Reversing anticoagulant effects of novel oral anticoagulants: Role of ciraparantag, andexanetalfa, and idarucizumab

Vascular Health and Risk Management

Volumn 12, Issue , 2016, Pages 35-44

  Hu, Tiffany Y ^a   Vaidya, Vaibhav R ^b   Asirvatham, Samuel J ^b  

^a MAYO CLINIC COLLEGE OF MEDICINE   (United States)

^b MAYO CLINIC   (United States)

Author keywords

Dabigatran; Idarucizumab; Novel oral anticoagulant; Reversal

Indexed keywords

ANDEXANET ALFA; ANTICOAGULANT AGENT; APIXABAN; CIRAPARANTAG; DABIGATRAN; EDOXABAN; ENOXAPARIN; IDARUCIZUMAB; RIVAROXABAN; TRANEXAMIC ACID; ANTIDOTE; ARGININE; BLOOD CLOTTING FACTOR 10A; COAGULATING AGENT; MONOCLONAL ANTIBODY; PIPERAZINE DERIVATIVE; RECOMBINANT PROTEIN;

ANTICOAGULATION; BLEEDING; BLOOD CLOTTING TIME; DISEASE DURATION; DRUG ANTAGONISM; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG SAFETY; HUMAN; INTERNATIONAL NORMALIZED RATIO; NONHUMAN; PARTIAL THROMBOPLASTIN TIME; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; THROMBIN TIME; THROMBOCYTE AGGREGATION; THROMBOSIS PREVENTION; TIME TO TREATMENT; TREATMENT WITHDRAWAL; ANALOGS AND DERIVATIVES; ANIMAL; BLOOD CLOTTING; BLOOD CLOTTING TEST; CHEMICALLY INDUCED; DRUG EFFECTS; DRUG MONITORING; HEMORRHAGE; ORAL DRUG ADMINISTRATION; PROCEDURES;

ADMINISTRATION, ORAL; ANIMALS; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTICOAGULANTS; ANTIDOTES; ARGININE; BLOOD COAGULATION; BLOOD COAGULATION TESTS; COAGULANTS; DRUG MONITORING; FACTOR XA; HEMORRHAGE; HUMANS; PIPERAZINES; RECOMBINANT PROTEINS;

EID: 84958775567     PISSN: 11766344     EISSN: 11782048     Source Type: Journal    
DOI: 10.2147/VHRM.S89130     Document Type: Review

References (50)

