12/8/2015 – Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity

Deborah M. Siegal, M.D., John T. Curnutte, M.D., Ph.D., Stuart J. Connolly, M.D., Genmin Lu, Ph.D., Pamela B. Conley, Ph.D., Brian L. Wiens, Ph.D., Vandana S. Mathur, M.D., Janice Castillo, B.S., Michele D. Bronson, Ph.D., Janet M. Leeds, Ph.D., Florie A. Mar, Ph.D., Alex Gold, M.D., and Mark A. Crowther, M.D.

New Engl J Med, Published online on November 11, 2015.
doi: 10.1056/NEJMoa1510991

Currently 3 selective oral anti-Xa drugs (apixaban, edoxaban, rivaroxaban) are available for prevention of stroke due to non-valvular atrial, and prevention or treatment of deep venous thrombosis and pulmonary thromboembolism. Intracranial hemorrhage (ICH) is a serious complication of anticoagulant therapy, but in the elderly population on chronic anticoagulation, anti-Xa agents appear to have a much lower incidence of ICH. Nevertheless, availability of a specific antidote is desirable in the case of any major vascular event, traumatic injury, or urgent invasive procedure. Andexanet is a recombinant factor Xa analogue which lacks procoagulant activity, but reversibly binds to an anti-Xa molecule with a half-life of about 1 hr. The binding of andexanet to anti-Xa prevents the latter from inhibiting endogenous factor Xa.
Siegal, et. al reported the results of a Phase II, dose-ranging trial of andexanet in 145 volunteers (aged 50 to 75 yr) treated with apixaban or rivaroxaban. The subjects were randomly assigned to andexanet or placebo at a 2:1 ratio for apixaban (ANNEXA-A, n=65), and a 3:1 ratio for rivaroxaban (ANNEXA-R, n=80). In 2-5 min after a bolus injection of andexanet (400 and 800 mg, respectively), the mean anti-Xa activity was reduced by 94% for rivaroxaban, and 92% for apixaban, whereas only a 20% decrease was observed for the placebo in both arms (P<0.001 vs. andexanet). The anti-Xa effects of apixaban and rivaroxaban re-emerged after 2 hrs at plasma levels similar to placebo. A sustained reversal of anti-Xa effects was demonstrated when a 2-hr infusion followed the bolus (400 mg + 4 mg/min, and 800 mg + 8 mg/min, respectively). Re-appearance of anti-Xa activity corresponded to the resurgence of apixaban or rivaroxaban unbound to andexanet. Similar active drug levels (lower than the baseline) between andexanet and placebo suggest that anti-Xa molecules bound to andexanet do not undergo major metabolism. The authors measured endogenous thrombin potential (ETP) as a surrogate for hemostatic recovery. Both anti-Xa agents lowered ETP below the (pre-anticoagulant) normal range, but immediately after the injection of andexanet, the mean ETP increased to the upper normal or slightly above the normal limit. In parallel, transient increases in prothrombin fragment 1.2 and D-dimer were also observed. A possible mechanism is speculated to be the binding of andexanet to tissue factor pathway inhibitor (TFPI), i.e., less inhibited extrinsic pathway. There are obvious limitations in this Phase II study. Dosing schemes used in the healthy older subjects may not be directly applicable to clinical patients who require urgent anticoagulant reversal. Pre-reversal anti-Xa activity could be more variable in the clinical setting, and different dosing and durations of infusions need to be further tested. Underlying thrombophilia may be prevalent in the perioperative setting, and a potential thrombotic risk of andexanet (e.g., TFPI inhibition) needs to be evaluated in a Phase III setting. Finally, clinical bleeding in anti-Xa treated patients is often multi-factorial, and additional studies are needed to validate laboratory methods for testing anti-Xa effects, and their reversal. Michael A. Mazzeffi, MD, MPH, Kenichi A. Tanaka, MD, MSc Department of Anesthesiology and Critical Care Medicine University of Maryland School of Medicine.