抗凝血酶治疗冠状动脉疾病的随机临床试验：从抗凝血酶-冠状动脉疾病试验中获得的细胞作用拮抗的经验教训。

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.

机构信息

Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.

出版信息

Circulation. 2011 May 3;123(17):1854-63. doi: 10.1161/CIRCULATIONAHA.110.001404. Epub 2011 Apr 18.

DOI:10.1161/CIRCULATIONAHA.110.001404

PMID:21502571

Abstract

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.

CLINICAL TRIAL REGISTRATION

URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00312052.

摘要

背景

凝血酶是血小板激活的关键介质。阿哌沙班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作用。二期试验从拮抗凝血酶的细胞效应-冠状动脉疾病（LANCELOT-CAD）试验研究了在 CAD 患者中进行长时间阿哌沙班治疗的安全性和耐受性。

方法和结果

有合格病史的受试者以双盲方式随机分为阿哌沙班组（50、100 或 200 mg 每日）或匹配安慰剂组，治疗 24 周，随后再随访 4 周。主要安全性终点为根据氯吡格雷不稳定型心绞痛预防复发事件（CURE）和心肌梗死溶栓（TIMI）分类的出血。次要目标包括血小板聚集和主要不良心脏事件。720 名受试者被随机分配。根据 CURE 标准（安慰剂，0.6%；阿哌沙班，3.9%；相对风险，6.82，P=0.03；50mg，3.9%；100mg，1.7%；200mg，5.9%；趋势 P=0.01）和 TIMI 标准（安慰剂，6.8%；阿哌沙班，10.3%；相对风险，1.52，P=0.17；50mg，9.9%；100mg，8.1%；200mg，12.9%；趋势 P=0.07），阿哌沙班组的总体出血率倾向于高于安慰剂组。主要不良心脏事件在阿哌沙班组中也略低。所有阿哌沙班方案均实现了高水平的血小板抑制。在高剂量阿哌沙班组中观察到肝转氨酶一过性升高和剂量依赖性 QTc 延长，但无明显并发症。