Decreasing incidence of stent thrombosis

Stent thrombosis (ST) remains a major pitfall of stent implantation in contemporary percutaneous coronary intervention (PCI) leading to high rates of death and non-fatal myocardial infarction. Many predictors of ST have been reported worldwide but the strongest have to be highlighted regarding the catastrophic prognosis of such an event. Because platelet aggregation has a pivotal role in ST pathogenesis, the new antiplatelet regimens combining aspirin and P2Y12 receptor inhibitors have led to a remarkable decrease in the ST incidence, especially in the setting of acute coronary syndrome (ACS). In this article, our purpose is to review the evolution of ST incidence since first stent use in PCI. We will also overview the main predictors of ST focusing on ACS and clopidogrel low response.     

Update on Glycoprotein IIb/IIIa Blockade in Endovascular Interventions

Platelet aggregation plays a central role in the ischemic complications of percutaneous coronary interventions (PCI) and the acute coronary syndromes (ACS). Although aspirin and heparin have been effective at decreasing adverse events in these settings, the perceived need for more potent inhibition of platelet aggregation has led to targeting of the platelet surface membrane glycoprotein IIb/IIIa (GP IIb/IIIa) receptor. Several agents have been developed; four: abciximab, tirofiban, eptifibatide, and lamifiban have been tested in clinical trials. Overall, the positive findings of these studies have supported the hypothesis that enhanced platelet blockade leads to improved clinical outcomes in the settings of PCI and ACS. In this article, an overview of the various GP IIb/IIIa receptor inhibitors is presented. The clinical trials of these agents as adjunctive therapy for patients undergoing PCI and in treatment of acute myocardial infarction are reviewed. Practical considerations relating to clinical efficacy, drug safety, and economic issues are discussed.     

The role of enoxaparin in interventional management of patients with acute coronary syndromes

Interventional management strategies involving early angiography and percutaneous coronary intervention (PCI) are increasingly widespread in the management of patients with acute coronary syndromes (ACS). Notwithstanding the benefits of early intervention, there is a significant risk of postprocedural thrombotic complications and a need to optimize antithrombotic regimens for use before and during PCI. It is clear that the current standard therapy with unfractionated heparin (UFH) and aspirin can be improved upon, in terms of both efficacy and safety. The low-molecular-weight heparin(s) (LMWHs) offer pharmacologic and practical advantages over UFH. The LMWH enoxaparin has recently emerged as the anticoagulant of choice for the acute management of ACS. Enoxaparin has also demonstrated sustained benefits over UFH in patients proceeding to PCI, and as a procedural anticoagulant. Combination therapy with enoxaparin and a glycoprotein IIb/IIIa inhibitor may further improve the efficacy and safety of antithrombotic treatment during coronary interventions, as a result of the drugs' complementary mechanisms of action. Early clinical evidence supports the use of enoxaparin in combination with glycoprotein IIb/IIIa inhibitors in high-risk patients with ACS. Ongoing, large-scale, randomized controlled studies will help to clarify the role of enoxaparin in interventional cardiology, either as the primary anticoagulant or as part of a combination regimen, and to define optimal regimens for treatment.     

Current knowledge of the platelet glycoprotein IIb/IIIa receptor antagonists for the treatment of coronary artery disease

Understanding of the pivotal role of the platelet surface membrane glycoprotein (GP) IIb/IIIa receptor in platelet aggregation at the injured coronary plaque in acute coronary syndromes has led to recent pharmacologic strategies that focus on inhibition of this final common pathway. Several intravenous medications directed specifically at this receptor (called platelet GP IIb/IIIa receptor antagonists; GPAs) have emerged. These include the human-murine chimeric monoclonal antibody Fab fragment abciximab, the peptide antagonist eptifibatide and the peptidomimetics tirofiban and lamifiban. To date, over 33,000 patients have been studied with these compounds in 11 large, randomized placebo controlled trials which have established the effectiveness of these drugs in conditions where platelet aggregation and thrombosis play major contributing roles such as in high-risk coronary intervention, myocardial infarction and unstable angina. GPAs have been proven to be effective in reducing ischemic complications when used as an adjunct to percutaneous coronary revascularization or the management of acute ischemic syndromes. They are well tolerated and safe, provided concomitant use with other antithrombotics (e.g. heparin) is carefully managed and platelet counts are monitored.     

