Cardiovascular-related adverse events of combined therapy with programmed death-1/programmed death-ligand 1 inhibitors in clinical trials: a systematic review and meta-analysis

Background: Immune checkpoint inhibitors [programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors] have revolutionized cancer treatment by improving survival in advanced cancer patients, but they are often associated with severe cardiovascular toxicity. This systematic review and meta-analysis of randomized controlled trials aimed to clarify the risk, incidence, high-risk populations, and underlying mechanisms of cardiovascular adverse events (CVAEs) related to PD-1/PD-L1 inhibitors. Methods: PubMed, Embase, and Cochrane Library were searched for clinical trials on PD-1/PD-L1 inhibitor-based combination therapies published from January 2015 to May 2022. A total of 23 randomized controlled trials were finally included. Data on CVAEs were extracted. A random-effects model with Logit transformation was used for meta-analysis; heterogeneity was assessed by I 2 . Results: We found the following: (a) Compared with the heterogeneous control regimens, PD-1/PD-L1 inhibitors showed a higher incidence of cardiovascular events [relative risk (RR) = 1.19, 95% confidence interval (CI): 1.11–1.29, I 2 = 45%, P < 0.001]. (b) Subgroup analysis of different cardiovascular events revealed that, compared with the control group, the incidence of coronary heart disease (RR = 1.77, 95% CI: 1.18–2.64, P = 0.005), arrhythmia (RR = 1.36, 95% CI: 1.03–1.79, P = 0.03), heart failure (RR = 2.14, 95% CI: 1.44–3.20, P = 0.0002), and hypotension (RR = 1.45, 95% CI: 1.07–1.96, P = 0.02) was significantly higher in the PD-1/PD-L1 inhibitor group. (c) Subgroup analysis of different types of cancer indicated that in the subgroups of lung cancer (RR = 1.44, 95% CI: 1.13–1.84, P = 0.003), multiple myeloma (RR = 2.57, 95% CI: 1.40–4.70, P = 0.002), urothelial cancer (RR = 1.60, 95% CI: 1.15–2.24, P = 0.005), and head and neck squamous cell carcinoma (RR = 1.54, 95% CI: 1.09–2.17, P = 0.02), the incidence of CVAEs of PD-1/PD-L1 inhibitors was significantly elevated. (d) When statistically analyzing the risk of cardiovascular events in PD-1/PD-L1 inhibitors combined with different treatment regimens, we found that the overall incidence of cardiovascular events was the highest in the group where PD-1/PD-L1 inhibitors were combined with targeted drug therapy (incidence rate = 0.40, 95% CI: 0.38–0.42, P < 0.001). Conclusions: PD-1/PD-L1 inhibitors increase the risk of cardiovascular toxicities, including coronary artery disease, arrhythmias, heart failure, and hypotension. Patients with lung cancer, multiple myeloma, urothelial cancer, and head and neck squamous cell carcinoma are at higher risk. The combination with targeted therapy yields the highest overall CVAE incidence, with hypertension being dominant across regimens.