Clinical pharmacology of direct and indirect factor xa inhibitors

Drugs

Volumn 70, Issue 16, 2010, Pages 2153-2170

  Rupprecht, Hans Juergen ^a   Blank, Ralf ^a  

^a Gesundheits und Pflegezentrum Russelsheim   (Germany)

Author keywords

Acute coronary syndromes; Angioplasty; Anticoagulants; Apixaban; Betrixaban; Deep vein thrombosis; Edoxaban; Eribaxaban; Fondaparinux sodium; Idrabiotaparinux sodium; Idraparinux sodium; Letaxaban; LY 517717; Myocardial infarction; Orthopaedic surgery; Otamixaban; Research and development; Rivaroxaban; SR 123781; Thromboembolism; Venous thrombosis; YM 150

Indexed keywords

ACETYLSALICYLIC ACID; ANTIVITAMIN K; APIXABAN; BETRIXABAN; BLOOD CLOTTING FACTOR 10A INHIBITOR; CYTOCHROME P450 3A4 INHIBITOR; DALTEPARIN; DIGOXIN; DU 176B; EDOXABAN; ENOXAPARIN; ERIBAXABAN; FIBRIN; FIBRINOGEN; FONDAPARINUX; HEPARIN; IDRABIOTAPARINUX; IDRAPARINUX; LETAXABAN; LOW MOLECULAR WEIGHT HEPARIN; N [2 [4 (1 METHYL 4 PIPERIDINYL) 1 PIPERAZINYL] 2 OXO 1 PHENYLETHYL] 1H INDOLE 6 CARBOXAMIDE; OTAMIXABAN; PD 0348292; PLACEBO; RIVAROXABAN; SR 123781; TAK 442; THIENOPYRIDINE DERIVATIVE; THROMBIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; WARFARIN; YM 150;

ACUTE CORONARY SYNDROME; ANTICOAGULATION; BLEEDING; BLOOD CLOT; BLOOD CLOT LYSIS; BLOOD CLOTTING; BLOOD CLOTTING TIME; CLINICAL PHARMACOLOGY; CLINICAL TRIAL; CREATININE CLEARANCE; DEEP VEIN THROMBOSIS; DRUG ABSORPTION; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG EFFECT; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG MONITORING; DRUG POTENCY; DRUG SAFETY; DRUG TREATMENT FAILURE; EMBOLISM; HEART ATRIUM FIBRILLATION; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HEPARIN INDUCED THROMBOCYTOPENIA; HUMAN; INTERNATIONAL NORMALIZED RATIO; LUNG EMBOLISM; MAXIMUM PLASMA CONCENTRATION; NON ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; PARTIAL THROMBOPLASTIN TIME; PERCUTANEOUS CORONARY INTERVENTION; PRACTICE GUIDELINE; PROTHROMBIN TIME; REVIEW; STROKE; SUPERFICIAL THROMBOPHLEBITIS; THROMBOCYTOPENIA; THROMBOEMBOLISM; THROMBOSIS PREVENTION; TREATMENT DURATION; TREATMENT INDICATION; VENOUS THROMBOEMBOLISM;

EID: 77958594714     PISSN: 00126667     EISSN: 11791950     Source Type: Journal    
DOI: 10.2165/11538030-000000000-00000     Document Type: Review

References (114)

