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Artesunate versus quinine for treating severe malaria

  1. David Sinclair1,*,
  2. Sarah Donegan1,
  3. David G Lalloo2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 16 MAR 2011

Assessed as up-to-date: 30 JAN 2011

DOI: 10.1002/14651858.CD005967.pub3


How to Cite

Sinclair D, Donegan S, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD005967. DOI: 10.1002/14651858.CD005967.pub3.

Author Information

  1. 1

    Liverpool School of Tropical Medicine, International Health Group, Liverpool, UK

  2. 2

    Liverpool School of Tropical Medicine, Clinical Research Group, Liverpool, Merseyside, UK

*David Sinclair, International Health Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. davesinkers@yahoo.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 16 MAR 2011

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This is not the most recent version of the article. View current version (13 JUN 2012)

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison.

Artesunate compared with quinine for treating severe malaria

Patient or population: Children with severe malaria

Settings: Malaria endemic areas

Intervention: Artesunate

Comparison: Quinine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

QuinineArtesunate

Death109 per 100083 per 1000
(71 to 98)
RR 0.76
(0.65 to 0.9)
5765
(4 studies1)
high2,3,4,5

Neurological sequelae at day 2811 per 100014 per 1000
(8 to 22)
RR 1.23
(0.74 to 2.03)
4857
(1 study6)
moderate7,8,9,10

Neurological sequelae at discharge28 per 100038 per 1000
(28 to 51)
RR 1.36
(1.01 to 1.83)
5163
(3 studies11)
moderate2,3,4,12

Time to hospital discharge (days)See commentSee commentNot estimable113
(3 studies11)
moderate2,13,4,14

Hypoglycaemia episodes30 per 100019 per 1000
(13 to 26)
RR 0.62
(0.45 to 0.87)
5765
(4 studies1)
high2,3,4,15

*The assumed risk was calculated by dividing the total number of events in the control group (across studies) by the total number of patients in the control group (across studies). This was numerically very similar to the median control group risk but is easier to link with the corresponding forest plot. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk Ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 One large multicentre trial (Dondorp 2010) and two small trials (Cao 1997, Eltahir 2010) have assessed artesunate vs quinine in children aged < 15 years. In addition one large multicentre study included a subgroup of children in this age group (Dondorp 2005)
2 No serious study limitations: All the trials adequately concealed allocation to be considered at low risk of bias. The trials were unblinded but this is unlikely to bias this objective outcome
3 No serious inconsistency: There was no statistical heterogeneity between the trials (I² = 0%).
4 No serious indirectness: Most of the data is from Dondorp 2010 which had centres in Mozambique, the Gambia, Ghana, Kenya, Tanzania, Nigeria, Uganda, Rwanda and the Democratic Republic of Congo, and used the established standard doses of artesunate and quinine (with loading dose). Of note the median age of children in this trial was 2.9 years in the quinine group and 2.8 in the artesunate group.
5 No serious imprecision: Both limits of the 95% CI of the pooled effect imply an appreciable clinical benefit with artesunate. The Number Needed To Treat to prevent one childhood death is 38.
6 Only one large multicentre trial (Dondorp 2010) reports this outcome.
7 Serious study limitations: 41/170 (24%) patients with neurological sequelae at discharge were not available for assessment at day 28.
8 No serious inconsistency: Not applicable as only one trial.
9 No serious indirectness: This trial (Dondorp 2010) had 11 centres throughout Africa and used the standard dosing of artesunate and quinine. The nature of the neurological sequelae is not described.
10 No serious Imprecision: The 95% CI around the absolute effect is narrow. The worst case scenario is a 1.2% increase in neurological sequelae at day 28
11 Three trials (Dondorp 2010, Dondorp 2005 and Cao 1997) report this outcome
12 Serious imprecision: The effect estimate is of a clinically important harm. However the 95% CI includes the possibility of no clinically important difference between the 2 interventions.
13 No serious inconsistency: None of the trials found evidence of an important difference between the two treatment groups
14 Serious imprecision: We were unable to pool the data as they were only reported as medians and range/intra quartile range. There is no evidence of a clinically important benefit with artesunate on this outcome.
15 No serious imprecision: The result is statistically significant in favour of artesunate. The current sample size is adequately powered to detect a 40% risk reduction with 80% power and 95% confidence.

 Summary of findings 2

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

Malaria is a febrile illness caused by infection with the Plasmodium parasite, which is transmitted from person to person by mosquitos. Five species of plasmodium are known to cause disease in humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P knowlesi (WHO 2010). P. falciparum is the most common malaria parasite worldwide, and is responsible for almost all of the severe disease and deaths (WHO 2000; WHO 2008).

Repeated exposure to malaria infection over 5 to 10 years can produce a naturally acquired immunity in humans, which is protective against the most severe forms of the disease (Doolan 2009). Consequently, in high transmission settings as seen in large parts of Africa, young children are most at risk prior to the acquisition of effective immunity, whereas in low transmission settings, or in travellers from non-endemic areas, adults are often equally vulnerable to severe disease (WHO 2000).

Severe malaria is diagnosed on the basis of a positive blood slide or antigen test for malaria, plus the presence of clinical or laboratory markers which indicate vital organ dysfunction. These markers include impaired consciousness, coma, convulsions, respiratory distress, shock (systolic blood pressure < 70 mmHg in adults, < 50 mmHg in children), jaundice, haemoglobinuria, or severe acidosis or anaemia (WHO 2010). Cerebral malaria is a specific type of severe malaria characterised by an unrousable coma. Even with correct treatment cerebral malaria can have a mortality rate approaching 20%, and persistent neurological sequelae are seen in a small proportion of survivors (Jaffar 1997).

The standard treatment for severe malaria has been an intravenous infusion or intramuscular injection of quinine (WHO 2000). A loading dose of 20 mg/kg is recommended to reduce the time needed to reach effective concentrations in the blood, with subsequent dosing at 10 mg/kg at eight hourly intervals (White 1983b; van Der Torn 1996). A Cochrane Review found a significant reduction in fever clearance time and parasite clearance time with a loading dose compared with no loading dose but concluded that data were insufficient to demonstrate an impact on mortality (Lesi 2004).

Adverse effects resulting from quinine therapy are common. Cinchonism (symptoms of quinine overdose) often occurs with conventional dose regimens. This usually mild and reversible symptom complex consists of tinnitus, deafness, dizziness, and vomiting, and may affect adherence (Alkadi 2007). Hypoglycaemia is a less common but more serious adverse effect (White 1983). Toxic levels of quinine can occur following rapid intravenous administration and can result in heart rhythm disturbances, blindness, coma, and even death (Alkadi 2007).

In addition, there is limited evidence that the efficacy of quinine in severe malaria may be declining in some parts of South-East Asia (Wongsrichanalai 2002).

 

Description of the intervention

Artesunate is one of a number of antimalarials derived from artemisinin, the active ingredient in a Chinese herbal remedy for fever Artemesia annua. The artemisinin derivatives are now the recommended treatment for uncomplicated (less severe) malaria, when they are given orally in combination with a partner drug, as Artemisinin-based Combination Therapy (ACT), to delay or prevent the development of artemisinin resistance (WHO 2010).

