(168) Evaluating the Cardiovascular Safety of Naltrexone/Bupropion in the United States

Background: CONTRAVE® is a branded fixed-dose extended-release combination of naltrexone/bupropion (FDC N/B) used for treatment of obesity or overweight (with weight-related comorbidities) as an adjunct to reduced-calorie diet and increased physical activity. FDC N/B has a labeled warning that cardiovascular morbidity and mortality have not been established.

Objectives: We assessed whether patients initiating FDC N/B or concomitant naltrexone and bupropion (N&B) were at elevated risk of major adverse cardiovascular events (MACE) or its components (non-fatal acute myocardial infarction [AMI], non-fatal stroke) compared to initiators of lorcaserin, an active comparator also indicated for weight loss.

Methods: We used Arcadia Data Research electronic health records linked with insurance claims between Sept 2014 and Feb 2020 to identify initiators with at least one healthcare encounter in the prior 180 days. Those under 18 years of age or with evidence of opioid use or prior weight loss surgery were excluded.
Following multiple imputation of key variables (e.g., glucose level, blood pressure), we used propensity score weighting (PSW) to adjust for baseline characteristics, comorbidities, concomitant medications, lifestyle factors, and clinical measures. Incidence rate ratios (IRR) were obtained, and hazard ratios (HR) with 95% confidence intervals (CI) were estimated using a weighted Cox model with robust standard errors in an intent-to-treat (ITT) approach.
We conducted separate analyses on the rate of MACE for FDC N/B versus lorcaserin and N&B versus lorcaserin. There was no comparison between FDC N/B and N&B.

Results: There were 12,475 initiators of FDC N/B, 7,243 of N&B, and 12,171 of lorcaserin. The average follow-up time was 1,705 days for FDC N/B and 1,702 days for lorcaserin. After PSW, baseline characteristics were similar between FDC N/B and lorcaserin groups; average age 47.9 years, 81.7% were women, 65.0% were white, with mean BMI 37.3 kg/m2. Baseline characteristics and follow-up times were comparable between the N&B and lorcaserin groups.
The MACE incidence rate was 0.77 per 1,000 person-years (1KPY) in FDC N/B initiators, 1.28/1KPY in N&B initiators, and 1.03/1KPY in lorcaserin initiators. The FDC N/B versus lorcaserin ITT analysis showed rates of MACE were statistically similar between FDC N/B and lorcaserin (HR 0.76, 95% CI: 0.48-1.20). Rates of AMI (HR: 0.74; 95% CI: 0.45-1.23) and stroke (HR: 1.05; 95% CI: 0.34-3.22) were similar. IRRs and HRs showed that apparent initiators of FDC N/B or N&B had similar rates of MACE and its components compared to apparent lorcaserin initiators.

Conclusions: We found no evidence that FDC N/B increased the rate of MACE, non-fatal AMI, or stroke relative to lorcaserin.