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。     

氯吡格雷抵抗的影响因素

氯吡格雷和阿司匹林联合应用已经成为急性冠状动脉综合征(ACS)及经皮冠状动脉介入(PCI)术后患者的标准治疗方案,可显著降低死亡或心血管事件的发生率。部分患者尽管长期服用常规剂量的氯吡格雷(300mg负荷量,维持量75mg/d),但临床上仍未能有效地防止血栓事件的发生,且血小板功能检测证实血小板聚集不能被有效抑制,这种现象称为氯吡格雷抵抗。氯吡格雷抵抗反映氯吡格雷抗血小板治疗失败。研究表明,氯吡格雷抵抗可能与血栓事件的复发密切相关,并受基因和非基因因素的影响。     

质子泵抑制剂与氯吡格雷相互作用的临床研究及防治策略

目前氯吡格雷与阿司匹林的双联抗血小板治疗方案正被广泛应用于急性冠脉综合征或接受经皮冠状动脉介入术后的患者。同时,质子泵抑制剂(PPI)则被推荐用来降低抗血小板药物引起的消化道并发症。但部分药效学及临床研究发现,PPI可能减弱了氯吡格雷的临床药效,增加了心血管不良事件的风险。此文就PPI与氯吡格雷的代谢途径,两者可能存在的相互作用以及防治策略作一综述。     

质子泵抑制剂对氯吡格雷抗血小板作用影响研究进展

<正> 氯吡格雷具有选择性拮抗二磷酸腺苷诱导的血小板聚集作用和抗栓作用,单独使用即可有效预防动脉粥样硬化患者缺血性事件的发生。目前研究认为,各种急性冠状动脉综合征(ACS)患者和所有接受经皮冠状动脉介入治疗(PCI)的患者均应给予阿司匹林和氯吡格雷联合治疗,且后者应于术后双重抗血小板治疗至少1年。在心血管获益的同时,氯     

氯吡格雷抵抗——不可忽视的临床问题

众所周知,在急性冠状动脉综合征(ACS)的发病机制和经皮冠状动脉介入治疗(PCI)术中及术后血栓形成的并发症中,血小板的聚集和激活起着举足轻重的作用[1]。因此,抗血小板治疗已成为ACS及PCI术后的常规疗法,其中阿司匹林及氯吡格雷则是最常用的药物。关于阿司匹林抵抗的报道较早,一些试验已经证实其发生与部分冠心病(CAD)患者接受PCI治疗后再发心血管不良事件相关[2]。最近研究表明,在服用常规剂量氯吡格雷的患者中,约有4%~30%的患者对氯吡格雷无反应或未达到预期的抗血小板作用[3-6]。有专家认为这一现象与接受抗血小板治疗的患者再发…     

氯吡格雷反应性的研究进展

对于急性冠状动脉综合征和经皮冠状动脉介入治疗患者,氯吡格雷联合阿司匹林的双联抗血小板治疗已成为药物治疗的核心手段。然而,越来越多的证据显示不同生物个体之间存在抗血小板治疗反应的多样性;特别是氯吡格雷低反应性,与临床上反复缺血、脑卒中、支架内血栓形成等不良事件相关;机制尚未完全阐明,涉及遗传、代谢、基因多态性、药物相互作用等方面。现就氯吡格雷反应性的研究进展做一综述。     

延长氯吡格雷联合阿司匹林治疗冠心病合并糖尿病PCI术后的疗效及安全性观察

目的分析延长氯吡格雷联合阿司匹林治疗冠心病合并糖尿病经皮冠状动脉介入术(PCI)后的临床疗效及安全性。方法收集2013年6月—2015年6月成功行PCI置入药物洗脱支架(DES)治疗的冠心病合并糖尿病病人78例,将78例病人分为延长DAPT组(试验组,34例)和对照组(44例)。对照组接受经皮冠状动脉介入术后给予氯吡格雷+阿司匹林抗血小板治疗,1年后停用氯吡格雷,单用阿司匹林;试验组接受经皮冠状动脉介入术后给予氯吡格雷+阿司匹林治疗,1年后再继续接受18个月氯吡格雷治疗,观察随访时间2年,记录主要不良心血管事件,包括死亡、非致命心肌梗死、靶器官重建率(TVR)和支架内再狭窄(ST),主要不良事件包括出血以及脑梗死。结果试验组不良事件发生率为17.6%,低于对照组的31.8%,差异有统计学意义(P0.05),两组间轻微出血发生率比较差异无统计学意义。结论延长氯吡格雷、阿司匹林用于经皮冠状动脉介入术后冠心病合并糖尿病病人,可降低不良事件发生率,且不增加出血事件,安全性良好。     

