Intervention Review

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

  1. Luis Javier Nannini1,*,
  2. Phillippa Poole2,
  3. Stephen J Milan3,
  4. Rebecca Holmes3,
  5. Rebecca Normansell3

Editorial Group: Cochrane Airways Group

Published Online: 10 NOV 2013

Assessed as up-to-date: 26 JUN 2013

DOI: 10.1002/14651858.CD003794.pub4


How to Cite

Nannini LJ, Poole P, Milan SJ, Holmes R, Normansell R. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD003794. DOI: 10.1002/14651858.CD003794.pub4.

Author Information

  1. 1

    Hospital E Peron, Pulmonary Section, G. Baigorria, Santa Fe - Rosario, Argentina

  2. 2

    University of Auckland, Department of Medicine, Auckland, New Zealand

  3. 3

    St George's, University of London, Population Health Sciences and Education, London, UK

*Luis Javier Nannini, Pulmonary Section, Hospital E Peron, Ruta 11 Y Jm Estrada, G. Baigorria, Santa Fe - Rosario, 2152, Argentina. nanninilj@circulomedicorosario.org.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 10 NOV 2013

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Characteristics of included studies [ordered by study ID]
Barnes 2006

MethodsParallel-group design
Randomisation: not clear
Blinding: double-blind, identical inhaler devices used
Allocation concealment: unclear
Excluded: not described
Withdrawals: described
Trial duration: 13 weeks
Baseline characteristics: comparable
Intention-to-treat analysis stated


Participants
  • Setting: 18 centres in Western and Eastern Europe
  • Participants randomly assigned: 141 (two groups: FP/SAL combination: 74; placebo: 67)
  • Baseline characteristics: 64 years; mean FEV1: 1.68 L; mean FEV1: 59 %predicted; mean FEV1 reversibility: 3.9 (of predicted)
  • Inclusion criteria: M/F 40 to 80 years of age; diagnosis of COPD (according to GOLD criteria); ≥ 2 on Medical Research Council (MRC) dyspnoea scale; poor reversibility of < 10% predicted normal
  • Exclusion criteria: current diagnosis of asthma; recent exacerbation (within four weeks); long-term oxygen therapy (LTOT); pulmonary rehabilitation; ICS, antileukotriene or tiotropium within 14 days of visit


InterventionsRun-in phase: four weeks. Treatment during this phase of the study not described

  • FPS 500/50 mcg twice daily
  • Placebo


Inhaler device: dry powder inhaler (DPI)


OutcomesExacerbations; withdrawals; adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices

Incomplete outcome data (attrition bias): MortalityLow riskAll withdrawals clearly accounted for, although slightly higher completion rate in the placebo group (95% in the placebo group, 88% in the treatment group)

Incomplete outcome data (attrition bias): All other outcomesLow riskAll withdrawals clearly accounted for, although slightly higher completion rate in the placebo group (95% in the placebo group, 88% in the treatment group)

Selective reporting (reporting bias)Low riskNo evidence of reporting bias

Bourbeau 2007

MethodsRandomised, double-blind, parallel-group, placebo-controlled. Duration three months


Participants
  • Setting: two respiratory centres: the Montreal Chest Institute and Hospital Laval, Canada
  • Participants randomly assigned: 40 (FPS: 19, placebo: 21)
  • Baseline characteristics: mean age: 64 years; mean FEV1 % predicted: 59%; COPD severity (GOLD): mild to very severe; males: 90%
  • Inclusion criteria: COPD (GOLD criteria), age ≥ 40 and ≤ 75 years; ≥ 10 pack-years smoking history; postbronchodilator FEV1 ≥ 25% of predicted; FEV1/forced vital capacity (FVC) ≤ 0.70
  • Exclusion criteria: asthma or atopy; any other active lung disease, requiring home oxygen or with raised carbon dioxide tension (> 44 mm Hg); α1-antitrypsin deficiency; recent exacerbation (in the past four weeks); controlled medical condition or hypersensitivity to inhaled corticosteroids and bronchodilators


InterventionsFour-week washout period from inhaled corticosteroids and long-acting beta2-agonists

  • FPS 500/50 mcg twice daily
  • Placebo twice daily


Additonal treatment groups not covered in this review

  • Fluticasone 500 mcg twice daily


Inhaler device: DPI (Diskus)


Outcomes
  • Numbers of CD8+ T lymphocytes and CD68+ macrophages, neutrophils and eosinophils
  • Spirometric measurements (FEV1 and FVC)
  • CRDQ (Chronic Respiratory Disease Questionnaire)
  • Bronchoalveolar lavage (BAL) and sputum induction (baseline, week 4 and week 12)
  • ATS-DLD 78 questionnaire
  • Lung volumes and carbon monoxide transfer factor (TLCO)
  • Adverse events


NotesPowered to detect differences in cell numbers from bronchoscopy and BAL rather than clinical outcomes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was performed using a central computer-generated list of random numbers, which was stratified by centre and used a block size of six set up by a data management/randomisation company

Allocation concealment (selection bias)Unclear riskAllocation procedure not described

Blinding (performance bias and detection bias)
All outcomes
Low riskA procedure was established by GEREQ, which was in possession of the treatment code, to ensure that the treatment code would be broken only in accordance with the protocol and the criteria set up for unbinding of the study

Observers were blinded not only to drug treatment but also to whether the biopsies were performed before or after treatment

Incomplete outcome data (attrition bias): MortalityHigh riskHigher attrition rates in placebo group (71% completed in placebo group vs 100% in treatment group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigher attrition rates in placebo group (71% completed in placebo group vs 100% in treatment group)

Selective reporting (reporting bias)Unclear risk"Analysis of bronchoalveolar lavage (BAL) and sputum induction results  has not yet been completed and will be the subject of a future publication"

Spirometric data and CRQ data not presented numerically—"No evidence of improvement in clinical outcomes was observed as measured by lung function as well as health-related quality of life questionnaires"

Calverley 2003

MethodsParallel-group study
Randomisation: unclear
Blinding: double-blind (identical inhaler devices)
Trial duration: 52 weeks with two-week run-in of treatment optimisation
Allocation concealment: unclear
Withdrawals: stated
Intention-to-treat analysis: stated


Participants
  • Setting: 109 centres in 15 countries
  • Participants randomly assigned: 510 (BDF: 254; placebo: 256). Additional treatment groups not covered in this review: budesonide: 257; formoterol: 255
  • Baseline characteristics: mean age: 64; mean FEV1 L: 1; mean FEV1 % predicted: 36; mean SGRQ: 48
  • 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 oral corticosteroids/antibiotics two to 12 months before first clinic visit
  • Exclusion criteria: history of asthma/rhinitis before 40 years of age; any relevant cardiovascular disorders; exacerbation of COPD requiring medical intervention within four weeks of run-in/during run-in phase; non-allowed medications: oxygen therapy; ICS (aside from study medication), disodium cromoglycate, leukotriene-antagonists, 5-LO inhibitors, bronchodilators (other than study medication and prn terbutaline 0.5 mg), antihistamines, medication containing ephedrine, beta-blocking agents


InterventionsRun-in phase: All participants received 30 mg oral prednisolone twice daily and 2 × 4.5 mg formoterol twice daily (two weeks)

  • BDF: 320/9 mcg twice daily
  • Placebo (lactose monohydrate)


Additional treatment groups not covered in this review

  • Budesonide: 400 mcg twice daily
  • Formoterol: 9 mcg twice daily


Inhaler device: Turbuhaler


OutcomesTime to first exacerbation; change in postmedication FEV1; number of exacerbations; time to and number of oral corticosteroid–treated episodes; am and pm PEF, slow vital capacity, health-related quality of life (HRQL); symptoms; use of reliever medication; adverse events


NotesClassified as 'poorly reversible population'

P values used to calculate pooled SEMs for the following outcomes: HRQL; FEV1; rescue medication


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (71% completion in the BDF group and 59% in the placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (71% completion in the BDF group and 59% in the placebo group)

Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Dal Negro 2003

MethodsParallel-group study
Randomisation: unclear
Blinding: double-blind
Method of randomisation: not reported
Allocation concealment: unclear
Trial duration: 52 weeks
Withdrawals: stated
Baseline characteristics: comparable intention-to-treat analysis: yes


Participants
  • Setting: single centre in Italy
  • Participants randomly assigned: 12 (FPS: six; placebo: six). Additional treatment groups not covered in this review: salmeterol: six
  • Baseline characteristics: age range: 53 to 78; moderate COPD; mean FEV1 (L): 1.46; mean FEV1 (% predicted): 48; mean PEF (L/min): 180; mean reversibility (% baseline): 3.2
  • Inclusion criteria: baseline FEV1 % predicted: ≤ 80%; FEV1 > 800 mL; FEV1/FVC ratio: ≤ 70% predicted; FEV1 change ≤ 12% predicted post 400 mg salmeterol; regular treatment with oral theophylline 20 mg twice daily; SABA as required (for at least six months); current/ex-smokers with smoking history of at least 10 pack-years
  • Exclusion criteria: current evidence of asthma or other pulmonary diseases; regular treatment with ICS; unstable respiratory disease requiring oral/parenteral corticosteroids within four weeks before the beginning of the study; changes in COPD medication in last four weeks before entering run-in; upper/lower respiratory tract infection within four weeks before last screening visit; unstable angina/unstable arrhythmias; recent myocardial infarction (MI)/heart failure; insulin-dependent diabetes mellitus; neuropsychiatric disorders; concurrent use of medications that affect COPD (e.g. beta-blockers) or interact with methylxanthine products (e.g. macrolides or fluoroquinolones); known/suspected hypersensitivity to ICS, beta2-agonist or lactose; evidence of alcohol abuse.


