Jurnal Malaria

Artesunate versus Quinine review
KEMRI-Wellcome Trust Research Programme, Health Services Research Group, Nairobi
MINI REVIEW
Artesunate versus quinine for treatment

of severe malaria in African children
Authors
Michael Gathu1, Newton Opiyo1, Bernhards Ogutu3, Mike English1, 2
1 KEMRI-Wellcome Trust Research Programme, Nairobi, Kenya.
2 Department of Paediatrics, University of Oxford, Oxford, UK.
3 KEMRI/Walter Reed Project.
Summary
Artesunate has recently replaced quinine as the first-line treatment for severe malaria in children. This
review summarizes the evidence available on the effectiveness and safety of artesunate as an alternative to
quinine for the treatment of severe malaria in children. The GRADE (G
Grading of Recommendations,
Assessment, Development and Evaluation) approach was used to critically appraise the quality of evidence.
After identifying one systematic review published in 2012, we sought to find any further randomized
controlled trials published on this matter but none were found. One recent paper found examined the costeffectiveness of the two treatments. Our interpretation is that high quality evidence suggests that artesunate
reduces the risk of mortality in children with severe malaria. Moderate quality evidence suggests that there
is a slight increase in neurological sequelae at discharge in the artesunate group but at day 28, most
sequelae have resolved and whether there is any difference between the two treatments is uncertain.
Moderate quality evidence suggests that artesunate reduces the incidence of hypoglycaemia but there are
no clear advantages in terms of fever clearance time and time to clear all parasites. Artesunate appears to
be affordable and is cost effective. Further studies establishing the risks of neurological sequelae and
hypoglycaemia during treatment may be warranted while monitoring for the potential emergence of
resistance seems prudent.
Introduction
Severe P. falciparum malaria is a leading cause of both morbidity and mortality especially in children below five
years of age [1] with estimates suggesting that malaria is responsible for 700,000 child deaths globally [2], and
596,000 child deaths in Africa [3]. Malaria therefore is a significant challenge to the achievement of Millennium
Development Goals (MDGs) 4 and 6.
For nearly three decades, the standard treatment for severe malaria in children has been intravenous (IV) infusion (or
intramuscular (IM)) quinine. However, quinine has a narrow therapeutic index meaning there is a small difference
between therapeutic and toxic doses. Indeed, adverse effects from quinine therapy, cinchonism, are common even at
therapeutic doses. These mild and often reversible symptoms include deafness, dizziness, diarrhea, vomiting and
tinnitus [4]. Hypoglycemia is a serious adverse effect more prevalent if quinine infusion rates exceed 5mg/kg/hr [5],
one reason why it is given as an IV infusion and not an IV bolus, and in pregnant women treated for malaria [6].
With quinine over-dosage or administration that is too rapid, the heart rhythm can be disturbed leading to coma and
even death [4].
Artesunate, an artemisinin derivative, has recently replaced quinine as the first line drug for the management of
severe malaria in children in WHO and Kenyan Division of Malaria Control (DoMC) guidelines [7, 8]. Artesunate
can be given as an IV bolus dose with peak concentration reached within one hour of administration. Artesunate
has, however, been associated with neurological damage in animals exposed to the drug as part of toxicity testing [9
-11]. However, studies have failed to show any evidence of neurotoxicity in human beings [12, 13] and the drug is
felt to be safe in man.
As the change in policy from quinine to artesunate will present a major shift in clinical practice for many in Africa,
here we present a summary of evidence supporting the change. Our aim is to help practitioners understand the
background for recommending artesunate as first line therapy for severe malaria in children.
Table 1: PICOTS elements
Population
Children under 15 years of age
Intervention
Artesunate
Comparison
Quinine
Outcomes
Outcome
Importance
Death
Critical
Neurological sequelae
Critical
Hypoglycaemia episodes
Critical
Time to clear parasites
Important
Fever clearance time
Important
Time
Setting
Malaria endemic areas
Death within 72 hours

Neurological sequelae at discharge and after 28 days
Hypoglycaemia episodes within 24 hours
Methods
Clinical questions
Specific clinical questions relevant to Kenyan and African health workers were identified using the Population,
Intervention, Comparisons, Outcomes, Time and Setting (PICOTS) format as recommended for systematic reviews
[14] to guide literature search. This information is summarized in table 1 on the previous page.
Search strategy and selection criteria

Articles to be potentially included in the review were identified by conducting direct searches of MEDLINE and The
Cochrane Library. MEDLINE was searched using the PubMed clinical queries filters by combining Medical Subject
Headings (MeSH) terms [15] derived from PubMed indicative of severe or complicated malaria, predictive of the
severity of illness (death, neurological sequelae, coma), interventions compared (quinine and artesunate) and
indicative of the target age group (children or infants). Having identified a high quality systematic review assumed to
have captured relevant earlier randomized clinical trials (RCTs), only publications from January 2011 to 17th January
2013, a period not covered by Sinclair et al.s systematic review were retrieved to supplement the findings of this
earlier review.
Study selection criteria

