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BMJ Clinical Evidence logoLink to BMJ Clinical Evidence
. 2011 Jun 6;2011:1502.

COPD

Robert Andrew McIvor 1,#, Marcel Tunks 2,#, David Charles Todd 3,#
PMCID: PMC3275305  PMID: 21639960

Abstract

Introduction

Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Classically, it is thought to be a combination of emphysema and chronic bronchitis, although only one of these may be present in some people with COPD. The main risk factor for the development and deterioration of COPD is smoking.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of maintenance drug treatment in stable COPD? What are the effects of smoking cessation interventions in people with stable COPD? What are the effects of non-drug interventions in people with stable COPD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 119 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alpha1 antitrypsin, antibiotics (prophylactic), anticholinergics (inhaled), beta2 agonists (inhaled), corticosteroids (oral and inhaled), general physical activity enhancement, inspiratory muscle training, nutritional supplementation, mucolytics, oxygen treatment (long-term domiciliary treatment), peripheral muscle strength training, psychosocial and pharmacological interventions for smoking cessation, pulmonary rehabilitation, and theophylline.

Key Points

The main risk factor for the development and deterioration of chronic obstructive pulmonary disease (COPD) is smoking.

Inhaled anticholinergics and beta2 agonists improve lung function and symptoms and reduce exacerbations in stable COPD compared with placebo.

  • It is unclear whether inhaled anticholinergics or inhaled beta2 agonists are the more consistently effective drug class in the treatment of COPD.

  • Short-acting anticholinergics seem to be associated with a small improvement in quality of life compared with beta2 agonists.

  • Long-acting inhaled anticholinergics may improve lung function compared with long-acting beta2 agonists.

  • Combined treatment with inhaled anticholinergics plus beta2 agonists may improve symptoms and lung function and reduce exacerbations compared with either treatment alone, although long-term effects are unknown.

Inhaled corticosteroids reduce exacerbations in COPD and reduce decline in FEV1, but the beneficial effects are small.

Long-term domiciliary oxygen treatment may improve survival in people with severe daytime hypoxaemia.

Theophylline may improve lung function compared with placebo, but adverse effects limit its usefulness in stable COPD.

We don't know whether mucolytic drugs, prophylactic antibiotics, or alpha1 antitrypsin improve outcomes in people with COPD compared with placebo.

Combined psychosocial and pharmacological interventions for smoking cessation can slow the deterioration of lung function, but have not been shown to reduce long-term mortality compared with usual care.

Multi-modality pulmonary rehabilitation can improve exercise capacity, dyspnoea, and health-related quality of life in people with stable COPD; general physical exercises and peripheral muscle training can improve exercise capacity; inspiratory muscle training may improve lung function and exercise capacity; but nutritional supplementation has not been shown to be beneficial.

Clinical context

About this condition

Definition

Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.[1] Classically, it is thought to be a combination of emphysema and chronic bronchitis, although only one of these may be present in some people with COPD. Emphysema is abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls, and without obvious fibrosis. Chronic bronchitis is chronic cough or mucous production for at least 3 months in at least 2 successive years when other causes of chronic cough have been excluded.[2]

Incidence/ Prevalence

COPD mainly affects middle-aged and older people. In 1998, the WHO estimated that COPD was the fifth most common cause of death worldwide, responsible for 4.8% of all mortality (estimated 2,745,816 deaths in 2002),[3] and morbidity is increasing. Estimated prevalence in the USA rose by 41% between 1982 and 1994, and age-adjusted death rates rose by 71% between 1966 and 1985. All-cause age-adjusted mortality declined over the same period by 22% and mortality from cardiovascular diseases by 45%.[2] In the UK, physician-diagnosed prevalence was 2% in men and 1% in women between 1990 and 1997.[4]

Aetiology/ Risk factors

COPD is largely preventable. The main cause in developed countries is exposure to tobacco smoke. In developed countries, 85% to 90% of people with COPD have smoked at some point.[1] The disease is rare in lifelong non-smokers (estimated prevalence 5% in 3 large representative US surveys of non-smokers from 1971–1984), in whom "passive" exposure to environmental tobacco smoke has been proposed as a cause.[5] [6] Other proposed causes include bronchial hyper-responsiveness, indoor and outdoor air pollution, and allergy.[7] [8] [9]

Prognosis

Airway obstruction is usually progressive in those who continue to smoke, resulting in early disability and shortened survival. Smoking cessation reverts the rate of decline in lung function to that of non-smokers.[10] Many people will need medication for the rest of their lives, with increased doses and additional drugs during exacerbations.

Aims of intervention

To alleviate symptoms; to prevent exacerbations; to preserve optimal lung function; to improve activities of daily living, quality of life, and survival; with minimal adverse effects from treatment.[11]

Outcomes

Mortality; lung function and exercise capacity: short-term and long-term changes in lung function, including changes in FEV1 ; peak expiratory flow; exercise tolerance; COPD exacerbation and worsening of symptoms: frequency, severity, and duration of exacerbations; symptom scores for dyspnoea; quality of life; and adverse effects. Scoring indices that evaluate both worsening of symptoms and quality-of-life scores include the St George's Respiratory Questionnaire, which is rated on a scale from 0 to 100 (a 4-point change is considered clinically important); the Transitional Dyspnoea Index, which is rated from –9 to +9 (a 1-point change is considered clinically important), and the Chronic Respiratory Disease Questionnaire (CRQ), which is rated from 1 to 7 (a 0.5-point change is considered clinically important). If systematic reviews or RCTs assessed individual components of these indices separately, we have reported these components under separate outcomes, for example the dyspnoea component of the CRQ under "COPD exacerbation and worsening of symptoms" and the emotive mastery component of the CRQ under "quality of life."

Methods

Clinical Evidence search and appraisal April 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2010, Embase 1980 to April 2010, and The Cochrane Database of Systematic Reviews 2010, Issue 2 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies, except for long-acting anticholinergics where a 6-month follow-up was required. We aimed for a minimum follow-up of 1 year for maintenance treatment, but, where we did not identify studies with this length of follow-up, reported on studies of shorter duration. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for COPD.

Important outcomes COPD exacerbation and worsening of symptoms, Lung function and exercise capacity, Mortality, Quality of life
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of maintenance drug treatment in stable COPD?
4 (1651) Lung function and exercise capacity Anticholinergics (short-term treatment) versus placebo 4 −1 −1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
1 (780) COPD exacerbation and worsening of symptoms Anticholinergics (short-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (780) Quality of life Anticholinergics (short-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
17 (17,606) Mortality Anticholinergics (long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
9 (4769) Lung function and exercise capacity Anticholinergics (long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality points deducted for incomplete reporting of results
9 (4835) COPD exacerbation and worsening of symptoms Anticholinergics (long-term treatment) versus placebo 4 0 0 0 0 High
4 (2386) Quality of life Anticholinergics (long-term treatment) versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 7 (at least 405) Lung function and exercise capacity Short-acting beta2 agonists (short-term treatment) versus placebo 4 −1 −1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity among RCTs
5 (379) COPD exacerbation and worsening of symptoms Short-acting beta2 agonists (short-term treatment) versus placebo 4 −1 −2 0 0 Very low Quality 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) Mortality Long-acting beta2 agonists (short-term or long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
7 (1797) Lung function and exercise capacity Long-acting beta2 agonists (short-term or long-term treatment) versus placebo 4 0 −1 0 0 Moderate Consistency point deducted for conflicting results for outcomes assessing exercise capacity
20 (8614) COPD exacerbation and worsening of symptoms Long-acting beta2 agonists (short-term or long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
12 (8375) Quality of life Long-acting beta2 agonists (short-term or long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
7 (2248) Lung function and exercise capacity Short-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting beta2 agonist alone 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 5 (at least 1529) COPD exacerbation and worsening of symptoms Short-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting beta2 agonist alone 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
5 (1529) Quality of life Short-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting beta2 agonist alone 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (1186) COPD exacerbation and worsening of symptoms Short-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting anticholinergic alone 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (94) Lung function and exercise capacity Short-acting anticholinergic plus long-acting inhaled beta2 agonist (short-term treatment) versus beta2 agonist alone 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (172) Lung function and exercise capacity Short-acting anticholinergic plus long-acting inhaled beta2 agonist (short-term treatment) versus short-acting anticholinergic plus short-acting inhaled beta2 agonist 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
6 (1917) Lung function and exercise capacity Short-acting anticholinergic versus short-acting beta2 agonist 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
5 (1529) COPD exacerbation and worsening of symptoms Short-acting anticholinergic versus short-acting beta2 agonist 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
5 (1529) Quality of life Short-acting anticholinergic versus short-acting beta2 agonist 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 2 (at least 471) Lung function and exercise capacity Short-acting anticholinergic versus long-acting beta2 agonist 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
4 (1241) COPD exacerbation and worsening of symptoms Short-acting anticholinergic versus long-acting beta2 agonist 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (467) Quality of life Short-acting anticholinergic versus long-acting beta2 agonist 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (1460) Mortality Long-acting anticholinergic versus long-acting beta2 agonist 4 0 0 0 0 High
2 (1382) Lung function and exercise capacity Long-acting anticholinergic versus long-acting beta2 agonist 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (1460) COPD exacerbation and worsening of symptoms Long-acting anticholinergic versus long-acting beta2 agonist 4 0 0 0 0 High
2 (807) Quality of life Long-acting anticholinergic versus long-acting beta2 agonist 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 11 (at least 740) Lung function and exercise capacity Theophylline (short-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (964) Lung function and exercise capacity Theophylline (long-term treatment) versus placebo 4 −2 0 0 0 Low Quality points deducted for incomplete reporting of results and for inclusion of a 3-armed RCT with 1 open-label arm
1 (110) COPD exacerbation and worsening of symptoms Theophylline (long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for sparse data
10 (445) Lung function and exercise capacity Oral corticosteroids versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
5 (424) Lung function and exercise capacity Inhaled corticosteroids (short-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
6 (15,407) Mortality Inhaled corticosteroids (long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for poor methodology in 1 very large RCT (analysis included people who had discontinued study medication)
6 (at least 3747) Lung function and exercise capacity Inhaled corticosteroids (long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
13 (9578) COPD exacerbation and worsening of symptoms Inhaled corticosteroids (long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
6 (3230) Quality of life Inhaled corticosteroids (long-term treatment) versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
9 (7342) Mortality Corticosteroid plus long-acting beta2 agonist versus placebo 4 0 0 0 0 High
10 (4070) Lung function and exercise capacity Corticosteroid plus long-acting beta2 agonist versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
7 (5804) COPD exacerbation and worsening of symptoms Corticosteroid plus long-acting beta2 agonist versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
8 (5205) Quality of life Corticosteroid plus long-acting beta2 agonist versus placebo 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
7 (6682) Mortality Corticosteroid plus long-acting beta2 agonist versus corticosteroid alone 4 0 0 0 0 High
6 (1831) Lung function and exercise capacity Corticosteroid plus long-acting beta2 agonist versus corticosteroid alone 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
5 (4930) COPD exacerbation and worsening of symptoms Corticosteroid plus long-acting beta2 agonist versus corticosteroid alone 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 5 (at least 3697) Quality of life Corticosteroid plus long-acting beta2 agonist versus corticosteroid alone 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
11 (10,013) Mortality Corticosteroid plus long-acting beta2 agonist versus beta2 agonist alone 4 –1 0 0 0 Moderate Quality point deducted for unclear allocation concealment in some RCTs
13 (10,695) Lung function and exercise capacity Corticosteroid plus long-acting beta2 agonist versus beta2 agonist alone 4 −2 0 0 0 Low Quality points deducted for incomplete reporting of results and unclear allocation concealment in some RCTs
at least 14 (at least 12,297) COPD exacerbation and worsening of symptoms Corticosteroid plus long-acting beta2 agonist versus beta2 agonist alone 4 −2 0 0 0 Low Quality points deducted for incomplete reporting of results and unclear allocation concealment in some RCTs
10 (9329) Quality of life Corticosteroid plus long-acting beta2 agonist versus beta2 agonist alone 4 −2 0 0 0 Low Quality points deducted for incomplete reporting of results and unclear allocation concealment in some RCTs
at least 7 (at least 5764) COPD exacerbation and worsening of symptoms Mucolytics (long-term treatment) versus placebo 4 −1 −2 −1 0 Very low Quality 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) Quality of life Mucolytics (long-term treatment) versus placebo 4 −1 −1 −1 0 Very low Quality 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) Lung function and exercise capacity Mucolytics (long-term treatment) versus placebo 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting. Directness point deducted for differences in additional medications between groups at baseline
11 (at least 888) COPD exacerbation and worsening of symptoms Prophylactic antibiotics versus placebo 4 −1 0 −2 0 Very low Quality 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) Quality of life Prophylactic antibiotics versus placebo 4 −1 0 −2 0 Very low Quality 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) Lung function and exercise capacity Prophylactic antibiotics versus placebo 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for possible drug–drug interactions
3 (250) Mortality Oxygen versus no oxygen (long-term treatment) 4 0 −1 0 0 Moderate Consistency point deducted for conflicting results in different populations
1 (28) Lung function and exercise capacity Oxygen versus no oxygen (long-term treatment) 4 −1 0 0 0 Moderate Quality point deducted for sparse data
1 (28) COPD exacerbation and worsening of symptoms Oxygen versus no oxygen (long-term treatment) 4 −1 0 0 0 Moderate Quality point deducted for sparse data
1 (56) Lung function and exercise capacity Alpha1 antitrypsin versus placebo (long-term treatment) 4 −1 0 −1 0 Low Quality 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) Mortality Psychosocial interventions versus usual care 4 0 0 −1 0 Moderate Directness point deducted for combined analysis at long-term analysis (analysis at 14 years, includes smoking cessation with ipratropium)
1 (5887) Lung function and exercise capacity Psychosocial interventions versus usual care 4 0 0 −1 0 Moderate Directness point deducted for combined analysis at long-term analysis (analysis at 11 years includes smoking cessation with ipratropium)
1 (5887) COPD exacerbation and worsening of symptoms Psychosocial interventions versus usual care 4 0 0 −1 0 Moderate Directness point deducted for combined analysis (includes smoking cessation with ipratropium)
1 (3925) Mortality Psychosocial plus pharmacological interventions versus usual care 4 0 0 −1 0 Moderate Directness point deducted for combined analysis for long-term results (analysis at 14 years includes smoking cessation without ipratropium)
1 (5887) Lung function and exercise capacity Psychosocial plus pharmacological interventions versus usual care 4 0 0 −1 0 Moderate Directness point deducted for combined analysis at 11 years (includes smoking cessation without ipratropium)
1 (5887) COPD exacerbation and worsening of symptoms Psychosocial plus pharmacological interventions versus usual care 4 0 0 −1 0 Moderate Directness point deducted for combined analysis at 11 years (includes smoking cessation without ipratropium)
1 (3923) Mortality Psychosocial plus pharmacological interventions versus psychosocial intervention alone 4 0 0 0 0 High
1 (5887) Lung function and exercise capacity Psychosocial plus pharmacological interventions versus psychosocial intervention alone 4 0 0 0 0 High
What are the effects of non-drug interventions in people with stable COPD?
at least 25 (at least 1220) Lung function and exercise capacity Pulmonary rehabilitation versus usual care 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 14 (at least 802) COPD exacerbation and worsening of symptoms Pulmonary rehabilitation versus usual care 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 15 (at least 765) Quality of life Pulmonary rehabilitation versus usual care 4 −1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 16 (at least 410) Lung function and exercise capacity Inspiratory muscle training (IMT) versus control or no IMT 4 −1 −1 −1 0 Very low Quality 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) COPD exacerbation and worsening of symptoms Inspiratory muscle training (IMT) versus control or no IMT 4 −1 0 −1 0 Low Quality 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) Lung function and exercise capacity Inspiratory muscle training (IMT) plus general exercise reconditioning versus general exercise reconditioning alone 4 −1 −1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for lack of consistent benefit
at least 13 (at least 330) Lung function and exercise capacity Inspiratory muscle training (IMT) versus sham IMT 4 −1 −1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for lack of consistent benefit
4 (96) COPD exacerbation and worsening of symptoms Inspiratory muscle training (IMT) versus sham IMT 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
2 (69) Quality of life Inspiratory muscle training (IMT) versus sham IMT 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
at least 7 (at least 261) Lung function and exercise capacity Peripheral muscle training versus no treatment or other exercise training 4 −1 0 −1 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for lack of consistent benefit
6 (249) Lung function and exercise capacity General physical activity enhancement versus control 4 −1 −1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for inconsistent effects
2 (61) COPD exacerbation and worsening of symptoms General physical activity enhancement versus control 4 −2 −1 0 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
3 (100) Quality of life General physical activity enhancement versus control 4 −2 −1 0 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
at least 6 (at least 156) Lung function and exercise capacity Nutritional supplementation versus placebo or usual diet 4 −1 −1 −2 0 Very low Quality 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
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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.

Glossary

Forced expiratory volume in 1 second (FEV1)

The volume breathed out in the first second of forceful blowing into a spirometer, measured in litres.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Peak expiratory flow

The maximum flow of gas that is expired from the lungs when blowing into a peak flow meter or a spirometer; the units are expressed as litres per minute.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Robert Andrew McIvor, McMaster University, Hamilton, Ontario, Canada.

Marcel Tunks, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

David Charles Todd, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

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BMJ Clin Evid. 2011 Jun 6;2011:1502.

Anticholinergics (inhaled)

Summary

Inhaled anticholinergics improve lung function and symptoms and reduce exacerbations in stable COPD compared with placebo.

It is unclear whether inhaled anticholinergics or inhaled beta 2 agonists are the more consistently effective drug class in the treatment of COPD.

Anticholinergics are associated with an increased rate of dry mouth.

Benefits and harms

Anticholinergics (short-term treatment) versus placebo:

We found 4 small[12] [13] [14] [15] and 4 large[16] [17] [18] [19] RCTs assessing the effects of ipratropium on lung function. Here, we report data from only the large RCTs. Two of the small RCTs[12] [13] found a significant effect in favour of ipratropium, and the remaining two[14] [15] found no significant difference among treatments. We also found one systematic review (search date 1999) assessing the effects on exercise capacity of any anticholinergic drug compared with placebo.[20] All the RCTs compared three or four interventions: ipratropium (at different doses in one trial), placebo, and a beta2 agonist.

