Search

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.

Aims: Cardiac functional and structural remodelling in patients with atrial fibrillation (AF) contributes to development of heart failure (HF) as their major cardiovascular comorbidity. Circulating biomarkers may reflect these cardiac alterations., Methods and Results: ENGAGE AF-TIMI 48 was a randomized trial of edoxaban versus warfarin in 21 105 patients with AF. We performed a nested biomarker study, analysing high-sensitivity troponin T (hsTnT, n = 8705), N-terminal pro-B-type natriuretic peptide (NT-proBNP, n = 8765), and growth differentiation factor-15 (GDF-15, n = 8705) at baseline and 12 months. Of the biomarker cohort, 5207 had a history of HF, among whom 3996 had known ejection fraction (EF): 926 with reduced EF (HFrEF; ≤40%), 1043 with mildly reduced EF (HFmrEF; 40-49%), and 2027 with preserved EF (HFpEF; ≥50%). Elevated baseline hsTnT, NT-proBNP, and GDF-15 were associated with higher risk of hospitalization for HF (HHF) or HF death overall and in subpopulations defined by HF history and EF (p < 0.001 for each). These associations of outcome with each biomarker were consistent regardless of a history of HF or EF (p-interaction >0.05 for each). Patients who had an increase in or had persistently elevated values in any of the three biomarkers over 12 months were at higher risk for HHF or HF death in the overall population (p < 0.001 for each biomarker and category)., Conclusion: Serial measurement of hsTnT, NT-proBNP, and GDF-15 revealed that higher baseline values, and increasing or persistently elevated values over 1 year are associated with higher risk of HF outcomes in patients with AF regardless of HF history or HF phenotype based on EF., Clinical Trial Registration: ClinicalTrials.gov unique identifier NCT00781391., (© 2023 European Society of Cardiology.)

