Intervention Review

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

  1. Luis Javier Nannini1,*,
  2. Phillippa Poole2,
  3. Stephen J Milan3,
  4. Annabel Kesterton4

Editorial Group: Cochrane Airways Group

Published Online: 30 AUG 2013

Assessed as up-to-date: 27 JUN 2013

DOI: 10.1002/14651858.CD006826.pub2


How to Cite

Nannini LJ, Poole P, Milan SJ, Kesterton A. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006826. DOI: 10.1002/14651858.CD006826.pub2.

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

  4. 4

    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: 30 AUG 2013

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Characteristics of included studies [ordered by study ID]
Bourbeau 2007

MethodsRandomised, double-blind, parallel-group, placebo-controlled trial

Trial duration: 16 weeks (including initial 4 week washout period from ICS and LABA)


ParticipantsSetting: 2 respiratory centres-the Montreal Chest Institute and Hopital Laval, Canada

Participants randomly assigned: 39 in total. 19 to combined salmeterol xinafoate/fluticasone propionate (FPS), and 20 to fluticasone propionate (FP). Completed 19 (100%) FPS, 17 (85%) FP

Severity: mild to very severe

Diagnostic criteria: post-bronchodilator FEV1 ≥ 25% of predicted value and FEV1/forced vital capacity (FVC) ≤ 0.70

Baseline characteristics: mean age: 62 (SD: 9) FPS, 64 (SD: 8) FP. Severity: mild 4, moderate 6, severe/very severe 9 FPS; mild 3, moderate 10, severe/very severe 7 FP. Sex: male 19 (100%) FPS, male 15 (75%) FP. Baseline lung function: mean % predicted FEV1 (SD) post-BD: 61 (24) FPS; 57 (19) FP. Smoking history: pack-years n (SD): 65 (33) FPS, 54 (24) FP
Inclusion criteria: age ≥ 40 and ≤ 75 years; smoking history (≥ 10 pack-years); post-bronchodilator FEV1 ≥ 25% of predicted value and FEV1/forced vital capacity (FVC) ≤ 0.70

Exclusion criteria: no history of asthma, atopy (as assessed by an allergy skin prick test during screening) or any other active lung disease. Patients on home oxygen or with raised carbon dioxide tension (> 44 mm Hg), α1-antitrypsin deficiency, recent exacerbation (in the last 4 weeks), uncontrolled medical condition or hypersensitivity to inhaled corticosteroids and bronchodilators


InterventionsRun-in period: After a 4-week washout period from inhaled corticosteroids and long-acting b2 agonists, participants were randomly assigned to one of the treatment groups for 12 weeks

Intervention: salmeterol xinafoate/fluticasone propionate (FPS; Advair/Seretide/Viani, control: GlaxoSmithKline) Diskus (50/500 mcg twice daily) versus fluticasone propionate (FP; Flovent/Flixotide, GlaxoSmithKline) Diskus (500 mcg twice daily)

Co-medication: short-acting bronchodilators, short- and long acting anticholinergics or theophylline was allowed throughout the study. Oral corticosteroids and/or antibiotics could be given only in short courses for exacerbation treatment

Inhaler device: Diskus


Outcomes
  • Bronchial biopsies collected at visit 2 (before treatment initiation) and after 12 weeks of treatment at visit 4
  • Pre- and post-bronchodilator spirometric measurements (FEV1 and FVC) and administration of the CRQ were performed at visit 2 and after 4 and 12 w of treatment
  • The ATS-DLD 78 questionnaire was administered at visit 2, and measurements of lung volumes and carbon monoxide transfer factor (TLCO) were made
  • Bronchoalveolar lavage (BAL) fluid was collected after the bronchoscopy procedure and sputum induction was performed on three occasions (2–4 days before bronchoscopy at randomisation, after 4 weeks of treatment and at the end of treatment). Analysis of these samples (outcome 4) has not yet been completed and will be the subject of a future publication
  • Time points: data collected over 12-week period


NotesThis study was funded by an unrestricted research grant from GlaxoSmithKline


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 which used a block size of six set up by a data management/randomisation company (GEREQ, Montreal, Quebec). A 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 unblinding the study (e.g. a serious adverse event possibly related to study treatment)

Allocation concealment (selection bias)Low riskAs above

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study

Incomplete outcome data (attrition bias): MortalityUnclear risk0% withdrew on FPS and 15% on fluticasone

Incomplete outcome data (attrition bias): All other outcomesUnclear risk0% withdrew on FPS and 15% on fluticasone

Selective reporting (reporting bias)Unclear riskNot reported data for change in FEV1 from baseline

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
Jadad score: 4


Participants
  • Setting: 109 centres in 15 countries
  • Participants randomly assigned: 511 (BDF: 254; BUD: 257). Additional treatment groups not covered in this review: PLA: 256; F: 255
  • Baseline characteristics: mean age: 64; mean FEV1 L: 1; mean FEV1 % predicted: 36; mean SGRQ: 48
  • Inclusion criteria: GOLD defined COPD (stages 3 and 4); ≥ 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 to 12 months before 1st clinic visit
  • 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: oxygen 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, β-blocking agents


InterventionsRun-in phase: All participants received 30 mg oral prednisolone BID and 2 × 4.5 mg formoterol BID (2 weeks). (1) BDF: 320/9 mcg bid. (2) BUD: 400 mcg bid. Additional treatment groups not covered in this review: (3) Placebo (lactose monohydrate). (4) F: 9 mcg bid. Inhaler device: Turbuhaler


OutcomesTime 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


NotesClassified 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

BiasAuthors' judgementSupport for judgement

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

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 risk29% withdrew on BDF and 40% withdrew on budesonide

Incomplete outcome data (attrition bias): All other outcomesHigh risk29% withdrew on BDF and 40% withdrew on budesonide

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

Doherty 2012

MethodsRandomised, placebo-controlled, double-blind, double-dummy, multicentre study

Trial duration: 52 weeks (26-week treatment period and 26-week safety extension)


ParticipantsSetting: 164 centres in North, Central and South America, Europe, Africa, and Asia

Participants randomly assigned: 225 to mometasone furoate and formoterol combined (MF/F), 253 to mometasone furoate (MF). Completed: 190 (84%) MF/F, 202 (80%) MF

Severity: moderate to very severe

Diagnostic criteria: males or females ≥ 40 years old with FEV1/FVC ≤ 0.70, with a post-bronchodilator FEV1 of 25% to 60% predicted

Baseline characteristics: mean age (SD), y: 59.2 (9.1) MF/F, 60.5 (8.5) MF. Sex: male (%) 168 (75%) MF/F, 197 (78%) MF. Baseline lung function: mean FEV1 reversibility %/mL (SD): 102 mL/8.69% (13.58) MF/F, 121 mL/9.67% (14.84) MF. Baseline lung function: mean % predicted FEV1 (SD) post BD: 38.1 (10.8) MF/F, 40.2 (11.7) MF. Smoking history; pack-years n (SD): 54.8 (186.4) MF/F, 41.1 (23.5) MF
Inclusion criteria: males or females ≥ 40 years old with FEV1/FVC ≤ 0.70, with a post-bronchodilator FEV1 of 25% to 60% predicted. Additional inclusion criteria were symptoms of COPD (e.g. chronic cough and sputum production not attributable to another disease) for at least 24 months before enrolment; current or ex-smokers with ≥ 10 pack-year history; no use of parenteral steroids, oral steroids or antibiotics within 4 weeks before screening; and clinically acceptable laboratory tests at screening. Female subjects of childbearing potential were required to use a medically acceptable, adequate form of birth control

Exclusion criteria: current diagnosis of asthma, exhibited marked bronchodilator reversibility (increase in FEV1 ≥ 400 mL) versus baseline pre-bronchodilator FEV1, had a COPD exacerbation within 4 weeks before randomisation or required long-term administration of supplemental oxygen (> 15 hours/d). Additional exclusion criteria included a history of: lung cancer; alpha-1-antitrypsin deficiency; previous lung surgery; cataract extractions in both eyes; glaucoma or intraocular pressure ≥ 22 mm Hg in either eye; and the presence of clinically significant medical illness(es) that, in the opinion of the principal investigator, could interfere with the study


InterventionsRun in: 2-week washout/run-in period, in which previous long-acting COPD treatments (LABA, ICS, LABA/ICS FDC, or long-acting anticholinergic [e.g. tiotropium]) were discontinued and substituted with an open-label, short-acting β2-agonist (SABA)/short-acting anticholinergic combination

Intervention: 2 inhalations BID of MF/F 200/5 μg

Control: 2 inhalations BID of MF 200 μg

Inhaler device: MDI (spacers were not used in this study)


Outcomes
  • Area under the curve from 0 to 12 hours post-dose (AUC 0–12 h) at the week 13 endpoint (last observation carried forward [LOCF]) to assess the added benefit of F on bronchodilation
  • AM predose (trough) FEV1 at the week 13 endpoint to assess the added benefit of MF on trough FEV1
  • Assessment of changes from baseline in FEV1 AUC 0–12 h at day 1, weeks 1, 13 and 26 and the 26-week endpoint (LOCF)
  • Assessment of changes from baseline in trough FEV1 at each visit and at the 26-week endpoint


 

The key secondary efficacy endpoints evaluated for the 26-week treatment period were:

