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

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

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

Objectives

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

Search methods

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

Selection criteria

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

Data collection and analysis

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

Main results

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

Authors' conclusions

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

Plain language summary

Combined inhalers versus placebo for the treatment of chronic obstructive pulmonary disease (COPD)

Review question

We reviewed the evidence on the effects of combined inhalers in people with COPD when compared with placebo. We particularly focused on whether combined inhalers are a good but safe treatment for adults with COPD.

Background

COPD is a serious respiratory condition that affects millions of people worldwide. In most cases, it is caused by smoking. COPD is often treated by using inhalers. Currently, three types of inhalers combine a steroid and a 'long-acting beta2-agonist' (LABA). Steroids work by reducing inflammation in the airways, and LABA work by relaxing the muscles in the airways and opening them up. Using combined inhalers is more convenient than taking the two drugs separately but is also more expensive. We looked for evidence on whether giving a combined inhaler is better or worse than giving placebo (dummy inhaler).

Study characteristics

Nineteen studies involving 10,400 people were included in this review. The studies lasted between 4 and 156 weeks. All of the people included in the studies had COPD of different severity. Both men and women were included, and most of the studies included only adults aged 45 or older.

All studies compared a combined inhaler with a placebo that was identical in appearance to the combined inhaler, so the people in the trials did not know whether they were taking the drug or the dummy inhaler. Some of the studies included two groups treated with the combined inhaler; one group was getting a higher dose and one group was getting a lower dose.

The evidence presented here is current to June 2013.

Most of the studies were sponsored by the pharmaceutical industry.

Key results

We found that people receiving a combined inhaler were less likely to have a flare-up (‘exacerbation’) of their COPD. The chance of having an exacerbation was reduced by about one quarter.

A small reduction in the risk of death was seen over three years, although most of the evidence about death comes from one large, long trial called TORCH. According to TORCH, approximately 42 people would need to be treated with a combined inhaler for three years to prevent one death.

We also found that people receiving combined inhalers had small improvements in quality of life, symptoms related to COPD and their breathing tests. However, these improvements may not have been very noticeable to them.

People treated with combined inhalers were more likely to have a lung infection called pneumonia. Again, most of the evidence about pneumonia comes from the TORCH trial. According to TORCH, when compared with placebo, for approximately every 17 people treated with combined inhaler, one extra person would get pneumonia.

People treated with combined inhalers were no more or less likely to experience serious unwanted events, including side effects, during treatment.

No consistent differences were found between the three different types of inhalers included in this review.

Quality of the evidence

The evidence presented in this review is generally considered to be of moderate quality. Most of the studies did not clearly explain how they decided which people would receive the combined inhaler and which would receive placebo, and this is an important part of a well-conducted study. Also, more people receiving placebo dropped out of the trials than those receiving a combined inhaler. This often happened because of exacerbations of COPD. This means that by the end of the trial, the groups might have been unbalanced, and this could affect the accuracy of the results.

Summary of findings(Explanation)

Summary of findings for the main comparison. Combined inhalers versus placebo (primary outcomes) for chronic obstructive pulmonary disease
  1. 1Downgraded because of risk of attrition bias.

    2Downgraded because of imprecision.

    3Downgraded because of risk of attrition bias and imprecision.

    4Weighted mean duration.

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

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

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Combined inhalers versus placebo (primary outcomes)
Annual exacerbation rates 1.35

0.99

(0.93 to 1.05)

Rate ratio 0.73

(0.69 to 0.78)

7473

(seven studies)

⊕⊕⊕⊝
moderate 1
 

Participants with at least one exacerbation

Duration of six months4

301 per 1000

251 per 1000

(221 to 286)

OR 0.78
(0.66 to 0.93)

3141

(eight studies)

⊕⊕⊕⊝
moderate 1
 

Mortality

Duration of 18 months4

60 per 1000 50 per 1000
(41 to 59)
OR 0.82
(0.68 to 0.99)
10129
(16 studies)
⊕⊕⊕⊝
moderate 2
 

Pneumonia

Duration of 18 months4

55 per 1000 85 per 1000
(73 to 101)
OR 1.62
(1.36 to 1.94)
9620
(14 studies)
⊕⊕⊕⊝
moderate 1
 

Hospitalisations due to COPD exacerbations

Duration of 18 months4

115 per 1000 108 per 1000
(95 to 121)
OR 0.93
(0.81 to 1.06)
9492
(12 studies)
⊕⊕⊝⊝
low 3
 
*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.

Summary of findings 2 Fluticasone/salmeterol (FPS) versus placebo for COPD

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

    2Weighted mean duration.

Fluticasone/salmeterol (FPS) versus placebo for COPD

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

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Fluticasone/salmeterol (FPS) versus placebo (PLA)

Adverse eventsany

Duration of two years2

780 per 1000 794 per 1000
(771 to 816)
OR 1.09
(0.95 to 1.25)
5574
(nine studies)
⊕⊕⊝⊝
Low 1
 

Adverse events'serious'

Duration of two years2

271 per 1000 287 per 1000
(261 to 314)
OR 1.08
(0.95 to 1.23)
5531
(nine studies)
⊕⊕⊝⊝
Low1
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.
GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Budesonide/formoterol (BDF) versus placebo for COPD

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

    3Weighted mean duration.

    4Delivered dose.

Budesonide/formoterol (BDF) versus placebo for COPD

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

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Budesonide/formoterol (BDF) versus placebo

Adverse eventany320/94

Duration of nine months 3

538 per 1000 623 per 1000
(574 to 669)
OR 1.42
(1.16 to 1.74)
1552
(two studies)
⊕⊕⊝⊝
low 1
 

Adverse eventany160/94

Duration of nine months 3

538 per 1000 606 per 1000
(557 to 652)
OR 1.32
(1.08 to 1.61)
1556
(two studies)
⊕⊕⊝⊝
low 1
 

Adverse events'serious'320/94

Duration of 10 months3

162 per 1000 184 per 1000
(155 to 219)
OR 1.17
(0.95 to 1.45)
2476
(four studies)
⊕⊕⊝⊝
low 2
 

Adverse events'serious'160/94

Duration of nine months 3

113 per 1000 132 per 1000
(102 to 171)
OR 1.2
(0.89 to 1.63)
1556
(two studies)
⊕⊕⊝⊝
low 2
 
*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.

Summary of findings 4 Mometasone/formoterol (MF/F) versus placebo for COPD

Summary of findings 4. Mometasone/formoterol (MF/F) versus placebo for COPD
  1. 1Downgraded because of risk of attrition bias, imprecision and heterogeneity.
    2Downgraded because of risk of attrition bias and imprecision.

    3Delivered dose.

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

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

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Mometasone/formoterol (MF/F) versus placebo

Adverse eventany400/103

Duration of six months

362 per 1000 357 per 1000
(298 to 424)
OR 0.98
(0.75 to 1.3)
890
(two studies)
⊕⊕⊝⊝
low 1
 

Adverse eventany200/103

Duration of six months

362 per 1000 317 per 1000
(260 to 382)
OR 0.82
(0.62 to 1.09)
894
(two studies)
⊕⊕⊝⊝
low 2
 

Adverse eventsserious400/103

Duration of six months

74 per 1000 80 per 1000
(50 to 125)
OR 1.09
(0.66 to 1.79)
890
(two studies)
⊕⊕⊝⊝
low 2
 

Adverse eventsserious200/103

Duration of six months

74 per 1000 53 per 1000
(32 to 89)
OR 0.71
(0.41 to 1.23)
894
(two studies)
⊕⊕⊝⊝
low 2
 
*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.

Background

Description of the condition

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in most industrialised countries, and it is projected to be the third leading cause of death worldwide by 2020 (GOLD 2012). The disease is predominantly caused by smoking. An estimated three million people are affected by COPD in the UK (NCGC2010). COPD is a heterogeneous syndrome that is characterised by reduced post-bronchodilator lung function (forced expiratory volume in one second/forced vital capacity (FEV1/FVC)) < 0.7 in all patients (GOLD 2012). Acute bronchodilator reversibility has traditionally been regarded as a characteristic of asthma, and only in the past few years has it been generally acknowledged that this clinical feature is also present in COPD (Hanania 2011), as it was found in the UPLIFT study (UPLIFT 2008), in which 53% of participants had an increase of at least 200 mL in FEV1 post-salbutamol. In TORCH, an increase in predicted FEV1 of 10% was an exclusion criterion (TORCH). Patients with COPD generally show progressive lung function loss, accompanied by worsening respiratory symptoms (e.g. dyspnoea, cough and sputum) and health status (GOLD 2012). These clinical features are a result of persisting and progressive airway inflammation (i.e. bronchial infiltration of neutrophils, macrophages, lymphocytes and mast cells) and increasing evidence of autoimmunity (Cosio 2009). Furthermore, it has been suggested that some phenotypes of COPD involve chronic systemic inflammation that has an impact on co-morbidities, such as cardiovascular disease (Garcia-Aymerich 2011).

Description of the intervention

This review focusses on combined inhalers that contain both an inhaled corticosteroid (ICS) and a long-acting beta2-agonist (LABA).

ICS, LABA and long-acting antimuscarinic agents (LAMA) have been shown to be effective in a range of outcomes in COPD. ICS have not been shown to reduce the rate of decline in FEV1, although short-term increases in FEV1 and significant reductions in exacerbations have been reported (Yang 2012). LABA and LAMA reduce exacerbation frequency and symptoms and improve quality of life. On the basis of the evidence, GOLD 2012 recommends that inhaled steroids should be used in patients with an FEV1 < 50% predicted (GOLD stages 3 and 4 or quadrant C and D in the 2012 update of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria) and a history of exacerbations (GOLD 2012). National Institute for Health and Care Excellence (NICE) guidelines recommend either a LABA with an ICS in a combined inhaler, or with a LAMA, if FEV1 is less than 50% predicted. Furthermore, the guidelines recommended combined ICS/LABA In people with stable COPD with an FEV1 ≥ 50% who remain breathless or have exacerbations despite maintenance therapy with a LABA (NCGC2010).

How the intervention might work

The evidence base for the addition of long-acting beta2-agonists to inhaled steroids in asthma is well established (Ducharme 2010; Ni Chroinin 2009). In asthma, the scientific rationale for combining LABA and ICS in a single inhaler relates to synergy of action. At a molecular level, ICS up-regulate the expression of beta2-agonist receptors in bronchial smooth muscle. At the same time, LABA increase the genomic actions of ICS by promoting passage to the cellular nuclei. Thus, beta2-agonists and ICS may interact in a beneficial way, with ICS preventing the loss of function of beta2-agonists with long-term use, whereas beta2-agonists may potentiate the local anti-inflammatory actions of ICS in people with asthma (Barnes 2002).

Some of these mechanisms may also be important in COPD. Several possible advantages associated with a combination of therapies have already been shown to improve outcomes. In particular, ICS in combination with LABA may have a greater effect than either treatment alone on the number of exacerbations, or on other outcomes such as quality of life (Nannini 2012; Nannini 2013). One clinical rationale is based on patient convenience, with the expectation that a simplified inhaler regimen may lead to greater treatment adherence (Barnes 2002).

Why it is important to do this review

This is an update of a previous review, which considered the effect of combined therapy compared with placebo, as well as both monocomponents separately, in people with COPD (Nannini 2004). The availability of several new studies has prompted us to split the review between comparisons with placebo and those with monocomponents. This review summarises the evidence from clinical trials comparing combined ICS and LABA with placebo. Reviews of the comparison between combined therapy and ICS (Nannini 2013) or long-acting beta2-agonists (Nannini 2012) are published separately.

Concerns have been raised recently regarding the safety of LABA in asthma (Walters 2007). Moreover, questions have surrounded the validity of summary estimates from clinical trials that assessed exacerbation rates without accounting for follow-up time or adjustment for between-participant variability (Suissa 2006). Two well-known COPD guidelines (GOLD 2012; NCGC2010) had issued a strong recommendation regarding ICS/LABA combined therapy. But others are more guarded: "Recommendation 5: ACP, ACCP, ATS, and ERS suggest that clinicians may administer combination inhaled therapies (long-acting inhaled anticholinergics, long-acting inhaled beta2-agonists, or inhaled corticosteroids) for symptomatic patients with stable COPD and FEV1 < 60% predicted (Grade: weak recommendation, moderate-quality evidence)" (ACP 2011). Finally, the largest randomised controlled trial (RCT) of combined therapy (TORCH) demonstrated a significant reduction in mortality versus placebo (P = 0.052). We wished to see whether other combined inhalers had a similar effect.

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

Randomised, double-blind, parallel-group clinical trials of at least four weeks' duration.

Types of participants

Adult patients (age > 40 years) with known, stable COPD fulfilling American Thoracic Society (ATS), European Respiratory Society (ERS) or Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria. Patients were to be clinically stable with no evidence of an exacerbation for one month before study entry. Patients with significant diseases other than COPD (e.g. with 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 versus placebo (FPS).

  • Budesonide/formoterol versus placebo (BDF).

  • Mometasone furoate/formoterol versus placebo (MF/F).

Concomitant therapy was permitted, as long as no systematic difference was noted between treatment groups; however, trials in which participants were randomly assigned to tiotropium and combined ICS/LABA therapy versus tiotropium and placebo were excluded from the review, as this comparison is already considered in Karner 2011.

Types of outcome measures

Primary outcomes
  • Exacerbations, measured as rate or number of participants experiencing an exacerbation.

  • All-cause mortality.

  • Pneumonia.

  • Hospitalisations due to COPD exacerbation (note that we accepted COPD reported as a serious adverse event as a surrogate marker for this outcome; the internationally recognised definition of a serious adverse event includes a life-threatening event or one that results in hospitalisation or prolonged hospitalisation).

Secondary outcomes
  • Change in forced expiratory volume in 1 second (FEV1) and change in forced vital capacity (FVC): trough, peak and average and other measures of pulmonary function.

  • Exercise performance: six-minute walk and other measures.

  • Quality of life scales: St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Disease Questionnaire (CRDQ).

  • Symptoms.

  • Inhaled rescue medication used during the treatment period and other concomitant medications used, including antibiotics and steroids.

  • 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.

  • Withdrawal due to adverse events.

Search methods for identification of studies

Electronic searches

We identified trials using the Cochrane Airways Group Specialised Register of trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we also handsearched respiratory journals and meeting abstracts (see Appendix 1 for more 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 most recent search was done in June 2013. We applied no restrictions on language of publication or publication type.

Searching other resources

We reviewed reference lists of all primary studies and review articles for additional references, and we contacted authors of identified randomised trials about other published and unpublished studies. In addition, we consulted the online trial registries of GlaxoSmithKline and AstraZeneca, manufacturers of FPS and BDF, respectively (www.ctr.gsk.co.uk; www.astrazenecaclinicaltrials.com).

Data collection and analysis

Selection of studies

Two review authors (LJN and PP) independently identified abstracts of trials that appeared potentially relevant. Using the full text of each study, these review authors independently selected trials for inclusion in the review. Consensus was by simple agreement, with third party adjudication used to resolve differences.

Data extraction and management

Two review authors (RN and RH) independently extracted data from included trials. RN entered the data into Review Manager, and this work was checked by RH. In some cases, we estimated information regarding outcomes from graphs. This was performed independently. Data extraction included the following items.

  • Design: method of randomisation, presence and type of run-in period, study design (parallel, cross-over).

  • 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: as above.

Assessment of risk of bias in included studies

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

Measures of treatment effect

For dichotomous variables, data are expressed as odds ratios (OR) with 95% confidence intervals (CI). Data for continuous variables were reported as mean differences (MD) with 95% CI.

Unit of analysis issues

The unit of analysis was the participant.

Dealing with missing data

We contacted study sponsors and primary investigators to obtain information that we could not verify by reviewing the study reports.

We used reported confidence intervals or P values to calculate standard deviations, or standard errors, when necessary.

Assessment of heterogeneity

For pooled effects, heterogeneity was assessed by using the I2 measurement. This estimates the degree of variation between studies not attributable to the play of chance. I2 was interpreted in relation to the following guidance (Higgins 2011).

  • 0% to 40%: may not be important.

  • 30% to 60%: may represent moderate heterogeneity.

  • 50% to 90%: may represent substantial heterogeneity.

  • 75% to 100%: may represent considerable heterogeneity (Higgins 2011).

We also considered the Chi2 test (P value < 0.10). We regarded I2 as our primary measure of heterogeneity.

Assessment of reporting biases

We evaluated publication bias by using visual inspection of funnel plots when an adequate number of trials were aggregated in the analyses (more than ten). 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

For continuous variables, we used a fixed-effect mean difference (MD) for outcomes measured on the same metric. A standardised mean difference (SMD) with 95% confidence interval (95% CI) was calculated for outcomes when data were combined from studies using different metrics. All similar studies were pooled using fixed-effect MD/SMD and 95% CI.

