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 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.     

Evolving pattern of platelet P2Y12 inhibition in patients with acute coronary syndromes

Abstract

Dual antiplatelet therapy consisting of clopidogrel in addition to aspirin has previously been the standard of care for patients with acute coronary syndromes (ACS) but international guidelines have been evolving over the last 4 years with the introduction of prasugrel and ticagrelor. In October 2009, prasugrel was approved in the UK by the National Institute of Health and Clinical Excellence (NICE) for use in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), diabetic patients with non-ST-elevation (NSTE) ACS undergoing PCI and patients with stent thrombosis while other ACS patients were to continue receiving clopidogrel. Ticagrelor was approved in October 2011 by NICE for use in patients with moderate-to-high risk NSTE ACS and STEMI undergoing primary PCI and was recommended in preference to clopidogrel in European guidelines. These recommendations were adopted in our region, constituting a population of 1.8 million. We studied the effect of changing patterns of P2Y₁₂ inhibitor usage on levels of platelet inhibition during maintenance therapy. Patients admitted to Northern General Hospital, Sheffield, with NSTE ACS or STEMI managed with primary PCI were enrolled over two periods of time: May 2010 to November 2011 (T1); and October 2012 to February 2013 (T2). Venous blood samples were obtained at 1 month after the onset of ACS. Light transmittance aggregometry (LTA) was performed and maximum aggregation response to ADP 20?μM was determined. A total of 116 patients were enrolled in T1 of whom 82 were receiving clopidogrel and 34 were receiving prasugrel. Twenty-nine patients were enrolled in T2, all of whom were receiving ticagrelor. Mean LTA results according to treatment with clopidogrel, prasugrel and ticagrelor were 57?±?18%, 41?±?20%, and 31?±?12%, respectively. Prasugrel was associated with significantly lower platelet aggregation responses than clopidogrel (p?<?0.001) and ticagrelor was associated with significantly lower platelet aggregation responses than both prasugrel (p?=?0.015) and clopidogrel (p?<?0.001). We conclude that international guidelines and NICE approval have led to increasing levels of P2Y₁₂ inhibition in ACS patients in this UK centre between May 2010 and February 2013. Ticagrelor was associated with significantly greater P2Y₁₂ inhibition than both clopidogrel and prasugrel during maintenance therapy.     

State of the art of new P2Y<Subscript>12</Subscript> antagonists

The interaction of ADP with its platelet receptor P2Y12 plays a crucial role in platelet activation and thrombogenesis. This article reviews the pharmacology and clinical trials of specific antagonists of P2Y12. Clopidogrel is a thienopyridine with proven antithrombotic efficacy, but it has some important drawbacks: (a) it is a pro-drug that needs to be metabolized to its active metabolite; (b) it has a delayed onset and offset of action and (c) there is high inter-individual variability in pharmacological response. Prasugrel is also a thienopyridine, with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel, accounting for lower incidence of ischemic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and higher incidence of both non-CABG-related bleeding complications. Two direct and reversible P2Y12 antagonists, Cangrelor and ticagrelor, are characterized by rapid onset and reversal of platelet inhibition. Cangrelor is not superior to clopidogrel in preventing thrombotic events in patients undergoing PCI. Ticagrelor is superior to clopidogrel in preventing major adverse cardiac events in ACS patients, but, like prasugrel, is associated with a higher frequency of non-CABG-related bleeding complications. A shorter period of drug discontinuation before surgery is necessary in ticagrelor-treated patients compared to clopiodgrel-treated patients to limit the severity of post-surgical bleeding.     

