The following are key points to remember about this review of andexanet alfa for reversing the anticoagulant effects of apixaban or rivaroxaban:

1. Direct oral anticoagulants, including apixaban, rivaroxaban, edoxaban, betrixaban, and dabigatran, have many advantages over warfarin, yet patients are still at risk for hemorrhagic events.
2. The US Food and Drug Administration has approved specific antidotes for apixaban, rivaroxaban, and dabigatran. Availability of these agents improves the overall safety of direct oral anticoagulants.
3. Andexanet alfa is approved for patients taking apixaban or rivaroxaban who require reversal of anticoagulation due to life-threatening or uncontrolled bleeding.
   • If andexanet alfa is not available, the “2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants” recommends administration of prothrombin complex concentrate or activated prothrombin complex. It also recommends off-label use of andexanet alfa for reversal of edoxaban or betrixaban.
4. Andexanet alfa is a modified recombinant human factor Xa (FXa) decoy protein that binds and sequesters apixaban or rivaroxaban; it also binds and inhibits tissue factor pathway inhibitor. Elimination half-life is 5 to 7 hours.
5. In clinical trials, andexanet alfa decreased anti-FXa activity by 94% and 92% in patients on apixaban and rivaroxaban, respectively. It restored thrombin generation in 100% of patients within 2-5 minutes.
6. The indicated dosage of andexanet alfa depends on the FXa inhibitor, FXa inhibitor dosage, and time since last FXa inhibitor dose:
   • The low-dose regimen is 400 mg intravenously (at a target rate of 30 mg/min) followed by an infusion of 4 mg/min for up to 2 hours.
   • The high-dose regimen is 800 mg intravenously (at a target dose of 30 mg/min) followed by an infusion of 8 mg/min for up to 2 hours.
7. Anticoagulation should be resumed as soon as medically appropriate following andexanet alfa therapy.
8. Thromboembolic events, including ischemic events, cardiac events, and sudden death, have occurred during andexanet alfa treatment and within 30 days after treatment. Patients should be monitored for signs and symptoms of thromboembolic events. In clinical trials, the other most common adverse reactions included local infusion site reactions, urinary tract infections, and pneumonia.
9. Prior to hospital discharge, patients should be counseled regarding the risk of thromboembolic events. They should be instructed to call 911 if they develop acute symptoms suggestive of thromboembolic event, such as persistent cough, chest pain or pressure, lower stomach or pelvic pain, unilateral weakness or facial drooping, difficulty thinking or speaking, blurred vision, or blood in the sputum or urine. They should also be instructed to seek medical attention for other symptoms such as leg swelling, pain, warmth, erythema, dyspnea, pallor, or paresthesia.
10. Andexanet alfa has not been adequately studied in pregnant patients; no information is available regarding its presence in breast milk.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Lipid Metabolism, Novel Agents, Arrhythmias and Clinical EP, Pulmonary Hypertension and Venous Thromboembolism

Keywords: Factor Xa, Factor Xa Inhibitors, Thrombin, Anticoagulants, Prothrombin, United States Food and Drug Administration, Antithrombins

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