InterventionsRun-in: two weeks' treatment with theophylline and as required SABA

  • FPS 50/250 mcg twice daily
  • Placebo


Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily


Participants were receiving concomitant therapy: SABA as required and theophylline 400 μg/d for 12 months

Inhaler device: Diskus


OutcomesFEV1, Delta FEV1, PEF am, symptom scores, rescue medication use, exacerbations (event rate and mean number per year)


NotesClassified as 'poorly reversible population'

Mild exacerbation: requirement for increase in SABA as required by > 2 occasions/24 h 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

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices

Incomplete outcome data (attrition bias): MortalityUnclear risk100% completion in both groups but only 12 participants

Incomplete outcome data (attrition bias): All other outcomesUnclear risk100% completion in both groups but only 12 participants

Selective reporting (reporting bias)Unclear riskAll stated outcomes reported but choice of end points used for significance calculations not always clear

Doherty 2012

MethodsRandomized, placebo-controlled, double-blind, double-dummy, parallel groups. Duration 26 weeks with a 26-week safety extension


Participants
  • Setting: 164 centres in North, Central and South America, Europe, Africa and Asia
  • Participants randomly assigned: 700 (MF/F 400/10: 225, MF/F 200/10: 239, placebo: 236)
  • Baseline characteristics: mean age 59.3; mean FEV1 % predicted: 38.2%; COPD severity: moderate to very severe; males 74.3%
  • Inclusion criteria: age ≥ 40 years; FEV1/FVC < 0.70, postbronchodilator FEV1 25% to 60% predicted; symptoms of COPD (e.g. chronic cough and sputum production not attributable to another disease) for at least 24 months before enrolment; clinically acceptable laboratory tests at screening; adequate form of birth control if of child-bearing potential
  • Exclusion criteria: asthma or significant reversibility; COPD exacerbation within four weeks; long-term oxygen; lung cancer; alpha-1-antitrypsin deficiency; lung surgery; cataract extractions in both eyes; glaucoma or intraocular pressure ≥ 22 mm Hg in either eye; clinically significant medical illness(es) that could interfere with the study


InterventionsTwo-week washout/run-in period, in which previous long-acting COPD treatments (LABA, ICS, LABA/ICS or long-acting anticholinergic (e.g. tiotropium)) were discontinued and substituted

with a short-acting beta2-agonist (SABA)/short-acting anticholinergic combination

  • MF/F 400/10 mcg twice daily (26 weeks + 26-week safety extension)
  • MF/F 200/10 mcg twice daily (26 weeks + 26-week safety extension)
  • Placebo (26 weeks)


Additional treatment groups not covered in this review

  • MF 400 mcg twice daily (26 weeks + 26-week safety extension)
  • F 10 μg twice daily (26 weeks + 26-week safety extension)
  • Inhaler device: MDI


Outcomes
  • MF/F 400/10 μg compared with MF 400 μg for FEV1 area under the curve from 0 to 12 hours postdose at 13-week end point
  • MF/F 400/10 μg and MF/F 200/10 μg compared with F 10 μg for AM predose (trough) FEV1
  • Changes from baseline in FEV1 area under the curve from 0 to 12 hours postdose day 1; weeks 1, 13, 26; and the 26-week end point
  • Changes from baseline in trough FEV1 each visit and at the 26-week end point
  • Serial spirometry tests
  • Respiratory health status (SGRQ)
  • COPD symptom-free nights
  • Partly stable COPD
  • Time to first COPD exacerbation
  • Adverse events


NotesPost hoc in a subgroup of participants with baseline FEV1 < 50% predicted (severe or very severe COPD) for coprimary end points

COPD exacerbations were categorised as mild, moderate or severe

A mild exacerbation was defined as a clinically judged deterioration of COPD symptoms (managed with increased short-acting bronchodilator use: ≥ 12 inhalations/d of

SABA/short-acting anticholinergic, or ≥ two nebulized treatments/d of 2.5 mg SABA/short-acting anticholinergic) on any two consecutive days

A moderate exacerbation was defined as a clinically judged deterioration of COPD with an acute change in symptoms that required antibiotic and/or oral steroid treatment for lower airway disease

A severe exacerbation was defined as a deterioration of COPD that resulted in emergency treatment or hospitalisation due to COPD


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"At baseline, subjects were randomised in a 1:1:1:1:1 ratio"—no further details, but likely to be low risk

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo-controlled, double-blind, double-dummy

Incomplete outcome data (attrition bias): MortalityUnclear riskModerate attrition rate across all treatment groups (84% completion in higher-dose treatment group, 85% in the lower-dose treatment group, 80% in the placebo group)

Incomplete outcome data (attrition bias): All other outcomesUnclear riskModerate attrition rate across all treatment groups (84% completion in higher-dose treatment group, 85% in the lower-dose treatment group, 80% in the placebo group)

Selective reporting (reporting bias)Unclear riskNot all outcomes are supported with data

Hanania 2003

MethodsParallel-group study
Randomisation: method unclear
Blinding: double-blind
Allocation concealment: unclear
Excluded: described
Withdrawals: described
Trial duration: 24 weeks with 2-week run-in period
Baseline characteristics: comparable
Intention-to-treat analysis: not stated


Participants
  • Setting: USA, multi-centre (76 hospitals)
  • Participants randomly assigned: 368 (FPS: 183; placebo: 185). Additional treatment groups not covered in this review: salmeterol: 177; fluticasone: 183
  • Baseline characteristics: mean age: 64; mean FEV1: 1.27 L (42% predicted)
  • Inclusion criteria: stable COPD; FEV1 40% to 65% predicted; FEV1/FVC < 70% predicted; symptoms of chronic bronchitis and moderate dyspnoea
  • Exclusion criteria: current diagnosis of asthma, use of oral steroids in past six weeks, abnormal electrocardiogram (ECG), LTOT, moderate to severe exacerbation in run-in. Other significant medical disorder


InterventionsRun-in: two weeks' treatment with placebo inhaler and as required SABA

  • FPS 50/250 mcg twice daily
  • Placebo


Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily
  • Fluticasone 250 mcg twice daily


Inhaler device: Diskus


OutcomesLung function: change in FEV1 from baseline to end of study (M); PEF data not stratified by reversibility; quality of life: CRDQ, chronic bronchitis symptoms questionnaire (CBSQ) not stratified by reversibility; Dyspnoea and symptoms: transitional dyspnoea index (TDI); baseline dyspnoea index not stratified by reversibility; exacerbations; rescue salbutamol use


NotesFEV1 reversibility < 12% or 200 mL (of baseline FEV1). Reversibility stratified data. Mean percentage increase in non-reversible participants = 8.8


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (70% completion in treatment group, 68% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (70% completion in treatment group, 68% in placebo group)

Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Lapperre 2009

MethodsRamdomised, placebo-controlled, parallel-group study. Duration 30 months


Participants
  • Setting: two university medical centres in The Netherlands
  • Participants randomly assigned: 57 (FPS: 28, placebo: 29)
  • Baseline characteristics: mean age: 60.5; mean percentage predicted FEV1: 61%; COPD severity: moderate to severe (GOLD); males: 85.5%
  • Inclusion criteria: age: 45 to 75 years; ≥ 10 pack-years smoking history; lung function GOLD stages II and III
  • Exclusion criteria: asthma, ICS within six months


InterventionsNo run-in

  • FPS 500/50 mcg twice daily for 30 months 
  • Placebo twice daily for 30 months


Additonal treatment groups not covered in this review

  • Fluticasone 500 mcg twice daily for the first six months, followed by placebo, twice daily, for 24 months
  • Fluticasone 500 mcg twice daily for 30 months


Inhaler device: DPI (Diskus)


Outcomes
  • Inflammatory cell counts in bronchial biopsies and induced sputum
  • Postbronchodilator spirometry rate of FEV1 decline
  • Hyperresponsiveness to methacholine PC20 assessed by standardised procedures
  • Dyspnoea score by modified Medical Research Council (MRC) dyspnoea scale
  • Health status by St George’s Respiratory Questionnaire (SGRQ)
  • Clinical COPD Questionnaire (CCQ)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAt entry, an independent randomisation centre provided participant and medication numbers by using a minimisation procedure that balanced treatment groups

Allocation concealment (selection bias)Unclear riskNo details given of allocation procedure

Blinding (performance bias and detection bias)
All outcomes
Low riskStudy medications were individually numbered, with 60 doses per inhaler; all active treatment medications and placebo were identical in appearance

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (75% completion in treatment group, 69% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (75% completion in treatment group, 69% in placebo group)

Selective reporting (reporting bias)Low riskAll outcome measures described are reported

Mahler 2002

MethodsParallel-group study
Randomisation: stratified by reversibility and investigative site
Blinding: double-blind
Allocation concealment: unclear
Excluded: described.
Withdrawals: described.
Trial duration: 24 weeks
Baseline characteristics: comparable
Intention-to-treat analysis: stated


Participants
  • Setting: multi-centre study (65 centres)
  • Participants randomly assigned: 346 (FPS: 165; placebo: 181); additional treatment groups not covered in this review: salmeterol: 160; fluticasone: 168
  • Baseline characteristics: mean age: 63; FEV1: 1.2 to 3 L
  • Inclusion criteria: participants with COPD according to ATS guidelines; baseline prebronchodilation FEV1 < 65% predicted and > 0.70 L; baseline prebronchodilation FEV1/FVC < 70% predicted; age > 40 years; 20 pack-years history smoking; day or night symptoms present on four of last seven days during run-in period
  • Exclusion criteria: history of asthma; corticosteroid use in last six weeks; abnormal ECG; oxygen therapy; moderate or severe exacerbation during run-in; significant concurrent disease


InterventionsRun-in: two weeks' treatment with placebo inhaler and as required SABA

  • FPS 500/50 mcg twice daily
  • Placebo


Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily
  • Fluticasone 500 mcg twice daily


Inhaler device: Diskus


OutcomesLung 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


NotesCOPD participants reversible and non-reversible; < 15% (baseline) improvement in FEV1 to salbutamol; reversibility stratified data; mean FEV1 reversibility 11.0%


