Risk of sudden unexplained death after use of dihydroartemisinin-piperaquine for malaria: a systematic review and Bayesian meta-analysis.
Risk of sudden unexplained death after use of dihydroartemisinin-piperaquine for malaria: a systematic review and Bayesian meta-analysis.
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DOI：
10.1016/s1473-3099(18)30297-4
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发表时间：
2018-08
期刊：
影响因子：
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通讯作者：
White NJ
中科院分区：
文献类型：
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作者：
Chan XHS;Win YN;Mawer LJ;Tan JY;Brugada J;White NJ
双氢青蒿素-哌喹是一种有效且耐受性良好的以青蒿素为基础的联合疗法，已被广泛评估用于预防和治疗疟疾。哌喹与目前使用的几种结构相关抗疟药物类似，可延长心室复极持续时间和心电图QT间期，导致对其致心律失常电位的担忧。我们的目的是评估接受双氢青蒿素-哌喹治疗的个体发生潜在致命性医源性室性心律失常的风险。我们做了系统回顾和贝叶斯元分析。我们检索了临床文献数据库（最后一次检索于2017年5月24日），检索了双氢青蒿素-哌喹在人体中的研究。世卫组织抗疟药物心脏毒性证据审查小组确定了更多未发表的研究。我们搜索了包含“双氢青蒿素-哌喹”作为标题、摘要或主题标题关键词的文章，并将同义词和变体拼写作为附加搜索词。我们排除了动物研究，但没有对语言或出版日期进行限制。符合条件的研究为前瞻性、随机对照试验或队列研究，在这些研究中，个体接受至少一个为期3天的双氢青蒿素-哌喹疗程，用于大规模给药、预防性治疗或无并发症疟疾病例管理，随访时间至少为3天。至少有两名独立审评员筛选了标题、摘要和全文，同意了研究资格，并将有关研究和参与者特征、不良事件监测方法、双氢青蒿素-哌喹暴露、随访损失和双氢青蒿素-哌喹治疗后死亡的信息提取到标准化数据库中。贝叶斯荟萃分析产生95%可信区间（CI）的双氢青蒿素-哌喹治疗后不明原因猝死的风险与基线心源性猝死率进行比较。我们的检索确定了94项符合条件的初级研究，包括197867名接受过双氢青蒿素-哌喹治疗的个体的数据；14项关于预防性治疗和无并发症疟疾病例管理的重复疗程的研究中有15 188项；在76项病例管理研究中，28174例作为单一疗程的非复杂疟疾治疗。有一例可能与药物有关的原因不明的突然死亡：莫桑比克一名16岁的健康妇女在服用第二剂双氢青蒿素-哌喹几小时后出现心悸，并在送往医院的途中晕倒死亡（未进行尸检或心电图检查）。双氢青蒿素-哌喹治疗后突然不明原因死亡的中位合并风险估计为1 / 757 950（95%可信区间为1 / 2 854 490至1 / 209 114）。这一风险估计值并不高于心源性猝死的基线发生率（在30天的风险期中，每10万人中有0.7 - 11.9人/年或1 / 1714280 - 1 / 100835）。大多数研究的偏倚风险较低，少数研究的偏倚风险不明确。双氢青蒿素-哌喹与不明原因猝死的低风险相关，不高于心源性猝死的基线率。对与再极化相关的心脏毒性的担忧不必限制其目前用于疟疾的预防和治疗。威康信托基金会、英国医学研究理事会、世卫组织、比尔及梅林达·盖茨基金会和牛津大学。
Dihydroartemisinin–piperaquine is an effective and well tolerated artemisinin-based combination therapy that has been assessed extensively for the prevention and treatment of malaria. Piperaquine, similar to several structurally related antimalarials currently used, can prolong cardiac ventricular repolarisation duration and the electrocardiographic QT interval, leading to concerns about its proarrhythmic potential. We aimed to assess the risk of potentially lethal iatrogenic ventricular arrhythmias in individuals receiving dihydroartemisinin–piperaquine. We did a systematic review and Bayesian meta-analysis. We searched clinical bibliographic databases (last on May 24, 2017) for studies of dihydroartemisinin–piperaquine in human beings. Further unpublished studies were identified with the WHO Evidence Review Group on the Cardiotoxicity of Antimalarials. We searched for articles containing “dihydroartemisinin-piperaquine” as title, abstract, or subject heading keywords, with synonyms and variant spellings as additional search terms. We excluded animal studies, but did not apply limits on language or publication date. Eligible studies were prospective, randomised, controlled trials or cohort studies in which individuals received at least one 3-day treatment course of dihydroartemisinin–piperaquine for mass drug administration, preventive therapy, or case management of uncomplicated malaria, with follow-up over at least 3 days. At least two independent reviewers screened titles, abstracts, and full texts, agreed study eligibility, and extracted information about study and participant characteristics, adverse event surveillance methodology, dihydroartemisinin–piperaquine exposures, loss-to-follow up, and any deaths after dihydroartemisinin–piperaquine treatment into a standardised database. The risk of sudden unexplained death after dihydroartemisinin–piperaquine with 95% credible intervals (CI) generated by Bayesian meta-analysis was compared with the baseline rate of sudden cardiac death. Our search identified 94 eligible primary studies including data for 197 867 individuals who had received dihydroartemisinin–piperaquine: 154 505 in mass drug administration programmes; 15 188 in 14 studies of repeated courses in preventive therapies and case management of uncomplicated malaria; and 28 174 as single-course treatments of uncomplicated malaria in 76 case-management studies. There was one potentially drug-related sudden unexplained death: a healthy woman aged 16 in Mozambique who developed heart palpitations several hours after the second dose of dihydroartemisinin–piperaquine and collapsed and died on the way to hospital (no autopsy or ECG was done). The median pooled risk estimate of sudden unexplained death after dihydroartemisinin–piperaquine was 1 in 757 950 (95% CI 1 in 2 854 490 to 1 in 209 114). This risk estimate was not higher than the baseline rate of sudden cardiac death (0·7–11·9 per 100 000 person-years or 1 in 1 714 280 to 1 in 100 835 over a 30-day risk period). The risk of bias was low in most studies and unclear in a few. Dihydroartemisinin–piperaquine was associated with a low risk of sudden unexplained death that was not higher than the baseline rate of sudden cardiac death. Concerns about repolarisation-related cardiotoxicity need not limit its current use for the prevention and treatment of malaria. Wellcome Trust, UK Medical Research Council, WHO, Bill & Melinda Gates Foundation, and University of Oxford.