Studies were included if they were RCTs conducted using IV, IM or rectal artesunate for the treatment of severe
falciparum malaria. Only studies that used quinine as the comparator were included. Studies that involved treatment
of uncomplicated malaria or malaria other than falciparum malaria were not included. Only studies that included
children less than fifteen years of age were included and they had to be conducted in low income settings.
In the first round of screening, identified literature were independently screened by two investigators (MG, ME) using
the predefined inclusion and exclusion criteria. The second round of screening involved reading abstracts and full
texts to select relevant studies which were then included. Any disagreements arising were resolved by discussion.
Data extraction
Data from the included studies were then extracted into
an in-house data extraction tool. Data extracted included study characteristics (design, settings), participants,
proportion of participants with outcomes of interest and
nature of interventions. The abstraction was done by 1
reviewer and counterchecked by the second reviewer.
Disagreements were resolved by consensus.
Table 2: GRADE quality of evidence ratings
HIGH
Further research is very unlikely to change

our confidence in the estimate of effect
MODERATE
Further research is likely to have an

important impact on our confidence in the
estimate of effect and may change the
estimate
LOW
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
We are very uncertain about the estimate
Quality appraisal
The quality of the evidence was assessed using the
Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach which classifies
aggregate level of quality of evidence into 4 categories:
high, moderate, low or very low [16] defined in table 2.
3
The GRADE tool provides three unique features. The first is that it has explicit and detailed criteria for upgrading or
downgrading the quality of evidence ratings. Secondly, it provides an evaluation of quality of evidence for each
outcome linked with the importance of each outcome. Third, it can provide a clear distinction between the strength
of recommendations and the quality of evidence.
Quality of evidence was assessed independently by 2 reviewers. Any disagreements that arose were resolved by
discussion. Results were then presented using summary-of-findings tables and GRADE evidence profiles. Outcomes
of the GRADE assessment were taken into account in results synthesis. However, no study was excluded as a result of
having an undesirable consequence or quality of evidence.
Results
One systematic review [17] was identified. It captured data from 8 RCTs of which four met our inclusion criteria [1821]. No further RCT was found but a report which examined the cost effectiveness of the two interventions was
identified.
All trials included in this review used artesunate as the intervention and quinine as the comparator. Three of the four
trials [19-21] administered both treatments using the recommended dosing schedules. All trials measured the blood
glucose levels of patients on admission. All four studies reported hypoglycaemia as an adverse effect. However, it
was not a pre-specified outcome in any of the studies. Two studies [18, 21] used a scheduled method of monitoring
for hypoglycaemia while [19] only assessed incidences of hypoglycaemia after inclusion into the study. The largest
study [20] had no clear of monitoring for hypoglycaemia making it possible for testing to be at the discretion of the
clinicians. As quinine is known to be associated with hypoglycaemia it is possible that this resulted in increased
testing in quinine treated patients introducing a possibility of bias. All four trials reported death as an outcome while
three trials [18-20] reported incidences of neurological sequelae present at discharge. Those with sequelae were
followed up after 28 days in one study [20]. Fever clearance time in hours was reported in two studies [18, 21].
Further details of each study are provided in table 3.
For binary outcomes (death, neurological sequelae and hypoglycaemia), pooling of results was possible across all
four studies. Fever clearance time and time to clear 100% of parasites which were continuous variables were
reported as medians with ranges in one study [18] and means in another study [21]. For these outcomes, we used
the method described by [22] to estimate the means from medians. Using the GRADE approach, we found that the
quality of evidence ranged from moderate to high for all outcomes that we considered.
Death
The findings indicate that treatment of severe malaria in children with artesunate reduces the risk of death by 24%
(95% Confidence Interval, CI 10% to 35%). The absolute risk reduction is 26 deaths per 1000 (95% CI 11 fewer to
38 fewer; n = 5765 participants, four RCTs). Three trials further reported analyses of death based on different
endpoints within and after 24 and 48 hours. There was no difference between the two treatment groups within 24
and 48 hours, the difference in number of deaths in the artesunate group compared with the quinine group
appearing after 48 hours from admission.
Artesunate is, associated with increased prevalence of neurological sequelae at the time of discharge (risk ratio, RR,
1.36, 95% CI 1.01 to 1.83; n = 5163, three trials). The absolute effect of this increase is 10 per 1,000 with a 95%
CI of 0 to 23 more per 1,000. One study [20] followed those with sequelae at discharge for 28 days. Of the 170
children, 41 (24%) were not available at follow up. The results, however, indicate that after 28 days, the majority of
these sequelae have resolved and there is no difference seen in the two treatment groups at this point (RR 1.23, 95%
CI 0.74 to 2.03). At 28 days, the absolute effect is an increase of 3 episodes of neurological sequelae per 1,000
with a 95% CI of 3 fewer to 12 more.
Artesunate reduced the frequency of hypoglycaemia episodes by 38% (95% CI 13 to 55%; n = 5765, 4 RCTs).
However, in the largest study with 5,425 participants, the method of monitoring the blood glucose level was not
specified which we deemed to be a potential source of bias.

