title: A Phase II, double-blind, randomized, parallel group, dose-finding study of the safety and tolerability of darexaban compared with warfarin in patients with non-valvular atrial fibrillation: the oral factor Xa inhibitor for prophylaxis of stroke in atrial fibrillation study 2 (OPAL-2).
abstract: BACKGROUND
  Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa.
  
  
  OBJECTIVE
  To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF).
  
  
  METHODS
  In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability.
  
  
  RESULTS
  A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity.
  
  
  CONCLUSIONS
  In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.
authors.affiliation: University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK.
authors.forename: G Y H
authors.initials: GY
authors.lastname: Lip
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, The Marie Josée and Henry R. Kravis Centre for Cardiovascular Health, Mount Sinai Medical Centre, New York, NY, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Halperin
authors.affiliation: Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Petersen
authors.affiliation: University of Utah, Salt Lake City, UT, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Rodgers
authors.affiliation: Department of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: D
authors.initials: D
authors.lastname: Pall
authors.affiliation: Astellas Pharma Global Development, Leiden, the Netherlands.|Department of Cardiology C5-P, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: R W
authors.initials: RW
authors.lastname: Renfurm
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D015536:Down-Regulation; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D001381:Azepines; D001549:Benzamides; D015415:Biomarkers; D065427:Factor Xa Inhibitors; D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; D014859:Warfarin; C569750:darexaban
keywords: anticoagulants; atrial fibrillation; clinical trial; hemorrhage; stroke