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

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 a Rate Ratio (RR). This method (GIV) was not available when the protocol was written for the review, so it was not prespecified.

We used pooled OR with 95% CI to calculate numbers needed to treat for an additional beneficial outcome (NNTB) or harm (NNTH) using Visual Rx. Control event rates were taken from the event rates in the individual trials and are reported with the corresponding duration of the trial because NNTs are time dependent (Cates 2012).

Subgroup analysis and investigation of heterogeneity

We separated the types of steroids and long-acting beta2-agonists, and for the new studies included in this update, we also separated differing dosages of the same drug. We planned the following a priori subgroups.

  • Disease severity (related to baseline FEV1 and placebo group exacerbation rate) according to GOLD staging of IIA or IIB (moderate COPD, characterised by deteriorating lung function (IIA = FEV1 ≤ 80% predicted; IIB = ≤ 50% predicted) with progression of symptoms) and III (severe COPD, characterised by severe airflow limitation (FEV1 < 30% predicted) and the presence of respiratory failure or clinical signs of right heart failure (GOLD 2012).

  • Prior inhaled corticosteroid plus long-acting beta2-agonist use (dichotomised as yes/no).

  • Concurrent therapy with routine beta2-agonist (short- or long-acting), corticosteroid (systemic or inhaled) or theophylline (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% post-bronchodilator (metered-dose inhaler (MDI) salbutamol 200 to 400 mcg).

  • Dose, duration and delivery method of therapy.

Sensitivity analysis

For pooled effects, heterogeneity was to be tested by using the I2 measurement of the degree of variation between studies, not attributable to the play of chance. If heterogeneity was found (I2 statistic > 30%), 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 using a sensitivity analysis based on the quality of the trials when possible.

Results

Description of studies

Results of the search

For details of the search history, see Table 1.

Table 1. Search history
VersionDetail
First published version—Issue 4, 2003 (all years to April 2002)References identified: 34
References retrieved: seven
Studies excluded: three (Cazzola 2000; Chapman 2002; Soriano 2002)
Studies identified from supplementary searching: four (Dal Negro 2003; Hanania 2003—both included; Cazzola 2002a; Cazzola 2004—both excluded).
Studies included: four
Second published version—Issue 3, 2004 (April 2003 to April 2004)References identified: 12
References retrieved: three (two papers full publications of previously included or cited studies (Dal Negro 2003; Hanania 2003). Handsearching identified two further references to the COSMIC 2003 study
Studies identified from supplementary searching: one (TRISTAN 2003)
New studies included: two
Total studies included: six
Third published version—Issue 3, 2005 (April 2004 to April 2005)References identified: 52
References retrieved: 46 (references to studies already included/excluded/ongoing: 24)
New unique studies identified: 10 (ongoing studies: two)
New studies included: zero
Total studies included: six
Fourth published version (April 2005 to April 2007)References identified: 66
References retrieved: 27 (references to studies already included/excluded/ongoing)
New unique studies identified: five (ongoing studies: zero)
New studies included: five
Total studies included: 11
Fifth published version (April 2007 to June 2013)

References identified: 129

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

New studies included: eight

Total studies included: 19

Included studies

Nineteen studies are included in this review. A previous ongoing study, Morgan 2004, has ow been linked to the TRISTAN trial. For a full description of baseline characteristics, methods used and inclusion and exclusion entry criteria for the individual studies, see Characteristics of included studies.

Design

All trials had a randomised, double-blind, parallel-group design and were of at least four weeks' duration. Methods of randomisation were described in six studies (Bourbeau 2007; Lapperre 2009; Mahler 2002; Sin 2008; Tashkin 2008; Tashkin 2012). The method of blinding was not fully described in all studies. Through correspondence from GlaxoSmithKline, trial methodology was confirmed for TRISTAN, and AstraZeneca confirmed the methodology for Szafranski 2003. Study characteristics were sufficiently described in two data sets without journal publication to justify their inclusion in the review (SFCT01 and SCO104925).

Participants

A total of 10,400 participants were randomly assigned to interventions within studies included in this review. Participants suffered from COPD, with variable definitions of COPD and reversibility. COPD was defined by national or international criteria as follows: ATS (Hanania 2003; Mahler 2002); ERS (TORCH; TRISTAN); or GOLD (Barnes 2006; Bourbeau 2007; Calverley 2003; Dal Negro 2003; Lapperre 2009; Sin 2008; Szafranski 2003; Zheng 2006). In seven studies, definitions were not specified or were based on lung function tests and smoking history (Doherty 2012; O'Donnell 2006; Rennard 2009; SCO104925; SFCT01; Tashkin 2008; Tashkin 2012). Participant populations in the studies suffered from moderate to very severe COPD, with the exception of Bourbeau 2007, in which participants with mild COPD were also enrolled, and Sin 2008, in which enrolled participants had FEV1 < 80% predicted. Two studies enrolled participants with reversible or non-reversible COPD (Hanania 2003; Mahler 2002). In TORCH, participants were not required to have had previous exacerbations requiring oral steroids or antibiotics to be included in the study. All participants were required to have a smoking history, with the exception of those enrolled in Zheng 2006, which included both smokers and never smokers.

Interventions

All 19 studies compared combination therapy with placebo, but the therapies varied. Thirteen studies compared FPS with placebo, four compared BDF and two compared MF/F. In three of the FPS studies, the combination of ICS/LABA was 250 mcg/50 mcg twice daily (Dal Negro 2003; Hanania 2003; O'Donnell 2006). In the remainder of the FPS studies, the dose was 500 mcg/50 mcg twice daily. Previous versions of this review did not consider these dosage groups separately, and as the participant numbers are small, this has not been changed in the current update. In Calverley 2003 and Szafranski 2003, the combination ICS/LABA was BDF 320 mcg/9 mcg twice daily, whereas both Rennard 2009 and Tashkin 2008 included two combined inhaler active treatment arms: BDF 320 mcg/9 mcg twice daily and 160 mcg/9 mcg twice daily. The two studies of MF/F, Doherty 2012 and Tashkin 2012, also included two combined inhaler active treatment arms: 400/10 twice daily and 200/10 twice daily.

The nature of the run-in period varied between studies, but studies generally included a two- to four-week washout period from inhaled long-acting medication. In one study, all participants had a two-week run-in treatment with oral corticosteroids, inhaled formoterol and as required a short acting beta2-agonist (SABA) (Calverley 2003). Full details are given in the tables of included studies.

Concomitant therapy was as-needed SABA, short-acting muscarinic antagonists (SAMA) and, in some studies, tiotropium. In five studies, theophylline was also used. Eleven per cent of participants in Hanania 2003 and all 18 participants in Dal Negro 2003 received theophylline, in addition to the study drugs. One participant in the FPS group in Bourbeau 2007 used theophylline. The exact proportion of participants in TRISTAN who were taking theophylline was not reported. In Zheng 2006, 2.7% of the active treatment group used theophylline compared with 7.4% of the placebo group. Oral steroids and/or antibiotics were used in all studies in the case of exacerbations.

Duration
Outcomes

The definition of an exacerbation varied between the included studies, and all definitions are summarised in Appendix 2. Hanania 2003 and Mahler 2002 withdrew participants whose condition was exacerbated. Lung function, if reported, was measured as FEV1 or peak expiratory flow (PEF). Quality of life assessment by SGRQ or CRDQ was available for Calverley 2003; Doherty 2012; Hanania 2003; Mahler 2002; Rennard 2009; SFCT01; Szafranski 2003; Tashkin 2008; Tashkin 2012; TORCH; TRISTAN; and Zheng 2006. In addition, breathlessness, cough and sputum score (BCSS) was reported by Rennard 2009 and Tashkin 2008. All-cause mortality was reported by TORCH.

Excluded studies

Studies that did not meet the entry criteria of this review are listed in Characteristics of excluded studies, together with a reason for exclusion.

Risk of bias in included studies

A summary of the risk of bias assessment for each trial is provided in Figure 1.

Figure 1.

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

Allocation

Most of our judgements on allocation procedures were unclear because of the paucity of information provided in the trial reports. We were able to ascertain a low risk of bias in four large studies (Szafranski 2003; Tashkin 2012; TORCH; TRISTAN) and in one smaller study (Sin 2008). However, as most included studies are industry-sponsored, they are extremely likely to have followed gold standards for both random sequence generation and concealment of allocation and therefore to be at low risk of bias.

Blinding

All studies were 'double-blinded', and the authors stated that identical inhaler devices were used to deliver active treatment and placebo; they therefore are likely to be at low risk of performance and detection bias. However, in all trials, further details of participant and assessor blinding were not given.

Incomplete outcome data

Most studies had high attrition rates and therefore were deemed to be at unclear or high risk of bias for all outcomes, including mortality. The TORCH trial, however, attempted to follow up all participants for their vital status and therefore was deemed to be at low risk of bias for this outcome. It should be noted that attrition rates reported in the included studies are in keeping with, if not lower than, those expected in COPD trials; therefore these studies are at low risk of bias when compared with similar trials in this field.

Selective reporting

Most included studies reported all prespecified outcomes and were deemed to be at low risk of reporting bias.

Other potential sources of bias

Both SCO104925 and SFCT01 are pharmaceutical company reports that have not been published in the peer-reviewed literature. However, the trials were sufficiently described to warrant their inclusion and are likely to be at low risk of bias.

Effects of interventions

See: Summary of findings for the main comparison Combined inhalers versus placebo (primary outcomes) for chronic obstructive pulmonary disease; Summary of findings 2 Fluticasone/salmeterol (FPS) versus placebo for COPD; Summary of findings 3 Budesonide/formoterol (BDF) versus placebo for COPD; Summary of findings 4 Mometasone/formoterol (MF/F) versus placebo for COPD

Primary outcomes

Rate of exacerbations
Pooled results of all combined inhalers versus placebo

When data from seven trials (N = 7495) were pooled, the overall reduction in the rate of exacerbations when FPS or BDF was used was 0.73 (95% CI 0.69 to 0.78; Analysis 1.1); the quality of this evidence when GRADE criteria were used was rated as moderate (Summary of findings for the main comparison).

FPS versus placebo

A significant reduction was noted in the rate of exacerbations with combination therapy when compared with placebo (RR 0.74, 95% CI 0.69 to 0.80, three studies, 4255 participants; Analysis 2.1). This result was not altered by removing TRISTAN, a study for which the summary estimate may have been biased by inadequate adjustment for between-participant variability (Suissa 2006); see Figure 2. Additional analyses were performed on exacerbations with specific definitions. Compared with placebo, FPS led to fewer exacerbations requiring oral steroids (RR 0.57, 95% CI 0.52 to 0.63, three studies), less requirement for antibiotics (RR 0.60, 95% CI 0.41 to 0.88) and fewer hospitalisations (RR 0.83, 95% CI 0.7 to 0.97, two studies).

Figure 2.

Forest plot of comparison: 1 Combined inhalers versus placebo (primary outcomes), outcome: 1.1 Exacerbation rates with combined inhalers versus placebo.

BDF versus placebo

A significant effect on pooled exacerbation rates favoured BDF compared with placebo (RR 0.71, 95% CI 0.62 to 0.81); see Figure 2. These results are based on data on 3240 participants from four trials (Szafranski 2003; Calverley 2003; Rennard 2009 and Tashkin 2008).

Number of people experiencing at least one exacerbation
FPS versus placebo

No significant difference was noted between FPS and placebo in terms of the number of participants experiencing at least one exacerbation (OR 0.83, 95% CI 0.64 to 1.07, seven studies, 1817 participants; Analysis 2.2)

MF/F versus placebo

The odds ratio for the numbers of participants experiencing at least one exacerbation for the 400/10 strength inhaler was 0.72 (95% CI 0.54 to 0.95, 882 participants; Doherty 2012; Tashkin 2012) and 0.76 (95% CI 0.58 to 1.01) for the 200/10 strength inhaler (886 participants; Doherty 2012; Tashkin 2012).

The point estimates are very similar, and the test for subgroup differences is negative. Thus it cannot be inferred from these results that one strength inhaler is significantly different from another (Chi² = 0.10, df = 1, P = 0.75, I2 = 0%).

Of interest, a post hoc observation was made that the treatment effect is more pronounced when only participants with moderate or severe exacerbations are considered, that is, those requiring antibiotics and/or systemic steroids, emergency treatment or hospitalisation (OR 0.57, 95% CI 0.38 to 0.86 for 400/10; and OR 0.62, 95% CI 0.42 to 0.92 for 200/10; Analysis 4.2).

Mortality
Pooled results of all combined inhalers versus placebo

When results were pooled, the overall reduction in mortality with FPS, BDF or MF/F compared with placebo was 0.82 (95% CI 0.68 to 0.99, 16 studies, N = 10,129); the quality of this evidence was rated as moderate (Summary of findings for the main comparison). Most of the weight for mortality comes from the TORCH trial, which is the only included trial that collected mortality as a primary outcome.(Figure 3).

Figure 3.

Forest plot of comparison: 1 Combined inhalers versus placebo (primary outcomes), outcome: 1.2 Mortality.

Because differing length of follow-up across studies hinders the calculation of a pooled NNTB, we have tabulated this for each study individually (see Table 2). The three-year NNTB (using the baseline risk of 15.2% in the placebo arm of TORCH) to prevent one extra death is 42 (95% CI 24 to 775).

Table 2. Rates and NNTB of mortality and NNTH of pneumonia
Study IDStudy duration

Placebo rate (%)

mortality

NNTB for mortality

Placebo rate (%)

pneumonia

NNTH for pneumonia
TORCH156 weeks15.242 (24 to 775)12.317 (27 to 12)
TRISTAN52 weeks1.94292 (164 to 5256)0.83197 (339 to 131)
Calverley 200352 weeks1.95249 (149 to 1307)3.648 (82 to 32)
Szafranski 200352 weeks4.5110 (66 to 581)0N/A
Rennard 200952 weeks0.83674 (379 to 12,149)4.7837 (63 to 25)
Tashkin 200826 weeks0.331689 (950 to 30,403)1164 (282 to 109)
Doherty 201226 weeks0.85659 (370 to 11,865)0.85193 (331 to 128)
Tashkin 201226 weeks0.471187 (668 to 21,377)0.47346 (595 to 229)
Mahler 200224 weeks1.66340 (191 to 6125)0N/A
O'Donnell 20068 weeks0N/A1.56107 (182 to 71)
FPS versus placebo

The adjusted hazard ratio (HR) from TORCH did not identify a significant effect of FPS over placebo (HR 0.825, 95% CI 0.681 to 1.002, P = 0.052; TORCH). When the number of deaths in each treatment group was analysed by odds ratio and was combined with data from four other studies, a significant reduction in the odds of death favoured FPS versus placebo (OR 0.79, 95% CI 0.65 to 0.97, N = 5543, 10 studies; Analysis 2.5). Data were separated according to the time point and were subgrouped for data reported at three years, data at one to three years, data at one year and data at six months.

BDF versus placebo

The four studies with duration of six months to one year involving 3250 participants did not detect a significant difference in mortality between BDF and placebo (OR 1.05, 95% CI 0.57 to 1.93; Analysis 3.3).

MF/F versus placebo

Neither of two very similar studies (Doherty 2012; Tashkin 2012) of 26 weeks' duration and including 1336 participants detected a significant difference between MF/F and placebo (OR 1.35, 95% CI 0.36 to 5.13; Analysis 4.3).

However, it should be noted that the confidence intervals for both MF/F and BDF are wide and overlap with those of FPS, so a decrease in mortality with MF/F or BDF cannot be excluded.

Pneumonia
Pooled results of all combined inhalers versus placebo

For combined inhalers, the pooled OR for pneumonia is 1.62 (95% CI 1.36 to 1.94, N = 9620, fixed-effect model) with a moderate level of heterogeneity (I2 = 32%); the quality of this evidence was rated as moderate (Summary of findings for the main comparison). When a random-effects model of analysis is used, the effect size is reduced but remains significant (OR 1.57, 95% CI 1.01 to 2.42). Most of the weight for this combined result again comes from the TORCH trial, which tested the FPS inhaler.

FPS versus placebo

Pooled data from nine FPS trials (N = 5447) show a significant increase in pneumonia among participants treated with FPS in comparison with placebo (OR 1.76, 95% CI 1.46 to 2.14; Figure 4).

Figure 4.

Forest plot of comparison: 1 Combined inhalers versus placebo (primary outcomes), outcome: 1.3 Pneumonia.

BDF versus placebo

Calverley 2003, Rennard 2009 and Tashkin 2008 reported data on pneumonia; no significant difference was detected between BDF and placebo (OR 0.92, 95% CI 0.57 to 1.47). The test for subgroup differences between BDF and FPS was significant (P = 0.01) when a fixed-effect model was used. However, when a random-effects model was applied, no significant difference between subgroups was found (P = 0.65).

