3B-05 - Risk of Major Adverse Cardiovascular Events in Patients Receiving Roflumilast for the Treatment of Chronic Obstructive Pulmonary Disease: A Retrospective Cohort Study Using Target Trial Emulation Framework

Background: Roflumilast has proven its efficacy in treating patients with severe chronic obstructive pulmonary disease (COPD) with optimized bronchodilator therapies. Despite the high prevalence of COPD patients with cardiac comorbidities, there is limited data on the cardiovascular safety of roflumilast use among patients with COPD.

Objectives: To assess whether initiating roflumilast is associated with a higher risk of major adverse cardiovascular events (MACE) compared to azithromycin in patients with COPD.

Methods: We emulated a target trial using MarketScan Claims data 2011−2023 where patients were randomly assigned to initiate roflumilast or chronic azithromycin. The study cohort comprised individuals aged ≥40 who were newly prescribed roflumilast or chronic azithromycin (index date) between 2012 and 2023 and had a diagnosis of COPD and COPD exacerbation in the year before the index date. Chronic azithromycin was defined as a prescription with more than a 30-day supply. Patients with contraindications to roflumilast (HIV infection, alpha-1-antitrypsin deficiency, liver decompensation) were excluded. The composite of new and recurrent MACE was captured with a diagnosis of stroke or acute myocardial infarction (AMI) during follow-up. We mimicked the randomization process by propensity score (PS) matching with a 1:1 ratio. We fitted a logistic regression model to estimate PS based on expert-informed covariates (COPD severity, medications, and comorbidities) assessed within the 1-year before the index date. We estimated the adjusted hazard ratio (aHR) via the multivariable Cox proportional hazards model. Sensitivity analyses included a 60-day delay between index date and MACE outcomes to assess reverse causation, different COPD exacerbation definitions, and exclusion of patients with a history of MACE.

Results: We identified 1,887 patients with roflumilast and 807 patients with azithromycin. Patients receiving roflumilast had a higher prevalence of heart failure, a greater number of exacerbations, and a higher use of long-acting bronchodilators. After PS matching, the incidence rate of MACE was 7.36% among those with roflumilast (n=747) versus 6.43% with azithromycin (n=747), aOR 1.28 [95% CI 0.87, 1.89]. The incidence rate of stroke was
4.42% among those with roflumilast (n=747) versus 3.08% with azithromycin (n=747), aOR 1.63 [95% CI 0.95, 2.78]. The incidence rate of AMI was 3.21% among those with roflumilast (n=747) versus 3.48% with azithromycin (n=747), aOR 1.04 [95% CI 0.59, 1.81]. The results were consistent in sensitivity analyses.

Conclusions: Evidence from this study suggests that using roflumilast does not meaningfully increase the risk for major adverse cardiovascular events.