Results from an interim analysis published in JAMA showed that the cardiovascular safety of the obesity treatment, naltrexone/bupropion “remains uncertain.”
Not many trials evaluating cardiovascular outcomes for obesity treatments have been conducted. With 2 drugs withdrawn from the market, there has been controversy over the cardiovascular safety of these agents. Study authors conducted a randomized, multicenter, placebo-controlled, double-blind noninferiority trial to determine whether naltrexone/bupropion increased major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction, compared with placebo in overweight and obese patients.
The study included 8,910 overweight or obese patients at increased cardiovascular risk from June 13, 2012 to January 21, 2013 across 266 U.S. centers. All study participants were offered an Internet-based weight management program and were randomized to naltrexone/bupropion 32mg/360mg daily or placebo. The primary outcome measure was time from randomization to first confirmed incidence of a MACE. The primary analysis was designed 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 25% interim analysis found that MACE occurred in 35 patients treated with naltrexone/bupropion vs. 59 patients treated with placebo (HR 0.59, 95% CI: 0.39-0.90). After 50% of planned events, MACE occurred in 90 patients treated with naltrexone/bupropion vs. 102 patients treated with placebo (HR 0.88, adjusted 99.7% CI: 0.57-1.34). Gastrointestinal events were more commonly seen in the naltrexone/bupropion group vs. placebo group (14.2% vs. 1.9%; P<0.001) as well as central nervous system symptoms (5.1% vs. 1.2%; P<0.001).
The study came to an early termination after the public release of confidential interim data by the sponsor. The sponsor agreed to the decision as recommended by the academic leadership of the study. Based on the interim analyses, the upper limit of the 95% CI of the HR for MACE in the naltrexone/bupropion arm did not exceed 2.0 compared with placebo. Due to the unforeseen early termination, “it is not possible to assess noninferiority for the prespecified upper limit of 1.4,” they concluded.
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