New anticoagulants: Focus on venous thromboembolism

Current Vascular Pharmacology

Volumn 7, Issue 3, 2009, Pages 309-329

  Gómez Outes, Antonio ^a   Lecumberri, Ramón ^b   Pozo, Carmen ^a   Rocha, Eduardo ^c  

^a Parque Empresarial Las Mercedes   (Spain)

^b UNIVERSITY CLINIC OF NAVARRA   (Spain)

^c UNIVERSITY OF NAVARRA   (Spain)

Author keywords

Anticoagulants; Apixaban; Dabigatran; Rivaroxaban; Venous thromboembolism

Indexed keywords

ACENOCOUMAROL; ACETYLSALICYLIC ACID; AMIODARONE; ANTICOAGULANT AGENT; ANTIVITAMIN K; APIXABAN; CYTOCHROME P450 INHIBITOR; DABIGATRAN; DABIGATRAN ETEXILATE; DU 176B; ENOXAPARIN; FLOVAGATRAN; FONDAPARINUX; GW 813893; HEPARIN; HERBACEOUS AGENT; IDRAPARINUX; LOW MOLECULAR WEIGHT HEPARIN; N [2 [4 (1 METHYL 4 PIPERIDINYL) 1 PIPERAZINYL] 2 OXO 1 PHENYLETHYL] 1H INDOLE 6 CARBOXAMIDE; PLACEBO; PROTEIN INHIBITOR; PROTON PUMP INHIBITOR; QUINIDINE; RIFAMPICIN; RIVAROXABAN; TAK 442; UNCLASSIFIED DRUG; UNINDEXED DRUG; VITAMIN K GROUP; WARFARIN; XIMELAGATRAN; BLOOD CLOTTING FACTOR 10A; NEW DRUG; THROMBIN;

ANTICOAGULATION; AREA UNDER THE CURVE; ARTERY THROMBOSIS; BILIRUBIN BLOOD LEVEL; BLEEDING; BLISTER; CLINICAL TRIAL; DEEP VEIN THROMBOSIS; DRUG ABSORPTION; DRUG ANTAGONISM; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG EFFECT; DRUG EFFICACY; DRUG EXCRETION; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG MONITORING; DRUG PROTEIN BINDING; DRUG SAFETY; HUMAN; LIVER TOXICITY; LOW DRUG DOSE; LUNG EMBOLISM; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PRURITUS; REVIEW; SECONDARY PREVENTION; SIDE EFFECT; SKIN TOXICITY; THROMBOEMBOLISM; TIME TO MAXIMUM PLASMA CONCENTRATION; VEIN THROMBOSIS; VENOUS THROMBOEMBOLISM; BIOLOGICAL MODEL; ORAL DRUG ADMINISTRATION;

ADMINISTRATION, ORAL; ANTICOAGULANTS; CLINICAL TRIALS AS TOPIC; DRUGS, INVESTIGATIONAL; FACTOR XA; HUMANS; MODELS, BIOLOGICAL; THROMBIN; VENOUS THROMBOEMBOLISM;

EID: 69149086784     PISSN: 15701611     EISSN: None     Source Type: Journal    
DOI: 10.2174/157016109788340785     Document Type: Review

References (152)

1. Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451: 914-8.
2. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008; 28: 370-2.
3. Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, et al. VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98: 756-64.
4. Schafer AI. Venous thrombosis as a chronic disease. N Engl J Med 1999; 340: 955-6.
5. Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI. American College of Chest Physicians. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(6 Suppl): 141S-159S.
6. 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 Ed. Chest 2008; 133(6 Suppl): 381S-453S.
7. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Ed.). Chest 2008; 133(6 Suppl): 454S-545S.
8. 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 Ed. Chest 2008; 133(6 Suppl): 160S-198S.
9. Goldsack NR, Chambers RC, Dabbagh K, Laurent GJ. Thrombin. Int J Biochem Cell Biol 1998; 30: 641-6.
10. Davie EW, Kulman JD. An overview of the structure and function of thrombin. Semin Thromb Hemost 2006; 32: 3-15.
11. Mann KG. The challenge of regulating anticoagulant drugs: focus on warfarin. Am Heart J 2005; 149(1 Suppl): S36-S42.
12. Yin ET, Wessler S. Heparin-accelerated inhibition of activated factor X by its natural inhibitor. Biochem Biophys Acta 1970; 201: 387-90.
13. Wessler S, Yin ET. Theory and practice of minidose heparin in surgical patients. Circulation 1973; 47: 671-6.
14. Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost 2007; 5(Suppl1): 60-4.
15. van Ryn J, Kink-Eiband M, Hauel N, Priepke H, Wienen W. Effects of dabigatran, a direct thrombin inhibitor, as compared to the direct factor Xa inhibitors, rivaroxaban and apixaban, on tissue factor-induced human platelet aggregation in platelet rich plasma. Blood 2007; 110: Abstract 1884.
16. Lesaffre E. Superiority, equivalence, and non-inferiority trials. Bull NYU Hosp Jt Dis 2008; 66: 150-4.
17. Committee for Medicinal Products for Human Use (CHMP). Guideline on the choice of the non-inferiority margin. EMEA/CPMP/EWP/2158/99. London, 27 July 2005. Available at URL: http://www.emea.europa.eu [accessed 2008, Aug 23].
18. Gao P, Ware JH. Assessing non-inferiority: a combination approach. Stat Med 2008; 27: 392-406.
19. Norrie J. Trials of venous thromboembolism prevention. Lancet 2007; 370: 915-7.
20. Gomez-Outes A, Rocha E, Martinez-Gonzalez J, Planès A. Efficacy of bemiparin vs. enoxaparin in total knee arthroplasty using different definitions of thromboembolism. Pathophysiol Haemost Thromb 2008; 36(Suppl1): P153.
21. Simonneau G, Laporte S, Mismetti P, Derlon A, Samii K, Samama CM, et al. FX140 Study Investigators. A randomized study comparing the efficacy and safety of nadroparin 2850 IU (0.3 mL) vs. enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism after colorectal surgery for cancer. J Thromb Haemost 2006; 4: 1693-700.
22. Steinhubl SR, Kastrati A, Berger PB. Variation in the definitions of bleeding in clinical trials of patients with acute coronary syndromes and undergoing percutaneous coronary interventions and its impact on the apparent safety of antithrombotic drugs. Am Heart J 2007; 154: 3-11.
23. Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products for prophylaxis of high intra- and post-operative venous thromboembolic risk. London, 15 November 2007. Doc. Ref. CPMP/EWP/707/98 Rev.1 corr. Available at URL: http://www.emea.europa.eu [accessed 2008, Aug 23].
24. Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products for the prophylaxis of venous thromboembolic risk in non-surgical patients. London, 1 June 2006. Doc. Ref. CPMP/EWP/6235/04. Available at URL: http://www.emea.europa.eu [accessed 2008, Aug 23].
25. Dahl OE, Borris LC, Bergqvist D, Schnack Rasmussen M, Eriksson BI, Kakkar AK, et al. International Surgical Thrombosis Forum. Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use. Int Angiol 2008; 27: 60-7.