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; stratified by reversibility and investigative site

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (68% completion in treatment group, 62% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (68% completion in treatment group, 62% in placebo group)

Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

O'Donnell 2006

MethodsParallel-group design
Randomisation: not clear
Blinding: double-blind
Allocation concealment: unclear
Excluded: not described
Withdrawals: described
Trial duration: 8 weeks
Baseline characteristics: comparable
Intention-to-treat analysis stated


Participants
  • Setting: 22 centres in North America
  • Participants randomly assigned: 126 (FPS: 62; placebo: 64)


Additional treatment groups not covered in this review

  • Salmeterol: 59


Baseline characteristics: 65 years; FEV1: 1.12 L
Inclusion criteria: M/F ≥ 40 years of age; diagnosis of COPD; ≥ 10 pack-years; baseline Borg dyspnoea index < 7; FEV1 < 70% predicted; functional residual capacity (FRC) ≥ 120% predicted
Exclusion criteria: current diagnosis of asthma; use of xanthines/LABA/oral corticosteroids/ICS


InterventionsRun-in: two weeks; single-blind placebo

  • FPS 500/50 mcg twice daily
  • Placebo


Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily


Inhaler device: DPI


OutcomesWithdrawals; exercise time; FEV1; adverse events


NotesStudy downloaded from ctr.gsk.co.uk


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices

Incomplete outcome data (attrition bias): MortalityLow riskLow attrition rates in both groups (95% completion in treatment group, 92% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesLow riskLow attrition rates in both groups (95% completion in treatment group, 92% in placebo group)

Selective reporting (reporting bias)Unclear riskDoes not contribute data to the analysis of exacerbations as rate ratios, mortality or hospitalisations

Rennard 2009

MethodsRandomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled. Duration 12 months


Participants
  • Setting: 237 centres in US, Europe and Mexico
  • Participants randomly assigned: 1469 (BDF 320/9: 494, BDF 160/9: 494, placebo 481)
  • Baseline characteristics: mean age: 62.3; mean % predicted FEV1: 39.7%; COPD severity: moderate to very severe; males: 63.5%
  • Inclusion criteria: age ≥ 40 years; COPD for > 2 years; ≥ 10 pack-years smoking history; pre-bronchodilator (FEV1) ≤ 50% predicted; pre-bronchodilator FEV1/forced vital capacity (FVC) < 70%; modified Medical Research Council dyspnoea scale score ≥ 2; COPD exacerbation within one to 12 months (see Tashkin 2008)
  • Exclusion criteria: asthma or allergic rhinitis before 40 years of age; oral steroid use; any significant disease or disorder that may jeopardise the safety of the participant (see Tashkin 2008)


InterventionsTwo-week run-in period, during which participants received ICS monotherapy if previously stable on ICS (alone or in combination) and ipratropium bromide at a fixed dose if previously receiving anticholinergics. Albuterol (salbutamol) was permitted for rescue use throughout the study

  • BDF 320/9 mcg twice daily
  • BDF 160/9 mg twice daily
  • Placebo twice daily


Additional treatment groups not covered in this review

  • Formoterol 9 mg twice daily


Inhaler device: pMDI/DPI


Outcomes
  • Predose and one hour postdose FEV1 over the 12-month treatment period
  • Participant-reported outcome variables regarding disease status (including PEF), collected via questionnaires and diaries
  • Health care utilisation
  • Safety variables, including adverse events, vital signs, ECG, physical examination, haematology and clinical chemistry


NotesSubgroup performed serial spirometry assessment

COPD exacerbation was defined as worsening of COPD requiring an oral corticosteroid

or hospitalisation


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, but no details given of sequence generation

Allocation concealment (selection bias)Unclear riskNo details of allocation procedure given

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy; blinding maintained until end of 12-month study period

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rate across all treatment groups (73% completion in higher-dose treatment group, 71% in lower-dose treatment group, 64% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rate across all treatment groups (73% completion in higher-dose treatment group, 71% in lower-dose treatment group, 64% in placebo group)

Selective reporting (reporting bias)Unclear riskAll primary and secondary outcomes reported, although numerical data not available for all outcomes

Average FEV1 was listed as a coprimary outcome in the methods section but as a secondary outcome in the results section

SCO104925

MethodsRandomized, double-blind, placebo-controlled, parallel-group. Duration 12 weeks


Participants
  • Setting: 11 centres: four centres in the Russian Federation, four centres in the United States, two centres in Chile and one centre in Estonia
  • Participants randomly assigned: 81 (FPS: 39, placebo: 42)
  • Baseline characteristics: mean age: 64.4; mean FEV1 5 predicted: not given; COPD severity: moderate to severe; males: 79%
  • Inclusion criteria: ≥ 40 years of age; clinical history of COPD with evidence of bronchitis; ≥ 10 pack-years smoking history; FEV1/FVC ≤ 70% and measured postalbuterol FEV1 ≥ 30% and ≤ 70% of predicted normal
  • Exclusion criteria: child-bearing potential


InterventionsNo run-in described

  • FPS 500/50 mcg
  • Placebo


Additional treatment groups not covered in this review

  • Fluticasone 500 mcg
  • Salmeterol 50 mcg


Outcomes
  • Predose resistance difference between 5 Hz and 15 Hz (R5 to R15) as measured by IOS
  • Predose and two hours postdose low-frequency reactance area (AX); two hours postdose R5 to R15; postalbuterol computed tomography (CT) parameters of area of airway wall (Aaw) and area of airway lumen (Ai)
  • Adverse events


NotesTrial designed to assess novel outcome measures, clinical efficacy. No relevant outcomes for meta-analysis apart from adverse events


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised but no details of sequence generation

Allocation concealment (selection bias)Unclear riskNo details of allocation procedure

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind, placebo-controlled"

Incomplete outcome data (attrition bias): MortalityUnclear riskModerate attrition rates in both groups (90% completion in treatment group, 90% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesUnclear riskModerate attrition rates in both groups (90% completion in treatment group, 90% in placebo group)

Selective reporting (reporting bias)Low riskAll outcome measures reported

SFCT01

MethodsParallel-group design
Randomisation: not clear
Blinding: double-blind
Allocation concealment: unclear
Excluded: not described
Withdrawals: described
Trial duration: 52 weeks
Baseline characteristics: comparable

Intention-to-treat analysis stated


Participants
  • Setting: 49 centres in Italy, 7 in Poland
  • Participants randomly assigned: 256 (FPS: 131; placebo: 125)


Additional treatment groups not covered in this review

  • Fluticasone: 131


Baseline characteristics: 65 years; FEV1: not reported
Inclusion criteria: M/F ≥ 40 years of age; diagnosis of COPD; ≥ 10 pack-years; FEV1 < 70% predicted and > 800 mL; reversibility < 10% predicted normal (and < 200 mL)
Exclusion criteria: not described


InterventionsRun-in: two weeks. All maintenance LABA and ICS treatment ceased

  • FPS 500/50 mcg twice daily
  • Placebo


Additional treatment groups not covered in this review

  • Fluticasone 500 mcg twice daily


Inhaler device: MDI


OutcomesWithdrawals; exacerbations; FEV1; adverse events


NotesUnpublished study downloaded from ctr.gsk.co.uk


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available

Allocation concealment (selection bias)Unclear riskInformation not available

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (66% completion in treatment group, 68% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (66% completion in treatment group, 68% in placebo group)

Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Sin 2008

MethodsDouble-blind, randomised, placebo-controlled, parallel-group. Duration four weeks


Participants
  • Setting: 11 centres,  Western Canada
  • Participants randomly assigned: 137 (FPS: 92, placebo: 45)
  • Baseline characteristics: mean age: 68.4; mean FEV1 % predicted: 46.4%; COPD severity: moderate to very severe; males: 62.7%
  • Inclusion criteria: age ≥ 40 years; clinical diagnosis of COPD (GOLD); FEV1 < 80% predicted; FEV1/FVC < 0.70; ≥ 10 pack-years smoking history
  • Exclusion criteria: exacerbations in last four weeks: known chronic systemic infections or inflammatory conditions; solid organ transplantation; myocardial infarction or cerebrovascular accident within the past three months; child-bearing potential; participation in a drug trial within the past four weeks; unlikely to survive longer than six months; URTI in last four weeks; unable to follow instructions; long-term oral theophylline use and unable or unwilling to stop
  • Use of oral corticosteroids or long-term immunosuppressive agents


InterventionsRun-in phase during which participants received fluticasone (500 mcg twice daily) for four weeks (short-acting beta2-agonists (e.g. salbutamol) and/or anticholinergic (ipratropium) were allowed as rescue medication) followed by a medication withdrawal phase, wherein inhaled corticosteroids, LABA and theophylline products were withdrawn for four weeks (SABA (e.g. salbutamol) and/or anticholinergic (ipratropium) inhalers allowed as rescue medications)

  • FPS 500/50 mcg twice daily
  • Placebo twice daily


Additonal treatment groups not covered in this review

  • Fluticasone 500 mcg twice daily


Inhaler device: DPI (Diskus)


Outcomes
  • Serum C-reactive protein (CRP), interleukin-6 (IL-6) and surfactant protein D (SPD)
  • Health status (SGRQ)
  • FEV1 and FVC


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was carried out centrally according to a computer-generated sequence stratified according to current smoking status with allocation concealment in a 1 (placebo arm) to 2 (fluticasone four arms) to 2 (fluticasone/salmeterol) distribution ratio

Allocation concealment (selection bias)Low risk“With allocation concealment”; however, further details not given

Blinding (performance bias and detection bias)
All outcomes
Low riskDuring this phase (RCT), all participants and study personnel will be blinded to the treatment assignment. (For safety reasons, during severe exacerbations (i.e. those requiring hospitalisation or emergency visit for COPD), the treating physician can break the "code" and place study participants on medications needed to treat the exacerbation)

