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Background/Introduction ETNA-AF (ETNA) is a multinational, prospective, observational study evaluating the experience with edoxaban in the clinical practice of patients with atrial fibrillation (AF). ENGAGE AF-TIMI 48 was a randomized double-blind trial that tested the clinical benefits of edoxaban versus warfarin. The recommended dose is 60 mg, dose-reduced to 30 mg daily in patients with at least 1 of 3 label-indicated criteria (renal impairment [creatinine clearance: 15–≤50 mL/min], weight ≤60 kg, or concomitant use of potent P-glycoprotein inhibitors). Purpose We assessed whether the effectiveness and safety of edoxaban in clinical practice were consistent with findings from the pivotal randomized clinical trial. Methods We obtained patient-level data from ETNA and ENGAGE AF-TIMI 48. We initially extracted patients from similar geographic regions, and then used propensity-score matching (PSM) to adjust key baseline characteristic differences between studies. The primary effectiveness endpoint was all stroke or systemic embolism (SSE) and mortality; the safety endpoint was major bleeding (MB). We used Cox proportional hazards models to compare event rates for the clinical outcomes between ETNA and ENGAGE AF-TIMI 48. Results 8,615 AF patients with CHADS2 score ≥2 received the 60 mg edoxaban recommended dose (5,462 ETNA; 3,153 ENGAGE AF-TIMI 48). After PSM, key baseline characteristics were well-balanced between the studies: mean age 71.0 years (SD: 9.07); for both ETNA and ENGAGE AF-TIMI 48 median CHA2DS2-VASc score and median HAS-BLED score were 4 and 2. The annualized incidence rate of SSE was 1.65% in ETNA vs 1.53% in ENGAGE AF-TIMI 48 (HR 0.98; 95% CI 0.49, 1.93; p=0.94). ETNA had similar annualized mortality, 2.81%, compared with ENGAGE AF-TIMI 48, 2.34%, (HR 1.49; 95% CI 0.84, 2.63; p=0.17). MB was less frequent in ETNA vs ENGAGE AF-TIMI 48 (1.10% vs 3.56%; HR 0.25; 95% CI 0.14, 0.44; p Conclusions The effectiveness of edoxaban in clinical practice from a large registry was consistent with efficacy findings from the randomized controlled trial. We observed a lower rate of bleeding events in the ETNA observational study compared with the ENGAGE AF-TIMI 48 trial. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Daiichi Sankyo Inc.

Background Patients with atrial fibrillation (AF) who initiated vitamin K antagonist (VKA) were at highest risk of stroke and bleeding in the first few months of therapy. Understanding of the temporal trend of clinical events in AF patients on non-VKA oral anticoagulant (NOAC) therapy should aid therapeutic decisions. Purpose To evaluate the temporal trend of clinical events in AF patients receiving edoxaban in routine clinical practice in the Global ETNA-AF program. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program evaluating the safety and effectiveness of edoxaban in patients from European and Asian countries. Thromboembolic, bleeding and death events were analysed separately for the 1st and 2nd year of the follow-up period, using a time-to-first-event estimation of cumulative incidence and annual rate via Kaplan-Meier method. Results A total of 27,617 patients were included in this analysis, 48.6% from Europe and 51.4% from Japan, Korea, and Taiwan. Baseline characteristics were consistent with typical AF population in real world studies (Table 1). Approximately 83% of patients received the recommended edoxaban dose. Annualized rates of ischaemic stroke and major bleeding (ISTH) were lower in the 2nd year than in the 1st year: ischaemic stroke 0.59% (95% CI, 0.50–0.70) vs 0.86% (95% CI, 0.75–0.98), p=0.015; major bleeding 0.87% (95% CI, 0.75–1.00) vs 1.15% (95% CI, 1.02–1.29), p=0.036. The trend toward lower rates of ischaemic stroke and major bleeding in the 2nd year was consistent across regions. All-cause mortality increased slightly from the 1st year to the 2nd year, which was not statistically significant and was not driven by cardiovascular (CV) mortality (Table 2). Conclusion In routine clinical practice in the Global ETNA-AF program, major bleeding and ischaemic stroke rates in >27,000 patients on edoxaban therapy declined from 1st year to 2nd year. Further analyses will investigate whether such trend is influenced by selection for healthier patients over time. Longer follow-up is needed to better understand long-term trends. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Table 1. Baseline characteristicsTable 2. Annualised clinical event rates

Background Use of vitamin K antagonists (VKAs) is associated with a crude event rate of 23% per year for worsening renal function (WRF). Although non-vitamin K antagonist oral anticoagulants (NOACs) have been associated with a lower risk of longitudinal decline in renal function compared with VKAs, available evidence on renal function decline in patients using NOACs is still limited. Furthermore, renal function is a dose reduction criterion for NOACs, which poses an important question about how physicians should treat patients whose renal function worsens over time. Purpose To evaluate the degree of renal function decline in AF patients treated with edoxaban after 2 years of follow-up, and to investigate clinical outcomes of patients with vs without WRF in the ETNA-AF-Europe study. Methods ETNA-AF-Europe is a multinational, multicentre, observational, post-authorisation safety study conducted in 825 sites in 10 European countries. Results are based on a data snapshot taken on 26th October 2020 which include data up to 2 years of follow-up. Patients were excluded from the analysis population if data to calculate estimated glomerular filtration rate [eGFR] were not available for at least one of the follow-up time-points of 1-year and 2-year. We categorised patients (n=9084) into two subgroups: 1) those with WRF (i.e. ≥25% decline in eGFR from baseline; n=918), and 2) those without WRF (n=8166). eGFR was estimated using the Cockcroft-Gault formula. Baseline characteristics and annualised event rates including 95% confidence intervals were analysed using descriptive analyses. Results Of the 13,417 patients in ETNA-AF-Europe who were included in the 2-year follow-up analysis, 9084 were included in this subgroup analysis, of whom 56.2% were male. Baseline eGFR were similar between patients with and without WRF when comparing across the different renal function categories (Table 1). The majority of the edoxaban-treated patients did not experience WRF (89.9%) during the 2 years of follow-up. The proportion of patients with WRF (10.1%) were older, more often frail and had higher rates of underlying comorbidities, such as diabetes, hypertension and heart failure (Table 1). Patients with WRF had higher annualised event rates of all-cause and cardiovascular death than those without (3.78% vs 1.90% and 2.06% vs 0.92%, respectively). Major bleeding and stroke rates were low, but numerically higher in patients with renal worsening compared to those without WRF (Figure 1). Intracranial haemorrhage rates remained low (0.17% vs 0.19%; Figure 1) in both subgroups. Conclusions This subgroup analysis provides real-world evidence for a low risk of WRF in AF patients treated with edoxaban over a 2-year period. Patients with WRF had higher mortality than those without, as well as numerically higher major bleeding and stroke rates. Importantly, intracranial haemorrhage rates remained low irrespective of WRF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH /

Aims To compare the safety and efficacy of edoxaban combined with P2Y12 inhibition following percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) presenting with an acute coronary syndrome (ACS) or chronic coronary syndrome (CCS). Methods and results In this pre-specified sub-analysis of the ENTRUST-AF PCI trial, participants were randomly assigned 1:1 to edoxaban- or vitamin K antagonist (VKA)-based strategy and randomization was stratified by ACS (edoxaban n = 388, VKA n = 389) vs. CCS (edoxaban n = 363, VKA = 366). Participants received edoxaban 60 mg once-daily plus a P2Y12 inhibitor for 12 months, or VKA combined with a P2Y12 inhibitor and aspirin 100 mg (for 1–12 months). The primary bleeding endpoint at 12 months occurred in 59 (15.2%) vs. 79 (20.3%) ACS patients [hazard ratio (HR): 0.73, 95% confidence interval (CI): 0.59–1.02, P = 0.063], and in 69 (19.0%) vs. 73 (19.9%) CCS patients (HR: 0.94, 95%CI: 0.68–1.31, P = 0.708) with edoxaban- and VKA-based therapy, respectively [P for interaction (P-int) = 0.2741]. The main secondary endpoint (composite of CV death, myocardial infarction, stroke, systemic embolic events, or definite stent thrombosis) in ACS patients was 33 (8.5%) vs. 28 (7.2%) (HR: 1.16, 95%CI: 0.70–1.92), compared with 16 (4.4%) vs. 18 (4.9%) (HR: 0.91, 95%CI: 0.47–1.78) CCS patients with edoxaban and VKA-based therapy, respectively (P-int = 0.5573). Conclusions In patients with AF who underwent PCI, the edoxaban-based regimen, as compared with VKA-based regimen, provides consistent safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation.

