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.     

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.     

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.     

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.     

New antiaggregants and their importance for the practitioner

Since the introduction of Aspirin in the 1950s many substances have been introduced with an antiplatelet effect. Only few have been proved to be superior to aspirin in some clinical settings. Ticlopidin and its biochemical analog clopidogrel block the ADP-induced platelet aggregation. Clopidogrel having a better profile in terms of adverse events has been established over ticlopidin. It can be used for secondary prevention in patients with stroke, myocardial infarction or peripheral arterial disease instead of aspirin, certainly in cases with aspirin intolerance or with relapsing cardiovascular event under treatment with aspirin. For a general substitution of aspirin through clopidogrel hard evidence is still lacking. The combination aspirin + clopidogrel has been proved superior to aspirin in the treatment of patients with unstable angina or myocardial infarction without ST-segment elevation. For an extension of this indication to other clinical entities further evidence is needed. GPIIb/IIIa blockers are a well established treatment modality in patients undergoing coronary catheter interventions. Oral GPIIb/IIIa blockers, probably because of their pharmacokinetic profile, have proved to be insufficient in protecting from cardiovascular events compared to aspirin. Practical aspects concerning use of the newer antiplatelet agents during pregnancy, preoperatively and in spinal anesthesia are discussed.     

Therapeutics of platelet glycoprotein IIb/IIIa receptor antagonism

The integrin glycoprotein IIb/IIIa receptor is the final common pathway to platelet aggregation. Administration of glycoprotein IIb/IIIa receptor antagonists reduces acute ischemic complications following plaque fissuring or rupture. Research on this subject was initially limited to patients undergoing percutaneous coronary intervention. Further studies evaluating the role of glycoprotein IIb/IIIa receptor antagonists in patients with non-ST segment elevation acute coronary syndrome have shown benefit of these drugs in reducing adverse cardiac events and death. Intravenous glycoprotein IIb/IIIa receptor inhibitors (abciximab, tirofiban, and eptifibatide) given in combination with traditional regimens are superior to placebo in management of non-ST elevation acute myocardial infarction. Oral glycoprotein IIb/IIIa receptor inhibitors (orbofiban, sibrafiban, and xemilofiban) are not effective in reducing ischemic events when used on a long-term basis after acute coronary syndrome. Pharmacokinetics, efficacy, and safety of glycoprotein IIb/IIIa receptor antagonists are elaborated.     

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.     

Role of abciximab in the treatment of coronary artery disease

Glycoprotein IIb/IIIa complex is a crucial membrane receptor for platelet aggregation, binding platelets to fibrinogen and establishing interplatelet bridges. This receptor is the common end point of the multiple activation pathways of a platelet. Antiplatelet agents, such as aspirin or thienopyridines, including ticlopidine and clopidogrel, inhibit one or more but not all, of these pathways. Inhibitors of the receptor are powerful platelet antiaggregants and include two groups of agents: non-competitive receptor blockers, such as abciximab, and competitive antagonists, such as tirofiban and eptifibatide. Abciximab is a monoclonal antibody that binds to the glycoprotein IIb/IIIa complex, thus blocking the interaction with fibrinogen. It is used for treatment of coronary artery disease, being well-studied in the setting of acute coronary syndromes and percutaneous coronary intervention, in which a rapid and effective antiaggregation is clinically important.     

Contemporary antiplatelet therapy in patients undergoing percutaneous coronary intervention

The proper use of antiplatelet agents in the cardiac catheterization laboratory is important for ensuring optimal results in patients undergoing percutaneous revascularization. Understanding the mechanisms by which these drugs exerts their effects is important for both interventional and non-interventional cardiologists. The effects of these agents on platelet function can be assessed and monitored using a variety of commercially available laboratory assays but so far these tests have not been adopted in routine clinical practice. Currently, aspirin, thienopyridines and glycoprotein IIb/IIIa inhibitors are the primary types of antiplatelet drugs being utilized. The use of these drugs and of several newer antiplatelet drugs in the treatment of patients undergoing percutaneous revascularization in the cardiac catheterization laboratory will be discussed, especially in the light of the recently published guidelines.     

Role of abciximab in the treatment of coronary artery disease

Glycoprotein IIb/IIIa complex is a crucial membrane receptor for platelet aggregation, binding platelets to fibrinogen and establishing interplatelet bridges. This receptor is the common end point of the multiple activation pathways of a platelet. Antiplatelet agents, such as aspirin or thienopyridines, including ticlopidine and clopidogrel, inhibit one or more but not all, of these pathways. Inhibitors of the receptor are powerful platelet antiaggregants and include two groups of agents: non-competitive receptor blockers, such as abciximab, and competitive antagonists, such as tirofiban and eptifibatide. Abciximab is a monoclonal antibody that binds to the glycoprotein IIb/IIIa complex, thus blocking the interaction with fibrinogen. It is used for treatment of coronary artery disease, being well-studied in the setting of acute coronary syndromes and percutaneous coronary intervention, in which a rapid and effective antiaggregation is clinically important.     

Abciximab: a review and update for clinicians

The glycoprotein (GP) IIb/IIIa receptor serves as the final common pathway of platelet-thrombus formation. Thus, the GP IIb/IIIa receptor has been identified as a target for the prevention of thrombus formation during acute coronary syndromes and/or percutaneous coronary intervention. While there are several intravenous GP IIb/IIIa inhibitors available, abciximab has proven to be a dependable agent with unique properties. Based on American College of Cardiology, American Heart Association and Society for Angiography and Interventions guidelines, compared with the other available intravenous GP IIb/IIIa inhibitors, abciximab receives the highest recommendation for use in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Abciximab is also unique in that there is no need for renal dosing and its effects are mostly reversible with platelet transfusions.     

