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. 2013 Nov 10;2013(11):CD003794.
doi: 10.1002/14651858.CD003794.pub4.

Combined corticosteroid and long-acting beta₂-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease

Luis Javier Nannini  1 , Phillippa Poole, Stephen J Milan, Rebecca Holmes, Rebecca Normansell
Affiliations

Combined corticosteroid and long-acting beta₂-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease

Luis Javier Nannini et al. Cochrane Database Syst Rev. .

Abstract

Background: Both long-acting beta2-agonists (LABA) and inhaled corticosteroids (ICS) have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their coadministration in a combination inhaler may facilitate adherence to medication regimens and improve efficacy.

Objectives: To determine the efficacy and safety of combined ICS and LABA for stable COPD in comparison with placebo.

Search methods: We searched the Cochrane Airways Group Specialised Register of trials, reference lists of included studies and manufacturers' trial registries. The date of the most recent search was June 2013.

Selection criteria: We included randomised and double-blind studies of at least four weeks' duration. Eligible studies compared combined ICS and LABA preparations with placebo.

Data collection and analysis: Two review authors independently assessed study risk of bias and extracted data. Dichotomous data were analysed as fixed-effect odds ratios (OR) or rate ratios (RR) with 95% confidence intervals (95% CI), and continuous data as mean differences with 95% confidence intervals.

Main results: Nineteen studies met the inclusion criteria (with 10,400 participants randomly assigned, lasting between 4 and 156 weeks, mean 42 weeks). Studies used three different combined preparations (fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol). The studies were generally at low risk of bias for blinding but at unclear or high risk for attrition bias because of participant dropouts. Compared with placebo, both fluticasone/salmeterol and budesonide/formoterol reduced the rate of exacerbations. Mometasone/formoterol reduced the number of participants experiencing one or more exacerbation. Pooled analysis of the combined therapies indicated that exacerbations were less frequent when compared with placebo (Rate Ratio 0.73; 95% CI 0.69 to 0.78, 7 studies, 7495 participants); the quality of this evidence when GRADE criteria were applied was rated as moderate. Participants included in these trials had on average one or two exacerbations per year, which means that treatment with combined therapy would lead to a reduction of one exacerbation every two to four years in these individuals. An overall reduction in mortality was seen, but this outcome was dominated by the results of one study (TORCH) of fluticasone/salmeterol. Generally, deaths in the smaller, shorter studies were too few to contribute to the overall estimate. Further longer studies on budesonide/formoterol and mometasone/formoterol are required to clarify whether this is seen more widely. When a baseline risk of death of 15.2% from the placebo arm of TORCH was used, the three-year number needed to treat for an additional beneficial outcome (NNTB) with fluticasone/salmeterol to prevent one extra death was 42 (95% CI 24 to 775). All three combined treatments led to statistically significant improvement in health status measurements, although the mean differences observed are relatively small in relation to the minimum clinically important difference. Furthermore, symptoms and lung function assessments favoured combined treatments. An increase in the risk of pneumonia was noted with combined inhalers compared with placebo treatment (OR 1.62, 95% CI 1.36 to 1.94), and the quality of this evidence was rated as moderate, but no dose effect was seen. The three-year NNTH for one extra case of pneumonia was 17, based on a 12.3% risk of pneumonia in the placebo arm of TORCH. Fewer participants withdrew from the combined treatment arms for adverse events or lack of efficacy.

Authors' conclusions: Combined inhaler therapy led to around a quarter fewer COPD exacerbations than were seen with placebo. A significant reduction in all-cause mortality was noted, but this outcome was dominated by one trial (TORCH), emphasising the need for further trials of longer duration. Increased risk of pneumonia is a concern; however, this did not translate into increased exacerbations, hospitalisations or deaths. Current evidence does not suggest any major differences between inhalers in terms of effects, but nor is the evidence strong enough to demonstrate that all are equivalent. To permit firmer conclusions about the effects of combined therapy, more data are needed, particularly in relation to the profile of adverse events and benefits in relation to different formulations and doses of inhaled ICS. Head-to-head comparisons are necessary to determine whether one combined inhaler is better than the others.