The artemisinin derivatives are generally regarded as safe in humans (Ribeiro 1998; Alkadi 2007; Nosten 2007). Animal studies using very high doses of artemisinins have demonstrated focal brain stem lesions particularly affecting the auditory pathways (Brewer 1994; Nontprasert 1998; Genovese 2000; Nontprasert 2000; Nontprasert 2002), but studies of brain stem function in humans, including audiometry, have failed to show any abnormality following repeated courses (Ribeiro 1998; Kissinger 2000). To date, only one nested case-control study has demonstrated a significant audiometric hearing loss in factory workers treated with artemether-lumefantrine for uncomplicated malaria compared with workers with no history of exposure to malaria infection or artemether-lumefantrine (Toovey 2004). This result needs to be interpreted with caution due to a number of design limitations.

 

How the intervention might work

Deaths from severe malaria often occur during the first 24 to 48 hours following hospital admission. Consequently, to be effective antimalarial drugs need to achieve rapid therapeutic blood concentrations following administration.

Compared to quinine, the artemisinin derivatives have been shown to clear malaria parasites from the blood faster, and to have a broader spectrum af activity (ter Kuile 1993; Adjuik 2004). Importantly they are effective against young ring forms of the parasite before they sequester in the microcirculation of vital organs, a major pathophysiological step in the development of severe disease (ter Kuile 1993; WHO 2000).

Artesunate is the most studied artemisinin-derivative for the treatment of severe malaria and may be given by intramuscular or intravenous injection. It has been shown to reliably reach peak concentrations within one hour of administration (Nealon 2002; Hien 2004).

Of the alternatives, artemether and arteether are available as oil-based, intramuscular formulations. Artemether is prone to erratic and partial absorption (Karbwang 1997; Murphy 1997; Mithwani 2003), and arteether to low peak concentrations and slow absorption (Looareesuwan 2002; Li 2004). Systematic reviews of artemether and arteether compared to quinine have so far failed to show a reduction in mortality compared to quinine therapy, although the data are limited (AQMSG 2001; Afolabi 2004; Kyu 2009).

 

Why it is important to do this review

A Cochrane Review prepared in year 2000 assessed the effects of the artemisinin derivatives, including artesunate, for treating severe malaria (McIntosh 2000). This review has since been superseded by a series of Cochrane Reviews examining the different artemisinin derivatives.

This review was first published in 2006 and demonstrated the superiority of artesunate for treating adults in Asia, but found insufficient data to make firm conclusions in children. This update includes two additional, recently completed trials, focusing on artesunate versus quinine in African children.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To compare artesunate with quinine for treating severe malaria.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized controlled trials.

 

Types of participants

Adults and children with severe malaria who are unable to take medication by mouth.

 

Types of interventions

 

Intervention

  • Intravenous, intramuscular or rectal artesunate.

 

Control

  • Intravenous or intramuscular quinine.

 

Types of outcome measures

 

Primary outcomes

  • Death.

 

Secondary outcomes

  • Neurological sequelae.
  • Coma recovery time.
  • Time to hospital discharge.
  • Fever clearance time.
  • Parasite clearance time.

 
Adverse effects

  • Serious adverse effects resulting in discontinuation of treatment (eg biochemical abnormalities, cardiac effects).
  • Hypoglycaemia (symptomatic or asymptomatic).
  • Other adverse events, including tinnitus, hearing impairment, nausea, and vomiting.

 

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and ongoing).

 

Electronic searches

 

Databases

We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; and ISI Web of Science. We also searched the metaRegister of Controlled trials (mRCT) using artesunate and quinine as search terms.

 

Searching other resources

 

Conference proceedings

We searched the following conference proceedings for relevant abstracts: The 5th Multilateral Initiative on Malaria (MIM) Pan-African malaria Conference, 2 to 6 November 2009, Nairobi, Kenya; the 4th MIM Pan-African Malaria Conference, 13 to 18 November 2005, Yaounde, Cameroon; the 4th European Congress on Tropical Medicine, 11 to 15 September 2005, Marseille, France; ACT NOW; the International Symposium on Malaria, 29 to 30 April 2004, Colombia, New York, USA; the 2nd International Malaria Research Conference, John Hopkins Malaria Research Institute, 25 to 26 March 2004, Maryland, USA; the 3rd MIM Pan-African Conference, 18 to 22 November 2002, Arusha, Tanzania; and the 3rd European Congress on Tropical Medicine and International Health, 8 to 12 September 2002, Lisbon, Portugal.

 

Researchers, organizations, and pharmaceutical companies

We contacted individual researchers working in the field and the World Health Organization (WHO) for details of unpublished and ongoing trials.

 

Reference lists

We checked the reference lists of existing reviews and of all trials identified by the above methods.

 

Data collection and analysis

 

Selection of studies

All trials identified by the search strategy were screened by two authors working independently (Katharine Jones (KJ), Sarah Donegan (SD) or David Sinclair (DS)) and full reports of potentially relevant trials were obtained. Two authors independently applied the inclusion criteria to the full reports using an eligibility form and scrutinized publications to ensure each trial was included in the review only once. Trial authors were contacted for clarification if necessary. Disagreement was resolved by discussion with David Lalloo (DL).

 

Data extraction and management

Two authors independently extracted data using a data extraction form. For each outcome we aimed to extract the number of participants randomised and the number analysed in each treatment group. For dichotomous outcomes, we recorded the number of participants experiencing the event and the number assessed in each treatment group. For continuous outcomes, we extracted arithmetic means and standard deviations for each treatment group, together with the numbers assessed in each group. Where medians were used we also extracted the range or intra-quartile range.

 

Assessment of risk of bias in included studies

DS and SD independently assessed the risk of bias for each trial using 'The Cochrane Collaboration's tool for assessing the risk of bias' (Higgins 2008). We followed the guidance to assess whether adequate steps had been taken to reduce the risk of bias across six domains: sequence generation; allocation concealment; blinding (of participants, personnel, and outcome assessors); incomplete outcome data; selective outcome reporting; and other sources of bias. We have categorized these judgments as 'yes' (low risk of bias), 'no' (high risk of bias), or 'unclear'. Where our judgement is unclear we attempted to contact the trial authors for clarification.

This information was used to guide the interpretation of the data that are presented.

 

Measures of treatment effect

Results were calculated using risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data. These effect estimates are presented with 95% confidence intervals (CI).

 

Dealing with missing data

If there was discrepancy between the number randomized and the number analysed, we calculated the percentage loss to follow up for each treatment group and reported this information.

Originally, we aimed to analyse data according to the intention-to-treat principle (all randomized participants should be analysed in the groups to which they were originally assigned). However, since for some trials it was unclear whether there was loss to follow up, we entered the number analysed into Review Manager 5 whenever these figures were available. By attempting to carry out a complete-case analysis in this way, we have tried to avoid making assumptions about the outcomes of participants that were lost to follow up.

