title: Extended duration of anticoagulation with edoxaban in patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE study.
abstract: BACKGROUND
  There are few data on the relative efficacy and safety of direct oral anticoagulants, such as edoxaban, compared with vitamin K antagonists during extended therapy for venous thromboembolism. This analysis evaluates the risk-benefit of extended treatment for up to 12 months with edoxaban compared with warfarin among patients enrolled in the Hokusai-VTE study who continued therapy beyond 3 months.
  
  
  METHODS
  The Hokusai-VTE trial (NCT00986154) was a randomised, double-blind, event driven non-inferiority trial in 8292 patients comparing edoxaban with warfarin in the treatment of patients with acute venous thromboembolism. All patients were treated for at least 3 months and treatment was continued for up to 12 months. The outcomes at 12 months were documented in all patients irrespective of treatment duration. 3633 patients treated with edoxaban and 3594 treated with warfarin who completed 3 months of treatment were eligible for this analysis. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism evaluated for each of the time intervals of 3 months, greater than 3 months to 6 months, greater than 6 months to less than 12 months, and at 12 months, as well as the cumulative incidence occurring between 3 and 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Both on-treatment and intention-to-treat analyses were done.
  
  
  RESULTS
  In the on-treatment analysis, the incidence of recurrent venous thromboembolism at 3 months was 1·1% (0·8-1·4; 44 of 4118 patients) in the edoxaban-treated group versus 1·2% (0·9-1·6; 51 of 4122) in the warfarin-treated group; between greater than 3 months and 6 months, 0·7% (0·3-1·5; eight of 1076) versus 0·5% (0·2-1·1; five of 1084); between greater than 6 months and less than 12 months, 0·2% (0·0-0·8; two of 896) versus 0·8% (0·03-1·7; seven of 851); and at 12 months, <0·1% (0·0-0·3; one of 1661) versus 0·1% (0·0-0·4; two of 1659). In the on-treatment analysis, the cumulative incidence of recurrent venous thromboembolism between 3 and 12 months was 0·3% (95% CI 0·2-1·5; 11 of 3633 patients) in the edoxaban-treated group and 0·4% (0·2-1·7; 14 of 3594) in the warfarin-treated group (HR 0·78, 95% CI 0·36-1·72). The cumulative incidence of clinically relevant bleeding (major or non-major) between 3 and 12 months was 3·9% (95% CI 3·3-4·6; 143 of 3633 patients) in the edoxaban-treated group and 4·1% (3·5-4·8; 147 of 3594 patients) in the warfarin-treated group (HR 0·97, 95% CI 0·77-1·22); cumulative incidence of major bleeding was 0·3% (95% CI 0·2-0·5; 11 of 3633 patients) in the edoxaban-treated group and 0·7% (0·4-1·0; 24 of 3594 patients) in the warfarin-treated group (HR 0·45, 95% CI 0·22-0·92). Similar results were obtained in the intention-to-treat analysis.
  
  
  CONCLUSIONS
  Extended treatment with edoxaban is effective and associated with less major bleeding than warfarin. Edoxaban once daily provides an attractive alternative to warfarin for patients with venous thromboembolism who require extended treatment for prevention of recurrent venous thromboembolism.
  
  
  BACKGROUND
  Daiichi Sankyo.
authors.affiliation: College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: Gary-Raskob@ouhsc.edu.
authors.forename: Gary
authors.initials: G
authors.lastname: Raskob
authors.affiliation: Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Ageno
authors.affiliation: Department of Haematological Medicine, Guy's and St Thomas' Hospitals, King's College London, London, UK.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Cohen
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Marjolein P A
authors.initials: MP
authors.lastname: Brekelmans
authors.affiliation: Clinical Development, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grosso
authors.affiliation: ITREAS Clinical Research, Amsterdam, Netherlands.
authors.forename: Annelise
authors.initials: A
authors.lastname: Segers
authors.affiliation: Division of Respiratory and Intensive Care Medicine, Hopital Europeen George Pompidou, INSERM UMR_S 970, CIC 1418, Université Paris Descartes, Paris, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Meyer
authors.affiliation: Vascular Medicine and Hemostasis, University of Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
authors.affiliation: Ottawa Hospital Research Institute, Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Wells
authors.affiliation: Clinical Development, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lin
authors.affiliation: Medical Affairs, Daiichi Sankyo Inc, Parsippany, NJ, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Winters
authors.affiliation: Thrombosis & Atherosclerosis Research Institute and McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Büller
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants; D057186:Comparative Effectiveness Research; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced* / Q000401:mortality; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism / Q000453:epidemiology / Q000517:prevention & control*; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use*; D012008:Recurrence; D018570:Risk Assessment; D055502:Secondary Prevention / Q000379:methods*; D013844:Thiazoles / Q000009:adverse effects* / Q000627:therapeutic use*; D054556:Venous Thromboembolism / Q000150:complications / Q000188:drug therapy / Q000453:epidemiology / Q000517:prevention & control*; D018497:Ventricular Dysfunction, Right / Q000150:complications; D014859:Warfarin / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; D006493:Heparin; C552171:edoxaban