Eikelboom J W, Hankey G J, Thom J, Claxton A, Yi Q, Gilmore G, Staton J, Barden A, Norman P E
Department of Medicine, HGH McMaster Clinic, McMaster University, Hamilton, Ontario, Canada.
J Thromb Haemost. 2005 Dec;3(12):2649-55. doi: 10.1111/j.1538-7836.2005.01640.x.
We aimed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin.
We performed a randomized, double-blind, placebo-controlled, crossover trial, comparing clopidogrel 75 mg day(-1) versus placebo, in 36 aspirin-treated patients with symptomatic objectively confirmed peripheral arterial disease.
The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid, urinary 11 dehydro thromboxane B2 concentrations, or soluble markers of platelet activation markers (P-selectin, CD40-ligand) and inflammation (high sensitivity serum C-reactive protein, interleukin-6). Clopidogrel significantly inhibited platelet aggregation induced by ADP (reduction 26.2%; 95% CI: 21.3-31.1%, P < 0.0001) and collagen (reduction 6.2%; 95% CI: 3.2-9.3%, P = 0.0003). The greatest inhibition of collagen-induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [lower tertile of arachidonic acid-induced platelet aggregation: 2.8% (95% CI: -0.8 to 6.3%) reduction in mean collagen-induced aggregation by clopidogrel; middle tertile: 4.0% (95% CI: 0.4-7.6%); upper tertile 12.6% (95% CI: 4.5-20.8%); P-value for interaction 0.01].
The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid-induced platelet aggregation by aspirin. This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin. Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor, thereby overcoming the problem of laboratory aspirin resistance.
我们旨在确定在未来心血管事件高危患者中，在阿司匹林基础上加用氯吡格雷是否会抑制阿司匹林抗血小板作用的实验室检测指标；以及在阿司匹林对血小板抑制作用最弱的患者中是否具有更强的血小板抑制作用。
我们进行了一项随机、双盲、安慰剂对照、交叉试验，在36例经客观证实有症状的阿司匹林治疗的外周动脉疾病患者中，比较氯吡格雷75毫克/天与安慰剂。
在阿司匹林基础上加用氯吡格雷并未抑制花生四烯酸诱导的血小板聚集、尿11-脱氢血栓素B2浓度，或血小板活化标志物（P-选择素、CD40配体）和炎症（高敏血清C反应蛋白、白细胞介素-6）的可溶性标志物。氯吡格雷显著抑制ADP诱导的血小板聚集（降低26.2%；95%可信区间：21.3-31.1%，P<0.0001）和胶原诱导的血小板聚集（降低6.2%；95%可信区间：3.2-9.3%，P=0.0003）。在阿司匹林对花生四烯酸诱导的聚集抑制作用最弱的患者中，观察到氯吡格雷对胶原诱导的血小板聚集的抑制作用最强[花生四烯酸诱导的血小板聚集的最低三分位数：氯吡格雷使平均胶原诱导的聚集降低2.8%（95%可信区间：-0.8至6.3%）；中间三分位数：4.0%（95%可信区间：0.4-7.6%）；最高三分位数12.6%（95%可信区间：4.5-20.8%）；交互作用P值为0.01]。
氯吡格雷最强的血小板抑制作用发生在阿司匹林对花生四烯酸诱导的血小板聚集抑制作用最弱的患者中。这增加了在阿司匹林对血小板抑制作用最弱的患者中，在阿司匹林基础上加用氯吡格雷临床获益可能最大的可能性。临床结局研究中的证实可能会使这些患者成为抑制ADP受体的抗血小板药物的靶向人群，从而克服实验室阿司匹林抵抗的问题。