From the two studies that reported fever clearance time, we found that there was no difference between the two
treatment groups with mean difference in fever clearance time being between 9.8 to 2 hours in favor of artesunate.
Time to clear 100% of parasites

Heterogeneity precluded pooling of results from two studies [18, 21] providing data on time to parasite clearance
after considering both fixed and random effects models (figure 1 and 2 below). Data from [18] suggest that
artesunate is superior to quinine in the clearance of parasites with a mean difference of 50 hours in favor of
artesunate (95% CI 73.55 to 26.79 hours). Data from [21] contrasts this and suggests no difference between the
two treatment groups with mean parasite clearance time of 20.8 hours even in the quinine treated group.
The detailed findings are contained in tables 3 and 4.
Table 3: Summary of results for binary outcomes

Outcome
No. of children
Risk ratio (95% Confidence Interpretation

Interval - CI)
Death
5765
0.76 (0.65 to 0.9)
Significant reduction of risk of mortality ranging

from 10% to 35%.
Neurological sequelae at
discharge
5163
1.36 (1.01 to 1.83)
Increase in risk of neurological sequelae in the

artesunate group.
Neurological sequelae at day

28
4857
1.23 (0.74 to 2.03)
No difference between the two treatment

groups.
5765
0.62 (0.45 to 0.87)
Reduced risk of developing hypoglycaemia in

children treated with artesunate.
Table 4: Summary of results for continuous outcomes
Outcome
No. of children
Absolute effect (95% CI)
Interpretation
138
2.22 hours lower (6.85

lower to 2.41 higher)
No difference.
Time to clear 100% of

parasites [18]
66

lower to 2.86 higher)
No difference.
Time to clear 100% of

parasites [21]
72

lower to 26.79 lower)
Reduced time to clear 100% of malaria

parasites in children in the artesunate arm.
Cost effectiveness
One study [23] explored the cost effectiveness of artesunate and quinine in four of the 11 sites in the African
Quinine Artesunate Malaria Treatment Trial (AQUAMAT) study [20]. The costs included cost of drugs which were
calculated as per the International Drug Price Indicator Guide, laboratory tests and intravenous fluids. Hospital
accommodation or (hotel costs) were also included and contributed roughly half of the total cost of inpatient care.
These were based on estimates obtained from the WHO-CHOICE (choosing interventions that are cost-effective)
framework. Cost of consumables such as syringes, needles, cannulas and infusion sets and costs associated with
nursing time were not included. Lifetime costs associated with neurological sequelae were also not included. The
authors found that artesunate, compared with quinine, leads to an incremental cost per disability-adjusted life year
(DALY) prevented of US$3.8 and an incremental cost per death prevented of US$123. This was despite the mean
cost of treating severe malaria in the artesunate arm being US$66.5 (95% CI: 63.7-69.2) compared to US$63.5
(95% CI: 61.7-65.2) in the quinine arm. Artesunate is thus a highly affordable and cost-effective alternative to
quinine for treating severe malaria in children.
Discussion
Interpretation of results
All the studies analyzed in this review are from Asian and African countries which are malaria endemic areas [1]
enabling appropriate generalization to Kenya and other African settings.
Risk of mortality
Evidence suggesting a treatment provides a reduction in mortality that is 10% is sufficient to change the national
malaria treatment policy [24]. There is high quality evidence suggesting that artesunate reduces the risk of mortality
in children in studies from 10.9% in the quinine arm to 8.3% in the artesunate arm, a 24% relative reduction. The
total number of participants represented by studies included in this review was over 5,600 children aged less than
15 years, sufficient to justify confidence in the results.
The majority of data available contrasts IV artesunate with IV or IM quinine providing high quality evidence of
improved survival with IV artesunate (28% relative reduction). Smaller numbers of children have been studied when
comparing IM artesunate with IV or IM quinine but data available still provide moderate quality evidence that
6
artesunate provides improved outcomes (23% relative reduction in mortality). Though no equivalence or noninferiority trials have been conducted comparing the efficacy of IV and IM artesunate directly, results provide
moderate quality evidence of benefit of artesunate over quinine irrespective of mode of administration of artesunate.
Available data indicate risks of discharge with clinically apparent sequelae of 3.9% and 2.8% in children treated with
artesunate and quinine respectively. The data provide moderate quality evidence suggesting that artesunate is
associated with an increased risk of neurological sequelae in children with severe malaria at the time of discharge.
The largest study [20] aimed to follow up children discharged with sequelae (n = 170) but only 129 were examined
at follow up introducing potential bias (a 24% loss to follow up). Moderate quality evidence on risk of sequelae
suggested no difference between the two treatment groups after 28 days with the absolute risk of sequelae in the
artesunate group estimated to be from 0.03% lower to 1.2% higher than in children treated with quinine. As clinical
sequelae are less common than mortality, data suggest an overall benefit from artesunate therapy if mortality and
sequelae are considered jointly.
Episodes of hypoglycaemia
After pooling findings from all four studies, we found moderate quality evidence suggests that artesunate reduces the
frequency of hypoglycaemia, a critical outcome, in comparison with quinine when treating children with severe
malaria (relative reduction = 38%, 95% CI 13% to 55%). However, a small minority of patients in studies was
subjected to scheduled monitoring for hypoglycaemia raising the possibility of differential testing rates in artesunate
and quinine treated children and potential bias.
Fever and parasite clearance time

