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Stroke
Published in Henry J. Woodford, Essential Geriatrics, 2022
For people taking NOACs, reversal is not so well defined. Dabigatran can be reversed by idarucizumab (a monoclonal antibody that binds to the drug).80 Andexanet alfa, a recombinant form of factor Xa, can be used for people taking apixaban or rivaroxaban. Alternatively, PCC can be considered for people taking apixaban, edoxaban or rivaroxaban.
Stroke and Transient Ischemic Attacks of the Brain and Eye
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Andexanet alfa is a modified recombinant inactive form of human factor Xa that acts as a decoy by binding and sequestering factor Xa inhibitors with a similar affinity to that of native factor Xa, thereby reducing anti–factor Xa activity, and reversing the anticoagulant effects of Xa inhibitors rapidly and nearly completely. In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti–factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours.57 Two dosage regimens of andexanet alfa are recommended, based on the factor Xa inhibitor taken, its dose, and the time since the last factor Xa inhibitor dose. Patients taking <10 mg of rivaroxaban or <5 mg of apixaban per dose should receive the low-dose regimen, a 400-mg IV bolus dose of andexanet alfa over 15–30 minutes, followed by a 4 mg/min continuous infusion over 2 hours. Patients taking >10 mg of rivaroxaban or >5 mg of apixaban per dose should receive the high-dose regimen, an 800-mg IV bolus dose of andexanet alfa, followed by an 8 mg/min continuous infusion for up to 120 minutes if their last dose was <8 hours before starting andexanet alfa; if the last dose was >8 hours before starting andexanet alfa, the low-dose regimen should be used. If the dose and/or timing since the last dose of the factor Xa inhibitor is unknown, the high-dose regimen should be used. The optimal dosage of andexanet alfa for patients taking other factor Xa inhibitors has not been established.
Venous thromboembolic disease in older adults
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Laurie G. Jacobs, Justin B. Kaplan, Ruchi Jain
DOACs fall into two major groups—direct inhibitors of thrombin (factor II) of which dabigatran is the only US Food and Drug Administration (FDA)-approved agent in the United States (US), and factor Xa inhibitors—rivaroxaban, apixaban, edoxaban, and betrixaban. Although all are approved for use in the United States, betrixaban does not have approval for prophylactic use in major orthopedic surgery. These agents are not interchangeable as they have significant pharmacokinetic differences that impact drug selection. In addition, dabigatran can be effectively reversed by idarucizumab, a monoclonal antibody fragment that binds with high affinity to dabigatran. In the RE-VERSE AD clinical trial (32) of patients with active bleeding, it reversed the anticoagulant effect in lab testing within minutes and hemostasis improved without significant thrombosis, although patient outcomes were unclear. Another agent, andexanet alfa (33), acts as a decoy to target and sequester factor Xa inhibitors and thereby reverse the anticoagulant activity of both oral direct Xa inhibitors (apixaban, edoxaban, and rivaroxaban) and injectable indirect Xa inhibitors (enoxaparin and fondaparinux). However, andexanet alfa is currently being evaluated by the FDA and is not yet available in the United States.
Protocolized management of bleeding in hospitals in The Netherlands in patients treated with direct oral anticoagulants
Published in Current Medical Research and Opinion, 2023
Darko Mitrovic, Lilian Stapel, Nic Veeger, Heleen Lameijer, Karina Meijer, Eric van Roon
Despite the fact that andexanet alfa has been on the market for almost 2 years before our research on protocols, it is hardly mentioned in protocols. For life-threatening bleeding, it is described as first choice treatment in only 14% of protocols and second choice treatment in 8%. An important reason for the reluctance to use andexanet alfa could be the limited clinical data available on the effectiveness of this antidote compared to other available drugs (mainly PCC) and price. Also, the new antidote is not yet applicable to all Xa inhibitors. This is evident in the andexanet alfa efficacy study conducted by the drug’s manufacturer, which demonstrated efficacy only for rivaroxaban and apixaban. Patients using edoxaban were not included11. Recent European Society of Cardiology (ESC) guideline suggests the use of andexanet alfa also in patients treated with edoxaban20.
Cost-effectiveness of andexanet alfa versus four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-related intracranial hemorrhage in the US
Published in Journal of Medical Economics, 2022
John Fanikos, Joshua N. Goldstein, Belinda Lovelace, Anne C. Beaubrun, Robert S. Blissett, Filipa Aragão
Andexanet alfa (coagulation factor Xa [recombinant] inactivated-zhzo) is a specific reversal agent that binds to and sequesters factor Xa inhibitor molecules, thereby rapidly reducing anti-factor Xa activity and restoring endogenous factor Xa activity11,12. In phase 3, randomized, placebo-controlled trials, andexanet alfa demonstrated significant and effective reversal of the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes following bolus and sustained throughout the 2-h intravenous (IV) infusion12. In the multicenter, prospective, single-arm, phase 3b/4 ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) trial, an analysis of 352 adults who had experienced acute major bleeding within 18 h of treatment with a direct factor Xa inhibitor demonstrated that treatment with andexanet alfa resulted in excellent or good hemostatic efficacy within 12 h in 82% of patients, a 30-day mortality rate of 14%, and an incidence of adjudicated thrombotic events of 9.7%11. A subgroup analysis of 98 patients treated for spontaneous ICH (sICH) showed that 79% of patients achieved excellent or good hemostasis over the 12-h period following treatment with andexanet alfa13. Andexanet alfa received US Food and Drug Administration (FDA) approval in May 2018 under the accelerated approval pathway for the treatment of life-threatening or uncontrolled bleeding resulting from factor Xa inhibitors apixaban and rivaroxaban14.
Andexanet alfa for the reversal of factor Xa inhibitors
Published in Expert Opinion on Biological Therapy, 2019
J Favresse, M Hardy, MA van Dievoet, AL Sennesael, J Douxfils, CM Samama, O Vornicu, AS Dincq, S Lessire, F Mullier
On the other hand, the lack of specific and well-designed studies assessing the efficacy and safety of current reversal agents in patients taking DOACs in case of life-threatening bleeding or surgery led to the development of specific reversal agents [6,7,19,26,32]. Since 2015, a specific reversal agent for dabigatran (idarucizumab, Praxbind®, Boehringer Ingelheim Pharmaceuticals, Ingelheim am Rhein, Germany) has been approved by the Food and Drug Administration (FDA) [7,45,46]. In May 2018, a specific reversal agent for apixaban and rivaroxaban (andexanet alfa, Andexxa®, Portola Pharmaceuticals, San Francisco, CA) has also been approved by the FDA in the United States [6,7]. In this review, we present the latest data regarding andexanet alfa and highlight the current limitation of this newly FDA-approved antidote.