The Problem of Persistent Platelet Activation in Acute Coronary Syndromes and Following Percutaneous Coronary Intervention

Platelets play a central role in the atherosclerotic inflammatory response, thrombotic vascular occlusion, microembolization, vasoconstriction, and plaque progression. Persistent platelet activation poses a serious problem among patients with acute coronary syndromes (ACS) and those who have undergone percutaneous coronary intervention (PCI), placing them at risk for ischemic events and subacute stent thrombosis. Patients undergoing PCI are at risk for further ischemic events because of procedure‐related platelet activation as well as the inherent persistent platelet hyperreactivity and enhanced thrombin generation associated with ACS. Persistent platelet activation following an acute coronary event and/or PCI supports incorporating antiplatelet strategies into the standard medical management of such patients. In this clinical setting, antiplatelet therapies are capable of improving outcomes. Aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors, the 3 major pharmacologic approaches to persistent platelet activation, target various levels of the hemostatic pathways and thrombus formation. Copyright © 2008 Wiley Periodicals, Inc.     

Combination Enoxaparin and Abciximab During Percutaneous Coronary Intervention: A New Standard of Care?

Evidence from randomized trials supports the administration of platelet glycoprotein (GP) IIb/IIIa blockade both to patients undergoing percutaneous coronary intervention (PCI) and those presenting with non-ST elevation acute coronary syndromes (ACSs). Similarly, the low molecular weight heparin (LMWH), enoxaparin, has demonstrated superior efficacy when compared with unfractionated heparin (UFH) in the treatment of patients with non-ST elevation ACS. Algorithms for seamless integration of pharmacotherpy through the course of hospitalization for patients who present with ACS and who require PCI will likely combine therapy with enoxaparin and platelet GP IIb/IIIa blockade (abciximab). Our preliminary experience with combination enoxaparin and abciximab as adjunctive pharmacotherapy for PCI suggests that this strategy is safe and effective and may offer advantages over a conventional strategy, which employs UFH.     

他汀类药对氯吡格雷抗血小板作用的影响

目的 前瞻性评价普伐他汀、氟伐他汀、阿托伐他汀对氯吡格雷抗血小板作用的影响.方法 人选连续1015例急性冠状动脉综合征或稳定性心绞痛行冠状动脉造影和(或)支架术患者,分为普伐他汀组(228例)、氟伐他汀组(179例)、阿托伐他汀组(481例)和对照组(127例).比较各组术后支架内血栓发生率、不同浓度(2、5、10、20 μmol)二磷酸腺苷(ADP)诱导的1 min(ADP-1)、5 min(ADP-5)和最大血小板聚集力(ADP-M)及其影响因素.结果 4组患者基础临床情况(除年龄、高血压及冠状动脉造影复查率外)和冠状动脉病变和(或)支架术情况相似,术后支架内血栓发生率(普伐他汀组0.9%、氟伐他汀组1.1%、阿托伐他汀组1.0%、对照组0.8%,P>0.05)和ADP-1、ADP-5、ADP-M与对照组相比差异均无统计学意义(P均>0.05).多因素回归分析显示,年龄(B=0.21,P=0.001)、氯吡格雷总量(B=7.30,P=0.002)及低分子肝素的使用(OR=6.71,P=0.01)是影响氯吡格雷抗血小板作用的独立决定因素.结论 普伐他汀、氟伐他汀和阿托伐他汀对氯吡格雷的抗血小板作用无明显影响,而年龄、氯吡格雷总量及低分子肝素使用是决定氯吡格雷抗血小板作用的独立因素.     

Direct thrombin inhibitors in acute coronary syndrome patients undergoing percutaneous coronary intervention: special effects in selected patients?

