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。     

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.     

Antiplatelet therapy in acute coronary syndromes

Acute coronary syndromes (ACS), characterized by unstable angina or a non-ST-segment elevation myocardial infarction, are caused by rupture of an atherosclerotic plaque, leading to platelet activation and aggregation, thrombus formation, and microembolization. Antiplatelet therapy is a cornerstone of therapy. Combined with aspirin, clopidogrel provides significant benefit for patients across the ACS spectrum. However, clopidogrel has limitations given its slow onset and the inconsistent level of inhibition that it achieves. Newer thienopyridine and non-thienopyridine P2Y12 receptor agonists offer the advantages of a rapid onset of action and greater and more consistent platelet inhibition.     

Current evidence for monitoring platelet reactivity in acute coronary syndrome: A plea for individualized antiplatelet treatment

Although clopidogrel is more effective in preventing thrombotic complications than aspirin alone in a broad spectrum of patients with ischemic heart disease, many of its limitations were recently brought to light including a delayed onset of action and highly unpredictable P2Y₁₂-receptor inhibition. New-generation ADP-receptor antagonists, such as prasugrel and ticagrelor, were designed and developed to overcome these limitations, providing a more rapid, more reliable and more potent P2Y₁₂-receptor inhibition. These pharmacodynamic benefits of new-generation antiplatelet agents were translated into significant clinical advantage among patients with acute coronary syndrome (ACS), especially in preventing stent thrombosis. However, the downsides of the unselected use of novel P2Y₁₂-receptor antagonists include higher risk of bleeding and increased costs. Platelet reactivity testing might become a useful tool to help balance between bleeding and thrombosis with P2Y₁₂-receptor antagonists; however, its role in clinical practice for patients undergoing percutaneous coronary intervention (PCI) remains uncertain. The aim of this viewpoint article is to summarize the currently available evidence supporting a role of platelet function testing in patients with ACS after PCI.     

Neue Pl?ttchenhemmstoffe und die Frage der dualen Hemmung

The introduction of clopidogrel for use with aspirin (ASA) as a dual antiplatelet therapy has markedly reduced the risk of atherothrombotic vessel occlusion in patients with acute coronary syndromes (ACS). However, stronger antiplatelet therapy has also been associated with significant increases in severe bleeding, resulting in no change in mortality rates. This raised the question of pharmacological alternatives, specifically new antagonists of the platelet P2Y(12)-ADP receptor, which exhibit better pharmacokinetic and dynamic properties than clopidogrel, as well as improved clinical safety.Prasugrel, the first of these newly developed agents and another thienopyridine, was more potent than clopidogrel in the TRITON-TIMI-38 study in reducing ischemic events in ACS patients, but also increased severe bleeding. Ticagrelor, a structurally different reversible antagonist of the P2Y(12) receptor, was superior to clopidogrel in the PLATO trial on ACS patients, but also increased the risk of severe bleeding in patients not requiring bypass surgery. Interestingly, ticagrelor reduced mortality in PLATO. There have been no satisfying explanations for this phenomenon to date. In addition to different patient populations and treatment protocols, the varying pharmacological properties of these substances are discussed as possible causes. A direct comparison of the two medications in a single study remains to be undertaken.     

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.     

Platelet adenosine diphosphate receptor antagonists: ticlopidine to ticagrelor-a long continuing journey

Platelet aggregation plays a central role in the pathogenesis of atherothrombosis. Platelet adenosine diphosphate (ADP) receptor antagonists (ticlopidine, clopidogrel, prasugrel, and ticagrelor) are a major advance in the treatment of atherothrombotic diseases, especially acute coronary syndromes (ACS). Ticlopidine was the first thienopyridine introduced into clinical practice, but its potentially serious haematological side-effects limited its use and it was quickly eclipsed by clopidogrel. Clinical trials established aspirin plus clopidogrel as the standard dual anti-platelet therapy in patients with ACS and patients undergoing percutaneous coronary intervention (PCI) with stenting. Clopidogrel was found to have pharmacokinetic and pharmacodynamic limitations. Prasugrel is the next approved thienopyridine that has shown superior efficacy in ACS patients undergoing PCI in comparison to clopidogrel, although at the cost of a higher bleeding risk. Ticagrelor is the latest non-thienopyridine ADP receptor blocker that is potent, effective, reversible, and relatively safer as compared to clopidogrel. Both prasugrel and ticagrelor are more potent than clopidogrel. The data so far suggests that ticagrelor has a wider applicability in usage in patients with ACS as compared to prasugrel. Prasugrel however seems to be better tolerated. Search is on for newer more potent but safer anti-platelet agents.     

