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Background: The prospective, single-arm, observational, phase 4 ETNA-AF Europe study collected real-world data about safety, effectiveness and therapeutic adherence in European patients with non-valvular atrial fibrillation newly prescribed with edoxaban and followed up for 4 years., Methods: Overall, 13 164 patients were included in the full-analysis set, which means that they had at least one documentation after baseline at 4 years. The current paper reports about the 3329 Italian patients out of the whole European population., Results: In the Italian cohort, median age was 76.0 (69.0-82.0) years, with 57.4% of the patients being ≥75 years old. The CHA2DS2-VASc score was >4 in 586 (18.1%) patients. At baseline, 670 (20.8%) patients were classified as frail by the investigators. Edoxaban 30 mg/day was prescribed to 1013 (31.8%) patients: these were older, with more comorbidities and a lower estimated creatinine clearance compared with those receiving 60 mg/day. All-cause mortality was 4.1%/year and there were very low yearly rates of bleeding and thromboembolic events: major bleeding, 0.9%; intracranial hemorrhage, 0.2%; ischemic stroke, 0.3%; systemic embolism, <0.1%. These events were more frequent in patients ≥75 years or in patients with renal impairment or treated with edoxaban 30 mg/day. Advancing age was not associated with an increased incidence of intracranial bleeding., Conclusions: These findings confirm the favorable long-term safety and effectiveness profile of edoxaban in non-valvular atrial fibrillation patients treated in routine clinical care in Italy.

In patients with prevalent or incident atrial fibrillation (AF) after successful transcatheter aortic valve implantation (TAVI) enrolled in the EdoxabaN Versus standard of care and theIr effectS on clinical outcomes in pAtients havinG undergonE Transcatheter Aortic Valve Implantation - in Atrial Fibrillation (ENVISAGE-TAVI AF) trial, the incidence of ischemic stroke (IS) and any stroke was numerically less in the edoxaban group than in the vitamin K antagonist (VKA) group. The present study aimed to identify risk factors associated with IS in an on-treatment subanalysis in patients from ENVISAGE-TAVI AF who received ≥1 dose of edoxaban or VKA. Baseline patient characteristics were compared in patients with and those without IS. Numerical variables were compared using a 1-way analysis of variance; categorical variables were compared using Fisher's exact test. Stepwise Cox regression determined patient characteristics associated with the first IS event. Of 1,377 patients, 41 (3.0%) experienced an IS, and 1,336 (97.0%) did not; baseline demographics and clinical characteristics were well balanced between groups. Most ISs occurred within 180 days of TAVI for edoxaban (57.9%) and VKA (68.2%). The rate of IS was 2.0/100 person-years for edoxaban versus 2.7/100 person-years for VKA. Independently associated with IS were history of systemic embolic events (hazard ratio 2.96, 95% confidence interval 1.26 to 7.00, p = 0.01) and pre-TAVI use of VKAs (hazard ratio 2.17, 95% confidence interval 1.12 to 4.20, p = 0.02). In conclusion, although the overall incidence of IS was small for patients with AF on edoxaban or VKA after successful TAVI, patients with a history of systemic embolic events or pre-TAVI use of VKAs may be at greater risk of IS after TAVI., Competing Interests: Declaration of competing interest Dr. Hengstenberg is a clinical proctor for Boston Scientific and Edwards Lifesciences and reports payment for speaker bureaus, support for attending meetings, and advisory board participation from Daiichi Sankyo in addition to institutional funding from Abbott Vascular, Amgen, Biosensors, Biotronik, Boehringer Ingelheim Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Ferrer, Medtronic, Novartis, Philips, Siemens, and Terumo. Dr. Unverdorben and Dr. Jin are employees of Daiichi Sankyo. Dr. Möllmann received personal fees from Abbott, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Edwards Lifesciences, and Pfizer and support for attending meetings from Abbott, AstraZeneca, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, and Pfizer. Dr. Van Mieghem reports grants or contracts from Abbott, Abiomed, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Medtronic, PulseCath BV, and Siemens. Dr. Thiele is the president of the German Society of Cardiology. Dr. Nordbeck reports speaker honoraria from Bayer, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, and Pfizer. Dr. Rassaf reports personal and other fees from AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, and Novartis. Dr. Moreno reports personal fees from Abbott Vascular, Amgen, Biosensors, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Ferrer, Medtronic, Philips, and Terumo. Dr. Mehran reports research grants to institution, support for attending meetings from Bayer and Daiichi Sankyo, and consulting fees from Daiichi Sankyo. Dr. Veltkamp reports grants or contracts from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, and Medtronic and consulting or advisory board participation for AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Javelin Ventures, and Portola Pharmaceuticals. Dr. Dangas reports research grants to institution, support for attending meetings from Bayer and Daiichi Sankyo, and consulting fees from Daiichi Sankyo. Dr. Lang has no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth to 18 years at risk for venous thromboembolism (VTE). Children requiring anticoagulant therapy were enrolled into 5 age cohorts (0 to < 6 months (N = 12), 0.5 to < 2 years (N = 13), 2 to < 6 years (N = 13), 6 to < 12 years (N = 13), and 12 to < 18 years (N = 15)) receiving tablet or oral suspension of edoxaban at doses expected to be equivalent to 30 or 60 mg once daily (q.d.) in adult subjects with VTE. Sixty-six pediatric subjects were enrolled and completed the study. Edoxaban plasma concentration peaked between 1 and 3 hours and declined rapidly until 4-8 hours. The range of mean total apparent clearance across 5 age cohorts at low and high doses was 0.47 to 1.11 L/h/kg. The ranges of mean volume of central compartment and apparent peripheral volume were 2.31 to 3.59 L/kg and 1.92 to 4.14 L/kg, respectively. Across all age groups, the estimated median exposures were within the 0.5- to 1.5-fold of the median area under the plasma drug concentration-time curve (AUC) in adult subjects receiving corresponding doses (30 mg q.d. for low dose and 60 mg q.d. for high dose). In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time, and anti-Factor Xa activity) showed a linear PK-PD relationship and were in line with previous adult data. The results support further evaluation of the pediatric doses in larger pivotal trials., (© 2024 Daiichi Sankyo Inc. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background:  We evaluated the pharmacokinetics (PK) of low-dose (15 mg) edoxaban in very elderly patients (≥80 years) with nonvalvular atrial fibrillation (NVAF) and high bleeding risk., Methods:  This subanalysis of the phase 3, randomized, double-blind, placebo-controlled, multicenter ELDERCARE-AF study evaluated edoxaban plasma concentrations and compared them with the Japanese population of the ENGAGE AF-TIMI 48 and Japanese severe renal impairment (SRI) studies., Results:  The PK analysis population included 451 patients, 53.8% of whom concomitantly used antiplatelet drugs, 41.0% had SRI, and 38.0% had low body weight. Edoxaban plasma concentrations at trough and 1 to 3 hours post-dose in ELDERCARE-AF were 17.3 ± 13.9 ( n  = 427) and 93.3 ± 57.8 ng/mL ( n  = 447), respectively. These values were slightly higher than the 15 mg group in ENGAGE AF-TIMI 48 ( n  = 79; 12.4 ± 12.1 and n  = 115; 78.7 ± 45.0 ng/mL, respectively), lower than the ENGAGE AF-TIMI 48 high-dose reduced to 30 mg group ( n  = 83; 25.1 ± 36.6 and n  = 111; 150 ± 91.6 ng/mL, respectively), but similar to the Japanese SRI study ( n  = 39; 18.4 ± 11.2 and n  = 40; 96.8 ± 48.3 ng/mL, respectively). ELDERCARE-AF patients with SRI and low body weight (≤45 kg) had higher concentrations than those without, and those taking antiplatelet drugs had lower concentrations than those who were not., Conclusion:  PK data support edoxaban 15 mg once daily for very elderly NVAF patients with high bleeding risk, with caution for patients with SRI and/or low body weight., Competing Interests: T.Y. received personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; grants and personal fees from Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd., and Bristol Myers Squibb K.K.; personal fees from Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., Toa Eiyo Ltd., Novartis Pharma K.K., and Otsuka Pharmaceutical Co., Ltd. outside the submitted work. Y.I., M.F., and T.H. are employees of Daiichi Sankyo Co., Ltd. S.H. is an employee of Certara, Inc. K.O. received grants and personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; personal fees from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K., Medtronic Japan Co., Ltd., Johnson and Johnson K.K., and Bayer Yakuhin, Ltd. outside the submitted work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Importance: In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data., Objective: To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin., Design, Setting, and Participants: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023., Interventions: Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin., Main Outcomes and Measures: Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component., Results: The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03), particularly gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004), with no significant difference in efficacy end points. Findings were supported by analyses of endogenous factor Xa inhibition, a marker of anticoagulant effect, which was comparable between younger patients receiving edoxaban, 60 mg, and older patients receiving edoxaban, 30 mg. In 2406 patients 80 years and older with or without dose-reduction criteria, patients receiving edoxaban, 30 mg, vs warfarin had lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046), whereas rates of stroke or systemic embolism were comparable., Conclusions and Relevance: In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria., Trial Registration: ClinicalTrials.gov Identifier: NCT00781391.

