Long-term comparative risk of cardiovascular complications in patients receiving immune checkpoint inhibitors versus traditional chemotherapy: A real-world TriNetX analysis.

Abstract

e24034 Background: Immune checkpoint inhibitors (ICIs) have transformed cancer care and expand across combination regimens, but they can cause immune-related adverse events including cardiovascular toxicity in routine use. Prior studies and cardio-oncology series highlight an early hazard period after ICI initiation, with myocarditis often within weeks (and substantial morbidity and mortality, with associated arrhythmic and conduction complications including atrial fibrillation. In contrast, comparative real-world data have focused on acute presentations, and it remains unclear whether ICI exposure confers additional long-term risk for common chronic cardiovascular syndromes such as heart failure or sustained arrhythmias. Methods: This was a retrospective cohort study (January 1, 2018- January 1, 2026) in TriNetX comparing patients prescribed ICIs (PD-1: pembrolizumab, nivolumab, cemiplimab; PD-L1: atezolizumab, durvalumab, avelumab; CTLA-4: ipilimumab) versus only traditional chemotherapy (e.g., platinum agents, gemcitabine, etoposide, cyclophosphamide). We excluded patients with prior history of outcomes and those exposed to cardiotoxic agents (anthracyclines, HER2-targeted therapy, proteasome inhibitors, VEGF/VEGFR pathway agents). Propensity score matching adjusted for age, sex, race/ethnicity, metastatic burden (proxy C77–C79), and baseline comorbidities (HTN, diabetes, CKD, CAD/prior MI, stroke/TIA, hyperlipidemia, obesity, COPD, sleep apnea, anemia, valvular disease). Final matched cohorts included ~65,800 patients per arm. Results: ICIs were associated with higher risk of myocarditis (OR 3.84; 95% CI 2.92–5.05) and pericarditis (OR 1.08; 95% CI 1.01–1.15). Chemotherapy was associated with higher risks of arrhythmia (OR 0.83; 95% CI 0.79–0.86), atrial fibrillation/flutter (OR 0.90; 95% CI 0.86–0.95), and heart failure (OR 0.91; 95% CI 0.83–0.99). No significant differences were observed for MI, stroke/TIA, systolic HF, or cardiac arrest. Conclusions: In a large matched real-world cohort, ICIs showed a strong signal for immune-mediated inflammatory cardiotoxicity (myocarditis/pericarditis), aligning with prior reports that these events often present early and commonly involve arrhythmic/conduction complications. Conversely, traditional chemotherapy showed higher risk of broader arrhythmias and heart failure. These results support regimen-specific cardio-oncology surveillance with a focus on early ICI monitoring and provide real-world reassurance regarding the longer-term cardiovascular safety profile of ICIs as their applications continue to expand.