Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
- PMID: 27573206
- PMCID: PMC5568772
- DOI: 10.1056/NEJMoa1607887
Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
Abstract
Background: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.
Methods: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.
Results: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.
Conclusions: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).
Figures
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Comment in
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Anticoagulation therapy: Reversal of factor Xa activity.Nat Rev Cardiol. 2016 Nov;13(11):636. doi: 10.1038/nrcardio.2016.153. Epub 2016 Sep 15. Nat Rev Cardiol. 2016. PMID: 27629510 No abstract available.
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Engineering Reversal - Finding an Antidote for Direct Oral Anticoagulants.N Engl J Med. 2016 Sep 22;375(12):1185-6. doi: 10.1056/NEJMe1610510. N Engl J Med. 2016. PMID: 27653570 No abstract available.
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[Comment on: Andexanet alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.].Anaesthesist. 2016 Dec;65(12):940-942. doi: 10.1007/s00101-016-0240-x. Anaesthesist. 2016. PMID: 27778054 German. No abstract available.
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Andexanet Alfa for Factor Xa Inhibitor Reversal.N Engl J Med. 2016 Dec 22;375(25):2499-500. doi: 10.1056/NEJMc1613270. N Engl J Med. 2016. PMID: 28002711 No abstract available.
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Andexanet Alfa for Factor Xa Inhibitor Reversal.N Engl J Med. 2016 Dec 22;375(25):2498. doi: 10.1056/NEJMc1613270. N Engl J Med. 2016. PMID: 28009494 No abstract available.
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Andexanet Alfa for Factor Xa Inhibitor Reversal.N Engl J Med. 2016 Dec 22;375(25):2498-9. doi: 10.1056/NEJMc1613270. N Engl J Med. 2016. PMID: 28009495 No abstract available.
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Concerns about andexanet.Blood Coagul Fibrinolysis. 2017 Jun;28(4):275. doi: 10.1097/MBC.0000000000000624. Blood Coagul Fibrinolysis. 2017. PMID: 28177945 No abstract available.
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