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A short IV bolus of a ‘decoy’ molecule almost immediately reverses rivaroxaban anticoagulation, according to a proof-of-concept study. The new agent relieves some concern about management of patients on novel factor Xa inhibitors who experience serious bleeding or need emergent surgery.

The data were presented December 9, 2013, at the 55^th American Society of Hematology Annual Meeting in New Orleans, LA, by Mark Crowther, MD, MSc, of McMaster University (Hamilton, Canada).

The investigational drug, andexanet alfa (Portola Pharmaceuticals, South San Francisco, CA), is a modified recombinant human factor Xa molecule that binds and sequesters factor Xa inhibitors, thereby restoring thrombin generation and normal hemostatic mechanisms.

Four Regimens Tested

For the phase 2 study, 36 healthy volunteers received rivaroxaban 20 mg daily for 6 days. On the sixth day, 3 hours after the last rivaroxaban dose, the subjects were randomized in a 6:3 ratio to andexanet alfa in 1 of 4 dosing regimens—a single IV bolus of 210 mg, 420 mg, or 600 mg, or a 720-mg bolus followed by a 240-mg infusion (4 mg/min for 1 hour)—or placebo.

On day 6, directly before andexanet alfa or placebo administration, rivaroxaban plasma concentration averaged 0.60 ± 0.21 μM for placebo-treated subjects and 0.57 ± 0.22 μM for andexanet-treated subjects. Immediately after completion of the graduated bolus doses, anti-factor Xa activity decreased dose-dependently by 20%, 53%, 70%, and 81%, respectively, and returned to baseline levels approximately 2 hours after treatment. In parallel, the plasma concentrations of unbound rivaroxaban were decreased by approximately 32%, 51%, 75%, and 70%, respectively, relative to pre-andexanet values.

Rivaroxaban-induced inhibition of thrombin generation and prolongation of both prothrombin time and activated clotting time were also rapidly reversed by administration of andexanet in a dose-dependent manner. As expected, tissue factor pathway inhibitor activity decreased due to its binding to andexanet.

In 48-day follow-up, the novel antidote was well tolerated; there were no thrombotic events or serious adverse events. According to a press release, no antibodies to factor X or factor Xa were observed in this or other phase 2 studies, which have included more than 80 subjects. The only adverse events seen in more than 10% of subjects and deemed to be related to andexanet were infusion-related reactions and postural dizziness.

The authors observe that these data are consistent with previously reported results for andexanet with another factor Xa inhibitor, apixaban. Thus, andexanet holds promise as a universal antidote for this class of novel oral anticoagulants. Additional doses or dose regimens may be studied to achieve more complete and sustained reversal of rivaroxaban anticoagulation, they add.

In the press release, John T. Curnutte, MD, PhD, of Portola Pharmaceuticals, stated, “Andexanet alfa’s . . . flexibility to provide short-term reversal through the administration of an intravenous bolus or sustained reversal by the addition of an extended infusion is critical in covering the multiple clinical scenarios where a reversal agent is needed. Importantly, we believe andexanet alfa’s highly specific mechanism of action may minimize complications that can be associated with agents that have off-target activity.”

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Source:
Crowther M. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for fXa inhibitors. Presented at: American Society of Hematology Annual Meeting; December 9, 2013; New Orleans, LA.

 

 

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