Author + information
- Published online May 10, 2011.
- R. Scott Wright, MD, FACC, FAHA, Chair, 2011 Writing Group Member¶,
- Jeffrey L. Anderson, MD, FACC, FAHA, Vice Chair, 2011 Writing Group Member¶,#,
- Cynthia D. Adams, RN, PhD, FAHA, 2011 Writing Group Member¶,
- Charles R. Bridges, MD, ScD, FACC, FAHA, 2011 Writing Group Member⁎,#,
- Donald E. Casey Jr, MD, MPH, MBA, FACP, FAHA, 2011 Writing Group Member†,
- Steven M. Ettinger, MD, FACC, 2011 Writing Group Member⁎⁎,
- Francis M. Fesmire, MD, FACEP, 2011 Writing Group Member§,
- Theodore G. Ganiats, MD, 2011 Writing Group Member†,
- Hani Jneid, MD, FACC, FAHA, 2011 Writing Group Member¶,
- A. Michael Lincoff, MD, FACC, 2011 Writing Group Member¶,#,
- Eric D. Peterson, MD, MPH, FACC, FAHA, 2011 Writing Group Member#,††,
- George J. Philippides, MD, FACC, FAHA, 2011 Writing Group Member¶,
- Pierre Theroux, MD, FACC, FAHA, 2011 Writing Group Member¶,#,
- Nanette K. Wenger, MD, MACC, FAHA, 2011 Writing Group Member¶,# and
- James Patrick Zidar, MD, FACC, FSCAI, 2011 Writing Group Member∥,#
2007 Writing Committee Members
Developed in Collaboration With the American College of Emergency Physicians, 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; Cynthia D. Adams, RN, PhD, FAHA;
Elliott M. Antman, MD, FACC, FAHA; Charles R. Bridges, ScD, MD, FACC, FAHA⁎>;
Robert M. Califf, MD, MACC; Donald E. Casey, Jr, MD, MPH, MBA, FACP†;
Judith S. Hochman, MD, FACC, FAHA; Thomas N. Levin, MD, FACC, FSCAI∥;
A. Michael Lincoff, MD, FACC; Eric D. Peterson, MD, MPH, FACC, FAHA;
Pierre Theroux, MD, FACC, FAHA; Nanette Kass Wenger, MD, FACC, FAHA;
R. Scott Wright, MD, FACC, FAHA
ACCF/AHA Task Force Members
Alice K. Jacobs, MD, FACC, FAHA, Chair; Jeffrey L. Anderson, MD, FACC, FAHA, Chair-Elect;
Nancy Albert, PhD, CCNS, CCRN, FAHA; Judith S. Hochman, MD, FACC, FAHA;
Mark A. Creager, MD, FACC, FAHA; Frederick G. Kushner, MD, FACC, FAHA;
Steven M. Ettinger, MD, FACC; Erik Magnus Ohman, MD, FACC; Robert A. Guyton, MD, FACC;
William G. Stevenson, MD, FACC, FAHA; Jonathan L. Halperin, MD, FACC, FAHA;
Clyde W. Yancy, MD, FACC, FAHA
Table of Contents
1.1 Organization of Committee and Evidence Review (UPDATED)......e219
1.2 Purpose of These Guidelines......e219
1.3 Overview of the Acute Coronary Syndromes......e219
1.3.1 Definition of Terms......e219
1.3.2 Pathogenesis of UA/NSTEMI......e223
1.3.3 Presentations of UA and NSTEMI......e223
1.4 Management Before UA/NSTEMI and Onset of UA/NSTEMI......e224
1.4.1 Identification of Patients at Risk of UA/NSTEMI......e224
1.4.2 Interventions to Reduce Risk of UA/NSTEMI......e224
1.5 Onset of UA/NSTEMI......e225
1.5.1 Recognition of Symptoms by Patient......e225
1.5.2 Silent and Unrecognized Events......e226
2. Initial Evaluation and Management......e226
2.1 Clinical Assessment......e226
2.1.1 Emergency Department or Outpatient Facility Presentation......e230
2.1.2 Questions to Be Addressed at the Initial Evaluation......e230
2.2 Early Risk Stratification......e230
2.2.1 Estimation of the Level of Risk......e231
2.2.2 Rationale for Risk Stratification......e232
2.2.4 Anginal Symptoms and Anginal Equivalents......e233
2.2.5 Demographics and History in Diagnosis and Risk Stratification......e234
2.2.6 Estimation of Early Risk at Presentation......e234
126.96.36.199 Physical Examination......e238
2.2.7 Noncardiac Causes of Symptoms and Secondary Causes of Myocardial Ischemia......e238
2.2.8 Cardiac Biomarkers of Necrosis and the Redefinition of AMI......e238
188.8.131.52 Creatine Kinase-MB......e239
184.108.40.206 Cardiac Troponins......e239
220.127.116.11.1 Clinical Use......e239
18.104.22.168.1.1 Clinical Use of Marker Change Scores......e242
22.214.171.124.1.2 Bedside Testing for Cardiac Markers......e242
126.96.36.199 Myoglobin and CK-MB Subforms Compared With Troponins......e242
188.8.131.52 Summary Comparison of Biomarkers of Necrosis: Singly and In Combination......e242
2.2.9 Other Markers and Multimarker Approaches......e243
184.108.40.206 B-Type Natriuretic Peptides......e244
2.3 Immediate Management......e244
2.3.1 Chest Pain Units......e245
2.3.2 Discharge From ED or Chest Pain Unit......e246
3. Early Hospital Care......e247
3.1 Anti-Ischemic and Analgesic Therapy......e248
3.1.1 General Care......e249
3.1.2 Use of Anti-Ischemic Therapies......e250
220.127.116.11 Morphine Sulfate......e253
18.104.22.168 Beta-Adrenergic Blockers......e254
22.214.171.124 Calcium Channel Blockers......e256
126.96.36.199 Inhibitors of The Renin-Angiotensin-Aldosterone System......e257
188.8.131.52 Other Anti-Ischemic Therapies......e257
184.108.40.206 Intra-Aortic Balloon Pump Counterpulsation......e258
220.127.116.11 Analgesic Therapy......e258
3.2 Recommendations for Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite......e258
3.2.1 Antiplatelet Therapy Recommendations (UPDATED)......e258
3.2.2 Anticoagulant Therapy Recommendations......e260
3.2.3 Additional Management Considerations for Antiplatelet and Anticoagulant Therapy (UPDATED)......e261
3.2.4 Antiplatelet Agents and Trials (Aspirin, Ticlopidine, Clopidogrel)......e262
18.104.22.168 Adenosine Diphosphate Receptor Antagonists and Other Antiplatelet Agents......e264
3.2.5 Anticoagulant Agents and Trials......e268
22.214.171.124 Unfractionated Heparin......e269
126.96.36.199 Low-Molecular-Weight Heparin......e270
188.8.131.52 LMWH Versus UFH......e270
184.108.40.206.1 Extended Therapy With LMWHS......e273
220.127.116.11 Direct Thrombin Inhibitors......e274
18.104.22.168 Factor XA Inhibitors......e276
22.214.171.124 Long-Term Anticoagulation......e277
3.2.6 Platelet GP IIb/IIIa Receptor Antagonists......e278
3.3 Initial Conservative Versus Initial Invasive Strategies (UPDATED)......e283
3.3.1 General Principles......e283
3.3.2 Rationale for the Initial Conservative Strategy......e284
3.3.3 Rationale for the Invasive Strategy......e284
3.3.4 Immediate Angiography......e284
3.3.5 Deferred Angiography......e285
3.3.6 Comparison of Early Invasive and Initial Conservative Strategies......e285
3.3.8 Care Objectives......e288
3.4 Risk Stratification Before Discharge......e290
3.4.1 Care Objectives......e291
3.4.2 Noninvasive Test Selection......e292
3.4.3 Selection for Coronary Angiography......e293
3.4.4 Patient Counseling......e293
4. Coronary Revascularization......e293
4.1 Recommendations for Revascularization With PCI and CABG in Patients With UA/NSTEMI......e293
4.1.1 Recommendations for PCI......e293
4.1.2 Recommendations for CABG......e295
4.2 General Principles......e295
4.3 Percutaneous Coronary Intervention......e296
4.3.1 Platelet Inhibitors and Percutaneous Revascularization......e297
4.4 Surgical Revascularization......e298
5. Late Hospital Care, Hospital Discharge, and Post-Hospital Discharge Care......e300
5.1 Medical Regimen and Use of Medications......e300
5.2 Long-Term Medical Therapy and Secondary Prevention......e301
5.2.1 Convalescent and Long-Term Antiplatelet Therapy (UPDATED)......e301
5.2.2 Beta Blockers......e302
5.2.3 Inhibition of the Renin-Angiotensin-Aldosterone System......e302
5.2.5 Calcium Channel Blockers......e303
5.2.6 Warfarin Therapy (UPDATED)......e303
5.2.7 Lipid Management......e303
5.2.8 Blood Pressure Control......e305
5.2.9 Diabetes Mellitus......e305
5.2.10 Smoking Cessation......e305
5.2.11 Weight Management......e306
5.2.12 Physical Activity......e306
5.2.13 Patient Education......e307
5.2.16 Nonsteroidal Anti-Inflammatory Drugs......e307
5.2.17 Hormone Therapy......e308
5.2.18 Antioxidant Vitamins and Folic Acid......e308
5.3 Postdischarge Follow-Up......e308
5.4 Cardiac Rehabilitation......e309
5.5 Return to Work and Disability......e310
5.6 Other Activities......e311
5.7 Patient Records and Other Information Systems......e311
6. Special Groups......e312
6.1.1 Profile of UA/NSTEMI in Women......e313
126.96.36.199 PHARMACOLOGICAL THERAPY......e313
188.8.131.52 CORONARY ARTERY REVASCULARIZATION......e314
184.108.40.206 INITIAL INVASIVE VERSUS INITIAL CONSERVATIVE STRATEGY......e314
6.1.3 Stress Testing......e316
6.2 Diabetes Mellitus (UPDATED)......e316
6.2.1 Profile and Initial Management of Diabetic and Hyperglycemic Patients With UA/NSTEMI......e317
6.2.2 Coronary Revascularization......e318
6.3 Post-CABG Patients......e319
6.3.1 Pathological Findings......e319
6.3.2 Clinical Findings and Approach......e319
6.4 Older Adults......e320
6.4.1 Pharmacological Management......e321
6.4.2 Functional Studies......e321
6.4.3 Percutaneous Coronary Intervention in Older Patients......e321
6.4.4 Contemporary Revascularization Strategies in Older Patients......e321
6.5 Chronic Kidney Disease (UPDATED)......e322
6.6 Cocaine and Methamphetamine Users......e323
6.6.1 Coronary Artery Spasm With Cocaine Use......e324
6.6.3 Methamphetamine Use and UA/NSTEMI......e325
6.7 Variant (Prinzmetal's) Angina......e325
6.7.1 Clinical Picture......e325
6.8 Cardiovascular “Syndrome X”......e327
6.8.1 Definition and Clinical Picture......e327
6.9 Takotsubo Cardiomyopathy......e328
7. Conclusions and Future Directions......e328
7.1 Recommendations for Quality of Care and Outcomes for Acute Coronary Syndromes (NEW SECTION)......e330
Appendixes 4-8 (NEW SECTION)......e343
For new or updated text, view the2011 Focused Update. Text supporting unchanged recommendations has not been updated.
