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

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 (FEV 1 ) ,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 b 2 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 mg FP + 50 mg 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 FEV 1 : mean (SE) change from baseline 24.4 (0.9)% (S) v 20.1 (0.9)% (SFC); adjusted difference 4.1 (95% CI 1.6 to 6.6) percentage points (p,0.001). Corresponding figures for the FEV 1 /FVC ratio were 23.7 (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.

Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD

“…81 Studies examining the effect of ICS withdrawal reported some deterioration in disease control. [82][83][84][85] However, a recent meta-analysis highlighted methodological flaws in evaluable studies of ICS withdrawal in COPD and calculated that withdrawal of ICS resulted only in a small and insignificant increase in exacerbations. 86 Nevertheless, a preferable approach would be to ensure the correct treatment strategy from the outset, with the use of ICS reserved for patients in whom the benefit will outweigh the risk.…”

Independent Risk Factors for Mortality in Patients with Chronic Obstructive Pulmonary Disease Who Undergo Comprehensive Cardiac Evaluations

“…If hospitalization was required, at the discretion of the clinician, exacerbation was considered severe. We included only moderate and severe exacerbations in the exacerbation group of COPD, as in other studies [15,16]. Spirometry (Elite-DX or CPFS; Medgraphics, Saint Paul, Minn., USA) was performed according to the American Thoracic Society guidelines [17].…”

Systemic Inflammation in Patients with Chronic Obstructive Pulmonary Disease: Results from the Cosmic Study

“…Data were collected from 295 COPD patients participating in the COSMIC (COPD and Seretide: A multi-center intervention and characterization) study (post-bronchodilator FEV 1 between 30% and 80% predicted; FEV 1 /FVC ratio < 70% predicted) at 39 outpatient centers in the Netherlands [16]. The central ethical committee in the Netherlands and the local medical ethics committees of the participating centers approved the study.…”