By Katelyn Sylvester, PharmD, CACP, BCPS 

For the past several decades, warfarin has been the only FDA-approved oral anticoagulant for stroke prevention in atrial fibrillation as well as the treatment and prevention of venous thromboembolism, but new treatments have recently emerged in the form of direct oral anticoagulants (DOACs). These newer anticoagulants are at least as effective as warfarin and have a similar or decreased risk of bleeding; especially major bleeding.

Despite the lower risk of major bleeding with these agents, some risk remains and may increase due to trauma or major surgery. Until recently, there has not been a specific reversal agent available for these agents in the event of significant bleeding or an unexpected urgent procedure. A few years ago, the reversal agent, idaraziumab (Praxbind), became available to reverse the effects of dabigatran (an oral direct thrombin inhibitor) and now andexanet alfa (Andexxa) is available to reverse the factor Xa Inhibitors (such as apixaban and rivaroxaban).

NATF is dedicated to offering readers a closer look at each DOAC and their reversal agents in order to empower patients to make informed healthcare decisions. Take a closer look at andexanet alfa:

What is andexanet alfa?

Andexanet alfa, also known as Andexxa or coagulation factor Xa (recombinant), inactivated-zhzo, is an antidote that reverses the anticoagulant effects of the factor Xa inhibitors (e.g. apixaban and rivaroxaban). It was approved by the FDA in May 2018 and made available to hospitals under an early supply program – a wider supply of commercial product is expected in 2019. Prior to the approval of andexanet, healthcare providers would manage bleeding and reversal of anticoagulation with supportive measures and blood factors which would replace the proteins in the body that were being blocked by the anticoagulant.

This new reversal agent is currently approved to reverse the effects of rivaroxaban and apixaban in the event of serious bleeding that cannot be controlled with supportive measures. It currently is not approved to reverse the effects of the other factor Xa inhibitors, betrixaban and edoxaban or the indirect Xa-inhibitors, such as enoxaparin. It is also not approved to reverse anticoagulation prior to procedures. Further studies are needed to confirm the safety and efficacy of andexanet to reverse the anticoagulant effects of the remaining direct and indirect acting factor Xa inhibitors and to determine if it is a safe and effective strategy to reverse anticoagulation prior to emergent procedures.

The ANNEXA-A and ANNEXA-R trials showed that andexanet alfa quickly reversed the anticoagulant effect of rivaroxaban and apixaban in healthy patients and the ANNEXA-4 trial provided safety and efficacy data for patients on factor Xa inhibitors who were actively bleeding and required reversal. The trials showed that andexanet alfa, when given to patients actively bleeding, results in improved clotting factor levels and stops bleeding in the majority of patients.

How does it work?

To understand how andexanet works, it is helpful to understand how the factor Xa inhibitors work. The factor Xa inhibitors block factor Xa, which is part of a system known as the “clotting cascade.” The clotting cascade is the system that allows blood to clot. By blocking factor Xa, apixaban and rivaroxaban reduce the risk of the body developing a blood clot in a place where it shouldn’t, but also decrease the body’s ability to form a clot when there is active bleeding. Andexanet alfa was designed to mimic factor Xa as a decoy. It binds to the anticoagulant, making it inactive and unable to block factor Xa. This allows the clotting cascade to act as it normally would in the event of bleeding – using factor Xa to form a clot and stop the bleeding.

Andexanet alfa is given as an infusion and requires administration in a hospital by a healthcare provider. It is given as a quick infusion at a higher dose, followed by a slower infusion over 2 hours. The dose of the infusion depends on the specific anticoagulant that the patient was taking, as well as the dose and the time since the last dose was ingested. The duration of effect of andexanet alfa is relatively short; just long enough to allow the body to initiate its normal clotting process. The healthcare team will monitor laboratory markers, as well as signs and symptoms of bleeding, to ensure that the medication was effective and to determine if other treatments are required.

What are the risks?

Patients who require anticoagulation either have already had a blot clot or are at risk of having a blood clot. By reversing anticoagulation, the risk of developing a blood clot increases back to where it was prior to treatment with the anticoagulant. To minimize the risk of developing a blood clot after administration of andexanet alfa, the healthcare team will evaluate the patient to determine if and when it is safe to re-start anticoagulation.





Katelyn Sylvester, PharmD, CACP, BCPS
Pharmacy Manager – Anticoagulation Services
PGY1 Pharmacy Residency Coordinator
Department of Pharmacy
Brigham and Women’s Hospital