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Meta-Analysis
. 2006 Jul 19;2006(3):CD001104.
doi: 10.1002/14651858.CD001104.pub2.

Long-acting beta2-agonists for poorly reversible chronic obstructive pulmonary disease

S Appleton  1 , P Poole, B Smith, A Veale, T J Lasserson, M M Chan
Affiliations
Meta-Analysis

Long-acting beta2-agonists for poorly reversible chronic obstructive pulmonary disease

S Appleton et al. Cochrane Database Syst Rev. .

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterised by partially reversible airflow limitation. Many patients have little reversibility to short acting bronchodilators, but long acting bronchodilators are frequently advocated.

Objectives: To determine the effectiveness of long acting beta-2 adrenoceptor agonists (LABAs) in COPD patients demonstrating poor reversibility to short-acting bronchodilators.

Search strategy: The Cochrane Airways Group Specialised Register was searched ('all years' to 2005) along with the reference lists from identified randomised controlled trials (RCTs).

Selection criteria: All RCTs comparing inhaled LABAs (salmeterol or formoterol) with placebo in the treatment of patients with stable, poorly reversible COPD. Studies were a minimum of four weeks in duration.

Data collection and analysis: Two authors independently performed data extraction and study quality assessment. If we required additional data, we contacted authors and pharmaceutical companies sponsoring the identified RCTs.

Main results: Twenty-three published and unpublished studies (6061 participants) were included in the review. There was a significant change in forced expiratory volume in 1 second (FEV1) in favour of salmeterol 50 mcg twice daily (BID) of 51 mls (95% confidence intervals (CI) 32 to 70), end of study morning peak expiratory flow (PEF) 14.89 L/min (95% CI 10.86 to 18.91). Supplemental short-acting bronchodilator usage was reduced by just under one puff per day. There were significant differences in the total, activity and impact domain scores of the St George's respiratory questionnaire in favour of salmeterol 50 mcg BID. Findings from other health status measurements and symptom scores were conflicting. There was no significant difference in exercise tolerance. The number of participants experiencing exacerbations was significantly reduced with salmeterol 50 mcg treatment compared with placebo (numbers needed to treat to benefit 21).

Authors' conclusions: This review shows that the treatment of patients with COPD with salmeterol 50 mcg produces modest increases in lung function. There were varying effects for other important outcomes such as health related quality of life or reduction in symptoms. However, there was a consistent reduction in exacerbations which may help people with COPD who suffer frequent deterioration of symptoms prompting healthcare utilisation. The strength of evidence for the use of salmeterol 100 mcg, formoterol 12 mcg, 18 mcg, 24 mcg was insufficient to provide clear indications for practice.

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Conflict of interest statement

None known.

