Andexanet Alfa – Antidote for factor Xa inhibitors

Andexanet Alfa – Antidote for factor Xa inhibitors

United States Food and Drug Administration (US FDA) has recently approved Andexanet Alfa as an antidote for factor Xa inhibitors rivaroxaban and apixaban. This is for use in case of life threatening bleeding to reverse the effects of these factor Xa inhibitors.

Andexanet Alfa is a recombinant modified human factor Xa decoy protein, which reverses the effect of factor Xa inhibitors like rivaroxaban by binding to these drugs. It does not have intrinsic catalytic activity. The drug competes with endogenous factor Xa to bind with factor Xa inhibitors, thus elevating levels of free endogenous factor Xa.

Andexanet Alfa has been evaluated in ANNEXA-4 prospective multicentric open label trial [1]. The medication was used in 67 patients who developed acute major bleeding within 18 hours of administration of a factor Xa inhibitor. The mean age was 77 years and bleeding was mostly gastrointestinal or intracranial. The drug was given within 4.8±1.8 hours of presentation to emergency department. After andexanet bolus median anti-factor Xa activity decreased by 89% in those receiving rivaroxaban and 93% in those on apixaban. The bolus dose was followed by a 2 hour infusion. Assessment at 12 hours showed good hemostasis in 79% of patients. Thrombotic events occurred in 18% during a 30 day follow up. The occurrence of thrombotic events is always a concern in the reversal of any anticoagulation, mostly attributed to the high thrombotic risk in these individuals in whom anticoagulation was clinically indicated. Due to this thrombotic risk, anticoagulation should be reinstituted soon after the control of bleeding when medically appropriate.

Till now, bleeding due to factor Xa inhibitor was treated with non specific agents like prothrombin complex concentrate, fresh frozen plasma and activated recombinant factor VIIA as specific antidote was not available [2].

The dose of andexanet alfa needed is based on whether it is used to reverse rivaroxaban or apixaban, the dose of the factor Xa inhibitor which was being used and the time since the last dose.

References

  1. Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M; ANNEXA-4 Investigators. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131-41.
  2. Heo YA. Andexanet alfa in the treatment of acute major bleeding related to apixaban and rivaroxaban: a profile of its use in the USA. Drugs Ther Perspect. 2018;34(11):507-512. 

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