It is important that the medical profession play a significant role in critically evaluating the use of diagnostic procedures and therapies in the detection, management, or prevention of disease states. Rigorous and expert analysis of the available data documenting absolute and relative benefits and risks of those procedures and therapies can produce helpful guidelines that improve the effectiveness of care, optimize patient outcomes, and favorably affect the overall cost of care by focusing resources on the most effective strategies.
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
1.1 Organization of Committee and Evidence Review (UPDATED)
For new or updated text, view the2011 Focused Update. Text supporting unchanged recommendations has not been updated.
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.
A complete list of the thousands of publications on various aspects of this subject is beyond the scope of these guidelines; only selected references are included. The Committee consisted of acknowledged experts in general internal medicine representing the American College of Physicians (ACP), family medicine from the American Academy of Family Physicians (AAFP), emergency medicine from the American College of Emergency Physicians (ACEP), thoracic surgery from the Society of Thoracic Surgeons (STS), interventional cardiology from the Society for Cardiovascular Angiography and Interventions (SCAI), and general and critical care cardiology, as well as individuals with recognized expertise in more specialized areas, including noninvasive testing, preventive cardiology, coronary intervention, and cardiovascular surgery. Both the academic and private practice sectors were represented. This document was reviewed by 2 outside reviewers nominated by each of the ACC and AHA and by 49 peer reviewers. These guidelines will be considered current unless the Task Force revises them or withdraws them from distribution.
These guidelines overlap several previously published ACC/AHA practice guidelines, including the ACC/AHA Guidelines for the Management of Patients With 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.
“Acute coronary syndrome” has evolved as a useful operational term to refer to any constellation of clinical symptoms that are compatible with acute myocardial ischemia (Fig. 1). It encompasses MI (ST-segment elevation and depression, Q wave and non-Q wave) and UA. These guidelines focus on 2 components of this syndrome: UA and NSTEMI. In practice, the term “possible ACS” is often assigned first by ancillary personnel, such as emergency medical technicians and triage nurses, early in the evaluation process. A guideline of the National Heart Attack Alert Program (6) summarizes the clinical information needed to make the diagnosis of possible ACS at the earliest phase of clinical evaluation (Table 2). The implication of this early diagnosis for clinical management is that a patient who is considered to have an ACS should be placed in an environment with continuous ECG monitoring and defibrillation capability, where a 12-lead ECG can be obtained expeditiously and definitively interpreted, ideally within 10 min of arrival in the ED. The most urgent priority of early evaluation is to identify patients with ST-elevation MI (STEMI) who should be considered for immediate reperfusion therapy and to recognize other potentially catastrophic causes of patient symptoms, such as aortic dissection.
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 MyocardialInfarction (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 mechanisms involve an imbalance that is caused primarily by a reduction in oxygen supply to the myocardium, whereas with the fifth mechanism noted below, the imbalance is principally due to increased myocardial oxygen requirements, usually in the presence of a fixed, restricted oxygen supply:
• 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 Management Before UA/NSTEMI and Onset of UA/NSTEMI
The ACS spectrum (UA/MI) has a variable but potentially serious prognosis. The major risk factors for development of coronary heart disease (CHD) and UA/NSTEMI are well established. Clinical trials have demonstrated that modification of those risk factors can prevent the development of CHD (primary prevention) or reduce the risk of experiencing UA/NSTEMI in patients who have CHD (secondary prevention). All practitioners should emphasize prevention and refer patients to primary care providers for appropriate long-term preventive care. In addition to internists and family physicians, cardiologists have an important leadership role in primary (and secondary) prevention efforts.
1.4.1 Identification of Patients at Risk of UA/NSTEMI
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 ).
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
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
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
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).
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)
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).
Family members, close friends, caregivers, or advocates should be included in these discussions and enlisted as reinforcement for rapid action when the patient experiences symptoms of a possible ACS (74,117,118) (Fig. 3). For patients known to their providers to have frequent angina, physicians may consider a selected, more tailored message that takes into account the frequency and character of the patient's angina and their typical time course of response to NTG. In many of these patients with chronic stable angina, if chest pain is significantly improved by 1 NTG, it is still appropriate to instruct the patient or family member/friend/caregiver to repeat NTG every 5 min for a maximum of 3 doses and to call 9-1-1 if symptoms have not resolved completely. Avoidance of patient delay associated with self-medication and prolonged reevaluation of symptoms are paramount. An additional consideration in high-risk CHD patients is to train family members in CPR and/or to have home access to an automatic external defibrillator, now available commercially to the public.
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.
For the most part, the answers to these questions form a sequence of contingent probabilities. Thus, the likelihood that the signs and symptoms represent ACS is contingent on the likelihood that the patient has underlying CAD. Similarly, the prognosis is contingent on the likelihood that the symptoms represent acute ischemia. However, in patients with symptoms of possible ACS, traditional risk factors for CAD are less important than are symptoms, ECG findings, and cardiac biomarkers. Therefore, the presence or absence of these traditional risk factors ordinarily should not be heavily weighed in determining whether an individual patient should be admitted or treated for ACS.
2.2 Early Risk Stratification
Recommendations for Early Risk Stratification
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)
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)
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)
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.
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.
Antman et al. developed the TIMI risk score (159), a simple tool composed of 7 (1-point) risk indicators rated on presentation (Table 8). The composite end points (all-cause mortality, new or recurrent MI, or severe recurrent ischemia prompting urgent revascularization within 14 d) increase as the TIMI risk score increases. The TIMI risk score has been validated internally within the TIMI 11B trial and 2 separate cohorts of patients from the Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave Myocardial Infarction (ESSENCE) trial (169). The model remained a significant predictor of events and appeared relatively insensitive to missing information, such as knowledge of previously documented coronary stenosis of 50% or more. The model's predictive ability remained intact with a cutoff of 65 years of age. The TIMI risk score was recently studied in an unselected ED population with chest pain syndrome; its performance was similar to that in the ACS population in which it was derived and validated (170). The TIMI risk calculator is available at www.timi.org. The TIMI risk index, a modification of the TIMI risk score that uses the variables age, systolic blood pressure, and heart rate, has not only been shown to predict short-term mortality in STEMI but has also been useful in the prediction of 30-d and 1-year mortality across the spectrum of patients with ACS, including UA/NSTEMI (171).
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 220.127.116.11 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.
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).
18.104.22.168 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.
22.214.171.124 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.
126.96.36.199 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).
188.8.131.52.1 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.
The proportion of patients showing a positive cTn value depends on the population of patients under evaluation. Approximately 30% of patients with typical rest chest discomfort without ST-segment elevation who would be diagnosed as having UA because of a lack of CK-MB elevation actually have NSTEMI when assessed with cardiac-specific troponin assays. The diagnosis of MI in the community at large when cTn is used results in a large increase in the incidence of MIs, by as much as 41% compared with use of only CK-MB alone, and a change in the case mix, with a survival rate that is better than that of MI identified by the previous criteria (228). Troponin elevation conveys prognostic information beyond that supplied by the clinical characteristics of the patient, the ECG at presentation, and the predischarge exercise test (200,201,229–231). Furthermore, a quantitative relationship exists between the amount of elevation of cTn and the risk of death (200,201) (Fig. 6). The incremental risk of death or MI in troponin-positive versus troponin-negative patients is summarized in Table 9. It should be cautioned, however, that cTn should not be used as the sole marker of risk, because patients without troponin elevations can still have a substantial risk of an adverse outcome.
Although cTn accurately identifies myocardial necrosis, it does not inform as to the cause or causes of necrosis; these can be multiple (224) and include noncoronary causes such as tachyarrhythmia, cardiac trauma by interventions, chest trauma from motor vehicle accidents, HF, LV hypertrophy, myocarditis, and pericarditis, as well as severe noncardiac conditions such as sepsis, burns, respiratory failure, acute neurological diseases, pulmonary embolism, pulmonary hypertension, drug toxicity, cancer chemotherapy, and renal insufficiency (230). Therefore, in making the diagnosis of NSTEMI, cTns should be used in conjunction with other criteria of MI, including characteristics of the ischemic symptoms and the ECG.
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).
184.108.40.206.1.1 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).
220.127.116.11.1.2 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.
18.104.22.168 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.
22.214.171.124 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).
Many patients with suspected ACS have combined assessments of troponin and CK-MB. When baseline troponin and CK-MB were used together for diagnostic and risk assessment across the spectrum of chest pain syndromes in a large database that consisted of several clinical trials, those with positive results for both markers were at highest short-term (24 h and 30 d) risk of death or MI (261). However, those with baseline troponin elevation without CK-MB elevation also were at increased 30-d risk, whereas risk with isolated CK-MB elevation was lower and not significantly different than if both markers were negative (261).
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.
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).
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).
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.
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.
126.96.36.199 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
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 (seeSection 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)
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
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.
Once a patient with documented high-risk ACS is admitted, standard medical therapy is indicated as discussed later. Unless a contraindication exists, these patients generally should be treated with ASA, a beta blocker, anticoagulant therapy, a GP IIb/IIIa inhibitor, and a thienopyridine (i.e., clopidogrel; initiation may be deferred until a revascularization decision is made). Critical decisions are required regarding the angiographic (invasive) strategy. One option is a routine angiographic approach in which coronary angiography and revascularization are performed unless a contraindication exists. Within this approach, a common past strategy has called for a period of medical stabilization. Increasingly, physicians are taking a more aggressive approach, with coronary angiography and revascularization performed within 24 h of admission; the rationale for the more aggressive approach is the protective effect of carefully administered anticoagulant and antiplatelet therapy on procedural outcome. The alternative approach, commonly referred to as the “initial conservative strategy” (see Section 3.3), is guided by ischemia, with angiography reserved for patients with recurrent ischemia or a high-risk stress test despite medical therapy. Regardless of the angiographic strategy, an assessment of LV function is recommended in patients with documented ischemia because of the imperative to treat patients who have impaired LV function with ACE inhibitors, beta blockers, and, when HF or diabetes mellitus is present, aldosterone antagonists; when the coronary anatomy is appropriate (e.g., 3-vessel coronary disease), CABG is appropriate (see Section 4). When the coronary angiogram is obtained, a left ventriculogram may be obtained at the same time. When coronary angiography is not scheduled, echocardiography, nuclear ventriculography, or magnetic resonance imaging or CT angiography can be used to evaluate LV function.
