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

Background: 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; COPD exacerbations; Inhaled Corticosteroids; Particle size.

Figure 1

Study flowchart. Patients with no outpatient contacts and not in ICS treatment the year prior to cohort entry were excluded from the study.

Figure 2

Cumulative incidence curves for severe chronic obstructive pulmonary disease (COPD) exacerbations for patients treated with extra-fine particle inhaled corticosteroids (ICS) compared to standard particle size ICS. P-values generated using Log rank test. Graph (A) (Entire cohort), graph (B) (Propensity score matched population), graph (C) (Subgroup exacerbators), and graph (D) (Subgroup Spray inhaler). Graphs (A, C, and D) are unadjusted curves, whereas graph (B) is based on the propensity score matched population.

Figure 3

Cumulative incidence curves for all-cause mortality for patients treated with extra-fine particle inhaled corticosteroids (ICS) compared to standard particle size ICS. P-values generated using Log rank test. Graph (A) (Entire cohort), graph (B) (Propensity score matched population), graph (C) (Subgroup exacerbators), and graph (D) (Subgroup Spray inhaler). Graphs (A, C, and D) are unadjusted curves, whereas graph (B) is based on the propensity score matched population.