新型口服抗凝剂出血并发症的治疗_West China Medical Journal

Authors：

岑志富 ¹ , 陈玉华 ² ,  崔凯军 ¹

1. ;
2. ;

Corresponding author：

崔凯军, Email: cuikaijun@hotmail.com

Keywords：

出血; 华法林; 新型口服抗凝剂

DOI：

10.7507/1002-0179.201508124

Video：

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近年来，新型口服抗凝剂（new oral anticoagulants，NOAC）已经逐渐成为替代华法林用于血栓栓塞性疾病的预防和治疗药物。目前经过Ⅲ期临床试验验证的 NOAC 主要包括：直接凝血酶抑制剂（达比加群）和 Xa 因子抑制剂（利伐沙班、阿哌沙班、依度沙班）。NOAC 抗凝效能比华法林强，而出血、与食品和药物相互作用的几率较低。此外，NOAC 具有更可预测的抗凝作用，剂量固定，不需常规的抗凝活性监测。自 NOAC 投入使用以来，在缺乏特异性拮抗剂逆转抗凝的情况下遭遇危及生命的出血性并发症或急诊手术已经成为临床医生关注的主要问题，该类药在有较高的出血风险的患者中使用有一定的限制。新的特异性抗体（如：Idarucizumab、Andexanetα、Ciraparantag）试验结果数据喜人，并可能很快投入临床使用。该文回顾分析了解 NOAC 的药物代谢动力学、出血性并发症的发生率及预后、逆转抗凝的方法以及特异拮抗剂的最新进展。

Citation： 岑志富, 陈玉华, 崔凯军. 新型口服抗凝剂出血并发症的治疗. West China Medical Journal, 2017, 32(6): 931-935. doi: 10.7507/1002-0179.201508124 Copy

1.	Investigators AF. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med, 1994, 154(13): 1449-1457.
2.	van der Meer FJ, Rosendaal FR, Vandenbroucke JP, et al. Bleeding complications in oral anticoagulation therapy. Arch Intern Med, 1993, 153(13): 1557-1562.
3.	Jackson SL, Peterson GM, Vial JH, et al. Outcomes in the management of atrial fibrillation: clinical trial results can apply in practice. Intern Med J, 2001, 31(6): 329-336.
4.	Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation, 2007, 115(21): 2689-2696.
5.	Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med, 1994, 120(11): 897-902.
6.	Garcia DA, Crowther MA. Reversal of warfarin: case-based practice recommendations. Circulation, 2012, 125(23): 2944-2947.
7.	Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of 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): e152S-e184S.
8.	Dowlatshahi D, Butcher KS, Asdaghi N, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke, 2012, 43(7): 1812-1817.
9.	Zubkov AY, Mandrekar JN, Claassen DO, et al. Predictors of outcome in warfarin-related intracerebral hemorrhage. Arch Neurol, 2008, 65(10): 1320-1325.
10.	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.
11.	Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med, 2009, 361(12): 1139-1151.
12.	Hart RG, Diener HC, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke, 2012, 43(6): 1511-1517.
13.	Dentali F, Riva N, Crowther M, et al. 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.
14.	Chatterjee S, Sardar P, Biondi-Zoccai G, et al. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and bayesian meta-analysis andmixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol, 2013, 70(12): 1486-1490.
15.	Camm AJ, Lip GY, De Caterina R, et al. 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. Europace, 2012, 14: 1385-1413. http://www.escardio.org/The-ESC/Governance/ESC-Committees/Board-Committees/Committee-for-Practice-Guidelines-CPG.
16.	Vı́lchez JA, Gallego P, Lip GY. Safety of new oral anticoagulant drugs: a perspective. Ther Adv Drug Saf, 2014, 5(1): 8-20.
17.	Huisman MV, Lip GY, Diener HC, et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost, 2012, 107(5): 838-847.
18.	Suryanarayan D, Schulman S. Potential antidotes for reversal of old and new oral anticoagulants. Thromb Res, 2014, 133(Suppl 2): S158-S166.
19.	Stangier J, Rathgen K, Stähle H, et al. 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.
20.	Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation, 2011, 124(14): 1573-1579.
21.	Schiele F, Van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood, 2013, 121(18): 3554-3562.
22.	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: A17765.
23.	Laulicht B, Bakhru S, Lee C, et al. Small molecule antidote for anticoagulants (abstract). Circulation, 2012, 126: 10021.
24.	Van Ryn J, Baruch L, Clemens A. Interpretation of point-of-care INR results in patients treated with dabigatran. Am J Med, 2012, 125(4): 417-420.
25.	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.
26.	Roehrig S, Straub A, Pohlmann J, et al. Discovery of the novel antithrombotic agent 5-chloro-N-((5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1, 3-oxazolidin-5-ylmethyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem, 2005, 48(19): 5900-5908.
27.	Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 2011, 365(10): 883-891.
28.	Turpie AG, Kreutz R, Llau J, et al. Management consensus guidance for the use of rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost, 2012, 108(5): 876-886.
29.	Wang X, Mondal S, Wang J, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs, 2014, 14(2): 147-154.
30.	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.
31.	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.
32.	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(4): 4228-4233.
33.	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.
34.	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.