1. Ansell J. Factor Xa or thrombin: is factor Xa a better tar-get? J Thromb Haemost 2007; 5 Suppl. 1: 60-4
2. Boneu B, Necciari J, Cariou R, et al. Pharmacokinetics andtolerance of the natural pentasaccharide (SR90107/ ORG31540) with high affinity to antithrombin III in man. Thromb Haemost 1995; 74: 1468-73
3. McKenzie CR, Abendschein DR, Eisenberg PR. Sustainedinhibition of whole-blood clot procoagulant activity by inhibition of thrombus-associated factor Xa. Arterioslcer Thromb Vasc Biol 1996; 16: 1285-91
4. Donat F, Duret JP, Santoni A, et al. The pharmacokineticsof fondaparinux sodium in healthy volunteers. Clin Phar-macokinet 2002; 41 Suppl. 2: 1-9 (Pubitemid 35155551)
5. Paolucci F, Clavies M, Donat F, et al. Fondaparinux so-dium mechanism of action: identification of specific binding to purified and human plasma-derived proteins. Clin Pharmacokinet 2002; 41: 11-8
6. Lieu C, Shi J, Donat F, et al. Fondaparinux sodium is notmetabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism ofconcomi-tant drugs. Clin Pharmacokinet 2002; 41 Suppl. 2: 19-26
7. Paatj RA, Burggraaf J, Schoemaker RC, et al. Absence ofinteraction between the synthetic pentasaccharide fonda-parinux sodium and oral warfarin. Clin Pharmacokinet 2002; 41 Suppl. 2: 27-9
8. Ollier C, Santoni A, Faaij RA, et al. Interaction of fonda-parinux sodium with acetylsalicylic acid and piroxicam in healthy male volunteers. Clin Pharmacokinet 2002; 41 Suppl. 2: 31-7
9. Mant T, Fournie P, Ollier C, et al. Absence of interaction offondaparinux sodium with digoxin in healthy volunteers. Clin Pharmacokinet 2002; 41 Suppl. 2: 39-45
10. Bijesterveld N, Moons A, Boekholdt S, et al. Ability of re-combinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550-4
11. Lassen MR, Bauer KA, Eriksson BJ, et al., for the EuropeanPentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous throm-boembolism in elective hip replacement surgery: a randomised double-blind comparison. Lancet 2002; 359: 1715-20
12. Turpie AGG, Bauer KA, Eriksson BI, et al., for the PEN-TATHLON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721-6
13. Bauer KA, Eriksson BI, Lassen MR, et al., for the Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-10
14. Eriksson BI, Bauer KA, Lassen MR, et al., for the Steering Committee of the Pentasaccharide in Hip Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298-304
15. Turpie AGG, Bauer KA, Eriksson BI, et al., for the SteeringCommittees of the Pentasaccharide Orthopedic Prophylactic Studies. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in major orthopaedic surgery: a meta-analysis of 4 randomized studies. Arch Intern Med 2002; 162: 1833-40
16. Turpie AGG, Bauer KA, Eriksson BI, et al. Efficacy andsafety of fondaparinux in major orthopedic surgery according to the timing of its first administration. Thromb Haemost 2003; 90: 364-6
17. Eriksson BI, Lassen MR, on behalf of the PENTHIFRA-PLUS Investigators. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracturesurgery: a multicenter, randomized placebo-controlled, double-blind study. Arch Intern Med 2003; 163: 1337-42
18. Turpie AGG, Bauer KA, Caprini JA, et al. Arixtra (fon-daparinux) combined with intermittent pneumatic compression vs intermittent pneumatic compression alone for prevention of venous thromboembolism after abdominal surgery: a randomized, double-blind comparison (APOLLO). J Thromb Haemost 2007; 5: 1854-61
19. Agnelli G, Bergqvist D, Cohen AT, et al., for the PEGASUS Investigators. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg 2005; 92: 1212-20
20. Cohen AT, Davidson BL, Gallus AS, et al., for theARTEMIS Investigators. Efficacy and safety of fonda-parinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332: 325-9
21. Eikelboom J, Cohen AT, Turpie AGG. Fondaparinux re-duces symptomatic pulmonary embolism and death in patients hospitalized with congestive heart failure: a sub-analysis of the randomized ARTEMIS trial [abstract no. P477]. Eur Heart J 2007; 28 Suppl. 1: 50
22. Decousus H, Prandoni P, Mismetti P, et al., for theCALISTO Study Group. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med 2010; 363: 1222-32
23. Buller HR, Davidson BL, Decousus H, et al., for the Ma-tisse Investigators. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004; 140: 867-73
