title: Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01601704.
authors.affiliation: Cleveland Clinic Center for Cardiovascular Research, Cleveland, Ohio.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
authors.affiliation: Cleveland Clinic Center for Cardiovascular Research, Cleveland, Ohio.
authors.forename: Kathy E
authors.initials: KE
authors.lastname: Wolski
authors.affiliation: Cleveland Clinic Center for Cardiovascular Research, Cleveland, Ohio.
authors.forename: Lisa
authors.initials: L
authors.lastname: Prcela
authors.affiliation: Center for Weight and Eating Disorders Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wadden
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill.
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
authors.affiliation: ASH Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, Illinois.
authors.forename: George
authors.initials: G
authors.lastname: Bakris
authors.affiliation: Takeda Pharmaceuticals, Deerfield, Illinois.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Perez
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Sanford-Burnham Medical Research Institute, Orlando.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
mesh_terms: D000368:Aged; D019440:Anti-Obesity Agents / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D015992:Body Mass Index; D016642:Bupropion / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000401:mortality; D016001:Confidence Intervals; D003219:Confidentiality; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D020407:Internet; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology; D009271:Naltrexone / Q000009:adverse effects*; D009765:Obesity / Q000150:complications / Q000188:drug therapy*; D050177:Overweight / Q000150:complications / Q000188:drug therapy; D018579:Patient Selection; D015990:Placebo Effect; D012307:Risk Factors; D018401:Sample Size; D014481:United States; D061217:Weight Reduction Programs
chemical_list: D019440:Anti-Obesity Agents; D016642:Bupropion; D009271:Naltrexone