Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development

Thrombosis and Haemostasis

Volumn 103, Issue 3, 2010, Pages 572-585

  Ufer, Mike ^a  

^a UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

Author keywords

Clinical trials; Drug design; Oral anticoagulants; Pharmacodynamics; Pharmacokinetics; Venous thrombosis

Indexed keywords

AMIODARONE; APIXABAN; ATORVASTATIN; BMS 561389; CYTOCHROME P450 3A4; DABIGATRAN; DABIGATRAN ETEXILATE; DICLOFENAC; DIGOXIN; ENOXAPARIN; GLYCOPROTEIN P; HEPARIN; PLACEBO; RAZAXABAN; RIVAROXABAN; SALICYLIC ACID; UNCLASSIFIED DRUG; WARFARIN;

AREA UNDER THE CURVE; BLEEDING; CLINICAL TRIAL; DEEP VEIN THROMBOSIS; DRUG ADSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; HEART DEATH; HUMAN; ISCHEMIA; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; ORTHOPEDIC SURGERY; PRIORITY JOURNAL; PROPHYLAXIS; REVIEW; TIME TO MAXIMUM PLASMA CONCENTRATION; VENOUS THROMBOEMBOLISM;

ANTICOAGULANTS; BENZIMIDAZOLES; HUMANS; MORPHOLINES; PYRAZOLES; PYRIDINES; PYRIDONES; THIOPHENES; TREATMENT OUTCOME;

EID: 77749289263     PISSN: 03406245     EISSN: None     Source Type: Journal    
DOI: 10.1160/TH09-09-0659     Document Type: Review

References (100)

