即时检测 CYP2C19基因型精准指导下高危非致残性缺血性脑血管事件的抗血小板治疗

目的探讨在即时检测CYP2C19基因型的精准指导下, 不同双重抗血小板方案治疗高危非致残性缺血性脑血管事件(HR-NICE)的有效性及安全性。方法采用单中心、前瞻性、随机、开放标签、终点盲法设计。连续收集2020年7月至2022年1月于徐州市中心医院脑卒中绿色通道及神经内科病房收治的HR-NICE患者, 对所有患者无创刮取颊黏膜行即时检测, 筛选CYP2C19功能缺失等位基因CYP2C19*2和CYP2C19*3的携带者, 携带1个功能缺失等位基因为CYP2C19中代谢, 携带2个功能缺失等位基因为CYP2C19慢代谢, 使用全自动医用PCR分析仪进行即时检测CYP2C19基因型, 将检测周转时间缩短至1 h。将CYP2C19基因型为中慢代谢的患者按照随机数字表法分为常规治疗组(氯吡格雷75 mg, 1次/d)、替格瑞洛组(替格瑞洛90 mg, 2次/d)和强化剂量组(氯吡格雷150 mg, 1次/d), 分别联合阿司匹林100 mg, 1次/d双重抗血小板治疗21 d。收集3组患者的一般基线资料、急性卒中Org10172治疗试验分型及90 d改良Rankin量表(mRS)评分、不良事...     

氯吡格雷抵抗的基因多态性研究进展

氯吡格雷对缺血性脑卒中患者的临床疗效存在差异,部分患者存在氯吡格雷抵抗现象。患者基因多态性可能影响氯吡格雷抗血小板聚集作用,ABCB1、CYP2C19和P2Y12受体等基因突变与氯吡格雷抵抗有一定的相关性。临床上进行相关基因型检测,并结合其他危险因素制定合理的给药方案,实行个体化治疗,可以提高缺血性卒中患者氯吡格雷林的疗效,降低缺血性卒中的发生率及复发率。     

应用血栓弹力图指导急性非心源性卒中患者选择敏感抗血小板聚集药物的临床研究

目的 应用血栓弹力图（thromboelastography,TEG）指导急性非心源性卒中患者选择敏感抗血小板聚 集药物,并评价临床治疗效果。 方法 连续选取首都医科大学附属北京朝阳医院西区神经内科2013年1月至2014年12月期间急性非心 源性卒中住院患者162例,分为个体化治疗组54例（阿司匹林100 mg联合氯吡格雷75 mg应用14 d,后 根据TEG结果选择阿司匹林或氯吡格雷单抗）,阿司匹林组（n =54）,氯吡格雷组（n =54）。三组患者 均于住院第7天抽静脉血,应用TEG仪检测花生四烯酸（arachidonic acid,AA）途径诱导的血小板抑制 率和二磷酸腺苷（adenosine diphosphate,ADP）受体途径诱导的血小板抑制率,并于入院时、第14天、3 个月行美国国立卫生研究院卒中量表（National Institutes of Health Stroke Scale,NIHSS）评分及日常生 活能力量表（Activity of Daily Living Scale,ADL）评分。比较三组之间基线资料及AA途径、ADP途径 诱导的血小板抑制率,并评估14 d及3个月NIHSS评分、ADL评分及再发缺血性卒中及脑出血发生事件。 结果 三组之间在年龄、性别、高血压、糖尿病、高血脂、吸烟、饮酒、既往卒中、冠状动脉粥样性 心脏病以及入院时NIHSS评分、ADL评分方面比较差异无显著性（P＞0.05）。个体化治疗组AA及ADP 途径诱导的血小板抑制率中位数分别为93.2%（77.45%,98.35%）、50.4%（27.62%,67.25%）,阿 司匹林组AA途径及氯吡格雷组ADP诱导的血小板抑制率中位数分别为73.05%（40.8%,92.75%）、 20.5%（5.1%,53.5%）,个体化治疗组AA或ADP途径诱导血小板抑制率较阿司匹林组及氯吡格雷组 相比差异有显著性（P＜0.05）。个体化治疗组、阿司匹林组、氯吡格雷组三组患者入院第14天NIHSS 评分中位数分别为3（2,4）、3.5（3,4）、4（3,4）,ADL评分中位数分别为80（70,90）、75（70,85）、 70（65,85）;第3个月NIHSS评分中位数分别为2（2,3）、3（2,3）、3（2,3）,ADL评分中位数分别为90 （85,95）、87.5（80,90）、85（80,90）,三组间两两比较个体化治疗组优于阿司匹林组及氯吡格雷组 （P＜0.05）,阿司匹林组与氯吡格雷组比较差异无显著性（P ＞0.05）。随访3个月三组均无脑出血发 生,个体化治疗组有1例再发缺血性事件,阿司匹林组有3例、氯吡格雷组有4例再发缺血性事件。 结论 急性非心源性卒中患者急性期给予双抗治疗后根据TEG结果选择敏感抗血小板聚集药物能 提高患者临床预后,不增加出血风险。     

