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Edeltraut Garbe,1 Fabian Hoti,2 Tania Schink,1 Kristian Svendsen,3 Haydar Al-Eid,4 Per Arkhammar,5 Marie Carlholm,6 Harald Fjällbrant,6 Stefan Franzén,7,8 Cecilia Hedlund,9 Bianca Kollhorst,10 Atul Kumar,11 Muriel Lobier,2 Vasili Mushnikov,2 Tore Persson,9 Xu Qiao,2 Aaro Salosensaari,12 Wiebke Schäfer,1 Nicholas M Sicignano,13 Gunnar Johansson,14 Eileen O Dareng15 1Department Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 2Biostatistics, Scientific Services, Real World Solutions, IQVIA, Espoo, Finland; 3Department of Pharmacy, UiT The Arctic University of Norway, Tromsø, Norway; 4United States Navy, Naval Medical Center, Portsmouth, Virginia, USA; 5Global Patient Safety Biopharma, AstraZeneca, Gothenburg, Sweden; 6Late-Stage Respiratory and Immunology, BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden; 7BPM Evidence Statistics, Medical Evidence, BioPharmaceuticals Medical, Gothenburg, Sweden; 8School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 9Biometrics, Late-stage Respiratory and Immunology, BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden; 10Department Biometry and Data Management, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 11Global Patient Safety Biopharma, AstraZeneca, Bangalore, India; 12Biostatistics, Scientific Services, Real World Solutions, IQVIA, Turku, Finland; 13Health ResearchTx LLC, Trevose, Pennsylvania, USA; 14Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; 15Safety Epidemiology and Risk Management, AstraZeneca, Cambridge, UKCorrespondence: Eileen O Dareng, AstraZeneca, City House, 126-130 Hills Road, Cambridge, CB2 1RY, United Kingdom, Tel +44 7789447801, Email eileen.dareng@astrazeneca.comPurpose: This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US).Patients and Methods: The study population consisted of patients aged ≥ 40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010– 2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI).Results: 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for “ever use” of roflumilast, compared to “never use”, were 1.12 (95% CI, 1.08– 1.17) in Germany, 1.00 (95% CI, 0.92– 1.08) in Norway, 0.98 (95% CI, 0.92– 1.04) in Sweden, and 1.16 (95% CI, 1.12– 1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among “current users” in Germany (HR: 0.93, 95% CI: 0.88– 0.98), Norway (HR: 0.77, 95% CI: 0.67– 0.87), and Sweden (HR: 0.80, 95% CI: 0.73– 0.88).Conclusion: There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.Keywords: roflumilast, 5-year all-cause mortality, COPD, electronic healthcare database, propensity score