中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 王晏文
双联抗血小板治疗是急性冠脉综合征的基础治疗,联用氯吡格雷明显获益于单用阿司匹林治疗,且可预防支架内血栓形成。然而,由于氯吡格雷抵抗许多患者仍发生缺血性事件,氯吡格雷的代谢变化较大,与基因型、伴随疾病及药物的相互作用均有关。该文将对氯吡格雷抵抗的定义、具体的量化标准、临床结局及解决该问题的有效策略作一综述。
氯吡格雷联合阿司匹林的双联抗血小板治疗已是急性冠脉综合征的基础治疗,亦能有效预防经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)术后支架内血栓形成[1]。但许多患者仍发生缺血性事件,究其原因,部分是由高血小板反应性(high residual platelet reactivity,HRPR)所致,HRPR可以定义为负荷量的抗血小板药物后仍表现为高血小板反应,亦被称为氯吡格雷抵抗[2]。4%~30%使用氯吡格雷的患者可能会出现氯吡格雷抵抗,而氯吡格雷抵抗的患者中高达40%可能会再发血栓事件[3]。笔者对氯吡格雷抵抗的定义、血小板功能测定、临床结局及解决方案的有效策略作一简要综述。
氯吡格雷是一个“前药”, 是一种无活性的噻吩吡啶类抗血小板聚集药物,其在小肠的吸收受到ABCB1基因编码的质子泵P糖蛋白(P-glycoprotein,P-gp)调控(主要是SR-26334),吸收后在肝脏细胞色素P450(CYP)氧化酶系的作用下大部分(约85%)被转化成无活性的代谢产物排出体外,小部分(约15%)产生具有活性的代谢产物(主要为一种硫醇衍生物),该活性代谢产物不可逆的阻断血小板膜上的二磷酸腺苷(ADP)受体,阻断ADP对腺苷环化酶的抑制作用,促进环磷酸腺苷依赖的舒血管物质磷酸蛋白的磷酸化,从而抑制凝血因子Ⅰ与血小板糖蛋白GP Ⅱb/Ⅲa受体结合及继发的ADP介导的糖蛋白GPⅡb/Ⅲa复合物的活化,进而抑制血小板聚集[4]。
经过规范的氯吡格雷治疗后,患者仍发生血栓栓塞事件的现象被称为氯吡格雷抵抗。关于氯吡格雷抵抗目前尚无统一的定义,但最被接受的定义是该药物失去了其作用的靶点[5]。因此,较客观证实抵抗的标准是基于可量化服药前后该药物作用受体的实验技术:残存的血小板反应性测定,但尚无准确监测血小板反应性的方法。因此,关于氯吡格雷抵抗经验上分为两种,①实验室氯吡格雷抵抗:在患者规范服用氯吡格雷负荷剂量(300 mg)24~72 h后或常规剂量(75 mg)7 d后所测得的血小板聚集率较基线水平下降小于10%;②临床氯吡格雷抵抗:患者在经过规范的氯吡格雷治疗后,再次或反复发生栓塞性血管事件。许多研究表明,氯吡格雷抵抗与心脑血管不良事件相关,但仍缺乏一种合适定义氯吡格雷抵抗的方法及合理的危险分层[5]。
目前有几种常用的评估血小板功能的方法,最古老且较确定的方法是光学比浊法,常被认为是金标准。该方法通过P2Y1和P2Y12受体的功能评估血小板对ADP的反应性。研究表明该方法监测氯吡格雷的HRPR与心脑血管不良事件相关[5-6],但因其重复率低及对P2Y12通路缺乏特异性而受到限制。目前因操作相对容易而被广泛应用的是血管扩张剂刺激的磷蛋白(vasodilator stimulated phosphoprotein,VASP)磷酸化测定和VerifyNow床边监测。
VASP是利用流式细胞仪测定氯吡格雷通过P2Y12通路产生的特殊的生化指标。对于使用P2Y12抑制剂的患者,VASP的磷酸化状态是一种特定细胞内残余P2Y12受体反应性的标志。这个试验优势是专门评估P2Y12受体的活动,结果报告为一个血小板反应性指数(PRI)的百分比值[7]。通过VASP测定的血小板反应性指数也与 PCI术后复发性缺血性事件相关[5-6],具有一个较强的负面预测能力[8]。与ADP诱导的光学比浊法测定不同,在 VASP测量中,不包括P2Y1受体诱导的血小板反应。
VerifyNow血小板功能分析,是一种浊度分析法,是一种非常实用的床边监测血小板聚集率的工具,监测P2Y12反应单元(P2Y12 reaction units,PRU)的值,PRU值越高反应越高,P2Y12介导的血小板聚集越高,且高PRU与心脑血管不良事件相关[7,9]。
由于缺乏通用的截止值,目前尚无定义氯吡格雷抵抗或低反应性的“金标准”。VASP法虽是评估氯吡格雷诱导血小板活化最具体的测试,但大多数临床研究采用的是LTA或VerifyNow法[6]。BONELLO等[5]2010年对最常用的血小板功能检测方法的HTPR共识值定义。见
表1 常用的血小板监测方法及其特点
但作者反对将该标准应用于每一个PCI患者。他们认为对高风险的PCI患者或已有支架内血栓史的患者应个体化利用该标准。他们亦认为也许没有针对每个检测方法的统一界定值,因不同的情况下其有不同的权重,例如需紧急行PCI术及维持性治疗阶段,其价值肯定不同。即使这些界定值可很好预测未来发生心脑血管不良事件的风险,但其对所有试验有利价值的预测却很低。且HTPR虽是心脑血管不良事件的风险,但并不是唯一的原因。
氯吡格雷需在肝脏CYP氧化酶系的作用下转化为有活性的物质进而发挥抗血小板聚集的作用。CYP氧化酶系是高度多态性的单胺氧化酶系,已报告一些等位基因编码的酶可改变一些代谢物的浓度及某些蛋白质的活性,从而改变药物的潜在作用。
