Safety and Tolerability of Atopaxar in the Treatment of Patients With Acute Coronary Syndromes The Lessons From Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes Trial
Safety and Tolerability of Atopaxar in the Treatment of Patients With Acute Coronary Syndromes The Lessons From Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes Trial
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DOI：
10.1161/circulationaha.110.000786
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发表时间：
2011-05-03
期刊：
影响因子：
37.8
通讯作者：
Flather, Marcus D.
中科院分区：
文献类型：
--
作者：
O'Donoghue, Michelle L.;Bhatt, Deepak L.;Flather, Marcus D.
atopaxar （E5555）是一种可逆的蛋白酶激活受体-1凝血酶受体拮抗剂，可干扰血小板信号传导。抗凝血酶-急性冠状动脉综合征（LANCELOT-ACS）试验的主要目的是评估阿托白在ACS患者中的安全性和耐受性。方法和结果：在非st段抬高ACS的72小时内，603名受试者随机接受阿托帕沙（400 mg负荷剂量，随后每天50、100或200 mg）或匹配的安慰剂治疗。氯吡格雷用于不稳定心绞痛预防复发事件（CURE）大出血或小出血的发生率在阿托帕沙联合组和安慰剂组之间无显著差异（分别为3.08%和2.17%;P = 0.63），且无剂量相关趋势（P = 0.80）。阿托帕沙组的CURE大出血发生率高于安慰剂组（1.8% vs 0%; P = 0.12）。阿托帕沙组和安慰剂组的心血管死亡、心肌梗死、卒中或复发性缺血发生率相似（8.03%比7.75%;P = 0.93）。安慰剂组CV死亡、心肌梗死或卒中的发生率为5.63%，联合阿托帕沙组为3.25% （P = 0.20）。疗效的剂量依赖性趋势未见。与安慰剂相比，阿托帕沙在48小时连续心电图监测（Holter）中显著减少缺血（相对风险，0.67;P = 0.02）。在最高剂量的阿托白中观察到瞬时剂量依赖性转氨酶升高和相对QTc延长。结论：在ACS患者中，动态心电图监测显示，阿托派可显著减少早期缺血，而不会显著增加大出血或小出血。需要更大规模的试验来充分确定阿托白的有效性和安全性。
Background-Atopaxar (E5555) is a reversible protease-activated receptor-1 thrombin receptor antagonist that interferes with platelet signaling. The primary objective of the Lessons From Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes (LANCELOT-ACS) trial was to evaluate the safety and tolerability of atopaxar in patients with ACS.Methods and Results-Six hundred and three subjects were randomized within 72 hours of non-ST-elevation ACS to 1 of 3 doses of atopaxar (400-mg loading dose followed by 50, 100, or 200 mg daily) or matching placebo. The incidence of Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) major or minor bleeding did not differ significantly between the combined atopaxar and placebo groups (3.08% versus 2.17%, respectively; P = 0.63), and there was no dose-related trend (P = 0.80). The incidence of CURE major bleeding was numerically higher in the atopaxar group compared with the placebo group (1.8% versus 0%; P = 0.12). The incidence of cardiovascular death, myocardial infarction, stroke, or recurrent ischemia was similar between the atopaxar and placebo arms (8.03% versus 7.75%; P = 0.93). The incidence of CV death, MI, or stroke was 5.63% in the placebo group and 3.25% in the combined atopaxar group (P = 0.20). Dose-dependent trends for efficacy were not seen. Atopaxar significantly reduced ischemia on continuous ECG monitoring (Holter) at 48 hours compared with placebo (relative risk, 0.67; P = 0.02). Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar.Conclusion-In patients after ACS, atopaxar significantly reduced early ischemia on Holter monitoring without a significant increase in major or minor bleeding. Larger trials are required to fully establish the efficacy and safety of atopaxar.