Long-term effects of baseline on-treatment platelet reactivity in patients with acute coronary syndrome and thrombocytopenia undergoing percutaneous coronary intervention

ObjectiveTo analyse the association between on-treatment platelet reactivity (TPR) and long-term outcomes of patients with acute coronary syndrome (ACS) and thrombocytopenia (TP) in the real world.MethodsThis prospective observational study enrolled patients with coronary artery disease (CAD) that underwent percutaneous coronary intervention (PCI). Patients with ACS and TP under dual antiplatelet therapy were selected for analysis. The 2- and 5-year clinical outcomes were evaluated among patients with high on-treatment platelet reactivity (HTPR), low on-treatment platelet reactivity (LTPR) and normal on-treatment platelet reactivity (NTPR), as tested by thromboelastogram at baseline.ResultsA total of 10 724 patients with CAD that underwent PCI were identified. Of these, 474 patients with ACS and TP met the inclusion criteria: 124 (26.2%) with HTPR, 163 (34.4%) with LTPR and 187 (39.5%) with NTPR. The 5-year rates of all-cause death, major adverse cardiovascular and cerebrovascular events, cardiac death, myocardial infarction, revascularization, stroke and bleeding were not significantly different among the three groups. Multivariate Cox regression analysis demonstrated that patients with HTPR were not independently associated with any of the 5-year endpoints compared with patients with NTPR.ConclusionsTPR at baseline was not independently associated with long-term outcomes in patients with ACS and TP that underwent PCI.     

Dual antiplatelet therapy unmasks distinct platelet reactivity in patients with coronary artery disease

Summary. Background: Platelet‐induced thrombosis is a major risk factor for recurrent ischemic events, although platelet function in patients with cardiovascular disease taking aspirin and clopidogrel is very poorly characterized. The aim of this study was to assess platelet reactivity in patients with cardiovascular disease taking aspirin and clopidogrel. Methods: We developed a rapid assay to measure platelet aggregation in response to arachidonic acid, collagen, adenosine diphosphate (ADP), epinephrine and thrombin receptor activating peptide (TRAP) in 80 healthy volunteers. We then recruited 200 consecutive patients from outpatient clinics and the cardiac catheterization laboratory and tested platelet function. Platelet aggregation induced by epinephrine is a marker of global platelet reactivity. We tested platelet function in 146 patients compliant with antiplatelet therapy. Platelet aggregation to epinephrine was divided into quartiles. The platelet response to the other agonists was analysed based on the response to epinephrine. Results: Platelet reactivity increased significantly across the quartiles in response to epinephrine in healthy volunteers and patients (P < 0.0001). A significant increase in response across quartiles was seen with all agonists in healthy volunteers (P < 0.001). In contrast, a significant increase in response across quartiles was only seen with ADP in patients (P < 0.0001). Hypertension, smoking and diabetes were significantly associated with increasing platelet reactivity to epinephrine (P < 0.05). Conclusion: This study shows that platelet response differs between healthy volunteers and patients on dual antiplatelet therapy. In patients with cardiovascular disease, dual antiplatelet therapy unmasks a distinct type of platelet reactivity in response to epinephrine and ADP but not other agonists.     

Biolimus-eluting stent with biodegradable polymer (Nobori®): an overview of recent clinical results,SORT OUT V and COMPARE II trials

Evaluation of: Christiansen E, Jensen L, Thayssen P et al. Biolimus eluting biodegradable polymer coated stent vs durable polymer coated sirolimus eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomized non inferiority trial. Lancet 381, 661–669 (2013); Smits P, Hofma S, Togni M et al. Abluminal biodegradable polymer biolimus-eluting stent vs durable polymer everolimus eluting stent (COMPARE II): a randomized, controlled, non inferiority trial. Lancet 381, 651–660 (2013).

