We performed a systematic literature search on October 22, 2015 (updated on August 21, 2017) of the databases MEDLINE, Embase, and Global Health for primary clinical studies of the quinoline and structurally related antimalarials for malaria-related indications in which electrocardiograms (ECGs) were recorded before and after drug administration (Search Strategy in S1 Appendix ). These published and additional unpublished studies were identified as part of the work of the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials [5 ].
Studies were eligible for inclusion in the review if they were prospective randomised-controlled trials or cohort studies published from 1988 onwards in which 5 or more participants were given a quinoline or structurally related antimalarial drug—amodiaquine, chloroquine, halofantrine, lumefantrine, mefloquine, piperaquine, primaquine, pyronaridine, or quinine—either as monotherapy or as part of an ACT. Studies that coadministered other drugs with QT-prolonging potential (e.g., azithromycin) as part of the trial intervention were excluded.
Study authors were contacted with a request for clinical study reports and protocols as well as anonymised individual patient-level data sets of the following prespecified variables identified from expert consultation [5 ]: age, weight, sex, body temperature, parasitaemia, haemoglobin or haematocrit, heart rate or RR interval duration, uncorrected QT interval duration, ECG abnormalities, and other cardiovascular adverse events. Studies were included in this meta-analysis if individual patient-level data were available for all requested variables from the screening or a baseline time point before antimalarial drug administration.
All included individual patient-level data were obtained in accordance with appropriate ethical approvals from countries and institutions of origin. Additional ethical approval for this systematic review and meta-analysis of fully anonymised individual patient data was not deemed necessary in keeping with University of Oxford Central University Research Ethics Committee guidance.
Studies were eligible for inclusion in the review if they were prospective randomised-controlled trials or cohort studies published from 1988 onwards in which 5 or more participants were given a quinoline or structurally related antimalarial drug—amodiaquine, chloroquine, halofantrine, lumefantrine, mefloquine, piperaquine, primaquine, pyronaridine, or quinine—either as monotherapy or as part of an ACT. Studies that coadministered other drugs with QT-prolonging potential (e.g., azithromycin) as part of the trial intervention were excluded.
Study authors were contacted with a request for clinical study reports and protocols as well as anonymised individual patient-level data sets of the following prespecified variables identified from expert consultation [5 ]: age, weight, sex, body temperature, parasitaemia, haemoglobin or haematocrit, heart rate or RR interval duration, uncorrected QT interval duration, ECG abnormalities, and other cardiovascular adverse events. Studies were included in this meta-analysis if individual patient-level data were available for all requested variables from the screening or a baseline time point before antimalarial drug administration.
All included individual patient-level data were obtained in accordance with appropriate ethical approvals from countries and institutions of origin. Additional ethical approval for this systematic review and meta-analysis of fully anonymised individual patient data was not deemed necessary in keeping with University of Oxford Central University Research Ethics Committee guidance.
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