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Original Investigation |

Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors A Randomized Clinical Trial

Steven E. Nissen, MD1; Kathy E. Wolski, MPH1; Lisa Prcela, RN1; Thomas Wadden, PhD2; John B. Buse, MD, PhD3; George Bakris, MD4; Alfonso Perez, MD5; Steven R. Smith, MD6
[+] Author Affiliations
1Cleveland Clinic Center for Cardiovascular Research, Cleveland, Ohio
2Center for Weight and Eating Disorders Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia
3University of North Carolina School of Medicine, Chapel Hill
4ASH Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, Illinois
5Takeda Pharmaceuticals, Deerfield, Illinois
6Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Sanford-Burnham Medical Research Institute, Orlando
JAMA. 2016;315(10):990-1004. doi:10.1001/jama.2016.1558.
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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 nonfatal myocardial 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, 32 mg/d, and bupropion, 360 mg/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-bupropion–treated 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 < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001).

Conclusions and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT01601704

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Figure 1.
Flow of Participants Through the Trial
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Figure 2.
Time to MACE in the 50% Interim Analysis and the Final End-of-Study Analysis

MACE indicates major adverse cardiovascular events. Segment of y-axes shown in blue is the range of 0% to 2.5%.

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Figure 3.
Time From Randomization to Permanent Study Drug Discontinuation
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Figure 4.
Change in Body Weight During the Trial

Error bars indicate 95% confidence intervals.

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Figure 5.
Changes in Systolic Blood Pressure and Heart Rate During the Trial

Error bars indicate 95% confidence intervals.

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