氯喹引起的致死性心脏不良事件分析:基于WHO个案病例安全报告全球数据库相关数据的研究

Analysis of fatal cardiac adverse events caused by chloroquine:a study based on the related data from the WHO global database of individual case safety reports

目的分析新型冠状病毒肺炎抗病毒治疗推荐药物氯喹引起致死心脏不良事件的临床特征,为临床安全用药提供参考。方法检索世界卫生组织个案病例安全报告全球数据库(VigiBase)氯喹引起的致死性心脏不良事件,对报告信息充分(VigiGrade完整评分≥0.80或附有详细的原始报告)案例的临床特征进行分析。不良事件分类编码采用国际药品注册协调会议(ICH)国际医学用语词典(MedDRA)22.1版的系统器官分类(SOC)和首选术语(PT)。结果截至2020年2月23日,VigiBase中共有45份氯喹相关致死性心脏损害报告,来自16个国家,30份报告信息充分。30份报告中20例为氯喹单次大剂量用药出现的致死性心脏不良事件,17例为过量用药(15例自杀或怀疑自杀,2例幼儿误服)导致,3例为临床治疗用药;18例表现为心律失常和心脏骤停;6例心电图显示QRS波延长或QT间期延长;6例合并低钾血症,其中4例为严重低血钾。30份报告中10例为氯喹多次用药引起的致死性心脏不良事件,4例使用氯喹时间为23 d^2个月,死于心力衰竭、心搏骤停或心肌梗死;6例使用氯喹时间为20个月~29年,均为心肌病,3例心内膜心肌活检证实为氯喹所致。结论心脏毒性是氯喹引起致死性不良事件的首要原因,单次大剂量氯喹主要表现为心律失常;长期用药主要表现为心肌病。

Objective To analyze the clinical characteristics of fatal cardiac adverse events associated with chloroquine,which was recommended for the antiviral treatment of novel coronavirus pneumonia,and provide reference for clinical safe drug use.Methods The fatal cardiac adverse events associated with chloroquine were searched from the World Health Organization global database of individual case safety reports(VigiBase).The clinical characteristics of the individual cases with well-documented reports(VigiGrade completeness score≥0.80 or with detailed original reports)were analyzed.The adverse events were coded using the systematic organ classification(SOC)and preferred term(PT)of Medical Dictionary for Regulatory Activities(MedDRA)version 22.1 of International Conference on Harmonization(ICH).Results Up to 23 February 2020,a total of 45 reports of fatal heart injuries related to chloroquine were reported in VigiBase,which were from 16 countries.Of them,30 reports were fully informative.Among the 30 reports,20 cases developed fatal cardiac adverse events after a single large dose of chloroquine.Of them,17 cases′fatal cardiac adverse events were caused by overdose of chloroquine(15 cases were suicide or suspected suicide,and 2 children took chloroquine by mistake);3 cases′fatal cardiac adverse events were caused in clinical treatment;18 cases showed arrhythmia and cardiac arrest;6 cases showed prolonged QRS wave or QT interval;6 cases were with hypokalemia,including 4 severe ones.Among the 30 reports,10 cases developed fatal cardiac adverse events after multiple administration of chloroquine,of which 4 cases were treated with chloroquine for 23 days to 2 months and died of heart failure,cardiac arrest or myocardial infarction;6 cases were treated with chloroquine for 20 months to 29 years and all of them had cardiomyopathy,which were confirmed by endomyocardial biopsy to be caused by chloroquine in 3 cases.Conclusion Cardiac toxicity was the primary cause of fatal adverse events caused by chloroquine;the main manifestation of single large dose of chloroquine was arrhythmia and the manifestation of multiple administration was cardiomyopathy.