  • respiratory health status scores, assessed with the St George’s Respiratory Questionnaire (SGRQ); and
  • COPD symptom-free nights (combined score of 0 upon awakening for wheezing, cough and difficulty breathing); partly stable COPD and time to first mild, moderate or severe COPD exacerbation


Time points: Efficacy and safety were evaluated over 6 months in the active treatment and placebo groups. 75% of participants in each active treatment group were randomly selected to participate in a 26-week safety extension, which began after the initial 26-week treatment period. Serial spirometry tests were performed at day 1, as well as at weeks 1, 13 and 26, which included measuring the pre-dose FEV1 30 minutes and immediately before the AM dose, and then at 5, 15 and 30 minutes and at 1, 2, 3, 4, 6, 8,10, 11 and 12 hours post-dose


NotesFunding: Merck Sharp & Dohme Corp


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskParticipants were randomly assigned in a 1:1 ratio, but no specific information was included in trial report to clarify how participants were randomly assigned

Allocation concealment (selection bias)Unclear riskNo specific information was included in trial report to clarify how participants were randomly assigned

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo-controlled, double-blind, double-dummy study. Double-blind treatment. All inhalers were MDIs

Active and placebo MF/F and MF inhalers were identical in appearance, as were active and placebo F inhalers

Incomplete outcome data (attrition bias): MortalityUnclear risk15% withdrew on MF/F and 20% on mometasone furoate

Incomplete outcome data (attrition bias): All other outcomesUnclear risk16% withdrew on MF/F and 20% on mometasone furoate

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

Hanania 2003

MethodsParallel-group study
Randomisation: method unclear
Blinding: double-blind
Allocation concealment: unclear
Excluded: described
Withdrawals: stated
Trial duration: 24 weeks with 2-week run-in period. Intention to treat analysis: not stated
Jadad score: 4


Participants
  • Setting: USA, multi-centre (76 hospitals)
  • Participants randomly assigned: 366 (FPS: 183; FP: 183). Additional treatment groups not covered in this review; SAL: 177; PLA: 185
  • 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 6 weeks, abnormal ECG, LTOT, moderate to severe exacerbation in run-in. Other significant medical disorder


InterventionsRun-in: 2 weeks' treatment with placebo inhaler and prn SABA. (1) FPS 50/250 mcg bid. (2) FP 250 mcg bid. Additional treatment groups not covered in this review: (3) SAL 50 mcg bid. (4) placebo. 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, CBSQ not stratified by reversibility. Dyspnoea and symptoms: transitional dyspnoea index, baseline dyspnoea index not stratified by reversibility. Exacerbations. Rescue salbutamol use


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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised; information not 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 risk30% withdrew on FPS and 27% on fluticasone

Incomplete outcome data (attrition bias): All other outcomesHigh risk30% withdrew on FPS and 27% on fluticasone

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

Lapperre 2009

MethodsDouble-blind, parallel-group, placebo-controlled, randomised trial

Trial duration: 30 months


ParticipantsSetting: 2 university medical centres in The Netherlands

Participants randomly assigned: 28 to fluticasone and salmeterol (FPS) and 26 to fluticasone (FP). Completed (%) 21 (75%) FPS, 22 (85%) FP

Severity: moderate to severe

Diagnostic criteria: Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 2 and 3

Baseline characteristics: mean age (SD), y: 62 (8) FPS, 62 (8) FP. Sex: male (%) 22 (88%) FPS, 23 (88%) FP. Baseline lung function: post-bronchodilator FEV1, mean % predicted FEV1 (SD): 61 (9.4) FPS, 64 (9.1) FP. Change in FEV1, % predicted

(Reversibility in FEV1 by 400 mcg salbutamol) 6.2 (6.3) FPS, 7.1 (4.0) FP. Smoking history: pack-years n (range) 47 (31-56) FPS, 44 (31-55) FP

Inclusion criteria: patients with COPD who were aged 45 to 75 years, were current or former smokers, had smoked for 10 or more pack-years and had lung function levels compatible with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 2 and 3
Exclusion criteria: asthma and receipt of ICS within 6 months before random assignment


InterventionsIntervention: fluticasone, 500 mcg twice daily, and salmeterol, 50 mcg twice daily, in a single inhaler for 30 months

Control: fluticasone, 500 mcg twice daily, for 30 months

Co-medication: short-acting bronchodilators

Inhaler device: Diskus dry-powder inhalers


Outcomes
  • Inflammatory cell counts in bronchial biopsies and induced sputum
  • Post-bronchodilator spirometry and hyperresponsiveness to methacholine PC20
  • Dyspnoea score by the modified Medical Research Council (MRC) dyspnoea scale (range 1 to 5)
  • Health status by the St. George’s Respiratory Questionnaire (SGRQ) (range 0 to 100; 100 = maximum disability) and the Clinical COPD Questionnaire (CCQ) (range 0 to 6; 6 = worst)


Time points: symptoms, health status, self-reported smoking status, medication adherence and spirometry measured every 3 months, and checked adherence by counting the doses in the inhalers. Bronchoscopy, sputum induction and methacholine challenge at baseline and at 6 and 30 months


NotesFunding: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen and Leiden University Medical Center


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 for centre, sex, smoking status, FEV1/IVC (˂ 60% or ≥ 60%) and methacholine PC20 (the provocative concentration of methacholine that causes a 20% decrease in FEV1) (˂ 2 mg/mL or ≥ 2 mg/mL)

Allocation concealment (selection bias)Low riskStudy medications were individually numbered, and all active treatment medication and placebo were identical in appearance

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Incomplete outcome data (attrition bias): MortalityHigh risk25% withdrew on FPS and 15% on fluticasone

Incomplete outcome data (attrition bias): All other outcomesHigh risk25% withdrew on FPS and 15% on fluticasone

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

Mahler 2002

MethodsParallel-group study
Randomisation: stratified by reversibility and investigative site
Blinding: double-blind
Allocation concealment: unclear
Trial duration: 24 weeks
Withdrawals: stated
Intention-to-treat analysis: stated Jadad score: 3


Participants
  • Setting: multi-centre study (65 centres)
  • Participants randomly assigned: 333 (FPS: 165; FP: 168). Additional treatment groups not covered in this review; SAL: 160; PLA: 181
  • Baseline characteristics: mean age: 63; FEV1: 1.2 to 3 L
  • Inclusion criteria: participants with COPD according to ATS guidelines. Baseline pre-bronchodilation FEV1 < 65% predicted and > 0.70 L. 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
  • 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


InterventionsRun-in: 2 weeks' treatment with placebo inhaler and prn SABA.

(1) FPS 500/50 mcg bid. (2) FP 500 mcg bid.

Additional treatment groups not covered in this review: (3) SAL 50 mcg bid. (4) Placebo.

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; information not 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 risk32% withdrew on FPS and 40% on fluticasone

Incomplete outcome data (attrition bias): All other outcomesHigh risk32% withdrew on FPS and 40% on fluticasone

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

NCT00358358

MethodsRandomised, double-blind, placebo-controlled, parallel-group study

Trial duration: 12 weeks


ParticipantsSetting: 11 centres; four centres in the Russian Federation, four in the United States, two in Chile, and one in Estonia

Participants randomly assigned: 39 to fluticasone propionate with salmeterol xinafoate (FPS) and 42 to fluticasone propionate (FP). N completed (%) 35 (90%) FPS, 35 (83%) FP.

Severity: mild to moderate

Diagnostic criteria: Participants had measured post-albuterol FEV1/FVC ≤ 70% at Visit 1 (screening) and measured post-albuterol FEV1 ≥ 30% and ≤ 70% of predicted normal

Baseline characteristics: mean age (SD), y: 63.6 (7.75) FPS, 64.2 (11.23) FP. Sex: male (%) 32 (82%) FPS, 29 (69%) FP. Participants had measured post-albuterol FEV1/FVC ≤ 70% at Visit 1 (screening) and measured post-albuterol FEV1 ≥ 30% and ≤ 70% of predicted normal
Inclusion criteria: Males or females of non-childbearing potential ≥ 40 years of age were eligible to participate if they had an established clinical history of COPD, evidence of bronchitis as a component of the COPD disease and a current or prior history of at least 10 pack-years of cigarette smoking. Participants had measured post-albuterol FEV1/FVC ≤ 70% at Visit 1 (screening) and measured post-albuterol FEV1 ≥ 30% and ≤ 70% of predicted normal
Exclusion criteria: diagnosis of asthma, active respiratory disorder other than COPD, evidence of clinically significant uncontrolled non-pulmonary disease, carcinoma not in complete remission for last 5 years, lung volume reduction surgery in previous 12 months, nocturnal positive pressure for sleep apnoea. Other inclusion and exclusion criteria evaluated at the first study visit


InterventionsIntervention: fluticasone propionate 500 mcg with salmeterol xinafoate 50 mcg (FSC 500/50)

Control: fluticasone propionate 500 mcg (FP 500)

Details of co-medication not stated

Inhaler: Advair DISKUS, Seretide Accuhaler


OutcomesPre-dose resistance difference between 5 Hz and 15 Hz (R5 to R15) as measured by IOS

Pre-dose and 2-hour post-dose low-frequency reactance area (AX); 2-hour post-dose R5 to R15; post-albuterol computed tomography (CT) parameters of area of airway wall (Aaw) and area of airway lumen (Ai)

