Scolaris Content Display Scolaris Content Display

Corticosteroide y agonista beta 2 de acción prolongada combinados en un inhalador versus agonistas beta2 de acción prolongada para la enfermedad pulmonar obstructiva crónica

Contraer todo Desplegar todo

Referencias

References to studies included in this review

Ir a:

Anzueto 2009 {published data only}

Anzueto A, Ferguson GT, Feldman G, Chinsky K, Seibert A, Emmett A, et al. Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. Journal of Chronic Obstructive Pulmonary Disease 2009;6(5):320‐9.

Calverley 2003 {published and unpublished data}

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].
Calverley 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(6):912‐9.
Calverley PMA, Cseke Z, Peterson S. Budesonide/formoterol reduces the use of oral corticosteroids in the treatment of COPD [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P436.
Calverley PMA, Kuna P, Olsson H. COPD exacerbations are reduced by budesonide/formoterol in a single inhaler [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P1587.
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].
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].
Calverley PMA, Ståhl E, Jones PW. Budesonide/formoterol improves the general health status of patients with COPD [Abstract]. American Thoracic Society 2005 International Conference; May 20‐25; San Diego, California. 2005:B93 [Poster 303].
Calverley PMA, Szafranski W, Andersson A. Budesonide/formoterol is a well‐tolerated long term maintenance therapy for COPD. European Respiratory Journal 2005;26 Suppl 49:Poster 1917.
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.
Halpin D, Stahl E, Lundback B, Anderson F, Peterson S. Treatment costs and number needed to treat (NNT) with budesonide/formoterol to avoid one exacerbation of COPD [Abstract]. American Thoracic Society 100th International Conference, May 21‐26. 2004:D22 [Poster 525].
Halpin DMG, Larsson T, Calverley PMA. How many patients with COPD must be treated with budesonide/formoterol compared with formoterol alone to avoid 1 day of oral steroid use? [Abstract]. American Thoracic Society 2005 International Conference; May 20‐25; San Diego, California. 2005:B93 [Poster 314].
Jones PW, Stahl E. Budesonide/formoterol in a single inhaler improves health status in patients with COPD [abstract]. American Thoracic Society 99th International Conference. 2003:B024 [Poster 419].
Jones PW, Ståhl E. Budesonide /formoterol sustains clinically relevant improvements in health status in COPD [Abstract]. European Respiratory Journal 2005;26 Suppl 49:Abstract 1352.
Jones PW, Ståhl E. Reducing exacerbations leads to a better health‐related quality of life in patients with COPD. 13th ERS Annual Congress, 27th September, 2003, Vienna. 2003:P1586.
Lofdahl CG. Reducing the impact of COPD exacerbations: Clinical efficacy of budesonide/formoterol. European Respiratory Review 2004;13(88):14‐21.
Lofdahl CG, Andreasson E, Svensson K, Ericsson A. Budesonide/formoterol in a single inhaler improves health status in patients with COPD without increasing healthcare costs [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P433.
Lofdahl CG, Ericsson A, Svensson K, Andreasson E. Cost effectiveness of budesonide/formoterol in a single inhaler for COPD compared with each monocomponent used alone. Pharmacoeconomics 2005;23(4):365‐75.

Dal Negro 2003 {published data only}

Dal Negro R, Micheletto C, Trevsian F, Tognella S. [A98] Salmeterol and fluticasone 50ug/250ug BiD versus salmeterol 50ug bid and versus placebo in the long term treatment of COPD. Proceedings of the 98th International American Thoracic Society Conference. 2002:http://www.abstracts‐on‐line.com/abstracts/ATS.
Dal Negro RW, Pomari C, Tognella S, Micheletto C. Salmeterol & fluticasone 50 microg/250 microg bid in combination provides a better long‐term control than salmeterol 50 microg bid alone and placebo in COPD patients already treated with theophylline. Pulmonary Pharmacology and Therapeutics 2003;16(4):241‐6.

Ferguson 2008 {published data only}

Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C. Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Respiratory Medicine 2008;102:1099‐108.
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 8th April 2008).

Hanania 2003 {published and unpublished data}

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.
Hanania NA, Ramsdell J, Payne K, Davis S, Horstman D, Lee B, et al. Improvements in airflow and dyspnea in COPD patients following 24 weeks treatment with salmeterol 50mcg and fluticasone propionate 250mcg alone or in combination via the diskus. American Journal of Respiratory and Critical Care Medicine 2001;163 Suppl(5):A279.
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.
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; Arlington, Virginia. 2003:Abstract 1081.
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.
SFCA3007. 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) 250mcg BID individually and in combination as Salmeterol 50mcg/Fluticasone Propionate 250mcg BID (SFC 50/250) compared to placebo in COPD subjects. GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk)2005.
Spencer M, Wire P, Lee B, Chang CN, Darken P, Horstman D. Patients with COPD using salmeterol/fluticasone propionate combination therapy experience improved quality of life. European Respiratory Journal 2003;22 Suppl 45:51s.
Spencer MD, Karia N, Anderson J. The clinical significance of treatment benefits with the salmeterol/fluticasone propionate 50/500mcg combination in COPD. European Respiratory Journal 2004;24 Suppl 48:290s.

Kardos 2007 {published and unpublished data}

Kardos P, Wencker M. Combination therapy with salmeterol and fluticasone propionate (SFC) is more effective than salmeterol (SAL) alone in reducing exacerbations of COPD. European Respiratory Journal 2005;26 Suppl 49:Abstract 1944.
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 and Critical Care Medicine 2007;175(2):144‐9.
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). GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk)2005.
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; Vol. 13 Suppl 22.
Vogelmeier CF, Wencker M, Glaab TH, Kardos P. Number needed to treat (NNT) to reduce exacerbations in severe COPD comparing salmeterol/fluticasone propionate (SFC) with salmeterol (SAL) treatment. Proceedings of the American Thoracic Society. 2006:A110.

Mahler 2002 {published and unpublished data}

Mahler DA, Darken P, Brown CP, Knobil K. Predicting lung function responses to combination therapy in chronic obstructive pulmonary disease (COPD). http://www.abstracts2view.com2003.
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 and Critical Care Medicine 2002;166(8):1084‐91.
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. GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk)2005.
Spencer M, Wire P, Lee B, Chang CN, Darken P, Horstman D. Patients with COPD using salmeterol/fluticasone propionate combination therapy experience improved quality of life. European Respiratory Journal 2003;22 Suppl 45:51s.
Spencer MD, Anderson JA. Salmeterol/fluticasone combination produces clinically important benefits in dyspnea and fatigue [Abstract]. American Thoracic Society 2005 International Conference; May 20‐25; San Diego, California. 2005:B93 [Poster 308].
Spencer MD, Karia N, Anderson J. The clinical significance of treatment benefits with the salmeterol/fluticasone propionate 50/500mcg combination in COPD. European Respiratory Journal 2004;24 Suppl 48:290s.

O'Donnell 2006 {published and unpublished data}

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.
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). GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk)2005.

Rennard 2009 {published data only}

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.

SCO100470 {unpublished data only}

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)2006.

Szafranski 2003 {published and unpublished data}

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.
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].
Calverley P, Pauwels R, Lofdahl CG, Svensson K, Higenbottam T, L‐G Carlsson, et al. Relationship between respiratory symptoms and medical treatment in exacerbations of COPD. European Respiratory Journal 2005;26(3):406‐13.
Calverley PMA. Effect of budesonide/formoterol on severe exacerbations and lung function in moderate to severe COPD. Thorax. BTS Winter meeting 2002:S145.
Calverley PMA, Szafranski W, Andersson A. Budesonide/formoterol is a well‐tolerated long term maintenance therapy for COPD. European Respiratory Journal 2005;26 Suppl 49:Poster 1917.
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.
Campbell LM, Szafranski W. Budesonide/formoterol in a single inhaler (Symbicort) provides sustained relief from symptoms in moderate to severe COPD. Thorax. BTS Winter meeting 2002:S143.
Campell LW, Szafranski W. Budesonide/Formoterol in a single inhaler (Symbicort) reduces severe exacerbations in patients with moderate‐severe COPD. Thorax. BTS Winter meeting 2002:S141.
Dahl R, Cukier A, Olsson H. Budesonide/formoterol in a single inhaler reduces severe and mild exacerbations in patients with moderate to severe COPD. European Respiratory Journal 2002;20 Suppl 38:242 [P1575].
Egede F, Menga G. Budesonide/formoterol in a single inhaler provides sustained relief from symptoms and night‐time awakenings in moderate‐severe COPD: results from symptoms and night‐time awakenings in moderate to severe COPD: results from a 1‐year study. European Respiratory Journal 2002;20 Suppl 38:242 [P1574].
Halpin D, Stahl E, Lundback B, Anderson F, Peterson S. Treatment costs and number needed to treat (NNT) with budesonide/formoterol to avoid one exacerbation of COPD [Abstract]. American Thoracic Society 100th International Conference, May 21‐26. 2004:D22 [Poster 525].
Jones PW, Stahl E, Svensson K. Improvement in health status in patients with moderate to severe COPD after treatment with budesonide/formoterol in a single inhaler. European Respiratory Journal 2002;20 Suppl 38:250 [P1613].
Korsgaard J, Sansores R. Budesonide/formoterol (single inhaler) provides sustained relief from shortness of breath and chest tightness in a 1‐year study of patients with moderate to severe COPD. European Respiratory Journal 2002;20 Suppl 38:242 [P1577].
Lange P, Saenz C. Budesonide/formoterol in a single inhaler is well tolerated in patients with moderate to severe COPD: results of a 1 year study. European Respiratory Journal 2002;20 Suppl 38:242 [P1573].
Lofdahl CG. Reducing the impact of COPD exacerbations: Clinical efficacy of budesonide/formoterol. European Respiratory Review 2004;13(88):14‐21.
Milanowski J, Nahabedian S. Budesonide/formoterol in a single inhaler acts rapidly to improve lung function and relieve symptoms in patients with moderate to severe COPD. European Respiratory Journal 2002;20 Suppl 38:242 [P1576].
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(1):74‐81.

Tashkin 2008 {published data only}

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;68(14):1975‐2000.

TORCH {published and unpublished data}

Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. New England Journal of Medicine 2007;356(8):775‐89.
Calverley PMA, Celli B, Ferguson G, Jenkins C, Jones PW, Pride NB, et al. Baseline characteristics of the first 5,000 COPD patients enrolled in the TORCH survival study. European Respiratory Journal 2003;22 Suppl 45:578s.
Celli B, Calverley PMA, Anderson JA, Ferguson GT, Jenkins C, Jones PW, et al. The TORCH (TOwards a Revolution in COPD Health) study: salmeterol/fluticasone propionate (SFC) improves health status, reduces exacerbations and improves lung function over three years. European Respiratory Journal 2006;28 Suppl 50:34s.
Ferguson GT, Calverley PMA, Anderson JA, et al. The TORCH (TOwards a Revolution in COPD Health) study: salmeterol/fluticasone propionate (SFC) improves survival in COPD over three years. European Respiratory Journal 2006;28 Suppl 50:34s.
Jenkins CR, Calverley PMA, Celli B, Ferguson G, Jones PW, Pride N, et al. Seasonal Patterns of Exacerbation Rates in the TORCH Survival Study. http://www.abstracts2view.com2007:A839.
Jones PW, Calverley P, Celli B, Ferguson G, Jenkins C, Pride N. Trans‐Regional Validity of the SGRQ in the TORCH Survival Study. http://www.abstracts2view.com2007:A122.
McGarvey LP, John M, Anderson JA, Zvarich MT, Wise RA. Ascertainment of cause‐specific mortality in COPD : operations of the TORCH Clinical Endpoint Committee. Thorax 2007;62:411‐5.
SCO30003. A multicentre, randomised, double‐blind, parallel group, placebo‐controlled study to investigate the long‐term effects of salmeterol/fluticasone propionate (SERETIDE®/VIANI®/ADVAIR®) 50/500mcg bd, salmeterol 50mcg bd and fluticasone propionate 500mcg bd, all delivered via the DISKUS®/ACCUHALER® inhaler, on the survival of subjects with chronic obstructive pulmonary disease (COPD) over 3 years of treatment. www.ctr.gsk.co.uk2006.
Vestbo J, Calverley P, Celli B, Ferguson G, Jenkins C, Jones P, et al. The TORCH (TOwards a Revolution in COPD Health) survival study protocol. European Respiratory Journal 2004;24(2):206‐10.
Wise RA, McGarvey LP, John M, Anderson JA Zvarich MT. Reliability of cause‐specific mortality adjudication in a COPD clinical trial. http://www.abstracts2view.com2007:A120.

