Antiplatelet medications and their indications in preventing and treating coronary thrombosis

Platelets play a pivotal role in the pathophysiology of unstable angina, acute myocardial infarction, and complications following percutaneous coronary intervention. Three classes of platelet-inhibiting drugs, aspirin, thienopyridines and platelet glycoprotein IIb/ IIIa inhibitors, are now commonly used for the prevention and treatment of disorders of coronary artery thrombosis. For the last several decades aspirin has been the sole option for antiplatelet therapy in the treatment and prevention of the manifestations of cardiovascular disease. However, a wider selection of antiplatelet agents, including the thienopyridines (ticlopidine and clopidogrel) and the platelet glycoprotein (GP)IIb/IIIa receptor antagonists, are now available and provide clinicians with the opportunity to potentially improve upon the previous gold standard of aspirin. This review summarizes these drugs and the scientific data that have led to their use in primary and secondary prevention, unstable angina, myocardial infarction, and percutaneous coronary intervention.     

Antiplatelet medications and their indications in preventing and treating coronary thrombosis

Platelets play a pivotal role in the pathophysiology of unstable angina, acute myocardial infarction, and complications following percutaneous coronary intervention. Three classes of platelet-inhibiting drugs, aspirin, thienopyridines and platelet glycoprotein IIb/IIIa inhibitors, are now commonly used for the prevention and treatment of disorders of coronary artery thrombosis. For the last several decades aspirin has been the sole option for antiplatelet therapy in the treatment and prevention of the manifestations of cardiovascular disease. However, a wider selection of antiplatelet agents, including the thienopyridines (ticlopidine and clopidogrel) and the platelet glycoprotein (GP)IIb/IIIa receptor antagonists, are now available and provide clinicians with the opportunity to potentially improve upon the previous gold standard of aspirin. This review summarizes these drugs and the scientific data that have led to their use in primary and secondary prevention, unstable angina, myocardial infarction, and percutaneous coronary intervention.     

Platelet glycoprotein IIb/IIIa-receptor inhibitors in patients with acute coronary syndromes or undergoing percutaneous coronary interventions: a review

BACKGROUND: Over 12.2 million Americans are affected by acute coronary syndromes (ACS) resulting from arterial thrombosis after atherosclerotic plaque rupture. The mechanism of thrombosis is based on the platelet activation pathway, facilitated by expression of the platelet glycoprotein (GP) lIb/Illa receptors. The platelet GP IIb/IIIa-receptor inhibitors represent a new class of drugs, of which abciximab, eptifibatide, and tirofiban have been approved for use in the medical management of ACS and as adjunctive therapy in percutaneous coronary interventions (PCIs). OBJECTIVE: This article reviews the results of published multicenter, randomized, placebo-controlled, double-blind trials of the efficacy and safety of platelet GP IIb/IIIa-receptor inhibitors in patients with coronary artery disease. METHODS: To identify articles for this review, a search of MEDLINE for the years 1994 through 2000 was conducted using the key words myocardial ischemia, unstable angina, angioplasty, stent, abciximab, eptifibatide, tirofiban, lamifiban, and platelet aggregation inhibitors. Relevant review articles were consulted as well as reports of clinical studies. CONCLUSIONS: Three GP IIb/IIIa-receptor inhibitors--abciximab, eptifibatide, and tirofiban-are approved by the US Food and Drug Administration as adjunctive therapy in patients undergoing PCI. Eptifibatide and tirofiban 'are also indicated for the medical management of patients with unstable angina and non-ST-segment-elevation myocardial infarction. The use of GP IIb/IIIa-receptor inhibitors as a component of management with fibrinolytic agents is under investigation. Studies comparing the efficacy of tirofiban and abciximab in patients undergoing planned PCI with intracoronary stent placement are in progress. Until data are available from long-term trials and head-to-head comparisons of these agents, it is not possible to generalize about their overall or comparative efficacy.     

Does timing matter? Upstream or downstream administration of antiplatelet therapy

Current treatment guidelines recommend an early, aggressive strategy in patients with non–ST-elevation acute coronary syndromes. Administration of antiplatelet therapy—a glycoprotein IIb-IIIa inhibitor with or without clopidogrel—before catheterization in patients with high-risk features confers substantially reduced risk of ischemic events while potentially increasing bleeding risk. Strategies for risk stratification are therefore important in the emergency department, with appropriate pharmacotherapy. This review will examine implications of the new guidelines for management of patients with unstable angina/non–ST-elevation myocardial infarction for emergency physicians, review current risk stratification paradigms, and evaluate appropriate use and timing of administration of glycoprotein IIb-IIIa inhibitors and clopidogrel for patients at varying levels of risk. We will also examine mechanisms for generating institutional care pathways that can enhance consistency and quality of care as well as communication among members of the medical team responsible for caring the patient with acute coronary syndrome.     

Glycoprotein IIb-IIIa inhibitors in the emergency department for patients with non-ST-elevation acute coronary syndromes: principles and practices

Non-ST-elevation acute coronary syndrome is associated with significant morbidity and mortality. Although the benefit of platelet inhibition by glycoprotein (GP) IIb-IIIa inhibitors in patients undergoing percutaneous coronary intervention (PCI) is well established, emergency physicians and cardiologists have different perspectives regarding their optimum administration, especially upstream before PCI. In this article, two emergency physicians and two cardiologists analyze data and discuss relevant issues, including the ischemic benefits vs. the risk of bleeding associated with GP IIb-IIIa inhibitors in appropriate patients, for example, those with an elevated troponin level or who undergo revascularization. The emergency physicians support early identification of high-risk non-ST-elevation acute coronary syndrome patients and early administration of GP IIb-IIIa inhibitors, which are linked to improved patient outcomes. The cardiologists emphasize risk stratification to identify patients in whom the expected reduction in ischemic complications outweighs the risk of increased bleeding with these agents. GP IIb-IIIa inhibitors should be considered in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) in whom PCI is planned, especially those with high-risk features or elevated serum troponin levels. It is reasonable to start this treatment upstream of intervention, pending further studies investigating the optimal timing of initiation of therapy in appropriate patients.     

The use of antiplatelet agents in acute cardiac care.

Antiplatelet therapy with aspirin has long been established as standard therapy in the management of conditions such as ST-elevation myocardial infarction and the acute coronary syndromes (unstable angina and non-ST-elevation myocardial infarction). Recently, several more potent platelet inhibitors have been developed and tested in randomized clinical trials. This article reviews the current state of the art of antiplatelet therapy.     

Pharmacological treatment of acute coronary syndromes

Many trials have examined the efficacy of medications used in acute coronary syndromes. This paper reviews those now recommended in patients with unstable angina and non-ST-segment elevation myocardial infarction. There are currently seven groups of drugs that are used in the management of such patients.     

The medical management of acute coronary syndromes and potential roles for new antithrombotic agents

Antithrombic therapy is recommended to prevent ischemic complications in patients with high-risk non-ST-segment elevation acute coronary syndromes, including patients with unstable angina/non-ST-segment elevation myocardial infarction and patients with ST-segment elevation myocardial infarction undergoing fibrinolysis with fibrin-specific agents. Ischemic benefit from these agents must be balanced against an increased risk of bleeding, which may itself carry adverse long-term consequences. Recent trials suggest that the low-molecular-weight heparin enoxaparin may be superior to unfractionated heparin for preventing ischemic complications, although it also may be associated with an increase in bleeding risk. In two other contemporary trials, the Factor Xa inhibitor fondaparinux improved mortality and morbidity in patients with unstable angina/non-ST-segment elevation myocardial infarction and in patients with ST-segment elevation myocardial infarction undergoing fibrinolytic reperfusion, without increasing bleeding risk. These data underscore the promise of new antithrombotic agents to improve outcomes in acute coronary syndrome (ACS) patients being medically managed.     

Abciximab and atherosclerotic heart disease: use in percutaneous coronary intervention,acute coronary syndromes and acute myocardial infarction

Abciximab irreversibly binds to the glycoprotein IIb/IIIa receptor on both activated and unactivated platelets inhibiting platelet aggregation. It has been studied in a variety of clinical settings including percutaneous coronary intervention (PCI), ST-elevation myocardial infarction, and non ST-elevation acute coronary syndromes. Abciximab has been demonstrated to reduce acute ischaemic events in the setting of percutaneous intervention with both percutaneous transluminal coronary angioplasy and stenting. It has been shown to be particularly effective when used in patients with acute myocardial infarction undergoing primary PCI. The data for its effective use in the medical phase of therapy for patients with acute coronary syndromes, however, is not as consistent. In this article we review the major trials evaluating the use of abciximab in these clinical scenarios compared with placebo and alternative glycoprotein IIb/IIIa inhibitors.     

