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ACC/AHA GUIDELINE REVISION

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine

Jeffrey L. Anderson, MD, FACC, FAHA, Chair, Writing Committee Member, Cynthia D. Adams, RN, PhD FAHA, Writing Committee Member, Elliott M. Antman, MD, FACC, FAHA, Writing Committee Member, Charles R. Bridges, ScD, MD, FACC, FAHA, Writing Committee Member^_*, Robert M. Califf, MD, MACC, Writing Committee Member, Donald E. Casey, Jr, MD, MPH, MBA, FACP, Writing Committee Member, William E. Chavey, II, MD, MS, Writing Committee Member, Francis M. Fesmire, MD, FACEP, Writing Committee Member, Judith S. Hochman, MD, FACC, FAHA, Writing Committee Member, Thomas N. Levin, MD, FACC, FSCAI, Writing Committee Member^||, A. Michael Lincoff, MD, FACC, Writing Committee Member, Eric D. Peterson, MD, MPH, FACC, FAHA, Writing Committee Member, Pierre Theroux, MD, FACC, FAHA, Writing Committee Member, Nanette Kass Wenger, MD, FACC, FAHA, Writing Committee Member, R. Scott Wright, MD, FACC, FAHA, Writing Committee Member, Sidney C. Smith, Jr, MD, FACC, FAHA, Chair, ACC/AHA Task Force Member, Alice K. Jacobs, MD, FACC, FAHA, Vice-Chair, ACC/AHA Task Force Member, Cynthia D. Adams, RN, MSN, APRN-BC, FAHA, ACC/AHA Task Force Member, Jeffrey L. Anderson, MD, FACC, FAHA, ACC/AHA Task Force Member, Elliott M. Antman, MD, FACC, FAHA, ACC/AHA Task Force Member^¶, Jonathan L. Halperin, MD, FACC, FAHA, ACC/AHA Task Force Member, Sharon A. Hunt, MD, FACC, FAHA, ACC/AHA Task Force Member, Harlan M. Krumholz, MD, FACC, FAHA, ACC/AHA Task Force Member, Frederick G. Kushner, MD, FACC, FAHA, ACC/AHA Task Force Member, Bruce W. Lytle, MD, FACC, FAHA, ACC/AHA Task Force Member, Rick Nishimura, MD, FACC, FAHA, ACC/AHA Task Force Member, Joseph P. Ornato, MD, FACC, FAHA, ACC/AHA Task Force Member^_**, Richard L. Page, MD, FACC, FAHA, ACC/AHA Task Force Member and Barbara Riegel, DNSc, RN, FAHA, ACC/AHA Task Force Member

	Table of Contents

Top Table of Contents Preamble 1. Introduction 1.5 Onset of UA/NSTEMI 1.5.2 Silent and Unrecognized... 2. Initial Evaluation and... 2.2 Early Risk Stratification 2.3 Immediate Management 3. Early Hospital Care 5. Late Hospital Care,... 6. Special Groups 6.7 Variant (Prinzmetal's)... 6.8 Cardiovascular "Syndrome X" 6.9 Takotsubo Cardiomyopathy 7. Conclusions and Future... Staff Appendix References

1 Introduction.....e4

1.1 Organization of Committee and Evidence Review.....e4

1.2 Purpose of These Guidelines.....e6

1.3 Overview of the Acute Coronary Syndromes.....e6

1.3.1 Definition of Terms.....e6

1.3.2 Pathogenesis of UA/NSTEMI.....e8

1.3.3 Presentations of UA and NSTEMI.....e9

1.4 Management Before UA/NSTEMI and Onset of UA/NSTEMI.....e9

1.4.1 Identification of Patients at Risk of UA/NSTEMI.....e10

1.4.2 Interventions to Reduce Risk of UA/NSTEMI.....e10

1.5 Onset of UA/NSTEMI.....e11

1.5.1 Recognition of Symptoms by Patient.....e11

1.5.2 Silent and Unrecognized Events.....e11

2 Initial Evaluation and Management.....e12

2.1 Clinical Assessment.....e12

2.1.1 Emergency Department or Outpatient Facility Presentation.....e16

2.1.2 Questions to Be Addressed at the Initial Evaluation.....e16

2.2 Early Risk Stratification.....e16

2.2.1 Estimation of the Level of Risk.....e18

2.2.2 Rationale for Risk Stratification.....e18

2.2.3 History.....e19

2.2.4 Anginal Symptoms and Anginal Equivalents.....e19

2.2.5 Demographics and History in Diagnosis and Risk Stratification.....e20

2.2.6 Estimation of Early Risk at Presentation.....e21

2.2.6.1 Electrocardiogram.....e23

2.2.6.2 Physical Examination.....e24

2.2.7 Noncardiac Causes of Symptoms and Secondary Causes of Myocardial Ischemia.....e24

2.2.8 Cardiac Biomarkers of Necrosis and the Redefinition of AMI.....e25

2.2.8.1 Creatine Kinase-MB.....e25

2.2.8.2 Cardiac Troponins.....e26

2.2.8.2.1 Clinical Use.....e26

2.2.8.2.1.1 Clinical Use of Marker Change Scores.....e28

2.2.8.2.1.2 Bedside Testing for Cardiac Markers.....e29

2.2.8.3 Myoglobin and CK-MB Subforms Compared With Troponins.....e29

2.2.8.4 Summary Comparison of Biomarkers of Necrosis: Singly and in Combination.....e29

2.2.9 Other Markers and Multimarker Approaches.....e29

2.2.9.1 Ischemia.....e29

2.2.9.2 Coagulation.....e30

2.2.9.3 Platelets.....e30

2.2.9.4 Inflammation.....e30

2.2.9.5 B-Type Natriuretic Peptides.....e31

2.3 Immediate Management.....e31

2.3.1 Chest Pain Units.....e32

2.3.2 Discharge From ED or Chest Pain Unit.....e33

3 Early Hospital Care.....e34

3.1 Anti-Ischemic and Analgesic Therapy.....e35

3.1.1 General Care.....e38

3.1.2 Use of Anti-Ischemic Therapies.....e39

3.1.2.1 Nitrates.....e39

3.1.2.2 Morphine Sulfate.....e40

3.1.2.3 Beta-Adrenergic Blockers.....e41

3.1.2.4 Calcium Channel Blockers.....e43

3.1.2.5 Inhibitors of the Renin-Angiotensin-Aldosterone System.....e44

3.1.2.6 Other Anti-Ischemic Therapies.....e44

3.1.2.7 Intra-Aortic Balloon Pump Counterpulsation.....e45

3.1.2.8 Analgesic Therapy.....e45

3.2 Recommendations for Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite.....e45

3.2.1 Antiplatelet Therapy Recommendations.....e45

3.2.2 Anticoagulant Therapy Recommendations.....e46

3.2.3 Additional Management Considerations for Antiplatelet and Anticoagulant Therapy.....e47

3.2.4 Antiplatelet Agents and Trials (Aspirin, Ticlopidine, Clopidogrel).....e49

3.2.4.1 Aspirin.....e49

3.2.4.2 Adenosine Diphosphate Receptor Antagonists and Other Antiplatelet Agents.....e51

3.2.5 Anticoagulant Agents and Trials.....e55

3.2.5.1 Unfractionated Heparin.....e56

3.2.5.2 Low-Molecular-Weight Heparin.....e57

3.2.5.3 LMWH Versus UFH.....e58

3.2.5.3.1 Extended Therapy with LMWHs.....e61

3.2.5.4 Direct Thrombin Inhibitors.....e61

3.2.5.5 Factor Xa Inhibitors.....e64

3.2.5.6 Long-Term Anticoagulation.....e65

3.2.6 Platelet GP IIb/IIIa Receptor Antagonists.....e66

3.2.7 Fibrinolysis.....e72

3.3 Initial Conservative Versus Initial Invasive Strategies.....e72

3.3.1 General Principles.....e72

3.3.2 Rationale for the Initial Conservative Strategy.....e73

3.3.3 Rationale for the Invasive Strategy.....e73

3.3.4 Immediate Angiography.....e73

3.3.5 Deferred Angiography.....e73

3.3.6 Comparison of Early Invasive and Initial Conservative Strategies.....e73

3.3.7 Subgroups.....e77

3.3.8 Care Objectives.....e77

3.4 Risk Stratification Before Discharge.....e79

3.4.1 Care Objectives.....e80

3.4.2 Noninvasive Test Selection.....e81

3.4.3 Selection for Coronary Angiography.....e82

3.4.4 Patient Counseling.....e82

4 Coronary Revascularization.....e83

4.1 Recommendations for Revascularization With PCI and CABG in Patients With UA/NSTEMI.....e83

4.1.1 Recommendations for PCI.....e83

4.1.2 Recommendations for CABG.....e83

4.2 General Principles.....e84

4.3 Percutaneous Coronary Intervention.....e85

4.3.1 Platelet Inhibitors and Percutaneous Revascularization.....e86

4.4 Surgical Revascularization.....e87

4.5 Conclusions.....e89

5 Late Hospital Care, Hospital Discharge, and Post-Hospital Discharge Care.....e89

5.1 Medical Regimen and Use of Medications.....e90

5.2 Long-Term Medical Therapy and Secondary Prevention.....e90

5.2.1 Antiplatelet Therapy.....e91

5.2.2 Beta Blockers.....e91

5.2.3 Inhibition of the Renin-Angiotensin-Aldosterone System.....e91

5.2.4 Nitroglycerin.....e92

5.2.5 Calcium Channel Blockers.....e92

5.2.6 Warfarin Therapy.....e92

5.2.7 Lipid Management.....e92

5.2.8 Blood Pressure Control.....e94

5.2.9 Diabetes Mellitus.....e95

5.2.10 Smoking Cessation.....e95

5.2.11 Weight Management.....e95

5.2.12 Physical Activity.....e96

5.2.13 Patient Education.....e96

5.2.14 Influenza.....e96

5.2.15 Depression.....e96

5.2.16 Nonsteroidal Anti-Inflammatory Drugs.....e96

5.2.17 Hormone Therapy.....e97

5.2.18 Antioxidant Vitamins and Folic Acid.....e98

5.3 Postdischarge Follow-Up.....e98

5.4 Cardiac Rehabilitation.....e99

5.5 Return to Work and Disability.....e100

5.6 Other Activities.....e101

5.7 Patient Records and Other Information Systems.....e102

6 Special Groups.....e102

6.1 Women.....e102

6.1.1 Profile of UA/NSTEMI in Women.....e102

6.1.2 Management.....e103

6.1.2.1 Pharmacological Therapy.....e103

6.1.2.2 Coronary Artery Revascularization.....e103

6.1.2.3 Initial Invasive Versus Initial Conservative Strategy.....e104

6.1.3 Stress Testing.....e106

6.1.4 Conclusions.....e106

6.2 Diabetes Mellitus.....e106

6.2.1 Profile and Initial Management of Diabetic and Hyperglycemic Patients With UA/NSTEMI.....e107

6.2.2 Coronary Revascularization.....e108

6.2.3 Conclusions.....e109

6.3 Post-CABG Patients.....e109

6.3.1 Pathological Findings.....e109

6.3.2 Clinical Findings and Approach.....e109

6.3.3 Conclusions.....e110

6.4 Older Adults.....e110

6.4.1 Pharmacological Management.....e111

6.4.2 Functional Studies.....e111

6.4.3 Percutaneous Coronary Intervention in Older Patients.....e111

6.4.4 Contemporary Revascularization Strategies in Older Patients.....e112

6.4.5 Conclusions.....e112

6.5 Chronic Kidney Disease.....e112

6.6 Cocaine and Methamphetamine Users.....e113

6.6.1 Coronary Artery Spasm With Cocaine Use.....e114

6.6.2 Treatment.....e115

6.6.3 Methamphetamine Use and UA/NSTEMI.....e115

6.7 Variant (Prinzmetal’s) Angina.....e115

6.7.1 Clinical Picture.....e116

6.7.2 Pathogenesis.....e116

6.7.3 Diagnosis.....e116

6.7.4 Treatment.....e117

6.7.5 Prognosis.....e117

6.8 Cardiovascular "Syndrome X".....e117

6.8.1 Definition and Clinical Picture.....e117

6.8.2 Treatment.....e118

6.9 Takotsubo Cardiomyopathy.....e119

7 Conclusions and Future Directions.....e119
Appendix 1.....e121
Appendix 2.....e126
Appendix 3.....e131
References.....e133

	Preamble

Top Table of Contents Preamble 1. Introduction 1.5 Onset of UA/NSTEMI 1.5.2 Silent and Unrecognized... 2. Initial Evaluation and... 2.2 Early Risk Stratification 2.3 Immediate Management 3. Early Hospital Care 5. Late Hospital Care,... 6. Special Groups 6.7 Variant (Prinzmetal's)... 6.8 Cardiovascular "Syndrome X" 6.9 Takotsubo Cardiomyopathy 7. Conclusions and Future... Staff Appendix References

The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly engaged in the production of such guidelines in the area of cardiovascular disease since 1980. The American College of Cardiology (ACC)/AHA Task Force on Practice Guidelines, whose charge is to develop, update, or revise practice guidelines for important cardiovascular diseases and procedures, directs this effort. Writing committees are charged with the task of performing an assessment of the evidence and acting as an independent group of authors to develop, update, or revise written recommendations for clinical practice.

Experts in the subject under consideration have been selected from both organizations to examine subject-specific data and write guidelines. The process includes additional representatives from other medical practitioner and specialty groups when appropriate. Writing committees are specifically charged to perform a formal literature review, weigh the strength of evidence for or against a particular treatment or procedure, and 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. When available, information from studies on cost will be considered; however, review of data on efficacy and clinical outcomes will constitute the primary basis for preparing recommendations in these guidelines.

The ACC/AHA Task Force on Practice Guidelines makes every effort to avoid any actual, potential, or perceived conflict of interest that may arise as a result of an industry relationship or personal interest of a member of the Writing Committee. Specifically, all members of the Writing Committee, as well as peer reviewers of the document, were asked to provide disclosure statements of all such relationships that may be perceived as real or potential conflicts of interest. Writing Committee members are also strongly encouraged to declare a previous relationship with industry that may be perceived as relevant to guideline development. If a Writing Committee member develops a new relationship with industry during their tenure, they are required to notify guideline staff in writing. The continued participation of the Writing Committee member will be reviewed. These statements are reviewed by the parent task force, reported orally to all members of the Writing Committee at each meeting, and updated and reviewed by the Writing Committee as changes occur. Please refer to the methodology manual for ACC/AHA Guideline Writing Committees further description of relationships with industry policy, available on the ACC and AHA World Wide Web sites (http://www.acc.org/qualityandscience/clinical/manual/manual%5Fi.htm and http://www.circ.ahajournals.org/manual/). See Appendix 1 for a list of Writing Committee member relationships with industry and Appendix 2 for a listing of peer reviewer relationships with industry that are pertinent to this guideline.

These practice guidelines are intended to assist health care providers in clinical decision making by describing a range of generally acceptable approaches for the diagnosis, management, and prevention of specific diseases or conditions. Clinical decision making should consider the quality and availability of expertise in the area where care is provided. These guidelines attempt to define practices that meet the needs of most patients in most circumstances. These guideline recommendations reflect a consensus of expert opinion after a thorough review of the available, current scientific evidence and are intended to improve patient care.

Patient adherence to prescribed and agreed upon medical regimens and lifestyles is an important aspect of treatment. Prescribed courses of treatment in accordance with these recommendations will only be effective if they are followed. Since lack of patient understanding and adherence may adversely affect treatment outcomes, physicians and other health care providers should make every effort to engage the patient in active participation with prescribed medical regimens and lifestyles.

If these guidelines are used as the basis for regulatory/payer decisions, the ultimate goal is quality of care and serving the patient’s best interests. The ultimate judgment regarding care of a particular patient must be made by the health care provider and patient in light of all the circumstances presented by that patient. There are circumstances in which derivations from these guidelines are appropriate.

The guidelines will be reviewed annually by the ACC/AHA Task Force on Practice Guidelines and will be considered current unless they are updated, revised, or sunsetted and withdrawn from distribution. The executive summary and recommendations are published in the August 7, 2007, issue of the Journal of the American College of Cardiology and August 7, 2007, issue of Circulation. The full-text guidelines are e-published in the same issue of the journals noted above, as well as posted on the ACC (www.acc.org) and AHA (www.americanheart.org) World Wide Web sites. Copies of the full text and the executive summary are available from both organizations.

Sidney C. Smith, Jr, MD, FACC, FAHA Chair, ACC/AHA Task Force on Practice Guidelines

	1. Introduction

Top Table of Contents Preamble 1. Introduction 1.5 Onset of UA/NSTEMI 1.5.2 Silent and Unrecognized... 2. Initial Evaluation and... 2.2 Early Risk Stratification 2.3 Immediate Management 3. Early Hospital Care 5. Late Hospital Care,... 6. Special Groups 6.7 Variant (Prinzmetal's)... 6.8 Cardiovascular "Syndrome X" 6.9 Takotsubo Cardiomyopathy 7. Conclusions and Future... Staff Appendix References

 
1.1 Organization of Committee and Evidence Review.   The ACC/AHA Task Force on Practice Guidelines was formed to make recommendations regarding the diagnosis and treatment of patients with known or suspected cardiovascular disease (CVD). Coronary artery disease (CAD) is the leading cause of death in the United States. Unstable angina (UA) and the closely related condition of non–ST-segment elevation myocardial infarction (NSTEMI) are very common manifestations of this disease.

The committee members reviewed and compiled published reports through a series of computerized literature searches of the English-language literature since 2002 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) to lowest (C). The final recommendations for indications for a diagnostic procedure, a particular therapy, or an intervention in patients with UA/NSTEMI summarize both clinical evidence and expert opinion.

Classification of Recommendations
The schema for classification of recommendations and level of evidence is summarized in Table 1, which also illustrates how the grading system provides an estimate of the size of the treatment effect and an estimate of the certainty of the treatment effect.

View this table: [in this window] [in a new window]   Table 1 Applying Classification of Recommendations and Level of Evidence

These guidelines overlap several previously published ACC/AHA practice guidelines, including the ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (1), the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention (2), the AHA/ACC Guidelines for Secondary Prevention for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2006 Update (3), and the ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina (4).

1.2 Purpose of These Guidelines.   These guidelines address the diagnosis and management of patients with UA and the closely related condition of NSTEMI. These life-threatening disorders are a major cause of emergency medical care and hospitalization in the United States. In 2004, the National Center for Health Statistics reported 1,565,000 hospitalizations for primary or secondary diagnosis of an acute coronary syndrome (ACS), 669,000 for UA and 896,000 for myocardial infarction (MI) (5). The average age of a person having a first heart attack is 65.8 years for men and 70.4 years for women, and 43% of ACS patients of all ages are women. In 2003, there were 4,497,000 visits to US emergency departments (EDs) for primary diagnosis of CVD (5). The prevalence of this presentation of CVD ensures that many health care 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/NSTEMI.

1.3 Overview of the Acute Coronary Syndromes.   1.3.1 Definition of Terms
Unstable angina/NSTEMI constitutes a clinical syndrome subset of the ACS that is usually, but not always, caused by atherosclerotic CAD and is associated with an increased risk of cardiac death and subsequent MI. In the spectrum of ACS, UA/NSTEMI is defined by electrocardiographic (ECG) ST-segment depression or prominent T-wave inversion and/or positive biomarkers of necrosis (e.g., troponin) in the absence of ST-segment elevation and in an appropriate clinical setting (chest discomfort or anginal equivalent) (Table 2, Fig. 1). The results of angiographic and angioscopic studies suggest that UA/NSTEMI often results from the disruption or erosion 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. 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 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.

View larger version (54K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Acute Coronary Syndromes The top half of the figure illustrates the chronology of the interface between the patient and the clinician through the progression of plaque formation, onset, and complications of UA/NSTEMI, along with relevant management considerations at each stage. The longitudinal section of an artery depicts the "timeline" of atherogenesis from (1) a normal artery to (2) lesion initiation and accumulation of extracellular lipid in the intima, to (3) the evolution to the fibrofatty stage, to (4) lesion progression with procoagulant expression and weakening of the fibrous cap. An acute coronary syndrome (ACS) develops when the vulnerable or high-risk plaque undergoes disruption of the fibrous cap (5); disruption of the plaque is the stimulus for thrombogenesis. Thrombus resorption may be followed by collagen accumulation and smooth muscle cell growth (6). After disruption of a vulnerable or high-risk plaque, patients experience ischemic discomfort that results from a reduction of flow through the affected epicardial coronary artery. The flow reduction may be caused by a completely occlusive thrombus (bottom half, right side) or subtotally occlusive thrombus (bottom half, left side). Patients with ischemic discomfort may present with or without ST-segment elevation on the ECG. Among patients with ST-segment elevation, most (thick white arrow in bottom panel) ultimately develop a Q-wave MI (QwMI), although a few (thin white arrow) develop a non–Q-wave MI (NQMI). Patients who present without ST-segment elevation are suffering from either unstable angina (UA) or a non–ST-segment elevation MI (NSTEMI) (thick red arrows), a distinction that is ultimately made on the basis of the presence or absence of a serum cardiac marker such as CK-MB or a cardiac troponin detected in the blood. Most patients presenting with NSTEMI ultimately develop a NQMI on the ECG; a few may develop a QwMI. The spectrum of clinical presentations ranging from UA through NSTEMI and STEMI is referred to as the acute coronary syndromes. This UA/NSTEMI guideline, as diagrammed in the upper panel, includes sections on initial management before UA/NSTEMI, at the onset of UA/NSTEMI, and during the hospital phase. Secondary prevention and plans for long-term management begin early during the hospital phase of treatment. *Positive serum cardiac marker. Modified with permission from Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001;104:365 (7); © 2001 Lippincott, Williams & Wilkins; The Lancet, 358, Hamm CW, Bertrand M, Braunwald E. Acute coronary syndrome without ST elevation: implementation of new guidelines, 1533–8. Copyright 2001, with permission from Elsevier (8); and Davies MJ. The pathophysiology of acute coronary syndromes. Heart 2000;83:361–6 (9). © 2000 Lippincott, Williams & Wilkins. CK-MB = MB fraction of creatine kinase; Dx = diagnosis; ECG = electrocardiogram.

Patients diagnosed as having STEMI are excluded from management according to these guidelines and should be managed as indicated according to the ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (1,10). Similarly, management of electrocardiographic true posterior MI, which can masquerade as NSTEMI, is covered in the STEMI guidelines (1). The management of patients who experience periprocedural myocardial damage, as reflected in the release of biomarkers of necrosis, such as the MB isoenzyme of creatine kinase (CK-MB) or troponin, also is not considered here.

