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

Autoři: Xin Hui S. Chan aff001;  Yan Naung Win aff001;  Ilsa L. Haeusler aff004;  Jireh Y. Tan aff001;  Shanghavie Loganathan aff001;  Sompob Saralamba aff001;  Shu Kiat S. Chan aff001;  Elizabeth A. Ashley aff002;  Karen I. Barnes aff009;  Rita Baiden aff011;  Peter U. Bassi aff012;  Abdoulaye Djimde aff013;  Grant Dorsey aff014;  Stephan Duparc aff015;  Borimas Hanboonkunupakarn aff001;  Feiko O. ter Kuile aff017;  Marcus V. G. Lacerda aff018;  Amit Nasa aff020;  François H. Nosten aff002;  Cyprian O. Onyeji aff022;  Sasithon Pukrittayakamee aff001;  André M. Siqueira aff018;  Joel Tarning aff001;  Walter R. J. Taylor aff001;  Giovanni Valentini aff025;  Michèle van Vugt aff026;  David Wesche aff027;  Nicholas P. J. Day aff001;  Christopher L-H Huang aff028;  Josep Brugada aff029;  Ric N. Price aff001;  Nicholas J. White aff001
Působiště autorů: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand aff001;  Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom aff002;  Health and Diseases Control Unit, Naypyidaw, Myanmar aff003;  WorldWide Antimalarial Research Network, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom aff004;  University College London Great Ormond Street Institute of Child Health, London, United Kingdom aff005;  Christ Church College, University of Oxford, Oxford, United Kingdom aff006;  Singapore Armed Forces Medical Corps, Singapore aff007;  Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Vientiane, Lao PDR aff008;  Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa aff009;  WorldWide Antimalarial Resistance Network, Cape Town, South Africa aff010;  INDEPTH Network Secretariat, Accra, Ghana aff011;  Department of Internal Medicine, Faculty of Clinical Sciences, College of Health Sciences, University of Abuja, Abuja, Nigeria aff012;  Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science Techniques and Technologies of Bamako, Bamako, Mali aff013;  Department of Medicine, University of California San Francisco, San Francisco, California, United States of America aff014;  Medicines for Malaria Venture, Geneva, Switzerland aff015;  Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand aff016;  Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom aff017;  Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil aff018;  Instituto Leônidas e Maria Deane (FIOCRUZ-Amazonas), Fundação Oswaldo Cruz, Manaus, Brazil aff019;  Sun Pharmaceutical Industries Ltd, Gurgaon, Haryana, India aff020;  Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand aff021;  Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria aff022;  The Royal Society of Thailand, Dusit, Bangkok, Thailand aff023;  Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil aff024;  Corporate R&D Department, Alfasigma S.p.A., Rome, Italy aff025;  Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands aff026;  Certara, Princeton, New Jersey, United States of America aff027;  Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom aff028;  Cardiovascular Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain aff029;  Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia aff030
Vyšlo v časopise: Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data. PLoS Med 17(3): e32767. doi:10.1371/journal.pmed.1003040
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pmed.1003040



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.


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.

Klíčová slova:

Antimalarials – Body temperature – Electrocardiography – Fevers – Heart rate – Malaria – Malarial parasites – Metaanalysis


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