Jens Ellingsen, 1 Gunnar Johansson, 2 Kjell Larsson, 3 Karin Lisspers, 2 Andrei Malinovschi, 4 Bjrn Stllberg, 2 Marcus Thuresson, 5 Christer Janson 1

1Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 2Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 3Integrative Toxicology, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 4Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden; 5Statisticon AB, Uppsala, Sweden

Correspondence: Jens EllingsenDepartment of Medical Sciences, Respiratory, Allergy and Sleep Research, Akademiska Sjukhuset, Uppsala SE-751 85, SwedenTel +46 18 611 13 93Fax +46 18 611 02 28Email jens.ellingsen@medsci.uu.se

Background: Life expectancy is significantly shorter for patients with chronic obstructive pulmonary disease (COPD) than the general population. Concurrent diseases are known to infer an increased mortality risk in those with COPD, but the effects of pharmacological treatments on survival are less established. This study aimed to examine any associations between commonly used drugs, comorbidities and mortality in Swedish real-world primary care COPD patients.Methods: Patients with physician-diagnosed COPD from a large primary care population were observed retrospectively, utilizing primary care records and mandatory Swedish national registers. The time to all-cause death was assessed in a stepwise multiple Cox proportional hazards regression model including demography, socioeconomic factors, exacerbations, comorbidities and medication.Results: During the observation period (1999 2009) 5776 (32.5%) of 17,745 included COPD patients died. Heart failure (hazard ratio [HR]: 1.88, 95% confidence interval [CI]: 1.74 2.04), stroke (HR: 1.52, 95% CI: 1.40 1.64) and myocardial infarction (HR: 1.40, 95% CI: 1.24 1.58) were associated with an increased risk of death. Use of inhaled corticosteroids (ICS; HR: 0.79, 95% CI: 0.66 0.94), beta-blockers (HR: 0.86, 95% CI: 0.76 0.97) and acetylsalicylic acid (ASA; HR: 0.87, 95% CI: 0.77 0.98) was dose-dependently associated with a decreased risk of death, whereas use of long-acting muscarinic antagonists (LAMA; HR: 1.33, 95% CI: 1.14 1.55) and N-acetylcysteine (NAC; HR: 1.26, 95% CI: 1.08 1.48) were dose-dependently associated with an increased risk of death in COPD patients.Conclusion: This large, retrospective, observational study of Swedish real-world primary care COPD patients indicates that coexisting heart failure, stroke and myocardial infarction were the strongest predictors of death, underscoring the importance of timely recognition and treatment of comorbidities. A decreased risk of death associated with the use of ICS, beta-blockers and ASA, and an increased risk associated with the use of LAMA and NAC, was also found.

Keywords: observational, LAMA, inhaled corticosteroids, beta-blockers, acetylsalicylic acid, chronic obstructive pulmonary disease

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