HULOT等[12]发现CYP系统中的CYP2C19酶作为氯吡格雷在体内代谢的主要代谢酶,其基因多态性的存在影响该酶的活性,从而影响了氯吡格雷抗血小板作用。CYP2C19*17等位基因可增加酶的活性与出血的发生率相关,携带CYP2C19*17等位基因者可增加出血风险率。CYP2C19*2等位基因则与氯吡格雷的低反应性相关,CYP2C19野生型(*1/*1)的患者能够较好的抑制血小板活性,携带无功能型者更容易出现氯吡格雷抵抗,表明氯吡格雷抵抗可能与CYP2C19基因的多态性有关[13],总体上来说,风险最高的为那些携带无功能等位基因*2纯合子者[13],不过其他研究发现杂合基因亦可引起氯吡格雷抵抗[13-16],功能丧失的等位基因翻译表达为较高的残余血小板反应性,与死亡、心肌梗死和支架内血栓形成等不良结果相关[14]。还有研究发现ABCB1基因多态性对氯吡格雷的生物利用度有明显的影响。携等位基因ABCB1、C3435T的患者比没有携带者的主要终点事件(死亡、非致命性卒中、心肌梗死等)的风险高[6]。有研究表明CYP3A4基因变异性与氯吡格雷抵抗有关,仅FRERE等[15]研究表明携带IVS10+12G>A的患者对氯吡格雷敏感,但未发现其研究的其他位点是否与氯吡格雷抵抗有关。COLLET等[16]的研究也未表明CYP3A4基因多态性与氯吡格雷抵抗的相关性。CATTANEO等[14] 研究则表明PON1是氯吡格雷生物代谢的关键酶,PON1 qq192纯合子个体支架内血栓形成的风险高于PON1 rr192的个体。但刘腾飞等[17]却认为PON1基因单核苷酸多态性位点rs854572与冠心病患者氯吡格雷抵抗的发生无关。
尽管遗传组学对氯吡格雷反应具有重要作用,只有18%确定为基因突变所致[6],表明氯吡格雷反应是一个非常复杂的基因相互作用的结果。
除了遗传因素,CYP3A4酶作用的药物之间的相互作用,如他汀类药物与氯吡格雷均需该酶代谢[18-19]亦是研究重点。然而其他研究并未证实[20-21]。但同时使用质子泵抑制药和氯吡格雷其风险是肯定的[22]。BONELLO等[8]发现使用钙离子拮抗药和血管紧张素转换酶抑制药者有发生氯吡格雷抵抗的倾向,但差异无统计学意义。FORBES等[23]则发现联合使用氯吡格雷和β受体阻断药或钙受体阻滞药不影响氯吡格雷的抗血小板作用。
其次,并发疾病如糖尿病,高体重指数(BMI)和射血分数较低亦与氯吡格雷的抵抗相关。糖尿病的高糖状态可能会导致高血栓形成倾向;YAZBEK等[24]发现糖尿病患者较非糖尿病患者血小板反应性和聚集性增强。LAPANTALO等[25]认为胰岛素抵抗与氯吡格雷抵抗相关。且既往研究表明并发糖尿病的冠心病患者确实存在氯吡格雷的血小板抑制效应[26]。NAKAQUWAL等[27]亦发现糖尿病是氯吡格雷低反应性的独立的危险因素。高BMI已被确定为氯吡格雷抵抗的一个独立的预测因素[28]。
此外,药物的依从性亦是心脑血管不良事件的一个潜在的重要因素。
无论是对氯吡格雷的低反应性或高反应性,为了预防氯吡格雷异常反应导致的不良结果,目前主要有2种不同的应对策略。一是利用血小板功能测定、基因型识别该类患者,通过调整氯吡格雷的剂量而达到所需的血小板抑制率。二是发现新一代的替代药物即有效性个体差异小的药物。
BONELLO等[37]推测可通过定制的氯吡格雷负荷剂量控制残余血小板反应性将降低支架内血栓形成的发生率。一项多中心随机对照研究中,VASP治疗组患者为了实现PCI前VASP指数<50%,接受了1 800 mg氯吡格雷,其1个月支架血栓形成率有显著降低(0.5%比4.2%,
BONELLO等[38]同样发现86%氯吡格雷抵抗的患者在使用了额外剂量的氯吡格雷后,实现了VASP指数< 50%,在类似的出血率的前提下,减少了1个月时心血管不良事件的发生率。因此,这种策略减少了重大心脏事件和支架血栓形成率,且在短期内不增加出血的风险,但有待于进一步的研究证明其长期持续受益。
BONELLO等[39]研究表明,增加非ST段抬高型急性冠脉综合征CY2C19*2功能缺失基因型的患者氯吡格雷的负荷剂量,可以达到PRI在50%以下;CUISSET等[40]却发现,只有一小部分CYP2C19*2等位基因携带者在使用负荷量600 mg及150 mg每日剂量时可显著减少HRPR。
目前尚不存在通过血小板功能检测预测支架血栓形成等不良心血管事件的共识。
由于氯吡格雷治疗的局限性及临床严重的缺血复发事件,研究人员集中于发现新一代的替代药物,实现更快和更高程度的血小板抑制作用。
普拉格雷作为第三代的噻吩吡啶类药物就是其中之一,60 mg负荷剂量的普拉格雷与300 mg负荷剂量的氯吡格雷相比,可达到更高和更一致的活性代谢物水平[41],普拉格雷治疗后30 min内抑制血小板聚集的程度与氯吡格雷后6 h的峰值相当[42]。因此,与标准和更高剂量的氯吡格雷相比,普拉格雷抑制ADP诱导血小板聚集更快,更一致,更有力[41,43]。
替格瑞洛,也称为AZD6140,是一种新型口服P2Y12受体拮抗药,可逆地结合P2Y12受体,从而防止ADP的结合。180 mg负荷量的替格瑞洛的血小板抑制效果优于600 mg的氯吡格雷。PLATO试验发现替格瑞洛与氯吡格雷相比,显著降低血管事件导致的死亡、心肌梗死、卒中等事件。且在整个研究期间(360 d)不增加整体的出血风险。这种新药不需要代谢活化即可发挥其效果。对于CAD稳定患者,替格瑞洛比氯吡格雷显示更大程度的血小板抑制作用[44]。
虽然血小板反应性测定尚不是ACS患者接受PCI术前的常规检查,但氯吡格雷抵抗却是心脑血管疾病专家需考虑的临床难题。尽管使用高剂量的氯吡格雷在该问题上有一定优势,而新型药物因无药物反应性的缺点而成为优先选择,如普拉格雷和替格瑞洛优先替代氯吡格雷在ST段抬高型心肌梗死及不稳定性心绞痛或非ST段抬高型心肌梗死患者中的应用。这两个强有力的抗血小板药物为氯吡格雷抵抗者提供了一个突破,可能很快取代氯吡格雷在日常临床实践中的应用,但这些药物的价格更昂贵,且在许多国家并无上市,因此其可及性是一个需考虑的问题。仍有一部分患者氯吡格雷是最优先的选择,尤其是考虑到经济方面的原因,氯吡格雷对于大多数患者而言,仍具有重要地位。总而言之,个体化的治疗仍是最易为患者所接受的治疗选择。
The authors have declared that no competing interests exist.
