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。     

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。     

Clinical, biochemical and genetical resistance to clopidogrel in a patient with the recurrent coronary stent thrombosis--a case report and review of the literature

The in-stent thrombosis is considered as a serious complication of percutaneous coronary intervention. The impaired response to the antiplatelet therapy may play an important role in this crucial problem. Recurrent thrombosis can be explained by genetic background. Because the phenomenon of clopidogrel resistance is associated with an increased risk of recurrent cardiovascular events, genetic variants of a platelet receptor P2Y(12) might be the risk factor. Although there is no test recommended to assess the response to the antiplatelet therapy, the presented case suggests platelet function analysis should be undertaken in patients with recurrent stent thrombosis.     

Optimizing antiplatelet therapy in acute coronary syndrome and percutaneous coronary intervention

Dual antiplatelet therapy with aspirin and clopidogrel is the standard of care for patients with acute coronary syndrome (ACS) and those undergoing percutaneous coronary intervention (PCI). It is well established that inhibition of platelet aggregation reduces the risk of recurrent thrombotic events and stent thrombosis. However, some patients show a reduced antiplatelet response to standard clopidogrel loading (300 mg) and maintenance (75 mg day^?1) doses, which has been associated with poorer patient outcomes. Pharmacodynamic and pharmacokinetic studies show that higher‐than‐standard clopidogrel dosing strategies facilitate more rapid platelet inhibition of a greater intensity as a result of greater plasma concentrations of the clopidogrel active metabolite. Recently completed studies suggest that in patients with ACS undergoing PCI, higher‐than‐standard clopidogrel dosing regimens provide greater inhibition of platelet function and improved clinical outcomes with a small but significant increase in major bleeding. Newer, more potent antiplatelet agents such as prasugrel and ticagrelor are other alternative strategies that result in more rapid, greater inhibition of platelet function and better outcomes than standard‐dose clopidogrel. Whether platelet reactivity‐guided therapy or genotyping for cytochrome P450 polymorphisms is useful in managing patients needs to be further defined. Most importantly, early and effective antiplatelet therapy results in the best short‐ and long‐term outcomes for patients with ACS or those undergoing PCI. © 2011 Wiley‐Liss, Inc.     

Clinical importance of aspirin and clopidogrel resistance

Aspirin and clopidogrel are important components of medical therapy for patients with acute coronary syndromes, for those who received coronary artery stents and in the secondary prevention of ischaemic stroke. Despite their use, a significant number of patients experience recurrent adverse ischaemic events. Interindividual variability of platelet aggregation in response to these antiplatelet agents may be an explanation for some of these recurrent events, and small trials have linked "aspirin and/or clopidogrel resistance", as measured by platelet function tests, to adverse events. We systematically reviewed all available evidence on the prevalence of aspirin/clopidogrel resistance, their possible risk factors and their association with clinical outcomes. We also identified articles showing possible treatments. After analyzing the data on different laboratory methods, we found that aspirin/clopidogrel resistance seems to be associated with poor clinical outcomes and there is currently no standardized or widely accepted definition of clopidogrel resistance. Therefore, we conclude that specific treatment recommendations are not established for patients who exhibit high platelet reactivity during aspirin/clopidogrel therapy or who have poor platelet inhibition by clopidogrel.     

Switching antiplatelet regimens: Alternatives to clopidogrel in patients with acute coronary syndrome undergoing PCI: A review of the literature and practical considerations for the interventional cardiologist

Dual antiplatelet therapy with aspirin plus a P2Y₁₂ receptor inhibitor is the cornerstone of treatment for patients with acute coronary syndrome and in those undergoing percutaneous coronary intervention. Clopidogrel is the most widely used P2Y₁₂ receptor inhibitor. Despite the clinical benefits associated with adjunctive clopidogrel therapy, a considerable number of patients continue to experience recurrent cardiovascular events. Importantly, the interindividual response to clopidogrel is variable and is affected by multiple factors, including genetic polymorphisms and drugs that interfere with the conversion of clopidogrel to its active metabolite. The individual variability to clopidogrel‐induced antiplatelet effects has significant clinical implications that can result in an increased risk of atherothrombotic recurrences, including stent thrombosis. The introduction of novel P2Y₁₂ receptor inhibitors, such as prasugrel or ticagrelor, characterized by more potent and consistent platelet inhibitory effects, represents an opportunity for clinicians to consider these alternative therapies to overcome the limitations of clopidogrel. Understanding the strategies and implications of switching antiplatelet treatment regimens is, therefore, key in the clinical setting. This article provides an overview of the literature on switching antiplatelet treatment strategies and practical considerations for the interventional cardiologist. © 2012 Wiley Periodicals, Inc.     

