Acute Coronary Syndromes (ACS): Pharmacotherapeutic Interventions—Treatment Guidelines for Patients With and Without Procedural Coronary Intervention (PCI)
Part I: Clinical Pathophysiology and Antiplatelet Agents
Author: Kurt Kleinschmidt, MD, FACEP, Assistant Professor, University of Texas Southwestern Medical Center, Dallas; Associate Director, Department of Emergency Medicine, Parkland Memorial Hospital, Dallas, Tex.
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Attention Subscribers This report on Acute Coronary Syndromes originally was published in Emergency Medicine Reports, a sister publication to Clinical Cardiology Alert. We thought it would be of interest to our readers. Look for additional bonus reports inserted with the May and June issues. As always, we welcome your questions and comments. |
Editor’s Note: Gideon Bosker, MD
Editor’s note—perhaps no aspect of emergency medicine is evolving more rapidly than the pharmacological and procedural landscape devoted to the management of patients with acute coronary syndromes (ACS). As every emergency physician and cardiologist understands, making the right choice—whether it is drug therapy, a procedural coronary intervention (PCI), or some combination of both strategies—can make the difference between a favorable and unfavorable outcome.
From an acute, clinical perspective, the challenge of formulating a management action plan that predictably yields optimal outcomes is compromised because there are many classes of agents (antiplatelet drugs, glycoprotein [GP] IIb/IIIa inhibitors, low molecular weight heparins [LMWHs], fibrinolytics), and many individual agents within those classes. More often than not, the trials evaluating the efficacy of specific pharmacotherapeutic interventions are difficult to compare, and the number of head-to-head studies contrasting the risks and benefits of individual agents within a class are almost nonexistent.
Complicating application of the trial data, some drugs may be more or less beneficial for a patient with ACS depending on whether a PCI is likely to be part of the treatment plan.
The multiplicity of interpretations regarding clinical trials, the variations among institutional protocols, proficiency or propensity for performing PCI, and personal preferences among physicians have produced a less-than-consistent approach to managing PCI patients. What’s more, even consensus guidelines, such as those recently issued by the American Heart Association and American College of Cardiology for Unstable Angina/Non-ST Elevation Myocardial Infarction (UA/NSTEMI), provide a range of options that are amenable to interpretation and drug substitutions.
Despite these limitations, evidentiary trials continue to support an aggressive approach to managing patients with ACS—an approach that is multi-modal, algorithmic, and risk-stratified driven, and that typically requires sequential administration of such agents as aspirin, beta-blockers, enoxaparin (or UFH), GP IIb/IIIa inhibitors, and/or fibrinolytic therapy. When PCI intervention is contemplated, the pharmacological cocktail for ACS may be modified as required, depending on whether a specific drug has demonstrated safety and efficacy in this setting. Outcome-effective management of patients with acute coronary ischemia requires prompt and accurate risk-stratification followed by a benefit-maximizing, risk-reducing combination of pharmacological and procedural interventions.
With these issues in clear focus, the purpose of this landmark review of ACS is to present a set of evidence-based guidelines and recommendations that emergency physicians and cardiologists can use to establish critical pathways for their institutions. Given the multiplicity of options and the profusion of recent literature on this subject, objectives of this three-part series include establishing an evidentiary infrastructure, presenting trial-based pathways, and providing an analysis base that can bring emergency physicians and their cardiology colleagues together on how best to manage life-threatening disorders characterized by acute coronary ischemia. In order to translate data and information into the world of practical, day-to-day clinical application, an evidence-based critical pathway for ACS has been generated for reader, academic, and institutional use. —Gideon Bosker, MD
Definition
Ischemic heart disease encompasses a wide spectrum of conditions, ranging from silent ischemia to acute myocardial infarction (AMI). Coronary ischemic syndromes have been classified into distinct diagnostic categories, including stable angina, unstable angina (UA), non-Q wave myocardial infarction (MI), and Q wave MI. Not surprisingly, the terminology for these conditions has evolved as new studies have shed light on the pathophysiology and natural history of these conditions.
On Sept. 8, 2000, The American College of Cardiology and American Heart Association (ACC/AHA) issued their Year 2000 ACC/AHA Guidelines for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. The guidelines have replaced the commonly used category, non-Q wave MI, with the clinical designation, Non-ST-segment Elevation Myocardial Infarction (NSTEMI). This change in terminology reflects the fact that among patients with MI, the presence or absence of ST-segment elevation does not always correlate with Q wave or non-Q wave MI, respectively. In other words, not all patients with ST-segment elevation develop Q waves, whereas some patients without ST-segment elevation on presentation eventually do develop Q waves.
From a practical perspective, this terminology also reflects that initial management of a patient with an ACS is based on the presence or absence of ST-segment elevation. While this review uses the new terminology, it must be recognized that most of the literature uses the term Q wave. UA includes many subtypes, including angina at rest, new-onset exertional angina, recent acceleration of angina, variant angina, and post-MI angina.1 The term acute coronary syndrome (ACS) refers to conditions that share similar pathophysiology. These include UA, NSTEMI, and ST-segment elevation MI (STEMI).1,2
Epidemiology
Coronary artery disease (CAD) is present in more than 7 million Americans and is the cause of more than 500,000 deaths annually.2 More than 1 million Americans have an AMI annually, and approximately 25% of all deaths are due to AMI.2 In 1996 there were 750,000 admissions for AMI, approximately one-half of which had ST-segment elevation and one-half of which did not.1,2
UA is one of the leading causes of hospital admission for patients with CAD, with more than 1 million hospitalizations annually in the United States.2,3 First year, direct medical costs associated with UA and AMI have been estimated at more than $12,000 per patient, which translates to an estimated national expenditure exceeding $16 billion.3 Among patients with UA who receive treatment, about 1-5% die and 2-10% experience an AMI within the first 28 days after hospital admission.4
Clinical Pathophysiology
Our understanding of the underlying lesions, pathophysiology, and natural history of ACS has evolved considerably during the past 25 years. It was hypothesized in the 1970s and early 1980s that the degree of vessel stenosis affected the frequency of ACS. However, it was later noted that the extent of luminal narrowing and severity of coronary stenonsis on angiography did not consistently correlate with the risk of thrombotic complications or the location of subsequent coronary artery occlusions.5
By the late 1980s, the concept of vulnerable atherosclerotic plaque had evolved, and it was observed that the presence of vulnerable lesions, some of which were associated with only minimal occlusion of the vessel, correlated with the development of ACS.5 Subsequently, intravascular ultrasound techniques have revealed that arteries accommodate plaque growth through outward displacement of the vessel wall, thereby preserving much of the patency of the vessel lumen. Most MIs result from coronary artery occlusions associated with a degree of stenoses of less than 50% on angiography.5 The unpredictable and episodic progression of plaques likely results from plaque disruption and subsequent thromboses, causing changes in plaque geometry and growth and intermittent ACS events.1
The natural history of ACS confirms that the pathogenesis of ischemic cardiovascular conditions is a complex process that is neither linear nor predictable. However, characteristic, pathologic phases that occur as part of the natural history of ACS include plaque formation (atherogenesis), plaque disruption (rupture or fissuring) or endothelial erosion, and thrombosis following plaque disruption. Inflammation contributes to the pathogenesis of ACS, as suggested by the fact that excised plaques from culprit lesions in UA patients have more inflammatory cell infiltration than do plaques from patients with stable angina.6
Atherogenesis: Atherogenesis frequently is initiated by endothelial cell changes, which may result from enhanced expression of adhesion molecules in intact cells. Factors that may initiate these changes include hypercholesteremia and certain constituents of cigarette smoke. It is postulated that endothelial cell changes permit blood monocytes to adhere to the altered endothelium and then enter the subendothelium. There, low-density lipoproteins (LDL-cholesterol) undergo oxidation, collect within the extracellular space, and bind to the macrophage receptors. This is the precursor phase to LDL sequestration by macrophages, which accumulate the LDLs (a process that results in the formation of foam cells).
