血小板功能检测与P2Y12受体拮抗剂个体化抗血小板治疗的研究进展

P2Y12受体拮抗剂广泛应用于急性冠脉综合征（ACS）及经皮冠状动脉介入治疗（PCI）后血栓事件的预防。由于抗血小板治疗反应多样性的存在,经典的P2Y12受体拮抗剂氯吡格雷的治疗期间高血小板反应性（HTPR）被证实与患者不良心血管事件的发生密切相关。尽管新药普拉格雷和替格瑞洛的抗栓疗效优于氯吡格雷,但是由于治疗期间低血小板反应性（LTPR）的存在,出血风险明显增加。如何权衡血栓和出血风险,实现个体化抗血小板治疗,已经成为临床的重要挑战。研究证实,血小板反应性（PR）与缺血和出血事件的发生密切有关,基于血小板功能检测（PFT）的治疗窗将有助于个体化抗血小板治疗。本文就PFT与P2Y12受体拮抗剂个体化抗血小板治疗的研究进展作一综述。     

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.     

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.     

Platelet Function Testing in Patients with Acute Coronary Syndrome

In patients with an acute coronary syndrome (ACS), inhibition of the platelet P2Y12 receptor is standard of care. The shortcomings of the most commonly used P2Y12 receptor inhibitor clopidogrel—that is its delayed onset of action, its interindividual response variability, and the phenomenon of high on-treatment platelet reactivity—led to the development of more potent P2Y12 receptor inhibitors (prasugrel and ticagrelor) that proved their superiority in terms of reducing thrombotic events compared to clopidogrel. Available randomized studies that aimed at investigating the value of a personalized antiplatelet treatment regimen based on platelet function monitoring results were negative with regard to the possible benefits of monitoring but were all limited by mainly enrolling elective and stable patients with coronary artery disease. Thus, it still warrants further investigation if a tailored, platelet function guided, antiplatelet therapy in ACS patients with the available P2Y12 receptor inhibitors prasugrel, ticagrelor, and clopidogrel can lead to improved patients outcome.     

Oral antiplatelet therapy for atherothrombotic disease: current evidence and new directions

Despite the proven efficacy of dual antiplatelet therapy with aspirin and one of the first-generation P2Y(12) antagonists (clopidogrel, prasugrel) in patients with atherothrombotic disease, residual ischemic risk remains substantial, and bleeding rates are increased. Incomplete protection against ischemic events can be attributed to the fact that these therapies each target a single platelet activation pathway, allowing continued platelet activation via other pathways, including the protease-activated receptor-1 (PAR-1) pathway stimulated by thrombin. Increased bleeding with dual antiplatelet therapy can be attributed to blockade of the thromboxane A(2) (by aspirin) and adenosine diphosphate (by P2Y(12) antagonist) platelet activation pathways that are essential to hemostasis. The second-generation P2Y(12) inhibitor ticagrelor plus aspirin demonstrated superior ischemic outcomes, including reduction in total mortality, versus clopidogrel plus aspirin, but event rates remain high, and major bleeding not related to coronary artery bypass grafting is increased. The novel P2Y(12) antagonist elinogrel, available in intravenous and oral formulations, may have a more favorable benefit-to-risk profile than existing agents in this class because of reversible and competitive binding to the P2Y(12) receptor. Inhibition of PAR-1 is an attractive, novel approach in antiplatelet therapy because it may provide incremental ischemic protection without increasing bleeding. The PAR-1 antagonist vorapaxar (SCH 530348) has been associated with favorable efficacy and safety in phase 2 trials. Two phase 3 trials are evaluating the efficacy and safety of vorapaxar in patients presenting with non-ST-segment elevation acute coronary syndromes and in patients with documented atherothrombotic disease.     

Antiplatelet treatment of cardiovascular disease: a translational research perspective

Platelet mediated thrombosis is the primary cause of ischemic event occurrence in patients with cardiovascular disease. The P2Y12 receptor plays a central role in thrombus generation and is therefore a major target for pharmacologic therapy. Although various clinical trials have demonstrated the efficacy of dual antiplatelet therapy with aspirin and clopidogrel, recurrent ischemic events occur in approximately 10% of patients with acute coronary artery syndromes. Recent translational research studies have explored the various limitations of dual antiplatelet therapy including wide response variability and resistance. The association of ischemic event occurrence with high on-treatment platelet reactivity to adenosine diphosphate has been reported in recent small studies suggesting that the latter may be a quantifiable and modifiable risk factor. Recent studies have identified a potential therapeutic target for P2Y12 inhibitors that may influence the future development of personalized antiplatelet treatment strategies aimed at the reduction of ischemic event occurrence in high risk patients. Finally, based on the current evidence platelet reactivity may become a standard of care risk factor measured in all patients with cardiovascular disease.     

