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Review |

New Approaches to Diagnosis and Management of Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction FREE

Robert A. O'Rourke, MD; Judith S. Hochman, MD; Marc C. Cohen, MD; Charles L. Lucore, MD; Jeffrey J. Popma, MD; Christopher P. Cannon, MD
[+] Author Affiliations

From the Divisions of Cardiology, Department of Medicine, University of Texas Health Science Center at San Antonio (Dr O'Rourke), Roosevelt Hospital, New York, NY (Dr Hochman), Hahnemann University Hospital, Philadelphia, Pa (Dr Cohen), and Brigham and Women's Hospital, Boston, Mass (Drs Popma and Cannon); and Prairie Cardiovascular Consultants, Ltd, Springfield, Ill (Dr Lucore). Dr O'Rourke has received research grants from Merck & Co, Inc, Pfizer & Co, Inc, DuPont Pharmaceuticals Company and Fujisawa Healthcare, Inc, and Aventis Pharmaceutical Company; Dr Hochman has received research grants from Merck & Co, Inc, Cor Therapeutics, Centocor, Inc, and Rhone-Poulenc Pharmaceutical Company; Dr Cohen has received grant and research support from Rhone-Poulenc Pharmaceutical Company; Dr Lucore has served as a consultant and participated on the speaker's bureau for Merck & Co, Inc, Eli Lilly and Company, Centocor, Inc, and Genentech, Inc, for continuing medical education programs and database studies in his institution; and Dr Cannon currently receives research grant support through the Department of Medicine of Brigham and Women's Hospital from Dade Behring, Merck & Co, Inc, Aventis Pharmaceutical Company, Bristol-Myers Squibb, and COR Therapeutics, Inc; is on the speaker bureau for Aventis Pharmaceutical Company, Bristol-Myers Squibb, Centocor, Inc, COR Therapeutics, Inc, Eli Lilly and Company, Merck & Co, Inc, and Sanofi, Inc; and has received honoraria for preparation of educational materials from Centocor, Inc, Eli Lilly and Company, Excerpta Medica, Ingenix, Inc, and Merck & Co, Inc.


Arch Intern Med. 2001;161(5):674-682. doi:10.1001/archinte.161.5.674.
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Recently, it has been demonstrated in multiple clinical research studies that non–Q-wave myocardial infarction shares many of the features of unstable angina pectoris and that both diseases initially are managed similarly. Important new antiplatelet drugs (glycoprotein IIb-IIIa inhibitors) and antithrombin agents (low-molecular-weight heparin) are currently recommended for patients with unstable angina pectoris/non–ST-segment elevation MI who are at high or intermediate risk on the basis of symptoms, electrocardiographic findings, and the presence or absence of serum markers (eg, troponin I, troponin T, and creatine kinase-MB). This review provides important information concerning the results of clinical studies of glycoprotein IIb-IIIa inhibitors (tirofiban hydrochloride and eptifibatide) when used with unfractionated heparin in patients with this syndrome or with low-molecular weight heparin (enoxaparin sodium) in similar patients. The Thrombolysis in Myocardial Infarction IIIB, Veterans Affairs Non–Q-Wave Infarction Studies in Hospital, and Fast Revascularization During Instability in Coronary Artery Disease II studies evaluating a conservative, ischemia-guided approach vs an early aggressive approach to such patients are presented, with a practical algorithm for treating such patients.

Figures in this Article

In 1994, the Agency for Health Care Policy and Research sponsored the development of an unstable angina guideline to "define diagnostic and management strategies likely to maximize therapeutic benefit for patients with unstable angina."1 Since then, greater understanding of risk factors in the setting of unstable angina pectoris (UAP) has enhanced our insight about how UAP should be managed. It is also now accepted that patients with non–Q-wave myocardial infarction (NQMI) share many similarities to patients with UAP, and thus, patients with non–ST-segment elevation ischemia are approached as a single (if still heterogeneous) group in terms of clinical management. A new guideline for the management of UAP and non–ST-segment elevation MI (non-STEMI) was published by the American College of Cardiology/American Heart Association in September 2000.2

Concurrent with this better understanding of UAP, important new agents with effects on platelet aggregation and thrombosis have become available and approved for the management of acute coronary syndromes (ACS). These include several platelet glycoprotein (Gp)IIb-IIIa receptor antagonists—tirofiban hydrochloride, eptifibatide, and abciximab—and a low-molecular-weight (LMW) heparin, enoxaparin sodium.

This brief review is intended to provide the practicing physician with practical information about how the UAP guidelines can be used by addressing how new approaches to risk stratification can be used to refine management strategies; it assesses the utility and role of therapies in UAP/non-STEMI on the basis of levels of evidence derived from clinical trials. New treatment algorithms are proposed that reflect improved understanding of contributors to risk in UAP/non-STEMI and incorporate recently approved pharmacological agents that have demonstrated efficacy in this clinical setting.

Erosion, fissuring, or rupture of an atherosclerotic plaque is the signal event in ACS. Immediately after plaque disruption, platelets adhere to the site of injury by means of specific Gp receptors to collagen and von Willebrand factor. This results in platelet activation, with a change in the platelets' shape, the release of storage granules that contain platelet agonists such as adenosine diphosphate and thromboxane A2, and a conformational change in the platelet fibrinogen receptor GpIIb-IIIa.3,4 This adhesion molecule, present in large numbers on the platelet surface (approximately 40 000 per platelet to 80 000 per platelet), is a member of the integrin family—a group of similar cell-surface receptors, each of which is composed of noncovalently linked α and β transmembrane subunits.

Plaque disruption also results in the release of tissue factor, a lipoprotein produced by smooth muscle cells, macrophages, and endothelial cells into the blood. Tissue factor activates the extrinsic pathway of the coagulation cascade with the resultant generation of thrombin.5,6 Thrombin then acts on fibrinogen, initiating its conversion to fibrin, which forms the scaffolding of the developing thrombus. In addition to its role in coagulation, thrombin activates platelets, stimulating them to adhere to and potentially seal the disrupted endothelial surface.