 

Assessment of heterogeneity

We looked for statistical heterogeneity by inspecting the forest plots for overlapping confidence intervals, applying the Chi2 test (P value < 0.10 considered statistically significant), and the I2 statistic (I2 value of 50% used to denote moderate levels of heterogeneity).

 

Assessment of reporting biases

We planned to construct funnel plots to look for evidence of publication bias, provided there were sufficient included trials to make this informative.

 

Data synthesis

We analysed the data using Review Manager 5, and where possible and appropriate we combined studies using a fixed effect model. If heterogeneity was detected but it was still considered clinically meaningful to combine studies, a random-effects model was used. Medians and ranges are only reported in tables.

If arithmetic means were reported, normality of the data was checked by calculating the ratio of the mean over the standard deviation (Altman 1996). If this test suggested the data were skewed (ie if the ratio was less than two), we commented on this in the text but still combined the results in a meta-analysis.

 

Subgroup analysis and investigation of heterogeneity

We planned to investigate heterogeneity by conducting pre-specified sub-group analyses for the primary outcome. The potential sources of heterogeneity were allocation concealment, blinding, participant age (children versus adults), and drug regimen (loading dose versus no loading dose of quinine and use of any additional antimalarials).

 

Sensitivity analysis

Post hoc, we conducted a sensitivity analysis to investigate the robustness of the results to differences in trial design, by subgrouping the trials according to allocation concealment, participant age (children versus adults), type of severe malaria (cerebral versus non-cerebral malaria), geographical region, drug regimen (loading dose versus no loading dose of quinine, and use of any additional antimalarials), route of administration (intravenous versus intramuscular route), and time since admission to hospital.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

 

Results of the search

The original search was conducted in November 2005 and identified 22 references of which four were duplicate trial reports. Six unique trials fulfilled the eligibility criteria and were included in the first version of this review.

An update search conducted in November 2010 identified a further six trials of which two were eligible and these are now included.

 

Included studies

The eight trials that met our inclusion criteria enrolled a total of 7429 participants (1664 adults and 5765 children).

 

Location

SIx trials were conducted in Asia; four took place in single centres in Vietnam (Anh 1989; Anh 1995; Cao 1997; Hien 1992), Newton 2003 had two centres in Thailand; and Dondorp 2005 had 11 centres throughout Bangladesh, Myanmar, India, and Indonesia. Of the two African studies; Eltahir 2010 was conducted at a single study site in Sudan, and Dondorp 2010 had 11 centres in nine African countries (Mozambique, The Gambia, Ghana, Kenya, Tanzania, Nigeria, Uganda, Rwanda, and the Democratic Republic of the Congo).

 

Source of funding

Four trials were funded by a medical research charity (Cao 1997; Dondorp 2005; Dondorp 2010; Newton 2003), one by the WHO (Anh 1995), one by a private sugar company (Eltahir 2010), and one received the study drugs from a pharmaceutical company (Anh 1989). Funding was not specified for Hien 1992.

 

Participants

Four trials enrolled only adults (Anh 1989; Anh 1995; Hien 1992; Newton 2003), of which three included only those with a diagnosis of cerebral malaria (Anh 1989, Anh 1995, Hien 1992). Three trials enrolled only children aged less than 15 years (Cao 1997; Dondorp 2010; Eltahir 2010), and one enrolled both adults and children (Dondorp 2005).

Dondorp 2005 and Dondorp 2010 used rapid diagnostic tests to confirm P. falciparum parasitaemia, and all the other trials used standard microscopy. Although standardized clinical definitions for severe malaria exist, the entry criteria were not consistent across trials.

 

Interventions

All trials compared artesunate with quinine, but the exact dosing and route of administration varied between trials.

Three trials (Dondorp 2005; Dondorp 2010; Eltahir 2010) administered both artesunate and quinine using the current recommended dosing schedules (artesunate: 2·4 mg/kg (intravenous or intramuscular) on admission, at 12 hours, at 24 hours, and then once daily until starting oral therapy, quinine: 20 mg/kg intravenous or intramuscular loading dose, then 10 mg/kg every 8 hours until starting oral therapy).

Anh 1989, Anh 1995, and Hien 1992 gave 60 mg artesunate intravenously at admission, 4 hours, 24 hours and 48 hours. Cao 1997 gave 3 mg/kg intramuscular on admission then 2 mg/kg intramuscular at 12, 24, 48, and 72 hours, and Newton 2003 gave 2.4 mg/kg intravenously on admission, 1.2 mg/kg at 12 hours, and then 1.2 mg/kg every 24 hours until able to swallow. Two trials did not give the loading dose of quinine (Anh 1995; Hien 1992).

In addition six trials gave an additional oral antimalarial to at least one of the treatment arms, which was unmatched between the treatment arms (Anh 1989; Anh 1995; Cao 1997; Eltahir 2010; Hien 1992; Newton 2003). Two trials, Hien 1992 and Cao 1997, included an additional rectal artemisinin arm that was not pertinent to this review.

 

Supportive care

All eight trials reported measuring blood glucose on admission, but only five trials reported any subsequent active monitoring for hypoglycaemia. Newton 2003 tested all participants several times a day, Cao 1997 tested all participants with coma, prostration, jaundice or more than one complication every four hours for the first 24 hours and then every six hours, Anh 1989 tested all participants on days 1, 3, 7, and 14, and Eltahir 2010 tested all participants every six hours. Dondorp 2005 only measured blood glucose in those participants with clinical signs of hypoglycaemia.

 

Outcome measures (defined in Appendix 2)

All eight trials reported death as an outcome

Three trials reported neurological sequelae at discharge (Cao 1997; Dondorp 2005; Dondorp 2010). Six trials reported coma recovery time (Anh 1989; Hien 1992; Anh 1995; Cao 1997; Newton 2003; Eltahir 2010), and two trials reported time to eat, sit, and speak (Dondorp 2005; Dondorp 2010).

Five trials reported fever clearance time (Hien 1992; Anh 1995; Cao 1997; Newton 2003; Eltahir 2010). Reporting of parasite clearance time varied between trials and included parasite clearance times of 50%, 90%, 95%, and 100%, of which parasite clearance time of 50% was the most common (Anh 1989; Hien 1992; Anh 1995; Cao 1997; Newton 2003).

Four trials reported time to hospital discharge (Cao 1997; Newton 2003; Dondorp 2005; Dondorp 2010), and four trials reported adverse effects including hypoglycaemia (Cao 1997; Newton 2003; Dondorp 2005; Dondorp 2010).

 

Length of follow up

Cao 1997 specified that participants were asked to return for a follow up visit three weeks after discharge from hospital, and Dondorp 2010 followed those with neurological sequelae for 28 days. None of the other trials reported the length of follow up.

 

Excluded studies

Sixteen trials detected by the search specifications were excluded from the review (see 'Characteristics of excluded studies').