Time points: pre-dose and 2 hours post-dose and change from baseline at 12 weeks


NotesFunding: GlaxoSmithKline


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot explicitly specified

Allocation concealment (selection bias)Unclear riskNot explicitly specified

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study

Incomplete outcome data (attrition bias): MortalityUnclear risk10% withdrew on FPS and 17% on fluticasone

Incomplete outcome data (attrition bias): All other outcomesUnclear risk10% withdrew on FPS and 17% on fluticasone

Selective reporting (reporting bias)Low riskAll outcomes pre-defined in the methods section are presented

SFCT01

MethodsParallel-group design
Randomisation: not clear
Blinding: double-blind
Allocation concealment: unclear
Excluded: not described
Withdrawals: described
Trial duration: 52 weeks
Withdrawals: stated
Intention-to-treat analysis: stated
Jadad score: 3


Participants
  • Setting: 49 centres in Italy, 7 in Poland
  • Participantsrandomly assigned: 256 (FP/SAL: 131; FP: 131)
    • Additional treatment groups not covered in this review: PLA: 125
  • Baseline characteristics: 65 years; FEV1: not reported
  • Inclusion criteria: M/F ≥ 40 years of age; diagnosis of COPD; ≥ 10 pack-year; FEV1 < 70% predicted and > 800 mL; reversibility < 10% predicted normal (and < 200 mL)
  • Exclusion criteria: not described


InterventionsRun-in: 2 weeks. All maintenance LABA and ICS treatment ceased.

(1) FPS 500/50 mcg bid. (2) FP 500 mcg bid.

Additional treatment groups not covered in this review: (3) Placebo. 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; information not 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 risk34.4% withdrew on FPS and 26% withdrew on fluticasone

Incomplete outcome data (attrition bias): All other outcomesHigh risk34.4% withdrew on FPS and 26% withdrew on fluticasone

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

Sin 2008

MethodsDouble-blind randomised, placebo-controlled trial

Trial duration: 4-week treatment period


ParticipantsSetting: 11 centres in western Canada

Participants randomly assigned: 92 to fluticasone propionate with salmeterol xinafoate (FPS) and 87 to fluticasone propionate (FP). N completed (%) 88 (96%) FPS, 85 (98%) FP

Severity: moderate

Diagnostic criteria: Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Spirometric criteria included FEV1 of less than 80% of predicted with an FEV1 to FVC ratio of less than 0.70 (post-bronchodilator values)

Baseline characteristics: mean age (SD), y: 69.6 (9.3) FPS, 70.2 (9.0) FP. Sex: male 60.9% FPS, 64.4%. Baseline lung function: mean FEV1 L (SD) 1.33 (0.62) FPS, 1.42 (0.53) FP Baseline lung function: mean % predicted FEV1 (SD): 45.8 (16.4) FPS, 49.2 (15.3) FP. Smoking history: pack-years n (SD): 56.5 (39.0-73.7) FPS, 63.0 (50.0-75.8) FP
Inclusion criteria: Spirometric criteria included FEV1 of less than 80% of predicted with an FEV1 to FVC ratio of less than 0.70 (post-bronchodilator values). Cigarette smoking history of more than 10 pack-years, clinical stability as defined by the absence of exacerbations for at least 4 weeks, age ≥ 40 years and absence of known chronic systemic infections or inflammatory conditions (e.g. rheumatoid arthritis, systemic lupus erythematosus, active sarcoidosis)

Exclusion criteria: any known disseminated malignancy, known chronic systemic infection or inflammatory condition (e.g. rheumatoid arthritis, systemic lupus erythematosus, active sarcoidosis), previous solid organ transplantation, myocardial infarction or cerebrovascular accident within the past 3 months before study enrolment, females of child-bearing age (i.e. must be amenorrhoeic for at least 12 months), participation in a drug trial within the 4 weeks before study enrolment, any participant who is unlikely to survive longer than 6 months, recent upper respiratory tract infection within the 4 weeks before enrolment, unable to follow instructions, patients taking chronic oral theophyllines and unable or unwilling to come off theophyllines for the study period, oral corticosteroids or long-term immunosuppressive agents


InterventionsRun-in period: All participants underwent a run-in phase, during which they received fluticasone (500 mg twice daily) for 4 weeks. This was followed by a medication withdrawal phase, wherein inhaled corticosteroids, LABAs and theophylline products were withdrawn for 4 weeks

Intervention: inhaled fluticasone/salmeterol combination (500/50 mcg twice daily)

Control: inhaled fluticasone (500 mcg twice daily)

Co-medication: all other medications, including short-acting β2-adrenoceptor agonists, anticholinergics and tiotropium, were permitted during all phases of the study

Inhaler device: Diskus inhaler


OutcomesPrimary outcome.

C-reactive protein (CRP) level.

Secondary outcomes.

  • Changes in other inflammatory mediators such as IL-6 and surfactant protein D (SP-D).
  • Changes in SGRQ scores.
  • Changes in FEV1.
  • Rates of exacerbations


Time points: visit 1 (enrolment), visit 2 (run-in phase; 1 m fluticasone), visit 3 (withdrawal phase), visit 4 (RCT phase)


NotesFunding: GlaxoSmithKline


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was performed centrally and was stratified according to current smoking status with allocation concealment in a 1 (placebo arm) to 2 (fluticasone arm) to 2 (fluticasone/salmeterol) distribution ratio

Allocation concealment (selection bias)Low riskAs above

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study

Incomplete outcome data (attrition bias): MortalityLow risk4% withdrew on FPS and 2% on fluticasone

Incomplete outcome data (attrition bias): All other outcomesLow risk4% withdrew on FPS and 2% on fluticasone

Selective reporting (reporting bias)Low riskAll outcomes pre-defined in the methods section are presented

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 patients received an enrolment code, and then after run-in, participants were allocated the next consecutive participant number
Allocation concealment: adequate
Blinding: All the Turbuhaler inhalers were identical to ensure that the participant, the pharmacist and the investigator were blinded to the allocated treatment
Withdrawals: stated
Intention-to-treat analysis: stated
Jadad score: 5


Participants
  • Setting: 89 centres in Central & South America, Europe and South Africa
  • Participants: 406 (BDF: 208; BUD: 198)


  • Additional treatment groups not covered in this review


    • F: 201; PLA: 205
  • 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 7 days of run-in; use of bronchodilators for reliever medication; ≥ 1 severe COPD exacerbation within 2 to 12 months before study entry
  • Exclusion criteria: history of asthma/rhinitis before age 40; use of beta-blockers; current respiratory tract disease other than COPD


InterventionsRun-in: 2 weeks. Treatment with prn SABA only.

(1) BDF 320/9 mcg bid. (2) BUD 400 μg bid.

Additional treatment groups not covered in this review: (3) Placebo. (4) F 9 μg bid.

Inhaler device: Turbuhaler


OutcomesSymptoms, adverse events, exacerbations, lung function


NotesClassified as 'poorly reversible' subgroup. Jadad score: 5. 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

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAs described above

Allocation concealment (selection bias)Low riskAs described above

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

Incomplete outcome data (attrition bias): MortalityHigh risk28% withdrew on BDF and 31% on budesonide

Incomplete outcome data (attrition bias): All other outcomesHigh risk28% withdrew on BDF and 31% on budesonide

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

Tashkin 2008

MethodsRandomised, double-blind, double-dummy, placebo-controlled, parallel-group study

Trial duration: 6 months


ParticipantsSetting: 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa

Participants randomly assigned: 277 to Symbicort (Sym) and 275 to budesonide (Bud). Completed: 238 (85.9%) Sym, 212 (77.1%) Bud

Severity: moderate to very severe

Diagnostic criteria: pre-bronchodilator FEV1 ≤ 50% of predicted normal. Prebronchodilator FEV1/FVC < 70%

Baseline characteristics: mean age (SD), y: 63.1 (9.0) Sym, 63.4 (8.8) bud. Sex: male,n (%) 188 (67.9%) Sym, 186 (67.6%) Bud. Baseline lung function: mean % predicted FEV1 (SD) post-bronchodilator: 39.05 (11.78) Sym, 39.72 (12.01) bud. Smoking history: pack-years medians: 40 Sym, 41 bud

Inclusion criteria: ≥ 40 years of age. Clinical diagnosis of COPD and symptoms for > 2 years, a history of at least 1 COPD exacerbation treated with a course of oral corticosteroids and/or antibiotics within 1 to 12 months before screening (visit 1), use of an inhaled SABA as rescue medication, pre-bronchodilator FEV1 ≤ 50% of predicted normal, pre-bronchodilator FEV1/FVC < 70%, Smoking history ≥ 10 pack-years, score ≥ 2 on the modified MRC dyspnoea scale, a breathlessness-cough-sputum scale (BSCC) score ≥ 2 per day for at least half of the 2-week run-in period

Exclusion criteria: history of asthma or allergic rhinitis before 40 years of age, significant/unstable cardiovascular disorder, clinically significant respiratory tract disorder other than COPD Homozygous α1-antitrypsin deficiency or any other clinically significant co-morbidities that could preclude participation in the study or interfere with the study results, as determined by the investigator. If additions or alterations to their usual COPD maintenance therapy needed or an increment in rescue therapy due to worsening symptoms within 30 days before screening or during the run-in period. Oral or ophthalmic non-cardioselective B-adrenoceptor antagonists, oral corticosteroids, pregnancy and breast feeding were excluded