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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 Combined inhalers versus placebo (primary outcomes), outcome: 1.1 Exacerbation rates with combined inhalers versus placebo.
3
3
Forest plot of comparison: 1 Combined inhalers versus placebo (primary outcomes), outcome: 1.2 Mortality.
4
4
Forest plot of comparison: 1 Combined inhalers versus placebo (primary outcomes), outcome: 1.3 Pneumonia.
5
5
Forest plot of comparison: 1 Combined inhalers versus placebo (primary outcomes), outcome: 1.4 Hospitalisations due to COPD exacerbations.
6
6
Funnel plot of comparison: 1 Combined inhalers versus placebo (primary outcomes), outcome: 1.2 Mortality.
1.1
1.1. Analysis
Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 1 Exacerbation rates with combined inhalers versus placebo.
1.2
1.2. Analysis
Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 2 Mortality.
1.3
1.3. Analysis
Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 3 Pneumonia.
1.4
1.4. Analysis
Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 4 Hospitalisations due to COPD exacerbations.
1.5
1.5. Analysis
Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 5 Number of participants with at least one exacerbation.
2.1
2.1. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 1 Exacerbations.
2.2
2.2. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 2 Number of participants with at least one exacerbation.
2.3
2.3. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 3 Participants with at least one exacerbation by type.
2.4
2.4. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 4 Exacerbations by type.
2.5
2.5. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 5 Mortality.
2.6
2.6. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 6 Change from baseline in St George's Respiratory Questionnaire (total score).
2.7
2.7. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 7 Change from baseline in Chronic Respiratory Disease Questionnaire scores.
2.8
2.8. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 8 Change from baseline in Transitional Dyspnoea Index (TDI) scores.
2.9
2.9. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 9 Change from baseline in predose FEV1.
2.10
2.10. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 10 Change from baseline in postdose FEV1.
2.11
2.11. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 11 Change from baseline in rescue medication usage (puffs/d).
2.12
2.12. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 12 Withdrawals—total.
2.13
2.13. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 13 Withdrawals due to adverse events.
2.14
2.14. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 14 Withdrawals due to lack of efficacy.
2.15
2.15. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 15 Adverse events—any.
2.16
2.16. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 16 Adverse events—'serious'.
2.17
2.17. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 17 Adverse events—pneumonia.
2.18
2.18. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 18 Adverse events—candidiasis.
2.19
2.19. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 19 Adverse events—hoarseness.
2.20
2.20. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 20 Adverse events—palpitations.
2.21
2.21. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 21 Adverse events—blood glucose increased.
2.22
2.22. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 22 Adverse event—skin bruising.
2.23
2.23. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 23 Adverse events—bronchitis.
2.24
2.24. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 24 Adverse events—upper respiratory tract infection.
2.25
2.25. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 25 Adverse events—nasopharyngitis.
2.26
2.26. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 26 Adverse events—cough.
2.27
2.27. Analysis
Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 27 Adverse events—headache.
3.1
3.1. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 1 Severe exacerbations.
3.2
3.2. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 2 Mean severe exacerbation rates per participant per year.
3.3
3.3. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 3 Mortality.
3.4
3.4. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 4 Change from baseline in St George's Respiratory Questionnaire (total score).
3.5
3.5. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 5 Quality of life—change scores.
3.6
3.6. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 6 Symptoms (change scores).
3.7
3.7. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 7 Breathlessness, cough and sputum score (BCSS) change from baseline—average over treatment period.
3.8
3.8. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 8 Rescue medication usage.
3.9
3.9. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 9 Mean FEV1 (% change from baseline).
3.10
3.10. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 10 Average 12‐hour FEV1 change from baseline—end of treatment (L).
3.11
3.11. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 11 Predose FEV1 [L] change from baseline to the average over the randomised treatment period.
3.12
3.12. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 12 1 Hour postdose FEV1 [L] change from baseline to the average over the randomised treatment period.
3.13
3.13. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 13 FEV1 at 12‐hour change from baseline—end of treatment (L).
3.14
3.14. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 14 Morning PEFR change from baseline, average over treatment period (L/min).
3.15
3.15. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 15 Evening PEFR mean change from baseline, average over treatment period (L/min).
3.16
3.16. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 16 Withdrawals—total.
3.17
3.17. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 17 Withdrawals due to adverse events.
3.18
3.18. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 18 Withdrawals due to lack of efficacy.
3.19
3.19. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 19 Adverse event—any.
3.20
3.20. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 20 Adverse events—'serious'.
3.21
3.21. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 21 Adverse events—pneumonia.
3.22
3.22. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 22 Adverse events—candidiasis.
3.23
3.23. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 23 Adverse events—dysphonia.
3.24
3.24. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 24 Adverse events—cataracts.
3.25
3.25. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 25 Adverse events—COPD.
3.26
3.26. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 26 Adverse events—tremor.
3.27
3.27. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 27 Adverse events—palpitations.
3.28
3.28. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 28 Adverse events—lumbar spine bone density change from baseline (g/cm2).
3.29
3.29. Analysis
Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 29 Adverse events—hip bone density change from baseline (g/cm2).
4.1
4.1. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 1 Number of participants with at least one exacerbation.
4.2
