COPD

Dr Huib AM Kerstjens; Professor Dirkje S Postma; Dr Nick ten Hacken

. 2008 Dec 15;2008:1502.

COPD

Huib AM Kerstjens ^1,^#, Dirkje S Postma ^2,^#, Nick ten Hacken ^3,^#

PMCID: PMC2907933 PMID: 19445783

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 maintenance drug treatment in 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 February 2007 (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 83 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, maintaining healthy weight, 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 anticholinergic drugs may improve lung function compared with long-acting beta₂ agonists.
Combined treatment with inhaled anticholinergics and 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.

Oral corticosteroids may improve short-term lung function, but have serious adverse effects.
Combined inhaled corticosteroids plus long-acting beta₂ agonists improve lung function and symptoms and reduce exacerbations compared with placebo, and may be more effective than either treatment alone.

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 their 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 and exercises can improve exercise capacity in people with stable COPD, but nutritional supplementation has not been shown to be beneficial.

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 both 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. 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 mucus production for at least 3 months in at least 2 successive years when other causes of chronic cough have been excluded.

Incidence/ Prevalence

COPD mainly affects middle-aged and elderly 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), 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%. In the UK, physician-diagnosed prevalence was 2% in men and 1% in women between 1990 and 1997.

Aetiology/ Risk factors

COPD is largely preventable. The main cause in resource-rich countries is exposure to tobacco smoke. In resource-rich countries, 85-90% of people with COPD have smoked at some point. 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. Other proposed causes include bronchial hyper-responsiveness, indoor and outdoor air pollution, and allergy.

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. 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.

Outcomes

Short-term and long-term changes in lung function, including changes in FEV₁; peak expiratory flow; exercise tolerance; frequency, severity, and duration of exacerbations; symptom scores for dyspnoea; quality of life; survival; and adverse effects. Symptom and quality-of-life scores include the St George's Respiratory Questionnaire, which is rated on a scale from 0-100 (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 1-7 (a 0.5-point change is considered clinically important).

Methods

Clinical Evidence search and appraisal March 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to February 2007, Embase 1980 to February 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. 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 and RCTs in any language, at least single blinded, and containing more than 20 people of whom more than 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. If we retrieved multiple systematic reviews that identified the same RCTs, we reported only the most recent reviews. We also carried out a search for cohort studies in reference to exercise and weight as it relates to COPD. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. This review deals only with treatment of stable COPD and not with treatment of acute exacerbations. We were interested in the maintenance treatment of stable COPD; therefore, we did not include single-dose or single-day cumulative dose-response trials. In this review, short-term treatment is defined as less than 6 months and long-term as 6 months or over. There is consensus that 6 months is the absolute minimum duration of treatment required to assess effects on decline in lung function. Where RCTs were found, no systematic search for observational studies was performed. We had articles translated as necessary and included all studies of sufficient quality. If we retrieved multiple systematic reviews that identified the same RCTs, we reported only the most recent review. To aid readability of the numerical data in our reviews, we round percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table.

GRADE evaluation of interventions for COPD

Important outcomes	Lung function and exercise capacity, COPD exacerbation and worsening of symptoms, quality of life, mortality, adverse effects
Number of 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	Short-term treatment with anticholinergic v 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	Short-term treatment with anticholinergic v placebo	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (780)	Quality of life	Short-term treatment with anticholinergic v placebo	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
At least 7 RCTs (at least 6854 people)	Lung function and exercise capacity	Long-term treatment with tiotropium v placebo	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for inclusion of RCTs with short follow-up
At least 7 RCTs (at least 6854 people)	COPD exacerbation and worsening of symptoms	Long-term treatment with tiotropium v placebo	4	−1	0	0	0	Moderate	Quality point deducted for short follow-up
At least 3 RCTs (at least 1622 people)	Quality of life	Long-term treatment with tiotropium v placebo	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
6 (4770)	Mortality	Long-term treatment with tiotropium v placebo	4	−1	0	0	0	Moderate	Quality point deducted for inclusion of RCTs with short follow-up
9 (264)	Lung function and exercise capacity	Short-term treatment with short-acting beta₂ agonists v placebo	4	−1	−1	0	0	Low	Quality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity among RCTs
9 (264)	COPD exacerbation and worsening of symptoms	Short-term treatment with short-acting beta₂ agonists v placebo	4	−1	−1	0	0	Low	Quality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity between RCTs
at least 2 RCTs (at least 206 people)	Lung function and exercise capacity	Short-term and long-term treatment with long-acting beta₂ agonists v placebo	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for inclusion of open-label RCTs
at least 12 RCTs (at least 4562 people)	COPD exacerbation and worsening of symptoms	Short-term and long-term treatment with long-acting beta₂ agonists v placebo	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for inclusion of open-label RCTs
at least 6 RCTs (at least 2086)	Quality of life	Short-term and long-term treatment with long-acting beta₂ agonists v placebo	4	−2	−1	0	0	Very low	Quality points deducted for incomplete reporting of results and for inclusion of open-label RCTs. Consistency point deducted for conflicting results
at least 16 RCTs (at least 8713 people)	Mortality	Short-term and long-term treatment with long-acting beta₂ agonists v placebo	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for inclusion of open-label RCTs
7 RCTs (2248)	Lung function and exercise capacity	Short-term treatment with short-acting anticholinergic plus short-acting inhaled beta₂ agonist v short-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
3 RCTs (1399)	COPD exacerbation and worsening of symptoms	Short-term treatment with short-acting anticholinergic plus short-acting inhaled beta₂ agonist v short-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 RCTs (1186)	COPD exacerbation and worsening of symptoms	Short-term treatment with short-acting anticholinergic plus short-acting inhaled beta₂ agonist v short-acting anticholinergic alone	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
5 (1529)	Quality of life	Short-term treatment with short-acting anticholinergic plus short-acting inhaled beta₂ agonist v short acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (94)	Lung function and exercise capacity	Short-term treatment with short-acting anticholinergic plus long-acting inhaled beta₂ agonist v 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-term treatment with short-acting anticholinergic plus long-acting inhaled beta₂ agonist v 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 (2048)	COPD exacerbation and worsening of symptoms	Anticholinergics v beta₂ agonists	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
5 (1925)	Mortality	Anticholinergics v beta₂ agonists	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
6 (1917)	Lung function and exercise capacity	Short-acting anticholinergic v 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 v short-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
At least 2 RCTs (at least 467 people)	Lung function and exercise capacity	Short-acting anticholinergic v long-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
4 RCTs and one report (1241)	COPD exacerbation and worsening of symptoms	Short-acting anticholinergic v long-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 RCTs (467)	Quality of life	Short-acting anticholinergic v long-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 RCTs (1382)	Lung function and exercise capacity	Long-acting anticholinergic v long-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
At least 2 RCTs (at least 1830 people)	COPD exacerbation and worsening of symptoms	Long-acting anticholinergic v long-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 (807)	Quality of life	Long-acting anticholinergic v long-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 RCTs (1460)	Mortality	Long-acting anticholinergic v long-acting beta₂ agonist	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
At least 15 RCTs (at least 527 people)	Lung function and exercise capacity	Theophylline v placebo (short-term treatment)	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 (964)	Lung function and exercise capacity	Theophylline v placebo (long-term treatment)	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for inclusion of an RCT with an open label arm
1 RCT (110)	COPD exacerbation and worsening of symptoms	Theophylline v placebo (long-term treatment)	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for sparse data
10 RCTs (445)	Lung function and exercise capacity	Corticosteroids (oral) v placebo	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
10 RCTs (at least 127 people)	Lung function and exercise capacity	Inhaled corticosteroids v placebo (short-term treatment)	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for sparse data
At least 7 RCTs (at least 4262 people)	Lung function and exercise capacity	Inhaled corticosteroids v placebo (long-term treatment)	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results. Consistency point added for dose response and deducted for conflicting results
At least 11 RCTs (at least 6166 people)	COPD exacerbation and worsening of symptoms	Inhaled corticosteroids v placebo (long-term treatment)	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 RCT (723)	Quality of life	Inhaled corticosteroids v placebo (long-term treatment)	4	−1	−1	0	0	Low	Quality point deducted for incomplete reporting of results. Consistency point deducted for different results at different endpoints
13 RCTs (7428 people)	Mortality	Inhaled corticosteroids v placebo (long-term treatment)	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
4 RCTs (1620)	Lung function and exercise capacity	Corticosteroid plus long-acting beta₂ agonist v placebo	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
3 RCTs (1642 people)	COPD exacerbation and worsening of symptoms	Corticosteroid plus long-acting beta₂ agonist v placebo	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 RCTs (712)	Quality of life	Corticosteroid plus long-acting beta₂ agonist v placebo	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 RCT (3057)	Mortality	Corticosteroid plus long-acting beta₂ agonist v placebo	4	0	0	0	0	High
4 RCTs (1607)	Lung function and exercise capacity	Corticosteroid plus long-acting beta₂ agonist v corticosteroid alone	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
3 RCTs (1649)	COPD exacerbation and worsening of symptoms	Corticosteroid plus long-acting beta₂ agonist v corticosteroid alone	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 RCTs (696)	Quality of life	Corticosteroid plus long-acting beta₂ agonist v corticosteroid alone	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (3067)	Mortality	Corticosteroid plus long-acting beta₂ agonist v corticosteroid alone	4	0	0	0	0	High
4 RCTs (1595)	Lung function and exercise capacity	Corticosteroid plus long-acting beta₂ agonist v long-acting beta₂ agonist alone	4	−1	−1	0	0	Low	Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
3 RCTs (1648)	COPD exacerbation and worsening of symptoms	Corticosteroid plus long-acting beta₂ agonist v long-acting beta₂ agonist alone	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 RCTs (712)	Quality of life	Corticosteroid plus long-acting beta₂ agonist v long-acting beta₂ agonist alone	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (3057)	Mortality	Corticosteroid plus long-acting beta₂ agonist v long-acting beta₂ agonist alone	4	0	0	0	0	High
At least 7 RCTs (at least 7335 people)	COPD exacerbation and worsening of symptoms	Mucolytic's v placebo	4	−1	−2	−1	0	Very low	Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results and for heterogeneity among RCTs. Directness point deducted for inclusion of people without COPD
9 RCTs (1055)	COPD exacerbation and worsening of symptoms	Antibiotics v 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
1 (28)	COPD exacerbation and worsening of symptoms	Long-term treatment with oxygen v no oxygen	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
3 RCTs (250)	Mortality	Long-term treatment with oxygen v no oxygen	4	0	−1	0	0	Moderate	Consistency point deducted for conflicting results
1 RCT (56)	Lung function and exercise capacity	Long-term treatment with alpha₁ antitrypsin v placebo	4	−2	0	0	0	Low	Quality point deducted for sparse data and incomplete reporting of results
What are the effects of interventions to promote smoking cessation in people with stable COPD?
1 RCT (number of participants not reported)	Lung function and exercise capacity	Psychosocial plus pharmacological interventions v usual care	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting
1 RCT (number of participants not reported)	COPD exacerbation and worsening of symptoms	Psychosocial plus pharmacological interventions v usual care	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting
1 RCT (number of participants not reported)	Mortality	Psychosocial plus pharmacological interventions v usual care	4	−1	−1	0	0	Low	Quality point deducted for incomplete reporting. Consistency point deducted for conflicting results
What are the effects of non-drug interventions in people with stable COPD?
At least 21 RCTs (at least 1019 people)	Lung function and exercise capacity	Pulmonary rehabilitation v usual care	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for disparity in results (minimal clinical effect) in one systematic review
At least 13 RCTs (at least 763 people)	Quality of life	Pulmonary rehabilitation v usual care	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
At least 17 RCTs (at least 410 people)	Lung function and exercise capacity	Inspiratory muscle training v control/no IMT	4	−1	−1	0	0	Low	Quality point deducted for incomplete reporting of results. Consistency point deducted for lack of consistent benefit
At least 6 RCTs (number of participants not reported)	Lung function and exercise capacity	Inspiratory muscle training plus general exercise reconditioning v 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 10 RCTs (at least 233 people)	Lung function and exercise capacity	Inspiratory muscle training v sham inspiratory muscle training	4	−1	−1	0	0	Low	Quality point deducted for incomplete reporting of results. Consistency point deducted for lack of consistent benefit
At least 1 RCT (at least 72 people)	Lung function and exercise capacity	Peripheral muscle strength training alone v no treatment/other exercise training	4	−1	0	−1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for wide range of interventions
3 RCTs (at least 58 people)	Lung function and exercise capacity	General physical activity enhancement alone v control	4	−2	−1	0	0	Very low	Quality point deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
2 RCTs (61)	COPD exacerbation and worsening of symptoms	General physical activity enhancement alone v control	4	−2	−1	0	0	Very low	Quality point deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
2 RCTs (61)	Quality of life	General physical activity enhancement alone v control	4	−2	−1	0	0	Very low	Quality point deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
At least 6 RCTs (at least 156 people)	Lung function and exercise capacity	Nutritional supplementation v placebo/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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Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds 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.

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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

Dr Huib AM Kerstjens, University Hospital Groningen, Groningen, The Netherlands.

Professor Dirkje S Postma, University Hospital Groningen, Groningen, The Netherlands.

Dr Nick ten Hacken, University Hospital Groningen, Groningen, The Netherlands.

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BMJ Clin Evid. 2008 Dec 15;2008:1502.

