This generally well-conducted review concluded that there was no evidence that parenteral artemisinin derivatives were associated with lower mortality or long-term morbidity in children with severe malaria compared to parenteral quinine. The paucity of good quality data compromised the reliability of the pooled results, but the overall conclusion reflected the evidence presented and is likely to be reliable.

To assess the efficacy of parenteral artemisinin derivatives verses parenteral quinine in treating severe malaria in children.

MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and LILACS were searched from inception to February 2008. No language restrictions were applied. Search terms were reported. Additionally, bibliographies of retrieved articles and proceedings of a 1993 scientific conference were searched. Field experts were contacted to identify further studies.

Randomised control trials (RCTs) comparing a parenteral artemisinin derivative with parenteral quinine in treating severe malaria were considered for inclusion. Eligible trials had to include children aged between 0 and 16 years or include children only. The World Health Organization (WHO) definition of severe malaria was used. Trials were excluded if they: included both adults and children; evaluated an artemisinin derivative in combination with another anti-malarial was compared to quinine; or compared two or more artemisinin derivatives/regimens.

The primary outcome was mortality. Secondary outcomes included: parasite clearance times; fever clearance times; coma resolution time; incidence of neurological sequelae; 28th day cure rate; and adverse effects.

The included children were aged up to 15 years; most had cerebral malaria. The anti-malarial treatments being evaluated were administered intramuscularly; 3.2mg/Kg artemisinin and beta-artemether were the most commonly used regimens. Most trials used a comparator of a 20mg/kg intravenous quinine loading dose, followed by 10mg eight hourly for seven days, then oral administration. Most trials were conducted in Africa.

Two reviewers assessed whether the articles were suitable for inclusion.

Two reviewers assessed study quality in terms of randomisation, allocation concealment, blinding, and loss to follow-up.

One reviewer extracted the number of patients experiencing an event and the clearance/resolution times. From these, risk ratios (RR) were calculated for binary outcomes, and mean differences for continuous outcomes, along with their corresponding 95% confidence intervals (CI).

Pooled risk ratios and weighted mean differences (WMD), with 95% confidence intervals, were calculated using a fixed-effect model unless significant heterogeneity was observed, in which case a random-effects model was used. Heterogeneity was assessed through visual examination of the forest plots and the χ² test (p<0.05). Potential sources of heterogeneity (trials conducted in Asia, and trial quality) were investigated using subgroup and sensitivity analyses.

Twelve RCTs were included in the review (n=1,524 children; range 37 to 576). Of the 12 studies, six reported adequate randomisation generation, and 8 reported adequate allocation concealment. Three trials were open label, four blinded microscopists, and blinding was not possible in the remaining trials due to the trial design. Loss to follow-up ranged from none (seven trials) to 20%. Only three trials provided a power calculation.

Overall, there were no significant differences in mortality between artemisinin and quinine (RR 0.90, 95% CI 0.73 to 1.12; 12 RCTs), but coma resolution was significantly faster with artemisinin (WMD -4.61, 95% CI -7.21 to -2.00; eight RCTs); the significant improvement in coma resolution was no longer observed when only trials with adequate concealment were considered. No significant heterogeneity was observed for these analyses.

There was no significant difference between artemisinin and quinine in terms of parasite (seven RCTs) or fever (eight RCTs) clearance times, neurological sequelae (10 RCTs), cure rates (five RCTs), or adverse events (11 RCTs).

Further results for mortality for each artemisinin drug, and sensitivity and subgroup analyses, were also reported.

There was no evidence that treatment of children with severe malaria with parenteral artemisinin derivatives was associated with lower mortality or long-term morbidity compared with parenteral quinine.

The review addressed a clear research question, supported by relevant inclusion criteria. Relevant sources were searched without language restrictions, and some attempts were made to locate unpublished studies. Study selection and the quality assessment were conducted in duplicate; however, it was unclear whether similar methods to reduce error and bias were employed during data extraction.

Trial quality was assessed using relevant criteria; the impact of adequate allocation on the results concealment was investigated. The authors considered a trial to be high quality based solely on the adequacy of the allocation concealment. Several trials did not report adequate randomisation sequence generation, most were unblinded, and drop-out rates were relatively high in some trials. Appropriate methods of analysis were employed, and potential sources of heterogeneity were investigated; one subgroup analysis was not pre-specified. Most of the trials were small, and the analyses may have been underpowered.

This was a generally well-conducted review, but the reliability of the pooled results may be reduced given the paucity of good quality data. However, the authors' overall conclusion reflected the evidence presented and is likely to be reliable.

Practice: The authors stated that the review does not justify a replacement of intravenous quinine by artemisinin derivatives when treating children with severe malaria in African and Asian countries where Plasmodium falciparum strains are known to be sensitive to quinine. However, since the efficacies between the two groups of drugs are comparable, the decision to replace quinine may be taken if other factors such as costs, user preference and logistics are taken into consideration.

Research: The authors stated that adequately sized trials investigating mortality, coma recovery time and neurological sequelae need to be conducted in the future to decide whether the drugs are equally effective.

WHO/Special Programme for Research and Training in Tropical Diseases (TDR).

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.