Summary of findings 3. Pyronaridine‐artesunate (PY‐AS) compared to mefloquine plus artesunate (MQ + AS) for adults and children with uncomplicated Plasmodium falciparum malaria.
| Pyronaridine‐artesunate (PY‐AS) compared to mefloquine plus artesunate (MQ + AS) for adults and children with uncomplicated Plasmodium falciparum malaria | ||||||
| Patient or population: adults and children with uncomplicated P falciparum malaria Setting: malaria transmission settings Intervention: pyronaridine‐artesunate (PY‐AS) Comparison: mefloquine plus artesunate (MQ + AS) | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (trials) | Certainty of the evidence (GRADE) | Comments | |
| Risk with MQ + AS | Risk with PY‐AS | |||||
| Total failure: day 28 (PCR‐adjusted) | 22 per 1000 | 8 per 1000 (3 to 23) | RR 0.37 (0.13 to 1.05) | 1117 (1 RCT) | ⊕⊕⊝⊝
LOWa,b,c Due to indirectness and imprecision |
Compared to MQ + AS, PY‐AS may result in fewer PCR‐adjusted failures at day 28. |
| Total failure: day 42 (PCR‐adjusted) | 29 per 1000 | 53 per 1000 (27 to 105) | RR 1.80 (0.90 to 3.57) | 1037 (1 RCT) | ⊕⊕⊝⊝
LOWa,b Due to indirectness and imprecision |
Compared to MQ + AS, PY‐AS may result in more PCR‐adjusted failures at day 42. |
| Total failure: day 28 (unadjusted) | 41 per 1000 | 15 per 1000 (7 to 32) | RR 0.36 (0.17 to 0.78) | 1120 (1 RCT) | ⊕⊕⊕⊝
MODERATEa Due to indirectness |
Compared to MQ + AS, PY‐AS probably results in fewer unadjusted failures at day 28. |
| Total failure: day 42 (unadjusted) | 83 per 1000 | 70 per 1000 (45 to 109) | RR 0.84 (0.54 to 1.31) | 1059 (1 RCT) | ⊕⊕⊝⊝
LOWa,b,d Due to indirectness and imprecision |
There is probably little or no difference between PY‐AS and MQ + AS in unadjusted failures at day 42. |
| Serious adverse events (42 days) | 7 per 1000 | 7 per 1000 (2 to 28) | RR 1.00 (0.25 to 3.97) | 1271 (1 RCT) | ⊕⊕⊝⊝
LOWa,b Due to indirectness and imprecision |
There may be little or no difference between PY‐AS and MQ + AS in serious adverse events. |
| First treatment, abnormal ALT increase (42 days) | 2 per 1000 | 18 per 1000 (2 to 133) | RR 7.48 (0.99 to 56.45) | 1271 (1 RCT) | ⊕⊕⊝⊝
LOWa,e Due to indirectness and imprecision |
Compared to MQ + AS, PY‐AS may result in higher events of abnormal ALT increase. (Aggregate analysis indicates this estimate may be accurate.) |
| First treatment, abnormal AST increase (42 days) | 0 per 1000 | 0 per 1000 (0 to 0) | RR 9.49 (0.55 to 162.64) | 1271 (1 RCT) | ⊕⊝⊝⊝
VERY LOWa,f Due to indirectness and imprecision |
We do not know if there is a difference between PY‐AS and MQ + AS in AST. |
| First treatment, abnormal bilirubin increase (42 days) | 2 per 1000 | 8 per 1000 (1 to 67) | RR 3.49 (0.43 to 28.29) | 1271 (1 RCT) | ⊕⊝⊝⊝
VERY LOWa,f Due to indirectness and imprecision |
We do not know if there is a difference between PY‐AS and MQ + AS in bilirubin. |
| *The risk in the intervention group (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). Abbreviations: ALT: alanine aminotransferase; AST: aspartate transaminase; CI: confidence interval; MQ + AS: mefloquine plus artesunate; PCR: polymerase chain reaction; PY‐AS: pyronaridine‐artesunate; RCT: randomized controlled trial; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
aDowngraded by one level for serious indirectness: of the 1271 children and adults aged greater than 5 years enrolled in this trial, 81.3% (1033) were enrolled and treated in trial sites in Asia (Cambodia, India, Thailand, and Vietnam), and only 18.7% (237) in Africa (Burkina Faso, Ivory Coast, and Tanzania). Further studies in African children are necessary for this result to be fully applicable. bDowngraded by one level for serious imprecision: the CI is large and includes both no effect and clinically important effects. cCertainty of the evidence differs from the 2014 review version due to the identification of additional data: the previous review reported no substantial difference between PY‐AS and MQ + AS for this outcome and therefore did not downgrade for imprecision. In this update we have reported a reduced rate in the PY‐AS arm. Because we concluded that there may be a difference, we necessarily downgraded for the imprecision. dCertainty of the evidence differs from the 2014 review version due to alterations in the data extraction protocol: the CI has become less precise, and our decision is more consistent with the certainty of evidence for other outcomes. eDowngraded by one level for serious imprecision: the low number of events recorded in the study is insufficient to confidently estimate the effect size. However, aggregate analysis of ALT increase across different comparator drugs provides indirect evidence that the point estimate may be accurate. fDowngraded by two levels for very serious imprecision: the CI is very large and includes both no effect and clinically important effects.