Background In patients undergoing AF catheter ablation (CA), uninterpreted DOACs reduced bleeding events without increasing ischemic events compared with vitamin K antagonist, and the continuation of anticoagulants is recommended for AF ablation. However, in the past studies, patients received once-daily DOACs in the evening, not in the morning of the procedure day. Moreover, there has been no study comparing uninterrupted 4 DOACs; therefore, the safety and effect of uninterpreted DOACs taken just in the morning of AF ablation is unknown. Objective The purpose of this study was to compare bleeding complications and thromboembolism events between 4 DOACs in patients undergoing AF ablation. Method This study was the retrospective single-center cohort study of consecutive patients who underwent AF ablation between April 2014 to July 2019. All patients continued DOAC uninterruptedly including just in the morning of the procedure. The primary endpoint included major bleeding events within the first 30 days after CA. The secondary endpoints included the composite events of ischemic stroke, systemic embolism, myocardial infarction, and vascular death. Result A total of 713 patients (mean age 64±12 years, 72% male) were included in this analysis; enrolled patients were 88, 238, 218, and 169 respectively in dabigatran, rivaroxaban, apixaban and edoxaban group. At the baseline, the ratio of age ≥75 years and CHADS2 score was higher in apixaban group, though all other baseline variables were similar between them. The primary endpoint was observed 0%, 2.1%, 0.45%, and 4.7% respectively in dabigatran, rivaroxaban, apixaban, and edoxaban group (P=0.013) without significant difference about secondary endpoint between them (P=0.3). Comparing twice-daily vs once-daily DOACs, the primary endpoint was observed significantly lower in the twice-daily group than in once-daily group (0.32% and 3.2% respectively, P=0.0054), without any significant difference about secondary endpoint (0% and 0.73% respectively, P=0.26). Conclusion Taking DOACs also in the morning of AF ablation, uninterrupted twice-daily DOACs are safer than once-daily DOACs without increasing ischemic event, although twice-daily DOACs, especially apixaban, were used in higher aged patients. Figure 1 Funding Acknowledgement Type of funding source: None

Objective To search for rates of major bleeding events in patients (pts) with age ≥80 or ≥90 years (y.) with ongoing anticoagulants referred to hospital. Methods Patients complaining any bleeding events were submitted to propensity score matching for major bleeding and stratified according to age ≥80 or ≥90 y. and warfarin or direct oral anticoagulants (DOACs). Setting A General Hospital, northwest Tuscany, five-year survey, 385,650 visits; catchment area 197,722 inhabitants, of whom 18,373 on warfarin and 14,808 on DOACs. Out of DOACs, dabigatran and rivaroxaban were available in the catchment area since 5 y., apixaban 4 y. and edoxaban 3 y; 5,553 pts received rivaroxaban, 4,602 dabigatran, 3,147 apixaban and 1,506 edoxaban. Endpoint Primary endpoint was one-week death, and incidence of major bleeding. Results Out of 7,474 pts considered, 2504 (33.5%) pts were older than 80 y., of whom 518 (6.8%) were older than 90 y; they were enrolled in the study. Overall, 253 (10.1%) showed history of stroke/TIA, 578 (22.9%) atrial fibrillation, 277 (11.1%) cancer, 177 (7.0%) congestive heart failure, 33 (1.3%) pulmonary thromboembolism. Of these 7,474 pts 1,040 (41.5%) showed major bleeding: 621 (24.8%) were gastrointestinal of which 258 (10.3%) of the upper tract and 363 (14.5%) of the lower tract; 794 (31.7%) were brain haemorrhage; the remaining patients showed other bleeding. Overall, 435 (5.8%) pts needed reversal anticoagulation, 325 (4.4%) red blood cell pack, and 2879 (38.5%) admission. Eventually, 127 pts have been readmitted to the hospital for ischemic stroke and 499 for new bleeding event. CHA2D2VASc-score was 2.5±1.5 and Charlston Comorbidity Index was 3.4±2.3. Out of 2,504 patients older than 80 y., 367 (14,7%) received anticoagulants (including heparin) of which 134 (5.4%) received warfarin versus 63 (2.5%) DOACs (p One-week mortality rate as follows: anticoagulants 35 (1.4%) versus DOACs 6 (0.2%), p Out of 518 patients older than 90 y., 98 (18.9%) received anticoagulants (including heparin) of whom 44 (8.5%) received warfarin; 11 (2.1%) DOACs (p One-week mortality rate as follows: anticoagulants 10 (1.9%) versus DOACs 1 (0.2%), p Conclusion Patients of 80 y. and even 90 y. or older, with ongoing warfarin, showed higher percentage of major bleeding events and mortality rate versus DOACs. Within DOACs, edoxaban was more likely to show lower rate of major bleeding events, without differences in death rate. Funding Acknowledgement Type of funding source: None

Aim We aimed to compare the safety and efficacy of edoxaban in combination with P2Y12 inhibition in the setting of percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) presenting with an acute coronary syndrome (ACS) or stable coronary artery disease (SCAD). Methods and results This is a pre-specified sub-analysis of the ENTRUST-AF PCI trial. Participants were randomly assigned 1:1 to an edoxaban or vitamin K antagonist (VKA) based strategy and randomisation was stratified by ACS (edoxaban n=388, vitamin K n=389) vs. SCAD (edoxaban n=363, vitamin K=366). Participants received edoxaban 60mg once daily plus a P2Y12 inhibitor for 12 months; or VKA in combination with a P2Y12 inhibitor and aspirin 100mg (for 1–12 months). The primary bleeding endpoint, a composite of International Society on Thrombosis and Haemostasis (ISTH) major or clinical relevant non-major bleeding, at 12 months occurred in 59 (18.52%/year) vs 79 (26.21%/year) ACS patients (Hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.591–1.018, P=0.0631), and in 69 (23.11%/year) vs 73 (25.02%/year) SCAD patients (HR 0.94, 95% CI 0.676–1.305, P=0.7082) with edoxaban and VKA based therapies, respectively (P for interaction [P-int]=0.2741). The main efficacy endpoint (composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, or definite stent thrombosis) occurred in 33 (9.59%/year) vs 28 (8.21%/year) ACS-patients (HR 1.16, 95% CI 0.697–1.916) compared with 16 (4.84%/year) vs 18 (5.47%/year) SCAD-patients (HR 0.91, 95% CI 0.465–1.781) with edoxaban and VKA based therapy, respectively (P-int=0.5573). Conclusions An antithrombotic regimen consisting of edoxaban and a P2Y12-inhibitor without aspirin provides equal safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation with ACS or SCAD. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH

Background In AF patients on direct oral anticoagulants (DOAC), safety and effectiveness vary with dose. This might impact treatment decisions. Purpose To investigate the effects of dosing of the DOAC edoxaban in AF patients on safety and effectiveness during 1-year observation in a real-world setting. Methods The Global ETNA-AF NIS included 26,823 patients. Baseline data by edoxaban dosing (60mg/30mg) and their influences on the safety (major bleeding [MB], clinically relevant non-major bleeding [CRNMB]), and effectiveness (stroke, systemic embolism, myocardial infarction [MI], death) were investigated (Table). Results Figure shows the breakdown by dose (60mg vs 30mg) and recommended (rec) vs non-recommended (non-rec) dosing. Patients on non-rec 30mg vs on rec 60mg edoxaban were older (mean ± SD: 74±9 vs 70±9 y); had lower creatinine clearance (72.2±20.6 vs 85.8±26.8 mL/min); and had more comorbidities, history of MB (2.1% vs 1.1%), and strokes (11.0% vs 8.6%). Non-rec 60mg vs rec 30mg patients were younger (75±9 vs 78±9 y), had fewer comorbidities, history of MB (1.2% vs 2.6%), and strokes (10.2% vs 16.4%). In non-rec 30mg vs rec 60mg, MB was not lower and ischaemic events were not higher. In non-rec 60mg vs rec 30mg, no increase in MB, CRNMB or ischaemic events was seen. Conclusion Edoxaban was prescribed at the label recommended dose in the vast majority of patients. Non-rec 30mg patients were sicker than rec 60mg patients while non-rec 60mg patients were less sick than rec 30mg patients. Overall event rates were low, and ischaemic event rates of non-rec 30mg and bleeding event rates of non-rec 60mg were not numerically higher than that of corresponding rec dosing groups. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