4.2. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 2 Number of participants having at least one moderate or severe exacerbation.
4.3
4.3. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 3 Mortality.
4.4
4.4. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (total score).
4.5
4.5. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 5 Change from baseline in FEV1 AUC0–12 hours (mL)—week 13.
4.6
4.6. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 6 Mean change from baseline AM predose FEV1 at 13 weeks (mL).
4.7
4.7. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 7 Withdrawals—total.
4.8
4.8. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 8 Withdrawals due to lack of efficacy.
4.9
4.9. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 9 Withdrawals due to adverse events.
4.10
4.10. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 10 Adverse events—any.
4.11
4.11. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 11 Adverse events—serious.
4.12
4.12. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 12 Adverse events—pneumonia.
4.13
4.13. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 13 Adverse events—candidiasis.
4.14
4.14. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 14 Adverse events—dysphonia.
4.15
4.15. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 15 Adverse events—cataract.
4.16
4.16. Analysis
Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 16 Adverse events—COPD requiring hospitalisation.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Barnes 2006 {published and unpublished data}
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Bourbeau 2007 {published data only}
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Dal Negro 2003 {published data only}
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Doherty 2012 {published data only}
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    1. NCT00383721. A randomized, 26‐week, placebo‐controlled efficacy and safety study with a 26‐week long‐term safety extension, of high‐ and medium‐dose inhaled mometasone furoate/formoterol fixed‐dose combination formulation compared with formoterol and high‐dose inhaled mometasone furoate monotherapy in subjects with moderate to severe COPD. http://clinicaltrials.gov/show/NCT00383721 (accessed 10 June 2013). []
Hanania 2003 {published and unpublished data}
    1. Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, et al. The efficacy and safety of fluticasone propionate (250 micro g)/salmeterol (50 micro g) combined in the diskus inhaler for the treatment of COPD. Chest 2003;124(3):834‐43. - PubMed
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    1. Horstman D, Darken P, Davis S, Lee B. Improvements in FEV1 and symptoms in poorly reversible COPD patients following treatment with salmeterol 50mcg/fluticasone propionate 250mcg combination [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P434.
    1. Mahler DA, Darken P, Brown CP, Knobil K. Predicting lung function responses to combination therapy in chronic obstructive pulmonary disease (COPD) [Abstract]. National COPD Conference November 14‐15, Arlington, Virginia. 2003:Abstract 1081.
    1. Mahler DA, Darken P, Brown CP, Knobil K. Predicting lung function responses to salmeterol/fluticasone propionate combination therapy in COPD [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P429.
Lapperre 2009 {published data only}
    1. Lapperre TS, Snoeck‐Stroband JB, Gosman MM, Jansen DF, Schadewijk A, Thiadens HA, et al. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Annals of Internal Medicine 2009; Vol. 151, issue 8:517‐27. - PubMed
Mahler 2002 {published and unpublished data}
    1. Mahler DA, Darken P, Brown CP, Knobil K. Predicting lung function responses to combination therapy in chronic obstructive pulmonary disease (COPD). http://www.abstracts2view.com (accessed 1 April 2004).
    1. Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the diskus device in the treatment of chronic obstructive pulmonary disease. American Journal of Respiratory Critical Care Medicine 2002;166(8):1084‐91. - PubMed
    1. SFCA3006. 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. http://www.gsk‐clinicalstudyregister.com/result_detail.jsp?protocolId=SFCA3006&stud... (accessed 8 June 2013).
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O'Donnell 2006 {published and unpublished data}
    1. Celli B, Emmett A, Crater G, Kalberg C. Salmeterol/fluticasone propionate (SFC) improves the inspiratory to total lung capacity ratio (IC/TLC) and exercise endurance time in patients with COPD. European Respiratory Journal 2006;28(Suppl 50):764s.
    1. Make B, Emmett A, Crater G, O'Dell D, Kalberg C. Improvement in exercise endurance time (EET) with fluticasone propionate/salmeterol correlations with spirometry and plethysmography. Proceedings of the American Thoracic Society; May 19‐24; San Diego. 2006.
    1. O'Donnell DE, Sciurba F, Celli B, Mahler DA, Webb KA, Kalberg CJ, et al. Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Chest 2006;130(3):647‐56. - PubMed
    1. SCO40030. A randomized, double‐blind, placebo‐controlled, parallel group clinical trial evaluating the effect of the fluticasone propionate/salmeterol combination product 250/50mcg bid via DISKUS and salmeterol 50mcg bid via DISKUS on lung hyperinflation in subjects with chronic obstructive pulmonary disease (COPD). http://www.gsk‐clinicalstudyregister.com/result_detail.jsp?protocolId=SCO40030&stud... (accessed 10 June 2013).
Rennard 2009 {published data only}
    1. A 12‐month double‐blind, double‐dummy, randomized, parallel group, multicenter efficacy & safety study of SYMBICORT® pMDI 2 × 160/4.5 mcg bid and 2 × 80/4.5mcg bid compared to formoterol TBH 2 × 4.5 mcg bid and placebo in patients with COPD. http://www.astrazenecaclinicaltrials.com/therapy‐areas/respiratory‐infla... (accessed 8 June 2013).
    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; Vol. 138, issue 4:468A.
    1. NCT00206167. A 12‐month double‐blind, double‐dummy, randomized, parallel group, multicenter efficacy and safety study of Symbicort® pMDI 2 × 160/4.5 μg Bid and 2 × 80/4.5 μg Bid compared to Formoterol Turbuhaler® 2 × 4.5 μg Bid and placebo in patients with COPD. http://clinicaltrials.gov/show/NCT00206167 (accessed 8 June 2013). []
    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. Adis Data Information BV., 2009; Vol. 69, issue 5:549‐65. - PMC - PubMed
    1. Rennard SI, Tashkin DP, McElhattan J, Goldman M, Silkoff PE. Long‐term tolerability of budesonide and formoterol administered in one pressurized metered‐dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease [Abstract]. Chest 2008; Vol. 134, issue 4_MeetingAbstracts:p103001.
SCO104925 {published data only}
    1. Evaluation of novel endpoints in subjects with chronic obstructive pulmonary disease (COPD) in a randomized, double‐blind, placebo‐controlled study of treatment with fluticasone propionate/salmeterol 500/50mcg combination and its individual components, fluticasone propionate 500mcg and salmeterol 50mcg. http://www.gsk‐clinicalstudyregister.com/quick‐search‐list.jsp?item=SCO104925&type=... studyId=SCO104925 (accessed 8 June 2013).
SFCT01 {unpublished data only}