Since their apparition, first generation drug-eluting stents (DESs) have raised concerns regarding the risk of late and very late stent thrombosis as compared to bare metal stents and require prolonged dual antiplatelet therapy. Aside from delayed strut endothelialisation, positive vessel remodelling and late stent mal-apposition due to chronic inflammation may be a leading cause for these stent thromboses. In fact, the persistence of the durable polymer after complete drug release is responsible for local hypersensitivity and inflammatory reactions. Third generation DESs with biocompatible or biodegradable polymer have subsequently been developed to address this issue. In this article, we evaluate and discuss the results of two recent publications investigating safety and efficacy of a third generation DES with biodegradable polymer as compared to first and second generation DESs with durable polymer.     

Clopidogrel discontinuation and platelet reactivity following coronary stenting

See also Lordkipanidzé M, Harrison P. Beware of being caught on the rebound. This issue, pp 21–3. Summary. Aims: Antiplatelet therapy with aspirin and clopidogrel is recommended for 1 year after drug‐eluting stent (DES) implantation or myocardial infarction. However, the discontinuation of antiplatelet therapy has become an important issue as recent studies have suggested a clustering of ischemic events within 90 days of clopidogrel withdrawal. The objective of this investigation was to explore the hypothesis that there is a transient ‘rebound’ increase in platelet reactivity within 3 months of clopidogrel discontinuation. Methods and Results: In this prospective study, platelet function was assessed in patients taking aspirin and clopidogrel for at least 1 year following DES implantation. Platelet aggregation was measured using a modification of light transmission aggregometry in response to multiple concentrations of adenosine diphosphate (ADP), epinephrine, arachidonic acid, thrombin receptor activating peptide and collagen. Clopidogrel was stopped and platelet function was reassessed 1 week, 1 month and 3 months later. Thirty‐two patients on dual antiplatelet therapy were recruited. Discontinuation of clopidogrel increased platelet aggregation to all agonists, except arachidonic acid. Platelet aggregation in response to ADP (2.5, 5, 10, and 20 μm ) and epinephrine (5 and 20 μm ) was significantly increased at 1 month compared with 3 months following clopidogrel withdrawal. Thus, a transient period of increased platelet reactivity to both ADP and epinephrine was observed 1 month after clopidogrel discontinuation. Conclusions: This study demonstrates a transient increase in platelet reactivity 1 month after clopidogrel withdrawal. This phenomenon may, in part, explain the known clustering of thrombotic events observed after clopidogrel discontinuation. This observation requires confirmation in larger populations.     

A case–control study on platelet reactivity in patients with coronary stent thrombosis

Summary. Background: The pathophysiology of stent thrombosis (ST) has evolved from the identification of single causative factors to a complex multifactorial model. Objectives: The aim of the present study was to investigate whether patients with a history of ST exhibit heightened platelet reactivity to clopidogrel and aspirin. Patients/methods: Pretreatment and on‐treatment platelet reactivity to clopidogrel and aspirin, as well as dual antiplatelet therapy resistance, was determined in 84 patients with a history of definite ST (cases: 41 early ST; 43 late ST) and in 103 control patients with a previously implanted coronary stent but no ST after the index procedure. Platelet function was evaluated with optical aggregometry, the VerifyNow P2Y12 and aspirin assays, the PFA‐100 Innovance P2Y* cartridge, the flow cytometric vasodilator‐stimulated phosphoprotein assay and urine 11‐dehydrothromboxane B₂ measurement before and after the administration of a 600‐mg loading dose of clopidogrel and 100 mg of aspirin. The study was registered at ClinicalTrials.gov, number NCT01012544. Results: Patients with a history of early ST clearly demonstrated higher on‐clopidogrel platelet reactivity than controls. Patients with both early and late ST exhibited heightened on‐aspirin platelet reactivity status, and dual antiplatelet therapy resistance was more frequent. Conclusions: Patients with a history of early ST exhibit a poor response to clopidogrel. Furthermore, both early and late ST are strongly and independently associated with heightened on‐aspirin platelet reactivity, and dual antiplatelet therapy resistance is more frequent.     

