Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial

Abstract

Background: Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria.

Methods: This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054.

Findings: 5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63-0·90; relative reduction 22·5%, 95% CI 8·1-36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49-0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66-0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64-0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43-0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects.

Interpretation: Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide.

Funding: The Wellcome Trust.

Figure 1

Trial profile *663 in Beira, 442 in Kilifi, 436 in Kumasi, 921 in Muheza, 540 in Korogwe, 502 in Banjul, 450 in Ilorin, 386 in Rwanda, 663 in Mbarara, and 422 in Kinshasa. †Two patients also had other criteria.

Figure 2

Kaplan-Meier curves comparing survival in African children with severe falciparum malaria treated with either parenteral artesunate or quinine The numbers in parentheses are the deaths during the indicated time. In eight patients the exact time of death during the night was missing and was estimated as 2359 h.

Figure 3

Treatment effect in protocol-specified subgroups The forest plot shows odds ratios and 95% CIs. The size of the squares is proportional to the size, and therefore weight, of the subgroup. The diamonds show the combined differences. The efficacy of antimalarial pretreatment was classified before study unblinding (webappendix p 12). Hyperparasitaemia means greater than 10% of red cells parasitised. OR=odds ratio. GCS=Glasgow coma scale. BCS=Blantyre coma scale. BE=base excess. *Site mortality classified as low if the site mortality rate was lower than the overall study mortality rate, and high if the site mortality rate was higher than the overall study mortality rate. †Classified according to centre policy (ten sites); classified according to individual data (one site). ‡Decompensated or compensated shock. I² denotes the percentage of total variation across sites resulting from heterogeneity rather than chance, with the p value of significance.

Figure 4

Neurological sequelae at discharge and after 28 days (range 3–8 weeks) in children with severe falciparum malaria *Some patients had severe impairment in more than one domain.

Figure 5

Meta-analysis of all randomised controlled trials that have compared parenteral artesunate and parenteral quinine in severe malaria The solid vertical line represents equality of the two groups; the dashed line is the overall treatment difference. The horizontal lines and the width of the diamonds show the CIs for the odds ratios. The size of the squares is proportional to the size, and therefore weight, of the trial. OR=odds ratio. *99% CIs for totals.