Relation of cytochrome P450 2C19 gene 681G>A single nucleotide polynmrphism to clopidogrel resistance after PCI in Chinese

Objectives Clopidogrel is a prodrug that has to be converted to an active metabolite by hepatic cytochrome P450(CYP) isoenzymes to inhibit platelet aggregation.Individualvariability of platelet inhibition by clopidogrel suggests a possibility for genetic factors having a significant influence on clopidogrel responsiveness.In this study,we sought to determine the association between the single nucleotide polymorphism of CYP 2C19 681G>A and the occurrence of clopidogrel resistance(CR) in Chinese.Methods The study enrolled 614 hospitalized patients who underwentsuccessful percutaneouscoronary intervention with drug-eluting stents were received the treatmentwith dual antiplatelet regimen(aspirin plus clopidogrel).All patients received loading doses of 600 mg clopidogrel and 300 mg aspirin.20μmol/L ADP-induced platelet aggregation ratio(PAR ) was assessed 24 h after clopi- dogrel administration.The maximum residual PAR≥70%was defined as CR.Genomic DNA was extracted from whole blood samples according to standard protocols,the single nucleotide polymorphism of the CYP2C19 681G>A was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in all the patients.Results CR was found in 126 patients(20.5%).There was CYP2C19 681G>A polymorphism in the study population.The frequencies of the three kinds of genotypes(GG,GA,A A) in CR group and non-CR (NCR)group were 32.5%,47.6%,19.8%and 48.0%, 45.0%,7.0%,respectively.The frequency of AA genotype was significantly higher in NCR group than that in CR group (OR =3.03,95%CI:1.889～5.784,P=0.003).The A allele carriers were more likely to develop clopidogrel resistance compared with that of G allele carriers(OR=1.85,95%CI: 1.392～2.459,P=0.002).Conclusions CYP2C19 681G/A polymorphism is associated with the risk of CR,and the A allele carriers may be a possible genetic susceptibility factor for patients with CR.     

细胞色素P450 2C19*2基因多态性联合钙通道阻滞剂与冠状动脉支架内血栓形成的相关性

目的:探讨经皮冠状动脉介入术(PCI)后接受氯吡格雷治疗的患者中,细胞色素P450 2C19(CYP2C19)*2基因多态性(681A)与支架内血栓形成的相关性,以及服用钙通道阻滞剂(CCBs)与支架内血栓形成的相关性。方法:检测1 738例冠心病PCI术后患者的CYP2C19基因多态性,并将这些患者分为CCBs组和非CCBs组,采用比浊法检测二磷酸腺苷(ADP)途径诱导的血小板最大聚集率(MPAR),比较两组患者MPAR及支架内血栓形成率的差异。结果:19例(2.4%)CYP2C19*2基因型的患者(包括CYP2C19*2/*2或*1/*2)和7例(0.75%)基因型为CYP2C19*1/*1的患者发生了明确的支架内血栓形成;CYP2C19*2基因型患者支架内血栓形成的发生率明显高于CYP2C19野生型纯合子患者(CYP2C19*1/*1)(风险比为4.26,95%可信区间为1.28～9.22,P<0.05);基因型为CYP2C19*1/*1的患者发生支架内血栓形成的风险最低,而基因型为CYP2C19*2/*2的患者支架内血栓形成的风险最高(风险比为0.568,95%可信区间为0.308～2.070,P<0.01);CCBs组和非CCBs组MPAR及支架内血栓形成率差异无统计学意义。结论:PCI术后接受氯吡格雷治疗的冠心病患者中,CYP2C19*2基因型患者支架内血栓形成的风险增加,而服用CCBs不会导致氯吡格雷抗血小板聚集作用减弱以及支架内血栓形成事件增加。     