Patients with MI and with definite ischemic ECG changes for whom acute reperfusion therapy is not suitable should be diagnosed and managed as patients with UA. The residual group of patients with an initial diagnosis of ACS will include many patients who will ultimately be proven to have a noncardiac cause for the initial clinical presentation that was suggestive of ACS. Therefore, at the conclusion of the initial evaluation, which is frequently performed in the ED but sometimes occurs during the initial hours of inpatient hospitalization, each patient should have a provisional diagnosis of 1) ACS (Fig. 1), which in turn is classified as a) STEMI, a condition for which immediate reperfusion therapy (fibrinolysis or percutaneous coronary intervention [PCI]) should be considered, b) NSTEMI, or c) UA (definite, probable, or possible); 2) a non-ACS cardiovascular condition (e.g., acute pericarditis); 3) a noncardiac condition with another specific disease (e.g., chest pain secondary to esophageal spasm); or 4) a noncardiac condition that is undefined. In addition, the initial evaluation should be used to determine risk and to treat life-threatening events.

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 biomarker of myocardial necrosis has been released (based on 2 or more samples collected at least 6 h apart, with a reference limit of the 99th percentile of the normal population) (11), the patient with ACS may be considered to have experienced UA, whereas the diagnosis of NSTEMI is established if a biomarker has been released. Markers of myocardial injury can be detected in the bloodstream with a delay of up to several hours after the onset of ischemic chest pain, which then allows the differentiation between UA (i.e., no biomarkers in circulation; usually transient, if any, ECG changes of ischemia) and NSTEMI (i.e., elevated biomarkers). Thus, at the time of presentation, patients with UA and NSTEMI can be indistinguishable and therefore are considered together in these guidelines.

1.3.2 Pathogenesis of UA/NSTEMI
These conditions are characterized by an imbalance between myocardial oxygen supply and demand. They are not a specific disease, such as pneumococcal pneumonia, but rather a syndrome, analogous to hypertension. A relatively few nonexclusive causes are recognized (12) (Table 3).

• The most common cause of UA/NSTEMI is reduced myocardial perfusion that results from coronary artery narrowing caused by a thrombus that developed on a disrupted atherosclerotic plaque and is usually nonocclusive. Microembolization of platelet aggregates and components of the disrupted plaque are believed to be responsible for the release of myocardial markers in many of these patients. An occlusive thrombus/plaque also can cause this syndrome in the presence of an extensive collateral blood supply.

• The most common underlying molecular and cellular pathophysiology of disrupted atherosclerotic plaque is arterial inflammation, caused by noninfectious (e.g., oxidized lipids) and, possibly, infectious stimuli, which can lead to plaque expansion and destabilization, rupture or erosion, and thrombogenesis. Activated macrophages and T lymphocytes located at the shoulder of a plaque increase the expression of enzymes such as metalloproteinases that cause thinning and disruption of the plaque, which in turn can lead to UA/NSTEMI.

• A less common cause is dynamic obstruction, which may be triggered by intense focal spasm of a segment of an epicardial coronary artery (Prinzmetal’s angina) (see Section 6.7). This local spasm is caused by hypercontractility of vascular smooth muscle and/or by endothelial dysfunction. Large-vessel spasm can occur on top of obstructive or destabilized plaque, resulting in angina of "mixed" origin or UA/NSTEMI. Dynamic coronary obstruction can also be caused by diffuse microvascular dysfunction; for example, due to endothelial dysfunction or the abnormal constriction of small intramural resistance vessels. Coronary spasm also is the presumed mechanism underlying cocaine-induced UA/NSTEMI.

• A third cause of UA/NSTEMI is severe narrowing without spasm or thrombus. This occurs in some patients with progressive atherosclerosis or with restenosis after a PCI.

• A fourth cause of UA/NSTEMI is coronary artery dissection (e.g., as a cause of ACS in peripartal women).

• The fifth mechanism is secondary UA, in which the precipitating condition is extrinsic to the coronary arterial bed. Patients with secondary UA usually, but not always, have underlying coronary atherosclerotic narrowing that limits myocardial perfusion, and they often have chronic stable angina. Secondary UA is precipitated by conditions that 1) increase myocardial oxygen requirements, such as fever, tachycardia, or thyrotoxicosis; 2) reduce coronary blood flow, such as hypotension; or 3) reduce myocardial oxygen delivery, such as anemia or hypoxemia.

These causes of UA/NSTEMI are not mutually exclusive.

1.3.3 Presentations of UA and NSTEMI
There are 3 principal presentations of UA: 1) rest angina (angina commencing when the patient is at rest), 2) new-onset (less than 2 months) severe angina, and 3) increasing angina (increasing in intensity, duration, and/or frequency) (Table 4) (14). Criteria for the diagnosis of UA are based on the duration and intensity of angina as graded according to the Canadian Cardiovascular Society classification (Table 5) (15). Non–ST-elevation MI generally presents as prolonged, more intense rest angina or angina equivalent.

1.4.1 Identification of Patients at Risk of UA/NSTEMI
Class I

1 Primary care providers should evaluate the presence and status of control of major risk factors for CHD for all patients at regular intervals (approximately every 3 to 5 years). (Level of Evidence: C)

2 Ten-year risk (National Cholesterol Education Program [NCEP] global risk) of developing symptomatic CHD should be calculated for all patients who have 2 or more major risk factors to assess the need for primary prevention strategies (16,17). (Level of Evidence: B)

3 Patients with established CHD should be identified for secondary prevention efforts, and patients with a CHD risk equivalent (e.g., atherosclerosis in other vascular beds, diabetes mellitus, chronic kidney disease, or 10-year risk greater than 20% as calculated by Framingham equations) should receive equally intensive risk factor intervention as those with clinically apparent CHD. (Level of Evidence: A)

Major risk factors for developing CHD (i.e., smoking, family history, adverse lipid profiles, diabetes mellitus, and elevated blood pressure) have been established from large, long-term epidemiological studies (18,19). These risk factors are predictive for most populations in the United States. Primary and secondary prevention interventions aimed at these risk factors are effective when used properly. They can also be costly in terms of primary care provider time, diversion of attention from other competing and important health care needs, and expense, and they may not be effective unless targeted at higher-risk patients (20). It is therefore important for primary care providers to make the identification of patients at risk, who are most likely to benefit from primary prevention, a routine part of everyone’s health care. The Third Report of the NCEP provides guidance on identifying such patients (18). Furthermore, the Writing Committee supports public health efforts to reach all adults at risk, not just those under the care of a primary care physician.

Patients with 2 or more risk factors who are at increased 10-year and lifetime risk will have the greatest benefit from primary prevention, but any individual with a single elevated risk factor is a candidate for primary prevention (19). Waiting until the patient develops multiple risk factors and increased 10-year risk contributes to the high prevalence of CHD in the United States (18,21). Such patients should have their risk specifically calculated by any of the several valid prognostic tools available in print (18,22), on the Internet (23), or for use on a personal computer or personal digital assistant (PDA) (18). Patients’ specific risk levels determine the absolute risk reductions they can obtain from preventive interventions and guide selection and prioritization of those interventions. For example, target levels for lipid lowering and for antihypertensive therapy vary by patients’ baseline risk. A specific risk number can also serve as a powerful educational intervention to motivate lifestyle changes (24).

The detection of subclinical atherosclerosis by noninvasive imaging represents a new, evolving approach for refining individual risk in asymptomatic individuals beyond traditional risk factor assessment alone. A recent AHA scientific statement indicates that it may be reasonable to measure atherosclerosis burden using electron-beam or multidetector computed tomography (CT) in clinically selected intermediate-CAD-risk individuals (e.g., those with a 10% to 20% Framingham 10-year risk estimate) to refine clinical risk prediction and to select patients for aggressive target values for lipid-lowering therapies (Class IIb, Level of Evidence: B) (25).

1.4.2 Interventions to Reduce Risk of UA/NSTEMI
The benefits of prevention of UA/NSTEMI in patients with CHD are well documented and of large magnitude (3,21,26–28). Patients with established CHD should be identified for secondary prevention efforts, and patients with a CHD risk equivalent should receive equally intensive risk factor intervention for high-risk primary prevention regardless of sex (29). Patients with diabetes mellitus and peripheral vascular disease have baseline risks of UA/NSTEMI similar to patients with known CHD, as do patients with multiple risk factors that predict a calculated risk of greater than 20% over 10 years as estimated by the Framingham equations (18). Such patients should be considered to have the risk equivalents of CHD, and they can be expected to have an absolute benefit similar to those with established CHD.

All patients who use tobacco should be encouraged to quit and should be provided with help in quitting at every opportunity (30). Recommendations by a clinician to avoid tobacco can have a meaningful impact on the rate of cessation of tobacco use. The most effective strategies for encouraging quitting are those that identify the patient’s level or stage of readiness and provide information, support, and, if necessary, pharmacotherapy targeted at the individual’s readiness and specific needs (26,31). Pharmacotherapy may include nicotine replacement or withdrawal-relieving medication such as bupropion. Varenicline, a nicotine acetylcholine receptor partial antagonist, is a newly approved nonnicotine replacement therapy for tobacco avoidance (32–35). Many patients require several attempts before they succeed in quitting permanently (36,37). Additional discussion in this area can be found in other contemporary documents (e.g., the ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina [4]).

All patients should be instructed in and encouraged to maintain appropriate low-saturated-fat, low-trans-fat, and low-cholesterol diets high in soluble (viscous) fiber and rich in vegetables, fruits, and whole grains. All patients also should be encouraged to be involved with a regular aerobic exercise program, including 30 to 60 min of moderate-intensity physical activity (such as brisk walking) on most and preferably all days of the week (3,38). For those who need to weigh less, an appropriate balance of increased physical activity (i.e., 60 to 90 min daily), caloric restriction, and formal behavioral programs is encouraged to achieve and maintain a body mass index between 18.5 and 24.9 kg/m² and a waist circumference of less than or equal to 35 inches in women and less than or equal to 40 inches in men. For those who need lipid lowering beyond lifestyle measures, the statin drugs have the best outcome evidence supporting their use and should be the mainstay of pharmacological intervention (21). The appropriate levels for lipid management are dependent on baseline risk; the reader is referred to the NCEP report (http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm) for details (17,18,39–41).

Primary prevention patients with high blood pressure should be treated according to the recommendations of the Seventh Joint National Committee on High Blood Pressure (JNC 7) (42,43). Specific treatment recommendations are based on the level of hypertension and the patient’s other risk factors. A diet low in salt and rich in vegetables, fruits, and low-fat dairy products should be encouraged for all hypertensive patients, as should a regular aerobic exercise program (44–47). Most patients will require more than 1 medication to achieve blood pressure control, and pharmacotherapy should begin with known outcome-improving medications (primarily thiazide diuretics as first choice, with the addition of beta blockers, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers, and/or long-acting calcium channel blockers) (42,48). Systolic hypertension is a powerful predictor of adverse outcome, particularly among the elderly, and it should be treated even if diastolic pressures are normal (49).

Detection of hyperglycemic risk (e.g., metabolic syndrome) and diabetes mellitus should be pursued as part of risk assessment. Lifestyle changes and pharmacotherapy are indicated in individuals with diabetes mellitus to achieve a glycosylated hemoglobin [HbA1c] level less than 7% but to avoid hypoglycemia (3,50,51).

Aspirin prophylaxis can uncommonly result in hemorrhagic complications and should only be used in primary prevention when the level of risk justifies it. Patients whose 10-year risk of CHD is 10% or more are most likely to benefit, and 75 to 162 mg of aspirin (ASA) per day as primary prophylaxis should be discussed with such patients (29,38,52–55).

	1.5 Onset of UA/NSTEMI

Top Table of Contents Preamble 1. Introduction 1.5 Onset of UA/NSTEMI 1.5.2 Silent and Unrecognized... 2. Initial Evaluation and... 2.2 Early Risk Stratification 2.3 Immediate Management 3. Early Hospital Care 5. Late Hospital Care,... 6. Special Groups 6.7 Variant (Prinzmetal's)... 6.8 Cardiovascular "Syndrome X" 6.9 Takotsubo Cardiomyopathy 7. Conclusions and Future... Staff Appendix References

 
1.5.1 Recognition of Symptoms by Patient.   Early recognition of symptoms of UA/NSTEMI by the patient or someone with the patient is the first step that must occur before evaluation and life-saving treatment can be obtained. Although many laypersons are generally aware that chest pain is a presenting symptom of UA/NSTEMI, they are unaware of the other common symptoms, such as arm pain, lower jaw pain, shortness of breath (56), and diaphoresis (57) or anginal equivalents, such as dyspnea or extreme fatigue (56,58). The average patient with NSTEMI or prolonged rest UA (e.g., longer than 20 min) does not seek medical care for approximately 2 h after symptom onset, and this pattern appears unchanged over the last decade (58–60). A baseline analysis from the Rapid Early Action for Coronary Treatment (REACT) research program demonstrated longer delay times among non-Hispanic blacks, older patients, and Medicaid-only recipients and shorter delay times among Medicare recipients (compared with privately insured patients) and patients who came to the hospital by ambulance (58). In the majority of studies examined to date, women in both univariate- and multivariate-adjusted analyses (in which age and other potentially confounding variables have been controlled) exhibit more prolonged delay patterns than men (61).

A number of studies have provided insight into why patients delay in seeking early care for heart symptoms (62). Focus groups conducted for the REACT research program (63,64) revealed that patients commonly hold a preexisting expectation that a heart attack would present dramatically with severe, crushing chest pain, such that there would be no doubt that one was occurring. This was in contrast to their actual reported symptom experience of a gradual onset of discomfort involving midsternal chest pressure or tightness, with other associated symptoms often increasing in intensity. The ambiguity of these symptoms, due to this disconnect between prior expectations and actual experience, resulted in uncertainty about the origin of symptoms and thus a "wait-and-see" posture by patients and those around them (62). Other reported reasons for delay were that patients thought the symptoms were self-limited and would go away or were not serious (65–67); that they attributed symptoms to other preexisting chronic conditions, especially among older adults with multiple chronic conditions (e.g., arthritis), or sometimes to a common illness such as influenza; that they were afraid of being embarrassed if symptoms turned out to be a "false alarm"; that they were reluctant to trouble others (e.g., health care providers, Emergency Medical Services [EMS]) unless they were "really sick" (65–67); that they held stereotypes of who is at risk for a heart attack; and that they lacked awareness of the importance of rapid action, knowledge of reperfusion treatment, or knowledge of the benefits of calling EMS/9-1-1 to ensure earlier treatment (62). Notably, women did not perceive themselves to be at risk (69).

	1.5.2 Silent and Unrecognized Events

Top Table of Contents Preamble 1. Introduction 1.5 Onset of UA/NSTEMI 1.5.2 Silent and Unrecognized... 2. Initial Evaluation and... 2.2 Early Risk Stratification 2.3 Immediate Management 3. Early Hospital Care 5. Late Hospital Care,... 6. Special Groups 6.7 Variant (Prinzmetal's)... 6.8 Cardiovascular "Syndrome X" 6.9 Takotsubo Cardiomyopathy 7. Conclusions and Future... Staff Appendix References

 
Patients experiencing UA/NSTEMI do not always present with chest discomfort (70). The Framingham Study was the first to show that as many as half of all MIs may be clinically silent and unrecognized by the patient (71). Canto et al. (72) found that one third of the 434,877 patients with confirmed MI in the National Registry of Myocardial Infarction presented to the hospital with symptoms other than chest discomfort. Compared with MI patients with chest discomfort, MI patients without chest discomfort were more likely to be older, to be women, to have diabetes, and/or to have prior heart failure [HF]. Myocardial infarction patients without chest discomfort delayed longer before they went to the hospital (mean 7.9 vs. 5.3 h) and were less likely to be diagnosed as having an MI when admitted (22.2% vs. 50.3%). They also were less likely to receive fibrinolysis or primary PCI, ASA, beta blockers, or heparin. Silent MI patients were 2.2 times more likely to die during the hospitalization (in-hospital mortality rate 23.3% vs. 9.3%). Unexplained dyspnea, even without angina, is a particularly worrisome symptom, with more than twice the risk of death than for typical angina in patients undergoing cardiovascular evaluation (56). Recently, the prognostic significance of dyspnea has been emphasized in patients undergoing cardiac evaluation. Self-reported dyspnea alone among 17,991 patients undergoing stress perfusion testing was an independent predictor of cardiac and total mortality and increased the risk of sudden cardiac death 4-fold even in those with no prior history of CAD (56).

Health care providers should maintain a high index of suspicion for UA/NSTEMI when evaluating women, patients with diabetes mellitus, older patients, those with unexplained dyspnea (56), and those with a history of HF or stroke, as well as those patients who complain of chest discomfort but who have a permanent pacemaker that may confound recognition of UA/NSTEMI on their 12-lead ECG (73).

	2. Initial Evaluation and Management

Top Table of Contents Preamble 1. Introduction 1.5 Onset of UA/NSTEMI 1.5.2 Silent and Unrecognized... 2. Initial Evaluation and... 2.2 Early Risk Stratification 2.3 Immediate Management 3. Early Hospital Care 5. Late Hospital Care,... 6. Special Groups 6.7 Variant (Prinzmetal's)... 6.8 Cardiovascular "Syndrome X" 6.9 Takotsubo Cardiomyopathy 7. Conclusions and Future... Staff Appendix References

 
2.1 Clinical Assessment.   Because symptoms are similar and the differentiation of UA/NSTEMI and STEMI requires medical evaluation, we will refer to prediagnostic clinical presentation as ACS, defined as UA or MI (NSTEMI or STEMI) (Fig. 2).

View larger version (35K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Algorithm for Evaluation and Management of Patients Suspected of Having ACS To facilitate interpretation of this algorithm and a more detailed discussion in the text, each box is assigned a letter code that reflects its level in the algorithm and a number that is allocated from left to right across the diagram on a given level. ACC/AHA = American College of Cardiology/American Heart Association; ACS = acute coronary syndrome; ECG = electrocardiogram; LV = left ventricular.

1 Patients with symptoms that may represent ACS (Table 2) 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 and biomarker determination (e.g., an ED or other acute care facility). (Level of Evidence: C)

2 Patients with symptoms of ACS (chest discomfort with or without radiation to the arm[s], back, neck, jaw or epigastrium; shortness of breath; weakness; diaphoresis; nausea; lightheadedness) should be instructed to call 9-1-1 and should be transported to the hospital by ambulance rather than by friends or relatives. (Level of Evidence: B)

3 Health care providers should actively address the following issues regarding ACS with patients with or at risk for CHD and their families or other responsible caregivers:

a The patient’s heart attack risk; (Level of Evidence: C)

b How to recognize symptoms of ACS; (Level of Evidence: C)

c The advisability of calling 9-1-1 if symptoms are unimproved or worsening after 5 min, despite feelings of uncertainty about the symptoms and fear of potential embarrassment; (Level of Evidence: C)

d A plan for appropriate recognition and response to a potential acute cardiac event, including the phone number to access EMS, generally 9-1-1 (74). (Level of Evidence: C)

4 Prehospital EMS providers should administer 162 to 325 mg of ASA (chewed) to chest pain patients suspected of having ACS unless contraindicated or already taken by the patient. Although some trials have used enteric-coated ASA for initial dosing, more rapid buccal absorption occurs with non–enteric-coated formulations. (Level of Evidence: C)

5 Health care providers should instruct patients with suspected ACS for whom nitroglycerin [NTG] has been prescribed previously to take not more than 1 dose of NTG sublingually in response to chest discomfort/pain. If chest discomfort/pain is unimproved or is worsening 5 min after 1 NTG dose has been taken, it is recommended that the patient or family member/friend/caregiver call 9-1-1 immediately to access EMS before taking additional NTG. In patients with chronic stable angina, if symptoms are significantly improved by 1 dose of NTG, it is appropriate to instruct the patient or family member/friend/caregiver to repeat NTG every 5 min for a maximum of 3 doses and call 9-1-1 if symptoms have not resolved completely. (Level of Evidence: C)

6 Patients with a suspected ACS with chest discomfort or other ischemic symptoms at rest for greater than 20 min, hemodynamic instability, or recent syncope or presyncope should be referred immediately to an ED. Other patients with suspected ACS who are experiencing less severe symptoms and who have none of the above high-risk features, including those who respond to an NTG dose, may be seen initially in an ED or an outpatient facility able to provide an acute evaluation. (Level of Evidence: C)

Class IIa

1 It is reasonable for health care providers and 9-1-1 dispatchers to advise patients without a history of ASA allergy who have symptoms of ACS to chew ASA (162 to 325 mg) while awaiting arrival of prehospital EMS providers. Although some trials have used enteric-coated ASA for initial dosing, more rapid buccal absorption occurs with non–enteric-coated formulations. (Level of Evidence: B)

2 It is reasonable for health care providers and 9-1-1 dispatchers to advise patients who tolerate NTG to repeat NTG every 5 min for a maximum of 3 doses while awaiting ambulance arrival. (Level of Evidence: C)

3 It is reasonable that all prehospital EMS providers perform and evaluate 12-lead ECGs in the field (if available) on chest pain patients suspected of ACS to assist in triage decisions. Electrocardiographs with validated computer-generated interpretation algorithms are recommended for this purpose. (Level of Evidence: B)

4 If the 12-lead ECG shows evidence of acute injury or ischemia, it is reasonable that prehospital ACLS providers relay the ECG to a predetermined medical control facility and/or receiving hospital. (Level of Evidence: B)

Patients with suspected ACS must be evaluated rapidly. Decisions made on the basis of the initial evaluation have substantial clinical and economic consequences (75). The first triage decision is made by the patient, who must decide whether to access the health care system. Media campaigns such as "Act in Time," sponsored by the National Heart, Lung, and Blood Institute (NHLBI), provide patient education regarding this triage decision (www.nhlbi.nih.gov/actintime). The campaign urges both men and women who feel heart attack symptoms or observe the signs in others to wait no more than a few minutes, 5 min at most, before calling 9-1-1 (76,77). Campaign materials point out that patients can increase their chance of surviving a heart attack by learning the symptoms and filling out a survival plan. They also are advised to talk with their doctor about heart attacks and how to reduce their risk of having one. The patient materials include a free brochure about symptoms and recommended actions for survival, in English (78) and Spanish (79), as well as a free wallet card that can be filled in with emergency medical information (80). Materials geared directly to providers include a Patient Action Plan Tablet (81), which contains the heart attack warning symptoms and steps for developing a survival plan, individualized with the patient’s name; a quick reference card for addressing common patient questions about seeking early treatment to survive a heart attack (82), including a PDA version (83); and a warning signs wall chart (84). These materials and others are available on the "Act in Time" Web page (www.nhlbi.nih.gov/health/public/heart/mi/core_bk.pdf) (77).

When the patient first makes contact with the medical care system, a critical decision must be made about where the evaluation will take place. The health care provider then must place the evaluation in the context of 2 critical questions: Are the symptoms a manifestation of an ACS? If so, what is the prognosis? The answers to these 2 questions lead logically to a series of decisions about where the patient will be best managed, what medications will be prescribed, and whether an angiographic evaluation will be required.

Given the large number of patients with symptoms compatible with ACS, the heterogeneity of the population, and a clustering of events shortly after the onset of symptoms, a strategy for the initial evaluation and management is essential. Health care providers may be informed about signs and symptoms of ACS over the telephone or in person by the patient or family members. 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.

