CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial

E F M Wouters¹, D S Postma², B Fokkens^3,, W C J Hop⁴, J Prins⁵, A F Kuipers⁶, H R Pasma⁷, C A J Hensing⁸, E C Creutzberg¹ for the COSMIC (COPD and Seretide: a Multi-Center Intervention and Characterization) Study Group

¹ Department of Respiratory Medicine, University Hospital Maastricht, The Netherlands
² Department of Respiratory Medicine, University Hospital Groningen, The Netherlands
³ GlaxoSmithKline BV, Zeist, The Netherlands
⁴ Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands
⁵ Department of Respiratory Medicine, West-Fries Gasthuis Hoorn, The Netherlands
⁶ Department of Respiratory Medicine, Isala Clinics Zwolle, The Netherlands
⁷ Department of Respiratory Medicine, Medical Center Leeuwarden, The Netherlands
⁸ Department of Respiratory Medicine, Diaconessenhuis Meppel The Netherlands

Correspondence to:
Correspondence to:
Dr E C Creutzberg
University Hospital Maastricht, Department of Respiratory Medicine, P O Box 5800, 6202 AZ Maastricht, The Netherlands; evacreutzberg{at}proteion.nl

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 ß₂ 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.

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; LABA, long acting ß₂ agonists; MEF_50­, maximal expiratory flow at 50% of FVC; PEF, peak expiratory flow

Keywords: chronic obstructive pulmonary disease; exacerbations; inhaled corticosteroids; lung function; symptoms

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