Inhaled Corticosteroids Particle Size and Risk of Hospitalization Due to Exacerbations and All-Cause Mortality in Patients with Chronic Obstructive Pulmonary Disease. A Nationwide Cohort Study

Abstract

Christian Kjer Heerfordt,1 Christian Rønn,1 Josefin Eklöf,1 Pradeesh Sivapalan,1 Zitta Barrella Harboe,2,3 Charlotte Hyldgaard,4 Andreas Fløe,5 Alexander G Mathioudakis,6,7 Mats Christian Højbjerg Lassen,8 Tor Biering-Sørensen,8,9 Jens-Ulrik Stæhr Jensen1,3,10 1Section of Respiratory Medicine, Department of Medicine, Copenhagen University Hospital Herlev and Gentofte, Hellerup, Denmark; 2 Department of Respiratory Medicine and Infectious Diseases, Copenhagen University Hospital, North Zealand, Hillerød, Denmark; 3Department of Clinical Medicine Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 4Diagnostic Centre, University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark; 5Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 6Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK; 7North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; 8Department of Cardiology, Herlev & Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; 9Faculty of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark; 10PERSIMUNE & CHIP: Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Jens-Ulrik Stæhr Jensen, Email [email protected]: Extra-fine particle inhaled corticosteroids (ICS) improve peripheral airway distribution, but their effect on risk of exacerbations and all-cause mortality in patients with chronic obstructive pulmonary disease (COPD) is unclear.Methods: This observational cohort study compares patients with COPD who received extra-fine particle ICS to those who received standard particle size ICS from 2010 to 2017 while followed in outpatient clinics. The primary outcome was the time to a COPD exacerbation that required hospitalization, with all-cause mortality as a secondary outcome. Data were analyzed using an adjusted Cox proportional hazards model and a competing risk analysis. Two predefined subgroup analyses of patients treated with pressurised metered dose inhalers (pMDIs) and patients with a previous exacerbation history, was carried out. Lastly, we created a propensity score matched cohort as a sensitivity analysis.Results: Of the 40,489 patients included, 38,802 (95.8%) received stand particle size ICS and 1,687 (4.2%) received extra-fine particle ICS. In total 7,058 were hospitalized with a COPD exacerbation, and 4,346 died. No significant protective effect of extra-fine particle ICS against hospitalization due to COPD exacerbations (HR 0.93, 95% CI 0.82– 1.05, p=0.23) or all-cause mortality (HR 1.00, 95% CI 0.85– 1.17, p=0.99) was found when compared to standard particle size ICS. However, in the subgroup analysis of patients treated with pMDIs, extra-fine particle ICS was associated with reduction in risk of exacerbations (HR 0.72, 95% CI 0.63– 0.82, p< 0.001) and all-cause mortality (HR 0.72, 95% CI 0.61– 0.86, p< 0.001).Conclusion: The administration of extra-fine particle ICS was not associated with reduced risk of exacerbations or all-cause mortality in our primary analysis. A subgroup consisting of patients treated with pMDIs suggested potential protective benefits.Keywords: COPD, Inhaled Corticosteroids, Particle size, COPD exacerbations

Keywords

• copd
• inhaled corticosteroids
• particle size
• copd exacerbations