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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(06): 998-1005
DOI: 10.1055/s-0041-1740180
New Technologies, Diagnostic Tools and Drugs

Andexanet Alfa for Specific Anticoagulation Reversal in Patients with Acute Bleeding during Treatment with Edoxaban

Alexander P. Benz 
1   Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Lizhen Xu
1   Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
,
John W. Eikelboom
1   Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Saskia Middeldorp
2   Department of Internal Medicine & Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands
,
Truman J. Milling Jr.
3   Departments of Neurology and Surgery and Perioperative Care, Seton Dell Medical School Stroke Institute, Dell Medical School, University of Texas at Austin, Austin, Texas, United States
,
Mark Crowther
4   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Patrick Yue
5   Portola Pharmaceuticals Inc., now Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, United States
,
Pamela Conley
5   Portola Pharmaceuticals Inc., now Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, United States
,
Genmin Lu
5   Portola Pharmaceuticals Inc., now Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, United States
,
Stuart J. Connolly
1   Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
,
on behalf of the ANNEXA-4 Investigators › Author Affiliations Funding ANNEXA-4 was funded by Portola Pharmaceuticals Inc., South San Francisco, California, United States, now Alexion, AstraZeneca Rare Disease, Boston, Massachusetts, United States, following acquisition by Alexion.
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Abstract

Background Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban.

Methods Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients.

Results Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population (n = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3–202.4) ng/mL at baseline to 24.0 (IQR: 77.7–83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1–77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0–91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died.

Conclusion In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.

Keywords

andexanet alfa - reversal - edoxaban - intracranial hemorrhage - bleeding

Supplementary Material



Publication History

Received: 28 April 2021

Accepted: 10 October 2021

Article published online:
07 January 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Held C, Hylek EM, Alexander JH. et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J 2015; 36 (20) 1264-1272
    CrossrefPubMedGoogle Scholar
  • 2 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383 (9921): 955-962
    Google Scholar
  • 3 Steiner T, Weitz JI, Veltkamp R. Anticoagulant-associated intracranial hemorrhage in the era of reversal agents. Stroke 2017; 48 (05) 1432-1437
    CrossrefPubMedGoogle Scholar
  • 4 Siegal DM, Curnutte JT, Connolly SJ. et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373 (25) 2413-2424
    CrossrefPubMedGoogle Scholar
  • 5 Connolly SJ, Crowther M, Eikelboom JW. et al; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380 (14) 1326-1335
    CrossrefPubMedGoogle Scholar
  • 6 Giugliano RP, Ruff CT, Braunwald E. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
    Google Scholar
  • 7 Büller HR, Décousus H, Grosso MA. et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
    CrossrefPubMedGoogle Scholar
  • 8 Weitz JI, Connolly SJ, Patel I. et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010; 104 (03) 633-641
    PubMedGoogle Scholar
  • 9 Salazar DE, Mendell J, Kastrissios H. et al. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. Thromb Haemost 2012; 107 (05) 925-936
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Ruff CT, Giugliano RP, Braunwald E. et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015; 385 (9984): 2288-2295
    CrossrefPubMedGoogle Scholar
  • 11 Yin OQP, Antman EM, Braunwald E. et al. Linking endogenous factor Xa activity, a biologically relevant pharmacodynamic marker, to edoxaban plasma concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. Circulation 2018; 138 (18) 1963-1973
    CrossrefPubMedGoogle Scholar
  • 12 Aisenberg J, Chatterjee-Murphy P, Friedman Flack K. et al. Gastrointestinal bleeding with edoxaban versus warfarin: results from the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction). Circ Cardiovasc Qual Outcomes 2018; 11 (05) e003998
    CrossrefPubMedGoogle Scholar
  • 13 Connolly SJ, Milling Jr TJ, Eikelboom JW. et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375 (12) 1131-1141
    CrossrefPubMedGoogle Scholar
  • 14 Milling Jr TJ, Connolly SJ, Conley PB. Andexanet alfa for bleeding with factor Xa inhibitors. Reply. N Engl J Med 2019; 381 (02) 192-193
    PubMedGoogle Scholar
  • 15 Sarode R, Milling Jr TJ, Refaai MA. et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128 (11) 1234-1243
    CrossrefPubMedGoogle Scholar
  • 16 Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 1934; 26 (04) 404-413
    CrossrefPubMedGoogle Scholar
  • 17 Pollack Jr CV, Reilly PA, van Ryn J. et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377 (05) 431-441
    CrossrefPubMedGoogle Scholar
  • 18 Nelson SE, Giugliano RP, Antman EM. et al; ENGAGE AF-TIMI 48 Steering Committee and Investigators. Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation with warfarin or edoxaban: An in-depth analysis from the ENGAGE AF-TIMI 48 randomized trial. J Clin Neurosci 2021; 86: 294-300
    CrossrefPubMedGoogle Scholar
  • 19 Lu G, Conley PB, Leeds JM. et al. A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers. Blood Adv 2020; 4 (04) 728-739
    CrossrefPubMedGoogle Scholar