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

Abstract

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 (ROR₀₂₅) > 1 or IC (IC₀₂₅) > 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 (IC₀₂₅/ROR₀₂₅ = 0.559/1.478), showing stronger signal strength than those taking ICIs alone (IC₀₂₅/ROR₀₂₅ = 0.118/1.086) or AGIs alone (IC₀₂₅/ROR₀₂₅ = 0.323/1.252). Importantly, compared with ICIs alone, combination therapy showed a decrease in signal strength for noninfectious myocarditis/pericarditis (IC₀₂₅/ROR₀₂₅ = 1.142/2.216 vs. IC₀₂₅/ROR₀₂₅ = 0.673/1.614), while an increase in signal value for embolic and thrombotic events (IC₀₂₅/ROR₀₂₅ = 0.147/1.111 vs. IC₀₂₅/ROR₀₂₅ = 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.

Keywords: FAERS database; angiogenesis inhibitor; cardiovascular toxicity; combination therapy; disproportionality analysis; immune checkpoint inhibitor.

Figure 1

Flow chart of cardiovascular adverse event (AE) cases and reports selection for AGI alone, ICI combined with AGI, and ICI alone (AE, adverse event; AGI, angiogenesis inhibitor; CV, cardiovascular; ICI, immune checkpoint inhibitor).

Figure 2

Comparison of the cardiovascular adverse events based on the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) for angiogenesis inhibitors (A, B), immune checkpoint inhibitors (C, D), and combination therapy (E, F) with the information component (IC) and reporting odds ratio (ROR) (IC, information component; ROR, reporting odds ratio).

Figure 3

Major outcomes (death, life-threatening and hospitalization) of cardiovascular adverse events based on the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) with significant values (cardiomyopathy, embolic and thrombotic events, hypertension, ischaemic heart disease and noninfectious myocarditis/pericarditis).

Figure 4

Comparison of overall cardiovascular adverse events (AEs) (A, B), embolic and thrombotic events (SMQ) (C, D) and noninfectious myocarditis/pericarditis (SMQ) (E, F) for angiogenesis inhibitors alone, immune checkpoint inhibitors alone, and combination therapy among cases with indications of malignant tumours with the information component (IC) and reporting odds ratio (ROR) (IC, information component; ROR, reporting odds ratio).