Anticholinergics (inhaled)

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Compared with placebo (short-term and long-term treatment): Short-term treatment with ipratropium may be more effective at improving FEV 1 and exercise capacity, and long-term treatment with tiotropium may be more effective at improving FEV 1 and forced vital capacity ( low-quality evidence ). Psychosocial plus pharmacological interventions compared with usual care: Nicotine gum plus a psychosocial smoking cessation and abstinence maintenance programme with or without ipratropium is more effective at reducing the decline in FEV 1 at 1–5 years in people with mild chronic COPD ( moderate-quality evidence ). Short-acting anticholinergic compared with short-acting beta2 agonist: Ipratropium and short-acting beta 2 agonists are equally effective at 85 days at improving FEV 1 (moderate-quality evidence). Short-acting anticholinergic compared with long-acting beta2 agonist: Ipratropium is less effective than salmeterol at improving FEV 1 at 12 weeks, but equally effective at improving the 6-minute walking distance test (moderate-quality evidence). Long-acting anticholinergic compared with long-acting beta2 agonist: Tiotropium is more effective than salmeterol at improving FEV 1 (moderate-quality evidence). COPD EXACERBATION AND WORSENING OF SYMPTOMS Compared with placebo (short-term and long-term treatment): Ipratropium in the short-term is no more effective at improving symptoms or the need for rescue bronchodilators, while tiotropium used in the long-term is more effective at 12–52 weeks at reducing COPD exacerbations (moderate-quality evidence). Short-acting anticholinergic compared with long-acting beta2 agonist: Ipratropium and the long-acting beta 2 agonists (salmeterol, and formoterol) are equally effective at improving COPD exacerbations (moderate-quality evidence). Long-acting anticholinergic compared with long-acting beta2 agonist: Tiotropium and salmeterol are equally effective at improving COPD exacerbations (moderate-quality evidence). Short-term treatment with a short-acting anticholinergic alone compared with short-acting anticholinergic plus short-acting inhaled beta2 agonist: Short-acting anticholinergic alone for 12 weeks seems to be as effective at improving exacerbations compared with the combination of short-acting anticholinergic drug (ipratropium) plus a short-acting beta 2 agonist (moderate-quality evidence). QUALITY OF LIFE Compared with placebo (short-term and long-term treatment): Short-term treatment with ipratropium is no more effective at improving quality of life, while long-term treatment with tiotropium is more effective at 6–12 months at improving quality of life (moderate-quality evidence). Short-acting anticholinergic compared with short-acting beta2 agonist: Ipratropium is modestly more effective at improving dyspnoea, fatigue, emotion, and mastery components of the CRQ (moderate-quality evidence). Short-acting anticholinergic compared with long-acting beta2 agonist: Ipratropium and the long-acting beta 2 agonists salmeterol and formoterol are equally effective at 12 weeks at improving quality of life as measured by the CRQ (moderate-quality evidence). Long-acting anticholinergic compared with long-acting beta2 agonist: Tiotropium and salmeterol are equally effective at improving St George’s Respiratory Questionnaire scores (moderate-quality evidence). MORTALITY Compared with placebo (long-term treatment): Tiotropium is no more effective at reducing all-cause mortality at 12–52 weeks (moderate-quality evidence). Long-acting anticholinergic compared with long-acting beta2 agonist: Tiotropium and salmeterol are equally effective at reducing all-cause mortality (moderate-quality evidence). Psychosocial plus pharmacological interventions compared with usual care: Smoking cessation interventions with and without ipratropium may be more effective at 14.5 years but not at 5 years at reducing all-cause mortality in people with mild chronic COPD (low-quality evidence). ADVERSE EFFECTS Anticholinergics are associated with an increased rate of dry mouth.

Benefits

Short-term treatment with anticholinergics versus placebo:

We found four small and four large RCTs assessing the effects of ipratropium on lung function. We also found one systematic review that assessed the effects on exercise capacity of any anticholinergic drug compared with placebo. All of the RCTs compared three or four interventions: ipratropium (at different doses in one trial), placebo, and a beta₂ agonist. Two of the small RCTs found a significant effect in favour of ipratropium, and the remaining two found no significant difference among treatments. The first two of the large RCTs (276 people and 405 people) compared ipratropium (36 micrograms 4 times daily) versus placebo and salmeterol for 12 weeks. In both RCTs, ipratropium significantly improved baseline FEV₁ compared with placebo (results presented graphically; reported as significant). The third large RCT (780 people) compared ipratropium (40 micrograms 4 times daily) versus placebo and formoterol (eformoterol) for 12 weeks. It found that ipratropium significantly improved FEV₁ compared with placebo (improvement in average FEV₁ over 12 hours after medication 137 mL, 95% CI 88 mL to 186 mL). It found no significant difference in morning pre-medication peak expiratory flow, symptoms, quality-of-life scores, or need for rescue bronchodilators (peak expiratory flow: difference between groups –0.5 L/min, 95% CI –7.4 L/min to +6.5 L/min; P = 0.898; symptoms: P = 0.439; absolute numbers not reported; quality of life: reported as not significant; P value not reported; need for rescue bronchodilator: P = 0.147; absolute numbers not reported). The fourth large RCT (183 people with moderate to severe COPD, mean FEV₁ 40% predicted, mean age 64 years) compared three treatments: ipratropium (80 micrograms 3 times daily), formoterol (18 micrograms twice daily), and placebo. It found no significant difference in shuttle walking distance at 12 weeks between ipratropium and placebo (mean increase from baseline: 15.3 m with ipratropium v 6.1 m with placebo; P value not reported, baseline mean distance 325 m). The systematic review (search date 1999) assessed changes in exercise capacity with anticholinergic drugs compared with placebo. Meta-analysis was not performed because of heterogeneity in design and outcomes assessed among studies. Sixteen of the 17 RCTs found that any anticholinergic drug improved exercise capacity compared with placebo.

Long-term treatment with tiotropium versus placebo:

We found two systematic reviews (search dates 2002 [3 RCTs, 2751 people] and 2006 [7 RCTs, 6854 people]). Two RCTs (2128 people) were identified by both reviews. Neither review specified a minimum follow-up of 6 months for inclusion of a study. The reviews found similar results for the effects of tiotropium on COPD exacerbations compared with placebo, and so we report data only from the larger review with the more recent search date. The review found that tiotropium significantly reduced COPD exacerbation rates at 12–52 weeks compared with placebo (1012/3648 [28%] with tiotropium v 998/2653 [38%] with placebo; OR 0.74, 95% CI 0.66 to 0.83). The review found that tiotropium also significantly improved FEV₁, forced vital capacity (FVC), and quality of life (assessed using St George's Respiratory Questionnaire [SGRQ]) at 6–12 months compared with placebo (FEV₁: 3 RCTs, 2574 people: WMD [units not specified] 129.54, 95% CI 110.27 to 148.83: FVC; 3 RCTs, 2572 people: WMD [units not specified] 226.54, 95% CI 151.51 to 301.56; mean change in SGRQ: 3 RCTs, 1622 people; WMD –3.3, 95% –4.6 to –2.0; absolute numbers not reported for any outcome). However, there was no significant difference between groups in all-cause mortality at 12–52 weeks (6 RCTs, 5215 people: 38/2467 [1.5%] with tiotropium v 39/2303 [1.7%] with placebo; OR 0.91, 95% CI 0.58 to 1.42). One of the studies identified by both reviews reported results from two 6-month RCTs, one of which was reported in another reference not identified by the review reported here.

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

See benefits of psychosocial plus drug interventions in effects of advice to stop smoking.

Inhaled anticholinergic alone versus inhaled anticholinergics plus beta₂ agonists:

See benefits of inhaled anticholinergics plus beta₂ agonists.

Inhaled anticholinergics versus beta₂ agonists:

See benefits of inhaled anticholinergics versus beta₂ agonists.

Harms

Short-term treatment with anticholinergics versus placebo:

One RCT found that ipratropium significantly increased the rate of dry mouth compared with placebo (P less than 0.05; absolute numbers not reported). One RCT found that ipratropium was associated with a significantly higher rate of adverse effects of the ear, nose, and throat compared with placebo (58/138 [42%] with ipratropium v 39/135 [29%] with placebo; P = 0.031).Three RCTs reported similar rates of adverse effects in the ipratropium and placebo groups (absolute numbers not reported; significance not assessed). One RCT reported that the most common adverse effects were viral infections, exacerbations of COPD, and headache. The review and three RCTs gave no information on adverse effects.

Long-term treatment with tiotropium versus placebo:

The review found that tiotropium significantly increased rate of dry mouth compared with placebo (4 RCTs, 2835 people; OR 4.6, 95% CI 3.0 to 7.1; absolute numbers not reported). However, there was no significant difference between groups in rate of MI or a combined outcome of arrhythmia or atrial fibrillation (MI; 3 RCTs, 2733 people; OR 1.0, 95% CI 0.2 to 3.9; arrhythmia or atrial fibrillation; 4 RCTs, 4561 people; OR 1.4, 95% CI 0.4 to 5.7; absolute numbers not reported).

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

For adverse effects of ipratropium, see harms of short-term treatment with ipratropium above.

Inhaled anticholinergic alone versus inhaled anticholinergics plus beta₂ agonists:

See harms of inhaled anticholinergics plus beta₂ agonists.

Inhaled anticholinergics versus beta₂ agonists:

See harms of inhaled anticholinergics versus beta₂ agonists.

Comment

The review included RCTs with a follow-up of 12 weeks. We stipulate in our Methods section that, for long-acting anticholinergics such as tiotropium, we include only those studies with a follow-up at least 6 months. However, we have reported the data from the review because, of the seven RCTs identified by the review, four RCTs had follow-up of at least six months; of the three remaining RCTs, follow-up was 25 weeks in one RCT and 12 weeks in two RCTs. We found one RCT comparing 18 micrograms tiotropium versus placebo once daily for 42 days that reported exercise capacity as an outcome. The follow-up of this RCT was 42 days, which is below Clinical Evidence inclusion criteria for inclusion of at least 6 months' follow-up for a long-acting anticholinergic, and so we have not included this study in the benefits section. The RCT found that tiotropium significantly increased post-dose exercise endurance time compared with placebo (187 people with moderate to severe COPD [FEV₁ 44% predicted]; difference in exercise endurance time: 105 seconds; P = 0.01).

Substantive changes

Anticholinergics One systematic review added. The review found that tiotropium, a long-acting anticholinergic, reduced COPD exacerbation rates at 12–52 weeks and improved FEV₁compared with placebo. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Beta₂ agonists (inhaled)

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Short-acting beta2 agonists compared with placebo (short-term treatment): Short-acting beta 2 agonists may be more effective at increasing FEV 1 in people with stable COPD, but we don't know whether they are more effective at increasing exercise tolerance ( low-quality evidence ). Long-acting beta2 agonists compared with placebo: Long-acting beta 2 agonists may be no more effective at improving shuttle walking tests (low-quality evidence). Short-acting beta2 agonist compared with short-acting anticholinergic: Short-acting beta 2 agonists and ipratropium are equally effective at 85 days at improving FEV 1 ( moderate-quality evidence ). Long-acting beta2 agonist compared with short-acting anticholinergic: Salmeterol is more effective than ipratropium at improving FEV 1 at 12 weeks, but salmeterol and ipratropium are equally effective at improving the 6-minute walking distance test (moderate-quality evidence). Long-acting beta2 agonist compared with long-acting anticholinergic: Salmeterol is less effective than tiotropium at improving FEV 1 (moderate-quality evidence). Short-term treatment with short-acting beta2 agonist alone compared with short-acting inhaled beta2 agonist plus short-acting anticholinergic: Short-acting beta 2 agonist alone is less effective at improving FEV 1 after 85 days of treatment (moderate-quality evidence). Short-term treatment with beta2 agonist alone compared with long-acting inhaled beta2 agonist plus short-acting anticholinergic: Beta 2 agonists alone may be modestly less effective at improving FEV 1 and evening peak expiratory flow (low-quality evidence). Long-acting beta2 agonist alone compared with corticosteroid plus long-acting beta2 agonist: We don’t know whether a long-acting beta 2 agonist alone is more effective at improving pre-dose FEV 1 in people with moderate to severe COPD ( low-quality evidence ). COPD EXACERBATION AND WORSENING OF SYMPTOMS Short-acting beta2 agonists compared with placebo (short-term treatment): Short-acting beta 2 agonists may be more effective at improving daily breathlessness scores in people with stable COPD (low-quality evidence). Long-acting beta2 agonists compared with placebo: Long-acting beta 2 agonists may be more effective at reducing the rate of COPD exacerbations (low-quality evidence). Long-acting beta2 agonist compared with short-acting anticholinergic: The long-acting beta 2 agonists (salmeterol, and formoterol) and ipratropium are equally effective at improving COPD exacerbations (moderate-quality evidence). Long-acting beta2 agonist compared with long-acting anticholinergic: Salmeterol and tiotropium are equally effective at improving COPD exacerbations (moderate-quality evidence). Short-term treatment with a short-acting beta2 agonist alone compared with short-acting inhaled beta2 agonist plus short-acting anticholinergic: Beta 2 agonists alone are less effective at 12 weeks at improving exacerbations (moderate-quality evidence). Long-acting beta2 agonist alone compared with corticosteroid plus long-acting beta2 agonist: An inhaled corticosteroid alone is less effective at reducing COPD exacerbations in people with moderate to severe disease (moderate-quality of evidence). QUALITY OF LIFE Long-acting beta2 agonists compared with placebo: We don't know whether long-acting beta 2 agonists are more effective at improving quality of life (very low-quality evidence). Short-acting beta2 agonist compared with a short-acting anticholinergic: Short-acting beta 2 agonists are modestly less effective than ipratropium at improving dyspnoea, fatigue, emotion, and mastery components of the chronic respiratory disease questionnaire (CRQ) (moderate-quality evidence). Long-acting beta2 agonist compared with short-acting anticholinergic: The long-acting beta 2 agonists (salmeterol, and formoterol) and ipratropium are equally effective at 12 weeks at improving quality of life as measured by the CRQ (moderate-quality evidence). Long-acting beta2 agonist compared with long-acting anticholinergic: Salmeterol and tiotropium are equally effective at improving St George’s Respiratory Questionnaire scores (moderate-quality evidence). Short-term treatment with a short-acting beta2 agonist alone compared with a short-acting inhaled beta2 agonist plus a short-acting anticholinergic: A short-acting beta 2 agonist alone is as effective as a combination of a short-acting beta 2 agonist plus a short-acting anticholinergic at 85 days at improving dyspnoea, fatigue, emotion, and mastery components of the CRQ (moderate-quality evidence). Long-acting beta2 agonist alone compared with corticosteroid plus long-acting beta2 agonist: Salmeterol alone is as effective as fluticasone plus salmeterol at improving CRQ scores in people with moderate to severe disease (moderate-quality evidence). MORTALITY Long-acting beta2 agonists compared with placebo: Long-acting beta 2 agonists may be no more effective at reducing mortality (low-quality evidence). Long-acting beta2 agonist compared with long-acting anticholinergic: Salmeterol and tiotropium are equally effective at reducing all-cause mortality (moderate-quality evidence). Long-acting beta2 agonist alone compared with corticosteroid plus long-acting beta2 agonist: Salmeterol alone is no more effective at 3 years than salmeterol plus fluticasone at reducing all-cause mortality in people with moderate to severe disease ( high-quality evidence ).

Benefits

Short-term treatment with short-acting beta₂ agonists versus placebo:

We found one systematic review (search date 2002, 9 crossover RCTs, 264 people with stable COPD) comparing short-acting beta₂ agonists versus placebo for at least 1 week. It found that beta₂ agonists delivered by metered-dose inhaler slightly but significantly increased FEV₁ compared with placebo (WMD 0.14 L, 95% CI 0.04 L to 0.25 L), and significantly improved daily breathlessness score (results reported as SMD; P less than 0.001). There was no significant difference between treatments in exercise tolerance (4 RCTs; SMD +0.18, 95% CI –0.11 to +0.47), although 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.

