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Meta-Analysis
. 2013 Oct 15;2013(10):CD010177.
doi: 10.1002/14651858.CD010177.pub2.

Long-acting beta2-agonists for chronic obstructive pulmonary disease

Kayleigh M Kew  1 , Chris Mavergames, Julia A E Walters
Affiliations
Meta-Analysis

Long-acting beta2-agonists for chronic obstructive pulmonary disease

Kayleigh M Kew et al. Cochrane Database Syst Rev. .

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a respiratory disease that causes progressive symptoms of breathlessness, cough and mucus build-up. It is the fourth or fifth most common cause of death worldwide and is associated with significant healthcare costs.Inhaled long-acting beta2-agonists (LABAs) are widely prescribed to manage the symptoms of COPD when short-acting agents alone are no longer sufficient. Twice-daily treatment with an inhaled LABA is aimed at relieving symptoms, improving exercise tolerance and quality of life, slowing decline and even improving lung function and preventing and treating exacerbations.

Objectives: To assess the effects of twice-daily long-acting beta2-agonists compared with placebo for patients with COPD on the basis of clinically important endpoints, primarily quality of life and COPD exacerbations.

Search methods: We searched the Cochrane Airways Group trials register, ClinicalTrials.gov and manufacturers' websites in June 2013.

Selection criteria: Parallel, randomised controlled trials (RCTs) recruiting populations of patients with chronic obstructive pulmonary disease. Studies were required to be at least 12 weeks in duration and designed to assess the safety and efficacy of a long-acting beta2-agonist against placebo.

Data collection and analysis: Data and characteristics were extracted independently by two review authors, and each study was assessed for potential sources of bias. Data for all outcomes were pooled and subgrouped by LABA agent (formoterol 12 μg, formoterol 24 μg and salmeterol 50 μg) and then were separately analysed by LABA agent and subgrouped by trial duration. Sensitivity analyses were conducted for the proportion of participants taking inhaled corticosteroids and for studies with high or uneven rates of attrition.

Main results: Twenty-six RCTs met the inclusion criteria, randomly assigning 14,939 people with COPD to receive twice-daily LABA or placebo. Study duration ranged from three months to three years; the median duration was six months. Participants were more often male with moderate to severe symptoms at randomisation; mean forced expiratory volume in 1 second (FEV1) was between 33% and 55% predicted normal in the studies, and mean St George's Respiratory Questionnaire score (SGRQ) ranged from 44 to 55 when reported.Moderate-quality evidence showed that LABA treatment improved quality of life on the SGRQ (mean difference (MD) -2.32, 95% confidence interval (CI) -3.09 to -1.54; I(2) = 50%; 17 trials including 11,397 people) and reduced the number of exacerbations requiring hospitalisation (odds ratio (OR) 0.73, 95% CI 0.56 to 0.95; I(2) = 10%; seven trials including 3804 people). In absolute terms, 18 fewer people per 1000 were hospitalised as the result of an exacerbation while receiving LABA therapy over a weighted mean of 7 months (95% CI 3 to 31 fewer). Scores were also improved on the Chronic Respiratory Disease Questionnaire (CRQ), and more people receiving LABA treatment showed clinically important improvement of at least four points on the SGRQ.The number of people who had exacerbations requiring a course of oral steroids or antibiotics was also lower among those taking LABA (52 fewer per 1000 treated over 8 months; 95% CI 24 to 78 fewer, moderate quality evidence).Mortality was low, and combined findings of all studies showed that LABA therapy did not significantly affect mortality (OR 0.90, 95% CI 0.75 to 1.08; I(2) = 21%; 23 trials including 14,079 people, moderate quality evidence). LABA therapy did not affect the rate of serious adverse events (OR 0.97, 95% CI 0.83 to 1.14; I(2) = 34%, moderate quality evidence), although there was significant unexplained heterogeneity, especially between the two formoterol doses.LABA therapy improved predose FEV1 by 73 mL more than placebo (95% CI 48 to 98; I(2) = 71%, low quality evidence), and people were more likely to withdraw from placebo than from LABA therapy (OR 0.74, 95% CI 0.69 to 0.80; I(2) = 0%). Higher rates of withdrawal in the placebo arm may reduce our confidence in some results, but the disparity is more likely to reduce the magnitude of difference between LABA and placebo than inflate the true effect; removing studies at highest risk of bias on the basis of high and unbalanced attrition did not change conclusions for the primary outcomes.

