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Artesunate versus quinine for treating severe malaria

  1. David Sinclair1,*,
  2. Sarah Donegan1,
  3. Rachel Isba1,
  4. David G Lalloo2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 13 JUN 2012

Assessed as up-to-date: 31 JAN 2011

DOI: 10.1002/14651858.CD005967.pub4


How to Cite

Sinclair D, Donegan S, Isba R, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database of Systematic Reviews 2012, Issue 6. Art. No.: CD005967. DOI: 10.1002/14651858.CD005967.pub4.

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. sinclad@liverpool.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 13 JUN 2012

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Characteristics of included studies [ordered by study ID]
Anh 1989

MethodsStudy design: An open label randomized controlled trial

Study dates: Feb to Dec 1989


ParticipantsNumber: 41 enrolled

Inclusion criteria: adults > 16 yr old with cerebral malaria (P. falciparum parasitaemia > 1000/mm3 and Glasgow Coma Scale of 14 or less not attributable to any cause other than malaria)

Exclusions: not specified


Interventions1. Artesunate: 60 mg intravenous (IV) at 0, 4, 24, and 48 h
2. Quinine: 20 mg/kg IV loading dose over 4 h at 0 h then 10 mg/kg IV every 8 h until able to swallow then 10 mg/kg by mouth every 8 h until day 7

Additional antimalarials: none reported


Outcomes1. Death
2. Coma recovery time
3. Parasite clearance time of 50%
4. Parasite clearance time of 95%


NotesLocation: Vietnamese hospital

Transmission: not specified

Funding: Roche Asian Research Foundation supplied artesunate (personal communication from author)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPersonal communication with author: Random numbers table

Allocation concealment (selection bias)High riskComment: Not done

Blinding (performance bias and detection bias)
Objective outcomes: Death
Low riskComment: An open-label trial is unlikely to bias an objective outcome like death

Blinding (performance bias and detection bias)
Subjective outcomes: Others
High riskComment: An open label trial. No attempt was made to blind participants, providers or outcome assessors

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up occurred

Selective reporting (reporting bias)Low riskNo evidence of selective reporting

Other biasLow riskNo other bias identified

Anh 1995

MethodsStudy design: An open label randomized controlled trial

Study dates: Jul 1992 to May 1995


ParticipantsNumber: 190 enrolled

Inclusion criteria: adults 15 to 65 yr with cerebral malaria (asexual P. falciparum parasitaemia and clinical signs of cerebral malaria alone or associated with other visceral complications)

Exclusion criteria: associated P. vivax parasitaemia, pregnancy, and concomitant diseases such as diabetes mellitus, stroke, meningitis, head trauma, pulmonary tuberculosis, or AIDS


Interventions1. Artesunate: 60 mg intravenous (IV) at 0, 4, 24, and 48 h
2. Quinine: 10 mg/kg IV over 4 h at 0 h then 10 mg/kg IV every 8 h until able to swallow then quinine by mouth at similar doses every 8 h until day 7

Additional antimalarials: artesunate treatment arm given one dose of mefloquine by mouth 15 mg/kg at day 7; quinine none


Outcomes1. Death within 24 h
2. Death after 24 h
3. Coma recovery time
4. Fever clearance time
5. Parasite clearance time of 50%
6. Parasite clearance time of 95%
7. Parasite clearance time of 100%

Not included in the review:
8. Time to sit
9. Time to take oral by self medication


NotesLocation: Vietnamese clinical research centre

Transmission: not specified

Funding: World Health Organization


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPersonal communication with author: Central randomization

Allocation concealment (selection bias)Low riskPersonal communication with author: Central randomization

Blinding (performance bias and detection bias)
Objective outcomes: Death
Low riskComment: An open-label trial is unlikely to bias an objective outcome like death

Blinding (performance bias and detection bias)
Subjective outcomes: Others
High riskComment: An open label trial. No attempt was made to blind participants, providers or outcome assessors