Health practitioners frequently receive telephone calls from patients or family members/friends/caregivers who are concerned that their symptoms could 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, health care providers, EMS dispatchers, and staff positioned to receive these calls should advise patients with possible accelerating angina or angina at rest that an evaluation cannot be performed solely via the telephone. This advice is essential because of the need for timely evaluation, including a physical examination, ECG, and appropriate blood tests to measure cardiac biomarkers.

Patients with known CAD—including those with chronic stable angina, recent MI, or prior intervention (i.e., coronary artery bypass graft surgery [CABG] or PCI)—who contact a physician or other appropriate member of the health care team because of worsening or recurrent symptoms should be instructed to proceed rapidly to an ED, preferably one equipped to perform prompt reperfusion therapy. When the discomfort is moderate to severe or sustained, they should be instructed to access the EMS system directly by calling 9-1-1. Patients who have been evaluated recently and who are calling for advice regarding modification of medications 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 (85). In a large study of consecutive patients with chest pain suspected to be of cardiac origin who were transported to the ED via ambulance, one third had a final diagnosis of MI, one third had a final diagnosis of UA, and one third had a final diagnosis of a noncardiac cause; 1.5% of these patients developed cardiopulmonary arrest before arrival at the hospital or in the ED (86).

Every community should have a written protocol that guides EMS system personnel in determining where to take patients with suspected or confirmed ACS. Active involvement of local health care providers, particularly cardiologists and emergency physicians, is needed to formulate local EMS destination protocols for these patients. In general, patients with suspected ACS should be taken to the nearest appropriate hospital; however, patients with known STEMI and/or cardiogenic shock should be sent as directly as possible to hospitals with interventional and surgical capability (1).

The advent of highly effective, time-dependent treatment for ACS, coupled with the need to reduce health care costs, adds further incentive for clinicians to get the right answer quickly and to reduce unnecessary admissions and length of hospital stay. Investigators have tried various diagnostic tools, such as clinical decision algorithms, cardiac biomarkers, serial ECGs, echocardiography, myocardial perfusion imaging, and multidetector (e.g., 64-slice) coronary CT angiography (CCTA), in an attempt to avoid missing patients with MI or UA. The most successful strategies to emerge thus far are designed to identify MI patients and, when clinically appropriate, screen for UA and underlying CAD. Most strategies use a combination of cardiac biomarkers, short-term observation, diagnostic imaging, and provocative stress testing. An increasing number of high-quality centers now use structured protocols, checklists, or critical pathways to screen patients with suspected MI or UA (87–99). It does not appear to matter whether the institution designates itself a chest pain center; rather, it is the multifaceted, multidisciplinary, standardized, and structured approach to the problem that appears to provide clinical, cost-effective benefit (100,101). One randomized trial has confirmed the safety, efficacy, and cost-effectiveness of the structured decision-making approach compared with standard, unstructured care (102).

Regardless of the approach used, all patients presenting to the ED with chest discomfort or other symptoms suggestive of MI or UA should be considered high-priority triage cases and should be evaluated and treated on the basis of a predetermined, institution-specific chest pain protocol. The protocol should include several diagnostic possibilities (Fig. 2) (103). The patient should be placed on a cardiac monitor immediately, with emergency resuscitation equipment, including a defibrillator, nearby. An ECG also should be performed immediately and evaluated by an experienced emergency medicine physician, with a goal of within 10 min of ED arrival. If STEMI is present, the decision as to whether the patient will be treated with fibrinolytic therapy or primary PCI should be made within the next 10 min (1). For cases in which the initial diagnosis and treatment plan are unclear to the emergency medicine physician or are not covered directly by an institutionally agreed-upon protocol, immediate cardiology consultation is advisable.

Morbidity and mortality from ACS can be reduced significantly if patients and bystanders recognize symptoms early, activate the EMS system, and thereby shorten the time to definitive treatment. Patients with possible symptoms of MI should be transported to the hospital by ambulance rather than by friends or relatives, because there is a significant association between arrival at the ED by ambulance and early reperfusion therapy in STEMI patients (104–107). In addition, emergency medical technicians and paramedics can provide life-saving interventions (e.g., early cardiopulmonary resuscitation [CPR] and defibrillation) if the patient develops cardiac arrest. Approximately 1 in every 300 patients with chest pain transported to the ED by private vehicle goes into cardiac arrest en route (108).

Several studies have confirmed that patients with ACS frequently do not call 9-1-1 and are not transported to the hospital by ambulance. A follow-up survey of chest pain patients presenting to participating EDs in 20 US communities who were either released or admitted to the hospital with a confirmed coronary event revealed that the average proportion of patients who used EMS was 23%, with significant geographic difference (range 10% to 48%). Most patients were driven by someone else (60%) or drove themselves to the hospital (16%) (109). In the National Registry of Myocardial Infarction 2, just over half (53%) of all patients with MI were transported to the hospital by ambulance (105).

Even in areas of the country that have undertaken substantial public education campaigns about the warning signs of ACS and the need to activate the EMS system rapidly, either there were no increases in EMS use (58,110–113) or EMS use increased (as a secondary outcome measure) but was still suboptimal, with a 20% increase from a baseline of 33% in all 20 communities in the REACT study (63) and an increase from 27% to 41% in southern Minnesota after a community campaign (114). Given the importance of patients using EMS for possible acute cardiac symptoms, communities, including medical providers, EMS systems, health care insurers, hospitals, and policy makers at the state and local level, need to have agreed-upon emergency protocols to ensure patients with possible heart attack symptoms will be able to access 9-1-1 without barriers, to secure their timely evaluation and treatment (115).

As part of making a plan with the patient for timely recognition and response to an acute event, providers should review instructions for taking NTG in response to chest discomfort/pain (Fig. 3). If a patient has previously been prescribed NTG, it is recommended that the patient be advised to take 1 NTG dose sublingually promptly for chest discomfort/pain. If symptoms are unimproved or worsening 5 min after 1 NTG dose has been taken, it also is recommended that the patient be instructed to call 9-1-1 immediately to access EMS. Although the traditional recommendation is for patients to take 1 NTG dose sublingually, 5 min apart, for up to 3 doses before calling for emergency evaluation, this recommendation has been modified by the UA/NSTEMI Writing Committee to encourage earlier contacting of EMS by patients with symptoms suggestive of ACS. While awaiting ambulance arrival, patients tolerating NTG can be instructed by health care providers or 9-1-1 dispatchers to take additional NTG every 5 min up to 3 doses. Self-treatment with prescription medication, including nitrates, and with nonprescription medication (e.g., antacids) has been documented as a frequent cause of delay among patients with ACS, including those with a history of MI or angina (65,116). Both the rate of use of these medications and the number of doses taken were positively correlated with delay time to hospital arrival (65).

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Patient (Advance) Instructions for NTG Use and EMS Contact in the Setting of Non–Trauma-Related Chest Discomfort/Pain If patients experience chest discomfort/pain and have been previously prescribed NTG and have it available (right side of algorithm), it is recommended that they be instructed (in advance) to take 1 dose of NTG immediately in response to symptoms. If chest discomfort/pain is unimproved or worsening 5 min after taking 1 NTG sublingually, it is recommended that the patient call 9-1-1 immediately to access EMS. In patients with chronic stable angina, if the symptoms are significantly improved after taking 1 NTG, it is appropriate to instruct the patient or family member/friend/caregiver to repeat NTG every 5 minutes for a maximum of 3 doses and call 9-1-1 if symptoms have not totally resolved. If patients are not previously prescribed NTG (left side of algorithm), it is recommended that they call 9-1-1 if chest discomfort/pain is unimproved or worsening 5 min after it starts. If the symptoms subside within 5 min of when they began, patients should notify their physician of the episode. (For those patients with new-onset chest discomfort who have not been prescribed NTG, it is appropriate to discourage them from seeking someone else’s NTG [e.g., from a neighbor, friend, or relative].) *Although some trials have used enteric-coated aspirin for initial dosing, more rapid buccal absorption occurs with non–enteric-coated formulations. EMS = emergency medical services; NTG = nitroglycerin.

The taking of aspirin by patients in response to acute symptoms has been reported to be associated with a delay in calling EMS (109). Patients should focus on calling 9-1-1, which activates the EMS system, where they may receive instructions from emergency medical dispatchers to chew aspirin (162 to 325 mg) while emergency personnel are en route, or emergency personnel can give an aspirin while transporting the patient to the hospital (119). Alternatively, patients may receive an aspirin as part of their early treatment once they arrive at the hospital if it has not been given in the prehospital setting (117).

Providers should target those patients at increased risk for ACS, focusing on patients with known CHD, peripheral vascular disease, or cerebral vascular disease, those with diabetes, and patients with a 10-year Framingham risk of CHD of more than 20% (120). They should stress that the chest discomfort will usually not be dramatic, such as is commonly misrepresented on television or in the movies as a "Hollywood heart attack." Providers also should describe anginal equivalents and the commonly associated symptoms of ACS (e.g., shortness of breath, a cold sweat, nausea, or lightheadedness) in both men and women (56,106), as well as the increased frequency of atypical symptoms in elderly patients (72).

2.1.1 Emergency Department or Outpatient Facility Presentation
It is recommended that patients with a suspected ACS with chest discomfort or other ischemic symptoms at rest for more than 20 min, hemodynamic instability, or recent syncope or presyncope to be referred immediately to an ED or a specialized chest pain unit. For other patients with a suspected ACS who are experiencing less severe symptoms and are having none of the above high-risk features, the recommendation is to be seen initially in an ED, a chest pain unit, or an appropriate outpatient facility. Outcomes data that firmly support these recommendations are not available; however, these recommendations are of practical importance because differing ACS presentations require differing levels of emergent medical interventions, such as fibrinolytics or emergency coronary angiography leading to PCI or surgery, or sophisticated diagnostic evaluation such as nuclear stress testing or CCTA. When symptoms have been unremitting for more than 20 min, the possibility of MI must be considered. Given the strong evidence for a relationship between delay in treatment and death (121–123), 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 greater than 20 to 30 min.

2.1.2 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:

• What is the likelihood that the signs and symptoms represent ACS secondary to obstructive CAD (Table 6)?

• What is the likelihood of an adverse clinical outcome (Table 7)? Outcomes of concern include death, MI (or recurrent MI), stroke, HF, recurrent symptomatic ischemia, and serious arrhythmia.

	2.2 Early Risk Stratification

Top Table of Contents Preamble 1. Introduction 1.5 Onset of UA/NSTEMI 1.5.2 Silent and Unrecognized... 2. Initial Evaluation and... 2.2 Early Risk Stratification 2.3 Immediate Management 3. Early Hospital Care 5. Late Hospital Care,... 6. Special Groups 6.7 Variant (Prinzmetal's)... 6.8 Cardiovascular "Syndrome X" 6.9 Takotsubo Cardiomyopathy 7. Conclusions and Future... Staff Appendix References

 
Recommendations for Early Risk Stratification.   Class I

1 A rapid clinical determination of the likelihood risk of obstructive CAD (i.e., high, intermediate, or low) should be made in all patients with chest discomfort or other symptoms suggestive of an ACS and considered in patient management. (Level of Evidence: C)

2 Patients who present with chest discomfort or other ischemic symptoms should undergo early risk stratification for the risk of cardiovascular events (e.g., death or [re]MI) that focuses on history, including anginal symptoms, physical findings, ECG findings, and biomarkers of cardiac injury, and results should be considered in patient management. (Level of Evidence: C)

3 A 12-lead ECG should be performed and shown to an experienced emergency physician as soon as possible after ED arrival, with a goal of within 10 min of ED arrival for all patients with chest discomfort (or anginal equivalent) or other symptoms suggestive of ACS. (Level of Evidence: B)

4 If the initial ECG is not diagnostic but the patient remains symptomatic and there is high clinical suspicion for ACS, serial ECGs, initially at 15- to 30-min intervals, should be performed to detect the potential for development of ST-segment elevation or depression. (Level of Evidence: B)

5 Cardiac biomarkers should be measured in all patients who present with chest discomfort consistent with ACS. (Level of Evidence: B)

6 A cardiac-specific troponin is the preferred marker, and if available, it should be measured in all patients who present with chest discomfort consistent with ACS. (Level of Evidence: B)

7 Patients with negative cardiac biomarkers within 6 h of the onset of symptoms consistent with ACS should have biomarkers remeasured in the time frame of 8 to 12 h after symptom onset. (The exact timing of serum marker measurement should take into account the uncertainties often present with the exact timing of onset of pain and the sensitivity, precision, and institutional norms of the assay being utilized as well as the release kinetics of the marker being measured.) (Level of Evidence: B)

8 The initial evaluation of the patient with suspected with ACS should include the consideration of noncoronary causes for the development of unexplained symptoms. (Level of Evidence: C)

Class IIa

1 Use of risk-stratification models, such as the Thrombolysis In Myocardial Infarction (TIMI) or Global Registry of Acute Coronary Events (GRACE) risk score or the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) risk model, can be useful to assist in decision making with regard to treatment options in patients with suspected ACS. (Level of Evidence: B)

2 It is reasonable to remeasure positive biomarkers at 6- to 8-h intervals 2 to 3 times or until levels have peaked, as an index of infarct size and dynamics of necrosis. (Level of Evidence: B)

3 It is reasonable to obtain supplemental ECG leads V₇ through V₉ in patients whose initial ECG is nondiagnostic to rule out MI due to left circumflex occlusion. (Level of Evidence: B)

4 Continuous 12-lead ECG monitoring is a reasonable alternative to serial 12-lead recordings in patients whose initial ECG is nondiagnostic. (Level of Evidence: B)

Class IIb

1 For patients who present within 6 h of the onset of symptoms consistent with ACS, assessment of an early marker of cardiac injury (e.g., myoglobin) in conjunction with a late marker (e.g., troponin) may be considered. (Level of Evidence: B)

2 For patients who present within 6 h of symptoms suggestive of ACS, a 2-h delta CK-MB mass in conjunction with 2-h delta troponin may be considered. (Level of Evidence: B)

3 For patients who present within 6 h of symptoms suggestive of ACS, myoglobin in conjunction with CK-MB mass or troponin when measured at baseline and 90 min may be considered. (Level of Evidence: B)

4 Measurement of B-type natriuretic peptide (BNP) or NT-pro-BNP may be considered to supplement assessment of global risk in patients with suspected ACS. (Level of Evidence: B)

Class III
Total CK (without MB), aspartate aminotransferase (AST, SGOT), alanine transaminase, beta-hydroxybutyric dehydrogenase, and/or lactate dehydrogenase should not be utilized as primary tests for the detection of myocardial injury in patients with chest discomfort suggestive of ACS. (Level of Evidence: C)

2.2.1 Estimation of the Level of Risk.   The medical history, physical examination, ECG, assessment of renal function, and cardiac biomarker 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 urgent coronary revascularization. Estimation of the level of risk is a multivariable problem that cannot be accurately quantified with a simple table; therefore, Tables 6 and 7 are meant to be illustrative of the general relationships between history, clinical and ECG findings, and the categorization of patients into those at low, intermediate, or high risk of the presence of obstructive CAD and the short-term risk of cardiovascular events, respectively. Optimal risk stratification requires accounting for multiple prognostic factors simultaneously by a multivariable approach (e.g., the TIMI and GRACE risk score algorithms [see below]).

2.2.2 Rationale for Risk Stratification.   Because patients with ischemic discomfort at rest as a group are heterogeneous in terms of risk of cardiac death and nonfatal ischemic events, an assessment of the prognosis guides 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, including platelet glycoprotein (GP) IIb/IIIa inhibitors (see Section 3.2) and invasive management strategy (see Section 3.3). 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 6 and 7). 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 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 MI, and the patient’s likelihood of survival should an MI occur.

Patients can present with ischemic discomfort but without ST-segment deviation 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 (12,125,126). 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 immediate risk, and STEMI, a presentation with a higher risk of early death and cardiac ischemic events. The risk is highest at the time of presentation and subsequently declines. Yet, the risk remains high past the acute phase. By 6 months, UA/NSTEMI mortality rates higher than that after STEMI can be seen (127); and by 12 months, the rates of death, MI, and recurrent instability in contemporary randomized controlled trials and registry studies exceed 10% and are often related to specific risk factors such as age, diabetes mellitus, renal failure, and impairment of left ventricular (LV) function. Whereas the early events are related to the activity of 1 culprit coronary plaque that has ruptured and is the site of thrombus formation, events that occur later are more related to the underlying pathophysiological mechanisms that trigger plaque activity and that mark active atherosclerosis (128–134).

A few risk scores have been developed that regroup markers of the acute thrombotic process and other markers of high risk to identify high-risk patients with UA/NSTEMI. The TIMI, GRACE, and PURSUIT risk scores are discussed in detail in Section 2.2.6.

2.2.3 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, acute ischemia, or 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 (135–139). In patients with suspected ACS but without preexisting clinical CHD, older age appears to be the most important factor. One study found that for males, age younger than 40 years, 40 to 55 years, and older than 55 years and for females, age younger than 50 years, 50 to 65 years, and older than 65 years was correlated with low, intermediate, and high risk for CAD, respectively (138). Another study found that the risk of CAD increased in an incremental fashion for each decade above age 40 years, with male sex being assigned an additional risk point (139,140). In these studies, being a male older than 55 years or a female older than 65 years outweighed the importance of all historical factors, including the nature of the chest pain (138,139).

2.2.4 Anginal Symptoms and Anginal Equivalents.   The characteristics of angina, which are thoroughly described in the ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina (4), include deep, poorly localized chest or arm discomfort that is reproducibly associated with physical exertion or emotional stress and is relieved promptly (i.e., in less than 5 min) with rest and/or the use of sublingual NTG. Patients with UA/NSTEMI 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 in the past. Although it is traditional to use the simple term "chest pain" to refer to the discomfort of ACS, patients often do not perceive these symptoms to be true pain, especially when they are mild or atypical. Terms such as "ischemic-type chest discomfort" or "symptoms suggestive of ACS" have been proposed to more precisely capture the character of ischemic symptoms. Although "chest discomfort" or "chest press" is frequently used in these guidelines for uniformity and brevity, the following caveats should be kept clearly in mind. Some patients may have no chest discomfort but present solely with jaw, neck, ear, arm, shoulder, back, or epigastric discomfort or with unexplained dyspnea without discomfort (56,141,142). 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/NSTEMI, but without the exertional history or known prior history of CAD, it may be difficult to recognize their cardiac origin. Other difficult presentations of the patient with UA/NSTEMI 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; less common isolated presentations, primarily in older adults, include nausea and vomiting, diaphoresis, and unexplained fatigue. Indeed, older adults and women with ACS not infrequently present with atypical angina or nonanginal symptoms. Rarely do patients with ACS present with syncope as the primary symptom or with other nonanginal symptoms.

Features that are not characteristic of myocardial ischemia include the following:

• Pleuritic pain (i.e., sharp or knifelike pain brought on by respiratory movements or cough)

• Primary or sole location of discomfort in the middle or lower abdominal region

• Pain that may be localized at the tip of 1 finger, particularly over the left ventricular apex or a costochondral junction

• Pain reproduced with movement or palpation of the chest wall or arms

• Very brief episodes of pain that last a few seconds or less

• Pain that radiates into the lower extremities

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 6).

Although typical characteristics substantially increase the probability of CAD, features not characteristic of typical angina, such as sharp stabbing pain or reproduction of pain on palpation, do not entirely 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 (143). The Acute Cardiac Ischemia Time-Insensitive Predictive Instrument (ACI-TIPI) project (144,145) 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.

The relief of chest pain by administration of sublingual NTG in the ED setting is not always predictive of ACS. One study reported that sublingual NTG relieved symptoms in 35% of patients with active CAD (defined as elevated cardiac biomarkers, coronary vessel with at least 70% stenosis on coronary angiography, or positive stress test) compared with 41% of patients without active CAD (146). Furthermore, the relief of chest pain by the administration of a "GI cocktail" (e.g., a mixture of liquid antacid, viscous lidocaine, and anticholinergic agent) does not predict the absence of ACS (147).

2.2.5 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 (148) but also with an increased risk of multivessel CAD. There are differences in the presentations of men and women with ACS (see Section 6.1). 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 (149). Women with suspected ACS are less likely to have obstructive CAD than are men with a similar clinical presentation, and when CAD is present in women, it tends to be less severe. On the other hand, when 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 (150,151).

Older adults (see Section 6.4) have increased risks of both underlying CAD (152,153) 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 years. 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; however, age itself exerts a strong, independent prognostic risk as well, perhaps at least in part because of comorbidities. Older adults also are 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, and cigarette smoking) are only weakly predictive of the likelihood of acute ischemia (145,154) and are far less important than are symptoms, ECG findings, and cardiac biomarkers. 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. However, the presence of these risk factors does appear to relate to poor outcomes in patients with established ACS. Although not as well investigated as the traditional risk factors, a family history of premature CAD has been demonstrated to be associated with increased coronary artery calcium scores greater than the 75th age percentile in asymptomatic individuals (155) and increased risk of 30-d cardiac events in patients admitted for UA/NSTEMI (156). Of special interest is that sibling history of premature CAD has a stronger relationship than parental history (157). However, several of these risk factors have important prognostic and therapeutic implications. Diabetes and the presence of extracardiac (carotid, aortic, or peripheral) vascular disease are major risk factors for poor outcome in patients with ACS (see Section 6.2). For both STEMI (158) and UA/NSTEMI (128), patients with these conditions have a significantly higher mortality rate and risk of acute HF. 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 a poor outcome.

The current or prior use of ASA at the time and presentation of ACS has been associated in 1 database with increased cardiovascular event risk (159). Although the rationale is not fully elucidated, it appears those taking prior ASA therapy have more multivessel CAD, are more likely to present with thrombus present, may present later in the evolution of ACS, or may be ASA resistant. Surprisingly, current smoking is associated with a lower risk of death in the setting of ACS (159–161), primarily because of the younger age of smokers with ACS and 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.

Being overweight and/or obese at the time of ACS presentation is associated with lower short-term risk of death; however, this "obesity paradox" is primarily a function of younger age at time of presentation, referral for angiography at an earlier stage of disease, and more aggressive ACS management (160). Although short-term risk may be lower for overweight/obese individuals, these patients have a higher long-term total mortality risk (161–165). Increased long-term cardiovascular risk appears to be primarily limited to severe obesity (166).

Cocaine use has been implicated as a cause of ACS, presumably owing 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 6.6) (167). Recently, the use of methamphetamine has grown, and its association with ACS also should be considered. It is important to inquire about the use of cocaine and methamphetamine in patients with suspected ACS, especially in younger patients (age less than 40 years) and others with few risk factors for CAD. Urine toxicology should be considered when substance abuse is suspected as a cause of or contributor to ACS.

2.2.6 Estimation of Early Risk at Presentation.   A number of risk assessment tools have been developed to assist in assessing risk of death and ischemic events in patients with UA/NSTEMI, thereby providing a basis for therapeutic decision making (Table 8; Fig. 4) (158,168,169). It should be recognized that the predictive ability of these commonly used risk assessment scores for nonfatal CHD risk is only moderate.

