Download PDF
Semin Thromb Hemost 2006; 32(8): 793-802
DOI: 10.1055/s-2006-955462
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

New Anticoagulants

Giancarlo Agnelli1 , Cecilia Becattini1
  • 1Internal and Cardiovascular Medicine & Stroke Unit, Department of Internal Medicine, University of Perugia, Perugia, Italy
Further Information

Publication History

Publication Date:
15 December 2006 (online)

    Permissions and Reprints

ABSTRACT

The anticoagulant drugs have an essential role in the prevention and treatment of thromboembolic diseases. The currently available anticoagulants have several limitations, including a narrow therapeutic window, the risk of bleeding complications and, for some drugs, the need for laboratory monitoring and parenteral administration. These limitations make the case for the development of new anticoagulants. An ideal anticoagulant should be effective, safe, simple to use, and widely applicable. The new anticoagulants currently under investigation are obtained by molecular technology that makes it possible to target their effect toward a selected step of the coagulation cascade. Based on their target, new anticoagulants can be classified into three groups: inhibitors of activation of coagulation, inhibitors of propagation of coagulation, and inhibitors of thrombin formation. Several new anticoagulants currently are in different phases of development. Some of them have been approved for clinical use, others are in advanced phase of clinical development, and some are still in the initial phase of investigation.

KEYWORDS

Anticoagulant therapy - antithrombotic therapy - anticoagulants - direct thrombin inhibitors - factor Xa inhibitors

