Randomized Trial of Atopaxar in the Treatment of Patients With Coronary Artery Disease The Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease Trial
Randomized Trial of Atopaxar in the Treatment of Patients With Coronary Artery Disease The Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease Trial
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DOI：
10.1161/circulationaha.110.001404
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发表时间：
2011-05-03
期刊：
影响因子：
37.8
通讯作者：
Bhatt, Deepak L.
中科院分区：
文献类型：
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作者：
Wiviott, Stephen D.;Flather, Marcus D.;Bhatt, Deepak L.
凝血酶是血小板活化的关键介质。Atopaxar是一种可逆的蛋白酶激活受体-1拮抗剂，可干扰凝血酶介导的血小板效应。从拮抗凝血酶的细胞效应-冠状动脉疾病中获得的II期经验（LANCELOT-CAD）试验检测了阿托帕沙延长治疗CAD受试者的安全性和耐受性。方法和结果-具有合格病史的受试者以双盲方式随机接受3种阿托帕沙给药方案（50，100，或200毫克，每天）或匹配的安慰剂24周，并随访了额外的4周。关键的安全性终点是根据氯吡格雷预防不稳定型心绞痛复发（CURE）和心肌梗死溶栓（TIMI）分类的出血。次要目的包括血小板聚集和主要不良心脏事件。720例受试者接受了随机化。根据CURE标准，与安慰剂相比，阿托帕沙的总体出血率倾向于更高（安慰剂，0.6%;阿托帕沙，3.9%;相对风险，6.82，P = 0.03; 50 mg，3.9%; 100 mg，1.7%; 200 mg，5.9%;趋势P = 0.01）（安慰剂，6.8%;阿托帕沙，10.3%;相对风险，1.52，P = 0.17; 50 mg，9.9%; 100 mg，8.1%; 200 mg，12.9%;趋势P = 0.07）。在大出血方面没有差异。阿托帕沙组的主要不良心脏事件在数值上较低。所有阿托帕沙方案均达到高水平的血小板抑制。在高剂量atopaxar治疗组中观察到肝转氨酶和剂量依赖性QTc间期延长的短暂升高，但无明显并发症。结论：在这项对CAD患者的剂量范围研究中，atopaxar治疗导致血小板抑制，更轻微的出血，以及在数字上但在统计学上较少的缺血性事件。需要更大规模的试验来确定这些模式是否转化为有临床意义的效果。
Background-Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease (LANCELOT-CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD.Methods and Results-Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6%; atopaxar, 3.9%; relative risk, 6.82, P = 0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%; P for trend = 0.01) and TIMI criteria (placebo, 6.8%; atopaxar, 10.3%; relative risk, 1.52, P = 0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%; P for trend = 0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups.Conclusions-In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects.