Early Glycoprotein IIb/IIIa Inhibitor Use for Non–ST-segment Elevation Acute Coronary Syndrome: Patient Selection and Associated Treatment Patterns

Objectives: The authors analyzed contemporary use of glycoprotein (GP) IIb/IIIa inhibitors in patients with non–ST-segment elevation acute coronary syndrome (NSTE ACS) to determine patient selection patterns with early (<24 hours) GP IIb/IIIa inhibitor use and the relationship between GP IIb/IIIa inhibitor therapy and use of other guidelines-recommended therapies for NSTE ACS. Methods: Using the CRUSADE Quality Improvement Initiative database, patient characteristics, in-hospital treatments, and outcomes for 65,424 patients with ischemic chest pain of <24 hours' duration and either positive cardiac markers or ischemic electrocardiographic changes were analyzed. Data were collected from 443 U.S. hospitals from January 2001 to June 2003. Results: Only 35% of eligible patients received GP IIb/IIIa inhibitors <24 hours after hospital admission. Approximately one third of patients received GP IIb/IIIa inhibitors in the emergency department, one third in the coronary care unit, and one third in the catheterization laboratory. Admission to a cardiologist's care was the most significant associated factor with early GP IIb/IIIa inhibitor use, along with elevated cardiac markers or ST-segment deviation. Patients at high risk for adverse cardiac events due to advanced age, congestive heart failure, or female gender were less likely to receive early GP IIb/IIIa inhibitor therapy. Patients who received early GP IIb/IIIa inhibitor therapy were more likely to receive other guidelines-recommended therapies. Conclusions: Despite the American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommendations, early GP IIb/IIIa inhibitor therapy remains underutilized in patients with NSTE ACS and administration of early GP IIb/IIIa inhibitors is directed toward lower-risk patients. Early GP IIb/IIIa inhibitor therapy is associated with improved overall adherence to the ACC/AHA guidelines.     

The effects of platelet inhibitors on blood use in cardiac surgery

Platelet inhibition via glycoprotein (GP) IIb/IIIa receptor antagonists has greatly reduced the need for emergent cardiac surgery. However, this change has come at a cost to both the patient and the cardiac surgical team in terms of increased bleeding risk. Current guidelines for patients requiring coronary artery bypass surgery include: 1) cessation of GP IIb/IIIa inhibitor; 2) delay of surgery for up to 12 h if abciximab, tirofiban, or eptafibitide is used; 3) utilization of ultrafiltration via zero balance technique; 4) maintenance of standard heparin dosing despite elevated bleeding times; and 5) transfusion of platelets as needed, rather than prophylactically. These agents present cardiac surgery teams with increased risk during CABG, although overall risk may be diminished by the substantial benefits to patients with acute coronary syndromes and percutaneous interventions, i.e., reduced infarction rates and improved vessel patency. With judicious planning, urgent coronary artery bypass can be safely performed on patients who have been treated with GP IIb/IIIa receptor inhibitors.     

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.     

Present and evolving role of eptifibatide in the treatment of acute coronary syndromes

Platelet-dependent thrombosis plays a central role in the pathophysiology of myonecrosis in both percutaneous coronary interventions (PCIs) and acute coronary syndromes (ACS). Extensive data from randomized clinical trials support the use of acute therapies that interfere with platelet aggregation to provide clinical benefit to patients presenting with ACS and undergoing PCI. Glycoprotein (GP) IIb/IIIa receptor antagonists represent a major advance in the therapy of patients undergoing PCI and those with non-ST segment elevation (NSTE) ACS. Eptifibatide, a small molecule GP IIb/IIIa receptor antagonist, is one such agent. A more consistent platelet-inhibitory effect over time and the short half-life of eptifibatide represent potential pharmacologic advantages compared with other drugs within this class. Large, randomized clinical trials have demonstrated the benefits of eptifibatide for treating patients with NSTE ACS and patients undergoing PCI, establishing its central role in modern management of these conditions. However, recent new advances in the pharmacotherapy of ACS and PCI are requiring us to reconsider the role of GP IIb/IIIa inhibitors; therefore, ongoing and future randomized clinical trials will re-examine GP IIb/IIIa inhibition and establish the role of GP IIb/IIIa inhibitors for the next decade.     

