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DOI: 10.1055/s-0037-1617033
Factor Xa inhibitors
New anticoagulants for secondary haemostasisFaktor-Xa-InhibitorenNeue Antikoagulanzien der sekundären HämostasePublikationsverlauf
Publikationsdatum:
05. Februar 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034925/200903/lookinside/thumbnails/10-1055s-0037-1617033_de-1.jpg)
Summary
Oral factor Xa (FXa) inhibitors are a promising alternative to current anticoagulants. This paper reviews the latest developments of oral direct FXa inhibitors and focuses on those which have been approved for the prevention of venous thromboembolism (VTE) after total hip or knee replacement or are in advanced development and have passed phase II (proof of principle) testing.
The most advanced drugs are apixaban, betrixaban, edoxaban, eribaxaban, rivaroxaban, LY517717, TAK-442, and YM150. Rivaroxaban (Xarelto→) is the first direct FXa inhibitor which has recently been approved for the prevention of VTE in adult patients after elective hip or knee replacement in several countries, including the European Union and Canada. Rivaroxaban has a flat dose-dependent anticoagulant response with a wide therapeutic window and low potential for drug-drug and drug-food interactions. Rivaroxaban can be given in fixed doses without coagulation monitoring.
This review describes the pharmacodynamic and pharmacokinetic profiles and the results of clinical trials with FXa inhibitors in the prevention and treatment of thromboembolic disorders.
Zusammenfassung
Orale Faktor-Xa(FXa)-Hemmer sind viel versprechende Alternativen zu den gebräuchli-chen Antikoagulanzien. In diesem Artikel werden Neuentwicklungen im Bereich der oralen direkten FXa-Hemmer vorgestellt mit Schwerpunkt auf solchen, die zur Prävention venöser Thromboembolien (VTE) nach Hüft- oder Kniegelenkersatz zugelassen sind oder sich in einem fortgeschrittenen Entwicklungsstadium befinden und die Phase-II-Studien zum Nachweis der Wirksamkeit (proof of principle) durchlaufen haben.
Apixaban, Betrixaban, Edoxaban, Eribaxaban, Rivaroxaban, LY517717, TAK-442 und YM150 sind die am weitesten entwickelten FXa-Hemmer. Rivaroxaban (Xarelto®) ist der erste direkte FXa-Hemmer, der u. a. in der Europäischen Union und in Kanada zur Prävention von VTE nach elektivem Hüft- oder Kniegelenksersatz bei Erwachsenen zugelassen ist. Für Rivaroxaban wurde eine flach verlaufende dosisabhängige antikoagulatorische Wirkung gezeigt. Sein breites therapeutisches Fenster und geringes Potenzial für Wechselwirkungen mit Pharmaka und Nahrungsmitteln erlaubt die Gabe in fixer Dosis ohne Überwachung der Blutgerinnung.
Diese Übersicht beschreibt das pharmakodynamische und pharmakokinetische Profil sowie die Ergebnisse klinischer Studien mit FXaHemmern zur Prävention und Behandlung von Thromboembolien.
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References
- 1 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: A901.
- 2 Agnelli G, Gallus A. Goldhaber et al. Treatment of proximal deep-vein thrombosis with the oral direct Factor Xa inhibitor rivaroxaban (BAY 59–7939): the ODIXa-DVT (oral direct Factor Xa inhibitor BAY 59–7939 in patients with acute symptomatic deep-vein thrombosis) study. Circulation 2007; 116: 180-187.
- 3 Agnelli G, Haas S, Ginsberg JS. et al. A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 2007; 5: 746-753.
- 4 Alexander JH. Safety of the factor Xa inhibitor, Apixaban, in combination with antiplatelet therapy after acute coronary syndrome: Results of the APPRAISE-I dose guiding trial. Presented at ESC 2008.
- 5 Biemond BJ, Perzborn E, Friederich PW. et al. Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 59–7939) – an oral, direct Factor Xa inhibitor. Thromb Haemost 2007; 97: 471-477.
- 6 Buller H, Deitchman D, Prins M. et al. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 6: 1313-1318.
- 7 Buller HR, Lensing AW, Prins MH. et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor Rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis. The EINSTEIN-DVT Dose-Ranging Study. Blood 2008; 112: 2242-2247.
- 8 Cohen AT, Armstrong D, Gazdzik T. et al. An adaptive-design dose-ranging study of PD 0348292, a new oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery. Blood 2008; 112: A980.
- 9 Depasse F, Busson J, Mnich J. et al. Effect of BAY 59–7939 – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. J Thromb Haemost 2005; 3: P1104.
- 10 Eisenberg PR, Siegel JE, Abendschein DR. et al. Importance of factor Xa in determining the procoagulant activity of whole-blood clots. J Clin Invest 1993; 91: 1877-1883.
- 11 Eriksson BI, Borris LC, Friedman RJ. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
- 12 Eriksson BI, Turpie AGG, Lassen MR. 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.
- 13 Eriksson BI, Turpie AGG, Lassen MR. et al. Once daily YM150, an oral direct Factor Xa inhibitor, for prevention of venous thromboembolism in patients undergoing elective primary hip replacement. Blood 2007; 110: A309.
- 14 Frost C, Yu Z, Nepal S. et al. Apixaban, an oral direct Factor Xa inhibitor: single-dose safety, pharmacokinetics and pharmacodynamics in healthy volunteers. J Thromb Haemost 2007; 5 (Suppl. 01) P-M-665.
