White William B, Chapple Christopher, Gratzke Christian, Herschorn Sender, Robinson Dudley, Frankel Jeffrey, Ridder Arwin, Stoelzel Matthias, Paireddy Asha, van Maanen Robert, Weber Michael A
Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT, USA.
Royal Hallamshire Hospital, University of Sheffield, Sheffield, UK.
J Clin Pharmacol. 2018 Aug;58(8):1084-1091. doi: 10.1002/jcph.1107. Epub 2018 Apr 12.
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.
一直有人担心，使用β-肾上腺素能受体激动剂治疗膀胱过度活动症可能会产生有害的心血管（CV）副作用。我们评估了β-肾上腺素能受体激动剂米拉贝隆单独使用以及与抗毒蕈碱药物索利那新联合治疗时的心血管安全性。SYNERGY试验是一项多国、多中心、随机、双盲、平行组、安慰剂和活性对照的3期试验。患者被随机分配接受索利那新5毫克+米拉贝隆50毫克（联合5+50毫克组）、索利那新5毫克+米拉贝隆25毫克（联合5+25毫克组）、索利那新5毫克单药治疗、米拉贝隆25毫克单药治疗、米拉贝隆50毫克单药治疗或安慰剂，进行为期12周的双盲治疗期。该研究共纳入3398名患者。各治疗组从基线到治疗结束时心电图参数的平均变化相似，尽管米拉贝隆治疗组的心率增加了1次/分钟。单药治疗组与安慰剂组之间以及单药治疗组与联合治疗组之间，QTcF从基线的变化没有临床意义上的差异。主要心血管事件极少：联合5+25毫克组853例中有1例（0.1%）发生非致命性心肌梗死，联合5+50毫克组848例中有2例（0.2%）发生非致命性中风，其他组无事件发生。基于生命体征、心电图和判定的心血管事件评估，米拉贝隆和索利那新联合使用的这种心血管安全性分析显示，心血管事件发生率与单药治疗相当。
