The
artemisinin derivatives are the preferred antimalaria drugs for treating severe
Plasmodium falciparum malaria. However, their clinical effectiveness compared to each other is unknown. Our objective, therefore, was to evaluate the efficacy and safety of the
artemisinin derivatives and
quinine for treating severe P.
falciparum malaria in children and adults using a network meta-analysis.
METHODS AND FINDINGS: Review protocol was registered with PROSPERO, CRD42020218190. We updated the search strategies of three Cochrane systematic reviews which included published and unpublished randomised control trials (RCTs) that have compared specific
artemisinin derivatives to
quinine in treating severe
malaria. Search included CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science and trial registries up to February 2021. We screened studies, extracted data, assessed risk of bias, and quality of evidence in duplicate. Separate network meta-analyses in the frequentist framework, using a random effects model, with
quinine as reference, were conducted for adults and children, and rankings were produced using p-scores to assess mortality, parasite clearance,
coma recovery,
fever clearance, neurological sequela and adverse events. Searches identified 818 citations, 33 RCTs were eligible. We pooled 7795 children and 3182 adults. The networks involved
artesunate,
artemether, rectal
artemisinin,
arteether and
quinine. Compared to
quinine,
artesunate reduced mortality in children (risk ratio (RR), 0.76; 95%CI [0.65 to 0.89], moderate quality), adults (RR, 0.55; 95%CI [0.40 to 0.75], moderate quality) and in
cerebral malaria (RR, 0.72; 95%CI [0.55 to 0.94], moderate quality). Compared to rectal
artemisinin and intramuscular
arteether, the efficacy and safety of parenteral
artesunate, and intramuscular
artemether in treating severe
malaria are not clear. Rankings showed that none of the
artemisinin drugs were consistently superior in all the outcomes assessed. Indirect evidence produced were of very low ratings due to suspected publication bias and imprecision.
CONCLUSIONS:
Artesunate reduces mortality compared to
quinine for both adults and children in Asia and Africa including
cerebral malaria. The
artemisinin derivatives remain the best treatment for severe
malaria but their comparative clinical effectiveness is yet to be fully explored.