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。     

双联抗血小板治疗并高危消化道出血的临床用药

急性冠脉综合征（ACS）及经皮冠状动脉介入术（PCI）后患者应用双联抗血小板（阿司匹林＋氯吡格雷）要优于单一抗血小板药物治疗。但随着阿司匹林及氯毗格雷为代表的抗血小板药物在冠状动脉疾病中的广泛应用,与该类药物相关的胃肠道损伤亦随之备受关注。     

氯吡格雷抵抗相关机制的研究现状

抗血小板药物是治疗急性冠状动脉综合征(acute coro-nary syndrome,ACS)和经皮冠状动脉介入术(PCI)后抗栓的基础药物.目前,氯吡格雷联合阿司匹林已经成为PCI术后预防支架内血栓形成的标准抗血小板方案.然而,大量体外实验证实个体对氯吡格雷的反应存在差异性.部分患者尽管长期服用常规剂量的氯吡格雷,但临床上仍不能有效地防止血栓事件的发生,且血小板功能检测证实血小板聚集不能被有效抑制.400037 重庆市,第三军医大学附属新桥医院全军心血管病研究所     

Secondary stroke prevention with antiplatelet therapy with emphasis on the cardiac patient: a neurologist's view

The prevention of secondary vascular events is of paramount importance in patients with a history of stroke or transient ischemic attack (TIA). Most cardiologists are aware of the benefits of clopidogrel plus aspirin versus those of other antiplatelet regimens in patients with acute coronary syndrome. Using a representative post-stroke patient as an example, this article reviews data evaluating the effectiveness of antiplatelet regimens in preventing secondary vascular events in stroke and TIA patients. These results differ from those seen in clinical trials of acute coronary syndrome patients. Clinical studies provide little evidence that clopidogrel, with or without aspirin, is more efficacious in this setting than aspirin alone. Moreover, the increased risk of bleeding episodes with clopidogrel and aspirin in combination probably outweighs any small reductions in secondary event risk. In contrast, extended-release dipyridamole (ER-DP) plus aspirin reduces secondary stroke risk to a significantly greater extent (23% relative risk reduction) than aspirin alone. Currently available clinical trial data support the use of ER-DP plus aspirin, but not clopidogrel plus aspirin, to prevent secondary vascular events after stroke or TIA.     

Influence of Platelet Reactivity on Clinical Outcome of Patients with Stable Coronary Artery Disease

Single antiplatelet therapy with aspirin is actually recommended for cardiovascular prevention in patients with stable coronary disease, whereas dual antiplatelet therapy (aspirin and clopidogrel) represents the established treatment in patients with acute coronary syndromes or stable angina undergoing percutaneous coronary intervention. However, recurrent ischemic events occur in patients on treatment with clopidogrel; this may be due to low responsiveness to this agent, a phenomenon influenced by environmental, clinical, and genetic factors. Different strategies have been tested to overcome this phenomenon, such as increase in clopidogrel loading and maintenance doses and use of newer P2Y12 inhibitors (prasugrel and ticagrelor), which are by now indicated for patients with acute coronary syndromes; the latter agents have been associated with stronger antiplatelet effect than clopidogrel even in patients with stable coronary disease, but further studies are needed to test their net clinical benefit in this setting (reduction of ischemic events without increase in bleeding).     

Antiplatelet agents in acute coronary syndromes

Plaque disruption, platelet activation, and intracoronary artery thrombus formation are the key events in the pathogenesis of acute coronary syndromes. Antiplatelet therapies significantly reduce the risk of ischemic complications both during the acute phase and in the long term in patients with acute coronary syndromes. Aspirin remains the cornerstone of antiplatelet therapy, but there is incremental benefit when clopidogrel or ticlopidine is added to aspirin. Dual antiplatelet therapy with the combination of clopidogrel and aspirin is becoming the new standard of care for the management of patients with non-ST-segment elevation acute coronary syndrome and undergoing percutaneous coronary intervention and is currently being further evaluated in ST-segment elevation acute coronary syndrome.     

