Integrating antithrombin and antiplatelet therapies with early invasive management for non–ST-segment elevation acute coronary syndromes

Integrating Antithrombin and Antiplatelet Therapies with Early Invasive Management for Non–ST-segment Elevation Acute Coronary Syndromes Abdallah G. Rebeiz, MD, Matthew T. Roe, MD, MHS, John H. Alexander, MD, MHS, Kenneth W. Mahaffey, MD, Christopher B. Granger, MD, Eric D. Peterson, MD, Robert M. Califf, MD, Robert A. Harrington, MD Non–ST-segment elevation acute coronary syndromes are a dramatic manifestation of coronary artery disease. Multiple clinical trials have shown that early cardiac catheterization improves clinical outcomes in patients with non–ST-segment elevation acute coronary syndromes. Many antithrombotic agents effectively manage unstable coronary syndromes and serve as adjuncts to percutaneous coronary intervention. Yet, the grow-

ing number of pharmacologic agents makes early management of non–ST-segment elevation acute coronary syndromes increasingly complex. We review the current evidence regarding the optimal integration of early antithrombotic and antiplatelet therapies with early coronary angiography and subsequent revascularization. Am J Med. 2004;116:119 –129. ©2004 by Excerpta Medica Inc.

N

patients, or whether aggressive treatment should be reserved for after angiography in patients selected to undergo percutaneous coronary intervention. Here, we evaluate the evidence regarding the treatment of patients with non–ST-segment elevation acute coronary syndromes using early comprehensive pharmacologic therapy in conjunction with early coronary angiography and subsequent revascularization.

on–ST-segment elevation acute coronary syndromes account for more than 1 million hospital admissions in the United States each year (1). Acute coronary syndromes are caused by atherosclerotic plaque ruptures that result in platelet and coagulation factor activation and intracoronary thrombus formation (2,3). Non–ST-segment elevation acute coronary syndromes encompass the diagnoses previously known as unstable angina and non–Q-wave myocardial infarction. A decade ago, managing unstable coronary syndromes consisted mainly of treatment with aspirin, unfractionated heparin, or both (4). Since then, large randomized clinical trials have demonstrated that many antithrombin and antiplatelet agents improve outcomes of patients with non–ST-segment elevation acute coronary syndromes. There is increasing evidence that an early strategy of coronary angiography and, when indicated, subsequent revascularization also improve outcomes (5–7). Preliminary registry data for 2003 indicate that in the United States, 43% of patients with non–ST-segment elevation acute coronary syndromes are cared for primarily by noncardiologists. Therefore, general internists and emergency department physicians are pivotal in stabilizing such patients. The use of early invasive strategies has led to the debate over whether aggressive use of antiplatelet agents and new thrombin inhibitors should be uniformly applied to the “upstream” (before catheterization) stabilization of these

From the Duke Clinical Research Institute and Division of Cardiology, Duke University Medical Center, Durham, North Carolina. Requests for reprints should be addressed to Abdallah G. Rebeiz, MD, Duke Clinical Research Institute, P.O. Box 17969, Durham, North Carolina 27715, or [email protected]. © 2004 by Excerpta Medica Inc. All rights reserved.

ANTITHROMBIN THERAPIES Unfractionated Heparin For many years, combination therapy with antithrombins and aspirin was the standard therapy for patients with non–ST-segment elevation acute coronary syndromes (4,8,9). Multiple randomized clinical trials comparing combination therapy with aspirin alone in patients with unstable coronary syndromes found that combination therapy decreased the risk of adverse events, although not significantly (4,8,10 –13). A meta-analysis of these trials showed a consistent reduction in the risk of death or myocardial infarction in patients treated with combination therapy (relative risk [RR] ⫽ 0.67; 95% confidence interval [CI]: 0.44 to 1.02) (14), suggesting that patients with non–ST-segment elevation acute coronary syndromes should be treated with antithrombin and antiplatelet therapy. A substantial failure rate was observed with unfractionated heparin, however, probably due to its unpredictable extent of anticoagulation (15), the difficulty in promptly reaching activated partial thromboplastin time targets (16), neutralization by protein binding and activated platelets (17,18), and a re0002-9343/04/$–see front matter 119 doi:10.1016/j.amjmed.2003.09.028

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al

bound in adverse events after discontinuing unfractionated heparin (19,20).

Low Molecular Weight Heparins Given the limitations of unfractionated heparin, interest in alternative antithrombins is growing. Low molecular weight heparins offer several advantages: a more predictable anticoagulation effect with a higher anti–factor Xa: IIa ratio that obviates anticoagulation monitoring (21), resistance to platelet factor 4 inhibition (17,18), and a lower incidence of heparin-induced thrombocytopenia (22). Patients with non–ST-segment elevation acute coronary syndromes have had better outcomes with enoxaparin than with unfractionated heparin treatment (23,24). In the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events (ESSENCE) trial (24), which randomly assigned 3171 patients to subcutaneous enoxaparin or intravenous unfractionated heparin, the composite endpoint of death, myocardial infarction, and recurrent angina at 30 days was significantly lower in the enoxaparin group than in the unfractionated heparin group (19.8% vs. 23.3%, P ⫽ 0.02). The Thrombolysis In Myocardial Infarction (TIMI) 11B trial had similar results (23). In a meta-analysis of these two trials, the beneficial effects of enoxaparin reached statistical significance as early as 2 days after random assignment (25). In the combined ESSENCE and TIMI 11B cohorts, the early absolute difference of almost 2.5% in event rates with enoxaparin compared with unfractionated heparin was maintained at 1-year follow-up (26). Based on these results, the recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines state that “enoxaparin is preferable to [unfractionated heparin] as an anticoagulant in patients with unstable angina/[non– ST-elevation myocardial infarction], in the absence of renal failure and unless coronary artery bypass grafting is planned within 24 hours” (27). The protocols for both ESSENCE and TIMI 11B dictated that percutaneous coronary intervention be performed with open-label unfractionated heparin as the procedural antithrombotic (23,24), which may explain why despite substantial and consistent benefit, enoxaparin use in unstable coronary syndromes is limited in clinical practice (28). During percutaneous coronary intervention, the use of enoxaparin, alone (29) or in combination with glycoprotein IIb/IIIa inhibitors (30), is safe and effective. Enoxaparin is also safe and effective for patients with non–STsegment elevation acute coronary syndromes who are in transition from upstream medical therapy to percutaneous coronary intervention (Figure 1) (31,32). The Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is a large, ongoing randomized trial 120