Figures

1
1
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
2
2
Forest plot of comparison: 1 Salmeterol (50 mcg) versus placebo, outcome: 1.1 Change in FEV1(mls) from baseline to end of study (parallel study).
3
3
Funnel plot demonstrating the distribution of effect sizes around the 'fixed' effect (vertical dotted line). The 'hollow' dots represent studies which were unpublished, the 'complete' dots represent data from published clinical trials
4
4
Graphic to demonstrate that 24 people with COPD would need to be treated with salmeterol 50mcg BID in order to prevent one exacerbation in the short term.
5
5
Graphic to demonstrate that 46 people with COPD would need to be treated with salmeterol 50mcg BID in order to prevent one withdrawal due to lack of efficacy.
1.1
1.1. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 1 Change in FEV1(mls) from baseline to end of study (parallel study).
1.2
1.2. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 2 Change in FEV1 (% predicted) from baseline to end of study (parallel study).
1.3
1.3. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 3 Pre‐bronchodilator FEV1(L) at end of study (parallel group studies).
1.4
1.4. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 4 FEV1 at end of study (crossover studies).
1.5
1.5. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 5 PEF at end of study (crossover study).
1.6
1.6. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 6 PEF (L/min) at end of study (parallel study).
1.7
1.7. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 7 Change in am PEF (parallel studies).
1.8
1.8. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 8 Change in am PEF (L/min ‐ parallel studies).
1.9
1.9. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 9 Six minute walk test, mean change (m) from baseline to end of study (crossover study).
1.10
1.10. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 10 Six minute walk test, distance (m) at end of study (parallel group studies).
1.11
1.11. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 11 Six minute walk, Borg score (<3) for breathlessness at end of study (parallel study).
1.12
1.12. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 12 Borg Score for dyspnoea, pre‐walk, at end of study (parallel group studies).
1.13
1.13. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 13 Borg Score for dyspnoea, post‐walk, at end of study (parallel group studies).
1.14
1.14. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 14 Change in HRQL from baseline to end of study: SGRQ.
1.15
1.15. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 15 Change in HRQL from baseline to end of study: SF‐36.
1.16
1.16. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 16 Change in HRQL from baseline to end of study: CRDQ.
1.17
1.17. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 17 Total SGRQ score.
1.18
1.18. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 18 HRQL at end of study: SF‐36.
1.19
1.19. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 19 HRQL at end of study: CRDQ scores.
1.20
1.20. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 20 Symptom scores at end of study: Transition Dyspnoea Index (parallel studies).
1.21
1.21. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 21 Symptom Scores at end of study: Baseline Dyspnoea Index (parallel group study).
1.22
1.22. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 22 Symptom Scores.
1.23
1.23. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 23 Symptom Scores‐daytime at end of study.
1.24
1.24. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 24 Symptom Scores‐nighttime at end of study.
1.25
1.25. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 25 Exacerbations, Number of subjects experiencing (parallel study).
1.26
1.26. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 26 Exacerbations, Number of subjects experiencing (cross‐over study).
1.27
1.27. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 27 Exacerbations per participant.
1.28
1.28. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 28 Rescue medication use (number of day time puffs of salbutamol).
1.29
1.29. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 29 Withdrawals due to lack of efficacy.
1.30
1.30. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 30 Rescue medication use (% days with additional salbutamol use).
1.31
1.31. Analysis
Comparison 1 Salmeterol (50 mcg) versus placebo, Outcome 31 Rescue medication use (% nights with additional salbutamol use).
2.1
2.1. Analysis