1. Investigators AF. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med, 1994, 154(13): 1449-1457.
2. van der Meer FJ, Rosendaal FR, Vandenbroucke JP, et al. Bleeding complications in oral anticoagulation therapy. Arch Intern Med, 1993, 153(13): 1557-1562.
3. Jackson SL, Peterson GM, Vial JH, et al. Outcomes in the management of atrial fibrillation: clinical trial results can apply in practice. Intern Med J, 2001, 31(6): 329-336.
4. Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation, 2007, 115(21): 2689-2696.
5. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med, 1994, 120(11): 897-902.
6. Garcia DA, Crowther MA. Reversal of warfarin: case-based practice recommendations. Circulation, 2012, 125(23): 2944-2947.
7. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of 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): e152S-e184S.
8. Dowlatshahi D, Butcher KS, Asdaghi N, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke, 2012, 43(7): 1812-1817.
9. Zubkov AY, Mandrekar JN, Claassen DO, et al. Predictors of outcome in warfarin-related intracerebral hemorrhage. Arch Neurol, 2008, 65(10): 1320-1325.
10. 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.
11. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med, 2009, 361(12): 1139-1151.
12. Hart RG, Diener HC, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke, 2012, 43(6): 1511-1517.
13. Dentali F, Riva N, Crowther M, et al. 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.
14. Chatterjee S, Sardar P, Biondi-Zoccai G, et al. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and bayesian meta-analysis andmixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol, 2013, 70(12): 1486-1490.
15. Camm AJ, Lip GY, De Caterina R, et al. 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. Europace, 2012, 14: 1385-1413. http://www.escardio.org/The-ESC/Governance/ESC-Committees/Board-Committees/Committee-for-Practice-Guidelines-CPG.
16. Vı́lchez JA, Gallego P, Lip GY. Safety of new oral anticoagulant drugs: a perspective. Ther Adv Drug Saf, 2014, 5(1): 8-20.
17. Huisman MV, Lip GY, Diener HC, et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost, 2012, 107(5): 838-847.
18. Suryanarayan D, Schulman S. Potential antidotes for reversal of old and new oral anticoagulants. Thromb Res, 2014, 133(Suppl 2): S158-S166.
19. Stangier J, Rathgen K, Stähle H, et al. 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.
20. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation, 2011, 124(14): 1573-1579.
21. Schiele F, Van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood, 2013, 121(18): 3554-3562.
22. 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: A17765.
23. Laulicht B, Bakhru S, Lee C, et al. Small molecule antidote for anticoagulants (abstract). Circulation, 2012, 126: 10021.
24. Van Ryn J, Baruch L, Clemens A. Interpretation of point-of-care INR results in patients treated with dabigatran. Am J Med, 2012, 125(4): 417-420.
25. 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.
26. Roehrig S, Straub A, Pohlmann J, et al. Discovery of the novel antithrombotic agent 5-chloro-N-((5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1, 3-oxazolidin-5-ylmethyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem, 2005, 48(19): 5900-5908.
27. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 2011, 365(10): 883-891.
28. Turpie AG, Kreutz R, Llau J, et al. Management consensus guidance for the use of rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost, 2012, 108(5): 876-886.
29. Wang X, Mondal S, Wang J, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs, 2014, 14(2): 147-154.
30. 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.
31. 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.
32. 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(4): 4228-4233.
33. 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.
34. 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.

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新型口服抗凝剂出血并发症的治疗

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