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Figure 4 GRACE Prediction Score Card and Nomogram for All-Cause Mortality From Discharge to 6 Months Reprinted with permission from Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA 2004;291:2727–33 (168). Copyright © 2004 American Medical Association.

The PURSUIT risk model, developed by Boersma et al. (172), based on patients enrolled in the PURSUIT trial, is another useful tool to guide the clinical decision-making process when the patient is admitted to the hospital. In the PURSUIT risk model, critical clinical features associated with an increased 30-d incidence of death and the composite of death or myocardial (re)infarction were (in order of strength) age, heart rate, systolic blood pressure, ST-segment depression, signs of HF, and cardiac biomarkers (172).

The GRACE risk model, which predicts in-hospital mortality (and death or MI), can be useful to clinicians to guide treatment type and intensity (168,173). The GRACE risk tool was developed on the basis of 11,389 patients in GRACE, validated in subsequent GRACE and GUSTO IIb cohorts, and predicts in-hospital death in patients with STEMI, NSTEMI, or UA (C statistic = 0.83). The 8 variables used in the GRACE risk model are older age (odds ratio [OR] 1.7 per 10 years), Killip class (OR 2.0 per class), systolic blood pressure (OR 1.4 per 20 mm Hg decrease), ST-segment deviation (OR 2.4), cardiac arrest during presentation (OR 4.3), serum creatinine level (OR 1.2 per 1-mg per dL increase), positive initial cardiac biomarkers (OR 1.6), and heart rate (OR 1.3 per 30-beat per min increase). The sum of scores is applied to a reference monogram to determine the corresponding all-cause mortality from hospital discharge to 6 mo. The GRACE clinical application tool can be downloaded to a handheld PDA to be used at the bedside and is available at www.outcomes-umassmed.org/grace (Fig. 4) (173). An analysis comparing the 3 risk scores (TIMI, GRACE, and PURSUIT) concluded that all 3 demonstrated good predictive accuracy for death and MI at 1 year, thus identifying patients who might be likely to benefit from aggressive therapy, including early myocardial revascularization (174).

The ECG provides unique and important diagnostic and prognostic information (see also Section 2.2.6.1 below). Accordingly, ECG changes have been incorporated into quantitative decision aids for the triage of patients presenting with chest discomfort (175). Although ST elevation carries the highest early risk of death, ST depression on the presenting ECG portends the highest risk of death at 6 months, with the degree of ST depression showing a strong relationship to outcome (176).

Dynamic risk modeling is a new frontier in modeling that accounts for the common observation that levels and predictors of risk constantly evolve as patients pass through their disease process. Excellent models have been developed based on presenting features, but information the next day about clinical (e.g., complications), laboratory (e.g., biomarker evolution), and ECG (e.g., ST resolution for STEMI) changes provides additional data relevant to decisions at key "decision-node" points in care (177). Dynamic modeling concepts promise more sophisticated, adaptive, and individually predictive modeling of risk in the future.

Renal impairment has been recognized as an additional high-risk feature in patients with ACS (178). Mild to moderate renal dysfunction is associated with moderately increased short- and long-term risks, and severe renal dysfunction is associated with severely increased short- and long-term mortality risks. Patients with renal dysfunction experience increased bleeding risks, have higher rates of HF and arrhythmias, have been underrepresented in cardiovascular trials, and may not enjoy the same magnitude of benefit with some therapies observed in patients with normal renal function (179) (see also Section 6.5).

Among patients with UA/NSTEMI, there is a progressively greater benefit from newer, more aggressive therapies such as low-molecular-weight heparin (LMWH) (169,180), platelet GP IIb/IIIa inhibition (181), and an invasive strategy (182) with increasing risk score.

2.2.6.1 Electrocardiogram
The ECG is critical not only to add support to the clinical suspicion of CAD but also to provide prognostic information based on the pattern and magnitude of the abnormalities (127,175,183,184). A recording made during an episode of the presenting symptoms is particularly valuable. Importantly, transient ST-segment changes (greater than or equal to 0.05 mV [i.e., 0.5 mm]) 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 ischemia can be assessed with greater diagnostic accuracy if a prior ECG is available for comparison (Table 6) (185).

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 6). The diagnosis of MI is confirmed with serial cardiac biomarkers in more than 90% of patients who present with ST-segment elevation of greater than or equal to 1 mm (0.1 mV) in at least 2 contiguous leads, and such patients should be considered 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 ultimately based on the detection of markers of myocardial necrosis in the blood (11,126,186).

Up to 25% of patients with NSTEMI and elevated CK-MB go on to develop Q-wave MI during their hospital stay, whereas the remaining 75% have non–Q-wave MI. Acute fibrinolytic therapy is contraindicated for ACS patients without ST-segment elevation, except for those with electrocardiographic true posterior MI manifested as ST-segment depression in 2 contiguous anterior precordial leads and/or isolated ST-segment elevation in posterior chest leads (187–189). Inverted T waves may also indicate UA/NSTEMI. In patients suspected of having ACS on clinical grounds, marked (greater than or equal to 2 mm [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) (190). Patients with this ECG finding often exhibit hypokinesis of the anterior wall and are at high risk if given medical treatment alone (191). Revascularization will often reverse both the T-wave inversion and wall-motion disorder (192). Nonspecific ST-segment and T-wave changes, usually defined as ST-segment deviation of less than 0.5 mm (0.05 mV) or T-wave inversion of less than or equal to 2 mm (0.2 mV), are less diagnostically helpful than the foregoing findings. Established Q waves greater than or equal to 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 MI (by definition, an NSTEMI), and at least 4% will be found to have UA (184,193,194).

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, myocarditis, Prinzmetal’s angina, early repolarization (e.g., in young black males), apical LV ballooning syndrome (Takotsubo cardiomyopathy; see Section 6.9), and Wolff-Parkinson-White syndrome represent several examples to be considered. Central nervous system events and drug therapy with tricyclic antidepressants or phenothiazines can cause deep T-wave inversion.

Acute MI due to occlusion of the left circumflex coronary artery can present with a nondiagnostic 12-lead ECG. Approximately 4% of acute MI patients show the presence ST elevation isolated to the posterior chest leads V₇ through V₉ and "hidden" from the standard 12 leads (187,195,196). The presence of posterior ST elevation is diagnostically important because it qualifies the patient for acute reperfusion therapy as an acute STEMI (1,197). The presence or absence of ST-segment elevation in the right ventricular (V₄R through V₆R) or posterior chest leads (V₇ through V₉) also adds prognostic information in the presence of inferior ST-segment elevation, predicting high and low rates of in-hospital life-threatening complications, respectively (196).

With reference to electrocardiographic true posterior MI, new terminology recently has been proposed based on the standard of cardiac magnetic resonance (CMR) imaging localization. CMR studies indicate that abnormally increased R waves, the Q-wave equivalent in leads V₁ and V₂, indicate an MI localized to the lateral LV wall and that abnormal Q waves in I and VL (but not V₆) indicate a mid-anterior wall MI. Thus, the electrocardiographic terms "posterior" and "high lateral MI" refer to anatomic "lateral wall MI" and "mid-anterior wall MI" (198). The impact of these findings and recommendations for standard electrocardiographic terminology are unresolved as of this writing.

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 (183,199,200). 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 biomarker measurements (199–202).

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. (203) reported that the diagnosis of acute non–Q-wave MI was 3 to 4 times more likely in patients with ischemic discomfort who had at least 3 ECG leads that showed ST-segment depression and maximal ST depression of greater than or equal to 0.2 mV. Investigators from the TIMI III Registry (199) reported that the 1-year incidence of death or new MI in patients with at least 0.5 mm (0.05 mV) of 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.

Physicians frequently seek out a previous ECG for comparison in patients with suspected ACS. Studies have demonstrated that patients with an unchanged ECG have a reduced risk of MI and a very low risk of in-hospital life-threatening complications even in the presence of confounding ECG patterns such as LV hypertrophy (204–206).

Because a single 12-lead ECG recording provides only a snapshot view of a dynamic process (207), the usefulness of obtaining serial ECG tracings or performing continuous ST-segment monitoring has been studied (175,208). Although serial ECGs increase the ability to diagnose UA and MI (208–212), the yield is higher with serial cardiac biomarker measurements (212–214). However, identification of new injury on serial 12-lead ECG (and not elevated cardiac biomarkers) is the principal eligibility criterion for emergency reperfusion therapy, so that monitoring of both is recommended. Continuous 12-lead ECG monitoring to detect ST-segment shifts, both symptomatic and asymptomatic, also can be performed with microprocessor-controlled programmable devices. An injury current was detected in an additional 16% of chest pain patients in 1 study (213). The identification of ischemic ECG changes on serial or continuous ECG recordings frequently alters therapy and provides independent prognostic information (212,215,216).

2.2.6.2 Physical Examination
The major objectives of the physical examination are to identify potential precipitating causes of myocardial ischemia, such as uncontrolled hypertension, thyrotoxicosis, or gastrointestinal bleeding, and comorbid conditions that could impact therapeutic risk and decision making, such as pulmonary disease and malignancies, as well as 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 if dissection is suspected, as well as heart rate and temperature) and should undergo a thorough cardiovascular and chest examination. Patients with evidence of LV dysfunction on examination (rales, S₃ gallop) or with acute mitral regurgitation 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 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 can be evidenced by pulsus paradoxus. Pneumothorax is suspected when acute dyspnea, pleuritic chest pain, and differential breath sounds are present.

The importance of cardiogenic shock in patients with NSTEMI should be emphasized. Although most literature on cardiogenic shock has focused on STEMI, the SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK (SHOCK) study (217) found that approximately 20% of all cardiogenic shock complicating MI was associated with NSTEMI. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-II (218) and PURSUIT (128) trials found that cardiogenic shock occurs in up to 5% of patients with NSTEMI and that mortality rates are greater than 60%. Thus, hypotension and evidence of organ hypoperfusion can occur and constitute a medical emergency in NSTEMI.

2.2.7 Noncardiac Causes of Symptoms and Secondary Causes of Myocardial Ischemia.   Information from the initial history, physical examination, and ECG (Table 6) can enable the physician to classify and exclude from further assessment patients "not having ischemic discomfort." This includes patients with noncardiac pain (e.g., pulmonary embolism, musculoskeletal pain, or esophageal discomfort) or cardiac pain not caused by myocardial ischemia (e.g., acute pericarditis). The remaining patients should undergo a more complete evaluation of the 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 can cause myocardial ischemia include aortic stenosis and hypertrophic cardiomyopathy. Factors that increase myocardial oxygen demand or decrease oxygen delivery to the heart can provoke or exacerbate ischemia in the presence of significant underlying CAD or secondary angina; previously unrecognized gastrointestinal bleeding that causes anemia is a common secondary cause of worsening angina or the development of symptoms of ACS. Acute worsening of chronic obstructive pulmonary disease (with or without superimposed infection) can lower oxygen saturation levels sufficiently to intensify ischemic symptoms in patients with CAD. Evidence of increased cardiac oxygen demand can be suspected in the presence of fever, signs of hyperthyroidism, sustained tachyarrhythmias, or markedly elevated blood pressure. Another cause of increased myocardial oxygen demand is arteriovenous fistula in patients receiving dialysis.

The majority of patients seen in the ED with symptoms of possible ACS will be judged after their workup not to have a cardiac problem. One clinical trial of a predictive instrument evaluated 10,689 patients with suspected ACS (75). To participate, patients were required to be greater than 30 years of age 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 evaluation, 7,996 patients (75%) were deemed not to have acute ischemia.

2.2.8 Cardiac Biomarkers of Necrosis and the Redefinition of AMI.   Cardiac biomarkers have proliferated over recent years to address various facets of the complex pathophysiology of ACS. Some, like the cardiac troponins, have become essential for risk stratification of patients with UA/NSTEMI and for the diagnosis of MI. Others, such as the inflammatory markers, are opening new perspectives on pathophysiology and risk stratification, and the use in clinical practice of selected new markers may be recommended for clinical use in the near future. Still other promising markers are being developed as part of translational research and await prospective validation in various populations. New developments are expected in the fields of proteomic and genomics, cell markers and circulating microparticles, and microtechnology and nanotechnology imaging.

Current markers of necrosis leak from cardiomyocytes after the loss of membrane integrity and diffuse into the cardiac interstitium, then into the lymphatics and cardiac microvasculature. Eventually, these macromolecules, collectively referred to as cardiac biomarkers, are detectable in the peripheral circulation. Features that favor their diagnostic performance are high concentrations in the myocardium and absence in nonmyocardial tissue, release into the blood within a convenient diagnostic time window and in proportion to the extent of myocardial injury, and quantification with reproducible, inexpensive, and rapid and easily applied assays (11). The cardiac troponins possess many of these features and have gained wide acceptance as the biomarkers of choice in the evaluation of patients with ACS for diagnosis, risk stratification, and treatment selection.

The traditional definitions of MI were revisited in 2000 in a consensus document of a joint committee of the European Society of Cardiology (ESC) and ACC (219) and at the time of publication is being updated by an expanded joint task force of the ESC, ACC, AHA, World Heart Federation (WHF), and World Health Organization. The new definitions are inspired by the emergence of new highly sensitive and specific diagnostic methods that allow the detection of areas of cell necrosis as small as 1 g. Myocardial necrosis in the task force document is defined by an elevation of troponin above the 99th percentile of normal. Myocardial infarction, which is necrosis related to ischemia, is further defined by the addition to the troponin elevation of at least 1 of the following criteria: ischemic ST and T-wave changes, new left bundle-branch block, new Q waves, PCI-related marker elevation, or positive imaging for a new loss of viable myocardium. Myocardial infarction can still be diagnosed in the absence of measurement of troponin when there is evidence of a new loss of viable myocardium, ST-segment elevation, or new left bundle-branch block with sudden cardiac death within 1 h of symptoms, or a postmortem pathological diagnosis. Coronary artery bypass graft-related MI is diagnosed by an increase of cardiac biomarkers to more than 5 to 10-fold the 99th percentile of normal, new Q waves or new left bundle-branch block on the ECG, or a positive imaging test. The task force further recommended further defining MI by the circumstances that cause it (spontaneous or in the setting of a diagnostic or therapeutic procedure), by the amount of cell loss (infarct size), and by the timing of MI (evolving, healing, or healed) (219,220). Providing fold-elevations above normal for diagnostic biomarkers, to allow for meaningful comparisons among clinical trials, is also endorsed.

At the present time, the implications of using the new ESC/ACC redefinition of MI have not been fully explored; much of the present database for UA/NSTEMI derives from CK/CK-MB–based definitions of MI. Moreover, troponin assays have rapidly evolved through several generations over the past decade, becoming increasingly more sensitive and specific. Thus, it is important to recognize that the recommendations in this section are formulated from studies that frequently utilize modified World Health Organization criteria or definitions of MI based on earlier-generation troponin assays.

2.2.8.1 Creatine Kinase-MB
Creatine kinase-MB, a cytosolic carrier protein for high-energy phosphates, has long been the standard marker for the diagnosis of MI. Creatine kinase-MB, however, is less sensitive and less specific for MI than the cardiac troponins. Low levels of CK-MB can be found in the blood of healthy persons, and elevated levels occur with damage to skeletal muscle (221).

When a cardiac troponin is available, the determination of CK-MB remains useful in a few specific clinical situations. One is the diagnosis of early infarct extension (reinfarction), because the short half-life of CK-MB compared with troponin permits the detection of a diagnostic new increase after initial peak. Although routine determination of CK-MB has been suggested for the diagnosis of an eventual infarct extension, a single CK-MB determination obtained when symptoms recur may serve as the baseline value for comparison with samples obtained 6 to 12 h later. Another situation is the diagnosis of a periprocedural MI, because the diagnostic and prognostic value of CK-MB in these situations has been extensively validated. When assessed, CK-MB should be measured by mass immunoassays and not by other methods previously used (222). The use of other, older biochemistry assays of nonspecific markers such as alanine transaminase, aspartate transaminase, and lactate dehydrogenase should generally be avoided in contemporary practice.

2.2.8.2 Cardiac Troponins
The troponin complex consists of 3 subunits: T (TnT), I (TnI), and C (TnC) (223). The latter is expressed by both cardiac and skeletal muscle, whereas TnT and TnI are derived from heart-specific genes. Therefore, the term "cardiac troponins" (cTn) in these guidelines refers specifically to either cTnT or cTnI. Cardiac troponin as a biomarker provides robust results that are highly sensitive and specific in detecting cell necrosis; an early release is attributable to a cytosolic pool and a late release to the structural pool (219,224).

Because cTnT and cTnI generally are not detected in the blood of healthy persons, the cutoff value for elevated cTnT and cTnI levels may be set to slightly above the upper limit of the performance characteristics of the assay for a normal healthy population. High-quality analytic methods are needed to achieve these high standards (225). One issue with the use of cTnI is the multiplicity of existing assays that have different analytical sensitivities, some being unable to detect the lower values with a reasonable precision (226). Physicians therefore need to know the sensitivity of the tests used for TnI in their hospitals at the cutoff concentrations used for clinical decisions. Such heterogeneity does not exist for cTnT, which exists as a single test; this test is now a third-generation immunoassay that uses recombinant monoclonal human antibodies (224). Rare patients may have blocking antibodies to part of the troponin molecule, which would result in false-negative results (227).

2.2.8.2.1 Clinical Use
Although troponins can be detected in blood as early as 2 to 4 h after the onset of symptoms, elevation can be delayed for up to 8 to 12 h. This timing of elevation is similar to that of CK-MB but persists longer, for up to 5 to 14 d (Fig. 5). An increasing pattern in serial levels best helps determine whether the event is acute, distinct from a previous event, subacute, or chronic.

View larger version (32K): [in this window] [in a new window] [Download PPT slide]   Figure 5 Timing of Release of Various Biomarkers After Acute Myocardial Infarction The biomarkers are plotted showing the multiples of the cutoff for acute myocardial infarction (AMI) over time. The dashed horizontal line shows the upper limit of normal (ULN; defined as the 99th percentile from a normal reference population without myocardial necrosis; the coefficient of variation of the assay should be 10% or less) The earliest rising biomarkers are myoglobin and CK isoforms (leftmost curve). CKMB (dashed curve) rises to a peak of 2 to 5 times the ULN and typically returns to the normal range within 2 to 3 d after AMI. The cardiac-specific troponins show small elevations above the ULN in small infarctions (e.g., as is often the case with NSTEMI) but rise to 20 to 50 times the ULN in the setting of large infarctions (e.g., as is typically the case in STEMI). The troponin levels may stay elevated above the ULN for 7 d or more after AMI. Modified from Shapiro BP, Jaffe AS. Cardiac biomarkers. In: Murphy JG, Lloyd MA, editors. Mayo Clinic Cardiology: Concise Textbook. 3rd ed. Rochester, MN: Mayo Clinic Scientific Press and New York: Informa Healthcare USA, 2007: 773–80 (70). Used with permission of Mayo Foundation for Medical Education and Research. CK = creatine kinase; CKMB = MB fraction of creatine kinase; CV = coefficient of variation; MI = myocardial infarction; NSTEMI = non–ST-elevation myocardial infarction; UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction.

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 6 Troponin I Levels to Predict the Risk of Mortality in Acute Coronary Syndromes Mortality rates are at 42 d (without adjustment for baseline characteristics) in patients with acute coronary syndrome. The numbers at the bottom of each bar are the numbers of patients with cardiac troponin I levels in each range, and the numbers above the bars are percentages. p less than 0.001 for the increase in the mortality rate (and the risk ratio for mortality) with increasing levels of cardiac troponin I at enrollment. Reprinted with permission from Antman EM, Tanasijevic MJ, Thompson 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;335:1342–9 (201). Copyright © 1996 Massachusetts Medical Society. All rights reserved.

In all of these situations, equivalent information is generally obtained with cTnI and cTnT, except in patients with renal dysfunction, in whom cTnI assessment appears to have a specific role (227). Among patients with end-stage renal disease and no clinical evidence of acute myocardial necrosis, 15% to 53% show increased cTnT, but fewer than 10% have increased cTnI; dialysis generally increases cTnT but decreases cTnI. The exact reasons for the high rates of elevation in the cTn, especially cTnT, in renal failure are not clear; they can relate to cardiac damage, differential clearance, or to other biochemical or metabolic abnormalities (227). Whatever the reasons and the sources, an elevation of cTn, including cTnT, in patients with renal insufficiency is associated with a higher risk of morbidity regardless of the presence of cardiac symptoms or documented CAD. Among 7,033 patients enrolled in the GUSTO IV trial with suspected ACS, TnT level was independently predictive of risk across the entire spectrum of renal function enrolled (233).

Aggressive preventive measures for patients with renal insufficiency have been suggested, because most deaths in renal failure are of cardiac origin (227). Unfortunately, some standard therapies, such as lipid lowering with statins or PCI, have been less effective in improving survival in certain patient populations with advanced renal insufficiency (234,235). Furthermore, patients with suspected UA/NSTEMI have particularly unfavorable outcomes when in renal failure, with an event rate that correlates with the decrease in creatinine clearance (236–239). A sequential change in cTn levels in the first 24 h of observation for a suspected ACS supports new myocardial injury, whereas unchanging levels are more consistent with a chronic disease state without ACS.

Troponin elevation has important therapeutic implications. It permits the identification of high-risk patients and of subsets of patients who will benefit from specific therapies. Thus, among patients with UA/NSTEMI, those with elevated cTn benefit from treatment with platelet GP IIb/IIIa inhibitors, whereas those without such elevation may not benefit or may even experience a deleterious effect. For example, in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, the rates of death or nonfatal MI with cTnT elevation were 23.9% with placebo versus 9.5% with abciximab (p = 0.002) (240). Similar results have been reported for cTnI and cTnT with use of tirofiban (241). The benefit of LMWH was also greater in UA/NSTEMI patients with positive cTn. In the Fragmin during Instability in Coronary Artery Disease (FRISC) trial, the rates of death or nonfatal MI through 40 d increased progressively in the placebo group from 5.7% in the lowest tertile to 12.6% and 15.7% in the second and third tertiles, respectively, compared with rates of 4.7%, 5.7%, and 8.9%, respectively, in the dalteparin group, which represents risk reductions in events by increasing tertiles of 17.5%, 43%, and 55% (242). Similar differential benefits were observed with enoxaparin versus unfractionated heparin (UFH) in the ESSENCE trial (169). By contrast and of interest, patients with UA/NSTEMI but without elevated cTnT in the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial benefited as much from clopidogrel, a platelet P2Y12 adenosine diphosphate (ADP) receptor inhibitor, as patients with elevated levels (243). The placebo-controlled Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment (ISAR-REACT)-2 trial compared triple-antiplatelet therapy with ASA, clopidogrel, and abciximab to double therapy with ASA and clopidogrel in patients with UA/NSTEMI undergoing PCI; 52% of patients were troponin positive, and 48% were troponin negative. The 30-d event rates were similar at 4.6% in patients with normal cTnT levels but were reduced by close to 30% with the triple therapy (13.1% vs. 18.3%) in patients with elevated levels (244). The reasons for the differential benefit could pertain to a benefit that does not emerge in the low-risk patient, or that is overshadowed by complications related to treatment.

