotherapy [6, 8, 9, 19]. It
has been demonstrated to have higher efficacy than placebo
regarding IPSS, OABSS total score and MVV/micturition
and similar efficacy to antimuscarinic agents in several stud-
ies including our study [11, 20]. Furthermore, Otsuki et al.
reported their efficacy even in cases of OAB refractory to
antimuscarinic [11].
Antimuscarinic-related adverse events, especially uri-
nary retention, are a point of concern among all urologist.
Abrams et al. reported that tolterodine is safe when given to
patients with BOO with no additional risk of acute urinary
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World Journal of Urology
retention or significant change in post-void residual (PVR)
urine [21]. In our study, despite the significant increase in
PVR in solifenacin group, it was not considered clinically
meaningful as we have reported only one case of retention
(2.2%) that requires catheterization. Similarly, in Yamagu-
chi et al. series, PVR was significantly increased with also
clinically insignificant result as they have reported urinary
retention in four patients (1.9%) in the combined tamsulosin
and solifenacin group who all recovered after catheteriza-
tion [22]. The previous results are consistent with the result
of Kaplan et al. series of 398 patients who have reported
7 patients (3%) with urine retention in solifenacin plus
tamsulosin group from whom only 3 patients (about 1.5%)
required catheterization [23].
One of the main advantages of mirabegron is that it has
no suppressive effects on urinary bladder contraction and
voiding function on uroflowmetry and PVR [6, 24]. Several
authors concluded that mirabegron therapy does not impair
voiding urodynamics [24]. Otsuki et al. reported that mira-
begron was safe and showed non-significant change in PVR
urine [11]. Similarly, in our study, PVR urine was mini-
mally impacted with no significant changes or incidence of
acute urinary retention in group A treated with mirabegron.
This is in contrast to Kakizaki et al. study who reported
increased PVR in 3 patients (1.1%) versus one patient in pla-
cebo group (0.4%) with no cases of urinary retention [20]. In
the contrary, Kaplan et al. observed urinary retention with
mirabegron in six patients (1.7%) with two of them required
catheterization (0.6%) compared with one patient in placebo
group (0.3%) [25].
As most of the BPO patients are elderly who have
impaired physiological function, the safety and tolerability
of antimuscarinic drugs must be kept in mind. Unfortunately,
anti-muscarinic drugs carry the risk for bothersome adverse
effects as dry mouth, constipation, tachycardia, cognitive
dysfunction that lead to poor adherence to treatment [26].
Wu et al. reported the incidence of adverse reactions with
solifenacin to be 11.7% versus 23.5% with tolterodine [27].
On the other hand, the overall side effects in our study were
as high as 26.1% with solifenacin. However, mirabegron is
known to be well tolerated with no major safety concern,
lacking many bothersome antimuscarinic adverse effects and
the reported side effect rate is almost nearly the same as the
placebo [19, 28]. Otsuki et al. [11] reported incidence of
side effects as low as 8.4% which is nearly similar to what
is reported in our study (10.9%) versus 3.9% in Kakizaki
et al. series [27].
There are tolerability concern with antimuscarinic attrib-
uted to its adverse effects as dry mouth and constipation.
Dry mouth represents one of the most common adverse
events with antimuscarinic and are also reported to be an
important factor determining persistence. Kaplan et  al.
reported dry mouth as the most frequent adverse effects
World Journal of Urology
of solifenacin when combined with tamsulosin (7%) [23].
Similarly, Wu et al. reported the incidence of dry mouth to
be 5.8% with solifenacin and 10.4% with tolterodine [27].
On the other hand, several studies have concluded that dry
mouth occurred at a similar incidence between mirabegron
and placebo treatment [8, 29]. Nitti et al. reported 1.5% inci-
dence of dry mouth with mirabegron [30]. The incidence of
dry mouth in the current study was 2.2% with mirabegron
versus 8.7% in solifenacin group.
Nitti et al. also reported constipation in less than 2% with
mirabegron that is nearly similar to our observation (2.2%).
This is in accordance with Kakizaki et al. who reported con-
stipation in less than 1% of cases and in contrast to 6.5%
incidence of constipation in solifenacin group in our series
[21].
The other adverse events with mirabegron in our series
include one case of tachycardia (2.2%) and two cases of
hypertension (4.3%) and this was not serious. Kakizaki et al.
reported even less cardiovascular side effects in only 1.1% of
cases with no significant difference to the placebo and again
none of them was serious [21].
Many elderly people suffer from constipation and dry
mouth; thus, mirabegron may be more convenient to admin-
ister in the elderly BPO patients with persistent OAB symp-
toms than antimuscarinic [30].
The favorable tolerability and safety profile of mirabegron
versus anti-muscarinic drugs may result in improved treat-
ment adherence which has important implications on the
QOL and patient outcome [9].
The current study has several limitations to be considered.
In the absence of pressure flow study (PFS), there is diag-
nostic uncertainty between BPO and detrusor underactivity.
We did not perform sample size calculation, the follow-up
was limited to only 12 weeks and so, longer follow-up period
is recommended. Moreover, the study was not placebo con-
trolled and not double blinded. However, despite these
limitations and according to our knowledge, this is the first
prospective study to address the comparison between mira-
begron and antimuscarinic as add-on therapy for presumed
BPO patients with residual OAB symptoms after tamsulosin
monotherapy and contributes valuable information for the
management of this group of patients.
Conclusion
Our results indicate that the addition of either mirabegron or
solifenacin to patients with persistent OAB symptoms after
tamsulosin monotherapy has significant efficacy in control-
ling these symptoms. The adequate balance between efficacy
and tolerability reported in this study with mirabegron may
result in better QOL and overall patient satisfaction if com-
pared with antimuscarinics.
Acknowledgements  This research received no specific grant from any
funding agency in the public, commercial, or not for profit sectors.
Author contributions  MGS: Protocol development, Data analysis and
Manuscript writing; AMT: Data collection, Manuscript writing; MHR:
Data analysis, Manuscript editing; ASE: Data collection and Manu-
script editing.
Compliance with ethical standards 
Conflict of interest  No conflict of interest is declared by the authors
and no funding for this project.
Research involving human participants  All procedures performed in
this study were in accordance with the ethical standards of the institu-
tional research committee and with the 1964 Helsinki Declaration and
its later amendments.
Informed consent  All included patients signed informed consent.
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