BACKGROUND:Clopidogrel is a widely used antithrombotic agent that inhibits the platelet P2Y(12) adenosine diphosphate (ADP) receptor. There is increasing interest in 'clopidogrel resistance'. OBJECTIVES:To determine whether 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP. METHODS:Platelet response to 20 microm ADP was analyzed by four independent whole blood flow cytometric assays: platelet surface activated GPIIb-IIIa, platelet surface P-selectin, monocyte-platelet aggregates and neutrophil-platelet aggregates. In 25 consecutive, non-aspirin-treated healthy subjects, we studied platelet response before and after clopidogrel administration. In addition, we studied the platelet response in 613 consecutive aspirinated patients with or without coronary artery disease (CAD, as determined by angiography) who had or had not been treated with clopidogrel. In these patients, we tested for homogeneity of variance across all durations of clopidogrel exposure and severity of CAD by estimating the 'goodness of fit' of two independent models. RESULTS:In the healthy subjects, pre-clopidogrel response to ADP predicted post-clopidogrel response to ADP. In the patients, clopidogrel, as expected, inhibited the platelet response to ADP. However, irrespective of the duration of clopidogrel administration, the severity of CAD, and the dose of aspirin, clopidogrel did not increase the variance in the platelet response to ADP in any of the four assays of platelet response. CONCLUSIONS:These studies provide evidence that 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP and this variability is not increased by clopidogrel administration.

译文

背景:氯吡格雷是一种广泛使用的抗血栓药,可抑制血小板P2Y(12)二磷酸腺苷(ADP)受体。人们对“氯吡格雷抵抗”的兴趣日益浓厚。
目的:要确定“氯吡格雷抵抗”是否由血小板对ADP的反应中先前存在的变异性引起。
方法:通过四个独立的全血流式细胞术分析血小板对20微米ADP的反应:血小板表面活化的GPIIb-IIIa,血小板表面P-选择素,单核细胞-血小板聚集体和中性白细胞-血小板聚集体。在连续25次非阿司匹林治疗的健康受试者中,我们研究了氯吡格雷给药前后的血小板反应。此外,我们研究了613名连续接受或未接受氯吡格雷治疗的有或没有冠状动脉疾病(CAD,通过血管造影术确定)的吸气患者的血小板反应。在这些患者中,我们通过评估两个独立模型的“拟合优度”,测试了氯吡格雷暴露的所有持续时间和CAD严重性的方差同质性。
结果:在健康受试者中,氯吡格雷对ADP的反应可预测氯吡格雷对ADP的反应。如预期的那样,在患者中,氯吡格雷抑制了血小板对ADP的反应。但是,不管使用氯吡格雷的持续时间,CAD的严重程度以及阿司匹林的剂量如何,在四种血小板反应测定中,氯吡格雷均不会增加血小板对ADP的反应方差。
结论:这些研究提供了证据,“氯吡格雷抵抗”是由血小板对ADP的反应中先前存在的变异性引起的,而使用氯吡格雷不会增加这种变异性。

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