Interventions for promoting physical activity in people with chronic obstructive pulmonary disease (COPD)

Abstract

Background: Escalating awareness of the magnitude of the challenge posed by low levels of physical activity in people with chronic obstructive pulmonary disease (COPD) highlights the need for interventions to increase physical activity participation. The widely-accepted benefits of physical activity, coupled with the increasing availability of wearable monitoring devices to objectively measure participation, has led to a dramatic rise in the number and variety of studies that aimed to improve the physical activity of people with COPD. However, little was known about the relative efficacy of interventions tested so far.

Objectives: In people with COPD, which interventions are effective at improving objectively-assessed physical activity?

Search methods: We identified trials from the Cochrane Airways Trials Register Register, which contains records identified from bibliographic databases including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, AMED, and PsycINFO. We also searched PEDro, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform portal and the Australian New Zealand Clinical Trials Registry (from inception to June 2019). We checked reference lists of all primary studies and review articles for additional references, as well as respiratory journals and respiratory meeting abstracts, to identify relevant studies.

Selection criteria: We included randomised controlled trials of interventions that used objective measures for the assessment of physical activity in people with COPD. Trials compared an intervention with no intervention or a sham/placebo intervention, an intervention in addition to another standard intervention common to both groups, or two different interventions.

Data collection and analysis: We used standard methods recommended by Cochrane. Subgroup analyses were possible for supervised compared to unsupervised pulmonary rehabilitation programmes in clinically-stable COPD for a range of physical activity outcomes. Secondary outcomes were health-related quality of life, exercise capacity, adverse events and adherence. Insufficient data were available to perform prespecified subgroup analyses by duration of intervention or disease severity. We undertook sensitivity analyses by removing studies that were at high or unclear risk of bias for the domains of blinding and incomplete outcome data.

Main results: We included 76 studies with 8018 participants. Most studies were funded by government bodies, although some were sponsored by equipment or drug manufacturers. Only 38 studies had physical activity as a primary outcome. A diverse range of interventions have been assessed, primarily in single studies, but improvements have not been systematically demonstrated following any particular interventions. Where improvements were demonstrated, results were confined to single studies, or data for maintained improvement were not provided. Step count was the most frequently reported outcome, but it was commonly assessed using devices with documented inaccuracy for this variable. Compared to no intervention, the mean difference (MD) in time in moderate- to vigorous-intensity physical activity (MVPA) following pulmonary rehabilitation was four minutes per day (95% confidence interval (CI) -2 to 9; 3 studies, 190 participants; low-certainty evidence). An improvement was demonstrated following high-intensity interval exercise training (6 minutes per day, 95% CI 4 to 8; 2 studies, 275 participants; moderate-certainty evidence). One study demonstrated an improvement following six months of physical activity counselling (MD 11 minutes per day, 95% CI 7 to 15; 1 study, 280 participants; moderate-certainty evidence), but we found mixed results for the addition of physical activity counselling to pulmonary rehabilitation. There was an improvement following three to four weeks of pharmacological treatment with long-acting muscarinic antagonist and long-acting beta2-agonist (LAMA/LABA) compared to placebo (MD 10 minutes per day, 95% CI 4 to 15; 2 studies, 423 participants; high-certainty evidence). These interventions also demonstrated improvements in other measures of physical activity. Other interventions included self-management strategies, nutritional supplementation, supplemental oxygen, endobronchial valve surgery, non-invasive ventilation, neuromuscular electrical stimulation and inspiratory muscle training.

Authors' conclusions: A diverse range of interventions have been assessed, primarily in single studies. Improvements in physical activity have not been systematically demonstrated following any particular intervention. There was limited evidence for improvement in physical activity with strategies including exercise training, physical activity counselling and pharmacological management. The optimal timing, components, duration and models for interventions are still unclear. Assessment of quality was limited by a lack of methodological detail. There was scant evidence for a continued effect over time following completion of interventions, a likely requirement for meaningful health benefits for people with COPD.

Conflict of interest statement

Angela Burge received a PhD stipend from the National Health and Medical Research Council (NHMRC), Australia. This Cochrane Review forms a part of those PhD studies. The National Health and Medical Research Council (NHMRC) supports the independent conduct and publication of this Cochrane Review.

Narelle Cox is the holder of a NHMRC Early Career Fellowship. She presented workshops relating to pulmonary rehabilitation at the 2018 National General Practitioners Meeting sponsored by Boeringher Ingelheim.

Michael Abramson holds investigator‐initiated grants from Pfizer and Boehringer‐Ingelheim for unrelated research, undertook unrelated consultancies for AstraZeneca and Sanofi, and received assistance with conference attendance from Boehringer‐Ingelheim and Sanofi.

Anne Holland has received fees from AstraZeneca and Boehringer Ingelheim for non‐promotional speaking engagements (unrelated to the present work).

Three review authors (AB, NC and AH) were co‐authors on an included study (Holland 2017), so an independent co‐author (MA) undertook the assessment of risks of bias.

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figures

1

Study flow diagram.

