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J Am Coll Cardiol, 2000; 36:970-1062 © 2000 by the American College of Cardiology Foundation |
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Table of Contents |
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 Top Table of Contents PreambleI. IntroductionII. Initial evaluation and...III. Hospital careIV. Coronary revascularizationV. Hospital discharge and...VI. Special groupsAppendix 1Appendix 2References |
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I.
Introduction ......972
A.
Organization of Committee and Evidence Review......972
B.
Purpose of These Guidelines......973
C.
Overview of the Acute Coronary Syndrome......973
1.
Definition of Terms......973
2.
Pathogenesis of UA/NSTEMI ......974
3.
Presentations of UA/NSTEMI......975
II.
Initial Evaluation and Management......976
A.
Clinical Assessment......976
1.
ED or Outpatient Facility Presentation......978
2.
Questions to be Addressed at the Initial Evaluation......978
B.
Early Risk Stratification......978
1.
Estimation of the Level of Risk......979
2.
Rationale for Risk Stratification ......979
3.
The History......980 Anginal Symptoms......980 Demographics and History in Diagnosis and Risk Stratification ......981
4.
Noncardiac Causes of Exacerbation of Symptoms Secondary to Myocardial Ischemia ......981
5.
Assessment of Risk of Death in Patients With UA/NSTEMI......982 Physical Examination......982
6.
Tools for Risk Stratification......983 Electrocardiogram......983
7.
Decision Aids That Combine Clinical Features and ECG Findings......984
8.
Biochemical Cardiac Markers......984 Creatine Kinase......984 Cardiac Troponins......984 Myoglobin......985 Comparison of Cardiac Markers......986
9.
Integration of Clinical History With Serum Marker Measurements......986 Bedside Testing for Cardiac Markers......987
10.
Other Markers......988
C.
Immediate Management......988
1.
Chest Pain Units......989 Potential Expansion of the Use of Chest Pain Units for Intermediate-Risk Patients ......991 Triage of Patients ......991
2.
Discharge From ED or Chest Pain Unit......991
III.
Hospital Care......992 Overview......992
A.
Anti-Ischemic Therapy ......993
1.
General Care......994
2.
Use of Anti-Ischemic Drugs ......994 Nitrates......994 Morphine Sulfate......996 ß-Adrenergic Blockers......996 Calcium Antagonists......997 Other......999
B.
Antiplatelet and Anticoagulation Therapy......999
1.
Antiplatelet Therapy (Aspirin, Ticlopidine, Clopidogrel)......1000 Aspirin......1000 Adenosine Diphosphate Receptor Antagonists and Other Antiplatelet Agents......1002
2.
Anticoagulants......1003 Unfractionated Heparin......1003 Low-Molecular-Weight Heparin......1004 LMWH Versus UFH......1004 Hirudin and Other Direct Thrombin Inhibitors......1006 Long-Term Anticoagulation......1007
3.
Platelet GP IIb/IIIa Receptor Antagonists......1007 Thrombolysis......1010
C.
Risk Stratification......1010
1.
Care Objectives......1011
2.
Noninvasive Test Selection ......1012
3.
Selection for Coronary Angiography......1013
4.
Patient Counseling......1013
D.
Early Conservative Versus Invasive Strategies......1013
1.
General Principles......1013 Rationale for the Early Conservative Strategy......1014 Rationale for the Early Invasive Strategy......1014 Immediate Angiography......1014 Deferred Angiography......1015
2.
Care Objectives......1015
IV.
Coronary Revascularization......1018
A.
General Principles......1018
B.
Percutaneous Coronary Intervention ......1020
1.
Platelet Inhibitors and Percutaneous Revascularization......1021
C.
Surgical Revascularization......1023
D.
Conclusions ......1025
V.
Hospital Discharge and Post–Hospital Discharge Care ......1025
A.
Medical Regimen......1026
1.
Long-Term Medical Therapy......1026
B.
Postdischarge Follow-Up......1026
C.
Use of Medications ......1028
D.
Risk Factor Modification......1028
E.
Medical Record ......1029
VI.
Special Groups......1029
A.
Women......1029
1.
Stress Testing......1030
2.
Management ......1030
3.
Data on UA/NSTEMI......1030
4.
Conclusions ......1031
B.
Diabetes Mellitus......1031
1.
Coronary Revascularization......1032
2.
Conclusions......1033
C.
Post-CABG Patients......1033
1.
Pathological Findings......1033
2.
Clinical Findings and Approach ......1033
3.
Conclusions......1034
D.
Elderly Patients......1034
1.
Pharmacological Management......1034
2.
Observations in UA/NSTEMI ......1034
3.
Interventions and Surgery......1035
4.
Conclusions ......1036
E.
Cocaine......1036
1.
Coronary Artery Spasm......1037
2.
Treatment ......1037
F.
Variant (Prinzmetal’s) Angina......1038
1.
Clinical Picture......1038
2.
Pathogenesis ......1038
3.
Diagnosis......1039
4.
Treatment ......1039
5.
Prognosis......1039
G.
Syndrome X......1039
1.
Definition and Clinical Picture......1039
2.
Treatment ......1040
Appendix 1. Definition of Terminology Related to UA......1040
Appendix 2. Abbreviations......1041
Staff......1044
References......1044
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Preamble |
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TopTable of ContentsPreambleI. IntroductionII. Initial evaluation and...III. Hospital careIV. Coronary revascularizationV. Hospital discharge and...VI. Special groupsAppendix 1Appendix 2References |
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The American College of Cardiology (ACC) and the American Heart Association (AHA) have jointly engaged in the production of such guidelines in the area of cardiovascular disease since 1980. This effort is directed by the ACC/AHA Task Force on Practice Guidelines, whose charge is to develop and revise practice guidelines for important cardiovascular diseases and procedures. Experts in the subject under consideration are selected from both organizations to examine subject-specific data and to write guidelines. The process includes additional representatives from other medical practitioner and specialty groups where appropriate. Writing groups are specifically charged to perform a formal literature review, to weigh the strength of evidence for or against a particular treatment or procedure, and to include estimates of expected health outcomes where data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that might influence the choice of particular tests or therapies are considered, as well as frequency of follow-up and cost-effectiveness.
