Direct oral anticoagulants: New drugs and new concepts

JACC: Cardiovascular Interventions

Volumn 7, Issue 12, 2014, Pages 1333-1351

  Levy, Jerrold H ^a   Spyropoulos, Alex C ^b   Samama, Charles M ^c   Douketis, James ^d  

^a DUKE UNIVERSITY   (United States)

^b DONALD AND BARBARA ZUCKER SCHOOL OF MEDICINE AT HOFSTRA NORTHWELL   (United States)

^c Institut Cochin   (France)

^d MCMASTER UNIVERSITY   (Canada)

Author keywords

Apixaban; Bleeding; Dabigatran; Direct oral anticoagulant; Edoxaban; Management; Pharmacology; Rivaroxaban

Indexed keywords

ANTICOAGULANT AGENT; APIXABAN; DABIGATRAN; DIRECT ORAL ANTICOAGULANT; EDOXABAN; ENOXAPARIN; FIBRINOGEN CONCENTRATE; RIVAROXABAN; UNCLASSIFIED DRUG;

ANTICOAGULANT THERAPY; BLEEDING; BLEEDING TENDENCY; BLOOD TRANSFUSION; CHILD PUGH SCORE; COMPARATIVE EFFECTIVENESS; CRYOPRECIPITATE; DEEP VEIN THROMBOSIS; DRUG CLEARANCE; DRUG EFFICACY; DRUG SAFETY; DRUG SUBSTITUTION; DRUG WITHDRAWAL; FLUID RESUSCITATION; GASTROINTESTINAL HEMORRHAGE; HIGH RISK PATIENT; HUMAN; KNEE ARTHROPLASTY; LIVER DYSFUNCTION; MODERATE RENAL IMPAIRMENT; PATIENT MONITORING; PHASE 3 CLINICAL TRIAL (TOPIC); POSTOPERATIVE THROMBOSIS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REDUCTION; REVIEW; RISK BENEFIT ANALYSIS; RISK FACTOR; THROMBOSIS PREVENTION; TREATMENT OUTCOME; ANIMAL; BLOOD; BLOOD CLOTTING; BLOOD CLOTTING TEST; CHEMICALLY INDUCED; DRUG EFFECTS; DRUG MONITORING; HEMORRHAGE; ORAL DRUG ADMINISTRATION; PREDICTIVE VALUE; PROCEDURES; RISK ASSESSMENT; THROMBOEMBOLISM;

ADMINISTRATION, ORAL; ANIMALS; ANTICOAGULANTS; BLOOD COAGULATION; BLOOD COAGULATION TESTS; DRUG MONITORING; DRUG SUBSTITUTION; HEMORRHAGE; HUMANS; PREDICTIVE VALUE OF TESTS; RISK ASSESSMENT; RISK FACTORS; THROMBOEMBOLISM; TREATMENT OUTCOME;

EID: 84922548691     PISSN: 19368798     EISSN: 18767605     Source Type: Journal    
DOI: 10.1016/j.jcin.2014.06.014     Document Type: Review

References (87)

