Sex Differences in Immune Checkpoint Inhibitor-related Cardiotoxicity: A Propensity Score-matched Cohort Study

Immune checkpoint inhibitors (ICIs) are widely used in cancer therapy but may cause cardiovascular immune-related adverse events (irAEs) with substantial morbidity and mortality. The impact of biological sex on ICI-associated cardiotoxicity remains incompletely defined in real-world populations.

To evaluate sex-based differences in cardiovascular immune-related adverse events following immune checkpoint inhibitor therapy.

We conducted a retrospective, propensity score-matched cohort study using the TriNetX global research network. Adults initiating ICI therapy were stratified by biological sex and matched 1:1 on demographics, cardiovascular comorbidities, and baseline cardiotoxic therapies. The primary outcome was incident myocarditis at 6 months, 1 year, and 2 years. Secondary outcomes included arrhythmias, conduction abnormalities, and cardiomyopathies. Relative risks (RRs) with 95% confidence intervals (CIs) were reported.

The matched cohort included 60,116 pairs of female and male patients with good overall covariate balance. Females had a lower risk of myocarditis at 6 months (RR 0.76; 95% CI 0.63-0.91; P=0.004), 1 year (RR 0.81; 95% CI 0.68-0.95; P=0.011), and 2 years (RR 0.81; 95% CI 0.69-0.94; P=0.008), along with lower risks of atrial fibrillation, ventricular arrhythmias, high-degree atrioventricular block, ischemic cardiomyopathy, and dilated cardiomyopathy. In contrast, females had a higher risk of Takotsubo cardiomyopathy across all time points.

ICI-associated cardiotoxicity is associated with sex-related differences, with higher rates of myocarditis and arrhythmic events in males and increased occurrence of Takotsubo cardiomyopathy in females. These findings suggest differences in cardiovascular risk patterns and highlight the need for further study to better understand their clinical relevance.