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This supplementary material provides detailed information about downgrading or upgrading the certainty of the evidence during the implementation of GRADE.
Outcomes |
Certainty of the evidence (GRADE) |
Reasons for certainty GRADEing |
Treatment failure: need for systemic corticosteroids (ITT) 46 weeks |
MODERATE |
Due to risk of bias
Studies carrying 13.3% of the analysis weight had an overall high risk of bias, and studies carrying a further 49.8% of the weight had some concerns. Studies with overall low risk of bias accounted for approximately a third of the weight of the analysis. Biases arose mostly in domains 2 and 3 (deviations from the intended interventions and missing data), often relating to assumptions that had to be made when there were differences between the way the study reported the outcome and how it was needed for the analysis, or uncertainty regarding the population used for the study analysis (−1 for risk of bias).
|
Treatment failure: need for systemic corticosteroids (of those starting inhaler) 45 weeks |
VERY LOW |
Due to inconsistency, imprecision, and very serious risk of bias
All studies were well‐matched to our review question. We resolved uncertainties in the definitions of outcomes through contact with study authors. Where outcome definitions or the populations used for analysis (e.g. ITT or those taking the study inhaler) were unclear or differed from what was defined in the review protocol, this was accounted for as missing data and deviation from the intended intervention in the risk of bias assessment (no downgrade for indirectness across outcomes).
|
Unscheduled physician visits 44 weeks |
LOW |
Due to very serious imprecision All studies were well‐matched to our review question. We resolved uncertainties in the definitions of outcomes through contact with study authors. Where outcome definitions or the populations used for analysis (e.g. ITT or those taking the study inhaler) were unclear or differed from what was defined in the review protocol, this was accounted for as missing data and deviation from the intended intervention in the risk of bias assessment (no downgrade for indirectness across outcomes).
Several studies did not appear in the analysis, but contact with study authors meant this was unlikely due to selective reporting (no downgrade for publication bias).
|
Unscheduled acute care, ED visit, or hospital admission 47 weeks |
VERY LOW |
Due to risk of bias and very serious imprecision All studies were well‐matched to our review question. We resolved uncertainties in the definitions of outcomes through contact with study authors. Where outcome definitions or the populations used for analysis (e.g. ITT or those taking the study inhaler) were unclear or differed from what was defined in the review protocol, this was accounted for as missing data and deviation from the intended intervention in the risk of bias assessment (no downgrade for indirectness across outcomes). Only 12 events in the analysis, leading to substantial imprecision in the estimate. Two studies did not observe any events and so did not contribute to the effect estimate (−2 imprecision). A large amount of heterogeneity between the two contributing study effects warranted downgrading for heterogeneity (I2 = 62%), but was captured by imprecision and very low grading. |
Serious adverse events 48 weeks |
VERY LOW |
Due to very serious risk of bias and imprecision All studies were well‐matched to our review question. We resolved uncertainties in the definitions of outcomes through contact with study authors. Where outcome definitions or the populations used for analysis (e.g. ITT or those taking the study inhaler) were unclear or differed from what was defined in the review protocol, this was accounted for as missing data and deviation from the intended intervention in the risk of bias assessment (no downgrade for indirectness across outcomes).
Studies contributing the majority of the weight in both adverse events analyses were at overall high risk of bias, primarily in domains 2 and 3 (deviations from intended interventions and missing data), and additionally in domains 4 and 5 (measurement of the outcome and selection of the reported result) for non‐serious adverse events (−2 for risk of bias).
|
Non‐serious adverse events 43 weeks |
VERY LOW
|
Due to very serious risk of bias and imprecision All studies were well‐matched to our review question. We resolved uncertainties in the definitions of outcomes through contact with study authors. Where outcome definitions or the populations used for analysis (e.g. ITT or those taking the study inhaler) were unclear or differed from what was defined in the review protocol, this was accounted for as missing data and deviation from the intended intervention in the risk of bias assessment (no downgrade for indirectness across outcomes).
Studies contributing the majority of the weight in both adverse events analyses were at overall high risk of bias, primarily in domains 2 and 3 (deviations from intended interventions and missing data), and additionally in domains 4 and 5 (measurement of the outcome and selection of the reported result) for non‐serious adverse events (−2 for risk of bias).
|
Duration of exacerbation ‐ time to symptom recovery and lung function recovery 52 weeks |
LOW
|
Due to risk of bias and imprecision All studies were well‐matched to our review question. We resolved uncertainties in the definitions of outcomes through contact with study authors. Where outcome definitions or the populations used for analysis (e.g. ITT or those taking the study inhaler) were unclear or differed from what was defined in the review protocol, this was accounted for as missing data and deviation from the intended intervention in the risk of bias assessment (no downgrade for indirectness across outcomes). Upper and lower confidence intervals include important benefit of increased or stable ICS (−1 imprecision). Several studies did not appear in the analysis, but contact with study authors meant this was unlikely due to selective reporting (no downgrade for publication bias). |