Short-term and long-term treatment with long-acting beta₂ agonists versus placebo:

We found no review on only short-term (follow-up less than 6 months) or only long-term (more than 6 months) treatment with long-acting beta₂ agonists compared with placebo. We found two systematic reviews (search dates 2002 [9 RCTs, 4198 people] and 2005 [31 RCTs, 10,674 people]), one additional RCT,and two subsequent RCTs on the effects of treatment with long-acting beta₂ agonists. The reviews did not separately assess the effects of short-term or long-term treatment. Six RCTs (2777 people) were identified by both reviews. The reviews found similar results for the effects of long-acting beta₂ agonists on COPD exacerbations compared with placebo, and so we report data only from the larger review with the more recent search date. The review found that long-acting beta₂ agonists (salmeterol and formoterol) significantly reduced rate of COPD exacerbations compared with placebo (12 RCTs, 4562 people: OR 0.74, 95% CI 0.64; 0.87; P = 0.0002; absolute numbers not reported). The review also found significant improvements in the chronic respiratory disease questionnaire (CRQ) and the transitional dyspnoea index (TDI) with long-acting beta₂ agonists compared with placebo (CRQ [2 RCTs, 545 people]: OR 1.71, 95% CI 1.21 to 2.42; P = 0.002; TDI [2 RCTs, 736 people]: OR 1.70, 95% CI 1.25 to 2.31; P = 0.0008; absolute numbers not reported). However, the review found no significant difference between long-acting beta₂ agonists and placebo in quality of life as rated by St George's Respiratory Questionnaire (2 RCTs; 805 people; OR 1.18, 95% CI 0.73 to 1.93; P = 0.50; absolute numbers not reported). There was also no significant difference between groups in mortality (15 RCTs, 5668 people: OR 1.16, 95% CI 0.68 to 1.98; P = 0.58; absolute numbers not reported). 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 included unpublished and open-label RCTs (numbers of each not reported). The minimum length of follow-up for inclusion was 1 week: the range of follow-up of the RCTs identified by the review was not clear. The length of treatment with the beta₂ agonist was not clear. Two RCTs (1095 people) identified by the second review were excluded from the meta-analysis carried out by the first review for this comparison. The review with the later search date 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. Two RCTs identified by the review and one additional RCT reported on exercise capacity, using varying inclusion criteria and methodologies. One RCT identified by the reviews compared three treatments: formoterol 18 micrograms twice daily, ipratropium, and placebo. It found no significant difference between formoterol and placebo in the shuttle walking test after 12 weeks' treatment (183 people with moderate to severe COPD; increase from baseline: 20.4 m with formoterol v 6.0 m with placebo; reported as non-significant, P value not reported, baseline mean distance 325 m). The second RCT identified by the reviews compared inhaled salmeterol 50 micrograms versus placebo twice daily for 2 weeks. It found that salmeterol significantly increased peak exercise endurance compared with placebo (23 people with moderate to severe COPD [mean FEV₁ 42% predicted]; crossover design; difference in peak exercise endurance time: 96 seconds; P = 0.02).The additional RCT compared the effects of three interventions on exercise capacity: formoterol (4.5, 9, or 18 micrograms twice daily), ipratropium (80 micrograms 3 times daily), or placebo for 1 week. It found that formoterol (all doses) slightly but significantly increased time to exhaustion compared with placebo (34 people; crossover design; 10.94 minutes with 4.5 micrograms formoterol; 10.20 minutes with placebo; P less than 0.0001 v placebo; 10.78 minutes with 9 micrograms formoterol; P less than 0.01 v placebo; 10.59 minutes with 18 micrograms formoterol; P less than 0.05 v placebo).The first subsequent RCT (657 people with COPD) compared formoterol 9 micrograms twice daily versus placebo.The RCT found that formoterol 9 micrograms significantly improved FEV₁ at 6 months compared with placebo (ITT analysis: change in FEV₁ from baseline [% change]: +5% with formoterol v –1.4% with placebo; AR 6.5%, 95% CI 2.5% to 10.7%; P less than 0.01). Both groups were allowed to take terbutaline 0.5 mg as needed. The second subsequent RCT (6184 people with COPD; 6112 people included in efficacy analysis) compared salmeterol 50 micrograms once daily plus fluticasone 500 micrograms twice daily, salmeterol alone (50 micrograms twice daily), fluticasone alone (500 micrograms twice daily), and placebo, and reported mortality at 3 years as the primary outcome.In this section, we report only the data for salmeterol (1542 people) versus placebo (1545 people): other comparisons are reported in the appropriate sections. At 3 years, data on mortality were available for 3045 people receiving assigned treatment after randomisation to the salmeterol (1521 people) and placebo (1524 people) groups. This population included people who had discontinued study medication. The RCT found no significant difference between salmeterol alone and placebo in all-cause mortality at 3 years (205/1521 [13%] with salmeterol v 231/1524 [15%] with placebo; HR 0.879, 95% CI 0.729 to 1.061; P = 0.18). 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 in the salmeterol and placebo groups was 59% (1811/3087), which is below Clinical Evidence reporting criteria of 80%, and so these data are not reported here.

Long-term treatment with short-acting beta₂ agonists versus placebo:

We found no systematic review of only long-term treatment with short-acting beta₂ agonists versus placebo. We found two reviews on the effects of treatment with long-acting beta₂ agonists, which did not separately report data on short-term and long-term treatment with beta₂ agonists (see benefits above for short-term treatment with long-acting beta₂ agonists).

Beta₂ agonists versus inhaled anticholinergics:

See benefits of inhaled anticholinergics versus beta₂ agonists.

Beta₂ agonists alone versus inhaled anticholinergics plus beta₂ agonists:

See benefits of inhaled anticholinergics plus beta₂ agonists.

Beta₂ agonists alone versus inhaled corticosteroids plus beta₂ agonists:

See benefits of inhaled corticosteroids plus beta₂ agonists.

Harms

One systematic review (search date 2005, 4 RCTs, 2404 people with COPD) found that long-acting beta₂ agonist use was associated with a significant increase in rate of respiratory deaths compared with placebo (21/1320 [2%] with long-acting beta₂ agonist v 8/1084 [1%] with placebo; RR 2.47, 95% CI 1.12 to 5.45; P = 0.03). Another systematic review (search date 2003) found that, in people with asthma or COPD, beta₂ agonists significantly increase the risk of adverse cardiovascular events compared with placebo (22 RCTs; 15,276 people with asthma or COPD; RR 2.54, 95% CI 1.59 to 4.05). A single dose of beta₂ agonist significantly increased heart rate and reduced serum potassium concentration compared with placebo (heart rate: 11 RCTs; 386 people with asthma or COPD; WMD 9.12, 95% CI 5.32 to 12.92; reduced serum potassium: 6 RCTs; 168 people with asthma or COPD; WMD –0.36, 95% CI –0.54 to –0.18).

Short-term treatment with short-acting beta₂ agonists versus placebo:

The review gave no information on adverse effects.

Short-term and long-term treatment with long-acting beta₂ agonists versus placebo:

The review gave no information on adverse effects associated with long-acting beta₂ agonists. However, it found no significant difference between long-acting beta₂ agonists and placebo in the proportion of people who withdrew from the RCT because of an adverse effect (12 RCTs, 5055 people: OR 0.86, 95% CI 0.72 to 1.02; P = 0.09; absolute numbers not reported).The most common immediate adverse effect is tremor, which is usually worse in the first few days of treatment. High doses of beta₂ agonists can reduce plasma potassium, cause dysrhythmia, and reduce arterial oxygen tension. The risk of adverse events may be higher in people with pre-existing cardiac arrhythmias and hypoxaemia. The additional RCT gave no information on adverse effects.The first subsequent RCT found that formoterol was well tolerated, with a similar rate of adverse effects compared with placebo (rates/1000 treatment days: 3.8 with formoterol v 4.5 with placebo; significance not assessed; P value not reported).No further information on adverse effects was given. The second subsequent RCT found that a similar proportion of people in the salmeterol and placebo groups experienced a drug-related adverse effect (12% with salmeterol v 13% with placebo; absolute numbers not reported; significance not assessed).The most common adverse effect reported was COPD exacerbation.

Long-term treatment with short-acting beta₂ agonists versus placebo:

We found no RCTs.

Beta₂ agonists versus inhaled anticholinergics:

See harms of inhaled anticholinergics versus beta₂ agonists.

Beta₂ agonists alone versus inhaled anticholinergics plus beta₂ agonists:

See harms of inhaled anticholinergics plus beta₂ agonists.

Beta₂ agonists alone versus inhaled corticosteroids plus beta₂ agonists:

See harms of inhaled corticosteroids plus beta₂ agonists.

Comment

None.

Substantive changes

Beta₂ agonists (inhaled) One systematic review added that found that long-acting beta₂ agonists improved rates of COPD exacerbation compared with placebo. The review found no significant difference between groups in mortality. One large RCT added that found no significant difference at 3 years in all-cause mortality between salmeterol alone and placebo. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Anticholinergics plus beta₂ agonists (inhaled)

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Short-term treatment with short-acting anticholinergic plus short-acting inhaled beta2 agonist compared with short-acting beta2 agonist alone: Ipratropium plus a short-acting beta 2 agonist is more effective at improving FEV 1 after 85 days of treatment ( moderate-quality evidence ). Short-term treatment with short-acting anticholinergic plus long-acting inhaled beta2 agonist compared with beta2 agonist alone: Combining a short-acting anticholinergic with a long-acting beta 2 agonist may be modestly more effective at improving FEV 1 and evening peak expiratory flow ( low-quality evidence ). Short-term treatment with a short-acting anticholinergic plus a long-acting inhaled beta2 agonist 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 three weeks at improving FEV 1 and peak expiratory flow rates (low-quality evidence). COPD EXACERBATION AND WORSENING OF SYMPTOMS Short-term treatment with a short-acting anticholinergic plus short-acting inhaled beta2 agonist compared with a short-acting beta2 agonist alone: Combining a short-acting anticholinergic drug (ipratropium) with a short-acting beta 2 agonist for 12 weeks is more effective at improving exacerbations compared with the beta 2 agonist alone (moderate-quality evidence). Short-term treatment with a short-acting anticholinergic plus short-acting inhaled beta2 agonist compared with a short-acting anticholinergic alone: Combining a short-acting anticholinergic drug (ipratropium) with a short-acting beta 2 agonist for 12 weeks seems to be as effective at improving exacerbations compared with the short-acting anticholinergic alone (moderate-quality evidence). QUALITY OF LIFE Short-term treatment with a short-acting anticholinergic plus a short-acting inhaled beta2 agonist compared with a short-acting beta2 agonist alone: Ipratropium plus a short-acting beta 2 agonist is no more effective at 85 days at improving dyspnoea, fatigue, emotion, and mastery components of the Chronic Respiratory Disease Questionnaire (moderate-quality evidence). NOTE We found no clinically important results comparing long-term treatment with a combination of anticholinergics and beta 2 agonists with no active treatment.

Benefits

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

We found two systematic reviews. The first review (search date 2002; 3 RCTs; 1399 people) found that short-acting anticholinergic (ipratropium) plus short-acting beta₂ agonist significantly reduced COPD exacerbations compared with beta₂ agonist alone at 12 weeks (RR 0.68, 95% CI 0.51 to 0.91; absolute numbers not reported). The second review (search date 2005, 7 RCTs, 2252 people) assessed the effects of ipratropium plus short-acting inhaled beta₂ agonist (metaproterenol, fenoterol, and salbutamol), and identified the 3 RCTs identified by the first review, but reported on different outcomes. The review found a small but significant improvement in mean peak FEV₁ response after 85 days treatment with ipratropium plus short-acting beta₂ agonist compared with short-acting beta₂ agonist alone (7 RCTs, 2248 people: WMD 0.07 L, 95% CI 0.05 L to 0.09 L; P less than 0.0001; absolute numbers not reported). However, at 85 days, the review found no significant difference between treatments in the dyspnoea, fatigue, emotion, and mastery components of the Chronic Respiratory Disease Questionnaire (CRQ) (5 RCTs, 1529 people; dyspnoea: WMD +0.01, 95% CI –0.06 to +0.08; P = 0.8; fatigue: WMD +0.01, 95% CI –0.10 to +0.13; P = 0.8; emotion: WMD +0.02, 95% CI –0.12 to +0.16; P = 0.8; mastery: WMD +0.03, 95% CI –0.09 to +0.15; P = 0.6; absolute numbers not reported).

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

The first review (search date 2002; 3 RCTs; 1399 people) found no significant difference in COPD exacerbations at 12 weeks between short-acting anticholinergic plus beta₂ agonist and short-acting anticholinergic alone (2 RCTs; 1186 people; RR 1.04, 95% CI 0.65 to 1.68; absolute numbers not reported).

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

We found one systematic review (search date 2006, 3 RCTs, 1610 people). 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. One published RCT (94 people) identified by the review compared the long-acting beta₂ agonist salmeterol (50 micrograms twice daily) plus ipratropium (40 micrograms 4 times daily) versus salmeterol alone (50 micrograms twice daily) for 12 weeks. It found that the combination significantly improved FEV₁ compared with the beta₂ agonist alone (mean improvement as a percentage of predicted FEV₁: 8% with combination v 5% with beta₂ agonist alone; P less than 0.01), and evening but not morning peak expiratory flow. It found no significant difference in daytime or night time symptoms.

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

One crossover RCT (172 people) compared ipratropium (40 micrograms 4 times daily) plus formoterol (12 micrograms twice daily) versus ipratropium (40 micrograms 4 times daily) plus salbutamol (200 micrograms 4 times daily) for 6 weeks. It found that formoterol plus ipratropium significantly improved FEV₁ and peak expiratory flow from baseline after 3 weeks of treatment compared with salbutamol plus ipratropium (improvement in mean morning peak expiratory flow from baseline over the previous 7 days with formoterol: 12 L/minute, 95% CI 6 L/minute to 19 L/minute; improvement in pre-medication FEV₁ from baseline: 116 mL, 95% CI 83 mL to 150 mL).

Long-term treatment with anticholinergic plus inhaled beta₂ agonists:

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

Harms

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

The first review gave no information on adverse effects.The second review found no significant difference between combination treatment and short-acting inhaled beta₂ agonist in the proportion of people reporting an adverse effect (5 RCTs, 1558 people: 112/789 [14%] with combination v 96/769 [13%] with beta₂ agonist; RR 1.13, 95% CI 0.88 to 1.45; P = 0.3).

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

The review gave no information on adverse effects.

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

The review found no significant difference between salmeterol plus ipratropium and salmeterol alone in the proportion of people reporting a treatment-related adverse effect (3 RCTs, 936 people: 205/473 [43%] with combination v 192/483 [40%] with beta₂ agonist; RR 1.04, 95% CI 0.90 to 1.21; P = 0.6).The data from the RCT were included in the meta-analysis of adverse effects carried out by the review and so are not discussed separately.

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

The RCT found a similar proportion of people reporting adverse effects in both treatment groups (16/172 [10%] with formoterol plus ipratropium v 22/172 [13%] with salbutamol plus ipratropium; significance not assessed).The RCT reported that the most common adverse effects experienced were dyspnoea, exacerbation of obstructive airway disease, and pharyngitis, all of which were more frequent with ipratropium plus salbutamol (dyspnoea: 5/172 [3%] with salbutamol v 2/172 [1%] with formoterol; exacerbation: 5/172 [3%] with salbutamol v 0/172 [0%] with formoterol; pharyngitis: 3/172 [2%] with salbutamol v 1/172 [1%] with formoterol; significance not assessed).

Long-term treatment with anticholinergic plus inhaled beta₂ agonists:

We found no RCTs.

Comment

None.