2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

3

Forest plot of comparison 1: Intervention vs. no intervention Outcome 1.1: Physical activity: change in step count (steps per day)

4

Forest plot of comparison 1: Intervention vs. no intervention Outcome 1.2: Physical activity: change in time in moderate‐to‐vigorous intensity physical activity (minutes per day)

5

Forest plot of comparison 1: Intervention vs. no intervention Outcome 1.4: Physical activity: change in time in light‐intensity physical activity (minutes per day)

6

Forest plot of comparison 1: Intervention vs. no intervention Outcome 1.3: Physical activity: change in total energy expenditure (kcal)

7

Forest plot of comparison 1: Intervention vs. no intervention Outcome 1.6: Physical activity: change in time in physical activity (total, minutes per day)

8

Forest plot of comparison 1: Intervention vs. no intervention Outcome 1.5: Physical activity: change in sedentary time (minutes per day)

9

Forest plot of comparison 1: Intervention vs. no intervention Outcome: 1.8 Physical activity: time in "lifestyle" physical activity (minutes per day)

10

Forest plot of comparison: 1 Intervention vs. no intervention Outcome: 1.7 Physical activity: time in light‐intensity physical activity (minutes per day)

11

Forest plot of comparison 1: Intervention vs. vs. no intervention Outcome 1.9: Physical activity: time in MVPA (minutes per day)

12

Forest plot of comparison 1: Intervention vs. no intervention Outcome 1.10: Physical activity: sedentary time (minutes per day)

13

Forest plot of comparison 2: Intervention vs. placebo Outcome 2.2: Physical activity: change in step count (steps per day)

14

Forest plot of comparison 2: Intervention vs. placebo Outcome 2.3: Physical activity: change in time in moderate‐to‐vigorous intensity physical activity (minutes per day)

15

Forest plot of comparison 2: Intervention vs. placebo Outcome 2.4: Physical activity: change in active energy expenditure (kcal)

1.1. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 1 change in step count (steps per day); Intervention: pulmonary rehabilitation/exercise training.

1.2. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 2 time/change in time in moderate‐to‐vigorous intensity physical activity (minutes per day); Intervention: pulmonary rehabilitation/exercise training.

1.3. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 3 change in time in light‐intensity physical activity (minutes per day); Intervention: pulmonary rehabilitation/exercise training.

1.4. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 4 change in total energy expenditure (kcal); Intervention: pulmonary rehabilitation/exercise training.

1.5. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 5 change in time in physical activity (total; minutes per day); Intervention: pulmonary rehabilitation/exercise training.

1.6. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 6 change in sedentary time (minutes per day); Intervention: pulmonary rehabilitation/exercise training.

1.7. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 7 time in "lifestyle" physical activity (minutes per day); Intervention: high‐intensity interval training.

1.8. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 8 time in light‐intensity physical activity (minutes per day); Intervention: high‐intensity interval training.

1.9. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 9 time in moderate‐to‐vigorous intensity physical activity (minutes per day); Intervention: high‐intensity interval training.

1.10. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 10 sedentary time (minutes per day); Intervention: high‐intensity interval training.

1.11. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 11 step count (steps per day); Intervention: physical activity counselling.

1.12. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 12 "IMA" (counts per minute); Intervention: self‐management.

1.13. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 13 physical activity level; Intervention: nutritional supplement.

1.14. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 14 total energy expenditure (MJ); Intervention: nutritional supplement.

1.15. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 15 subgroup analysis (supervised vs. unsupervised); change in step count (steps per day); Intervention: pulmonary rehabilitation/exercise training.

1.16. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 16 supgroup analysis (supervised vs. unsupervised); change in time in light‐intensity physical activity (minutes per day); Intervention: pulmonary rehabilitation/exercise training.

1.17. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 17 subgroup analysis (supervised vs. unsupervised); change in total energy expenditure (kcal); Intervention: pulmonary rehabilitation/exercise training.

1.18. Analysis

Comparison 1 Physical activity: intervention vs. no intervention, Outcome 18 subgroup analysis (supervised vs. unsupervised); change in sedentary time (minutes per day); Intervention: pulmonary rehabilitation/exercise training.

2.1. Analysis

Comparison 2 Physical activity: intervention vs. placebo/sham, Outcome 1 step count (steps per day); Intervention: self‐management (health mentoring).

2.2. Analysis

Comparison 2 Physical activity: intervention vs. placebo/sham, Outcome 2 change in step count (steps per day); Intervention: LAMA/LABA.

2.3. Analysis

Comparison 2 Physical activity: intervention vs. placebo/sham, Outcome 3 change in time in moderate‐to‐vigorous intensity physical activity (minutes per day): Intervention: LAMA/LABA.

2.4. Analysis

Comparison 2 Physical activity: intervention vs. placebo/sham, Outcome 4 change in active energy expenditure (kcal); Intervention: LAMA/LABA.

2.5. Analysis

Comparison 2 Physical activity: intervention vs. placebo/sham, Outcome 5 step count (steps per day); Intervention: nutritional supplement.

2.6. Analysis

Comparison 2 Physical activity: intervention vs. placebo/sham, Outcome 6 energy expenditure for ambulation (kcal/step/FFM kg); Intervention: nutritional supplement.

2.7. Analysis

Comparison 2 Physical activity: intervention vs. placebo/sham, Outcome 7 change in step count (steps per day); Intervention: neuromuscular electrical stimulation.