Foam-laden macrophages and endothelial cells then secrete growth factors, resulting in smooth muscle cell proliferation. Subendothelial lipids eventually coalesce and form the lipid core of growing atherosclerotic plaques. Additional toxic products (among them, free radicals released by macrophages) produce local cell injury and denuding of endothelium. Platelets adhere to endothelial cell injury sites and release additional growth factors that result in more proliferation of intimal smooth muscle cells, promoting plaque growth. Smooth muscle cells also stimulate development of an extracellular matrix through collagen formation. This matrix consists of a fibrous cap that becomes an interface between the lipid core and the endothelium.
Upon analysis of excised plaques, angiographically- demonstrated lesions may consist primarily of smooth muscle proliferation. However, many plaques also have a thrombus incorporated within their matrix. It is postulated that thrombi are a potent stimulus for smooth muscle cell proliferation, as are cytokines or growth factors released from inflammatory cells. Other stimuli, including such infectious agents as Chlamydia pneumoniae and cytomegalovirus also have been identified as precipitants of atherogenesis.6
Plaque accretion and instability can result from disruptions to its various components. For example, a minor disruption might produce a small thrombus that becomes organized and may eventually lyse or, alternatively, be replaced by the vascular repair response. It should be emphasized that vascular repair can produce rapid plaque growth.1,5 In this regard, serial angiograms performed before and after an episode of UA, without an intervening coronary intervention, have shown progression of CAD in about 75% of patients.6
Atherosclerotic plaques may be stable or vulnerable (i.e., prone to rupture). Vulnerable plaques often have a thin fibrous cap, a large lipid core, soft cholesterol ester lipids (rather than free cholesterol monohydrate), and an inflammatory cell infiltrate.5,7 The arterial lumen may be well preserved at the site of a vulnerable plaque. Cap thickness results from the balance between new collagen production by smooth muscle cells and degradation secondary to inflammatory activity of macrophages.
Plaque Disruption: A number of mechanisms may cause plaque disruption. Plaques rich in extracellular matrix and smooth muscle cells may not necessarily be vulnerable or lipid rich, but they may, nevertheless, simply erode over time.1 Passive or active forces may disrupt vulnerable plaques. Propensity to rupture depends on circumferential wall stress or cap "fatigue" location, size, and consistency of the atheromatous core; and blood flow characteristics, especially the effect of flow on the proximal aspect of the plaques (ie, configuration and angulation of the plaque).1
Passive physical forces typically cause disruption at the shoulder of the plaque, between the plaque and the adjacent vessel wall. The cap is weakest at the shoulder because it is thinner and more infiltrated with foam cells. Disruption may be triggered by myriad events, such as emotional stress or physical activity. A surge in sympathetic activity, with an increase in blood pressure, heart rate, force of cardiac contraction, and coronary blood flow, may lead to plaque disruption.1 Vasospasm due to any cause may compress a plaque, causing rupture. Macrophages may induce active disruption. They degrade extracellular matrix by phagocytosis, and they secrete proteolytic enzymes such as plasminogen activators and matrix metalloproteinases (collagenases, gelatinases, and stromelysins) that may weaken the fibrous cap, predisposing it to rupture.1
Thrombosis: Initiated by plaque disruption or injury, thrombosis is a complicated process mediated by thrombin and platelets. The size of the thrombosis, and therefore, the degree of occlusion and clinical outcome, are affected by many factors. Thrombosis size is decreased by minor plaque disruption, high vessel blood flow, and increased fibrinolytic activity. Thrombosis is enhanced by larger plaque disruptions, low blood flow, hypercoagulable (such as increased fibrinogen) or hypofibrinolytic states, and increased platelet reactivity.1,5,7 Thrombi may be labile, resulting in recurrent episodes of occlusion. Thrombosis may be intramural alone or may occlude the arterial lumen to varying extents.
After a plaque is disrupted, platelets adhere to denuded endothelium and form a monolayer. Platelets adhere via their GP Ia/IIa receptors binding to subendothelial collagen and their GP Ib receptors binding to the von Willebrand factor. (See Figure 1)
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The process of adhesion and thrombin formation both activate the adhered platelets, resulting in the secretion of adenosine diphosphate (ADP), thromboxane A2, and serotonin. These mediators, along with local shear forces, attract and activate other platelets.1 (See Figure 2)
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Platelet activation includes activation of their GP IIb/IIIa receptors, one of the most densely expressed receptors known. Platelet activation results in a conformational change of the GP IIb/IIIa receptors, increasing their affinity for fibrinogen. Once adjacent platelets have activated GP IIb/IIIa receptors, fibrinogen can bridge between the platelets, and aggregation occurs. (See Figure 3) This is the "final common pathway" for platelet aggregation, resulting in a platelet plug at the subendothelial disruption site.
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In addition to the aforementioned platelet-related events, plaque disruption also results in the release of tissue factor from foam cells, activating factor VII and the extrinsic coagulation pathway. (See Figure 4) Activation of the extrinsic coagulation pathway results in the production of thrombin and fibrin, which stabilize the platelet plug. Activated factor VII and tissue factor combine to also activate factor IX within the intrinsic pathway, initiating further production of thrombin and fibrin. (See Figure 4) In addition to converting fibrinogen to fibrin, thrombin also amplifies the coagulation cascade by activating factors V and VIII and is a powerful platelet agonist.8
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Coronary artery thrombi vary both in content and location within the vessel and can be described in many ways, including being mural, occlusive, platelet-rich, fibrin-rich, organized, multi-layered, or re-endothelialized.7 The differences in thrombi content may explain why fibrinolytic drugs benefit patients with MI but fail those with UA. Thrombus formation results in decreased blood flow through the occluded vessel, enabling fibrin to be added to the thrombus, which results in stabilization of the thrombus. The UA thrombi are likely to be relatively newer and smaller; primarily consist of platelets, with little fibrin; and look "white" on coronary angioscopy. Conversely, the thrombi associated with an AMI often are more complicated and evolved. They are more likely to have older thrombin deep within the clot, with loose and recently formed superficial layers, or to have undergone some reabsorption or reorganization. Because the coronary artery usually is occluded totally by thrombus in AMI, there is significant stasis of blood flow.
