Thromb Haemost 2009; 102(05): 892-899
DOI: 10.1160/TH09-02-0134
Theme Issue Article
Schattauer GmbH

Direct inhibitors of coagulation proteins – the end of the heparin and low-molecular-weight heparin era for anticoagulant therapy?

Volker Laux
1   Acute Care Research, Global Drug Discovery Research, Bayer Schering Pharma, Wuppertal, Germany
,
Elisabeth Perzborn
1   Acute Care Research, Global Drug Discovery Research, Bayer Schering Pharma, Wuppertal, Germany
,
Stefan Heitmeier
1   Acute Care Research, Global Drug Discovery Research, Bayer Schering Pharma, Wuppertal, Germany
,
Georges von Degenfeld
1   Acute Care Research, Global Drug Discovery Research, Bayer Schering Pharma, Wuppertal, Germany
,
Elke Dittrich-Wengenroth
1   Acute Care Research, Global Drug Discovery Research, Bayer Schering Pharma, Wuppertal, Germany
,
Anja Buchmüller
1   Acute Care Research, Global Drug Discovery Research, Bayer Schering Pharma, Wuppertal, Germany
,
Christoph Gerdes
1   Acute Care Research, Global Drug Discovery Research, Bayer Schering Pharma, Wuppertal, Germany
,
Frank Misselwitz
1   Acute Care Research, Global Drug Discovery Research, Bayer Schering Pharma, Wuppertal, Germany
› Author Affiliations
Further Information

Publication History

Received: 27 February 2009

Accepted after minor revision: 17 May 2009

Publication Date:
27 November 2017 (online)

Summary

Heparins, either unfractionated or low-molecular-weight (UFH and LMWHs), and vitamin K antagonists (VKAs) are currently the anticoagulants of choice for the prevention of post-operative venous thromboembolism (VTE) and for the treatment of acute venous and arterial thromboembolism. While VKAs are widely used in the US, LMWHs are the standard of care in the EU. Although efficacious, these agents are associated with a number of drawbacks, such as the risk of heparin-induced thrombocytopenia, the need for frequent coagulation monitoring in the case of UFH and VKAs, and the parenteral mode of administration in the case of heparins, which can lead to problems associated with patient compliance. There is a need for new anticoagulants that overcome these limitations. Direct, small-molecule inhibitors of coagulation proteins targeting a single enzyme in the coagulation cascade – particularly thrombin or Factor Xa – have been developed in recent years. Two agents, the direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitor rivaroxaban, have recently been approved in the EU and several other countries for the prevention of VTE after total hip or knee replacement surgery. Here we will review data that suggest that the antithrombin-independent mechanism of action of these agents, particularly that of direct Factor Xa inhibitors, leads to increased efficacy with similar safety profiles compared with the antithrombin-dependent heparins. Although the end of the heparins era is not to be expected, the new anticoagulants presented in this review potentially represent the future of anticoagulation.