Coronary thrombosis is a pivotal event in the pathogenesis ofacute coronary syndromes (ACS) as well as in the incidence ofthrombotic complications resulting from percutaneous coronaryinterventions (PCIs).¹ Platelet adhesion and aggregation atthe site of spontaneous or provoked plaque rupture is an importantcontributor of such intracoronary thrombus formation. As activationof the platelet glycoprotein (GP) IIb/IIIa receptor is the finalcommon pathway in the process leading to platelet aggregation,inhibitors of the platelet GP IIb/IIIa are potent agents toprevent progression to myocardial infarction (MI) and death.In a recent meta-analysis of six phase III randomized trials,which enrolled 31 402 ACS patients without ST-elevationwho were not scheduled for early PCI, GP IIb/IIIa inhibitorswere associated     

Low-molecular-weight heparin and other antithrombotic agents in the setting of a primarily medical treatment of unstable coronary artery disease

Antithrombotic treatment of acute coronary syndromes (ACS) comprises aspirin and (low-molecular-weight) heparin. Adjunctive treatment with intravenous glycoprotein IIb/IIIa receptor antagonists may be used in high-risk individuals, especially when they undergo percutaneous coronary interventions. Results from large-scale trials studying the efficacy and safety of oral glycoprotein IIb/IIIa blockers in patients with ACS have been disappointing. Thrombolytic therapy is not indicated in ACS.     

Interpretation of new treatment guidelines for non-ST-segment elevation acute coronary syndromes: "ischemia-guided" versus "early invasive" strategies

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines has recently published recommendations regarding the diagnosis and management of patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). Conventional therapy for non-ST-segment elevation acute coronary syndrome (NSTE ACS) has traditionally employed an "ischemia-guided" approach in which diagnostic cardiac catheterization and revascularization are only used in patients with objective-evidence of residual myocardial ischemia as identified by recurrent symptoms or provocative stress testing. More recent studies, however, have demonstrated improved clinical outcomes with the use of an "early invasive" approach, employing routine coronary angiography early in the patient's hospital course, followed by percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery where appropriate. Improved clinical outcomes associated with an "early invasive" strategy may have evolved as a consequence of recent advances in both adjunctive pharmacotherapy and revascularization technique. For example, use of GP IIb/IIIa inhibitors and/or low-molecular-weight heparin prior to catheterization have been shown to reduce clinical events in NSTE ACS patients, and may reduce the risk of an invasive approach by plaque passivation prior to interventional therapy. Perhaps more importantly, the combined use of GP IIb/IIIa inhibitors and intracoronary stenting may reduce the potential early hazard of an invasive approach by specifically decreasing the incidence of death and non-fatal myocardial infarction associated with percutaneous intervention. In spite of the benefits of this synergistic combination of pharmacology and mechanical revascularization, risk stratification remains important in identifying high-risk individuals most likely to benefit from an "early invasive" approach.     

Platelet Inhibition in Cardiovascular Disease Management: Aspirin and Beyond

Intracoronary thrombosis is the central event in the pathophysiology of the acute coronary syndromes and of the complications of percutaneous coronary intervention. Hemostasis and thrombosis involve a complex series of interactions of both platelets and the coagulation system. Standard antithrombotic therapy for cardiovascular disease typically combines use of antiplatelet therapy with aspirin and antithrombin therapy with heparin. Ticlopidine appears to be a reasonable alternative as an antiplatelet agent in the patient who is intolerant of aspirin. The combination of ticlopidine and aspirin may be especially effective in preventing coronary events in the post-coronary stenting patient. Clopidogrel may offer incremental benefit beyond aspirin in a broad array of vascular diseases, but the cost effectiveness of such a strategy remains to be determined. Finally, potent antiplatelet therapy with platelet glycoprotein IIb/IIIa receptor inhibition clearly improves angioplasty outcomes and may have a role in the treatment of patients with acute coronary syndromes.     

