Reversing factor Xa inhibitors - clinical utility of andexanet alfa

Abstract

Approximately half of patients started on an oral anticoagulant in the USA now receive one of the newer direct oral anticoagulants (DOACs). Although there is an approved reversal agent for the direct thrombin inhibitor dabigatran, a specific reversal agent for the anti-factor Xa (FXa) DOACs has yet to be licensed. Unlike the strategy to reverse the only oral direct thrombin inhibitor with idarucizumab, which is a humanized monoclonal antibody fragment, a different approach is necessary to design a single agent that can reverse multiple anti-FXa medications. Andexanet alfa is a FXa decoy designed to reverse all anticoagulants that act through this part of the coagulation cascade including anti-FXa DOACs, such as apixaban, edoxaban and rivaroxaban, and indirect FXa inhibitors such as low-molecular-weight heparins. This narrative reviews the development of andexanet alfa and explores its basic science, pharmacokinetics/pharmacodynamics, animal models, and human studies.

Keywords: DOAC; andexanet alfa; apixaban; factor Xa; reversal; rivaroxaban.

Figure 1

Mechanism of action of r-Antidote. Notes: (A) The prothrombinase complex, which consists of factor Xa and its cofactor factor Va, assembles on a membrane surface where it converts prothrombin (II) to thrombin (IIa). The membrane-binding Gla domain (hatched oval) and active site S of factor Xa are essential for factor Xa function. Factor Xa-directed NOACs bind reversibly to the active site of factor Xa and attenuate its capacity to activate II. (B) Fondaparinux, a synthetic pentasaccharide, binds AT and catalyzes the inhibition of factor Xa, thus attenuating prothrombin activation. (C) r-Antidote, which has its active S converted to A to prevent procoagulant activity, binds the NOACs but does not compete with factor Xa for incorporation into the prothrombinase complex because it lacks the membrane-binding Gla-domain. By binding NOACs, r-Antidote reverses factor Xa inhibition and restores that capacity of prothrombinase to generate thrombin and to effect hemostasis. (D) r-Antidote competes with factor Xa for fondaparinux-activated antithrombin, thereby allowing prothrombinase to generate thrombin. Reprinted with permission from Yeh CH, Fredenburgh JC, Weitz JI. The real decoy: an antidote for factor Xa-directed anticoagulants. Circ Res. 2013;113(8):954–957. Available from: http://circres.ahajournals.org/content/113/8/954.long. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer. Please contact healthpermissions@wolterskluwer.com for further information. Abbreviations: A, alanine; AT, antithrombin; NOACs, new oral anticoagulants; S, serine.

Figure 2

Design of andexanet alfa. Notes: Serine, the active site of FXa, was substituted with alanine, rendering the molecule unable to cleave and activate prothrombin. The Gla domain of FXa was removed to prevent its assembly into the prothrombinase complex, thus removing any anticoagulant effects. Copyright ©2016 Milling TJ Jr, Kaatz S. Preclinical and clinical data for factor Xa and “Universal” reversal agents. Am J Med. 2016;129(11s):S80–S88. Abbreviations: FXa, factor Xa; Gla, gamma-carboxyglutamic acid.

Figure 3

Time courses of anti-factor Xa activity before and after administration of andexanet. Notes: Anti-factor Xa activity among persons who had received anticoagulation treatment with apixaban or rivaroxaban was measured before and after the administration of andexanet or placebo on study day 4. Dashed lines indicate the end of administration of the bolus or infusion. (A) Data from participants in the apixaban study (ANNEXA-A) who received andexanet, as a 400 mg intravenous bolus, or placebo. (B) Data from participants in the rivaroxaban study (ANNEXA-R) who received andexanet, as an 800 mg intravenous bolus, or placebo. (C) Data from participants in the apixaban study who received andexanet, as a 400 mg intravenous bolus with a 4 mg/minute infusion for 120 minutes, or placebo. (D) Data from participants in the rivaroxaban study who received andexanet, as an 800 mg intravenous bolus with an 8 mg/minute infusion for 120 minutes, or placebo. Different scales along the x-axis in each graph are used to enable visualization of the immediate, short-term dynamics as well as the longer-term dynamics of anti-factor Xa activity after andexanet treatment; the points on the graph represent the mean anti-factor Xa activity level, and I bars indicate the standard error. There was a significant difference (P<0.05) in the percent change in anti-factor Xa activity (relative to the pre-bolus activity level) between andexanet and placebo until 2 hours after administration of the bolus or infusion. From N Engl J Med., Andexanet alfa for the reversal of factor Xa inhibitor activity. 2015;373(25):2413–2424. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.