免疫检查点抑制剂所致心脏毒性:一项基于FAERS的2014年至2019年药物警戒研究

Cardiotoxicity Induced by Immune Checkpoint Inhibitors: A Pharmacovigilance Study From 2014 to 2019 Based on FAERS.

作者信息

Chen Chenxin, Chen Ting, Liang Jizhou, Guo Xiaojing, Xu Jinfang, Zheng Yi, Guo Zhijian, Chi Lijie, Wei Lianhui, Chen Xiao, Ye Xiaofei, He Jia

机构信息

Department of Health Statistics, Second Military Medical University, Shanghai, China.

Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai, China.

出版信息

Front Pharmacol. 2021 Feb 12;12:616505. doi: 10.3389/fphar.2021.616505. eCollection 2021.

Abstract

This study was to scientifically and systematically explore the association between cardiotoxicity and immune checkpoint inhibitors (ICIs) and also to characterize the spectrum of ICI-related cardiac complications. From the first quarter of 2014 to the fourth quarter of 2019, data from the FDA Adverse Event Reporting System database were selected to conduct the disproportionality analysis. Reporting odds ratios and information components were used to evaluate the signal after statistical shrinkage transformation. In total, 7,443,137 cases and 36,326,611 drug-adverse event pairs were collected, among which 9,271 cases were identified to be related to ICI-induced cardiotoxicities. The number of male patients was much higher than that of females (5,579 vs. 3,031) and males presented a slightly higher reporting frequency than females in general, which was statistically significant (ROR = 1.04, 95%CI: 0.99-1.09, < 0.001). Simultaneously, the proportion of serious or life-threatening outcomes in males was significantly higher than in females (ROR = 1.05, 95%CI: 0.96-1.15, < 0.001). Importantly, ICIs were associated with over-reporting frequencies of cardiotoxicities in general (ROR025 = 1.06, IC025 = 0.08). PD-1 and PD-L1 were found to be related to cardiac adverse events, corresponding to ROR025 = 1.06, IC025 = 0.08, and ROR025 = 1.06, IC025 = 0.08, respectively, while anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) was significantly associated with some specific adverse events rather than common adverse events. The spectrum of cardiotoxicities induced by ICIs mostly differed among individual agents, but also demonstrated some common features. Dyspnea ( = 2,527, 21.25%), myocarditis ( = 614, 5.16%), atrial fibrillation ( = 576, 4.84%), cardiac failure ( = 476, 4.00%), and pericardial effusion ( = 423, 3.56%) were the top five cardiac adverse events reported in the database. Among them, myocarditis was the only one caused by all ICIs with strong signal value and high risk, warranting further attention. Overall, this investigation mainly showed the profile of cardiotoxicities caused by ICIs, which varied between different ICI therapies, but also shared some similarities in specific symptoms such as myocarditis. Therefore, it is vital and urgent to recognize and manage ICI-related cardiotoxicities, known to frequently occur in clinical practice, at the earliest point.

摘要

本研究旨在科学、系统地探索心脏毒性与免疫检查点抑制剂(ICI)之间的关联,并描述ICI相关心脏并发症的范围。从2014年第一季度到2019年第四季度,选取美国食品药品监督管理局不良事件报告系统数据库中的数据进行不成比例分析。报告比值比和信息成分用于在统计收缩转换后评估信号。总共收集了7443137例病例和36326611对药物-不良事件,其中9271例被确定与ICI引起的心脏毒性有关。男性患者数量远高于女性(5579例对3031例),总体上男性的报告频率略高于女性,差异具有统计学意义(报告比值比=1.04,95%置信区间:0.99-1.09,P<0.001)。同时,男性严重或危及生命结局的比例显著高于女性(报告比值比=1.05,95%置信区间:0.96-1.15,P<0.001)。重要的是,ICI总体上与心脏毒性的报告频率过高相关(报告比值比0.25=1.06,信息成分0.25=0.08)。发现程序性死亡受体1(PD-1)和程序性死亡配体1(PD-L1)与心脏不良事件相关,对应的报告比值比0.25分别为1.06和信息成分0.25为0.08,以及报告比值比0.25为1.06和信息成分0.25为0.08,而抗细胞毒性T淋巴细胞相关蛋白4(CTLA-4)与一些特定不良事件而非常见不良事件显著相关。ICI诱导的心脏毒性范围在个体药物之间大多不同,但也表现出一些共同特征。呼吸困难(n=2527,21.25%)、心肌炎(n=614,5.16%)、心房颤动(n=576,4.84%)、心力衰竭(n=476,4.00%)和心包积液(n=423,3.56%)是数据库中报告的前五大心脏不良事件。其中,心肌炎是所有ICI都可引起的唯一一种具有强信号值和高风险的不良事件,值得进一步关注。总体而言,本调查主要展示了ICI引起的心脏毒性概况,不同ICI疗法之间存在差异,但在心肌炎等特定症状方面也有一些相似之处。因此,尽早识别和处理临床实践中常见的ICI相关心脏毒性至关重要且迫在眉睫。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36c6/7907652/e4e2928f1859/fphar-12-616505-g001.jpg

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