3.1 Anti-Ischemic and Analgesic Therapy
Recommendations for Anti-Ischemic Therapy
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)
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)
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)
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 invasivecoronary procedures, as well as to emergency or urgent cardiovascular surgery and cardiac anesthesia (2,300).
The approach to the achievement of the twin goals described here includes the initiation of pharmacological management and planning of a definitive treatment strategy for the underlying disease process. Most patients are stable at presentation or stabilize after a brief period of intensive pharmacological management and, after appropriate counseling, will be able to participate in the choice of an approach for definitive therapy (see Section 3.3 for a full discussion of conservative vs. invasive strategy selection). A few patients will require prompt triage to emergency or urgent cardiac catheterization and/or the placement of an IABP.
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
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).
Intravenous NTG may be initiated at a rate of 10 mcg per min through continuous infusion via nonabsorbing tubing and increased by 10 mcg per min every 3 to 5 min until some relief of symptoms or blood pressure response is noted. If no response is seen at 20 mcg per min, increments of 10 and, later, 20 mcg per min can be used. If symptoms and signs of ischemia are relieved, there is no need to continue to increase the dose to effect a blood pressure response. If symptoms and signs of ischemia are not relieved, the dose should be increased until a blood pressure response is observed. Once a partial blood pressure response is observed, the dosage increase should be reduced and the interval between increments lengthened. Side effects of NTG include headache and hypotension. Systolic blood pressure generally should not be titrated to less than 110 mm Hg in previously normotensive patients or to greater than 25% below the starting mean arterial blood pressure if hypertension was present. Nitroglycerin should be avoided in patients with initial systolic blood pressure less than 90 mm Hg or 30 mm Hg or more below baseline or with marked bradycardia or tachycardia. Although recommendations for a maximal dose are not available, a ceiling of 200 mcg per min is commonly used. Even prolonged (2 to 4 weeks) infusion at 300 to 400 mcg per min does not increase methemoglobin levels (306).
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).
188.8.131.52 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.
184.108.40.206 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).
Patients with marked first-degree AV block (i.e., ECG PR interval greater than 0.24 s), any form of second- or third-degree AV block in the absence of a functioning implanted pacemaker, a history of asthma, severe LV dysfunction or HF (e.g., rales or S3 gallop) or at high risk for shock (see above) should not receive beta blockers on an acute basis (4). Patients with evidence of a low-output state (e.g., oliguria) or sinus tachycardia, which often reflects low stroke volume, significant sinus bradycardia (heart rate less than 50 beats per minute), or hypotension (systolic blood pressure less than 90 mm Hg) should not receive acute beta-blocker therapy until these conditions have resolved. Patients at highest risk for cardiogenic shock due to intravenous beta blockade in the COMMIT trial were those with tachycardia or in Killip Class II or III (317). However, beta blockers are strongly recommended before discharge in those with compensated HF or LV systolic dysfunction for secondary prevention (321). Patients with significant chronic obstructive pulmonary disease who may have a component of reactive airway disease should be given beta blockers very cautiously; initially, low doses of a beta-1–selective agent should be used. If there are concerns about possible intolerance to beta blockers, initial selection should favor a short-acting beta-1–specific drug such as metoprolol or esmolol. Mild wheezing or a history of chronic obstructive pulmonary disease mandates a short-acting cardioselective agent at a reduced dose (e.g., 12.5 mg of metoprolol orally) rather than the complete avoidance of a beta blocker.
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.
220.127.116.11 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.
Calcium channel blockers may be used to control ongoing or recurring ischemia-related symptoms in patients who already are receiving adequate doses of nitrates and beta blockers, in patients who are unable to tolerate adequate doses of 1 or both of these agents, and in patients with variant angina (see Section 6.7). In addition, these drugs have been used for the management of hypertension in patients with recurrent UA (325). Rapid-release, short-acting dihydropyridines (e.g., nifedipine) must be avoided in the absence of concomitant beta blockade because of increased adverse potential (326,327,328). Verapamil and diltiazem should be avoided in patients with pulmonary edema or evidence of severe LV dysfunction (329–331). Amlodipine and felodipine are reasonably well tolerated by patients with mild LV dysfunction (329–334), although their use in UA/NSTEMI has not been studied. The CCB evidence base in UA/NSTEMI is greatest for verapamil and diltiazem (328,331).
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 × 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.
18.104.22.168 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.
22.214.171.124 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 KATP 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.
126.96.36.199 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.
188.8.131.52 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.
3.2.1 Antiplatelet Therapy Recommendations (UPDATED)
For new or updated text, view the2011 Focused Update. Text supporting unchanged recommendations has not been updated.
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 (seeSection 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)
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)
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)
Abciximab should not be administered to patients in whom PCI is not planned. (Level of Evidence: A)
3.2.2 Anticoagulant Therapy Recommendations
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)
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 (UPDATED)
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. 9C; 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)
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)
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)
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)
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).
No trial has directly compared the efficacy of different doses of ASA in patients who present with UA/NSTEMI; however, information can be gleaned from a collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in high-risk patients (i.e., acute or previous vascular disease or other predisposing conditions) (375). This collaborative meta-analysis pooled data from 195 trials involving more than 143,000 patients and demonstrated a 22% reduction in the odds of vascular death, MI, or stroke with antiplatelet therapy across a broad spectrum of clinical presentations that included patients presenting with UA/NSTEMI. Indirect comparisons of the proportional effects of different doses of ASA ranging from less than 75 mg to up to 1500 mg daily showed similar reductions in the odds of vascular events with doses between 75 and 1500 mg daily; when less than 75 mg was administered daily, the proportional benefit of ASA was reduced by at least one half compared with the higher doses. An analysis from the CURE trial suggested that there was no difference in the rate of thrombotic events according to ASA dose, but there was a dose-dependent increase in bleeding in patients receiving ASA (plus placebo): the major bleeding rate was 2.0% in patients taking less than 100 mg of ASA, 2.3% with 100 to 200 mg, and 4.0% with greater than 200 mg per d (243,376). Therefore, maintenance doses of 75 to 162 mg of ASA are preferred.
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).
In patients who are already receiving ASA, it should be continued. The protective effect of ASA has been sustained for at least 1 to 2 years in clinical trials in UA/NSTEMI. Longer term follow-up data in this population are lacking. Long-term efficacy can be extrapolated from other studies of ASA therapy in CAD. Studies in patients with prior MI, stroke, or transient ischemic attack have shown statistically significant benefit during the first 2 years and some additional but not statistically significant benefit during the third year (363). In the absence of large comparison trials of different durations of antiplatelet treatment in patients with CVD or in primary prevention, it seems prudent to continue ASA indefinitely unless side effects are present (1,4,365). Thus, patients should be informed of the evidence that supports the use of ASA in UA/NSTEMI and CAD in general and instructed to continue the drug indefinitely, unless a contraindication develops. It is important to emphasize to patients that there is a sound rationale for concomitant use of ASA even if other antithrombotic drugs, such as clopidogrel or warfarin, are administered concurrently (Fig. 11) and that withdrawal or discontinuation of ASA or clopidogrel has been associated with recurrent episodes of ACS, including stent thrombosis (378–380). Finally, because of a drug interaction between ibuprofen and ASA, patients should be advised to use an alternative NSAID or to take their ibuprofen dose at least 30 min after ingestion of immediate-release ASA or at least 8 h before ASA ingestion to avoid any potential diminution of the protective effects of ASA. No recommendations about the concomitant use of ibuprofen and enteric-coated low-dose ASA can be made on the basis of available data (381).
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.
184.108.40.206 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 = 1,313) 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.
Pathological and clinical evidence particularly highlights the need for longer-term ADP-receptor blockade in patients who receive DES (399). DESs consistently have been shown to reduce stent restenosis. However, this same antiproliferative action can delay endothelialization, predisposing to stent thrombosis including late (beyond 3–6 months) or very late (after 1 year) thrombosis after stent placement (399,399a,400). These concerns have raised questions about the ideal duration of dual antiplatelet therapy (DAT) and the overall balance of benefit/risk of DES compared with bare-metal stents (401). A number of comparisons of outcomes up to 4 years after DES and bare-metal stent implantation, including the initial FDA approval trials, have been published (400,402–404,404a–404f). These confirm a marked reduction in restenosis and consequent repeat revascularization procedures with DES (404c). However, although results have varied, they also suggest a small incremental risk (of about 0.5%) of stent thrombosis (404a–404c). Reassuringly, they have not shown an overall increase in death or MI after DES versus bare-metal stents, suggesting offsetting advantages of improved revascularization versus increased stent thrombosis risk. These observations also emphasize the need for a continued search for more biocompatible stents that minimize restenosis without increasing the risks of thrombosis.
In the ISAR-REACT-2 trial, patients undergoing PCI were assigned to receive either abciximab (bolus of 0.25 mg per kg of body weight, followed by a 0.125-mg per kg per min [maximum, 10 mg per min] infusion for 12 h, plus heparin 70 U per kg of body weight) or placebo (placebo bolus and infusion of 12 h, plus heparin bolus, 140 U per kg) (244). All patients received 600 mg of clopidogrel at least 2 h before the procedure, as well as 500 mg of oral or intravenous ASA. Of 2,022 patients enrolled, 1,012 were assigned to abciximab and 1,010 to placebo. The primary end point was reached in 90 patients (8.9%) assigned to abciximab versus 120 patients (11.9%) assigned to placebo, a 25% reduction in risk with abciximab (RR = 0.75, 95% CI 0.58 to 0.97, p = 0.03) (244). Among patients without an elevated cTn level, there was no difference in the incidence of primary end-point events between the abciximab group (23 [4.6%] of 499 patients) and the placebo group (22 [4.6%] of 474 patients; RR = 0.99, 95% CI 0.56 to 1.76, p = 0.98), whereas among patients with an elevated cTn level, the incidence of events was significantly lower in the abciximab group (67 [13.1%] of 513 patients) than in the placebo group (98 [18.3%] of 536 patients), which corresponds to an RR of 0.71 (95% CI 0.54 to 0.95, p = 0.02; p = 0.07 for interaction). There were no significant differences between the 2 groups with regard to the risk of major or minor bleeding or the need for transfusion. Thus, it appears beneficial to add an intravenous GP IIb/IIIa inhibitor to thienopyridine treatment if an invasive strategy is planned in patients with high-risk features (e.g., elevated cTn level; Figs. 7, 8, and 9).
