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Review
Platelet Glycoprotein IIb/IIIa Inhibition in Unstable Angina and Non-ST Segment Elevation Myocardial Infarction: Application of
February 2003
Introduction. Over the past decade, appreciable reductions in mortality, reinfarction and length of hospital stay have been reported in large-scale trials of patients with acute coronary syndromes (ACS). Every year, approximately 1.5 million patients are admitted to hospitals in the United States with unstable angina (UA) and non-ST segment elevation myocardial infarction (NSTEMI). In the last few years, there have been many advances in the evaluation and management of this patient population, including effective medical treatments such as antiplatelet, anticoagulant and cholesterol-lowering therapies, angiotensin-converting enzyme inhibition and ß-blockade. Determining which medical treatment strategy is appropriate for any given patient can be difficult and requires a multi-factorial assessment and data from evidence-based medicine to optimize patient outcomes.
The American College of Cardiology (ACC) and the American Heart Association (AHA) have jointly developed guidelines for the diagnosis and management of patients with non ST-segment elevation ACS based on available evidence (September 2000).1 Since this initial publication, many landmark trials have been published and have prompted a revised update of the guidelines by the ACC/AHA task force committee just 18 months later.2 This brief review will focus on the evolving role of platelet glycoprotein (GP) IIb/IIIa inhibitors in the management of patients with UA/NSTEMI and will highlight data reviewed in current guidelines.
Overview. ACS result from an abrupt change in the balance of myocardial cellular perfusion and myocardial cellular metabolic demand. UA can be caused by nonocclusive thrombus on preexisting plaque, coronary spasm, progressive atherosclerotic narrowing, arterial inflammation and precipitating factors extrinsic to the coronary vascular bed. The most common mechanism is atherosclerotic plaque rupture, erosion and/or fissuring, followed by thrombosis.4 Plaque disruption exposes the lipid core containing tissue factor, collagen and other substrates that activate the coagulation cascade and accelerate platelet adhesion, activation and aggregation. Myocardial cell death can then occur from either epicardial coronary artery thrombosis or distal atherothrombotic embolization and occlusion of the coronary microcirculation.5
The approach to patients with ACS has evolved with increased understanding of the vascular biology underlying an acute coronary event and increased ability to identify and accurately risk-stratify patient populations. Data from randomized clinical trials support early referral for coronary angiography and, if appropriate, coronary revascularization in patients deemed to be at higher risk. Percutaneous coronary interventions (PCI) with adjunctive intravenous platelet glycoprotein (GP) IIb/IIIa receptor inhibitors have become the standard of care within this higher-risk patient population. At the present time, three U.S. Food and Drug Administration-approved GP IIb/IIIa inhibitors are available for use: abciximab (ReoPro), tirofiban (Aggrastat) and eptifibatide (Integrilin).
The ACC/AHA guideline revision provides recommendations in 6 areas (Table 1).2 The recommendations are made in 3 classes: Class I recommendations confer the highest rating and indicate evidence and/or general agreement that a given therapy is useful and effective. Class II recommendations are assigned when there is conflicting evidence and/or divergence of opinion about the usefulness and efficacy of therapy. Class III recommendations are essentially a contraindication and indicate evidence and/or general agreement that the therapy is not effective or may be harmful. The weight of evidence is ranked highest (A) if the data are derived from multiple randomized clinical trials; intermediate (B) if the data are derived from a limited number of randomized trials or observational registries; and lowest (C) when expert panel consensus forms the basis for the recommendation.2
Risk assessment. The ability to assign relative risk to patients presenting with ACS assists the clinician in determining the appropriate strategy for an individual patient. The information required for this assessment is derived from the patient’s history and physical examination, electrocardiogram (ECG), and serum biomarkers of myonecrosis [creatinine phosphokinase (CK) or troponin]. These patients with ACS can then be categorized as high, intermediate or low risk for the development of subsequent cardiovascular events (recurrent ischemia, MI, death) (Table 2).6 Characteristics associated with a high risk of death or nonfatal MI include a history of accelerating symptoms in the 48 hours before assessment; prolonged (> 20 minutes) pain at rest; evidence of congestive heart failure (CHF); age over 65 years; ST-segment changes; or elevated cardiac biomarkers (CK, troponin). The Thrombolysis in Myocardial Infarction (TIMI) risk score for UA/NSTEMI was developed from multivariate analysis to predict the risk of death, MI or recurrent ischemia requiring urgent revascularization.7 Seven factors were identified that were individually correlated with the increased occurrence of these adverse cardiac events (Table 3).7 The patients determined to be at highest risk using this score manifest the greatest magnitude of benefit in clinical outcomes when treated with more aggressive antithrombotic and interventional strategies.