2.8. Analysis

Comparison 2 Physical activity: intervention vs. placebo/sham, Outcome 8 change in up/down transitions (number); Intervention: neuromuscular electrical stimulation.

2.9. Analysis

Comparison 2 Physical activity: intervention vs. placebo/sham, Outcome 9 change in time upright (hours); Intervention: neuromuscular electrical stimulation.

3.1. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 1 movement intensity (m/s2); Interventions: nordic walking with education vs. education.

3.2. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 2 change in step count (steps per day); Interventions: exercise training (COPE‐active) with self‐management vs. self management.

3.3. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 3 change in time in light‐intensity physical activity (minutes per day); Interventions: upper body resistance training with health education vs. health education.

3.4. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 4 step count (steps per day); Interventions: LAMA/LABA and exercise training with behaviour modification vs. placebo with behaviour modification.

3.5. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 5 time walking (minutes per day); Interventions: LAMA/LABA and exercise training with behaviour modification vs. placebo with behaviour modification.

3.6. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 6 walking intensity (m/s2); Interventions: LAMA/LABA and exercise training with behaviour modification vs. placebo with behaviour modification.

3.7. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 7 step count (steps per day); Interventions: exercise training and LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

3.8. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 8 time walking (minutes per day); Interventions: exercise training and LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

3.9. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 9 walking intensity (m/s2); Interventions: exercise training and LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

3.10. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 10 step count (steps per day); Interventions: exercise training with LAMA/LABA and behaviour modification vs. LAMA/LABA and behaviour modification.

3.11. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 11 time walking (minutes per day); Interventions: exercise training with LAMA/LABA and behaviour modification vs. LAMA/LABA and behaviour modification.

3.12. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 12 walking intensity (m/s2); Interventions: exercise training with LAMA/LABA and behaviour modification vs. LAMA/LABA and behaviour modification.

3.13. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 13 change in step count (steps per day); Interventions: exercise training and physical activity counselling with pedometer vs. pedometer.

3.14. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 14 change in step count (weekday, steps per day); Interventions: physical activity counselling with optional supervised exercise vs. optional supervised exercise.

3.15. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 15 METs; Interventions: physical activity counselling with optional supervised exercise vs. optional supervised exercise.

3.16. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 16 step count (steps per day); Interventions: physical activity counselling with pedometer vs. pedometer.

3.17. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 17 time active (minutes per day); Interventions: physical activity counselling (app) with pedometer vs. pedometer.

3.18. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 18 time inactive (minutes per day); Interventions: physical activity counselling (app) with pedometer vs. pedometer.

3.19. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 19 peak performance (steps per minute); Interventions: physical activity counselling (app) with pedometer vs. pedometer.

3.20. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 20 step count (steps per day); Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

3.21. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 21 time in moderate‐to‐vigorous intensity physical activity (minutes per day); Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

3.22. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 22 time in physical activity (total, minutes per day); Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

3.23. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 23 time sedentary (minutes per day); Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

3.24. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 24 change in step count (steps per day); Interventions: physical activity counselling with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

3.25. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 25 change in time in moderate‐to‐vigorous intensity physical activity (minutes per day); Interventions: physical activity counselling with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

3.26. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 26 change in time walking (minutes per day); Interventions: physical activity counselling with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

3.27. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 27 change in time in physical activity (total, minutes per day); Interventions: physical activity counselling with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

3.28. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 28 change in time in light‐intensity physical activity (minutes per day); Interventions: exercise‐specific self‐efficacy training with upper body resistance training vs. upper body resistance training.

3.29. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 29 step count (steps per day); Interventions: LAMA with behaviour modification vs. placebo with behaviour modification.

3.30. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 30 time walking (minutes per day); Interventions: LAMA with behaviour modification vs. placebo with behaviour modification.

3.31. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 31 walking intensity (m/s2); Interventions: LAMA with behaviour modification vs. placebo with behaviour modification.

3.32. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 32 step count (steps per day); Interventions: LAMA/LABA with behaviour modification vs. placebo with behaviour modification.

3.33. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 33 time walking (minutes per day); Interventions: LAMA/LABA with behaviour modification vs. placebo with behaviour modification.

3.34. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 34 walking intensity (m/s2); Interventions: LAMA/LABA with behaviour modification vs. placebo with behaviour modification.

3.35. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 35 step count (steps per day); Interventions: LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

3.36. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 36 time walking (minutes per day); Interventions: LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

3.37. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 37 walking intensity (m/s2); Interventions: LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

3.38. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 38 change in step count (steps per day); Interventions: nutritional supplement with pulmonary rehabilitation vs. placebo with pulmonary rehabilitation.

