Management of Bleeding Associated with New Oral Anticoagulants

Seminars in Thrombosis and Hemostasis

Volumn 41, Issue 7, 2015, Pages 788-801

  Franchini, Massimo ^a   Bonfanti, Carlo ^a   Mannucci, Pier Mannuccio ^b  

^a CARLO POMA HOSPITAL   (Italy)

^b FONDAZIONE IRCCS CA GRANDA OSPEDALE MAGGIORE POLICLINICO   (Italy)

Author keywords

antidote; apixaban; bleeding; dabigatran; edoxaban; new oral anticoagulants; rivaroxaban

Indexed keywords

ACTIVATED CARBON; ACTIVATED PROTHROMBIN COMPLEX; ANDEXANET ALFA; ANTICOAGULANT AGENT; ANTIDOTE; APIXABAN; BLOOD CLOTTING FACTOR 8 INHIBITOR; CIRAPARANTAG; DABIGATRAN ETEXILATE; EDOXABAN; HEMOSTATIC AGENT; IDARUCIZUMAB; PROTHROMBIN COMPLEX; RECOMBINANT BLOOD CLOTTING FACTOR 7A; RIVAROXABAN; THROMBIN INHIBITOR; BLOOD CLOTTING FACTOR 10A INHIBITOR;

ATRIAL FIBRILLATION; BLEEDING; BRAIN HEMORRHAGE; CEREBROVASCULAR ACCIDENT; CONFERENCE PAPER; DRUG EFFECT; DRUG EFFICACY; DRUG SAFETY; GASTROINTESTINAL HEMORRHAGE; HEMODIALYSIS; HUMAN; MORTALITY; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); THROMBOEMBOLISM; VENOUS THROMBOEMBOLISM; ALGORITHM; CHEMICALLY INDUCED; HEMORRHAGE; ORAL DRUG ADMINISTRATION; PRACTICE GUIDELINE;

ADMINISTRATION, ORAL; ALGORITHMS; CLINICAL TRIALS, PHASE III AS TOPIC; FACTOR XA INHIBITORS; HEMORRHAGE; HUMANS; PRACTICE GUIDELINES AS TOPIC; THROMBOEMBOLISM;

EID: 84943601987     PISSN: 00946176     EISSN: 10989064     Source Type: Journal    
DOI: 10.1055/s-0035-1556046     Document Type: Conference Paper

References (142)

