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. 2013 May 31;2013(5):CD007891.
doi: 10.1002/14651858.CD007891.pub3.

Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease

Emma J Welsh  1 , Christopher J Cates, Phillippa Poole
Affiliations

Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease

Emma J Welsh et al. Cochrane Database Syst Rev. .

Abstract

Background: Combination therapy (inhaled corticosteroids and long-acting beta2-agonists) and tiotropium are both used in the treatment of chronic obstructive pulmonary disease (COPD). There is uncertainty about the relative benefits and harms of these treatments.

Objectives: To compare the relative effects of inhaled combination therapy and tiotropium on markers of exacerbations, symptoms, quality of life, lung function, pneumonia and serious adverse events in patients with chronic obstructive pulmonary disease.

Search methods: We searched the Cochrane Airways Group Specialised Register of trials (November 2012) and reference lists of articles. We also contacted authors of the studies.

Selection criteria: We included only parallel, randomised controlled trials comparing inhaled combination corticosteroid and long-acting beta2-agonist against inhaled tiotropium bromide.

Data collection and analysis: Two authors independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. We resolved discrepancies through discussion.

Main results: One large, two-year trial (INSPIRE) and two smaller, shorter trials on a total of 1528 participants were found. The results from these trials were not pooled. The number of withdrawals from each arm of the INSPIRE trial was large and imbalanced and outcome data were not collected for patients who withdrew, raising concerns about the reliability of data from this study.In INSPIRE, there were more deaths on tiotropium than on fluticasone/salmeterol (Peto odds ratio (OR) 0.55; 95% confidence interval (CI) 0.33 to 0.93). This was a statistically significant difference, however the number of withdrawals from each of the arms was 11 times larger than the observed number of deaths for participants on fluticasone/salmeterol and seven times larger for participants on tiotropium. There were more all-cause hospital admissions in patients on fluticasone/salmeterol than those on tiotropium in INSPIRE (Peto OR 1.32; 95% CI 1.04 to 1.67). There was no statistically significant difference in hospital admissions due to exacerbations, the primary outcome of INSPIRE. There was no significant difference in exacerbations in patients on fluticasone/salmeterol compared to tiotropium when compared as either an odds ratio or a rate ratio (mean number of exacerbations per patient per year). Exacerbations requiring treatment with oral corticosteroids were less frequent in patients on fluticasone/salmeterol (rate ratio 0.81; 95% CI 0.67 to 0.99). Conversely exacerbations requiring treatment with antibiotics were more frequent in patients treated with fluticasone/salmeterol (rate ratio 1.19; 95% CI 1.02 to 1.38). There were more cases of pneumonia in patients on fluticasone/salmeterol than in those on tiotropium (Peto OR 2.13; 95% CI 1.33 to 3.40). Confidence intervals for these outcomes do not reflect the additional uncertainty arising from unknown outcome data for patients who withdrew.

Authors' conclusions: Since the proportion of missing outcome data compared to the observed outcome data is enough to induce a clinically relevant bias in the intervention effect, the relative efficacy and safety of combined inhalers and tiotropium remains uncertain. Further large, long-term randomised controlled trials comparing combination therapy to tiotropium are required, including adequate follow-up of all participants randomised (similar to the procedures undertaken in TORCH and UPLIFT). Additional studies comparing alternative inhaled long-acting beta2-agonist/steroid combination therapies with tiotropium are also required.

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Conflict of interest statement

None known.

Figures

1
1
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
1.1
1.1. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 1 Mortality (all‐cause).
1.2
1.2. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 2 Hospital admission.
1.3
1.3. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 3 Exacerbations (all‐cause): number of patients experiencing one or more exacerbations over two years.
1.4
1.4. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 4 Exacerbations (mean number of exacerbations per patient per year).
1.5
1.5. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 5 Pneumonia.
1.6
1.6. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 6 Quality of life.
1.7
1.7. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 7 FEV1 (litres).
1.8
1.8. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 8 Serious adverse events (non‐fatal).
1.9
1.9. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 9 Adverse events.
1.10
1.10. Analysis
Comparison 1 Fluticasone/salmeterol (FPS) versus tiotropium (TIO), Outcome 10 Withdrawal.
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Update of

References

References to studies included in this review

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References to studies excluded from this review

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NCT01397890 {published data only}
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References to ongoing studies

NCT01513460 {published data only}
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