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.     

P2Y12-ADP receptor antagonists: Days of future and past

Antiplatelet therapy is the cornerstone of the therapeutic arsenal in coronary artery disease.Thanks to a better understanding in physiology,pharmacology and pharmacogenomics huge progress were made in the field of platelet reactivity inhibition thus allowing theexpansion of percutaneous coronary intervention.Stent implantation requires the combination of two antiplatelet agents acting in a synergistic way.Asprin inhibit the cyclo-oxygenase pathway of platelet activation while clopidogrel is a P2Y12 adenosine diphosphate(ADP)-receptor antagonist.This dual antiplatelet therapy has dramatically improved the prognosis of stented patients.However,due to pharmacological limitations of clopidogrel(interindividual variability in its biological efficacy,slow onset of action,mild platelet reactivity inhibition)ischemic recurrences remained high following stent implantation especially in acute coronary syndrome patients.Thus,more potent P2Y12-ADP receptor inhibitors were developped including prasugrel,ticagrelor and more recently cangrelor to overcome these pitfalls.These new agents reduced the rate of thrombotic events in acute coronary syndrome patients at the cost of an increased bleeding risk.The abundance in antiplatelet agents allow us to tailor our strategy based on the thrombotic/bleeding profile of each patient.Recently,the ACCOAST trial cast a doubt on the benefit of pre treatment in non-ST segment elevation acute coronary syndrome.The aim of the present review is to summarize the results of the main studies dealing with antiplatelet therapy in stented/acute coronary syndromes patients.     

Platelet Function and Inhibition in Ischemic Heart Disease

Platelets play an important role in the pathogenesis of thrombosis, the most common cause for the development of acute coronary syndromes such as complications occurring during percutaneous coronary intervention. Platelets act with a multiple step mechanism, in which different surface molecules are involved representing important therapeutic targets of antiplatelet agents. Despite clopidogrel efficacy which has been demonstrated in several studies, recurrent ischemic events remain considerably high in patients on treatment due to low clopidogrel responsiveness, a phenomenon influenced by environmental, clinical, and genetic factors. New P2Y12 blockers such as prasugrel and ticagrelor have been successfully introduced in clinical practice, whereas cangrelor, with a rapid offset and reversible platelet inhibition, may represent a useful bridging therapy in patients undergoing surgery. Moreover, the simultaneous inhibition of thrombin platelet aggregation by protease-activated receptor inhibitors may be an adjunctive approach in patients with coronary artery disease.     

The P2Y 12 receptor as a therapeutic target in cardiovascular disease

Coronary thrombosis complicating rupture of atherosclerotic plaque is the predominant cause of acute coronary syndromes and platelets play a crucial role in this thrombus formation. Whilst aspirin has been successful in reducing cardiovascular morbidity and mortality, appreciation of its limited antiplatelet effects has stimulated the search for more effective antiplatelet agents. The thienopyridines, ticlopidine and clopidogrel, act, via metabolites, on the platelet ADP receptor subtype now designated P2Y 12 (formerly P 2T , P2T AC , P2Y ADP or P2Y cyc ) and these agents have proven clinical efficacy. Analogues of the natural P2Y 12 receptor antagonist ATP have been developed that act directly on the receptor and have a rapid onset of action. One such antagonist, AR-C69931MX, is being developed for clinical use. AR-C69931MX is a potent antagonist of ADPinduced platelet activation, aggregation and secretion and also antagonises platelet responses, including procoagulant activity, induced by all other agonists in view of the central role of the P2Y 12 receptor in amplifying platelet responses. Phase II studies of intravenous AR-C69931MX in patients with acute coronary syndromes show that this agent has a rapid onset of action, rapidly achieving steady-state inhibition of platelet aggregation, with a half-life of only a few minutes. AR-C69931MX appears to be safe and well tolerated as adjunctive therapy in these patients, and more effective inhibition of platelet function is achieved than with clopidogrel. Orally active ATP analogues are also being developed that may be more effective than clopidogrel. Limitations of platelet glycoprotein IIb/IIIa antagonists leave scope for development of alternative antiplatelet agents.     

