DISCUSSION
In present study, combination therapy of Mirabegron with Tamsulosin was
superior to Tamsulosin monotherapy with respect to improvement in OABSS
and IPSS including the storage sub score (IPSS-S) as per higher
improvements in the IPSS-S (-9.40±2.57 vs-4.60±2.35) and nocturnal
frequency (-5.05±1.78 vs-1.57±1.38) was observed in the intervention
arm. TEAE/side effects were minor and without any study disruption.
Mirabegron-tamsulosin combination therapy could be considered
efficacious and safe versus tamsulosin monotherapy in improving BPH
induced OABS without the need of an initial run in alpha blocker therapy
(the desirable lack of increase in PVR/AUR possibly could be attributed
to this).Table-2 depicts a summary review of salient features of similar
studies published in the English literature.
Ichihara et al7 demonstrated the efficacy and
safety of 50mg Mirabegron as an add-on treatment for residual OABS after
0.2mg of Tamsulosin therapy in symptomatic BPH patients. These authors
demonstrated a significant difference in the mean change in the overall
OABSS by -0.87 and -2.21 in the Tamsulosin monotherapy and combination
group respectively over an eight week period(p=0.012) along with similar
significant improvements in the IPSS-S and QOL index in the Mirabegron
add-on group which was in line with the present study.
Kakizaki et al8 in another randomized
placebo-controlled study demonstrated that Mirabegron (50mg) was
effective and safe in controlling OABS as an add-on treatment to after 4
weeks of initial tamsulosin(0.2mg) monotherapy. They demonstrated a
significant difference in the mean change in micturition episodes/24hrs
by -1.27 and -0.75 in the Mirabegron add-on and (Tamsulosin+placebo)
groups respectively (p<0.001). The authors also established a
significant difference in the mean change in OABSS and the total IPSSof
-2.78/ -2.13 and -2.13/ -4.25 respectively in the (Mirabegron addon and
Tamsulosin+placebo) groups respectively which was in harmony with the
present study.
In a meta-analysis and systemic review of three RCTs comprising 1317
patients conducted by Shunye et al10 the
authors calculated a significant difference in the mean difference of
total OABSS with a 95% CIof -0.69 (-1.00 to -0.38) betweenthe
combination (Mirabegron + Tamsulosin) and (Tamsulosin + placebo) groups
respectively (p < 0.001)and concluded that Mirabegron was an
effective treatment for BPH induced OABS.
In another prospective study by Matsuo et
al11 on 50 men with LUTS(>65
years with persistent OABS post 12 weeks α1 blocker therapy)stratified
into younger (65-74 years) and the older groups (75-84 years)prior to
alocating Mirabegron (50mg) additional therapy. These authors
demonstrated that the total OABS score pre/post therapy was
6.5±2.7/4.4±1.6 (p= 0.004) and 5.6±1.3/4.2±1.2 (p<0.001) for
younger and older age groupsrespectively with significant improvement in
storage subscore of IPSS in both the groups.
Wada et al12 in another prospective study
conducted on 26 Japanese men with persistent OABSpost 8 weeks Tamsulosin
therapy,too demostrated a significant improvement in theirOABSS from
8.5±2.3 to 4.7±2.5 with Mirabegron add-on therapy (p< 0.001)
with concomitant similar improvement in the IPSS and IPSS-S.
In the present study there was significant improvement in the OABSS,
total IPSS and IPSS-S, on the basis of which it appeared that the
initial combination therapy could be considered efficacious for the
management of BPH with predominant/co-existing OABS versus tamsulosin
monotherapy. However in the present study the voiding sub score (IPSS-V)
was unaffected by Mirabegron versus placebo which was in harmony with
other similar studies8,11 . This could be
explained and attributed to the fact that Mirabegron actions on detrusor
smooth muscle and voiding dysfunctions are mainly due to bladder outlet
obstruction/urethral abnormalities. The significant change observed
within groups in the IPSS-V in the present study could be explained by
the mechanism of action of
Tamsulosin13 .Tables 3(a-b) briefly depicts
the salient outcome parameters (OABSS/IPSS) in various RCTs on
mirabegron published in the literature.
