氯吡格雷药物基因组学及个体化治疗研究进展与展望

通过与阿司匹林联合应用,氯吡格雷已经成为治疗急性冠脉综合征和预防经皮冠状动脉介入术后支架内血栓形成和再发缺血事件的经典口服抗血小板药物。尽管如此,氯吡格雷抗血小板的反应性和疗效存在显著的个体间差异。近年来的研究证实,除临床环境因素外,遗传变异是导致氯吡格雷抗血小板反应性个体间差异的重要因素之一。多项大规模临床药物基因组学研究发现,参与氯吡格雷代谢的关键酶—CYP2C19功能缺失型等位基因与氯吡格雷治疗期间高血小板反应性及心血管一级缺血终点事件的发生密切相关。另外,与氯吡格雷代谢相关的其他基因变异型也被证实可能与氯吡格雷抗血小板反应性及不良心血管事件相关。在此基础上,利用药物基因组学基因型检测指导氯吡格雷个体化抗血小板治疗,可能部分克服氯吡格雷治疗期间的高血小板反应性,但研究结果之间仍存在争议,尚需深入研究以提供更有力的证据。除此之外,未来有必要进一步深入研究基因型检测联合血小板功能监测共同指导氯吡格雷抗血小板个体化治疗的效果。     

他汀类药物对氯吡格雷抵抗的影响

双联抗血小板治疗被广泛应用于冠状动脉疾病的治疗,尤其是急性冠状动脉综合征(ACS)或经皮冠状动脉介入治疗(PCI)术后患者。其中一部分应用氯吡格雷治疗患者由于对氯吡格雷反应性差而未达到很好的治疗效果,这就是"氯吡格雷抵抗"现象。近年通过对不同他汀类药物种类、药物剂量、联用时其他因素的干扰等研究表明,他汀类药物直接独立影响个体对氯吡格雷抗血小板的反应证据不足,但这些研究为进一步研究氯吡格雷抵抗机制及明确他汀类药物与氯吡格雷相互作用提供依据,从而指导临床医师及时调整抗血小板治疗患者的用药方案,以避免恶性血栓栓塞事件发生,本文综述了他汀类药物与氯吡格雷的相互作用。     

冠心病患者氯吡格雷低反应性的研究进展

氯吡格雷是临床常用的抗血小板药物,但近年来的研究发现,部分患者存在氯吡格雷低反应性,也就是氯吡格雷抵抗或氯吡格雷无反应性,即描述服用氯吡格雷而不能提供充分抗血小板作用的一种现象。氯吡格雷低反应者血小板聚集率高,易发生心血管事件。现对目前有关氯吡格雷低反应性的定义、可能发生的机制和解决方法进行综述。     

术前抗血小板药物应用策略对冠状动脉旁路移植术的影响

<正>目前,广泛应用的抗血小板药物包括阿司匹林和氯吡格雷,新型抗血小板药物如普拉格雷、替格雷洛和坎格雷洛等正处于临床研究试用阶段。已证实阿司匹林等抗血小板药物可以降低冠状动脉旁路移植手术(CABG)的病死率和缺血事件发生率。急性冠状动脉综合征(ACS)的指南和最新研究提示,阿司匹林和氯吡格雷联合治疗可以降低心血管事     

经皮冠状动脉介入术后抗血小板个体化治疗研究进展

氯吡格雷抵抗是目前心血管疾病领域的研究热点,它与经皮冠状动脉介入术后出现主要心脏不良事件密切相关。氯吡格雷抵抗主要与基因多态性及药物之间的相互作用有关。临床上通过基因检测采取个体化抗血小板治疗:调整氯吡格雷剂量或换用新型抗血小板药物(替格瑞洛、普拉格雷等)。现就抗血小板药物个体化治疗在预防经皮冠状动脉介入术后主要心脏不良事件中的研究进展做一综述。     

