Emerging anticoagulants for the treatment of venous thromboembolism

Jeffrey I. Weitz

doi:10.1160/TH06-05-0234

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(03): 274-284
DOI: 10.1160/TH06-05-0234

Theme Issue Article

Schattauer GmbH

Emerging anticoagulants for the treatment of venous thromboembolism

Jeffrey I. Weitz

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

› Author Affiliations

Abstract

Summary

Anticoagulant therapy is the cornerstone of treatment of venous thromboembolism (VTE). Such treatment is divided into two stages. Rapid initial anticoagulation is given to minimize the risk of thrombus extension and fatal pulmonary embolism, whereas extended anticoagulation is aimed at preventing recurrent VTE, thereby reducing the risk of postphlebitic syndrome. With currently available drugs, immediate anticoagulation can only be achieved with parenteral agents, such as heparin, low-molecular-weight heparin, or fondaparinux. Extended treatment usually involves the administration of vitamin K antagonists,such as warfarin. Emerging anticoagulants have the potential to streamline VTE treatment. These agents include idraparinux, a long-acting synthetic pentasaccharide that is given subcutaneously on a once-weekly basis, and new oral anticoagulants that target thrombin or factor Xa. This paper i) reviews the pharmacology of these agents, ii) outlines their potential strengths and weaknesses, iii) describes the results of clinical trials with these new drugs, and iv) identifies the evolving role of new anticoagulants in the management of VTE.

Keywords

Coagulation inhibitors - heparins / glycosaminoglycans - pulmonary embolism - deep vein thrombosis

