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Thromb Haemost 2007; 97(03): 487-492
DOI: 10.1160/TH06-04-0188
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients

Urooj M. Zafar
1   Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
,
Michael E. Farkouh
1   Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
,
Julio Osende
1   Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
,
Daichi Shimbo
1   Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
,
Stella Palencia
1   Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
,
Julia Crook
2   University of Massachussetts Medical School, Worcester, Massachussetts, USA
,
Robert Leadley
3   Pfizer Research and Development, Ann Arbor, Michigan, USA
,
Valentin Fuster
1   Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
,
James H. Chesebro
2   University of Massachussetts Medical School, Worcester, Massachussetts, USA
› InstitutsangabenFinancial support: This study was funded by Parke Davis Pharmaceuticals.
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Publikationsverlauf

Received 03. April 2006

Accepted after revision 29. Februar 2006

Publikationsdatum:
28. November 2017 (online)

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Summary

It was the objective of this study to evaluate the anti-thrombotic potency of direct factor-Xa inhibition with ZK-807834 in stable coronary patients, using an ex-vivo model of arterial thrombus formation. Tissue factor pathway is important in atherothrom-bosis. Direct factor-Xa blockade may more potently reduce thrombosis and prevent coronary events. Badimon Perfusion Chamber 5-minute quantitative studies have shown 40-55% arterial thrombus reduction with abciximab, 23% with Clopidogrel, but none with heparin. Coronary patients (n= 18, 59 ± 9 years, 55% males) were blindly randomized to four groups receiving 24-hour infusion of a low, medium or high dose of direct factor-Xa inhibitor ZK-807834, or placebo. Arterial thrombus formation was measured in Badimon Chamber at baseline, end-of-infusion [Eol], and four hours and eight hours after Eol, and factor-X activity, prothrombin time [PT] ratio and plasma drug levels were measured simultaneously. For the low-, medium- and high-dose ZK-807834 groups, mean percent-reduction in thrombus size from baseline to Eol were 29%, 34% and 68%, respectively (p<0.00l), and at 8-h post Eol were 11%, 19% and 27%, respectively (p<0.01). Mean PT-ratio prolongation showed a strong linear relationship (Pearson’s r=0.93) with ZK-807834 plasma concentration. Mean percent-reduction in factor-X activity from baseline was 13%, 42% and 58%, respectively. Placebo had no effect on thrombus size or factor-X activity. In conclusion, direct factor-Xa inhibition with ZK-807834 markedly reduces ex-vivo arterial thrombus formation and factor-X activity in a dose-dependent manner. Plasma levels of ZK-807834 show a strong linear correlation with PT ratio. This direct factor-Xa inhibitor may reduce the need for additional potent glycoprotein llbllla inhibition.

