Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden.
Lancet. 2010 Oct 16;376(9749):1320-8. doi: 10.1016/S0140-6736(10)61274-3.
In the PLATO trial of ticagrelor versus clopidogrel for treatment of acute coronary syndromes, ticagrelor reduced the composite outcome of cardiovascular death, myocardial infarction, and stroke, but increased events of major bleeding related to non-coronary artery bypass graft (CABG). CYP2C19 and ABCB1 genotypes are known to influence the effects of clopidogrel. In this substudy, we investigated the effects of these genotypes on outcomes between and within treatment groups.
DNA samples obtained from patients in the PLATO trial were genotyped for CYP2C19 loss-of-function alleles (*2, *3, *4, *5, *6, *7, and *8), the CYP2C19 gain-of-function allele *17, and the ABCB1 single nucleotide polymorphism 3435C→T. For the CYP2C19 genotype, patients were stratified by the presence or absence of any loss-of-function allele, and for the ABCB1 genotype, patients were stratified by predicted gene expression (high, intermediate, or low). The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke after up to 12 months' treatment with ticagrelor or clopidogrel.
10 285 patients provided samples for genetic analysis. The primary outcome occurred less often with ticagrelor versus clopidogrel, irrespective of CYP2C19 genotype: 8·6% versus 11·2% (hazard ratio 0·77, 95% CI 0·60-0·99, p=0·0380) in patients with any loss-of-function allele; and 8·8% versus 10·0% (0·86, 0·74-1·01, p=0·0608) in those without any loss-of-function allele (interaction p=0·46). For the ABCB1 genotype, event rates for the primary outcome were also consistently lower in the ticagrelor than in the clopidogrel group for all genotype groups (interaction p=0·39; 8·8%vs 11·9%; 0·71, 0·55-0·92 for the high-expression genotype). In the clopidogrel group, the event rate at 30 days was higher in patients with than in those without any loss-of-function CYP2C19 alleles (5·7%vs 3·8%, p=0·028), leading to earlier separation of event rates between treatment groups in patients with loss-of-function alleles. Patients on clopidogrel who had any gain-of-function CYP2C19 allele had a higher frequency of major bleeding (11·9%) than did those without any gain-of-function or loss-of-function alleles (9·5%; p=0·022), but interaction between treatment and genotype groups was not significant for any type of major bleeding.
Ticagrelor is a more efficacious treatment for acute coronary syndromes than is clopidogrel, irrespective of CYP2C19 and ABCB1 polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment.
AstraZeneca.
在替格瑞洛对比氯吡格雷治疗急性冠脉综合征的 PLATO 试验中，替格瑞洛降低了心血管死亡、心肌梗死和中风的复合终点，但增加了与非冠状动脉旁路移植术（CABG）相关的大出血事件。CYP2C19 和 ABCB1 基因型已知会影响氯吡格雷的作用。在这项子研究中，我们研究了这些基因型对治疗组内和组间结局的影响。
从 PLATO 试验的患者中提取 DNA 样本，对 CYP2C19 失活等位基因（*2、*3、*4、*5、6、7 和8）、CYP2C19 获得性功能等位基因17 和 ABCB1 单核苷酸多态性 3435C→T 进行基因分型。对于 CYP2C19 基因型，根据是否存在任何失活等位基因对患者进行分层，对于 ABCB1 基因型，根据预测的基因表达（高、中或低）对患者进行分层。主要疗效终点是替格瑞洛或氯吡格雷治疗 12 个月后心血管死亡、心肌梗死或中风的复合终点。
10 285 名患者提供了用于基因分析的样本。替格瑞洛与氯吡格雷相比，无论 CYP2C19 基因型如何，主要结局的发生率均较低：任何失活等位基因患者中为 8.6% vs 11.2%（风险比 0.77，95%CI 0.60-0.99，p=0.0380）；无任何失活等位基因患者中为 8.8% vs 10.0%（0.86，0.74-1.01，p=0.0608）（交互作用 p=0.46）。对于 ABCB1 基因型，在所有基因型组中，替格瑞洛组的主要结局事件发生率也始终低于氯吡格雷组（交互作用 p=0.39；8.8% vs 11.9%；0.71，0.55-0.92 为高表达基因型）。在氯吡格雷组中，有任何失活 CYP2C19 等位基因的患者 30 天的事件发生率高于无任何失活 CYP2C19 等位基因的患者（5.7% vs 3.8%，p=0.028），导致失活等位基因患者治疗组之间的事件发生率更早分离。服用氯吡格雷且有任何 CYP2C19 获得性功能等位基因的患者大出血发生率较高（11.9%），而无任何获得性功能或失活等位基因的患者发生率较低（9.5%；p=0.022），但治疗和基因型组之间的相互作用对任何类型的大出血均不显著。
替格瑞洛是治疗急性冠脉综合征比氯吡格雷更有效的药物，无论 CYP2C19 和 ABCB1 多态性如何。替格瑞洛的使用消除了目前推荐的双重抗血小板治疗前进行基因检测的需要。
阿斯利康。