CYP2C19基因多态性与冠心病患者PCI术后氯吡格雷抵抗的关系

目的:探讨CYP2C19基因多态性对冠心病患者经皮冠状动脉介入治疗(PCI)术后氯吡格雷抵抗(CR)的影响。方法:选择在我院接受治疗并进行PCI手术的冠心病患者100例,其中CR 24例,无氯吡格雷抵抗(NCR)76例。根据CYP2C19基因型,患者被分为快代谢型CYP2C19*1/*1 (49例),中间代谢型CYP2C19*1/*2(28例)和*1/*3 (11例),慢代谢型CYP2C19*2/*2 (9例)和*2/*3 (3例)。分析不同基因型与CR、最大血小板聚集率(MPA)、主要不良心血管事件(MACE)发生的关系。结果:以快代谢型CYP2C19*1/*1基因型为基础,中间代谢型CYP2C19*1/*2和*1/*3 (OR=4.16、5.03,P均0.05)及慢代谢型CYP2C19*2/*2和*2/*3 (OR=7.04、17.6,P均0.01)发生CR的风险显著增加,中间代谢型分别增加4.16和5.03倍,慢代谢型分别增加7.04和17.60倍;与快代谢基因型比较,中、慢代谢基因型的MPA和MACE发生率均显著增加(P0.05或0.01);CR组MACE发生率显著高于NCR组(20.8%比5.3%,P=0.02)。结论:CYP2C19基因多态性对冠心病患者PCI术后氯吡格雷抵抗有一定的影响,带有中、慢代谢基因型冠心病患者更易发生氯吡格雷抵抗以及有更高的最大血小板聚集率和主要不良心血管事件发生率。     

冠状动脉介入术后外周血微小核糖核酸-145表达与急性冠状动脉综合征患者氯吡格雷抵抗的相关性研究

目的:探究血小板微小核糖核酸-145(miR-145)、细胞色素P450 2C19(CYP2C19)基因型与急性冠状动脉综合征(ACS)患者经皮冠状动脉介入术(PCI)术后氯吡格雷抵抗(CR)及预后的相关性。方法:选取2018年1月至2019年12月,在本院行PCI术的ACS患者102例进行研究,患者术后均进行常规双联抗血小板治疗,根据患者是否存在CR分为CR组25例和氯吡格雷非抵抗(NCR)组77例。比较两组患者一般资料;分析比较两组患者miR-145表达水平,CYP2C19*2位点、*3位点基因多态性;记录1年内ACS患者PCI术后发生主要不良心血管事件(MACE)的情况;以Logistic回归分析ACS患者PCI术后发生不良预后的危险因素。结果:CR组ACS患者血小板miR-145相对表达量明显高于NCR组(P0.05);CR组ACS患者CYP2C19*2位点中*1/*1基因型占比明显低于NCR组(P0.05),*1/*2基因型占比明显高于CR组(P0.05);CR组ACS患者CYP2C19*3位点中*1/*1基因型占比低于NCR组(P0.05),*1/*3基因型、*3/*3基因型占比明显高于NCR组(P0.05);CR组ACS患者PCI术后MACE总发生率明显高于NCR组(P0.05);miR-145是ACS患者PCI术后的保护因素(P0.05),CYP2C19*2位点是ACS患者PCI术后的危险因素(P0.05)。结论:血小板miR-145表达水平、CYP2C19基因多态性有助于评估ACS患者PCI术后CR及预后情况,临床需要密切关注。     