26. Lensing AW, Buller HR, Prandoni P, Batchelor D, Molenaar AH, Cogo A, et al. Contrast venography, the gold standard for the diagnosis of deep-vein thrombosis: improvement in observer agreement. Thromb Haemost 1992; 67: 8-12.
27. Quinlan DJ, Eikelboom JW, Dahl OE, Eriksson BI, Sidhu PS, Hirsh J. Association between asymptomatic deep vein thrombosis detected by venography and symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery. J Thromb Haemost 2007; 5: 1438-43.
28. Goodacre S, Sampson F, Thomas S, van Beek E, Sutton A. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging 2005; 5: 6.
29. Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous thrombosis. McMaster diagnostic imaging practice guidelines initiative. Ann Intern Med 1998; 128: 663-77.
30. Tomkowski WZ, Davidson BL, Wisniewska J, Malek G, Kober J, Kuca P, et al. Accuracy of compression ultrasound in screening for deep venous thrombosis in acutely ill medical patients. Thromb Haemost 2007; 97: 191-4.
31. Gómez-Outes A, Lecumberri R, Lafuente-Guijosa A, Martínez-González J, Carrasco P, Rocha E. Correlation between thrombus regression and recurrent venous thromboembolism. Examining venographic and clinical effects of low-molecular-weight heparins: a meta-analysis. J Thromb Haemost 2004; 2: 1581-7.
32. Prandoni P, Lensing AW, Prins MH, Bernardi E, Marchiori A, Bagatella P, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 955-60.
33. Piovella F, Crippa L, Barone M, Vigano D'Angelo S, Serafini S, Galli L, et al. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica 2002; 87: 515-22.
34. Hull RD, Marder VJ, Mah AF, Biel RK, Brant RF. Quantitative assessment of thrombus burden predicts the outcome of treatment for venous thrombosis: a systematic review. Am J Med 2005; 118: 456-64.
35. Young L, Ockelford P, Milne D, Rolfe-Vyson V, Mckelvie S, Harper P. Post-treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality. J Thromb Haemost 2006; 4: 1919-24.
36. Schulman S, Kearon C. Subcommittee on control of anticoagulation of the scientific and standardization committee of the international society on thrombosis and haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-4.
37. van Gogh Investigators, Buller HR, Cohen AT, Davidson B, Decousus H, Gallus AS, Gent M, et al. Idraparinux vs. standard therapy for venous thromboembolic disease. N Engl J Med 2007; 357: 1094-104.
38. Boudes PF. The challenges of new drugs benefits and risks analysis: lessons from the ximelagatran FDA Cardiovascular Advisory Committee. Contemp Clin Trials 2006; 27: 432-40.
39. Reuben A. Hy's law. Hepatology 2004; 39: 574-8.
40. Day SJ, Altman DG. Statistics notes: blinding in clinical trials and other studies. BMJ 2000; 321: 504.
41. Kwong LM, Muntz JE. Thromboprophylaxis dosing: the relationship between timing of first administration, efficacy, and safety. Am J Orthop 2002; 31(11 Suppl): 16-20.
42. Raskob GE, Hirsh J. Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest 2003; 124(6 Suppl): 379S-385S.
43. Tribout B, Colin-Mercier F. New vs. established drugs in venous thromboprophylaxis: efficacy and safety considerations related to timing of administration. Am J Cardiovasc Drugs 2007; 7: 1-15.
44. Gomez-Outes A, Lecumberri R, Rocha E, Martinez-Gonzalez J, Prandoni P, Planès A. Optimal timing of initiation of bemiparin thromboprophylaxis in total hip/knee replacement. Pathophysiol Haemost Thromb 2008; 36(Suppl 1): O26.
45. Pradaxa® (dabigatran etexilate) summary of product characteristics. Available from URL: http://www.emea.europa.eu [Accessed 2008 Aug 23].
46. Mungall D. BIBR-1048 Boehringer Ingelheim. Curr Opin Investig Drugs 2002; 3: 905-7.
47. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002; 45: 1757-66.
48. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-95.
49. Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G, Stähle 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.
