Semin Thromb Hemost 2008; 34(1): 039-057
DOI: 10.1055/s-2008-1066023
© Thieme Medical Publishers

Current and Future Prospects for Anticoagulant Therapy: Inhibitors of Factor Xa and Factor IIa

Job Harenberg1 , Martin Wehling1
  • 1Clinical Pharmacology Mannheim, Vascular Pharmacotherapy, Faculty of Medicine, University of Heidelberg, Mannheim, Germany
Further Information

Publication History

Publication Date:
07 April 2008 (online)

ABSTRACT

Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed.

REFERENCES

  • 1 Hirsh J, O'Donnell M, Eikelboom J W. Beyond unfractionated heparin and warfarin: current and future advances.  Circulation. 2007;  116 552-560
  • 2 Bates S M, Weitz J I. The status of new anticoagulants.  Br J Haematol. 2006;  134 3-19
  • 3 Eikelboom J W, Weitz J I. A replacement for warfarin: the search continues.  Circulation. 2007;  116 131-133
  • 4 Saiah E, Soares C. Small molecule coagulation cascade inhibitors in the clinic.  Curr Top Med Chem. 2005;  5 1677-1695
  • 5 Bauer K A. New anticoagulants.  Hematology Am Soc Hematol Educ Program. 2006;  450-456
  • 6 Turpie A GG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases.  Arterioscler Thromb Vasc Biol. 2007;  27 1238-1247
  • 7 Ma Q, Fareed J. Idraparinux sodium. Sanofi-Aventis.  IDrugs. 2004;  7 1028-1034
  • 8 Herbert J M, Herault J P, Bernat A et al.. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting pentasaccharide.  Blood. 1998;  91 4197-4205
  • 9 Bijsterveld N R, Vink R, Van Arken B E et al.. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers.  Br J Haematol. 2004;  124 653-658
  • 10 The 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
  • 11 The van Gogh Investigators . Idraparinux versus standard therapy for venous thromboembolic disease.  N Engl J Med. 2007;  357 1094-1104
  • 12 The van Gogh Investigators . Extended prophylaxis of venous thromboembolism with idraparinux.  N Engl J Med. 2007;  357 1105-1112
  • 13 Harenberg J, Joerg I, Hagedorn A, Giese C, Mikus G, Weiss C. Anticoagulant effects of idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations after the vanGogh Trials.  Eur J Clin Pharmacol. 2008;  , in press
  • 14 Savi P, Herault J P, Duchaussoy P et al.. Reversible biotinylated oligosaccharides, a new approch for a better management of the anticoagulant therapy.  J Thromb Haemost Suppl. 2007;  , abstract P-W-645
  • 15 Harenberg J, Joerg I, Hagedorn A, Giese C. Bleeding and thromboembolic events after termination of therapy with idraparinux for prevention of recurrent venous thromboembolism-observation after the van Gogh Trials.  Blood. 2007;  110 , abstract 1877
  • 16 Rezaie A R. DX-9065a inhibition of factor Xa and the prothrombinase complex: mechanism of inhibition and comparison with therapeutic heparins.  Thromb Haemost. 2003;  89 112-121
  • 17 Dyke C K, Becker R C, Kleiman N S et al.. First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation.  Circulation. 2002;  105 2385-2391
  • 18 Alexander J H, Yang H, Becker R C on behalf of the XANADU-ACS Investigators et al. First experience with direct, selective factor Xa inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XANADU-ACS trial.  J Thromb Haemost. 2005;  3 439-447
  • 19 Ansell J. Factor Xa or thrombin: is factor Xa a better target?.  J Thromb Haemost. 2007;  5(Suppl 1) 60-64
  • 20 Kubitza D, Haas S. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases.  Expert Opin Investig Drugs. 2006;  15 843-855
  • 21 Eriksson B I, Lars C, Borris L C for the ODIXa-HIP Study Investigators 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
  • 22 Agnelli G, Gallus A, Goldhaber S Z for the ODIXa-DVT Study Investigators et al.. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939) The ODIXa-DVT Study.  Circulation. 2007;  116 180-187
  • 23 Buller H R. Once-daily treatment with an oral, direct factor Xa inhibitor- rivaroxaban (BAY 59-7939)-in patients with acute, symptomatic deep vein thrombosis: the EINSTEIN-DVT dose-finding study [abstract].  Eur Heart J. 2006;  27(Suppl) 761
  • 24 Pinto D J, Orwat M J, 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
  • 25 Lassen M R, Davidson B L, 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 2368-2375
  • 26 Buller H R. A dose finding study of the oral direct factor Xa inhibitor apixaban in the treatment of patients with acute symptomatic deep vein thrombosis-The Botticelli Investigators.  J Thromb Haemost. 2007;  5(Suppl) , abstract O-S-003
  • 27 Norman P. Medicinal Chemistry-12th RSC-SCI Symposium (Part I), Enzyme Inhibitors. Cambridge, UK; IDdb Meeting Report 2003
  • 28 Agnelli G, Haas S K, Krueger K A, Ginsberg J S, Dmitrienko A, Brandt J T. A phase II study of the safety and efficacy of a novel oral fXa inhibitor (LY517717) for the prevention of venous thromboembolism following TKR or THR.  J Thromb Haemost. 2007;  5 746-753
  • 29 Iwatsuki Y, Shigenaga T, Moritani Y et al.. Biochemical and pharmacological profiles of YM150, an oral direct factor Xa inhibitor.  Blood. 2006;  108 , abstract 911
  • 30 Eriksson B I, Turpie A GG, Lassen M R for the Onyx Study Group et al. 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 1660-1665
  • 31 Zafar M U, Vorchheimer D A, Gaztanaga J 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;  98 883-888
  • 32 Linkins L A, Weitz J I. Pharmacology and clinical potential of direct thrombin inhibitors.  Curr Pharm Des. 2005;  11 3877-3884
  • 33 Weitz J I. Factor Xa or thrombin: is thrombin a better target?.  J Thromb Haemost. 2007;  5(Suppl 1) 65-67
  • 34 Weitz J I, Buller H R. Direct thrombin inhibitors in acute coronary syndromes: present and future.  Circulation. 2002;  105 1004-1011
  • 35 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;  101 171-181
  • 36 Wolzt M, Sarich T S, Eriksson U G. Pharmacokinetics and pharmacodynamics of ximelagatran.  Semin Vasc Med. 2005;  5 245-253
  • 37 Harenberg J, Jörg I, Weiss C. Observations of alanine aminotransferase and aspratate aminotransferase in THRIVE studies treated orally with ximelagatran.  Int J Toxicol. 2006;  25 165-169
  • 38 Harenberg J, Jörg I, Weiss C. Incidence of recurrent venous thromboembolism of patients after termination of treatment with ximelagatran.  Eur J Clin Pharmacol. 2006;  62 173-177
  • 39 Lee W M, Larrey D, Olsson R et al.. Hepatic findings in long-term clinical trials of ximelagatran.  Drug Saf. 2005;  28 351-370
  • 40 Gurewich V. Ximelagatran-promises and concerns.  JAMA. 2005;  293 736-739
  • 41 Stangier K J, Rathgen K, Staehle H, Gansser D, Roth W. 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
  • 42 Eriksson B I, Dahl O E, Buller H R 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
  • 43 Ezekowitz M D, Reilly P A, 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

Job HarenbergM.D. 

Clinical Pharmacology Mannheim, Vascular Pharmacotherapy, Faculty of Medicine, University of Heidelberg

Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany

Email: job.harenberg@med.ma.uni-heidelberg.de