Comparison 2 Salmeterol (100 mcg) versus placebo, Outcome 1 Change in FEV1(L) from baseline to end of study (parallel study).
2.2
2.2. Analysis
Comparison 2 Salmeterol (100 mcg) versus placebo, Outcome 2 Six minute walk test, Borg score (<3) for breathlessness at end of study (parallel study).
2.3
2.3. Analysis
Comparison 2 Salmeterol (100 mcg) versus placebo, Outcome 3 Change in HRQL from baseline to end of study: SGRQ.
2.4
2.4. Analysis
Comparison 2 Salmeterol (100 mcg) versus placebo, Outcome 4 Change in HRQL from baseline to end of study: SF‐36.
2.5
2.5. Analysis
Comparison 2 Salmeterol (100 mcg) versus placebo, Outcome 5 Exacerbations, number of subjects experiencing.
3.1
3.1. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 1 Change in FEV1(mls) from baseline to end of study.
3.2
3.2. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 2 Change in HRQL from baseline to end of study: SGRQ (total score).
3.3
3.3. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 3 Change in HRQL from baseline to end of study: SGRQ (symptoms).
3.4
3.4. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 4 Change in HRQL from baseline to end of study: SGRQ (activity).
3.5
3.5. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 5 Change in HRQL from baseline to end of study: SGRQ (impact).
3.6
3.6. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 6 Exacerbations, Number of subjects experiencing (parallel study).
3.7
3.7. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 7 Symptom Scores ‐ cough at end of study.
3.8
3.8. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 8 Rescue medication use (end of study).
3.9
3.9. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 9 Morning PEF (L/min) at end of study (parallel study).
3.10
3.10. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 10 Change in clinic PEF (L/min).
3.11
3.11. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 11 Symptom Scores ‐ breathlessness score at end of study.
3.12
3.12. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 12 Symptom scores at end of study: Transition Dyspnoea Index (parallel studies).
3.13
3.13. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 13 Change in supplemental short‐acting beta agonist usage.
3.14
3.14. Analysis
Comparison 3 Salmeterol 50mcg versus placebo: subgroup analyses (reporting of baseline reversibility criteria), Outcome 14 Withdrawals due to lack of efficacy.
4.1
4.1. Analysis
Comparison 4 Formoterol (12mcg) versus placebo, Outcome 1 Pre‐bronchodilator End of study FEV1(L).
4.2
4.2. Analysis
Comparison 4 Formoterol (12mcg) versus placebo, Outcome 2 Pre‐bronchodilator end of study PEF (L/min).
4.3
4.3. Analysis
Comparison 4 Formoterol (12mcg) versus placebo, Outcome 3 Number of subjects experiencing exacerbations over 12 months.
4.4
4.4. Analysis
Comparison 4 Formoterol (12mcg) versus placebo, Outcome 4 Quality of life: change from baseline to end of study SGRQ scores.
5.1
5.1. Analysis
Comparison 5 Formoterol (18mcg) versus placebo, Outcome 1 FEV1‐Mean change from baseline as % or % predicted.
5.2
5.2. Analysis
Comparison 5 Formoterol (18mcg) versus placebo, Outcome 2 FVC‐ Mean change from baseline.
5.3
5.3. Analysis
Comparison 5 Formoterol (18mcg) versus placebo, Outcome 3 Change in PEF (L/min), morning.
5.4
5.4. Analysis
Comparison 5 Formoterol (18mcg) versus placebo, Outcome 4 Shuttle Walking Test Distance (change from baseline).
5.5
5.5. Analysis
Comparison 5 Formoterol (18mcg) versus placebo, Outcome 5 Post shuttle walk test Borg dyspnea score.
5.6
5.6. Analysis
Comparison 5 Formoterol (18mcg) versus placebo, Outcome 6 Rescue medication use.
5.7
5.7. Analysis
Comparison 5 Formoterol (18mcg) versus placebo, Outcome 7 Symptom scores at end of study: change from baseline.
5.8
5.8. Analysis
Comparison 5 Formoterol (18mcg) versus placebo, Outcome 8 Change in quality of life (% units) at end of study: SGRQ.
6.1
6.1. Analysis
Comparison 6 Formoterol (24mcg) versus placebo, Outcome 1 End of study pre‐bronchodilator FEV1(L).
6.2
6.2. Analysis
Comparison 6 Formoterol (24mcg) versus placebo, Outcome 2 Daily morning PEF (L/min).
6.3
6.3. Analysis
Comparison 6 Formoterol (24mcg) versus placebo, Outcome 3 number of subjects experiencing exacrbations over 12 months.
6.4
6.4. Analysis
Comparison 6 Formoterol (24mcg) versus placebo, Outcome 4 Number of subjects experiencing exacerbations over duration of study.
6.5
6.5. Analysis
Comparison 6 Formoterol (24mcg) versus placebo, Outcome 5 Quality of life at 12 months: Change form baseline SGRQ scores.
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References

