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