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