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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Artemisinin derivatives versus quinine for cerebral malaria in African children: a systematic review

HH Kyu and E Fernandez.

Review published: 2009.

CRD summary

This review concluded that artemisinin derivatives (artemether and arteether) were not inferior to quinine for preventing death from cerebral malaria in children. The evidence presented showed no statistically significant difference between groups, but did not demonstrate non-inferiority. Although the review was generally well conducted, the validity of this inference and the reliability of the authors' conclusion is uncertain.

Authors' objectives

To summarise the existing evidence on the efficacy of artemisinin derivatives (artemether and arteether) versus quinine, for treating cerebral malaria (Plasmodium falciparum) in children.

Searching

The reviewers searched the following databases from inception to May 2008 for relevant studies: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Search terms were reported. No language restrictions were applied. The ClinicalTrials.gov website was also searched. A number of relevant authors were contacted. Reference lists of relevant papers and systematic reviews were scanned.

Study selection

Eligible studies were randomised controlled trials (RCTs) that compared either artemether or arteether with quinine for the treatment of cerebral malaria in children (up to 15 years old).

The primary outcome was mortality at hospital. Secondary outcomes included time elapsed before recovery from coma, fever clearance time, parasite clearance time, neurological sequelae, and adverse events.

Included trials were conducted in Cameroon, Gambia, Kenya, Malawi, Nigeria, Sudan, Uganda and Zambia; publication dates ranged from 1996 to 2005. Ages of included patients ranged from 0 to 15 years. Most trials used artemether rather than arteether; most artemether or arteether regimens were 3.2 mg/kg intravenously for the first day, then 1.6mg /kg at regular intervals; quinine regimens were typically 20 mg/kg intravenous loading dose, then 10mg/kg at regular intervals.

The two authors independently assessed studies for inclusion; disagreements were resolved by consensus.

Assessment of study quality

Two authors independently assessed study quality according to the following criteria: allocation sequence generation, allocation concealment, blinding, and analysis (whether intention-to-treat was used).

Data extraction

Data required to calculate relative risks (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences with 95% confidence intervals for continuous data, were extracted by both authors independently. Discrepancies were resolved by consensus.

Methods of synthesis

For dichotomous outcomes, relative risks with 95% confidence intervals, and for continuous outcomes mean differences with 95% confidence intervals, were pooled using separate fixed-effect models. Heterogeneity was assessed using the I2 statistic.

Sensitivity analyses were performed to assess the effect of allocation concealment and the route of administration in the treatment group on reported outcomes.

Publication bias was assessed using a funnel plot.

Results of the review

Nine RCTs were included in the review (n=1,480 children; range 37 to 576). It appeared that seven trials used artemether and two trials used arteether. Three trials reported adequate blinding. Seven trials reported adequate randomisation. Five trials reported adequate allocation concealment. Six trials reported use of intention-to-treat analysis.

Death: No statistically significant differences were found between the artemisinin derivative and quinine groups (RR 0.91, 95% CI 0.73 to 1.14; nine RCTs; I2=0%)

Neurological sequelae at recovery or discharge: No statistically significant differences were found in the risk of neurological sequelae between the artemisinin derivative and quinine groups (RR 0.94, 95% CI 0.75 to 1.17; six RCTs; I2=0%)

Coma recovery time and fever clearance: Overall there was no statistically significant difference between groups for coma recovery time (WMD -2.53 hours, 95% CI -5.58 to 0.52; RCTs; I2=55.3%) or fever clearance time (WMD -2.34 hours, 95% CI -6.97 to 1.28; six RCTs; I2=78.3%). Artemether showed a significantly shorter coma recovery time (WMD -3.50 hours, 95% CI -6.71 to -0.29; four RCTs, I2=54.4%) compared with quinine, while arteether did not.

Sensitivity analyses: The reviewers reported a number of sensitivity analyses; their results were reported as consistent with the main results.

Publication bias: The reviewers reported that the funnel plot was asymmetric, but that this could not be taken to indicate publication bias given the small number of included trials.

Authors' conclusions

Artemisinin derivatives were not inferior to quinine in preventing death in children with cerebral malaria.

CRD commentary

This review addressed a clear review question using appropriate and clearly stated study selection criteria. A range of relevant sources were searched, and language restrictions were not applied, reducing the risk of language bias. The risk of publication bias was assessed, but the results of this assessment may not be reliable due to the small number of trials included. The review process was conducted in duplicate, reducing the risk of reviewer error and bias.

Validity assessment and data extraction seemed appropriate. Sufficient primary study details were reported, increasing review transparency. As all included trials were conducted in Africa, the generalisability of the results to other regions is uncertain. Fixed-effect analyses were used for all outcomes in the synthesis. Statistically significant heterogeneity was identified for coma recovery time and fever clearance times, suggesting that the analysis may not have been appropriate for these outcomes. The authors' conclusion inferred non-inferiority from pooled results, indicating no statistically significant difference between groups. The authors did not define non-inferiority. However, showing no significant difference is not the same as demonstrating that one treatment is at least as good as the other.

Thus, although in most respects the review was well conducted, the validity of this inference and hence the reliability of the authors' conclusion, is uncertain.

Implications of the review for practice and research

The authors did not state any implications for research or practice.

Funding

Not stated.

Bibliographic details

Kyu HH, Fernandez E. Artemisinin derivatives versus quinine for cerebral malaria in African children: a systematic review. Bulletin of the World Health Organization 2009; 87(12): 896-904. [PMC free article: PMC2789363] [PubMed: 20454480]

Indexing Status

Subject indexing assigned by NLM

MeSH

Africa; Anti-Infective Agents /pharmacology /therapeutic use; Antimalarials /pharmacology /therapeutic use; Artemisinins /pharmacology /therapeutic use; Child; Child, Preschool; Clinical Trials as Topic; Female; Humans; Infant; Malaria, Cerebral /drug therapy; Male; Outcome Assessment (Health Care); Quinine /pharmacology /therapeutic use

AccessionNumber

12010000396

Database entry date

23/02/2011

Record Status

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 20454480