The ACC/AHA Task Force on Practice Guidelines makes every effort to avoid any actual or potential conflicts of interest that might arise as a result of an outside relationship or a personal interest of a member of the writing panel. Specifically, all members of the writing panel are asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. These statements are reviewed by the parent task force, reported orally to all members of the writing panel at the first meeting, and updated as changes occur.
These practice guidelines are intended to assist physicians in clinical decision making by describing a range of generally acceptable approaches for the diagnosis, management, or prevention of specific diseases or conditions. These guidelines represent an attempt to define practices that meet the needs of most patients in most circumstances. The ultimate judgment regarding the care of a particular patient must be made by the physician and patient in light of all of the available information and the circumstances presented by that patient.
The executive summary and recommendations are published in the September 5, 2000, issue of Circulation. The full text is published in the Journal of the American College of Cardiology. Reprints of the full text and the executive summary are available from both organizations. These guidelines have been officially endorsed by the American College of Emergency Physicians* and the Society for Cardiac Angiography and Interventions.
Raymond J. Gibbons, MD, FACC
Chair, ACC/AHA Task Force on Practice Guidelines
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I. Introduction |
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TopTable of ContentsPreambleI. IntroductionII. Initial evaluation and...III. Hospital careIV. Coronary revascularizationV. Hospital discharge and...VI. Special groupsAppendix 1Appendix 2References |
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The committee members reviewed and compiled published reports through a series of computerized literature searches of the English-language literature since 1994 and a final manual search of selected articles. Details of the specific searches conducted for particular sections are provided when appropriate. Detailed evidence tables were developed whenever necessary with the specific criteria outlined in the individual sections. The recommendations made were based primarily on these published data. The weight of the evidence was ranked highest (A) if the data were derived from multiple randomized clinical trials that involved large numbers of patients and intermediate (B) if the data were derived from a limited number of randomized trials that involved small numbers of patients or from careful analyses of nonrandomized studies or observational registries. A lower rank (C) was given when expert consensus was the primary basis for the recommendation.
The customary ACC/AHA classifications I, II, and III are used in tables that summarize both the evidence and expert opinion and provide final recommendations for both patient evaluation and therapy:
Class I:
Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective
Class II:
Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment
Class IIa:
Weight of evidence/opinion is in favor of usefulness/efficacy
Class IIb:
Usefulness/efficacy is less well established by evidence/opinion
Class III:
Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful
A complete list of the thousands of publications on various aspects of this subject is beyond the scope of these guidelines; only selected references are included. The Committee consisted of acknowledged experts in general internal medicine representing the American College of Physicians–American Society of Internal Medicine (ACP-ASIM), family medicine from the American Academy of Family Physicians (AAFP), emergency medicine from the American College of Emergency Physicians (ACEP), thoracic surgery from the Society of Thoracic Surgeons (STS), and general cardiology, as well as individuals with recognized expertise in more specialized areas, including noninvasive testing, preventive cardiology, coronary intervention, and cardiovascular surgery. Both the academic and private practice sectors were represented. The Agency for Healthcare Research and Quality UCSF-Stanford Evidence-Based Practice Center provided support for the guidelines. This document was reviewed by 3 outside reviewers nominated by ACC, 3 outside reviewers nominated by AHA, 3 outside reviewers nominated by ACEP, 1 outside reviewer nominated by AAFP, 1 outside reviewer nominated by ACP-ASIM, 1 outside reviewer nominated by the European Society of Cardiology, 1 outside reviewer nominated by STS, and 29 outside reviewers nominated by the Committee. This document was approved for publication by the governing bodies of ACC and AHA. These guidelines will be reviewed 1 year after publication and yearly thereafter by the Task Force to determine whether revision is necessary. These guidelines will be considered current unless the Task Force revises them or withdraws them from distribution.
These guidelines overlap several previously published ACC/AHA practice guidelines, including the ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction and the ACC/AHA/ACP-ASIM Guidelines for the Management of Patients With Chronic Stable Angina.
B. Purpose of these guidelines. These guidelines address the diagnosis and management of patients with UA and the closely related condition NSTEMI. These life-threatening disorders are a major cause of emergency medical care and hospitalization in the United States. In 1996 alone, the National Center for Health Statistics reported 1,433,000 hospitalizations for UA or NSTEMI (2). Nearly 60% of hospital admissions of patients with UA as the primary diagnosis were among persons >65 years old, and 46% of such patients of all ages were women. In 1997, there were 5,315,000 visits to US emergency departments (EDs) for the evaluation of chest pain and related symptoms (3). The prevalence of this presentation of CAD ensures that many healthcare providers who are not cardiovascular specialists will encounter patients with UA/NSTEMI in the course of the treatment of other diseases, especially in outpatient and ED settings. These guidelines are intended to assist both cardiovascular specialists and nonspecialists in the proper evaluation and management of patients with an acute onset of symptoms suggestive of these conditions. These clinical practice guidelines also provide recommendations and supporting evidence for the continued management of patients with these conditions in both inpatient and outpatient settings. The diagnostic and therapeutic strategies that are recommended are supported by the best available evidence and expert opinion. The application of these principles with carefully reasoned clinical judgment reduces, but does not eliminate, the risk of cardiac damage and death in patients who present with symptoms suggestive of UA.
C. Overview of the acute coronary syndrome.
1. Definition of terms
UA/NSTEMI constitutes a clinical syndrome that is usually, but not always, caused by atherosclerotic CAD and associated with an increased risk of cardiac death and myocardial infarction (MI). The results of angiographic and angioscopic studies suggest that UA/NSTEMI often results from the disruption of an atherosclerotic plaque and a subsequent cascade of pathological processes that decrease coronary blood flow. Most patients who die during UA/NSTEMI do so because of sudden death or the development (or recurrence) of acute MI (AMI). The efficient diagnosis and optimal management of these patients must derive from information readily available at the time of the initial clinical presentation. The clinical presentation of patients with a life-threatening acute coronary syndrome (ACS) often overlaps that of patients subsequently found not to have CAD. Moreover, some forms of MI cannot always be differentiated from UA at the time of initial presentation.