Background: The risks of heart failure (HF) events compared with stroke/systemic embolic events (SEE) or major bleeding (MB) in heart failure with reduced ejection fraction (HFrEF) vs heart failure with preserved ejection fraction (HFpEF) in a large atrial fibrillation (AF) population have not been well-studied., Objectives: This study sought to assess HF outcomes, according to HF history and HF phenotypes (HFrEF vs HFpEF), and compare these events with SEE and MB, among patients with AF., Methods: We analyzed patients enrolled in the ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48) trial. Cumulative incidence of heart failure hospitalization (HHF) or HF death was assessed and compared with the rates of fatal and nonfatal stroke/SEE and MB over a median follow-up of 2.8 years., Results: Overall, 12,124 (57.4%) had a history of HF (37.7% HFrEF, 40.1% HFpEF, 22.1% with unknown ejection fraction). The rate per 100 person-years (py) of HHF or HF death (4.95; 95% CI: 4.70-5.20) was higher than of fatal and nonfatal stroke/SEE (1.77; 95% CI: 1.63-1.92) and MB (2.66; 95% CI: 2.47-2.86) among patients with HF history. HFrEF patients experienced a higher rate of HHF or HF death compared with HFpEF patients (7.15 vs 3.65; P < 0.001), while the rates of fatal and nonfatal stroke/SEE and MB were similar by HF phenotype. Patients with HF history had a higher rate of mortality after a HHF (1.29; 95% CI: 1.17-1.42) than after a stroke/SEE (0.69; 95% CI: 0.60-0.78) or after MB (0.61; 95% CI: 0.53-0.70). Overall, patients with nonparoxysmal AF had a higher rate of HF and stroke/SEE events regardless of HF history., Conclusions: Patients with AF and HF, regardless of ejection fraction, are at a higher risk of HF events with higher subsequent mortality rates than of stroke/SEE or MB. While HFrEF is associated with a higher risk of HF events than HFpEF, the risk of stroke/SEE and MB is similar between HFrEF and HFpEF., Competing Interests: Funding Support and Author Disclosures The ENGAGE AF-TIMI 48 study (NCT00781391) was supported by Daiichi Sankyo Pharma Development. Dr Giugliano has received clinical trials/research support to his institution from Daiichi Sankyo, Anthos Therapeutics, and Amgen; and honoraria for continuing medical education lectures and/or consulting from Amarin, the American College of Cardiology, Amgen, Astra Zeneca, CryoLife, CVS Caremark, and Daiichi Sankyo. Dr Ruff has received research grants through his institution from Anthos Therapeutics, Boehringer Ingelheim, Daiichi Sankyo, MedImmune, and the National Institutes of Health; and honoraria for serving on the scientific advisory board and consulting for Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, MedImmune, Pfizer, and Portola. Dr Antman has received grant support through his institution from Daiichi-Sankyo. Dr Braunwald has received research grant support to his institution from Daiichi Sankyo; and outside the submitted work has received research grants through his institution from AstraZeneca, Daiichi Sankyo, Merck, and Novartis; and has received consultancy fees from Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, Novo Nordisk, and Verve. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has served as a consultant for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The Atrial fibrillation Better Care (ABC) pathway is endorsed by guidelines to improve care of patients with atrial fibrillation (AF). However, whether the benefit of ABC pathway-concordant care is consistent across anticoagulants remains unclear. We assessed the association between ABC-concordant care and outcomes in this post hoc analysis from the ENGAGE AF-TIMI 48 trial, which was reported prior to the initial description of the ABC pathway., Methods and Results: Patients were retrospectively classified as receiving ABC-concordant care based on optimal anticoagulation, adequate rate control, management of co-morbidities and lifestyle measures. Associations between ABC-concordance and outcomes were assessed with adjustment for components of the CHA2DS2-VASc and HAS-BLED scores. Of 20 926 patients, 7915 (37.8%) satisfied criteria of ABC-concordant care, which was associated with significantly lower incidence of stroke or systemic embolic event [stroke/SEE: hazard ratio (HRadj): 0.54; 95% confidence interval (CI): 0.47-0.63], major bleeding (HRadj 0.66; 95% CI: 0.58-0.75), major adverse cardiac events (HRadj 0.53; 95% CI: 0.48-0.58), primary net clinical outcome (composite of stroke/SEE, major bleeding or death; HRadj 0.61; 95% CI: 0.56-0.65), cardiovascular (CV) hospitalization (HRadj 0.78; 95% CI: 0.74-0.83), CV death (HRadj 0.52; 95% CI: 