MF/F versus placebo

Data from Doherty 2012 and Tashkin 2012 suggest no significant difference between treatments in diagnoses of pneumonia (OR 2.39, 95% CI 0.68 to 8.36, N = 1336), but the test for a subgroup difference between MF/F and FPS was negative for both fixed-effect and random-effects models (P = 0.64 and 0.66, respectively).

Table 2 gives the range of numbers needed to treat for an additional harmful outcome (NNTH) across the studies for pneumonia. A pooled NNTH was not calculated because of the wide differences in duration and the likely impact this would have on the calculation of a pooled event rate. The three-year NNTH (when the baseline risk of 12.3% was used in the combination therapy arm of TORCH) for one extra participant to suffer from pneumonia was 17 (95% CI 27 to 12).

Hospitalisations due to COPD
Pooled results of combined inhalers versus placebo

No significant difference was observed between active treatment and placebo for hospitalisation (OR 0.93, 95% CI 0.81 to 1.06, N = 9492; Figure 5); the quality of this evidence was rated as low (Summary of findings for the main comparison).

Figure 5.

Forest plot of comparison: 1 Combined inhalers versus placebo (primary outcomes), outcome: 1.4 Hospitalisations due to COPD exacerbations.

Secondary outcomes

Quality of life
FPS versus placebo

Treatment with FPS improved SGRQ scores by an average of -2.9 units versus placebo (95% CI -3.61 to -2.18, four studies, N = 3346). Pooled data from Mahler 2002 and Hanania 2003 indicated a statistically significant improvement in CRDQ for those treated with FPS compared with placebo (5 units, 95% CI 2.48 to 7.52).

BDF versus placebo

A significant effect favoured BDF compared with placebo: -3.29 units on the SGRQ (95% CI -4.45 to -2.13) for the 320/9 strength inhaler, and -3.39 units (95% CI -4.70 to -2.07) for the 160/9 strength inhaler. A high level of heterogeneity was noted when these data were pooled (I2 = 70%). Random-effects modelling also generated a significant effect (MD -4.11, 95% CI -6.18 to -2.04 for 320/9; and MD -3.39, 95% CI -4.70 to -2.07 for 160/9). The magnitude of improvement in the Szafranski 2003 BDF group was 3.9 units from baseline and was not dissimilar from the change scores from post run-in treatment in Calverley 2003 (see graphical presentation of data in the published article, page 916). However, the placebo group deteriorated more in Calverley 2003, which possibly reflects the withdrawal of active treatment, with the subsequent loss of predosing effects achieved with high-dose oral corticosteroids and LABA. In comparison, BDF may have maintained the predosing treatment effects of quality of life more successfully.

MF/F versus placebo

Treatment with MF/F resulted in a significant improvement in SGRQ scores when compared with placebo. This was true for both 400/10 (MD -3.80, 95% CI -5.75 to -1.86) and 200/10 (MD -3.91, 95% CI -6.01 to -1.81) inhalers.

Symptom score
FPS versus placebo

FPS led to improved symptom scores (transitional dyspnoea index) when compared with placebo (MD 1.04, 95% CI 0.56 to 1.53).

BDF versus placebo

Data were pooled for Calverley 2003 and Szafranski 2003. There was a significant effect in favour of BDF when compared with placebo (MD -0.63, 95% CI -0.90 to -0.37).

Rennard 2009 and Tashkin 2008 reported change from baseline in the breathlessness, cough and sputum score. Both trials described a significant improvement in average score over the treatment period for both strengths of combined inhalers (MD -0.43, 95% CI -0.59 to -0.26 for 320/9; and MD -0.44, 95% CI -0.60 to -0.28 for 160/9).

Lung function
FPS versus placebo

Pooled analysis of data was conducted without findings from the Dal Negro 2003 study. Owing to the small size of this study, we were concerned that the standard deviation (SD) represented an inaccurate estimate for the SD of the population, and that the small variance increased the weight of the study out of all proportion to its size. Data pooled from seven studies revealed an MD in predose FEV1 of 0.16 L (95% CI 0.14 to 0.19, N = 1408). Pooled data from Zheng 2006 and TORCH for postdose FEV1 indicated a significant improvement in favour of FPS over placebo of 0.09 L (95% CI 0.07 to 0.11). Results from Rennard 2009 demonstrate a clear improvement in average 0- to 12-hour FEV1 for inhalers of both strengths.

BDF versus placebo

FEV1 data for mean percentage change from baseline were reported by two trials (Calverley 2003; Szafranski 2003). There was a significant increase in FEV1 in favour of BDF versus placebo (MD 14.40% 95%CI 11.91 to 16.90).

Predose FEV1 and one hour postdose FEV1 data were reported by one study, which included 858 participants (Tashkin 2008). A significant improvement was noted for both outcomes for combined inhalers of both strengths compared with placebo. Rennard 2009 reported average 12-hour FEV1 and FEV1 at 12 hours compared with baseline. Again, a significant improvement was noted for both outcomes and for inhalers of both strengths when compared with placebo.

Both Rennard 2009 and Tashkin 2008 reported change from baseline morning and evening PEF, with significant benefit over placebo noted for inhalers of both strengths.

MF/F versus placebo

Both Doherty 2012 and Tashkin 2012 reported mean change from baseline in predose FEV1 at 13 weeks and demonstrated a significant improvement for both 400/10 (MD 114.64, 95% CI 77.79 to 151.50) and 200/10 (MD 66.00, 95% CI 14.37 to 117.63) inhalers when compared with placebo. It should be noted that no significant difference was seen between the 400/10 and 200/10 groups (test for subgroup differences: Chi2 = 2.77, df = 1, P = 0.10).

Mean change from baseline FEV1 area under the curve (AUC) 0 to 12 hours is also reported by Doherty 2012 and Tashkin 2012 and shows significant improvement in favour of active treatment for inhalers of both strengths (MD 162.04, 95% CI 126.54 to 197.53 for 400/10; and MD 122.01, 95% CI 86.64 to 157.39 for 200/10).

Rescue medication
FPS versus placebo

Pooled data from Mahler 2002 and Hanania 2003 indicated a significant reduction in mean puffs per day of short-acting beta2-agonist usage for FPS versus placebo (MD -1.19 puffs/d, 95% CI -1.83 to -0.55).

Mahler 2002 reported significant increases in the percentage of nights with no awakenings requiring short-acting beta2-agonist in favour of FPS versus placebo (5.7% vs -4.3%, respectively; P < 0.031).

TRISTAN reported a significant difference in median percentage of days without use of relief medication (FPS 14% vs placebo 0%, P < 0.001).

BDF versus placebo

BDF treatment reduced the requirement for reliever medication when compared with placebo. Combined results of Szafranski 2003; Calverley 2003; Rennard 2009 and Tashkin 2008 for the 320/9 strength inhaler show a reduction in use of rescue medication when compared with placebo (-0.98 puffs/d, 95% CI -1.18 to -0.79). Pooled results from Rennard 2009 and Tashkin 2008 compare the 160/9 strength inhaler with placebo and also reveal a reduction in the use of rescue medication (-1.28 puffs/d, 95% CI -1.55 to -1.00)

Safety and tolerability
FPS versus placebo

No significant difference was noted between FPS and placebo in the occurrence of overall reported adverse events (OR 1.09, 95% CI 0.95 to 1.25) or serious adverse events (OR 1.08, 95% CI 0.95 to 1.23, N = 5574, nine studies). In both cases, the quality of evidence was rated as low (Summary of findings 2).

Pneumonia, candidiasis, nasopharyngitis, hoarseness and upper respiratory tract infection (URTI) occurred more frequently among FPS-treated participants.

  • Pneumonia: OR 1.80, 95% CI 1.49 to 2.18, nine studies, N = 5447.

  • Candidiasis: OR 5.73, 95% CI 3.07 to 10.67, seven studies, N = 2039.

  • Hoarseness: OR 8.79, 95% CI 1.11 to 69.62, two studies, N = 585.

  • Nasopharyngitis: OR 1.28, 95% CI 1.05 to 1.56, two studies, N = 3535.

  • URTI: OR 1.23, 95% CI 1.04 to 1.47, five studies, N = 4963.

BDF

Rennard 2009 and Tashkin 2008 report overall adverse event data and demonstrate a significant difference favouring placebo for inhalers of both 320/9 and 160/9 strength (OR 1.42, 95% CI 1.16 to 1.74 for 320/9; and OR 1.32, 95% CI 1.08 to 1.61 for 160/9). In both cases, the quality of this evidence was rated as low (Summary of findings 3).

When only serious adverse events were considered, the odds ratios were 1.17 (95% CI 0.95 to 1.45) for the 320/9 strength inhaler and 1.20 (95% CI 0.89 to 1.63) for the 160/9 strength inhaler; again, the quality of this evidence was rated as low (Summary of findings 3).

No difference was noted between active treatment and placebo for specific adverse events associated with ICS use, with the exception of reported episodes of candidiasis, which were noted to be significantly higher among those receiving active treatment. In addition, more cases of dysphonia were reported in the active treatment group receiving the higher-dose inhaler, but not in the lower-dose group. However, the test for subgroup differences was negative, so we cannot be certain of a dose effect.

MF/F

No significant difference in the occurrence of overall reported adverse events was reported between either strength of MF/F inhaler and placebo (OR 0.98, 95% CI 0.75 to 1.30 for 400/10; and OR 0.82, 95% CI 0.62 to 1.09 for 200/10). This finding was consistent when only serious adverse events were considered. The quality of this evidence was rated as low in both cases (Summary of findings 4).

Also, no significant differences were noted between the groups when specific adverse events associated with ICS use were considered, although the overall numbers of events were small.

Withdrawals
FPS versus placebo

Significantly fewer withdrawals from treatment were seen with FPS than with placebo (OR 0.69, 95% CI 0.62 to 0.78). Withdrawals due to adverse events and lack of efficacy also occurred less frequently on treatment with FPS than with placebo (withdrawal due to adverse event: OR 0.74, 95% CI 0.64 to 0.86, twelve studies, 5491 participants; withdrawal due to lack of efficacy: OR 0.30, 95% CI 0.22 to 0.41, eight studies, 5115 participants).

BDF versus placebo

Data were pooled from Calverley 2003; Rennard 2009; Szafranski 2003; and Tashkin 2008 for withdrawals due to adverse events, and from Calverley 2003; Rennard 2009 and Szafranski 2003 for withdrawals due to lack of efficacy or worsening COPD.

A significant difference favoured active treatment in withdrawals due to worsening of COPD symptoms when BDF was compared with placebo (OR 0.56, 95% CI 0.43 to 0.74, three studies, 2392 participants).

No significant difference was noted between BDF and placebo in the likelihood of withdrawal due to any adverse event (OR 0.85, 95% CI 0.70 to 1.03).

MF/F versus placebo

Significantly fewer withdrawals from treatment were seen with MF/F than with placebo for inhalers of both strengths (OR 0.56, 95% CI 0.40 to 0.77 for 400/10; and OR 0.55, 95% CI 0.40 to 0.76 for 200/10).

Of note, a significant difference favoured MF/F when withdrawals due to lack of efficacy of treatment or worsening of COPD symptoms were considered. This was true for inhalers of both strengths (OR 0.24, 95% CI 0.08 to 0.74 for 400/10; and OR 0.31, 95% CI 0.11 to 0.84 for 200/10).

Discussion

Summary of main results

We reviewed data from 19 randomised controlled trials (10,400 participants) assessing the efficacy and safety of combined inhaled corticosteroids and long-acting beta2-agonists versus placebo for the treatment of COPD. Thirteen studies involved a combined inhaler of fluticasone and salmeterol, four involved budesonide and formoterol and two involved mometasone and formoterol. The findings of this review complement those of two others assessing the effects of combination inhalers with their components, that is, LABA or ICS (Nannini 2012; Nannini 2013). Despite the addition of eight new studies for this update, most of the weight is still coming from the TORCH study, which is the largest trial of combined therapy (FPS) in COPD.

Primary outcomes

The main findings related to the primary outcomes of exacerbations, mortality, pneumonia and hospitalisations appear in the Summary of findings for the main comparison. All eligible studies addressed at least one of the primary outcomes.

Combined therapy reduced the rate of moderate exacerbations compared with placebo by about a quarter (Analysis 1.1). But, as was found in the Cochrane reviews comparing combined inhalers with LABA alone or ICS alone (Nannini 2013), this did not translate to a statistically significant reduction in COPD hospitalisation rates. One explanation is that those receiving combined treatment who respond may have fewer and/or milder exacerbations, but equally the smaller number of hospitalisations means that less statistical power was present to show a significant difference. On the other hand, adverse effects were more common with combined treatment than with placebo, particularly the development of pneumonia. The NNTH for this outcome in studies of at least 52 weeks' duration varied from 17 to 197. Concern about pneumonia as an adverse event associated with ICS treatment has persisted ever since TORCH was published in 2006. Indeed our analysis shows that the excess of pneumonia is seen only with FPS, not with the other combined inhalers. If the TORCH study was not included, the significant OR disappeared, but heterogeneity among trials is still evident (Analysis 1.3), making it difficult to decide whether this effect is a true one. This may suggest ongoing difficulties with the accurate identification of pneumonia, or variations in participant populations, actions of medicines or the nature of lower respiratory tract infections and their treatment over the time course of a study. It is also possible that the heterogeneity in the pneumonia outcome is due to differential withdrawal rates. Withdrawal due to lack of efficacy in the FPS subgroup was greater in the placebo arm (Analysis 2.14), as was seen with BDF (Analysis 3.18) and MF/F studies (Analysis 4.8). It is interesting to note that withdrawals due to adverse events were not different between arms in BDF (Analysis 3.17), whereas for MF/F studies, withdrawals due to adverse events were greater in the placebo arm (Analysis 4.9). These findings suggest something different about the three-year TORCH study compared with the others. Whatever the case, it is reassuring that this apparent excess of pneumonia cases did not translate into greater numbers of hospitalisations or exacerbations, or greater mortality rates. In fact, quite the opposite was noted—exacerbation rates and mortality were reduced with combined treatment.

We found that treatment with a combined inhaler led to a significant reduction in mortality compared with placebo when data from all studies were pooled. As with other outcomes, TORCH had a major influence on mortality; however, it should be noted that the TORCH investigators did not claim a significant reduction in mortality with FPS over placebo (P = 0.052). The difference between the study report and the OR reported in this Cochrane review may be due to variations in statistical methods. TORCH used a hazard ratio that was adjusted for repeated measurement. Furthermore, although mortality was recorded in many of the studies, it was a primary outcome in TORCH. In that study, cause-specific mortality was also reported, but the definition of a primary cause of death continues to pose challenges in a population of patients who may suffer from co-morbidities such as lung cancer (McGarvey 2007).

Secondary outcomes

We were unable to pool secondary outcomes and reported results for each type of combined inhaler separately. Although the only way to test whether one product is better than another is a head-to-head comparison, we found that the results for all secondary outcomes, except adverse events, were relatively similar, that is, each combined inhaler showed a small benefit over placebo in effects on health-related quality of life, symptoms, lung function, use of rescue medication and withdrawal rates. In some cases, the benefits reached accepted levels of clinical significance, but only just. Minimal clinical important differences (MCID) are sometimes used to help clinicians interpret trial findings in a meaningful way. The MCID for predose FEV1 is thought to be approximately 100 mL (Donohue 2005). Leidy 2003 suggests that changes of 1.0 in the BCSS represent substantial symptomatic improvement, changes of approximately 0.6 can be interpreted as moderate and changes of 0.3 can be considered small. A four-unit difference is the generally accepted MCID for SGRQ score (Jones 2005). Mean differences reflect an unknown range of results from individual participants, and although an MCID may be achieved on average, this neither confirms nor rules out meaningful improvement over placebo for all. Furthermore, for some of these outcomes, a high degree of heterogeneity was noted, some of which may be due to differences in study protocols.

Overall completeness and applicability of evidence

Participants and outcomes reported were typical of those described for COPD patients. The most abundant evidence comes from studies on the FPS combination, which was the only one to show a mortality benefit. Fewer data are available for the MF/F combination, but nothing has been discovered to suggest that it behaves differently from the other inhalers.

Quality of the evidence

Most trials were industry-sponsored. The risk of bias in blinding was considered low for all trials. The risk of bias from attrition was considered higher because of the number of participants withdrawn (over 20% in most trials), especially as this group may represent a more severely involved subgroup (Kesten 2007). In addition, we found significantly greater participant withdrawal in the placebo arm across all three combined inhalers (Analysis 2.12, Analysis 3.16 and Analysis 4.7). However, the completion rate in the included trials was generally equal to, or better than, that of other trials involving participants with COPD. Selective reporting was generally considered to be of low risk.

