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

Issued Date

2020-03-01

Resource Type

Article

ISSN

15491676

DOI

10.1371/journal.pmed.1003040

Other identifier(s)

2-s2.0-85081531972

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

PLoS medicine. Vol.17, No.3 (2020), e1003040

Suggested Citation

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 Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data. PLoS medicine. Vol.17, No.3 (2020), e1003040. doi:10.1371/journal.pmed.1003040 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/53749

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Title

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

Author(s)

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

Other Contributor(s)

Certara USA, Inc.
 Singapore Army
 University of Cambridge
 Fundacao Oswaldo Cruz
 Menzies School of Health Research
 University of California, San Francisco
 UCL
 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
 INDEPTH Network

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.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/53749

Collections

Scopus 2020