0.46-0.58), and all-cause mortality (HRadj 0.56; 95% CI: 0.51-0.62), P < 0.001 for each. These associations were qualitatively consistent for both edoxaban and warfarin and across patient subgroups., Conclusion: Atrial fibrillation Better Care pathway-concordant care is associated with reductions across multiple CV endpoints and all-cause mortality, with benefit in edoxaban- and warfarin-treated patients and across patient subgroups. Increasing implementation of ABC-concordant care may improve clinical outcomes of patients with AF irrespective of anticoagulant., Competing Interests: Conflict of interest: S.A.M. has received research grant support, through her institution, from AstraZeneca, Amgen, Abbott Laboratories, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, Roche Diagnostics, and Takeda. E.M.A. has received grant support, through his institution, from Daiichi Sankyo and Eli Lilly. E.B. has received grant support, through his institution, from AstraZeneca, Daiichi Sankyo, Merck and Co, and Novartis; and has received consulting fees from Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, NovoNordisk, and Verve. G.Y.H.L. is a consultant and speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingelheim and Daichii Sankyo. No fees are received personally. R.P.G. has received institutional research grants to the TIMI Study Group at Brigham and Women’s Hospital from Amgen, Anthos Therapeutics, and Daiichi Sankyo; has received honoraria from Amgen, Centrix, Daiichi Sankyo, Dr. Reddy’s Laboratories, Medical Education Resources, Medscape, Menarini, Merck, Pfizer, SAJA Pharmaceuticals, Servier, Shanghai Medical Telescope and Voxmedia; and has received consulting fees from Amarin, Amgen, CryoLife, CSL Behring, CVS Caremark, Daiichi Sankyo, Esperion, Gilead, Hengrui, Inari, Janssen, Novartis, Pfizer, PhaseBio Pharmaceuticals, St. Lukes and Samsung. C.T.R. has received institutional research grants to the TIMI Study Group at Brigham and Women’s Hospital from Anthos, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Janssen, National Institutes of Health, Novartis; honoraria for consultancies with Anthos, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Pfizer. Consultancies with Anthos, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Pfizer; the TIMI Study Group has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Daiichi Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc., MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, The Medicines Company, Zora Biosciences., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher dose edoxaban (60/30 mg) and lower dose edoxaban (30/15 mg) were non-inferior to warfarin for stroke and systemic embolism (SSE) and significantly reduced major bleeding in AF patients in the global study to assess the safety and effectiveness of edoxaban vs standard practice of dosing with warfarin in patients with atrial fibrillation (ENGAGE AF-TIMI 48) trial. Whether the efficacy and safety of these dosing strategies vs. warfarin are consistent in patients with AF and PAD has not been described., Methods and Results: Of 21 105 patients with AF randomized to warfarin, edoxaban 60/30 mg, or edoxaban 30/15 mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACEs), SSE, and major bleeding. Patients with PAD had higher risk of MACEs [adjusted hazard ratio (HRadj) 1.33, 95% confidence interval (CI) 1.12-1.57, P = 0.001] and cardiovascular (CV) death (HRadj 1.49, 95% CI 1.21-1.83, P &lt; 0.001) than those without PAD, but not major bleeding. The efficacy of edoxaban 60/30 mg vs. warfarin was consistent regardless of PAD (SSE HR; PAD 1.16, 95% CI 0.42-3.20; no-PAD 0.86, 95% CI 0.74-1.02, P-interaction 0.57) as was major bleeding (PAD 0.96, 95% CI 0.54-1.70; no-PAD 0.80, 95% CI 0.70-0.91, P-interaction 0.54). Edoxaban 30/15 mg was inferior for SSE, with significant heterogeneity when stratified by PAD status (P-interaction 0.039)., Conclusion: Patients with AF and PAD are at heightened risk of MACEs and CV death vs. those without PAD. The efficacy and safety of edoxaban 60/30 mg vs. warfarin in AF are consistent regardless of PAD; however, edoxaban 30/15 mg is inferior for stroke prevention in AF patients with PAD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00781391., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding., Methods and Results: ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36-2.23 and adj-HR 1.27; 95% CI 1.07-1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02-1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36-0.65; NRI 0.42; 95% CI 0.33-0.51, respectively]., Conclusion: Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

