Electrocardiographic effects of four antimalarials for pregnant women with uncomplicated malaria on the Thailand-Myanmar border: a randomised controlled trial.
Saito M., Yotyingaphiram W., Cargill Z., Gilder ME., Min AM., Phyo AP., San TD., Poe H., Chu C., White NJ., Nosten F., McGready R.
Quinoline antimalarials cause drug-induced electrocardiograph QT prolongation, a potential risk factor for torsade de pointes. The effects of currently used antimalarials on the electrocardiogram were assessed in pregnant women with malaria. Pregnant women with microscopy-confirmed parasitaemia of any malaria species were enrolled in an open-label randomised controlled trial on the Thailand-Myanmar border in 2010-2016. Patients were randomised to the standard regimen dihydroartemisinin-piperaquine (DP), artesunate-mefloquine (ASMQ), or an extended regimen of artemether-lumefantrine (AL+). Recurrent vivax infections were treated with chloroquine. Standard 12-lead electrocardiograms were assessed on day 0, 4-6 hour following the last dose and day 7. QT was corrected for the heart rate by a linear mixed-effects model derived population-based correction formula (QTcP = QT/RR<sup>0.381</sup>). A total of 86 AL+, 82 ASMQ, 88 DP and 21 chloroquine treated episodes were included. No patients had an uncorrected QT interval nor QTcP > 480ms at any time. QTcP corresponding to peak drug concentration was longer in DP group (adjusted predicted mean difference 17.84 ms, 95% CI 11.58 to 24.10, p<0.001) and chloroquine group (18.31 ms, 95% CI 8.78 to 27.84, p<0.001) than in the AL+ group, but not different in the ASMQ group (2.45 ms, 95% CI -4.20 to 9.10, p=0.47). There was no difference between DP and chloroquine (p=0.91). QTc prolongation resulted mainly from widening of JT interval. In pregnant women, none of the antimalarial drug treatments exceeded conventional thresholds for an increased risk of torsade de pointes.