Updated October 2019
By Katelyn Sylvester, PharmD, CACP, BCPS
For decades, warfarin was the only FDA-approved oral anticoagulant for stroke prevention in atrial fibrillation (Afib) and for the treatment and prevention of venous thromboembolism (VTE), 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 for these agents in the event of significant bleeding or an unexpected urgent procedure. A few years ago, the reversal agent, idarucizumab (Praxbind), became available to reverse the effects of dabigatran (Pradaxa, an oral direct thrombin inhibitor). Now, andexanet alfa (Andexxa) is available to reverse the factor Xa Inhibitors (such as apixaban and rivaroxaban).
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. It was approved by the FDA in May 2018 to reverse the effects of rivaroxaban and apixaban in the event of serious bleeding that cannot be controlled with supportive measures. It is currently 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. Andexanet alfa has been made available to hospitals under an early supply program and a wider supply of commercial product is expected in 2019.
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.
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. However, further studies are needed to confirm the safety and efficacy of andexanet in reversing the remaining direct and indirect acting factor Xa inhibitors (e.g., betrixaban, edoxaban, and enoxaparin) and to determine if it’s a safe and effective strategy to reverse anticoagulation prior to emergent procedures.
How does it work?
To understand how andexanet works, it’s 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 they 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 administered 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 is taking, as well as the dosage and the time since the last dose was ingested. Andexanet alfa’s duration of effect is relatively short and is 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 have either already had a blot clot or are at risk of developing a clot. By reversing anticoagulation, the risk of developing a clot increases back to where it was prior to treatment with the anticoagulant. To minimize the risk of a clot after administration of andexanet alfa, the healthcare team will evaluate the patient to determine if and when it’s safe to restart anticoagulation.
Katelyn Sylvester, PharmD, CACP, BCPS
Pharmacy Manager – Anticoagulation Services
PGY1 Pharmacy Residency Coordinator
Department of Pharmacy
Brigham and Women’s Hospital