Topol Eric J, Easton Donald, Harrington Robert A, Amarenco Pierre, Califf Robert M, Graffagnino Carmen, Davis Stephen, Diener Hans-Christophe, Ferguson James, Fitzgerald Desmond, Granett Jeffrey, Shuaib Ashfaq, Koudstaal Peter J, Theroux Pierre, Van de Werf Frans, Sigmon Kristina, Pieper Karen, Vallee Marc, Willerson James T
Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Circulation. 2003 Jul 29;108(4):399-406. doi: 10.1161/01.CIR.0000084501.48570.F6. Epub 2003 Jul 21.
This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients.
Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.
Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.
这是关于口服IIb/IIIa受体拮抗剂洛曲非班大规模评估的主要报告，在血小板拮抗剂、方案设计以及相当比例的患者纳入脑血管疾病方面，该试验具有独特性。
血管疾病患者根据年龄和预测的肌酐清除率随机分为每日两次服用30或50毫克洛曲非班组，或除了由医师研究者酌情给予75至325毫克/天剂量的阿司匹林外，服用安慰剂组。随访长达2年。主要终点是全因死亡率、心肌梗死、中风、需要住院治疗的复发性缺血以及紧急血管重建的综合指标。在来自23个国家和690家医院的9190名患者中，41%在入组时患有脑血管疾病，59%患有冠状动脉疾病。安慰剂组患者的死亡率为2.3%，洛曲非班组患者为3.0%（风险比1.33，95%置信区间1.03至1.72，P = 0.026），死亡增加的原因与血管相关。主要终点无显著差异（分别为17.5%和16.4%；风险比0.94，95%置信区间0.85至1.03，P = 0.19）。洛曲非班组严重出血更频繁（8.0%比2.8%；P < 0.001）。在接受较高剂量阿司匹林（>162毫克/天）的患者中，无论是否服用洛曲非班，严重出血都更常见。
口服血小板糖蛋白IIb/IIIa阻滞剂洛曲非班导致死亡率增加33%，其源于血管，且不受试验入组时动脉粥样硬化累及类型的影响。尽管阿司匹林剂量并非随机分配，但服用>162毫克/天剂量时出血增加这一发现值得关注。