Authors' conclusions: Moderate-quality evidence from 26 studies showed that inhaled long-acting beta2-agonists are effective over the medium and long term for patients with moderate to severe COPD. Their use is associated with improved quality of life and reduced exacerbations, including those requiring hospitalisation. Overall, findings showed that inhaled LABAs did not significantly reduce mortality or serious adverse events.

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Conflict of interest statement

None known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Funnel plot of comparison: 1 All LABA versus placebo [subgrouped by drug], outcome: 1.1 Quality of life (SGRQ total score).
4
4
Funnel plot of comparison: 1 All LABA versus placebo [subgrouped by drug], outcome: 1.4 Severe exacerbations (hospitalisations).
1.1
1.1. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 1 Quality of life (SGRQ total score).
1.2
1.2. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 2 Quality of life (number of people achieving the MCID on the SGRQ).
1.3
1.3. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 3 Quality of life (CRQ).
1.4
1.4. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 4 Severe exacerbations (hospitalisations).
1.5
1.5. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 5 Severe/moderate exacerbations (hospitalisation or course of meds or ER visit.
1.6
1.6. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 6 Moderate exacerbations (course of antibiotics and/or steroids).
1.7
1.7. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 7 Mortality (all‐cause).
1.8
1.8. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 8 People with one or more non‐fatal serious adverse event.
1.9
1.9. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 9 Predose FEV1 (mL).
1.10
1.10. Analysis
Comparison 1 All LABA versus placebo [subgrouped by drug], Outcome 10 Withdrawal.
2.1
2.1. Analysis
Comparison 2 Formoterol 12 μg versus placebo [subgrouped by trial duration], Outcome 1 Quality of life (SGRQ).
2.2
2.2. Analysis
Comparison 2 Formoterol 12 μg versus placebo [subgrouped by trial duration], Outcome 2 Severe exacerbations (hospitalisations).
2.3
2.3. Analysis
Comparison 2 Formoterol 12 μg versus placebo [subgrouped by trial duration], Outcome 3 Moderate exacerbations (course of antibiotics and/or steroids).
2.4
2.4. Analysis
Comparison 2 Formoterol 12 μg versus placebo [subgrouped by trial duration], Outcome 4 Mortality (all‐cause).
2.5
2.5. Analysis
Comparison 2 Formoterol 12 μg versus placebo [subgrouped by trial duration], Outcome 5 Patients with one or more serious adverse event.
2.6
2.6. Analysis
Comparison 2 Formoterol 12 μg versus placebo [subgrouped by trial duration], Outcome 6 Predose FEV1 (mL).
2.7
2.7. Analysis
Comparison 2 Formoterol 12 μg versus placebo [subgrouped by trial duration], Outcome 7 Withdrawal.
3.1
3.1. Analysis
Comparison 3 Formoterol 24 μg versus placebo [subgrouped by trial duration], Outcome 1 Quality of life (SGRQ).
3.2
3.2. Analysis
Comparison 3 Formoterol 24 μg versus placebo [subgrouped by trial duration], Outcome 2 Severe exacerbations (hospitalisations).
3.3
3.3. Analysis
Comparison 3 Formoterol 24 μg versus placebo [subgrouped by trial duration], Outcome 3 Moderate exacerbations (course of antibiotics and/or steroids).
3.4
3.4. Analysis
Comparison 3 Formoterol 24 μg versus placebo [subgrouped by trial duration], Outcome 4 Mortality (all‐cause).
3.5
3.5. Analysis
Comparison 3 Formoterol 24 μg versus placebo [subgrouped by trial duration], Outcome 5 People with one or more non‐fatal serious adverse events.
3.6
3.6. Analysis
Comparison 3 Formoterol 24 μg versus placebo [subgrouped by trial duration], Outcome 6 Withdrawal.
4.1
4.1. Analysis
Comparison 4 Salmeterol 50 μg versus placebo [subgrouped by trial duration], Outcome 1 Quality of life (SGRQ).
4.2
4.2. Analysis
Comparison 4 Salmeterol 50 μg versus placebo [subgrouped by trial duration], Outcome 2 Severe exacerbations (hospitalisations).
4.3
4.3. Analysis
Comparison 4 Salmeterol 50 μg versus placebo [subgrouped by trial duration], Outcome 3 Moderate exacerbations (course of antibiotics and/or steroids).
4.4
4.4. Analysis
Comparison 4 Salmeterol 50 μg versus placebo [subgrouped by trial duration], Outcome 4 Mortality (all‐cause).
4.5
4.5. Analysis
Comparison 4 Salmeterol 50 μg versus placebo [subgrouped by trial duration], Outcome 5 People with one or more non‐fatal serious adverse events.
4.6
4.6. Analysis
Comparison 4 Salmeterol 50 μg versus placebo [subgrouped by trial duration], Outcome 6 Predose FEV1 (mL).
4.7
4.7. Analysis
Comparison 4 Salmeterol 50 μg versus placebo [subgrouped by trial duration], Outcome 7 Withdrawal.
5.1
5.1. Analysis
Comparison 5 [Sensitivity analysis—ICS use] All LABA versus placebo, Outcome 1 Quality of life (SGRQ).
5.2
5.2. Analysis
Comparison 5 [Sensitivity analysis—ICS use] All LABA versus placebo, Outcome 2 Severe exacerbations (hospitalisations).
6.1
6.1. Analysis
Comparison 6 [Sensitivity analysis—attrition] All LABA versus placebo, Outcome 1 Quality of life (SGRQ).
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD010177