Oral antiplatelet agents in ACS: from pharmacology to clinical differences

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Numerous clinical trials have established the value of antiplatelet therapies for ACS. Aspirin (ASA), thienopyridines and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS. Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Recently, a third generation of thienopyridines has been introduced represented by prasugrel that has demonstrated promising results in ACS patients treated with percutaneous coronary intervention (PCI). A number of nonthienopyridine oral antiplatelet drugs are under development, and one of them, ticagrelor has already been tested in a major phase III clinical trial, PLATO, with the inclusion of a broad spectrum of patients with ACS. The present review aims to discuss the present knowledge about the safety and efficacy of oral antiplatelet treatment of patients with ACS.     

Anticoagulation in acute coronary syndrome. An update

The acute coronary syndrome (ACS) is one of the most frequent diagnoses in cardiology. The therapeutic corner-stones of ACS are PCI (percutaneous coronary intervention) and inhibition of blood coagulation. Current antiplatelet therapy consists of aspirin in combination with clopidogrel and glycoprotein IIb/IIIa blockade if needed. Prasugel is a new antiplatelet agent that is in the process of being approved for routine clinical use. In terms of antithrombotic therapy latest developments focus on drugs with anti-factor Xa activity, such as fondaparinux, or direct anti-thrombin activity, such as bivalirudin. This review discusses latest developments in the field of anti-platelet and anti-thrombotic therapy for ACS.     

Increased incidence of in-stent thrombosis related to cocaine use: case series and review of literature

The purpose of this article was to determine the incidence of in-stent thrombosis (IST) after coronary stent implantation in patients with cocaine abuse. A retrospective review was done of medical records of consecutive patients who underwent coronary stent implantation for obstructive coronary artery disease at a single inner-city institution from January 1997 to October 2006. Patients with temporal cocaine use were identified by positive urine drug screen. IST was confirmed angiographically. Of the 81 patients with active cocaine use that underwent coronary stent implantation, 4 (5%) suffered IST (mean period from stent implantation, 28.5 +/- 14 days). All procedures were performed successfully and received intravenous IIb/IIIa antagonist intraprocedurally. All patients were prescribed dual antiplatelet therapy with aspirin and clopidogrel at discharge; however, all 4 patients that suffered from IST continued cocaine abuse were noncompliant with the prescribed dual antiplatelet therapy. Of these 4 patients, 2 presented with ST segment elevation myocardial infarction (50%), whereas 2 presented with non-ST-segment elevation myocardial infarction (50%). One was managed medically. Two received repeat percutaneous coronary intervention, and 1 underwent coronary artery bypass surgery. The patient that underwent surgery died in the postoperative period. The remaining 3 patients survived. Patients with active cocaine abuse who undergo successful coronary stent revascularization have a high (5%) incidence of stent thrombosis. A majority of patients that suffer stent thrombosis continue cocaine abuse and are noncompliant with antiplatelet therapy.     

Antithrombotic therapy of acute coronary syndromes

Recent advances in the diagnosis and the treatment of acute coronary syndromes (ACS) have led to a substantial reduction of major coronary events, to an improvement in patient outcome and the definition of new guidelines. Current strategies for the treatment of patients with non-ST-elevation ACS recommend a combined antithrombotic therapy (including aspirin, clopidogrel, anticoagulation with low-molecular weight or unfractionated heparins or FXa-inhibitors or direct antithrombins and, eventually glycoprotein IIb/IIIa receptor antagonists). This combined antithrombotic therapy allows to increase the benefit of an early invasive strategy including coronary angiogram with stent percutaneous coronary angioplasty. The purpose of this review is to discuss and highlight the recommendations for the appropriate use of antithrombotic strategies in the setting of angioplasty in ACS patients.     