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

Figure 1. Proposed dose-transition algorithm for patients with non–ST-segment elevation acute coronary syndromes treated with 1 mg/kg of subcutaneous enoxaparin and requiring percutaneous coronary intervention. Cath Lab ⫽ catheterization laboratory; IV ⫽ intravenous; PCI ⫽ percutaneous coronary intervention.

comparing enoxaparin with unfractionated heparin in patients treated with an early invasive strategy (33). The use of other low molecular weight heparins such as dalteparin (34) and nadroparin (35) in managing patients with non–ST-segment elevation acute coronary syndromes has also been studied. The FRagmin during InStability in Coronary artery disease (FRISC) trial showed that dalteparin was superior to placebo (34), whereas the FRagmin In unstable Coronary artery disease (FRIC) trial reported no differences between dalteparin and unfractionated heparin in the composite of death, myocardial infarction, and recurrent ischemia (36). Similarly, a randomized trial involving patients with unstable coronary syndromes found no difference in adverse events between nadroparin and unfractionated heparin (35). Even though a recent systematic overview of 31 trials and registries concluded that low molecular weight heparins are safe and effective in the management of non–ST-segment elevation acute coronary syndromes and percutaneous coronary intervention, there does not appear to be a class effect, since only enoxaparin has demonstrated consistent benefit (37).

Direct Thrombin Inhibitors The use of direct thrombin inhibitors during early pharmacologic management of unstable coronary syndromes (38) and during percutaneous coronary intervention has been studied extensively (38 – 40). The Global Use of Strategies To Open occluded coronary arteries (GUSTO)-IIb trial randomly assigned a cross-section of patients who had acute coronary syndromes, with and without persistent ST-segment elevation, to unfractionated heparin or recombinant hirudin for 3 to 5 days (38). Among patients with non–ST-segment elevation acute coronary syndromes, the incidence of adverse events at 30 days was similar in both treatment arms; however, hirudin therapy was associated with significantly more

Volume 116

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al

hemorrhagic complications requiring transfusion (9.7% vs. 8.6%, P ⫽ 0.04), as well as intracranial bleeding events (0.2% vs. 0.02%, P ⫽ 0.06), as compared with unfractionated heparin. GUSTO-IIb patients who underwent early percutaneous coronary intervention during study drug infusion had a significantly reduced incidence of myocardial infarction with hirudin than with heparin at 30 days (4.9% vs. 7.6%, P ⫽ 0.04) and 6 months (6.7% vs. 9.7%, P ⫽ 0.04) (41). However, patients treated with hirudin had a higher incidence of bleeding during the hospitalization period. Thus, hirudin appears to have a modest clinical benefit but a narrow window of safety. In a systematic overview of 11 randomized trials that compared direct thrombin inhibitors with unfractionated heparin in patients with a range of illnesses (e.g., ST-segment elevation myocardial infarction, unstable angina, and percutaneous coronary intervention), those treated with direct thrombin inhibitors had a significantly lower incidence of death or myocardial infarction at 7 days (P ⫽ 0.001) and 30 days (P ⫽ 0.02). This benefit was primarily due to a reduction in myocardial infarction, with no significant effect on mortality (42). The TIMI 8 trial compared bivalirudin with unfractionated heparin in patients with unstable angina. The trial was terminated early by the sponsor because the development of bivalirudin was suspended. Still, among the 133 enrolled patients, bivalirudin was associated with a lower incidence of death or myocardial infarction than was unfractionated heparin (2.9% vs. 9.2%, P ⫽ 0.16) at 14 days after treatment (43). The role of bivalirudin in the early management of patients with non–ST-segment elevation acute coronary syndromes should be studied prospectively, especially since there are promising data on the efficacy and safety of bivalirudin during elective percutaneous coronary intervention (44).

Factor Xa Inhibitors A class of synthetic antithrombotics that selectively inhibit factor Xa has recently emerged (45– 48). Fondaparinux is a pentasaccharide that inhibits factor Xa via antithrombin III. Fondaparinux compares similarly with enoxaparin in preventing and treating venous thromboembolic disease (49,50) and is safe for treating ST-segment elevation (51). Another factor Xa inhibitor, DX9065a, is the first of a class of small-molecule, direct inhibitors, and has been shown to be safe for patients with stable coronary artery disease (52). Preliminary data indicate that DX-9065a is also safe and effective in patients scheduled for percutaneous coronary intervention.