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.)

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.)

Aims: This post hoc analysis of ELIMINATE-AF evaluated requirements of unfractionated heparin (UFH) and procedure-related bleeding in atrial fibrillation (AF) patients undergoing ablation with uninterrupted edoxaban or vitamin K antagonist (VKA) therapy., Methods and Results: Patients were randomized 2:1 to once-daily edoxaban 60 mg (or dose-reduced 30 mg) or dose-adjusted VKA (target international normalized ratio: 2.0-3.0). Uninterrupted anticoagulation was mandated for 21-28 days' pre-ablation and 90 days' post-ablation. During ablation, UFH administration targeted an activated clotting time (ACT) of 300-400 s. Periprocedural bleeding was differentiated between procedure-related (bleeding at puncture side, cardiac tamponade) and unrelated events. Of 614 randomized patients, 553 received study drug and underwent catheter ablation (edoxaban n = 375; VKA n = 178). The median (Q1-Q3) time from last dose to ablation procedure was 14.8 (13.3-16.5) vs. 16.5 (14.8-19.5) h (edoxaban vs. VKA group, respectively). Mean ACT (SD) ≥300 s was observed in 52% edoxaban- vs. 76% VKA-treated patients, despite a higher mean (SD) UFH dose in the edoxaban vs. VKA group [14 261 (6397) IU vs. 11 473 (4300) IU; exploratory P-value < 0.0001]. In the edoxaban group, 13 patients (3.5%) had procedure-related bleeds of whom 9 had received an UFH dose above the median (13 000 IU). In the VKA arm, 7 patients (3.9%) had procedure-related bleeds of whom 3 had received an UFH dose above the median (10 225 IU)., Conclusion: The rate of procedure-related major/clinically relevant non-major bleeding did not differ between the treatment arms despite higher doses of UFH used with edoxaban vs. VKA to achieve a target ACT during AF ablation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Diabetes mellitus is an independent risk factor for stroke and atrial fibrillation. Therefore, the risk/benefit profile of the oral factor Xa inhibitor edoxaban stratified by diabetes is of clinical interest., Methods: 21,105 patients enrolled in ENGAGE AF-TIMI 48 were stratified into 2 pre-specified groups: without (N = 13,481) and with diabetes (N = 7,624)., Results: On average, patients with diabetes were younger, and had a higher body mass index, CHA 2 DS 2 -VASc score and baseline endogenous Factor Xa activity. After multivariate adjustments, patients with diabetes had a similar rate of stroke and systemic embolism compared to those without diabetes (adjusted hazard ratio (HR adj ) 1.08; 95% confidence interval (CI) 0.94-1.24; p = 0.28). However, the risk of major bleeding was significantly higher in patients with diabetes (HR adj 1.28; 95% CI 1.14-1.44; p < 0.001). The treatment effect of edoxaban (vs warfarin) was not modified by diabetes (all p-interactions > 0.05), a finding supported by the preserved edoxaban concentrations and inhibition of Factor Xa regardless of diabetes. The HRs of stroke and systemic embolism in patients receiving the higher-dose edoxaban regimen vs warfarin were 0.93 and 0.84 (p-interaction = 0.54) in those with and without diabetes respectively. The higher-dose edoxaban regimen reduced major bleeding (by 19-21%) and cardiovascular death (by 7-17%) regardless of diabetes (p-interactions = 0.81 and 0.33 respectively)., Conclusion: Patients with diabetes in ENGAGE AF-TIMI 48 had higher bleeding risk, but after adjustment similar stroke risk, compared to those without diabetes. The higher-dose edoxaban regimen had similar efficacy compared to warfarin, while reducing bleeding and cardiovascular mortality, irrespective of diabetes., Competing Interests: Declaration of competing interest Dr. Plitt reports receiving honoraria for educational activities from Bristol Myers Squibb. Dr. Ruff reports receiving research grants through institution: Boehringer Ingelheim, Daiichi Sankyo, MedImmune, National Institutes of Health. Honoraria for scientific advisory boards and consulting: Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, MedImmune, Pfizer, Portola. Dr. Goudev reports receiving a research grant from Daiici Sankyo for Engage AT-TIMI 48 trial. Dr. Morais reports receiving honoraria from pharmaceutical companies for consulting activities and lectures: Amgen, Astra Zeneca, Bayer Healthcare, Boehringer Ingelheim, Novartis, Servier. Research grant from Daiichi Sankyo for Engage AT-TIMI 48 trial. Dr. Ostojic reports receiving a research grant from Daiichi Sankyo for Engage AT-TIMI 48 trial. Dr. Grosso reports employment at Daiichi Sankyo. Dr. Lanz reports employment at Daiichi Sankyo. Dr. Park reports 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, Zora Biosciences. Dr. Antman reports receiving grant support through his institution from Daiichi Sankyo. Dr. Braunwald reports a research grant to his institution from Daiichi-Sankyo. Outside the submitted work, Dr. Braunwald reports research grants to his institution from AstraZeneca, GlaxoSmithKline, Merck, and Novartis; uncompensated consultancy and lectures from Merck and Novartis; consultancy with The Medicines Company and Theravance; payment for lectures from Medscape; and subcontract to his institution for his role as Network Chair for the NHLBI Heart Failure Network from Duke University. Dr. Giugliano reports clinical trials/research support: Amgen and Daiichi Sankyo. Honoraria for CME Lectures: Amgen, Daiichi Sankyo, Merck, and Servier. Consultant: Akcea, Amarin, American College of Cardiology, Amgen, Angel Med, Beckman-Coulter, Boehringer-Ingelheim, Bristol-Myers-Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lexicon, Merck, Portola, Pfizer, Servier, St Jude, Stealth Peptides., (Copyright © 2020 Elsevier B.V. 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.

