CYP2C19中间代谢型个体化抗血小板治疗

目的通过血栓弹力图(TEG)监测ADP诱导的血小板抑制率,观察冠心病患者CYP2C19基因检测中间代谢型(*1/*2和*1/*3)服用氯吡格雷与替格瑞洛的疗效比较。方法自2014年10月开始选取入解放军总医院心血管内科住院治疗行经皮冠状动脉介入(PCI)术,且CYP2C19基因检测为中间代谢型(*1/*2和*1/*3)的冠心病患者48例,其中男34例,女14例,分为氯吡格雷组(25例)及替格瑞洛组(23例),术后在口服阿司匹林0.1 g,1次/d的基础上分别服用氯吡格雷(75 mg,1次/d),及替格瑞洛(90 mg,2次/d),分别于服药后1、4、12周观察ADP诱导的血小板抑制率的变化,并比较两组主要不良心血管事件的发生情况。结果 3个时间点1、4、12周与氯吡格雷组比较,替格瑞洛组治疗后,ADP诱导的血小板抑制率升高,差异均具有统计学意义(P0.05)。结论冠心病患者CYP2C19基因检测中间代谢型(*1/*2和*1/*3)服用替格瑞洛替代氯吡格雷明显升高ADP诱导的血小板抑制率,减少主要不良心血管事件。     

衢州地区冠心病患者CYP2C19基因多态性分析

目的 探讨衢州地区冠心病患者CYP2C19基因多态性的分布情况。方法 采用PCR荧光探针法对浙江省衢州市人民医院306例冠心病患者进行CYP2C19基因检测。结果 在306例冠心病患者中,CYP2C19基因型的分布频率由高到低为*1/*2、*1/*1、*2/*2、*1/*3、*2/*3、*3/*3,所占比例分别为39.87%、38.56%、10.13%、8.17%、3.27%、0.00%。快代谢型(*1/*1)占38.56%,中间代谢型(*1/*2、*1/*3)占48.04%,慢代谢型(*2/*2、*2/*3、*3/*3)占13.40%,不同性别、不同年龄患者CYP2C19基因型和代谢型差异均无统计学意义(P> 0.05)。结论 衢州地区冠心病患者CYP2C19功能缺失型等位基因所占比例较高,患者用药前应进行CYP2C19基因检测,制定个体化治疗方案,实现精准治疗。     

CYP2C19基因多态性与血栓弹力图检测氯吡格雷药效相关性研究

目的 通过血栓弹力图(TEG)检测脑卒中患者血小板ADP抑制率并结合患者CYP2C19基因型检测结果,了解CYP2C19基因多态性对氯吡格雷药效的影响.方法 选取912例诊断为脑卒中的患者,利用ARMS-PCR法测定CYP2C19基因型,并将6个基因型分为3组:Ⅰ组为正常基因纯合子组(*1/*1),Ⅱ组为正常基因与突变...     

江西省赣南地区缺血性脑卒中患者氯吡格雷的药物基因组学研究

目的 了解江西省赣南地区缺血性脑卒中患者服用氯吡格雷的药物基因多态性的分布情况及其与治疗急性缺血性脑卒中疗效的相关性。方法 严格按照病例纳入和排除标准,连续募集2021年1月1日-2021年6月30日期间,在我院住院诊断为缺血性脑卒中的患者,均给予常规剂量氯吡格雷(75mg)治疗,并于入院当天检测血小板聚集率行CYP2C19等位基因型(CYP2C192和CYP2C193)检测,并记录在院临床资料。受试者均随访半年内主要心脑血管缺血和出血事件的发生率。结果 364例缺血性脑卒中患者中,CYP2C192携带者共176例(48.35%),其中CYP2C192/1携带者132例(36.26%);CYP2C193携带者共39例(10.71%)。CYP2C192携带者与氯吡格雷常规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CYP2C193携带者中无上述相关性(P=0.654)。结论 CYP2C19等位基因与急性缺血性脑卒中患者的氯吡格雷抗血小板反应性及预后密切相关,有利于指导缺血性脑卒中患者的抗血小板药物应用。     