1. Bristol-Myers Squibb, Pfizer EEIG. Eliquis (apixaban) Summary of Product Characteristics. 2014. Available at: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product- Information/human/002148/WC500107728.pdf. Accessed November 17, 2014.
2. Bristol-Myers Squibb Company, Pfizer Inc. Eliquis (apixaban) Prescribing Information. 2014. Available at: http://packageinserts.bms.com/pi/pi-eliquis.pdf. Accessed November 17, 2014.
3. Bayer Pharma AG. Xarelto (rivaroxaban) Summary of Product Characteristics. 2014. Available at: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/000944/WC500057108.pdf. Accessed November 17, 2014.
4. Janssen Pharmaceuticals Inc. Xarelto (rivaroxaban) Prescribing Information. 2014. Available at: http://www.xareltohcp.com/sites/default/files/pdf/xarelto-0.pdf.. Accessed November 17, 2014.
5. Boehringer Ingelheim International GmbH. Pradaxa (dabigatran etexilate) Summary of Product Characteristics. 2014. Available at: http://www.ema.europa.eu/docs/en-GB/document- library/EPAR-Product-Information/human/000829/WC500041059.pdf. Accessed November 17, 2014.
6. Boehringer Ingelheim Pharmaceuticals Inc. Pradaxa (dabigatran etexilate) Prescribing Information. 2014. Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing Information/PIs/Pradaxa/Pradaxa.pdf. Accessed November 17, 2014.
7. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
8. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369:1406-15.
9. Eikelboom JW, Weitz JI. New anticoagulants. Circulation 2010;121:1523-32.
10. Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology 2013;118:1466-74.
11. Samama MM, Guinet C. Laboratory assessment of new anticoagulants. Clin Chem Lab Med 2011; 49:761-72.
12. Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev 2007;21: 37-48.
13. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidencebased clinical practice guidelines. Chest 2012;141: e419S-94S.
14. Bristol-Myers Squibb Canada Inc., Pfizer Canada Inc. Eliquis (apixaban) Product Monograph. 2014. Available at: http://www.bmscanada.ca/static/products/en/pm-pdf/ELIQUIS-EN-PM. pdf. Accessed November 17, 2014.
15. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009;361:594-604.
16. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375:807-15.
17. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363: 2487-98.
18. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369: 799-808.
19. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708.
20. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.
21. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
22. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699-708.
23. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-75.
24. 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; 372:31-9.
25. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358:2776-86.
26. Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009;373:1673-80.
27. Eriksson BI, Kakkar AK, Turpie AGG, et al. Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg Br 2009;91: 636-44.
28. Turpie AGG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105:444-53.
29. Lassen MR, Gent M, Kakkar AK, et al. The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme. J Bone Joint Surg Br 2012;94:1573-8.
30. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510.
31. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
32. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
33. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19.
34. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007;370:949-56.
35. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, noninferiority trial. Thromb Haemost 2011;105:721-9.
36. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5: 2178-85.
37. The RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009;24:1-9.
38. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52.
39. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764-72.
40. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368:709-18.
41. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
42. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation 2013;128: 237-43.
43. Schulman S, Beyth RJ, Kearon C, Levine MN, American College of Chest Physicians. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:257S-98S.
44. Dale B, Eikelboom JW, Weitz JI, et al. Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction? J Thromb Thrombolysis 2013;35:295-301.
45. Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral Factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med 2011;62:41-57.
46. Bristol-Myers Squibb. Coumadin (warfarin sodium) Prescribing Information. 2011. Available at: http://packageinserts.bms.com/pi/pi-coumadin.pdf. Accessed May 15, 2014.
47. Troconiz IF, Tillmann C, Liesenfeld KH, Schafer HG, Stangier J. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery. J Clin Pharmacol 2007;47:371-82.
48. Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and excretion of rivaroxaban, an oral, direct Factor Xa inhibitor, in rats, dogs and humans. Drug Metab Dispos 2009;37:1056-64.
49. Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013;76: 455-66.
50. Zhang D, He K, Raghavan N, et al. Comparative metabolism of 14C-labeled apixaban in mice, rats, rabbits, dogs, and humans. Drug Metab Dispos 2009;37:1738-48.
51. Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, singlecentre study. Clin Pharmacokinet 2010;49: 259-68.
52. Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-51.
53. Stangier J, Stahle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol 2008;48: 1411-9.
54. Kubitza D, Roth A, Becka M, et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban - an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2013;76:89-98.
55. Graff J, Harder S. Anticoagulant therapy with the oral direct Factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment. Clin Pharmacokinet 2013;52:243-54.
56. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct Factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 2006;46: 549-58.
57. Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther 2013;51:549-61.
58. Mendell J, Tachibana M, Shi M, Kunitada S. Effects of food on the pharmacokinetics of edoxaban, an oral direct Factor Xa inhibitor, in healthy volunteers. J Clin Pharmacol 2011;51:687-94.
59. Turpie AGG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxaban - an oral, direct Factor Xa inhibitor. Thromb Haemost 2012;108:876-86.
60. Lindhoff-Last E, Ansell J, Spiro T, Samama MM. Laboratory testing of rivaroxaban in routine clinical practice: when, how, and which assays. Ann Med 2013;45:423-9.
61. Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct Factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010;104: 1263-71.
62. van Ryn J, Baruch L, Clemens A. Interpretation of point-of-care INR results in patients treated with dabigatran. Am J Med 2012;125:417-20.
63. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012;23:138-43.
64. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007;64:292-303.
65. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012;120:2954-62.
66. Gogarten W, Vandermeulen E, Van Aken H, Kozek S, Llau JV, Samama CM. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol 2010;27:999-1015.
67. Sié 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.
68. Heidbuchel H, Verhamme P, Alings M, et al. 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.
69. Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of longterm anticoagulation therapy (RE-LY) randomized trial. Circulation 2012;126:343-8.
70. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from ROCKET AF. Circulation 2014;129:1850-9.
71. Weinz C, Buetehorn U, Daehler HP, et al. Pharmacokinetics of BAY 59-7939 - an oral, direct Factor Xa inhibitor - in rats and dogs. Xenobiotica 2005;35:891-910.
72. Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013; 109:596-605.
73. Pragst I, Zeitler SH, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012;10: 1841-8.
74. Godier A, Miclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012; 116:94-102.
75. Lambourne MD, Eltringham-Smith LJ, Gataiance S, Arnold DM, Crowther MA, Sheffield WP. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost 2012;10: 1830-40.
76. Perzborn E, Gruber A, Tinel H, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost 2013;110:162-72.
77. Martin AC, Le Bonniec B, Fischer AM, et al. 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; 168:4228-33.
78. Zhou W, Zorn M, Nawroth P, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke 2013;44: 771-8.
79. 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;124:1573-9.
80. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski 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;108:217-24.
81. Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost 2012;107: 253-9.
82. Körber MK, Langer E, Ziemer S, Perzborn E, Gericke C, von Heymann C. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost 2014;20:735-40.
83. Khoo TL, Weatherburn C, Kershaw G, Reddel CJ, Curnow J, Dunkley S. The use of FEIBA(R) in the correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol 2013;35:222-4.
84. Levi M, Moore K, Castillejos C, et al. Comparison of three- and four-factor prothrombin complex concentrates on the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost 2014;12: 1428-36.
85. 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.
86. 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.
87. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121: 3554-62.