New anticoagulants

Summary

Heparins and vitamin K antagonists have been the cornerstones of anticoagulation therapy for several decades. Although they are very effective at inhibiting the coagulation process, they have several practical limitations. This was a challenge for the development of therapies that will overcome these drawbacks while matching the efficacy of the two classes of anticoagulants. Advances were achieved in the development of safer, convenient, more specific treatments, which should provide predictable anticoagulant responses and substantially improve the prevention and management of thromboembolic disorders. In the search for new agents matching the ideal anticoagulant profile, different steps in the coagulation cascade have been targeted, including direct thrombin inhibition, and inhibition of factor Xa, factor IXa, the factor Vlla-tissue factor complex and the factor Va-factor Vllla complex. The most advanced clinical development has been achieved with direct factor Xa- and factor IIa-inhibitors which may replace conventional anticoagulants for long-term prevention and treatment of venous and arterial thromboembolic complications.

Zusammenfassung

Heparine und Vitamin-K-Antagonisten waren die tragenden Säulen der gerinnungshemmenden Therapie in den vergangenen Jahrzehnten. Diese Pharmaka sind zwar sehr wirksame Antikoagulanzien, haben jedoch einige Nachteile bei der praktischen Anwendung. Dies führte zur Entwicklung neuer gerinnungshemmender Medikamente, die im Vergleich zu den konventionellen eine mindestens ebenbürtige Wirksamkeit haben, jedoch ohne deren Limitierungen aufzuweisen. Fortschritte wurden hinsichtlich Verträglichkeit, einfacher Anwendung und spezifischer Wirkung erzielt, was zu Verbesserungen der Prädiktivität und des Thrombosemanagements führte. Auf der Suche nach einem Antikoagulans mit idealem Profil wurden verschiedene Stufen der Gerinnungskaskade gezielt gehemmt, z. B. Thrombin, Faktor X, Faktor IX sowie Komplexe von Faktor VIIa und Tissue-Faktor bzw. Faktor Va und Faktor VIIIa. Die klinische Entwicklung der direkten Faktor-Xa- und Faktor-IIa-Inhibitoren ist am weitesten vorangeschritten, was möglicherweise zum Ersatz der konventionellen Antikoagulanzien in der Langzeitprophylaxe und Therapie venöser und arterieller thromboembolischer Komplikationen führt.

Keywords

Anticoagulants - factor Xa inhibitors - factor IIa inhibitors - heparins - vitamin K antagonists

Schlüsselwörter

Antikoagulanzien - Faktor-Xa-Inhibitoren - Faktor-IIa-Inhibitoren - Vitamin-K-Antagonisten

