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Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity
Open accessAbstract
BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).
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“Andexanet alpha, a modified recombinant human factor Xa that lacks enzymatic activity, reverses the anticoagulant activity of apixaban and rivaroxaban in healthy probands within minutes after administration and for the duration of infusion, with a transient increase in markers of coagulation activity of uncertain clinical relevance.508”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [508]
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Metadata
- Authors
- Siegal, D. M., Curnutte, J. T., Connolly, S. J., Lu, G., Conley, P. B., Wiens, B. L., Mathur, V. S., Castillo, J., Bronson, M. D., Leeds, J. M., Mar, F. A., Gold, A., & Crowther, M. A.
- Affiliations
- Population Health Research Institute (CA)
- Portola Pharmaceuticals (United States) (US)
- McMaster University (CA)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2015-12-17
- Volume
- 373
- Issue
- 25
- Pages
- 2413-2424
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2174386486
- Cited by
- 1,047
- References
- 22
- Citations by year
- 2026: 21 · 2025: 34 · 2024: 48 · 2023: 56 · 2022: 44 · 2021: 57 · 2020: 91 · 2019: 126 · 2018: 133 · 2017: 175 · 2016: 249 · 2015: 11
- FWCI
- 137.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
- Keywords
- andexanet alfa, factor Xa inhibitors, apixaban, rivaroxaban, anticoagulant reversal, bleeding complications, anti-Xa activity, thrombin generation, unbound drug concentration, D-dimer, prothrombin fragments, older adults, drug safety, pharmacokinetics, pharmacodynamics, thromboprophylaxis, thrombolysis
- MeSH terms
- Rivaroxaban, Administration, Oral, Aged, Antidotes, Blood Coagulation, Double-Blind Method, Female, Hemorrhage, Humans, Male, Middle Aged, Peptide Fragments, Protein Precursors, Prothrombin, Pyrazoles, Pyridones, Recombinant Proteins, Factor Xa, Factor Xa Inhibitors
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