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Glycoprotein IIb-IIIa Inhibitors in the Emergency Department for Patients with Non-ST-Elevation Acute Coronary Syndromes: Principles and Practices
The Journal of Emergency Medicine, Vol. 36, No. 2, pp. 162–170, 2009 Copyright © 2009 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/09 $–see front matter
doi:10.1016/j.jemermed.2007.10.020
Selected Topics: Cardiology Commentary
GLYCOPROTEIN IIb-IIIa INHIBITORS IN THE EMERGENCY DEPARTMENT FOR PATIENTS WITH NON-ST-ELEVATION ACUTE CORONARY SYNDROMES: PRINCIPLES AND PRACTICES Cedric W. Lefebvre,
MD,
* James W. Hoekstra,
MD,*
Marc Bonaca,
MD,†
and Robert Giugliano,
MD‡
*Department of Emergency Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, †Division of Cardiovascular Medicine and ‡TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts Reprint Address: Cedric W. Lefebvre, MD, Department of Emergency Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Watlington Hall, 4th Floor, Winston-Salem, NC 27157-1089
e Abstract—Non-ST-elevation acute coronary syndrome is associated with significant morbidity and mortality. Although the benefit of platelet inhibition by glycoprotein (GP) IIb-IIIa inhibitors in patients undergoing percutaneous coronary intervention (PCI) is well established, emergency physicians and cardiologists have different perspectives regarding their optimum administration, especially upstream before PCI. In this article, two emergency physicians and two cardiologists analyze data and discuss relevant issues, including the ischemic benefits vs. the risk of bleeding associated with GP IIb-IIIa inhibitors in appropriate patients, for example, those with an elevated troponin level or who undergo revascularization. The emergency physicians support early identification of high-risk nonST-elevation acute coronary syndrome patients and early administration of GP IIb-IIIa inhibitors, which are linked to improved patient outcomes. The cardiologists emphasize risk stratification to identify patients in whom the expected reduction in ischemic complications outweighs the risk of increased bleeding with these agents. GP IIb-IIIa inhibitors should be considered in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) in whom PCI is planned, especially those with high-risk features or elevated serum troponin levels. It is reasonable to start this treatment upstream of intervention, pending further studies investigating the optimal timing of initiation of therapy in appropriate patients. © 2009 Elsevier Inc.
RECEIVED: 20 March 2007; FINAL ACCEPTED: 4 October 2007
SUBMISSION RECEIVED:
e Keywords—non-ST-elevation acute coronary syndrome; GP IIb-IIIa inhibitors; emergency department; percutaneous coronary intervention; risk stratification
PATHOGENESIS OF ACUTE CORONARY SYNDROME Non-ST-elevation acute coronary syndrome (NSTE ACS) is associated with significant morbidity and mortality. Atherosclerotic plaques of the coronary vasculature are the most common cause of ischemic heart disease, and rupture of these plaques is the most common pathogenesis of NSTE ACS. After plaque rupture has occurred, platelet adhesion, platelet activation, and activation of the coagulation cascade result in formation of a platelet-rich thrombus in the coronary artery. In NSTE ACS, this thrombus is usually only partially occlusive but may cause intermittent downstream myocardial ischemia or downstream microvascular infarction due to microemboli. Antiplatelet medications such as aspirin, clopidogrel, and glycoprotein (GP) IIb-IIIa inhibitors may attenuate thrombotic progression and slow the evolution toward occlusive thrombosis (1). In addition, plaque stabilization by GP IIb-IIIa inhibitors has been shown to increase microvascular perfusion in the myocardium during percutaneous coronary intervention (PCI),
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alleviating the “closed muscle” phenomenon with microvascular ischemia (2).
THEORETICAL BENEFITS OF EARLY ADMINISTRATION OF GP IIb-IIIa INHIBITORS The benefit of platelet inhibition by GP IIb-IIIa inhibitors as adjunctive therapy in patients undergoing PCI is well established (3–10). GP IIb-IIIa inhibitor utilization is especially beneficial in patients who are at highest risk for adverse outcomes, especially those who have an elevated troponin level and those who undergo revascularization by either PCI or coronary artery bypass grafting (CABG) (4,9). In addition to lending benefit during PCI, GP IIb-IIIa inhibition seems to provide benefit to NSTE ACS patients in the period before PCI (i.e., “upstream,” before arrival in the catheterization laboratory). This benefit is mostly due to a reduction in recurrent myocardial infarction (MI) or recurrent ischemia during this period of medical stabilization (4). Several landmark clinical trials have examined the use of intravenous GP IIb-IIIa inhibitors in patients presenting with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) (Table 1). These studies provide the bulk of the evidence regarding GP IIb-IIIa inhibitor use cited in current practice guidelines. The benefit of early GP IIb-IIIa inhibition is particularly relevant to emergency physicians, who diagnose and manage NSTE ACS patients early in their course. Despite the American College of Cardiology and American Heart Association (ACC/AHA) recommendation for early administration of GP IIb-IIIa inhibitors in high-risk NSTE ACS patients (those with elevated cardiac biomarkers, electrocardiogram changes consistent with ischemia, ongoing chest pain), these agents are underutilized in NSTE ACS patients nationwide (13–15). Therefore, greater attention must be applied to the role of GP IIb-IIIa inhibitors in the early management of high-risk NSTE ACS in the emergency department (ED). The benefit of upstream administration of GP IIb-IIIa inhibitors in patients with NSTE ACS has been demonstrated in several clinical trials (3– 6,9,10,16). Recent data suggest that upstream use of tirofiban is associated with improved reperfusion and reduction in myocardial injury in high-risk NSTE ACS patients undergoing early invasive reperfusion strategies, in comparison with administration during PCI (17). In the C7E3 fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, administration of abciximab 18 to 24 h before PCI in high-risk patients with NSTE ACS was associated with a decrease in the frequency of myocardial infarction and a reduced likelihood of ischemic episodes in the period before this intervention (3). The Platelet Glycop-
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rotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial investigators demonstrated a 1.5% absolute risk reduction in death and non-fatal MI at 96 h and through 30 days after upstream administration of eptifibatide vs. placebo in high-risk NSTE ACS patients. They reported a decreased incidence of ischemic composite endpoints in NSTE ACS patients during the period of drug infusion before PCI, as well as in patients who received medical management only (4). Similar results occurred in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, which included 1915 patients with UA/NSTEMI who were treated with aspirin and randomly assigned to receive tirofiban, heparin, or both (5). The frequency of composite endpoints (death, MI, refractory ischemia within 7 days) was significantly lower in the group receiving both tirofiban and heparin when compared with patients receiving heparin alone (tirofiban alone was associated with higher early mortality, and this third arm was dropped from the trial). The benefit of adding tirofiban to heparin was due primarily to a reduction in MI, which persisted through 30 days (5). The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial also demonstrated fewer composite endpoints at 48 h in patients presenting with NSTE unstable angina who received GP IIb-IIIa inhibitors 48 h before intervention. Reductions in ischemic outcomes were also seen in NSTE ACS patients who were medically managed (6).
EARLY ADMINISTRATION OF GP IIb-IIIa INHIBITORS: THE EMERGENCY MEDICINE PERSPECTIVE A meta-analysis of these randomized controlled trials of GP IIb-IIIa inhibitors by Boersma et al. demonstrated both pre- and post-PCI benefits with GP IIb-IIIa inhibitor treatment of high-risk NSTE ACS (10). Boersma’s analysis of CAPTURE, PURSUIT, and PRISM-PLUS demonstrated a statistically significant reduction in death and MI in the pre-PCI medical management period, as well as a more robust reduction in ischemic outcomes associated with PCI. The results of this analysis drove the ACC/AHA Guidelines recommendations for GP IIb-IIIa inhibitor therapy pre-PCI. Similarly, logistic regression of retrospective analyses of data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) and National Registry of MI registries demonstrated a 7% to 12% decrease of in-hospital mortality associated with early GP IIb-IIIa inhibitor therapy, with statistically significant reductions
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Table 1. Clinical Trials of GP IIb-IIIa Antagonists and Outcomes in Patients With UA/NSTEMI Trial
n, Population
GUSTO IV-ACS (11) n ⫽ 7800 UA/NSTEMI not going to coronary intervention
PRISM (6) PRISM-PLUS (5)
PURSUIT (4)
ISAR-REAC T 2 (9)
CAPTURE (3) ACUITY (12)
Endpoint Death or MI at 30 days
Randomized Treatments 1. Placebo 2. Abciximab for 24 h 3. Abciximab for 48 h
Other Therapy
Key Results
ASA, UFH
* Heparin was either enoxaparin or unfractionated heparin (investigator’s choice). ACS ⫽ acute coronary syndrome; ASA ⫽ aspirin; CI ⫽ confidence interval; GP IIb-IIIa inhibitor ⫽ glycoprotein IIb-IIIa inhibitor; LMWH ⫽ low molecular weight heparin; MI ⫽ myocardial infarction; NSTEMI ⫽ non-ST-segment elevation myocardial infarction; OR ⫽ odds ratio; RR ⫽ relative risk; UA ⫽ unstable angina; UFH ⫽ unfractionated heparin.
