Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.,PLOS Medicine

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Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.
PLOS Medicine ( IF 10.5 ) Pub Date : 2020-03-05 , DOI: 10.1371/journal.pmed.1003040
Xin Hui S Chan _{1,

2} , Yan Naung Win _{1,

3} , Ilsa L Haeusler _{4,

5} , Jireh Y Tan ₁ , Shanghavie Loganathan _{1,

6} , Sompob Saralamba ₁ , Shu Kiat S Chan _{1,

7} , Elizabeth A Ashley _{2,

8} , Karen I Barnes _{9,

10} , Rita Baiden ₁₁ , Peter U Bassi ₁₂ , Abdoulaye Djimde ₁₃ , Grant Dorsey ₁₄ , Stephan Duparc ₁₅ , Borimas Hanboonkunupakarn _{1,

16} , Feiko O Ter Kuile ₁₇ , Marcus V G Lacerda _{18,

19} , Amit Nasa ₂₀ , François H Nosten _{2,

21} , Cyprian O Onyeji ₂₂ , Sasithon Pukrittayakamee _{1,

16,

23} , André M Siqueira _{18,

24} , Joel Tarning _{1,

2,

4} , Walter R J Taylor _{1,

2} , Giovanni Valentini ₂₅ , Michèle van Vugt ₂₆ , David Wesche ₂₇ , Nicholas P J Day _{1,

2} , Christopher L-H Huang ₂₈ , Josep Brugada ₂₉ , Ric N Price _{1,

2,

30} , Nicholas J White _{1,

2}

Affiliation

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.
Health and Diseases Control Unit, Naypyidaw, Myanmar.
WorldWide Antimalarial Research Network, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
University College London Great Ormond Street Institute of Child Health, London, United Kingdom.
Christ Church College, University of Oxford, Oxford, United Kingdom.
Singapore Armed Forces Medical Corps, Singapore.
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Vientiane, Lao PDR.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
WorldWide Antimalarial Resistance Network, Cape Town, South Africa.
INDEPTH Network Secretariat, Accra, Ghana.
Department of Internal Medicine, Faculty of Clinical Sciences, College of Health Sciences, University of Abuja, Abuja, Nigeria.
Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science Techniques and Technologies of Bamako, Bamako, Mali.
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Medicines for Malaria Venture, Geneva, Switzerland.
Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil.
Instituto Leônidas e Maria Deane (FIOCRUZ-Amazonas), Fundação Oswaldo Cruz, Manaus, Brazil.
Sun Pharmaceutical Industries Ltd, Gurgaon, Haryana, India.
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
The Royal Society of Thailand, Dusit, Bangkok, Thailand.
Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Corporate R&D Department, Alfasigma S.p.A., Rome, Italy.
Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Certara, Princeton, New Jersey, United States of America.
Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom.
Cardiovascular Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.

Background

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.

Methods and findings

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.

Conclusions

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.

中文翻译：

影响疟疾心电图 QT 间期的因素：对个体患者数据的系统回顾和荟萃分析。

背景

心电图 QT 间期延长是最广泛使用的室性心律失常潜在风险标记，因此是药物心脏毒性评估的重要组成部分。几种抗疟药与 QT 间期延长有关。然而，心电图变化的解释因抗疟药物峰值浓度与疟疾恢复的同时发生而变得混乱。因此，我们回顾了所有可用数据，以描述疟疾疾病和人口因素对 QT 间期的影响，以改进对疟疾治疗和预防中心电图变化的评估。

方法和结果

我们对个体患者数据进行了系统回顾和荟萃分析。我们检索了临床书目数据库（最新日期为 2017 年 8 月 21 日），以查找针对人类参与者的疟疾相关适应症的喹啉和结构相关抗疟药的研究，其中系统记录了心电图。世界卫生组织 (WHO) 证据审查小组 (ERG) 确定了关于抗疟药心脏毒性的未发表研究。使用欧洲联盟治疗结果的药物流行病学研究 (PROTECT) 药物不良事件清单评估偏倚风险。采用广义加性模型的贝叶斯分层多变量回归研究了疟疾和人口因素对治疗前 QT 间期的影响。这项荟萃分析纳入了来自 43 项研究的 10,452 名个体（9,778 名疟疾患者，其中 343 名患有严重疾病，以及 674 名健康参与者）。 7,170 例（68.6%）出现发热（体温≥37.5°C），抗疟治疗后无一例出现室性心律失常。与健康参与者相比，无并发症的恶性疟疾患者的 QT 间期较短（−61.77 毫秒；95% 可信区间 [CI]：−80.71 至 −42.83），且 QT 间期对心率变化的敏感性更高。这些影响在严重疟疾中更大（-110.89 毫秒；95% CI：-140.38 至 -81.25）。体温每升高 1°C 与临床显着的 QT 缩短 2.80 毫秒（95% CI：-3.17 至 -2.42）独立相关。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一致收集的其他因素的影响。