血小板功能实验预测氯吡格雷用于缺血性卒中二级预防的有效性和安全性分析

目的 探讨透射光法血小板聚集实验（light transmittance aggregom etry,LTA）、血栓弹力图 （thromboelastography,TEG）和血小板功能分析仪（platelet function analyzer,PFA）三种血小板功能实验 对轻型缺血性卒中患者临床结局的预测价值。 方法 前瞻性连续收集2017年5月-2019年2月诊治为急性轻型缺血性卒中且长期服用氯吡格雷进 行卒中二级预防的患者。分别采用LTA、TEG和PFA三种方法检测患者服用氯吡格雷5 d后的血小板反 应性。2019年8月进行统一随访,主要终点事件为缺血性卒中复发,安全性结局为抗血小板药物相关 的出血事件。比较缺血性卒中复发与未复发组、出血组与未出血组间LTA、TEG、PFA分别测定的血小 板反应性差异及CYP2C19基因型分布的差异。采用受试者工作特征曲线分析血小板反应性对缺血性 卒中复发的预测价值。 结果 研究共纳入76例患者,中位随访时间为13个月,其中5例（6.58%）患者缺血性卒中复发,17 例（22.37%）患者发生出血事件。LTA[82.00%（76.00%～85.00%）vs 44.00%（27.00%～60.50%）, P =0.005]和TEG[43.30%（34.40%～61.60%）vs 69.00%（52.45%～86.10%）,P =0.032]检测的复发 组血小板反应性显著高于未复发组;LTA和TEG检测结果对缺血性卒中复发有较好的预测价值[曲 线下面积（area under the curve,AUC）分别为0.88（95%CI 0.73～1.00）和0.79（95%CI 0.61～0.97）]。 CYP2C19基因型和PFA检测结果均与缺血性卒中复发无关。三种血小板功能实验的结果与出血事件的 发生率无关。 结论 当氯吡格雷用于缺血性卒中二级预防时,LTA和TEG实验对一年缺血性卒中复发有一定预测 价值,但PFA预测能力欠佳。三种血小板功能实验结果与出血事件的发生无关。     