- 15 Fuji T, Fujita S, Tachibana S. et al. Randomized, double-blind, multi-dose efficacy, safety and bio -marker study of the oral factor Xa inhibitor DU-176b compared with placebo for prevention of venous thromboembolism in patients after total knee arthroplasty. Blood 2008; 112: 34.
- 16 Furugohri T, Isobe K, Honda Y. et al. DU-176b, a potent and orally active factor Xa inhibitor: In vitro and in vivo pharmacological profiles. J Thromb Haemost 2008; 6: 1542-1549.
- 17 Gerotziafas GT, Elalamy I, Depasse F. et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct Factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007; 5: 886-888.
- 18 Gibson CM, Mega JL, Hammett CJ. et al. Randomized Comparison of Rivaroxaban, an Oral Direct Factor Xa Inhibitor, with Placebo in Patients with Acute Coronary Syndromes: The ATLAS ACS-TIMI 46 Trial. Circulation 2008; 118: 2311.
- 19 Gomez K, McVey JH, Tuddenham E. Inhibition of coagulation by macromolecular complexes. Haematologica 2005; 90: 1570-1576.
- 20 Graff J, von Hentig N, Misselwitz F. et al. Effects of the oral, direct Factor Xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol 2007; 47: 1398-1407.
- 21 Haertlein B, Parry TJ, Chen C. et al. Rivaroxaban – an oral, direct factor Xa inhibitor – prevents arterial thrombotic occlusion in electrolytically injured rat carotid arteries. Blood 2007; 110: A3.
- 22 He K, He B, Grace JE. et al. Preclinical pharmacokinetic and metabolism of apixaban, a potent and selective Factor Xa inhibitor. Blood 2006; 108: A910.
- 23 Iwatsuki Y, Shigenaga T, Moritani Y. et al. Biochemical and pharmacological profiles of YM150, an oral direct Factor Xa inhibitor. Blood 2006; 108: A911.
- 24 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.
- 25 Kohrt JT, Bigge CF, Bryant JW. et al. The discovery of (2R,4R)-N-(4-chlorophenyl)-N-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor. Chem Biol Drug Des 2007; 70: 100-112.
- 26 Kubitza D, Becka M, Roth A. et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008; 24: 2757-2765.
- 27 Kubitza D, Becka M, Voith B. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59–7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
- 28 Kubitza D, Becka M, Wensing G. et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939 an oral, direct Factor Xa inhibitor after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: 873-880.
- 29 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.
- 30 Lassen MR, Davidson BL, Gallus A. et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 12: 2368-2375.
- 31 Lassen MR, Gallus AS, Pineo GF. et al. Randomized double-blind comparison of apixaban with enoxaparin for thromboprophylaxis after knee replacement: the ADVANCE-1 trial. Blood 2008; 112: A31.
- 32 Luettgen JM, Wang Z, Seiffert DA. et al. Inhibition of measured thrombin generation in human plasma by apixaban: A predictive mathematical model based on experimentally determined rate constants. J Thromb Haemost 2006; 5 (Suppl. 01) P-T-633.
- 33 Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 2003; 23: 17-25.
- 34 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 1: 1504-1514.
- 35 Mann KG, Jenny RJ, Krishnaswamy S. Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Annu Rev Biochem 1988; 57: 915-956.
- 36 McKenzie CR, Abendschein DR, Eisenberg PR. Sustained inhibition of whole-blood clot procoagulant activity by inhibition of thrombus-associated factor Xa. Arterioscler Thromb Vasc Biol 1996; 16: 1285-1291.
- 37 Mueck W, Becka M, Kubitza D. et al. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban an oral, direct Factor Xa inhibitor in healthy subjects. Int J Clin Pharmacol Ther 2007; 45: 335-344.
- 38 Mueck W, Eriksson BI, Bauer KA. et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct factor xa inhibitor – in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47: 203-216.
- 39 Perzborn E, Arndt B, Fischer E. et al. Antithrombotic effects of rivaroxaban – an oral, direct Factor Xa inhibitor – in animal models of arterial and venous thrombosis: comparison with enoxaparin, an anti-thrombin-dependent anticoagulant. Eur Heart J 2006; 27 suppl P4571-762.
- 40 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 2008; 112: A528.
- 41 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: 514-521.
- 42 Prager NA, Abendschein DR, McKenzie CR. et al. Role of thrombin compared with factor Xa in the procoagulant activity of whole blood clots. Circulation 1995; 92: 962-967.
- 43 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.
- 44 Tersteegen A, Schmidt S, Burkhardt N. Rivaroxaban – an oral, direct factor Xa inhibitor – binds rapidly to factor Xa. J Thromb Haemost 2007; 5 (Suppl. 02) P-W-651.
- 45 Turpie AGG, Bauer KA, Davidson BL. et al. A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost 2009; 101: 68-76.
- 46 Turpie AGG, Bauer KA, Davidson BL. et al. Once-Daily Oral Rivaroxaban Compared with Subcutaneous Enoxaparin Every 12 Hours for Thromboprophylaxis after Total Knee Replacement: RECORD4. Blood 2008; 112: A35.
- 47 Turpie AGG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008; 29: 155-165.
- 48 Weinz C, Schwartz T, Pleiss U. et al. Metabolism and distribution of [14C] BAY 59–7939 – an oral, direct Factor Xa inhibitor – in rat, dog and human. Drug Metab Rev 2004; 36: A196.
- 49 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: A33.
- 50 Wong PC, Crain EJ, Xin B. et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 6: 820-829.
- 51 Zafar MU, Vorchheimer DA, Gaztanaga J. et al. Anti-thrombotic 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.