Existing reports comparing fever clearance time or time to clear malaria parasitaemia in children with severe malaria
treated with artesunate and quinine are sparse [18, 21]. Data available while of moderate to low quality are unable
to support an advantage of artesunate over quinine for these important outcomes.
Implementation
Artesunate has recently replaced quinine as the preferred treatment for children with severe malaria. The cost
implications of adopting artesunate appear small [23] although logistic issues of adequate procurement and supply
as multiple countries switch to this new therapy may occur [25]. In addition, work will need to be done to promote
change in provider prescribing practices at a national scale.
Recommended dosage
IV administration of artesunate is encouraged. However, IM administration is also an option. Artesunate should be
given in doses of 2.4mg/kg at 0, 12, and 24h then 2.4mg/kg daily till the child is able to begin oral therapy. An
alternative schedule that is simpler has been suggested [26] but experience with this regimen is limited. When the
child is able to tolerate oral medication, oral artemether-lumefantrine (AL) is given as per the recommended dosage.
Implications for research

Continued efforts to assess the prevalence, nature and natural history of sequelae following admission and treatment
for severe malaria in children seem warranted, perhaps linked to work to assess the risk of hypoglycaemia during
treatment. Work to monitor the implementation of the new guidance and uptake of artesunate should be undertaken
and ideally monitoring systems to identify the potential emergence of resistance, as has been seen in South East
Asian countries [27], should be established.
Conclusion
The available evidence suggests that artesunate reduces the risk of mortality in children with severe malaria.
Moderate quality evidence suggests that artesunate reduces the incidence of hypoglycaemia episodes but there is no
difference between artesunate and quinine in the fever clearance time. Moderate quality evidence also suggests that
artesunate increases the risk of neurological sequelae in children with severe malaria at the time of discharge.
However, after 28 days the majority of sequelae have resolved and difference in risk between the two treatments is
uncertain. The evidence supports the change in policy towards use of artesunate.
References
hyperinsulinemia in falciparum malaria. The New
England journal of medicine 1983, 309(2):61-66.
1. WHO Global Malaria Programme: World Malaria

Report 2012. In. Geneva: World Health Organization;
2012.
7. World Health Organization: Guidelines for the

treatment of malaria, 2nd edition Rev. 1. In. Geneva:
World Health Organization; 2011.
2. Black RE, Cousens S, Johnson HL, Lawn JE, Rudan

I, Bassani DG, Jha P, Campbell H, Walker CF,
Cibulskis R et al: Global, regional, and national causes
of child mortality in 2008: a systematic analysis. The
Lancet 2010, 375(9730):1969-1987.
8. Ministry of Public Health and Sanitation & Ministry

of Medical Services: National Guidelines for the
Diagnosis, Treatment and Prevention of Malaria in
Kenya. In. Edited by Control DoM. Nairobi: Ministry of
Public Health and Sanitation; 2010.
3. WHO Global Malaria Programme: World Malaria

Report 2011. In. Geneva: World Health Organization;
2011.
9. N o n t p r a s e r t A , N o s t e n - B e r t r a n d M ,
Pukrittayakamee S, Vanijanonta S, Angus BJ, White NJ:
Assessment of the neurotoxicity of parenteral
artemisinin derivatives in mice. The American journal of
tropical medicine and hygiene 1998, 59(4):519-522.
4. AlKadi HO: Antimalarial drug toxicity: a review.

Chemotherapy 2007, 53(6):385-391.
5. Okitolonda W, Delacollette C, Malengreau M,
Henquin JC: High incidence of hypoglycaemia in
African patients treated with intravenous quinine for
severe malaria. Br Med J (Clin Res Ed) 1987, 295
(6600):716-718.
10. Nontprasert A, Pukrittayakamee S, NostenBertrand M, Vanijanonta S, White NJ: Studies of the

neurotoxicity of oral artemisinin derivatives in mice. The
American journal of tropical medicine and hygiene
2000, 62(3):409-412.
6. White NJ, Warrell DA, Chanthavanich P,

Looareesuwan S, Warrell MJ, Krishna S, Williamson
DH, Turner RC: Severe hypoglycemia and
11. Nontprasert A, Pukrittayakamee S, Prakongpan S,

Supanaranond W, Looareesuwan S, White NJ:
8
Assessment of the neurotoxicity of oral

dihydroartemisinin in mice. Transactions of the Royal
severe falciparum malaria: a randomised trial. Lancet

2005, 366(9487):717-725.
Society of Tropical Medicine and Hygiene 2002, 96

(1):99-101.
20. Dondorp A, Fanello CI, Hendriksen IC, Gomes E,

Seni A, Chhaganlal KD, Bojang K, Olaosebikan R,
Anunobi N, Maitland K 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):1647-1657.
12. Kissinger E, Hien TT, Hung NT, Nam ND, Tuyen