InterventionsRun-in period: 2-week run-in period, during which participants continued ICS monotherapy if they had previously been receiving ICS alone or in combination with a LABA, and participants who had previously been receiving anticholinergic therapies were placed on stable doses of ipratropium bromide. A SABA agonist was allowed for rescue use. At visit 2 (after the run-in period), any ICS therapy was discontinued, and all participants were then given study rescue medication (salbutamol pMDI) for as-needed use

Intervention: Symbicort 160/4.5 µg × 2 inhalations (320/9 µg) bid

Control: budesonide 160 µg × 2 inhalations (320 µg) bid

Co-medication: ephedrine-free (or other bronchodilator-free) antitussives and mucolytics, nasal corticosteroids, stable-dose non-nebulised ipratropium bromide (not to be used within 8 hours of each clinic visit), oral or ophthalmic cardioselective β-adrenoceptor antagonists, study-provided salbutamol as rescue medication (not to be used within 6 hours of each clinic visit). Medications allowed for exacerbations after randomisation: oral and parenteral corticosteroids, acute use of xanthines, increased use of inhaled β2-adrenoceptor agonists  and ipratropium bromide, nebulised β2-adrenoceptor agonists and ipratropium bromide

Inhaler device: formoterol DPI (Turbuhaler), budesonide via an HFA pMDI


OutcomesPrimary outcomes: pre-dose FEV1 and 1 hour post-dose FEV1

Secondary outcomes:  

  • Secondary pulmonary function variables: 12-hour spirometry, pre-dose and 1-hour post-dose IC, morning and evening PEFR
  • Secondary efficacy variables: dyspnoea, HR-QOL using the SGRQ, COPD exacerbations
  • Secondary symptom variables: cough and sputum score, sleep score, rescue medication use


Time points: screening visit (visit 1), a 2-week run-in period, a randomisation visit (visit 2), four subsequent visits during the 26-week treatment period and a follow-up telephone call 30 days after the last study visit. Visits 3 to 6 were scheduled at 1, 2, 4 and 6 months after randomisation


NotesFunding: AstraZeneca


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned in balanced blocks according to a computer-generated randomisation scheme at each site to one of six treatments administered twice daily

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment unclear

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Incomplete outcome data (attrition bias): MortalityHigh risk14.1% withdrew on BDF and 22.9% on budesonide

Incomplete outcome data (attrition bias): All other outcomesHigh risk14.1% withdrew on BDF and 22.9% on budesonide

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

Tashkin 2012

MethodsRandomised, placebo-controlled, parallel-group, multicenter, double-blind, double-dummy study

Trial duration: 26 weeks


ParticipantsSetting: 131 centres located in South America, Asia, Africa, Europe and North America

Participants randomly assigned: 217 to mometasone furoate and formoterol (MF/F) and 210 to mometasone furoate (MF). N completed (%): 176 (81%) MF/F, 164 (78%) MF

Severity: moderate to very severe COPD

Diagnostic criteria: pre-bronchodilator FEV1/forced vital capacity (FVC) ratio ≤ 0.70

Baseline characteristics: mean age (SD), y: 59.7 (9.1) (MF/F), 59.8 (8.9) (MF). Sex: male (%) 171 (79%) (MF/F), 164 (78%) (MF). Baseline FEV1 AUC(0–12 h); LS mean mL 1186 (MF/F), 1255 (MF). Smoking history: mean pack-years (SD) 39.73 (28.43) (MF/F), 40.03 (29.28) (MF)
Inclusion criteria: adult males and females who were current or former smokers with a smoking history of ≥ 10 pack-years, ≥ 40 years of age, diagnosis of moderate to very severe COPD, based on a 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 ≥ 24 months, post-bronchodilator FEV1 ≤ 60% predicted normal and ≥ 25% predicted normal at screening, Females with childbearing potential were required to use a medically acceptable form of birth control

Exclusion criteria: patients with an increase in absolute volume ≥ 400 mL at the screening visit or before the baseline visit within 30 minutes after administration of 4 inhalations of albuterol/salbutamol (total dose of 360 to 400 mcg) or nebulised 2.5 mg albuterol-salbutamol. Patients requiring long-term administration of oxygen (.15 hours per day) or who experienced an exacerbation of COPD requiring medical intervention within four weeks before randomisation, β-blocking agents, or treatment with additional excluded medication (other than SABA-short-acting anticholinergic to be used as rescue medication) were not enrolled, Patients with a history of significant medical illness or a disorder that might interfere with the study or that required treatment that might interfere with the study, pregnancy or breast-feeding, a diagnosis of asthma, lung cancer, or alpha-1-antitrypsin deficiency or a history of lobectomy, pneumonectomy, lung volume reduction surgery, cataract extractions in both eyes or other significant ocular problems (glaucoma, trauma, opacification)


InterventionsRun-in period: open-label run-in period in which long-acting bronchodilators and corticosteroids were discontinued and were substituted with a short-acting β2-agonist (SABA)-anticholinergic fixed-dose combination

Intervention: MF/F 400/10 mcg bid

Control: MF 400 mcg bid

Co-medication: unclear

Inhaler device: MDI


OutcomesMean change from baseline in FEV1 area under the curve from 0 to 12 hours post-dose (AUC0–12 h) at the week 13 endpoint

Mean change from baseline in morning pre-dose FEV1 at the week 13 endpoint

Change in health status as assessed according to total scores on the St George’s Respiratory Questionnaire (SGRQ)

Change in symptom-free nights

Time-to-first mild, moderate or severe COPD exacerbation

The proportion of participants with partly stable COPD

Time points: All randomly assigned participants had study visits at screening, baseline(day 1) and weeks 1, 4, 13 and 26 in the treatment period. Participants in the safety extension had additional visits at weeks 39 and 52


NotesFunding: Merck Sharp & Dohme Corp


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. Randomisation was stratified according to the participant's smoking status at the time of randomisation. Random treatment assignment was provided to the investigative site by means of an interactive voice response system at the time participants were randomly assigned

Allocation concealment (selection bias)Low riskSee above

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind

Incomplete outcome data (attrition bias): MortalityHigh risk19% withdrew on MF/F and 22% on MF

Incomplete outcome data (attrition bias): All other outcomesHigh risk19% withdrew on MF/F and 22% on MF

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

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
Withdrawals: stated
Intention-to-treat analysis: stated
Jadad score: 5


Participants
  • Setting: 444 centres in North America, Central America and Asia Pacific
  • Participants randomly assigned: 3091 (FP/SAL: 1546; FP: 1551)
  • Additional treatment groups not covered in this review:
    • SAL: 1542; PLA: 1545
  • 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; LVRS/lung transplant; requirement for > 12 hours/d LTOT; long-term OCS therapy; serious uncontrolled disease likely to interfere with medication/cause of death in next three years


InterventionsRun-in: 2 weeks. All maintenance treatment with ICS and LABA ceased. (1) FP/SAL combination 500/50 mcg BID. (2) FP 500 mcg BID. Additional treatment groups not covered in this review: (3) Placebo. (4) SAL 50 mcg BID 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 riskAs described above

Allocation concealment (selection bias)Low riskAs described above

Blinding (performance bias and detection bias)
All outcomes
Low riskIdenitical 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 risk34.1% withdrew on FPS and 38.3% on fluticasone

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
Withdrawals: described
Trial duration: 2-week run-in period, 52 weeks treatment, 2-week follow-up
Intention-to-treat analysis: stated
Jadad score: 5


Participants
  • Setting: 196 centres in Europe, South Africa and Australia
  • Participants randomly assigned: 733 (FPS: 358; FP: 375)
  • Additional treatment groups not covered in this review:
    • SAL: 372; PLA: 361
  • 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 of predicted FEV1 30 minutes after inhaling 400 mcg salbutamol; at least 10 pack-year 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
  • 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


InterventionsRun-in: 2 weeks. All maintenance treatment with ICS and LABA ceased. (1) FPS 50 mcg/500 mcg bid. (2) FP 500 mcg bid. Additional treatment groups not covered in this review: (3) SAL 50 mcg bid. (4) Placebo. 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 riskAs described above

Allocation concealment (selection bias)Low riskAs described above

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

Incomplete outcome data (attrition bias): MortalityHigh risk25% withdrew on FPS and 29% on fluticasone

Incomplete outcome data (attrition bias): All other outcomesHigh risk25% withdrew on FPS and 29% on fluticasone

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

Zhong 2012

MethodsMulticentre, randomised, parallel-group, double-blind, double-dummy study

Trial duration: 24 weeks


ParticipantsSetting: 12 centres in China

Participants randomly assigned: 156 to budesonide/formoterol (BUD/FORM), 152 to budesonide (BUD). N completed (%) 133 (85.3%) BUD/FORM, 117 (77.0%) BUD

Severity: moderate to very severe

Diagnostic criteria: FEV1 ≤ 50% predicted; FEV1/FVC < 70%

Baseline characteristics: mean age (SD), y: 65.70 (8.75) BUD/FORM, 64.71 (9.61) BUD. Sex: male (%) 153 (98.1%) BUD/FORM, 140 (92.1) BUD. COPD severity: moderate: 7 (4.5%), severe: 98 (62.8%), very severe: 51 (32.7%) BUD/FORM, moderate: 5 (3.3%) severe: 94 (61.8%), very severe: 53 (34.9%) BUD. Baseline lung function (post-bronchodilator): mean % predicted FEV1 (SD): 36.15 (10.97) BUD/FORM, 36.28 (10.40) BUD