CYP2C19基因型与复发性脑梗死患者氯吡格雷抵抗的关系研究

目的通过CYP2C19基因检测及血小板聚集率综合评估氯吡格雷抵抗,指导复发性脑梗死患者合理用药。方法对2018年1-10月就诊于嘉兴市第二医院神经内科,诊断为复发性脑梗死的患者进行CYP2C19基因测序,分别收集氯吡格雷快代谢、中代谢、慢代谢基因型患者各30例,比较3组患者年龄、性别、BMI、吸烟、高血压、糖尿病及高脂血症等一般临床资料。3组均给予常规剂量氯吡格雷75 mg/d治疗,检测患者使用氯吡格雷前及使用7 d后的血小板聚集率。根据血小板聚集抑制率判断氯吡格雷抵抗情况,分析CYP2C19基因型与患者氯吡格雷抵抗的关系。筛选出氯吡格雷抵抗者(血小板聚集抑制率10%)分至氯吡格雷抵抗组,改用西洛他唑100 mg 2次/日,氯吡格雷半反应(10%≤血小板聚集抑制率30%)及氯吡格雷敏感(血小板聚集抑制率≥30%)者分至非氯吡格雷抵抗组,继续氯吡格雷75 mg/d治疗。3个月后再次检测血小板聚集率,比较不同药物的血小板聚集抑制情况,并观察终点事件发生情况(主要终点:再发脑梗死;次要终点:脑出血和死亡)。结果最终入组患者90例,其中男性49例(54.4%),年龄40～89岁,平均年龄68.27±10.14岁。快、中、慢代谢3组糖尿病(P=0.036)和氯吡格雷抵抗发生率(P0.001)差异均有统计学意义,其中慢代谢组合并糖尿病比率高于中代谢组(P=0.010),慢代谢组氯吡格雷抵抗发生率高于快代谢组(P0.001)及中代谢组(P=0.006)。氯吡格雷抵抗组患者22例(24.4%),非氯吡格雷抵抗组患者68例(75.6%)。Logistic回归分析提示,吸烟(OR 7.792,95%CI 1.899～31.968,P=0.004)、糖尿病(OR 4.466,95%CI 1.122～17.778,P=0.034)及CYP2C19基因慢代谢(OR 13.713,95%CI 2.352～79.959,P=0.004)是复发性脑梗死患者氯吡格雷抵抗的独立危险因素。非氯吡格雷抵抗组(49.51%±4.33%vs 63.73%±7.84%,P0.001)和氯吡格雷抵抗组(55.42%±6.63%vs 76.95%±7.42%,P0.001)患者3个月后的血小板平均聚集率较7 d时均下降,差异有统计学意义。3个月后较非氯吡格雷抵抗组,氯吡格雷抵抗组血小板聚集抑制率更高(21.53%±4.30%vs 14.23%±6.90%,P0.001)。入组患者随访3个月均无终点事件发生。结论吸烟、合并糖尿病及CYP2C19慢代谢基因型是复发性脑梗死患者氯吡格雷抵抗的独立危险因素。西洛他唑能有效抑制血小板聚集,可以作为氯吡格雷抵抗的复发性脑梗死患者的替代性用药。     

CYP2C19基因多态性对氯吡格雷药效的影响

氯吡格雷一种广泛应用的抗血小板聚集药物,在缺血性脑血管病二级预防中起着重要的作用。然而,在临床实践中不断发现,不同的患者对氯吡格雷的反应性差异比较大,某些患者对氯吡格雷的反应性较低或无反应,称之为氯吡格雷低反应或氯吡格雷抵抗,氯吡格雷的低反应或抵抗在缺血性脑血管病复发中起到重要的作用。参与氯吡格雷反应下降的因素有很多,包括基因的多态性(如细胞色素P450、ABCB1及P2Y12基因多态性)、药物的互相作用(质子泵抑制剂、他汀类等)、患者的依从性、Ⅱ型糖尿病、慢性肾病等,但目前机制尚未完全清楚。而CYP2C19作为细胞色素P450(CYP450)家族中一类重要的亚型,在多种药物代谢中体现出其重要性。氯吡格雷作为一种常见的抗血小板药物,其代谢也受CYP2C19基因多态性的影响,不同基因型患者对氯吡格雷的治疗反应性不同。文中就CYP2C19的几个主要基因多态性位点对氯吡格雷代谢的影响作综述。     

短暂性脑缺血发作与轻型卒中抗血小板治疗

目的：探讨短暂性脑缺血发作与轻型卒中抗血小板治疗效果。方法选取63例缺血性脑卒中患者为研究对象,并随机分成A、B、C 3组,每组21例,C组采用氯吡格雷治疗,B组采用阿司匹林治疗,A组采用氯吡格雷联合阿司匹林治疗,对比3组治疗前后血栓弹力图（TEG）检测二磷酸腺苷（ADP）及花生四烯酸（AA）途径诱导的血小板抑制率。结果治疗后3组患者ADP、AA途径诱导的血小板抑制率均明显高于治疗前（P＜0.05）,AA途径诱导下血小板抑制率中 A组和B组显著高于C组（P＜0.05）,ADP途径诱导的血小板抑制率中A组、C组显著高于B组（P＜0.05）。结论氯吡格雷联合阿司匹林从两个途径抑制血小板聚集的效果优于单用阿司匹林或氯吡格雷,且出血风险低,值得推广应用。     