Incomplete outcome data (attrition bias): MortalityUnclear riskHigher attrition in placebo group (96% completion in treatment group, 87% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesUnclear riskHigher attrition in placebo group (96% completion in treatment group, 87% in placebo group)

Selective reporting (reporting bias)Unclear riskAll outcome measures stated in protocol have been reported, with exception of “Other secondary molecules such as IL-8, tumour necrosis factor-alpha, monocyte chemoattractant protein and other molecules will be measured at a later date as part of a post hoc exploratory work”. Also SPD levels reported extensively but did not feature in the protocol

Szafranski 2003

MethodsParallel-group study
Randomisation: randomised, double-blind, placebo-controlled parallel-group trial
Duration: 52 weeks
Methods of randomisation: computer-generated scheme at AstraZeneca, Lund, Sweden. At each centre, eligible participants received an enrolment code, and then after run-in, participants were allocated the next consecutive participant number.
Allocation concealment: adequate
Blinding: All Turbuhaler inhalers were identical to ensure that the participant, the pharmacist and the investigator were blinded to the allocated treatment
Excluded: not stated
Withdrawals: stated
Intention-to treat-analysis: stated


Participants
  • Setting: 89 centres in Central and South America, Europe and South Africa
  • Participants: 413 (BDF: 208; placebo: 205)


Additional treatment groups not covered in this review

  • Formoterol: 201; budesonide: 198


Baseline characteristics: mean age: 64 years; mean FEV1 % predicted: 36%; mean reversibility: 6% predicted normal
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 seven days of run-in; use of bronchodilators for reliever medication; ≥ 1 severe COPD exacerbation within two to 12 months before study entry
Exclusion criteria: history of asthma/rhinitis before age 40; using beta-blockers; current respiratory tract disease other than COPD


InterventionsRun-in: two weeks. Treatment with prn SABA only

  • BDF 320/9 mcg twice daily
  • Placebo


Additional treatment groups not covered in this review

  • Budesonide 400 μg twice daily
  • Formoterol 9 μg twice daily


Inhaler device: Turbuhaler


OutcomesSymptoms, adverse events, exacerbations, lung function


NotesClassified 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 standard errors of the mean (SEMs) for following outcomes: symptoms; rescue medication usage


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated scheme

Allocation concealment (selection bias)Low riskAt each centre, eligible participants received an enrolment code, and then after run-in, participants were allocated to the next consecutive participant number

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (72% completion in treatment group, 56% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (72% completion in treatment group, 56% in placebo group)

Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Tashkin 2008

MethodsRandomised, double-blind, double-dummy, placebo-controlled, parallel-group. Duration six months


Participants
  • Setting: 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa
  • Participants randomly assigned: 858 (BDF 320/9: 277, BDF 160/9: 281, placebo 300)
  • Baseline characteristics: mean age: 63.3; mean FEV1 % predicted: 40.1%; COPD severity: moderate to very severe; males: 67.1%
  • Inclusion criteria: ≥ 40 years, pre-bronchodilator FEV1 ≤ 50% predicted, pre-bronchodilator FEV1/forced vital capacity < 70%; symptoms for ≥ two years; ≥ 10 pack-years smoking history; ≥ one COPD exacerbation within one to 12 months; ≥ 2 Modified Medical Research Council dyspnoea scale score; ≥ 2 BCSS score for at least half of the two-week run-in period
  • Exclusion criteria: asthma or allergic rhinitis before 40 years of age; significant/unstable cardiovascular disorder; clinically significant respiratory tract disorder other than COPD; alpha-1 antitrypsin deficiency; oral steroid use; any other significant disease or disorder that may jeopardise the safety of the participant; oral or ophthalmic non-cardioselective beta-adrenoceptor antagonist use; pregnancy and breast-feeding


InterventionsTwo-week run-in period; participants continued ICS monotherapy if they had previously been receiving ICS alone or in combination with LABA, and participants who had previously been receiving anticholinergic therapies were placed on stable doses of ipratropium bromide. A short-acting beta2-agonist was allowed for rescue use

  • BDF 320/9 twice daily
  • BDF 160/9 twice daily
  • Placebo twice daily


Additional treatment groups not covered in this review

  • Budesonide 320 mcg twice daily + formoterol 9 mcg twice daily
  • Budesonide 320 mcg twice daily
  • Formoterol 9 mcg twice daily


Inhaler device: MDI and Turbohaler (double-dummy)


Outcomes
  • Predose and one hour postdose FEV1 over the six-month treatment period
  • Participant-reported outcome variables regarding disease status (including PEF), collected via questionnaires and diaries
  • Health care utilisation
  • Safety variables, including adverse events, vital signs, ECG, physical examination, hematology and clinical chemistry
  • Serial spirometry
  • Pharmacokinetics


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomly assigned in balanced blocks according to computer-generated randomisation to one of the treatments administered twice daily

Allocation concealment (selection bias)Unclear riskNo details of allocation procedure

Blinding (performance bias and detection bias)
All outcomes
Low riskRandomised, double-blind, double-dummy

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (86% completion in both treatment groups, 74% completion in placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (86% completion in both treatment groups, 74% completion in placebo group)

Selective reporting (reporting bias)Low riskAll outcomes reported, no evidence of reporting bias

Tashkin 2012

MethodsRandomized, placebo-controlled, double-blind, double-dummy, parallel groups. Duration 26 weeks with 26-week safety extension


Participants
  • Setting: 131 centres located in South America, Asia, Africa, Europe and North America
  • Participants randomly assigned: 636 (MF/F 400/10: 217, MF/F 200/10: 207, placebo 212)
  • Baseline characteristics: mean age: 59.8; mean FEV1 % predicted: not stated; COPD severity: moderate to very severe; males: 79%
  • Inclusion criteria: ≥ 40 years; current or ex-smokers with ≥ 10 pack-years history; moderate to very severe COPD (pre-bronchodilator FEV1/forced vital capacity (FVC) ratio ≤ 0.70), symptoms of COPD (chronic cough and sputum production not attributable to another disease process) for at least 24 months; postbronchodilator FEV1 ≤ 60% predicted normal and ≥ 25% predicted normal at screening; medically acceptable form of birth control
  • Exclusion criteria: significant reversibility (> 400 mL postalbuterol/salbutamol); long-term oxygen; exacerbation of COPD requiring medical intervention within four weeks before randomisation; beta-blocking agents; or treatment with additional excluded medication (other than SABA short-acting anticholinergic to be used as rescue medication); history of significant medical illness or a disorder that might interfere with the study; pregnancy or breast-feeding; asthma; lung cancer; alpha-1-antitrypsin deficiency; lobectomy; pneumonectomy; lung volume reduction surgery; cataract extractions in both eyes; or other significant ocular problems (glaucoma, trauma, opacification)


InterventionsTwo-week open-label wash out/run-in period in which long-acting bronchodilators and corticosteroids were discontinued and substituted with a short-acting beta2-agonist-anticholinergic fixed-dose combination

  • MF/F 400/10 mcg twice daily
  • MF/F 200/10 mcg twice daily
  • Placebo


Additonal treatment groups not covered in this review

  • MF 400 mcg twice daily
  • Formoterol 10 mcg twice daily


Inhaler device: MDI


Outcomes
  • Mean change from baseline in FEV1 area under the curve (AUC) from 0 to 12 hours postdose (AUC 0 to 12 hours) at the week 13 end point
  • Mean change from baseline in morning predose FEV1 at the week 13 end point
  • Change in health status as assessed according to total scores on St George’s Respiratory Questionnaire (SGRQ)
  • Change in symptom-free nights
  • Time to first mild, moderate or severe COPD exacerbation
  • Proportion of participants with partly stable COPD
  • Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe sponsor’s statistician produced a computer-generated randomisation schedule with treatment codes in blocks using SAS. Randomization was stratified according to the participant's smoking status at the time of randomisation

Allocation concealment (selection bias)Low riskRandomised treatment assignment was provided to the investigative site by means of an interactive voice response system at the time participants were randomly assigned

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo-controlled, double-blind, double-dummy study

NB: Sponsor's statistician was used

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in all groups (81% completion in higher-dose treatment group and 82% in lower-dose treatment group, 75% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in all groups (81% completion in higher-dose treatment group and 82% in lower-dose treatment group, 75% in placebo group)

Selective reporting (reporting bias)Unclear riskNumerical data for multiple outcomes not presented, as failed to reach significance

TORCH

MethodsParallel-group design
Randomisation: permuted block randomisation with stratification for smoking status and country
Blinding: double-blind (identical inhaler devices)
Allocation concealment: adequate
Excluded: described
Withdrawals: described
Trial duration: 156 weeks
Baseline characteristics: comparable
Intention-to-treat analysis: stated


Participants
  • Setting: 444 centres in North America, Central America and Asia Pacific
  • Participants randomly assigned: 3091 (FPS: 1546; placebo: 1545)


Additional treatment groups not covered in this review

  • Salmeterol: 1542; fluticasone: 1551


Baseline characteristics: 65 years; male: 76%
Inclusion criteria: M/F 40 to 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
Exclusion criteria: asthma or respiratory diseases other than COPD; lung volume reduction surgery (LVRS)/lung transplant; requirement for > 12 hours/d LTOT; long-term oral corticosteroid therapy; serious uncontrolled disease likely to interfere with medication/cause death in next three years


InterventionsRun-in: two weeks. All maintenance treatment with ICS and LABA ceased

  • FPS combination 500/50 mcg twice daily
  • Placebo


Additional treatment groups not covered in this review

  • Fluticasone 500 mcg twice daily
  • Salmeterol 50 mcg twice daily


Inhaler device: DPI


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


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated scheme. Permuted block randomisation with stratification for smoking status and country

Allocation concealment (selection bias)Unclear riskCentralised randomisation schedule but no details of allocation procedures