CYP2C19 681G>A和636G>A基因多态性对冠心病行PCI术后服用氯吡格雷患者血小板活性及临床预后的影响

目的观察CYP2C19 681G>A、636G>A(CYP2C19*2、*3)基因多态性对冠心病行冠状动脉介入术后服用氯吡格雷患者残余血小板活性及临床预后的影响。方法入选2011年6月至2011年12月因冠心病行经皮冠状动脉介入术者共202例,根据CYP2C19基因型不同,分为正常纯合子组78例(CYP2C19*1/*1)、单突变基因携带组100例(CYP2C19*1/*2、CYP2C19*1/*3)、双突变基因携带组24例(CYP2C19*2/*2、CYP2C19*2/*3),对比三组间临床基本资料、残余血小板活性、半年内主要心血管事件及出血事件发生率。结果三组间仅钙离子拮抗剂使用率存在差异(正常纯合子组、单突变基因携带组和双突变基因携带组分别为15.4%、29.0%和45.8%,P=0.007),其余临床资料基本相似。口服氯吡格雷5天(正常纯合子组、单突变基因携带组和双突变基因携带组分别为51.60%±17.21%、55.89%±14.92%和62.00%±9.75%,P=0.060)及3个月时(49.45%±16.90%、55.98%±19.03%和57.64%±18.42%,P=0.248)二磷酸腺苷诱导的血小板聚集率在三组间均未见明显差异。双突变基因携带组半年内非致死性心肌梗死发生率明显升高(正常纯合子组、单突变基因携带组和双突变基因携带组分别为0%、0%和8.3%,P=0.001),而心绞痛复发、支架内血栓形成、急性左心衰竭、心源性死亡及出血事件发生率三组间未见明显差异。结论 CYP2C19 681G>A和CYP2C19 636G>A基因多态性与经皮冠状动脉介入术后服用氯吡格雷的冠心病患者早期残余血小板活性及临床预后相关。     

CYP2C19基因多态性与氯吡格雷抵抗的关系及对冠心病PCI患者短期预后的影响

目的探讨冠心病(CHD)患者CYP2C19基因多态性与氯吡格雷抵抗的关系及对接受经皮冠状动脉介入治疗(PCI)的CHD患者短期预后的影响。方法接受PCI治疗的CHD患者352例,均行PCI治疗,治疗后进行基因型测定、血小板活性测定及氯吡格雷抵抗测定。对比CYP2C19基因野生亚型组和突变亚型组患者的基线资料、氯吡格雷抵抗率及血小板凝集率,统计CYP2C19基因型的各亚型比例,随访1年,对比野生亚型组和突变亚型组的预后情况。结果野生亚型组和突变亚型组基线资料比较差异无统计学意义(P>0.05)。352例患者CYP2C19基因型检测结果显示,野生亚型组166例,突变亚型组186例。CYP2C19基因型共有6种:(*1/*1)、(*1/*2)、(*1/*3)、(*2/*2)(*2/*3)(*3/*3),各亚型比例分别为166例(47.2%)、138例(39.2%)、27例(7.7%)、10例(2.8%)、10例(2.8%)和1例(0.3%)。突变亚型组的氯吡格雷抵抗率、血小板凝集率均高于野生亚型组(P<0.05)。Kaplan-Meier生存分析发现,在PCI患者中,CYP2C19野生亚型组患者预后明显优于突变亚型组(P<0.05)。结论 CYP2C19基因多态性显著影响PCI预后,CHD患者PCI术后CYP2C19*2、CYP2C19*3基因变异型的氯吡格雷抵抗率更高,心血管不良事件发生率明显升高。     

CYP2C19指导ACS行PCI患者抗血小板药物选择的研究

目的:根据急性冠状动脉综合征(ACS)行经皮冠状动脉介入治疗(PCI)患者CYP2C19基因型的不同选择抗血小板药物及剂量进行治疗,观察其抗血小板效应及出血风险,为个体化抗血小板药物的选择提供参考。方法:入选231例行PCI的ACS患者并检测其CYP2C19基因型,根据基因型的不同分为快代谢组(CYP2C19*1/*1)、中代谢组(CYP2C19*1/*2、CYP2C19*1/*3)、慢代谢组(CYP2C19*2/*2、CYP2C19*3/*3、CYP2C19*2/*3),并分别给予快代谢组常规双联抗血小板治疗(氯吡格雷75mg qd+阿司匹林100mg qn),中代谢组氯吡格雷剂量加倍(氯吡格雷150mg qd+阿司匹林100mg qn),慢代谢组换用新型抗血小板药物(替格瑞洛90mg bid+阿司匹林100mg qn),比较各组用药3个月后血小板抑制率变化情况及出血事件的发生情况。结果:根据基因型所分3组的临床基线资料及PCI结果无统计学差异。中代谢组及慢代谢组患者用药3个月后,血小板抑制率均较快代谢组血小板抑制率升高,慢代谢组血小板抑制率较中代谢组明显升高,差别具有统计学意义(均P0.05)。结论:PCI术后的ACS患者中,携带CYP2C19*2、CYP2C19*3等位基因的高危患者,采用氯吡格雷剂量加倍及换用替格瑞洛均可充分抑制血小板,且换用替格瑞洛优于氯吡格雷剂量加倍。     