Inclusion criteria: male or female outpatients ≥ 40 years with diagnosis of COPD; pre-bronchodilator FEV1 ≤ 50% predicted; FEV1/FVC < 70%; at least 1 COPD exacerbation (defined as use of oral/IV corticosteroids and/or antibiotics and/or emergency room treatment/hospitalisation due to respiratory symptoms) during 2 to 12 months before the study; a smoking history of ≥ 10 pack-years

Exclusion criteria: a history of asthma; seasonal allergic rhinitis with onset < 40 years; COPD exacerbation within 4 w of study entry or during the run-in period; post-bronchodilator FEV1 ≥ 80% of predicted normal value during the reversibility test at baseline; any other serious diseases or disorders that were considered to influence the study results or to increase the risk of participation in the study


InterventionsRun-in period: 2-week oral prednisolone acetate 20 mg/d + prn terbutaline 0.25 mg/dose

Intervention: budesonide/formoterol (160/4.5 mcg/dose) 2 inhalations BID

Control: budesonide (200 mcg/dose) 2 inhalations BID

Co-medication: terbutaline 0.25 mg/dose prn. No other bronchodilator was permitted

Inhaler device: Turbuhaler


Outcomes1-hour post-dose FEV1

FVC (pre-dose and 1 hour post-dose)

FEV1 (pre-dose and 15 minutes post-dose)

St George’s Respiratory Questionnaire (SGRQ) score

COPD symptom scores

Morning and evening PEF

COPD exacerbations

Time points: weeks 0, 2, 4, 8, 12, 19, 24


NotesFunding: Astra Zeneca


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe randomisation schedule was generated using a computer program at AstraZeneca, Sweden. Participants were randomly assigned in equal proportions to either BUD/FORM and placebo, or BUD and placebo

Allocation concealment (selection bias)Low riskTreatment codes were not broken for the planned analyses of data until all decisions on the evaluable data from each individual participant had been made and documented

Blinding (performance bias and detection bias)
All outcomes
Low riskAll participants used the two dry powder inhalers during the treatment period: one containing active drug and one containing placebo (double-dummy design)

Incomplete outcome data (attrition bias): MortalityHigh risk14.7% withdrew on BDF and 23% on budesonide

Incomplete outcome data (attrition bias): All other outcomesHigh risk14.7% withdrew on BDF and 23% on budesonide

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

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aaron 2007Combined ICS/LABA therapy not compared with ICS

Bathoorn 2008Trial focuses on treatment of COPD exacerbations

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

Calverley 2005Combined ICS/LABA therapy not compared with ICS

Cukier 2007Nebulised saline versus nebulised salbutamol and a cross-over trial

D5899C00001Combined ICS/LABA therapy not compared with ICS

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

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

GlaxoSmithKline 2004Trial includes patients with asthma

GlaxoSmithKline 2004aTrial includes patients with asthma

GlaxoSmithKline 2006Focus is on sputum cell measures of inflammation

Golabi 2006Cross-over trial comparing tiotropium versus salmeterol/fluticasone

Haque 2006Focuses on macrophages and glucoreceptor proteins and a cross-over trial

INSPIRETrial compared tiotropium versus seretide

Jiang 2011Combined ICS/LABA therapy not compared with ICS

Jung 2012Combined ICS/LABA therapy not compared with ICS

Laties 2010Combined ICS/LABA therapy not compared with ICS

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

Mittmann 2010Participants were randomly assigned to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo

Mittmann 2011Participants were randomly assigned to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo

NCT00269126Cross-over study examining effect of adding fluticasone to salmeterol

NCT00476099Combined ICS/LABA therapy not compared with ICS

NCT00549146ICS dose in the ICS/LABA condition was < 80% the ICS dose in the ICS-only condition. The steroid dose in the ICS/LABA combination therapy group is not equivalent to the steroid dose in the ICS-only group; the trial was designed to compare double the dose of ICS with an ICS/LABA combination

Rennard 2008No steroid control arm

Rennard 2009No steroid control arm

Rennard 2009aNo steroid control arm

Rennard 2010No steroid control arm

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

Schermer 2007ICS dose in the ICS/LABA condition was < 80% the ICS dose in the ICS-only condition. The steroid dose in the ICS/LABA combination therapy group is not equivalent to the steroid dose in the ICS-only group; the trial was designed to compare double the dose of ICS with an ICS/LABA combination

SCO100250Combined ICS/LABA therapy not compared with ICS

SCO40043Combined ICS/LABA therapy not compared with ICS

Sethi 2006Bacterial colonisation in sputum and a cross-over trial

Shaker 2009Trial compared budesonide versus placebo

Sharafkhaneh 2011Combined ICS/LABA therapy not compared with ICS

Southard 2011Combined ICS/LABA therapy not compared with ICS

Stallberg 2008Trial focuses on treatment of COPD exacerbations

Sutherland 2006Trial compares seretide versus salmeterol

Trofimenko 2006Trial not blinded and no steroid control arm

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 2007Comparison of patients' preferences among 4 dry powder inhalers

Worth 2009Combined ICS/LABA therapy not compared with ICS

Worth 2009aCombined ICS/LABA therapy not compared with ICS

Worth 2010Combined ICS/LABA therapy not compared with ICS

Zheng 2006Combined ICS/LABA therapy not compared with ICS

 
Comparison 1. All Combined Inhalers - Primary Outcomes

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

 1 Exacerbation rates (exacerbations requiring oral corticosteroids)6Rate ratio (Fixed, 95% CI)0.87 [0.80, 0.94]

    1.1 Fluticasone/salmeterol
2Rate ratio (Fixed, 95% CI)0.88 [0.80, 0.98]

    1.2 Budesonide/formoterol
4Rate ratio (Fixed, 95% CI)0.84 [0.73, 0.97]

   1.3 Mometasone/formoterol
0Rate ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Number of participants with one or more exacerbation72781Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.70, 1.09]

    2.1 Fluticasone/salmeterol
51876Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.76, 1.31]

   2.2 Budesonide/formoterol
00Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 Mometasone/formoterol
2905Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.45, 0.98]

 3 Hospitalisations due to COPD exacerbations107060Odds Ratio (M-H, Fixed, 95% CI)0.93 [0.80, 1.07]

    3.1 Fluticasone/salmeterol
54784Odds Ratio (M-H, Fixed, 95% CI)0.93 [0.79, 1.10]

    3.2 Budesonide/formoterol
31371Odds Ratio (M-H, Fixed, 95% CI)0.85 [0.60, 1.20]

    3.3 Mometasone/formoterol
2905Odds Ratio (M-H, Fixed, 95% CI)1.46 [0.66, 3.21]

 4 Mortality127518Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.64, 0.94]

    4.1 Fluticasone/salmeterol
64836Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.62, 0.92]

    4.2 Budesonide/formoterol
41777Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.54, 2.37]

    4.3 Mometasone/formoterol
2905Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.27, 2.91]

 5 Pneumonia127320Odds Ratio (M-H, Fixed, 95% CI)1.08 [0.91, 1.28]

    5.1 Fluticasone/salmeterol
75044Odds Ratio (M-H, Fixed, 95% CI)1.06 [0.89, 1.27]

    5.2 Budesonide/formoterol
31371Odds Ratio (M-H, Fixed, 95% CI)1.11 [0.47, 2.63]

    5.3 Mometasone/formoterol
2905Odds Ratio (M-H, Fixed, 95% CI)1.92 [0.66, 5.57]

 
Comparison 2. Fluticasone/salmeterol (FPS) versus fluticasone (FP)

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

 1 Exacerbation rates2Rate ratio (Fixed, 95% CI)0.88 [0.80, 0.98]

    1.1 Poorly reversible population
2Rate ratio (Fixed, 95% CI)0.88 [0.80, 0.98]

 2 Number of participants with one or more exacerbation51876Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.76, 1.31]

    2.1 Partially reversible population (mixed population)
2703Odds Ratio (M-H, Fixed, 95% CI)0.85 [0.59, 1.22]

    2.2 Poorly reversible population
2994Odds Ratio (M-H, Fixed, 95% CI)1.22 [0.80, 1.88]

    2.3 Unclear reversibility
1179Odds Ratio (M-H, Fixed, 95% CI)1.19 [0.31, 4.59]

 3 End of treatment mean number of exacerbations per participant1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    3.1 Poorly reversible population
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Number of participants with one or more exacerbations by type1262Odds Ratio (M-H, Fixed, 95% CI)1.15 [0.69, 1.92]

    4.1 Requirement for oral steroids
1262Odds Ratio (M-H, Fixed, 95% CI)1.15 [0.69, 1.92]

   4.2 Requirement for antibiotic treatment
00Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   4.3 Requirement for oral steroid or antibiotic treatment
00Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   4.4 Hospitalisation
00Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Exacerbations by type2Rate ratio (Random, 95% CI)Subtotals only