The optimal timing of administration of the loading dose of clopidogrel for those who are managed with an early invasive strategy cannot be determined with certainty from PCI-CURE because there was no comparison of administration of the loading dose before diagnostic angiography (“upstream treatment”) versus at the time of PCI (“in-lab treatment”). However, based on the early separation of the curves, when there is delay to coronary angiography, patients should receive clopidogrel as initial therapy (Figs. 7, 8, and 9). The Clopidogrel for the Reduction of Events During Observation (CREDO) trial (405), albeit not designed specifically to study UA/NSTEMI patients, provides partially relevant information on the question of timing of the loading dose. Patients with symptomatic CAD and evidence of ischemia who were referred for PCI and those who were thought to be highly likely to require PCI were randomized to receive clopidogrel (300 mg) or matching placebo 3 to 24 h before PCI. All subjects received a maintenance dose of clopidogrel (75 mg daily) for 28 d. Thus, CREDO is really a comparison of the administration of a loading dose before PCI versus not administering a loading dose at all. There is no explicit comparison within CREDO of a pre-PCI loading dose versus a loading dose in the catheterization laboratory. In CREDO, the relative risk for the composite end point of death/MI/urgent target-vessel revascularization was 0.82, in favor of the group who received a loading dose before PCI compared with the opposite arm that did not receive a loading dose, but this did not reach statistical significance (p = 0.23). Subgroup analyses within CREDO suggest that if the loading dose is given at least 6 or preferably 15 h before PCI, fewer events occur compared with no loading dose being administered (406). One study from the Netherlands that compared pretreatment with clopidogrel before PCI versus administration of a loading dose at the time of PCI in patients undergoing elective PCI showed no difference in biomarker release or clinical end points (407).
Thus, there now appears to be an important role for clopidogrel in patients with UA/NSTEMI, both in those who are managed conservatively and in those who undergo PCI, especially stenting, or who ultimately undergo CABG surgery (408). However, it is not entirely clear how long therapy should be maintained (409,410). Whereas increased hazard is clearly associated with premature discontinuation of dual antiplatelet therapy after DES (405,411,412), the benefit of extended therapy beyond 1 year is uncertain (401,404d,404e). Hence, the minimum requirements for DAT duration should be vigorously applied for each DES type. However, 1 year of DAT may be ideal for all UA/NSTEMI patients who are not at high risk of bleeding given the secondary preventive effects of DAT, perhaps especially after DES. On the other hand, the limited database at this point in time does not support a recommendation for DAT beyond 1 year for all DES-treated patients (401,404d,404e). For patients with clinical features associated with an increased risk of stent thrombosis, such as diabetes or renal insufficiency or procedural characteristics such as multiple stents or a treated bifurcation lesion, extended DAT may be reasonable. Data on the relative merits of DES versus bare-metal stents in “off-label” patients (such as multivessel disease or MI), who are at higher risk and experience higher event rates, and of the ideal duration of DAT in these patients, are limited and are currently insufficient to draw separate conclusions (401,404d,404e).
Because of the importance of dual-antiplatelet therapy with ASA and a thienopyridine after implantation of a stent, especially if a DES is being considered, clinicians should ascertain whether the patient can comply with 1 year of dual-antiplatelet therapy. Patients should also be instructed to contact their treating cardiologist before stopping any antiplatelet therapy, because abrupt discontinuation of antiplatelet therapy can put the patient at risk of stent thrombosis, an event that may result in MI or even death (411). Health care providers should postpone elective surgical procedures until beyond 12 months after DES implantation (411). If a surgical procedure must be performed sooner than 12 months, an effort should be made to maintain the patient on ASA and minimize the period of time of discontinuation of a thienopyridine (411).
In the CURE study, which predominantly involved medical management of patients with UA/NSTEMI, the relative risk reduction in events was of a similar magnitude (approximately 20%) during the first 30 d after randomization as during the ensuing cumulative 8 months (413). In contrast, clopidogrel was not beneficial in a large trial of high-risk primary prevention patients (414).
Because clopidogrel, when added to ASA, increases the risk of bleeding during major surgery, it has been recommended that clopidogrel be withheld for at least 5 d (243) and up to 7 d before surgery in patients who are scheduled for elective CABG (376,415). In many hospitals in which patients with UA/NSTEMI undergo rapid diagnostic catheterization within 24 h of admission, clopidogrel is not started until it is clear that CABG will not be scheduled within the next several days. However, unstable patients should receive clopidogrel or be taken for immediate angiography (Figs. 7, 8, and 9). A loading dose of clopidogrel can be given to a patient on the catheterization table if a PCI is to be performed immediately. If PCI is not performed, clopidogrel can be given after the catheterization. However, when clopidogrel is given before catheterization and urgent surgical intervention is indicated, some experience suggests that “early” bypass surgery may be undertaken by experienced surgeons at acceptable incremental bleeding risk. Among 2,858 UA/NSTEMI patients in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) Registry undergoing CABG, 30% received acute clopidogrel therapy, the majority of these (87%) within 5 d of surgery. “Early” CABG after clopidogrel was associated with a significant increase in any blood transfusion (OR 1.36, 95% CI 1.10 to 1.68) and the need for 4 or more units of blood (OR 1.70, 95% CI 1.32 to 2.1). In-hospital rates of death were low (3% to 4%), and no difference was noted in rates of death, reinfarction, or stroke with “early” CABG in patients treated with versus without acute clopidogrel (394). The Writing Committee believes that more data on the overall relative benefits versus risks of proceeding with early bypass surgery in the presence of clopidogrel therapy are desirable and necessary in order to formulate better-informed recommendations for the timing of surgery in the UA/NSTEMI patient.
Sulfinpyrazone, dipyridamole, prostacyclin, and prostacyclin analogs have not been demonstrated to be of benefit in UA or NSTEMI and are not recommended. The thromboxane synthase blockers and thromboxane A2 receptor antagonists have been evaluated in ACS and have not shown any advantage over ASA. A number of other antiplatelet drugs are currently available, and still others are under active investigation. Clopidogrel is currently the preferred thienopyridine because of its extensive evidence base, its more rapid onset of action, especially after a loading dose (417,418), and its better safety profile than ticlopidine (396).
Evidence has emerged that there is considerable interpatient variability in the response to clopidogrel, with a wide range of inhibition of platelet aggregation after a given dose (419). Patients with diminished responsiveness to clopidogrel appear to be at increased risk of ischemic events (420,421). The reasons for the large interpatient variability in responsiveness to clopidogrel are under investigation, but variation in absorption, generation of the active metabolite, and drug interactions are leading possibilities. Maneuvers to overcome poor responsiveness to clopidogrel may involve an increase in the dose (422). However, techniques for monitoring for poor response to clopidogrel and the appropriate dosing strategy when it is uncovered remain to be established.
3.2.5 Anticoagulant Agents and Trials
A number of drugs are available to clinicians for management of patients with UA/NSTEMI. Although the medical literature sometimes refers to such drugs as “antithrombins,” the Writing Committee has chosen to refer to them as anticoagulants because they often inhibit 1 or more proteins in the coagulation cascade before thrombin. Evaluation of anticoagulant strategies is an active area of investigation. It is difficult to draw conclusions that 1 anticoagulant strategy is to be preferred over another given the uncertainty of whether equipotent doses were administered, the different durations of treatment studied across the trials, and the fact that many patients were already receiving 1 open-label anticoagulant before they were randomized in a trial to another anticoagulant (which makes it uncertain what residual effect the open-label anticoagulant had in the trial). Other aspects of the data set that confound interpretation of the impact of specific anticoagulant strategies include a range of antiplatelet strategies administered concomitantly with the anticoagulant and the addition of a second anticoagulant, either because of clinician preference or as part of protocol design (423–425) as patients moved from the medical management phase to the interventional management phase of treatment for UA/NSTEMI.
The Writing Committee also wishes to draw attention to the fact that active-control noninferiority trials are being performed with increasing frequency as it becomes ethically increasingly difficult to perform placebo-controlled trials. In this update, for example, noninferiority (“equivalence”) comparisons on primary or major secondary end points were important in the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) (425), Organization to Assess Strategies for Ischaemic Syndromes (OASIS-5) (424), and Randomized Evaluation of PCI Linking Angiomax to reduced Clinical Events (REPLACE-2) (426) studies. Although practically useful, noninferiority analyses depend on assumptions not inherent in classic superiority analytical designs and thus present additional limitations and interpretative challenges (427–429). Noninferiority trials require an a priori choice of a “noninferiority margin,” typically defined in terms of a fraction of standard treatment effect to be preserved compared with a putative placebo (e.g., 0.5) and which rests on clinical judgment and statistical issues (428). Because noninferiority trials do not have a placebo control, these assumptions cannot be easily verified. Thus, whether the new therapy indeed is therapeutically “equivalent” is less certain than in a superiority trial. Hence, additional caution in weighing and applying the results of noninferiority trials is appropriate.
The Writing Committee believes that a number of acceptable anticoagulant strategies can be recommended with a Class I status but emphasizes the fact that a preference for a particular strategy is far from clear (Figs. 7, 8, and 9). It is suggested that each institution agree on a consistent approach to minimize the chance of medication errors and double anticoagulation when personal preferences are superimposed on an already-initiated treatment plan. Factors that should be weighed when one considers an anticoagulant strategy (or set of strategies to cover the range of patient scenarios) include established efficacy, risk of bleeding in a given patient, cost, local familiarity with dosing regimens (particularly if PCI is planned), anticipated need for surgery, and the desire to promptly reverse the anticoagulant effect if bleeding occurs.
Unfractionated heparin exerts its anticoagulant effect by accelerating the action of circulating antithrombin, a proteolytic enzyme that inactivates factor IIa (thrombin), factor IXa, and factor Xa. It prevents thrombus propagation but does not lyse existing thrombi (430). Unfractionated heparin is a heterogeneous mixture of polysaccharide chains of molecular weights that range from 5,000 to 30,000 Daltons and have varying effects on anticoagulant activity. Unfractionated heparin binds to a number of plasma proteins, blood cells, and endothelial cells. The LMWHs are obtained through chemical or enzymatic depolymerization of the polysaccharide chains of heparin to provide chains with different molecular weight distributions. Approximately 25% to 50% of the pentasaccharide-containing chains of LMWH preparations contain more than 18 saccharide units, and these are able to inactivate both thrombin and factor Xa. Low-molecular-weight heparin chains that are fewer than 18 saccharide units retain their ability to inactivate factor Xa but not thrombin. Therefore, LMWHs are relatively more potent in facilitating inhibition of factor Xa than in the inactivation of thrombin. Distinct advantages of LMWH over UFH include decreased binding to plasma proteins and endothelial cells and dose-independent clearance, with a longer half-life that results in more predictable and sustained anticoagulation with once- or twice-a-day subcutaneous administration. An advantage of LMWHs is that they do not usually require laboratory monitoring of activity. The pharmacodynamic and pharmacokinetic profiles of the different commercial preparations of LMWHs vary, with their mean molecular weights ranging from 4,200 to 6,000 Daltons. Accordingly, their ratios of anti–factor Xa to anti–factor IIa vary, ranging from 1.9 to 3.8 (431). By contrast, the direct thrombin inhibitors specifically block thrombin without the need for a cofactor. Hirudin binds directly to the anion binding site and the catalytic sites of thrombin to produce potent and predictable anticoagulation (432).