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up are recorded

Selective reporting (reporting bias)Low riskNo evidence of selective reporting

Other biasLow riskNo other bias identified

Cao 1997

MethodsStudy design: A 3-arm open label randomized controlled trial

Study dates: Aug 1992 to Mar 1995


ParticipantsNumber: 72 enrolled

Inclusion criteria: children < 15 yr with severe malaria (asexual P. falciparum parasitaemia plus at least 1 of the following: coma (Blantyre Coma Scale less than or equal to 3), severe anaemia (capillary haematocrit < 15%) with parasitaemia (> 10,000/µL); hyperparasitaemia (> 10% parasitized red blood cells or parasitaemia > 500,000/µL); jaundice (obvious clinically or serum bilirubin > 48 µmol/L); hypoglycaemia (blood glucose < 2.2 mmol/L); spontaneous bleeding (eg gastrointestinal haemorrhage); shock (systolic blood pressure < 50 mmHg if aged < 6 yr, or < 70 mmHg if aged 6 to 14 yr); repeated generalized convulsions (3 or more in 24 h despite cooling); renal impairment (serum creatinine > 177 µmol/L, or urine output < 12 mL/kg/24 h that fails to improve despite rehydration)

Exclusion criteria: severe diarrhoea, mixed infection with P. vivax, prior treatment with quinine > 60 mg/kg, artemisinin > 20 mg/kg, or artesunate > 2 mg/kg during the illness episode, or any antimalarial treatment continuing for > 48 h


Interventions1. Artesunate: 3 mg/kg intramuscular (IM) at 0 h then 2 mg/kg IM at 12, 24, 48, and 72 h
2. Quinine: 20 mg/kg intravenous (IV) loading dose over 4 h (omitted if pretreatment with quinine) then 10 mg/kg IV every 8 h up to day 7
3. [Not relevant to review: rectal artemisinin]

Additional antimalarials given: artesunate treatment arm received one dose of mefloquine by mouth 15 mg/kg at 96 h; quinine treatment arm given one dose of sulfadoxine-pyrimethamine 500 mg/25 mg on day 7


Outcomes1. Death
2. Number survived with neurological sequelae
3. Fever clearance time (all patients, excluding superinfections)
4. Coma resolution
5. Parasite clearance time of 50%
6. Parasite clearance time of 90%
7. Parasite clearance time of 100%
8. Period in hospital
9. Hypoglycaemia
10. Adverse effects

Not included in this review:
11. Number survived well
12. Time to death from admission
13. Number with acute renal failure
14. Shock
15. Convulsions
16. Deterioration of coma score
17. Gastrointestinal bleeding
18. Anaemia
19. Chest infection
20. Urinary tract infection
21. Other infection
22. Reticulocyte count at admission, on day 5, at discharge
23. Haematocrit at admission, on day 5, at discharge


NotesLocation: Vietnamese hospital

Transmission: not specified

Funding: Wellcome Trust of Great Britain


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPersonal communication with author: Computer generated

Allocation concealment (selection bias)Low riskQuote: 'Randomization slips were kept in sealed, consecutively numbered envelopes and opened only after a decision to include the patient in the study had been made'

Blinding (performance bias and detection bias)
Objective outcomes: Death
Low riskComment: An open-label trial is unlikely to bias an objective outcome like death

Blinding (performance bias and detection bias)
Subjective outcomes: Others
High riskComment: An open label trial. No attempt was made to blind participants, providers or outcome assessors

Incomplete outcome data (attrition bias)
All outcomes
Low riskPersonal communication from author: 100% analysed, no losses to follow-up.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting

Other biasLow riskNo other bias identified

Dondorp 2005

MethodsStudy design: An open label multi-centre randomized controlled trial

Study dates: Jun 2003 to May 2005


ParticipantsNumber: 1461 enrolled

Inclusion criteria: adults and children > 2 yr with severe malaria (positive blood antigen stick test for P. falciparum and a diagnosis of severe malaria, according to the admitting physician)

Exclusion criteria: convincing history of full treatment with quinine (40 mg/kg on the first day and 30 mg/kg on any subsequent day) or an artemisinin derivative for more than 24 h before admission, known allergy to 1 of the artemisinin derivatives or quinine


Interventions1. Artesunate: 2.4 mg/kg intravenous (IV) at 0, 12, and 24 h then 2.4 mg/kg IV every 24 h until able to swallow then 2 mg/kg by mouth until day 7
2. Quinine: 20 mg/kg IV loading dose then 10 mg/kg every 8 h until able to swallow then 10 mg/kg by mouth every 8 h until day 7