Personalized antiplatelet therapy for coronary artery disease patients: is this the future?

Clopidogrel has decreased the rate of thrombotic events in patients undergoing percutaneous coronary intervention. However, two major limitations of the drug have been involved in the persistence of a relatively high rate of adverse events. The recent literature suggested that improved platelet reactivity inhibition using a higher or tailored dose of clopidogrel, or a more potent agent, could reduce the rate of events. The development of new antiplatelet agents and the increasing availability of platelet assays are likely to profoundly modify current practice and favor personalized antiplatelet therapy.     

Individualizing dual antiplatelet therapy duration after percutaneous coronary intervention: from randomized control trials to personalized medicine

Introduction: Improved stent technologies have lead to reduced minimum durations of dual antiplatelet therapy (DAPT) to prevent stent thrombosis. However, the anti-ischemic benefits seen in extended DAPT in both stent and non-stent related lesions have called into question the optimum duration of DAPT after stent placement.

Areas covered: We review the evidence for varying durations of DAPT after drug eluting stent placement including for patients on oral anticoagulation; decision tools available for clinicians to optimize patient selection for extended therapy and insight into application of these risk assessment tools in clinical practice.

Expert commentary: The use of risk assessment tools in optimizing DAPT duration after stent placement provides an opportunity for improved outcomes by means of a personalized approach to care while allowing clinicians to engage with patients in shared-decision making.     

阿托伐他汀联合氯吡格雷对急性冠脉综合征PCI术后血小板活化指标、斑块稳定性及血小板膜糖蛋白的影响

目的探讨阿托伐他汀联合氯吡格雷对急性冠脉综合征经皮冠状动脉介入(PCI)术后血小板活化指标、斑块稳定性的影响。方法择期PCI术的急性冠脉综合征患者120例随机分为2组。对照组给予常规治疗,观察组在对照组基础上给予阿托伐他汀。检测2组术后血小板活化指标、炎性因子及血管内皮功能的变化,比较2组术后1年心血管事件发生率和再狭窄率。结果观察组PCI术后CD62p、CD63p、GPⅡb/Ⅲa均显著低于对照组(P0.05);观察组术后CRP、TNF-α、IL-6水平显著低于对照组(P0.05);观察组术后NO显著高于对照组,EF-1显著低于对照组(P0.05);观察组术后1年心血管事件发生率和术后再狭窄率显著低于对照组(P0.05)。结论阿托伐他汀联合氯吡格雷汀能有效控制急性冠脉综征PCI术后血小板活化,降低炎性水平,维持斑块稳定。     

Relationship between post‐treatment platelet reactivity and ischemic and bleeding events at 1‐year follow‐up in patients receiving prasugrel

Summary. Background: Post‐treatment platelet reactivity (PR) is associated with ischemic and bleeding events in patients receiving P2Y12 receptor antagonists. Objectives: We aimed to study the relationship between post‐treatment PR after a 60‐mg loading dose (LD) of prasugrel and 1‐year thrombotic and bleeding events. Method: Patients were prospectively included in this multicenter study if they had a successful percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and received prasugrel. The platelet reactivity index (PRI) was measured using the Vasodilator‐Stimulated Phosphoprotein index (VASP) after a prasugrel LD. Endpoints included the rate of thrombotic events and bleeding events at 1 year. Results: Among the 301 patients enrolled, 9 (3%) were lost to follow‐up at 1 year. The rates of thrombotic and bleeding events at 1 year were of 7.5% and 6.8%, respectively. Receiver‐operating curve (ROC) analysis demonstrated an optimal cut‐off value of 53.5% of PRI to predict thrombotic events at 1 year. Using this cut‐off value we observed that patients exhibiting high on‐treatment platelet reactivity (HTPR) had a higher rate of thrombotic events (22.4% vs. 2.9%; P < 0.001). In parallel the optimal cut‐off value of PRI to predict bleeding was 16%. Patients with a PRI ≤ 16% had a higher rate of bleeding events compared with those with a PRI > 16% (15.6% vs. 3.3%; P < 0.001). In multivariate analysis, the PRI predicted both thrombotic and bleeding events (OR: 1.44, 95% confidence interval [CI]: 1.2–1.72; P < 0.001 and OR: 0.75, 95% CI: 0.59–0.96; P = 0.024 [respectively, per 10% increase]). Conclusion: Platelet reactivity measurement after a prasugrel LD predicts both ischemic and bleeding events at 1 year follow‐up for ACS patients undergoing PCI.     