This stasis permits fibrin and red blood cells to become superimposed on the original platelet-rich thrombus. On angioscopy, the thrombi of AMI appear red because of the trapped red cells and fibrin.6 Fibrinolytic agents target fibrin within the thrombus. The varied complexity and content of the thrombi associated with AMI likely reflects why normal (TIMI grade III) blood flow is achieved in only 50-60% of patients who receive fibrinolytics.7 Within a thrombus is a catalytically active thrombin called clot-bound thrombin, which is likely of great importance. Thrombolysis re-exposes "clot-bound thrombin" to the circulation, reinitiating thrombosis by activating both platelets and thrombin. This process may contribute significantly to the vessel reocclusion that occurs after thrombolysis.
Clinical Presentation
Pathogenesis of CAD is linked to progression of atherosclerosis and, more specifically, to factors precipitating plaque disruption and subsequent thrombosis formation. Symptoms of ischemia, on the other hand, reflect an imbalance between myocardial blood (oxygen) supply and oxygen demand. Accordingly, ischemic coronary pain at rest can result from transient decreases in oxygen supply secondary to 1) thrombus formation; 2) embolization; or 3) transient increases in vasomotor tone producing diminished blood flow to the myocardium.
As principal mediators of ACS, activated platelets release several vasoactive substances that, in the presence of endothelial dysfunction (impaired vasodilation), can result in vasoconstriction near the lesion and a transient decrease in blood flow. Patient symptoms depend on many factors, including the degree of occlusion and the presence of collateral circulation. Plaque disruption, accompanied by isolated mural thrombosis formation, but without clinical symptoms, may be more common than once suspected. Patients with stable CAD may have angina or silent ischemia that results from increases in myocardial oxygen demand that outstrip the ability of a stenosed coronary artery to deliver the required oxygen load.
ACS patients present with variable symptomatology somewhere on the disease continuum that typically results from an abrupt reduction in coronary artery flow secondary to acute thrombosis. UA patients may have small erosions or fissuring on the plaques with small changes in plaque structure or small thromboses. Arterial occlusions, and accordingly, patient symptoms, may be transient if the thrombi are labile. NSTEMI may result from more severe plaque damage and a more persistent thrombotic occlusion. Patients with NSTEMI likely have high rates of spontaneous reperfusion as reflected by the fact that only 25% of this subgroup have complete coronary occlusions on early angiography. STEMI, with transmural necrosis of the involved myocardium, may be attenuated by spontaneous thrombolysis, resolution of vasoconstriction, or the presence of collateral circulation. Acute STEMI most likely results from larger plaque fissures and the formation of fixed and persistent thrombi.1
Acute Management
Overview: The goals of acute management of ACS are to relieve symptoms; prevent progression of the disease to AMI; minimize loss of myocardial muscle and function; reduce mortality; and treat specific complications of ischemia, such as dysrhythmias or pulmonary edema. Acute pharmacotherapeutic interventions aimed at minimizing or aborting pathogenic processes producing ischemic coronary events usually will require a multi-modal, "cocktail" approach—a polypharmacy strategy that addresses the complex pathogenesis of ACS. Accordingly, multiple agents will be required, each reflecting activity against a distinct precipitant of plaque disruption, thrombosis formation, or coronary vasoconstriction. This will include agents directed at thrombin generation, platelet aggregation, fibrin deposition, and inflammation.
Aspirin, heparin, and increasingly, LMWHs such as enoxaparin, routinely are used in the treatment of these syndromes. The need to target multiple pathogenic end points has stimulated the development of new antithrombotic drugs. Several new agents have been evaluated, particularly for the treatment of ACS. (See Table 1)
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Table 1. Antithrombin and Antiplatelet Agents |
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| Antithrombin Agents | |
| AT III dependent | |
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Heparin |
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LMWH
AT III independent
Hirudin
Hirulog
Antiplatelet Agents Cyclooxygenase inhibitor
Aspirin
GP IIb/IIIa inhibitors
ADP inhibitors
Thromboxane synthetase inhibitor
Thrombolytic Agents Alteplase (t-PA) Reteplase (r-PA) Streptokinase Tenecteplase (TNK-tPA)
Many trials have been conducted to evaluate these agents, used as monotherapy and in combination. Unfortunately, sorting out these trials and their implications for clinical practice has been difficult because the trial names lead to an "alphabet soup" of confusion, and they have reported on different patient groups evaluated with different protocols. (See Table 2)
| Table 2. Abbreviations and Acronyms of Major Trials | |
| ADMIRAL | = Abciximab before Direct angioplasty and stenting in acute Myocardial Infarction Regarding Acute and Long-term follow-up |
| ASSENT | = ASsessment of the Safety and Efficacy of a New Thrombolytic agent |
| ASSET | = Anglo-Scandinavian Study of Early Thrombolysis |
| CADILLAC | = Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications |
| CAPTURE | = C7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment |
| ECSG | = European Cooperative Study Group |
| EPIC | = Evaluation of c7E3 for Prevention of Ischemic Complications |
| EPILOG | = Evaluation in PTCA to Improve Long-term Outcome by GP IIb/IIIa receptor blockade |
| EPISTENT | = Evaluation of Platelet Inhibition in STENTing |
| ESSENCE | = Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events |
| FRAXIS | = FRAXiparin in Ischemic Syndromes |
| FRIC | = FRagmin In Coronary artery disease |
| FRISC | = FRagmin during InStability in Coronary artery disease |
| GISSI | = Gruppo Italiano per lo Studio della Streptochinasi nell' Infarcto miocardico |
| GUSTO | = Global Utilization of Streptokinase and T-PA in Occluded arteries |
| HART | = Hypertension Audit of Risk factor Therapy |
| IMPACT | = Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis |
| NICE | = National Investigators Collaborating on Enoxaparin |
| PACT | = Plasminogen activator and Angioplasty Compatibility Trial |
| PAMI | = Primary Angioplasty in Myocardial Infarction |
| PARADIGM | = Platelet Aggregation Receptor Antagonist Dose Investigation for reperfusion Gain in Myocardial infarction |
| PARAGON | = Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in the Global Organization Network |
| PRISM | = Platelet Receptor Inhibition in ischemic Syndrome Management |
| PRISM PLUS | = PRISM in Patients Limited by Unstable Signs |
| PURSUIT | = Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy |
| RAPPORT | = Reopro And Primary PTCA Organization and Randomized Trial |
| RESTORE | = Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis |
| SPEED | = Strategies to Promote Early reperfusion in the Emergency Department |
| SWIFT | = Should We Intervene Following Thrombolysis |
| TAMI | = Thrombolysis and Angioplasty in Myocardial Infarction |
| TIMI | = Thrombolysis In Myocardial Infarction |
| VANQWISH | = Veterans Affairs Non-Q Wave Infarction Strategies in Hospital |
The relationships of some of these trials relative to different treatment modalities are summarized in Figure 5.
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Antiplatelet Therapy
Overview: Platelet activation and aggregation involve multiple steps, each of which is a potential target for pharmacotherapeutic inhibition. Another goal of therapy is "passivation," which refers to the conversion of platelets that are already activated, highly reactive, and thrombogenic—to a non-reactive, non-thrombogenic state. Passivation occurs in approximately eight hours in a normal artery; however, an artery with atherosclerotic disease may require days or longer.7 Aspirin has been the primary antiplatelet agent used in ACS. Other antiplatelet agents include inhibitors of GP IIb/IIIa receptors, ADP, and thromboxane synthetase.