广东河源地区脑梗死患者氯吡格雷CYP2C19相关基因多态性分析

目的分析广东河源地区脑梗死患者CYP2C19基因多态性特点,以利于指导用药和疾病防治。方法对316例脑梗死患者进行检测,并比较与梅州地区和汕头地区差异。结果在316份检测标本中,快代谢型(CYP2C19*1/*1)占40.82%,中代谢型(CYP2C19*1/*2、CYP2C19*1/*3)占43.04%,慢代谢型(CYP2C19*2/*2、CYP2C19*2/*3、CYP2C19*3/*3)占16.14%。与同为客家族群的广东梅州地区差异无统计学意义(P>0.05),与广东汕头地区差异有统计学意义(P<0.05)。结论河源地区脑梗死患者CYP2C19基因主要为中代谢型及快代谢型。     

广州地区心血管病患者CYP2C19~* 1、CYP2C19~* 17基因多态性对氯吡格雷疗效的影响

目的探讨广州地区汉族心血管病患者CYP2C19~* 1、CYP2C19~* 17基因多态性的频率分布及其对氯吡格雷疗效的影响。方法选取中山大学孙逸仙纪念医院2015年4月16日-2016年5月12日648例汉族心血管病住院患者,采用双探针实时荧光PCR法测定CYP2C19~* 1、CYP2C19~* 17基因型。选出符合纳入标准的167例,比较CYP2C19~* 1、CYP2C19~* 17基因型患者的血小板聚集率。结果广州地区汉族心血管病患者中CYP2C19~* 1~* 1基因频率为98.30%(637/648),CYP2C19~* 1~* 17基因频率为1.70%(11/648),无纯合突变。CYP2C19~* 1~* 17基因型患者服用氯吡格雷后血小板聚集率低于CYP2C19~* 1~* 1基因型组,差异有统计学意义(P0.05)。结论广州汉族人群中,携带CYP2C19~* 17基因型的心血管病患者可增加出血的风险,基因检测有助于完善个体化合理用药。     

广东佛山地区人群CYP2C19基因多态性及氯吡格雷药效反应的影响因素分析

目的探讨佛山地区人群依赖细胞色素P450的加单氧酶系(CYP2C19)基因多态性及对该地区冠心病患者氯吡格雷药效反应的影响因素分析。方法选取2016年8月至2018年2月在我院住院的冠心病患者375例,均连续服用氯吡格雷75 mg/d 5天以上者,进行CYP2C19基因型及血小板聚集功能检测,根据血小板聚集功能检测来判断氯吡格雷药效反应性,>50%为氯吡格雷抵抗。统计CYP2C19基因型及等位基因的分布规律,比较氯吡格雷抵抗及氯吡格雷反应组的基因分布和基本资料,并行Logistic多因素分析。结果 375名冠心病患者中突变纯合型占12.27%,突变杂合型占45.60%,野生型占42.13%;氯吡格雷抵抗组和氯吡格雷反应组在基因表型和等位基因频率分布上有明显差异(P<0. 05),突变纯合型在氯吡格雷抵抗组显著高于氯吡格雷抵反应组;氯吡格雷抵抗组与氯吡格雷反应组的年龄、性别、糖尿病、高血压、高胆固醇血症、血小板计数、纤维蛋白原水平比较,差异无统计学意义(P>0.05),氯吡格雷抵抗组CYP2C19突变纯合和突变杂合型所占比例高于氯吡格雷反应组,差异有统计学意义(P<0.05);经Logistic分析,CYP2C19突变纯合型(OR=2.557)和突变杂合型(OR=2.027)为氯吡格雷抵抗的危险因素。结论佛山地区人群CYP2C19基因型与广东其它地区人群分布相似,突变纯合型和突变杂合型为佛山地区人群发生氯吡格雷抵抗的危险因素,应采取有效措施进行干预。     

湖州地区人群CYP2C19基因多态性研究

目的 探讨湖州地区人群中细胞色素 P4502C19 ( CYP2C19) 基因多态性分布,为临床合理用药提供指导。方法 采用荧光 PCR 技术检测湖州地区拟进行氯吡格雷用药患者的 CYP2C19 基因多态性,探讨其基因型和代谢型在人群中的分布,并分析与不同地区的差异。结果 在 688 例患者中等位基因分布频率分别为 CYP2C19* 1 为 61. 48% ,CYP2C19* 2 为 32. 19% ,CYP2C19* 3 为 5. 60% ,CYP2C19* 17 为 0. 73% 。患者代谢型主要为中间代谢型( 46. 80% ) ,其次为快代谢型( 37. 79% ) 、慢代谢型( 14. 39% ) 、超快代谢型( 1. 02% ) 。不同性别患者间基因多态性差异无统计学意义( P > 0. 05) ; 湖州地区与国内大多地区汉族人群基因型和代谢型分布差异无统计学意义( P > 0. 05) ,而与省内杭州地区基因型分布和代谢型分布差异均有统计学意义( P < 0. 05) 。结论 湖州地区人群 CYP2C19 基因型以杂合型为主,代谢型以中间代谢型为主,但慢...     

