氯吡格雷抵抗

氯吡格雷是临床常用的抗血小板药物,现发现部分患者存在氯吡格雷抵抗,笔者对氯吡格雷抵抗的定义、发生率及可能发生的机制进行分析,探讨氯吡格雷抵抗的检测和解决方法,为临床识别和预防氯吡格雷抵抗提供参考.     

氯毗格雷抵抗

氯吡格雷是，临床常用的抗血小板药物，现发现部分患者存在氯吡格雷抵抗，笔者对氯吡格雷抵抗的定义、发生率及可能发生的机制进行分析，探讨氯吡格雷抵抗的检测和解决方法，为临床识别和预防氯吡格雷抵抗提供参考。     

卒中患者氯吡格雷抵抗临床检测研究进展

<正>氯吡格雷抵抗是缺血性卒中复发的主要原因之一,通过实验室检测可发现患者是否存在氯吡格雷抵抗,通过患者的血小板功能检测、基因多态性分析等能筛查氯吡格雷干预后血小板活性,并明确氯吡格雷抵抗机制,进一步为卒中患者的二级预防提供临床指导,本文对氯吡格雷抵抗实验室检测方法研究进展进行综述,以期对缺血性事件复发风险及个体化治疗提供依据。     

冠心病患者CYP2C19基因多态性及临床不良事件发生与氯吡格雷抵抗的关系

目的通过分析经皮冠状动脉介入治疗(PCI)术后冠心病患者的CYP2C19基因型结果、临床相关危险因素和主要心血管不良事件发生情况与氯吡格雷抵抗的关系,探讨影响氯吡格雷抵抗发生、发展的因素,为临床治疗提供有效依据。方法收集2017年1月至2018年12月该院收治并进行过基因检测的346例冠心病患者资料,分析其CYP2C19基因型和代谢型分布特征,筛选出251例使用氯吡格雷的PCI术后冠心病患者,进行血小板聚集功能试验检测,根据血小板最大聚集率(MAR)分为氯吡格雷敏感组(MAR<50%)和氯吡格雷抵抗组(MAR≥50%)。利用荧光PCR法进行CYP2C19基因多态性检测,根据基因型结果分为快代谢型(*1/*1)、中代谢型(*1/*2、*1/*3)和慢代谢型(*2/*2、*2/*3、*3/*3)。比较氯吡格雷抵抗组与氯吡格雷敏感组不同代谢型的患者比例、相关危险因素情况及临床心血管不良事件发生情况。结果慢代谢型患者的MAR较中代谢型、快代谢型患者高,差异均有统计学意义(P<0.05)。入选的251例患者中,氯吡格雷抵抗组CYP2C19代谢型分别为快代谢型38例(34.5%)、中代谢型57例(51.8%)、慢代谢型15例(13.6%),氯吡格雷抵抗组与氯吡格雷敏感组在快代谢型中的患者比例差异有统计学意义(P<0.05)。氯吡格雷抵抗组的高血压患者比例(91.8%)与氯吡格雷敏感组(63.8%)比较,差异有统计学意义(P<0.05)。氯吡格雷抵抗组临床心血管不良事件发生率(94.5%)高于氯吡格雷敏感组(84.4%),差异有统计学意义(P <0.05)。结论CYP2C19基因突变和高血压可能是氯吡格雷抵抗发生的两个重要影响因素,并且氯吡格雷抵抗增加了PCI术后冠心病患者临床心血管不良事件发生的风险。     