On resting platelets, the GpIIb-IIIa receptor has a low affinity for fibrinogen. However, on platelet activation, the affinity of the GpIIb-IIIa receptor for fibrinogen increases. Each fibrinogen molecule is capable of binding to the receptors on 2 different platelets simultaneously, forming stable intercellular bridges. Platelets are thus linked to one another at the site of injury by molecules of fibrinogen. The resulting platelet plug is stabilized by strands of fibrin. Further adhesion of platelets to each other results in propagation of a platelet-rich clot, leading eventually to a reduced lumen and ischemia at rest or with minimal exertion. The critical role of the GpIIb-IIIa receptor in the final common pathway of platelet aggregation has led to the development of a number of specific and nonspecific GpIIb-IIIa receptor antagonists.

Defining the most appropriate approach to therapy requires accurate patient identification and careful stratification of risk (Table 1). When patients present with chest pain, initial electrocardiographic (ECG) findings (ST-segment depression, ST-segment elevation, or T-wave inversion), and laboratory test results (levels of creatine kinase [CK] and troponin) can provide important information to assist in the risk stratification of patients (Figure 1). In the Thrombolysis in Myocardial Infarction III (TIMI-III) registry, ST-segment deviation of at least 0.5 mm was found to be an independent predictor of death or MI at 1 year. In other previous studies, ST-segment elevation of at least 1.0 mm was an independent risk factor. New or presumably new T-wave inversion on admission electrocardiograms did not confer increased risk compared with no ECG changes in the TIMI-III registry.7 However, Savonitto et al8 studied 12 142 patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries IIB trial and found that the ECG category and CK level at admission remained highly predictive of death and MI after multivariate adjustment for the significant baseline predictors of subsequent coronary events. They showed that the ECG result and CK level on admission could identify a difference in mortality between subjects with T-wave inversion and normal CK level (1.7%) and subjects with ST-segment elevation or depression and elevated CK level (14.4%).8 However, in a Thrombin Inhibition in Myocardial Ischemia (TRIM) substudy, Holmvang and associates9 found an independent risk for subsequent MI or death in patients with UAP and T-wave inversions in 5 or more leads. In a later publication, using continuous ambulatory ECG recording, TRIM investigators reached a different conclusion.14 Although attempts have been made to find specific ECG characteristics of acute coronary ischemia in patients with left bundle-branch block, none has yet effectively stratified risk in this high-risk group.7,10

Table Graphic Jump LocationTable 1. Revised Risk Classification of Patients With UAP/Non−ST-Segment Elevation MI*
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Figure 1.

Algorithm for the assessment of patients presenting with chest pain and suspected or definite coronary artery disease. MI indicates myocardial infarction; ECG, electrocardiogram; CK-MB, creatine kinase-MB fraction; SX, symptoms; CHD Pt, patients with coronary heart disease; and ACS protocol, acute coronary syndrome protocol for patients with unstable angina or non–ST-segment elevation myocardial infarction. Stress testing indicates pharmacological stress testing (adenosine diphosphate or dipyridamole) with myocardial perfusion imaging, or dobutamine echocardiography.

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Even with an initially normal ECG, further progression of symptoms of UAP in patients with coronary heart disease or recurrent ischemia episodes in the presence of signs or symptoms of congestive heart failure (eg, third heart sound, mitral regurgitation, bibasilar rales) should be sufficient to place a patient in the ACS protocol (Figure 1).

Improved understanding of the significance of troponin levels (in particular, troponins I and T) allows for further refinement of the ACS paradigm.1113,15 In a recent analysis of data from the TIMI IIIB trial, troponin I levels provided useful prognostic information and permitted the early identification of high-risk patients.11 The mortality rate at 42 days was significantly greater in patients with troponin I levels of at least 0.4 µg/L compared with those with troponin I levels of less than 0.4 µg/L (3.7% vs 1%; P<.001). The association between elevated troponin I levels (highly sensitive for myocardial injury) and increased mortality was evident even in those patients with normal CK-MB levels. In addition, there were significant increases in mortality with increasing levels of troponin I (P<.001). A similar relationship has also been shown for troponin T.13

In the future, other biochemical markers such as C-reactive protein1618 and fibrinogen19 may also play a useful role in the assessment of risk for major cardiac events and death in the patient presenting with chest pain.

The goals of therapy in UAP/non-STEMI is to improve the balance etween myocardial oxygen supply and demand, and to prevent patients from experiencing further cardiac events related to their underlying disease and, in particular, to the recently ruptured plaque and platelet aggregation (white thrombus). A modification of existing therapeutic guidelines for the management of UAP to reflect the availability of newer antiplatelet and antithrombin drugs, including tirofiban, eptifibatide, and enoxaparin in UAP/non-STEMI is indicated in Table 2. As in the past, aspirin, β-blockers, unfractionated heparin, and intravenous (IV) nitroglycerin are administered to most patients with UAP. Angiotensin-converting enzyme inhibitors usually are added for patients with depressed left ventricular function, congestive heart failure, or diabetes. Long-acting calcium antagonists are sometimes used for refractory chest pain. Guidelines concerning the usefulness of the newer agents for particular patients, as well as for an early conservative or early invasive approach to therapy, are provided. Indications for an early invasive approach are as follows: (1) intermediate- and high-risk patients with recurrent pain, despite intensive medical therapy, or with positive results of testing for inducible ischemia; (2) intermediate- to high-risk angina in patients with previous coronary angioplasty or coronary artery bypass surgery; and (3) hemodynamic instability, congestive heart failure, and/or ejection fraction of less than 0.40.1,2,9

Table Graphic Jump LocationTable 2. Proposed Application of Antiplatelet and Antithrombin Therapy in Treatment of Patients With UAP/Non−ST Segment Elevation MI*

Considering the role of platelet activation and thrombin generation after plaque disruption in the pathogenesis of UAP/NQMI, a cornerstone of therapy in this clinical setting has been altering or preventing these responses to vascular injury with antiplatelet and antithrombin agents. The benefits of aspirin and heparin, the prototype agents used in this setting, are well established, and their use is currently standard in the management of UAP/non-STEMI; however, aspirin and heparin have shortcomings.20 Recently, new agents with antithrombin or antiplatelet activity have become available for use in the clinical setting of UAP/non-STEMI, as replacements for, or as adjuncts to, standard therapies.

