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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: Edited (no change to conclusions)
  2. Published Online: 30 AUG 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
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%).

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in most industrialised countries but is projected to be the third leading cause of death worldwide by 2020 (GOLD 2011). An estimated three million people are affected by COPD in the UK alone (NCGC 2010). In the most recent global guidelines, COPD is defined as "a common preventable and treatable disease, characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and co-morbidities contribute to the overall severity in individual patients" (GOLD 2011).

The disease is caused predominantly by smoking. Smoke and other irritants trigger airway inflammation (i.e. bronchial infiltration of neutrophils, macrophages, lymphocytes and mast cells and increasing evidence of autoimmunity) (Cosio 2009). As a result, patients generally show progressive loss of lung function, accompanied by worsening respiratory symptoms, more frequent exacerbations and deterioration in health status (GOLD 2011]. In addition to these effects on patients, exacerbations are costly to the healthcare system.

All cases of COPD are characterised by airway obstruction, which is defined as a reduced post-bronchodilator lung function ratio (forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 0.7), but in reality, COPD is a heterogeneous syndrome (GOLD 2011). It has been suggested that some phenotypes of COPD involved more chronic systemic inflammation, which has an impact on co-morbidities, such as cardiovascular disease (Garcia-Aymerich 2011). Some patients deteriorate more quickly than others, and variability in the degree of airways reversibility exhibited to bronchodilators has been noted. Previously, COPD severity was defined solely by FEV1 % predicted compared with normal. The most recent definition grades severity of COPD using a combination of symptoms, lung function and number of exacerbations per year (GOLD 2011).

All patients with COPD should be considered for smoking cessation interventions, pulmonary rehabilitation, annual influenza vaccination and five-yearly pneumococcal vaccination (GOLD 2011). Smoking cessation is the only intervention that slows the decline in lung function (Kohansal 2009). In the absence of a significant disease-modifying effect, use of medication in COPD is largely guided by patient symptoms and exacerbation frequency. An increasing array of medicines are used in COPD, both alone and in combination. Some of these medicines are relatively expensive, so it is important to assess their relative benefits, so as to guide rational usage. It should be noted that in the decades to come, a disproportionate burden of the costs of COPD will be borne by developing countries, where smoking rates, and thus COPD prevalence, remain high.

Inhaled corticosteroids (ICS), long-acting beta2-agonists (LABAs) and long-acting anti-muscarinic agents (LAMAs) have been shown to be effective for some clinical outcomes in COPD, such as symptoms, exercise tolerance, quality of life and exacerbations.

Use of ICS may be associated with short-term increases in FEV1 and significant reduction in exacerbations (Yang 2012). On the other hand, use of ICS has been associated with an increase in the number of cases of pneumonia (TORCH; GOLD 2011) and of other adverse outcomes such as hoarseness and oral candidiasis. GOLD 2011 recommended that ICS should be used in patients with an FEV1 < 50% predicted (GOLD stages 3 and 4 or quadrant C and D) and a history of ≥ 2 exacerbations (GOLD 2011). National Institute for Health and Clinical Excellence (NICE) guidelines have recommended adding a LABA (or LAMA) to an ICS in a combination inhaler, if FEV1 is < 50% predicted. NICE has also recommended use of a combined LABA/ICS inhaler in people with stable COPD with an FEV1 ≥ 50% who remain breathless or have exacerbations despite maintenance therapy with a LABA (NICE 2010; GOLD 2011).

 

Description of the intervention

The two medicines of interest in this review are LABAs and ICS, with a particular focus on the comparison between use of a combination inhaler of LABA and ICS versus ICS alone. These medicines are taken by inhaler twice a day.

 

How the intervention might work

Both ICS and LABA components have been shown to prevent some COPD exacerbations and to improve health-related quality of life. LABAs also improve symptoms and exercise tolerance (Appleton 2006). Inhaled corticosteroids reduce the frequency and severity of exacerbations (Yang 2012) but have not yet been shown to slow disease progression or improve mortality rates (TORCH). It is postulated that ICS work by reducing airways inflammation, but the dose response is not the same as that seen in asthma (GOLD 2011). Other possibilities include the effects on chronic systemic inflammation and on autoimmunity. Finally, some evidence of a synergistic action has been reported when ICS and LABAs are jointly administered. LABAs and ICS may interact in a beneficial way, with corticosteroids preventing loss of function of beta2-agonists with long-term use, whereas beta2-agonists may potentiate the local anti-inflammatory actions of corticosteroids (Barnes 2002).

 

Why it is important to do this review

The aim of this series of reviews is to document available evidence for the relative effectiveness of two commonly used treatments in COPD (ICS and LABAs) when given in combination. The convenience and complementary effects of anti-inflammatory and bronchodilator when combined in a single inhaler is appealing but needs to be borne out in trials. The possibility of harmful effects needs to be explored, especially in the light of concerns over pneumonia associated with ICS.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To assess the efficacy and safety of combined long-acting beta2-agonist and inhaled corticosteroid (LABA/ICS) preparations, as measured by clinical endpoints and pulmonary function testing, compared with inhaled corticosteroids (ICS) alone, in the treatment of adults with chronic obstructive pulmonary disease (COPD).

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised, double-blind, parallel-group clinical trials of at least four weeks' duration comparing combination ICS and LABA with its component ICS alone.

 

Types of participants

Adult patients (age > 40 years) with known, stable COPD fulfilling American Thoracic Society (ATS), European Respiratory Society (ERS) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria. Patients were to be clinically stable and without evidence of an exacerbation for one month before study entry. Patients with significant diseases other than COPD-a diagnosis of asthma, cystic fibrosis, bronchiectasis or other lung diseases-were excluded; however, patients with partial reversibility on pulmonary function testing were included.

 

Types of interventions

  • Fluticasone propionate/salmeterol (FPS) versus fluticasone propionate (FP)
  • Budesonide/formoterol (BDF) versus budesonide (BD)
  • Mometasone furoate/formoterol (MF/F) versus mometasone furoate (MF)

Study duration was a minimum of four weeks. Concomitant therapy was permitted; however, trials in which participants were randomly assigned to tiotropium+combined ICS/LABA therapy versus tiotropium+ICS were excluded from the review, as this comparison is already considered in Karner 2011.

Studies in which the ICS dose in the ICS/LABA arm  was less than 80% of the ICS dose in the ICS-only arm were excluded.

 

Types of outcome measures

 

Primary outcomes

  • All exacerbations
  • Hospitalisations due to COPD exacerbation
  • Mortality
  • Pneumonia

 

Secondary outcomes

  • Change in FEV1 and change in FVC: trough, peak and average; and other measures of pulmonary function
  • Exercise performance-six-minute walk and other measures
  • Quality of life (as measured on a validated scale, e.g. St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Disease Questionnaire (CRDQ))
  • Self-rated symptom score/symptoms of breathlessness
  • Inhaled rescue medication used during the treatment period and concomitant medication usage, including antibiotics and steroids
  • Number of days (or nights) participant experienced symptoms
  • Area under the curve as the beta2-agonist response after the first and last morning doses of LABA/ICS
  • Per cent response to salbutamol from baseline FEV1, with tachyphylaxis noted
  • Pharmacoeconomic advantages
  • Adverse events-palpitations, tremor, hoarseness/dysphonia, oral candidiasis, cataracts, skin bruising, bone fracture, bone density, plasma cortisol level
  • Rate of withdrawal due to lack of efficacy or COPD deterioration .
  • Rate of withdrawal due to adverse events

 

Search methods for identification of studies

 

Electronic searches

We searched the Cochrane Airways Group Specialised Register of trials, which is maintained by the Trials Search Co-ordinator for the Group. The Register contains trial reports identified through systematic searches of bibliographic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO, and by handsearching of respiratory journals and meeting abstracts (please see Appendix 1 for further details). All records in the Specialised Register coded as 'COPD' were searched using the following terms:

(((beta* and agonist*) and long*) or ((beta* and adrenergic*) and long*) and (*steroid or steroid* OR corticosteroid*)) or (fluticasone and salmeterol) or Seretide or Advair or (formoterol and budesonide) or Symbicort

The search was conducted in June 2013, and no restriction on the language of the publication was applied.

 

Searching other resources

We reviewed reference lists of all primary studies and review articles for additional references. We contacted authors of identified randomised trials about other published and unpublished studies. In addition, we contacted Allen & Hanburys Ltd, for GlaxoSmithKline (GSK), the manufacturer of fluticasone/salmeterol (Advair/Seretide/Viani), and AstraZeneca, which manufactures budesonide/formoterol (Symbicort), and consulted their online registers of trials.

 

Data collection and analysis

 

Selection of studies

Step I. Two review authors independently identified abstracts of trials that appeared potentially relevant.

Step II. Using the full text of each study, two review authors independently selected trials for inclusion in the review. Simple agreement was required, and third party adjudication was used to resolve differences.

Step III. After a preliminary review of all studies to confirm the basic requirements, two review authors assessed the methodological quality of included trials with particular emphasis on concealment of allocation, which was ranked using the Cochrane risk of bias tool (Higgins 2011).

 

Data extraction and management

Two review authors independently extracted data from included trials and entered results into the Cochrane Collaboration software program (RevMan 5.2). In some cases, we estimated information regarding outcomes from graphs. Data extraction included the following items.

  • Population: age, gender, smoking status, study setting (country, practice setting), inclusion and exclusion criteria.
  • Intervention: dose, delivery device, duration.
  • Control: concurrent treatments (ipratropium, beta2-agonist, inhaled and systemic corticosteroids).
  • Outcomes: Pulmonary function measures (baseline and follow-up FEV1 and FVC), timing of pulmonary function measures, 6-minute walk, urgent visits, admissions, self-rated symptom score/symptoms, quality-of-life instruments, adverse events (palpitations, dry mouth, blurred vision, urinary obstruction and constipation), assessors, adjudicator of clinical endpoints. Mortality outcome data were collected from studies of longer than one year's duration, when they were available.
  • Design: method of randomisation, presence and type of run-in period, study design (parallel, cross-over).

 

Assessment of risk of bias in included studies

The risk of bias in included studies was assessed using the Cochrane Collaboration's risk of bias tool (Higgins 2011). Two review authors (SJM, AK) assessed the risk of bias for all included studies with regard to random sequence generation, allocation concealment, blinding, incomplete outcome data and selective outcome reporting. Each item was assessed as high, low or unclear risk of bias when relevant information was reported in the randomised controlled trial.

 

Measures of treatment effect

For continuous variables, a fixed-effect mean difference (MD) was used for outcomes measured on the same metric. Standardised mean difference (SMD) and 95% confidence interval (CI) were calculated for outcomes for which data were combined from studies using different metrics. All similar studies were to be pooled using fixed-effect MD/SMD and 95% CIs. When mean treatment differences were reported, data were entered as generic inverse variance (GIV), provided a standard error for the difference could be extracted or imputed. When this method was used, the effect size was reported from the original papers, for example, as rate ratio. This method (GIV) was not available when the protocol was written for the review, so it was not prespecified.

For dichotomous variables, a fixed-effect odds ratio (OR) with 95% CI was calculated for individual studies. All similar studies were pooled using fixed-effect OR and 95% CIs.

The reported confidence interval or P value was used to calculate standard deviations, or standard errors, for results when these were not reported and could not be obtained from the authors of the papers.

 

Unit of analysis issues

The unit of analysis was the participant, so dichotomous outcomes were analysed for participants who suffered one or more events (such as admission to hospital).

 

Dealing with missing data

If outcome data or information on trial design was missing, we attempted to contact authors for clarification.

 

Assessment of heterogeneity

For pooled effects, heterogeneity was tested using the I2 measurement of the degree of variation between studies, not attributable by the play of chance. If heterogeneity was found (I2 statistic > 20%), a random-effects model was used to determine the impact of heterogeneity on the overall pooled effect. In addition, the robustness of the results was tested when possible, using a sensitivity analysis based on the quality of the trials.

I2 (Higgins 2011) was also considered and interpreted in relation to the following guidance.

  • 0% to 40%: might not be important.
  • 30% to 60%: may represent moderate heterogeneity.
  • 50% to 90%: may represent substantial heterogeneity.
  • 75% to 100%: may represent considerable heterogeneity.

The Chi2 test was similarly considered (P value < 0.10), but we regarded I2 as our primary measure of heterogeneity.

 

Assessment of reporting biases

We planned to evaluate publication bias using visual inspection of funnel plots if the number of trials aggregated in the analyses was adequate (> 10). However, we recognised that an asymmetrical funnel plot can reflect heterogeneity, outcome reporting bias and small study effects and therefore is not necessarily a reflection of publication bias.