Optimal duration of dual antiplatelet therapy post percutaneous coronary intervention in acute coronary syndrome

Dual antiplatelet therapy (DAPT), with aspirin plus a P2Y12 inhibitor agent, is the cornerstone treatment after percutaneous coronary intervention for acute coronary syndrome. Based on randomized clinical trial using aspirin and clopidogrel, a DAPT duration of 12 months has been recommended after an acute coronary syndrome. Despite the development of more potent antiplatelet agents (i.e. prasugrel and ticagrelor) and the reduction in ischemic recurrences after acute coronary syndrome, 12 months DAPT currently remains the gold standard. However, a significant proportion of patients experience recurrent ischemic events beyond the first 12 months after an acute coronary syndrome. Meanwhile, with more effective antiplatelet agent, bleeding has become a major safety concern on DAPT. Therefore, the ischemic and bleeding risk balance is central considering the duration of DAPT after an acute coronary syndrome. This review aims to report the evidence for an optimization and individualization of DAPT duration after an acute coronary syndrome.     

Clinical and prognostic implications of the initial response to aspirin in patients with acute coronary syndrome

Increased platelet reactivity and decreased response to antiplatelet drugs may result in recurrent ischemic events after acute coronary syndrome (ACS). We evaluated laboratory response to aspirin in patients with ACS before and after percutaneous coronary intervention (PCI) and assessed its effect on major adverse clinical events. Sixty-three consecutive patients with ACS were tested for response to aspirin by light transmittance aggregometry (LTA) and the IMPACT-R test (with arachidonic acid) before and 2 to 4 days after PCI and clopidogrel loading. Patients were followed for clinical events up to 15 months from PCI. Response to aspirin improved significantly after PCI and clopidogrel treatment (mean arachidonic acid-induced LTA decreased from 34.9 ± 3.35% before PCI to 15.2 ± 2.2% and surface coverage increased from 2.2 ± 0.27% to 6.2 ± 0.6%, p <0.0001 for the 2 methods). Improved response to aspirin after PCI correlated with response to clopidogrel (LTA and IMPACT-R, p <0.01). Patients with good laboratory response to aspirin before but not after PCI had a significantly lower major cardiovascular event rate during 15-month follow-up in multivariate analysis. In conclusion, laboratory response to aspirin is highly dynamic in patients with ACS. Improved response to aspirin after PCI may result from stabilization of coronary artery disease and/or clopidogrel treatment. Laboratory response to aspirin before PCI and clopidogrel loading is a sensitive marker for platelet reactivity that correlates with clinical outcome in patients with ACS.     

Clinical evidence of interaction between clopidogrel and proton pump inhibitors

Clopidogrel is approved for reduction of atherothrombotic events in patients with cardiovascular(CV)and cerebrovascular disease.Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after acute coronary syndrome or percutaneous coronary intervention,compared with aspirin alone.Due to concern about gastrointestinal bleeding in patients who are receiving clopidogrel and aspirin therapy,current guidelines recommend combined use of a proton pump inhibitor(PPI)to decrease the risk of bleeding.Data from previous pharmacological studies have shown that PPIs,which are extensively metabolized by the cytochrome system,may decrease the ADP-induced platelet aggregation of clopidogrel. Results from retrospective cohort studies have shown a higher incidence of major CV events in patients re-ceiving both clopidogrel and PPIs than in those without PPIs.However,other retrospective analyses of randomized clinical trials have not shown that the concomitant PPI administration is associated with increased CV events among clopidogrel users.These controversial results suggest that large specific studies are needed. This article reviews the metabolism of clopidogrel and PPIs,existing clinical data regarding the interaction between clopidogrel and PPIs,and tries to provide recommendations for health care professionals.     

Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives.

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions. Clopidogrel, in combination with aspirin, is currently the antiplatelet treatment of choice for prevention of stent thrombosis, and clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major cardiovascular events. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. Numerous in vitro studies have shown that individual responsiveness to clopidogrel is not uniform in all patients and is subject to inter- and intraindividual variability. Notably, there is a growing degree of evidence that recurrence of ischemic complications may be attributed to poor response to clopidogrel. The mechanisms leading to poor clopidogrel effects are not fully elucidated and are likely multifactorial. Although the gold standard definition to assess antiplatelet drug response has not been fully established, there is sufficient evidence to support that persistence of enhanced platelet reactivity despite the use of clopidogrel is a clinically relevant entity. This paper reviews the impact of individual response variability to clopidogrel on clinical outcomes and current and future directions for its management.     

Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions. Clopidogrel, in combination with aspirin, is currently the antiplatelet treatment of choice for prevention of stent thrombosis, and clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major cardiovascular events. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. Numerous in vitro studies have shown that individual responsiveness to clopidogrel is not uniform in all patients and is subject to inter- and intraindividual variability. Notably, there is a growing degree of evidence that recurrence of ischemic complications may be attributed to poor response to clopidogrel. The mechanisms leading to poor clopidogrel effects are not fully elucidated and are likely multifactorial. Although the gold standard definition to assess antiplatelet drug response has not been fully established, there is sufficient evidence to support that persistence of enhanced platelet reactivity despite the use of clopidogrel is a clinically relevant entity. This paper reviews the impact of individual response variability to clopidogrel on clinical outcomes and current and future directions for its management.     

急性冠脉综合征患者介入治疗早期增加阿司匹林和氯吡格雷剂量对主要不良心血管事件的影响

目的:观察急性冠脉综合征（ACS）患者经皮冠状动脉介入治疗（PCI）早期不同剂量阿司匹林、氯吡格雷对主要不良心血管事件（MACE）的影响。方法: 选择2007年12月～2009年12月ACS行PCI术的患者102例,所有患者按入院先后随机分为两组,1组为加量组（n=54）,患者入院后阿司匹林300 mg顿服,然后300 mg,每日1次,口服1个月后改为100 mg,每日1次,长期口服;氯吡格雷150 mg ,每日1次,1周后改为75 mg,每日1次,口服1年。另1组为对照组（n=48）,患者入院后阿司匹林100 mg,每日1次,以后长期按此剂量口服。氯吡格雷75 mg,每日1次,口服1年。两组患者其他治疗低分子肝素等方法相同。分别于PCI术后1个月、6个月时比较MACE的发生情况。结果: 两组患者临床基线特征基本一致,病变血管分布情况差异无统计学意义。其MACE发生情况在第一个月时,加量组低于对照组,但差异未到达显著水平（7% vs.15%）;在第6个月时,加量组低于对照组,差异具有统计学意义（2% vs. 17%,P<0.05）。结论: ACS患者在一般治疗的基础上,介入治疗时早期增加阿司匹林、氯吡格雷的剂量可降低PCI术后MACE的发生率。     

Optimal management of platelet function after coronary stenting

Opinion statement Coronary stenting elicits vessel wall damage, and subsequent activation of platelets is implicated as a major component of complications such as acute, subacute, and late stent thrombosis. As such, dual antiplatelet therapy using aspirin and clopidogrel has become a routine adjunct to coronary stenting. Use of aspirin and clopidogrel with or without glycoprotein IIb/IIIa inhibitors after coronary stenting reduces the complication rate and improves long-term outcomes. Dual antiplatelet therapy using aspirin and clopidogrel is recommended for at least 4 weeks with bare metal stents, and for 3 to 6 months with drug-eluting stents for prevention of major adverse cardiac events. After coronary stenting, 1 year of dual antiplatelet therapy is recommended for prevention of future cardiac events. However, despite the use of antiplatelet agents, stent thrombosis occurs in approximately 1% of patients, with an increased likelihood of occurrence in high-risk patients or a lesion subset of patients. Although the incidence of stent thrombosis is low, stent thrombosis usually presents as acute coronary syndrome and the mortality rate is up to 45%. Thus, considering the widespread use of stents, a considerable number of people are inadequately protected from thrombotic events despite current standard antiplatelet therapy using aspirin and clopidogrel. A concern with clopidogrel is the loading time and loading dose required to achieve and maintain optimal inhibition of platelet aggregation. The current recommendation for ensuring maximum antiplatelet activity is administration of a 300-mg loading dose of clopidogrel initiated at least 6 hours prior to percutaneous coronary intervention (PCI), and ideally the day before. If this is not possible, a loading dose of 600 mg of clopidogrel should be administered at least 2 hours before PCI. Recently, new combinations of antiplatelet agents (ie, triple therapy using aspirin, clopidogrel, and cilostazol) and new drugs with potent antiplatelet effects (ie, Prasugrel [currently being developed by Sankyo Pharmaceuticals and Ube Pharmaceuticals in Japan and by Eli Lilly and Co. (Indianapolis, IN) in the United States], Cangrelor [currently being developed by AstraZeneca Pharmaceuticals, Wilmington, DE], and AZD6140) have been evaluated in clinical trials; such treatments may help reduce the number of cardiac events after coronary stenting.