Bivalirudin is a synthetic analog of hirudin that binds reversibly to thrombin and inhibits clot-bound thrombin. More upstream in the coagulation cascade are factor Xa inhibitors, such as the synthetic pentasaccharide fondaparinux, that act proximally to inhibit the multiplier effects of the downstream coagulation reactions and thereby reduce the amount of thrombin that is generated. Advantages of fondaparinux compared with UFH include decreased binding to plasma proteins and endothelial cells and dose-independent clearance, with a longer half-life that results in more predictable and sustained anticoagulation with fixed-dose, once-a-day subcutaneous administration. An advantage of these agents over UFH is that like the LMWHs, fondaparinux does not require laboratory monitoring of activity. Fondaparinux is cleared renally, as is the anti–Xa activity of enoxaparin. The factor Xa inhibitors do not have any action against thrombin that is already formed or that is generated despite their administration, which possibly contributes to the observation of an increased rate of catheter thrombosis when factor Xa inhibitors such as fondaparinux are used alone to support PCI procedures. In the case of both the direct thrombin inhibitors and fondaparinux, it is not possible to reverse the effect with protamine because they lack a protamine-binding domain; reversal of their action in the event of bleeding requires discontinuation of their administration and, if needed, transfusion of coagulation factors (e.g., fresh-frozen plasma).
In summary, whereas anticoagulant therapy forms a basic element of UA/NSTEMI therapy, recommendation of an anticoagulant regimen has become more complicated by a number of new choices suggested by contemporary trials, some of which do not provide adequate comparative information for common practice settings. The Writing Committee believes that inadequate unconfounded comparative information is available to recommend a preferred regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. Additional experience may change this viewpoint in the future. On the other hand, these available trials are less confounded for the large number of patients treated with an initial noninvasive or delayed invasive strategy: they suggest an anticoagulant preference for these patients treated with a noninvasive strategy in the order of fondaparinux, enoxaparin, and UFH (least preferred), using the specific regimens tested in these trials. Bivalirudin has not been tested in a noninvasive strategy and hence cannot be recommended currently. Even in this group, the order of preference often depends on a single, albeit large, trial, so that additional clinical trial information will be welcomed.
The optimal duration of anticoagulation therapy remains undefined. Evidence for recurrence of events after cessation of short-duration intravenous UFH and results of studies in STEMI patients demonstrating superiority of anticoagulant agents that are administered for the duration of the hospital stay suggest that anticoagulation duration of more than 2 d for those who are managed with a conservative strategy may be beneficial, but this requires further study (433,434).
220.127.116.11 Unfractionated Heparin
Six relatively small randomized, placebo-controlled trials with UFH have been reported (435–440). The results of studies that compared the combination of ASA and heparin with ASA alone are shown in Figure 10. In the trials that used UFH, the reduction in the rate of death or MI during the first week was 54% (p = 0.016), and in the trials that used either UFH or LMWH, the reduction was 63%. Two published meta-analyses have included different studies. In 1 meta-analysis, which involved 3 randomized trials and an early end point (less than 5 d) (369), the risk of death or MI with the combination of ASA and heparin was reduced by 56% (p = 0.03). In the second meta-analysis, which involved 6 trials and end points that ranged from 2 to 12 weeks, the RR was reduced by 33% (p = 0.06) (441). Most of the benefits of the various anticoagulants are short term, however, and are not maintained on a long-term basis. Reactivation of the disease process after the discontinuation of anticoagulants may contribute to this loss of early gain among medically treated patients that has been described with UFH (442), dalteparin (371), and hirudin (443,444). The combination of UFH and ASA appears to mitigate this reactivation in part (442,445), although there is hematologic evidence of increased thrombin activity after the cessation of intravenous UFH (“rebound”) even in the presence of ASA (446). Uncontrolled observations suggested a reduction in the “heparin rebound” by switching from intravenous to subcutaneous UFH for several days before the drug is stopped.
Unfractionated heparin has important pharmacokinetic limitations that are related to its nonspecific binding to proteins and cells. These pharmacokinetic limitations of UFH translate into poor bioavailability, especially at low doses, and marked variability in anticoagulant response among patients (447). As a consequence of these pharmacokinetic limitations, the anticoagulant effect of heparin requires monitoring with the activated partial thromboplastin time (aPTT), a test that is sensitive to the inhibitory effects of UFH on thrombin (factor IIa), factor Xa, and factor IXa. Many clinicians have traditionally prescribed a fixed initial dose of UFH (e.g., 5,000 U bolus, 1,000 U per h initial infusion); clinical trials have indicated that a weight-adjusted dosing regimen can provide more predictable anticoagulation than the fixed-dose regimen (448–450). The weight-adjusted regimen recommended is an initial bolus of 60 U per kg (maximum 4,000 U) and an initial infusion of 12 U per kg per h (maximum 1,000 U per h). The therapeutic range of the various nomograms differs due to variation in the laboratory methods used to determine aPTT. The American College of Chest Physicians consensus conference(451) has therefore recommended dosage adjustments of the nomograms to correspond to a therapeutic range equivalent to heparin levels of 0.3 to 0.7 U per ml by anti–factor Xa determinations, which correlates with aPTT values between 60 and 80 s. In addition to body weight, other clinical factors that affect the response to UFH include age and sex, which are associated with higher aPTT values, and smoking history and diabetes mellitus, which are associated with lower aPTT values (447,452). At high doses, heparin is cleared renally (451).
Even though weight-based UFH dosing regimens are used, the aPTT should be monitored for adjustment of UFH dosing. Because of variation among hospitals in the control aPTT values, nomograms should be established at each institution that are designed to achieve aPTT values in the target range (e.g., for a control aPTT of 30 s, the target range [1.5 to 2.5 times control] would be 45 to 75 s). Delays in laboratory turnaround time for aPPT results also can be a source of variability in care, resulting in over- or under-anticoagulation for prolonged time periods, and should be avoided. Measurements should be made 6 h after any dosage change and used to adjust UFH infusion until the aPTT exhibits a therapeutic level. When 2 consecutive aPTT values are therapeutic, the measurements may be made every 24 h and, if necessary, dose adjustment performed. In addition, a significant change in the patient's clinical condition (e.g., recurrent ischemia, bleeding, or hypotension) should prompt an immediate aPTT determination, followed by dose adjustment, if necessary.
Serial hemoglobin/hematocrit and platelet measurements are recommended at least daily during UFH therapy. In addition, any clinically significant bleeding, recurrent symptoms, or hemodynamic instability should prompt their immediate determination. Serial platelet counts are necessary to monitor for heparin-induced thrombocytopenia. Mild thrombocytopenia may occur in 10% to 20% of patients who are receiving heparin, whereas significant thrombocytopenia (platelet count less than 100,000) occurs in 1% to 5% of patients and typically appears after 4 to 14 d of therapy (453–457). A rare but dangerous complication (less than 0.2% incidence) is autoimmune UFH-induced thrombocytopenia with thrombosis, which can occur both shortly after initiation of UFH or, rarely, in a delayed (i.e., after 5 to 19 d or more), often unrecognized form (458–460). A high clinical suspicion mandates the immediate cessation of all heparin therapy (including that used to flush intravenous lines).
Most of the trials that evaluated the use of UFH in UA/NSTEMI have continued therapy for 2 to 5 d. The optimal duration of therapy remains undefined.
18.104.22.168 Low-Molecular-Weight Heparin
In a pilot open-label study, 219 patients with UA were randomized to receive ASA (200 mg per d), ASA plus UFH, or ASA plus nadroparin (an LMWH) (370). The combination of ASA and LMWH significantly reduced the total ischemic event rate, the rate of recurrent angina, and the number of patients requiring interventional procedures.
The FRISC study (371) randomized 1,506 patients with UA or non–Q-wave MI to receive subcutaneous administration of the LMWH dalteparin (120 IU per kg twice daily) or placebo for 6 d and then once a day for the next 35 to 45 d. Dalteparin was associated with a 63% risk reduction in death or MI during the first 6 d (4.8% vs. 1.8%, p = 0.001), which matched the favorable experience observed with UFH. Although an excess of events was observed after the dose reduction to once daily after 6 d, a significant decrease was observed at 40 d with dalteparin in the composite outcome of death, MI, or revascularization (23.7% vs. 18.0%, p = 0.005), and a trend was noted toward a reduction in rates of death or MI (10.7% vs. 8.0%, p = 0.07).
Because the level of anticoagulant activity cannot be easily measured in patients receiving LMWH (e.g., aPTT or activated clotting time [ACT]), interventional cardiologists have expressed concern about the substitution of LMWH for UFH in patients scheduled for catheterization with possible PCI. However, in a study involving 293 patients with UA/NSTEMI who received the usual dose of enoxaparin, Collett et al. (461) showed that PCI can be performed safely.
An alternative approach is to use LMWH during the period of initial stabilization. The dose can be withheld on the morning of the procedure, and if an intervention is required and more than 8 h has elapsed since the last dose of LMWH, UFH can be used for PCI according to usual practice patterns. Because the anticoagulant effect of UFH can be more readily reversed than that of LMWH, UFH is preferred in patients likely to undergo CABG within 24 h.
22.214.171.124 LMWH Versus UFH
Nine randomized trials have directly compared LMWH with UFH (Table 17). Two trials evaluated dalteparin, another evaluated nadroparin, and 6 evaluated enoxaparin. Heterogeneity of trial results has been observed. Trials with dalteparin and nadroparin reported similar rates of death or nonfatal MI compared with UFH, whereas 5 of 6 trials of enoxaparin found point estimates for death or nonfatal MI that favored enoxaparin over UFH; the pooled OR was 0.91 (95% CI 0.83 to 0.99). The benefit of enoxaparin appeared to be driven largely by a reduction in nonfatal MI, especially in the cohort of patients who had not received any open-label anticoagulant therapy before randomization.
There are few data to assess whether the heterogeneous results are explained by different populations, study designs, various heparin dose regimens, properties of the various LMWHs (more specifically, different molecular weights and anti–factor Xa/anti–factor IIa ratios), concomitant therapies, or other unrecognized influences. Although it is tempting to compare the relative treatment effects of the different LMWH compounds, the limitations of such indirect comparisons must be recognized. The only reliable method of comparing 2 treatments is through a direct comparison in a well-designed clinical trial or series of trials. The comparison of different therapies (e.g., different LMWHs) with a common therapy (e.g., UFH) in different trials does not allow a conclusion to be made about the relative effectiveness of the different LMWHs because of the variability in both control group and experimental group event rates due to protocol differences, differences in concomitant therapies due to geographic and time variability, and the play of chance. Similar considerations apply to comparisons among platelet GP IIb/IIIa inhibitors.
In the Enoxaparin Versus Tinzaparin (EVET) trial, 2 LMWHs, enoxaparin and tinzaparin, administered for 7 d, were compared in 436 patients with UA/NSTEMI. Enoxaparin was associated with a lower rate of death/MI/recurrent angina at 7 and 30 d compared with tinzaparin (467,468). Bleeding rates were similar with the 2 LMWHs.