Serum troponin has consistently emerged as a potent stratifier of risk, with elevations of this biomarker associated with adverse outcomes (Figure 1).8 However, not all troponin-positive patients are at the same level of risk, and a significant gradient of increased risk of mortality with increasing troponin level has been observed (Figure 2).9 In combination with TIMI risk score, troponin elevations can help predict treatment effect from individual agents.10–12 For low molecular weight heparin (LMWH), platelet GP IIb/IIIa inhibitors and an early invasive strategy, greater clinical benefit is observed in troponin-positive patients than in troponin-negative patients. In recent trials with the GP IIb/IIIa inhibitors, there was a 50–70% reduction in subsequent death or MI in troponin-positive patients who received GP IIb/IIIa inhibitors and little or no benefit of these agents in patients who were troponin-negative.12,13 Similarly, in the recent TACTICS-TIMI (Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy — Thrombolysis In Myocardial Infarction) 18 study, an early invasive strategy conferred a dramatic 40% reduction in recurrent events for troponin-positive patients, whereas no benefit was seen for troponin-negative patients.10 Thus, risk stratification is an integral part of the initial patient evaluation and appropriate management triage for patients with ACS.
The ACC/AHA Guidelines for UA/NSTEMI state that patients who are at intermediate or high risk for adverse outcomes should be admitted to a critical care environment with ready access to invasive cardiovascular diagnosis and therapy if needed.2 Class I recommendations for an early invasive strategy include patients with the following: recurrent angina at rest or low-level activity despite therapy, elevated troponins, new ST-segment changes, recurrent angina with symptoms of CHF, high-risk findings on noninvasive stress testing, hemodynamic instability, sustained ventricular tachycardia, PCI within the previous 6 months, or prior coronary artery bypass surgery (CABG). The use of platelet GP IIb/IIIa inhibitors receives a Class I recommendation in addition to aspirin and heparin in patients in whom catheterization and PCI are planned.2
ACS and GP IIb/IIIa inhibitors. The introduction of platelet GP IIb/IIIa antagonists represents an important advance in the treatment of patients with ACS who are undergoing PCI. These agents take advantage of the fact that platelets play a primary role in the development of ischemic complications that may occur in patients with ACS during revascularization procedures. The September 2000 ACC/AHA guidelines emphasized the value of GP IIb/IIIa inhibitors in patients with ACS undergoing PCI, and the revised guidelines further refine this recommendation with additional data from recent clinical trials. The clinical decision on the use of a particular GP IIb/IIIa inhibitor should be driven by scientifically established relevant clinical safety and efficacy endpoints.
