An Approved Reversal Agent for Factor Xa Inhibitors

One of the first concerns expressed by patients with atrial fibrillation advised to start a direct oral anticoagulant (DOAC) for stroke prevention is the absence of a reversal agent. Although their concern may be out of proportion to the potential need for a reversal agent, major bleeding does occur in 2-3% of patients taking a DOAC and can be life-threatening. When patients taking a DOAC have a major bleeding episode, the primarily recommendation is supportive care while the drug effect resolves. 

There are now FDA-approved options to reverse the effects of DOACs. The first DOAC to become commercially available was dabigatran, a direct thrombin inhibitor. Idarucizumab is a monoclonal antibody fragment that binds free and thrombin-bound dabigatran, and neutralizes its activity.¹ It received expedited FDA approval in 2015. 

Unlike dabigatran, the next few DOACs that became commercially available (e.g., rivaroxaban, apixaban, and edoxaban) were factor Xa inhibitors, so idarucizumab is not effective for these drugs. Data from a 2011 study show that prothrombin complex concentrate (PCC), which has high concentrations of coagulation factors II, VII, IX, and X, can immediately and completely reverse the anticoagulant effect of rivaroxaban in healthy volunteers; however, it has no influence on the anticoagulant action of dabigatran at the PCC dose used in the study.² PCC is indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in patients with acute major bleeding. However, PCC is not FDA approved to reverse Xa inhibitors.

In May 2018, the FDA approved antidote andexanet alfa, the first reversal agent for factor Xa inhibitors. Andexanet alfa is a recombinant modified human factor Xa protein that is considered a decoy because it is inactive as a coagulation factor, but still binds to factor Xa inhibitors and sequesters them in the vascular space. The data to support its approval comes from two sister studies, ANNEXA-A and ANNEXA-R, which evaluated the ability of andexanet alfa to reverse apixaban or rivaroxaban in older healthy participants, and was published as a joint manuscript in 2015.³ Andexanet alfa was found to completely reverse the effect of each drug in 2-5 minutes. It is given initially as a bolus to reverse the drug and then as a continuous infusion for 2 hours to give a persistent effect. This should allow time for hemostasis in patients with bleeding. Once the infusion is stopped, however, the drug effect recovers back to the expected effect that the Xa inhibitor would have after 2 hours of metabolism — to the same level as patients who received a placebo. There does not appear to be a clinically meaningful rebound or prothrombotic effect after the antidote wears off, but it is important to recognize that the effect of the Xa inhibitors, which have a half-life of about 8 hours, returns to about half the effect present when the antidote was given.

Also interesting to note about this drug is that it was developed by a third party and not by the manufacturers of rivaroxaban or apixaban, it received both U.S. Orphan Drug and FDA Breakthrough Therapy designations, and was approved under the FDA’s Accelerated Approval pathway based primarily on the effect of the drug in healthy volunteers in the ANNEXA-A and ANNEXA-R studies. The FDA also considered preliminary data from the ongoing ANNEXA-4 trial, which is currently evaluating andexanet alfa in a global, single-arm, open-label study in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with acute major bleeding (ClinicalTrials.gov Identifier: NCT02329327). It is also interesting that at this stage, the FDA only approved andexanet alfa for the reversal of rivaroxaban and apixaban, but not edoxaban or enoxaparin, which should be equally effective.

At the time of this writing, andexanet alfa had just been added to the formulary at Northwestern Memorial Hospital and had been administered to four patients. However, there are several issues to consider. The first is cost. Also, when should it be given and by whom? At Northwestern, use is restricted to attending emergency room physicians, critical care neurologists, and neurosurgeons. Will bleeding recur after the infusion of the antidote is stopped, particularly when a patient recently took a dose of a factor Xa inhibitor? Aside from FDA labeling and the hypothetical benefits of specificity, what is the clinical advantage of andexanet alfa compared to PCC in a patient having a major gastrointestinal bleed while taking a factor Xa inhibitor? Nonetheless, the availability of a safe and specific antidote for rivaroxaban and apixaban should be comforting to patients with atrial fibrillation who are taking these medications, and reassuring for physicians who may encounter such patients with major bleeding.

References

1. Pollack CV Jr, Reilly RA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373:511-520.
2. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-1579.
3. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373:2413-2424.