The use of the VerifyNow system to monitor antiplatelet therapy: a review of the current evidence

Multiple studies have demonstrated the effectiveness of dual or triple antiplatelet therapy with aspirin, clopidogrel and glycoprotein (GP) IIb/IIIa therapy in patients with acute coronary syndromes as well as in patients undergoing coronary stent implantation. In the last few years, it is becoming clear that not all patients receive the full benefits with the current standard dosages of antiplatelet therapy. Specifically, numerous studies have revealed a wide interindividual variability in the response to these antiplatelet agents and, more importantly, both nonresponsiveness as well as a heightened residual platelet reactivity have been linked to the occurrence of adverse cardiovascular events. Therefore, assays that identify those patients with an impaired responsiveness or a heightened platelet reactivity despite dual antiplatelet therapy may contribute to better risk stratification and will probably improve clinical outcome when appropriate action is initiated. Likewise, a considerable number of patients do not achieve the minimal inhibition of aggregation threshold with the current recommended weight-adjusted dosages of GP IIb/IIIa therapy. Identifying and optimizing the absolute degree of platelet inhibition in this subgroup of patients will probably improve clinical outcome. The VerifyNow platform is one of the most user friendly point-of-care platelet function test systems because it produces rapid results at the patient bedside. The purpose of the present paper is to give insight into the principal mechanisms of the VerifyNow system, to discuss its clinical utility for the monitoring of antiplatelet therapy and to discuss the proposed cut-off levels to segregate responders from non-responders for the different types of antiplatelet therapy.     

Antiplatelet drug therapy: role of pharmacodynamic and genetic testing

Antiplatelet therapy represents the cornerstone of treatment for the short- and long-term prevention of atherothrombotic disease processes, in particular in high-risk settings such as in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Currently, dual antiplatelet therapy with aspirin and clopidogrel represents the most commonly used treatment regimen in these settings. However, a considerable number of patients continue to experience adverse outcomes, including both bleeding and recurrent ischemic events. Numerous investigations have demonstrated that this phenomenon may be, in part, attributed to the broad variability in individual response profiles to this standard antiplatelet treatment regimen, as identified by various assays of platelet function testing. In addition, recent studies have demonstrated that genetic polymorphisms may also have an important role in determining levels of platelet inhibition and may be considered as a tool to identify patients at risk of adverse events. This article provides an overview on antiplatelet drug response variability, an update on definitions, including the role of pharmacodynamic testing, underlying mechanisms - with emphasis on recent understandings on pharmacogenetics and drug-drug interactions - and current and future perspectives on individualized antiplatelet therapy.     

The use of the VerifyNow system to monitor antiplatelet therapy: A review of the current evidence

Multiple studies have demonstrated the effectiveness of dual or triple antiplatelet therapy with aspirin, clopidogrel and glycoprotein (GP) IIb/IIIa therapy in patients with acute coronary syndromes as well as in patients undergoing coronary stent implantation. In the last few years, it is becoming clear that not all patients receive the full benefits with the current standard dosages of antiplatelet therapy. Specifically, numerous studies have revealed a wide interindividual variability in the response to these antiplatelet agents and, more importantly, both nonresponsiveness as well as a heightened residual platelet reactivity have been linked to the occurrence of adverse cardiovascular events. Therefore, assays that identify those patients with an impaired responsiveness or a heightened platelet reactivity despite dual antiplatelet therapy may contribute to better risk stratification and will probably improve clinical outcome when appropriate action is initiated. Likewise, a considerable number of patients do not achieve the minimal inhibition of aggregation threshold with the current recommended weight-adjusted dosages of GP IIb/IIIa therapy. Identifying and optimizing the absolute degree of platelet inhibition in this subgroup of patients will probably improve clinical outcome. The VerifyNow platform is one of the most user friendly point-of-care platelet function test systems because it produces rapid results at the patient bedside. The purpose of the present paper is to give insight into the principal mechanisms of the VerifyNow system, to discuss its clinical utility for the monitoring of antiplatelet therapy and to discuss the proposed cut-off levels to segregate responders from non-responders for the different types of antiplatelet therapy.     

