title: Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients.
abstract: 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 atherothrombosis. 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 [EoI], and four hours and eight hours after EoI, 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 EoI were 29%, 34% and 68%, respectively (p < 0.001), and at 8-h post EoI 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 IIbIIIa inhibition.
authors.affiliation: Zena and Michael A. Wiener, Cardiovascular Institute, New York, NY 10029, USA.
authors.forename: M Urooj
authors.initials: MU
authors.lastname: Zafar
authors.forename: Michael E
authors.initials: ME
authors.lastname: Farkouh
authors.forename: Julio
authors.initials: J
authors.lastname: Osende
authors.forename: Daichi
authors.initials: D
authors.lastname: Shimbo
authors.forename: Stella
authors.initials: S
authors.lastname: Palencia
authors.forename: Julia
authors.initials: J
authors.lastname: Crook
authors.forename: Robert
authors.initials: R
authors.lastname: Leadley
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.forename: James H
authors.initials: JH
authors.lastname: Chesebro
mesh_terms: D000578:Amidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D001777:Blood Coagulation / Q000187:drug effects*; D003324:Coronary Artery Disease / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D010477:Perfusion; D011517:Prothrombin Time; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013552:Swine; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000578:Amidines; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011725:Pyridines; C114592:Fidexaban