Abciximab: ReoPro. Abciximab is a recombinant human-murine chimeric Fab fragment that binds nonselectively with high affinity to the platelet GP IIb/IIIa receptor. Rapid clearance of free drug from the circulation by the reticuloendothelial system provides a very short plasma half-life of 10 minutes, while high receptor affinity results in a long biologic half-life of 12–24 hours. Abciximab can redistribute from the originally bound platelet to newly produced platelets, thus prolonging and tapering the antiplatelet effect.14 GP IIb/IIIa receptor occupancy by abciximab exceeds 30% at 8 days and 10% at 15 days, with residual binding documented as late as 21 days after therapy. This observation may have clinical relevance since prolonged platelet inhibition most likely plays a role in vessel passivation.15 The ability of abciximab to bind to the aVß3 (vitronectin) receptor and the leukocyte receptor (MAC-1) may also contribute to the anti-inflammatory properties of this drug.16
In a subgroup analysis of 489 patients with UA in the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial, abciximab was associated with a 62% reduction in the 30-day composite endpoint of death, MI or urgent revascularization (4.8% versus 12.8%; p = 0.012).17 At 3-year follow-up, abciximab was associated with a 60% reduction in mortality among patients with UA/NSTEMI (5.1% versus 12.7%; p = 0.01).18 The Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) trial included 1,328 patients with UA and found a reduction of that same composite endpoint from 12.2% in the placebo group to 4.8% in patients receiving abciximab plus low-dose heparin.19 In the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, a total of 1,265 patients with refractory UA were studied to determine the ability of abciximab to stabilize patients prior to angioplasty.20 Abciximab treatment for 18–24 hours prior to PTCA was associated with a 71% reduction in the incidence of MI (0.6% versus 2.1%; p = 0.029) prior to the intervention, and a 29% reduction in the 30-day composite endpoint of death, MI or urgent revascularization (11.3% versus 15.9%; p = 0.012).20 The Global Utilization of Strategies to Open Occluded Coronary Arteries IV-Acute Coronary Syndromes (GUSTO IV-ACS) trial enrolled 7,800 patients with UA/NSTEMI in whom early revascularization was not intended.21 All patients received aspirin, unfractionated or low-molecular-weight heparin, and were then randomized to placebo or abciximab (24 or 48 hour infusions). Although the primary endpoint, death or MI at 30 days, was not significantly different between placebo and abciximab treated groups for the study population as a whole, patients with diabetes mellitus had a significant (p = 0.022) reduction in mortality to 30 days (7.8% placebo versus 5.0% abciximab). Furthermore, in pooled analyses of the EPIC, EPILOG and EPISTENT (Evaluation of Platelet Inhibition in Stenting) trials, the significant long-term (3-year) survival advantage attributable to abciximab (mortality 6.3% placebo, 5.0% abciximab; p = 0.030)22 was not explained by suppression in early (30-day) adverse cardiovascular events.23 Interestingly, the long-term abciximab survival advantage could be predicted by an easily derived patient clinical risk profile.24
Table 1. Overview of 2002 Guidelines Update
1. Assess likelihood of coronary artery disease
2. Risk stratification
3. Anti-ischemic therapy
4. Antithrombotic therapy
5. Invasive versus conservative strategy
6. Secondary prevention and risk factor modification
Table 1 reproduced with permission from MedReviews, LLC from Lepor NL: Use of glycoprotein IIb/IIIa receptor inhibitors in acute coronary syndromes. Rev Cardiovasc Med 2002;3(Suppl 1):S3–S12.6
Table 2. Short-term risk of death or nonfatal MI in patients with unstable angina.
Estimation of the short-term risks of death and nonfatal cardiac ischemic events in unstable angina is a complex multivariable problem that cannot be fully specified in a table such as this; therefore, this table is meant to offer general guidance and illustration rather than rigid algorithms.
MI = myocardial infarction; CABG = coronary artery bypass graft; CAD = coronary artery disease; NTG = nitroglycerin; MR = mitral regurgitation; ECG = electrocardiogram; TnT = Troponin T; TnI = Troponin I
Table 3. TIMI risk score for UA/NSTEMI: Seven independent predictors. Modified from Antman et al., JAMA 2000;284:835–842.7
1. Age > 65 years
2. > 3 CAD risk factors (e.g., high cholesterol, family history, hypertension, diabetes mellitus, smoking)
3. Prior coronary artery disease
4. Aspirin in the last 7 days
5. > 2 angina-related events in Tirofiban: Aggrastat. This low-molecular-weight nonpeptide compound has a longer plasma half-life of 1.8 hours and a shorter biologic half-life of seconds as a result of reversible low affinity binding kinetics to the IIb/IIIa receptor. Renal elimination of tirofiban requires dosing adjustment in patients with renal insufficiency, and tirofiban has no interaction with the vitronectin or MAC-1 receptors.
The Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial evaluated the effects of tirofiban, heparin or both as medical treatment in 1,915 high-risk patients with ACS.25 Study drug infusion averaged 71.3 hours with subsequent angiography and angioplasty at the discretion of the investigator. The tirofiban-only arm was discontinued due to excess mortality at 7 days. Subgroup analysis of 475 patients undergoing PCI during the trial demonstrated a significant reduction in the composite endpoint of death, MI, refractory ischemia or rehospitalization for UA in the tirofiban plus heparin arm versus heparin alone (8.8% versus 15.3%).25 Interestingly, ischemic events (death, MI) to 30 days following treatment with tirofiban in PRISM-PLUS were 3.0% versus 0.7% (placebo). The relative increment in events following tirofiban therapy may be secondary to the abrupt recovery of platelet function that accompanies treatment cessation and was not observed at 30 days following abciximab therapy (death, MI 0.7% abciximab versus 1.1% placebo) in the previously mentioned CAPTURE trial.26 The Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trial evaluated the effect of a 36-hour infusion of tirofiban compared to heparin in 2,139 high-risk patients undergoing PCI.27 The primary endpoint was a composite of death, MI, coronary artery bypass surgery for failed angioplasty or recurrent ischemia, repeat target vessel revascularization for recurrent ischemia, or stenting due to abrupt vessel closure within 30 days. The composite endpoint occurred in 10.3% of the tirofiban-with-heparin group and 12.2% in the placebo group (p = 0.160).27 The Do Tirofiban and ReoPro Give Similar Efficacy Trial (TARGET) study is the only head-to-head trial comparing GP IIb/IIIa inhibitor use during PCI.28 Though patients with ACS were not a prespecified subgroup, the primary endpoint of death or nonfatal MI at 30 days occurred in 9.3% of patients in the tirofiban group and 6.3% in the abciximab group of ACS patients.28 This relative increased event rate of 49% observed in the tirofiban treated patients (versus abciximab) achieved statistical significance in subgroup analysis.
Eptifibatide: Integrilin. Eptifibatide is a peptide that competitively and specifically inhibits the GP IIb/IIIa receptor, resulting in a long plasma half-life (150 minutes) and short biologic half-life (2.5 hours). Like tirofiban, eptifibatide undergoes renal clearance, requiring appropriate dosing adjustments in patients with renal insufficiency. Eptifibatide, like tirofiban, does not bind to MAC-1 receptors and has no clinically relevant affinity for the vitronectin receptor.29
In the second Integrilin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis (IMPACT II) trial, a total of 4,010 patients undergoing PCI were evaluated in a placebo-arm, low-dose eptifibatide (135 µg/kg bolus + 0.5 µg/kg/min) arm, and high-dose (135 µg/kg bolus + 0.75 µg/kg/min) arm for 20–24 hours.30 Based on an intention-to-treat analysis, there was no significant difference observed between the placebo group and those receiving eptifibatide in the 30-day composite endpoint of death, MI or urgent revascularization.
The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial assessed the role of up to a 72 hour infusion of 2 doses of eptifibatide in patients with ACS.31 Patients undergoing early PCI (at the discretion of the investigator) demonstrated a 30% reduction in death or nonfatal MI at 30 days (16.7% versus 11.6%; p = 0.01).31 More recently, the Enhanced Suppression of the Platelet Receptor IIb/IIIa with Eptifibatide Therapy (ESPRIT) trial evaluated the efficacy of this agent as an adjunct to coronary stenting.32 Fourteen percent of the 2,064 patients enrolled had UA/NSTEMI. A significant reduction in 30-day cumulative event rates of 35% was seen in this relatively low-risk elective PCI patient population.32 Though a 21% cumulative event reduction was seen at 1 year in the overall study population, patients presenting with higher risk ACS had no significant reduction of death or MI at 1 year.
