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White, William B.; Chapple, Christopher; Gratzke, Christian; Herschorn, Sender; Robinson, Dudley; Frankel, Jeffrey; Ridder, Arwin; Stoelzel, Matthias; Paireddy, Asha; Maanen, Robert van; Weber, Michael A. (2018): Cardiovascular Safety of the (3)-Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial. In: Journal of Clinical Pharmacology, Vol. 58, No. 8: pp. 1084-1091
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Abstract

There have been concerns that treatment of overactive bladder with (3)-adrenoceptor agonists may potentially have detrimental cardiovascular (CV) side effects. We evaluated the CV safety of mirabegron, a (3)-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 3trial. Patients were randomized to receive solifenacin 5mg+mirabegron 50mg (combination 5+50mg), solifenacin 5mg+mirabegron 25mg (combination 5+25mg), solifenacin 5mg monotherapy, mirabegron 25mg monotherapy, mirabegron 50mg 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 1beat/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+25mg group, 2 of 848 (0.2%) with a nonfatal stroke in the combination 5+50mg 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.