Background Ischemic stroke after transchatheter aortic valve implantation (TAVI) was recognized. Previous study showed that the median time of a stroke was 2.0 days (IQR, 1.0–5.0) after TAVI. One of the main mechanisms for ischemic stroke after TAVI was hyper-coagulation activity associated with TAVI procedure. However, the change of coagulation status in patients with oral anticoagulant (OAC) therapy was not investigated fully. Purpose We investigated the difference of blood coagulation parameters between the patients with vitamin K antagonist (VKA) and those with direct oral anticoagulants (DOAC). Methods We enrolled 253 patients underwent transfemoral TAVI between February 2017 and March 2019 in our hospital. Of 253 patients, 71 patients (age: 85, male: 20%) took OAC therapy (VKA: 21 patients, DOAC: 50 patients). Patients who took apixaban was 32 patients, rivaroxaban was 7, edoxaban was 11. Prothrombin activation fragment 1+2 (F1+2) as a molecular marker of thrombin generation, thrombin-anti-thrombin complex (TAT) as a marker of thrombin neutralization, soluble fibrin monomer complex (SFMC) as a marker of thrombophilia and fibrin/fibrinogen degradation product (FDP) as a marker of fibrinolysis were measured before and immediately after TAVI, and on 1 and 2 day postoperatively. We also assessed ischemic stroke after TAVI between 2 groups according to BARC-2 criteria. Results In patients with VKA, the value of PT-INR the day before TVAI was 1.2 (1.1–1.4). The level of F1+2 in patients with VKA was significantly greater on day 0 postoperatively than those with DOAC [855 pmol/l (595–1135) vs 614 pmol/l (452–774) P=0.003]. The level of SFMC in patients with VKA was significantly greater on day 0 postoperatively than those with DOAC [37.4 μg/ml (17.3–64.5) vs. 15.7 μg/ml (8.8–27.3) P=0.002]. The level of FDP in patients with VKA was significantly greater on day 0 postoperatively than those with DOAC [VKA: 5.8 μg/ml (3.8–7.9), DOAC: 4.0 μg/ml (3.1–5.3) P=0.023]. There were no patients with ischemic stroke among 2 groups. Conclusion This study revealed that coagulation activity was increased after TAVI. Furthermore, the coagulation activity in patients with VKA was significantly higher than that with DOAC at especially immediately after TAVI. Careful attention should be paid to hyper-coagulation status after TAVI in patients with VKA. Funding Acknowledgement Type of funding source: None

Background Pivotal randomized trials of non-vitamin K antagonist oral anticoagulants (NOACs) adopted Cockcroft-Gault (CG) formula to calculate estimated glomerular filtration rate (eGFR) to determine the dosages of NOACs. However, Modified Diet in Renal Disease (MDRD]) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae are commonly used in clinical practice. In the present study, we investigated the agreements/disagreements of eGFRs calculated using different equations in Asian AF patients. Second, we studied the impacts of using different equations on the dosages of NOACs used, and finally, clinical outcomes compared to warfarin were assessed. Methods This retrospective study used medical data from a multicenter healthcare provider in Taiwan which included 39,239 AF patients whose data about body weight (BWs) and serum Creatinine (sCr) were available. Among these patients, there were 11,185 and 2,323 AF patients treated with NOACs and warfarin, respectively. Results At the cutoff values of eGFR of 50 mL/min, the agreements were 78% between MDRD and CG, and 81% between CKD-EPI and CG. The disagreements between different equations were largely due to over-estimations (21% for MDRD and 17% for CKD-EPI), especially for patients aged >75 years and BWs Among patients receiving NOACs whose dosages were defined as “on-label” based on MDRD or CKD-EPI, only those whose dosages were “truly on-label” based on CG were associated with a lower risk of ischemic stroke/systemic embolism (IS/SE) (adjusted hazard ratio [aHR] 0.78, 95% CI 0.61–1.00), major bleeding (aHR 0.34, 95% CI 0.26–0.45) and IS/SE or major bleeding (aHR 0.55, 95% CI 0.46–0.66) compared to warfarin (Figure). The risk of IS/SE (aHR 0.82, 95% CI 0.39–1.72), major bleeding (aHR 0.57, 95% CI 0.25–1.32) and IS/SE or major bleeding (aHR 0.69, 95% CI 0.40–1.19) were similar between warfarin and patients treated with NOACs whose dosages were disconcordant between eGFRs calculated using MDRD and CG (Figure). Conclusions The adoptions of MDRD or CKD-EPI rather than CG would result in inappropriate dosing of NOACs (mainly overdosing) which would attenuate the advantages of NOACs compared to warfarin. Therefore, the CG equation should be used as the “gold standard” for the calculations of eGFRs to guide the NOAC dosages. Funding Acknowledgement Type of funding source: None

Background In the phase 3 RCT ENGAGE AF-TIMI 48, both the higher-dose (HDER/edoxaban 60/30mg) and lower-dose edoxaban regimen (LDER/edoxaban 30/15mg) were non-inferior to well-managed warfarin for the prevention of stroke or systemic embolic events in patients with atrial fibrillation (AF). While LDER was associated with a 41% relative increase in ischemic stroke as compared to warfarin, LDER showed a larger relative reduction in bleeding events than HDER. An interaction tree analysis was performed to identify subgroups of patients likely to derive greater benefit from LDER vs. HDER based on a serious net outcome (SNO) that combines the most serious stroke and bleeding events: disabling/fatal ischemic stroke or life-threatening/fatal bleeding. Methods and results LDER (N=7002) had a higher risk for disabling/fatal ischemic stroke (HR 1.37, 95% CI 1.06–1.77; p=0.017), but fewer life-threatening/fatal bleeds (0.61 (0.44, 0.84), p=0.002) than HDER (N=7012). The SNO was similar with LDER vs HDER in the total population (0.95 (0.78–1.16), p=0.61). In the 30% of patients who had either malignancy or paroxysmal AF (Figure) the SNO was significantly lower with LDER vs HDER (HR 0.59 (0.40–0.86)), driven by large reductions in bleeding without an increase in ischemic stroke in this subgroup (figure). Meanwhile the remaining 70% of patients with neither malignancy nor paroxysmal AF tended to have a higher risk with LDER vs. HDER (HR 1.15 (0.91–1.46), P-interaction 0.003). Conclusions In our current post-hoc analysis we were able to demonstrate that the combined rate of serious stroke and bleeding events was similar in patients treated with LDER and HDER. Moreover, patients with a malignancy as well as those with paroxysmal AF derived a greater net benefit from LDER vs. HDER regarding serious AF-/anticoagulation-related outcome events. These results need to be viewed as hypothesis-generating which may, if confirmed, aid physicians in individualizing edoxaban dosing. Funding Acknowledgement Type of funding source: None

Background Atrial fibrillation (AF) is a risk factor for dementia and oral anticoagulant (OAC) use is associated with a decreased risk of dementia in patients with AF. Objective We sought to find whether the risk of dementia would be different between patients treated with non-vitamin K antagonist oral anticoagulants (NOACs) and those treated with warfarin. Methods Using the Korean National Health Insurance database from January 2014 to December 2017, we identified OAC naïve non-valvular AF patients aged 40 years or older. For the comparison, warfarin and NOAC groups were balanced using the inverse probability of treatment weighting method (IPTW). The primary outcome was incident dementia. Patients were censored at the occurrence of dementia, discontinuation of index treatment, or the end of the study period (December 31, 2018). Results Among 72,846 of total study patients, 25,948 were treated with warfarin and 46,898 were treated with NOAC (17,193 with rivaroxaban, 9,882 with dabigatran, 11,992 with apixaban, and 7,831 with edoxaban). Crude incidence of dementia was 4.65 per 100 person-years in warfarin group and 4.98 per 100 person years in NOAC group. Baseline characteristics were well-balanced after IPTW (mean age 72 years, 93% CHA2DS2-VASc ≥2, 58% men). Compared to warfarin, NOAC showed a comparable risk of dementia (hazard ratio [HR] 0.944, 95% confidence interval [CI] 0.934–1.059), vascular dementia (HR 0.921, 95% CI 0.814–1.043) and Alzheimer dementia (HR 1.101, 95% CI 1.019–1.191). When comparing individual NOACs with warfarin, edoxaban was associated with a lower risk of dementia (HR 0.830, 95% CI 0.740–0.931). Rivaroxaban (HR 0.767, 95% CI 0.648–0.907) and edoxaban (HR 0.786, 95% CI 0.620–0.996) were associated with a lower risk of vascular dementia than warfarin. In subgroup analyses, NOAC was associated with a lower incidence of dementia than warfarin particularly in patients with prior stroke (HR 0.891, 95% CI 0.820–0.968) and in patients aged 65–74 years (HR 0.815, 95% CI 0.709–0.936). Conclusion In this large Asian population with AF, NOAC showed a comparable result with warfarin on the risk of dementia. Edoxaban was associated with a lower risk of dementia. NOAC appeared more beneficial especially in those with AF who had a history of prior stroke and aged 65–74 years. Funding Acknowledgement Type of funding source: None