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices

Incomplete outcome data (attrition bias): MortalityLow riskMortality was the primary outcome, and vital status was checked in those who withdrew

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates for other outcomes in both groups (66% completion in treatment group, 56% completion in placebo group)

Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

TRISTAN

MethodsParallel-group design
Randomisation: computer-generated; numbers were generated off-site; once a treatment number had been assigned to a participant, it could not be assigned to any other participant
Blinding: double-blind; participants received identically packaged and presented placebos
Excluded: described
Withdrawals: described
Trial duration: two-week run-in period; 52 weeks treatment; 2-week follow-up
Baseline characteristics: comparable intention-to-treat analysis: stated


Participants
  • Setting: 196 centres in Europe, South Africa and Australia
  • Participants randomly assigned: 719 (FPS: 358; placebo: 361)


Additional treatment groups not covered in this review

  • Salmeterol: 372; fluticasone: 375


Baseline characteristics: mean age 63 years; mean FEV1 1.26 L (44% predicted)
Inclusion criteria: baseline FEV1 25% to 75% predicted; FEV1/ FVC ratio ≤ 70%; poor reversibility: < 10% increase in predicted FEV1 30 minutes after inhalation of 400 mcg salbutamol; at least 10 pack-years smoking history; history of exacerbations (at least one in the last year) requiring OCS and/or antibiotics; at least one episode of acute COPD per year in the previous three years
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 two-week run-in period


InterventionsRun-in: two weeks. All maintenance treatment with ICS and LABA ceased

  • FPS 50 mcg/500 mcg twice daily
  • Placebo


Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily
  • Fluticasone 500 mcg twice daily


Inhaler device: DPI


OutcomesFEV1; 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


NotesFEV1 reversibility (% predicted normal); mean reversibility (% predicted) 3.8


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation schedule

Allocation concealment (selection bias)Low riskNumbers were generated off-site. Once a treatment number had been assigned to a participant, it could not be assigned to any other participant. Participants who satisfied the eligibility criteria were assigned the next sequential treatment number from the list

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler device

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (75% completion in treatment group and 61% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (75% completion in treatment group and 61% in placebo group)

Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Zheng 2006

MethodsRandomised, double-blind, placebo-controlled, parallel-group. Duration 24 weeks


Participants
  • Setting: 12 hospitals in China
  • Participants randomly assigned: 445 (FPS: 297, placebo: 148)
  • Baseline characteristics: mean age: 66.32; mean FEV1 % predicted: 47%; COPD severity: moderate to very severe; males: 88.5%
  • Inclusion criteria: 40 to 79 years; COPD as per GOLD criteria; poor reversibility of airflow obstruction (increase of < 10%); FEV1/FVC ratio (postbronchodilator) < 70%
  • Exclusion criteria: asthma, lung cancer, sarcoidosis, active tuberculosis, lung  fibrosis, bronchiectasis, serious uncontrolled other system disorders; long-term oxygen therapy (LTOT); had received inhaled corticosteroids at a dose of > 1000 μg/d (beclomethasone or budesonide) or > 500 μg/d (fluticasone) or had received systemic corticosteroids in the last four weeks before entry to the run-in period


InterventionsTwo-week run-in period during which participants stopped taking ICSs and LABAs

  • FPS 500/50 twice daily
  • Placebo


Inhaler device: DPI (Diskus)


Outcomes
  • Prebronchodilator FEV1
  • St George’s Respiratory Questionnaire (SGRQ)
  • Use of relief bronchodilator and nighttime awakenings from Daily Record Cards
  • Postbronchodilator FEV1
  • COPD exacerbations
  • Adverse events


NotesTrial included non-smokers (11% from FPS arm and 14% from placebo arm)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk“Randomization was stratified at week 0 by smoking status”—sequence generation not described but likely to be low risk

Allocation concealment (selection bias)Unclear riskAllocation procedure not described

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind. FPS combination product 50/500 μg twice daily or matched placebo twice daily for 24 weeks of treatment

Incomplete outcome data (attrition bias): MortalityUnclear riskModerate attrition rates in both groups (88% completion in treatment group and 89% in placebo group)

Incomplete outcome data (attrition bias): All other outcomesUnclear riskModerate attrition rates in both groups (88% completion in treatment group and 89% in placebo group)

Selective reporting (reporting bias)Low riskAll stated outcomes reported

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aaron 2004Irrelevant comparison

Aaron 2007Patients were randomised to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo

Bathoorn 2008Trial focuses on treatment of COPD exacerbations

Bleecker 2011Assessment of effects of Gly16Arg genotype in response to budesonide/ formoterol in two clinical trials

Borgstrom 2003Healthy volunteers

Cazzola 2000Single-blind assessment of additive benefit of inhaled fluticasone to salmeterol. Although dosage was identical to Seretide/Advair (i.e. FP 500ug: SAL 50mcg), treatment was administered through separate inhalers

Cazzola 2002aSingle-blind randomised crossover study comparing combination salmeterol and fluticasone with formoterol and budesonide - excluded as duration of study was too short (12 hours)

Cazzola 2003Acute phase COPD

Cazzola 2004Randomised trial comparing combination salmeterol/fluticasone with separately administered fluticasone and theophylline for 4 months. Excluded as the comparison was not within the scope of the review

Cazzola 2004bThe duration of this study was too short (<1 week)

Chapman 2002Review article

Cukier 2007Crosssover trial investigating use of nebulised saline versus nebulised salbutamol

De Backer 2011Assessment of the acute effect of budesonide/formoterol

Donohue 2004Irrelevant comparison

Ferguson 2006Trial did not compare combined ICS/LABA therapy versus placebo

GlaxoSmithKline 2004Trial includes patients with asthma

GlaxoSmithKline 2004aTrial includes patients with asthma

Golabi 2006Crossover trial comparing tiotropium versus salmeterol/fluticasone

Haque 2006Focus on macrophages and glucoreceptor proteins

INSPIRETrial compared tiotropium versus seretide

Jiang 2011Study not blinded

Jung 2012Patients were randomised to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo

Kardos 2007Comparison of combination therapy long-acting beta-agonist

Lindberg 2007Crossover study examining effect of only a single dose (two inhalations) of budesonide/formoterol
, salmeterol/fluticasone, salbutamol or placebo

Lindenberg 2006Crossover study examining effect of only a single dose (two inhalations) of budesonide/formoterol, salmeterol/fluticasone, salbutamol or placebo

Mittmann 2010Patients were randomised to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo

Mittmann 2011Patients were randomised to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo

NCT00144911Combined ICS/LABA not compared to placebo

NCT00269126Crossover study examining effect of adding fluticasone to salmeterol

NCT00476099Combined ICS/LABA not compared to placebo

Noschese 2003Non-randomised study.

Sagcan 2007Focus of study is on sleep quality of COPD patients

SAM40116Within study treatment group imbalances in dosage of steroids/combination therapy based upon historical steroid dose

Schermer 2007Combined ICS/LABA not compared to placebo

SCO100250Trial compared fluticasone/salmeterol versus salmeterol

SCO100470Comparison of combination therapy long-acting beta-agonist

SCO40034Comparison of tiotropium and combination therapy

SCO40043Trial compared fluticasone/salmeterol versus salmeterol

Sethi 2006Trial focuses on bacterial colonisation of sputum

Shaker 2009Trial compared budesonide versus placebo

Sharafkhaneh 2011Combined ICS/LABA not compared to placebo

Soriano 2002Non-randomised retrospective survival analysis

Southard 2011Combined ICS/LABA not compared to placebo

Stallberg 2008Trial focuses on treatment of COPD exacerbations

Sun 2004Irrelevant comparison

Sutherland 2006Trial focuses on Seretide compared to salmeterol

Trofimenko 2006Study not blinded and no placebo arm

Vestbo 2004Review article.

Welte 2009Trial focuses on budesonide/formoterol added to tiotropium

Welte 2009aTrial focuses on budesonide/formoterol added to tiotropium

Welte 2009bTrial focuses on budesonide/formoterol added to tiotropium

Welte 2009cTrial focuses on budesonide/formoterol added to tiotropium

Welte 2009dTrial focuses on budesonide/formoterol added to tiotropium

Wilson 2007Study compares patients' preferences of 4 dry powder inhalers

Worth 2009Study duration less than minimum of four weeks

Worth 2009aStudy duration less than minimum of four weeks

Worth 2010Study duration less than minimum of four weeks

Wouters 2005Study excluded as it assessed the withdrawal of FP from combination therapy

Zhong 2011Combined ICS/LABA not compared to placebo

Zhong 2012Combined ICS/LABA not compared to placebo

 
Comparison 1. Combined inhalers versus placebo (primary outcomes)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Exacerbation rates with combined inhalers versus placebo7Rate Ratio (Fixed, 95% CI)0.73 [0.69, 0.78]

    1.1 Fluticasone/salmeterol
3Rate Ratio (Fixed, 95% CI)0.74 [0.69, 0.80]

    1.2 Budesonide/formoterol
4Rate Ratio (Fixed, 95% CI)0.71 [0.62, 0.81]

 2 Mortality1610129Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.68, 0.99]

    2.1 Fluticasone/salmeterol
105543Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.65, 0.97]

    2.2 Budesonide/formoterol
43250Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.57, 1.93]

    2.3 Mometasone/formoterol
21336Odds Ratio (M-H, Fixed, 95% CI)1.35 [0.36, 5.13]

 3 Pneumonia149620Odds Ratio (M-H, Fixed, 95% CI)1.62 [1.36, 1.94]

    3.1 Fluticasone/salmeterol
95447Odds Ratio (M-H, Fixed, 95% CI)1.76 [1.46, 2.14]

    3.2 Budesonide/formoterol
32837Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.57, 1.47]

    3.3 Mometasone/formoterol
21336Odds Ratio (M-H, Fixed, 95% CI)2.39 [0.68, 8.36]

 4 Hospitalisations due to COPD exacerbations129492Odds Ratio (M-H, Random, 95% CI)0.92 [0.80, 1.06]

    4.1 Fluticasone/salmeterol
75309Odds Ratio (M-H, Random, 95% CI)0.89 [0.75, 1.04]

    4.2 Budesonide/formoterol
32847Odds Ratio (M-H, Random, 95% CI)1.17 [0.87, 1.58]

    4.3 Mometasone/formoterol
21336Odds Ratio (M-H, Random, 95% CI)0.57 [0.31, 1.07]

 5 Number of participants with at least one exacerbation93141Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.66, 0.93]

