1-Acute coronary syndrome.pdf

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CHAPTER 78

Acute Coronary SyndromeMichael C. Kurz, Amal Mattu, and William J. Brady

Acute coronary syndrome (ACS) refers to the constellation of clinical diseases occurring as a result of acute myocardial ischemia. ACS includes a spectrum of clinical presentations ranging from unstable angina (UA) to non–ST segment elevation myocardial infarction (NSTEMI) and ST segment elevation myo-cardial infarction (STEMI). ACS and in particular acute myocar-dial infarction (AMI) remain the leading causes of death in much of the developed world.

HISTORICAL PERSPECTIVE

Several advances in the mid-20th century drastically changed the approach to acute coronary care. The development of external defibrillators and cardiac pacemakers as well as new pharmaco-logic agents provided physicians with effective approaches for treating life-threatening dysrhythmias. The introduction of selec-tive coronary arteriography by Sones in 1959 revolutionized the management of patients with coronary artery disease (CAD). In 1960, Kouwenhoven inaugurated the era of cardiopulmonary resuscitation (CPR).

These developments led to the recognition that the time between onset of symptoms and the initiation of therapy is critical. Day organized a cardiac arrest team in 1960 and established the first coronary care unit 2 years later, reducing AMI mortality by half. In the 1980s, DeWood performed coronary angiography early in the course of AMI and demonstrated coronary occlusion in the infarct-related artery. The early experience of Rentrop with the intracoronary administration of streptokinase in AMI ushered in the era of thrombolysis, now termed fibrinolytic therapy.

Recognition that the majority of sudden deaths from ischemic heart disease occur outside the hospital led to numerous advances for preadmission ACS care. In 1969, advanced prehospital cardiac care was initiated in Belfast with Pantridge’s mobile cardiac care units. In 1970, Nagel reported the benefits of preadmission telemetry for field providers of advanced cardiac life support in patients experiencing dysrhythmias or sudden cardiac death. In the 1980s portable 12-lead electrocardiograms (ECGs) were intro-duced into the emergency medical services (EMS) environment. Although the ECG is the cornerstone of the diagnostic evaluation of ACS, diagnostic tools such as echocardiography, stress testing, nuclear imaging, and computed tomography (CT) play increas-ingly important roles, particularly when the diagnosis is not straightforward.

Fibrinolytic therapy and interventional, catheter-based tech-niques revolutionized the treatment of patients with STEMI during the 1980s. Combination therapies with antiplatelet, anti-thrombotic, and fibrinolytic agents continue to be studied for STEMI patients. Interventional success is improving with the use

of newer stenting devices and various platelet and coagulation system inhibitors. STEMI systems of care address the management of STEMI from a systems-based perspective, starting with EMS in the prehospital setting, through the emergency department (ED) to the cardiac catheterization laboratory, and to the coronary care unit. This systems-based approach stresses a number of factors crucial in the management of STEMI, including the time-sensitivity of treatment, the multidisciplinary composition of the management team, and the multistep nature of the overall process. In addition to further development of the STEMI systems of care approach, current efforts focus on the establishment of regional cardiac centers and the expansion of interventional capabilities to smaller hospitals. Furthermore, appropriate methods of evalua-tion of potential ACS patients without obvious STEMI or other diagnostic findings continue to mature. The observation unit–based “rule-out myocardial infarction (MI)” strategy has been shortened in total time, rendered more efficient in process, and made safer with respect to medical management and detection of ACS events. Although this strategy of chest pain evaluation is more efficient than previous approaches, further improvements in reducing the missed MI in the ED are under development.

EPIDEMIOLOGY

Ischemic heart disease and CAD continue to be the leading causes of death among adults in many developed countries. Ischemic heart disease accounts for nearly 1 million deaths in the United States annually, of which approximately 160,000 occur in persons 65 years of age or younger. More than half of all deaths from cardiovascular disease occur in women, and CAD remains a major cause of morbidity and mortality in women beyond their middle to late fifties. The incidence of cardiovascular disease is expected to continue to increase owing to lifestyle and behavioral changes that promote heart disease.1

A significant reduction in age-adjusted mortality from CAD has occurred in the United States over the past four decades.2,3 In large part, the decline has been accompanied by diminished mortality from AMI. This decrease is a result of a reduction in the incidence of AMI by 25% and a sharp drop in the case-fatality rate. Reduc-tion in cigarette smoking, management of lipids, and improved management of hypertension and diabetes mellitus undoubtedly play a role, along with significant advances in medical treatment.

In 2005, 5.8 million patients were evaluated for chest pain or related complaints in EDs in the United States, constituting 5% of all ED visits. In 2004, 4.1 million visits to the ED had a primary diagnosis of cardiovascular disease, and over 1.5 million patients were hospitalized for a primary or secondary diagnosis of ACS.4-7 In addition, approximately 2% of patients with ACS are discharged

Section ThreeCARDIAC SYSTEM

998 PART III ◆ Medicine and Surgery / Section Three • Cardiac System

artery lesions; it may be relieved by exercise or NTG. The ECG reveals ST segment elevation that is impossible to discern from AMI electrocardiographically and, at times, clinically.

Acute Myocardial Infarction

Acute myocardial infarction is defined as myocardial cell death and necrosis of the myocardium. The four-decade-old World Health Organization (WHO) definition for AMI has been replaced by clinical criteria developed jointly by the European Society for Cardiology and American College of Cardiology (ACC) that focus on defining infarction as any evidence of myocardial necro-sis. This definition for an acute, evolving, or recent MI requires a typical rise and fall of a cardiac biochemical marker, currently troponin, with clinical symptoms, ECG changes, or coronary artery abnormalities based on interventional evaluation.11 The actual definition,11 referred to as the “Universal Definition of Myocardial Infarction,” includes the following; either one of these criteria satisfies the diagnosis for an acute, evolving, or recent MI:

1. Typical rise and gradual fall or more rapid rise and fall of biochemical markers of myocardial necrosis with at least one value above the 99th percentile of the upper reference limit (URL) and with at least one of the following clinical parameters:• Ischemic symptoms• ECG changes indicative of ischemia (T wave changes or

ST segment elevation or depression)• Development of pathologic Q waves on the ECG• Imaging evidence of presumably new findings, such as a

loss of viable myocardium or a regional wall motion abnormality

2. Pathologic findings of an AMIFurthermore, regarding an established MI, any one of the fol-

lowing criteria satisfies this diagnosis11:• Development of new pathologic Q waves on serial ECGs.

The patient may or may not remember previous symptoms. Biochemical markers of myocardial necrosis may have normalized, depending on the length of time since the infarct developed.

• Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a nonischemic cause.

• Pathologic findings of a healed or healing MI.Considering the myriad clinical situations in which MI is

encountered, the five primary “types” of infarction are described by the following categorization:

• Type 1—Spontaneous MI related to ischemia resulting from a primary coronary event, such as plaque erosion rupture, erosion, fissuring, or dissection with accompanying thrombus formation and vasospasm. Type 1 infarctions represent the “true” ACS event.

• Type 2—MI secondary to ischemia caused by either increased oxygen demand or decreased supply, as seen in coronary artery spasm, coronary embolism, severe anemia, compromising arrhythmias, or significant systemic hypotension.

• Type 3—Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischemia, accompanied by presumably new ST segment elevation or new left bundle branch block (LBBB) pattern. Fresh coronary thrombus is noted via either angiography or autopsy; death occurs before appropriate sampling of the blood to detect the abnormal cardiac biomarker.

• Type 4—MI associated with coronary instrumentation, such as occurring after percutaneous coronary intervention (PCI). For PCIs in patients with normal baseline troponin values,

from the ED. In the United States, approximately 900,000 persons every year experience an AMI, of whom 20% die before reaching the hospital, and 30% die within 30 days.8,9 The majority of fatali-ties from CAD occur outside the hospital, usually from an ACS-related dysrhythmia within 2 hours of onset of symptoms. For many patients who experience a nonfatal AMI, their lives are limited by an impaired functional status, anginal symptoms, and a diminished quality of life. The economic cost of ACS is estimated to be $100 to $120 billion annually.10

SPECTRUM OF DISEASE

Coronary heart disease includes the spectrum from asymptomatic CAD and stable angina to UA, AMI, and sudden cardiac death. ACS includes the “acute” subtypes of coronary heart disease, including UA, AMI, and sudden cardiac death.

Stable Angina

Stable angina pectoris is transient, episodic chest discomfort resulting from myocardial ischemia. This discomfort is typically predictable and reproducible, with the frequency of attacks con-stant over time. Physical or psychological stress (physical exertion, emotional stress, anemia, dysrhythmias, or environmental expo-sures) may provoke an attack of angina that resolves spontane-ously over a constant, predictable period of time with rest or nitroglycerin (NTG).

The Canadian Cardiovascular Society classification for angina is defined as follows: class I, no angina with ordinary physical activity; class II, slight limitation of normal activity as angina occurs with walking, climbing stairs, or emotional stress; class III, severe limitation of ordinary physical activity as angina occurs on walking one or two blocks on a level surface or climbing one flight of stairs in normal conditions; and class IV, inability to perform any physical activity without discomfort as anginal symptoms occur at rest.

Unstable Angina

Unstable angina is broadly defined as angina occurring with minimal exertion or at rest, new-onset angina, or a worsening change in a previously stable anginal syndrome in terms of fre-quency or duration of attacks, resistance to previously effective medications, or provocation with decreasing levels of exertion or stress. Rest angina is defined as angina occurring at rest, lasting longer than 20 minutes, and occurring within 1 week of presenta-tion. New-onset angina is angina of at least class II severity with onset within the previous 2 months. Increasing or progressive angina is diagnosed when a previously known angina becomes more frequent, longer in duration, or increased by one class within the previous 2 months of at least class III severity. Symptoms that last longer than 20 minutes despite cessation of activity are con-sistent with angina at rest and reflect UA.

UA is often referred to as preinfarction angina, accelerating or crescendo angina, intermediate coronary syndrome, and preocclusive syndrome, underscoring its difference from stable angina. UA should be considered a possible harbinger of AMI and hence should be treated aggressively. A patient with a diagnosis of angina in the ED should be presumed to have UA until a thorough clinical evaluation reliably determines otherwise.