Intention-to-treat analyses were conducted in all studies, but for outcomes such as mean exacerbation rates, withdrawal of severe frequent exacerbators from the studies may have distorted study findings because of the lower exacerbation rates seen with active treatment. Loss of participants with more frequent exacerbations from the studies may thus limit the accuracy of mean event rates. The question of exacerbations and the appropriate statistical analysis of rate ratios cast some doubt regarding the validity of some of the findings in this review. In particular, the large long-term studies (i.e. those in excess of six months), which are adequately powered to detect statistically significant findings, may overestimate the treatment effects of this therapy (Suissa 2006). The method of weighting counts of exacerbations as described by Suissa 2006 (using duration of person follow-up time as a denominator in calculating the mean group rate of exacerbations rather than an unweighted approach) was undertaken in Calverley 2003; Szafranski 2003;and TORCH. In these studies, the effects were consistent and significantly favoured combination therapy over placebo. However, the major primary outcome after mortality rate was hospitalisation due to COPD exacerbation, and this did not show any difference between treatments.

Visual inspection of a funnel plot for the mortality outcome does not suggest publication bias (Figure 6).

Figure 6.

Funnel plot of comparison: 1 Combined inhalers versus placebo (primary outcomes), outcome: 1.2 Mortality.

Potential biases in the review process

The Cochrane Airways Group provided an excellent level of support in the identification of potentially relevant trials. To minimise the risk of selection and publication bias, an exhaustive search of the published literature and the unpublished literature, with no language restrictions, for potentially relevant clinical trials was underpinned by a systematic search strategy. Trial selection and data extraction followed a prespecified protocol, and the process was independently conducted by two review authors. 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 2004) and upon related reviews (Nannini 2012; Nannini 2013). For this update, we checked all previous data and added hospital admissions using COPD-related serious adverse events as a surrogate marker. To enhance clarity, several outcomes in the FPS subgroup with few contributing studies have been deleted from the current update. We have added data for MF/F versus placebo, as these studies took place after the previous review.

Our finding that combined inhaler therapy reduced death is concordant with that of another review of all inhaled medications in COPD, which concluded that ICS/LABA was associated with the lowest risk of death among all treatments (Dong 2013).

Authors' conclusions

Implications for practice

For people with moderate or severe COPD, clinical benefit is derived when a long-acting beta2-agonist and an inhaled corticosteroid are coadministered, compared with treatment with placebo, in terms of fewer exacerbations and possibly reduced risk of death. Furthermore, small benefits for quality of life and symptoms are noted. However, the effect of combined treatment on all-cause mortality is heavily weighted by one trial, which in itself was not reported to show a significant reduction. (This point added value to this review because the TORCH study alone did not achieve significance in mortality.) Despite positive effects on exacerbations and mortality, no effect on hospitalisation was reported. Moreover, a paradoxical finding indicates that fluticasone/salmeterol led to an increased risk of pneumonia. The NNTH to cause one additional case of pneumonia may be as low as 17, whereas the NNTB to prevent one death during the study period is 42.

Guidelines suggest that patients with symptomatic moderate to severe COPD should be given LABA or LAMA and possibly ICS; therefore it could be argued that this review is redundant. However, this review increased the level of evidence supporting the use of combined therapy (LABA/ICS) in COPD category "D" (GOLD 2012). On the other hand, this review shows that use of a combination inhaler is not associated with large benefit in terms of symptoms or quality of life over placebo. The high attrition rate presented in many studies (in TORCH, 56% completed in the placebo group) could have overshadowed the benefits of those outcomes. Our review therefore supports the current widely accepted guidance for a stepwise approach to treatment of patients with mild or moderate disease. Combined therapy seems best indicated for COPD patients with postbronchodilator FEV1 < 60% and frequent exacerbations and/or hospitalisations.

Whether a combination is better than the two components taken separately was not addressed in this review.

Implications for research

Any study should carefully document trial participants using the new GOLD COPD grading criteria. A more standardised approach to recording of serious adverse events such as pneumonia, hospitalisation, intensive care support or death would provide a more accurate picture of the benefits and harms of the long-term effects of this form of therapy.

Pharmacoeconomic analyses would be helpful to assist purchasers of health care in making decisions about the cost-effectiveness of combined inhalers. Responder analyses should be reported; this might give an idea as to which COPD phenotypes may provide the greatest benefit.

Assessment of BDF and MF/F in larger and longer trials is required to reveal whether these preparations confer benefits for mortality similar to those provided by FPS. Head-to-head trials of combined inhalers are needed if benefits are to be compared in a robust fashion.

Combined therapy should be compared with separate administration of long-acting beta2-agonist and inhaled corticosteroid at different doses in large-scale multi-centre studies using a double-dummy design, to assess whether combined therapy confers benefits over the simple addition of beta2-agonist to different doses of inhaled steroid treatment in separate inhalers. A lower dose of ICS might still confer therapeutic benefit while reducing the incidence of pneumonia. The high attrition rate reported in many studies might be contemplated in future studies, to maintain the capacity of calculated sample size to show significant differences in outcomes such as quality of life, hospitalisation and death rates.

Acknowledgements

The review authors are indebted to the Hamamelis Trust, which very generously funded the return travel for Dr Nannini to London to spend a week working on the development of the review. Thanks to Liz Stovold, Susan Hansen and Veronica Stewart for advice and support in developing our literature searching strategy and for assistance in retrieval of full-text papers. We also would 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 the TRISTAN and Wouters 2005 studies, and those of Goran Tornling, Moira Coughlan and Roger Metcalf of AstraZeneca in helping 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, and Dr Dal Negro (Dal Negro 2003) for confirming the SD in his study. We are grateful to Nancy Santesso for preparing the Summary of findings table for our review, and to SM, who updated the table for the current version of the review.

In 2013, the review 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 provided by 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

Download statistical data

Comparison 1. Combined inhalers versus placebo (primary outcomes)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Exacerbation rates with combined inhalers versus placebo7 Rate Ratio (Fixed, 95% CI)0.73 [0.69, 0.78]
1.1 Fluticasone/salmeterol3 Rate Ratio (Fixed, 95% CI)0.74 [0.69, 0.80]
1.2 Budesonide/formoterol4 Rate Ratio (Fixed, 95% CI)0.71 [0.62, 0.81]
2 Mortality1610129Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.68, 0.99]
2.1 Fluticasone/salmeterol105543Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.65, 0.97]
2.2 Budesonide/formoterol43250Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.57, 1.93]
2.3 Mometasone/formoterol21336Odds Ratio (M-H, Fixed, 95% CI)1.35 [0.36, 5.13]
3 Pneumonia149620Odds Ratio (M-H, Fixed, 95% CI)1.62 [1.36, 1.94]
3.1 Fluticasone/salmeterol95447Odds Ratio (M-H, Fixed, 95% CI)1.76 [1.46, 2.14]
3.2 Budesonide/formoterol32837Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.57, 1.47]
3.3 Mometasone/formoterol21336Odds Ratio (M-H, Fixed, 95% CI)2.39 [0.68, 8.36]
4 Hospitalisations due to COPD exacerbations129492Odds Ratio (M-H, Random, 95% CI)0.92 [0.80, 1.06]
4.1 Fluticasone/salmeterol75309Odds Ratio (M-H, Random, 95% CI)0.89 [0.75, 1.04]
4.2 Budesonide/formoterol32847Odds Ratio (M-H, Random, 95% CI)1.17 [0.87, 1.58]
4.3 Mometasone/formoterol21336Odds Ratio (M-H, Random, 95% CI)0.57 [0.31, 1.07]
5 Number of participants with at least one exacerbation93141Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.66, 0.93]
5.1 Fluticasone/salmeterol71817Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.64, 1.07]
5.2 Mometasone/formoterol21324Odds Ratio (M-H, Fixed, 95% CI)0.74 [0.58, 0.94]
Analysis 1.1.

Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 1 Exacerbation rates with combined inhalers versus placebo.

Analysis 1.2.

Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 2 Mortality.

Analysis 1.3.

Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 3 Pneumonia.

Analysis 1.4.

Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 4 Hospitalisations due to COPD exacerbations.

Analysis 1.5.

Comparison 1 Combined inhalers versus placebo (primary outcomes), Outcome 5 Number of participants with at least one exacerbation.

Comparison 2. Fluticasone/salmeterol (FPS) versus placebo (PLA)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Exacerbations33777Rate ratio (Fixed, 95% CI)0.74 [0.69, 0.80]
1.1 Poorly reversible population33777Rate ratio (Fixed, 95% CI)0.74 [0.69, 0.80]
2 Number of participants with at least one exacerbation71817Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.64, 1.07]
2.1 Reversible population1126Odds Ratio (M-H, Fixed, 95% CI)0.32 [0.06, 1.66]
2.2 Partially reversible population (mixed population)2713Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.69, 1.44]
2.3 Poorly reversible population3841Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.54, 1.15]
2.4 Unclear reversibility1137Odds Ratio (M-H, Fixed, 95% CI)0.31 [0.09, 1.05]
3 Participants with at least one exacerbation by type2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Requirement for oral steroids2417Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.61, 1.68]
3.2 Requirement for antibiotic treatment1140Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.26, 2.44]
3.3 Requirement for oral steroid or antibiotic treatment1140Odds Ratio (M-H, Fixed, 95% CI)3.32 [0.13, 82.80]
3.4 Hospitalisation1140Odds Ratio (M-H, Fixed, 95% CI)3.32 [0.13, 82.80]
4 Exacerbations by type3 Rate ratio (Fixed, 95% CI)Subtotals only
4.1 Requirement for oral steroids3 Rate ratio (Fixed, 95% CI)0.57 [0.52, 0.63]
4.2 Requirement for antibiotic treatment1 Rate ratio (Fixed, 95% CI)0.60 [0.41, 0.88]
4.3 Hospitalisation2 Rate ratio (Fixed, 95% CI)0.83 [0.70, 0.97]
5 Mortality105543Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.65, 0.97]
5.1 Mortality: three-year data13057Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.66, 0.99]
5.2 Mortality: one-year data3987Odds Ratio (M-H, Fixed, 95% CI)0.46 [0.13, 1.65]
5.3 Mortality: six-month data31154Odds Ratio (M-H, Fixed, 95% CI)0.54 [0.11, 2.75]
5.4 Mortality: three-month data3345Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Change from baseline in St George's Respiratory Questionnaire (total score)4 Mean Difference (Fixed, 95% CI)-2.90 [-3.61, -2.18]
6.1 Poorly reversible population4 Mean Difference (Fixed, 95% CI)-2.90 [-3.61, -2.18]
7 Change from baseline in Chronic Respiratory Disease Questionnaire scores2712Mean Difference (IV, Fixed, 95% CI)5.0 [2.48, 7.52]
7.1 Partially reversible population (mixed population)2712Mean Difference (IV, Fixed, 95% CI)5.0 [2.48, 7.52]
8 Change from baseline in Transitional Dyspnoea Index (TDI) scores2707Mean Difference (IV, Fixed, 95% CI)1.04 [0.56, 1.53]
8.1 Partially reversible population (mixed population)2707Mean Difference (IV, Fixed, 95% CI)1.04 [0.56, 1.53]
9 Change from baseline in predose FEV15 Mean Difference (Fixed, 95% CI)0.16 [0.14, 0.19]
9.1 Reversible population3 Mean Difference (Fixed, 95% CI)0.19 [0.15, 0.24]
9.2 Poorly reversible population4 Mean Difference (Fixed, 95% CI)0.15 [0.11, 0.18]
10 Change from baseline in postdose FEV12 Mean Difference (Fixed, 95% CI)0.09 [0.07, 0.11]
10.1 Poorly reversible population2 Mean Difference (Fixed, 95% CI)0.09 [0.07, 0.11]
11 Change from baseline in rescue medication usage (puffs/d)2703Mean Difference (IV, Fixed, 95% CI)-1.19 [-1.83, -0.55]
11.1 Partially reversible population (mixed population)2703Mean Difference (IV, Fixed, 95% CI)-1.19 [-1.83, -0.55]
12 Withdrawals—total135769Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.62, 0.78]
12.1 Reversible population1121Odds Ratio (M-H, Fixed, 95% CI)2.95 [0.30, 29.18]
12.2 Partially reversible population (mixed population)2709Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.60, 1.13]
12.3 Poorly reversible population64632Odds Ratio (M-H, Fixed, 95% CI)0.68 [0.60, 0.76]
12.4 Unclear reversibility4307Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.25, 1.17]
13 Withdrawals due to adverse events115491Odds Ratio (M-H, Fixed, 95% CI)0.74 [0.64, 0.86]
13.1 Reversible population1123Odds Ratio (M-H, Fixed, 95% CI)0.36 [0.01, 8.90]
13.2 Partially reversible population (mixed population)1354Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.31, 1.51]
13.3 Poorly reversible population64630Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.65, 0.89]
13.4 Unclear reversibility4384Odds Ratio (M-H, Fixed, 95% CI)0.31 [0.11, 0.93]
14 Withdrawals due to lack of efficacy85115Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.22, 0.41]
14.1 Partially reversible population (mixed population)1346Odds Ratio (M-H, Fixed, 95% CI)0.29 [0.08, 1.04]
14.2 Poorly reversible population64632Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.21, 0.42]
14.3 Unclear reversibility1137Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.08, 1.11]
15 Adverse events—any95574Odds Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.25]
15.1 Reversible population1126Odds Ratio (M-H, Fixed, 95% CI)1.20 [0.59, 2.46]
15.2 Partially reversible population (mixed population)2717Odds Ratio (M-H, Fixed, 95% CI)1.42 [1.03, 1.96]
15.3 Poorly reversible population54650Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.88, 1.21]
15.4 Unclear reversibility181Odds Ratio (M-H, Fixed, 95% CI)0.58 [0.19, 1.79]
16 Adverse events—'serious'95531Odds Ratio (M-H, Fixed, 95% CI)1.08 [0.95, 1.23]
16.1 Reversible population1123Odds Ratio (M-H, Fixed, 95% CI)0.53 [0.05, 6.05]
16.2 Partially reversible population2709Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.38, 1.35]
16.3 Poorly reversible population64699Odds Ratio (M-H, Fixed, 95% CI)1.10 [0.97, 1.26]
17 Adverse events—pneumonia95447Odds Ratio (M-H, Fixed, 95% CI)1.80 [1.49, 2.18]
17.1 Reversible population1126Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.47]
17.2 Partially reversible population (mixed population)2709Odds Ratio (M-H, Fixed, 95% CI)5.55 [0.26, 116.46]
17.3 Poorly reversible population44394Odds Ratio (M-H, Fixed, 95% CI)1.80 [1.48, 2.18]
17.4 Unclear reversibility2218Odds Ratio (M-H, Fixed, 95% CI)3.31 [0.13, 83.73]
18 Adverse events—candidiasis72039Odds Ratio (M-H, Fixed, 95% CI)5.73 [3.07, 10.67]
18.1 Reversible population1126Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.06, 16.88]
18.2 Partially reversible population (mixed population)2717Odds Ratio (M-H, Fixed, 95% CI)11.13 [3.36, 36.90]
18.3 Poorly reversible population31115Odds Ratio (M-H, Fixed, 95% CI)4.40 [2.01, 9.62]
18.4 Unclear reversibility181Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
19 Adverse events—hoarseness2585Odds Ratio (M-H, Fixed, 95% CI)1.61 [0.61, 4.26]
19.1 Poorly reversible population2585Odds Ratio (M-H, Fixed, 95% CI)1.61 [0.61, 4.26]
20 Adverse events—palpitations1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
20.1 Poorly reversible population1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
21 Adverse events—blood glucose increased1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
21.1 Poorly reversible population1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
22 Adverse event—skin bruising1445Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
22.1 Poorly reversible population1445Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
23 Adverse events—bronchitis1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
23.1 Poorly reversible population1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
24 Adverse events—upper respiratory tract infection54963Odds Ratio (M-H, Fixed, 95% CI)1.23 [1.04, 1.47]
24.1 Partially reversible population (mixed population)2709Odds Ratio (M-H, Fixed, 95% CI)1.25 [0.81, 1.92]
24.2 Poorly reversible population34254Odds Ratio (M-H, Fixed, 95% CI)1.23 [1.02, 1.48]
25 Adverse events—nasopharyngitis23535Odds Ratio (M-H, Fixed, 95% CI)1.28 [1.05, 1.56]
25.1 Poorly reversible population23535Odds Ratio (M-H, Fixed, 95% CI)1.28 [1.05, 1.56]
26 Adverse events—cough3612Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.23, 1.27]
26.1 Reversible population1126Odds Ratio (M-H, Fixed, 95% CI)3.15 [0.13, 78.72]
26.2 Partially reversible population (mixed population)1346Odds Ratio (M-H, Fixed, 95% CI)0.49 [0.18, 1.31]
26.3 Poorly reversible population1140Odds Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.48]
27 Adverse events—headache43922Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.84, 1.31]
27.1 Reversible population1123Odds Ratio (M-H, Fixed, 95% CI)0.22 [0.02, 2.01]
27.2 Partially reversible population (mixed population)2709Odds Ratio (M-H, Fixed, 95% CI)1.38 [0.91, 2.10]
27.3 Poorly reversible population13090Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.73, 1.26]
Analysis 2.1.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 1 Exacerbations.