    5.1 Fluticasone/salmeterol
71817Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.64, 1.07]

    5.2 Mometasone/formoterol
21324Odds Ratio (M-H, Fixed, 95% CI)0.74 [0.58, 0.94]

 
Comparison 2. Fluticasone/salmeterol (FPS) versus placebo (PLA)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Exacerbations33777Rate ratio (Fixed, 95% CI)0.74 [0.69, 0.80]

    1.1 Poorly reversible population
33777Rate ratio (Fixed, 95% CI)0.74 [0.69, 0.80]

 2 Number of participants with at least one exacerbation71817Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.64, 1.07]

    2.1 Reversible population
1126Odds Ratio (M-H, Fixed, 95% CI)0.32 [0.06, 1.66]

    2.2 Partially reversible population (mixed population)
2713Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.69, 1.44]

    2.3 Poorly reversible population
3841Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.54, 1.15]

    2.4 Unclear reversibility
1137Odds Ratio (M-H, Fixed, 95% CI)0.31 [0.09, 1.05]

 3 Participants with at least one exacerbation by type2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Requirement for oral steroids
2417Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.61, 1.68]

    3.2 Requirement for antibiotic treatment
1140Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.26, 2.44]

    3.3 Requirement for oral steroid or antibiotic treatment
1140Odds Ratio (M-H, Fixed, 95% CI)3.32 [0.13, 82.80]

    3.4 Hospitalisation
1140Odds Ratio (M-H, Fixed, 95% CI)3.32 [0.13, 82.80]

 4 Exacerbations by type3Rate ratio (Fixed, 95% CI)Subtotals only

    4.1 Requirement for oral steroids
3Rate ratio (Fixed, 95% CI)0.57 [0.52, 0.63]

    4.2 Requirement for antibiotic treatment
1Rate ratio (Fixed, 95% CI)0.60 [0.41, 0.88]

    4.3 Hospitalisation
2Rate ratio (Fixed, 95% CI)0.83 [0.70, 0.97]

 5 Mortality105543Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.65, 0.97]

    5.1 Mortality: three-year data
13057Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.66, 0.99]

    5.2 Mortality: one-year data
3987Odds Ratio (M-H, Fixed, 95% CI)0.46 [0.13, 1.65]

    5.3 Mortality: six-month data
31154Odds Ratio (M-H, Fixed, 95% CI)0.54 [0.11, 2.75]

    5.4 Mortality: three-month data
3345Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Change from baseline in St George's Respiratory Questionnaire (total score)4Mean Difference (Fixed, 95% CI)-2.90 [-3.61, -2.18]

    6.1 Poorly reversible population
4Mean Difference (Fixed, 95% CI)-2.90 [-3.61, -2.18]

 7 Change from baseline in Chronic Respiratory Disease Questionnaire scores2712Mean Difference (IV, Fixed, 95% CI)5.0 [2.48, 7.52]

    7.1 Partially reversible population (mixed population)
2712Mean Difference (IV, Fixed, 95% CI)5.0 [2.48, 7.52]

 8 Change from baseline in Transitional Dyspnoea Index (TDI) scores2707Mean Difference (IV, Fixed, 95% CI)1.04 [0.56, 1.53]

    8.1 Partially reversible population (mixed population)
2707Mean Difference (IV, Fixed, 95% CI)1.04 [0.56, 1.53]

 9 Change from baseline in predose FEV15Mean Difference (Fixed, 95% CI)0.16 [0.14, 0.19]

    9.1 Reversible population
3Mean Difference (Fixed, 95% CI)0.19 [0.15, 0.24]

    9.2 Poorly reversible population
4Mean Difference (Fixed, 95% CI)0.15 [0.11, 0.18]

 10 Change from baseline in postdose FEV12Mean Difference (Fixed, 95% CI)0.09 [0.07, 0.11]

    10.1 Poorly reversible population
2Mean Difference (Fixed, 95% CI)0.09 [0.07, 0.11]

 11 Change from baseline in rescue medication usage (puffs/d)2703Mean Difference (IV, Fixed, 95% CI)-1.19 [-1.83, -0.55]

    11.1 Partially reversible population (mixed population)
2703Mean Difference (IV, Fixed, 95% CI)-1.19 [-1.83, -0.55]

 12 Withdrawals—total135769Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.62, 0.78]

    12.1 Reversible population
1121Odds Ratio (M-H, Fixed, 95% CI)2.95 [0.30, 29.18]

    12.2 Partially reversible population (mixed population)
2709Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.60, 1.13]

    12.3 Poorly reversible population
64632Odds Ratio (M-H, Fixed, 95% CI)0.68 [0.60, 0.76]

    12.4 Unclear reversibility
4307Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.25, 1.17]

 13 Withdrawals due to adverse events115491Odds Ratio (M-H, Fixed, 95% CI)0.74 [0.64, 0.86]

    13.1 Reversible population
1123Odds Ratio (M-H, Fixed, 95% CI)0.36 [0.01, 8.90]

    13.2 Partially reversible population (mixed population)
1354Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.31, 1.51]

    13.3 Poorly reversible population
64630Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.65, 0.89]

    13.4 Unclear reversibility
4384Odds Ratio (M-H, Fixed, 95% CI)0.31 [0.11, 0.93]

 14 Withdrawals due to lack of efficacy85115Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.22, 0.41]

    14.1 Partially reversible population (mixed population)
1346Odds Ratio (M-H, Fixed, 95% CI)0.29 [0.08, 1.04]

    14.2 Poorly reversible population
64632Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.21, 0.42]

    14.3 Unclear reversibility
1137Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.08, 1.11]

 15 Adverse events—any95574Odds Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.25]

    15.1 Reversible population
1126Odds Ratio (M-H, Fixed, 95% CI)1.20 [0.59, 2.46]

    15.2 Partially reversible population (mixed population)
2717Odds Ratio (M-H, Fixed, 95% CI)1.42 [1.03, 1.96]

    15.3 Poorly reversible population
54650Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.88, 1.21]

    15.4 Unclear reversibility
181Odds Ratio (M-H, Fixed, 95% CI)0.58 [0.19, 1.79]

 16 Adverse events—'serious'95531Odds Ratio (M-H, Fixed, 95% CI)1.08 [0.95, 1.23]

    16.1 Reversible population
1123Odds Ratio (M-H, Fixed, 95% CI)0.53 [0.05, 6.05]

    16.2 Partially reversible population
2709Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.38, 1.35]

    16.3 Poorly reversible population
64699Odds Ratio (M-H, Fixed, 95% CI)1.10 [0.97, 1.26]

 17 Adverse events—pneumonia95447Odds Ratio (M-H, Fixed, 95% CI)1.80 [1.49, 2.18]

    17.1 Reversible population
1126Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.47]

    17.2 Partially reversible population (mixed population)
2709Odds Ratio (M-H, Fixed, 95% CI)5.55 [0.26, 116.46]

    17.3 Poorly reversible population
44394Odds Ratio (M-H, Fixed, 95% CI)1.80 [1.48, 2.18]

    17.4 Unclear reversibility
2218Odds Ratio (M-H, Fixed, 95% CI)3.31 [0.13, 83.73]

 18 Adverse events—candidiasis72039Odds Ratio (M-H, Fixed, 95% CI)5.73 [3.07, 10.67]

    18.1 Reversible population
1126Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.06, 16.88]

    18.2 Partially reversible population (mixed population)
2717Odds Ratio (M-H, Fixed, 95% CI)11.13 [3.36, 36.90]

    18.3 Poorly reversible population
31115Odds Ratio (M-H, Fixed, 95% CI)4.40 [2.01, 9.62]

    18.4 Unclear reversibility
181Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 19 Adverse events—hoarseness2585Odds Ratio (M-H, Fixed, 95% CI)1.61 [0.61, 4.26]

    19.1 Poorly reversible population
2585Odds Ratio (M-H, Fixed, 95% CI)1.61 [0.61, 4.26]

 20 Adverse events—palpitations1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    20.1 Poorly reversible population
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 21 Adverse events—blood glucose increased1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    21.1 Poorly reversible population
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 22 Adverse event—skin bruising1445Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    22.1 Poorly reversible population
1445Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 23 Adverse events—bronchitis1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    23.1 Poorly reversible population
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 24 Adverse events—upper respiratory tract infection54963Odds Ratio (M-H, Fixed, 95% CI)1.23 [1.04, 1.47]

    24.1 Partially reversible population (mixed population)
2709Odds Ratio (M-H, Fixed, 95% CI)1.25 [0.81, 1.92]

    24.2 Poorly reversible population
34254Odds Ratio (M-H, Fixed, 95% CI)1.23 [1.02, 1.48]

 25 Adverse events—nasopharyngitis23535Odds Ratio (M-H, Fixed, 95% CI)1.28 [1.05, 1.56]

    25.1 Poorly reversible population
23535Odds Ratio (M-H, Fixed, 95% CI)1.28 [1.05, 1.56]

 26 Adverse events—cough3612Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.23, 1.27]

    26.1 Reversible population
1126Odds Ratio (M-H, Fixed, 95% CI)3.15 [0.13, 78.72]

    26.2 Partially reversible population (mixed population)
1346Odds Ratio (M-H, Fixed, 95% CI)0.49 [0.18, 1.31]

    26.3 Poorly reversible population
1140Odds Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.48]

 27 Adverse events—headache43922Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.84, 1.31]

    27.1 Reversible population
1123Odds Ratio (M-H, Fixed, 95% CI)0.22 [0.02, 2.01]

    27.2 Partially reversible population (mixed population)
2709Odds Ratio (M-H, Fixed, 95% CI)1.38 [0.91, 2.10]

    27.3 Poorly reversible population
13090Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.73, 1.26]

 
Comparison 3. Budesonide/formoterol (BDF) versus placebo (PLA)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Severe exacerbations2Rate ratio (Fixed, 95% CI)0.74 [0.62, 0.88]

