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Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials

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Summary

Background

The peripheral blood eosinophil count might help identify those patients with chronic obstructive pulmonary disease (COPD) who will experience fewer exacerbations when taking inhaled corticosteroids (ICS). Previous post-hoc analyses have proposed eosinophil cutoffs that are both arbitrary and limited in evaluating complex interactions of treatment response. We modelled eosinophil count as a continuous variable to determine the characteristics that determine both exacerbation risk and clinical response to ICS in patients with COPD.

Methods

We analysed data from three AstraZeneca randomised controlled trials of budesonide–formoterol in patients with COPD with a history of exacerbations and available blood eosinophil counts. Patients with any history of asthma were excluded. Negative binomial regression analysis was done using splines for modelling of continuous variables to study the primary outcome of annual exacerbation rate adjusted for exposure time and study design. The trials are registered with ClinicalTrials.gov, NCT00206167, NCT00206154, and NCT00419744.

Findings

4528 patients were studied. A non-linear increase in exacerbations occurred with increasing eosinophil count in patients who received formoterol alone. At eosinophil counts of 0·10 × 109 cells per L or more, a significant treatment effect was recorded for exacerbation reduction with budesonide–formoterol compared with formoterol alone (rate ratio 0·75, 95% CI 0·57–0·99; pinteraction=0·015). Interactions were observed between eosinophil count and the treatment effects of budesonide–formoterol over formoterol on St George's Respiratory Questionnaire (pinteraction=0·0043) and pre-bronchodilator FEV1 (linear effect p<0·0001, pinteraction=0·067). Only eosinophil count and smoking history were independent predictors of response to budesonide–formoterol in reducing exacerbations (eosinophil count, pinteraction=0·013; smoking history, pinteraction=0·015).

Interpretation

In patients with COPD treated with formoterol, blood eosinophil count predicts exacerbation risk and the clinical response to ICS.

Funding

AstraZeneca.

Introduction

Pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD) is underpinned by inhaled long-acting muscarinic antagonist (LAMA) and β2 agonist (LABA) bronchodilators in monotherapy or dual therapy, in addition to fixed-dose inhaled corticosteroids (ICS) and LABA combinations.1 Despite their widespread use,2 the role of ICS in the management of COPD has been questioned3, 4 and concerns about pneumonia have been raised.5 Identification of those patients who are most likely to respond to ICS should contribute to personalised approaches to care. The peripheral blood eosinophil count has been proposed as a potential biomarker in COPD.6 Post-hoc analyses of previous clinical trials have consistently identified differences in exacerbation rates between patients treated with ICS who have high eosinophil counts and low eosinophil counts.7, 8, 9 However, these analyses were limited in their evaluation of complex interactions—such as patient characteristics—and by the selection of arbitrary eosinophil cutoffs, with variation between analyses in the use of relative eosinophil counts (% eosinophils) or absolute eosinophil counts. An alternative statistical approach to investigate predictors of ICS response in COPD would use an unbiased continuous analysis, with the assessment of eosinophil count as a continuous variable. We hypothesised that blood eosinophil counts could be calculated at which differential ICS clinical benefit might occur. To do this, we investigated the clinical effect—determined from exacerbation rates, lung function, and quality of life—of inhaled ICS–LABA (budesonide–formoterol) in patients with COPD, modelled by eosinophil count at study entry. We also investigated the value of using the eosinophil count as a biomarker in COPD by adding it to a modified version of a previously published, validated, and freely available score to predict short-term risk of COPD exacerbations (SCOPEX).10 These analyses were done using data from studies within the AstraZeneca clinical trial database.

Section snippets

Study selection, design, and population

Studies from the AstraZeneca clinical trial database were reviewed to identify randomised, double-blind, double-dummy, parallel-group, multicentre trials of budesonide–formoterol fixed-dose combination in patients with COPD, who had blood eosinophils collected at the screening visit. We identified three studies, from which the primary findings have been reported previously (Tashkin and colleagues,11 NCT00206154; Rennard and colleagues,12 NCT00206167; and Sharafkhaneh and colleagues,13 NCT00419744

Results

Of the 4612 patients (excluding patients allocated to budesonide 160 μg alone) randomised in the three studies, 4528 had available baseline eosinophil counts and were included in the pooled analysis (appendix p 9). Patient characteristics at study entry are presented in table 1. 2928 (65%) patients were men, and the mean age was 63 years (range 40–90). Mean post-bronchodilator FEV1 (% of predicted) was 39·2 (SD 11·8) and the mean pooled annualised exacerbation rate, before study entry, was 1·68

Discussion

This post-hoc analysis is currently the largest to show a treatment effect interaction of the budesonide–formoterol combination as compared with formoterol alone and eosinophil count in patients with COPD and a history of exacerbations, with respect to exacerbations, lung function, and health status. We have shown that treatment with budesonide–formoterol attenuates exacerbations and is independent of the eosinophil count, whereas exacerbation frequency increases with increasing blood

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