 

Risk of bias in included studies

See Figure 1 for a summary of the risk of bias assessments. Further details are presented in the 'Characteristics of included studies' tables.

 FigureFigure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

The generation of the allocation sequence was adequate in all eight trials and allocation concealment was adequate in six trials with only Anh 1989 and Newton 2003 using open randomization.

 

Blinding

In all eight trials, investigators were aware of treatment allocation. Participants were blind to the intervention in Hien 1992, and microscopists and data analysts were blind to the intervention in Dondorp 2005 and Dondorp 2010.

 

Incomplete outcome data

Newton 2003, Dondorp 2005 and Dondorp 2010 clearly state that no participants were lost to follow up. We were able to obtain individual patient data for one trial in which primary outcomes were available for all included participants (Cao 1997). For the remaining trials the number of participants randomised was used as the denominator in the analysis (Anh 1989; Hien 1992; Anh 1995; Eltahir 2010). As these were inpatient trials significant attrition is unlikely.

 

Selective reporting

No evidence of selective outcome reporting was detected.

 

Other potential sources of bias

No other sources of bias were identified.

 

Effects of interventions

See:  Summary of findings for the main comparison;  Summary of findings 2

 

Death

Treatment with artesunate significantly reduced the risk of death both in adults (RR 0.61, 95% CI 0.50 to 0.75; 1664 participants, five trials,  Analysis 1.1, Figure 2) and children (RR 0.76, 95% CI 0.65 to 0.90; 5765 participants, four trials,  Analysis 1.1, Figure 2). This reduction was consistent across all trials regardless of participant age or geographic region (I2 test for statistical heterogeneity = 0%,  Analysis 1.1).

 FigureFigure 2. Forest plot of comparison: 1 Artesunate vs quinine, outcome: 1.1 Death: participant age [Relative effect].

Mortality was lower in the trials recruiting children and consequently the absolute reduction in mortality is lower than that seen in adults (Absolute risk reduction: Adults: 94 fewer deaths per 1,000 patients, 95% CI 60 fewer to 120 fewer, Children: 26 fewer deaths per 1,000 patients, 95% CI 11 fewer to 38 fewer, see  Summary of findings 2 and  Summary of findings for the main comparison). This age effect is confounded by region, with the majority of the data in children coming from Africa (where the trial mortality was relatively low), and all the data in adults coming from Asia (where the trial mortality was higher).

Three trials report a subgroup analyses of deaths occurring within the first 48 hours following admission (Cao 1997; Dondorp 2005; Newton 2003) and one trial reports the number of deaths occurring within the first 24 hours (Dondorp 2010). Although the difference between groups did not reach statistical significance during these early time periods there were consistently fewer deaths in the groups treated with artesunate (6163 participants, four trials,  Analysis 1.2).

In view of the significant variation in trial design we conducted sensitivity analyses excluding trials with inadequate allocation concealment, trials only included patients with cerebral malaria, and those with no loading dose of quinine, but these did not alter the significance of the result.

The two large multicentre trials (Dondorp 2005; Dondorp 2010) conducted multiple subgroup analyses according to the presence or absence of coma, anaemia, shock, acidosis, respiratory distress, or hyperparasitaemia at the time of admission. Mortality was consistently lower with artesunate in all of these subgroups but some were underpowered to show statistically significant differences.

Artesunate appears superior to quinine irrespective of intramuscular or intravenous administration ( Analysis 1.3).

 

Neurological sequelae

At the time of hospital discharge, neurological sequelae were more common in those treated with artesunate than with quinine (RR 1.41, 95% CI 1.05 to 1.88; 6422 participants, three trials,  Analysis 1.4, Figure 3). Of these three trials, only Dondorp 2005 included adults, and the incidence of neurological sequelae seems to be very low in this group ( Analysis 1.4, Figure 3).

 FigureFigure 3. Forest plot of comparison: 1 Artesunate vs quinine, outcome: 1.9 Neurological sequelae at discharge.

One trial in children (Dondorp 2010) followed participants up until day 28 to see if these sequelae resolved. Of the 170 children with sequelae at the time of discharge, 129 (75.9%) were available for assessment on day 28, and 68 of these (52.7%) had fully recovered. At this time point the difference between groups was not statistically significant (RR 1.23, 95% CI 0.74 to 2.03; 4857 participants, one trial,  Analysis 1.5).

 

Coma recovery time

Six trials report a measure of coma recovery time (Anh 1989; Anh 1995; Cao 1997; Eltahir 2010; Hien 1992; Newton 2003). The frequency of clinical monitoring to assess coma recovery varied between these trials and is likely to have influenced the result (see Appendix 2).

Three trials reported mean coma recovery time but the data from Eltahir 2010 were incompletely reported. There is no evidence of a difference between the groups, the data are skewed and the results inconsistent (231 participants, two trials,  Analysis 1.6). Three trials reported median coma recovery time and again the results were inconsistent and no conclusions can be made (see Appendix 3).

In addition the two large multicentre trials (Dondorp 2005; Dondorp 2010) report median time to speak, and Dondorp 2010 reports median time to localise pain (see Appendix 3). Dondorp 2010 found the time to speak and localise pain to be slightly prolonged in those treated with artesunate but the clinical significance of this is unclear (Appendix 3).

 

Time to hospital discharge

Three trials reported this outcome as a median (Cao 1997; Dondorp 2005, Dondorp 2010). The results were consistent and showed no evidence of a difference between the groups (see Appendix 3). One trial reported this outcome as a mean (Newton 2003) with no evidence of a difference between the groups, but the data appeared skewed (113 participants, one trial,  Analysis 1.7).

 

Fever clearance time

Three trials reported this outcome as a mean (Hien 1992; Anh 1995; Eltahir 2010). There is no evidence of a difference between the groups, although the data appeared to be skewed (317 participants, three trials,  Analysis 1.8). Two trials reported this outcome as a median (Cao 1997; Newton 2003), and found no statistically significant difference between groups (see Appendix 3). The frequency with which fever was monitored differed between the trials (see Appendix 2).

 

Parasite clearance time

Five trials report a measure of mean parasite clearance time.

Artesunate appears superior to quinine at reducing the mean 50% PCT (MD -8.14 hrs, 95% CI -11.55 to -4.73; 292 participants, three trials,  Analysis 1.9), mean 90% PCT (MD -18.50 hrs, 95% CI -24.13 to -12.87; 61 patients; one trial,  Analysis 1.9), mean 95% PCT (MD -10.69 hrs, 95% CI -20.27 to -1.10, 231 patients; two trials;  Analysis 1.9), and mean 100% PCT (MD -9.77h 95% CI -18.11 to -1.44, 419 patients; four trials;  Analysis 1.9).

Two additional trials (Newton 2003; Cao 1997) reported median 50% and 90% parasite clearance times (see Appendix 3).

The frequency with which trials repeated malaria blood films differed between the trials (see Appendix 2).