50. Trocóniz IF, Tillmann C, Liesenfeld KH, Schäfer HG, Stangier J. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery. J Clin Pharmacol 2007; 47: 371-82.
51. Eriksson BI, Dahl OE, Ahnfelt L, Kälebo P, Stangier J, Nehmiz G, et al. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost 2004; 2: 1573-80.
52. Eriksson BI, Dahl OE, Büller HR, Hettiarachchi R, Rosencher N, Bravo ML, et al. BISTRO II Study Group. 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.
53. 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: 386-99.
54. Stangier J, Stähle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47: 47-59.
55. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, 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: 2178-85.
56. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. RE-NOVATE Study Group. Dabigatran etexilate vs. enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949-56.
57. The RE-MOBILIZE Writing Committee. The oral thrombin inhibitor dabigatran etexilate vs. the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009; 24: 1-9.
58. Planès A. Prevention of venous thromboembolism after orthopedic surgery: the EXPRESS study. J Thromb Haemost 2004; 2: 2037-9.
59. Caprini JA, Hwang E, Hantel S, Schnee J, Eriksson BI. The oral direct thrombin inhibitor dabigatran etexilate is effective and safe for prevention of major venous thromboembolism following orthopaedic surgery. J Thromb Haemost 2007; 5(Suppl 2): O-W-050.
60. Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-Azad K, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100: 1419-26.
61. The Petro-ex Investigators. Safety and efficacy of extended exposure to several doses of a new oral direct thrombin inhibitor dabigatran etexilate in atrial fibrillation. Cerebrovasc Dis 2006; 21(Suppl 4): Abstract 5.
62. Gyzander E, Deinum J. Enzyme kinetic characterisation of the active form of the novel oral direct thrombin inhibitor AZD0837. J Thromb Haemost 2007; 5(Suppl 2): P-S-066.
63. Johansson S, Eriksson U, Schutzer KM, Fransson B, Panfilov S, Alenhag EL, et al. Effect on cytochrome P450 2C9 and 3A activity by the oral direct thrombin inhibitor AZD0837 given in immediate-release and extended release formulations. Eur Heart J 2008; 29(Suppl): P4564.
64. Mattsson C, Lundin A, Ulvinge J. Characterisation of the active form of the novel oral direct thrombin inhibitor AZD0837 in coagulation assays. J Thromb Haemost 2007; 5(Suppl 2): P-T-636.
65. Walfridsson H, Johansson B, Englund A, Kennebäck G, Schwieler J, Kongstad O, et al. Assessment of the electrophysiological effects of the oral direct thrombin inhibitor AZD0837, in subjects undergoing an invasive electrophysiological procedure. J Thromb Haemost 2007; 5(Suppl 2): P-W-674.
66. Olsson B, Rasmussen LH, Tveit A, Jensen E, Wessman P, Panfilov S, et al. Safety and tolerability of the oral direct thrombin inhibitor AZD0837 in prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF). J Thromb Haemost 2007; 5(Suppl 2): O-W-053.
67. Wang, Y, Mealy N, Serradell N, Bolos J, Rosa E. Flovagatran sodium. Drugs Fut 2007; 32: 310.
68. Chahwala S, Chander C. Identification and in vitro characterization of TGN 255, a novel synthetic intravenous low molecular weight direct thrombin inhibitor. J Thromb Haemost 2005; 3(Suppl 1): P2306.
69. Combe S, Allen G, Kennedy A. Pharmacokinetics of TGN 255, a novel intravenous low molecular weight direct thrombin inhibitor, in healthy volunteers. J Thromb Haemost 2005; 3(Suppl 1): P1714.
70. Combe S, Chander C, Kennedy A. Pharmacodynamics of TGN 255, a novel intravenous low molecular weight direct thrombin inhibitor, in healthy subjects. J Thromb Haemost 2005; 3(Suppl 1): P1115.
71. Combe S, D'Souza R, Mysliwiec M, Padmanabhan N, Sulowicz W, Thomas M, et al. Effect of TGN 255, a novel intravenous direct thrombin inhibitor, on the prolongation of ACT in patients undergoing haemodialysis. J Thromb Haemost 2005; 3(Suppl 1): P1614.
