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Background Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, improving survival outcomes across various malignancies. While nearly 45% of individuals with cancer become eligible for ICI, these treatments can be associated with life-threatening cardiovascular adverse events (CVAE), which remain poorly characterized in real-world populations. This study aimed to evaluate CVAE incidence and risk factors in patients initiating ICI therapy.Methods We conducted a cohort study using Medicare claims data from 2011 to 2020. Patients with cancer initiating ≥1ICI therapy without prior CVAE were included. The primary outcome was first occurrence of CVAE after ICI initiation, including arrhythmia, heart failure(HF), stroke, myocardial infarction(MI), cardiomyopathy, coronary revascularization and myopericarditis. Secondary outcomes were the individual components of the primary outcome. Patients were followed from ICI initiation until the earliest occurrence of CVAE, death, switch to another therapy, 6 months post-ICI discontinuation or end of continuous insurance coverage. We estimated cumulative incidence of outcomes overall and by cancer type subgroup, and used multivariable Cox regression to identify risk factors, including socio-demographics, cancer type, treatment regimen, comorbidities.Results Among 17,319 cancer patients initiating ≥1 ICI, 5,074 (29.30%) patients developed CVAE during a mean ± sd follow-up of 266 ± 234 days. In the ICI cohort, the incidence rate of CVAE per1,000 person-years were arrhythmia (317 cases), HF (142 cases), stroke (74 cases), MI (35 cases ), cardiomyopathy (20 cases), coronary revascularization (9 cases), myopericarditis (8 cases)( figure 1). Male sex, Black race, advanced age, hypertension and diabetes were independently associated with higher risk of incident CVAE(figure 2). Compared to programmed cell death-1(PD-1) monotherapy, greater risk of CVAE was observed with cytotoxic T-lymphocyte-associated protein4(CTLA-4) monotherapy (adjusted hazard ratio [aHR],1.45; 95% confidence interval [CI], 1.16-1.82) and CTLA-4 plus PD-1 combination therapy (aHR,1.52; 95% CI, 1.36-1.70). Lung cancer (49.3%), urological cancer (14.1%) and skin cancer (11.4%) were the most common putative cancer indications. Across ICI indicated cancer, the risk of CVAE was highest in lung cancer patients (versus skin cancer patients, aHR,1.61; 95% CI 1.45-1.78).Conclusions This real-world study described the incidence of CVAE after ICI initiation among Medicare beneficiaries. The most common CVAE observed were arrhythmias, HF, stroke and MI. Male sex, Black race, advanced age, hypertension, diabetes, lung cancer, and combination therapy were independently associated with higher CVAE risk among cancer patients on ICI. These results underscore the importance of cardiovascular risk stratification and monitoring for cancer patients on ICI therapy to optimize net benefit of ICI.Abstract 402 Figure 1Cumulative incidence of cardiovascular adverse events among cancer patients on Immune Checkpoint Inhibitors therapy. Note: CVAE, cardiovascular adverse events; The black line represents the earliest occurrence of CVAE, other lines represent individual components of CVAE; The graph depicts the cumulative incidence of CVAE before the sample size decreases to 10%Abstract 402 Figure 2Multivariate Cox regression analyses of cardiovascular adverse event among cancer patients on Immune Checkpoint Inhibitors therapy. Note: †Age presented as mean ± standard deviation; *highlighted P value <0.05; aHR, adjusted hazard ratio; CI, confidence interval;CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1/PD-L1, programmed cell death protein 1/death-ligand 1 protein