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30-day death or MI 8.0% (placebo) vs. 8.2% and 9.1% in the 24-h and 48-h abciximab groups, respectively (OR 1.0; 95% CI 0.83–1.24 and 1.1; 95% CI, 0.94–1.39). 1-year mortality 7.8% (placebo) vs. 8.2% and 9.0% in the two abciximab arms. Patients with elevated troponin levels had higher mortality with 48-h infusion of abciximab (8.5% vs. 5.8%; p ⫽ 0.02). n ⫽ 3232 Death/MI/refractory 1. UFH ASA Primary endpoint 3.8% with tirofiban vs. 5.6% UA/NSTEMI ischemia at 48 h 2. Tirofiban with UFH (RR 0.67; 95% CI 0.48–0.92) at 48 h. n ⫽ 1915 Death/MI/refractory 1. UFH ASA Primary endpoint at 7 days lower with low-dose UA/NSTEMI ischemia at 7 2. UFH ⫹ low-dose tirofiban plus heparin (12.9% vs. 17.9%) vs. days tirofiban UFH alone; benefit persisted through 30 days. 3. High-dose tirofiban High-dose tirofiban alone arm stopped early due to excess 7-day mortality (4.6% vs. 1.1% for UFH alone). n ⫽ 10,948 Death/non-fatal MI 1. Placebo ASA, UFH Primary endpoint at 30 days lower with UA/NSTEMI at 30 days 2. Low-dose eptifibatide eptifibatide (14.2% vs. 15.7%; p ⫽ 0.04). 3. High-dose eptifibatide Incidence of primary endpoint lower in both those who underwent early PCI (11.6% vs. 16.7%) as well as in those managed medically (14.5% vs. 15.6%). n ⫽ 2022 Death/MI/urgent 1. Placebo ASA, UFH, clopidogrel Primary endpoint at 30 days lower with UA/NSTEMI just before PCI target vessel 2. Abciximab 600 mg loading abciximab (8.9% vs. 11.9%; RR 0.75; p ⫽ revasc within 30 dose 0.03). Benefit isolated to patients with elevated days baseline troponin levels (RR 0.71; p ⫽ 0.02) and not seen in those with normal baseline troponin (RR 0.99; p ⫽ 0.98). n ⫽ 1265 Death/MI/urgent 1. Placebo ASA, UFH Primary endpoint at 30 days lower with UA/NSTEMI with PCI next day revasc at 30 days 2. Abciximab abciximab (11.3% vs. 15.9%; p ⫽ 0.012). Similar outcomes at 6 months. n ⫽ 13,819 Composite ischemia 1. Heparin* ⫹ GP ASA, clopidogrel Bivalirudin with GP IIb-IIIa inhibitor was Moderate- to high-risk UA/ (death, MI, urgent IIb-IIIa inhibitor recommended noninferior to heparin with a GP IIb-IIIa NSTEMI with early invasive revasc), major 2. Bivalirudin ⫹ GP (⬃63% before cath) inhibitor in terms of ischemia (7.7% vs. 7.3%, strategy bleeding, net IIb-IIIa inhibitor respectively), major bleeding (5.3% vs. 5.7%), clinical outcome 3. Bivalirudin and net clinical result (11.8% vs. 11.7%). at 30 days Bivalirudin alone vs. UFH with GP IIb-IIIa inhibitor was non-inferior in terms of ischemia (7.8 vs. 7.3%; p ⫽ 0.32) and had reduced rates of major bleeding (3.0% vs. 5.7%; p ⬍ 0.001) and net clinical endpoint (10.1% vs. 11.7%; p ⫽ 0.02).
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noted in the National Registry of Myocardial Infarction database (15). Although these results are compelling, conclusions regarding causation are difficult to draw from a retrospective analysis of registry data. Several studies have established the beneficial role of GP IIb-IIIa inhibitors in high-risk PCI (4,18 –20). Although upstream GP IIb-IIIa inhibitors afford considerable benefit to high-risk NSTE ACS patients, debate remains about the utility of these agents in low- to moderate-risk patients. The Intracoronary Stenting and Anti-Thrombotic Regimen–Rapid Early Action for Coronary Treatment (ISAR-REACT) trial revealed little benefit from GP IIb-IIIa inhibitor administration at 30 days in low- to moderate-risk patients undergoing elective PCI who were pre-treated with clopidogrel (21). This was supported by findings in the ISAR-REACT 2 trial, in which patients without elevated troponin levels who were treated with GP IIb-IIIa inhibitors experienced the same incidence of adverse events (death, MI, and urgent revascularization) as the placebo group. In high-risk NSTE ACS patients with elevated troponin levels, however, intravenous GP IIb-IIIa inhibitors in this study were associated with a reduction of adverse events (9). These studies suggest that GP IIb-IIIa inhibitor therapy lends therapeutic advantage in the early management of high-risk NSTE ACS patients and nicely illustrate the importance of risk stratification of patients presenting to the ED with NSTE ACS. Hence, there is strong evidence to support the early/ upstream use of GP IIb-IIIa inhibitors in high-risk patients. When treated early in their hospital course with GP IIb-IIIa inhibitors, high-risk NSTE ACS patients proceeding to PCI and those to be managed medically seem to benefit. Therefore, emergency physicians should deliver the beneficial effects of upstream GP IIb-IIIa antagonism to their high-risk NSTE ACS patients.
EARLY ADMINISTRATION OF GP IIb-IIIa INHIBITORS: THE CARDIOVASCULAR MEDICINE PERSPECTIVE The current ACC/AHA guidelines for treatment of UA/ NSTEMI assign a class I indication to the use of GP IIb-IIIa inhibitors in addition to aspirin and heparin in patients with UA/NSTEMI in whom catheterization and PCI are planned (22,23). In patients in whom catheterization is planned, both “upstream” and “in-lab” treatment is considered acceptable. In patients with UA/ NSTEMI in whom medical management is planned, the guidelines provide a class IIa recommendation for the use of eptifibatide or tirofiban in the setting of continuing ischemia or high-risk features. In contrast, abciximab is not indicated (receiving a class III recommendation) in medi-
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cally treated patients who are not undergoing early catheterization, due to the absence of benefit and an increased risk of bleeding as observed in the Global Utilization of Strategies to Open Occluded Coronary Arteries IV–Acute Coronary Syndromes (GUSTO IV-ACS) trial. The greatest benefits of GP IIb-IIIa inhibitors in patients with UA/NSTEMI probably occur in the acute and peri-procedural settings. In the PURSUIT trial, benefit was seen by 96 h (4). This benefit—31% relative risk reduction (primary endpoint 11.6% eptifibatide vs. 16.7% controls)—was greatest in patients who were managed with early intervention and was smaller—7% relative risk reduction—in those managed medically ( p ⫽ 0.23). This initial benefit is durable and has been demonstrated through 30 days or longer in clinical trials. Additional, longer-term benefit after index hospitalization is more difficult to evaluate and is unlikely to be substantial, because these agents are generally administered for only 12 to 72 h. In the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Timing trial (24), 9207 patients with NSTE ACS managed with an early invasive approach were randomly assigned to early GP IIb-IIIa inhibitor therapy or deferred, selective use of GP IIb-IIIa inhibitors at the time of PCI. The rate of ischemic complications at 30 days was 7.1% for upstream vs. 7.9% for selective use in the catheterization laboratory (p ⫽ NS for non-inferiority of the latter approach), despite an average difference of only 4 h in the initiation of GP IIb-IIIa inhibitors between the two treatment arms. Thus, the investigators could not rule out a 25% or more increase in ischemic complications with a downstream GP IIb-IIIa inhibitor strategy. In particular, higher-risk patient subgroups (troponin positive, higher Thrombolysis in Myocardial Infarction [TIMI] Risk Score) and those who did not receive early thienopyridine treatment tended to have better outcomes with upstream GP IIb-IIIa inhibitors. GP IIb-IIIa inhibitors should be considered in patients with UA/NSTEMI in whom PCI is planned, with the intention of decreasing rates of recurrent ischemia, recurrent MI, and mortality. Specifically, patients with high-risk features or elevated serum troponin levels are optimal candidates for this therapy. It is reasonable to start this treatment upstream of intervention pending further studies investigating the optimal timing of initiation of therapy (25).