Acute coronary syndrome has evolved as a useful operational term to refer to any constellation of clinical symptoms that are compatible with acute myocardial ischemia (Fig. 1). It encompasses AMI (ST-segment elevation and depression, Q wave and non–Q wave) as well as UA. These guidelines focus on 2 components of this syndrome: UA and NSTEMI. In practice, the term possible ACS is often assigned first by ancillary personnel, such as emergency medical technicians and triage nurses, early in the evaluation process. A guideline of the National Heart Attack Alert Program (NHAAP) (4) summarizes the clinical information needed to make the diagnosis of possible ACS at the earliest phase of clinical evaluation (Table 1). The implication of this early diagnosis for clinical management is that a patient who is considered to have an ACS should be placed in an environment with continuous electrocardiographic (ECG) monitoring and defibrillation capability, where a 12-lead ECG can be obtained expeditiously and definitively interpreted within 10 min. The most urgent priority of early evaluation is to identify patients with AMI who should be considered for immediate reperfusion therapy and to recognize other potentially catastrophic causes of sudden patient decompensation, such as aortic dissection.
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In these guidelines, UA and NSTEMI are considered to be closely related conditions whose pathogenesis and clinical presentations are similar but of differing severity; that is, they differ primarily in whether the ischemia is severe enough to cause sufficient myocardial damage to release detectable quantities of a marker of myocardial injury, most commonly troponin I (TnI), troponin T (TnT), or CK-MB. Once it has been established that no biochemical marker of myocardial necrosis has been released (with a reference limit of the 99th percentile of the normal population) (6), the patient with ACS may be considered to have experienced UA, whereas the diagnosis of NSTEMI is established if a marker has been released. In the latter condition, ECG ST-segment or T-wave changes may be persistent, whereas they may or may not occur in patients with UA, and if they do, they are usually transient. Markers of myocardial injury may be detected in the bloodstream hours after the onset of ischemic chest pain, which allows the differentiation between UA (i.e., no markers in circulation; usually transient, if any, ECG changes of ischemia) and NSTEMI (i.e., elevated biochemical markers). Thus, at the time of presentation, patients with UA and NSTEMI may be indistinguishable and therefore are considered together in these guidelines.
2. Pathogenesis of UA/NSTEMI
These conditions are characterized by an imbalance between myocardial oxygen supply and demand. They are not specific diseases such as pneumococcal pneumonia, but rather a syndrome, analogous to hypertension. Five nonexclusive causes are recognized (7) (Table 2). With the first 4 causes, the imbalance is caused primarily by a reduction in oxygen supply to the myocardium, whereas with the fifth cause, the imbalance is due principally to increased myocardial oxygen requirements, usually in the presence of a fixed restricted oxygen supply.
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II. Initial evaluation and management |
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TopTable of ContentsPreambleI. IntroductionII. Initial evaluation and...III. Hospital careIV. Coronary revascularizationV. Hospital discharge and...VI. Special groupsAppendix 1Appendix 2References |
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Given the large number of patients with symptoms compatible with ACS, the heterogeneity of the population, and the clustering of events shortly after the onset of symptoms (Fig. 3), a strategy for the initial evaluation and management is essential. Healthcare providers may be informed about signs and symptoms of ACS over the telephone or in person (and perhaps in the future over the Internet). The objectives of the initial evaluation are first to identify signs of immediate life-threatening instability and then to ensure that the patient is moved rapidly to the most appropriate environment for the level of care needed based on diagnostic criteria and an estimation of the underlying risk of specific negative outcomes.
Recommendation for Telephone Triage
Class I
1. Patients with symptoms that suggest possible ACS should not be evaluated solely over the telephone but should be referred to a facility that allows evaluation by a physician and the recording of a 12-lead ECG. (Level of Evidence: C)
Health practitioners frequently receive telephone calls from patients who are concerned that their symptoms may reflect heart disease. Most such calls regarding chest discomfort of possible cardiac origin in patients without known CAD do not represent an emergency; rather these patients usually seek reassurance that they do not have heart disease or that there is little risk due to their symptoms. Despite the frequent inclination to dismiss such symptoms over the telephone, physicians should advise patients with possible accelerating angina or angina at rest that such an evaluation cannot be carried out solely via the telephone. This advice is essential because of the need for a physical examination and an ECG and the potential importance of blood tests to measure cardiac markers.
Patients with known CAD—including those with chronic stable angina or recent MI or who have had coronary artery bypass graft surgery (CABG) or a PCI—who contact a physician because of worsening or recurrence of symptoms should be urged to go directly to an ED equipped to perform prompt reperfusion therapy. Alternatively, they may enter the emergency medical services system directly by calling 9-1-1. Patients who have recently been evaluated and who are calling for advice regarding modification of medication as part of an ongoing treatment plan represent exceptions.
Even in the most urgent subgroup of patients who present with acute-onset chest pain, there usually is adequate time for transport to an environment in which they can be evaluated and treated (12). In a large study of consecutive patients with chest pain suspected to be of cardiac etiology who were transported to the ED via ambulance, one third had a final diagnosis of AMI, one third had a final diagnosis of UA, one third had a final diagnosis of a noncardiac cause. Only 1.5% of these patients developed cardiopulmonary arrest before arrival at the hospital or in the ED (13). These findings suggest that patients with acute chest pain might be better served by transport to an adequately staffed and equipped ED than by sending them to a less well staffed and equipped facility, thereby compromising the quality of the care environment in an attempt to shorten the initial transport time.
Patients must retain the ultimate responsibility for deciding whether to seek medical attention and, if so, in what environment. The physician cannot be expected to assume responsibility for a patient with a potentially serious acute cardiac disorder who does not present in person for urgent evaluation and declines after being advised to do so. Physicians should be cautious not to inappropriately reassure patients who are inclined not to seek further medical attention.
