title: Management of bleeding in patients treated with direct oral anticoagulants.
abstract: BACKGROUND
  Recently, a new generation of direct-acting oral anticoagulants (DOACs) with a greater specificity towards activated coagulation factors was introduced based on encouraging results for efficacy and safety in clinical studies. An initial limitation of these new drugs was the absence of an adequate strategy to reverse the effect if a bleeding event occurs or an urgent invasive procedure has to be carried out.
  
  
  METHODS
  Specific reversing agents for DOACs have become available, however, and are now evaluated in clinical studies. For the anti-factor Xa agents (rivaroxaban, apixaban, and edoxaban) a number of studies have shown that the administration of prothrombin complex concentrate resulted in a correction of the prolonged prothrombin time and restored depressed thrombin generation after rivaroxaban treatment in a controlled trial in healthy human subjects. In view of the relatively wide availability of prothrombin complex concentrates, this would be an interesting option if the results can be confirmed in patients on oral factor Xa inhibitors who present with bleeding complications. More specific reversal can be achieved with andexanet, a new agent currently in development that competitively binds to the anti-factor Xa agents. For the direct thrombin inhibitor dabigatran, the administration of prothrombin complex concentrates showed variable results in various volunteer trials and efficacy at relatively high doses in animal studies. Recently, a Fab fragment of a monoclonal antibody (idarucizumab) was shown to be an effective reversal agent for dabigatran in human studies.
  
  
  CONCLUSIONS
  For the new generation of DOACs, several reversal strategies and specific antidotes are under evaluation, although most interventions need further evaluation in clinical trials.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center (E-2), University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. m.m.levi@amc.uva.nl.|Department of Medicine, University of Amsterdam, Amsterdam, The Netherlands. m.m.levi@amc.uva.nl.
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019468:Disease Management; D065427:Factor Xa Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D006470:Hemorrhage / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D011517:Prothrombin Time; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use; D012307:Risk Factors; D000069552:Rivaroxaban / Q000493:pharmacokinetics / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011728:Pyridones; D013844:Thiazoles; C522181:apixaban; D000069552:Rivaroxaban; C552171:edoxaban
keywords: Anticoagulants; Apixaban; Dabigatran; Direct-acting oral anticoagulants; Edoxaban; Hemorrhage; Rivaroxaban