72. Nelson DA, Nelson KT, Miller MW, Dupe R, Chahwala SB, Kennedy A, et al. Pharmacodynamic and efficacy profile of TGN 255, a novel direct thrombin inhibitor, in canine cardiopulmonary bypass and simulated mitral valve repair. J Extra Corpor Technol 2008; 40: 116-22.
73. Perzborn 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.
74. Laux V, Perzborn E, Kubitza D, Misselwitz F. Preclinical and clinical characteristics of rivaroxaban: a novel, oral, direct factor Xa inhibitor. Semin Thromb Hemost 2007; 33: 515-23.
75. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-21.
76. 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.
77. Kubitza D, Becka M, Roth A, Mueck W. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008; 24: 2757-65.
78. Weinz C, Radtke M, Schmeer K, Kern A, Pleiss U. In vitro metabolism of BAY 59-7939, an oral direct factor Xa inhibitor. Drug Metab Rev 2004; 36(Suppl 1): Abstract 195.
79. Xarelto® (rivaroxaban) summary of product characteristics. Available from URL: http://www.emea.europa.eu [Accessed 2008 Nov 30].
80. Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct factor Xa inhibitor - in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47: 203-16.
81. 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.
82. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Rivaroxaban (BAY 59-7939) - an oral, direct factor Xa inhibitor -has no clinically relevant interaction with naproxen. Br J Clin Pharmacol 2007; 63: 469-76.
83. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban - an oral, direct factor Xa inhibitor - are not affected by aspirin. J Clin Pharmacol 2006; 46: 981-90.
84. Kubitza D, Mueck W, Becka M. Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation. Drug Saf 2008; 31: 67-77.
85. Mueck W, Becka M, Kubitza D, Voith B, Zuehisdorf M. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct factor Xa inhibitor - in healthy subjects. Int J Clin Pharmacol Ther 2007; 45: 335-44.
86. Kubitza D, Becka M, Voith B, Zuehlsdorf M. Effect of enoxaparin on the safety, tolerability, pharmacodynamics and pharmacokinetics of BAY 59-7939 - an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 3(Suppl 1): P1704.
87. Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. Dose-escalation study of rivaroxaban (BAY 59-7939) - an oral, direct Factor Xa inhibitor - for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Res 2007; 120: 685-93.
88. Turpie AG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kälebo P, et al. OdiXa-Knee Study Group. BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 2005; 3: 2479-86.
89. Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. ODIXa-HIP Study Investigators. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4: 121-8.
90. Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. ODIXa-HIP Study Investigators. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114: 2374-81.
91. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. RECORD1 Study Group. Rivaroxaban vs. enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-75.
92. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. RECORD2 Investigators. Extended duration rivaroxaban vs. short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372: 31-9.
93. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al. RECORD3 Investigators. Rivaroxaban vs. enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-86.
94. Turpie AG, Bauer KA, Davidson B, Gent M, Kwong L, Lassen MR, et al. Once-daily oral rivaroxaban compared with subcutaneous enoxaparin every 12 hours for thromboprophylaxis after total knee replacement: RECORD4. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 35.
95. Agnelli G, Gallus A, Goldhaber SZ, Haas S, Huisman MV, Hull RD, et al. ODIXa-DVT Study Investigators. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 2007; 116: 180-7.
