The thienopyridines

Platelet adhesion, activation, and aggregation are key processes in the pathogenesis of coronary disease. Inhibition of these processes forms the cornerstone of therapy for coronary artery disease and particularly of acute coronary syndromes (ACS). Aspirin was the only available antiplatelet therapy for over 100 years, and it improves clinical outcome in a wide range of clinical situations. However, aspirin only inhibits platelet activation mediated by thromboxane A2, allowing platelet activation to occur through innumerable other pathways. As a result, adverse ischemic events are common when aspirin alone is used for the treatment of coronary disease, including ACS, during coronary interventions (particularly during stent implantation), and following coronary vascular brachytherapy (VBT). In these clinical situations, the presence of either thrombus, deep injury to the vessel wall, or delayed vascular reendothelialization leads to intense and often prolonged platelet activation, overwhelming the relatively weak effects of aspirin. The development of the thienopyridines, a class of antiplatelet drugs that reduce adenosine diphosphate-(ADP) mediated platelet activation, has significantly improved clinical outcomes in many coronary conditions. Widespread use of ticlopidine, the first available thienopyridine, was limited by frequent side-effects, including life-threatening neutropenia and thrombotic thrombocytopenic purpura. Following the introduction of clopidogrel, a thienopyridine with an excellent safety profile, dual antiplatelet therapy with aspirin and clopidogrel has become standard therapy following coronary stent implantation and coronary VBT. In patients presenting with ACS, the addition of clopidogrel to aspirin has now been proven to reduce ischemic events. The most important limitation of dual antiplatelet therapy is the increased bleeding risk as compared with aspirin alone, particularly in patients undergoing coronary artery bypass grafting during the index hospitalization. However, for many patients with ACS, combination therapy is appropriate.     

Recent developments in the use of antiplatelet agents to prevent cardiovascular events

Platelets are pivotal contributors to arterial thrombosis. Dual antiplatelet therapy with aspirin and clopidogrel has become the standard of care for the secondary prevention of cardiovascular events in patients with acute coronary syndromes and after percutaneous coronary intervention. Clinical evidence of the continued risk of cardiovascular events plus pharmacodynamic evidence of substantial variability in on-treatment platelet reactivity has supported the development of new therapeutic strategies, using established agents and new antiplatelet drugs. This article will highlight recent pivotal clinical trials seeking to advance the use of antiplatelet therapy in patients with cardiovascular disease.     

Clinical Implications of Platelet—Vessel Interaction

The interaction of platelets with endothelial and inflammatory cells might trigger atherogenesis. Different pathways are responsible for this contribution of platelets to atherogenesis. A significant association has been described between increased platelet activation and the extent of atherosclerosis. Platelet reactivity also plays a key role in determining outcomes of patients undergoing percutaneous coronary intervention (PCI). Despite dual antiplatelet therapy, platelet reactivity increases early after the procedure proportionally to the degree of vascular damage and endothelial dysfunction induced by coronary interventions, and large increases in platelet reactivity are also associated with an increased risk of periprocedural myonecrosis. The interaction between platelets and vessel wall has important clinical implications, especially in patients treated with PCI. These include the appropriate selection of antiplatelet drugs when more aggressive procedures are needed, the prognostic significance of periprocedural variations of platelet reactivity, and the correct timing for platelet function testing.     

Optimization of platelet therapy.

Percutaneous coronary intervention produces vessel wall injury and activation of platelets that are responsible for producing peri-procedural ischemic complications. The importance of adequate antiplatelet therapy during coronary intervention to reduce platelet mediated ischaemic complications has been recognized for some time. Until recently, adjunctive treatment with aspirin was the only available antiplatelet therapy after coronary intervention that had demonstrated benefit. During the last decade, newer and more potent agents have demonstrated consistent reductions in ischaemic events after intervention and appear to have some enduring effect. Additionally, optimization of antiplatelet therapy with aspirin and the thienopyridines after coronary stenting has been an important advance allowing for the current liberal use of coronary stents.     

经皮冠状动脉介入治疗患者血小板功能检测的临床应用现状与展望

经皮冠状动脉介入治疗术后抗血小板治疗是预防主要不良心脏事件的重要措施。为了评估抗血小板治疗的疗效,指导抗血小板药物的应用,研究出了多种血小板功能检测方法,并在临床上广泛应用。理想的血小板功能检测应该能够：（1）指导个体化抗血小板治疗;（2）预测主要不良心血管事件;（3）评估出血风险。现就目前常用检测方法的有效性和局限性以及未来的发展方向作一综述。     

Perioperative Management of Antiplatelet-Drugs in Cardiac Surgery

The management of coronary patients scheduled for a coronary artery bypass grafting (CABG), who are receiving one or more antiplatelet drugs, is plenty of controversies. It has been shown that withdrawal of antiplatelet drugs is associated with an increased risk of a thrombotic event, but surgery under an altered platelet function also means an increased risk of bleeding in the perioperative period. Because of the conflict recommendations, this review article tries to evaluate the outcome of different perioperative antiplatelet protocols in patients with coronary artery disease undergoing CABG.     

