Background: Immune checkpoint inhibitors (ICI) can persistently augment immune and inflammatory pathways. While cardiovascular (CV) immune-related adverse events (irAE) such as myocarditis are well identified, less is known about other potential CV effects of ICI [1]. Given the association between inflammation, atherosclerosis, and CV disease, it has been suggested that ICI may also increase the risk of major adverse CV events (MACE).

Objectives: To evaluate the risk of myocarditis and MACE in patients with melanoma after initiation of ICI.

Methods: We conducted a before-after study of patients identified in the Optum’s de-identified Clinformatics® Data Mart Database, from 2011 to 2021, who received approved ICI and had International Classification of Diseases (ICD) 9/10 claims diagnoses of melanoma. We required patients in the cohort to have a minimum of 12 months of observable data before receiving ICI. We identified myocarditis and MACE (i.e. myocardial infarction, coronary revascularization, stroke, and heart failure with hospitalization) using ICD-9/10 codes. We identified patients who were diagnosed with myocarditis after ICI initiation. We compared MACE rates in the year before ICI initiation and the year after and the incidence rate ratio (IRR) using exact Poisson distribution regression. We also evaluated time to first MACE before and after ICI, using Cox proportional hazard models with robust sandwich estimate of the covariance matrix to account for correlated outcomes in the same patient. Patients were censored at last follow-up or death. To evaluate the predictors of MACE after ICI initiation, we conducted a Poisson regression model which included different covariates including prior CV risk factors, use of glucocorticoids and use of drugs with CV toxicity.

Results: From a cohort of 34865 patients who received ICI we identified 4024 patients with melanoma. Mean age was 67.4 years (SD 14.1) and 35.8% were female; 2134 (53%) received monotherapy PD-1/PD-L1, 932 (23.2%) monotherapy CTLA-4, and 958 (23.8%) combination therapy. We identified 10 patients with myocarditis and 224 (5.6%) with ≥ 1 MACE in the year after ICI initiation; about half of the patients with myocarditis had a MACE compared to 5% in those without myocarditis (P<0.001).

The incidence rate of MACE in the year prior to ICI was 56.16 per 1000 person-years compared to 80.91 per 1000 person-years in the year after ICI (IRR 1.44 95%CI 1.21-1.72). Predictors independently associated with MACE after ICI were older age, prior MACE, other CV risk factors/disease (i.e. heart failure, cardiomyopathy, myocarditis, conduction abnormality) and hypertension. Prior use of glucocorticoids or CV toxic cancer drugs was not associated with higher risk of MACE.

Conclusion: Our results suggest that in addition to myocarditis, ICI are associated with a higher risk of MACE in patients with melanoma during the first year after ICI initiation. Additional studies are needed to evaluate the long-term effects of ICI on CV outcomes and their potential impact in patients with other types of cancer.

REFERENCES: [1] Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A. Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment. J Am Heart Assoc. 2020 Jan 21;9(2):e013757. doi: 10.1161/JAHA.119.013757. Epub 2020 Jan 21. PMID: 31960755; PMCID: PMC7033840.

Acknowledgements: This research was supported by funds from the University Cancer Foundation and the Duncan Family Institute for Cancer Prevention and Risk Assessment via the Cancer Survivorship Research Seed Money Grants at the University of Texas MD Anderson Cancer Center and by the MD Anderson’s Cancer Center Support Grant, P30 CA016672

Disclosure of Interests: Maria Suarez-Almazor: None declared, Juan Ruiz: None declared, Bo Zhao works at Medasource Inc, providing statistical consulting services for Johnson & Johnson Pharmaceutical company, Nicolas Palaskas Consultant for Kiniksa Pharmaceuticals and Replimmune, Anita Deswal Served as consultant for Bayer, Hui Zhao: None declared, Jennifer McQuade Consultant for Roche, BMS, Merck.