 

Adverse effects

No trial reported discontinuation of medication. With the exception of hypoglycaemia and tinnitus, all adverse effects reported could be attributable to malaria. Artesunate was associated with a statistically significant reduction in episodes of hypoglycaemia (RR 0.55, 95% 0.41 to 0.74; 7137 participants, 4 trials,  Analysis 1.10, Figure 4).

 FigureFigure 4. Forest plot of comparison: 1 Artesunate vs quinine, outcome: 1.15 Hypoglycaemia episodes: by age of participants.

Additional comments on adverse events taken from the original trial reports are given in Appendix 4.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

 

Potential benefits of treating severe malaria with artesunate instead of quinine

Treating severe malaria with artesunate instead of quinine reduces the risk of death by 39% in adults (95% CI 25% to 50%), and 24% in children (95% CI 10% to 35%).

Artesunate also reduces episodes of hypoglycaemia during treatment by 45% (95% CI 26% to 59%).

 

Potential harms of treating severe malaria with artesunate instead of quinine

In adults neurological sequelae following treatment for severe malaria appears to be very low (< 1 %) and no difference has been shown between artesunate and quinine.

In children, treatment with artesunate appears to increase the incidence of neurological sequelae at the time of hospital discharge but the majority of these sequelae seem to resolve with time, and there is no evidence of a difference between the two treatments 28 days later.

 

Overall completeness and applicability of evidence

This review includes trials from multiple countries within Africa and Asia where malaria is most prevalent. Although there are no trials from South America it would be reasonable to generalise these findings to all geographic regions.

There is now adequate evidence to be confident of the results in both adults and children. However, it should be noted that these trials did not include a significant number of pregnant women.

Based on this trial data the absolute benefit in children appears lower than that seen in adults, primarily due to the lower mortality seen in children. This observation may be related to regional differences rather than participant age as the majority of child data is from Africa, and all the adult data is from Asia. Potential reasons for the lower risk of mortality seen in children in Dondorp 2010 include: inclusion of 'less severe' malaria, increased efficacy of quinine in Africa or true differences in the risk of death related to acquisition of partial immunity in Africa.

 

Quality of the evidence

Although several of the smaller trials suffer from methodological problems such as open randomization, unmatched additional oral antimalarials, or non-standard dosing, these do not affect the overall quality of the evidence as the majority of the data is from large multicentre trials which do not suffer the same problems.

We consider the evidence for a reduction in mortality with artesunate to be high quality, and further research to establish this is unnecessary (see  Summary of findings for the main comparison and  Summary of findings 2).

The increase in neurological sequelae is of a smaller magnitude than the reduction in deaths and seems to be temporary. The balance of benefits and harms is in favour of benefit with artesunate.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

Intravenous artesunate should be the treatment of choice for adults and children presenting with severe malaria in any geographical region.

 
Implications for research

Further research to examine the efficacy of artesunate versus quinine in children and adults is unnecessary. The safety of artesunate in pregnancy still needs to be determined, and trials are underway to examine the effects of artesunate when given repeatedly for multiple episodes of malaria. Toxicity from repeated dosing can not be ruled out on the basis of the evidence included in this review. Particular attention should be paid to the incidence of neurological sequelae.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Advice and support were provided by Prof Paul Garner, Manager of the Effective Health Care Research Programme Consortium (Effective Health Care RPC) at the Liverpool School of Tropical Medicine. This protocol was developed during a contract with the Effective Health Care RPC, which is funded by the UK Department for International Development (DFID). The authors would like to thank Dr Katharine Jones, first author on the original review, for her contributions to this point; Dr Jones stood down as an author at this update.

This document is an output from a project funded by the DFID for the benefit of developing countries. The views expressed are not necessarily those of DFID.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. Artesunate vs quinine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death: participant age87429Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.62, 0.80]

    1.1 Adults (Age > 15/16 years)
51664Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.50, 0.75]

    1.2 Children (Age < 15 years)
45765Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.65, 0.90]

 2 Death: time since admission to hospital [sensitivity analysis]4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Death within 24 hours
15417Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.69, 1.04]

    2.2 Death after 24 hours
15072Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.48, 0.88]

    2.3 Death within 48 hours
31646Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.57, 1.05]

    2.4 Death after 48 hours
31646Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.38, 0.74]

 3 Death: intravenous vs intramuscular artesunate [sensitivity analysis]87429Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.63, 0.80]

    3.1 Intravenous artesunate
75435Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.60, 0.80]

    3.2 Intramuscular artesunate
21994Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.60, 0.98]

 4 Neurological sequelae at discharge36422Risk Ratio (M-H, Fixed, 95% CI)1.41 [1.05, 1.88]

    4.1 Adults (age > 15/16 years)
11259Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.60, 14.64]

    4.2 Children (Age < 15 years)
35163Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.01, 1.83]

 5 Neurological sequelae at day 2814857Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.74, 2.03]

   5.1 Adults (Age > 15/16 years)
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 Children (Age < 15 years)
14857Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.74, 2.03]

 6 Coma recovery time (hours)2231Mean Difference (IV, Random, 95% CI)2.11 [-19.17, 23.40]

 7 Time to hospital discharge (days)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 8 Fever clearance time (hours)3317Mean Difference (IV, Random, 95% CI)-2.74 [-14.07, 8.60]

 9 Parasite clearance time (hours)5Mean Difference (IV, Random, 95% CI)Subtotals only

    9.1 Time to clear 50% of parasites
3292Mean Difference (IV, Random, 95% CI)-8.14 [-11.55, -4.73]

    9.2 Time to clear 90% of parasites
161Mean Difference (IV, Random, 95% CI)-18.5 [-24.13, -12.87]

    9.3 Time to clear 95% of parasites
2231Mean Difference (IV, Random, 95% CI)-10.69 [-20.27, -1.10]

    9.4 Time to clear all parasites
4419Mean Difference (IV, Random, 95% CI)-9.77 [-18.11, -1.44]

 10 Hypoglycaemia episodes: by age of participants57137Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.41, 0.74]

    10.1 Adults (> 15/16 years)
21372Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.19, 0.68]

    10.2 Children (Age < 15 years)
45765Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.45, 0.87]

 11 Hypoglycaemia episodes: by method of monitoring57137Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.41, 0.74]

    11.1 Routine monitoring
3251Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.25, 0.85]

    11.2 Clinical monitoring
11461Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.13, 0.79]

    11.3 Unclear
15425Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.45, 0.92]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Search methods: detailed search strategies


Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSbISI Web of Science

1malariamalariamalariamalariamalariamalaria

2quininequininequininequininequininequinine

3artesunatequinimaxquinimaxquinimaxartesunateartesunate

4artemisinin*CINCHONA ALKALOIDSCINCHONA ALKALOIDSCINCHONA-ALKALOIDartemisininarsumax

53 or 42 or 3 or 42 or 3 or 42 or 3 or 43 or 43 or 4

61 and 2 and 5artesunateartesunateartesunate1 and 2 and 51 and 2 and 5

7arsumaxarsumaxarsumax

86 or 76 or 76 or 7

91 and 5 and 81 and 5 and 81 and 5 and 8

10limit 9 to humanlimit 9 to human



aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2008); upper case: MeSH or EMTREE heading; lower case: free text term.