ADVERSE EFFECTS OF GP IIb-IIIa INHIBITOR UTILIZATION Excessive bleeding is the major safety concern associated with the use of GP IIb-IIIa inhibitors. Bleeding rates vary by trial, concomitant therapy, and dosing of medications. Furthermore, definitions of bleeding also vary
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among published clinical trials (Table 2). Careful consideration of clinical factors, such as renal dysfunction and bleeding risk, are important in optimizing the risk/ benefit ratio associated with these agents.
BLEEDING: THE EMERGENCY MEDICINE PERSPECTIVE With the exception of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial, which employed higher concomitant heparin doses—that were associated with higher rates of major bleeding— more recent studies have demonstrated a relatively small increased risk of major bleeding, thrombocytopenia, and need for transfusion of blood products in patients treated with GP IIb-IIIa inhibitors (3– 6,18). The majority of this bleeding is catheter related, with higher rates in the elderly and in patients with chronic renal insufficiency. Major bleeding seems to be associated with elevated doses of combination therapy, including GP IIb-IIIa inhibitors, heparin, and clopidogrel, particularly in patients undergoing surgical revascularization (4,21). A recent analysis of the CRUSADE registry indicated that as many as 65% of patients over 75 years of age receive excessive doses of GP IIb-IIIa inhibitor in community practice. Similarly, doses of heparin in this same population are excessive in 38% of cases. Elevations in either antithrombins or GP IIb-IIIa inhibitors are associated with increased bleeding rates in CRUSADE, with the highest bleeding rates seen in patients who receive excessive doses of both medications (14). Therefore, risk stratification of ACS patients should take into account factors that would place a patient at risk for bleeding complications. Administration of GP IIb-IIIa inhibitors should be avoided in patients with recent surgery or cerebrovascular events, current oral anticoagulation therapy, persistent hypertension, or thrombocytopenia. Doses should be reduced in patients with a creatinine clearance rate ⬍ 50 cc/min as guided by the CockcroftGault equation. Otherwise, especially in younger patient groups, the risk of bleeding associated with GP IIb-IIIa inhibitor administration seems to be relatively small, and the risk/benefit ratio in this regard favors their use in appropriate patients.
BLEEDING: THE CARDIOVASCULAR MEDICINE PERSPECTIVE A meta-analysis of several large trials did show increased rates of major bleeding associated with GP IIbIIIa inhibitors (odds ratio 1.62; 95% confidence interval 1.36 –1.94); however, their use was not associated with a
higher rate of intracranial hemorrhage (28). A subsequent pooled analysis of 27,889 patients again did not show a higher rate of intracranial hemorrhage in patients treated with GP IIb-IIIa inhibitors alone or with heparin when compared with heparin alone; however, overall event rates were low (29). The current ACC/AHA guidelines recommend heparin or low-molecular-weight heparin (LMWH) in patients with NSTE ACS in addition to aspirin (22,23). In the A-to-Z trial, 3987 patients with ACS were treated with tirofiban and aspirin and then randomly assigned to receive unfractionated heparin (UFH) or LMWH (30). There was no difference in the primary endpoint (death, MI, refractory ischemia) between heparins; however, higher rates of bleeding were seen with LMWH. The A-to-Z investigators concluded that LMWH was a suitable alternative to UFH in patients treated with aspirin and tirofiban. The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial enrolled 10,027 patients with NSTEMI to be treated with an early invasive strategy and randomly assigned them to receive enoxaparin or UFH (31). There was no difference between heparins in the primary endpoint; however, enoxaparin was associated with increased TIMI major bleeding, particularly in CABG-related events. GP IIb-IIIa inhibitor use was similar between the two randomized treatment groups (56.5%, enoxaparin; 58.2%, UFH). In the ACUITY trial, two alternative strategies to reduce bleeding were investigated in a population of moderate-risk patients with NSTE ACS managed with an early invasive strategy (32). Use of bivalirudin monotherapy was associated with significantly lower major bleeding (3.0% vs. 5.7%, p ⬍ 0.001) and was noninferior with respect to ischemic complications compared with heparin (either enoxaparin or UFH) plus GP IIb-IIIa inhibition. Patients receiving bivalirudin with GP IIb-IIIa inhibition experienced similar rates of ischemic complications and bleeding compared with heparin plus GP IIb-IIIa inhibition; thus, there seemed to be no particular advantage in using bivalirudin instead of a heparin, if a GP IIb-IIIa inhibitor was being administered. Lastly, in the ACUITY Timing trial, deferred selective, or “in-lab,” use of GP IIb-IIIa inhibition was associated with less bleeding than with routine upstream use (4.9% vs. 6.1%, p ⫽ 0.009, respectively) (24). Thus, in patients at low to moderate risk of ischemic complications or moderate to high risk of bleeding, alternative antithrombotic strategies may be reasonable, recognizing the existing trade-off between protection from ischemic complications and increased bleeding risk that is associated with the administration of upstream GP IIb-IIIa inhibitors.
Trial
Bleeding Definition
Randomized Treatments
Other Therapy
Major Bleeding
Key Results Bleeding occurred most often in patients undergoing coronary procedures. Minor and insignificant bleeding as well as need for transfusion higher in the abcix-treated groups vs. placebo. Bleeding higher in elderly and female patients. No difference in TIMI major or minor bleeding, no difference in intracranial hemorrhage. Bleeding and transfusion somewhat more frequent with combination therapy but not statistically significant.
GUSTO IV-ACS (11)
TIMI major, minor, or insignificant during hospitalization or 7 days from randomization
1. Placebo 2. Abcix for 24 h 3. Abcix for 48 h
ASA, UFH
Overall 1.2%; 1.8% receiving 48 h abcix, 1.0% receiving 24 h abcix, 0.9% receiving placebo ( p ⬍ 0.0001 - 48 h vs. placebo)
PRISM (6)
TIMI major or minor
1. UFH 2. Tirofiban
ASA
0.4% in both groups
PRISM-PLUS (5)
PRISM-PLUS major/minor as well as TIMI scale
1. UFH 2. UFH ⫹ low-dose tiro 3. High-dose tiro
ASA
PURSUIT (4)
GUSTO and TIMI scales
1. Placebo 2. Low-dose epti 3. High-dose epti
ASA, UFH
4% in tiro and hep vs. 3% in hep group ( p ⫽ 0.34). TIMI major bleeding 1.4% with tiro and hep vs. 0.8% in hep group ( p ⫽ 0.23) GUSTO severe 1.5% vs. 0.9% ( p ⬍ 0.001). TIMI major 10.6% vs. 9.1% ( p ⫽ 0.02)
ISAR-REACT 2 (9)
TIMI scale
1. Placebo 2. Abcix
ASA, UFH, clopidogrel 600 mg loading dose
TIMI major bleed rate 1.4% in each group
CAPTURE (3)
TIMI scale
1. Placebo 2. Abcix
ASA, UFH
Overall 3.8% had major bleeding; 1.8% in placebo group vs. 3.8% in abcix group ( p ⫽ 0.043)
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Table 2. Bleeding Rates in Clinical Trials of GP IIb-IIIa Antagonists in Patients with UA/NSTEMI
Bleeding and transfusion more common in patients receiving epti. CABG-related bleeding accounted for 80% of major bleeding complications. No significant difference between groups in major or minor bleeding or for need of transfusion. Both major and minor bleeding as well as transfusions were significantly more common in abcix group
Abcix ⫽ abciximab; ACS ⫽ acute coronary syndrome; epti ⫽ eptifibatide; hep ⫽ heparin; TIMI ⫽ Thrombolysis in Myocardial Infarction; tiro ⫽ tirofiban. TIMI major bleeding: intracranial hemorrhage or bleeding with hemoglobin decrease ⬎ 5 g/dL or hematocrit decrease ⬎15% (26). TIMI minor bleeding: if identifiable site of bleeding, hemoglobin decrease of ⬎ 3 g/dL or hematocrit decrease ⬎ 10%. If no identifiable site of bleeding, hemoglobin decrease ⬎ 4 g/dL or hematocrit decrease ⬎ 12% (26). TIMI minimal bleeding: any clinically overt sign of hemorrhage with hemoglobin decrease ⬍ 3 g/dL or hematocrit decrease ⬍ 9% (26). GUSTO severe or life-threatening bleeding: intracranial hemorrhage or bleeding with hemodynamic compromise requiring intervention (27). GUSTO moderate bleeding: bleeding requiring blood transfusion not associated with hemodynamic compromise (27). GUSTO mild bleeding: all other bleeding events (27). PRISM-PLUS major bleeding: decrease in hemoglobin levels ⬎ 4 g/dL, need for transfusion ⬎ 2 units of blood, need for corrective surgery, intracranial or retroperitoneal hemorrhage, or any combination of these events (5). PRISM-PLUS minor bleeding: all other bleeding events (5).
