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HONOLULU -- Andexanet alfa (Andexxa), the reversal agent for anticoagulants in the factor Xa inhibitor class, worked for patients who developed acute major bleeding while on one of these agents, the full report of the ANNEXA-4 study confirmed.
A bolus of the antidote saw median anti-factor Xa activity drop more than 90% -- from 149.7 ng/mL to 11.1 ng/mL among those who had received apixaban (Eliquis) and from 211.8 ng/mL to 14.2 ng/mL for rivaroxaban (Xarelto).
An infusion of andexanet following the initial bolus resulted in 82% of patients showing excellent or good hemostatic efficacy 12 hours after the end of the 2-hour infusion, Truman Milling, Jr., MD, of the University of Texas at Austin Dell Medical School, reported at the International Stroke Conference here.
The 352-person study was published simultaneously in the New England Journal of Medicine.
Andexanet is the sole antidote on the market for factor Xa inhibitors, having received accelerated FDA approval in May 2018 following the release of an interim ANNEXA-4 analysis of the first 227 patients recruited.
In the full report, the magnitude of reduction in anti-factor Xa activity was not a predictor of hemostatic efficacy in general except among patients with intracranial hemorrhaging (area under the curve 0.64, 95% CI 0.53-0.74).
"The larger number of patients suggests that andexanet is effective at decreasing the anti-factor Xa activity of the drug," commented Jean Connors, MD, of Brigham and Women's Hospital in Boston. "That's huge, because I do think that the first step to try to improve outcomes is reducing the anticoagulant effect."
What was also "fantastic" was the correlation found between plasma anticoagulant level and outcomes, "and that's step two," Connors said, adding that this helps answer the question of whether a person who has already had a brain bleed can have outcomes changed by the reversal agent.
Recently, andexanet got a IIa recommendation for reversing rivaroxaban and apixaban in life-threatening bleeding in the 2019 focused update to atrial fibrillation (Afib) guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society.
ANNEXA-4 included patients in North America and Europe who had acute major bleeding -- predominantly intracranial bleeds (64%) or GI bleeds (26%) -- within 18 hours of getting a factor Xa inhibitor.
The overall rates of death and thrombotic events in 30 days were 14% and 10%, respectively, Milling's group found.
"Not surprisingly, a majority of events occurred in patients in whom resumption of oral anticoagulation was delayed or in patients who did not restart anticoagulation. After restarting of oral anticoagulation, no patient had a thrombotic event during the 30-day follow-up," the researchers said.
Four out of five patients had Afib as the primary indication for anticoagulation. Mean age was 77 years.
Notably, no patient developed antibodies to factor Xa or factor X or neutralizing antibodies to andexanet.
That there are no such antibodies suggests that andexanet should still work months later if a patient develops another brain bleed, Connors said.
Milling acknowledged that potential confounders in the study include platelet function and variation in bleeding source (venous or arterial).
Moreover, the lack of a control group in ANNEXA-4 has the investigators starting a randomized trial later this year.
The trial was funded by Portola Pharmaceuticals.
Milling disclosed ties to the Population Health Research Institute at McMaster University, Janssen, CSL Behring, Octapharma, and Portola.
Connors disclosed personal fees from Bristol-Myers Squibb, Pfizer, and Portola, and research funding from CSL Behring.
Primary Source: NEJM