老年急性冠状动脉综合征患者血小板P选择素、血管性血友病因子的变化及氯吡格雷干预的临床研究

目的观察老年急性冠状动脉综合征(ACS)患者血小板P选择素和血管性血友病因子(vWF)的变化,及抗血小板聚集药物氯吡格雷干预后的临床相关研究,探讨它们在ACS发病机制中的作用和相互联系。方法选取60例老年ACS患者,其中急性心肌梗死(AMI)患者30例,不稳定型心绞痛(UAP)患者30例,另设对照组30例。随机将UAP分为常规治疗组和氯吡格雷(75mg/d)组,AMI组应用抗血小板聚集药物(氯吡格雷300mg+阿司匹林)联合治疗,采用全血法流式细胞术及血浆酶联免疫吸附法测定各组治疗前后血小板P选择素、vWF水平变化,同时探讨P选择素与vWF的相关关系。结果老年ACS患者P选择素、vWF水平[AMI组P选择素(9.74±1.97)%,vWF(272.24±28.62)%;UAP组P选择素(8.87±1.78)%,vWF(215.81±22.01)%]显著高于正常对照组[P选择素(2.27±1.30)%,vWF(112.45±13.22)%](P<0.001)。常规治疗组和氯吡格雷组均可降低UAP患者P选择素与vWF水平[常规治疗组P选择素治疗前(8.60±1.39)%,治疗后(5.60±2.18)%,降低(2.97±1.82)%,vWF治疗前(217.52±25.68)%,治疗后(170.17±20.88)%,降低(47.34±24.31)%;氯吡格雷组P选择素治疗前(9.15±2.11)%,治疗后(4.24±1.73)%,降低(4.89±2.02)%,vWF治疗前(214.10±18.35)%,治疗后(151.72±12.66)%,降低(62.38±21.58)%],但氯吡格雷组较常规治疗组降低的程度更明显(P<0.05),AMI组联合治疗后P选择素与vWF水平均低于治疗前[P选择素(2.27±1.30)%,vWF(112.45±13.22)%](P<0.001),但仍高于对照组(P<0.001)。老年ACS患者P选择素水平与vWF水平成正相关(r=0.365,P<0.05)。结论P选择素、vWF与ACS的发病过程有关,可能是老年ACS不稳定斑块的识别和预测指标。     

Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes.

OBJECTIVES: In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients. BACKGROUND: Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y(12) receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study). METHODS: Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals. RESULTS: AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (+/-SD)]: clopidogrel 64% [+/-22%], AZD6140 90 mg 79% [+/-22%], AZD6140 180 mg 95% [+/-8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel. CONCLUSIONS: AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients.     

Platelet function in clopidogrel-treated patients with acute coronary syndrome.

Percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS) is associated with increased risk of thrombotic complications. ACS enhances platelet activation; whether pretreatment with clopidogrel is sufficient to suppress platelet function in patients with ACS is not known. This study assessed platelet function in patients with and without ACS prior to PCI and after pretreatment with a single dose of 600 mg clopidogrel. Blood samples of 402 patients prior to PCI with (n = 119) or without (n = 283) ACS were collected at least 2 h after 600 mg clopidogrel administration. Maximal platelet aggregation in response to ADP (5 and 20 micromol/l), collagen (4 microg/ml) and TRAP (25 micromol/l) was measured with optical aggregometry. Surface expression of glycoprotein IIb/IIIa and P-selectin was assessed with flow cytometry at baseline and after stimulation with 5 and 20 micromol/l ADP. Agonist-induced platelet aggregation did not differ significantly between patients with and without ACS (P > or = 0.15). Parameters of platelet activation (glycoprotein IIb/IIIa and P-selectin surface expression) were significantly higher in ACS patients at baseline and after 5 and 20 micromol/l ADP stimulation (P < 0.0001). Patients with ACS continue to exhibit increased platelet activation after pretreatment with 600 mg clopidogrel. This finding supports the need for additional platelet function inhibition during PCI in patients with ACS.     

应用血栓弹力图评估ACS患者替格瑞洛与氯吡格雷抗血小板的疗效

目的通过血栓弹力图(TEG)检测血小板聚集率,观察接受双联抗血小板药物治疗的急性冠状动脉综合征(ACS)患者应用替格瑞洛或氯吡格雷的抗血小板疗效。方法选取清华大学第一附属医院心脏中心住院的84例急性冠状动脉综合征患者,随机分为两组,氯吡格雷组(n=42)与替格瑞洛组(n=42),通过TEG检测方法比较两组患者服用氯吡格雷和替格瑞洛后的血小板抑制率情况。结果氯吡格雷组中11例出现氯吡格雷抵抗,发生率为26.19%,替格瑞洛组中1例患者出现替格瑞洛抵抗,发生率为2.38%,两组发生率的比较差异有统计学意义(χ2=9.722,P=0.002);氯吡格雷组中有1例(2.38%)发生阿司匹林抵抗;替格瑞洛组中有2例(4.76%)发生阿司匹林抵抗,两者发生率比较差异无显著统计学意义(χ2=0.346,P=0.557)。结论接受标准抗血小板治疗的部分急性冠状动脉综合征患者存在抗血小板抵抗,TEG监测结果显示,替格瑞洛的抗血小板聚集效果明显优于氯吡格雷。     