伏立康唑治疗侵袭性真菌感染致肝损伤影响因素及CYP2C19基因多态性

目的探究伏立康唑治疗侵袭性真菌感染致肝损伤影响因素及CYP2C19基因多态性。方法选取2017年1月-2019年12月海南医学院第一附属医院采用伏立康唑治疗的IFI患者135例为样本进行前瞻性研究,均在治疗原发疾病基础上采用伏立康唑静脉注射进行抗真菌感染治疗,监测血药浓度并观察治疗效果和药物不良反应,同时检测CYP2C19基因多态性,比较各组伏立康唑药物谷浓度(Cmin)、治疗效果和不良反应,分析影响患者肝损伤的因素。结果 135例IFI患者CYP2C19*1/*1、CYP2C19*1/*2、CYP2C19*1/*3、CYP2C19*2/*2、CYP2C19*2/*3和CYP2C19*3/*3基因型占比分别为45.19%、21.48%、12.59%、5.93%、9.63%和5.19%;根据CYP2C19基因多态性将患者分为快代谢型(EM)61例、中等代谢型(IM)46例和慢代谢型(PM)28例共三组;不同代谢类型IFI患者伏立康唑Cmin比较差异有统计学意义(P0.05),治疗效果比较,无统计学差异,PM组不良反应发生率高于EM和IM组,且肝损伤发生率比较差异有统计学意义(P0.05);年龄、用药前合并肝损伤和PM代谢类型为伏立康唑治疗IFI导致肝损害的独立危险因素(P0.05)。结论我国IFI患者CYP2C19*2和CYP2C19*3突变较为常见,对伏立康唑代谢速度造成明显影响,同时可能导致肝损伤发生风险增加,因此对PM代谢型患者用药过程中应加强肝功能监测。     

湖北地区心血管疾病患者CYP2C19基因多态性分布情况及临床意义

目的了解湖北地区心血管疾病患者细胞色素P4502C19(CYP2C19)基因多态性分布情况及其对临床的指导意义,为个体化治疗提供依据。方法选取2015年1月—2016年3月在武汉大学人民医院住院的心血管疾病患者900例,采用基因芯片法检测患者CYP2C19基因型,同时收集其临床资料,包括年龄、性别、体重及诊断等相关指标进行分析。结果 900例患者,其中男性594例(66%),女性306例(34%);共检出6种CYP2C19基因型,其中*1/*2(636 GG,681 GA)基因型患者最多,占42.3%;其余依次为*1/*1(636 GG,681 GG)基因型患者(36.6%)、*2/*2(636 GG,681 AA)基因型患者(13.0%)、*1/*3(636 GA,681 GG)基因型患者(5.1%)、*2/*3(636 GA,681 GA)基因型患者(2.8%)和*3/*3(636 AA,681 GG)基因型患者(0.2%)。表型中IM型最高,占47.4%;其次为EM型和PM型,分别占36.6%和16.0%。等位基因CYP2C19*1的频率最高,占60.3%,等位基因CYP2C19*2和CYP2C19*3的频率分别为35.6%和4.2%。结论湖北地区心血管疾病患者CYP2C19基因型以*1/*2(636 GG,681 GA)基因型为主,表型IM型最多,等位基因以CYP2C19*1最常见。     

Interaction between clopidogrel and proton pump inhibitors

The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel.     

