Abstract Background Atrial fibrillation (AF) patients with a history of ischaemic stroke (IS) have a higher risk for recurrent IS events and were largely excluded from the pivotal, randomised, controlled phase 3 trials on oral anticoagulants. Thus, the effectiveness and safety of edoxaban in these patients need to be studied in a real-world setting. Purpose To compare edoxaban real-world effectiveness and safety in AF patients with or without an IS history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients receiving edoxaban for stroke prevention. This snapshot analysis summarises baseline characteristics with medical history and 2-year annualised rates of all-cause death, cardiovascular (CV) death, stroke (haemorrhagic, ischaemic, any), and bleeding (including major bleeding [MB], major gastrointestinal [GI] bleeding, intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding [CRNMB], and any bleeding) in patients with or without IS history. Results Data from 27,333 patients (3215 with prior IS and 24,118 without) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with IS history were significantly older, more likely ≥75 years of age, and had a lower mean body weight and creatinine clearance (P<0.0001 for all; Table). Patients with IS history also had significantly higher baseline stroke (CHA2DS2-VASc) and bleeding (HAS-BLED) risk scores (P<0.0001 for both; Table). A significantly higher percentage of patients with IS history had previous transient ischaemic attacks (TIA), MB, and ICH (P<0.0001 for all; Table). Patients with IS history more likely received edoxaban 30 mg vs 60 mg at baseline (P<0.0001). Effectiveness and safety outcomes hazard ratios are shown in the Figure. Patients with IS history had significantly higher rates of all-cause death (4.5% vs 3.0%; P<0.0001), CV death (1.9% vs 1.4%; P=0.004), IS (2.5% vs 0.5%; P<0.0001), any stroke (3.1% vs 0.7%; P<0.0001), and TIA (0.5% vs 0.2%; P=0.0002). Patients with IS history had significantly higher annualised rates of MB (1.6% vs 1.0%; P<0.0001), major GI bleeding (0.8% vs 0.5%; P=0.003), ICH (0.6% vs 0.3%; P<0.0001), haemorrhagic stroke (0.5% vs 0.2%; P<0.0001), CRNMB (2.3% vs 1.3%; P<0.0001), and any bleeding (6.1% vs 4.1%; P<0.0001). Conclusions Patients with AF who have a history of IS are more likely elderly; have histories of MB, ICH, and TIA; and have high baseline stroke and bleeding risk scores. Patients with IS history receiving edoxaban have a considerably higher likelihood of experiencing IS or TIA, whereas the risk of experiencing any bleeding event (with the exception of ICH) is only modestly higher than in those without IS history. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo