Comparative cardiovascular toxicity of immune checkpoint inhibitors: A real-world cohort study

Immune checkpoint inhibitors (ICIs) improve cancer outcomes but can cause immune-mediated cardiovascular toxicity, including myocarditis, which is associated with substantial morbidity and mortality. Pharmacovigilance data suggest possible differences in cardiovascular risk between programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors, yet direct real-world comparisons remain limited.

We performed a retrospective cohort study using the TriNetX global research network to compare cardiovascular outcomes in adults initiating PD-1 versus PD-L1 inhibitors. Patients were compared using a 1:1 propensity score-matched design to balance baseline characteristics, with outcomes analyzed within the matched cohorts and reported as relative risks (RR) with 95% confidence intervals (CI). The primary outcome was incident myocarditis assessed at 1 year and 2 years. Secondary outcomes included pericarditis, heart failure, atrial fibrillation, ventricular arrhythmias, long QT syndrome, cardiomyopathy phenotypes, and atrioventricular block.

After matching, 32,468 patients were included in each cohort with excellent covariate balance. PD-1 inhibitors were associated with a higher risk of myocarditis at 1 year (RR 1.49, 95% CI 1.13-1.96) and 2 years (RR 1.49, 95% CI 1.15-1.94). Pericarditis was more frequent with PD-1 inhibitors at 1 year (RR 1.28, 95% CI 1.01-1.64). Heart failure, arrhythmias, and cardiomyopathy phenotypes were largely similar between treatment groups.

PD-1 inhibitors were associated with a higher risk of immune-mediated cardiac inflammation than PD-L1 inhibitors, while non-inflammatory cardiovascular outcomes were comparable. These findings have implications for cardio-oncology risk stratification, support closer early cardiovascular monitoring in patients initiating PD-1 therapy, and warrant prospective validation.