Mona Bafadhel1, Stefan Peterson2, Miguel A De Blas3, Peter M Calverley4, Stephen I Rennard5, Kai Richter6, Malin Fagerås7. 1. Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Electronic address: mona.bafadhel@ndm.ox.ac.uk. 2. StatMind, Lund, Sweden. 3. Global Medical Affairs, AstraZeneca, Cambridge, UK. 4. School of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK. 5. Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, UK; Department of Internal Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of Nebraska Medical Center, Omaha, NE, USA. 6. Global Medical Affairs, AstraZeneca, Molndal, Sweden; Country Medical Director, AstraZeneca, Wedel, Germany. 7. Global Medical Affairs, AstraZeneca, Molndal, Sweden.
Abstract
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.
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.
Authors: Arnaud Bourdin; Gerard Criner; Gilles Devouassoux; Mark Dransfield; David M G Halpin; MeiLan K Han; C Elaine Jones; Ravi Kalhan; Peter Lange; Sally Lettis; David A Lipson; David A Lomas; José M Echave-Sustaeta María-Tomé; Neil Martin; Fernando J Martinez; Holly Quasny; Lynda Sail; Thomas M Siler; Dave Singh; Byron Thomashow; Henrik Watz; Robert Wise; Nicola A Hanania Journal: Chronic Obstr Pulm Dis Date: 2021-01