    1. SCO30002. A multicentre, randomised, double‐blind, parallel group, placebo‐controlled study to compare the efficacy and safety of inhaled salmeterol/fluticasone propionate combination product 25/250 µg two puffs bd and fluticasone propionate 250µg two puffs bd alone, all administered via metered dose inhalers (MDI), in the treatment of subjects with chronic obstructive pulmonary disease (COPD) for 52 weeks. http://www.gsk‐clinicalstudyregister.com/quick‐search‐list.jsp?item=SCO30002&type=G... (accessed 10 June 2013).
Sin 2008 {published data only}
    1. NCT00120978. Advair ‐ CRP study. http://clinicaltrials.gov/show/NCT00120978 (accessed 10 June 2013). []
    1. Sin DD, Man SF, Marciniuk DD, Ford G, FitzGerald M, Wong E, et al. ABC (Advair, Biomarkers in COPD) Investigators. Can inhaled fluticasone alone or in combination with salmeterol reduce systemic inflammation in chronic obstructive pulmonary disease? Study protocol for a randomized controlled trial [NCT00120978]. BMC Pulmonary Medicine 2006;6(3):3. - PMC - PubMed
    1. Sin DD, Man SF, Marciniuk DD, Ford G, FitzGerald M, Wong E, et al. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease [see comment]. American Journal of Respiratory and Critical Care Medicine 2008; Vol. 177, issue 11:1207‐14. - PubMed
Szafranski 2003 {published and unpublished data}
    1. Anderson P. Budesonide/formoterol in a single inhaler (Symbicort) provides early and sustained improvement in lung function in moderate to severe COPD [Abstract]. Thorax 2002;57(Suppl III):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). http://www.astrazenecaclinicaltrials.com/diseases‐and‐conditions/disease... (accessed 9 June 2013).
    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; Orlando. 2004:C22 [Poster 505].
    1. Calverley P, Pauwels R, Lofdahl CG, Svensson K, Higenbottam T, et al. Relationship between respiratory symptoms and medical treatment in exacerbations of COPD. European Respiratory Journal 2005;26(3):406‐13. - PubMed
    1. Calverley PMA. Effect of budesonide/formoterol on severe exacerbations and lung function in moderate to severe COPD. BTS Winter Meeting; London. December 2002:S145.
Tashkin 2008 {published data only}
    1. Astrazeneca (D5899C00002). A 6‐month double‐blind, double‐dummy, randomized, parallel group, multicenter efficacy & safety study of Symbicort® pMDI 2 × 160/4.5mg & 80/4.5mg bid compared to Formoterol TBH, Budesonide pMDI (& the combination) & placebo in COPD patients. www.astrazenecaclinicaltrials.com (accessed 8 April 2008).
    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; Vol. 134, issue 4:105001s.
    1. Tashkin DP, Rennard SI, Martin P, Ramachandran S, Martin UJ, Silkoff PE, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered‐dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease : results of a 6‐month randomized clinical trial. Drugs 2008; Vol. 68, issue 14:1975‐2000. - PubMed
Tashkin 2012 {published data only}
    1. Kerwin E, Tashkin DP, Matiz‐Bueno CE, Doherty DE, Shekar T, Banerjee S, et al. Clinical efficacy and safety of combined mometasone furoate and formoterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) [Abstract]. Journal of Allergy and Clinical Immunology 2012; Vol. 129, issue 2 Suppl:AB201 [759].
    1. NCT00383435. A randomized, 26‐week, placebo‐controlled efficacy and safety study with a 26‐week long‐term safety extension, of high‐ and medium‐dose inhaled mometasone furoate/formoterol fixed‐dose combination formulation compared with formoterol and high‐dose inhaled mometasone furoate monotherapy in subjects with moderate to severe COPD. http://clinicaltrials.gov/show/NCT00383435 (accessed 9 June 2013). []
    1. Tashkin DP, Doherty DE, Kerwin E, Matiz‐Bueno CE, Knorr B, Shekar T, et al. Efficacy and safety of a fixed‐dose combination of mometasone furoate and formoterol fumarate in subjects with moderate to very severe COPD: results from a 52‐week Phase III trial. International Journal of Chronic Obstructive Pulmonary Disease 2012;7:43‐55. - PMC - PubMed
TORCH {published and unpublished data}
    1. Briggs AH, Glick HA, Lozano‐Ortega G, Spencer M, Calverley PM, Jones PW, et al. Is treatment with ICS and LABA cost‐effective for COPD? Multinational economic analysis of the TORCH study. European Respiratory Journal 2010;35(3):532‐9. - PubMed
    1. Calverley P, Celli B, Anderson JA, Ferguson GT, Jenkins C, Jones PW, et al. The Towards a Revolution in COPD Health (TORCH) study: salmeterol/fluticasone propionate improves survival in COPD over three years. Respirology 2006;11(Suppl 5):A149.
    1. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.[see comment]. New England Journal of Medicine 2007; Vol. 356, issue 8:775‐89. - PubMed
    1. Calverley PM, Celli B, Anderson JA, Ferguson GT, Jenkins C, Jones PW, et al. The towards a revolution in COPD health (TORCH) study: fluticasone propionate /salmeterol improves survival in COPD over three years. Chest 2006;130(4):122s.
    1. Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Cardiovascular events in patients with chronic obstructive pulmonary disease: TORCH study results. Thorax 2010;65:719‐25. - PubMed
TRISTAN {published and unpublished data}
    1. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361(9356):449‐56. - PubMed
    1. Calverley PMA, Pauwels RA, Vestbo J, Jones PW, Pride NB, Gulsvik A, et al. Salmeterol/Fluticasone propionate combination for one year provides greater clinical benefit than its individual components. Proceedings of the 98th International American Thoracic Society Conference; May 17‐22; Atlanta. 2002:A98 [Poster 306].
    1. Calverley PMA, Pauwels RA, Vestbo J, Jones PW, Pride NB, Gulsvik A, et al. Clinical improvements with salmeterol / fluticasone propionate combination in differing severities of COPD.. American Thoracic Society 99th International Conference; May 16‐21; Seattle 2003:A035 [Poster D50].
    1. Calverly PMA, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, et al. Safety of salmeterol/fluticasone propionate combination in the treatment of chronic obstructive pulmonary disease. European Respiratory Journal 2002;20 Suppl 38:242 [P1572].
    1. Hunjan MK, Chandler F. Numbers needed to treat (NNT) to avoid an exacerbation in patients with chronic obstructive pulmonary disease (COPD) using salmeterol/fluticasone propionate combination (SFC) and associated costs [Abstract]. American Thoracic Society 100th International Conference; May 21‐26; Orlando. 2004:D22 [Poster 503].
Zheng 2006 {published data only}
    1. SCO100540. A multi‐centre, randomised, double‐blind, parallel group study to investigate the efficacy and safety of the salmeterol/fluticasone propionate combination at a strength of 50/500µg BD, compared with placebo via Accuhaler™, added to usual chronic obstructive pulmonary disease (COPD) therapy, in subjects with COPD for 24 weeks. http://www.gsk‐clinicalstudyregister.com/result_detail.jsp?protocolId=100540&studyI... (accessed 9 July 2013).
    1. Zheng J, Zhong N, Yang L, Wu Y, Chen P, Wen Z, et al. The efficacy and safety of fluticasone propionate 500 mg/salmeterol 50 mg combined via diskus/accuhaler in Chinese patients with chronic obstructive pulmonary disease (COPD). Chest 2006;130(4):182s.
    1. Zhong N, Zheng J, Yang L, Wu Y, Chen P, Wen Z, et al. The efficacy and safety of salmeterol 50µg/fluticasone propionate 500µg combined via accuhaler in Chinese patients with chronic obstructive pulmonary disease [Abstract]. Respirology 2006;11(Suppl 5):A150.

