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Title: Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data
Authors: Xin Hui S. Chan
Yan Naung Win
Ilsa L. Haeusler
Jireh Y. Tan
Shanghavie Loganathan
Sompob Saralamba
Shu Kiat S. Chan
Elizabeth A. Ashley
Karen I. Barnes
Rita Baiden
Peter U. Bassi
Abdoulaye Djimde
Grant Dorsey
Stephan Duparc
Borimas Hanboonkunupakarn
Feiko O. Ter Kuile
Marcus V.G. Lacerda
Amit Nasa
François H. Nosten
Cyprian O. Onyeji
Sasithon Pukrittayakamee
André M. Siqueira
Joel Tarning
Walter R.J. Taylor
Giovanni Valentini
Michèle van Vugt
David Wesche
Nicholas P.J. Day
Christopher L.H. Huang
Josep Brugada
Ric N. Price
Nicholas J. White
Certara USA, Inc.
Singapore Army
University of Cambridge
Fundacao Oswaldo Cruz
Menzies School of Health Research
University of California, San Francisco
Liverpool School of Tropical Medicine
Christ Church
Mahidol University
University of Abuja
Obafemi Awolowo University
Nuffield Department of Clinical Medicine
Universitat de Barcelona
Amsterdam UMC - University of Amsterdam
University of Cape Town
Medicines for Malaria Venture
Sun Pharmaceutical Industries Limited
R&D Department
University of Sciences Techniques and Technologies of Bamako
Health and Diseases Control Unit
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU)
WorldWide Antimalarial Resistance Network
Royal Institute of Thailand
Keywords: Medicine
Issue Date: 1-Mar-2020
Citation: PLoS medicine. Vol.17, No.3 (2020), e1003040
Abstract: 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.
ISSN: 15491676
Appears in Collections:Scopus 2020

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