 

Appendix 2. Definitions of outcome measures used in the review


TrialDeathNeurological sequelae at dischargeComa recovery timeTime to dischargeFever clearance timeParasite clearance timeHypoglycaemiaAdverse effects

Anh 1989DeathNot reportedMean value (h) reported but not definedNot reportedNot reportedMean value (h) reported but not defined. Parasite counts every 8 h until 2 consecutive slides were negative and then every 24 hNot reportedNot reported

Anh 1995DeathNot reportedMean value (h). Defined as time until consciousness regained. Glasgow Coma Scale measured every 12 h until regained consciousnessNot reportedMean value (h) reported but not defined. Axillary temperature was recorded every 6 h until 4 consecutive temperatures were < 37.5 °CMean value (h) reported but not defined. Parasite count measured every 6 h until 3 consecutive blood smears were negativeNot reportedNot reported

Cao 1997DeathNumber survived with neurological sequelae. Case definition for neurological sequelae: abnormal neurological signs and/or symptoms at time of discharge from hospital that were not present before onset of the episode of malaria as reported by the child's parents. All children had a full neurological examination on admission and at discharge from hospital (personal communication from author)Median value (h) reported. Defined as time (h) for Blantyre Coma Score to become 5/5. Coma score assessed every 4 h (or more frequently if critically ill) for the first 24 h, and then every 6 h until dischargeMedian value (d) reportedMedian value (h) reported. Defined as time until temperature first dropped to 37.5 °C or below and remained below this level for at least 24 h. Axillary temperature measured every 4 h (or more frequently if critically ill) for the first 24 h, and then every 6 h until dischargeMedian value (h) reported but not defined. Parasite count measured every 4 h (or more frequently if critically ill) for the first 24 h, and then every 6 h until discharge. Once 2 successive peripheral blood films had revealed no P. falciparum, no further blood film was made unless indicated clinicallyBlood glucose < 2.2 mmol/L. Blood glucose measured every 4 h for first 24 h and then every 6 h until discharge from hospital if indicated (coma, prostration, jaundice, or > 1 complication - personal communication from author)Acute renal failure requiring dialysis, shock, convulsions, deterioration of coma score, gastrointestinal bleeding, anaemia requiring blood transfusion, chest infection, urinary tract infection, other infections, derangement of biochemical markers

Dondorp 2005DeathNeurological sequelae at discharge from hospitalNot reportedMedian value (d) reportedNot reportedNot reportedBlood glucose < 2.2 mmol/L. Blood glucose checked in all patients on admission and then monitored on clinical indicationNot reported

Dondorp 2010DeathSevere neurological complications (initially assessed at discharge from hospital but the protocol was changed after 11% of patients had been enrolled, so that children who had not fully recovered at discharge were assessed 28 days after enrollment).Not reportedMedian value (d) reportedNot reportedNot reportedNot reportedNot reported

Eltahir 2010DeathNot reportedMean value measured from administration of first antimalarial until the Glasgow coma score reached 15. Vital signs and coma scale were monitored every 15 mins for the first hour, then every 2 hours until 24 ours then every 6 hours.Not reportedMean value measured from administration of first antimalarial until the axillary temp first dropped below 37.5 and remained below for 24 hoursMean value measured from administration of the first antimalarial until the first of two sequential negative blood films. Blood films were taken every 4 hours.Blood glucose levels were measured every 6 hours.Not reported

Hien 1992DeathNot reportedMean, median, and mode values reported in hours. Defined as time to regain full consciousness (Glasgow Coma Scale of 15/15). Glasgow Coma Scale measured at 3-h intervals until full recovery of consciousness, and at 6-h intervals thereafterNot reportedMean value (h) reported. Defined as time (h) until "fever clearance". The axillary temperature was measured at 3-h intervals until "fever clearance", and at 6-h intervals thereafterMean value (h) reported but not defined. Parasite counts performed every 4 h for 12 h, then every 6 h until 3 consecutive films were negativeNot reportedNone reported

Newton 2003DeathNot reportedMedian value (h) reported. Defined as time to reach a Glasgow Coma Scale of 15 in those participants with a score < 11/15 on admission. Glasgow Coma Scale measured every 15 min for first h, at 2 h, and then every 2 h until 12 h, every 4 h from 12 to 24 h, and every 6 h from 24 h until the score reached 15Not reportedMedian value (h) reported. Defined as time until the axillary temperature first dropped below 37.5 °C and remained below that level for 24 h. Axillary temperature measured every 15 min for the first h, at 2 h, and then every 2 h until 12 h, every 4 h from 12 to 24 h, and every 6 h from 24 h until fever clearedMedian value (h) reported. Defined as time to a 50% reduction in parasite density. Parasite counts were measured at 0, 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 h, and then every 6 h until 6 h after parasite clearancePlasma glucose less than or equal to 2.2 mmol/L. Plasma glucose measured at 0, 4, 8, 12, 16, 20, and 24 h and then every 6 hSeizures, bleeding and sepsis after admission, pulmonary oedema, oliguria, time in intensive care unit



 

Appendix 3. Time-to-event data: medians, ranges, and modes


OutcomeTrialArtesunateQuinineComparative results reported in article

Coma recovery time (h): median (range), numberHien 199235 (5 to 453); mode = 17; mean = 68.948 (7 to 144), mode = 43; mean = 58.1'Not significantly different'.

Cao 199742 (4 to 228), n = 1031 (4 to 66), n = 2-

Newton 200317 (1 to 125), n = 1618 (1 to 188), n = 16'P = 0.6'

Eltahir 2010mean = 8.1 (SD not given), n = 4mean = 9.1, (SD not given), n = 5'P=0.4'

Time to localise pain (h): median (IQR), numberDondorp 201012 (6 to 24), n = 69812 (6 to 24), n = 726'Hazard Ratio 0·87 (0·78–0·98), P = 0.0093'

Time to speak (h/days): median (IQR), numberDondorp 20051 day (0.2 to 0.35), n = 7301 day (0.2 to 0.21), n = 731'P = 0.73'

Dondorp 201020 hrs (8 to 42), n = 66418 hrs (11 to 36), n = 695'Hazard Ratio 0·88 (0·79–0·99), P = 0.016'

Time to hospital discharge (d): median (range/IQR), numberCao 19978 (5 to 20), n = 338 (5 to 24), n = 29'P = 0.99'

Dondorp 20055 (0 to 54), n = 6235 (0 to 45), n = 567'P = 0.20'

Dondorp 20103 (IQR 2 to 5), n = 24783 (IQR 2 to 5) n = 2412'P = 0.059'

Fever clearance time (until first below 37.5 °C) (h): median (range), numberCao 19974 (4 to 198), n = 358 (0 to 96), n = 35'P = 0.17'

Newton 200311 (1 to 83), n = 4213 (1 to 184), n = 42'P = 0.2'

