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Meta-Analysis
. 2011 Mar 16:(3):CD008532.
doi: 10.1002/14651858.CD008532.pub2.

Combination inhaled steroid and long-acting beta(2)-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease

Charlotta Karner  1 , Christopher J Cates
Affiliations
Meta-Analysis

Combination inhaled steroid and long-acting beta(2)-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease

Charlotta Karner et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: The long-acting bronchodilator tiotropium and single inhaler combination therapy of inhaled corticosteroids and long-acting beta(2)-agonists are both commonly used for maintenance treatment of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of using tiotropium and combination therapy together for the treatment of chronic obstructive pulmonary disease are unclear.

Objectives: To assess the relative effects of inhaled corticosteroid and long-acting beta(2)-agonist combination therapy in addition to tiotropium compared to tiotropium or combination therapy alone in patients with chronic obstructive pulmonary disease.

Search strategy: We searched the Cochrane Airways Group Specialised Register of trials (July 2010) and reference lists of articles.

Selection criteria: We included parallel, randomised controlled trials of three months or longer, comparing inhaled corticosteroid and long-acting beta(2)-agonists combination therapy in addition to inhaled tiotropium against tiotropium alone or combination therapy alone.

Data collection and analysis: We independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.

Main results: Three trials (1021 patients) were included comparing tiotropium in addition to inhaled corticosteroid and long-acting beta(2)-agonist combination therapy to tiotropium alone. The duration, type of combination treatment and definition of outcomes varied. The limited data led to wide confidence intervals and there was no significant statistical difference in mortality, participants with one or more hospitalisations, episodes of pneumonia or adverse events. The results on exacerbations were heterogeneous and were not combined. The mean health-related quality of life and lung function were significantly different when combination therapy was added to tiotropium, although the size of the average benefits of additional combination therapy were small, St George's Respiratory Questionnaire (MD -2.49; 95% CI -4.04 to -0.94) and forced expiratory volume in one second (MD 0.06 L; 95% CI 0.04 to 0.08).One trial (60 patients) compared tiotropium plus combination therapy to combination therapy alone. The results from the trial were insufficient to draw firm conclusions for this comparison.

Authors' conclusions: To date there is uncertainty regarding the long-term benefits and risks of treatment with tiotropium in addition to inhaled corticosteroid and long-acting beta(2)-agonist combination therapy on mortality, hospitalisation, exacerbations of COPD and pneumonia. The addition of combination treatment to tiotropium has shown improvements in average health-related quality of life and lung function.

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Figures

Figure 1
Figure 1. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study
Figure 2
Figure 2. Forest plot of comparison: 1 tiotropium + LABA/ICS combination vs tiotropium + placebo, outcome: 1.1 Mortality (all cause)
Figure 3
Figure 3. Forest plot of comparison: 1 tiotropium + LABA/ICS combination vs tiotropium + placebo, outcome: 1.2 Hospital admission (all causes)
Figure 4
Figure 4. Forest plot of comparison: 1 tiotropium + LABA/ICS combination vs tiotropium + placebo, outcome: 1.3 Hospital admission (exacerbation)
Figure 5
Figure 5. Forest plot of comparison: 1 tiotropium + LABA/ICS combination vs tiotropium + placebo, outcome: 1.4 Exacerbation
Figure 6
Figure 6. Forest plot of comparison: 1 tiotropium + LABA/ICS combination vs tiotropium + placebo, outcome: 1.5 Pneumonia
Figure 7
Figure 7. Forest plot of comparison: 1 tiotropium plus LABA/ICS combination versus tiotropium plus placebo, outcome: 1.6 Quality of life SGRQ scale
See this image and copyright information in PMC

Comment in

References

References to studies included in this review

    1. Aaron SD, Vandemheen K, Ferguson D, FitzGerald M, Maltais F, Boureau J, et al. The Canadian optimal therapy of COPD trial: Design, organization and patient recruitment. Canadian Respiratory Journal. 2004;11(8):581–5. - PubMed
    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. [see comment][summary for patients in Ann Intern Med. 2007 Apr 17;146(8):I12; PMID: 17310044] - PubMed

    2. *

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References to studies excluded from this review

    1. Ando F, Ruggeri P, Girbino G, Cazzola M. Tiotropium and salmeterol/fluticasone combination do not cause oxygen desaturation in COPD. Respiratory Medicine. 2008;102(6):815–8. - PubMed
    1. Bateman E, Van-Dyk M, Chang A. A pilot study comparing tiotropium to salmeterol plus fluticasone in moderate COPD [Abstract] European Respiratory Journal. 2005;26(Suppl 49) Abstract No. 851.
    1. Bateman ED, van Dyk M, Sagriotis A. Comparable spirometric efficacy of tiotropium compared with salmeterol plus fluticasone in patients with COPD: A pilot study. Pulmonary Pharmacology and Therapeutics. 2008;21(1):20–5. - PubMed
    1. Biscione G, Crigna G, Auciello L, Pasqua F, Cazzola M. Addition of tiotropium (T) to a regular treatment with long-acting beta-agonist + inhaled corticosteroid (LABA + ICS) in patients with severe to very-severe COPD under inpatient pulmonary rehabilitation program (PRP) [Abstract]; European Respiratory Society Annual Congress; Vienna, Austria. 2009.Sep 12-16, p. P526.
    1. Golabi P, Topaloglu N, Karakurt S, Celikel T. Effects of tiotropium and salmeterol/fluticasone combination on lung hyperinflation dyspnea and exercise tolerance in COPD [Abstract] European Respiratory Journal. 2006;28(Suppl 50):33s. E304.

References to studies awaiting assessment

    1. Fang L, Liang X, Zhang F, Liu L, Fu W, Zhao Z, et al. Combination of inhaled salmeterol/fluticasone and tiotropium in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Zhonghua Jiehe He Huxi Zazhi [Chinese Journal of Tuberculosis and Respiratory Diseases] 2008;31(11):811–4. - PubMed

Additional references

    1. Appleton S, Jones T, Poole P, Pilotto L, Adams R, Lasserson TJ, et al. Ipratropium bromide versus long-acting beta-2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2006;(3) DOI: 10.1002/14651858.CD006101. - PMC - PubMed
    1. Barr RG, Bourbeau J, Camargo CA. Tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2005;(2) DOI: 10.1002/14651858.CD002876.pub2. - PMC - PubMed
    1. Beeh KM, Beier J. The short, the long and the “ultra-long”: why duration of bronchodilator action matters in chronic obstructive pulmonary disease. Advances in Therapy. 2010;27(3):150–9. - PubMed
    1. Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. European Respiratory Journal. 2008;31(2):416–69. - PubMed
    1. Effing T, Monninkhof EEM, van der Valk PP, Zielhuis GGA, Walters EH, van der Palen JJ, et al. Self-management education for patients with chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2007;(4) DOI: 10.1002/14651858.CD002990.pub2. - PubMed

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