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Background-In the Gauging Responsiveness With A VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) trial, 6 months of high-dose clopidogrel did not reduce cardiovascular events compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity (OTR) after percutaneous coronary intervention, defined as OTR >= 230 P2Y12 reaction units according to the VerifyNow P2Y12 platelet function test. The aim of this analysis was to examine the relationship between outcomes and OTR over the course of the trial.<br/>Methods and Results-OTR was measured at 12 to 24 hours and 30 +/- 7 days after percutaneous coronary intervention. Cox proportional hazards models with OTR as a time-varying covariate were used to determine the association between OTR and the primary end point of cardiovascular death, myocardial infarction, and stent thrombosis. Of the 2800 enrolled patients, 2796 (99.98%) had evaluable platelet function data. OTR <208 P2Y12 reaction units was significantly associated with a lower risk of the primary end point at 60 days (hazard ratio, 0.18; 95% confidence interval, 0.04 to 0.79; P = 0.02) and at 6 months (hazard ratio, 0.43; 95% confidence interval, 0.23 to 0.82; P = 0.01). After adjustment for other significant predictors of outcome, OTR <208 P2Y12 reaction units remained independently associated with the primary end point at 60 days (hazard ratio, 0.23; 95% confidence interval, 0.05 to 0.98; P = 0.047) and tended to be associated at 6 months (adjusted hazard ratio, 0.54; 95% confidence interval, 0.28 to 1.04; P = 0.065).<br/>Conclusions-In the GRAVITAS trial, achievement of on-clopidogrel reactivity <208 P2Y12 reaction units at 12 to 24 hours after percutaneous coronary intervention or during follow-up was associated with a lower risk for cardiovascular events. The efficacy of an individualized strategy to target a level of OTR below this threshold merits investigation.
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DOI:10.1016/j.ahj.2009.02.012
PMID:3287121714888908016229222322221937630684940349594022278843
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Magsci
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Chinese hamster ovary cells selected for resistance to colchicine display pleiotropic cross-resistance to a wide range of amphiphilic drugs. The drug-resistant phenotype is due to a membrane alteration which reduces the rate of drug permeation. Surface labelling studies reveal that drug-resistant Chinese hamster ovary cell membranes possess a carbohydrate-containing component of 170 000 daltons apparent molecular weight which is not observed in wild type cells. Through studies of the metabolic incorporation of carbohydrate and protein precursors, and through the use of selective proteolysis, this component is shown to be a cell surface glycoprotein. Since this glycoprotein appears unique to mutant cells displaying altered drug permeability, we have designated it the ja:math glycoprotein. The relative amount of surface labelled ja:math glycoprotein correlates with the degree of drug resistance in a number of independent mutant and revertant clones. A similar high molecular weight glycoprotein is also present in drug-resistant mutants from another hamster cell line. Observations on the molecular basis of pleiotropic drug resistance are interpreted in terms of a model wherein certain surface glycoproteins control drug permeation by modulating the properties of hydrophobic membrane regions.
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The addition of to aspirin treatment reduces ischemic events in a wide range of patients with . However, recurrent ischemic event occurrence during dual antiplatelet therapy, including stent thrombosis, remains a major concern. Platelet function measurements during treatment demonstrated a variable and overall modest level of P2Y(12) inhibition. High on-treatment platelet reactivity to (ADP) was observed in selected patients. Multiple studies have now demonstrated a clear association between high on-treatment platelet reactivity to ADP measured by multiple methods and adverse clinical event occurrence. However, the routine measurement of platelet reactivity has not been widely implemented and recommended in the guidelines. Reasons for the latter include: 1) a lack of consensus on the optimal method to quantify high on-treatment platelet reactivity and the cutoff value associated with clinical risk; and 2) limited data to support that alteration of therapy based on platelet function measurements actually improves outcomes. This review provides a consensus opinion on the definition of high on-treatment platelet reactivity to ADP based on various methods reported in the literature and proposes how this measurement may be used in the future care of patients.
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Clopidogrel has been used to prevent recurrent ischemic events after acute coronary syndrome and/or coronary stent implantation. An impaired platelet response to this drug (residual high platelet reactivity) has been identified as a risk factor for recurrent ischemic events. The platelet response to clopidogrel is highly heritable (73%) suggesting a substantial genetic component. Two sequential cytochrome P450-dependent oxidative steps are required to convert clopidogrel to its active metabolite. The first step leads to the formation of 2-oxo-clopidogrel, which is then metabolized to the active metabolite. Cytochrome P450s are large highly polymorphic family of mono-oxygenases. Many alleles have been reported, and some of these are able to modify the activity of proteins, reducing or increasing the concentration of active metabolites and the drug effect. Loss-of-function variants in the hepatic cytochrome 2C19 (mainly *2 allele) system have been found to be the predominant genetic mediators of clopidogrel response. Variant carriers have higher treatment platelet reactivity and higher risk of adverse cardiac events including stent thrombosis, myocardial infarction, and death. Although value of CYP2C19 genotyping has been demonstrated in ACS population treated with PCI, there is still a wide interindividual variability within each genotype to systematically advocate this genetic testing in clinical practice. The CYP2C19*2 variant only explained 12% of the platelet response to clopidogrel. In the near future, it is highly probable that additional gene variants or epigenetic phenomenon will emerge as significant contributors to clopidogrel response that will allow recommending genetic testing for routine use. The purpose of this review is to discuss the contribution of individual genetic differences responsible for variations of action and clopidogrel efficacy.
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[62] CARDIOVASCULAR DEATH AND NONFATAL MYOCARDIAL INFARCTION IN ACUTE CORONARY SYNDROME PATIENTS ARE PREDICTED BY RESIDUAL PLATELET REACTIVITY TO ADP IN THE ABSENCE OF CYP2C19*2 ALLELE:
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Abstract Context High on-treatment platelet reactivity is associated with atherothrombotic events following coronary stent implantation. Objective To evaluate the capability of multiple platelet function tests to predict clinical outcome. Design, Setting, and Patients Prospective, observational, single-center cohort study of 1069 consecutive patients taking clopidogrel undergoing elective coronary stent implantation between December 2005 and December 2007. On-treatment platelet reactivity was measured in parallel by light transmittance aggregometry, Verify Now P2Y12 and Platelet works assays, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/adenosine diphosphate (ADP) cartridge and Innovance PFA P2Y). Cutoff values for high on-treatment platelet reactivity were established by receiver operating characteristic curve (ROC) analysis. Main Outcome Measurement The primary end point was defined as a composite of all-cause death, nonfatal acute myocardial infarction, stent thrombosis, and ischemic stroke. The primary safety end point included TIMI (Thrombolysis In Myocardial Infarction) criteria major and minor bleeding. Results Kaplan-Meier analysis demonstrated that at 1-year follow-up, the primary end point occurred more frequently in patients with high on-treatment platelet reactivity when assessed by light transmittance aggregometry (52 [11.7%; 95% confidence interval {CI}, 8.9%-15.0%] vs 36 [6.0%;95%CI, 4.2%-8.2%] P.001; n=1049),Verify Now (54 [13.3%; 95% CI, 10.2%-17.0%] vs 37 [5.7%; 95% CI, 4.1%-7.8%]P.001; n=1052), Platelet works (33 [12.6%; 95% CI, 8.8%-17.2%] vs 21 [6.1%;95% CI, 3.8%-9.2%] P=.005; n=606), and Innovance PFA P2Y (18 [12.2%; 95%CI; 7.4%-18.6%] vs 28 [6.3%; 95% CI, 4.3%-8.9%] P=.02; n=588). ROC-curve analysis demonstrated that light transmittance aggregometry (area under the curve[AUC], 0.63; 95% CI, 0.58-0.68), Verify Now (AUC, 0.62; 95% CI, 0.57-0.67), and Platelet works (AUC, 0.61; 95% CI, 0.53-0.69) had modest ability to discriminate between patients with and without primary end point at 1-year follow-up. The IMPACT-R(n=905) and the Siemens PFA Collagen/ADP (n=812) were unable to discriminate between patients with and without the primary end point at 1-year follow-up (all AUCs included 0.50 in the CI). None of the tests identified patients at risk for bleeding. Conclusions Of the platelet function tests assessed, light transmittance aggregometry,Verify Now, Platelet works, and Innovance PFA P2Y were significantly associated with the primary end point. However, the predictive accuracy of these 4 tests was only modest. None of the tests provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation. Trial Registration clinical trials.gov Identifier: NCT00352014 [corrected].