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.)

Aims: To investigate the relationship between body mass index (BMI) and outcomes in patients with atrial fibrillation (AF)., Methods and Results: In the ENGAGE AF-TIMI 48 trial, patients with AF were randomized to warfarin (international normalized ratio 2.0-3.0) or edoxaban. The cohort (N = 21 028) included patients across BMI categories (kg/m2): underweight (<18.5) in 0.8%, normal (18.5 to <25) in 21.4%, overweight (25 to <30) in 37.6%, moderately obese (30 to <35) in 24.8%, severely obese (35 to <40) in 10.0%, and very severely obese (≥40) in 5.5%. In an adjusted analysis, higher BMI (continuous, per 5 kg/m2 increase) was significantly and independently associated with lower risks of stroke/systemic embolic event (SEE) [hazard ratio (HR) 0.88, P = 0.0001], ischaemic stroke/SEE (HR 0.87, P < 0.0001), and death (HR 0.91, P < 0.0001), but with increased risks of major (HR 1.06, P = 0.025) and major or clinically relevant non-major bleeding (HR 1.05, P = 0.0007). There was a significant interaction between sex and increasing BMI category, with lower risk of ischaemic stroke/SEE in males and increased risk of bleeding in women. Trough edoxaban concentration and anti-Factor Xa activity were similar across BMI groups >18.5 kg/m2, while time in therapeutic range for warfarin improved significantly as BMI increased (P < 0.0001). The effects of edoxaban vs. warfarin on stroke/SEE, major bleeding, and net clinical outcome were similar across BMI groups., Conclusion: An increased BMI was independently associated with a lower risk of stroke/SEE, better survival, but increased risk of bleeding. The efficacy and safety profiles of edoxaban were similar across BMI categories ranging from 18.5 to >40., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain., Methods: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS 2 score ≥2. We performed a nested prospective biomarker study in 8705 patients, analyzing baseline high-sensitivity troponin T (hsTnT), NT-proBNP (N-terminal B-type natriuretic peptide), and growth differentiation factor-15 (GDF-15), as well as in serial samples after 12 months. The ABC-stroke (age, prior stroke/transient ischemic attack, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. Hazard ratios were adjusted for estimated glomerular filtration rate and the components of the CHA 2 DS 2 -VASc and HAS-BLED scores, respectively. Discrimination and reclassification were compared with these established scores., Results: Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L (25th-75th percentiles, 9.6-20.4 ng/L), 811 pg/mL (386-1436 pg/mL), and 1661 pg/mL (1179-2427 pg/mL), respectively. Elevated hsTnT, NT-proBNP, and GDF-15 were independently associated with higher rates of stroke or systemic embolic events, and elevated hsTnT and GDF-15 were independently associated with higher rates of major bleeding ( P<0.001 for each). The ABC-stroke and ABC-bleeding scores were well calibrated and yielded higher c indexes than the CHA 2 DS 2 -VASc score for stroke or systemic embolic events (0.67 [95% CI, 0.65-0.70] versus 0.59 [95% CI, 0.57-0.62]; P<0.001) and HAS-BLED score for major bleeding (0.69 [95% CI, 0.66-0.71] versus 0.62 [95% CI, 0.60-0.64]; P<0.001), respectively. The ABC-stroke and ABC-bleeding scores stratified patients within CHA 2 DS 2 -VASc and HAS-BLED risk categories ( P<0.001 for both). Patients with ABC-bleeding scores predicting a high 1-year risk of bleeding (>2%) derived greater benefit from treatment with edoxaban compared with warfarin., Conclusions: The ABC-stroke and ABC-bleeding scores evaluated in this anticoagulated clinical trial cohort were well calibrated and outperformed the CHA 2 DS 2 -VASc and HAS-BLED scores, respectively. These scores may help identify patients most likely to derive a benefit from treatment with non-vitamin K antagonist oral anticoagulants., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Aims: Pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantations and generator changes are frequently performed in patients receiving direct oral anticoagulants. In an exploratory analysis, we investigated the outcome of patients undergoing such device procedures in the ENGAGE AF-TIMI 48 trial., Methods and Results: During the trial, 1217 device procedures were performed in 1145 patients, with intervention dates available for 1203 procedures. Two hundred and twenty-five procedures (in 212 patients) were performed >30 days after study drug was stopped and are not included in the event analysis. For most interventions (n = 728, 74%), study drug was interrupted >3 days (median for the entire cohort: 5 days, interquartile range 0-11 days); 250 interventions were performed with ≤3 days study drug interruption. During the first 30 days after the procedure, six strokes/systemic embolic events (SEEs) (three each in the lower-dose edoxaban and warfarin arm) and one major bleeding event (in the lower-dose edoxaban arm) occurred; no stroke/SEEs or major bleeds occurred around the 295 device procedures in the higher-dose edoxaban arm. Two ischaemic and one major bleeding event occurred after the 288 device procedures performed with ≤3 days periprocedural interruption of study drug., Conclusion: In this first experience of patients undergoing device surgery with edoxaban, a low risk of ischaemic and bleeding events was observed during the first 30 days post-procedure. Our data are in line with current recommendations of no or only brief interruption of non-vitamin K antagonist oral anticoagulants prior to cardiac device surgery.