脑卒中患者CYP2C19基因多态性与氯吡格雷临床疗效研究

目的:探讨武汉地区部分脑卒中患者氯吡格雷代谢相关CYP2C19基因多态性与氯吡格雷临床疗效的关系。方法:选取武汉大学人民医院神经内科收治的脑卒中患者292例,采用光比浊法检测患者服用氯吡格雷前后的血小板聚集率,计算其血小板抑制率;采用基因芯片法测定患者的CYP2C19基因(*1,*2和*3),并将患者按照基因检测结果分为不同代谢类型:快代谢型(*1/*1),中间代谢型(*1/*2和*1/*3)及慢代谢型(*2/*2,*2/*3和*3/*3)。采用统计学方法分析CYP2C19不同代谢类型患者血小板抑制率的差异。结果:根据CYP2C19基因多态性位点进行代谢分型,快代谢型占37.33%,中间代谢型占46.92%,慢代谢型占15.75%。3种代谢类型患者服用氯吡格雷前后的血小板抑制率分别为(54.39±18.93)%,(30.02±21.53)%及(10.34±3.83)%,3种代谢型患者之间血小板抑制率比较均有统计学意义,其中快代谢型患者显著高于中间代谢型和慢代谢型患者(P<0.05)。结论:脑卒中患者中CYP2C19*2、*3基因变异者使用氯吡格雷抗凝的疗效较差,测定CYP2C19基因型对于脑卒中患者使用氯吡格雷治疗可能具有重要的指导意义。     

光学比浊法与血栓弹力图法评价氯吡格雷疗效的一致性研究及氯吡格雷抵抗相关风险因素分析

目的以血栓弹力图法(TEG)为比对方法,研究光学比浊法(LTA)检测血小板聚集率在氯吡格雷疗效评价方面的作用,观察二者是否具有良好的一致性,并根据LTA检测结果,对影响氯吡格雷疗效的可能风险因素进行评估。方法收集2018年11月至2019年5月于北京天坛医院就诊的患者67例,均服用氯吡格雷(波立维)抗血小板药物治疗,分别采用TEG及LTA检测血小板功能,评价两种方法的一致性,并对相关参数进行相关分析。根据LTA检测结果将患者划分为氯吡格雷抵抗组和氯吡格雷非抵抗组,比较两组患者的临床资料及实验室指标,并采用Logistic回归分析氯吡格雷抵抗可能的风险因素。结果 LTA及TEG在评价血小板功能方面具有良好的一致性(P0.05),且LTA检测的由ADP诱导的血小板最大聚集率(PAg-ADP%)与TEG检测的血小板聚集抑制率(ADP%)存在直线相关关系(r=-0.493,P=0.000)。与氯吡格雷非抵抗组比较,氯吡格雷抵抗患者年龄更大,平均血小板体积(MPV)较大,差异有统计学意义(P0.05)。多元Logistic回归分析显示年龄(OR=1.106,95%CI 1.038～1.178,P=0.002)、MPV(OR=1.968,95%CI 1.079～3.588,P=0.027)构成氯吡格雷抵抗的独立风险因素。结论 LTA可作为早期评价氯吡格雷疗效的有效可靠的检测方法。高龄、高水平MPV构成氯吡格雷抵抗的独立风险因素。     

氯吡格雷抵抗的研究进展

氯吡格雷是临床上广泛使用的抗血小板药物,在长期临床应用中发现,部分使用氯吡格雷治疗的患者仍会有血栓性血管事件的发生,即氯吡格雷抵抗现象。氯吡格雷抵抗受多方面因素的影响,其确切机制尚未明确。现就有关氯吡格雷抵抗的研究进行综述。     

阿司匹林、氯吡格雷抵抗相关基因多态性及其与复发性脑梗死的关系

目的 观察阿司匹林与氯吡格雷抵抗相关基因的多态性,探究其与复发性脑梗死的关系。方法 选取2019年4月至2020年12月我院神经内科收治的脑梗死患者98例,回顾性分析脑梗死患者阿司匹林及氯吡格雷抵抗相关基因多态性与性别、复发性脑梗死的关系。结果 在脑梗死患者中,阿司匹林重度抵抗型患者在规范抗血小板治疗情况下较敏感型患者更容易出现复发性脑梗死(P<0.05);阿司匹林中/重度抵抗型合并氯吡格雷中/慢代谢型患者比阿司匹林敏感型和(或)氯吡格雷快代谢型患者更容易出现复发性脑梗死(P<0.05);不同氯吡格雷药物相关基因表型复发性脑梗死占比差异无统计学意义(P>0.05);不同性别阿司匹林、氯吡格雷抵抗相关基因型分布差异无统计学意义(P>0.05)。结论 治疗脑梗死时进行阿司匹林、氯吡格雷抵抗相关基因型检测十分重要,需要根据检测结果,适当调整治疗方案,以期提高脑梗死治疗效果。     

