Abraham Morse, MD, MBA
Harvard Medical School
Khullar V, Amarenco G, Angulo JC, et al. Efficacy and tolerability of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol. 2013;63:283-295.
Mirabegron is a newly FDA-approved medication for the treatment of overactive bladder that works through the beta-3 adrenergic receptor pathway. All of the other contemporary overactive bladder medications work through their ability to block muscarinic cholinergic receptors. Because of this fundamentally different mechanism of action, there is hope that mirabegron may prove to be a significant new addition to the armamentarium of overactive bladder treatments. The study by Khullar et al is a large double-blind, multicenter, randomized trial that compares two different doses of mirabegron to placebo. In addition, it includes a parallel group of patients treated with tolterodine extended release.
Men and women ≥ 18 years with symptoms of overactive bladder for ≥ 3 months were eligible for study participation. In addition, for treatment randomization, patients had to have a frequency of eight or more micturitions in a 24-hour period and three or more episodes of urgency (with or without incontinence) as recorded during a three-day diary. Potential study participants were excluded if they were felt to have stress incontinence, “stress predominant mixed incontinence,” or an average 24-hour urine volume of greater than three liters.
Following a two-week “placebo run-in,” subjects were randomized to one of four treatment groups: placebo (n = 494), mirabegron 50 mg (n = 493), mirabegron 100 mg (n = 496), or tolterodine ER (n = 495). Treatments were given once daily for 12 weeks. After the end of the 12-week treatment period, patients were followed for an additional 30 days to assess for any late adverse events.
The co-primary outcome measures were the change from baseline to final visit in the mean number of incontinence episodes and the mean number of micturitions per 24 hours. Secondary endpoints included change from baseline to final visit in mean voided volume per micturition, and the percentage of patients with greater than 50% decrease in the mean number of incontinence episodes, as well as the percentage of patients with zero incontinence episodes. Health-related quality of life was assessed using the OAB Questionnaire (OAB-q), the Patient Perception of Bladder Condition (PPBC), and the Treatment Satisfaction Visual Analog Scale (TS-VAS).
Safety was evaluated with adverse event reporting, laboratory assessments, vital signs, physical examination, electrocardiogram, and measurement of post-void residual volumes. Cardiovascular-related adverse events were monitored closely.
The full analysis set included randomized patients who received at least 1 dose of study drug, had at least 1 baseline and 1 post-baseline micturition measurement. Any subject who took at least one dose of study drug was included in the safety analysis. Change from baseline variables were analyzed using ANCOVA (analysis of co-variance).
There were no significant differences in demographic or pre-study variables across groups. Twenty-eight percent of participants were male; the mean age was 59 years (37% were ≥ 65 years and 8% were ≥ 75 years); and 99% were Caucasian. Almost half of the patients were previously treated with medication for OAB.
Treatment with both doses of mirabegron was associated with statistically significant reductions from baseline in the mean number of incontinence episodes and number of micturitions per 24 hours compared to placebo.
Treatment with mirabegron (50 and 100 mg doses) and tolterodine ER (4 mg) were associated with statistically significant improvements in the TS-VAS, OAB-q and PPBC.
In general, side effects were mild to moderate and there was no significant increase in overall adverse events when comparing the active drug groups to placebo. The incidence of dry mouth was similar in the placebo and mirabegron 50 and 100 mg groups at 2.6, 2.8, and 2.8%, respectively. The incidence of dry mouth in the tolterodine group was 10.1%. The incidence of hypertension in the 50 and 100 mg mirabegron groups was 5.9 and 5.4%, respectively. Hypertension in the tolterodine and placebo groups was 8.1 and 7.7%, respectively. Overall, the number of patients discontinuing the study drug due to side effects was low across all treatment groups. The incidence of adjudicated cardiovascular events was similar in the mirabegron and placebo groups.
This manuscript documents a well-designed, adequately powered, and well executed study of an interesting new option in the pharmacologic treatment of overactive bladder. While the study was not designed as a head-to-head comparison of mirabegron with an anticholinergic, tolterodine ER was included as an active control, and the efficacy of mirabegron appears to be comparable to that of tolterodine and better than placebo. As with many overactive bladder medication trials, the magnitude of the improvement in the placebo group is impressive and suggests to me that therapy with behavioral treatments and pelvic floor function improvements as well as of advice about dietary irritants and bladder training should always be implemented with patients whenever possible at least concurrently with pharmacologic management. Overall, reductions in incontinence episodes seemed more clinically significant than the very modest although statistically significant decreases in urinary frequency.
Tolerability of mirabegron does appear to be superior to modern anticholinergics in terms of the incidence of dry mouth, although the overall discontinuation rates in this study were similar. There were no cardiovascular changes in excess of tolterodine or placebo in this study which helps allay the understandable pre-market concerns about potential cardiovascular effects of a beta agonist. However, postmarketing surveillance should continue carefully since this study could have missed rare but serious cardiovascular changes due to modest sample size and short duration.