Abstract Background Heart failure (HF) is an established risk factor for stroke and systemic embolic events (SEE) in subjects with atrial fibrillation (AF), but it is debated whether this risk varies according to left ventricular ejection fraction (LVEF). Methods We investigated the impact of HF in the ETNA-AF-Europe registry, a prospective, multi-centre, post-authorisation, observational study enrolling patients treated with edoxaban for AF in 825 sites from 10 European countries. This 2-year follow-up analysis is based on a data snapshot from 26 October 2020. HF was defined as a) history of HF or b) ischaemic cardiomyopathy or c) EF <40% or d) dyspnoea not due to chronic obstructive pulmonary disease together with ≥1 of the following: ischaemic heart disease, valvular heart disease, or hypertension treated with ≥3 drugs. Patients' characteristics are summarised descriptively and clinical outcomes are reported as annualised event rates. The hazard ratio (HR) with 95% confidence intervals (CI) for the association of HF with the outcomes was assessed in Cox regression models with stepwise variable selection. Results Of the 13,133 patients, 1,854 (14.1%) had HF; LVEF was available for 1,489 (80.3%), and was <40% in 671 (43.9%) and ≥40% in 857 (56.1%). Patients with HF were more often men and slightly older than those without (Table 1). As expected, they also had more cardiovascular (CV) comorbidities and higher CHA2DS2-VASC and, to a lesser extent, HAS-BLED scores (Table 1). At the end of the 2-year follow-up, the rates of ischaemic stroke/transient ischaemic attack (TIA)/SEE, major bleeding, intracranial haemorrhage (ICH), CV death, and all-cause death were higher in patients with than without HF (Figure 1). When patients with HF were categorized according to LVEF, ischaemic stroke/TIA/SEE was more frequent in those with LVEF ≥40% vs those with LVEF <40%. By contrast, more patients with LVEF <40% died due to any as well as CV causes. The rates of major bleeding and ICH were comparable between the two subgroups (Figure 1). Univariable Cox regression analysis confirmed the association of HF with major bleeding (HR 2.01, 95% CI [1.49–2.71]) and all-cause death (2.62 [2.28–3.02]), but not with ischaemic stroke/TIA/SEE (1.06 [0.72–1.55]). The results were consistent when LVEF was taken into account: the HRs for LVEF <40% or LVEF ≥40%, respectively, were 1.60 (0.99–2.60) and 1.55 (1.02–2.38) for major bleeding, 2.11 (1.69–2.63) and 1.59 (1.28–1.97) for all-cause death, and 0.66 (0.31–1.41) and 1.19 (0.71–1.98) for ischaemic stroke/TIA/SEE. Conclusions In this real-world, large cohort of patients with AF on edoxaban, those with HF at baseline faced more ischaemic, bleeding, and death events, and having HF increased the risk of major bleeding and death, with no differences according to LVEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.