A focus on the prognosis and management of ischemic heart disease in patients without evidence of obstructive coronary artery disease

Ischemic heart disease without evidence of obstructive coronary artery disease is a common phenotype comprising different coronary syndromes with either stable or unstable clinical presentation. In this context, the clinical outcome and management appear extremely variable, due to different etiologies. Of note, coronary microvascular dysfunction is the pathogenetic mechanism linking different clinical scenarios in most of the cases. Hence, in this article, we aim to provide a systematic approach of reviewing the prognosis and management of angina or myocardial infarction without evidence of obstructive coronary artery disease. Moreover, we will propose a new scheme of classification by distinguishing between angina with normal coronary artery and myocardial infarction with normal coronary artery in order to facilitate clinicians to perform a proper management workflow.     

The role of tirofiban in acute coronary syndromes

Platelet activation and aggregation play an important and essential role in the formation of intracoronary thrombus in acute coronary syndromes (ACS). ACS still carries unacceptably high rates of morbidity and mortality despite intensive antianginal therapy and the wide use of aspirin and heparin. Two glycoprotein IIb/IIIa receptor inhibitors are now licensed for concomitant use with heparin and aspirin in ACS. Glycoprotein IIb/IIIa receptor inhibitors block the final step for platelet aggregation and fibrinogen binding, thus preventing thrombus formation. Tirofiban is a potent, synthetic, non-peptide and specific glycoprotein IIb/IIIa receptor inhibitor. In three major international trials involving over 7200 patients (PRISM, PRISM-PLUS and RESTORE), tirofiban was shown to be well tolerated and to reduce the risk of ischaemic complications in patients with unstable angina, non-Q-wave myocardial infarction and high-risk patients undergoing revascularisation when used in combination with aspirin and heparin. These and ongoing studies are discussed.     

Bench to Bedside: Pathophysiology of Acute Coronary Syndromes and Implications for Therapy

Our understanding of the pathophysiology of unstable angina (UA) and non-ST-segment elevation (NSTE) myocardial infarction (MI) [commonly referred to as NSTE acute coronary syndrome(s) (ACS)] has evolved considerably over the years, with atherothrombosis playing a pivotal role. This review discusses the molecular interactions in coronary thrombosis that may serve as therapeutic targets for more effective management of these syndromes. The purposes of this review are: 1) to discuss current understanding of the pathophysiology of NSTE ACS; 2) to describe recent studies with novel antithrombotic agents [e.g., low-molecular-weight heparin, thienopyridines, glycoprotein (GP) IIb-IIIa inhibitors] in patients with NSTE ACS; and 3) to highlight recommendations for management of patients with NSTE ACS in the recently updated American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines, including the appropriate use of antithrombotic therapies.     

Indications for coronary artery bypass graft surgery

ACBGS is indicated in patients with stable angina who have left main coronary artery disease; three-vessel disease; three or four of the clinical variables set forth in the Veterans Administration Cooperative Study; obstruction in proximal third of left anterior descending coronary artery as part of two- or three-vessel disease; and two- or three-vessel disease and exercise-induced ischemic ST-segment depression greater than or equal to 1.5 mm. ACBGS may increase survival in patients with limited exercise capacity. Finally, ACBGS may be indicated to increase the quality of life in patients with disabling angina that is refractory to medical treatment. Patients with unstable angina who have an inadequate response to intensive medical therapy should have emergency ACBGS. Indications for elective ACBGS in patients with unstable angina who respond adequately to medical therapy are the same as those for stable angina. Patients with rupture of the ventricular septum, acute severe mitral regurgitation, and cardiogenic shock with vessels suitable for ACBGS should have urgent ACBGS after acute myocardial infarction. Patients with postinfarction angina after the first few days following acute myocardial infarction, especially non-Q-wave infarction, should be considered for ACBGS. Indications for elective ACBGS in postinfarction patients are the same as those in stable angina. Patients with coronary artery disease, especially those with a significant amount of ischemic myocardium, who must undergo cardiac surgery for valvular heart disease or for congenital heart disease should probably have ACBGS performed at the time of surgery.     