Such also appears to be the case with the GP IIb/IIIa antagonists and with an invasive management strategy that includes application of interventional procedures. Indeed, in 2 trials that compared an early routine invasive strategy to a routine noninvasive strategy, the FRISC-II and Treat Angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy (TACTICS) TIMI-18 trials, patients who profited from the early invasive treatment strategy were those at high risk as determined by cTnT levels and the admission ECG. In the FRISC study, the invasive strategy reduced the 12-month risk of death or MI by 40% (13.2% vs. 22.1%, p = 0.001) in the cohort with both ST depression and a cTnT level of 0.03 mcg per liter or greater, but the absolute gain of the invasive strategy was insignificant in the cohorts with either ST depression, cTnT level elevation, or neither of these findings (245). In the TACTICS TIMI-28 study, subgroups of patients with no ECG changes, a low TIMI score, and no cTn elevation showed no benefit from the invasive strategy, whereas those with positive cTn, independent of the presence of elevated CK-MB levels, showed markedly reduced odds of adverse clinical events of 0.13 at 30 d (95% confidence interval [CI] = 0.04 to 0.39) and 0.29 at 180 d (95% CI = 0.16 to 0.52) (246).

2.2.8.2.1.1 Clinical Use of Marker Change Scores
A newer method to both identify and exclude MI within 6 h of symptoms is to rely on changes in serum marker levels (delta values) over an abbreviated time interval (e.g., 2 h) as opposed to the traditional approach of performing serial measurements over 6 to 8 h (212,214,247–250). Because assays are becoming more sensitive and precise, this method permits the identification of increasing values while they are still in the normal or indeterminate range of the assay. By relying on delta values for the identification or exclusion of MI, higher-risk patients with positive delta values can be selected earlier for more aggressive anti-ischemic therapy (e.g., GP IIb/IIIa inhibitors), and lower-risk patients with negative delta values can be considered for early stress testing (212,214,249–251). One study of 1,042 patients found the addition of a 3-h delta CK-MB to result in a sensitivity of 93% and a specificity of 94% for MI (248). In another study of 2,074 consecutive ED chest pain patients, a 2-h delta CK-MB in conjunction with a 2-h delta troponin I measurement had a sensitivity for acute MI of 93% and specificity of 94% in patients whose initial ECG was nondiagnostic for injury. When combined with physician judgment and selective nuclear stress testing, the sensitivity for MI was 100% with specificity of 82%, and the sensitivity for 30-d ACS was 99.1% with specificity of 87% (214). Because there are no manufacturer-recommended delta cutoff values, the appropriate delta values for identification and exclusion of MI should take into account the sensitivity and precision of the specific assay utilized and should be confirmed by in-house studies. It also is important for delta values to be measured on the same instrument owing to subtle variations in calibration among individual instruments, even of the same model.

Another method to exclude MI within 6 h of symptom onset is the multimarker approach, which utilizes the serial measurement of myoglobin (i.e., a very early marker) in combination with the serial measurements of cTn and/or CK-MB (i.e., a later marker) (252–256). Studies have reported that multimarker measurements at baseline and 90 min have a sensitivity for MI of approximately 95% with a high negative predictive value, thus allowing for the early exclusion of MI when combined with clinical judgment (254,255). However, because of the low specificity of the multimarker strategy (mainly due to the lower specificity of myoglobin), a positive multimarker test is inadequate to diagnose MI and requires confirmation with a later-appearing definitive marker (254,257).

   2.2.8.2.1.2 Bedside Testing for Cardiac Markers
Cardiac markers can be measured in the central chemistry laboratory or with point-of-care instruments in the ED with desktop devices or handheld bedside rapid qualitative assays (229). When a central laboratory is used, results should be available as soon as possible, with a goal of within 60 min. Point-of-care systems, if implemented at the bedside, have the advantage of reducing delays due to transportation and processing in a central laboratory and can eliminate delays due to the lack of availability of central laboratory assays at all hours. Certain portable devices can simultaneously measure myoglobin, CK-MB, and troponin I (249). These advantages of point-of-care systems must be weighed against the need for stringent quality control and appropriate training of ED personnel in assay performance and the higher costs of point-of-care testing devices relative to determinations in the central laboratory. In addition, these point-of-care assays at present are qualitative or, at best, semiquantitative. To date, bedside testing has not succeeded in becoming widely accepted or applied.

2.2.8.3 Myoglobin and CK-MB Subforms Compared With Troponins
Myoglobin, a low-molecular-weight heme protein found in both cardiac and skeletal muscle, is not cardiac specific, but it is released more rapidly from infarcted myocardium than are CK-MB and cTn and can 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 its brief duration of elevation of less than 24 h. Thus, an isolated early elevation in patients with a nondiagnostic ECG should not be relied on to make the diagnosis of MI but should be supplemented by a more cardiac-specific marker (258). Creatine kinase-MB subforms are also efficient for the early diagnosis of MI and have a similar specificity to that of CK-MB but require special expertise, with no real advantage over better standardized and more easily applied cTn testing.

2.2.8.4 Summary Comparison of Biomarkers of Necrosis: Singly and in Combination
Table 10 compares the advantages and disadvantages of cardiac biomarkers of necrosis that are currently used for the evaluation and management of patients with suspected ACS but without ST-segment elevation on the 12-lead ECG. Given the overlapping time frame of the release pattern of cardiac biomarkers, it is important that clinicians incorporate the time from the onset of the patient’s symptoms into their assessment of the results of biomarker measurements (11,252,259,260) (Fig. 5).

In summary, the cTns are currently the markers of choice for the diagnosis of MI. They have a sensitivity and specificity as yet unsurpassed, which allows for the recognition of very small amounts of myocardial necrosis. These small areas of infarction are the consequence of severe ischemia and/or distal microembolization of debris from an unstable thrombogenic plaque. The unstable plaques are likely responsible for the high-risk situation. Thus, cTns as biomarkers are not only markers of cell necrosis but also of an active thrombogenic plaque, and hence, they indicate prognosis and are useful in guiding therapies. Although not quite as sensitive or specific as the cTns, CK-MB by mass assay is a second-choice marker that remains useful for the diagnosis of MI extension and of periprocedural MI. Routine use of myoglobin and other markers is not generally recommended.

Because many methods exist, many with multiple test generations, for cardiac biomarker testing in practice and in published reports, physicians should work with their clinical laboratories to ensure use of and familiarity with contemporary test technology, with appropriate, accurate ranges of normal and diagnostic cutoffs, specific to the assay used.

2.2.9 Other Markers and Multimarker Approaches.   Besides markers of myocardial necrosis, markers of pathophysiological mechanisms implicated in ACS are under investigation and could become useful to determine pathophysiology, individualize treatment, and evaluate therapeutic effects. In considering the clinical application of new biomarkers, it is important to determine that they provide incremental value over existing biomarkers. A multimarker approach to risk stratification of UA/NSTEMI (e.g., simultaneous assessment of cTnI, C-reactive protein [CRP], and BNP) has been advocated as a potential advance over single biomarker assessment (262,263). Further evaluation of a multimarker approach will be of interest.

2.2.9.1 Ischemia
Other new biochemical markers for the detection of myocardial necrosis are either less useful or have been less well studied than those mentioned above. An example is ischemia-modified albumin found soon after transient coronary occlusion and preceding any significant elevations in myoglobin, CK-MB, or cTnI. This modified albumin depends on a reduced capacity of human albumin to bind exogenous cobalt during ischemia (264,265). Choline is released upon the cleavage of phospholipids and could also serve as a marker of ischemia. Growth-differentiation factor-15 (GDF-15), a member of the transforming growth factor-β cytokine superfamily that is induced after ischemia-and-reperfusion injury, is a new biomarker that has been reported to be of incremental prognostic value for death in patients with UA/NSTEMI (265a).

2.2.9.2 Coagulation
Markers of activity of the coagulation cascade, including elevated plasma levels of fibrinogen, the prothrombin fragments, fibrinopeptide, and D-dimers, are elevated in ACS but have little discriminative ability for a specific pathophysiology, diagnosis, or treatment assessments (266,267). In experimental studies, markers of thrombin generation are blocked by anticoagulants but reactivate after their discontinuation (268) and are not affected by clopidogrel (269).

2.2.9.3 Platelets
Platelet activation currently is difficult to assess directly in vivo. New methods, however, are emerging that should allow a better and more efficient appraisal of their state of activation and of drug effects (270–272). Alternative markers of platelet activity are also being studied, including CD40L, platelet-neutrophil coaggregates, P-selectin, and platelet microparticles.

2.2.9.4 Inflammation
Systemic markers of inflammation are being widely studied and show promise for providing additional insights into pathophysiological mechanisms proximal to and triggering thrombosis, as well as suggesting novel therapeutic approaches. White blood cell counts are elevated in patients with MI, and this elevation has prognostic implications. Patients without biochemical evidence of myocardial necrosis but who have elevated CRP levels on admission or past the acute-phase reaction after 1 month and who have values in the highest quartile are at an increased risk of an adverse outcome (273–275). Elevated levels of interleukin-6, which promotes the synthesis of CRP, and of other proinflammatory cytokines also have been studied for their prognostic value (276). Other potentially useful markers are levels of circulating soluble adhesion molecules, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin (277); the pregnancy–associated plasma protein-A, which is a zinc-binding matrix metalloproteinase released with neorevascularization and believed to be a marker of incipient plaque rupture (278); myeloperoxidase, a leukocyte-derived protein that generates reactive oxidant species that contribute to tissue damage, inflammation, and immune processes within atherosclerotic lesions (279); and others. At this writing, none of these have been adequately studied or validated to be recommended for routine clinical application in UA/NSTEMI.

2.2.9.5 B-Type Natriuretic Peptides
One newer biomarker of considerable interest that now may be considered in the guidelines recommendations is BNP. B-type natriuretic peptide is a cardiac neurohormone released upon ventricular myocyte stretch as proBNP, which is enzymatically cleaved to the N-terminal proBNP (NT-proBNP) and, subsequently, to BNP. The usefulness of assessing this neurohormone was first shown for the diagnosis and evaluation of HF. Since then, numerous prospective studies and data from large data sets have documented its powerful prognostic value independent of conventional risk factors for mortality in patients with stable and unstable CAD (263,280–284). A review of available studies in ACS showed that when measured at first patient contact or during the hospital stay, the natriuretic peptides are strong predictors of both short- and long-term mortality in patients with STEMI and UA/NSTEMI (280). Increasing levels of NT-proBNP are associated with proportionally higher short- and long-term mortality rates; at 1 year, mortality rates with increasing quartiles were 1.8%, 3.9%, 7.7%, and 19.2%, respectively (p less than 0.001) in the GUSTO-IV trial of 6,809 patients (284). This prognostic value was independent of a previous history of HF and of clinical or laboratory signs of LV dysfunction on admission or during hospital stay (280). B-type natriuretic peptide and NT-proBNP levels can now be measured easily and rapidly in most hospital laboratories.

	2.3 Immediate Management

Top Table of Contents Preamble 1. Introduction 1.5 Onset of UA/NSTEMI 1.5.2 Silent and Unrecognized... 2. Initial Evaluation and... 2.2 Early Risk Stratification 2.3 Immediate Management 3. Early Hospital Care 5. Late Hospital Care,... 6. Special Groups 6.7 Variant (Prinzmetal's)... 6.8 Cardiovascular "Syndrome X" 6.9 Takotsubo Cardiomyopathy 7. Conclusions and Future... Staff Appendix References

 
Recommendations.   Class I

1 The history, physical examination, 12-lead ECG, and initial cardiac biomarker tests should be integrated to assign patients with chest pain into 1 of 4 categories: a noncardiac diagnosis, chronic stable angina, possible ACS, and definite ACS. (Level of Evidence: C)

2 Patients with probable or possible ACS but whose initial 12-lead ECG and cardiac biomarker levels are normal should be observed in a facility with cardiac monitoring (e.g., chest pain unit or hospital telemetry ward), and repeat ECG (or continuous 12-lead ECG monitoring) and repeat cardiac biomarker measurement(s) should be obtained at predetermined, specified time intervals (see Section 2.2.8). (Level of Evidence: B)

3 In patients with suspected ACS in whom ischemic heart disease is present or suspected, if the follow-up 12-lead ECG and cardiac biomarkers measurements are normal, a stress test (exercise or pharmacological) to provoke ischemia should be performed in the ED, in a chest pain unit, or on an outpatient basis in a timely fashion (within 72 h) as an alternative to inpatient admission. Low-risk patients with a negative diagnostic test can be managed as outpatients. (Level of Evidence: C)

4 In low-risk patients who are referred for outpatient stress testing (see above), precautionary appropriate pharmacotherapy (e.g., ASA, sublingual NTG, and/or beta blockers) should be given while awaiting results of the stress test. (Level of Evidence: C)

5 Patients with definite ACS and ongoing ischemic symptoms, positive cardiac biomarkers, new ST-segment deviations, new deep T-wave inversions, hemodynamic abnormalities, or a positive stress test should be admitted to the hospital for further management. Admission to the critical care unit is recommended for those with active, ongoing ischemia/injury or hemodynamic or electrical instability. Otherwise, a telemetry step-down unit is reasonable. (Level of Evidence: C)

6 Patients with possible ACS and negative cardiac biomarkers who are unable to exercise or who have an abnormal resting ECG should undergo a pharmacological stress test. (Level of Evidence: B)

7 Patients with definite ACS and ST-segment elevation in leads V₇ to V₉ due to left circumflex occlusion should be evaluated for immediate reperfusion therapy. (Level of Evidence: A)

8 Patients discharged from the ED or chest pain unit should be given specific instructions for activity, medications, additional testing, and follow-up with a personal physician. (Level of Evidence: C)

Class IIa
In patients with suspected ACS with a low or intermediate probability of CAD, in whom the follow-up 12-lead ECG and cardiac biomarkers measurements are normal, performance of a noninvasive coronary imaging test (i.e., CCTA) is reasonable as an alternative to stress testing. (Level of Evidence: B)

By integrating information from the history, physical examination, 12-lead ECG, and initial cardiac biomarker tests, clinicians can assign patients to 1 of 4 categories: noncardiac diagnosis, chronic stable angina, possible ACS, and definite ACS (Fig. 2).

Patients who arrive at a medical facility in a pain-free state, have unchanged or normal ECGs, are hemodynamically stable, and do not have elevated cardiac biomarkers represent more of a diagnostic than an urgent therapeutic challenge. Evaluation begins in these patients by obtaining information from the history, physical examination, and ECG (Tables 6 and 7) to be used to confirm or reject the diagnosis of UA/NSTEMI.

Patients with a low likelihood of CAD should be evaluated for other causes of the noncardiac presentation, including musculoskeletal pain; gastrointestinal disorders, such as esophageal spasm, gastritis, peptic ulcer disease, or cholecystitis; intrathoracic disease, such as musculoskeletal discomfort, pneumonia, pleurisy, pneumothorax, pulmonary embolus, dissecting aortic aneurysm, myocarditis, or pericarditis; and neuropsychiatric disease, such as hyperventilation or panic disorder (Fig. 2, B1). Patients who are found to have evidence of 1 of these alternative diagnoses should be excluded from management with these guidelines and referred for appropriate follow-up care (Fig. 2, C1). Reassurance should be balanced with instructions to return for further evaluation if symptoms worsen or if the patient fails to respond to symptomatic treatment. Chronic stable angina may also be diagnosed in this setting (Fig. 2, B2), and patients with this diagnosis should be managed according to the ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina (4).

Patients with possible ACS (Fig. 2, B3 and D1) are candidates for additional observation in a specialized facility (e.g., chest pain unit) (Fig. 2, E1). Patients with definite ACS (Fig. 2, B4) are triaged on the basis of the pattern of the 12-lead ECG. Patients with ST-segment elevation (Fig. 2, C3) are evaluated for immediate reperfusion therapy (Fig. 2, D3) and managed according to the ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (1), whereas those without ST-segment elevation (Fig. 2, C2) are either managed by additional observation (Fig. 2, E1) or admitted to the hospital (Fig. 2, H3). Patients with low-risk ACS (Table 6) without transient ST-segment depressions greater than or equal to 0.05 mV (0.5 mm) or T-wave inversions greater than or equal to 0.2 mV (2 mm), without positive cardiac biomarkers, and with a negative stress test or CCTA (Fig. 2, H1) may be discharged and treated as outpatients (Fig. 2, I1). Low-risk patients may have a stress test within 3 d of discharge.

2.3.1 Chest Pain Units
To facilitate a more definitive evaluation while avoiding the unnecessary hospital admission of patients with possible ACS (Fig. 2, B3) and low-risk ACS (Fig. 2, F1), as well as the inappropriate discharge of patients with active myocardial ischemia without ST-segment elevation (Fig. 2, C2), special units have been established that are variously referred to as "chest pain units" and "short-stay ED coronary care units." Personnel in these units use critical pathways or protocols designed to arrive at a decision about the presence or absence of myocardial ischemia and, if present, to characterize it further as UA or NSTEMI and to define the optimal next step in the care of the patient (e.g., admission, acute intervention) (87,214,285,286). The goal is to arrive at such a decision after a finite amount of time, which usually is between 6 and 12 h but may extend up to 24 h depending on the policies in individual hospitals. Typically, the patient undergoes a predetermined observation period with serial cardiac biomarkers and ECGs. At the end of the observation period, the patient is reevaluated and then generally undergoes functional cardiac testing (e.g., resting nuclear scan or echocardiography) and/or stress testing (e.g., treadmill, stress echocardiography, or stress nuclear testing) or noninvasive coronary imaging study (i.e., CCTA) (see Section 2.3.2). Those patients who have a recurrence of chest pain strongly suggestive of ACS, a positive biomarker value, a significant ECG change, or a positive functional/stress test or CCTA are generally admitted for inpatient evaluation and treatment. Although chest pain units are useful, other appropriate observation areas in which patients with chest pain can be evaluated may be used as well, such as a section of the hospital’s cardiac telemetry ward.

The physical location of the chest pain unit or the site where patients with chest pain are observed is variable, ranging from a specifically designated area of the ED to a separate hospital unit with the appropriate equipment to observational status (24-h admission) on a regular hospital telemetry ward (287). Similarly, the chest pain unit may be administratively a part of the ED and staffed by emergency physicians or may be administered and staffed separately or as part of the hospital cardiovascular service. Capability of chest pain units generally includes continuous monitoring of the patient’s ECG, ready availability of cardiac resuscitation equipment and medications, and appropriate staffing with nurses and physicians. The ACEP has published guidelines that recommend a program for the continuous monitoring of outcomes of patients evaluated in such units and the impact on hospital resources (288). A consensus panel statement from ACEP emphasized that chest pain units should be considered as part of a multifaceted program that includes efforts to minimize patient delays in seeking medical care and delays in the ED itself (288).

It has been reported, both from studies with historical controls and from randomized trials, that the use of chest pain units is cost-saving compared with an in-hospital evaluation to "rule out MI" (289,290). The potential cost savings of a chest pain unit varies depending on the practice pattern for the disposition of chest pain patients at individual hospitals (289). Hospitals with a high admission rate of low-risk patients to rule out MI (70% to 80%) will experience the largest cost savings by implementing a chest pain unit approach but will have the smallest impact on the number of missed MI patients. In contrast, hospitals with relatively low admission rates of such patients (30% to 40%) will experience greater improvements in the quality of care because fewer MI patients will be missed but will experience a smaller impact on costs because of the low baseline admission rate.

Farkouh et al. (102) extended the use of a chest pain unit in a separate portion of the ED to include patients at an intermediate risk of adverse clinical outcome on the basis of the previously published Agency for Health care Research and Quality guidelines for the management of UA (124) (Table 7). They reported a 46% reduction in the ultimate need for hospital admission in intermediate-risk patients after a median stay of 9.2 h in the chest pain unit. Extension of the use of chest pain units to intermediate-risk patients in an effort to reduce inpatient costs is facilitated by making available diagnostic testing modalities such as treadmill testing and stress imaging (echocardiographic, nuclear, or magnetic resonance) or CCTA 7 d a week (291).

Patients with chest discomfort for whom a specific diagnosis cannot be made after a review of the history, physical examination, initial 12-lead ECG, and cardiac biomarker data should undergo a more definitive evaluation. Several categories of patients should be considered according to the algorithm shown in Figure 2:

• Patients with possible ACS (Fig. 2, B3) are those who had a recent episode of chest discomfort at rest not entirely typical of ischemia but who are pain free when initially evaluated, have a normal or unchanged ECG, and have no elevations of cardiac biomarkers.

• Patients with a recent episode of typical ischemic discomfort that either is of new onset or is severe or that exhibits an accelerating pattern of previous stable angina (especially if it has occurred at rest or is within 2 weeks of a previously documented MI) should initially be considered to have a "definite ACS" (Fig. 2, B4). However, such patients may be at a low risk if their ECG obtained at presentation has no diagnostic abnormalities and the initial serum cardiac biomarkers (especially cardiac-specific troponins) are normal (Fig. 2, C2 and D1). As indicated in the algorithm, patients with either "possible ACS" (Fig. 2, B3) or "definite ACS" (Fig. 2, B4) but with nondiagnostic ECGs and normal initial cardiac markers (Fig. 2, D1) are candidates for additional observation in the ED or in a specialized area such as a chest pain unit (Fig. 2, E1). In contrast, patients who present without ST-segment elevation but who have features indicative of active ischemia (ongoing pain, ST-segment and/or T-wave changes, positive cardiac biomarkers, or hemodynamic instability; Fig. 2, D2) should be admitted to the hospital (Fig. 2, H3).

2.3.2 Discharge From ED or Chest Pain Unit
The initial assessment of whether a patient has UA/NSTEMI and which triage option is most suitable generally should be made immediately on the patient’s arrival at a medical facility. Rapid assessment of a patient’s candidacy for additional observation can be accomplished based on the status of the symptoms, ECG findings, and initial serum cardiac biomarker measurement.

Patients who experience recurrent ischemic discomfort, evolve abnormalities on a follow-up 12-lead ECG or on cardiac biomarker measurements, or develop hemodynamic abnormalities such as new or worsening HF (Fig. 2, D2) should be admitted to the hospital (Fig. 2, H3) and managed as described in Section 3.