References to studies excluded from this review

Aaron 2004 {published data only}
    1. Aaron SD, Vandemheen K, Ferguson D, FitzGerald M, Maltais F, Boureau J, et al. The Canadian optimal therapy of COPD trial: Design, organization and patient recruitment. Canadian Respiratory Journal 2004;11(8):581‐5. - PubMed
Aaron 2007 {published data only}
    1. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone‐salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.[see comment][summary for patients in Ann Intern Med. 2007 Apr 17;146(8):I12; PMID: 17310044]. Annals of Internal Medicine 2007; Vol. 146, issue 8:545‐55. - PubMed
    1. Kaplan A. Effects of tiotropium combined with either salmeterol or salmeterol/fluticasone in moderate to severe COPD. Primary Care Respiratory Journal 2007;16(4):258‐60. - PMC - PubMed
Bathoorn 2008 {published data only}
    1. Bathoorn E, Liesker JJ, Postma DS, Boorsma M, Bondesson E, Koëter GH, et al. Anti‐inflammatory effects of combined budesonide/formoterol in COPD exacerbations. COPD 2008; Vol. 5, issue 5:282‐90. - PubMed
Bleecker 2011 {published data only}
    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(Meeting Abstracts):A4086.
Borgstrom 2003 {published data only}
    1. Borgstrom L, Lipniunas P. Budesonide/formoterol in Turbuhaler® is not affected by storage in hot and humid conditions. A clinical pharmacokinetic comparison with fluticasone in Diskus™ [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P1580.
Cazzola 2000 {published data only}
    1. Cazzola M, Lorenzo G, Perna F, Calderaro F, Testi R, Centanni S. Additive effects of salmeterol and fluticasone or theophylline in COPD. Chest 2000;118(6):1576‐81. - PubMed
Cazzola 2002a {unpublished data only}
    1. Cazzola M, Santus P, Marco F, Boveri B, Castagna F, Carlucci P. Bronchodilator effect of an inhaled combination therapy with salmeterol + fluticasone and formoterol + budesonide in patients with COPD. European Respiratory Journal 2002;20 Suppl 38:386 [P2396]. - PubMed
Cazzola 2003 {published data only}
    1. Cazzola M, Salzillo A, Giglio C, Noschee P, D'Amato G. Formoterol/budesonide (FBC) in the treatment of acute exacerbation of COPD [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P1859.
Cazzola 2004 {published data only}
    1. Cazzola M, Noschese P, Centanni S, Santus P, Marco F, Spicuzza L, et al. Salmeterol/fluticasone propionate in a single inhaler device versus theophylline + fluticasone propionate in patients with COPD. Pulmonary Pharmacology and Therapeutics 2004;17(3):141‐5. - PubMed
    1. Cazzola M, Noschese P, D'Amato G, Santus P, Centanni S. Salmeterol/fluticasone propionate in a single inhaler device (SLM/FP) versus theophyline (THEO) + FP in patients with COPD. European Respiratory Journal 2002;20 Suppl 38:386 [P2393].
Cazzola 2004b {published data only}
    1. Cazzola M, Santus P, Marco F, Carlucci P, Belloni E, Mondoni M, et al. Onset of action of budesonide/formoterol in single inhaler vs. formoterol in patients with COPD [abstract]. American Thoracic Society 99th International Conference; May 16‐21; Seattle. 2003:B024 [Poster 410].
    1. Cazzola M, Santus P, Marco F, Carlucci P, Mondoni M, Matera MG, et al. Onset of action of formoterol/budesonide in single inhaler vs. formoterol in patients with COPD. Pulmonary Pharmacology and Therapeutics 2004;17(3):121‐5. - PubMed
Chapman 2002 {published data only}
    1. Chapman KR. Seretide for obstructive lung disease. Expert Opinion on Pharmacotherapy 2002;3(3):341‐50. - PubMed
Cukier 2007 {published data only}
    1. Cukier A, Ferreira CAS, Stelmach R, Ribeiro M, Cortopassi F, Calverley PMA. The effect of bronchodilators and oxygen alone and in combination on self‐paced exercise performance in stable COPD. Respiratory Medicine 2007;101(4):743‐53. - PubMed
De Backer 2011 {published data only}
    1. Backer L, Backer J, Vos W, Holsbeke C, Vinchurkar S, Backer W. Double blind, placebo controlled crossover study in COPD patients to assess the acute effect of budesonide/formoterol using HRCT and lung function tests [Abstract]. European Respiratory Society Annual Congress; September 24‐28; Amsterdam. 2011; Vol. 38, issue 55:600s [P3362].
Donohue 2004 {published data only}
    1. Donohue JF, Kalberg C, Emmett A, Merchant K, Knobil K. A short‐term comparison of fluticasone propionate/salmeterol with ipratropium bromide/albuterol for the treatment of COPD. Treatments in Respiratory Medicine 2004;3(3):173‐81. - PubMed
    1. Donohue JF, Kalberg C, Emmett A, Merchant K, Knobil K. Fluticasone/salmeterol combination (250/50) provides greater improvement in lung function and symptoms than the combination of ipratropium/albuterol in patients with COPD. Chest 2003;124(4):128S.