GLYCOPROTEIN IIB/IIIA ANTAGONISTS: DO THEY HAVE A ROLE IN THE MANAGEMENT OF UNSTABLE ANGINA?

Plaque rupture, platelet aggregation and thrombosis have central roles in the pathogenesis of acute coronary syndromes. Despite several trials showing the benefit of aspirin and heparin in patients presenting with unstable angina and acute myocardial infarction, these patients are still at risk. This has prompted the development and evaluation of several new therapeutic agents including low molecular weight heparin, new antiplatelet drugs (e.g. ticlopidine and clopidogrel), direct thrombin inhibitors, and intravenous and oral glycoprotein IIb/IIIa antagonists. The IIb/IIIa receptor is the final common pathway involved in platelet aggregation. Thus, whatever the stimulus for platelet activation, subsequent aggregation is mediated by the IIb/IIIa receptor binding fibrinogen. A variety of antibody, peptide and non-peptide compounds that block the IIb/IIIa receptor have been developed, and several studies have investigated the role of these agents in patients with acute coronary syndromes both within and outside the setting of percutaneous intervention. This article summarises the studies to date using IIb/IIIa antagonists, and discusses their role in patients with non-ST segment elevation acute coronary syndromes.     

Percutaneous transluminal coronary angioplasty in patients over 75 years old with acute myocardial infarct or unstable angina pectoris

Both increasing frequency and technical improvements of percutaneous transluminal coronary angioplasty (PTCA) have focussed attention on possible applications of PTCA in elderly patients with coronary artery disease. From January 1986 to June 1989, among 1872 patients treated with PTCA in our hospital, 42 patients (2.3%) were 75 or more years old. Of these patients, 14 presented with unstable angina, 28 patients suffered from acute myocardial infarction. PTCA was performed on stenoses of left anterior descending artery (43%), circumflex coronary artery (18%), and right coronary artery (39%), respectively. In patients with unstable angina, PTCA in 81% could reduce diameter stenoses of culprit lesions to 50% or less. 43% of patients with acute myocardial infarction had received previous thrombolytic therapy with streptokinase or urokinase applied either systemically or intracoronarily. On cardiac catheterization, 39% of patients presenting with acute myocardial infarction showed total occlusion of the infarct-related vessel. In 75% of patients with acute myocardial infarction, after PTCA, patency of the infarct-related artery (diameter stenoses 50% or less) was observed. In-hospital mortality of patients with acute myocardial infarction subjected to PTCA was 10%, two patients dying in prolonged cardiogenic shock, one in septic shock. In 20% of cases, coronary dissection was observed after PTCA. Non-Q-wave infarction developed in one patient. Three patients had a peripheral vascular complication, and in one patient a transient ischemic attack was observed. No severe catheter-related complications occurred after thrombolytic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selection of glycoprotein IIb/IIIa inhibitors for upstream use in patients with diabetes experiencing unstable angina or non‐ST segment elevation myocardial infarction. What have we learned in the last 10 years?

Coronary disease accounts for the majority of deaths among patients with diabetes and the thrombotic milieu accelerated by diabetes results in unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI) or death. Upstream use of a glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor with percutaneous coronary intervention (PCI) as part of an early invasive approach is preferred. However substantial numbers of patients present to rural or non-teaching hospitals without immediate access to a catheterization laboratory. Enhanced GP IIb/IIIa receptor mobilization, TXA2 production and platelet activation together present an extensive thrombotic challenge that may not be overcome with current doses of GP IIb/IIIa inhibitors when used without PCI. Heterogeneity of platelet aggregometric analysis may have identified GP IIb/IIIa doses used in clinical trials that may not fully overcome the thrombotic challenge in patients with diabetes. GUSTO-IV ACS failed to demonstrate a difference in mortality when used without PCI. The PURSUIT trial provided evidence that eptifibatide decreases death or non-fatal myocardial infarction (MI) in the main group and in the diabetic subgroup. Reductions in this primary endpoint were driven by the reduction in non-fatal MI. The PRISM and PRISM-PLUS trials demonstrated a reduction in death, MI or refractory ischaemia at 48 h or 7 days in the main cohort but not specifically in patients with diabetes. Data supporting use of GP IIb/IIIa inhibitors are inconsistent, raising the question of whether these agents should be used at all without PCI. Variability in experimental methodology of platelet aggregometry and selection of anticoagulant used during dose finding studies may have generated doses that are insufficient to overcome the thrombotic burden. A new marker of active inflammation, sCD40L is found to be upregulated at subtherapeutic doses of GP IIb/IIIa inhibitors, suggesting that rebound inflammatory processes may partially account for absence of clear evidence of benefit with some GP IIb/IIIa inhibitors in patients with diabetes experiencing UA/NSTEMI.     

