title: Reversal agents for use with direct and indirect anticoagulants.
abstract: OBJECTIVE
  The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market.
  
  
  CONCLUSIONS
  Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance.
  
  
  CONCLUSIONS
  As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.
authors.affiliation: Department of Pharmaceutical Services, Beaumont Health, Royal Oak, MIDepartment of Pharmacy Practice, Wayne State University, Detroit, MI. maureen.smythe@beaumont.org.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Smythe
authors.affiliation: University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, COUniversity of Colorado Hospital, Aurora, CO.
authors.forename: Toby
authors.initials: T
authors.lastname: Trujillo
authors.affiliation: Department of Pharmaceutical Services, Brigham and Women's Hospital, Boston, MA.
authors.forename: John
authors.initials: J
authors.lastname: Fanikos
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000925:Anticoagulants / Q000009:adverse effects*; D001120:Arginine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000069604:Dabigatran / Q000037:antagonists & inhibitors*; D015951:Factor Xa / Q000627:therapeutic use*; D065427:Factor Xa Inhibitors / Q000009:adverse effects; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D010879:Piperazines / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; C580915:PRT064445; D010879:Piperazines; D011994:Recombinant Proteins; D001120:Arginine; C000594745:idarucizumab; D015951:Factor Xa; D000069604:Dabigatran; C000593571:PER977