    1. Kalberg C, Emmett A, Bourne E, Merchant K, Knobil K. Fluticasone propionate/salmeterol provides greater relief of dyspnea than ipratropium/albuterol in patients with COPD [Abstract]. American Thoracic Society 100th International Conference, May 21‐26; Orlando. 2004:C22 [Poster 528].
    1. Knobil K, Kalberg C, Merchant K, Emmett A, Cicale M. Maintenance of bronchodilator response for advair diskus 250/50 (fluticasone propionate/salmeterol) but not ipratropium/albuterol in patients with COPD [Abstract]. Chest 2004;126(4):807S.
    1. Knobil K, Merchant K, Kalberg C, Emmett A, Cicale M. A comparison of patient perceived improvement in symptoms after initiating therapy with either advair diskus (fluticasone propionate/salmeterol) 250/50 or ipratropium/albuterol [Abstract]. Chest 2004;126(4 Suppl):806S‐b ‐ 807S‐b.
Ferguson 2006 {published data only}
    1. Ferguson GT. Cardiovascular safety of simultaneous therapy with advair and combivent in the treatment of COPD [Abstract]. Proceedings of the American Thoracic Society; May 19‐24; San Diego. 2006:A109 [Poster J2].
GlaxoSmithKline 2004 {published data only}
    1. GlaxoSmithKline SAS. A Randomised, Double‐Blind, Double‐Dummy, Parallel‐Group Comparison of SERETIDE DISKUS/ACCUHALER (50/100µg Strength) twice daily (bid) with Budesonide 400µg bid in Adolescents and Adults with Reversible Airways Obstruction. GlaxoSmithKline Clinical Trial Register 2004.
GlaxoSmithKline 2004a {published data only}
    1. GlaxoSmithKline SAS. A Randomised, Double‐Blind, Double‐Dummy, Parallel‐Group Comparison of Seretide DISKUS/ACCUHALER (50/250ìg Strength) b.i.d. with Budesonide 800ìg b.i.d. in Adolescents and Adults with Reversible Airways Obstruction. GlaxoSmithKline Clinical Trial Register 2004.
Golabi 2006 {published data only}
    1. Golabi P, Topaloglu N, Karakurt S, Celikel T. Effects of tiotropium and salmeterol/fluticasone combination on lung hyperinflation dyspnea and exercise tolerance in COPD [Abstract]. European Respiratory Journal 2006;28(Suppl 50):33s.
Haque 2006 {published data only}
    1. Haque RA, Torrego A, Essilfie‐Quaye S, Kharitonov SA, Johnson M, Adcock IM, et al. Effect of salmeterol and fluticasone on glucocorticoid receptor translocation in sputum macrophages and peripheral blood mononuclear cells from patients with chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society; May 19‐24; San Diego. 2006:A848.
INSPIRE {published data only}
    1. GlaxoSmithKline (SCO40036). Multicentre, randomised, double‐blind, double‐dummy, parallel group, 104‐week study to compare the effect of the salmeterol/fluticasone propionate combination product (SERETIDE*) 50/500mcg delivered twice daily via the DISKUS*/ACCUHALER* inhaler with tiotropium bromide 18 mcg delivered once daily via the HandiHaler inhalation device on the rate of health care utilisation exacerbations in subjects with severe chronic obstructive pulmonary disease (COPD). http://ctr.gsk.co.uk (accessed 8 April 2008).
    1. Seemungal T, Stockley R, Calverley P, Hagan G, Wedzicha JA. Investigating new standards for prophylaxis in reduction of exacerbations ‐ The INSPIRE study methodology. Journal of Chronic Obstructive Pulmonary Disease 2007;4(3):177‐83. - PubMed
    1. Wedzicha J, Stockley R, Seemungal T, Hagan G, Calverley P. The INSPIRE study: effect of salmeterol/fluticasone propionate versus tiotropium bromide on COPD exacerbations. Respirology 2007;12(Suppl 4):A112.
Jiang 2011 {published data only}
    1. Jiang YP, Zhao YF, Yang Y. Effect of seretide on quality of life in COPD: Measured with COPD assessment test [Abstract]. Respirology (Carlton, Vic.) 2011;16(Suppl 2):100 [344].
Jung 2012 {published data only}
    1. Jung KS, Park HY, Park SY, Kim SK, Kim YK, Shim JJ, et al. Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: a randomized controlled study. Respiratory Medicine 2012; Vol. 106, issue 3:382‐9. - PubMed
Kardos 2007 {published and unpublished data}
    1. Kardos P, Wencker M. Combination therapy with salmeterol and fluticasone propionate (SFC) is more effective than salmeterol (SAL) alone in reducing exacerbations of COPD [Abstract]. European Respiratory Journal 2005;26 Suppl 49:Abstract 1944.
    1. Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. American Journal of Respiratory & Critical Care Medicine 2007;175(2):144‐9. - PubMed
    1. SCO30006. A randomised, double‐blind, parallel‐group study to investigate the protective effect of the combination of fluticasone and salmeterol (500/50µg bid via the DISKUS) compared with salmeterol (50µg bid via the DISKUS) on the incidence of moderate to severe exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) (GOLD III/IV). http://www.gsk‐clinicalstudyregister.com/result_detail.jsp?protocolId=SCO30006&stud... (accessed 10 June 2013).