REFERENCES

  • 1 Hirsh J, Raschke R. Heparin and low-molecular-weight heparin.  Chest. 2004;  126 S188-S203
    CrossrefPubMedSearch in Google Scholar
  • 2 Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists.  Chest. 2004;  126 204S-233S
    CrossrefPubMedSearch in Google Scholar
  • 3 Weitz J I, Hirsh J, Samama M M. New anticoagulant drugs.  Chest. 2004;  126 265S-286S
    CrossrefPubMedSearch in Google Scholar
  • 4 Furie B, Furie B C. Molecular and cellular biology of blood coagulation.  N Engl J Med. 1992;  326 800-806
    CrossrefPubMedSearch in Google Scholar
  • 5 Mann K G, Butenas S, Brummel K. The dynamics of thrombin formation.  Arterioscler Thromb Vasc Biol. 2003;  23 17-25
    CrossrefPubMedSearch in Google Scholar
  • 6 Abraham E, Reinhart K, Svoboda P et al.. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.  Crit Care Med. 2001;  29 2081-2089
    CrossrefPubMedSearch in Google Scholar
  • 7 Abraham E, Reinhart K, Opal S et al.. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.  JAMA. 2003;  290 238-247
    Search in Google Scholar
  • 8 Taylor Jr F B. Role of tissue factor and factor VIIa in the coagulant and inflammatory response to LD100 Escherichia coli in the baboon.  Haemostasis. 1996;  26 83-91
    PubMedSearch in Google Scholar
  • 9 Jang Y, Guzman L A, Lincoff A M et al.. Influence of blockade at specific levels of the coagulant cascade on restenosis in a rabbit atherosclerotic femoral artery injury model.  Circulation. 1995;  92 3041-3050
    PubMedSearch in Google Scholar
  • 10 Lincoff A M. First clinical investigation of a tissue-factor inhibitor administered during percutaneous coronary revascularization: a randomized, double-blinded, dose-escalation trial- assessing safety and efficacy of FFR-FVIIa in percutaneous transluminal coronary angioplasty (ASIS) trial.  J Am Coll Cardiol. 2000;  36 312 , (abst)
    PubMedSearch in Google Scholar
  • 11 Cappello M, Vlasuk G P, Bergum P W, Huang S, Hotez P J. Ancylostoma caninum anticoagulant peptide: a hookworm-derived inhibitor of human coagulation factor Xa.  Proc Natl Acad Sci USA. 1995;  92 6152-6156
    PubMedSearch in Google Scholar
  • 12 Stassen P, Bergum P W, Gansemans Y et al.. Anticoagulant repertoire of the hookworm Ancylostoma caninum .  Proc Natl Acad Sci USA. 1996;  93 2149-2154
    CrossrefPubMedSearch in Google Scholar
  • 13 Lee A, Agnelli G, Bűller H et al.. Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement.  Circulation. 2001;  104 74-78
    PubMedSearch in Google Scholar
  • 14 Rezaie A R. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex.  Blood. 2001;  97 2308-2313
    CrossrefPubMedSearch in Google Scholar
  • 15 Brufatto N, Nesheim M E. 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
    CrossrefPubMedSearch in Google Scholar
  • 16 Boneu B, Necciari J, Cariou R et al.. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/ORG31540) with high affinity to antithrombin III in man.  Thromb Haemost. 1995;  74 1468-1473
    PubMedSearch in Google Scholar
  • 17 Eriksson B I, Bauer K A, Lassen M R, Turpie A G. Steering Committee of the Pentasaccharide in hip fracture . Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery.  N Engl J Med. 2001;  345 1298-1304
    CrossrefPubMedSearch in Google Scholar
  • 18 Lassen M R, Bauer K A, Eriksson B I, Turpie A G. European Pentasaccharide elective surgery study (EPHESUS) Steering Committee . Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison.  Lancet. 2002;  359 1715-1720
    CrossrefPubMedSearch in Google Scholar
  • 19 Turpie A G, Bauer K A, Eriksson B I, Lassen M R. PENTATHLON 2000 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 1721-1726
    CrossrefPubMedSearch in Google Scholar
  • 20 Bauer K A, Eriksson B I, Lassen M R, Turpie A G. 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 1305-1310
    CrossrefPubMedSearch in Google Scholar
  • 21 Turpie A G, Bauer K A, Eriksson B I, Lassen M R. Fondaparinux versus enoxaparin for prevention of venous thromboembolism in major orthopaedic surgery. A meta-analysis of 4 randomized, double blind studies.  Arch Intern Med. 2002;  162 1833-1840
    CrossrefPubMedSearch in Google Scholar
  • 22 Büller H R, Agnelli G, Hull R D, Hyers T M, Prins M H, Raskob G E. Antithrombotic therapy for venous thromboembolic disease.  Chest. 2004;  126 S401-S428
    CrossrefPubMedSearch in Google Scholar
  • 23 Eriksson B I, Lassen M R. PENTasaccharide in Hip-FRAture Surgery Plus Investigators . Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo controlled, double-blind study.  Arch Intern Med. 2003;  163 1337-1342
    CrossrefPubMedSearch in Google Scholar
  • 24 Agnelli G, Bergqvist D, Cohen A, Gallus A, Gent M. A randomized double-blind study to compare the efficacy and safety of fondaparinux with dalteparin in the prevention of venous thromboembolism after high-risk abdominal surgery: the Pegasus Study.  J Thromb Haemost. 2003;  1(suppl) OC006 , (abst)
    PubMedSearch in Google Scholar
  • 25 Cohen A T, Gallus A S, Lassen M R et al.. Fondaparinux vs. placebo for the prevention of venous thromboembolism in acutely ill medical patients (artemis).  J Thromb Haemost. 2003;  1(suppl) 2046 , (abst)
    CrossrefPubMedSearch in Google Scholar
  • 26 Buller H R, Davidson B L, 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
    PubMedSearch in Google Scholar