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| [11] |
Erratum for JAMA. 2010 Feb 24;303(8):754-62.
[本文引用:1]
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Abstract OBJECTIVES: The aim of this study was to assess the association between the loss-of-function cytochrome P450 2C19 (CYP2C19)*2 variant (10 studies, 11,959 patients) or the use of proton pump inhibitors (PPIs) (13 studies, 48,674 patients) and ischemic outcomes (major adverse cardiovascular events [MACE]) in patients treated with clopidogrel. BACKGROUND: In clopidogrel-treated patients, increased cardiovascular risk has been identified with the loss-of-function CYP2C19*2 allele or the use of PPIs, some of them CYP2C19 inhibitors. To further estimate the effect of a reduction in activity of this enzyme, the authors performed a meta-analysis of the studies available. METHODS: The meta-analysis was performed on 23 studies using the odds ratio (OR) as the parameter of efficacy, with a fixed-effect model. The end points were MACE, mortality, or stent thrombosis. RESULTS: Of the 11,959 patients, carriers of the loss-of-function CYP2C19*2 allele (28% [n = 3,418]) displayed a 30% increase in the risk for MACE compared with noncarriers (9.7% vs. 7.8%; OR: 1.29; 95% confidence interval [CI]: 1.12 to 1.49; p < 0.001). This single gene variant (CYP2C19*2) was also associated with an excess of mortality (1.8% vs. 1.0%; OR: 1.79; 95% CI: 1.10 to 2.91; p = 0.019; n = 6,225) and of stent thrombosis (2.9% vs. 0.9%; OR: 3.45; 95% CI: 2.14 to 5.57; p < 0.001; n = 4,905). This increased risk was apparent in both heterozygotes and homozygotes and was independent of the baseline cardiovascular risk. PPI users (42% [n = 19,614]) displayed increased risk for MACE (21.8% vs. 16.7%; OR: 1.41; 95% CI: 1.34 to 1.48; p < 0.001) and mortality (12.7% vs. 7.4%; OR: 1.18; 95% CI: 1.07 to 1.30; p < 0.001; n = 23,977) compared with nonusers. The impact of PPI use was, however, significantly influenced by baseline cardiovascular risk, being significant only in high-risk patients. CONCLUSIONS: In this global meta-analysis, reduced CYP2C19 function appears to expose clopidogrel-treated patients to excess cardiovascular risk and mortality. Conflicting results among studies may be explained by differences in types and/or levels of risk of patients. Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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| [13] |
Abstract We report a switch in antiplatelet medication based on platelet function and CYP2C19 genotype test results in a 74-year-old man with severe coronary arterial disease. Upon bare metal stent implantation at age 66, clopidogrel therapy (75 mg/ day) was initiated to supplement aspirin. Over the next eight years, the patient required multiple percutaneous coronary interventions for de novo coronary stenosis and in-stent restenosis. Platelet reactivity measured while on clopidogrel therapy was high, consistent with clopidogrel resistance. CYP2C19 genotype testing then revealed homozygosity for the *2 null allele. The *2/*2 designation indicates poor metabolizer status, indicating deficient capacity of the cytochrome p450 2C19 enzyme for activation of clopidogrel. A medication switch to prasugrel,which does not rely on activation by the 2C19 enzyme, reduced platelet reactivity by 86%. The patient has suffered no cardiovascular events in the 18 months since initiation of prasugrel therapy.
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目的 探讨对氧磷酶1(PON1)基因rs854572单核苷酸多态性与氯吡格雷抵抗(CR)发生的相关性.方法 采用病例-对照研究的方法,共人选850例沈阳军区总医院冠心病住院患者,采用光学比浊法测定20μmol/L二磷酸腺苷(ADP)诱导的残余血小板聚集 率(RPA),当RPA≥70％时,即定义为CR.将入选患者分为CR组(n=215)和非氯吡格雷抵抗(NCR)组(n=635),采用焦磷酸测序法测 定PON1基因rs854572单核苷酸多态性的基因型及等位基因分布频率.结果 PON1基因rs854572多态位点在两组间基凶型分布频率皆符合Hardy-Weinberg平衡定律,三种基凶型(CC、CG和GG)分布频率在 CR组和NCR组分别为23.7％、49.3％、27.0％和24.1％、50.2％、25.7％,三种基因型在两组间分布频率差异无统计学意义 (P=0.93).C、G等位基因分布频率在两组间差异亦无统计学意义(P=0.763).Logistic回归校正性别、年龄、体重指数、吸烟、高血 压、高脂血症及糖尿病等冠心病易患因素后,PON1基因rs854572单核苷酸多态性仍与冠心病患者CR的发生无相关关系.结论 PON1基因单核苷酸多态位点rs854572与冠心病患者CR的发生无关.
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We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4.Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34+/-23, 58+/-15 (P=0.027), 74+/-10 (P=0.002), and 89+/-7 (P=0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55+/-12 versus 42+/-12% platelet aggregation; P=0.002), as did troleandomycin (78+/-18 versus 45+/-18% platelet aggregation; P<0.0003), whereas rifampin enhanced platelet aggregation inhibition (33+/-18 versus 56+/-20% platelet aggregation, P=0.001).CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.