Additional antimalarials: both arms except in India and Bangladesh were given doxycycline (100 mg every 12 h for 7 d) once able to swallow


Outcomes1. In-hospital death
2. Death within 48 h of entry
3. Death after 48 h of entry
4. In-hospital death (blood-smear positive)
5. Neurological sequelae
6. Time to discharge (median, intra quartile range, and range)
7. Hypoglycaemia after entry

Not included in the review:
8. Combined outcome: in hospital death or neurological sequelae
9. Fetal death
10. Time to speak (median, intra quartile range, and range)
11. Time to eat (median, intra quartile range, and range)
12. Time to sit (median, intra quartile range, and range)
13. Convulsions after entry
14. Shock developing after entry
15. Blackwater fever developing after entry
16. Dialysis after entry
17. Vasopressor treatment after entry
18. Mechanical ventilation after entry


NotesLocation: hospitals in Bangladesh, Myanmar, India, and Indonesia

Transmission: not specified

Funding: Wellcome Trust grant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: 'The two-step randomisation was produced with a computer generated randomisation list'

Allocation concealment (selection bias)Low riskQuote: 'After informed consent was obtained, we signed and dated a numbered sealed envelope across the seal, then opened it to reveal a unique study number. This number did not indicate the treatment allocation, but referred to a separate sealed hardcover box, containing the study drug, case record form, and all disposables needed for drug administration and blood sampling'

Blinding (performance bias and detection bias)
Objective outcomes: Death
Low riskComment: An open-label trial is unlikely to bias an objective outcome like death

Blinding (performance bias and detection bias)
Subjective outcomes: Others
High riskComment: An open label trial.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up are recorded.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting

Other biasLow riskNo other bias identified

Dondorp 2010

MethodsStudy design: An open label, multi-centre randomized controlled trial

Study dates: Oct 2005 to July 2010


ParticipantsNumber: enrolled

Inclusion criteria: Age < 15 years (age criteria varied slightly between sites at the request of the respective ethics review boards), a positive rapid diagnostic test for P. falciparum, severe malaria (physicians opinion), written consent

Exclusions: Prior full treatment with parenteral quinine, or an artemisinin derivative for more than 24 h.


InterventionsEach study site used either the intravenous or intramuscular route for both treatment arms

1. Artesunate (Guilin, China): 2·4 mg/kg on admission, at 12 h, at 24 h, and then once daily until starting oral therapy.
2. Quinine dihydrochloride (Indus Pharma, Pakistan): 20 mg salt per kg loading dose infused over 4 h (in 5–10 mL/kg of 5% dextrose), followed by a 10 mg salt per kg infusion over 2–8 h three times daily until starting oral therapy.

(For intramuscular treatment the doses were the same as for intravenous treatment; quinine was diluted in normal saline to a concentration of 60 mg/mL, and injected into the anterior thigh. The loading dose was given as a split dose into each thigh).

Once able to tolerate oral medication (but after a minimum of 24 h of parenteral treatment), all participants received oral artemether-lumefantrine (Novartis, Switzerland) for 3 days with milk or fat)


Outcomes1. Death
2. Death or sequelae at 28 days
3. Malaria attributable mortality
4. Case fatality in HIV +ve children
5. Time to discharge
3. Neurological sequelae
4. Adverse events

Not included in the review:
1. Development of coma
2. Convulsions developing after 6 hours
3. Severe anaemia after admission
4. Blackwater fever
5. Time to speak (median, intra quartile range)
6. Time to eat (median, intra quartile range)
7. Time to sit unsupported (median, intra quartile range)
8. Time to localise pain (median, intra quartile range)


NotesLocation: 11 centres in nine African countries (Mozambique, The Gambia, Ghana, Kenya,
Tanzania, Nigeria, Uganda, Rwanda, and Democratic Republic of the Congo).

Transmission: variable

Funding: The Wellcome Trust


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: 'Randomisation was done by people unrelated to the study and provided to the study sites in blocks of 20'.