细胞色素P450 2C19基因多态性与急性冠脉综合征患者PCI治疗后血小板再活化及预后的关系

目的探讨细胞色素P450 2C19(CYP2C19)基因多态性与接受经皮冠状动脉腔内介入(percutaneous coronary intervention,PCI)治疗的急性冠脉综合征(acute coronary syndrome,ACS)患者术后血小板再活化(posttreatment platelet reactivity,HPPR)的关系及对其临床预后的影响。方法选择2011年1月至2012年6月在广州市第一人民医院心内科住院,诊断为ACS并接受PCI治疗的患者362例。于PCI治疗后测定5μmol/L腺苷二磷酸(ADP)诱导的血小板聚集率(platelet aggregation ratio,PAR),以受试者工作曲线(ROC曲线)确定预测患者术后主要心血管事件(major adverse coronary event,MACE)发生的最佳PAR值(44.5%)后将患者分为HPPR组(PAR≥44.5%)和对照组(PAR<44.5%)。应用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP)检测患者CYP2C19基因681(G/A)位点的基因型和等位基因,观察两组患者CYP2C19(681G/A)基因型、等位基因分布情况及住院期间与术后6个月随访期内MACE的发生情况。结果 HPPR组CYP2C19(681AA)基因型及携带681A等位基因频率均显著高于对照组,差异有统计学意义(25.9%vs.10.4%,P<0.01;48.7%vs.24.0%,P<0.01)。HPPR组明确的支架血栓事件及随访期间MACE的发生率均高于对照组,差异有统计学意义(5.3%vs.0.8%,χ2=7.433,P=0.012;14.3%vs.7.2%,χ2=4.563,P=0.047)。多因素Logistic回归分析结果显示携带CYP2C19(681A)基因、HPPR均是ACS患者PCI治疗后MACE发生的独立预测因子(P<0.05)。结论 ACS患者CYP2C19基因681(G/A)位点单核苷酸多态性与PCI治疗后HPPR存在相关性;ACS患者CYP2C19基因的突变导致患者对抗血小板治疗的低反应性,并增加患者PCI治疗后血栓事件和MACE发生的风险。     

CYP2C19基因多态性与介入治疗后氯吡格雷药物疗效的相关性研究

目的探讨PCI术后CYP2C19基因多态性与不同剂量氯吡格雷药物效果的相关性。方法通过基因芯片检测技术,筛选PCI术后CYP2C19基因突变为CYP2C19*2/*2、CYP2C19*2/*3或CYP2C19*3/*3的患者67例,随机分为常规组22例、2倍组22例和3倍组23例。常规组75 mg氯吡格雷、2倍组150 mg氯吡格雷、3倍组225 mg氯吡格雷,1次/d。分别于PCI术后1、3、6个月通过血栓弹力图检测各组氯吡格雷药物抑制率及再发心血管缺血事件发生率。结果 PCI术后6个月内,2倍组和3倍组患者心血管缺血事件发生率较常规组明显降低(81.8%vs 31.8%vs 21.7%,P<0.01),2倍组与3倍组比较差异无统计学意义(P>0.05)。术后1、3、6个月2倍组和3倍组氯吡格雷药物抑制率较常规组显著升高(P<0.01),2倍组与3倍组比较差异无统计学意义(P>0.05)。3组出血风险比较差异无统计学意义(P>0.05)。结论 CYP2C19基因变异患者增加氯吡格雷药物服用剂量,可在一定程度上提高血小板的抑制,降低心血管缺血事件发生率,且不增加出血事件的发生率。     