Aspirin: Aspirin is the mainstay of ACS therapy. No other antiplatelet agent has a more impressive risk-benefit ratio and costs so little. Aspirin acts rapidly, achieving platelet inhibition within 1 hour. Aspirin dosages have varied among clinical trials, with 81-325 mg being the usual range. Clinicians should avoid enteric-coated aspirin in the setting of ACS because its onset of action is delayed 3-4 hours. Aspirin permanently inactivates the platelet enzyme cyclooxygenase for the eight- to 10-day life of the platelet. This results in decreased production of thromboxane A2, which is pro-aggregatory and causes vasoconstriction. However, by blocking thromboxane A2 production at the cyclooxygenase level, prostacyclin (a vasodilator, platelet inhibitor, and protector of gastrointestinal mucosa integrity) synthesis also is inhibited.
The importance of platelet inhibition in MI was confirmed in ISIS-2, in which aspirin produced a 23% reduction in mortality and reduced the rate of hospital reinfarction from 2.9% to 1.9%.9 Other trials also have demonstrated that aspirin decreases death and MI following UA by 31-50%.10-12 In patients at high risk for atherosclerotic disease, regular aspirin use reduces eventual nonfatal MI by 30%, nonfatal stroke by 30%, and vascular deaths by 17%.13
Despite its great benefits, aspirin has its limitations. It is a weak antiplatelet agent and does not inhibit platelet aggregation caused by thromboxane A2-independent pathways (eg, via ADP or collagen stimulation). Aspirin has no effect on thrombin, which likely plays a major role in platelet activation in acute ischemic syndromes. Aspirin also does not inhibit platelet adhesion or suppress platelet secretion of thrombogenic mediators. In addition, there are individual differences in patient response. Finally, aspirin, like most antiplatelet agents, increases the risk of bleeding complications.
Thromboxane Synthetase Inhibitors: Ridogrel selectively inhibits thromboxane synthetase, thereby limiting thromboxane production without affecting prostacyclin. Since inhibition of prostacylin synthesis has the potential to promote thrombogenesis, these more selective agents should, in theory, be more effective than aspirin. The effectiveness of ridogrel and aspirin for ACS were compared in the Ridogrel vs. Aspirin Patency Trial (RAPT).14 All patients received streptokinase. The primary end point was arterial patency between seven and 14 days and secondary end points were clinical markers of reperfusion and safety. No differences in efficacy or safety were observed.14
Adenosine Diphosphate Inhibitors: ADP is secreted by activated platelets and stimulates additional platelet activation and aggregation via the platelet P2T cell surface receptor. Ticlopidine (Ticlid) and clopidogrel (Plavix) are structurally similar to P2T antagonists. These agents selectively and irreversibly inhibit ADP binding to the P2T cell surface receptor, stopping platelet activation via this route. However, they also interfere with a specific ADP-dependent step of GP IIb/IIIa complex activation, resulting in less platelet aggregation and, ultimately, less thrombus formation.4 As a result, these agents provide broader inhibition of platelet aggregation than aspirin because they not only limit ADP-receptor stimulated aggregation but also aggregation triggered by a number of other stimuli. However, they are similar to aspirin in that their effect on platelet aggregation is incomplete and aggregation still occurs.4
The first ADP antagonist introduced, ticlopidine, has been shown to be better than placebo for reducing the risk of stroke, AMI, and vascular death in patients with atherosclerotic disease.13 It is comparable to aspirin for reducing risk of stroke, MI, and vascular death.13
The Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial involved 19,185 patients in a randomized, double-blinded assessment of safety and efficacy.15 Patients with ischemic stroke, AMI, or symptomatic atherosclerotic peripheral arterial disease were randomly assigned to receive aspirin or clopidogrel for 1-3 years. The combined end point of ischemic stroke, AMI, or vascular death occurred in 5.3% of the clopidogrel patients and in 5.8% of aspirin-treated cohort, a relative risk reduction of 8.7% (P = .043) in favor of the clopidogrel group.
Patients with peripheral arterial disease had particularly good benefit. Aspirin was associated with significantly more gastrointestinal hemorrhage, while clopidogrel caused significantly more rash. Severe neutropenia occurred in 0.1% of both treatment groups.15 The CAPRIE trial suggested that clopidogrel is at least as effective as aspirin, if not more effective, for the secondary prevention of ischemic events. However, the efficacy of ADP-inhibitors for ACS is inferior to that of aspirin. Accordingly, clopidogrel should be used as a second-line agent for antiplatelet therapy, particularly in patients unable to tolerate aspirin therapy.
Thromboxane A2 receptor antagonists have numerous limitations. Compared to aspirin, these agents are relatively costly at $1 to $3 per tablet.16 Moreover, ticlopidine requires 3-5 days for onset of action and, therefore, is not useful for ACS. Clopidogrel’s onset is 2 hours, still slower than the 30-60 minute onset for aspirin. Complications with ticlopidine include diarrhea, pruritis, urticaria, and skin rash. Hepatocellular enzyme elevation occurs in as many as 8% of patients. Most significant are the hematologic side effects, particularly neutropenia. An absolute neutrophil count (ANC) of fewer than 1200 occurs in 2.4% of patients and an ANC of fewer than 450 in 0.8% of patients. While the neutropenia typically occurs between 3 weeks and 3 months after initiation of therapy, it may occur later and its onset may be sudden. Thrombocytopenia may occur and can present like immune thrombocytopenia or thrombotic thrombocytopenic purpura (TTP). Clopidogrel’s side effect profile is safer and comparable to that of aspirin. Abdominal discomfort and rash each occur in approximately 4% of patients, while hematologic complications are rare.16
Glycoprotein IIB/IIIA Inhibitors: Pharmacology, Actions, and Side Effects
Overview: Many substances can activate platelet aggregation, especially GP IIb/IIIa receptors, which mediate the obligatory last step, or final common pathway, for platelet aggregation. GP IIb/IIIa receptors are platelet-specific, and there are approximately 50,000 per platelet.17,18 Platelet activation causes these receptors to become activated and exteriorized, and to undergo a conformational change. The GP IIb/IIIa receptor is a functional receptor for such adhesive macromolecules as fibrinogen, fibronectin, vitronectin, and vWF. Each of these molecules can interact with multiple platelets via GP IIb/IIIa receptors.
Molecules that interact with GP IIb/IIIa receptors contain the arginine-glycine-aspartic acid (RGD) sequence, which serves as the minimal recognition sequence for the receptor. Fibrinogen contains this RGD sequence on each of its a-chains, as well as a dodecapeptide on its g-chain that also is capable of binding to the receptor. However, whereas the RGD sequence is recognized by many other integrin receptors, the dodecapeptide is specific for fibrinogen binding to platelets. During clot formation, activated platelets, with active GP IIb/IIIa receptors, recognize the RGD sequence in fibrinogen. Platelets and fibrinogen bind, initiating platelet aggregation, resulting in a hemostatic plug.17,18 (See Figure 3.)
Virtually all platelet aggregation can be stopped by inhibition of 80% of the GP IIb/IIIa receptors.19 GP IIb/IIIa receptor antagonists—all of which contain the RGD sequence—include abciximab (ReoPro), tirofiban (Aggrastat), eptifibatide (Integrilin), and lamifiban. The first 3 have received FDA approval, while lamifiban has been used in Canada.