Lung function and exercise capacity

Anticholinergics (short-term treatment) compared with placebo Short-term treatment with ipratropium may be more effective at improving FEV1 and exercise capacity (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[16]
RCT
3-armed trial 		276 people Change in FEV1 12 weeks
with ipratropium (36 micrograms 4 times daily)
with placebo
Absolute results reported graphically
Reported as significant (ipratropium v placebo) 		Effect size not calculated ipratropium
[17]
RCT
3-armed trial 		405 people Change in FEV1 12 weeks
with ipratropium (36 micrograms 4 times daily)
with placebo
Absolute results reported graphically
Reported as significant (ipratropium v placebo) 		Effect size not calculated ipratropium
[18]
RCT
3-armed trial 		780 people Improvement in average FEV1 over 12 hours after medication
with ipratropium (40 micrograms 4 times daily)
with placebo
Absolute results not reported
Difference between groups: 137 mL (ipratropium v placebo)
95% CI 88 mL to 186 mL 		Effect size not calculated ipratropium
[18]
RCT
3-armed trial 		780 people Morning pre-medication peak expiratory flow
with ipratropium (40 micrograms 4 times daily)
with placebo
Absolute results not reported
Difference between groups: –0.5 L/minute (ipratropium v placebo)
95% CI –7.4 L/minute to +6.5 L/minute
P = 0.90 		Not significant
Exercise capacity
[20]
Systematic review		 Number of people not reported
17 RCTs in this analysis		 Changes in exercise capacity
with anticholinergic drugs
with placebo
Meta-analysis was not performed because of heterogeneity in design and outcomes assessed among studies
[19]
RCT
3-armed trial 		183 people with moderate to severe COPD, mean FEV1 40% predicted, mean age 64 years Mean increase in shuttle walking distance 12 weeks
15.3 m with ipratropium (80 micrograms three times daily)
6.1 m with placebo
Reported as not significant (ipratropium v placebo)
P value not reported 		Not significant
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COPD exacerbation and worsening of symptoms

Anticholinergics (short-term treatment) compared with placebo Ipratropium in the short term seems no more effective at improving symptoms or the need for rescue bronchodilators (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Need for rescue bronchodilators
[18]
RCT
3-armed trial 		780 people Need for rescue medication
with ipratropium (40 micrograms 4 times daily)
with placebo
Absolute results not reported
P = 0.15 (ipratropium v placebo) 		Not significant
Symptoms
[18]
RCT
3-armed trial 		780 people Symptoms
with ipratropium (40 micrograms 4 times daily)
with placebo
Absolute results not reported
P = 0.44 (ipratropium v placebo) 		Not significant
Open in a new tab

No data from the following reference on this outcome.[16] [17] [19] [20]

Quality of life

Anticholinergics (short-term treatment) compared with placebo Short-term treatment with ipratropium is no more effective at improving quality of life (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life scores
[18]
RCT
3-armed trial 		780 people Quality-of-life scores
with ipratropium (40 micrograms 4 times daily)
with placebo
Absolute results not reported
Reported as not significant (ipratropium v placebo)
P value not reported 		Not significant
Open in a new tab

No data from the following reference on this outcome.[16] [17] [19] [20]

Mortality

No data from the following reference on this outcome.[16] [17] [18] [19] [20]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[15]
RCT		 Number of people not reported Dry mouth
with ipratropium
with placebo
Absolute results not reported
P <0.05 		Effect size not calculated placebo
[17]
RCT
3-armed trial 		405 people Adverse effects affecting the ear, nose, and throat 12 weeks
58/138 (42%) with ipratropium (36 micrograms 4 times daily)
39/135 (29%) with placebo
P = 0.031 (ipratropium v placebo) 		Effect size not calculated placebo
[18]
RCT
3-armed trial 		780 people Adverse effects (any)
with ipratropium (40 micrograms 4 times daily)
with placebo
Absolute results not reported
[16] [19]
RCT
3-armed trial 		459 people in total in the two RCTs Adverse effects (any)
with ipratropium
with placebo
Absolute results not reported
Significance not assessed in either RCT
Open in a new tab

No data from the following reference on this outcome.[12] [13] [14] [20]

Anticholinergics (long-term treatment) versus placebo:

We found three systematic reviews (search dates 2009,[21] 2006,[22] and 2004[23]) comparing tiotropium versus placebo, none of which specified a minimum follow-up of 6 months for inclusion of a study; and one additional RCT.[24]

Mortality

Anticholinergics (long-term treatment) compared with placebo Tiotropium seems no more effective at reducing all-cause mortality at 2 to 48 months (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
All-cause mortality
[21]
Systematic review		 17,051 people with COPD
16 RCTs in this analysis		 All-cause mortality 2 to 48 months
with tiotropium
with placebo
Absolute numbers not reported
RR 0.97
95% CI 0.86 to 1.09
P = 0.61 		Not significant
[24]
RCT		 555 people aged at least 40 years with COPD All-cause mortality 9 months
3/266 (1%) with tiotropium 18 micrograms once daily
6/288 (2%) with placebo
Significance not assessed 		Effect size not calculated
Open in a new tab

No data from the following reference on this outcome.[22] [23]

Lung function and exercise capacity

Anticholinergics (long-term treatment) compared with placebo Long-term treatment with tiotropium seems more effective at improving FEV1 and FVC (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[22]
Systematic review		 4214 people with COPD
8 RCTs in this analysis		 Mean change in trough FEV1 from baseline 6 weeks to 12 months
with tiotropium
with placebo
Absolute numbers not reported
WMD 0.12 L
95% CI 0.11 L to 0.13 L
P = 0.0001 		Effect size not calculated tiotropium
[22]
Systematic review		 2375 people with COPD
7 RCTs in this analysis		 Mean change in trough FVC from baseline 6 weeks to 12 months
with tiotropium
with placebo
Absolute numbers not reported
WMD 0.28 L
95% CI 0.25 L to 0.31 L
P = 0.0001 		Effect size not calculated tiotropium
[24]
RCT		 555 people aged at least 40 years with COPD Change in pre-dose FEV1 9 months
with tiotropium 18 micrograms once daily
with placebo
Absolute results reported graphically
P = 0.0001 		Effect size not calculated tiotropium
[24]
RCT		 555 people aged at least 40 years with COPD Change in pre-dose FVC 9 months
with tiotropium 18 micrograms once daily
with placebo
Absolute results reported graphically
P <0.003 		Effect size not calculated tiotropium
[24]
RCT		 555 people aged at least 40 years with COPD Change in pre-dose inspiratory capacity (IC) 9 months
with tiotropium 18 micrograms once daily
with placebo
Absolute results reported graphically
P = 0.005 		Effect size not calculated tiotropium
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No data from the following reference on this outcome.[21] [23]

COPD exacerbation and worsening of symptoms

Anticholinergics (long-term treatment) compared with placebo Tiotropium used long term is more effective at 12 to 52 weeks at reducing COPD exacerbations (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbation
[22]
Systematic review		 4280 people with COPD
8 RCTs in this analysis		 COPD exacerbations 6 weeks to 12 months
599/2249 (27%) with tiotropium
637/2031 (31%) with placebo
OR 0.76
95% CI 0.66 to 0.87
P = 0.0001 		Small effect size tiotropium
[24]
RCT		 555 people aged at least 40 years with COPD Mean annualised number of COPD exacerbations 9 months
1.05 with tiotropium 18 micrograms once daily
1.83 with placebo
P = 0.03 		Effect size not calculated tiotropium
[24]
RCT		 555 people aged at least 40 years with COPD Time to first exacerbation during 9-month trial
201 days with tiotropium
181 days with placebo
P <0.01 		Effect size not calculated tiotropium
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No data from the following reference on this outcome.[21] [23]

Quality of life

Anticholinergics (long-term treatment) compared with placebo Long-term treatment with tiotropium seems more effective at 6 to 12 months at improving quality of life (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[22]
Systematic review		 1831 people with COPD
3 RCTs in this analysis		 Mean change in St George's Respiratory Questionnaire (SGRQ) 6 to 12 months
with tiotropium
with placebo
Absolute numbers not reported
WMD –3.35
95% CI –4.54 to –2.16
P = 0.0001 		Effect size not calculated tiotropium
[24]
RCT		 555 outpatients aged at least 40 years with COPD Mean change in SGRQ 9 months
–8.5 units with tiotropium 18 micrograms once daily
–4.3 units with placebo
P <0.05 		Effect size not calculated tiotropium
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No data from the following reference on this outcome.[21] [23]

Adverse effects

No data from the following reference on this outcome.[21] [22] [23] [24]

Ipratropium plus smoking cessation programme versus smoking cessation programme plus usual care:

See option on psychosocial plus drug interventions in effects of advice to stop smoking. For adverse effects of ipratropium, see harms of short-term treatment with ipratropium above.

Inhaled anticholinergics versus beta2 agonists:

See option on inhaled anticholinergics versus beta2 agonists.

Inhaled anticholinergic alone versus inhaled anticholinergics plus beta2 agonists:

See option on inhaled anticholinergics plus beta2 agonists.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[22]
Systematic review		 2052 people with COPD
4 RCTs in this analysis		 Dry mouth 6 weeks to 12 months
12% with tiotropium
3% with placebo
Absolute numbers not reported
OR 4.56
95% CI 2.95 to 7.06
P = 0.0001 		Moderate effect size placebo
[23]
Systematic review		 1675 person-years; 7819 people in the systematic review; number of RCTs and people in this analysis not specified Arrhythmia other than tachycardia or atrial fibrillation 3 months to >6 months
1.31 per 100 person-years with tiotropium
0.49 per 100 person-years with placebo
Absolute numbers not reported
RR 2.71
95% CI 1.1 to 6.65
P <0.05 		Moderate effect size placebo
[23]
Systematic review		 1675 person-years; 7819 people in the systematic review; number of RCTs and people in this analysis not specified Urinary retention 3 months to >6 months
0.78 per 100 person-years with tiotropium
0.08 per 100 person-years with placebo
Absolute numbers not reported
RR 10.93
95% CI 1.26 to 94.9
P <0.05 		Large effect size placebo
[24]
RCT		 555 people aged at least 40 years with COPD Proportion of people with at least one adverse effect 9 months
162/266 (61%) with tiotropium 18 micrograms once daily
193/288 (67%) with placebo
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.[21]

Further information on studies

The primary quality-of-life outcome assessed by the RCT was the proportion of people achieving the minimum important difference of 4 units in SGRQ. We report mean change in score to allow better comparison with the other RCT we report.

Comment

The systematic reviews included some RCTs with a follow-up of less than the 6 months specified in the Clinical Evidence inclusion criteria for the comparison of tiotropium compared with placebo. One review included 4392 patients followed for 6 months or longer, 108 followed for 25 weeks, and 1578 followed for <6 months;[22] however, we have reported it because the follow-up period was sufficient in most participants. For one review, we have reported analysis of adverse effects only.[23] This review included several shorter trials, with only 52% of patients exposed to tiotropium for >6 months.[23] Data from the other review[21] demonstrated through sensitivity analysis that duration of follow-up (whether >6 months or <6 months) did not affect the conclusions regarding cardiovascular adverse events or overall mortality.[21] We have not reported one well-publicised review of the cardiovascular safety of anticholinergics because it pooled ipratropium with tiotropium, and placebo with active-treatment comparisons.[25]

Substantive changes

Anticholinergics New evidence added.[21] [22] [23] [24] Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Beta2 agonists (inhaled)

Summary

Inhaled beta 2 agonists improve lung function and symptoms and reduce exacerbations in stable COPD compared with placebo.

It is unclear whether inhaled anticholinergics or inhaled beta 2 agonists are the more consistently effective drug class in the treatment of COPD.

Benefits and harms

Short-acting beta2 agonists (short-term treatment) versus placebo:

We found two systematic reviews (search dates 2002[26] and 2004[27]) and one subsequent RCT.[28]

Lung function and exercise capacity

Compared with placebo Short-acting beta2 agonists (short-term treatment) may be more effective at increasing FEV1 in people with stable COPD, but we don't know whether they are more effective at increasing exercise tolerance (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[26]
Systematic review		 196 people
6 RCTs in this analysis		 FEV1
with short-acting beta2 agonists (delivered by metered-dose inhaler)
with placebo
Absolute results not reported
WMD 0.14 L
95% CI 0.04 L to 0.25 L
The trials were small and the results heterogeneous
The meta-analysis used post-crossover results, but because the treatment is short acting there is unlikely to be persistence of treatment effects after crossover 		Effect size not calculated short-acting beta2 agonists
[28]
RCT
4-armed trial 		209 people with COPD % change in area under the curve (AUC) in FEV1 6 weeks
10.5% with levosalbutamol 0.63 mg three times daily
1.6% with placebo
P <0.003 		Effect size not calculated levosalbutamol 0.63 mg
[28]
RCT
4-armed trial 		209 people with COPD % change in AUC in FEV1 6 weeks
9.2% with levosalbutamol 1.25 mg three times daily
1.6% with placebo
P <0.003 		Effect size not calculated levosalbutamol 1.25 mg
[28]
RCT
4-armed trial 		209 people with COPD % change in AUC in FEV1 6 weeks
15.3% with racemic salbutamol 2.5 mg three times daily
1.6% with placebo
P <0.003 		Effect size not calculated racemic salbutamol 2.5 mg
Exercise capacity
[26]
Systematic review		 188 people
4 RCTs in this analysis		 Distance walked
with short-acting beta2 agonists (delivered by metered-dose inhaler)
with placebo
Absolute results not reported
SMD +0.18 m
95% CI –0.11 m to +0.47 m
The trials were small and the results heterogeneous
The meta-analysis used post-crossover results, but, because the treatment is short acting, there is unlikely to be persistence of treatment effects after crossover 		Not significant
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No data from the following reference on this outcome.[27]

COPD exacerbation and worsening of symptoms

Compared with placebo Short-acting beta2 agonists (short-term treatment) may be more effective at improving daily breathlessness scores in people with stable COPD (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[26]
Systematic review		 188 people
4 RCTs in this analysis		 Daily breathlessness score
with short-acting beta2 agonists (delivered by metered-dose inhaler)
with placebo
Absolute results not reported
WMD –1.33
95% CI –1.65 to –1.01
P <0.001
The trials were small and the results heterogeneous
The meta-analysis used post-crossover results, but, because the treatment is short acting, there is unlikely to be persistence of treatment effects after crossover 		Effect size not calculated short-acting beta2 agonists
[28]
RCT
4-armed trial 		209 people with COPD Withdrawals because of COPD exacerbations
2% with levosalbutamol 0.63 mg three times daily
4% with levosalbutamol 1.25 mg three times daily
10% with racemic salbutamol 2.5 mg three times daily
0% with placebo
Absolute numbers not reported
P = 0.01 for racemic salbutamol v placebo
Significance not assessed for either dose of levosalbutamol v placebo 		Effect size not calculated placebo
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No data from the following reference on this outcome.[27]

Mortality

No data from the following reference on this outcome.[26] [27] [28]

Quality of life

No data from the following reference on this outcome.[26] [27] [28]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[27]
Systematic review		 15,276 people with asthma or COPD
22 RCTs in this analysis		 Adverse cardiovascular events
with beta2 agonists (short- and long-acting)
with placebo
Absolute results not reported
RR 2.54
95% CI 1.59 to 4.05 		Moderate effect size placebo
[27]
Systematic review		 386 people with asthma or COPD
11 RCTs in this analysis		 Increased heart rate
with beta2 agonists (single dose of either short- or long-acting)
with placebo
Absolute results not reported
WMD 9.12
95% CI 5.32 to 12.92 		Effect size not calculated placebo
[27]
Systematic review		 168 people with asthma or COPD
6 RCTs in this analysis		 Reduction in serum potassium concentration
with beta2 agonists (single dose of either short- or long-acting)
with placebo
Absolute results not reported
WMD –0.36
95% CI –0.54 to –0.18 		Effect size not calculated placebo
Open in a new tab

No data from the following reference on this outcome.[26] [28]

Short-acting beta2 agonists (long-term treatment) versus placebo:

We found no systematic review of only long-term treatment with short-acting beta2 agonists versus placebo.

Long-acting beta2 agonists (short-term or long-term treatment) versus placebo:

We found no review on only short-term (follow-up <6 months) or only long-term (>6 months) treatment with long-acting beta2 agonists compared with placebo. We found 4 systematic reviews (search dates 2002,[29] 2005,[30] [31] and 2007[32]), 5 additional RCTS,[19] [33] [34] [35] [36] and 5 subsequent RCTs that combined data on a range of treatment duration.[37] [38] [39] [40] [41] In addition, we found one systematic review that reported on adverse effects.[27]

Mortality

Compared with placebo Long-acting beta2 agonists (short-term or long-term treatment) seem no more effective at reducing mortality (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[32]
Systematic review		 8400 people with COPD
13 RCTs in this analysis		 All-cause mortality 1 to 36 months
4.9% with long-acting beta2 agonist
6.5% with placebo
Absolute numbers not reported
RR 1.6
95% CI 0.8 to 2.4
P >0.05 		Not significant
Open in a new tab

No data from the following reference on this outcome.[29] [30] [31] [19] [33] [34] [35] [36] [37] [38] [39] [40] [41]

Lung function and exercise capacity

Compared with placebo Long-acting beta2 agonists (short-term or long-term treatment) seem more effective at improving lung function, but we don't know whether they are more effective at improving capacity for exercise (endurance time and shuttle walking distance) (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[34]
RCT		 657 people with COPD Change in FEV1 from baseline 6 months
+5% with formoterol 9 micrograms twice daily
–1.4% with placebo
AR 6.5%
95% CI 2.5% to 10.7%
P <0.01 		Effect size not calculated formoterol
[37]
RCT
5-armed trial 		717 people with COPD Change in pre-dose FEV1 from baseline 12 weeks
+16.9% with arformoterol 15 micrograms twice daily
+18.9% with arformoterol 25 micrograms twice daily
+14.9% with arformoterol 50 micrograms once daily
+17.4% with salmeterol 42 micrograms twice daily
+6.0% with placebo
P <0.001 for all active treatments v placebo 		Effect size not calculated long-acting beta2 agonist
[38]
RCT
3-armed trial 		163 people with COPD Change in pre-dose FEV1 from baseline 28 days
+220 mL with indacaterol 400 micrograms once daily
+210 mL with indacaterol 800 micrograms once daily
P <0.0001 for either dose of indacaterol v placebo 		Effect size not calculated indacaterol
Exercise capacity
[19]
RCT
3-armed trial 		183 people with moderate to severe COPD
In review [29] [30] 		Increase shuttle walking test (increase in distance from baseline) 12 weeks
20.4 m with formoterol 18 micrograms twice daily
6.0 m with placebo
Reported as not significant (formoterol v placebo)
P value not reported 		Not significant
[39]
RCT
Crossover design 		20 people with clinically stable COPD Mean difference in endurance shuttle walking test (ESWT) 2.5 hours post treatment
with salmeterol 50 micrograms single dose
with placebo single dose
Absolute numbers not reported
P = 0.02 		Effect size not calculated salmeterol
[36]
RCT
Crossover design 		23 people with moderate to severe COPD (mean FEV1 42% predicted)
In review [29] [30] 		Difference in peak exercise endurance time 12 weeks
with salmeterol 50 micrograms (inhaled)
with placebo
Absolute results not reported
Difference between groups of 96 seconds
P = 0.02 		Effect size not calculated salmeterol
[33]
RCT
Crossover design
5-armed trial 		34 people Time to exhaustion 1 week
10.94 minutes with formoterol 4.5 micrograms
10.78 minutes with formoterol 9 micrograms
10.59 minutes with formoterol 18 micrograms
10.20 minutes with placebo
P <0.0001 (formoterol 4.5 micrograms v placebo)
P <0.01 (formoterol 9 micrograms v placebo)
P <0.05 (formoterol 18 micrograms v placebo) 		Effect size not calculated formoterol
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No data from the following reference on this outcome.[31] [32] [35] [40] [41]

COPD exacerbation and worsening of symptoms

Compared with placebo Long-acting beta2 agonists (short-term or long-term treatment) seem more effective at reducing the rate of COPD exacerbations and at improving symptoms (assessed by the Chronic Disease Respiratory Questionnaire and Transitional Dyspnoea Index) (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[32]
Systematic review		 6453 people with COPD
14 RCTs in this analysis		 Cumulative incidence of severe COPD exacerbations 1 to 36 months
7.5% with long-acting beta2 agonist
10.8% with placebo
Absolute numbers not reported
RR 0.80 (random effects model)
95% CI 0.69 to 0.82 		Small effect size long-acting beta2 agonist
[37]
RCT
5-armed trial 		717 people with COPD Frequency of COPD exacerbations
19/141 (13.5%) with arformoterol 15 micrograms twice daily
19/143 (13.3%) with arformoterol 25 micrograms twice daily
17/146 (11.6%) with arformoterol 50 micrograms once daily
20/144 (13.9%) with salmeterol 42 micrograms twice daily
24/143 (16.8%) with placebo
P >0.05 for all treatments v placebo 		Not significant
[38]
RCT
3-armed trial 		163 people with COPD Number of COPD exacerbations 28 days
3/68 (4%) with indacaterol 400 micrograms
0/67 (0%) with indacaterol 800 micrograms
2/28 (7%) with placebo
Significance not assessed
Symptom severity
[30]
Systematic review		 545 people
2 RCTs in this analysis		 Improvement in the Chronic Respiratory Disease Questionnaire (CRQ)
with long-acting beta2 agonists
with placebo
Absolute results not reported
OR 1.71
95% CI 1.21 to 2.42
P = 0.002 		Small effect size long-acting beta2 agonists
[30]
Systematic review		 736 people
2 RCTs in this analysis		 Improvement in transitional dyspnoea index (TDI)
with long-acting beta2 agonists
with placebo
Absolute results not reported
OR 1.70
95% CI 1.25 to 2.31
P = 0.0008 		Small effect size long-acting beta2 agonists
Open in a new tab

No data from the following reference on this outcome.[29] [31] [19] [33] [34] [35] [36] [39] [40] [41]

Quality of life

Compared with placebo Long-acting beta2 agonists (short-term or long-term treatment) may be no more effective at improving quality of life (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[32]
Systematic review		 6453 people with COPD
14 RCTs in this analysis		 Mean change in St George's Respiratory Questionnaire 1 to 36 months
with long-acting beta2 agonist (salmeterol or formoterol)
with placebo
Absolute numbers not reported
WMD –3.26
95% CI –4.57 to –1.96 		Effect size not calculated long-acting beta2 agonist
Open in a new tab

No data from the following reference on this outcome.[29] [30] [31] [19] [33] [34] [35] [36] [37] [38] [39] [40] [41]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[31]
Systematic review		 2404 people with COPD
4 RCTs in this analysis		 Mortality attributed to treatment-related respiratory problems
21/1320 (2%) with long-acting beta2 agonist
8/1084 (1%) with placebo
RR 2.47
95% CI 1.12 to 5.45
P = 0.03 		Moderate effect size placebo
[30]
Systematic review		 5055 people
12 RCTs in this analysis		 Proportion of people who withdrew because of an adverse effect
with long-acting beta2 agonists
with placebo
Absolute results not reported
OR 0.86
95% CI 0.72 to 1.02
P = 0.09 		Not significant
[34]
RCT		 657 people with COPD Rate of adverse effects (rates/1000 treatment days) 6 months
3.8 with formoterol 9 micrograms twice daily
4.5 with placebo
Significance not assessed
[35]
RCT
4-armed trial 		6184 people with COPD; 6112 people included in efficacy analysis Proportion of people experiencing a drug-related adverse effect
12% with salmeterol (50 micrograms twice daily)
13% with placebo
Absolute numbers not reported
Significance not assessed
[27]
Systematic review		 15,276 people with asthma or COPD
22 RCTs in this analysis		 Adverse cardiovascular events
with beta2 agonists (short- and long-acting)
with placebo
Absolute results not reported
RR 2.54
95% CI 1.59 to 4.05 		Moderate effect size placebo
[27]
Systematic review		 386 people with asthma or COPD
11 RCTs in this analysis		 Increased heart rate
with beta2 agonists (single dose of either short- or long-acting)
with placebo
Absolute results not reported
WMD 9.12
95% CI 5.32 to 12.92 		Effect size not calculated placebo
[40]
RCT
5-armed trial 		1465 people with COPD Heart rate difference from baseline 12 weeks
–2.4 bpm with arformoterol 15 micrograms twice daily
–0.6 bpm with arformoterol 25 micrograms twice daily
–0.3 bpm with arformoterol 50 micrograms once daily
–0.0 bpm with salmeterol 42 micrograms twice daily
–1.8 bpm with placebo
P >0.05 for any active treatment v placebo 		Not significant
[41]
RCT
3-armed trial 		351 people with COPD Arrhythmia 12 weeks
with formoterol 20 micrograms nebulised twice daily
with formoterol 12 micrograms dry powder twice daily
with placebo
Absolute numbers not reported
P >0.05 for either dose of formoterol v placebo 		Not significant
[27]
Systematic review		 168 people with asthma or COPD
6 RCTs in this analysis		 Reduction in serum potassium concentration
with beta2 agonists (single dose of either short- or long-acting)
with placebo
Absolute results not reported
WMD –0.36
95% CI –0.54 to –0.18 		Effect size not calculated placebo
Open in a new tab

No data from the following reference on this outcome.[29] [32] [33] [36] [37] [38] [19] [39]

Beta2 agonists versus inhaled anticholinergics:

See option on inhaled anticholinergics versus beta2 agonists.