References

References to studies included in this review

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Campbell 2005 {published data only}
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Dahl 2001 {published data only}
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Dahl 2010 {published data only}
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Doherty 2012 {published data only}
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Hanania 2003 {published data only}
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Hanrahan 2008 {published data only}
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Mahler 1999 {published data only}
    1. Ferguson G, Funck‐Brentano C, Fischer T, Darken P, Troy S, Compton C, et al. Cardiovascular safety of salmeterol in patients with COPD. American Journal of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A228.
    1. Ferguson GT, Funck‐Brentano C, Fischer T, Darken P, Reisner C. Cardiovascular safety of salmeterol in COPD. Chest 2003;123(6):1817‐24. - PubMed
    1. GlaxoSmithKline. A randomized, double‐blind, double‐dummy, comparative clinical trial of 12‐week courses of salmeterol xinafoate versus ipratropium bromide versus placebo (PRN Ventolin) in subjects with chronic obstructive pulmonary disease. SLGA4005. www.gsk‐clinicalstudyregister.com (accessed 20 December 2012).
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Mahler 2002 {published data only}
    1. Ferguson G, Funck‐Brentano C, Fischer T, Darken P, Troy S, Compton C, et al. Cardiovascular safety of salmeterol in patients with COPD. American Journal of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A228.
    1. Ferguson GT, Funck‐Brentano C, Fischer T, Darken P, Reisner C. Cardiovascular safety of salmeterol in COPD. Chest 2003;123(6):1817‐24. - PubMed
    1. GlaxoSmithKline. A randomized, double‐blind, placebo‐controlled, parallel‐group trial evaluating the safety and efficacy of the DISKUS formulations of salmeterol (SAL) 50mcg BID and fluticasone propionate (FP) 500mcg BID individually and in combination as salmeterol 50mcg/fluticasone propionate 500mcg BID (SFC 50/500) compared to placebo in COPD subjects. SFCA3006. www.gsk‐clinicalstudyregister.com (accessed 10 December 2012).
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Nelson 2007 {published data only}
    1. Gross NJ, Lapidus R, Dunn LJ, Lynn LD, Denis‐Mize K, Rinehart M. Nebulized formoterol is an effective bronchodilator and improves the quality of life for COPD patients [Abstract]. American Thoracic Society International Conference; 2007 May 18‐23; San Francisco, Poster A10.
    1. Gross NJ, Nelson HS, Lapidus RJ, Dunn L, Lynn L, Rinehart M, et al. Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients. Respiratory Medicine 2008;102(2):189‐97. - PubMed
    1. Nelson HS, Gross NJ, Levine B, Kerwin EM, Rinehart M, Denis‐Mize K, et al. Cardiac safety profile of nebulized formoterol in adults with COPD: a 12‐week, multicenter, randomized, double‐blind, double‐dummy, placebo‐ and active‐controlled trial. Clinical Therapeutics 2007;29(10):2167‐78. - PubMed
    1. Nelson HS, Gross NJ, Rinehart M, Denis‐Mize K. Cardiovascular safety of nebulized formoterol in COPD patients: a double‐blind, placebo‐controlled study. Chest 2007;132(4):529b‐530.