Analysis 2.2.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 2 Number of participants with at least one exacerbation.

Analysis 2.3.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 3 Participants with at least one exacerbation by type.

Analysis 2.4.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 4 Exacerbations by type.

Analysis 2.5.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 5 Mortality.

Analysis 2.6.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 6 Change from baseline in St George's Respiratory Questionnaire (total score).

Analysis 2.7.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 7 Change from baseline in Chronic Respiratory Disease Questionnaire scores.

Analysis 2.8.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 8 Change from baseline in Transitional Dyspnoea Index (TDI) scores.

Analysis 2.9.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 9 Change from baseline in predose FEV1.

Analysis 2.10.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 10 Change from baseline in postdose FEV1.

Analysis 2.11.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 11 Change from baseline in rescue medication usage (puffs/d).

Analysis 2.12.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 12 Withdrawals—total.

Analysis 2.13.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 13 Withdrawals due to adverse events.

Analysis 2.14.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 14 Withdrawals due to lack of efficacy.

Analysis 2.15.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 15 Adverse events—any.

Analysis 2.16.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 16 Adverse events—'serious'.

Analysis 2.17.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 17 Adverse events—pneumonia.

Analysis 2.18.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 18 Adverse events—candidiasis.

Analysis 2.19.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 19 Adverse events—hoarseness.

Analysis 2.20.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 20 Adverse events—palpitations.

Analysis 2.21.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 21 Adverse events—blood glucose increased.

Analysis 2.22.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 22 Adverse event—skin bruising.

Analysis 2.23.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 23 Adverse events—bronchitis.

Analysis 2.24.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 24 Adverse events—upper respiratory tract infection.

Analysis 2.25.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 25 Adverse events—nasopharyngitis.

Analysis 2.26.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 26 Adverse events—cough.

Analysis 2.27.

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 27 Adverse events—headache.

Comparison 3. Budesonide/formoterol (BDF) versus placebo (PLA)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Severe exacerbations2 Rate ratio (Fixed, 95% CI)0.74 [0.62, 0.88]
1.1 Poorly reversible2 Rate ratio (Fixed, 95% CI)0.74 [0.62, 0.88]
2 Mean severe exacerbation rates per participant per year2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Poorly reversible population2 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Mortality43250Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.57, 1.93]
4 Change from baseline in St George's Respiratory Questionnaire (total score)4 Mean Difference (IV, Fixed, 95% CI)Subtotals only
4.1 320/9 mcg42350Mean Difference (IV, Fixed, 95% CI)-3.73 [-4.83, -2.63]
4.2 160/9 mcg21442Mean Difference (IV, Fixed, 95% CI)-3.39 [-4.70, -2.07]
5 Quality of life—change scores2 SGRQ (Fixed, 95% CI)-6.06 [-7.90, -4.22]
5.1 Poorly reversible2 SGRQ (Fixed, 95% CI)-6.06 [-7.90, -4.22]
6 Symptoms (change scores)2 Symptom scale (Fixed, 95% CI)-0.63 [-0.90, -0.37]
6.1 Poorly reversible2 Symptom scale (Fixed, 95% CI)-0.63 [-0.90, -0.37]
7 Breathlessness, cough and sputum score (BCSS) change from baseline—average over treatment period2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
7.1 320/9 mcg21533Mean Difference (IV, Fixed, 95% CI)-0.43 [-0.59, -0.26]
7.2 160/9 mcg21536Mean Difference (IV, Fixed, 95% CI)-0.44 [-0.60, -0.28]
8 Rescue medication usage4 Mean Difference (Fixed, 95% CI)Subtotals only
8.1 320/9 mcg4 Mean Difference (Fixed, 95% CI)-0.98 [-1.18, -0.79]
8.2 160/9 mcg2 Mean Difference (Fixed, 95% CI)-1.28 [-1.55, -1.00]
9 Mean FEV1 (% change from baseline)2 Mean Difference (Fixed, 95% CI)14.40 [11.91, 16.90]
9.1 Poorly reversible2 Mean Difference (Fixed, 95% CI)14.40 [11.91, 16.90]
10 Average 12-hour FEV1 change from baseline—end of treatment (L)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
10.1 320/9 mcg1246Mean Difference (IV, Fixed, 95% CI)0.19 [0.12, 0.26]
10.2 160/9 mcg1245Mean Difference (IV, Fixed, 95% CI)0.16 [0.10, 0.22]
11 Predose FEV1 [L] change from baseline to the average over the randomised treatment period1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
11.1 320/9 mcg1577Mean Difference (IV, Fixed, 95% CI)0.08 [0.04, 0.12]
11.2 160/9 mcg1581Mean Difference (IV, Fixed, 95% CI)0.06 [0.03, 0.09]
12 1 Hour postdose FEV1 [L] change from baseline to the average over the randomised treatment period1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
12.1 320/9 mcg1577Mean Difference (IV, Fixed, 95% CI)0.17 [0.14, 0.20]
12.2 160/9 mcg1581Mean Difference (IV, Fixed, 95% CI)0.16 [0.13, 0.19]
13 FEV1 at 12-hour change from baseline—end of treatment (L)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
13.1 320/9 mcg1246Mean Difference (IV, Fixed, 95% CI)0.1 [0.03, 0.17]
13.2 160/9 mcg1245Mean Difference (IV, Fixed, 95% CI)0.07 [0.00, 0.14]
14 Morning PEFR change from baseline, average over treatment period (L/min)2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
14.1 320/9 mcg21530Mean Difference (IV, Fixed, 95% CI)19.12 [15.69, 22.55]
14.2 160/9 mcg21535Mean Difference (IV, Fixed, 95% CI)14.63 [11.47, 17.80]
15 Evening PEFR mean change from baseline, average over treatment period (L/min)2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
15.1 320/9 mcg21529Mean Difference (IV, Fixed, 95% CI)16.09 [12.61, 19.57]
15.2 160/9 mcg21531Mean Difference (IV, Fixed, 95% CI)12.74 [9.56, 15.91]
16 Withdrawals—total4 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
16.1 320/9 mcg42475Odds Ratio (M-H, Fixed, 95% CI)0.57 [0.48, 0.68]
16.2 160/9 mcg21556Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.50, 0.78]
17 Withdrawals due to adverse events4 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
17.1 320/9 mcg42475Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.61, 1.01]
17.2 160/9 mcg21556Odds Ratio (M-H, Fixed, 95% CI)0.95 [0.70, 1.30]
18 Withdrawals due to lack of efficacy3 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
18.1 320/9 mcg31898Odds Ratio (M-H, Fixed, 95% CI)0.46 [0.34, 0.63]
18.2 160/9 mcg1975Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.60, 1.71]
19 Adverse event—any2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
19.1 320/9 mcg21552Odds Ratio (M-H, Fixed, 95% CI)1.42 [1.16, 1.74]
19.2 160/9 mcg21556Odds Ratio (M-H, Fixed, 95% CI)1.32 [1.08, 1.61]
20 Adverse events—'serious'4 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
20.1 320/9 mcg42476Odds Ratio (M-H, Fixed, 95% CI)1.17 [0.95, 1.45]
20.2 160/9 mcg21556Odds Ratio (M-H, Fixed, 95% CI)1.20 [0.89, 1.63]
21 Adverse events—pneumonia3 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
21.1 320/9 mcg32062Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.52, 1.52]
21.2 160/9 mcg21556Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.45, 1.42]
22 Adverse events—candidiasis2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
22.1 320/9 mcg21552Odds Ratio (M-H, Fixed, 95% CI)3.45 [1.88, 6.34]
22.2 160/9 mcg21556Odds Ratio (M-H, Fixed, 95% CI)2.05 [1.07, 3.92]
23 Adverse events—dysphonia2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
23.1 320/9 mcg21552Odds Ratio (M-H, Fixed, 95% CI)4.07 [1.52, 10.90]
23.2 160/9 mcg21556Odds Ratio (M-H, Fixed, 95% CI)1.17 [0.37, 3.67]
24 Adverse events—cataracts1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
24.1 320/9 mcg1975Odds Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.97]
24.2 160/9 mcg1975Odds Ratio (M-H, Fixed, 95% CI)1.95 [0.18, 21.59]
25 Adverse events—COPD2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
25.1 320/9 mcg21552Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.69, 1.22]
25.2 160/9 mcg21556Odds Ratio (M-H, Fixed, 95% CI)1.16 [0.88, 1.53]
26 Adverse events—tremor1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
26.1 320/9 mcg1577Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
26.2 160/9 mcg1581Odds Ratio (M-H, Fixed, 95% CI)7.55 [0.39, 146.88]
27 Adverse events—palpitations1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
27.1 320/9 mcg1577Odds Ratio (M-H, Fixed, 95% CI)3.26 [0.13, 80.37]
27.2 160/9 mcg1581Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
28 Adverse events—lumbar spine bone density change from baseline (g/cm2)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
28.1 320/9 mcg1149Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.03, -0.01]
28.2 160/9 mcg1149Mean Difference (IV, Fixed, 95% CI)0.0 [-0.01, 0.01]
29 Adverse events—hip bone density change from baseline (g/cm2)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
29.1 320/9 mcg1149Mean Difference (IV, Fixed, 95% CI)0.0 [-0.01, 0.01]
29.2 160/9 mcg1147Mean Difference (IV, Fixed, 95% CI)0.01 [0.00, 0.02]
Analysis 3.1.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 1 Severe exacerbations.

Analysis 3.2.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 2 Mean severe exacerbation rates per participant per year.

Analysis 3.3.

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

Analysis 3.4.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 4 Change from baseline in St George's Respiratory Questionnaire (total score).

Analysis 3.5.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 5 Quality of life—change scores.

Analysis 3.6.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 6 Symptoms (change scores).

Analysis 3.7.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 7 Breathlessness, cough and sputum score (BCSS) change from baseline—average over treatment period.

Analysis 3.8.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 8 Rescue medication usage.

Analysis 3.9.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 9 Mean FEV1 (% change from baseline).

Analysis 3.10.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 10 Average 12-hour FEV1 change from baseline—end of treatment (L).

Analysis 3.11.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 11 Predose FEV1 [L] change from baseline to the average over the randomised treatment period.

Analysis 3.12.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 12 1 Hour postdose FEV1 [L] change from baseline to the average over the randomised treatment period.

Analysis 3.13.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 13 FEV1 at 12-hour change from baseline—end of treatment (L).

Analysis 3.14.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 14 Morning PEFR change from baseline, average over treatment period (L/min).

Analysis 3.15.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 15 Evening PEFR mean change from baseline, average over treatment period (L/min).

Analysis 3.16.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 16 Withdrawals—total.

Analysis 3.17.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 17 Withdrawals due to adverse events.

Analysis 3.18.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 18 Withdrawals due to lack of efficacy.

Analysis 3.19.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 19 Adverse event—any.

Analysis 3.20.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 20 Adverse events—'serious'.

Analysis 3.21.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 21 Adverse events—pneumonia.

Analysis 3.22.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 22 Adverse events—candidiasis.

Analysis 3.23.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 23 Adverse events—dysphonia.

Analysis 3.24.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 24 Adverse events—cataracts.

Analysis 3.25.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 25 Adverse events—COPD.

Analysis 3.26.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 26 Adverse events—tremor.

Analysis 3.27.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 27 Adverse events—palpitations.

Analysis 3.28.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 28 Adverse events—lumbar spine bone density change from baseline (g/cm2).

Analysis 3.29.

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 29 Adverse events—hip bone density change from baseline (g/cm2).

Comparison 4. Mometasone/formoterol (MF/F) versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Number of participants with at least one exacerbation2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 400/10 mcg2882Odds Ratio (M-H, Fixed, 95% CI)0.72 [0.54, 0.95]
1.2 200/10 mcg2886Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.58, 1.01]
2 Number of participants having at least one moderate or severe exacerbation2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 400/10 mcg2882Odds Ratio (M-H, Fixed, 95% CI)0.57 [0.38, 0.86]
2.2 200/10 mcg2886Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.42, 0.92]
3 Mortality2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 400/10 mcg2890Odds Ratio (M-H, Fixed, 95% CI)1.72 [0.41, 7.25]
3.2 200/10 mcg2894Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.20, 4.98]
4 Change from baseline in St George's Respiratory Questionnaire (total score)2 Mean Difference (Fixed, 95% CI)Subtotals only
4.1 400/10 mcg2866Mean Difference (Fixed, 95% CI)-3.80 [-5.75, -1.86]
4.2 200/10 mcg2869Mean Difference (Fixed, 95% CI)-3.91 [-6.01, -1.81]
5 Change from baseline in FEV1 AUC0–12 hours (mL)—week 132 Mean Difference (IV, Fixed, 95% CI)Subtotals only
5.1 400/10 mcg2862Mean Difference (IV, Fixed, 95% CI)162.04 [126.54, 197.53]
5.2 200/10 mcg2869Mean Difference (IV, Fixed, 95% CI)122.01 [86.64, 157.39]
6 Mean change from baseline AM predose FEV1 at 13 weeks (mL)2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
6.1 400/10 mcg2856Mean Difference (IV, Fixed, 95% CI)114.64 [77.79, 151.50]
6.2 200/10 mcg2859Mean Difference (IV, Fixed, 95% CI)70.43 [33.63, 107.23]
7 Withdrawals—total2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 400/10 mcg2890Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.40, 0.77]
7.2 200/10 mcg2894Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.40, 0.76]
8 Withdrawals due to lack of efficacy2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 400/10 mcg2890Odds Ratio (M-H, Fixed, 95% CI)0.24 [0.08, 0.74]
8.2 200/10 mcg2894Odds Ratio (M-H, Fixed, 95% CI)0.31 [0.11, 0.84]
9 Withdrawals due to adverse events2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
9.1 400/10 mcg2890Odds Ratio (M-H, Fixed, 95% CI)1.07 [0.58, 1.98]
9.2 200/10 mcg2894Odds Ratio (M-H, Fixed, 95% CI)0.37 [0.16, 0.84]
10 Adverse events—any2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 400/10 mcg2890Odds Ratio (M-H, Fixed, 95% CI)0.98 [0.75, 1.30]
10.2 200/10 mcg2894Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.62, 1.09]
11 Adverse events—serious2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
11.1 400/10 mcg2890Odds Ratio (M-H, Fixed, 95% CI)1.09 [0.66, 1.79]
11.2 200/10 mcg2894Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.41, 1.23]
12 Adverse events—pneumonia2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 400/10 mcg2890Odds Ratio (M-H, Fixed, 95% CI)3.14 [0.84, 11.65]
12.2 200/10 mcg2894Odds Ratio (M-H, Fixed, 95% CI)1.67 [0.40, 7.04]
13 Adverse events—candidiasis2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
13.1 400/10 mcg2890Odds Ratio (M-H, Fixed, 95% CI)2.22 [0.50, 9.91]
13.2 200/10 mcg2894Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.17, 5.87]
14 Adverse events—dysphonia1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
14.1 400/10 mcg1461Odds Ratio (M-H, Fixed, 95% CI)2.11 [0.19, 23.41]
14.2 200/10 mcg1475Odds Ratio (M-H, Fixed, 95% CI)1.98 [0.18, 22.02]
15 Adverse events—cataract1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
15.1 400/10 mcg1429Odds Ratio (M-H, Fixed, 95% CI)0.98 [0.06, 15.72]
15.2 200/10 mcg1419Odds Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.48]
16 Adverse events—COPD requiring hospitalisation2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
16.1 400/10 mcg2890Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.40, 1.60]
16.2 200/10 mcg2894Odds Ratio (M-H, Fixed, 95% CI)0.36 [0.15, 0.86]
Analysis 4.1.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 1 Number of participants with at least one exacerbation.

Analysis 4.2.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 2 Number of participants having at least one moderate or severe exacerbation.

Analysis 4.3.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 3 Mortality.

Analysis 4.4.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (total score).

Analysis 4.5.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 5 Change from baseline in FEV1 AUC0–12 hours (mL)—week 13.

Analysis 4.6.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 6 Mean change from baseline AM predose FEV1 at 13 weeks (mL).

Analysis 4.7.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 7 Withdrawals—total.

Analysis 4.8.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 8 Withdrawals due to lack of efficacy.

Analysis 4.9.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 9 Withdrawals due to adverse events.

Analysis 4.10.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 10 Adverse events—any.

Analysis 4.11.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 11 Adverse events—serious.

Analysis 4.12.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 12 Adverse events—pneumonia.

Analysis 4.13.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 13 Adverse events—candidiasis.

Analysis 4.14.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 14 Adverse events—dysphonia.

Analysis 4.15.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 15 Adverse events—cataract.

Analysis 4.16.

Comparison 4 Mometasone/formoterol (MF/F) versus placebo, Outcome 16 Adverse events—COPD requiring hospitalisation.

Appendices

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

Electronic searches: core databases

Database Frequency 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

Conference Years 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 the RCT filter are adapted to identify trials in other electronic databases.