1. Kearon C., Akl E. A., Comerota A. J., et al. American College of Chest Physicians. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest: 2012; 141 (2, Suppl): e419S e494S
2. Goldhaber S. Z., Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet: 2012; 379 9828 1835 1846
3. Hart R. G., Pearce L. A., Aguilar M. I. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med: 2007; 146 12 857 867
4. Linkins L. A., Choi P. T., Douketis J. D. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med: 2003; 139 11 893 900
5. Fang M. C., Go A. S., Chang Y., et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med: 2007; 120 8 700 705
6. Franchini M., Mannucci P. M. A new era for anticoagulants. Eur J Intern Med: 2009; 20 6 562 568
7. Franchini M., Mannucci P. M. New anticoagulants for treatment of venous thromboembolism. Eur J Intern Med: 2012; 23 8 692 695
8. Ageno W., Gallus A. S., Wittkowsky A., Crowther M., Hylek E. M., Palareti G.; American College of Chest Physicians. 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
9. Weitz J. I., Eikelboom J. W., Samama M. M.; American College of Chest Physicians. New antithrombotic drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest: 2012; 141 (2, Suppl): e120S e151S
10. Beyer-Westendorf J., Ageno W. Benefit-risk profile of non-vitamin K antagonist oral anticoagulants in the management of venous thromboembolism. Thromb Haemost: 2015; 113 2 231 246
11. Verdecchia P., Angeli F., Bertolini C., et al. Safety and efficacy of nonvitamin K oral anticoagulants in nonvalvular atrial fibrillation: a Bayesan meta-analysis approach. Expert Opin Drug Saf: 2015; 14 1 7 20
12. Dzik W. S. Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion: 2012; 52 01 45S 55S
13. Miesbach W., Seifried E. New direct oral anticoagulants-current therapeutic options and treatment recommendations for bleeding complications. Thromb Haemost: 2012; 108 4 625 632
14. Nitzki-George D., Wozniak I., Caprini J. A. Current state of knowledge on oral anticoagulant reversal using procoagulant factors. Ann Pharmacother: 2013; 47 6 841 855
15. Siegal D. M., Garcia D. A., Crowther M. A. How I treat target-specific oral anticoagulant-associated bleeding. Blood: 2014; 123 8 1152 1158
16. PRADAXA. (dabigatran etexilate mesylate) capsules for oral use [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2013. Available at: http://bidocs.boehringeringelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf. Accessed on October 28, 2014.
17. Eisert W. G., Hauel N., Stangier J., Wienen W., Clemens A., van Ryn J. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol: 2010; 30 10 1885 1889
18. Stangier J., Rathgen K., Stähle H., Mazur D. 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 4 259 268
19. Eriksson B. I., Dahl O. E., Rosencher N., et al. RE-MODEL Study Group. 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 11 2178 2185
20. Eriksson B. I., Dahl O. E., Rosencher N., et al. RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet: 2007; 370 9591 949 956
21. Eriksson B. I., Dahl O. E., Huo M. H., et al. RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II∗). A randomised, double-blind, non-inferiority trial. Thromb Haemost: 2011; 105 4 721 729
22. Ginsberg J. S., Davidson B. L., Comp P. C., et al. 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 1 9
23. Friedman R. J., Dahl O. E., Rosencher N., et al. RE-MOBILIZE, RE-MODEL, RE-NOVATE Steering Committees. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res: 2010; 126 3 175 182
24. Schulman S., Kearon C., Kakkar A. K., et al. RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med: 2009; 361 24 2342 2352
25. Schulman S., Kakkar A. K., Goldhaber S. Z., et al. RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation: 2014; 129 7 764 772
26. Schulman S., Kearon C., Kakkar A. K., et al. RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med: 2013; 368 8 709 718
27. Schulman S., Eriksson H., Goldhaber S. Z., et al. Major bleeding events with dabigatran versus warfarin in patients with acute venous thromboembolism: a pooled analysis of RE-COVER and RE-COVER II. [abstract no. PC107] J Thromb Haemost: 2014; 12 01 62 63
28. Connolly S. J., Ezekowitz M. D., Yusuf S., et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med: 2009; 361 12 1139 1151