Background The prevalence of atrial fibrillation (AF) and the need for appropriate anticoagulation increase with age. The benefit/risk profile of direct oral anticoagulants such as edoxaban in elderly population with AF in regular clinical practice is therefore of particular interest. Purpose Analyses of Global ETNA-AF data were performed to report patient characteristics, edoxaban treatment, and 1-year clinical events by age subgroups. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program conducted in Europe, Japan, Korea, Taiwan, and other Asian countries. Demographics, baseline characteristics, and 1-year clinical event data were analysed in four age subgroups. Results Of 26,823 patients included in this analysis, 50.4% were ≥75 years old and 11.6% were ≥85 years. Increase in age was generally associated with lower body weight, lower creatinine clearance, higher CHA2DS2-VASc and HAS-BLED scores, and a higher percentage of patients receiving the reduced dose of 30 mg daily edoxaban. At 1-year, rates of ISTH major bleeding and ischaemic stroke were generally low across all age subgroups. The proportion of intracranial haemorrhage within major bleeding events was similar across age groups. All-cause mortality increased with age more than cardiovascular mortality. Conclusion Data from Global ETNA-AF support the safety and effectiveness of edoxaban in elderly AF patients (including ≥85 years) in routine clinical care with only a small increase in intracranial haemorrhage. The higher all-cause mortality with increasing age is not driven by cardiovascular causes. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

Introduction Direct oral anticoagulation (DOAC) therapy represents the standard of care in patients with atrial fibrillation (AF) and increased stroke risk. In a real world setting withholding DOAC medication before elective AF ablation is considered to reduce procedural bleeding risks. The aim of this study was to determine the individual DOAC level prior to the ablation procedure, to identify predisposing factors affecting traceable DOAC levels and to screen for associated severe adverse events. Methods Between September 2016 and March 2019 blood samples were obtained from patients on DOAC before an elective AF ablation. Per institutional standard all patients have been instructed to pause DOAC medication prior ablation for one or two doses depending on the patient profile and type of medication. The time interval between ablation and last DOAC intake was calculated in hours. Patient characteristics, procedural data and in-hospital complications were noted from all patients. Results A total of 1000 patients (60% male, age: 68y, GFR 83.25: BMI: 28, CHADSVASC score 3) undergoing AF ablation were included. Two groups were defined. Group A (n=416, 41.6%): patients treated with “single pill” DOAC (Rivaroxaban (n=288, 28.8%) and Edoxaban (n=128, 12.8%)). Group B (n=584, 58.4%): patients treated with twice a day DOAC (Apixaban (n=505, 50.5%) and Dabigatran (n=79, 7.9%)). The only difference in patient characteristics was an increased prior bleeding history in group B. The DOAC pause was significantly longer in group A (mean 40h) compared to group B (mean 32h), p=0.026. In a total of 217 patients (21.7%) DOAC levels where traceable prior to AF ablation. Traceable DOAC levels were significantly more common in group B (n=144/584, 24.7%) compared to group A (n=73/416, 17.5%). Adverse events occurred in 5.7% of patients (0.4% stroke, 0.3% tamponade, 2.5% hematoma, 1.9% AV-fistel, 0.7% pseudoaneurysma). T-Test analysis showed no significant difference in the occurrence of adverse events between both groups. Conclusion Despite of interrupting DOACs before an elective AF ablation therapeutic substance levels can be detected in >20% of patients. The rate of adverse events was not different between “single pill” vs. twice a day DOAC intake. Funding Acknowledgement Type of funding source: None

Background Adherence and persistence to non-VKA oral anticoagulants (NOACs) are important to achieve optimal clinical outcomes in patients with atrial fibrillation (AF). Dosing frequency may play a role in adherence and persistence to NOAC therapy. Among the NOACs that are currently available, edoxaban and rivaroxaban are given once daily (QD) while dabigatran and apixaban are given twice daily (BID). Purpose The objective of the study was to compare the adherence and persistence in AF patients receiving QD versus BID NOAC regimens in Germany. Methods Using an administrative database from our institution (Deutsche Analysedatenbank für Evaluation und Versorgungsforschung) between January 2013 and December 2017, a retrospective cohort study was conducted to compare the 6-month adherence in NOAC-naïve AF patients who initiated anticoagulant therapy. Continuous enrolment for 12 months before anticoagulant initiation was required to assess baseline characteristics. Adherence was measured using proportion of days covered (PDC) and medication possession ratio (MPR). Proportions of patients with PDC ≥80% and MPR ≥80% were also measured. Treatment discontinuation was defined as a prescription supply gap of ≥90 days. Inverse probability treatment weighting using propensity score was applied to control for differences in baseline characteristics. Results A total of 8249 (1236 edoxaban, 7013 rivaroxaban) and 7359 (6053 apixaban, 1306 dabigatran) patients who received QD and BID regimens were included. The two regimen groups were well balanced after weighting. Patients who received QD regimens had a significantly higher mean PDC at 6 months compared to those who received BID regimens (0.78 vs. 0.72, p Conclusions Adherence to once-daily regimens of NOAC was significantly higher compared to adherence to twice-daily NOAC regimens. Future research is needed to examine the relationship between adherence to NOAC treatment and clinical outcomes in AF patients, and factors affecting persistence. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This study was sponsored by Daiichi Sankyo Inc

Background Clinicians are encouraged to anticoagulate frail and older patients. Both groups were underrepresented in pivotal AF stroke prevention trials. Large, more geographically generalizable data are needed for safety and treatment efficacy in these groups. Aim: ETNA-AF-Europe registry assessed key clinical outcomes and risk scores in frail and older patients compared to their counterparts. Methods ETNA-AF-Europe is a large, prospective, post-authorisation, observational study of patients with AF being prescribed edoxaban. The registry captured frailty as a single, mandatory field as perceived by physicians. Baseline characteristics evaluation and 1-year outcomes of patients were extracted by presence of frailty and age (≥ vs. Results Of, 13,090 enrolled patients, 10.6% were considered frail with coding complete for 12,212 patients. Whilst 27.9% of patients were aged ≥80, of these only 25.3% were frail. Frail patients differed from non-frail and had similar baseline characteristics to those aged ≥80 years. Frail patients were more frequently female, with lower BMI and higher HAS-BLED risk score (Table), and incurred the highest rates of overall and cardiovascular deaths and major bleeding, even more than those aged ≥80 (Figure). Despite this, intracranial haemorrhage (ICH) was surprisingly low and comparable. Conclusions In this large, Europe wide group of patients with AF anticoagulated with edoxaban, patients considered frail by physicians are not always older. A clinical frailty perception is associated with a 4-fold higher short-term mortality. Whilst major bleeding is higher in this frail cohort, ICH is comparably low. The HAS-BLED score in frail patients prescribed edoxaban, appears to predict non-neurological bleeding. These data provide confidence for prescribing edoxaban in frail AF patients to prevent stroke. One-year outcomes Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH, Munich, Germany