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361(12):1139-1151.
2. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365(11):981-992.
3. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.
4. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e44S-e88S.
5. Fanola CL. Current and emerging strategies in the management of venous thromboembolism: benefit-risk assessment of dabigatran. Vasc Health Risk Manag. 2015;11:271-282.
6. Ment J. Direct oral anticoagulants: key considerations for use to prevent stroke in patients with nonvalvular atrial fibrillation. Vasc Health Risk Manag. 2015;11:317-332.
7. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22): 2093-2104.
8. Fuji T, Fujita S, Kawai Y, et al. Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V. Thromb J. 2015;13:27.
9. Fuji T, Wang CJ, Fujita S, et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. Thromb Res. 2014;134(6):1198-1204.
10. NICE. Edoxaban for Treating and Preventing Deep Vein Thrombosis and Pulmonary Embolism. London: National Institute for Health and Care Excellence. Available from: https://www.nice.org.uk/guidance/ta354. Accessed 2015.
11. Lixiana Edoxaban. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002629/human_med_001874.jsp&mid=WC0b01ac058001d124. Accessed October 24, 2015.
12. Chan NC, Bhagirath V, Eikelboom JW. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015;11:343-351.
13. Blann A. Nonvitamin K antagonist oral anticoagulants (NOACs): the tide continues to come in. Vasc Health Risk Manag. 2015;11:489-492.
14. 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.
15. Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450-2458.
16. Kakkos SK, Kirkilesis GI, Tsolakis IA. Editor's choice - efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg. 2014;48(5):565-575.
17. Weitz JI, Pollack CV Jr. Practical management of bleeding in patients receiving non-vitamin K antagonist oral anticoagulants. Thromb Haemost. 2015;114(5). Epub 2015 Jul 9.
18. Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol. 2015; 35:1736-1745.
19. Ebright J, Mousa SA. Oral anticoagulants and status of antidotes for the reversal of bleeding risk. Clin Appl Thromb Hemost. 2015; 21(2):105-114.
20. Wysokinski WE, McBane RD ii. Periprocedural bridging management of anticoagulation. Circulation. 2012;126(4):486-490.
21. Liotta EM, Levasseur-Franklin KE, Naidech AM. Reversal of the novel oral anticoagulants dabigatran, rivoraxaban, and apixaban. Curr Opin Crit Care. 2015;21(2):127-133.
22. Paikin JS, Hirsh J, Chan NC, Ginsberg JS, Weitz JI, Eikelboom JW. Timing the first post-operative dose of anticoagulants: lessons learned from clinical trials. Chest. 2015;148:587-595.
23. Schulman S, Carrier M, Lee AY, et al. Perioperative management of dabigatran: a prospective cohort study. Circulation. 2015; 132(3):167-173.
24. Pollack CV Jr. Coagulation assessment with the new generation of oral anticoagulants. Emerg Med J. Epub 2015 May 18.
25. Wang X, Mondal S, Wang J, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs. 2014;14(2):147-154.
26. van Ryn J, Sieger P, Kink-Eiband M, Gansser D, Clemens A. Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro. Blood. 2009;114(22):440-440.
27. Chai-Adisaksopha C, Hillis C, Lim W, Boonyawat K, Moffat K, Crowther M. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thromb Haemost. 2015;13:1790-1798.
28. Sarode R, Milling TJ Jr, 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.
29. Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6(4):622-631.
30. Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131(1):82-90.
31. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573-1579.
32. Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428-1436.
33. Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108(2):217-224.
34. Idarucizumab. Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm467396.htm. Accessed: November 2, 2015.
35. Boehringer Ingelheim's Investigational Antidote for Pradaxa33(dabigatran etexilate mesylate) receives FDA breakthrough therapy designation. Available from: http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2015/4-23-2015-fda-grants-priority-review-boehringer-ingelheims-biologics-license-application-idarucizumab.html. Accessed October 10, 2015.
36. Portola pharmaceuticals receives breakthrough therapy designation from FDA for andexanet alfa (PRT4445*), investigational factor Xa inhibitor antidote. Available from: http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle&ID=1879666. Accessed August 5, 2015.
37. Laulicht B, Bakhru S, Lee C, et al. Small molecule antidote for anticoagulants. Circulation. 2012;126:A11395.
38. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014; 371(22):2141-2142.
39. Perosphere and daiichi sankyo enter into a clinical trial collaboration agreement for phase 3 studies of PER977 to investigate reversal of the anticoagulant activity of the investigational factor Xa-inhibitor edoxaban. Available from: http://perosphere.com/content/media/documents/PerosphereandDaiichiSankyoEnterintoaClinicalTrialAgreementforPhase3.pdf. Accessed October 10, 2015.
40. Lu G, Kotha J, Cardenas JM, et al. In vitro characterization of andexanet alfa (PRT064445), a specific fXa inhibitor antidote versus aripazine (PER977), a non-specific reversal agent. Circulation. 2014;130: A18218.
41. 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(4):446-451.
42. Crowther M, Vandana M, Michael K, 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 (abstract). Blood. 2013;122(21):3636.
43. Crowther M, Levy G, Lu G, et al. ANNEXA-A: a phase 3 randomized, double-blind, placebo-controlled trial, demonstrating reversal of apixaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Circulation. 2014;130:2105-2126.
44. Crowther M, Gold A, Lu G, et al. ANNEXA (TM)-A PART 2: a phase 3 randomized, double-blind, placebo-controlled trial demonstrating sustained reversal of apixaban-induced anticoagulation in older subjects by andexanet ALFA (PRT064445), a universal antidote for factor XA (FXA) inhibitors. J Thromb Haemost. 2015;13:84-85.
45. Lu G, Lin J, Coffey G, Curnutte JT, Conley PB. Interaction of andexanet alfa, a universal antidote to fXA inhibitors, with tissue factor pathway inhibitor enhances reversal of fXA inhibitor-induced anticoagulation. J Thromb Haemost. 2015;13:634-635.
46. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013; 121(18):3554-3562.
47. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015;386:680-690.
48. Glund S, Moschetti V, Norris S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015;113(5):943-951.
49. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511-520.
50. Laulicht B, Bakhru S, Steiner S, et al. PER977 (ciraparantag) reverses edoxaban anticoagulation at steady state and has no effect on reanticoagulation at the next scheduled dose. Eur Heart J. 2015;36 (Abstract Supplement).