Background: To assess long-term effectiveness and safety of edoxaban in Europe., Methods and Results: ETNA-AF-Europe, a prospective, multinational, multi-centre, post-authorisation, observational study was conducted in agreement with the European Medicines Agency. The primary and secondary objectives assessed real-world safety (including bleeding and deaths) and effectiveness (including stroke, systemic embolic events and clinical edoxaban use), respectively. Median (interquartile range) age of the 13,164 patients was 75.0 (68.0-80.0) years; CHA 2 DS 2 -VASc and HAS-BLED scores were 3.0 (2.0-4.0) and 2.0 (1.0-2.0), respectively. Follow-up duration was 3.98 (3.21-4.05) years. Patients on edoxaban 30 mg (n = 3042) at baseline were older (80.0 vs 73.0 years), more likely assessed as frail by investigators (27.0% vs 6.6%) and had more comorbidities than those on edoxaban 60 mg (n = 9617; missing dosing information for n = 505). Annualised event rates of all-cause and cardiovascular death in the overall population, edoxaban 60 mg and edoxaban 30 mg groups were 4.1%, 2.8% and 8.4%, and 1.0%, 0.7% and 2.0%, respectively. Annualised rates of stroke were relatively constant throughout the follow-up, transient ischaemic attack and systemic embolism were < 1% in the overall population. Rates of any major and major gastrointestinal bleeding were low, with slightly higher rates for edoxaban 30 vs 60 mg group. Intracranial haemorrhage was uncommon (0.2%)., Conclusions: In European patients with AF, long-term therapy with edoxaban is associated with low and relatively constant annualised rates of stroke and major bleeding. Differences in outcomes between the two approved doses are attributable to differences in clinical characteristics., Competing Interests: Declaration of competing interest P.K. receives research support for basic, translational, and clinical research projects from European Union Big- Data@Heart (grant agreement EU IMI 116074) CATCH ME (grant agreement ID: 633196) AFFECT-EU (grant agreement ID: 847770); Leducq foundation, Medical Research Council (UK); German Centre for Cardiovascular Research supported by the German Ministry of Education and Research; from several drug and device companies active in atrial fibrillation and has received honoraria from several such companies in the past, but not in the last three years. P.K. is listed as inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). P.K. is employed as Director of the Department of Cardiology, University Heart and Vascular Centre UKE Hamburg and Professor of Cardiovascular Medicine (part-time), University of Birmingham, UK. He is Speaker of the board of AFNET, Germany, and Board member of the ESC. A.B. is founder and clinical trial design advisor of Amore Health Ltd., reports support from Daiichi Sankyo for attending meetings and advisory boards; receives honorarium from Daiichi Sankyo, Pfizer, BMS, Bayer, Novartis, Roche, Napp, Boehringer Ingelheim for lecturing and scientific advice outside the submitted work. C.d.A. has received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Atricure, Biosense Webster, Boston Scientific, Acutus Medical and research grants on behalf of the centre from Biotronik, Medtronic Abbott, Microport, Boston Scientific, Biosense Webster, Acutus Medical. J.R.d.G. reports personal fees from Daiichi Sankyo during the conduct of the study; grants from Abbott, Atricure, Bayer, Boston Scientific, Daiichi Sankyo, Johnson & Johnson and Medtronic; personal fees from Atricure, Bayer, Berlin Chemie, Daiichi Sankyo, Johnson & Johnson, Menarini, Medtronic, Novartis, and Servier; and other from RhythmCARE outside the submitted work. J.C.D. has received honoraria for lectures from Bayer, Boehringer Ingelheim, and Bristol Myers Squibb. J.C.D. has also received research grants from Boston Scientific, Sorin Group, Biotronik, and Abbott. P.K. has received speaker's and committee membership from Daiichi Sankyo, and received consulting fee (<€5000) from Alexion and Novo Nordisk. He is the Lead Investigator of the HRB Stroke Clinical Trials Network Ireland, which has received grant funding from the Irish government, Irish Heart Foundation, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, Amgen, and A Menarini. E.L.-d.-S. reports personal fees from Daiichi Sankyo; grants and personal fees from Servier, ZOLL Medical, and Becton Dickinson; grants from AstraZeneca, MedImmune LLC and Novartis, during the conduct of the study. P.M. is an ETNA-AF investigator and has received lecture and research fees from Daiichi Sankyo, Bayer, Boehringer Ingelheim, and Pfizer/BMS. E.-M.F., M.L., P.L., and R.S. are employees of Daiichi Sankyo Europe GmbH, Munich, Germany. J.S. has received consultant and/or speaker fees from Abbott, Alexion, Astra-Zeneca, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer-Ingelheim, Boston Scientific, BMS, Daiichi Sankyo, Medscape, Medtronic, Menarini, Merck/MSD, Organon, Pfizer, Saja, Servier, and WebMD. He reports ownership of Swiss EP and CorXL. J.W. reports personal fees and non-financial support from Biotronik, Boehringer Ingelheim, and Daiichi Sankyo; personal fees from Akzea, Bayer Vital, MSD, Berlin-Chemie and Siemens Healthineers, outside the submitted work. T.W.W. has received fees, honoraria and research funding from AstraZeneca, Boehringer Ingelheim, Bayer, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Medtronic, Menarini Pharma, Novartis, and Sanofi Aventis. R.D.C. reports grants, personal fees and non-financial support from Daiichi Sankyo, during the conduct of the study; and reports consulting fees, honoraria and other financial or non-financial interests: Amgen, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Janssen, Milestone, Novartis, Sanofi, Menarini, Guidotti, and Roche, outside the submitted work. Consultancy fees from Daiichi Sankyo Europe for the Chairing of the ETNA-AF Europe registry., (Copyright © 2023. Published by Elsevier B.V.)

Background: Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events., Methods: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization., Results: 21 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05-1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05-1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use., Conclusions: In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391., Competing Interests: Dr Bergmark received grant support through the following institutions: Pfizer, Ionis, AstraZeneca, and Abbott and consulting fees/honoraria: Abiomed, Philips, Bain, Abbott, Terumo, CSI, Endovascular Engineering, and SpectraWAVE. Dr De Caterina received institutional grants from BMS/Pfizer and Daiichi Sankyo and consultancy and speaker’s fees from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Novartis, Portola, and Roche. Dr Antman received grants from Daiichi Sankyo during the conduct of the study. Dr Ruff received an institutional research grant to the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Brigham and Women’s Hospital, from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis, and is a consultant for Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, and Pfizer. Drs Rutman, Mercuri, and Lanz report being an employee of Daiichi Sankyo. Dr Braunwald received research grant support through Brigham and Women’s Hospital from AstraZeneca, Daiichi Sankyo, Merck, and Novartis and is consulting for Amgen, Boehringer Ingelheim/Lilly, Bristol Myers Squibb (MyoKardia), Cardurion, and Verve. Dr Giugliano received grants from Daiichi Sankyo during the conduct of the study; grant support from Amgen, Anthos Therapeutics, and Ionis; honoraria for lectures/continuing medical education programs from Amgen, Centrix, Daiichi Sankyo, Dr Reddy’s Laboratories, Medical Education Resources, Medscape, Menarini, Merck, Pfizer, SAJA Pharmaceuticals, Servier, Shanghai Medical Telescope, and Voxmedia; is a consultant for Amarin, Amgen, Artivion, Inc, Bayer, Boston Scientific, Caladrius, CSL Behring, CVS Caremark, Daiichi Sankyo, Esperion, Gilead, Hengrui, Inari, Janssen, Novartis, Paratek, Pfizer, PhaseBio Pharmaceuticals, and Samsung. Drs Bergmark, Park, Melloni, Antman, Ruff, Braunwald, and Giugliano are members of the TIMI Study Group, which has received grant support through Brigham and Women’s Hospital (Boston, MA) from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo, Eisai, Intarcia, Ionis, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. The other authors report no conflicts.

Background: Clinical trials showed the safety of Edoxaban, a non-vitamin K-dependent oral anticoagulant (NOAC), and its efficacy to prevent stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients and also to prevent and treat venous thromboembolism. However, additional research is needed to evaluate the safety and effectiveness of Edoxaban in a real-world scenario in the Brazilian population., Objective: In order to understand the risks and benefits of Edoxaban use in routine clinical settings, the EdoBRA study is being conducted to gain insight into the safety and effectiveness of Edoxaban use in non-preselected patients with NVAF in Brazil., Methods: The EdoBRA study is a multicenter, prospective, observational study conducted in 36 sites in Brazil. NVAF patients ≥ 18 years treated with commercially available Edoxaban who initiated treatment for at least 14 days and no longer than 90 days prior to enrollment, and who are not simultaneously participating in any interventional study are eligible for this study. Seven hundred patients are planned to be enrolled and one-year of follow up, with data collections expected at baseline and 3, 6, and 12 months after the study enrollment. The primary safety objective is ISTH Clinically Relevant Bleeding, and the secondary effectiveness objective focuses on relevant cardiovascular outcomes related to NVAF., Conclusion: EdoBRA observational study will generate relevant additional information about NOAC Edoxaban on various aspects of patient management in routine care, such as its safety and effectiveness profile in patients with NVAF in Brazil.

Background: The ELDERCARE-AF trial showed that low-dose edoxaban benefits elderly patients with nonvalvular atrial fibrillation considered ineligible for standard oral anticoagulants due to high bleeding risk, but whether this applied to patients with extremely low body weight was unclear., Methods and Results: This was a prespecified subanalysis by body weight (≤45, >45 kg) of the phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven ELDERCARE-AF trial, which compared low-dose edoxaban (15 mg once daily) with placebo in Japanese patients considered ineligible for oral anticoagulants at the recommended therapeutic strength or the approved doses. The primary efficacy and safety end points were stroke or systemic embolism and major bleeding (International Society on Thrombosis and Hemostasis definition), respectively. The ≤45-kg weight group included 374/984 patients (38.0%), and the >45-kg group included 610/984 patients (62.0%). The stroke or systemic embolism rate was lower with edoxaban than placebo in both weight groups (≤45 kg: hazard ratio [HR], 0.36 [95% CI, 0.16-0.80]; >45 kg: HR, 0.31 [95% CI, 0.13-0.73]; interaction P =0.82). Major bleeding incidence was numerically higher with edoxaban than placebo (≤45 kg: HR, 3.05 [95% CI, 0.84-11.11]; >45 kg: HR, 1.40 [95% CI, 0.56-3.48), with no interaction with body weight (interaction P =0.33). All-cause mortality was higher in the ≤45-kg group, with no significant difference between treatment groups., Conclusions: The benefit of edoxaban 15 mg was consistent in elderly patients with atrial fibrillation and extremely low body weight, though clinicians must remain vigilant about the risk of major bleeding, especially gastrointestinal bleeding., Registration Information: ClinicalTrials.gov. Identifier: NCT02801669.