Appendix 2. Definitions of exacerbations

Study IDDefinition of exacerbation
Barnes 2006No definition found
Bourbeau 2007No definition found
Calverley 2003

Mild exacerbations = number of days with intake of four or more puffs of rescue medication

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

Dal Negro 2003

Mild exacerbation = requiring increased use of salbutamol prn by > 2 occasions/24 hour period on two or more consecutive days compared with the baseline mean of last seven days of run-in period

Moderate exacerbation = requiring treatment with antibiotics and/or oral corticosteroids

Severe exacerbation = requiring emergency hospital treatment and/or hospitalisation

Doherty 2012

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

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

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

Hanania 2003

Moderate exacerbation = requiring treatment with antibiotics and/or corticosteroids

Severe exacerbation = requiring hospitalisation

Lapperre 2009No definition found
Mahler 2002“exacerbations defined by treatment”—no further details
O'Donnell 2006No definition found
Rennard 2009“a course of oral steroids and/or hospitalisation due to a worsening of COPD”
SCO104925No definition found
SFCT01No definition found
Sin 2008“Exacerbations were defined as worsening of COPD symptoms leading to hospitalisation, a visit to the emergency room, or use of an antimicrobial agent and/or systemic corticosteroids as an outpatient”
Szafranski 2003

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

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

Tashkin 2008“Worsening of COPD symptoms that required treatment with oral corticosteroids and/or hospitalisation”
Tashkin 2012

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

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

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

TORCH“A symptomatic deterioration requiring treatment with antibiotic agents, systemic corticosteroids, hospitalisation, or a combination of these”
TRISTAN“Exacerbations were defined a priori as a worsening of COPD symptoms that required treatment with antibiotics, oral corticosteroids, or both. Episodes that required corticosteroid treatment or hospital admission were noted separately”
Zheng 2006“A worsening of symptoms that required treatment with antibiotics or oral corticosteroids and/or hospitalisation” (analysed separately as those requiring antibiotics, those requiring corticosteroids, those requiring hospitalisation)

Appendix 3. Definitions of pneumonia

Study IDDefinition of pneumonia
Barnes 2006No definition found
Bourbeau 2007No definition found
Calverley 2003No definition found
Dal Negro 2003No definition found
Doherty 2012“Including the AE terms of pneumonia, pneumonia viral, pneumonia aspiration, and lobar pneumonia”
Hanania 2003No definition found
Lapperre 2009No definition found
Mahler 2002No definition found
O'Donnell 2006No definition found
Rennard 2009

“Pneumonia events were reported by physicians based on the Medical Dictionary for Regulatory Activities (version 10.0) pneumonia-related preferred

terms (pneumonia, bronchopneumonia, lobar pneumonia or pneumonia staphylococcal)”

SCO104925No definition found
SFCT01No definition found
Sin 2008No definition found
Szafranski 2003No definition found
Tashkin 2008“Diagnosis of pneumonia was generally based on clinical judgment, without radiological confirmation in all cases”
Tashkin 2012“Including the AE terms of pneumonia, pneumonia viral, pneumonia aspiration, and lobar pneumonia”
TORCH“Since the finding was unexpected, there was no prospective definition of pneumonia in the study protocol (e.g. confirmation on chest radiography)”
TRISTANNo definition found
Zheng 2006No definition found

What's new

Last assessed as up-to-date: 26 June 2013.

DateEventDescription
26 June 2013New search has been performedNew literature search run.
26 June 2013New citation required and conclusions have changedInclusion of a new combination inhaler (Mometasone furoate/formoterol (MF/F)). Eight new studies included (Bourbeau 2007; Doherty 2012; Lapperre 2009; Rennard 2009; SCO104925; Sin 2008; Tashkin 2008; Tashkin 2012). Background was rewritten, outcomes were redefined, withdrawals were included as an outcome, and methods now reflect the latest version of the Cochrane Handbook for Systematic Reviews of Interventions. We presented data in subgroups according to different doses of the same drug for this update. Conclusions are strengthened by the addition of eight new studies.

History

Protocol first published: Issue 3, 2002
Review first published: Issue 4, 2003

DateEventDescription
11 November 2009AmendedSpelling corrections and minor reformatting
8 April 2008AmendedConverted to new review format.
26 February 2008AmendedSummary of findings table now added to review prepared centrally in GRADEpro by the Summary of Findings table working party (Nancy Santesso)
2 August 2007New citation required and conclusions have changedSeven new studies met the entry criteria of the review (Barnes 2006; Kardos 2007; TORCH; SCO100470; SCO40030; SFCT01; SCO10054). New unpublished data have been incorporated for three studies previously included (Hanania 2003; Mahler 2002; TRISTAN).

What was known before:
Statistically significant findings in favour of combination treatment over placebo. Conflicting findings when combination treatment compared with monocomponent therapies.

What new data contribute to the review:
Data on all primary and secondary endpoints. Combined estimates now indicate that combination fluticasone and salmeterol is significantly more effective than fluticasone alone in reducing the rate of exacerbations.
30 April 2004New citation required and conclusions have changedTwo new studies are included in this update (Calverly 2003; Hanania 2003). One study previously reported in abstract form has now been published and baseline and outcome data incorporated in this version of the review (Dal Negro 2003).

Data on lung function have been pooled on a WMD rather than a SMD. Pooled SEMs have been calculated from the published p values, and have been used to calculate some exacerbation outcomes, as well as symptoms, quality of life and lung function for some of the comparators.

The Discussion and Conclusion reflect the incorporation of the new data, and the data calculated from previously published and included studies.

Contributions of authors

In the 2013 update, LJN and PP updated the background section with input from SJM; SJM and RN updated the methods section. Studies were selected and appraised by LJN and PP, and data were extracted by RN and RH and then were entered by RN and checked by RH. RN and RH conducted the analysis with input from RH, LJN and PP. The results section was written by RN with input from RH, LJN and PP. The discussion, conclusion and abstract were written by LJN and PP with input from RN and RH.

LJN and PP developed the protocol. In previous versions of the review, studies were assessed by LJN and Toby Lasserson (TJL). TJL and LJN checked data and entered them into RevMan 2011. TJL and LJN conducted the analysis. TJL and LJN developed the discussion with input from PP. Chris Cates (CJC) participated in the 2004 and 2007 updates of the review and offered statistical advice and input in calculating SEM and SD for the included studies when appropriate.

Declarations of interest

None known.

Sources of support

Internal sources

  • Hamamelis Trust, UK.

  • St George's, University of London, UK.

External sources

  • NIHR, UK.

    Progam grant

Differences between protocol and review

We have provided estimates of mortality from all included studies.

Since the protocol of this Cochrane review was published, several different aspects of review methodology have changed in light of more 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 used to determine study quality in previous versions of the review.

  • 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 the strength of 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 a single inhaler for chronic obstructive pulmonary disease.

  • In 2012, we added the comparison of mometasone furoate/formoterol versus placebo.

  • In 2012 we presented data subgrouped according to dose.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Barnes 2006

MethodsParallel-group design
Randomisation: not clear
Blinding: double-blind, identical inhaler devices used
Allocation concealment: unclear
Excluded: not described
Withdrawals: described
Trial duration: 13 weeks
Baseline characteristics: comparable
Intention-to-treat analysis stated
Participants
  • Setting: 18 centres in Western and Eastern Europe

  • Participants randomly assigned: 141 (two groups: FP/SAL combination: 74; placebo: 67)

  • Baseline characteristics: 64 years; mean FEV1: 1.68 L; mean FEV1: 59 %predicted; mean FEV1 reversibility: 3.9 (of predicted)

  • Inclusion criteria: M/F 40 to 80 years of age; diagnosis of COPD (according to GOLD criteria); ≥ 2 on Medical Research Council (MRC) dyspnoea scale; poor reversibility of < 10% predicted normal

  • Exclusion criteria: current diagnosis of asthma; recent exacerbation (within four weeks); long-term oxygen therapy (LTOT); pulmonary rehabilitation; ICS, antileukotriene or tiotropium within 14 days of visit

Interventions

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

  • FPS 500/50 mcg twice daily

  • Placebo

Inhaler device: dry powder inhaler (DPI)

OutcomesExacerbations; withdrawals; adverse events
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available
Allocation concealment (selection bias)Unclear riskInformation not available
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices
Incomplete outcome data (attrition bias): MortalityLow riskAll withdrawals clearly accounted for, although slightly higher completion rate in the placebo group (95% in the placebo group, 88% in the treatment group)
Incomplete outcome data (attrition bias): All other outcomesLow riskAll withdrawals clearly accounted for, although slightly higher completion rate in the placebo group (95% in the placebo group, 88% in the treatment group)
Selective reporting (reporting bias)Low riskNo evidence of reporting bias

Bourbeau 2007

MethodsRandomised, double-blind, parallel-group, placebo-controlled. Duration three months
Participants
  • Setting: two respiratory centres: the Montreal Chest Institute and Hospital Laval, Canada

  • Participants randomly assigned: 40 (FPS: 19, placebo: 21)

  • Baseline characteristics: mean age: 64 years; mean FEV1 % predicted: 59%; COPD severity (GOLD): mild to very severe; males: 90%

  • Inclusion criteria: COPD (GOLD criteria), age ≥ 40 and ≤ 75 years; ≥ 10 pack-years smoking history; postbronchodilator FEV1 ≥ 25% of predicted; FEV1/forced vital capacity (FVC) ≤ 0.70

  • Exclusion criteria: asthma or atopy; any other active lung disease, requiring home oxygen or with raised carbon dioxide tension (> 44 mm Hg); α1-antitrypsin deficiency; recent exacerbation (in the past four weeks); controlled medical condition or hypersensitivity to inhaled corticosteroids and bronchodilators

Interventions

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

  • FPS 500/50 mcg twice daily

  • Placebo twice daily

Additonal treatment groups not covered in this review

  • Fluticasone 500 mcg twice daily

Inhaler device: DPI (Diskus)

Outcomes
  • Numbers of CD8+ T lymphocytes and CD68+ macrophages, neutrophils and eosinophils

  • Spirometric measurements (FEV1 and FVC)

  • CRDQ (Chronic Respiratory Disease Questionnaire)

  • Bronchoalveolar lavage (BAL) and sputum induction (baseline, week 4 and week 12)

  • ATS-DLD 78 questionnaire

  • Lung volumes and carbon monoxide transfer factor (TLCO)

  • Adverse events

NotesPowered to detect differences in cell numbers from bronchoscopy and BAL rather than clinical outcomes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was performed using a central computer-generated list of random numbers, which was stratified by centre and used a block size of six set up by a data management/randomisation company
Allocation concealment (selection bias)Unclear riskAllocation procedure not described
Blinding (performance bias and detection bias)
All outcomes
Low risk

A procedure was established by GEREQ, which was in possession of the treatment code, to ensure that the treatment code would be broken only in accordance with the protocol and the criteria set up for unbinding of the study

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

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

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

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

Calverley 2003

MethodsParallel-group study
Randomisation: unclear
Blinding: double-blind (identical inhaler devices)
Trial duration: 52 weeks with two-week run-in of treatment optimisation
Allocation concealment: unclear
Withdrawals: stated
Intention-to-treat analysis: stated
Participants
  • Setting: 109 centres in 15 countries

  • Participants randomly assigned: 510 (BDF: 254; placebo: 256). Additional treatment groups not covered in this review: budesonide: 257; formoterol: 255

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

  • Inclusion criteria: GOLD defined COPD (stages III and IV); ≥ 40 years; COPD symptoms > 2 years; smoking history ≥ 10 pack-years; FEV1/VC ≤ 70% pre-BD; FEV1 ≤ 50% predicted; use of SABAs as reliever medication; ≥ 1 COPD exacerbation requiring oral corticosteroids/antibiotics two to 12 months before first clinic visit

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

Interventions

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

  • BDF: 320/9 mcg twice daily

  • Placebo (lactose monohydrate)

Additional treatment groups not covered in this review

  • Budesonide: 400 mcg twice daily

  • Formoterol: 9 mcg twice daily

Inhaler device: Turbuhaler

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

Classified as 'poorly reversible population'

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available
Allocation concealment (selection bias)Unclear riskInformation not available
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices
Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (71% completion in the BDF group and 59% in the placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (71% completion in the BDF group and 59% in the placebo group)
Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Dal Negro 2003

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

  • Participants randomly assigned: 12 (FPS: six; placebo: six). Additional treatment groups not covered in this review: salmeterol: six

  • Baseline characteristics: age range: 53 to 78; moderate COPD; mean FEV1 (L): 1.46; mean FEV1 (% predicted): 48; mean PEF (L/min): 180; mean reversibility (% baseline): 3.2

  • Inclusion criteria: baseline FEV1 % predicted: ≤ 80%; FEV1 > 800 mL; FEV1/FVC ratio: ≤ 70% predicted; FEV1 change ≤ 12% predicted post 400 mg salmeterol; regular treatment with oral theophylline 20 mg twice daily; SABA as required (for at least six months); current/ex-smokers with smoking history of at least 10 pack-years

  • Exclusion criteria: current evidence of asthma or other pulmonary diseases; regular treatment with ICS; unstable respiratory disease requiring oral/parenteral corticosteroids within four weeks before the beginning of the study; changes in COPD medication in last four weeks before entering run-in; upper/lower respiratory tract infection within four weeks before last screening visit; unstable angina/unstable arrhythmias; recent myocardial infarction (MI)/heart failure; insulin-dependent diabetes mellitus; neuropsychiatric disorders; concurrent use of medications that affect COPD (e.g. beta-blockers) or interact with methylxanthine products (e.g. macrolides or fluoroquinolones); known/suspected hypersensitivity to ICS, beta2-agonist or lactose; evidence of alcohol abuse.

Interventions

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

  • FPS 50/250 mcg twice daily

  • Placebo

Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily

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

Inhaler device: Diskus

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

Classified as 'poorly reversible population'

Mild exacerbation: requirement for increase in SABA as required by > 2 occasions/24 h on two or more consecutive days compared with baseline mean of last seven days of run-in

Moderate exacerbation: condition requiring treatment with antibiotics and/or oral corticosteroids

Severe exacerbation: condition requiring emergency hospital treatment and/or hospitalisation

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available
Allocation concealment (selection bias)Unclear riskInformation not available
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices
Incomplete outcome data (attrition bias): MortalityUnclear risk100% completion in both groups but only 12 participants
Incomplete outcome data (attrition bias): All other outcomesUnclear risk100% completion in both groups but only 12 participants
Selective reporting (reporting bias)Unclear riskAll stated outcomes reported but choice of end points used for significance calculations not always clear

Doherty 2012

MethodsRandomized, placebo-controlled, double-blind, double-dummy, parallel groups. Duration 26 weeks with a 26-week safety extension
Participants
  • Setting: 164 centres in North, Central and South America, Europe, Africa and Asia

  • Participants randomly assigned: 700 (MF/F 400/10: 225, MF/F 200/10: 239, placebo: 236)

  • Baseline characteristics: mean age 59.3; mean FEV1 % predicted: 38.2%; COPD severity: moderate to very severe; males 74.3%

  • Inclusion criteria: age ≥ 40 years; FEV1/FVC < 0.70, postbronchodilator FEV1 25% to 60% predicted; symptoms of COPD (e.g. chronic cough and sputum production not attributable to another disease) for at least 24 months before enrolment; clinically acceptable laboratory tests at screening; adequate form of birth control if of child-bearing potential

  • Exclusion criteria: asthma or significant reversibility; COPD exacerbation within four weeks; long-term oxygen; lung cancer; alpha-1-antitrypsin deficiency; lung surgery; cataract extractions in both eyes; glaucoma or intraocular pressure ≥ 22 mm Hg in either eye; clinically significant medical illness(es) that could interfere with the study

Interventions

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

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

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

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

  • Placebo (26 weeks)

Additional treatment groups not covered in this review

  • MF 400 mcg twice daily (26 weeks + 26-week safety extension)

  • F 10 μg twice daily (26 weeks + 26-week safety extension)

  • Inhaler device: MDI

Outcomes
  • MF/F 400/10 μg compared with MF 400 μg for FEV1 area under the curve from 0 to 12 hours postdose at 13-week end point

  • MF/F 400/10 μg and MF/F 200/10 μg compared with F 10 μg for AM predose (trough) FEV1

  • Changes from baseline in FEV1 area under the curve from 0 to 12 hours postdose day 1; weeks 1, 13, 26; and the 26-week end point

  • Changes from baseline in trough FEV1 each visit and at the 26-week end point

  • Serial spirometry tests

  • Respiratory health status (SGRQ)

