<p>To estimate major clinical event rates for patients with atrial fibrillation (AF) and atherosclerotic disease treated with edoxaban in routine practice, and to evaluate how well such patients were represented in ENGAGE AF-TIMI 48, the seminal randomized trial comparing edoxaban against warfarin for AF. ETNA-AF-Europe is a prospective cohort of AF patients receiving edoxaban in routine care. We compared patients with coronary or peripheral artery disease (CAD/PAD) to: (1) those without CAD/PAD in ETNA-AF-Europe, and (2) CAD/PAD patients in ENGAGE AF-TIMI 48. Of 13,164 patients in ETNA-AF-Europe, 23.3% had CAD/PAD. Compared with those without, patients with CAD/PAD had higher rates of stroke/systemic embolism (0.87%/year vs. 0.59%/year; HR 1.5, 95%-CI 1.14–1.88), acute coronary syndrome (1.24%/year vs. 0.37%/year; HR 3.3, 95%-CI 2.60–4.27), major bleeding (1.06%/year vs. 0.81%/year; HR 1.3, 95%-CI 1.04–1.63), cardiovascular death (1.59%/year vs. 0.85%/year; HR 1.9, 95%-CI 1.54–2.26), and all-cause death (6.02%/year vs. 3.53%/year; HR 1.7, 95%-CI 1.55–1.89). Compared with CAD/PAD patients in ENGAGE-AF TIMI-48, those in ETNA-AF-Europe had fewer cardiovascular comorbidities, less prevalent aspirin use (20.2% vs. 50.3%), and lower rates of stroke/systemic embolism (0.87%/year vs. 1.5%/year), major bleeding (1.04%/year vs. 3.0%/year), and cardiovascular death (1.59%/year vs. 3.7%), but higher non-cardiovascular mortality (4.43%/year vs. 1.6%/year). In routine practice, deaths and bleeding were the most common events in edoxaban-treated patients with AF. This pattern was consistent between those with and without atherosclerosis. ENGAGE-AF TIMI-48 participants with CAD/PAD had substantially higher cardiovascular but lower non-cardiovascular risks than those treated in daily practice.</p><p>Trial registration number: NCT02944019 (ClinicalTrials.gov Identifier).</p> Graphical Abstract <p></p>