Full Text

References

References
1 Lilienfeld DE, Chan E, Ehland J. et al. Mortality from pulmonary embolism in the United States: 1962 to 1984. Chest 1990; 98: 1067-72.
2 Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med 2004; 164: 17-26.
3 Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337: 688-98.
4 Levine M, Gent M, Hirsh J. et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-81.
5 Koopman MM, Prandoni P, Piovella F. et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group.N EnglJ Med 1996; 334: 682-7.
6 O'Brien B, Levine M, Willan A. et al. Economic evaluation of outpatient treatment with low-molecularweight heparin for proximal vein thrombosis. Arch Intern Med 1999; 159: 2298-304.
7 Gould MK, Dembitzer AD, Sanders GD. et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis A cost-effectiveness analysis. Ann Intern Med 1999; 130: 789-99.
8 Harrison L, McGinnis J, Crowther M. et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998; 158: 2001-3.
9 Warkentin TE, Levine MN, Hirsh J. et al. Heparininduced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N EnglJ Med 1995; 332: 1330-5.
10 Ansell J, Hirsh J, Poller L. et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 204S-33S.
11 Higashi MK, Veenstra DL, Kondo LM. et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287: 1690-8.
12 Sconce EA, Khan TI, Wynne HA. et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal fora new dosing regimen. Blood 2005; 106: 2329-33.
13 Holbrook AM, Pereira JA, Labiris R. et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165: 1095-106.
14 Kearon C. Long-term management of patients after venous thromboembolism. Circulation 2004; 110 (09) (Suppl. 01) I10-8.
15 Petitou M, Duchaussoy P, Herbert JM. et al. The synthetic pentasaccharide fondaparinux: first in the class of antithrombotic agents that selectively inhibit coagulation factor Xa. Semin Thromb Hemost 2002; 28: 393-402.
16 Bauer KA. New pentasaccharides for prophylaxis of deep vein thrombosis: pharmacology. Chest 2003; 124 (Suppl. 06) 364S-70S.
17 Wiebe EM, Stafford AR, Fredenburgh JC. et al. Mechanism of catalysis of inhibition of factor IXa by antithrombin in the presence of heparin or pentasaccharide. J Biol Chem 2003; 278: 35767-74.
18 Paolucci F, Frasa H, Van Aarle F. et al. Two sensitive and rapid chromogenic assays of fondaparinux sodium (Arixtra) in human plasma and other biological matrices. Clin Lab 2003; 49: 451-60.
19 Linkins LA, Julian JA, Rischke J. et al. In vitro comparison of the effect of heparin, enoxaparin and fondaparinux on tests of coagulation. Thromb Res 2002; 107: 241-4.
20 Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood. 2005 106. 3791-6.
21 Ahmad S, Jeske WP, Walenga JM. et al. Synthetic pentasaccharides do not cause platelet activation by antiheparin-platelet factor 4 antibodies. Clin Appl Thromb Hemost 1999; 05: 259-66.
22 Savi P, Chong BH, Greinacher A. et al. Effect of fondaparinux on platelet activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin. Blood 2005; 105: 139-44.
23 Kuo KH, Kovacs MJ. Fondaparinux: a potential new therapy for HIT. Hematology 2005; 10: 271-5.
24 Harenberg J, Jorg I, Fenyvesi T. Treatment of heparin-induced thrombocytopenia with fondaparinux. Haematologica 2004; 89: 1017-8.
25 Hassell K. The management of patients with heparin-induced thrombocytopenia who require anticoagulant therapy. Chest 2005; 127 (Suppl. 02) 1S-8S.
26 Lagrange F, Vergnes C, Brun JL. et al. Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro . Thromb Haemost 2002; 87: 831-5.
27 Dempfle CE. Minor transplacental passage of fondaparinux in vivo. N Engl J Med 2004; 350: 1914-5.
28 Koopman MM, Buller HR. Shortand long-acting synthetic pentasaccharides. J Intern Med 2003; 254: 335-42.
29 No authors listed. Idraparinux sodium: SANORG 34006, SR 34006. Drugs RD 2004; 05: 164-5.
30 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agents BAY59-7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 03: 514-21.
31 Kubitz D, Becka M, Voith B. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol 2005; 78: 412-21.
32 Turpie AG, Fisher WD, Bauer KA. et al. BAY59-7939: 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: 2479-86.
33 Eriksson BI, Borris L, Dahl OE. et al. Oral direct factor Xa inhibition with BAY59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 04: 121-8.
34 Eriksson BI, Borris L, Dahl OE. et al. Prevention of venous thromboembolism after total hip replacement with once-daily BAY59-7939- an oral direct factor Xa inhibitor. Blood. 2005 106. 86a (Abstract #280)
35 Eriksson BI, Turpie AGG, Lassen MR. et al. YM 150, an oral direct factor Xa inhibitor, as prophylaxis for venous thromboembolism in patients with elective primary hip replacement surgery. A dose escalation study Blood. 2005 106. 530a (Abstract #1865)
36 Agnelli G, Haas SK, Krueger KA. et al. A phase II study of the safety and efficacy of a novel oral fXa inhibitor (LY517717) for the prevention of venous thromboembolism following TKR and THR. Blood. 2005 106. 85a (Abstract #278)
37 Gustafsson D, Nystrom J, Carlsson S. et al. The direct thrombin inhibitor melagatran and its oral prodrug H376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 2001; 101: 171-81.
38 Eriksson UG, Bredberg U, Gislen K. et al. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. EurJ Clin Pharmacol 2003; 59: 35-43.
39 Bredberg E, Andersson TB, Frison L. et al. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 2003; 42: 765-77.
40 Eriksson UG, Johansson S, Attman PO. et al. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet 2003; 42: 743-53.
41 Johansson LC, Frisson L, Logren U. et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42: 381-92.
42 Lee WM, Larrey D, Olsson R. et al. Hepatic findings in long-term clinical trials of ximelagatran. Drug Saf 2005; 28: 351-70.
43 McRae SJ, Ginsberg JS. New anticoagulants for venous thromboembolic disease. Curr Opin Cardiol 2005; 20: 502-8.
44 Levi M. New antithrombotics in the treatment of thromboembolic disease. Eur J Intern Med 2005; 16: 230-7.
45 Gustafsson D. Oral direct thrombin inhibitors in clinical development. J Intern Med 2003; 254: 322-34.
46 Mungall D. BIBR-1048 Boehringer Ingelheim. Curr Opin Investig Drugs 2002; 03: 905-7.
47 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: 555-63.
48 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; 02: 1573-80.
49 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: 103-11.
50 Matziolis G, Perka C, Disch A. et al. Effects of fondaparinux compared with dalteparin, enoxaparin and unfractionated heparin on human osteoblasts. Calcif Tissue Int 2003; 73: 370-9.
51 Handschin AE, Trentz OA, Hoerstrup SP. et al. Effect of low molecular weight heparin (dalteparin) and fondaparinux (Arixtra) on human osteoblasts in vitro . Br J Surg 2005; 92: 177-83.
52 Koch P. Delayed-type hypersensitivity skin reactions due to heparins and heparinoidsTolerance of recombinant hirudins and of the new synthetic anticoagulant fondaparinux. Contact Dermatitis 2003; 49: 276-80.
53 Jappe U, Juschka U, Kuner N. et al. Fondaparinux: a suitable alternative in cases of delayed-type allergy to heparins and semisynthetic heparinoids? A study of 7 cases. Contact Dermatitis 2004; 51: 67-72.
54 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: 867-73.
55 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: 1695-02.
56 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; 02: 47-53.
57 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: 681-9.
58 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: 1713-21.
59 Diener HC. Executive Steering Committee on behalf of the SPORTIF III and V Investigators Stroke prevention using the oral direct thrombin inhibitor ximelagatran in patients with non-valvular atrial fibrillation Pooled analysis from the SPORTIF III and V studies. Cerebrovasc Dis 2006; 21: 279-93.
60 Bijsterveld NR, Moons AH, Boekholdt SM. et al. Ability of recombinant factor VIIa to reverse the anti coagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550-4.
61 Bijsterveld NR, Vink R, van Aken BE. et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. BrJ Haematol 2004; 124: 653-8.
62 O'Connell KA, Wood JJ, Wise RP. et al. Thromboembolic adverse effects after use of recombinant human coagulation factor VIIa. J Am Med Assoc 2006; 295: 293-8.
63 Sinha U, Ku P, Malinowski J. et al. Antithrombotic and hemostatic capacity of factor Xa versus thrombin inhibitors in models of venous and arteriovenous thrombosis. Eur J Pharmacol 2000; 395: 51-9.
64 Fager G, Cullberg M, Eriksson-Lepkowska M. et al. Pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, are not influenced by acetylsalicylic acid. Eur J Clin Pharmacol 2003; 59: 283-9.
65 Meyer G, Marjanovic Z, Valcke J. et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002; 162: 1729-35.
66 Lee AY, Levine MN, Baker RI. et al. Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-53.
67 Lee AY, Rickles FR, Julian JA. et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23: 2123-9.