UA can also be defined from a pathophysiologic perspective. Plaque rupture accompanied by thrombus formation and vaso-spasm illustrate the intracoronary events of UA. This is frequently characterized by an electrocardiographic abnormality, including T wave and ST segment changes.

Variant angina—also known as Prinzmetal’s angina—is caused by coronary artery vasospasm at rest with minimal fixed coronary

CHAPTER 78 / Acute Coronary Syndrome 999

thrombotic response to rupture of coronary artery plaque and subsequent ACS. Platelet-rich thrombi are also more resistant to fibrinolysis than fibrin- and erythrocyte-rich thrombi. The result-ing thrombus can occlude the vessel lumen, leading to myocardial ischemia, hypoxia, acidosis, and eventually infarction. The con-sequences of the occlusion depend on the extent of the throm-botic process, the characteristics of the preexisting plaque, the extent of the vessel obstruction, and the availability of collateral circulation.

In the setting of UA, acute stenosis of the vessel is noted; complete obstruction, however, is encountered in only 20% of cases. In these cases, it is likely that extensive collateral vessel cir-culation prevents total cessation of blood flow, averting frank infarction.13 With AMI, the occlusive fibrin-rich thrombus is fixed and persistent, resulting in myonecrosis of the cardiac tissue sup-plied by the affected artery. Angiographic studies demonstrate that the preceding coronary plaque lesion is often less than 50% ste-notic, indicating that the most important factors in the infarction are the acute events of plaque rupture, platelet activation, and thrombus formation rather than the severity of the underlying coronary artery stenosis.

Another important aspect of ACS is vasospasm. After signifi-cant coronary vessel occlusion, local mediators and vasoactive substances are released, inducing vasospasm, which further com-promises blood flow. Central and sympathetic nervous system input increases within minutes of the occlusion, resulting in vasomotor hyperreactivity and coronary vasospasm. Sympathetic stimulation by endogenous hormones, such as epinephrine and serotonin may also result in increased platelet aggregation and neutrophil-mediated vasoconstriction. Approximately 10% of MIs occur as a result of coronary artery spasm and subsequent thrombus formation without significant underlying CAD. This mechanism may be more prevalent during UA and other coronary syndromes that do not result in infarction.

Further myocardial injury occurs at the cellular level as inflam-matory, thrombotic, and other debris from the occlusive plaque lesion is released and embolizes into the distal vessel. Such embo-lization can result in obstruction at the microvasculature, leading to hypoperfusion and ischemia of the distal myocardial tissue, even after reopening of the more proximal, initial, obstructing lesion. In particular, the introduction of calcium, oxygen, and cel-lular elements into ischemic myocardium can lead to irreversible myocardial damage that causes reperfusion injury, prolonged ven-tricular dysfunction (known as myocardial stunning), or reperfu-sion dysrhythmias. Neutrophils probably play an important role in reperfusion injury, occluding capillary lumens, decreasing blood flow, accelerating the inflammatory response, and resulting in the production of chemoattractants, proteolytic enzymes, and reactive oxygen species.

CLINICAL FEATURES

Clinical features associated with ACS vary based on the patient type, including gender, comorbid conditions, and age consider-ations. Women, patients with diabetes mellitus, and the elderly, among other populations, can exhibit differing presentations of ACS. Women demonstrate less remarkable, if not subtle, ACS pre-sentations. Diabetic patients frequently exhibit nontraditional symptoms of AMI, such as dyspnea. The elderly commonly note only weakness, confusion, or other nonclassic symptoms as the primary manifestation of ACS. The detection of AMI, ACS, and symptomatic obstructive coronary lesions are all part of the focus on ED management. The primary focus of the diagnostic effort changes significantly at different phases of the ED evalua-tion. Early, usually within the initial 15 minutes of presentation, the principal task is the identification of STEMI. Once STEMI has been excluded (and the patient remains clinically stable), the

elevations of cardiac biomarkers above the 99th percentile URL are indicative of periprocedural myocardial necrosis. By convention, increases of biomarkers greater than 3 times the 99th percentile URL are designated as defining PCI-related MI. A subtype related to a documented stent thrombosis is similarly recognized.

• Type 5—MI associated with coronary artery bypass grafting (CABG). For CABG in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of periprocedural myocardial necrosis. By convention, increases of biomarkers greater than five times the 99th percentile URL plus any of the following are designated as defining CABG-related MI:• New pathologic Q waves or new LLLB• Angiographically documented new graft or native

coronary artery occlusion• Imaging evidence of new loss of viable myocardium

This categorization is more than a simple semantic description of AMI. Diagnostic and management issues clearly are different depending on the subtype of MI encountered. For instance, the type 1 event should be approached with attention to platelet, coagulation system, and vasospasm considerations, whereas the type 2 infarction should have attention paid to the frequent primary, inciting pathophysiologic situations that are actually causing the AMI.

AMI is further classified by findings on the ECG at presentation, as either STEMI or NSTEMI. Previous descriptors, such as trans-mural and nontransmural, as well as Q wave and non–Q wave MI, fail to adequately describe the coronary event and its related pathophysiology, electrocardiographic presentation, and patho-logic outcome. The differentiation between STEMI and NSTEMI has important implications in terms of management, outcome, and prognosis for patients with AMI. In fact, the ACC and the American Heart Association (AHA) have separate clinical guide-lines for the management of patients with UA/NSTEMI and those patients with STEMI.6,7,12

PATHOPHYSIOLOGY

The underlying pathophysiology of ACS is myocardial ischemia as a result of inadequate perfusion to meet myocardial oxygen demand. Myocardial oxygen consumption is determined by heart rate, afterload, contractility, and wall tension. Inadequate perfu-sion most commonly results from coronary arterial vessel stenosis as a result of atherosclerotic CAD. Usually the reduction of coro-nary blood flow does not cause ischemic symptoms at rest until the vessel stenosis exceeds 95%. Myocardial ischemia, however, may occur with exercise and increased myocardial oxygen con-sumption with as little as 60% vessel stenosis.13

CAD is characterized by thickening and obstruction of the coronary vessel arterial lumen by atherosclerotic plaques. Although atherosclerosis is usually diffuse and multifocal, individual plaques vary greatly in composition. Fibrous plaques are considered stable but can produce anginal symptoms with exercise and increased myocardial oxygen consumption because of the reduction in coro-nary artery blood flow through the fixed, stenotic lesions. Vulner-able or unstable fibrolipid plaques consist of a lipid-rich core separated from the arterial lumen by a fibromuscular cap. These lesions are likely to rupture, resulting in a cascade of inflammatory events, thrombus formation, and platelet aggregation that can cause acute obstruction of the arterial lumen and myocardial necrosis.14

Thrombus formation is considered an integral factor in ACS, including all subtypes ranging from UA to NSTEMI and STEMI. These syndromes are initiated by endothelial damage and atherosclerotic plaque disruption, which leads to platelet activa-tion and thrombus formation. Platelets play a major role in the


evaluation over the next several hours then focuses on the detec-tion of ACS, including UA and NSTEMI. If excluded (and again, in a stable patient), the identification of symptomatic coronary obstructive lesions is the evaluation’s goal; this last task can be accomplished during the initial ED presentation or later at follow-up.

Preadmission Evaluation

Appropriate pharmacotherapy for persistent anginal chest pain in the preadmission setting includes sublingual NTG, oral aspirin (acetylsalicylic acid [ASA]) that is preferably chewed, and intrave-nous morphine sulfate; the acronym MONA summarizes pread-mission pharmacotherapeutic interventions (morphine, oxygen, nitroglycerin, and aspirin). Establishment of the diagnosis of ACS in this setting is difficult, however, as chest pain is a poor predictor of the diagnosis and adjunctive tools are limited.15 Pre-admission 12-lead ECG offers high specificity (99%) and positive predictive value (93%) for AMI in patients with atraumatic chest pain while increasing the paramedic scene time by an average of only 3 minutes. This approach offers many advantages, including (1) earlier detection of STEMI, (2) ability to base the destination on the availability of PCI, and (3) more rapid reperfusion therapy.7 Preadmission 12-lead ECG would be necessary in the limited populations in whom preadmission fibrinolytic therapy might be applicable, such as those with prolonged out-of-hospital times (90-120 minutes).

Emergency Department Evaluation

The History

The character of the chest discomfort as well as the onset, location, radiation, duration, prior presence, and any exacerbating or alle-viating factors should be sought. Associated symptoms, especially of a cardiac, pulmonary, gastrointestinal, and neurologic nature, should be elicited. Results from any prior cardiac testing should be obtained.

Traditionally, a history of risk factors for CAD is sought; these include male gender, age, tobacco smoking, hypertension, diabetes mellitus, hyperlipidemia, family history, artificial or early meno-pause, and chronic cocaine abuse. Approximately 80% of a popu-lation of more than 122,000 patients with known CAD had at least one of the four conventional risk factors (diabetes mellitus, ciga-rette smoking, hypertension, or hyperlipidemia).16 Cardiac risk factor burden has little impact on the ED diagnosis of ACS; however, in patients older than 40 years, ACS is 22 times more likely if four of the five major risk factors (diabetes mellitus, smoking, hypertension, hyperlipidemia, and family history) are present (compared with none).17 Nevertheless, Bayesian analysis indicates that risk factors are a populational phenomenon and do not increase or decrease the likelihood of any condition in any one patient. Thus the presence of an individual risk factor or a collection of risk factors is far less important in diagnosing acute cardiac ischemia in the ED than the history of presenting illness, prior diagnosis of ischemic cardiac disease in the patient, the presence of ST segment or T wave changes, or cardiac marker abnormalities.18

Risk assessment tools, such as the PURSUIT (Platelet Glycopro-tein IIb-IIIa in Unstable Angina: Receptor Suppression Using Inte-grilin Therapy) risk model, the GRACE (Global Registry of Acute Coronary Events) risk model, and the TIMI (Thrombolysis in Myocardial Infarction) risk score, can be used to determine risk of death and ischemia in NSTEMI and STEMI. The TIMI risk score assigns a point each for seven factors based on history, cardiac markers, and the ECG. It can be accessed at www.timi.org.6 Although these tools may aid in decision-making and in risk

CHARACTERISTICMORE LIKELY TO BE ANGINA

LESS LIKELY TO BE ANGINA

Type of pain Dull, pressure Sharp, stabbing

Duration 2-5 min, often 15-20 min

Seconds or hours

Onset Gradual Rapid

Location Substernal Lateral chest wall, back

Reproducible With exertion With inspiration

Associated symptoms Present Absent

Palpation of chest wall Not painful Painful, exactly reproduces pain complaint

Adapted from Zink BJ: Angina and unstable angina. In Gibler WB, Aufderheide TP (eds): Emergency Cardiac Care. St. Louis, Mosby, 1994.

Table 78-1Clinical Characteristics of Classic Anginal Chest Discomfort

stratification for patients to properly determine their disposition (telemetry bed vs. intensive care unit), none of them are designed to identify patients who may safely be discharged home.

There are several nontraditional risk factors for coronary disease. Antiphospholipid syndrome, rheumatoid arthritis, human immunodeficiency virus (HIV),19 and particularly systemic lupus erythematosus (SLE) are associated with a higher risk of cardio-vascular disease.20 Women with SLE who are 35 to 44 years of age are over more than 50 times more likely to have an MI than a similar age- and gender-matched Framingham population.21

The Classic History

The term angina refers to “tightening,” not pain. Classic angina pectoris may not be pain at all but rather a “discomfort,” with a “squeezing,” “pressure,” “tightness,” “fullness,” “heaviness,” or “burning” sensation. Classically, it is substernal or precordial in location and may radiate to the neck, jaw, shoulders, or arms. If the discomfort does extend down the arm, it classically involves the ulnar aspect. Discomfort in the left chest and radiation to left-sided structures is typical, but location and radiation to both sides or to only the right side may be consistent with angina. Radiation of the discomfort to the right arm or shoulder, or to both arms or shoulders, exceeds radiation to the left arm or shoulder in terms of likelihood of the chest pain being caused by ACS, although all exceed a positive likelihood ratio of 2.22,23

Furthermore, classic features of angina pectoris include exacer-bation with exertion, a heavy meal, stress, or cold, and alleviation with rest. The onset of pain at rest in no way excludes the diagnosis of angina. Anginal discomfort characteristically lasts from 2 to 5 minutes up to 20 minutes, and it is rare for it to last only a few seconds or to endure for hours or incessantly, “all day” (Table 78-1).

Symptoms characteristically associated with angina pectoris, or other entities of ACS, include dyspnea, nausea, vomiting, dia-phoresis, weakness, dizziness, excessive fatigue, or anxiety (Table 78-2). If these symptoms arise, either alone or in combination, as a presenting pattern of known ischemic coronary disease, they are termed anginal equivalent symptoms. Recognition that coronary ischemia may arise with an anginal equivalent rather than a classic symptom is the key to understanding the atypical presentation of ACS. Complaints of “gas,” “indigestion,” or “heartburn” in the absence of a known history of gastroesophageal reflux disease, or if the heartburn is different from the patient’s usual gastroesopha-geal reflux, or reproducible pain on abdominal palpation should raise suspicion of ACS. Gastroesophageal reflux disease is a common misdiagnosis in cases of missed ACS.


SYMPTOM BAYER ET AL*† TINKER‡URETSKY

ET AL§ PATHY||

Typical

Chest pain 515 51 75 75

Atypical

Dyspnea 118 19 14 77

Syncope 72 4 1 27

Confusion 46 1 51

Stroke 32 6 26

Fatigue 36 2 4 10

Nausea or emesis 28 1 10

Sudden death 31 31

Giddiness 18 3 22

Diaphoresis 18 2

Arterial embolus 3 19

Palpitation 4 14

Renal failure 11

Pulmonary embolus

8

Restlessness 4

Abdominal pain 5

Arm pain only 1

Cough 1

Silent

No symptoms

Total 777* 87¶ 102** 387¶

Adapted from Scott PA, Gibler WB, Dronen SC: Acute myocardial infarction presenting as flank pain and tenderness: Report of a case. Am J Emerg Med 9:547, 1991.*Patients able to report multiple symptoms; therefore total exceeds 777.†Bayer AJ, et al: Changing presentation of myocardial infarction with increasing age. J Am Geriatr Soc 34:263, 1986.‡Tinker GM: Clinical presentation of myocardial infarction in the elderly. Age Ageing 10:237-240, 1981.§Uretsky BF, Farquhar DS, Berezin AF, et al: Symptomatic myocardial infarction without chest pain: Prevalence and clinical course. Am J Cardiol 40:498-503, 1977.||Pathy MS: Clinical presentation of myocardial infarction in the elderly. Br Heart J 29:190-198, 1967.¶Patients classified by principal symptom, although all patients with complaint of chest or epigastric discomfort were placed in typical group.**Same as ¶, except patients with epigastric complaints were placed in atypical group.

Table 78-2Symptoms of Acute Myocardial Infarction: Typical and Atypical

The Atypical History

A description of typical symptoms (crushing, retrosternal chest pain or pressure) is often lacking in ACS; this may be a result of atypical features of the pain (e.g., character, location, duration, exacerbating and alleviating factors) or the presence of anginal equivalent symptoms (e.g., dyspnea, nausea, vomiting, diaphore-sis, indigestion, syncope). Patients with an ultimate diagnosis of AMI or UA can have pain that is pleuritic, positional, or repro-duced by palpation. Some patients describe their pain as burning or indigestion, sharp, or stabbing (see Table 78-2).23,24

In a large study of nearly 435,000 patients ultimately diagnosed with AMI, one third did not have chest pain on presentation.25 Multiple studies have identified risk factors for atypical pre-sentation of ACS: diabetes mellitus, older age, female gender, nonwhite ethnicity, dementia, no prior history of MI or

hypercholesterolemia, no family history of coronary disease, and previous history of congestive heart failure (CHF) or stroke.25-27 In patients with AMI or UA, atypical presenting complaints include dyspnea, nausea, diaphoresis, syncope, or pain in the arms, epigastrium, shoulder, or neck.

Atypical features of ACS are present with increasing frequency in sequentially older populations. Before age 85, chest pain is found in the majority of patients with acute MI, although dyspnea, stroke, weakness, and altered mental status are notably present. In those older than 85 years, however, atypical symptoms are more common than chest pain, with 60 to 70% of patients older than 85 having an anginal equivalent complaint, especially dyspnea.27 Coincident ACS is more likely to occur in the elderly; patients with another acute condition (e.g., trauma, infection) should be scru-tinized for concurrent ACS.28

Patients with diabetes mellitus are at heightened risk for ACS as well as an atypical presentation, such as dyspnea, nausea or vomiting, confusion, or fatigue. Medically unrecognized AMI can occur in 40% of patients with diabetes mellitus compared with 25% of a nondiabetic population, and myocardial scar unaccom-panied by antemortem diagnosis of MI is three times more likely in diabetics.29

As with age and diabetes, female gender is an important risk factor for MI without chest pain. In some series, less than 60% of women reported chest discomfort at the time of their MI, with others reporting dyspnea, indigestion, or vague symptoms, such as weakness, unusual fatigue, cold sweats, sleep disturbance, anxiety, or dizziness.30

Finally, nonwhite racial and ethnic populations may have atypi-cal symptoms in ACS.25 Compelling data demonstrate a disparity in treatment approach related to race in patients with acute mani-festations of coronary heart disease.31 Whether this is related to the atypical nature of presenting symptoms in different racial groups is not clear. Although certain features of the chest pain history serve to increase or decrease the likelihood of ACS, none of them is strong enough to endorse discharge of the patient based on the history alone.24

Physical Examination

The physical examination focuses on the cardiac, pulmonary, abdominal, and neurologic examinations, looking for signs of complications of ACS as well as alternative diagnoses for chest pain and the anginal equivalent syndromes (Table 78-3). Altered mental status, diaphoresis, and signs of CHF are all ominous find-ings in patients with symptoms consistent with ACS. Historical studies using untrained physicians identified chest wall tenderness

Acute myocardial infarction Unstable angina

Stable angina Prinzmetal’s angina

Pericarditis Myocardial or pulmonary contusion

Pneumonia Pulmonary embolism

Pneumothorax Pulmonary hypertension

Pleurisy Aortic dissection

Boerhaave’s syndrome Gastroesophageal reflux

Peptic ulcer disease Gastritis or esophagitis

Esophageal spasm Mallory-Weiss syndrome

Cholecystitis or biliary colic Pancreatitis

Herpes zoster Musculoskeletal pain

Table 78-3Key Entities in the Differential Diagnosis of Chest Pain


Cardiogenic shock is hypotension with end-organ hypoperfu-sion resulting from decreased cardiac output that is unresponsive to restoration of adequate preload. Patients at risk include those with large infarcts, prior MI, low ejection fraction on presentation (<35%), older age, and diabetes mellitus. Although some differen-tial diagnoses can usually be reasonably excluded (e.g., sepsis, anaphylaxis, adrenal crisis, and hypovolemic or hemorrhagic states), other causes of shock with similar presentations should be considered, such as aortic dissection, pulmonary embolism (PE), pericardial tamponade, and ventricular free wall rupture accom-panying acute MI. Adjunctive diagnostic measures include bedside echocardiography and invasive hemodynamic monitoring, with the latter demonstrating systemic hypotension, low cardiac output, elevated filling pressures, and increased systemic vascular resis-tance. Therapeutic measures include vasopressor and inotropic support, intra-aortic balloon counterpulsation, and early revascu-larization; fibrinolytic therapy does not decrease mortality in car-diogenic shock.

Left ventricular free wall rupture is uncommon. Approximately one third of cases occur in the first 24 hours, and the remainder occur 3 to 5 days after transmural MI. Clinically, free wall rupture may occur with sudden death, pulseless electrical activity, or pre-cipitous deterioration in the presence of AMI. Subacute presenta-tions include agitation, chest discomfort, and repetitive vomiting. Signs of pericardial effusion on the ECG or echocardiogram are suggestive of the diagnosis in the setting of acute or recent MI. Free wall rupture is almost universally fatal, although prompt diagnosis followed by emergent surgical intervention may rarely be lifesaving; pericardiocentesis is indicated as an immediate tem-porizing intervention.