 

Data synthesis

We combined trials using RevMan 5.2. Continuous variables were combined using an MD or an SMD and were reported together with a 95% CI. We combined dichotomous variables using an OR with 95% CI. The pooled OR and its 95% CI were used to calculate numbers needed to treat for an additional harmful/beneficial outcome (NNTH/NNTB) using Visual Rx. The control event rates used to calculate illustrative NNTHs and NNTBs were taken from the event rates in the individual trials and have been reported along with the corresponding duration of the trial (because NNTH and NNTB are time dependent; Cates 2012).

 

Subgroup analysis and investigation of heterogeneity

Although we separated steroids and long-acting beta2-agonists by type, we pooled studies with differing dosages of the same drug. We planned a priori subgroups as follows.

  • Disease severity (related to baseline FEV1 and placebo group exacerbation rate) according to GOLD staging = 2A, 2B (moderate COPD, characterised by deteriorating lung function (A = FEV1 < 80% predicted; B = FEV1 < 50% predicted) and progression of symptoms) and 3 (severe COPD, characterised by severe airflow limitation (FEV1 < 30% predicted) and the presence of respiratory failure or clinical signs of right heart failure (GOLD 2011)).
  • Prior inhaled corticosteroid plus long-acting beta2-agonist use (dichotomised as yes/no).
  • Concurrent therapy with routine beta2-agonist use (short- or long-acting) and corticosteroid (systemic or inhaled) or theophylline use (dichotomised as yes/no).
  • Reversibility of airflow obstruction with beta2-agonist therapy (dichotomised as partial/none). Definition: > 12% and > 200 mL from baseline FEV1 or > 12% as a per cent of the predicted normal value following metered-dose inhaler (MDI) salbutamol 200 to 400.
  • Dose, duration and delivery method of therapy.

 

Sensitivity analysis

In addition, sensitivity analyses were performed using the following domains.

  • Methodological quality: using a quality-weighted analysis to allow for the use of all trials.
  • Random-effects versus fixed-effect modelling.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

 

Results of the search

For details of the search history, see  Table 1. For the study flow diagram, see Figure 1.

 FigureFigure 1. Study flow diagram.

 

Included studies

Fifteen studies, with a total of 7814 participants, met the review entry criteria. For a full description of baseline characteristics, methods used and inclusion and exclusion entry criteria of individual studies, see Characteristics of included studies.

 
Design

All trials had a randomised, double-blind, parallel-group design. Details of randomisation and blinding are included in Characteristics of included studies.

 
Participants

Participants suffered from COPD, with variable definitions of COPD and reversibility. COPD was defined by national or international criteria, including ATS (Hanania 2003; Mahler 2002), ERS (TORCH; TRISTAN) and GOLD (Calverley 2003; Lapperre 2009; Sin 2008; Szafranski 2003). In seven studies, the definition was based on lung function tests (Bourbeau 2007; Doherty 2012; NCT00358358; SFCT01, Tashkin 2008; Tashkin 2012; Zhong 2012). Participant populations in the studies suffered from moderate and severe COPD. Hanania 2003 and Mahler 2002 enrolled participants with both reversible and non-reversible COPD.

 
Interventions

Three comparisons were made. The first was fluticasone propionate/salmeterol (FPS) versus fluticasone (9 studies, 5132 participants: Bourbeau 2007; Hanania 2003; Lapperre 2009; Mahler 2002; NCT00358358; SFCT01; Sin 2008; TORCH; TRISTAN), the second budesonide/formoterol versus budesonide (4 studies, 1777 participants: Calverley 2003; Szafranski 2003; Tashkin 2008; Zhong 2012) and the third mometasone furoate and formoterol combined (MF/F) versus mometasone furoate (MF). Only two studies were identified, with a total of 905 participants (Doherty 2012; Tashkin 2012).

In one of the fluticasone propionate/salmeterol studies, the combination of ICS/LABA was FPS at a dose of 250 mcg/50 mcg twice daily versus fluticasone propionate (FP) 250 mcg twice daily (Hanania 2003). In the remainder of the FPS studies (Bourbeau 2007; Lapperre 2009; Mahler 2002; NCT00358358; SFCT01; Sin 2008; TORCH; TRISTAN), the dose was 500 mcg/50 mcg twice daily versus FP 500 mcg twice daily.

In two of the budesonide/formoterol studies (Calverley 2003 and Szafranski 2003), the combination ICS/LABA was budesonide/formoterol (BDF) (320 mcg/9 mcg twice daily). This was compared with budesonide (BD; 400 mcg twice daily). The dosage of the combined preparation and of the separate medications remained stable throughout the studies. In Calverley 2003, all participants had a two-week run-in treatment with oral corticosteroids, inhaled formoterol and prn short-acting beta2-agonists. In Tashkin 2008, the comparison was made between BDF (160/4.5 mcg/dose) 2 inhalations twice daily versus BD (160 mcg/dose) 2 inhalations twice daily, and in Zhong 2012, the comparison was between BDF (160/4.5 mcg/dose) 2 inhalations twice daily versus BD (200 mcg/dose) 2 inhalations twice daily.

In the two mometasone furoate and formoterol combined (MF/F) versus mometasone furoate (MF) studies (Doherty 2012; Tashkin 2012), the comparison was between MF/F 400/10 mcg twice daily versus MF 400 mcg twice daily. For details of co-medication and run-in periods on all 15 studies, please see Characteristics of included studies.

 
Duration

 
Outcomes

Exacerbations were stratified by medication given (oral steroid and/or antibiotic treatment in Calverley 2003; SFCT01; Szafranski 2003; TORCH; TRISTAN) or hospitalisation (TORCH; TRISTAN). In Tashkin 2008, exacerbations were defined as worsening of COPD symptoms that required treatment with oral corticosteroids and/or hospitalisation. Sin 2008 and Zhong 2012 also included the use of antibiotics, an emergency room visit or both in their definition. Doherty 2012 and Tashkin 2012 stratify exacerbations into mild, moderate or severe. Exacerbation data were not reported in Lapperre 2009, NCT00358358 or Bourbeau 2007. Hanania 2003 and Mahler 2002 withdrew participants whose condition was exacerbated.

Lung function, if reported, was measured as FEV1 or peak expiratory flow (PEF) in all studies. Quality of life assessments by the SGRQ or the CRDQ were available for Calverley 2003; Doherty 2012; Hanania 2003; Lapperre 2009; Mahler 2002; SFCT01; Szafranski 2003; Tashkin 2008; Tashkin 2012; TORCH; TRISTAN; Sin 2008; and Zhong 2012. Quality of life assessment was not reported for NCT00358358 or Bourbeau 2007. All-cause mortality was reported by TORCH. Mortality data were also reported for Doherty 2012; NCT00358358; Tashkin 2008; Tashkin 2012; and Zhong 2012,, although death was not one of their pre-defined outcomes.

 

Excluded studies

A total of 48 studies were excluded-36 (75%) because the comparison was not made between combined LABA/ICS versus ICS; 5 (10%) because participants were also randomly assigned to receive tiotropium as a co-intervention; 2 (4%) because asthma patients were combined in the study; 2 (4%) because ICS dose in the ICS/LABA condition was less than 80% of the ICS dose in the ICS-only condition; 1 (2%) because investigators provided an aggregated report of two studies; 1 (2%) because it examined the acute effect of combined LABA/ICS and 1 (2%) because the focus was on sleep quality in COPD. A list of excluded studies is provided in Characteristics of excluded studies.

 

Risk of bias in included studies

Intention-to treat (ITT) analyses were reported in all studies for their primary outcomes. TORCH reported incomplete data for FEV1 and SGRQ scores. Concealment of allocation was reported in Calverley 2003; Szafranski 2003; TORCH; and TRISTAN. Blinding of treatment was reported for all studies. Identical delivery devices for treatment groups were reported in Calverley 2003; Szafranski 2003; TORCH; and TRISTAN.

An overview of the judgements we have made regarding the risk of bias for each study is given in Figure 2.

 FigureFigure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

In nine of the fifteen studies, the risk of selection bias was judged as low, and in the remaining six, the risk was viewed as unclear. Among the FPS versus fluticasone trials (9 studies, 5132 participants), five (Bourbeau 2007; Lapperre 2009; Sin 2008; TORCH; TRISTAN) were judged to be at low risk of selection bias, and in the remaining four (Hanania 2003; Mahler 2002 SFCT01; NCT00358358), the risk was considered to be unclear. Three of the four BDF versus BD studies (1777 participants; Szafranski 2003; Tashkin 2008; Zhong 2012) were regarded as having low risk of selection bias in terms of sequence generation, although the issue of allocation concealment in Tashkin 2008 was unclear; in Calverley 2003, the risk of selection bias in terms of sequence generation and allocation concealment was regarded as unclear.

Of the two MF/F versus MF trials (905 participants), Tashkin 2012 was judged to be at low risk of selection bias, and for Doherty 2012, the risk was considered to be unclear. A summary of the selection bias is provided in Figure 2.

 

Blinding

The risk of performance and detection bias was judged to be low in all fifteen trials.

 

Incomplete outcome data

Dropout rates were uniformly high (> 20%) in the long-term (longer than 6 months) studies, and most studies were judged to be at high risk of attrition bias, whereas the shorter-term studies (Bourbeau 2007; Doherty 2012; NCT00358358; Sin 2008) had lower dropout rates and were judged to be at low (dropout rate < 10%) or unclear (dropout rate 10% to 20%) risk of attrition bias. The TORCH study, however, ascertained the mortality results for those participants who withdrew from the study and so was judged to have low risk of attrition bias for mortality (Figure 2).

 

Selective reporting

In only one trial was the risk of reporting bias considered unclear: Bourbeau 2007. In all other cases, the risk of reporting bias was judged to be low.

 

Effects of interventions

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

 

Primary outcomes

 

Exacerbation rates

 
Pooled results for FPS, BDF and MF/F versus ICS alone

A significant reduction was noted in the rate of exacerbations requiring oral corticosteroids with combination therapy when compared with ICS (6 studies: N = 5601; rate ratio (RR) 0.87; 95% CI 0.80 to 0.94;  Analysis 1.1; Figure 3). A summary of definitions of exacerbations in the included studies is provided in  Table 2. The mean exacerbation rate in the ICS-only arms of the included studies was 1.21 exacerbations per patient per year (range 0.88 to 1.60), and we would expect an equivalent rate of 1.05 (95% CI 0.97 to 1.14) with combination therapy (see  Summary of findings for the main comparison).

 FigureFigure 3. Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.1 Exacerbation rates (exacerbations requiring oral corticosteroids).

 
FPS versus FP

Two studies compared FPS versus FP (TORCH; TRISTAN). A significant reduction was noted in the rate of exacerbations with combination therapy when compared with FP (2 studies; N = 3789; RR 0.88; 95% CI 0.80 to 0.98;  Analysis 1.1).

 
BDF versus BD

Four studies compared BDF versus BD (Calverley 2003, Szafranski 2003; Tashkin 2008; Zhong 2012). A significant effect on pooled exacerbation rates was seen with BDF versus BD (4 studies; N = 1777; RR 0.84; 95% CI 0.73 to 0.97;  Analysis 1.1).

 
MF/F versus MF

The two studies comparing MF/F versus MF did not report rate data for exacerbations.

 

Number of participants with one or more exacerbation

No significant difference was seen with combination therapy when compared with ICS (7 studies: N = 2781, OR 0.87, 95% CI 0.70 to 1.09;  Analysis 1.2; Figure 4).

 FigureFigure 4. Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.2 Number of participants with one or more exacerbation.

 
FPS versus FP

No significant difference was observed between FPS and FP in the reports of participants with one or more exacerbations (3 studies (SFCT01; Sin 2008; TRISTAN); N = 1173, OR 1.22, 95% CI 0.81 to 1.84); this outcome was not reported in TORCH. However, some evidence suggests that FPS leads to a lower rate of exacerbations requiring oral steroids (2 studies (TORCH; TRISTAN); N = 3824; RR 0.89, 95% CI 0.81 to 0.98;  Analysis 2.5).

 
BDF versus BD

No studies that compared BDF versus BD reported this outcome.

 
MF/F versus MF

A significant difference was noted between MF/F and MF with respect to the numbers of participants with moderate and severe exacerbations (2 studies (Doherty 2012; Tashkin 2012); N = 905, OR 0.67, 95% CI 0.45 to 0.98;  Analysis 4.1).

 

Hospitalisations due to COPD exacerbations

 
Pooled results for FPS, BDF and MF/F versus ICS alone

No significant difference was described between combined LABA/ICS and ICS-alone treatments in hospitalisations due to COPD exacerbations (10 studies: Calverley 2003; Doherty 2012; Hanania 2003; Mahler 2002; SFCT01; Tashkin 2008; Tashkin 2012; TORCH; TRISTAN; Zhong 2012; N = 7060, OR 0.93, 95% CI 0.80 to 1.07;  Analysis 1.3; Figure 5).

 FigureFigure 5. Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.3 Hospitalisations due to COPD exacerbations.

