Artemether injection for treating people with severe malaria

What is the aim of this review?

Injection of artesunate is recommended by the World Health Organization (WHO) for treating adults and children that have severe malaria as studies have shown that it results in fewer deaths compared to quinine treatment.

Artemether is an alternative artemisinin-based medicine but is only available as a pre-mixed oil-based solution for intramuscular injection. Artemether is now widely available and is used in many African countries, although it is not specifically recommended by the WHO. The aim of this review was to examine the effects of treating people that have severe malaria with artemether injected intramuscularly compared to treatment with other antimalarial medicines given intramuscularly or intravenously.

Key messages

Artemether may not be more effective than quinine at preventing deaths from severe malaria in children. However, in adults artemether is probably more effective than quinine at preventing deaths. With respect to other patient-oriented outcomes such as fever and parasite clearance time, artemether seems to be more effective than quinine in children and adults. For adults, artemether had a large effect on death compared to quinine but other outcomes were largely not reported or showed no significant difference. Artemether has not been compared to artesunate in children. Although there is a paucity of direct evidence comparing artemether with artesunate in adults, artemether probably increases the risk of death compared to artesunate. In settings where artesunate is not available, artemether remains a better alternative to quinine for the treatment of severe malaria.

What was studied in the review?

The review authors examined the available research that evaluated the effects of treating people that have severe malaria with artemether injected intramuscularly compared to treatment with other antimalarial medicines given intramuscularly or intravenously. Nineteen studies looked at the effects of treatment with intramuscular artemether on people with severe malaria compared to treatment with other antimalarial medicines given intramuscularly or intravenously. These studies were undertaken in Africa (12 studies) and Asia (seven studies). This is an update of a 2014 Cochrane Review and includes a new trial from Central African Republic.

What are the main results of the review?

Artemether versus quinine

For children, intramuscular artemether is probably as good as quinine at preventing deaths from severe malaria (moderate-certainty evidence). Artemether may shorten time to coma resolution by about five hours (low-certainty evidence), and may reduce the number of children with signs of brain damage at the time of hospital discharge (low-certainty evidence).

In older children (> 15 years) and adults, treatment with artemether probably results in fewer deaths than quinine (moderate-certainty evidence).

Artemether versus artesunate

In adults, artemether performs worse than artesunate in terms of mortality (moderate-certainty evidence), but no trials have been conducted in young children.

How up to date is this review?

The review authors searched for studies up to 7 September 2018.

Authors' conclusions: 

Artemether appears to be more effective than quinine in children and adults. Artemether compared to artesunate has not been extensively studied, but in adults it appears inferior. These findings are consistent with the WHO recommendations that artesunate is the drug of choice, but artemether is acceptable when artesunate is not available.

Read the full abstract...
Background: 

In 2011 the World Health Organization (WHO) recommended parenteral artesunate in preference to quinine as first-line treatment for people with severe malaria. Prior to this recommendation many countries, particularly in Africa, had begun to use artemether, an alternative artemisinin derivative. This Cochrane Review evaluates intramuscular artemether compared with both quinine and artesunate.

Objectives: 

To assess the efficacy and safety of intramuscular artemether versus any other parenteral medication in the treatment of severe malaria in adults and children.

Search strategy: 

We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library), MEDLINE, Embase, and LILACS, ISI Web of Science, conference proceedings, and reference lists of articles. We also searched the WHO International Clinical Trial Registry Platform, ClinicalTrials.gov, and the metaRegister of Controlled Trials (mRCT) for ongoing trials up to 7 September 2018. We checked the reference lists of all studies identified by the search. We examined references listed in review articles and previously compiled bibliographies to look for eligible studies.

Selection criteria: 

Randomized controlled trials (RCTs) comparing intramuscular artemether with intravenous/intramuscular quinine or artesunate for treating severe malaria.

Data collection and analysis: 

The primary outcome was all-cause death. Two review authors independently screened each article by title and abstract, and examined potentially relevant studies for inclusion using an eligibility form. Two review authors independently extracted data and assessed risk of bias of included studies. We summarized dichotomous outcomes using risk ratios (RRs) and continuous outcomes using mean differences (MDs), and have presented both measures with 95% confidence intervals (CIs). Where appropriate, we combined data in meta-analyses and used the GRADE approach to summarize the certainty of the evidence.

Main results: 

We included 19 RCTs, enrolling 2874 adults and children with severe malaria, carried out in Africa (12 trials) and in Asia (7 trials).

Artemether versus quinine

For children, there is probably little or no difference in the risk of death between intramuscular artemether and quinine (RR 0.97, 95% CI 0.77 to 1.21; 13 trials, 1659 participants, moderate-certainty evidence). Coma resolution time may be about five hours shorter with artemether (MD −5.45, 95% CI −7.90 to −3.00; six trials, 358 participants, low-certainty evidence). Artemether may make little difference to neurological sequelae (RR 0.84, 95% CI 0.66 to 1.07; seven trials, 968 participants, low-certainty evidence). Compared to quinine, artemether probably shortens the parasite clearance time by about nine hours (MD −9.03, 95% CI −11.43 to −6.63; seven trials, 420 participants, moderate-certainty evidence), and may shorten the fever clearance time by about three hours (MD −3.73, 95% CI −6.55 to −0.92; eight trials, 457 participants, low-certainty evidence).

For adults, treatment with intramuscular artemether probably results in fewer deaths than treatment with quinine (RR 0.59, 95% CI 0.42 to 0.83; four trials, 716 participants, moderate-certainty evidence).

Artemether versus artesunate

Artemether and artesunate have not been directly compared in randomized trials in children.

For adults, mortality is probably higher with intramuscular artemether (RR 1.80, 95% CI 1.09 to 2.97; two trials, 494 participants, moderate-certainty evidence).

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