(C-233) Emulating a Clinical Trial to Assess the Fitness of Real-World Data for Evaluating the Cardiovascular Safety of Fixed-Dose Combination Naltrexone/Bupropion in the United States

Background: The fixed-dose combination of extended-release naltrexone and bupropion (FDC N/B), CONTRAVE®, is indicated to treat obesity or overweight (with weight-related comorbidities) as an adjunct to diet and exercise. The labeling of FDC N/B includes Limitations of Use language that its cardiovascular safety has not been established, but an observational 2024 study by Burns, et al., found no evidence that FDC N/B increased the rate of major adverse cardiovascular events (MACE) or its components (acute myocardial infarction [AMI], stroke, cardiovascular death) relative to a comparator also indicated for weight loss.

Objectives: To test the fitness of the Arcadia Data Research electronic health record (EHR) data to quantify the relative occurrence of AMI between weight loss medicines against the gold standard of a randomized controlled trial using target trial emulation.

Methods: The 2018 CAMELLIA-TIMI 61 trial compared lorcaserin, the comparator in Burns, et al., relative to placebo on the risk of MACE. We used EHR and claims data to identify initiators of lorcaserin and individuals who underwent weight loss counseling and were overweight or obese, the latter group being a proxy for the trial’s placebo group. In this analysis, we focused on the MACE component AMI, which was identified using ICD 9/10 codes. Eligibility criteria were replicates of the trial and identified patients at high risk of cardiovascular disease without certain heart, lung, or kidney conditions. Following multiple imputation of key variables, we computed Propensity Score (PS) matching weights. Crude incidence rates (IR) were obtained, and hazard ratios (HR) with 95% confidence intervals (CIs) were estimated using a PS weighted Cox proportional hazards model.

Results: From June 2012 to February 2020, there were 48,280 lorcaserin prescription or dispensing records, and 7,738,422 records related to weight loss counseling. After applying eligibility criteria, the analytical cohort consisted of 999 lorcaserin initiators and 163,075 weight loss counseling initiators. After PS weighting, baseline characteristics were similar between the groups; average follow-up time was 5.0 years for the lorcaserin group and 4.9 years for the weight loss counseling group. The IR for AMI was 4.9 per 1,000 person-years compared to 6.6 per 1,000 person-years among those initiating counseling, a non-significant difference. The HR of 1.02 (95% CI: 0.61–1.71) for AMI in the emulation analysis fell within the CIs of the trial results for AMI (HR 0.99, 95% CI: 0.82–1.19). No cardiovascular deaths were reported.

Conclusions: Our results were consistent with both the CAMELLIA-TIMI 61 trial and the 2024 observational study from Burns, et al., and demonstrated the robustness of the findings in different data and settings.