氯吡格雷抵抗的药物基因组学研究进展

目前,氯吡格雷联合阿司匹林双重抗血小板是治疗急性冠状动脉综合征和经皮冠状动脉介入术后抗栓的基础药物。然而,氯吡格雷抗血小板作用的反应存在个体差异,氯吡格雷抵抗现象日益受到关注。但氯吡格雷抵抗的机制仍不完全清楚,明确抵抗的原因和机制将使冠状动脉疾病患者受益匪浅。现就氯吡格雷抵抗的定义、检测方法、可能机制及药物基因组学进行综述。     

氯吡格雷治疗后血小板高反应性研究现状

<正>氯吡格雷是目前冠状动脉支架术后抗血小板治疗的基石,在美国食品与药物管理局(FDA)批准普拉格雷之前,氯吡格雷是惟一被指南推荐使用的噻吩吡啶类抗血小板药物。然而,即使接受足量、长期的氯吡格雷治疗,部分患者仍有心脑血管血栓事件发生,谓之"氯吡格雷抵抗"。氯吡格雷抵抗     

氯吡格雷抗血栓以外的作用研究进展

<正>氯吡格雷是动脉粥样硬化性疾病的基础治疗药物之一,用于心肌梗死和缺血性脑卒中的二级预防、冠状动脉支架置入术后心血管事件预防及急性冠状动脉综合征(ACS)的治疗。氯吡格雷与血小板表面P2Y12受体不可逆结合,阻断二磷酸腺苷介导的血小板膜糖蛋白Ⅱb/Ⅲa的激活,进而抑制血小板聚集。随着研究的深入,发现除抗血栓作用以外,氯吡格雷可能还有抗炎、抗动脉粥样硬化、内皮保护和抗血管生成等方面的作用,我们拟对氯吡格雷在抗血栓以外的药理作用研究进展进行综述。氯吡格雷与炎症动脉粥样硬化性血栓是ACS、短暂性脑缺血发作和急     

氯吡格雷抵抗研究现状

氯吡格雷对血小板的抑制作用具有个体差异性。氯吡格雷抵抗是指那些接受了标准的抗血小板治疗的病人仍然发生不良的心血管事件。导致氯吡格雷抵抗的原因是多方面的,主要有P2Y12受体及CYP3A的基因多态性、药物吸收及活性代谢物清除的个体差异、血小板高反应性等。目前对氯吡格雷抵抗仍然缺乏统一的标准,正确认识、发现、解决氯吡格雷抵抗需要更深入的研究。     

择期经皮冠状动脉介入治疗患者抗血小板策略新证据——CREATIVE研究解读

正经皮冠状动脉介入治疗(PCI)后使用双联抗血小板(DAPT)药物是当前所有指南推荐用于预防血栓事件的标准治疗方案~([1-3])。在稳定性和不稳定性心绞痛患者人群中,使用氯吡格雷有着更多的临床证据,在临床实践中是国人主要使用的P2Y12受体拮抗剂。但氯吡格雷低反应性又是临床实践中需要面临的棘手问题,加倍剂量的氯吡格雷或新一代抗血小板药物中的P2Y12受体拮抗剂包括替格瑞洛、普拉格雷以及静脉制剂坎格雷洛,     

氯吡格雷抵抗的临床研究进展

氯吡格雷是一种抗血小板药物,是新型二磷酸腺苷受体拮抗剂,已广泛应用于各种血栓性疾病尤其是急性冠脉综合征和经皮冠状动脉介入治疗术后的抗血栓治疗。但近年来,在长期随访中研究发现,部分患者存在氯吡格雷抵抗现象,即应用氯吡格雷治疗的患者仍会发生心血管血栓事件。本文就氯吡格雷的作用机制、氯吡格雷抵抗定义、氯吡格雷抵抗韵发生机制及临床意义等作一综述。     

Antiplatelet drug response variability and the role of platelet function testing: A practical guide for interventional cardiologists