29. Connolly S. J., Wallentin L., Ezekowitz M. D., et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation: 2013; 128 3 237 243
30. Greig S. L., McKeage K. Dabigatran etexilate: a review of its use in the treatment of acute venous thromboembolism and prevention of venous thromboembolism recurrence. Drugs: 2014; 74 15 1785 1800
31. Camm A. J., Lip G. Y., De Caterina R., et al. ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J: 2012; 33 21 2719 2747
32. Raghavan N., Frost C. E., Yu Z., et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos: 2009; 37 1 74 81
33. Deeks E. D. Apixaban: a review of its use in the prevention of venous thromboembolism after knee or hip replacement surgery. Drugs: 2012; 72 9 1271 1291
34. Lassen M. R., Raskob G. E., Gallus A., Pineo G., Chen D., Portman R. J. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med: 2009; 361 6 594 604
35. Lassen M. R., Raskob G. E., Gallus A., Pineo G., Chen D., Hornick P.; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet: 2010; 375 9717 807 815
36. Lassen M. R., Gallus A., Raskob G. E., Pineo G., Chen D., Ramirez L. M.; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med: 2010; 363 26 2487 2498
37. Eriksson B. I., Quinlan D. J., Eikelboom J. W. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med: 2011; 62 41 57
38. Agnelli G., Buller H. R., Cohen A., et al. AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med: 2013; 369 9 799 808
39. Agnelli G., Buller H. R., Cohen A., et al. PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med: 2013; 368 8 699 708
40. Granger C. B., Alexander J. H., McMurray J. J., et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med: 2011; 365 11 981 992
41. Connolly S. J., Eikelboom J., Joyner C., et al. AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med: 2011; 364 9 806 817
42. Ogata K., Mendell-Harary J., Tachibana M., et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol: 2010; 50 7 743 753
43. Bounameaux H., Camm A. J. Edoxaban: an update on the new oral direct factor Xa inhibitor. Drugs: 2014; 74 11 1209 1231
44. Bauersachs R. Edoxaban: a new oral direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders. Clin Investig: 2014; 4 7 619 639
45. Fuji T., Wang C. J., 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
46. Fuji T., Wang C. J., Fujita S., Kawai Y., Kimura T., Tachibana S. Safety and efficacy of edoxaban, an oral factor xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan. J Arthroplasty: 2014; 29 12 2439 2446
47. Fuji T., Fujita S., Kawai Y., et al. Safety and efficacy of edoxaban in patients undergoing hip fracture surgery. Thromb Res: 2014; 133 6 1016 1022
48. Büller H. R., Décousus H., Grosso M. A., et al. Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med: 2013; 369 15 1406 1415
49. Giugliano R. P., Ruff C. T., Braunwald E., et al. ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med: 2013; 369 22 2093 2104
50. Perzborn E., Strassburger J., Wilmen A., et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939-an oral, direct Factor Xa inhibitor. J Thromb Haemost: 2005; 3 3 514 521
51. Eriksson B. I., Borris L. C., Friedman R. J., et al. RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med: 2008; 358 26 2765 2775
52. Kakkar A. K., Brenner B., Dahl O. E., et al. RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet: 2008; 372 9632 31 39
53. Lassen M. R., Ageno W., Borris L. C., et al. RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med: 2008; 358 26 2776 2786
54. Turpie A. G., Lassen M. R., Davidson B. L., et al. RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet: 2009; 373 9676 1673 1680
55. Turpie A. G., Lassen M. R., Eriksson B. I., et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost: 2011; 105 3 444 453
56. Bauersachs R., Berkowitz S. D., Brenner B., et al. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med: 2010; 363 26 2499 2510
57. Büller H. R., Prins M. H., Lensin A. W., et al. EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med: 2012; 366 14 1287 1297
58. Prins M. H., Lensing A. W., Bauersachs R., et al. EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J: 2013; 11 1 21
59. Patel M. R., Mahaffey K. W., Garg J., et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med: 2011; 365 10 883 891
60. Miller C. S., Grandi S. M., Shimony A., Filion K. B., Eisenberg M. J. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol: 2012; 110 3 453 460