Patients with atrial fibrillation (AF) are at an approximately 0.5% to 3% increased risk of thromboembolism during and immediately after catheter ablation. Treatment guidelines recommend periprocedural oral anticoagulation plus unfractionated heparin during ablation. Rivaroxaban and dabigatran are the only non-vitamin K oral anticoagulants for which there are randomized controlled trials assessing uninterrupted anticoagulation in patients undergoing catheter ablation of AF. Edoxaban, a direct factor Xa inhibitor, is noninferior vs warfarin for the prevention of stroke or systemic embolism with less major bleeding in patients with nonvalvular AF. The ELIMINATE-AF (Evaluation of Edoxaban Compared With VKA in Subjects Undergoing Catheter Ablation of Nonvalvular Atrial Fibrillation) trial is a multinational, multicenter, prospective, randomized, open-label, parallel-group, blinded-endpoint evaluation (PROBE) study to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for a dose reduction) vs vitamin K antagonists (VKA) in patients with nonvalvular AF undergoing catheter ablation (http://www.ClinicalTrials.gov: NCT02942576). A total of 560 patients are planned for randomization to edoxaban or VKA (2:1 ratio) to obtain 450 patients fully compliant with the protocol. Patients will complete 21 to 28 days of anticoagulation prior to the ablation and a 90-day post-ablation period. The primary efficacy endpoint is the composite of all-cause death, stroke, and major bleeding. The primary safety endpoint is major bleeding. A magnetic resonance imaging substudy will assess the incidence of silent cerebral lesions post-ablation. ELIMINATE-AF will define the efficacy and safety of edoxaban for uninterrupted oral anticoagulation during catheter ablation of AF., (© 2018 Wiley Periodicals, Inc.)