Substantive changes

Anticholinergics plus beta₂ agonists (inhaled anticholinergics plus beta₂ agonists improved FEV₁ compared with either drug alone) One systematic review added found a small but significant improvement in mean peak FEV₁ response after 85 days treatment with ipratropium plus short-acting beta₂ agonist compared with short-acting beta₂ agonist alone.One systematic review added that found no new evidence on the effects of short-acting anticholinergic plus long-acting inhaled beta₂ agonist compared with beta₂ agonist alone. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Anticholinergics versus beta₂ agonists (inhaled)

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Short-acting anticholinergic compared with short-acting beta2 agonist: Ipratropium and short-acting beta 2 agonists are equally effective at 85 days at improving FEV 1 ( moderate-quality evidence ). Short-acting anticholinergic compared with long-acting beta2 agonist: Ipratropium is less effective than salmeterol at improving FEV 1 at 12 weeks, but equally effective at improving the 6-minute walking distance test (moderate-quality evidence). Long-acting anticholinergic compared with long-acting beta2 agonist: Tiotropium is more effective than salmeterol at improving FEV 1 (moderate-quality evidence). COPD EXACERBATION AND WORSENING OF SYMPTOMS Anticholinergics compared with beta2 agonists: Anticholinergics and beta 2 agonists are equally effective at reducing the risk of COPD exacerbations (moderate-quality evidence). Short-acting anticholinergic compared with long-acting beta2 agonist: Ipratropium and the long-acting beta 2 agonists salmeterol and formoterol are equally effective at improving COPD exacerbations (moderate-quality evidence). Long-acting anticholinergic compared with long-acting beta2 agonist: Tiotropium and salmeterol are equally effective at improving COPD exacerbations (moderate-quality evidence). QUALITY OF LIFE Short-acting anticholinergic compared with short-acting beta2 agonist: Ipratropium is modestly more effective at improving dyspnoea, fatigue, emotion, and mastery components of the Chronic Respiratory Disease Questionnaire (CRQ) (moderate-quality evidence). Short-acting anticholinergic compared with long-acting beta2 agonist: Ipratropium and the long-acting beta 2 agonists salmeterol and formoterol are equally effective at 12 weeks at improving quality of life as measured by the CRQ (moderate-quality evidence). Long-acting anticholinergic compared with long-acting beta2 agonist: Tiotropium and salmeterol are equally effective at improving St George’s Respiratory Questionnaire scores (moderate-quality evidence). MORTALITY Anticholinergics compared with beta2 agonists: Anticholinergics and beta 2 agonists are equally effective at reducing mortality (moderate-quality evidence). Long-acting anticholinergic compared with long-acting beta2 agonist: Tiotropium and salmeterol are equally effective at reducing all-cause mortality (moderate-quality evidence). NOTE We found no clinically important results comparing long-acting anticholinergics with short-acting beta 2 agonists in the treatment of people with COPD.

Benefits

We found five systematic reviews comparing anticholinergics versus beta₂ agonists. 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. Below, we report comparisons as reported in the reviews, and specify the duration of treatment where possible. One review (search 2005, 8 RCTs, 3713 people) compared anticholinergics as a class versus beta₂ agonists as a class. It found no significant difference between drug classes in mortality rate and 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).

Short-acting anticholinergic versus short-acting beta₂ agonist:

We found one systematic review (search date 2005, 11 RCTs, 3912 people) comparing ipratropium versus short-acting beta₂ agonists (metaproterenol, fenoterol, and salbutamol). The review found no significant difference between ipratropium and short-acting beta₂ agonists in mean FEV₁ peak response after 85 days treatment (6 RCTs, 1917 people: WMD 0.00 L, 95% CI –0.02 L to +0.01 L; P = 0.6). However, at 85 days, the review found small but significant improvements with ipratropium in the dyspnoea, fatigue, emotion, and mastery components of the CRQ compared with short-acting beta₂ agonists (5 RCTs, 1529 people: dyspnoea: WMD 0.16, 95% CI 0.09 to 0.23; P less than 0.001; fatigue: WMD 0.13, 95% CI 0.02 to 0.23; P = 0.02; emotion: WMD 0.17, 95% CI 0.05 to 0.29; P = 0.006; mastery: WMD 0.18, 95% CI 0.06 to 0.30; P = 0.004).

Short-acting anticholinergic versus long-acting beta₂ agonist:

We found two systematic reviews (search date 2006, 8 RCTs, 3713 people, and search date 2006, 6 RCTs, 2604 people). Three RCTs were identified by both reviews. The reviews reported data on ipratropium versus salmeterol and ipratropium versus formoterol separately and reported on different outcomes. The first review found no significant difference in rate of exacerbation of COPD between ipratropium and salmeterol or formoterol (ipratropium v salmeterol: 2 RCTs, 538 people: OR [salmeterol v ipratropium] 0.81, 95% CI 0.56 to 1.19; P = 0.29; ipratropium v formoterol: 2 RCTs [reported in 3 publications], 703 people: OR [formoterol v ipratropium] 0.78, 95% CI 0.44 to 1.37; P = 0.39; absolute numbers not reported). The second review found that ipratropium was significantly less effective at improving FEV₁ at 12 weeks compared with salmeterol, although the difference was of borderline significance (change in FEV₁ from baseline [2 RCTs, 458 people]: WMD –0.06 L, 95% CI –0.11 L to 0.00 L; P = 0.05). The review found no significant difference between ipratropium and salmeterol at 12 weeks in total improvement in the CRQ or in exercise capacity, as measured by the 6-minute walking distance test (CRQ score [2 RCTs, 467 people]: WMD –0.58, 95% CI –3.50 to +2.35; P = 0.7; 6-minute walking distance [2 RCTs, 471 people]: WMD +10.47 m, 95% CI –1.24 m to +22.19 m; P = 0.08). The second review did not pool data on formoterol. Both reviews included unpublished data obtained directly from drug companies.

Long-acting anticholinergic versus short-acting beta₂ agonist:

We found no systematic review or RCTs.

Long-acting anticholinergic versus long-acting beta₂ agonist:

We found three systematic reviews. 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. One review (search date 2006, 2 RCTs, 1460 people) found that tiotropium led to a significantly larger improvement in FEV₁ compared with salmeterol (2 RCTs, 1382 people: WMD 28.97, 95% CI 6.45 to 51.49; P 0.01). The review found no significant difference between tiotropium and salmeterol in risk of exacerbation of COPD (2 RCTs, 1460 people: 159/730 [22%] with tiotropium v 178/730 [24%] with salmeterol; OR 0.86, 95% CI 0.67 to 1.11; P = 0.24). The two other reviews (search date 2002, 2 RCTs, 1830 people and search date 2006, 2 RCTs, 807 people) found similar results for this comparison and outcome. One review found no significant difference between tiotropium and salmeterol in all-cause mortality (2 RCTs, 1460 people: 2/730 [0.2%] with tiotropium v 6/730 [0.8%] with salmeterol; OR 0.38, 95% CI 0.09 to 1.66; P = 0.20). One review found no significant difference between tiotropium and salmeterol in improvement in St George's Respiratory Questionnaire score (2 RCTs, 807 people: OR [salmeterol v tiotropium] 0.79, 95% CI 0.60 to 1.05; absolute numbers not reported).One review compared tiotropium versus formoterol (1 RCT, 74 people) but reported no data for this comparison.

Harms

The review comparing anticholinergics as a class versus beta₂ agonists as a class 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) (see harms of anticholinergics and harms of beta₂ agonists).

Short-acting anticholinergic versus short-acting beta₂ agonist:

The review found that a significantly smaller proportion of people taking ipratropium had an adverse effect compared with those taking short-acting beta₂ agonists (6 RCTs, 1858 people: 84/928 [9%] with ipratropium v 111/930 [12%] with beta₂ agonist; RR 0.75, 95% CI 0.57 to 0.97; P = 0.03). However, there was significant heterogeneity (I² = 60%) among studies in this analysis. The reason for the heterogeneity was not reported.

Short-acting anticholinergic versus long-acting beta₂ agonist:

The first review found no significant difference between ipratropium and salmeterol and formoterol in the proportion of people withdrawing from a study because of adverse effects (ipratropium v salmeterol: 2 RCTs, 538 people: OR 0.45, 95% CI 0.07 to 2.95; P = 0.40; ipratropium v formoterol: 2 RCTs, 703 people: OR 1.84, 95% CI 0.64 to 5.31; P = 0.26; absolute numbers not reported).The second review found similar results for ipratropium and salmeterol for this comparison (4 RCTs, 1365 people: 30/682 [4%] with ipratropium v 21/683 [3%] with salmeterol; RR 1.42, 95% CI 0.82 to 2.45; P = 0.2). The second review found no significant difference between ipratropium and salmeterol in the proportion of people reporting an adverse effect (4 RCTs, 1365 people: 365/682 [53.5%] with ipratropium v 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.

Long-acting anticholinergic versus short-acting beta₂ agonist:

We found no RCTs.

Long-acting anticholinergic versus long-acting beta₂ agonist:

Two reviews gave no information on adverse effects. One review found that the proportion of people withdrawing from a study because of adverse effects was significantly larger in the salmeterol group compared with the tiotropium group (2 RCTs, 807 people: OR [salmeterol v tiotropium] 2.16, 95% CI: 1.36 to 3.43; P = 0.001; absolute numbers not reported). No further information on adverse effects reported.

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

Anticholinergics versus beta₂ agonists Five systematic reviews updated that found no significant differences between various anticholinergics and beta₂ agonists for the majority of outcomes. One review reported that ipratropium led to small improvements in the dyspnoea, fatigue, emotion, and mastery components of the Chronic Respiratory Disease Questionnaire compared with salmeterol. One review found that tiotropium led to a larger improvement in FEV₁ compared with salmeterol. Categorisation of anticholinergics versus beta₂ agonists changed from Likely to be beneficial to Unknown effectiveness as both treatments are effective, and it is unclear if one is consistently more effective than the other.

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Theophylline

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Compared with placebo (short-term treatment): Theophylline is modestly more effective at improving FEV 1 but is no more effective at improving maximum walking distance at 6 minutes ( moderate-quality evidence ). Compared with placebo (long-term treatment): Theophylline may be more effective at improving FEV 1 , including prebronchodilator FEV 1 but not postbronchodilator FEV 1 ( low-quality evidence ). COPD EXACERBATION AND WORSENING OF SYMPTOMS Compared with placebo (long-term treatment): Theophylline may be more effective at 12 months at reducing the frequency and duration of acute COPD exacerbations (low-quality evidence). NOTE 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

Short-term treatment:

We found one systematic review (search date 2005, 22 small RCTs, number of people not reported) comparing theophylline versus placebo for 1 week to 3 months. It found that theophylline slightly but significantly improved FEV₁ compared with placebo (15 RCTs, 527 people: WMD 100 mL, 95% CI 40 mL to 160 mL). It found no significant difference between theophylline and placebo in maximum walking distance at 6 minutes (2 RCTs, 58 people: WMD 33.38 m, 95% CI –11.44 m to +78.20 m). The review identified RCTs with a minimum follow-up of 7 days (range of follow-up of RCTs was not reported).

Long-term treatment:

We found two RCTs assessing the effects of theophylline compared with placebo in the long-term. The first RCT (854 people) compared four treatments for 12 months: open label theophylline (220 mg or 300 mg slow-release formulation); double-blinded formoterol 12 micrograms twice daily; formoterol 24 micrograms twice daily; or placebo. It found that theophylline significantly improved FEV₁ compared with placebo (mean difference in FEV₁ with theophylline v placebo +120 mL, CI not reported; P less than 0.001). The second RCT (110 people) found that, at 12 months, theophylline (100 mg twice daily) significantly reduced the frequency and duration of acute COPD exacerbations, and improved prebronchodilator FEV₁ compared with placebo (ITT analysis [all those randomised]: frequency of COPD exacerbation [per year]: 0.79 with theophylline v 1.70 with placebo; P = 0.047; duration of COPD exacerbation: 4.58 days with theophylline v 12.47 days with placebo; P = 0.045; mean change in FEV₁ [from baseline]: +6.3 mL with theophylline v –53.3 mL with placebo; P = 0.038).However, there was no significant difference between groups in post-bronchodilator FEV₁ (mean change in FEV₁ [from baseline]: –55.9 mL with theophylline v –55.7 mL with placebo; P = 0.495).

Harms

Short-term treatment:

The systematic review found that theophylline significantly increased the risk of nausea compared with placebo (3 RCTs, 39 people; RR 7.67, 95% CI 1.47 to 39.94; absolute numbers not reported). The therapeutic range for theophyllines is small, with blood concentrations of 10–15 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.

Long-term treatment:

The first RCT found that people receiving conventional dose theophylline were twice as likely to discontinue treatment compared with those taking placebo (P less than 0.002; absolute numbers not reported).The second, smaller RCT found no significant difference between theophylline and placebo in the proportion of people reporting an adverse effect (10/57 [18%] with theophylline v 3/53 [6%] with placebo; P = 0.076).Nausea and diarrhoea were the most frequently reported adverse effects.

Comment

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 One RCT added that found that, at 12 months, theophylline reduced the frequency and duration of acute COPD exacerbations, and improved FEV₁ compared with placebo. Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Corticosteroids (oral)

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Compared with placebo: Oral corticosteroids used in the short term for 2–4 weeks are more effective at increasing the proportion of people with at least a 20% improvement in baseline FEV 1 in people with stable COPD ( moderate-quality evidence ). NOTE We found no direct information 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

Short-term treatment:

We found one systematic review (search date 1989, 10 RCTs, 445 people), comparing oral corticosteroids versus placebo in people with stable COPD. Treatment usually lasted 2–4 weeks. It found that oral corticosteroids significantly increased the proportion of people with at least a 20% improvement in baseline FEV₁ compared with placebo (WMD 10%, 95% CI 2% to 18%). When five RCTs not meeting all quality criteria were included in the analysis, the difference in effect size was 11% (95% CI 4% to 18%).

Long-term treatment:

We found no RCTs examining the effects of oral corticosteroids in the long-term on decline in lung function.