Routine Screening for CYP2C19 Polymorphisms for Patients being Treated with Clopidogrel is not Recommended

Recent efforts directed at potential litigation in Hawai‘i have resulted in a renewed interest for genetic screening for cytochrome P450 2C19 (CYP2C19) polymorphisms in patients treated with clopidogrel. Clopidogrel is an antiplatelet agent, frequently used in combination with aspirin, for the prevention of thrombotic complications with acute coronary syndrome and in patients undergoing percutaneous coronary interventions.Cytochrome P-450 (CYP) 2C19 is an enzyme involved in the bioactivation of clopidogrel from a pro-drug to an active inhibitor of platelet action. Patients of Asian and Pacific Island background have been reported to have an increase in CYP2C19 polymorphisms associated with loss-of-function of this enzyme when compared to other ethnicities. This has created an interest in genetic testing for CYP2C19 polymorphisms in Hawai‘i.Based upon our review of the current literature, we do not feel that there is support for the routine screening for CYP2C19 polymorphisms in patients being treated with clopidogrel; furthermore, the results of genetic testing may not be helpful in guiding therapeutic decisions. We recommend that decisions on the type of antiplatelet treatment be made based upon clinical evidence of potential differential outcomes associated with the use of these agents rather than on the basis of genetic testing.     

Vascular endothelial growth factor gene expression in patients' ischemic skeletal muscle with diabetic foot

OBJECTIVE: To investigate the relationship between the endogenous vascular endothelial growth factor (VEGF) gene expression in diabetics' calf ischemic skeletal muscle and the pathogeny of diabetic foot. METHODS: Twenty-four patients (33 limbs) were divided into 3 groups: diabetes mellitus (DM) without lower extremity ischemia (n = 5) (10 limbs); arteriosclerosis obliterans (ASO) without diabetes mellitus (n = 10) (13 limbs); diabetic lower limb arteriosclerosis obliterans (DLASO) (n = 9) (10 limbs). Control group consisted of normal volunteers (NOR) (n = 5) (10 limbs). The calf skeletal muscle tissue was obtained through muscle biopsy. RT-PCR was applied to determine the expression of hVEGF165mRNA. RESULTS: There was no expression in the calf skeletal muscle tissue of normal volunteers and DM. The calf skeletal muscle tissue in DLASO had the expression of hVEGF165mRNA (0.021 +/- 0.013) micro g, but obviously lower than ASO (0.133 +/- 0.024) micro g, (t = 13.32, P < 0.01). CONCLUSIONS: The endogenous VEGF gene expression in ischemic lower extremity of DLASO is obviously lower than that of ASO. It is the important endogenic cause of the genesis and development of diabetic foot ulcer.     

Clopidogrel and proton pump inhibitors: insufficient evidence of interaction

As both proton pump inhibitors (PPIs) and clopidogrel are metabolized by CYP2C19, an enzyme of the cytochrome P450 system, this could lead to drug competition. Recent studies have raised concerns that interaction of PPIs and clopidogrel could reduce the efficacy of clopidogrel and thus increase events such as myocardial infarction. This has resulted in opposing opinions and controversial recommendations. Optimal protection of patients at high risk for cardiovascular events is warranted. On the other hand, optimal gastroprotection for patients at risk for gastrointestinal bleeding is of clinical relevance. Despite the large number of studies, current evidence does not support the existence of an interaction between PPIs and clopidogrel. In agreement with international guidelines the approach of providing this combination therapy to those patients with an accepted indication for gastroprotection and secondary cardiovascular prevention is justified.     

细胞色素P450同工酶2C9和3A4基因多态性及其功能意义

细胞色素P450同工酶2C9(CVP2C9)和P450同工酶3A4(CYP3A4)是人类肝脏中重要的药物代谢酶,催化超过60％的临床常用药物。CYP2C9和CYP3A4基因具有高度多态性,到目前为止发现并命名的有CYP2C9*1 ～ *30和CYP3A4*1～*19。此文从基因结构、突变等位基因、与药物代谢的关系、与H...     

河北省汉族人群CYP450 2C9和VKORC1基因多态性与华法林剂量相关性研究

目的 了解河北省汉族人群CYP450 2C9和VKORC1的基因多态性分布与其他不同民族之间的差异,探讨CYP450 2C9~*3+1075C/A和VKORC1-1639A/G基因多态性与华法林剂量的关系.方法 随机选取门诊体检的健康人487名,检测CYP450 2C9~*3+1075C/A和VKORC1-1639A/G基因型及其分布频率,并与国外多个民族的CYP450 2C9~*3+1075C/A和VKORC1-1639A/G的基因多态性进行比较.选取服用华法林稳定剂量的患者101例,检测其基闪型并结合其个体差异和华法林的稳定剂量进行分析.结果 487名正常人CYP450 2C9*3+1075C/A基因型中,AA型为449名(92.2%),AC型36名(7.4%),CC型2名(0.4%);VKORC1-1639A/G基因型中AA型为415名(85.2%),GA型72名(14.8%),未发现GG型(0.0%).采用多元逐步回归得出有关华法林稳定剂量的方程:In(D)=0.346+0.017(体重)-0.376(CYP450 2C9~*3+1075C/A)+0.148(VKORC1-1639A/G)-0.002(年龄)(r=0.827,P=0.02).结论 汉族人群CYP450 2C9和VKORC1存在明显的基因多态性.CYP450 2C9~*3+1075C/A和VKORC1-1639A/G的基因型和患者个体之间的体重、年龄差异是影响华法林稳定剂量的因素.     