  • COPD symptom-free nights

  • Partly stable COPD

  • Time to first COPD exacerbation

  • Adverse events

Notes

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

COPD exacerbations were categorised as mild, moderate or severe

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

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

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

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"At baseline, subjects were randomised in a 1:1:1:1:1 ratio"—no further details, but likely to be low risk
Allocation concealment (selection bias)Unclear riskInformation not available
Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo-controlled, double-blind, double-dummy
Incomplete outcome data (attrition bias): MortalityUnclear riskModerate attrition rate across all treatment groups (84% completion in higher-dose treatment group, 85% in the lower-dose treatment group, 80% in the placebo group)
Incomplete outcome data (attrition bias): All other outcomesUnclear riskModerate attrition rate across all treatment groups (84% completion in higher-dose treatment group, 85% in the lower-dose treatment group, 80% in the placebo group)
Selective reporting (reporting bias)Unclear riskNot all outcomes are supported with data

Hanania 2003

MethodsParallel-group study
Randomisation: method unclear
Blinding: double-blind
Allocation concealment: unclear
Excluded: described
Withdrawals: described
Trial duration: 24 weeks with 2-week run-in period
Baseline characteristics: comparable
Intention-to-treat analysis: not stated
Participants
  • Setting: USA, multi-centre (76 hospitals)

  • Participants randomly assigned: 368 (FPS: 183; placebo: 185). Additional treatment groups not covered in this review: salmeterol: 177; fluticasone: 183

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

  • Inclusion criteria: stable COPD; FEV1 40% to 65% predicted; FEV1/FVC < 70% predicted; symptoms of chronic bronchitis and moderate dyspnoea

  • Exclusion criteria: current diagnosis of asthma, use of oral steroids in past six weeks, abnormal electrocardiogram (ECG), LTOT, moderate to severe exacerbation in run-in. Other significant medical disorder

Interventions

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

  • FPS 50/250 mcg twice daily

  • Placebo

Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily

  • Fluticasone 250 mcg twice daily

Inhaler device: Diskus

OutcomesLung function: change in FEV1 from baseline to end of study (M); PEF data not stratified by reversibility; quality of life: CRDQ, chronic bronchitis symptoms questionnaire (CBSQ) not stratified by reversibility; Dyspnoea and symptoms: transitional dyspnoea index (TDI); baseline dyspnoea index not stratified by reversibility; exacerbations; rescue salbutamol use
NotesFEV1 reversibility < 12% or 200 mL (of baseline FEV1). Reversibility stratified data. Mean percentage increase in non-reversible participants = 8.8
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available
Allocation concealment (selection bias)Unclear riskInformation not available
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices
Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (70% completion in treatment group, 68% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (70% completion in treatment group, 68% in placebo group)
Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Lapperre 2009

MethodsRamdomised, placebo-controlled, parallel-group study. Duration 30 months
Participants
  • Setting: two university medical centres in The Netherlands

  • Participants randomly assigned: 57 (FPS: 28, placebo: 29)

  • Baseline characteristics: mean age: 60.5; mean percentage predicted FEV1: 61%; COPD severity: moderate to severe (GOLD); males: 85.5%

  • Inclusion criteria: age: 45 to 75 years; ≥ 10 pack-years smoking history; lung function GOLD stages II and III

  • Exclusion criteria: asthma, ICS within six months

Interventions

No run-in

  • FPS 500/50 mcg twice daily for 30 months 

  • Placebo twice daily for 30 months

Additonal treatment groups not covered in this review

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

  • Fluticasone 500 mcg twice daily for 30 months

Inhaler device: DPI (Diskus)

Outcomes
  • Inflammatory cell counts in bronchial biopsies and induced sputum

  • Postbronchodilator spirometry rate of FEV1 decline

  • Hyperresponsiveness to methacholine PC20 assessed by standardised procedures

  • Dyspnoea score by modified Medical Research Council (MRC) dyspnoea scale

  • Health status by St George’s Respiratory Questionnaire (SGRQ)

  • Clinical COPD Questionnaire (CCQ)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAt entry, an independent randomisation centre provided participant and medication numbers by using a minimisation procedure that balanced treatment groups
Allocation concealment (selection bias)Unclear riskNo details given of allocation procedure
Blinding (performance bias and detection bias)
All outcomes
Low riskStudy medications were individually numbered, with 60 doses per inhaler; all active treatment medications and placebo were identical in appearance
Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (75% completion in treatment group, 69% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (75% completion in treatment group, 69% in placebo group)
Selective reporting (reporting bias)Low riskAll outcome measures described are reported

Mahler 2002

MethodsParallel-group study
Randomisation: stratified by reversibility and investigative site
Blinding: double-blind
Allocation concealment: unclear
Excluded: described.
Withdrawals: described.
Trial duration: 24 weeks
Baseline characteristics: comparable
Intention-to-treat analysis: stated
Participants
  • Setting: multi-centre study (65 centres)

  • Participants randomly assigned: 346 (FPS: 165; placebo: 181); additional treatment groups not covered in this review: salmeterol: 160; fluticasone: 168

  • Baseline characteristics: mean age: 63; FEV1: 1.2 to 3 L

  • Inclusion criteria: participants with COPD according to ATS guidelines; baseline prebronchodilation FEV1 < 65% predicted and > 0.70 L; baseline prebronchodilation FEV1/FVC < 70% predicted; age > 40 years; 20 pack-years history smoking; day or night symptoms present on four of last seven days during run-in period

  • Exclusion criteria: history of asthma; corticosteroid use in last six weeks; abnormal ECG; oxygen therapy; moderate or severe exacerbation during run-in; significant concurrent disease

Interventions

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

  • FPS 500/50 mcg twice daily

  • Placebo

Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily

  • Fluticasone 500 mcg twice daily

Inhaler device: Diskus

OutcomesLung function: change in FEV1 from baseline to end of study (M); quality of life: CRDQ, CBSQ not stratified by reversibility; dyspnoea and symptoms: end of study dyspnoea (TDI) Exacerbations. Rescue salbutamol use
NotesCOPD participants reversible and non-reversible; < 15% (baseline) improvement in FEV1 to salbutamol; reversibility stratified data; mean FEV1 reversibility 11.0%
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised; stratified by reversibility and investigative site
Allocation concealment (selection bias)Unclear riskInformation not available
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices
Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (68% completion in treatment group, 62% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (68% completion in treatment group, 62% in placebo group)
Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

O'Donnell 2006

MethodsParallel-group design
Randomisation: not clear
Blinding: double-blind
Allocation concealment: unclear
Excluded: not described
Withdrawals: described
Trial duration: 8 weeks
Baseline characteristics: comparable
Intention-to-treat analysis stated
Participants
  • Setting: 22 centres in North America

  • Participants randomly assigned: 126 (FPS: 62; placebo: 64)

Additional treatment groups not covered in this review

  • Salmeterol: 59

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

Interventions

Run-in: two weeks; single-blind placebo

  • FPS 500/50 mcg twice daily

  • Placebo

Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily

Inhaler device: DPI

OutcomesWithdrawals; exercise time; FEV1; adverse events
NotesStudy downloaded from ctr.gsk.co.uk
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available
Allocation concealment (selection bias)Unclear riskInformation not available
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices
Incomplete outcome data (attrition bias): MortalityLow riskLow attrition rates in both groups (95% completion in treatment group, 92% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesLow riskLow attrition rates in both groups (95% completion in treatment group, 92% in placebo group)
Selective reporting (reporting bias)Unclear riskDoes not contribute data to the analysis of exacerbations as rate ratios, mortality or hospitalisations

Rennard 2009

MethodsRandomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled. Duration 12 months
Participants
  • Setting: 237 centres in US, Europe and Mexico

  • Participants randomly assigned: 1469 (BDF 320/9: 494, BDF 160/9: 494, placebo 481)

  • Baseline characteristics: mean age: 62.3; mean % predicted FEV1: 39.7%; COPD severity: moderate to very severe; males: 63.5%

  • Inclusion criteria: age ≥ 40 years; COPD for > 2 years; ≥ 10 pack-years smoking history; pre-bronchodilator (FEV1) ≤ 50% predicted; pre-bronchodilator FEV1/forced vital capacity (FVC) < 70%; modified Medical Research Council dyspnoea scale score ≥ 2; COPD exacerbation within one to 12 months (see Tashkin 2008)

  • Exclusion criteria: asthma or allergic rhinitis before 40 years of age; oral steroid use; any significant disease or disorder that may jeopardise the safety of the participant (see Tashkin 2008)

Interventions

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

  • BDF 320/9 mcg twice daily

  • BDF 160/9 mg twice daily

  • Placebo twice daily

Additional treatment groups not covered in this review

  • Formoterol 9 mg twice daily

Inhaler device: pMDI/DPI

Outcomes
  • Predose and one hour postdose FEV1 over the 12-month treatment period

  • Participant-reported outcome variables regarding disease status (including PEF), collected via questionnaires and diaries

  • Health care utilisation

  • Safety variables, including adverse events, vital signs, ECG, physical examination, haematology and clinical chemistry

Notes

Subgroup performed serial spirometry assessment

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

or hospitalisation

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised, but no details given of sequence generation
Allocation concealment (selection bias)Unclear riskNo details of allocation procedure given
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy; blinding maintained until end of 12-month study period
Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rate across all treatment groups (73% completion in higher-dose treatment group, 71% in lower-dose treatment group, 64% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rate across all treatment groups (73% completion in higher-dose treatment group, 71% in lower-dose treatment group, 64% in placebo group)
Selective reporting (reporting bias)Unclear risk

All primary and secondary outcomes reported, although numerical data not available for all outcomes

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

SCO104925

MethodsRandomized, double-blind, placebo-controlled, parallel-group. Duration 12 weeks
Participants
  • Setting: 11 centres: four centres in the Russian Federation, four centres in the United States, two centres in Chile and one centre in Estonia

  • Participants randomly assigned: 81 (FPS: 39, placebo: 42)

  • Baseline characteristics: mean age: 64.4; mean FEV1 5 predicted: not given; COPD severity: moderate to severe; males: 79%

  • Inclusion criteria: ≥ 40 years of age; clinical history of COPD with evidence of bronchitis; ≥ 10 pack-years smoking history; FEV1/FVC ≤ 70% and measured postalbuterol FEV1 ≥ 30% and ≤ 70% of predicted normal

  • Exclusion criteria: child-bearing potential

Interventions

No run-in described

  • FPS 500/50 mcg

  • Placebo

Additional treatment groups not covered in this review

  • Fluticasone 500 mcg

  • Salmeterol 50 mcg

Outcomes
  • Predose resistance difference between 5 Hz and 15 Hz (R5 to R15) as measured by IOS

  • Predose and two hours postdose low-frequency reactance area (AX); two hours postdose R5 to R15; postalbuterol computed tomography (CT) parameters of area of airway wall (Aaw) and area of airway lumen (Ai)

  • Adverse events

NotesTrial designed to assess novel outcome measures, clinical efficacy. No relevant outcomes for meta-analysis apart from adverse events
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised but no details of sequence generation
Allocation concealment (selection bias)Unclear riskNo details of allocation procedure
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind, placebo-controlled"
Incomplete outcome data (attrition bias): MortalityUnclear riskModerate attrition rates in both groups (90% completion in treatment group, 90% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesUnclear riskModerate attrition rates in both groups (90% completion in treatment group, 90% in placebo group)
Selective reporting (reporting bias)Low riskAll outcome measures reported

SFCT01

Methods

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

Intention-to-treat analysis stated

Participants
  • Setting: 49 centres in Italy, 7 in Poland

  • Participants randomly assigned: 256 (FPS: 131; placebo: 125)

Additional treatment groups not covered in this review

  • Fluticasone: 131

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

Interventions

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

  • FPS 500/50 mcg twice daily

  • Placebo

Additional treatment groups not covered in this review

  • Fluticasone 500 mcg twice daily

Inhaler device: MDI

OutcomesWithdrawals; exacerbations; FEV1; adverse events
NotesUnpublished study downloaded from ctr.gsk.co.uk
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised; no other information available
Allocation concealment (selection bias)Unclear riskInformation not available
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices
Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (66% completion in treatment group, 68% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (66% completion in treatment group, 68% in placebo group)
Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Sin 2008

MethodsDouble-blind, randomised, placebo-controlled, parallel-group. Duration four weeks
Participants
  • Setting: 11 centres,  Western Canada

  • Participants randomly assigned: 137 (FPS: 92, placebo: 45)

  • Baseline characteristics: mean age: 68.4; mean FEV1 % predicted: 46.4%; COPD severity: moderate to very severe; males: 62.7%

  • Inclusion criteria: age ≥ 40 years; clinical diagnosis of COPD (GOLD); FEV1 < 80% predicted; FEV1/FVC < 0.70; ≥ 10 pack-years smoking history

  • Exclusion criteria: exacerbations in last four weeks: known chronic systemic infections or inflammatory conditions; solid organ transplantation; myocardial infarction or cerebrovascular accident within the past three months; child-bearing potential; participation in a drug trial within the past four weeks; unlikely to survive longer than six months; URTI in last four weeks; unable to follow instructions; long-term oral theophylline use and unable or unwilling to stop

  • Use of oral corticosteroids or long-term immunosuppressive agents

Interventions

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

  • FPS 500/50 mcg twice daily

  • Placebo twice daily

Additonal treatment groups not covered in this review

  • Fluticasone 500 mcg twice daily

Inhaler device: DPI (Diskus)

Outcomes
  • Serum C-reactive protein (CRP), interleukin-6 (IL-6) and surfactant protein D (SPD)

  • Health status (SGRQ)

  • FEV1 and FVC

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was carried out centrally according to a computer-generated sequence stratified according to current smoking status with allocation concealment in a 1 (placebo arm) to 2 (fluticasone four arms) to 2 (fluticasone/salmeterol) distribution ratio
Allocation concealment (selection bias)Low risk“With allocation concealment”; however, further details not given
Blinding (performance bias and detection bias)
All outcomes
Low riskDuring this phase (RCT), all participants and study personnel will be blinded to the treatment assignment. (For safety reasons, during severe exacerbations (i.e. those requiring hospitalisation or emergency visit for COPD), the treating physician can break the "code" and place study participants on medications needed to treat the exacerbation)
Incomplete outcome data (attrition bias): MortalityUnclear riskHigher attrition in placebo group (96% completion in treatment group, 87% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesUnclear riskHigher attrition in placebo group (96% completion in treatment group, 87% in placebo group)
Selective reporting (reporting bias)Unclear riskAll outcome measures stated in protocol have been reported, with exception of “Other secondary molecules such as IL-8, tumour necrosis factor-alpha, monocyte chemoattractant protein and other molecules will be measured at a later date as part of a post hoc exploratory work”. Also SPD levels reported extensively but did not feature in the protocol

Szafranski 2003

MethodsParallel-group study
Randomisation: randomised, double-blind, placebo-controlled parallel-group trial
Duration: 52 weeks
Methods of randomisation: computer-generated scheme at AstraZeneca, Lund, Sweden. At each centre, eligible participants received an enrolment code, and then after run-in, participants were allocated the next consecutive participant number.
Allocation concealment: adequate
Blinding: All Turbuhaler inhalers were identical to ensure that the participant, the pharmacist and the investigator were blinded to the allocated treatment
Excluded: not stated
Withdrawals: stated
Intention-to treat-analysis: stated
Participants
  • Setting: 89 centres in Central and South America, Europe and South Africa

  • Participants: 413 (BDF: 208; placebo: 205)

Additional treatment groups not covered in this review

  • Formoterol: 201; budesonide: 198

Baseline characteristics: mean age: 64 years; mean FEV1 % predicted: 36%; mean reversibility: 6% predicted normal
Inclusion criteria: age ≥ 40 years; COPD for ≥ 2 years; smoking history ≥ 10 pack-years; FEV1 ≤ 50% predicted; FEV1/FVC ≤ 70%; symptom score ≥ 2 during at least seven days of run-in; use of bronchodilators for reliever medication; ≥ 1 severe COPD exacerbation within two to 12 months before study entry
Exclusion criteria: history of asthma/rhinitis before age 40; using beta-blockers; current respiratory tract disease other than COPD

Interventions

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

  • BDF 320/9 mcg twice daily

  • Placebo

Additional treatment groups not covered in this review

  • Budesonide 400 μg twice daily

  • Formoterol 9 μg twice daily

Inhaler device: Turbuhaler

OutcomesSymptoms, adverse events, exacerbations, lung function
Notes

Classified as 'poorly reversible' subgroup; exacerbation defined as requirement of oral steroids and/or antibiotics and/or hospitalisation for respiratory symptoms; mild exacerbation defined as requirement of ≥ 4 inhalations per day

P values used to calculate pooled standard errors of the mean (SEMs) for following outcomes: symptoms; rescue medication usage

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated scheme
Allocation concealment (selection bias)Low riskAt each centre, eligible participants received an enrolment code, and then after run-in, participants were allocated to the next consecutive participant number
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices
Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (72% completion in treatment group, 56% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (72% completion in treatment group, 56% in placebo group)
Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Tashkin 2008

MethodsRandomised, double-blind, double-dummy, placebo-controlled, parallel-group. Duration six months
Participants
  • Setting: 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa

  • Participants randomly assigned: 858 (BDF 320/9: 277, BDF 160/9: 281, placebo 300)