The Role of Clopidogrel in the Management of Patients with Ischemic Heart Disease

Antiplatelet therapy plays a pivotal role in the treatment of patients across the entire spectrum of coronary artery disease. Platelets are believed to be integrally involved in both the development and progression of atherosclerotic heart disease, as well as in its acute thrombotic complications. While aspirin remains the traditional antiplatelet agent in patients with CAD, adverse vascular events continue to occur in patients on aspirin therapy. Clopidogrel is a relatively new antiplatelet agent and is currently one of the most widely prescribed drugs for the treatment of symptomatic coronary artery disease. As a member of the class of drugs known as the thienopyridines, clopidogrel irreversibly prevents platelet activation by blocking one of the three known adenosine 5'-diphosphate (ADP) receptors on its surface. The findings of a number of seminal clinical trials have expanded the indications for the use of clopidogrel in patients with coronary artery disease. When used in conjunction with aspirin, these studies have demonstrated an incremental benefit of clopidogrel above and beyond that of aspirin alone. This article reviews the data supporting the use of clopidogrel in patients with atherosclerotic heart disease, and makes recommendations for its use based on the available evidence.     

Platelet Function Testing and Tailored Antiplatelet Therapy

Dual antiplatelet therapy, consisting of aspirin and a P2Y12 receptor inhibitor, has dramatically reduced the incidence of atherothrombotic events for patients with acute coronary syndrome and those undergoing a percutaneous coronary intervention (PCI). However, the platelet inhibitory effect of clopidogrel, the most commonly used P2Y12 inhibitor, is variable between patients. Patients exhibiting high platelet reactivity (HPR) despite clopidogrel treatment are at higher risk of recurrent atherothrombotic events after PCI. In order to reduce the incidence of HPR, the more potent P2Y12 receptor inhibitors prasugrel and ticagrelor are used. However, these drugs increase the risk of bleeding. As there is evidence of a therapeutic window for platelet inhibition, platelet function tests could be helpful for tailoring antiplatelet therapy based on the patient’s thrombotic and bleeding risk. In the present article, we review the most commonly used platelet function tests and the current evidence for tailoring of antiplatelet therapy in PCI patients.     

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.     

Monitoring of platelet function in the setting of glycoprotein IIb/IIIa inhibitor therapy

The role of the platelet in the pathogenesis of acute coronary syndromes is clearly established. In addition, the beneficial effects of oral and intravenous platelet inhibitor therapies were demonstrated in multiple, large, randomized clinical trials. However, despite these advances, current antiplatelet therapy fails to prevent coronary events in a substantial proportion of patients. One possible explanation for this phenomenon is that antiplatelet medications are administered without monitoring of the response to therapy. For example, oral antiplatelet therapy is administered as a standard dose for all patients, while intravenous inhibitors of the platelet glycoprotein (GP) IIb/IIIa receptor are dosed based on patient body weight. A major limitation of measuring platelet function has been that no practical test exists. The historic gold standard, bleeding time, was a very crude measure of platelet function with limited clinical utility. The current "gold standard," turbidimetric aggregometery, requires a central laboratory and is cumbersome to perform. Fortunately, a number of new tests with rapid turnaround time can be performed at the patient's bedside. This article discusses the details regarding the performance, advantages, disadvantages, and available data related to clinical use of each test in populations with coronary disease and patients treated with antiplatelet therapy.     

Investigational antiplatelet drugs for the treatment and prevention of coronary artery disease

Antiplatelet therapy for the prevention and treatment of coronary artery disease (CAD) has undergone dramatic changes and improvements. Aspirin remains the first-line antiplatelet drug for clinical use. Newer platelet inhibitors such as the thienopyridine agents, ticlopidine and clopidogrel, have also been shown to be effective in treating CAD. There have been ongoing efforts to evaluate newer antiplatelet drugs, with the potential to improve clinical efficacy and safety. Some of the more promising antiplatelet agents include new adenosine diphosphate receptor antagonists such as prasugrel, cangrelor, and ticagrelor (AZD6140). In addition, a new thromboxane receptor antagonist, NCX-4016, a newly discovered protease-activated receptor antagonist that targets thrombin-induced platelet aggregation, and anti-von Willebrand factor aptamers show tremendous promise in refining antiplatelet therapy by targeting different receptors and molecules.     

Clopidogrel in acute coronary heart disease

Platelets play a central role in the pathogenesis of atherothrombosis. Rupture of a coronary artery plaque creates a nidus for platelet aggregation and thrombus formation, which may result in vessel occlusion and subsequent myocardial infarction or death. Despite conventional antiplatelet therapy with aspirin, the risk of recurrent ischemic events remains high. More potent antiplatelet agents have therefore been developed, including the thienopyridines ticlopidine and clopidogrel. By irreversibly blocking the platelet adenosine diphosphate receptor, these drugs powerfully inhibit platelet activation, degranulation, and aggregation. Large clinical trials have demonstrated that combination antiplatelet therapy with clopidogrel and aspirin significantly reduces the risk of adverse cardiac events in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. The optimal loading dose and length of treatment, however, are yet to be firmly established, and there is a need to clearly identify those patients who will benefit most from additional glycoprotein IIb/IIIa inhibition.     