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are recommended as first choice therapy for thrombo-embolic prevention in patients with non-valvular atrial fibrillation (AF) and an elevated CHA2DS2-VASc score. A critical determinant for both safety and effectiveness of NOAC treatment is adherence to the prescribed medication regimen. Real-life adherence is suboptimal for many cardiovascular drugs. Measuring and improving NOAC adherence is primordial for optimising AF care. Purpose We measured adherence to any of the four NOACs in a population of AF patients who participate to a clinical trial during which they received targeted education on AF and its treatment. Methods This analysis is part of a prospective, multicenter, randomized controlled trial which is currently ongoing at three Belgian hospitals (AF-EduCare study). Ambulatory or hospitalised AF patients of that trial, treated with a NOAC, and who received a short targeted education session about AF and NOAC therapy at initiation, form the study group of this analysis. Monitoring of NOAC intake was performed by an electronic Medication Event Monitoring System (MEMS), starting immediately after initiation of the study and the education session (for 3 months). A special cap fits on a medication bottle and records the exact date and time of bottle openings. An LCD screen on the cap displays the number of openings of the medication bottle over a period of 24 hours, providing feedback about the correct intake. Dabigatran was replaced by a proxy medication as Dabigatran should be stored in the original package in order to protect it from moisture. Regimen adherence was calculated as the number of days on which one bottle opening in case of Rivaroxaban or Edoxaban and two bottle openings in case of Apixaban or Dabigatran is/are registered, divided by the total number of monitored days and multiplied by 100. Results A total of 233 patients (mean age 71.0±7.7 years; 71.2% males; CHA2DS2-VASc score 3.4±1.5; mean duration of AF history 5.8±7.5 years) were given a MEMS. Of these patients 32.2%, 31.3%, 26.2% and 10.3% were respectively on Edoxaban, Apixaban, Rivaroxaban and Dabigatran. Regimen adherence for these NOACs was 95.9±9.3%, 91.6±13.7%, 95.6±5.6% and 94.0±7.1% respectively. Overall, 94.4% of the patients had an adherence >80% and 81.1% had an adherence >90%. Adherence for the once and twice daily regimens was 95.8±0.7% and 92.2±1.3%, respectively (p=0.0003; Mann-Whitney U test). Conclusions This is a first prospective study investigating adherence for all NOACs using electronic monitoring. In this sample of AF patients who underwent a targeted education session before the 3 month monitoring period, mean adherence to NOAC intake was >90% for all NOACS. This high adherence may be related to both the education and the use of MEMS, which provided direct feedback to the patient. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The AF-EduCare study is a project supported by the Fund for Scientific Research, Flanders (T002917N).

Background Direct oral anticoagulants have been demonstrated to have advantages in several patient populations compared with warfarin. However, the safety and efficacy are controversial between direct oral anticoagulants and warfarin in patients with chronic kidney disease, especially on dialysis, who have been excluded from randomised controlled trials. Purpose The purpose of this study was to investigate the safety and the efficacy of direct oral anticoagulants as compared to warfarin in patients on dialysis. Methods A meta-analysis was conducted on clinical studies in patients requiring oral anticoagulation and dialysis. PubMed, the Cochrane Library, and Web of Science were queried for the terms “dialysis”, “warfarin”, and “apixaban OR dabigatran OR rivaroxaban OR edoxaban”. The same terms or relevant studies were also queried on the website of the U.S. National Institute of Health and relevant reviews. The clinical endpoints were stroke/systemic embolism and major bleeding. Pooled estimates were calculated using a random-effects model. Results Six observational studies (18487 patients) were included in this study. The risk of major bleeding (odds ratio (OR) 0.45; 95% confidence interval (CI) 0.31–0.65; p Conclusions Direct oral anticoagulants are associated with a lower risk of major bleeding and a similar risk of stroke/systemic embolism compared to warfarin in patients on dialysis. To validate these findings, randomised controlled trials are warranted. Funding Acknowledgement Type of funding source: None

Background Although patients taking direct oral anticoagulants (DOACs) do not require routine coagulation monitoring, the distribution of anti-factor Xa activity (AXA) values, prothrombin time (PT), PT-international normalized ratio (INR) and activated partial thromboplastin time (APTT) in patients on apixaban, edoxaban and rivaroxaban therapy is still not clear. Purpose The aim is to set the standard values of AXA values, PT, PT-INR and APTT in patients using DOACs. Methods We measured AXA, using chromogenic assay with the HemosIL Liquid Heparin kit, PT, PT-INR and APTT at trough and peak times in 224 patients with non-valvular atrial fibrillation and venous thromboembolism, of whom 90 received apixaban, 100 received edoxaban and 34 received rivaroxaban. The peak time was defined as 3 hours after the intake of apixaban or rivaroxaban, and 2 hours after the intake of edoxaban. The trough time was defined as that immediately before the intake. The AXA values, PT, PT-INR and APTT were measured at least 72 hours after the start of treatment. The dosage of DOACs is defined according to the prescribing information in Japan. Results (The order of results below is apixaban, edoxaban and rivaroxaban, respectively.) The average AXA values were 2.29, 0.23 and 0.39 (IU/mL) at trough time, and 3.04, 1.01 and 1.70 (IU/mL) at peak time. The average PT values were 17.9, 12.9 and 13.1 (s) at trough time, and 19.7, 15.5 and 17.5 (s) at peak time. The average PT-INR values were 1.49, 1.07 and 1.08 at trough time, and 1.65, 1.29 and 1.45 at peak time. The average APPT values were 34.5, 31.3 and 32.0 (s) at trough time, and 39.5, 35.9 and 39.8 (s) at peak time. Conclusion Our findings reveal the standard values of AXA, PT, PT-INR and APTT in patients using apixaban, edoxaban and rivaroxaban in each dosage. The DOACs should be changed if the measured value is out of those standard values in 90% confidence interval. Funding Acknowledgement Type of funding source: None

Background Vitamin K antagonists (VKA) and non-VKA oral anticoagulants (NOACs) are used to prevent thromboembolic conditions in patients with atrial fibrillation (AF). Unlike VKA, NOACs have fixed dosage schemes, do not require regular laboratory tests, and have fewer drug and food interactions. The use of NOACs has increased substantially in recent years in Germany. However, there is limited evidence on the comparative effectiveness and safety between different NOACs and VKA in real-world settings. Purpose The objective of the study was to compare the clinical outcomes, including systemic embolism (SE), ischemic stroke (IS), and major bleeding, of edoxaban with other NOACs (apixaban, dabigatran, rivaroxaban) and VKA in AF patients in Germany. Methods Using an administrative database from our institution (Deutsche Analysedatenbank für Evaluation und Versorgungsforschung) between January 2013 and December 2017, a retrospective cohort study was conducted to compare the effectiveness (risk of SE or IS) and safety (risk of major bleeding) in NOAC-naïve AF patients who initiated anticoagulant therapy. Continuous enrolment for 12 months before anticoagulant initiation was required to assess baseline characteristics. Patients were followed up until (1) the first outcome event (SE, IS, or major bleeding), (2) disenrollment from health plans, or (3) discontinuation of the index NOAC or VKA or therapy switch, whichever occurred first. Inverse probability treatment weighting (IPTW) using propensity score was applied to control for differences in baseline characteristics. Cox proportional hazards models were used to estimate the hazard ratios (HR) for each outcome comparing edoxaban versus other NOACs and VKA. Sensitivity analyses were conducted with follow-up period cut-off at 1 year. Results A total of 1236 edoxaban, 6053 apixaban, 1306 dabigatran, 7013 rivaroxaban, and 5430 VKA patients were included. Patient cohorts were well balanced after weighting. The adjusted risks of SE or IS were lower for edoxaban compared to apixaban (HR 0.83, 95% CI 0.69–0.99), dabigatran (HR 0.54, 95% CI 0.40–0.74), rivaroxaban (HR 0.72, 95% CI 0.60–0.87), and VKA (HR 0.65, 95% CI 0.53–0.78) (all p Conclusions Edoxaban was associated with a significantly lower risk of SE or IS compared to other NOACs and VKA, indicating improved effectiveness. Edoxaban also had a favourable safety profile with a significantly lower risk of major bleeding compared to dabigatran, rivaroxaban, and VKA. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This study was sponsored by Daiichi Sankyo Inc.