[本文引用:1]
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| [19] |
Abstract AIMS: Clopidogrel is a pro-drug which is converted to an active, unstable drug by cytochrome P450 (CYP). The active drug irreversibly blocks one specific platelet adenosine 5'-diphosphate (ADP) receptor (P2Y12). It has been recently suggested that the most abundant human CYP isoform, 3A4, activates clopidogrel. Since certain lipophilic statins (i.e. simvastatin, atorvastatin, lovastatin) are a substrate of CYP3A4, we were interested in potential drug interactions between clopidogrel and statins. METHODS: In patients with coronary artery disease (n=47) in whom clopidogrel treatment was initiated for balloon angioplasty and stent implantation, blood samples were taken at 0, 5 and 48 h after oral administration of clopidogrel (loading dose 300 mg, followed by 75 mg daily). ADP-stimulated (1, 10, 100 micromol/l) expression of P-selectin (CD62P) on platelets was measured by flow cytometry, and used as a marker for the antiplatelet effect of clopidogrel. RESULTS: Pre-treatment with statins (atorvastatin, simvastatin) reduced significantly (10 micromol/l ADP stimulation) the inhibitory effects of clopidogrel during the loading phase (relative reduction after 5 h 29.3%) and, to a lesser extent during the maintenance phase (relative reduction after 48 h 16.6%). In addition we found a considerable individual heterogeneity in the response and three patients (6%) were identified in whom clopidogrel exerted almost no effect. CONCLUSION: Certain statins which are substrates of the CYP3A4 isoform competitively inhibit the metabolic activation of clopidogrel. As a result the relative clopidogrel induced platelet inhibition (P-selectin-expression) is diminished--but still there is a relative clopidogrel effect of more than 80% in the maintenance phase. It may be reasonable to test the therapeutic efficacy of clopidogrel in those patients who require long-term treatment.
[本文引用:1]
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| [20] |
Some, but not all, post hoc analyses have suggested that the antiplatelet effects of clopidogrel are inhibited by atorvastatin. We sought to address this issue prospectively by performing serial measurements of 19 platelet characteristics using conventional aggregometry, rapid analyzers, and flow cytometry.The Interaction of Atorvastatin and Clopidogrel Study (Interaction Study) was designed for patients undergoing coronary stenting. All patients (n = 75) received 325 mg of aspirin daily for at least 1 week and 300 mg of clopidogrel immediately prior to stent implantation. They had been taking atorvastatin (n = 25), any other statin (n = 25), or no statin (n = 25) for at least 30 days prior to stenting. The main outcome measure was comparison of platelet biomarkers 4 and 24 hours after clopidogrel administration between study groups.At baseline, patients from both statin groups exhibited diminished platelet aggregation and reduced platelet expression of G-protein-coupled protease-activated thrombin receptor (PAR)-1. There were no significant differences in measured platelet characteristics among the study groups 4 and 24 hours after clopidogrel intake, with the exception of a lower collagen-induced aggregation at 24 hours and a constantly diminished expression of PAR-1 in patients treated with any statin.Statins in general, and atorvastatin in particular, do not affect the ability of clopidogrel to inhibit platelet function in patients undergoing coronary stenting. These prospective data also suggest that statins may inhibit platelets directly via yet unknown mechanism(s) possibly related to the regulation of the PAR-1 thrombin receptors.
[本文引用:1]
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The antiplatelet effect of clopidogrel may be attenuated by short-term coadministration of lipophilic statins. We investigated whether the coadministration of atorvastatin for 5 weeks in patients with acute coronary syndromes (ACS) could affect the antiplatelet potency of clopidogrel.Forty-five hypercholesterolemic patients with the first episode of an ACS were included in the study. Patients were randomized to receive daily either 10 mg of atorvastatin (n=21) or 40 mg of pravastatin (n=24). Thirty patients who underwent percutaneous coronary intervention (PCI) received a loading dose of 375 mg of clopidogrel, followed by 75 mg/d for at least 3 months. In the remaining 15 patients who refused to undergo PCI, clopidogrel therapy was not administered. Eight normolipidemic patients with the first episode of an ACS were also included and received only clopidogrel. The serum levels of soluble CD40L and the adenosine 5'-diphosphate- or thrombin receptor activating peptide-14-induced platelet aggregation, as well as P-selectin and CD40L surface expression, were studied at baseline (within 30 minutes after admission) and 5 weeks later. Neither atorvastatin nor pravastatin significantly influenced the clopidogrel-induced inhibition of platelet activation, nor did clopidogrel influence the therapeutic efficacy of atorvastatin.Atorvastatin does not affect the antiplatelet potency of clopidogrel when coadministered for 5 weeks in ACS patients.
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| [22] |
CONTEXT: Prior mechanistic studies reported that omeprazole decreases the platelet inhibitory effects of clopidogrel, yet the clinical significance of these findings is not clear. OBJECTIVE: To assess outcomes of patients taking clopidogrel with or without a proton pump inhibitor (PPI) after hospitalization for acute coronary syndrome (ACS). DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 8205 patients with ACS taking clopidogrel after discharge from 127 Veterans Affairs hospitals between October 1, 2003, and January 31, 2006. Vital status information was available for all patients through September 30, 2006. MAIN OUTCOME MEASURES: All-cause mortality or rehospitalization for ACS. RESULTS: Of 8205 patients taking clopidogrel after discharge, 63.9% (n = 5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n = 2961) were not prescribed PPI. Death or rehospitalization for ACS occurred in 20.8% (n = 615) of patients taking clopidogrel without PPI and 29.8% (n = 1561) ofpatients taking clopidogrel plus PPI. In multivariable analyses, use of clopidogrel plus PPI was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95% confidence interval [CI], 1.11-1.41). Among patients taking clopidogrel after hospital discharge and prescribed PPI at any point during follow-up (n = 5244), periods of use of clopidogrel plus PPI (compared with periods of use of clopidogrel without PPI) were associated with a higher risk of death or rehospitalization for ACS (adjusted hazard ratio, 1.27; 95% CI, 1.10-1.46). In analyses of secondary outcomes, patients taking clopidogrel plus PPI had a higher risk of hospitalizations for recurrent ACS compared with patients taking clopidogrel without PPI (14.6% vs 6.9%; AOR, 1.86 [95% CI, 1.57-2.20]) and revascularization procedures (15.5% vs 11.9%; AOR, 1.49 [95% CI, 1.30-1.71]), but not for all-cause mortality (19.9% vs
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The safety and pharmacodynamic compatibility of clopidogrel with medications commonly used in patients with atherosclerosis, such as, a beta-adrenergic receptor antagonist (atenolol) and a calcium uptake inhibitor (nifedipine) were assessed. Atenolol and nifedipine interactions with clopidogrel were studied in patients with peripheral arterial obstructive disease taking a well-established regimen of nifedipine (N group of 6 patients) and in patients with coronary artery disease taking a well-established regimen of either atenolol (A group of 8 patients) or of atenolol and nifedipine (AN group of 8 patients). The study was conducted as a double-blind, randomized, crossover comparison of clopidogrel, 75 mg once daily, and placebo treatment for 7 days, with a 14-day washout between treatments. Pharmacodynamic interactions between atenolol and nifedipine, either alone or in combination, and clopidogrel were assessed primarily on the clinical control of angina or hypertension and, secondarily, by comparing the extent of inhibition of ADP (5 microM)-induced platelet aggregation achieved between the 3 groups. The mean number of anginal episodes per patient during the placebo week was 1.50, 9.0 and 11.5 in the A, N and AN groups, respectively; during the week of clopidogrel treatment, it was 1.39, 7.3 and 9.0, respectively, indicating no change in occurrence. Likewise, review of the use of nitrates (long or short acting) did not suggest any major change in usage during any period of the study. ECGs did not change between the three recording times (at screening and at the end of each treatment period). Vital signs were also unchanged throughout. Percent inhibition of platelet aggregation on day 7 was 31% in the N group, 39% in the A group, 28% in the AN group, and 33% overall. In conclusion, the coadministration of clopidogrel did not interfere with the clinical control of hypertension or angina established with atenolol or nifedipine, or both. Clopidogrel retained its full
DOI:10.1016/j.bse.2006.05.012
PMID:328011442498698701241268229222322221044042584993634057768037143
URL
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Patients with diabetes mellitus (DM) have accelerated atherosclerosis, which is the main underlying factor contributing to the high risk of atherothrombotic events in these patients. Atherothrombotic complications are the leading cause of morbidity and mortality in patients with DM. Among factors contributing to the prothrombotic condition which characterise patients with DM, platelet hyperreactivity plays a pivotal role. Platelets of DM patients are characterised by dysregulation of several signalling pathways leading to intensified adhesion, activation and aggregation. Multiple mechanisms are involved in platelet dysfunction of patients with DM, which can be categorised as follows: a) hyperglycaemia, b) insulin deficiency and resistance, c) associated metabolic conditions, and d) other cellular abnormalities.The present manuscript aims to provide an overview on the current status of knowledge on platelet abnormalities that characterise patients with DM.
