Outcomes

Anticipated absolute effects per year

Relative Effect

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Risk with Quinine (Control)

Risk difference with Artesunate  (95% CI)

Death

109 per 1000

26 fewer per 1000 (between 11 and 38 fewer)

RR 0.76 (0.65, 0.9)

5765 (4 studies)

High¹

Neurological sequalae at discharge

28 per 1000

10 more per 1000 (from 0 to 23 more)

RR 1.36 (1.01, 1.83)

5163 (3 studies)

Moderate²

Neurological sequalae at 28 days follow up

11 per 1000

3 more per 1000 (from 3 fewer to 11 more)

RR 1.23 (0.74, 2.03)

4857 (1 study)

Moderate³

Hypoglycaemia episodes

30 per 1000

11 fewer per 1000 (from 17 to 4 fewer)

RR 0.62 (0.45, 0.87)

5765 (4 studies)

high

Adverse Events: Children treated with artesunate had more neurological effects than those treated with quinine when discharged from the hospital. These were transient effects and at follow up there were no significant differences between groups. Children treated with quinine were more likely to have an episode of hypoglycemia.

1.       No serious study limitations: All the trials adequately concealed allocation to be considered at low risk of bias. The trials were unblended but this is unlikely to bias this objective outcome. no serious inconsistency: There was no statistical heterogeneity between the trials (I² = 0%). 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. 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.

2.       No serious study limitations: All the trials adequately concealed allocation to be considered at low risk of bias. The trials were unblended but this is unlikely to bias this objective outcome. no serious inconsistency: There was no statistical heterogeneity between the trials (I² = 0%). 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.

3.       No serious study limitations: All the trials adequately concealed allocation to be considered at low risk of bias. No serious inconsistency: None of the trials found evidence of an important difference between the two treatment groups. 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. 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.

4.       No serious study limitations: All the trials adequately concealed allocation to be considered at low risk of bias. The trials were unblended but this is unlikely to bias this objective outcome. no serious inconsistency: There was no statistical heterogeneity between the trials (I² = 0%). 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. 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.

Outcomes

Anticipated absolute effects per year

Relative Effect

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Risk without ITN use (Control)

Risk difference with ITN use  (95% CI)

Death

241 per 1000

94 fewer per 1000 (from 80 to 120 fewer)

0.61 (0.50, 0.75)

1664 (1 study)

High¹

Neurological sequalae at discharge

3 per 1000

6 more per 1000 (from 1 fewer to 41 more)

2.97 (0.6-14.64)

1259

Moderate²

Neurological sequalae at 28 days follow up

Not assessed

-

-

-

-

Hypoglycaemia episodes

47 per 1000

30 fewer per 1000 (from 15 to 38 fewer)

0.36 (0.19, 0.68)

1372 (2 studies)

High³

Adverse Events: Adults treated with artesunate were slightly more likely to suffer neurological sequealae but this different was not statistically significant. Adults treated with quinine were more likely to have an episode of hypoglycemia.

1.       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 outcome such as death. No serious inconsistency: the point estimates of all five trials favoured artesunate. No significant statistical heterogeneity was detected (I²=0%). 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 multicenter trial which did give the loading dose. No serious imprecision: both limits of the 95% CI imply a clinically important benefit with artesunate.

2.       No serious study limitations: This trial was unblended but the nature of the sequalae makes an observer or reporting bias unlikely. 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 sequalae which occurred in this trial (the additional two were in children): Five were psychiatric sequalae, four were a persistent problem with balance, and two had hemiparesis.  Serious imprecision: neurological sequalae 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.

3.       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. No serious indirectness: This evidence is from multiple sites within Asia (Bangladesh, India, Myanmar and Indonesia) and both trials used standard drug doses. The data from Dondorp 2005 does include some children. No serious inconsistency: There was no statistical heterogeneity (I²=0%). 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.

Findings

Interpretation

Equity - Which of the PROGRESS groups examined

The studies included both adults and children (<15 years) and both males and females were included. The studies were conducted in multiple regions of Asia and Africa.

The results are likely generalizable, however, pregnant women were excluded therefore the efficacy of artesunate in this population still needs to be examined.

Equity Applicability

The dosing schedules varied between studies. Three studies used the current recommended dosing schedules of artesunate (2.4 mg/kg (intravenous or intramuscular) on admission, at 12 hours, at 24 hours, and then once daily until starting oral therapy). Other studies gave 60 mg artesunate intravenously at admission, 4 hours, 24 hours and 48 hours. One study used 3 mg/kg intramuscular on admission then 2 mg/kg

intramuscular at 12, 24, 48, and 72 hours. The final study used 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.

This review does not comment on the effectiveness of different dosing schedules. Policymakers will need to determine which dosing schedule is feasible within their local setting or adhere to the current recommended guidelines.

The studies included participants from multiple regions of Asia and Africa.

The results of this review are likely applicable in other regions with malaria transmission, such as South America.

Cost-equity

The authors of this review provided an economic commentary to compare the economic costs of artesunate treatment to quinine treatment. The total cost of care per patient was higher for artesunate than quinine (difference in costs in Asia: $10.60 USD; $3.00 USD in Africa).

Policymakers need to determine whether treatment with artesunate, given its higher per patient cost, is feasible and weigh the additional treatment costs with the benefits of lives saved.

Monitoring & Evaluation for PROGRESS groups

More research is determined to understand the efficacy and safety of artesunate versus quinine among pregnant women.

Research is needed to determine the benefits of artesunate for pregnant women. More research is needed to determine the long-term safety of artesunate for both adults and children and whether toxicity is possible with repeated treatments.