 
FPS versus FP

Data related to this outcome were obtained from five studies for the comparison of FPS versus FP (Hanania 2003; Mahler 2002; SFCT01; TORCH; TRISTAN; N = 4799, OR 0.93, 95% CI 0.79 to 1.10), and no significant difference was noted between combined LABA/ICS and ICS alone.

 
BDF versus BD

Three studies (Calverley 2003; Tashkin 2008; Zhong 2012) provided relevant data (N = 1371, OR 0.85, 95% CI 0.60 to 1.20), and no significant difference was described between BDF and BD in hospitalisations due to COPD exacerbations.

 
MF/F versus MF

Similarly, the two studies comparing MF/F versus MF (Doherty 2012; Tashkin 2012) reported no significant benefit derived from the LABA with respect to hospitalisations due to COPD exacerbations (N = 905, OR 1.46, 95% CI 0.66 to 3.21).

 

Mortality

 
Pooled results for FPS, BDF and MF/F versus ICS alone

When data were combined for both treatments and their respective comparators, the odds of death were significantly lower after combination treatment than after mono-component steroid (12 studies; N = 7518, OR 0.78, 95% CI 0.64 to 0.94;  Analysis 1.4; Figure 6). Because differing lengths of follow-up across studies and differing event rates in the control arm hinder the calculation of pooled NNTB values, we have tabulated this for each study individually (see  Table 3). The three-year NNTB (using the baseline risk of 16% in the ICS arm of TORCH) to prevent one extra death is 32 (95% CI 19 to 123). In contrast, in lower-risk participants (using the baseline risk of 0.8% in the ICS arm of TRISTAN), the one-year NNTB is much higher at 547 to prevent one extra death (95% CI 340 to 2100).

 FigureFigure 6. Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.4 Mortality.

 
FPS versus FP

Trials varied in length from 12 to 156 weeks. Compared with FP, a significant reduction was noted in the odds of death at the end of treatment (6 studies; Hanania 2003; Mahler 2002; NCT00358358; SFCT01; TORCH; TRISTAN; N = 4836, OR 0.76, 95% CI 0.62 to 0.92).

 
BDF versus BD

The length of studies ranged from 24 to 52 weeks. Investigators did not identify a significant difference between BDF and BD with regard to mortality (4 studies; Calverley 2003; Szafranski 2003; Tashkin 2008; Zhong 2012; N = 1777, OR 1.13, 95% CI 0.54 to 2.37).

 
MF/F versus MF

Two trials were identified: one 26 weeks in duration (Tashkin 2012) and the other 52 weeks (Doherty 2012). No significant difference was reported between MF/F and MF on this outcome (N = 905, OR 0.89, 95% CI 0.27 to 2.91).

 

Pneumonia

 
Pooled results for FPS, BDF and MF/F versus ICS alone

When data were combined for both treatments and their respective comparators, the odds of pneumonia were not significantly different after combination treatment than after mono-component steroid (12 studies; N = 7315, OR 1.08, 95% CI 0.91 to 1.28;  Analysis 1.5; Figure 7).

 FigureFigure 7. Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.5 Pneumonia.

 
FPS versus FP

No significant difference between FPS and FP was observed in the number of participants with pneumonia at the end of treatment (7 studies; Hanania 2003; Mahler 2002; NCT00358358; SFCT01; Sin 2008; TORCH; TRISTAN; N = 5015, OR 1.06, 95% CI 0.89 to 1.27).

 
BDF versus BD

The three studies that reported pneumonia (Calverley 2003; Tashkin 2008; Zhong 2012) did not identify a significant difference between BDF and BD (N = 1371, OR 1.11, 95% CI 0.47 to 2.63).

 
MF/F versus MF

Both studies (Tashkin 2012 and Doherty 2012) included pneumonia in their range of outcomes. No significant difference between MF/F and MF was noted in the number of participants with pneumonia at the end of treatment (N = 905, OR 1.92, 95% CI 0.66 to 5.57).

 

Secondary outcomes

 

Change in lung function (FEV1)

 
FPS versus FP

A significant difference in pre-dose FEV1 change from baseline favoured FPS (2 studies; Hanania 2003; Mahler 2002; N = 699, MD 0.05 L, 95% CI 0.02 to 0.09;  Analysis 2.11).

Similarly, a significant difference in post-dose FEV1 change from baseline favoured FPS (6 studies; Hanania 2003; Lapperre 2009; Mahler 2002; SFCT01; TORCH; TRISTAN; N = 4833, MD 0.05 L, 95% CI 0.04 to 0.06;  Analysis 2.12).

Data incorporated in this analysis from SFCT01 and TRISTAN were end of treatment data rather than change from baseline data.

 
BDF versus BD

The pre-dose FEV1 change from baseline to the average over the randomised treatment period (1 study; N = 552, MD 0.08 L, 95% CI 0.05 to 0.11;  Analysis 3.9) was significant. Only one study (Tashkin 2008) contributed to this outcome, and it included a partially reversible population (a mixed population).

The 1-hour post-dose FEV1 change from baseline to the average over the randomised treatment period (1 study; N = 552, MD 0.17 L, 95% CI 0.14 to 0.20;  Analysis 3.10) was also significant. Again, only one study (Tashkin 2008) contributed to this outcome, and it included a partially reversible population (a mixed population).

 
MF/F versus MF

We analysed change from baseline in FEV1 AUC0-12 h at week 13 (2 studies; Doherty 2012; Tashkin 2012; N = 905, MD 116.59 mL, 95% CI 68.59 to 164.59;  Analysis 4.5) and at week 26 (same two studies; MD 109.34 mL, 95% CI 57.87 to 160.81;  Analysis 4.4). In both cases, a significant benefit favoured MF/F. An effect in favour of MF/F was also observed in mean change from baseline in morning pre-dose FEV1 at 13 weeks (MD 0.08 L, 95% CI 0.04 to 0.11;  Analysis 4.6).

 

Quality of life

 
FPS versus FP

A significant improvement favoured FPS over FP: -1.30 units on the SGRQ (3 studies; SFCT01; TORCH; TRISTAN; N = 3001, SGRQ units -1.30, 95% CI -2.04 to -0.57;  Analysis 2.8). Because of the high rate of attrition in TORCH, the data were presented for only a subset of those who were randomly assigned (2007/3091). Removing this study from the analysis resulted in a similar effect estimate (SGRQ units -1.56, 95% CI -2.66 to -0.46).

Data from two studies reporting quality of life as mean change in CRDQ suggested high levels of statistical variation (I2 = 77%). Neither fixed-effect nor random-effects modelling revealed significant differences (2.12 units, 95% CI -0.50 to 4.75; and 2.34 units, 95% CI -3.15 to 7.82, respectively).

 
BDF versus BD

A significant effect favoured BDF versus BD on the SGRQ (change from baseline). Four studies contributed data (Calverley 2003; Szafranski 2003; Tashkin 2008; Zhong 2012; N = 1777, MD -2.80, 95% CI -3.99 to -1.61;  Analysis 3.4). The effect was observed in a partially reversible population (mixed population) (1 study; Tashkin 2008; N = 552, MD -2.57, 95% CI -4.68 to -0.46) and in a poorly reversible population (3 studies; Calverley 2003; Szafranski 2003; Zhong 2012; N = 1225, MD -2.91, 95% CI -4.35 to -1.47).

 
MF/F versus MF

No significant effect difference was reported for MF/F versus MF on the SGRQ (change from baseline), with data contributed by both Doherty 2012 and Tashkin 2012 (2 studies; N = 905, MD -0.29, 95% CI -2.16 to 1.57;  Analysis 4.3).

 

Symptom score

 
FPS versus FP

Pooled data from Mahler 2002 and Hanania 2003 indicated no significant difference between FPS and FP in TDI scores (2 studies; N = 690, MD 0.31, 95% CI -0.45 to 1.08;  Analysis 2.9).

 
BDF versus BD

A significant benefit for BDF versus BD was observed in symptom change scores (3 studies; Calverley 2003; Szafranski 2003; Zhong 2012; N = 1225, MD -0.45, 95% CI -0.67 to -0.22;  Analysis 3.5).

 
MF/F versus MF

Symptoms were considered in Doherty 2012 and Tashkin 2012 in terms of COPD symptom-free nights. In both studies, no significant difference was noted between MF/F and MF with respect to this outcome, although insufficient data were recorded to allow a meta-analysis.

 

Rescue medication

 
FPS versus FP

Pooled data from Mahler 2002 and Hanania 2003 indicated a significant reduction in mean puffs per day of short-acting beta2-agonist usage in favour of FPS over FP (2 studies; N = 686, MD -0.80, 95% CI -1.31 to -0.29;  Analysis 2.15).

TRISTAN reported a significant difference in median % of days without use of relief medication in favour of FPS over FP (P < 0.001).

 
BDF versus BD

BDF treatment reduced the requirement for reliever medication when compared with BD (4 studies; Calverley 2003; Szafranski 2003; Tashkin 2008; Zhong 2012; N = 1777, MD -0.72, 95% CI -0.92 to -0.52;  Analysis 3.13).

 
MF/F versus MF

No data were reported for this outcome.

 

Safety and tolerability

 
FPS versus FP

No significant difference was noted between FPS and FP in the odds of any adverse event ( Analysis 2.19 through to  Analysis 2.21).

 
BDF versus BD

A significant difference between BDF and BD was observed in the adverse events included in this review for nasopharyngitis (1 study; Tashkin 2008; N = 552, OR 2.42, 95% CI 1.09 to 5.39;  Analysis 3.22), with fewer cases in the BD group. Because this finding is provided by only one study, and because the level of significance (P = 0.03) is marginal, any evaluation of this outcome should be cautious until additional data become available. No significant difference between BDF and BD was reported for any other adverse event considered in the review for this comparison ( Analysis 3.22).

 
MF/F versus MF

No significant difference was observed between MF/F and MF in the odds of any adverse event ( Analysis 4.10 through to  Analysis 4.12).

 

Withdrawals

 
FPS versus FP

Study withdrawal occurred significantly less frequently on FPS than on FP (9 studies; Bourbeau 2007; Hanania 2003; Lapperre 2009; Mahler 2002; NCT00358358; SFCT01; Sin 2008; TORCH; TRISTAN; N = 5132, OR 0.86, 95% CI 0.76 to 0.97;  Analysis 2.16). When expressed as withdrawal due to lack of efficacy, no significant difference between treatments was described (5 studies; Mahler 2002; SFCT01; Sin 2008; TORCH; TRISTAN; N = 4592, OR 0.77, 95% CI 0.53 to 1.13;  Analysis 2.17). However, fewer withdrawals resulted from adverse events among FPS-treated participants than among those treated with FP (7 studies; Bourbeau 2007; Mahler 2002; NCT00358358; SFCT01; Sin 2008; TORCH; TRISTAN; N = 4712, OR 0.75, 95% CI 0.64 to 0.87;  Analysis 2.18).

 
BDF versus BD

Data were pooled from Calverley 2003, Szafranski 2003 and Zhong 2012 for withdrawals due to worsening COPD symptoms and adverse events, and a very marginal significant difference in withdrawals due to worsening of COPD symptoms was noted when BDF was compared with BD (3 studies; N = 1225, OR 0.68, 95% CI 0.46 to 0.99;  Analysis 3.18). Because the statistical significance of this effect is so very marginal, any evaluation of this finding should await the availability of additional data.

No significant difference was noted between BDF and BD in the likelihood of withdrawal due to adverse events other than COPD deterioration (4 studies; Calverley 2003, Szafranski 2003; Tashkin 2008; Zhong 2012; N = 1777, OR 0.95, 95% CI 0.66 to 1.37;  Analysis 3.19).

 
MF/F versus MF

No significant difference regarding withdrawals was observed in the comparison between MF/F and MF (2 studies; Doherty 2012; Tashkin 2012; N = 905, OR 0.78, 95% CI 0.56 to 1.09;  Analysis 4.7), and no significant difference was noted regarding withdrawals due to adverse events (2 studies; Doherty 2012; Tashkin 2012; N = 905, OR 1.38, 95% CI 0.71 to 2.68;  Analysis 4.8) or withdrawals due to treatment failure (2 studies; Doherty 2012; Tashkin 2012; N = 905, OR 0.68, 95% CI 0.19 to 2.44;  Analysis 4.9).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

We reviewed data from 15 randomised controlled trials (7814 participants;  Table 4) assessing the effectiveness and safety of combined inhaled corticosteroid and long-acting beta2-agonist in the treatment of chronic obstructive pulmonary disease (COPD) versus ICS alone for the clinically important primary outcomes of exacerbations, mortality, hospitalisation and pneumonia. Overall, available evidence suggests that combination therapy with ICS and LABA shows an advantage over ICS alone in reducing exacerbations and mortality throughout the study period, with no significant effect on hospitalisation or pneumonia. The greatest quantity of evidence comes from populations of poorly reversible participants who have more severe COPD. It should be noted that most of the evidence for a reduction in mortality (weighting of 90%) comes from the TORCH study, which compared FPS and FP in participants with an FEV1 < 60% predicted. Furthermore, the mortality benefit is confined to the FPS combination only and is not seen in the others. If we remove the TORCH study, mortality rates are not significantly different between combination treatment and ICS alone. Furthermore, the TORCH study did not show any statistically significant mortality benefit at 2 years, only at 3 years, so we can only be sure that benefit would accrue over the longer period. Finally, about 14% of those in the TORCH study died, whereas mortality rates in the other studies reporting this outcome were in the order of 3%, and all were less than 12 months in duration. The TORCH study was the only study in this review that showed significantly fewer withdrawals in the combination group than in the ICS group, but it was also the only study that ascertained the vital status of all participants, including those who withdrew from the study.