    5.1 Hospitalisation
1Rate ratio (Random, 95% CI)0.95 [0.82, 1.11]

   5.2 Requirement for antibiotic treatment
0Rate ratio (Random, 95% CI)0.0 [0.0, 0.0]

   5.3 Requirement for oral steroid or antibiotic treatment
0Rate ratio (Random, 95% CI)0.0 [0.0, 0.0]

    5.4 Requirement for oral steroids
2Rate ratio (Random, 95% CI)0.89 [0.81, 0.98]

 6 Mortality64836Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.62, 0.92]

    6.1 Mortality: three-year data
13067Odds Ratio (M-H, Fixed, 95% CI)0.75 [0.62, 0.92]

    6.2 Mortality: one-year data
2994Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.23, 4.57]

    6.3 Mortality: six-month data
2694Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.4 Mortality: three-month data
181Odds Ratio (M-H, Fixed, 95% CI)0.35 [0.01, 8.85]

 7 Mortality-cause specific2Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    7.1 COPD-related death
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.2 Cancer
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.3 Cardiovascular
2Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Change from baseline in St George's Respiratory Questionnaire (total score)3SGRQ units (Fixed, 95% CI)-1.30 [-2.04, -0.57]

    8.1 Poorly reversible population
3SGRQ units (Fixed, 95% CI)-1.30 [-2.04, -0.57]

 9 Change from baseline in Transitional Dyspnoea Index (TDI)2690Mean Difference (IV, Random, 95% CI)0.31 [-0.45, 1.08]

    9.1 Partially reversible population (mixed population)
2690Mean Difference (IV, Random, 95% CI)0.31 [-0.45, 1.08]

 10 Change from baseline in Chronic Respiratory Disease Questionnaire scores2696Mean Difference (IV, Random, 95% CI)2.34 [-3.15, 7.82]

    10.1 Partially reversible population (mixed population)
2696Mean Difference (IV, Random, 95% CI)2.34 [-3.15, 7.82]

 11 Change from baseline in predose FEV12Mean Difference (Fixed, 95% CI)0.05 [0.02, 0.09]

    11.1 Reversible population
2Mean Difference (Fixed, 95% CI)0.07 [0.01, 0.12]

    11.2 Poorly reversible population
2Mean Difference (Fixed, 95% CI)0.04 [-0.01, 0.09]

 12 Change from baseline in post-dose FEV16Mean Difference (Fixed, 95% CI)0.05 [0.04, 0.06]

    12.1 Reversible population
2Mean Difference (Fixed, 95% CI)0.15 [0.09, 0.21]

    12.2 Poorly reversible population
6Mean Difference (Fixed, 95% CI)0.05 [0.03, 0.06]

 13 End of treatment am PEF (L/min)2Mean Difference (Fixed, 95% CI)Totals not selected

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

 14 Absolute shuttle walk test1Metres (Fixed, 95% CI)Totals not selected

    14.1 Poorly reversible population
1Metres (Fixed, 95% CI)0.0 [0.0, 0.0]

 15 Change from baseline in rescue medication usage (puffs/d)2686Mean Difference (IV, Fixed, 95% CI)-0.80 [-1.31, -0.29]

    15.1 Partially reversible population (mixed population)
2686Mean Difference (IV, Fixed, 95% CI)-0.80 [-1.31, -0.29]

 16 Withdrawals95106Odds Ratio (M-H, Fixed, 95% CI)0.86 [0.76, 0.97]

    16.1 Partially reversible population (mixed population)
2694Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.63, 1.20]

    16.2 Poorly reversible population
34062Odds Ratio (M-H, Fixed, 95% CI)0.86 [0.76, 0.98]

    16.3 Unclear reversibility
4350Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.35, 1.66]

 17 Withdrawal due to lack of efficacy/exacerbation54574Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.53, 1.13]

    17.1 Partially reversible population (mixed population)
1333Odds Ratio (M-H, Fixed, 95% CI)1.02 [0.20, 5.12]

    17.2 Poorly reversible population
34062Odds Ratio (M-H, Fixed, 95% CI)0.72 [0.48, 1.08]

    17.3 Unclear reversibility
1179Odds Ratio (M-H, Fixed, 95% CI)1.93 [0.34, 10.82]

 18 Withdrawals due to adverse events74723Odds Ratio (M-H, Fixed, 95% CI)0.75 [0.64, 0.87]

    18.1 Partially reversible population (mixed population)
1342Odds Ratio (M-H, Fixed, 95% CI)0.48 [0.22, 1.02]

    18.2 Poorly reversible population
34082Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.65, 0.90]

    18.3 Unclear reversibility
3299Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.22, 2.28]

 19 Adverse events-any event85094Odds Ratio (M-H, Fixed, 95% CI)0.93 [0.80, 1.09]

    19.1 Partially reversible population (mixed population)
2703Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.66, 1.30]

    19.2 Poorly reversible population
34092Odds Ratio (M-H, Fixed, 95% CI)0.94 [0.78, 1.13]

    19.3 Unclear reversibility
3299Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.49, 1.54]

 20 Adverse events-serious75055Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.82, 1.34]

    20.1 Partially reversible population (mixed population)
2703Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.39, 1.50]

    20.2 Poorly reversible population
34092Odds Ratio (M-H, Fixed, 95% CI)1.10 [0.84, 1.45]

    20.3 Unclear reversibility
2260Odds Ratio (M-H, Fixed, 95% CI)1.09 [0.41, 2.85]

 21 Adverse events (specific adverse events)8Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    21.1 Pneumonia
75044Odds Ratio (M-H, Fixed, 95% CI)1.06 [0.89, 1.27]

    21.2 Candidiasis
61817Odds Ratio (M-H, Fixed, 95% CI)1.02 [0.70, 1.48]

    21.3 Hoarseness
1262Odds Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.14]

    21.4 Palpitations
1262Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    21.5 Upper respiratory tract infection
54717Odds Ratio (M-H, Fixed, 95% CI)1.14 [0.96, 1.36]

    21.6 Bronchitis
33441Odds Ratio (M-H, Fixed, 95% CI)1.23 [0.94, 1.61]

    21.7 Nasopharyngitis
23179Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.86, 1.29]

    21.8 Cough
1342Odds Ratio (M-H, Fixed, 95% CI)1.02 [0.32, 3.24]

    21.9 Dyspnoea
1262Odds Ratio (M-H, Fixed, 95% CI)1.0 [0.06, 16.16]

    21.10 Headache
64881Odds Ratio (M-H, Fixed, 95% CI)0.95 [0.77, 1.17]

    21.11 Urinary tract infection
2343Odds Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 2.02]

 
Comparison 3. Budesonide/formoterol (BDF) versus budesonide (BD)

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

 1 Exacerbations4Rate Ratio (Fixed, 95% CI)0.84 [0.73, 0.97]

    1.1 Partially reversible
1Rate Ratio (Fixed, 95% CI)1.00 [0.76, 1.31]

    1.2 Poorly reversible
3Rate Ratio (Fixed, 95% CI)0.79 [0.67, 0.93]

 2 Mean exacerbation rates per participant per year3Rate Ratio (Fixed, 95% CI)0.84 [0.72, 0.99]

    2.1 Poorly reversible population
3Rate Ratio (Fixed, 95% CI)0.84 [0.72, 0.99]

 3 Mortality41777Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.54, 2.37]

   3.1 Mortality as primary outcome
00Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Mortality data collected as secondary/unpublished outcome
41777Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.54, 2.37]

 4 Quality of life-SGRQ total (change scores)4Mean Difference (Fixed, 95% CI)-2.80 [-3.99, -1.61]

    4.1 Partially reversible population (mixed population)
1Mean Difference (Fixed, 95% CI)-2.57 [-4.68, -0.46]

    4.2 Poorly reversible population
3Mean Difference (Fixed, 95% CI)-2.91 [-4.35, -1.47]

 5 Symptoms (change scores)3Mean Difference (Fixed, 95% CI)-0.45 [-0.67, -0.22]

    5.1 Poorly reversible
3Mean Difference (Fixed, 95% CI)-0.45 [-0.67, -0.22]

 6 Breathlessness, cough and sputum score (BCSS) change from baseline-average over treatment period1Mean Difference (Fixed, 95% CI)-0.11 [-0.38, 0.16]

    6.1 Partially reversible (mixed population)
1Mean Difference (Fixed, 95% CI)-0.11 [-0.38, 0.16]

 7 Awakening-free nights, percentage change from baseline2Mean Difference (Fixed, 95% CI)-0.05 [-0.16, 0.06]

    7.1 Partially reversible (mixed population)
1Mean Difference (Fixed, 95% CI)1.98 [-3.17, 7.13]

    7.2 Poorly reversible population
1Mean Difference (Fixed, 95% CI)-0.05 [-0.16, 0.06]

 8 Mean FEV1 (% increase from baseline)2% increase (Fixed, 95% CI)10.17 [7.71, 12.62]

    8.1 Poorly reversible
2% increase (Fixed, 95% CI)10.17 [7.71, 12.62]

 9 Pre-dose FEV1 [L] change from baseline to the average over the randomised treatment period1Mean Difference (Fixed, 95% CI)0.08 [0.05, 0.11]

    9.1 Partially reversible population (mixed population)
1Mean Difference (Fixed, 95% CI)0.08 [0.05, 0.11]

 10 1-Hour post-dose FEV1 [L] change from baseline to the average over the randomised treatment period1Mean Difference (Fixed, 95% CI)0.17 [0.14, 0.20]

