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Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors: a review of design, development and potential place in therapy

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Abstract

Direct oral anticoagulants are associated with rates of major bleeding which are not negligible, albeit lower than those associated with vitamin K antagonists. No specific reversal agent for factor Xa (FXa) direct inhibitors is currently available for clinical use. A modified activated human FXa decoy protein, andexanet alfa, is being developed that binds FXa direct inhibitors in their active site, thus reversing their anticoagulant effect. The purpose of this article is to review the design, development and clinical trials of andexanet alfa. Andexanet alfa was shown to reverse FXa inhibitors anticoagulant activity both in thrombosis animal models, healthy volunteers and patients with acute major bleeding. Andexanet alfa has been studied in double-blind, placebo-controlled phase II and III studies. A preliminary report of the phase III study showed that an effective hemostasis was obtained after andexanet alfa infusion in the majority of the patients with acute major bleeding associated with FXa inhibitors. Additional studies are ongoing and andexanet alfa is expected to be launched in the market in the near future.

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References

  1. Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M (2015) Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 13(11):2012–2020

    Article  CAS  PubMed  Google Scholar 

  2. Weitz JI (2016) Factor XI and factor XII as targets for new anticoagulants. Thromb Res 141(Suppl 2):S40–S45

    Article  CAS  PubMed  Google Scholar 

  3. Sartori MT, Prandoni P (2016) How to effectively manage the event of bleeding complications when using anticoagulants. Expert Rev Hematol 9(1):37–50

    Article  CAS  PubMed  Google Scholar 

  4. Levy JH (2016) Discontinuation and management of direct-acting anticoagulants for emergency procedures. Am J Emerg Med 34(11S):14–18

    Article  PubMed  Google Scholar 

  5. Jones D (2015) Anticoagulant antidotes start yielding Phase III promise. Nat Rev Drug Discov 14:5–6

    Article  CAS  PubMed  Google Scholar 

  6. Quarterwatch. Annual report issue, June 29, 2016 —Data from 2015 Q4. http://ismp.org/QUARTERWATCH/pdfs/2015Q4.pdf

  7. Cohen D (2014) Concerns over data in key dabigatran trial. BMJ 349:g4747. https://doi.org/10.1136/bmj.g4747

    Article  PubMed  Google Scholar 

  8. Majeed A, Ågren A, Holmström M, Bruzelius M, Chaireti R, Odeberg J, Hempel EL, Magnusson M, Frisk T, Schulman S (2017) Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 130(15):1706–1712

    Article  PubMed  Google Scholar 

  9. https://www.imshealth.com/files/web/IMSH%20Institute/Reports/The%20Global%20Use%20of%20Medicines%20Outlook%20Through%202016/Medicines_Outlook_Through_2016_Report.pdf. Accessed 11 June 2017

  10. Sarich TC, Seltzer JH, Berkowitz SD, Costin’ J, Curnutte JT, Gibson CM, Hoffman M, Kaminskas E, Krucoff MW, Levy JH, Mintz PD, Reilly PA, Sager PT, Singer DE, Stockbridge N, Weitz JI, Kowey PR (2015) Novel oral anticoagulants and reversal agents: Considerations for clinical development. Am Heart J 169(6):751–757

    Article  CAS  PubMed  Google Scholar 

  11. Di Nisio M, Ageno W, Rutjes AW, Pap AF, Büller HR (2016) Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists. Thromb Haemost 115(2):424–432

    Article  PubMed  Google Scholar 

  12. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369(9):799–808

    Article  CAS  PubMed  Google Scholar 

  13. Lip GY, Pan X, Kamble S, Kawabata H, Mardekian J, Masseria C, Bruno A, Phatak H (2016) Major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin: a “real-world” observational study in the United States. Int J Clin Pract 70(9):752–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Beyer-Westendorf J, Förster K, Pannach S, Ebertz F, Gelbricht V, Thieme C, Michalski F, Köhler C, Werth S, Sahin K, Tittl L, Hänsel U, Weiss N (2014) Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 124(6):955–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Laliberté F, Cloutier M, Nelson WW, Coleman CI, Pilon D, Olson WH, Damaraju CV, Schein JR, Lefebvre P (2014) Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin 30(7):1317–1325

    Article  PubMed  Google Scholar 

  16. Wilke T, Bauer S, Mueller S, Kohlmann T, Bauersachs R (2017) Patient preferences for oral anticoagulation therapy in atrial fibrillation: a systematic literature review. Patient 10(1):17–37

    Article  PubMed  Google Scholar 

  17. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle&ID=2020507. Accessed 11 June 2017

  18. Greinacher A, Thiele T, Selleng K (2015) Reversal of anticoagulants: an overview of current developments. Thromb Haemost 113(5):931–942

    Article  PubMed  Google Scholar 

  19. Ghadimi K, Dombrowski KE, Levy JH, Welsby IJ (2016) Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Expert Rev Hematol 9(2):115–122

