Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease
Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease
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DOI：
10.1001/jama.2011.1703
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发表时间：
2011-11-23
影响因子：
120.7
通讯作者：
Sabatine, Marc S.
中科院分区：
文献类型：
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作者：
Mega, Jessica L.;Hochholzer, Willibald;Sabatine, Marc S.
背景CYP 2C 19基因的变异影响抗血小板药物氯吡格雷每日标准维持剂量75 mg的药理学和临床反应。（每天最多300 mg）改善功能丧失型CYP 2C 19基因型患者对氯吡格雷的反应。设计、设置和患者ELEVATE-TIMI 56是一项多中心、随机、一项从2010年10月至2011年9月在32个研究中心招募333名心血管疾病患者并进行基因分型的双盲试验。干预措施根据基因型，维持氯吡格雷剂量4个治疗期，每个治疗期持续约14天。总共有247名CYP 2C 19 *2功能丧失等位基因的非携带者接受了75和150 mg/d的氯吡格雷治疗（每期2期），而86名承运人（80个杂合子，6个纯合子）分别接受75，150，225，主要指标血小板功能检测结果（血管舒张剂刺激的磷蛋白[VASP]磷酸化和VerifyNow P2 Y（12）测定）和不良事件。CYP 2C 19 *2杂合子治疗时血小板反应性显著高于非携带者（VASP血小板反应性指数[PRI]：平均值，70.0%; 95% CI，66.0%-74.0%，vs 57.5%; 95% CI，55.1%-59.9%，VerifyNow P2 Y（12）反应单位[PRU]：平均值，225.6; 95%CI，207.7-243.4，vs 163.6; 95%CI，154.4-173.9;两次比较P <0.001）。在CYP 2C 19 *2杂合子中，高达300 mg/天的剂量显著降低血小板反应性，VASPPRI降至48.9%（95% CI，44.6%-53.2%），PRU降至127.5（95% CI，109.9-145.2）（两种剂量之间的趋势P <0.001）。而52%的CYP 2C 19 *2杂合子在75 mg氯吡格雷治疗时无应答（>= 230 PRU），只有10%在225或300 mg氯吡格雷治疗时无应答（两者P <0.001）。每日225 mg氯吡格雷可将CYP 2C 19 *2杂合子的血小板反应性降低至非携带者中标准氯吡格雷75 mg的水平（血小板反应性的平均比值，VASP PRI，0.92; 90% CI，0.85-0.99，PRU，0.94; 90% CI，0.84-1.04）。在CYP 2C 19 *2纯合子中，即使每天服用300 mg氯吡格雷，平均VASP PRI仍为68.3%（95% CI，44.9%-91.6%）和平均PRU，287.0（95%CI，170.2-403.8）。结论在稳定性心血管疾病患者中，在CYP 2C 19 *2杂合子中，将氯吡格雷的维持剂量增加3倍至每日225 mg，可达到与非携带者中标准75 mg剂量相似的血小板反应性水平;相比之下，对于CYP 2C 19 *2纯合子，高达300 mg/天的剂量不会导致相当程度的血小板抑制。
Context Variants in the CYP2C19 gene influence the pharmacologic and clinical response to the standard 75-mg daily maintenance dose of the antiplatelet drug clopidogrel.Objective To test whether higher doses (up to 300 mg daily) improve the response to clopidogrel in the setting of loss-of-function CYP2C19 genotypes.Design, Setting, and Patients ELEVATE-TIMI 56 was a multicenter, randomized, double-blind trial that enrolled and genotyped 333 patients with cardiovascular disease across 32 sites from October 2010 until September 2011.Interventions Maintenance doses of clopidogrel for 4 treatment periods, each lasting approximately 14 days, based on genotype. In total, 247 noncarriers of a CYP2C19*2 loss-of-function allele were to receive 75 and 150 mg daily of clopidogrel (2 periods each), whereas 86 carriers (80 heterozygotes, 6 homozygotes) were to receive 75, 150, 225, and 300 mg daily.Main Outcome Measures Platelet function test results (vasodilator-stimulated phosphoprotein [VASP] phosphorylation and VerifyNow P2Y(12) assays) and adverse events.Results With 75 mg daily, CYP2C19*2 heterozygotes had significantly higher on-treatment platelet reactivity than did noncarriers (VASP platelet reactivity index [PRI]: mean, 70.0%; 95% CI, 66.0%-74.0%, vs 57.5%; 95% CI, 55.1%-59.9%, and VerifyNow P2Y(12) reaction units[PRU]: mean, 225.6; 95% CI, 207.7-243.4, vs 163.6; 95% CI, 154.4-173.9; P < .001 for both comparisons). Among CYP2C19*2 heterozygotes, doses up to 300 mg daily significantly reduced platelet reactivity, with VASPPRI decreasing to 48.9%(95% CI, 44.6%-53.2%) and PRU to 127.5(95% CI, 109.9-145.2) (P < .001 for trend across doses for both). Whereas 52% of CYP2C19*2 heterozygotes were nonresponders (>= 230 PRU) with 75 mg of clopidogrel, only 10% were nonresponders with 225 or 300 mg(P < .001 for both). Clopidogrel, 225 mg daily, reduced platelet reactivity in CYP2C19*2 heterozygotes to levels achieved with standard clopidogrel, 75 mg, in noncarriers (mean ratios of platelet reactivity, VASP PRI, 0.92; 90% CI, 0.85-0.99, and PRU, 0.94; 90% CI, 0.84-1.04). In CYP2C19*2 homozygotes, even with 300 mg daily of clopidogrel, mean VASP PRI was 68.3% (95% CI, 44.9%-91.6%) and mean PRU, 287.0 (95% CI, 170.2-403.8).Conclusion Among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers; in contrast, for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition.