New oral anticoagulants in development

Jeffrey I. Weitz

doi:10.1160/TH09-07-0434

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(01): 62-70
DOI: 10.1160/TH09-07-0434

Review Article

Schattauer GmbH

New oral anticoagulants in development

Jeffrey I. Weitz

¹Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University and Henderson Research Centre, Hamilton, Ontario, Canada

› Author Affiliations

Abstract

Summary

Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low-molecular-weight heparins and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism. Consequently, coagulation monitoring and frequent dose adjustments are needed to ensure that a therapeutic level of anticoagulation is achieved. This is burdensome for patients and physicians, and costly for the healthcare system. These limitations have prompted the development of new oral anticoagulants that target thrombin or factor Xa and can be given in fixed doses without coagulation monitoring. This paper focuses on the new oral anticoagulants in the most advanced stages of development.

Keywords

Anticoagulants - arterial thromboembolism - direct factor Xa inhibitors - direct thrombin inhibitors, venous thromboembolism

Full Text

References

References
1 Kearon C, Kahn SR, Agnelli G. et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 454S-545S.
2 Singer DE, Albers GW, Dalen JE. et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 546S-592S.
3 Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. J Am Med Assoc 1999; 282: 2058-2067.
4 Friedman RJ, Gallus AS, Cushner FD. et al. Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin 2008; 24: 87-97.
5 Warwick D, Friedman RJ, Agnelli G. et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. J Bone Joint Surg Br 2007; 89: 799-807.
6 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983-988.
7 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857-867.
8 Ansell J, Hirsh J, Hylek E. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008; 133: 160S-198S.
9 Baker WL, Cios DA, Sander SD. et al. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 2009; 15: 244-252.
10 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 01: 1504-1514.
11 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.
12 Kumar R, Beguin S, Hemker HC. The effect of fibrin clots and clot-bound thrombin on the development of platelet procoagulant activity. Thromb Haemost 1995; 74: 962-968.
13 Weitz JI, Crowther M. Direct thrombin inhibitors. Thromb Res 2002; 106: V275-V284.
14 Francis CW, Berkowitz SD, Comp PC. et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003; 349: 1703-1712.
15 Colwell CW, Jr. Berkowitz SD, Lieberman JR. et al. Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. J Bone Joint Surg Am 2005; 87: 2169-2177.
16 Fiessinger JN, Huisman MV, Davidson BL. et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. J Am Med Assoc 2005; 293: 681-689.
17 Schulman S, Wahlander K, Lundstrom T. et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003; 349: 1713-1721.
18 Albers GW, Diener HC, Frison L. et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. J Am Med Assoc 2005; 293: 690-698.
19 Eriksson BI, Bauer KA, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298-1304.
20 Turpie AG, Bauer KA, Eriksson BI. et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002; 162: 1833-1840.
21 Lassen MR, Bauer KA, Eriksson BI. et al. Postoperative fondaparinux versus pre-operative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359: 1715-1720.
22 Bauer KA, Eriksson BI, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-1310.
23 Buller HR, Davidson BL, Decousus H. et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003; 349: 1695-1702.
24 Buller HR, Davidson BL, Decousus H. et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004; 140: 867-873.
25 Depasse F, Busson J, Mnich J. et al. Effect of BAY 59–7939 ۳ a novel, oral, direct Factor Xa inhibitor ۳ on clot-bound Factor Xa activity in vitro . J Thromb Haemost. 2005 3: Abstract P1104.
26 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939 ۳ an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 03: 514-521.
27 Brufatto N, Nesheim ME. The use of prothrombin(S525C) labeled with fluorescein to directly study the inhibition of prothrombinase by antithrombin during prothrombin activation. J Biol Chem 2001; 276: 17663-17671.
28 Brufatto N, Ward A, Nesheim ME. Factor Xa is highly protected from antithrombin-fondaparinux and antithrombin-enoxaparin when incorporated into the prothrombinase complex. J Thromb Haemost 2003; 01: 1258-1263.
29 Rezaie AR. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin۳antithrombin complex. Blood 2001; 97: 2308-2313.
30 Mann KG, Jenny RJ, Krishnaswamy S. Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Annu Rev Biochem 1988; 57: 915-956.
31 Sanford M, Plosker GL. Dabigatran etexilate. Drugs 2008; 68: 1699-1709.
32 Pradaxa® (dabigatran etexilate); Summary of product characteristics. Available at: http://www.pradaxa.com/Include/media/pdf/Pradaxa_SPC_EMEA.pdf Accessed May 18, 2009.
33 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.
34 Xarelto® Summary of Product Characteristics. Available at: http://www.xarelto. com/html/downloads/Xarelto_Summary_of_Product_Characteristics_May 2009.pdf. Accessed July 3, 2009.
35 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.