ANTIPLATELET AGENTS Platelet activation and aggregation are pivotal in the pathophysiology of acute coronary syndromes (53). As-

pirin, a platelet cyclooxygenase inhibitor (54), has beneficial effects in patients with coronary events, including suspected myocardial infarction and unstable angina (55,56). Therefore, all patients with suspected unstable coronary syndrome should receive aspirin. However, increasing evidence suggests that “resistance” to aspirin— defined as failure of 325 mg of aspirin daily for at least 7 days to suppress agonist-induced platelet aggregation— portends an increased risk of adverse events in stable patients with cardiovascular disease (57). The antiplatelet effect from aspirin is inadequate in 5% to 45% of patients; estimates vary based on measurement of platelet aggregation (58,59). The prevalence of aspirin resistance as measured by optical platelet aggregometry is 5.2% (57). Whether resistance to aspirin leads to poor outcomes in patients with non–ST-segment elevation acute coronary syndromes is unknown. The platelet inhibitor clopidogrel has demonstrated notable variability in patients undergoing percutaneous coronary intervention (60), but it is unclear whether some patients are resistant to clopidogrel.

Glycoprotein IIb/IIIa Receptor Inhibitors In the final step of platelet aggregation, fibrinogen crosslinks platelets via surface glycoprotein IIb/IIIa receptors (2,3). Inhibitors of these receptors reduce adverse cardiac events in patients with non–ST-segment elevation acute coronary syndromes (61,62) and those undergoing percutaneous coronary intervention (63,64). A meta-analysis of 19 randomized controlled trials showed that glycoprotein IIb/IIIa inhibitors confer a marked and sustained decrease in mortality among patients undergoing percutaneous coronary intervention (65). These data, coupled with evidence favoring an early invasive approach to treating patients with non–ST-segment elevation acute coronary syndromes (5–7), suggest that these agents are ideal for aggressive platelet inhibition in early stabilization and subsequent intervention. In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, the addition of tirofiban to standard medical therapy led to a significant reduction in the 7-day frequency of death, myocardial infarction, or recurrent ischemia (12.9% vs. 17.9%, P ⫽ 0.004), a benefit that persisted at 30 days and at 6 months (61). Patients who underwent percutaneous coronary intervention derived the most benefit. The rate of death or myocardial infarction was reduced significantly during the initial protocol-mandated 48-hour waiting period before angiography and revascularization (0.9% in the tirofiban-plus-heparin arm vs. 2.6% in the heparin-only arm, P ⫽ 0.01). Reducing adverse events in the hours preceding revascularization is critical; refractory ischemia in the 48 hours after therapy has been associated

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

Volume 116 121

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al

Figure 2. Kaplan-Meier estimates of the censored occurrence of death or myocardial infarction showing significant curve divergence before percutaneous coronary intervention (during the upstream period of medical treatment), with further benefit after coronary intervention. GP ⫽ glycoprotein; PCI ⫽ percutaneous coronary intervention. Reproduced with permission from Boersma et al (66).

with a twofold risk of death or myocardial infarction at 30 days. In the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression using Integrilin Therapy (PURSUIT) trial, early glycoprotein IIb/IIIa inhibition with eptifibatide led to significantly fewer deaths or myocardial infarctions at 30 days compared with placebo (14.2% vs. 15.7%, P ⫽ 0.04). Among patients who underwent percutaneous coronary intervention within 72 hours, eptifibatide provided greater benefit than did placebo. In this cohort, the rate of death or myocardial infarction was lowest relative to placebo when eptifibatide treatment preceded percutaneous revascularization (1.7% vs. 5.5%, P ⬍0.001), supporting the use of early aggressive platelet glycoprotein IIb/IIIa receptor inhibition in patients with unstable coronary syndromes (62). A meta-analysis of the C7E3 Fab AntiPlatelet Therapy in Unstable REfractory angina (CAPTURE), PRISM-PLUS, and PURSUIT trials determined that patients treated with a glycoprotein IIb/IIIa inhibitor before revascularization had a 34% relative reduction in the rate of death or myocardial infarction (P ⫽ 0.001). Furthermore, upstream use of glycoprotein IIb/IIIa inhibitors in managing non–ST-segment elevation acute coronary syndromes was associated with a 41% relative reduction in death or myocardial infarction within 48 hours after percutaneous coronary intervention (Figure 2) (66). Paradoxically, in the GUSTO IV–ACS trial, patients with unstable coronary syndromes did not benefit from either a 24- or 48-hour infusion of abciximab (67). However, the study protocol prohibited early coronary angiography during the study drug infusion, whereas in trials such as PRISM-PLUS and PURSUIT, early catheterization and percutaneous coronary intervention were 122

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

performed during study drug infusions. The ACC/AHA guidelines discourage abciximab use in patients with unstable coronary syndromes who will not undergo percutaneous coronary intervention (class III) (27). In a metaanalysis of all major trials (including GUSTO IV–ACS) addressing glycoprotein IIb/IIIa inhibition in patients with non–ST-segment elevation acute coronary syndromes, glycoprotein IIb/IIIa inhibitors were associated with a significant reduction in death or myocardial infarction at 5 days (5.7% vs. 6.9%, P ⫽ 0.0003) and 30 days (10.8% vs. 11.8%, P ⫽ 0.02) as compared with placebo (68). The benefits of early glycoprotein IIb/IIIa inhibitor use extends to patients with non–ST-segment elevation acute coronary syndromes who require surgical revascularization. In PURSUIT (69), patients treated with eptifibatide instead of placebo before undergoing coronary artery bypass grafting had a significantly reduced incidence of death or myocardial infarction at 6 months (27.6% vs. 32.7%, P ⫽ 0.03). Data from a U.S. registry of more than 60,000 patients suggest that only 25% of eligible patients with non–STsegment elevation myocardial infarction receive glycoprotein IIb/IIIa inhibitors (70). Those treated early with these agents had lower unadjusted in-hospital mortality than did those who received placebo (3.3% vs. 9.6%, P ⬍0.0001). Furthermore, mortality in these patients remained significantly lower after adjustment for patient risk, treatment propensity, and hospital characteristics (odds ratio ⫽ 0.88; 95% CI: 0.79 to 0.97).