 
  • References

  • 1 Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. (8th Edition). Chest 2008; 133: 234S-256S.
  • 2 Hirsh J, Bauer KA, Donati MB. et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. (8th Edition). Chest 2008; 133: 141S-159S.
  • 3 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.
  • 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 Esko JD, Lindahl U. Molecular diversity of heparan sulfate. J Clin Invest 2001; 108: 169-173.
  • 6 Information on heparin. Available at: http://www.fda.gov/cder/drug/infopage/heparin/default.htm Accessed February 23, 2009
  • 7 Safety of Chinese heparin. Available at: http://www.idbiotech.com/spip.php?ar ticle26&lang=en Accessed February 23, 2009
  • 8 European Medicines Agency recommends measures to manage contamination of heparin-containing medicines. Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/heparin/27772208en.pdf Accessed February 23, 2009
  • 9 Hirsh J, Anand SS, Halperin JL. et al. Guide to anticoagulant therapy: Heparin: A statement for healthcare professionals from the American Heart Association. Circulation 2001; 103: 2994-3018.
  • 10 Rosenberg RD. The heparin-antithrombin system: a natural anticoagulant mechanism. 3rd Edition. ed. Philadelphia, PA: Lippincott; 1994
  • 11 Warkentin TE, Greinacher A, Koster A. et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. (8th Edition). Chest 2008; 133: 340S-380S.
  • 12 Weitz JI, Hudoba M, Massel D. et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-391.
  • 13 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 01: 1504-1514.
  • 14 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; 03: 514-521.
  • 15 Gulseth MP, Michaud J, Nutescu EA. Rivaroxaban: an oral direct inhibitor of factor Xa. Am J Health Syst Pharm 2008; 65: 1520-1529.
  • 16 Piccini JP, Patel MR, Mahaffey KW. et al. Rivaroxaban, an oral direct factor Xa inhibitor. Expert Opin Investig Drugs 2008; 17: 925-937.
  • 17 Rezaie AR. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex. Blood 2001; 97: 2308-2313.
  • 18 Herault JP, Bernat A, Pflieger AM. et al. Comparative effects of two direct and indirect factor Xa inhibitors on free and clot-bound prothrombinase. J Pharmacol Exp Ther 1997; 283: 16-22.
  • 19 Saiah E, Soares C. Small molecule coagulation cascade inhibitors in the clinic. Curr Top Med Chem 2005; 05: 1677-1695.
  • 20 Bauer KA. New anticoagulants: anti IIa vs anti Xa is – one better?. J Thromb Thrombolysis 2006; 21: 67-72.
  • 21 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.
  • 22 Hauel NH, Nar H, Priepke H. et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002; 45: 1757-1766.
  • 23 Nishio H, Ieko M, Nakabayashi T. New therapeutic option for thromboembolism – dabigatran etexilate. Expert Opin Pharmacother 2008; 09: 2509-2517.
  • 24 Ansell J. Factor Xa or thrombin: is factor Xa a better target?. J Thromb Haemost 2007; 05 (Suppl. 01) 60-64.
  • 25 Becker RC. Factor Xa-A pleuripotential protease. J Thromb Thrombolysis 2003; 15: 5-9.
  • 26 Borensztajn K, Peppelenbosch MP, Spek CA. Factor Xa: at the crossroads between coagulation and signaling in physiology and disease. Trends Mol Med 2008; 14: 429-440.
  • 27 Perzborn E, Harwardt M. Direct Thrombin Inhibitors, but Not Factor Xa Inhibitors, Enhance Thrombin Formation in Human Plasma by Interfering with the Thrombin–Thrombomodulin–Protein C System. Blood. (ASH Annual Meeting Abstracts) 2008 112. Abstract 528.
  • 28 Perzborn E, Arndt B, Fischer E. et al. An in vivo risk–benefit comparison of the effects of rivaroxaban – an oral, direct Factor Xa inhibitor – with thrombin inhibitors, warfarin and clopidogrel. J Thromb Haemost. 2007 05. Suppl 2: Abstract P-W-638.
  • 29 Lang D, Weinz C, Schwarz T. 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.
  • 30 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.
  • 31 Eriksson BI, Borris LC, Friedman RJ. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
  • 32 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.
  • 33 Turpie AGG, Lassen MR, Davidson B. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673-1680.
  • 34 Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa. Semin Thromb Hemost 2008; 34: 39-57.
  • 35 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.
  • 36 Abe K, Siu G, Edwards S. et al. Animal models of thrombosis help predict the human therapeutic concentration of PRT54021, a potent oral Factor Xa inhibitor. Blood. 2006 108. Abstract 901.
  • 37 Turpie AG, Gent M, Bauer K. et al. Evaluation of the Factor Xa (FXa) inhibitor, PRT054021 (PRT021), against enoxaparin in a randomized trial for the prevention of venous thromboembolic events after total knee replacement (EXPERT). J Thromb Haemost. 2007 05. Abstract P-T-652.
  • 38 Fuji T, Fujita S, Tachibana S. et al. Randomized, double-blind, multi-dose efficacy, safety and biomarker study of the oral Factor Xa inhibitor DU-176b compared with placebo for prevention of venous thromboembolism in patients after total knee arthroplasty. Blood (ASH Annual Meeting Abstracts) 2008; 112: 34.
  • 39 Raskob G, Cohen A, Eriksson B. et al. Randomized double-blind multi-dose trial of the oral factor-Xa inhibitor DU-176b versus LMW Heparin (Dalteparin) for prevention of venous thromboembolism after total hip replacement. Eur Heart J 2008; 29: 609.
  • 40 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. Blood. 2008 112. Abstract 33.
  • 41 Lever R, Page CP. Novel drug development opportunities for heparin. Nat Rev Drug Discov 2002; 01: 140-148.