96. Buller HR, Lensing AW, Prins MH, Agnelli G, Cohen A, Gallus AS, et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor Rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis. The EINSTEIN-DVT Dose-Ranging Study. Blood 2008; 112: 2242-7.
97. Wong PC, Crain EJ, Xin B, Wexler RR, Lam PY, Pinto DJ, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 6: 820-9.
98. He K, He B, Grace JE, Xin B, Zhang D, Pinto DJ, et al. Preclinical pharmacokinetic and metabolism of apixaban, a potent and selective Factor Xa inhibitor. Blood 2006; 108: Abstract 910.
99. Frost C, Yu Z, Moore K, Nepal S, Barrett Y, Mosqueda-Garcia R, et al. Apixaban, an oral direct factor Xa inhibitor: multiple-dose safety, pharmacokinetics, and pharmacodynamics in healthy subjects. J Thromb Haemost 2007; 5(Suppl 2): P-M-664.
100. Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 5: 2368-75.
101. Feng Y, Li LY, Shenker A, Pfister M, Yu Z. Exposure-clinical outcome modelling and simulation to facilitate dose selection of apixaban in subjects undergoing elective total knee replacement surgery. J Thromb Haemost 2007; 5(Suppl 2): P-M-663.
102. Lassen MR, Gallus AS, Pineo GF, Raskob GE, ADVANCE-1 investigators. Randomized double-blind comparison of apixaban with enoxaparin for thromboprophylaxis after knee replacement: The ADVANCE-1 Trial. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 31.
103. On behalf of the Botticelli investigators, the writing committee, Buller H, Deitchman D, Prins M, Segers A. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep-vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 6: 1313-8.
104. Alexander J. Safety of the factor Xa inhibitor, Apixaban, in combination with antiplatelet therapy after acute coronary syndrome: Results of the APPRAISE-I dose guiding trial. Presentation at the European Society of Cardiology (ESC) Congress 2008: Munich September 2nd 2008.
105. Abe K, Siu G, Edwards S, Lin PH, Zhu BY, Marzec U, et al. Animal models of thrombosis help predict the human therapeutic concentration of PRT54021, a potent oral factor Xa inhibitor. Blood 2006; 108: Abstract 901.
106. Turpie AG, Gent M, Bauer K, Davidson BL, Fisher W, Huo M, et al. Evaluation of the factor Xa (FXA) inhibitor, PRT054021 (PRT021), against enoxaparin in a randomized trial for the prevention of venous thromboembolic events after total knee replacement (EXPERT). J Thromb Haemost 2007; 5(Suppl 2): P-T-652.
107. Iwatsuki Y, Shigenaga T, Moritani Y, Suzuki M, Ishihara T, Hirayama F, et al. Biochemical and pharmacological profiles of YM150, an oral direct factor Xa inhibitor. Blood 2006; 108: Abstract 911.
108. Eriksson BI, Turpie AG, Lassen MR, Prins MH, Agnelli G, Kälebo P, et al. ONYX study group. A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery. J Thromb Haemost 2007; 5: 1660-5.
109. Eriksson BI, Turpie AGG, Lassen MR, Prins MH, Agnelli G, Kälebo P, et al. Once daily YM150, an oral direct factor Xa inhibitor, for prevention of venous thromboembolism in patients undergoing elective primary hip replacement. Blood 2007; 110: Abstract 309.
110. Zafar MU, Vorchheimer DA, Gaztanaga J, Velez M, Yadegar D, Moreno PR, et al. Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost 2007; 98: 883-8.
111. Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, et al. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 2008; 6: 1542-9.
112. Morishima Y, Shirasaki Y, Kito F, Honda Y, Shibano T. A wide safety margin of a factor Xa inhibitor, DU-176b, between antithrombotic effect and exacerbation of intracerebral hemorrhage in rats: comparison with a thrombin inhibitor. Circulation 2006; 18(Suppl): Abstract 632.