    1.1 Poorly reversible
2Rate ratio (Fixed, 95% CI)0.74 [0.62, 0.88]

 2 Mean severe exacerbation rates per participant per year2Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 Poorly reversible population
2Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Mortality43250Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.57, 1.93]

 4 Change from baseline in St George's Respiratory Questionnaire (total score)4Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 320/9 mcg
42350Mean Difference (IV, Fixed, 95% CI)-3.73 [-4.83, -2.63]

    4.2 160/9 mcg
21442Mean Difference (IV, Fixed, 95% CI)-3.39 [-4.70, -2.07]

 5 Quality of life—change scores2SGRQ (Fixed, 95% CI)-6.06 [-7.90, -4.22]

    5.1 Poorly reversible
2SGRQ (Fixed, 95% CI)-6.06 [-7.90, -4.22]

 6 Symptoms (change scores)2Symptom scale (Fixed, 95% CI)-0.63 [-0.90, -0.37]

    6.1 Poorly reversible
2Symptom scale (Fixed, 95% CI)-0.63 [-0.90, -0.37]

 7 Breathlessness, cough and sputum score (BCSS) change from baseline—average over treatment period2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    7.1 320/9 mcg
21533Mean Difference (IV, Fixed, 95% CI)-0.43 [-0.59, -0.26]

    7.2 160/9 mcg
21536Mean Difference (IV, Fixed, 95% CI)-0.44 [-0.60, -0.28]

 8 Rescue medication usage4Mean Difference (Fixed, 95% CI)Subtotals only

    8.1 320/9 mcg
4Mean Difference (Fixed, 95% CI)-0.98 [-1.18, -0.79]

    8.2 160/9 mcg
2Mean Difference (Fixed, 95% CI)-1.28 [-1.55, -1.00]

 9 Mean FEV1 (% change from baseline)2Mean Difference (Fixed, 95% CI)14.40 [11.91, 16.90]

    9.1 Poorly reversible
2Mean Difference (Fixed, 95% CI)14.40 [11.91, 16.90]

 10 Average 12-hour FEV1 change from baseline—end of treatment (L)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    10.1 320/9 mcg
1246Mean Difference (IV, Fixed, 95% CI)0.19 [0.12, 0.26]

    10.2 160/9 mcg
1245Mean Difference (IV, Fixed, 95% CI)0.16 [0.10, 0.22]

 11 Predose FEV1 [L] change from baseline to the average over the randomised treatment period1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    11.1 320/9 mcg
1577Mean Difference (IV, Fixed, 95% CI)0.08 [0.04, 0.12]

    11.2 160/9 mcg
1581Mean Difference (IV, Fixed, 95% CI)0.06 [0.03, 0.09]

 12 1 Hour postdose FEV1 [L] change from baseline to the average over the randomised treatment period1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    12.1 320/9 mcg
1577Mean Difference (IV, Fixed, 95% CI)0.17 [0.14, 0.20]

    12.2 160/9 mcg
1581Mean Difference (IV, Fixed, 95% CI)0.16 [0.13, 0.19]

 13 FEV1 at 12-hour change from baseline—end of treatment (L)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    13.1 320/9 mcg
1246Mean Difference (IV, Fixed, 95% CI)0.1 [0.03, 0.17]

    13.2 160/9 mcg
1245Mean Difference (IV, Fixed, 95% CI)0.07 [0.00, 0.14]

 14 Morning PEFR change from baseline, average over treatment period (L/min)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    14.1 320/9 mcg
21530Mean Difference (IV, Fixed, 95% CI)19.12 [15.69, 22.55]

    14.2 160/9 mcg
21535Mean Difference (IV, Fixed, 95% CI)14.63 [11.47, 17.80]

 15 Evening PEFR mean change from baseline, average over treatment period (L/min)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    15.1 320/9 mcg
21529Mean Difference (IV, Fixed, 95% CI)16.09 [12.61, 19.57]

    15.2 160/9 mcg
21531Mean Difference (IV, Fixed, 95% CI)12.74 [9.56, 15.91]

 16 Withdrawals—total4Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 320/9 mcg
42475Odds Ratio (M-H, Fixed, 95% CI)0.57 [0.48, 0.68]

    16.2 160/9 mcg
21556Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.50, 0.78]

 17 Withdrawals due to adverse events4Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    17.1 320/9 mcg
42475Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.61, 1.01]

    17.2 160/9 mcg
21556Odds Ratio (M-H, Fixed, 95% CI)0.95 [0.70, 1.30]

 18 Withdrawals due to lack of efficacy3Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    18.1 320/9 mcg
31898Odds Ratio (M-H, Fixed, 95% CI)0.46 [0.34, 0.63]

    18.2 160/9 mcg
1975Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.60, 1.71]

 19 Adverse event—any2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    19.1 320/9 mcg
21552Odds Ratio (M-H, Fixed, 95% CI)1.42 [1.16, 1.74]

    19.2 160/9 mcg
21556Odds Ratio (M-H, Fixed, 95% CI)1.32 [1.08, 1.61]

 20 Adverse events—'serious'4Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    20.1 320/9 mcg
42476Odds Ratio (M-H, Fixed, 95% CI)1.17 [0.95, 1.45]

    20.2 160/9 mcg
21556Odds Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.63]

 21 Adverse events—pneumonia3Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    21.1 320/9 mcg
32062Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.52, 1.52]

    21.2 160/9 mcg
21556Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.45, 1.42]

 22 Adverse events—candidiasis2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    22.1 320/9 mcg
21552Odds Ratio (M-H, Fixed, 95% CI)3.45 [1.88, 6.34]

    22.2 160/9 mcg
21556Odds Ratio (M-H, Fixed, 95% CI)2.05 [1.07, 3.92]

 23 Adverse events—dysphonia2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    23.1 320/9 mcg
21552Odds Ratio (M-H, Fixed, 95% CI)4.07 [1.52, 10.90]

    23.2 160/9 mcg
21556Odds Ratio (M-H, Fixed, 95% CI)1.17 [0.37, 3.67]

 24 Adverse events—cataracts1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    24.1 320/9 mcg
1975Odds Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.97]

    24.2 160/9 mcg
1975Odds Ratio (M-H, Fixed, 95% CI)1.95 [0.18, 21.59]

 25 Adverse events—COPD2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    25.1 320/9 mcg
21552Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.69, 1.22]

    25.2 160/9 mcg
21556Odds Ratio (M-H, Fixed, 95% CI)1.16 [0.88, 1.53]

 26 Adverse events—tremor1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    26.1 320/9 mcg
1577Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    26.2 160/9 mcg
1581Odds Ratio (M-H, Fixed, 95% CI)7.55 [0.39, 146.88]

 27 Adverse events—palpitations1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    27.1 320/9 mcg
1577Odds Ratio (M-H, Fixed, 95% CI)3.26 [0.13, 80.37]

    27.2 160/9 mcg
1581Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 28 Adverse events—lumbar spine bone density change from baseline (g/cm2)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    28.1 320/9 mcg
1149Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.03, -0.01]

    28.2 160/9 mcg
1149Mean Difference (IV, Fixed, 95% CI)0.0 [-0.01, 0.01]

 29 Adverse events—hip bone density change from baseline (g/cm2)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    29.1 320/9 mcg
1149Mean Difference (IV, Fixed, 95% CI)0.0 [-0.01, 0.01]

    29.2 160/9 mcg
1147Mean Difference (IV, Fixed, 95% CI)0.01 [0.00, 0.02]

 
Comparison 4. Mometasone/formoterol (MF/F) versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants with at least one exacerbation2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 400/10 mcg
2882Odds Ratio (M-H, Fixed, 95% CI)0.72 [0.54, 0.95]

    1.2 200/10 mcg
2886Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.58, 1.01]

 2 Number of participants having at least one moderate or severe exacerbation2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 400/10 mcg
2882Odds Ratio (M-H, Fixed, 95% CI)0.57 [0.38, 0.86]

    2.2 200/10 mcg
2886Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.42, 0.92]

 3 Mortality2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 400/10 mcg
2890Odds Ratio (M-H, Fixed, 95% CI)1.72 [0.41, 7.25]

    3.2 200/10 mcg
2894Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.20, 4.98]

 4 Change from baseline in St George's Respiratory Questionnaire (total score)2Mean Difference (Fixed, 95% CI)Subtotals only

    4.1 400/10 mcg
2866Mean Difference (Fixed, 95% CI)-3.80 [-5.75, -1.86]

    4.2 200/10 mcg
2869Mean Difference (Fixed, 95% CI)-3.91 [-6.01, -1.81]

 5 Change from baseline in FEV1 AUC0–12 hours (mL)—week 132Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 400/10 mcg
2862Mean Difference (IV, Fixed, 95% CI)162.04 [126.54, 197.53]

    5.2 200/10 mcg
2869Mean Difference (IV, Fixed, 95% CI)122.01 [86.64, 157.39]

 6 Mean change from baseline AM predose FEV1 at 13 weeks (mL)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 400/10 mcg
2856Mean Difference (IV, Fixed, 95% CI)114.64 [77.79, 151.50]

    6.2 200/10 mcg
2859Mean Difference (IV, Fixed, 95% CI)70.43 [33.63, 107.23]

 7 Withdrawals—total2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 400/10 mcg
2890Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.40, 0.77]

    7.2 200/10 mcg
2894Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.40, 0.76]

