Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients
M. Urooj Zafar 1, Michael E. Farkouh 1, Julio Osende 1, Daichi Shimbo 1, Stella Palencia 1, Julia Crook 2, Robert Leadley 3, Valentin Fuster 1, James H. Chesebro2
1 Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA; 2 University of Massachussetts Medical School, Worcester, Massachussetts, USA; 3 Pfizer Research and Development, Ann Arbor, Michigan, USA
coronary disease, thrombosis, coagulation, myocardial infarction, Platelets
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, endof- 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.