Real-world data on effectiveness and safety of a single non-vitamin K antagonist oral anticoagulant in the Chinese population with atrial fibrillation (AF) are limited. This study reports characteristics of patients treated with edoxaban and factors associated with dosing patterns from routine care in China. ETNA-AF-China (NCT04747496) is a multicentre, prospective, observational study enrolling edoxaban-treated patients from four economic regions with a targeted 2-year follow-up. Of the 4930 patients with AF (mean age: 70.2 ± 9.5 years; male, 57.1%), the mean creatinine clearance (CrCl), CHA 2 DS 2 -VASc, and HAS-BLED scores were 71.2 mL/min, 2.9, and 1.6. Overall, 6.4% of patients were perceived as frail by investigators. Available label dose reduction criteria (N = 4232) revealed that 3278 (77.5%) patients received recommended doses and 954 (22.5%) non-recommended doses. Northeast (53.0%) and West (43.1%) regions had the highest prescriptions of 60 mg and 30 mg recommended doses, respectively. Non-recommended 30 mg doses were more frequently prescribed in patients with antiplatelet use and history of heart failure than recommended 60 mg. Multivariate analysis identified advanced age as the strongest associated factor with non-recommended doses. Frailty had the strongest association with 30 mg except for age, and history of TIA was the most relevant factor associated with 60 mg. In conclusion, patients in the ETNA-AF-China study were predominantly aged 65 years and older, had mild-to-moderate renal impairment and good label adherence. Advanced age was associated with non-recommended doses, with frailty most common for non-recommended 30 mg and a history of TIA for the non-recommended 60 mg dose., (© 2024. The Author(s).)

Clinical trial registration number: NCT02950168, NCT02951039., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AB, CC, JJ, and MU are employees of Daiichi Sankyo. PC reports grants and personal fees from Daiichi Sankyo; personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer/BMS; and nonfinancial support from the European Society of Cardiology (ESC) and the Italian Cardiology Association (ANMCO). CvH reports grants and personal fees from Daiichi Sankyo; personal fees from Artcline GmbH, CSL Behring, HICC GbR, Mitsubishi Pharma, Novo Nordisk Pharma, Shionogi Pharma, and Sobi Pharma; receipt of a mandate from the German Society of Anaesthesiology and Intensive Care Medicine (DGAI) to write the German Guidelines on Preoperative Anemia; receipt of a mandate from the Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI) to take part in the writing group of the guidelines on the Prevention of Venous Thromboembolism of the Gesellschaft für Thrombose- und Hämostaseforschung (GTH); participation in the writing group of the Patient Blood Management Guideline in cardiac surgery on behalf of the European Society of Cardiothoracic Anaesthesiologists (EACTA) in conjunction with the European Society of Cardiothoracic Surgery (EACTS); and receipt of a mandate to take part in the writing group of the guidelines on the Diagnostics and Treatment of Peripartum Haemorrhage of the Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG). SK reports consulting fees from Daiichi Sankyo. AS reports nothing to disclose. MS reports grants and personal fees from Daiichi Sankyo and personal fees from Daiichi Sankyo; TV report grants and personal fees from Daiichi Sankyo; and personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo, and LEO Pharma.

Introduction: Limited data were published on the management of direct oral anticoagulants in the insertion of pacemaker and cardiac monitoring devices. This study describes the management and outcomes of edoxaban, a direct oral factor Xa inhibitor, in patients undergoing pacemaker or monitoring device implantation in routine clinical practice., Methods and Results: EMIT-AF/VTE collected data of patients from Europe, Korea, and Taiwan. Timing and duration of periprocedural interruption of edoxaban were at the treating physician's discretion. Pacemakers or monitoring devices were implanted into 136 patients who were evaluated from 5 days pre- until 30 days post-procedure. The primary outcomes were the incidences of acute thromboembolic events (ATE), ischemic events, and International Society on Thrombosis and Haemostasis-defined Major Bleeding; secondary outcomes included incidence of clinically relevant non-major bleeding (CRNMB) and perioperative edoxaban interruption times. Conformance with European Heart Rhythm Association (EHRA) Guidance on interruption of direct oral anticoagulant therapy was variable: of the cardiac monitoring device patients, where no interruption of therapy would be expected, nonetheless, 62.5% had interruption of treatment, whereas in pacemaker procedures, where interruption would be expected, 23.4% had no interruption. No ATE or ischemic events occurred. One case of CRNMB and two of minor bleeding occurred. All bleedings occurred more than 3 days after the procedure., Conclusion/relevance: The periprocedural complication risk for edoxaban treated patients undergoing pacemaker or invasive cardiac monitoring implantation was low. This population of patients was well managed in routine practice., (© 2021 Wiley Periodicals LLC.)

Background: The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied., Methods: We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding., Results: A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P = 0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P = 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11)., Conclusions: In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.)., (Copyright © 2021 Massachusetts Medical Society.)

Milademetan is a small-molecule inhibitor of murine double minute 2 (MDM2) that is in clinical development for advanced solid tumors and hematological cancers, including liposarcoma and acute myeloid leukemia. Milademetan is a CYP3A and P-glycoprotein substrate and moderate CYP3A inhibitor. The current study aims to understand the drug-drug interaction (DDI) risk of milademetan as a CYP3A substrate during its early clinical development. A clinical DDI study of milademetan (NCT03614455) showed that concomitant administration of single-dose milademetan with the strong CYP3A inhibitor itraconazole or posaconazole increased milademetan mean area under the curve from zero to infinity (AUC inf ) by 2.15-fold (90% confidence interval [CI], 1.98-2.34) and 2.49-fold (90% CI, 2.26-2.74), respectively, supporting that the milademetan dose should be reduced by 50% when concomitantly administered with strong CYP3A inhibitors. A physiologically-based pharmacokinetic (PBPK) model of milademetan was subsequently developed to predict the magnitude of CYP3A-mediated DDI potential of milademetan with moderate CYP3A inhibitors. The PBPK model predicted an increase in milademetan exposure of 1.72-fold (90% CI, 1.69-1.76) with fluconazole, 1.91-fold (90% CI, 1.83-1.99) with erythromycin, and 2.02-fold (90% CI, 1.93-2.11) with verapamil. In addition, it estimated that milademetan's original dose (160 mg once daily) could be resumed from its half-reduced dose 3 days after discontinuation of concomitant strong CYP3A inhibitors. The established PBPK model of milademetan was qualified and considered to be robust enough to support continued development of milademetan., (© 2021 Daiichi Sankyo Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using 125 I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis., (© 2021. The Author(s).)