    1. Nelson HS, ZuWallack R, Levine B, Kerwin EM, Denis‐Mize K, Rinehart M. Safety profile of formoterol fumarate delivered by nebulization to COPD patients [Abstract]. American Thoracic Society International Conference; 2007 May 18‐23; San Francisco, Poster A11.
Rennard 2001 {published data only}
    1. Ferguson G, Funck‐Brentano C, Fischer T, Darken P, Troy S, Compton C, et al. Cardiovascular safety of salmeterol in patients with COPD. American Journal of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A228.
    1. Ferguson GT, Funck‐Brentano C, Fischer T, Darken P, Reisner C. Cardiovascular safety of salmeterol in COPD. Chest 2003;123(6):1817‐24. - PubMed
    1. GlaxoSmithKline. A randomized, double‐blind, double‐dummy, comparative clinical trial of 12‐week courses of salmeterol xinafoate versus ipratropium bromide versus placebo (PRN Ventolin®) in subjects with chronic obstructive pulmonary disease. SLGA4004. www.gsk‐clinicalstudyregister.com (accessed 7 December 2012).
    1. Rennard SI, Anderson W, ZuWallack R, Broughton J, Bailey W, Friedman M, et al. Use of a long‐acting inhaled beta2‐adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2001;163(5):1087‐92. - PubMed
Rennard 2009 {published data only}
    1. Bleecker ER, Meyers DA, Bailey WC, Sims AM, Bujac SR, Goldman M, et al. ADRB2 polymorphisms and budesonide/formoterol responses in COPD. Chest 2012;142(2):320‐8. [1931‐3543: (Electronic)] - PMC - PubMed
    1. Celli BR, Tashkin DP, Rennard SI, McElhattan J, Martin UJ. Bronchodilator responsiveness and onset of effect with budesonide/formoterol pMDI in COPD. Respiratory Medicine 2011;105(8):1176‐88. - PubMed
    1. Laties A, Rennard SI, Tashkin DP, Suchower LJ, Martin UJ. Effect of budesonide/formoterol pressurized metered‐dose inhaler (bud/fm pMDI) on ophthalmologic assessments in moderate to very severe chronic obstructive pulmonary disease (COPD) patients: results from a 1‐year, randomized, controlled clinical trial [Abstract]. Chest 2010;138(4):468A.
    1. Nelson HS, Tashkin DP, Rennard SI, Martin P, Goldman M, Silkoff PE. Onset of bronchodilation with budesonide and formoterol administered in one pressurized metered‐dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease [Abstract]. Chest 2008;134(4):105002s. - PubMed
    1. Rennard SI, Tashkin DP, McElhattan J, Goldman M, Ramachandran S, Martin UJ, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered‐dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1‐year randomized controlled clinical trial. Drugs 2009;69(5):549‐65. [0012‐6667] - PMC - PubMed
Rossi 2002 {published data only}
    1. Amgott TR, Kristufek P, Levine B, Byrne A, Till D. Effect of inhaled formoterol and oral slow‐release theophylline on peak expiratory flow and symptoms in patients with COPD. American Journal of Respiratory and Critical Care Medicine 2000;161(Suppl 3):A582.
    1. Kristufek P, Amgott TR, Levine B, Byrne A, Colacchio C. Comparison of the efficacy and safety of inhaled formoterol dry powder and oral slow‐release theophylline in patients with COPD. American Journal of Respiratory and Critical Care Medicine 2000;161(Suppl 3):A489.