Patients who are pain free, have either a normal or nondiagnostic ECG or one that is unchanged from previous tracings, and have a normal set of initial cardiac biomarker measurements are candidates for further evaluation to screen for nonischemic discomfort (Fig. 2, B1) versus a low-risk ACS (Fig. 2, D1). If the patient is low risk (Table 7) and does not experience any further ischemic discomfort and a follow-up 12-lead ECG and cardiac biomarker measurements after 6 to 8 h of observation are normal (Fig. 2, F1), the patient may be considered for an early stress test to provoke ischemia or CCTA to assess for obstructive CAD (Fig. 2, G1). This test can be performed before the discharge and should be supervised by an experienced physician. Alternatively, the patient may be discharged and return for stress testing as an outpatient within 72 h. The exact nature of the test may vary depending on the patient’s ability to exercise on either a treadmill or bicycle and the local expertise in a given hospital setting (e.g., availability of different testing modalities at different times of the day or different days of the week) (292). Patients who are capable of exercise and who are free of confounding features on the baseline ECG, such as bundle-branch block, LV hypertrophy, or paced rhythms, can be evaluated with routine symptom-limited conventional exercise stress testing. Patients who are incapable of exercise or who have an uninterpretable baseline ECG should be considered for pharmacological stress testing with either nuclear perfusion imaging or 2-dimensional echocardiography, or magnetic resonance (175,293,294). Alternatively, it is reasonable to perform a non-invasive coronary imaging test (i.e., CCTA). An imaging-enhanced test also may be more predictive in women than conventional ECG exercise stress testing (see Section 6.1.).

Two imaging modalities, CMR and multidetector computed tomography for coronary calcification and CCTA, are increasingly becoming clinically validated and applied and hold promise as alternative or supplementary imaging modalities for assessing patients who present with chest pain syndromes (25,294,295). Cardiac magnetic resonance has the capability of assessing cardiac function, perfusion, and viability in the same setting. Its advantages are excellent resolution (approximately 1 mm) of cardiac structures and avoidance of exposure to radiation and iodinated contrast. Disadvantages include long study time, confined space (claustrophobia), and (current) contraindication to the presence of pacemakers/defibrillators. To evaluate for ischemic heart disease, an adenosine first-pass gadolinium perfusion study is combined with assessment of regional and global function and viability (gadolinium delayed study). Direct coronary artery imaging is better assessed by CCTA (see below). One study indicated a sensitivity of 89% and specificity of 87% for combined adenosine stress and gadolinium delayed enhancement (viability) CMR testing for CAD (296). Dobutamine CMR stress testing can be used as an alternative to adenosine perfusion CMR (e.g., in asthmatic patients).

Coronary CT angiography with current multidetector technology (i.e., 64 slices beginning in 2005) has been reported to give 90% to 95% or greater sensitivity and specificity for occlusive CAD in early clinical trial experience (297–299). For evaluation of potential UA/NSTEMI, coronary artery calcium scoring followed by CCTA is typically done in the same sitting. The advantages of CCTA are good to excellent resolution (approximately 0.6 mm) of coronary artery anatomy and short study time (single breath hold). Disadvantages are radiation dose (8 to 24 mSv), contrast dye exposure, and necessity to achieve a slow, regular heart rate (beta blockers are usually required). A lack of large controlled comparative trials and reimbursement issues are current limitations to these technologies. In summary, the high negative predictive value of CCTA is its greatest advantage: if no evidence of either calcified or noncalcified (soft/fibrous) plaque is found, then it is highly unlikely that the patient’s symptoms are due to UA/NSTEMI of an atherosclerotic origin. (Note that primary [micro]vascular dysfunction causes of chest pain are not excluded.) In contrast, the positive predictive value of CCTA in determining whether a given plaque or stenosis is causing the signs and symptoms of possible UA/NSTEMI is less clear because although it gives valuable anatomic information, it does not provide functional or physiological assessment. Coronary CT angiography has been judged to be useful for evaluation of obstructive CAD in symptomatic patients (Class IIa, Level of Evidence: B) (25) and appropriate for acute chest pain evaluation for those with intermediate and possibly low pretest probability of CAD when serial ECG and biomarkers are negative (294). It may be particularly appropriate for those with acute chest pain syndromes with intermediate pretest probability of CAD in the setting of nondiagnostic ECG and negative cardiac biomarkers (294).

Because LV function is so integrally related to prognosis and greatly affects therapeutic options, strong consideration should be given to the assessment of LV function with echocardiography or another modality (i.e., CMR, radionuclide, CCTA, or contrast angiography) in patients with documented ischemia. In sites at which stress tests are not available, low-risk patients may be discharged and referred for outpatient stress testing in a timely fashion. Prescription of precautionary anti-ischemic treatment (e.g., ASA, sublingual NTG, and beta blockers) should be considered in these patients while awaiting results of stress testing. Specific instructions also should be given on whether or not to take these medications (e.g., beta blockers) before testing, which may vary depending on the test ordered and patient-specific factors. These patients also should be given specific instructions on what to do and how to seek emergency care for recurrence or worsening of symptoms while awaiting the stress test.

Patients who develop recurrent symptoms during observation suggestive of ACS or in whom the follow-up studies (12-lead ECG, cardiac biomarkers) show new abnormalities (Fig. 2, F2) should be admitted to the hospital (Fig. 2, H3). Patients in whom ACS has been excluded should be reassessed for need for further evaluation of other potentially serious medical conditions that may mimic ACS symptomatology (e.g., pulmonary embolism and aortic dissection).

Because continuity of care is important in the overall management of patients with a chest pain syndrome, the patient’s primary physician (if not involved in the care of the patient during the initial episode) should be notified of the results of the evaluation and should receive a copy of the relevant test results. Patients with a noncardiac diagnosis and those with low risk or possible ACS with a negative stress test should be counseled to make an appointment with their primary care physician as outpatients for further investigation into the cause of their symptoms (Fig. 2, I1). They should be seen by a physician as soon after discharge from the ED or chest pain unit as practical and appropriate, that is, usually within 72 h.

Patients with possible ACS (Fig. 5, B3) and those with a definite ACS but a nondiagnostic ECG and normal cardiac biomarkers when they are initially seen (Fig. 2, D1) at institutions without a chest pain unit (or equivalent facility) should be admitted to an inpatient unit. The inpatient unit to which such patients are to be admitted should have the same provisions for continuous ECG monitoring, availability of resuscitation equipment, and staffing arrangements as described above for the design of chest pain units.

	3. Early Hospital Care

Top Table of Contents Preamble 1. Introduction 1.5 Onset of UA/NSTEMI 1.5.2 Silent and Unrecognized... 2. Initial Evaluation and... 2.2 Early Risk Stratification 2.3 Immediate Management 3. Early Hospital Care 5. Late Hospital Care,... 6. Special Groups 6.7 Variant (Prinzmetal's)... 6.8 Cardiovascular "Syndrome X" 6.9 Takotsubo Cardiomyopathy 7. Conclusions and Future... Staff Appendix References

 
Patients with UA/NSTEMI, recurrent symptoms suggestive of ACS and/or ECG ST-segment deviations, or positive cardiac biomarkers who are stable hemodynamically should be admitted to an inpatient unit for bed rest with continuous rhythm monitoring and careful observation for recurrent ischemia (a step-down unit) and managed with either an invasive or conservative strategy (Table 11). Patients with continuing discomfort and/or hemodynamic instability should be hospitalized for at least 24 h in a coronary care unit characterized by a nursing-to-patient ratio sufficient to provide 1) continuous rhythm monitoring, 2) frequent assessment of vital signs and mental status, 3) documented ability to perform defibrillation quickly after the onset of ventricular fibrillation, and 4) adequate staff to perform these functions. Patients should be maintained at that level of care until they have been observed for an adequate period of time, generally at least 24 h, without any of the following major complications: sustained ventricular tachycardia or fibrillation, sinus tachycardia, high-degree atrioventricular (AV) block, sustained hypotension, recurrent ischemia documented by symptoms or ST-segment change, new mechanical defect (ventricular septal defect or mitral regurgitation), or HF. Shorter periods of monitoring might be appropriate for selected patients who are successfully reperfused and who have normal LV function and minimal or no necrosis.

3.1 Anti-Ischemic and Analgesic Therapy.   Recommendations for Anti-Ischemic Therapy
Class I

1 Bed/chair rest with continuous ECG monitoring is recommended for all UA/NSTEMI patients during the early hospital phase. (Level of Evidence: C)

2 Supplemental oxygen should be administered to patients with UA/NSTEMI with an arterial saturation less than 90%, respiratory distress, or other high-risk features for hypoxemia. (Pulse oximetry is useful for continuous measurement of SaO₂.) (Level of Evidence: B)

3 Patients with UA/NSTEMI with ongoing ischemic discomfort should receive sublingual NTG (0.4 mg) every 5 min for a total of 3 doses, after which assessment should be made about the need for intravenous NTG, if not contraindicated. (Level of Evidence: C)

4 Intravenous NTG is indicated in the first 48 h after UA/NSTEMI for treatment of persistent ischemia, HF, or hypertension. The decision to administer intravenous NTG and the dose used should not preclude therapy with other proven mortality-reducing interventions such as beta blockers or ACE inhibitors. (Level of Evidence: B)

5 Oral beta-blocker therapy should be initiated within the first 24 h for patients who do not have 1 or more of the following: 1) signs of HF, 2) evidence of a low-output state, 3) increased risk_^* for cardiogenic shock, or 4) other relative contraindications to beta blockade (PR interval greater than 0.24 s, second or third degree heart block, active asthma, or reactive airway disease). (Level of Evidence: B)

6 In UA/NSTEMI patients with continuing or frequently recurring ischemia and in whom beta blockers are contraindicated, a nondihydropyridine calcium channel blocker (e.g., verapamil or diltiazem) should be given as initial therapy in the absence of clinically significant LV dysfunction or other contraindications. (Level of Evidence: B)

7 An ACE inhibitor should be administered orally within the first 24 h to UA/NSTEMI patients with pulmonary congestion or LV ejection fraction (LVEF) less than or equal to 0.40, in the absence of hypotension (systolic blood pressure less than 100 mm Hg or less than 30 mm Hg below baseline) or known contraindications to that class of medications. (Level of Evidence: A)

8 An angiotensin receptor blocker should be administered to UA/NSTEMI patients who are intolerant of ACE inhibitors and have either clinical or radiological signs of HF or LVEF less than or equal to 0.40. (Level of Evidence: A)

9 Because of the increased risks of mortality, reinfarction, hypertension, HF, and myocardial rupture associated with their use, nonsteroidal anti-inflammatory drugs (NSAIDs), except for ASA, whether nonselective or cyclooxygenase (COX)-2–selective agents, should be discontinued at the time a patient presents with UA/NSTEMI. (Level of Evidence: C)

Class IIa

1 It is reasonable to administer supplemental oxygen to all patients with UA/NSTEMI during the first 6 h after presentation. (Level of Evidence: C)

2 In the absence of contradictions to its use, it is reasonable to administer morphine sulfate intravenously to UA/NSTEMI patients if there is uncontrolled ischemic chest discomfort despite NTG, provided that additional therapy is used to manage the underlying ischemia. (Level of Evidence: B)

3 It is reasonable to administer intravenous (IV) beta blockers at the time of presentation for hypertension to UA/NSTEMI patients who do not have 1 or more of the following: 1) signs of HF, 2) evidence of low-output state, 3) increased risk_^* for cardiogenic shock, or 4) other relative contraindications to beta blockade (PR interval greater than 0.24 s, second or third degree heart block, active asthma, or reactive ariway disease). (Level of Evidence: B)

4 Oral long-acting nondihydropyridine calcium channel blockers are reasonable for use in UA/NSTEMI patients for recurrent ischemia in the absence of contraindications after beta blockers and nitrates have been fully used. (Level of Evidence: C)

5 An ACE inhibitor administered orally within the first 24 h of UA/NSTEMI can be useful in patients without pulmonary congestion or LVEF less than or equal to 0.40 in the absence of hypotension (systolic blood pressure less than 100 mm Hg or less than 30 mm Hg below baseline) or known contraindications to that class of medications. (Level of Evidence: B)

6 Intra-aortic balloon pump (IABP) counterpulsation is reasonable in UA/NSTEMI patients for severe ischemia that is continuing or recurs frequently despite intensive medical therapy, for hemodynamic instability in patients before or after coronary angiography, and for mechanical complications of MI. (Level of Evidence: C)

Class IIb

1 The use of extended-release forms of nondihydropyridine calcium channel blockers instead of a beta blocker may be considered in patients with UA/NSTEMI. (Level of Evidence: B)

2 Immediate-release dihydropyridine calcium channel blockers in the presence of adequate beta blockade may be considered in patients with UA/NSTEMI with ongoing ischemic symptoms or hypertension. (Level of Evidence: B)

Class III

1 Nitrates should not be administered to UA/NSTEMI patients with systolic blood pressure less than 90 mm Hg or greater than or equal to 30 mm Hg below baseline, severe bradycardia (less than 50 beats per minute), tachycardia (more than 100 beats per minute) in the absence of symptomatic HF, or right ventricular infarction. (Level of Evidence: C)

2 Nitroglycerin or other nitrates should not be administered to patients with UA/NSTEMI who had received a phosphodiesterase inhibitor for erectile dysfunction within 24 h of sildenafil or 48 h of tadalafil use. The suitable time for the administration of nitrates after vardenafil has not been determined. (Level of Evidence: C)

3 Immediate-release dihydropyridine calcium channel blockers should not be administered to patients with UA/NSTEMI in the absence of a beta blocker. (Level of Evidence: A)

4 An intravenous ACE inhibitor should not be given to patients within the first 24 h of UA/NSTEMI because of the increased risk of hypotension. (A possible exception may be patients with refractory hypertension.) (Level of Evidence: B)

5 It may be harmful to administer intravenous beta blockers to UA/NSTEMI patients who have contraindications to beta blockade, signs of HF or low-output state, or other risk factors_^* for cardiogenic shock. (Level of Evidence: A)

6 Nonsteroidal anti-inflammatory drugs (except for ASA), whether nonselective or COX-2–selective agents, should not be administered during hospitalization for UA/NSTEMI because of the increased risks of mortality, reinfarction, hypertension, HF, and myocardial rupture associated with their use. (Level of Evidence: C)

The optimal management of UA/NSTEMI has the twin goals of the immediate relief of ischemia and the prevention of serious adverse outcomes (i.e., death or myocardial [re]infarction). This is best accomplished with an approach that includes anti-ischemic therapy (Table 12), antithrombotic therapy (Table 13), ongoing risk stratification, and the use of invasive procedures. Patients who are at intermediate or high risk for adverse outcomes, including those with ongoing ischemia refractory to initial medical therapy and those with evidence of hemodynamic instability, should be admitted whenever possible to a critical care environment with ready access to invasive cardiovascular diagnosis and therapeutic procedures. Ready access is defined as ensured, timely access to a cardiac catheterization laboratory with personnel who have appropriate credentials and experience in invasive coronary procedures, as well as to emergency or urgent cardiovascular surgery and cardiac anesthesia (2,300).

3.1.1 General Care
The severity of symptoms dictates some of the general care that should be given during the initial treatment. Patients should be placed on bed rest while ischemia is ongoing but can be mobilized to a chair and use a bedside commode when symptom free. Subsequent activity should not be inappropriately restrictive; instead, it should be focused on the prevention of recurrent symptoms and liberalized as judged appropriate when response to treatment occurs. Patients with cyanosis, respiratory distress, or other high-risk features should receive supplemental oxygen. Adequate arterial oxygen saturation should be confirmed with direct measurement (especially with respiratory distress or cyanosis) or pulse oximetry. No evidence is available to support the administration of oxygen to all patients with ACS in the absence of signs of respiratory distress or arterial hypoxemia. Its use based on the evidence base can be limited to those with questionable respiratory status and documented hypoxemia. Nevertheless, it is the opinion of the Writing Committee that a short period of initial routine oxygen supplementation is reasonable during initial stabilization of the patient, given its safety and the potential for underrecognition of hypoxemia. Inhaled oxygen should be administered if the arterial oxygen saturation (SaO₂) declines to less than 90%. Finger pulse oximetry is useful for the continuous monitoring of SaO₂ but is not mandatory in patients who do not appear to be at risk of hypoxemia. Patients should undergo continuous ECG monitoring during their ED evaluation and early hospital phase, because sudden, unexpected ventricular fibrillation is the major preventable cause of death in this early period. Furthermore, monitoring for the recurrence of ST-segment shifts provides useful diagnostic and prognostic information, although the system of monitoring for ST-segment shifts must include specific methods intended to provide stable and accurate recordings.

3.1.2 Use of Anti-Ischemic Therapies
3.1.2.1 Nitrates
Nitroglycerin reduces myocardial oxygen demand while enhancing myocardial oxygen delivery. Nitroglycerin, an endothelium-independent vasodilator, has both peripheral and coronary vascular effects. By dilating the capacitance vessels (i.e., the venous bed), it increases venous pooling to decrease myocardial preload, thereby reducing ventricular wall tension, a determinant of myocardial oxygen demand (MVO₂). More modest effects on the arterial circulation decrease systolic wall stress (afterload), which contributes to further reductions in MVO₂. This decrease in myocardial oxygen demand is in part offset by reflex increases in heart rate and contractility, which counteract the reductions in MVO₂ unless a beta blocker is concurrently administered. Nitroglycerin dilates normal and atherosclerotic epicardial coronary arteries and smaller arteries that constrict with certain stressors (e.g., cold, mental or physical exercise). With severe atherosclerotic coronary obstruction and with less severely obstructed vessels with endothelial dysfunction, physiological responses to changes in myocardial blood flow are often impaired (i.e., loss of flow-mediated dilation), so maximal dilation does not occur unless a direct-acting vasodilator like NTG is administered. Thus, NTG promotes the dilation of large coronary arteries, as well as collateral flow and redistribution of coronary blood flow to ischemic regions. Inhibition of platelet aggregation also occurs with NTG (300), but the clinical significance of this action is not well defined.

Intravenous NTG can benefit patients whose symptoms are not relieved in the hospital with three 0.4-mg sublingual NTG tablets taken 5 min apart (Tables 12 and 14) and with the initiation of an oral or intravenous beta blocker (when there are no contraindications), as well as those with HF or hypertension. Note that NTG is contraindicated after the use of sildenafil within the previous 24 h or tadalafil within 48 h or with hypotension (301–303). The suitable delay before nitrate administration after the use of vardenafil has not been determined, although blood pressure had generally returned to baseline by 24 h (304). These drugs inhibit the phosphodiesterase that degrades cyclic guanosine monophosphate, and cyclic guanosine monophosphate mediates vascular smooth muscle relaxation by nitric oxide. Thus, NTG-mediated vasodilatation is markedly exaggerated and prolonged in the presence of phosphodiesterase inhibitors. Nitrate use within 24 h after sildenafil or the administration of sildenafil in a patient who has received a nitrate within 24 h has been associated with profound hypotension, MI, and even death (303). Similar concerns apply to tadalafil and vardenafil (301,304).

Topical or oral nitrates are acceptable alternatives for patients who require antianginal therapy but who do not have ongoing refractory ischemic symptoms. Tolerance to the hemodynamic effects of nitrates is dose and duration dependent and typically becomes important after 24 h of continuous therapy with any formulation. Patients who require continued intravenous NTG beyond 24 h may require periodic increases in infusion rate to maintain efficacy. An effort must be made to use non–tolerance-producing nitrate regimens (lower doses and intermittent dosing). When patients have been free of ischemic discomfort and other manifestations of ischemia for 12 to 24 h, an attempt should be made to reduce the dose of intravenous NTG and to switch to oral or topical nitrates. It is not appropriate to continue intravenous NTG in patients who remain free of signs and symptoms of ischemia. When ischemia recurs during continuous intravenous NTG therapy, responsiveness to nitrates can often be restored by increasing the dose and, after symptoms have been controlled for several hours, attempting to add a nitrate-free interval. This strategy should be pursued as long as symptoms are not adequately controlled. In stabilized patients, intravenous NTG should generally be converted within 24 h to a nonparenteral alternative (Table 14) administered in a non–tolerance-producing regimen to avoid the potential reactivation of symptoms. A practical method for converting intravenous to topical NTG has been published (307).

Most studies of nitrate treatment in UA/NSTEMI have been small and uncontrolled, and there are no randomized, placebo-controlled trials that address either symptom relief or reduction in cardiac events. One small randomized trial compared intravenous NTG with buccal NTG and found no significant difference in the control of ischemia (308). An overview of small studies of NTG in MI from the prefibrinolytic era suggested a 35% reduction in mortality rates (309); in contrast, both the Fourth International Study of Infarct Survival (ISIS-4) (310) and Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico (GISSI-3) (311) trials formally tested this hypothesis in patients with suspected MI in the reperfusion era and failed to confirm this magnitude of benefit. However, these large trials are confounded by frequent prehospital and hospital use of NTG in the "control" groups. Nevertheless, a strategy of routine as opposed to selective use of nitrates did not reduce mortality. The abrupt cessation of intravenous NTG has been associated with exacerbation of ischemic changes on the ECG (312), and a graded reduction in the dose of intravenous NTG is advisable. Thus, the rationale for NTG use in UA/NSTEMI is extrapolated from pathophysiological principles and extensive, although uncontrolled, clinical observations (300).

3.1.2.2 Morphine Sulfate
Morphine sulfate (1 to 5 mg IV) is reasonable for patients whose symptoms are not relieved despite NTG (e.g., after 3 serial sublingual NTG tablets) or whose symptoms recur despite adequate anti-ischemic therapy. Unless contraindicated by hypotension or intolerance, morphine may be administered with intravenous NTG, with careful blood pressure monitoring, and may be repeated every 5 to 30 min as needed to relieve symptoms and maintain patient comfort.

Morphine sulfate has potent analgesic and anxiolytic effects, as well as hemodynamic effects, that are potentially beneficial in UA/NSTEMI. No randomized trials have defined the unique contribution of morphine to the initial therapeutic regimen or its optimal administration schedule. Morphine causes venodilation and can produce modest reductions in heart rate (through increased vagal tone) and systolic blood pressure to further reduce myocardial oxygen demand. The major adverse reaction to morphine is an exaggeration of its therapeutic effect, causing hypotension, especially in the presence of volume depletion and/or vasodilator therapy. This reaction usually responds to supine or Trendelenburg positioning or intravenous saline boluses and atropine when accompanied by bradycardia; it rarely requires pressors or naloxone to restore blood pressure. Nausea and vomiting occur in approximately 20% of patients. Respiratory depression is the most serious complication of morphine; severe hypoventilation that requires intubation occurs very rarely in patients with UA/NSTEMI treated with morphine. Naloxone (0.4 to 2.0 mg IV) may be administered for morphine overdose with respiratory or circulatory depression. Other narcotics may be considered in patients allergic to morphine. A cautionary note on morphine use has been raised by data from a large observational registry (n = 443 hospitals) that enrolled patients with UA/NSTEMI (n = 57,039) (313). Those receiving morphine (30%) had a higher adjusted likelihood of death (propensity-adjusted OR = 1.41, 95% CI 1.26 to 1.57), which persisted across all subgroups (313). Although subject to uncontrolled selection biases, these results raise a safety concern and suggest the need for a randomized trial. Meanwhile, the Writing Committee has downgraded the recommendation for morphine use for uncontrolled ischemic chest discomfort from a Class I to a Class IIa recommendation.