CYP2C19基因多态性与冠心病患者氯吡格雷疗效的相关性研究

目的对CYP2C19基因多态性与冠心病患者氯吡格雷疗效的相关性进行分析探讨,为今后的临床工作,提供有价值的参考信息。方法选取2015年1月至2016年1月该院收治的,拟接受经皮冠状动脉介入术(PCI)进行治疗的冠心病患者128例作为研究对象,对其均开展氯吡格雷治疗,负荷剂量为300mg,维持剂量为75mg,将受试者分成氯吡格雷抵抗组与反应组,对比两组患者药物代谢CYP2C19基因型,观察CYP2C19基因型对氯吡格雷反应性的影响。结果该组受试者中,氯吡格雷抵抗者27例,检出CYP2C19慢代谢基因型携带者共计16例,慢代谢基因型患者VASP-PRI与快代谢基因型、中间代谢基因型患者比较,差异有统计学意义(P0.05);氯吡格雷抵抗组与氯吡格雷反应组临床不良终点事件发生率比较差异有统计学意义(P0.05)。结论氯吡格雷抵抗的危险因素中,包括CYP2C19慢代谢基因型,氯吡格雷抵抗会使临床不良终点事件发生风险增加,临床应对其给予足够的重视。     

大剂量氯吡格雷治疗进展性脑卒中40例临床疗效及护理

目的:探讨大剂量氯吡格雷治疗进展性脑卒中患者的临床疗效及护理干预。方法:将80例脑卒中患者随机分为观察组和对照组各40例,对照组首次采用常规剂量的氯吡格雷治疗,观察组首次采用大剂量氯吡格雷治疗,两组给予相同的护理方法,比较两组治疗效果。结果:观察组治疗后神经功能及生活能力评分均优于对照组(P0.05)。结论:首次使用大剂量氯吡格雷治疗进展性脑卒中患者,能显著提高临床疗效,同时实施有效的护理措施对提高患者的生活质量具有重要意义。     

Clopidogrel use in coronary artery disease

Platelet adhesion, activation and aggregation are central to the pathophysiology of the acute coronary syndromes. Clopidogrel, an oral thienopyridine derivative, is a platelet adenosine diphosphate receptor antagonist capable of inhibiting platelet activation. During the last decade, the utility of clopidogrel has been evaluated in several common clinical scenarios in a large number of patients. The benefits of clopidogrel in patients with stable coronary artery disease undergoing elective percutaneous coronary interventions and in patients presenting with acute coronary syndromes are now well established. This review outlines the pharmacology of clopidogrel, highlights the results of clopidogrel trials in the setting of acute coronary syndromes, and presents areas of uncertainty and potential future work.     

Clopidogrel use in coronary artery disease

Platelet adhesion, activation and aggregation are central to the pathophysiology of the acute coronary syndromes. Clopidogrel, an oral thienopyridine derivative, is a platelet adenosine diphosphate receptor antagonist capable of inhibiting platelet activation. During the last decade, the utility of clopidogrel has been evaluated in several common clinical scenarios in a large number of patients. The benefits of clopidogrel in patients with stable coronary artery disease undergoing elective percutaneous coronary interventions and in patients presenting with acute coronary syndromes are now well established. This review outlines the pharmacology of clopidogrel, highlights the results of clopidogrel trials in the setting of acute coronary syndromes, and presents areas of uncertainty and potential future work.     