Unmet needs in oral antiplatelet therapy with ADP receptor blocking agents

Antiplatelet agents like aspirin and clopidogrel are treatment cornerstones for acute coronary syndromes (ACS). Drawbacks of dual therapy with these agents include slow onset and offset of effect and wide response variability. Clopidogrel may provide little benefit if administered too close to percutaneous coronary intervention (PCI) and increase major bleeding risk if given too close to coronary artery bypass grafting (CABG) or other surgery. It may not provide sufficient antiplatelet coverage prior to CABG if stopped too long before intervention and leave patients without antiplatelet coverage due to hyporesponsiveness. Prasugrel has made steps towards addressing these limitations by exhibiting more efficient metabolism, more rapid onset of effect, and greater and more consistent platelet inhibition than clopidogrel. The TRITON-TIMI38 trial in ACS patients undergoing PCI showed prasugrel produced greater ischemic event protection than clopidogrel but significantly increased major bleeding risk. AZD6140, the first reversible oral P2Y₁₂ inhibitor, provides more rapid onset of effect and greater and more consistent platelet inhibition than clopidogrel. In DISPERSE2, a phase II trial in ACS patients, AZD6140 did not increase bleeding risk, reduced bleeding risk among CABG patients, and produced numerical reductions in myocardial infarction risk. AZD6140 is being compared with clopidogrel in PLATO, a phase III trial in approximately 18000 ACS patients.     

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.     

Effect of clopidogrel on bleeding after coronary artery bypass surgery.

OBJECTIVE: Platelet dysfunction is a common cause of bleeding after coronary artery bypass graft surgery. This study explores the effects of clopidogrel on bleeding complications after coronary artery bypass graft surgery. DESIGN: Prospective observational study of patients undergoing coronary artery bypass graft. SETTING: Tertiary care center. PATIENTS: A total of 247 patients undergoing coronary artery bypass graft surgery. INTERVENTIONS: None. MEASUREMENTS: Primary end point was need for reexploration secondary to bleeding. Secondary end points included need for transfusion of blood products and chest tube output. MAIN RESULTS: Eight (3.3%) of 247 patients required reexploration secondary to bleeding. Clopidogrel recipients had higher incidence of reexploration for bleeding (9.8 vs. 1.6, p =.01) with an odds ratio of 6.9 (95% confidence interval, 1.6-30). Clopidogrel also increased the percentage of patients receiving packed red blood cell transfusion (72.6 vs. 51.6%, p =.007), the number of packed red blood cell units (3 vs. 1.6, p =0.0004), and the number of cryoprecipitate units (2.4 vs. 1.2, p =.04) transfused after coronary artery bypass graft surgery. Among clopidogrel recipients, a trend for increased transfusion of platelet units (4.3 vs. 1.7, p =.05) and fresh frozen plasma units (1.1 vs. 0.6, p =.08) also was found. CONCLUSIONS: Preoperative use of clopidogrel in combination with aspirin is associated with increased need for surgical reexploration as well as risk of packed red blood cell and cryoprecipitate transfusions after coronary artery bypass graft surgery.     

The challenge of ST-segment elevation myocardial infarction

BACKGROUND/INTRODUCTION: Acute coronary syndromes (ACS) represent a spectrum of ischaemic myocardial events that share a similar pathophysiology. ST-segment elevation myocardial infarction (STEMI), the most severe form of ACS short of sudden cardiac death, is a significant public health problem with an estimated 500,000 STEMI events every year in the United States. TREATMENT/THERAPY: The mortality and morbidity associated with STEMI is significant. Early reperfusion therapy is the most important aspect of the treatment of STEMI. There are two main methods of reperfusion therapy: percutaneous coronary intervention (PCI) and fibrinolytic therapy, with PCI being the preferred method. In addition to standard reperfusion therapy, antithrombotics (unfractionated heparin and low molecular weight heparins) and antiplatelet agents (aspirin, clopidogrel and glycoprotein IIb/IIIa inhibitors) are critical adjuncts, effective in the treatment of acute STEMI. CONCLUSIONS: The survival of patients with STEMI depends on rapid diagnosis and optimal early treatment. Guidelines for the management of patients with STEMI recommend PCI within 90 min of presentation and that fibrinolytics are administered within 30 min. However, only a fraction of patients undergo reperfusion within the recommended time. Improvements in protocols for identifying STEMI cases are therefore required to allow reperfusion therapy to be initiated sooner. Secondary prevention is another important aspect of STEMI management, and patients should be encouraged to adopt strategies that reduce the risk of subsequent ischaemic events.     