The antiplatelet agent aspirin irreversibly inhibits the enzyme cyclooxygenase, thereby permanently preventing affected platelets from synthesizing thromboxane A2, a potent vasoconstrictor and stimulator of platelet aggregation. Although numerous clinical trials and a large meta-analysis support the use of aspirin for the prevention and treatment of ACS,21 this agent has well-known limitations. These include little or no effect on agonists of platelet aggregation other than thromboxane A2, failure to prevent the initial adhesion of platelets to injured endothelium, inability to prevent fibrinogen from binding to its receptor, and inhibition of prostacyclin synthesis. Even low doses of aspirin can cause significant gastric irritation and bleeding.22 Finally, in some patients, platelets do not always respond to aspirin or may exhibit enhanced aggregation with aspirin treatment; such patients who do not respond to aspirin (who may represent 30%-40% of all patients who present with ACS) may be those who have recurrent ischemic events despite aspirin therapy.23

The common antithrombin in clinical use is heparin.24 Heparin binds to antithrombin III, enhancing its ability to inactivate factor Xa and thrombin and, to a lesser extent, clotting factors IXa, XIa, and XIIa. By reducing the generation of thrombin and fibrin, this complex retards the thrombotic process. Although the efficacy of heparin in the treatment of UAP/non-STEMI has been established,25 it has several deficiencies as a therapeutic agent. The primary limitation of heparin is the highly variable dose-response relationship26; this necessitates monitoring of the patient's coagulation status and may limit therapeutic effectiveness. A further complication may result from the nonspecific binding of heparin to plasma proteins and endothelial cells, and inactivation by platelet factor 4. Furthermore, heparin can actually stimulate platelet aggregation, which may exacerbate thrombus formation. Finally, its prolonged use for several days can lead to thrombocytopenia in a small percentage of patients.

Table 3 describes the outcomes of death or MI in patients in 4 clinical trials of platelet GpIIb-IIIa antagonists in ACS.

Table Graphic Jump LocationTable 3. Outcomes of Death or MI in 4 Clinical Trials of Platelet GpIIb-IIIa Antagonists in Acute Coronary Syndromes Without PCI
Tirofiban

Tirofiban (Aggrastat) is a nonpeptide tyrosine derivative whose structure mimics the arginine-glycine-aspartic acid (RGC) by which fibrinogen binds to the IIb-IIIa receptor, thereby competing with fibrinogen for binding sites. Tirofiban inhibits platelet aggregation, depending on dose and serum concentration. Usually, it leads to more than 90% inhibition within 30 minutes of initiation of the recommended regimen. Inhibition of platelet aggregation by tirofiban is rapidly reversible. The use of tirofiban in addition to aspirin and heparin in the medical management of UAP/NQMI was examined in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial.27

The PRISM-PLUS trial examined the clinical efficacy of tirofiban vs placebo in preventing acute ischemic events in 1915 high-risk patients with UAP/NQMI.27 Patients were randomized to 1 of the following 3 treatment arms: tirofiban, tirofiban plus unfractionated heparin, or unfractionated heparin, all in the presence of aspirin, unless contraindicated.27,28 The tirofiban arm was discontinued early because of an increased 7-day mortality at an interim analysis.28 However, when given in combination with weight-adjusted heparin, tirofiban hydrochloride at a dose of 0.4 µg/kg per minute for 30 minutes followed by 0.1 µg/kg per minute reduced the 7-day composite event rate of death, infarction, or refractory angina. The mean (±SD) duration of infusion for the study drugs was 71.3 ± 20.0 hours; angiography and angioplasty were performed, when clinically indicated, after 48 hours of therapy.

In patients treated with tirofiban plus heparin, the composite primary end point of death, MI, or refractory ischemia event rate was significantly lower than in the heparin-alone group at 7 days (12.9% vs 17.9%; risk ratio, 0.68; 95% confidence interval [CI], 0.53-0.88; P = .004). The incidence of the composite end point was also reduced significantly (P = .03) in the tirofiban-plus-heparin group vs the heparin-alone group at 30 days and 6 months. For the harder composite end points of death or MI, the frequency of events was reduced significantly at 7 (P = .006) and 30 days (P = .03). The benefits of tirofiban plus heparin vs heparin alone were maintained across various subpopulations (eg, age, sex, and diagnostic status). The benefits of tirofiban plus heparin vs heparin alone were seen in patients treated medically, in patients undergoing coronary angioplasty (percutaneous coronary intervention [PCI]), and in patients undergoing coronary artery bypass graft (CABG) surgery.27

Bleeding complications and thrombocytopenia were rare, and there was no incidence of intracranial bleeding. Major bleeding according to TIMI criteria occurred in 0.8% of patients receiving heparin alone and in 1.4% of those receiving tirofiban plus heparin (P>.05). There were also no significant differences in the number of blood transfusions. Thrombocytopenia, defined as a reduction in platelet count below 90 × 109/L, was marginally higher in the tirofiban plus heparin group (1.9% vs 0.8% for heparin-alone group; P = .07), but was rapidly reversible on cessation of the infusion.

Eptifibatide

Eptifibatide (Integrilin) is a cyclic heptapeptide modeled after the snake venom disintegrin barbourin. The key structural feature of eptifibatide is a cyclic lysine-glycine-asparagine that targets the ligand-adhesions site (ie, RGD-binding sequence) of GpIIb-IIIa with high affinity. The cyclic structure of the compound helps provide stability and decrease enzymatic degradation. Like tirofiban, eptifibatide inhibits platelet aggregation in a dose-dependent and reversible manner. Eptifibatide was studied for the acute treatment of patients with UAP/NQMI in the Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial.29

In the PURSUIT trial,29 eptifibatide was compared with placebo for the acute treatment in 10 948 patients with UAP/NQMI as manifested by a short-term episode of ischemic chest pain (verified by means of ECG findings or CK-MB levels) during the previous 24 hours. Patients were randomized into 1 of the following 3 groups: high-dose eptifibatide (infusion of 180 µg/kg bolus plus 2.0 µg/kg per minute), low-dose eptifibatide (180-µg/kg bolus plus infusion of 1.3 µg/kg per minute), or placebo. Drug or placebo treatment was administered in a double-blind manner until hospital discharge of CABG or for up to 72 hours (96 hours for patients undergoing percutaneous transluminal coronary angioplasty). Patients received aspirin and unfractionated heparin with a target activated partial thromboplastin time of 55 to 75 seconds. The primary end point was a composite of death or MI at 30 days.

