Incidence of immune checkpoint inhibitor mediated cardiovascular toxicity: A systematic review and meta‐analysis

BACKGROUND: Immune checkpoint inhibitors (ICI) are a novel class of anti-cancer therapy becoming increasingly associated with fatal cardiovascular toxicities (CVTs). The aim is to determine the incidence of CVTs in cohorts treated with ICIs as sole anti-cancer therapy. METHODS: A systematic literature search of scientific and medical databases was performed using PRISMA principles to identify relevant cohorts (PROSPERO registration CRD42021272470). Data for specific CVTs (pericardial disease, myocarditis, heart failure, arrhythmia, myocardial infarction/ischaemia and angina), CVT-related death and CV risk factors were extracted. Presence of CVTs in ICI-monotherapy versus combination-ICI therapy, and programmed death 1/programmed death ligand 1- (PD1/PDL1-) versus cytotoxic T-lymphocyte-associated protein 4- (CTLA4-) inhibitor groups were dichotomised and meta-analysed using random-effect models. RESULTS: Forty-eight studies (11,207 patients) were identified, from which 146 CVTs were observed (incidence 1.30%). ICI-monotherapy led to more CVTs than combination therapy (119/9009; 1.32% vs. 18/2086; 0.86%). Across monotherapies, PD1/PDL1-inhibitors had lower incidence of CVTs compared to CTLA4-inhibitors (62/6950; 0.89% vs. 57/2059; 2.77%). Based on eight studies that were meta-analysed, no significant difference was observed comparing monotherapy versus combination-ICI therapy (RR-0.69, 95% CI -1.47 to 0.09) for all CVTs, or PD1/PDL1- to CTLA4-inhibitors (RR-0.27, 95% CI -2.06 to 1.53), for all CVTs including CVT-death. CV risk factors could not be attributed to an ICI group as data was population based rather than individual based. CONCLUSION: ICI-mediated CVTs are rare and potentially fatal. The role of CV risk factors in their development remains unclear.