Kereiakes D J, Kleiman N S, Ambrose J, Cohen M, Rodriguez S, Palabrica T, Herrmann H C, Sutton J M, Weaver W D, McKee D B, Fitzpatrick V, Sax F L
Christ Hospital Cardiovascular Research Center, Cincinnati, Ohio 45219, USA.
J Am Coll Cardiol. 1996 Mar 1;27(3):536-42. doi: 10.1016/0735-1097(95)00500-5.
The objectives of this double-blind, placebo-controlled, randomized dose-ranging study were 1) to examine the safety and tolerability of tirofiban (MK-383), a new nonpeptide platelet IIb/IIIa receptor antagonist, on a background of intravenous heparin and aspirin therapy; 2) to study the pharmacodynamics and pharmacokinetics of tirofiban; and 3) to evaluate the incidence of adverse cardiac outcomes (urgent repeat revascularization, myocardial infarction and death) with tirofiban versus placebo in a high risk subset of patients undergoing coronary angioplasty.
Abrupt vessel closure complicates 4% to 8% of angioplasty procedures. Recent data have suggested that agents that antagonize the platelet glycoprotein IIb/IIIa receptor may reduce the incidence of adverse ischemic outcomes after coronary angioplasty.
Seventy-three patients received tirofiban in three sequential dose panels and 20 patients received placebo. Patients within each panel were randomized to receive either tirofiban or placebo in a 3:1 randomization design. Bolus doses of 5, 10 and 10 microg/kg and continuous infusion (16 to 24 h) doses of 0.05, 0.10 and 0.15 microg/kg per min were administered in panels I, II and III, respectively. Patients received concomitant heparin and aspirin for the angioplasty procedure. Data on patients receiving placebo (heparin and aspirin only) were pooled across panels for comparisons. The pharmacodynamic effect of tirofiban on ex vivo platelet aggregation to 5 micromol/liter adenosine diphosphate (ADP) and bleeding times were measured. Clinical outcomes were assessed in all patients, but the power to detect clinically meaningful differences (a one-third reduction in clinical events) between groups was limited (5%).
Tirofiban was associated with a dose-dependent inhibition of ex vivo ADP-mediated platelet aggregation that was sustained during intravenous infusion and resolved rapidly after drug cessation. Adverse bleeding events, largely related to vascular access site hemorrhage, were slightly increased at the highest dose. Adverse clinical outcomes were infrequent in all patients and were not different among the small number of patients within each group.
This study establishes a rational and generally well tolerated dosing regimen for administration of tirofiban as adjunctive therapy in high risk angioplasty patients. The impact of tirofiban on adverse clinical outcomes after angioplasty awaits definition by a larger clinical trial.
本双盲、安慰剂对照、随机剂量范围研究的目的为：1）在静脉注射肝素和阿司匹林治疗的背景下，研究新型非肽类血小板IIb/IIIa受体拮抗剂替罗非班（MK-383）的安全性和耐受性；2）研究替罗非班的药效学和药代动力学；3）在接受冠状动脉血管成形术的高危患者亚组中，评估替罗非班与安慰剂相比不良心脏事件（紧急重复血运重建、心肌梗死和死亡）的发生率。
4%至8%的血管成形术会并发血管突然闭塞。最近的数据表明，拮抗血小板糖蛋白IIb/IIIa受体的药物可能会降低冠状动脉血管成形术后不良缺血事件的发生率。
73例患者分三个连续剂量组接受替罗非班治疗，20例患者接受安慰剂治疗。每个剂量组的患者按3:1随机化设计随机接受替罗非班或安慰剂。第一、二、三组分别给予5、10和10微克/千克的静脉推注剂量，以及每分钟0.05、0.10和0.15微克/千克的持续输注（16至24小时）剂量。患者在血管成形术过程中同时接受肝素和阿司匹林治疗。将接受安慰剂（仅肝素和阿司匹林）治疗患者的数据合并用于各剂量组间的比较。测定替罗非班对体外血小板对5微摩尔/升二磷酸腺苷（ADP）聚集的药效学作用及出血时间。对所有患者评估临床结局，但检测组间具有临床意义差异（临床事件减少三分之一）的效能有限（5%）。
替罗非班与体外ADP介导的血小板聚集的剂量依赖性抑制相关，这种抑制在静脉输注期间持续存在，停药后迅速消退。不良出血事件主要与血管穿刺部位出血有关，在最高剂量时略有增加。所有患者中不良临床事件均不常见，每组少数患者之间无差异。
本研究为高危血管成形术患者使用替罗非班作为辅助治疗确立了合理且总体耐受性良好给药方案。替罗非班对血管成形术后不良临床结局的影响有待更大规模临床试验明确。
