Cardiovascular toxicity profiles of immune checkpoint inhibitors with or without angiogenesis inhibitors: a real-world pharmacovigilance analysis based on the FAERS database from 2014 to 2022

Background Immune checkpoint inhibitors (ICIs) combined with angiogenesis inhibitors (AGIs) have become increasingly available for multiple types of cancers, although the cardiovascular safety profiles of this combination therapy in real-world settings have not been elucidated to date. Therefore, we aimed to comprehensively investigate the cardiovascular toxicity profiles of ICIs combined with AGIs in comparison with ICIs alone. Methods The Food and Drug Administration Adverse Event Reporting System (FAERS) database from the 1 st quarter of 2014 to the 1 st quarter of 2022 was retrospectively queried to extract reports of cardiovascular adverse events (AEs) associated with ICIs alone, AGIs alone and combination therapy. To perform disproportionality analysis, the reporting odds ratios (RORs) and information components (ICs) were calculated with statistical shrinkage transformation formulas and a lower limit of the 95% confidence interval (CI) for ROR (ROR 025 ) > 1 or IC (IC 025 ) > 0 with at least 3 reports was considered statistically significant. Results A total of 18 854 cardiovascular AE cases/26 059 reports for ICIs alone, 47 168 cases/67 595 reports for AGIs alone, and 3 978 cases/5 263 reports for combination therapy were extracted. Compared to the entire database of patients without AGIs or ICIs, cardiovascular AEs were overreported in patients with combination therapy (IC 025 /ROR 025 = 0.559/1.478), showing stronger signal strength than those taking ICIs alone (IC 025 /ROR 025 = 0.118/1.086) or AGIs alone (IC 025 /ROR 025 = 0.323/1.252). Importantly, compared with ICIs alone, combination therapy showed a decrease in signal strength for noninfectious myocarditis/pericarditis (IC 025 /ROR 025 = 1.142/2.216 vs . IC 025 /ROR 025 = 0.673/1.614), while an increase in signal value for embolic and thrombotic events (IC 025 /ROR 025 = 0.147/1.111 vs . IC 025 /ROR 025 = 0.591/1.519). For outcomes of cardiovascular AEs, the frequency of death and life-threatening AEs was lower for combination therapy than ICIs alone in noninfectious myocarditis/pericarditis (37.7% vs . 49.2%) as well as in embolic and thrombotic events (29.9% vs . 39.6%). Analysis among indications of cancer showed similar findings. Conclusion Overall, ICIs combined with AGIs showed a greater risk of cardiovascular AEs than ICIs alone, mainly due to an increase in embolic and thrombotic events while a decrease in noninfectious myocarditis/pericarditis. In addition, compared with ICIs alone, combination therapy presented a lower frequency of death and life-threatening in noninfectious myocarditis/pericarditis and embolic and thrombotic events.