Fever clearance time (until remains below 37.5 °C for 24 h) (h): median (range), numberCao 199784 (4 to 198), n = 3581 (0 to 246), n = 30'P = 0.62'

Newton 200341 (3 to 138), n = 3265 (12 to 383), n = 27'P = 0.2'

Time to parasite clearance of 50% (h): median (range), numberCao 19975.7 (2.0 to 15.3), n = 3513.2 (2.4 to 103.0), n = 32'P < 0.0001'

Newton 20039.1 (0.3 to 37.2), n = 568.0 (0.2 to 46.0), n = 49'P = 0.3'

Time to parasite clearance of 90% (h): median (range), numberCao 199712.0 (3.7 to 35.0), n=3527.7 (7.5 to 107.0), n=32'P < 0.0001'

Newton 200320.5 (2.8 to 50.11), n=5424.7 (0.9 to 67.7), n=48'P = 0.08'

Time to parasite clearance of 100% (h): median (range), numberCao 199736.0 (16.0 to126.0), n=3484.0 (12.0 to 240.0), n=32'P < 0.0001'



 

Appendix 4. Adverse event reporting


Study IDAdditional comments on adverse events

Anh 1989No comment on adverse events

Anh 1995No comment on adverse events

Cao 1997'All 3 drug regimens were well tolerated, and no patient had to discontinue treatment because of adverse effects.'

This study also conducted some cardiac monitoring on a non-randomised subset of patients and does not report any significant differences between groups.

Dondorp 2005'With the exception of hypoglycaemia there were no serious adverse effects that could be attributed to either
treatment.'

Dondorp 2010'We detected no severe adverse effects that could be attributed directly to drug toxicity. Although one patient treated with artesunate developed a mild urticarial rash, no severe type 1 hypersensitivity reactions were recorded.'

Eltahir 2010'Following quinine infusion, 12 patients developed tinnitus and one hypoglycaemia. Abdominal pain and nausea were observed in three and four patients in artesunate and quinine groups, respectively.'

Hien 1992No comment on adverse events

Newton 2003'Patients treated with quinine consistently developed cinchonism and had a significantly higher frequency of hypoglycemia. One patient had a probable adverse reaction to artesunate. This patient presented with parasitaemia of 31%, a plasma lactate level of 14.5 mmol/L, and a serum bilirubin level of 23 mg/dL and developed a widespread erythematous urticarial rash 17 h after treatment with intravenous artesunate was initiated.'



 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 30 January 2011.


DateEventDescription

12 April 2011AmendedDates corrected (review assessed as up-to-date is 31 January 2011, not 2010 as previously stated).



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 2, 2006
Review first published: Issue 4, 2007


DateEventDescription

16 February 2011New citation required and conclusions have changedTwo new trials of artesunate versus quinine in African children have been added.

28 November 2010New search has been performedMajor update. New Search November 2010. David Sinclair has joined the author team and become contact author, and Katharine Jones has stepped down from the author team.

30 July 2009New search has been performedNew search conducted; no new trials for inclusion. Contact person changed.

5 August 2008AmendedConverted to new review format with minor editing.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Katharine Jones and Sarah Donegan assessed the eligibility and methodological quality of trials, extracted and analysed data, and completed the first published version of the review. David Sinclair replaced Katharine Jones for the 2011 update of this review. David Lalloo contributed to the design and writing of the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Dr David Lalloo was part of the data and safety monitoring committee for the two Dondorp trials. This committee is independent, does not run or gain anything from the trial, and has a main role of protecting participants.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • Liverpool School of Tropical Medicine, UK.
  • University of Liverpool, UK.

 

External sources

  • Department for International Development (DFID), UK.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

2007, Issue 4 (first review version): We removed the requirement for all participants to fulfil the World Health Organization's definition for severe malaria (Gilles 2000) in view of the large number of participants this would have excluded from the review as the largest included trial used a clinical case definition.

We changed the intervention from "parenteral artesunate" to "intravenous, intramuscular, or rectal artesunate" to clarify that trials using artesunate suppositories would be included in the review.

We subgrouped "neurological sequelae" into "neurological sequelae at discharge" and "neurological sequelae at day 28".

We added a number of sensitivity analyses post-hoc after noting significant variation in study design across trials.

We presented data for hypoglycaemia in a forest plot rather than a table as stated in the protocol to reflect the clinical importance of this outcome.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractResumen
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
Anh 1989 {unpublished data only}
  • Anh TK. Efficacy of qinghaosu in Plasmodium falciparum malaria. World Health Organization report [M20/181/38].
  • Anh TK, Kim NV, Bich NN, Huong N.ng, Phuong N.v, et al. Randomized comparative study of artesunate intravenously and quinine in loading dose IV on severe and complicated malaria. Unpublished report.
Anh 1995 {published data only}
  • Anh TK. Standard dose quinine & IV artesunate in treatment of severe and complicated falciparum malaria [WHO/Geneva/TDCRC/CRH]. Malaria Symposium & Workshop, Vungtau 1992.
  • Anh TK, Binh TQ, Kim NV, et al. Comparative study of intravenous artesunate followed by oral mefloquine versus intravenous quinine in the treatment of severe and complicated malaria in Vietnam. Symposium on Tropical Medicine, Sanya, China. Institute Guangzhou University of TCM, 1995; Vol. 12:8-9.
  • Anh TK, Binh TQ, Kim NV, et al. Comparative study of intravenous artesunate followed by oral mefloquine versus intravenous quinine in the treatment of severe and complicated malaria in Viet Nam. Unpublished report 1995.
Cao 1997 {published data only}
  • Cao XT, Bethell DB, Pham TP, Ta TT, Tran TN, Nguyen TT, et al. Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1997;91(3):335-42.
Dondorp 2005 {published data only}
Dondorp 2010 {published data only}
  • Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010;376(9753):1647-57.
Eltahir 2010 {published data only}
  • Eltahir HG, Omer AA, Mohamed AA, Adam I. Comparison of artesunate and quinine in the treatment of Sudanese children with severe Plasmodium falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 2010;104(10):684-6.
Hien 1992 {published data only}
  • Hien TT, Arnold K, Vinh H, Cuong BM, Phu NH, Chau TT, et al. Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1992;86(6):582-3.
  • Vinh H, Arnold K, Cuong B, Phu N, Chau T, Hao N. Treatment of cerebral malaria comparing artemisinin suppositories with intravenous artesunate and intravenous quinine. XIIIth International Congress for Tropical Medicine and Malaria; Pattaya, Thailand. 1992:9.
Newton 2003 {published data only}
  • Newton PN, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, et al. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clinical Infectious Diseases 2003;37(1):7-16.

