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Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials

https://doi.org/10.1016/S2213-2600(15)00106-XGet rights and content

Summary

Background

The short-term benefits of inhaled corticosteroids for patients with chronic obstructive pulmonary disease (COPD) are greater in patients with evidence of eosinophilic airway inflammation. We investigated whether blood eosinophil count is a useful biomarker of the long-term effect of the inhaled corticosteroid fluticasone furoate on exacerbation frequency.

Methods

We did a post-hoc analysis of data from two replicate, randomised, double-blind trials of 12 months' duration (Sept 25, 2009 to Oct 21, 2011 and Oct 17, 2011) in which once a day vilanterol 25 μg was compared with 25 μg vilanterol plus 50 μg, 100 μg, or 200 μg fluticasone furoate in patients with moderate-to-severe COPD and a history of one or more exacerbation in the previous year. We compared exacerbation rates according to two baseline eosinophil cell count strata (<2% and ≥2%), and according to four baseline percentage groupings. We also assessed lung function and incidence of pneumonia per strata in treatment groups.

Findings

We included 3177 patients in the analyses, with 2083 patients (66%) having an eosinophil count of 2% or higher at study entry. Across all doses of inhaled corticosteroids, fluticasone furoate and vilanterol reduced exacerbations by 29% compared with vilanterol alone (mean 0·91 vs 1·28 exacerbations per patient per year; p<0·0001) in patients with eosinophil counts of 2% or higher, and by 10% (0·79 vs 0·89; p=0·2827) in patients with eosinophil counts lower than 2%. Reductions in exacerbations with fluticasone furoate and vilanterol, compared with vilanterol alone, were 24% in patients with baseline eosinophil counts of ≥2–<4%, 32% for those with counts of 4–<6%, and 42% for those with eosinophil counts of ≥6%. In patients treated with vilanterol alone, exacerbation rates increased progressively with increasing eosinophil count percentage category. Improvement in trough forced expiratory volume in 1 s (FEV1) and the increased risk of pneumonia with fluticasone furoate and vilanterol compared with vilanterol alone were not associated with eosinophil count.

Interpretation

Blood eosinophil count is a promising biomarker of response to inhaled corticosteroids in patients with COPD. Blood eosinophil count could potentially be used to stratify patients for different exacerbation rate reduction strategies.

Funding

GlaxoSmithKline (study ID 201595).

Introduction

Inhaled corticosteroids reduce the risk of moderate and severe chronic obstructive pulmonary disease (COPD) exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations.1, 2, 3, 4, 5 However, treatment benefits are slight and are offset by an increased risk of adverse effects, notably pneumonia.6 Therefore, identification of a simple biomarker associated with treatment response would be useful. Several studies show that an increased induced sputum eosinophil count is associated with the short-term response to oral7, 8, 9 and inhaled10, 11 corticosteroids. Sputum eosinophil counts are also predictive of COPD exacerbation after withdrawal of inhaled corticosteroids.12 Other, longer-term, studies show that titration of corticosteroid treatment to normalise sputum eosinophil counts reduces risk of severe exacerbations of COPD.13, 14

Assessment of eosinophilic airway inflammation with induced sputum samples is technically demanding and not always successful, decreasing the usefulness of the test in routine clinical practice. Blood eosinophil count might be a more practical alternative because there is a reasonable correlation between blood and sputum eosinophil count in patients with COPD (a differential count of 2% or higher in blood has a positive predictive value of 90% for a raised eosinophil count in induced sputum).15 About 60% of patients with COPD have blood eosinophil counts of 2% or higher;8, 15 such counts have been associated with an increased risk of severe exacerbations16 and a blood eosinophil count above the median is associated with increased mortality from exacerbations of airway disease.17 Blood eosinophil count is an attractive potential biomarker to direct treatment decisions because it is simple to assess and values are repeatable.8, 15 Use of blood eosinophil counts as a biomarker of corticosteroid response is supported by studies showing that the benefits of oral prednisolone in patients with an acute exacerbation of COPD are confined to patients with blood eosinophil counts higher than 2%.8, 18

We did a post-hoc analysis of data from two large, randomised trials2 of 12 months' duration (Sept 25, 2009 to Oct 21, 2011 and Oct 17, 2011) that investigated the effects of the addition of 50 μg, 100 μg, or 200 μg inhaled fluticasone furoate to once daily vilanterol (25 μg) in patients with COPD. Our hypothesis was that a higher baseline blood eosinophil count would be related to the magnitude of the reduction in exacerbation rate in response to the addition of fluticasone furoate. We assessed reduction in annual rate of exacerbations and improvement in 1 s (FEV1); we also assessed pneumonia events.

Section snippets

Study design and patients

The study designs for the primary studies HZC102871 (NCT01009463, study 1) and HZC102970 (NCT01017952, study 2) have been described previously.2 Patients were eligible to participate if they were aged 40 years or older; had a diagnosis of moderate-to-severe COPD; a smoking history of ten or more pack-years; a ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV1 of 70% or less of predicted);19 and a documented history of one

Results

5266 patients were screened for these studies, of which 3255 were randomly assigned. Most patients who were not assigned either did not meet the inclusion or exclusion criteria (n=550) or did not meet the continuation criteria during run-in as described in our first Article.2 Of the 3255 who were randomly assigned, 78 did not have a baseline screening eosinophil count (mostly because of errors in sample handling, such as haemolysis). The remaining 3177 patients were included in the analysis.

Discussion

Inhaled corticosteroids reduce acute exacerbations in patients with moderate-to-severe COPD; however, individual patient responses are variable and important potential adverse effects exist, including increased risk of pneumonia (panel).1, 2, 4, 6, 20 Investigators have identified blood eosinophil count as a potential biomarker of response to corticosteroid therapy.8, 18 In our analysis, we show that patients with high blood eosinophil count gain greater benefit from treatment with inhaled

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