Prevalence of Five Pharmacologically Most Important CYP2C9 and CYP2C19 Allelic Variants in the Population from the Republic of Srpska in Bosnia and Herzegovina

The enzymes of the cytochrome P450 superfamily play a critical role in phase I drug metabolism. Among them, CYP2C9 and CYP2C19 are clinically important, as they can mediate severe toxicity, therapy failure, and increased susceptibility to cancer and other diseases caused by chemicals. The aim of this study was to determine the prevalence of pharmacologically most important allelic variants of the CYP2C9 and CYP2C19 genes in the general population of the Republic of Srpska (Bosnia and Herzegovina) and to compare them with other populations. For this purpose we determined the genotype profile and allele frequency of 216 randomly selected healthy volunteers using real-time polymerase chain reaction (RT-PCR). The prevalence of the CYP2C9 *2 and *3 alleles was 13.6 and 7.4 %, respectively. Based on these frequencies, of the 216 participants four (1.86 %) were predicted to be poor metabolisers, 78 (36.11 %) intermediate, and the remaining 134 (62.03 %) normal metabolisers. Based on the prevalence of CYP2C19 *2 and *17 variants – 16.2 and 20.4 %, respectively – nine (4.17 %) were predicted to be poor, 57 (26.39 %) rapid, and nine (4.17 %) ultra-rapid metabolisers. We found no significant differences in allele frequencies in our population and populations from other European countries. These findings suggest that genetically determined phenotypes of CYP2C9 and CYP2C19 should be taken into consideration to minimise individual risk and improve benefits of drug therapy in the Republic of Srpska.Key words: cytochrome P450 enzymes, pharmacogenetics, polymorphic allele     

Significance of cytochrome P450 2C9 genotype for the bleeding complications in patients treated with acenocoumarol

INTRODUCTION: For the primary and secondary prevention of thromboembolic events are used the oral anticoagulants, the drugs having a low therapeutic index and frequent bleeding complication rate. Establishing the proper therapeutic dose of these drugs for different patients is complicated by a variety of conditions, such as the comorbidity, age, other drugs used, diet, and pharmacogenetic factors. One of the latters is the polymorphism of the cytochrome P450 CYP2C9 enzyme. AIM: The influence of CYP2C9 polymorphism on the effectiveness of the--in Hungary for oral anticoagulation exclusively used--acenocoumarol therapy and on the occurrence of bleeding complications was investigated. METHODS: Genotyping of 421 patients including 183 men and 238 women, (mean age 66.2 +/- 11.8 years) who took acenocoumarol (Syncumar) for at least 6 months was performed. Based on anamnestic and laboratory data, the correlation between the genotype and the acenocoumarol dose and bleeding complications were retrospectively analysed. RESULTS: The frequency-distribution for the CYP2C9*1, *2, and *3 alleles were found to be: 0.814, 0.110, and 0.076, respectively. In the 145 patients bearing the alleles with reduced activity (CYP2C9*2 and/or *3), the optimised dose of the acenocoumarol was significantly (p < 0.001) lower than in patients with the wild type allele (2.12 +/- 0.96 mg/day and 2.90 +/- 1.45 mg/day, respectively). Although the occurrence of minor bleeding complications in the former group was significantly (p < 0.005) higher [OR = 1.99 (CI: 1.20-3.33)], there was no difference in major bleeding complications. In patients taking an acenocoumarol dose lower than 2 mg/day, the occurrence of an INR value higher than 6 in the anamnesis was significantly (p < 0.05) more frequent. Evaluating separately the variant alleles we have concluded, that in the presence of allele *2 a lower acenocoumarol dose was required than in wild-type subjects, and even lower in the presence of allele *3. CONCLUSIONS: The frequency-distribution of the CYP2C9 alleles was as reported by others. In patients bearing alleles with reduced enzymatic activity, the occurrence of minor bleeding complications and the INR values higher than 6 were significantly more frequent. In patients with a lower acenocoumarol demand at the introduction of this therapy, a caution is required. In order to test the hypothesis that before the initiation of acenocoumarol therapy the determination of CYP2C9 polymorphism is cost-effective and could improve the optimization of anticoagulation and reduce the risk of bleeding complications a large prospective randomised trial is required.     

