Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Regeneron Genetics Center, LLC, Tarrytown, New York, USA.
Clin Transl Sci. 2024 Nov;17(11):e70079. doi: 10.1111/cts.70079.
Antiplatelet therapy with a P2Y receptor inhibitor, in combination with aspirin, is standard of care for medical management of patients with coronary artery disease, and flexibility in prescribing options among these medications offers great potential for individualizing patient care. Previously, we showed that a loss-of-function missense mutation (G143E) in carboxylesterase 1 (CES1), the primary enzyme responsible for clopidogrel degradation, significantly impacts on-clopidogrel platelet aggregation and recurrent cardiovascular event risk. In the current investigation, we conducted a prospective randomized crossover study of clopidogrel (75 mg/day for 7 days) and ticagrelor (180 mg/day for 7 days) in 50 individuals stratified by CES1 G143E genotype (N = 34 143GG and 16 143GE) to determine the effect of drug choice on inhibition of platelet aggregation (IPA). Consistent with prior reports, we observed strong association between G143E and adenosine diphosphate-stimulated platelet aggregation following clopidogrel administration (IPA = 71.6 vs. 48.0% in 143E-allele carriers vs. non-carriers, respectively, p = 3.8 × 10). Similar significant effects on platelet aggregation were also noted between 143E-allele carriers versus non-carriers in response to stimulation with arachidonic acid (45.8 vs. 25.8%, p = 0.04), epinephrine (44.4 vs. 18.8%, p = 0.03), and collagen (5 μg/mL, 25.8 vs. 11.4%, p = 3.7 × 10). In contrast, no relationship between CES1 G143E and IPA was observed following ticagrelor administration regardless of the platelet agonist used. Collectively, these data suggest that on-clopidogrel platelet aggregation is substantially modified by CES1 G143E genotype, that this variant does not modify ticagrelor pharmacodynamics, and that more consistent inhibition of platelet aggregation may be achieved by using ticagrelor in patients who carry clopidogrel response-modifying alleles in CES1.
抗血小板治疗联合使用 P2Y 受体抑制剂和阿司匹林是冠心病患者的标准治疗方法，这些药物的处方选择具有很大的灵活性，可以为患者提供个体化的治疗方案。此前，我们发现，负责氯吡格雷降解的主要酶羧肽酶 1（CES1）中的功能丧失性错义突变（G143E）显著影响氯吡格雷治疗时的血小板聚集和复发性心血管事件风险。在本研究中，我们对 50 名患者进行了前瞻性随机交叉研究，这些患者根据 CES1 G143E 基因型进行分层（N=34 名 143GG 基因型和 16 名 143GE 基因型），使用氯吡格雷（每天 75mg，连用 7 天）和替格瑞洛（每天 180mg，连用 7 天），以确定药物选择对血小板聚集抑制（IPA）的影响。与之前的报告一致，我们观察到氯吡格雷治疗后 G143E 与二磷酸腺苷刺激的血小板聚集之间存在很强的关联（在 143E 等位基因携带者中，IPA=71.6%，而非携带者中 IPA=48.0%，p=3.8×10）。在对花生四烯酸（45.8% vs. 25.8%，p=0.04）、肾上腺素（44.4% vs. 18.8%，p=0.03）和胶原（5μg/ml，45.8% vs. 25.8%，p=3.7×10）刺激时，143E 等位基因携带者与非携带者之间也观察到了类似的显著的血小板聚集效应。相反，无论使用何种血小板激动剂，替格瑞洛治疗后，CES1 G143E 与 IPA 之间均无关联。总之，这些数据表明，氯吡格雷治疗时的血小板聚集受 CES1 G143E 基因型的显著影响，该变体不会改变替格瑞洛的药效动力学，在携带 CES1 中氯吡格雷反应修饰等位基因的患者中使用替格瑞洛可能会实现更一致的血小板聚集抑制。