By design, low-dose eptifibatide therapy was discontinued after a prespecified interim analysis showed no significant excess in adverse events in the high-dose eptifibatide group. The rate of death or MI at 30 days was significantly lower in patients treated with high-dose eptifibatide compared with placebo (14.2% vs 15.7%; relative risk reduction, 9.5%; P = .04). The risk reduction was 19% (8.1% vs 10.0%; P = .001) at 30 days and 10% (12.2% vs 13.6%; P = .02) at 6 months. After only 72 hours and while the patients were still undergoing infusion with the study drug, a significant (P<.001) reduction in the rate of death or MI events was observed in the eptifibatide group (5.9%) compared with the placebo group (7.6%). A markedly reduced frequency of events was observed in patients undergoing early PCI while still taking the study drug within the first 72 hours, compared with the placebo group with a 38% reduction in death or MI (9.0% vs 14.4%; P≤.03). However, among patients treated medically with late PCI or CABG after the infusion was finished, at 72 hours, there was no benefit from eptifibatide therapy.

The frequency of thrombocytopenia and the occurrence of stroke were not significantly different between groups. The incidence of minor bleeding according to TIMI criteria was 13.1% in the eptifibatide group vs 7.6% in the placebo group; the frequency of major bleeding was 10.8% (eptifibatide group) vs 9.3% (placebo group) (P = .02). Red blood cell transfusions were required in 11.6% of the patients treated with eptifibatide compared with 9.2% of the patients treated with placebo.

Enoxaparin is an LMW heparin with an average molecular weight of 4500 d. Heparin chains with molecular weight of less than 5400 d (corresponding to <18 saccharides) cannot bind antithrombin and thrombin simultaneously, and thus cannot inactivate thrombin. However, the ability of short chains containing the critical pentasaccharide sequence to inhibit factor Xa is relatively preserved; enoxaparin thus has an anti–factor Xa/IIa ratio of 3.9:1 compared with 1:1 for unfractionated heparin.

Unlike unfractionated heparin, enoxaparin exhibits little nonspecific binding to plasma proteins. Its bioavailabilty following subcutaneous administration is high (91%), and its dose-response profile is predictable. Enoxaparin is also associated with a much lower incidence of heparin-induced thrombocytopenia than unfractionated heparin.

The efficacy of enoxaparin in the short-term treatment of patients with UAP and NQMI was studied in the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events (ESSENCE) and TIMI 11B trials.31,32

The ESSENCE trial compared enoxaparin and unfractionated heparin in the treatment of 3171 patients with UAP/NQMI.31 Patients were randomized to subcutaneous enoxaparin sodium (1 mg/kg every 12 hours) or unfractionated heparin to maintain an activated partial thromboplastin time of 60 to 90 seconds. All patients received aspirin. Therapy was administered for a minimum of 48 hours and a maximum of 8 days or until hospital discharge (median duration, 2.6 days). The primary end point was a composite of death, MI, or recurrent angina within 14 days of enrollment. Secondary end points included the same composite of death, MI, or recurrent angina at 48 hours and 30 days as well as a double composite of death or MI at 48 hours, 14 days, and 30 days.

The occurrence of the primary composite end point was reduced significantly in the enoxaparin group compared with the unfractionated heparin group (16.6% vs 19.8%; P = .02). At 30 days, the incidence of the composite end point was still significantly lower in the enoxaparin group (19.8% vs 23.3% for unfractionated heparin; P = .02). Death or MI was also reduced by 16% (6.2% for enoxaparin vs 7.7% for unfractionated heparin; P = .08). The rate of revascularization procedures (PCI and CABG) was significantly reduced in the enoxaparin group (27.0% vs 32.2% for unfractionated heparin; P = .001). There was no difference in major bleeding complications between trial groups.

The 1-year follow-up of the ESSENCE trial showed that there was still a significantly lower incidence of the triple end point in the enoxaparin group (32.0% vs 35.7%; P = .02).33 The positive trend observed at 30 days for death or MI also persisted at 1 year (11.5% for enoxaparin vs 13.5% for unfractionated heparin; P = .08).

The TIMI 11B trial was similar in design to ESSENCE.32 Unlike ESSENCE, patients received 30 mg of enoxaparin sodium as an IV bolus, followed by subcutaneous injection of 1 mg/kg twice daily or IV unfractionated heparin until hospital discharge or day 8. Patients in the enoxaparin group also received subcutaneous enoxaparin sodium, 1 mg/kg twice daily, or a placebo during a long-term phase that lasted an additional 35 days. The primary end point was a composite of death, MI, or severe recurrent ischemia requiring urgent revascularization, evaluated at 14 days (for the short-term phase) and at 43 days (for the long-term phase).

Preliminary results of the TIMI 11B have recently been reported.34 After 14 days, use of enoxaparin correlated significantly with a reduction in this composite end point (16.6% for unfractionated heparin vs 14.2% for enoxaparin; P = .03). During the outpatient phase of the trial, the significant advantage of enoxaparin over unfractionated heparin was maintained to day 43, but no additional benefit of continued treatment was evident.

Importantly, there was no significant difference between the enoxaparin and unfractionated heparin groups in the incidence of instrumented or spontaneous major hemorrhage during the in-hospital phase. In contrast, long-term treatment with enoxaparin during the outpatient phase led to a significant increase in major hemorrhage events, when compared with placebo (2.9% with enoxaparin vs 1.5% with placebo; P = .02).

The relative role of an early-invasive strategy for patients with UAP/NQMI (early cardiac catheterization with PCI or CABG [if appropriate]), compared with an early conservative strategy (cardiac catheterization, PCI, and CABG reserved for patients who fail to respond to medical therapy) remains a subject of debate. Intermediate- to high-risk patients with recurrent pain despite intensive medical therapy, or positive results of a test for inducible ischemia, are likely to benefit from an early invasive approach. It also seems reasonable to use an early invasive strategy in patients with previous angioplasty or CABG. On the other hand, low-risk patients can probably be treated effectively with an early conservative approach. The 2 published studies of patients in which this question has been best examined are the TIMI IIIB35,36 and Veterans Affairs Non–Q-Wave Infarction Studies in Hospital (VANQWISH) trials.37 The Fast Revascularization During Instability in Coronary Artery Disease (FRISC) study, with randomization after 5 to 7 days of therapy with a LMW heparin, dalteparin sodium, is also relevant.37