The GP IIb/IIIa receptor is an excellent target for inhibition of platelet aggregation because it is specific for platelets and it is the "final common pathway" for platelet aggregation, regardless of the specific mechanism responsible for platelet activation.20 However, inhibition of the GP IIb/IIIa receptor does not abolish other platelet functions such as adhesion, activation, or secretion. These agents also do not block thrombin generation occuring on the surface of activated platelets. Consequently, IIb/IIIa antagonists may work best in combination with agents that block thrombin generation. They also do not affect tissue factor induced coagulation, and they do not prevent inflammation.17,20
From a clinical and pathophysiological perspective, early use of GP IIb/IIIa inhibitors (see Table 3.) prevents disrupted coronary arterial surfaces from supporting platelet deposition. This clinically advantageous event has been termed passivation. Heightened platelet activity associated with ACS is known to be associated with abrupt closure after angioplasty and coronary reocclusion after thrombolysis. Passivation may include limiting production of platelet-derived vasoconstrictors in the short term and growth factors in the long term. Decreased platelet aggregation may enable arterial surfaces to heal more favorably, reducing the likelihood of (re)infarction.21
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Abciximab: Pharmacology and Antiplatelet Effects. Abciximab is a recombinant monoclonal antibody fragment (Fab) that blocks IIb/IIIa receptors. It has a high affinity for the GP IIb/IIIa receptor and, consequently, binds rapidly and irreversibly to platelets. Because of its large size, the unbound plasma fraction is rapidly cleared by the reticuloendothelial system. The rapid binding and clearance of abciximab results in a very short serum half-life and, therefore, it must be given as a continuous intravenous infusion. Maximum receptor blockade and inhibition of aggregation occurs two hours after a bolus injection and returns toward normal within 12 hours. However, because of its high affinity for the receptor, it has a long biologic half-life and aggregation may return toward baseline as late as 12-36 hours after discontinuation of the infusion.20
Abciximab undergoes gradual redistribution after administration, with antibody redistributing to newly produced platelets, prolonging the antihemostatic effect.4 GP IIb/IIIa receptor occupancy by abciximab exceeds 30% at eight days and 10% at 15 days, and it has been found on receptors as far out as 21 days.19,20 Recovery in platelet aggregability is gradual and smoothly transitioned after abciximab therapy. It is relatively rapid after tirofiban or eptifibatide discontinuation. The gradual tapering of antiplatelet effect theoretically could attenuate the propensity for rebound.
The pharmacology of abciximab could result in less of it being available to bind additional GP IIb/IIIa receptors expressed on platelet surfaces from the alpha granule storage pool. This may explain the erosion in the magnitude and the dispersion in consistency of platelet inhibition during a continuous 12-hour infusion of abciximab. Indeed, although greater than 95% of patients will exhibit more than 80% GP IIb/IIIa receptor inhibition after the bolus dose of abciximab, approximately 15% will be less than 80% inhibited at 8-10 hours into the continuous infusion.20 However, despite this loss of receptor inhibition over time, the clinical benefit of adjunctive abciximab therapy during PCI is quite robust. This suggests that the benefit of abciximab might not be solely explained by the degree of GP IIb/IIIa platelet inhibition, but also may be related to other differences in pharmacodynamics such as the gradual redistribution or the nonspecific receptor affinity.
Abciximab is not very specific because it inhibits the GP IIb/IIIa receptor simply because of its size. In fact, it not only inhibits the b3 chain of the GP IIb/IIIa receptor, but also the receptor avb3 (vitronectin) and the leukocyte receptor MAC-1. The vitronectin receptor is found not only on platelets, but also on smooth muscle cells, endothelial cells (including those that overlie an atherosclerotic plaque) monocytes, and polymorphonuclear leukocyctes.20,22 Of special interest, the vitronectin receptors on smooth muscle cells have been associated with an intimal hyperplasia response that follows vascular injury, including that associated with PCI.
As a result, it has been proposed that the vitronectin receptor may contribute to restenosis,20 although it is uncertain whether inhibition of vitronectin contributes to the effectiveness of abciximab in humans. Animal studies demonstrate that vitronectin receptor inhibition can prevent intimal hyperplasia and the late vessel lumen loss after balloon angioplasty or stenting.20 In laboratory animals, vitronectin blockade attenuates injury-induced smooth muscle migration and neointimal hyperplasia. Vitronectin receptors upregulate upon activation of smooth muscle and endothelial cells. These receptors may affect cell attachment, proliferation, migration, and survival; therefore, they may affect intimal hyperplasia and angiogenesis. These effects may play a role in new plaque formation and restenosis.22
Vitronectin receptors on activated platelets also have been implicated in both platelet adhesion to osteopontin (which is present in atherosclerotic plaques) and platelet-mediated thrombin generation. As a result, dual receptor blockade (GP IIb/IIIa and vitronectin) has been demonstrated to provide more potent inhibition of platelet-supported thrombin generation than monoreceptor blockade by specific monoclonal antibodies or after blockade by eptifibatide or tirofiban in combination with heparin.20
Abciximab also binds and inhibits the leukocyte MAC-1 (amb3) receptor, recognizing the am subunit. Activation of this receptor increases the intensity of interactions among white blood cells (WBCs) and platelets, thereby accelerating the inflammatory response to vessel injury. Following stent deployment, adhesion of WBCs is significantly reduced by abciximab, as is leukocyte accumulation in balloon-damaged blood vessels. These inflammation-reducing effects may decrease the restenosis rate in patients undergoing PCI.20,22
Tirofiban and Eptifibatide: Pharmacology and Antiplatelet Effects. Other GP IIb/IIIa receptor inhibitors, eptifibatide and tirofiban, are peptide and nonpeptide agents, respectively. Unlike abciximab, they are small molecules that competitively, and specifically, inhibit the RGD sequence of the GP IIb/IIIa receptor. They do not affect other receptors such as vitronectin. Because the GP IIb/IIIa receptor affinity of these agents is lower than that of abciximab, they have a short duration of action at the platelet target receptor, a short biologic half-life, and their antiplatelet effect is readily reversible. They dissociate from the receptors within seconds (vs hours for abciximab). They also undergo slow hepatic and renal clearance. Because of their low affinity and their slow clearance, they have a relatively long plasma half-life.20,22
In vitro experiments have shown that tirofiban and eptifibatide, but not abciximab, enhance leukocyte-platelet aggregation in whole blood. Because leukocyte-platelet interactions affect atherogenesis, restenosis, and reperfusion injury, these agents may elicit a potentially deleterious cellular response despite their ability to inhibit platelet aggregation.22 Eptifibatide is derived from the venom of the Southeastern pygmy rattlesnake while tirofiban is obtained from the venom of an African saw-scaled viper. Receptor inhibition is achieved within 15 minutes for eptifibatide and 5 minutes for tirofiban. Once the infusion is stopped, platelet aggregation function returns toward baseline within 30 minutes to 4 hours, much more rapidly than is the case with abciximab.19 As expected, these agents require much larger molar concentrations (drug-to-receptor dose) to maintain receptor blockade than does abciximab.18
Oral agents in the GP IIb/IIIa inhibitor class also are being developed, among them xemilofiban, orbofiban, and sibrafiban. The clinical focus of these agents has been long-term therapy for the secondary prevention of ACS. Unfortunately, thus far, phase III trials have not demonstrated clinically significant efficacy; as a result, they have no role in the management of ischemic syndromes.3
Complications and Adverse Effects: The most important complications associated with GP IIb/IIIa inhibitors are bleeding, thrombocytopenia, and reactions to readministration. Abciximab is designated as a Pregnancy Class C agent while eptifibatide and tirofiban are designated as Class B agents.