    1. Kristufek P, Levine B, Della Cioppa G, Byrne A, Till D. Bronchodilatory effects of formoterol in patients with chronic obstructive pulmonary disease (COPD) are not influenced by concomitant corticosteroid use. European Respiratory Journal 2001;18(Suppl 33):514s.
    1. Kristufek P, Levine B, Till D, Byrne A. Inhaled formoterol (Foradil®) improves lung function in patients with both reversible and poorly reversible COPD. American Journal of Respiratory and Critical Care Medicine 2001;163(Suppl 5):A280.
    1. Rossi A, Kristufek P, Levine BE, Thomson MH, Till D, Kottakis J, et al. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow‐release theophylline in the treatment of COPD. Chest 2002;121(4):1058‐69. [0012‐3692] - PubMed
SLMF4010 2005 {published data only}
    1. GlaxoSmithKline. Multicentre, randomised, parallel group, placebo‐controlled, double‐blind study, stratified on tobacco status at enrolment, evaluating during 6 months the efficacy of salmeterol powder for inhalation, 50µg two times per day for the reduction of thoracic distension in subjects with chronic obstructive pulmonary disease (COPD). SLMF4010. www.gsk‐clinicalstudyregister.com (accessed 9 December 2012).
Szafranski 2003 {published data only}
    1. Anderson P. Budesonide/formoterol in a single inhaler (Symbicort®) provides early and sustained improvement in lung function in moderate to severe COPD. Thorax 2002;57(Suppl 3):iii43.
    1. AstraZeneca SD. A placebo‐controlled 12 month efficacy study of the fixed combination budesonide/formoterol compared with budesonide and formoterol as monotherapies in patients with chronic obstructive pulmonary disease (COPD). SD‐039‐CR‐0629. http://www.astrazenecaclinicaltrials.com/ (accessed 25 November 2012).
    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; 2004 May 21‐26; Orlando, C22 Poster 505.
    1. Calverley P, Pauwels Dagger R, Lofdahl CG, Svensson K, Higenbottam T, Carlsson LG, et al. Relationship between respiratory symptoms and medical treatment in exacerbations of COPD. European Respiratory Journal 2005;26(3):406‐13. [0903‐1936] - PubMed
    1. Calverley PM, Szafranski W, Andersson. Budesonide/formoterol is a well‐tolerated long term maintenance therapy for COPD [Abstract]. European Respiratory Journal 2005;26(Suppl 49):Abstract 1917.
Tashkin 2008 [SHINE] {published data only}
    1. AstraZeneca. A 6‐month double‐blind, double‐dummy, randomized, parallel group, multicenter efficacy & safety study of SYMBICORT® pMDI 2 x 160/4.5mg & 80/4.5mg bid compared to formoterol TBH, budesonide pMDI (& the combination) & placebo in COPD patients. D5899C00002. http://www.astrazenecaclinicaltrials.com/ (accessed23 November 2012).
    1. Bleecker ER, Meyers DA, Bailey WC, Sims AM, Bujac SR, Goldman M, et al. Effect of β2‐adrenergic receptor gene polymorphism Gly16Arg on response to budesonide/formoterol pressurized metered‐dose inhaler in chronic obstructive pulmonary disease [Abstract]. American Journal of Respiratory and Critical Care Medicine 2011;183:A4086.
    1. Celli BR, Tashkin DP, Rennard SI, McElhattan J, Martin UJ. Bronchodilator responsiveness and onset of effect with budesonide/formoterol pMDI in COPD. Respiratory Medicine 2011;105(8):1176‐88. - PubMed
    1. Nelson HS, Tashkin DP, Rennard SI, Martin P, Goldman M, Silkoff PE. Onset of bronchodilation with budesonide and formoterol administered in one pressurized metered‐dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease [Abstract]. Chest 2008;134(4):105002s. - PubMed
