Randomized Controlled Trial of the Electrocardiographic Effects of Four Antimalarials for Pregnant Women with Uncomplicated Malaria on the Thailand-Myanmar Border

Abstract

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/RR0.381). 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.

Anti‐malarial drugs: Mechanisms underlying their proarrhythmic effects

“…A randomised non-inferiority trial treating uncomplicated malaria in African children compared dihydroartemisinin plus piperaquine phosphate to artemether-lumefantrine treatment. It found that the proportion of patients with prolonged QTc interval at day 2 corrected by the Bazett's method was higher in the dihydroartemisinin plus piperaquine phosphate (9.1%) than the artemether-lumefantrine group (6.9%) (Bassat et al, 2009) consistent with other studies (Saito et al, 2021;WANECAM, 2018). However, this was not confirmed when applying the Fridericia's correction which in combination to the absence of adverse cardiac events (e.g.…”

Safety of dihydroartemisinin-piperaquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria among children in Africa: a systematic review and meta-analysis of randomized control trials

“…In this review more patients from DHA-PQ treatment arm had cough than that of AL [ 49 ] and similarly, gastrointestinal adverse events were more frequent in patients who were treated with DHA-PQ in another study done in South East Asia and Africa [ 50 – 53 ]. Studies from the Thailand-Myanmar border [ 54 , 55 ] and elsewhere in Africa [ 56 – 58 ] have reported that DHA-PQ cause drug induced electrocardiographic QT prolongation, but a recent study also reported that the QT prolongation caused by piperaquine is not associated with an increased risk of sudden death [ 59 ]. In breastfeeding infants DHA–PQ has previously been linked to an increased risk of vomiting [ 60 ].…”

“…However, the absence of effect with AL implies that the mechanism is given to DHA–PQ, most likely piperaquine [ 17 ]. Regardless of the treatment groups, most of these adverse events are associated with age (≤ 18 years), efavirenz-based ART [ 52 ], efavirenz-based ART [ 53 ], and administration of DHA-PQ with food could increase piperaquine exposure and it needs to be administered in fasting state [ 53 , 54 , 61 ].…”

Safety of Dihydroartemisinin-piperaquine Versus Artemether-lumefantrine for the Treatment of Uncomplicated Plasmodium Falciparum Malaria Among Children in Africa: A Systematic Review and Meta-analysis of Randomized Control Trials

“…Studies from the Thailand-Myanmar border [39,40] and elsewhere in Africa [41][42][43][44] have reported that DHA-PQ cause drug induced electrocardiographic QT prolongation. Regardless of the treatment groups, most of these adverse events are associated with age (≤18 years) [37], efavirenz-based ART [37], efavirenz-based ART [45], and administration of DHA-PQ with food could increase piperaquine exposure and it needs to be administered in fasting state [40][41][42].…”