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Although large studies have confirmed the safety and efficacy of GP IIb-IIIa inhibitors in combination with UFH, enoxaprin, or bivalirudin, careful assessment for contraindications and for risk of bleeding must be made before their use, and dosing should be adjusted for clinical factors such as renal dysfunction when indicated.
LOGISTIC CONSIDERATIONS: EARLY CLOPIDOGREL vs. GP IIb-IIIa INHIBITOR THERAPY Blockade of platelet activation is a cornerstone in the stabilization of coronary plaque in the management of ACS. Combination therapy with the oral antiplatelet agents aspirin and clopidogrel maximizes platelet inhibition. The PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) and the Clopidogrel for Reduction of Events During Observation (CREDO) investigations showed clear benefit in early administration of clopidogrel in NSTE ACS patients undergoing PCI (33,34). The reduction in risk of cardiovascular death or MI was seen during the period after randomization and before PCI. Based on these findings, in the 2007 ACC/AHA guidelines, the use of clopidogrel in patients for whom coronary intervention is planned receives a class I, level A recommendation (22).
EARLY CLOPIDOGREL vs. GP IIb-IIIa INHIBITOR THERAPY: THE EMERGENCY MEDICINE PERSPECTIVE There is an increased risk of postoperative bleeding in patients undergoing surgical revascularization within 5 days of receiving clopidogrel (35). The drawback of early clopidogrel use in potential CABG patients makes application of this therapeutic tactic in all early NSTE ACS patients problematic. In light of this bleeding risk, the 2007 ACC/AHA guidelines for the management of patients with unstable angina and NSTEMI recommend withholding clopidogrel for 5–7 days before elective CABG. Unfortunately, patients presenting to the ED with NSTE ACS have uncharacterized coronary vasculature, making it difficult to identify patients in whom early clopidogrel therapy might be beneficial or undesirable. The 2007 update to these ACC/AHA guidelines discusses the issue of early administration of clopidogrel. It concludes that clopidogrel should be administered to ACS patients who are not expected to proceed to PCI, and to ACS patients not eligible for CABG. Once coronary anatomy has been identified and CABG is not planned, clopidogrel should be administered to capitalize on the longer-term benefits of this agent (22). Careful
consideration should be exercised in the early administration of clopidogrel to patients in whom PCI is likely and in whom surgical intervention is a possibility. This should prompt discussion among cardiologists, cardiothoracic surgeons, and emergency physicians regarding the role of clopidogrel in management of early NSTE ACS in the ED and whether such a role even exists in certain patient subgroups. The half-lives of small-molecule GP IIb-IIIa inhibitors (eptifibatide, tirofiban) are short, and they are readily reversible within hours of discontinuing the infusion. This makes GP IIb-IIIa inhibitor therapy more logistically advantageous in high-risk patients in whom PCI is probable, especially because as many as 19% of these patients may proceed to CABG (31). This same group of high-risk patients is most likely to have adverse outcomes in the precatheterization period. As such, their antiplatelet therapy should be aggressive, with at least aspirin and a GP IIb-IIIa inhibitor, and clopidogrel in appropriate patients.
EARLY CLOPIDOGREL vs. GP IIb-IIIa INHIBITOR THERAPY: THE CARDIOVASCULAR MEDICINE PERSPECTIVE The benefit of GP IIb-IIIa inhibitors is less clearly defined in patients with UA/NSTEMI for whom PCI is planned in addition to treatment with aspirin, heparin, and clopidogrel (triple therapy). The 2007 ACC/AHA guidelines update considers addition of GP IIb-IIIa inhibitors to triple therapy a class IIa recommendation with level of evidence B (22). More recently, the ISARREACT 2 trial enrolled 2022 patients with NSTE ACS undergoing PCI and treated with aspirin, clopidogrel 600 mg, and heparin, and randomly assigned patients to receive abciximab or placebo (9). A 25% relative reduction in risk (8.9% vs. 11.9%) of the primary endpoint (death, MI, or urgent target vessel revascularization occurring within 30 days) was observed in the group receiving abciximab. The benefit of abciximab was isolated to the subgroup of patients with elevated troponin levels at baseline (i.e., the NSTEMI cohort). Interestingly, there were no significant differences between abciximab and placebo in the rates of major bleeding, minor bleeding, or transfusion (Table 2). Thus, for patients with NSTEMI managed with an early invasive strategy, GP IIb-IIIa inhibitors generally should be administered (regardless of whether clopidogrel is administered), whereas the incremental benefit of adding clopidogrel (even at 600 mg) in this high-risk group of patients has not been demonstrated. In contrast, patients who were managed conservatively or with neg-
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ative markers of myonecrosis did experience fewer ischemic complications with clopidogrel (compared with placebo) in the CURE trial (35). Thus, the incremental benefit of adding a GP IIb-IIIa inhibitor to clopidogrel in these lower-risk patients is less clear (28).
FUTURE DIRECTIONS AND CONCLUSION Ongoing studies of various antithrombotic regimens in patients with NSTE ACS should further define the optimal role of GP IIb-IIIa inhibitors in the ED. The Early Glycoprotein IIb-IIIa in Non-ST-Elevation Acute Coronary Syndrome (EARLY ACS) trial is investigating the benefit of early GP IIb-IIIa inhibition before PCI in the setting of NSTE ACS. This prospective, placebo-controlled, multicenter study aims to randomize 10,500 high-risk NSTE ACS patients to either early eptifibatide or placebo before coronary angiography 12–72 h later (25). Because the main analysis is stratified by the intention to administer early clopidogrel (vs. clopidogrel loading after diagnostic angiography, if no CABG is planned), this trial will provide new data regarding the use of upstream vs. downstream GP IIb-IIIa inhibitors on a background of other contemporary antithrombotics, including clopidogrel. Until such studies are completed, analysis of available data must be utilized to direct the early use of GP IIb-IIIa inhibitors in appropriate patients. The emergency medicine authors of this article encourage early administration of GP IIb-IIIa inhibitors in high-risk NSTE ACS patients in whom an invasive strategy or medical management is planned. Unless bleeding risks are evident, the risk/benefit ratio favors this approach. Further, although clopidogrel may be beneficial in high-risk NSTE ACS patients, early application of this agent is complicated by the risk of postoperative bleeding if the patient proceeds to CABG. Therefore, the issue of early use of clopidogrel, in addition to GP IIb-IIIa inhibitors for patients in whom initial invasive strategy is planned, requires more discussion and protocol development regarding optimal timing. The cardiologists authoring this article recommend early administration of GP IIb-IIIa inhibitors in high-risk NSTE ACS patients, particularly patients with a positive troponin level, in whom an invasive strategy is planned. They also emphasize careful consideration of bleeding risks. The cardiologists do not support the routine early use of clopidogrel in addition to GP IIb-IIIa inhibitors when invasive therapy is planned, due to limited data demonstrating its additional benefit and evidence of increased risk of bleeding if CABG is required. Clopidogrel should be considered, however, in high-risk NSTE ACS patients in whom a conservative course is planned.
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Acknowledgment—Editorial assistance for this manuscript was provided by Adelphi Inc. and funded by Schering-Plough. James Hoekstra, MD – Speaker Bureau: BMS, Schering Plough, and Sanofi-Aventis, Consultant: Schering Plough, Sanofi-Aventis, Esai, Medicines Co.; Robert Guigliano, MD – Research grant support: Schering-Plough, Merck, Nuvelo, Consultant: ScheringPlough, Merck, Sanofi-Aventis, CV Therapeutics, Speakers Bureau: Schering-Plough, Bristol-Myers-Squibb, Sanofi-Aventis, CV Therapeutics, Glaxo-Smith-Kline; Cedric Lefebvre, MD – None; Marc Bonaca, MD – None.