Beta2 agonists alone versus inhaled anticholinergics plus beta2 agonists:

See option on inhaled anticholinergics plus beta2 agonists.

Beta2 agonists alone versus inhaled corticosteroids plus beta2 agonists:

See option on inhaled corticosteroids plus beta2 agonists.

Further information on studies

Owing to heterogeneity among studies in reporting of effects on FEV1, the review did not pool data for this outcome. However, the review reported that most RCTs found an improvement in FEV1 with long-acting beta2 agonists compared with placebo. The review reported that RCTs found no significant difference between long-acting beta2 agonists and placebo in effects on exercise as measured by various walking tests, but the review did not pool data for this comparison.

The RCT also carried out a last observation carried forward analysis for the outcome of FEV1. However, the withdrawal rate from the RCT was high and the proportion of people followed up at 3 years for this outcome was 56% (851/1524) in the placebo group, and 63% (960/1521) in the salmeterol alone group. These follow-up rates are below Clinical Evidence reporting criteria of 80%, and so these data are not reported here.

Comment

Clinical guide:

High doses of beta2 agonists can reduce plasma potassium, cause dysrhythmia, and reduce arterial oxygen tension.[42] The risk of adverse events may be higher in people with pre-existing cardiac arrhythmias and hypoxaemia.[43]

Substantive changes

Beta2 agonists (inhaled) New evidence added.[28] [32] [37] [38] [39] [40] [41] Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Anticholinergics plus beta2 agonists (inhaled)

Summary

Combined treatment with inhaled anticholinergics and beta 2 agonists may improve symptoms and lung function and reduce exacerbations compared with either treatment alone, although long-term effects are unknown.

We found no clinically important information from RCTs comparing long-term treatment with a combination of anticholinergics and beta 2 agonists versus no active treatment.

Benefits and harms

Short-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting beta2 agonist alone:

We found two systematic reviews (search date 2002, 3 RCTs, 1399 people;[29] and search date 2008, 7 RCTs, 2252 people).[44] The second review assessed the effects of ipratropium plus short-acting inhaled beta2 agonist (metaproterenol, fenoterol, and salbutamol), and identified the three RCTs identified by the first review, but reported on different outcomes.[44]

Lung function and exercise capacity

Short-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) compared with short-acting beta2 agonist alone Ipratropium plus a short-acting beta2 agonist seems more effective than short-acting beta2 agonist alone at improving FEV1 after 85 days of treatment (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[44]
Systematic review		 2248 people
7 RCTs in this analysis		 Mean peak FEV1 response 85 days
with ipratropium plus short-acting beta2 agonist
with short-acting beta2 agonist alone
Absolute results not reported
WMD 0.07 L
95% CI 0.05 L to 0.09 L
P <0.0001 		Effect size not calculated ipratropium plus short-acting beta2 agonist
Open in a new tab

No data from the following reference on this outcome.[29]

COPD exacerbation and worsening of symptoms

Short-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) compared with a short-acting beta2 agonist alone Combining a short-acting anticholinergic drug (ipratropium) with a short-acting beta2 agonist for 12 weeks is more effective at improving exacerbations, but ipratropium plus a short-acting beta2 agonist seems no more effective at 85 days at improving the dyspnoea component of the Chronic Respiratory Disease Questionnaire (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[29]
Systematic review		 1399 people
3 RCTs in this analysis		 COPD exacerbations 12 weeks
with short-acting anticholinergic (ipratropium) plus short-acting beta2 agonist
with short-acting beta2 agonist alone
Absolute results not reported
RR 0.68
95% CI 0.51 to 0.91 		Small effect size short-acting anticholinergic plus short-acting beta2 agonist
Symptom severity
[44]
Systematic review		 1529 people
5 RCTs in this analysis		 Dyspnoea component of the Chronic Respiratory Disease Questionnaire (CRQ) 85 days
with ipratropium plus short-acting beta2 agonist
with short-acting beta2 agonist alone
Absolute results not reported
WMD +0.01
95% CI –0.06 to +0.08
P = 0.8 		Not significant
Open in a new tab

Quality of life

Short-acting anticholinergic plus a short-acting inhaled beta2 agonist (short-term treatment) compared with a short-acting beta2 agonist alone Ipratropium plus a short-acting beta2 agonist seems no more effective than short-acting beta2 agonist alone at 85 days at improving fatigue, emotion, and mastery components of the Chronic Respiratory Disease Questionnaire (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[44]
Systematic review		 1529 people
5 RCTs in this analysis		 Fatigue component of the Chronic Respiratory Disease Questionnaire (CRQ) 85 days
with ipratropium plus short-acting beta2 agonist
with short-acting beta2 agonist alone
Absolute results not reported
WMD +0.01
95% CI –0.10 to +0.13
P = 0.8 		Not significant
[44]
Systematic review		 1529 people
5 RCTs in this analysis		 Emotion component of the CRQ 85 days
with ipratropium plus short-acting beta2 agonist
with short-acting beta2 agonist alone
Absolute results not reported
WMD +0.02
95% CI –0.12 to +0.16
P = 0.8 		Not significant
[44]
Systematic review		 1529 people
5 RCTs in this analysis		 Mastery component of the CRQ 85 days
with ipratropium plus short-acting beta2 agonist
with short-acting beta2 agonist alone
Absolute results not reported
WMD +0.03
95% CI –0.09 to +0.15
P = 0.6 		Not significant
Open in a new tab

No data from the following reference on this outcome.[29]

Mortality

No data from the following reference on this outcome.[29] [44]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[44]
Systematic review		 1588 people
5 RCTs in this analysis		 Proportion of people reporting an adverse effect
112/789 (14%) with ipratropium plus short-acting beta2 agonist
96/769 (13%) with short-acting inhaled beta2 agonist
RR 1.13
95% CI 0.88 to 1.45
P = 0.3 		Not significant
Open in a new tab

No data from the following reference on this outcome.[29]

Short-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) versus short-acting anticholinergic alone:

We found one systematic review (search date 2002, 3 RCTs, 1399 people).[29]

COPD exacerbation and worsening of symptoms

Short-acting anticholinergic plus short-acting inhaled beta2 agonist (short-term treatment) compared with a short-acting anticholinergic alone Combining a short-acting anticholinergic drug (ipratropium) with a short-acting beta2 agonist for 12 weeks seems as effective a short-acting anticholinergic alone at improving exacerbations (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[29]
Systematic review		 1186 people
2 RCTs in this analysis		 COPD exacerbations 12 weeks
with short-acting anticholinergic plus beta2 agonist
with short-acting anticholinergic alone
Absolute results not reported
RR 1.04
95% CI 0.65 to 1.68 		Not significant
Open in a new tab

Mortality

No data from the following reference on this outcome.[29]

Lung function and exercise capacity

No data from the following reference on this outcome.[29]

Quality of life

No data from the following reference on this outcome.[29]

Adverse effects

No data from the following reference on this outcome.[29]

Short-acting anticholinergic plus long-acting inhaled beta2 agonist (short-term treatment) versus beta2 agonist alone:

We found one systematic review (search date 2008, 3 RCTs, 1610 people).[45] The review, which included unpublished data from drug companies, did not pool data for many outcomes. Two of the RCTs identified by the review were unpublished and so are not reported further.

Lung function and exercise capacity

Short-acting anticholinergic plus long-acting inhaled beta2 agonist (short-term treatment) compared with beta2 agonist alone Combining a short-acting anticholinergic with a long-acting beta2 agonist may be modestly more effective that beta2 agonist alone at improving FEV1 (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function (FEV1)
[46]
RCT		 94 people
In review [45] 		Mean improvement in FEV1 as a percentage of predicted FEV1 12 weeks
8% with salmeterol (50 micrograms twice daily) plus ipratropium (40 micrograms 4 times daily)
5% with salmeterol alone (50 micrograms twice daily)
P <0.01 		Effect size not calculated salmeterol plus ipratropium
Open in a new tab

Mortality

No data from the following reference on this outcome.[45] [46]

COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[45] [46]

Quality of life

No data from the following reference on this outcome.[45] [46]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[45]
Systematic review		 936 people
3 RCTs in this analysis		 Proportion of people reporting a treatment-related adverse effect
205/473 (43%) with salmeterol plus ipratropium
192/483 (40%) with salmeterol alone
RR 1.04
95% CI 0.90 to 1.21
P = 0.6 		Not significant
Open in a new tab

Short-acting anticholinergic plus long-acting inhaled beta2 agonist (short-term treatment) versus short-acting anticholinergic plus short-acting inhaled beta2 agonist:

We found one cross-over RCT.[47]

Lung function and exercise capacity

Short-acting anticholinergic plus a long-acting inhaled beta2 agonist (short-term treatment) compared with a short-acting anticholinergic plus a short-acting inhaled beta2 agonist Formoterol plus ipratropium may be more effective than salbutamol plus ipratropium at 3 weeks at improving FEV1 and peak expiratory flow rates (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[47]
RCT
Crossover design 		172 people Improvement in pre-medication FEV1 from baseline 3 weeks
with ipratropium (40 micrograms 4 times daily) plus formoterol (12 micrograms twice daily)
with ipratropium (40 micrograms 4 times daily) plus salbutamol (200 micrograms 4 times daily)
Absolute results not reported
116 mL
95% CI 83 mL to 150 mL 		Effect size not calculated ipratropium plus formoterol
[47]
RCT
Crossover design 		172 people Improvement in mean morning peak expiratory flow from baseline over the previous 7 days 3 weeks
with ipratropium (40 micrograms 4 times daily) plus formoterol (12 micrograms twice daily)
with ipratropium (40 micrograms 4 times daily) plus salbutamol (200 micrograms 4 times daily)
Absolute results not reported
12 L/minute
95% CI 6 L/minute to 19 L/minute 		Effect size not calculated ipratropium plus formoterol
Open in a new tab

Mortality

No data from the following reference on this outcome.[47]

COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[47]

Quality of life

No data from the following reference on this outcome.[47]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[47]
RCT
Crossover design 		172 people Proportion of people reporting adverse effects
16/172 (10%) with ipratropium (40 micrograms 4 times daily) plus formoterol (12 micrograms twice daily)
22/172 (13%) with ipratropium (40 micrograms 4 times daily) plus salbutamol (200 micrograms 4 times daily)
Significance not assessed
[47]
RCT
Crossover design 		172 people Proportion of people reporting dyspnoea
2/172 (1%) with ipratropium (40 micrograms 4 times daily) plus formoterol (12 micrograms twice daily)
5/172 (3%) with ipratropium (40 micrograms 4 times daily) plus salbutamol (200 micrograms 4 times daily)
Significance not assessed
[47]
RCT
Crossover design 		172 people Proportion of people reporting exacerbation of obstructive airway disease
0/172 (0%) with ipratropium (40 micrograms 4 times daily) plus formoterol (12 micrograms twice daily)
5/172 (3%) with ipratropium (40 micrograms 4 times daily) plus salbutamol (200 micrograms 4 times daily)
Significance not assessed
[47]
RCT
Crossover design 		172 people Proportion of people reporting pharyngitis
1/172 (1%) with ipratropium (40 micrograms 4 times daily) plus formoterol (12 micrograms twice daily)
3/172 (2%) with ipratropium (40 micrograms 4 times daily) plus salbutamol (200 micrograms 4 times daily)
Significance not assessed
Open in a new tab

Anticholinergic plus inhaled beta2 agonists (long-term treatment):

We found no review or RCTs of long-term treatment with anticholinergics plus beta2 agonists compared with placebo or either drug alone.

Further information on studies

Adverse effects data from the RCT are included in the meta-analysis of adverse effects carried out by the review and so are not discussed separately.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Anticholinergics versus beta2 agonists (inhaled)

Summary

It is unclear whether inhaled anticholinergics or inhaled beta 2 agonists are the more consistently effective drug class in the treatment of COPD.

Short-acting anticholinergics seem to be associated with a small improvement in quality of life compared with beta 2 agonists.

Long-acting inhaled anticholinergic drugs may improve lung function compared with long-acting beta 2 agonists.

We found no clinically important results from RCTs comparing long-acting anticholinergics versus short-acting beta 2 agonists in the treatment of people with COPD.

Benefits and harms

Short-acting anticholinergic versus short-acting beta2 agonist:

We found 5 systematic reviews comparing anticholinergics versus beta2 agonists.[29] [48] [30] [44] [45] The reviews did not report data in terms of short- or long-term duration of treatment as defined in our Methods section, but by length of drug action. We report comparisons as reported in the reviews, and specify the duration of treatment where possible. One review compared anticholinergics as a class versus beta2 agonists as a class (see further information on studies for results).[30] One review (search date 2008, 11 RCTs, 3912 people) compared ipratropium versus short-acting beta2 agonists (metaproterenol, fenoterol, and salbutamol).[44]

Lung function and exercise capacity

Short-acting anticholinergic compared with short-acting beta2 agonist Ipratropium and short-acting beta2 agonists seem equally effective at 85 days at improving FEV1 (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[44]
Systematic review		 1917 people
6 RCTs in this analysis		 Mean FEV1 peak response 85 days of treatment
with ipratropium
with short-acting beta2 agonists
Absolute results not reported
WMD 0.00 L
95% CI –0.02 L to +0.01 L
P = 0.6 		Not significant
Open in a new tab

COPD exacerbation and worsening of symptoms

Short-acting anticholinergic compared with short-acting beta2 agonist Ipratropium seems modestly more effective than a short-acting beta2 agonist at improving the dyspnoea component of the Chronic Respiratory Disease Questionnaire (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[44]
Systematic review		 1529 people
5 RCTs in this analysis		 Improvement in the dyspnoea component of the Chronic Respiratory Disease Questionnaire 85 days of treatment
with ipratropium
with short-acting beta2 agonists
Absolute results not reported
WMD 0.16
95% CI 0.09 to 0.23
P <0.001 		Effect size not calculated ipratropium
Open in a new tab

Quality of life

Short-acting anticholinergic compared with short-acting beta2 agonist Ipratropium seems modestly more effective than a short-acting beta2 agonist at improving fatigue, emotion, and mastery components of the Chronic Respiratory Disease Questionnaire (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[44]
Systematic review		 1529 people
5 RCTs in this analysis		 Improvement in the fatigue component of the Chronic Respiratory Disease Questionnaire (CRQ) 85 days of treatment
with ipratropium
with short-acting beta2 agonists
Absolute results not reported
WMD 0.13
95% CI 0.02 to 0.23
P = 0.02 		Effect size not calculated ipratropium
[44]
Systematic review		 1529 people
5 RCTs in this analysis		 Improvement in the emotion component of the CRQ 85 days of treatment
with ipratropium
with short-acting beta2 agonists
Absolute results not reported
WMD 0.17
95% CI 0.05 to 0.29
P = 0.006 		Effect size not calculated ipratropium
[44]
Systematic review		 1529 people
5 RCTs in this analysis		 Improvement in the mastery component of the CRQ 85 days of treatment
with ipratropium
with short-acting beta2 agonists
Absolute results not reported
WMD 0.18
95% CI 0.06 to 0.30
P = 0.004 		Effect size not calculated ipratropium
Open in a new tab

Mortality

No data from the following reference on this outcome.[44]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[44]
Systematic review		 1858 people
6 RCTs in this analysis		 Proportion of people reporting an adverse effect
84/928 (9%) with ipratropium
111/930 (12%) with short-acting beta2 agonists
RR 0.75
95% CI 0.57 to 0.97
P = 0.03
There was significant heterogeneity (I2 = 60%) among studies in this analysis. The reason for the heterogeneity was not reported 		Small effect size ipratropium
Open in a new tab

Short-acting anticholinergic versus long-acting beta2 agonist:

We found 5 systematic reviews comparing anticholinergics versus beta2 agonists.[29] [48] [30] [44] [45] The reviews did not report data in terms of short- or long-term duration of treatment as defined in our Methods section, but by length of drug action. We report comparisons as reported in the reviews, and specify the duration of treatment where possible. One review compared anticholinergics as a class versus beta2 agonists as a class (see further information on studies for results).[30] Two systematic reviews (search date 2006, 8 RCTs, 3713 people,[30] and search date 2008, 6 RCTs, 2604 people[45]) compared short-acting anticholinergics versus long-acting beta2 agonists. Three RCTs were identified by both reviews. Both reviews included unpublished data obtained directly from drug companies. The reviews reported data on ipratropium versus salmeterol and ipratropium versus formoterol separately and reported on different outcomes.

Lung function and exercise capacity

Short-acting anticholinergic compared with long-acting beta2 agonist Ipratropium seems less effective than salmeterol at improving FEV1 at 12 weeks, but equally effective at improving the 6-minute walking distance test (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[45]
Systematic review		 458 people
2 RCTs in this analysis		 Change in FEV1 from baseline 12 weeks
with ipratropium
with salmeterol
Absolute results not reported
WMD –0.06 L
95% CI –0.11 L to 0 L
P = 0.05
Difference between groups was of borderline significance 		Effect size not calculated salmeterol
Exercise capacity
[45]
Systematic review		 471 people
2 RCTs in this analysis		 Change in 6-minute walking distance 12 weeks
with ipratropium
with salmeterol
Absolute results not reported
WMD +10.47 m
95% CI –1.24 m to +22.19 m
P = 0.08 		Not significant
Open in a new tab

COPD exacerbation and worsening of symptoms

Short-acting anticholinergic compared with long-acting beta2 agonist Ipratropium and the long-acting beta2 agonists salmeterol and formoterol seem equally effective at improving COPD exacerbations (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[30]
Systematic review		 538 people
2 RCTs in this analysis		 Risk of COPD exacerbation
with ipratropium
with salmeterol
Absolute results not reported
OR (salmeterol v ipratropium) 0.81
95% CI 0.56 to 1.19
P = 0.29 		Not significant
[30]
Systematic review		 703 people
2 RCTs in this analysis		 Risk of COPD exacerbation
with ipratropium
with formoterol
Absolute results not reported
OR (formoterol v ipratropium) 0.78
95% CI 0.44 to 1.37
P = 0.39 		Not significant
Open in a new tab

Quality of life

Short-acting anticholinergic compared with long-acting beta2 agonist Ipratropium and the long-acting beta2 agonists salmeterol and formoterol seem equally effective at 12 weeks at improving total score on the Chronic Respiratory Disease Questionnaire (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[45]
Systematic review		 467 people
2 RCTs in this analysis		 Total improvement in the Chronic Respiratory Disease Questionnaire (CRQ) 12 weeks
with ipratropium
with salmeterol
Absolute results not reported
WMD –0.58
95% CI –3.50 to +2.35
P = 0.7 		Not significant
Open in a new tab

Mortality

No data from the following reference on this outcome.[30] [45]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[30]
Systematic review		 538 people
2 RCTs in this analysis		 Proportion of people withdrawing from a study because of adverse effects
with ipratropium
with salmeterol
Absolute results not reported
OR 0.45
95% CI 0.07 to 2.95
P = 0.40 		Not significant
[30]
Systematic review		 703 people
2 RCTs in this analysis		 Proportion of people withdrawing from a study because of adverse effects
with ipratropium
with formoterol
Absolute results not reported
OR 1.84
95% CI 0.64 to 5.31
P = 0.26 		Not significant
[45]
Systematic review		 1365 people
4 RCTs in this analysis		 Proportion of people withdrawing from a study because of adverse effects
30/682 (4%) with ipratropium
21/683 (3%) with salmeterol
RR 1.42
95% CI 0.82 to 2.45
P = 0.2
Further details on types of adverse effect associated with treatments not reported 		Not significant
[45]
Systematic review		 1365 people
4 RCTs in this analysis		 Proportion of people reporting an adverse effect
365/682 (53.5%) with ipratropium
363/683 (53.1%) with salmeterol
RR 1.00
95% CI 0.91 to 1.10
P = 1
Further details on types of adverse effect associated with treatments not reported 		Not significant
Open in a new tab

Long-acting anticholinergic versus short-acting beta2 agonist:

We found no systematic review or RCTs. One review compared anticholinergics as a class versus beta2 agonists as a class (see further information on studies for results).[30]

Long-acting anticholinergic versus long-acting beta2 agonist:

We found 5 systematic reviews comparing anticholinergics versus beta2 agonists.[29] [48] [30] [44] [45] The reviews did not report data in terms of short- or long-term duration of treatment as defined in our Methods section, but by length of drug action. We report comparisons as reported in the reviews, and specify the duration of treatment where possible. One review compared anticholinergics as a class versus beta2 agonists as a class (see further information on studies for results).[30] Three systematic reviews compared long-acting anticholinergic versus long-acting beta2 agonist.[29] [48] [30] There is some overlap in the RCTs identified by the reviews; however, no single RCT was identified by all three reviews. The reviews reported on different outcomes and different comparisons of long-acting anticholinergic versus long-acting beta2 agonist.