The -308 G/A tumor necrosis factor-alpha gene dimorphism: a risk factor for unstable angina.

Since the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) may play a major role in the pathophysiology of acute coronary syndromes, 299 consecutive male patients hospitalized for coronary artery disease (i.e., lumen lost > or = 50%) were genotyped for the functional -308G/A TNF-alpha polymorphism using restriction fragment length polymorphism method, in order to evaluate its potential association with the risk of unstable angina and/or myocardial infarction. A higher frequency of carriers of the A allele was observed in patients with unstable angina (n = 58) when compared to control patients with stable angina (n = 95) (39.66% vs. 23.16% respectively, p = 0.029, odds ratio = 2.2) but not in patients with myocardial infarction (n = 146) (23.97% vs. 23.16%, p = NS). Furthermore, we evidenced an interaction of the polymorphism studied with body mass index in patients with unstable angina. Thus, when stratified analysis was performed, results in patients with a body mass index < or = 27 showed a more striking association between A allele carriage frequency and unstable angina (p = 0.012, odds ratio = 3.0). These results suggest the crucial role of TNF-alpha in the mechanisms responsible for unstable angina in accordance with the concept of vulnerable plaque. On the other hand, mechanisms controlling myocardial infarction appear more complex and heterogeneous.     

Bivalirudin for primary percutaneous coronary intervention in acute myocardial infarction: the HORIZONS-AMI trial

The combination of unfractionated heparin (UFH) plus glycoprotein IIb/IIIa inhibitors (GPIs) has been a frequently used anti-thrombotic treatment strategy for acute coronary syndrome patients, including those with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. However, the ischemic benefit of the UFH plus GPI combination came at the expense of high rates of bleeding complications and thrombocytopenia, both of which have been independently associated with increased mortality. By contrast, bivalirudin monotherapy compared with the combination of UFH plus GPI resulted in improved net clinical outcomes, based on similar ischemic protection with significant reductions in bleeding complications in randomized trials including patients with stable angina, those with unstable angina and those with non-ST-segment elevation myocardial infarction. More recently, the HORIZONS-AMI randomized, open-label, multicenter trial has compared the efficacy and safety of bivalirudin alone versus UFH plus a GPI in 3602 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Clinical results derived from this large study, including the final 3-year follow-up data, will be reviewed in the present clinical trial report.     

Combination therapy with anticoagulants and platelet-active drugs

Platelets and the coagulation system cannot be regarded as completely separate systems. Both systems become activated upon vessel injury and multiple functional interactions exist. Thus with a combination therapy with anticoagulants and platelet-active drugs, drug interactions relevant for hemostasis must be expected. This includes a synergistic inhibition of the hemostatic system but also possible synergistic effects on bleeding complications. This concise review discusses the clinical efficacy of a combination therapy with anticoagulants and platelet-active drugs in patients with acute coronary syndromes (unstable angina, myocardial infarction).     

The use of low-molecular-weight heparin in acute coronary syndromes

The initiating event in unstable angina (USA) and non-Q-wave myocardial infarction (NQMI) is the rupture of an atherosclerotic plaque resulting in local thrombosis. The current standard treatment is the administration of aspirin and heparin. The introduction of low-molecular-weight heparin (LMWH) offers a potential alternative therapy. Clinical trials have begun to examine the efficacy and safety of using LMWH in the management of acute coronary syndromes. Two pivotal studies have evaluated the effects of LMWH preparations on patients with USA or NQMI: The ESSENCE and the TIMI 11B trials. These studies suggest that LMWH plus aspirin is more effective and safer than unfractionated heparin in preventing myocardial infarction, recurrent angina, or death. Because of these differences, the American College of Cardiology and the American Heart Association have updated their guidelines for the treatment of USA and NQMI.