The inhibitory potency of clopidogrel on ADP-induced platelet activation is not attenuated when it is co-administered with atorvastatin (20 mg/day) for 5 weeks in patients with acute coronary syndromes

The antiplatelet potency of clopidogrel may be attenuated by short-term co-administration of lipophilic statins metabolized through the cytochrome P-450, isoform 3A4. We investigated whether the co-administration of atorvastatin (20?mg/day) for 5 weeks, in patients with acute coronary syndromes (ACS) could affect the antiplatelet activity of clopidogrel. Fifty-one patients with the first episode of an ACS were included in the study. All patients underwent percutaneous coronary intervention (PCI) and received a loading dose of 375 mg of clopidogrel, followed by 75 mg/day for at least 3 months. Twenty-six of them presented with low density lipoprotein (LDL) cholesterol levels >100?mg/dl (2.6 mmol/l) (measured within 24 h from the onset of symptoms) and received daily 20 mg/day of atorvastatin. The ADP- or TRAP-induced platelet aggregation, as well as P-selectin and CD40L surface expression, were studied at baseline (within 30 min after admission) and 5 weeks afterwards. Atorvastatin did not influence either the clopidogrel-induced inhibition of platelet aggregation initiated by 5 or 10 microM ADP or the clopidogrel-induced reduction of the membrane expression of P-selectin and CD40L induced by ADP. In conclusion, atorvastatin, even at a dose of 20 mg/day does not affect the antiplatelet efficacy of clopidogrel when co-administered for 5 weeks in ACS patients.     

Dynamic platelet adhesion in patients with an acute coronary syndrome: The effect of antiplatelet therapy

Platelet adhesion and aggregation are key functions leading to thrombus formation. The effect of aspirin, clopidogrel, and ticagrelor on platelet aggregation has been well established, however, there is limited data on the effect of these drugs on platelet adhesion. We therefore evaluated the effect of these drugs on platelet adhesion in acute coronary syndrome (ACS) patients. Citrated blood was collected from 50 ACS patients loaded with 325 mg of aspirin (baseline) and at 5 days after the administration of aspirin 100 mg/day and clopidogrel (600 mg loading dose, 75 mg/day) (n = 26) or ticagrelor (180 mg loading dose, 90 mg × 2/day) (n = 24). High on-treatment platelet reactivity (HTPR) to clopidogrel was estimated by vasodilator stimulated phosphoprotein (VASP) phosphorylation assay. Platelet adhesion to collagen was studied for 6 min under high shear stress and was evaluated using the time to platelet recruitment (TPR), the perimeter and average area of each adherent object, number of adherent objects, and the total percent of surface coverage (SC%). Six ACS patients exhibited HTPR to clopidogrel and excluded from the platelet adhesion assays. TPR and SC% values were similar among patient groups at baseline and controls. However, all other adhesion parameters were different in ACS patients, indicating the formation of more aggregates in regard to controls. At 5 days post-treatment with either clopidogrel or ticagrelor, the TPR values were increased and the SC% values were reduced to a similar extent compared with baseline. However, significant differences were observed in the ticagrelor group in the perimeter, number of adherent objects, and the average area of each adherent object indicating a more potent inhibition of adherence-induced platelet aggregation than clopidogrel. In conclusion, aspirin does not affect platelet adherence to collagen, whereas clopidogrel and ticagrelor inhibit to a similar extent dynamic platelet adhesion at 5 days post-treatment in ACS patients. However, ticagrelor exhibits a greater inhibitory effect on reducing adhesion-induced platelet aggregation.     

Inhibition of platelet aggregation with prasugrel and clopidogrel: An integrated analysis in 846 subjects

This integrated analysis compared speed of onset, level of platelet inhibition, and response variability to prasugrel and clopidogrel in healthy subjects and in patients with stable coronary artery disease with data pooled from 24 clinical pharmacology studies. Data from subjects (N = 846) were categorized into the following treatment groups: prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD), clopidogrel 300 mg LD/75 mg MD, or clopidogrel 600 mg LD/75 mg MDs. Maximum platelet aggregation (MPA) and inhibition of platelet aggregation (IPA) to 5 and 20 μM ADP were assessed by turbidimetric aggregometry. A linear mixed-effect model compared the MPA and IPA between treatments over time points evaluated in the integrated database, and covariates affecting platelet inhibition were identified. Prasugrel 60 mg LD resulted in faster onset, greater magnitude, and more consistent levels of inhibition of platelet function compared to either clopidogrel 300 mg or 600 mg LDs. Greater and more consistent levels of platelet inhibition were observed with the prasugrel 10 mg MD compared to the clopidogrel 75 mg MD. This integrated analysis confirms the findings of earlier individual studies, that prasugrel achieves faster onset of greater extent and more consistent platelet inhibition compared to the approved and higher loading doses of clopidogrel. Gender, race, body weight, and age were identified as statistically significant covariates impacting platelet inhibition.     

