New Anticoagulants

ABSTRACT

The limitations of heparin and warfarin have prompted the search for new anticoagulants for the prevention and treatment of venous and arterial thromboembolism. Although many such agents are in development, only a few have reached phase II or higher levels of clinical testing. This article reviews venous and arterial thrombogenesis, discusses the regulation of coagulation, identifies the molecular targets for new anticoagulants currently under development, describes the agents in more advanced stages of clinical testing, and provides clinical perspective on the opportunities for new anticoagulant drugs.

KEYWORDS

Anticoagulants - thromboembolism - heparin - warfarin - thrombin inhibitor - factor Xa inhibitors

REFERENCES

• 1 Hirsh J, Warkentin T E, Shaugnessy S G. et al . Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety.  Chest . 2001;  119 64S-94S
• 2 Hirsh J, Dalen J E, Anderson D R. et al . Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.  Chest . 2001;  119 8S-21S
• 3 Fuster V, Badimon L, Badimon J J, Chesebro J H. The pathogenesis of coronary artery disease and the acute coronary syndromes.  N Engl J Med . 1992;  326 310-318
• 4 Furie B, Furie B C. Molecular and cellular biology of blood coagulation.  N Engl J Med . 1992;  326 800-806
• 5 Broze Jr J G>. Tissue factor pathway inhibitor.  Thromb Haemost . 1995;  74 90-93
• 6 Walsh P N. Roles of platelets and factor XI in the initiation of blood coagulation by thrombin.  Thromb Haemost . 2001;  86 75-82
• 7 Esmon C T, Ding W, Yasuhiro K. et al . The protein C pathway: new insights.  Thromb Haemost . 1997;  78 70-74
• 8 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
• 9 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
• 10 Cappello M, Vlasuk G P, Bergum P W. et al . Ancylostoma caninum anticoagulant peptide: a hookworm-derived inhibitor of human coagulation factor Xa.  Proc Natl Acad Sci U S A . 1995;  92 6152-6156
• 11 Stanssens P, Bergum P W, Gansemans Y. et al . Anticoagulant repertoire of the hookworm Ancylostoma caninum Proc Natl Acad Sci U S A .  1996;  93 2149-2154
• 12 Lee A, Agnelli G, Büller 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
• 13 Taylor Jr B F. 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
• 14 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
• 15 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 (abstr).  J Am Coll Cardiol . 2000;  36 312
• 16 Weitz J I, Crowther M. Direct thrombin inhibitors.  Thromb Res . 2002;  106 V275-V284
• 17 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
• 18 Bijsterveld N R, Moons A H, Boekholdt S M. et al . Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers.  Circulation . 2002;  106 2550-2554
• 19 Eriksson B I, Bauer K A, Lassen M R. 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 Lassen M R, Bauer K A, Eriksson B I. et al . 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
• 21 Turpie A G, Bauer K A, Eriksson B I. et al . 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
• 22 Bauer K A, Eriksson B I, Lassen M R. 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 Bauer K A, Eriksson B I, Lassen M R. et al . Influence of the duration of fondaparinux prophylaxis in preventing venous thromboembolism following hip fracture surgery (abstr).  Blood . 2002;  100 304
• 24 Matisse Investigators. Fondaparinux (Arixtra) in comparison to low-molecular weight heparin for the initial treatment of symptomatic deep venous thrombosis or pulmonary embolism: the Matisse clinical outcome studies (abstr).  Blood . 2002;  100 302
• 25 The Matisse Investigators. Subcutaneous fondaparniux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.  N Engl J Med . 2003;  349 1695-1702
• 25a 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
• 26 Ferguson J J. Meeting highlights: American Heart Association scientific sessions 2001.  Circulation . 2002;  105 e37-e41.
• 27 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
• 28 Persist Investigators. A novel long-acting synthetic factor Xa inhibitor (idraparinux sodium) to replace warfarin for secondary prevention in deep vein thrombosis: a phase II evaluation (abstr).  Blood . 2002;  100 301
• 29 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
• 30 Manns B J, Lee H, Doig C J. et al . An economic evaluation of activated protein C treatment for severe sepsis.  N Engl J Med . 2002;  347 993-1000
• 31 Ettingshausen C E, Veldmann A, Beeg T. et al . Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans.  Semin Thromb Hemost . 1999;  25 537-541
• 32 White B, Livingstone W, Murphy C. et al . An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia.  Blood . 2000;  96 3719-3724
• 33 Faust S N, Levin M, Harrison O B. et al . Dysfunction of endothelial protein C activation in severe meningococcal sepsis.  N Engl J Med . 2001;  345 408-416
• 34 Maruyama I. Recombinant thrombomodulin and activated protein C in the treatment of disseminated intravascular coagulation.  Thromb Haemost . 1999;  82 718-721
• 35 Wallis R B. Hirudins: from leeches to man.  Semin Thromb Hemost . 1996;  22 185-196
• 36 Toschi V, Lettino M, Gallo R. et al . Biochemistry and biology of hirudin.  Coron Artery Dis . 1996;  7 420-428
• 37 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
