Inhaled Pharmacotherapy and Stroke Risk in Patients with Chronic Obstructive Pulmonary Disease: A Nationwide Population Based Study Using Two-Stage Approach

Hui-Wen Lin,Chi-Li Chung,Chia-Ming Yu,You Shuei Lin,Mauo-Ying Bien,Chun-Nin Lee,C Mary Schooling

doi:10.1371/journal.pone.0130102

Abstract

Background and PurposePatients with chronic obstructive pulmonary disease (COPD) are at higher risk of stroke than those without COPD. This study aims to explore the impact of inhaled pharmacotherapy on stroke risk in COPD patients during a three-year follow-up, using a nationwide, population-based study and a matched cohort design.MethodsThe study cohort comprised 10,413 patients who had received COPD treatment between 2004 and 2006; 41,652 randomly selected subjects comprised the comparison cohort. Cox proportional hazard regressions and two-stage propensity score calibration were performed to determine the impact of various inhaled therapies including short-acting muscarinic antagonists, long-acting muscarinic antagonists, short-acting β-agonists (SABAs), long-acting β-agonists (LABAs), and LABA plus inhaled corticosteroid (ICS), on the risk after adjustment for patient demographic characteristics and comorbid disorders.ResultsOf the 52,065 sampled patients, 2,689 (5.2%) developed stroke during follow-up, including 727 (7.0%) from the COPD cohort and 1,962 (4.7%) from the comparison cohort (p < 0.001). Treatment with SABA was associated with 1.67-fold (95% CI 1.45–1.91; p < 0.001) increased risk of stroke in COPD patients. By contrast, the cumulative incidence of stroke was significantly lower in those treated with LABA plus ICS than those treated without (adjusted hazard ratio 0.75, 95% CI 0.60–0.94, p = 0.014).ConclusionsAmong COPD patients, the use of inhaled SABA is associated with an increased risk of stroke, and combination treatment with inhaled LABA and ICS relates to a risk reduction. Further prospective research is needed to verify whether LABA plus ICS confers protection against stroke in patients with COPD.

Highlights

Chronic obstructive pulmonary disease (COPD), characterized by enhanced airway inflammatory response to noxious gas and persistent airflow limitation [1], is a leading cause of morbidity and mortality globally and leads to a growing and substantial socioeconomic burden [2]
Treatment with SABA was associated with 1.67-fold increased risk of stroke in chronic obstructive pulmonary disease (COPD) patients
Among COPD patients, the use of inhaled SABA is associated with an increased risk of stroke, and combination treatment with inhaled LABA and inhaled corticosteroids (ICSs) relates to a risk reduction

Summary

Introduction

Chronic obstructive pulmonary disease (COPD), characterized by enhanced airway inflammatory response to noxious gas and persistent airflow limitation [1], is a leading cause of morbidity and mortality globally and leads to a growing and substantial socioeconomic burden [2]. Current COPD guideline advocates that inhaled bronchodilators, including short-acting muscarinic antagonists (SAMAs), short-acting β-agonists (SABAs), long-acting muscarinic antagonists (LAMAs) or long-acting β-agonists (LABAs) are used first for treatment of COPD, and inhaled corticosteroids (ICSs) are added for patients with frequent exacerbations [1]. These agents, either alone or in combination, were reported to have modifying effects on COPD inflammation [7]. Patients with chronic obstructive pulmonary disease (COPD) are at higher risk of stroke than those without COPD. This study aims to explore the impact of inhaled pharmacotherapy on stroke risk in COPD patients during a three-year follow-up, using a nationwide, population-based study and a matched cohort design

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