Non-recommended dosing occurs in ~25-50% of non-vitamin K antagonist oral anticoagulant prescriptions, with limited data for edoxaban. We analyzed edoxaban dosing patterns in atrial fibrillation patients from the Global ETNA-AF program, relating patterns to baseline characteristics and 1-year clinical outcomes. The following dosing groups were compared: non-recommended 60 mg ("overdosed") vs. recommended 30 mg; non-recommended 30 mg ("underdosed") vs. recommended 60 mg. Most (22,166/26,823; 82.6%) patients received recommended doses. Non-recommended dosing was more frequent near label-specified dose-reduction thresholds. Ischemic stroke (IS; HR 0.85, 95% CI 0.50-1.47; p = 0.6) and major bleeding (MB; HR 1.47, 95% CI 0.97-2.71; p = 0.07) did not differ between recommended 60 mg and "underdosed" groups, whereas all-cause (HR 1.61, 95% CI 1.23-2.08; p = 0.0003) and cardiovascular deaths (HR 1.61, 95% CI 1.11-2.38; p = 0.01) were higher in the "underdosed" group. Compared with recommended 30 mg, the "overdosed" group had lower IS (HR 0.51, 95% CI 0.28-0.98; p = 0.04) and all-cause death (HR 0.74, 95% CI 0.55-0.98; p = 0.03) without higher MB (HR 0.74, 95% CI 0.46-1.22; p = 0.2). In conclusion: non-recommended dosing was infrequent, but more common near dose-reduction thresholds. "Underdosing" was not associated with better clinical outcomes. The "overdosed" group had lower IS and all-cause death without higher MB.

Cardiovascular Division National Hospital Organization Osaka National Hospital Osaka 540 0006 Japan

Department of Cardiology University Heart and Vascular Centre Hamburg University Medical Center Hamburg Eppendorf 20246 Hamburg Germany

Department of Cardiovascular Medicine The Cardiovascular Institute Tokyo 106 0031 Japan

Division of Cardiology Department of Medicine Taipei Veterans General Hospital Taipei 11220 Taiwan

Fondazione VillaSerena per la Ricerca 65013 Città Sant'Angelo Italy

German Center for Cardiovascular Research Partner Site Hamburg Kiel Lübeck 20246 Hamburg Germany

Global Specialty Medical Affairs Daiichi Sankyo Inc Basking Ridge NJ 07920 USA

Institute of Cardiovascular Sciences University of Birmingham IBR 136 Wolfson Drive Birmingham B15 2TT UK

Institute of Clinical Medicine Cardiovascular Research Center National Yang Ming Chiao Tung University Taipei 11217 Taiwan

Institute of Computer Science Academy of Sciences of the Czech Republic 18207 Prague Czech Republic

Pisa University Hospital University of Pisa 56126 Pisa Italy

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