    1. Tashkin DP, Rennard SI, Martin P, Goldman M, Silkoff PE. Efficacy of budesonide/formoterol administered via one pressurized metered‐dose inhaler over 6 months in patients with chronic obstructive pulmonary disease [Abstract]. Chest 2008;134(4):105001s.
Tashkin 2012 {published data only}
    1. Doherty D, Tashkin D, Kerwin E, Eduardo Matiz‐Bueno C, Shekar T, Banerjee S, et al. Efficacy and safety of mometasone furoate/formoterol in subjects with moderate to very severe chronic obstructive pulmonary disease: results from two phase three 26‐week trials [Abstract]. Chest 2011;140(4):535A.
    1. Kerwin E, Tashkin D, Matiz‐Bueno CE, Doherty D, Shekar T, Banerjee S, et al. Quality of life following 26 weeks of mometasone furoate/formoterol therapy: results from two phase three trials in subjects with moderate to very severe chronic obstructive pulmonary disease [Abstract]. Chest 2011;140(4):558A.
    1. Matiz‐Bueno CE, Doherty D, Kerwin E, Tashkin D, Shekar T, Banerjee S, et al. The long‐term safety characteristics of mometasone furoate/formoterol for the treatment of moderate to very severe chronic obstructive pulmonary disease: pooled findings from two 1‐year multicenter clinical trials [Abstract]. Chest 2011;140(4):548A.
    1. Tashkin D, Doherty D, Kerwin E, Matiz‐Bueno CE, Shekar T, Banerjee S, et al. The effect of mometasone furoate/formoterol combination therapy on chronic obstructive pulmonary disease (COPD) exacerbations: results from two phase three trials in subjects with moderate to very severe COPD [Abstract]. Chest 2011;140(4):549A.
    1. Tashkin DP, Doherty DE, Kerwin E, Matiz‐Bueno CE, Knorr B, Shekar T, et al. Efficacy and safety characteristics of mometasone furoate/formoterol fumarate fixed‐dose combination in subjects with moderate to very severe COPD: findings from pooled analysis of two randomized, 52‐week placebo‐controlled trials. International Journal of COPD 2012;7:73‐86. - PMC - PubMed
Vogelmeier 2008 {published data only}
    1. Arievich H, Potena A, Fonay K, Vogelmeier CF, Overend T, Smith J, et al. Formoterol given either alone or together with tiotropium reduces the rate of exacerbations in stable COPD patients [Abstract]. European Respiratory Journal 2006;28(Suppl 50):440s [P2514].
    1. Vogelmeier C, Kardos P, Harari S, Gans SJ, Stenglein S, Thirlwell J. Formoterol mono‐ and combination therapy with tiotropium in patients with COPD: a 6‐month study. Respiratory Medicine 2008;102(11):1511‐20. - PubMed
    1. Vogelmeier CF, Harari SA, Fonay K, Beier J, Overend T, Till D, et al. Formoterol and tiotropium both improve lung function in stable COPD patients with some additional benefit when given together [Abstract]. European Respiratory Journal 2006;28(Suppl 50):429s [P2506].
Wadbo 2002 {published data only}
    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(5):1138‐46. [0903‐1936] - PubMed
Watkins 2002 {published data only}
    1. Watkins M, Wire P, Yates J, Fischer T, Chang C, Horstman D, et al. Sustained Fev increases in COPD patients induced by Salmeterol 50 mcg twice daily via the diskus inhaler. American Journal of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A228. - PubMed