比伐芦定在高出血风险患者介入治疗中抗凝疗效和安全性评价

目的：评价比伐芦定在高出血风险急性冠脉综合征（ACS）患者介入治疗中抗凝疗效和安全性。 方法：随机将入选的ACS患者分为比伐芦定组（104例）和肝素组（102例）,PCI术中分别采用比伐芦定和普通肝素进行抗凝治疗,并根据术中冠脉病变情况决定是否联用血小板糖蛋白IIb/IIIa拮抗剂(glycoprotein IIb/IIIa inhibitor, GPI)。比较两组间一般情况及PCI相关资料,并对两组30天内的出血、支架血栓事件及主要不良心血管事件（MACE）进行统计分析。 结果：两组间支架血栓事件及MACE发生率无显著性差异（P>0,05）, 比伐芦定组出血发生率显著降低（P<0.05）,其中以轻度出血发生率减少更为显著,严重出血方面两组间无统计学性差异（1.9% vs2.9%,P>0.05）,但比伐芦定组有较低的严重出血风险趋势。 结论：比伐芦定在高出血风险的ACS患者的PCI治疗中抗凝治疗是安全有效的,并降低出血风险。     

Bivalirudin in Percutaneous Coronary Interventions and Acute Coronary Syndromes: New Concepts, New Directions

Inhibition of thrombin and platelets during percutaneous coronary intervention (PCI), using a combination of unfractionated heparin and aspirin, is designed primarily to minimize the rare but devastating potential acute thrombotic complications of the procedure. Direct thrombin inhibitors, such as bivalirudin (formerly Hirulog, The Medicines Company, Cambridge, MA), offer specific theoretic advantages over unfractionated heparin as antithrombin therapy. This review focuses on the pharmacologic promise and the clinical performance of bivalirudin in PCI, and in the pharmacologic management of acute coronary syndromes. Clinical experience with bivalirudin in PCI preceded recent dramatic advances in mechanical interventional techniques and the emergence of novel potent platelet inhibitors. The role of bivalirudin and other direct thrombin inhibitors in the modern era of coronary intervention therefore requires further elucidation.     

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.     

高危急性冠状动脉综合征介入治疗早期或即刻应用替罗非班对主要不良心血管事件的影响

目的 观察高危非ST段抬高急性冠状动脉综合征(NSTE-ACS)经皮冠状动脉介入治疗(PCI)术前早期应用和术前即刻应用替罗非班对血小板功能和180 d主要不良心血管事件(MACE)的影响,探讨替罗非班的最佳应用时机.方法 2006年7月至2007年7月,160例备行PCI的高危NSTE-ACS患者随机分配到PCI前早期应用组(冠状动脉造影前4～6 h应用替罗非班)和PCI前即刻应用组(导丝通过冠状动脉病变后应用替罗非班).观察两组入院后、冠状动脉造影前和PCI后的血小板聚集率,随访术后24 h、3 d、7 d、30 d和180 d MACE.记录使用替罗非班治疗期间的出血并发症和血小板减少症的发生率.结果 应用替罗非班后,两组血小板聚集率均显著降低(P＜0.05).PCI前早期应用组冠状动脉造影前的血小板聚集率显著低于PCI前即刻应用组(8%比42%,P＜0.05).两组PCI后24 h和3 d内均未发生MACE,7 d MACE发生率均为1.3%.PCI前早期应用组术后30 d(3.8%比6.3%,P＞0.05)和180 d(13.0%比16.7%,P＞0.05)MACE发生率均低于PCI术前即刻应用组.两组180 d无MACE发生的生存率分别为87.0%和83.7%(P＞0.05).增龄(OR=1.164,P＜0.001)、高血压(OR=4.165,P=0.037)和2型糖尿病(OR=13.628,P＜0.001)是发生MACE的独立危险因素.替罗非班的应用时机对MACE发生率有一定程度的影响(OR=2.416,P=0.153).在使用替罗非班治疗期间,两组重度出血并发症发生率(2.5%比1.3%.P＞0.05)差异无统计学意义,中度出血并发症和轻度血小板减少症发生率均为1.25%.结论 在阿司匹林和氯吡格雷抗血小板治疗的基础上,高危NSTE-ACS患者PCI前早期应用替罗非班比PCI前即刻应用,能及早强化抗血小板治疗,有减少PCI后MACE发生率的趋势.增龄、高血压和2型糖尿病是高危NSTE-ACS患者PCI联合替罗非班治疗中发生MACE的独立危险因素.     