  • Baseline characteristics: mean age: 63.3; mean FEV1 % predicted: 40.1%; COPD severity: moderate to very severe; males: 67.1%

  • Inclusion criteria: ≥ 40 years, pre-bronchodilator FEV1 ≤ 50% predicted, pre-bronchodilator FEV1/forced vital capacity < 70%; symptoms for ≥ two years; ≥ 10 pack-years smoking history; ≥ one COPD exacerbation within one to 12 months; ≥ 2 Modified Medical Research Council dyspnoea scale score; ≥ 2 BCSS score for at least half of the two-week run-in period

  • Exclusion criteria: asthma or allergic rhinitis before 40 years of age; significant/unstable cardiovascular disorder; clinically significant respiratory tract disorder other than COPD; alpha-1 antitrypsin deficiency; oral steroid use; any other significant disease or disorder that may jeopardise the safety of the participant; oral or ophthalmic non-cardioselective beta-adrenoceptor antagonist use; pregnancy and breast-feeding

Interventions

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

  • BDF 320/9 twice daily

  • BDF 160/9 twice daily

  • Placebo twice daily

Additional treatment groups not covered in this review

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

  • Budesonide 320 mcg twice daily

  • Formoterol 9 mcg twice daily

Inhaler device: MDI and Turbohaler (double-dummy)

Outcomes
  • Predose and one hour postdose FEV1 over the six-month treatment period

  • Participant-reported outcome variables regarding disease status (including PEF), collected via questionnaires and diaries

  • Health care utilisation

  • Safety variables, including adverse events, vital signs, ECG, physical examination, hematology and clinical chemistry

  • Serial spirometry

  • Pharmacokinetics

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomly assigned in balanced blocks according to computer-generated randomisation to one of the treatments administered twice daily
Allocation concealment (selection bias)Unclear riskNo details of allocation procedure
Blinding (performance bias and detection bias)
All outcomes
Low riskRandomised, double-blind, double-dummy
Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (86% completion in both treatment groups, 74% completion in placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (86% completion in both treatment groups, 74% completion in placebo group)
Selective reporting (reporting bias)Low riskAll outcomes reported, no evidence of reporting bias

Tashkin 2012

MethodsRandomized, placebo-controlled, double-blind, double-dummy, parallel groups. Duration 26 weeks with 26-week safety extension
Participants
  • Setting: 131 centres located in South America, Asia, Africa, Europe and North America

  • Participants randomly assigned: 636 (MF/F 400/10: 217, MF/F 200/10: 207, placebo 212)

  • Baseline characteristics: mean age: 59.8; mean FEV1 % predicted: not stated; COPD severity: moderate to very severe; males: 79%

  • Inclusion criteria: ≥ 40 years; current or ex-smokers with ≥ 10 pack-years history; moderate to very severe COPD (pre-bronchodilator FEV1/forced vital capacity (FVC) ratio ≤ 0.70), symptoms of COPD (chronic cough and sputum production not attributable to another disease process) for at least 24 months; postbronchodilator FEV1 ≤ 60% predicted normal and ≥ 25% predicted normal at screening; medically acceptable form of birth control

  • Exclusion criteria: significant reversibility (> 400 mL postalbuterol/salbutamol); long-term oxygen; exacerbation of COPD requiring medical intervention within four weeks before randomisation; beta-blocking agents; or treatment with additional excluded medication (other than SABA short-acting anticholinergic to be used as rescue medication); history of significant medical illness or a disorder that might interfere with the study; pregnancy or breast-feeding; asthma; lung cancer; alpha-1-antitrypsin deficiency; lobectomy; pneumonectomy; lung volume reduction surgery; cataract extractions in both eyes; or other significant ocular problems (glaucoma, trauma, opacification)

Interventions

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

  • MF/F 400/10 mcg twice daily

  • MF/F 200/10 mcg twice daily

  • Placebo

Additonal treatment groups not covered in this review

  • MF 400 mcg twice daily

  • Formoterol 10 mcg twice daily

Inhaler device: MDI

Outcomes
  • Mean change from baseline in FEV1 area under the curve (AUC) from 0 to 12 hours postdose (AUC 0 to 12 hours) at the week 13 end point

  • Mean change from baseline in morning predose FEV1 at the week 13 end point

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

  • Change in symptom-free nights

  • Time to first mild, moderate or severe COPD exacerbation

  • Proportion of participants with partly stable COPD

  • Adverse events

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe sponsor’s statistician produced a computer-generated randomisation schedule with treatment codes in blocks using SAS. Randomization was stratified according to the participant's smoking status at the time of randomisation
Allocation concealment (selection bias)Low riskRandomised treatment assignment was provided to the investigative site by means of an interactive voice response system at the time participants were randomly assigned
Blinding (performance bias and detection bias)
All outcomes
Low risk

Placebo-controlled, double-blind, double-dummy study

NB: Sponsor's statistician was used

Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in all groups (81% completion in higher-dose treatment group and 82% in lower-dose treatment group, 75% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in all groups (81% completion in higher-dose treatment group and 82% in lower-dose treatment group, 75% in placebo group)
Selective reporting (reporting bias)Unclear riskNumerical data for multiple outcomes not presented, as failed to reach significance

TORCH

MethodsParallel-group design
Randomisation: permuted block randomisation with stratification for smoking status and country
Blinding: double-blind (identical inhaler devices)
Allocation concealment: adequate
Excluded: described
Withdrawals: described
Trial duration: 156 weeks
Baseline characteristics: comparable
Intention-to-treat analysis: stated
Participants
  • Setting: 444 centres in North America, Central America and Asia Pacific

  • Participants randomly assigned: 3091 (FPS: 1546; placebo: 1545)

Additional treatment groups not covered in this review

  • Salmeterol: 1542; fluticasone: 1551

Baseline characteristics: 65 years; male: 76%
Inclusion criteria: M/F 40 to 80 years of age; diagnosis of COPD (ERS); < 10% reversibility of predicted FEV1; FEV1/FVC ratio < 70%; FEV1 < 60% predicted; ≥ 10 pack-year smoking history
Exclusion criteria: asthma or respiratory diseases other than COPD; lung volume reduction surgery (LVRS)/lung transplant; requirement for > 12 hours/d LTOT; long-term oral corticosteroid therapy; serious uncontrolled disease likely to interfere with medication/cause death in next three years

Interventions

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

  • FPS combination 500/50 mcg twice daily

  • Placebo

Additional treatment groups not covered in this review

  • Fluticasone 500 mcg twice daily

  • Salmeterol 50 mcg twice daily

Inhaler device: DPI

OutcomesAll-cause mortality; change in SGRQ; exacerbations (requiring antibiotics, steroids, hospitalisation or combination of these); lung function; withdrawals; adverse events
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated scheme. Permuted block randomisation with stratification for smoking status and country
Allocation concealment (selection bias)Unclear riskCentralised randomisation schedule but no details of allocation procedures
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler devices
Incomplete outcome data (attrition bias): MortalityLow riskMortality was the primary outcome, and vital status was checked in those who withdrew
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates for other outcomes in both groups (66% completion in treatment group, 56% completion in placebo group)
Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

TRISTAN

MethodsParallel-group design
Randomisation: computer-generated; numbers were generated off-site; once a treatment number had been assigned to a participant, it could not be assigned to any other participant
Blinding: double-blind; participants received identically packaged and presented placebos
Excluded: described
Withdrawals: described
Trial duration: two-week run-in period; 52 weeks treatment; 2-week follow-up
Baseline characteristics: comparable intention-to-treat analysis: stated
Participants
  • Setting: 196 centres in Europe, South Africa and Australia

  • Participants randomly assigned: 719 (FPS: 358; placebo: 361)

Additional treatment groups not covered in this review

  • Salmeterol: 372; fluticasone: 375

Baseline characteristics: mean age 63 years; mean FEV1 1.26 L (44% predicted)
Inclusion criteria: baseline FEV1 25% to 75% predicted; FEV1/ FVC ratio ≤ 70%; poor reversibility: < 10% increase in predicted FEV1 30 minutes after inhalation of 400 mcg salbutamol; at least 10 pack-years smoking history; history of exacerbations (at least one in the last year) requiring OCS and/or antibiotics; at least one episode of acute COPD per year in the previous three years
Exclusion criteria: respiratory disorders other than COPD; oxygen treatment; systemic corticosteroids, high doses of inhaled corticosteroids (> 1000 mcg daily beclomethasone dipropionate, budesonide or flunisolide or > 500 mcg daily fluticasone) or antibiotics in the four weeks before the two-week run-in period

Interventions

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

  • FPS 50 mcg/500 mcg twice daily

  • Placebo

Additional treatment groups not covered in this review

  • Salmeterol 50 mcg twice daily

  • Fluticasone 500 mcg twice daily

Inhaler device: DPI

OutcomesFEV1; PEF; exercise tolerance; quality of life: SGRQ; dyspnoea and symptoms (symptom score for shortness of breath, cough and sputum production); exacerbations (defined as requirement for antibiotics, oral steroids or both); rescue salbutamol use
NotesFEV1 reversibility (% predicted normal); mean reversibility (% predicted) 3.8
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation schedule
Allocation concealment (selection bias)Low riskNumbers were generated off-site. Once a treatment number had been assigned to a participant, it could not be assigned to any other participant. Participants who satisfied the eligibility criteria were assigned the next sequential treatment number from the list
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical inhaler device
Incomplete outcome data (attrition bias): MortalityHigh riskHigh attrition rates in both groups (75% completion in treatment group and 61% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesHigh riskHigh attrition rates in both groups (75% completion in treatment group and 61% in placebo group)
Selective reporting (reporting bias)Low riskNo apparent indication of reporting bias

Zheng 2006

  1. a

    AUC: Area under the curve; BCSS: Breathless, Cough and Sputum Score; BDF: Budesonide/formoterol combination; CBSQ: Chronic Bronchitis Symptom Questionnaire; COPD: chronic obstructive pulmonary disease; CRDQ: Chronic Respiratory Disease Questionnaire; DPI: Dry powder inhaler; ERS: European Respiratory Society; FEV1: Forced expiratory volume in one second; FPS: Fluticasone/salmeterol combination; FVC: Forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonists; LAMA: long-acting muscarinic antagonist; LTOT: Long-term oxygen therapy; MDI: Metered-dose inhaler; MMRC: Modified Medical Research Council; PEF: Peak expiratory flow; SABA: short-acting beta-agonist; SAMA: Short-acting muscarinic antagonist; SD: Standard deviation; SGRQ: St George's Respiratory Questionnaire.

MethodsRandomised, double-blind, placebo-controlled, parallel-group. Duration 24 weeks
Participants
  • Setting: 12 hospitals in China

  • Participants randomly assigned: 445 (FPS: 297, placebo: 148)

  • Baseline characteristics: mean age: 66.32; mean FEV1 % predicted: 47%; COPD severity: moderate to very severe; males: 88.5%

  • Inclusion criteria: 40 to 79 years; COPD as per GOLD criteria; poor reversibility of airflow obstruction (increase of < 10%); FEV1/FVC ratio (postbronchodilator) < 70%

  • Exclusion criteria: asthma, lung cancer, sarcoidosis, active tuberculosis, lung  fibrosis, bronchiectasis, serious uncontrolled other system disorders; long-term oxygen therapy (LTOT); had received inhaled corticosteroids at a dose of > 1000 μg/d (beclomethasone or budesonide) or > 500 μg/d (fluticasone) or had received systemic corticosteroids in the last four weeks before entry to the run-in period

Interventions

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

  • FPS 500/50 twice daily

  • Placebo

Inhaler device: DPI (Diskus)

Outcomes
  • Prebronchodilator FEV1

  • St George’s Respiratory Questionnaire (SGRQ)

  • Use of relief bronchodilator and nighttime awakenings from Daily Record Cards

  • Postbronchodilator FEV1

  • COPD exacerbations

  • Adverse events

NotesTrial included non-smokers (11% from FPS arm and 14% from placebo arm)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk“Randomization was stratified at week 0 by smoking status”—sequence generation not described but likely to be low risk
Allocation concealment (selection bias)Unclear riskAllocation procedure not described
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind. FPS combination product 50/500 μg twice daily or matched placebo twice daily for 24 weeks of treatment
Incomplete outcome data (attrition bias): MortalityUnclear riskModerate attrition rates in both groups (88% completion in treatment group and 89% in placebo group)
Incomplete outcome data (attrition bias): All other outcomesUnclear riskModerate attrition rates in both groups (88% completion in treatment group and 89% in placebo group)
Selective reporting (reporting bias)Low riskAll stated outcomes reported

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Aaron 2004Irrelevant comparison
Aaron 2007Patients were randomised to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo
Bathoorn 2008Trial focuses on treatment of COPD exacerbations
Bleecker 2011Assessment of effects of Gly16Arg genotype in response to budesonide/ formoterol in two clinical trials
Borgstrom 2003Healthy volunteers
Cazzola 2000Single-blind assessment of additive benefit of inhaled fluticasone to salmeterol. Although dosage was identical to Seretide/Advair (i.e. FP 500ug: SAL 50mcg), treatment was administered through separate inhalers
Cazzola 2002aSingle-blind randomised crossover study comparing combination salmeterol and fluticasone with formoterol and budesonide - excluded as duration of study was too short (12 hours)
Cazzola 2003Acute phase COPD
Cazzola 2004Randomised trial comparing combination salmeterol/fluticasone with separately administered fluticasone and theophylline for 4 months. Excluded as the comparison was not within the scope of the review
Cazzola 2004bThe duration of this study was too short (<1 week)
Chapman 2002Review article
Cukier 2007Crosssover trial investigating use of nebulised saline versus nebulised salbutamol
De Backer 2011Assessment of the acute effect of budesonide/formoterol
Donohue 2004Irrelevant comparison
Ferguson 2006Trial did not compare combined ICS/LABA therapy versus placebo
GlaxoSmithKline 2004Trial includes patients with asthma
GlaxoSmithKline 2004aTrial includes patients with asthma
Golabi 2006Crossover trial comparing tiotropium versus salmeterol/fluticasone
Haque 2006Focus on macrophages and glucoreceptor proteins
INSPIRETrial compared tiotropium versus seretide
Jiang 2011Study not blinded
Jung 2012Patients were randomised to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo
Kardos 2007Comparison of combination therapy long-acting beta-agonist
Lindberg 2007Crossover study examining effect of only a single dose (two inhalations) of budesonide/formoterol
, salmeterol/fluticasone, salbutamol or placebo
Lindenberg 2006Crossover study examining effect of only a single dose (two inhalations) of budesonide/formoterol, salmeterol/fluticasone, salbutamol or placebo
Mittmann 2010Patients were randomised to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo
Mittmann 2011Patients were randomised to tiotropium+combined ICS/LABA therapy versus tiotropium+placebo
NCT00144911Combined ICS/LABA not compared to placebo
NCT00269126Crossover study examining effect of adding fluticasone to salmeterol
NCT00476099Combined ICS/LABA not compared to placebo
Noschese 2003Non-randomised study.
Sagcan 2007Focus of study is on sleep quality of COPD patients
SAM40116Within study treatment group imbalances in dosage of steroids/combination therapy based upon historical steroid dose
Schermer 2007Combined ICS/LABA not compared to placebo
SCO100250Trial compared fluticasone/salmeterol versus salmeterol
SCO100470Comparison of combination therapy long-acting beta-agonist
SCO40034Comparison of tiotropium and combination therapy
SCO40043Trial compared fluticasone/salmeterol versus salmeterol
Sethi 2006Trial focuses on bacterial colonisation of sputum
Shaker 2009Trial compared budesonide versus placebo
Sharafkhaneh 2011Combined ICS/LABA not compared to placebo
Soriano 2002Non-randomised retrospective survival analysis
Southard 2011Combined ICS/LABA not compared to placebo
Stallberg 2008Trial focuses on treatment of COPD exacerbations
Sun 2004Irrelevant comparison
Sutherland 2006Trial focuses on Seretide compared to salmeterol
Trofimenko 2006Study not blinded and no placebo arm
Vestbo 2004Review article.
Welte 2009Trial focuses on budesonide/formoterol added to tiotropium
Welte 2009aTrial focuses on budesonide/formoterol added to tiotropium
Welte 2009bTrial focuses on budesonide/formoterol added to tiotropium
Welte 2009cTrial focuses on budesonide/formoterol added to tiotropium
Welte 2009dTrial focuses on budesonide/formoterol added to tiotropium
Wilson 2007Study compares patients' preferences of 4 dry powder inhalers
Worth 2009Study duration less than minimum of four weeks
Worth 2009aStudy duration less than minimum of four weeks
Worth 2010Study duration less than minimum of four weeks
Wouters 2005Study excluded as it assessed the withdrawal of FP from combination therapy
Zhong 2011Combined ICS/LABA not compared to placebo
Zhong 2012Combined ICS/LABA not compared to placebo

Ancillary