References to studies excluded from this review

Boyd 1995 {published data only}
    1. Boyd G, Crawford C. Salmeterol (SALM) for treatment of patients with chronic obstructive pulmonary disease (COPD). European Respiratory Journal 1995;8(Suppl 19):167S. - PubMed
    1. Boyd G, Morice AH, Pounsford JC, Siebert M, Peslis N, Crawford C. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD) [published erratum appears in European Respiratory Journal 1997 Jul;10(7):1696]. European Respiratory Journal 1997;10(4):815‐21. - PubMed
    1. GlaxoSmithKline. A multicentre, randomised, double‐blind, parallel group study to compare the efficacy and safety of inhaled salmeterol xinafoate 50 microg bd and inhaled salmeterol xinafoate 100 microg bd with placebo, all administered via the metered‐dose inhaler, in the treatment of patients with chronic obstructive pulmonary disease. www.gsk‐clinicalstudyregister.com (accessed 11 December 2012).
    1. Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. American Journal of Respiratory and Critical Care Medicine 1997;155(4):1283‐9. - PubMed
    1. Jones PW, Wilson K, Sondhi S. Cost‐effectiveness of salmeterol in patients with chronic obstructive pulmonary disease: An economic evaluation. Respiratory Medicine 2003;97(1):20‐6. [0954‐6111] - PubMed
Celli 2003 {published data only}
    1. Celli B, Halpin D, Hepburn R, Byrne N, Keating ET, Goldman M. Symptoms are an important outcome in chronic obstructive pulmonary disease clinical trials: results of a 3‐month comparative study using the Breathlessness, Cough and Sputum Scale (BCSS). Respiratory Medicine 2003;97(Suppl A):S35‐43. [0954‐6111] - PubMed
Chapman 2002 {published data only}
    1. Chapman K, Kuipers AF, Goldstein R, James MH. The addition of salmeterol 50mcg bid to anticholinergic treatment in COPD [Abstract]. American Journal of Respiratory and Critical Care Medicine 1999;159(3):A523.
    1. Chapman KR, Arvidsson P, Chuchalin AG, Dhillon DP, Faurschou P, Goldstein RS, et al. The addition of salmeterol 50 microg bid to anticholinergic treatment in patients with COPD: a randomized, placebo controlled trial. Chronic obstructive pulmonary disease. Canadian Respiratory Journal 2002;9(3):178‐85. [1198‐2241] - PubMed
    1. GlaxoSmithKline. A multi‐centre, double‐blind, parallel group study to evaluate the efficacy of SEREVENT 50 microg BID versus placebo BID all administered via the multi dose powder inhaler (DISKUS/ACCUHALERÆË) in terms of symptoms in the treatment of patients with chronic obstructive pulmonary disease. www.gsk‐clinicalstudyregister.com (accessed 15 December 2012).
Dal Negro 2003 {published data only}
    1. Dal Negro R, Micheletto C, Trevisan F, Tognella S, Pomari C. Salmeterol & fluticasone 50 µg/250 µg bid vs salmeterol 50µg bid and vs placebo in the long‐term treatment of COPD. American Journal of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A228.
    1. Dal Negro RW, Pomari C, Tognella S, Micheletto C. Salmeterol & fluticasone 50 mug/250 mug bid in combination provides a better long‐term control than salmeterol 50 mug bid alone and placebo in COPD patients already treated with theophylline. Pulmonary Pharmacology and Therapeutics 2003;16(4):241‐6. - PubMed
Rutten‐van Molken 1999 {published data only}
    1. GlaxoSmithKline. Long‐term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. www.gsk‐clinicalstudyregister.com (accessed 8 December 2012).
    1. Rutten‐van Molken M, Roos B, Noord JA. An empirical comparison of the St George's Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Disease Questionnaire (CRQ) in a clinical trial setting. Thorax 1999;54(11):995‐1003. - PMC - PubMed
