title: Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity.
abstract: BACKGROUND
  Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.
  
  
  METHODS
  Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.
  
  
  RESULTS
  Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.
  
  
  CONCLUSIONS
  Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).
authors.affiliation: From McMaster University (D.M.S., S.J.C., M.A.C.) and the Population Health Research Institute (S.J.C.) - both in Hamilton, ON, Canada; and Portola Pharmaceuticals, South San Francisco (J.T.C., G.L., P.B.C., B.L.W., J.C., M.D.B., J.M.L., F.A.M., A.G.) and Mathur Consulting, Woodside (V.S.M.) - both in California.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Siegal
authors.forename: John T
authors.initials: JT
authors.lastname: Curnutte
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Connolly
authors.forename: Genmin
authors.initials: G
authors.lastname: Lu
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Conley
authors.forename: Brian L
authors.initials: BL
authors.lastname: Wiens
authors.forename: Vandana S
authors.initials: VS
authors.lastname: Mathur
authors.forename: Janice
authors.initials: J
authors.lastname: Castillo
authors.forename: Michele D
authors.initials: MD
authors.lastname: Bronson
authors.forename: Janet M
authors.initials: JM
authors.lastname: Leeds
authors.forename: Florie A
authors.initials: FA
authors.lastname: Mar
authors.forename: Alex
authors.initials: A
authors.lastname: Gold
authors.forename: Mark A
authors.initials: MA
authors.lastname: Crowther
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000931:Antidotes / Q000494:pharmacology / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects; D004311:Double-Blind Method; D015951:Factor Xa / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D065427:Factor Xa Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D000069552:Rivaroxaban / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000931:Antidotes; D065427:Factor Xa Inhibitors; C580915:PRT064445; D010446:Peptide Fragments; D011498:Protein Precursors; D011720:Pyrazoles; D011728:Pyridones; D011994:Recombinant Proteins; C522181:apixaban; C029733:prothrombin fragment 1; C044183:prothrombin fragment 2; D011516:Prothrombin; D000069552:Rivaroxaban; D015951:Factor Xa