New oral anticoagulants and their reversal

Current Drug Safety

Volumn 10, Issue 3, 2015, Pages 208-216

  Pinto, Ian ^a   Giri, Anshu ^a   Arshad, Umbreen ^a   Gajra, Ajeet ^a  

^a SUNY UPSTATE MEDICAL UNIVERSITY   (United States)

Author keywords

Apixaban; Dabigitran; New oral anticoagulants; Reversal agents; Reversal apixaban; Reversal dabigitran; Reversal of oral anticoagulants; Reversal rivaroxiban; Rivaroxiban; Target specific oral anticoagulants

Indexed keywords

ANTICOAGULANT AGENT; ANTIDOTE; ANTIVITAMIN K; APIXABAN; DABIGATRAN; PROTHROMBIN COMPLEX; RECOMBINANT BLOOD CLOTTING FACTOR 7A; RIVAROXABAN;

ARTICLE; BLEEDING; BLEEDING TIME; DRUG EFFICACY; ELECTIVE SURGERY; EMERGENCY SURGERY; HUMAN; NONHUMAN; PERIOPERATIVE PERIOD; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RENAL REPLACEMENT THERAPY; STANDARDIZATION; THROMBOEMBOLISM; ANIMAL; BLOOD; BLOOD CLOTTING; BLOOD CLOTTING TEST; BLOOD LOSS, SURGICAL; CHEMICALLY INDUCED; DRUG EFFECTS; EMERGENCY; HEMORRHAGE; ORAL DRUG ADMINISTRATION; PREDICTIVE VALUE; RISK FACTOR; TREATMENT OUTCOME;

ADMINISTRATION, ORAL; ANIMALS; ANTICOAGULANTS; ANTIDOTES; BLOOD COAGULATION; BLOOD COAGULATION TESTS; BLOOD LOSS, SURGICAL; ELECTIVE SURGICAL PROCEDURES; EMERGENCIES; HEMORRHAGE; HUMANS; PERIOPERATIVE CARE; PREDICTIVE VALUE OF TESTS; RISK FACTORS; TREATMENT OUTCOME;

EID: 84947795797     PISSN: 15748863     EISSN: None     Source Type: Journal    
DOI: 10.2174/1574886310666150416123530     Document Type: Article

References (62)

1. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47(5): 285-95.
2. Ahrens I. Development and clinical applications of novel oral anticoagulants. Part I. Clinically approved drugs. Discov Med 2012; 13(73): 433-43.
3. Ahrens I. Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Discov Med 2012; 13(73): 445-50.
4. Connolly SJ. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361(12): 1139-51.
5. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators: Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875-6.
6. Ezekowitz MD, Wallentin L, Connolly S, et al. Dabigatran and Warfarin in Vitamin K Antagonist-Naive and -Experienced Cohorts with Atrial Fibrillation. Circulation 2010; 122: 2246-53.
7. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm?source=go vdelivery&utm_medium=email&utm_source=govdeliver y.
8. Vaughan Sarrazin, Jones, Mazur, Chrischilles. Cram Bleeding rates in Veterans Affairs patients with atrial fibrillation who switch from warfarin to dabigatran. Am J Med 2014; 27(12):1179-85.
9. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554-62.
10. Laulicht B, Bakhru S, Jiang X, et al. Antidote for new oral anticoagulants: mechanism of action and binding specificity of PER977 [abstract]. J Thromb Haemost 2013; 11: AS47.1.
11. Van Ryn J. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrates. Haematologica 2008; 93: 148.
12. Van Ryn J. The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood 2011; 118(21): 1004.
13. Zhou W. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011; 42(12): 3594-9.
14. Pragst I. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012; 10(9): 1841-8.
15. van Ryn J. Reversal of Dabigatran-induced bleeding by coagulation factor concentrates in a rat-tail bleeding model and lack of effect on assays of coagulation. Anesthesiology 2014; 120(6): 1429-40
16. Grottke O. Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model. Crit Care 2014; 18(1): R27.
17. Marlu, R. 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): 217-24.
18. Eerenberg ES. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebocontrolled, crossover study in healthy subjects. Circulation 2011; 124(14): 1573-9.
19. Boehringer Ingelheim's Investigational antidote for Pradaxa (dabigatran etexilate mesylate) receives FDA breakthrough therapy designation. 2014. Available from http: //us.boehringeringelheim. com/news_events/press_releases/press_release_archive/ 2014/06- 26-14-boehringer-ingelheim-investigational-antidote-pra daxadabigatran- etexilate-mesylate-fda-breakthrough-therapy-des ignation.html.
20. Boehringer Ingelheim. Reversal of dabigatran anticoagulant effect with idarucizumab. ClinicalTrials.gov. Bethesda, MD: National Library of Medicine (US); 2000 Available from https: //clinicalt rials.gov/ct2/show/NCT02104947?term=nct02104947&rank=1NL M identifier: NCT02104947.
21. Laulicht B, Bakhru S, Lee C, et al. Small molecule antidote for anticoagulants [abstract]. Circulation 2012; 126: 10021.
22. Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct Factor Xa inhibitor. Nat Rev Drug Discov 2011; 10(1): 61-75.
23. Turpie AG. Rivaroxaban as an oral anticoagulant for stroke prevention in atrial fibrillation. Ther Clin Risk Manag 2014; 10: 197-205.
24. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005; 78(4): 412-21.
25. http: //www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zo om=100.
26. Kubitza D, Becka M, Roth A, Mueck W. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008; 24(10): 2757- 65.
27. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet 2009, 48(1): 1-22.
28. Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa Inhibitor. Br J Clin Pharmacol 2010; 70: 703-12.
29. Cohen AT, Spiro TE, Buller HR, et al. MAGELLAN Investigators: Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368(6): 513-23.
30. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358(26): 2765-75.
31. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a doubleblind, randomised controlled trial. Lancet 2008, 372(9632): 31-39.
32. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.N Engl J Med 2008, 358(26): 2776-86.
33. Turpie AG, Lassen MR, Davidson BL et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomisedtrial. Lancet 2009; 373(9676): 1673-80.
34. Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011; 32(19): 2387-94.
35. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366(1): 9-19.
36. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 11(26): 2499-510.
37. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 11(14): 1287-97.
38. Weinz C, Buetehom U, Daehler HP, et al. Pharmacokinetics of BAY 59-7939 - an oral, direct factor Xa inhibitor - in rats and dogs. Xenobiotica 2005; 35(9): 891-910.
39. Godier A, Miclot A, Le Bonniec B, et al. Evaluation of the prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesia 2012; 116: 94-102.
40. Perzborn E, Gruber A, Tinel H, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Throm and Haem 2013; 110(1): 162-72.
41. Dinkelaar J, Molenaar PJ, Ninivaggi M, et al. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J Thromb Haemost 2013; 11: 1111-8.
42. 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; 4: 446-51.
43. Crowther M, 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 American Society of Hematology Annual Meeting, New Orleans, LA, December 9, 2013.
44. Portola Pharmaceuticals. Portola Pharmaceuticals begins enrollment in phase 3 study of FDA-designated breakthrough therapy andexanet alf and factor Xa inhibitor XARELTO(R). 2014. Available from http: //investors.portola.com/phoenix.zhtml?c=1981 36&p=irol-newsroomArticle&ID=19 29823.
45. Granger CB. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365(11): 981-92.
46. Nutescu E. Apixaban: a novel oral inhibitor of factor Xa. Am J Health Syst Pharm 2012; 69(13): 1113-26.
47. Heidbuchel H, VP, Alings M, Antz M, Hacke W, Oldgren J. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094-106.
48. Cui Y, SY, Wang J, Yu Z, et al. Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects. Clin Pharmacol 2014; 6: 61.
49. Escolar G. Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood. PLoS One 2013; 8(11): e78696.
50. Martin, AC. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol 2013; 168(4): 4228-33.
51. Kaatz S. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87(Suppl 1): p. S141-5.
52. Crowther M, Kitt M, Lorenz T, et al. A phase 2 randomized, double-blind, placebo-controlled trial of PRT4445, a novel, universal antidote for direct and indirect factor Xa inhibitors. Presented at International Society on Thrombosis and Haemostasis Congress, Amsterdam, the Netherlands, July 2, 2013.
53. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094-106.
54. Sie P, Samama CM, Godier A. et al. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis 2011; 104: 669-76.
55. Product Information PRADEXAR Oral Tablets, Dabigatran Oral Tablets. http: //bidocs.boehringeringelheim.com/BIWebAccess/Vie wServlet.ser?doc Base=renetnt&folderPath=/Prescribing%20Infor mation/PIs/Pradaxa/Pradaxa.pdf.
56. Warkentin TE, Margetts P, Connolly SJ, et al. Eikelboom JWRecombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012; 119(9): 2172.
57. Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 2012; 46(9): e21.
58. Khadzhynov D, Wagner F, Formella S, et al. AEffective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013; 109(4): 596.
59. Liesenfeld. Pharmacometric characterization of dabigatran hemodialysis. Clin Pharmacokinet 2013; 52(6): 453-62.
60. Stangier J. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49(4): 259-68.
61. Singh T. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol 2013; 8(9): 1533-9.
62. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergentreversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87(Suppl 1): S141-S145.