Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
PLoS Med. 2020 Mar 5;17(3):e1003040. doi: 10.1371/journal.pmed.1003040. eCollection 2020 Mar.
Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.
We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.
Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.
心电图 QT 间期延长是预测室性心律失常潜在风险的最广泛应用的风险标志物，也是药物心脏毒性评估的重要组成部分。几种抗疟药物与 QT 间期延长有关。然而，由于抗疟药物浓度峰值与疟疾恢复相吻合，心电图变化的解释变得复杂。因此，我们回顾了所有可用数据，以描述疟疾疾病和人口统计学因素对 QT 间期的影响，以便改善疟疾治疗和预防中对心电图变化的评估。
我们进行了一项系统评价和个体患者数据的荟萃分析。我们在临床文献数据库中进行了检索（最后检索日期为 2017 年 8 月 21 日），检索了针对人类参与者的与疟疾相关适应症的喹啉和结构相关抗疟药物的研究，其中系统地记录了心电图。未发表的研究由世界卫生组织（WHO）心脏毒性抗疟药物评估小组（ERG）确定。使用欧洲药物流行病学研究治疗结局协会（PROTECT）不良药物事件检查表评估风险偏倚。使用广义加性模型的贝叶斯分层多变量回归来研究疟疾和人口统计学因素对预处理 QT 间期的影响。荟萃分析包括 43 项研究中的 10452 名个体（9778 名疟疾患者，包括 343 名重症患者和 674 名健康参与者）。7170 名（68.6%）有发热（体温≥37.5°C），无患者在抗疟治疗后出现室性心律失常。与健康参与者相比，患有无并发症的恶性疟原虫疟疾的患者 QT 间期更短（-61.77 毫秒；95%可信区间[CI]：-80.71 至-42.83），心率变化对 QT 间期的敏感性增加。在重症疟疾中，这些影响更大（-110.89 毫秒；95%CI：-140.38 至-81.25）。体温每升高 1°C，与临床显著 QT 缩短相关 2.80 毫秒（95%CI：-3.17 至-2.42）。研究的局限性包括无法评估可能影响 QT 间期但在疟疾临床试验中未得到一致收集的其他因素的影响。
有必要调整疟疾和与发热恢复相关的 QT 延长，以避免将疟疾相关的 QT 变化归因于抗疟药物的作用。这将改善临床研究和实践中对抗疟相关心脏毒性的风险评估。对于 QT 间期延长药物是重要治疗选择的其他发热性疾病，可能也需要类似的调整。