Harms

Many reviews have described the considerable harms of systemic corticosteroids, including osteoporosis and induction of diabetes.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Corticosteroids (inhaled)

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Inhaled corticosteroids compared with placebo (short-term treatment): Inhaled corticosteroids may be no more effective at improving FEV 1 in people with moderate to severe COPD ( low-quality evidence ). Inhaled corticosteroids compared with placebo (long-term treatment): High doses of inhaled corticosteroids seem more effective at improving FEV 1 in people with moderate to severe COPD ( moderate-quality evidence ). Inhaled corticosteroid alone compared with inhaled corticosteroid plus long-acting beta2 agonist: An inhaled corticosteroid alone is less effective at improving pre-dose FEV 1 in people with moderate to severe COPD (moderate-quality evidence). COPD EXACERBATION AND WORSENING OF SYMPTOMS Inhaled corticosteroids compared with placebo (long-term treatment): Inhaled corticosteroids are more effective at improving dyspnoea and at reducing COPD exacerbations in people with moderate to severe COPD (moderate-quality evidence). Inhaled corticosteroid alone compared with inhaled corticosteroid plus long-acting beta2 agonist: An inhaled corticosteroid alone is no more effective at reducing COPD exacerbations in people with moderate to severe disease (moderate-quality evidence). QUALITY OF LIFE Inhaled corticosteroids compared with placebo (long-term treatment): Inhaled corticosteroids may improve Chronic Respiratory Disease Questionnaire (CRQ) scores after 24 weeks in people with moderate to severe COPD (low-quality evidence). Inhaled corticosteroid alone compared with inhaled corticosteroid plus long-acting beta2 agonist: Fluticasone alone is as effective as fluticasone plus salmeterol at improving CRQ scores in people with moderate to severe disease (moderate-quality evidence). MORTALITY Inhaled corticosteroids compared with placebo (long-term treatment): Inhaled corticosteroids are no more effective at reducing mortality at 3 years in people with moderate to severe COPD (moderate-quality evidence). Inhaled corticosteroid alone compared with inhaled corticosteroid plus long-acting beta2 agonist: Fluticasone alone is less effective than salmeterol plus fluticasone at 3 years at lowering the rate of all-cause mortality in people with moderate to severe disease ( high-quality evidence ). ADVERSE EFFECTS Long-term treatment with inhaled corticosteroids may predispose to adverse effects such as skin bruising, oral candidiasis, and pneumonia.

Benefits

Short-term treatment with inhaled corticosteroids versus placebo:

We found no systematic review. We found one non-systematic review, which identified 10 RCTs of less than 6 months' duration. Nine short-term trials (10 days to 10 weeks, 10–127 people) found no significant difference between inhaled corticosteroids and placebo in improvement in lung function (FEV₁ ).

Long-term treatment with inhaled corticosteroids versus placebo:

We found two systematic reviews and two additional RCTs examining the effect of inhaled corticosteroids on decline in FEV₁. We found three systematic reviews examining the effect of inhaled corticosteroids on exacerbations, and one review and one large subsequent RCT reporting on mortality.

FEV₁:

The first systematic review compared the effects on FEV₁ of any dose of inhaled corticosteroids versus placebo. It found no significant difference between inhaled corticosteroids and placebo in the rate of decline of FEV₁ (search date 2002; 6 RCTs with follow-up at least 24 months; 3571 people; reduction in annual decline in FEV₁ for corticosteroid v placebo: +5 mL, 95% CI –1.2 mL to +11.2 mL). The second systematic review (search date 2003, 4 RCTs all of which were included in the first systematic review, 2416 people) compared the effects on FEV₁ of high-dose inhaled corticosteroids versus placebo. It found that high-dose inhaled corticosteroids significantly reduced decline in lung function compared with placebo after 24 months; reduction in annual decline in FEV₁ with high-dose inhaled corticosteroids v placebo: 9.9 mL, 95% CI 2.3 mL to 17.5 mL). The two additional RCTs both compared four treatments: combination treatment with inhaled corticosteroids plus long acting beta₂ agonist; inhaled corticosteroids alone; inhaled beta₂ agonists alone; and placebo. The first additional RCT (691 people) found that 500 micrograms fluticasone significantly improved FEV₁ and dyspnoea compared with placebo at 6 months (difference between fluticasone and placebo in FEV₁: 105 mL; P less than 0.05; difference in Transitional Dyspnoea Index (TDI): 1.0; P less than 0.05). The second additional RCT (723 people) found that fluticasone increased post-dose FEV₁ and health-related quality of life after 24 weeks compared with placebo (increase in FEV₁ from baseline: 147 mL with fluticasone v 58 mL with placebo; P less than 0.048; improvement in Chronic Respiratory Disease Questionnaire (CRQ) score from baseline: 10.4 with fluticasone v 5.0 with placebo; P = 0.002; CI not reported). However, it found no significant difference in symptoms at 24 weeks (mean TDI score: 1.7 with fluticasone v 1.0 with placebo; P = 0.057).

Exacerbation rate:

The third systematic review (search 2001; 9 RCTs of at least 6 months' duration; 3976 people) found that inhaled corticosteroids significantly reduced exacerbations compared with placebo (RR 0.70, 95% CI 0.58 to 0.84; absolute numbers not reported). The fourth systematic review (search date 2002; 6 RCTs, 5 of which were also in the third systematic review; 1741 people with stable moderate to severe COPD) found that inhaled corticosteroids significantly reduced COPD exacerbations compared with placebo (RR 0.76, 95% CI 0.72 to 0.80; absolute numbers not reported).The fifth systematic review (search date 2005; 12 RCTs of at least 6 months' duration, 5475 people with COPD; 7 of the RCTs were also identified by the third review,and 5 were identified by the fourth review ) found that, over a mean follow-up of 20 months, inhaled corticosteroids significantly reduced COPD exacerbations compared with placebo (10 RCTs, number of people not reported: RR 0.67, 95% CI 0.59 to 0.77; absolute numbers not reported).

Mortality:

The fifth review found no significant difference between groups in mortality (12 RCTs, 4370 people: RR 0.81, 95% CI 0.60 to 1.08; absolute numbers not reported).The subsequent RCT (6184 people with COPD; 6112 people included in efficacy analysis) compared salmeterol 50 micrograms once daily plus fluticasone 500 micrograms twice daily, salmeterol alone (50 micrograms twice daily), fluticasone alone (500 micrograms twice daily), and placebo, and reported mortality at 3 years as the primary outcome.In this section, we report only the data for fluticasone (1551 people) versus placebo (1545 people): other comparisons are reported in the appropriate sections. At 3 years, data on mortality were available for 3058 people receiving assigned treatments after randomisation to the fluticasone (1534 people) and placebo (1524) groups. This population included people who had discontinued study medication. The RCT found no significant difference between fluticasone alone and placebo in all-cause mortality at 3 years (246/1534 [16%] with fluticasone v 231/1524 [15%] with placebo; HR 1.060, 95% CI 0.886 to 1.268; P = 0.53). 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 in the fluticasone and placebo groups was 59% (1798/3058), which is below Clinical Evidence reporting criteria of 80%, and so these data are not reported here.

Inhaled corticosteroids alone versus inhaled corticosteroids plus beta₂ agonists:

See benefits of inhaled corticosteroids plus beta₂ agonists.

Harms

Short-term treatment with inhaled corticosteroids:

The non-systematic review gave no information on adverse effects.

Long-term treatment with inhaled corticosteroids versus placebo:

The first and second reviews gave no information on adverse effects. The third review found that inhaled corticosteroids significantly increased the risks of oropharyngeal candidiasis and skin bruising compared with placebo (candidiasis: RR 2.1, 95% CI 1.5 to 3.1; skin bruising: RR 2.1, 95% CI 1.6 to 2.8; absolute numbers not reported). The fourth systematic review found that corticosteroids significantly increased oral thrush, dysphonia, and bruising compared with placebo, but found no significant difference in cataracts (oral thrush: 6 RCTs; 5562 people; RR 2.98, 95% CI 2.09 to 4.26; dysphonia: 4 RCTs; 3772 people; RR 2.02, 95% CI 1.43 to 2.83; bruising: 3 RCTs; 3332 people; RR 1.62, 95% CI 1.18 to 2.22; cataracts: 2 RCTs; 1867 people; RR 1.05, 95% CI 0.84 to 1.31; absolute numbers not reported). The review found that corticosteroids reduced bone mineral density in the femoral neck and lumbar spine compared with placebo over 3–4 years (1 RCT of inhaled triamcinolone; 972 people; reduction in bone mineral density: femoral neck: 1.57%, 95% CI 2.40% to 0.74%; lumbar spine: 1.07%, 95% CI 1.86% to 0.28%). The review found no excess risk of fractures with corticosteroids over 3 years (1 RCT; 972 people; RR 0.70, 95% CI 0.36 to 1.37; absolute numbers not reported).The lifetime risk of fractures in people who take corticosteroids for longer than 3–4 years is not known. The fifth systematic review found no significant difference between inhaled corticosteroids and placebo in rate of people withdrawing from study because of adverse effects (RR 0.92, 95% CI 0.74 to 1.14; number of RCTs and people included in analysis not reported; absolute numbers not reported). The first additional RCT found that more people taking fluticasone than taking placebo had oropharyngeal candidiasis, but found that other adverse effects were similar between treatments (candidiasis: 10% with fluticasone v less than 1% with placebo; P value not reported). The second additional RCT reported that serious adverse-event rates, and adverse-event rates leading to withdrawal of treatment were similar among all treatment groups (serious adverse-event rate about 5% in all groups; rate of adverse events leading to withdrawal about 5% in all groups; P values not reported).The subsequent RCT found that a similar proportion of people in the fluticasone group and the placebo group had a drug-related adverse effect (19% with fluticasone v 13% with placebo; absolute numbers not reported; significance not assessed).The most common adverse effect reported was COPD exacerbation.

Inhaled corticosteroids alone versus inhaled corticosteroids plus beta₂ agonists:

See harms of inhaled corticosteroids plus beta₂ agonists.

Comment

Many of the studies of inhaled corticosteroids have been done in people with moderate to severe disease (FEV₁ less than 50% predicted) and hence apply to that population. The Global Initiative on Obstructive Pulmonary Disease has therefore advocated the use of inhaled corticosteroids only in people with an FEV₁ less than 50% predicted, and frequent exacerbations (at least 3 exacerbations in the last 3 years).

Substantive changes

Corticosteroids (inhaled) One review added that found that inhaled corticosteroids reduced COPD exacerbations compared with placebo at a mean follow-up of 20 months. However, the review found no significant difference between groups in mortality. One large RCT added that found no significant difference at 3 years between fluticasone and placebo in all-cause mortality. Benefits of treatment are thought to outweigh adverse effects of long-term treatment. Corticosteroids (inhaled) recategorised from Trade-off between benefits and harms to Beneficial.

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Corticosteroids plus long-acting beta₂ agonists (inhaled)

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Corticosteroid plus long-acting beta2 agonist compared with placebo: An inhaled corticosteroid plus a long-acting beta 2 agonist is more effective at improving pre-dose FEV 1 in people with moderate to severe COPD ( moderate-quality evidence ). Corticosteroid plus long-acting beta2 agonist compared with corticosteroid alone: An inhaled corticosteroid plus a long-acting beta 2 agonist is more effective at improving pre-dose FEV 1 in people with moderate to severe COPD (moderate-quality evidence). Corticosteroid plus long-acting beta2 agonist compared with long-acting beta2 agonist alone: We don’t know whether an inhaled corticosteroid plus a long-acting beta 2 agonist is more effective at improving pre-dose FEV 1 in people with moderate to severe COPD ( low-quality evidence ). COPD EXACERBATION AND WORSENING OF SYMPTOMS Corticosteroid plus long-acting beta2 agonist compared with placebo: An inhaled corticosteroid plus a long-acting beta 2 agonist is more effective at reducing COPD exacerbation rates in people with moderate to severe disease (moderate-quality evidence). Corticosteroid plus long-acting beta2 agonist compared with corticosteroid alone: An inhaled corticosteroid plus a long-acting beta 2 agonist is no more effective at reducing COPD exacerbations in people with moderate to severe disease (moderate-quality of evidence). Corticosteroid plus long-acting beta2 agonist compared with long-acting beta2 agonist alone: An inhaled corticosteroid plus a long-acting beta 2 agonist is more effective at reducing COPD exacerbations in people with moderate to severe disease (moderate-quality of evidence). QUALITY OF LIFE Corticosteroid plus long-acting beta2 agonist compared with placebo: Fluticasone plus salmeterol is more effective at improving Chronic Respiratory Disease Questionnaire (CRQ) scores in people with moderate to severe disease (moderate-quality evidence). Corticosteroid plus long-acting beta2 agonist compared with corticosteroid alone: Fluticasone plus salmeterol is as effective as fluticasone alone at improving CRQ scores in people with moderate to severe disease (moderate-quality evidence). Corticosteroid plus long-acting beta2 agonist compared with long-acting beta2 agonist alone: Fluticasone plus salmeterol is as effective as salmeterol alone at improving CRQ scores in people with moderate to severe disease (moderate-quality evidence). MORTALITY Corticosteroid plus long-acting beta2 agonist compared with placebo: Fluticasone plus salmeterol is no more effective at reducing all-cause mortality in people with moderate to severe disease ( high-quality evidence ). Corticosteroid plus long-acting beta2 agonist compared with corticosteroid alone: Salmeterol plus fluticasone is more effective at 3 years than fluticasone alone at reducing all-cause mortality in people with moderate to severe disease (high-quality evidence). Corticosteroid plus long-acting beta2 agonist compared with long-acting beta2 agonist alone: Salmeterol plus fluticasone is no more effective at 3 years than salmeterol alone at reducing all-cause mortality in people with moderate to severe disease (high-quality evidence).

Benefits

We found one systematic review (search date 2005, 6 RCTs, 4118 people with moderate to severe disease)and one large subsequent RCT. The review compared inhaled corticosteroid plus a long-acting beta₂ agonist (combined in one inhaler) versus inhaled corticosteroid alone, inhaled long-acting beta₂ agonist alone, or placebo.The review searched for two combination regimens: fluticasone plus salmeterol; and budesonide plus formoterol.

Corticosteroid plus long-acting beta₂ agonist versus placebo:

The review found that combination treatment (pooled analysis of both combination regimes) significantly reduced COPD exacerbations compared with placebo (3 RCTs; 1642 people with moderate to severe COPD; RR 0.76, 95% CI 0.68 to 0.84; absolute numbers not reported). The review found significant improvements in health-related quality of life with fluticasone plus salmeterol compared with placebo (mean change in CRQ: 2 RCTs, 712 people: WMD 5.0, 95% CI 2.48 to 7.52; P = 0.0001). The review did not pool data for budesonide plus formoterol versus placebo for this outcome. The review found that fluticasone plus salmeterol significantly improved pre-dose FEV₁ compared with placebo (2 RCTs; 697 people; WMD 0.16 L, 95% CI 0.12 L to 0.20 L). The review found similar results for the combination of budesonide plus formoterol compared with placebo (2 RCTs; 923 people; % increase in FEV₁ 14.40%, 95% CI 11.91% to 16.90%). The meta-analysis for the comparison of budesonide plus formoterol versus placebo was done using a fixed-effects model. The subsequent RCT (6184 people with COPD; 6112 people included in efficacy analysis) compared: salmeterol (50 micrograms once daily) plus fluticasone (500 micrograms twice daily); salmeterol alone (50 micrograms twice daily); fluticasone alone (500 micrograms twice daily); and placebo, and reported mortality at 3 years as the primary outcome. At 3 years, data on mortality were available for 3057 people receiving assigned treatments after randomisation to the combination-treatment (1533 people) and placebo (1524 people) groups. This population included people who had discontinued study medication. The RCT found no significant difference in all-cause mortality at 3 years between salmeterol plus fluticasone and placebo, although the rate was lower with combination treatment (193/1533 [13%] with combination v 231/1524 [15%] with placebo; HR 0.825, 95% CI 0.681 to 1.002; P = 0.052). 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 in the combination and placebo groups was 61% (1862/3057), which is below Clinical Evidence reporting criteria of 80%, and so these data are not reported here.