Major bleeding was doubled in patients receiving GP IIb/IIIa inhibitors in the EPIC and CAPTURE trials. However, vascular sheaths were left in for hours after the trial drug infusions were stopped, venous access site management was not optimal, and weight-based heparin dosing was not used. Subsequent trials that corrected for the aforementioned problems demonstrated major bleeding rates comparable to placebo, ranging from 0.4-7.8%. Mild bleeding generally is slightly more common with the use of GP IIb/IIIa inhibitors.23
Prompt reversal of the effects of GP IIb/IIIa inhibitors may be required in patients who develop a bleeding diathesis and in those individuals who require immediate coronary artery bypass graft (CABG) surgery.24 Eptifibatide and tirofiban have short biologic, but long plasma half-lives; they are cleared by the kidney. Normal hemostasis should return within hours of stopping an infusion of these agents if renal function is good. Hemodialysis may reverse the hemostasis defect, although this has not been tested. Platelet transfusion is of no benefit because the number of drug molecules overwhelms the number of GP IIb/IIIa receptors. Conversely, abciximab’s long biologic and short plasma half-life results in slow elimination. Platelet transfusions may reverse the hemostatic defect despite the redistribution of drug onto the new platelets. This is because there are relatively few abciximab molecules and their effects will be diluted by the large number of new platelets that are introduced.24
In the GP IIb/IIIa trials, mild thrombocytopenia (< 100,000 platelets/mm3) occurred in approximately 5% of patients while moderate thrombocytopenia (< 50,000 platelets/mm3) occurred in 2% of the abciximab patients and in less than 1% of the eptifibatide and tirofiban patients. Severe thrombocytopenia (< 20,000 platelets/mm3) rarely occurred with eptifibatide or tirofiban, but it did affect 0.7% of patients receiving abciximab. It has been proposed that abciximab is more likely to cause thrombocytopenia because it may have a complex interaction with heparin, leading to thrombocytopenia.24
The chimeric antibody fragments of abciximab are immunogenic. Low titers of antichimeric antibody develop in approximately 6-7% of patients receiving abciximab.4,24 Titers peak 1 week to 1 month after administration and then gradually decline. Immunoglobulin G antibodies do not interfere with efficacy and are not associated with anaphylactic reactions. The significance of the antibody is unclear. Readministration of abciximab is not associated with an increased risk of anaphylaxis or altered benefit. However, severe thrombocytopenia has occurred in 2.4% of patients upon readministration of abciximab.24
Cost: Despite significant acquisition costs, GP IIb/IIIa inhibitors may be cost-effective by reducing the need for revascularization and/or hospital stay. Economic analyses are just being released. The acquisition costs for 24-72 hour infusions of these medications range from $1260 to $2160. Abciximab costs approximately $1400 per patient for a standard 12-hour infusion. The infusion time for eptifibatide and tirofiban is variable and cost varies according to infusion time. Many trials have used 48- to 96-hour infusions, and the procurement cost is more than $1000 for these agents.25
Investigators have performed pharmacoeconomic analyses of GP IIb/IIIa inhibitors used in various PCI and ACS trials. In the PCI setting, the cost savings are secondary to reduced cardiac events with abciximab and tirofiban and partially offset drug acquisition costs. In general, it was concluded that only the very high-risk patients (elevated cardiac markers, persistent angina, etc.) have cost-effectiveness ratios that would be considered acceptable.25
GP IIb/IIIa Inhibitor Trials of Unstable Angina or NSTEMI With Mandated Procedural Coronary Intervention
The role of GP IIb/IIIa inhibitors in the setting of PCI has been established by 7 randomized, blinded, placebo-controlled trials involving a total of approximately 15,000 patients. The 6 larger trials are summarized in Table 4. All patients in these trials received aspirin and heparin. Except for CAPTURE, all trials administered the study drug or placebo as a bolus immediately before PCI, followed by infusions of variable durations. The rapidly reversible, small molecules, eptifibatide and tirofiban, were infused for 24 hours or 36 hours, respectively. Conversely, the slowly reversible abciximab was infused for only 12 hours. In the CAPTURE trial, the study drug was infused for 20-24 hours before angioplasty and 1 hour after. In EPISTENT, patients received ticlopidine for 4 weeks after stenting, according to standard practice for stent implantation.
EPIC Trial: The EPIC trial was the first major study evaluating the effectiveness and safety of a GP IIb/IIIa inhibitor. Its design was based on the concept that platelet aggregation may be triggered by revascularization procedures inasmuch as reocclusion is common following percutaneous transluminal coronary angioplasty (PTCA). The purpose of the EPIC trial was to determine if abciximab could reduce reocclusion following PTCA.26 It included 2099 patients at high risk for vessel closure (UA, unfavorable coronary artery lesion morphology, AMI within 12 hours that needed rescue percutaneous intervention, or early postinfarction angina). Many of these patients did not have acute coronary ischemia. Patients were randomized to one of three treatment arms: 1) abciximab bolus without infusion; 2) abciximab bolus plus infusion; or 3) placebo bolus plus placebo infusion. Study drugs were initiated just prior to PCI and administered for 12 hours after the procedure. The primary end point was the composite of death, AMI, or need for revascularization at 30 days.
The absolute reduction (4.5%) in the composite end point by abciximab bolus plus infusion was significant compared to placebo.26 The reduction in the composite end point was still evident at 6 months and at 3 years.26,27 It should be noted that in the EPIC study, a doubling of major hemorrhage was observed with abciximab, primarily during CABG surgery or at the femoral puncture site. There was no difference in intracranial hemorrhage. Bleeding was more severe in patients who received relatively more of the fixed heparin dose. It was felt that bleeding resulted from the lack of weight-based heparin dosing, inadequate venous access care, and leaving the access sheath in place for several hours after the infusion had been completed.
EPILOG Trial: The purpose of the EPILOG trial was to see whether the efficacy of abciximab could be maintained while reducing the rate of major bleeding complications as compared to the results of EPIC.28 To decrease hemorrhage, patients received weight-based heparin, meticulous access site care, and early sheath removal. Patients were less ill than in the EPIC trial because it was felt that the benefit of abciximab in those with more acute ischemic syndromes had already been demonstrated. As with EPIC, both elective and urgent PCIs were studied. Patients received one of the following three regimens: 1) placebo plus standard-dose heparin (100 units per kilogram with a maximum of 10,000 units); 2) abciximab with standard-dose heparin; or 3) abciximab plus low-dose heparin (70 units per kilogram with a maximum of 7000 units). Study drugs were started just before the PCI and infused for 12 hours after the procedure. The composite end point included death, AMI, and need for urgent revascularization.