    10.1 Partially reversible population (mixed population)
1Mean Difference (Fixed, 95% CI)0.17 [0.14, 0.20]

 11 Morning PEFR change from baseline, average over treatment period (L/min)1Mean Difference (Fixed, 95% CI)14.08 [8.64, 19.52]

    11.1 Poorly reversible population
1Mean Difference (Fixed, 95% CI)14.08 [8.64, 19.52]

 12 Evening PEFR mean change from baseline, average over treatment period (L/min)1Mean Difference (Fixed, 95% CI)12.59 [7.21, 17.97]

    12.1 Partially reversible population (mixed population)
1Mean Difference (Fixed, 95% CI)12.59 [7.21, 17.97]

 13 Rescue medication use4Mean Difference (Fixed, 95% CI)-0.72 [-0.92, -0.52]

    13.1 Partially reversible population (mixed population)
1Mean Difference (Fixed, 95% CI)-0.65 [-1.09, -0.21]

    13.2 Poorly reversible
3Mean Difference (Fixed, 95% CI)-0.73 [-0.96, -0.51]

 14 Sleep score (0 to 4)-change from baseline1Mean Difference (Fixed, 95% CI)-0.04 [-0.14, 0.06]

    14.1 Partially reversible population (mixed population)
1Mean Difference (Fixed, 95% CI)-0.04 [-0.14, 0.06]

 15 Dyspnoea score (0 to 4)-change from baseline2Mean Difference (Fixed, 95% CI)-0.12 [-0.20, -0.04]

    15.1 Partially reversible population (mixed population)
1Mean Difference (Fixed, 95% CI)-0.12 [-0.22, -0.02]

    15.2 Poorly reversible population
1Mean Difference (Fixed, 95% CI)-0.12 [-0.23, -0.01]

 16 Cough score (0 to 4)-change from baseline2Mean Difference (Fixed, 95% CI)-0.01 [-0.08, 0.06]

    16.1 Partially reversible population (mixed population)
1Mean Difference (Fixed, 95% CI)0.0 [-0.11, 0.11]

    16.2 Poorly reversible population
1Mean Difference (Fixed, 95% CI)-0.02 [-0.12, 0.08]

 17 Sputum score (0 to 4)-change from baseline1Mean Difference (Fixed, 95% CI)0.02 [-0.09, 0.13]

    17.1 Partially reversible population (mixed population)
1Mean Difference (Fixed, 95% CI)0.02 [-0.09, 0.13]

 18 Withdrawals due to worsening COPD symptoms31225Odds Ratio (M-H, Fixed, 95% CI)0.68 [0.46, 0.99]

    18.1 Poorly reversible population
31225Odds Ratio (M-H, Fixed, 95% CI)0.68 [0.46, 0.99]

 19 Withdrawals due to adverse events41777Odds Ratio (M-H, Fixed, 95% CI)0.95 [0.66, 1.37]

    19.1 Partially reversible population (mixed population)
1552Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.43, 1.43]

    19.2 Poorly reversible population
31225Odds Ratio (M-H, Fixed, 95% CI)1.07 [0.68, 1.69]

 20 Adverse event-any (one or more)2860Odds Ratio (M-H, Fixed, 95% CI)0.90 [0.68, 1.19]

    20.1 Partially reversible population (mixed population)
1552Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.71, 1.40]

    20.2 Poorly reversible population
1308Odds Ratio (M-H, Fixed, 95% CI)0.72 [0.44, 1.19]

 21 Adverse events-serious events31469Odds Ratio (M-H, Fixed, 95% CI)0.93 [0.72, 1.21]

    21.1 Partially reversible population (mixed population)
1552Odds Ratio (M-H, Fixed, 95% CI)1.19 [0.70, 2.03]

    21.2 Poorly reversible population
2917Odds Ratio (M-H, Fixed, 95% CI)0.86 [0.64, 1.16]

 22 Adverse events (specific adverse events)3Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    22.1 Pneumonia
31371Odds Ratio (M-H, Fixed, 95% CI)1.11 [0.47, 2.63]