Clopidogrel Clopidogrel, an oral antiplatelet agent from the thienopyridine family, irreversibly inhibits the platelet adenosine diphosphate receptor. Clopidogrel and aspirin are synergistic (71,72). When given for 4 weeks following percutaneous coronary intervention, thienopyridines such as clopidogrel or ticlopidine reduce postprocedural adverse events (73). Use of clopidogrel following coronary intervention is standard practice. In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12,562 patients with non– ST-segment elevation acute coronary syndromes received aspirin with either clopidogrel or placebo for 3 to 12 months (73,74). Clopidogrel was started immediately upon presentation with unstable coronary symptoms, irrespective of planned treatment strategy. Patients did not receive upstream treatment with glycoprotein IIb/IIIa inhibitors. The rate of death, myocardial infarction, or stroke was lower in the clopidogrel arm than the placebo arm at 30 days (RR ⫽ 0.79; 95% CI: 0.67 to 0.92), a benefit that persisted at 1 year (9.3% vs. 11.4%, P ⬍0.001), regardless of whether or not patients underwent coronary revascularization following randomization (74).

Volume 116

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al

Figure 3. Kaplan-Meier estimates of all-cause mortality at 1 year for patients enrolled in the FRagmin during InStability in Coronary artery disease (FRISC) II trial. CI ⫽ confidence interval; RR ⫽ relative risk. Reproduced with permission from Elsevier (Lancet. 2000;356:9 –16).

Among the 2658 patients in the CURE trial who underwent percutaneous coronary intervention, clopidogrel treatment prior to coronary intervention significantly reduced the combined incidence of death, myocardial infarction, and urgent target vessel revascularization at 30 days compared with placebo (4.5% vs. 6.4%, P ⫽ 0.03). Since all patients undergoing coronary intervention received open-label clopidogrel for 4 weeks following percutaneous revascularization, the beneficial effect was associated solely with pretreatment with clopidogrel (75). However, this analysis has several limitations: the study was limited to a patient subgroup and was not a randomized trial per se; percutaneous coronary intervention was performed at the treating physician’s discretion; and most patients did not receive platelet glycoprotein IIb/IIIa inhibitors. Clopidogrel pretreatment was supported in the Clopidogrel for Reduction of Events During Observation (CREDO) trial, in which clopidogrel loading at least 6 hours before percutaneous coronary intervention was observed to be most effective (76). Clopidogrel loading doses of 450 mg to 600 mg are well tolerated and achieve maximum antiplatelet activity more rapidly than 300-mg doses (77,78). Use of a high loading dose is reasonable when given fewer than 6 hours prior to percutaneous coronary intervention. The incidence of major bleeding among patients in the CURE trial was higher among patients assigned to clopidogrel than those taking placebo (3.7% vs. 2.7%, P ⫽ 0.001) (74). Among those who underwent coronary artery bypass grafting, 1.3% of clopidogrel-treated patients had major bleeding compared with 1.1% of placebo patients. When the study drug was discontinued more than 5 days before surgery, the rates of major hemorrhagic events within 7 days after coronary artery bypass grafting were comparable. However, major bleeding rates among

patients who discontinued the study drug fewer than 5 days before surgery were 9.6% for the clopidogrel group and 6.3% for the placebo group (P ⫽ 0.06). The increased bleeding rates have generated debate about using clopidogrel in the initial management of patients with non–ST-segment elevation acute coronary syndromes. Clopidogrel pretreatment for a median of 6 days before percutaneous coronary intervention is associated with a 1.5% absolute reduction in the incidence of myocardial infarction before revascularization (P ⫽ 0.04) and a 1.7% reduction in the 30 days following intervention (75). However, in the United States, 10% to 20% of patients with acute coronary syndromes undergo coronary artery bypass grafting during the index hospitalization, with surgery a median of fewer than 4 days after admittance (79). In the CURE cohort (80), the composite endpoint of death, myocardial infarction, stroke, and severe ischemia at 24 hours was reduced significantly in the clopidogrel group as compared with in the placebo group (RR ⫽ 0.66; P ⬍0.01). How early treatment with clopidogrel affects patients in the setting of routine coronary angiography during the 24 to 48 hours after admission remains unknown. The ACC/AHA guidelines recommend that patients with non–ST-segment elevation acute coronary syndromes who undergo catheterization within 24 to 36 hours of admission should not receive clopidogrel until it is certain that coronary artery bypass grafting will not be performed within the following several days (27).