The trial was suspended after enrolling only 2792 of the planned 4800 patients because both clinically significant superiority was demonstrated in both abciximab treatment arms. There was a significant reduction of the composite end point at both 30 days and 6 months. (See Table 4.) Of special clinical significance was the finding that major bleeding was comparable between the placebo group and both of the abciximab groups.28
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EPISTENT Trial: The EPISTENT trial was performed to determine whether GP IIb/IIIa inhibitors would be beneficial in patients receiving intracoronary stents (metal scaffolding devices inserted angiograpgically in vessel lumens).29 Patients in the EPISTENT trial were similar to those in EPILOG (ie, they were not having an acute ischemic event, but were about to receive elective or urgent PCI).
In this trial, 2399 patients were randomized to receive one of the following three PCIs and pharmacotherapeutic agents: 1) stent plus placebo; 2) stent plus abciximab, or 3) angioplasty plus abciximab. The primary end point was death, AMI, or the need for urgent revascularization within the first 30 days. All patients also received ticlopidine for 4 weeks after stenting, according to contemporary post-interventional practice. The groups receiving abciximab reached the composite, morbid end point in significantly fewer patients (see Table 4) without a significant increase in major bleeding.29
CAPTURE Trial: The CAPTURE trial was unique among the abciximab trials for several reasons.30 First, unlike other abciximab evaluations, all patients in CAPTURE presented with active UA within the previous 72 hours. This study assessed the effect of 18-24 hours of medical stabilization with abciximab prior to PTCA. Abciximab was given before PCI and continued for only one hour after the procedure was completed. All patients underwent angiography upon presentation and had significant CAD with a "culprit" lesion deemed suitable for angioplasty. However, angioplasty was not done at the time of the original angiography. Patients were randomized within 24 hours of angiography to receive placebo or abciximab during the 18-24 hours before angioplasty was performed and for 1 hour after the procedure. The primary end point was a composite of death due to any cause, AMI, or need for urgent revascularization at 30 days.
The end points were significantly improved in the abciximab group at 30 days, but the difference was not maintained at 6 months.30 (See Table 4.) The decreased long-term efficacy in comparison to the EPIC trial may have resulted from the lack of post-procedural abciximab infusion. During the 18-24 hour infusion of drug prior to PCI, those who received abciximab had 67% fewer patients progress to AMI than did patients receiving placebo (2.1% vs 0.6%; P = .029). In comparison to placebo, major bleeding occurred twice as often in the abciximab group. (See Table 4.) However, major bleeding was less common in the CAPTURE trial than in the EPIC trial. This may have resulted from using a lower heparin dose and more meticulous access site care than that reported in the EPIC trial. Bleeding may have been reduced further in the CAPTURE trial by removing the sheath early. The authors recommended that the heparin dose be restricted to 70 IU/kg during PTCA.30
IMPACT-II Trial. The IMPACT-II trial assessed the role of eptifibatide in 4010 patients undergoing elective, urgent, or emergent PCI.31 The trial included three arms: 1) bolus plus high-dose infusion; 2) bolus plus low-dose infusion; and 3) placebo. The primary end point was the composite of death, AMI, or need for urgent revascularization within the first 30 days. Although there was a significant reduction in coronary events at the end of the 24-hour infusion in the eptifibatide groups, there were no significant differences at 30 days.31 (See Table 4.) The authors suggest that the lack of efficacy may have resulted from inadequate eptifibatide dosing or insufficient duration of infusion. There are, in fact, data suggesting that the dose may have achieved only 30-50% of platelet inhibition vs. the 80% required.31
RESTORE Trial: The RESTORE trial assessed the role of tirofiban in 2141 patients with ACS of 72 hours duration or less.32 (See Table 4.) Patients were randomized to receive tirofiban or placebo for 36 hours after PCI. The primary end point was the composite of death, AMI, or need for urgent revascularization in the first 30 days. There was a significant reduction in coronary events at 2 and 7 days, but no significant difference at 30 days.32 (See Table 4.) Major hemorrhage was comparable between groups. The authors indicated that the lack of efficacy at 30 days, as compared to abciximab in EPIC, may have resulted from different end point definitions between the trials. The composite end point in the EPIC trial included only emergency revascularization procedures, whereas the RESTORE trial considered all revascularizations ascribed to ischemia during the 30-day post-infusion period.32
GP IIb/IIIa Inhibitor Trials of Unstable Angina or Non-Q wave MI with Procedural Coronary Intervention not Mandated
The data for GP IIb/IIIa inhibitors in patients without PCI also suggest some possible advantages for one agent vs. another. The following trials (also know as the "Four Ps") targeted patients with ACS who did not have permanent ST-segment elevation. (See Table 5.) The objective of these investigations was to assess the role of the GP IIb/IIIa inhibitors in high-risk patients who were not necessarily going to have a PCI performed. One of the principal challenges when reviewing these studies is determining the outcome of patients who had PCI performed vs. those who did not. The use of PCI in these studies was not randomized. The preliminary results of GUSTO 4 ACS also address this issue.
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PARAGON Trial: The PARAGON trial involved 2282 patients with UA, NSTEMI, or temporary ST-segment elevation who presented within 12 hours of onset and had ECG changes.21 The 5 arms included a placebo group plus groups receiving lamifiban at both low and high doses, with or without heparin for 3-5 days of treatment. Percutaneous coronary intervention was discouraged during the first 48 hours. The primary end point was the composite of death due to all causes, AMI, or reinfarction within 30 days. There was no difference between groups at 30 days. (See Table 5.) However, at 6 months, low-dose lamifiban yielded a significantly lower composite end point than did placebo. Major bleeding occurred significantly more in patients who received heparin plus any dose of lamifiban. (See Table 5.) It was surprising that a very short-acting drug provided no benefits at 30 days but there was a significant difference at six months.21
PURSUIT Trial: The PURSUIT trial assessed the role of eptifibatide in 10,948 patients with ACS who presented with chest pain accompanied by either ECG changes or elevated markers.33 Patients received either placebo, eptifibatide bolus plus a high-dose infusion, or eptifibatide bolus plus a low-dose infusion. Percutaneous coronary intervention was used at the discretion of the physicians. The primary end point was the composite of death or AMI at 30 days. The outcomes of patients who received only medical therapy vs. those who had PCI performed were difficult to differentiate. At 30 days, there was a significant reduction of the composite end point within the high-dose eptifibatide group. (See Table 5.)