The advantages of LMWH preparations are the ease of subcutaneous administration and the absence of a need for monitoring. Furthermore, the LMWHs stimulate platelets less than UFH (469) and are less frequently associated with heparin-induced thrombocytopenia (456). In the ESSENCE trial, minor bleeding occurred in 11.9% of enoxaparin patients and 7.2% of UFH patients (p less than 0.001), and major bleeding occurred in 6.5% and 7.0%, respectively (169). In TIMI 11B, the rates of minor bleeding in hospital were 9.1% and 2.5%, respectively (p less than 0.001), and the rates of major bleeding were 1.5% and 1.0% (p = 0.14) (180). In the FRISC study, major bleeding occurred in 0.8% of patients given dalteparin and in 0.5% of patients given placebo, and minor bleeding occurred in 61 (8.2%) of 746 patients and 2 (0.3%) of 760 patients, respectively (371).
The anticoagulant effect of LMWH is less effectively reversed with protamine than that of UFH. In addition, LMWH administered during PCI does not permit monitoring of the ACT to titrate the level of anticoagulation. In the ESSENCE and TIMI 11B trials, special rules were set to discontinue enoxaparin before PCI and CABG. Because of limited experience with enoxaparin at the time the ESSENCE and TIMI 11B trials were conducted, UFH was administered during PCI to achieve ACT values of greater than 350 s. In the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial, enoxaparin was compared to UFH during PCI in patients with high-risk UA/NSTEMI (423) (Fig. 12). More bleeding was observed with enoxaparin, with a statistically significant increase in TIMI-defined major bleeding (9.1% vs. 7.6%, p = 0.008) but a nonsignificant excess in GUSTO-defined severe bleeding (2.7% vs. 2.2%, p = 0.08) and transfusions (17.0% vs. 16.0%, p = 0.16). A post hoc analysis from SYNERGY suggested that some of the excess bleeding seen with enoxaparin could be explained by crossover to UFH at the time of PCI (470). This remains to be validated prospectively, but at the present time, it appears reasonable to minimize the risk of excessive anticoagulation during PCI by avoiding crossover of anticoagulants (i.e., maintain consistent anticoagulant therapy from the pre-PCI phase throughout the procedure itself).
An economic analysis of the ESSENCE trial suggested cost savings with enoxaparin (471). For patients who are receiving subcutaneous LMWH and in whom CABG is planned, it is recommended that LMWH be discontinued and UFH be used during the operation. Additional experience with regard to the safety and efficacy of the concomitant administration of LMWHs with GP IIb/IIIa antagonists and fibrinolytic agents is currently being acquired.
126.96.36.199.1 Extended Therapy with LMWHs
The FRISC, Fragmin in unstable coronary artery disease study (FRIC), TIMI 11B, and Fast Revascularization during InStability in Coronary artery disease-II (FRISC-II) trials evaluated the potential benefit of the prolonged administration of LMWH after hospital discharge (Table 17). In the FRISC trial, doses of dalteparin were administered between 6 d and 35 to 45 d; in FRIC, patients were rerandomized after the initial 6-d treatment period to receive dalteparin for an additional 40 d, and the outpatient treatment period lasted 5 to 6 weeks in TIMI 11B and 1 week in the FRAXiparine in Ischaemic Syndromes (FRAXIS) trial. The FRISC-II trial used a different study design. Dalteparin was administered to all patients for a minimum of 5 d (472). Patients were subsequently randomized to receive placebo or the continued administration of dalteparin twice per day for up to 90 d. Analysis of the results from the time of randomization showed a significant reduction with dalteparin in the composite end point of death or MI at 30 d (3.1% vs. 5.9%, p = 0.002) but not at 3 months (6.7% vs. 8.0%, p = 0.17). The composite of death, MI, or revascularization during the total treatment period was reduced at 3 months (29.1% vs. 33.4%, p = 0.031). The benefits of prolonged dalteparin administration were limited to patients who were managed medically and to those with elevated TnT levels at baseline. Although these results make a case for the prolonged use of an LMWH in selected patients who are managed medically or in whom angiography is delayed, their relevance to contemporary practice is less clear now that clopidogrel is used more frequently and there is a much greater tendency to proceed to an early invasive strategy.
188.8.131.52 Direct Thrombin Inhibitors
Hirudin, the prototype of the direct thrombin inhibitors, has been extensively studied but with mixed results. The GUSTO-IIb trial randomly assigned 12,142 patients with suspected MI to 72 h of therapy with either intravenous hirudin or UFH (473). Patients were stratified according to the presence of ST-segment elevation on the baseline ECG (4,131 patients) or its absence (8,011 patients). The primary end point of death, nonfatal MI, or reinfarction at 30 d occurred in 9.8% of the UFH group versus 8.9% of the hirudin group (OR 0.89, p = 0.058). For patients without ST-segment elevation, the rates were 9.1% and 8.3%, respectively (OR 0.90, p = 0.22). At 24 h, the risk of death or MI was significantly lower in the patients who received hirudin than in those who received UFH (2.1% vs. 1.3%, p = 0.001). However, the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial of hirudin as adjunctive therapy to thrombolytic therapy in patients with STEMI showed no benefit of the drug over UFH either during study drug infusion or later (474). The GUSTO-IIb and TIMI 9B trials used hirudin doses of 0.1 mg per kg bolus and 0.1 mg per kg per h infusion for 3 to 5 d after the documentation of excess bleeding with higher doses used in the GUSTO-IIA and TIMI 9A trials (0.6 mg per kg bolus and 0.2 mg per kg per h infusion) (473,475).
The OASIS program evaluated hirudin in patients with UA/NSTEMI. OASIS 1 (476) was a pilot trial of 909 patients that compared the low hirudin dose of 0.1 mg per kg per h infusion and the medium hirudin dose of 0.15 mg per h infusion with UFH. The latter dose provided the best results, with a reduction in the rate of death, MI, or refractory angina at 7 d (6.5% with UFH vs. 3.3% with hirudin, p = 0.047). This medium dose was used in the large OASIS 2 (477) trial that consisted of 10,141 patients with UA/NSTEMI who were randomized to receive UFH (5,000 IU bolus plus 15 U per kg per h) or recombinant hirudin (0.4 mg per kg bolus and 0.15 mg per kg per h) infusion for 72 h. The primary end point of cardiovascular death or new MI at 7 d occurred in 4.2% in the UFH group versus 3.6% patients in the hirudin group (RR 0.84, p = 0.064). A secondary end point of cardiovascular death, new MI, or refractory angina at 7 d was significantly reduced with hirudin (6.7% vs. 5.6%, RR 0.83, p = 0.011). There was an excess of major bleeding incidents that required transfusion with hirudin (1.2% vs. 0.7% with heparin, p = 0.014) but no excess in life-threatening bleeding incidents or strokes. A meta-analysis of the GUSTO-IIB, TIMI 9B, OASIS 1, and OASIS 2 trials showed a relative risk of death or MI of 0.90 (p = 0.015) with hirudin compared with UFH at 35 d after randomization; RR values were similar for patients receiving thrombolytic agents (0.88) and not receiving thrombolytic agents (0.90) (477).
The relative benefits of hirudin versus UFH in ACS patients undergoing PCI were evaluated in the 1,410-patient subset in GUSTO-IIb who underwent PCI during the initial drug infusion. A reduction in nonfatal MI and the composite of death and MI was observed with hirudin that was associated with a slightly higher bleeding rate (478).
Hirudin (lepirudin) is presently indicated by the US Food and Drug Administration only for anticoagulation in patients with heparin-induced thrombocytopenia (456) and for the prophylaxis of deep vein thrombosis in patients undergoing hip replacement surgery. It should be administered as a 0.4 mg per kg IV bolus over 15 to 20 s followed by a continuous intravenous infusion of 0.15 mg per kg per h, with adjustment of the infusion to a target range of 1.5 to 2.5 times the control aPTT values. Argatroban is another direct thrombin inhibitor that is approved for the management of patients with heparin-induced thrombocytopenia (479). However, in ACS, the monovalent direct thrombin inhibitors (including argatroban) are ineffective antithrombotic agents compared with UFH, and thus, argatroban should generally not be used in management of ACS (480). The recommended initial dose of argatroban is an intravenous infusion of 2 mcg per kg per min, with subsequent adjustments to be guided by the aPTT (medical management) or ACT (interventional management).
The REPLACE 2 investigators compared bivalirudin (bolus 0.75 mg per kg followed by infusion of 1.75 mg per kg per h with provisional GP IIb/IIIa inhibition) with UFH 65 U per kg bolus with planned GP IIb/IIIa inhibition in patients undergoing urgent or elective PCI (426). Only 14% had been treated for UA within 48 h before enrollment. Prespecified definitions of noninferiority were satisfied for bivalirudin, with the benefits of a significantly lower bleeding rate (481). Follow-up through 1 year also suggested similar mortality for the 2 approaches (482).