CARDIAC CATHETERIZATION The conservative strategy of treating patients with non– ST-segment elevation acute coronary syndromes consists of medical management, whereas coronary angiography is reserved for patients with spontaneous or inducible ischemia. The early invasive approach consists of routine cardiac catheterization and revascularization during the index hospitalization. In earlier clinical trials, early invasive strategies did not reduce adverse cardiac events significantly (81,82). However, interventional cardiology and the management of acute coronary syndromes have evolved with the use of coronary stents and new adjunctive pharmacotherapy, and recent clinical trials have consistently demonstrated that an early invasive approach benefits patients with non–ST-segment elevation acute coronary syndromes (5–7). In the FRISC II trial (5), an early invasive strategy resulted in improved outcomes compared with a conservative approach, with a 6-month rate of death or myocardial infarction of 9.4% versus 12.1% (P ⫽ 0.03). The early invasive strategy resulted in significantly lower mortality at 1 year (2.2% vs. 3.9%, P ⫽ 0.02) and 2 years (3.7% vs.

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

Volume 116 123

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al

Table. Clinical Trials Comparing Conservative and Early Invasive Approaches in Treating Patients with Non–ST-segment Elevation Acute Coronary Syndromes No. of Patients

Trial (Reference)

Inclusion Criteria

Antithrombin

Glycoprotein IIb/ IIIa Inhibitor

TIMI IIIB (82)

1473

Chest pain and ECG changes other than persistent ST-segment elevation, or previously documented coronary artery disease

Unfractionated heparin to target activate partial thromboplastin time ⫽ 1.5 to 2.0 times control

None

VANQWISH (81)

920

Non-Q-wave myocardial infarction

Dose-adjusted intravenous unfractionated heparin

None

FRISC II (5)

2457

Chest pain and either (a) ECG changes other than persistent ST-segment elevation or (b) positive markers

Subcutaneous dalteparin

None

TACTICS-TIMI 18 (6)

2220

Chest pain and (a) ECG changes other than persistent STsegment elevation or (b) positive markers

Intravenous unfractionated heparin

Tirofiban at randomization

RITA 3 (7)

1810

Chest pain and ECG changes other than persistent ST-segment elevation

Subcutaneous enoxaparin

None

ISAR-COOL (*)

410

Chest pain and (a) ECG changes other than persistent STsegment elevation or (b) positive troponin levels

Unfractionated heparin

Tirofiban at randomization

ECG ⫽ electrocardiographic; FRISC ⫽ FRagmin during InStability in Coronary artery disease; ISAR-COOL ⫽ Intracoronary Stenting with Antithrombotic Regimen Cooling-Off; NS ⫽ not significant; RITA ⫽ Randomised Intervention Treatment of Angina; TACTICS ⫽ Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy; TIMI ⫽ Thrombolysis In Myocardial Infarction; VANQWISH ⫽ The Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital. * ISAR-COOL Investigators. Extended antithrombotic pretreatment in patients with unstable coronary syndromes treated invasively—the Intracoronary Stenting with Antithrombotic Regimen Cooling-Off (ISAR-COOL) Trial. Presented at: American Heart Association Scientific Sessions; November 20, 2002; Chicago, Illinois.

5.4%, P ⫽ 0.04) (83), which is a pivotal finding, especially since event rates continued to diverge (Figure 3) (84). These results have been supported by many large, randomized clinical trials of early coronary angiography and adverse events in patients with non–ST-segment elevation acute coronary syndromes (Table) (6,7). However, there is a pivotal upstream time window during which platelet or thrombin activation in the unstable plaque needs to be inhibited to reduce early adverse events and optimize early revascularization.

RISK STRATIFICATION Patients with acute coronary syndromes without ST-segment elevation present with a range of symptoms, from chest discomfort with normal electrocardiograms 124

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

(ECGs) and serum markers of myocardial necrosis to frank non–ST-segment elevation myocardial infarction. Early risk stratification has become pivotal in determining the therapies for these conditions. As a general rule, patients with high-risk features benefit most from upstream aggressive pharmacologic therapies and an early invasive strategy. The following features portend a worse outcome in non–ST-segment elevation acute coronary syndromes: elevated serum levels of troponin (1,85,86) or creatine kinase-MB, ST-segment changes (1,86,87), increasing age, prior revascularization, and evidence of heart failure (1,88). Patients with elevated troponin levels benefit most from therapies such as low molecular weight heparins (89), enoxaparin (85), or glycoprotein IIb/IIIa inhibitors (90,91). They are also more likely to benefit from early

Volume 116

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al

Median Time to Catheterization (Invasive Arm)

Rates of Primary Endpoint

Primary Endpoint

P Value

1.5 days

Death, myocardial infarction, or positive exercise treadmill test at 6 weeks

Invasive: 18.1% Conservative: 16.2%

NS

2 days

Death or myocardial infarction at 23 months

Invasive: 32.9% Conservative: 30.3%

NS

4 days

Death or myocardial infarction at 6 months

Invasive: 9.4% Conservative: 12.1%

0.03

22 hours

Death, myocardial infarction, or rehospitalization for acute coronary syndromes at 6 months

Invasive: 15.9% Conservative: 19.4%

0.03

2 days

Death, myocardial infarction, or refractory ischemia at 4 months

Invasive: 9.6% Conservative: 14.5%

0.001

2.4 hours

Death or myocardial infarction at 30 days

Invasive: 5.9% Conservative: 11.6%

0.04

coronary angiography and subsequent revascularization than are patients with normal troponin levels (86,92). Serum markers of inflammation also have independent prognostic value in patients with unstable coronary syndromes (93–95). Among patients with unstable angina, elevated C-reactive protein level is an independent predictor of adverse cardiac events (96). New markers of inflammation and platelet activation, such as soluble CD40 ligand, can identify high-risk patients who derive particular benefit from aggressive platelet inhibition (95). Such assays may help develop customized, patient-specific therapies for non–ST-segment elevation acute coronary syndromes. The development of genetic assays should also lead to improved therapies. A substantial number of patients with non–ST-segment elevation acute coronary syndromes present with normal ECGs and serum marker levels. For these patients, there are limited data regarding the effectiveness of aggressive antiplatelet and antithrombotic regimens and an early invasive strategy. Current data support conservative pharmacologic management, including aspirin and heparin, in these patients. Coronary angiography should be reserved for those exhibiting ischemia either on provocative testing or sponta-

neously despite anti-ischemic therapy. A FRISC II substudy suggests that elevated serum interleukin 6 levels identify a high-risk patient subgroup that benefits particularly from early coronary angiography (97). Whether serum assays of inflammatory markers should be used routinely remains to be studied prospectively.