Keywords

Coagulation - coronary disease - myocardial infarction - thrombosis - platelets
 

  • References

  • 1 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med 1992; 326: 242-250.
    CrossrefPubMedSuche in Google Scholar
  • 2 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326: 310-318.
    CrossrefPubMedSuche in Google Scholar
  • 3 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657-671.
    CrossrefPubMedSuche in Google Scholar
  • 4 Rauch U, Osende JI, Fuster V. et al. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med 2001; 134: 224-238.
    CrossrefPubMedSuche in Google Scholar
  • 5 Nelken NA, Soifer SJ, O'Keefe J. et al. Thrombin receptor expression in normal and atherosclerotic human arteries. J Clin Invest 1992; 90: 1614-1621.
    CrossrefPubMedSuche in Google Scholar
  • 6 Wysokinski W, McBane R, Chesebro JH. et al. Reversibility of platelet thrombosis in vivo. Quantitative analysis in porcine carotid arteries. Thromb Haemost 1996; 76: 1108-1113.
    Thieme ConnectPubMedSuche in Google Scholar
  • 7 Oler A, Whooley MA, Oler J. et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A metaanalysis. J Am Med Assoc 1996; 276: 811-815.
    CrossrefPubMedSuche in Google Scholar
  • 8 Eikelboom JW, Anand SS, Malmberg K. et al. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 2000; 355: 1936-1942.
    CrossrefPubMedSuche in Google Scholar
  • 9 Orvim U, Barstad RM, Vlasuk GP. et al. Effect of selective factor Xa inhibition on arterial thrombus formation triggered by tissue factor/factor VIIa or collagen in an ex vivo model of shear-dependent human thrombogenesis. Arterioscler Thromb Vasc Biol 1995; 15: 2188-2194.
    CrossrefPubMedSuche in Google Scholar
  • 10 McClanahan TB, Hicks GW, Morrison AL. et al. The antithrombotic effects of CI-1031 (ZK-807834) and enoxaparin in a canine electrolytic injury model of arterial and venous thrombosis. Eur J Pharmacol 2001; 432: 187-194.
    CrossrefPubMedSuche in Google Scholar
  • 11 Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002; 347: 969-974.
    CrossrefPubMedSuche in Google Scholar
  • 12 Brouwer MA, van den Bergh PJ, Aengevaeren WR. et al. Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial. Circulation 2002; 106: 659-665.
    CrossrefPubMedSuche in Google Scholar
  • 13 van Es RF, Jonker JJ, Verheugt FW. et al. Aspirin and coumadin after acute coronary syndromes (the ASPECT- 2 study): a randomised controlled trial. Lancet 2002; 360: 109-113.
    CrossrefPubMedSuche in Google Scholar
  • 14 Hirsh J. Heparin. N Engl J Med 1991; 324: 1565-1574.
    CrossrefPubMedSuche in Google Scholar
  • 15 Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865-1875.
    CrossrefPubMedSuche in Google Scholar
  • 16 Waxman L, Smith DE, Arcuri KE. et al. Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa. Science 1990; 248: 593-6.
    CrossrefPubMedSuche in Google Scholar
  • 17 Nutt EM, Jain D, Lenny AB. et al. Purification and characterization of recombinant antistasin: a leech-derived inhibitor of coagulation factor Xa. Arch Biochem Biophys 1991; 285: 37-44.
    CrossrefPubMedSuche in Google Scholar
  • 18 Hara T, Yokoyama A, Tanabe K. et al. DX-9065a, an orally active, specific inhibitor of factor Xa, inhibits thrombosis without affecting bleeding time in rats. Thromb Haemost 1995; 74: 635-639.
    Thieme ConnectPubMedSuche in Google Scholar
  • 19 Shimbo D, Osende J, Chen J. et al. Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin. Thromb Haemost 2002; 88: 733-738.
    Thieme ConnectPubMedSuche in Google Scholar
  • 20 Hauptmann J, Sturzebecher J. Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. Thromb Res 1999; 93: 203-241.
    CrossrefPubMedSuche in Google Scholar
  • 21 Sato K, Kawasaki T, Hisamichi N. et al. Antithrombotic effects of YM-60828, a newly synthesized factor Xa inhibitor, in rat thrombosis models and its effects on bleeding time. Br J Pharmacol 1998; 123: 92-96.
    CrossrefPubMedSuche in Google Scholar
  • 22 Abendschein DR, Baum PK, Verhallen P. et al. A novel synthetic inhibitor of factor Xa decreases early reocclusion and improves 24-h patency after coronary fibrinolysis in dogs. J Pharmacol Exp Ther 2001; 296: 567-572.
    PubMedSuche in Google Scholar
  • 23 Green D, Hirsh J, Heit J. et al. Low molecular weight heparin: a critical analysis of clinical trials. Pharmacol Rev 1994; 46: 89-109.
    PubMedSuche in Google Scholar
  • 24 Post JM, Sullivan ME, Abendschein D. et al. Human in vitro pharmacodynamic profile of the selective factor Xa inhibitor ZK-807834 (CI-1031). Thromb Res 2002; 105: 347-352.
    CrossrefPubMedSuche in Google Scholar
  • 25 Karnicki K, McBane 2nd RD, Miller R. et al. Inhibition and reversal of platelet-rich arterial thrombus in vivo: direct vs. indirect factor Xa inhibition. J Thromb Haemost 2004; 2: 2162-2169.
    CrossrefPubMedSuche in Google Scholar
  • 26 Toschi V, Gallo R, Lettino M. et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-599.
    CrossrefPubMedSuche in Google Scholar
  • 27 Badimon JJ, Meyer B, Feigen LP. et al. Thrombosis triggered by severe arterial lesions is inhibited by oral administration of a glycoprotein IIb/IIIa antagonist. Eur J Clin Invest 1997; 27: 568-574.
    CrossrefPubMedSuche in Google Scholar
  • 28 Dangas G, Badimon JJ, Smith DA. et al. Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol 1999; 33: 1294-1304.
    CrossrefPubMedSuche in Google Scholar
  • 29 Badimon JJ, Lettino M, Toschi V. et al. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999; 99: 1780-1787.
    CrossrefPubMedSuche in Google Scholar
  • 30 Badimon L, Badimon JJ, Galvez A. et al. Influence of arterial damage and wall shear rate on platelet deposition. Ex vivo study in a swine model. Arteriosclerosis 1986; 6: 312-320.
    CrossrefPubMedSuche in Google Scholar
  • 31 Reverter JC, Beguin S, Kessels H. et al. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and „clinical restenosis“. J Clin Invest 1996; 98: 863-874.
    CrossrefPubMedSuche in Google Scholar
  • 32 Hayes R, Chesebro JH, Fuster V. et al. Antithrombotic effects of abciximab. Am J Cardiol 2000; 85: 1167-1172.
    CrossrefPubMedSuche in Google Scholar
  • 33 Helft G, Osende JI, Worthley SG. et al. Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc Biol 2000; 20: 2316-2321.
    CrossrefPubMedSuche in Google Scholar
  • 34 Yusuf S, Zhao F, Mehta SR. 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.
    CrossrefPubMedSuche in Google Scholar
  • 35 Fuster V, Badimon JJ, Chesebro JH. Atherothrombosis: mechanisms and clinical therapeutic approaches. Vasc Med 1998; 3: 231-239.
    CrossrefPubMedSuche in Google Scholar