Evaluation of the effects on the QT interval of 4 artemisinin-based combination therapies for the treatment of uncomplicated malaria by use of a correction-free and heart rate-free method

28 Jan 2019

Nouhoum Ouologuem, Stephan Duparc, Pascal Voiriot, Mathieu Felices, Sodiomon B Sirima, Issaka Sagara, Issiaka Soulama, Jean-Bosco Ouedraogo, Abdoul H Beavoguia, Isabelle Borghini-Furher, Yasmin Khan, Abdoulaye Djimide and Christian Funck-Brentano

Scientific Reports

Abstract

BACKGROUND

Several antimalarial drugs are known to prolong QTc interval, a marker of proarrhythmic risk. The cardiac safety and effects of four different artemisinin-based combination therapies on the QTc interval were investigated in African patients with uncomplicated malaria.

METHODS

Patients were treated with one of four treatment arms using recommended doses: dihydroartemisinin-piperaquine (DHA-PQP), pyronaridine-artesunate (PA), artesunate-amodiaquine (ASAQ) or artemether-lumefantrine (AL). Twelve-lead ECGs were recorded in 2,091 patients at baseline and on Day 3 and centrally read. Different methods were investigated to correct QT interval for the decrease in heart rate resulting from the successful treatment of malaria.

FINDINGS

None of the QT correction methods satisfactorily corrected the QT interval. The change of QTc interval from baseline (ΔQTc) was evaluated in the absence of a change in heart rate (ΔRR) using the intercept of the ΔQTc-ΔRR relationship. With this approach, the estimated change (90% confidence interval) of QTc was 21·1 (18·7, 23·4)ms, 1·5 (-0·7, 3·7)ms, 23·0 (19·5, 26·5)ms and 11·0 (7·9, 14·1)ms for DHA-PQP, PA, ASAQ and AL, respectively. There was no evidence of cardiac toxicity with any treatment during the study.

INTERPRETATION

These results indicate that treatment with DHA-PQP and ASAQ markedly prolongs the QT interval while such an effect is mild with AL and less likely with PA. Our data support the use of the intercept of the ΔQT-ΔRR relationship to accurately assess the effects of antimalarials on ventricular repolarization.

FUNDING

European & Developing Countries Clinical Trials Partnership, The Hague, The Netherlands and Medicines for Malaria Venture, Geneva, Switzerland.

View the full article on the Scientific Reports (Nature Research) website.