If the mortality benefit seen in this review in association with the combined inhaler is confirmed in other three-year studies, the mechanism needs elucidation, and this is likely to be important. The TORCH investigators did find a significant difference between LABA/ICS and ICS alone, but not between LABA/ICS and placebo, although the P value for this comparison was 0.052. To date, the only approaches used in COPD to reduce mortality rates are smoking cessation and long-term oxygen therapy (LTOT) in hypoxic patients. On the basis of our findings, at best, 33 people with moderate to severe COPD need to be treated with a combination FPS inhaler for three years to prevent one excess death, compared with those treated with ICS alone. This reduction appears to involve COPD-related deaths. On the other hand, no evidence of a mortality benefit has been obtained for the other combination inhalers over their component ICS. From this review, we can conclude that combination treatment is related to fewer exacerbations, and probably to fewer severe exacerbations, than ICS alone, as is discussed later. Exacerbations are risky times for death; therefore this is a plausible explanation, but to be sure, we would need to use individual participant data to gather additional details on the causes and timing of death and modelling of the amount of variance in mortality that is explained by the reduced exacerbations. In contrast, the small change in lung function seems insufficient to account for a mortality benefit, but this needs to be tested in other, longer-term trials. It is interesting to contrast the finding of a possible mortality benefit of LABA/ICS combinations in COPD with the situation in asthma. In that disease, use of a LABA alone is associated with an increased death rate, but when combined with ICS, this is no longer the case (Rodrigo 2012).

Greater consistency was seen with the interventions for exacerbations, and the number of exacerbations was reduced by both FPS and BDF as was the proportion of participants with an exacerbation that was reduced by MF/F, compared with the component ICS alone. It is interesting to note that for the FPS studies, the reduction in the proportion of participants with an exacerbation was not significant, but those who experienced exacerbations had fewer of them, and fewer of these participants needed treatment with oral steroids. Yet, the differences in exacerbations with combination therapy did not translate to fewer hospitalisations for COPD, and this is difficult to explain. Hospitalisations are among the most costly aspects of COPD management, causing a negative impact on expectancy and quality of life. It is plausible that the hospital stays were shorter. Most studies clearly defined hospitalisation as a stay of at least 24 hours. Moreover, hospitalisations are relatively rare events that can be quantified only by larger and longer studies. To exemplify this point, on average about 7% of patients per year were hospitalised for COPD in the TORCH study, in part because of the lack of the inclusion criterion of a moderate to severe exacerbation 52 weeks before enrolment, as was required in more recent trials.

This review was unable to shed light on the debate as to whether or not ICS increase pneumonia in COPD, as it was administered in both intervention arms. This can be tested only when the comparator does not contain ICS. We found no significant difference, with one interpretation being that LABAs do not reduce the risk of pneumonia with ICS. However, we also found that pneumonia was not a frequent adverse event when it was defined by chest x-ray. The shorter studies in  Analysis 1.5 identified only 60 cases of pneumonia among 4222 participants (1.4%), in contrast to the three-year TORCH study, which reported 587 episodes of pneumonia from a sample of 3098 participants who received ICS treatment (19%). The results of  Analysis 1.4 were the same, whether or not the TORCH study was included.

An internal consistency of the findings for primary outcomes and secondary outcomes was evident. All combination inhalers were associated with better lung function at the end of the study than was their ICS component, but this difference was relatively small. Two combinations (BDF and FPS) were associated with better quality of life, decreased use of rescue medication and withdrawals due to adverse events, but not with withdrawals due to lack of efficacy. The causes for withdrawals and for adverse events were coded slightly differently among the trials and thus were not combined, although this will be considered for future reviews. Improvement in quality of life was seen only when measured with the SGRQ, not with the CDRQ. The differences were small and were much less than a minimum clinically important difference (Jones 2002). This suggests that the clinical effects may be imperceptible to patients, or that any benefits may be offset by other harms. Fewer exacerbations may result in lower healthcare costs; although this review does not show a reduction in costly hospitalisations, bed days could still be reduced.

 

Overall completeness and applicability of evidence

In the review are fifteen studies, with a total of 7814 participants. All eligible studies addressed at least one of the primary outcomes. The participants and outcomes were typical of COPD patients. The most plentiful data are available for the FPS combination, which was the only one to show a mortality benefit. Fewer data are available for the MF/F combination, but no evidence suggests that it behaves differently from the other inhalers. A sufficient number of trials in the analysis provided the opportunity to include funnel plots for the primary analyses; they are presented in Figure 8.

 FigureFigure 8. Funnel plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.4 Mortality.

We did not compare the efficacy and safety of combination therapy with the same treatment delivered in two separate inhalers, so we cannot comment on the relative effectiveness of a combination inhaler in comparison with the individual components delivered separately. Whilst we recognise that inhaled corticosteroids are rarely likely to be used as monotherapy in COPD, the trials in this review provide the best evidence for assessing the additional benefit of adding LABA to ICS.

 

Quality of the evidence

According to the results section, the risks of bias in allocation, blinding, attrition and selective reporting were judged to be low.

 

Potential biases in the review process

The Cochrane Airways Group provides an excellent level of support in the identification of potentially relevant trials. However, concern with respect to study selection bias or publication bias in this process is inevitable. A matter of concern is that failure to identify unpublished trials may lead to an incomplete estimation of the effects of combined therapy versus ICS alone. However, an exhaustive search of the published literature, without language restrictions, for potentially relevant clinical trials was underpinned by a systematic search strategy to minimise the likelihood of bias. Of the 15 included studies, 13 were identified through the Cochrane Airways Group Register, an additional study (NCT00358358) was identified by the group from www.clinicaltrials.gov and SFCT01 was obtained via the GlaxoSmithKline Clinical Trials Register. Trial selection and data extraction followed a prespecified protocol, and the process was independently conducted by two investigators. Nevertheless, we acknowledge that additional unidentified trials may exist.

 

Agreements and disagreements with other studies or reviews

This Cochrane review confirms and builds upon an earlier one (Nannini 2007) In terms of exacerbations; reduction in moderate COPD exacerbation rates with combined therapy is now shown for three LABA/ICS combinations over ICS alone. A recent publication describing all inhaled medications in COPD concluded that LABA/ICS was associated with the lowest risk of death among all treatments (Dong 2013). Another systematic review (Drummond 2008) found in subgroup analyses that the highest risks of pneumonia were seen in those treated with the highest ICS dose (RR 1.46, 95% CI 1.10 to 1.92), a shorter duration of ICS use (RR 2.12, 95% CI 1.47 to 3.05) and combined ICS and bronchodilator therapy (RR 1.57, 95% CI 1.35 to 1.82), which does not disagree with our findings. We found a lower rate of pneumonia than was found by other studies when diagnosis was obtained by chest x-ray.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

In participants with moderate and severe COPD, clinical benefit is evident when LABA and ICS are co-administered rather than ICS alone. Even though patients do not all perceive a better quality of life, they may live longer and have fewer exacerbations with combination therapy versus ICS alone. However, the evidence does not support the likelihood of being exacerbation-free or having fewer hospitalisations during the treatment period. The reduction in exacerbations varies, depending on the frequency of these events in individual patients. The mortality benefit will take at least two years to be evident and has been shown only for the FPS combination. Available evidence is most plentiful for the FPS combination and is heavily weighted by the three-year TORCH trial.

What is unclear is whether combination LABA/ICS therapy is better than LABA or ICS administered separately, or 4 times daily use of short-acting beta2-agonists with ICS. All of the combination inhalers in this review were given twice a day. In addition to potential adherence benefits associated with the combination inhaler, its use guarantees that a patient receives both medicines simultaneously, which may not be the case if they are administered via separate inhalers. Further, evidence that LABAs and ICS have complementary and synergistic effects when delivered as combination therapy from a single inhaler is increasing (Hanania 2008). Although we conclude that unopposed ICS with no LABA co-administration is an inferior strategy in COPD, the minimum effective dose of inhaled steroids remains unclear. The three combination inhalers showed similar effects on review outcomes, including adverse effects, but should ideally be subjected to simple head-to-head comparisons over long periods of time. We have not been able to identify differences between the combination inhalers on the basis of currently available evidence.

 
Implications for research

The findings of the TORCH study need to be confirmed, as it is the only trial to show a decrease in mortality over the study period. We suggest that the circumstances surrounding any death should be fully documented and categorised as to likely clinical mechanism, and that all patients should have their vital status ascertained (whether they complete the study or drop out). If confirmed, a multipartite programme of clinical and basic science research should be enlisted to elucidate the mechanism of reduction in mortality, given that this is the only pharmaceutical yet shown to reduce mortality in COPD.

Future studies might address the impact of any reduction in exacerbations on health care utilisation (e.g. bed days, unscheduled general practitioner or emergency room visits). This could help inform a cost-benefit analysis.

Which combination and which dose and duration of ICS should be selected in COPD have not yet been explored adequately. We also do not know whether use of a combination is superior to separate administration of the two inhalers. Obviously the best way to test these relative benefits and adverse effects for each of the combinations is to perform a simple and direct long-term comparison among, for example, FPS, BDF and MF/F treatments. This might best be done in well-categorised, stable COPD patients receiving primary care.

New combinations of ICS with 24-hour LABAs such as indacaterol, vilanterol or olodaterol are emerging. Are these just "me too" medicines, or do they offer an advantage? Updating this review within a short space of time will be imperative.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

The authors are indebted to the Hamamellis Trust, which very generously funded the return travel for Dr Nannini to London so he could spend a week working on the development of the review. Thanks to Liz Stovold, Susan Hansen and Veronica Stewart for technical and clerical support. We would also like to acknowledge the efforts of Inge Vestbo, Diane Grimley and Karen Richardson of GSK, who helped us in our attempts to obtain unpublished information on TRISTAN, and those of Goran Tornling, Moira Coughlan and Roger Metcalf of AstraZeneca, who helped us obtain data for Szafranski 2003. We thank Dr Nick Hanania and Prof Donald Mahler for corresponding with us in our attempts to obtain unpublished data from their studies.

In 2012 the authors responsible for the update of this review would particularly like to acknowledge the excellent support and assistance received from Emma Welsh, Liz Stovold and Emma Jackson of the Cochrane Airways Review Group, together with the greatly appreciated guidance received from Chris Cates (Cochrane Airways Review Group Co-ordinating Editor). The support provided by librarians Judith Scammel, Jane Appleton and Hilary Garrett at St Georges University London is also greatly appreciated.

CRG Funding Acknowledgement: The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Airways Group.

Disclaimer: The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the NIHR, the NHS or the Department of Health.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
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]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

 

Electronic searches: core databases


DatabaseFrequency of search

CENTRAL (The Cochrane Library)Monthly

MEDLINE (Ovid)Weekly

EMBASE (Ovid)Weekly

PsycINFO (Ovid)Monthly

CINAHL (EBSCO)Monthly

AMED (EBSCO)Monthly



 

 

Handsearches: core respiratory conference abstracts


ConferenceYears searched

American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards

American Thoracic Society (ATS)2001 onwards

Asia Pacific Society of Respirology (APSR)2004 onwards

British Thoracic Society Winter Meeting (BTS)2000 onwards

Chest Meeting2003 onwards

European Respiratory Society (ERS)1992, 1994, 2000 onwards

International Primary Care Respiratory Group Congress (IPCRG)2002 onwards

Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards



 

 

MEDLINE search strategy used to identify trials for the CAGR

 

COPD  search

1. Lung Diseases, Obstructive/

2. exp Pulmonary Disease, Chronic Obstructive/

3. emphysema$.mp.

4. (chronic$ adj3 bronchiti$).mp.

5. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.

6. COPD.mp.

7. COAD.mp.

8. COBD.mp.

9. AECB.mp.

10. or/1-9

 

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases.

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 27 June 2013.


DateEventDescription

4 June 2014AmendedPLS title amended



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 3, 2002
Review first published: Issue 4, 2007


DateEventDescription

27 June 2013New search has been performedLiterature search run

27 June 2013New citation required and conclusions have changedEight new studies for budesonide/formoterol and two studies for a new combined therapy, mometasone furoate/formoterol. New author team. Summary of findings table added, new methods applied; see differences between protocol and review.