3.39. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 39 change in step count (steps per day); Interventions: supplemental oxygen with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

3.40. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 40 change in time in moderate‐intensity physical activity (minutes per day); Interventions: supplemental oxygen with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

3.41. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 41 change in time in vigorous‐intensity physical activity (minutes per day); Interventions: supplemental oxygen with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

3.42. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 42 change in time in light‐intensity physical activity (minutes per day); Interventions: supplemental oxygen with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

3.43. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 43 change in total energy expenditure (kcal); Interventions: supplemental oxygen with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

3.44. Analysis

Comparison 3 Physical activity: intervention with common intervention vs. common intervention, Outcome 44 change in sedentary time (minutes per day); Interventions: supplemental oxygen with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

4.1. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 1 change in step count (steps per day); Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.2. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 2 change in time in moderate‐to‐vigorous intensity physical activity (minutes per day); Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.3. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 3 change in number of bouts of moderate‐to‐vigorous intensity physical activity; Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.4. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 4 change in time in bouts of moderate‐to‐vigorous intensity physical activity(minutes per day); Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.5. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 5 change in sedentary time (minutes per day); Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.6. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 6 change in sedentary time (awake; minutes per day); Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.7. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 7 change in number of sedentary bouts; Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.8. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 8 change in time in sedentary bouts (minutes per day); Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.9. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 9 change in METs; Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.10. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 10 change in total energy expenditure (kcal); Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

4.11. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 11 change in step count (steps per day); Interventions: water‐based exercise training vs. land‐based exercise training.

4.12. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 12 change in total energy expenditure (kcal); Interventions: water‐based exercise training vs. land‐based exercise training.

4.13. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 13 step count (steps per day); Interventions: Tai Chi vs. pulmonary rehabilitation.

4.14. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 14 step count (steps per day); Interventions: outdoor walking vs. cycle ergometry.

4.15. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 15 step count (steps per day); Interventions: physical activity counselling vs. pulmonary rehabilitation.

4.16. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 16 total energy expenditure (kcal); Interventions: exercise training with tapered supervision vs. supervised exercise training.

4.17. Analysis

Comparison 4 Physical activity: intervention vs. intervention, Outcome 17 mid day activity (vector magnitude units per minute); Interventions: supplemental oxygen (lightweight ambulatory) vs. supplemental oxygen (E‐cylinder).

5.1. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 1 change in SGRQ total score; Intervention: pulmonary rehabilitation/exercise training.

5.2. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 2 change in SGRQ domain scores. Intervention: pulmonary rehabilitation/exercise training (ground‐based walking).

5.3. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 3 change in CRQ domain scores; Intervention: pulmonary rehabilitation/exercise training.

5.4. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 4 CAT score; Intervention: high‐intensity interval training.

5.5. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 5 SGRQ domain scores (%change); Intervention: exercise training [inpatient].

5.6. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 6 SGRQ domain scores; Intervention: physical activity counselling.

5.7. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 7 CCQ domain scores: Intervention: physical activity counselling.

5.8. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 8 change in CCQ domain scores; Intervention: physical activity counselling (telecoaching).

5.9. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 9 change in CRQ domain and total scores; Intervention: physical activity counselling.

5.10. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 10 change in SGRQ domain and total scores; Intervention: physical activity counselling.

5.11. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 11 change in CRQ domain scores; Intervention: self‐management (SPACE).

5.12. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 12 CCQ total score; Intervention: self‐management.

5.13. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 13 EQ5D index score; Intervention: self‐management.

5.14. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 14 EQ5D visual analogue scale score; Intervention: self‐management.

5.15. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 15 SGRQ domain scores; Intervention: self‐management (telephone health coaching).

5.16. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 16 EQ5D score; Intervention: self‐management (telephone health coaching).

5.17. Analysis

Comparison 5 Health‐related quality of life: intervention vs. no intervention, Outcome 17 CRQ domain scores; Intervention: four‐wheeled walker.

6.1. Analysis

Comparison 6 Health‐related quality of life: intervention vs. placebo/sham, Outcome 1 change in SF36 component scores; Intervention: singing.

6.2. Analysis

Comparison 6 Health‐related quality of life: intervention vs. placebo/sham, Outcome 2 change in CRQ total score; Intervention: neuromuscular electrical stimulation.

6.3. Analysis

Comparison 6 Health‐related quality of life: intervention vs. placebo/sham, Outcome 3 change in SGRQ total score; Intervention: neuromuscular electrical stimulation.

6.4. Analysis

Comparison 6 Health‐related quality of life: intervention vs. placebo/sham, Outcome 4 change in EQ5D index score; Intervention: neuromuscular electrical stimulation.

6.5. Analysis

Comparison 6 Health‐related quality of life: intervention vs. placebo/sham, Outcome 5 change in EQ5D visual analogue scale score; Intervention: neuromuscular electrical stimulation.

7.1. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 1 SF36 component scores (score

7.2. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 2 change in CRQ domain scores; Interventions: exercise training (COPE‐active) with self‐management vs. self management.

7.3. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 3 change in CCQ domain scores; Interventions: exercise training (COPE‐active) with self‐management vs. self management.

7.4. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 4 CRQ domain scores; Interventions: LAMA/LABA and exercise training with behaviour modification vs. placebo with behaviour modification.

7.5. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 5 CRQ domain scores; Interventions: exercise training and LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

7.6. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 6 CRQ domain scores; Interventions: exercise training with LAMA/LABA and behaviour modification vs. LAMA/LABA and behaviour modification.

7.7. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 7 change in SGRQ domain and total scores; Intervention: exercise training and physical activity counselling with pedometer vs. pedometer.