Background Direct-acting oral anticoagulants (DOACs) are now the preferred choice over warfarin in patients with atrial fibrillation (AF). The comparative efficacy and safety of DOACs over warfarin in patients with and without diabetes mellitus (DM) has not been fully evaluated. Purpose To evaluate the efficacy and safety of DOACs compared to warfarin in patients with non-valvular atrial fibrillation with and without DM. Methods A comprehensive review of the literature was performed to identify RCTs with data on DOACs compared to warfarin in the subgroups of DM and nonN-DM. Our outcome of interest were stroke/systemic embolization (SSE) and major bleeding. A random-effects meta-analysis was performed. We further performed a network meta-analysis to assess the most effective of all the therapies for the above mentioned subgroups. Results Our search identified 4 RCTs with 71,683 randomized patients, of which 22,087 were DM and 49,596 were non-DM. The mean duration of follow up was 2.3 years. Our results showed that the DOACS were associated with lower odds for SSE in diabetics (OR 0.80; 95% CI 0.67–0.95; p-value=0.01) and non-diabetics (OR 0.81; 95% CI 0.71–0.92; p-value Conclusion In this meta-analysis of RCT, we found that DOACs are more effective and similarly safe compared to warfarin irrespective of the diabetic status of the patient. Funding Acknowledgement Type of funding source: None

Aims We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding. Methods and results ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36–2.23 and adj-HR 1.27; 95% CI 1.07–1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02–1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36–0.65; NRI 0.42; 95% CI 0.33–0.51, respectively]. Conclusion Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF.

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Background The life-span of patients with congenital heart disease strongly increased during the last decades due to advances in diagnostic and therapeutic approaches. Some cardiac malformations may involve an increased risk of thrombo-embolic complications. Further, adult patients with congenital heart disease (ACHD) are at increased risk to develop cardiac arrhythmia, such as atrial flutter or fibrillation. Therefore, various constellations may indicate anti-thrombotic and/ or anti-coagulative preventive or therapeutic regimen. Concomitantly, progress was made in the development of anticoagulative pharmacotherapy in the last decade with the development of the novel oral anticoagulants (NOACs). Purpose Aim of the study is to assess the use of oral anticoagulants, particularly of the NOACs dabigatran, rivaroxaban, apixaban, and edoxaban in ACHD in an unselected real-world scenario. Methods Data are derived from the German BARMER health insurance comprising approx. 9 million insurants. Within the years 2005 - 2017, we identified all adult patients that were hospitalized with a main or secondary diagnosis of a congenital heart disease by ICD-10 (Q20–28). Patients were categorized into simple, moderate, and high complexity cardiac lesions of heart disease. Oral anticoagulants were identified by ATC codes and assigned to the patient if prescribed at least twice. Results Overall, we included 13,344 ACHD patients (137,079 patient years). The use of oral anticoagulants increased from 8.3% in 2005, to 13.1% in 2010, 19.8% in 2015 and up to 22.5% of patients in 2017. Correspondingly, the use of vitamin K antagonists increased, reaching a plateau at approx. 14% since 2012. More interestingly, however, the prescription of NOACs constantly increased from 1.6% in 2012 to 8.4% in 2017. Therefore, NOACs were used for anticoagulation in 37% (n=802) of ACHD patients in 2017. Among those treated with NOACs, apixaban was used in 44.1% of patients, compared to rivaroxaban in 38.5%, edoxaban in 10.5% and dabigatran in 6.9%. With regard to heart disease complexity, oral anticoagulation was used in 21% ACHD with simple defects (1,065 of 5,080 patients), 19% of ACHD with moderate complexity disease (430 of 2,296), and 30% in complex ACHD patients (644 of 2,138). NOACs were applied to 6.2% of simple ACHD patients, 7.7% of ACHD patients with moderate complexity disease and 14.6% of complex ACHD patients. In 2017, 22.5% of ACHD (2,139) were anticoagulated. Thereof, Vit K ant. were used in 62.5%, apixaban in 16.5% and rivaroxaban in 14.4% (see figure). 2017: Use of oral anticoagulants in ACHD Conclusion Over 20% of ACHD patients require anticoagulation in the current era. Interestingly, despite the lack of prospective studies increasingly NOACs are replacing vitamin K antagonists in the ACHD population. In 2017 NOACs accounted for 37% of all anticoagulated patients in our study. The use of NOACs was not restricted to simple lesions but up to 30% of complex ACHD patients received NOACs in the current era.

Introduction Edoxaban has been approved for stroke prevention in patients with atrial fibrillation based on its comparable efficacy and superior safety compared to warfarin in the pivotal ENGAGE AF-TIMI 48 trial. ETNA-AF Europe (NCT02944019) was initiated in agreement with the EMA to evaluate benefits and risks of edoxaban treatment in unselected patients in routine clinical practice. Methods 13,980 patients from across 825 hospital and office-based physicians from 10 European countries (Austria, Belgium, Germany, Ireland, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom) were enrolled, and will be followed-up for 4 years. This snapshot analysis includes baseline and first outcome data of 7,672 patients (56.3% of all enrolled patients) that have completed their first 1-year follow-up visit (mean follow-up: 343.5 days). Results The average age of patients was 73.4 years, the mean weight was 81.9 kg (Table 1). Frequent comorbidities include hypertension (77.2%), valvular heart disease (17.4%), congestive heart failure (5.8%) and history of myocardial infarction (4.2%). Patients receiving the 30 mg dose (22.9%) were older, had a lower creatinine clearance and had a higher risk for both stroke and bleeding as compared to those on the 60 mg dose (77.1%). Overall, the incidence of clinical events was low: all-cause mortality: 3.56%/y, major bleeding 0.95%/y, intracranial haemorrhage 0.28%/y, any stroke or systemic embolic events 0.88%/y. Patient characteristics at Year 1 Patient characteristics All patients Edoxaban 60 mg Edoxaban 30 mg [7,672] [5,916 (77.1%)] [1,756 (22.9%)] Age [years] mean (SD) 73.4 (9.26) 71.8 (8.98) 79.1 (7.81) Body weight [kg] mean (SD) 81.9 (17.33) 84.1 (16.80) 74.3 (16.93) CrCl (CG) [mL/min] mean (SD) 75.0 (30.29) 82.5 (29.14) 51.2 (19.75) CHA2DS2-VASc mean (SD) 3.1 (1.38) 2.9 (1.34) 3.8 (1.28) HAS-BLED mean (SD) 2.5 (1.10) 2.4 (1.07) 2.9 (1.08) First occurrence of all-cause mortality (n, %/year) 257 (3.56%) 129 (2.31%) 128 (7.90%) First occurrence of intracranial haemorrhage (n, %/year) 20 (0.28%) 16 (0.29%) 4 (0.25%) First occurrence of major bleeding (n, %/year) 68 (0.95%) 49 (0.88%) 19 (1.18%) First occurrence of stroke/SEE (n, %/year) 63 (0.88%) 45 (0.81%) 18 (1.11%) CG, Cockcroft-Gault; CrCl, creatinine clearance; SD, standard deviation; SEE, systemic embolic events. Conclusions We found low bleeding and stroke rates in 7,672 unselected, mainly elderly AF patients treated with edoxaban in routine clinical practice. These findings were consistent across edoxaban doses and reinforce the effectiveness and safety of NOACs such as edoxaban in routine clinical care in Europe. Acknowledgement/Funding Daiichi Sankyo Europe GmbH, Munich, Germany