11 November 2009AmendedSpelling mistakes corrected and minor changes to wording. Changes made to formatting.

8 April 2008AmendedConverted to new review format.

21 August 2007New citation required and conclusions have changedThis review contains evidence from 5 studies previously included in a review of combination therapy in COPD (Nannini L, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2004, Issue 3), with new data from two studies (TORCH; SFCT01).

New findings
There is a significant reduction on mortality with combination therapy compared with ICS alone. Exacerbation rates are lower with combination therapy compared with ICS. Additional work should focus on budesonide and formoterol, and the collection of data on pneumonia.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

LJN and PP developed the protocol. Studies were assessed by LJN and TJL (an author on the previous version of the review). TJL and LJN checked data and entered them into RevMan 5.2. TJL and LJN conducted the analysis. TJL and LJN developed the discussion with input from PP. CJC participated in the 2004 and 2007 updates of the review and offered statistical advice and input with calculating SEMs and SDs for the included studies where appropriate.

In the 2012 update, LJN and PP updated the background section with input from SJM, and SJM updated the methods section. Studies were selected and appraised by LJN and PP, and data were extracted by SJM and AK and then were entered by SJM and checked by AK. SJM conducted the analysis with input from AK, LJN and PP. The results section was written by SJM with input from AK, LJN and PP. The discussion and conclusions were written by LJN and PP with input from SJM and AK.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

The review authors who have been involved in this review have done so with no known conflicts of interest. None of the authors is considered a paid consultant by any pharmaceutical company that produces agents discussed in this review.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • St George's University of London, UK.

 

External sources

  • NIHR, UK.
    Program grant for Stephen Milan and Annabel Kesterton

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

We have now included estimates of mortality from all included studies.

Since the time that the protocol of this Cochrane Review was published, several aspects of review methodology have changed in light of recent recommendations regarding the methodology of Cochrane Reviews.

  • Risk of bias assessment (Cochrane Handbook for Systematic Reviews of Interventions, Chapter 8). This has now displaced the Jadad scores that we generated previously in determining study quality.
  • Generic inverse variance (Cochrane Handbook for Systematic Reviews of Interventions, Chapters 7 and 9). This method of meta-analysing adjusted effect estimates from clinical trials has enabled us to measure exacerbation outcomes as rate ratios.
  • Summary of findings tables. We have adopted the GRADE methodology for assessing strength evidence and determining effect size in absolute terms for key outcomes in this review (GRADE working group).
  • In 2012 the inclusion criteria were clarified as randomised, double-blind, parallel-group clinical trials of at least 4 weeks' duration. This was done to bring consistency to the inclusion criteria of the three Cochrane reviews considering combined corticosteroid and long-acting beta2-agonist in one inhaler for chronic obstructive pulmonary disease.
  • In 2012 we added the comparison of mometasone furoate/formoterol versus mometasone furoate.
  • Studies in which the ICS dose in the ICS/LABA condition was < 80% of the ICS dose in the ICS-only condition were excluded.

 

Index terms

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Medical Subject Headings (MeSH)

Adrenal Cortex Hormones [*administration & dosage; adverse effects]; Adrenergic beta-2 Receptor Agonists [*administration & dosage; adverse effects]; Albuterol [administration & dosage; adverse effects; analogs & derivatives]; Androstadienes [administration & dosage; adverse effects]; Bronchodilator Agents [administration & dosage; adverse effects]; Budesonide [administration & dosage; adverse effects]; Drug Combinations; Drug Therapy, Combination [adverse effects; methods]; Ethanolamines [administration & dosage; adverse effects]; Nebulizers and Vaporizers; Pneumonia [chemically induced]; Pulmonary Disease, Chronic Obstructive [*drug therapy; mortality]; Randomized Controlled Trials as Topic; Steroids [*administration & dosage; adverse effects]