NL, Dinh BV, Mann C, Phu NH, Loc PP, Simpson JA et
al: Clinical and neurophysiological study of the effects
of multiple doses of artemisinin on brain-stem function
in Vietnamese patients. The American journal of
tropical medicine and hygiene 2000, 63(1-2):48-55.
21. 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):684686.
13. Ribeiro IR, Olliaro P: Safety of artemisinin and its

derivatives. A review of published and unpublished
clinical trials. Medecine tropicale : revue du Corps de
sante colonial 1998, 58(3 Suppl):50-53.
14. Menzies D: Systematic reviews and meta-analyses.
The international journal of tuberculosis and lung
disease : the official journal of the International Union
against Tuberculosis and Lung Disease 2011, 15
(5):582-593.
22. Hozo SP, Djulbegovic B, Hozo I: Estimating the

mean and variance from the median, range, and the
size of a sample. BMC medical research methodology
2005, 5:13.
23. Lubell Y, Riewpaiboon A, Dondorp AM, von
Seidlein L, Mokuolu OA, Nansumba M, Gesase S, Kent
A, Mtove G, Olaosebikan R et al: Cost-effectiveness of
parenteral artesunate for treating children with severe
malaria in sub-Saharan Africa. Bulletin of the World
Health Organization 2011, 89(7):504-512.
15. Haynes RB, McKibbon KA, Wilczynski NL, Walter

SD, Werre SR: Optimal search strategies for retrieving
scientifically strong studies of treatment from Medline:
analytical survey. BMJ (Clinical research ed) 2005, 330
(7501):1179.
16. Guyatt GH, Oxman AD, Vist GE, Kunz R, FalckYtter Y, Alonso-Coello P, Schunemann HJ: GRADE: an
emerging consensus on rating quality of evidence and
strength of recommendations. BMJ (Clinical research
ed) 2008, 336(7650):924-926.
24. WHO Global Malaria Programme: Guidelines for

the treatment of Malaria. In. Geneva: World Health
Organization; 2010.
25. Musila N, Opiyo N, English M: Treatment of
African children with severe malaria - towards evidence
-informed clinical practice using GRADE. Malaria
Journal 2011, 10(1).
17. Sinclair D, Donegan S, Isba R, Lalloo DG:

Artesunate versus quinine for treating severe malaria.
Cochrane database of systematic reviews (Online)
2012, 6:CD005967.
26. Kremsner PG, Taylor T, Issifou S, Kombila M,

Chimalizeni Y, Kawaza K, Bouyou Akotet MK, Duscha
M, Mordmller B, Ksters K et al: A Simplified
Intravenous Artesunate Regimen for Severe Malaria.
Journal of Infectious Diseases 2011.
18. Cao XT, Bethell DB, Pham TP, Ta TT, Tran TN,
Nguyen TT, Pham TT, Day NP, White NJ: 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):335-342.
27. World Health Organization: Global plan for

artemisinin resistance containment. In. Geneva: WHO
Press; 2011.
19. Dondorp A, Nosten F, Stepniewska K, Day N,

White N: Artesunate versus quinine for treatment of
9
Characteristics of included studies

Table 1 Characteristics of included studies
AUTHOR/YEAR
CHARACTERISTICS
(Cao et al. 1997)
Study design
The study was a 3-arm open label randomized trial with a 21 days follow up period.
Randomization was done through computer generated slips sealed in consecutive
numbered envelopes that were only opened after decision to include patient was finalized.
There was no loss to follow-up.
Population
72 children < 15 years of age with severe asexual P. falciparum malaria combined with
one of these: coma, severe anaemia, hyperparasitaemia, jaundice, spontaneous bleeding,
shock, repeated generalized convulsions, renal impairment, or hypoglycaemia.
Exclusion: severe diarrhea, comorbidity with P. vivax malaria, prior treatment with
>60mg/kg quinine or >2mg/kg artesunate during period of illness or any other
antimalarial for a period exceeding 48 hours.
Study setting
Single center in Vietnam
Intervention
3mg/kg IM artesunate on admission then 2mg/kg IM artesunate after 12, 24, 48 and 72
hours then a single oral dose of 15mg/kg mefloquine at 96 hours
Comparison
20mg/kg IV quinine loading dose over 4 hours, omitted if the child had been pretreated
with quinine, followed by 10mg/kg IV quinine every 8 hours for 7 days plus single dose of
500mg/25mg sulfadoxine-pyrimethamine on the 7th day.
Outcomes of interest
1. Death
2. Number survived with neurological sequelae
3. Fever clearance time in hours (reported as median and assessed every 4 hours for first
10
(Dondorp et al.
Study design
2005)
24 hours and every 6 hours thereafter until discharge). It was defined as the time until
temperature first dropped to 37.5oC and remained below 37oC for a minimum of 24
hours.
4. Time to clear 100% of parasites in hours (reported as median and assessed every 4
hours for first 24 hours and every 6 hours thereafter until discharge). It was defined as
the time when the peripheral blood film revealed no parasites on 2 successive
measurements.
5. Hypoglycaemia episodes by routine monitoring (blood glucose was measured at 4h
intervals for first 24 hours then every 6 hours thereafter)
The study was an open-label multicenter RCT.
Randomization was done through computer generated slips sealed in envelopes that were
only signed and dated after informed consent was obtained. The envelope only guided the
researchers to a separate sealed box that contained the drug, case record form and all
consumables needed. There was no loss to follow-up.
Population
1461 adults and children >2 years of age with severe malaria confirmed rapid diagnostic
test and diagnosis by admitting physician. (Only data for children <15 years is considered
in this summary.)
Exclusion: convincing history of full quinine treatment (40mg/kg 24h after admission and
30mg/kg on subsequent days) or artemisinin derivative for >24h before admission or
known allergy to quinine or artemisinin derivatives.
Study setting
11 centers in Bangladesh, India, Myanmar (Burma) and Indonesia.
Intervention
2.4mg/kg IV artesunate at 0, 12h and 24h then once daily 2.4mg/kg dose till they are able
to start oral therapy as per recommended dosing schedules then 2mg/kg single oral dose
till day 7.
100mg doxycycline was given orally twice a day for 7 days once patient was able to
11
swallow except in India and Bangladesh except for children < 8 years.
Comparison
20mg/kg IV loading dose quinine then 10mg/kg every 8 hours until they are able to start
oral therapy then 10mg/kg oral dose every 8 hours till day 7.
100mg doxycycline was given orally twice a day for 7 days once patient was able to
swallow except in India and Bangladesh except for children < 8 years.
(Dondorp et al.
Study design
2010)
1. In-hospital death
2. Incidence of neurological sequelae
3. Hypoglycaemia episodes by clinical monitoring (only incidence of hypoglycaemia after
inclusion)
The study was an open-label multicenter RCT.
Randomization was done by outsiders unrelated to the study and delivered in blocks of 20.
These study numbers were stored in sealed envelopes. The envelope was only opened by a
physician or nurse after informed consent was received. The study number guided the
researchers to a matching separate sealed box that contained the drug, case record form
and all consumables needed.
170 children with neurological sequelae at discharge were to be reviewed after 28 days.
There was loss to follow-up (41/170 = 24%) which created a risk of bias.
IM and IV routes of administration were used in both intervention and comparison arms.
Patients were randomized to either IV or IM administration. Ratio of patients in each group
is not specified. The mode of administration is not considered in data analysis i.e.
artesunate is compared to quinine.
Population
5425 children <15 years of age with severe malaria confirmed by rapid diagnostic test,
diagnosis by admitting physician and written consent by relative or guardian.
Exclusion: convincing history of full parenteral quinine treatment or artemisinin derivative for
12
>24h before admission.