Milademetan (DS-3032, RAIN-32) is an orally available mouse double minute 2 (MDM2) antagonist with potential antineoplastic activity owing to increase in p53 activity through interruption of the MDM2-p53 interaction. This phase I, dose-escalating study assessed the safety, tolerability, efficacy, and pharmacokinetics of milademetan in 18 Japanese patients with solid tumors who relapsed after or were refractory to standard therapy. Patients aged ≥ 20 years received oral milademetan once daily (60 mg, n = 3; 90 mg, n = 11; or 120 mg, n = 4) on days 1 to 21 in a 28-day cycle. Dose-limiting toxicities, safety, tolerability, maximum tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. The most frequent treatment-emergent adverse events included nausea (72.2%), decreased appetite (61.1%), platelet count decreased (61.1%), white blood cell count decreased (50.0%), fatigue (50.0%), and anemia (50.0%). Dose-limiting toxicities (three events of platelet count decreased and one nausea) were observed in the 120-mg cohort. The plasma concentrations of milademetan increased in a dose-dependent manner. Stable disease was observed in seven out of 16 patients (43.8%). Milademetan was well tolerated and showed modest antitumor activity in Japanese patients with solid tumors. The recommended dose for phase II was considered to be 90 mg in the once-daily 21/28-day schedule. Future studies would be needed to further evaluate the potential safety, tolerability, and clinical activity of milademetan in patients with solid tumors and lymphomas. The trial was registered with Clinicaltrials.jp: JapicCTI-142693., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: The efficacy and safety of the oral factor Xa inhibitor edoxaban compared to warfarin stratified by CHA 2 DS 2 VASc scores have not been described., Methods: The ENGAGE AF-TIMI 48 trial randomized patients with atrial fibrillation to once-daily edoxaban or warfarin. We classified patients based on CHA 2 DS 2 VASc score and compared pharmacokinetics (edoxaban concentration), pharmacodynamics (anti-factor Xa [FXa] with edoxaban, time-in-therapeutic range for warfarin), efficacy (stroke or systemic embolism [SSE]), safety (major bleeding [MB], intracranial hemorrhage), and cardiovascular mortality, for the approved edoxaban regimen vs warfarin., Results: The distribution CHA 2 DS 2 VASc score were:≤3, N = 4159 (29.6%); 4, N = 4066 (28.9%); 5, N = 3165 (22.5%); and ≥6, N = 2681 (19.1%). Increasing rates of SSE (1.05 to 2.99%/year) and MB (2.27 to 4.66%/year) were observed in the warfarin arm as the CHA 2 DS 2 VASc score increased. The hazard ratios per unit increase of CHA 2 DS 2 VASc score were 1.29 (1.21-1.38) and 1.26 (1.17-1.36) for SSE, and 1.20 (1.13-1.27) and 1.19 (1.12-1.27) for MB, with warfarin and edoxaban, respectively. Time-in-therapeutic range in warfarin-treated patients was similar and high (median 68%-69%) across CHA 2 DS 2 VASc scores, whereas edoxaban trough concentration, exogenous anti-FXa activity and %inhibition of endogenous FXa were higher at increasing CHA 2 DS 2 VASc scores. Edoxaban reduced SSE, MB, intracranial hemorrhage, and cardiovascular mortality vs warfarin to a similar degree across the range of CHA 2 DS 2 VASc scores (P-int = 0.90, 0.96, 0.21, and 0.37, respectively). Because of higher event rates the number of events prevented with edoxaban tended to be greater in patients with higher CHA 2 DS 2 VASc scores., Conclusion: The benefit and safety of edoxaban versus warfarin is maintained across CHA 2 DS 2 VASc scores. While the relative risk reductions remain similar, edoxaban provides incrementally larger absolute reductions in outcomes over warfarin in patients with higher CHA 2 DS 2 VASc scores., Competing Interests: Disclosure The authors report the following potential conflicts of interest: Dr. De Groot - research grant through his institution: Abbott, Atricure, Bayer, Boston Scientific, Daiichi Sankyo, Johnson&Johnson, Medtronic. Honoraria for scientific advisory boards and consulting: Atricure, Bayer, Daiichi Sankyo, Johnson&Johnson, Medtronic, Novartis, Servier. Dr. Ruff - research grants through institution: Anthos, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, National Institutes of Health. Honoraria for scientific advisory boards and consulting: Anthos, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Pfizer, Portola. Dr. Murphy - research grants from Abbott Laboratories, Amarin, Amgen, AstraZeneca, Critical Diagnostics, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia Therapeutics, Merck and Co., Roche Diagnostics, Takeda, Gilead, Poxel, Novartis, MedImmune, Janssen Research Development, and Genzyme. Ms. Hamershock - grant support through her institution rom Daiichi Sankyo. Dr. Vehmeijer nothing to report. Dr. Oude Ophuis - grant support to his institution from Daiichi Sankyo, personal fees from TIMI during the conduct of the study; grant support and personal fees from Boston Scientific and Abbott; personal fees from AstraZeneca and Merck Sharp & Dohme; and nonfinancial support from Biosensor, WCN, and Vascular Research Network outside the submitted work. Ms. Grip - grant support through her institution from Daiichi Sankyo. Dr. Lanz - employment at Daiichi Sankyo. Dr. Mercuri - employment at Daiichi Sankyo. Dr. Antman - grant support through his institution from Daiichi Sankyo. Dr. Giugliano - grant support through his institution from Daiichi Sankyo and Anthos; personal fees for CME lectures and/or consulting from Boheringer-Ingelheim, Bristol-Myers-Squibb, CryoLife, Daiichi Sankyo, Eli Lilly and Company, Janssen, Merck, Pfizer, SAJA Pharmaceuticals and Servier. Drs. Ruff, Antman, and Giugliano and Ms Murphy, Hamershock and Grip report Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital for research they are not directly involved in from Abbott, Amgen, Anthos, Aralez, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Quark Pharmaceuticals, Regeneron, Roche, Siemens, Takeda, The Medicines Company, Zora Biosciences., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the standard of care for stroke prevention in patients with atrial fibrillation (AF). However, DOAC prescriptions at dosages that do not adhere to labeling are common in daily practice. This analysis from the observational Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program focuses on edoxaban-treated patients from South Korea and Taiwan to identify patient baseline characteristics that may be associated with non-recommended dosing., Methods: We report baseline data from ETNA-AF, including patient demographics, clinical characteristics, and bleeding/stroke history of patients receiving recommended or non-recommended edoxaban dosing., Results: A total of 2677 patients were enrolled. Among 1543 patients who did not meet dose-reduction criteria, 1033 (66.9%) were prescribed the recommended 60-mg dose, and 510 (33.1%) were prescribed the non-recommended 30-mg dose. Among 1134 patients meeting ≥1 of the dose-reduction criteria, 863 (76.1%) were prescribed the recommended 30-mg dose; 271 (23.9%) were prescribed the nonrecommended 60-mg dose. Compared with the recommended 60-mg group, the nonrecommended 30-mg group had a higher proportion of patients aged ≥75 years, higher stroke and bleeding risks, and a history of major bleeding. The non-recommended 60-mg group had a lower proportion of patients aged ≥75 years, a higher history of stroke, and lower history of bleeding compared with the recommended 30-mg group., Conclusion: The baseline data from ETNA-AF indicate that physicians take patient clinical characteristics (e.g., bleeding risks) into consideration when deviating from the dosing recommendation per label., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Previously, we reported that a direct thrombin inhibitor melagatran paradoxically increased thrombin generation in human plasma in the presence of thrombomodulin. The aim of this study is to test the hypothesis that melagatran may exert a deleterious effect on tissue-type plasminogen activator (t-PA)-induced fibrinolysis via enhancement of thrombin generation and subsequent activation of thrombin-activatable fibrinolysis inhibitor (TAFI) and factor XIII (FXIII). Clot formation in human plasma containing t-PA and thrombomodulin was induced by tissue factor. The absorbance at 405 nm was measured to obtain clot lysis time. Effects of melagatran and a factor Xa inhibitor edoxaban on clot lysis time were determined. In the presence of thrombomodulin, melagatran significantly prolonged clot lysis time, but edoxaban shortened it. In the absence of thrombomodulin, melagatran did not inhibit fibrinolysis. Prolongation of clot lysis time by melagatran was reversed by activated protein C (which suppressed thrombin generation increased by melagatran) and a TAFIa inhibitor. Melagatran significantly suppressed plasmin generation, while edoxaban significantly increased it. However, both melagatran and edoxaban suppressed FXIII activation. In the clot formed in the presence of melagatran and edoxaban, the fibrin fibre was thin compared with control, showing no clear difference in the clot structures between melagatran and edoxaban. These results indicated that melagatran, not edoxaban, prolonged clot lysis time through the paradoxical enhancement of thrombin generation, and subsequent TAFI activation and inhibition of plasmin generation. Neither FXIII activation nor change in fibrin clot structure contributed to the inhibition of fibrinolysis by melagatran., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Intracranial hemorrhage (ICH) is a known risk of oral anticoagulation; delineating ICH attributes may provide nuanced guidance regarding atrial fibrillation management. We evaluated ICH characteristics and outcomes from Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48), a randomized trial that compared two edoxaban regimens (higher-dose edoxaban regimen 60/30 mg (HDER), lower-dose edoxaban regimen 30/15 mg (LDER)) with warfarin in patients with atrial fibrillation. Patients who suffered ICH vs those who did not were compared and independent predictors of ICH were calculated. We also assessed ICH subtype and etiology. Of 21,105 randomized patients, 322 (1.53%) had ≥ 1 ICH for a total of 368 events. Intraparenchymal hemorrhage (HDER: HR 0.52 [95% CI 0.35-0.77], LDER: HR 0.22 [0.13-0.38]) and subdural hematoma (HDER: HR 0.29 [0.15-0.55], LDER: HR 0.26 [0.13-0.50]) were lower with both HDER and LDER vs warfarin. Subarachnoid hemorrhage frequency was similar in the HDER vs warfarin groups but lower in LDER. Compared to warfarin, edoxaban was associated with lower risk of spontaneous ICH (HDER: HR 0.47 [0.31-0.69], LDER: HR 0.34 [0.22-0.53]) and traumatic ICH (HDER: HR 0.32 [0.17-0.61], LDER: HR 0.31 [0.16-0.59]). In multivariable analysis, randomization to warfarin, increased age, and risk of falling remained independent predictors of ICH. In ENGAGE AF-TIMI 48, ICH was decreased in edoxaban-treated patients compared to warfarin-treated patients, including ICH of both spontaneous and traumatic causes. Both edoxaban regimens lowered intraparenchymal and subdural hemorrhages compared to warfarin. Patient characteristics and medical history may help guide anticoagulation management., Competing Interests: Declaration of Competing Interest S.E.N. has received compensation from Springer Nature and grant funding from the Brain Aneurysm Foundation. RPG: Dr. Giugliano reports grants from Daiichi Sankyo, during the conduct of the study; personal fees from Akcea, personal fees from Amarin, personal fees from American College of Cardiology, grants and personal fees from Amgen, personal fees from Angel Med, personal fees from Beckman-Coulter, personal fees from Boeringer-Ingelheim, personal fees from Bristol Myers Squibb, personal fees from CVS Caremark, grants and personal fees from Daiichi Sankyo, personal fees from GlaxoSmithKline, personal fees from Janssen, personal fees from Lexicon, grants and personal fees from Merck, personal fees from Portola, personal fees from Pfizer, personal fees from St Jude, personal fees from Stealth Peptide, outside the submitted work; and Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital for research he is not directly involved in from AstraZeneca; Bayer; Eisai; GlaxoSmithKline; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Novartis; Poxel; Pfizer; Quark Pharmaceuticals; Takeda. EMA: Dr. Antman reports receiving grant support through his institution from Daiichi Sankyo. JGP: Dr. Park reports no conflicts of interest. ADN: Dr. Norden reports that he is an employee and shareholder of COTA, Inc. NSR: Dr. Rost reports no conflicts of interest. SS: Dr. Silverman reports no conflicts of interest. ABS: Dr. Singhal reports grant support through his institution (Massachusetts General Hospital) from Boehringer-Ingelheim; research support from the NIH (grant numbers U10 NS086729, U01NS095869, R01NS105875 and R01DC012584); research support from Dana Foundation; stock and/or stock options from Biogen and Zafgen; consulting fees from Omniox, and honoraria from Medlink, Wolters-Kluwer Health, and UptoDate. HJL: Dr. Lanz is an employee of Daiichi Sankyo. EB: Dr. Braunwald reports grant support through his institution from Daiichi Sankyo, Astra Zeneca, Glaxo SmithKline, Merck, Duke University, Novartis, and the Medicines company; consulting fees from Cardurion, MyoKardia, Sanofi, and Verve; lecture fees from Medscape; uncompensated consultancies and lectures for Merck, the Medicines company, and Novartis. CTR: Dr. Ruff reports grant support through his institution (Brigham and Women’s Hospital) from Daiichi Sankyo and has served as a consultant and received honoraria from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Pfizer, Janssen and Portola; and grant support through his institution outside the submitted work from MedImmune, NIH and Boehringer Ingelheim., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The purpose of this study was to evaluate the impact of P-glycoprotein (P-gp) efflux on edoxaban absorption in gastrointestinal tracts quantitatively by a physiologically based pharmacokinetic (PBPK) model constructed with clinical and non-clinical observations (using GastroPlus™ software). An absorption process was described by the advanced compartmental absorption and transit model with the P-gp function. A human PBPK model was constructed by integrating the clinical and non-clinical observations. The constructed model was demonstrated to reproduce the data observed in the mass-balance study. Thus, elimination pathways can be quantitatively incorporated into the model. A constructed model successfully described the difference in slopes of plasma concentration (Cp)-time curve at around 8 - 24 hr post-dose between intravenous infusion and oral administration. Furthermore, the model without P-gp efflux activity can reproduce the Cp-time profile in the absence of P-gp activity observed from the clinical DDI study results. Since the difference of slopes between intravenous infusion and oral administration also disappeared by the absence of P-gp efflux activity, P-gp must be a key molecule to govern edoxaban's PK behavior. The constructed PBPK model will help us to understand the significant contribution of P-gp in edoxaban's disposition in gastrointestinal tracts quantitatively., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, the lower dose edoxaban regimen (LDER) and the higher dose edoxaban regimen (HDER) were noninferior to well-managed warfarin for stroke prevention in atrial fibrillation., Objectives: The objective of the present analysis of the ENGAGE AF TIMI-48 trial was to comprehensively compare the net clinical outcome (NCO) of LDER (30 mg once daily, dose reduced to 15 mg in selective patients) versus HDER (60 mg once daily, dose reduced to 30 mg in selective patients)., Methods: This study performed a pre-specified analysis of the ENGAGE AF-TIMI 48 trial, comparing patients on LDER versus HDER., Results: The pre-defined primary NCO (stroke/systemic embolism [SEE], major bleeding, death) was less frequent with LDER (7.26% vs. 8.01%; hazard ratio: 0.90; 95% confidence interval: 0.84 to 0.98; p = 0.014). The secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) and tertiary pre-defined NCOs (stroke, SEE, life-threatening bleeding, or all-cause mortality) were similar between the 2 dosing regimens. Patients randomized to LDER versus HDER had a significantly higher risk of stroke/SEE (2.04% vs. 1.56%; hazard ratio: 1.31; 95% confidence interval: 1.12 to 1.52; p < 0.001). Conversely, major bleeding, intracranial hemorrhage, major gastrointestinal bleeding, and life-threatening bleeding occurred significantly less frequently with LDER compared with those of HDER. These findings were supported by multiple pharmacokinetic findings., Conclusions: In the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the 2 dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation. (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48]; NCT00781391)., Competing Interests: Funding Support And Author Disclosures The ENGAGE AF-TIMI 48 trial was supported by Daiichi-Sankyo Pharma Development. Dr. Steffel has received consultant and/or speaker fees from Abbott, Amgen, AstraZeneca, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Medscape, Medtronic, Merck/Merck Sharp & Dohme, Novartis, Roche Diagnostics, Pfizer, Portola, Saja, Servier, and WebMD; has ownership in CorXL; and has received grant support, through his institution, from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Daiichi-Sankyo, and Medtronic. Dr. Ruff has received consulting fees from Bayer, Daiichi-Sankyo, Portola, and Boehringer Ingelheim; and has received grant support, through his institution, from Daiichi-Sankyo, Anthos Therapeutics, AstraZeneca, Eisai, and Intarcia. Dr. Braunwald has received consulting fees from Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, NovoNordisk, and Verve; and has received grant support, through his institution, from AstraZeneca, Daiichi-Sankyo, Merck & Co., and Novartis. Dr. Park has received grant support, through his institution, from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, The Medicines Company, and Zora Biosciences. Ms. Murphy has received grant support, through her institution, from Daiichi-Sankyo. Dr. Connolly has received research grants and consultation fees from Bayer, Bristol Myers Squibb, Pfizer, Portola, Daiichi-Sankyo, and Boehringer Ingelheim. Dr. Antman has received grant support, through his institution, from Daiichi-Sankyo. Dr. Giugliano has received consulting fees from Bristol Myers Squibb, Janssen, Daiichi-Sankyo, Merck, Pfizer, Portola, SAJA Pharmaceuticals, and Servier; and has received grant support, through his institution, from Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Merck, Johnson & Johnson, Pfizer, and Sanofi. Dr. Yin was previously employed by Daiichi-Sankyo and has reported that she has no other relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men., Methods: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS 2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis-defined major bleeding (safety)., Results: In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P <0.001). Treatment with edoxaban in women resulted in greater peak edoxaban concentration and inhibition of endogenous factor Xa in comparison with men, resulting in similar endogenous factor Xa activity between the sexes 2 to 4 hours after dose. Treatment with higher-dose edoxaban regimen (versus warfarin) resulted in similar reduction in the risk of stroke/systemic embolic events (women: hazard ratio [HR], 0.87 [0.69-1.11], men: HR, 0.87 [0.71-1.06]; P -interaction=0.97) and major bleeding (women: HR, 0.74 [0.59-0.92], men: HR, 0.84 [0.72-0.99]; P -interaction=0.34) in women and men. However, women assigned to higher-dose edoxaban regimen experienced greater reductions in hemorrhagic stroke (HR, 0.30 [95% CI, 0.15-0.59] versus HR, 0.70 [95% CI, 0.46-1.06]), intracranial bleeding (HR, 0.20 [95% CI, 0.10-0.39] versus HR, 0.63 [95% CI, 0.44-0.89]), and life-threatening or fatal bleeding (HR, 0.25 [95% CI, 0.15-0.42] versus HR, 0.72 [95% CI, 0.54-0.96]) than men (each P -interaction<0.05)., Conclusions: Despite many differences in baseline characteristics between women and men and higher baseline endogenous factor Xa levels in women, the intensity of anticoagulation achieved with edoxaban between the sexes was similar. Treatment with higher-dose edoxaban regimen resulted in an even greater reduction in hemorrhagic stroke and several serious bleeding outcomes in women than in men, whereas the efficacy profile was similar between sexes.

