Département de Cardiologie, CHU Timone, Marseille, France.
Am J Cardiol. 2011 Sep 15;108(6):760-5. doi: 10.1016/j.amjcard.2011.05.045. Epub 2011 Jul 30.
The cytochrome P450 (CYP) 2C19*2 loss-of-function allele has been associated with impaired clopidogrel response and worse prognosis in clopidogrel-treated patients. The benefit of tailored therapy according to platelet function test results remains unclear, and the potential effect of genotypes on this benefit has not been addressed in unstable patients. The present study was designed to evaluate the benefit of tailored therapy with a higher maintenance dose according to CYP2C19 genotypes in patients identified as nonresponders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. Three hundred forty-six consecutive patients were enrolled and received a loading dose of 600 mg, including 86 2 carriers (13 homozygotes and 73 heterozygotes) and 260 2 noncarriers. Clopidogrel response, assessed with platelet reactivity index vasoactive-stimulated phosphoprotein, was significantly affected by genotype, with lower clopidogrel response in CYP2C192 allele carriers (p = 0.01). Accordingly, the rate of clopidogrel nonresponse was higher in CYP2C192 allele carriers (53% vs 41%, p = 0.04). All clopidogrel nonresponders (n = 151), including 105 *2 noncarriers and 46 *2 carriers, received high 150-mg clopidogrel maintenance doses at discharge to overcome initial low response. After 1 month, high maintenance doses overcame clopidogrel low response in only 44% of the whole population and significantly less frequently in 2 carriers than in noncarriers (28% vs 50%, p = 0.01). In conclusion, higher clopidogrel maintenance doses were able to overcome clopidogrel low response in fewer than half of clopidogrel low responders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. The benefit of this tailored therapy was significantly reduced in CYP2C192 carriers. Therefore, these patients might require alternative strategies with new P2Y₁₂ blockers.
细胞色素 P450（CYP）2C192 失活等位基因与氯吡格雷治疗患者的氯吡格雷反应受损和预后不良相关。根据血小板功能试验结果进行针对性治疗的益处尚不清楚，并且基因型对不稳定患者的这种益处的潜在影响尚未得到解决。本研究旨在评估根据 CYP2C19 基因型对接受经皮冠状动脉介入治疗的非 ST 段抬高急性冠状动脉综合征的非反应患者进行更高维持剂量的针对性治疗的益处。共纳入 346 例连续患者，给予负荷剂量 600mg，其中 86 例为2 携带者（13 例纯合子和 73 例杂合子），260 例为2 非携带者。用血小板反应性指数血管活性刺激磷酸蛋白评估氯吡格雷反应，基因型明显影响氯吡格雷反应，CYP2C192 等位基因携带者的氯吡格雷反应较低（p = 0.01）。因此，CYP2C192 等位基因携带者的氯吡格雷无反应率较高（53%比 41%，p = 0.04）。所有氯吡格雷无反应者（n = 151），包括 105 例2 非携带者和 46 例2 携带者，出院时给予高剂量 150mg 氯吡格雷维持剂量以克服初始低反应。1 个月后，高维持剂量仅在整个人群中的 44%和2 携带者中显著低于非携带者（28%比 50%，p = 0.01）克服氯吡格雷低反应。总之，在接受非 ST 段抬高急性冠状动脉综合征经皮冠状动脉介入治疗的氯吡格雷低反应者中，不到一半的患者能够通过更高的氯吡格雷维持剂量克服氯吡格雷低反应。这种针对性治疗的益处在 CYP2C19*2 携带者中显著降低。因此，这些患者可能需要新的 P2Y₁₂ 阻滞剂等替代策略。