61. Adam S. S., McDuffie J. R., Ortel T. L., Williams J. Jr.W. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med: 2012; 157 11 796 807
62. Dentali F., Riva N., Crowther M., Turpie A. G., Lip G. Y., Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation: 2012; 126 20 2381 2391
63. Kwong J. S., Lam Y. Y., Yan B. P., Yu C. M. Bleeding of new oral anticoagulants for stroke prevention in atrial fibrillation: a meta-analysis of randomized controlled trials. Cardiovasc Drugs Ther: 2013; 27 1 23 35
64. Ruff C. T., Giugliano R. P., 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
65. Castellucci L. A., Cameron C., Le Gal G., et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA: 2014; 312 11 1122 1135
66. Castellucci L. A., Cameron C., Le Gal G., et al. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ: 2013; 347 f5133
67. Fox B. D., Kahn S. R., Langleben D., Eisenberg M. J., Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ: 2012; 345 e7498
68. Kakkos S. K., Kirkilesis G. I., Tsolakis I. A. 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
69. van der Hulle T., Kooiman J., den Exter P. L., Dekkers O. M., Klok F. A., Huisman M. V. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost: 2014; 12 3 320 328
70. Castellucci L. A., Le Gal G., Rodger M. A., Carrier M. Major bleeding during secondary prevention of venous thromboembolism in patients who have completed anticoagulation: a systematic review and meta-analysis. J Thromb Haemost: 2014; 12 3 344 348
71. Nunes J. P., Rodrigues R. P., Gonçalves F. R. Comparative analysis and meta-analysis of major clinical trials with oral factor Xa inhibitors versus warfarin in atrial fibrillation. Open Heart: 2014; 1 1 e000080
72. 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
73. Tripodi A. The laboratory and the new oral anticoagulants. Clin Chem: 2013; 59 2 353 362
74. van Ryn J., Stangier J., Haertter S., et al. Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost: 2010; 103 6 1116 1127
75. Stangier J., Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis: 2012; 23 2 138 143
76. Barrett Y. C., 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 6 1263 1271
77. Mani H., Rohde G., Stratmann G., et al. Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. Thromb Haemost: 2012; 108 1 191 198
78. Samama M. M., Contant G., Spiro T. E., et al. Rivaroxaban Anti-Factor Xa Chromogenic Assay Field Trial Laboratories. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost: 2012; 107 2 379 387
79. Douxfils J., Tamigniau A., Chatelain B., et al. Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost: 2013; 110 4 723 731
80. Hillarp A., Baghaei F., Fagerberg Blixter I., et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost: 2011; 9 1 133 139
81. Samama M. M., Martinoli J. L., LeFlem L., et al. Assessment of laboratory assays to measure rivaroxaban-an oral, direct factor Xa inhibitor. Thromb Haemost: 2010; 103 4 815 825
82. Douxfils J., Chatelain C., Chatelain B., Dogné J. M., Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost: 2013; 110 2 283 294
83. Wong P. C., Crain E. J., Xin B., et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost: 2008; 6 5 820 829
84. Becker R. C., Yang H., Barrett Y., et al. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban-an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis: 2011; 32 2 183 187
85. Southworth M. R., Reichman M. E., Unger E. F. Dabigatran and postmarketing reports of bleeding. N Engl J Med: 2013; 368 14 1272 1274
86. U.S. Food and Drug Administration. FDA drug safety communication: update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) [media release]. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm. Accessed on February 2, 2012
87. European Medicines Agency. European Medicines Agency updates on safety of Pradaxa [media release]. Available at: http://www.ema.europa.eu/docs/en-GB/document-library/Press-release/2011/11/WC500117818.pdf. Accessed on November 18, 2011
88. Larsen T. B., Rasmussen L. H., Skjoth F., et al. Efficacy and safety of dabigatran etexilate and warfarin in real-world patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol: 2013; 61 22 2264 2273
89. Graham D. J., Reichman M. E., Wernecke M., et al. Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation: 2015; 131 2 157 164