Based on the search of literature the present study is the first such
RCT to compare the efficacy of Mirabegron combination with
tamsulosin-placebo (without using add on therapy protocol for post
tamsulosin residual symptoms) in improving the nocturnal frequency in
patients of BPH which appears to be the core bothersome symptom in about
30% males with LUTS14 . In the current study
the mean change ± SD in nocturnal frequency with was -5.05±1.78 and
-1.57±1.38 in groups I and II respectively. In the present study
statistically greater improvement with Mirabegron was enhanced by the
worse baseline nocturnal frequency observed in the intervention group
versus the tamsulosin arm (5.75±2.03 vs 3.90±1.35) which appeared to
suggest that improvement in nocturnal frequency may be a better
determinant versus nocturia score for deciding the severity of OABS.
In another randomized placebo-controlled study by Kuo et
al15 conducted on 1126 OABS patients the
authors demonstrated an adjusted mean difference of -0.13(-0.33, 0.00)
and -0.01(-0.18, 0.21) for Mirabegron vs placebo and Tolterodine vs
placebo respectively and these researchers independently observed a
significant decrease in the nocturnal frequency with Mirabegron versus
the placebo.
Effect on PVR/AUR: Various past studies on Mirabegron
have demonstrated ambiguous results regardingits effect on PVR in men
with BPH-LUTS (Table 2c). In a study by Wada et
al12 on 26 men with post tamsulosin residual
OABS the authors demonstrated that Mirabegron was not associated with
any significant increase in PVR (p=0.23) which was similar to our study
with non-significant numerical decrease in PVR with Mirabegron therapy.
The mean change ±SD in PVR in our study was -7.20±42.66 / 30.2789.62 in
the Mirabegron /Tamsulosin combination and Tamsulosin/ placebo groups
respectively.
The combination of Mirabegron and antimuscarinic agents has been used
synergistically for managing OABS which does not appear to adversely
impact the rate of complications related to reduced bladder
contractility like increasing PVR/voiding symptoms/AUR. The mechanism of
as to why this synergistic combination fails to act in unison remains to
be elucidated16 . This confusion is further
compounded by fact that biased inclusion criteria in many such studies
which had recruited several patients with higher baseline PVR of ≤ 200ml
and the lack of long term studies on antimuscarinic drugs in OABS either
as monotherapy or in combination and such void in data has resulted in
physicians using Mirabegron-antimuscarinics with caution especially in
high risk symptomatic patients aged ≥ 75 years with an initial PVR
>200ml17 .
Lack of significant rise in the PVR/AUR in the currents study could
possibly be explained by the mutual antagonistic action of both
drugs/combination on bladder emptying18.Tamsulosin serves as a bladder neck relaxant and acts on the voiding
component preventing urine/ PVR accumulation, thereby acting in positive
antagonism to Mirabegron’s effect on bladder contractility. The merit of
this combination therapy is further enhanced by the long term available
scarce data depicting no increase in AUR with long term alpha blocker
therapy in contrast to antimuscarinics19-22.In an experimental study by Alexandre et al23the authors investigated on the effects of mirabegron in the mouse
urethral smooth muscle and concluded that the mirabegron result was
attributed to β3 -adrenoceptor agonism in combination
with α1A and α1D -adrenoceptor antagonism. Though Tamsulosin has been
used in combination with other drugs like (tadalafil) in BPH patients
with predominant storage LUTS it, however merits further evaluation with
larger trials24,25 .
In the present study significant improvement was also demonstrated in
uroflowmetry parameters like voided volume/micturition (VV/micturition)
and maximum flow (Qmax) in Mirabegron add on group. The
mean change ±SD in VV/micturition was 129.40±149.24 (Mirabegron +
Tamsulosin) and 86.92±288.99 (Tamsulosin +placebo). Kakizaki et
al8 demonstrated similar results in terms of
voided volume in their study. The mean change in the
Qmax in our study was -4.04±4.35 for the combination
group and -0.72±3.51 for the (Tamsulosin + placebo) group, which was
significant and similar to the study conducted by Ichihara et
al7 .
Effect on QOL: In the present study the mean change in
QOL index in both groups was -3.05±0.55 and -2.38±1.00 respectively and
the overall QOL had improved significantly (p<0.001) in the
combination group. Similarly, Ichihara et
al7 , in their study observed significant
improvement in QOL index in combination group (p-0.020).