子宫内膜异位症患者AHSG基因突变及芳香酶P450表达的相关性研究

目的:探讨子宫内膜异位症患者α2-HS-糖蛋白(AHSG)基因突变及芳香酶P450在子宫内膜异位症患者内膜的表达。方法:以50例Ⅳ期子宫内膜异位症患者(评分>40)及62例非子宫内膜异位症对照者的外周血白细胞为样本,利用聚合酶链反应(polymerase chain reaction,PCR)技术分析了α2-HS-糖蛋白(AHSG)基因突变。取对照组在位子宫内膜及Ⅳ期子宫内膜异位症患者在位及异位子宫内膜为标本,采用免疫组织化学方法测定各组内膜组织腺细胞中芳香酶P450的表达,根据阳性率和表达强度进行量化评分(组织化学评分)。结果:Ⅳ期子宫内膜异位症组中AHSG基因的三种基因型野生型(wide-type,W)、杂合型(wide-mutation,WM)、突变型(mutate-type,M)各占44%;46%、10%,而对照组则分别为71%、25.8%、3.2%。将突变型与杂合型合并与野生型比较,两组间差异有显著性(χ2=8.317,P=0.004),其OR为3.111(95%CI为1.422~6.805),携带变异基因的患病风险率高。AHSG*1、AHSG*2等位基因频率总体分布差异有显著性(χ2=8.723,P=0.003),携带AHSG*2等位基因患病危险度高,OR为2.561(95%CI为1.358~4.831)。Ⅳ期子宫内膜异位症组在位子宫内膜腺胞芳香酶P450的表达为(2.1±1.2)分,显著高于对照组为(0.9±1.1)分,两组比较,差异有统计学意义(P<0.01)。Ⅳ期子宫内膜异位症组异位内膜腺胞芳香酶P450的表达为(1.5±1.0)分,显著低于在位子宫内膜组,两组比较,差异有统计学意义(P<0.05)。结论:AHSG*2基因可使患Ⅳ期卵巢子宫内膜异位囊肿的遗传易感性升高。子宫内膜异位症患者在位、异位内膜腺细胞芳香酶P450表达增加,可促进异位病灶的生长,表达不同反映了不同类型的子宫内膜异位症组织雌激素调节水平不同。     

Clinical impact of enhanced inhibition of P2Y12-mediated platelet aggregation in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention

The combination of aspirin and clopidogrel at a loading dose of 300 mg followed by a maintenance dose of 75 mg daily is a well-established antiplatelet therapy for the secondary prevention of thrombotic complications in the settings of acute coronary syndrome and/or percutaneous coronary intervention (PCI). Despite the demonstrated clinical benefits associated with this antiplatelet therapy, there is accumulating evidence that a consistent proportion of patients persist in having high levels of platelet aggregation following standard clopidogrel dose. Importantly, the high platelet reactivity after clopidogrel treatment has been associated with higher risk for cardiovascular ischemic events, including stent thrombosis. This has warranted the need for alternative oral antiplatelet regimens that achieve a higher degree of platelet inhibition. Several functional studies have shown that a higher clopidogrel loading dose (600 mg) compared with standard dose, and novel oral adenosine diphosphate platelet receptor (P2Y12) antagonists compared with clopidogrel achieve a faster onset of action, increased platelet inhibition, and a more predictable drug response. These more favorable pharmacodynamic characteristics are of particular interest in the setting of primary PCI for ST-segment elevation myocardial infarction (STEMI), in which rapid and consistent inhibition of platelet activation and aggregation is desirable for therapeutic success. The present article reviews data on the clinical impact of enhanced P2Y12 inhibition with either higher clopidogrel dosing or new oral antiplatelet agents, including prasugrel and ticagrelor, in the setting of STEMI, focusing on results in the setting of primary PCI.