Coronary Calcium: New Insights, Recent Data, and Clinical Role

Antiplatelet therapy with aspirin and a platelet P2Y12 receptor antagonist reduces thrombotic and ischemic events after percutaneous coronary intervention and acute coronary syndrome. The platelet inhibitory effect of the thienopyridine clopidogrel varies widely among individuals, and high on-treatment platelet reactivity has been associated with a substantial hazard for post-PCI cardiovascular events, including stent thrombosis. The clinical availability of ex vivo methods to measure the antiplatelet effect of P2Y12 antagonists raises the possibility that incorporating platelet function testing into clinical practice could facilitate a stratified and efficient approach to antiplatelet therapy following PCI, although data from definitive randomized trials supporting a routine approach are currently lacking.     

Optimizing Platelet P2Y12 Inhibition for Patients Undergoing PCI

Guidelines recommend that dual antiplatelet therapy using aspirin and clopidogrel should be administered to the majority of patients with acute coronary syndromes, including those undergoing percutaneous coronary intervention (PCI). However, the results of a large randomized, placebo‐controlled study suggest that a 300‐mg loading dose of clopidogrel must be administered at least 15 h prior to PCI in order to achieve a significant reduction in peri‐PCI thrombotic events. Other data suggest that 2 h of pretreatment may be sufficient if a 600‐mg loading dose is used. Since it is often difficult to achieve an adequate pretreatment goal with clopidogrel in clinical practice, more rapid achievement of platelet P2Y₁₂ inhibition may improve patient outcomes. Prasugrel, [6‐[2‐(3,4‐diflurophenyl) cyclopropyl1‐1‐y1] amino‐2‐propylthio‐9?‐D‐ribofuranosyl‐9H‐purine (AZD6140), and cangrelor are platelet P2Y₁₂ receptor antagonists currently in development that offer faster acting inhibition of adenosine diphosphate (ADP)—induced platelet aggregation. These agents act upon the same platelet receptor as clopidogrel, but are distinguished by their routes of administration, reversibility, and pharmacodynamic properties. Prasugrel is an orally administered agent that provides faster, higher, and more consistent inhibition of platelet aggregation than clopidogrel. The results of Phase II testing suggest that the risk of bleeding is similar in prasugrel‐ and clopidogrel‐treated patients. AZD6140 is another orally administered platelet inhibitor with rapid and reversible action. Again, Phase II testing suggests similar bleeding risk for clopidogrel. Preliminary evidence suggests that clinical outcomes may be better in prasugrel‐ and AZD6140‐treated patients than in clopidogrel‐treated patients. Cangrelor is an intravenously administered, reversible, short‐acting agent with a rapid onset of activity. Bleeding risk and clinical outcomes data are similar in cangrelor‐ and abciximab‐treated patients. The results of ongoing Phase III clinical trials involving more than 40,000 patients will demonstrate whether these agents fulfill their potential to improve outcomes in PCI‐treated patients by providing faster, higher, and more consistent inhibition of platelet aggregation.     

Dual Antiplatelet Therapy with Prasugrel or Ticagrelor Versus Clopidogrel in Interventional Cardiology

For several years, clopidogrel plus aspirin has been the dual antiplatelet therapy (DAPT) of choice for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation. More recently, prasugrel and ticagrelor have demonstrated greater efficacy than clopidogrel. In TRITON-TIMI 38, the risk of TIMI major bleeding unrelated to coronary artery bypass graft (CABG) surgery was similar for prasugrel and clopidogrel after excluding subgroups with increased bleeding risk (previous stroke or transient ischemic event; age ≥75 years; weight <60 kg). In the PLATO trial, rates of TIMI major bleeding were similar for ticagrelor and clopidogrel, but ticagrelor was associated with a significantly higher rate of non-CABG-related TIMI major bleeding. Current evidence suggests that prasugrel or ticagrelor plus aspirin should be the DAPT of choice in patients with ACS undergoing PCI unless they are at particularly high risk of bleeding. No studies have yet compared prasugrel and ticagrelor in ACS patients, however prasugrel and ticagrelor have different side effect profiles, and the choice of agent should be made either as a default choice and/or on an individual patient basis. Ongoing trials in ACS patients will increase the evidence base for new P2Y₁₂ receptor inhibitors and help to establish the most effective DAPT regimens.     

Platelet reactivity in diabetic patients undergoing coronary stenting for acute coronary syndrome treated with clopidogrel loading dose followed by prasugrel maintenance therapy

Background

Diabetes has been identified as a risk factor for impaired clopidogrel response, and these patients might have greater benefit with new P2Y12 blockers such as prasugrel. The present study was designed to assess response to thienopyridine in diabetic patients undergoing PCI for ACS.