Background: The optimal antithrombotic treatment after percutaneous coronary intervention (PCI) with stenting in patients with atrial fibrillation (AF) is unknown. In the ENGAGE AF-TIMI 48 trial, edoxaban was noninferior to a vitamin K antagonist (VKA) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF. The effects of edoxaban in combination with single- or dual-antiplatelet therapy in the setting of PCI are unexplored., Design: The ENTRUST-AF PCI trial is a multinational, multicenter, randomized, open-label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF. Patients are randomized between 4 hours and 5 days after successful PCI to either an edoxaban-based strategy (experimental arm; 60 mg [or 30 mg according to dose reduction criteria] once daily plus a P2Y 12 antagonist [default clopidogrel, 75 mg once daily] for 12 months) or a VKA-based strategy (control arm; VKA plus a P2Y 12 antagonist [as above] plus acetylsalicylic acid [100 mg once daily] for 30 days to 12 months). The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis-defined major or clinically relevant nonmajor bleeding. The main efficacy end point is the composite of cardiovascular death, stroke, systemic embolic events, spontaneous myocardial infarction, and definite stent thrombosis., Summary: The ENTRUST-AF PCI trial tests the hypothesis that an edoxaban-based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual-antiplatelet therapy in patients with AF in need of oral anticoagulation. The relative risk of ischemic events between groups will be compared., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) ablation procedures are increasingly being performed in patients receiving direct oral anticoagulants (DOACs). Experience regarding the safety of edoxaban in this context is limited. In an exploratory analysis we therefore investigated the outcome of patients undergoing transcatheter AF ablation in the ENGAGE AF-TIMI 48 trial., Methods & Results: During the trial, 193 transcatheter AF ablation procedures were performed in 169 patients. For the majority of ablations (n=157, 81%), study drug was interrupted >3days (median time of interruption: 18days, interquartile range 3-30days); 86 ablations were performed with ≤10days, and 36 ablations with ≤3days study drug interruption. During the first 30days after the ablation, one ischemic stroke was observed in the warfarin group and none in the higher-dose edoxaban regimen (HDER) or lower-dose edoxaban regimen (LDER) group. Three clinically relevant non-major (CRNM) bleeding events were observed in the warfarin group; one major bleed was seen in the HDER group; one minor bleed occurred in the LDER group. All bleeding events occurred among the patients with ≤10days study drug interruption; in contrast, no ischemic events or deaths were observed in these patients., Conclusions: In this pilot evaluation of the ENGAGE AF-TIMI 48 trial, treatment with edoxaban was associated with a low risk of ischemic and bleeding events during the first 30days post ablation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10-30 minutes of administration and sustained for at least 24 hours.

Background: Four nonvitamin K antagonist oral anticoagulants (NOACs) are approved for the prevention of stroke in patients with nonvalvular atrial fibrillation and for the treatment of venous thromboembolism. These include the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. Bleeding is a complication for all anticoagulants and concerns regarding bleeding risk and the suitability of effective reversal strategies may be a barrier to their prescription. Despite the reduced risk of bleeding compared with vitamin K antagonists, questions persist regarding the management of bleeding related to NOAC use., Main Text: To date, although a number of assays are responsive to NOACs, no single routine laboratory test has been identified to accurately measure the clinical anticoagulation state of patients on NOACs or established as a reliable predictor of bleeding risk. In addition, the establishment of a reliable human bleeding model to test novel inhibitors of the coagulation cascade has proved challenging. Although routine monitoring of anticoagulant levels is not necessary in patients taking NOACs, anticoagulant reversal and a means of measuring reversal may be required for patients who present with bleeding or require urgent surgery. Prothrombin complex concentrates are pooled plasma products containing varying amounts of inactive vitamin K-dependent clotting factors in addition to vitamin K-dependent proteins and can replenish factors in the intrinsic and extrinsic coagulation cascade, reversing an anticoagulant effect. Only one agent, idarucizumab, has been approved for rapid reversal of dabigatran-induced anticoagulation and one more agent, andexanet alfa, has been submitted for approval to reverse the anticoagulatory effects of direct and indirect factor Xa inhibitors., Conclusions: This review discusses the laboratory tests available for assessing anticoagulation, human models of bleeding, and the use of current strategies-including prothrombin complex concentrates for reversal of anticoagulation by NOACs-to manage bleeding in patients.