36 Kubitza D, Becka M, Mueck W. et al. The effect of extreme age, and gender, on the pharmacology and tolerability of rivaroxaban ۳ an oral, direct Factor Xa inhibitor. Blood. 2006 108: Abstract 905.
37 Kubitza D, Becka M, Zuehlsdorf M. et al. Effects of single-dose BAY 59–7939 – an oral, direct Factor Xa inhibitor – in subjects with extreme body weight. Blood. 2005 106: Abstract 1872.
38 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.
39 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.
40 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.
41 Kubitza D, Becka M, Mueck W. et al. Co-administration of rivaroxaban - a novel, oral, direct Factor Xa inhibitor - and clopidogrel in healthy subjects. Eur Heart J. 2007 28 (Suppl 1): 189 Abstract P1272.
42 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.
43 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.
44 Zhang D, He K, Raghavan N. et al. Comparative metabolism of 14C-labeled apixaban in mice, rats, rabbits, dogs, and humans. Drug Metab Dispos 2009; 37: 1738-1748.
45 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; 03: 103-111.
46 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; 05: 2178-2185.
47 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.
48 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.
49 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.
50 Ezekowitz MD, Reilly P, 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.
51 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.
52 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361: 1139-1151.
53 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; 04: 121-128.
54 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; 03: 2479-2486.
55 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.
56 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.
57 Eriksson BI, Borris LC, Friedman RJ. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
58 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.
59 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.
60 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.
61 Turpie AG, Lassen MR, Kakkar AK. et al. Pooled Analysis of Four Pivotal Studies of Rivaroxaban for the Prevention of Venous Thromboembolism after Orthopaedic Surgery: Effect on Symptomatic Venous Thromboembolism, Death, and Bleeding. Blood (ASH Annual Meeting Abstracts) 2008; 112: 36.
62 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.
63 Buller HR, Lensing AW, Prins MH. 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: 2242-2247.
64 Mega J, Braunwald E, Mohanavelu S. 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.
65 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; 05: 2368-2375.
66 Feng Y, Li LY, Shenker A. et al. Exposure-clinical outcome modeling and simulation to facilitate dose selection of apixaban in subjects undergoing elective total knee replacement surgery. J Thromb Haemost. 2007 5 (Suppl 1): Abstract P-M-663.
67 Lassen M, Gallus A, Pineo G. et al. Randomized double-blind comparison of apixaban with enoxaparin for thromboprophylaxis after knee replacement: the ADVANCE-1 trial. Blood (ASH Annual Meeting Abstracts) 2008; 112: 31.
68 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. Presented at the 22nd congress of the International Society on Thrombosis and Haemostasis, Boston, July 11–16, 2009.
69 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; 06: 1313-1318.
70 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.
71 Ansell J, Hollowell J, Pengo V. et al. Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the international study of anticoagulation management (ISAM). J Thromb Thrombolysis 2007; 23: 83-91.
72 Kwong LM, Lees M, Sengupta N. Rivaroxaban for prevention of venous thromboembolism after total knee arthroplasty: impact on healthcare costs based on the RECORD3 Study. Blood. 2007 110: Abstract 1874.
73 Diamantopoulos A, Forster F, Brosa M. et al. Cost-effectiveness of rivaroxaban versus enoxaparin for thromboprophylaxis after total knee replacement in the UK and Spain. Value Health (International Society for Pharmacoeconomics and Outcomes Research Meeting) 2008; 11: A533.
74 Diamantopoulos A, Forster F, Lees M. et al. Cost-effectiveness of rivaroxaban versus enoxaparin for thromboprophylaxis after total hip replacement in the UK. Value Health (International Society for Pharmacoeconomics and Outcomes Research Meeting) 2008; 11: A534.
75 Samama MM, Le Flem L, Guinet C. et al. Effects of the Novel, Oral, Direct Factor Xa Inhibitor Rivaroxaban on Coagulation Assays. ASH Annual Meeting Abstracts 2008; 112: 3028.
76 Gruber A, Marzec UM, Buetehorn U. et al. Potential of Activated Prothrombin Complex Concentrate and Activated Factor VII to Reverse the Anticoagulant Effects of Rivaroxaban in Primates. Blood (ASH Annual Meeting Abstracts) 2008; 112: 3825.
77 Perzborn E. FEIBA reverses the effects of a high dose of rivaroxaban in rats. Pathophysiol Haemost Thromb. 2008 36: A40 Abstract P061.
78 Lu G, DeGuzman F, Lakhotia S. et al. Recombinant antidote for reversal of anticoagulation by Factor Xa inhibitors. Blood (ASH Annual Meeting Abstracts) 2008; 112: 983.
79 The RE-MOBILIZE Writing Committee.. The oral thrombin inhibitor dabigatran etexilate vs the Nortt American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2008; 24: 1-9.
80 Turpie AGG, Bauer KA, Davidson B. 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: 35.