Clopidogrel in acute coronary syndrome: implications of recent study findings

The platelet ADP receptor antagonist clopidogrel is recommended for the treatment of patients with acute coronary syndrome and/or percutaneous coronary intervention. Patients who received a coronary stent in particular should be protected by sufficient antiplatelet therapy to prevent stent thrombosis. Clopidogrel is a prodrug and has to undergo extensive metabolization before the active metabolite can irreversibly bind to platelets. This makes clopidogrel treatment susceptible to genetic and drug interactions. Recent study findings suggest that initial treatment with a higher dose of clopidogrel may be superior to the currently approved dose. It is not clear whether this approach will be sufficient to entirely overcome clopidogrel hyporesponsiveness, which worsens outcomes in up to one-third of patients. Newer antiplatelet agents are emerging but clopidogrel remains the best established treatment option, with more than 120,000 patients treated in randomized trials and 12 years of clinical postmarketing experience.     

Differential effects of esomeprazole on the antiplatelet activity of clopidogrel in healthy individuals and patients after coronary stent implantation

Clopidogrel plus aspirin is a standard antiplatelet aggregation regimen in cardiovascular diseases, especially after implantation of a coronary stent. Interaction between clopidogrel and proton pump inhibitors theoretically reduces clopidogrel's antiaggregation effect, but the evidence is controversial. A total of 30 healthy subjects and 74 patients with a coronary stent were given a 300 mg loading dose of aspirin and 300 mg clopidogrel and then 100 mg aspirin/75 mg clopidogrel daily for 14 days. Subgroups were concomitantly treated or not treated with esomeprazole (20 mg/day). Clopidogrel significantly reduced adenosine diphosphate-induced platelet aggregation in healthy and stent-implanted subjects on days 7 and 14. Healthy subjects receiving esomeprazole showed a significantly higher platelet aggregation rate than those not receiving esomeprazole, but esomeprazole had no effect in patients with a stent. Aspirin plus clopidogrel did not result in significant gastrointestinal complications. These differential effects of esomeprazole on the antiplatelet activity of clopidogrel in healthy individuals and patients after coronary stent implantation merit further investigation.     

Antiplatelet therapy in acute coronary syndromes: the emergency physician's perspective

The platelet plays a central role in the pathogenesis of coronary thrombosis after atherosclerotic plaque rupture, and its active inhibition forms a cornerstone of the management of acute coronary syndromes (ACS). Early treatment with clopidogrel in addition to aspirin is more effective than aspirin alone in reducing recurrent ischemic events in patients presenting with ACS, and is a useful adjunct to percutaneous coronary intervention, especially with stenting. There is a potential for increased bleeding complications in patients on clopidogrel therapy who subsequently undergo urgent coronary artery bypass graft surgery. Consequently, many emergency physicians withhold clopidogrel treatment until it is clear that urgent coronary artery bypass graft surgery will not be required. The potential untoward effects seem to be minimized by withholding antiplatelet therapy 3-5 days before surgery. Intravenous glycoprotein (GP) IIb/IIIa receptors inhibitors are also particularly useful in patients who undergo percutaneous coronary intervention, and may have some utility in the medical management of patients with high-risk non-ST-segment elevation ACS, starting in the emergency department. For patients presenting to the emergency department with ACS, the benefits and risks of initiating clopidogrel or GP IIb/IIIa inhibitor therapy need to be considered on an individual basis.     

Prasugrel: Clinical development and therapeutic application

Dual antiplatelet therapy with aspirin and clopidogrel is a cornerstone of the management of patients with acute coronary syndromes and following percutaneous coronary intervention. Despite the proven benefits, clear limitations of clopidogrel exist. Prasugrel is a third-generation thienopyridine antiplatelet agent with pharmacologic characteristics that overcome some of the limitations of clopidogrel, but at the expense of increased bleeding. The promising results seen with prasugrel in large, randomized trials led to its recent approval by the US Food and Drug Administration for reducing thrombotic cardiovascular events in patients with acute coronary syndromes managed with percutaneous coronary intervention. This article will review the limitations of standard antiplatelet therapy and discuss the clinical application of prasugrel.     

Clopidogrel and proton pump inhibitors: is there a significant drug-drug interaction?