1. ED or outpatient facility presentation. Recommendation
Class I
1. Patients with a suspected ACS with chest discomfort at rest for >20 min, hemodynamic instability, or recent syncope or presyncope should be strongly considered for immediate referral to an ED or a specialized chest pain unit. Other patients with a suspected ACS may be seen initially in an ED, a chest pain unit, or an outpatient facility. (Level of Evidence: C)
Although no data are available that compare outcome as a function of the location of the initial assessment, this recommendation is based on evidence that symptoms and signs of an ACS may lead to a clinical decision that requires a sophisticated level of intervention. When symptoms have been unremitting for >20 min, the possibility of STEMI must be considered. Given the strong evidence for a relationship between delay in treatment and death (14–16), an immediate assessment that includes a 12-lead ECG is essential. Patients who present with hemodynamic instability require an environment in which therapeutic interventions can be provided, and for those with presyncope or syncope, the major concern is the risk of sudden death. Such patients should be encouraged to seek emergency transportation when it is available. Transport as a passenger in a private vehicle is an acceptable alternative only if the wait for an emergency vehicle would impose a delay of >20 to 30 min.
Patients without any of these high-risk features may be seen initially in an outpatient facility.
2. Questions to be addressed at the initial evaluation
The initial evaluation should be used to provide information about the diagnosis and prognosis. The attempt should be made to simultaneously answer 2 questions:
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B. Early risk stratification. Recommendations for Early Risk Stratification
Class I
1. A determination should be made in all patients with chest discomfort of the likelihood of acute ischemia caused by CAD as high, intermediate, or low. (Level of Evidence: C)
2. Patients who present with chest discomfort should undergo early risk stratification that focuses on anginal symptoms, physical findings, ECG findings, and biomarkers of cardiac injury. (Level of Evidence: B)
3. A 12-lead ECG should be obtained immediately (within 10 min) in patients with ongoing chest discomfort and as rapidly as possible in patients who have a history of chest discomfort consistent with ACS but whose discomfort has resolved by the time of evaluation. (Level of Evidence: C)
4. Biomarkers of cardiac injury should be measured in all patients who present with chest discomfort consistent with ACS. A cardiac-specific troponin is the preferred marker, and if available, it should be measured in all patients. CK-MB by mass assay is also acceptable. In patients with negative cardiac markers within 6 h of the onset of pain, another sample should be drawn in the 6- to 12-h time frame (e.g., at 9 h after the onset of symptoms). (Level of Evidence: C)
Class IIa
1. For patients who present within 6 h of the onset of symptoms, an early marker of cardiac injury (e.g., myoglobin or CK-MB subforms) should be considered in addition to a cardiac troponin. (Level of Evidence: C)
Class IIb
1. C-reactive protein (CRP) and other markers of inflammation should be measured. (Level of Evidence: B)
Class III
1. Total CK (without MB), aspartate aminotransferase (AST, SGOT), ß-hydroxybutyric dehydrogenase, and/or lactate dehydrogenase should be the markers for the detection of myocardial injury in patients with chest discomfort suggestive of ACS. (Level of Evidence: C)
1. Estimation of the level of risk
The medical history, physical examination, ECG, and biochemical cardiac marker measurements in patients with symptoms suggestive of ACS at the time of the initial presentation can be integrated into an estimation of the risk of death and nonfatal cardiac ischemic events. The latter include new or recurrent MI, recurrent UA, disabling angina that requires hospitalization, and/or urgent coronary revascularization. Estimation of the level of risk is a multivariable problem that cannot be accurately quantified with a simple table; therefore, Tables 5 and 6 are meant to be illustrative of the general relationships between clinical and ECG findings and the categorization of patients into those at a low, an intermediate, or a high risk of events.
2. Rationale for risk stratification
Because patients with ischemic discomfort at rest as a group are at an increased risk of cardiac death and nonfatal ischemic events, an assessment of the prognosis often sets the pace of the initial evaluation and treatment. An estimation of risk is useful in 1) selection of the site of care (coronary care unit, monitored step-down unit, or outpatient setting) and 2) selection of therapy, especially platelet glycoprotein (GP) IIb/IIIa inhibitors (see Section III. B) and coronary revascularization (see Section IV). For all modes of presentation of an ACS, a strong relationship exists between indicators of the likelihood of ischemia due to CAD and prognosis (Tables 5 and 6). Patients with a high likelihood of ischemia due to CAD are at a greater risk of an untoward cardiac event than are patients with a lower likelihood of CAD. Therefore, an assessment of the likelihood of CAD is the starting point for the determination of prognosis in patients who present with symptoms suggestive of an ACS. Other important elements for prognostic assessment are the tempo of the patient’s clinical course, which relates to the short-term risk of future cardiac events, principally AMI, and the patient’s likelihood of survival should an AMI occur.
Patients may present with ischemic discomfort but without ST-segment elevation on the 12-lead ECG in a variety of clinical scenarios, including no known prior history of CAD, a prior history of stable CAD, soon after MI, and after myocardial revascularization with CABG or PCI (7,17,18). As a clinical syndrome, ischemic discomfort without ST-segment elevation (UA and NSTEMI) shares ill-defined borders with severe chronic stable angina, a condition associated with lower risk, and with STEMI, a presentation with a higher risk of early death and cardiac ischemic events. This fact is illustrated by data from the Duke Cardiovascular Databank that describe the rate of cardiac death in 21,761 patients treated for CAD without interventional procedures at Duke University Medical Center between 1985 and 1992 and that were published in the AHCPR-NHLBI guidelines (1), now supplemented with data from large clinical trials in ACS (10) (Fig. 3). The highest risk of cardiac death was at the time of presentation, and the risk declined so that by 2 months, mortality rates for patients with ACS were at the same level as those for patients with chronic stable angina. Data from randomized controlled trials of patients with UA/NSTEMI have also shown that the rate of nonfatal cardiac ischemic events such as recurrent MI and recurrent angina is highest during the initial hospitalization and declines thereafter (4,10,19–21).
