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

Urooj M. Zafar; Michael E. Farkouh; Julio Osende; Daichi Shimbo; Stella Palencia; Julia Crook; Robert Leadley; Valentin Fuster; James H. Chesebro

doi:10.1160/TH06-04-0188

Thrombosis and Haemostasis, Table of Contents

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

Authors

Urooj M. Zafar

¹Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
Michael E. Farkouh

¹Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
Julio Osende

¹Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
Daichi Shimbo

¹Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
Stella Palencia

¹Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
Julia Crook

²University of Massachussetts Medical School, Worcester, Massachussetts, USA
Robert Leadley

³Pfizer Research and Development, Ann Arbor, Michigan, USA
Valentin Fuster

¹Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
James H. Chesebro

²University of Massachussetts Medical School, Worcester, Massachussetts, USA

Abstract

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

Full Text

References

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