Artemether injection for treating people with severe malaria

In this review, researchers from The Cochrane Collaboration examined the effects of treating people that have severe malaria with artemether injected intramuscularly, and compared it to treatment with other antimalarial drugs given intramuscularly or intravenously. After searching for relevant trials up to 9 April 2014, we included 18 randomized controlled trials that recruited 2662 adults and children and were conducted mainly in Africa and Asia.

What is severe malaria and how might artemether injection reduce deaths

Severe malaria is caused by infection with the Plasmodium parasite, which is transmitted to people through the bite of an infected female Anopheles mosquito. It is a serious medical condition and can cause vomiting, anaemia, convulsions and death. People need to be treated as quickly as possible.

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

What the research says

Artemether versus quinine:

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

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

Artemether versus artesunate:

In adults from Asia, artesunate probably prevents more deaths than artemether (moderate quality evidence), but no trials have been conducted in young children from Africa.

Authors conclusions

Although there is a lack of direct evidence comparing artemether with artesunate, artemether is probably less effective than artesunate at preventing deaths from severe malaria. In circumstances where artesunate is not available, artemether is an alternative to quinine.

Authors' conclusions: 

Although there is a lack of direct evidence comparing artemether with artesunate, artemether is probably less effective than artesunate at preventing deaths from severe malaria. In circumstances where artesunate is not available, artemether is an alternative to quinine.

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 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 treating 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 clinical trial registry platform, ClinicalTrials.gov and the metaRegister of Controlled Trials (mRCT) for ongoing trials up to 9 April 2014.

Selection criteria: 

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

Data collection and analysis: 

The primary outcome was all-cause death.Two authors independently assessed trial eligibility, risk of bias and extracted data. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD), and presented both measures with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses and assessed the quality of the evidence using the GRADE approach.

Main results: 

We included 18 RCTs, enrolling 2662 adults and children with severe malaria, carried out in Africa (11) and in Asia (7).

Artemether versus quinine

For children in Africa, there is probably little or no difference in the risk of death between intramuscular artemether and quinine (RR 0.96, 95% CI 0.76 to 1.20; 12 trials, 1447 participants, moderate quality evidence). Coma recovery may be about five hours shorter with artemether (MD -5.45, 95% CI -7.90 to -3.00; six trials, 358 participants, low quality evidence), and artemether may result in fewer neurological sequelae, but larger trials would be needed to confirm this (RR 0.84, 95% CI 0.66 to 1.07; seven trials, 968 participants, low quality evidence). 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 quality 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 quality evidence).

For adults in Asia, 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 quality evidence).

Artemether versus artesunate

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

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

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