In TIMI IIIB, there was no significant difference in the primary end point (death, nonfatal MI, or unsatisfactory exercise test) at 42 days between the early invasive and early conservative strategies in patients with UAP/NQMI (16.2% vs 18.1%, respectively; P>.05).35 However, the number of patients rehospitalized within 6 weeks was significantly greater (P<.001) in the early conservative group (14.1% vs 7.8%). Also, the number of antianginal medications taken by patients in the early conservative group was significantly greater (P = .02). Favoring the early conservative strategy, there were 35% fewer cardiac catheterizations (P<.001), 30% fewer angioplasties (P<.001), and 6% fewer CABG surgeries (P = .49) in the early conservative strategy group by 6 weeks. The incidence of death or nonfatal infarction did not differ after 1 year by strategy, but fewer patients in the early invasive strategy underwent late repeated hospital admissions.36

In the VANQWISH study, 920 patients with NQMI confirmed by means of a greater than 1.5-fold elevation in serum CK-MB fraction were randomly assigned to an invasive (n = 462) or conservative strategy (n = 458) within 24 to 72 hours.37 The invasive strategy included coronary angiography as the initial diagnostic test after randomization, with myocardial revascularization performed at the discretion of the treating physician. In the conservative approach, only patients with spontaneous ischemia or positive stress test findings before discharge underwent coronary angiography.37 The primary end point for the trial was the composite of death or nonfatal MI.

There was no significant difference (P = .35) in the occurrence of death or nonfatal MI between patients treated with the invasive (26.9%) or conservative strategy (29.9%) after an average follow-up of 23 months (range, 12-44 months). In contrast, death or nonfatal MI was significantly more prevalent in patients undergoing an invasive vs a conservative strategy before hospital discharge (P = .004), at hospital discharge (P = .007), at 1 month (P = .01), and at 1 year (P = .05). Of the 21 deaths during the first 30 days after revascularization in the invasive group, 11 followed CABG, indicating a 10.4% perioperative mortality. Of note, in the invasive group, mortality 30 days after PCI occurred in none of 98 patients. There were 49% fewer cardiac catheterizations and 25% fewer revascularizations (PCI and CABG) in the conservative strategy group. Of interest, the presence of diabetes mellitus was an independent high risk factor for death or MI in both strategies.

The results of the VANQWISH study do not favor an early invasive strategy in managing most NQMI but rather an ischemia-guided conservative approach. In fact, this study suggests that early invasive treatment with CABG of high-risk patients may actually be harmful. A risk model for predicting mortality in non–Q-wave myocardial infarction favored an invasive vs conservative strategy in patients with previous MI, diabetes, peripheral vascular disease, hypertension, anterior wall ST-segment depression, and a widened QRS duration.38

The FRISC II study, in which 3048 patients with ACS were treated with dalteparin for 5 to 7 days, was reported more recently.39 Patients without acute problems who were not at high risk for revascularization (eg, aged >75 years or previous CABG) were then randomized to continued dalteparin therapy or placebo (double-blind) and to an invasive or noninvasive treatment strategy. Only 54% to 57% had elevated troponin levels. Patients in the noninvasive group underwent revascularization only for refractory or recurrent symptoms despite maximal medical therapy, severe ischemia on symptom-limited exercise testing, or acute MI. At 6 months, there were no differences in the death or MI event rates between continued treatment with dalteparin and placebo. However, death or MI occurred in 9.4% of patients assigned to the invasive strategy and in 12.1% of those assigned to the noninvasive strategies (P<.03). At 1 year, the mortality rate in the invasive strategy was 2.2% compared with 3.9% in the noninvasive strategy (P = .02). It may be concluded from the FRISC II study that patients with UAP/non-STEMI who are not at very high risk for revascularization, and who receive 5 to 10 days of treatment with LMW heparin, aspirin, nitrates, and β-blockers, have a better outcome with a routine invasive than a routine conservative approach.

There are notable differences between these randomized trials. Baseline patient characteristics indicate that risk was highest in the VANQWISH trial and lowest in the FRISC II trial, which had the fewest smokers and less previous MI, hypertension, diabetes, and non-STEMI. The FRISC II trial was further biased toward lower risk by excluding those older than 75 years and patients with previous CABG and by treating all patients with LMW heparin for a median of 6 days before initiating the invasive strategy. The TIMI-IIIB populations seemed intermediate in risk, but again, the subgroup with NQMI had a much higher risk for death or reinfarction than subjects with UAP.

Unpublished data from the recently completed Treat Angina with Aggrastat (Tirofiban) and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI) study18 suggest that high-risk patients treated within the first 48 hours after hospitalization with a GpIIb-IIIa inhibitor do better with a subsequent early aggressive therapy rather than with a conservative approach.

A treatment algorithm reflecting early invasive and early conservative approaches to therapy in patients with UAP or non-STEMI is shown in Figure 2. Initial medical treatment of intermediate- to high-risk patients includes aspirin, β-blockers, and nitrates along with a reversible GpIIb-IIIa inhibitor (tirofiban or eptifibatide) plus unfractionated heparin or an LMW heparin, enoxaparin. Currently, there are no direct comparison data in randomized patients with ACS available to support the choice of one reversible GpIIb-IIIa receptor antagonist vs another, or of enoxaparin alone vs a GpIIb-IIIa inhibitor plus unfractionated heparin. Moreover, the safety and efficacy of combining a reversible GpIIb-IIIa receptor antagonist with an LMW heparin has not been approved by the Food and Drug Administration. In a recent preliminary report of 525 patients with UAP/non-STEMI randomized to receive tirofiban and enoxaparin vs tirofiban and unfractionated heparin, major and minor bleeding was equally low in each group.40

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Figure 2.

Algorithm for treating patients with acute coronary syndromes of unstable angina or non–ST-segment elevation myocardial infarction (MI). UFH indicates unfractionated heparin; Gp, glycoprotein; LMW, low-molecular-weight; PCI, percutaneous coronary intervention; and ACE-I, angiotensin-converting enzyme inhibitors. Plus sign indicates evidence of high-risk ischemia on exercise treadmill testing or pharmacological stress imaging.

