免疫检查点抑制剂诱导的心脏毒性：系统综述和Meta分析

免疫检查点抑制剂（ICIs）可改善多种癌症的预后；然而，可能会出现严重的不良反应，包括心血管不良反应（CVAE）。

To determine the incidence of CVAEs and analyze data on the management of myocarditis in patients exposed to ICIs.

确定接触ICIs的患者中CVAE的发生率，并分析心肌炎治疗的数据。

PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception were searched on April 4, 2023.

2023年4月4日检索了PubMed、Embase和Cochrane对照试验中心注册库。

Two 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.

进行了两项单独的研究。研究1的关键纳入标准是涉及接受ICI治疗的恶性肿瘤成年人的1至4期试验和毒性数据；研究2，关于ICI诱导的CVAE患者的临床表现和治疗的出版物（病例报告和回顾性分析）。每组剂量递增或少于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2中。

The 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.

遵循PRISMA指南和Cochrane系统评价手册。数据由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综述。使用随机效应模型对数据进行汇总。

In 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.

在研究1中，共有589项独特试验中的83315名独特参与者被纳入荟萃分析。在临床试验中，由抗程序性细胞死亡1和/或程序性细胞凋亡配体1诱导的CVAE的发生率为0.80%（95%CI，0%-1.66%），除了与较高CVAE风险相关的头孢利单抗外，其他化合物之间没有差异。易普利姆玛治疗后CVAE的发生率为1.07%（95%CI，0%-2.58%）。双重ICI治疗后心肌炎的发生率明显升高。然而，双重ICI、ICI联合化疗或酪氨酸激酶抑制剂的CVAE发生率并不高。缺乏关于ICI诱导的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%）死于心肌炎。来自40名心肌炎患者的前瞻性数据表明，对呼吸肌受累进行系统筛查，加上主动通气、及时使用阿巴西普和添加鲁索利替尼，可能会降低死亡率。

Immune 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.

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的死亡风险仍然很高，这证明了在缺乏随机临床试验证据的情况下需要监测和管理策略。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果的关键因素。前瞻性临床试验或至少是治疗和结果的前瞻性注册是非常有必要的。