颅外颈动脉支架置入术后抗血小板聚集治疗的对比研究

目的 通过对颅外颈动脉支架置入术后单用阿司匹林或氯吡格雷1年的随访,比较两种抗血小板聚集药物的效果,并比较不同Essen评分组间两种抗血小板聚集药物的疗效。方法 收集2014年1月～2015年1月于重庆医科大学附属第一医院及第三军医大学附属新桥医院接受颅外颈动脉支架置入术的缺血性脑卒中患者219例,术后予以双联抗血小板聚集(阿司匹林100 mg/d及氯吡格雷75 mg/d),应用1个月(69例)或3个月(150例),然后单用阿司匹林(124例)100 mg/d或氯吡格雷(95例)75 mg/d; 并对纳入患者进行Essen评分,分为低危组(41例)及高危组(178例); 随访1年时的主要终点(同侧脑梗死、非同侧脑梗死、心肌梗死、死亡)及次要终点(颅内或颅外出血)。结果 阿司匹林组与氯吡格雷组基线特征均无明显差异。随访1年阿司匹林组主要终点事件同侧脑梗死、非同侧脑梗死、心肌梗死、病死率(分别为2.4%、0.8%、0.8%、0)与氯吡格雷组(分别为1.1%、0、0、0)比较均无明显差异(P>0.05)。阿司匹林组次要终点事件颅内出血、颅外出血发生率(分别为1.6%、3.2%)与氯吡格雷组(分别为1.1%、1.1%)比较亦无明显差异(P>0.05)。Essen评分低危组中阿司匹林组主要终点事件同侧脑梗死、非同侧脑梗死、心肌梗死、病死率(分别为4.3%、0、0、0)与氯吡格雷组(分别为0、0、0、0)比较亦无明显差异(P>0.05); 高危组中阿司匹林组主要终点事件同侧脑梗死、非同侧脑梗死、心肌梗死、病死率(分别为2.0%、1.0%、1.0%、0)与氯吡格雷组(分别为1.3%、0、0、0)比较均无明显差异(P>0.05)。结论 颅外颈动脉支架置入术后双联抗血小板治疗聚集1或3个月再单用阿司匹林或氯吡格雷抗血小板聚集治疗1年内其主要终点事件及次要终点事件发生率无明显差异; 不同Essen评分组间两种抗血小板聚集药物的主要终点事件亦无明显差异。     

急性缺血性脑卒中患者CYP2C 19基因分型与临床预后的相关性分析

目的探讨急性缺血性脑卒中患者CYP2C 19基因分型与临床预后的相关性。方法选取本院收治的156例应用氯吡格雷治疗的急性缺血性脑卒中患者作为研究对象,对患者进行CYP2C19*2和CYP2C19*3基因型检测,根据检测结果分为野生型组(GG)和突变型组(GA/AA)。对比两组的血小板抑制率、氯吡格雷疗效及临床预后情况。结果野生型组患者的平均血小板抑制率为(42. 42±2. 74)%,突变型组为(32. 41±2. 69)%,突变型组的平均血小板抑制率显著低于野生型组(P <0. 05)。突变型组的氯吡格雷抵抗发生率为26. 32%,显著高于野生型组的1. 25%(P <0. 05)。突变型组的预后不良发生率显著高于野生型组,卒中复发率及心脑血管不良事件总发生率也显著高于野生型组(P <0. 05)。与野生型组相比,突变型组患者随访期间累积无再发心脑血管不良事件的生存率明显更低(P <0. 05)。结论急性缺血性脑卒中患者的CYP2C 19基因分型与血小板抑制率、临床预后密切相关,携带CYP2C19突变型基因型的患者,血小板抑制率更低,氯吡格雷敏感性越差,预后不良风险越高。     