113. Fuji T, Fujita S, Tachibana S, Kawai Y. Randomized, double-blind, multi-dose efficacy, safety and biomarker study of the oral factor Xa inhibitor DU-176b compared with placebo for prevention of venous thromboembolism in patients after total knee arthroplasty. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 34.
114. Weitz JI, Connolly SJ, Kunitada S, Jin J, Patel I. Randomized, parallel group, multicenter, multinational study evaluating safety of DU-176b compared with warfarin in subjects with non-valvular atrial fibrillation. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 33.
115. Raskob G, Cohen A, Eriksson B, Macdonald A, Puskas F, Shi M, et al. Randomized double-blind multi-dose trial of the oral factor-Xa inhibitor DU-176b vs. LMW Heparin (Dalteparin) for prevention of venous thromboembolism after total hip replacement. Eur Heart J 2008; 29(Suppl 1): P3712.
116. Agnelli G, Haas S, Ginsberg JS, Krueger KA, Dmitrienko A, Brandt JT. A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 2007; 5: 746-53.
117. Abboud MA, Needle SJ, Burns-Kurtis CL, Valocik RE, Koster PF, Amour AJ, et al. Antithrombotic potential of GW813893: a novel, orally active, active-site directed factor Xa inhibitor. J Cardiovasc Pharmacol 2008; 52: 66-71.
118. Norman P. Proteinase Inhibitor Design - Fourth SCI-RSC Symposium, Proteinase 2004: Strategies for New Medicines (Part I), London, UK. IDdb Meeting Report 2004.
119. Kohrt JT, Bigge CF, Bryant JW, Casimiro-Garcia A, Chi L, Cody WL, et al. The discovery of (2R,4R)-N-(4-chlorophenyl)-N-(2-fluoro-4- (2-oxopyridin-1(2H)-yl)phenyl)-4-ethoxypyrrolidine- 1,2-dicarboxamide PD 0348292), an orally efficacious factor Xa inhibitor. Chem Biol Drug Des 2007; 70: 100-12.
120. Cohen AT, Armstrong D, Gazdzik T, Ryge C, Pak R, Mandema J, et al. An adaptive-design dose-ranging study of PD 0348292, a new oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 980.
121. Guertin KR, Choi YM. The discovery of the factor Xa inhibitor otamixaban: from lead identification to clinical development. Curr Med Chem 2007; 14: 2471-81.
122. Cohen M, Bhatt DL, Alexander JH, Montalescot G, Bode C, Henry T, et al. SEPIA-PCI Trial Investigators. Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial. Circulation 2007; 115: 2642-51.
123. Herbert JM, Hérault JP, Bernat A, van Amsterdam RG, Lormeau JC, Petitou M, et al. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide. Blood 1998; 91: 4197-205.
124. Trellu M, Perez Y, Ortiz J, Cheng S, Paty I. Bioequipotency of idraparinux and biotinylated idraparinux after single dose in healthy subjects. J Thromb Haemost 2007; 5(Suppl 2): P-T-678.
125. Ma Q, Fareed J. Idraparinux sodium. Sanofi-Aventis. IDrugs 2004; 7: 1028-34.
126. PERSIST investigators. A novel long-acting synthetic factor Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis. A phase II evaluation. J Thromb Haemost 2004; 2: 47-53.
127. van Gogh Investigators, Buller HR, Cohen AT, Davidson B, Decousus H, Gallus AS, Gent M, et al. Extended prophylaxis of venous thromboembolism with idraparinux. N Engl J Med 2007; 357: 1105-12.
128. The Amadeus investigators. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial. Lancet 2008; 371: 315-21.
129. Harenberg J, Jörg I, Vukojevic Y, Mikus G, Weiss C. Anticoagulant effects of Idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations from the van Gogh trials. Eur J Clin Pharmacol 2008; 64: 555-63.
130. Harenberg J, Vukojevic Y, Mikus G, Joerg I, Weiss C. Long elimination half-life of idraparinux may explain major bleeding and recurrent events of patients from the van Gogh trials. J Thromb Haemost 2008; 6: 890-2.
131. Savi P, Herault JP, Duchaussoy P, Millet L, Schaeffer P, Petitou M, et al. Reversible biotinylated oligosaccharides. A new approach for a better management of anticoagulant therapy. J Thromb Haemost 2008; 6: 1697-706.
132. Buller HR, Destors JM, Gallus AS, Prins MH, Raskob GE. Idrabio-taparinux, a biotinylated long-acting anticoagulant, in the treatment of deep venous thrombosis (EQUINOX study): Safety, efficacy, and reversibility by avidin. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 32.