TRISTAN {published and unpublished data}

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.
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. http://www.abstracts2view.com2003:A035 [Poster D50].
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 http://www.abstracts‐on‐line.com/abstracts/ATS. 2002:A98 [Poster 306].
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].
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. 2004:D22 [Poster 503].
Hunjan MK, Williams DT. Costs of avoiding exacerbations in patients with chronic obstructive pulmonary disease (COPD) treated with salmeterol/ fluticasone propionate combination (seretide) and salmeterol. European Respiratory Journal 2004;24 Suppl 48:291s.
Hunjan MK, Williams DT. Salmeterol/ fluticasone propionate combination is clinically effective in avoiding exacerbations in patients with moderate/severe COPD. European Respiratory Journal 2004;24 Suppl 48:513s.
Jones PW, Edin HM, Anderson J. Salmeterol/fluticasone propionate combination improves health status in COPD patients. Proceedings of the 98th International American Thoracic Society Conference http://www.abstracts‐on‐line.com/abstracts/ATS. 2002:A39 [Poster K39].
Jones PW, Ståhl E. Budesonide /formoterol sustains clinically relevant improvements in health status in COPD [Abstract]. European Respiratory Journal 2005;26 Suppl 49:Abstract 1352.
Jones PW, Vestbo J, Pauwels RA, Calverley PMA, Anderson JA, Spencer MD. Informative drop out in COPD studies. Investigation of health status of withdrawals in the TRISTAN study. 13th ERS Annual Congress, 27 Spetember 2003, Vienna. 2003:P1593.
Nitschmann S. Inhalational combination therapy in chronic obstructive lung disease. Tristan study. German Internist 2004;45(6):727‐8.
Pauwels R, Vestbo J, Calverley PMA, Jones PW, Pride NB, Gulsvik A. Characterization of exacerbations in the TRISTAN study of salmeterol/fluticasone propionate (SFC) combination in moderate to severe COPD. http://www.abstracts2view.com2003.
Pauwels RA, Calverly PMA, Vestbo J, Jones PW, Pride N, Gulsvik A, et al. Reduction of exacerbations with salmeterol/fluticasone combination 50/500 mcg bd in the treatment of chronic obstructive pulmonary disease. European Respiratory Journal 2002;20 Suppl 38:240 [P1569].
SFCB3024. A multicentre, randomised, double‐blind, parallel group, placebo‐controlled study to compare the efficacy and safety of the salmeterol/FP combination product at a strength of 50/500mcg bd with salmeterol 50mcg bd alone and FP 500mcg bd alone, delivered via the DISKUS™/ACCUHALER™, in the treatment of subjects with chronic obstructive pulmonary disease (COPD) for 12 months. GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk)2005.
Spencer M, Briggs AH, Grossman RF, Rance L. Development of an economic model to assess the cost effectiveness of treatment interventions for chronic obstructive pulmonary disease. Pharmacoeconomics 2005;23(6):619‐37.
Spencer MD, Karia N, Anderson J. The clinical significance of treatment benefits with the salmeterol/fluticasone propionate 50/500mcg combination in COPD. European Respiratory Journal 2004;24 Suppl 48:290s.
Vestbo J, Calverley PMA, Pauwels R, Jones P, Pride N, Gulsvik A, et al. Absence of gender susceptibility to the combination of salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease. European Respiratory Journal 2002;20 Suppl 38:240 [P1570].
Vestbo J, Pauwels R, Anderson JA, Jones P, Calverley P. Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease. Thorax 2005;60(4):301‐4.
Vestbo J, Pauwels RS, Calverley PMA, Jones PW, Pride NB, Gulsvik A. Salmeterol / fluticasone propionate combination produces improvement in lung function detectable within 24 Hours in moderate to severe COPD. http://www.abstracts2view.com2003.
Vestbo J, Soriano JB, Anderson JA, Calverley P, Pauwels R, Jones P. Gender does not influence the response to the combination of salmeterol and fluticasone propionate in COPD. Respiratory Medicine 2004;98(11):1045‐50.

References to studies excluded from this review

Ir a:

Aaron 2007 {published data only}

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. Annals of Internal Medicine 2007;146(8):545‐55.
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.

Bourbeau 2007 {published data only}

Bourbeau J, Christodoulopoulos P, Maltais F, Yamauchi Y, Olivenstein R, Hamid Q. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: A randomised controlled trial. Thorax 2007;62(11):938‐43.

Cukier 2007 {published data only}

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.

Golabi 2006 {published data only}

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}

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. 2006:A848.

INSPIRE {published data only}

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 8th April 2008).
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.
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.

Lindberg 2007 {published data only}

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 2007;12(5):732‐9.
Lindberg A, Szalai Z, Pullertis T, Radeczky El. Budesonide/formoterol (B/F) has an onset of action that is similar to salbutamol and faster than salmeterol/fluticasone in patients with COPD. European Respiratory Journal 2006;28 Suppl 50:214s.

Schermer 2007 {published data only}

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..

Sethi 2006 {published data only}

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. 2006:A115.

Sutherland 2006 {published data only}

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}

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.

Zheng 2006 {published data only}

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.
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.

Appleton 2006

Appleton S, Poole P, Smith B, Veale A, Lasserson TJ, Chan MM, et al. Long‐acting beta2‐agonists for poorly reversible chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD001104]

Burge 2000

Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, MaslenTK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297‐303. [ISOLDE]

Calverley 2005

Calverley P, Pauwels 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.

Cazzola 2008

Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. European Respiratory Journal 2008;31:416‐68.

Celli 2008

Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. American Journal of Respiratory and Critical Care Medicine 2008;178(4):332‐8.

Dahl 2001

Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne AM, Thomson MH, et al. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. American Journal of Resiratory Critical Care Medicine 2001;164(5):778–84.

GOLD 2010

Global Strategy for Diagnosis, Management, Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease. http://www.goldcopd.org2010.

Higgins 2008

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane‐handbook.org.

Jones 2005

Jones PW. St George’s Respiratory Questionnaire: MCID. COPD: Journal of Chronic Obstructive Pulmonary Disease 2005;2:75‐9.

Karner 2011

Karner C, Cates CJ. Long‐acting beta2‐agonist in addition to tiotropium versus either tiotropium or long‐acting beta2‐agonist alone for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 2. [DOI: 10.1002/14651858.CD008989]

Karner 2011a

Karner C, Cates CJ. The effect of adding inhaled corticosteroids to tiotropium and long‐acting beta2‐agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 9. [DOI: 10.1002/14651858.CD009039.pub2]

Karner 2011b

Karner C, Cates CJ. Combination inhaled steroid and long‐acting beta2‐agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/14651858.CD008532.pub2]

Karner 2012

Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 7. [DOI: 10.1002/14651858.CD009285.pub2]

Leidy 2003

Leidy NK, Schmier JK, Jones MKC, et al. Evaluating symptoms in chronic obstructive pulmonary disease: validation of the Breathlessness, Cough and Sputum Scale. Respiratory Medicine 2003;97 Suppl A:59‐70.

Mahler 1999

Mahler DA, Donohue JF, Barbee RA, Goldman MD, Gross NJ, Wisniewski ME, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999;115(4):957‐65.

Miravitlles 2004

Miravitlles M, Ferrer M, Pont A, Zalacain R, Alvarez‐Sala JL, Masa F, et al. Effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a 2 year follow up study. Thorax 2004;59(5):387‐95.

Miravitlles 2007

Miravitlles M, Anzueto A, Legnani D, Forstmeier L, Fargel M. Patient's perception of exacerbations of COPD ‐ the PERCEIVE study. Respiratory Medicine 2007;101(3):453‐60.

Nannini 2007a

Nannini L, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long‐acting beta‐agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2007, Issue 4. [DOI: 10.1002/14651858.CD006826]

Nannini 2010

Nannini LJ, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long‐acting beta‐agonist in one inhaler versus inhaled steroids for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD006826]

NICE 2010

National Collaborating Centre for Chronic Conditions. Managament of chronic obstructive pulmonary disease in primary and secondary care. http://www.nice.org.uk 2010;available at http://guidance.nice.org.uk/CG101/Guidance/pdf/English:1‐673.

Osman 1997

Osman IM, Godden DJ, Friend JA, Legge JS, Douglas JG. Quality of life and hospital re‐admission in patients with chronic obstructive pulmonary disease. Thorax 1997;52(1):67‐71.

RevMan 5 [Computer program]

Copenhagen, The Nordic Cochrane Centre: The Cochrane Collaboration. Review Manager (RevMan) Version 5.1. Copenhagen, The Nordic Cochrane Centre: The Cochrane Collaboration, 2008.

Roisin 2000

Rodriguez‐Roisin R. Toward a consensus definition of for COPD exacerbations. Chest 2000;117(5):398s‐401s.

Singh 2009

Singh S, Amin AV, Loke YK. Long‐term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta‐analysis. Archives of Internal Medicine 2009;169(3):219‐29. [PUBMED: 19204211]

Singh 2010

Singh Sonal, Loke YK. An overview of the benefits and draw backs of inhaled corticosteroids in chronic obstructive pulmonary disease. International Journal of Chronic Obstructive Pulmonary Disease 2010;5:189‐95.

Spencer 2011

Spencer S, Karner C, Cates CJ, Evans DJ. Inhaled corticosteroids versus long‐acting beta2‐agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 12. [DOI: 10.1002/14651858.CD007033.pub3]

Suissa 2006

Suissa S. Statistical treatment of exacerbations in therapeutic trials of chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2006;173(8):842‐6.

Sutherland 2003

Sutherland ER, Allmers H, Ayas NT, Venn AJ, Martin RJ. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta‐analysis. Thorax 2003;58:937‐41.

Visual Rx [Computer program]

Cates CJ. Visual Rx 2.0. 2003.

Welsh 2011

Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long‐acting beta2‐agonist versus tiotropium for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 7. [DOI: 10.1002/14651858.CD007891.pub2]

Yang 2007

Yang IA, Fong KM, Sim EHA, Black PN, Lasserson TJ. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2007, Issue 2. [DOI: 10.1002/14651858.CD002991]

References to other published versions of this review

Ir a:

Nannini 2002

Nannini L, Poole P. Combined corticosteroid and longacting bronchodilator in one inhaler for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2002, Issue 3. [DOI: 10.1002/14651858.CD003794]

Nannini 2004

Nannini L, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long‐acting beta‐agonist in one inhaler for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD003794.pub2]

Nannini 2007

Nannini L, Lasserson TJ, Poole P. Combined corticosteroid and long‐acting beta‐agonist in one inhaler for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2007, Issue 4. [DOI: 10.1002/14651858.CD006829]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

Anzueto 2009

Methods

Randomised, double‐blind parallel study. Duration: 52 weeks.