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doi:10.1016/j.jemermed.2007.10.020
Selected Topics: Cardiology Commentary
GLYCOPROTEIN IIb-IIIa INHIBITORS IN THE EMERGENCY DEPARTMENT FOR PATIENTS WITH NON-ST-ELEVATION ACUTE CORONARY SYNDROMES: PRINCIPLES AND PRACTICES Cedric W. Lefebvre,
MD,
* James W. Hoekstra,
MD,*
Marc Bonaca,
MD,†
and Robert Giugliano,
MD‡
*Department of Emergency Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, †Division of Cardiovascular Medicine and ‡TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts Reprint Address: Cedric W. Lefebvre, MD, Department of Emergency Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Watlington Hall, 4th Floor, Winston-Salem, NC 27157-1089
e Abstract—Non-ST-elevation acute coronary syndrome is associated with significant morbidity and mortality. Although the benefit of platelet inhibition by glycoprotein (GP) IIb-IIIa inhibitors in patients undergoing percutaneous coronary intervention (PCI) is well established, emergency physicians and cardiologists have different perspectives regarding their optimum administration, especially upstream before PCI. In this article, two emergency physicians and two cardiologists analyze data and discuss relevant issues, including the ischemic benefits vs. the risk of bleeding associated with GP IIb-IIIa inhibitors in appropriate patients, for example, those with an elevated troponin level or who undergo revascularization. The emergency physicians support early identification of high-risk nonST-elevation acute coronary syndrome patients and early administration of GP IIb-IIIa inhibitors, which are linked to improved patient outcomes. The cardiologists emphasize risk stratification to identify patients in whom the expected reduction in ischemic complications outweighs the risk of increased bleeding with these agents. GP IIb-IIIa inhibitors should be considered in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) in whom PCI is planned, especially those with high-risk features or elevated serum troponin levels. It is reasonable to start this treatment upstream of intervention, pending further studies investigating the optimal timing of initiation of therapy in appropriate patients. © 2009 Elsevier Inc.
RECEIVED: 20 March 2007; FINAL ACCEPTED: 4 October 2007
SUBMISSION RECEIVED:
e Keywords—non-ST-elevation acute coronary syndrome; GP IIb-IIIa inhibitors; emergency department; percutaneous coronary intervention; risk stratification
PATHOGENESIS OF ACUTE CORONARY SYNDROME Non-ST-elevation acute coronary syndrome (NSTE ACS) is associated with significant morbidity and mortality. Atherosclerotic plaques of the coronary vasculature are the most common cause of ischemic heart disease, and rupture of these plaques is the most common pathogenesis of NSTE ACS. After plaque rupture has occurred, platelet adhesion, platelet activation, and activation of the coagulation cascade result in formation of a platelet-rich thrombus in the coronary artery. In NSTE ACS, this thrombus is usually only partially occlusive but may cause intermittent downstream myocardial ischemia or downstream microvascular infarction due to microemboli. Antiplatelet medications such as aspirin, clopidogrel, and glycoprotein (GP) IIb-IIIa inhibitors may attenuate thrombotic progression and slow the evolution toward occlusive thrombosis (1). In addition, plaque stabilization by GP IIb-IIIa inhibitors has been shown to increase microvascular perfusion in the myocardium during percutaneous coronary intervention (PCI),
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alleviating the “closed muscle” phenomenon with microvascular ischemia (2).
THEORETICAL BENEFITS OF EARLY ADMINISTRATION OF GP IIb-IIIa INHIBITORS The benefit of platelet inhibition by GP IIb-IIIa inhibitors as adjunctive therapy in patients undergoing PCI is well established (3–10). GP IIb-IIIa inhibitor utilization is especially beneficial in patients who are at highest risk for adverse outcomes, especially those who have an elevated troponin level and those who undergo revascularization by either PCI or coronary artery bypass grafting (CABG) (4,9). In addition to lending benefit during PCI, GP IIb-IIIa inhibition seems to provide benefit to NSTE ACS patients in the period before PCI (i.e., “upstream,” before arrival in the catheterization laboratory). This benefit is mostly due to a reduction in recurrent myocardial infarction (MI) or recurrent ischemia during this period of medical stabilization (4). Several landmark clinical trials have examined the use of intravenous GP IIb-IIIa inhibitors in patients presenting with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) (Table 1). These studies provide the bulk of the evidence regarding GP IIb-IIIa inhibitor use cited in current practice guidelines. The benefit of early GP IIb-IIIa inhibition is particularly relevant to emergency physicians, who diagnose and manage NSTE ACS patients early in their course. Despite the American College of Cardiology and American Heart Association (ACC/AHA) recommendation for early administration of GP IIb-IIIa inhibitors in high-risk NSTE ACS patients (those with elevated cardiac biomarkers, electrocardiogram changes consistent with ischemia, ongoing chest pain), these agents are underutilized in NSTE ACS patients nationwide (13–15). Therefore, greater attention must be applied to the role of GP IIb-IIIa inhibitors in the early management of high-risk NSTE ACS in the emergency department (ED). The benefit of upstream administration of GP IIb-IIIa inhibitors in patients with NSTE ACS has been demonstrated in several clinical trials (3– 6,9,10,16). Recent data suggest that upstream use of tirofiban is associated with improved reperfusion and reduction in myocardial injury in high-risk NSTE ACS patients undergoing early invasive reperfusion strategies, in comparison with administration during PCI (17). In the C7E3 fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, administration of abciximab 18 to 24 h before PCI in high-risk patients with NSTE ACS was associated with a decrease in the frequency of myocardial infarction and a reduced likelihood of ischemic episodes in the period before this intervention (3). The Platelet Glycop-
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rotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial investigators demonstrated a 1.5% absolute risk reduction in death and non-fatal MI at 96 h and through 30 days after upstream administration of eptifibatide vs. placebo in high-risk NSTE ACS patients. They reported a decreased incidence of ischemic composite endpoints in NSTE ACS patients during the period of drug infusion before PCI, as well as in patients who received medical management only (4). Similar results occurred in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, which included 1915 patients with UA/NSTEMI who were treated with aspirin and randomly assigned to receive tirofiban, heparin, or both (5). The frequency of composite endpoints (death, MI, refractory ischemia within 7 days) was significantly lower in the group receiving both tirofiban and heparin when compared with patients receiving heparin alone (tirofiban alone was associated with higher early mortality, and this third arm was dropped from the trial). The benefit of adding tirofiban to heparin was due primarily to a reduction in MI, which persisted through 30 days (5). The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial also demonstrated fewer composite endpoints at 48 h in patients presenting with NSTE unstable angina who received GP IIb-IIIa inhibitors 48 h before intervention. Reductions in ischemic outcomes were also seen in NSTE ACS patients who were medically managed (6).
EARLY ADMINISTRATION OF GP IIb-IIIa INHIBITORS: THE EMERGENCY MEDICINE PERSPECTIVE A meta-analysis of these randomized controlled trials of GP IIb-IIIa inhibitors by Boersma et al. demonstrated both pre- and post-PCI benefits with GP IIb-IIIa inhibitor treatment of high-risk NSTE ACS (10). Boersma’s analysis of CAPTURE, PURSUIT, and PRISM-PLUS demonstrated a statistically significant reduction in death and MI in the pre-PCI medical management period, as well as a more robust reduction in ischemic outcomes associated with PCI. The results of this analysis drove the ACC/AHA Guidelines recommendations for GP IIb-IIIa inhibitor therapy pre-PCI. Similarly, logistic regression of retrospective analyses of data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) and National Registry of MI registries demonstrated a 7% to 12% decrease of in-hospital mortality associated with early GP IIb-IIIa inhibitor therapy, with statistically significant reductions
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Table 1. Clinical Trials of GP IIb-IIIa Antagonists and Outcomes in Patients With UA/NSTEMI Trial
n, Population
GUSTO IV-ACS (11) n ⫽ 7800 UA/NSTEMI not going to coronary intervention
PRISM (6) PRISM-PLUS (5)
PURSUIT (4)
ISAR-REAC T 2 (9)
CAPTURE (3) ACUITY (12)
Endpoint Death or MI at 30 days
Randomized Treatments 1. Placebo 2. Abciximab for 24 h 3. Abciximab for 48 h
Other Therapy
Key Results
ASA, UFH
* Heparin was either enoxaparin or unfractionated heparin (investigator’s choice). ACS ⫽ acute coronary syndrome; ASA ⫽ aspirin; CI ⫽ confidence interval; GP IIb-IIIa inhibitor ⫽ glycoprotein IIb-IIIa inhibitor; LMWH ⫽ low molecular weight heparin; MI ⫽ myocardial infarction; NSTEMI ⫽ non-ST-segment elevation myocardial infarction; OR ⫽ odds ratio; RR ⫽ relative risk; UA ⫽ unstable angina; UFH ⫽ unfractionated heparin.