Dual antiplatelet therapy with aspirin and clopidogrel is among the most efficacious treatment for patients after acute coronary syndromes and for those who have had a percutaneous coronary intervention and coronary stent implantation. Patients who are treated with dual antiplatelet therapy are usually also ordered medications that reduce the secretion of gastric acid (such as H2 receptor blockers or proton pump inhibitors [PPIs]) in order to decrease the risk of gastrointestinal bleeding and dyspepsia. Numerous observational studies reported that omeprazole (a PPI) attenuates the antiplatelet activity and clinical effectiveness of clopidogrel and causes adverse cardiovascular events. Based on these findings, several medical agencies in the world have issued communications regarding the negative interaction between clopidogrel and PPIs, urging clinicians to evaluate the need for starting treatment with a PPI in patients taking clopidogrel. There are studies that reported contradicting findings, suggesting that there is no significant interaction between clopidogrel and PPIs. Only one prospective, randomized, double-blind, placebo-controlled clinical trial examined the interaction between clopidogrel and omeprazole and did not demonstrate cardiovascular harm among the patients who were treated with clopidogrel and omeprazole, as compared to those who were treated with clopidogrel and placebo. In this article, the authors review the current studies that reported a possible drug-drug interaction between clopidogrel and PPIs, particularly omeprazole.     

氯吡格雷在冠心病患者中对阿托伐他汀降脂的影响

目的：研究氯吡格雷在冠心痛中对不同剂量阿托伐他汀降低血脂幅度方面的影响。方法：126位冠心痛患者，入院后随机服用阿托伐他汀10mg／d和20mg／d，其中入院后行PCI治疗者同时服用氯吡格雷，稳定型心绞痛未行PCI治疗者不服用氯吡格雷，按服用阿托伐他汀剂量和氯吡格雷分为四组，A组为阿托伐他汀10mg／d＋氯吡格雷，共43例，B组为阿托伐他汀20mg／d＋氯吡格雷，共29例，C组为单用阿托伐他汀10mg／d，共37例，D组为单用阿托伐他汀20mg／d，共17例，分别在入院24h内和服用氯吡格雷后1个月测定患者血脂，比较A组和C组，B组和D组患者血脂变化幅度。结果：治疗1个月后A组和C组、B组和D组血脂，包括总胆固醇，甘油三脂，LDL-C，HDL-C，ApoA。ApoB，Lpa下降幅度差异无统计学意义（P〉0．05）。结论：治疗1个月后氯吡格雷对阿托伐他汀在降脂方面的作用无影响。     

CYP2C19基因多态性与氯吡格雷抵抗的研究进展

阿司匹林联合氯吡格雷是冠状动脉支架植入术后常规的抗血小板治疗方案。然而,近年来的研究显示接受上述治疗的部分患者血小板的抑制率较低,即氯吡格雷抵抗,与冠脉支架植入术后支架内血栓事件的发生存在因果关系。而导致氯吡格雷抵抗的原因复杂,研究表明CYP2C19基因多态性与其明显相关,对高危人群进行CYP2C19基因多态性检测有利于识别氯吡格雷抵抗,并及时增加氯吡格雷剂量或更换新型血小板P2Y12受体拮抗剂,可降低术后支架内血栓的发生。     

Clopidogrel use in coronary heart disease and percutaneous coronary intervention.

Antiplatelet therapy has proven efficacy in the management of atherothrombosis. Clopidogrel, a thienopyridine, is a potent antiplatelet agent that achieves its antiplatelet effects by inhibiting the binding of adenosine 5' diphosphate to its platelet receptor. Large clinical trials have demonstrated a role for clopidogrel in the management of symptomatic atherosclerosis, acute coronary syndromes, and patients undergoing percutaneous coronary intervention. In this review, we discuss the pharmacology of clopidogrel including the mechanism of action, review the major clinical trials that have defined the current role of clopidogrel in coronary heart disease and percutaneous coronary intervention, and, finally, examine the concept of clopidogrel resistance and its potential clinical implications.