Participants

  1. Setting: 98 centre in USA and Canada. (study code SCO100250, clinicaltrials.gov# NCT00115492)

  2. Participants randomised: 797 (FPS: 394; salmeterol: 403)

  3. Baseline characteristics: Mean age: 65.4. Mean FEV1: 0.98L

  4. Inclusion criteria: aged ≥40 yrs. History ≥ 10 pack‐years, a pre‐albuterol FEV1/FVC ≤ 0.70, a

  5. FEV1 ≤ 50% of predicted normal and a documented history of at least 1 COPD exacerbation the year prior to the study that required treatment with antibiotics, oral corticosteroids, and/or hospitalisation.

  6. Exclusion criteria: current diagnosis of asthma, a respiratory disorder other than COPD, historical or current evidence of a clinically significant uncontrolled disease, or had a COPD exacerbation that was not resolved at screening

Interventions

Run‐in 4 weeks with open‐label fluticasone/salmeterol 250/50 Diskus BID. Following run‐in, subjects were randomised to FPS 250/50 or salmeterol twice‐daily via DISKUS for 52 weeks. Clinic visits were conducted at screening, day 1 (randomisation), and after 4, 8, 12, 20, 28, 36, 44, and 52 weeks. Treatments were assigned in blocks using a centre‐based randomisation schedule. Assignment to blinded study medication was stratified based on subjects' FEV1 response to albuterol at screen visit. Oral corticosteroids and antibiotics were allowed for the acute treatment of a COPD exacerbation.

Outcomes

The primary efficacy endpoint was the annual rate of moderate/severe exacerbations. Secondary endpoints were the time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre‐dose FEV1. Related endpoints included the annual rate of all exacerbations, time to onset of each moderate/severe exacerbation, and diary records of dyspnoea scores, nighttime awakenings due to COPD, and use of supplemental albuterol.

Notes

The run‐in with combined therapy precluded exacerbations due to ICS withdrawal.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Assigned in block centre‐based randomisation schedule and stratified according to salbutamol response in FEV1 at baseline.

Allocation concealment (selection bias)

Unclear risk

Information not available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical Diskus inhaler device.

Incomplete outcome data (attrition bias)
Mortality

High risk

39% discontinued on salmeterol and 32% on FPS.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

39% discontinued on salmeterol and 32% on FPS.

Selective reporting (reporting bias)

Low risk

Contributes data to all primary outcomes.
Calverley 2003

Methods

Parallel group study. Randomisation: unclear. Blinding: double‐blind (identical inhaler devices). Trial duration: 12 months with two week run‐in of treatment optimisation. Allocation concealment: unclear. Withdrawals: stated. Intention‐to‐treat analysis: stated.

Participants

  1. Setting: 109 centres in 15 countries.

  2. Participants randomised: 509 (BDF: 254; formoterol: 255). Additional treatment groups not covered in this review: Budesonide: 257; PLA: 256.

  3. Baseline characteristics: mean age: 64; mean FEV1 L: 1; mean FEV1 % predicted: 36; mean SGRQ: 48.

  4. Inclusion criteria: GOLD defined COPD (stages III and IV); ≥ 40 years; COPD symptoms >2 years; smoking history ≥ 10 pack years; FEV1/VC ≤ 70% pre‐BD; FEV1 ≤ 50% predicted; use of SABAs as reliever medication; >/= 1 COPD exacerbation requiring OCS/antibiotics 2‐12 months before 1st clinic visit.

  5. Exclusion criteria: History of asthma/rhinitis before 40 years of age; any relevant cardiovascular disorders; exacerbation of COPD requiring medical intervention within 4 weeks of run‐in/during run‐in phase; non‐allowed medications: O2 therapy; ICS ‐ (aside from study medication), disodium cromoglycate, leukotriene‐antagonists, 5‐LO inhibitors, BD (other than study medication and prn terbutaline 0.5 mg), antihistamines, medication containing ephedrine, ß‐blocking agents.

Interventions

Run‐in phase: All participants received 30 mg oral prednisolone BiD and 2 x 4.5 mcg formoterol BiD (2 weeks).

  1. BDF: 320/9 mcg bid.

  2. formoterol: 9 mcg bid.

Additional treatment groups not covered in this review:

  1. Budesonide: 400 mcg bid.

  2. Placebo (lactose monohydrate).

Inhaler device: Turbuhaler.

Outcomes

Time to first exacerbation; change in post‐medication FEV1; number of exacerbations; time to and number of OCS‐treated episodes; am and pm PEF, slow VC, HRQL, symptoms, use of reliever medication, AEs.

Notes

Classified as 'poorly reversible population'. P values used to calculate pooled SEMs for the following outcomes: Health related quality of life; FEV1; rescue medication.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomised; no other information reported.

Allocation concealment (selection bias)

Unclear risk

Information not available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

High risk

44% withdrew on formoterol and 29% on BDF.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

44% withdrew on formoterol and 29% on BDF.

Selective reporting (reporting bias)

High risk

No data available for analysis of exacerbations as dichotomous data or hospitalisations.
Dal Negro 2003

Methods

Parallel group study. Trial duration: 12 months. Baseline characteristics: comparable. Intention‐to‐treat analysis: Yes.

Participants

  1. Setting: Single centre in Italy.

  2. Participants randomised: 12 (FPS: 6; salmeterol: 6). Additional treatment groups not covered in this review: placebo: 6.

  3. Baseline characteristics: Age range: 53‐78; moderate COPD; mean FEV1 (L): 1.46; mean FEV1 (% predicted): 48; mean PEF (L/min): 180; mean reversibility (% baseline): 3.2.

  4. Inclusion criteria: baseline FEV1 % predicted: ≤ 80%; FEV1 > 800 mL; FEV1/FVC ratio: ≤ 70% predicted; FEV1 change of ≤ 12% predicted post 400 mg salmeterol; regular treatment with oral theophylline 20 mg BiD; SABA prn (for at least 6 months); current/ex‐smokers with smoking history of at least 10 pack years.

  5. Exclusion criteria: Current evidence of asthma or other pulmonary diseases; regular treatment with ICS; unstable respiratory disease requiring oral/parenteral CS within 4 weeks prior to the beginning of the study; changes in COPD medication in last 4 weeks before entering run‐in; upper/lower respiratory tract infection within 4 weeks before last screening visit; unstable angina/unstable arrhythmias; recent MI/heart failure; insulin‐dependent diabetes mellitus; neuropsychiatric disorders; concurrent use of medications that affect COPD (e.g. ß‐blockers), or interact with methylxanthine products, e.g. macrolides or fluoroquinolones; known/suspected hypersensitivity to ICS, ß‐agonist or lactose; evidence of alcohol abuse.

Interventions

Run‐in: 2 weeks treatment with theophylline and prn SABA.

  1. FPS 50/250 mcg bid.

  2. salmeterol 50mcg bid.

Additional treatment groups not covered in this review

  1. placebo.

Participants were on concomitant therapy: SABA prn and theophylline 400ug/day, for 12 months.

Inhaler device: Diskus.

Outcomes

FEV1, Delta FEV1, PEF am, symptom scores, rescue medication use, exacerbations (event rate and mean number per year).

Notes

Classified as 'poorly reversible population'. Mild exacerbation: requirement for increase in SABA prn by >2 occasions/24hrs on two or more consecutive days compared with baseline mean of last seven days of run‐in Moderate exacerbation: condition requiring treatment with antibiotics and/or oral corticosteroids Severe exacerbation: Condition requiring emergency hospital treatment and/or hospitalisation.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomised; no other information reported.

Allocation concealment (selection bias)

Unclear risk

Information not available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

Unclear risk

Only 12 participants.

Incomplete outcome data (attrition bias)
All other outcomes

Unclear risk

Only 12 participants.

Selective reporting (reporting bias)

High risk

No data available for the primary outcomes.
Ferguson 2008

Methods

Randomised, double‐blind, parallel group study (study code SCO40043). Treatments were assigned in blocks using a centre based randomisation schedule. Patients were stratified based on FEV1 response to albuterol at screening. Study duration: 52 weeks.

Participants

  1. Setting: Conducted at 94 research sites in the United States and Canada.

  2. Participants randomised: 782 (FPS: 394; salmeterol: 388).

  3. Baseilne characteristics: Mean age: 64 years; mean FEV1: 0.94L.

  4. Inclusion criteria: 40 years of age or older with a diagnosis of COPD,16 a cigarette smoking history of greater than or equal to 10 pack‐years, a pre‐albuterol FEV1/FVC of 0.70 or less, a FEV1 of 50% of predicted normal or less and a history of one or more exacerbations of COPD in the year prior to the study that required treatment with oral corticosteroids, antibiotics, or hospitalisation.

  5. Exclusion criteria: diagnosis of asthma, a significant lung disease other than COPD, a clinically significant and uncontrolled medical disorder including but not limited to cardiovascular, endocrine or metabolic, neurological, psychiatric, hepatic, renal, gastric, and neuromuscular diseases, or had a COPD exacerbation that was not resolved at screening.

Interventions

4‐week run‐in period with open‐label FPS 250/50 via DISKUS. FPS 250/50 or salmeterol 50 mg twice daily via DISKUS for 12 months. As‐needed albuterol was provided for use throughout the study. Nine visits after screening.

Outcomes

Annual rate of moderate to severe exacerbations. Time to first moderate to severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre‐dose FEV1. Related endpoints were the annual rate of all exacerbations (mild and moderate to severe), duration of moderate to severe exacerbations, time to onset of each moderate to severe exacerbation. Exacerbation recovery time (determined by length of oral corticosteroid and antibiotic courses and hospital stays) and diary records of dyspnoea, nighttime awakenings due to COPD, and use of supplemental albuterol.

Notes

In 782 patients with COPD (mean FEV1 Z0.94 0.36 L, 33% predicted normal), treatment with fluticasone propionate/salmeterol 250/50 significantly reduced (1) the annual rate of moderate to severe exacerbations by 30.5% compared with salmeterol (1.06 and 1.53 per subject per year, respectively, P < 0.001.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Treatments were assigned in blocks using a centre based randomisation schedule. Patients were stratified based on FEV1 response to albuterol at screening.

Allocation concealment (selection bias)

Unclear risk

No details in the paper.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Following run in, patients were randomised to FPS 250/50 or salmeterol 50 mg (Serevent; GlaxoSmithKline) twice daily via DISKUS.

Incomplete outcome data (attrition bias)
Mortality

High risk

38% discontinued on salmeterol and 30% on FPS.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

38% discontinued on salmeterol and 30% on FPS.

Selective reporting (reporting bias)

High risk

Does not contribute data to the analysis of hospitalisations.
Hanania 2003

Methods

Parallel group study. Trial duration: 24 weeks with 2‐week run‐in period. Baseline characteristics: comparable. Intention‐to‐treat analysis: not stated.

Participants

  1. Setting: USA, multi‐centre (76 hospitals).

  2. Patients randomised: 360 (FPS: 183; salmeterol: 177). Additional treatment groups not covered in this review: placebo: 185; fluticasone: 183.

  3. Baseline characteristics: mean age: 64; mean FEV1: 1.27 L (42% predicted).

  4. Inclusion criteria: stable COPD, FEV1 40‐65% predicted, FEV1/FVC < 70% predicted, symptoms of chronic bronchitis and moderate dyspnoea.

  5. Exclusion criteria: current diagnosis of asthma, use of oral steroids in past 6 weeks, abnormal ECG, LTOT, moderate ‐ severe exacerbation in run‐in. Other significant medical disorder.

Interventions

Run‐in: 2 weeks treatment with placebo inhaler and prn SABA.

  1. FPS 50/250 mcg bid.

  2. salmeterol 50 mcg bid.