Rupture of the interventricular septum may also occur; it may arise similarly to cardiogenic shock and free wall rupture of the ventricle. The clue to this diagnosis on physical examination is the development of a new, harsh, loud holosystolic murmur heard best at the left lower sternal border. The diagnosis can be con-firmed by echocardiography with color flow Doppler imaging. The presentation of acute, catastrophic deterioration with a new, harsh systolic murmur should prompt immediate cardiac surgery consultation for repair of a septal defect or ruptured papillary muscle of the mitral valve. Medical therapy including vasopressor and inotropic support, as well as intra-aortic balloon counterpul-sation, is an important bridge to the definitive surgical treatments of valve repair or replacement.

Pericarditis, when associated with AMI, can occur early or in a delayed fashion; the former is termed infarct pericarditis, and the latter is known as post-MI syndrome or Dressler’s syndrome. Infarct pericarditis is associated with transmural insult and thus princi-pally involves the pinnacle of the infarct zone near the epicardium. Although the characteristic ST segment changes may be obscured by ST segment abnormalities related to the infarction itself, if they are evident, they are logically quite localized. Infarct pericarditis is a common cause of new chest pain in the first week after MI. This pain is characteristically pleuritic and worse in the supine position. Embolic complications are more common in patients with infarct pericarditis; linked to this is the higher rate of ven-tricular aneurysm development in this population.

Dressler’s syndrome, unlike infarct pericarditis, does not require transmural involvement. It is a relatively uncommon, late compli-cation occurring from 1 week to several months after the MI. Clinical features include fever, malaise, pleuropericardial pain, and at times the presence of a rub on cardiac auscultation. Labora-tory findings are highly nonspecific and include an elevated erythrocyte sedimentation rate and leukocyte count. The ECG may show ST segment–T wave findings of pericarditis, although as with infarct pericarditis, these changes may be overshadowed by the evolving changes of the recent MI. PR segment depression is a telltale clue. Pericardial or pleural effusions may be evident

or “reproducible” chest wall tenderness in up to 15% of patients ultimately diagnosed with AMI, but these data are highly suspect. The real incidence of truly reproducible chest wall tenderness (i.e., when the patient reliably identifies to the examiner that the pain produced on palpation is identical to the pain causing the patient’s presentation) in ACS is probably very small. It is suggested that patients with chest pain that is fully pleuritic, positional, or repro-ducible by palpation (the three Ps) are at low risk (yet not no risk) for ACS.22

Outcomes in Atypical Presentations

Not surprisingly, atypical presentation of patients with ACS is associated with a delay in diagnosis and poorer outcomes. In the Second National Registry of Myocardial Infarction (NRMI-2) study, patients with MI without chest pain were significantly more likely to die in the hospital (23 vs. 9% for patients with chest pain) and were more likely to experience stroke, hypotension, or heart failure that required intervention, possibly reflecting the older age and greater comorbidity in this group.25 Patients with atypical symptomatology seek medical care later and are less likely to receive standard therapies, such as aspirin, beta-adrenergic block-ers, heparin, fibrinolysis, and emergent reperfusion therapy.25 Patients 65 years of age or younger with NSTEMI have a 1% chance of dying during their hospitalization, but this risk is increased to 10% for patients ages 85 years and older.28

Missed Diagnosis of Acute Coronary Syndrome

Approximately 2% to 4% of patients with acute MI in the ED are discharged without diagnosis.32 Missed ACS is the mis-diagnosis that accounts for the largest amount of payment by emergency physicians in medical malpractice claims. Atypical presenting symptoms are an obvious causative consideration. Patients with undiagnosed ACS discharged from the ED are younger, more likely to be women or nonwhite, more likely to have atypical complaints, and less likely to have ECG evidence of acute ischemia.32,33 Among all patients with cardiac ischemia, women younger than 55 years seem to be at highest risk for inappropriate discharge. With respect to ECG findings, 53% of patients with missed AMI and 62% of patients with missed UA have normal or nondiagnostic ECGs. Finally, the risk-adjusted mortality ratio for all patients with acute cardiac ischemia is 1.9 times higher among nonhospitalized patients.32 Factors associ-ated with misdiagnosis of ACS in medical malpractice closed claims analysis include physicians with less experience who docu-ment histories less clearly, admit fewer patients, and misinterpret the ECG.

Early Complications of Acute Myocardial Infarction

Bradydysrhythmia and atrioventricular (AV) conduction block occur in 25 to 30% of patients with AMI; sinus bradycardia is most commonly seen.34-36 Symptomatic bradydysrhythmias in the first few hours after inferior AMI tend to be atropine responsive; con-duction abnormalities that appear beyond 24 hours of MI tend not to respond to atropine.37 Patients with AV block in the setting of anterior AMI tend to respond poorly to therapy and have a poor prognosis.

Tachydysrhythmias are quite common in the setting of AMI and may be atrial in origin (e.g., sinus tachycardia and atrial fibril-lation) or ventricular (e.g., ventricular tachycardia and fibrilla-tion). Not all require treatment, such as a compensatory sinus tachycardia in patients with AMI complicated by CHF. Primary ventricular fibrillation occurs in an estimated 4 to 5% of patients with AMI, with 60% of those cases occurring in the first 4 hours and 80% within 12 hours.


pseudoaneurysm of the femoral artery with hemorrhage into the thigh compartment or retroperitoneal area. The diagnosis is made based on a high degree of clinical suspicion in a patient with recent femoral artery cannulization. Physical examination find-ings, including extensive bruising in the thigh and bruits over the femoral artery, are suggestive; ultrasonography or CT of the thigh or retroperitoneal area can confirm the diagnosis.

DIAGNOSTIC INVESTIGATIONS

Electrocardiography

In the patient with chest discomfort or other symptoms suggestive of ACS, the 12-lead ECG helps establish the diagnosis and deter-mines candidacy for therapy and risk assessment. In the setting of STEMI, the ECG provides crucial data regarding the diagnosis—anatomically arrayed ST segment elevation of at least 1 to 2 mV in at least two leads. Furthermore, the ECG provides pivotal infor-mation regarding therapeutic intervention—ST segment elevation establishes candidacy for emergent reperfusion therapy, either fibrinolysis or PCI. Regarding risk assessment, a number of ECG findings, such as ST segment deviation, LBBB, left ventricular hypertrophy (LVH), and QT interval prolongation, indicate an increased cardiovascular hazard.

Other 12-lead ECG determinations include cardiac rhythm, evolution of the ACS event, response to therapy, and clinical infor-mation suggesting an alternative diagnosis. Of course, rhythm determination is quite important, particularly if a compromising dysrhythmia is present. Lastly, an alternative diagnosis, such as PE or acute myopericarditis, can be suggested by the ECG.

In ACS, morphologic changes may occur in the T wave, the ST segment, the QRS complex, and even the PR segment (e.g., ST segment depression in atrial infarction or infarct-related peri-carditis). Various rhythm disturbances also occur. Notably, the ECG may be normal or nonspecifically abnormal in the presence of ACS, including AMI. The ECG is limited by individual varia-tions in coronary anatomy and preexisting coronary disease (e.g., previous MI, collateral circulation, coronary bypass surgery) and because it does not view the posterior, lateral, and apical left ven-tricular walls well.37 In context, a single ECG is neither 100% sensi-tive nor 100% specific for AMI and reflects a single point in time.

Over-reliance on a normal or nonspecifically abnormal ECG in a sensation-free patient with anginal chest pain should be avoided. Patients with an initial nondiagnostic ECG who later develop AMI during that hospitalization are often sensation free or minimally uncomfortable on presentation. These patients frequently lack a past history of ischemic heart disease. Furthermore, the total elapsed time from chest pain onset in patients with normal ECGs does not assist in ruling out the possibility of AMI in patients with chest pain with a single ECG. Although the negative predictive value is quite high, it is not 100%, even up to 12 hours after the onset of the patient’s chest symptoms.41 The patient’s history of the event—and the physician’s interpretation of the history—is the most important diagnostic study.

Electrocardiographic Abnormalities in Acute Coronary Syndromes

The earliest electrocardiographic finding in AMI is the hyperacute T wave, which maintains its vector but becomes tall and peaked within minutes of the interruption of blood flow. It is usually broad based and slightly asymmetrical. The hyperacute T wave progresses to ST segment elevation in classic MI. This hyperacuity may not be appreciated on the initial ECG. The differential diag-nosis of the tall T wave includes hyperacute T waves of ischemia, hyperkalemia, benign early repolarization (BER), LVH, LBBB, and pericarditis (Fig. 78-1).

and can be serous or bloody. Echocardiography assesses pericar-dial fluid and risk of tamponade. The pericardial reaction is believed to be immune mediated, and treatment includes anti-inflammatory agents.

Stroke may also complicate AMI, most commonly ischemic or thromboembolic. The major predisposing mechanisms with a recent MI are embolization from left ventricular mural thrombus with decreased ejection fraction, embolization from the left atrial appendage with atrial fibrillation, and hypercoagulability with concomitant carotid arterial disease. The rate of stroke is higher in the setting of MI (0.9% tapering to 0.1% at day 28 after MI) than in control subjects (0.014%).38

Hemorrhagic stroke is an obvious concern in the patient under-going fibrinolytic therapy. The rate of hemorrhagic stroke with varying fibrinolytic agents is less than 1%, although the rate climbs in older patients. PCI lowers the overall risk of stroke compared with fibrinolytic therapy. Analysis of only fibrinolytic-eligible patients from the NRMI-2 database yields more than 24,000 patients treated with alteplase and more than 4000 who received primary angioplasty. The difference in stroke rate is highly signifi-cant (1.6% in the fibrinolytic group vs. 0.7% in the angioplasty group). Considering hemorrhagic strokes, the difference is again dramatic (1.0% in the fibrinolytic group vs. 0.1% in the angio-plasty group).39

Hyperglycemia in the setting of AMI may be viewed as a com-plication, as well as a complicating disease process in AMI. Hyper-glycemia is present in up to one half of all patients with STEMI, yet only one fifth to one fourth of those patients are recognized diabetics. Elevated glucose at the time of admission has indepen-dent negative implications for mortality rates in AMI patients. Although fasting blood sugar the day after presentation is a better predictor, an admission blood glucose level higher than 200 mg/dL is linked to similar mortality rates among diabetics and non-diabetics. There is a 4% mortality increase for nondiabetic patients for every 18-mg/dL elevation in blood glucose level. Hyperglyce-mia seems to induce a complex set of unfavorable cellular and biochemical circumstances, including negative effects on coronary flow and microvascular perfusion, as well as adverse effects on platelet function, fibrinolysis, and coagulation. Intravenous insulin therapy for glucose normalization is linked to improved outcomes in patients with STEMI as well as those in the medical intensive care unit. ACC/AHA guidelines acknowledge that tight control of blood glucose during and after STEMI decreases acute and 1-year mortality rates.40

Adverse events of ACS therapy should also be considered as potential complications, including hemorrhage associated with medications and resulting from invasive procedures. The various antiplatelet, anticoagulant, and fibrinolytic therapies (as noted earlier) are all associated with hemorrhage as a major complicat-ing issue. In fact, within a single class of medications, many of these agents are so similar in efficacy that superiority is deter-mined by the rate of occurrence of adverse effects. Aggressive supportive care coupled with “antidote” therapy is the most appropriate approach to patients with hemorrhagic complication from medications. Protamine can be helpful in the reversal of the heparins. Fresh frozen plasma (FFP) and platelet infusions are of value in certain anticoagulant and antiplatelet scenarios. The low-molecular-weight heparins (LMWHs) cannot be reversed. Fibri-nolytic agents also cannot be reversed; rather, therapy including FFP and packed red blood cell (PRBC) transfusions is most appro-priate. These various antidotal agents should be considered only with life-threatening hemorrhage. The clinician at the bedside, who can evaluate the risks and benefits of these treatments in the setting of a complicated ACS event, is in the best position to determine management strategies.