Background:  The effects of anticoagulants at extremes of body weight (BW) are not well described. The aim of this study was to analyze the pharmacokinetics/pharmacodynamics and clinical outcomes in patients randomized to warfarin, higher dose edoxaban (HDER), and lower dose edoxaban (LDER) regimens at extremes of BW in ENGAGE AF-TIMI 48., Methods and Results:  We analyzed three BW groups: low BW (LBW: <5th percentile, ≤55 kg, N  = 1,082), middle BW (MBW: 45th-55th percentile, 79.8-84 kg, N  = 2,153), and high BW (HBW: >95th percentile, ≥120 kg, N  = 1,093). In the warfarin arm, LBW patients had higher rates of stroke/systemic embolism (SSE: 6.5 vs. 4.7 in MBW vs. 1.6% in HBW, P trend  < 0.001), major bleeding (MB: 9.3 vs. 7.7 vs. 6.5%, P trend  = 0.08), and worse net clinical outcome of systemic embolic event, MB, or death (31.5 vs. 19.1 vs. 16.0%, P trend  < 0.0001). The time-in-therapeutic range with warfarin was lowest in LBW patients (63.0 vs. 69.3 vs. 70.1% patients, P trend  < 0.001). The pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across BW groups. The risk of SSE was similar between HDER and warfarin for each of the three weight groups ( P int  = 0.52, P int-trend  = 0.86). MB was reduced by LDER versus warfarin ( P int  = 0.061, P int-trend  = 0.023), especially in LBW patients. Net clinical outcomes were improved by HDER versus warfarin ( P int  = 0.087, P int-trend  = 0.027), especially in LBW patients., Conclusion:  Patients with LBW in ENGAGE AF-TIMI 48 had in general a more fragile clinical status and poorer international normalized ratio control. The pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across extremes of BW, resulting in similar efficacy compared with warfarin, while major or clinically relevant non-MB and net outcomes were most favorable with edoxaban as compared to warfarin in LBW patients., Competing Interests: G.B. reports personal fees from Boehringer, Boston, Biotronik, and Medtronic, outside the submitted work; C.T.R. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences; J.F.K. is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Roche, The Medicines Company, and Zora Biosciences; M.S. reports to be an employee of Daiichi Sankyo Inc.; H.J.L. reports to be an employee of Daiichi Sankyo Inc.; E.M.A. reports grants from Daiichi Sankyo, during the conduct of the ENGAGE study; E.B. reports grants from Daiichi Sankyo during the conduct of the ENGAGE study, grants from Astra Zeneca, Daiichi Sankyo, Merck, Novartis, and personal fees from Amgen, Cardurion, MyoKardia, Novo Nordisk, Verve, outside the submitted work; R.P.G. reports grants from Merck, during the conduct of the study; personal fees from Akcea, grants and personal fees from Amarin, personal fees from American College of Cardiology, grants and personal fees from Amgen, personal fees from Angel Med, Beckman-Coulter, Boehringer-Ingelheim, Bristol Myers Squibb, CVS Caremark, grants and personal fees from Daiichi Sankyo, personal fees from GlaxoSmithKline, Janssen, Lexicon, grants and personal fees from Merck, personal fees from Portola, Pfizer, St. Jude, Stealth Peptide, outside the submitted work; and institutional research grant to the TIMI Study Group at Brigham and Women's Hospital for research he is not directly involved in from AstraZeneca, Bayer, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Novartis, Poxel, Pfizer, Quark Pharmaceuticals, and Takeda., (Thieme. All rights reserved.)

Background: Annually > 10% of patients with atrial fibrillation on oral anticoagulation undergo invasive procedures. Optimal peri-procedural management of anticoagulation, as judged by major bleeding and thromboembolic events, especially in the elderly, is still debated., Methods: Procedures from 1442 patients were evaluated. Peri-procedural edoxaban management was guided only by the experience of the attending physician. The primary safety outcome was the rate of major bleeding. Secondary outcomes included the peri-procedural administration of edoxaban, other bleeding events, and the main efficacy outcome, a composite of acute coronary syndrome, non-hemorrhagic stroke, transient ischemic attack, systemic embolic events, deep vein thrombosis, pulmonary embolism, and mortality., Results: Of the 1442 patients, 280 (19%) were < 65, 550 (38%) were 65-74, 514 (36%) 75-84, and 98 (7%) were 85 years old or older. With increasing age, comorbidities and risk scores were higher. Any bleeding complications were uncommon across all ages, ranging from 3.9% in patients < 65 to 4.1% in those 85 years or older; major bleeding rates in any age group were ≤ 0.6%. Interruption rates and duration increased with advancing age. Thromboembolic events were more common in the elderly, with all nine events occurring in those > 65, and seven in patients aged > 75 years., Conclusion: Despite increased bleeding risk factors in the elderly, bleeding rates were small and similar across all age groups. However, there was a trend toward more thromboembolic complications with advancing age. Further efforts to identify the optimal management to reduce ischemic complications are needed., Trial Registration: NCT# 02950168, October 31, 2016.

Aims: In ENSURE-AF (NCT02072434), the oral Factor Xa inhibitor edoxaban showed similar efficacy and safety vs enoxaparin-warfarin in patients undergoing electrical cardioversion of nonvalvular atrial fibrillation (AF). This ancillary analysis compares primary efficacy and safety end points for patients receiving vs not receiving concomitant antiplatelet therapy (APT) in ENSURE-AF., Methods: The primary efficacy end point was a composite of stroke, systemic embolic events, myocardial infarction, and cardiovascular death during 28 days on study drug after cardioversion plus 30 days of follow-up. The primary safety end point was the composite of major and clinically relevant non-major bleeding occurring between the first and the last dose of study drug., Results: Of 2199 patients enrolled, 1095 were randomized to edoxaban and 1104 to enoxaparin-warfarin. Patients receiving concomitant APT were older; more naïve to vitamin K antagonist; had lower creatinine clearance; and more likely to have history of coronary artery disease, hypertension, diabetes, or ischemic stroke/transient ischemic attack. In patients receiving vs not receiving concomitant APT, primary efficacy event rate was numerically higher (0.92% vs 0.60%, p = 0.64) and primary safety event rate was significantly higher (3.21% vs 0.92%, p = 0.0096). Stepwise logistic regression analysis identified age and APT as covariates correlated with bleeding. There was a trend toward increased bleeding risk in elderly patients receiving vs not receiving concomitant APT., Conclusion: In ENSURE-AF, thromboembolic events were rare and absolute bleeding event rates were higher with concomitant APT. These findings may be relevant for AF-patients considered for dual therapy; even for a short treatment duration of 1 month.