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30-day death or MI 8.0% (placebo) vs. 8.2% and 9.1% in the 24-h and 48-h abciximab groups, respectively (OR 1.0; 95% CI 0.83–1.24 and 1.1; 95% CI, 0.94–1.39). 1-year mortality 7.8% (placebo) vs. 8.2% and 9.0% in the two abciximab arms. Patients with elevated troponin levels had higher mortality with 48-h infusion of abciximab (8.5% vs. 5.8%; p ⫽ 0.02). n ⫽ 3232 Death/MI/refractory 1. UFH ASA Primary endpoint 3.8% with tirofiban vs. 5.6% UA/NSTEMI ischemia at 48 h 2. Tirofiban with UFH (RR 0.67; 95% CI 0.48–0.92) at 48 h. n ⫽ 1915 Death/MI/refractory 1. UFH ASA Primary endpoint at 7 days lower with low-dose UA/NSTEMI ischemia at 7 2. UFH ⫹ low-dose tirofiban plus heparin (12.9% vs. 17.9%) vs. days tirofiban UFH alone; benefit persisted through 30 days. 3. High-dose tirofiban High-dose tirofiban alone arm stopped early due to excess 7-day mortality (4.6% vs. 1.1% for UFH alone). n ⫽ 10,948 Death/non-fatal MI 1. Placebo ASA, UFH Primary endpoint at 30 days lower with UA/NSTEMI at 30 days 2. Low-dose eptifibatide eptifibatide (14.2% vs. 15.7%; p ⫽ 0.04). 3. High-dose eptifibatide Incidence of primary endpoint lower in both those who underwent early PCI (11.6% vs. 16.7%) as well as in those managed medically (14.5% vs. 15.6%). n ⫽ 2022 Death/MI/urgent 1. Placebo ASA, UFH, clopidogrel Primary endpoint at 30 days lower with UA/NSTEMI just before PCI target vessel 2. Abciximab 600 mg loading abciximab (8.9% vs. 11.9%; RR 0.75; p ⫽ revasc within 30 dose 0.03). Benefit isolated to patients with elevated days baseline troponin levels (RR 0.71; p ⫽ 0.02) and not seen in those with normal baseline troponin (RR 0.99; p ⫽ 0.98). n ⫽ 1265 Death/MI/urgent 1. Placebo ASA, UFH Primary endpoint at 30 days lower with UA/NSTEMI with PCI next day revasc at 30 days 2. Abciximab abciximab (11.3% vs. 15.9%; p ⫽ 0.012). Similar outcomes at 6 months. n ⫽ 13,819 Composite ischemia 1. Heparin* ⫹ GP ASA, clopidogrel Bivalirudin with GP IIb-IIIa inhibitor was Moderate- to high-risk UA/ (death, MI, urgent IIb-IIIa inhibitor recommended noninferior to heparin with a GP IIb-IIIa NSTEMI with early invasive revasc), major 2. Bivalirudin ⫹ GP (⬃63% before cath) inhibitor in terms of ischemia (7.7% vs. 7.3%, strategy bleeding, net IIb-IIIa inhibitor respectively), major bleeding (5.3% vs. 5.7%), clinical outcome 3. Bivalirudin and net clinical result (11.8% vs. 11.7%). at 30 days Bivalirudin alone vs. UFH with GP IIb-IIIa inhibitor was non-inferior in terms of ischemia (7.8 vs. 7.3%; p ⫽ 0.32) and had reduced rates of major bleeding (3.0% vs. 5.7%; p ⬍ 0.001) and net clinical endpoint (10.1% vs. 11.7%; p ⫽ 0.02).
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noted in the National Registry of Myocardial Infarction database (15). Although these results are compelling, conclusions regarding causation are difficult to draw from a retrospective analysis of registry data. Several studies have established the beneficial role of GP IIb-IIIa inhibitors in high-risk PCI (4,18 –20). Although upstream GP IIb-IIIa inhibitors afford considerable benefit to high-risk NSTE ACS patients, debate remains about the utility of these agents in low- to moderate-risk patients. The Intracoronary Stenting and Anti-Thrombotic Regimen–Rapid Early Action for Coronary Treatment (ISAR-REACT) trial revealed little benefit from GP IIb-IIIa inhibitor administration at 30 days in low- to moderate-risk patients undergoing elective PCI who were pre-treated with clopidogrel (21). This was supported by findings in the ISAR-REACT 2 trial, in which patients without elevated troponin levels who were treated with GP IIb-IIIa inhibitors experienced the same incidence of adverse events (death, MI, and urgent revascularization) as the placebo group. In high-risk NSTE ACS patients with elevated troponin levels, however, intravenous GP IIb-IIIa inhibitors in this study were associated with a reduction of adverse events (9). These studies suggest that GP IIb-IIIa inhibitor therapy lends therapeutic advantage in the early management of high-risk NSTE ACS patients and nicely illustrate the importance of risk stratification of patients presenting to the ED with NSTE ACS. Hence, there is strong evidence to support the early/ upstream use of GP IIb-IIIa inhibitors in high-risk patients. When treated early in their hospital course with GP IIb-IIIa inhibitors, high-risk NSTE ACS patients proceeding to PCI and those to be managed medically seem to benefit. Therefore, emergency physicians should deliver the beneficial effects of upstream GP IIb-IIIa antagonism to their high-risk NSTE ACS patients.
EARLY ADMINISTRATION OF GP IIb-IIIa INHIBITORS: THE CARDIOVASCULAR MEDICINE PERSPECTIVE The current ACC/AHA guidelines for treatment of UA/ NSTEMI assign a class I indication to the use of GP IIb-IIIa inhibitors in addition to aspirin and heparin in patients with UA/NSTEMI in whom catheterization and PCI are planned (22,23). In patients in whom catheterization is planned, both “upstream” and “in-lab” treatment is considered acceptable. In patients with UA/ NSTEMI in whom medical management is planned, the guidelines provide a class IIa recommendation for the use of eptifibatide or tirofiban in the setting of continuing ischemia or high-risk features. In contrast, abciximab is not indicated (receiving a class III recommendation) in medi-
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cally treated patients who are not undergoing early catheterization, due to the absence of benefit and an increased risk of bleeding as observed in the Global Utilization of Strategies to Open Occluded Coronary Arteries IV–Acute Coronary Syndromes (GUSTO IV-ACS) trial. The greatest benefits of GP IIb-IIIa inhibitors in patients with UA/NSTEMI probably occur in the acute and peri-procedural settings. In the PURSUIT trial, benefit was seen by 96 h (4). This benefit—31% relative risk reduction (primary endpoint 11.6% eptifibatide vs. 16.7% controls)—was greatest in patients who were managed with early intervention and was smaller—7% relative risk reduction—in those managed medically ( p ⫽ 0.23). This initial benefit is durable and has been demonstrated through 30 days or longer in clinical trials. Additional, longer-term benefit after index hospitalization is more difficult to evaluate and is unlikely to be substantial, because these agents are generally administered for only 12 to 72 h. In the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Timing trial (24), 9207 patients with NSTE ACS managed with an early invasive approach were randomly assigned to early GP IIb-IIIa inhibitor therapy or deferred, selective use of GP IIb-IIIa inhibitors at the time of PCI. The rate of ischemic complications at 30 days was 7.1% for upstream vs. 7.9% for selective use in the catheterization laboratory (p ⫽ NS for non-inferiority of the latter approach), despite an average difference of only 4 h in the initiation of GP IIb-IIIa inhibitors between the two treatment arms. Thus, the investigators could not rule out a 25% or more increase in ischemic complications with a downstream GP IIb-IIIa inhibitor strategy. In particular, higher-risk patient subgroups (troponin positive, higher Thrombolysis in Myocardial Infarction [TIMI] Risk Score) and those who did not receive early thienopyridine treatment tended to have better outcomes with upstream GP IIb-IIIa inhibitors. GP IIb-IIIa inhibitors should be considered in patients with UA/NSTEMI in whom PCI is planned, with the intention of decreasing rates of recurrent ischemia, recurrent MI, and mortality. Specifically, patients with high-risk features or elevated serum troponin levels are optimal candidates for this therapy. It is reasonable to start this treatment upstream of intervention pending further studies investigating the optimal timing of initiation of therapy (25).