CONCLUSION The increasing number of antithrombotic and antiplatelet agents available for the treatment of unstable coronary syndromes adds to the complexity of early pharmacologic management of patients with non–ST-segment elevation acute coronary syndromes. Thus, the internist or emergency department physician now faces a number of decisions when integrating current data into clinical practice. When interpreting the results of large studies, a careful analysis of different endpoints used is essential. During the last decade, randomized trials have used different primary endpoints. The primary endpoint of the CURE trial, for instance, was a combination of death, myocardial infarction, and stroke (74), whereas those for trials of plate-

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

Volume 116 125

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al

7.

8.

9.

10.

Figure 4. Proposed algorithm for the early medical and interventional management of patients with non–ST-segment elevation acute coronary syndromes.

let glycoprotein IIb/IIIa inhibitors generally consisted of a combination of death, myocardial infarction, and refractory ischemia (59,62). The criteria to define nonfatal myocardial infarction endpoints have also varied. Some trials used a combination of symptoms, biomarker elevations, or ECG changes (24), whereas others required only biomarker elevation above the normal range (62). Based on available evidence, we have provided an algorithm for the early management of patients with non–STsegment elevation acute coronary syndromes (Figure 4). An approach that incorporates all evidence-based interventions should reduce adverse events and improve outcomes.

11.

12.

13.

14.

15.

16.

ACKNOWLEDGMENT We thank Dr. Jennifer King of the Duke Clinical Research Institute for editorial assistance.

17. 18.

REFERENCES 1. Braunwald E, Antman E, Beasley J, et al. ACC/AHA guidelines for the management of patients with unstable angina and non–STsegment elevation myocardial infarction. J Am Coll Cardiol. 2000; 36:970 –972. 2. Chesebro J, Fuster V. Thrombosis in unstable angina. N Engl J Med. 1992;327:192–194. 3. Fuster V, Badimon L, Badimon J, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250. 4. Theroux P, Outmet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319:1105–1111. 5. FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC II) Investigators. Invasive compared with noninvasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicentre study. Lancet. 1999; 354:708 –715. 6. The TACTICS-TIMI 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary 126

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

19.

20. 21.

22.

23.

24.

Volume 116

syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001;344:1879 –1887. Fox K, Poole-Wilson P, Henderson R, et al. Interventional versus conservative treatment for patients with unstable angina or non– ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Lancet. 2002;360:743–751. The RISC Study Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet. 1990;336:827– 830. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services. Clinical Practice Guideline Number 10: Unstable Angina: Diagnosis and Management. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services; 1994. AHCPR Publication 94-0602. Cohen M, Adams P, Hawkins L, et al. Usefulness of antithrombotic therapy in resting angina pectoris or non–Q-wave myocardial infarction in preventing death and myocardial infarction (a pilot study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group). Am J Cardiol. 1990;66:1287–1292. Cohen M, Adams P, Parry G, et al. Combination antithrombotic therapy in unstable rest angina and non–Q-wave infarction in nonprior aspirin users: primary end points analysis from the ATACS trial: Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation. 1994;89:81–88. Holdright D, Patel D, Cunningham D, et al. Comparison of the effect of heparin and aspirin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina. J Am Coll Cardiol. 1994;24:39 –45. Gurfinkel E, Manos E, Mejail R, et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol. 1995;26:313–318. Oler A, Whooley M, Oler J, et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis. JAMA. 1996;276:811–815. Granger C, Hirsh J, Califf R, et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial. Circulation. 1996;93: 870 –878. Newby L, Harrington R, Bhapkar M, et al. An automated strategy for bedside aPTT determination and unfractionated heparin infusion adjustment in acute coronary syndromes: insights from PARAGON A. J Thromb Thrombolysis. 2002;14:33–42. Hirsh J, Levine M. Low molecular weight heparin. Blood. 1992;79: 1–17. Melandri G, Semprini F, Cervi V, et al. Comparison of efficacy of low molecular weight heparin (Parnaparin) with that of unfractionated heparin in the presence of activated platelets in healthy subjects. Am J Cardiol. 1993;72:450 –454. Granger C, Miller J, Bovill E, et al. Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circulation. 1995;91: 1929 –1935. Theroux P, Waters D, Lam J, et al. Reactivation of unstable angina after discontinuation of heparin. N Engl J Med. 1992;327:141–145. Samama M, Bara L, Gerotziafas G. Mechanisms for the antithrombotic activity in man of low-molecular-weight heparins (LMWHs). Haemostasis. 1994;24:105–117. Warkentin T, Levine M, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332:1330 –1335. The TIMI 11B Investigators. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction: results of the TIMI 11B trial. Circulation. 1999;100: 1593–1601. Cohen M, Demers C, Gurfinkel E, et al. A comparison of low-

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al

25.

26.

27.

28.

29.

30.

31.

32.

33. 34.

35.

36.

37.