24. Buller HR, Davidson BL, Decousus H, et al., for the Ma-tisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the treatment of pulmonary embolism. N Engl J Med 2003; 349: 1695-702
25. Yusuf S, Mehta SR, Chrolavicius S, et al., for the FifthOrganization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354: 1464-76
26. Fox KA, Bassand JP, Mehta SR, et al., for the OASIS 5 Investigators. Influence of renal function on the efficacy and safety of fondaparinux relative to enoxaparin in non ST-segment elevation acute coronary syndromes. Ann Intern Med 2007; 147: 304-10
27. Mehta SR, Granger CB, Eikelboom W, et al. Efficacy andsafety of fondaparinux versus enoxaparin inpatients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol 2007; 50: 1742-51
28. Yusuf S, Mehta SR, Chrolavicius S, et al., for the OASIS-6Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006; 295: 1519-30
29. The FUTURA/OASIS-8 Trial Group, Steg PG, Jolly SS,et al. Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/ OASIS-8 randomized trial. JAMA. Epub 2010 Aug 31
30. Warkentin TE, Maurer BT, Aster RH. Heparin-inducedthrombocytopenia associated with fondaparinux. N Engl J Med 2007; 356: 2653-5
31. Kuo K, Kovacs M. Fondaparinux: a potential new therapy for HIT. Hematology 2005; 10: 271-5
32. Turpie AG. The safety of fondaparinux for the preventionand treatment of venous thromboembolism. Expert Opin Drug Saf 2005; 4: 707-21
33. Matziolis G, Perka C, Disch A, et al. Effects of fondapar-inux compared with dalteparin, enoxaparin and unfrac-tionated heparin on human osteoblasts. Calcif Tissue Int 2003; 73: 370-9
34. Handschin A, Trentz O, Hoerstrup S, et al. Effect of lowmolecular weight heparin (dalteparin) and fondaparinux (Arixtra) on human osteoblasts in vitro. Br J Surg 2005; 92: 177-83
35. Geerts WH, Bergqvist D, Pineo GF. Prevention of venousthromboembolism. Chest 2008; 133: 381-453
36. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines forthe diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: the Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J 2007; 28: 1598-660
37. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007; 50: e1-e157
38. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotictherapy for venous thromboembolic disease. Chest 2008; 133: 454-545
39. Buller HR, Cohen AT, Davidson B, et al., for the van GoghInvestigators. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007; 357: 1094-104
40. Buller HR, Cohen AT, Davidson B, for the van Gogh Investi-gators. Extended prophylaxis of venous thromboembo-lism with idraparinux. N Engl J Med 2007; 357: 1105-12
41. The Amadeus Investigators. Comparison of idraparinuxwith vitamin K antagonists for prevention of thrombo-embolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial. Lancet 2008; 371: 315-21
42. Buller HR. Idrabiotaparinux, a biotinylated long-actinganticoagulant, in the treatment of deep-venous thrombosis (EQUINOX study): safety, efficacy, and reversibility by avidin [abstract no. 32]. Blood 2008; 112: 18
43. Gross PL, Weitz JI. New anticoagulants for treatment ofvenous thromboembolism. Arterioscler Thromb Vasc Biol 2008; 28: 380-6
44. Evaluation of weekly subcutaneous biotinylated idrapar-inux versus oral adjusted-dose warfarin to prevent strokeand systemic thromboembolic events in patients with atrial fibrillation (BOREALIS-AF) [ClinicalTrials.gov identifier NCT00580216]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http:// www.clinicaltrials.gov [Accessed 2010 Sep 5].
45. Herbert JM, Herault JP, Bernat A, et al. SR123781A, a syn-thetic heparin mimetic. Thromb Haemost 2001; 85: 852-60
46. Becker DL, Fredenburgh JC, Stafford AR, et al. Exosites 1and 2 are essential for protection of fibrin-bound throm-bin from heparin-catalyzed inhibition by antithrombin and heparin cofactor II. J Biol Chem 1999; 274: 6226-33
47. Herault JP, Capelle M, Bernat A, et al. Effect of SanOrg-123781A, a synthetic hexadecasaccharide, on clot-bound thrombin and factor Xa in vitro and in vivo. J Thromb Haemost 2003; 1: 1959-65
48. Lassen MR, Dahl O, Mismetti P, et al. SR123781A: a newonce-daily synthetic oligosaccharide anticoagulant for thromboprophylaxis after total hip replacement surgery. The DRIVE (Dose Ranging Study in Elective Total Hip Replacement Surgery) study. J Am Coll Cardiol 2008; 51 (15): 1498-504