血浆细胞色素P4502C19基因多态性与皖北汉族急性冠脉综合征患者氯吡格雷抵抗及冠脉介入术后近期预后的关系

目的:探讨皖北汉族急性冠状动脉综合征(ACS)患者血浆细胞色素P4502C19(CYP2C19)基因多态性分布特征及其与氯吡格雷抵抗(CR)的关系,并评价其对接受经皮冠状动脉介入治疗(PCI)患者近期预后的影响。方法:入选298例住院并接受阿司匹林和氯吡格雷双联抗血小板治疗的皖北汉族ACS患者。采用基因芯片技术和荧光定量PCR检测每位患者CYP2C19基因的多态性,根据结果分为快代谢型(CYP2C19*1/*1)、中等代谢型(CYP2C19*1/*2,CYP2C19*1/*3)和慢代谢型(CYP2C19*2/*2,CYP2C19*2/*3,CYP2C19*3/*3)3组。采用光学比浊法检测每位患者服用氯吡格雷前和用药后7d的血小板聚集率(PAR),以用药前后差值≤10%定义为CR。所有患者均行PCI,计算血管病变支数和Gensini评分。对患者住院期间严密观察,出院后通过电话或门诊随访≥3个月。结果:慢代谢型组较中等代谢型组,中等代谢型组较快代谢型组发生CR的比例均增高(均P0.05)。3组冠状动脉病变支数和Gensini评分差异均无统计学意义。多因素Logistic回归分析显示,携带CYP2C19突变基因是ACS患者发生CR的独立预测因子(OR:2.122,P0.01)。随访3个月以上,慢代谢型组和中等代谢型组较快代谢型组有更高的心血管事件发生率(P0.05)。结论:皖北汉族ACS患者血浆CYP2C19基因多态性与CR的发生存在相关性,且基因突变增加了患者PCI术后心血管事件发生的风险,影响临床预后。     

急性冠脉综合征PCI术后患者CYP2C19*2、CYP2C19*3基因多态性与氯吡格雷抵抗及临床预后的关系

目的 探讨急性冠脉综合征经皮冠状动脉介入治疗（Percutaneous Coronary Intervention,PCI）术后患者CYP2C19*2、CYP2C19*3基因多态性与氯吡格雷抵抗及临床预后的关系。方法 入选310例急性冠脉综合征行PCI术的患者,采用生物传感器基因芯片技术检测所有患者CYP2C19*2、CYP2C19*3基因型,根据基因型分为强代谢组（未携带突变基因,681GG/636GG）,中代谢组（携带一个突变基因,681GA/636GG,681GG/636GA）,弱代谢组（携带两个突变基因,681GA/636GA,681AA/636GG,681GG/636AA）。采用全流式细胞术定义氯吡格雷抵抗。分析各组之间氯吡格雷抵抗发生率的差异。观察各组12个月随访支架内血栓与心血管事件发生率。结果 强代谢组、中代谢组、弱代谢组分别为137例（44.2%）、134例（43.2%）、39例（12.6%）,三组之间氯吡格雷抵抗发生率有统计学差异。12个月随访中弱代谢组联合心血管不良事件发生率显著高于强代谢组(P<0.05),其中非致死心梗和支架内血栓发生率显著高于强代谢组(P<0.05),而死亡及再次血运重建率两组比较差异无统计学意义(P>0.05);中弱代谢组再次住院率也显著高于强代谢组。结论 急性冠脉综合征患者PCI术后CYP2C19*2、CYP2C19*3基因变异氯吡格雷抵抗发生率更高,支架内血栓及心血管不良事件发生率明显升高。     

Factors determining clinical effectiveness of clopidogrel and prognosis of patients with stable ischemic heart disease

