Lower urinary tract symptoms (LUTS), including overactive bladder (OAB) symptoms, commonly occur in older men. The EPIC study showed that storage symptoms were more frequent and bothersome than emptying symptoms in men, so the appropriate management approach for male LUTS is to consider both types of symptoms.
α1-blockers relieve dynamic obstruction of the prostate and urethra, as well as storage symptoms. Therefore, in general, α1 blockers are generally used as first-line drugs for male LUTS, with it being recommended that α1 blockers (or phosphodiesterase 5 inhibitors) be used regardless of prostate size.
However, monotherapy with an α1 blocker often does not improve storage symptoms, including OAB, and therefore, combination therapy of an α1 blocker plus an antimuscarinic has been recommended. However, there are tolerability problems with the latter due to side effects such as dry mouth, constipation and risk of urinary retention.
Mirabegron, a β3 adrenergic agonist, is an alternative treatment option to antimuscarinics for OAB symptoms, with proven efficacy in men and women. The primary objective of the present study was to evaluate the efficacy of mirabegron versus placebo in men with OAB who were receiving tamsulosin treatment for LUTS. Secondary objectives were to evaluate safety, other OAB symptoms, and quality of life outcomes.
Methods
Design, setting and participants . Japanese and Korean men with OAB treated with tamsulosin for LUTS (January 2016 to July 2017).
Intervention . 4-week single-blind screening: tamsulosin plus placebo orally once daily; 12-week double-blind treatment: patients randomly assigned (n = 568) to mirabegron 50 mg or placebo, as an adjunct to tamsulosin.
Outcome measurements and statistical analysis . Primary endpoint: change from baseline to end of treatment in mean number of voids/24 h. Secondary endpoints: change in other daily variables and patient-reported outcomes from baseline to end of treatment. The primary endpoint was analyzed using analysis of covariance, including treatment group and region as fixed factors and baseline as a covariate.
Results
Patient demographics and baseline characteristics
A total of 779 patients gave written informed consent and entered the evaluation period. Of these, 730 patients received tamsulosin 0.2 mg plus placebo. In the subsequent treatment period, 568 patients were randomized to receive placebo or mirabegron 50 mg plus tamsulosin 0.2 mg. In total, 544 patients completed the study (272 in the placebo group and 272 in the 50 mg mirabegron group).
Efficacy Endpoints
The adjusted mean change (95% CI) in the mean number of voids/24 h from baseline to the end of treatment was –1.27 (–1.65 to –0.89) in the mirabegron group versus – 0.75 (–1.13 to –0.38) in the placebo group, with a statistically significant adjusted mean difference between groups: (–0.52 [–0.82 to –0.21]; p < 0.001).
In terms of patient-related outcomes, mirabegron demonstrated statistically significant changes from baseline to end of treatment in the Overactive Bladder Symptom Questionnaire (OABSS) total score and the International Prostate Symptom Score (IPSS) total score versus placebo .
Adjusted mean differences were also statistically significant versus placebo for the OABSS daytime frequency subscales, urgency and urge incontinence, IPSS storage, and OAB quality of life and symptom bother subscales and quality of life subscale total scores.
With respect to secondary efficacy endpoints, mirabegron demonstrated statistically significant changes from baseline to end of treatment in mean voided volume/void versus placebo.
Subgroup analysis
Mirabegron showed statistically significantly greater reductions from baseline to end of treatment compared to placebo in the mean number of voids/24 h in the following subgroups: age <65 years, BMI <25 kg/m2, OAB duration ≥ 12 months, postvoid residual < median and ≥ median and Qmax ≥ 15 ml/s.
Security endpoints
Overall, 23.4% of mirabegron versus 22.5% of placebo patients reported one or more adverse events, and 3.9% and 6.3%, respectively, reported drug-related TEAEs. Most adverse events were mild or moderate in severity. Serious adverse events were reported in six patients (2.1%) in the mirabegron group and in three patients (1.1%) in the placebo group.
No patients in the mirabegron 50 mg group reported adverse events that led to permanent discontinuation of the study drug, compared to three patients (1.1%) in the placebo group. The most common adverse event was nasopharyngitis (6.4% in the mirabegron group and 6.0% in the placebo group). The overall incidence of cardiovascular adverse events was 1.1% for each group.
Discussion
The current study is the first double-blind, placebo-controlled trial of mirabegron add-on therapy to tamsulosin, and supports data from previous studies that were neither double-blind nor placebo-controlled. In the current study, the addition of mirabegron 50 mg once daily to tamsulosin for 12 weeks was effective in reducing overactive bladder symptoms, demonstrating superior efficacy to placebo in reducing the mean number of voids/24 h.
Change in voiding frequency was selected as the primary endpoint for this study because frequent voiding is observed in almost all patients with OAB, and voiding frequency shows relatively small variations among patients. In the current study, mirabegron also demonstrated superior efficacy to placebo in changes in IPSS and OABSS total scores from baseline to the end of treatment, and in mean voided volume/void.
The increases in mean voided volume observed in this study therefore indicate that the decrease in micturition frequency is due to a therapeutic effect of the drug and not a reduction in fluid intake. For episodes of urgency, urge urinary incontinence, and nocturia, differences between the mirabegron and placebo groups did not reach conventional levels of statistical significance, although the OABSS urgency and urgency incontinence subscale scores showed statistically significant differences between mirabegron. and placebo.
The incidence of adverse events in the mirabegron 50 mg group was similar to that in the placebo group, in line with previously reported results for men receiving mirabegron. The incidence of constipation in the mirabegron group was only 0.7%, indicating that mirabegron has a low potential to cause anticholinergic AEs, which are generally associated with antimuscarinic treatments. No marked differences were found in the incidence of adverse cardiovascular events of particular interest between the treatment groups.
Limitations of the study are the lack of comparison with antimuscarinics (future studies could benefit from including a tamsulosin plus antimuscarinic comparator arm), the omission of severe urgency as an inclusion criterion, and an unbalanced proportion of patients per country.
Conclusions Add-on therapy of mirabegron to tamsulosin in men with symptoms of LUTS and OAB showed superiority over placebo in decreasing voiding frequency over 12 weeks and increasing mean voided volume/void, as well as changes in total scores of OABSS and IPSS from the beginning to the end of treatment. Additionally, mirabegron showed a statistically significant and clinically meaningful improvement versus placebo in IPSS-quality of life score and OAB symptom bothersomeness, among other parameters. Mirabegron was well tolerated and there were no major safety concerns regarding urinary retention or cardiovascular events. |