49. Hexadecasaccharide (SR123781A) in Patients With UnstableAngina or Non-ST-Segment Elevation Myocardial Infarction (SHINE) [ClinicalTrials.gov identifier NCT00123565]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Sep 5]
50. Perzborn E. Factor Xa inhibitors. New anticoagulants forsecondary hemostasis. Haemostaseologie 2009; 29: 260-7
51. Rezale AR. Prothrombin protects Factor Xa in the pro-thrombinase complex from inhibition by the heparin-antithrombin complex. Blood 2001; 97: 2308-13
52. Eriksson BI, Quinlan DJ, Weitz JI, et al. Comparativepharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009; 48: 1-22
53. Perzborn E, Strassburger J, Wilmen A, et al. In vitro andin vivo studies of the novel antithrombotic agent BAY 59-7939: an oral, direct factor Xa inhibitor. J Thromb Haemost 2005; 3: 514-21
54. Laux V, Perzborn E, Kubitza D, et al. Preclinical and clini-cal characteristics of rivaroxaban: a novel, oral, direct factor Xa inhibitor. Semin Thromb Hemost 2007; 33: 515-23
55. Kubitza D, Becka M, Volth B, et al. Safety, pharmaco-dynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-21
56. Kubitza D, Becka M, Wensing G, et al. Safety, phar-macodynamics, and pharmacokinetics of BAY 59-7939-an oral, direct factor Xa inhibitor-after multiple dosing in healthy male volunteers. Eur J Clin Pharmacol 2005; 61: 873-80
57. Mueck W, Borris LC, Dahl OE, et al. Population pharmaco-kinetics and pharmacodynamics of once-and twice-daily rivaroxaban for the prevention of venous thromboembo-lism in patients undergoing total hip replacement. Thromb Haemost 2008; 100: 453-61
58. Mueck W, Becka M, Kubitza D, et al. Population model ofthe pharmacokinetics and pharmacodynamics of rivar-oxaban-an oral, direct factor Xa inhibitor-in healthy subjects. Int J Clin Pharmacol Ther 2007; 45: 335-44
59. Biemond BJ, Perzborn E, Friederich PW, et al. Preventionand treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 59-7939): an oral, direct factor Xa inhibitor. Thromb Haemost 2007; 97: 471-7
60. Walenga JM, Prechel M, Jeske WP, et al. Rivaroxaban-anoral, direct factor Xa inhibitor-has potential for the management of patients with heparin-induced thrombo-cytopenia. Br J Haematol 2008; 143: 92-9
61. Kubitza D, Becka M, Roth A, et al. Dose-escalation studyof the pharmacokinetics and pharmacodynamics of riv-aroxaban in healthy elderly subjects. Curr Med Res Opin 2008; 24: 2757-65
62. Mueck W, Eriksson BI, Bauer KA, et al. Populationpharmacokinetics and pharmacodynamics of rivaroxaban-an oral, direct factor Xa inhibitor-in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47: 203-16
63. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxabanversus enoxaparin for thromboprophylaxis after hip ar-throplasty. N Engl J Med 2008; 358: 2765-75
64. Kaltkar AK, Brenner B, Dahl OE, et al. Extended durationrivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthro-plasty: a double-blind, randomised controlled trial. Lancet 2008; 372: 31-9
65. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban ver-sus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 258: 2776-86
66. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxabanversus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673-80
67. Turpie AGG, Lassen RM, Kakkar AK, et al. A pooledanalysis of four pivotal studies of rivaroxaban for the prevention of venous thromboembolism after orthopaedic surgery: effect on symptomatic venous thromboembo-lism, death, and bleeding [abstract no. 36]. 50th American Society of Haematology (ASH) Annual Meeting and Exposition; 2008 Dec 6-9; San Francisco (CA)
68. Perzborn E, Roehrig S, Straub A, et al. Rivaroxaban: a neworal factor xa inhibitor. Arterioscler Thromb Vasc Biol 2010; 30: 376-81
69. Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment ofproximal 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
70. Buller HR, Lensing AW, Prins MH, et al. A dose-rangingstudy 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
71. Buller H. EINSTEIN DVT: oral rivaroxaban versus stan-dard therapy in the initial treatment of symptomatic deep vein thrombosis and long-term prevention of recurrent venous thromboembolism. European Society of Cardiology meeting, Stockholm, August 31, 2010 [online]. Available from URL: http://www.escardio. org/congresses/esc-2010/congress-reports/Pages/708-4-EINSTEIN-DVT.aspx [Accessed 2010 Sep 13]