38.

39.

40.

41.

42.

molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337:447–452. Antman E, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non–Q-wave myocardial infarction: TIMI 11B-ESSENCE meta-analysis. Circulation. 1999; 100:1602–1608. Antman E, Cohen M, McCabe C, et al. Enoxaparin is superior to unfractionated heparin for preventing clinical events at 1-year follow-up of TIMI 11B and ESSENCE. Eur Heart J. 2002;23:308 –314. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction. Circulation. 2002;106:1893–1900. Granger C. Strategies of patient care in acute coronary syndromes: rationale for the Global Registry of Acute Coronary Events (GRACE) registry. Am J Cardiol. 2000;86:4 –9. Rabah M, Premmeneur J, Graham M, et al. Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris. Am J Cardiol. 1999;84:1391–1395. Bhatt D, Lee B, Casterella P, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol. 2003;41:20 –25. Collet J, Montalescot G, Lison L, et al. Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina pectoris. Circulation. 2001;103:658 –663. Kereiakes DJ, Montalescot G, Antman E, et al. Low-molecularweight heparin therapy for non-ST-elevation acute coronary syndromes and during percutaneous coronary intervention: an expert consensus. Am Heart J. 2002;144:615–624. The SYNERGY Executive Committee. The SYNERGY trial: study design and rationale. Am Heart J. 2002;143:952–960. The FRISC Investigators. Low-molecular-weight heparin during instability in coronary artery disease, FRagmin during InStability in Coronary artery disease (FRISC) study group. Lancet. 1996;347: 561–568. The FRAX.I.S Investigators. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non–Q-wave myocardial infarction: FRAX.I.S. Eur Heart J. 1999;20:1553–1562. The FRIC Investigators. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable CAD. Circulation. 1997;96: 61–68. Wong G, Giugliano R, Antman E. Use of low-molecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention. JAMA. 2003;289:331– 342. The GUSTO IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med. 1996;335:775–782. Serruys P, Herrman J, Simon R, et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med. 1995;333:757–763. Bittl J, Strony J, Brinker J, et al. Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or post-infarction angina. N Engl J Med. 1995;333:764 – 769. Roe M, Granger C, Puma J, et al. Comparison of benefits and complications of hirudin versus heparin for patients with acute coronary syndromes undergoing early percutaneous coronary intervention. Am J Cardiol. 2001;88:1403–1406. The Direct Thrombin Inhibitor Trialists’ Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54. 55.

56.

57.

58.

59.

results of a meta-analysis based on individual patients’ data. Lancet. 2002;359:294 –302. Antman EM, McCabe CH, Braunwald E. Bivalirudin as a replacement for unfractionated heparin in unstable angina/non–ST-elevation myocardial infarction: observations from the TIMI 8 trial. Am Heart J. 2002;143:229 –234. The REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention. JAMA. 2003;289:853–863. Petitou M, Lormeau J, Choay J. Chemical synthesis of glycosaminoglycans: new approaches to antithrombotic drugs. Nature. 1991;350:30 –33. Olson S, Bjork I, Sheffer R, et al. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions: resolution of the antithrombin conformational change contribution to heparin rate enhancement. J Biol Chem. 1992;267:12528 –12538. Kaiser B, Jeske W, Walenga J, Fareed J. Inactivation of factor Xa by the synthetic inhibitor DX-9065a causes strong anticoagulant and antiplatelet actions in human blood. Blood Coagul Fibrinol. 1999; 10:495–501. Herbert J, Petitou M, Lormeau J, et al. SR 90107A/Org31540, a novel anti-factor Xa antithrombotic agent. Cardiovasc Drug Rev. 1997;15:1–26. Turpie A, Bauer K, Eriksson B, et al. Fondaparinux vs. enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery. Arch Intern Med. 2002;162:1833–1840. The REMBRANDT Investigators. Treatment of proximal deep vein thrombosis with a novel synthetic compound (SR90107A/ ORG31540) with pure anti-factor Xa activity: a phase II evaluation. Circulation. 2000;102:2726 –2731. The PENTALYSE Investigators. A synthetic factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. The PENTALYSE study. Eur Heart J. 2001;22: 1716 –1724. Dyke C, Becker R, Kleiman N, et al. First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation. Circulation. 2002; 105:2385–2391. Willerson J, Golino P, Eidt J, et al. Specific platelet mediators and unstable coronary artery lesions: experimental evidence and potential clinical implications. Circulation. 1989;80:198 –205. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med. 1994;330: 1287–1294. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy. I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81–106. Antiplatelet Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324:71–86. Gum P, Kottke-Marchant K, Welsh P, et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol. 2003; 41:961–965. Gum P, Kottke-Marchant K, Poggio E, et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol. 2001;88:230 –235. Pappas J, Westengard J, Bull B. Population variability in the effect of aspirin on platelet function. Implications for clinical trials and therapy. Arch Pathol Lab Med. 1994;118:801–804.