Abciximab as an adjunctive therapy for patients undergoing percutaneous coronary interventions

INTRODUCTION: Platelets play a central role in the pathophysiology of acute coronary syndromes (ACS) and activation of platelet glycoprotein (GP) IIb/IIIa receptor is critical to platelet aggregation. Abciximab, a human murine chimeric antibody to the GPIIb/IIIa receptor, is an important biological therapy in the management of patients presenting with ACS. AREAS COVERED: The objective of this review is to define the role of abciximab in the management of ACS by interpreting the available data from randomized clinical trials using abciximab in various clinical scenarios, particularly in percutaneous coronary intervention (PCI). We also review different modes of delivery and describe the adverse effects of abciximab including thrombocytopenia. Where possible, we attempt to compare abciximab to the other available GPIIb/IIIa inhibitors. We hope the reader will gain a better understanding of the benefits and risks of abciximab and the important role it has in the management of cardiology patients. EXPERT OPINION: Abciximab was a breakthrough drug in the management of high risk ACS patients undergoing PCI. However, with newer available therapies and improvement in PCI technology, dose and delivery of this drug have evolved as we try to extract maximum benefit while minimizing the adverse effects associated with it.     

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.     

Antiplatelet therapy from clinical trials to clinical practice

A platelet-rich clot at the site of severe coronary stenosis, plaque erosion, or a recent plaque rupture is the common etiology of acute ischemic syndromes. Thus, antiplatelet therapy is the cornerstone in the management of these conditions. Aspirin in a dose ranging from 160 to 325 mg once daily should be administered to virtually all patients. In patients with severe disease, particularly those who have no acute angiography, clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals) in a dose of 75 mg once daily should add to the benefit of aspirin for up to a year after the event. Clopidogrel also is an alternative to aspirin where a true aspirin allergy exists. Intravenous platelet glycoprotein IIb/IIIa receptor inhibitors demonstrated a robust benefit when used in conjunction with coronary intervention and thus far have no role in medical therapy alone. Oral platelet glycoprotein IIb/IIIa receptor inhibitors are of no clinical value.     

ST-elevation myocardial infarction: the role of adjunctive antiplatelet therapy

Antiplatelet therapy to reduce the risks of recurrent myocardial infarction and restenosis after primary percutaneous coronary intervention is critically important to optimize the early treatment of ST-segment elevation myocardial infarction (STEMI). Traditionally, acetylsalicylic acid (ASA; aspirin) has been recommended for patients with suspected STEMI, but this agent targets only one of several pathways of platelet aggregation. Antiplatelet agents with different inhibitory mechanisms may act synergistically with ASA. Glycoprotein IIb/IIIa inhibitors are generally not used with fibrinolytic agents in acute STEMI management; indeed, glycoprotein IIb/IIIa inhibitors plus bolus fibrinolytics increase the risk of intracranial hemorrhage. Aggressive antiplatelet therapy with clopidogrel reduces mortality in STEMI patients and offers significant clinical benefits, without an associated increase in major bleeding events. Recent trials support the development of an early and aggressive approach to more complete platelet inhibition using clopidogrel, in combination with ASA, for patients with STEMI.     

Glycoprotein IIIA gene (PlA) polymorphism and aspirin resistance: is there any correlation?