1. Ansell J, Hirsh J, Dalen J, et al. Managing oral anticoagulant therapy. Chest 2001; 119 (1 Suppl): 22S-38S.
2. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 (1 Suppl): 8S-21S.
3. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. Br Med J 2004; 329: 15-19.
4. Moore TJ, Cohen MR, Furberg CD. Serious adverse drug events reported to the Food and Drug Administration, 1998-2005. Arch Intern Med 2007; 167 : 1752-1759.
5. Gage BF, Lesko LJ. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 2008; 25: 45-51.
6. Daly AK. Pharmacogenomics of anticoagulants: steps toward personal dosage. Genome Med 2009; 1: 10.
7. Heneghan C, Alonso-Coello P, Garcia-Alamino JM, et al. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 2006; 367: 404-411.
8. Barnes GD, Froehlich JB. Anticoagulation: where we are and where we need to go. J Thromb Thrombolysis 2009; 28: 220-223.
9. Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005; 3: 1843-1853.
10. Hauel NH, Nar H, Priepke H, et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002; 45: 1757-1766.
11. Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36: 386-399.
12. European Medicines Agency (EMEA). European public assessment report: Pradaxa. Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/pradaxa/H- 829-PI-en.pdf Accessed Nov 3, 2009.
13. Wienen W, Stassen JM, Priepke H, et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007; 98: 155-162.
14. Wienen W, Stassen JM, Priepke H, et al. Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis. J Thromb Haemost 2007; 5: 1237-1242.
15. Wienen W, Stassen JM, Priepke H, et al. 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: 333-338.
16. Wong PC, Crain EJ, Watson CA, et al. Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared to the thrombin inhibitor dabigatran in rabbits. J Thromb Haemost 2009; 7: 1313-1320.
17. Stangier J, Rathgen K, Stahle H, et al. 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.
18. Stangier J, Stahle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol 2008; 48: 1411-1419.
19. Stangier J, Stahle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47: 47-59.
20. Stangier J, Rathgen K, Stahle H, et al. Coadministration of dabigatran etexilate and atorvastatin: assessment of potential impact on pharmacokinetics and pharmacodynamics. Am J Cardiovasc Drugs 2009; 9: 59-68.
21. Stangier J, Stahle H, Rathgen K, et al. Coadministration of the oral direct thrombin inhibitor dabigatran etexilate and diclofenac has little impact on the pharmacokinetics of either drug (Abstract). XXIst Congress of the International Society of Thrombosis and Haemostasis 2007;P-T-677: Available at: http://isth2007.abstractsondemand.com/ Accessed Nov 3, 2009.
22. Stangier J, Stahle H, Rathgen K, et al. No interaction of the oral direct thrombin inhibitor dabigatran etexilate and digoxin (Abstract). XXIst Congress of the International Society of Thrombosis and Haemostasis 2007;P-W-672: Available at: http://isth2007.abstractsondemand.com/ Accessed Nov 3, 2009.
23. Stangier J, Eriksson BI, Dahl OE, 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: 555-563.
24. Eriksson BI, Dahl OE, Ahnfelt L, 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: 1573-1580.
25. Troconiz IF, Tillmann C, Liesenfeld KH, et al. 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: 371-382.
26. Liesenfeld KH, Schafer HG, Troconiz IF, et al. 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: 527-537.
27. Ezekowitz MD, Reilly PA, Nehmiz G, 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: 1419-1426.
28. Eriksson BI, Dahl OE, Buller HR, 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: 103-111.
29. Eriksson BI, Dahl OE, Rosencher N, 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: 949-956.
30. Eriksson BI, Dahl OE, Rosencher N, 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: 2178-2185.
31. Ginsberg JS, Davidson BL, Comp PC, 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.
32. Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009; 157: 805-810.
33. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
34. 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-yl}methyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem 2005; 48: 5900-5908.
35. Lang D, Freudenberger C, Weinz C. In vitro metabolism of rivaroxaban, an oral, direct factor Xa inhibitor, in liver microsomes and hepatocytes of rats, dogs, and humans. Drug Metab Dispos 2009; 37: 1046-1055.
36. Weinz C, Radtke M, Schmeer K. et al. In vitro metabolism of BAY 59-7939 - an oral, direct factor Xa inhibitor [abstract no. 195]. Drug Metab Rev 2004; 36 (Suppl. 1): 98.
37. Bayer Schering Pharma. Xarelto: summary of product characteristics - EU. 2009: Available at: http://www.xarelto.com Accessed Nov 3, 2009.
