Gender differences in cardiotoxicities associated with immune checkpoint inhibitor therapy in cancer patients

Abstract

Background: Immune checkpoint inhibitors (ICIs) are increasingly being used for cancer therapy. Cardiotoxicity from ICIs has largely been underestimated since cardiovascular monitoring is not routinely performed after initiating immunotherapy. Cardiotoxic side effects are uncommon but are serious complications of ICIs with a high morbidity and mortality. Aims and Objectives: To determine gender differences in the risk of CVEs in cancer patients that receive immunotherapy. To determine the risk of CVEs in males and females who received different number of ICI injections. To study other possible risk factors for adverse CVEs in patients who received immunotherapy with ICIs. Materials and Methods: In this observational, retrospective, pharmacovigilance study, we used MarketScan Databases to compare cardiovascular adverse events reported in patients who received ICIs. The data used in this study was fully integrated and de-identified data. The study included 16,574 patients who had cancer and underwent ICI therapy between January 1, 2011, and December 31, 2018. ICI drugs in this study included nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and ipilimumab. The time to an event and the end of follow-up was counted from the time of first ICI injection. Our primary exposure variable was gender. Results: This study demonstrated that time to adverse CVE in cancer patients that receive ICI therapy is affected by the gender. The hazard time to CVEs between the male and female gender varied by age. There was no difference in CVEs between males and females at a younger age. The hazard time to CVEs increased with age above 60 years in males when compared to females. The hazard of time to CVE in males was 1.18 times the hazard in females at the mean study age of 60.5 years. Adjusted Kaplan–Meier survival curves for males and females stratified by ICI injection categories showed that those with fewer number of ICI injections had a shorter time to CVE. Conclusions: The number of ICI injections and the gender both impact adverse cardiovascular events in cancer patients. Managing and reducing cardiotoxicity is vital for safe delivery of this effective therapy. Future studies should assess whether late onset chronic cardiotoxicity can occur with ICI therapy.