Cangrelor: a review on its mechanism of action and clinical development

In patients with acute coronary syndromes and undergoing percutaneous coronary intervention, numerous large-scale clinical trials have shown that adjunctive treatment with the P2Y₁₂ receptor antagonist clopidogrel in addition to aspirin reduces ischemic events. These studies underscore the importance of blockade of the P2Y₁₂ signaling pathway in these settings. However, recent findings have shown that clopidogrel therapy may have some shortcomings. These include its broad range of interindividual-response profiles, where patients with low P2Y₁₂ inhibitory effects have an increased risk of recurrent ischemic events, including stent thrombosis, and its irreversible mechanism of action. These observations underscore the need for novel antiplatelet agents overcoming these limitations. Cangrelor (AR-C69931MX) is an intravenous, direct-acting and reversible P2Y₁₂ receptor antagonist. Cangrelor has a rapid onset and offset of action and achieves significantly greater degrees of platelet inhibition compared with clopidogrel. This article provides an overview of the current status of knowledge on cangrelor, focusing on its pharmacologic properties, clinical development and potential future applications.     

冠状动脉介入治疗术后三联抗血小板治疗对冠心病合并糖尿病患者的影响

目的 探讨冠心病合并糖尿病患者冠状动脉介入治疗(percutaneous coronary intervention,PCI)术后阿司匹林、氯吡格雷及西洛他唑三联抗血小板治疗对血小板功能及短期预后的影响.方法 318例患者分为双联抗血小板组和三联抗血小板组,于术前、术后7天及术后30天测定p-选择素及血小板聚集率(platelet aggregation rate,PAR),并且统计1个月内主要心血管不良事件(major adverse cardiovascular events,MACE)发生率.结果 术后7天、术后30天三联组较双联组P-选择素表达率均显著降低,差异均有统计学意义[(5.25±2.09)％ vs(6.03±2.12)％,(2.67±1.67)％ vs (3.24±1.98)％,P＜0.05].术后7天、术后30天三联组较双联组PAR均显著降低,差异均有统计学意义[(22.02±6.02)％ vs (29.06±5.71)％,(20.03±4.62)％ vs (26.78±4.35)％,P＜0.05].随访1个月,三联组及双联组MACE发生率分别为1.85％(3/162)、7.05％(11/156),差异有统计学意义(P＜0.05).出血的发生率分别为9.26％(15/162)、7.05％(11/156),差异无统计学意义(P＞0.05).结论 三联抗血小板治疗能够更有效地抑制冠心病合并糖尿病患者血小板的活化和聚集,降低PCI术后MACE事件发生率且不增加出血风险.     

Acute coronary syndromes: considerations for improved acceptance and implementation of management guidelines

The management of acute coronary syndrome in Europe is covered by various European Society of Cardiology guidelines, which although valuable, are complex and may not always provide clear guidance in everyday clinical practice. Consequently, implementation of the guideline recommendations is frequently suboptimal. To complicate matters further, a wealth of new data from large trials examining novel anti-thrombotic agents will become or are already available, necessitating guideline updates. This article summarizes the gaps between current guideline-recommended treatment of acute coronary syndrome and daily practice as dictated by the evidence base, including recent trials. Reasons for the suboptimal implementation of the current European Society of Cardiology guidelines and possible solutions to making these more practice oriented are presented.     

