Andexanet proven effective as an antidote to factor Xa inhibitors


By Tony James

22 Sep 2016

Early experience with andexanet alfa in patients experiencing a serious bleed on rivaroxaban, apixaban or enoxaparin has shown it effectively inhibits the anti-factor Xa drugs and is associated with clinical haemostasis.

Presented at the ESC congress in Rome and published simultaneously in the New England Journal of Medicine the ongoing ANNEXA-4 study enrolled patients who had taken a factor-Xa inhibitor in the past 18 hours and had acute major bleeding.

A preliminary report described the first 67 cases. There were 33 with gastrointestinal bleeding, 28 with intracranial haemorrhage and six with bleeding at other sites.

Bolus administration of andexanet reduced anti-factor Xa activity by 89% in patients treated with rivaroxaban and by 93% in those receiving apixaban.

Clinical haemostasis 12 hours later was assessed as good in 37 of 47 patients assessable for efficacy, but 12 of 67 patients had a thrombotic event in the following 30 days.

Writing in an accompanying editorial Beverley J. Hunt from the Thrombosis and Haemophilia Centre, St. Thomas’ Hospital, London and Marcel Levi from the Academic Medical Center, University of Amsterdam, stressed the benefits of direct oral anticoagulants including rivaroxaban, apixaban, dabigatran and edoxaban compared to conventional treatment with warfarin in patients with atrial fibrillation or venous thromboembolism.

For example, they avoided difficulties with warfarin including the need for INR monitoring, slow onset and offset, unpredictable pharmacokinetics, and interactions with coexisting illness and other medications.

“For all these reasons, the arrival of direct oral anticoagulants was a breath of fresh air, since the new agents had a predictable effect and thus no need for regular monitoring,” they wrote.

“Despite evidence of [their] safety…there has been concern that, unlike vitamin K antagonists, they arrived without an antidote.”

Idarucizumab is now available as an antidote for dabigatran, targeting the active site of the thrombin inhibitor, but all other direct oral anticoagulants bind to active coagulation factor X, the editorialists explained.

“In a display of creative research, investigators developed andexanet, a recombinant modified human factor Xa decoy protein, as an antidote for these drugs,” they said. It is also effective against low molecular weight heparins and fondaparinux.

“Despite the attitude-changing excitement this reversing agent brings, we suggest that the actual need for an antidote for direct oral anticoagulants is small in typical clinical practice,” they stated.

“The rate of intracranial bleeding associated with direct oral anticoagulants is less than that associated with warfarin, and the clinical severity of haemorrhage seems to be reduced. The effects of the drugs wear off quickly, and unlike the case with warfarin, stopping the drug may be all that is required in most scenarios.”

However, they concluded that more research was needed to show whether fast reversal of the anticoagulants actually improves clinical outcomes, and for how long anticoagulation should be ceased once it is reversed.

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