  • 27 The MATISSE Investigators . Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.  N Engl J Med. 2003;  349 1695-1702
    CrossrefPubMedSearch in Google Scholar
  • 28 Coussement P K, Bassand J P, Convens C et al.. A synthetic factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction: the PENTALYSE study.  Eur Heart J. 2001;  22 1716-1724
    CrossrefPubMedSearch in Google Scholar
  • 29 Ferguson J J. Meeting highlights: American Heart Association scientific sessions 2001.  Circulation. 2002;  105 e37-e41
    CrossrefPubMedSearch in Google Scholar
  • 30 Herbert J M, Herault J P, Bernat A et al.. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide.  Blood. 1998;  91 4197-4205
    PubMedSearch in Google Scholar
  • 31 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
    CrossrefPubMedSearch in Google Scholar
  • 32 Lassen M R, Davidson B L, Gallus A et al.. A phase II, randomized, double blind, five-arm, parallel-group, dose-response study of a new oral directly-acting factor Xa inhibitor, razaxaban, for prevention of deep vein thrombosis in knee-replacement surgery-on behalf of the Razaxaban Investigators.  Blood. 2003;  102(suppl) 11 , (abst 41)
    PubMedSearch in Google Scholar
  • 33 Esmon C T, Ding W, Yasuhiro K et al.. The protein C pathway: new insights.  Thromb Haemost. 1997;  78 70-74
    PubMedSearch in Google Scholar
  • 34 Bernard G R, Vincent J L, Laterre P F et al.. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709
    CrossrefPubMedSearch in Google Scholar
  • 35 Moll S, Lindley C, Pescatore S et al.. Phase 1 study of a novel recombinant human soluble thrombomodulin ART-123.  J Thromb Haemost. 2004;  2 1745-1751
    CrossrefPubMedSearch in Google Scholar
  • 36 Kearon C, Comp P, Douketis J et al.. A dose-response study of a recombinant soluble thrombomodulin (ART-123) in the prevention of venous thromboembolism after total hip replacement.  J Thromb Haemost. 2005;  3 962-968
    CrossrefPubMedSearch in Google Scholar
  • 37 Weitz J I, Bűller H R. Direct thrombin inhibitors in acute coronary syndromes: present and future.  Circulation. 2002;  105 1004-1011
    CrossrefPubMedSearch in Google Scholar
  • 38 Weitz J I, Crowther M. Direct thrombin inhibitors.  Thromb Res. 2002;  106 V275-V284
    CrossrefPubMedSearch in Google Scholar
  • 39 Agnelli G, Cosmi B, Di Filippo P et al.. A randomised, double-blind, placebo-controlled trial of dermatan sulphate for prevention of deep vein thrombosis in hip fracture.  Thromb Haemost. 1992;  67 203-208
    PubMedSearch in Google Scholar
  • 40 Taliani M R, Agnelli G, Nenci G G, Gianese F. Dermatan suphate in patients with heparin induced thrombocytopenia.  Br J Haematol. 1999;  104 87-89
    CrossrefPubMedSearch in Google Scholar
  • 41 Wallis R B. Hirudins: from leeches to man.  Semin Thromb Hemost. 1996;  22 185-196
    PubMedSearch in Google Scholar
  • 42 Toschi V, Lettino M, Gallo R, Badimon J J, Chesebro J H. Biochemistry and biology of hirudin.  Coron Artery Dis. 1996;  7 420-428
    PubMedSearch in Google Scholar
  • 43 Lefevre G, Duval M, Gauron S et al.. Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin.  Clin Pharmacol Ther. 1997;  62 50-59
    CrossrefPubMedSearch in Google Scholar
  • 44 Eriksson B I, Ekman S, Lindbratt S et al.. Prevention of thromboembolism with use of recombinant hirudin: results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement.  J Bone Joint Surg Am. 1997;  79 326-333
    PubMedSearch in Google Scholar
  • 45 Eriksson B I, Wille-Jørgensen P, Kalebo P et al.. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement.  N Engl J Med. 1997;  337 1329-1335
    CrossrefPubMedSearch in Google Scholar
  • 46 Organization to Assess Strategies for Ischemic Syndromes Investigators . Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study: Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators.  Circulation. 1997;  96 769-777
    PubMedSearch in Google Scholar
  • 47 Organization to Assess Strategies for Ischemic Syndromes Investigators . Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularization procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators.  Lancet. 1999;  353 429-438
    CrossrefPubMedSearch in Google Scholar
  • 48 Antman E M. and the TIMI 9A Investigators . Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial.  Circulation. 1994;  90 1624-1630
    PubMedSearch in Google Scholar
  • 49 Neuhaus K L, von Essen R, Tebbe U et al.. Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study: a study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK).  Circulation. 1994;  90 1638-1642
    PubMedSearch in Google Scholar
  • 50 The GUSTO IIa Investigators . Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes: the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa investigators.  Circulation. 1994;  90 1631-1637
    PubMedSearch in Google Scholar
  • 51 The GUSTO Investigators . An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction: the GUSTO Investigators.  N Engl J Med. 1993;  329 673-682
    CrossrefPubMedSearch in Google Scholar
  • 52 The GUSTO IIb Investigators . A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes: the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators.  N Engl J Med. 1996;  335 775-782
    CrossrefPubMedSearch in Google Scholar