MeSH check words

Humans

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Bourbeau 2007 {published data only}
  • Bourbeau J, Christodoulopoulos P, Maltais F, Yamauchi Y, Olivenstein R, Hamid Q. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial. Thorax 2007; Vol. 62, issue 11:938-43.
Calverley 2003 {published and unpublished data}
  • AstraZeneca SD. A placebo-controlled 12-month efficacy study of the fixed combination budesonide/formoterol compared to budesonide and formoterol as monotherapies in patients with chronic obstructive pulmonary disease (COPD). AstraZeneca Clinical Trials 2002.
  • Borgstrom L, Asking L, Olsson H, Peterson S. Lack of interaction between disease severity and therapeutic response with budesonide/formoterol in a single inhaler [Abstract]. American Thoracic Society 100th International Conference; May 21-26; 2004, Orlando, Florida. C22 [Poster 505].
  • Calverley PM, Bonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. European Respiratory Journal 2003;22(6):912-9.
  • Calverley PMA, Cseke Z, Peterson S. Budesonide/formoterol reduces the use of oral corticosteroids in the treatment of COPD [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P436.
  • Calverley PMA, Kuna P, Olsson H. COPD exacerbations are reduced by budesonide/formoterol in a single inhaler [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P1587.
  • Calverley PMA, Olsson H, Symbicort International COPD Study Group. Budesonide/formoterol ina single inhaler sustains improvements in lung function over 12 months compared with monocomponents and placebo in patients with COPD [abstract]. American Thoracic Society 99th International Conference; May 16-21, 2003; Seattle, Washington. B024 [Poster 418].
  • Calverley PMA, Peterson S. Combining budesonide/formoterol in a single inhale reduces exacerbation frequency in COPD [abstract]. American Thoracic Society 99th International Conference; May 16-21, 2003; Seattle, Washington. D092 [Poster 211].
  • Calverley PMA, Ståhl E, Jones PW. Budesonide/formoterol improves the general health status of patients with COPD [Abstract]. American Thoracic Society 2005 International Conference; May 20-25, 2005; San Diego, California. B93 [Poster 303].
  • Calverley PMA, Szafranski W, Andersson A. Budesonide/formoterol is a well-tolerated long term maintenance therapy for COPD. European Respiratory Journal 2005;26 Suppl 49:Poster 1917.
  • Calverley PMA, Thompson NC, Olsson H. Budesonide/formoterol in a single inhaler sustains lung function improvements in COPD [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P435.
  • Halpin D, Ståhl E, Lundback B, Anderson F, Peterson S. Treatment costs and number needed to treat (NNT) with budesonide/formoterol to avoid one exacerbation of COPD [Abstract]. American Thoracic Society 100th International Conference; May 21-26, 2004; Orlando, Florida. D22 [Poster 525].
  • Halpin DMG, Larsson T, Calverley PMA. How many patients with COPD must be treated with budesonide/formoterol compared with formoterol alone to avoid 1 day of oral steroid use? [Abstract]. American Thoracic Society 2005 International Conference; May 20-25, 2005; San Diego, California. B93 [Poster 314].
  • Jones PW, Stahl E. Budesonide/formoterol in a single inhaler improves health status in patients with COPD [abstract]. American Thoracic Society 99th International Conference; May 16-21, 2003; Orlando, Florida. B024 [Poster 419].
  • Jones PW, Ståhl E. Budesonide /formoterol sustains clinically relevant improvements in health status in COPD [Abstract]. European Respiratory Journal 2005;26 Suppl 49:Abstract 1352.
  • Jones PW, Ståhl E. Reducing exacerbations leads to a better health-related quality of life in patients with COPD. 13th ERS Annual Congress; September 27, 2003; Vienna, Austria. P1586.
  • Lofdahl CG. Reducing the impact of COPD exacerbations: Clinical efficacy of budesonide/formoterol. European Respiratory Review 2004;13(88):14-21.
  • Lofdahl CG, Andreasson E, Svensson K, Ericsson A. Budesonide/formoterol in a single inhaler improves health status in patients with COPD without increasing healthcare costs [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P433.
  • Lofdahl CG, Ericsson A, Svensson K, Andreasson E. Cost effectiveness of budesonide/formoterol in a single inhaler for COPD compared with each monocomponent used alone. Pharmacoeconomics 2005;23(4):365-75.
Doherty 2012 {published data only}
  • Doherty DE, Kerwin E, Tashkin DP, Matiz-Bueno CE, Shekar T, Banerjee S, et al. Combined mometasone furoate and formoterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD): phase 3 efficacy and safety study [Abstract]. Journal of Allergy and Clinical Immunology 2012; Vol. 129, issue 2 Suppl:AB75 [283].
  • Doherty DE, Tashkin DP, Kerwin E, Knorr BA, Shekar T, Banerjee S, et al. Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD. International Journal of Chronic Obstructive Pulmonary Disease 2012; Vol. 7, issue 1178-2005 (Electronic). 1176-9106 (Linking):57-71.
  • NCT00383721. A Randomized, 26-Week, Placebo-Controlled Efficacy and Safety Study With a 26-Week Long-Term Safety Extension, of High- and Medium-Dose Inhaled Mometasone Furoate/Formoterol Fixed-Dose Combination Formulation Compared With Formoterol and High-Dose Inhaled Mometasone Furoate Monotherapy in Subjects With Moderate to Severe COPD, 2006. http://clinicaltrials.gov/show/NCT00383721. [CRS-ID: 4900100000059605]
Hanania 2003 {published and unpublished data}
  • Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, et al. The efficacy and safety of fluticasone propionate (250 micro g)/salmeterol (50 micro g) combined in the diskus inhaler for the treatment of COPD. Chest 2003;124(3):834-43.
  • Hanania NA, Ramsdell J, Payne K, Davis S, Horstman D, Lee B, et al. Improvements in airflow and dyspnea in COPD patients following 24 weeks treatment with salmeterol 50mcg and fluticasone propionate 250mcg alone or in combination via the diskus. American Journal of Respiratory & Critical Care Medicine 2001;163(5 Suppl):A279.
  • Horstman D, Darken P, Davis S, Lee B. Improvements in FEV1 and symptoms in poorly reversible COPD patients following treatment with salmeterol 50mcg/fluticasone propionate 250mcg combination [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P434.
  • Mahler DA, Darken P, Brown CP, Knobil K. Predicting lung function responses to combination therapy in chronic obstructive pulmonary disease (COPD) [Abstract]. National COPD Conference; November 14-15, 2003; Arlington, Virginia. Abstract 1081.
  • Mahler DA, Darken P, Brown CP, Knobil K. Predicting lung function responses to salmeterol/fluticasone propionate combination therapy in COPD [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P429.
  • SFCA3007. A randomized, double-blind, placebo-controlled, parallel-group trial evaluating the safety and efficacy of the DISKUS formulations of salmeterol (SAL) 50mcg BID and fluticasone propionate (FP) 250mcg BID individually and in combination as salmeterol 50mcg/fluticasone propionate 250mcg BID (SFC 50/250) compared to placebo in COPD subjects. GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk) 2005.
  • Spencer M, Wire P, Lee B, Chang CN, Darken P, Horstman D. Patients with COPD using salmeterol/fluticasone propionate combination therapy experience improved quality of life. European Respiratory Journal 2003;22 Suppl 45:51s.
  • Spencer MD, Karia N, Anderson J. The clinical significance of treatment benefits with the salmeterol/fluticasone propionate 50/500mcg combination in COPD. European Respiratory Journal 2004;24 Suppl 48:290s.
Lapperre 2009 {published data only}
  • Lapperre TS, Snoeck-Stroband JB, Gosman MM, Jansen DF, van Schadewijk A, Thiadens HA, et al. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Annals of Internal Medicine 2009; Vol. 151, issue 8:517-27.
Mahler 2002 {published and unpublished data}
  • Mahler DA, Darken P, Brown CP, Knobil K. Predicting lung function responses to combination therapy in chronic obstructive pulmonary disease (COPD), 2003. http://www.abstracts2view.com.
  • Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the diskus device in the treatment of chronic obstructive pulmonary disease. American Journal of Respiratory Critical Care Medicine 2002;166(8):1084-91.
  • SFCA3006. A randomized, double-blind, placebo-controlled, parallel-group trial evaluating the safety and efficacy of the DISKUS formulations of salmeterol (SAL) 50mcg BID and fluticasone propionate (FP) 500mcg BID individually and in combination as salmeterol 50mcg/fluticasone propionate 500mcg BID (SFC 50/500) compared to placebo in COPD subjects. GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk) 2005.
  • Spencer M, Wire P, Lee B, Chang CN, Darken P, Horstman D. Patients with COPD using salmeterol/fluticasone propionate combination therapy experience improved quality of life. European Respiratory Journal 2003;22 Suppl 45:51s.
  • Spencer MD, Anderson JA. Salmeterol/fluticasone combination produces clinically important benefits in dyspnea and fatigue [Abstract]. American Thoracic Society 2005 International Conference; May 20-25, 2005; San Diego, California. B93 [Poster 308].
  • Spencer MD, Karia N, Anderson J. The clinical significance of treatment benefits with the salmeterol/fluticasone propionate 50/500mcg combination in COPD. European Respiratory Journal 2004;24 Suppl 48:290s.
NCT00358358 {published data only}
  • NCT00358358. Trial SCO104925. See detailed description, 2006. http://clinicaltrials.gov/show/NCT00358358. [CRS-ID: 4900100000059665]
SFCT01 {unpublished data only}
  • SFCT01. A Multicentre, Randomised, Double-Blind, Parallel Group, Placebo-Controlled Study to Compare the Efficacy and Safety of Inhaled Salmeterol/Fluticasone Propionate Combination Product 25/250 µg Two Puffs Bd and Fluticasone Propionate 250µg Two Puffs Bd Alone, All Administered Via Metered Dose Inhalers (MDI), in the Treatment of Subjects with Chronic Obstructive Pulmonary Disease (COPD) for 52 Weeks. GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk) 2005.
Sin 2008 {published data only}
  • NCT00120978. Advair-CRP Study. http://clinicaltrials.gov/show/NCT00120978 2004. [CRS-ID: 4900100000059673]
  • Sin DD, Man SF, Marciniuk DD, Ford G, FitzGerald M, Wong E, et al. Can inhaled fluticasone alone or in combination with salmeterol reduce systemic inflammation in chronic obstructive pulmonary disease? Study protocol for a randomized controlled trial [NCT00120978]. BMC Pulmonary Medicine 2006;6(6):3.
  • Sin DD, Man SF, Marciniuk DD, Ford G, FitzGerald M, Wong E, et al. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2008; Vol. 177, issue 11:1207-14.
Szafranski 2003 {published and unpublished data}
  • Anderson P. Budesonide/formoterol in a single inhaler (Symbicort) provides early and sustained improvement in lung function in moderate to severe COPD [Abstract]. Thorax 2002;57(Suppl III):iii43.
  • AstraZeneca SD. A placebo-controlled 12 month efficacy study of the fixed combination budesonide/formoterol compared with budesonide and formoterol as monotherapies in patients with chronic obstructive pulmonary disease (COPD). AstraZeneca Clinical Trials 2001.
  • Borgstrom L, Asking L, Olsson H, Peterson S. Lack of interaction between disease severity and therapeutic response with budesonide/formoterol in a single inhaler [Abstract]. American Thoracic Society 100th International Conference; May 21-26, 2004; Orlando, Florida. C22 [Poster 505].
  • Calverley P, Pauwels R, Lofdahl CG, Svensson K, Higenbottam T, et al. Relationship between respiratory symptoms and medical treatment in exacerbations of COPD. European Respiratory Journal 2005;26(3):406-13.
  • Calverley PMA. Effect of budesonide/formoterol on severe exacerbations and lung function in moderate to severe COPD. Thorax. BTS Winter Meeting 2002:S145.
  • Calverley PMA, Szafranski W, Andersson A. Budesonide/formoterol is a well-tolerated long term maintenance therapy for COPD. European Respiratory Journal 2005;26 Suppl 49:Poster 1917.
  • Calverley PMA, Thompson NC, Olsson H. Budesonide/formoterol in a single inhaler sustains lung function improvements in COPD [Abstract]. European Respiratory Journal 2003;22 Suppl 45:P435.
  • Campbell LM, Szafranski W. Budesonide/formoterol in a single inhaler (Symbicort) provides sustained relief from symptoms in moderate to severe COPD. Thorax. BTS Winter Meeting 2002:S143.
  • Campell LW, Szafranski W. Budesonide/Formoterol in a single inhaler (Symbicort) reduces severe exacerbations in patients with moderate-severe COPD. Thorax. BTS Winter Meeting 2002:S141.
  • Dahl R, Cukier A, Olsson H. Budesonide/formoterol in a single inhaler reduces severe and mild exacerbations in patients with moderate to severe COPD. European Respiratory Journal 2002;20 Suppl 38:242 [P1575].
  • Egede F, Menga G. Budesonide/formoterol in a single inhaler provides sustained relief from symptoms and night-time awakenings in moderate-severe COPD: results from symptoms and night-time awakenings in moderate to severe COPD: results from a 1-year study. European Respiratory Journal 2002;20 Suppl 38:242 [P1574].
  • Halpin D, Stahl E, Lundback B, Anderson F, Peterson S. Treatment costs and number needed to treat (NNT) with budesonide/formoterol to avoid one exacerbation of COPD [Abstract]. American Thoracic Society 100th International Conference; May 21-26, 2004; Orlando, Florida. D22 [Poster 525].
  • Jones PW, Stahl E, Svensson K. Improvement in health status in patients with moderate to severe COPD after treatment with budesonide/formoterol in a single inhaler. European Respiratory Journal 2002;20 Suppl 38:250 [P1613].
  • Korsgaard J, Sansores R. Budesonide/formoterol (single inhaler) provides sustained relief from shortness of breath and chest tightness in a 1-year study of patients with moderate to severe COPD. European Respiratory Journal 2002;20 Suppl 38:242 [P1577].
  • Lange P, Saenz C. Budesonide/formoterol in a single inhaler is well tolerated in patients with moderate to severe COPD: results of a 1 year study. European Respiratory Journal 2002;20 Suppl 38:242 [P1573].
  • Lofdahl CG. Reducing the impact of COPD exacerbations: clinical efficacy of budesonide/formoterol. European Respiratory Review 2004;13(88):14-21.
  • Milanowski J, Nahabedian S. Budesonide/formoterol in a single inhaler acts rapidly to improve lung function and relieve symptoms in patients with moderate to severe COPD. European Respiratory Journal 2002;20 Suppl 38:242 [P1576].
  • Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. European Respiratory Journal 2003;21(1):74-81.
Tashkin 2008 {published data only}
  • Astrazeneca (D5899C00002). A 6-month double-blind, double-dummy, randomized, parallel group, multicenter efficacy & safety study of Symbicort® pMDI 2 × 160/4.5mg & 80/4.5mg bid compared to Formoterol TBH, Budesonide pMDI (& the combination) & placebo in COPD patients. www.astrazenecaclinicaltrials.com (accessed 8 April 2008).
  • Bleecker ER, Meyers DA, Bailey WC, Sims A-M, Bujac SR, Goldman M, et al. ADRB2 polymorphisms and budesonide/formoterol responses in COPDADRB2 polymorphisms and treatment response in COPD. Chest 2012;142(2):320-8.