A transition of P2Y12 antagonists for acute coronary syndrome: benefits,risks and costs

P2Y₁₂ receptor antagonists have become cornerstone pharmacological agents in antiplatelet therapy for patients with acute coronary syndrome or undergoing percutaneous coronary intervention. While clopidogrel remains in extensive use in clinical practice, it cannot meet the needs in many clinical conditions because of its pharmacological limitations. In recent years, newly developed P2Y₁₂ antagonists, such as prasugrel and ticagrelor, have proven to be of higher efficacy and less resistance. With the introduction of these new medicines, the current antiplatelet strategy is undergoing a transitional period. Insufficient platelet inhibition (high platelet reactivity) leads to an increased risk of ischemic events whereas exceeding platelet inhibition can lead to an increased risk of bleeding. This review discusses the pharmacological features, benefits, risks and cost-effectiveness of different P2Y₁₂ antagonists in various clinical settings. A balance between these factors will determine the choice of P2Y₁₂ antagonists for personalized antiplatelet therapy. We conclude that it is a promising option to apply the new drugs, due to their superior therapeutic performance versus that of clopidogrel in the long run.     

Prasugrel loading dose in diabetic patients with acute STEMI – Always sufficiently effective? Observation in two cases and review of current knowledge

The activation and subsequent platelet aggregation play a key role in the formation of arterial thrombosis and therefore is the key therapeutic target in the treatment of acute coronary syndromes. Dual antiplatelet therapy containing aspirin and P2Y12 ADP receptor antagonist forms currently the basis in acute ST – elevation myocardial infarction (STEMI) pharmacological treatment. Nevertheless, there is a wide variability in pharmacodynamic response to administration of clopidogrel, the most frequently used P2Y12 ADP receptor antagonist. High platelet reactivity after clopidogrel administration is associated with increased risk of stent thrombosis and points to the suitability of laboratory monitoring of antiplatelet therapy efficacy in clinical practice. Laboratory monitoring of antiplatelet therapy by ex vivo platelet function tests may help to identify individuals with poor antiplatlet response. Recently, there is a growing number of data reporting a failure in antiplatelet response following clopidogrel administration, which is specifically associated with insulin resistance and diabetes mellitus. Prasugrel, a new, potent P2Y12 ADP receptor antagonist, provides faster and more consistent inhibition of platelet function compared with clopidogrel. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance and prasugrel resistance has not yet been reliably described. We report two cases of patients with diabetes mellitus type 2 at the stage of organ complications, in whom a prasugrel loading dose of 60 mg did not reach adequate antiplatelet response in 60 min after prasugrel administration. The antiplatelet response was measured by light transmission aggregometry and by VASP protein phosphorylation assessment.     

In-stent thrombosis when switching ticagrelor to clopidogrel after percutaneous coronary intervention

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker has been proven to reduce subsequent cardiovascular events and in-stent thrombosis in patients undergoing percutaneous coronary intervention. Newer P2Y12 antagonists with faster onset and greater inhibition of platelet activity have improved cardiovascular outcomes but have created uncertainty with the appropriate dosing when switching between agents. Currently, there are no evidence-based guidelines to aid clinicians when switching between P2Y12 receptor blockers. Here we describe two patients that developed in-stent thrombosis when switching from ticagrelor to clopidogrel using a 300 mg clopidogrel loading dose. Both patients presented with ST elevation myocardial infarction and underwent stent placement but then developed in-stent thrombosis 48 hours after switching from ticagrelor to clopidogrel. These cases illustrate the severe consequences of suboptimal platelet inhibition and the need for prospective trials thoroughly powered to assess clinical outcomes in order to determine the most appropriate strategy when switching from ticagrelor to clopidogrel.     

Genotypic and Phenotypic Assessment of Platelet Function and Response to P2Y12 Antagonists

The P2Y12-ADP receptor antagonists are the cornerstone of oral antiplatelet therapy in the secondary prevention of coronary artery disease, especially after acute coronary syndrome or percutaneous coronary intervention. Currently, the therapeutic agents available to block the receptor include clopidogrel and prasugrel; ticagrelor is not available everywhere. Clopidogrel was the gold standard, but recently it has been challenged by prasugrel and ticagrelor. One pitfall of clopidogrel is that in some patients it cannot induce optimal platelet reactivity inhibition in connection with several factors, including some genetic polymorphisms of enzymes participating in its bioabsorption or metabolism. This variability of response can be evaluated by platelet reactivity monitoring. This comprehensive review provides the available data regarding the genotypic and phenotypic interaction with the response to P2Y12-ADP receptor antagonists and discusses the concept of personalized antiplatelet therapy based on a genotypic or phenotypic profile.     