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In the early conservative strategy, patients are treated medically for at least 48 hours, after which they undergo exercise ECG or pharmacological stress testing with myocardial perfusion imaging, or dobutamine echocardiography.4143 If results of the stress testing are negative or low-risk positive, drug therapy with a GpIIb-IIIa inhibitor and/or heparin can be discontinued at day 3 or 4. If the stress test results are positive and indicate an intermediate to high risk, angiography followed by possible PCI or CABG is warranted. Similarly, angiography with possible PCI or CABG is warranted should rest episodes of chest pain recur despite intensive medical therapy. When an indication for angiography is documented, enoxaparin therapy (LMW heparin) usually is stopped immediately. Multiple unpublished studies suggest that this may not be necessary. In contrast, therapy with the reversible GpIIb-IIIa receptor inhibitors plus unfractionated heparin should be continued.

If an early invasive strategy is chosen, it is recommended that IV therapy be initiated with a reversible GpIIb-IIIa receptor inhibitor (tirofiban or eptifibatide) plus unfractionated heparin as soon as the diagnosis of UAP or non-STEMI is made. There are accumulating data to support enoxaparin as an alternative option. If PCI is performed, drug therapy is continued for at least 12 hours after PCI. In contrast, reversible GpIIb-IIIa inhibitor therapy should be stopped as soon as it is determined that the patient is a candidate for CABG surgery. If after coronary angiography the decision is made to continue medical therapy, the physician has the option of continuing IV therapy with tirofiban or eptifibatide plus unfractionated heparin for an additional 12 to 24 hours, or switching the patient to subcutaneous injection of enoxaparin.

Unstable angina and non-STEMI have many similarities, and the development of new pharmaceutical agents that affect platelet aggregation and thrombus formation have altered the effective therapy for these two acute coronary syndromes. Risk stratification with clinical, ECG, and cardiac serum markers is crucial for targeting new therapies to intermediate- and high-risk patients. Low-molecular-weight heparin (enoxaparin) reduces events, compared with unfractionated heparin. The early use of glycoprotein IIb-IIIa inhibitors in addition to aspirin, heparin, and β-blockers improves outcomes in patients who are stabilized with medical therapy and in patients referred for coronary intervention because of continued or recurrent chest pain. These new antithrombotic agents should become the new standard of care for intermediate- to high-risk patients with UAP/non-STEMI. The evidence favoring use of an invasive vs a conservative approach is mixed; thus, pending further ongoing studies, individual clinical judgment is required. High-risk patients can be identified for an early invasive strategy; however, many patients do well with a conservative, ischemia-based approach.

Accepted for publication September 21, 2000.

Supported by an educational grant from Merck & Co, Inc, San Antonio, Tex (Dr O'Rourke).

Corresponding author and reprints: Robert A. O'Rourke, MD, Division of Cardiology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78284.

Braunwald  EMark  DBJones  RH  et al.  Clinical Practice Guideline Number 10 Unstable Angina: Diagnosis and Management.  Rockville, Md Agency for Health Care Policy and Research and the National Heart, Lung, and Blood Institute, Public Health Service, US Dept of Health and Human Services1994;AHCPR publication 94-0602.
Braunwald  EAntman  EMBeasley  JW  et al.  ACC/AHA guidelines for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2000;36970- 1062
Coller  BS Blockade of platelet GP IIB/IIIa receptors as an antithrombotic strategy. Circulation. 1995;922343- 2380
Topol  EJByzova  TVPlow  EF Platelet GPIIb/IIIa blockers. Lancet. 1999;353227- 231
Davie  EWFujikawa  KKisiel  W The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 1991;3010363- 10370
Furie  BFurie  BC Molecular and cellular biology of blood coagulation. N Engl J Med. 1992;326800- 806
Cannon  CPMcCabe  CHStone  PH  et al.  The electrocardiogram predicts one-year outcome of patients with unstable angina and non–Q-wave myocardial infarction: results of the TIMI III Registry ECC Ancillary Study. J Am Coll Cardiol. 1997;30133- 140
Savonitto  SArdissino  DGranger  C  et al.  Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA. 1999;281707- 713
Holmvang  LLuscher  MSClemmensen  PClemmensen  PThygesen  KGrande  PTRIM Study Group, Very early risk stratification using combined ECG and biochemical assessment in patients with unstable coronary artery disease (a Thrombin Inhibition in Myocardial Ischemia [TRIM] substudy). Circulation. 1998;982004- 2009
Shlipak  MLyons  WGo  A  et al.  Should the electrocardiogram be used to guide therapy for patients with left bundle-branch block and suspected myocardial infarction? JAMA. 1999;281714- 719
Antman  EMTanasijevic  MJThompson  B  et al.  Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;3351342- 1349
Hamm  CWRavkilde  JGerhardt  W  et al.  The prognostic value of troponin T in unstable angina. N Engl J Med. 1992;327146- 150
Ohman  EMArmstrong  PWChristenson  RH  et al.  Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med. 1996;3351333- 1341
Nøgaard  BLAndersen  KDellborg  MAbrahamsson  PRavkilde  JThygesen  KTRIM study group, Admission risk assessment by cardiac troponin T in unstable coronary artery disease: additional prognostic information from continuous ST segment monitoring. J Am Coll Cardiol. 1999;331519- 1527
Antman  EMSacks  DBRifai  N  et al.  Time to positivity of a rapid bedside assay for cardiac-specific troponin T predicts prognosis in acute coronary syndromes: a Thrombolysis in Myocardial Infarction (TIMI) 11A substudy. J Am Coll Cardiol. 1998;31326- 330
Haverkate  FThompson  SGPyke  SKM  et al.  Production of C-reactive protein and risk for coronary events in stable and unstable angina. Lancet. 1997;349462- 466
Mach  FLovis  CGaspoz  JM  et al.  C-reactive protein as a marker for acute coronary syndromes. Eur Heart J. 1997;181897- 1902
Morrow  DARifal  NAntman  EM  et al.  C-reactive protein is a potent predictor of mortality independently and in combination with troponin T in acute coronary syndromes: a TIMI 11 A substudy. J Am Coll Cardiol. 1998;311460- 1465
Ma  JHennekens  CHRidker  PMStampfer  MJ A prospective study of fibrinogen and risk of myocardial infarction in the Physician's Health Study. J Am Coll Cardiol. 1999;331347- 1352
Braunwald  EJones  RHMark  DB  et al.  Diagnosis and managing unstable angina. Circulation. 1994;90613- 622
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;30881- 106
Guslandi  M Gastric toxicity of antiplatelet therapy with low-dose aspirin. Drugs. 1997;531- 5
Buchanan  MRBrister  SJ Individual variation in the effects of ASA on platelet function: implications for the use of ASA clinically. Can J Cardiol. 1995;11221- 227
Hirsh  JFuster  V Guide to anticoagulant therapy, I: heparin. Circulation. 1994;891449- 1468
Theroux  POimet  HMcCans  J  et al.  Aspirin, heparin or both to treat acute unstable angina. N Engl J Med. 1988;3191105- 1111
Handeland  GFAbildgaard  UHolm  HAArnesen  K-E Dose adjusted heparin treatment of deep-venous thrombosis: a comparison of unfractionated heparin and low molecular weight heparin. Eur J Clin Pharmacol. 1990;39107- 112
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators, Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave myocardial infarction. N Engl J Med. 1998;3381488- 1497
The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators, A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med. 1998;3381498- 1505
The PURSUIT Trial Investigators, Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes: platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using Integrilin therapy. N Engl J Med. 1998;339436- 443
The PARAGON Investigators, International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhbitor), heparin, or both in unstable angina: platelet IIb/IIIa antagonism for the reduction of acute coronary syndrome events in a global organization network. Circulation. 1998;972386- 2395
Cohen  MDemers  CGurfinkel  E  et al. Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study Group, A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337447- 452
Antman  EMThombolysis in Myocardial Infarction (TIMI) 11B Trial Investigators, Enoxaparin versus unfractionated heparin for unstable angina or non–Q-wave myocardial infarction: a double-blind, placebo-controlled, parallel-group, multicenter trial: rationale, study design, and methods. Am Heart J. 1998;135(suppl pt 3)S353- S360
Goodman  SBigonzi  FRadley  D  et al.  One-year follow-up of the ESSENCE trial (enoxaparin versus heparin in unstable angina and non–Q-wave myocardial infarction).  Paper presented at 20th Congress of the European Society of Cardiology August 23, 1998 Vienna, Austria.
Antman  EMMcCabe  CHGurfinkel  EP  et al.  Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 11B trial. Circulation. 1999;1001593- 1601
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;891545- 1556
Anderson  VHCannon  CPStone  PH  et al.  One-year results of the thrombolysis in myocardial infarction (TIMI) IIIB Clinical Trial: a randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non–Q wave myocardial infarction. J Am Coll Cardiol. 1995;261643- 1656
Boden  WEO'Rourke  RACrawford  MH  et al.  Outcomes in patients with acute non–Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative strategy. N Engl J Med. 1998;3381785- 1792
O'Hern  MO'Rourke  RAWade  MJ  et al.  A risk stratification model to predict mortality in non–Q-wave myocardial infarction randomized to an early invasive or conservative management strategy [abstract]. Circulation. 2000;102 (II-753) Abstract 3638.
Walletin  LFRISC II (FRagmin and Fast Revasularization During InStability in Coronary Artery Disease) Investigators, Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomized multicentre study. Lancet. 1999;354708- 715
Cohen  MTheroux  PFrey  MJ  et al.  Antithrombotic combination using tirofiban and enoxaparin: the ACUTE II study [abstract]. Circulation. 2000;102 (II-826) Abstract 3982.
Larsson  HAreskog  MAreskog  NH  et al.  Should the exercise test (ET) be performed at discharge or one month later after an episode of unstable angina or non–Q-wave myocardial infarction? Int J Card Imaging. 1991;77- 14
Nyman  ILarsson  HAreskog  MAreskog  NHWallentin  L The predictive value of silent ischemia at an exercise test before discharge after an episode of unstable coronary artery disease: RISC Study Group. Am Heart J. 1992;123324- 331
Brown  KA Management of unstable angina: the role of noninvasive risk stratification. J Nucl Cardiol. 1997;4S164- S168