Corticosteroid plus long-acting beta₂ agonist versus corticosteroid alone:

The review found no significant difference in COPD exacerbations between combination treatment and corticosteroid alone (pooled analysis of both combination regimes: 3 RCTs; 1649 people; RR 0.91, 95% CI 0.81 to 1.02; absolute numbers not reported).The review found that fluticasone plus salmeterol significantly improved pre-dose FEV₁ compared with fluticasone (2 RCTs; 690 people; WMD 0.05 L, 95% CI 0.02 L to 0.09 L). The review found similar results for the combination of budesonide plus formoterol compared with budesonide alone (2 RCTs; 917 people; % increase in FEV₁ 10.17%, 95% CI 7.71% to 12.62%). Meta-analysis was done using a fixed-effects model. The review found no significant difference in health-related quality of life between fluticasone plus salmeterol and fluticasone alone (mean change in CRQ: 2 RCTs, 696 people: WMD +2.34, 95% CI –3.15 to +7.82; P = 0.4). The review did not meta-analyse data for budesonide plus formoterol versus budesonide alone for this outcome. The subsequent RCT (6184 people with COPD; 6112 people included in efficacy analysis) compared: salmeterol (50 micrograms once daily) plus fluticasone (500 micrograms twice daily); salmeterol alone (50 micrograms twice daily); fluticasone alone (500 micrograms twice daily); and placebo, and reported mortality at 3 years as the primary outcome.At 3 years, data on mortality were available for 3067 people receiving assigned treatments after randomisation to the combination treatment (1533 people) and fluticasone (1534 people) groups. This population included people who had discontinued study medication. The RCT found significantly lower all-cause mortality at 3 years with salmeterol plus fluticasone compared with fluticasone alone (193/1533 [13%] with combination v 246/1534 [16%] with fluticasone alone; HR 0.774, 95% CI 0.641 to 0.934; P = 0.007). 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 in the combination and placebo groups was 64% (1958/3067), which is below Clinical Evidence reporting criteria of 80%, and so these data are not reported here.

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

The review found that combination treatment (meta-analysis of both combination regimes) significantly reduced COPD exacerbations compared with beta₂ agonist alone (3 RCTs; 1648 people; RR 0.85, 95% CI 0.77 to 0.95; absolute numbers not reported).The review found significant improvements in health-related quality of life with fluticasone plus salmeterol compared with salmeterol alone (mean change in CRQ: 2 RCTs, 712 people: WMD 2.83, 95% CI 0.25 to 5.41; P = 0.03). The review did not pool data for budesonide plus formoterol versus formoterol alone for this outcome. The review found that fluticasone plus salmeterol significantly improved pre-dose FEV₁ compared with salmeterol alone (2 RCTs; 677 people; WMD 0.06 L, 95% CI 0.02 L to 0.10 L).However, the review found no significant difference between budesonide plus formoterol and formoterol alone for this outcome (2 RCTs; 918 people; % increase in FEV₁ +3.06%, 95% CI –0.86% to +6.97%). Data for budesonide plus formoterol was analysed using a random-effects model because of heterogeneity between studies. The subsequent RCT (6184 people with COPD; 6112 people included in efficacy analysis) compared: salmeterol (50 micrograms once daily) plus fluticasone (500 micrograms twice daily); salmeterol alone (50 micrograms twice daily); fluticasone alone (500 micrograms twice daily); and placebo, and reported mortality at 3 years as the primary outcome.At 3 years, data on mortality were available for 3054 people receiving assigned treatments after randomisation to the combination treatment (1533 people) and salmeterol (1521 people) groups. This population included people who had discontinued study medication. The RCT found no significant difference in all-cause mortality at 3 years between salmeterol plus fluticasone and salmeterol alone (193/1533 [12.6%] with combination v 205/1521 [13.4%] with salmeterol; HR 0.932, 95% CI 0.765 to 1.134; P = 0.48).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 in the combination and salmeterol groups was 64% (1971/3057), which is below Clinical Evidence reporting criteria of 80%, and so these data are not reported here.

Harms

Corticosteroid plus long-acting beta₂ agonist versus placebo:

The review found a significantly higher rate of candidiasis with fluticasone plus salmeterol compared with placebo (3 RCTs, 1436 people: 56/705 [8%] with combination v 9/731 [1%] with placebo; RR 6.41, 95% CI 3.20 to 12.83; P less than 0.0001). However, the review found no significant difference between either combination treatment and placebo in proportion of people reporting an adverse effect (fluticasone plus salmeterol: 540/705 [77%] with combination v 528/731 [72%] with placebo; RR 1.06, 95% CI 1.00 to 1.12; P = 0.06; budesonide plus formoterol [serious adverse effect]: 2 RCTs, 923 people: 108/462 [23%] with combination v 103/461 [22%] with placebo; RR 1.05, 95% CI 0.83 to 1.33; P = 0.7). The subsequent RCT found that similar proportions of people in the fluticasone plus salmeterol group and in the placebo group had a drug-related adverse effect (18% with combination v 13% with placebo; absolute numbers not reported; significance not assessed).The most common adverse effect reported was COPD exacerbation.

Corticosteroid plus long-acting beta₂ agonist versus corticosteroid alone:

The review found no significant difference between fluticasone plus salmeterol compared with fluticasone alone in proportion of people reporting candidiasis (3 RCTs, 1435 people: 56/705 [7.9%] with combination v 55/730 [7.5%] with fluticasone; RR 1.05, 95% CI 0.74 to 1.51; P = 0.8). The review also found no significant difference between either combination treatment and corticosteroid alone in proportion of people reporting an adverse effect (fluticasone plus salmeterol: 540/705 [77%] with combination v 569/730 [78%] with fluticasone alone; RR 0.98, 95% CI 0.93 to 1.04; P = 0.5; budesonide plus formoterol [serious adverse effect]: 2 RCTs, 917 people: 111/462 [24%] with combination v 123/455 [27%] with budesonide; RR 0.89, 95% CI 0.72 to 1.12; P = 0.3). The subsequent RCT found that a similar proportion of people in the fluticasone plus salmeterol group and the fluticasone alone group had a drug-related adverse effect (18% with combination v 19% with fluticasone alone; absolute numbers not reported; significance not assessed).The most common adverse effect reported was COPD exacerbation.

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

The review found a significantly higher rate of candidiasis with fluticasone plus salmeterol compared with salmeterol alone (3 RCTs, 1418 people: 56/705 [8%] with combination v 14/713 [2%] with salmeterol; RR 4.06, 95% CI 2.28 to 7.22; P less than 0.0001). However, the review found no significant difference between either combination treatment and beta₂ agonist alone in the proportion of people reporting an adverse effect (fluticasone plus salmeterol: 540/705 [77%] with combination v 528/713 [74%] with salmeterol; RR 1.04, 95% CI 0.98 to 1.10; P = 0.2; budesonide plus formoterol [serious adverse effect]: 2 RCTs, 918 people: 108/462 [23%] with combination v 122/456 [27%] with formoterol; RR 0.88, 95% CI 0.70 to 1.10; P = 0.2). The subsequent RCT found that a similar proportion of people in the fluticasone plus salmeterol group and the salmeterol alone group had a drug-related adverse effect (18% with combination v 12% with salmeterol; absolute numbers not reported; significance not assessed).The most common adverse effect reported was COPD exacerbation.

Comment

These studies have been done mainly in people with moderate to severe disease (FEV₁ less than 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 less than 50% predicted and frequent exacerbations (i.e. at least 3 exacerbations in the last 3 years). The review included one RCT that does not meet Clinical Evidence inclusion criteria for sample size. The review did not include it in the meta-analysis, and we have not reported separate results.

Substantive changes

Corticosteroids plus long-acting beta₂ agonists One large RCT added found lower mortality at 3 years with salmeterol plus fluticasone compared with fluticasone aloneHowever, there was no significant difference between salmeterol plus fluticasone and either placebo or salmeterol alone for this outcome. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Mucolytic drugs

Summary

COPD EXACERBATION AND WORSENING OF SYMPTOMS Compared with placebo: We don’t know whether mucolytics are more effective at 2–36 months at reducing exacerbations in people with COPD ( very low-quality evidence ).

Benefits

Long-term treatment:

We found two systematic reviews. Not all participants included in the reviews had COPD (see comment below). The first systematic review (search date, 2005, 6 RCTs in people with COPD; 20 RCTs in people with chronic bronchitis not defined further; 7335 people) found that mucolytics for 2–36 months significantly reduced the average number of exacerbations and days of disability compared with placebo (exacerbations [23 RCTs, 5055 people]: WMD: –0.05 exacerbations/month, 95% CI –0.05 exacerbations/month to –0.04 exacerbations/month; days of disability [10 RCTs, 1916 people]: WMD: –0.56 days/month, 95% CI –0.77 days/months to –0.35 days/month).The second systematic review (search date 1995; 9 RCTs, 8 of which were included in the first review) compared N-acetylcysteine versus placebo for 3–24 months. It found that N-acetylcysteine reduced exacerbations compared with placebo (overall weighted effect size: 1.37, 95% CI 1.25 to 1.50; reduction 235). The results of the reviews should be interpreted with caution. It was unclear how many people included in the reviews had COPD. In both reviews, there was significant heterogeneity among the RCTs, and symptom scores could not be pooled. One large RCT (523 people) identified by the reviews included people with only smoking-related COPD. 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).

Harms

The first systematic review found a significantly lower rate of adverse effects with mucolytics compared with placebo (15 RCTs, 4149 people: 386/2074 [19%] with mucolytic v 463/2075 [22%] with placebo; RR 0.84, 95% CI 0.74 to 0.94).However, the review reported that data from several large studies have been omitted from the meta-analysis. The second review reported that the adverse effects of N-acetylcysteine were mainly mild gastrointestinal complaints. It found no significant difference between groups in rate of adverse effects (reported as not significant; P value not reported; no further information on adverse effects given.

Comment

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

Substantive changes

Mucolytics One systematic review updated that found that mucolytics for 2–36 months reduced the average number of exacerbations and days of disability compared with placebo. However, results should be interpreted with caution as many of the RCTs identified by the review included people with chronic bronchitis rather than COPD. Categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Antibiotics (prophylactic)

Summary

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 ).

Benefits

Short-term treatment:

We found no systematic review or RCTs.

Long-term treatment:

We found one systematic review (search date not reported; 9 RCTs; 1055 people; see comment below) of prophylactic antibiotics (tetracycline, penicillin, trimethoprim, sulphadimidine, and sulphaphenazole) in people with COPD or chronic bronchitis. All trials were performed before 1970. The duration of the RCTs ranged from 3 months to 5 years. The review found that antibiotics significantly reduced the risk of any exacerbation during the study compared with placebo (RR 0.91, 95% CI 0.84 to 0.99). It found that antibiotics slightly reduced the number of exacerbations per person per year, but the reduction was not significant (WMD: –0.15, 95% CI –0.34 to +0.04). It found that antibiotics significantly reduced the number of days of disability per person per month treated (WMD –0.95, 95% CI –1.89 to –0.01; 22% reduction).

Harms

In general, there was a poor reporting of possible adverse effects in most trials. Nevertheless, the review found that antibiotics slightly increased adverse effects compared with placebo (number of adverse effects; WMD per person per year treated: 0.01, 95% CI 0 to 0.02).

Comment

The results of this review should be interpreted with caution. 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 over 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

No new evidence

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Oxygen treatment (long-term domiciliary treatment)

Summary

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 or endurance time at 12 months in people with mild to moderate hypoxaemia ( moderate-quality evidence ). 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 (moderate-quality evidence).

Benefits

Short-term treatment with oxygen:

We found no systematic review or RCTs.

Long-term treatment with oxygen versus no oxygen:

We found one systematic review (search date 2005, 6 RCTs). 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). The review found that domiciliary daily oxygen supplementation for at least 15 hours in people with severe daytime hypoxaemia significantly reduced mortality over 5 years compared with no oxygen supplementation (1 RCT, 87 people: 19/42 [45%] with oxygen supplementation v 30/45 [67%] with no oxygen; RR 0.68, 95% CI 0.46 to 1.00). However, in people with mild to moderate hypoxaemia (PaO₂ 56–65 mm Hg or greater than 55 mm Hg), the review found no significant difference between groups in mortality at 36–85 months (2 RCTs, 163 people: 42/82 [51%] with oxygen supplementation v 35/81 [43%] with no oxygen; RR 1.18, 95% CI 0.86 to 1.63). The review found no significant difference in dyspnoea score (assessed using Borg scale) or in endurance time at 12 months' follow-up with oxygen compared with no oxygen in people with mild to moderate hypoxaemia (dyspnoea: 1 RCT, 28 people: +4.5 with oxygen v +5.7 with no oxygen; WMD –1.20, 95% CI –2.47 to +0.07; endurance time: +7.1 min with oxygen v +4.9 min with no oxygen; WMD +2.20 min, 95% CI –0.73 min to +5.13 min).

Harms

Short-term treatment with oxygen:

We found no RCTs.

Long-term treatment with oxygen versus no oxygen:

The systematic review gave no information on adverse effects.

Comment

Only one of the RCTs identified by the review was double blinded.One RCT (203 people; PaO₂ less than 7.4 kPa) identified by the review compared continuous with 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).

Clinical guide:

Domiciliary oxygen treatment seems to be more effective in people with severe hypoxaemia (PaO₂ less than 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

Oxygen (long-term domiciliary treatment) One review updated, which found lower mortality with long-term oxygen treatment in people with severe hypoxaemia compared with no oxygen treatment at 5 years' follow-up. However, the review found no significant difference in mortality in people with mild to moderate hypoxaemia. Categorisation unchanged (Likely to be beneficial for long-term treatment in people with severe hypoxaemia).

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Alpha₁ antitrypsin

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Long-term treatment with alpha1 antitrypsin compared with placebo: We don’t know whether alpha 1 antitrypsin is more effective at improving FEV 1 at 3 years in people with COPD ( low-quality evidence ). NOTE We found no direct information about alpha 1 antitrypsin in the short-term treatment of people with COPD.

Benefits

We found no systematic review.

Short-term treatment with alpha₁ antitrypsin:

We found no RCTs.

Long-term treatment with alpha₁ antitrypsin versus placebo:

We found one RCT (56 people with alpha₁ antitrypsin deficiency and moderate emphysema, FEV₁ 30–80% predicted) comparing alpha₁ antitrypsin infusions 250 mg/kg versus placebo infusion (albumin) given monthly for at least 3 years. It found no significant difference in the decline in FEV₁ after 1 year (decline in FEV₁: 79 mL with alpha₁ antitrypsin v 59 mL with placebo, CI not reported; P = 0.25).

Harms

The RCT reported no adverse effects in people taking alpha₁ antitrypsin or placebo.

Comment

We found no clear evidence from observational studies on 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 3.5–7.0 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 35–49% 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, CI not reported; P = 0.02).