不同抗血小板聚集治疗方案对高原缺血性卒中治疗对比研究

目的 研究应用不同的抗血小板聚集治疗方案对高原缺血性卒中临床治疗效果的影响。 方法 收集青海省人民医院神经内科自2014年3月-2015年3月收治的发病24 h内的急性缺血性卒中 患者90例,随机分为阿司匹林单药治疗组和氯吡格雷联合阿司匹林治疗组,两组患者均进行相应的 内科综合治疗,其中阿司匹林单药治疗组在前者基础上服用阿司匹林（100 mg/d）,氯吡格雷和阿司 匹林联合治疗组则在综合治疗的基础上采用氯吡格雷-阿司匹林联合治疗方案（阿司匹林100 mg/d, 氯吡格雷75 mg/d）,对比两组患者治疗后14 d和28 d美国国立卫生研究院卒中量表（National Institutes of Health Stroke Scale,NIHSS）评分变化情况、进展性卒中发生率以及出血转化率和死亡率情况。 结果 两组治疗后比同组治疗前NIHSS均有显著降低,联合治疗组治疗后14 d及28 d NIHSS评分为5（3, 7）和4（3,6）,显著低于单药治疗组同期NI HSS评分[7（5,9）和6（4,8）]（P分别为0.03和0.02）。联合 治疗组中进展性卒中发生率为11.1%（5例）,显著低于单药治疗组的35.5%（16例）（P =0.04）。两组 28 d内缺血性卒中后出血转化率及死亡率方面无显著差异。 结论 氯吡格雷联合阿司匹林治疗方案表现出对急性高原性缺血性卒中良好的治疗效果,且不增 加出血转化的风险。     

A comparison of three platelet function tests in ischemic stroke patients with antiplatelet therapy

Predicting the effectiveness of antiplatelet drugs is critical to precision antiplatelet therapy. However, there is a lack of an acceptable method, although there are a variety of methods for detecting platelet function. In this study, we compared three major platelet function tests to assess their performance and found better methods for platelet function evaluation after aspirin or clopidogrel treatment in ischemic stroke patients by comparative study. A total of 249 ischemic stroke patients were enrolled who were treated with aspirin or clopidogrel or both. Three platelet function tests including light transmittance aggregometry (LTA), thromboelastography (TEG), platelet function analyzer (PFA) were performed as well as CYP2C19 genotype determination. Correlation analyses and kappa statistics were used. All three methods were effective in evaluating aspirin function. However, only LTA and TEG had good correlation and consistency (r = -0.37, kappa = 0.634). TEG-ADP was the least sensitive for clopidogrel, as the platelet inhibition ratio did not differ between the clopidogrel-user group and the control (P = 0.074), while LTA and PFA were sensitive (P ＜ 0.001). Correlations between platelet assays were poor for clopidogrel (the absolute value of r range from 0.13 to 0.35) and so was the agreement (Kappa from 0.232 to 0.314). LTA and PFA have a good correlation with CYP2C19 genotyping (P = 0.034 and 0.014). In conclusion, all three tests were able to evaluate aspirin effect, LTA-AA and TEG-AA had a good correlation. TEG perform badly for clopidogrel effect detection. The fair-to-modest agreement among assays indicated further study was indispensable.     

用血栓弹力图评价阿司匹林及氯吡格雷在缺血性卒中患者中血小板抑制效应的研究

目的用血栓弹力图评价缺血性卒中患者正规使用阿司匹林及氯吡格雷后血小板抑制率的变化。方法血栓弹力图检测我院123例住院患者抗血小板药物治疗后花生四烯酸(AA)通路和ADP受体途径诱导的血小板抑制率,患者抗血小板药物治疗包括阿司匹林组(n=7)、氯吡格雷组(n=8)、阿司匹林+氯吡格联合组(n=108)。结果 123例患者中,阿司匹林组AA诱导的血小板抑率为(87.04±22.71)%,氯吡格雷组ADP诱导的血小板抑制率平均值为(46.61±24.43)%,阿司匹林+氯吡格雷组AA和ADP诱导的血小板抑制率为分别(77.87±27.98)%和(50.23±29.27)%。服用阿司匹林和氯吡格雷的患者分别有115和116例,其AA和ADP途径血小板抑制率分别为(78.42±27.69)%;(49.99±28.88)%,差异具有显著统计学意义(P=0.000)。其中对阿司匹林和氯吡格雷敏感者(血小板抑制率≥50%)分别为97例(84.34%)和89例(75.72%),而不敏感者(血小板抑制率<50%)分别为18例(15.65%)和27例(23.28%),两种药物疗效间差异无显著统计学意义(χ2=3.706,P=0.054)。结论服用100mg/d阿司匹林,在绝大多数缺血性脑血管病患者中能产生较强的血小板抑制效应,而服用75mg/d氯吡格雷对血小板抑制稍弱,但多数患者仍能达有效的血小板抑制作用。     