38. 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: 514-521.
39. Gerotziafas GT, Elalamy I, Depasse F, et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007; 5: 886-888.
40. Biemond BJ, Perzborn E, Friederich PW, et al. Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 597939) - an oral, direct factor Xa inhibitor. Thromb Haemost 2007; 97: 471-477.
41. Kubitza D, Becka M, Wensing G, et al. 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: 873-880.
42. Weinz C, Schwarz T, Kubitza D, et al. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2009; 37: 1056-1064.
43. Weinz C, Buetehorn U, Daehler HP, et al. Pharmacokinetics of BAY 59-7939 - an oral, direct Factor Xa inhibitor - in rats and dogs. Xenobiotica 2005; 35: 891-910.
44. Kubitza D, Becka M, Voith B, et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
45. Kubitza D, Becka M, Roth A, et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008; 24: 2757-2765.
46. Mueck W, Becka M, Kubitza D, et al. 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: 335-344.
47. Kubitza D, Becka M, Mueck W, et al. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban - an oral, direct factor Xa inhibitor - are not affected by aspirin. J Clin Pharmacol 2006; 46: 981-990.
48. Kubitza D, Becka M, Zuehlsdorf M, et al. 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: 549-558.
49. Kubitza D, Becka M, Mueck W, et al. Rivaroxaban (BAY 59-7939) - an oral, direct Factor Xa inhibitor - has no clinically relevant interaction with naproxen. Br J Clin Pharmacol 2007; 63: 469-476.
50. Kubitza D, Becka M, Zuehlsdorf M, et al. 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: 218-226.
51. Zhao X, Sun P, Zhou Y, et al. Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects. Br J Clin Pharmacol 2009; 68: 77-88.
52. Mueck W, Eriksson BI, Bauer KA, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct factor Xa inhibitor - in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47: 203-216.
53. Turpie AG, Fisher WD, Bauer KA, et al. 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: 2479-2486.
54. Eriksson BI, Borris L, Dahl OE, et al. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4: 121-128.
55. Fisher WD, Eriksson BI, Bauer KA, et al. Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies. Thromb Haemost 2007; 97: 931-937.
56. Eriksson BI, Borris LC, Dahl OE, 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: 685-693.
57. Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114: 2374-2381.
58. Mueck W, Borris LC, Dahl OE, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 2008; 100: 453-461.
59. Agnelli G, Gallus A, Goldhaber SZ, et al. 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: 180-187.
60. Buller HR, Lensing AW, Prins MH, et al. A dose-ranging study evaluating oncedaily 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: 2242-2247.
61. Mega J, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, doubleblind, phase II trial. Lancet 2009; 374: 29-38.
62. Kakkar AK, Brenner B, Dahl OE, et al. 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: 31-39.
63. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673-1680.
64. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
65. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-2786.
66. Evaluation of the Efficacy and Safety of Rivaroxaban (BAY 59-7939) for the Prevention of Stroke and Non-central Nervous System Systemic Embolism in Subjects With Non-valvular Atrial Fibrillation. Available at: http://clinicaltrials.gov/ct2/show/NCT00494871 Accessed Nov 3, 2009.
67. Once - Daily Oral Direct Factor Xa Inhibitor Rivaroxaban In The Long-Term Prevention Of Recurrent Symptomatic Venous Thromboembolism In Patients With Symptomatic Deep-Vein Thrombosis Or Pulmonary Embolism. The Einstein-Extension Study.Available at: Available at: http://clinicaltrials.gov/ct2/show/ NCT00439725 Accessed Nov 3, 2009.
68. Oral Direct Factor Xa Inhibitor Rivaroxaban In Patients With Acute Symptomatic Pulmonary Embolism With Or Without Symptomatic Deep-Vein Thrombosis: Einstein-PE Evaluation. Available at: http://clinicaltrials.gov/ct2/show/ NCT00439777 Accessed Nov 3, 2009.
69. An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome.Available at: http://clinicaltrials.gov/ct2/show/NCT00809965 Accessed Nov 3, 2009.
70. Quan ML, Lam PY, Han Q, et al. Discovery of 1-(3′- aminobenzisoxazol-5′-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2′-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor. J Med Chem 2005; 48: 1729-1744.
71. Pinto DJ, Orwat MJ, Koch S, et al. Discovery of 1-(4-methoxyphenyl)-7- oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H -pyrazolo[3,4-c] pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 2007; 50: 5339-5356.