Background The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) demonstrated noninferiority of once-daily 60 mg (30 mg dose-reduced) edoxaban compared with warfarin for prevention of stroke/systemic embolism in patients with atrial fibrillation. No previous analysis has explored the impact of treatment with edoxaban versus warfarin on rates of hospitalizations. Methods Detailed healthcare resource utilization data from ENGAGE AF-TIMI 48 for the 14 024 randomized patients who received at least one dose of study drug were used to compare the rates of bleeding- and cardiovascular-related hospitalizations for edoxaban versus warfarin. Hospitalization rates were calculated for each treatment group, and relative rates were estimated using Poisson regression. The influence of patient characteristics on the impact of edoxaban versus warfarin was evaluated through the inclusion of interaction terms. Results The overall rate of cardiovascular- or bleeding-related hospitalization was significantly lower for edoxaban than warfarin (relative rate [RR], 0.91 [95% CI, 0.85-0.97], P =0.003). Rates of hospitalizations for cardiovascular reasons (RR, 0.91 [95% CI, 0.85-0.97], P =0.004), stroke (RR, 0.80 [95% CI, 0.72-0.88], P <0.0001), and for each stroke subtype (ischemic: RR, 0.89 [95% CI, 0.81-0.99], P =0.03; hemorrhagic: RR, 0.60 [95% CI, 0.54-0.68], P <0.0001) were also lower for edoxaban. Notably, significantly greater reductions with edoxaban versus warfarin were seen for ischemic stroke-related hospitalizations in vitamin K antagonist naive patients and patients with CHADS 2 scores 4 to 6, previous stroke or transient ischemic attack, age ≥75, and no previous coronary artery disease. For nonstroke bleeding-related hospitalizations, greater reductions with edoxaban were seen in vitamin K antagonist naive patients, patients with CHADS 2 scores 4 to 6, and patients with moderate renal dysfunction. Conclusions Edoxaban 60 mg (30 mg dose-reduced) was associated with a significantly lower overall rate of cardiovascular- or bleeding-related hospitalization and significant reductions in the subcategories of cardiovascular-related, stroke-related, bleed-related, and nonstroke cardiovascular-related hospitalizations, when compared with warfarin. These results suggest the potential for cost offsets with edoxaban, with even greater reductions in higher-risk patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.

Background: Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding., Methods: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis., Results: A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36)., Conclusions: In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: In ENSURE-AF study, edoxaban had similar efficacy and safety profile versus enoxaparin-warfarin (enox-warf) in patients undergoing electrical cardioversion of non-valvular atrial fibrillation., Objectives: To evaluate the efficacy and safety of edoxaban versus enox-warf in patients who were vitamin K antagonists (VKA) naïve or experienced at time of randomisation into ENSURE-AF trial., Methods: The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death during the overall study period, 28 days on study drug after cardioversion and 30 days follow-up. The primary safety endpoint was the composite of major and clinically relevant nonmajor bleeding during the on-medication period from time of first dose to last dose of study drug taken + 3 days., Results: Of 2199 patients enrolled in ENSURE-AF, 1095 were randomised to edoxaban and 1104 to enox-warf. There were numerically fewer primary efficacy endpoint events with edoxaban than enox-warf irrespective of whether VKA experienced or naïve (0.5% vs. 0.9%, 0.3% vs. 1.4%, respectively). There were no significant differences in the primary safety endpoint [odds ratio (OR) 2.09, 95% confidence interval (CI) 0.72-6.81 in anticoagulant experienced patients, OR 0.77, 95% CI 0.15-3.60 in anticoagulant naïve patients] and in major bleeding rates regardless of treatment or VKA experience (OR 0.69, 95%CI 0.06-6.04, OR 0.48, 95% CI 0.01-9.25, respectively)., Conclusions: Edoxaban had comparable efficacy and safety to optimized anticoagulation with enox-warf. The primary efficacy and safety endpoint outcomes were broadly similar between VKA experienced or naïve patients.

Background: Guidance for periprocedural anticoagulant management is mainly based on limited data from Phase III or observational studies and expert opinion., Hypothesis: EMIT-AF/VTE was designed to document the risks of bleeding and thromboembolic events in more than 1000 patients on edoxaban undergoing diagnostic and therapeutic procedures in clinical practice., Methods: Routine care in a multinational multicenter, prospective observational study. Participants were adult patients with atrial fibrillation and/or venous thromboembolism treated with edoxaban for stroke prevention or for secondary prevention in venous thromboembolic disease, undergoing a wide range of diagnostic and therapeutic procedures. Edoxaban therapy was interrupted periprocedurally at the treating physician's discretion. Patients were evaluated from 5 days pre- until 30 days postprocedure. Primary outcome was the incidence of International Society on Thrombosis and Haemostasis defined major bleeding; secondary outcomes included incidence of clinically relevant non-major bleeding, acute coronary syndrome, and acute thromboembolic events., Results: Outcomes and management are reported for the first procedures in 1155 unselected patients. Five cases of major bleeding (0.4%) and eight of clinically relevant non-major bleeding (0.7%) were documented, five (38%) of which occurred outside the period of likely edoxaban effect (last edoxaban dose ≥3 days prior to bleeding). Five (0.4%) deaths from any cause, seven acute thromboembolic events (0.6%) including two cardiac deaths (0.2%) in six patients, and one acute coronary event (0.1%) occurred., Conclusions: The periprocedural bleeding and acute thromboembolic event risks for patients treated with edoxaban were low. This can help inform both clinical routine and guidelines for the periprocedural management of edoxaban., (© 2020 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Aims: Non-vitamin K antagonist oral anticoagulants represent a new option for prevention of embolic events in patients with atrial fibrillation (AF). However, little is known about the impact of non-cardiac comorbidities on the efficacy and safety profile of these drugs., Methods and Results: In a post hoc analysis of the ENGAGE AF-TIMI 48 trial, we analysed 21 105 patients with AF followed for an average of 2.8 years and randomized to either a higher-dose edoxaban regimen (HDER), a lower-dose edoxaban regimen, or warfarin. We used the updated Charlson Comorbidity Index (CCI) to stratify the patients according to the burden of concomitant disease (CCI = 0, 1, 2, 3, and ≥4). The treatment groups were then compared for safety, efficacy, and net clinical outcomes across CCI categories. There were 32.0%, 7.3%, 42.1%, 12.7%, and 6.0% of patients with CCI scores of 0, 1, 2, 3, and ≥4, respectively. A CCI score ≥4 was associated with significantly higher rates of thromboembolic events, bleeding, and death compared to CCI = 0 (P < 0.05 for each). The annualized rates of the primary net clinical outcome (stroke/systemic embolism, major bleeding, or death) for CCI = 0, 1, 2, 3, or ≥4 were 5.9%, 8.7%, 6.6%, 10.3%, and 13.6% (Ptrend < 0.001). There were no significant interactions between treatment with HDER vs. warfarin and efficacy, safety, and net outcomes across the CCI groups (P-interaction > 0.10 for each)., Conclusion: Although increasing CCI scores are associated with worse outcomes, the efficacy, safety, and net clinical outcomes of edoxaban vs. warfarin were independent of the degree of comorbidity present., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aim: Dried blood spot (DBS) is a sampling approach that offers several advantages over plasma and whole blood (WB) sampling, but several factors, such as hematocrit and temperature, can adversely affect quantitation. Methodology & results: In an open-label, three-way crossover study in healthy subjects, we explored the correlation between DBS, WB and plasma samples, and between DBS samples from finger-prick and venipuncture blood for measuring edoxaban and its metabolite M-4 using LC-MS/MS. The methods were validated comprehensively. The incurred sample reanalysis experiments demonstrated quantitation reproducibility in all three matrices. Overall, there was a good correlation (near perfect concordance for edoxaban) among plasma, WB and DBS measurements. M-4 concentrations in DBS and WB were lower than in plasma. Conclusion: These results indicate using DBS may be used as an alternative methodology to measure edoxaban pharmacokinetics.

Direct oral anticoagulants, including edoxaban, primarily do not need routine monitoring of the anticoagulant effect. However, extremely high/low plasma concentrations of edoxaban (PC-Ed) should be properly evaluated, especially when patients under anticoagulation therapy are at an emergency state. For this purpose, PC-Ed determined by an anti-Xa assay (indirect PC-Ed) is more convenient and, therefore, more useful compared with PC-Ed determined by an LC-MS/MS (direct PC-Ed) in daily clinical practice. Consecutive 97 patients with non-valvular atrial fibrillation (NVAF) under edoxaban therapy were evaluated, in whom edoxaban 60/30 mg doses were prescribed for 48/49 patients, 71 (73.2%) were men, and the average age was 69 years. CHADS 2 score 0, 1, and ≥ 2 were 26.8%, 44.3%, and 28.9%, while CHA 2 DS 2 -VASc score 0, 1, and ≥ 2 were 14.4%, 16.5%, and 69.1%, respectively. Median values of direct and indirect PC-Ed by LC-MS/MS and anti-Xa assay were 187.1 and 176.1 ng/mL at peak (2-4 h post-dose) and 14.4 and 17.5 ng/mL at trough (pre-dose), respectively. The PC-Ed at peak and trough by two methods were significantly correlated, and the correlation coefficients were r = 0.973 and 0.963 (both, p < 0.0001), respectively. By a Bland-Altman plot, mean differences between the direct and indirect PC-Ed [lower to upper percent limit of agreement] were - 4.87 [- 46.71 to 36.98] and 4.66 [- 1.37 to 10.69] ng/mL at peak and trough, respectively. Moreover, mean % error for difference between the direct and indirect PC-Ed [lower to upper percent limit of agreement] was - 1.22 [- 20.59 to 18.14] and 31.75 [- 14.03 to 77.53] % at peak and trough, respectively, where the % error extremely increased around the lower limit of detection (LLOD) in the anti-Xa assay. Strong similarity was observed between the direct and indirect PC-Ed, especially at peak. The indirect PC-Ed was higher than the direct PC-Ed, especially around the LLOD, suggesting the need for caution when we use the anti-Xa assay for measurement of trough PC-Ed (UMIN 000032492).