7.8. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 8 change in CRQ domain scores; Interventions: physical activity counselling (app) with optional supervised exercise vs. optional supervised exercise.

7.9. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 9 change in SGRQ total score; Interventions: physical activity counselling with pedometer vs. pedometer.

7.10. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 10 SGRQ total: Interventions: physical activity counselling (app) with pedometer vs. pedometer.

7.11. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 11 SF36: Interventions: physical activity counselling (app) with pedometer vs. pedometer.

7.12. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 12 change in SGRQ domain scores; Interventions: physical activity counselling (web‐based) with pedometer vs. pedometer.

7.13. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 13 SGRQ domain scores; Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

7.14. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 14 RAND36 domain scores; Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

7.15. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 15 change in CRQ dyspnoea domain score; Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

7.16. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 16 SGRQ scores; Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

7.17. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 17 CRQ domain scores; Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

7.18. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 18 change in CRQ total score; Interventions: physical activity counselling with pulmonary rehabilitation vs. sham intervention with pulmonary rehabilitation.

7.19. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 19 change in CRQ scores; Interventions: self‐management (health coaching) with pulmonary rehabilitation referral vs. pulmonary rehabilitation referral.

7.20. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 20 CRQ domain scores; Interventions: LAMA with behaviour modification vs. placebo with behaviour modification.

7.21. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 21 CRQ domain scores; Interventions: LAMA/LABA with behaviour modification vs. placebo with behaviour modification.

7.22. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 22 CRQ domain scores; Interventions: LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

7.23. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 23 change in SGRQ domain and total scores; Interventions: ACE inhibitor with pulmonary rehabilitation vs. placebo with pulmonary rehabilitation.

7.24. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 24 change in SGRQ total score; Interventions: nutritional supplement with pulmonary rehabilitation vs. placebo with pulmonary rehabilitation.

7.25. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 25 change in EQ5D; Interventions: nutritional supplement with pulmonary rehabilitation vs. placebo with pulmonary rehabilitation.

7.26. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 26 change in CRQ domain scores; Interventions: supplemental oxygen with pulmonary rehabilitation vs. sham intervention with pulmonary rehabilitation.

7.27. Analysis

Comparison 7 Health‐related quality of life: intervention with common intervention vs. common intervention, Outcome 27 CRQ domain scores; Interventions: non‐invasive ventilation with pulmonary rehabilitation vs. pulmonary rehabilitation.

8.1. Analysis

Comparison 8 Exercise capacity: intervention vs. placebo/sham, Outcome 1 change in 6MWD (metres); Intervention; neuromuscular electrical stimulation.

9.1. Analysis

Comparison 9 Exercise capacity: intervention vs. no intervention, Outcome 1 change in 6MWD (metres); Intervention: pulmonary rehabilitation/exercise training.

9.2. Analysis

Comparison 9 Exercise capacity: intervention vs. no intervention, Outcome 2 change in ISWD (metres); Intervention: pulmonary rehabilitation/exercise training.

9.3. Analysis

Comparison 9 Exercise capacity: intervention vs. no intervention, Outcome 3 change in ESWT (seconds); Intervention: pulmonary rehabilitation/exercise training.

9.4. Analysis

Comparison 9 Exercise capacity: intervention vs. no intervention, Outcome 4 6MWD (metres); Intervention: high‐intensity interval training.

9.5. Analysis

Comparison 9 Exercise capacity: intervention vs. no intervention, Outcome 5 work rate (watts); Intervention: high‐intensity interval training.

9.6. Analysis

Comparison 9 Exercise capacity: intervention vs. no intervention, Outcome 6 change in ISWD (metres); Intervention: self‐management (SPACE).

9.7. Analysis

Comparison 9 Exercise capacity: intervention vs. no intervention, Outcome 7 change in ESWT (seconds); Intervention: self‐management (SPACE).

9.8. Analysis

Comparison 9 Exercise capacity: intervention vs. no intervention, Outcome 8 6MWD (metres); Intervention: exercise training [inpatient].

10.1. Analysis

Comparison 10 Health‐related quality of life: intervention vs. intervention, Outcome 1 change in CRQ domains; Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

10.2. Analysis

Comparison 10 Health‐related quality of life: intervention vs. intervention, Outcome 2 change in CRQ domains; Interventions: water‐based exercise training vs. land‐based exercise training.

10.3. Analysis

Comparison 10 Health‐related quality of life: intervention vs. intervention, Outcome 3 SGRQ domain and total scores; Interventions: Tai Chi vs. pulmonary rehabilitation.

10.4. Analysis

Comparison 10 Health‐related quality of life: intervention vs. intervention, Outcome 4 CRQ total score; Interventions: outdoor walking vs. cycle ergometry.

10.5. Analysis

Comparison 10 Health‐related quality of life: intervention vs. intervention, Outcome 5 Maugeri Respiratory Failure questionnaire; Interventions: exercise training with tapered supervision vs. supervised exercise training.

10.6. Analysis

Comparison 10 Health‐related quality of life: intervention vs. intervention, Outcome 6 SF36 domain scores; Interventions: self‐management vs. education and symptom monitoring.

11.1. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 1 6MWD (metres); Interventions: Nordic walking with education vs. education.