Evaluation of platelet response to different clopidogrel dosing regimens in patients with acute coronary syndrome in clinical practice

High-post clopidogrel platelet reactivity in acute coronary syndrome (ACS) patients is associated with adverse outcomes and may be related to clopidogrel dosing. Clinical studies evaluating different clopidogrel doses have resulted in conflicting conclusions. Clopidogrel dosing regimens have evolved over time, enabling us to evaluate platelet reactivity in real-life ACS patients undergoing percutaneous coronary intervention and treated with three different clopidogrel doses. Platelet reactivity was assessed with light transmitted aggregometry on the third day post clopidogrel loading in 404 consecutive ACS patients. Of them, 198 were treated with a standard regimen (300?mg loading, 75?mg/day maintenance dose), 95 with a high loading regimen (600?mg loading, 75?mg/day maintenance dose) and 111 with a high loading/high maintenance regimen (600?mg loading, 150?mg/day maintenance). Compared with the standard regimen, the high loading regimen resulted in significantly lower mean platelet reactivity to adenosine diphosphate (ADP) with a lower proportion of patients exhibiting clopidogrel non-responsiveness (11% vs. 28%, p?=?0.004). Compared with the high loading regimen, the high loading/high maintenance regimen resulted in significantly lower mean platelet reactivity to ADP, but without a further drop in the number of non-responders (8.1% vs. 11%, p?=?0.16). In conclusion, greater overall inhibition can be achieved with higher loading and maintenance doses in ACS patients. However, despite high clopidogrel doses, a sizable proportion of patients remained “resistant” to the effects of clopidogrel.     

Platelet aggregation upon acetylsalicylic acid and clopidogrel treatment and glycoprotein IIb/IIIa content in patients with acute coronary syndrome

Interaction between aggregating activity of platelets and glycoprotein (GP) IIb/IIIa (fibrinogen receptor) content on their surface was investigated in patients with acute coronary syndrome (ACS). Eighty nine ACS patients were included into the study - 69 with and 20 without elevation of ST segment. Blood was collected within the first hour of admission to the clinic (1 day), and then at 3-5 and 8-12 days. All patients received standard antiaggregant therapy - acetylsalicylic acid - ASA (thromboxane A2 synthesis inhibitor) and clopidogrel (ADP receptor antagonist). Platelet aggregation was analyzed at the first time point when patients had already taken ASA but not clopidogrel, and then (3-5 and 8- 12 days) upon combined therapy with both preparations. Aggregation was induced by 5 and 20 uM ADP and measured by turbidimetric method. In comparison with the initial level (1 day, ASA) at days 3-5, i.e. after development of clopidogrel effect, platelet aggregation was decreased by 54 and 40% upon its stimulation with 5 and 20 uM ADP, and was not further changed at days 8-12. GP IIb/IIIa content on platelet surface was determined by binding of 125I-labelled monoclonal antibody CRC64. GP IIb/IIIa number varied from 31100 to 73000 per platelet with the mean level of 48500 +/- 8400 (mean +/- standard deviation). No differences were detected between mean GP IIb/IIIa number at 1, 3-5 and 8-12 days after ACS onset. Upon repeat GP IIb/IIIa measurement coefficient of variation was 6.1% demonstrating the stability of this parameter in each patient. Positive correlation between platelet aggregation and GP IIb/IIIa content was detected at the first day - correlation coefficients (r) 0.425 and 0.470 for 5 and 20 uM ADP (n=57, p<0.001). However positive association between these parameters was not revealed at 3-5 and 8-12 days, when patients received not only ASA but clopidogrel as well (r from -0.054 to -0.237, p>0.05). These results indicates that variations of GP IIb/IIIa content affect platelet aggregating activity within first hours of ACS upon ASA treatment. However after saturation with clopidogrel this factor has no significant influence on platelet aggregation, at least on aggregation induced by ADP which receptor is the target of this antiaggregant. Under such conditions aggregation parameters are presumably influenced first of all by individual characteristics of clopidogrel pharmacokinetics.     