Mortality

Long-acting anticholinergic compared with long-acting beta2 agonist Tiotropium and salmeterol are equally effective at reducing all-cause mortality (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
All-cause mortality
[48]
Systematic review		 1460 people
2 RCTs in this analysis		 All-cause mortality
2/730 (0.2%) with tiotropium
6/730 (0.8%) with salmeterol
OR 0.38
95% CI 0.09 to 1.66
P = 0.20 		Not significant
Open in a new tab

Lung function and exercise capacity

Long-acting anticholinergic compared with long-acting beta2 agonist Tiotropium seems more effective than salmeterol at improving FEV1 (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[48]
Systematic review		 1382 people
2 RCTs in this analysis		 Improvement in FEV1
with tiotropium
with salmeterol
Absolute results not reported
WMD 28.97
95% CI 6.45 to 51.49
P = 0.01 		Effect size not calculated tiotropium
Open in a new tab

COPD exacerbation and worsening of symptoms

Long-acting anticholinergic compared with long-acting beta2 agonist Tiotropium and salmeterol are equally effective at improving COPD exacerbations (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbation
[48]
Systematic review		 1460 people
2 RCTs in this analysis		 Proportion of people with an exacerbation of COPD
159/730 (22%) with tiotropium
178/730 (24%) with salmeterol
OR 0.86
95% CI 0.67 to 1.11
P = 0.24 		Not significant
Open in a new tab

Quality of life

Long-acting anticholinergic compared with long-acting beta2 agonist Tiotropium and salmeterol seem equally effective at improving St George's Respiratory Questionnaire scores (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[30]
Systematic review		 807 people
2 RCTs in this analysis		 Improvement in St George's Respiratory Questionnaire score
with tiotropium
with salmeterol
Absolute results not reported
OR (salmeterol v tiotropium) 0.79
95% CI 0.60 to 1.05 		Not significant
Open in a new tab

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[30]
Systematic review		 807 people
2 RCTs in this analysis		 Proportion of people withdrawing from a study because of adverse effects
with tiotropium
with salmeterol
Absolute results not reported
OR (salmeterol v tiotropium) 2.16
95% CI 1.36 to 3.43
P = 0.001
No further information on adverse effects reported 		Moderate effect size tiotropium
Open in a new tab

No data from the following reference on this outcome.[29] [48]

Further information on studies

The review compared anticholinergics as a class versus beta2 agonists as a class. It found no significant difference between drug classes in mortality rate or risk of exacerbation of COPD (mortality [5 RCTs, 1925 people]: OR 4.36, 95% CI 0.73 to 25.93, P = 0.11; exacerbation of COPD [6 RCTs, 2048 people]: OR 0.94, 95% CI 0.76 to 1.17, P = 0.59; absolute numbers not reported). The review also found no significant difference between drug classes in proportion of people withdrawing from a trial because of adverse effects (OR 1.53, 95% CI 0.88 to 2.64; P = 0.13; absolute numbers not reported). The review also compared tiotropium versus formoterol (1 RCT, 74 people), but reported no data for this comparison.

Comment

It has been suggested that older people have a greater bronchodilator response with anticholinergic drugs than with beta2 agonists, but we found no evidence for this.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Theophylline

Summary

Theophylline may improve lung function compared with placebo, but adverse effects limit its usefulness in stable COPD.

Theophylline has a narrow therapeutic range and is associated with adverse effects such as diarrhoea, headache, irritability, seizures, and cardiac arrhythmias. The usefulness of theophyllines is limited by adverse effects and the need for frequent monitoring of blood concentrations.

Benefits and harms

Theophylline (short-term treatment) versus placebo:

We found two systematic reviews (search dates 2005[49] [50]) and one small subsequent RCT.[51]

Lung function and exercise capacity

Compared with placebo Theophylline (short-term treatment) seems modestly more effective at improving FEV1, but seems no more effective at improving maximum walking distance at 6 minutes (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[50]
Systematic review		 704 people with COPD
10 RCTs in this analysis		 Improvement in pre-dose FEV1 2 days to 12 months
with theophylline
with placebo
Absolute numbers not reported
WMD 0.108 L
95% CI 0.05 L to 0.16 L
P <0.05 		Effect size not calculated theophylline
[50]
Systematic review		 166 people with COPD
6 RCTs in this analysis		 Improvement in pre-dose FVC 2 days to 12 months
with theophylline
with placebo
Absolute numbers not reported
WMD 0.186 L
95% CI 0.04 L to 0.34 L
P <0.05 		Effect size not calculated theophylline
[51]
RCT		 36 people with COPD Improvement in pre-dose FEV1 4 weeks
with oral theophylline 200 mg or 300 mg
with placebo
Absolute results reported graphically
P = 0.78 		Not significant
[51]
RCT		 36 people with COPD Improvement in pre-dose FVC 4 weeks
with oral theophylline 200 mg or 300 mg
with placebo
Absolute results reported graphically
P = 0.64 		Not significant
Exercise capacity
[49]
Systematic review		 58 people
2 RCTs in this analysis		 Maximum walking distance 6 minutes
with theophylline
with placebo
Absolute results not reported
WMD +33.38 m
95% CI –11.44 m to +78.20 m 		Not significant
Open in a new tab

Mortality

No data from the following reference on this outcome.[49] [50] [51]

COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[49] [50] [51]

Quality of life

No data from the following reference on this outcome.[49] [50] [51]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[49]
Systematic review		 39 people
3 RCTs in this analysis		 Nausea
with theophylline
with placebo
Absolute results not reported
RR 7.67
95% CI 1.47 to 39.94 		Large effect size placebo
Open in a new tab

No data from the following reference on this outcome.[50] [51]

Theophylline (long-term treatment) versus placebo:

We found two RCTs assessing the effects of theophylline compared with placebo in the long term.[52] [53]

Lung function and exercise capacity

Compared with placebo Theophylline (long-term treatment) may be more effective at improving FEV1, including pre-bronchodilator FEV1 but not post-bronchodilator FEV1 (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[52]
RCT
4-armed trial 		854 people Mean difference in FEV1 12 months
with theophylline (220 mg or 300 mg slow-release formulation)
with placebo
Absolute results not reported
Difference between groups: +120 mL (theophylline v placebo)
CI not reported
P <0.001
The theophylline arm was open label 		Effect size not calculated theophylline
[53]
RCT		 110 people Mean change in pre-bronchodilator FEV1 (change from baseline) 12 months
+6.3 mL with theophylline (100 mg twice daily)
–53.3 mL with placebo
P = 0.04 		Effect size not calculated theophylline
[53]
RCT		 110 people Mean change in post-bronchodilator FEV1 (change from baseline) 12 months
–55.9 mL with theophylline (100 mg twice daily)
–55.7 mL with placebo
P = 0.50 		Not significant
Open in a new tab

COPD exacerbation and worsening of symptoms

Compared with placebo Theophylline (long-term treatment) seems more effective at 12 months at reducing the frequency and duration of acute COPD exacerbations (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations (frequency and duration)
[53]
RCT		 110 people Frequency of acute COPD exacerbations (per year) 12 months
0.79 with theophylline (100 mg twice daily)
1.70 with placebo
P = 0.047 		Effect size not calculated theophylline
[53]
RCT		 110 people Duration of acute COPD exacerbations (per year) 12 months
4.58 days with theophylline (100 mg twice daily)
12.47 days with placebo
P = 0.045 		Effect size not calculated theophylline
Open in a new tab

No data from the following reference on this outcome.[52]

Mortality

No data from the following reference on this outcome.[52] [53]

Quality of life

No data from the following reference on this outcome.[52] [53]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[52]
RCT
4-armed trial 		854 people Discontinuation of treatment 12 months
with theophylline (220 mg or 300 mg slow-release formulation)
with placebo
Absolute results not reported
P <0.002 (theophylline v placebo)
The theophylline arm was open label 		Effect size not calculated placebo
[53]
RCT		 110 people Proportion of people reporting an adverse effect 12 months
10/57 (18%) with theophylline (100 mg twice daily)
3/53 (6%) with placebo
P = 0.076 		Not significant
Open in a new tab

Further information on studies

Six of 16 people (in a trial containing 36 people) had serum theophylline concentrations below the therapeutic threshold. This may have biased results toward placebo.

Comment

Clinical guide:

The therapeutic range for theophyllines is small, with blood concentrations of 10 mg/L to 15 mg/L required for optimal effects. Nausea and other adverse effects associated with the use of theophylline, such as diarrhoea, headache, irritability, seizures, and cardiac arrhythmias, may occur within the therapeutic range.[54] The usefulness of theophylline, especially when used in conventional doses, is limited by adverse effects associated with its use, and by the need for frequent monitoring of blood concentrations.

Substantive changes

Theophylline New evidence added.[50] [51] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Corticosteroids (oral)

Summary

Oral corticosteroids may improve short-term lung function, but have serious adverse effects.

We found no direct information from RCTs about the effects of oral corticosteroids on decline in lung function in the long term.

Long-term systemic corticosteroids are associated with serious adverse effects, including osteoporosis and diabetes.

Benefits and harms

Oral corticosteroids versus placebo:

We found one systematic review (search date 1989, 10 RCTs, 445 people), comparing oral corticosteroids versus placebo in people with stable COPD.[55] Treatment usually lasted 2 to 4 weeks. We found no RCTs examining the effects of oral corticosteroids in the long term on decline in lung function.

Lung function and exercise capacity

Compared with placebo Oral corticosteroids used in the short term for 2 to 4 weeks seem more effective at increasing the proportion of people with at least a 20% improvement in baseline FEV1 in people with stable COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[55]
Systematic review		 445 people
10 RCTs in this analysis		 Proportion of people with at least a 20% improvement in baseline FEV1
with oral corticosteroid
with placebo
Absolute results not reported
WMD 10%
95% CI 2% to 18%
When 5 RCTs not meeting all quality criteria were included in the analysis, the difference in effect size was 11% (95% CI 4% to 18%) 		Effect size not calculated oral corticosteroid
Open in a new tab

Mortality

No data from the following reference on this outcome.[55]

COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[55]

Quality of life

No data from the following reference on this outcome.[55]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[56]
Systematic review		 Number of people not reported Adverse effects
with
with
Open in a new tab

Further information on studies

None.

Comment

We found one narrative review of oral corticosteroids in patients with COPD, which focused on possible effects on bone mineral density of treatments for COPD including oral corticosteroids, but we do not discuss it here because it does not contribute further to the conclusions.[57]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Corticosteroids (inhaled)

Summary

Inhaled corticosteroids reduce exacerbations in COPD and reduce decline in FEV 1 , but the beneficial effects are small.

Combined inhaled corticosteroids plus long-acting beta 2 agonists improve lung function and symptoms and reduce exacerbations compared with placebo, and may be more effective than either treatment alone.

Long-term treatment with inhaled corticosteroids may predispose to adverse effects such as skin bruising, oral candidiasis, and pneumonia.

Benefits and harms

Inhaled corticosteroids (short-term treatment) versus placebo:

We found one systematic review (search date 2007).[58]

Lung function and exercise capacity

Compared with placebo Inhaled corticosteroids (short-term treatment) seems no more effective at improving FEV1 in people with moderate to severe COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[58]
Systematic review		 424 people with COPD
5 RCTs in this analysis		 Change in pre-bronchodilator FEV1 2 to 6 months
with inhaled corticosteroid
with placebo
Absolute numbers not reported
WMD 0.06 L
95% CI 0.03 to 0.09
P = 0.0002
A statistically significant, but modest effect 		Effect size not calculated inhaled corticosteroid
Open in a new tab

Mortality

No data from the following reference on this outcome.[58]

COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[58]

Quality of life

No data from the following reference on this outcome.[58]

Adverse effects

No data from the following reference on this outcome.[58]

Inhaled corticosteroids (long-term treatment) versus placebo:

We found 6 systematic reviews (search dates 2001,[59] 2002,[60]2003,[29] 2007,[58] and 2008[61] [62]), and 3 additional RCTs.[63] [64] [35]

Mortality

Compared with placebo Inhaled corticosteroids (long-term treatment) seem no more effective at reducing mortality at 3 years in people with moderate to severe COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[62]
Systematic review		 9223 people with COPD
5 RCTs in this analysis		 All-cause mortality 12 months
128/4636 (2.8%) with inhaled corticosteroids
148/4597 (3.2%) with placebo
RR 0.86
95% CI 0.68 to 1.09
P = 0.2 		Not significant
[35]
RCT
4-armed trial 		6184 people with COPD; 6112 people included in efficacy analysis Mortality 3 years
246/1534 (16%) with fluticasone (500 micrograms twice daily)
231/1524 (15%) with placebo
HR 1.06 (fluticasone v placebo)
95% CI 0.89 to 1.27
P = 0.53 		Not significant
Open in a new tab

No data from the following reference on this outcome.[59] [60] [29] [58] [61] [63] [64]

Lung function and exercise capacity

Compared with placebo Inhaled corticosteroids (long-term treatment) seem more effective at improving FEV1 in people with moderate to severe COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[58]
Systematic review		 2333 people with COPD
4 RCTs in this analysis		 Reduction in annual decline in FEV1 at least 2 years
with inhaled corticosteroids
with placebo
Absolute numbers not reported
+5.8 mL/year
95% CI –0.28 mL/year to +11.9 mL/year
P >0.05 		Not significant
[63]
RCT
4-armed trial 		691 people Improvement in FEV1 6 months
with fluticasone (500 micrograms)
with placebo
Absolute results not reported
Difference in FEV1: 105 mL (fluticasone v placebo)
P <0.05 		Effect size not calculated fluticasone
[64]
RCT
4-armed trial 		723 people Increase in post-dose FEV1 from baseline 6 months
147 mL with fluticasone
58 mL with placebo
P <0.05 (fluticasone v placebo) 		Effect size not calculated fluticasone
Open in a new tab

No data from the following reference on this outcome.[59] [60] [29] [61] [62] [35]

COPD exacerbation and worsening of symptoms

Compared with placebo Inhaled corticosteroids (long-term treatment) seem more effective at improving dyspnoea and at reducing COPD exacerbations in people with moderate to severe COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[61]
Systematic review		 8164 people with COPD
11 RCTs in this analysis		 Risk of COPD exacerbation 1 to 4.5 years
with inhaled corticosteroid
with placebo
Absolute numbers not reported
RR 0.82
95% CI 0.73 to 0.92
P <0.05
Sensitivity analysis suggested that there was benefit only in people with severe disease (FEV1 <50%) 		Small effect size inhaled corticosteroids
Symptom severity
[63]
RCT
4-armed trial 		691 people Improvement in transitional dyspnoea index (TDI) 6 months
with fluticasone (500 micrograms)
with placebo
Absolute results not reported
Difference in TDI 1.0
P <0.05 		Effect size not calculated fluticasone
[64]
RCT
4-armed trial 		723 people Mean TDI score 6 months
1.7 with fluticasone
1.0 with placebo
P = 0.057 		Not significant
Open in a new tab

No data from the following reference on this outcome.[59] [60] [29] [58] [62] [35]

Quality of life

Compared with placebo Inhaled corticosteroids (long-term treatment) seem more effective at improving health-related quality of life in people with COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Health-related quality of life
[58]
Systematic review		 2507 people with COPD
5 RCTs in this analysis		 Rate of change in St George's Respiratory Questionnaire (SGRQ) per year
with inhaled corticosteroids
with placebo
Absolute numbers not reported
WMD –1.22 units/year
95% CI –1.83 units/year to –0.60 units/year
P >0.05 		Not significant
[64]
RCT
4-armed trial 		723 people Improvement in Chronic Respiratory Disease Questionnaire (CRQ) score from baseline 6 months
10.4 with fluticasone
5.0 with placebo
P = 0.002 		Effect size not calculated fluticasone
Open in a new tab

No data from the following reference on this outcome.[59] [60] [29] [61] [62] [63] [35]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[59]
Systematic review		 3976 people
9 RCTs in this analysis		 Oropharyngeal candidiasis
with inhaled corticosteroids
with placebo
Absolute results not reported
RR 2.1
95% CI 1.5 to 3.1 		Moderate effect size placebo
[29]
Systematic review		 5562 people with stable moderate to severe COPD
6 RCTs in this analysis		 Oral thrush
with inhaled corticosteroids
with placebo
Absolute results not reported
RR 2.98
95% CI 2.09 to 4.26 		Moderate effect size placebo
[29]
Systematic review		 3772 people with stable moderate to severe COPD
4 RCTs in this analysis		 Dysphonia
with inhaled corticosteroids
with placebo
Absolute results not reported
RR 2.02
95% CI 1.43 to 2.83 		Moderate effect size placebo
[58]
Systematic review		 3864 people with stable, moderate to severe COPD
4 RCTs in this analysis		 Bruising
with inhaled corticosteroids
with placebo
Absolute numbers not reported
OR 1.86
95% CI 1.39 to 2.48
P <0.05 		Small effect size placebo
[29]
Systematic review		 1867 people with stable moderate to severe COPD
2 RCTs in this analysis		 Cataracts
with inhaled corticosteroids
with placebo
Absolute results not reported
RR 1.05
95% CI 0.84 to 1.31 		Not significant
[29]
Systematic review		 972 people with stable moderate to severe COPD
Data from 1 RCT		 Reduction in bone mineral density (BMD) (femoral neck and lumbar spine) over 3 to 4 years
with inhaled triamcinolone
with placebo
Absolute results not reported
Reduction in BMD in femoral neck with triamcinolone compared with placebo: 1.57%
95% CI 2.40% to 0.74%
Reduction in BMD in lumbar spine with triamcinolone compared with placebo: 1.07%
95% CI 1.86% to 0.28% 		Effect size not calculated placebo
[29]
Systematic review		 972 people with stable moderate to severe COPD
Data from 1 RCT		 Excess risk of fractures 3 years
with inhaled triamcinolone
with placebo
Absolute results not reported
RR 0.70
95% CI 0.36 to 1.37 		Not significant
[62]
Systematic review		 8131 people with COPD
In review [57]
3 RCTs in this analysis		 Fracture risk 3 years
195/4073 (4.8%) with inhaled corticosteroid
178/4058 (4.4%) with placebo
Absolute numbers not reported
RR 1.09
95% CI 0.89 to 1.33
P = 0.4 		Not significant
[60]
Systematic review		 Number of people and RCTs in analysis not reported Proportion of people withdrawing from study because of adverse effects mean follow-up of 20 months
with inhaled corticosteroids
with placebo
Absolute results not reported
RR 0.92
95% CI 0.74 to 1.14 		Not significant
[63]
RCT
4-armed trial 		691 people Oropharyngeal candidiasis 6 months
10% with fluticasone (500 micrograms)
<1% with placebo
Absolute numbers not reported
P value not reported
[64]
RCT
4-armed trial 		723 people Rate of serious adverse effects 6 months
5% with fluticasone
5% with placebo
Absolute numbers not reported
P value not reported
[64]
RCT
4-armed trial 		723 people Rate of adverse effects leading to withdrawal of treatment 6 months
5% with fluticasone
5% with placebo
Absolute numbers not reported
P value not reported
[35]
RCT
4-armed trial 		6184 people with COPD; 6112 people included in efficacy analysis Proportion of people experiencing a drug-related adverse effect 3 years
19% with fluticasone (500 micrograms twice daily)
13% with placebo
Absolute numbers not reported
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.[61]

Inhaled corticosteroids alone versus inhaled corticosteroids plus beta2 agonists:

See option on inhaled corticosteroids plus beta2 agonists.

Further information on studies

The RCT also carried out a last observation carried forward analysis for the outcome of FEV1. However, the withdrawal rate from the RCT was high and the proportion of people followed up at 3 years for this outcome was 56% (851/1524) in the placebo group and 62% (947/1534) in the fluticasone alone group. These do not meet Clinical Evidence follow-up reporting criteria of 80%, and so these data are not reported here.

Comment

Clinical guide:

Many of the RCTs of inhaled corticosteroids have been done in people with moderate to severe COPD (FEV1 <50% predicted) and hence apply only to that population. The lifetime risk of fractures in people who take corticosteroids for longer than 3 to 4 years is unknown. The Global Initiative on Obstructive Pulmonary Disease has therefore advocated the use of inhaled corticosteroids only in people with an FEV1 <50% predicted, and frequent exacerbations (at least 3 exacerbations in the past 3 years).[1]

Substantive changes

Corticosteroids (inhaled) New evidence added.[58] [61] [62] Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Corticosteroids plus long-acting beta2 agonists (inhaled)

Summary

Combined inhaled corticosteroids plus long-acting beta 2 agonists improve lung function, symptoms, and health-related quality of life and reduce exacerbations compared with placebo, and may be more effective than either treatment alone.

