Artemisinin-based combination therapy for ... - The Cochrane Library

this analysis into participants who had P. vivax co-infection at
baseline and those negative for P. vivax at baseline.
Extracting data on gametocyte carriage was difficult due to the
variety of ways that these data are presented in individual papers. In
order to try to present useful data we contacted the lead author of
all trials that reported on gametocytes for additional information
which fitted our specified outcomes.
Haematological outcomes were also presented in a multitude of
ways which prevented meta-analysis. We have therefore presented
these data as a narrative summary with forest plots where possible.
Other secondary outcomes have been presented using forest plots,
tables, or narrative summaries as appropriate.
We extracted the number of serious adverse events and deaths and
have presented these data in a forest plot. We have only included
those trials that specifically report serious adverse events.
Data on early vomiting were extracted as a measure of tolerability
of these combinations, and are presented as a forest plot. Other
adverse events are presented in tables with a narrative summary.
Assessment of risk of bias in included studies
DS and BZ independently assessed the risk of bias for each trial
using ’The Cochrane Collaboration’s tool for assessing the risk of
bias’ (Higgins 2008). Differences of opinion were discussed with
PG. We followed the guidance to assess whether adequate steps
had been taken to reduce the risk of bias across six domains: sequence
generation; allocation concealment; blinding (of participants,
personnel, and outcome assessors); incomplete outcome
data; selective outcome reporting; and other sources of bias. We
have categorized these judgments as ’yes’ (low risk of bias), ’no’
(high risk of bias), or ’unclear’. Where our judgement is unclear
we attempted to contact the trial authors for clarification.
This information was used to guide the interpretation of the data
that are presented.
Measures of treatment effect
We analysed the data using Review Manager 5. Dichotomous data
are presented and combined using risk ratios. For continuous data
summarized by arithmetic means and standard deviations, data
have been combined using mean differences. Risk ratios and mean
differences are accompanied by 95% confidence intervals. Medians
and ranges are only reported in tables.
Dealing with missing data
If data from the trial reports were insufficient, unclear, or missing,
we attempted to contact the trial authors for additional information.
If we judged the missing data to render the result uninterpretable
we excluded the data from the meta-analysis and clearly
stated the reason. The potential effects of missing data have been
explored through a series of sensitivity analyses (Appendix 3).
Assessment of heterogeneity
We assessed for heterogeneity amongst trials by inspecting the
forest plots, applying the Chi² test with a 10% level of statistical
significance, and also using the I² statistic with a value of 50%
used to denote moderate levels of heterogeneity.
Data synthesis
The included trials have been given identity codes which include
the first author, the year the study was conducted (not the year
it was published) and the three-letter international country code.
Studies in forest plots are also listed in chronological order (by the
final date of enrolment). We hope this will aid with interpretation
of the review and forest plots.
Treatments have been compared directly using pair-wise comparisons.
For outcomes that are measured at different time points we
have stratified the analysis by the time point. The primary outcome
analysis is also stratified by geographical region as a crude
marker for differences in transmission and resistance patterns.
Meta-analysis has been performed within geographic regions
where appropriate after assessment and investigation of heterogeneity.
A random-effects model was used where the Chi² test P
value was less than 0.1 or the I² statistic was greater than 50%.
In addition, Olliaro-Vaillant plots have been used to simultaneously
display the absolute and relative benefits of individual ACTs
at day 28.
Subgroup analysis and investigation of heterogeneity
We investigated potential sources of heterogeneity through the following
subgroup analyses: geographical region, intensity of malaria
transmission (low to moderate versus high malaria transmission),
known parasite resistance, allocation concealment, participant age,
and drug dose (comparing regimens where there are significant
variations in drug dose).
Sensitivity analysis
We conducted a series of sensitivity analyses to investigate the robustness
of the methodology used in the primary analysis. Our
aim was to restore the integrity of the randomization process by
adding excluded groups back into the analysis in a stepwise fashion
(see Appendix 3 for details). Where these analyses altered the
direction or significance of the measure of effect the revised results
are presented and discussed.
R E S U L T S
Artemisinin-based combination therapy for treating uncomplicated malaria (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Description of studies
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