90. Hernandez I., Baik S. H., Piñera A., Zhang Y. Risk of bleeding with Dabigatran in atrial fibrillation. JAMA Intern Med: 2015; 175 1 18 24
91. Beyer-Westendorf J., Förster K., Pannach S., et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood: 2014; 124 6 955 962
92. Beyer-Westendorf J., et al. Pattern and management of bleeding complications with new oral anticoagulants. Results of the prospective Dresden NOAC Registry (NCT01588119). J Thromb Haemost: 2013; 11 02 774 [Abstract]
93. Fenger-Eriksen C., Münster A. M., Grove E. L. New oral anticoagulants: clinical indications, monitoring and treatment of acute bleeding complications. Acta Anaesthesiol Scand: 2014; 58 6 651 659
94. Liew A., Eikelboom J. W., O'Donnell M., Hart R. G. Assessment of anticoagulation intensity and management of bleeding with old and new oral anticoagulants. Can J Cardiol: 2013; 29 (7, Suppl): S34 S44
95. Pollack C. Jr.V. Managing bleeding in anticoagulated patients in the emergency care setting. J Emerg Med: 2013; 45 3 467 477
96. Tran H., Joseph J., Young L., et al. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Intern Med J: 2014; 44 6 525 536
97. Siegal D. M., Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis: 2013; 35 3 391 398
98. Franchini M., Lippi G. Prothrombin complex concentrates: an update. Blood Transfus: 2010; 8 3 149 154
99. Dickneite G., Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost: 2014; 111 2 189 198
100. Zhou W., Schwarting S., Illanes S., et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke: 2011; 42 12 3594 3599
101. Pragst I., Zeitler S. H., Doerr B., et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost: 2012; 10 9 1841 1848
102. van Ryn J., Kink-Eiband M., Clemens A. The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood: 2011; 118 21 2316 (abstract)
103. Herzog E., Kaspereit F., Krege W., Van Ryn J. R., Dickneite G., Pragst I. Non-clinical safety and efficacy of prothrombin complex concentrates (PCC) for the reversal of dabigatran mediated anticoagulation. [abstract] J Thromb Haemost: 2013; 11 02 693
104. 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 1 94 102
105. Dinkelaar J., Molenaar P. J., Ninivaggi M., de Laat B., Brinkman H. J., Leyte A. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J Thromb Haemost: 2013; 11 6 1111 1118
106. Korber M. K., Langer E., Ziemer S., Perzborn E., Gericke C., Heymann Cv. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost: 2014; 20 7 735 740
107. Eerenberg E. S., Kamphuisen P. W., Sijpkens M. K., Meijers J. C., Buller H. R., 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
108. Escolar G., Fernandez-Gallego V., Arellano-Rodrigo E., et al. 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
109. Levi M., Moore T., Castillejos C., et al. Effects of three-factor and four-factor prothrombin complex concentrates on the pharmacodynamics of rivaroxaban. [abstract] J Thromb Haemost: 2013; 11 02 167
110. Brown K., Wickremasingha P., Parasrampuria D., Kochan J., Dishy V., Shi M. The impact of prothrombin complex concentrate on the coagulopathy effects of edoxaban. J Am Coll Cardiol: 2014; 63 12 A2095 (abstract)
111. Galan A. M., Arellano-Rodrigo E., Sanz V., et al. Effects of rivaroxaban and dabigatran on hemostasis and reversion of their antithrombotic effects by different coagulation factors: evidence raised from a clinical study in healthy volunteers. [abstract] J Thromb Haemost: 2013; 11 02 418
112. Arellano-Rodrigo E., Galan A. M., Sanz V., et al. Alterations induced by rivaroxaban on hemostasis can be reversed by different coagulation factor concentrates: in vitro experimental studies with steady and circulating human blood. [abstract] J Thromb Haemost: 2013; 11 02 953
113. Perzborn E., Gruber A., Tinel H., et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost: 2013; 110 1 162 172
114. Chan H. HW, Atkinson H. M., Goncharenko M., Berry L. R., Chan A. KC. Reversal of dabigatran using recombinant activated factor VII and activated prothrombin complex concentrates in thromboelastography assay. J Thromb Haemost: 2011; 9 02 576 577
115. Marlu R., Hodaj E., Paris A., Albaladejo P., Cracowski J. L., 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
116. Khoo T. LWC, Weatherburn C., Kershaw G., Reddel C. J., Curnow J., Dunkley S. The use of FEIBA® in the correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol: 2013; 35 2 222 224