    22.2 Candidiasis
21063Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.42, 1.80]

    22.3 Dysphonia
21063Odds Ratio (M-H, Fixed, 95% CI)1.30 [0.48, 3.51]

    22.4 Palpitations
1552Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.06, 15.95]

    22.5 Laryngeal pharyngitis
2819Odds Ratio (M-H, Fixed, 95% CI)2.05 [0.98, 4.29]

    22.6 Bronchitis
1552Odds Ratio (M-H, Fixed, 95% CI)1.25 [0.49, 3.22]

    22.7 Sinusitis
1552Odds Ratio (M-H, Fixed, 95% CI)2.01 [0.60, 6.77]

    22.8 Diarrhoea
1552Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.20, 4.96]

    22.9 Upper airway infection
1308Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.10, 1.08]

    22.10 Nasopharyngitis
1552Odds Ratio (M-H, Fixed, 95% CI)2.42 [1.09, 5.39]

    22.11 Hypertension
1511Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.23, 1.90]

    22.12 Back pain
1511Odds Ratio (M-H, Fixed, 95% CI)2.06 [0.61, 6.92]

    22.13 Chest pain
1511Odds Ratio (M-H, Fixed, 95% CI)2.06 [0.61, 6.92]

    22.14 Headache
1552Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.06, 15.95]

    22.15 Dyspnoea
21063Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.32, 3.16]

    22.16 Cough
1552Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

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

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

 1 Patients with one or more exacerbation2905Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.45, 0.98]

    1.1 Poorly reversible population
1478Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.53, 1.42]

    1.2 Unclear reversibility
1427Odds Ratio (M-H, Fixed, 95% CI)0.43 [0.22, 0.82]

 2 Mortality2905Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.27, 2.91]

    2.1 Poorly reversible population
1478Odds Ratio (M-H, Fixed, 95% CI)1.51 [0.33, 6.81]

    2.2 Unclear reversibility
1427Odds Ratio (M-H, Fixed, 95% CI)0.32 [0.03, 3.10]

 3 Change from baseline in SGRQ (total score)2Mean Difference (Fixed, 95% CI)-0.29 [-2.16, 1.57]

    3.1 Poorly reversible population
1Mean Difference (Fixed, 95% CI)-0.17 [-2.68, 2.34]

    3.2 Unclear reversibility
1Mean Difference (Fixed, 95% CI)-0.44 [-3.23, 2.35]

 4 Change from baseline in FEV1 AUC0-12 h (mL) week 262Mean Difference (Fixed, 95% CI)109.34 [57.87, 160.81]

    4.1 Poorly reversible population
1Mean Difference (Fixed, 95% CI)119.0 [48.96, 189.04]

    4.2 Unclear reversibility
1Mean Difference (Fixed, 95% CI)98.0 [22.11, 173.89]

 5 Change from baseline in FEV1 AUC0-12 h (mL) week 132Mean Difference (Fixed, 95% CI)116.59 [68.59, 164.59]

    5.1 Poorly reversible population
1Mean Difference (Fixed, 95% CI)126.0 [54.16, 197.84]

    5.2 Unclear reversibility
1Mean Difference (Fixed, 95% CI)109.0 [44.49, 173.51]

 6 Mean change from baseline AM pre-dose FEV1 at 13 weeks (mL)2Mean Difference (Fixed, 95% CI)0.08 [0.04, 0.11]

    6.1 Poorly reversible population
1Mean Difference (Fixed, 95% CI)0.07 [0.02, 0.12]

    6.2 Unclear reversibility
1Mean Difference (Fixed, 95% CI)0.08 [0.03, 0.14]

 7 Withdrawals-total2905Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.56, 1.09]

    7.1 Poorly reversible population
1478Odds Ratio (M-H, Fixed, 95% CI)0.73 [0.45, 1.17]

    7.2 Unclear reversibility
1427Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.52, 1.33]

 8 Withdrawals due to adverse event2905Odds Ratio (M-H, Fixed, 95% CI)1.38 [0.71, 2.68]

    8.1 Poorly reversible population
1478Odds Ratio (M-H, Fixed, 95% CI)1.81 [0.69, 4.74]

    8.2 Unclear reversibility
1427Odds Ratio (M-H, Fixed, 95% CI)1.08 [0.43, 2.71]

 9 Withdrawal due to treatment failure2905Odds Ratio (M-H, Fixed, 95% CI)0.68 [0.19, 2.44]

    9.1 Poorly reversible population
1478Odds Ratio (M-H, Fixed, 95% CI)0.37 [0.04, 3.60]

    9.2 Unclear reversibility
1427Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.19, 4.85]

 10 Adverse event-any2905Odds Ratio (M-H, Fixed, 95% CI)1.11 [0.84, 1.46]

    10.1 Poorly reversible population
1478Odds Ratio (M-H, Fixed, 95% CI)1.35 [0.94, 1.95]

    10.2 Unclear reversibility
1427Odds Ratio (M-H, Fixed, 95% CI)0.85 [0.56, 1.30]

 11 Adverse event-serious2905Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.63, 1.67]

    11.1 Poorly reversible population
1478Odds Ratio (M-H, Fixed, 95% CI)1.02 [0.53, 1.95]

    11.2 Unclear reversibility
1427Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.50, 2.15]

 12 Adverse events (specific adverse events)212823Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.75, 1.25]

    12.1 Cataract
2905Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.05, 2.20]

    12.2 COPD requiring hospitalisation
2905Odds Ratio (M-H, Fixed, 95% CI)1.46 [0.66, 3.21]

    12.3 Pneumonia
2905Odds Ratio (M-H, Fixed, 95% CI)1.92 [0.66, 5.57]

    12.4 Candidiasis
2905Odds Ratio (M-H, Fixed, 95% CI)0.47 [0.16, 1.36]

    12.5 Lenticular opacities
1478Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.05, 6.22]

    12.6 Upper respiratory tract infection
2905Odds Ratio (M-H, Fixed, 95% CI)1.72 [0.77, 3.84]

    12.7 Headache
2905Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.39, 1.70]

    12.8 Cough
2905Odds Ratio (M-H, Fixed, 95% CI)0.51 [0.15, 1.73]

    12.9 Hypertension
2905Odds Ratio (M-H, Fixed, 95% CI)0.94 [0.34, 2.63]

    12.10 Chest pain
1427Odds Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.93]

    12.11 Influenza
2905Odds Ratio (M-H, Fixed, 95% CI)0.47 [0.14, 1.55]

    12.12 Nasopharyngitis
2905Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.49, 1.99]

    12.13 Bronchitis
1478Odds Ratio (M-H, Fixed, 95% CI)5.73 [0.66, 49.40]

    12.14 Pyrexia
1478Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.32, 3.95]

    12.15 Back pain
2956Odds Ratio (M-H, Fixed, 95% CI)0.75 [0.21, 2.67]

    12.16 Peripheral oedema
1478Odds Ratio (M-H, Fixed, 95% CI)2.26 [0.20, 25.09]

    12.17 Dysphonia
1478Odds Ratio (M-H, Fixed, 95% CI)0.44 [0.09, 2.32]

 
Summary of findings for the main comparison. All combined inhalers-participants with one or more exacerbations

Combined steroid/LABA inhalers versus LABA alone for people with COPD

Patient or population: patients with COPD
Settings: community
Intervention: All combined inhalers-primary outcomes

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

Assumed riskCorresponding risk

ControlAll combined inhalers-primary outcomes

Exacerbation rates per participant per year1.211 1.05

(0.97 to 1.14)
Rate ratio 0.87 (0.80 to 0.94)5601
(6 studies)
⊕⊕⊕⊝
moderate2

Mortality71 per 100056 per 1000
(47 to 67)
OR 0.78
(0.64 to 0.94)
7518
(12 studies)
⊕⊕⊕⊕
high3

Pneumonia85 per 100091 per 1000
(78 to 107)
OR 1.08
(0.91 to 1.28)
7320
(12 studies)
⊕⊕⊝⊝
low2,4

Hospitalisations due to COPD exacerbations127 per 1000119 per 1000
(104 to 134)
OR 0.93
(0.8 to 1.07)
7060
(10 studies)
⊕⊕⊝⊝
low2,4

Adverse eventsserious

Fluticasone/salmeterol (FPS) versus fluticasone (FP)
54 per 100057 per 1000
(45 to 71)
OR 1.05
(0.82 to 1.34)
5055
(7 studies)
⊕⊕⊝⊝
low2,4

Adverse eventsserious events Budesonide/formoterol (BDF) versus budesonide (BD)207 per 1000195 per 1000
(158 to 240)
OR 0.93
(0.72 to 1.21)
1469
(3 studies)
⊕⊝⊝⊝
very low2,4,5

Adverse eventsserious Mometasone/formoterol (MF/F) versus Mometasone (MF)78 per 100080 per 1000
(50 to 123)
OR 1.03
(0.63 to 1.67)
905
(2 studies)
⊕⊕⊝⊝
low2,4

*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.

 1Mean exacerbation rate in the ICS arms of the included studies (range 0.88 to 1.60 per participant per year).
2(-1 limitations) due to high risk of attrition bias.
3We did not deduct a point for attrition bias because most of the data on mortality were derived from TORCH.
4(-1 imprecision) confidence interval cannot rule out differences in either direction.
5A point is deducted to reflect the considerable heterogeneity in this analysis (I2 = 66%).
 
Table 1. Search history

VersionDetail

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

2nd published version-Issue 3, 2004 (April 2003 to 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)). Handsearching identified two further references to the COSMIC 2003 study
Studies identified from supplementary searching: 1 (TRISTAN)
New studies included: 2
Total studies included: 6

3rd 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: 2)
New studies included: 0
Total studies included: 6

4th published version-April 2005 to April 2007References identified: 66
References retrieved: 27 (references to studies already included/excluded/ongoing)
New unique studies identified: 8 (ongoing studies: 0)
New studies included: 1
Total studies included: 7

Present version-April 2007 to June 2013References identified: 209
References retrieved: 63 (references to studies already included/excluded/ongoing: 6)
New unique studies identified: 57 (ongoing studies: 0)
New studies included: 8
Total studies included: 15

 
Table 2. Exacerbations

TrialCOPD exacerbation definition

Bourbeau 2007Exacerbations not reported

Calverley 2003Mild exacerbations = number of days with intake of 4 or more puffs of rescue medication

Severe exacerbation = intake of a course of oral steroids and/or antibiotics and/or hospitalisation due to respiratory symptoms

Doherty 2012/

Tashkin 2012
Mild exacerbation = clinically judged deterioration of COPD symptoms (managed with increased short-acting bronchodilator use: ≥ 12 inhalations/d of SABA/short-acting anticholinergic, or ≥ 2 nebulised treatments/d of 2.5 mg SABA/short-acting anticholinergic) on any two consecutive days

Moderate exacerbation = clinically judged deterioration of COPD with an acute change in symptoms that required antibiotic and/or oral steroid treatment for lower airway disease

Severe exacerbation = deterioration of COPD that resulted in emergency treatment or hospitalisation due to COPD

Lapperre 2009Exacerbations not reported

NCT00358358Exacerbations not reported

SFCT01No definition found

Sin 2008“Exacerbations were defined as worsening of COPD symptoms leading to hospitalisation, a visit to the emergency room, or use of an antimicrobial agent and/or systemic corticosteroids as an outpatient”

Szafranski 2003Mild exacerbations = a day with ≥ 4 inhalations of reliever medication above the mean run-in use

Severe exacerbation = use of oral steroids and/or antibiotics and/or hospitalisation due to respiratory symptoms

Tashkin 2008“Worsening of COPD symptoms that required treatment with

oral corticosteroids and/or hospitalisation”

TORCH“A symptomatic deterioration requiring treatment with antibiotic agents,

systemic corticosteroids, hospitalisation, or a combination of these”

TRISTAN“Exacerbations were defined a priori as a worsening of COPD symptoms that required treatment with antibiotics, oral corticosteroids, or both. Episodes that

required corticosteroid treatment or hospital admission were noted separately”

Zhong 2012“An exacerbation was defined as use of oral/IV corticosteroids and/or antibiotics and/or emergency room treatment/hospitalisation due to respiratory symptoms”

 
Table 3. Rates of NNT and mortality

Study IDStudy durationICS rate (%)NNT *

Calverley 200352 weeks2.3202 (123 to 741)

SFCT0152 weeks0NA

NCT0035835812 weeks2.38195 (119 to 717)

Hanania 200324 weeks0NA

Mahler 200224 weeks0NA

Zhong 201224 weeks0NA

Szafranski 200352 weeks2.5186 (113 to 683)

TORCH156 weeks1633 (20 to 123)

Doherty 201252 weeks1.19386 (236 to 1417)

TRISTAN52 weeks0.8572 (350 to 2100)

Tashkin 200826 weeks0.73627 (383 to 2299)

Tashkin 201226 weeks1.43322 (197 to 1182)

 *Number needed to treat to prevent one death.
 
Table 4. Included studies

Study IDNo. of participants randomisedStudy duration (weeks)InterventionControl

Bourbeau 20073916FPS (50/500 mcg bid)FP (500 mg bid)

Calverley 200351152BDF (320/9 mcg bid)BUD (400 mcg bid)

Doherty 201247826MF/F (200/5 mcg bid)MF (200 mcg bid)

Hanania 200336624FPS (50/250 mcg bid)FP (250 mcg bid)

Lapperre 200954130FPS (50/500 mcg bid)FP (500 mcg bid)

Mahler 200233324FPS (50/500 mcg bid)FP (500 mcg bid)

NCT003583588112FPS (50/500 mcg bid)FP (500 mcg bid)

SFCT0125652FPS (50/500 mcg bid)FP (500 mcg bid)

Sin 20081794FPS (50/500 mcg bid)FP (500 mcg bid)

Szafranski 200340652BDF (320/9 mcg bid)BUD (400 mcg bid)

Tashkin 200855226BDF (160/4.5 mcg) 2 inhalations bidBUD (160 mcg) 2 inhalations bid

Tashkin 201242726MF/F (400/10 mcg bid)MF (400 mcg bid)

TORCH3091156FPS (50/500 mcg bid)FP (500 mcg bid)

TRISTAN73352FPS (50/500 mcg bid)FP (500 mcg bid)

Zhong 201230824BDF (160/4.5 mcg) 2 inhalations bidBUD (200 mcg) 2 inhalations bid

 FPS = fluticasone/salmeterol;
FP = fluticasone;
BDF = budesonide/formoterol;
BUD = budesonide;
MF/F = mometasone/formoterol;
MF =  mometasone.