Tratamiento antiagregante plaquetario personalizado

It is well established that high on-treatment platelet reactivity to adenosine diphosphate during clopidogrel therapy is an independent risk factor for ischemic event occurrences in a postpercutaneous coronary intervention patients. However, the precise role of platelet function testing remains debated. Platelet function testing to ensure optimal platelet inhibition has been recommended by some authorities to improve outcomes in patients treated with clopidogrel. Recent prospective, randomized trials of personalized antiplatelet therapy have failed to demonstrate a benefit of platelet function testing in improving outcomes. In this review article, we discuss the mechanisms responsible for clopidogrel nonreponsiveness, recent trials of platelet function testing, and other new developments in the field of personalized antiplatelet therapy.     

Differential effect of aspirin on platelet aggregation in patients with coronary artery disease in relation with associated risk factors

Platelets play a key role in the pathogenesis of atherosclerosis and acute coronary syndromes and antiplatelet therapy offers a clinical benefit. Although aspirin is the most widely used agent, there are several conditions in which aspirin may fail to provide a full antithrombotic benefit. Furthermore, data concerning the relationship between platelet function, aspirin, and the associated risk factors are limited. In the present study. ADP and collagen-induced platelet aggregation of 200 consecutive patients with suspected coronary artery disease (CAD) who underwent coronary angiography were evaluated. The patients were classified into three groups according to the number of stenotic vessels. One hundred and eight patients were using 300 mg/day of aspirin. The associated cardiovascular risk factors were also considered. The collagen-induced platelet aggregation of smokers was significantly higher than non-smokers (P < 0.05). Although platelet aggregation was higher in diabetic and hypertensive patients, the difference was not statistically significant. No significant correlation was found between platelet aggregation and other risk factors. The collagen-induced platelet aggregation of the subjects with non-stenotic vessels was reduced by aspirin (P < 0.05). Aspirin did not sufficiently inhibit ADP and collagen-induced aggregation in patients with CAD. This finding supports the idea that the nonplatelet-mediated effects of aspirin could be more important than its antiplatelet effect in clinical use and the use of new potent antiplatelet drugs may complete its antiplatelet effect.     

心肌梗死合并脑梗死的抗血小板药物治疗

心肌梗死和脑梗死是目前严重危害人类健康的血管性疾病,由其引起的死亡率占到所有死因的第一位。动脉粥样硬化病变基础上血栓形成是心脑血管疾病(冠状动脉疾病和脑血管病)多种进行性表现的常见基础过程。抗血小板治疗是动脉粥样硬化患者药物治疗的基石。过去20年来,抗血小板药物治疗在冠状动脉疾病上取得重大进展。但在治疗过程中由于脑血管病患者发生缺血和出血的风险增加,因此用于冠状动脉疾病和脑血管病患者抗血小板治疗药物组合的风险和益处是不确定和复杂的。本文提供了目前关于抗血小板治疗最前沿的证据,抗血小板药物用于二级预防冠状动脉疾病和脑血管病在动脉粥样硬化病变基础上血栓形成事件的进展。     

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.     

Facilitating Optimal Care of Acute Coronary,Cerebrovascular and Peripheral Vascular Syndromes in the Emergency Department: The Role of Oral Antiplatelet Therapy

The benefits of aspirin use in the emergent care of MI and stroke have been well established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of clopidogrel and aspirin has demonstrated benefit for the management of acute coronary syndromes, ischemic cerebrovascular disease and peripheral vascular disease in several large trials. This article reviews the pathophysiology of platelet activation, landmark trials on oral antiplatelet agents, and the current recommendation for the use of oral antiplatelet agents in the emergency department.     

Single antiplatelet therapy after percutaneous coronary intervention in patients allergic to aspirin

Dual antiplatelet therapy including aspirin and a P2Y₁₂ ADP receptor antagonist is given after percutaneous coronary intervention to avoid catastrophic complication of stent thrombosis. Dual antiplatelet therapy is associated with increased bleeding risk and may not be tolerated by many patients. This article presents the patients, which had to be given single antiplatelet therapy after percutaneous coronary intervention and discusses the possible factors responsible for the success of single antiplatelet therapy strategy in these patients, in the current era of newer antiplatelet agents and coronary stents.     

Coronary stent occlusion after platelet transfusion: a case series

Early stent occlusion after myocardial infarction is associated with increased morbidity and mortality, and antiplatelet drugs are applied to prevent these complications. We report on 3 patients with gastrointestinal bleeding or who were scheduled for emergency surgery and who received donor platelet transfusion early in the course after stenting. These patients had symptomatic coronary artery stenoses and were treated with antiplatelet therapy. Stent occlusion was diagnosed 6 to 17 hours after donor platelet transfusion, suggested by electrocardiographic and, in 1 patient, angiographic findings. One patient died of intractable bleeding from the gastrointestinal tract. Our observations emphasize the risks involved in platelet transfusion, and support withholding such therapy, unless vitally indicated, in patients who have undergone recent bare-metal coronary artery stent implantation.