Atopaxar: a review of its mechanism of action and role in patients with coronary artery disease

Platelet activation and aggregation is a complex and key process in thrombus formation after the rupture of an atherosclerotic plaque, which can lead to an acute coronary syndrome. Aspirin, an irreversible inhibitor of thromboxane A(2) synthesis, in combination with an inhibitor of P2Y(12) ADP platelet receptors (clopidogrel, prasugrel or ticagrelor), represents the current standard of care of antiplatelet therapy for patients with acute coronary syndrome and in those patients undergoing percutaneous coronary intervention. Despite the benefit of these agents, the risk of thrombotic events and bleeding complications may still occur while on such antiplatelet treatment regimens, thus representing an important limitation. Thrombin is one of the most important platelet activators. The inhibition of thrombin-mediated platelet activation by means of protease-activated receptor-1 inhibitors represents an attractive therapeutic option for patients with atherothrombotic disease processes. This article provides an overview on atopaxar (E5555), an orally active protease-activated receptor-1 antagonist that has recently completed Phase II clinical investigation.     

Prasugrel: a new antiplatelet drug for the prevention and treatment of cardiovascular disease

Prasugrel, trade name Effient, is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration. It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine. Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic P2Y12 receptor on the platelet surface. Prasugrel has been shown to be a potent antiplatelet agent with a faster, more consistent, and greater inhibition of platelet aggregation compared with clopidogrel. It is debatable, however, how effectively these pharmacologic benefits will translate to clinical benefits. The results of the large TRITON-TIMI 38 trial, which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents, demonstrated a significant reduction in ischemic events, including stent thrombosis, with prasugrel, but with an increased risk of major bleeding. The exact role of prasugrel in the management of ischemic heart disease is still being defined, but the risk:benefit ratio will likely play a major role in directing the best place for therapy with this new agent.     

微小核糖核酸与抗血小板药物反应异质性的相关研究进展

抗血小板药物在心脑血管血栓性疾病的防治过程中发挥核心作用,但存在药物反应异质性所致的严重缺血/出血风险。寻找能够预测抗血小板药物反应性个体差异的生物标志物,对于个体化应用抗血小板药物具有重要的临床价值。近年研究发现,血小板蕴含丰富的微小核糖核酸(microRNA),其中具有调控血小板P2Y12受体编码基因(P2RY12)表达的microRNA与P2Y12受体拮抗剂抗血小板反应性的相关性备受关注。本文将针对与抗血小板药物反应性相关的血小板microRNA的生物学特征、相关性研究和可能机制作一综述。     

Intensified P2Y12 inhibition for high-on treatment platelet reactivity

High on treatment platelet reactivity (HPR) during treatment with clopidogrel has been consistently found to be strong risk factor for recurrent ischemic events after percutaneous coronary intervention (PCI). Insufficient P2Y12 receptor inhibition contributes to HPR measured by the VerifyNow (VN) assay. Prasugrel and ticagrelor are more potent P2Y12 inhibitors than clopidogrel and commonly substituted for clopidogrel when HPR is documented, however benefit of VN guided intensified antiplatelet therapy is uncertain. We identified patients who had undergone platelet reactivity testing after PCI with VN after pretreatment with clopidogrel (n?=?252) in a single center observational analysis. Patients who had HPR defined as PRU?>?208 were switched to alternate P2Y12 inhibitors. Primary clinical endpoint was 1-year post PCI combined cardiovascular death, myocardial infarction (MI), and stent thrombosis. One hundred and eight (43%) subjects had HPR and were switched to prasugrel (n?=?60) and ticagrelor (n?=?48). Risk of recurrent 1-year primary endpoint remained higher for HPR patients switched to either ticagrelor or prasugrel as compared to subjects who had low on treatment platelet reactivity (n?=?144) (LPR) on clopidogrel [Hazard Ratio: 3.5 (95% CI 1.1–11.1); p?=?0.036)]. Propensity score matched analysis demonstrated higher event rates in patients with HPR on alternate P2Y12 inhibitor as compared to patients with LPR (log-rank: p?=?0.044). The increased risk of recurrent events associated with HPR measured by VN is not completely attenuated by switching to more potent P2Y12 inhibitors. Non-P2Y12 mediated pathways likely contribute to increased incidence of thrombotic events after PCI in subjects with HPR.