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The glycoprotein (GP) IIb/IIIa receptor serves as the final common pathway of platelet-thrombus formation. Thus, the GP IIb/IIIa receptor has been identified as a target for the prevention of thrombus formation during acute coronary syndromes and/or percutaneous coronary intervention. While there are several intravenous GP IIb/IIIa inhibitors available, abciximab has proven to be a dependable agent with unique properties. Based on American College of Cardiology, American Heart Association and Society for Angiography and Interventions guidelines, compared with the other available intravenous GP IIb/IIIa inhibitors, abciximab receives the highest recommendation for use in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Abciximab is also unique in that there is no need for renal dosing and its effects are mostly reversible with platelet transfusions.     

New therapy with monoclonal antibodies--abciximab, chimeric anti-GP IIb/IIIa antibody

Platelet aggregation is now believed to be mediated by fibrinogen binding to activated GP IIb/IIIa. Antigen binding site of mouse anti-human GP IIb/IIIa monoclonal antibody 7E3, which can inhibit fibrinogen binding to activated human platelet GP IIb/IIIa, was combined with constant region of human IgG to reduce immunogenicity. Monovalent Fab of this mouse-human chimeric antibody named abciximab effectively reduced the onset of cardiovascular accidents when administered in combination with heparin and aspirin in patients undergoing coronary interventions. Although several anti-GP IIb/IIIa other than monoclonal antibodies were developed, clinical efficiency of abciximab is still superior to other agents while its effects on preventing myocardial infarction in unstable angina patients are uncertain.     

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.     

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.     

The platelet in diabetes: focus on prevention of ischemic events

Accelerated atherosclerosis and the increased risk of thrombotic vascular events in diabetes may result from dyslipidemia, endothelial dysfunction, platelet hyperreactivity, an impaired fibrinolytic balance, and abnormal blood flow. There is also a correlation between hyperglycemia and cardiovascular (CV) events. The importance of platelets in the atherothrombotic process has led to investigation of using antiplatelet agents to reduce CV risk. A meta-analysis conducted by the Antiplatelet Trialists' Collaboration demonstrated that aspirin reduced the risk of ischemic vascular events as a secondary prevention strategy in numerous high-risk groups, including patients with diabetes. Based on results from placebo-controlled randomized trials, the American Diabetes Association recommends low-dose enteric-coated aspirin as a primary prevention strategy for people with diabetes at high risk for CV events. Clopidogrel is recommended if aspirin allergy is present. There is occasionally a need for an alternative to aspirin or for additive antiplatelet therapy. Aspirin in low doses inhibits thromboxane production by platelets but has little to no effect on other sites of platelet reactivity. Agents such as ticlopidine and clopidogrel inhibit ADP-induced platelet activation, whereas the platelet glycoprotein (Gp) IIb/IIIa complex receptor antagonists block activity at the fibrinogen binding site on the platelet. These agents appear to be useful in acute coronary syndromes (ACSs) in diabetic and nondiabetic patients. A combination of clopidogrel plus aspirin was more effective than placebo plus standard therapy (including aspirin) in reducing a composite CV outcome in patients with unstable angina and non-ST segment elevation myocardial infarction. In a meta-analysis of six trials in diabetic patients with ACSs, intravenous GpIIb-IIIa inhibitors reduced 30-day mortality when compared with control subjects. Results from controlled prospective clinical trials justify the use of enteric-coated low-dose aspirin (81-325 mg) as a primary or secondary prevention strategy in adult diabetic individuals (aged >30 years) at high risk for CV events. Recent studies support the use of clopidogrel in addition to standard therapy, as well as the use of GpIIb-IIIa inhibitors in ACS patients.     

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.     

Role of low-molecular-weight heparin in invasive management of non-ST-elevation acute coronary syndromes

OBJECTIVE: To review the available literature addressing the role of low-molecular-weight heparin (LMWH) as an alternative to unfractionated heparin (UFH) in percutaneous coronary intervention (PCI) for treatment of non-ST-elevation acute coronary syndromes (NSTEACS). DATA SOURCES: A MEDLINE search (1966-March 2004) identified pertinent articles using the key words acute coronary syndromes, unstable angina, non-ST-elevation myocardial infarction, low-molecular-weight heparin, enoxaparin, dalteparin, glycoprotein IIb/IIIa receptor antagonists, abciximab, tirofiban, eptifibatide, percutaneous transluminal coronary angioplasty, and percutaneous coronary intervention. The references of these articles were reviewed for additional pertinent references. STUDY SELECTION AND DATA EXTRACTION: All human trials of LMWH in PCI for treatment of NSTEACS were evaluated. All pertinent studies were included in the review. DATA SYNTHESIS: Administration of LMWH with or without a glycoprotein IIb/IIIa inhibitor during PCI appears to be similar to UFH in terms of efficacy. LMWH, especially in combination with a glycoprotein IIb/IIIa inhibitor, may increase risk of bleeding compared with UFH. CONCLUSIONS: Available clinical trials do not provide definitive evidence to suggest superiority of LMWH over UFH when managing NSTEACS during PCI; however, dosing strategies are available if an LMWH is to be used in this setting.     

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.     

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.