3.1.2.3 Beta-Adrenergic Blockers
Beta blockers competitively block the effects of catecholamines on cell membrane beta receptors. Beta-1 adrenergic receptors are located primarily in the myocardium; inhibition of catecholamine action at these sites reduces myocardial contractility, sinus node rate, and AV node conduction velocity. Through these actions, they blunt the heart rate and contractility responses to chest pain, exertion, and other stimuli. They also decrease systolic blood pressure. All of these effects reduce MVO₂. Beta-2 adrenergic receptors are located primarily in vascular and bronchial smooth muscle; the inhibition of catecholamine action at these sites produces vasoconstriction and bronchoconstriction (300). In UA/NSTEMI, the primary benefits of beta blockers are due to inhibition of beta-1 adrenergic receptors, which results in a decrease in cardiac work and myocardial oxygen demand. Slowing of the heart rate also has a favorable effect, acting not only to reduce MVO₂ but also to increase the duration of diastole and diastolic pressure-time, a determinant of forward coronary flow and collateral flow.

Beta blockers, administered orally, should be started early in the absence of contraindications. Intravenous administration may be warranted in patients with ongoing rest pain, especially with tachycardia or hypertension, in the absence of contraindications (see below) (Table 12).

The benefits of routine early intravenous use of beta blockers in the fibrinolytic era have been challenged by 2 later randomized trials of intravenous beta blockade (314,315) and by a post hoc analysis of the use of atenolol in the GUSTO-I trial (316). A subsequent systematic review of early beta-blocker therapy in STEMI found no significant reduction in mortality (27). Most recently, the utility of early intravenous followed by oral beta blockade (metoprolol) was tested in 45,852 patients with MI (93% had STEMI, 7% had NSTEMI) in the COMMIT study (317). Neither the composite of death, reinfarction, or cardiac arrest nor death alone was reduced for up to 28 d in the hospital. Overall, a modest reduction in reinfarction and ventricular fibrillation (which was seen after day 1) was counterbalanced by an increase in cardiogenic shock, which occurred early (first day) and primarily in those who were hemodynamically compromised or in HF or who were stable but at high risk of development of shock. Thus, early aggressive beta blockade poses a substantial net hazard in hemodynamically unstable patients and should be avoided. Risk factors for shock were older age, female sex, time delay, higher Killip class, lower blood pressure, higher heart rate, ECG abnormality, and previous hypertension. There was a moderate net benefit for those who were relatively stable and at low risk of shock. Whether to start beta blockade intravenously or orally in these latter stable patients is unclear, and patterns of use vary. In an attempt to balance the evidence base overall for UA/NSTEMI patients, beta blockers are recommended in these guidelines to be initiated orally, in the absence of contraindications (e.g., HF), within the first 24 h. Greater caution is now suggested in the early use of intravenous beta blockers, which should be targeted to specific indications and should be avoided with HF, hypotension, and hemodynamic instability.

The choice of beta blocker for an individual patient is based primarily on pharmacokinetic and side effect criteria, as well as on physician familiarity (Table 15). There are no comparative studies between members of this class in the acute setting. Beta blockers without intrinsic sympathomimetic activity are preferred, however. Agents studied in the acute setting include metoprolol, propranolol, and atenolol. Carvedilol may be added to the list of agents studied for post-MI use. Comparative studies among different beta blockers in the chronic setting after UA/NSTEMI also are not available to establish a preference among agents. In patients with HF, 1 study suggested greater benefit with carvedilol, with mixed beta-blocking and alpha-adrenergic-blocking effects, than metoprolol, a relatively selective beta-1 blocker (318). In patients with hypertension, the relative cardiovascular benefit of atenolol has been questioned on the basis of recent clinical trial analyses (319,320).

In the absence of these concerns, previously studied regimens may be used. Intravenous metoprolol may be given in 5-mg increments by slow intravenous administration (5 mg over 1 to 2 min), repeated every 5 min for a total initial dose of 15 mg. In patients who tolerate the total 15-mg IV dose, oral therapy can be initiated 15 min after the last intravenous dose at 25 to 50 mg every 6 h for 48 h. Thereafter, patients should receive a maintenance dose of up to 100 mg twice daily. Alternatively, intravenous propranolol may be administered as an initial dose of 0.5 to 1.0 mg, followed in 1 to 2 h by 40 to 80 mg by mouth every 6 to 8 h. Monitoring during intravenous beta-blocker therapy should include frequent checks of heart rate and blood pressure and continuous ECG monitoring, as well as auscultation for rales and bronchospasm. Beta blockade also may be started orally, in smaller initial doses if appropriate, within the first 24 h, in cases in which a specific clinical indication for intravenous initiation is absent or the safety of aggressive early beta blockade is a concern. Carvedilol, 6.25 mg by mouth twice daily, uptitrated individually at 3- to 10-d intervals to a maximum of 25 mg twice daily, can reduce mortality and reinfarction when given to patients with recent (3 to 21 d) MI and LV dysfunction (321). After the initial intravenous load, if given, patients without limiting side effects may be converted to an oral regimen. The target resting heart rate is 50 to 60 beats per minute unless a limiting side effect is reached. Selection of the oral agent should include the clinician’s familiarity with the agent. Maintenance doses are given in Table 15.

Initial studies of beta-blocker benefits in ACS were small and uncontrolled. An overview of double-blind, randomized trials in patients with threatening or evolving MI suggests an approximately 13% reduction in the risk of progression to MI (322). These trials were conducted prior to the routine use of ASA, heparin, clopidogrel, GP IIb/IIIa inhibitors, and revascularization. These trials lack sufficient power to assess the effects of these drugs on mortality rates for UA. Pooled results from the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC), Evaluation of PTCA and Improve Long-term Outcome by c7E3 GP IIb/IIIa receptor blockade (EPILOG), Evaluation of Platelet IIb/IIIa Inhibitor for STENTing (EPISTENT), CAPTURE, and ReoPro in Acute myocardial infarction and Primary PTCA Organization and Randomization Trial (RAPPORT) studies were used to evaluate the efficacy of beta-blocker therapy in patients with ACS who were undergoing PCI (323). At 30 d, death occurred in 0.6% of patients receiving beta-blocker therapy versus 2.0% of patients not receiving such therapy (p less than 0.001). At 6 months, death occurred in 1.7% of patients receiving beta-blocker therapy versus 3.7% not receiving this therapy (p less than 0.001). Thus, patients receiving beta-blocker therapy who undergo PCI for UA or MI have a lower short-term mortality (323).

Overall, the rationale for beta-blocker use in all forms of CAD, including UA, is generally favorable, with the exception of initial HF. In the absence of contraindications, the new evidence appears sufficient to make beta blockers a routine part of care. A related group shown to benefit are high- or intermediate-risk patients who are scheduled to undergo cardiac or noncardiac surgery (324). A recent exception to beta-blocker benefit was COMMIT, a large trial of mostly STEMI patients, which showed no overall mortality effect. Subgroup analysis suggested this to be due to an increased risk in those with initial HF or risk factors for cardiogenic shock (317). In contrast to this adverse experience with early, aggressive beta blockade, carvedilol, begun in low doses 3 to 10 d after MI in patients with LV dysfunction (ejection fraction of 0.40 or less) and gradually uptitrated, decreased subsequent death or nonfatal recurrent MI when given in conjunction with modern ACS therapies in the most contemporary oral beta blocker post-MI trial, CAPRICORN (Carvedilol Post-Infarct Survival Control in LV Dysfunction) (321).

In conclusion, evidence for the beneficial effects of the use of beta blockers in patients with UA is based on limited randomized trial data along with pathophysiological considerations and extrapolation from experience with CAD patients who have other types of ischemic syndromes (stable angina or compensated chronic HF). The duration of benefit with long-term oral therapy is uncertain and likely varies with the extent of revascularization.

3.1.2.4 Calcium Channel Blockers
Calcium channel blockers (CCBs) reduce cell transmembrane inward calcium flux, which inhibits both myocardial and vascular smooth muscle contraction; some also slow AV conduction and depress sinus node impulse formation. Agents in this class vary in the degree to which they produce vasodilation, decreased myocardial contractility, AV block, and sinus node slowing. Nifedipine and amlodipine have the most peripheral arterial dilatory effects but few or no AV or sinus node effects, whereas verapamil and diltiazem have prominent AV and sinus node effects and some peripheral arterial dilatory effects as well. All 4 of these agents, as well as other approved agents, have coronary dilatory properties that appear to be similar. Although different CCBs are structurally and, potentially, therapeutically diverse, superiority of 1 agent over another in UA/NSTEMI has not been demonstrated, except for the increased risks posed by rapid-release, short-acting dihydropyridines such as nifedipine (Table 16). Beneficial effects in UA/NSTEMI are believed to be due to variable combinations of decreased myocardial oxygen demand (related to decreased afterload, contractility, and heart rate) and improved myocardial flow (related to coronary arterial and arteriolar dilation) (300,325). These agents also have theoretically beneficial effects on LV relaxation and arterial compliance. Major side effects include hypotension, worsening HF, bradycardia, and AV block.

Several randomized trials during the 1980s tested CCBs in UA/NSTEMI and found that they relieve or prevent signs and symptoms of ischemia to a degree similar to the beta blockers. The Danish Study Group on Verapamil in Myocardial Infarction (DAVIT) (332,333) studied 3,447 patients with suspected UA/NSTEMI. A benefit was not proved, but death or nonfatal MI tended to be reduced. The Diltiazem Reinfarction Study (DRS) studied 576 patients with UA/NSTEMI (329). Diltiazem reduced reinfarction and refractory angina at 14 d without an increase in mortality rates. Retrospective analysis of the non–Q-wave MI subset of patients in the Multicenter Diltiazem Postinfarction Trial (MDPIT) suggested similar findings (334). The Holland Interuniversity Nifedipine/metoprolol Trial (HINT), tested nifedipine and metoprolol in a 2 x 2 factorial design in 515 patients (327). The study was stopped early because of concern for harm with the use of nifedipine alone. In contrast, patients already taking a beta blocker appeared to benefit from the addition of nifedipine (risk ratio [RR] 0.68) (335).

Meta-analyses combining UA/NSTEMI studies of all CCBs have suggested no overall benefit (322,336), whereas those excluding nifedipine (e.g., for verapamil alone) have reported favorable effects on outcomes (332). Retrospective analyses of DAVIT and MDPIT suggested that verapamil and diltiazem can have a detrimental effect on mortality rates in patients with LV dysfunction (329,330). In contrast, verapamil reduced diuretic use in DAVIT-2, (333). Furthermore, subsequent prospective trials with verapamil administered to MI patients with HF who were receiving an ACE inhibitor suggested a benefit (330,337). The Diltiazem as Adjunctive Therapy to Activase (DATA) trial also suggested that intravenous diltiazem in MI patients can be safe; death, MI, and recurrent ischemia were decreased at 35 d and 6 months (338).

In summary, definitive evidence for a benefit of CCBs in UA/NSTEMI is predominantly limited to symptom control. For immediate-release nifedipine, an increase in serious events is suggested when administered early without a beta blocker. The heart rate–slowing CCB drugs (verapamil and diltiazem) can be administered early to patients with UA/NSTEMI without HF without overall harm and with trends toward a benefit. Therefore, when beta blockers cannot be used, and in the absence of clinically significant LV dysfunction, heart rate–slowing CCBs are preferred. Greater caution is indicated when combining a beta blocker and CCB for refractory ischemic symptoms, because they may act in synergy to depress LV function and sinus and AV node conduction. The risks and benefits in UA/NSTEMI of newer CCBs, such as the dihydropyridines amlodipine and felodipine, relative to the older agents in this class that have been reviewed here, remain undefined, which suggests a cautious approach, especially in the absence of beta blockade.

3.1.2.5 Inhibitors of the Renin-Angiotensin-Aldosterone System
Angiotensin-converting enzyme inhibitors have been shown to reduce mortality rates in patients with MI or who recently had an MI and have LV systolic dysfunction (339–341), in patients with diabetes mellitus with LV dysfunction (342), and in a broad spectrum of patients with high-risk chronic CAD, including patients with normal LV function (343). Follow-up of patients with LV dysfunction after MI in the TRACE (TRAndolapril Cardiac Evaluation) trial showed that the beneficial effect of trandolapril on mortality and hospitalization rate was maintained for at least 10 to 12 years (344). A systematic review assessing potential ASA–ACE inhibitor interactions showed clinically important benefits with ACE inhibitor therapy, irrespective of whether concomitant ASA was used, and only weak evidence of a reduction in the benefit of ACE inhibitor therapy added to ASA (345); these data did not solely involve patients with MI. Accordingly, ACE inhibitors should be used in patients receiving ASA and in those with hypertension that is not controlled with beta blockers. Recent data on ACE inhibitor patients with stable CAD are summarized in the section on long-term medical therapy (see Section 5.2.3).

In patients with MI complicated by LV systolic dysfunction, HF, or both, the angiotensin receptor blocker valsartan was as effective as captopril in patients at high risk for cardiovascular events after MI. The combination of valsartan and captopril increased adverse events and did not improve survival (346). Although not in the acute care setting, treatment of patients with chronic HF with candesartan (at least half of whom had an MI) in the CHARM (Candesartan in Heart failure Assessment in Reduction of Mortality)-Overall program showed a reduction in cardiovascular deaths and hospital admissions for HF, independent of ejection fraction or baseline treatment (347).

The selective aldosterone receptor blocker eplerenone, used in patients with MI complicated by LV dysfunction and either HF or diabetes mellitus, reduced morbidity and mortality in the Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS) (348). This complements data from the earlier Randomized ALdactone Evaluation Study (RALES), in which aldosterone receptor blockade with spironolactone decreased morbidity and death in patients with severe HF, half of whom had an ischemic origin (349). Indications for long-term use of aldosterone receptor blockers are given in Section 5.2.3.

3.1.2.6 Other Anti-Ischemic Therapies
Other less extensively studied therapies for the relief of ischemia, such as spinal cord stimulation (350) and prolonged external counterpulsation (351,352), are under evaluation. Most experience has been gathered with spinal cord stimulation in "intractable angina" (353), in which anginal relief has been described. They have not been applied in the acute setting for UA/NSTEMI.

The K_ATP channel openers have hemodynamic and cardioprotective effects that could be useful in UA/NSTEMI. Nicorandil is such an agent that has been approved in a number of countries but not in the United States. In a pilot double-blind, placebo-controlled study of 245 patients with UA, the addition of this drug to conventional treatment significantly reduced the number of episodes of transient myocardial ischemia (mostly silent) and of ventricular and supraventricular tachycardia (354). Further evaluation of this class of agents is underway.

Ranolazine is a newly approved (January 2006) agent that exerts antianginal effects without reducing heart rate or blood pressure (355). Currently, ranolazine is indicated alone or in combination with amlodipine, beta-blockers, or nitrates for the treatment of chronic angina that has failed to respond to standard antianginal therapy. The recommended initial dose is 500 mg orally twice daily, which can be escalated as needed to a maximum of 1000 mg twice daily. The mechanism of action of ranolazine has not been fully characterized but appears to depend on membrane ion-channel effects (similar to those after chronic amiodarone) (356). It is contraindicated in patients with QT-prolonging conditions. Preliminary results of a large (N = 6,560) patient trial of ranolazine, begun within 48 h of UA/NSTEMI, suggested safety and symptom relief (reduction in angina) but did not achieve the primary efficacy end point of a reduction in the composite of cardiovascular death, MI, or recurrent ischemia (hazard ratio [HR] 0.92, 95% CI 0.83 to 1.02) (357,357a). Thus, ranolazine may be safely administered for symptom relief after UA/NSTEMI, but it does not appear to significantly improve the underlying disease substrate.

3.1.2.7 Intra-Aortic Balloon Pump Counterpulsation
Experience with IABP for refractory ischemia dates back more than 30 years. In a prospective registry of 22,663 IABP patients, 5,495 of whom had acute MI, placement of an IABP in MI patients primarily was performed for cardiogenic shock, for hemodynamic support during catheterization and/or angioplasty, before high-risk surgery, for mechanical complications of MI, or for refractory post-MI UA. Balloon insertions were successful in 97.7% of patients, and major complications occurred in 2.7% of patients during a median use of 3 d (358). The placement of an IABP could be useful in patients with recurrent ischemia despite maximal medical management and in those with hemodynamic instability until coronary angiography and revascularization can be completed.

3.1.2.8 Analgesic Therapy
Because of the known increased risk of cardiovascular events among patients taking COX-2 inhibitors and NSAIDs (359–361), patients who are taking them at the time of UA/NSTEMI should discontinue them immediately (see Section 5.2.16 for additional discussion). A secondary analysis of the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (EXTRACT)-TIMI-25 data (362) demonstrated an increased risk of death, reinfarction, HF, or shock among patients who were taking NSAIDs within 7 d of enrollment. Longer term management is considered in Section 5.2.16.

3.2 Recommendations for Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite.   Recommendations are written as the reader follows the algorithms for antiplatelet/anticoagulant therapy and triage for angiography (Figs. 7, 8, and 9). Letters after recommendations refer to the specific box in the algorithm. See Table 13 for dosing recommendations.

View larger version (28K): [in this window] [in a new window] [Download PPT slide]   Figure 7 Algorithm for Patients With UA/NSTEMI Managed by an Initial Invasive Strategy When multiple drugs are listed, they are in alphabetical order and not in order of preference (e.g., Boxes B1 and B2). *See dosing Table 13. See Table 11 for selection of management strategy. Evidence exists that GP IIb/IIIa inhibitors may not be necessary if the patient received a preloading dose of at least 300 mg of clopidogrel at least 6 h earlier (Class I, Level of Evidence B for clopidogrel administration) and bivalirudin is selected as the anticoagulant (Class IIa, Level of Evidence B). ASA = aspirin; GP = glycoprotein; IV = intravenous; LOE = level of evidence; UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction; UFH = unfractionated heparin.

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Figure 8 Algorithm for Patients With UA/NSTEMI Managed by an Initial Conservative Strategy When multiple drugs are listed, they are in alphabetical order and not in order of preference (e.g., Boxes C, C1, and C2). *See dosing Table 13. See Table 11 for selection of management strategy. Recurrent symptoms/ischemia, heart failure, serious arrhythmia. ASA = aspirin; EF = ejection fraction; GP = glycoprotein; IV = intravenous; LOE = level of evidence; LVEF = left ventricular ejection fraction; UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction; UFH = unfractionated heparin.

View larger version (31K): [in this window] [in a new window] [Download PPT slide]   Figure 9 Management After Diagnostic Angiography in Patients With UA/NSTEMI *See dosing Table 13. Evidence exists that GP IIb/IIIa inhibitors may not be necessary if the patient received a preloading dose of at least 300 mg of clopidogrel at least 6 h earlier (Class I, Level of Evidence B for clopidogrel administration) and bivalirudin is selected as the anticoagulant (Class IIa, Level of Evidence B). Additional bolus of UFH is recommended if fondaparinux is selected as the anticoagulant (see dosing Table 13). For patients in whom the clinician believes coronary atherosclerosis is present, albeit without any significant, flow-limiting stenoses, long-term treatment with antiplatelet agents and other secondary prevention measures should be considered. ASA = aspirin; CABG = coronary artery bypass graft; CAD = coronary artery disease; GP = glycoprotein; IV = intravenous; LD = loading dose; PCI = percutaneous coronary intervention; pre angio = before angiography; UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction; UFH = unfractionated heparin.

1 Aspirin should be administered to UA/NSTEMI patients as soon as possible after hospital presentation and continued indefinitely in patients not known to be intolerant of that medication. (Level of Evidence: A) (Figs. 7 and 8; Box A)

2 Clopidogrel (loading dose followed by daily maintenance dose)_^* should be administered to UA/NSTEMI patients who are unable to take ASA because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: A) (Figs. 7 and 8; Box A)

3 In UA/NSTEMI patients with a history of gastrointestinal bleeding, when ASA and clopidogrel are administered alone or in combination, drugs to minimize the risk of recurrent gastrointestinal bleeding (e.g., proton-pump inhibitors) should be prescribed concomitantly. (Level of Evidence: B)

4 For UA/NSTEMI patients in whom an initial invasive strategy is selected, antiplatelet therapy in addition to aspirin should be initiated before diagnostic angiography (upstream) with either clopidogrel (loading dose followed by daily maintenance dose)_^* or an intravenous GP IIb/IIIa inhibitor. (Level of Evidence: A) Abciximab as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is the preferred choice of GP IIb/IIIa inhibitor. (Level of Evidence: B)

5 For UA/NSTEMI patients in whom an initial conservative (i.e., noninvasive) strategy is selected (see Section 3.3), clopidogrel (loading dose followed by daily maintenance dose)_^* should be added to ASA and anticoagulant therapy as soon as possible after admission and administered for at least 1 month (Level of Evidence: A) and ideally up to 1 year. (Level of Evidence: B) (Fig. 8; Box C2)

6 For UA/NSTEMI patients in whom an initial conservative strategy is selected, if recurrent symptoms/ischemia, HF, or serious arrhythmias subsequently appear, then diagnostic angiography should be performed. (Level of Evidence: A) (Fig. 8; Box D) Either an intravenous GP IIb/IIIa inhibitor (eptifibatide or tirofiban; Level of Evidence: A) or clopidogrel (loading dose followed by daily maintenance dose; Level of Evidence: A)_^* should be added to ASA and anticoagulant therapy before diagnostic angiography (upstream). (Level of Evidence: C)

Class IIa

1 For UA/NSTEMI patients in whom an initial conservative strategy is selected and who have recurrent ischemic discomfort with clopidogrel, ASA, and anticoagulant therapy, it is reasonable to add a GP IIb/IIIa antagonist before diagnostic angiography. (Level of Evidence: C)

2 For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to initiate antiplatelet therapy with both clopidogrel (loading dose followed by daily maintenance dose)_^* and an intravenous GP IIb/IIIa inhibitor. (Level of Evidence: B) Abciximab as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is the preferred choice of GP IIb/IIIa inhibitor.(Level of Evidence: B)

3 For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit upstream administration of an intravenous GP IIb/IIIa antagonist before diagnostic angiography if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 h earlier than planned catheterization or PCI. (Level of Evidence: B)

Class IIb
For UA/NSTEMI patients in whom an initial conservative (i.e., noninvasive) strategy is selected, it may be reasonable to add eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy. (Level of Evidence: B) (Fig. 8; Box C2)

Class III
Abciximab should not be administered to patients in whom PCI is not planned. (Level of Evidence: A)

3.2.2 Anticoagulant Therapy Recommendations
Class I
Anticoagulant therapy should be added to antiplatelet therapy in UA/NSTEMI patients as soon as possible after presentation.

a For patients in whom an invasive strategy is selected, regimens with established efficacy at a Level of Evidence: A include enoxaparin and UFH (Fig. 7; Box B1), and those with established efficacy at a Level of Evidence: B include bivalirudin and fondaparinux (Fig. 7; Box B1).

b For patients in whom a conservative strategy is selected, regimens using either enoxaparin or UFH (Level of Evidence: A) or fondaparinux (Level of Evidence: B) have established efficacy. (Fig. 8; Box C1) See also Class IIa recommendation below.

c In patients in whom a conservative strategy is selected and who have an increased risk of bleeding, fondaparinux is preferable. (Level of Evidence: B) (Fig. 8; Box C1)