Background/Introduction Catheter ablation (CA) has been established as a first-line therapy in the treatment of non-valvular atrial fibrillation (NVAF), and uninterrupted direct oral anticoagulants (DOACs) have become mainstream for the management of periprocedural thromboembolic events. Since 2014, edoxaban has been used for anticoagulation therapy for AF in Japan. However, evidence for uninterrupted use of edoxaban during the periprocedural period of CA in NVAF patients is limited. Purpose KYU-RABLE is a prospective, multicenter, single-arm interventional study, conducted in 23 institutions in Japan to evaluate the efficacy and safety of uninterrupted periprocedural oral edoxaban in patients undergoing CA. The plasma concentration of edoxaban and its relation with plasma coagulative biomarker levels during the periprocedural period were also evaluated. Methods A total of 537 Japanese NVAF patients were enrolled in Japan from December 2017 to September 2018. Edoxaban 60mg (30 mg in patients indicated for dose adjustment) was administered once daily in the morning for at least 4 weeks before CA and continued for at least 4 weeks after CA. On the day of CA, edoxaban was administered immediately after confirmation of hemostat. The primary endpoint was the composite incidence of thromboembolism and major bleeding events during 4 weeks from the procedural day. Plasma concentration of edoxaban and plasma levels of coagulative biomarkers including D-dimer, soluble fibrin monomer complex (SFMC) and prothrombin fragment 1+2 (F1+2) were also measured. Results Among the total 513 patients who underwent CA, 75.2% had radiofrequency CA and 23.0% had cryoballoon CA. The majority of CA patients (65%) received edoxaban 60mg/day, while others (35%) received 30mg/day. As for the primary endpoint, one major bleeding (cardiac tamponade) event was observed and no thromboembolism occurred. Clinically relevant non-major bleeding events occurred in six patients (1.2%), the most were puncture site hemorrhage. The plasma concentration of edoxaban at CA was dependent upon the duration from last administration of edoxaban before CA. However, plasma levels of coagulative biomarkers (D-dimer, SFMC, F1+2) were maintained within appropriate range during the periprocedural period, irrespective of the edoxaban concentration. We also report changes of plasma levels of coagulative biomarkers in sub group analyses by CHADS2 scores and types of AF. Conclusion The KYU-RABLE study demonstrated the first evidence of the efficacy and safety of uninterrupted periprocedural edoxaban administered once daily on the morning for NVAF patients underwent CA. Edoxaban treatment was associated with a low risk of periprocedural bleeding and thromboembolic complications. Furthermore, these low event risks were considered to be associated with the maintained plasma level of coagulative biomarkers, regardless of the change in edoxaban plasma concentration. Acknowledgement/Funding Daiichi Sankyo Co. Ltd.

Background The impact on outcomes of oral anticoagulants in pts at extremes of body weight have not been well-characterized. Aim To analyse the outcomes of pts with atrial fibrillation (AF) enrolled in ENGAGE AF-TMI 48 randomized to warfarin (W) targeting INR 2.0–3.0, higher (HDE) or lower dose regimens of edoxaban (LDE), focusing on subgroups of patients at the extremes of weight. Methods and results Among 21105 pts enrolled in the trial we identified 3 subgroups: 1082 with low body weight (LBW) (95th percentile, >120 kg). Baseline characteristics differed markedly (LWB pts were older and more likely Asian, women, with prior TIA/stroke, renal dysfunction) resulting in a trend towards higher rates of stroke/systemic embolism (SSE: 6.5% vs 4.7% in MBW vs 1.6% in HBW) and major bleeding (MB: 9.3% vs 7.7% in MBW vs 6.5% in HBW) in the warfarin arm. The risks of SSE (Pint = 0.52) were similar between W and HDE regardless of body weight, while the relative reduction in MB was greatest in LBW patients (HR reduction45%, 23%, 1% across weight groups; Pint = 0.35) (Figure). Net clinical outcomes (SEE/major bleeding/death) tended to be most favourable for LBW pts (HR 0.67 [0.50–0.90]; Pint 0.084) (Figure). Main outcomes during follow up Conclusions In ENGAGE AF-TIMI 48 the profile of AF pts with LBW markedly differed suggesting a more fragile clinical status. Use of dose-adjusted edoxaban, as compared to W, was associated with similar efficacy regardless of weight, while bleeding and net outcomes were most favourable in LBW pts.

Background Although the prescription of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with non-valvular atrial fibrillation (AF) has been rapidly increasing in Asian countries since their introduction, limited evidence exists on the effectiveness and safety of warfarin and all 4 available NOACs from current clinical practice in the Asian population. We aimed to evaluate comparative effectiveness and safety of warfarin and all 4 available NOACs Methods We studied a retrospective observational cohort of oral anticoagulant (OAC) naïve non-valvular AF patients treated with warfarin or NOACs (rivaroxaban, dabigatran, apixaban, or edoxaban) from January 2015 to December 2017, based on the Korean Health Insurance Review and Assessment database. For the comparisons, warfarin to 4 NOACs and NOAC to NOAC comparison cohorts were balanced using inverse probability of treatment weighting (IPTW). Ischemic stroke, intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), major bleeding (MB) and a composite clinical outcome were evaluated. Results A total of 116,804 patients were included (25,420 with warfarin, 35,965 with rivaroxaban, 17,745 with dabigatran, 22,177 with apixaban, and 15,496 with edoxaban). Patients treated with warfarin were younger (mean age 67 years) compared to NOAC users (71 to 73 years) and had lower mean CHA2DS2-VASc score (3.18) than the NOAC groups (3.58 to 3.76). Among the NOAC users, patients prescribed apixaban were older (mean age 73 years) than other NOAC groups (71 to 72 years), had higher mean CHA2DS2-VASc score (3.76) than others (3.55 to 3.63) and higher burden of comorbidities. More than half of patients were prescribed reduced dose regimes. After IPTW, all baseline covariates were well balanced across 5 treatment groups. Compared with warfarin, all NOACs were associated with lower risks of ischemic stroke, ICH, GIB, MB and composite outcome (Figure A). Apixaban and edoxaban showed a lower rate of ischemic stroke compared with rivaroxaban and dabigatran (Figure B). Apixaban, dabigatran and edoxaban had a lower rate of GIB and MB compared with rivaroxaban. The composite clinical outcome was non-significantly different for apixaban vs edoxaban. Conclusions In this large contemporary observational Asian cohort, all 4 NOACs were associated with lower rates of ischemic stroke and major bleeding compared to warfarin. Differences in clinical outcomes between NOACs may give useful guidance for physicians to choose drugs to fit their particular patient clinical profile.

Background As populations age, prevalence of atrial fibrillation (AF) and ensuing need for oral anticoagulation increase. Benefits and risks of nonvitamin K antagonist oral anticoagulants such as edoxaban in the frail, elderly population with AF in regular clinical care is of special interest. Purpose Data from Global ETNA-AF capturing almost 2ehz745.1164 patients treated with edoxaban in Europe, Japan, and Korea/Taiwan, was analyzed to compare outcomes in patients Methods Global ETNA-AF is a multinational, multicentre, prospective, noninterventional program (EU: NCT02944019, Japan: UMINehz745.116417011, Korea/Taiwan: NCT02951039). Demographics, baseline characteristics, and 1-year outcome data were reported for 19416 patients classified into 3 age categories. Results At 1-year follow-up, rates of major bleeding (including intracranial haemorrhage [ICH]) and ischaemic stroke were generally low. All-cause and CV mortality increased with age; CV mortality was a minor proportion of all-cause mortality in all age groups. Rates of major bleeding and ischaemic stroke increased slightly with age, but to a lesser extent than all-cause and CV mortality. There was no increase in the rate of ICH with age. Conclusion Global data from this set of unselected patients support the use of edoxaban as a safe and effective treatment in elderly and very elderly patients with AF in regular clinical care. Acknowledgement/Funding Daiichi Sankyo

Objective To evaluate rates of major bleeding (mBleed) associated with anticoagulant treatments in patients (pts) with age ≥75 years (y), referred to hospital in northwest Tuscany. Methods We analysed 4-y survey; 302,687 visits; catchment area 197,722 inhabitants, of whom 15,267 on Warfarin (W) and 10,397 on direct oral anticoagulants (DOACs). DOACs were available in the catchment area since 4 y (dabigatran and rivaroxaban), 3 y (apixaban), and 2 y (edoxaban). Overall, 3,373 pts received dabigatran, 4,046 rivaroxaban, 2,141 apixaban, and 839 edoxaban. Pts with hemorrhage were submitted to propensity score matching for mBleed and stratified according to age ≥75 y, and W or DOACs. Primary endpoint was one-month death in pts with age ≥75 y. Results Out of 1,919 mBleed enrolled, those of pts aged ≥75 y were 1,127 (59%) versus (vs) 792 (41%) aged Patients on W showed higher rate of mBleed (n=175; 9.1%) compared to DOACs (n=53; 2.8%); p Warfarin or DOACs and outcomes Major Bleeding (pts ≥75 y) p value versus pts Patients with age >75 years and bleeding Conclusion In pts with age ≥75 y, rate of mBleed and short-term mortality were significantly higher than in pts aged