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Psychosocial interventions alone for smoking cessation

Summary

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

Benefits

We found no systematic review or RCTs examining the effects of psychosocial interventions such as professional advice or counselling alone on the outcomes of interest in this review (FEV₁, peak expiratory flow, exacerbations, dyspnoea score, quality of life, or survival), specifically in people with COPD (see comment below).

Harms

We found no RCTs.

Comment

Despite the extensive literature on smoking cessation, we did not identify useful studies of psychosocial interventions alone, or studies solely in people with COPD: most studies 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. 2008 Dec 15;2008:1502.

Pharmacological interventions alone for smoking cessation

Summary

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

Benefits

We found one systematic review (search date 2002). 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 identified two RCTs, both of which examined pharmacological interventions plus psychosocial interventions ( see benefits of psychosocial plus pharmacological interventions).

Harms

We found no RCTs.

Drug safety alert

FDA issues drug safety alert 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 (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. 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. 2008 Dec 15;2008:1502.

Psychosocial plus pharmacological interventions for smoking cessation

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Psychosocial plus pharmacological interventions compared with usual care: Nicotine gum plus a psychosocial smoking cessation and abstinence maintenance programme with or without ipratropium is more effective at reducing the decline in FEV 1 at 1–5 years in people with mild chronic COPD ( moderate-quality evidence ). COPD EXACERBATION AND WORSENING OF SYMPTOMS Smoking cessation interventions compared with usual care: Smoking cessation interventions are more effective at 5 years at reducing cough, phlegm, wheezing, and dyspnoea in people with mild chronic COPD (moderate-quality evidence). MORTALITY Psychosocial plus pharmacological interventions compared with usual care: smoking cessation interventions with and without ipratropium may be more effective at 14.5 years but not at 5 years at reducing all-cause mortality in people with mild chronic COPD ( low-quality evidence ).

Benefits

One systematic review (search date 2002) identified two RCTs examining psychosocial plus pharmacological interventions in people with COPD. The first RCT (5887 smokers, age 35–60 years, with spirometric signs of early COPD, mean prebronchodilator FEV₁ 2640 mL, mean of 30 cigarettes smoked/day) compared three treatments: smoking cessation intervention plus placebo; smoking cessation intervention plus ipratropium; and usual care. 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. The RCT 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). It found that the smoking cessation intervention (with and without ipratropium) significantly improved FEV₁ compared with usual care after 1 and 5 years, and that the smoking cessation intervention plus ipratropium significantly improved FEV₁ compared with the smoking cessation intervention alone at 1 and 5 years (change in FEV₁ at 1 year: –34.3 mL with usual care v +11.2 mL with smoking cessation intervention v +38.8 mL with intervention plus ipratropium; P less than 0.005 for each between treatment comparison; at 5 years, completer analysis [about 90% of participants]: –267 mL with usual care v –208 mL with smoking cessation intervention v –184 mL with intervention plus ipratropium; P 0.002 or less for all comparisons). In further analyses, both treatments using a smoking cessation intervention were combined. After 11 years, smoking intervention reduced the decline in FEV₁ compared with usual care (change from baseline: –502 mL with intervention v +587 mL with usual care; P = 0.001). 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 smoking cessation intervention significantly reduced cough, phlegm, wheezing, and dyspnoea compared with usual care at 5 years (by intention-to-treat analysis, cough for at least 3 months/year: 15% with intervention v 23% with usual care; phlegm for at least 3 months/year: 12% with intervention v 20% with usual care; presence of wheezing: 25% with intervention v 31% with usual care; presence of dyspnoea: 19% with intervention v 24% with usual care, all P less than 0.0001). There was no significant difference between the three treatments in all-cause mortality at 5 years (2.6% with usual care v 2.2% with smoking cessation intervention v 2.7% with intervention plus ipratropium; P = 0.58). Smoking cessation intervention (with and without ipratropium) significantly reduced all-cause mortality compared with usual care at 14.5 years (8.83/1000 person-years with smoking cessation intervention v 10.83/1000 person-years with placebo; HR for mortality 1.18, 95% CI 1.02 to 1.37). The second RCT (404 people with mild or moderate COPD, smoking an average of 28 cigarettes a day, mean age 54 years) compared bupropion plus counselling versus placebo plus counselling for 12 weeks with 6 months' follow-up, but only reported abstinence rates and adverse effects. This study did not provide data about the effects on FEV₁ changes, peak expiratory flow, exacerbations, dyspnoea score, quality of life, or survival. It found that bupropion (slow-release 150 mg twice daily) 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; see comment below).

Harms

In the first RCT, 31% (about 1216 people) were still using nicotine gum after 1 year. About 25% of these reported at least one adverse effect, but most were minor and transient. The most common adverse effects were: indigestion (5% for men and 4% for women); mouth irritation (6.2% for men and 6.5% for women); mouth ulcers (4% for men and 5% for women); nausea (2% for men and 4% for women); and hiccups (3% for men and 4% for women). The smoking cessation intervention increased weight at 1 and 5 years in both men and women compared with usual care, but the significance was not reported (weight gain, 1 year: 2.61 kg with intervention v 0.61 kg with usual care for men and 2.63 kg v 1.10 kg for women; 5 years: 3.9 kg with intervention v 2.60 kg with usual care for men and 4.75 kg v 2.84 kg for women). The second RCT found similar rates of discontinuation due to adverse effects between treatment groups (6% with placebo v 7% with bupropion). It found higher rates of serious adverse effects with placebo (2.5% with placebo v 0.5% with bupropion).

Drug safety alert

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Pulmonary rehabilitation

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Compared with usual care: Multi-modality pulmonary rehabilitation may be more effective at improving maximal exercise capacity and functional exercise capacity ( low-quality evidence ). QUALITY OF LIFE Compared with usual care: Multi-modality pulmonary rehabilitation is more effective at improving Chronic Respiratory Disease Questionnaire (CRQ) scores ( moderate-quality evidence ).

Benefits

We found two systematic reviews and one subsequent RCT investigating pulmonary rehabilitation. The first systematic review (search date 2004, 31 RCTs) found that pulmonary rehabilitation significantly improved dyspnoea, fatigue, emotional function, and mastery compared with usual care (Chronic Respiratory Disease Questionnaire [CRQ]: dyspnoea: 11 RCTs, 610 people; WMD 1.06, 95% CI 0.85 to 1.26; fatigue: 11 RCTs, 618 people; WMD 0.92, 95% CI 0.71 to 1.13; emotional function: 11 RCTs, 618 people; WMD 0.76, 95% CI 0.52 to 1.00; mastery: 11 RCTs, 618 people; WMD 0.97, 95% CI 0.74 to 1.20). In all domains the effect was larger than the minimally clinically important difference of 0.5 units. The review found that pulmonary rehabilitation improved maximal exercise capacity and functional exercise capacity compared with usual care (incremental cycle ergometer test: 13 RCTs, 511 people; WMD 8.43 watts, 95% CI 3.45 watts to 13.41 watts; 6-minute walk test: 16 RCTs, 669 people; WMD 48.46 m, 95% CI 31.64 m to 68.28 m). The confidence interval for functional exercise capacity is outside the minimal clinically significant difference of between 37 m and 71 m for the 6-minute walk test. There is no generally accepted minimal clinically important difference for the cycle ergometer test. The second systematic review (search date 2000; 20 RCTs, 12 of which were also included in the first systematic review) found that pulmonary rehabilitation significantly improved exercise capacity and shortness of breath compared with control (walking test: 20 RCTs; 979 people with symptomatic COPD or impaired exercise capacity; standard effect size 0.71, 95% CI 0.43 to 0.99; CRQ: shortness of breath: 12 RCTs; 723 people; standard effect size 0.62, 95% CI 0.26 to 0.91). The subsequent RCT (40 men with COPD) found that, at 16 weeks, pulmonary rehabilitation led to significant improvements in exercise capacity (6-minute walking distance test) and in the dyspnoea component of the CRQ compared with control (change in 6-minute walking distance from baseline: from 347 m to 410 m with pulmonary rehabilitation v from 330 m to 308 m with control; P less than 0.01; change in dyspnoea from baseline: from 2.9 to 3.7 with pulmonary rehabilitation v from 3.6 to 3.4 with control; P less than 0.01).Randomisation was not concealed.

Harms

The systematic reviews found no adverse effects with pulmonary rehabilitation. The subsequent RCT gave no information on adverse effects.

Comment

There are indications that the effects of pulmonary rehabilitation without reinforcement do not last longer than 1 year.

Substantive changes

Pulmonary rehabilitation One RCT added which found that, at 16 weeks, pulmonary rehabilitation led to significant improvements in exercise capacity and dyspnoea symptoms compared with control. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Inspiratory muscle training (alone)

Summary

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 dyspnoea at rest ( low-quality evidence ). 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). IMT compared with sham IMT: IMT may be more effective at improving inspiratory muscle strength, dyspnoea at rest and during exercise, and work rate maximum, but may be no more effective at improving inspiratory muscle endurance, exercise capacity, FEV 1, and forced vital capacity (low-quality evidence).

Benefits

We found two systematic reviews and one subsequent RCT on the effects of inspiratory muscle training (IMT) in people with COPD.The systematic reviews used different definitions for the intervention of IMT. Eight RCTs were identified by both reviews.

IMT versus control or no IMT:

The first review (search date 2000, 15 RCTs, number of people included not reported) found that IMT (with or without general exercise rehabilitation) significantly improved inspiratory muscle strength, endurance, and dyspnoea (transitional index) compared with control (see table 1 ).It found no significant difference between groups in inspiratory muscle endurance (maximal voluntary ventilation), laboratory exercise capacity, exercise-related dyspnoea, and functional exercise capacity (see table 1 ).The second review (search date 2003, 19 RCTs, number of people not reported) found no significant difference between IMT and no IMT in inspiratory muscle strength (see table 1 ).However, the review meta-analysed data from only two small RCTs for this comparison.

Table 1.

Effects of inspiratory muscle training in people with COPD (see text).

Reference	Comparison	Outcome assessed	Number of RCTs (number of people)	Result
	IMT (with or without general exercise rehabilitation) v control	Inspiratory muscle strength	15 RCTs (383 people)	WMD 0.56 cm H₂O, 95% CI 0.35 cm H₂O to 0.77 cm H₂O
		Inspiratory muscle endurance	7 RCTs (number of people not reported)	WMD 0.41 seconds, 95% CI 0.14 seconds to 0.68 seconds
		Transitional dyspnoea Index	2 RCTs; number of people not reported	WMD 2.3, 95% CI 1.44 to 3.15
		Inspiratory muscle endurance (maximal voluntary ventilation)	4 RCTs (number of people not reported)	WMD 0.21 L/minute, 95% CI –0.29 L/minute to +0.70 L/minute
		Laboratory exercise capacity	5 RCTs (number of people not reported)	VO₂ max: WMD +0.04 L/minute, 95% CI –0.36 L/minute to +0.29 L/minute
				VE max: WMD +0.03 L/minute, 95% CI –0.03 L/minute to +0.35 L/minute
		Functional exercise capacity (6- or 12-minute walking distance)	8 RCTs (number of people not reported)	WMD +0.22 m, 95% CI –0.05 m to +0.48 m
		Borg exercise-related dyspnoea	5 RCTs (number of people not reported)	WMD –0.55, 95% CI –0.90 to +0.19
	IMT versus no IMT	Inspiratory muscle strength	2 RCTs (27 people)	WMD +9.67 cm H₂O, 95% CI –4.50 cm H₂O to +23.85 cm H₂O; P = 0.18
	IMT plus general exercise reconditioning versus general exercise reconditioning alone	Inspiratory muscle strength	6 RCTs (number of people not reported)	WMD 0.47 cm H₂O, 95% CI 0.15 cm H₂O to 0.79 cm H₂O
		Inspiratory muscle endurance	3 RCTs (number of people not reported)	WMD 0.55 seconds, 95% CI 0.14 seconds to 0.97 seconds
		Muscle strength in people with inspiratory muscle weakness	3 RCTs (number of people not reported)	WMD +16 cm H₂O; P less than 0.001; CI not reported
		Muscle strength in people without inspiratory muscle weakness	3 RCTs (number of people not reported)	WMD –3 cm H₂O; P = 0.54; CI not reported
		Functional exercise capacity (6- or 12-minute walk test)	4 RCTs (number of people not reported)	WMD +0.20 m, 95% CI –0.21 m to +0.61 m
	IMT versus sham IMT	Inspiratory muscle strength	10 RCTs (233 people)	WMD 12.28 cm H₂O, 95% CI 7.50 cm H₂O to 17.06 cm H₂O; P less than 0.001
		Inspiratory threshold loading	4 RCTs (74 people)	WMD 1.03 kPa, 95% CI 0.31 kPa to 1.74 kPa; P = 0.005
		Borg scale for respiratory effort	2 RCTs (40 people)	WMD –2.28, 95% CI –3.09 to –1.46; P less than 0.001
		Transitional dyspnoea index	3 RCTs (59 people)	WMD 3.43, 95% CI 1.91 to 4.95; P less than 0.001
		Inspiratory muscle endurance	4 RCTs (111 people)	WMD +4.11 min, 95% CI –0.55 min to +8.77 min; P = 0.08
		Exercise capacity	2 RCTs (40 people)	WMD –0.15 L/min, 95% CI –0.32 L/min to +0.02 L/min; P = 0.07
		12-minute walking distance	2 RCTs (81 people)	WMD +17.06 m, 95% CI –15.43 m to +49.55 m; P = 0.3
		Forced vital capacity	3 RCTs (56 people)	WMD +0.22 L, 95% CI –0.11 L to +0.54 L; P = 0.19
		FEV₁	4 RCTs (70 people)	WMD +0.05 L, 95% CI –0.02 L to 0.12 L; P = 0.15
	IMT versus sham IMT	Maximum inspiratory pressure	1 RCT (33 people)	Change from baseline: from 62.7 cm H₂O to 80.7 cm H₂O with IMT v from 66.5 cm H₂O to 71.7 cm H₂0 with sham IMT; P less than 0.05
		Maximum threshold pressure		Change from baseline: from 38.5 cm H₂O to 60.1 cm H₂O with IMT v 40.5 cm H₂O to 42.8 cm H₂O with sham IMT; P less than 0.05
		6-minute walking distance		Change from baseline: from 445.7 m to 472.8 m with IMT v from 508.0 m to 513.2 m with sham IMT; P less than 0.05
		Dyspnoea (assessed using CRQ)		Change from baseline: from 3.4 to 4.9 with IMT v from 2.8 to 3.7 with sham IMT; P = 0.026
		Fatigue (assessed using CRQ)		Change from baseline: from 3.9 to 4.8 with IMT v from 3.7 to 4.0 with sham IMT; P = 0.01
		Inspiratory capacity		Change from baseline: from 1.8 L to 2.0 L with IMT v from 1.7 L to 1.8 L with sham IMT; P value not reported; reported as not significant
		Exercise capacity		Change from baseline: from 64.4 W to 64.4 W with IMT v from 65.9 W to 70.0 W with sham IMT; P value not reported; reported as not significant
		Total score of the CRQ		Change from baseline: from 4.5 to 5.3 with IMT v from 4.1 to 4.5 with sham IMT; P value not reported; reported as not significant
		Emotional function (CRQ)		Change from baseline: from 5.1 to 5.6 with IMT v from 4.6 to 4.9 with sham IMT; P value not reported; reported as not significant

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CRQ, Chronic Respiratory Disease Questionnaire; IMT, Inspiratory muscle training

IMT plus general exercise reconditioning versus general exercise reconditioning alone:

The first review found that IMT plus general exercise reconditioning significantly improved inspiratory muscle strength and inspiratory muscle endurance compared with general exercise reconditioning alone (see table 1 ). Combination treatment significantly improved muscle strength in people with inspiratory muscle weakness, but not in those without inspiratory muscle weakness. It found no significant difference in functional exercise capacity between groups.