Additional treatment groups not covered in this review

  1. placebo

  2. fluticasone 250 mcg bid.

Inhaler device: Diskus.

Outcomes

Lung function: Change in FEV1 from baseline to end of study (M). PEF data not stratified by reversibility. Quality of life: CRDQ, CBSQ not stratified by reversibility. Dyspnoea and symptoms: Transitional Dyspnoea index, Baseline dyspnoea index not stratified by reversibility. Exacerbations. Rescue salbutamol use.

Notes

FEV1 reversibility < 12% or 200 mL (of baseline FEV1) Reversibility stratified data. Mean % increase non‐reversible patients = 8.8.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomised; other information not available.

Allocation concealment (selection bias)

Unclear risk

Information not available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

High risk

32% withdrew on salmeterol and 30% on FPS.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

32% withdrew on salmeterol and 30% on FPS.

Selective reporting (reporting bias)

High risk

Does not contribute data to analysis of exacerbations as rate ratios, mortality or hospitalisation.

Kardos 2007

Methods

Randomised controlled trial, parallel group design.
Trial duration: 52 weeks (4 week run‐in).
Baseline characteristics: comparable.
Intention‐to‐treat analysis stated.

Participants

  1. Setting: 95 centres in Germany.

  2. Participants randomised: 994 (two groups: FPS combination: 507; salmeterol: 487).

  3. Baseline characteristics: 64 years. 40% predicted FEV1; mean reversibility 7% predicted; Mean duration of COPD: 11 years.

  4. Inclusion criteria: M/F ≥40 years of age; diagnosis of severe or very severe COPD (according to GOLD criteria III or IV); FEV1 <50% predicted at visit 1 (FEV1 ±20% of visit one at visit two); 2 exacerbations prompting medical consultation in previous 12 months; Smoking history of >10 pack years.

  5. Exclusion criteria: Exacerbtion in 4 weeks prior to visit 1; LTOT; chronic systemic steroids.

Interventions

Run‐in: 4 weeks on stable medication.

  1. FPS 500/50 mcg bid.

  2. salmeterol 50 mcg bid.

Inhaler device: DPI.

Outcomes

Withdrawals; Exacerbations (defined according to Rodriguez Roisin Chest article at stages II and III); FEV1; Rescue medication; symptoms; SGRQ; adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer generated randomisation schedule.

Allocation concealment (selection bias)

Low risk

Centrally generated schedule.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identicial inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

High risk

21% discontinued on salmeterol and 20% on FPS.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

21% discontinued on salmeterol and 20% on FPS.

Selective reporting (reporting bias)

Low risk

Contributes data to all primary outcomes.
Mahler 2002

Methods

Randomised controlled parallel group study. Trial duration: 24 weeks. Baseline characteristics: comparable. Intention‐to‐treat analysis: stated.

Participants

  1. Setting: multi‐centre study (65 centres).

  2. Patients randomised: 325 (FPS: 165; salmeterol: 160). Additional treatment groups not covered in this review: placebo: 181; fluticasone: 168.

  3. Baseline characteristics: Mean age: 63; FEV1: 1.2‐3 L.

  4. Inclusion criteria: Participants with COPD according to ATS guidelines. Baseline pre‐bronchodilation FEV1 < 65% predicted and > 0.70L. Baseline pre‐bronchodilation FEV1/FVC < 70% predicted. Age > 40, 20 pack‐year history smoking, day or night symptoms present on 4 out of last 7 days during run‐in period.

  5. Exclusion criteria: history of asthma, corticosteroid use in last 6 weeks, abnormal ECG, oxygen therapy, moderate or severe exacerbation during run‐in, significant concurrent disease.

Interventions

Run‐in: 2 weeks treatment with placebo inhaler and prn SABA.

  1. FPS 500/50 mcg bid.

  2. salmeterol 50 mcg bid.

Additional treatment groups not covered in this review

  1. placebo

  2. fluticasone 500 mcg bd.

Inhaler device: Diskus.

Outcomes

Lung function: Change in FEV1 from baseline to end of study (M). Quality of life: CRDQ, CBSQ not stratified by reversibility. Dyspnoea and symptoms: End of study dyspnoea (TDI). Exacerbations. Rescue salbutamol use.

Notes

COPD subjects reversible and non‐reversible, < 15% (baseline) improvement in FEV1 to salbutamol. Reversibility stratified data. Mean FEV1 reversibility 11.0%.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomised; stratified by reversibility and investigative site.

Allocation concealment (selection bias)

Unclear risk

Information not available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

High risk

28% withdrew on salmeterol and 32% on FPS.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

28% withdrew on salmeterol and 32% on FPS.

Selective reporting (reporting bias)

High risk

Does not contribute data to analysis of exacerbations as rate ratios, mortality or hospitalisations.

O'Donnell 2006

Methods

Randomised controlled parallel group design.
Trial duration: 8 weeks.
Baseline characteristics: comparable. Intention‐to‐treat analysis stated.

Participants

  1. Setting: 22 centres in North America.

  2. Participants randomised: 126 (FPS: 62; salmeterol: 59).

  3. Baseline characteristics: 65 years; FEV1: 1.12L.

  4. Inclusion criteria: M/F >/=40 years of age; diagnosis of COPD; >/=10 pack year; baseline Borg dyspnoea index <7; FEV1 <70% predicted; FRC ≥120% predicted.

  5. Exclusion criteria: Current diagnosis of asthma; use of xanthines/LABAs/OCS/ICS.

Interventions

Run‐in: 2 weeks, single‐blind placebo.

  1. FPS 500/50 mcg bid.

  2. salmeterol 50mcg bid.

Additional treatment groups not covered in this review

  1. placebo.

Inhaler device: DPI.

Outcomes

Withdrawals; exercise time; FEV1; adverse events.

Notes

Study downloaded from ctr.gsk.co.uk

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomised; other information not available.

Allocation concealment (selection bias)

Unclear risk

Information not available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

Low risk

One patient withdrew on salmeterol and three on FPS.

Incomplete outcome data (attrition bias)
All other outcomes

Low risk

One patient withdrew on salmeterol and three on FPS.

Selective reporting (reporting bias)

High risk

Does not contribute data to the analysis of exacerbations as rate ratios, mortality or hospitalisations.

Rennard 2009

Methods

Randomised, double‐blind, double dummy, parallel group, active and placebo‐controlled, multi‐centre trial.

Participants

  1. Setting: It was conducted from 2005 to 2007 at 237 sites in the US, Europe and Mexico.

  2. Participants randomised: 1483 (BDF 320/9: 494; BDF 160/9: 494; formoterol: 495).

  3. Baseline characteristics: Mean age: 63 years. FEV1 1L.

  4. Inclusion criteria: Moderate to very severe COPD with previous exacerbations age > 40 years, diagnosis of symptomatic COPD for >2 years, >10 pack‐year smoking history, pre‐bronchodilator FEV1 of < 50% of predicted normal and pre‐bronchodilator FEV1/FVC of <70%. Patients were to have a Modified Medical Research Council dyspnoea scale score of >2 and a history of at least one COPD exacerbation requiring oral corticosteroids or antibacterials within 1–12 months before the first study visit.

  5. Exclusion criteria: Same as Tashkin 2008.

Interventions

4 weeks run‐in where ICS was permitted. Four groups: Budesonide/formoterol HFA pressurized metered‐dose inhaler 160/4.5 BID. Budesonide/formoterol HFA pressurized metered‐dose inhaler 80/4.5 BID. Formoterol dry powder inhaler 4.5 BID. Placebo. Duration: 12 months.

Outcomes

1) pre‐dose and 1‐hour post‐dose FEV1 2) FVC measured at all clinic visits, and 3) morning and evening peak expiratory flow(PEF) recorded daily. 4)exacerbations. 5) dyspnoea. 6) health status.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation in one of four treatments.

Allocation concealment (selection bias)

Unclear risk

Information not available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Patients received both a pressurized metered‐dose inhaler (pMDI) and a dry powder inhaler (DPI) containing either active treatment or double‐dummy placebo as appropriate.

Incomplete outcome data (attrition bias)
Mortality

High risk

32% discontinued on formoterol and 28% on BDF.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

32% discontinued on formoterol and 28% on BDF.

Selective reporting (reporting bias)

High risk

Does not contribute data to analysis of exacerbations as dichotomous data or hospitalisations.
SCO100470

Methods

RCT, parallel group design. Trial duration: 24 weeks.
Baseline characteristics: comparable. Intention‐to‐treat analysis: stated.

Participants

  1. Setting: 135 centres in Europe and Asia Pacific.

  2. Participants randomised: 1050 (two groups: FPS combination: 518; salmeterol: 532).

  3. Baseline characteristics: Mean age: 64 years; FEV1: 1.67L; am PEF: 274; SGRQ: 48.

  4. Inclusion criteria: M/F 40‐80 years of age; diagnosis of COPD (according to GOLD criteria); ≥ 2 on MRC dyspnoea scale; poor reversibility of < 10% predicted normal (and < 200 mL); FEV1/FVC ratio < 70% predicted; ≥10 pack year smoking history.

  5. Exclusion criteria: Not described.

Interventions

  1. salmeterol 50 mcg bid.

  2. FPS 500/50 mcg bid.

Inhaler device: DPI.

Outcomes

Withdrawals; FEV1; morning PEF; quality of life (SQRG); symptoms (TDI) adverse events.

Notes

Unpublished study downloaded from ctr.gsk.co.uk

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as randomised; other information not available.

Allocation concealment (selection bias)

Unclear risk

Information not available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

Unclear risk

14% withdrew on salmeterol and 11% on FPS.

Incomplete outcome data (attrition bias)
All other outcomes

Unclear risk

14% withdrew on salmeterol and 11% on FPS.

Selective reporting (reporting bias)

High risk

Does not contribute data to analysis of exacerbations as rate ratio, dichotomous data or hospitalisations.

Szafranski 2003

Methods

Parallel group study. Intention‐to‐treat analysis: stated.

Participants

  1. Setting: 89 centres in Central and South America, Europe and South Africa.

  2. Participants randomised: 409 (BDF: 208; formoterol: 201).

  3. Baseline characteristics: Mean age: 64 years mean FEV1 %predicted: 36%, mean reversibility 6% predicted normal.

  4. Inclusion criteria: Age ≥ 40 years; COPD for ≥ 2 years; smoking history ≥ 10 pack years; FEV1 ≤ 50% predicted; FEV1/FVC ≤ 70%; Symptom score ≥ 2 during at least 7 days of run‐in; use of bronchodilators for reliever medication; ≥ 1 severe COPD exacerbation within 2‐12 months before study entry.

  5. Exclusion criteria: history of asthma/rhinitis before age of 40; using beta‐blockers; current respiratory tract disease other than COPD.

Interventions

Run‐in: 2 weeks. Treatment with prn SABA only.

  1. BDF 320/9 mcg bid.

  2. formoterol 9ug bid.

Additional treatment groups not covered in this review

  1. budesonide 400 mcg bid

  2. placebo.

Inhaler device: Turbuhaler.

Outcomes

Symptoms, adverse events, exacerbations, lung function.

Notes

Classified as 'poorly reversible' subgroup. Exacerbation defined as requirement of oral steroids and/or antibiotics and/or hospitalisation for respiratory symptoms. Mild exacerbation defined as requirement of >/= 4 inhalations per day. P values used to calculate pooled SEMs for following outcomes: Symptoms; rescue medication usage.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated scheme.

Allocation concealment (selection bias)

Low risk

At each centre, eligible patients received an enrolment code and then after run‐in, participants were allocated the next consecutive patient number.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

High risk

32% withdrew on formoterol and 28% on BDF.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

32% withdrew on formoterol and 28% on BDF.