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Aspirin is the most commonly used antiplatelet drug for treatment of a serious vascular event, most notably and . Significant fraction of aspirin treated patients is resistant to the antiplatelet effects of the drugs. Previous studies have suggested that a genetic basis for aspirin resistance exists. Therefore the present study was taken up to investigate the role of C3435T polymorphism (rs 1045642) of multiple drug resistance-1 (MDR-1) gene with aspirin resistance in patients. Five hundred and sixty patients and 560 age and sex matched healthy controls were involved in the study. Baseline clinical data were collected and follow-up telephone interviews were conducted with patients at 3, 6 and 12 months post event to determine outcome. Blood samples were collected and genotypes determined. Significant difference was observed in the genotype distribution and allele frequency between patients and controls. The results were confirmed by a step wise multiple logistic regression analysis controlling all other confounding risk factors [adjusted Odds ratio=3.132 (95% CI; 2.043-4.800; p<0.001)]. There was a significant difference in genotype distribution between drug responders and non-responders. The risk of aspirin resistance was significantly high in patients with TT genotype in comparison to those with CC genotype [(TT vs. CC, 蠂(2)=6.268; p=0.012, Odds ratio=1.85) (95% CI; 1.142-3.017) (adjusted Odds ratio=2.465; 95% CI; 1.895-4.625 <0.001)]. As far as the subtypes are concerned TT genotype associated significantly with aspirin resistance in intracranial large artery . Our results indicate that the risk of aspirin resistance is more in patients with 3435TT genotype than in those with CC genotype. However, this is a preliminary study and a large study of replication is needed to confirm our results.
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Optimal antiplatelet inhibition is essential in patients undergoing neurointerventional procedures; however, variability in can contribute to thromboembolic and hemorrhagic complications. The present study evaluated the influence of mellitus and cigarette smoking on reactivity.Between 2011 and 2013, 71 consecutive patients underwent aneurysmal coil embolization (CE) or carotid artery stenting () and received (7565mg daily) and aspirin (10065mg daily) before the treatment. The patients were divided into 2 groups: CE (n65=6531) and (n65=6540). The patients underwent prospective assessment of preoperative platelet function using VerifyNow assay and received adjunctive (20065mg daily, triple antiplatelet therapy) in case of hyporesponse. Patients with hyper-response underwent dose reduction (, 12.5-5065mg daily).resistance was noted in 15 patients (37.5%) in the group and in 4 patients (12.9%) in the CE group (P65=65.031). hyper-response was noted in 2 patients (5%) in the group and in 11 patients (54.8%) in the CE group (P65<65.001). There was a significant difference in the baseline clinical characteristics between the 2 groups. In the multivariate logistic regression analysis, and age were independent predictors of hyporesponse, whereas current smoker was an independent predictor of hyper-response.Significant differences in baseline clinical characteristics were present when comparing patients undergoing endovascular treatment of unruptured and carotid artery . mellitus and current smoker status were independent factors related to reactivity to .
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We carried out a prospective evaluation of a new () assay in order to detect patients with high-risk coronary subacute stent thrombosis (SAT) despite regimen. Twenty healthy donors (group 1) without any medication were compared to 16 stented patients (group 2) treated by ticlopidin or initiated 2 days before stenting and aspirin (250 mg/day). No difference in platelet reactivity was noted between group 1 and group 2 treated only with aspirin (72.00% +/- 4.17% vs. 69.73% +/- 5.62%, respectively; P = NS). Significant differences were found between patients of group 2 treated with aspirin alone (69.73% +/- 5.62%), after 2.0 days (60.14% +/- 9.60%; P < 0.05), and after 4.8 +/- 1.3 days (48.37% +/- 11.19%; P < 0.05) with -aspirin. Among 1,684 consecutive stented patients, 16 patients who presented an SAT (group 3) were compared with 30 other stented patients free of SAT (group 4). We found a significant difference between group 3 (63.28% +/- 9.56%) and group 4 (39.80% +/- 10.9%; P < 0.0001). analysis may be useful for the detection of coronary SAT.
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Dual antiplatelet therapy with aspirin and decreases the rate of stent thrombosis in patients undergoing percutaneous coronary intervention (). However, despite intensified antiplatelet treatment, up to 4.7% of the patients undergoing coronary stenting develop , suggesting incomplete platelet inhibition due to resistance. We evaluated the percentage of non-responders among 105 patients with (CAD) undergoing elective . All patients were treated regularly with aspirin 100 mg/d and received a loading dose of 600 mg followed by a maintenance dose of 75 mg/d before . non-responders were defined by an inhibition of ADP (5 and 20 Mol/L) induced that was less than 10% when compared to baseline values 4 h after intake. Semi-responders were identified by an inhibition of 10 to 29%. Patients with an inhibition over 30% were regarded as responders. We found that 5 (ADP 5 Mol/L) to 11% (ADP 20 Mol/L) of the patients were non-responders and 9 to 26% were semi-responders. Among the group of non-responders there were two incidents of subacute stent thrombosis after . We conclude that a subgroup of patients undergoing does not adequately respond to , which may correspond to the occurrence of thromboischemic complications. Point-of-care testing may help to identify these patients who may then benefit from an alternative antiplatelet therapy.