• References

• 1 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: 238-47.
• 2 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 or THR. Blood 2005; 106: A278.
• 3 Alexander JH, Yang H, Becker RC. 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: 439-47.
• 4 Bernard GR, Vincent JL, Laterre PF. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
• 5 Bittl JA, Feit F. A randomized comparison of bivalirudin and heparin in patients undergoing coronary angioplasty for postinfarction angina. Hirulog Angioplasty Study Investigators. Am J Cardiol 1998; 82: 43P-49P.
• 6 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.
• 7 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: 1695-702.
• 8 Direct Thrombin Inhibitor Trialists’ Collaborative Group.. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet 2002; 359: 294-302.
• 9 Eriksson BI, Dahl OE, Büller 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; 3: 103-11.
• 10 Eriksson BI, Turpie AGG, Lassen MR. et al. YM150, 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: A1865.
• 11 Eriksson BI, Borris L, Dahl OE. et al. Oral, direct Factor Xa inhibition with BAY 59–7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4: 121-8.
• 12 Giangrande PL. Fondaparinux (Arixtra): a new anticoagulant. Int J Clin Pract 2002; 56: 615-7.
• 13 Haas S. Medical indications and considerations for future clinical decision making. Thromb Res 2003; 109 (Suppl. 01) S31-S37.
• 14 Hart RG, Benavente O, McBride R. et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: 492-501.
• 15 Hinder M. Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, with tirofiban in healthy volunteers. Thromb Haemost 2005; 93: 794-5.
• 16 Hinder M, Frick A, Rosenburg R. et al. Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid. Thromb Haemost 2006; 95: 224-8.
• 17 Hirsh J, Guyatt G, Albers G. et al. The seventh ACCP conference of antithrombotic and thrombolytic therapy: Evidence-based guidelines. Chest 2004; 126: 172S-173S.
• 18 Hirsh J, Raschke R. Heparin and low-molecularweight heparin. Chest 2004; 126: 188S-203S.
• 19 Huisman MV, Borris LC, Dahl OE. et al. An oral, direct Factor Xa inhibitor, rivaroxaban: once-daily regimen for thromboprophylaxis after hip replacement. Pathophysiol Haemost Thromb 2006; 35: A1-A1163.
• 20 Kubitza D, Becka M, Wensing G. et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939-an oral, direct factor Xa inhibitorafter multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: 873-80.
• 21 Kubitza D, Haas S. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opin Investig Drugs 2006; 15: 843-55.
• 22 Lee A, Agnelli G, Buller 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: 74-8.
• 23 MICHELANGELO OASIS 5 Steering Committee.. Design and rationale of the MICHELANGELO Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 trial program evaluating fondaparinux, a synthetic factor Xa inhibitor, in patients with non-ST-segment elevation acute coronary syndromes. Am Heart J 2005; 150: 1107.
• 24 Morishima Y, Furogohri T, Isobe K. et al. In vitro characteristics, anticoagulant effects and in vivo antithrombotic efficacy of a novel, potent and orally active direct factor Xa inhibitor, DU-176b. ASHAnnual MeetingAbstracts 2004; 104: 1862.
• 25 Paccaly A, Frick A, Rohtagi S. et al. Pharmacokinetics of otamixaban, a direct factor Xa inhibitor, in healthy male subjects: Pharmacokinetic model development for phase 2/3 simulation of exposure. J Clin Pharmacol 2006; 46: 37-44.
• 26 Paccaly A, Ozoux ML, Chu V. et al. Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor. Thromb Haemost 2005; 94: 1156-63.
• 27 PERSIST Investigators.. A novel long-acting synthetic factor Xa inhibitor (SanOrg43006) to replace warfarin for secondary prevention in deep vein thrombosis. A phase II evaluation. J Thromb Haemost 2004; 2: 47-53.
• 28 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; 3: 514-21.
• 29 Stangier J, Nehmiz G, Reilly P. et al. Pharmacokinetics of BIBR 953 ZW, a novel low molecular weight direct thrombin inhibitor in healthy volunteers. 18th Congress ISTH 2001 (July 6–12, Paris), OC2347.
• 30 Turpie AG, Bauer KA, Eriksson BI. et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002; 162: 1833-40.
• 31 Turpie AG, Fisher WD, Bauer KA. et al. BAY 59–7939: 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; 3: 2479-86.
• 32 Wallentin LC, Ezekowith M, Simmers TA. et al. Safety and efficacy of a new oral direct thrombin inhibitor dabigatran in atrial fibrillation – A dose finding trial with comparison to warfarin. Eur Soc Cardiol Cong. 2005 (Sept 3–7. Stockholm) P2949.
• 33 Weitz JI, Hudoba M, Massel D. et al. Clot-bound thrombin is protected from inhibition by heparinantithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
• 34 Weitz JI. Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost 2006; 96: 274-84.
• 35 Yusuf S, Mehta SR, Chrolavicius S. et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006; 295: 1519-30.
• 36 Zafar MU, Gaztanga J, Velez M. et al. A phase-I study to assess the antithrombotic properties of Du-176b: an orally active direct factor-Xa inhibitor. J. Am. Coll. Cardiol. 2006; 47: 288A 908-161.