Supplementary material 7 to: Focused review format prototype
Flemyng E, Mitchell D
https://doi.org/null
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Differences between the protocol and previous versions
Differences between the protocol and previous versions that have been carried forward in this update include:
- changing the original primary outcome of treatment failure (need for oral corticosteroids) in participants who required the study inhaler to a secondary outcome. Though of interest, this definition is a 'modified intention-to-treat' population or 'conditional' outcome which breaks randomisation, and its reliability and risk of bias are impacted by the absolute and relative number of participants initiating the study inhaler in each group;
- assessing the primary outcome of treatment failure (need for oral corticosteroids) within all randomised participants, to capture the effect of being randomised to follow the exacerbation strategy regardless of how many participants had an exacerbation in each group during the study period;
- defaulting to the use of frequency data from primary studies for exacerbations and treatment failures (number of participants as the unit of analysis) instead of event rates (events as the unit of analysis per person-years);
- defaulting to a fixed-effect model for synthesis and performing a sensitivity analysis using a random-effects model if there was notable heterogeneity in the meta-analysis;
- pooling parallel and cross-over studies where the primary study reported adjusted data or suitable data from the first period, or where we had access to 2 x 2 data to adjust for period effects, which was done by applying a formula to account for intercorrelation of matched pairs (Elbourne 2002);
- using Peto odds ratios instead of Mantel-Haenzel methods where there were very few events in a meta-analysis;
- assessing magnitude of inhaled corticosteroids dose increase (two-fold versus four-fold) as a subgroup analysis;
- performing all subgroup analyses on the intention-to-treat primary outcome instead of the treated-population conditional outcome that was previously the primary outcome;
- being explicit about the criteria for removing studies in planned and post hoc sensitivity analyses, and the categories for subgroups;
- extending the definition of serious adverse events in the list of outcomes to include prolongation of hospitalisation or disability as the standard definition. We also noted in the analysis whether definitions used within studies differed;
- extending the definition of exacerbations to include a set of criteria predefined in the included studies, because guidelines were not always cited but it was clear that a list of criteria had to be met before the study medication could be initiated.
Important note: For some studies, the number of treatment failures was only reported for those who started their study inhaler, or it was not clear how many participants were analysed and under what criteria treatment failures were counted. The only way to include these studies in the redefined primary analysis based on the full randomised population was to make assumptions about the data and use the reported number of treatment failures with the denominator for the full randomised population. This assumes that no participants who did not need their inhaler failed treatment and required oral steroids. The potential impact of making this assumption is dealt with explicitly in the review through the risk of bias assessment and reporting, and with sensitivity analyses using instead the number taking their study inhaler as the denominator.