Zafar M Urooj, Farkouh Michael E, Osende Julio, Shimbo Daichi, Palencia Stella, Crook Julia, Leadley Robert, Fuster Valentin, Chesebro James H
Zena and Michael A. Wiener, Cardiovascular Institute, New York, NY 10029, USA.
Thromb Haemost. 2007 Mar;97(3):487-92.
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.
本研究的目的是使用动脉血栓形成的体外模型，评估ZK-807834直接抑制因子Xa对稳定型冠心病患者的抗血栓形成效力。组织因子途径在动脉粥样硬化血栓形成中起重要作用。直接抑制因子Xa可能更有效地减少血栓形成并预防冠心病事件。Badimon灌注室5分钟定量研究表明，阿昔单抗可使动脉血栓减少40%-55%，氯吡格雷可使动脉血栓减少23%，而肝素则无此作用。冠心病患者（n = 18，年龄59±9岁，男性占55%）被随机分为四组，分别接受低、中、高剂量的直接因子Xa抑制剂ZK-807834或安慰剂的24小时输注。在基线、输注结束时（EoI）以及EoI后4小时和8小时，在Badimon室测量动脉血栓形成情况，并同时测量因子X活性、凝血酶原时间（PT）比值和血浆药物水平。对于低、中、高剂量ZK-807834组，从基线到EoI时血栓大小的平均减少百分比分别为29%、34%和68%（p < 0.001），在EoI后8小时分别为11%、19%和27%（p < 0.01）。平均PT比值延长与ZK-807834血浆浓度呈强线性关系（Pearson相关系数r = 0.93）。从基线起因子X活性的平均减少百分比分别为13%、42%和58%。安慰剂对血栓大小或因子X活性无影响。总之，ZK-807834直接抑制因子Xa以剂量依赖方式显著减少体外动脉血栓形成和因子X活性。ZK-807834的血浆水平与PT比值呈强线性相关。这种直接因子Xa抑制剂可能减少对额外强效糖蛋白IIbIIIa抑制的需求。