Figures

Place holder to copy figure label and caption
Figure 1.

Algorithm for the assessment of patients presenting with chest pain and suspected or definite coronary artery disease. MI indicates myocardial infarction; ECG, electrocardiogram; CK-MB, creatine kinase-MB fraction; SX, symptoms; CHD Pt, patients with coronary heart disease; and ACS protocol, acute coronary syndrome protocol for patients with unstable angina or non–ST-segment elevation myocardial infarction. Stress testing indicates pharmacological stress testing (adenosine diphosphate or dipyridamole) with myocardial perfusion imaging, or dobutamine echocardiography.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Algorithm for treating patients with acute coronary syndromes of unstable angina or non–ST-segment elevation myocardial infarction (MI). UFH indicates unfractionated heparin; Gp, glycoprotein; LMW, low-molecular-weight; PCI, percutaneous coronary intervention; and ACE-I, angiotensin-converting enzyme inhibitors. Plus sign indicates evidence of high-risk ischemia on exercise treadmill testing or pharmacological stress imaging.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Revised Risk Classification of Patients With UAP/Non−ST-Segment Elevation MI*
Table Graphic Jump LocationTable 2. Proposed Application of Antiplatelet and Antithrombin Therapy in Treatment of Patients With UAP/Non−ST Segment Elevation MI*
Table Graphic Jump LocationTable 3. Outcomes of Death or MI in 4 Clinical Trials of Platelet GpIIb-IIIa Antagonists in Acute Coronary Syndromes Without PCI