Selective reporting (reporting bias)

High risk

Does not contribute data to analysis of exacerbations as dichotomous data, hospitalisations or pneumonia.

Tashkin 2008

Methods

6‐month, randomised, double‐blind, double‐dummy, placebo‐controlled, parallel group, multi‐centre study.

Participants

  1. Setting: 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa.

  2. Participants randomised: 1129 (BDF 320/9: 277; BDF: 160/9: 281; BUD 320 + formoterol 9: 287; formoterol: 284).

  3. Baseline characteristics: Mean age: 63.5 years; FEV1: 1.04L.

  4. Inclusion criteria: Moderate to very severe COPD with previous exacerbations age > 40 years, diagnosis of symptomatic COPD for >2 years, >10 pack‐year smoking history, pre‐bronchodilator FEV1 of < 50% of predicted normal and pre‐bronchodilator FEV1/FVC of <70%. Patients were to have a Modified Medical Research Council dyspnoea scale score of >2 and a history of at least one COPD exacerbation requiring oral corticosteroids or antibacterials within 1–12 months before the first study visit.

  5. Exclusion criteria: I) a history of asthma; (ii) a history of allergic rhinitis before 40 years of age; (iii) significant/unstable cardiovascular disorder; (iv) clinically significant respiratory tract disorder (v) homozygous α‐1 antitrypsin deficiency. Oral or ophthalmic non‐cardioselective β‐adrenoceptor antagonists, oral corticosteroids, pregnancy and breast‐feeding.

Interventions

After 2 weeks of treatment based on previous therapy (ICSs and short‐acting bronchodilators allowed during the run‐in period), patients received one of the following treatments
administered twice daily: budesonide/formoterol pressurised metered dose inhaler (pMDI) 160/4.5 μg BID; budesonide/formoterol pMDI 80/4.5 μg BID; budesonide pMDI 160 μg BID plus formoterol dry powder inhaler (DPI) 4.5 μg BID; budesonide pMDI 160 μg BID; formoterol DPI 4.5 μg BID; or placebo.

Outcomes

Pre‐dose and 1 hour post‐dose FEV1. 12‐hour spirometry, pre‐dose and 1‐hour post‐dose Inspiratory Capacity. Pre‐dose morning and evening PEF. Dyspnoea, health‐related quality of life. COPD exacerbations.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Balanced blocks according to a computer‐generated randomisation scheme at each site.

Allocation concealment (selection bias)

Unclear risk

Information not available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

To maintain blinding, patients received both a pressurized metered‐dose inhaler (pMDI) and a dry powder inhaler (DPI) containing either active treatment or placebo, or combinations of active treatment and placebo, as appropriate. (Double blind, double dummy design)

Incomplete outcome data (attrition bias)
Mortality

High risk

21% discontinued on LABA and 14% on combination therapy.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

21% discontinued on LABA and 14% on combination therapy.

Selective reporting (reporting bias)

Unclear risk

Does not contribute data to analysis of exacerbations as dichotomous data or hospitalisations.
TORCH

Methods

RCT, parallel group design. Trial duration: 156 weeks. Baseline characteristics: comparable. Intention‐to‐treat analysis: stated.

Participants

  1. Setting: 444 centres in North America, Central America and Asia Pacific.

  2. Participants randomised: 3088 (FPS: 1546; salmeterol: 1542).

  3. Baseline characteristics: 65 years; Male: 76%.

  4. Inclusion criteria: M/F 40‐80 years of age; diagnosis of COPD (ERS); <10% reversibility of predicted FEV1; FEV1/FVC ratio <70%; FEV1< 60% predicted; ≥10 pack year smoking history.

  5. Exclusion criteria: Asthma or respiratory diseases other than COPD; LVRS/lung transplant; requirement for >12hrs/day LTOT; long‐term OCS therapy; 'serious uncontrolled disease likely to interfere with medication/cause death in next three years'.

Interventions

Run‐in: 2 weeks. All maintenance treatment with ICS and LABA ceased.

  1. FPS combination 500/50 mcg BID.

  2. salmeterol 50 mcg BID.

Additional treatment groups not covered in this review

  1. fluticasone 500 mcg BID

  2. placebo.

Inhaler device: DPI.

Outcomes

All cause mortality; change in SGRQ; exacerbations (requiring antibiotics, steroids, hospitalisation or combination of these); lung function; withdrawals; adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated scheme. Permuted block randomisation with stratification for smoking status and country.

Allocation concealment (selection bias)

Low risk

Centralised randomisation scheme.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

Low risk

Mortality was the primary outcome and vital status was checked in those who withdrew.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

36.9% withdrew on salmeterol and 34.1% on FPS.

Selective reporting (reporting bias)

High risk

Does not contribute data to analysis of exacerbations as dichotomous data.
TRISTAN

Methods

RCT, parallel group design. Trial duration: 2 week run‐in period, 52 weeks treatment, 2‐week follow‐up. Baseline characteristics: comparable. Intention‐to‐treat analysis: stated.

Participants

  1. Setting: 196 centres in Europe, South Africa and Australia.

  2. Participants randomised: 730 (FPS: 358; salmeterol: 372).

  3. Baseline characteristics: Mean age 63 years, mean FEV1 = 1.26 L (44% predicted).

  4. Inclusion criteria: Baseline FEV1 25 ‐ 75% predicted; FEV1/ FVC ratio ≤ 70%; Poor reversibility: < 10% increase of predicted FEV1 30 minutes after inhaling 400 mcg salbutamol; at least 10 pack years smoking history; history of exacerbations (at least 1 in the last year) requiring OCS and/or antibiotics. At least one episode of acute COPD per year in the previous 3 years.

  5. Exclusion criteria: respiratory disorders other than COPD. Oxygen treatment, systemic corticosteroids, high doses of inhaled corticosteroids (> 1000 mcg daily beclomethasone dipropionate, budesonide or flunisolide or > 500 mcg daily fluticasone) or antibiotics in the four weeks before the 2 week run‐in period.

Interventions

Run‐in: 2 weeks. All maintenance treatment with ICS and LABA ceased.

  1. FPS 50 mcg/500 mcg bid.

  2. salmeterol 50 mcg bid.

Additional treatment groups not covered in this review

  1. placebo

  2. fluticasone 500 mcg bid.

Inhaler device: DPI.

Outcomes

FEV1; PEF; exercise tolerance; quality of life: SGRQ; dyspnoea and symptoms (symptom score for shortness of breath, cough and sputum production); exacerbations (defined as requirement for antibiotics, oral steroids or both); rescue salbutamol use.

Notes

FEV1 reversibility (% predicted normal). Mean Reversibility (% predicted) = 3.8.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation scheme.

Allocation concealment (selection bias)

Low risk

Centralised, third party randomisation.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical inhaler devices.

Incomplete outcome data (attrition bias)
Mortality

High risk

32% withdrew on salmeterol and 25% on FPS.

Incomplete outcome data (attrition bias)
All other outcomes

High risk

32% withdrew on salmeterol and 25% on FPS.

Selective reporting (reporting bias)

High risk

Does not contribute data to analysis of exacerbations as dichotomous data or hospitalisations.

DPI: Dry powder inhaler

Characteristics of excluded studies [ordered by study ID]

Ir a:

Study

Reason for exclusion

Aaron 2007

All the arms had tiotropium

Bourbeau 2007

Inflammatory outcomes for FPS

Cukier 2007

Combination of oxygen and bronchodilators

Golabi 2006

Combined with tiotropium and different outcomes

Haque 2006

Bench research of glucocorticoids receptors

INSPIRE

ARM with LAMA (tiotropium)

Lindberg 2007

Short term. Outcome was onset of action. No LABA alone arm

Schermer 2007

Only one arm with FPS

Sethi 2006

Outcome was bacterial colonization for FPS

Sutherland 2006

Genetic study of FPS

Trofimenko 2006

FPS with no comparison

Zheng 2006

FPS with no comparison

Data and analyses

Open in table viewer
Comparison 1. Combined inhalers versus long‐acting beta‐agonists (primary outcomes)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbation rates (combined inhaler versus LABA alone) Show forest plot

9

Rate ratio (Random, 95% CI)

0.76 [0.68, 0.84]
Analysis 1.1
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 1 Exacerbation rates (combined inhaler versus LABA alone).

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 1 Exacerbation rates (combined inhaler versus LABA alone).

1.1 Fluticasone/salmeterol

5

Rate ratio (Random, 95% CI)

0.77 [0.66, 0.89]

1.2 Budesonide/formoterol

4

Rate ratio (Random, 95% CI)

0.73 [0.64, 0.83]

2 Number of participants with one or more exacerbation Show forest plot

6

3357

Odds Ratio (M‐H, Random, 95% CI)

0.83 [0.70, 0.98]
Analysis 1.2
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 2 Number of participants with one or more exacerbation.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 2 Number of participants with one or more exacerbation.

2.1 Fluticasone/salmeterol

6

3357

Odds Ratio (M‐H, Random, 95% CI)

0.83 [0.70, 0.98]

2.2 Budesonide/formoterol

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Hospitalisations Show forest plot

3

Rate ratio (Random, 95% CI)

Subtotals only
Analysis 1.3
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 3 Hospitalisations.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 3 Hospitalisations.

3.1 Fluticasone/salmeterol

3

Rate ratio (Random, 95% CI)

0.79 [0.55, 1.13]

4 Mortality Show forest plot

10

10681

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.76, 1.11]
Analysis 1.4
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 4 Mortality.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 4 Mortality.

4.1 Fluticasone/salmeterol

6

7408

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.76, 1.13]

4.2 Budesonide/formoterol

4

3273

Odds Ratio (M‐H, Random, 95% CI)

1.03 [0.40, 2.67]

5 Pneumonia Show forest plot

12

11076

Odds Ratio (M‐H, Random, 95% CI)

1.55 [1.20, 2.01]
Analysis 1.5
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 5 Pneumonia.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 5 Pneumonia.

5.1 Fluticasone/salmeterol

9

8242

Odds Ratio (M‐H, Random, 95% CI)

1.75 [1.25, 2.45]

5.2 Budesonide/formoterol

3

2834

Odds Ratio (M‐H, Random, 95% CI)

1.09 [0.69, 1.73]

6 Pneumonia subgrouped by dose Show forest plot

12

11076

Odds Ratio (M‐H, Random, 95% CI)

1.56 [1.26, 1.93]
Analysis 1.6
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 6 Pneumonia subgrouped by dose.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 6 Pneumonia subgrouped by dose.

6.1 Lower dose FPS (250/50 bid)

3

1934

Odds Ratio (M‐H, Random, 95% CI)

2.19 [1.35, 3.53]

6.2 Higher dose FPS (500/50 bid)

6

6308

Odds Ratio (M‐H, Random, 95% CI)

1.55 [0.92, 2.61]

6.3 Lower dose BDF (160/9 bid)

2

1164

Odds Ratio (M‐H, Random, 95% CI)

1.10 [0.53, 2.26]

6.4 Higher dose BDF (320/9 bid)

3

1670

Odds Ratio (M‐H, Random, 95% CI)

1.08 [0.60, 1.97]
Open in table viewer
Comparison 2. Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbations by type Show forest plot

5

Rate ratio (Random, 95% CI)

Subtotals only
Analysis 2.1
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 1 Exacerbations by type.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 1 Exacerbations by type.

1.1 Requirement for oral steroids

4

Rate ratio (Random, 95% CI)

0.71 [0.62, 0.81]

1.2 Hospitalisation

3

Rate ratio (Random, 95% CI)

0.79 [0.55, 1.13]

2 Mortality by duration Show forest plot

6

7408

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.76, 1.13]
Analysis 2.2
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 2 Mortality by duration.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 2 Mortality by duration.

