Uhry Sabrina, Bessereau Jacques, Camoin-Jau Laurence, Paganelli Franck, Bonello Laurent
Département de Cardiologie, Hôpital Universitaire Nord de Marseille, Assistance Publique Hôpitaux de Marseille, Aix-Marseille Université, France.
Hosp Pract (1995). 2012 Apr;40(2):104-17. doi: 10.3810/hp.2012.04.976.
In patients with acute coronary syndromes undergoing percutaneous coronary intervention, the combination of aspirin and clopidogrel, a P2Y12 adenosine diphosphate (ADP) receptor antagonist, is the gold standard of antiplatelet therapy. Two more potent P2Y12 ADP receptor antagonists are now available. Pharmacodynamic studies have revealed a large interindividual variability in the biological response to clopidogrel that is primarily related to variable active metabolite generation, depending on clinical factors, drug-drug interactions, and genetic polymorphisms. Several assays to measure platelet function are available and have revealed a high prevalence of high on-treatment platelet reactivity (HTPR). Patients exhibiting HTPR after a clopidogrel loading dose have a higher risk of thrombotic recurrence after percutaneous coronary intervention. A recent consensus has defined HTPR for the main platelet assays available (using receiver operating characteristic curve analysis) to define the optimal cutoff value for each assay in order to predict thrombotic recurrences. In this article, we present several lines of evidence that suggest a therapeutic window of platelet reactivity inhibition with P2Y12 ADP receptor antagonists. Such a paradigm shift is supported by the results of the Platelet Inhibition and Patient Outcomes (PLATO) trial and the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38, which showed the superiority of ticagrelor and prasugrel on thrombotic events compared with clopidogrel; however, these 2 medications had an increased bleeding rate. With the results of these trials, in addition to the evidence of a therapeutic window with P2Y12 ADP receptor antagonists, we summarize the potential of platelet reactivity monitoring and pharmacogenomics to tailor therapy.
在接受经皮冠状动脉介入治疗的急性冠状动脉综合征患者中，阿司匹林与P2Y12二磷酸腺苷（ADP）受体拮抗剂氯吡格雷联合使用是抗血小板治疗的金标准。现在有另外两种更强效的P2Y12 ADP受体拮抗剂。药效学研究显示，氯吡格雷的生物学反应存在很大的个体间差异，这主要与活性代谢产物生成的变化有关，具体取决于临床因素、药物相互作用和基因多态性。有几种测量血小板功能的检测方法，这些方法显示高治疗中血小板反应性（HTPR）的发生率很高。在接受氯吡格雷负荷剂量后出现HTPR的患者，经皮冠状动脉介入治疗后血栓复发风险更高。最近的一项共识通过接受者操作特征曲线分析为现有的主要血小板检测方法定义了HTPR，以确定每种检测方法的最佳临界值，从而预测血栓复发。在本文中，我们提供了几条证据，表明P2Y12 ADP受体拮抗剂存在血小板反应性抑制的治疗窗。血小板抑制与患者预后（PLATO）试验以及通过优化心肌梗死溶栓治疗中普拉格雷的血小板抑制来评估治疗结果改善的试验（TRITON-TIMI）38的结果支持了这种范式转变，这些试验表明，与氯吡格雷相比，替格瑞洛和普拉格雷在血栓事件方面具有优势；然而，这两种药物的出血率有所增加。基于这些试验的结果，除了P2Y12 ADP受体拮抗剂存在治疗窗的证据外，我们还总结了血小板反应性监测和药物基因组学在定制治疗方面的潜力。
