Coagulation

DOAC reversal agent reduces anti-factor Xa activity


The DOAC reversal agent andexanet has been shown to rapidly and markedly reduce anti-factor Xa activity in patients with acute major bleeding associated with the use of a factor Xa inhibitor.

The final results of the ANNEXA-4 study, published in NEJM, also showed that “82% of patients had excellent or good haemostatic efficacy at 12 hours.”

A randomised controlled trial has yet to confirm this, however a 2019 update of the AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation has included the recommendation that andexanet alfa can be useful for the reversal of rivaroxaban and apixaban in the event of life-threatening or uncontrolled bleeding.

The US Food and Drug Administration (FDA) approved andexanet in 2018 under their Accelerated Approval pathway.

The cohort study comprised 352 patients from 63 centres across North America and Europe who presented with acute major bleeding within 18 hours of apixaban, rivaroxaban or edoxaban (at any dose) or enoxaparin (at a dose of at least 1mg/kg/day).

Patients had a mean age of 77 years, and were typically anticoagulated to prevent stroke as a consequence of atrial fibrillation. Bleeding sites were typically intracranial (64%) and gastrointestinal (26%).

The study found andexanet reduced anti–factor Xa activity by 92% in apixaban patients – from 149.7 ng/ml (123.7 IU/ml) at baseline to 11.1 ng/ml (9.2 IU/ml) by the end of the bolus administration.

A similar sized reduction was seen in patients on rivaroxaban – a 92% reduction in anti–factor Xa activity from 211.8 ng/ml (175 IU/ml) to 14.2 ng.ml (11.7 IU/ml). A 75% reduction in anti–factor Xa activity was seen in patients on enoxaparin.

The majority of patients (82%) were adjudicated as having excellent or good hemostatic efficacy at 12 hours.

Two patients experienced an infusion reaction and none developed antibodies to Factor Xa or X or neutralising antibodies to andexanet.

The study identified thrombotic events in 10% of patients during a 30-day follow-up and deaths mainly due to cardiovascular causes in 14% of the patients.

“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 study said.

The ANNEXA-4 study was sponsored by Portola Pharmaceuticals.

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