Cardiovascular Toxicity Associated With Immune Checkpoint Inhibitors: Interpreting the Discrepancy Between Clinical...

Real-world data on cardiovascular immune-related adverse events (CV-irAEs) in cancer patients treated with immune checkpoint inhibitors (ICIs) present findings that differ from those reported in meta-analyses of clinical trials. This study aims to estimate the incidence of CV-irAEs from observational studies among patients undergoing ICI therapy for various malignancies and investigate the discrepancy between the results of meta-analyses and observational studies. A systematic literature review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. The PubMed database was searched for observational studies that included cancer patients treated with ICIs. Α single-arm meta-analysis using the metaprop command in Stata Statistical Software: Release 16 (StataCorp LLC, College Station, Texas, United States) was performed for the following outcomes: myocarditis, pericardial disease, arrhythmias, cardiac failure, Takotsubo cardiomyopathy, ischemic heart disease, heart valve disease, venous thromboembolism and artery disease. ICI treatment agents were classified into three major classes: PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, or their combinations. Heterogeneity was quantified using the I2 statistic and small study effect, and potential publication bias was assessed by inspecting funnel plots, as well as by Egger's test. A total of 42 studies were included. The incidence of CV-irAEs within the entire population undergoing treatment with ICIs was assessed as follows: total CV-irAEs: 8% (95% confidence interval (CI): 6%, 10%), arrhythmias: 18% (95%CI: 10%, 27%), myocarditis: 11% (95%CI: 5%, 18%), cardiac failure: 8% (95%CI: 2%, 15%), ischemic heart disease: 6% (95%CI: 3%, 11%), pericardial disease: 5% (95%CI: 1%, 10%), artery disease 5% (95%CI: 1%, 12%), and venous thromboembolism: 3% (95%CI: 0%, 8%); cardiomyopathy and heart valve disease had minimal number of observed episodes, thus the pooled incidence results are referring as zero, 0% (95%CI: 0%, 0%) and total CV deaths: 1% (95%CI: 0%, 3%). Median time to CV-irAEs was estimated at 119 days (interquartile range (IQR) 53-180). The most common CV-irAEs were arrhythmias, myocarditis, and cardiac failure with life-threatening complications. Data derived from meta-analyses of clinical trials in most cases indicated that the total incidence of CV-irAEs varied between 0.05% and 1.30%, while in large pharmacovigilance databases, it ranged from 0.125% to 6.7%. In our meta-analysis of post-market surveillance studies, higher estimates were obtained, which offer an insight into the long-term prevalence and outcomes for patients experiencing CV complications associated with ICIs. Longer follow-up period and different definitions of cardiotoxicity may account for the higher cardiotoxicity rates that seem to reflect an emerging threat.