GRADE Evaluation of interventions for COPD.
Important outcomesCOPD exacerbation and worsening of symptoms, Lung function and exercise capacity, Mortality, Quality of life
Studies (Participants)OutcomeComparisonType of evidenceQualityConsistencyDirectnessEffect size for (ORs and RRs)GRADEComment
What are the effects of maintenance drug treatment in stable COPD?
4 (1651)[16][17][18][19]Lung function and exercise capacityAnticholinergics (short-term treatment) versus placebo4−1−100LowQuality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
1 (780)[18]COPD exacerbation and worsening of symptomsAnticholinergics (short-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
1 (780)[18]Quality of lifeAnticholinergics (short-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
17 (17,606)[21][22][23][24]MortalityAnticholinergics (long-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
9 (4769)[22][24]Lung function and exercise capacityAnticholinergics (long-term treatment) versus placebo4−1000ModerateQuality points deducted for incomplete reporting of results
9 (4835)[22][24]COPD exacerbation and worsening of symptomsAnticholinergics (long-term treatment) versus placebo40000High
4 (2386)[22][24]Quality of lifeAnticholinergics (long-term treatment) versus placebo4–1000ModerateQuality point deducted for incomplete reporting of results
at least 7 (at least 405)[26][28]Lung function and exercise capacityShort-acting beta2 agonists (short-term treatment) versus placebo4−1−100LowQuality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity among RCTs
5 (379)[26]COPD exacerbation and worsening of symptomsShort-acting beta2 agonists (short-term treatment) versus placebo4−1−200Very lowQuality point deducted for incomplete reporting of results. Consistency points deducted for heterogeneity among RCTs included in review and different results for different measures of the same outcome
13 (8400)[32]MortalityLong-acting beta2 agonists (short-term or long-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
7 (1797)[29][30][19][33][34][36][37][38][39]Lung function and exercise capacityLong-acting beta2 agonists (short-term or long-term treatment) versus placebo40−100ModerateConsistency point deducted for conflicting results for outcomes assessing exercise capacity
20 (8614)[32][37][38][30]COPD exacerbation and worsening of symptomsLong-acting beta2 agonists (short-term or long-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
12 (8375)[32]Quality of lifeLong-acting beta2 agonists (short-term or long-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
7 (2248)[44]Lung function and exercise capacityShort-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting beta2 agonist alone4−1000ModerateQuality point deducted for incomplete reporting of results
at least 5 (at least 1529)[29][44]COPD exacerbation and worsening of symptomsShort-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting beta2 agonist alone4−1000ModerateQuality point deducted for incomplete reporting of results
5 (1529)[44]Quality of lifeShort-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting beta2 agonist alone4−1000ModerateQuality point deducted for incomplete reporting of results
2 (1186)[29]COPD exacerbation and worsening of symptomsShort-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting anticholinergic alone4−1000ModerateQuality point deducted for incomplete reporting of results
1 (94)[46]Lung function and exercise capacityShort-acting anticholinergic plus long-acting inhaled beta2 agonist (short-term treatment) versus beta2 agonist alone4−2000LowQuality points deducted for sparse data and incomplete reporting of results
1 (172)[47]Lung function and exercise capacityShort-acting anticholinergic plus long-acting inhaled beta2 agonist (short-term treatment) versus short-acting anticholinergic plus short-acting inhaled beta2 agonist4−2000LowQuality points deducted for sparse data and incomplete reporting of results
6 (1917)[44]Lung function and exercise capacityShort-acting anticholinergic versus short-acting beta2 agonist4−1000ModerateQuality point deducted for incomplete reporting of results
5 (1529)[44]COPD exacerbation and worsening of symptomsShort-acting anticholinergic versus short-acting beta2 agonist4−1000ModerateQuality point deducted for incomplete reporting of results
5 (1529)[44]Quality of lifeShort-acting anticholinergic versus short-acting beta2 agonist4−1000ModerateQuality point deducted for incomplete reporting of results
at least 2 (at least 471)[45]Lung function and exercise capacityShort-acting anticholinergic versus long-acting beta2 agonist4−1000ModerateQuality point deducted for incomplete reporting of results
4 (1241)[30]COPD exacerbation and worsening of symptomsShort-acting anticholinergic versus long-acting beta2 agonist4−1000ModerateQuality point deducted for incomplete reporting of results
2 (467)[45]Quality of lifeShort-acting anticholinergic versus long-acting beta2 agonist4−1000ModerateQuality point deducted for incomplete reporting of results
2 (1460)[48]MortalityLong-acting anticholinergic versus long-acting beta2 agonist40000High
2 (1382)[48]Lung function and exercise capacityLong-acting anticholinergic versus long-acting beta2 agonist4−1000ModerateQuality point deducted for incomplete reporting of results
2 (1460)[48]COPD exacerbation and worsening of symptomsLong-acting anticholinergic versus long-acting beta2 agonist40000High
2 (807)[30]Quality of lifeLong-acting anticholinergic versus long-acting beta2 agonist4−1000ModerateQuality point deducted for incomplete reporting of results
at least 11 (at least 740)[49][50][51]Lung function and exercise capacityTheophylline (short-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