Fibrinolysis is regulated by the thrombin/thrombin-activatable fibrinolysis inhibitor (TAFI) system. Thus, anticoagulants and inhibitors of TAFI are expected to accelerate fibrinolysis. The combined effects of an anticoagulant and a TAFIa inhibitor on fibrinolysis remain unknown. The aim of this study was to evaluate the combined effect of edoxaban, an oral direct factor Xa (FXa) inhibitor, and a TAFIa inhibitor, potato tuber carboxypeptidase inhibitor (PCI) on tissue-type plasminogen activator (t-PA)-induced clot lysis in human plasma in vitro. Pooled human plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban and/or PCI. Clot formation was induced by 2.5 pM tissue factor and 4 µM phospholipids and clot lysis time was examined. Plasma plasmin-α2 antiplasmin complex (PAP) concentration was measured as a marker of plasmin generation. Edoxaban or PCI alone significantly shortened the t-PA-induced clot lysis time and plasma PAP concentration. The combination of these compounds significantly accelerated the clot lysis compared with the inhibitors alone. Addition of PCI (0.3, 1, and 3 μg/mL) to 75 ng/mL edoxaban increased plasma PAP concentration compared with edoxaban alone; however, compared with PCI alone only the combination of 0.3 μg/mL PCI + 75 ng/mL edoxaban showed the significant increase in PAP concentration. Concomitant use of an oral direct FXa inhibitor, edoxaban, and a TAFIa inhibitor, PCI, significantly accelerate fibrinolysis via enhancement of plasmin generation. These results suggest that the combination of edoxaban and a TAFIa inhibitor might be beneficial for the treatment of thromboembolic diseases.

Background: Randomized controlled trials showed the nonvitamin K oral anticoagulant (NOAC) edoxaban was effective and safe for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolism (VTE; including pulmonary embolism and deep vein thrombosis). Additional research is needed to evaluate the effects of edoxaban in routine clinical practice. Therefore, the Edoxaban Treatment in routine cliNical prActice (ETNA) program is being conducted to provide routine clinical care data on characteristics and outcomes in patients with AF or VTE receiving edoxaban., Methods: The Global ETNA program integrates prospectively collected data from edoxaban patients in regional ETNA noninterventional studies across Europe, Japan, and East and Southeast Asia into indication-specific databases for AF and VTE. Targeted enrollment is >31 000 patients (AF >26 000; VTE >4500), with a follow-up of 2 years for AF and 1 year for VTE. Data integration will be possible using consistent terminology, parameter definitions, and data collection across the regional noninterventional studies. Safety and effectiveness data will be assessed. Crude rates of outcomes including bleeding and thromboembolic events will be reported., Results: Globally, enrollment began in early 2015 and is ongoing., Conclusions: Global ETNA will generate the largest integrated prospective repository of routine clinical care data for a single NOAC in patients with AF or VTE. It will provide important information on the safety of edoxaban in routine clinical care and gather further information on its effectiveness., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

The aims of this study were to determine the distribution of plasma concentration of edoxaban (PC-Ed) with their 90% interval (on therapy range) and its correlation with anticoagulation markers in patients with non-valvular atrial fibrillation (NVAF). Consecutive 97 NVAF patients under edoxaban therapy were evaluated (60/30 mg dose, n = 48/49; men/women, n = 71/26; age, 69 years). CHADS 2 score 0, 1, and ≥ 2 were 27%, 44%, and 29%, respectively. The mean (90% interval) of PC-Ed by LC-MS/MS was 194.3 (49.4-345.3) and 17.0 (4.8-40.7) ng/mL at peak (2-4 h post-dose) and trough (pre-dose), respectively. Correlation of prothrombin time (PT) with PC-Ed was higher than that of activated partial thromboplastin time (aPTT). Among 6 PT reagents, Coagupia PT-N and Simplastin Excel S (both PT reagents) showed the highest predictive capability for the upper outlier of PC-Ed at peak and trough. Among 4 aPTT reagents, only Thrombocheck APTT measured at peak had a significant predictive capability. When using PT reagents, both peak and trough sampling showed a similar predictive capability for the upper outliers of PC-Ed with a high sensitivity, but a relatively low specificity. We demonstrated the distributions of plasma concentration, PT with 6 reagents, and aPTT with 4 reagents under edoxaban therapy in Japanese patients with NVAF, showing their 90% intervals. For predicting the upper outlier of PC-Ed, PT was more sensitive compared with aPTT, whereas predicting capability for the outliers of PC-Ed was mostly similar between peak and trough samplings among PT reagents (UMIN 000032492).

Background: Catheter ablation (CA) has been reported to reduce risk of stroke in patients with nonvalvular atrial fibrillation (NVAF) in retrospective studies. However, the risks and benefits of CA have not been well elucidated in patients with NVAF and who have suffered a recent ischemic stroke in prospective randomized trials. Thus, the aim of the STABLED clinical trial is to investigate the efficacy and safety of CA with anticoagulant therapy using edoxaban in patients with NVAF and a history of recent ischemic stroke., Methods and Design: The STABLED trial is a multicenter, prospective, randomized, open-label, standard medication-controlled study in Japan. The target patient number is 250, comprising 125 patients receiving standard medication and 125 receiving CA. For patients allocated to the CA group, ablation is to be performed between 1 to 6 months from the onset of index stroke. The observation period will be 3 years from the day of random allocation of the final patient to any of the groups. The primary outcome measure is the composite of recurrence of ischemic stroke, systemic embolism, all-cause death, and hospitalization for heart failure., Conclusion: This study will investigate the effectiveness and safety of CA and basic anticoagulation treatment with edoxaban for patients with NVAF who have suffered a recent ischemic stroke. The aim is to determine the best evidence for an optimal treatment strategy for patients with NVAF and recent stroke., Trial Registration: UMIN000031424/NCT03777631., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Numerous scales exist for the classification of major bleeding events. Limited data compare the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. Here, we analyze bleeding outcomes according to the ISTH (International Society on Thrombosis and Hemostasis), TIMI (Thrombolysis in Myocardial Infarction), GUSTO (Global Usage of Strategies to Open Occluded Arteries), and BARC (Bleeding Academic Research Consortium) bleeding scales in the ENGAGE AF (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation)-TIMI 48 trial (NCT00781391) of edoxaban versus warfarin., Methods: A total of 21 105 patients with atrial fibrillation at risk for stroke (CHADS 2 score ≥2) were enrolled in the ENGAGE AF-TIMI 48 trial comparing warfarin with a higher- (60/30 mg daily) or lower- (30/15 mg daily) dose edoxaban regimen. Median follow-up was 2.8 years. Bleeding events occurring among on-treatment patients were examined. Annualized event rates were calculated by the ISTH, TIMI, GUSTO, and BARC scales and compared across treatment arms. Cox proportional hazards for a first bleeding event of each type were calculated for higher-dose edoxaban regimen vs warfarin and lower-dose edoxaban regimen versus warfarin., Results: A total of 10 311 bleeding events were reported. In a comparison of the most severe events in each scale, ISTH major bleeding was the most common (n=1289), followed by TIMI major (n=548), GUSTO severe/life-threatening (n=347), and BARC 3c+5 (n=276) bleeding. Lower bleeding risk with edoxaban compared with warfarin was seen regardless of bleeding scale (higher-dose edoxaban regimen range: hazard ratio [HR], 0.47 [95% CI, 0.35-0.62] for BARC 3c+5 versus HR, 0.80 [95% CI, 0.71-0.91] for ISTH major; lower-dose edoxaban regimen range: HR, 0.32 [95% CI, 0.23-0.45] for BARC 3c+5 versus HR, 0.47 [95% CI, 0.41-0.55] for ISTH major). Furthermore, a gradient of more pronounced risk reduction with edoxaban was observed with greater severity of first bleeding event (higher-dose edoxaban regimen: HR, 0.47 [95% CI, 0.35-0.62] for BARC 3c+5 bleeds versus HR, 0.86 [95% CI, 0.81-0.91] for any BARC bleed; lower-dose edoxaban regimen: HR, 0.32 [95% CI, 0.23-0.45] for BARC 3c+5 bleeds versus HR, 0.68 [95% CI, 0.63-0.72] for any BARC bleed). The direction of this trend was consistent for both gastrointestinal bleeding and nongastrointestinal bleeding., Conclusions: Among patients with atrial fibrillation at risk for stroke, there was a >4-fold difference in the frequency of the most severe bleeding events across commonly used bleeding scales. Furthermore, the relative safety of edoxaban compared with warfarin tended to increase with greater severity of bleeding., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Aims: ENSURE-AF (NCT02072434) was the largest prospective randomized clinical trial of anticoagulation for cardioversion in atrial fibrillation (AF), which also provides the largest prospective dataset for transoesophageal echocardiography (TOE) prior to cardioversion. This ancillary analysis investigated determinants of TOE-detected left atrium thrombi (LAT) in patients scheduled for electrical cardioversion (ECV)., Methods and Results: The ENSURE-AF multicentre PROBE evaluation trial compared edoxaban 60 mg once daily (QD) with enoxaparin/warfarin in 2199 subjects undergoing ECV of non-valvular AF. Patients were stratified by the use of TOE, anticoagulant experience, and selected edoxaban dose. Electrical cardioversion was cancelled or deferred when TOEdetected LAT. In total, 1183 subjects were stratified to the TOE arm and LAT was reported in 91 (8.2%). In univariate analysis, age ≥75 years (26.4% vs. 16.9%, P = 0.0308), lower weight (86.5 ± 15.0 vs. 90.7 ± 18.0 kg, P = 0.0309), lower creatinine clearance (80.1 ± 30.6 vs. 93.2 ± 33.9 mL/min, P = 0.0007), heart failure (59.3% vs. 43.0%, P = 0.0029), and diuretic treatment (53.9% vs. 40.1%, P = 0.0141) were more prevalent in the LAT group. Non-significant trends were seen for higher mean CHA2DS2-VASc score (3.0 ± 1.41 vs. 2.7 ± 1.48, P = 0.0571) and more prevalent anticoagulation use prior to enrolment (60.4% vs. 50.3%, P = 0.0795) in the LAT group. In logistic regression analysis, age (P = 0.0202) and heart failure (P = 0.0064) were independently associated with LAT., Conclusion: Elective ECV is commonly cancelled or deferred due to TOE-detected LAT in patients with non-valvular AF. Age ≥75 years and heart failure were associated with the presence of LAT., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI)., Methods: ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed., Findings: From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority)., Interpretation: In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events., Funding: Daiichi Sankyo., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The KYU-RABLE study, a prospective, multicenter, single-arm interventional study, evaluated the efficacy and safety of uninterrupted oral edoxaban in patients undergoing catheter ablation (CA) for atrial fibrillation (AF)., Methods and results: We enrolled patients with AF from 23 centers in Japan. Edoxaban 60 mg (30 mg in patients indicated for dose adjustment) was administered uninterrupted, once daily in the morning for ≥4 weeks before CA and 4 weeks ±7 days after CA with one dose delayed on the procedural day. The primary endpoint was a composite of thromboembolism and major bleeding during 4 weeks from the procedural day. Among the 513 eligible patients who underwent CA, 63.5% received edoxaban 60 mg/day and 36.1% received 30 mg/day. For the primary endpoint, no thromboembolism and 1 major bleeding event (0.2%, cardiac tamponade) were observed. The plasma edoxaban concentration decreased depending on the time from the last administration to the CA procedure. However, plasma levels of coagulative biomarkers were within appropriate ranges regardless of the interval from the last administration of edoxaban., Conclusions: The present study provided evidence of the efficacy and safety of uninterrupted edoxaban administered once daily in the morning, with one dose delayed on procedural day, in patients with AF undergoing CA. Edoxaban was associated with a low risk of periprocedural thromboembolic and bleeding complications.

