ImportanceImmune checkpoint inhibitors (ICIs) improve outcomes in a wide range of cancers; however, serious adverse effects, including cardiovascular adverse effects (CVAEs), can occur.ObjectiveTo determine the incidence of CVAEs and analyze data on the management of myocarditis in patients exposed to ICIs.Data SourcesPubMed, Embase, and Cochrane Central Register of Controlled Trials from inception were searched on April 4, 2023.Study SelectionTwo separate studies were performed. Key inclusion criteria for study 1 were phases 1 to 4 trials involving adults with malignant neoplasms treated with an ICI and toxicity data; for study 2, publications (case reports and retrospective analyses) on clinical manifestations and treatment of patients with ICI-induced CVAEs. Studies with dose escalation or fewer than 11 patients in each group and all case reports, retrospective analyses, letters, reviews, and editorials were excluded from study 1. Studies not published in English were excluded from study 2.Data Extraction and SynthesisThe PRISMA guidelines and Cochrane Handbook for Systematic Reviews were followed. Data were extracted independently by 2 researchers. A meta-analysis of the incidence of CVAEs in clinical trials and a systematic review of the evidence for the management of myocarditis were performed. Data were pooled using a random-effects model.Main Outcomes and MeasuresIn study 1, the primary outcome was incidence CVAEs in clinical trials with ICIs and ICI combination therapies. Study 2 examined evidence supporting specific management strategies that may decrease the mortality rate of myocarditis. The primary outcomes were planned before data collection began.ResultsIn study 1, a total of 83 315 unique participants in 589 unique trials were included in the meta-analysis. Incidence of CVAEs induced by anti–programmed cell death 1 and/or programmed cell death ligand 1 was 0.80% (95% CI, 0%-1.66%) in clinical trials, with no differences between the compounds, except for cemiplimab, which was associated with a higher risk of CVAEs. Incidence of CVAEs following ipilimumab treatment was 1.07% (95% CI, 0%-2.58%). The incidence of myocarditis was significantly higher following treatment with dual ICIs. However, CVAE incidence was not higher with dual ICIs, ICI combination with chemotherapy, or tyrosine kinase inhibitors. Evidence from randomized clinical trials on recommended monitoring and treatment strategies for ICI-induced myocarditis was lacking. Study 2 showed that myocarditis-associated mortality occurred in 83 of 220 patients (37.7%). Prospective data from 40 patients with myocarditis indicated that systematic screening for respiratory muscle involvement, coupled with active ventilation, prompt use of abatacept, and the addition of ruxolitinib, may decrease the mortality rate.Conclusions and RelevanceImmune checkpoint inhibitor–induced CVAEs and/or myocarditis were recorded in 1.07% of patients in clinical trials. The CVAE mortality risk remains high, justifying the need for monitoring and management strategies for which evidence from randomized clinical trials is absent. Early recognition, ICI therapy cessation, prompt initiation of corticosteroid therapy, and escalation of therapy are all crucial elements for achieving optimal outcomes. Prospective clinical trials or at least prospective registration of treatments and outcomes are highly warranted.

中文翻译：

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免疫检查点抑制剂诱导的心脏毒性


重要性免疫检查点抑制剂 （ICI） 可改善多种癌症的预后;然而，可能会发生严重的不良反应，包括心血管不良反应 （CVAE）。目的确定 CVAEs 的发生率并分析暴露于 ICIs 的患者心肌炎管理数据.数据源PubMed、Embase 和 Cochrane 对照试验中心注册库从建库开始检索。研究 1 的关键纳入标准是 1 至 4 期试验，涉及接受 ICI 治疗的恶性肿瘤成人和毒性数据;对于研究 2，关于 ICI 诱发的 CVAE 患者临床表现和治疗的出版物（病例报告和回顾性分析）。剂量递增或每组少于 11 名患者的研究以及所有病例报告、回顾性分析、信件、评论和社论均被排除在研究 1 之外。未以英文发表的研究被排除在研究之外 2.数据提取和综合遵循 PRISMA 指南和 Cochrane 系统评价手册。资料由 2 名研究人员独立提取。对临床试验中 CVAE 的发生率进行了荟萃分析，并对心肌炎管理的证据进行了系统评价。使用随机效应模型合并数据。主要结局和措施在研究 1 中，主要结局是 ICIs 和 ICI 联合疗法临床试验中 CVAE 的发生率。研究 2 检查了支持可能降低心肌炎死亡率的特定管理策略的证据。主要结局是在数据收集开始之前计划的。结果在研究 1 中，荟萃分析共纳入了 589 项独特试验的 83 315 名独特参与者。在临床试验中，抗程序性细胞死亡 1 和/或程序性细胞死亡配体 1 诱导的 CVAE 发生率为 0.80% （95% CI，0%-1.66%），化合物之间没有差异，除了 cemiplimab，它与 CVAE 的风险较高相关。ipilimumab 治疗后 CVAE 的发生率为 1.07% （95% CI，0%-2.58%）。双重 ICIs 治疗后心肌炎的发生率显著升高。然而，双重 ICIs、ICI 联合化疗或酪氨酸激酶抑制剂的 CVAE 发生率并不高。缺乏来自 ICI 诱发心肌炎推荐监测和治疗策略的随机临床试验证据。研究 2 显示，220 名患者中有 83 名 （37.7%） 发生心肌炎相关死亡率。来自 40 名心肌炎患者的前瞻性数据表明，系统筛查呼吸肌受累，联合主动通气，及时使用阿巴西普和加用芦可替尼，可能会降低死亡率。结论和相关性在临床试验中，1.07% 的患者记录了免疫检查点抑制剂诱导的 CVAE 和/或心肌炎。CVAE 死亡风险仍然很高，这证明了在没有随机临床试验证据的情况下需要监测和管理策略是合理的。早期识别、停止 ICI 治疗、迅速开始皮质类固醇治疗和升级治疗都是实现最佳结局的关键因素。前瞻性临床试验或至少对治疗和结果进行前瞻性注册是非常必要的。