BACKGROUND: Platelet glycoprotein (GP) IIb/IIIa receptors play an inevitable role in platelet aggregation. The GP IIIa gene is polymorphic (PlA1/PlA2) and the presence of a PlA2 allele might be associated with an increased risk for acute coronary syndrome (ACS). OBJECTIVE: To examine the prevalence of the PlA2 allele in patients with ACS and in subjects with or without aspirin resistance. METHODS: The prevalence of the PlA2 allele was assessed in 158 patients with ACS and PlA2 compared with its prevalence in 199 healthy volunteers. The antiplatelet efficacy of aspirin was examined in all patients with ACS, as well as in 69 individuals who had suffered ischemic stroke and in 58 high-risk subjects without any known ischemic vascular events. RESULTS: PlA2 prevalence was significantly higher in patients with ACS (59/158) than in the control group (51/199; p < 0.05). Carriers of the PlA2 allele had a significantly higher risk of developing ACS, even after an adjustment to the risk factors (OR 5.74; 95% CI 1.75 to 18.8; p = 0.004). The occurrence of the PlA2 allele was significantly higher among patients with aspirin resistance than in subjects who demonstrated an appropriate response to the drug (allele frequencies, 0.21 vs 0.14; p < 0.05). All patients homozygous for the PlA2 allele had an inadequate platelet response to aspirin. CONCLUSIONS: Our results support the hypothesis that carriers of the PlA2 allele might have an increased risk for ACS. PlA2 homozygosity was associated with an inadequate response to aspirin therapy. Our data further suggest that patients with PlA2 allele homozygosity might benefit from antiplatelet therapy based on adenosine diphosphate antagonists throughout secondary treatment for prevention of ACS.     

Drugs for percutaneous coronary interventions

Many combinations of anticoagulants and antiplatelet drugs have been used to treat patients undergoing a percutaneous coronary intervention (PCI). Among anticoagulants, enoxaparin has some theoretical advantages over unfractionated heparin, but in clinical trials no advantage in outcome has been demonstrated in PCI. Bivalirudin, a direct thrombin inhibitor, has been associated with a lower risk of bleeding than unfractionated heparin. Among antiplatelet drugs, use of clopidogrel plus aspirin has led to a reduction in cardiovascular events; all patients undergoing PCI should receive both. Addition of a GP IIb/IIIa inhibitor may lower mortality rates further, particularly in high-risk patients such as diabetics.     

Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia

Summary Thrombocyte glycoprotein IIb/IIIa inhibitors prevent fibrinogen binding and thereby thrombocyte aggregation. The inhibition of thrombocyte activation at the damaged coronary plaque is the target of the new therapeutic strategies in treating acute coronary syndrome. This reduces the ischemic complications associated with the non-STelevation myocardial infarction (NSTEMI) and percutaneous coronary intervention (PCI). Thrombocytopenia is a known complication of glycoprotein (GP) IIb/IIIa inhibitors. Although, in general, GP IIb/IIIa inhibitor-induced thrombocytopenia is a harmless side effect which responds readily to thrombocyte transfusion, it can occasionally be a very serious complication associated with serious bleeding. In addition patients developing thrombocytopenia have unfavorable outcome (e.g., death, myocardial infarction, bypass surgery or additional PCI) in comparison to patients without thrombocytopenia. Advanced age (> 65 years), low BMI and a low initial thrombocyte count (<180 000/μl) are independent risk factors of thrombocytopenia. The risk of bleeding is higher with this form of thrombocytopenia not only due to the low thrombocyte count but also to the impaired function of the remaining thrombocytes. It is important to closely monitor platelet count during GP IIb/IIIa antagonist treatment. Platelet count monitoring two, six, twelve and 24 hour after starting the treatment reveals most cases of acute thrombocytopenia. Side effects can be avoided by the early discontinuation of the GP IIb/IIIa antagonist treatment. This article reviews the diagnosis and treatment of glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia and summarizes the differential diagnosis from heparin-induced thrombocytopenia and laboratory-related pseudothrombocytopenia.