Association of Pregabalin vs. Duloxetine with Cardiovascular Events: A Retrospective Cohort Study Among US Veterans With Chronic Musculoskeletal Pain

Pregabalin and duloxetine are widely prescribed non-opioid medications for chronic musculoskeletal pain. Pregabalin may increase the risk of heart failure, and duloxetine increases heart rate and blood pressure; however, little is known about their comparative cardiovascular safety. This study compared cardiovascular outcomes between new users of pregabalin and new users of duloxetine among US Veterans with chronic musculoskeletal conditions. We conducted a retrospective cohort study of US Veterans, aged 18-89 years, with chronic non-cancer musculoskeletal pain who started pregabalin or duloxetine between 2015 and 2021. Veterans with serious illnesses were excluded. The primary outcome was a major adverse cardiovascular event (MACE), a composite of acute myocardial infarction (AMI), stroke, heart failure (HF), or cardiovascular death. We identified cardiovascular events through Veterans Affairs and linked Medicare data and mortality data from the National Death Index. We adjusted for confounding through inverse probability of treatment weighting utilizing a propensity score incorporating 158 covariates. Outcomes were analyzed using Cox proportional hazard regression models. This study included 26,684 new users of pregabalin and 152,808 new users of duloxetine (83% male, 69% reported White race, median age = 56 years). During a total follow-up of 141,112 person-years, there were 1,798 total MACE events. The rate of MACE was higher for pregabalin users compared to duloxetine users (unadjusted HR: 1.61 (95% CI: 1.43-1.81), adjusted HR: 1.24 (95% CI: 1.08-1.41)), driven by higher rates of HF and AMI among pregabalin users. These findings present new considerations regarding the comparative cardiovascular safety of therapeutic options for chronic musculoskeletal pain.