Two large clinical trials, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) (10) and Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q wave Coronary Events (ESSENCE) (22), have evaluated the clinical and ECG characteristics associated with an increased risk of death and nonfatal MI in 24,774 patients with UA/NSTEMI. The critical clinical features associated with an increased risk of death were age (>65 years), presence of positive markers for myocardial necrosis on admission, lighter weight, more severe (CCS Class III or IV) chronic angina before the acute admission, rales on physical examination, and ST-segment depression on the admission ECG. In the PURSUIT trial, either tachycardia or bradycardia and lower blood pressure were associated with a higher risk of death or MI. These findings allow the stratification of patients with UA/NSTEMI into those at higher risk and those at lower risk.
3. The history
Patients with suspected UA/NSTEMI may be divided into those with and those without a history of documented CAD. Particularly when the patient does not have a known history of CAD, the physician must determine whether the patient’s presentation, with its constellation of specific symptoms and signs, is most consistent with chronic ischemia, with acute ischemia, or with an alternative disease process. The 5 most important factors derived from the initial history that relate to the likelihood of ischemia due to CAD, ranked in the order of importance, are 1) the nature of the anginal symptoms, 2) prior history of CAD, 3) sex, 4) age, and 5) the number of traditional risk factors present (23–25).
Anginal symptoms. The characteristics of angina are described in the ACC/AHA/ACP-ASIM Guidelines for the Management of Patients With Chronic Stable Angina (26). Angina is characterized as a deep, poorly localized chest or arm discomfort that is reproducibly associated with physical exertion or emotional stress and is relieved promptly (i.e., <5 min) with rest and/or the use of sublingual nitroglycerin (NTG) (Table 5). Patients with UA may have discomfort that has all of the qualities of typical angina except that the episodes are more severe and prolonged, may occur at rest, or may be precipitated by less exertion than previously. Some patients may have no chest discomfort but present solely with jaw, neck, ear, arm, or epigastric discomfort. If these symptoms have a clear relationship to exertion or stress or are relieved promptly with NTG, they should be considered equivalent to angina. Occasionally, such "anginal equivalents" that occur at rest are the mode of presentation of a patient with UA, but without the exertional history, it may be difficult to recognize the cardiac origin. Other difficult presentations of the patient with UA include those without any chest (or equivalent) discomfort. Isolated unexplained new-onset or worsened exertional dyspnea is the most common anginal equivalent symptom, especially in older patients; others include nausea and vomiting, diaphoresis, and unexplained fatigue. Elderly patients, especially women with ACS, often present with atypical angina.
Features that are not characteristic of myocardial ischemia include the following:
Documentation of the evaluation of a patient with suspected UA/NSTEMI should include the physician’s opinion of whether the discomfort is in 1 of 3 categories: high, intermediate, or low likelihood of acute ischemia caused by CAD (Table 5).
Although typical characteristics substantially raise the probability of CAD, features not characteristic of chest pain, such as sharp stabbing pain or reproduction of pain on palpation, do not exclude the possibility of ACS. In the Multicenter Chest Pain Study, acute ischemia was diagnosed in 22% of patients who presented to the ED with sharp or stabbing pain and in 13% of patients with pain with pleuritic qualities. Furthermore, 7% of patients whose pain was fully reproduced with palpation were ultimately recognized to have ACS (27). The Acute Cardiac Ischemia Time-Insensitive Predictive Instrument (ACI-TIPI) project (28,29) found that older age, male sex, the presence of chest or left arm pain, and the identification of chest pain or pressure as the most important presenting symptom all increased the likelihood that the patient was experiencing acute ischemia.
Demographics and history in diagnosis and risk stratification. In most studies of ACS, a prior history of MI has been associated not only with a high risk of obstructive CAD (30) but also with an increased risk of multivessel CAD.
There are differences in the presentations of men and women with ACS (see Section VI. A). A smaller percentage of women than men present with STEMI, and of the patients who present without ST-segment elevation, fewer women than men have MIs (31). Women with suspected ACS are less likely to have CAD than are men with a similar clinical presentation, and when CAD is present in women, it tends to be less severe. If STEMI is present, the outcome in women tends to be worse even when adjustment is made for the older age and greater comorbidity of women. However, the outcome for women with UA is significantly better than the outcome for men, and the outcomes are similar for men and women with NSTEMI (32,33).
Older patients (see Section VI. D) have increased risks of both underlying CAD (34,35) and multivessel CAD; furthermore, they are at higher risk for an adverse outcome than are younger patients. The slope of the increased risk is steepest beyond age 70. This increased risk is related in part to the greater extent and severity of underlying CAD and the more severe LV dysfunction in older patients, but age itself appears to exert an independent prognostic risk as well, perhaps because of comorbidities. Elderly patients are also more likely to have atypical symptoms on presentation.
In patients with symptoms of possible ACS, some of the traditional risk factors for CAD (e.g., hypertension, hypercholesterolemia, cigarette smoking) are only weakly predictive of the likelihood of acute ischemia (29,36) and are far less important than are symptoms, ECG findings, and cardiac markers. Therefore, the presence or absence of these traditional risk factors ordinarily should not be used to determine whether an individual patient should be admitted or treated for ACS. Although a family history of premature CAD raises interesting issues of the genetic contribution to the development of this syndrome, it has not been a useful indicator of diagnosis or prognosis in patients evaluated for possible symptoms of ACS. However, several of these risk factors have important prognostic and therapeutic implications. Diabetes and the presence of extracardiac (peripheral or carotid) arterial disease are major risk factors for poor outcome in patients with ACS (see Section VI. B). For both ST-segment elevation (37) and non–ST-segment elevation ACS (10), patients with these conditions have a significantly higher mortality rate and risk of acute heart failure. For the most part, this increase in risk is due to a greater extent of underlying CAD and LV dysfunction, but in many studies, diabetes carries prognostic significance over and above these findings. Similarly, a history of hypertension is associated with an increased risk of poor outcome.
Surprisingly, current smoking is associated with a lower risk of death in the setting of ACS (38–40), predominantly because of the less severe underlying CAD. This "smokers’ paradox" seems to represent a tendency for smokers to develop thrombi on less severe plaques and at an earlier age than nonsmokers.