冠心病患者经皮冠状动脉介入治疗术后抗血小板药物治疗监测及平均血小板体积变化

目的比较血栓弹力图(TEG)和光学比浊法(LTA)在监测冠心病患者经皮冠状动脉介入治疗(PCI)术后抗血小板药物中的相关性;观察PCI术后双联抗血小板治疗患者平均血小板体积(MPV)变化。方法回顾2013年3月至2014年5月在北京大学第一医院行PCI并接受规范双联抗血小板治疗的患者177例;回顾分析其TEG测定的二磷酸腺苷(ADP)、花生四烯酸(AA)诱导的血小板抑制率,服用抗血小板药物前后MPV,以及其中99例患者LTA测定的血小板聚集率。结果 ADP、ARA诱导的LTA血小板聚集率与TEG血小板抑制率无相关性(P均0.05)。氯吡格雷低反应性LTA和TEG检出率分别为30.3%和45.5%,阿司匹林低反应性检出率分别为19.2%和31.3%,低反应性检出率LTA低于TEG法(P0.05)。177例患者中,氯吡格雷低反应组和敏感组、阿司匹林低反应性组和敏感组服药后MPV均较服药前降低(P均0.01);服药前及服药后氯吡格雷低反应性组MPV均低于敏感组(P均0.05);氯吡格雷及阿司匹林低反应组服药后PLT高于服药前(P均0.05)。结论 TEG和LTA两种方法相关性较差,抗血小板药物低反应检出率均较高,值得临床医生注意;服用双联抗血小板药物后MPV降低;服药后PLT上升患者更易发生药物低反应性;MPV偏低患者氯吡格雷低反应性发生可能性更大。     

Triple antithrombotic therapy in patients with atrial fibrillation undergoing PCI: current evidence and practice

Introduction: Patients with atrial fibrillation taking oral anticoagulation and undergoing percutaneous coronary intervention with stent insertion are recommended to receive antithrombotic therapy with aspirin and P2Y₁₂ receptor antagonist. This combinatory regime encompasses triple therapy (TT). Although TT reduces the risk of ischemic events such as stroke and stent thrombosis, it is associated with an increased bleeding risk.

Areas covered: The efficacy and safety profile of TT is uncertain with undetermined optimal duration and therapeutic combination. This review summarizes relevant trials evaluating TTs application and introduces exploration of duration and dosage in addition to other contributory factors including stent type and choice of antithrombotic agents.

Expert commentary: TT has shown to be effective for reduction of ischemic risk. However, trials have failed to demonstrate the regime’s superiority in efficacy over alternatives such as dual therapy (single antiplatelet plus anticoagulant) and continue to denote an increased bleeding risk. Further research driven by a balance between thromboembolic and bleeding end points is required to demonstrate TTs potential beneficence, along with optimal duration identification and antithrombotic choice. Individualized patient risk stratification, along with risk factor optimization should also be incorporated.     

Clopidogrel’s role in the management of atherosclerotic disease: a focus on acute coronary syndromes

Recent advances in our understanding of the role of the platelet in the atherosclerotic process beyond the acute formation of arterial blood clots, such as inflammation, have highlighted the role of antiplatelet agents as being much more than just ‘blood thinners.’ Some of the most important cardiovascular trials performed in the last 20 years have studied antiplatelet therapies. However, despite their long history, current global health implications and proven benefit, there remain substantial gaps in our understanding as to how to best utilize the limited number of antiplatelet agents available. This article will discuss the mechanism of action of the antiplatelet class known as thienopyridines, the pharmacodynamics and pharmacokinetics of the thienopyridine agent clopidogrel (Plavix^®, Bristol-Myers Squibb and Sanofi Pharmaceuticals) as well as the literature supporting its clinical benefits and areas of ongoing research that will help clarify the optimal utilization of clopidogrel for the treatment of cardiovascular disease.