Cardiovascular toxicities associated with immune checkpoint inhibitors: An updated comprehensive disproportionality analysis of the FDA adverse event reporting system

What is known and objective: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes for a wide range of cancers but can also lead to cardiovascular toxicities. This study was to scientifically and systematically explore the association between cardiovascular toxicities and immune checkpoint inhibitors (ICIs) and also to characterize the main features of ICI-related cardiovascular toxicities. Methods: From January 2012 to December 2020, data in the Food and Drug Administration Adverse Event Reporting System (FAERS) database were retrieved for disproportionality analysis. The definition of adverse events (AEs) relied on the Medical Dictionary for Regulatory Activities (MedDRA). We used the reporting odds ratio (ROR) with 95% confidence intervals (Cis) to evaluate the association between ICIs and cardiovascular AEs. Clinical characteristics of patients with ICI-associated cardiovascular toxicities were collected, and the time to onset following different ICI regimens was further investigated. Results and discussion: We identified a total of 13,713 ICI-associated cardiovascular toxicities which appeared to influence more men (56.90%) than women (36.79%), with a median age of 67 (interquartile range [IQR] 58-74) years. ICI-associated cardiovascular AEs were most frequently reported in lung, pleura, thymus and heart cancer patients (34.49%). Compared with the full database, ICI therapies were detected with pharmacovigilance of myocardial disorders (ROR: 2.64; 95% CI: 2.55-2.75) and pericardial disorders (ROR: 4.51; 95% CI: 4.30-4.74). Concerning myocardial and pericardial disorders, a significant increased ROR was found for all anti-PD-1 and anti-PD-L1 monotherapies, with the exception of anti-CTLA-4 monotherapies. Regarding cardiac arrhythmias, only tremelimumab among ICI monotherapies was associated with an increased ROR (1.92, 1.09-4.72; 4 cases). Compared with ICI monotherapy, ICI combination therapy detected an increase in cardiovascular toxicity spectrum, but did not prolong the onset time. What is new and conclusion: We observed that the spectrum and risk of ICI-associated cardiovascular AEs differed between therapeutic regimens. The poor clinical outcome and early onset of these events should attract clinical attention.