117. Herrmann R., Thom J., Wood A., Phillips M., Muhammad S., Baker R. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost: 2014; 111 5 989 995
118. Lambourne M. D., Eltringham-Smith L. J., Gataiance S., Arnold D. M., Crowther M. A., Sheffield W. P. 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 9 1830 1840
119. 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 2 253 259
120. Lee F. MH, Chan A. KC, Lau K. K., Chan H. H. Reversal of new, factor-specific oral anticoagulants by rFVIIa, prothrombin complex concentrate and activated prothrombin complex concentrate: a review of animal and human studies. Thromb Res: 2014; 133 5 705 713
121. Ebright J., Mousa S. A. Oral anticoagulants and status of antidotes for the reversal of bleeding risk. Clin Appl Thromb Hemost: 2015; 21 2 105 114
122. Majeed A., Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol: 2013; 26 2 191 202
123. Lauw M. N., Coppens M., Eikelboom J. W. Recent advances in antidotes for direct oral anticoagulants: their arrival is imminent. Can J Cardiol: 2014; 30 4 381 384
124. Suryanarayan D., Schulman S. Potential antidotes for reversal of old and new oral anticoagulants. Thromb Res: 2014; 133 02 S158 S166
125. Lévy S. Newer clinically available antithrombotics and their antidotes. J Interv Card Electrophysiol: 2014; 40 3 269 275
126. Schiele F., van Ryn J., Canada K., et al. A specific antidote for dabigatran: functional and structural characterization. Blood: 2013; 121 18 3554 3562
127. Van Ryn J., Litzenburger T., Waterman A., et al. Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro and in vivo models. J Am Coll Cardiol: 2011; 57 14 E1130
128. van Ryn J., Litzenburger T., Gan G., Coble K., Schurer J. (2012) In vitro characterization, pharmacokinetics and reversal of supratherapeutic doses of dabigatran-induced bleeding in rats by a specific antibody fragment antidote to dabigatran. ASH Annual Meet Abstr 120 21 3418
129. Toth J., Gan G., van Ryn J., et al. (2012) Reversal of dabigatran's anticoagulant activity in the monkey by a specific antidote and pharmacokinetic and pharmacodynamic modeling. ASH Annual Meet Abstr 120 21 22
130. van Ryn J., Spronk H. M., Rossaint R., Grottke O. Ex vivo prothrombin complex concentrates and a specific antidote are effective in reversing dabigatran-induced coagulopathy in pigs. (abstract) Blood: 2013; 122 21 A2387
131. Glund S., Stangier J., Schmohl M., et al. A specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male volunteers. (abstract) Circulation: 2013; 128 22 A17765
132. Lu G., DeGuzman F. R., Hollenbach S. J., 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
133. Hollenbach S. J., Lu G., Tan S., et al. (2012) PRT064445 but not recombinant FVIIa reversesrivaroxaban induced anticoagulation as measured by reduction in blood loss in a rabbit liver laceration model. ASH Annual Meet Abstr 120 21 3414
134. Crowther M. A., Kitt M., McClure M., et al. Randomized, double-blind, placebo-controlled single ascending dose pharmacokinetic and pharmacodynamic study of PRT064445, a universal antidote for factor Xa inhibitors. (abstract) Arterioscler Thromb Vasc Biol: 2013; 33 5 A10
135. Crowther M. A., Kitt M., 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. (abstract) J Thromb Haemost: 2013; 11 02 AS20
136. Crowther M. A., 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. (abstract) Blood: 2013; 122 21 A3636
137. Laulicht B., Bakhru S., Lee C., et al. Small molecule antidote for anticoagulants. (abstract) Circulation: 2012; 126 21 10021
138. 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 02 AS47
139. Xarelto (rivaroxaban) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Available at: www.xareltohcp.com/sites/default/files/pdf/xarelto-0.pdf#zoom=100. Accessed on October 28, 2014.
140. Eliquis (apixaban) prescribing information. Princeton, NJ: Bristol-Myers Squibb Company. Available at: http://packageinserts.bms.com/pi/pi-eliquis.pdf. Accessed on October 28, 2014.
141. 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. 51st ASH Annual Meeting and Exposition. 2009 Abstract no. 1065.
142. Sipahi I., Celik S., Tozun N. A comparison of results of the US food and drug administration's mini-sentinel program with randomized clinical trials: the case of gastrointestinal tract bleeding with dabigatran. JAMA Intern Med: 2014; 174 1 150 151