Benefits and harms

Corticosteroid plus long-acting beta2 agonist versus placebo:

We found one systematic review (search date 2007)[65] and three additional RCTs.[66] [67] [68]

Mortality

Compared with placebo Combined inhaled corticosteroids plus long-acting beta2 agonists are more effective at reducing all-cause mortality in people with moderate to severe disease (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[65]
Systematic review		 5752 people with COPD
7 RCTs in this analysis		 Mortality 6 months to 3 years
209/2946 (7%) with inhaled corticosteroid plus long-acting beta2 agonist
255/2806 (9%) with placebo
OR 0.79
95% CI 0.65 to 0.96
P = 0.02 		Effect size not calculated inhaled corticosteroid plus long-acting beta2 agonist
[65]
Systematic review		 3057 people with COPD
Data from 1 RCT		 Mortality 3 years
193/1533 (13%) with fluticasone plus salmeterol
231/1524 (15%) with placebo
HR 0.83
95% CI 0.68 to 1.00
P = 0.04 		Not significant
[66]
RCT
6-armed trial 		1704 people with COPD Mortality 6 months
3/277 (1.1%) with budesonide 160 micrograms plus formoterol 4.5 micrograms in one metered-dose inhaler twice daily
4/281 (1.4%) with budesonide 80 micrograms plus formoterol 4.5 micrograms in one metered-dose inhaler twice daily
0/287 (0.0%) with budesonide 160 micrograms plus formoterol 4.5 micrograms in separate metered-dose inhalers twice daily
1/300 (0.3%) with placebo
Significance not assessed
[67]
RCT		 445 Chinese people with COPD Mortality 6 months
2/297 (0.7%) with salmeterol 50 micrograms plus fluticasone 500 micrograms
0/148 (0%) with placebo
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.[68]

Lung function and exercise capacity

Compared with placebo An inhaled corticosteroid plus a long-acting beta2 agonist seems more effective at improving pre-dose FEV1 in people with moderate to severe COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[65]
Systematic review		 1420 people with COPD
5 RCTs in this analysis		 Improvement in pre-dose FEV1 up to 24 weeks
with fluticasone plus salmeterol
with placebo
Absolute numbers not reported
WMD 0.16 L
95% CI 0.14 L to 0.19 L
P <0.00001 		Effect size not calculated fluticasone plus salmeterol
[65]
Systematic review		 923 people with COPD
2 RCTs in this analysis		 Improvement in FEV1 from baseline 12 months
with budesonide plus formoterol
with placebo
Absolute numbers not reported
14.4%
95% CI 11.91% to 16.90%
P <0.00001 		Effect size not calculated budesonide plus formoterol
[68]
RCT
3-armed trial 		224 people with COPD Increase in pre-dose FEV1 percentage predicted 4 weeks
3.8% with fluticasone 500 micrograms plus salmeterol 50 micrograms twice daily
1.0% with placebo
P <0.05 		Effect size not calculated fluticasone plus salmeterol
[66]
RCT
6-armed trial 		1704 people with COPD Improvement in pre-dose FEV1 6 months
0.09 L with budesonide 160 micrograms plus formoterol 4.5 micrograms in one metered-dose inhaler twice daily
0.07 L with budesonide 80 micrograms plus formoterol 4.5 micrograms in one metered-dose inhaler twice daily
0.08 L with budesonide 160 micrograms plus formoterol 4.5 micrograms in separate metered-dose inhalers twice daily
0.01 L with placebo
P <0.05 for all treatment arms v placebo 		Effect size not calculated budesonide plus formoterol
[67]
RCT		 445 Chinese people with COPD Improvement in pre-dose FEV1 6 months
177 mL with salmeterol 50 micrograms plus fluticasone 500 micrograms
8 mL with placebo
P <0.001 for adjusted result (180 mL) 		Effect size not calculated salmeterol plus fluticasone
Open in a new tab

COPD exacerbation and worsening of symptoms

Compared with placebo An inhaled corticosteroid plus a long-acting beta2 agonist is more effective at reducing COPD exacerbation rates in people with moderate to severe disease (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[65]
Systematic review		 4222 people with COPD
3 RCTs in this analysis		 Rate of exacerbations 6 months to years
with fluticasone plus salmeterol
with placebo
Absolute numbers not reported
RR 0.74
95% CI 0.69 to 0.80
P <0.00001 		Small effect size fluticasone plus salmeterol
[65]
Systematic review		 913 people with COPD
2 RCTs in this analysis		 Rate of exacerbations 12 months
with budesonide plus formoterol
with placebo
Absolute numbers not reported
RR 0.74
95% CI 0.62 to 0.88
P <0.0005 		Small effect size budesonide plus formoterol
[67]
RCT		 445 Chinese people with COPD Annualised exacerbation rate 24 weeks
0.81 with salmeterol 50 micrograms plus fluticasone 500 micrograms
1.35 with placebo
RR 0.61
95% CI 0.45 to 0.84
P = 0.002 		Effect size not calculated salmeterol plus fluticasone
[68]
RCT
3-armed trial 		224 people with COPD Number of COPD exacerbations (including withdrawals due to exacerbation) 4 weeks
9/92 (10%) with fluticasone 500 micrograms plus salmeterol 50 micrograms twice daily
13/45 (29%) with placebo
Significance not assessed
People who withdrew were analysed separately from those who did not, with trends favouring fluticasone plus salmeterol 		Effect size not calculated
Open in a new tab

No data from the following reference on this outcome.[66]

Quality of life

Compared with placebo Corticosteroids plus long-acting beta2 agonists seem more effective at improving health-related quality of life in people with moderate to severe disease (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Health-related quality of life
[65]
Systematic review		 712 people with COPD
2 RCTs in this analysis		 Mean change from baseline in Chronic Respiratory Disease Questionnaire 6 months
10 with fluticasone plus salmeterol
5 with placebo
WMD 5.0
95% CI 2.48 to 7.52
P = 0.0001 		Effect size not calculated fluticasone plus salmeterol
[65]
Systematic review		 3346 people with COPD
4 RCTs in this analysis		 Mean change in St George's Respiratory Questionnaire (SGRQ) 6 months to 3 years
with fluticasone plus salmeterol
with placebo
Absolute numbers not reported
–2.9 units
95% CI –3.61 units to –2.18 units
P <0.00001 		Effect size not calculated fluticasone plus salmeterol
[65]
Systematic review		 923 people with COPD
2 RCTs in this analysis		 Mean change in SGRQ 12 months
with budesonide plus formoterol
with placebo
Absolute numbers not reported
–6.06 units v placebo
95% CI –7.90 units to –4.22 units
P <0.00001 		Effect size not calculated budesonide plus formoterol
[68]
RCT
3-armed trial 		224 people with COPD Change in SGRQ 4 weeks
–2.4 with fluticasone 500 micrograms plus salmeterol 50 micrograms twice daily
+1.5 with placebo
P <0.05 		Effect size not calculated fluticasone plus salmeterol
Open in a new tab

No data from the following reference on this outcome.[66] [67]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[65]
Systematic review		 5493 people with COPD
8 RCTs in this analysis		 Any adverse effects up to 3 years
2215/2808 (78.9%) with fluticasone plus salmeterol
2116/2685 (78.8%) with placebo
OR 1.1 for overall events
95% CI 0.96 to 1.27
P = 0.18 		Not significant
[65]
Systematic review		 923 people with COPD
2 RCTs in this analysis		 Serious adverse effects 12 months
108/462 (23%) with budesonide plus formoterol
103/461 (22%) with placebo
OR 1.06
95% CI 0.78 to 1.45
P = 0.7 		Not significant
[67]
RCT		 445 Chinese people with COPD Incidence of adverse effects 6 months
165/297 (56%) with salmeterol 50 micrograms plus fluticasone 500 micrograms
81/148 (55%) with placebo
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.[66] [68]

Corticosteroid plus long-acting beta2 agonist versus corticosteroid alone:

We found one systematic review (search date 2007)[69] and two subsequent RCTs.[68] [66]

Mortality

Corticosteroid plus long-acting beta2 agonist compared with corticosteroid alone Fluticasone plus salmeterol is more effective at 3 years than fluticasone alone at reducing all-cause mortality in people with moderate to severe disease. However, we don't know how budesonide plus formeterol compares with budesonide alone (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[69]
Systematic review		 4061 people with COPD
3 RCTs in this analysis		 Mortality 1 to 3 years
196/2022 (10%) with fluticasone plus salmeterol
249/2029 (12%) with fluticasone
OR 0.76
95% CI 0.62 to 0.93
P = 0.0072 		Small effect size fluticasone plus salmeterol
[69]
Systematic review		 917 people with COPD
3 RCTs in this analysis		 Mortality 1 year
11/462 (2.4%) with budesonide plus formoterol
11/455 (2.4%) with budesonide
OR 0.98
95% CI 0.42 to 2.29
P = 0.96 		Not significant
[66]
RCT
6-armed trial 		1704 people with COPD Mortality 6 months
3/277 (1.1%) with budesonide 160 micrograms plus formoterol 4.5 micrograms in one metered-dose inhaler twice daily
4/281 (1.4%) with budesonide 80 micrograms plus formoterol 4.5 micrograms in one metered-dose inhaler twice daily
0/287 (0.0%) with budesonide 160 micrograms plus formoterol 4.5 micrograms in separate metered-dose inhalers twice daily
2/275 (0.7%) with budesonide 160 micrograms twice daily
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.[68]

Lung function and exercise capacity

Compared with corticosteroid alone An inhaled corticosteroid plus a long-acting beta2 agonist seems more effective at improving pre-dose FEV1 in people with moderate to severe COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[69]
Systematic review		 690 people with COPD
2 RCTs in this analysis		 Improvement in pre-dose FEV1 6 months
with fluticasone plus salmeterol
with fluticasone
Absolute numbers not reported
WMD 0.05 L
95% CI 0.02 L to 0.09 L
P = 0.006 		Effect size not calculated fluticasone plus salmeterol
[69]
Systematic review		 917 people with COPD
3 RCTs in this analysis		 Increase in FEV1, mean difference between groups 1 year
with budesonide plus formoterol
with budesonide
Absolute numbers not reported
10.17%
95% CI 7.71% to 12.62%
Meta-analysis using fixed-effects model
P <0.00001 		Effect size not calculated budesonide plus formoterol
[68]
RCT
3-armed trial 		224 people with COPD Increase in FEV1 percentage predicted 4 weeks
3.8% with fluticasone 500 micrograms plus salmeterol 50 micrograms twice daily
1.6% with fluticasone 500 micrograms twice daily
Significance not assessed 		Effect size not calculated
Open in a new tab

No data from the following reference on this outcome.[66]

COPD exacerbation and worsening of symptoms

Compared with corticosteroid alone An inhaled corticosteroid plus a long-acting beta2 agonist seems more effective at reducing COPD exacerbations in people with moderate to severe disease (moderate-quality of evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[69]
Systematic review		 4706 people with COPD
4 RCTs in this analysis		 Risk of COPD exacerbation 1 to 3 years
with long-acting beta2 agonist (LABA) plus corticosteroid
with corticosteroid alone
Absolute numbers not reported
RR 0.91
95% CI 0.85 to 0.97
P = 0.0075 		Small effect size LABA
[68]
RCT
3-armed trial 		224 people with COPD Number of COPD exacerbations (including withdrawals due to exacerbation) 4 weeks
9/92 (10%) with fluticasone 500 micrograms plus salmeterol 50 micrograms twice daily
6/87 (7%) with fluticasone 500 micrograms alone
Significance not assessed
People who withdrew were analysed separately from those who did not, with trends favouring fluticasone
Open in a new tab

No data from the following reference on this outcome.[66]

Quality of life

Compared with corticosteroid alone A corticosteroid plus a long-acting beta2 agonist seems more effective at improving health-related quality of life in people with moderate to severe disease (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Health-related quality of life
[69]
Systematic review		 696 people with COPD
2 RCTs in this analysis		 Mean change in Chronic Respiratory Disease Questionnaire (CRQ) 6 months
with fluticasone plus salmeterol
with fluticasone
Absolute numbers not reported
WMD +2.34
95% CI –3.15 to +7.82
P = 0.4 		Not significant
[69]
Systematic review		 3001 people with COPD
3 RCTs in this analysis		 Mean change in St George’s Respiratory Questionnaire (SGRQ) 1 to 3 years
with fluticasone plus salmeterol
with fluticasone
Absolute numbers not reported
WMD –1.3
95% CI –2.04 to –0.57
P <0.0005 		Effect size not calculated fluticasone plus salmeterol
[69]
Systematic review		 917 people with COPD
2 RCTs in this analysis		 Mean change in SGRQ 12 months
with budesonide plus formoterol
with budesonide
Absolute numbers not reported
WMD –3.26
95% CI –5.10 to –1.42
P = 0.0005 		Effect size not calculated budesonide plus formoterol
Open in a new tab

No data from the following reference on this outcome.[68] [66]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[69]
Systematic review		 4795 people with COPD
5 RCTs in this analysis		 Proportion of people reporting an adverse effect 6 months to 3 years
1993/2382 (83.7%) with fluticasone plus salmeterol
2038/2413 (84.5%) with fluticasone alone
OR 0.94
95% CI 0.80 to 1.10
P = 0.41 		Not significant
[69]
Systematic review		 5033 people with COPD
5 RCTs in this analysis		 Episodes of pneumonia 6 months to 3 years
224/2501 (9%) with long-acting beta2 agonist (LABA) plus corticosteroid
202/2532 (8%) with fluticasone alone
OR 1.13
95% CI 0.92 to 1.38
P = 0.23 		Not significant
Open in a new tab

No data from the following reference on this outcome.[68] [66]

Corticosteroid plus long-acting beta2 agonist versus beta2 agonist alone:

We found two systematic reviews (search dates 2009[70] and 2007[71]).

Mortality

Corticosteroid plus long-acting beta2 agonist compared with long-acting beta2 agonist alone Fluticasone plus salmeterol seems no more effective at 3 years than salmeterol alone at reducing all-cause mortality in people with moderate to severe disease (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[70]
Systematic review		 10,013 people with COPD
11 RCTs in this analysis		 All-cause mortality 1 month to >12 months
240/5292 (4.5%) with corticosteroid plus long-acting beta2 agonist (LABA)
261/4721 (5.5%) with LABA
RR 0.90
95% CI 0.76 to 1.06
P value not reported; reported as not significant 		Not significant
Open in a new tab

No data from the following reference on this outcome.[71]

Lung function and exercise capacity

Compared with long-acting beta2 agonist alone An inhaled corticosteroid plus a long-acting beta2 agonist may be more effective at improving pre-dose FEV1 in people with moderate to severe COPD (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[70]
Systematic review		 10,695 people with COPD
13 RCTs in this analysis		 Increase in pre-dose FEV1 1 month to >12 months
with corticosteroid plus long-acting beta2 agonist (LABA)
with LABA
Absolute numbers not reported
WMD 0.06 L
95% CI 0.04 L to 0.07 L
P = 0.0001 		Effect size not calculated corticosteroid plus LABA
Open in a new tab

No data from the following reference on this outcome.[71]

COPD exacerbation and worsening of symptoms

Compared with long-acting beta2 agonist alone An inhaled corticosteroid plus a long-acting beta2 agonist may be more effective at reducing COPD exacerbations in people with moderate to severe disease (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[70]
Systematic review		 12,297 people with COPD
14 RCTs in this analysis		 Exacerbations requiring hospital admission or withdrawal 1 month to >12 months
757/6685 (11.3%) with corticosteroid plus long-acting beta2 agonist (LABA)
704/5612 (12.5%) with LABA
RR 0.91
95% CI 0.82 to 1.01
P value not reported; reported as not significant 		Not significant
[70]
Systematic review		 9590 people with COPD
11 RCTs in this analysis		 Exacerbations requiring systemic corticosteroids 1 month to >12 months
794/4532 (18%) with corticosteroid plus LABA
1015/5058 (20%) with LABA
RR 0.84
95% CI 0.74 to 0.96
P = 0.008 		Small effect size corticosteroid plus LABA
Open in a new tab

No data from the following reference on this outcome.[71]

Quality of life

Compared with long-acting beta2 agonist alone A corticosteroid plus a long-acting beta2 agonist may be more effective at improving health-related quality of life in people with moderate to severe disease (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Health-related quality of life
[71]
Systematic review		 680 people with COPD
2 RCTs in this analysis		 Mean change in Chronic Respiratory Disease Questionnaire (CRQ) 6 months
with fluticasone plus salmeterol
with salmeterol alone
Absolute results not reported
WMD 2.83
95% CI 0.25 to 5.41
P = 0.03 		Effect size not calculated fluticasone plus salmeterol
[70]
Systematic review		 8657 people with COPD
8 RCTs in this analysis		 Mean change in St George’s Respiratory Questionnaire 1 month to >12 months
with corticosteroid plus long-acting beta2 agonist (LABA)
with LABA
Absolute numbers not reported
WMD –1.88
95% CI –2.44 to –1.33
P = 0.0001 		Effect size not calculated corticosteroid plus LABA
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[71]
Systematic review		 6671 people with COPD
7 RCTs in this analysis		 Proportion of people reporting any adverse effect 6 months to 3 years
2481/3338 (74.3%) with fluticasone plus salmeterol
2464/3333 (73.9%) with salmeterol alone
RR 1.02
95% CI 0.91 to 1.15
P = 0.72 		Not significant
[70]
Systematic review		 9752 people with COPD
11 RCTs in this analysis		 Episodes of pneumonia 1 month to >12 months
263/5212 (5%) with LABA plus corticosteroid
153/4540 (3%) with LABA
RR 1.63
95% CI 1.35 to 1.98
P = 0.0001 		Small effect size LABA
[70]
Systematic review		 6262 people with COPD
8 RCTs in this analysis		 Oropharyngeal candidiasis 1 month to >12 months
292/3521 (8%) with LABA plus corticosteroid
200/2741 (7%) with LABA
RR 1.59
95% CI 1.07 to 2.37
P = 0.002 		Small effect size LABA
[70]
Systematic review		 9206 people with COPD
10 RCTs in this analysis		 Viral upper respiratory tract infections 1 month to >12 months
441/4844 (9%) with LABA plus corticosteroid
342/4362 (8%) with LABA
WMD RR 1.22
95% CI 1.07 to 1.39
P = 0.004 		Small effect size LABA
[70]
Systematic review		 6543 people with COPD
6 RCTs in this analysis		 MI 1 month to >12 months
34/3278 (1.0%) with LABA plus corticosteroid
33/3265 (1.0%) with LABA
RR 1.03
95% CI 0.64 to 1.64
P = 0.91 		Not significant
Open in a new tab

Further information on studies

None.

Comment

Clinical guide:

The RCTs we found have been done mainly in people with moderate to severe disease (FEV1 <50%) and hence apply to that population. The Global Initiative on Obstructive Pulmonary Disease has, therefore, advocated inhaled corticosteroids and the combination of inhaled corticosteroids plus long-acting beta2 agonists only in people with FEV1 <50% predicted and frequent exacerbations (i.e., at least 3 exacerbations in the past 3 years).[1]

Substantive changes

Corticosteroids plus long-acting beta2 agonists New evidence added.[65] [66] [67] [68] [70] Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Mucolytic drugs

Summary

We don't know whether mucolytic drugs improve outcomes in people with COPD compared with placebo.