ADVERSE EFFECTS OF GP IIb-IIIa INHIBITOR UTILIZATION Excessive bleeding is the major safety concern associated with the use of GP IIb-IIIa inhibitors. Bleeding rates vary by trial, concomitant therapy, and dosing of medications. Furthermore, definitions of bleeding also vary
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among published clinical trials (Table 2). Careful consideration of clinical factors, such as renal dysfunction and bleeding risk, are important in optimizing the risk/ benefit ratio associated with these agents.
BLEEDING: THE EMERGENCY MEDICINE PERSPECTIVE With the exception of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial, which employed higher concomitant heparin doses—that were associated with higher rates of major bleeding— more recent studies have demonstrated a relatively small increased risk of major bleeding, thrombocytopenia, and need for transfusion of blood products in patients treated with GP IIb-IIIa inhibitors (3– 6,18). The majority of this bleeding is catheter related, with higher rates in the elderly and in patients with chronic renal insufficiency. Major bleeding seems to be associated with elevated doses of combination therapy, including GP IIb-IIIa inhibitors, heparin, and clopidogrel, particularly in patients undergoing surgical revascularization (4,21). A recent analysis of the CRUSADE registry indicated that as many as 65% of patients over 75 years of age receive excessive doses of GP IIb-IIIa inhibitor in community practice. Similarly, doses of heparin in this same population are excessive in 38% of cases. Elevations in either antithrombins or GP IIb-IIIa inhibitors are associated with increased bleeding rates in CRUSADE, with the highest bleeding rates seen in patients who receive excessive doses of both medications (14). Therefore, risk stratification of ACS patients should take into account factors that would place a patient at risk for bleeding complications. Administration of GP IIb-IIIa inhibitors should be avoided in patients with recent surgery or cerebrovascular events, current oral anticoagulation therapy, persistent hypertension, or thrombocytopenia. Doses should be reduced in patients with a creatinine clearance rate ⬍ 50 cc/min as guided by the CockcroftGault equation. Otherwise, especially in younger patient groups, the risk of bleeding associated with GP IIb-IIIa inhibitor administration seems to be relatively small, and the risk/benefit ratio in this regard favors their use in appropriate patients.
BLEEDING: THE CARDIOVASCULAR MEDICINE PERSPECTIVE A meta-analysis of several large trials did show increased rates of major bleeding associated with GP IIbIIIa inhibitors (odds ratio 1.62; 95% confidence interval 1.36 –1.94); however, their use was not associated with a
higher rate of intracranial hemorrhage (28). A subsequent pooled analysis of 27,889 patients again did not show a higher rate of intracranial hemorrhage in patients treated with GP IIb-IIIa inhibitors alone or with heparin when compared with heparin alone; however, overall event rates were low (29). The current ACC/AHA guidelines recommend heparin or low-molecular-weight heparin (LMWH) in patients with NSTE ACS in addition to aspirin (22,23). In the A-to-Z trial, 3987 patients with ACS were treated with tirofiban and aspirin and then randomly assigned to receive unfractionated heparin (UFH) or LMWH (30). There was no difference in the primary endpoint (death, MI, refractory ischemia) between heparins; however, higher rates of bleeding were seen with LMWH. The A-to-Z investigators concluded that LMWH was a suitable alternative to UFH in patients treated with aspirin and tirofiban. The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial enrolled 10,027 patients with NSTEMI to be treated with an early invasive strategy and randomly assigned them to receive enoxaparin or UFH (31). There was no difference between heparins in the primary endpoint; however, enoxaparin was associated with increased TIMI major bleeding, particularly in CABG-related events. GP IIb-IIIa inhibitor use was similar between the two randomized treatment groups (56.5%, enoxaparin; 58.2%, UFH). In the ACUITY trial, two alternative strategies to reduce bleeding were investigated in a population of moderate-risk patients with NSTE ACS managed with an early invasive strategy (32). Use of bivalirudin monotherapy was associated with significantly lower major bleeding (3.0% vs. 5.7%, p ⬍ 0.001) and was noninferior with respect to ischemic complications compared with heparin (either enoxaparin or UFH) plus GP IIb-IIIa inhibition. Patients receiving bivalirudin with GP IIb-IIIa inhibition experienced similar rates of ischemic complications and bleeding compared with heparin plus GP IIb-IIIa inhibition; thus, there seemed to be no particular advantage in using bivalirudin instead of a heparin, if a GP IIb-IIIa inhibitor was being administered. Lastly, in the ACUITY Timing trial, deferred selective, or “in-lab,” use of GP IIb-IIIa inhibition was associated with less bleeding than with routine upstream use (4.9% vs. 6.1%, p ⫽ 0.009, respectively) (24). Thus, in patients at low to moderate risk of ischemic complications or moderate to high risk of bleeding, alternative antithrombotic strategies may be reasonable, recognizing the existing trade-off between protection from ischemic complications and increased bleeding risk that is associated with the administration of upstream GP IIb-IIIa inhibitors.
Trial
Bleeding Definition
Randomized Treatments
Other Therapy
Major Bleeding
Key Results Bleeding occurred most often in patients undergoing coronary procedures. Minor and insignificant bleeding as well as need for transfusion higher in the abcix-treated groups vs. placebo. Bleeding higher in elderly and female patients. No difference in TIMI major or minor bleeding, no difference in intracranial hemorrhage. Bleeding and transfusion somewhat more frequent with combination therapy but not statistically significant.
GUSTO IV-ACS (11)
TIMI major, minor, or insignificant during hospitalization or 7 days from randomization
1. Placebo 2. Abcix for 24 h 3. Abcix for 48 h
ASA, UFH
Overall 1.2%; 1.8% receiving 48 h abcix, 1.0% receiving 24 h abcix, 0.9% receiving placebo ( p ⬍ 0.0001 - 48 h vs. placebo)
PRISM (6)
TIMI major or minor
1. UFH 2. Tirofiban
ASA
0.4% in both groups
PRISM-PLUS (5)
PRISM-PLUS major/minor as well as TIMI scale
1. UFH 2. UFH ⫹ low-dose tiro 3. High-dose tiro
ASA
PURSUIT (4)
GUSTO and TIMI scales
1. Placebo 2. Low-dose epti 3. High-dose epti
ASA, UFH
4% in tiro and hep vs. 3% in hep group ( p ⫽ 0.34). TIMI major bleeding 1.4% with tiro and hep vs. 0.8% in hep group ( p ⫽ 0.23) GUSTO severe 1.5% vs. 0.9% ( p ⬍ 0.001). TIMI major 10.6% vs. 9.1% ( p ⫽ 0.02)
ISAR-REACT 2 (9)
TIMI scale
1. Placebo 2. Abcix
ASA, UFH, clopidogrel 600 mg loading dose
TIMI major bleed rate 1.4% in each group
CAPTURE (3)
TIMI scale
1. Placebo 2. Abcix
ASA, UFH
Overall 3.8% had major bleeding; 1.8% in placebo group vs. 3.8% in abcix group ( p ⫽ 0.043)
GPIIb-IIIa Inhibitors in the ED
Table 2. Bleeding Rates in Clinical Trials of GP IIb-IIIa Antagonists in Patients with UA/NSTEMI
Bleeding and transfusion more common in patients receiving epti. CABG-related bleeding accounted for 80% of major bleeding complications. No significant difference between groups in major or minor bleeding or for need of transfusion. Both major and minor bleeding as well as transfusions were significantly more common in abcix group
Abcix ⫽ abciximab; ACS ⫽ acute coronary syndrome; epti ⫽ eptifibatide; hep ⫽ heparin; TIMI ⫽ Thrombolysis in Myocardial Infarction; tiro ⫽ tirofiban. TIMI major bleeding: intracranial hemorrhage or bleeding with hemoglobin decrease ⬎ 5 g/dL or hematocrit decrease ⬎15% (26). TIMI minor bleeding: if identifiable site of bleeding, hemoglobin decrease of ⬎ 3 g/dL or hematocrit decrease ⬎ 10%. If no identifiable site of bleeding, hemoglobin decrease ⬎ 4 g/dL or hematocrit decrease ⬎ 12% (26). TIMI minimal bleeding: any clinically overt sign of hemorrhage with hemoglobin decrease ⬍ 3 g/dL or hematocrit decrease ⬍ 9% (26). GUSTO severe or life-threatening bleeding: intracranial hemorrhage or bleeding with hemodynamic compromise requiring intervention (27). GUSTO moderate bleeding: bleeding requiring blood transfusion not associated with hemodynamic compromise (27). GUSTO mild bleeding: all other bleeding events (27). PRISM-PLUS major bleeding: decrease in hemoglobin levels ⬎ 4 g/dL, need for transfusion ⬎ 2 units of blood, need for corrective surgery, intracranial or retroperitoneal hemorrhage, or any combination of these events (5). PRISM-PLUS minor bleeding: all other bleeding events (5).