    1. Vogelmeier C. Combination therapy with salmeterol and fluticasone propionate (SFC) improves quality of life (QoL) more than salmeterol (SAL) alone in COPD. 42nd Nordic Lung Conference Trondheim 2005;Suppl 22:13.
Lindberg 2007 {published data only}
    1. Lindberg A, Szalai Z, Pullerits T, Radeczky E. Fast onset of effect of budesonide/formoterol versus salmeterol/fluticasone and salbutamol in patients with chronic obstructive pulmonary disease and reversible airway obstruction. Respirology (Carlton, Vic.) 2007;12(5):732‐9. - PubMed
Lindenberg 2006 {published data only}
    1. Lindenberg A, Szalai Z, Pullertis T, Radeczky E, Lindberg A. Budesonide/formoterol (B/F) has an onset of action that is similar to salbutamol and faster than salmeterol/fluticasone in patients with COPD [Abstract]. European Respiratory Journal 2006;28(Suppl 50):214s [P1273].
Mittmann 2010 {published data only}
    1. Mittmann N, Hernandez P, Mellstram C, Brannman L, Welte T, Mellström C, et al. Cost‐effectiveness of budesonide/formoterol added to tiotropium in COPD patients in Canada, Australia and Sweden [Abstract].. European Respiratory Society Annual Congress; September 18‐22; Barcelona. 2010:[5183].
Mittmann 2011 {published data only}
    1. Mittmann N, Hernandez P, Mellstrom C, Brannman L, Welte T. Cost effectiveness of budesonide/formoterol added to tiotropium bromide versus placebo added to tiotropium bromide in patients with chronic obstructive pulmonary disease: Australian, Canadian and Swedish healthcare perspectives. PharmacoEconomics 2011; Vol. 29, issue 5:403‐14. - PubMed
NCT00144911 {published data only}
    1. NCT00144911. See Detailed Description. http://clinicaltrials.gov/show/NCT00144911 (accessed 9 July 2013). []
NCT00269126 {published data only}
    1. NCT00269126. See Detailed Description. http://clinicaltrials.gov/show/NCT00269126 (accessed 9 July 2013). []
NCT00476099 {published data only}
    1. NCT00476099. A 48‐Week, Double Blind, Double Dummy, Randomised, Multinational, Multicentre, 3‐Arm Parallel Group Clinical Study of "Fixed Combination" Beclometasone Dipropionate Plus Formoterol Fumarate Administered Via pMDI With HFA‐134a Propellant Versus "Fixed Combination" Budesonide Plus Formoterol DPI Versus Formoterol DPI in Patients With Stable Severe Chronic Obstructive Pulmonary Disease (COPD). Http://clinicaltrials.gov/show/NCT00476099 (accessed 9 July 2013). []
Noschese 2003 {published data only}
    1. Noschese P, Michele F, D'Amato G, Cazzola M. Comparison of the acute effects of formoterol (F) and formoterol/budesonide combination (FBC) on blood gas tensions in patients with acute exacerbation of COPD (AECOPD)[Abstract]. European Respiratory Journal 2003;22 Suppl 45:P156.
Sagcan 2007 {published data only}
    1. Sagcan G, Memis U, Cuhadaroglu C, Sen C, Duygu E. The effects of formoterol/budesonide on sleep quality of COPD patients [Abstract]. European Respiratory Journal 2007;30(Suppl 51):507s [E3049].
SAM40116 {unpublished data only}
    1. SAM40116. A 12‐Week Multi‐centre, Randomised, Double Blind, Parallel Group Study to Compare the Efficacy of Salmeterol/Fluticasone Propionate (Seretide TM) 50/100 mcg or 50/250 mcg Twice Daily and Fluticasone Propionate (Flixotide TM) 250 mcg or 500 mcg Twice Daily via the Diskus TM in Subjects With Asthma/COPD Symptoms. GlaxoSmithKline Clinical Trials Register http:ctr.gsk.co.uk (accessed 2005).
Schermer 2007 {published data only}
    1. Schermer TR, Albers JM, Verblackt HW, Costongs RJ, Westers P. Lower inhaled steroid requirement with a fluticasone/salmeterol combination in family practice patients with asthma or COPD. Family Practice 2007;24(2):181‐8. - PubMed
SCO100250 {unpublished data only}
    1. GlaxoSmithKline (SCO100250). A Randomized, Double‐Blind, Parallel‐Group, 52‐Week Study to Compare the Effect of Fluticasone Propionate/Salmeterol DISKUS 250/50mcg bid With Salmeterol DISKUS 50mcg bid on the Annual Rate of Moderate/Severe Exacerbations in Subjects With Chronic Obstructive Pulmonary Disease (COPD). http://ctr.gsk.co.uk (accessed 8 April 2008).
SCO100470 {unpublished data only}
    1. SCO100470. A Multicentre, Randomised, Double‐Blind, Parallel Group, 24‐Week Study to Compare the Effect of the Salmeterol/Fluticasone Propionate Combination Product 50/250mcg, With Salmeterol 50mcg Both Delivered Twice Daily via the DISKUS/ACCUHALER Inhaler on Lung Function and Dyspnoea in Subjects With Chronic Obstructive Pulmonary Disease (COPD). GlaxoSmithKline Clinical Trials Register http:ctr.gsk.co.uk (accessed 2006).
SCO40034 {unpublished data only}