Benefits and harms

Mucolytics (long-term treatment) versus placebo:

We found two systematic reviews (search dates 2008[72] and 1995[73]). Not all people included in the reviews had COPD (see comment, below). We also found one subsequent RCT.[74]

COPD exacerbation and worsening of symptoms

Compared with placebo We don't know whether mucolytics (short-term treatment) are more effective at up to 36 months at reducing exacerbations in people with COPD (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[72]
Systematic review		 5055 people
23 RCTs in this analysis		 Average number of exacerbations 2 to 36 months
with mucolytics
with placebo
Absolute results not reported
WMD –0.05 exacerbations/month
95% CI –0.05 exacerbations/month to –0.04 exacerbations/month
The results of the review should be interpreted with caution
It was unclear how many people included in the review had COPD, and there was significant heterogeneity among the RCTs (symptom scores could not be pooled) 		Effect size not calculated mucolytics
[73]
Systematic review		 Number of people not reported
9 RCTs in this analysis		 Average number of exacerbations 3 to 24 months
with N-acetylcysteine
with placebo
Absolute results not reported
Overall weighted effect size 1.37
95% CI 1.25 to 1.50
Reduction 235
The result of the review should be interpreted with caution
It was unclear how many people included in the review had COPD, and there was significant heterogeneity among the RCTs (symptom scores could not be pooled) 		Effect size not calculated N-acetylcysteine
[74]
RCT		 709 Chinese people with COPD, with at least 2 exacerbations per year over 2 years Exacerbation risk 12 months
325 exacerbations in 354 people with carbocisteine 250 mg twice daily
439 exacerbations in 355 people with placebo
RR 0.75
95% CI 0.63 to 0.91
P = 0.04 		Small effect size carbocisteine
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Quality of life

Compared with placebo Mucolytics (long-term treatment) may be more effective at reducing days of disability at up to 36 months in people with COPD, but may be no more effective at improving St George's Respiratory Questionnaire scores at 12 months (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[72]
Systematic review		 1916 people
10 RCTs in this analysis		 Days of disability 2 to 36 months
with mucolytics
with placebo
Absolute results not reported
WMD –0.56 days/month
95% CI –0.77 days/months to –0.35 days/month
The results of the review should be interpreted with caution
It was unclear how many people included in the review had COPD, and there was significant heterogeneity among the RCTs (symptom scores could not be pooled) 		Effect size not calculated mucolytics
[74]
RCT		 709 Chinese people with COPD, with at least 2 exacerbations per year over 2 years Change in St George's Respiratory Questionnaire (SGRQ) score 12 months
–4.06 with carbocisteine 250 mg twice daily
–0.05 with placebo
P = 0.13 		Not significant
Open in a new tab

No data from the following reference on this outcome.[73]

Mortality

No data from the following reference on this outcome.[72] [73] [74]

Lung function and exercise capacity

Mucolytics (long-term treatment) compared with placebo Carbocisteine may be no more effective than placebo at improving lung function in people with COPD (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[74]
RCT		 709 Chinese people with COPD, with at least 2 exacerbations per year over 2 years Lung function 12 months
with carbocisteine 250 mg twice daily
with placebo
Absolute numbers not reported
P value not reported
Reported as not significant 		Not significant
Open in a new tab

No data from the following reference on this outcome.[72] [73]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[72]
Systematic review		 4149 people
15 RCTs in this analysis		 Proportion of people with an adverse effect 2 to 36 months
386/2074 (19%) with mucolytics
463/2075 (22%) with placebo
RR 0.84
95% CI 0.74 to 0.94
The results of the review should be interpreted with caution. The review reported that data from several large studies have been omitted from the meta-analysis
It was unclear how many people included in the review had COPD, and there was significant heterogeneity among the RCTs (symptom scores could not be pooled) 		Small effect size mucolytics
[73]
Systematic review		 Number of people not reported
9 RCTs in this analysis		 Rate of adverse effects 3 to 24 months
with N-acetylcysteine
with placebo
Absolute results not reported
Reported as not significant
P value not reported
The review reported that the adverse effects of N-acetylcysteine were mainly mild gastrointestinal (GI) complaints; no further information on adverse effects given
The result of the review should be interpreted with caution
It was unclear how many people included in the review had COPD, and there was significant heterogeneity among the RCTs (symptom scores could not be pooled) 		Not significant
[74]
RCT		 709 Chinese people with COPD, with at least 2 exacerbations per year over 2 years Adverse effects 12 months
57/354 (16.1%) with carbocisteine 250 mg twice daily
56/355 (15.8%) with placebo
Significance not assessed
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Further information on studies

Less than one third of the people in the RCT were taking inhaled corticosteroids, anticholinergics, beta2 agonists, or xanthines at baseline. There was also a trend towards more use of each class of medication at baseline in the treatment group. These factors may have biased the results in favour of carbocisteine.

Comment

One large RCT (523 people) identified by the reviews included people with only smoking-related COPD.[75] The RCT found no significant difference in FEV1 decline and exacerbations between N-acetylcysteine 600 mg daily and placebo at 3 years (difference in yearly decline in FEV1: 8 mL, 95% CI –25 mL to +10 mL; exacerbations/year: 1.25 with N-acetylcysteine v 1.29 with placebo; HR 0.99, 95% CI 0.89 to 1.10). However, pre-specified subgroup analysis was done for people who did or did not use inhaled corticosteroids at entry. The RCT found that N-acetylcysteine reduced exacerbations in people who did not take inhaled corticosteroids compared with placebo (155 people; HR 0.79, 95% CI 0.63 to 0.99).

Clinical guide:

The relative effects of mucolytics cannot be determined based on the current evidence, and so a direct comparison is required.

Substantive changes

Mucolytics New evidence added.[74] Categorisation unchanged (Unknown effectiveness) as all the RCTs we found had methodological flaws.

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Antibiotics (prophylactic)

Summary

We don't know whether prophylactic antibiotics improve outcomes in people with COPD compared with placebo.

Benefits and harms

Prophylactic antibiotics versus placebo:

We found no systematic review or RCTs assessing the effects of prophylactic antibiotics in the short term. We found one systematic review (search date not reported, 9 RCTs, 1055 people; all trials performed before 1970; see comment below) comparing prophylactic antibiotics (tetracycline, penicillin, trimethoprim, sulfadimidine, and sulfaphenazole) versus placebo in people with COPD or chronic bronchitis in RCTs of duration from 3 months to 5 years.[76] We also found one subsequent RCT comparing erythromycin versus placebo.[77]

COPD exacerbation and worsening of symptoms

Compared with placebo We don't know whether prophylactic antibiotics are more effective at reducing exacerbations in people with COPD (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
COPD exacerbations
[76]
Systematic review		 746 people
10 RCTs in this analysis		 Proportion of people with an exacerbation
269/382 (70%) with prophylactic antibiotics
285/364 (78%) with placebo
RR 0.91
95% CI 0.84 to 0.99
The results of the review should be interpreted with caution (see comment) 		Small effect size prophylactic antibiotics
[76]
Systematic review		 779 people
8 RCTs in this analysis		 Number of exacerbations per person per year
with prophylactic antibiotics
with placebo
Absolute results not reported
WMD –0.15
95% CI –0.34 to +0.04
The results of the review should be interpreted with caution (see comment) 		Not significant
[77]
RCT		 109 people with COPD, FEV1 30% to 70% expected Number of moderate to severe exacerbations 12 months
81 exacerbations in 53 people with erythromycin 250 mg twice daily
125 exacerbations in 56 people with placebo
RR 0.65
95% CI 0.49 to 0.86
P = 0.003 		Small effect size prophylactic antibiotics
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Quality of life

Compared with placebo We don't know whether prophylactic antibiotics are more effective at reducing the number of days of disability per person per month treated in people with COPD (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Days of disability
[76]
Systematic review		 755 people
7 RCTs in this analysis		 Number of days of disability per person per month treated
with prophylactic antibiotics
with placebo
Absolute results not reported
WMD –0.95
95% CI –1.89 to –0.01 (22% reduction)
The results of the review should be interpreted with caution (see comment) 		Effect size not calculated prophylactic antibiotics
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No data from the following reference on this outcome.[77]

Mortality

No data from the following reference on this outcome.[76] [77]

Lung function and exercise capacity

Compared with placebo We don't know whether prophylactic antibiotics are more effective at maintaining lung function (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[77]
RCT		 109 outpatients with COPD, FEV1 30% to 70% expected Decline in FEV1 from baseline 12 months
0.12 L (from 1.25 L to 1.13 L) with erythromycin 250 mg twice daily
0.08 L (from 1.33 L to 1.25 L with placebo
P = 0.97 		Not significant
Open in a new tab

No data from the following reference on this outcome.[76]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[76]
Systematic review		 934 people
10 RCTs in this analysis		 Number of adverse effects
with prophylactic antibiotics
with placebo
Absolute results not reported
Mean difference per person per year treated: 0.01
95% CI 0 to 0.02 		Effect size not calculated placebo
[77]
RCT		 109 outpatients with COPD, FEV1 30% to 70% expected Proportion of people with adverse effects 12 months
14/53 (26%) with erythromycin 250 mg twice daily
12/56 (21%) with placebo
P >0.05 		Not significant
Open in a new tab

Further information on studies

The results of this RCT should be interpreted with caution as the effect may have been mediated by drug interactions with medications such as fluticasone or salmeterol rather than by antibiotic or direct anti-inflammatory effect.

Comment

Clinical guide:

The results of the review should be interpreted with caution.[76] It was unclear from the descriptions of the original studies how many participants had COPD (rather than chronic bronchitis without obstruction). Additionally, the data in the review are >30 years old, so the pathogens and the pattern of antibiotic sensitivity may have changed, and there is currently a wider range of antibiotics in use. Most people believe that prophylactic antibiotics do not have a place in routine treatment because of concerns about the development of antibiotic resistance and the possibility of adverse effects.

Substantive changes

Antibiotics (prophylactic) New evidence added.[77] Categorisation unchanged (Unknown effectiveness) as the evidence is contradictory and much comes from trials completed before 1970.

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Oxygen treatment (long-term domiciliary treatment)

Summary

Long-term domiciliary oxygen treatment may improve survival in people with severe daytime hypoxaemia.

Benefits and harms

Oxygen compared with no oxygen (short-term treatment):

We found no systematic review or RCTs.

Oxygen versus no oxygen (long-term treatment):

We found one systematic review (search date 2007, 6 RCTs).[78] The review did not pool data for many outcomes because of differences in trial design and participant selection. The review identified one RCT in people with severe daytime hypoxaemia (arterial oxygen tension [PaO2] 5.3–8.0 kPa).[79]

Mortality

Long-term treatment with oxygen compared with no oxygen Daily domiciliary oxygen supplementation seems more effective at reducing mortality at 5 years in people with severe daytime hypoxaemia but not in people with mild to moderate hypoxaemia (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Mortality
[78]
Systematic review		 87 people with severe daytime hypoxaemia
Data from 1 RCT		 Mortality 5 years
19/42 (45%) with domiciliary daily oxygen supplementation
30/45 (67%) with no oxygen supplementation
RR 0.68
95% CI 0.46 to 1.00 		Small effect size domiciliary daily oxygen supplementation
[78]
Systematic review		 163 people with mild to moderate hypoxaemia (PaO2 56–65 mmHg or >55 mmHg)
2 RCTs in this analysis		 Mortality 36 to 85 months
42/82 (51%) with domiciliary daily oxygen supplementation
35/81 (43%) with no oxygen supplementation
RR 1.18
95% CI 0.86 to 1.63 		Not significant
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Lung function and exercise capacity

Long-term treatment with oxygen compared with no oxygen Daily domiciliary oxygen supplementation seems no more effective at improving endurance time at 12 months in people with mild to moderate hypoxaemia (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Exercise capacity
[78]
Systematic review		 28 people with mild to moderate hypoxaemia
Data from 1 RCT		 Change in endurance time 12 months
+7.1 minutes with domiciliary daily oxygen supplementation
+4.9 minutes with no oxygen supplementation
WMD +2.20 minutes
95% CI –0.73 minutes to +5.13 minutes 		Not significant
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COPD exacerbation and worsening of symptoms

Long-term treatment with oxygen compared with no oxygen Daily domiciliary oxygen supplementation seems no more effective at improving dyspnoea scores at 12 months in people with mild to moderate hypoxaemia (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[78]
Systematic review		 28 people with mild to moderate hypoxaemia
Data from 1 RCT		 Dyspnoea score (assessed using Borg scale) 12 months
+4.5 with domiciliary daily oxygen supplementation
+5.7 with no oxygen supplementation
WMD –1.20
95% CI –2.47 to +0.07 		Not significant
Open in a new tab

Quality of life

No data from the following reference on this outcome.[78]

Adverse effects

No data from the following reference on this outcome.[78]

Further information on studies

Only one of the RCTs identified by the review was double blinded.

One RCT (203 people, PaO2 <7.4 kPa) identified by the review compared continuous v nocturnal domiciliary oxygen treatment. Continuous oxygen was associated with a significant reduction in mortality over 24 months (OR 0.45, 95% CI 0.25 to 0.81).

Comment

Clinical guide:

Domiciliary oxygen treatment seems to be more effective in people with severe hypoxaemia (PaO2 <8.0 kPa) than in people with moderate hypoxaemia (conflicting findings among the studies) or those who have arterial desaturation only at night.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Alpha1 antitrypsin

Summary

We don't know whether alpha 1 antitrypsin improves outcomes in people with COPD compared with placebo.

We found insufficient information from a single RCT assessing alpha 1 antitrypsin in the short-term treatment of people with COPD.

Benefits and harms

Alpha1 antitrypsin versus placebo (short-term treatment):

We found no systematic review or RCTs.

Alpha1 antitrypsin versus placebo (long-term treatment):

We found one systematic review (search date 2007),[81] which included one RCT.[82] The review[81] also identified several observational studies (see comment).

Lung function and exercise capacity

Compared with placebo We don't know whether long-term treatment with alpha1 antitrypsin is more effective at improving FEV1 at 3 years in people with moderate emphysema (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[82]
RCT		 56 people with alpha1 antitrypsin deficiency and moderate emphysema, FEV1 30% to 80% predicted
In review [81] 		Decline in FEV1 1 year
59 mL with alpha1 antitrypsin infusions 250 mg/kg
79 mL with placebo (albumin) infusions
P = 0.25 		Not significant
Open in a new tab

Mortality

No data from the following reference on this outcome.[81]

COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[81]

Quality of life

No data from the following reference on this outcome.[81]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[82]
RCT		 56 people with alpha1 antitrypsin deficiency and moderate emphysema, FEV1 30% to 80% predicted
In review [81] 		Adverse effects
with alpha1 antitrypsin infusions 250 mg/kg
with placebo (albumin) infusions
Absolute results not reported
Open in a new tab

Further information on studies

None.

Comment

Observational studies identified in the systematic review[81] did not provide clear evidence of the effect of alpha1 antitrypsin. For example, one cohort study (1048 people either homozygous for alpha1 antitrypsin deficiency or with an alpha1 antitrypsin concentration 11 micromol/L or less, with mean FEV1 49% ± 30% predicted) compared weekly infusions of alpha1 antitrypsin 60 mg/kg versus placebo for 3.5 to 7.0 years. It found that alpha1 antitrypsin significantly reduced mortality after an average of 5 years (RR of death 0.64, 95% CI 0.43 to 0.94). It found no significant difference between treatments in the decline in FEV1, but in a subgroup of people with a mean FEV1 of 35% to 49% predicted, alpha1 antitrypsin significantly reduced the decline in FEV1 (mean difference in FEV1 27 mL/year, 95% CI 3 mL/year to 51 mL/year; P = 0.03). A second cohort study (295 people homozygous for alpha1 antitrypsin deficiency with FEV1 below 65% predicted) compared 198 people who received weekly infusions of alpha1 antitrypsin 60 mg/kg (duration not reported) versus 97 people who had never received alpha1 antitrypsin. It found that alpha1 antitrypsin significantly reduced the decline in FEV1 (50 mL/year with alpha1 antitrypsin v 80 mL/year with no alpha1 antitrypsin; 95% CI not reported; P = 0.02).[81]

Substantive changes

Alpha1 antitrypsin New evidence added.[81] Categorisation unchanged (Unknown effectiveness) as there remains insufficient evidence to judge this intervention.

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Psychosocial interventions alone for smoking cessation

Summary

Psychosocial interventions alone for smoking cessation in people with COPD may reduce the decline in FEV 1 in people with signs of early COPD.

Benefits and harms

Psychosocial interventions versus usual care:

We found two systematic reviews (search dates 2007[83] and 2002[84]), which identified one three-armed RCT assessing the effects of a psychosocial intervention.[10]

Mortality

Smoking cessation interventions with and without ipratropium compared with usual care A psychosocial smoking cessation intervention alone seems no more effective at reducing all-cause mortality at 5 years in people with signs of early COPD, but smoking cessation interventions with and without ipratropium seem more effective at reducing all-cause mortality at 14.5 years (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
All-cause mortality
[85]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
Further report of reference [10] 		All-cause mortality 5 years
44/1962 (2%) with smoking cessation intervention plus placebo
51/1964 (3%) with usual care
P = 0.47 (smoking cessation intervention plus placebo v usual care) 		Not significant
[87]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		All-cause mortality 14.5 years
8.83/1000 person-years with smoking cessation intervention with or without ipratropium
10.83/1000 person-years with usual care
HR for mortality 1.18
95% CI 1.02 to 1.37
Combined analysis of smoking cessation programme with and without ipratropium (by intention-to-treat analysis) v usual care 		Small effect size smoking cessation intervention with or without ipratropium
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Lung function and exercise capacity

Smoking cessation programme with or without ipratropium compared with usual care A psychosocial smoking cessation programme alone seems more effective at reducing the decline in FEV1 at 1 to 5 years in people with signs of early COPD, and a psychosocial smoking cessation programme with or without ipratropium seems more effective at reducing the decline in FEV1 at 11 years (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[10]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Change in FEV1 1 year
+11.2 mL with smoking cessation programme
–34.3 mL with usual care
P <0.005 (smoking cessation programme v usual care) 		Effect size not calculated smoking cessation intervention
[10]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Change in FEV1 5 years
–208 mL with smoking cessation programme
–267 mL with usual care
P = 0.002 or less (smoking cessation programme v usual care)
Results from completer analysis (about 90% of people) 		Effect size not calculated smoking cessation intervention
[88]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Decline in FEV1 (change from baseline) 11 years
–502 mL with smoking cessation intervention with or without ipratropium
+587 mL with usual care
P = 0.001
Combined analysis of smoking cessation programme with or without ipratropium v usual care 		Effect size not calculated smoking cessation intervention with or without ipratropium
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COPD exacerbation and worsening of symptoms

Smoking cessation interventions with or without ipratropium compared with usual care Smoking cessation interventions with or without ipratropium seem more effective at reducing cough, phlegm, wheezing, and dyspnoea at 5 years in people with signs of early COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptoms
[89]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD, mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Proportion of people with cough for at least 3 months/year 5 years
15% with smoking cessation intervention with or without ipratropium
23% with usual care
Absolute numbers not reported
P <0.0001
Combined analysis of smoking cessation programme with and without ipratropium (by intention-to-treat [ITT] analysis) v usual care 		Effect size not calculated smoking cessation intervention with or without ipratropium
[89]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Proportion of people with phlegm for at least 3 months/year 5 years
12% with smoking cessation intervention with or without ipratropium
20% with usual care
Absolute numbers not reported
P <0.0001
Combined analysis of smoking cessation programme with and without ipratropium (by ITT analysis) v usual care 		Effect size not calculated smoking cessation intervention with or without ipratropium
[89]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Proportion of people with wheezing 5 years
25% with smoking cessation intervention with or without ipratropium
31% with usual care
Absolute numbers not reported
P <0.0001
Combined analysis of smoking cessation programme with and without ipratropium (by ITT analysis) v usual care 		Effect size not calculated smoking cessation intervention with or without ipratropium
[89]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Proportion of people with dyspnoea 5 years
19% with smoking cessation intervention with or without ipratropium
24% with usual care
Absolute numbers not reported
P <0.0001
Combined analysis of smoking cessation programme with and without ipratropium (by ITT analysis) v usual care 		Effect size not calculated smoking cessation intervention with or without ipratropium
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No data from the following reference on this outcome.[10]

Quality of life

No data from the following reference on this outcome.[10] [83] [89]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[10] [90]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Adverse effects
with smoking cessation with or without ipratropium
with usual care
[91]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Weight gain 1 year
2.61 kg for men, 2.63 kg for women with smoking cessation with or without ipratropium
0.61 kg for men, 1.10 kg for women with usual care
Significance not assessed
[91]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Weight gain 5 years
3.9 kg for men, 4.75 kg for women with smoking cessation with or without ipratropium
2.6 kg for men, 2.84 kg for women with usual care
Significance not assessed
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Psychosocial intervention alone versus psychosocial intervention plus pharmacological treatment:

See option on psychosocial intervention plus pharmacological treatment for smoking cessation.

Further information on studies

The smoking cessation intervention consisted of an intensive 12-session smoking cessation programme combining behaviour modification and use of nicotine gum (nicotine polacrilex 2 mg) with a continuing 5-year maintenance programme that included monitoring of weight gain and nutritional counselling.

Comment

Despite the extensive literature on smoking cessation, we found only one RCT that assessed psychosocial interventions alone, and found no RCTs solely in people with COPD: most RCTs focused on combinations of interventions, continuous abstinence or point prevalence rates of smoking cessation as single outcome measures, and populations including either healthy people or healthy people and people with disease.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Pharmacological interventions alone for smoking cessation

Summary

Combined psychosocial and pharmacological interventions for smoking cessation can slow the deterioration of lung function, but have not been shown to reduce long-term mortality compared with usual care.

We found no direct information from RCTs about the effects of pharmacological interventions alone for smoking cessation in people with COPD.

Benefits and harms

Pharmacological interventions alone for smoking cessation:

We found one systematic review (search date 2002).[84] It found no RCTs examining the effects of pharmacological smoking cessation interventions alone for the outcomes of interest in this review (FEV1 , peak expiratory flow, exacerbations, dyspnoea score, quality of life, or survival) specifically in people with COPD. The review[84] identified two RCTs, both of which examined pharmacological interventions plus psychosocial interventions (see option on psychosocial plus pharmacological interventions).[10] [92]

Further information on studies

None.

Drug safety alert

FDA issues drug safety alert on the risk of serious neuropsychiatric symptoms (July 2009).

A drug safety alert has been issued on the risk of serious neuropsychiatric symptoms, which include changes in behaviour, hostility, agitation, depressed mood, suicidal thoughts and behaviour, and attempted suicide, associated with bupropion (www.fda.gov).