Platelet function monitoring in patients on clopidogrel: What should we learn from GRAVITAS?

Combined inhibition of platelet aggregation is essential to prevent recurrent ischemic episodes in patients with acute coronary syndromes and after percutaneous coronary interventions (PCIs). In combination with aspirin, the ADP receptor antagonist clopidogrel is used widespread for this purpose; however, platelet reactivity after clopidogrel differs substantially between patients and high on-treatment platelet reactivity (HTPR) persists in a substantial proportion of cases. Since more than 20 prior observational studies linked HTPR to higher risk of ischemic events, including cardiovascular death, myocardial infarction, and stent thrombosis, monitoring post-clopidogrel platelet reactivity after PCI might be beneficial for risk assessment and to tailor the antiplatelet therapy to the patients' needs. However, there is no consensus on the role of routine platelet function monitoring in clinical guidelines. This article aims to review the available evidence regarding the clinical relevance of platelet function monitoring, highlighting possible reasons for the controversy between guidelines and observational studies.     

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.     

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.     

The Problem of Persistent Platelet Activation in Acute Coronary Syndromes and Following Percutaneous Coronary Intervention

Platelets play a central role in the atherosclerotic inflammatory response, thrombotic vascular occlusion, microembolization, vasoconstriction, and plaque progression. Persistent platelet activation poses a serious problem among patients with acute coronary syndromes (ACS) and those who have undergone percutaneous coronary intervention (PCI), placing them at risk for ischemic events and subacute stent thrombosis. Patients undergoing PCI are at risk for further ischemic events because of procedure‐related platelet activation as well as the inherent persistent platelet hyperreactivity and enhanced thrombin generation associated with ACS. Persistent platelet activation following an acute coronary event and/or PCI supports incorporating antiplatelet strategies into the standard medical management of such patients. In this clinical setting, antiplatelet therapies are capable of improving outcomes. Aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors, the 3 major pharmacologic approaches to persistent platelet activation, target various levels of the hemostatic pathways and thrombus formation. Copyright © 2008 Wiley Periodicals, Inc.     

Personalizing antiplatelet therapies: What have we learned from recent trials?

Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is currently the standard of care for the prevention of ischemic events in patients with acute coronary syndrome or undergoing percutaneous coronary intervention. Several studies have shown that not all patients benefit from the treatment to the same degree and demonstrated that high on-treatment platelet reactivity may be associated with an increased risk of thrombotic events, while low on-treatment platelet reactivity may be linked to a higher risk of bleeding. Personalized antiplatelet treatment strategies based on platelet function monitoring and genetic testing constitute a promising tool for the prevention of both stent thrombosis and bleeding events, but conclusive evidence that such approaches can improve clinical outcomes is lacking. This review presents the most recent studies on tailored antiplatelet therapy in the management of coronary heart disease, with a focus on the prognosis value of platelet function testing.     

The Assessment of the Platelet Function During the Acute Phase of ST-segment Elevation Myocardial Infarction in Essential Thrombocythemia

We encountered a case of ST-segment elevation myocardial infarction (STEMI) as the first clinical manifestation of essential thrombocythemia (ET). Platelet function tests revealed high thrombogenicity during primary percutaneous coronary intervention compared with general cardiovascular patients, whereas the platelet function two weeks after admission was effectively suppressed by dual antiplatelet therapy. The patient, who lacked cytoreduction, suffered from recurrent STEMI because of poor compliance with antiplatelet drugs. The risk of acute coronary occlusion may be high during the acute phase of STEMI in ET patients because of high thrombogenicity. Insufficient antiplatelet therapy and no cytoreduction are also risk factors for recurrent coronary events.     

Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?

OBJECTIVES: We sought to determine whether patients receiving chronic clopidogrel therapy undergoing nonemergent stenting who display high on-treatment preprocedural platelet aggregation measured by standard light transmittance aggregometry and thrombelastography (TEG) will be at increased risk for poststenting ischemic events. BACKGROUND: Patients exhibiting heightened platelet reactivity to adenosine diphosphate (ADP) might be at increased risk for recurrent ischemic events after coronary stenting. METHODS: A total of 100 consecutive patients receiving chronic antiplatelet therapy consisting of aspirin (325 mg qd) and clopidogrel (75 mg qd) were studied before undergoing nonemergent stenting. Patients were followed for 1 year after coronary stenting for the occurrence of death, myocardial infarction, stent thrombosis, stroke, or ischemia requiring a hospital stay. RESULTS: All patients were aspirin responsive. Patients with ischemic events (23 of 100, 23%) within 1 year had greater on-treatment prestent ADP-induced platelet aggregation than patients without ischemic events by aggregometry and TEG (p < 0.001 for both measurements). Of patients with an ischemic event, 70% and 87% displayed high on-treatment platelet reactivity at baseline by aggregometry and TEG, respectively. High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables significantly related to ischemic events (p < 0.001 for both assays). The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with no significant differences in bleeding events. CONCLUSIONS: Patients receiving chronic clopidogrel therapy undergoing nonemergent percutaneous coronary intervention who exhibit high on-treatment ADP-induced platelet aggregation are at increased risk for postprocedural ischemic events. These findings might have implications for the alteration in clopidogrel maintenance dose and use of glycoprotein IIb/IIIa inhibitors in selected patients.     

Is There a Role for Platelet Function Testing for Patients on Chronic Dual Antiplatelet Therapy?

Antiplatelet therapy is one on the cornerstones in managing patients with coronary artery disease who have undergone percutaneous interventions. Aspirin plus a thienopyridine (ticlopidine, clopidogrel, prasugrel) are the components of dual antiplatelet therapy (DAPT). Clopidogrel remains the primary thienopyridine in use. There is a significant amount of heterogeneity in patients’ response to the drug, both pharmacologically and clinically. It is apparent that those with high residual platelet reactivity on therapy are at an increased risk for future cardiovascular events. Therefore, platelet function testing makes sense and should be done routinely in patients on DAPT. These data provide physicians with an ability to adjust or change the antiplatelet therapy in response to the residual platelet reactivity. Options include increasing the dose of the present drug or changing to an alternative. The recent evidence regarding these data is reviewed in this article.     

不同的质子泵抑制剂与氯吡格雷相互作用的研究进展

大量研究表明阿司匹林和氯吡格雷联合抗血小板可以降低急性冠状动脉综合征及冠状动脉支架植入术后复发心血管事件的概率。但由于联合抗血小板治疗会增加出血的风险,所以目前临床推荐加用质子泵抑制剂以预防胃肠道溃疡和出血。氯吡格雷和质子泵抑制剂均通过细胞色素P450同工酶系统代谢,质子泵抑制剂通过竞争性抑制细胞色素P450同工酶CYP2C19,而降低氯吡格雷的抗血小板活性,增加复发心血管事件的概率。最近的研究发现不同的质子泵抑制剂影响程度不同,泮托拉唑和埃索美拉唑对氯吡格雷作用影响较小,而奥美拉唑、雷贝拉唑和兰索拉唑对氯吡格雷的抗血小板活性抑制作用较大。     

Genetic determinants of responsiveness to antiplatelet therapy

Antiplatelet drugs are well-established therapies for acute coronary syndromes and for the primary and secondary prevention of coronary artery disease, stroke, and peripheral vascular disease. However, wide interindividual variability exists in the degree of platelet suppression among patients treated with antiplatelet drugs, and many individuals develop atherothrombotic events while on therapy. Although many potential mechanisms may contribute to the response variation observed, there is accumulating evidence that polymorphisms of genes from multiple biologic pathways involved in platelet activation are at least partly responsible for variable platelet responsiveness and potentially responsible for clinical failure of antiplatelet therapy.