Allocation concealment (selection bias)Low riskQuote: 'Study numbers were kept inside opaque sealed paper envelopes. After full informed written consent was obtained, the next envelope, which contained a unique study box number, was opened by the study physician or nurse. Then the corresponding numbered sealed box was opened. This box contained the study drug, case record form (labelled with the unique study number), and all disposables needed for drug administration and blood
sampling'.

Blinding (performance bias and detection bias)
Objective outcomes: Death
Low riskComment: An open-label trial is unlikely to bias an objective outcome like death

Blinding (performance bias and detection bias)
Subjective outcomes: Others
High riskQuote: 'Although the trial was open label at each site, none of the investigators or triallists, apart from for the trial statistician (TEP), had access to the summaries of treatment allocations. When notes or case record forms were reviewed, all study drug details were removed to preserve masking'

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants are included in the primary analysis. A secondary per-protocol analysis including only those with proven malaria who received the full course of treatment excluded 149 (5.5%) from the artesunate arm and 161 (5.9%) from the quinine arm

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.

Other biasLow riskOne study site did study adults as well as children but these participants are not reported in the paper, or analysis.

Eltahir 2010

MethodsStudy design: An open label randomized controlled trial

Study dates: Aug to Sep 2009


ParticipantsNumber: 66 enrolled

Inclusion criteria: Children with slide-confirmed, severe P. falciparum malaria, written informed consent

Exclusions: None stated


Interventions1. Intravenous artesunate (Guilin; China): 2.4 mg/kg body weight given at 0, 12, and 24 h, and then daily.
2. Intravenous quinine (Shanghai; China): 20 mg/kg loading dose infused over 4 h then 10 mg/kg infused over 2–4 h three times a day.

Once oral therapy was tolerated participants received artesunate+ sulfadoxine-pyrimethamine or quinine tablets to complete treatment.


Outcomes1. Death
2. Coma recovery time
3. Parasite clearance time
4. Fever clearance time
5. Adverse events

Not included in the review:


NotesLocation: Sudan

Transmission: unstable

Funding: Sudanese Sugar Company and Assalaya Sugar Factory, Sudan


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: 'Individuals were randomised (by computer-generated numbers)'

Allocation concealment (selection bias)Low riskQuote: 'computer generated numbers were sealed in individual envelopes and securely stored'

Blinding (performance bias and detection bias)
Objective outcomes: Death
Low riskComment: An open-label trial is unlikely to bias an objective outcome like death

Blinding (performance bias and detection bias)
Subjective outcomes: Others
High riskComment: An open label trial. No attempt was made to blind participants, providers or outcome assessors

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up

Selective reporting (reporting bias)Low riskNo evidence of selective reporting

Other biasLow riskNo other bias identified

Hien 1992

MethodsStudy design: A 3-arm open label randomized controlled trial

Study dates: 1989 to 1990


ParticipantsNumber: 61 enrolled

Inclusion criteria: cerebral malaria (P. falciparum parasitaemia with clinical signs of malaria and a Glasgow Coma Scale < 10)

Exclusion criteria: not specified


Interventions1. Artesunate: 60 mg intravenous (IV) at 0, 4, 24, and 48 h
2. Quinine: 500 mg IV over 4 h then 500 mg IV every 8 h until able to swallow then 500 mg by mouth every 8 h until day 14
3. [Not relevant to review: rectal artemisinin]

Additional antimalarials: artesunate treatment arm given one dose of mefloquine (by mouth 500 mg) once able to swallow


Outcomes1. Fever clearance time
2. Parasite clearance time of 50%

3. Parasite clearance time of 90%
4. Parasite clearance time of 100%
5. Time to regain full consciousness
6. Death

Not included in the review:


NotesLocation: intensive care unit in Vietnam

Transmission: not specified

Funding: artesunate was provided by Professor Li Guo Qiao


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPersonal communication from author: We did randomization by hand using tables of randomization from a statistic book

Allocation concealment (selection bias)Low riskPersonal communication from author: All treatment codes were sealed in opaque envelopes which were only opened when patients had been recruited into trial based on inclusion criteria

Blinding (performance bias and detection bias)
Objective outcomes: Death
Low riskComment: An open-label trial is unlikely to bias an objective outcome like death

Blinding (performance bias and detection bias)
Subjective outcomes: Others
High riskComment: An open label trial. No attempt was made to blind participants, providers or outcome assessors

