July 25, 2018

Andexanet Alfa: Newly Approved Reversal Agent for Oral Anticoagulants

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By Karah Bogoslavsky, PharmD candidate and Lisa C Hutchison, PharmD, MPH
Donald W. Reynolds Institute on Aging at UAMS

 

Bleeding is a serious complication of treatment with oral anticoagulants or blood thinners. Andexanet alfa (AndexXa) has recently been approved for the reversal of life-threatening or uncontrolled bleeding in patients treated with apixaban (Eliquis) and rivaroxaban (Xarelto).1 It joins idarucizumab (Praxbind) which is marketed for bleeding with dabigatran (Pradaxa).  Similar to idarucizumab, andexanet alfa binds free rivaroxaban or apixaban in the blood so they are no longer able to work. There were two major trials that were used to test the efficacy of andexanet alfa, the ANNEXA-A/ANNEXA-R trial and the ANNEXA-4 trial.2,3

The ANNEXA-A/ANNEXA-R study tested andexanet alfa bleeding reversal activity in healthy volunteers 50 to 75 years old, with an average age of 58 years old.2 Bleeding activity was rapidly reduced within 2 to 5 minutes as compared to placebo. After administration of andexanet alfa was completed, the reversal of bleeding activity persisted for 2 hours. This finding is consistent with the half-life of the drug, which is approximately 1 hour.

The ANNEXA-4 study is an ongoing open label study of patients with acute major bleeding from apixaban or rivaroxaban.3 The average age was 77 years old, and two thirds of patients had atrial fibrillation.  Effectiveness was rated as “excellent” if the bleeding stopped within 1 hour after the infusion and “good” if it stopped within 4 hours.  Of the 77 enrolled patients, 20 were not included in final analysis due to low or missing anti-factor Xa activity.  Of the 47 patients in the effective population, 31 patients had “excellent” hemostasis and 6 had “good” hemostasis, 12 hours after the andexanet alfa infusion.  Effective normalization between the bleeding and blood clotting activity was achieved 12 hours after infusion of andexanet alfa in 79% of the patients studied.

However, treatment with andexanet alfa has been associated a high rate of thrombosis including heart attacks, stroke, cardiac arrest, and sudden death. In the ANNEXA-4 study, events that involved dislodged blood clots occurred in 18% of the patients in the safety population, and 15% of the patients died during the 30-day follow-up.3 It is unknown whether andexanet alfa has a prothrombotic effect of its own, or if the absence of an anticoagulant in a high risk patient is the cause of this high rate of thrombosis and follow-up was limited to 30 days.

Andexanet alfa comes in a 100 mg vial and requires storage under refrigeration until reconstitution with sterile water for injection. A specific reconstitution technique is described in the package insert.1 Dosage is 400 mg infusion for lower doses of apixaban or rivaroxaban, and 800 mg infusion for higher doses.

The availability of a reversal agent for apixiban and rivaroxaban levels the playing field between them and dabigatran; however, much is still unknown regarding the risk of newer oral anticoagulants and reversal agents in older adults.4 Since the rate of serious bleeding is lower in the newer anticoagulants, and their effects wear off quickly, in most cases stopping the drug will be sufficient treatment for bleeding and no antidote will be required.  Limiting use of andexanet alfa to individuals with life-threatening hemorrhage is most prudent, given the risk of thrombosis and unknown long-term outcomes in older adults.

References

  1. Andexxa (andexanet alfa) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals, Inc; May 2018.
  2. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med 2016; 375:1131.
  3. Siegal DM1, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015 Dec 17;373(25):2413-24. doi: 10.1056/NEJMoa1510991. Epub 2015 Nov 11.
  4. Hunt BJ, Levi M. Engineering reversal—finding an antidote for direct oral anticoagulants. N Engl J Med 2016; 375:1185-6.