References to studies excluded from this review

  1. Top of page
  2. AbstractResumen
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
Aguwa 2010 {published data only}
  • Aguwa CN, Ukwe CV, Adibe MO. A comparative study of quinine and artemether in the treatment of severe malaria in Nigerian children [Tropical Journal of Pharmaceutical Research]. 2010 9;1:11-17.
Awad 2003 {published data only}
  • Awad MI, Alkadru AM, Behrens RH, Baraka OZ, Eltayeb IB. Descriptive study on the efficacy and safety of artesunate suppository in combination with other antimalarials in the treatment of severe malaria in Sudan. American Journal of Tropical Medicine and Hygiene 2003;68(2):153-8.
Barnes 2004 {published data only}
  • Barnes KI, Mwenechanya J, Tembo M, McIlleron H, Folb PI, Ribeiro I, et al. Efficacy of rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study. Lancet 2004;363(9421):1598-605.
Bounyasong 2001 {published data only}
  • Bounyasong S. Randomized trial of artesunate and mefloquine in comparison with quinine sulfate to treat P. falciparum malaria pregnant women. Journal of Medical Association of Thailand 2001;84(9):1288-99.
Haroon 2005 {published data only}
  • Haroon N, Amichandwala K, Solu M. Comparative efficacy of quinine and artesunate in the treatment of severe malaria: A randomized controlled trial. JK Science 2005;7(1):32-5.
Krudsood 2003 {published data only}
  • Krudsood S, Wilairatana P, Vannaphan S, Treeprasertsuk S, Silachamroon U, Phomrattanaprapin W, et al. Clinical experience with intravenous quinine, intramuscular artemether and intravenous artesunate for the treatment of severe malaria in Thailand. Southeast Asian Journal of Tropical Medicine and Public Health 2003;34(1):54-61.
Li 1990 {published data only}
  • Li G, Guo X, Fu L. A randomised comparative study of artesunate versus quinine dihydrochloride in the treatment of falciparum malaria. Clinical Trials on Qinghaosu and its Derivatives; Guangzhou, China. 1990; Vol. 1:50-8.
McGready 2001a {published data only}
  • McGready R, Cho T, Samuel, Villegas L, Brockman A, van Vugt M, et al. Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene 2001;95(6):651-6.
McGready 2001b {published data only}
  • McGready R, Cho T, Keo NK, Thwai KL, Villegas L, Looareesuwan S, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clinical Infectious Diseases 2001;33(12):2009-16.
Mohanty 2004 {published data only}
  • Mohanty AK, Rath BK, Mohanty R, Samal AK, Mishra K. Randomized control trial of quinine and artesunate in complicated malaria. Indian Journal of Pediatrics 2004;71(4):291-5.
Newton 2001 {published data only}
  • Newton PN, Chierakul W, Ruangveerayuth R, Silamut K, Teerapong P, Krudsood S, et al. A comparison of artesunate alone with combined artesunate and quinine in the parenteral treatment of acute falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 2001;95(5):519-23.
Osanuga 2009 {published data only}
  • Osonuga OA, Osonuga IO. Parasitaemia changes in the course of treatment of severe malaria patients with artemether and quinine (A preliminary study). Macedonian Journal of Medical Sciences 2009;2(4):319-323.
Phu 2010 {published data only}
  • Phu NH, Tuan PQ, Day N, Mai NT, Chau TT, Chuong LV, et al. Randomized controlled trial of artesunate or artemether in Vietnamese adults with severe falciparum malaria. Malaria 2010;9(97):doi: 10.1186/1475-2875-9-97.
Pukrittayakamee 2004 {published data only}
  • Pukrittayakamee S, Chotivanich K, Chantra A, Clemens R, Looareesuwan S, White NJ. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrobial Agents and Chemotherapy 2004;48(4):1329-34.
Win 1992 {published data only}
  • Win K, Than M, Thwe Y. Comparison of combinations of parenteral artemisinin derivatives plus oral mefloquine with intravenous quinine plus oral tetracycline for treating cerebral malaria. Bulletin of the World Health Organization 1992;70(6):777-82.
Zhao 2001 {published data only}
  • Zhao J. Artesunate for 321 patients with falciparum malaria in the Republic of Mali. Chinese Journal of New Drugs and Clinical Remedies 2001;20(4):275-7.

Additional references

  1. Top of page
  2. AbstractResumen
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
Adjuik 2004
Afolabi 2004
  • Afolabi BB, Okoromah CAN. Intramuscular arteether for treating severe malaria. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD004391. DOI: 10.1002/14651858.CD004391.pub2..
Alkadi 2007
Altman 1996
AQMSG 2001
  • The Artemether-Quinine Meta-analysis Study Group. A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine 2001;95(6):637-50.
Brewer 1994
  • Brewer T, Grate SJ, Peggins JO, Weina PJ, Petras JM, Levine BS, et al. Fatal neurotoxicity of arteether and artemether. American Journal of Tropical Medicine and Hygiene 1994;51(3):251-9.
Doolan 2009
Genovese 2000
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Gilles 2000
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Hien 2004
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Higgins 2008
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Kissinger 2000
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Lesi 2004
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Looareesuwan 2002
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McIntosh 2000
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Mithwani 2003
  • Mithwani S, Aarons L, Kokwaro GO, Majid O, Muchohi S, Edwards G, et al. Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria. British Journal of Clinical Pharmacology 2003;57(2):146-52.
Murphy 1997
  • Murphy SA, Mberu E, Muhia D, English M, Crawley J, Waruiru C, et al. The disposition of intramuscular artemether in children with cerebral malaria; a preliminary study. Transactions of the Royal Society of Tropical Medicine and Hygiene 1997;91(3):331-4.
Nealon 2002
  • Nealon C, Dzeing A, Müller-Römer U, Planche T, Sinou V, Kombila M, et al. Intramuscular bioavailability and clinical efficacy of artesunate in gabonese children with severe malaria. Antimicrobial Agents and Chemotherapy 2002;46(12):3933-9.
Nontprasert 1998
  • Nontprasert N, Nosten-Bertrand M, Pukrittayakamee S, Vanijanonta S, Angus BJ, White N. Assessment of the neurotoxicity of parenteral artemisinin derivatives in mice. American Journal of Tropical Medicine and Hygiene 1998;59(4):519-22.
Nontprasert 2000
  • Nontprasert A, Pukrittayakamee S, Nosten-Bertrand M, Vanijanonta S, White NJ. Studies of the neurotoxicity of oral artemisinin derivatives in mice. American Journal of Tropical Medicine and Hygiene 2000;62(3):409-12.
Nontprasert 2002
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Nosten 2007
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Review Manager 5
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Ribeiro 1998
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ter Kuile 1993
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Toovey 2004
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van Der Torn 1996
  • van der Torn M, Thuma PE, Mabeza GF, Biemba G, Moyo VM, McLaren CE, et al. Loading dose of quinine in African children with cerebral malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1998;92(3):325-31.
White 1983
  • White NJ, Warrell DA, Chanthavanich P, Looareesuwan S, Warrell MJ, Krishna S, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. New England Journal of Medicine 1983;309(2):61-6.
White 1983b
  • White NJ, Looareesawan S, Warrell DA, Warrell MJ, Chanthavanich P, Bunnag D, et al. Quinine Loading Dose in Severe Malaria. American Journal of Tropical Medicine and Hygiene 1983;32:1-5.
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