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Abstract
Background: Guidelines recommend inhaled corticosteroids (ICS) as maintenance treatment for patients with chronic obstructive pulmonary disease (COPD) with a post-bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and frequent exacerbations, although they have only a small preventive effect on the accelerated decline in lung function. Combined treatment with ICS and long acting β2 agonists (LABA) may provide benefit to the stability of COPD, but it is unknown if withdrawal of ICS will result in disease deterioration.
Methods: The effects of 1 year withdrawal of the ICS fluticasone propionate (FP) after a 3 month run-in treatment period with FP combined with the LABA salmeterol (S) (500 μg FP + 50 μg S twice daily; SFC) were investigated in patients with COPD in a randomised, double blind study. 497 patients were enrolled from 39 centres throughout the Netherlands; 373 were randomised and 293 completed the study.
Results: The drop out rate after randomisation was similar in the two groups. Withdrawal of FP resulted in a sustained decrease in FEV1: mean (SE) change from baseline −4.4 (0.9)% (S) v −0.1 (0.9)% (SFC); adjusted difference 4.1 (95% CI 1.6 to 6.6) percentage points (p<0.001). Corresponding figures for the FEV1/FVC ratio were −3.7 (0.8)% (S) v 0.0 (0.8)% (SFC) (p = 0.002). The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups, respectively (adjusted rate ratio 1.2; 95% CI 0.9 to 1.5; p = 0.15). The mean annual incidence rate of mild exacerbations was 1.3 (S) v 0.6 (SFC), p = 0.020. An immediate and sustained increase in dyspnoea score (scale 0–4; mean difference between groups 0.17 (0.04), p<0.001) and in the percentage of disturbed nights (6 (2) percentage points, p<0.001) occurred after withdrawal of fluticasone.
Conclusions: Withdrawal of FP in COPD patients using SFC resulted in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights. This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration, even under treatment with a LABA.
- COPD, chronic obstructive pulmonary disease
- FEV1, forced expiratory volume in 1 second
- FVC, forced vital capacity
- LABA, long acting β2 agonists
- MEF50, maximal expiratory flow at 50% of FVC
- PEF, peak expiratory flow
- chronic obstructive pulmonary disease
- exacerbations
- inhaled corticosteroids
- lung function
- symptoms
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Footnotes
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↵† Deceased.
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COSMIC investigators: Dr R Aalbers, Dr F Beaumont, Dr W Boersma, Prof Dr J Bogaard, M Bunnik, J Creemers, W Dalinghaus, C de Graaff, Dr J de Jong, Dr P de Jong, D de Munck, D de Vries, I de Vries, W den Hertog, H Dik, E Dubois, M Eland, W Evers, S Gans, W Geraedts, Dr H Heijerman, A Hendriks, Dr Ho, Dr B Hol, J Kersbergen, H Los, P Luursema, B Pannekoek, Dr W Pieters, R Quanjel, E Quanjel-Wisselo, R Rammeloo, J Retera, Dr A Roldaan, Dr A Rudolphus, L Sala, N Schlösser, Dr A Schols, Dr A Schreurs, Dr J Simons, A Sips, Dr F Smeenk, W Strankinga, I Utama, F van Beek, H van de Woude, P van den Berg, Dr J van den Bosch, J van den Bosch, W van der Brink, Dr F van den Elshout, Dr B van der Bruggen- Bogaarts, J van der Zeijden, A van Harreveld, Dr A van Keimpema, Dr J van Noord, H van Pagée, R van Snippenburg, P van Spiegel, Dr J Verbraecken, J Westbroek.E F M Wouters and D S Postma designed the study, analysed the data, reviewed and interpreted the results and wrote the manuscript. B Fokkens† designed the study. W C J Hop performed the statistical analysis of the data and wrote the manuscript. J Prins, A F Kuipers, H R Pasma and C A J Hensing reviewed and interpreted the results. E C Creutzberg analysed the data, reviewed and interpreted the results and wrote the manuscript. All authors have access to all data in the study and held final responsibility for the decision to submit for publication.
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GlaxoSmithKline provided funding for the study (protocol number SER9602).
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The study sponsor, GlaxoSmithKline, was involved in the study design, together with the principal investigators, in the collection and analysis of data, which were made freely available to the investigators, and in the decision to submit the paper for publication.
Conflict of interest: E F M Wouters, D S Postma and E C Creutzberg have been consultants for and received research grants from GlaxoSmithKline. B Fokkens† was an employee of GlaxoSmithKline. W C J Hop is a statistical consultant for GlaxoSmithKline. J Prins, A F Kuipers, H R Pasma and C A J Hensing received research grants from GlaxoSmithKline.
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