Study setting
11 centers in nine countries (Kenya, Mozambique, Ghana, Gambia, Tanzania, Uganda,

Nigeria, Rwanda and the Democratic Republic of Congo).
Intervention
2.4mg/kg IV or IM artesunate at 0, 12h and 24h then once daily 2.4mg/kg dose till they
are able to start oral therapy as per recommended dosing schedules then oral artemetherlumefantrine (AL) after a minimum of 24h of parenteral treatment. IM artesunate was
injected into the anterior thigh.
Comparison
20mg/kg IV loading dose quinine over 4h in 5-10mL/kg of 5% dextrose then 10mg/kg over
2-8h thrice daily until they are able to start oral therapy then oral artemether-lumefantrine
(AL) after a minimum of 24h or parenteral treatment.
IM quinine was given in same concentration but diluted in normal saline to a concentration
of 60mg/ml in the anterior thigh. The loading dose was split equally and injected into each
anterior thigh.
(Eltahir et al. 2010)
Study design
1. Death
2. Death or neurological sequelae at day 28
3. Hypoglycaemia episodes (method of monitoring is not mentioned)
The study was an open-label RCT.
Randomization was done by computer generated numbers stored in sealed envelopes.
There was no loss to follow-up.
Population
Study setting
66 children (age limit not defined) with severe P. falciparum malaria confirmed by
microscopy and written informed consent from parent or guardian.
Exclusion: none stated.
Single study site in Central Sudan
13
Intervention
Comparison
2.4mg/kg IV artesunate at 0, 12h and 24h then once daily 2.4mg/kg dose till they are able
to start oral therapy as per recommended dosing schedules then 2.4mg/kg daily. Once
able to take oral medication, artesunate sulfadoxine/pyrimethamine was given.
20mg/kg IV loading dose quinine over 4h then 10mg/kg over 2-4h thrice daily. Once able
to take oral medication, was given. Once able to take oral medication quinine tablets were
given.
1. Death
2. Time to clear 100% of parasites (reported as a mean and defined as interval between
start of treatment to time when first of two sequential negative slides is obtained based
on blood slides taken every 4 hours)
3. Fever clearance time (reported as a mean and measured from start of treatment to time
when axillary temperature first dropped below 37.5oC and remained below 37.5oC for
24 hours). It was assessed every 15 minutes for the first hour then every 2 hours until 24
hours then every 6 hours until parasite clearance.
4. Hypoglycaemia episodes by routine monitoring (blood glucose was measured every 6
hours)
14
Quality of Evidence and Summary