    Article  CAS  PubMed  Google Scholar 

  20. Yeh CH, Fredenburgh JC, Weitz JI (2013) The real decoy: an antidote for factor Xa-directed anticoagulants. Circ Res 113(8):954–957

    Article  CAS  PubMed  Google Scholar 

  21. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U (2013) A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 19(4):446–451

    Article  CAS  PubMed  Google Scholar 

  22. Lu G, Hollenbach SJ, Baker DC, Tan S, Hutchaleelaha A, Curnutte JT, Conley PB (2017) Preclinical safety and efficacy of andexanet alfa in animal models. J Thromb Haemost 15(9):1747–1756

    Article  CAS  PubMed  Google Scholar 

  23. Milling TJ Jr, Kaatz S (2016) Preclinical and clinical data for factor Xa and “universal” reversal agents. Am J Med 129(11S):S80–S88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Crowther MA, Kitt M, McClure M et al. (2013) Randomized double-blind, placebo controlled single ascending dose pharmacokinetik and pharmacodynamic study of PRT064445, a universal antidote for factor Xa inhibitors. Arterioscl Thromb Vasc Biol 33(5 Suppl.) (abstract)

  25. Crowther MA, Lu G, Conley P et al (2014) Sustained reversal of apixaban anticoagulation with andexanet alpha using a bolus plus infusion regimen in a phase II placebo controlled trial. Eur Heart J 35(Suppl.):137 (abstract)

    Google Scholar 

  26. Crowther MA, Mathur V, Kitt M et al (2013) A phase 2 randomized, double blind placebo controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alpha (PRT064445), an antidote for factor Xa inhibitors. ASH 2013; 55th ASH annual meeting, New Orleans (abstract)

  27. Crowther MA, Levy G, Lu G et al. (2014) 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. ASH 2014, 56th ASH annual meeting, San Francisco (abstract)

  28. Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA (2015) Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 373(25):2413–2424

    Article  CAS  PubMed  Google Scholar 

  29. Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M; ANNEXA-4 Investigators (2016) Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 375(12):1131–1141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Stöllberger C, Schneider B (2017) Concerns about andexanet. Blood Coagul Fibrinolysis 28:275

    Article  PubMed  Google Scholar 

  31. Heidbuchel H, Verhamme P, Alings M et al (2015) Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 17(10):1467–1507

    Article  PubMed  Google Scholar 

  32. Huisman MV, Fanikos J (2016) Idarucizumab and factor Xa reversal agents: role in hospital guidelines and protocols. Am J Med 129(11S):S89–S96. https://doi.org/10.1016/j.amjmed.2016.06.010

    Article  CAS  PubMed  Google Scholar 

  33. Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, Eikelboom JW, Florido R, Hucker W, Mehran R, Messé SR, Pollack CV Jr, Rodriguez F, Sarode R, Siegal D, Wiggins BS (2017) ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 70(24):3042–3067

    Article  PubMed  Google Scholar 

  34. Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN (2013) 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 128(11):1234–1243

    CAS  PubMed  Google Scholar 

  35. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M (2011) Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebocontrolled, crossover study in healthy subjects. Circulation 124(14):1573–1579

    Article  CAS  PubMed  Google Scholar 

  36. Zahir H, Brown KS, Vandell AG et al (2015) Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 131(1):82–90

    Article  CAS  PubMed  Google Scholar 

  37. Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI, Subcommittee on Control of Anticoagulation (2016) When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 14(3):623–627

    Article  CAS  PubMed  Google Scholar 

  38. Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI (2017) Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med 377(5):431–441

    Article  CAS  PubMed  Google Scholar 

  39. Shah N, Rattu MA (2014) Reversal agents for anticoagulants: focus on andexanet alfa. AMSRJ 1(1):16–28

    Article  Google Scholar 

  40. Wood JP, Ellery PER, Maroney SA, Mast AE (2014) Biology of tissue factor pathway inhibitor. Blood 123(19):2934–2943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI (2015) Idarucizumab for dabigatran revers. N Engl J Med 373(6):511–520

    Article  CAS  PubMed  Google Scholar 

  42. https://www.portola.com/clinical-development/andexanet-alfa-fxa-inhibitor-antidote/. Accessed 11 June 2017

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Authors and Affiliations

  1. Department of Angiology and Blood Coagulation, S. Orsola-Malpighi University Hospital, Pad. 2, via Albertoni, 15, 40138, Bologna, Italy

    Michelangelo Sartori & Benilde Cosmi

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  1. Michelangelo Sartori
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  2. Benilde Cosmi
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Correspondence to Michelangelo Sartori.

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Sartori, M., Cosmi, B. Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors: a review of design, development and potential place in therapy. J Thromb Thrombolysis 45, 345–352 (2018). https://doi.org/10.1007/s11239-018-1617-2

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