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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