Summary of Findings
Question 1: What is the evidence that artesunate reduces the risk of mortality in children with severe malaria?
Population:
Population: Children
Intervention:
Intervention: Artesunate
Comparison:
Comparison: Quinine
Bibliography:
Bibliography: (Cao et al. 1997), (Dondorp et al. 2005), (Dondorp et al. 2010), (Eltahir et al. 2010)
Quality assessment
No of
Design
Risk of bias
Inconsistency
Indirectness
No of patients
Imprecision
studies
Other
Artesunate
Quinine
considerations
Effect
Relative
Quality
Importance
CRITICAL
Absolute
(95% CI)
Death1
randomised
no serious
no serious
no serious
no serious
trials
risk of bias
inconsistency
indirectness
imprecision
none
240/2879
315/2886
RR 0.76
26 fewer per 1000
(8.3%)
(10.9%)
(0.65 to 0.9)
(from 11 fewer to 38
HIGH
fewer)
Death: intravenous artesunate2
randomised
no serious
no serious
no serious
no serious
trials
risk of bias
inconsistency
indirectness
imprecision
none
247/2542
337/2488
RR 0.72
38 fewer per 1000
(9.7%)
(13.5%)
(0.62 to 0.84)
(from 22 fewer to 51
HIGH
fewer)
15
CRITICAL
Death: intramuscular artesunate2
randomised
no serious
no serious
no serious
no serious
trials
risk of bias
inconsistency
indirectness
imprecision3
none
95/970
131/1024
RR 0.77 (0.6
29 fewer per 1000
(9.8%)
(12.8%)
to 0.98)
(from 3 fewer to 51
HIGH
fewer)
Similar high quality evidence exists for other mortality endpoints.
Efficacy of IM or IV artesunate is deduced from their superiority to quinine. No equivalence or non-inferiority trial has been conducted. Dondorp et al
2010 is included in both categories

3
Although the number of events was less than the optimal information size (OIS), the CI around the absolute effect was sufficiently narrow.
16
CRITICAL
Question 2: What is the evidence that artesunate reduces the incidence of neurological sequelae in children with severe malaria?
Population:
Intervention:
Comparison:
Comparison: Quinine
Bibliography:
Bibliography: (Cao et al. 1997), (Dondorp et al. 2005), (Dondorp et al. 2010)
Quality assessment
No of
Design
Risk of bias
Inconsistency
Indirectness
No of patients
Imprecision
studies
Other
Artesunate
Quinine
considerations
Effect
Relative
Quality
Importance
CRITICAL
Absolute
(95% CI)
Neurological sequelae at discharge
randomised
no serious
no serious
no serious
trials
risk of bias
inconsistency
indirectness
serious1,2
none
101/2612
72/2551
RR 1.36
10 more per 1000 (from
(3.9%)3
(2.8%)
(1.01 to
0 more to 23 more)
MODERATE
1.83)
Neurological sequelae at day 28
randomised
trials
serious4
no serious
no serious
inconsistency
indirectness
serious5
none
34/2459
27/2398
RR 1.23
3 more per 1000 (from 3
(1.4%)3
(1.1%)
(0.74 to
fewer to 12 more)
LOW
2.03)
Sequelae is a critical outcome, however, the 95% CI includes 1.0 indicating that there is no difference between the two treatment groups.
17
CRITICAL
Although the incidence of sequelae at time of discharge increases in the artesunate arm, the majority were reversible and majority had resolved when the
patients were followed up 28 days later. At this point there was no difference between the two treatment groups.
4
41/170 (24%) of patients were unavailable for assessment on day 28.
The CI around relative effects is wide and the CI around absolute effects crosses over from benefit (fewer events) to harm (more events).
18
Question 3: What is the evidence that artesunate reduces episodes of hypoglycaemia in children with severe malaria?
Population:
Intervention:
Comparison:
Comparison: Quinine
Bibliography:
Bibliography: (Cao et al. 1997), (Dondorp et al. 2005), (Dondorp et al. 2010), (Eltahir et al. 2010)
Quality assessment
No of
Design
Risk of
studies
Inconsistency
Indirectness
No of patients
Imprecision
bias
Other
Artesunate
Quinine
considerations
Effect
Relative
Quality
Importance
CRITICAL
Absolute
(95% CI)
randomised
serious1
trials
no serious
no serious
no serious
inconsistency
indirectness
imprecision2
none
54/2879
87/2886
RR 0.62
11 fewer per 1000 (from
(1.9%)
(3%)
(0.45 to
4 fewer to 17 fewer)
MODERATE
0.87)
Hypoglycemia episodes by scheduled monitoring
randomised
no serious
no serious
no serious
very
trials
risk of bias
inconsistency
indirectness
serious3,4,5
none
6/70 (8.6%)
10/68
RR 0.59
60 fewer per 1000 (from
(14.7%)
(0.24 to
112 fewer to 63 more)
LOW
1.43)
Dondorp et. al (2010) which contributed most of the data did not specify their method of monitoring. This kind of unscheduled monitoring could be
19
CRITICAL
biased.
2
The sample size for these studies was too small. The studies had a combined total of 70 patients in the intervention group compared to 68 for the control
group.
4
The total event rates in both treatment groups were too low and did not meet the optimal information size (OIS) criterion.
The CI around the relative and absolute effects includes both appreciable benefit and harm from the intervention.
20
Question 4: What is the evidence that artesunate reduces the time to clear all malaria parasites in children with severe malaria?
Population:
Intervention:
Comparison:
Comparison: Quinine
Bibliography:
Bibliography: (Cao et al. 1997), (Eltahir et al. 2010)
Quality assessment
No of
Design
Risk of bias
Inconsistency
Indirectness
No of patients
Imprecision
studies
Other
Artesunate
Quinine
considerations
Effect
Relative
Quality
Importance
MD 50.17 lower
IMPORTANT
(73.55 to 26.79
MODERATE
Absolute
(95% CI)
Time to clear all parasites (Better indicated by lower values)
11
randomised
no serious
no serious
no serious
trials
risk of bias
inconsistency
indirectness
serious2
none
37
35
3,4
lower)
Time to clear all parasites (Better indicated by lower values)
15
randomised
no serious
no serious
no serious
very
trials
risk of bias
inconsistency
indirectness
serious2,6
none
33
33
MD 2.00 lower (6.7
lower to 2.7 higher)3
LOW
(Cao et. al. 1997)
The sample size for the study did not meet the optimal information size (OIS) criterion since it only recruited a total of 66 patients.
21
IMPORTANT
MD - mean difference; all units are in hours.
Cao et. al (1997) reported medians and ranges. Means were estimated using the method described by Hozo et. al (2005)
(Eltahir et. al. 2010)
The CI around the absolute effects includes both appreciable benefit and harm from the intervention.
22
Question 5: What is the evidence that artesunate reduces the fever clearance time in children with severe malaria?
Population:
Intervention
Intervention:
tion: Artesunate
Comparison:
Comparison: Quinine
Bibliography:
Bibliography: (Cao et al. 1997), (Eltahir et al. 2010)
Quality assessment
No of
Design
Risk of bias
Inconsistency
Indirectness
No of patients
Imprecision
studies
Other
Artesunate
Quinine
considerations
Effect
Relative
Quality
Importance
IMPORTANT
Absolute
(95% CI)
Fever clearance time (Better indicated by lower values)
randomised
trials
no serious
risk of bias
no serious
inconsistency
no serious
indirectness
very
serious
none
70
68
MD 2.22 lower (6.85 lower
1,2
3,4
to 2.41 higher)
The sample size for the study did not meet the optimal information size (OIS) criterion since it only recruited a total of 66 patients.
The CI around the absolute effects includes both appreciable benefit and harm from the intervention.
MD - mean difference; all units are in hours.
Cao et. al (1997) reported medians and ranges. Means were estimated using the method described by Hozo et. al (2005)
23
LOW