IMT versus sham IMT:

The second review found that IMT significantly improved inspiratory muscle strength, inspiratory threshold loading, Borg scale for respiratory effort, and transitional dyspnoea index compared with sham IMT (see table 1 ). However, it found no significant difference between treatments in inspiratory muscle endurance, exercise capacity, 12-minute walk test, forced vital capacity and FEV₁ (see table 1 ). The subsequent RCT (33 people with COPD) compared a high-intensity (loads of up to –103 cm H₂O) inspiratory muscle training programme versus sham IMT. At 8 weeks, the RCT found significant improvements in maximum inspiratory pressure, maximum threshold pressure, 6-minute walk distance, dyspnoea (assessed using Chronic Respiratory Disease Questionnaire [CRQ]) and fatigue (assessed using CRQ) with IMT compared with sham IMT. However, the RCT found no significant difference between treatments in inspiratory capacity, exercise capacity, total score of the CRQ, and emotional function (CRQ) (see table 1 ).

Harms

The systematic reviews and subsequent RCT gave no information on adverse effects.

Comment

None.

Substantive changes

Inspiratory muscle training One review added that found no significant difference between IMT and no IMT in inspiratory muscle strength.However, the review pooled data from only two small RCTs for this comparison. The review and a subsequent RCT found that IMT significantly improved inspiratory threshold loading and walking distance test compared with sham IMT. Results for other outcomes assessed differed between the review and the RCT. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Peripheral muscle strength training (alone)

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Compared with no treatment or other exercise training: Although peripheral muscle strength training improves upper-body and leg strength, it may be no more effective at improving walking endurance, FEV 1 , forced vital capacity, or maximal exercise capacity ( low-quality evidence ).

Benefits

We found one systematic review (search date not reported), which found that resistance training improved upper-body and knee extensor strength compared with no treatment or other exercise training (upper-body strength: 3 RCTs; 136 people; effect size 0.70, 95% CI 0.28 to 1.11; knee extensor strength: 5 RCTs; 202 people; effect size 0.90, 95% CI 0.42 to 1.38). The review did not present a meta-analysis of pulmonary function, maximal exercise capacity, and walking endurance. These outcomes were generally similar with resistance training and no treatment or other exercise training (pulmonary function: 1 RCT; 14 people; FEV₁ effect size –0.22, 95% CI –0.79 to +0.34; forced vital capacity effect size –0.24, 95% CI –0.80 to +0.33; 1 RCT; 48 people; maximal inspiratory pressure effect size –0.40, 95% CI –0.67 to –0.13; maximal expiratory pressure effect size –0.47, 95% CI –0.74 to –0.20; 1 RCT; 62 people; maximal inspiratory pressure effect size 0.57, 95% CI 0.44 to 0.71; maximal exercise capacity: 1 RCT; 45 people; maximal oxygen consumption [VO₂] effect size 0.57, 95% CI 0.34 to 0.80; minute ventilation [VE] effect size 0.49, 95% CI 0.26 to 0.72; 1 RCT; 95 people; VO₂ effect size 0.00, 95% CI –0.19 to +0.19; VE effect size 0.56, 95% CI 0.36 to 0.76; 1 RCT; 72 people; VO₂ effect size –0.11, 95% CI –0.35 to +0.13; VE effect size 0.05, 95% CI –0.19 to +0.28; 1 RCT; 34 people; VO₂ effect size –1.10, 95% CI –1.42 to –0.78; bike effect size 0.36, 95% CI 0.08 to 0.65; 1 RCT; 48 people; VO₂ effect size 0.08, 95% CI –0.18 to +0.34; bike effect size 0.07, 95% CI –0.20 to +0.33; 1 RCT; 62 people; VO₂ effect size 0.14, 95% CI 0.01 to 0.27; bike effect size 0.08, 95% CI –0.05 to +0.21; walking endurance: 1 RCT; 45 people; 6-minute walk test effect size 0.76, 95% CI 0.52 to 1.00; 1 RCT; 50 people; 6-minute walk test effect size 1.49, 95% CI 1.08 to 1.90; 1 RCT; 14 people; 12-minute walk test effect size 0.14, 95% CI –0.41 to +0.71; 1 RCT; 72 people; shuttle walk test effect size 0.28, 95% CI 0.04 to 0.52; 1 RCT; 48 people; 6-minute walk test effect size –0.06, 95% CI –0.33 to +0.20; 1 RCT; 62 people; 6-minute walk test effect size 0.26, 95% CI 0.13 to 0.38). One RCT in the review found that peripheral muscle training improved cycling endurance compared with no treatment, and two RCTs in the review found that endurance training improved cycling endurance compared with peripheral muscle training (1 RCT; 34 people; effect size 4.42, 95% CI 3.46 to 5.38; 1 RCT; 72 people; effect size –1.09; 1 RCT; 48 people; –0.74). One RCT in the review found that peripheral muscle training improved psychological wellbeing compared with before treatment, although four RCTs in the review found similar psychological wellbeing with peripheral muscle treatment and no treatment or other exercise training (36-item short form questionnaire: 1 RCT; 50 people; health-perception effect size 0.22, 95% CI –0.19 to +0.63; health-role effect size 2.03, 95% CI 1.62 to 2.44; emotion effect size 1.39, 95% CI 0.99 to 1.80; mental effect size 1.36, 95% CI 0.95 to 1.77; energy effect size 2.08, 95% CI 1.67 to 2.49; CRQ: 1 RCT; 45 people; shortness of breath effect size –0.12, 95% CI –0.35 to +0.10; emotion effect size 0, 95% CI –0.22 to +0.22; fatigue effect size –0.26, 95% CI –0.49 to –0.04; mastery effect size –0.84, 95% CI –1.08 to –0.59; 1 RCT; 72 people; shortness of breath effect size –0.09, 95% CI –0.33 to +0.15; emotion effect size +0.19, 95% CI –0.04 to +0.43; fatigue effect size –0.10, 95% CI –0.34 to +0.14; mastery effect size 0.00, 95% CI –0.24 to +0.24; 1 RCT; 48 people; total effect size 0, 95% CI –0.26 to +0.26; 1 RCT; 62 people; total effect size 0.37, 95% CI 0.24 to 0.50).

Harms

The review found that no studies reported adverse events or withdrawal caused by adverse effects of peripheral muscle training.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Dec 15;2008:1502.

General physical activity enhancement (alone)

Summary

LUNG FUNCTION AND EXERCISE CAPACITY Compared with control: General physical activity enhancement (walking, cycling, or swimming) may be more effective at improving exercise tolerance ( very low-quality evidence ). 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). 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).

Benefits

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). The review did not present meta-analysis of outcomes. Three RCTs found that physical activity enhancement significantly improved exercise tolerance compared with control (1 RCT; 23 people; 6-minute walk distance: difference 5 m, CI not reported; 1 RCT; 48 people; walking test: difference 5942 joules, CI not reported; 1 RCT; 43 people; walking test: difference 3861 joules, CI not reported; 1 RCT; 58 people; differences reported as significant), but one RCT found no difference (38 people; 6-minute walking test: difference 29 m, CI not reported). One RCT found that physical activity enhancement improved quality of life (1 RCT; 23 people; mean change in Chronic Respiratory Disease Questionnaire [CRQ] score: dyspnoea [range 5–35]: 6 with exercise v 0 with control; fatigue [range 4–28]: 5 with exercise v 0 with control; emotion [range 7–49]: 5 with exercise v 2 with control; mastery [range 4–28]: 4 with exercise v –1 with control; significance not reported for COPD subgroup), but one RCT found no significant difference (1 RCT; 38 people; mean change in the St George's Respiratory Questionnaire total score: –2.1 with exercise v –2.1 with control; difference 0.1, 95% CI –9.9 to + 10.0). One RCT found that physical activity enhancement improved dyspnoea (data reported above), but one RCT found no significant difference (1 RCT; 38 people; mean change in Borg dyspnoea scale after walking test: 0.4 with exercise v 0.9 with control; difference –0.5, 95% CI –1.5 to +0.6).

Harms

The systematic review gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Dec 15;2008:1502.

Maintaining healthy weight

Summary

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 ).

Benefits

Nutritional supplementation versus placebo or usual diet:

We found two systematic reviews. The first systematic 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, triceps skinfold thickness, 6-minute walk distance, FEV₁ , maximal inspiratory pressure, and maximal expiratory pressure 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 0.00 to +0.71; 6-minute walk distance: 3 RCTs; 77 people; SMD –0.01, 95% CI –0.46 to +0.44; FEV₁: 6 RCTs, 156 people; SMD –0.12, 95% CI –0.44 to +0.20; maximal inspiratory pressure: 6 RCTs, 152 people; SMD +0.22, 95% CI –0.10 to +0.55; maximal expiratory pressure: 6 RCTs, 152 people; SMD +0.28, 95% CI –0.05 to +0.60). The second systematic review identified 21 RCTs, which were classified according to the type (different composition of carbohydrates/fat), duration of supplementation (one meal, less than 2 weeks, more than 2 weeks), and presence of anabolic substances. 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 described above. 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).

Harms

The two systematic reviews gave no information on adverse effects.

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. 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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PERMALINK

COPD

Dr Huib AM Kerstjens, MD; PhD

Professor Dirkje S Postma, MD; PhD

Dr Nick ten Hacken, MD; PhD

Roles

Abstract

Introduction

Methods and outcomes

Results

Conclusions

Key Points

About this condition

Definition

Incidence/ Prevalence

Aetiology/ Risk factors

Prognosis

Aims of intervention

Outcomes

Methods

Table.

Glossary

Disclaimer

Contributor Information

References

Anticholinergics (inhaled)

Summary

Benefits

Short-term treatment with anticholinergics versus placebo:

Long-term treatment with tiotropium versus placebo:

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

Inhaled anticholinergic alone versus inhaled anticholinergics plus beta2 agonists:

Inhaled anticholinergics versus beta2 agonists:

Harms

Short-term treatment with anticholinergics versus placebo:

Long-term treatment with tiotropium versus placebo:

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

Inhaled anticholinergic alone versus inhaled anticholinergics plus beta2 agonists:

Inhaled anticholinergics versus beta2 agonists:

Comment

Substantive changes

Beta2 agonists (inhaled)

Summary

Benefits

Short-term treatment with short-acting beta2 agonists versus placebo:

Short-term and long-term treatment with long-acting beta2 agonists versus placebo:

Long-term treatment with short-acting beta2 agonists versus placebo:

Beta2 agonists versus inhaled anticholinergics:

Beta2 agonists alone versus inhaled anticholinergics plus beta2 agonists:

Beta2 agonists alone versus inhaled corticosteroids plus beta2 agonists:

Harms

Short-term treatment with short-acting beta2 agonists versus placebo:

Short-term and long-term treatment with long-acting beta2 agonists versus placebo:

Long-term treatment with short-acting beta2 agonists versus placebo:

Beta2 agonists versus inhaled anticholinergics:

Beta2 agonists alone versus inhaled anticholinergics plus beta2 agonists:

Beta2 agonists alone versus inhaled corticosteroids plus beta2 agonists:

Comment

Substantive changes

Anticholinergics plus beta2 agonists (inhaled)

Summary

Benefits

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

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

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

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

Long-term treatment with anticholinergic plus inhaled beta2 agonists:

Harms

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

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

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

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

Long-term treatment with anticholinergic plus inhaled beta2 agonists:

Comment

Substantive changes

Anticholinergics versus beta2 agonists (inhaled)

Summary

Benefits

Short-acting anticholinergic versus short-acting beta2 agonist:

Short-acting anticholinergic versus long-acting beta2 agonist:

Inhaled anticholinergic alone versus inhaled anticholinergics plus beta₂ agonists:

Inhaled anticholinergics versus beta₂ agonists:

Inhaled anticholinergic alone versus inhaled anticholinergics plus beta₂ agonists:

Inhaled anticholinergics versus beta₂ agonists:

Beta₂ agonists (inhaled)

Short-term treatment with short-acting beta₂ agonists versus placebo:

Short-term and long-term treatment with long-acting beta₂ agonists versus placebo:

Long-term treatment with short-acting beta₂ agonists versus placebo:

Beta₂ agonists versus inhaled anticholinergics:

Beta₂ agonists alone versus inhaled anticholinergics plus beta₂ agonists:

Beta₂ agonists alone versus inhaled corticosteroids plus beta₂ agonists:

Short-term treatment with short-acting beta₂ agonists versus placebo:

Short-term and long-term treatment with long-acting beta₂ agonists versus placebo:

Long-term treatment with short-acting beta₂ agonists versus placebo:

Beta₂ agonists versus inhaled anticholinergics:

Beta₂ agonists alone versus inhaled anticholinergics plus beta₂ agonists:

Beta₂ agonists alone versus inhaled corticosteroids plus beta₂ agonists:

Anticholinergics plus beta₂ agonists (inhaled)

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

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

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

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

Long-term treatment with anticholinergic plus inhaled beta₂ agonists:

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

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

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

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

Long-term treatment with anticholinergic plus inhaled beta₂ agonists:

Anticholinergics versus beta₂ agonists (inhaled)

Short-acting anticholinergic versus short-acting beta₂ agonist:

Short-acting anticholinergic versus long-acting beta₂ agonist:

Long-acting anticholinergic versus short-acting beta₂ agonist:

Long-acting anticholinergic versus long-acting beta₂ agonist:

Short-acting anticholinergic versus short-acting beta₂ agonist:

Short-acting anticholinergic versus long-acting beta₂ agonist:

Long-acting anticholinergic versus short-acting beta₂ agonist:

Long-acting anticholinergic versus long-acting beta₂ agonist:

FEV₁:

Inhaled corticosteroids alone versus inhaled corticosteroids plus beta₂ agonists:

Inhaled corticosteroids alone versus inhaled corticosteroids plus beta₂ agonists:

Corticosteroids plus long-acting beta₂ agonists (inhaled)

Corticosteroid plus long-acting beta₂ agonist versus placebo:

Corticosteroid plus long-acting beta₂ agonist versus corticosteroid alone:

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

Corticosteroid plus long-acting beta₂ agonist versus placebo:

Corticosteroid plus long-acting beta₂ agonist versus corticosteroid alone:

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