Antiplatelet Therapy in Acute Coronary Syndrome (ACS) and PCI: Practical Strategies to Improve Outcomes

Antiplatelet therapy is essential to reduce the risk for ischemic events in patients with acute coronary syndromes (ACS). A fundamental issue in prescribing antiplatelet therapy remains balancing an increased risk for bleeding with efficacy in thrombosis prevention, emphasizing the need to individualize ACS treatment. The current standard is the combination of aspirin with clopidogrel and/or a glycoprotein IIb/IIIa inhibitor. However, evidence indicates reduced platelet inhibition with clopidogrel in carriers of certain genotypes of cytochrome P450 2C19, and American and European regulators recently issued warnings concerning the concomitant use of clopidogrel with drugs that inhibit cytochrome P450 2C19, such as the proton pump inhibitor omeprazole. Clinical trial data illustrate that more potent inhibition of platelets with prasugrel, the newest thienopyridine with a different metabolic pathway from that of clopidogrel, or ticagrelor, a nonthienopyridine, results in faster onset of action and more predictable responses and provides improved efficacy. This increased potency, however, is accompanied by an increased risk for bleeding. Outcomes with antiplatelet therapy also can differ on the basis of patient factors, including co-morbid diabetes mellitus, chronic kidney disease, and patient age. The optimal timing and dosing of antiplatelet therapy in patients who undergo percutaneous intervention has not been fully determined, and questions remain concerning which patients with unstable angina or non-ST elevation myocardial infarction are candidates for early invasive treatment. Clinicians, therefore, should understand the importance of tailoring antithrombotic regimens to individual patients to optimize treatment safety and efficacy.Online Access:http://cmeaccess.com/cme/ajc_acs_program/This CME Multimedia Activity is also available through the Web site of The American Journal of Cardiology (http://www.ajconline.org). Click on the Multimedia tab at the top of the page and then select “CME Multimedia Activities” to access this program through the Journal Homepage.     

Update: orale Thrombozyteninhibitoren in der Kardiologie

The antithrombotic therapy in patients with atherosclerotic vascular disease is subject of several new therapeutic approaches. Simultaneous treatment with acetylsalicylic acid (ASS) and a thienopyridin (clopidogrel) represents the standard of care for patients with acute coronary syndrome and following coronary stenting recommended by many guidelines. Without true evidence this drug combination is used for the prevention of arterial thrombosis in many other vascular interventions (e.g. carotid or aortic stenting). The main problems of this dual antiplatelet therapy are the slow onset of action and the high interindividual variation in the degree of platelet inhibition. The thienopyridin prasugrel is a more potent platelet inhibitor with a more rapid onset of action and smaller interindividual variations in platelet inhibition. The therapeutic superiority of prasugrel was proven in patients with acute coronary syndrome undergoing coronary interventions. As a higher rate of bleeding complications was seen in patient subgroups further clinical studies with prasugrel are ongoing. Newer developments are focusing on ticagrelor, a new ADP-receptor antagonist, which has been proven superior to clopidogrel in clinical studies and triple therapy utilizing ASS, clopidogrel, and one of the new highly specific antithrombotics (e.g. factors Xa-antagonists or direct thrombin inhibitors).     

The platelet hyporesponsiveness to clopidogrel in acute coronary syndrome patients treated with 75 mg/day clopidogrel may be overcome within 1 month of treatment

