Cardiac Conduction Disorders in Melanoma Patients Treated with CTLA-4-Containing Versus PD-1-Only Immune Checkpoint Inhibitor Therapy: A Propensity Score-Matched Real-World Analysis

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Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced melanoma, but the comparative cardiac safety of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-containing regimens versus programmed cell death protein 1 (PD-1)-only regimens in real-world populations remains poorly characterized. We compared cardiac outcomes between melanoma patients exposed to CTLA-4 blockade (ipilimumab) and those treated with anti-PD-1 therapy alone (nivolumab or pembrolizumab) using a large multicenter electronic health record database. Methods: This retrospective cohort study used de-identified data from the TriNetX Research Network (111 US healthcare organizations). Adults with melanoma (ICD-10-CM C43) who received ipilimumab (CTLA-4 exposed) were compared with those who received nivolumab or pembrolizumab without ipilimumab (anti–PD-1 only); both groups were therefore treated with immune checkpoint inhibitors, isolating the effect of CTLA-4 exposure. Propensity score matching (1:1) balanced demographics, cardiovascular comorbidities, and baseline antiarrhythmic use. The primary outcome was a cardiac conduction disorder composite; outcomes were assessed at 1 and 3 years. Results: Of 7313 CTLA-4-exposed and 11,481 anti-PD-1-only patients, 6841 matched pairs were analyzed (all standardized mean differences <0.03). CTLA-4 exposure was associated with a significantly higher incidence of cardiac conduction disorders that was already present at 1 year (3.8% vs. 2.1%; RR 1.82; 95% CI 1.48–2.24; p < 0.001) and persisted at 3 years (5.1% vs. 3.7%; RR 1.36; 95% CI 1.16–1.60; p < 0.001). Atrioventricular block was higher at both 1 year (RR 2.10; 95% CI 1.59–2.78) and 3 years (RR 1.49; 95% CI 1.20–1.85), and complete heart block was markedly increased at 3 years (0.5% vs. 0.2%; RR 3.28; 95% CI 1.67–6.43; p < 0.001). Heart failure was modestly higher with CTLA-4 exposure at both timepoints (1-year RR 1.35; 3-year RR 1.17). Conclusions: Among melanoma patients treated with immune checkpoint inhibitors, CTLA-4-containing therapy is associated with a higher burden of cardiac conduction disorders, including a roughly three-fold excess of complete heart block, that is evident within the first year and sustained thereafter. Because the CTLA-4-exposed cohort comprised both ipilimumab monotherapy and nivolumab plus ipilimumab and the subgroup analyses localized the excess risk to the combination regimen, this association reflects CTLA-4-containing (predominantly combination) therapy rather than ipilimumab monotherapy in isolation. These findings support electrocardiographic surveillance beginning during, not only after, treatment for patients receiving CTLA-4-containing immunotherapy.

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