Antidote Reduces Anticoagulant Activity by 90 Percent

A specifically designed agent found to be fast and well-tolerated in treating anticoagulated bleeding, according to a study published in The New England Journal of Medicine.

The interim results of an ongoing ANNEXA-4 study revealed that the antidote, andexanet alfa, was able to reduce anticoagulant activity in patients with acute major bleeding by approximately 90% within 30 minutes. Participants were also receiving a factor Xa (fXa) inhibitor, which results in “excellent or good” homeostasis at 12 hours in a majority of the patients.

“Andexanet is the first specific agent designed for reversal of factor X inhibitors,” said co-principal study investigator Mark Crowther. “Although it has been shown to reduce anti-fXa activity in volunteers, until now we did not have experience in acutely bleeding patients. In these patients andexanet reduced the anticoagulant effect of the factor Xa inhibitors and was associated with effective haemostasis in most patients.”

There were 67 patients with a mean age of 77-years-old included in the interim results. Patients required urgent reversal of acute major bleeding within 18 hours of receiving either a direct fXa inhibitor, apixaban, rivaroxaban, and edoxaban, or an indirect (enoxaparin) fXa inhibitor.

In 49% of patients, the primary site of bleed was gastrointestinal, and 42% of patients were intracranial.

Since the study was not randomized for ethical reasons, all of the patients were given andexanet first in an immediate bolus over 15 to 30 minutes, followed by a 2-hour infusion. The dosing was determined by which fXa inhibitor the patient was exposed to, and when.

Patients were assessed during several periods: baseline; end-of bolus; end of the 2-hour infusion and at 4, 8, and 12 hours; and 3 and 30 days post-infusion. For the efficacy assessment, 47 patients were included.

The results of the assessment showed that patients given rivaroxaban (n=26) had an 89% decrease in anti-fXa activity from baseline to end-of-bolus, and a corresponding 93% decrease for those in the apixaban (n=20) group. At 12 hours, clinical hemostatic efficacy was rated as “good to excellent” in 79% of patients.

“This preliminary report of the ongoing ANNEXA-4 study shows us that andexanet rapidly reverses anti-factor Xa activity in acutely bleeding patients and this is associated with excellent or good hemostasis in most,” said lead study investigator Stuart J. Connolly, MD.

Although 18% of patients experienced thrombotic events during the 30-day follow up, this did not come as a surprise to researchers.

“This rate of events is not unexpected considering the thrombotic potential of the patients and the fact that in most of them anticoagulation was discontinued at the time of bleeding and not restarted,” Connolly said.