Reversal Agents Safely Stop Effects of Novel Oral Anticoagulants

ORLANDO, FL—In emergency cases when rapid anticoagulation reversal is needed to prevent or stop major bleed events, a ‘decoy protein’ is showing potential to become the default antidote to undo the effects of several factor Xa inhibitors.

In a phase 2 trial previously presented, intravenous administration of andexanet alfa (Portola Pharmaceuticals)—a modified recombinant human factor Xa molecule that binds and sequesters factor Xa inhibitors, thereby restoring thrombin generation and normal hemostatic mechanisms—quickly and safely stopped the anticoagulation effects of rivaroxaban in 36 healthy volunteers.

New data presented today at the American Heart Association 2015 Scientific Sessions by Mark A. Crowther, MD, of McMaster University (Hamilton, Canada), supports the use of andexanet alfa to reverse both the effects of rivaroxaban and apixaban, without any adverse outcomes. The findings were simultaneously published in the New England Journal of Medicine.

Investigators randomized 65 and 80 healthy volunteers treated with apixaban (5 mg twice daily) or rivaroxaban (20 mg daily), respectively, to receive either placebo or andexanet alfa (as an 800-mg IV bolus with or without an infusion of 8 mg per minute for 2 hours).

The mean percent reduction in anti–factor Xa activity (primary endpoint) was greater among patients who received a bolus of the reversal drug rather than placebo in both the apixaban (94% vs 21%) and rivaroxaban groups (92% vs 18%). Additionally, thrombin generation was much more likely to be restored within 2 to 5 minutes of receiving andexanet alfa compared with placebo regardless of which factor Xa inhibitor was used (P < .001 for all comparisons).

Results were maintained when andexanet alfa was given as a bolus plus infusion. Also, there were no occurrences of serious adverse or thrombotic events.

“The ongoing ANNEXA-4 phase 3b-4 study is evaluating the efficacy and safety of andexanet in patients with factor Xa inhibitor-associated acute major bleeding,” the authors report.

Earlier at the meeting, Joanne van Ryn, PhD, of Boehringer Ingelheim (Ridgefield, CT), presented results of an in vitro study with idarucizumab (Praxbind, Boehringer Ingelheim), the recently approved antidote to dabigatran (a direct thrombin inhibitor). That analysis shows no interference of this drug with the anticoagulation properties of factor Xa inhibitors, heparins, and other direct thrombin inhibitors.

1. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of Factor Xa inhibitor activity. N Engl J Med. 2015; Epub ahead of print.
2. van Ryn J. Reversal of dabigatran anticoagulation by idarucizumab in the presence of coagulation factor concentrates and the lack of potential nonspecific effects of idarucizumab on heparins, factor Xa inhibitors and other direct thrombin inhibitors like bivalirudin, hirudin or argatroban. Presented at: American Heart Association Scientific Sessions; November 9, 2015; Orlando, FL.

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  • Siegal et al was funded by Portola Pharmaceuticals and with additional support from Bayer, Bristol-Myers Squibb, Johnson &amp; Johnson, and Pfizer.
  • Crowther reports serving as a consultant for Portola Pharmaceuticals and serving on the advisory boards of multiple pharmaceutical companies.
  • van Ryn is an employee of Boehringer Ingelheim.