72. Zhang D, He K, Raghavan N, et al. Comparative Metabolism of C-14 Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans. Drug Metab Dispos 2009; 37: 1738-1748.
73. He K, He B, Grace JE, et al. Preclinical Pharmacokinetic and Metabolism of Apixaban, a Potent and Selective Factor Xa Inhibitor. ASH Annual Meeting Abstracts 2006; 108: 910.
74. Wang L, Raghavan N, He K, et al. Sulfation of o-demethyl apixaban: enzyme identification and species comparison. Drug Metab Dispos 2009; 37: 802-808.
75. Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man - fact or myth. Pharm Res 1997; 14: 763-766.
76. 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: 820-829.
77. Luettgen JM, Bozarth TA, Bozarth JM, et al. In Vitro Evaluation of Apixaban, a Novel, Potent, Selective and Orally Bioavailable Factor Xa Inhibitor. ASH Annual Meeting Abstracts 2006; 108: 4130.
78. Jiang X, Crain EJ, Luettgen JM, et al. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost 2009; 101: 780-782.
79. Luettgen JM, Wang Z, Seiffert DA, et al. Inhibition of measured thrombin generation in human plasma by apixaban: A predictive mathematical model based on experimentally determined rate constants. J Thromb Haemost 2007; 5 (Suppl. 2): P-T-633.
80. Wong PC, Watson CA, Crain EJ. Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits. J Thromb Haemost 2008; 6: 1736-1741.
81. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37: 74-81.
82. Frost C, Yu Z, Nepal S. et al. Apixaban, a direct factor Xa Inhibitor: single-dose pharmacokinetics and pharmacodynamics of an intravenous formulation (abstract No. 142). J Clin Pharmacol 2008; 48: 1132.
83. Frost C, Yu Z, Moore K, et al. Apixaban, an oral direct factor Xa inhibitor: multiple-dose safety, pharmacokinetics and pharmacodynamics in healthy subjects. J Thromb Haemost 2007; 5: P-M-664.
84. Frost C, Lee L, Li LY. et al. Apixaban does not affect the pharmacokinetics of digoxin (abstract No. 60). J Clin Pharmacol 2007; 47: 1196.
85. Frost C, Yu Z, Nepal S, et al. Apixaban, an oral direct factor Xa inhibitor: singledose safety, pharmacokinetics and pharmacodynamics in healthy subjects. J Thromb Haemost 2007; 5: P-M-665.
86. Lassen MR, Davidson BL, Gallus A, et al. 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: 2368-2375.
87. Buller H, Deitchman D, Prins M, et al. 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: 1313-1318.
88. Alexander JH, Becker RC, Bhatt DL, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009; 119: 2877-2885.
89. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361: 594-604.
90. Lassen MR, Gallus AS, Pineo GF, et al. The ADVANCE-2 study: A randomized double-blind trial comparing apixaban with enoxaparin for thromboprophylaxis after total knee replacement (abstract LB-MO-005). J Thromb Haemost 2009; 7 (Suppl.2): 1204.
91. Study of Apixaban for the Prevention of Thrombosis-related Events in Patients With Acute Medical Illness (ADOPT). Available at: http:// clinicaltrials.gov/ct2/show/NCT00457002 Accessed Nov 3, 2009.
92. A Phase III Study of Apixaban in Patients With Atrial Fibrillation (AVERROES). Available at: http://clinicaltrials.gov/ct2/show/NCT00496769 Accessed Nov 3, 2009.
93. Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE). Available at: Available at: http://clinicaltrials.gov/ ct2/show/ NCT00412984 Accessed Nov 3, 2009.
94. Efficacy and Safety Study of Apixaban for Extended Treatment of Deep Vein Thrombosis or Pulmonary Embolism. Available at: http://clinicaltrials.gov/ct2/ show/NCT00633893 Accessed Nov 3, 2009.
95. Wolowacz SE, Roskell NS, Plumb JM, et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis. Thromb Haemost 2009; 101: 77-85.
96. Eriksson B, Turpie AG, Lassen MR, et al. A Pooled Analysis of Four Pivotal Studies of Rivaroxaban for the Prevention of Venous Thromboembolism after Orthopaedic Surgery: Effects of Specified Co-Medications. ASH Annual Meeting Abstracts 2008; 112: 1986.
97. Van Thiel DH, Kalodiki E, Wahi R, et al. Interpretation of Benefit-Risk of Enoxaparin as Comparator in the Record Program: Rivaroxaban Oral Tablets (10 milligrams) for Use in Prophylaxis in Deep Vein Thrombosis and Pulmonary Embolism in Patients Undergoing Hip or Knee Replacement Surgery. Clin Appl Thromb Hemost 2009; 15: 389-394.
98. McCullagh L, Tilson L, Walsh C, et al. A Cost-Effectiveness Model Comparing Rivaroxaban and Dabigatran Etexilate with Enoxaparin Sodium as Thromboprophylaxis after Total Hip and Total Knee Replacement in the Irish Healthcare Setting. Pharmacoeconomics 2009; 27: 829-846.
99. Donnan GA, Dewey HM, Chambers BR. Warfarin for atrial fibrillation: the end of an era? Lancet Neurol 2004; 3: 305-308.
100. Laux V, Perzborn E, Heitmeier S, et al. Direct inhibitors of coagulation proteins - the end of the heparin and low-molecular-weight heparin era for anticoagulant therapy? Thromb Haemost 2009; 102: 892-899.