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A low response to has been associated with an increased risk of stent thrombosis. However, the definition of a nonresponse to remains controversial, and different tests have been used to assess the response. The present study was designed to assess the predictive value of ()-induced platelet aggregation (-Ag) and the Platelet Reactivity Index of for the occurrence of stent thrombosis in patients admitted for non-ST-elevation undergoing percutaneous coronary intervention. A total of 598 consecutive patients with non-ST-elevation undergoing coronary stenting were prospectively included. They received 600 mg of >or=12 hours before percutaneous coronary intervention. Acute or subacute definite or probable stent thrombosis occurred in 11 patients (1.8%). These patients had significantly greater -Ag compared to patients free of stent thrombosis (68 +/- 14% vs 56 +/- 19%, p = 0.002) but only a trend toward a greater Platelet Reactivity Index of (62 +/- 14% vs 53 +/- 23%, p = 0.19). The construction of receiver operating characteristic curves to examine the most predictive value of -Ag for stent thrombosis gave a threshold of -Ag of >67% to identify low responders. These patients were at a greater risk of stent thrombosis than the responders (4.3% vs 0.8%, odds ratio 5.8, 95% confidence interval 1.9 to 24.6, p = 0.003). In conclusion, in patients with non-ST-elevation undergoing percutaneous coronary intervention, -Ag is a good parameter to identify nonresponders who are at increased risk of stent thrombosis, with a cutoff value of -Ag of >67%.
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OBJECTIVES: We investigated whether patients who suffered subacute stent thrombosis (SAT) have higher post-treatment reactivity than those who do not encounter stent thrombosis. BACKGROUND: High post-treatment platelet reactivity has been reported after coronary stenting after clopidogrel therapy and may be an important factor in the occurrence of SAT. METHODS: We identified patients with SAT treated at two tertiary care centers over a 1.5-year period. Light transmittance aggregation induced by adenosine diphosphate (ADP) and arachidonic acid, total and activated glycoprotein (GP) IIb/IIIa after stimulation with ADP, and vasodilator-stimulated phosphoprotein phosphorylation levels to measure P2Y12 receptor inhibition were determined (n = 20) and compared with an age-matched group of patients without SAT (n = 100). High post-treatment platelet reactivity was defined as >75th percentile ADP-induced aggregation in the group without SAT. RESULTS: The SAT patients had higher mean platelet reactivity than those without SAT by all measurements (p < 0.05): 49 +/- 4% versus 33 +/- 2% for 5 micromol/l ADP-induced aggregation and 65 +/- 3% versus 51 +/- 2% for 20 micromol/l ADP-induced aggregation (p < 0.001), 69 +/- 5% versus 46 +/- 9% for P2Y12 reactivity ratio (p = 0.03), and 138 +/- 19 mean fluorescence intensity (MFI) versus 42 +/- 4 MFI for stimulated GP IIb/IIIa expression (p < 0.001). Of patients with SAT, 60% had high platelet reactivity. CONCLUSIONS: High post-treatment platelet reactivity and incomplete P2Y12 receptor inhibition are risk factors for SAT. Measures to uniformly determine platelet reactivity after coronary stenting and treatment strategies to improve P2Y12 receptor inhibition in patients with high post-treatment platelet reactivity should be further investigated.
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Elsevier’s Scopus, the largest abstract and citation database of peer-reviewed literature. Search and access research from the science, technology, medicine, social sciences and arts and humanities fields.
[本文引用:1]
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Summary.68 Low response to antiplatelet therapy may be a risk factor for the development of ischemic complications in patients with non-ST segment elevation acute coronary syndrome (NSTE ACS) undergoing coronary stenting. We prospectively studied the platelet response to both clopidogrel and aspirin in 106 NSTE ACS consecutive patients undergoing percutaneous coronary intervention (PCI) with stenting. A single post-treatment blood sample was obtained just before PCI and analyzed by platelet aggregometry using both ADP and arachidonic acid (AA) as agonists to explore the responses to clopidogrel and aspirin, respectively. Patients were divided into quartiles according to the ADP or AA induced maximal intensity of platelet aggregation. Patients of the highest quartile (quartile 4) were defined as the ‘low-responders’. Twelve recurrent cardiovascular (CV) events occurred during the 1-month follow-up. Clinical outcome was significantly associated with platelet response to clopidogrel [Quartile 4 vs. 1, 2, 3: OR (95% CI) 22.4 (4.6–109)]. Low platelet response to aspirin was significantly correlated with clopidogrel low response (65= 0.003) but contributed less to CV events [OR (95%CI): 5.76 (1.54–35.61)]. A post-treatment ADP-induced platelet aggregation performed just before PCI identifies low responders to dual antiplatelet therapy with an increased risk of recurrent CV events.
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| [35] |
Abstract BACKGROUND: Clopidogrel and aspirin are the most commonly used antiplatelet therapies for percutaneous coronary intervention (PCI). We assessed the effect of various clopidogrel and aspirin regimens in prevention of major cardiovascular events and stent thrombosis in patients undergoing PCI. METHODS: The CURRENT-OASIS 7 trial was undertaken in 597 centres in 39 countries. 25,086 individuals with acute coronary syndromes and intended early PCI were randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel, and high-dose (300-325 mg daily) versus low-dose (75-100 mg daily) aspirin. Randomisation was done with a 24 h computerised central automated voice response system. The clopidogrel dose comparison was double-blind and the aspirin dose comparison was open label with blinded assessment of outcomes. This prespecified analysis is of the 17,263 individuals who underwent PCI. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Analyses were by intention to treat, adjusted for propensity to undergo PCI. This trial is registered with ClinicalTrials.gov, number NCT00335452 . FINDINGS: 8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel (8558 and 8702 completed 30-day follow-up, respectively), and 8624 to high-dose and 8639 to low-dose aspirin (8622 and 8638 completed 30-day follow-up, respectively). Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events [3·9%] vs 392 events [4·5%]; adjusted hazard ratio 0·86, 95% CI 0·74-0·99, p=0·039) and definite stent thrombosis (58 [0·7%] vs 111 [1·3%]; 0·54 [0·39-0·74], p=0·0001). High-dose and low-dose aspirin did not differ for the primary outcome (356 [4·1%] vs 366 [4·2%]; 0·98, 0·84-1·13, p=0·76). Major bleeding was more common with double-dose than with standard-dose clopidogrel (139 [1·6%] vs 99 [1·1%]; 1·41, 1·09-1·83, p=0·009) and did not differ between high-dose and low-dose aspirin (128 [1·5%] vs 110 [1·3%]; 1·18, 0·92-1·53, p=0·20). INTERPRETATION: In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI. FUNDING: Sanofi-Aventis and Bristol-Myers Squibb. Copyright 08 2010 Elsevier Ltd. All rights reserved.