The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months. The primary efficacy outcome was a surrogate end point of the relative change in MRV-quantified thrombus volume from baseline to Day 14-21. A total of 85 eligible patients from 26 study sites were randomized to edoxaban monotherapy (n=56) versus parenteral anticoagulation as a 'bridge' to warfarin (n=29). The mean relative change in MRV-quantified thrombus volume from baseline to Day 14-21 was similar in patients treated with edoxaban and parenteral anticoagulation as a 'bridge' to warfarin (-50.1% vs -58.9%; 95% confidence interval of treatment difference, -12.7%, 30.2%). However, thrombus extension was observed in eight patients in the edoxaban monotherapy group and in none in the warfarin group. Rates of recurrent venous thromboembolism (3.6% vs 3.6%, p=0.45) and clinically relevant non-major bleeding (5.4% vs 7.1%, p=0.34) were also similar. No major bleeds occurred in either on-treatment group during the study period. In conclusion, MRV can assess change in thrombus volume in patients with acute DVT randomized to two different anticoagulant regimens.ClinicalTrials.gov IDENTIFIER NCT01662908: INVESTIGATIONAL NEW DRUG IND APPLICATION EDOXABAN IND # 63266., (© The Author(s) 2016.)

Background: The oral factor Xa inhibitor edoxaban has demonstrated safety and efficacy in stroke prevention in patients with atrial fibrillation and in the treatment and secondary prevention of venous thromboembolism. This study investigated the reversal of edoxaban's effects on bleeding measures and biomarkers by using a 4-factor prothrombin complex concentrate (4F-PCC)., Methods and Results: This was a phase 1 study conducted at a single site. This was a double-blind, randomized, placebo-controlled, 2-way crossover study to determine the reversal effect of descending doses of 4F-PCC on bleeding duration and bleeding volume following edoxaban treatment. A total of 110 subjects (17 in part 1, 93 in part 2) were treated. Intravenous administration of 4F-PCC 50, 25, or 10 IU/kg following administration of edoxaban (60 mg) dose-dependently reversed edoxaban's effects on bleeding duration and endogenous thrombin potential, with complete reversal at 50 IU/kg. Effects on prothrombin time were partially reversed at 50 IU/kg. A similar trend was seen for bleeding volume., Conclusions: The 4F-PCC dose-dependently reversed the effects of edoxaban (60 mg), with complete reversal of bleeding duration and endogenous thrombin potential and partial reversal of prothrombin time following 50 IU/kg. Edoxaban alone and in combination with 4F-PCC was safe and well tolerated in these healthy subjects. A dose of 50 IU/kg 4F-PCC may be suitable for reversing edoxaban anticoagulation., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT02047565., (© 2014 American Heart Association, Inc.)

Background: Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed., Methods and Results: A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P<0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (P=0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated., Conclusions: The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

One hour after suicidal ingestion of about 150 g of trichloroethylene, a 32-year-old male was admitted to hospital. On admission, the patient's state of consciousness deteriorated from somnolence to coma. Based on blood level data, an absorbed trichloroethylene dose of at least 35 g was estimated. Additionally, ethanol, which is a strong inhibitor of trichloroethylene metabolism, had been ingested. With respect to the high dose of trichloroethylene, hyperventilation therapy was performed for 28 h. Concentrations of trichloroethylene and its metabolites in blood and urine were determined by gas chromatography. Due to hyperventilation and inhibition of trichloroethylene metabolism, not more than 30% of the absorbed dose was metabolized and excreted via kidneys. Under normal respiratory conditions and in the absence of ethanol, this fraction amounts to about 75%. Obviously, hyperventilation and ethanol-induced inhibition of metabolism led to considerably enforced pulmonary elimination of the absorbed trichloroethylene.