Cocaine use has been implicated as a cause of ACS, presumably due to the ability of this drug to cause coronary vasospasm and thrombosis in addition to its direct effects on heart rate and arterial pressure and its myocardial toxic properties (see Section VI. E). It is important to inquire about the use of cocaine in patients with suspected ACS, especially younger patients (<40 years).
4. noncardiac causes of exacerbation of symptoms secondary to myocardial ischemia. Recommendation
Class I
1. The initial evaluation of the patient with suspected ACS should include a search for noncoronary causes that could explain the development of symptoms. (Level of Evidence: C)
Information from the initial history, physical examination, and ECG (Table 5) will enable the physician to recognize and exclude from further assessment patients classified as "not having ischemic discomfort." This includes patients with noncardiac pain (e.g., musculoskeletal discomfort, esophageal discomfort) or cardiac pain not caused by myocardial ischemia (e.g., acute pericarditis). The remaining patients should undergo a more complete evaluation of secondary causes of UA that might alter management. This evaluation should include a physical examination for evidence of other cardiac disease, an ECG to screen for arrhythmias, measurement of body temperature and blood pressure, and determination of hemoglobin or hematocrit. Cardiac disorders other than CAD that may cause myocardial ischemia include aortic stenosis and hypertrophic cardiomyopathy. In secondary angina, factors that increase myocardial oxygen demand or decrease oxygen delivery to the heart may provoke or exacerbate ischemia in the presence of significant underlying CAD. Previously unrecognized gastrointestinal bleeding is a common secondary cause of worsened CAD and the development of ACS symptoms due to anemia. Acute worsening of chronic obstructive pulmonary disease (COPD) (with or without superimposed infection) may lower oxygen saturation levels sufficiently to intensify ischemic symptoms in patients with CAD. Evidence of increased cardiac oxygen demand can be judged from the presence of fever, signs of hyperthyroidism, sustained tachyarrhythmias, or markedly elevated blood pressure. Another cause of increased myocardial oxygen demand is arteriovenous (AV) fistula in patients receiving dialysis.
The majority of patients seen in the ED with symptoms of possible ACS will be judged after their workup to not have a cardiac problem. A recent clinical trial of a predictive instrument evaluated 10,689 patients with suspected ACS (11). To participate, patients were required to be >30 years old with a chief symptom of chest, left arm, jaw, or epigastric pain or discomfort; shortness of breath; dizziness; palpitations; or other symptoms suggestive of acute ischemia. After the evaluation, 7,996 patients (75%) were deemed not to have acute ischemia.
5. Assessment of risk of death in patients with UA/NSTEMI
In patients who meet the diagnostic criteria for UA/NSTEMI, the recent tempo of ischemic symptoms is the strongest predictor of risk of death. The AHCPR guidelines Unstable Angina: Diagnosis and Management identified low-risk patients as those without rest or nocturnal angina and with a normal or an unchanged ECG (1). High-risk patients were identified as those with pulmonary edema; ongoing rest pain for >20 min in duration; angina with S3 gallop, rales, or new or worsening mitral regurgitation (MR) murmur; hypotension; or dynamic ST-segment change of 
1 mm. Patients without low- or high-risk features were termed to be at "intermediate risk."
These simple clinical criteria were prospectively tested in a consecutive sample of patients who presented with symptoms suggestive of ACS (41). After prescreening was conducted to exclude patients with AMI or cardiac arrest, patients receiving thrombolytic therapy, and patients diagnosed as having noncardiac conditions, only 6% of the remaining patients diagnosed with UA were categorized as being at low risk. This low-risk population experienced no death or MI in the 30 days after the initial presentation to the ED. In contrast, the 30-day mortality rate was 1.2% for patients at intermediate risk and 1.7% for patients deemed at high risk. These observations confirmed the management recommendations made in the earlier guidelines. Patients with low-risk UA can be managed expeditiously as outpatients. Patients with high-risk UA deserve rapid clinical stabilization in an acute care environment in the hospital. Patients at intermediate risk require individualization of management based on clinical judgment. These patients should usually be admitted to the hospital and require monitoring but do not ordinarily require an intensive care unit.
The tempo of angina is characterized by an assessment of changes in the duration of episodes, their frequency, and the anginal threshold. In particular, it is useful to determine whether the amount of physical or emotional stress that provokes symptoms has declined, whether symptoms are occurring at rest, and whether they awaken the patient from sleep. The integration of these factors into a score can improve the predictions of outcome (42,43). Although new-onset angina itself is associated with greater risk than is continued stable angina, most of its contribution to an adverse prognosis is determined by its severity, frequency, and tempo (42,44).
Multiple studies have demonstrated that prior MI is a major risk factor for poor outcome in both STEMI and UA/NSTEMI (10). Patients with symptoms of acute and/or chronic heart failure are also at a substantially higher risk.
Physical examination. The major objectives of the physical examination are to identify potential precipitating causes of myocardial ischemia such as uncontrolled hypertension or thyrotoxicosis and comorbid conditions such as pulmonary disease and to assess the hemodynamic impact of the ischemic event. Every patient with suspected ACS should have his or her vital signs measured (blood pressure in both arms, heart rate, temperature) and undergo a thorough cardiovascular and chest examination. Patients with evidence of LV dysfunction on examination (rales, S3 gallop) or with acute MR have a higher likelihood of severe underlying CAD and are at a high risk of a poor outcome. Just as the history of extracardiac vascular disease is important, the physical examination of the peripheral vessels can also provide important prognostic information. The presence of bruits or pulse deficits that suggest extracardiac vascular disease (carotid, aortic, peripheral) identifies patients with a higher likelihood of significant CAD.
Elements of the physical examination can be critical in making an important alternative diagnosis in patients with chest pain. In particular, several disorders carry a significant threat to life and function if not diagnosed acutely. Aortic dissection is suggested by pain in the back, unequal pulses, or a murmur of aortic regurgitation. Acute pericarditis is suggested by a pericardial friction rub, and cardiac tamponade may be evidenced by pulsus paradoxus. Pneumothorax is suspected when acute dyspnea, pleuritic chest pain, and differential breath sounds are present.