Procedural complications include arterial injury with hemor-rhage related to percutaneous interventions; the most typical is a


As the AMI progresses, ST segment elevation may become evident. Morphologic variations of ST segment elevation can be seen from the J (or junction) point at the end of the QRS complex to the apex of the T wave. This upsloping portion of the ST segment usually progresses as it elevates from flat to convex, domed or “tombstoned”; if flat, it is characteristically horizontal or oblique. At times the ST segment may be concave or scooped in its elevation with AMI.42 This morphology may progress to a convex shape or may stay the same throughout the infarction. The concave morphology, if noted in all elevated ST segments, is atypi-cal for AMI and more commonly seen with other ST segment elevation syndromes (Table 78-4 and Fig. 78-2).43,44

ST segment elevation is measured in millimeters; one block on the ECG tracing is equivalent to 1 mm in height. The baseline is

Figure 78-1. Hyperacute T wave of acute myocardial infarction. A, Note the broad, tall T waves in leads V3 and V4 in this patient with chest pain and diaphoresis. These are the hyperacute T waves of early ST segment elevation myocardial infarction. The ST segment is just beginning to rise in leads V3 and V4; leads V1 and V2 are also suspicious. B, This tracing is from the same patient, roughly 30 minutes after the electrocardiogram in A. Note the prominent ST segment elevation in leads V1 to V4.

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5

A

B

Acute myocardial infarction Acute pericarditis

Left ventricular hypertrophy Left ventricular aneurysm

Ventricular paced rhythm Benign early repolarization

Normal variant Osborn wave of hypothermia

Hyperkalemia Brugada’s syndrome

Pulmonary embolism Acute cerebral hemorrhage

Prinzmetal’s angina Postelectrical cardioversion

Table 78-4Differential Diagnosis of ST Segment Elevation on the Electrocardiogram

usually considered to be the TP segment, although some clinicians advocate use of the terminal point of the PR segment. In general, the most definable, constant baseline evident on the ECG should be used.

ST segment elevation, both benign and pathologic, is common (see Table 78-4). Most normal ECGs, especially those of men, may have some degree of ST segment elevation—indeed, upward of 90%. This elevation is seen in the precordial leads and is usually 1 mm or more in men and 1 mm or less in women. The ST segment elevation is concave and is more prominent as the cor-responding S wave becomes deeper. Because of the common occurrence of this finding, it is not a normal variant but rather a normal finding.44-47 A helpful point in differentiating normal ST segment elevation from the pathologic ST segment elevation of AMI is that the latter is a dynamic phenomenon; ECGs recorded sequentially over time with waxing and waning symptoms should demonstrate some fluctuation in the degree of ST segment devia-tion in the presence of ACS.

ST segment depression generally represents subendocardial or noninfarction ischemia. Ischemic ST segment depression is typically horizontal or downsloping; an upsloping contour may be seen but is less frequently associated with ischemia. Sub-endocardial ischemic ST segment depression may be diffuse, spanning anterior and inferior leads. The differential diagnosis of ST segment depression includes myocardial ischemia or infarc-tion, repolarization abnormality of ventricular hypertrophy (the “strain” pattern), bundle branch block, ventricular paced rhythm (VPR), digoxin effect, hyperkalemia, hypokalemia, PE,


Figure 78-2. Analysis of ST segment–T wave morphology in acute myocardial infarction (AMI), benign early repolarization (BER), and acute pericarditis. An analysis of the ST segment–T wave morphology (from the beginning at the J point to the end at the apex of the T wave) may be particularly helpful in distinguishing among the various causes of ST segment elevation (STE) and identifying the AMI case. A, The initial upsloping portion of the ST segment is usually either flat (horizontally or obliquely) or convex in the patient with AMI. This morphologic observation, however, should be used only as a guideline; it is not infallible. B, Non-AMI causes of STE are seen here with concavity of the ST segment–T wave (left BER, middle pericarditis, right BER). C, Patients with STE related to AMI may demonstrate concavity of this portion of the waveform.

A

B

C

Figure 78-3. ST segment depression (STD) in acute coronary syndrome. A, Horizontal STD unstable angina pectoris (USAP). B, Horizontal STD (non–ST segment elevation [STE] acute myocardial infarction). C, Downsloping STD (USAP). D, Upsloping STD (USAP). E, Horizontal STD as seen in lead III in a patient with anterior wall acute myocardial infarction, an example of reciprocal STD, also known as reciprocal change.

A B

C D

E

intracranial hemorrhage, myocarditis, rate-related ST segment depression, postcardioversion of tachydysrhythmias, and pneu-mothorax (Fig. 78-3).

ST segment depression in ACS (1) may be seen in non–ST segment elevation AMI, (2) may precede ST segment elevation in

ST segment elevation AMI, (3) may reflect a “mirror image” of ST segment elevation from posterior MI when found in the right-sided precordial leads (i.e., ST segment depression in V1 to V3 in posterior MI), and (4) may represent reciprocal ST segment depression seen with ST segment elevation AMI. With reciprocal ST segment depression, such changes are seen in leads on the “opposite” side of the heart from simultaneous ST segment eleva-tion. For example, the ST segment depression seen in leads V1 to V3 with a posterior MI is actually a reciprocal finding resulting from the ST segment elevation that would be recorded in posterior leads V8 and V9. Inferior MI with ST segment elevation more frequently manifests reciprocal ST segment depression than does the anterior counterpart. The reciprocal ST segment depression in inferior MI is best seen in lead aVL, which is 150 degrees removed from lead III when the positive poles of these leads in the frontal plane are considered. Anterior ST segment elevation AMI may feature reciprocal ST segment depression in at least one of the inferior leads (II, III, or aVF). Reciprocal changes in the setting of STEMI increase the specificity and positive predictive value of the ECG in AMI.45,46

Ischemic ST segment depression is typically horizontal or downsloping; an upsloping contour may be seen but is less fre-quently associated with ischemia. Subendocardial ischemic ST segment depression may be diffuse, spanning anterior and inferior leads. The differential diagnosis of ST segment depression includes myocardial ischemia or infarction, repolarization abnormality of ventricular hypertrophy (the “strain” pattern), bundle branch block, VPR, digoxin effect, hyperkalemia, hypokalemia, PE, intra-cranial hemorrhage, myocarditis, rate-related ST segment depres-sion, postcardioversion of tachydysrhythmias, and pneumothorax (see Fig. 78-3).

T wave inversions, although frequently nonspecific, should suggest possible myocardial ischemia. Normally the T wave is upright in the left-sided leads I, II, and V3 to V6 and inverted in the right-sided lead aVR. T wave vectors are variable in leads III, aVL, and aVF. They are usually normally inverted in V1 and are occasionally normally inverted in lead V2. The T wave inversions of ACS are classically narrow and symmetrically inverted. The preceding ST segment is typically isoelectric and may be bowed slightly upward or concave. Associated ST segment depression may occur. T wave inversions are best evaluated in comparison with the most recent prior ECG, given the multitude of normal variations (Fig. 78-4).


A notable subgroup of ischemic T wave inversions is associated with Wellens syndrome, which classically manifests with either deep symmetrical T wave inversions (type I) or biphasic T wave changes (type II) in the anterior precordial leads. The presence of biphasic T waves is suggestive of ischemic heart disease. Other electrocardiographic features include isoelectric or minimally elevated (<1 mm) ST segments and no precordial Q waves. This finding may manifest in the anginal or pain-free state and may or may not be accompanied by cardiac marker elevations, which is indicative of a lesion of the left anterior descending artery.

Although T wave inversion is sought as a harbinger of ACS, it can also occur as an evolutionary change after MI. In MI without culprit artery reperfusion, as the ST segments return to baseline the T waves may invert, although not particularly deeply. In hearts that are reperfused, T wave inversion may follow ST segment elevation, in either a biphasic or a deeply inverted mor-phology, an appearance much like the T wave changes of Wellens syndrome.48,49

The clinician must also consider pseudonormalization of the T wave as a potential electrocardiographic indicator of ACS. Pseudonormalization occurs when, during an acute episode of chest discomfort or anginal equivalent, an apparently normal-appearing T wave on the ECG replaces the “normally” inverted T wave that existed prior to the development of symptoms. The T wave assumes a normal appearance and may indicate ACS at this presentation.

The differential diagnosis of T wave inversion is broad and includes ACS, ventricular hypertrophy, bundle branch block, VPR, myocarditis, pericarditis, PE, pneumothorax, Wolff-Parkinson-White syndrome, cerebrovascular accident, hypokalemia, gastro-intestinal disorders, hyperventilation, persistent juvenile T wave pattern, and normal variants.

