Aims The risk and incidence of cardiovascular (CV) immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in cancer patients remain unknown. Methods and results We systematically reviewed all randomized clinical trials (RCTs) including at least one ICI-containing arm and available CV adverse event (CVAE) data in cancer patients in the ClinicalTrials.gov registry, Medline, and the Cochrane CENTRAL Register of Controlled Trials, up to 31 August 2020 (CRD42020165672). The primary outcome was the summary risk of 16 different CVAEs associated with ICI exposure vs. controls (placebo and non-placebo) in RCTs. CVAEs with an increased risk associated with ICI exposure were considered as CV irAEs. Summary incidences of CV irAEs identified in our primary outcome analyses were computed using all RCTs including at least one ICI-containing arm. We used a random-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% confidence intervals (CIs) and logit transformation and inverse variance weighting to compute summary incidences. Sixty-three unique RCTs with at least one ICI-containing arm (32 518 patients) were retrieved, among which 48 (29 592 patients) had a control arm. Among the 16 CVAEs studied, ICI use was associated with an increased risk of 6 CV irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischaemia with higher risks for myocarditis (Peto OR: 4.42, 95% CI: 1.56–12.50, P < 0.01; I2 = 0%, P = 0.93) and dyslipidemia (Peto OR: 3.68, 95% CI: 1.89–7.19, P < 0.01; I2 = 0%, P = 0.66). The incidence of these CVAEs ranged from 3.2 (95% CI 2.0–5.1) to 19.3 (6.7–54.1) per 1000 patients, in studies with a median follow-up ranging from 3.2 to 32.8 months. Conclusion In RCTs, ICI use was associated with six CV irAEs, not confined to myocarditis and pericarditis.

中文翻译：

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与免疫检查点抑制剂相关的心血管免疫毒性：一项安全性荟萃分析

目标 癌症患者与免疫检查点抑制剂 (ICI) 相关的心血管 (CV) 免疫相关不良事件 (irAE) 的风险和发生率仍然未知。方法和结果 我们系统地回顾了所有随机临床试验 (RCT)，包括在 ClinicalTrials.gov 注册、Medline 和 Cochrane CENTRAL 对照试验注册中癌症患者的至少一个包含 ICI 的手臂和可用的 CV 不良事件 (CVAE) 数据，截至 2020 年 8 月 31 日 (CRD42020165672)。主要结果是 RCT 中与 ICI 暴露与对照（安慰剂和非安慰剂）相关的 16 种不同 CVAE 的汇总风险。与 ICI 暴露相关的风险增加的 CVAE 被视为 CV irAE。在我们的主要结果分析中确定的 CV irAEs 的总结发生率是使用所有 RCT 计算的，包括至少一个包含 ICI 的手臂。我们使用随机效应荟萃分析来获得具有 95% 置信区间 (CI) 的 Peto 优势比 (OR)，并使用 logit 变换和逆方差加权来计算汇总发生率。检索了 63 项具有至少一个包含 ICI 的手臂（32 518 名患者）的独特 RCT，其中 48 人（29 592 名患者）有一个对照组。在研究的 16 种 CVAE 中，ICI 的使用与 6 种 CV irAE 的风险增加相关，包括心肌炎、心包疾病、心力衰竭、血脂异常、心肌梗死和脑动脉缺血，心肌炎的风险更高（Peto OR：4.42，95% CI : 1.56–12.50, P < 0.01; I2 = 0%, P = 0.93) 和血脂异常 (Peto OR: 3.68, 95% CI: 1.89–7。19，P＜0.01; I2 = 0%，P = 0.66）。在中位随访时间为 3.2 至 32.8 个月的研究中，这些 CVAE 的发生率范围为每 1000 名患者 3.2（95% CI 2.0-5.1）至 19.3（6.7-54.1）。结论 在 RCT 中，ICI 的使用与 6 种 CV irAE 相关，不仅限于心肌炎和心包炎。