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome and is also of particular importance in those who undergo percutaneous coronary intervention with stent implantation. Dual antiplatelet therapy with aspirin and clopidogrel is associated with improvement in long‐term clinical outcomes in such patients and is presently the antiplatelet therapy of choice for secondary prevention of thrombotic events. However, a significant number of patients experience recurrent events despite antiplatelet therapy. Although poor patient compliance can account for some of these events, particularly in those patients who receive a drug‐eluting stent, increasing evidence indicates that there is variability in response to antiplatelet therapy and patients who have higher levels of platelet reactivity are at increased risk for recurrent ischemic events. However, the lack of a consistent definition of inadequate platelet response, as well as the lack of a standardized measurement technique, has made it difficult to define how to treat these patients. To translate findings associated with variability in platelet response into improved patient care, it is necessary to gain a better understanding of what variable platelet response is, how it is measured, who it should be measured in, and what its clinical relevance is. The objective of this review is to evaluate the data regarding interindividual response variability to antiplatelet therapy with the aim of providing practical considerations and where possible, recommendations, regarding this topic for interventional cardiologists. © 2008 Wiley‐Liss, Inc.     

心房颤动合并冠状动脉支架置入术患者的联合抗栓优化策略

心房颤动患者合并冠状动脉支架置入术后应接受口服抗凝药和双联抗血小板药的三联抗栓治疗。然而,华法林联合阿司匹林和氯吡格雷的三联抗栓治疗出血风险高,哪种联合方式更加安全有效便成为抗栓治疗优化策略的关注焦点。现就心房颤动合并冠状动脉支架置入术患者的各种联合抗栓治疗方案的有效性及安全性综述如下。     

Poor responsiveness to antiplatelet drugs in acute coronary syndromes: clinical relevance and management

Cardiovascular diseases are the most common cause of mortality and morbidity in Western countries, accounting for more than 40% of total mortality. An optimal pharmacological management in these patients is of major importance and antiplatelet agents remain the cornerstone of acute coronary syndrome (ACS) therapy at hospital admission and during percutaneous coronary interventions (PCI). The recently described poor biological responses to aspirin and clopidogrel have been source of major concern, especially in era of drug eluting stent implantation. Indeed, insufficient platelet inhibition at the time of PCI has been consistently associated with an increased risk of complications and recurrence of ischemic events. Despite the lack of uniformly accepted definitions of aspirin and clopidogrel poor response, we sought to describe the current evidence and gaps in knowledge. While trials on the potential benefit of an increased antiplatelet maintenance dose after PCI have shown only marginal benefits, the strengthening of the initial antiplatelet regimens by additional loading doses of clopidogrel, by the administration of glycoprotein IIb/IIIa receptor inhibitors or phosphodiesterase inhibitors might further improve outcomes during ACS and PCI in patients with poor responsiveness to conventional dual antiplatelet therapy. Overall, tailoring the antiplatelet treatment on the basis of the individual biological response improves the short-term outcome after PCI. New and more potent antiplatelet drugs may overcome the clinical consequences of the poor response to antiplatelet agents.     

Percutaneous coronary intervention with stent implantation in haemophilic A patient with unstable angina

The prevalence of coronary artery disease (CAD) and acute coronary syndromes in patients with haemophilia is much lower than in general population and there is a lack of information regarding safe interventional or surgical treatment of CAD in haemophiliacs. This report presents a case of patient with moderate haemophilia A and unstable angina pectoris, who underwent successful coronary angioplasty. The patient was pretreated with factor VIII (before and after the procedure) and the incision site was sealed with vessel closure device. Additionally, the article discusses the issue of the safety of standard, postpercutaneous coronary intervention antiplatelet therapy in patients with haemophilia.     

Effectiveness and safety of combined antiplatelet and anticoagulant therapy: a critical review of the evidence from randomized controlled trials

