Cardiovascular Safety of the β₃‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

Abstract

There have been concerns that treatment of overactive bladder with β -adrenoceptor agonists may potentially have detrimental cardiovascular (CV) side effects. We evaluated the CV safety of mirabegron, a β -adrenoceptor agonist, alone and in combination therapy with the antimuscarinic agent solifenacin. The SYNERGY trial was a multinational, multicenter, randomized, double-blind, parallel-group, placebo and active-controlled phase 3 trial. Patients were randomized to receive solifenacin 5 mg + mirabegron 50 mg (combination 5 + 50 mg), solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg monotherapy, mirabegron 25 mg monotherapy, mirabegron 50 mg monotherapy, or placebo for a 12-week double-blind treatment period. A total of 3398 patients were included in the study. Mean changes from baseline to the end of therapy in ECG parameters were similar across treatment groups, although there was an increase in heart rate of 1 beat/minute in the mirabegron treatment groups. There were no clinically meaningful differences in change from baseline in QTcF between monotherapies and placebo and between monotherapies and combination therapy. There were very few major CV events: 1 of 853 (0.1%) with a nonfatal myocardial infarction in the combination 5 + 25 mg group, 2 of 848 (0.2%) with a nonfatal stroke in the combination 5 + 50 mg group, and no events in the other groups. This CV safety analysis of the combination of mirabegron and solifenacin showed rates of CV events comparable with those for monotherapy treatments based on assessments of vital signs, electrocardiograms, and adjudicated CV events.

Mirabegron Vs Placebo Add-on Therapy in Men With Overactive Bladder Symptoms Receiving Tamsulosin for Underlying Benign Prostatic Hyperplasia: A Safety Analysis From the Randomized, Phase 4 PLUS Study

“…However, in support of the findings from PLUS, previous monotherapy studies with mirabegron and tamsulosin have not indicated that either of the therapies have significant effects on ECG parameters. 26,27 Furthermore, a recent large population-based study from Canada reported that mirabegron was not associated with a higher risk of cardiovascular events compared with other OAB treatments. 28 The investigators tracked hospitalizations and emergency visits for arrhythmias, tachycardia, myocardial infarction, and stroke over a 1-year period.…”

Mirabegron in Overactive Bladder and Its Role in Exit Strategy After Botulinum Toxin Treatment in Children

“…In adults, cardiovascular side effects such as hypertension and prolonged QT interval on ECG are one of the main concerns under Mirabegron treatment (9). Extra caution should be taken in patients who have a history of hypertension and long QT syndrome (13).…”

“…More recently, in 2021, Mirabegron is approved by the FDA for use in neurogenic detrusor overactivity (NDO) treatment in children (8). Mirabegron works by acting on the smooth muscles of the bladder, causing relaxation which results in the increase in bladder capacity without changing micturition pressure, voiding contraction, and post-void residual (7,9). Mirabegron can be used as monotherapy or in combination with anticholinergics (7,10,11).…”

Drug causes of intracerebral haemorrhage

“…6 However, in an international, multicentre randomized double-blind parallel-group placebo-controlled trial of solifenacin and mirabegron, there were very few major cardiovascular events, including stroke, with no significant difference between control and treatment groups. 7 Pooled data from 13 studies has also found no evidence of increased stroke risk from mirabegron use compared to placebo after controlling for baseline cardiovascular characteristics. 8 However, mirabegron is now contraindicated in patients with severe uncontrolled hypertension and regular monitoring of blood pressure is recommended, particularly in patients with preexisting hypertension.…”