Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors A Randomized Clinical Trial
Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors A Randomized Clinical Trial
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DOI：
10.1001/jama.2016.1558
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发表时间：
2016-03-08
影响因子：
120.7
通讯作者：
Smith, Steven R.
中科院分区：
文献类型：
--
作者：
Nissen, Steven E.;Wolski, Kathy E.;Smith, Steven R.
关于肥胖治疗的心血管结局试验很少。两种已上市药物的撤回引起了关于肥胖药物心血管安全性的争议。目的：确定与安慰剂相比，纳曲酮联合安非他酮是否会增加超重和肥胖患者的主要不良心血管事件（MACE，定义为心血管死亡、非致死性卒中或非致死性心肌梗死）。设计、环境和参与者：2012年6月13日至2013年1月21日，随机、多中心、安慰剂对照、双盲非劣效性试验，在美国266个中心纳入8910例心血管风险增加的超重或肥胖患者。在主办方公开发布保密的中期数据后，该研究的学术领导建议终止试验，主办方同意。干预措施为所有参与者提供了一个基于互联网的体重管理程序。参与者随机接受安慰剂（n=4454）或纳曲酮32mg/d和安非他酮360mg/d （n=4456）。主要结局和测量从随机分组到首次确认发生MACE的时间。初步分析计划在378个预期事件后评估非劣效性风险比（HR）为1.4，在大约87个事件后进行保密中期分析（25%中期分析），评估非劣效性风险比为2.0，以考虑监管批准。结果在8910名随机分组的参与者中，平均年龄为61.0岁（SD， 7.3岁），54.5%为女性，32.1%有心血管疾病史，85.2%有糖尿病，中位体重指数为36.6（四分位数范围为33.1-40.9）。在25%的中期分析中，59名安慰剂组患者（1.3%）和35名纳曲酮-丁丙醇组患者（0.8%；HR, 0.59; 95% CI, 0.39-0.90）发生了MACE。在50%的计划事件发生后，安慰剂组102例（2.3%）患者发生MACE，纳曲酮-安非他酮组90例（2.0%）患者发生MACE （HR, 0.88；调整后的99.7% CI, 0.57-1.34）。纳曲酮-安非他酮组的不良反应更为常见，包括胃肠道事件（14.2% vs 1.9%）
IMPORTANCE Few cardiovascular outcomes trials have been conducted for obesity treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the cardiovascular safety of obesity agents.OBJECTIVE To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatalmyocardial infarction) compared with placebo in overweight and obese patients.DESIGN, SETTING, AND PARTICIPANTS Randomized, multicenter, placebo-controlled, double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed.INTERVENTIONS An Internet-based weight management program was provided to all participants. Participants were randomized to receive placebo (n=4454) or naltrexone, 32mg/d, and bupropion, 360mg/d (n=4456).MAIN OUTCOMES AND MEASURES Time from randomization to first confirmed occurrence of a MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after 378 expected events, with a confidential interim analysis after approximately 87 events (25% interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval.RESULTS Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropiontreated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were more common in the naltrexone-bupropion group, including gastrointestinal events in 14.2% vs 1.9% (P