2.1 Mortality: three year data

1

3054

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.75, 1.14]

2.2 Mortality: >one and <three year data

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Mortality: one year data

5

4354

Odds Ratio (M‐H, Random, 95% CI)

0.94 [0.51, 1.70]

2.4 Mortality: 6 month data

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Change from baseline in St George's Respiratory Questionnaire (total score) Show forest plot

6

SGRQ units (Random, 95% CI)

‐1.58 [‐2.15, ‐1.01]
Analysis 2.3
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (total score).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (total score).

4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms) Show forest plot

4

St George's RQ score (Random, 95% CI)

‐2.78 [‐3.88, ‐1.68]
Analysis 2.4
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).

5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity) Show forest plot

4

SGRQ units (Random, 95% CI)

‐1.31 [‐2.38, ‐0.24]
Analysis 2.5
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).

6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact) Show forest plot

4

SGRQ units (Random, 95% CI)

‐1.41 [‐2.33, ‐0.50]
Analysis 2.6
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).

7 End of treatment St George's Respiratory Questionnaire scores (total score) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Analysis 2.7
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 7 End of treatment St George's Respiratory Questionnaire scores (total score).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 7 End of treatment St George's Respiratory Questionnaire scores (total score).

8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Analysis 2.8
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms).

9 Change from baseline in Chronic Respiratory Disease Questionnaire scores Show forest plot

2

680

Mean Difference (IV, Random, 95% CI)

2.83 [0.25, 5.41]
Analysis 2.9
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 9 Change from baseline in Chronic Respiratory Disease Questionnaire scores.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 9 Change from baseline in Chronic Respiratory Disease Questionnaire scores.

10 End of treatment Transitional dyspnea index (TDI) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Analysis 2.10
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 10 End of treatment Transitional dyspnea index (TDI).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 10 End of treatment Transitional dyspnea index (TDI).

11 End of treatment symptom scores Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Analysis 2.11
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 11 End of treatment symptom scores.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 11 End of treatment symptom scores.

12 Change from baseline in Transitional Dyspnoea Index (TDI) Show forest plot

2

677

Mean Difference (IV, Random, 95% CI)

0.61 [‐0.47, 1.68]
Analysis 2.12
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 12 Change from baseline in Transitional Dyspnoea Index (TDI).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 12 Change from baseline in Transitional Dyspnoea Index (TDI).

13 Change in MRC rated dyspnoea Show forest plot

1

symptoms (Random, 95% CI)

Totals not selected
Analysis 2.13
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 13 Change in MRC rated dyspnoea.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 13 Change in MRC rated dyspnoea.

14 Change from baseline in dyspnoea score Show forest plot

2

Mean Difference (Random, 95% CI)

‐0.09 [‐0.13, ‐0.05]
Analysis 2.14
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 14 Change from baseline in dyspnoea score.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 14 Change from baseline in dyspnoea score.

15 Mean Change nighttime awakenings Show forest plot

2

1554

Mean Difference (IV, Random, 95% CI)

‐1.34 [‐2.07, ‐0.61]
Analysis 2.15
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 15 Mean Change nighttime awakenings.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 15 Mean Change nighttime awakenings.

16 Change from baseline in predose FEV1 Show forest plot

5

Litres (Random, 95% CI)

0.07 [0.05, 0.10]
Analysis 2.16
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 16 Change from baseline in predose FEV1.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 16 Change from baseline in predose FEV1.

16.1 Reversible population

3

Litres (Random, 95% CI)

0.07 [0.02, 0.12]

16.2 Partially reversible population (mixed population)

2

Litres (Random, 95% CI)

0.08 [0.04, 0.12]

16.3 Poorly reversible population

2

Litres (Random, 95% CI)

0.06 [0.01, 0.12]

17 Change from baseline in postdose FEV1 Show forest plot

3

Litres (Random, 95% CI)

0.05 [0.03, 0.06]
Analysis 2.17
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 17 Change from baseline in postdose FEV1.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 17 Change from baseline in postdose FEV1.

18 End of treatment FEV1 (Litres) Show forest plot

2

1780

Mean Difference (IV, Random, 95% CI)

0.01 [‐0.02, 0.03]
Analysis 2.18
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 18 End of treatment FEV1 (Litres).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 18 End of treatment FEV1 (Litres).

19 FEV1 (% predicted ‐ absolute scores) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Analysis 2.19
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 19 FEV1 (% predicted ‐ absolute scores).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 19 FEV1 (% predicted ‐ absolute scores).

20 Change from baseline in am PEF (L/min) Show forest plot

2

L/min (Random, 95% CI)

11.61 [7.91, 15.30]
Analysis 2.20
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 20 Change from baseline in am PEF (L/min).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 20 Change from baseline in am PEF (L/min).

21 Change from baseline in rescue medication usage (puffs/day) Show forest plot

4

2435

Mean Difference (IV, Random, 95% CI)

‐0.38 [‐0.61, ‐0.16]
Analysis 2.21
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 21 Change from baseline in rescue medication usage (puffs/day).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 21 Change from baseline in rescue medication usage (puffs/day).

22 End of treatment rescue medication usage (puffs/day) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Analysis 2.22
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 22 End of treatment rescue medication usage (puffs/day).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 22 End of treatment rescue medication usage (puffs/day).

23 Adverse events ‐ any event Show forest plot

9

8250

Odds Ratio (M‐H, Random, 95% CI)

1.05 [0.93, 1.19]
Analysis 2.23
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 23 Adverse events ‐ any event.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 23 Adverse events ‐ any event.

24 Adverse events ‐ candidiasis Show forest plot

6

3118

Odds Ratio (M‐H, Random, 95% CI)

3.75 [2.33, 6.04]
Analysis 2.24
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 24 Adverse events ‐ candidiasis.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 24 Adverse events ‐ candidiasis.

25 Adverse events ‐ pneumonia Show forest plot

9

8242

Odds Ratio (M‐H, Random, 95% CI)

1.75 [1.25, 2.45]
Analysis 2.25
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 25 Adverse events ‐ pneumonia.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 25 Adverse events ‐ pneumonia.

26 Adverse events ‐ headache Show forest plot

8

7237

Odds Ratio (M‐H, Random, 95% CI)

1.06 [0.90, 1.26]
Analysis 2.26
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 26 Adverse events ‐ headache.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 26 Adverse events ‐ headache.

27 Adverse events ‐ upper respiratory tract infection Show forest plot

7

6198

Odds Ratio (M‐H, Random, 95% CI)

1.32 [1.12, 1.55]
Analysis 2.27
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 27 Adverse events ‐ upper respiratory tract infection.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 27 Adverse events ‐ upper respiratory tract infection.

28 Withdrawals Show forest plot

9

8226

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.77, 0.94]
Analysis 2.28
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 28 Withdrawals.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 28 Withdrawals.

29 Withdrawals due to lack of efficacy Show forest plot

6

6739

Odds Ratio (M‐H, Random, 95% CI)

0.53 [0.39, 0.72]
Analysis 2.29
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 29 Withdrawals due to lack of efficacy.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 29 Withdrawals due to lack of efficacy.

30 Withdrawals due to adverse events Show forest plot

8

7895

Odds Ratio (M‐H, Random, 95% CI)

0.90 [0.79, 1.02]
Analysis 2.30
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 30 Withdrawals due to adverse events.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 30 Withdrawals due to adverse events.

Open in table viewer
Comparison 3. Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Quality of life ‐ SGRQ (change scores) Show forest plot

4

3442

SGRQ (Random, 95% CI)

‐2.69 [‐3.82, ‐1.55]
Analysis 3.1
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 1 Quality of life ‐ SGRQ (change scores).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 1 Quality of life ‐ SGRQ (change scores).

2 Quality of life ‐ SGRQ (change scores) Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Totals not selected
Analysis 3.2
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 2 Quality of life ‐ SGRQ (change scores).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 2 Quality of life ‐ SGRQ (change scores).

3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms) Show forest plot

2

2233

Mean Difference (IV, Random, 95% CI)

‐3.43 [‐5.13, ‐1.72]
Analysis 3.3
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).

4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity) Show forest plot

2

2215

Mean Difference (IV, Random, 95% CI)

‐1.57 [‐2.87, ‐0.27]
Analysis 3.4
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).

5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact) Show forest plot

2

2222

Mean Difference (IV, Random, 95% CI)

‐2.28 [‐3.60, ‐0.95]
Analysis 3.5
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).

6 Mean FEV1 (% increase from baseline) Show forest plot

1

Std. Mean Difference (IV, Random, 95% CI)

Totals not selected
Analysis 3.6
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 6 Mean FEV1 (% increase from baseline).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 6 Mean FEV1 (% increase from baseline).

7 Mean change from baseline in pre dose FEV1 to the average over the randomised treatment period. Show forest plot

2

1203

Mean Difference (IV, Random, 95% CI)

0.05 [0.00, 0.09]
Analysis 3.7
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 7 Mean change from baseline in pre dose FEV1 to the average over the randomised treatment period..

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 7 Mean change from baseline in pre dose FEV1 to the average over the randomised treatment period..

8 Symptoms ‐ breathlessness (change scores) Show forest plot

2

2308

Mean Difference (IV, Random, 95% CI)

‐0.07 [‐0.12, ‐0.01]
Analysis 3.8
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 8 Symptoms ‐ breathlessness (change scores).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 8 Symptoms ‐ breathlessness (change scores).

9 Change from baseline in cough score Show forest plot

2

2308

Mean Difference (IV, Random, 95% CI)

‐0.06 [‐0.11, ‐0.00]
Analysis 3.9
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 9 Change from baseline in cough score.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 9 Change from baseline in cough score.

10 Change from baseline in rescue medication usage (puffs/day) Show forest plot

2

2310

Mean Difference (IV, Random, 95% CI)

‐0.33 [‐0.57, ‐0.09]
Analysis 3.10
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 10 Change from baseline in rescue medication usage (puffs/day).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 10 Change from baseline in rescue medication usage (puffs/day).

11 Adverse events ‐ 'serious' events Show forest plot

4

3243

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.69, 1.25]
Analysis 3.11
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 11 Adverse events ‐ 'serious' events.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 11 Adverse events ‐ 'serious' events.

12 Adverse events ‐ candidiasis Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only
Analysis 3.12
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 12 Adverse events ‐ candidiasis.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 12 Adverse events ‐ candidiasis.

13 Withdrawals due to adverse events Show forest plot

4

3243

Odds Ratio (M‐H, Random, 95% CI)

0.88 [0.65, 1.19]
Analysis 3.13
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 13 Withdrawals due to adverse events.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 13 Withdrawals due to adverse events.

14 Withdrawals due to worsening COPD symptoms Show forest plot

2

918

Odds Ratio (M‐H, Random, 95% CI)

0.49 [0.32, 0.74]
Analysis 3.14
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 14 Withdrawals due to worsening COPD symptoms.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 14 Withdrawals due to worsening COPD symptoms.

