Andexanet alfa for the reversal of factor Xa inhibitor activity.

Siegal DM, Curnutte JT, Connolly SJ, et al.
N Engl J Med 2015;373:2413-2424
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Review by : D. Faraoni
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The direct factor Xa inhibitors apixaban and rivaroxaban are increasingly used for the prevention and the treatment of thromboembolism. As for the direct thrombin inhibitor dabigatran, one of the major concerns with the use of these drugs is the lack of an antidote, or specific reversal agent, that can be used when the anticoagulant effect needs to be reversed, for example in case of bleeding.

Andexanet alpha is a specific reversal agent that has been designed to neutralize the effect of both direct and indirect factor Xa inhibitors. This molecule is a recombinant human factor Xa that is inactive but has a high affinity to factors Xa inhibitors. Andexanet alpha has the potential to inhibit the effect of factor Xa inhibitors, sequestering the drugs into the vascular space and allowing factor Xa to work normally.

In this study, Siegal et al. report the results of two double-blind, placebo-controlled studies that were designed to assess the efficacy of andexanet alpha for the reversal of the anticoagulant effect of apixaban (ANNEXA-A) and rivaroxaban (ANNEXA-R), respectively, in healthy volunteers (age ranging from 50 to 75 years old). After 4 days of treatment with one of the anticoagulants, the volunteers received an intravenousloading dose of 400 mg andexanet alpha, followed by a continuous infusion of 4 mg/min for 120 minutes if they received apixaban, or an intravenous loading dose of 800 mg andexanet alpha, followed by a continuous infusion of 8 mg/min for 120 minutes if they received rivaroxaban. The primary endpoint in both studies was the percent change in anti-factor Xa activity, measured by chromogenic assay of factor Xa enzymatic activity.

Anti-factor Xa activity was significantly reduced after the administration of andexanet alpha in volunteers receiving apixaban or rivaroxaban. The effects were sustained during the administration of the continuous infusion and the level of factor Xa inhibitor returned to placebo levels within 1-3 hours following the interruption of the infusion. Comparable observations were reported for thrombin generation.

These studies report promising results regarding the reversal of anticoagulation in patients treated with direct factor Xa inhibitors. Further studies are needed to assess the efficacy of this specific antidote in bleeding situations. Since the anti-Xa activity returned to placebo level within 1-3 hours after the administration of the infusion, the reversal strategy might take into account the plasmatic concentration of the factor Xa inhibitors at baseline and the pharmacokinetics of both the anticoagulant and the antidote. We can expect that the reversal of factor Xa inhibitors will require close monitoring of anti-Xa activity before and after the administration of andexanet alpha.

– David Faraoni

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