Objective To look for outcomes of patients (pts) with major gastrointestinal haemorrhage (mGIH) and ongoing anticoagulants out of four-year survey of community hospital with catchment area 197,722 inhabitants, of whom 15,267 with Warfarin (W) and 10,397 with direct oral anticoagulants (DOACs). DOACs were available for prescription in the catchment area since 4 years (dabigatran and rivaroxaban), 3 years (apixaban), and 2 years (edoxaban). Methods Haemorrhage (n=1,919) were submitted to propensity score matching for major bleeding; mGIH were enrolled and stratified according to ongoing W or DOACs. Primary endpoint was one-month death. Results Out of 476 mGIH, 73 pts received anticoagulants; 22 DOACs and 51 W; p=0.0006. Of note mGIH on W accounted for 2.7% (51/1,919) per year of pts, and 0.08% (51/15,267) of the catchment area. Conversely, mGIH on DOACs accounted as follows: dabigatran (n=10/476) 0.53%, rivaroxaban (n=6/476) 0.32%, apixaban (n=5/476) 0.35%, and edoxaban (n=1/476) 0.11% per year of pts; p=0.117. Rate of mGIH and DOACs versus (vs) rate of mGIH and W as follows: less than (−) 5 fold (2.7x100/0.53) of dabigatran vs W, p=0.004; −8 fold (2.7x100/0.32) of rivaroxaban vs W, p=0.0002; −7 fold (2.7x100/0.35) of apixaban vs W; p=0.ehz745.10188, and −25 fold (2.7x100/0.11) of edoxaban vs W; p=0.ehz745.101801. However no difference versus the catchment area per year (0.723): 0.07% (10/3,373) dabigatran, 0.04% (6/4,046) rivaroxaban, 0.08% (5/2,141) apixaban, 0.06% (1/839) edoxaban. Overall, one-month death accounted for 10/476 (2.1%). Of note 236 mGI were from the upper tract and 240 from the lower tract. Among upper tract, 10 pts received DOACs (4 dabigatran, 4 rivaroxaban, 2 apixaban, and 0 edoxaban) and 21 received W. One-month death was 0/10 DOACs versus 1/21 W, p=0.483. Among lower tract, 12 pts received DOACs (6 dabigatran, 2 rivaroxaban, 3 apixaban, and 1 edoxaban) and 30 pts received W; one-month death was 0 for every groop. Anticoagulant reversal treatment was given to 6/22 (27%) pts with DOACs versus 18/51 (35%) with W, p=0.014; transfusion to 6/22 (27%) versus 11/51 (22%), respectively, p=0.306; admission 19/22 (86%) versus 42/51 (82%), respectively, p=0.004. Sensitivity/specificity ratio of variables and biomarkers for aggressive pharmacological approach were obtained by area under ROC curve (AUC) >0.50. PTT value >37 sec (AUC 0.57) showed sensitivity 15%, specificity 90%; INR value >1.4 (0.50), sens 15%, spec 80%. In addition, warfarin (0.49) sens 15%, spec 80%; age ≥75 years (0.48) sen 60%, spec 40%. Gastrointestinal bleeding: flow-chart. Conclusion Out of four-year survey, pts with ongoing DOACs were less likely to have mGIH when compared to W. Patients with W were more likely to receive reversal tratment; pts with DOACs were more likely to undergo admission. Short-term mortality of pts with W was higher than DOACs. Aggressive pharmacological approach should be driven by PTT, INR, ongoing warfarin, and older age.

Background Edoxaban is a new oral anticoagulant with factor X activated (FXa) inhibition properties. It is approved for the prevention of ictus and embolism in patients with atrial fibrillation and for the treatment of venous thrombosis and lung embolism. However, little is known about its effects on endothelial cell functions. Objectives To study the edoxaban effects on key endothelial functions as proliferation, wound-healing, angiogenesis and peripheral blood mononuclear cells (PBMCs) adhesion. Methods Human umbilical endothelial cells (HUVECs) were obtained from donated umbilical cords after signed informed consent of the mothers. Cell proliferation and viability were measured by a real-time cell analyzer by noninvasive electrical impedance monitoring. Migration was study in wound-healing assays. Angiogenesis was measured after 16 hours of HUVECs' seeding in a three dimensional matrix and PBMCs adhesion to HUVECs' monolayers was assessed in the presence or in the absence of edoxaban and/or FXa. Measurements on each assay was compared between control conditions and edoxaban's or FXa's treatments and between treatments with FXa and the combination of FXa and edoxaban. Results Edoxaban (1 Nm – 1 μm) was a safe, non-toxic molecule for HUVECs. It significantly promoted HUVECs' growth at concentrations between 10–500 Nm, been the maximal response at 100 nM. The proliferative effect of edoxaban 100 nM was also observed in the presence of FXa 9 nM, which also induced proliferation by itself. In spite of this proliferative effect, edoxaban (50–100 nM) did not increased healing (cells' migration) after a wound, but counteracted the healing effects of FXa 9 nM. Edoxaban (100–500 nM) alone did not influence angiogenesis, but partially restore the anti-angiogenic effect of FXa on HUVECs. Finally, and very interestingly, edoxaban (50–500 nM) significantly inhibited PBMCs adhesion to endothelial cells' monolayers, and even blocked the FXa (50 nM)- and tumor necrosis factor (TNF; 10μg/ml)-induced adhesion. PBMCs adhesion to endothelial cells Conclusions Edoxaban is a safe and proliferative-inducer drug in endothelial cells in vitro. It counteracts the anti-angiogenic and pro-migratory effects of FXa on HUVECs, but more importantly, edoxaban significantly reduced PBMCs adhesion to endothelial cells monolayers in comparison to control experiments and compared to stimulated cells, independently of the pro-inflammatory drug used. Acknowledgement/Funding Daiichi-Sankyo España S.A.U.

Background Edoxaban, a direct FXa inhibitor, has been proven non-inferior in efficacy and safer compared to warfarin in the ENGAGE AF-TIMI 48 trial. In routine care, the safety of edoxaban has not been formally established. ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study (NCT02944019) conducted in 825 sites in 10 European countries. Here 13,980 edoxaban-treated patients with AF were enrolled between November 2016 and February 2018, and will be followed-up for 4 years. Methods 7,672 patients (73.4±9.26 years, 57.5% male) enrolled in the ETNA-AF Europe registry completed the one-year follow-up and were stratified into low-, intermediate- and high-risk for stroke and bleeding using the CHA2DS2-VASc and HASBLED score, respectively. We here analysed the occurrence of stroke, bleeding, intracranial haemorrhage and mortality in such categories. Results The mean CHA2DS2-VASc score at baseline was 3.1±1.38 and the mean HAS-BLED score was 2.5±1.1. Not surprisingly, patients at higher risk were older, had a lower body weight, more comorbidities, and a lower creatinine clearance. A higher proportion of patients at high risk received the reduced 30 mg edoxaban dose. Overall, the yearly event rates of stroke, intracranial haemorrhage, major bleeding and death were low. However, these rates increased consistently in patients with higher stroke and bleeding risks. Residual stroke risk on anticoagulation was comparable to the risk of major bleeding (Table 1). Outcomes by stroke and bleeding risk CHA2DS2-VASc: mean 3.1±1.38 HAS-BLED: mean 2.5±1.1 All patients Low risk (0, 1 if female) Intermediate risk (1, 2 if female) High risk (≥2, 3 if female) Low risk (0, 1) Intermediate risk (2, 3) High risk (≥4) Patients, N 233 1,133 6,304 1,224 4,932 1,516 7,672 First occurrence of outcomes, n (%/year) All-cause mortality 2 (0.92%) 12 (1.11%) 242 (4.09%) 14 (1.21%) 161 (3.47%) 82 (5.78%) 257 (3.56%) Intracranial haemorrhage 0 (0.00%) 1 (0.09%) 19 (0.32%) 2 (0.17%) 10 (0.22%) 8 (0.56%) 20 (0.28%) Major bleeding 0 (0.00%) 6 (0.56%) 62 (1.05%) 2 (0.17%) 43 (0.93%) 23 (1.63%) 68 (0.95%) Stroke/SEE 0 (0.00%) 4 (0.37%) 59 (1.00%) 3 (0.26%) 41 (0.89%) 19 (1.34%) 63 (0.88%) SEE, systemic embolic event. Conclusions In this unselected cohort of patients with AF anticoagulated with edoxaban, high CHA2DS2-VASc and HAS-BLED scores were associated with higher risks of stroke, bleeding and death. Indirectly compared with the expected rates in non-anticoagulated patients, our data underpin the value of anticoagulants such as edoxaban in patients at high risk of stroke and bleeding. Acknowledgement/Funding The ETNA-AF Registry was funded by Daiichi Sankyo Europe GmbH, Munich, Germany.