CHICAGO — Andexanet alfa safely and effectively reversed the anticoagulant effects of apixaban among older patients, according to data presented at the American Heart Association Scientific Sessions.
Mark Crowther, MD, MSc, reported results of ANNEXA-A, a phase 3, randomized, double blind, placebo-controlled trial that assessed investigational use of andexanet alfa (Portola Pharmaceuticals) for the reversal of apixaban-induced anticoagulation in older patients.
Andexanet alfa, a modified, recombinant human Factor Xa inhibitor molecule, is a universal antidote for Factor Xa inhibitors. Previously reported randomized phase 2 data indicated that andexanet alfa significantly reversed anti-Factor Xa activity and the inhibition of thrombin generation among healthy participants who were anticoagulated with apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), rivaroxaban (Xarelto, Janssen Pharmaceuticals) or enoxaparin (Lovenox, Sanofi Aventis).
The ANNEXA study was divided into two parts. Part 1 investigated a bolus regimen and part 2 investigated a bolus followed by a 2-hour continuous infusion. Crowther presented data from the first part of the study.
In part 1, 34 participants aged 50 to 75 years were randomly assigned at a 3:1 ratio to andexanet alfa (n=24) or placebo (n=9). All participants received apixaban 5 mg twice daily for 4 days; placebo or a 400 mg IV bolus of andexanet alfa was administered on the fourth day, 3 hours after the final dose of apixaban. Researchers collected safety data through day 43, according to the abstract.
The primary efficacy endpoint was the reversal of apixaban-induced anti-Factor Xa activity (mean change from baseline at 2 or 5 minutes after the end of the bolus). Additional efficacy endpoints included a ≥80% reduction in anti-Factor Xa levels, reduction in plasma concentrations of free apixaban and restoration of thrombin generation.
The researchers observed a gradual diminution in the effect of apixaban over 12 hours after infusion. Anticoagulation was significantly inhibited before infusion; this was almost completely reversed immediately after infusion of the 400-mg apixaban dose. The trial met its primary endpoint, with a 94% change from baseline to anti-Factor Xa activity (P<.0001) and a >90% reversal in all patients in the treated group compared with placebo.
A ≥80% reduction in anti-Factor Xa occurred in all andexanet recipients vs. zero in the placebo group (P<.0001). Free apixaban concentration also decreased after andexanet alfa administration (P<.0001), and a change in thrombin generation also was observed (P<.0001), with a return to baseline in all andexanet alfa recipients.
Crowther noted that safety data were consistent with that observed in prior studies of andexanet alfa. There were no incidences of premature discontinuation, thrombotic events, Factor X or Factor Xa antibodies, or significant toxicities.
“Andexanet alfa administration was well tolerated and met all of the prespecified primary and secondary efficacy endpoints,” Crowther said. “It produced near-complete normalization of all of the coagulation parameters within 2 minutes of completion of the infusion. As shown before, the effect lasted 1 to 2 hours, with a gradual loss of the effect consistent with the half-life of the product.”
For more information:
Crowther M. CS.03: Management of Cardiovascular Disease. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.
Disclosure: Crowther reports serving on speakers’ bureaus for Bayer, Celgene, Leo Pharma and Shire; consulting or serving on advisory boards for Leo Pharma and Portola Pharmaceuticals; and ownership interest in Portola Pharmaceuticals.