References to studies included in this review

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    1. Noord JA, Munck DR, Bantje TA, Hop WCJ, Bommer AM. Long‐term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. European Respiratory Journal 2000;15(5):878‐85. - PubMed
Wadbo 2002 {published and unpublished data}
    1. Stahl E, Wadbo M, Bengtsson T, Strom K, Lofdahl C‐G. Health‐related quality of life, symptoms, exercise capacity and lung function during treatment for moderate to severe COPD. Journal of drug assessment 2002;5:81‐94.
    1. Stahl E, Wadbo M, Bengtsson T, Strom K, Lofdahl CG. Health‐related quality of life, symptoms, exercise capacity and lung function during treatment for moderate to severe COPD. Journal of Outcomes Research 2001;5:11‐24.
    1. Wadbo M, Lofdahl CG, Larsson K, Skoogh BE, Tornling G, Arwestrom E, et al. Effects of formoterol and ipratropium bromide in COPD: a 3‐month placebo‐controlled study. European Respiratory Journal 2002;20:1138‐46. - PubMed

References to studies excluded from this review

Aalbers 2002 {published data only}
    1. Aalbers R, Ayres J, Backer V, Decramer M, Lier PA, Magyar P, et al. Formoterol in patients with chronic obstructive pulmonary disease: a randomized, controlled, 3‐month trial. European Respiratory Journal 2002;19:936‐43. - PubMed
Anderson 1997 {published data only}
    1. Anderson WH, Wisniewski M, Anzueto A, Jenkinson S, Goldman M, Ramsdell J, et al. The safety and efficacy of salmeterol in patients with COPD: Results from SLGA4005, a multicentre trial. Chest 1997;112(3 Suppl):79s‐80s.
Bailey 1997 {published data only}
    1. Bailey W, Yancey S, Rickard K. Peak flow and symptom monitoring in COPD: a 12 week comparison of placebo, Atrovent and Serevent. American Journal or Respiratory & Critical Care Medicine 1997;155(4):A278.
Barnes 1993 {published data only}
    1. Barnes NC. New developments in the treatment of asthma and chronic obstructive pulmonary disease. Respiratory Medicine 1993;87(Suppl B):53‐6. - PubMed
Boulet 1992 {published data only}
    1. Boulet LP. Bronchodilator effect of salmeterol and inhibition of bronchial hyperreactivity. Revue des Maladies Respiratoires 1992;9(Suppl 1):R11‐13. - PubMed
Brogden 1992 {published data only}
    1. Brogden RN, Faulds D. Salmeterol xinafoate: Aareview of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Drugs 1991;42(5):895‐912. - PubMed
Brusasco 2003 {published data only}
    1. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58:399‐404. - PMC - PubMed
Calverley 2003a {published and unpublished data}
    1. Borgstrom L, Asking L, Olsson H, Peterson S. Lack of interaction between disease severity and therapeutic response with budesonide/formoterol in a single inhaler [Abstract]. American Thoracic Society 100th International Conference, May 21‐26. 2004:C22, Poster 505.
    1. Calverley PMA, Olsson H, Symbicort International COPD Study Group. Budesonide/formoterol ina single inhaler sustains improvements in lung function over 12 months compared with monocomponents and placebo in patients with COPD [abstract]. American Thoracic Society 99th International Conference. 2003:B024, Poster 418.
    1. Calverley PMA, Peterson S. Combining budesonide/formoterol in a single inhale reduces exacerbation frequency in COPD [abstract]. American Thoracic Society 99th International Conference. 2003:D092, Poster 211.
    1. Calverley PMA, Thompson NC, Olsson H. Budesonide/formoterol in a single inhaler sustains lung function improvements in COPD [Abstract]. European Respiratory Journal 2003;22(Suppl 45):P435.
    1. Calverly PM, Bonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. European Respiratory Journal 2003;22:912‐9. - PubMed
Cazzola 1994 {published data only}
    1. Cazzola M, Santangelo G, Piccolo A, Salzillo A, Matera MG, D'Amato G, et al. Effects of salmeterol and formoterol in patients with chronic obstructive pulmonary disease. Pulmonary Pharmacology 1994;7:103‐7. - PubMed
Cazzola 1995 {published data only}
    1. Cazzola M, Matera MG, Santangelo G, Vinciguerra A, Rossi F, D'Amato G. Salmeterol and formoterol in partially reversible severe chronic obstructive pulmonary disease: a dose‐response study. Respiratory Medicine 1995;89:357‐62. - PubMed
Chazan 1995 {published data only}
    1. Chazan R, Jaworski A, Grubek‐Jaworska H, Droszcz W. Effect of 16 week use of salmeterol on ECP levels, pulmonary function tests and bronchial hyperreactivity in patients with chronic obstructive pulmonary disease. Polski Tygodnik Lekarski 1995;50(40‐44):48‐49. - PubMed
D'Urzo 2001 {published data only}
    1. D'Urzo AD, Salvo MC, Ramirez‐Rivera A, Almeida J, Sichletidis L, Rapatz G, Kottakis J, FOR‐INT‐03 Study Group. In patients with COPD, treatment with a combination of formoterol and ipratropium is more effective than a combination of salbutamol and ipratropium : a 3‐week, randomized, double‐blind, within‐patient, multicenter study. Chest 2001;119(5):1347‐56. - PubMed
Dahl 2001 {published data only}
    1. Dahl R, Greefhorst L, Nowak D, Nonikov V, Byrne A, Thomson M, et al. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. American Journal of Respiratory & Critical Care Medicine 2001;164:778‐84. - PubMed