Recently, the importance of cardiogenic shock in patients with NSTEMI was emphasized. Although most literature on cardiogenic shock has focused on STEMI, the SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK (SHOCK) (45), Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-II (45a), and PURSUIT (10) trials have found that cardiogenic shock occurs in up to 5% of patients with NSTEMI and that mortality rates are >60%. Thus, hypotension and evidence of organ hypoperfusion constitute a medical emergency in NSTEMI.
6. tools for risk stratification.
Electrocardiogram
The ECG is critical not only to add support to the clinical suspicion of CAD but also to provide prognostic information that is based on the pattern and magnitude of the abnormalities (46–49). A recording made during an episode of the presenting symptoms is particularly valuable. Importantly, transient ST-segment changes (0.05 mV) that develop during a symptomatic episode at rest and that resolve when the patient becomes asymptomatic strongly suggest acute ischemia and a very high likelihood of underlying severe CAD. Patients whose current ECG suggests acute CAD can be assessed with greater diagnostic accuracy if a prior ECG is available for comparison (Table 5) (50,51).
Although it is imperfect, the 12-lead ECG lies at the center of the decision pathway for the evaluation and management of patients with acute ischemic discomfort (Fig. 1, Table 5). The diagnosis of AMI is confirmed with serial cardiac markers in >90% of patients who present with ST-segment elevation of 0.1 mV in 2 contiguous leads, and such patients should be considered potential candidates for acute reperfusion therapy. Patients who present with ST-segment depression are initially considered to have either UA or NSTEMI; the distinction between the 2 diagnoses is based ultimately on the detection in the blood of markers of myocardial necrosis (6,18,52).
Patients with UA and reversible ST-segment depression have an increase in thrombin activity reflected in elevated levels of circulating fibrinopeptides and complex lesions that suggest thrombosis on coronary angiography (53). Up to 25% of patients with NSTEMI and elevated CK-MB go on to develop Q-wave MI, whereas the remaining 75% have non–Q-wave MI. Acute reperfusion therapy is contraindicated for ACS patients without ST-segment elevation, except for those with isolated acute posterior infarction manifested as ST-segment depressions in leads V1 to V3 and/or isolated ST-segment elevation in posterior chest leads (54). Inverted T waves may also indicate ischemia or non–Q-wave infarction. In patients suspected on clinical grounds to have ACS, marked (0.2 mV) symmetrical precordial T-wave inversion strongly suggests acute ischemia, particularly that due to a critical stenosis of the left anterior descending coronary artery (LAD) (55). Patients with this ECG finding often exhibit hypokinesis of the anterior wall and are at high risk with medical treatment (56). Revascularization will often reverse both the T-wave inversion and wall motion disorder (57). Nonspecific ST-segment and T-wave changes, usually defined as ST-segment deviation of <0.05 mV or T-wave inversion of 
0.2 mV, are less helpful than the foregoing findings. Established Q waves 0.04 s are also less helpful in the diagnosis of UA, although by suggesting prior MI, they do indicate a high likelihood of significant CAD. Isolated Q waves in lead III may be a normal finding, especially in the absence of repolarization abnormalities in any of the inferior leads. A completely normal ECG in a patient with chest pain does not exclude the possibility of ACS, because 1% to 6% of such patients eventually are proved to have had an AMI (by definition, an NSTEMI), and 4% will be found to have UA (47,58,59).
The common alternative causes of ST-segment and T-wave changes must be considered. In patients with ST-segment elevation, the diagnoses of LV aneurysm, pericarditis, Prinzmetal’s angina, early repolarization, and Wolff-Parkinson-White syndrome should be considered. Central nervous system events and drug therapy with tricyclic antidepressants or phenothiazines can cause deep T-wave inversion.
Several investigators have shown that a gradient of risk of death and cardiac ischemic events can be established based on the nature of the ECG abnormality (48,60,61). Patients with ACS and confounding ECG patterns such as bundle-branch block, paced rhythm, or LV hypertrophy are at the highest risk for death, followed by patients with ST-segment deviation (ST-segment elevation or depression); at the lowest risk are patients with isolated T-wave inversion or normal ECG patterns. Importantly, the prognostic information contained within the ECG pattern remains an independent predictor of death even after adjustment for clinical findings and cardiac marker measurements (60–63).
In addition to the presence or absence of ST-segment deviation or T-wave inversion patterns as noted earlier, there is evidence that the magnitude of the ECG abnormality provides important prognostic information. Thus, Lloyd-Jones et al. (64) reported that the diagnosis of acute non–Q-wave MI was 3 to 4 times more likely in patients with ischemic discomfort who had 3 ECG leads that showed ST-segment depression and/or ST-segment depression of 0.2 mV. Investigators from the Thrombolysis In Myocardial Ischemia (TIMI) III registry (60) reported that the 1-year incidence of death or new MI in patients with 0.05-mV ST-segment deviation was 16.3% compared with 6.8% for patients with isolated T-wave changes and 8.2% for patients with no ECG changes.
Because a single 12-lead ECG recording provides only a snapshot view of a dynamic process, the usefulness of obtaining serial ECG tracings or performing continuous ST-segment monitoring was studied (46). Although serial ECGs increase the ability to diagnose AMI (65–67), the yield is higher with serial cardiac marker measurements (68). Continuous 12-lead ECG monitoring to detect ST-segment shifts, both symptomatic and asymptomatic, can be performed with microprocessor-controlled, programmable devices. Clinical experience suggests that continuous ECG monitoring identifies episodes of ischemia that are missed with standard 12-lead ECGs obtained on presentation and that such episodes of transient ischemia provide independent prognostic information that indicates an increased risk of death, nonfatal MI, and the need for urgent revascularization (69,70). However, the ultimate clinical usefulness of continuous 12-lead ECG monitoring requires additional clarification.
7. Decision aids that combine clinical features and ECG findings
ECG findings have been incorporated into mathematics-based decision aids for the triage of patients who present with chest pain (46). The goals of these decision aids include the identification of patients at low risk of cardiac events, those with cardiac ischemia or AMI and the estimation of prognosis (28,58,71–76).
