title: Ex vivo reversal of the anticoagulant effects of edoxaban.
abstract: BACKGROUND
  Edoxaban is an oral, once-daily direct factor Xa (FXa) inhibitor. Although rapidly cleared, strategies to reverse edoxaban-mediated effects on anticoagulation are needed in cases of excessive bleeding or emergency. This study evaluated the effect of two prohemostatic agents, recombinant factor VIIa (rFVIIa) and factor VIII inhibitor bypass activity (FEIBA), on the anticoagulatory effects of supratherapeutic concentrations of edoxaban in human whole blood ex vivo.
  
  
  METHODS
  Blood samples were collected from six healthy volunteers. Edoxaban (500 or 1000 ng/mL), alone or followed by rFVIIa (0.8 or 1.8μg/mL) or FEIBA (0.75 or 1.5 U/mL), was added to an aliquot of each sample. Biomarkers, including prothrombin time (PT), activated partial thromboplastin time (aPTT), extrinsic FXa activity (anti-FXa), intrinsic factor X activity, and D-dimer, were assessed at 0.25, 0.5, 1, 2, and 4 hours after adding rFVIIa or FEIBA.
  
  
  RESULTS
  Decreases in measures of PT (p<0.0001), aPTT (p<0.0001), and anti-FXa (p<0.0001) were observed when rFVIIa or FEIBA was added to edoxaban-containing blood samples. Intrinsic FX activity was increased up to 20% and 31% of normal in the presence of edoxaban by rFVIIa and FEIBA, respectively. The impact of these agents on the anticoagulant effects of edoxaban were observed within 15 minutes and remained relatively unchanged at each timepoint thereafter.
  
  
  CONCLUSIONS
  The findings of this ex vivo study suggest that rFVIIa and FEIBA rapidly reversed edoxaban-mediated anticoagulation effects based on PT and aPTT, but had minimal effect based on intrinsic FX activity. No dose response was observed for rFVIIa or FEIBA.
authors.affiliation: Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ 08837, Edison, NJ, USA. Electronic address: Abdel.Halim@drugscan.com.
authors.forename: Abdel-Baset
authors.initials: AB
authors.lastname: Halim
authors.affiliation: Cochin-Broca-Hôtel-Dieu University Hospital, 27, rue du Fg Saint-Jacques, 75679 Paris Cedex 14, France; Biomnis Laboratory, 78 avenue de Verdun, BP 110 94208 Ivry-sur-Seine Cedex, France. Electronic address: meyermichel.samama@biomnis.com.
authors.forename: Meyer M
authors.initials: MM
authors.lastname: Samama
authors.affiliation: Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ 08837, Edison, NJ, USA. Electronic address: jmendell@dsi.com.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mendell
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000494:pharmacology*; D015942:Factor VIIa / Q000494:pharmacology*; D006490:Hemostatics / Q000494:pharmacology*; D006801:Humans; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011725:Pyridines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D001779:Blood Coagulation Factors; D006490:Hemostatics; D011725:Pyridines; D011994:Recombinant Proteins; D013844:Thiazoles; C103587:recombinant FVIIa; C065655:anti-inhibitor coagulant complex; D015942:Factor VIIa; C552171:edoxaban
keywords: Anticoagulant reversal; Edoxaban; FEIBA; Factor Xa; rFVIIa