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Although large studies have confirmed the safety and efficacy of GP IIb-IIIa inhibitors in combination with UFH, enoxaprin, or bivalirudin, careful assessment for contraindications and for risk of bleeding must be made before their use, and dosing should be adjusted for clinical factors such as renal dysfunction when indicated.
LOGISTIC CONSIDERATIONS: EARLY CLOPIDOGREL vs. GP IIb-IIIa INHIBITOR THERAPY Blockade of platelet activation is a cornerstone in the stabilization of coronary plaque in the management of ACS. Combination therapy with the oral antiplatelet agents aspirin and clopidogrel maximizes platelet inhibition. The PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) and the Clopidogrel for Reduction of Events During Observation (CREDO) investigations showed clear benefit in early administration of clopidogrel in NSTE ACS patients undergoing PCI (33,34). The reduction in risk of cardiovascular death or MI was seen during the period after randomization and before PCI. Based on these findings, in the 2007 ACC/AHA guidelines, the use of clopidogrel in patients for whom coronary intervention is planned receives a class I, level A recommendation (22).
EARLY CLOPIDOGREL vs. GP IIb-IIIa INHIBITOR THERAPY: THE EMERGENCY MEDICINE PERSPECTIVE There is an increased risk of postoperative bleeding in patients undergoing surgical revascularization within 5 days of receiving clopidogrel (35). The drawback of early clopidogrel use in potential CABG patients makes application of this therapeutic tactic in all early NSTE ACS patients problematic. In light of this bleeding risk, the 2007 ACC/AHA guidelines for the management of patients with unstable angina and NSTEMI recommend withholding clopidogrel for 5–7 days before elective CABG. Unfortunately, patients presenting to the ED with NSTE ACS have uncharacterized coronary vasculature, making it difficult to identify patients in whom early clopidogrel therapy might be beneficial or undesirable. The 2007 update to these ACC/AHA guidelines discusses the issue of early administration of clopidogrel. It concludes that clopidogrel should be administered to ACS patients who are not expected to proceed to PCI, and to ACS patients not eligible for CABG. Once coronary anatomy has been identified and CABG is not planned, clopidogrel should be administered to capitalize on the longer-term benefits of this agent (22). Careful
consideration should be exercised in the early administration of clopidogrel to patients in whom PCI is likely and in whom surgical intervention is a possibility. This should prompt discussion among cardiologists, cardiothoracic surgeons, and emergency physicians regarding the role of clopidogrel in management of early NSTE ACS in the ED and whether such a role even exists in certain patient subgroups. The half-lives of small-molecule GP IIb-IIIa inhibitors (eptifibatide, tirofiban) are short, and they are readily reversible within hours of discontinuing the infusion. This makes GP IIb-IIIa inhibitor therapy more logistically advantageous in high-risk patients in whom PCI is probable, especially because as many as 19% of these patients may proceed to CABG (31). This same group of high-risk patients is most likely to have adverse outcomes in the precatheterization period. As such, their antiplatelet therapy should be aggressive, with at least aspirin and a GP IIb-IIIa inhibitor, and clopidogrel in appropriate patients.
EARLY CLOPIDOGREL vs. GP IIb-IIIa INHIBITOR THERAPY: THE CARDIOVASCULAR MEDICINE PERSPECTIVE The benefit of GP IIb-IIIa inhibitors is less clearly defined in patients with UA/NSTEMI for whom PCI is planned in addition to treatment with aspirin, heparin, and clopidogrel (triple therapy). The 2007 ACC/AHA guidelines update considers addition of GP IIb-IIIa inhibitors to triple therapy a class IIa recommendation with level of evidence B (22). More recently, the ISARREACT 2 trial enrolled 2022 patients with NSTE ACS undergoing PCI and treated with aspirin, clopidogrel 600 mg, and heparin, and randomly assigned patients to receive abciximab or placebo (9). A 25% relative reduction in risk (8.9% vs. 11.9%) of the primary endpoint (death, MI, or urgent target vessel revascularization occurring within 30 days) was observed in the group receiving abciximab. The benefit of abciximab was isolated to the subgroup of patients with elevated troponin levels at baseline (i.e., the NSTEMI cohort). Interestingly, there were no significant differences between abciximab and placebo in the rates of major bleeding, minor bleeding, or transfusion (Table 2). Thus, for patients with NSTEMI managed with an early invasive strategy, GP IIb-IIIa inhibitors generally should be administered (regardless of whether clopidogrel is administered), whereas the incremental benefit of adding clopidogrel (even at 600 mg) in this high-risk group of patients has not been demonstrated. In contrast, patients who were managed conservatively or with neg-
GPIIb-IIIa Inhibitors in the ED
ative markers of myonecrosis did experience fewer ischemic complications with clopidogrel (compared with placebo) in the CURE trial (35). Thus, the incremental benefit of adding a GP IIb-IIIa inhibitor to clopidogrel in these lower-risk patients is less clear (28).
FUTURE DIRECTIONS AND CONCLUSION Ongoing studies of various antithrombotic regimens in patients with NSTE ACS should further define the optimal role of GP IIb-IIIa inhibitors in the ED. The Early Glycoprotein IIb-IIIa in Non-ST-Elevation Acute Coronary Syndrome (EARLY ACS) trial is investigating the benefit of early GP IIb-IIIa inhibition before PCI in the setting of NSTE ACS. This prospective, placebo-controlled, multicenter study aims to randomize 10,500 high-risk NSTE ACS patients to either early eptifibatide or placebo before coronary angiography 12–72 h later (25). Because the main analysis is stratified by the intention to administer early clopidogrel (vs. clopidogrel loading after diagnostic angiography, if no CABG is planned), this trial will provide new data regarding the use of upstream vs. downstream GP IIb-IIIa inhibitors on a background of other contemporary antithrombotics, including clopidogrel. Until such studies are completed, analysis of available data must be utilized to direct the early use of GP IIb-IIIa inhibitors in appropriate patients. The emergency medicine authors of this article encourage early administration of GP IIb-IIIa inhibitors in high-risk NSTE ACS patients in whom an invasive strategy or medical management is planned. Unless bleeding risks are evident, the risk/benefit ratio favors this approach. Further, although clopidogrel may be beneficial in high-risk NSTE ACS patients, early application of this agent is complicated by the risk of postoperative bleeding if the patient proceeds to CABG. Therefore, the issue of early use of clopidogrel, in addition to GP IIb-IIIa inhibitors for patients in whom initial invasive strategy is planned, requires more discussion and protocol development regarding optimal timing. The cardiologists authoring this article recommend early administration of GP IIb-IIIa inhibitors in high-risk NSTE ACS patients, particularly patients with a positive troponin level, in whom an invasive strategy is planned. They also emphasize careful consideration of bleeding risks. The cardiologists do not support the routine early use of clopidogrel in addition to GP IIb-IIIa inhibitors when invasive therapy is planned, due to limited data demonstrating its additional benefit and evidence of increased risk of bleeding if CABG is required. Clopidogrel should be considered, however, in high-risk NSTE ACS patients in whom a conservative course is planned.
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Acknowledgment—Editorial assistance for this manuscript was provided by Adelphi Inc. and funded by Schering-Plough. James Hoekstra, MD – Speaker Bureau: BMS, Schering Plough, and Sanofi-Aventis, Consultant: Schering Plough, Sanofi-Aventis, Esai, Medicines Co.; Robert Guigliano, MD – Research grant support: Schering-Plough, Merck, Nuvelo, Consultant: ScheringPlough, Merck, Sanofi-Aventis, CV Therapeutics, Speakers Bureau: Schering-Plough, Bristol-Myers-Squibb, Sanofi-Aventis, CV Therapeutics, Glaxo-Smith-Kline; Cedric Lefebvre, MD – None; Marc Bonaca, MD – None.
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