Flow chart to illustrate separation of review between three comparisons. Six RCTs met the original entry criteria of the review. All of these had a placebo and long‐acting beta2‐agonist arm, and five assessed combination against steroids. Seven new studies with one or more control comparisons were identified: five had a placebo arm, three had a long‐acting beta2agonist arm, and two had an inhaled steroid treatment arm.
Figuras y tablas -
Figure 1

Flow chart to illustrate separation of review between three comparisons. Six RCTs met the original entry criteria of the review. All of these had a placebo and long‐acting beta2‐agonist arm, and five assessed combination against steroids. Seven new studies with one or more control comparisons were identified: five had a placebo arm, three had a long‐acting beta2agonist arm, and two had an inhaled steroid treatment arm.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Study flow diagram for 2007‐2011 literature searches.
Figuras y tablas -
Figure 2

Study flow diagram for 2007‐2011 literature searches.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figuras y tablas -
Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Forest plot of comparison: 1 Combined inhalers versus long‐acting beta2‐agonists (primary outcomes), outcome: 1.1 Exacerbation rates (combined treatment versus beta2‐agonist).
Figuras y tablas -
Figure 4

Forest plot of comparison: 1 Combined inhalers versus long‐acting beta2‐agonists (primary outcomes), outcome: 1.1 Exacerbation rates (combined treatment versus beta2‐agonist).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Forest plot of comparison: 1 Combined inhalers versus Long‐acting beta2‐agonists (Primary Outcomes), outcome: 1.2 Mortality.
Figuras y tablas -
Figure 5

Forest plot of comparison: 1 Combined inhalers versus Long‐acting beta2‐agonists (Primary Outcomes), outcome: 1.2 Mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Forest plot of comparison: 1 Combined inhalers versus long‐acting beta2‐agonists (primary outcomes), outcome: 1.3 Pneumonia.
Figuras y tablas -
Figure 6

Forest plot of comparison: 1 Combined inhalers versus long‐acting beta2‐agonists (primary outcomes), outcome: 1.3 Pneumonia.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 1 Exacerbation rates (combined inhaler versus LABA alone).
Figuras y tablas -
Analysis 1.1

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 1 Exacerbation rates (combined inhaler versus LABA alone).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 2 Number of participants with one or more exacerbation.
Figuras y tablas -
Analysis 1.2

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 2 Number of participants with one or more exacerbation.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 3 Hospitalisations.
Figuras y tablas -
Analysis 1.3

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 3 Hospitalisations.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 4 Mortality.
Figuras y tablas -
Analysis 1.4

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 4 Mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 5 Pneumonia.
Figuras y tablas -
Analysis 1.5

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 5 Pneumonia.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 6 Pneumonia subgrouped by dose.
Figuras y tablas -
Analysis 1.6

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 6 Pneumonia subgrouped by dose.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 1 Exacerbations by type.
Figuras y tablas -
Analysis 2.1

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 1 Exacerbations by type.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 2 Mortality by duration.
Figuras y tablas -
Analysis 2.2

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 2 Mortality by duration.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (total score).
Figuras y tablas -
Analysis 2.3

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (total score).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).
Figuras y tablas -
Analysis 2.4

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).
Figuras y tablas -
Analysis 2.5

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).
Figuras y tablas -
Analysis 2.6

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 7 End of treatment St George's Respiratory Questionnaire scores (total score).
Figuras y tablas -
Analysis 2.7

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 7 End of treatment St George's Respiratory Questionnaire scores (total score).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms).
Figuras y tablas -
Analysis 2.8

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 9 Change from baseline in Chronic Respiratory Disease Questionnaire scores.
Figuras y tablas -
Analysis 2.9

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 9 Change from baseline in Chronic Respiratory Disease Questionnaire scores.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 10 End of treatment Transitional dyspnea index (TDI).
Figuras y tablas -
Analysis 2.10

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 10 End of treatment Transitional dyspnea index (TDI).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 11 End of treatment symptom scores.
Figuras y tablas -
Analysis 2.11

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 11 End of treatment symptom scores.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 12 Change from baseline in Transitional Dyspnoea Index (TDI).
Figuras y tablas -
Analysis 2.12

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 12 Change from baseline in Transitional Dyspnoea Index (TDI).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 13 Change in MRC rated dyspnoea.
Figuras y tablas -
Analysis 2.13

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 13 Change in MRC rated dyspnoea.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 14 Change from baseline in dyspnoea score.
Figuras y tablas -
Analysis 2.14

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 14 Change from baseline in dyspnoea score.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 15 Mean Change nighttime awakenings.
Figuras y tablas -
Analysis 2.15

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 15 Mean Change nighttime awakenings.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 16 Change from baseline in predose FEV1.
Figuras y tablas -
Analysis 2.16

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 16 Change from baseline in predose FEV1.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 17 Change from baseline in postdose FEV1.
Figuras y tablas -
Analysis 2.17

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 17 Change from baseline in postdose FEV1.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 18 End of treatment FEV1 (Litres).
Figuras y tablas -
Analysis 2.18

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 18 End of treatment FEV1 (Litres).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 19 FEV1 (% predicted ‐ absolute scores).
Figuras y tablas -
Analysis 2.19

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 19 FEV1 (% predicted ‐ absolute scores).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 20 Change from baseline in am PEF (L/min).
Figuras y tablas -
Analysis 2.20

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 20 Change from baseline in am PEF (L/min).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 21 Change from baseline in rescue medication usage (puffs/day).
Figuras y tablas -
Analysis 2.21

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 21 Change from baseline in rescue medication usage (puffs/day).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 22 End of treatment rescue medication usage (puffs/day).
Figuras y tablas -
Analysis 2.22

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 22 End of treatment rescue medication usage (puffs/day).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 23 Adverse events ‐ any event.
Figuras y tablas -
Analysis 2.23

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 23 Adverse events ‐ any event.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 24 Adverse events ‐ candidiasis.
Figuras y tablas -
Analysis 2.24

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 24 Adverse events ‐ candidiasis.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 25 Adverse events ‐ pneumonia.
Figuras y tablas -
Analysis 2.25

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 25 Adverse events ‐ pneumonia.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 26 Adverse events ‐ headache.
Figuras y tablas -
Analysis 2.26

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 26 Adverse events ‐ headache.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 27 Adverse events ‐ upper respiratory tract infection.
Figuras y tablas -
Analysis 2.27

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 27 Adverse events ‐ upper respiratory tract infection.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 28 Withdrawals.
Figuras y tablas -
Analysis 2.28

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 28 Withdrawals.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 29 Withdrawals due to lack of efficacy.
Figuras y tablas -
Analysis 2.29

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 29 Withdrawals due to lack of efficacy.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 30 Withdrawals due to adverse events.
Figuras y tablas -
Analysis 2.30

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 30 Withdrawals due to adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 1 Quality of life ‐ SGRQ (change scores).
Figuras y tablas -
Analysis 3.1

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 1 Quality of life ‐ SGRQ (change scores).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 2 Quality of life ‐ SGRQ (change scores).
Figuras y tablas -
Analysis 3.2

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 2 Quality of life ‐ SGRQ (change scores).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).
Figuras y tablas -
Analysis 3.3

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).
Figuras y tablas -
Analysis 3.4

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).
Figuras y tablas -
Analysis 3.5

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 6 Mean FEV1 (% increase from baseline).
Figuras y tablas -
Analysis 3.6

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 6 Mean FEV1 (% increase from baseline).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 7 Mean change from baseline in pre dose FEV1 to the average over the randomised treatment period..
Figuras y tablas -
Analysis 3.7

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 7 Mean change from baseline in pre dose FEV1 to the average over the randomised treatment period..

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 8 Symptoms ‐ breathlessness (change scores).
Figuras y tablas -
Analysis 3.8

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 8 Symptoms ‐ breathlessness (change scores).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 9 Change from baseline in cough score.
Figuras y tablas -
Analysis 3.9

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 9 Change from baseline in cough score.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 10 Change from baseline in rescue medication usage (puffs/day).
Figuras y tablas -
Analysis 3.10

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 10 Change from baseline in rescue medication usage (puffs/day).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 11 Adverse events ‐ 'serious' events.
Figuras y tablas -
Analysis 3.11

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 11 Adverse events ‐ 'serious' events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 12 Adverse events ‐ candidiasis.
Figuras y tablas -
Analysis 3.12

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 12 Adverse events ‐ candidiasis.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 13 Withdrawals due to adverse events.
Figuras y tablas -
Analysis 3.13

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 13 Withdrawals due to adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 14 Withdrawals due to worsening COPD symptoms.
Figuras y tablas -
Analysis 3.14

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 14 Withdrawals due to worsening COPD symptoms.

Ir a la figura de la revisiónAbrir en una pestaña nueva
Summary of findings for the main comparison. Combined inhalers compared to LABAs for COPD

Combined inhalers compared to LABAs for COPD

Patient or population: COPD
Intervention: Combined inhalers
Comparison: LABA inhalers

Setting: community

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

LABA inhalers

Combined inhalers

Annual Exacerbation Rates
Follow‐up: median 1 year

1 per person per year

0.76 per person per year

(0.32 exacerbations fewer to 0.16 exacerbations fewer)

Rate ratio 0.76

(0.68 to 0.84)

99211
(9 studies)

⊕⊕⊝⊝
low2,3

The control arm exacerbation rates ranged from 0.9 to 1.5 per year in the studies of at least one year duration that included participants with severe COPD who had at least one exacerbation in the previous year.4

Number of people experiencing one or more exacerbations

Follow up: median 1 year

47 per 100

42 per 100

(38 to 46)

OR 0.83 (0.70 to 0.98)

3357

(6 studies)

⊕⊕⊕⊝
moderate5

The evidence summarised for this outcome comes only from studies evaluating fluticasone/salmeterol. As such evidence for this outcome does not apply to budesonide/formoterol.

Annual hospitalisation rates

Follow‐up: 1 to 3 years

0.16 per person per year6

0.15 per person per year

(0.1 to 0.21)

Rate ratio 0.79

(0.55 to 1.13)

48791

(3 studies)

⊕⊕⊝⊝

very low2,3,7

Mortality
Follow‐up: median 1 year

8 per 1000

7 per 1000
(5 to 9)

OR 0.92
(0.76 to 1.11)

10681
(10 studies)

⊕⊕⊕⊝
moderate7

The majority of data on mortality was derived from TORCH (vital status was ascertained in the patients who withdrew from treatment in this study). Control arm event rates varied from 0.4% to 5% in the one year studies.

Pneumonia
Follow‐up: median 1 year

27 per 1000

41 per 1000
(32 to 54)8

OR 1.55
(1.2 to 2.01)

11076
(12 studies)

⊕⊕⊕⊝
moderate2

See Table 2 for control arm event rates in all studies

*The basis for the assumed risk (was the median control group risk across studies of one year duration). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 This is the number of participants randomised in the studies. The analysis took account of the amount of time the participants were enrolled for prior to withdrawal.

2 Risk of bias (‐1): High withdrawal rates in all the longer trials.
3 Inconsistency (‐1): Significant heterogeneity between trial results.
4 Exacerbations were moderate or severe requiring oral corticosteroids, antibiotics or leading to hospital admission.

5 Publication bias (‐1): Data from a key study of fluticasone and salmeterol (TORCH) and from studies evaluating budesonide/formoterol were not available as binary data and did not contribute to this measurement of exacerbations. Whilst the analysis of the data as rates in these studies is likely to reflect the individual trial protocols, we cannot be sure that their absence from this outcome measure has little or no impact on the pooled odds ratio.