2 (964)[52][53]Lung function and exercise capacityTheophylline (long-term treatment) versus placebo4−2000LowQuality points deducted for incomplete reporting of results and for inclusion of a 3-armed RCT with 1 open-label arm
1 (110)[53]COPD exacerbation and worsening of symptomsTheophylline (long-term treatment) versus placebo4−1000ModerateQuality point deducted for sparse data
10 (445)[55]Lung function and exercise capacityOral corticosteroids versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
5 (424)[58]Lung function and exercise capacityInhaled corticosteroids (short-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
6 (15,407)[62][35]MortalityInhaled corticosteroids (long-term treatment) versus placebo4−1000ModerateQuality point deducted for poor methodology in 1 very large RCT (analysis included people who had discontinued study medication)
6 (at least 3747)[58][63][64]Lung function and exercise capacityInhaled corticosteroids (long-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
13 (9578)[61][63][64]COPD exacerbation and worsening of symptomsInhaled corticosteroids (long-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
6 (3230)[58][64]Quality of lifeInhaled corticosteroids (long-term treatment) versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
9 (7342)[65][66][67]MortalityCorticosteroid plus long-acting beta2 agonist versus placebo40000High
10 (4070)[65][68][66][67]Lung function and exercise capacityCorticosteroid plus long-acting beta2 agonist versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
7 (5804)[65][67][68]COPD exacerbation and worsening of symptomsCorticosteroid plus long-acting beta2 agonist versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
8 (5205)[65][68]Quality of lifeCorticosteroid plus long-acting beta2 agonist versus placebo4−1000ModerateQuality point deducted for incomplete reporting of results
7 (6682)[69][66]MortalityCorticosteroid plus long-acting beta2 agonist versus corticosteroid alone40000High
6 (1831)[69][68]Lung function and exercise capacityCorticosteroid plus long-acting beta2 agonist versus corticosteroid alone4−1000ModerateQuality point deducted for incomplete reporting of results
5 (4930)[69][68]COPD exacerbation and worsening of symptomsCorticosteroid plus long-acting beta2 agonist versus corticosteroid alone4−1000ModerateQuality point deducted for incomplete reporting of results
at least 5 (at least 3697)[69]Quality of lifeCorticosteroid plus long-acting beta2 agonist versus corticosteroid alone4−1000ModerateQuality point deducted for incomplete reporting of results
11 (10,013)[70]MortalityCorticosteroid plus long-acting beta2 agonist versus beta2 agonist alone4–1000ModerateQuality point deducted for unclear allocation concealment in some RCTs
13 (10,695)[70]Lung function and exercise capacityCorticosteroid plus long-acting beta2 agonist versus beta2 agonist alone4−2000LowQuality points deducted for incomplete reporting of results and unclear allocation concealment in some RCTs
at least 14 (at least 12,297)[70]COPD exacerbation and worsening of symptomsCorticosteroid plus long-acting beta2 agonist versus beta2 agonist alone4−2000LowQuality points deducted for incomplete reporting of results and unclear allocation concealment in some RCTs
10 (9329)[71][70]Quality of lifeCorticosteroid plus long-acting beta2 agonist versus beta2 agonist alone4−2000LowQuality points deducted for incomplete reporting of results and unclear allocation concealment in some RCTs
at least 7 (at least 5764)[72][73][74]COPD exacerbation and worsening of symptomsMucolytics (long-term treatment) versus placebo4−1−2−10Very lowQuality point deducted for incomplete reporting of results. Consistency points deducted for conflicting results and for heterogeneity among RCTs. Directness point deducted for inclusion of people without COPD
11 (2625)[72][74]Quality of lifeMucolytics (long-term treatment) versus placebo4−1−1−10Very lowQuality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity among RCTs. Directness point deducted for inclusion of people without COPD
1 (709)[74]Lung function and exercise capacityMucolytics (long-term treatment) versus placebo4–10–10LowQuality point deducted for incomplete reporting. Directness point deducted for differences in additional medications between groups at baseline
11 (at least 888)[76][77]COPD exacerbation and worsening of symptomsProphylactic antibiotics versus placebo4−10−20Very lowQuality point deducted for incomplete reporting of results. Directness points deducted for inclusion of people without COPD and uncertainty about generalisability of results as some included trials were >30 years old
7 (755)[76]Quality of lifeProphylactic antibiotics versus placebo4−10−20Very lowQuality point deducted for incomplete reporting of results. Directness points deducted for inclusion of people without COPD and uncertainty about generalisability of results as some included trials were >30 years old
1 (109)[77]Lung function and exercise capacityProphylactic antibiotics versus placebo4–10–10LowQuality point deducted for sparse data. Directness point deducted for possible drug–drug interactions
3 (250)[78]MortalityOxygen versus no oxygen (long-term treatment)40−100ModerateConsistency point deducted for conflicting results in different populations
1 (28)[78]Lung function and exercise capacityOxygen versus no oxygen (long-term treatment)4−1000ModerateQuality point deducted for sparse data
1 (28)[78]COPD exacerbation and worsening of symptomsOxygen versus no oxygen (long-term treatment)4−1000ModerateQuality point deducted for sparse data
1 (56)[81]Lung function and exercise capacityAlpha1 antitrypsin versus placebo (long-term treatment)4−10−10LowQuality point deducted for sparse data. Directness point deducted for narrowness of population (people with diagnosis of emphysema)
What are the effects of smoking cessation interventions in people with stable COPD?
