Abstract
Several antimalarial drugs are known to prolong ventricular repolarization as evidenced by QT/QTc interval prolongation. This can lead to Torsades de Pointes, a potentially lethal ventricular arrhythmia. Whether this is the case with artemisinin-based combination therapies (ACTs) remains uncertain. Assessment of the extent of QTc prolongation with antimalarials is hampered by important variations of heart rate during malaria crises and previous studies have reported highly variable values of QTc prolongations with ACTs. We assessed QTc prolongation with four ACTs, using high quality ECG recording and measurement techniques, during the first episode of malaria in 2,091 African patients enrolled in the WANECAM study which also monitored clinical safety. Using an original and robust method of QTc assessment, independent from heart rate changes and from the method of QT correction, we were able to accurately assess the extent of mean maximum QTc prolongation with the four ACTs tested. There was no evidence of proarrhythmia with any treatment during the study although dihydroartemisinin-piperaquine, artesunate-amodiaquine and artemether-lumefantrine significantly prolonged QTc. The extent of prolongation of ventricular repolarization can be accurately assessed in studies where heart rate changes impede QTc assessment.
Highlights
According to the World Health Organization, the number of malaria cases fell from an estimated 262 million in 2000 to 216 million in 2016
The present report describes the ECG results obtained during the first episode of malaria in the WANECAM study, registered at the Pan African Clinical Trials Registry under the number PACTR201105000286876, during which high quality ECGs were collected as part of the safety evaluations
The effects of 4 different artemisinin-based combination therapies (ACT) on the ECG were compared as part of the WANECAM study which included several thousand patients with uncomplicated malaria
Summary
According to the World Health Organization, the number of malaria cases fell from an estimated 262 million in 2000 to 216 million in 2016. Malaria represents a difficult case with respect to correcting the QT interval for changes in heart rate and highly variable QTc prolongation values have been reported in studies of antimalarial drugs[11,12,13,14]. Following efficacious treatment of typically anxious patients, who are often young children, heart rate decreases as a result of fever and anxiety regression. This heart rate change, which is due to regression of malaria symptoms rather than to the administered drugs, makes it difficult to properly assess the effect of antimalarial drugs on QTc interval duration during therapeutic use. Particular emphasis was put on the type of QT interval correction to be used and a new approach is proposed on how to assess the effects of drugs on QT interval duration when measurements are made at very different heart rates before and during drug exposure, a situation which is encountered with many drugs other than antimalarial drugs
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