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up are recorded

Selective reporting (reporting bias)Low riskNo evidence of selective reporting

Other biasLow riskNo other bias identified

Newton 2003

MethodsStudy design: An open label randomized controlled trial

Study dates: May to July 1994 and 1995 to 2001


ParticipantsNumber: 113 enrolled, 100 analysed

Inclusion criteria: adults aged 15 yr or above with severe malaria (single-species P. falciparum parasitaemia > 0.1% plus at least 1 of following: Glasgow Coma Scale < 11; haematocrit < 20% with asexual parasitaemia > 100,000/µL; total serum bilirubin > 50 µmol/L with asexual parasitaemia > 100,000/µL; serum creatinine > 264 mol/µL with urine output < 400 mL/24 h; systolic blood pressure < 80 mmHg with cool extremities; asexual parasitaemia > 10%; plasma lactate level > 4 mmol/L; plasma glucose level < 2.2 mmol/L; plasma venous bicarbonate level < 15 mmol/L

Exclusion criteria: pregnancy, contraindications to study drugs, artesunate, mefloquine, or significant quinine (> 2 g) intake in the previous 24 h


Interventions1. Artesunate: 2.4 mg/kg intravenous (IV) at 0 h then 1.2 mg/kg at 12 h then 1.2 mg/kg every 24 h until able to swallow then 12 mg/kg by mouth every 24 h over 7 days
2. Quinine: 20 mg/kg IV over 4 h loading dose then 10 mg/kg IV every 8 until able to swallow then 10 mg/kg by mouth until day 7

Additional antimalarials: once able to swallow some participants in both arms were given additional antimalarials, but the drug given varied during the trial; AS: no additional antimalarial (n = 22), mefloquine 15 mg/kg (n = 1), mefloquine 25 mg/kg in 2 doses (n = 22), doxycycline 100 mg every 12 h for 7 d (n = 14); quinine: no additional antimalarial (n = 20), tetracycline 250 mg every 12 h for 7 d (n = 19), doxycycline 100 mg every 12 h for 7 days (n = 15)


Outcomes1. Fever clearance time
2. Parasite clearance time of 50%

3. Parasite clearance time of 90%
4. Parasite clearance time of 100%
5. Time to regain full consciousness
6. Death
6. Hypoglycaemia
7. Adverse effects

Not included in the review:


NotesLocation: 2 hospitals in Thailand

Transmission: seasonal low intensity

Funding: Wellcome Trust of Great Britain


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPersonal communication with author: Random codes were created in Excel using the 'Randbetween' command.

Allocation concealment (selection bias)High riskQuote: 'The randomization was open'

Blinding (performance bias and detection bias)
Objective outcomes: Death
Low riskComment: An open-label trial is unlikely to bias an objective outcome like death

Blinding (performance bias and detection bias)
Subjective outcomes: Others
High riskComment: An open label trial. No attempt was made to blind participants, providers or outcome assessors

Incomplete outcome data (attrition bias)
All outcomes
Low risk13 patients were excluded after randomization for not meeting the criteria for severe malaria 5 (%) in the artesunate arm and 8 (%) in the quinine arm

Selective reporting (reporting bias)Low riskNo evidence of selective reporting

Other biasLow riskNo other bias identified

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aguwa 2010Artemether versus quinine

Awad 2003Not a randomized controlled trial

Barnes 2004Not severe malaria

Bounyasong 2001Not severe malaria

Haroon 2005A quasi-randomized controlled trial in which the first patient was allocated a treatment at random and then future patients were allocated their treatment using an alternating pattern

Krudsood 2003Not a randomized controlled trial

Li 1990Not severe malaria

McGready 2001aNot severe malaria

McGready 2001bNot a randomized controlled trial

Mohanty 2004Not a randomized controlled trial (quasi-randomized)

Newton 2001Treatment comparison is artesunate versus artesunate and quinine

Osanuga 2009Artemether versus quinine

Phu 2010Artesunate versus artemether

Pukrittayakamee 2004Not severe malaria

Win 1992Not a randomized controlled trial

Zhao 2001Not severe malaria

 
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]

 
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% CI) 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 two 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.