1 (3926)[85]MortalityPsychosocial interventions versus usual care400−10ModerateDirectness point deducted for combined analysis at long-term analysis (analysis at 14 years, includes smoking cessation with ipratropium)
1 (5887)[10]Lung function and exercise capacityPsychosocial interventions versus usual care400−10ModerateDirectness point deducted for combined analysis at long-term analysis (analysis at 11 years includes smoking cessation with ipratropium)
1 (5887)[89]COPD exacerbation and worsening of symptomsPsychosocial interventions versus usual care400−10ModerateDirectness point deducted for combined analysis (includes smoking cessation with ipratropium)
1 (3925)[85]MortalityPsychosocial plus pharmacological interventions versus usual care400−10ModerateDirectness point deducted for combined analysis for long-term results (analysis at 14 years includes smoking cessation without ipratropium)
1 (5887)[10]Lung function and exercise capacityPsychosocial plus pharmacological interventions versus usual care400−10ModerateDirectness point deducted for combined analysis at 11 years (includes smoking cessation without ipratropium)
1 (5887)[89]COPD exacerbation and worsening of symptomsPsychosocial plus pharmacological interventions versus usual care400−10ModerateDirectness point deducted for combined analysis at 11 years (includes smoking cessation without ipratropium)
1 (3923)[85]MortalityPsychosocial plus pharmacological interventions versus psychosocial intervention alone40000High
1 (5887)[10]Lung function and exercise capacityPsychosocial plus pharmacological interventions versus psychosocial intervention alone40000High
What are the effects of non-drug interventions in people with stable COPD?
at least 25 (at least 1220)[97][98][99][105][102][101][104]Lung function and exercise capacityPulmonary rehabilitation versus usual care4−1000ModerateQuality point deducted for incomplete reporting of results
at least 14 (at least 802)[97][98][99][104]COPD exacerbation and worsening of symptomsPulmonary rehabilitation versus usual care4−1000ModerateQuality point deducted for incomplete reporting of results
at least 15 (at least 765)[97][104][102][100][101][103]Quality of lifePulmonary rehabilitation versus usual care4−1000ModerateQuality point deducted for incomplete reporting of results
at least 16 (at least 410)[106][107]Lung function and exercise capacityInspiratory muscle training (IMT) versus control or no IMT4−1−1−10Very lowQuality point deducted for incomplete reporting of results. Consistency point deducted for lack of consistent benefit. Directness point deducted for inclusion of co-intervention (general exercise rehabilitation)
2 (number of people not reported)[106]COPD exacerbation and worsening of symptomsInspiratory muscle training (IMT) versus control or no IMT4−10−10LowQuality point deducted for incomplete reporting of results. Directness point deducted for inclusion of co-intervention (general exercise rehabilitation)
at least 6 (number of people not reported)[106]Lung function and exercise capacityInspiratory muscle training (IMT) plus general exercise reconditioning versus general exercise reconditioning alone4−1−100LowQuality point deducted for incomplete reporting of results. Consistency point deducted for lack of consistent benefit
at least 13 (at least 330)[108][107]Lung function and exercise capacityInspiratory muscle training (IMT) versus sham IMT4−1−100LowQuality point deducted for incomplete reporting of results. Consistency point deducted for lack of consistent benefit
4 (96)[108]COPD exacerbation and worsening of symptomsInspiratory muscle training (IMT) versus sham IMT4−2000LowQuality points deducted for sparse data and incomplete reporting of results
2 (69)[108]Quality of lifeInspiratory muscle training (IMT) versus sham IMT4−2000LowQuality points deducted for sparse data and incomplete reporting of results
at least 7 (at least 261)[109]Lung function and exercise capacityPeripheral muscle training versus no treatment or other exercise training4−10−10LowQuality point deducted for incomplete reporting of results. Consistency point deducted for lack of consistent benefit
6 (249)[112][113]Lung function and exercise capacityGeneral physical activity enhancement versus control4−1−100LowQuality point deducted for incomplete reporting of results. Consistency point deducted for inconsistent effects
2 (61)[114][115]COPD exacerbation and worsening of symptomsGeneral physical activity enhancement versus control4−2−100Very lowQuality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
3 (100)[114][115][113]Quality of lifeGeneral physical activity enhancement versus control4−2−100Very lowQuality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
at least 6 (at least 156)[116]Lung function and exercise capacityNutritional supplementation versus placebo or usual diet4−1−1−20Very lowQuality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity among RCTs. Directness points deducted for lack of standardisation of interventions and variations among studies
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.