Clinical consequences of aspirin and clopidogrel resistance: an overview

The aim of this review is to introduce the concept of personalized medicine in secondary stroke prevention with antiplatelet medication. In the last years, many studies have been conducted regarding aspirin resistance and genotyping of clopidogrel metabolism. A review of the currently published data on this issue emphasizes the importance of focusing on the individualizing approach in antiplatelet therapy to achieve maximal therapeutic beneficial effect. However, many authors suggest that, before new information from ongoing trials become available, good clinical practice should dictate the use of low dose of aspirin that was shown to be effective in the prevention of stroke and death in patients with ischemic cerebrovascular disease, because higher doses do not have significantly better efficacy than lower doses in secondary stroke prevention, but lower‐dose aspirin is associated with less side effects. On the other hand, many factors are associated with clopidogrel resistance, and recent genetic studies showed that the CYP2C19*2 genotype (loss‐of‐function allele) is related to poor metabolism of clopidogrel, but larger studies are needed to definitively confirm or rule out the clinical significance of this genetic effect. The aim of personalized approach in secondary stroke prevention is to take the most appropriate medicine in the right dose in accordance with the clinical condition of the patient and associated risk factors.     

强化抗血小板治疗在缺血性脑卒中复发高危患者二级预防中的临床研究

目的观察强化抗血小板药物氯吡格雷在缺血性脑卒中复发高危患者二级预防中的长期疗效及安全性。方法采用艾森卒中风险评分（ESRS）量表筛选住院的急性非心源性缺血性脑卒中复发高危患者100例,随机分为氯吡格雷组和阿司匹林组,每组50例。两组均给予脑卒中常规治疗,氯吡格雷组予氯吡格雷75mg及阿司匹林100mg口服,1周后仅予氯吡格雷75mg,口服。阿司匹林组予阿司匹林200mg,口服,1周后改为100mg,口服。随访3个月和1年,观察两组缺血性脑卒中复发率及药物不良反应发生率。结果随访3个月时,脑卒中复发率：阿司匹林组为6．3％,氯吡格雷组为2．0％,差异无统计学意义（P〉0．05）;药物不良反应发生率：阿司匹林组为14％,氯吡格雷组为2％,差异有统计学意义（P〈0．05）。随访1年时,脑卒中复发率：阿司匹林组为13％,氯吡格雷组为2％,差异有统计学意义（P〈0．05）;药物不良反应发生率：阿司匹林组为38％,氯吡格雷组为6％,差异有统计学意义（P〈0．01）。结论缺血性脑卒中复发高危患者二级预防中强化抗血小板治疗可降低脑卒中复发风险,长期应用获益较高,安全性好。     

Pharmacogenomics of clopidogrel: evidence and perspectives

Clopidogrel has become the mainstay oral antiplatelet regimen to prevent recurrent ischemic events after acute coronary syndromes or stent placement. However, there is marked interindividual variability in the antiplatelet effects of clopidogrel, and a reduced response to this drug may be a risk factor for ischemic complications. Pharmacogenomic analyses, including candidate-gene and genome-wide association studies, have confirmed that genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 dominantly affect the antiplatelet effects of clopidogrel. CYP2C19 reduced-function alleles have been associated with a significant decrease in clopidogrel responsiveness and a higher risk of adverse cardiac events including stent thrombosis, myocardial infarction, and death in several prospective studies, although these effects were not reproduced in a recent large randomized study that included a randomized control group. The US Food and Drug Administration addressed this issue by adding a boxed warning to the clopidogrel label and suggesting that adjusting the clopidogrel dose or using alternative antiplatelet agents should be potentially implemented for high-risk individuals who are identified based on the CYP2C19 genotype. Although it is promising that CYP2C19 genotyping could be used to guide personalized antiplatelet clopidogrel therapy, currently there is insufficient evidence to recommend routine genetic testing. Prospective randomized clinical trials are necessary to validate this pharmacogenomic approach to clopidogrel therapy. In the most recent trial, paraoxonase-1 (PON1) was identified as a crucial new enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite and the clinical activity of clopidogrel. Further studies are needed to investigate the comprehensive influence of a number of different polymorphisms of CYP2C19 and PON1 variant alleles or other genetic variants on clopidogrel in various ethnic populations.     