    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. Noord JA, Munck D, Bantje TA, Hop WCJ, Bommer AM. Efficacy and safety of salmeterol (SLM) and ipratropium bromide (IPB) in patients with chronic obstructive pulmonary disease (COPD). American Journal of Respiratory and Critical Care Medicine 1998;157(Suppl 3):A799.
    1. Noord JA, Munck DR, Bantje TA, Hop WC, Akveld ML, 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
Steffensen 1996 {published data only}
    1. Steffensen I, Faurschou P, Riska H, Rostrup J, Wegener T. Inhaled formoterol dry powder in the treatment of patients with reversible obstructive airway disease. A 3‐month, placebo‐controlled comparison of the efficacy and safety of formoterol and salbutamol, followed by a 12‐month trial with formoterol. Allergy 1995;50(8):657‐63. [0105‐4538: (Print)] - PubMed
    1. Steffensen IE, Faurschou P. Formoterol as inhalation powder in the treatment of patients with reversible obstructive lung diseases. A 3‐month placebo‐controlled comparison of the effects of formoterol and salbutamol, followed by a 12‐month period with formoterol alone. Ugeskr‐Laeger 1996;158(49):7092‐6. - PubMed
Stockley 2006 {published data only}
    1. GlaxoSmithKline. A multi‐centre, randomised, double‐blind, placebo‐controlled, parallel‐group study to investigate the effect of 12 months treatment with salmeterol (50mcg bd), delivered via the DISKUS* inhaler, on the incidence of moderate and severe exacerbations in subjects with chronic obstructive pulmonary disease (COPD) when added to their usual treatment regimen. www.gsk‐clinicalstudyregister.com (accessed 8 December 2012).
    1. Stockley R, Davis EA, Sondhi S, Rice L. [Salmeterol provides sustained health status improvement over 12 months in patients with COPD [abstract]]. European Respiratory Society Annual Congress; 2002 Sep 14‐18; Stockholm, Abstract P1567.
    1. Stockley R, Rice L, Chopra N. [Salmeterol added to usual therapy gives a rapid improvement in lung function that is sustained at 6 and 12 months in patients with COPD [abstract]]. American Thoracic Society 99th International Conference; 2003 May 16‐21; Seattle, A035 Poster D71.
    1. Stockley R, Rice L, Chopra N. [Salmeterol added to usual therapy significantly reduces the frequency of moderate/severe exacerbations in patients with COPD [abstract]]. American Thoracic Society 99th International Conference; 2003 May 16‐21; Seattle, A108 Poster C51.
    1. Stockley RA, Chopra N. [Salmeterol, added to usual therapy, is an effective bronchodilator over 12 months of treatment in chronic obstructive pulmonary disease (COPD) [abstract]]. European Respiratory Society Annual Congress; 2002 Sep 14‐18; Stockholm, Abstract P1568.

References to studies awaiting assessment

Fattore 2005 {published data only}
    1. Fattore G, Torbica A, Mangone M. Cost‐analysis of four treatment strategies in the management of moderate‐to‐severe COPD: an application of non‐parametric bootstrap. [Italian]. Pharmacoeconomics Italian Research Articles 2005; Vol. 7, issue 2:135‐43. [1590‐9158]

References to ongoing studies

NCT01437397 {unpublished data only}
    1. NCT01437397. Efficacy, safety and tolerability of aclidinium bromide/formoterol fumarate compared with formoterol fumarate in patients with moderate to severe chronic obstructive pulmonary disease (COPD) (LAC). clinicaltrials.gov (accessed 30 July 2013).
NCT01572792 {unpublished data only}
    1. NCT01572792. Efficacy, safety and tolerability of two fixed dose combinations of aclidinium bromide/formoterol fumarate, aclidinium bromide, formoterol fumarate and placebo for 28‐weeks treatment in patients with moderate to severe, stable chronic obstructive pulmonary disease (COPD). clinicaltrials.gov (accessed 30 July 2013).

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