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

Volume 116 127

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al 60. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107:2908 –2913. 61. The PRISM-PLUS Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms. N Engl J Med. 1998;338:1488 –1497. 62. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med. 1998;339:436 –443. 63. The EPISTENT Investigators. Randomised placebo-controlled and balloon angioplasty controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb-IIIa blockade. Lancet. 1998;352:87–92. 64. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet. 2000;356:2037–2044. 65. Karvouni E, Katritsis D, Ioannidis J. Intravenous glycoprotein IIb/ IIIa receptor antagonists reduce mortality after percutaneous coronary intervention. J Am Coll Cardiol. 2003;41:26 –32. 66. Boersma E, Akkerhuis M, Theroux P, et al. Platelet glycoprotein IIb/IIIa receptor inhibition in non–ST-elevation acute coronary syndromes. Early benefit during medical treatment only, with additional protection during coronary intervention. Circulation. 1999;100:2045–2048. 67. Simoons ML, Armstrong P, Califf R, et al, the GUSTO IV–ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet. 2001;357:1915–1924. 68. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet. 2002;359:189 – 198. 69. Marso S, Bhatt D, Roe M, et al. Enhanced efficacy of eptifibatide administration in patients with acute coronary syndrome requiring in-hospital coronary artery bypass grafting. Circulation. 2000;102: 2952–2958. 70. Peterson E, Pollack CV Jr, Roe M, et al. Early use of glycoprotein IIb-IIIa inhibitors in non–ST-elevation acute myocardial infarction: observations from the National Registry of Myocardial Infarction 4. J Am Coll Cardiol. 2003;42:45–53. 71. Moshfegh K, Redondo M, Julmy F, et al. Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy. J Am Coll Cardiol. 2000;36:699 –705. 72. Bossavy J, Thalamas C, Sagnard L, et al. A double-blind randomized comparison of combined aspirin and ticlopidine therapy versus aspirin or ticlopidine alone on experimental arterial thrombogenesis in humans. Blood. 1998;92:1518 –1525. 73. Mehta S, Yusuf S, on behalf of the CURE Investigators. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme: rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J. 2000;21:2033–2041. 74. The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494 –502. 75. Mehta S, Yusuf S, Peters R, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527–533. 128

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

76. Steinhubl S, Berger P, Mann J, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. JAMA. 2002;288:2411–2420. 77. Seyfarth HJ, Koksch M, Roethig G, et al. Effect of 300- and 450-mg clopidogrel loading doses on membrane and soluble P-selectin in patients undergoing coronary stent implantation. Am Heart J. 2002;143:118 –123. 78. Muller I, Seyfarth M, Rudiger S, et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart. 2001;85:92–93. 79. Lincoff A, Harrington R, Califf R, et al. Management of patients with acute coronary syndromes in the United States by platelet glycoprotein IIb/IIIa inhibition: receptor suppression using integrilin therapy (PURSUIT) trial. Circulation. 2000;102:1093– 1100. 80. Yusuf S, Mehta S, Zhao F, et al. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation. 2003;107: 966 –972. 81. Boden W, O’Rourke R, Crawford M, et al. Outcomes in patients with acute non–Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. N Engl J Med. 1998;338:1785–1792. 82. The TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non–Q-wave myocardial infarction. Results of the TIMI IIIB trial. Circulation. 1994;89:1545–1556. 83. Lagerqvist B, Husted S, Kontny F, et al, for the FRISC II Investigators. A long-term perspective on the protective effects of an early invasive strategy in unstable coronary artery disease. J Am Coll Cardiol. 2002;40:1902–1914. 84. Wallentin L, Lagerqvist B, Husted S, et al. Outcome at 1 year after an invasive compared with a noninvasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial. Lancet. 2000;356:9 –16. 85. Morrow D, Antman E, Tanasijevic M, et al. Cardiac troponin I for stratification of early outcomes and the efficacy of enoxaparin in unstable angina: a TIMI 11 B substudy. J Am Coll Cardiol. 2000;36: 1812–1817. 86. Diderholm E, Andren B, Frostfeldt G, et al. The prognostic and therapeutic implications of increased troponin T levels and ST depression in unstable coronary artery disease: the FRISC II invasive troponin T electrocardiogram substudy. Am Heart J. 2002;143: 760 –767. 87. Sabatine M, McCabe C, Morrow D, et al. Identification of patients at high risk for death and cardiac ischemic events after hospital discharge. Am Heart J. 2002;143:966 –970. 88. Boersma E, Pieper K, Steyerberg E, et al. Predictors of outcome in patients with acute coronary syndromes without persistent STsegment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation. 2000;101: 2557–2567. 89. Lindahl B, Venge P, Wallentin L, the FRISC Study Group. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. J Am Coll Cardiol. 1997;29:43–48. 90. Heeschen C, Hamm C, Goldmann B, et al. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Lancet. 1999;354:1757–1762. 91. Newby L, Ohman E, Christenson R, et al. Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin T-positive status: the PARAGON-B troponin T substudy. Circulation. 2001;103:2891–2896. 92. Morrow D, Cannon C, Rifai N, et al. Ability of minor elevations of troponin I and T to predict benefit from an early invasive strategy in

Volume 116

Management of Non–ST-segment Elevation Acute Coronary Syndromes/Rebeiz et al patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA. 2001;286:2405– 2412. 93. Toss H, Lindahl B, Siegbahn A, et al. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. Circulation. 1997;96:4204 –4210. 94. Lenderink T, Boersma E, Heeschen C, et al. Elevated troponin T and C-reactive protein predict impaired outcome for 4 years in patients with refractory unstable angina, and troponin T predicts benefit of treatment with abciximab in combination with PTCA. Eur Heart J. 2003;24:77–85.

95. Heeschen C, Dimmeler S, Hamm C, et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med. 2003;348:1104 –1111. 96. Zebrack J, Anderson J, Maycock C, et al. Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction. Am J Cardiol. 2002;82:145–149. 97. Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. JAMA. 2001;286:2107–2113.

January 15, 2004

THE AMERICAN JOURNAL OF MEDICINE威

Volume 116 129