Q waves are generally representative of irreversible myocardial necrosis but are rarely the sole manifestation of AMI. Pathologic Q waves may emerge within the first hour of infarction but most commonly develop 8 to 12 hours into the infarction. It follows that ST segment elevation with concomitant Q waves does not preclude consideration of emergent reperfusion therapy. Q waves may persist after MI as enduring markers of previous infarction on the ECG; in some cases, however, Q waves disappear with time regardless of whether the infarcted territory was reperfused.

Anatomic Location of Acute Myocardial Infarction

The regional distribution of an AMI can be derived from noting the pattern of the various morphologic changes that are described (Table 78-5). Anterior infarctions are primarily evidenced by changes in the precordial leads V1 to V4 (Fig. 78-5). Septal involve-ment is reflected by changes in V1 and V2. Extension to the lateral

Figure 78-4. T wave inversions of acute coronary syndrome (ACS). A and B, T wave inversions in patients with ACS. C, T wave inversion in a patient with non-–ST segment elevation (STE) acute myocardial infarction. D, Deeply inverted T waves in a patient with proximal left anterior descending artery stenosis, Wellens syndrome.

A

B

C

D

LOCATION LEADS ST SEGMENT

Anterior wall MI V1 through V4 Elevation

Lateral wall MI I, aVL, V5, and V6 Elevation

Inferior wall MI II, III, and aVF Elevation

Right ventricular wall MI V4R Elevation

Posterior wall MI V8 and V9 ElevationV1 through V3 Depression

Adapted from Aufderheide TP, Brady WJ: Electrocardiography in the patient with myocardial ischemia or infarction. In Gibler WB, Aufderheide TP (eds): Emergency Cardiac Care. St. Louis, Mosby, 1994.MI, myocardial infarction.

Table 78-5Regional ST Segment Changes in Acute Myocardial Infarction

wall (i.e., anterolateral MI) is evident if the pathologic changes extend beyond leads V1 to V4 to include leads V5, V6, I, and aVL. In anterior ST segment elevation AMI, reciprocal ST segment depression may occur in leads III and aVF. The anterior wall is served by the left anterior descending artery. The first diagonal branch of the left anterior descending artery is likely to be involved when the ST segment elevation extends to leads I and aVL. Isolated occlusion of the diagonal branch of the left anterior descending artery displays similar findings, but of smaller amplitude, to those seen with left anterior descending artery occlusion (ST segment elevation in leads V2 and V3, and possibly leads V1 and V4, or both, along with ST segment depression in lead II and either III, aVF, or both).50

Lateral infarctions are frequently seen in concert with anterior infarction (anterolateral), inferior infarctions (inferolateral), or inferior infarctions with posterior extension (inferoposterolat-eral). This is because the lateral wall of the heart is variably served by the left anterior descending, right coronary, and left circumflex coronary arteries. Thus lateral involvement is manifested by changes in some or all of the lateral leads I, aVL, V5, and V6. So-called “high lateral infarctions” are restricted to leads I and aVL (Fig. 78-6) and are suggestive of occlusion of the left circumflex coronary artery; ST segment elevation in these leads may be accompanied by reciprocal ST segment depression in leads III, aVF, and V1. Based on cardiac magnetic resonance imaging local-ization of some of these lesions, new Q waves appearing in leads I and aVL (but not V6) indicate a “mid-anterior wall MI,” previ-ously referred to as a “high lateral MI.”6

Inferior infarctions are characterized by morphologic changes in limb leads II, III, and aVF. The inferior wall of the heart and the


anterior ischemia during inferior infarction. ST segment elevation inferiorly that is greater in lead III than in lead II, accompanied by ST segment depression in lead aVL, I, or both, is 90% sensitive and 71% specific for right coronary artery occlusion.37 ST segment elevation in lead V1 in the presence of an ST segment elevation inferior MI (with elevation greater in lead III than in lead II) sug-gests concomitant right ventricular infarction. Coexistent recipro-cal change with inferior STEMI is associated with larger infarct size and increased mortality. Occlusion of the left circumflex

AV node are served by the right coronary artery in roughly 90% of cases (right dominant); in the remainder, the left circumflex artery serves that function (left dominant). An inferior ST segment elevation AMI is present if two or more contiguous inferior leads (III, aVF, II) are involved; reciprocal ST segment depression is frequently seen in lead aVL, lead I, or both (Fig. 78-7) and perhaps in the anterior precordial leads: V1 less than V2 and V3. ST segment depression in leads V1 to V3 in the presence of inferior MI can be caused by reciprocal change, posterior extension, or simultaneous

Figure 78-5. Anterior wall acute myocardial infarction (AMI). ST segment elevation is evident in leads V1 to V4. The morphology seems obliquely straight. Emergency cardiac catheterization revealed a 90% stenotic lesion in the left anterior descending artery; the patient did well after placement of a coronary stent but showed serum marker evidence of AMI.

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5

Figure 78-6. Anterolateral acute myocardial infarction. ST segment elevation is seen in leads I, aVL, V5, and V6. A proximal left anterior descending artery lesion with thrombus was noted at emergent percutaneous coronary intervention.

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5

Figure 78-7. Inferior acute myocardial infarction with reciprocal changes. Marked ST segment elevation is seen inferiorly (leads II, III, and aVF). Classic reciprocal ST segment depression is evident in leads I and aVL.

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5


Figure 78-8. Isolated posterior wall acute myocardial infarction (PMI); complexes from right precordial leads and posterior leads. The right precordial leads V1 and V2 reveal typical findings of PMI with prominent R wave (A), ST segment depression (STD) (B), and upright T wave (C). The posterior leads V8 and V9 in the same case demonstrate ST segment elevation (STE) (arrows), confirming isolated PMI.

RIGHT PRECORDIAL LEADS

POSTERIOR LEADS

V2

A

B

C

V1

AB

V8 V9

artery may be occult on the 12-lead ECG. If it is responsible for inferior ST segment elevation, the ST segment elevation in lead III would not be expected to exceed that seen in lead II, and lead aVL may display an isoelectric or elevated ST segment.37

Posterior infarctions are estimated to contribute to 15 to 20% of all AMIs and are usually seen along with inferior or inferolateral infarctions. Posterior infarctions occur in isolation in about 4% of AMI cases (demonstrating elevated ST segments only in acces-sory leads V7 through V9).6 The culprit lesion may be in the right coronary artery, its posterior descending branch, or the left cir-cumflex artery. In that the 12-lead ECG features no electrodes placed directly over the posterior wall of the heart, one has only the reciprocal ST segment changes in the right precordial leads (V1 to V3) with which to infer acute STEMI of the posterior wall. Findings include (1) horizontal ST segment depression; (2) a tall, upright T wave; (3) a tall, wide R wave; and (4) an R wave amplitude/S wave amplitude ratio greater than 1 (Fig. 78-8). The combination of horizontal ST segment depression with an upright T wave increases the diagnostic accuracy of the 12-lead ECG for posterior MI. In that the tall R wave in the right precor-dial leads is actually the mirror image of a posterior Q wave, its emergence may be delayed in posterior infarction. Additional leads (posterior leads V8 and V9) increase the sensitivity for detec-tion of acute posterior MI. Patients with inferior MI who have either ST segment depression in leads V1 to V3 or ST segment elevation in the posterior leads V8 and V9 generally have larger infarction zones, lower resultant ejection fractions, and higher cardiovascular morbidity and mortality than patients with iso-lated inferior MI.39 Cardiac magnetic resonance imaging suggests that these “posterior” infarctions producing tall R waves in leads V1 and V2 are actually lateral left ventricular wall MIs.6 A consen-sus document suggests reclassifying posterior infarctions as inferobasal infarctions.11

Right ventricular infarctions rarely occur in isolation and are usually associated with inferior or inferoposterior MI, although only about one third of inferior infarctions have associated infarc-tion of the right ventricle. At times, an anterior MI involves some (but less than half) of the right ventricular wall. It follows that occlusion in any of the major coronary arteries may lead to right ventricular infarction, although the right coronary is most

commonly involved. Clinically, right ventricular infarction fea-tures include elevated jugular venous pressure and hypotension in the setting of inferior wall MI. These findings, however, are also suggestive of pericardial tamponade. Nitrate-induced hypotension is also suggestive of right ventricular infarction, and of tampon-ade. Initial therapy for both would include volume loading and avoidance of vasodilators or other agents that may lower the blood pressure.

ST segment elevation in lead V1 in the setting of inferior MI (i.e., ST segment elevation in leads II, III, and aVF rather than in the setting of concomitant ST segment elevation in all anterior precordial leads) is suggestive of right ventricular infarction; this is not surprising in that lead V1 is the most rightward of the pre-cordial leads. These changes occasionally extend into lead V2 with right ventricular infarction. ST segment elevation is usually greater in lead III than in lead II when right ventricular infarction coexists with inferior AMI.51 This logically follows in that (in the frontal plane) the positive vector of lead III is more rightward than that of lead II. Application of “right-sided” precordial leads is the best means to diagnose right ventricular infarction with the ECG. These leads, as a mirror image of the left precordial leads, demon-strate ST segment elevation with right ventricular infarction in leads V3R to V6R, with V4R having the highest sensitivity. ECG changes in the right-sided precordial leads with right ventricular infarction may be subtle owing to the smaller muscle mass of the right ventricle and the resulting diminution in QRS size (Fig. 78-9). Patients with inferior MI with concomitant right ventricu-lar infarction have larger infarcts and experience more in-hospital complications and higher mortality rates.52

Left Main Coronary Artery Occlusion. In a patient with symptoms of ACS, ST segment elevation in lead aVR should prompt consid-eration of occlusion of the left main coronary artery. Pooled data demonstrate that ST segment elevation in lead aVR (>0.5 mV) is approximately 78% sensitive and 83% specific for left main coro-nary artery disease; alternatively, this finding in lead aVR may represent multivessel disease, acute proximal left anterior descend-ing occlusion, or (less commonly) left circumflex or right coro-nary occlusion.53 If ST segment elevation occurs in both lead aVR and lead V1, greater elevation in the former lead favors left main disease, whereas if it is greater in the latter lead, occlusion in the left anterior descending artery is more likely.54

Electrocardiographic Differential Diagnosis of ST Segment Elevation

ST segment elevation on the ECG in the context of a presentation compatible with ACS is considered to represent acute myocardial ischemia until proved otherwise. Several other conditions, par-ticularly LBBB and LVH, also feature ST segment elevation that mimics infarction (see Table 78-4).47 Caution is required when interpreting ST segment elevation as to the decision to administer systemic fibrinolytic therapy.55

Benign early repolarization is a normal electrocardiographic variant that does not imply, or exclude, ACS or CAD. BER includes the following electrocardiographic characteristics: (1) ST segment elevation; (2) upward concavity of the initial portion of the ST segment; (3) notching of the terminal portion of the QRS complex at the J point (i.e., junction of the QRS complex with the ST segment); (4) symmetrical, concordant T waves of large ampli-tude; (5) diffuse ST segment elevation on the ECG; and (6) relative temporal stability over the short term, although these changes may regress with old age. J point elevation is usually less than 3.5 mm, and the concave ST segment is usually elevated less than 2 mm (although it may be elevated as much as 5 mm in some cases) in the precordial leads and 0.5 mm in the limb leads. Maximal ST segment elevation in BER is typically seen in leads V2 to V5. Iso-lated BER in the limb leads is quite rare and should prompt


Figure 78-9. Right ventricular infarction demonstrated with right-sided precordial leads (RV1 to RV6). This tracing is taken from the same patient as in Figure 78-7. The ST segment elevation of inferior acute myocardial infarction is still present, as is the reciprocal ST segment depression in leads I and aVL. The precordial leads are right-sided chest leads, as might be inferred from the relatively low voltage. ST segment elevation is noted in leads RV3 to RV6 (V3R to V6R), consistent with right ventricular infarction.