It should be stressed, however, that outcomes were different among different regions of the world in this multinational trial. Patients enrolled in Latin America or Eastern Europe derived less benefit than those enrolled in Western Europe or the United States. The difference may have resulted from regional differences in the use of PCI. Patients had catheterization performed 79% of the time in North America, 58% in Europe, 46% in Latin America, and 20% in Eastern Europe. The observed treatment benefit varied directly with the frequency of catheterization. This suggests that the greatest benefits of eptifibatide were experienced by patients undergoing a PCI. More bleeding and more transfusions were required in the eptifibatide group, albeit most occurred at the femoral access site. Most major bleeding occurred in patients undergoing a CABG.33
PRISM Trial: The PRISM trial evaluated 3232 patients who were randomized to receive a 48-hour infusion of tirofiban or heparin.34 Patients had onset of chest pain within 24 hours and either ECG changes, enzyme elevation, or prior documentation of CAD. PCI was discouraged during the 48-hour infusion. The primary end point was the composite of death, AMI, or refractory ischemia at two days. There was a significant reduction of the composite end point at 2 days; however, the difference was not maintained at 30 days. (See Table 5.) For patients who were treated with medical therapy alone, the rate of death or AMI was reduced from 6.2% in the heparin group to 3.6% in the tirofiban group at 30 days (P < .01). Bleeding complications were comparable between groups.34
PRISM PLUS Trial: The PRISM PLUS trial evaluated 1915 patients with very high-risk ACS without ST elevation, even more so than the patients in the PRISM trial.35 Patients presented within 12 hours of symptom onset and were randomized to receive a 48-hour infusion of tirofiban, heparin, or of both. PCI was discouraged during the 48-hour infusion period but was encouraged thereafter. The study drug was used during interventions, unlike in PRISM. The primary end point was the composite of death from any cause, AMI, refractory ischemia at 7 days, or rehospitalization at 7 days, 30 days, or 6 months. The tirofiban-alone arm was discontinued early because of excess events (5% died during the first 7 days). The composite end point was significantly improved in the tirofiban plus heparin group vs. the heparin alone group at 7 and 30 days and at 6 months. (See Table 5.)
The primary difference between the groups was the occurrence of refractory ischemia. Among patients who were treated with medical management, those who received tirofiban and heparin had a lower composite end point at 30 days (14.8%) than did those treated with heparin alone (16.8%). Bleeding complications were comparable between groups.35 The tirofiban-alone arm was stopped early because of excess mortality. This mortality was surprising because no such excess was observed in the composite end point or in refractory ischemia. In addition, the PRISM trial also had a tirofiban-alone arm that had a significant reduction in the composite end point at 2 days.
GUSTO 4 Trial: Initial data from the GUSTO 4 trial were presented August 2000 at the European Society of Cardiology Congress.36 The trial involved 7800 patients with UA or NSTEMI, without a planned PCI, who were randomized to receive: 1) a 24-hour infusion of abciximab; 2) a 48-hour infusion of abciximab; or 3) placebo. The primary outcome was the composite of death or AMI at 30 days. There was no significant difference between groups, with the primary outcome occurring in 8.2%, 9.1%, and 8.0%, respectively. Major bleeding was comparable between groups (0.6%, 1.0%, and 0.3%, respectively).36
Management of Unstable Angina and NSTEMI: Summary of Benefits Using GP IIb/IIIa Inhibitors
The aforementioned trials provide evidence-based support for management of subgroups of patients with ACS. In patients receiving PCI, abciximab has demonstrated consistent benefit. In contrast, neither eptifibatide nor tirofiban significantly decreased ischemic events after PCI in the RESTORE and IMPACT-II trials, respectively. In the EPIC, EPILOG, and EPISTENT trials, abciximab produced 4.5-6.4% absolute reductions in the 30-day composite end point, and these benefits persisted at 6 months in the EPIC and EPILOG trials (EPISTENT did not assess 6-month outcomes). The benefits also persisted at more extended follow-up. At one-year, patients in the EPILOG trial had a significant reduction of the composite end point from 16.1% in the placebo group to 9.6% in the abciximab groups (P < .001).37 At 3 years, patients in the EPIC trial also had a significant reduction of the composite end point from 47.2% in the placebo group to 41.1% in the abciximab bolus plus infusion group (P = .009).27 In the EPISTENT trial, the composite end point of mortality or AMI at 1 year was significantly reduced in the stent plus abciximab group (5.3%) compared to the stent plus placebo group (11.0%; P < .001).38
The CAPTURE trial, which evaluated abciximab and mandatory PCI, found significant benefit at 30 days but not at 6 months. Various factors may be responsible for the lack of enduring benefits. Patients received abciximab for only 1 hour after PCI in the CAPTURE trial vs. for 12 hours after PCI in both the EPIC and EPILOG trials. The 12-hour administration period post-procedure may be very important for establishing the long-term (6 months to 3 years) benefit of abciximab. This difference supports the concept of arterial passivation, in which the agent affects the vessel wall surface so as to inhibit further platelet-thrombin deposition. The significance of the pharmacologic differences between abciximab and the small molecule agents is unclear (see Table 3); however, they might contribute to the potential passivation associated with abciximab.
The GP IIb/IIIa inhibitors work comparably during the 12- to 36-hour intravenous infusions. The prolonged platelet-bound biologic half-life of abciximab might account for its prolonged effect on platelet function. The longer duration of action may have been the reason for abciximab’s success with a 12-hour infusion vs. the 20- to 72-hour infusions used with eptifibatide or tirofiban. The highest risk for thrombotic events after PCI is within 48 hours. The prolonged and tapered effect of abciximab neutralizes platelets while the vessel heals itself, providing "artificial" passivation when the patient’s thrombosis risk profile gradually progresses from high risk to low risk.7
The role of GP IIb/IIIa inhibitors in patients who are not necessarily having a PCI is controversial. All of the trials (PURSUIT, PRISM, PRISM-PLUS, and PARAGON) included patients who did and did not receive PCI and, importantly, the use of PCI was not randomized. Differentiating the outcomes of patients who received only medical therapy vs. those having a PCI is not easy. These groups were not differentiated in the PARAGON trial and no differences were found between the groups in the PURSUIT trial. As noted above, the PURSUIT trial also was interesting because the benefit among geographic locations varied directly with the frequency of catheterizations performed in the locations, supporting the concept that GP IIb/IIIa inhibitors might be optimal in the PCI population.
The PRISM trial noted a significant reduction in the combination of death and AMI at 30 days in those treated only medically with tirofiban. However, the data presented on the population receiving only medical therapy were limited. Patients treated with tirofiban and heparin, without PCI, had an improved 30-day composite outcome compared to those treated with only heparin in the PRIME-PLUS trial. Once again, the data pertaining to those treated only medically were limited. The CAPTURE trial, despite having mandated PCI, did start with an 18- to 24-hour infusion of abciximab before PCI. During this medical only treatment phase of the study, the AMI rate was reduced from 2.1% to 0.6% in the abciximab arm.
The GP IIb/IIIa inhibitors have not been compared directly in any trials. The first one planned is the Do Tirofiban and Abciximab for Revascularization Give Equivalent outcomes Trial (TARGET). It will be a randomized, double-blind comparison of these agents during PCI. Concerns exist that it may be too small to attain statistical power. In addition, there is a question that a 30-day end point may not be long enough to adequately assess the extended benefits noted in previous trials with abciximab. Indeed, benefits with tirofiban and eptifibatide have not been demonstrated at 30 days, let alone at 6 months, in trials involving mandated PCI.20
Major bleeding has not been a significant problem in most of the studies, except the EPIC and CAPTURE trials. However, these trials did not use the same safety considerations applied in later trials such as stopping the heparin infusion after the PCI, pulling the vascular sheaths early, and performing meticulous access site care.
It must be emphasized that trials involving GP IIb/IIIa inhibitors have involved high-risk patients, many of whom had ischemic ECG changes or positive cardiac enzymes. This point applies especially to the four-P trials of patients without mandated PCI. Even if one felt there was evidence suggesting that patients not receiving PCI would benefit from treatment with GP IIb/IIIa inhibitors, many patients admitted to the emergency department with ACS would not be eligible for these agents according to the entry criteria of the trials.
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