Clopidogrel response in ischemic stroke patients: Is polymorphism or gender more important? Results of the CRISP study

Clopidogrel (CLP) is a second generation thienopyridine drug commonly used in secondary prevention of ischemic stroke (IS). Its antiplatelet response maybe variable due to genetic and non-genetic factors. Adipokines may affect platelet aggregation through ADP mediated platelet signalling. However, the combined effect of CYP genetic variants and adipokines on antiplatelet response of clopidogrel is unclear. Patients of IS/Transient ischemic attack (TIAs) within 3 months were prospectively screened following clopidogrel treatment. Major exclusions were cardioembolic and non atherosclerotic strokes. Antiplatelet effect of clopidogrel along with adipokine (Leptin and adiponectin) levels and genotyping of CYP, P2Y12 gene were investigated. Rare genetic variants were confirmed by DNA sequencing. 204 patients with ischemic stroke/TIAs were screened and 163 were recruited. 85 (52.1%) patients were poor responders to clopidogrel. Antiplatelet response to clopidogrel was weaker in females [Median 8.0 (IQR: 3.0–14.0)] compared to males [Median 5.0 (IQR: 2.0–10.0)]. In female subgroup analysis, association was found among high leptin levels and PPI (+) usage in poor responders. None of the genetic variants (CYP2C19*2,*3,*4*, CYP2C9*3, CYP2B6 and P2Y12) were found to influence the antiplatelet effects (p > 0.05). On multivariable logistic regression, a poor clopidogrel response was associated with female gender (Adjusted OR 2.55, 95% CI: 1.05–6.18) and PPI usage (Adjusted OR 2.42, 95% CI: 1.09–5.34). Despite a high prevalence of clopidogrel resistance in the North Indian stroke patients, female gender rather than genetic polymorphisms of CYP and P2Y12 genes may influence its antiplatelet effect. Further research may ascertain the role of gender on clopidogrel response.     

Relationship between CYP2C19*2, *3 gene polymorphism and the recurrence in ischemic stroke patients treated with clopidogrel in China: A meta-analysis

BackgroundThe relationship between CYP2C19 *2,*3 gene variants and the recurrence in ischemic stroke patients treated with clopidogrel is still controversial according to the available published literature. To evaluate correlations between CYP2C19 *2,*3 gene variants, metabolic typing according to *2, *3 SNPs (the polymorphism of rs4244285, rs4986893) and stroke recurrence, we performed this study through meta-analysis.MethodsLiteratures reporting the relationship between CYP2C19*2 and *3 polymorphism and the recurrence in ischemic stroke patients treated with clopidogrel were searched in CNKI, Wanfang Database, VIP, China Biomedical Database, PubMed and Cochrane Library from the establishment database to December 2020. Meta-analysis was performed with RevMan 5.3.ResultsA total of 9 articles with 10 trials involving 1333 ischemic stroke patients were included. The results of meta-analysis showed CYP2C19*2 GA/AA genotype had a higher risk of recurrent stroke than GG in patients with ischemic stroke treated with clopidogrel(P<0.05) (GA+AA vs. GG:OR=2.50, 95% CI:1.66～3.75;GA vs. GG:OR=2.16, 95% CI:1.41～3.31;AA vs. GG:OR=4.40, 95% CI:2.39～8.08; AA vs. GA:OR=2.15, 95% CI:1.20-3.84; allele A vs. G:OR=2.08, 95% CI:1.58-2.75). There was no significant difference in stroke recurrence risk between CYP2C19*3 GA vs. GG genotype (P=0.65)(OR=0.86,95% CI:0.44～1.67). Compared with extensive metabolizer (EM), patients with intermediate metabolizer (IM) and poor metaholizer (PM) of CYP2C19 had a higher risk of stroke recurrent after clopidogrel treatment (IM+PM vs. EM:OR=2.20, 95%CI:1.58～3.08, P<0.05; IM vs. EM:OR=2.06,95% CI: 1.45～2.91, P<0.05;PM vs. EM: OR=3.32,95% CI:1.98～5.56, P<0.05; PM vs. IM: OR=1.45,95% CI: 0.91～2.32,P=0.11).ConclusionAmong ischemic stroke patients taking clopidogrel, CYP2C19*2 gene mutation and CYP2C19 metabolizer were associated with stroke recurrence, CYP2C19*2 and *3 gene carriers were more likely to stroke recurrent than CYP2C19*1 gene carriers.     