11.2. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 2 change in ISWD (metres); Interventions: exercise training (COPE‐active) with self‐management vs. self management.

11.3. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 3 change in ESWT (seconds); Interventions: exercise training (COPE‐active) with self‐management vs. self management.

11.4. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 4 6MWD (metres); Interventions: exercise training and LAMA/LABA with behaviour modification vs. placebo with behaviour modification.

11.5. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 5 ESWT (seconds); Interventions: exercise training and LAMA/LABA with behaviour modification vs. placebo with behaviour modification.

11.6. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 6 6MWD (metres); Interventions: exercise training and LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

11.7. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 7 ESWT (seconds); Interventions: exercise training and LABA with LAMA and behaviour modification vs. LAMA and behaviour modification.

11.8. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 8 6MWD (metres); Interventions: exercise training with LAMA/LABA and behaviour modification vs. LAMA/LABA and behaviour modification.

11.9. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 9 ESWT (seconds); Interventions: exercise training with LAMA/LABA and behaviour modification vs. LAMA/LABA and behaviour modification.

11.10. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 10 change in ESWT (seconds); Intervention: physical activity counselling and exercise training with pedometer vs. pedometer.

11.11. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 11 6MWD (metres); Interventions: physical activity counselling (app) with optional supervised exercise vs. optional supervised exercise.

11.12. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 12 6MWD (metres); Interventions: physical activity counselling (app) with pedometer vs. pedometer.

11.13. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 13 6MWD (metres); Interventions: physical activity counselling with pulmonary rehabilitation vs. pulmonary rehabilitation.

11.14. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 14 change in 6MWD (metres); Interventions: physical activity counselling with pulmonary rehabilitation vs. sham with pulmonary rehabilitation.

11.15. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 15 6MWD (metres); Interventions: LAMA with behaviour modification vs. placebo with behaviour modification.

11.16. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 16 ESWT (seconds); Interventions: LAMA with behaviour modification vs. placebo with behaviour modification.

11.17. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 17 6MWD (metres); Interventions: LAMA/LABA with behaviour modification vs. placebo with behaviour modification.

11.18. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 18 ESWT (s); Interventions: LAMA/LABA with behaviour modification vs. placebo with behaviour modification.

11.19. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 19 6MWD (metres); Interventions: LAMA/LABA with behaviour modification vs. LAMA with behaviour modification.

11.20. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 20 ESWT (seconds); Interventions: LAMA/LABA with behaviour modification vs. LAMA with behaviour modification.

11.21. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 21 change in ISWD (metres); Interventions: supplemental oxygen with pulmonary rehabilitation vs. sham intervention with pulmonary rehabilitation.

11.22. Analysis

Comparison 11 Exercise capacity: intervention with common intervention vs. common intervention, Outcome 22 change in ESWT (seconds); Interventions: supplemental oxygen with pulmonary rehabilitation vs. sham intervention with pulmonary rehabilitation.

12.1. Analysis

Comparison 12 Exercise capacity: intervention vs. intervention, Outcome 1 change in 6MWD (metres); Interventions: home‐based pulmonary rehabilitation vs. centre‐based pulmonary rehabilitation.

12.2. Analysis

Comparison 12 Exercise capacity: intervention vs. intervention, Outcome 2 change in 6MWD (metres); Interventions: water‐based exercise training vs. land‐based exercise training.

12.3. Analysis

Comparison 12 Exercise capacity: intervention vs. intervention, Outcome 3 change in ISWD (metres); Interventions: water‐based exercise training vs. land‐based exercise training.

12.4. Analysis

Comparison 12 Exercise capacity: intervention vs. intervention, Outcome 4 change in VO2max (ml/min); Interventions: water‐based exercise training vs. land‐based exercise training.

12.5. Analysis

Comparison 12 Exercise capacity: intervention vs. intervention, Outcome 5 6MWD (metres); Interventions: Tai Chi vs. pulmonary rehabilitation.

12.6. Analysis

Comparison 12 Exercise capacity: intervention vs. intervention, Outcome 6 6MWD (metres); Interventions: exercise training with tapered supervision vs. supervised exercise training.