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Artesunate versus Quinine review

KEMRI-Wellcome Trust Research Programme, Health Services Research Group, Nairobi

Artesunate versus quinine for treatment

Artesunate versus Quinine review

KEMRI-Wellcome Trust Research Programme, Health Services Research Group, Nairobi

Table 1: PICOTS elements

Children under 15 years of age

Time to clear parasites

Fever clearance time

Malaria endemic areas

Death within 72 hours

Artesunate versus Quinine review

KEMRI-Wellcome Trust Research Programme, Health Services Research Group, Nairobi

Search strategy and selection criteria

Study selection criteria

Table 2: GRADE quality of evidence ratings

Further research is very unlikely to change

Further research is likely to have an

Further research is very likely to have an

We are very uncertain about the estimate

Artesunate versus Quinine review

KEMRI-Wellcome Trust Research Programme, Health Services Research Group, Nairobi

Artesunate versus Quinine review

KEMRI-Wellcome Trust Research Programme, Health Services Research Group, Nairobi

Fever clearance time

Time to clear 100% of parasites

Table 3: Summary of results for binary outcomes

Risk ratio (95% Confidence Interpretation

0.76 (0.65 to 0.9)

Significant reduction of risk of mortality ranging

1.36 (1.01 to 1.83)

Increase in risk of neurological sequelae in the

Neurological sequelae at day

1.23 (0.74 to 2.03)

No difference between the two treatment

0.62 (0.45 to 0.87)

Reduced risk of developing hypoglycaemia in

Artesunate versus Quinine review

KEMRI-Wellcome Trust Research Programme, Health Services Research Group, Nairobi

Table 4: Summary of results for continuous outcomes

Absolute effect (95% CI)

Fever clearance time

2.22 hours lower (6.85

Time to clear 100% of

1.10 hours lower (5.06

Time to clear 100% of

50.17 hours lower (73.55

Reduced time to clear 100% of malaria

Artesunate versus Quinine review

KEMRI-Wellcome Trust Research Programme, Health Services Research Group, Nairobi

Fever and parasite clearance time

Artesunate versus Quinine review

KEMRI-Wellcome Trust Research Programme, Health Services Research Group, Nairobi

Implications for research

1. WHO Global Malaria Programme: World Malaria

7. World Health Organization: Guidelines for the

2. Black RE, Cousens S, Johnson HL, Lawn JE, Rudan

8. Ministry of Public Health and Sanitation & Ministry

3. WHO Global Malaria Programme: World Malaria

4. AlKadi HO: Antimalarial drug toxicity: a review.

10. Nontprasert A, Pukrittayakamee S, NostenBertrand M, Vanijanonta S, White NJ: Studies of the

6. White NJ, Warrell DA, Chanthavanich P,

11. Nontprasert A, Pukrittayakamee S, Prakongpan S,