Artesunate compared with quinine for treating severe malaria

Patient or population: Adults 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

Death241 per 1000147 per 1000
(121 to 181)
RR 0.61
(0.5 to 0.75)
1664
(5 studies1)
high2,3,4,5

Neurological sequelae at day 28-----Not reported

Neurological sequelae at discharge3 per 10009 per 1000
(2 to 44)
RR 2.97
(0.6 to 14.64)
1259
(1 study6)
moderate7,8,9,10

Time to hospital discharge (days)See commentSee commentNot estimable113
(2 studies11)
moderate12,13,14,15

Hypoglycaemia episodes47 per 100017 per 1000
(9 to 32)
RR 0.36
(0.19 to 0.68)
1372
(2 studies11)
high12,16,14,17

*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% CI) 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 2005) and four smaller trials (Anh 1989, Anh 1995, Hien 1992, Newton 2003) have assessed artesunate vs quinine in adults
2 No serious study limitations: two of the smaller studies did not conceal allocation and none of the studies were blinded. However the majority of the data is from studies which did conceal allocation and the lack of blinding is unlikely to introduce bias for an objective outcome such as death.
3 No serious inconsistency: The point estimates of all five trials favoured artesunate. No significant statistical heterogeneity was detected (I² = 0%).
4 No serious indirectness: All five trials were from Asia, but from a variety of settings (Vietnam, Bangladesh, India, Myanmar, Indonesia and Thailand), and included age groups above 15/16 years. Of the four small trials; two did not give the loading dose of quinine, but there was no statistical heterogeneity between these two trials and the large multicentre trial which did give the loading dose.
5 No serious imprecision: Both limits of the 95% CI imply a clinically important benefit with artesunate.
6 Only one trial reported the incidence of neurological sequelae in adults (Dondorp 2005). This is unpublished data received from the authors.
7 No serious study limitations: This trial was unblinded but the nature of the sequelae makes an observer or reporting bias unlikely
8 No serious inconsistency: Not applicable as only one trial
9 No serious indirectness: This trial had sites in four different countries in Asia and used the established standard doses of artesunate and quinine (with loading dose). Of the 10 sequelae which occurred in this trial (the additional two were in children): Five were psychiatric sequelae, four were a persistent problem with balance, and two had a hemiparesis.
10 Serious imprecision: Neurological sequelae appear to be a rare event following severe malaria in adults. However the 95% CI includes the possibility of a clinically important harm with artesunate.
11 Two trials (Dondorp 2005 and Newton 2003) report this outcome.
12 No serious study limitations: Dondorp 2005 adequately concealed allocation to be considered at low risk of bias, Newton 2003 did not but is a much smaller trial. Neither trial was blinded
13 No serious inconsistency: Neither trial found a statistically significant difference in time to hospital discharge
14 No serious indirectness: This evidence is from multiple sites within Asia (Bangladesh, India, Myanmarand Indonesia) and both trials used standard drug doses. The data from Dondorp 2005 does include some children.
15 Serious imprecision: We were unable to pool data due to the way data were presented but there is no evidence of a benefit on this outcome with artesunate.
16 No serious inconsistency: There was no statistical heterogeneity (I² = 0%)
17 No serious imprecision: This result is statistically significant in favour of artesunate. The current sample size is adequately powered to detect a 75% risk reduction with 80% power and 95% confidence.
 
Table 1. Search methods: detailed search strategy

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.
 
Table 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

 
Table 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'

 
Table 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.'

 
Table 5. Summary of cost-effectiveness studies

 Lubell 2009Lubell 2011

Location(s)AsiaSub-Saharan Africa

PopulationMostly adults (86%)Children

Type of analysisCost-effectivenessCost-effectiveness

Perspective takenProviderProvider

Main cost categoriesDrug cost (but not administration costs)

Inpatient care cost
Drugs

Fluids

Laboratories

Hotel

CurrencyUSDUSD

Price year20082009

Sensitivity analysis?YesYes

Time horizonImmediateImmediate

Total cost per treatment episode artesunate vs. quinine$43.0 vs. $32.4$66.5 vs. $63.5

Number needed to treat1341

Incremental cost per death averted$135.6$123

Incremental cost per DALY avertedNot calculated$3.8