Aim of the study was to elucidate genetic and drug factors affecting efficacy of clopidogrel in patients with ischemic heart disease - inhabitants of central region of Russian Federation. We included 399 patients with IHD (79% men, mean age 58.3+/-9 years) receiving long term therapy with clopidogrel 75 mg/day (during stable manifestations of the disease) or 75-150 mg/day in combination with aspirin (in relation with recent elective percutaneous interventions). We studied carriage of polymorphisms of genes controlling intestinal absorption of clopidogrel (ABCB1 C3435T), activation of clopidogrel in the liver (CYP2C19 *1 *2), and also registered concomitant administration of proton pump inhibitors (PPI). Then we determined relationship of these factors to development of vascular complications (vascular death/myocardial infarction/requirement in revascularization) during 18 months followup. Among studied genetic factors carriage of allele variants CYP2C19 *1/*2 and *2/* (found in 25.5 and 1.8% of patients, respectively), possessed prognostic significance. In the group of clopidogrel monotherapy carriage of at least one *2 allele was associated with increased rate of vascular complications (33.3% vs. 11.3%) including thrombotic complications (27.7% vs. 3.2%; =0.01). In patients receiving 75 mg/day of clopidogrel in combination with aspirin total rate of thrombotic complications as well as of all adverse unfavorable outcomes was higher in *2 carriers compared with wild type homozygotes (14.0% vs.8.7% and 21.0% vs. 15.8%, respectively). In patients receiving double dose clopidogrel in combination with aspirin we found no worsening of outcomes associated with CYP2C19*2 carriage. In the multifactorial risk model independent predictors of vascular complications turned out to be CYP2C19 *2/*2 homozygosity (RR 4.9; =0.02) and concomitant PPI administration ( 1.8; p=0.05).     

Clopidogrel Resistance: case reports of CYP2C19 gene variants in suspected coronary stent thrombosis

Clopidogrel is a widely used anti-platelet agent for the prevention of arterial thrombosis. Clopidogrel is administered as a pro-drug and metabolised to its active metabolite by the hepatic cytochrome P450 2C19 (CYP2C19) enzyme. The active metabolite is responsible for the anti-platelet activity of clopidogrel. Recent studies demonstrate that single nucleotide polymorphisms, (SNP's), in the gene for CYP2C19 result in significantly reduced production of the active metabolite of clopidogrel. Additional studies demonstrate that patients with SNP's in the CYP2C19 gene, including CYP2C19*2,*3,*4, and *5, have reduced production of the active metabolite of clopidogrel, reduced inhibition of platelet aggregation and increased incidence of coronary, cerebrovascular, and coronary stent thrombosis. We have been interested in determining the CYP2C19 genotype in cases of coronary stent thrombosis whilst on clopidogrel treatment and provide two case reports of coronary stent thrombosis whilst taking clopidogrel with subsequent CYP2C19 genotyping. As patients at risk of atherothrombosis in general, and stent thrombosis in particular, may be receiving or considered for anti-platelet therapy including clopidogrel, genotyping for CYP2C19 SNP's may be of benefit in the selection of appropriate anti-platelet therapy.     

CYP2C19＊2基因多态性与经皮冠状动脉介入治疗后氯吡格雷抗血小板临床疗效的相关性

目的探讨CYP2C19＊2（c．681G〉A,rs4244285）基因多态性与经皮冠状动脉介入（percutaneouscoronaryintervention,PCI）治疗后氯吡格雷抗血小板临床疗效的相关性。方法选择478例接受PCI治疗的急性冠脉综合征（acutecoronarysyndrome,ACS）患者,采用TaqMan基因分型技术检测其CYP2C19＊2的基因多态性。患者术后均采用氯吡格雷抗血小板治疗并定期随访,分析不同基因型与PCI治疗后支架内血栓、主要心血管事件（majoradversecardiacevents,MACE）发生率及生存时间的相关性。采用COX单因素分析检测PCI治疗后发生MACE的相关因素,采用COX多因素分析检测PCI治疗后MACE的危险因素。结果本研究人群中的CYP2C19＊2的基因型分布符合Hardy—Weinberg平衡。478例患者纯合野生型（GG）238例（49．8％）,杂合型（GA）加纯合突变型（AA）240例（50．2％）。分析结果显示,对于支架内血栓（P=0．025）及MACE（P=0．09）,携带681GG基因型的患者预后较携带681A等位基因（AA／AG基因型）的好。单因素COX回归结果显示,CYP2C19＊2的基因型、糖尿病病史、原发性高血压（高血压）病史[RR（95％CI）为2．796（1．245—6．281）、2．157（1．039—4．478）和3．564（1．364-9．312）]是发生MACE的相关因素。多因素COX回归分析结果显示,CYP2C19＊2的基因型、高血压病史是发生MACE的危险因素。结论CYP2C19＊2的基因多态性与PCI治疗后氯吡格雷抗血小板临床疗效有关,CYP2C19＊2基因突变能够降低氯吡格雷抗血小板效果,增加PCI治疗后发生支架内血栓、MACE的风险。     

