Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial
Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial
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DOI：
10.1001/jama.2020.12443
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发表时间：
2020-08-25
影响因子：
120.7
通讯作者：
Rihal, Charanjit
中科院分区：
文献类型：
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作者：
Pereira, Naveen L.;Farkouh, Michael E.;Rihal, Charanjit
CYP2C19基因型指导处方经皮冠状动脉介入治疗（PCI）后口服P2Y12抑制剂治疗是否能改善急性冠状动脉综合征和稳定型冠状动脉疾病患者的缺血结局？在这项随机临床试验中，5302名接受PCI治疗的患者和1849名CYP2C19功能缺失等位基因的患者在初步分析中，基因型引导下选择口服P2Y12抑制剂治疗与使用氯吡格雷的常规治疗相比，在12个月心血管死亡、心肌梗死、卒中、支架血栓形成或严重复发性缺血的复合终点方面无显著差异(分别为4.0%和5.9%；风险比0.66)。意义在接受PCI治疗的CYP2C19功能缺失等位基因患者中，与传统的氯吡格雷治疗相比，基因型引导选择口服P2Y12抑制剂并没有显著减少缺血事件，基于该研究在12个月时检测到的治疗效果。经皮冠状动脉介入治疗（PCI）后，经氯吡格雷治疗的CYP2C19*2或*3功能丧失（LOF）变异患者发生缺血性事件的风险增加。基因型引导下选择口服P2Y12抑制剂治疗是否能改善缺血性预后尚不清楚。目的探讨基因型引导口服P2Y12抑制剂策略对CYP2C19 LOF患者PCI术后缺血结局的影响。设计、环境和参与者：5302例急性冠状动脉综合征（ACS）或稳定型冠状动脉疾病（CAD）患者接受PCI治疗的开放标签随机临床试验。从2013年5月到2018年10月，患者在美国、加拿大、韩国和墨西哥的40个中心入组；后续行动的最后日期是2019年10月。干预措施随机分配到基因型引导组的患者（n=2652）进行了即时基因分型。CYP2C19 LOF携带者给予替格瑞洛和非携带者氯吡格雷。随机分配到常规组（n=2650）的患者在12个月后服用氯吡格雷并进行基因分型。主要终点是心血管死亡、心肌梗死、卒中、支架血栓形成和12个月时严重复发性缺血的复合终点。次要终点是12个月时的大出血或小出血。主要分析是CYP2C19 LOF变异患者，次要分析包括所有随机患者。该试验有85%的能力检测到0.50的最小风险比。结果在5302例随机患者中（中位年龄62岁，25%为女性），82%为ACS， 18%为稳定CAD；94%的人完成了试验。在1849名CYP2C19 LOF变异患者中，903名患者中有764名（85%）接受基因型引导治疗，946名患者中有932名（99%）接受氯吡格雷治疗。12个月时，基因型引导治疗组903名CYP2C19 LOF携带者中有35名（4.0%）出现主要终点，常规治疗组946名携带者中有54名（5.9%）出现主要终点（风险比[HR]， 0.66 [95% CI, 0.43-1.02]； P= 0.06）。11个预先设定的次要终点均未显示出显著差异，包括基因型引导组CYP2C19 LOF携带者在12个月时的大出血或小出血（1.9%）与常规治疗组（1.6%）（HR, 1.22 [95% CI, 0.60-2.51]； P= 0.58）。在所有随机患者中，基因型引导组2641例中有113例（4.4%）出现主要终点，常规组2635例中有135例（5.3%）出现主要终点（HR, 0.84 [95% CI, 0.65-1.07]； P= 0.16）。结论及相关性在CYP2C19 LOF携带者合并ACS和稳定型CAD行PCI的患者中，基因型引导下选择口服P2Y12抑制剂与常规氯吡格雷治疗相比，在心血管死亡、心肌梗死、卒中、支架血栓形成等复合终点上无统计学差异。根据预先设定的分析计划和研究在12个月时检测的治疗效果，重度再缺血。这项开放标签随机试验比较了基因型引导的口服P2Y12抑制剂选择策略与传统氯吡格雷处方对急性冠状动脉综合征和稳定心血管疾病的CYP2C19*2/CYP2C19*3功能丧失等位基因携带者经皮冠状动脉介入治疗（PCI）后12个月缺血结局的影响。
Key PointsQuestionDoes CYP2C19 genotype-guided prescription of oral P2Y12 inhibitor therapy after percutaneous coronary intervention (PCI) improve ischemic outcomes in patients with acute coronary syndromes and stable coronary artery disease? FindingsIn this randomized clinical trial that included 5302 patients undergoing PCI and included 1849 patients with CYP2C19 loss-of-function alleles in the primary analysis, genotype-guided selection of oral P2Y12 inhibitor therapy, compared with conventional therapy using clopidogrel, resulted in no significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, or severe recurrent ischemia at 12 months (4.0% vs 5.9%, respectively; hazard ratio, 0.66). MeaningAmong patients with CYP2C19 loss-of-function alleles who underwent PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy, did not significantly reduce ischemic events based on the treatment effect that the study was powered to detect at 12 months.ImportanceAfter percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown. ObjectiveTo determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 LOF carriers after PCI. Design, Setting, and ParticipantsOpen-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019. InterventionsPatients randomized to the genotype-guided group (n=2652) underwent point-of-care genotyping. CYP2C19 LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n=2650) were prescribed clopidogrel and underwent genotyping after 12 months. Main Outcomes and MeasuresThe primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with CYP2C19 LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50. ResultsAmong 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with CYP2C19 LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903 CYP2C19 LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02]; P=.06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51]; P=.58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07]; P=.16). Conclusions and RelevanceAmong CYP2C19 LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months. Trial RegistrationClinicalTrials.gov Identifier: NCT01742117This open-label randomized trial compares the effect of a genotype-guided oral P2Y12 inhibitor selection strategy vs conventional clopidogrel prescribing on 12-month ischemic outcomes after percutaneous coronary intervention (PCI) in CYP2C19*2/CYP2C19*3 loss-of-function allele carriers with acute coronary syndromes and stable cardiovascular disease.