Comment

One systematic review (search date 2001, 157 studies) assessed the effectiveness of bupropion and nicotine replacement treatment for smoking cessation, but did not focus solely on people with COPD.[93] [94] It found a low incidence of adverse events with nicotine replacement therapy, irrespective of the type of replacement. The most common adverse effects were localised reactions: skin sensitivity and irritation (with patches); throat irritation, nasal irritation, and runny nose (with nasal spray); hiccups, burning and smarting sensation in the mouth, sore throat, coughing, dry lips, and mouth ulcers (with nicotine sublingual tablets); and hiccups, gastrointestinal disturbances, jaw pain, and orodental problems (with nicotine gum). Sleep disturbances and alteration of mood may arise because of nicotine withdrawal. A small number of studies were done in specific subgroups (including smokers with lung disease). Results for individual subgroups were generally non-significant, but their direction was consistent with the overall pooled results. The systematic review did not report results separately in people with COPD. Regarding the safety of bupropion, the review concluded that seizure is the most significant and important potential adverse effect. However, this review did not identify RCTs that reported any seizures. Common adverse events of bupropion are: rash, pruritus, urticaria, irritability, insomnia, dry mouth, headache, and tremor. The adverse-effect profile of slow-release bupropion seems better than that of immediate-release bupropion. The results for specific subgroups (including smokers with pulmonary disease) were generally consistent with the overall pooled results, although results in people with COPD were not reported separately.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Psychosocial plus pharmacological interventions for smoking cessation

Summary

Combined psychosocial and pharmacological interventions for smoking cessation can slow the deterioration of lung function, but have not been shown to reduce long-term mortality compared with usual care.

Benefits and harms

Psychosocial plus pharmacological interventions versus usual care:

We found one systematic review (search date 2002),[83] which identified two RCTs examining psychosocial plus pharmacological interventions compared with usual care in people with COPD.[10] [92] One RCT reported only abstinence rates and adverse effects.[92] This study did not provide data about the effects on FEV1 changes, peak expiratory flow, exacerbations, dyspnoea score, quality of life, or survival.

Mortality

Psychosocial plus pharmacological interventions compared with usual care Smoking cessation interventions with and without ipratropium seem more effective at 14.5 years but not at 5 years at reducing all-cause mortality in people with signs of early COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
All-cause mortality
[85]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD, mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
Further report of reference [10] 		All-cause mortality 5 years
54/1961 (2.7%) with smoking cessation intervention plus ipratropium
51/1964 (2.6%) with usual care
P = 0.765 (smoking cessation intervention plus ipratropium v usual care) 		Not significant
[87]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		All-cause mortality 14.5 years
8.83/1000 person-years with smoking cessation intervention with or without ipratropium
10.83/1000 person-years with usual care
HR for mortality 1.18
95% CI 1.02 to 1.37
Combined analysis of smoking cessation programme with and without ipratropium (by intention-to-treat analysis) v usual care 		Small effect size smoking cessation intervention with or without ipratropium
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Lung function and exercise capacity

Psychosocial plus pharmacological interventions compared with usual care A psychosocial smoking cessation programme with or without ipratropium seems more effective at reducing the decline in FEV1 at 1 to 11 years in people with signs of early COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[10]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Change in FEV1 1 year
+38.8 mL with smoking cessation intervention plus ipratropium
–34.3 mL with usual care
P <0.005 (smoking cessation intervention plus ipratropium v usual care) 		Effect size not calculated smoking cessation intervention plus ipratropium
[10]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Change in FEV1 5 years
–184 mL with smoking cessation intervention plus ipratropium
–267 mL with usual care
P = 0.002 or less (smoking cessation intervention plus ipratropium v usual care)
Results from completer analysis (about 90% of people) 		Effect size not calculated smoking cessation intervention plus ipratropium
[88]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Decline in FEV1 (change from baseline) 11 years
–502 mL with smoking cessation intervention with or without ipratropium
+587 mL with usual care
P = 0.001
Combined analysis of smoking cessation programme with or without ipratropium v usual care 		Effect size not calculated smoking cessation intervention with or without ipratropium
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COPD exacerbation and worsening of symptoms

Smoking cessation interventions with or without ipratropium compared with usual care Smoking cessation interventions with or without ipratropium seem more effective at reducing cough, phlegm, wheezing, and dyspnoea at 5 years in people with signs of early COPD (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptoms
[89]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Proportion of people with cough for at least 3 months/year 5 years
15% with smoking cessation intervention with or without ipratropium
23% with usual care
Absolute numbers not reported
P <0.0001
Combined analysis of smoking cessation programme with and without ipratropium (by intention-to-treat [ITT] analysis) v usual care 		Effect size not calculated smoking cessation intervention with or without ipratropium
[89]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Proportion of people with phlegm for at least 3 months/year 5 years
12% with smoking cessation intervention with or without ipratropium
20% with usual care
Absolute numbers not reported
P <0.0001
Combined analysis of smoking cessation programme with and without ipratropium (by ITT analysis) v usual care 		Effect size not calculated smoking cessation intervention with or without ipratropium
[89]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Proportion of people with wheezing 5 years
25% with smoking cessation intervention with or without ipratropium
31% with usual care
Absolute numbers not reported
P <0.0001
Combined analysis of smoking cessation programme with and without ipratropium (by ITT analysis) v usual care 		Effect size not calculated smoking cessation intervention with or without ipratropium
[89]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Proportion of people with dyspnoea 5 years
19% with smoking cessation intervention with or without ipratropium
24% with usual care
Absolute numbers not reported
P <0.0001 		Effect size not calculated smoking cessation intervention with or without ipratropium
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Quality of life

No data from the following reference on this outcome.[83] [89]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[10] [90]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Adverse effects (any)
with smoking cessation with or without ipratropium
with usual care
[91]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Weight gain 1 year
2.61 kg for men, 2.63 kg for women with smoking cessation with or without ipratropium
0.61 kg for men, 1.10 kg for women with usual care
Significance not assessed
[91]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Weight gain 5 years
3.9 kg for men, 4.75 kg for women with smoking cessation with or without ipratropium
2.6 kg for men, 2.84 kg for women with usual care
Significance not assessed
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Psychosocial plus pharmacological interventions versus psychosocial intervention alone:

We found one systematic review (search date 2002),[83] which identified two RCTs examining psychosocial plus pharmacological interventions compared with psychosocial intervention alone in people with COPD.[10] [92] One RCT reported only abstinence rates and adverse effects.[92] This study did not provide data about the effects on FEV1 changes, peak expiratory flow, exacerbations, dyspnoea score, quality of life, or survival.

Mortality

Psychosocial plus pharmacological interventions compared with psychosocial intervention alone Nicotine gum plus a psychosocial smoking cessation and abstinence maintenance programme with ipratropium is no more effective at reducing mortality at 5 years in people with signs of early COPD (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
All-cause mortality
[85]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
Further report of reference [10] 		All-cause mortality 5 years
54/1961 (3%) with smoking cessation intervention plus ipratropium
44/1962 (2%) with smoking cessation intervention alone
Absolute numbers not reported
P = 0.304 (smoking cessation intervention plus ipratropium v smoking cessation intervention alone) 		Not significant
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Lung function and exercise capacity

Psychosocial plus pharmacological interventions compared with psychosocial intervention alone Nicotine gum plus a psychosocial smoking cessation and abstinence maintenance programme with ipratropium is more effective at reducing the decline in FEV1 at 1 to 5 years in people with signs of early COPD (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[10]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Change in FEV1 1 year
+38.8 mL with smoking cessation intervention plus ipratropium
+11.2 mL with smoking cessation alone
P <0.005 (smoking cessation intervention plus ipratropium v smoking cessation intervention alone) 		Effect size not calculated smoking cessation intervention plus ipratropium
[10]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Change in FEV1 5 years
–184 mL with smoking cessation intervention plus ipratropium
–208 mL with smoking cessation alone
P = 0.002 or less (smoking cessation intervention plus ipratropium v smoking cessation intervention alone)
Results from completer analysis (about 90% of people) 		Effect size not calculated smoking cessation intervention plus ipratropium
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COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[10]

Quality of life

No data from the following reference on this outcome.[10]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[10] [90]
RCT
3-armed trial 		5887 smokers, aged 35 to 60 years, with spirometric signs of early COPD; mean pre-bronchodilator FEV1 2640 mL, mean of 30 cigarettes smoked/day
In review [83] 		Adverse effects (any)
with smoking cessation intervention plus ipratropium
with smoking cessation alone
[92]
RCT		 404 people with mild or moderate COPD, smoking an average of 28 cigarettes a day, mean age 54 years
In review [83] 		Proportion of people discontinuing treatment because of adverse effects 6 months
7% with bupropion (slow-release 150 mg twice daily) plus counselling
6% with placebo plus counselling
Absolute numbers not reported
Significance not assessed
[92]
RCT		 404 people with mild or moderate COPD, smoking an average of 28 cigarettes a day, mean age 54 years
In review [83] 		Proportion of people with a serious adverse event 6 months
0.5% with bupropion (slow-release 150 mg twice daily) plus counselling
2.5% with placebo plus counselling
Absolute numbers not reported
Significance not assessed
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Further information on studies

The smoking cessation intervention consisted of an intensive 12-session smoking cessation programme combining behaviour modification and use of nicotine gum (nicotine polacrilex 2 mg) with a continuing 5-year maintenance programme that included monitoring of weight gain and nutritional counselling.

Smoking cessation intervention significantly reduced self-reported lower respiratory illnesses resulting in physician visits compared with usual care at 5 years (results presented graphically; P = 0.0008).

The RCT found that bupropion plus counselling significantly increased continuous abstinence rates from weeks 4 to 26 compared with counselling alone (16% with bupropion plus counselling v 9% with counselling alone; P = 0.05).

Drug safety alert

FDA issues drug safety alert on the risk of serious neuropsychiatric symptoms (July 2009).

A drug safety alert has been issued on the risk of serious neuropsychiatric symptoms, which include changes in behaviour, hostility, agitation, depressed mood, suicidal thoughts and behaviour, and attempted suicide, associated with bupropion (www.fda.gov).

Comment

One RCT identified by the review[83] found that the smoking cessation intervention (with or without ipratropium) increased the proportion of sustained quitters at 5 years, with a similar proportion remaining abstinent at 11 years, compared with usual care (22% at 5 years and 21.9% at 11 years with smoking cessation intervention v 5% at 5 years and 6% at 11 years with usual care; P value not reported).[96] [10]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Pulmonary rehabilitation

Summary

Multi-modality pulmonary rehabilitation can improve exercise capacity, dyspnoea, and health-related quality of life in people with stable COPD.

Benefits and harms

Pulmonary rehabilitation versus usual care:

We found two systematic reviews (search date 2004, 31 RCTs;[97] and search date 2000, 20 RCTs, 12 of which were also included in the first systematic review[98]), which assessed effects of pulmonary rehabilitation on lung function and rates of COPD exacerbations. The reviews included RCTs of both hospital- and home-based programmes. We found 4 subsequent RCTs assessing similar outcomes for hospital-based rehabilitation.[99] [100] [101] [102] Another systematic review (search date 2006, 6 RCTs, 5 of which were included in the first systematic review[97]) specifically assessed the effects of pulmonary rehabilitation on anxiety and depression.[103] In addition, we found two subsequent RCTs[104] [105] assessing exclusively home-based pulmonary rehabilitation.

Lung function and exercise capacity

Compared with usual care Multi-modality pulmonary rehabilitation seems more effective at improving exercise capacity (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Exercise capacity
[97]
Systematic review		 511 people
13 RCTs in this analysis		 Difference in incremental cycle ergometer test
with pulmonary rehabilitation
with usual care
Absolute results not reported
WMD 8.43 watts
95% CI 3.45 watts to 13.41 watts
There is no generally accepted minimal clinically important difference for the cycle ergometer test 		Effect size not calculated pulmonary rehabilitation
[97]
Systematic review		 669 people
16 RCTs in this analysis		 Difference in 6-minute walk distance (6MWD)
with pulmonary rehabilitation
with usual care
Absolute results not reported
WMD 48.46 m
95% CI 31.64 m to 68.28 m
The lower limit CI for functional exercise capacity is above the minimal clinically significant difference of between 30 m and 42 m for the 6-minute walk test 		Effect size not calculated pulmonary rehabilitation
[98]
Systematic review		 979 people with symptomatic COPD or impaired exercise capacity
20 RCTs in this analysis		 Difference in walking test
with pulmonary rehabilitation
with usual care
Absolute results not reported
Standard effect size 0.71
95% CI 0.43 to 0.99 		Effect size not calculated pulmonary rehabilitation
[99]
RCT		 40 men with COPD Change in 6MWD from baseline 16 weeks
from 347 m to 410 m with pulmonary rehabilitation
from 330 m to 308 m with control
P <0.01
Randomisation was not concealed 		Effect size not calculated pulmonary rehabilitation
[105]
RCT		 78 people with COPD Change in 6MWD from baseline 3 months
from 312 m to 328 m (+16 m) with pulmonary rehabilitation
from 305 m to 298 m (–7 m) with standard care
P <0.001 for comparisons from baseline (significant increase with pulmonary rehabilitation; significant decrease with standard care)
Increase with pulmonary rehabilitation was below the accepted minimal clinically important difference 		Effect size not calculated pulmonary rehabilitation
[102]
RCT		 54 people with mild to moderate COPD (FEV1 30–80% predicted) Change in 6MWD from baseline 8 weeks
from 262 m to 382 m (+120 m) with pulmonary rehabilitation
from 227 m to 242 m (+15 m) with control
P <0.05 for comparison between groups 		Effect size not calculated pulmonary rehabilitation
[101]
RCT		 30 people with COPD Change in 6MWD from baseline 12 weeks
+40.6 with pulmonary rehabilitation
+16.5 with control
P <0.05
Improvement with pulmonary rehabilitation was below the threshold of clinical importance 		Effect size not calculated pulmonary rehabilitation
[104]
RCT		 39 people with COPD Mean difference in 6MWD 8 weeks
from 89 m to 142 m (+53 m) with home-based pulmonary rehabilitation
from 84 m to 69 m (–15 m) with control
P <0.001
Assessors were not blinded 		Effect size not calculated home-based pulmonary rehabilitation
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No data from the following reference on this outcome.[100] [103]

COPD exacerbation and worsening of symptoms

Multi-modality pulmonary rehabilitation compared with usual care Multi-modality pulmonary rehabilitation seems more effective at improving shortness of breath and dyspnoea (as assessed using the Chronic Respiratory Disease Questionnaire) (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[97]
Systematic review		 610 people
11 RCTs in this analysis		 Difference in dyspnoea component of Chronic Respiratory Disease Questionnaire (CRQ)
with pulmonary rehabilitation
with usual care
Absolute results not reported
WMD 1.06
95% CI 0.85 to 1.26
The effect was larger than the minimally clinically important difference of 0.5 units 		Effect size not calculated pulmonary rehabilitation
[98]
Systematic review		 723 people
12 RCTs in this analysis		 Difference in shortness of breath (measured by CRQ)
with pulmonary rehabilitation
with usual care
Absolute results not reported
Standard effect size 0.62
95% CI 0.26 to 0.91 		Effect size not calculated pulmonary rehabilitation
[99]
RCT		 40 men with COPD Change in dyspnoea component of CRQ from baseline 16 weeks
from 2.9 to 3.7 with pulmonary rehabilitation
from 3.6 to 3.4 with control
P <0.01
Randomisation was not concealed 		Effect size not calculated pulmonary rehabilitation
[104]
RCT		 39 people with COPD Mean difference in dyspnoea component of CRQ 8 weeks
from 11.8 to 19.6 (+7.8) with home-based pulmonary rehabilitation
from 12.4 to 13.5 (+1.1) with control
P = 0.003 		Effect size not calculated home-based pulmonary rehabilitation
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No data from the following reference on this outcome.[100] [101] [102] [103] [105]

Quality of life

Compared with usual care Multi-modality pulmonary rehabilitation seems more effective at improving the fatigue, emotional function, and mastery components of the Chronic Respiratory Disease Questionnaire, and at improving the symptoms, activity, and impact domains of the St George's Respiratory Questionnaire, and at modestly improving anxiety and depression (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[97]
Systematic review		 618 people
11 RCTs in this analysis		 Difference in fatigue component of Chronic Respiratory Disease Questionnaire (CRQ)
with pulmonary rehabilitation
with usual care
Absolute results not reported
WMD 0.92
95% CI 0.71 to 1.13
The effect was larger than the minimally clinically important difference of 0.5 units 		Effect size not calculated pulmonary rehabilitation
[104]
RCT		 39 people with COPD Mean difference in fatigue component of CRQ 8 weeks
from 9.8 to 17.4 (+7.6) with home-based pulmonary rehabilitation
from 11.6 to 13.2 (+1.6) with control
P <0.004 		Effect size not calculated home-based pulmonary rehabilitation
[97]
Systematic review		 618 people
11 RCTs in this analysis		 Difference in emotional function component of CRQ
with pulmonary rehabilitation
with usual care
Absolute results not reported
WMD 0.76
95% CI 0.52 to 1.00
The effect was larger than the minimally clinically important difference of 0.5 units 		Effect size not calculated pulmonary rehabilitation
[104]
RCT		 39 people with COPD Mean difference in emotional function component of CRQ 8 weeks
from 22.1 to 33.5 (+11.4) with home-based pulmonary rehabilitation
from 27.0 to 29.7 (+2.7) with control
P <0.008 		Effect size not calculated home-based pulmonary rehabilitation
[97]
Systematic review		 618 people
11 RCTs in this analysis		 Difference in mastery component of CRQ
with pulmonary rehabilitation
with usual care
Absolute results not reported
WMD 0.97
95% CI 0.74 to 1.20
The effect was larger than the minimally clinically important difference of 0.5 units 		Effect size not calculated pulmonary rehabilitation
[102]
RCT		 54 people with mild to moderate COPD (FEV1 30–80% predicted) Difference in symptoms domain of St George's Respiratory Questionnaire (SGRQ) from baseline 8 weeks
from 60 to 38 (–22) with pulmonary rehabilitation
from 60 to 46 (–14) with control
P <0.05 		Effect size not calculated pulmonary rehabilitation
[102]
RCT		 54 people with mild to moderate COPD (FEV1 30–80% predicted) Difference in activity domain of SGRQ from baseline 8 weeks
from 67 to 43 (–24) with pulmonary rehabilitation
from 70 to 67 (–3) with control
P <0.05 		Effect size not calculated pulmonary rehabilitation
[102]
RCT		 54 people with mild to moderate COPD (FEV1 30–80% predicted) Difference in impact domain of SGRQ from baseline 8 weeks
from 36 to 17 (–19) with pulmonary rehabilitation
from 33 to 33 (no change) with with control
P <0.05 		Effect size not calculated pulmonary rehabilitation
[100]
RCT		 24 people with severe COPD Difference in symptoms domain of SGRQ from baseline 8 weeks
from 51 to 40 (–11) with pulmonary rehabilitation
from 50 to 49 (–1) with control
P <0.05 		Effect size not calculated pulmonary rehabilitation
[100]
RCT		 24 people with severe COPD Difference in activity domain of SGRQ from baseline 8 weeks
from 75 to 63 (–12) with pulmonary rehabilitation
from 75 to 79 (+4) with control
P <0.05 		Effect size not calculated pulmonary rehabilitation
[100]
RCT		 24 people with severe COPD Difference in impact domain of SGRQ from baseline 8 weeks
from 47 to 37 (–10) with pulmonary rehabilitation
from 49 to 45 (–4) with control
P >0.05 		Not significant
[101]
RCT		 30 people with COPD Difference in symptoms domain of SGRQ from baseline 12 weeks
+10.6 with pulmonary rehabilitation
–0.5 with control
Significance not assessed
[101]
RCT		 30 people with COPD Difference in activity domain of SGRQ from baseline 12 weeks
+2.5 with pulmonary rehabilitation
+2.7 with control
Significance not assessed
[101]
RCT		 30 people with COPD Difference in impact domain of SGRQ from baseline 12 weeks
+9.7 with pulmonary rehabilitation
+3.4 with control
Significance not assessed
[103]
Systematic review		 269 people with COPD
3 RCTs in this analysis		 Difference in health-related quality of life (HRQL) anxiety score 12 months
with pulmonary rehabilitation
with standard care
Absolute numbers not reported
SMD –0.33
95% CI –0.57 to –0.09
P = 0.008 		Effect size not calculated pulmonary rehabilitation
[103]
Systematic review		 269 people with COPD
3 RCTs in this analysis		 Difference in depression score 12 months
with pulmonary rehabilitation
with standard care
Absolute numbers not reported
SMD –0.58
95% CI –0.93 to –0.23
P = 0.001 		Effect size not calculated pulmonary rehabilitation
[100]
RCT		 24 people with severe COPD Change in Beck Depression Inventory 8 weeks
from 14 to 6 (–8) with pulmonary rehabilitation
from 18 to 16 (–2) with control
P <0.01 		Effect size not calculated pulmonary rehabilitation
[100]
RCT		 24 people with severe COPD Change in State Trait Anxiety Inventory 8 weeks
from 9 to 8 (–1) with pulmonary rehabilitation
from 19 to 21 (+2) with control
P >0.05 		Not significant
Open in a new tab

No data from the following reference on this outcome.[98] [99] [105]

Mortality

No data from the following reference on this outcome.[97] [98] [99] [100] [101] [102] [103] [104] [105]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[97]
Systematic review
31 RCTs in this analysis		 Adverse effects
with pulmonary rehabilitation
with usual care
Absolute results not reported
[98]
Systematic review		 979 people with COPD
20 RCTs in this analysis		 Adverse effects
with pulmonary rehabilitation
with usual care
Absolute results not reported
Open in a new tab

No data from the following reference on this outcome.[99] [100] [101] [102] [103] [104] [105]

Further information on studies

None.