    1. A Multicentre, Randomised, Double‐blind, Double Dummy, Parallel Group 12‐Week Exploratory Study to Compare the Effect of the Salmeterol/Fluticasone Propionate Combination Product (SERETIDE) 50/500mcg bd via the DISKUS/ACCUHALER Inhaler With Tiotropium Bromide 18 mcg od via the Handihaler Inhalation Device on Efficacy and Safety in Patients With Chronic Obstructive Pulmonary Disease (COPD). GlaxoSmithKline Clinical Trials Register http:ctr.gsk.co.uk (accessed 2005).
SCO40043 {unpublished data only}
    1. SCO40043. A Randomized, Double‐Blind, Parallel‐Group, 52‐Week Study to Compare the Effect of Fluticasone Propionate/Salmeterol DISKUS® 250/50mcg bid With Salmeterol DISKUS® 50mcg bid on the Annual Rate of Moderate/Severe Exacerbations in Subjects With Chronic Obstructive Pulmonary Disease (COPD). http://ctr.gsk.co.uk (accessed 8 April 2008).
Sethi 2006 {published data only}
    1. Sethi S, Grove L, Wrona C, Maloney J. Prevalence of bacterial colonization in COPD is not altered by fluticasone/salmeterol. Proceedings of the American Thoracic Society; May 19‐22; San Diego. 2006:A115.
Shaker 2009 {published data only}
    1. Shaker SB, Dirksen A, Ulrik CS, Hestad M, Stavngaard T, Laursen LC, et al. The effect of inhaled corticosteroids on the development of emphysema in smokers assessed by annual computed tomography. COPD 2009;6(2):104‐11. - PubMed
Sharafkhaneh 2011 {published data only}
    1. Sharafkhaneh A, Southard J, Goldman M, Uryniak T, Martin UJ. Long‐term effect of budesonide/formoterol pressurized metered‐dose inhaler on exacerbations and pulmonary function in patients with chronic obstructive pulmonary disease [Abstract]. American Journal of Respiratory and Critical Care Medicine 2011;183(Meeting Abstracts):A1599.
Soriano 2002 {published data only}
    1. Soriano JB, Vestbo J, Pride NB, Kiri V, Maden C, Maier WC. Survival in COPD patients after regular use of fluticasone propionate and salmeterol in general practice. European Respiratory Journal 2002;20(4):797‐8. - PubMed
Southard 2011 {published data only}
    1. Southard JG, Sharafkhaneh A, Goldman M, Uryniak T, Martin UJ. Long‐term tolerability of budesonide/formoterol pressurized metered‐dose inhaler in patients with chronic obstructive pulmonary disease and a history of exacerbations [Abstract]. American Journal of Respiratory and Critical Care Medicine 2011;183(Meeting Abstracts):A1597.
Stallberg 2008 {published data only}
    1. Stallberg B, Andersson EBC, Ekstrom T, Selroos O, Vogelmeier C, Larsson K. Budesonide /formoterol for the treatment of COPD exacerbations in the primary healthcare setting [Abstract]. European Respiratory Society Annual Congress; October 4‐8; Berlin. 2008:[P3610].
Sun 2004 {published data only}
    1. Sun D, Yang J, Xu X. Combined seretide and zafirlukast in the treatment of chronic obstructive pulmonary disease (COPD) [Abstract]. American Thoracic Society 100th International Conference; May 21‐26; Orlando. 2004:C22 [Poster 524].
Sutherland 2006 {published data only}
    1. Sutherland ER, Moss TA, Stevens AD, Pak J, Martin RJ. Modulation of sputum gene expression in COPD by fluticasone /salmeterol. European Respiratory Journal 2006;28(Suppl 50):662s.
Trofimenko 2006 {published data only}
    1. Trofimenko IN, Chernyak BA. The efficacy of salmeterol/fluticasone (SF) for 6 month's therapy at severe COPD patients. European Respiratory Journal 2006;28(Suppl 50):30s.
Vestbo 2004 {published data only}
    1. Vestbo J. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease. Dan. Ugeskrift for Laeger 2004;166(4):271‐4. - PubMed
Welte 2009 {published data only}
    1. Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2009;180(8):741‐50. - PubMed
Welte 2009a {published data only}
    1. Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, et al. Addition of budesonide/formoterol to tiotropium reduces the number of exacerbation days compared with tiotropium alone [Abstract]. Chest 2009;136(4):26S‐f.
Welte 2009b {published data only}
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Welte 2009c {published data only}
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Welte 2009d {published data only}
    1. Welte T, Miravitlles M, Hernandez P, Peterson S, Polanowski T, Kessler R, et al. Budesonide/formoterol added to tiotropium improves exacerbations and exacerbation‐related antibiotic use in patients with COPD [Abstract]. European Respiratory Society Annual Congress; September 12‐16; Vienna. 2009:[P2012].
Wilson 2007 {published data only}
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Worth 2009a {published data only}
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Worth 2010 {published data only}
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References to other published versions of this review

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