Del Torre 1992 {published data only}
    1. Torre L, Melica EV, Torre M. Effectiveness of salmeterol in patients with emphysema. Current Therapeutic Research 1992;52(6):888‐98.
Donohue 2002 {published data only}
    1. Donohue J, Bateman E, Lee A, Kesten S. A 6‐month, placebo‐controlled study comparing lung function and health status changes in copd patients treated with tiotropium or salmeterol. Chest 2002;122:47‐55. - PubMed
Germouty 1992 {published data only}
    1. Germouty J, Aubert J, Clavier J, Paramelle B, Voisin C. Tolérance à longe terme du Formotérol chez des bronchopathes chroniques obstructifs. Allergie et Immunologie 1992;24(9):342‐7. - PubMed
Howder 1993 {published data only}
    1. Howder CL. Anti‐muscarinic and Beta2 adrenoceptor bronchodilators in obstructive airways disease. Respiratory Care 1993;38(12):1364‐88.
Joseph 1994 {published data only}
    1. Joseph JC. Chronic obstructive pulmonary disease U.S. Pharmacist 1994;19(12):H3‐14.
Kotaniemi 1994 {published data only}
    1. Kotaniemi JT. Salmeterol in asthma and COPD: a long term follow‐up. American Journal of Critical Care Medicine 1994;149(4):A207.
Mahler 1997 {published data only}
    1. Mahler D, ZuWallach R, Rickard K, Yancey S, Wisniewski M, Anderson W. Effects of salmeterol and ipratropium bromide on dyspnea as measured by the six minute walk and baseline dyspnea index/transitional dyspnea index (BDI/TDI). American Journal of Respiratory & Critical Care Medicine 1997;155:A278.
Maltais 1995 {published data only}
    1. Maltais F, Bourbeau J. Medical management of emphysema. Chest Surgery Clinics of North America 1995;5(4):673‐89. - PubMed
Matera 1995 {published data only}
    1. Matera MG, Cazzola M, Vinciguerraaa A, Perna F, Calderaro F, Caputi M, et al. Comparison of hte bronchodilating effects of salmeterol, salbutamol and ipratropium bromide in patients with chronic obstructive pulmonary disease. Pulmonary Pharmacology 1995;8:267‐71. - PubMed
Matera 1996 {published data only}
    1. Matera MG, Caputi M, Cazzola M. A combination with clinical recommended dosages of salmeterol and ipratropium is not more effective than salmeterol alone in patients with chronic obstructive pulmonary disease. Respiratory Medicine 1996;90:497‐9. - PubMed
Melani 1996 {published data only}
    1. Melani AS, Pirelli M, Gregorio A. Effects of inhaled salmeterol and orally dose‐titrated theophylline on exercise capaity of stable COPD patients. European Respiratory Journal 1996;9:391s.
Newman 1996 {published data only}
    1. Newman AM, Wiggins J, Smith M, Taak NK, Barnes P. Salmeterol xinafoate (100 mcg BD) in the treatment of chronic obstructive pulmonary disease (COPD). European Respiratory Journal 1996;9:183s.
Patakas 1995 {published data only}
    1. Patakas D, Andreadis D, Mavrofridis E, Argyropoulou P, Sarigiannidis A. Comparison of the effect of salmeterol and ipratropium bromide, on exercise performance and breathlessness in patients with chronic obstructive pulmonary disease (COPD). European Respiratory Journal 1995;8(Suppl 19):94s. - PubMed
Pingleton 1996 {published data only}
    1. Pingleton S. Pulmonary Medicine. JAMA 1996;275(23):1849‐50. - PubMed
Ramirez‐Venegas 1997 {published data only}
    1. Ramirez‐Venegas A, Ward J, Lentine T, Mahler D. Salmeterol reduces dyspnea and improves lung function in patients with COPD. Chest 1997;112:336‐40. - PubMed
Schultze‐Wern.1990 {published data only}
    1. Schultze‐Werninghaus G. Multicentre 1‐year trial on Formoterol, a new long acting Beta2‐agonist, in chronic obstructive airways disease. Lung 1990;168(Suppl):83‐9. - PubMed
Schultze‐Wern. 1996 {published data only}
    1. Schultze‐Werninghaus G. Salmeterol, a long‐acting beta2‐agonist in airways obstruction. Effects, side effects and therapeutic assessment [Der langwirksame inhalative Beta2‐agonist Salmeterol bei obstrucktiven Atemwegserkrankungen. Wirkungen, Nebenwirkungen und Stellenwert]. Allegro Journal 1996;5(8):453‐60.
SLMF 4010 {published data only}
    1. SLMF 4010. Multicentre, randomised, parallel group, placebo‐controlled, double‐blind, study, stratified on tobacco status at enrollment, evaluating during 6 months the efficacy of salmeterol powder for inhalation, 50 µg two times per day for the reduction of thoracic distension in subjects with chronic obstructive pulmonary disease (COPD). GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk) 2005.
Szafranski 2003 {published data only}
    1. Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. European Respiratory Journal 2003;21:74‐81. - PubMed
Vollmer 1995a {published data only}
    1. Vollmer M, Schmidt EW, Ulmer WT. Effect duration and treatment effectiveness of salmeterol, fenoterol and salbutamol in severe forms of respiratory tract obstruction. Pneumologie 1995;49(10):528‐34. - PubMed
Vollmer 1995b {published data only}
    1. Vollmer M, Schmidt EW, Ulmer WT. Responder and non‐responder in the bronchodilator test? Variability of short‐term responses to beta2‐adrenoceptor agonists in chronic airways obstruction. Pneumologie 1995;49(11):584‐9. - PubMed