• 38 Maraganore J M, Bourdon P, Jablonski J. et al . Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin.  Biochemistry . 1990;  29 7095-7101
• 39 Skrzypczak-Jankun E, Carperos V E, Ravichandran K L. et al . Structure of the hirugen and hirulog 1 complexes of alpha-thrombin.  J Mol Biol . 1991;  221 1379-1393
• 40 Witting J I, Bourdon P, Maraganore J M. et al . Hirulog-1 and -B2 thrombin specificity.  Biochem J . 1992;  287 663-664
• 41 Fox I, Dawson A, Loynds P. et al . Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans.  Thromb Haemost . 1993;  69 157-163
• 42 Robson R. The use of bivalirudin in patients with renal impairment.  J Invasive Cardiol . 2000;  12 33F-36F
• 43 Bittl J A, Strony J, Brinker J A. et al . Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or post infarction angina. Hirulog Angioplasty Study Investigators.  N Engl J Med . 1995;  333 764-769
• 44 Bittl J A, Chaitman B R, Feit F. et al . Bivalirudin versus heparin during coronary angioplasty for unstable or post-infarction angina: the final report of the Bivalirudin Angioplasty Study.  Am Heart J . 2001;  142 952-959
• 45 Lincoff A M, Kleiman N S, Kottke-Marchant K. et al . Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET).  Am Heart J . 2002;  143 847-853
• 46 Lincoff A M, Bittl J A, Harrington R A. et al . Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 Trial.  JAMA . 2003;  289 853-863
• 47 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
• 48 Banner D W, Hadvary P. Inhibitor binding to thrombin: x-ray crystallographic studies.  Adv Exp Med Biol . 1993;  340 27-33
• 49 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
• 50 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
• 51 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
• 52 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
• 53 Glynn O. The express study: preliminary results.  Int J Clin Pract . 2003;  57 57-59
• 54 Colwell C W, Berkowitz S D, Davidson B L. et al . Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study.  J Thromb Haemost . 2003;  1 2119-2130
• 55 Francis C W, Davidson B L, Berkowitz S D. et al . Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty.  Ann Intern Med . 2002;  137 648-655
• 56 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
• 57 Eriksson H, Wahlander K, Gustafsson D. et al . 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
• 58 Eriksson H, Wahlander K, Lundstrom T. et al . Extended secondary prevention with the oral direct thrombin inhibitor ximelagatran for 18 months after 6 months of anticoagulation in patients with venous thromboembolism: a randomized, placebo-controlled trial.  Blood . 2002;  100 297
• 59 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 1445-141
• 60 Petersen P. A long-term follow-up of ximelagatran as an oral anticoagulant for the prevention of stroke and systemic embolism in patients with atrial fibrillation (abstr).  Blood . 2001;  98 2953
• 61 Halperin J L, 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.  Am Heart J . 2003;  146 431-438
• 62 Guevara A, Labarca J, Gonzalez-Martin G. Heparin-induced transaminase elevations: a prospective study.  Int J Clin Pharmacol Ther Toxicol . 1993;  31 137-141
• 63 Walenga J M, Jeske W P, Samama M M. et al . Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent.  Expert Opin Investig Drugs . 2002;  11 397-407
• 64 Daud A N, Ahsan A, Iqbal O. et al . Synthetic heparin pentasaccharide depolymerization by heparinase I: molecular and biological implications.  Clin Appl Thromb Hemost . 2001;  7 58-64
• 65 Prandoni P, Bruchi O, Sabbion P. et al . Prolonged thromboprophylaxis with oral anticoagulants after total hip arthroplasty: a prospective controlled randomized study.  Arch Intern Med . 2002;  162 1966-1971
• 66 Hull R D, Pineo G F, Francis C. et al . Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators.  Arch Intern Med . 2000;  160 2208-2215
• 67 Cohen A T, Bailey C S, Alikhan F, Cooper D J. Extended thromboprophylaxis with low molecular weight heparin reduces symptomatic venous thromboembolism following lower limb arthroplasty: a meta-analysis.  Thromb Haemost . 2001;  85 940-941
• 68 Levine M N, Hirsh J, Gent M. et al . Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis.  Thromb Haemost . 1995;  74 606-611
• 69 Schulman S, Rhedin A S, Lindmarker P. et al . A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism.  N Engl J Med . 1995;  332 1661-1665
• 70 Schulman S, Granqvist S, Holmstrom M. et al . The duration of oral anticoagulant therapy after a second episode of venous thromboembolism.  N Engl J Med . 1997;  336 393-398
• 71 Kearon C, Gent M, Hirsh J. et al . A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.  N Engl J Med . 1999;  340 901-907
• 72 Agnelli G, Prandoni P, Santamaria M G. et al . Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis.  N Engl J Med . 2001;  345 165-169
• 73 Albers G W, Dalen J, Laupacis A. et al . Antithrombotic therapy in atrial fibrillation.  Chest . 2001;  119 194S-206S
• 74 Yusuf S, Zhao F, Mehta S R. et al . Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.  N Engl J Med . 2001;  345 494-502
• 75 Hurlen M H, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction.  N Engl J Med . 2002;  347 969-974