CYP2C19*2 and prognosis after an acute coronary syndrome: Insights from a Portuguese center

BackgroundClopidogrel requires oxidation dependent on the cytochrome P450 enzyme 2C19 (CYP2C19) to form its active metabolite. The importance of loss-of-function alleles (particularly CYP2C19*2, 681G>A) in poor platelet response to clopidogrel is well recognized.ObjectiveTo investigate the prevalence and prognostic impact of the CYP2C19*2 allele in a local acute coronary syndrome (ACS) population.MethodsWe performed a prospective, longitudinal study of 95 patients admitted for an ACS between March and October 2009 to a single coronary care unit. Patients aged under 75 who survived hospital stay and for whom clopidogrel was prescribed were included. At discharge, CYP2C19 was genotyped using a commercially available kit. Patients were divided into two groups: Group A (non-carriers, normal metabolizers, CYP2C19*1/*1), n = 69; and Group B (carriers, slow metabolizers, CYP2C19*2/*1 or *2/*2), n = 26. The primary endpoint was a combined outcome of cardiovascular death, non-fatal myocardial infarction or re-admission for unstable angina; median follow-up was 136.0 (79.0–188.0) days.ResultsThe median age of the population was 62.0 (51.0–68.0) years, and 83.2% were male. The CYP2C19*2 (A) allele had a frequency of 14.2%. There were no differences between the groups with respect to demographic data or history of cardiovascular disease. Coronary anatomy, left ventricular ejection fraction and renal function were also similar. The groups were also homogenous with respect to GRACE risk score (118.0 (95.0–136.5) vs. 115.0 (96.0–133.0), p = 0.68), medical treatment and percutaneous revascularization during hospital stay. Event-free survival was higher for Group A (94.0% vs. 75.0%, log-rank p = 0.010). Three readmissions for MI were documented, all in the slow metabolizers group.ConclusionIn our ACS population, the CYP2C19*2 allele was a medium-term prognostic marker.     

Evaluation of the INNOVANCE PFA P2Y assay and its association with CYP2C19 genotypes

The purpose of this study was to evaluate associations between INNOVANCE PFA P2Y (PFA P2Y) test results and CYP2C19 genotypes and provide baseline data for PFA P2Y testing to establish a therapeutic monitoring strategy for clopidogrel. A total of 75 new patients with acute coronary syndrome with planned percutaneous coronary intervention were enrolled between June 2012 and September 2012. All patients received clopidogrel at an initial loading dose of 600?mg followed by a 75-mg daily maintenance dose. Blood samples were obtained on the third morning after clopidogrel loading. PFA P2Y, VerifyNow P2Y12 and VASP assays were used to determine platelet inhibition due to clopidogrel, and the Verigene CYP2C19 test was used for CYP2C19 genotyping. The genotype frequency of 75 patients was as follows: CYP2C19 *1/*1 (wild type), 28 (37.3%); *1/*2, 31 (41.3%); *1/*3, 4 (5.3%); *2/*2, 5 (6.7%); *2/*3, 5 (6.7%); *1/*17, 1 (1.3%); and *2/*17, 1 (1.3%). Classified according to CYP2C19 genotypes, there were 29 (38.7%) extensive metabolizers (EM) or ultra rapid metabolizers (UM), 35 (46.7%) intermediate metabolizers (IM), and 10 (13.3%) poor metabolizers (PM). Median (interquartile range) PFA P2Y closure times (seconds) were 119 (101–260), 300 (130–300) and 300 (300–300) in the PM, IM and EM or UM groups, respectively (p?<?0.05). Median (interquartile range) VerifyNow PRUs were 294 (213–297), 215 (165–320) and 189 (118–279); and the VASP platelet reactivity index (%) was 52.7 (33.3–91.9), 59.9 (41.4–72.8) and 38.9 (26.8–62.2) in the PM, IM and EM or UM groups, respectively (p?>?0.05). Compared with non-carriers, carriers of reduced function CYP2C19 alleles tended to have higher platelet reactivity after clopidogrel treatment. The cut-off for PM versus other groups (IM and EM or UM) was ≤141 seconds (AUC 0.704, sensitivity 70%, specificity 76.6%) on the ROC curve. A statistically significant correlation between PFA P2Y (seconds) and VerifyNow (PRU) was found (ρ?=??0.47, p?<?0.0001). In conclusion, the PFA P2Y test showed a statistically significant association with CYP2C19 metabolizer phenotypes based on CYP2C19 genotyping and effectively determined the risk groups resistant to clopidogrel therapy, including PM.     