Class IIa
For UA/NSTEMI patients in whom an initial conservative strategy is selected, enoxaparin or fondaparinux is preferable to UFH as anticoagulant therapy, unless CABG is planned within 24 h. (Level of Evidence: B)

3.2.3 Additional Management Considerations for Antiplatelet and Anticoagulant Therapy
Class I

1 For UA/NSTEMI patients in whom an initial conservative strategy is selected and no subsequent features appear that would necessitate diagnostic angiography (recurrent symptoms/ischemia, HF, or serious arrhythmias), a stress test should be performed. (Level of Evidence: B) (Fig. 8; Box O)

a If, after stress testing, the patient is classified as not at low risk, diagnostic angiography should be performed. (Level of Evidence: A) (Fig. 8; Box E1)

b If, after stress testing, the patient is classified as being at low risk (Fig. 8; Box E2), the instructions noted below should be followed in preparation for discharge (Fig. 8; Box K) (Level of Evidence: A):

1 Continue ASA indefinitely. (Level of Evidence: A)

2 Continue clopidogrel for at least 1 month (Level of Evidence: A) and ideally up to 1 year. (Level of Evidence: B)

3 Discontinue intravenous GP IIb/IIIa inhibitor if started previously. (Level of Evidence: A)

4 Continue UFH for 48 h or administer enoxaparin or fondaparinux for the duration of hospitalization, up to 8 d, and then discontinue anticoagulant therapy. (Level of Evidence: A)

2 For UA/NSTEMI patients in whom CABG is selected as a postangiography management strategy, the instructions noted below should be followed (Fig. 9; Box G).

a Continue ASA. (Level of Evidence: A)

b Discontinue clopidogrel 5 to 7 d before elective CABG. (Level of Evidence: B) More urgent surgery, if necessary, may be performed by experienced surgeons if the incremental bleeding risk is considered acceptable. (Level of Evidence: C)

c Discontinue intravenous GP IIb/IIIa inhibitor (eptifibatide or tirofiban) 4 h before CABG. (Level of Evidence: B)

d Anticoagulant therapy should be managed as follows:

1 Continue UFH. (Level of Evidence: B)

2 Discontinue enoxaparin_^* 12 to 24 h before CABG and dose with UFH per institutional practice. (Level of Evidence: B)

3 Discontinue fondaparinux 24 h before CABG and dose with UFH per institutional practice. (Level of Evidence: B)

4 Discontinue bivalirudin 3 h before CABG and dose with UFH per institutional practice. (Level of Evidence: B)

3 For UA/NSTEMI patients in whom PCI has been selected as a postangiography management strategy, the instructions noted below should be followed (Fig. 9 C; Box H):

a Continue ASA. (Level of Evidence: A)

b Administer a loading dose of clopidogrel if not started before diagnostic angiography. (Level of Evidence: A)

c Administer an intravenous GP IIb/IIIa inhibitor (abciximab, eptifibatide, or tirofiban) if not started before diagnostic angiography for troponin-positive and other high-risk patients (Level of Evidence: A). See Class IIa recommendation below if bivalirudin was selected as the anticoagulant.

d Discontinue anticoagulant therapy after PCI for uncomplicated cases. (Level of Evidence: B)

4 For UA/NSTEMI patients in whom medical therapy is selected as a postangiography management strategy and in whom no significant obstructive CAD on angiography was found, antiplatelet and anticoagulant therapy should be administered at the discretion of the clinician. (Level of Evidence: C) For patients in whom evidence of coronary atherosclerosis is present (e.g., luminal irregularities or intravascular ultrasound-demonstrated lesions), albeit without flow-limiting stenoses, long-term treatment with ASA and other secondary prevention measures should be prescribed. (Fig. 9; Box I) (Level of Evidence: C)

5 For UA/NSTEMI patients in whom medical therapy is selected as a postangiography management strategy and in whom CAD was found on angiography, the following approach is recommended (Fig. 9; Box J):

a Continue ASA. (Level of Evidence: A)

b Administer a loading dose of clopidogrel if not given before diagnostic angiography. (Level of Evidence: A)

c Discontinue intravenous GP IIb/IIIa inhibitor if started previously. (Level of Evidence: B)

d Anticoagulant therapy should be managed as follows:

1 Continue intravenous UFH for at least 48 h or until discharge if given before diagnostic angiography. (Level of Evidence: A)

2 Continue enoxaparin for duration of hospitalization, up to 8 d, if given before diagnostic angiography. (Level of Evidence: A)

3 Continue fondaparinux for duration of hospitalization, up to 8 d, if given before diagnostic angiography. (Level of Evidence: B)

4 Either discontinue bivalirudin or continue at a dose of 0.25 mg per kg per h for up to 72 h at the physician’s discretion, if given before diagnostic angiography. (Level of Evidence: B)

6 For UA/NSTEMI patients in whom a conservative strategy is selected and who do not undergo angiography or stress testing, the instructions noted below should be followed (Fig. 8; Box K):

a Continue ASA indefinitely. (Level of Evidence: A)

b Continue clopidogrel for at least 1 month (Level of Evidence: A) and ideally up to 1 year. (Level of Evidence: B)

c Discontinue IV GP IIb/IIIa inhibitor if started previously. (Level of Evidence: A)

d Continue UFH for 48 h or administer enoxaparin or fondaparinux for the duration of hospitalization, up to 8 d, and then discontinue anticoagulant therapy. (Level of Evidence: A)

7 For UA/NSTEMI patients in whom an initial conservative strategy is selected and in whom no subsequent features appear that would necessitate diagnostic angiography (recurrent symptoms/ischemia, HF, or serious arrhythmias), LVEF should be measured. (Level of Evidence: B) (Fig. 8; Box L)

Class IIa

1 For UA/NSTEMI patients in whom PCI is selected as a postangiography management strategy, it is reasonable to omit administration of an intravenous GP IIb/IIIa antagonist if bivalirudin was selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 h earlier. (Level of Evidence: B) (Fig. 9)

2 If LVEF is less than or equal to 0.40, it is reasonable to perform diagnostic angiography. (Level of Evidence: B) (Fig. 8; Box M)

3 If LVEF is greater than 0.40, it is reasonable to perform a stress test. (Level of Evidence: B) (Fig. 8; Box N)

Class IIb
For UA/NSTEMI patients in whom PCI is selected as a postangiography management strategy, it may be reasonable to omit an intravenous GP IIb/IIIa inhibitor if not started before diagnostic angiography for troponin-negative patients without other clinical or angiographic high-risk features. (Level of Evidence: C)

Class III
Intravenous fibrinolytic therapy is not indicated in patients without acute ST-segment elevation, a true posterior MI, or a presumed new left bundle-branch block. (Level of Evidence: A)

Antithrombotic therapy is essential to modify the disease process and its progression to death, MI, or recurrent MI in the majority of patients who have ACS due to thrombosis on a plaque. A combination of ASA, an anticoagulant, and additional antiplatelet therapy represents the most effective therapy. The intensity of treatment is tailored to individual risk, and triple-antithrombotic treatment is used in patients with continuing ischemia or with other high-risk features and in patients oriented to an early invasive strategy (Table 11; Figs. 7, 8, and 9). Table 13 shows the recommended doses of the various agents. A problematic group of patients are those who present with UA/NSTEMI but who are therapeutically anticoagulated with warfarin. In such patients, clinical judgment is needed with respect to initiation of the antiplatelet and anticoagulant therapy recommended in this section. A general guide is not to initiate anticoagulant therapy until the international normalized ratio (INR) is less than 2.0. However, antiplatelet therapy should be initiated even in patients therapeutically anticoagulated with warfarin, especially if an invasive strategy is planned and implantation of a stent is anticipated. In situations where the INR is supratherapeutic, the bleeding risk is unacceptably high, or urgent surgical treatment is necessary, reversal of the anticoagulant effect of warfarin may be considered with either vitamin K or fresh-frozen plasma as deemed clinically appropriate on the basis of physician judgment.

3.2.4 Antiplatelet Agents and Trials (Aspirin, Ticlopidine, Clopidogrel)
3.2.4.1 Aspirin
Some of the strongest evidence available about the long-term prognostic effects of therapy in patients with coronary disease pertains to ASA (363). By irreversibly inhibiting COX-1 within platelets, ASA prevents the formation of thromboxane A2, thereby diminishing platelet aggregation promoted by this pathway but not by others. This platelet inhibition is the plausible mechanism for the clinical benefit of ASA, both because it is fully present with low doses of ASA and because platelets represent one of the principal participants in thrombus formation after plaque disruption. Alternative or additional mechanisms of action for ASA are possible, such as an anti-inflammatory effect (364), but they are unlikely to be important at the low doses of ASA that are effective in UA/NSTEMI. Among all clinical investigations with ASA, trials in UA/NSTEMI have consistently documented a striking benefit of ASA compared with placebo independent of the differences in study design, such as time of entry after the acute phase, duration of follow-up, and dose used (365–368) (Fig. 10).

View larger version (40K): [in this window] [in a new window] [Download PPT slide]   Figure 10 Older Trials of Antiplatelet and Anticoagulant Therapy in UA/NSTEMI *Best results group. GPIIb/IIIa with no heparin. All trials except PRISM compared GP IIb-IIIa with UFH versus UFH. Meta-analysis of randomized trials in UA/NSTEMI that have compared ASA with placebo, the combination of UFH and ASA with ASA alone, the combination of an LMWH and ASA with ASA alone, and the combination of a platelet GP IIb/IIIa antagonist, UFH, and ASA with UFH plus ASA. The risk ratio values, 95% CIs, and probability value for each trial are shown. The timing of the end point (death or MI) varied. Results with the platelet GP IIb/IIIa antagonists are reported at the 30-d time point. Incremental gain is observed from single therapy with ASA to double therapy with ASA and UFH and to triple antithrombotic therapy with ASA, UFH, and a platelet GP IIb/IIIa antagonist. In the CAPTURE trial, nearly all patients underwent PCI after 20 to 24 h per study design. Data are taken from PURSUIT (128), PRISM-PLUS (130), Lewis et al. (365), Cairns et al. (366), Théroux et al. (367), RISC group (368), ATACS group (369), Gurfinkel et al. (370), FRISC group (371), CAPTURE (372), PARAGON (373), and PRISM (374). anta. = antagonist; ASA = aspirin; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; CAPTURE = c7E3 Fab AntiPlatelet Therapy in Unstable REfractory angina; CI = confidence interval; FRISC = FRagmin during InStability in Coronary artery disease; GP = glycoprotein; hep. = heparin; LMWH = low-molecular-weight heparin; MI = myocardial infarction; NA = not applicable; PARAGON = Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network; PCI = percutaneous coronary intervention; PRISM = Platelet Receptor Inhibition in ischemic Syndrome Management; PRISM-PLUS = Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms; PURSUIT = Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy; RISC = Research on InStability in Coronary artery disease; UA/NSTEMI = unstable angina/non--ST-elevation myocardial infarction; UFH = unfractionated heparin; VA = Veterans Affairs.

The prompt action of ASA and its ability to reduce mortality rates in patients with suspected MI enrolled in the Second International Study of Infarct Survival (ISIS-2) trial led to the recommendation that ASA be initiated immediately in the ED once the diagnosis of ACS is made or suspected. Aspirin therapy also can be started in the prehospital setting when ACS is suspected. On the basis of prior randomized trial protocols and clinical experience, the initial dose of ASA should be between 162 and 325 mg. Although some trials have used enteric-coated ASA for initial dosing, more rapid buccal absorption occurs with non–enteric-coated formulations (377). After stenting, a higher initial maintenance dose of ASA of 325 mg per d has been recommended for 1 month after bare-metal stent implantation and 3 to 6 months after drug-eluting stent (DES) implantation (2). This was based primarily on clinical trials that led to approval of these stents, which used the higher doses initially. However, a dosage change to a range of 162 to 325 mg per d initially has been subsequently recommended, based on risk of excess bleeding and an update of current evidence for ASA dosing (Table 13; Fig. 11).

View larger version (34K): [in this window] [in a new window] [Download PPT slide]   Figure 11 Long-Term Antitcoagulant Therapy at Hospital Discharge After UA/NSTEMI *For aspirin (ASA) allergic patients, use clopidogrel alone (indefinitely), or try aspirin desensitization. For clopidogrel allergic patients, use ticlopidine, 250 mg by mouth twice daily. Continue ASA indefinitely and warfarin longer term as indicated for specific conditions such as atrial fibrillation; LV thrombus; cerebral, venous, or pulmonary emboli. When warfarin is added to aspirin plus clopidogrel, an INR of 2.0 to 2.5 is recommended. INR = international normalized ratio; LOE = Level of Evidence; LV = left ventricular; UA/NSTEMI = unstable angina/non–ST-elevated myocardial infarction.

Contraindications to ASA include intolerance and allergy (primarily manifested as asthma with nasal polyps), active bleeding, hemophilia, active retinal bleeding, severe untreated hypertension, an active peptic ulcer, or another serious source of gastrointestinal or genitourinary bleeding. Gastrointestinal side effects such as dyspepsia and nausea are infrequent with the low doses. Primary prevention trials have reported a small excess in intracranial bleeding, which is offset in secondary prevention trials by the prevention of ischemic stroke. It has been proposed that there is a negative interaction between ACE inhibitors and ASA, with a reduction in the vasodilatory effects of ACE inhibitors, presumably because ASA inhibits ACE inhibitor–induced prostaglandin synthesis. This interaction does not appear to interfere importantly with the clinical benefits of therapy with either agent (382). Therefore, unless there are specific contraindications, ASA should be administered to all patients with UA/NSTEMI.

3.2.4.2 Adenosine Diphosphate Receptor Antagonists and Other Antiplatelet Agents
Two thienopyridines—ticlopidine and clopidogrel—are ADP receptor (P2Y12) antagonists that are approved for antiplatelet therapy (383). The platelet effects of ticlopidine and clopidogrel are irreversible but take several days to achieve maximal effect in the absence of a loading dose. The administration of a loading dose can shorten the time to achievement of effective levels of antiplatelet therapy. Because the mechanisms of the antiplatelet effects of ASA and ADP antagonists differ, a potential exists for additive benefit with the combination. In patients with a history of gastrointestinal bleeding, when ASA or a thienopyridine is administered alone or in combination, drugs to minimize the risk of recurrent gastrointestinal bleeding (e.g., proton-pump inhibitors) should be prescribed concomitantly (384–386).

Ticlopidine has been used successfully for the secondary prevention of stroke and MI and for the prevention of stent closure and graft occlusion (387). The adverse effects of ticlopidine limit its usefulness: gastrointestinal problems (diarrhea, abdominal pain, nausea, and vomiting), neutropenia in approximately 2.4% of patients, severe neutropenia in 0.8% of patients, and, rarely, thrombotic thrombocytopenia purpura (388). Neutropenia usually resolves within 1 to 3 weeks of discontinuation of therapy but very rarely may be fatal. Thrombotic thrombocytopenia purpura, which is a very uncommon, life-threatening complication, requires immediate plasma exchange. Monitoring of ticlopidine therapy requires a complete blood count that includes a differential count every 2 weeks for the first 3 months of therapy.

Extensive clinical experience with clopidogrel is derived in part from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial (389). A total of 19,185 patients were randomized to receive ASA 325 mg per d or clopidogrel 75 mg per d. Entry criteria consisted of atherosclerotic vascular disease manifested as recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease. Follow-up extended for 1 to 3 years. The RR of ischemic stroke, MI, or vascular death was reduced by 8.7% in favor of clopidogrel from 5.8% to 5.3% (p = 0.04). The benefit was greatest for patients with peripheral arterial disease. This group had a 24% relative risk reduction (p = 0.03). There was a slightly increased, but minimal, incidence of rash and diarrhea with clopidogrel treatment and slightly more bleeding with ASA. There was no excess neutropenia with clopidogrel, which contrasts with ticlopidine. The results provide evidence that clopidogrel is at least as effective as ASA and appears to be modestly more effective. In 1 report, 11 severe cases of thrombotic thrombocytopenia purpura were described as occurring within 14 d after the initiation of clopidogrel; plasma exchange was required in 10 of the patients, and 1 patient died (390). These cases occurred among more than 3 million patients treated with clopidogrel.

Clopidogrel is reasonable antiplatelet therapy for secondary prevention, with an efficacy at least similar to that of ASA. Clopidogrel is indicated in patients with UA/NSTEMI who are unable to tolerate ASA due to either hypersensitivity or major gastrointestinal contraindications, principally recent significant bleeding from a peptic ulcer or gastritis. In patients with a history of gastrointestinal bleeding while taking ASA, when a thienopyridine is administered, drugs to minimize the risk of recurrent gastrointestinal bleeding (e.g., proton-pump inhibitors) should be prescribed concomitantly (384–386). When treatment with thienopyridines is considered during the acute phase, it should be recognized that there is a delay before attainment of the full antiplatelet effect. Clopidogrel is preferred to ticlopidine because it more rapidly inhibits platelets and appears to have a more favorable safety profile.

An oral loading dose (300 mg) of clopidogrel is typically used to achieve more rapid platelet inhibition. The optimal loading dose with clopidogrel has not been rigorously established. The greatest amount of general clinical experience and randomized trial data exist for a clopidogrel loading dose of 300 mg, which is the approved loading dose. Higher loading doses (600 to 900 mg) have been evaluated (391,392). They appear to be safe and more rapidly acting; however, it must be recognized that the database for such higher loading doses is not sufficiently robust to formulate definitive recommendations. Most studies to date with higher loading doses of clopidogrel have examined surrogates for clinical outcomes, such as measurements of 1 or more markers of platelet aggregation or function. When groups of patients are studied, a general dose response is observed with increasing magnitude and speed of onset of inhibition of platelet aggregation in response to agonists such as ADP as the loading dose increases. However, considerable interindividual variation in antiplatelet effect also is observed with all loading doses of clopidogrel, which makes it difficult to predict the impact of different loading doses of clopidogrel in a specific patient. Small to moderate-sized trials have reported favorable outcomes with a 600-mg versus a 300-mg loading dose in patients undergoing PCI (393); however, large-scale randomized trials are still needed to definitively compare the efficacy and safety of different loading regimens of clopidogrel. This is of particular importance because it is known that patients undergoing CABG surgery shortly after receiving 300 mg of clopidogrel have an increased risk of bleeding (394); the relative risk of bleeding associated with higher loading doses of clopidogrel remains to be established. The Writing Committee endorses the performance of appropriately designed clinical trials to identify the optimal loading dose of clopidogrel.

Two randomized trials compared clopidogrel with ticlopidine. In 1 study, 700 patients who successfully received a stent were randomized to receive 500 mg of ticlopidine or 75 mg of clopidogrel, in addition to 100 mg of ASA, for 4 weeks (395). Cardiac death, urgent target-vessel revascularization, angiographically documented thrombotic stent occlusion, or nonfatal MI within 30 d occurred in 3.1% of patients who received clopidogrel and 1.7% of patients who received ticlopidine (p = 0.24), and noncardiac death, stroke, severe peripheral vascular hemorrhagic events, or any adverse event that resulted in the discontinuation of the study medication occurred in 4.5% and 9.6% of patients, respectively (p = 0.01). The CLopidogrel ASpirin Stent International Cooperative Study (CLASSICS) (396) was conducted in 1,020 patients. A loading dose of 300 mg of clopidogrel followed by 75 mg per d was compared to a daily dose of 75 mg without a loading dose and with a loading dose of 150 mg of ticlopidine followed by 150 mg twice per day (patients in each of the 3 arms also received ASA). The first dose was administered 1 to 6 h after stent implantation; the treatment duration was 28 d. The trial showed better tolerance to clopidogrel with or without a loading dose than to ticlopidine. Stent thrombosis or major complications occurred at the same frequency in the 3 groups.

The CURE trial randomized 12,562 patients with UA and NSTEMI presenting within 24 h to placebo or clopidogrel (loading dose of 300 mg followed by 75 mg daily) and followed them for 3 to 12 months (243). All patients received ASA. Cardiovascular death, MI, or stroke occurred in 11.5% of patients assigned to placebo and 9.3% assigned to clopidogrel (RR = 0.80, p less than 0.001). In addition, clopidogrel was associated with significant reductions in the rate of in-hospital severe ischemia and revascularization, as well as the need for fibrinolytic therapy or intravenous GP IIb/IIIa receptor antagonists. These results were observed across a wide variety of subgroups. A reduction in recurrent ischemia was noted within the first few hours after randomization.

There was an excess of major bleeding (2.7% in the placebo group vs. 3.7% in the clopidogrel group, p = 0.003) and of minor bleeding but not of life-threatening bleeding. The risk of bleeding was increased in patients undergoing CABG surgery within the first 5 d of stopping clopidogrel. The CURE study was conducted at centers in which there was no routine policy regarding early invasive procedures; revascularization was performed during the initial admission in only 23% of the patients. Although the addition of a platelet GP IIb/IIIa inhibitor in patients receiving ASA, clopidogrel, and heparin in CURE was well tolerated, fewer than 10% of patients received this combination. Therefore, additional information on the safety of an anticoagulant and a GP IIb/IIIa inhibitor in patients already receiving ASA and clopidogrel should be obtained. Accurate estimates of the treatment benefit of clopidogrel in patients who received GP IIb/IIIa antagonists remain ill-defined.

The CURE trial also provides strong evidence for the addition of clopidogrel to ASA on admission in the management of patients with UA and NSTEMI in whom a noninterventional approach is intended, an especially useful approach in hospitals that do not have a routine policy about early invasive procedures. The event curves for the 2 groups separate early. The optimal duration of therapy with clopidogrel in patients who have been managed exclusively medically has not been determined, but the favorable results in CURE were observed over a period averaging 9 months and for up to 1 year.

The PCI-CURE study was an observational substudy of the patients undergoing PCI within the larger CURE trial (397). In the PCI-CURE study, 2,658 patients had previously been randomly assigned to double-blind treatment with clopidogrel (n = 1313) as per the CURE protocol or placebo (n = 1,345). Patients were pretreated with ASA and the study drug for a median of 10 d. After PCI, most patients received open-label thienopyridine for approximately 4 weeks, after which the blinded study drug was restarted for a mean of 8 months. Fifty-nine patients (4.5%) in the clopidogrel group had the primary end point (a composite of cardiovascular death, MI, or urgent target-vessel revascularization) within 30 d of PCI compared with 86 (6.4%) in the placebo group (RR = 0.70, 95% CI 0.50 to 0.97, p = 0.03). Overall, including events before and after PCI, there was a 31% reduction in cardiovascular death or MI (p = 0.002). Thus, in patients with UA and NSTEMI receiving ASA and undergoing PCI, a strategy of clopidogrel pretreatment followed by up to 1 year of clopidogrel use (and probably at least 1 year in those with DES; see below) is beneficial in reducing major cardiovascular events compared with placebo and appears to be cost-effective (the incremental cost-effectiveness ratio for clopidogrel plus ASA compared with ASA alone was $15,400 per quality-adjusted life-year) (398). Therefore, clopidogrel should be used routinely in patients who undergo PCI.