72. Buller HR, on behalf of the Einstein Investigators. Oncedaily oral rivaroxaban versus placebo in the long-term prevention of recurrent symptomatic venous thromboembolism: the Einstein Study [late breaking abstract]. 51st American Society of Haematology (ASH) Annual Meeting and Exposition; 2009 Dec 6; New Orleans (LA)
73. ROCKET AF Study Investigators. Rivaroxaban-oncedaily, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J 2010 Mar; 159 (3): 340-7.e1
74. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxabanversus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind phase II trial. Lancet 2009; 374: 3-4
75. 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-carbox-amide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 2007; 50: 5339-56
76. Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, directand highly selective factor Xa inhibitor: in vitro, antithrom-botic and antihemostatic studies. J Thromb Haemost 2008; 6: 820-9
77. Wong PC, Watson CA, Crain EJ. Arterial antithromboticand bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits. J Thromb Haemost 2008; 6: 1736-41
78. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolismand pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37 (1): 74-81
79. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or en-oxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361: 594-604
80. Lassen MR, Raskob GE, Gallus A , et al., for the ADVANCE-2Investigators. Apixaban versus enoxaparin for thrombo-prophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807-15
81. Carreiro J, Ansell J. Apixaban, an oral direct Factor Xa in-hibitor: awaiting the verdict. Expert Opin Investig Drugs 2008 Dec; 17 (12): 1937-45
82. Bristol-Myers Squibb and Pfizer initiate new study in theapixaban phase 3clinical trial program. June 10, 2008 [press release; online]. Available from URL: http://www.pfizer.be/Media/Press+bulletins/Research+and+development+ and+business+development/Apixaban+enters+new+Phase+III.htm [Accessed 2010 Jul 20]
83. Liebman H, Ramirez L, Julian J, et al. Apixaban in patientswith metastatic cancer: a randomized phase II feasibility study [poster]. International Society on Thrombosis and Haemostasis (ISTH) XXII Congress; 2009 Jul 11-16; Boston (MA)
84. Buller H, Deitchman D, Prins M, et al. Efficacy and safetyof 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
85. Eikelboom JW, O'Donnell M,Yusuf S, et al. Rationale anddesign of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients whohave failed or are unsuitable for vitamin K antagonist treatment. Am Heart J 2010 Mar; 159 (3): 348-53.e1
86. Connolly S. AVERROES: apixaban versus acetylsalicylicacid to prevent strokes. European Society of Cardiology meeting, Stockholm, August 31, 2010 [online]. Available from URL: http://www.escardio.org/congresses/esc-2010/ congress-reports/Pages/708-3-AVERROES.aspx [Accessed 2010 Sep 13]
87. Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixabanfor Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 2010 Mar; 159 (3): 331-9
88. Alexander JH, Becker RC, Bhatt DL, et al. Apixaban, anoral, 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: 2877-85
89. Abe K, Siu G, Edwards S, et al. Animal models of throm-bosis help predict the human therapeutic concentration of PRT054021, a potent oral factor Xa inhibitor [abstract]. Blood 2006; 108: A901
90. Turpie AGG, Bauer KA, Davidson BL, et al. A random-ized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost 2009; 101: 68-76
91. Turpie AGG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008; 29: 155-6
92. Phase 2 study of the safety, tolerability and pilot efficacyof oral factor Xa inhibitor betrixaban compared to warfarin (EXPLORE-Xa) [ClinicalTrials.gov identifier NCT00742859]. US National Institutes of Health, Clinical Trials.gov [online]. Available from URL: http://www.cli nicaltrials.gov [Accessed 2010 Sep 5]
93. Furugohri T, Isobe K, Honda Y, et al. DU-176b, a potentand orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 2008; 6: 1542-9
94. Zafar MU, Vorchheimer DA, Gaztanaga I, et al. Anti-thrombotic 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