Aims: Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested., Methods and Results: The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90 days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02-1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N = 10) and 1.7% of VKA patients (N = 3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P = 0.62)., Conclusion: Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Hypertension is a risk factor for both stroke and bleeding in patients with atrial fibrillation. Data are sparse regarding the interaction between blood pressure and the efficacy and safety of direct oral anticoagulants. In the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48), 19,679 patients with atrial fibrillation and hypertension were categorized according to average systolic blood pressure (SBP) and diastolic blood pressure (DBP). The primary efficacy and safety end points were the time to the first stroke or systemic embolic event and the time to the first International Society of Thrombosis and Hemostasis major bleeding event, respectively. Risk was calculated using Cox proportional hazards models based on average SBP and DBP and adjusting for 18 clinical characteristics. The efficacy and safety of a higher dose edoxaban regimen (60/30 mg) versus warfarin were evaluated with stratification by average SBP and DBP. Stroke/systemic embolic event occurred significantly more frequently in patients with elevated average SBP (hazard ratio, 2.01; 95% CI, 1.50-2.70 for SBP ≥150 mm Hg relative to 130-139 mm Hg) or DBP (hazard ratio, 2.36; 95% CI, 1.76-3.16 for DBP ≥90 mm Hg relative to 75-<85 mm Hg). The higher dose edoxaban regimen reduced stroke/systemic embolic event across the full range of SBP (P interaction =0.55) and DBP (P interaction =0.44) compared with warfarin. The higher dose edoxaban regimen reduced the risk of major bleeding events, including intracranial hemorrhage, without modification by average SBP (P interaction =0.29). The relative safety of edoxaban was most pronounced in patients with elevated DBP (P interaction =0.007). The efficacy and safety of edoxaban were consistent across the full range of SBP, while the superior safety of edoxaban was most pronounced among patients with elevated DBP.

Background: Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents., Objectives: This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease., Methods: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration., Results: Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HR adj ]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HR adj : 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [p int ] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (p int  = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups., Conclusions: Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The synthesis and structure-activity relationships of a novel series of 3-aminothieno[2,3-b]pyridine-2-carboxamides were explored. Our efforts were focused on modifying the C-4 substituent of the thienopyridine ring to develop orally available bone anabolic agents. 4-Alkoxy derivatives were found to be novel ALPase enhancers without inhibitory effect on P450 activity. Among these derivatives, compound 6k was orally administered to ovariectomized rats, and it was found to significantly improve areal bone mineral density at a dose of 30 mg/kg/day., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The available routine care data have demonstrated the safety of different NOACs; however, such data for edoxaban are scarce. Here, we report baseline characteristics of 13,638 edoxaban-treated patients with AF enrolled between November 2016 and February 2018., Methods: ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study conducted in 825 sites in 10 European countries. Patients will be followed up for four years., Results: Overall, 13,980 patients were enrolled of which 342 patients were excluded from the analysis. Mean patient age was 73.6 years with an average creatinine clearance of 69.4 mL/min. 56.6% were male. The calculated CHA 2 DS 2 -VASc and HAS-BLED mean scores were 3.1 and 2.6, respectively. Overall, 3.3, 14.6 and 82.0% of patients had low (CHA 2 DS 2 -VASc = 0), intermediate (CHA 2 DS 2 -VASc = 1) and high (CHA 2 DS 2 -VASc≥2) risks of stroke, respectively. High-risk patients (those with prior stroke, prior major bleeding, prior intracranial bleed or CHA 2 DS 2 -VASc ≥4) comprised 38.4% of the overall population. For 75.1% of patients edoxaban was their first anticoagulant prescription, whilst 16.9% switched from a VKA and 8.0% from another NOAC. A total of 23.4% of patients in ETNA-AF-Europe received the reduced dose of edoxaban 30 mg. Overall, 83.8% of patients received an edoxaban dose in line with the criteria outlined in the label., Conclusion: Edoxaban was predominantly initiated in older, often anticoagulation-naïve, unselected European patients with AF, with a good overall adherence to the approved label., Trial Registration: NCT02944019; Date of registration: October 24, 2016.

A direct oral anticoagulant, edoxaban, is as effective as vitamin K antagonists for the treatment of venous thromboembolism (VTE). However, the mechanism underlying the treatment effect on VTE remains to be determined. The aims of this study were to evaluate the effect of edoxaban on tissue plasminogen activator (t-PA)-induced clot lysis in human plasma and to determine the roles of plasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) in the profibrinolytic effect by edoxaban. Pooled human normal plasma or TAFI-deficient plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban or an activated TAFI inhibitor, potato tuber carboxypeptidase inhibitor (PCI). Clot was induced by adding tissue factor and phospholipids. Clot lysis time and plasma plasmin-α2 antiplasmin complex (PAP) concentration were determined. Clot structure was imaged with a scanning electron microscope. In normal plasma, edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) and PCI significantly shortened clot lysis time. PCI increased PAP concentration and a correlation between PAP concentration and percent of clot lysis was observed. Edoxaban also dose-dependently elevated PAP concentration. In TAFI-deficient plasma, the effects of edoxaban and PCI on clot lysis and PAP concentration were markedly diminished as compared with normal plasma. Fibrin fibers were thinner in clots formed in the presence of edoxaban. In conclusion, edoxaban at clinically relevant concentrations accelerates t-PA-induced fibrinolysis via increasing plasmin generation in human plasma. The effects of edoxaban is mainly dependent on TAFI. The profibrinolytic effect of edoxaban might contribute to the efficacy for the treatment of VTE.

Background: ETNA-VTE-Japan is an ongoing prospective observational study conducted as part of a postmarketing observational study to investigate the safety and effectiveness of edoxaban in Japanese patients for whom the drug has been newly prescribed to treat venous thromboembolism (VTE) and prevent VTE recurrence. The results of an interim analysis of data collected at 3 months are presented., Methods and results: A total of 1,732 patients were enrolled. The safety and effectiveness analyses included data from 1,703 and 1,699 patients, respectively. In the safety analysis set, 39.4% of patients were aged ≥75 years, 58.2% had body weight ≤60 kg, and 22.2% had creatinine clearance <50 mL/min. Approximately 90% of patients received a dose in accordance with the package insert. Approximately 80% of patients continued treatment; the mean treatment period was 74.5 days. The incidence of bleeding adverse events and major bleeding was 6.3% and 1.4%, respectively. The incidence of VTE recurrence and symptomatic VTE recurrence in the on-treatment population was 0.8% and 0.4%, respectively. Safety and effectiveness profiles of edoxaban in patients receiving the low dose (30 mg/day), generally administered to patients with high bleeding risk, were similar to those of the standard dose (60 mg/day)., Conclusions: The results confirm no major concerns about the safety and effectiveness of edoxaban in Japanese patients with VTE in the first 3 months of treatment. (Trial registration No.: UMIN000016387.).

Aims: Prior studies suggested that the risks of ischaemic stroke and bleeding in patients of Asian race with atrial fibrillation (AF) may be higher than that of non-Asians. In the analysis of ENGAGE AF-TIMI 48 trial, we compared clinical outcomes, edoxaban concentration, and anti-factor Xa (anti-FXa) activity, between Asian and non-Asian races., Methods and Results: There were 2909 patients of Asian race and 18 195 non-Asian race in the ENGAGE AF-TIMI 48 trial. The risks of thromboembolism and bleeding events were compared for Asians and non-Asians treated with warfarin. The trough levels of edoxaban concentration and anti-FXa activity were also compared and correlated with the efficacy and safety of edoxaban vs. warfarin. Compared to non-Asian patients, the Asian population was on average 2 years younger and 20 kg lighter. In the warfarin group, the adjusted risk of ischaemic stroke did not differ significantly for patients of Asian and non-Asian race [adjusted hazard ratio (aHR) = 1.12, P = 0.56). Asians treated with warfarin had a higher-adjusted risk of intracranial haemorrhage (ICH: aHR 1.71, P = 0.03) compared with non-Asians. The trough edoxaban concentration and anti-FXa activity were 20-25% lower for Asians compared with non-Asians. Compared to warfarin, higher dose edoxaban significantly reduced ICH while preserving the efficacy of stroke prevention in both Asians and non-Asians. Two of three net clinical outcomes appeared to be more favourably reduced with edoxaban in Asians compared with non-Asians (Pint = 0.063 for primary, 0.037 for secondary, and 0.032 for third net clinical outcomes, respectively)., Conclusion: Compared to warfarin, higher dose edoxaban preserved the efficacy for stroke prevention and was associated with a favourable safety profile for Asians, which may be due to the lower trough edoxaban concentration and anti-FXa activity achieved in patients of Asian race., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)