Methods and results

107 diabetic patients undergoing PCI for ACS were included and treated by clopidogrel 600 mg loading dose and switched to prasugrel 10 mg daily after PCI. Platelet reactivity was assessed by PRI VASP. High-on-treatment platelet reactivity (HTPR) was defined by PRI VASP > 50% and Low-on-treatment platelet reactivity (LTPR) as PRI VASP below the 75th percentile (PRI VASP < 20%). After clopidogrel, mean PRI VASP was 47 ± 21% and 54 patients (50%) were non responders. At one month, mean PRI VASP on prasugrel 10 mg daily was 31 ± 13%, 9 patients (8%) had HTPR and 23 patients (22%) had LTPR. In multivariate analysis, factors associated with platelet reactivity were waist circumference for HTPR on clopidogrel and body weight for HTPR and LTPR on prasugrel. 10 patients (9%) suffered from BARC bleeding complications. Patients with bleeding complications had significantly lower PRI VASP values: 22 ± 9 vs. 32 ± 13, p = 0.02 and ROC curves identified a cut-off value of VASP = 28% to predict bleeding complications.

Conclusion

The present study confirmed that many diabetic patients treated with clopidogrel for ACS have inadequate platelet inhibition. Switch to prasugrel is effective with acceptable safety in this specific population. We observed a significant relationship between on-treatment platelet reactivity and bleeding complications.     

Contemporary Antiplatelet Pharmacotherapy in the Management of Acute Coronary Syndromes

Purpose of review

Antiplatelet therapies are pivotal treatments in the management of acute coronary syndrome (ACS) with or without revascularization. In recent years, the use of P2Y12 antagonists prior to catheterization, so-called pretreatment, has been questioned, particularly in patients who may be at higher bleeding risks. The purpose of this review was to evaluate the current literature on contemporary and novel antiplatelet therapy in the pretreatment and treatment of ACS.

Recent findings

The P2Y12 receptor antagonists are associated with substantial reductions in morbidity and mortality for all types of ACS but only clopidogrel and ticagrelor have sufficient evidence for use in the pretreatment setting. The data regarding prasugrel support the use in patients undergoing percutaneous intervention (PCI). The glycoprotein IIa/IIIb antagonists are the most optimal for use in high-risk ACS as an adjuvant therapy during and after PCI.

Summary

In summary, although all P2Y12 antagonists have morbidity- and mortality-reducing effects in ACS, only clopidogrel and ticagrelor have sufficient evidence in the pretreatment setting. Newer antiplatelet therapies, most notably the protease-activated receptor 1 antagonists, are evolving and promising but are associated with greater bleeding risks.

     

急性冠脉综合征患者PCI术后应用国产硫酸氢氯吡格雷的疗效

比较急性冠脉综合征（ACS）患者择期PCI术后国产氯吡格雷（泰嘉,Talcom）和进口氯吡格雷（波立维,Plavix）应用的有效性和安全性。方法：158例行择期PCI的ACS患者随机分为：国产氯吡格雷组和进口氯吡格雷组,各79例。随访12个月以上,观察两组术后不良心血管事件及药物不良反应情况。结果：进口氯吡格雷组心源性死亡1例、非致死性心肌梗死1例、靶血管再次血运重建1例、脑卒中1例。国产氯吡格雷组心源性死亡0例、非致死性心肌梗死1例、靶血管再次血运重建2例、脑卒中1例。两组心血管不良事件发生率无显著差异（5.06%比5.06%,P〉0.05）。药物不良反应：进口氯吡格雷组胃肠道反应5例、出血1例、血小板减少1例。国产氯吡格雷组胃肠道反应7例、出血1例、血小板减少2例,两组不良反应发生率无显著差异（8.86%比12.66%,P〉0.05）。结论：与进口氯吡格雷相比,国产氯吡格雷应用于PCI术后患者是安全、有效的。     

Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials

Cangrelor is an intravenous antagonist of the P2Y(12) receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 μmol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: -1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower in patients treated with cangrelor. A rapid platelet inhibitory effect was achieved during cangrelor infusion and a rapid offset of action after treatment discontinuation. This CHAMPION platelet function substudy represents the largest pharmacodynamic experience with cangrelor, demonstrating its potent P2Y(12) receptor inhibitory effects, and rapid onset/offset of action. Although there was no significant pharmacodynamic interaction when transitioning to clopidogrel therapy, further studies are warranted given that enrollment in this study was limited due to premature interruption of the main trial.     

