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Update to Chapter 25: Antithrombotic Therapy

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Specific antidotes for novel oral anticoagulants (NOACs) recently have been 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 controlled trials in healthy human subjects (Eerenberg et al, 2011; Levi et al, 2014). More specific reversal can be achieved with andexanet, a recombinant modified human factor Xa decoy protein. Andexanet is also an effective antidote for other anti–factor Xa inhibitors, including low-molecular-weight heparins and fondaparinux. Clinical studies in patients with major bleeding and in those undergoing emergency surgery showed immediate and complete reversal of the anticoagulant effect (Connolly et al, 2016; Siegal et al, 2015). However, the administration of andexanet combined with the cessation of anticoagulants after the episode of bleeding was associated with a high thrombosis rate (12 of 67 patients [18%]). It is impossible to know whether andexanet had an intrinsic prothrombotic effect or whether the high rate of thrombosis was related to the absence of an antithrombotic agent in a high-risk situation.

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For the direct thrombin inhibitor dabigatran, the administration of prothrombin complex concentrate showed variable results in various volunteer trials and efficacy at relatively high doses in animal studies (Eerenberg et al, 2011; Honickel et al, 2015). Idarucizumab, a monoclonal antibody targeting the active site of the thrombin inhibitor, was developed as an antidote for dabigatran and was licensed in 2015 after it was shown to restore hemostasis in patients who had a serious hemorrhage or required an urgent invasive procedure (Eikelboom et al, 2015; Glund et al, 2015).

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Connolly  S, Milling  T, Eikelboom  J, Gibson  CM, Curnutte  JT, Gold  A,  et al: Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 375(12):1131–1141, 2016.
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Eerenberg  ES, Kamphuisen  PW, Sijpkens  MK, Meijers  JC, Buller  HR, Levi  M: Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124(14):1573–1579, 2011.
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Eikelboom  JW, Quinlan  DJ, van Ryn  J, Weitz  JI: Idarucizumab: The antidote for reversal of dabigatran. Circulation 132(25):2412–2422, 2015.
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Glund  S, Stangier  J, Schmohl  M, Gansser  D, Norris  S, van Ryn  J,  et al: Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: A randomised, placebo-controlled, double-blind phase 1 trial. Lancet 386(9994):680–690, 2015.
[PubMed: 26088268]
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Honickel  M, Maron  B, van Ryn  J, Braunschweig  T, Ten Cate  H, Spronk  HM,  et al: Therapy with activated prothrombin complex concentrate is effective in reducing dabigatran-associated blood loss in a porcine polytrauma model. Thromb Haemost 115(1):271–284, 2015.
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Levi  M, Moore  KT, Castillejos  CF, Kubitza  D, Berkowitz  SD, Goldhaber  SZ,  et al: Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost 12(9):1428–1436, 2014.
[PubMed: 24811969]
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Siegal  DM, Curnutte  JT, Connolly  SJ, Lu  G, Conley  PB, Wiens  BL,  et al: Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 373(25):2413–2424, 2015.
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