Direct thrombin inhibitors in cardiac disease

Most acute coronary syndromes (ACS) are triggered by platelet-rich thrombus superimposed on disrupted atherosclerotic plaque. Thrombin and platelets both play a role in this process. Whereas unfractionated heparin and aspirin have served as cornerstones in the treatment of ACS, several limitations of heparin provide the impetus to seek out better anticoagulants. Direct thrombin inhibitors such as bivalirudin, hirudin, and argatroban offer several pharmacologic advantages over heparin. Additionally, bivalirudin also appears to provide clinical advantages over unfractionated heparin therapy in ACS patients and those undergoing percutaneous coronary intervention.     

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.     

Clinical and prognostic implications of the initial response to aspirin in patients with acute coronary syndrome

Increased platelet reactivity and decreased response to antiplatelet drugs may result in recurrent ischemic events after acute coronary syndrome (ACS). We evaluated laboratory response to aspirin in patients with ACS before and after percutaneous coronary intervention (PCI) and assessed its effect on major adverse clinical events. Sixty-three consecutive patients with ACS were tested for response to aspirin by light transmittance aggregometry (LTA) and the IMPACT-R test (with arachidonic acid) before and 2 to 4 days after PCI and clopidogrel loading. Patients were followed for clinical events up to 15 months from PCI. Response to aspirin improved significantly after PCI and clopidogrel treatment (mean arachidonic acid-induced LTA decreased from 34.9 ± 3.35% before PCI to 15.2 ± 2.2% and surface coverage increased from 2.2 ± 0.27% to 6.2 ± 0.6%, p <0.0001 for the 2 methods). Improved response to aspirin after PCI correlated with response to clopidogrel (LTA and IMPACT-R, p <0.01). Patients with good laboratory response to aspirin before but not after PCI had a significantly lower major cardiovascular event rate during 15-month follow-up in multivariate analysis. In conclusion, laboratory response to aspirin is highly dynamic in patients with ACS. Improved response to aspirin after PCI may result from stabilization of coronary artery disease and/or clopidogrel treatment. Laboratory response to aspirin before PCI and clopidogrel loading is a sensitive marker for platelet reactivity that correlates with clinical outcome in patients with ACS.     

Glycoprotein IIb/IIIa antagonists in acute coronary syndromes: where are we now?

Vascular inflammation, coronary constriction, and thrombus formation are central to all acute coronary syndromes (ACSs). Adhesion and aggregation of activated platelets, initially described during thrombosis, now appear pivotal to all three processes. Several platelet adhesion receptors participate but the integrin glycoprotein (GP) IIb/IIIa occupies a critical role. GPIIb/IIIa antagonists used as an adjunct to percutaneous coronary intervention show clear benefit. However in the setting of ACS results have been disappointing. Indeed, trials of oral GPIIb/IIIa antagonists in patients with ACS were associated with increased mortality. Difficulties with drug dosing and variable pharmacodynamics may contribute to suboptimal receptor occupancy, incomplete inhibition of platelet aggregation, paradoxical partial agonist activity, and proinflammatory effects. Moreover, variable responses of patients to GPIIb/IIIa antagonists may reflect population heterogeneity.     

Prevention of activation of blood coagulation during acute coronary ischemic syndromes: beyond aspirin and heparin.

Many of the acute coronary ischemic syndromes are triggered by spontaneous or mechanical disruption of atherosclerotic plaques with resultant activation of platelets and coagulation. Given the central role of platelets and thrombin in arterial thrombosis, current strategies for its prevention and treatment focus on both inhibition of platelet aggregation and control of thrombin generation and activity. Although aspirin and unfractionated heparin are the cornerstones of current treatment strategies, both have limitations. This review will describe these limitations and discuss new antithrombotic agents developed for use in acute coronary ischemic syndromes and as adjuncts for percutaneous coronary revascularization procedures.