Avoidance of cardiac toxicity during the application of immune checkpoint inhibitors: a safety systematic review combining network meta-analysis and pharmacovigilance study.

Background: Although immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment, the incidence of cardiac toxicity associated with ICIs remains unclear. This study aimed to evaluate the cardiac toxicity risks associated with ICI and identify the most common types of cardiac toxicity caused by ICI. A further objective was to determine the types of ICI that require the most monitoring of cardiac toxicity through systematic review and network meta-analysis, assisted by pharmacovigilance studies. Design: Systematic review and network meta-analysis, complemented by a pharmacovigilance study of the FAERS database. Data source and methods: A systematic search of electronic databases up to November 2025 was conducted. Randomized controlled trials (RCTs) were eligible if they compared ICIs with appropriate controls without restrictions. Data were analyzed using random-effects pairwise and network meta-analyses to evaluate cardiac toxicity. Disproportionality analysis was performed using FAERS data from 2011 to 2026 (Q1), employing PRR, ROR, IC, and EBGM to quantify the risk and incidence of cardiac toxicity associated with ICIs. Results: In total, 135 RCTs were included in the network meta-analysis. Pairwise meta-analysis demonstrated that ICIs can induce cardiac toxicity in four key manifestations, which were selected through pairwise meta-analysis: acute myocardial infarction, cardiac arrest, myocarditis, and ventricular tachycardia. Network meta-analysis indicated that both PD-1/PD-L1 monotherapy and combination therapies present a higher risk of cardiac toxicity. The risks associated with PD-1 and PD-L1 agents were relatively elevated when used as monotherapies. Furthermore, combinations of PD-1 (nivolumab, pembrolizumab) and PD-L1 (avelumab) with CTLA-4 or other small molecule targeted inhibitors were associated with increased risk of the four aforementioned cardiac toxicities. Disproportionality analysis revealed that both PD-1 and PD-L1 inhibitors carry risks of myocarditis, and the combination of bevacizumab, relatlimab, and ipilimumab may cause increased cardiac toxicity. Conclusions: ICIs, particularly PD-1/PD-L1 inhibitors, increase the risk of cardiac toxicity. PD-1 (nivolumab, pembrolizumab) and PD-L1 (atezolizumab, avelumab) agents present a higher risk of myocarditis and acute myocardial infarction. Moreover, combination regimens involving PD-1/PD-L1 further elevate the risk of cardiac toxicity, underscoring the necessity for vigilant monitoring in patients with underlying heart disease. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261357478.