Andexanet Alfa – Antidote for factor Xa inhibitors

Andexanet Alfa – Antidote for 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. In other words, it is a modified recombinant inactive form of human factor Xa which bind and sequester factor Xa inhibitor molecules. 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]. In the interim report published in 2016, 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.

The full study report of ANNEXA-4 was published in 2019 [2]. ANNEXA-4 evaluated 352 patients who had acute major bleeding within 18 hours of administration of a factor Xa inhibitor. Acute intracranial hemorrhage was present in 64% of the patients. Patients in the study received a bolus of andexanet followed by two hour infusion. Coprimary outcomes evaluated were the percentage change in anti-factor Xa activity and percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion. Excellent or good hemostatic efficacy at 12 hours was documented in 82% of patients. 92% reduction in median anti-factor Xa activity was noted in those who were on apixaban and rivaroxaban after the andexanet bolus.

Before the availability of specific antidote, bleeding due to factor Xa inhibitor was treated with non specific agents like prothrombin complex concentrate, fresh frozen plasma and activated recombinant factor VIIA [3]. 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. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ Jr; ANNEXA-4 Investigators. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019 Apr 4;380(14):1326-1335. 
3. 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.