I

II

aVR

aVL

III aVF RV3 RV6

RV1

RV2

RV4

RV5

Figure 78-10. Noninfarctional ST segment elevation (STE). A, Benign early repolarization (BER) with concave STE. B, Acute pericarditis with concave STE and PR segment depression (upper two examples); concave STE without PR segment abnormalities (lower left example); and “reciprocal” STD and PR segment elevation in lead aVR (lower right example).

A

B

reconsideration of AMI (Figs. 78-10A and 78-11). Reportedly, 31% of predominantly white individuals younger than 60 years who are resuscitated after idiopathic ventricular fibrillation have early repolarization changes in the inferolateral leads, as opposed to only 5% in a well-matched cohort of patients without syncope or heart disease. Whereas significant malignant dysrhythmias may occur in patients with this electrocardiographic finding, there are many who do well over a lifetime.56

Pericarditis, in the acute phase, features diffuse ST segment elevation as well. In pericarditis the ST segments are concave with an initial upsloping contour and are usually less than 5 mm in height. Occasionally the initial contour is obliquely flat, but convex or domed ST segment morphology is suggestive of AMI. The ST segment elevation is usually seen in all leads with the exception of aVR (where it is depressed); V1 is variable. Focal pericardial inflammation manifests as a more accentuated change in the leads

reflecting the affected region. PR segment depression is an insensi-tive yet specific associated electrocardiographic finding in pericar-ditis, which is typically best seen in the inferior leads and in lead V6; correspondingly, PR segment elevation may be evident in lead aVR (Fig. 78-12; see Fig. 78-10B). In that ST segment changes are encountered in such patients, the most appropriate term applied is myopericarditis, rather than pericarditis. Recall that the pericar-dium is electrically silent; thus, electrocardiographic changes result from epicardial irritation and ST segment elevation—hence the term myopericarditis.

Left ventricular aneurysm (LVA), wherein a focal area of myo-cardium paradoxically bulges outward during systole, has charac-teristic electrocardiographic changes that can be difficult to differentiate from those of AMI. Considerable overlap exists between populations of patients with potential for AMI and LVA, and the electrocardiographic changes of LVA tend to be regional rather than diffuse.56 Anatomically, LVA is most commonly found anteriorly, and changes are most often seen in leads V1 to V6 as well as leads I and aVL. ST segment elevation may be of any mor-phology (e.g., convex or concave), and Q waves may be present (Fig. 78-13). The calculation of the ratio of the amplitude of the T wave to the QRS complex may help distinguish acute anterior MI from LVA. If the ratio of the amplitude of the T wave to the QRS complex exceeds 0.36 in any single lead, the ECG probably reflects acute MI. If the ratio is less than 0.36 in all leads, however, the findings are probably a result of ventricular aneurysm.57

Left bundle branch block is a confounding pattern that reduces the ECG’s ability to detect ACS. A new, or presumably new, LBBB is strongly suggestive of ACS when noted in the appropriate clini-cal presentation. Preexisting LBBB, however, shares many similari-ties to various electrocardiographic findings of ACS. In the right precordial leads (leads V1 to V3), ST segment elevation and tall, vaulted, upright T waves mimic those seen in acute anterior MI. The QS pattern of LBBB in these leads resembles the Q waves seen in infarction. Depressed ST segments with T wave inversions are seen in some or all of the lateral leads (leads V5, V6, I, and aVL) in LBBB; both of these resemble ischemic changes seen in ACS. Yet these findings in LBBB are merely expressions of the “rule of appropriate discordance.” The ST segment and T wave vectors are expectedly discordant, or opposite in direction, to the major vector of the QRS complex in those leads. Because LBBB is a fre-quent finding on the ECG of a patient at risk for CAD, the normal findings in LBBB (Fig. 78-14) and the presentation of ST segment AMI in a patient with LBBB must be distinguished.

Sgarbossa used the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial database to


Figure 78-12. Pericarditis. This tracing demonstrates several classic signs of pericarditis: (1) sinus tachycardia; (2) diffuse, concave upward ST segment elevation; (3) PR segment depression, best seen in lead II; and (4) PR segment elevation in lead aVR.

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5

Figure 78-13. Left ventricular aneurysm: representative example of 12-lead electrocardiogram from patient with anterior left ventricular aneurysm. Note well-developed, completed Q waves in leads V2 through V5 and absence of reciprocal changes in contralateral leads. (Adapted from Aufderheide TP, Brady WJ: Electrocardiography in the patient with myocardial ischemia or infarction. In Gibler WB, Aufderheide TP [eds]: Emergency Cardiac Care. St. Louis, Mosby, 1994, p 196-216.)

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5

Figure 78-11. Benign early repolarization. Note the upwardly concave ST segment elevation, best seen in leads V4 to V6. The T waves are relatively large in the same leads. Subtle notching is also seen at the J point in leads V4 and V5. Prior electrocardiograms of this patient were unchanged.

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5


(3) ST segment depression of at least 1 mm in lead V1, V2, or V3 (Fig. 78-16).60

Left ventricular hypertrophy may mimic or obscure ACS on the ECG. LVH may feature prominent left-sided forces, manifesting as large rS or QS complexes in the right precordial leads—yet these changes seldom extend beyond V1 and V2 in the case of LVH. Consistent with the rule of appropriate discordance, the leads demonstrating such a pattern feature discordant ST segment elevation and tall, vaulted T waves, paralleling the changes of AMI. The initial portion of the elevated ST segment in LVH is generally concave, as opposed to the obliquely straight or convex pattern that usually (but not always) is seen with ST segment elevation in AMI. In LVH, the left precordial leads (and at times leads I and aVL) may show evidence of repolarization abnormal-ity (or strain pattern), with ST segment depression and asym-metrically inverted T waves. The presence of this strain pattern in the left precordial leads is reassuring when ST segment elevation and tall T waves in the right precordial leads are being attributed to LVH rather than to AMI because one is essentially the mirror image of the other. The changes in LVH should be static over time (Fig. 78-17).

Takotsubo cardiomyopathy is referred to as left apical ballooning or “broken heart” syndrome. Takotsubo cardiomyopathy features ST segment elevation (or deep T wave inversions) without evi-dence of obstructive CAD. Positive serum markers for cardiac ischemia may be present, as well as hemodynamic compromise. It occurs principally in postmenopausal women and characteristi-cally is triggered by intense emotional stress. Ballooning of the left ventricular apex is seen on ventriculography or echocardiography. Prognosis is excellent, typically with recovery of normal wall motion within a month or less.6,60

Non–ST Segment Elevation Myocardial Infarction

Non–ST segment elevation myocardial infarction supplants non–Q wave MI, previously termed subendocardial infarction. Precise ter-minology is difficult because Q waves may disappear with time and the criteria for “significant” Q waves vary. Moreover, transient ST segment elevation may simply be missed on ECG. Nonetheless, it is useful to describe the entity wherein there is serum marker evidence of MI in the appropriate clinical scenario but no cap-tured ST segment elevation.

Pathophysiologically, total occlusion of the diseased artery may not have occurred, or the infarct zone may have been partially spared by collateral circulation or therapeutic intervention. ECG manifestations of NSTEMI include ST segment depression and T wave inversion, which may be deep and symmetrical. Absence of

obtain a population of patients with LBBB and enzymatic evi-dence of AMI.58 Three independent electrocardiographic predic-tors of MI in the presence of LBBB were identified: (1) ST segment elevation of at least 1 mm that is concordant with the QRS complex; (2) ST segment depression of at least 1 mm in lead V1, V2, or V3; and (3) ST segment elevation of at least 5 mm that is discordant with the QRS complex. These findings were assigned weighted scores of 5, 3, and 2, respectively. For accuracy in diag-nosis, a specificity of 90% requires a score of at least 3. Thus if an ECG features only discordant ST segment elevation of 5 mm or more but neither of the other two criteria, further testing is recom-mended before one can conclude that the ECG is indicative of AMI (Fig. 78-15).58 Subsequent literature yields mixed reviews of the Sgarbossa criteria for diagnosis of AMI in the presence of LBBB.58,59 Ultimately the approach to the patient with LBBB and possible MI remains complicated; diagnostic adjuncts to the history and physical examination (e.g., serial ECGs, comparison with prior ECGs, echocardiography, serum cardiac marker mea-surement) should be liberally used when the ECG does not show obvious evidence of AMI as noted by the Sgarbossa criteria.58 A new LBBB, together with a clinical impression of AMI, remains an indication for fibrinolytic therapy or PCI.