Antiplatelet and anticoagulant drugs are effective for the prevention of arterial and venous thrombosis but patients continue to experience major cardiovascular events despite their use. Strategies to improve the effectiveness of antithrombotic therapies include selecting the optimal drug and dosing regimen, the use of combinations of antiplatelet and anticoagulant drugs and the development of new more effective drugs to replace existing therapies. Evidence from randomized controlled trials indicates that the combination of aspirin and an anticoagulant is more effective than aspirin alone for the prevention of recurrent cardiovascular events in patients with acute coronary syndrome and is more effective than anticoagulation alone for the prevention of thromboembolic events in patients with mechanical heart valves, but at a cost of increased bleeding. Randomized controlled trials provide no evidence for improved effectiveness of combination therapy compared with antiplatelet therapy alone for the prevention of recurrent cardiovascular events in patients with non-cardioembolic stroke or peripheral artery disease, or compared with anticoagulant therapy alone for the prevention of stroke in patients with atrial fibrillation. Despite lack of evaluation in randomized controlled trials, combination therapy is commonly used in patients with separate indications for antiplatelet therapy (e.g., acute coronary syndrome, recent coronary artery stent) and anticoagulant therapy (e.g., atrial fibrillation with at least one additional risk factor for stroke). Randomized trials are urgently required to evaluate the effectiveness and safety of combining antiplatelet and anticoagulant therapy in these settings.     

普拉格雷在冠心病介入治疗中的研究进展

口服双重抗血小板药物阿司匹林加噻吩吡啶,已获准在经皮冠状动脉介入治疗（PCI）中使用。第二代噻吩吡啶类衍生物氯吡格雷是给予PCI患者双重抗血小板治疗的选择性药物。但是,氯吡格雷存在两个缺陷:①氯吡格雷需要代谢产生其活性的形式,故抗血小板活性延迟;②已证明不同患者给予氯吡格雷后的反应存在很大差异性。为了克服氯吡格雷的上述缺陷,新一代更有效的普拉格雷（即第三代噻吩吡啶类衍生物）,临床评价其可以快速起效。本文对第三代口服噻吩吡啶普拉格雷进行了综述,旨在总结普拉格雷的利弊并概述该药在临床使用中最谨慎的方案。     

Coronary stenting in stable patients: identification of a low-risk subgroup that may not require adjunctive antiplatelet therapy.

The present study prospectively evaluated adjunctive antiplatelet therapy in patients without insulin-requiring diabetes during elective coronary stenting. Three hundred patients were randomized to one of three treatment groups: clopidogrel pretreatment, adjunctive abciximab, or control. Stenting was successful in 98% and no deaths occurred. Thirty-day and 1-year major adverse coronary events (MACEs) was similar in all groups. A subgroup of 109 patients undergoing single-vessel stenting of type A/B1 lesions with short guidewire times had no postprocedure myocardial infarction or 30-day MACE. We conclude that patients with these characteristics may safely undergo elective coronary stenting without adjunctive antiplatelet therapy.     

Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent?

AIMS: To identify factors associated with the use of single or dual antiplatelet therapy in patients prescribed warfarin following coronary stenting and to investigate whether single (aspirin or thienopyridine) vs. dual antiplatelet therapy plus warfarin leads to an excess of adverse outcomes. METHODS AND RESULTS: We analysed data from 800 patients with an acute coronary syndrome who underwent coronary stenting (130 patients received a drug-eluting stent) and were discharged on warfarin and either dual (n = 580) or single (n = 220) antiplatelet therapy. The use of single antiplatelet therapy was more common in Europe than in the USA (34 vs. 17%, P < 0.001). There was no difference in major bleeding in hospital or in 6-month mortality or myocardial infarction. In the single antiplatelet group, the use of either aspirin or thienopyridine (clopidogrel or ticlopidine) in combination with warfarin resulted in similar outcomes. CONCLUSION: Use of single vs. dual antiplatelet therapy and warfarin following stenting is common. In this observational study, there was no difference in mortality or myocardial infarction at 6 months; however, larger trials are needed to assert any firm recommendations.     

CYP2C19基因型与经皮冠状动脉介入术后心肌损伤和远期主要不良心血管事件的研究进展

经皮冠状动脉介入(PCI)术后患者建议使用双联抗血小板治疗以降低主要不良心血管事件(MACE)的发生风险,但在临床实践过程中,仍有部分患者没有达到预期疗效,出现氯吡格雷抵抗,严重影响患者预后。因此CYP2C19基因型与PCI术后心肌损伤以及远期MACE的关系值得我们进一步探讨,本文将对以上问题作一综述。