Management of Bleeding Associated with New Oral Anticoagulants

Massimo Franchini; Carlo Bonfanti; Pier Mannuccio Mannucci

doi:10.1055/s-0035-1556046

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2015; 41(07): 788-801
DOI: 10.1055/s-0035-1556046

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Management of Bleeding Associated with New Oral Anticoagulants

Massimo Franchini

¹Department of Hematology and Transfusion Medicine, C. Poma Hospital, Mantova, Italy

,

Carlo Bonfanti

¹Department of Hematology and Transfusion Medicine, C. Poma Hospital, Mantova, Italy

,

Pier Mannuccio Mannucci

²IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan, Italy

› Institutsangaben

Abstract

In the last few years, a great improvement in the management of clinical thromboembolism has been made thanks to the availability of novel oral anticoagulants. These drugs, which act by directly inhibiting thrombin (dabigatran) or activated factor X (apixaban, rivaroxaban, and edoxaban), offer several practical advantages over the traditional vitamin K antagonists (VKA), such as a more predictable anticoagulant effect with no need for routine coagulation monitoring and a limited drug and food interaction. Several phase III clinical trials have now been completed, overall demonstrating that non-VKA oral antagonists (NOACs) are at least as efficacious and safe as VKA in the prevention and treatment of thromboembolism. Nevertheless, patients receiving NOACs represent a new challenge because no antidotes are currently available for these drugs. In this review, after a description of the main pharmacologic characteristics and the main results of the clinical trials of NOACs, we will focus on the management of bleeding associated with these anticoagulant agents. A treatment algorithm of NOACs-associated bleeding is finally provided, with the aim of helping physicians in their daily care activity.

Keywords

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

Volltext

Referenzen

References
1 Kearon C, Akl EA, Comerota AJ , 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 SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet 2012; 379 (9828) 1835-1846
3 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146 (12) 857-867
4 Linkins LA, Choi PT, Douketis JD. 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 MC, Go AS, 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 PM. A new era for anticoagulants. Eur J Intern Med 2009; 20 (6) 562-568
7 Franchini M, Mannucci PM. New anticoagulants for treatment of venous thromboembolism. Eur J Intern Med 2012; 23 (8) 692-695
8 Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, 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 JI, Eikelboom JW, Samama MM ; 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 WS. Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion 2012; 52 (Suppl. 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 JA. Current state of knowledge on oral anticoagulant reversal using procoagulant factors. Ann Pharmacother 2013; 47 (6) 841-855
15 Siegal DM, Garcia DA, Crowther MA. 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 WG, 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 BI, Dahl OE, 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 BI, Dahl OE, 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 BI, Dahl OE, Huo MH , 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 JS, Davidson BL, Comp PC , 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 RJ, Dahl OE, 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 AK , 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 AK, Goldhaber SZ , 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 AK , 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 SZ , 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 (Suppl. 01) 62-63
28 Connolly SJ, Ezekowitz MD, 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 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 (3) 237-243
30 Greig SL, 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 AJ, Lip GY, 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 CE, Yu Z , et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37 (1) 74-81
33 Deeks ED. 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 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 (6) 594-604
35 Lassen MR, Raskob GE, 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 MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM ; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363 (26) 2487-2498
37 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
38 Agnelli G, Buller HR, 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 HR, 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 CB, Alexander JH, McMurray JJ , 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 SJ, 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 AJ. 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 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
46 Fuji T, Wang CJ, 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 HR, Décousus H, Grosso MA , 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 RP, Ruff CT, 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 BI, Borris LC, Friedman RJ , et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358 (26) 2765-2775
52 Kakkar AK, Brenner B, Dahl OE , 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 MR, Ageno W, Borris LC , et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358 (26) 2776-2786
54 Turpie AG, Lassen MR, Davidson BL , 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 AG, 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 (3) 444-453
56 Bauersachs R, Berkowitz SD, Brenner B , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
57 Büller HR, Prins MH, Lensin AW , 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 MH, Lensing AW, 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 MR, Mahaffey KW, 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 CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. 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 SS, McDuffie JR, Ortel TL, Williams Jr JW. 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 AG, Lip GY, 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 JS, Lam YY, Yan BP, Yu CM. 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 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
65 Castellucci LA, 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 LA, 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 BD, Kahn SR, Langleben D, Eisenberg MJ, 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 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
69 van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. 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 LA, Le Gal G, Rodger MA, 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 JP, Rodrigues RP, Gonçalves FR. 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 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 (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 MM, Contant G, Spiro TE , 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 MM, Martinoli JL, 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 JM, Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013; 110 (2) 283-294
83 Wong PC, Crain EJ, 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 RC, 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 MR, Reichman ME, Unger EF. 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 TB, Rasmussen LH, Skjøth 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 DJ, Reichman ME, 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 SH, 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 (Suppl. 02) 774 [Abstract]
93 Fenger-Eriksen C, Münster AM, Grove EL. New oral anticoagulants: clinical indications, monitoring and treatment of acute bleeding complications. Acta Anaesthesiol Scand 2014; 58 (6) 651-659
94 Liew A, Eikelboom JW, O'Donnell M, Hart RG. 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 Jr CV. 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 DM, 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 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 (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 JR, 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 (Suppl. 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 PJ, Ninivaggi M, de Laat B, Brinkman HJ, 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 MK, 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 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
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 (Suppl. 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 AM, 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 (Suppl. 02) 418
112 Arellano-Rodrigo E, Galan AM, 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 (Suppl. 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 HHW, Atkinson HM, Goncharenko M, Berry LR, Chan AKC. Reversal of dabigatran using recombinant activated factor VII and activated prothrombin complex concentrates in thromboelastography assay. J Thromb Haemost 2011; 9 (Suppl. 02) 576-577
115 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
116 Khoo TLWC, Weatherburn C, Kershaw G, Reddel CJ, 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 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 (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 FMH, Chan AKC, Lau KK, Chan HH. 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 SA. 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 MN, Coppens M, Eikelboom JW. 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 (Suppl. 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 HM, 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 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
133 Hollenbach SJ, 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 MA, 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 MA, 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 (Suppl. 02) AS20
136 Crowther MA, 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 (Suppl. 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