 8 Withdrawals due to lack of efficacy2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 400/10 mcg
2890Odds Ratio (M-H, Fixed, 95% CI)0.24 [0.08, 0.74]

    8.2 200/10 mcg
2894Odds Ratio (M-H, Fixed, 95% CI)0.31 [0.11, 0.84]

 9 Withdrawals due to adverse events2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 400/10 mcg
2890Odds Ratio (M-H, Fixed, 95% CI)1.07 [0.58, 1.98]

    9.2 200/10 mcg
2894Odds Ratio (M-H, Fixed, 95% CI)0.37 [0.16, 0.84]

 10 Adverse events—any2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 400/10 mcg
2890Odds Ratio (M-H, Fixed, 95% CI)0.98 [0.75, 1.30]

    10.2 200/10 mcg
2894Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.62, 1.09]

 11 Adverse events—serious2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 400/10 mcg
2890Odds Ratio (M-H, Fixed, 95% CI)1.09 [0.66, 1.79]

    11.2 200/10 mcg
2894Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.41, 1.23]

 12 Adverse events—pneumonia2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 400/10 mcg
2890Odds Ratio (M-H, Fixed, 95% CI)3.14 [0.84, 11.65]

    12.2 200/10 mcg
2894Odds Ratio (M-H, Fixed, 95% CI)1.67 [0.40, 7.04]

 13 Adverse events—candidiasis2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    13.1 400/10 mcg
2890Odds Ratio (M-H, Fixed, 95% CI)2.22 [0.50, 9.91]

    13.2 200/10 mcg
2894Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.17, 5.87]

 14 Adverse events—dysphonia1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 400/10 mcg
1461Odds Ratio (M-H, Fixed, 95% CI)2.11 [0.19, 23.41]

    14.2 200/10 mcg
1475Odds Ratio (M-H, Fixed, 95% CI)1.98 [0.18, 22.02]

 15 Adverse events—cataract1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    15.1 400/10 mcg
1429Odds Ratio (M-H, Fixed, 95% CI)0.98 [0.06, 15.72]

    15.2 200/10 mcg
1419Odds Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.48]

 16 Adverse events—COPD requiring hospitalisation2Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 400/10 mcg
2890Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.40, 1.60]

    16.2 200/10 mcg
2894Odds Ratio (M-H, Fixed, 95% CI)0.36 [0.15, 0.86]

 
Summary of findings for the main comparison. Combined inhalers versus placebo (primary outcomes) for chronic obstructive pulmonary disease

Combined inhalers versus placebo (primary outcomes) for chronic obstructive pulmonary disease (COPD)

Patient or population: patients with COPD
Settings: community
Intervention: combined inhalers

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlCombined inhalers versus placebo (primary outcomes)

Annual exacerbation rates1.350.99

(0.93 to 1.05)
Rate ratio 0.73

(0.69 to 0.78)
7473

(seven studies)
⊕⊕⊕⊝
moderate1

Participants with at least one exacerbation

Duration of six months4
301 per 1000251 per 1000

(221 to 286)
OR 0.78
(0.66 to 0.93)
3141

(eight studies)
⊕⊕⊕⊝
moderate1

Mortality

Duration of 18 months4
60 per 100050 per 1000
(41 to 59)
OR 0.82
(0.68 to 0.99)
10129
(16 studies)
⊕⊕⊕⊝
moderate2

Pneumonia

Duration of 18 months4
55 per 100085 per 1000
(73 to 101)
OR 1.62
(1.36 to 1.94)
9620
(14 studies)
⊕⊕⊕⊝
moderate1

Hospitalisations due to COPD exacerbations

Duration of 18 months4
115 per 1000108 per 1000
(95 to 121)
OR 0.93
(0.81 to 1.06)
9492
(12 studies)
⊕⊕⊝⊝
low3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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.

 1Downgraded because of risk of attrition bias.
2Downgraded because of imprecision.
3Downgraded because of risk of attrition bias and imprecision.
4Weighted mean duration.
 
Summary of findings 2. Fluticasone/salmeterol (FPS) versus placebo for COPD

Fluticasone/salmeterol (FPS) versus placebo for COPD

Patient or population: patients with COPD
Settings: community
Intervention: fluticasone/salmeterol (FPS)

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlFluticasone/salmeterol (FPS) versus placebo (PLA)

Adverse eventsany

Duration of two years2
780 per 1000794 per 1000
(771 to 816)
OR 1.09
(0.95 to 1.25)
5574
(nine studies)
⊕⊕⊝⊝
Low1

Adverse events'serious'

Duration of two years2
271 per 1000287 per 1000
(261 to 314)
OR 1.08
(0.95 to 1.23)
5531
(nine studies)
⊕⊕⊝⊝
Low1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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.

 1Downgraded because of risk of attrition bias and imprecision.
2Weighted mean duration.
 
Summary of findings 3. Budesonide/formoterol (BDF) versus placebo for COPD

Budesonide/formoterol (BDF) versus placebo for COPD

Patient or population: patients with COPD
Settings: community
Intervention: budesonide/formoterol (BDF)

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlBudesonide/formoterol (BDF) versus placebo

Adverse eventany320/94

Duration of nine months 3
538 per 1000623 per 1000
(574 to 669)
OR 1.42
(1.16 to 1.74)
1552
(two studies)
⊕⊕⊝⊝
low1

Adverse eventany160/94

Duration of nine months 3
538 per 1000606 per 1000
(557 to 652)
OR 1.32
(1.08 to 1.61)
1556
(two studies)
⊕⊕⊝⊝
low1

Adverse events'serious'320/94

Duration of 10 months3
162 per 1000184 per 1000
(155 to 219)
OR 1.17
(0.95 to 1.45)
2476
(four studies)
⊕⊕⊝⊝
low2

Adverse events'serious'160/94

Duration of nine months 3
113 per 1000132 per 1000
(102 to 171)
OR 1.2
(0.89 to 1.63)
1556
(two studies)
⊕⊕⊝⊝
low2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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.

 1Downgraded because of risk of attrition bias and imprecision and heterogeneity.
2Downgraded because of risk of attrition bias and imprecision.
3Weighted mean duration.
4Delivered dose.
 
Summary of findings 4. Mometasone/formoterol (MF/F) versus placebo for COPD

Mometasone/formoterol (MF/F) versus placebo for COPD

Patient or population: patients with chronic obstructive pulmonary disease
Settings: community
Intervention: mometasone/formoterol (MF/F)

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlMometasone/formoterol (MF/F) versus placebo

Adverse eventany400/103

Duration of six months
362 per 1000357 per 1000
(298 to 424)
OR 0.98
(0.75 to 1.3)
890
(two studies)
⊕⊕⊝⊝
low1

Adverse eventany200/103

Duration of six months
362 per 1000317 per 1000
(260 to 382)
OR 0.82
(0.62 to 1.09)
894
(two studies)
⊕⊕⊝⊝
low2

Adverse eventsserious400/103

Duration of six months
74 per 100080 per 1000
(50 to 125)
OR 1.09
(0.66 to 1.79)
890
(two studies)
⊕⊕⊝⊝
low2

Adverse eventsserious200/103

Duration of six months
74 per 100053 per 1000
(32 to 89)
OR 0.71
(0.41 to 1.23)
894
(two studies)
⊕⊕⊝⊝
low2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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.

 1Downgraded because of risk of attrition bias, imprecision and heterogeneity.
2Downgraded because of risk of attrition bias and imprecision.
3Delivered dose.
 
Table 1. Search history

VersionDetail

First published version—Issue 4, 2003 (all years to April 2002)References identified: 34
References retrieved: seven
Studies excluded: three (Cazzola 2000; Chapman 2002; Soriano 2002)
Studies identified from supplementary searching: four (Dal Negro 2003; Hanania 2003—both included; Cazzola 2002a; Cazzola 2004—both excluded).
Studies included: four

Second published version—Issue 3, 2004 (April 2003 to April 2004)References identified: 12
References retrieved: three (two papers full publications of previously included or cited studies (Dal Negro 2003; Hanania 2003). Handsearching identified two further references to the COSMIC 2003 study
Studies identified from supplementary searching: one (TRISTAN 2003)
New studies included: two
Total studies included: six

Third published version—Issue 3, 2005 (April 2004 to April 2005)References identified: 52
References retrieved: 46 (references to studies already included/excluded/ongoing: 24)
New unique studies identified: 10 (ongoing studies: two)
New studies included: zero
Total studies included: six

Fourth published version (April 2005 to April 2007)References identified: 66
References retrieved: 27 (references to studies already included/excluded/ongoing)
New unique studies identified: five (ongoing studies: zero)
New studies included: five
Total studies included: 11

Fifth published version (April 2007 to June 2013)References identified: 129

New unique studies identified: eight (ongoing studies: zero)

New studies included: eight

Total studies included: 19

 
Table 2. Rates and NNTB of mortality and NNTH of pneumonia

Study IDStudy durationPlacebo rate (%)

mortality
NNTB for mortalityPlacebo rate (%)

pneumonia
NNTH for pneumonia

TORCH156 weeks15.242 (24 to 775)12.317 (27 to 12)

TRISTAN52 weeks1.94292 (164 to 5256)0.83197 (339 to 131)

Calverley 200352 weeks1.95249 (149 to 1307)3.648 (82 to 32)

Szafranski 200352 weeks4.5110 (66 to 581)0N/A

Rennard 200952 weeks0.83674 (379 to 12,149)4.7837 (63 to 25)

Tashkin 200826 weeks0.331689 (950 to 30,403)1164 (282 to 109)

Doherty 201226 weeks0.85659 (370 to 11,865)0.85193 (331 to 128)

Tashkin 201226 weeks0.471187 (668 to 21,377)0.47346 (595 to 229)

Mahler 200224 weeks1.66340 (191 to 6125)0N/A

O'Donnell 20068 weeks0N/A1.56107 (182 to 71)