A New Option for Reversing the Anticoagulant Effect of Factor Xa Inhibitors: Andexanet Alfa (ANDEXXA)

Abstract

The use of direct oral anticoagulants over traditional warfarin has increased in the United States over the past 10 years because of advantages such as ease of use, predictable pharmacokinetic response, and safety. In 2015, the U.S. Food and Drug Administration approved idarucizumab (Praxbind) for the reversal of the direct thrombin inhibitor dabigatran, but no reversal agent has been available for oral factor Xa (FXa) inhibitors until recently. Andexanet alfa was approved in May 2018, under the brand name ANDEXXA, for the reversal of 2 of FXa inhibitors, apixaban and rivaroxaban, when life-threatening or uncontrolled bleeding occurs. This accelerated approval was based on change in anti-FXa activity from baseline that indicated a reversal of the anticoagulant effect. Any expanded Food and Drug Administration indication will be contingent on results demonstrating improved hemostasis and efficacy for reversing other FXa inhibitors.

Introduction

The use of direct oral anticoagulants has increased since dabigatran was made available in 2010, with an estimated 3.8 million patient-years of exposure by the end of 2016.¹ Dabigatran is a direct thrombin inhibitor, whereas other direct oral anticoagulants work by inhibiting factor Xa (FXa; Table 1). These agents have demonstrated either superiority or noninferiority for thromboembolic outcomes and a similar or statistically reduced risk for major bleeding compared with traditional anticoagulation in clinical trials for various indications. However, harm from all oral anticoagulants remains a significant drug safety problem because of a high rate of injury, causing bleeding in 8%-19% of patients treated for a year.1, 2, 3 In 1 study, anticoagulants that predominantly included warfarin, rivaroxaban, dabigatran, and enoxaparin accounted for 17.6% of all emergency department visits for adverse drug events, which led to a 48.8% hospitalization rate.⁴ It is significant that patients with atrial fibrillation experiencing a major bleed from an FXa inhibitor have a 15%-20% 30-day mortality rate, with up to 48% mortality for those experiencing an intracranial hemorrhage.5, 6, 7, 8 In the event of extensive bleeding, an effective, widely available antidote for the anticoagulant is desired. In 2015, the U.S. Food and Drug Administration (FDA) approved idarucizumab (Praxbind) for the reversal of the direct thrombin inhibitor dabigatran.⁹ Because of differing mechanisms of action, idarucizumab is not effective for reversing the FXa inhibitors rivaroxaban, apixaban, edoxaban, or betrixaban (Table 1). After several delays due to manufacturing concerns as well as requests for data that included all of the oral FXa inhibitors plus enoxaparin, the FDA granted approval of andexanet alfa in May 2018, under the brand name ANDEXXA, for the reversal of 2 of the FXa inhibitors, apixaban and rivaroxaban, when life-threatening or uncontrolled bleeding occurs.¹⁰ This accelerated approval was based on change in anti-FXa activity from baseline that indicated a reversal of anticoagulation. Any expanded FDA indication will be contingent on results demonstrating improved hemostasis and the ability of andexanet alfa to reverse other FXa inhibitors.10, 11, 12