Andexanet alfa for the reversal of factor Xa inhibitor activity

New England Journal of Medicine

Volumn 373, Issue 25, 2015, Pages 2413-2424

  Siegal, Deborah M ^a   Curnutte, John T ^c   Connolly, Stuart J ^a,b   Lu, Genmin ^c   Conley, Pamela B ^c   Wiens, Brian L ^c   Mathur, Vandana S ^d   Castillo, Janice ^c   Bronson, Michele D ^c   Leeds, Janet M ^c   Mar, Florie A ^c   Gold, Alex ^c   Crowther, Mark A ^a  

^a ST JOSEPH S HOSPITAL   (Canada)

^b MCMASTER UNIVERSITY   (Canada)

^c Portola Pharmaceuticals   (United States)

^d Mathur Consulting   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANDEXANET ALFA; APIXABAN; BLOOD CLOTTING FACTOR 10A; D DIMER; PLACEBO; PROTHROMBIN; RIVAROXABAN; THROMBIN; ANTIDOTE; BLOOD CLOTTING FACTOR 10A INHIBITOR; PEPTIDE FRAGMENT; PROTEIN PRECURSOR; PROTHROMBIN FRAGMENT 1; PROTHROMBIN FRAGMENT 2; PYRAZOLE DERIVATIVE; PYRIDONE DERIVATIVE; RECOMBINANT PROTEIN;

ADULT; AGED; ANTICOAGULATION; ARTICLE; CONSTIPATION; CONTINUOUS INFUSION; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG SAFETY; DRUG WITHDRAWAL; DYSGEUSIA; ENZYME INHIBITION; FEMALE; HOT FLUSH; HUMAN; HUMAN EXPERIMENT; MALE; MULTICENTER STUDY; NORMAL HUMAN; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; THROMBOEMBOLISM; TREATMENT DURATION; TREATMENT OUTCOME; URTICARIA; BLOOD CLOTTING; CHEMICALLY INDUCED; DRUG EFFECTS; HEMORRHAGE; METABOLISM; MIDDLE AGED; ORAL DRUG ADMINISTRATION;

ADMINISTRATION, ORAL; AGED; ANTIDOTES; BLOOD COAGULATION; DOUBLE-BLIND METHOD; FACTOR XA; FACTOR XA INHIBITORS; FEMALE; HEMORRHAGE; HUMANS; MALE; MIDDLE AGED; PEPTIDE FRAGMENTS; PROTEIN PRECURSORS; PROTHROMBIN; PYRAZOLES; PYRIDONES; RECOMBINANT PROTEINS; RIVAROXABAN;

EID: 84950127054     PISSN: 00284793     EISSN: 15334406     Source Type: Journal    
DOI: 10.1056/NEJMoa1510991     Document Type: Article

References (26)

1. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-92.
2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-91.
3. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-104.
4. Bayer-Westendorf J. Rates, management and outcomes of bleeding complications during rivaroxaban therapy in daily care - results from the Dresden NOAC registry. Blood 2014; 124: 955-62.
5. Tamayo S, Frank Peacock W, Patel M, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: A pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol 2015; 38: 63-8.
6. 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: 1264-72.
7. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19: 446-51.
8. Crowther M, Lu G, Conley PB, et al. Reversal of factor Xa inhibitors-induced anticoagulation in healthy subjects by andexanet alfa. Crit Care Med 2014; 42(12): A1469.
9. Crowther MA, Levy G, Lu G, et al. A phase 2 randomized, double-blind, placebo- controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Presented at the 56th annual meeting of the American Society of Hematology, San Francisco, December 6-9, 2014 (https://ash.confex.com/ash/2014/webprogram/Paper73672.html).
10. Crowther MA, Mathur V, Kitt M, et al. A phase 2 randomized, double-blind, placebo- controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for Fxa inhibitors. Presented at the 55th annual meeting of the American Society of Hematology, New Orleans, December 7-10, 2013 (https://ash.confex.com/ash/2013/webprogram/Paper56863.html).
11. Crowther MA, Kittl E, Lorenz T, et al. A phase 2 randomized, double-blind, placebo- controlled trial of PRT064445, a novel, universal antidote for direct and indirect factor Xa inhibitors. J Thromb Haemost 2013; 11(Suppl2): OC 20.1.
12. Lu G, DeGuzman F, Hollenbach S, et al. Reversal of low molecular weight heparin and fondaparinux by a recombinant antidote (r-Antidote, PRT064445). Circulation 2010; 122: A12420.
13. Wilcoxin F. Probability tables for individual comparisons by ranking methods. Biometrics 1947; 3: 119-22.
14. Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple testing procedures. J Statist Plann Inference 2001; 99: 25-40.
15. Pernod G, Albaladejo P, Godier A, et al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the Working Group on Perioperative Haemostasis (GIHP)- March 2013. Arch Cardiovasc Dis 2013; 106: 382-93.
16. Rose M, Beasley B. Apixaban clinical review addendum. Silver Spring, MD: Center for Drug Evaluation and Research, 2012 (http://www.accessdata.fda.gov/drugsatfda-docs/nda/2012/202155Orig1s000MedR.pdf).
17. Beasley N, Dunnmon P, Rose M. Rivaroxaban clinical review: FDA draft briefing document for the Cardiovascular and Renal Drugs Advisory Committee, 2011 (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm270796.pdf).
18. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373: 511-20.
19. Hollenbach S, Lu G, Deguzman F, Curnutte J, Conley P, Sinha U. Bolus administration of PRT064445, a recombinant factor Xa inhibitor antidote, reverses blood loss and PD markers in a rat model following enoxaparin-induced anticoagulation. Presented at the European Society of Cardiology Congress, Munich, Germany, August 25-29, 2012.
20. Lu G, DeGuzman F, Lakhotia S, Hollenbach S, Phillips D, Sinha U. Recombinant antidote for reversal of anticoagulation by factor Xa inhibitors. Blood 2008; 112: 983.
21. Hollenbach S, Lu G, Tan S, et al. PRT064445 but not rfVIIa or PCC reverses rivaroxaban induced anticoagulation as measured by reduction in blood loss in a rabbit liver laceration model. Presented at the 54th annual meeting of the American Society of Hematology, Atlanta, December 8-11, 2012.
22. Pine P, Hollenbach S, Tan S, et al. Andexanet alfa reverses edoxaban-induced anticoagulation in a rabbit liver laceration model of acute bleeding. Presented at the European Society of Cardiology Congress, London, August 29-September 2, 2015.
23. Bytniewski P, Machała W, Romanowski L, Wisniewski W, Kosowski K. The dynamics of D-dimer level fluctuation in patients after the cemented and cementless total hip and total knee replacement. J Orthop Surg Res 2014; 9: 89.
24. Crowther MA, McDonald E, Johnston M, Cook D. Vitamin K deficiency and D-dimer levels in the intensive care unit: A prospective cohort study. Blood Coagul Fibrinolysis 2002; 13: 49-52.
25. Omote M, Asakura H, Takamichi S, et al. Changes in molecular markers of hemostatic and fibrinolytic activation under various sampling conditions using vacuum tube samples from healthy volunteers. Thromb Res 2008; 123: 390-5.
26. Chowdary P, Lethagen S, Friedrich U, et al. Safety and pharmacokinetics of anti- TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: A randomized first human dose trial. J Thromb Haemost 2015; 13: 743-54.