GP IIb/IIIa antagonists — ACC/AHA recommendations. Based on the data in the clinical trials outlined above, platelet GP IIb/IIIa inhibitors are recommended in high-risk UA/NSTEMI patients, in addition to aspirin and heparin, in which catheterization and PCI are planned (Class I, Level A).2 The revised guidelines provide broader support for a routine invasive treatment strategy in high-risk ACS patients due to recent trials demonstrating benefit in intermediate- and high-risk patients, especially those patients with ECG changes and positive troponin on admission (Class I, Level A).10,33,34 In patients in whom a noninterventional approach is planned, clopidogrel (in addition to aspirin and heparin) has been added as a new Class I recommendation based on recent clinical trials performed in hospitals in which there was no routine use of early invasive procedures (Class I, Level A).35,36 No head-to-head comparison of clopidogrel, a GP IIb/IIIa inhibitor, or their combination has been reported, although recent subset analyses of patients from randomized studies appear to demonstrate safety of this combination.35,36 Pending further data on combination therapy, a Class IIa recommendation was given to the addition of a GP IIb/IIIa inhibitor for patients who are receiving aspirin, clopidogrel and heparin and who are referred for an invasive strategy.2 The benefit of GP IIb/IIIa inhibitors in patients who do not undergo PCI is less robust. The current guideline revision assigns eptifibatide or tirofiban a Class IIa recommendation for “upstream” management in high-risk patients in whom an invasive strategy is not planned.2
The benefit of GP IIb/IIIa inhibitors is mainly limited to patients at high-risk and, notably, to troponin-positive patients whether or not they undergo revascularization.12,13 Because of the large benefit of GP IIb/IIIa inhibition during PCI, the ACC/AHA guidelines emphasize the use of GP IIb/IIIa inhibitors in patients managed with an invasive strategy, while the use of GP IIb/IIIa inhibitors for high-risk patients in whom PCI is not planned is assigned a Class IIa recommendation. An early invasive strategy is recommended for high-risk patients and therefore the new guidelines provide a link between risk assessment, strategy selection and adjunctive GP IIb/IIIa inhibition for this group of patients with UA/NSTEMI.
Summary. The benefit of platelet GP IIb/IIIa receptor antagonists in the treatment of patients presenting with high-risk ACS undergoing PCI has been well demonstrated. Differences in pharmacokinetics and pharmacodynamic properties of the three GP IIb/IIIa inhibitors may partially explain the differences seen in outcomes in large randomized trials. The variability of effectiveness observed even between the small-molecule agents would appear to argue against a purely “class effect”. Indeed, the efficacy of tirofiban and eptifibatide has been established in ACS, whereas another small molecule GP IIb/IIIa inhibitor, lamifiban, was not found to be associated with significant clinical benefit.37 In patients presenting with ACS, the TARGET trial provides the only direct comparison of a small molecule (tirofiban) agent versus abciximab and this trial demonstrated superiority for abciximab in reducing ischemic endpoints.28 For diabetic patients with ACS, abciximab is the only GP IIb/IIIa inhibitor observed to provide a significant survival advantage in patients undergoing PCI and thus is singled out in the most recent guidelines as the agent of choice for use in diabetic patients undergoing stent implantation.38 Abciximab also has the greatest weight of data supporting safety of use in patients with severe renal insufficiency, likely due to its non-renal mode of metabolism/elimination.
Based on evidence accumulated over the last decade, the most current ACC/AHA guidelines recommend a platelet GP IIb/IIIa antagonist in patients with moderate- to high-risk ACS in whom catheterization and PCI are planned (Class I, Level A). Eptifibatide or tirofiban should be administered in patients with high-risk ACS in whom an invasive management strategy is not planned (Class IIa, Level A). Consensus recommendations concerning the optimal choice of GP IIb/IIIa inhibitor for PCI, although vigorously debated, have yet to be agreed upon. An evidence-based approach at this time would favor abciximab as the standard GP IIb/IIIa inhibitor for administration during PCI, especially in patients with high-risk features including diabetes mellitus.24,38,39 Based on the accumulation of data, abciximab is still the gold standard GP IIb/IIIa inhibitor for patients with ACS undergoing PCI.
1. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction. Summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36:970–1062.
2. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST segment elevation myocardial infarction — 2002 Summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 2002;106:1893–1900.
3. Braunwald E. Unstable angina: An etiologic approach to management. Circulation 1998;98:2219–2222.
4. Tollerson TR, Harrington RA. Thrombosis in acute coronary syndromes and coronary interventions. In: Lincoff AM, Topol EJ (eds). Platelet Glycoprotein IIb/IIIa Inhibitors in Cardiovascular Disease. Totowa, New Jersey: Humana Press, Inc., 1999.
5. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000;101:570–580.
6. Lepor NE. Use of glycoprotein IIb/IIIa receptor inhibitors in acute coronary syndromes. Rev Cardiovasc Med 2002;3(Suppl 1):S3–S12.
7. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision-making. JAMA 2000;284:835–842.
8. Ottani F, Galvani M, Nicolini FA, et al. Elevated cardiac troponin levels predict the risk of adverse outcome in patients with acute coronary syndromes. Am Heart J 2000;140:917–927.
