Andexanet Alfa, Reversal Agent for Factor Xa Inhibitors, Boosts Hemostasis

Andexanet alfa (Andexxa; AstraZeneca), compared with usual care, improves hemostasis in patients who have an intracranial bleed while taking a factor Xa inhibitor, according to top-line results of ANNEXA-I, a phase IV postmarketing trial.

No specific numbers were cited in a press release issued Monday by the drugmaker, which said the trial was halted based on a recommendation from the data and safety monitoring board after a planned interim analysis.

Andexanet alfa—a modified form of the human factor Xa molecule that binds tightly to the factor Xa inhibitors, canceling out their effects—received accelerated approval from the US Food and Drug Administration in 2018. The agent is indicated for reversing the effects of two direct factor Xa inhibitors, rivaroxaban (Xarelto; Bayer/Janssen) and apixaban (Eliquis; Bristol-Myers Squibb).

The accelerated approval was based on studies showing that the drug rapidly reverses the effects of factor Xa inhibitors in healthy volunteers, however, and the FDA said that continued approval could be dependent on whether the agent would be shown to improve hemostasis when randomized against usual care. Now, ANNEXA-I appears to have provided that evidence.

The trial was stopped after prespecified criteria for superior hemostatic efficacy were met in a planned interim analysis. A total of 450 patients with an intracranial bleed while taking rivaroxaban, apixaban, or a third factor Xa inhibitor, edoxaban (Savaysa; Daiichi Sankyo), had been randomized to andexanet alfa or usual care and followed for at least a month. Usual care included use of four-factor prothrombin complex concentrate and any other treatments (or no treatment) deemed appropriate.

The primary endpoint was effective hemostasis, met when patients fulfilled all three of the following criteria:

• Change in NIHSS score from baseline to 12 hours of 6 points or less
• No greater than a 35% increase in hematoma volume at 12 hours
• No rescue therapies administered between 3 and 12 hours after randomization

AstraZeneca said it will work on closing out the trial, filing for full approval in the US and Europe, and submitting the results for publication and for presentation at a future medical meeting.

Andexanet alfa was the second anticoagulation-reversal agent cleared by the FDA, after idarucizumab (Praxbind), an antidote for the direct thrombin inhibitor dabigatran (Pradaxa; both Boehringer Ingelheim).