CYP2C19功能缺失性等位基因与老年冠心病患者支架植入术后氯吡格雷抗血小板反应性和疗效的药物基因组学研究

目的：探讨编码CYP2C19酶的基因（CYP2C19）功能缺失性（LOF）等位基因与老年冠心病患者支架植入术后氯吡格雷抗血小板反应性和临床心血管终点事件的关联性。方法连续募集2011年9月1日至2012年12月1日期间在解放军总医院住院拟行经皮冠状动脉介入术（PCI）、年龄≥65岁的老年冠心病患者,术前给予氯吡格雷负荷剂量（300mg）治疗,手术当日测定血小板聚集率,采用SNaPshot法进行CYP2C19 LOF等位基因型（CYP2C19＊2和CYP2C19＊3）检测,并记录在院临床资料。所有患者均在PCI术后1年规律服用阿司匹林和氯吡格雷,随访1年内主要心血管缺血和出血事件的发生率。结果在436例符合入选标准的老年冠心病患者中,CYP2C19＊2携带者与氯吡格雷负荷剂量治疗后的抗血小板反应性之间存在显著相关性（P＝0.001）,但在CYP2C19＊3携带者中未见上述相关性（P＝0.884）。CYP2C19＊2和至少一个CYP2C19 LOF携带者1年内心血管终点事件的发生率较非携带者均明显增加（P＜0.05）。与非携带者相比,CYP2C19＊2携带者因心绞痛再入院的发生率明显增加[校正比值比（OR）：1.67,95%可信区间（CI）：1.05～2.65,P＝0.010]。至少一个CYP2C19 LOF携带者的联合心血管事件（校正OR：1.22,95%CI：1.03～1.98,P＝0.049）和因心绞痛再入院（校正OR：1.67,95%CI：1.04～2.68,P＝0.032）的发生率较非携带者明显增加。结论 CYP2C19 LOF等位基因与老年冠心病患者PCI术后的氯吡格雷抗血小板反应性密切相关,并可明显削弱PCI术后双联抗血小板的治疗效果,导致PCI术后1年内的心血管终点事件发生风险明显增加。     

A case of subacute thrombosis associated with clopidogrel resistance after implantation of a zotarolimus-eluting stent

A 73-year-old woman was admitted to our hospital with anterior acute myocardial infarction due to subacute thrombosis after coronary stenting with a zotarolimus-eluting stent (ZES), which is a newly developed drug-eluting stent that has been widely used since May 2009 in Japan. Five days before, she underwent implantation with a ZES in the left anterior descending artery due to stable angina pectoris. After stenting, the intravascular ultrasonography showed no malapposition from the proximal to the distal edge of the stent. She received aspirin 100 mg/day and clopidogrel 75 mg/day from 2 weeks before the stent was implanted. When we investigated the single nucleotide polymorphisms of CYP2C19 in this patient, both CYP2C19*2 and CYP2C19*3 were detected, and she was classified as a poor metabolizer. This report is the first to describe subacute stent thrombosis following the implantation of a newly developed ZES in a Japanese patient, which may be related to clopidogrel resistance.     

Usefulness of high clopidogrel maintenance dose according to CYP2C19 genotypes in clopidogrel low responders undergoing coronary stenting for non ST elevation acute coronary syndrome

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 CYP2C19*2 allele carriers (p = 0.01). Accordingly, the rate of clopidogrel nonresponse was higher in CYP2C19*2 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 CYP2C19*2 carriers. Therefore, these patients might require alternative strategies with new P2Y?? blockers.