Prediction of Long-Term Benefits of Inhaled Steroids by Phenotypic Markers in Moderate-to-Severe COPD: A Randomized Controlled Trial

Abstract

Background: The decline in lung function can be reduced by long-term inhaled corticosteroid (ICS) treatment in subsets of patients with chronic obstructive pulmonary disease (COPD). We aimed to identify which clinical, physiological and non-invasive inflammatory characteristics predict the benefits of ICS on lung function decline in COPD.

Methods: Analysis was performed in 50 steroid-naive compliant patients with moderate to severe COPD (postbronchodilator forced expiratory volume in one second (FEV1), 30-80% of predicted, compatible with GOLD stages II-III), age 45-75 years, >10 packyears smoking and without asthma. Patients were treated with fluticasone propionate (500 μg bid) or placebo for 2.5 years. Postbronchodilator FEV1, dyspnea and health status were measured every 3 months; lung volumes, airway hyperresponsiveness (PC20), and induced sputum at 0, 6 and 30 months. A linear mixed effect model was used for analysis of this hypothesis generating study.

Results: Significant predictors of attenuated FEV1-decline by fluticasone treatment compared to placebo were: fewer packyears smoking, preserved diffusion capacity, limited hyperinflation and lower inflammatory cell counts in induced sputum (p<0.04).

Conclusions: Long-term benefits of ICS on lung function decline in patients with moderate-to-severe COPD are most pronounced in patients with fewer packyears, and less severe emphysema and inflammation. These data generate novel hypotheses on phenotype-driven therapy in COPD.

Trial registration: ClinicalTrials.gov NCT00158847.

Fig 1. Study flow diagram.

Total number of patients randomized and compliant (>70% medication use) per treatment group. At each stage of the study (0, 6 and 30 months) the numbers are listed of those who underwent bronchoscopy amongst the number of patients remaining in the study. We reproduced this flowchart from ‘Lapperre TS et al. (2009) Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 151: 517–527, with permission’.

Fig 2. Long-term predictors of FEV₁ decline by fluticasone treatment.

(A) Prediction by packyears smoking of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. ^#Index category (Idx) is defined relative to median value, and represents the more favourable outcome by fluticasone. Reference category (Ref) is complementary. The group numbers of the patients are mentioned in each graph. For example: Fig 2A shows the decline in FEV₁ in ml/yr on the Y axis for patients with many pack years and patients with few pack years with fluticasone or placebo treatment, respectively, on the X axis. All P values are based on the results of the linear mixed effects model. The treatment*time interaction term corresponding to the difference in decline in FEV₁ between fluticasone and placebo in the low pack year stratum had a P value of 0.037. The interaction term (treatment*stratum*time) reflects the additional effect of pack years smoking stratum to the effect of treatment with inhaled fluticasone compared to placebo on longitudinal changes in FEV₁. The corresponding P value for pack years smoking is 0.023. A favourable effect on decline in FEV₁ would be a decrease in decline caused by inhaled corticosteroids. The figure shows that a lower number of packyears (= index category) decreases the decline in FEV₁ significantly. (B) Prediction by baseline FEV₁ of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (C) Prediction by RV/TLC of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (D) Prediction by TLCO of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (E) Prediction by total number of cell counts in induced sputum of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (F) Prediction by PC₂₀ methacholine of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo. (G) Prediction by percentage of eosinophils in sputum of the decline of FEV₁ by 2.5 year fluticasone treatment (ml) and placebo, stratified by median values of the predictor by 30 months treatment with fluticasone compared to placebo.