6 Annualised rates of hospitalisation have been estimated from the three year study TORCH.

7 Imprecision (‐1): Confidence interval includes possible harm and benefit.

8 See Table 2 for a range of NNT(H) results for risk of pneumonia across the trials of different durations.

Figuras y tablas -
Summary of findings for the main comparison. Combined inhalers compared to LABAs for COPD
Ir a la tabla de la revisión
Table 1. Search history

Version

Detail

1st published version ‐ Issue 4, 2003 (All years to April 2002)

References identified: 34
References retrieved: 7
Studies excluded 3 (Cazzola 2000; Chapman 2002; Soriano 2002)
Studies identified from supplementary searching: 4 (Dal Negro 2003; Hanania 2003 ‐ both included; Cazzola 2002a; Cazzola 2004 ‐ both excluded).
Studies included: 4

Update: Issue 3, 2004 (April 2003‐April 2004)

References identified: 12
References retrieved: 3 (2 papers full publication of a previously included or cited studies study (Dal Negro 2003; Hanania 2003). Hand searching identified two further references to the COSMIC 2003 study.
Studies identified from supplementary searching: 1 (TRISTAN 2003)
New studies included: 2
Total studies included: 6

Update: Issue 3, 2005 (April 2004‐April 2005)

References identified: 52
References retrieved: 46 (references to studies already included/excluded/ongoing: 24)
New unique studies identified: 10 (ongoing studies: 2)
New studies included: 0
Total studies included: 6

Update: April 2005 ‐ April 2007

References identified: 66
References retrieved: 27 (references to studies already included/excluded/ongoing: )
New unique studies identified: 8 (ongoing studies: 0)
New studies included: 4
Total studies included: 10

Update: April 2007‐ November 2011

References identified: 207
References retrieved: 4 (references to studies already included/excluded/ongoing: )
New unique studies identified: 4 (ongoing studies: 0)
New studies included: 4
Total studies included: 14

Figuras y tablas -
Table 1. Search history
Ir a la tabla de la revisión
Table 2. Rates and NNT(H) for pneumonia

Study ID

Study duration

Rate on LABA alone %

NNT (calculated from pooled OR using Visual Rx)

O'Donnell 2006

8 weeks

0

NA

Hanania 2003

24 weeks

0.6

291 (192 to 525)

Mahler 2002

24 weeks

0

NA

SCO100470

24 weeks

0.8

219 (145 to 395)

Tashkin 2008

26 weeks

1.76

107 (59 to 291)

Kardos 2007

48 weeks

1.4

126 (84 to 228)

TRISTAN

52 weeks

2.4

75 (50 to 135)

Calverley 2003

52 weeks

2.7

67 (45 to 120)

Anzueto 2009

52 weeks

2.5

76 (42 to 207)

Rennard 2009

52 weeks

3.43

56 (31 to 152)

Ferguson 2008

52 weeks

3.9

50 (28 to 135)

TORCH

156 weeks

13.3

17 (12 to 29)
Figuras y tablas -
Table 2. Rates and NNT(H) for pneumonia
Ir a la tabla de la revisión
Comparison 1. Combined inhalers versus long‐acting beta‐agonists (primary outcomes)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbation rates (combined inhaler versus LABA alone) Show forest plot

9

Rate ratio (Random, 95% CI)

0.76 [0.68, 0.84]

1.1 Fluticasone/salmeterol

5

Rate ratio (Random, 95% CI)

0.77 [0.66, 0.89]

1.2 Budesonide/formoterol

4

Rate ratio (Random, 95% CI)

0.73 [0.64, 0.83]

2 Number of participants with one or more exacerbation Show forest plot

6

3357

Odds Ratio (M‐H, Random, 95% CI)

0.83 [0.70, 0.98]

2.1 Fluticasone/salmeterol

6

3357

Odds Ratio (M‐H, Random, 95% CI)

0.83 [0.70, 0.98]

2.2 Budesonide/formoterol

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Hospitalisations Show forest plot

3

Rate ratio (Random, 95% CI)

Subtotals only

3.1 Fluticasone/salmeterol

3

Rate ratio (Random, 95% CI)

0.79 [0.55, 1.13]

4 Mortality Show forest plot

10

10681

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.76, 1.11]

4.1 Fluticasone/salmeterol

6

7408

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.76, 1.13]

4.2 Budesonide/formoterol

4

3273

Odds Ratio (M‐H, Random, 95% CI)

1.03 [0.40, 2.67]

5 Pneumonia Show forest plot

12

11076

Odds Ratio (M‐H, Random, 95% CI)

1.55 [1.20, 2.01]

5.1 Fluticasone/salmeterol

9

8242

Odds Ratio (M‐H, Random, 95% CI)

1.75 [1.25, 2.45]

5.2 Budesonide/formoterol

3

2834

Odds Ratio (M‐H, Random, 95% CI)

1.09 [0.69, 1.73]

6 Pneumonia subgrouped by dose Show forest plot

12

11076

Odds Ratio (M‐H, Random, 95% CI)

1.56 [1.26, 1.93]

6.1 Lower dose FPS (250/50 bid)

3

1934

Odds Ratio (M‐H, Random, 95% CI)

2.19 [1.35, 3.53]

6.2 Higher dose FPS (500/50 bid)

6

6308

Odds Ratio (M‐H, Random, 95% CI)

1.55 [0.92, 2.61]

6.3 Lower dose BDF (160/9 bid)

2

1164

Odds Ratio (M‐H, Random, 95% CI)

1.10 [0.53, 2.26]

6.4 Higher dose BDF (320/9 bid)

3

1670

Odds Ratio (M‐H, Random, 95% CI)

1.08 [0.60, 1.97]
Figuras y tablas -
Comparison 1. Combined inhalers versus long‐acting beta‐agonists (primary outcomes)
Ir a la tabla de la revisión
Comparison 2. Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbations by type Show forest plot

5

Rate ratio (Random, 95% CI)

Subtotals only

1.1 Requirement for oral steroids

4

Rate ratio (Random, 95% CI)

0.71 [0.62, 0.81]

1.2 Hospitalisation

3

Rate ratio (Random, 95% CI)

0.79 [0.55, 1.13]

2 Mortality by duration Show forest plot

6

7408

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.76, 1.13]

2.1 Mortality: three year data

1

3054

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.75, 1.14]

2.2 Mortality: >one and <three year data

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Mortality: one year data

5

4354

Odds Ratio (M‐H, Random, 95% CI)

0.94 [0.51, 1.70]

2.4 Mortality: 6 month data

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Change from baseline in St George's Respiratory Questionnaire (total score) Show forest plot

6

SGRQ units (Random, 95% CI)

‐1.58 [‐2.15, ‐1.01]

4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms) Show forest plot

4

St George's RQ score (Random, 95% CI)

‐2.78 [‐3.88, ‐1.68]

5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity) Show forest plot

4

SGRQ units (Random, 95% CI)

‐1.31 [‐2.38, ‐0.24]

6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact) Show forest plot

4

SGRQ units (Random, 95% CI)

‐1.41 [‐2.33, ‐0.50]

7 End of treatment St George's Respiratory Questionnaire scores (total score) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

9 Change from baseline in Chronic Respiratory Disease Questionnaire scores Show forest plot

2

680

Mean Difference (IV, Random, 95% CI)

2.83 [0.25, 5.41]

10 End of treatment Transitional dyspnea index (TDI) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

11 End of treatment symptom scores Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

12 Change from baseline in Transitional Dyspnoea Index (TDI) Show forest plot

2

677

Mean Difference (IV, Random, 95% CI)

0.61 [‐0.47, 1.68]

13 Change in MRC rated dyspnoea Show forest plot

1

symptoms (Random, 95% CI)

Totals not selected

14 Change from baseline in dyspnoea score Show forest plot

2

Mean Difference (Random, 95% CI)

‐0.09 [‐0.13, ‐0.05]

15 Mean Change nighttime awakenings Show forest plot

2

1554

Mean Difference (IV, Random, 95% CI)

‐1.34 [‐2.07, ‐0.61]

16 Change from baseline in predose FEV1 Show forest plot

5

Litres (Random, 95% CI)

0.07 [0.05, 0.10]

16.1 Reversible population

3

Litres (Random, 95% CI)

0.07 [0.02, 0.12]

16.2 Partially reversible population (mixed population)

2

Litres (Random, 95% CI)

0.08 [0.04, 0.12]

16.3 Poorly reversible population

2

Litres (Random, 95% CI)

0.06 [0.01, 0.12]

17 Change from baseline in postdose FEV1 Show forest plot

3

Litres (Random, 95% CI)

0.05 [0.03, 0.06]

18 End of treatment FEV1 (Litres) Show forest plot

2

1780

Mean Difference (IV, Random, 95% CI)

0.01 [‐0.02, 0.03]

19 FEV1 (% predicted ‐ absolute scores) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

20 Change from baseline in am PEF (L/min) Show forest plot

2

L/min (Random, 95% CI)

11.61 [7.91, 15.30]

21 Change from baseline in rescue medication usage (puffs/day) Show forest plot

4

2435

Mean Difference (IV, Random, 95% CI)

‐0.38 [‐0.61, ‐0.16]

22 End of treatment rescue medication usage (puffs/day) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

23 Adverse events ‐ any event Show forest plot

9

8250

Odds Ratio (M‐H, Random, 95% CI)

1.05 [0.93, 1.19]

24 Adverse events ‐ candidiasis Show forest plot

6

3118

Odds Ratio (M‐H, Random, 95% CI)

3.75 [2.33, 6.04]

25 Adverse events ‐ pneumonia Show forest plot

9

8242

Odds Ratio (M‐H, Random, 95% CI)

1.75 [1.25, 2.45]

26 Adverse events ‐ headache Show forest plot

8

7237

Odds Ratio (M‐H, Random, 95% CI)

1.06 [0.90, 1.26]

27 Adverse events ‐ upper respiratory tract infection Show forest plot

7

6198

Odds Ratio (M‐H, Random, 95% CI)

1.32 [1.12, 1.55]

28 Withdrawals Show forest plot

9

8226

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.77, 0.94]

29 Withdrawals due to lack of efficacy Show forest plot

6

6739

Odds Ratio (M‐H, Random, 95% CI)

0.53 [0.39, 0.72]

30 Withdrawals due to adverse events Show forest plot

8

7895

Odds Ratio (M‐H, Random, 95% CI)

0.90 [0.79, 1.02]
Figuras y tablas -
Comparison 2. Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes
Ir a la tabla de la revisión
Comparison 3. Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Quality of life ‐ SGRQ (change scores) Show forest plot

4

3442

SGRQ (Random, 95% CI)

‐2.69 [‐3.82, ‐1.55]

2 Quality of life ‐ SGRQ (change scores) Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Totals not selected

3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms) Show forest plot

2

2233

Mean Difference (IV, Random, 95% CI)

‐3.43 [‐5.13, ‐1.72]

4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity) Show forest plot

2

2215

Mean Difference (IV, Random, 95% CI)

‐1.57 [‐2.87, ‐0.27]

5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact) Show forest plot

2

2222

Mean Difference (IV, Random, 95% CI)

‐2.28 [‐3.60, ‐0.95]

6 Mean FEV1 (% increase from baseline) Show forest plot

1

Std. Mean Difference (IV, Random, 95% CI)

Totals not selected

7 Mean change from baseline in pre dose FEV1 to the average over the randomised treatment period. Show forest plot

2

1203

Mean Difference (IV, Random, 95% CI)

0.05 [0.00, 0.09]

8 Symptoms ‐ breathlessness (change scores) Show forest plot

2

2308

Mean Difference (IV, Random, 95% CI)

‐0.07 [‐0.12, ‐0.01]

9 Change from baseline in cough score Show forest plot

2

2308

Mean Difference (IV, Random, 95% CI)

‐0.06 [‐0.11, ‐0.00]

10 Change from baseline in rescue medication usage (puffs/day) Show forest plot

2

2310

Mean Difference (IV, Random, 95% CI)

‐0.33 [‐0.57, ‐0.09]

11 Adverse events ‐ 'serious' events Show forest plot

4

3243

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.69, 1.25]

12 Adverse events ‐ candidiasis Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13 Withdrawals due to adverse events Show forest plot

4

3243

Odds Ratio (M‐H, Random, 95% CI)

0.88 [0.65, 1.19]

14 Withdrawals due to worsening COPD symptoms Show forest plot

2

918

Odds Ratio (M‐H, Random, 95% CI)

0.49 [0.32, 0.74]
Figuras y tablas -
Comparison 3. Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes
Ir a la tabla de la revisión