  • Tashkin DP, Rennard SI, Martin P, Goldman M, Silkoff PE. Efficacy of budesonide/formoterol administered via one pressurized metered-dose inhaler over 6 months in patients with chronic obstructive pulmonary disease [Abstract]. Chest 2008; Vol. 134, issue 4:105001s.
  • Tashkin DP, Rennard SI, Martin P, Ramachandran S, Martin UJ, Silkoff PE, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease : results of a 6-month randomized clinical trial. Drugs 2008; Vol. 68, issue 0012-6667 (Print):1975-2000.
Tashkin 2012 {published data only}
  • Kerwin E, Tashkin DP, Matiz-Bueno CE, Doherty DE, Shekar T, Banerjee S, et al. Clinical efficacy and safety of combined mometasone furoate and formoterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) [Abstract]. Journal of Allergy and Clinical Immunology 2012; Vol. 129, issue 2 Suppl:AB201 [759].
  • NCT00383435. A Randomized, 26-Week, Placebo-Controlled Efficacy and Safety Study With a 26-Week Long-Term Safety Extension, of High- and Medium-Dose Inhaled Mometasone Furoate/Formoterol Fixed-Dose Combination Formulation Compared With Formoterol and High-Dose Inhaled Mometasone Furoate Monotherapy in Subjects With Moderate to Severe COPD, 2006. http://clinicaltrials.gov/show/NCT00383435. [CRS-ID: 4900100000059603]
  • Tashkin DP, Doherty DE, Kerwin E, Matiz-Bueno CE, Knorr B, Shekar T, et al. Efficacy and safety of a fixed-dose combination of mometasone furoate and formoterol fumarate in subjects with moderate to very severe COPD: results from a 52-week Phase III trial. International Journal of Chronic Obstructive Pulmonary Disease 2012; Vol. 7, issue 1178-2005 (Electronic). 1176-9106 (Linking):43-55.
TORCH {published and unpublished data}
  • Briggs AH, Glick HA, Lozano-Ortega G, Spencer M, Calverley PM, Jones PW, et al. Is treatment with ICS and LABA cost-effective for COPD? Multinational economic analysis of the TORCH study. European Respiratory Journal 2010; Vol. 35, issue 3:532-9.
  • Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.[see comment]. New England Journal of Medicine 2007; Vol. 356, issue 8:775-89.
  • Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Cardiovascular events in patients with chronic obstructive pulmonary disease: TORCH study results. Thorax 2010;65:719-25.
  • Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. New England Journal of Medicine 2007;356(8):775-89.
  • Calverley PMA, Celli B, Ferguson G, Jenkins C, Jones PW, Pride NB, et al. Baseline characteristics of the first 5,000 COPD patients enrolled in the TORCH survival study. European Respiratory Journal 2003;22 Suppl 45:578s.
  • Celli B, Calverley PMA, Anderson JA, Ferguson GT, Jenkins C, Jones PW, et al. The TORCH (TOwards a Revolution in COPD Health) study: salmeterol/fluticasone propionate (SFC) improves health status, reduces exacerbations and improves lung function over three years. European Respiratory Journal 2006;28 Suppl 50:34s.
  • Celli B, Vestbo J, Jenkins CR, Jones PW, Ferguson GT, Calverley PM, et al. Sex differences in mortality and clinical expressions of patients with chronic obstructive pulmonary disease: the TORCH experience. American Journal of Respiratory and Critical Care Medicine 2011;183(3):317-22.
  • Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. American Journal of Respiratory and Critical Care Medicine 2008;174(4):332-8.
  • Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. European Respiratory Journal 2009;34(3):641-7.
  • Ferguson GT, Calverley PM, Anderson JA, Jenkins CR, Jones PW, Willits LR, et al. Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study. Chest 2009; Vol. 136, issue 0012-3692:1456-65.
  • Ferguson GT, Calverley PMA, Anderson JA, et al. The TORCH (TOwards a Revolution in COPD Health) study: salmeterol/fluticasone propionate (SFC) improves survival in COPD over three years. European Respiratory Journal 2006;28 Suppl 50:34s.
  • GlaxoSmithKline SCO30003. A multicentre, randomised, double-blind, parallel group, placebo-controlled study to investigate the long-term effects of salmeterol/fluticasone propionate (SERETIDE/VIANI/ADVAIR) 50/500mcg bd, salmeterol 50mcg bd and fluticasone propionate 500mcg bd, all delivered via the DISKUS/ACCUHALER inhaler, on the survival of subjects with chronic obstructive pulmonary disease (COPD) over 3 years of treatment. GlaxoSmithKline Clinical Trial Register 2006.
  • Houghton CM, Lawson N, Borrill ZL, Wixon CL, Yoxall S, Langley SJ, et al. Comparison of the effects of salmeterol/fluticasone propionate with fluticasone propionate on airway physiology in adults with mild persistent asthma. Respiratory Research 2007;8:52.
  • Jenkins CR, Calverley PMA, Celli B, Ferguson G, Jones PW, Pride N, et al. Seasonal patterns of exacerbation rates in the TORCH survival study, 2007. http://www.abstracts2view.com A839.
  • Jenkins CR, Celli B, Anderson JA, Ferguson GT, Jones PW, Vestbo J, et al. Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. European Respiratory Journal 2012;39(1):38-45.
  • Jenkins CR, Jones PW, Calverley PM, Celli B, Anderson JA, Ferguson GT, et al. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respiratory Research 2009;10:59.
  • Johnson M, Agusti AG, Barnes NC. Reflections on TORCH: potential mechanisms for the survival benefit of salmeterol/fluticasone propionate in COPD patients. COPD 2008;5(6):369-75.
  • Jones PW, Anderson JA, Calverley PM, Celli BR, Ferguson GT, Jenkins C, et al. TORCH Investigators. Health status in the TORCH study of COPD: treatment efficacy and other determinants of change. Respiratory Research 2011;12:71.
  • Jones PW, Calverley P, Celli B, Ferguson G, Jenkins C, Pride N. Trans-regional validity of the SGRQ in the TORCH survival study, 2007. http://www.abstracts2view.com A122.
  • McGarvey LP, John M, Anderson JA, Zvarich MT, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007;62:411-5.
  • NCT00268216. See detailed description, 2000. http://clinicaltrials.gov/show/NCT00268216. [CRS-ID: 4900100000059729]
  • SCO30003. A multicentre, randomised, double-blind, parallel group, placebo-controlled study to investigate the long-term effects of salmeterol/fluticasone propionate (SERETIDE®/VIANI®/ADVAIR®) 50/500mcg bd, salmeterol 50mcg bd and fluticasone propionate 500mcg bd, all delivered via the DISKUS®/ACCUHALER® inhaler, on the survival of subjects with chronic obstructive pulmonary disease (COPD) over 3 years of treatment, 2006. www.ctr.gsk.co.uk.
  • Vestbo J, Anderson JA, Calverley PM, Celli B, Ferguson GT, Jenkins C, et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax 2009;64(11):939-43.
  • Vestbo J, Calverley P, Celli B, Ferguson G, Jenkins C, Jones P, et al. The TORCH (TOwards a Revolution in COPD Health) survival study protocol. European Respiratory Journal 2004;24(2):206-10.
  • Wise RA, McGarvey LP, John M, Anderson JA, Zvarich MT. Reliability of cause-specific mortality adjudication in a COPD clinical trial, 2007. http://www.abstracts2view.com A120.
TRISTAN {published and unpublished data}
  • Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361(9356):449-56.
  • Calverley PMA, Pauwels RA, Vestbo J, Jones PW, Pride NB, Gulsvik A, et al. Clinical improvements with salmeterol / fluticasone propionate combination in differing severities of COPD, 2003. http://www.abstracts2view.com A035 [Poster D50].
  • Calverley PMA, Pauwels RA, Vestbo J, Jones PW, Pride NB, Gulsvik A, et al. Salmeterol/Fluticasone propionate combination for one year provides greater clinical benefit than its individual components. Proceedings of the 98th International American Thoracic Society Conference http://www.abstracts-on-line.com/abstracts/ATS; May 17-22, 2002; Atlanta, Georgia. A98 [Poster 306].
  • Calverly PMA, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, et al. Safety of salmeterol/fluticasone propionate combination in the treatment of chronic obstructive pulmonary disease. European Respiratory Journal 2002;20 Suppl 38:242 [P1572].
  • Hunjan MK, Chandler F. Numbers needed to treat (NNT) to avoid an exacerbation in patients with chronic obstructive pulmonary disease (COPD) using salmeterol/fluticasone propionate combination (SFC) and associated costs [Abstract]. American Thoracic Society 100th International Conference; May 21-26, 2004; Orlando, Florida. D22 [Poster 503].
  • Hunjan MK, Williams DT. Costs of avoiding exacerbations in patients with chronic obstructive pulmonary disease (COPD) treated with salmeterol/ fluticasone propionate combination (seretide) and salmeterol. European Respiratory Journal 2004;24 Suppl 48:291s.
  • Hunjan MK, Williams DT. Salmeterol/ fluticasone propionate combination is clinically effective in avoiding exacerbations in patients with moderate/severe COPD. European Respiratory Journal 2004;24 Suppl 48:513s.
  • Jones PW, Edin HM, Anderson J. Salmeterol/fluticasone propionate combination improves health status in COPD patients. Proceedings of the 98th International American Thoracic Society Conference http://www.abstracts-on-line.com/abstracts/ATS; May 17-22, 2002; Atlanta, Georgia. A39 [Poster K39].
  • Jones PW, Ståhl E. Budesonide /formoterol sustains clinically relevant improvements in health status in COPD [Abstract]. European Respiratory Journal 2005;26 Suppl 49:Abstract 1352.
  • Jones PW, Vestbo J, Pauwels RA, Calverley PMA, Anderson JA, Spencer MD. Informative drop out in COPD studies: investigation of health status of withdrawals in the TRISTAN study. Proceedings of the 13th ERS Annual Congress; September 27, 2003; Vienna, Austria. P1593.
  • Nitschmann S. Inhalational combination therapy in chronic obstructive lung disease. Tristan study. German Internist 2004;45(6):727-8.
  • Pauwels R, Vestbo J, Calverley PMA, Jones PW, Pride NB, Gulsvik A. Characterization of exacerbations in the TRISTAN study of salmeterol / fluticasone propionate (SFC) combination in moderate to severe COPD, 2006. http://www.abstracts2view.com.
  • Pauwels RA, Calverly PMA, Vestbo J, Jones PW, Pride N, Gulsvik A, et al. Reduction of exacerbations with salmeterol/fluticasone combination 50/500 mcg bd in the treatment of chronic obstructive pulmonary disease. European Respiratory Journal 2002;20 Suppl 38:240 [P1569].
  • SFCB3024. A multicentre, randomised, double-blind, parallel group, placebo-controlled study to compare the efficacy and safety of the salmeterol/FP combination product at a strength of 50/500mcg bd with salmeterol 50mcg bd alone and FP 500mcg bd alone, delivered via the DISKUS™/ACCUHALER™, in the treatment of subjects with chronic obstructive pulmonary disease (COPD) for 12 months. GlaxoSmithKline Clinical Trials Register (http:ctr.gsk.co.uk) 2005.
  • Spencer M, Briggs AH, Grossman RF, Rance L. Development of an economic model to assess the cost effectiveness of treatment interventions for chronic obstructive pulmonary disease. Pharmacoeconomics 2005;23(6):619-37.
  • Spencer MD, Karia N, Anderson J. The clinical significance of treatment benefits with the salmeterol/fluticasone propionate 50/500mcg combination in COPD. European Respiratory Journal 2004;24 Suppl 48:290s.
  • Vestbo J, Calverley PMA, Pauwels R, Jones P, Pride N, Gulsvik A, et al. Absence of gender susceptibility to the combination of salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease. European Respiratory Journal 2002;20 Suppl 38:240 [P1570].
  • Vestbo J, Pauwels R, Anderson JA, Jones P, Calverley P. Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease. Thorax 2005;60(4):301-4.
  • Vestbo J, Pauwels RS, Calverley PMA, Jones PW, Pride NB, Gulsvik A. Salmeterol / fluticasone propionate combination produces improvement in lung function detectable within 24 hours in moderate to severe COPD, 2003. http://www.abstracts2view.com.
  • Vestbo J, Soriano JB, Anderson JA, Calverley P, Pauwels R, Jones P. Gender does not influence the response to the combination of salmeterol and fluticasone propionate in COPD. Respiratory Medicine 2004;98(11):1045-50.
Zhong 2012 {published data only}
  • Zhong N, Zheng J, Wen F, Yang L, Chen P, Xiu Q, et al. Efficacy and safety of budesonide/formoterol via a dry powder inhaler in Chinese patients with chronic obstructive pulmonary disease. Current Medical Research and Opinion 2012; Vol. 28, issue 2:257-65.
  • Zhong N, Zheng J, Wen F, Yang L, Chen P, Xiu Q, et al. Efficacy and safety of inhalation of budesonide/formoterol via turbuhaler in Chinese patients with chronic obstructive pulmonary disease [Abstract]. Chest 2011; Vol. 140, issue 4:5225A.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Aaron 2007 {published data only}
  • Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.[see comment]. Annals of Internal Medicine 2007; Vol. 146, issue 8:545-55.
Bathoorn 2008 {published data only}
  • Bathoorn E, Liesker JJ, Postma DS, Boorsma M, Bondesson E, Koëter GH, et al. Anti-inflammatory effects of combined budesonide/formoterol in COPD exacerbations. COPD 2008; Vol. 5, issue 5:282-90.
Bleecker 2011 {published data only}
  • Bleecker ER, Meyers DA, Bailey WC, Sims AM, Bujac SR, Goldman M, et al. Effect of β2-adrenergic receptor gene polymorphism Gly16Arg on response to budesonide/formoterol pressurized metered-dose inhaler In chronic obstructive pulmonary disease [Abstract]. American Journal of Respiratory and Critical Care Medicine 2011; Vol. 183, issue Meeting Abstracts:A4086.
Calverley 2005 {published data only}
  • Calverley PM, Szafranski W, Andersson A. Budesonide/formoterol is a well-tolerated long term maintenance therapy for COPD [Abstract]. European Respiratory Journal 2005; Vol. 26 Suppl 49:Abstract No. 1917.
Cukier 2007 {published data only}
  • Cukier A, Ferreira CAS, Stelmach R, Ribeiro M, Cortopassi F, Calverley PMA. The effect of bronchodilators and oxygen alone and in combination on self-paced exercise performance in stable COPD. Respiratory Medicine 2007;101(4):743-53.
D5899C00001 {published data only}
  • A 12-Month Double-blind, Double-dummy, Randomized, Parallel-group, Multicenter Efficacy & Safety Study of SYMBICORT® pMDI 2 × 160/4.5 mcg bid and 2 × 80/4.5mcg bid Compared to Formoterol TBH 2 × 4.5 mcg bid and Placebo in Patients with COPD. AstraZeneca 2008.
De Backer 2011 {published data only}
  • De Backer L, De Backer J, Vos W, Van Holsbeke C, Vinchurkar S, De Backer W. Double blind, placebo controlled crossover study in COPD patients to assess the acute effect of budesonide/formoterol using HRCT and lung function tests [Abstract]. European Respiratory Society Annual Congress; September 24-28, 2011; Amsterdam, The Netherlands Vol. 38, issue 55:600s [P3362].
Ferguson 2006 {published data only}
  • Ferguson GT. Cardiovascular safety of simultaneous therapy with Advair and Combivent in the treatment of COPD [Abstract]. Proceedings of the American Thoracic Society; June 15, 2006; San Diego, California A109 [Poster J2].
GlaxoSmithKline 2004 {published data only}
  • GlaxoSmithKline SAS40007. A Randomised, Double-Blind, Double-Dummy, Parallel-Group Comparison of SERETIDE DISKUS/ACCUHALER (50/100 µg Strength) twice daily (bid) with Budesonide 400 µg bid in Adolescents and Adults with Reversible Airways Obstruction. http://ctr.gsk.co.uk/Summary/fluticasone_salmeterol/IV_SAS40007.pdf. GlaxoSmithKline Clinical Trial Register, 2004.