133. Hoppensteadt D, Cunanan J, Geniaux E, Lorenz M, Viskov C, Ythier-Moury P, et al. AVE5026: A novel, extractive heparinoid with enriched anti-Xa activity and enhanced antithrombotic activity. Blood 2007; 110: Abstract 1881.
134. Lassen MR, Dahl OE, Mismetti P, Destrée D. AVE5026, a new anticoagulant for the prevention of venous thromboembolism in total knee replacement surgery - TREK: a dose ranging study. Blood 2007; 110: Abstract 311.
135. Ma Q, Schultz C, Tobu M, Hoppensteadt D, Cornelli U, Fareed J. Pharmacodynamics and pharmacokinetics of anti-Xa potency adjusted heparin derived oligosaccharides in nonhuman primates: implications in dosage optimization. J Thromb Haemost 2003; 1(Suppl 1): P2079.
136. Hoppensteadt D, Jeske W, Walenga JM, Fareed J. AVE5026: A new hemisynthetic ultra low molecular weight heparin with enriched anti-Xa activity and enhanced antithrombotic activity for management of cancer associated thrombosis. J Clin Oncol 2008; 26(Suppl): 14653.
137. Vignoli A, Marchetti M, Cantalino E, Russo L, Balducci D, Falanga A. Low-molecular weight heparin (LMWH) bemiparin and ultra-low-MWH RO-14 inhibit lung, breast and leukemia cancer cell-induced endothelial angiogenesis; Thromb Res 2007; 120(Suppl2): PO-13.
138. Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Favreau L. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 1980; 65: 64-73.
139. Ockelford PA, Carter CJ, Cerskus A, Smith CA, Hirsh J. Comparison of the in vivo hemorrhagic and antithrombotic effects of a low antithrombin III affinity heparin fraction. Thromb Res 1982; 27: 679-90.
140. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 8th Ed. Chest 2008; 133(6 Suppl): 340S-380S.
141. Walenga JM, Prechel M, Jeske WP, Hoppensteadt D, Maddineni J, Iqbal O, et al. Rivaroxaban - an oral, direct factor Xa inhibitor - has potential for the management of patients with heparin-induced thrombocytopenia. Br J Haematol 2008; 143: 92-9.
142. Nutescu EA, Shapiro NL, Chevalier A. New anticoagulant agents: direct thrombin inhibitors. Cardiol Clin 2008; 26: 169-87.
143. Jappe U. Allergy to heparins and anticoagulants with a similar pharmacological profile: an update. Blood Coagul Fibrinolysis 2006; 17: 605-13.
144. Bircher AJ, Harr T, Hohenstein L, Tsakiris DA. Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options. Allergy 2006; 61: 1432-40.
145. Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 2008; 111: 4871-9.
146. Rosencher N, Bonnet MP, Sessler DI. Selected new antithrombotic agents and neuraxial anaesthesia for major orthopaedic surgery: management strategies. Anaesthesia 2007; 62: 1154-60.
147. Michota F, Merli G. Anticoagulation in special patient populations: are special dosing considerations required? Cleve Clin J Med 2005; 72(Suppl1): S37-42.
148. Lecumberri R, Páramo JA, Rocha E. Anticoagulant treatment and survival in cancer patients. The evidence from clinical studies. Haematologica 2005; 90: 1258-66.
149. Prandoni P. How I treat venous thromboembolism in patients with cancer. Blood 2005; 106: 4027-33.
150. Akl EA, Barba M, Rohilla S, Terrenato I, Sperati F, Muti P, et al. Low-molecular-weight heparins are superior to vitamin K antagonists for the long term treatment of venous thromboembolism in patients with cancer: a Cochrane systematic review. J Exp Clin Cancer Res 2008; 27: 21.
151. Akl EA, van Doormaal FF, Barba M, Kamath G, Kim SY, Kuipers S, et al. Parenteral anticoagulation may prolong the survival of patients with limited small cell lung cancer: a Cochrane systematic review. J Exp Clin Cancer Res 2008; 27: 4.
152. Davidson BL, Sullivan SD, Kahn SR, Borris L, Bossuyt P, Raskob G. The economics of venous thromboembolism prophylaxis: a primer for clinicians. Chest 2003; 124(6 Suppl): 393S-396S.