Cardiovascular Risk Associated With Naltrexone-Bupropion Therapy for Obesity
Is obesity treatment with naltrexone-bupropion associated with increased risk for major adverse cardiovascular events (MACE)?
This was a randomized, placebo-controlled, double-blind, noninferiority trial of overweight and obese patients at increased cardiovascular risk, enrolled between June 13, 2012, and January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended early termination of the trial and the sponsor agreed. Participants were randomized to receive placebo (n = 4,454) or naltrexone, 32 mg/d, and bupropion, 360 mg/d (n = 4,456). All patients received an Internet-based weight management program. The primary outcome of interest for this analysis was first confirmed occurrence of MACE (including cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction). 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.
A total of 8,910 participants were randomized. Mean age was 61.0 years (standard deviation, 7.3 years), and 54.5% were female. The study population included 32.1% with a history of cardiovascular disease, and 85.2% with diabetes. Median body mass index was 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-bupropion–treated patients (0.8%; HR, 0.59; 95% confidence interval [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% versus 1.9% (p < 0.001) and central nervous system symptoms in 5.1% versus 1.2% (p < 0.001).
The investigators concluded that among overweight or obese patients at increased cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion treatment, compared with placebo, did not exceed 2.0. However, because of the unanticipated early termination of the trial, it is not possible to assess noninferiority for the prespecified upper limit of 1.4. Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial.
Effective therapies that help patients lose weight but do not increase risk for cardiovascular disease are needed. Thus, outcome trials in this area are warranted.
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