References to studies awaiting assessment

Della Cioppa 2001 {unpublished data only}
    1. Della Cioppa G, Byrne A, Till D, Wood R. Formoterol demonstrates bronchodilator efficacy in patients with reversible or poorly reversible chronic obstructive pulmonary disease, regardless of concomitant corticosteroid use [abstract]. European Respiratory Journal 2001;18(Suppl 33):177s.
Greefhorst 2000 {published data only}
    1. Greefhorst AP, Dahi R, Nowak D, Nonikov V, Byrne A, Colcchio C, et al. Effect of inhaled formoterol and ipratropium bromide on quality of life, "bad days" and exacerbations in patients with COPD. American Thoracic Society 2000 Toronto (Abstracts‐On‐Disk). 2000.
Kristufek 2001 {unpublished data only}
    1. Kristufek P, Levine B, Till D, Byrne A. Inhaled formoterol (Foradil(r)) improves lung function in patients with both reversible and poorly reversible COPD [abstract]. American Journal of Respiratory and Critical Care Medicine 2001;163(5 Suppl):A280.
Littner 2001 {unpublished data only}
    1. Littner M, Yates J, Fischer T, Horstman D, Wire P. Improvements in FEV1 and symptoms in poorly‐reversible COPD patients following 24 weeks of treatment with the salmeterol/fluticasone propionate combination 50/500 BID via the Diskus Inhaler [abstract]. European Respiratory Journal 2001;18(Suppl 33):176s.
Sybrecht 1999 {published data only}
    1. Sybrecht GW. Inhaled formoterol was an effective and safe treatment in COPD patients. European Respiratory Society Annual Congress (Abstracts‐on‐Disk). 1999:P2510.

References to ongoing studies

TORCH {published data only}
    1. The TORCH Study Group. The TORCH (TOwards a Revolution in COPD Health) survival study protocol. European Respiratory Journal 2004;24:206‐10. - PubMed

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