References

Braunwald  EMark  DBJones  RH  et al.  Clinical Practice Guideline Number 10 Unstable Angina: Diagnosis and Management.  Rockville, Md Agency for Health Care Policy and Research and the National Heart, Lung, and Blood Institute, Public Health Service, US Dept of Health and Human Services1994;AHCPR publication 94-0602.
Braunwald  EAntman  EMBeasley  JW  et al.  ACC/AHA guidelines for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2000;36970- 1062
Coller  BS Blockade of platelet GP IIB/IIIa receptors as an antithrombotic strategy. Circulation. 1995;922343- 2380
Topol  EJByzova  TVPlow  EF Platelet GPIIb/IIIa blockers. Lancet. 1999;353227- 231
Davie  EWFujikawa  KKisiel  W The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 1991;3010363- 10370
Furie  BFurie  BC Molecular and cellular biology of blood coagulation. N Engl J Med. 1992;326800- 806
Cannon  CPMcCabe  CHStone  PH  et al.  The electrocardiogram predicts one-year outcome of patients with unstable angina and non–Q-wave myocardial infarction: results of the TIMI III Registry ECC Ancillary Study. J Am Coll Cardiol. 1997;30133- 140
Savonitto  SArdissino  DGranger  C  et al.  Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA. 1999;281707- 713
Holmvang  LLuscher  MSClemmensen  PClemmensen  PThygesen  KGrande  PTRIM Study Group, Very early risk stratification using combined ECG and biochemical assessment in patients with unstable coronary artery disease (a Thrombin Inhibition in Myocardial Ischemia [TRIM] substudy). Circulation. 1998;982004- 2009
Shlipak  MLyons  WGo  A  et al.  Should the electrocardiogram be used to guide therapy for patients with left bundle-branch block and suspected myocardial infarction? JAMA. 1999;281714- 719
Antman  EMTanasijevic  MJThompson  B  et al.  Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;3351342- 1349
Hamm  CWRavkilde  JGerhardt  W  et al.  The prognostic value of troponin T in unstable angina. N Engl J Med. 1992;327146- 150
Ohman  EMArmstrong  PWChristenson  RH  et al.  Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med. 1996;3351333- 1341
Nøgaard  BLAndersen  KDellborg  MAbrahamsson  PRavkilde  JThygesen  KTRIM study group, Admission risk assessment by cardiac troponin T in unstable coronary artery disease: additional prognostic information from continuous ST segment monitoring. J Am Coll Cardiol. 1999;331519- 1527
Antman  EMSacks  DBRifai  N  et al.  Time to positivity of a rapid bedside assay for cardiac-specific troponin T predicts prognosis in acute coronary syndromes: a Thrombolysis in Myocardial Infarction (TIMI) 11A substudy. J Am Coll Cardiol. 1998;31326- 330
Haverkate  FThompson  SGPyke  SKM  et al.  Production of C-reactive protein and risk for coronary events in stable and unstable angina. Lancet. 1997;349462- 466
Mach  FLovis  CGaspoz  JM  et al.  C-reactive protein as a marker for acute coronary syndromes. Eur Heart J. 1997;181897- 1902
Morrow  DARifal  NAntman  EM  et al.  C-reactive protein is a potent predictor of mortality independently and in combination with troponin T in acute coronary syndromes: a TIMI 11 A substudy. J Am Coll Cardiol. 1998;311460- 1465
Ma  JHennekens  CHRidker  PMStampfer  MJ A prospective study of fibrinogen and risk of myocardial infarction in the Physician's Health Study. J Am Coll Cardiol. 1999;331347- 1352
Braunwald  EJones  RHMark  DB  et al.  Diagnosis and managing unstable angina. Circulation. 1994;90613- 622
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;30881- 106
Guslandi  M Gastric toxicity of antiplatelet therapy with low-dose aspirin. Drugs. 1997;531- 5
Buchanan  MRBrister  SJ Individual variation in the effects of ASA on platelet function: implications for the use of ASA clinically. Can J Cardiol. 1995;11221- 227
Hirsh  JFuster  V Guide to anticoagulant therapy, I: heparin. Circulation. 1994;891449- 1468
Theroux  POimet  HMcCans  J  et al.  Aspirin, heparin or both to treat acute unstable angina. N Engl J Med. 1988;3191105- 1111
Handeland  GFAbildgaard  UHolm  HAArnesen  K-E Dose adjusted heparin treatment of deep-venous thrombosis: a comparison of unfractionated heparin and low molecular weight heparin. Eur J Clin Pharmacol. 1990;39107- 112
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators, Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave myocardial infarction. N Engl J Med. 1998;3381488- 1497
The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators, A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med. 1998;3381498- 1505
The PURSUIT Trial Investigators, Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes: platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using Integrilin therapy. N Engl J Med. 1998;339436- 443
The PARAGON Investigators, International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhbitor), heparin, or both in unstable angina: platelet IIb/IIIa antagonism for the reduction of acute coronary syndrome events in a global organization network. Circulation. 1998;972386- 2395
Cohen  MDemers  CGurfinkel  E  et al. Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study Group, A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337447- 452
Antman  EMThombolysis in Myocardial Infarction (TIMI) 11B Trial Investigators, Enoxaparin versus unfractionated heparin for unstable angina or non–Q-wave myocardial infarction: a double-blind, placebo-controlled, parallel-group, multicenter trial: rationale, study design, and methods. Am Heart J. 1998;135(suppl pt 3)S353- S360
Goodman  SBigonzi  FRadley  D  et al.  One-year follow-up of the ESSENCE trial (enoxaparin versus heparin in unstable angina and non–Q-wave myocardial infarction).  Paper presented at 20th Congress of the European Society of Cardiology August 23, 1998 Vienna, Austria.
Antman  EMMcCabe  CHGurfinkel  EP  et al.  Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 11B trial. Circulation. 1999;1001593- 1601
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;891545- 1556
Anderson  VHCannon  CPStone  PH  et al.  One-year results of the thrombolysis in myocardial infarction (TIMI) IIIB Clinical Trial: a randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non–Q wave myocardial infarction. J Am Coll Cardiol. 1995;261643- 1656
Boden  WEO'Rourke  RACrawford  MH  et al.  Outcomes in patients with acute non–Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative strategy. N Engl J Med. 1998;3381785- 1792
O'Hern  MO'Rourke  RAWade  MJ  et al.  A risk stratification model to predict mortality in non–Q-wave myocardial infarction randomized to an early invasive or conservative management strategy [abstract]. Circulation. 2000;102 (II-753) Abstract 3638.
Walletin  LFRISC II (FRagmin and Fast Revasularization During InStability in Coronary Artery Disease) Investigators, Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomized multicentre study. Lancet. 1999;354708- 715
Cohen  MTheroux  PFrey  MJ  et al.  Antithrombotic combination using tirofiban and enoxaparin: the ACUTE II study [abstract]. Circulation. 2000;102 (II-826) Abstract 3982.
Larsson  HAreskog  MAreskog  NH  et al.  Should the exercise test (ET) be performed at discharge or one month later after an episode of unstable angina or non–Q-wave myocardial infarction? Int J Card Imaging. 1991;77- 14
Nyman  ILarsson  HAreskog  MAreskog  NHWallentin  L The predictive value of silent ischemia at an exercise test before discharge after an episode of unstable coronary artery disease: RISC Study Group. Am Heart J. 1992;123324- 331
Brown  KA Management of unstable angina: the role of noninvasive risk stratification. J Nucl Cardiol. 1997;4S164- S168

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