Bivalirudin was investigated further in the ACUITY trial (425) (Figs. 13 and 14).⇓⇓ The ACUITY trial used a 2 × 2 factorial design to compare a heparin (UFH or enoxaparin) with or without upstream GP IIb/IIIa inhibition versus bivalirudin with or without upstream GP IIb/IIIa inhibition; a third arm tested bivalirudin alone and provisional GP IIb/IIIa inhibition. The study was randomized but open-label (unblinded). The main comparisons in the ACUITY trial were of heparin with GP IIb/IIIa inhibition versus bivalirudin with GP IIb/IIIa inhibition versus bivalirudin with provisional GP IIb/IIIa inhibition. Three primary 30-d end points were prespecified: composite ischemia, major bleeding, and net clinical outcomes (composite ischemia or major bleeding). Bivalirudin plus GP IIb/IIIa inhibitors compared with heparin plus GP IIb/IIIa inhibitors resulted in noninferior 30-d rates of composite ischemia (7.7% vs. 7.3%), major bleeding (5.3% vs. 5.7%), and net clinical outcomes (11.8% vs. 11.7%) (Fig. 13). Bivalirudin alone compared with heparin GB plus IIb/IIIa inhibitors resulted in noninferior rates of composite ischemia (7.8% vs. 7.3%, p = 0.32, RR 1.08, 95% CI 0.93 to 1.42), significantly reduced major bleeding (3.0% vs. 5.7%, p less than 0.001, RR 0.53, 95% CI 0.43 to 0.65), and superior 30-d net clinical outcomes (10.1% vs. 11.7% respectively, p = 0.015, RR 0.86, 95% CI 0.77 to 0.97). For the subgroup of 5,753 patients who did receive a thienopyridine before angiography or PCI, the composite ischemic end point occurred in 7.0% in the bivalirudin-alone group versus 7.3% in the group that received heparin plus GP IIb/IIIa inhibition (RR 0.97, 95% CI 0.80 to 1.17), whereas in the 3,304 patients who did not receive a thienopyridine before angiography or PCI, the composite ischemic event rate was 9.1% in the bivalirudin-alone group versus 7.1% in the heparin plus GP IIb/IIIa inhibition group (RR 1.29, 95% CI 1.03 to 1.63; p for interaction 0.054) (Fig. 14) (425). The Writing Committee believes that this observation introduces a note of caution about the use of bivalirudin alone, especially when there is a delay to angiography when high-risk patients who may not be represented by the ACUITY trial population are being managed, or if early ischemic discomfort occurs after the initial antithrombotic strategy has been implemented (Figs. 7, 8, and 9). The Writing Committee therefore recommends that patients meeting these criteria be treated with concomitant GP IIb/IIIa inhibitors or a thienopyridine, administered before angiography to optimize outcomes whether a bivalirudin-based or heparin-based anticoagulant strategy is used. This approach is also supported by the findings of the ACUITY timing study that showed a trend toward higher rates of ischemic events, which did not meet inferiority criteria, in the deferred GP IIb/IIIa inhibitor group compared with the upstream GP IIb/IIIa inhibitor. Death/MI/unplanned revascularization for ischemia occurred in 7.1% of routine upstream GP IIb/IIIa inhibitor group versus 7.9% of deferred selective inhibitor group; RR 1.12 (95% CI 0.97 to 1.29) (482a,482b). Similarly, in the ACUITY PCI substudy (482c,482d), subjects who did not receive a thienopyridine pre-PCI had higher rates of the composite ischemic end point in the bivalirudin-alone group compared with the heparin plus GP IIb/IIIa group. In both the REPLACE 2 and ACUITY trials, bivalirudin with provisional GP IIb/IIIa blockade was associated with a lower risk of bleeding, whereas this was not the case in ACUITY with the combination of bivalirudin and planned GP IIb/IIIa blockade, suggesting that dosing regimens and concomitant GP IIb/IIIa blockade plays an important role in bleeding risk (483). The impact of switching anticoagulants after randomization, which has been associated with excess bleeding (423,484), is unclear for bivalirudin. It should be noted that the ACUITY protocol called for angiography within 24 to 48 h of randomization and that the median time to catheterization (from the time the study drug was started) was approximately 4 h; thus, the study results of this trial cannot be extrapolated beyond the group of patients treated in an early invasive fashion.
184.108.40.206 Factor Xa Inhibitors
The OASIS 5 investigators evaluated the use of fondaparinux in UA/NSTEMI (424) (Fig. 15). OASIS 5 compared 2 anticoagulant strategies given for a mean of 6 d; one of which was amended during the conduct of the trial. In OASIS 5, patients with UA/NSTEMI were randomized to a control strategy of enoxaparin 1.0 mg per kg SC twice daily (reduced to 1.0 mg per kg once daily for patients with an estimated creatinine clearance less than 30 ml per min) coupled with UFH when PCI was performed (no additional UFH if the last dose of enoxaparin was less than 6 h before). If the last dose of enoxaparin was given more than 6 h before, the recommendation was that an intravenous bolus of UFH 65 U per kg be administered if a GP IIb/IIIa inhibitor was to be used and 100 U per kg if no GP IIb/IIIa inhibitor was to be used. The opposite arm was a strategy of fondaparinux 2.5 mg SC once daily to be supplemented as follows if PCI was performed: within 6 h of the last subcutaneous dose of fondaparinux, no additional study drug was given if a GP IIb/IIIa inhibitor was used, and 2.5 mg of fondaparinux was given intravenously if no GP IIb/IIIa inhibitor was used; more than 6 h since the last dose of fondaparinux, an additional intravenous dose of fondaparinux 2.5 mg was recommended if a GP IIb/IIIa inhibitor was used or 5.0 mg IV if no GP IIb/IIIa inhibitor was used. As explained by the OASIS 5 investigators, the rationale for the recommendation to use UFH during PCI in the enoxaparin arm was based on lack of approval for enoxaparin for PCI in the US by the Food and Drug Administration, lack of available trial data on the use of enoxaparin during PCI when OASIS 5 was designed, and lack of any recommendations about the use of enoxaparin in the available ACC/AHA or ESC PCI guidelines (personal communication, OASIS 5 Investigators, July 7, 2006). The UFH dosing recommendation in the enoxaparin arm was formulated in consultation with the maker of enoxaparin and was not altered when the SYNERGY trial did not show superiority of enoxaparin over UFH (423). Of note, during the conduct of the trial, catheter-associated thrombus was reported 3 times more frequently with the fondaparinux strategy (0.9% vs. 0.3%). After approximately 12,000 of the 20,078 patients ultimately enrolled in the trial had been randomized, the protocol was amended to remind the investigators to be certain that the intravenous dose of fondaparinux was properly flushed in the line and to permit the use of open-label UFH. As described by the OASIS 5 investigators (personal communication, OASIS 5 Investigators, July 7, 2006), investigators gave open-label UFH both before and during PCI, with the dose being determined at their discretion.
The number of patients with primary outcome events at 9 d (death, MI, or refractory ischemia) was similar in the 2 groups (579 with fondaparinux [5.8%] vs. 573 with enoxaparin [5.7%]; HR in the fondaparinux group 1.01; 95% CI 0.90 to 1.13), which satisfied prespecified noninferiority criteria. The number of events that met this combined primary efficacy outcome showed a nonsignificant trend toward a lower value in the fondaparinux group at 30 d (805 vs. 864, p = 0.13) and at the end of the study (180 d; 1,222 vs. 1,308, p = 0.06; Fig. 12). The rate of major bleeding at 9 d was lower with fondaparinux than with enoxaparin (217 events [2.2%] vs. 412 events [4.1%]; HR 0.52; p less than 0.001). The composite of the primary outcome and major bleeding at 9 d favored fondaparinux (737 events [7.3%] vs. 905 events [9.0%]; HR 0.81; p less than 0.001) (Fig. 15). Fondaparinux was associated with a significantly reduced number of deaths at 30 d (295 vs. 352, p = 0.02) and at 180 d (574 vs. 638, p = 0.05). Fondaparinux also was associated with significant reductions in death, MI, and stroke (p = 0.007) at 180 d.
Thus, fondaparinux is another anticoagulant that has been given a Class I recommendation in the management of UA/NSTEMI, as noted in Figures 7, 8, and 9. As tested in OASIS 5, the fondaparinux (plus UFH) strategy was associated with lower bleeding rates, clearly an attractive feature given the relationship between bleeding events and increased risk of death and ischemic events (486). The excess bleeding in the enoxaparin arm may have been in part a result of the combination of enoxaparin and UFH during PCI.
At present, based on experience in both OASIS 5 and OASIS 6 (433), it appears that patients receiving fondaparinux before PCI should receive an additional anticoagulant with anti–IIa activity to support PCI (see Table 13). To date, the only anticoagulant that has been evaluated with fondaparinux during PCI is UFH, and based on limited experience, the OASIS investigators recommend an UFH dose of 50 to 60 U per kg IV when fondaparinux-treated patients are taken to PCI (personal communication, OASIS 5 Investigators, July 7, 2006). However, a cautionary note is that this UFH recommendation is not fully evidence-based, given its inconsistent and uncontrolled use in OASIS 5. Hence, additional clinical trial information is needed to establish more rigorously the safety of intravenous UFH at the time of PCI in patients receiving fondaparinux as initial medical treatment (Table 13). Because the anticoagulant effect of UFH can be more readily reversed than that of fondaparinux, UFH is preferred over fondaparinux in patients likely to undergo CABG within 24 h.
220.127.116.11 Long-Term Anticoagulation
The long-term administration of warfarin has been evaluated in a few, mostly small studies. Williams et al. (436) randomized 102 patients with UA to UFH for 48 h followed by open-label warfarin for 6 months and reported a 65% risk reduction in the rate of MI or recurrent UA. The Antithrombotic Therapy in Acute Coronary Syndromes (ATACS) trial (369) randomized 214 patients with UA/NSTEMI to ASA alone or to the combination of ASA plus UFH followed by warfarin. At 14 d, there was a reduction in the composite end point of death, MI, and recurrent ischemia with the combination therapy (27.0% vs. 10.5%, p = 0.004). In a small randomized pilot study of 57 patients allocated to warfarin or placebo in addition to ASA, less evidence was noted of angiographic progression in the culprit lesion after 10 weeks of treatment with warfarin (33% for placebo vs. 4% for warfarin) and more regression was observed (487). The OASIS pilot study (488) compared a fixed dosage of warfarin 3 mg per d or a moderate dose titrated to an INR of 2.0 to 2.5 in 197 patients and given for 7 months after the acute phase. Low-intensity warfarin had no benefit, whereas the moderate-intensity regimen reduced the risk of death, MI, or refractory angina by 58% and the need for rehospitalization for UA by 58%. However, these results were not reproduced in the larger OASIS 2 trial (477) of 3,712 patients randomized to the moderate-intensity regimen of warfarin or standard therapy, with all patients receiving ASA. The rate of cardiovascular death, MI, or stroke after 5 months was 7.7% with the anticoagulant and 8.4% without (p = 0.37) (489). Thus, the role, if any, of long-term warfarin in patients with UA/NSTEMI remains to be defined.
The Coumadin Aspirin Reinfarction Study (CARS) conducted in post-MI patients was discontinued prematurely owing to a lack of evidence of a benefit of reduced-dose ASA (80 mg per d) combined with either 1 or 3 mg of warfarin daily compared with 160 mg per d of ASA alone (490). The Combination Hemotherapy And Mortality Prevention study found no benefit to the use of warfarin (to an INR of 1.5 to 2.5) plus 81 mg per d of ASA versus 162 mg per d of ASA alone with respect to total mortality (the primary end point), cardiovascular mortality, stroke, or nonfatal MI (mean follow-up of 2.7 years) after an index MI (491). Low- or moderate-intensity anticoagulation with fixed-dose warfarin thus is not recommended for routine use after hospitalization for UA/NSTEMI. Warfarin should be prescribed, however, for UA/NSTEMI patients with established indications for warfarin, such as atrial fibrillation, left ventricular thrombus, and mechanical prosthetic heart valves.
The Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2) open-label trial randomized 999 patients after ACS to low-dose ASA, high-intensity oral anticoagulation (INR 3.0 to 4.0), or combined low-dose ASA and moderate intensity oral anticoagulation (INR 2.0 to 2.5) (492). After a median of 12 months, the primary end point of MI, stroke, or death was reached in 9% receiving ASA, 5% given anticoagulants (p = 0.048), and 5% receiving combination therapy (p = 0.03). Major and minor bleeding events occurred in 1% and 5%, 1% and 8%, and 2% and 15% of patients, respectively.