GlaxoSmithKline 2004a {published data only}
  • GlaxoSmithKline SAS40006. A Randomised, Double-Blind, Double-Dummy, Parallel-Group Comparison of Seretide DISKUS/ACCUHALER (50/250g Strength) b.i.d. with Budesonide 800g b.i.d. in Adolescents and Adults with Reversible Airways Obstruction. http://ctr.gsk.co.uk/Summary/fluticasone_salmeterol/IV_SAS40006.pdf. GlaxoSmithKline Clinical Trial Register, 2004.
GlaxoSmithKline 2006 {published data only}
  • GlaxoSmithKline SCO30005. A 13-Week, Double-Blind, Parallel-Group, Multicentre Study to Compare the Bronchial Anti-inflammatory Activity of the Combination of Salmeterol/ Fluticasone Propionate (SERETIDE™/ADVAIR™/VIANI™) 50/500 mcg Twice Daily Compared With Placebo Twice Daily in Patients With Chronic Obstructive Pulmonary Disease. GlaxoSmithKline Clinical Trial Register, 2006.
Golabi 2006 {published data only}
  • Golabi P, Topaloglu N, Karakurt S, Celikel T. Effects of tiotropium and salmeterol/fluticasone combination on lung hyperinflation dyspnea and exercise tolerance in COPD [Abstract]. European Respiratory Journal 2006;28(Suppl 50):33s.
Haque 2006 {published data only}
  • Haque RA, Torrego A, Essilfie-Quaye S, Kharitonov SA, Johnson M, Adcock IM, et al. Effect of salmeterol and fluticasone on glucocorticoid receptor translocation in sputum macrophages and peripheral blood mononuclear cells from patients with chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society; May 23-26, 2006; San Diego, California. A848.
INSPIRE {published data only}
  • GlaxoSmithKline (SCO40036). Multicentre, randomised, double-blind, double-dummy, parallel group, 104-week study to compare the effect of the salmeterol/fluticasone propionate combination product (SERETIDE*) 50/500mcg delivered twice daily via the DISKUS*/ACCUHALER* inhaler with tiotropium bromide 18 mcg delivered once daily via the HandiHaler inhalation device on the rate of health care utilisation exacerbations in subjects with severe chronic obstructive pulmonary disease (COPD). http://ctr.gsk.co.uk (accessed 8 April 2008).
  • Seemungal T, Stockley R, Calverley P, Hagan G, Wedzicha JA. Investigating new standards for prophylaxis in reduction of exacerbations-the INSPIRE study methodology. Journal of Chronic Obstructive Pulmonary Disease 2007;4(3):177-83.
  • Wedzicha J, Stockley R, Seemungal T, Hagan G, Calverley P. The INSPIRE study: effect of salmeterol/fluticasone propionate versus tiotropium bromide on COPD exacerbations. Respirology 2007;12(Suppl 4):A112.
Jiang 2011 {published data only}
  • Jiang YP, Zhao YF, Yang Y. Effect of seretide on quality of life in COPD: measured with COPD assessment test [Abstract]. Respirology (Carlton, Vic.) 2011; Vol. 16, issue Suppl 2:100 [344].
Jung 2012 {published data only}
  • Jung KS, Park HY, Park SY, Kim SK, Kim YK, Shim JJ, et al. Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: a randomized controlled study. Respiratory Medicine 2012; Vol. 106, issue 3:382-9.
Laties 2010 {published data only}
  • Laties A, Rennard SI, Tashkin DP, Suchower LJ, Martin UJ. Effect of budesonide/formoterol pressurized metered-dose inhaler (bud/fm pmdi) on ophthalmologic assessments in moderate to very severe chronic obstructive pulmonary disease (COPD) patients: results from a 1-year, randomized, controlled clinical trial [Abstract]. Chest 2010; Vol. 138, issue 4:468A.
Lindberg 2007 {published data only}
  • Lindberg A, Szalai Z, Pullerits T, Radeczky E. Fast onset of effect of budesonide/formoterol versus salmeterol/fluticasone and salbutamol in patients with chronic obstructive pulmonary disease and reversible airway obstruction. Respirology (Carlton, Vic.) 2007; Vol. 12, issue 5:732-9.
Mittmann 2010 {published data only}
  • Mittmann N, Hernandez P, Mellsträm C, Brannman L, Welte T, Mellström C, et al. Cost-effectiveness of budesonide/formoterol added to tiotropium in COPD patients in Canada, Australia and Sweden [Abstract]. European Respiratory Society Annual Congress; September 18-22, 2010; Barcelona, Spain [5183].
Mittmann 2011 {published data only}
  • Mittmann N, Hernandez P, Mellstrom C, Brannman L, Welte T. Cost effectiveness of budesonide/formoterol added to tiotropium bromide versus placebo added to tiotropium bromide in patients with chronic obstructive pulmonary disease: Australian, Canadian and Swedish healthcare perspectives. PharmacoEconomics 2011; Vol. 29, issue 5:403-14.
NCT00269126 {published data only}
  • NCT00269126. See detailed description, 2005. http://clinicaltrials.gov/show/NCT00269126. [CRS-ID: 4900100000059651]
NCT00476099 {published data only}
  • NCT00476099. A 48-Week, Double Blind, Double Dummy, Randomised, Multinational, Multicentre, 3-Arm Parallel Group Clinical Study of "Fixed Combination" Beclometasone Dipropionate Plus Formoterol Fumarate Administered Via pMDI With HFA-134a Propellant Versus "Fixed Combination" Budesonide Plus Formoterol DPI Versus Formoterol DPI in Patients With Stable Severe Chronic Obstructive Pulmonary Disease (COPD), 2006. http://clinicaltrials.gov/show/NCT00476099. [CRS-ID: 4900100000059631]
NCT00549146 {published data only}
  • NCT00549146. Trial: SCO40055, 2003. http://clinicaltrials.gov/show/NCT00549146. [CRS-ID: 4900100000059661]
Rennard 2008 {published data only}
  • Rennard SI, Tashkin DP, McElhattan J, Goldman M, Silkoff PE. Long-term tolerability of budesonide and formoterol administered in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease [Abstract]. Chest 2008; Vol. 134, issue 4:103003s.
Rennard 2009 {published data only}
  • Rennard SI, Tashkin DP, McElhattan J, Goldman M, Ramachandran S, Martin UJ, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. Adis Data Information BV., 2009; Vol. 69, issue 0012-6667:549-65.
Rennard 2009a {published data only}
  • Rennard SI, Tashkin DP, McElhattan J, Goldman M, Ramachandran S, Martin UJ, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs 2009;69:549-65.
Rennard 2010 {published data only}
  • Rennard SI, Tashkin DP, Suchower LJ, Martin UJ. Effect of budesonide/formoterol pressurized metered-dose inhaler (BUD/FM pMDI) on bone mineral density (BMD) in moderate to very severe chronic obstructive pulmonary disease (COPD) patients: results from a 1-year, randomized, controlled clinical trial [Abstract]. Chest 2010; Vol. 138, issue 4:863A.
Sagcan 2007 {published data only}
  • Sagcan G, Memis U, Cuhadaroglu C, Sen C, Duygu E. The effects of formoterol/budesonide on sleep quality of COPD patients [Abstract]. European Respiratory Journal 2007; Vol. 30, issue Suppl 51:507s [E3049].
Schermer 2007 {published data only}
  • Schermer TR, Albers JM, Verblackt HW, Costongs RJ, Westers P. Lower inhaled steroid requirement with a fluticasone/salmeterol combination in family practice patients with asthma or COPD. Family Practice 2007; Vol. 24, issue 2:181-8.
SCO100250 {unpublished data only}
  • GlaxoSmithKline (SCO100250). A randomized, double-blind, parallel-group, 52-week study to compare the effect of fluticasone propionate/salmeterol DISKUS 250/50mcg bid with salmeterol DISKUS 50mcg bid on the annual rate of moderate/severe exacerbations in subjects with chronic obstructive pulmonary disease (COPD). http://ctr.gsk.co.uk (accessed 8 April 2008).
SCO40043 {unpublished data only}
  • SCO40043. A randomized, double-blind, parallel-group, 52-week study to compare the effect of fluticasone propionate/salmeterol DISKUS® 250/50mcg bid with salmeterol DISKUS® 50mcg bid on the annual rate of moderate/severe exacerbations in subjects with chronic obstructive pulmonary disease (COPD). http://ctr.gsk.co.uk (accessed 8 April 2008).
Sethi 2006 {published data only}
  • Sethi S, Grove L, Wrona C, Maloney J. Prevalence of bacterial colonization in COPD is not altered by fluticasone/salmeterol. Proceedings of the American Thoracic Society; May 23-26. 2006; San Diego, California. A115.
Shaker 2009 {published data only}
  • Shaker SB, Dirksen A, Ulrik CS, Hestad M, Stavngaard T, Laursen LC, et al. The effect of inhaled corticosteroids on the development of emphysema in smokers assessed by annual computed tomography. COPD 2009; Vol. 6, issue 2:104-11.
Sharafkhaneh 2011 {published data only}
  • Sharafkhaneh A, Southard J, Goldman M, Uryniak T, Martin UJ. Long-term effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations and pulmonary function in patients with chronic obstructive pulmonary disease [Abstract]. American Journal of Respiratory and Critical Care Medicine 2011; Vol. 183, issue Meeting Abstracts:A1599.
Southard 2011 {published data only}
  • Southard JG, Sharafkhaneh A, Goldman M, Uryniak T, Martin UJ. Long-term tolerability of budesonide/formoterol pressurized metered-dose inhaler In patients with chronic obstructive pulmonary disease and a history of exacerbations [Abstract]. American Journal of Respiratory and Critical Care Medicine 2011; Vol. 183, issue Meeting Abstracts:A1597.
Stallberg 2008 {published data only}
  • Stallberg B, Andersson EBC, Ekstrom T, Selroos O, Vogelmeier C, Larsson K. Budesonide /formoterol for the treatment of COPD exacerbations in the primary healthcare setting [Abstract]. European Respiratory Society Annual Congress; October 4-8, 2008; Berlin, Germany [P3610].
Sutherland 2006 {published data only}
  • Sutherland ER, Moss TA, Stevens AD, Pak J, Martin RJ. Modulation of sputum gene expression in COPD by fluticasone /salmeterol. European Respiratory Journal 2006;28(Suppl 50):662s.
Trofimenko 2006 {published data only}
  • Trofimenko IN, Chernyak BA. The efficacy of salmeterol/fluticasone (SF) for 6 month's therapy at severe COPD patients. European Respiratory Journal 2006;28(Suppl 50):30s.
Welte 2009 {published data only}
  • Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2009; Vol. 180, issue 8:741-50.
Welte 2009a {published data only}
  • Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, et al. Addition of budesonide/formoterol to tiotropium reduces the number of exacerbation days compared with tiotropium alone [Abstract]. Chest 2009; Vol. 136, issue 4:26S-f.
Welte 2009b {published data only}
  • Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, et al. Budesonide/formoterol added to tiotropium provides rapid improvements in lung function and ability to undertake morning activities [Abstract]. Chest 2009; Vol. 136, issue 4:24S-g.
Welte 2009c {published data only}
  • Welte T, Hartman L, Polanowski T, Hernandez P, Miravitlles M, Peterson S, et al. Budesonide/formoterol added to tiotropium is well tolerated and reduces risk of severe exacerbations in COPD patients [Abstract]. American Thoracic Society International Conference; May 15-20, 2009; San Diego, California A6188 [Poster #215].
Welte 2009d {published data only}
  • Welte T, Miravitlles M, Hernandez P, Peterson S, Polanowski T, Kessler R, et al. Budesonide/formoterol added to tiotropium improves exacerbations and exacerbation-related antibiotic use in patients with COPD [Abstract]. European Respiratory Society Annual Congress; September 12-16, 2009; Vienna, Austria [P2012].
Wilson 2007 {published data only}
  • Wilson DS, Gillion MS, Rees PJ. Use of dry powder inhalers in COPD. International Journal of Clinical Practice 2007; Vol. 61, issue 12:2005-8.
Worth 2009 {published data only}
  • Worth H, Foerster K, Peterson S, Nihlen U, Magnussen H, et al. Budesonide/formoterol improves exercise tolerance compared with placebo and formoterol in COPD patients [Abstract]. European Respiratory Society Annual Congress; September 12-16, 2009; Vienna, Austria [201].
Worth 2009a {published data only}
  • Worth H, Peterson S, Nihlen U, Magnussen H. Improved exercise tolerance with budesonide/formoterol vs placebo and formoterol in COPD patients [Abstract]. American Thoracic Society International Conference; May 15-20, 2009; San Diego, California A6193 [Poster #220].
Worth 2010 {published data only}
  • Worth H, Förster K, Eriksson G, Nihlén U, Peterson S, Magnussen H. Budesonide added to formoterol contributes to improved exercise tolerance in patients with COPD. Respiratory Medicine 2010; Vol. 104, issue 10:1450-9.
Zheng 2006 {published data only}
  • Zheng J, Zhong N, Yang L, Wu Y, Chen P, Wen Z, et al. The efficacy and safety of fluticasone propionate 500 mg/salmeterol 50 mg combined via diskus/accuhaler in Chinese patients with chronic obstructive pulmonary disease (COPD). Chest 2006;130(4):182s.
  • Zhong N, Zheng J, Yang L, Wu Y, Chen P, Wen Z, et al. The efficacy and safety of salmeterol 50µg/fluticasone propionate 500µg combined via accuhaler in Chinese patients with chronic obstructive pulmonary disease [Abstract]. Respirology 2006;11(Suppl 5):A150.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Appleton 2006
Barnes 2002
Cates 2012
  • Cates C J. Inhaled corticosteroids in COPD: quantifying risks and benefits. Thorax [published online first] 14 December 2012. [DOI: 10.1136/thoraxjnl-2012-202959]
Cosio 2009
Dong 2013
  • Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications inpatients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax 2013;68(2):48-56.
Drummond 2008
  • Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 2008;26;300(20):2407-16.
Garcia-Aymerich 2011
  • Garcia-Aymerich J, Gómez FP, Benet M, Farrero E, Basagaña X, Gayete À, et al. Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes. Thorax [published online first] 21 December 2010;66(5):430-7.
GOLD 2011
  • Global Strategy for Diagnosis, Management, Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011. http://www.goldcopd.org.
Hanania 2008
Higgins 2011
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org.
Jones 2002
Karner 2011
  • Karner C, Cates CJ. Combination inhaled steroid and long-acting beta2-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/14651858.CD008532.pub2]
Kohansal 2009
  • Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. American Journal of Respiratory and Critical Care Medicine 2009;180(1):3-10.
NCGC 2010
  • London: National Clinical Guideline Centre. Management of chronic obstructive pulmonary disease in adults in primary and secondary care, 2010. http://guidance.nice.org.uk/CG101/Guidance/pdf/English.
NICE 2010
  • CG101 Chronic obstructive pulmonary disease (update): NICE guideline, 2010. http://guidance.nice.org.uk/CG101/NICEGuidance/pdf/English.
RevMan 5.2
  • The Cochrane Collaboration. Copenhagen: The Nordic Cochrane Centre. Review Manager (RevMan). Version 5.2. The Cochrane Collaboration. Copenhagen: The Nordic Cochrane Centre, 2012.
Rodrigo 2012
  • Rodrigo GJ. Castro-Rodríguez JA. Safety of long-acting beta agonists for the treatment of asthma: clearing the air. Thorax 2012 21 April 2011;67:342-9.
Visual Rx
  • Cates CJ. Visual Rx. 3.0, 2008, www.nntonline.net.
Yang 2012

References to other published versions of this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Nannini 2003
  • Nannini L, Lasserson TJ, Poole P. Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/14651858.CD003794]
Nannini 2004
  • Nannini L, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD003794.pub2]
Nannini 2007
  • Nannini L, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler versus inhaled steroids for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2007, Issue 4. [DOI: 10.1002/14651858.CD006826]