Platelets are involved in thrombus formation and inflammation following vascular injury, while clopidogrel exerts antithrombotic and anti-inflammatory actions. We investigated various platelet-derived prothrombotic and proinflammatory mediators as well as the platelet aggregatory response in patients with acute coronary syndromes (ACS) receiving clopidogrel, as a function of the patient responsiveness to drug treatment. Blood samples were obtained from 40 patients with recent (<24?h) ACS before clopidogrel loading 600?mg (followed by a maintenance dose of 75?mg/day) as well as 5-days and 30-days afterwards. Twelve patients exhibited platelet reactivity index (PRI) values higher than 50% evaluated by the Vasodilator Stimulated Phosphoprotein (VASP) test at 5 days and were characterized as nonresponders. The platelet response to adenosine diphosphate (ADP) and thrombin receptor agonist peptide-14 (TRAP) was studied by flow cytometry and light transmission aggregometry. A maximum reduction of ADP- or TRAP-induced platelet aggregation in 28 clopidogrel responding patients was observed at 5 days postclopidogrel loading, whereas in nonresponders, it was achieved at 30-days along with a significant decrease in the PRI values. Similar results were obtained for the membrane expression of CD40L and the production of platelet-derived microparticles. By contrast, the maximum inhibition of P-selectin expression and platelet-leukocyte conjugate formation was observed at 30-days in both patient groups. A maintenance dose of 75?mg clopidogrel differentially affects the platelet aggregation and platelet-derived prothrombotic and proinflammatory mediators in ACS patients within the first month of the treatment, a phenomenon that is highly influenced by the drug response variability. Since these factors may be involved in the major adverse cardiovascular events in ACS patients, especially in those undergoing percutaneous coronary intervention, the above findings may be clinically important.     

Ticagrelor: The First Reversibly Binding Oral P2Y12 Receptor Antagonist

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y₁₂ receptor antagonist that blocks ADP‐induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y₁₂ receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate greater separation between antithrombotic effects and bleeding effects with ticagrelor than with thienopyridines. Unlike the thienopyridines, ticagrelor does not require metabolic activation. It is quickly absorbed and exhibits a rapid antiplatelet effect, with higher and more consistent levels of inhibition of platelet aggregation (IPA) being maintained across the dosing interval than with clopidogrel. IPA levels decline with plasma drug levels after discontinuation of dosing. In the phase II DISPERSE‐2 trial of 990 patients with non‐ST‐elevation acute coronary syndromes (ACS), ticagrelor treatment with 90 mg and 180 mg twice daily showed comparable rates of major and minor bleeding compared with clopidogrel 75 mg while there were numerically fewer myocardial infarctions. Ticagrelor resulted in greater IPA in clopidogrel‐naïve patients and produced substantial additional reductions in platelet aggregation activity in patients pretreated with clopidogrel. Ticagrelor treatment was well tolerated in DISPERSE‐2, and discontinuation rates were comparable to those observed for clopidogrel. An increased risk of mild to moderate dyspnea and mostly asymptomatic ventricular pauses were observed in phase II studies. The mechanisms for these effects are currently being investigated. The efficacy and safety of ticagrelor are being further evaluated in the phase III PLATO trial, involving approximately 18,000 patients with ACS, including both ST‐elevation and non‐ST‐elevation ACS.     

Antiplatelet therapy in acute coronary syndrome (ACS): applying new science to clinical decisions

The platelet is central to the pathogenesis of acute coronary syndromes (ACS), and antiplatelet therapy has demonstrated a significant reduction in the risk for ischemic events in patients with ACS. For patients with unstable angina or non-ST elevation myocardial infarctions, regardless of whether a conservative or invasive (i.e., percutaneous intervention) treatment approach is used, current guidelines recommend combination antiplatelet therapies, including aspirin with the thienopyridines clopidogrel or prasugrel and/or a glycoprotein IIb/IIIa inhibitor. However, there remains a significant incidence of arterial thrombosis in patients receiving currently available antiplatelet therapy, indicating the need for improved and/or alternative agents and targets. Recent landmark clinical trials of new oral antiplatelet therapies, including the thienopyridine prasugrel and the investigational reversible oral adenosine diphosphate antagonist ticagrelor, indicate they have a faster onset of action, result in a more predictable response, and provide improved efficacy compared to clopidogrel, the current standard of care. Other promising potential targets under investigation to reduce the contribution of the platelet to ACS pathophysiology include von Willebrand factor, thromboxane A₂, and protease-activated receptor-1. Of these, the protease-activated receptor-1 antagonist vorapaxar (SCH 530348) is furthest along in clinical development, with phase II data showing profound inhibition of platelet aggregation and a large phase III development program under way. A fundamental lingering issue is whether improved prevention and treatment of thrombosis can be separated from an increase in hemorrhage or bleeding, and clinicians must continue to consider the potential risks and benefits when individualizing antiplatelet therapy for patients with ACS.Online Access:http://cmeaccess.com/cme/ajc_acs_program/This CME Multimedia Activity is also available through the Web site of The American Journal of Cardiology (http://www.ajconline.org). Click on the Multimedia tab at the top of the page and then select “CME Multimedia Activities” to access this program through the Journal Homepage.     

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.