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. 2007 Oct 17:(4):CD003794.
doi: 10.1002/14651858.CD003794.pub3.

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

L Nannini  1 , C J Cates, T J Lasserson, P Poole
Affiliations

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

L Nannini et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Long-acting beta-agonists and inhaled corticosteroids have both been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. Their co-administration in a combined inhaler may facilitate adherence to medication regimens, and improve efficacy.

Objectives: To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations, compared to placebo, in the treatment of adults with chronic obstructive pulmonary disease.

Search strategy: We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search is April 2007.

Selection criteria: Studies were included if they were randomised and double-blind. Studies could compare any combined inhaled corticosteroids and long-acting beta-agonist preparation with placebo.

Data collection and analysis: Two authors independently assessed trial quality and extracted data. One author entered the data.

Main results: Eleven studies met the inclusion criteria (6427 participants randomised). Two different combination preparations (fluticasone/salmeterol and budesonide/formoterol) were used. Study quality was good. Fluticasone/salmeterol and budesonide/formoterol both reduced the rate of exacerbations. Pooled analysis of both combination therapies indicated that exacerbations were less frequent when compared with placebo, Rate Ratio: 0.74 (95% CI 0.7 to 0.8). The clinical impact of this effect depends on the frequency of exacerbations experienced by patients. The patients included in these trials had on average 1-2 exacerbations per year which means that treatment with combination therapy would lead to a reduction of one exacerbation every two to four years in these individuals. There is an overall reduction in mortality, but this outcome is dominated by the results of TORCH and further studies on budesonide/formoterol are required. The three year number needed to treat to prevent one extra death is 36 (95% CI 21 to 258), using a baseline risk of 15.2% from the placebo arm of TORCH. Both treatments led to statistically significant improvement in health status measurements, although the clinical importance of the differences observed is open to interpretation. Symptoms and lung function assessments favoured combination treatments. There was an increase in the risk of pneumonia with combined inhalers. The three year number needed to treat for one extra case of pneumonia is 13 (95% CI 9 to 20), using a baseline risk of 12.3% from the placebo arm of TORCH. Fewer participants withdrew from studies assessing combined inhalers due to adverse events and lack of efficacy.

Authors' conclusions: Compared with placebo, combination therapy led to a significant reduction of a quarter in exacerbation rates. There was a significant reduction in all-cause mortality with the addition of data from the TORCH trial. The increased risk of pneumonia is a concern, and better reporting of this outcome in future studies would be helpful. In order to draw firmer conclusions about the effects of combination therapy in a single inhaler more data are necessary, particularly in relation to the profile of adverse events and benefits in relation to different doses of inhaled corticosteroids.

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Figures

Figure 1
Figure 1. Flow chart to illustrate separation of review between three comparisons. Six RCTs met the original entry criteria of the review. All of these had a placebo and long-acting beta-agonist arm, and five assessed combination against steroids. Seven new studies with one or more control comparisons were identified: five had a placebo arm, three had a long-acting beta-agonist arm, and two had an inhaled steroid treatment arm
Figure 2
Figure 2. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study
Figure 3
Figure 3. Summary of findings table for exacerbations, mortality, quality of life, pneumonia and adverse events
Figure 4
Figure 4. Forest plot of pooled rate ratios for combination fluticasone and salmeterol and placebo, with the summary estimate for TRISTAN included (primary analysis) and removed (sensitivity analysis)
Figure 5
Figure 5. Pooled effect estimate on mortality for all combined inhalers versus placebo
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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    1. *

    2. Barnes NC, Qiu Y-S, Pavord ID, Parker D, Davis PA, Zhu J, et al. Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease. American Journal of Respiratory & Critical Care Medicine. 2006;173(7):736–43. - PubMed
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References to studies excluded from this review

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References to studies awaiting assessment

    1. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Annals of Internal Medicine. 2007;146(8):545–55. - PubMed
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References to ongoing studies

    1. *

    2. Salmetrol xinafoate/fluticasone propionate combination product in the treatment of chronic obstructive pulmonary disease. 2001 http://www.nrr.nhs.uk/ Dr Mike Morgan. Publication ID: N0123137844.

Additional references

    1. Appleton S, Poole P, Smith B, Veale A, Lasserson TJ, Chan MM, et al. Long-acting beta2-agonists for poorly reversible chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2006;(3) Art. No.: CD001104. DOI: 10.1002/14651858.CD001104.pub2. - PMC - PubMed
    1. American Thoracic Society Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Journal of Respiratory & Critical Care Medicine. 1995;152(5 Pt 2):S77–121. - PubMed
    1. Boyd G, Crawford C. Salmeterol for the treatment of patients with chronic obstructive pulmonary disease (COPD) European Respiratory Journal. 1995;8(Suppl 19):167. - PubMed
    1. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial y of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. British Medical Journal. 2000;320(7245):1297–1303. - PMC - PubMed
    1. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA. Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study. Thorax. 2003;58(8):654–8. - PMC - PubMed

References to other published versions of this review

    1. Nannini L, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2003;(4) Art. No.: CD003794. DOI: 10.1002/14651858.CD003794.pub2. - PubMed
    1. Nannini L, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2004;(3) - PubMed

    1. * Indicates the major publication for the study

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