TEAE: In the present study, two patients in the Mirabegron +
Tamsulosin group (headache and tachycardia) and one patient from the
Tamsulosin + placebo group (headache) developed adverse reactions which
were self-limiting and were managed symptomatically without any drug
discontinuity. Mirabegron appeared to score high on its safety aspect in
the select group of BPH-LUTS patients with predominantly co-existing
OABS.
Limitations: Despite the adequate power and sample size
of this study we admit to certain limitations. An age stratified sample
size was omitted which could have made this study more robust. Dose
escalation was omitted in this study due to protocol restrictions and
patient safety concerns. Size stratification of the prostate at
presentation was not considered in this study bearing in mind that
bothersome LUTS are usually largely independent of prostate size.
Considering the longer duration (12 weeks) of other published
trials26, 27 on Mirabegron, one could question
our shorter duration of study. For reasons described previously the
present eight 8 week follow up was done in this protocol considering the
fact that both drugs in the study had rapid onset of action and majority
of their usually observed side effects if any would be exhibited well
within this frame. This study did not evaluate the long term adverse
events if any as due to protocol restrictions. However a longer duration
of study could have enhanced this void in data on the long term
safety/efficacy/AUR/PVR elevation if any with prolonged Mirabegron
therapy. Nevertheless, the major findings of this study would still hold
relevance albeit excluding the absence of long term adverse effect
monitoring data. Considering this area of research to be relatively
recent, we expect in future trials of larger sizes and longer durations
to further validate our safety data.
There was no attempt to establish the role of Mirabegron as an add on
therapy for post tamsulosin residual OABS if any, as the conventional
initial run in tamsulosin therapy was omitted. Another limitation
observed in the study was the relative minor mismatch in baseline
comparability between both groups in the IPSS-ss/NF. However this was
negated by the fact that the combination group showed greater
improvements in the above mentioned parameters at the end of the study
(NF -2.20±0.65 vs -0.70±0.56 p<0.001, IPSS-S -9.40±2.57 vs
-4.60±2.35 p<0.001) despite inferior baseline parameter values
(NF 5.75±2.03 vs 3.90±1.35 and IPSS-S 12.68±2.71 vs 10.97±3.02) versus
the comparator group. We feel that the aberration of baseline
comparability was minor which could have been minimised by inclusion of
a larger age stratified sample size of patients. As a result of scarcity
of studies of similar nature, future studies of the same nature on a
larger scale may be required to support the findings of the present
study.
We did not attempt examine the effect of Mirabegron in patients of OABS
without BPH in this study, however in a post marketing study by
Takahashi et al26 using Mirabegron 12 weeks
therapy for OABS patients [with/without BPH on 4540 (3176 diagnosed
with BPH)] in which the occurrences of AUR and the concomitant use of
α1-blockers were specifically investigated, the authors concluded that
Mirabegron was well-tolerated and effective for majority of their
patients with OABS with or without concomitant BPH. In a multicentre,
randomized, double-blind, placebo-controlled, parallel comparison phase
IV study on Mirabegron conducted exclusively on 464 males with OABS by
Shin et al27 the authors concluded that
mirabegron therapy was well tolerated for 26 weeks, without additional
adverse effects compared to placebo. Finally no comparison of mirabegron
combination therapy with anti-cholinergics (darifenacin) for BPH induced
OABS was done in this study; as this has been previously examined and
reported that initial combination therapy with tamsulosin/darifenacin
was safe and effective in select patients of BPH with accompanying
OABS28 .
Conclusions: In summary despite these limitations we can
confidently conclude that mirabegron combination therapy was safe and
effective in ameliorating BPH induced OABS versus tamsulosin monotherapy
in majority of our patients with minimal side effects and good
tolerability. This efficacy could be further potentiated by the utility
of Mirabegron with Tamsulosin combination as a potential viable start-up
therapeutic option for select patients of BPH with predominantly
coexisting OABS without the ill confounded fear of a potential rise in
the post void residue culminating in any urinary retention.
ACKNOWLEDGEMENTS – Nil