Reversal of the novel oral anticoagulants dabigatran, rivoraxaban, and apixaban

Abstract

In the absence of evidence in bleeding patients, animal models and ex-vivo studies suggest administration of coagulant factors in the form of hemostatic agents may be of benefit in reversing the effect of direct thrombin and factor Xa inhibitors. Specific reversal agents and clinical data in patients with hemorrhage remain an unmet need.

A Systems Pharmacology Model for Predicting Effects of Factor Xa Inhibitors in Healthy Subjects: Assessment of Pharmacokinetics and Binding Kinetics

“…Partial reversal of PT prolongation has been seen after administration of prothrombin complex concentrates in healthy volunteers. The use of other procoagulant reversal agents, like activated prothrombin complex concentrate or recombinant factor VIIa (rFVIIa), has not been evaluated 47. Andexanet alfa, a potential first‐in‐class recombinant, modified Factor Xa molecule is being developed as an antidote for patients receiving a Factor Xa inhibitor 48.…”

“…The use of other procoagulant reversal agents, like activated prothrombin complex concentrate or recombinant factor VIIa (rFVIIa), has not been evaluated. 47 Andexanet alfa, a potential first-in-class recombinant, modified Factor Xa molecule is being developed as an antidote for patients receiving a Factor Xa inhibitor. 48 However, some important information for modeling and simulation (i.e., the interaction of drug and Andexanet) are currently not available, which need to be included for model prediction.…”

Direct Oral Anticoagulants in Emergency Trauma Admissions

“…In the presence of circulatory instability the usual vasopressors are used, while patients receiving massive transfusions may require plasma/plate let products and fibrinogen concentrates (5,6). Should conventional measures prove inadequate, offlabel administration of prothrombin complex concentrates or activated prothrombin complex concentrate and/or recombinant factor VIIa (rFVIIa) in the recommended dosages can be considered (5,6,22,23,(27)(28)(29)(30) (Figure 2). In experimental studies (dabigatran) and tests on healthy volunteers (apixaban, edoxaban, and rivaroxaban), the best effect has been documented for prothrombin complex concentrate (29-32, e27-e33); no prospective randomized trials have been conducted.…”

“…In a subgroup of patients plasma concentrations of dabigatran could again be demonstrated after 24 h, so renewed administration of idarucizumab should be considered in the event of repeated emergency interventions or new bleeding. The highest single dose yet investigated in healthy probands is 8 g. On the basis of experimental data, activated charcoal can be given to inhibit absorption of dabigatran if the last dose of the anticoagulant was taken less than 2 h beforehand (22,23,26,27). There are only a small number of studies on the interaction of dabigatran and dialysis, so the risk of bleeding at the sites of access must be borne in mind (5, 15, 26, 27, e18).…”

Atrial Fibrillation and Stroke in Elderly Patients

“…62 Idarucizumab (Praxbind), a specific antibody against dabigatran, completely reverses the anticoagulant effect of dabigatran within minutes and has been approved by the U.S. Food and Drug Administration (FDA) for this purpose. 63 Andexanet, a recombinant modified human factor Xa decoy protein, reverses the anticoagulant activity of apixaban and rivaroxaban within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects.…”