The antiplatelet effect of clopidogrel is not attenuated by statin treatment in stable patients with ischemic heart disease

Recent studies suggest that cytochrome P450 (CYP) 3A4 metabolized statins attenuate the antiaggregatory effect of clopidogrel. We evaluated how CYP3A4 metabolized statins and non-CYP3A4 metabolized statins influence platelet aggregation when given concomitantly with clopidogrel. Sixty-six stable patients with ischemic heart disease were included in this parallel group study. All patients were on clopidogrel and aspirin. Thirty-three patients received a CYP3A4 metabolized statin (simvastatin or atorvastatin), and 33 were treated with a non-CYP3A4 metabolized statin (pravastatin). The antiplatelet effect of clopidogrel was assessed at inclusion and 21 days after statin discontinuation. Platelet function was evaluated by two methods 1) optical platelet aggregometry after stimulation with 20 and 30 microM ADP, and 2 and 4 mg/l collagen, respectively, 2) a Platelet FunctionAnalyzer-100. The primary effect measure was final platelet aggregation after stimulation with 20 microM ADP. No difference was observed between patients treated with a CYP3A4 metabolized statin and patients receiving a non-CYP3A4 metabolized statin (30% point (7-42) versus 20% point (9-32), p = 0.83). Platelet aggregation was not improved by discontinuation of statins for 21 days. Indeed, we found that statin treatment given concomitantly with clopidogrel resulted in an improved platelet inhibition when compared to clopidogrel given alone. The antiplatelet effect of clopidogrel is not attenuated by concomitant treatment with a CYP3A4 metabolized statin in patients with clinical stable ischemic heart disease.     

氯吡格雷联合阿司匹林治疗对轻型卒中与短暂性脑缺血发作患者功能预后的影响：CHANCE与POINT试验联合分析

目的 评价氯吡格雷联合阿司匹林双抗治疗对轻型缺血性卒中与TIA患者功能预后的影响。 方法 提取CHANCE和POINT试验所有的个体数据。这两项试验中,所有纳入患者在症状发作12 h （POINT）或24 h（CHANCE）以内随机接受氯吡格雷联用阿司匹林或单用阿司匹林治疗。结局指标为3个 月时功能预后不良（mRS≥2）,三等级定义卒中复发[致残性或致死性卒中复发（mRS≥2）、非致残性 卒中复发（mRS 0或1）、无卒中复发]。 结果 共10 013例患者纳入分析,其中来自CHANCE试验5132例（51.3%）,来自POINT试验4881例 （48.7%）;氯吡格雷联用阿司匹林组4995例（49.9%）,单用阿司匹林组5018例（50.1%）。氯吡格雷联 用阿司匹林组3个月时功能预后不良的患者比例低于单用阿司匹林组（11.6% vs 12.6%,校正OR 0.82, 95%CI 0.72～0.94,P =0.005）。氯吡格雷联用阿司匹林组致残性或致死性卒中复发（4.6% vs 6.1%, 校正OR 0.73,95%CI 0.61～0.87,P <0.001）、非致残性卒中复发（1.9% vs 3.0%,校正OR 0.62,95%CI 0.47～0.80,P <0.001）和卒中复发的整体致残性（校正cOR 0.70,95%CI 0.60～0.81,P <0.001）低于单 用阿司匹林组。 结论 与单用阿司匹林治疗相比,氯吡格雷联用阿司匹林治疗可进一步改善轻型缺血性卒中和TIA 患者3个月时功能预后,减少致残性卒中复发。