Similarly, a large (n = 3,630) Norwegian open-label study (WARIS-2) compared ASA (160 mg per d), high-intensity warfarin (INR target 2.8 to 4.2), or ASA (75 mg per d) combined with moderate-intensity warfarin (INR 2.0 to 2.5) over a mean of 4 years after MI (41% with non–Q-wave MI) (493). One third of patients underwent an intervention over the study period. The primary outcome of death, nonfatal MI, or thromboembolic stroke occurred in 20% of ASA patients, 16.7% of warfarin patients, and 15% of combination therapy patients (p = 0.03). The annual major bleeding rate was 0.62% in both warfarin arms and 0.17% with ASA alone (p less than 0.001). Thus, moderate-intensity warfarin with low-dose ASA appears to be more effective than ASA alone when applied to MI patients treated primarily with a noninterventional approach, but it is associated with a higher bleeding risk.
An indication for warfarin (e.g., for atrial fibrillation, mechanical prosthetic valve, or left ventricular thrombus) in addition to ASA and clopidogrel, which are indicated for most high-risk patients, arises occasionally after UA/NSTEMI. There are no prospective trials and few observational data to establish the benefit and risk of such “triple antithrombotic” therapy (494,495). In the 2004 STEMI guidelines (1), a Class IIb, Level of Evidence: C recommendation was given for the use of warfarin (INR 2.0 to 3.0) in combination with ASA (75 to 162 mg) and clopidogrel (75 mg per d) for patients with a stent implanted and concomitant indications for anticoagulation. Similarly, the 2005 PCI guidelines (2) stated that warfarin in combination with clopidogrel and low-dose ASA should be used with great caution and only when INR is carefully regulated (2.0 to 3.0). Despite a limited amount of subsequent observational data (495), the evidence base remains small, which leaves this recommendation at the Class IIb, Level of Evidence: C. When triple-combination therapy is selected for clear indications and is based on clinical judgment that benefit will outweigh the incremental risk of bleeding, then therapy should be given for the minimum time and at the minimally effective doses necessary to achieve protection. An expanded evidence base on this issue is strongly needed. Figure 11 provides recommendations for long-term management of dual- and triple-antithrombotic therapy after UA/NSTEMI.
3.2.6 Platelet GP IIb/IIIa Receptor Antagonists
The GP IIb/IIIa receptor is abundant on the platelet surface. When platelets are activated, this receptor undergoes a change in conformation that increases its affinity for binding to fibrinogen and other ligands. The binding of molecules of fibrinogen to receptors on different platelets results in platelet aggregation. This mechanism is independent of the stimulus for platelet aggregation and represents the final and obligatory pathway for platelet aggregation (496). The platelet GP IIb/IIIa receptor antagonists act by occupying the receptors, preventing fibrinogen from binding, and thereby preventing platelet aggregation. Experimental and clinical studies have suggested that occupancy of at least 80% of the receptor population and inhibition of platelet aggregation to ADP (5 to 20 micromoles per liter) by at least 80% results in potent antithrombotic effects (497). The various GP IIb/IIIa antagonists, however, possess significantly different pharmacokinetic and pharmacodynamic properties (498).
Abciximab is a Fab fragment of a humanized murine antibody that has a short plasma half-life but strong affinity for the receptor, which results in some receptor occupancy that persists in part for weeks. Platelet aggregation gradually returns to normal 24 to 48 h after discontinuation of the drug. Abciximab also inhibits the vitronectin receptor (alphavbeta3) on endothelial cells and the MAC-1 receptor on leukocytes (499,500). The clinical relevance of occupancy of these receptors is unknown.
Eptifibatide is a cyclic heptapeptide that contains the KGD (Lys-Gly-Asp) sequence; tirofiban is a nonpeptide mimetic of the RGD (Arg-Gly-Asp) sequence of fibrinogen (498,501–503). Receptor occupancy with these 2 synthetic antagonists is, in general, in equilibrium with plasma levels. They have half-lives of 2 to 3 h and are highly specific for the GP IIb/IIIa receptor. Platelet aggregation returns to normal in 4 to 8 h after discontinuation of these drugs, a finding that is consistent with their relatively short half-lives (504). Glycoprotein IIb/IIIa antagonists can bind to different sites on the receptor, which results in somewhat different binding properties that can modify their platelet effects and, potentially and paradoxically, activate the receptor (505). Oral antagonists to the receptor, previously under investigation, have been abandoned because of negative results of 5 large trials of 4 of these compounds (506–509).
The efficacy of GP IIb/IIIa antagonists in prevention of the complications associated with percutaneous interventions has been documented in numerous trials, many of them composed totally or largely of patients with UA (372,510–512) (Table 18). Two trials with tirofiban and 1 trial with eptifibatide have also documented their efficacy in UA/NSTEMI patients, only some of whom underwent interventions (128,130). Two trials were completed with the experimental drug lamifiban (373,513) and 1 with abciximab (514). Few direct comparative data are available for these various antiplatelet agents. The TARGET study (Do Tirofiban and ReoPro Give Similar Efficacy Trial) assessed differences in safety and efficacy of tirofiban and abciximab in 4,809 patients undergoing PCI with intended stenting (515). The composite of death, nonfatal MI, or urgent target-vessel revascularization at 30 d occurred more frequently in the tirofiban group (7.6% vs. 6.0%). The advantage of abciximab was observed exclusively among patients presenting with UA/NSTEMI (63% of the population) (515). A possible explanation for the inferior performance of in-laboratory initiation of tirofiban for PCI in the setting of ACS was an insufficient loading dose of tirofiban to achieve optimal early (periprocedural) antiplatelet effect (516).
Abciximab has been studied primarily in PCI trials, in which its administration consistently resulted in reductions in rates of MI and the need for urgent revascularization (Table 18). In subgroups of patients within those trials who had ACS, the risk of ischemic complications within the first 30 d after PCI was reduced by 60% to 80% with abciximab therapy. Two trials with abciximab specifically studied patients with acute ischemic syndromes. The CAPTURE trial enrolled patients with refractory UA (372). After angiographic identification of a culprit lesion suitable for angioplasty, patients were randomized to either abciximab or placebo administered for 20 to 24 h before angioplasty and for 1 h thereafter. The rate of death, MI, or urgent revascularization within 30 d (primary outcome) was reduced from 15.9% with placebo to 11.3% with abciximab (RR 0.71, p = 0.012). At 6 months, death or MI had occurred in 10.6% of the placebo-treated patients versus 9.0% of the abciximab-treated patients (p = 0.19). Abciximab is approved for the treatment of UA/NSTEMI as an adjunct to PCI or when PCI is planned within 24 h.
The GUSTO IV-ACS trial (514) enrolled 7,800 patients with UA/NSTEMI who were admitted to the hospital with more than 5 min of chest pain and either ST-segment depression and/or elevated TnT or TnI concentration. All received ASA and either UFH or LMWH. They were randomized to an abciximab bolus and a 24-h infusion, an abciximab bolus and a 48-h infusion, or placebo. In contrast to other trials with GP IIb/IIIa antagonists, GUSTO IV-ACS enrolled patients in whom early (less than 48 h) revascularization was not intended. At 30 d, death or MI occurred in 8.0% of patients taking placebo, 8.2% of patients taking 24-h abciximab, and 9.1% of patients taking 48-h abciximab, differences that were not statistically significant. At 48 h, death occurred in 0.3%, 0.7%, and 0.9% of patients in these groups, respectively (placebo vs. abciximab 48 h, p = 0.008). The lack of benefit of abciximab was observed in most subgroups, including patients with elevated concentrations of troponin who were at higher risk. Although the explanation for these results is not clear, they indicate that abciximab at the dosing regimen used in GUSTO IV-ACS is not indicated in the management of patients with UA or NSTEMI in whom an early invasive management strategy is not planned.
Tirofiban was studied in the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) (374) and Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) (130) trials. PRISM directly compared tirofiban with heparin in 3,232 patients with accelerating angina or angina at rest and ST-segment or T-wave changes and with cardiac marker elevation, a previous MI, or a positive stress test or angiographically documented coronary disease (374). The primary composite outcome (death, MI, or refractory ischemia at the end of a 48-h infusion period) was reduced from 5.6% with UFH to 3.8% with tirofiban (RR 0.67, p = 0.01). At 30 d, the frequency of the composite outcome was similar in the 2 groups (17.1% for UFH vs. 15.9% for tirofiban, p = 0.34), but a trend toward reduction in the rate of death or MI was present with tirofiban (7.1% vs. 5.8%, p = 0.11), and a significant reduction in mortality rates was observed (3.6% vs. 2.3%, p = 0.02). The benefit of tirofiban was mainly present in patients with an elevated TnI or TnT concentration at baseline.
The PRISM-PLUS trial enrolled 1,915 patients with clinical features of UA/NSTEMI within the previous 12 h and the presence of ischemic ST-T changes or CK and CK-MB elevation (130). Patients were randomized to tirofiban alone, UFH alone, or the combination for a period varying from 48 to 108 h. The tirofiban-alone arm was dropped during the trial because of an excess mortality rate. The combination of tirofiban and UFH compared with UFH alone reduced the primary composite end point of death, MI, or refractory ischemia at 7 d from 17.9% to 12.9% (RR 0.68, p = 0.004). This composite outcome also was significantly reduced at 30 d (22%, p = 0.03) and at 6 months (19%, p = 0.02). The end point of death or nonfatal MI was reduced at 7 d (43%, p = 0.006), at 30 d (30%, p = 0.03), and at 6 months (22%, p = 0.06). A high rate of angiography in this trial could have contributed to the important reduction in event rates. Computer-assisted analysis of coronary angiograms obtained after 48 h of treatment in PRISM-PLUS also showed a reduction in the thrombus load at the site of the culprit lesion and improved coronary flow in patients who received the combination of tirofiban and UFH (134). Tirofiban, in combination with heparin, has been approved for the treatment of patients with ACS, including patients who are managed medically and those undergoing PCI.
Eptifibatide was studied in the PURSUIT trial, which enrolled 10,948 patients who had chest pain at rest within the previous 24 h and ST-T changes or CK-MB elevation (128). The study drug was added to standard management until hospital discharge or for 72 h, although patients with normal coronary arteries or other mitigating circumstances had shorter infusions. The infusion could be continued for an additional 24 h if an intervention was performed near the end of the 72-h infusion period. The primary outcome rate of death or nonfatal MI at 30 d was reduced from 15.7% to 14.2% with eptifibatide (RR 0.91, p = 0.042). Within the first 96 h, a substantial treatment effect was seen (9.1% vs. 7.6%, p = 0.01). The benefits were maintained at 6-month follow-up. Eptifibatide has been approved for the treatment of patients with ACS (UA/NSTEMI) who are treated medically or with PCI. It is usually administered with ASA and heparin.
The cumulative event rates observed during the phase of medical management and at the time of PCI in the CAPTURE, PRISM-PLUS, and PURSUIT trials are shown in Figure 16 (523). By protocol design, almost all patients underwent PCI in CAPTURE. In PRISM-PLUS, angiography was recommended. A percutaneous revascularization was performed in 31% of patients in PRISM-PLUS and in 13% of patients in PURSUIT. Each trial showed a statistically significant reduction in the rate of death or MI during the phase of medical management; the reduction in event rates was magnified at the time of the intervention.