  • 53 Metz B K, White H D, Granger C B et al.. Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: results from the GUSTO-IIb Trial: Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIb) Investigators.  J Am Coll Cardiol. 1998;  31 1493-1498
    CrossrefPubMedSearch in Google Scholar
  • 54 Serruys P W, Herrman J P, Simon R et al.. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty: Helvetica Investigators.  N Engl J Med. 1995;  333 757-763
    CrossrefPubMedSearch in Google Scholar
  • 55 Maraganore J M, Bourdon P, Jablonski J, Ramachandran K L, Fenton II J W. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin.  Biochemistry. 1990;  29 7095-7101
    CrossrefPubMedSearch in Google Scholar
  • 56 Ginsberg J S, Michael T, Nurmohamed M T et al.. Use of hirulog in the prevention of venous thrombosis after major hip or knee surgery.  Circulation. 1994;  90 2385-2389
    PubMedSearch in Google Scholar
  • 57 Hursting M J, Alford K L, Becker J C et al.. Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor.  Semin Thromb Hemost. 1997;  23 503-516
    Thieme ConnectPubMedSearch in Google Scholar
  • 58 Banner D W, Hadvary P. Inhibitor binding to thrombin: x-ray crystallographic studies.  Adv Exp Med Biol. 1993;  340 27-33
    PubMedSearch in Google Scholar
  • 59 Swan S K, Hursting M J. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction.  Pharmacotherapy. 2000;  20 318-329
    CrossrefPubMedSearch in Google Scholar
  • 60 Gustafsson D, Nystrom J E, Carlsson S et al.. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.  Thromb Res. 2001;  101 171-181
    CrossrefPubMedSearch in Google Scholar
  • 61 Eriksson B I, Bergqvist D, Kalebo P et al.. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial.  Lancet. 2002;  360 1441-1447
    CrossrefPubMedSearch in Google Scholar
  • 62 Eriksson B I, Agnelli G, Cohen A T et al.. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee joint replacement.  Thromb Haemost. 2003;  89 288-296
    PubMedSearch in Google Scholar
  • 63 Eriksson B I, Agnelli G, Cohen A T et al.. The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement. The EXPRESS study.  J Thromb Haemost. 2003;  1 2490-2496
    CrossrefPubMedSearch in Google Scholar
  • 64 Francis C W, Davidson B L, Berkowitz S D et al.. Ximelagatran versus warfarin for the prevention of VTE after total knee arthroplasty.  Ann Intern Med. 2002;  137 648-655
    PubMedSearch in Google Scholar
  • 65 Francis C W, Berkowitz S D, Comp P C 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
    CrossrefPubMedSearch in Google Scholar
  • 66 Colwell C W, Berkowitz S D, Davidson B L et al.. Randomized, double blind comparison of Ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism (VTE) after total knee replacement (TKR) EXULT-b.  Blood. 2003;  102 11 , (abst 39)
    PubMedSearch in Google Scholar
  • 67 Eriksson H, Wahlander K, Gustafsson D, Welin L T, Frison L, Schulman S. Thrive Investigators. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I.  J Thromb Haemost. 2003;  1 41-47
    CrossrefPubMedSearch in Google Scholar
  • 68 Fiessinger J N, Huisman M V, Davidson B L. the THRIVE Investigators . Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis a randomized trial.  JAMA. 2005;  293 681-689
    CrossrefPubMedSearch in Google Scholar
  • 69 Schulman S, Wahlander K, Lundstrom T, Clason S B, Eriksson H. for the THRIVE III Investigators . Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.  N Engl J Med. 2003;  349 1713-1721
    CrossrefPubMedSearch in Google Scholar
  • 70 Petersen P, Grind M, Adler J et al.. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding tolerability, and safety study.  J Am Coll Cardiol. 2003;  41 1445-1451
    CrossrefPubMedSearch in Google Scholar
  • 71 Executive Steering Committee on behalf of the SPORTIF III Investigators . Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): a randomized trial.  Lancet. 2003;  362 1691-1698
    CrossrefPubMedSearch in Google Scholar
  • 72 SPORTIF Executive Steering Committee for the SPORTIF V Investigators . Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. A randomized trial.  JAMA. 2005;  293 690-698
    CrossrefPubMedSearch in Google Scholar
  • 73 Halperin J L. for the Executive Steering Committee, SPORTIF III and V Study Investigators . Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: rationale, objectives, and design of a pair of clinical studies and baseline patient characteristics (SPORTIF III and V).  Am Heart J. 2003;  146 431-438
    CrossrefPubMedSearch in Google Scholar
  • 74 Wallentin L, Wilcox R G, Weaver W D et al.. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial.  Lancet. 2003;  362 789-797
    CrossrefPubMedSearch in Google Scholar
  • 75 Eriksson B I, Dahl O E, Ahnfelt I et al.. Dose escalating safety of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: Bistro I.  J Thromb Haemost. 2004;  2 1573-1580
    CrossrefPubMedSearch in Google Scholar
  • 76 Eriksson B I, Dahl O E, Büller H R et al.. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for the prevention of thromboembolic events following total hip or knee replacement: the Bistro II randomized trial.  J Thromb Haemost. 2005;  3 103-111
    CrossrefPubMedSearch in Google Scholar

Giancarlo AgnelliM.D. 

Internal and Cardiovascular Medicine & Stroke Unit Department of Internal Medicine, University of Perugia, Ospedale Silvestrini

06129 Perugia, Italy

Email: agnellig@unipg.it