Thienopyridine therapy and risk for cardiovascular events in secondary prevention

Platelets are critical modulators of atherothrombotic events. In the acute setting, platelets are activated and aggregate on the surface of atherosclerotic plaque that has ruptured, fissured, or developed erosions. The overlying thrombus leads to sudden development of arterial luminal obstruction, inducing ischemia and cellular necrosis. Inhibiting platelet reactivity is an important therapeutic goal in patients at risk for acute cardiovascular events. The thienopyridines are potent inhibitors of platelet aggregation and block the binding of adenosine 5′-diphosphate to purinergic receptors on the surface of the platelet membrane. The thienopyridine class includes ticlopidine, clopidogrel, and prasugrel. Clopidogrel is the most intensively studied. In recent years it has become apparent that approximately 20% to 25% of patients who would be expected to benefit from clopidogrel therapy are resistant to this drug, largely due to a polymorphism in the gene for cytochrome P450 2C19. The efficacy of clopidogrel can also be reduced if patients are receiving concomitant therapy with a proton pump inhibitor such as omeprazole. Prasugrel is a third-generation thienopyridine with faster time to onset and greater consistency in inhibiting platelet activity, and it has shown superiority to clopidogrel for reducing cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary interventions.     

Novel Anti-platelet Agents: Focus on Thrombin Receptor Antagonists

Platelets are the key in the pathogenesis of atherothrombotic disease such as acute coronary syndromes, stroke, and peripheral arterial disease. Current anti-platelet treatments are mainly based on inhibition of two important pathways of platelet activation: thromboxane A2 (TXA2) mediated (aspirin) and adenosine diphosphate (ADP)–P2Y12 receptor mediated (clopidogrel, prasugrel, and ticagrelor). Despite the dual anti-platelet therapy with aspirin and P2Y12 inhibitors have reduced ischemic events in patients with acute coronary syndromes (ACS), the rate of recurrent ischemic complication after ACS remains high. Combination of multiple anti-platelet agents is also associated with increased risk of bleeding. Thrombin is a potent platelet agonist and the increase of its activity has been reported in patients with ACS. Platelet effects of thrombin are mediated by protease-activated receptors (PAR), and PAR-1 is the most important receptor in human platelets. Two PAR-1 antagonists, vorapaxar and atopaxar, have undergone clinical investigation. In this review, we will describe the pharmacology of PAR-1 antagonists and will review and discuss results of randomized clinical trials with PAR-1 antagonists.     

Role of New Antiplatelet Drugs on Cardiovascular Disease: Update on Cangrelor

Dual therapy with a P2Y₁₂ receptor antagonist in addition to aspirin is the antiplatelet treatment of choice in patients with acute coronary syndromes or undergoing percutaneous coronary intervention (PCI). However, available oral P2Y₁₂ antagonists have several limitations, mostly due to their pharmacological profile, which can affect outcomes in certain clinical settings. Cangrelor is an intravenous, direct-acting, potent P2Y₁₂ inhibitor with rapid onset and offset of action, which has been recently approved for clinical use in patients undergoing PCI. In clinical trials, cangrelor has demonstrated greater efficacy than clopidogrel with a favorable safety profile among PCI patients not receiving pretreatment with oral P2Y₁₂ antagonists. However, its definitive role in contemporary practice is yet to be determined. This review aims to provide a comprehensive overview of the current status of knowledge on cangrelor, focusing on its pharmacological properties, clinical development, and the potential applications of this newly available agent.     

不同维持量氯吡格雷对ACS患者血小板聚集功能影响的观察

目的评估不同维持剂量氯吡格雷对择期PCI的ACS患者血小板聚集率的影响,探讨高维持剂量氯吡格雷对ACS患者的有效性及安全性。方法选择接受药物治疗、择期PCI的急性冠脉综合征患者150例,随机分为2组(各75例),2组均服用300mg负荷量氯吡格雷,然后分别给予氯吡格雷150mg/d、75mg/d治疗14d,14d后所有患者接受75mg/d氯吡格雷治疗直至PCI术后1年。分别于服药前、服药后第14天采2组患者静脉血,采用光学比浊法测定血小板聚集率(PA),同时计算血小板聚集抑制率(PAI)。观察住院14天内2组终点事件发生情况。结果试验组和对照组服药前血小板聚集率的差别无统计学意义(89.63±4.89vs.90.27±4.84,p>0.05);试验组服药第14天的血小板聚集率较对照组明显下降(41.36±5.13vs.51.69±3.98,p<0.05),血小板聚集抑制率较对照组明显增强(48.27±6.29vs.38.58±5.48,p<0.05),均有统计学差异。住院14天内,两组均无心血管死亡、严重的颅内出血和严重血小板减少,亚急性血栓形成发生率(1.3%vs4.0%,P>0.05)相近,轻微出血发生率(2.7%vs4.0%,P>0.05)无统计学差异。结论对高危急性冠脉综合症患者,150mg/日高氯吡格雷维持量可以明显降低血小板聚集率,从而降低血栓事件,且不增加短期出血风险,具有较好的耐受性和安全性。     

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.