References

References to studies included in this review Alison 2019 {published data only}

Altenburg 2015 {published data only} Arbillaga‐Etxarri 2018 {published data only} Beeh 2014 {published and unpublished data} Bender 2016 {published data only} Benzo 2016 {published data only (unpublished sought but not used)} Blumenthal 2014 {published data only} Borges 2014 {published and unpublished data} Breyer 2010 {published data only (unpublished sought but not used)} Burtin 2015 {published data only} Casaburi 2012 {published data only} Chaplin 2017 {published data only} Charususin 2018 {published data only} Cruz 2016 {published data only} Curtis 2016 {published data only} Dal Negro 2012 {published data only (unpublished sought but not used)} De Blok 2006 {published data only} Demeyer 2017 {published and unpublished data} De Roos 2017 {published and unpublished data} Duiverman 2008 {published data only} Effing 2011 {published data only} Egan 2010 {published and unpublished data} Felcar 2018 {published data only} Gamper 2019 {published data only} Goris 2003 {published data only} Hartman 2016 {published data only} Holland 2017 {published data only} Hornikx 2015 {published data only} Hospes 2009 {published data only (unpublished sought but not used)} Jolly 2018 {published data only} Kanabar 2015 {published and unpublished data} Kawagoshi 2015 {published data only} Larson 2014 {published data only (unpublished sought but not used)} Loeckx 2018 {published data only} Lord 2012 {published data only (unpublished sought but not used)} Louvaris 2016 {published and unpublished data} Maddocks 2016 {published data only} Magnussen 2017 {published and unpublished data} Mantoani 2018 {published data only} Mendoza 2015 {published data only} Mitchell 2013 {published and unpublished data} Moy 2015a {published data only} Nakamura 2016 {published data only} NCT00144326 {published data only} NCT01351792 {published data only} Ng 2015 {published and unpublished data} Nguyen 2009 {published data only} Nolan 2017 {published and unpublished data} O'Neill 2018 {published data only} Ogasawara 2018 {published data only} Orme 2018 {published data only} Polkey 2018 {published data only} Priori 2017 {published and unpublished data} Probst 2011 {published data only} Rinaldo 2017 {published data only} Saini 2017 {published data only} Sandland 2008 {published data only} Schuz 2015 {published and unpublished data} Sena 2013 {published and unpublished data} Singh 1998 {published data only (unpublished sought but not used)} Steele 2019 {published data only} Tabak 2014a {published data only} Tabak 2014b {published data only} Tahirah 2015 {published and unpublished data} Troosters 2014 {published data only (unpublished sought but not used)} Troosters 2018 {published data only} Tsai 2016 {published and unpublished data} Van de Bool 2017 {published data only} Varas 2018 {published and unpublished data} Vasilopoulou 2017 {published and unpublished data} Vorrink 2016 {published data only} Wan 2017 {published and unpublished data} Watz 2016 {published and unpublished data} Watz 2017 {published data only} Widyastuti 2018 {published data only} Wootton 2017 {published and unpublished data} References to studies excluded from this review ACTRN12611001034921 {published data only} Aksu 2006 {published data only} Arnedillo 1998 {published data only} Atkins 1984 {published data only} Barnes‐Harris 2019 {published data only} Bartlett 2017 {published data only} Baumann 2006 {published data only} Behnke 2000 {published data only} Behnke 2005 {published data only} Bernardi 2017 {published data only} Bertici 2013 {published data only} Biscione 2009 {published data only} Bohning 1990 {published data only} Boland 2015 {published data only} Börekçi 2008 {published data only} Borges 2012 {published data only} Bourbeau 2000 {published data only} Budnevskiy 2015 {published data only} Bunker 2012 {published data only} Bustamante 2013 {published data only} Camillo 2011 {published data only} Cebollero 2018 {published data only} Chen 2018 {published data only} Corrado 1995 {published data only} Coultas 2011 {published data only} Coultas 2017 {published data only} De Backer 2014 {published data only} Deering 2011 {published data only} De Souza 2017 {published data only} Durheim 2015 {published data only} Dyer 2011 {published data only} EUCTR2016‐003675‐21‐ES {published data only} Faulkner 2010 {published data only} Fernandez 1998 {published data only} Foy 2006 {published data only} Friis 2017 {published data only} Furness 2014 {published data only} Garcia Aymerich 2016 {published data only} Gohl 2004 {published data only} Gohl 2006 {published data only} Gomez 2006 {published data only} Gosselink 1990 {published data only} Grabenhorst 2013 {published data only} Greulich 2013 {published data only} Guell 2008 {published data only} Gurgun 2011 {published data only} Hartman 2012 {published data only} Hataji 2017 {published data only} Herrejon 2010 {published data only} Hillegass 2012 {published data only} Horton 2018 {published data only} Ichinose 2017 {published data only} Ides 2012 {published data only} Innocenti 2000 {published data only} Johnson‐Warrington 2016 {published data only} Jonsdottir 2015 {published data only} Kato 2017 {published data only} Kim 2003 {published data only} Kruis 2014 {published data only} Langer 2018 {published data only} Larraz 2010 {published data only} Lee 2007 {published data only} Liang 2018 {published data only} Liu 2019 {published data only} Lum 2007 {published data only} Mahesh 2017 {published data only} Marques 2019 {published data only} Martinez 2008 {published data only} McGlone 2006 {published data only} McMahon 2000 {published data only} Mesquita 2017 {published data only} Moore 2009 {published data only} Morris 2012 {published data only} Moy 2009 {published data only} Moy 2012 {published data only} Murphy 2005 {published data only} Nagata 2018 {published data only} NCT00620022 {published data only} NCT01012765 {published data only} NCT01380652 {published data only} NCT01486186 {published data only} NCT01722370 {published data only} NCT01854008 {published data only} NCT01867970 {published data only} NCT01871025 {published data only} NCT02100709 {published data only} NCT02172794 {published data only} NCT02629965 {published data only} NCT02656667 {published data only} NCT03751670 {published data only} NL1729 {published data only} Norweg 2006 {published data only} Nyberg 2017 {published data only} Paneroni 2016 {published data only} Pasqua 2010 {published data only} Pinnock 2013 {published data only} Pitta 2008 {published data only} Pomidori 2012 {published data only} Raphael 2014 {published data only} Ringbaek 2009 {published data only} Robbins 2000 {published data only} Rodriguez‐Trigo 2011 {published data only} Romagnoli 2005 {published data only} Roman 2013 {published data only} Schacher 2006 {published data only} Schönhofer 1997 {published data only} Senthilnathan 2018 {published data only} Sewell 2005 {published data only} Sewell 2010 {published data only} Sirichana 2013 {published data only} Soicher 2009 {published data only} Spencer 2012 {published data only} Steele 2008 {published data only} Strijbos 1991 {published data only} Sutanto 2018 {published data only} TCTR20170214002 {published data only} Troosters 2010 {published data only} Troosters 2011 {published data only} Tse 2013 {published data only} Turnbull 2013 {published data only} Turner‐Lawlor 2005 {published data only} U1111‐1169‐0718 {published data only} UMIN000001833 {published data only} Valenson 2016 {published data only} Voncken‐Brewster 2013 {published data only} Wilson 2015 {published data only} Zanini 2002 {published data only} References to ongoing studies ACTRN12615000121561 {published data only} ACTRN 12616000360415 {published data only} ACTRN12616001534471 {published data only} ACTRN12616001586404 {published data only} ACTRN12617000242325 {published data only} ACTRN12617000499381 {published data only} ACTRN12617000653369 {published data only} ANZCTR12611000292976 {published data only} Beekman 2014 {published data only} ChiCTR1800017405 {published data only} DRKS00004931 {published data only} DRKS00010777 {published data only} EUCTR2006‐005534‐20‐GB {published data only} EUCTR2013‐003619‐24‐ES {published data only} EUCTR2016‐001238‐89‐ES {published data only} EUCTR2016‐001805‐18‐SE {published data only} Fastenau 2014 {published data only} ISRCTN11017699 {published data only} ISRCTN13899108 {published data only} ISRCTN15949009 {published data only} ISRCTN17942821 {published data only} ISRCTN19684749 {published data only} ISRCTN27860457 {published data only} ISRCTN45695543 {published data only} ISRCTN80279999 {published data only} NCT01037387 {published data only} NCT01537627 {published data only} NCT01539434 {published data only} NCT01783808 {published data only} NCT01905982 {published data only} NCT01998724 {published data only} NCT02099799 {published data only} NCT02205242 {published data only} NCT02398643 {published data only} NCT02455206 {published data only} NCT02471235 {published data only} NCT02478359 {published data only} NCT02557178 {published data only} NCT02667171 {published data only} NCT02691104 {published data only} NCT02702791 {published data only} NCT02707770 {published data only} NCT02720822 {published data only} NCT02864420 {published data only} NCT02895152 {published data only} NCT02917915 {published data only} NCT02924870 {published data only} NCT02956213 {published data only} NCT02966561 {published data only} NCT02999685 {published data only} NCT03073954 {published data only} NCT03080662 {published data only} NCT03084874 {published data only} NCT03114241 {published data only} NCT03127878 {published data only} NCT03201198 {published data only} NCT03275116 {published data only} NCT03280355 {published data only} NCT03321279 {published data only} NCT03359473 {published data only} NCT03513068 {published data only} NCT03584269 {published data only} NCT03584295 {published data only} NCT03620630 {published data only} NCT03654092 {published data only} NCT03655028 {published data only} NCT03660644 {published data only} NCT03746873 {published data only} NCT03749655 {published data only} NCT03750292 {published data only} NCT03793192 {published data only} NCT03794921 {published data only} NCT03807310 {published data only} NCT03810755 {published data only} NCT03817294 {published data only} NCT03869112 {published data only} NCT03899558 {published data only} NL3827 {published data only} NL5277 {published data only} RBR‐3zmh3r {published data only} UMIN000027190 {published data only} UMIN000031173 {published data only} UMIN000033093 {published data only} Zanaboni 2016 {published data only} Additional references Adeloye 2015 Alahmari 2015 Andersson 2015 Anton 2016 Arne 2009 Casperson 1985 Choudhury 2014 Deeks 2017 Dhillon 2015 Esteban 2010 Esteban 2014 Fastenau 2013 Furlanetto 2010 Furlanetto 2014 Gagnon 2015 Garcia‐Aymerich 2006 Garcia‐Rio 2012 Gimeno‐Santos 2011 GOLD 2019 GRADEpro GDT 2014 [Computer program] Higgins 2017 Hill 2013 Iwakura 2016 Johnson‐Warrington 2014 Lahham 2016 Langer 2016 Lee 2012 Lee 2015 Lefebvre 2011 Mantoani 2016 Marcus 2006 McCarthy 2015 Michie 2013 Moher 2009 Nasis 2015 O’Donnell 2014 Pitta 2005 Pitta 2006a Pitta 2006b Review Manager 2014 [Computer program] Schünemann 2017 Shrikrishna 2012 Singh 2016 Trost 2002 U.S. Department of Health and Human Services 2018 UN 2015 Vaes 2014 Van Remoortel 2013 Van Remoortel 2014 Vorrink 2011 Waschki 2011 Waschki 2015 Watz 2009 Watz 2014a WHO 2010 WHO 2017 References to other published versions of this review Burge 2017