Comment

There are indications that the effects of pulmonary rehabilitation without reinforcement do not last longer than 1 year. For example, we have reported results for one RCT[102] for the 8-week treatment period. However, the RCT also reported results at 12 weeks — 4 weeks after the end of treatment. The RCT reported that, although improvements from baseline in 6-minute walk distance and in St George's Respiratory Questionnaire scores were still significant at 12 weeks in favour of pulmonary rehabilitation, these parameters began to deteriorate in the period after the end of treatment.

Substantive changes

Pulmonary rehabilitation New evidence added.[100] [101] [102] [103] [104] [105] Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Inspiratory muscle training (alone)

Summary

Inspiratory muscle training may improve lung function and exercise capacity in people with COPD.

Benefits and harms

Inspiratory muscle training (IMT) versus control or no IMT:

We found two systematic reviews (search date 2000, 15 RCTs, number of people included not reported;[106] and search date 2003, 19 RCTs[107]).

Lung function and exercise capacity

Inspiratory muscle training (IMT) compared with control/no IMT IMT (with or without general exercise rehabilitation) may be more effective at improving inspiratory muscle strength, endurance, and exercise-related dyspnoea at rest (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[106]
Systematic review		 383 people
15 RCTs in this analysis		 Inspiratory muscle strength
with inspiratory muscle training (IMT) (with or without general exercise rehabilitation)
with control
Absolute results not reported
WMD 0.56 cm H2O
95% CI 0.35 cm H2O to 0.77 cm H2O 		Effect size not calculated IMT
[106]
Systematic review		 Number of people not reported
7 RCTs in this analysis		 Inspiratory muscle endurance
with IMT (with or without general exercise rehabilitation)
with control
Absolute results not reported
WMD 0.41 seconds
95% CI 0.14 seconds to 0.68 seconds 		Effect size not calculated IMT
[106]
Systematic review		 Number of people not reported
4 RCTs in this analysis		 Inspiratory muscle endurance (maximal voluntary ventilation)
with IMT (with or without general exercise rehabilitation)
with control
Absolute results not reported
WMD +0.21 L/minute
95% CI –0.29 L/minute to +0.70 L/minute 		Not significant
[107]
Systematic review		 27 people
2 RCTs in this analysis		 Inspiratory muscle strength
with IMT
with no IMT
Absolute numbers not reported
WMD +9.67 cm H2O
95% CI –4.50 cm H2O to +23.85 cm H2O
P = 0.18 		Not significant
Exercise capacity
[106]
Systematic review		 Number of people not reported
5 RCTs in this analysis		 Laboratory exercise capacity (VO2 max)
with IMT (with or without general exercise rehabilitation)
with control
Absolute results not reported
WMD +0.04 L/minute
95% CI –0.36 L/minute to +0.29 L/minute 		Not significant
[106]
Systematic review		 Number of people not reported
5 RCTs in this analysis		 Laboratory exercise capacity (VE max)
with IMT (with or without general exercise rehabilitation)
with control
Absolute results not reported
WMD +0.03 L/minute
95% CI –0.03 L/minute to +0.35 L/minute 		Not significant
[106]
Systematic review		 Number of people not reported
8 RCTs in this analysis		 Functional exercise capacity (6- or 12-minute walking distance)
with IMT (with or without general exercise rehabilitation)
with control
Absolute results not reported
WMD +0.22 m
95% CI –0.05 m to +0.48 m 		Not significant
[106]
Systematic review		 Number of people not reported
5 RCTs in this analysis		 Borg exercise-related dyspnoea
with IMT (with or without general exercise rehabilitation)
with control
Absolute results not reported
WMD –0.55
95% CI –0.90 to +0.19 		Not significant
Open in a new tab

COPD exacerbation and worsening of symptoms

Inspiratory muscle training (IMT) compared with control/no IMT IMT (with or without general exercise rehabilitation) may be more effective at improving non-exercise-related dyspnoea at rest (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[106]
Systematic review		 Number of people not reported
2 RCTs in this analysis		 Dyspnoea (as measured by the Transitional Dyspnoea Index)
with IMT (with or without general exercise rehabilitation)
with control
Absolute results not reported
WMD 2.3
95% CI 1.44 to 3.15 		Effect size not calculated IMT
Open in a new tab

No data from the following reference on this outcome.[107]

Mortality

No data from the following reference on this outcome.[106] [107]

Quality of life

No data from the following reference on this outcome.[106] [107]

Inspiratory muscle training (IMT) plus general exercise reconditioning versus general exercise reconditioning alone:

We found one systematic review (search date 2000, 15 RCTs, number of people included not reported).[106]

Lung function and exercise capacity

Inspiratory muscle training (IMT) plus general exercise reconditioning compared with general exercise reconditioning alone IMT plus general exercise reconditioning may be more effective at improving inspiratory muscle strength and inspiratory muscle endurance, but may have no additional benefits on exercise capacity in people with inspiratory muscle weakness (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[106]
Systematic review		 Number of people not reported
6 RCTs in this analysis		 Inspiratory muscle strength
with inspiratory muscle training (IMT) plus general exercise reconditioning
with general exercise reconditioning alone
Absolute results not reported
WMD 0.47 cm H2O
95% CI 0.15 cm H2O to 0.79 cm H2O 		Effect size not calculated IMT plus general exercise reconditioning
[106]
Systematic review		 Number of people not reported; subgroup analysis of people with inspiratory muscle weakness at baseline
3 RCTs in this analysis		 Inspiratory muscle strength
with IMT plus general exercise reconditioning
with general exercise reconditioning alone
Absolute results not reported
WMD +16 cm H2O (CI not reported)
P <0.001 		Effect size not calculated IMT plus general exercise reconditioning
[106]
Systematic review		 Number of people not reported; subgroup analysis of people without inspiratory muscle weakness at baseline
3 RCTs in this analysis		 Inspiratory muscle strength
with IMT plus general exercise reconditioning
with general exercise reconditioning alone
Absolute results not reported
WMD –3 cm H2O (CI not reported)
P = 0.54 		Not significant
[106]
Systematic review		 Number of people not reported
3 RCTs in this analysis		 Inspiratory muscle endurance
with IMT plus general exercise reconditioning
with general exercise reconditioning alone
Absolute results not reported
WMD 0.55 seconds
95% CI 0.14 seconds to 0.97 seconds 		Effect size not calculated IMT plus general exercise reconditioning
Exercise capacity
[106]
Systematic review		 Number of people not reported
4 RCTs in this analysis		 Functional exercise capacity (6- or 12-minute walk test)
with IMT plus general exercise reconditioning
with general exercise reconditioning alone
Absolute results not reported
WMD +0.20 m
95% CI –0.21 m to +0.61 m 		Not significant
Open in a new tab

Mortality

No data from the following reference on this outcome.[106]

COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[106]

Quality of life

No data from the following reference on this outcome.[106]

Adverse effects

No data from the following reference on this outcome.[106]

Inspiratory muscle training (IMT) versus sham IMT:

We found two systematic reviews (search dates 2003, 19 RCTs, number of people not reported;[107] and 2007, 17 RCTs, 502 people[108]). The second review is largely an update of the first, but we report both here, as the updated review[108] does not report data for all the outcomes reported in the first review.[107]

Lung function and exercise capacity

Inspiratory muscle training (IMT) compared with sham IMT IMT may be more effective at improving inspiratory muscle strength, endurance, Borg dyspnoea rating, and exercise walking distance (6-minute walking test), but may be no more effective at improving exercise capacity, VO2, and forced vital capacity (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[108]
Systematic review		 330 people with COPD
13 RCTs in this analysis		 Inspiratory muscle strength 5 weeks to 6 months
with inspiratory muscle training (IMT)
with sham IMT
Absolute results not reported
WMD 11.58 cm H2O
95% CI 8.75 cm H2O to 14.42 cm H2O
P <0.001 		Effect size not calculated IMT
[108]
Systematic review		 143 people
4 RCTs in this analysis		 Inspiratory threshold loading 5 to 24 weeks
with IMT
with sham IMT
Absolute results not reported
WMD 1.36 kPa
95% CI 0.79 kPa to 1.94 kPa
P <0.001 		Effect size not calculated IMT
[108]
Systematic review		 109 people
4 RCTs in this analysis		 Borg scale for respiratory effort 5 to 24 weeks
with IMT
with sham IMT
Absolute results not reported
WMD –1.76
95% CI –2.35 to –1.16
P <0.001 		Effect size not calculated IMT
[108]
Systematic review		 147 people
4 RCTs in this analysis		 Inspiratory muscle endurance 5 to 8 weeks
with IMT
with sham IMT
Absolute results not reported
WMD +4.43 minutes
95% CI +0.66 minutes to +8.21 minutes
P = 0.02 		Effect size not calculated IMT
[107]
Systematic review		 56 people
3 RCTs in this analysis		 Forced vital capacity
with IMT
with sham IMT
Absolute results not reported
WMD +0.22 L
95% CI –0.11 L to +0.54 L
P = 0.19 		Not significant
[107]
Systematic review		 70 people
4 RCTs in this analysis		 FEV1
with IMT
with sham IMT
Absolute results not reported
WMD +0.05 L
95% CI –0.02 L to +0.12 L
P = 0.15 		Not significant
Exercise capacity
[108]
Systematic review		 87 people
5 RCTs in this analysis		 Exercise capacity 5 to 24 weeks
with IMT
with sham IMT
Absolute results not reported
WMD –0.05 L/minute
95% CI –0.17 L/minute to +0.07 L/minute
P = 0.38 		Not significant
[108]
Systematic review		 103 people
2 RCTs in this analysis		 6-minute walk distance (6MWD) 5 to 10 weeks
with IMT
with sham IMT
Absolute results not reported
WMD 32.13 m
95% CI 11.55 m to 52.72 m
P = 0.002 		Effect size not calculated IMT
Open in a new tab

COPD exacerbation and worsening of symptoms

Inspiratory muscle training (IMT) compared with sham IMT IMT may be more effective at improving dyspnoea (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[108]
Systematic review		 96 people
5 RCTs in this analysis		 Transitional dyspnoea index 8 weeks to 12 months
with IMT
with sham IMT
Absolute results not reported
WMD 2.55
95% CI 0.92 to 4.19
P = 0.002 		Effect size not calculated IMT
Open in a new tab

Quality of life

Compared with sham inspiratory muscle training (IMT) IMT may be marginally more effective at improving quality of life as assessed by the Chronic Respiratory Disease Questionnaire, although the extent of the improvement may not be clinically meaningful (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Health-related quality of life
[108]
Systematic review		 69 people
2 RCTs in this analysis		 Chronic Respiratory Disease Questionnaire (CRQ) total score 5 to 8 weeks
with inspiratory muscle training (IMT)
with sham IMT
Absolute results not reported
WMD 0.33
95% CI 0.19 to 0.47
P <0.001 		Effect size not calculated IMT
Open in a new tab

Mortality

No data from the following reference on this outcome.[108]

Adverse effects

No data from the following reference on this outcome.[107] [108]

Further information on studies

None.

Comment

None.

Substantive changes

Inspiratory muscle training New evidence added.[108] Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Peripheral muscle strength training (alone)

Summary

Although peripheral muscle strength training improves upper-body and leg strength, it may be no more effective at improving walking endurance; however, it may improve exercise capacity in people with COPD.

Benefits and harms

Peripheral muscle training versus no treatment or other exercise training:

We found one systematic review (search date 2008, 18 RCTs, 534 people).[109] The review included RCTs comparing resistive training versus control, resistive training versus aerobic training, and resistive training plus aerobic training versus aerobic training.

Lung function and exercise capacity

Compared with no treatment or other exercise training Peripheral muscle strength training may be no more effective at improving walking endurance at 6 to 12 weeks, although it may be more effective at improving exercise capacity at 8 to 12 weeks (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[109]
Systematic review		 158 people with COPD
4 RCTs in this analysis		 6-minute walk distance (6MWD) 6 to 12 weeks
with peripheral muscle training
with no treatment
Absolute numbers not reported
Effect size +0.30
95% CI –0.02 to +0.61
P = 0.06 		Not significant
[109]
Systematic review		 103 people with COPD
3 RCTs in this analysis		 6MWD 12 weeks
with peripheral muscle training
with aerobic training
Absolute results not reported
Effect size +0.05
95% CI –0.34 to +0.43
P = 0.82 		Not significant
Exercise capacity
[109]
Systematic review		 52 people with COPD
2 RCTs in this analysis		 Cycling endurance 8 to 12 weeks
with peripheral muscle training
with no treatment
Absolute results not reported
Effect size 0.87
95% CI 0.29 to 1.44
P = 0.004 		Effect size not calculated peripheral muscle training
[109]
Systematic review		 63 people with COPD
2 RCTs in this analysis		 Cycling endurance 8 to 12 weeks
with peripheral muscle training
with aerobic training
Absolute results not reported
Effect size –0.89
95% CI –1.82 to –0.36
P = 0.0008 		Effect size not calculated peripheral muscle training
Open in a new tab

Quality of life

No data from the following reference on this outcome.[109]

COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[109]

Mortality

No data from the following reference on this outcome.[109]

Adverse effects

No data from the following reference on this outcome.[109]

Further information on studies

None.

Comment

We found two small systematic reviews assessing the effects of upper-extremity muscle-strength training on COPD.[110] [111] Owing to significant methodological heterogeneity, neither review performed a meta-analysis. The reviews both concluded that upper-extremity muscle-strength training improves upper-extremity exercise capacity but has an uncertain, if any, effect on dyspnoea and on health-related quality of life.[110] [111]

Substantive changes

Peripheral muscle strength training (alone) New evidence added.[109] Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Jun 6;2011:1502.

General physical activity enhancement (alone)

Summary

General physical exercises can improve exercise capacity in people with stable COPD.

Benefits and harms

General physical activity enhancement versus control:

We found one systematic review (search date 1999) investigating general physical activity enhancement (walking, cycling, or swimming, and/or training of most large muscle groups).[112] The review did not present meta-analyses of outcomes and so we report data from individual RCTs. We found one subsequent RCT assessing a pedometer-based exercise enhancement programme.[113]

Lung function and exercise capacity

Compared with control General physical activity enhancement (walking, cycling, or swimming) may be more effective at improving exercise tolerance (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Exercise capacity
[112]
Systematic review		 48 people
Data from 1 RCT		 Walking test
with physical activity
with control
Absolute results not reported
Difference 5942 joules
95% CI presented graphically 		Effect size not calculated physical activity
[112]
Systematic review		 43 people
Data from 1 RCT		 Walking test
with physical activity
with control
Absolute results not reported
Difference 3861 joules
95% CI presented graphically 		Effect size not calculated physical activity
[112]
Systematic review		 38 people
Data from 1 RCT		 6-minute walking distance test (6MWD)
with physical activity
with control
Absolute results not reported
Difference 29 m
95% CI presented graphically 		Not significant
[112]
Systematic review		 23 people
Data from 1 RCT		 6MWD
with physical activity
with control
Absolute results not reported
Difference 5 m
95% CI presented graphically 		Not significant
[113]
RCT		 39 people with COPD Change in 6MWD from baseline 12 weeks
from 365 m to 387 m (+22 m) with pedometer-based exercise counselling programme
from 351 m to 361 m (+10 m) with control
P = 0.09
Improvement in exercise counselling group not clinically significant 		Not significant
[112]
Systematic review		 58 people
Data from 1 RCT		 Cycle ergometer
with physical activity
with control
Absolute results not reported
24.7 watts
95% CI presented graphically 		Effect size not calculated physical activity
Open in a new tab

COPD exacerbation and worsening of symptoms

Compared with control We don’t know whether general physical activity enhancement is more effective at improving dyspnoea (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Shortness of breath
[114]
RCT		 23 people
In review [112] 		Mean change in dyspnoea component of Chronic Respiratory Disease Questionnaire (CRQ) score (range 5–35)
6 with physical activity
0 with control
Significance not reported for COPD subgroup
[115]
RCT		 38 people
In review [112] 		Mean change in Borg dyspnoea scale after walking test
0.4 with physical activity
0.9 with control
Difference –0.5
95% CI –1.5 to +0.6 		Not significant
Open in a new tab

No data from the following reference on this outcome.[113]

Quality of life

Compared with control We don't know whether general physical activity enhancement is more effective at improving quality-of-life scores (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[114]
RCT		 23 people
In review [112] 		Mean change in fatigue component of Chronic Respiratory Disease Questionnaire (CRQ) score (range 4–28)
5 with physical activity
0 with control
Significance not reported for COPD subgroup
[114]
RCT		 23 people
In review [112] 		Mean change in emotion component of CRQ score (range 7–49)
5 with physical activity
2 with control
Significance not reported for COPD subgroup
[114]
RCT		 23 people
In review [112] 		Mean change in mastery component of CRQ score (range 4–28)
+4 with physical activity
–1 with control
Significance not reported for COPD subgroup
[115]
RCT		 38 people
In review [112] 		Mean change in the St George's Respiratory Questionnaire (SGRQ) total score
–2.1 with physical activity
–2.1 with control
Difference +0.1
95% CI –9.9 to +10.0 		Not significant
[113]
RCT		 39 people with COPD Change in SGRQ total from baseline 12 weeks
from 37.7 to 34.2 (–3.5) with pedometer-based exercise counselling programme
from 35.2 to 38.3 (+3.1) with control
P = 0.05 		Not significant
Open in a new tab

Mortality

No data from the following reference on this outcome.[112] [113]

Adverse effects

No data from the following reference on this outcome.[112] [113]

Further information on studies

None.

Comment

None.

Substantive changes

General physical activity enhancement (alone) New evidence added.[113] Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Jun 6;2011:1502.

Nutritional supplementation

Summary

Nutritional supplementation has not been shown to be beneficial at improving lung function and exercise capacity of people with COPD.

Benefits and harms

Nutritional supplementation versus placebo or usual diet:

We found two systematic reviews.[116] [117] The second systematic review identified 21 RCTs, which were classified according to the type (different composition of carbohydrates/fat), duration of supplementation (1 meal, <2 weeks, >2 weeks), and presence of anabolic substances.[117] Overall, 11 RCTs examined supplementation for at least 2 weeks, without the use of anabolic substances, in a total of 327 people. Nine of the RCTs were common to the first systematic review.[116]

Lung function and exercise capacity

Compared with placebo/usual diet Nutritional supplementations may be no more effective at improving lung function or exercise capacity in people with stable COPD (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Lung function
[116]
Systematic review		 156 people
6 RCTs in this analysis		 FEV1
with nutritional supplementation for 2 weeks
with placebo or usual diet
Absolute results not reported
SMD –0.12
95% CI –0.44 to +0.20 		Not significant
[116]
Systematic review		 152 people
6 RCTs in this analysis		 Maximal inspiratory pressure
with nutritional supplementation for 2 weeks
with placebo or usual diet
Absolute results not reported
SMD +0.22
95% CI –0.10 to +0.55 		Not significant
[116]
Systematic review		 152 people
6 RCTs in this analysis		 Maximal expiratory pressure
with nutritional supplementation for 2 weeks
with placebo or usual diet
Absolute results not reported
SMD +0.28
95% CI –0.05 to +0.60 		Not significant
Exercise capacity
[116]
Systematic review		 77 people
3 RCTs in this analysis		 6-minute walk distance
with nutritional supplementation for 2 weeks
with placebo or usual diet
Absolute results not reported
SMD –0.01
95% CI –0.46 to +0.44 		Not significant
Open in a new tab

Mortality

No data from the following reference on this outcome.[116] [117]

COPD exacerbation and worsening of symptoms

No data from the following reference on this outcome.[116] [117]

Quality of life

No data from the following reference on this outcome.[116] [117]

Adverse effects

No data from the following reference on this outcome.[116] [117]

Further information on studies

The review found similar weight gain with nutritional supplementation and placebo or usual diet for at least 2 weeks (search date 2006, 12 RCTs, 419 people; SMD +0.16, 95% CI –0.09 to +0.42; absolute numbers not reported). It also found similar changes in arm muscle circumference, and triceps skinfold thickness with nutritional supplementation and placebo or usual diet for at least 2 weeks (arm muscle circumference: 8 RCTs, 214 people; SMD +0.07, 95% CI –0.27 to +0.41; triceps skinfold thickness: 6 RCTs, 124 people; SMD +0.35, 95% CI 0 to +0.71).

The review found that nutritional supplementation increased mean weight gain compared with control (mean weight gain: +1.87 kg with nutritional supplementation v –0.03 kg with control; significance not reported). Again, no consistent effects on anthropometric measures or pulmonary function were demonstrated (data not reported).

Comment

The two systematic reviews are difficult to interpret because of heterogeneity among the RCTs. The interventions were not standardised, and varied in terms of energy, protein, fat, and carbohydrate content, and in terms of route of administration and duration and frequency of supplementation. The RCTs did not frequently control for reaching a positive energy balance, but the studies that accomplished an increased (net) energy input also demonstrated functional improvements.[118] Other variations between the studies included: outcome variables, severity of COPD and comorbidities, setting of interventions (at home, pulmonary rehabilitation, admitted to hospital), addition of exercise and anabolic steroids, and methodological quality.

Substantive changes

No new evidence

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