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| [36] |
High platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after percutaneous coronary intervention (PCI), but a treatment strategy for this issue is not well defined.To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI.Randomized, double-blind, active-control trial (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety [GRAVITAS]) of 2214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents at 83 centers in North America between July 2008 and April 2010.High-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for 6 months.The primary end point was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety end point was severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition. A key pharmacodynamic end point was the rate of persistently high on-treatment reactivity at 30 days.At 6 months, the primary end point had occurred in 25 of 1109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.58-1.76; P = .97). Severe or moderate bleeding was not increased with the high-dose regimen (15 [1.4%] vs 25 [2.3%], HR, 0.59; 95% CI, 0.31-1.11; P = .10). Compared with standard-dose clopidogrel, high-dose clopidogrel provided a 22% (95% CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30 days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P < .001).Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis.clinicaltrials.gov Identifier: NCT00645918.
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| [37] |
Stent thrombosis remains a significant pitfall of percutaneous coronary intervention (). A recent trial observed that an adjusted loading dose (LD) of according to platelet monitoring decreases the rate of major adverse cardiovascular events after . We investigated if such a strategy of a tailored LD according to platelet reactivity monitoring could decrease the rate of stent thrombosis. This multicenter prospective randomized study included 429 patients with a low response after a 600-mg LD undergoing . Patients were randomized to a control group (n = 214) and to a ()-guided group (n = 215). In the -guided group, patients received up to 3 additional 600-mg LDs of to obtain a index <50% before . The primary end point was the rate of stent thrombosis at 1 month. Secondary end points were rates of major adverse cardiovascular events and bleeding. Patients in the 2 groups had a high body mass index and were often diabetic (control vs -guided group 28 +/- 5.1 vs 27.9 +/- 4.7 kg/m(2), p = 0.8, and 39% vs 33%, p = 0.2, respectively). was performed in most patients for in the 2 groups (52.3% vs 50.7%, p = 0.8). Despite a 2,400-mg LD of , 8% of patients in the -guided group remained low responders. The rate of stent thrombosis was significantly lower in the -guided group (0.5% vs 4.2%, p <0.01). The rate of major adverse cardiovascular events was also higher in the control group (8.9% vs 0.5%, p <0.001). There was no difference in the rate of bleeding (2.8% vs 3.7%, p = 0.8). In conclusion, a tailored LD according to platelet reactivity monitoring decreases the rate of early stent thrombosis after without increasing bleeding.
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| [38] |
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| [39] |
We aimed to investigate the biological impact of a tailored clopidogrel loading dose (LD) according to platelet reactivity monitoring in carriers of the cytochrome (CYP) 2C19*2 loss-of-function polymorphism undergoing percutaneous coronary intervention for an acute coronary syndromes.CYP2C19*2 polymorphism is associated with reduced clopidogrel metabolism and a worse prognosis after percutaneous coronary intervention.A prospective multicenter study enrolling 411 patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention was performed. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index, and a cutoff value of 鈮 50% was used to define high on-treatment platelet reactivity (HTPR). The genetic polymorphism of CYP2C19 was determined by allele-specific polymerase chain reaction. In patients carrying CYP2C19*2 and exhibiting HTPR after a first 600-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 600 mg LDs to obtain a VASP index <50%.One hundred thirty-four patients (35.3%) carried at least one 2C19*2 allele (11 homozygotes [2.7%] and 123 heterozygotes [32.6%]). The VASP index in these patients was significantly higher than in homozygotic patients for the wild-type alleles (61.7 卤 18.4% vs. 49.2 卤 24.2%; p < 0.001). Of the 134 carriers of the loss-of-function polymorphism, 103 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (69.7 卤 10.1% vs. 50.6 卤 17.6%; p < 0.0001). Finally, dose adjustment according to platelet reactivity monitoring, enabled 88% of 2C19*2 carriers exhibiting HTPR to reach a VASP index <50%.Increased and tailored clopidogrel loading dose according to platelet reactivity monitoring overcome HTPR in carriers of the loss-of-function CYP2C19*2 polymorphism.
[本文引用:1]
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| [40] |
The () 2C19*2 loss-of-function allele has been associated with impaired response and worse prognosis in -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 genotypes in patients identified as nonresponders who underwent percutaneous coronary intervention for non-ST-segment elevation . 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. response, assessed with platelet reactivity index vasoactive-stimulated , was significantly affected by genotype, with lower response in *2 allele carriers (p = 0.01). Accordingly, the rate of nonresponse was higher in *2 allele carriers (53% vs 41%, p = 0.04). All nonresponders (n = 151), including 105 *2 noncarriers and 46 *2 carriers, received high 150-mg maintenance doses at discharge to overcome initial low response. After 1 month, high maintenance doses overcame 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 maintenance doses were able to overcome low response in fewer than half of low responders who underwent percutaneous coronary intervention for non-ST-segment elevation . The benefit of this tailored therapy was significantly reduced in *2 carriers. Therefore, these patients might require alternative strategies with new 鈧佲倐 blockers.
[本文引用:1]
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| [41] |
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| [42] |
This study was designed to compare the degree of inhibition of platelet aggregation (IPA) of prasugrel with that of clopidogrel in stable aspirin-treated patients with coronary artery disease (CAD).Subjects (n=101) were randomly assigned to the following loading dose (LD) (day 1)/maintenance dose (MD) (days 2-28) combinations: prasugrel, 40 mg/5 mg; 40 mg/7.5 mg; 60 mg/10 mg; 60 mg/15 mg; or clopidogrel, 300 mg/75 mg. Turbidometric platelet aggregation was measured at multiple timepoints during the study. At 4 h after dosing, with 20 microM ADP, both prasugrel LDs achieved significantly higher mean IPA levels (60.6% and 68.4 vs. 30.0%, respectively; all P<0.0001) and lower percentage (3 vs. 52%, P<0.0001) of pharmacodynamic non-responders (defined as IPA <20%) than clopidogrel. Prasugrel 10 and 15 mg MDs achieved consistently higher mean IPA than clopidogrel 75 mg at day 28 (all P<0.0001). At pre-MD on day 28, there were no non-responders in the 10 and 15 mg prasugrel group, compared with 45% in the clopidogrel group (P=0.0007).In this population, prasugrel (40-60 mg LD and 10-15 mg MD) achieves greater IPA and a lower proportion of pharmacodynamic non-responders compared with the approved clopidogrel dosing.
[本文引用:1]
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| [43] |
Abstract BACKGROUND: Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. METHODS AND RESULTS: In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 micromol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks (P50% IPA (98% versus 31%, P70% IPA (90% versus 16%, P<0.0001) in the ticagrelor group than in the clopidogrel group, respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72-hour slope [% IPA/h] -1.04 versus -0.48, P<0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel (P=NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo (P=NS). CONCLUSIONS: Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00528411 .
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| [44] |
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