New anticoagulants: Moving on from scientific results to clinical implementation

Annals of Medicine

Volumn 43, Issue 8, 2011, Pages 606-616

  Eerenberg, Elise S ^a   Van Es, Josien ^a   Sijpkens, Meertien K ^a   Büller, Harry R ^a   Kamphuisen, Pieter W ^a  

^a ACADEMIC MEDICAL CENTER   (Netherlands)

Author keywords

Anticoagulants; Antidote; Clinical trials; Factor Xa; Monitoring; Thrombin; Thrombosis

Indexed keywords

ACTIVATED PROTHROMBIN COMPLEX; AMIODARONE; ANTIVITAMIN K; ATORVASTATIN; BLOOD CLOTTING FACTOR; CLARITHROMYCIN; DABIGATRAN; DABIGATRAN ETEXILATE; DIGOXIN; ENOXAPARIN; HYPERICUM PERFORATUM EXTRACT; KETOCONAZOLE; PANTOPRAZOLE; QUINIDINE; RANITIDINE; RECOMBINANT BLOOD CLOTTING FACTOR 7A; RIFAMPICIN; RIVAROXABAN; THROMBIN; VERAPAMIL; WARFARIN;

ACUTE CORONARY SYNDROME; ANTICOAGULATION; ARTICLE; BLEEDING; BLOOD CLOTTING; CLINICAL PRACTICE; DRUG EFFICACY; DRUG SAFETY; DYSPEPSIA; HEART ATRIUM FIBRILLATION; HUMAN; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); STROKE; VENOUS THROMBOEMBOLISM;

ACUTE CORONARY SYNDROME; ANTICOAGULANTS; ARTHROPLASTY, REPLACEMENT, HIP; ATRIAL FIBRILLATION; BENZIMIDAZOLES; BETA-ALANINE; DIET; DRUG INTERACTIONS; FACTOR VIIA; FACTOR XA; HUMANS; KIDNEY; LIFE STYLE; MONITORING, PHYSIOLOGIC; MORPHOLINES; RECOMBINANT PROTEINS; STROKE; THIOPHENES; VENOUS THROMBOEMBOLISM; VITAMIN K;

EID: 80555156215     PISSN: 07853890     EISSN: 13652060     Source Type: Journal    
DOI: 10.3109/07853890.2011.606829     Document Type: Article

References (63)

1. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:160-98.
2. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):381-453S.
3. Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecularweight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a metaanalysis of randomized, controlled trials. Ann Intern Med. 2004;140:175-83.
4. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet. 2009;48:1-22.
5. Weitz JI. New oral anticoagulants in development. Thromb Haemost. 2010;103:62-70.
6. Ryn van J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-27.
7. Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. Invitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost. 2007;98:155-62. (Pubitemid 47078782)
8. Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats. Thromb Haemost. 2007;98:333-8. (Pubitemid 47250236)
9. Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G, Stahle H, et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol. 2005;45:555-63. (Pubitemid 40562946)
10. 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(12):1411-9.
11. 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(3):371-82. (Pubitemid 46294714)
12. Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36(2):386-99. (Pubitemid 351185753)
13. Pezborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer KH, 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;3:514-21. (Pubitemid 41632877)
14. Pradaxa (dabigatran etexilate). Summary of product characteristics. Boehringer Ingelheim International GmbH. Available at: http://www.medicines.org. uk/emc/medicine/20760/SPC/(accessed 2011).
15. Connoly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Varrone J, Wang S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
16. Weinz C, Buetehorn U, Daehler HP, Kohlsdorfer C, Pleiss U, Sandmann S, et al. Pharmacokinetics of BAY 59-7939-an oral, direct Factor Xa inhibitor-in rats and dogs. Xenobiotica. 2005;35:891-910. (Pubitemid 41759174)
17. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939-an oral, direct Factor Xa inhibitor-after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61:873-80. (Pubitemid 41803696)
18. Xarelto. Summary of product characteristics. Available at: http://www.xarelto.com/html/downloads/Xarelto-Summary-of-Product- Characteristics-May2009.pdf (accessed 2009).
19. Halibi A, Maatouk H, Klause N, Lufft V, Kubitza D, Zuehlsdor M, et al. Effects of renal impairment on the pharmacology of rivaroxaban (BAY 59-7939)-an oral, direct, factor Xa inhibitor. Blood. 2006;108:Abstract 913. 2006.
20. Gensch C, Hoppe U, Bohm M, Laufs U. Late-breaking clinical trials presented at the American Heart Association Congress in Chicago 2010. Clin Res Cardiol. 2011;100:1-9.
21. Halibi A, Kubitza D, Zuehlsdorf M, Becka M, Mueck W, Maatouk H. Effect of hepatic impairment on the pharmacokinetics, pharmacodynamics and tolerability of rivaroxaban-an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2007;5(suppl 2):Abstract P-M-635. 2007.
22. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited Influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol. 2007;47:218-26. (Pubitemid 46146488)
23. FDA. Briefing information for the March 19, 2009 Cardiovascular and Renal Drugs Advisory Committee. Rivaroxaban: Advisory Committee Briefing Book. 2009.
24. 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.
25. Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, Rosencher N, Bravo ML, et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost. 2005;3:103-11. (Pubitemid 41647122)
26. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, 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. (Pubitemid 47617868)
27. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, 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. (Pubitemid 47393577)
28. Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH, et al. 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.
29. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-52.
30. Oldgren J, Budaj A, Granger CB, Harper R, Khder Y, Werf Fvd, et al. Randomised dabigatran etexilate dose finding study in patients with acute coronary syndromes post index event with additional risk factors for cardiovascular compications also receiving aspirin and clopidogrel: RE-DEEM. Poster presented at: American Heart Association Scientific Sessions; 14-18 Nov 2009; Orlando (FL). 209.
31. Piccini JP, Patel MR, Mahaffey KW, Fox KA, Califf RM. Rivaroxaban, an oral direct factor Xa inhibitor. Expert Opin Investig Drugs. 2008;17:925-37. (Pubitemid 351864329)
32. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765-75. (Pubitemid 351930851)
33. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus shortterm enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372:31-9.
34. Lassen MR, Ageno W, Borris LC, Liberman JR, Rosencher N, Bandel TJ, et al. Rivaroxaban versus enoxaparin for thromboprohylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-86. (Pubitemid 351930852)
35. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373:1673-80.
36. C ao YB, Zhang JD, Shen H, Jiang YY. Rivaroxaban versus enoxaparin for thromboprophylaxis after total hip or knee arthroplasty: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2010;66:1099-108.
37. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363: 2499-510.
38. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009; 374:29-38.
39. Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121:1523-32.
40. Levi M, Hovingh GK, Cannegieter SC, Vermeulen M, Buller HR, Rosendaal FR. Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based. Blood. 2008;111:4471-6.
41. Mismetti P, Laporte S. New oral antithrombotics: a need for laboratory monitoring. For. J Thromb Haemost. 2010;8: 621-6.
42. Bounameaux H, Reber G. New oral antithrombotics: a need for laboratory monitoring. Against. J Thromb Haemost. 2010;8:627-30.
43. Boneu B, de Moerloose P. How and when to monitor a patient treated with low molecular weight heparin. Semin Thromb Hemost. 2001;27:519-22. (Pubitemid 32989377)
44. Walenga JM, Hoppensteadt DA. Monitoring the new antithrombotic drugs. Semin Thromb Hemost. 2004;30:683-95. (Pubitemid 40041604)
45. Graff J, von Hentig N, Misselwitz F, Kubitza D, Becka M, Breddin HK, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol. 2007;47:1398-407. (Pubitemid 47624591)
46. Samama MM, Martinoli JL, LeFlem L, Guinet C, Plu-Bureau, Depasse F, et al. Assessment of laboratory assays to measure rivaroxaban-an oral, direct factor Xa inhibitor. Thromb Haemost. 2010;103:815-25.
47. Liesenfeld KH, Schafer HG, Troconiz IF, Tillmann C, Eriksson BI, Stangier J. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol. 2006;62:527-37. (Pubitemid 44571573)
48. 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. (Pubitemid 47283865)
49. Love JE, Ferrell C, Chandler WL. Monitoring direct thrombin inhibitors with a plasma diluted thrombin time. Thromb Haemost. 2007;98:234-42.
50. Stangier J, Wetzel K, Wienen W, van RJ, Rathgen K. Measurement of the pharmacodynamic effect of dabigatran etexilate: thrombin clotting time. J Thromb Haemost. 2009;PP-TH-134.
51. Mitchell LG, Dietrich K, Stang L, Etchers W, Qayyum S. Comparison of hemoclot to standard coagulation assays for monitoring the direct thrombin inhibitor (dabigatran) in pediatric patients: an in vitro study. J Thromb Haemost. 2009;PP-WE-448.
52. Samama MM, Amiral J, Guinet C, Perzborn E, Depasse F. An optimised, rapid chromogenic assay, specific for measuring direct factor Xa inhibitors (rivaroxaban) in plasma. Thromb Haemost. 2010;104:1078-9.
53. Castellone DD, Peerschke EEIB. A chromogenic method for quantitation of direct thrombin inhibitors: a case study. J Thromb Haemost. 2007;5(Suppl 2):P-S-127.
54. Bates SM, Weitz JI. Coagulation assays. Circulation. 2005;112:e53-e60.
55. Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost. 2009;7:107-10.
56. Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6:622-31. (Pubitemid 351404929)
57. Ryn van J, Dö r r B, Kaspereit F, Krege W, Zeitler S, Pragst I. Beriplex P/N reverses bleeding in an acute renal injury model after dabigatran overdose in rabbits (presented at the 21st International Congress on Thrombosis). Pathophysiol Haemost Thromb. 2010;37:A94-P486.
58. Ryn van J, Ruehl D, Priepke H, Hauel N, Wienen W. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrate (presented at the 13th Congress of the European Hematology Association). Haematologica. 2008;93:148-0370.
59. Pezborn E, Trabandt A, Selbach K, Tinel H. Prothrombin complex concentrate reverses the effects of high-dose rivaroxaban in rats (presented at the 21st International Congress on Thrombosis). Pathophysiol Haemost Thromb. 2010; 37:A10-OC251.
60. Bijsterveld NR, Moons AH, Boekholdt SM, van Aken BE, Fennema H, Peters RJ, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106:2550-4. (Pubitemid 35340690)
61. Pezborn E, Harwardt M. Recombinant factor VIIa partially reverses the effects of the factor Xa inhibitor rivaroxaban on thrombin generation, but not the effects of thrombin inhibitors, in vitro. J Thromb Haemost. 2007;5(suppl 2):P-W-640.
62. Gruber A, Marzec M, Buetehorn U, Hanson SR, Pezborn E. Recombinant factor VIIa reverses the effects of a high dose of rivaroxaban in baboons. Pathophysiol Haemost Thromb. 2008;36(suppl 1):157-200 P 059.
63. Ryn van J, Neubauer M, Flieg R, Krause B, Storr M, Hauel N, et al. Successful removal of dabigatran in fl owing blood with an activated charcoal hemoperfusion column in an in vitro test system (presented at the 21st International Congress on Thrombosis). Pathophysiol Haemost Thromb. 2010; 37(suppl 1):P485.