8. Biochemical cardiac markers
Biochemical cardiac markers are useful for both the diagnosis of myocardial necrosis and the estimation of prognosis. The loss of membrane integrity of myocytes that undergo necrosis allows intracellular macromolecules to diffuse into the cardiac interstitium and then into the lymphatics and cardiac microvasculature (77). Eventually, these macromolecules, which are collectively referred to as biochemical cardiac markers, are detectable in the peripheral circulation. For optimum diagnostic usefulness, a marker of myocardial damage in the bloodstream should be present in a high concentration in the myocardium and absent from nonmyocardial tissue (52,77,78). It should be rapidly released into the blood after myocardial injury with a direct proportional relationship between the extent of myocardial injury and the measured level of the marker. Finally, the marker should persist in blood for a sufficient length of time to provide a convenient diagnostic time window with an easy, inexpensive, and rapid assay technique. Although no biochemical cardiac marker available at the present satisfies all of these requirements, as discussed later, the cardiac-specific troponins have a number of attractive features and are gaining acceptance as the biochemical markers of choice in the evaluation of patients with ACS (6).
For patients who present without ST-segment elevation, in whom the diagnosis may be unclear, biochemical cardiac markers are useful to confirm the diagnosis of MI. In addition, they provide valuable prognostic information, because there is a quantitative relationship between the magnitude of elevation of marker levels and the risk of an adverse outcome (79).
Creatine kinase. CK-MB has until recently been the principal serum cardiac marker used in the evaluation of ACS. Despite its common use, CK-MB has several limitations. Low levels of CK-MB in the blood of healthy persons limit its specificity for myocardial necrosis. CK-MB may also be elevated with severe damage of skeletal muscle (52,80,81). CK-MB isoforms exist in only 1 form in myocardial tissue (CK-MB2) but in different isoforms (or subforms) in plasma (CK-MB1). The use of an absolute level of CK-MB2 of >1 U/L and a ratio of CK-MB2 to CK-MB1 of >1.5 has improved sensitivity for the diagnosis of MI within the first 6 h compared with conventional assays for CK-MB, but this test has the same lack of absolute cardiac specificity as that of CK-MB itself (82). Moreover, the assay is not widely available.
Cardiac troponins. The troponin complex consists of 3 subunits: TnT, TnI, and troponin C (TnC) (81). Monoclonal antibody–based immunoassays have been developed to detect cardiac-specific TnT (cTnT) and cardiac-specific TnI (cTnI), because the amino acid sequences of the skeletal and cardiac isoforms of both TnT and TnI have sufficient dissimilarity. Because cardiac and smooth muscle share isoforms for TnC, no immunoassays of TnC have been developed for clinical purposes. Therefore, in these guidelines, the term "cardiac troponins" refers to either cTnT or cTnI or to both.
Because cTnT and cTnI are not detected in the blood of healthy persons, the cutoff value for elevated cTnI and cTnI levels may be set to slightly above the upper limit of the assay for a normal healthy population, leading some investigators to use the term "minor myocardial damage" or "microinfarction" for patients with detectable troponin but no CK-MB in the blood (83). Case reports exist that confirm histological evidence of focal myocyte necrosis (e.g., microinfarction) in patients with elevated cardiac troponin levels and normal CK-MB values (6,84,85), indicating that myocardial necrosis can be recognized with increased sensitivity. It is estimated that 
30% of patients who present with rest pain without ST-segment elevation and would otherwise be diagnosed as having UA because of a lack of CK-MB elevation actually have NSTEMI when assessed with cardiac-specific troponin assays.
Elevated levels of cTnT or cTnI convey prognostic information beyond that supplied by the clinical characteristics of the patient, the ECG at presentation, and a predischarge exercise test (61,62,86–88). Furthermore, among patients without ST-segment elevation and normal CK-MB levels, elevated cTnI or cTnT concentrations identify those at an increased risk of death (61,62). Finally, there is a quantitative relationship between the quantity of cTnI or cTnT that is measured and the risk of death in patients who present with an ACS (61,62,89) (Fig. 4). The incremental risk of death or MI in troponin-positive vs. troponin-negative patients is summarized in Tables 7 and 8. However, troponins should not be relied on as the sole markers for risk, because patients without troponin elevations may still exhibit a substantial risk of an adverse outcome. Neither marker is totally sensitive and specific in this regard. With currently available assays, cTnI and cTnT are of equal sensitivity and specificity in the detection of cardiac damage (90). The choice should be made on the basis of cost and the availability of instrumentation at the institution.
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Myoglobin. Although myoglobin, a low-molecular-weight heme protein found in both cardiac and skeletal muscle, is not cardiac specific, it is released more rapidly from infarcted myocardium than is CK-MB or the troponins and may be detected as early as 2 h after the onset of myocardial necrosis. However, the clinical value of serial determinations of myoglobin for the diagnosis of MI is limited by the brief duration of its elevation (<24 h) and by its lack of cardiac specificity. Thus, an isolated elevated concentration of myoglobin within the first 4 to 8 h after the onset of chest discomfort in patients with a nondiagnostic ECG should not be relied on to make the diagnosis of AMI but should be supplemented by a more cardiac-specific marker, such as CK-MB, cTnI, or cTnT (106,107). However, because of its high sensitivity, a negative test for myoglobin when blood is sampled within the first 4 to 8 h after onset is useful in ruling out myocardial necrosis.
Comparison of cardiac markers. The Diagnostic Marker Cooperative Study was a large, prospective, multicenter, double-blind study of patients who presented to the ED with chest pain in whom the diagnostic sensitivity and specificity for MI for total CK-MB (activity and mass), CK-MB subforms, myoglobin, and cTnI and cTnT were compared (108). CK-MB subforms and myoglobin were most efficient for the early diagnosis (within 6 h) of MI, whereas cTnI and cTnT were highly cardiac specific and were particularly efficient for the late diagnosis of MI.
Table 9 compares the advantages and disad