95. Raskob G, Cohen A, Eriksson B, et al. Oral direct factorXa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement: a randomised double-blind dose-response study. Thromb Haemost 2010; 104 (3): 642-9
96. Comparative investigation of low molecular weight (LMW)heparin/edoxaban tosylate (DU176b) versus (LMW) heparin/ warfarin in the treatment of symptomatic deep-vein blood clots and/or lung blood clots (the Edoxaban Hokusai-VTE Study) [ClinicalTrials.gov identifier NCT00986154]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Sep 5].
97. Weitz JI, Connolly SJ, Kunitada S, et al. Randomized,parallel group, multicenter, multinational study evaluating safety of DU-176b compared with warfarin in subjects with non-valvular atrial fibrillation [abstract]. Blood 2008; 112: A33
98. Global study to assess the safety and effectiveness of DU-176bvs standard practice of dosing with warfarin in patientswith atrial fibrillation (Engage AF TIMI 48) [Clinical-Trials.gov identifier NCT00781391]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www. clinicaltrials.gov [Accessed 2010 Sep 5].
99. Kohrt JT, Bigge CF, Bryant JW, et al. The discovery of (2R,4R)-N-(4-chlorophenyl)-N-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl) -4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor. Chem Biol Drug Des 2007; 70: 100-12
100. Cohen AT, Armstrong D, Gazdzik T, et al. An adaptive-design dose-ranging study of PD 0346292, a new oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery [abstract]. Blood 2008; 112: A980
101. Agnelli G, Haas S, Ginsberg JS, et al. A phase II study ofthe oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 2007 Apr; 5 (4): 746-53
102. Iwatsuki Y, Shigenaga T, Moritani Y, et al. Biochemicaland pharmacological profiles of YM150, an oral direct factor Xa inhibitor [abstract]. Blood 2006; 108: A911
103. Eriksson BI, Turpie AGG, Lassen MR, et al. A dose esca-lation 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
104. Eriksson BI, Turpie AGG, Lassen MR, et al. Prevention ofvenous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty: a dose finding study (ONYX-2). J Thromb Haemost 2010 Apr; 8 (4): 714-21
105. A study to assess the effect of YM150 for prevention of ve-nous thromboembolism in patients undergoing major abdominal surgery [ClinicalTrials.gov identifier NCT00942435]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Sep 5].
106. A study evaluating efficacy and safety of YM150 comparedto enoxaparin in subjects undergoing hip replacement surgery (ONYX-3) [ClinicalTrials.gov identifier NCT00902928]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Sep 5].
107. Weitz JI, Cao C, Eriksson B, et al. Phase II dose-findingstudy with TAK-442, an oral factor Xa inhibitor, in patients undergoing elective knee arthroplasty [abstract no. 170]. 51st ASH Annual Meeting and Exposition; 2009 Dec
108. New Orleans (LA)Safety and efficacy of TAK-442 in subjects with acutecoronary syndromes [ClinicalTrials.gov identifier NCT00677053]. US National Institutes of Health, Clinical-Trials.gov [online]. Available from URL: http://www. clinicaltrials.gov [Accessed 2010 Sep 5].
109. Chu V, Brown K, Colussi D, et al. Pharmacological char-acterization of a novel factor Xa inhibitor, FXV673. Thromb Res 2001; 103: 309-24
110. Rebello SS, Bentley RG, Morgan SR, et al. Antithromboticefficacy of a novel factor Xa inhibitor, FXV637, in a canine model of coronary artery thrombolysis. Br J Pharmacol 2001; 133: 1190-8
111. Paccaly A, Frick A, Rohatagi S, et al. Pharmacokinetics ofotamixaban, a direct factor Xa inhibitor, in healthy male subjects; pharmacokinetic model development for phase 2/3 stimulation of exposure. J Clin Pharmacol 2006; 46: 37-44
112. Hinder M, Frick A, Jordaan P, et al. Direct and rapid in-hibition of factor Xa by otamixaban: a pharmacokinetic and pharmacodynamic investigation in patients with coronary artery disease. Clin Pharmacol Ther 2006; 80: 691-702
113. Cohen M, Bhatt DL, Alexander JH, et al. 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: 642-51
114. Sabatine MS, Antman EM, Widimsky P, et al. Otamixabanfor the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomized, double-blind, active controlled, phase II trial. Lancet 2009; 374: 787-95