Ventricular paced rhythms can mimic and mask the manifesta-tions of AMI. VPRs originating in the right ventricular apex create a wide QRS complex, with a pseudo-LBBB pattern. As with LBBB, the right precordial leads in VPR typically feature predomi-nantly negative QRS complexes with discordant ST segments and T waves that are elevated and tall or vaulted, respectively. Unlike LBBB, however, VPR originating in the right ventricular apex often yields a predominantly negative QRS complex in leads V5 and V6 as well (which is oriented leftward and slightly downward, whereas the impulse generated from the pacemaker wire is ori-ented superiorly). Furthermore, small vertical pacemaker spikes immediately preceding the QRS complex should be a clue to VPR, although these deflections are at times hard to detect on the 12-lead ECG.

Limited data exist to guide the clinician in interpretation of the 12-lead ECG in this setting. As with the LBBB scenario, the VPR pattern represents a significant confounding variable in the evalu-ation of the patient with chest pain suspected of having ACS. Sgarbossa and associates advanced criteria for detection of AMI in the presence of VPR that are similar to those for LBBB.58,60 These, too, are derived from the GUSTO-I database, but from a smaller group of patients. The criteria are essentially the same as the LBBB criteria: (1) ST segment elevation of at least 5 mm that is discordant with the QRS complex; (2) ST segment elevation of at least 1 mm that is concordant with the QRS complex; and

Figure 78-14. Left bundle branch block (LBBB) (normal). This tracing demonstrates the classic findings of LBBB: (1) QRS complex width greater than 0.12 second; (2) absence of Q wave in lead V6; (3) broad monophasic R wave in leads V5, V6, I, and aVL; (4) discordant ST segment–T wave changes in leads V1 to V3 (simulating acute myocardial infarction), I, and aVL. A first-degree atrioventricular block is also apparent.

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5


Figure 78-15. Acute myocardial infarction (AMI) in left bundle branch block (LBBB). A, Using the Sgarbossa criteria,58 there is strong evidence of AMI because of the concordant ST segment elevation greater than 1 mm in leads II, V5, and V6; also suggestive is the ST segment depression seen in V2. B, Again, applying the Sgarbossa criteria to this tracing with underlying LBBB, AMI is strongly suggested.58 There is concordant ST segment elevation in leads V5 and V6 that appears to exceed 1 mm; furthermore, there is excessively discordant ST segment elevation in leads V2 and V3, probably greater than 5 mm.

II aVL

III

B

aVF V3 V6

V2 V5

I

II

II

A

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5


Figure 78-16. Permanent right ventricular paced pattern with acute myocardial infarction (AMI); ventricular paced rhythm. A, Appropriate ST segment–T wave findings in the patient with a paced rhythm. B, Serial electrocardiogram from the patient in A, revealing evolution of changes worrisome for AMI, including concordant ST segment elevation in leads I and aVL consistent with lateral wall AMI.

aVR

II aVL V2 V5

III aVF V3 V6

I aVR V1 V4

V1 V4I 1653

1723

II aVL V2 V5

III aVF V3 V6

A

B


Electrocardiographic Adjuncts in the Diagnosis of Acute Coronary Syndrome

Additional lead ECGs can increase sensitivity for AMI by evaluat-ing regions of the heart prone to electrical silence on the 12-lead tracing. Most commonly, additional lead ECGs use posterior (leads V8 and V9) and right ventricular (V4R) electrodes, thus constituting the 15-lead ECG (Fig. 78-18). Posterior leads V8 and V9 are placed under the tip of the left scapula and at the left para-spinal area, at the same level as leads V4 to V6. Morphologic

STEMI, however, does not necessarily translate to better outcomes. A study analyzing more than 250,000 AMI patients from the NRMI-2, NRMI-3, and NRMI-4 databases determined that patients with ST segment depression on the initial ECG have an in-hospital mortality rate of 15.8%—similar to that of patients with ST segment elevation or LBBB (15.5%).61 ST segment depres-sion may herald true posterior infarction on the 12-lead ECG. Acute posterior (inferobasal) MI is one entity wherein emergent fibrinolysis or PCI is indicated in the absence of ST segment eleva-tion on the 12-lead ECG.

Figure 78-17. Left ventricular hypertrophy (LVH) with repolarization abnormality. This tracing demonstrates classic repolarization abnormality, with ST segment depression in the left-sided precordial leads following large-amplitude R waves. The T waves in these leads are asymmetrically inverted. The right precordial leads (V1 and V2) show a mirror image of the changes seen in V3 to V6, with slight ST segment elevation (contour initially concave) and asymmetric tall T waves. See Figure 78-20B for evidence of evolving acute myocardial infarction in a patient with LVH and repolarization abnormality.

I

II

aVR

aVL

III aVF V3 V6

V1

V2

V4

V5

Figure 78-18. Fifteen-lead electrocardiogram (ECG) with inferior, lateral, posterior, and right ventricular acute myocardial infarction (AMI). The standard 12-lead ECG reveals the typical ST segment elevation (STE) in the inferior and lateral leads as well as ST segment depression (STD) with prominent R wave in the right precordial leads. Posterior AMI is indicated by both the right precordial STD with prominent R wave and the STE in posterior leads V8 and V9. Note that the degree of STE is less pronounced than that seen in the inferior leads because of a relatively longer distance from the posterior epicardium to surface leads. The right ventricular infarction is noted in this case, using the simplified approach with only RV4, which demonstrates STE of relatively small magnitude.

aVR

II aVLV5

III aVFV6

V1

V1

V1

V8

V9

V4

RV4

I


Figure 78-19. Schematic of thorax depicting single anterior and posterior complexes in posterior wall acute myocardial infarction (AMI). The standard electrocardiographic precordial (anterior) leads image the posterior wall of the left ventricle from the anterior perspective of the thorax. Acute infarction of this region manifests electrocardiographic changes that are frequently the reverse of the typical abnormalities of AMI. In this schematic example, lead V1 reveals ST segment depression with an upright T wave and prominent R wave. Use of the posterior lead V9 demonstrates ST segment elevation, consistent with AMI.

V1V9

Isolated acuteposterior wall MI

PosteriorAnterior

Figure 78-20. Serial electrocardiography. A, Representative example of lead III in a patient with chest pain and an initially nondiagnostic electrocardiogram depicting the evolution of ST segment elevation (STE) acute myocardial infarction (AMI). B, Representative example of lead V2 in a patient with the left ventricular hypertrophy pattern. Serial sampling of this patient with ongoing chest pain and a confounding electrocardiographic pattern reveals the progression to STE AMI. C, Representative example of lead V3 in a patient with left bundle branch block and evolving AMI. D, Representative examples of lead III in a patient with chest pain and noninfarctional STE; note the lack of change (degree of elevation as well as morphology of elevation) over time in this patient with benign early repolarization.

0713 0726 0739 0756

0456 0516 0642

Lead III

Lead V2

2315 2329 2347 2358 0008

A

B

C

D

1315 1321 1332

Lead V3

Lead III

changes in the posterior leads may be subtle, principally because of the increased distance between these electrodes and the poste-rior wall of the heart (Fig. 78-19).

Electrocardiographic imaging of the right ventricle is enhanced with the use of the right-sided chest leads V1R to V6R (also termed RV1 to RV6). These are placed in mirror image fashion across the right precordium. Of the right precordial leads, V4R has the highest sensitivity for right ventricular infarction and is the lead of choice to include in the 15-lead tracing. Morphologically, less pronounced changes can be expected in the right-sided chest leads because of the relatively thinner wall of the right ventricle.

Use of the 15-lead ECG may improve diagnostic precision but does not appear to affect the rate of AMI diagnosis, use of reperfu-sion therapy, disposition, or outcome in patients with chest pain evaluated for ACS.62 In the subset of ED patients identified as candidates for admission to the cardiac care unit (i.e., high-risk patients), the 15-lead ECG increased the sensitivity of ACS detec-tion by 12%.63 Possible applications for additional lead ECGs include the following: (1) ST segment changes (depression or elevation) in leads V1 to V3, either in an isolated lead or in more than one; (2) equivocal ST segment elevation in the inferior (II, III, aVF) or lateral (I, aVL) limb leads or both; (3) all inferior STEMI; and (4) hypotension in the setting of ACS. Additional lead applications can be used, including the 18- and 24-lead ECG; electrocardiographic body mapping with use of multiple ECG leads, such as the 80-lead ECG, can also be used. In general, the clinician is able to image larger segments of the heart with more electrocardiographic leads in use. It is suggested that these addi-tional lead ECGs, including body mapping, can increase the rate of STEMI diagnosis and thus the number of patients who are candidates for emergent reperfusion therapy.

Serial ECGs and ST segment trend monitoring overcome the limitations of the snapshot 12-lead ECG. The use of increased electrocardiographic surveillance demonstrates diagnostic benefit in patients with recurrent or continuous chest pain, particularly in patients with an initially normal nondiagnostic or possible ST segment mimicking syndrome (e.g., ST segment elevation poten-tially resulting from BER) ECG. Examination of ST segment trends (measured every 20 seconds for at least the first hour) and automated serial ECGs (at least every 20 minutes) in ED patients with chest pain can significantly increase the sensitivity and speci-ficity for detection of AMI (16%) and ACS compared with the initial ECG (Fig. 78-20).64 In more than 600 patients admitted with nondiagnostic initial ECGs and symptoms consistent with ACS, 12 hours of continuous 12-lead ECG monitoring in a coro-nary care unit setting revealed that only serum cardiac marker


beta-adrenergic blocking therapy). Furthermore, the presence of CHF on the chest radiograph increases risk in AMI patients who may benefit from an aggressive therapeutic approach.

There is radiographic evidence of pulmonary congestion in approximately one third of AMI patients. AMI patients who develop CHF have increased mortality, as reported by the Killip classification. The chronicity of the CHF syndrome may also be suggested by the heart size. Patients with AMI complicated by pulmonary edema who have a normal heart size most often have no past history of CHF. In fact, AMI is the most frequent cause of pulmonary edema with a normal cardiac size. In other instances, patients with AMI and cardiomegaly with or without pulmonary edema frequently have a preexisting history of CHF, anterior wall infarct, and multiple-vessel CAD (Fig. 78-21).

Serum Markers

Biochemical markers play a pivotal role in the diagnosis, risk stratification, and guidance of treatment. The European Society of Cardiology and the ACC define the criteria for AMI diagnosis on biochemical grounds because specific markers, particularly the troponins, indicate irreversible cell damage.11 In the past, detection of AMI by characteristic enzyme elevations over 48 to 72 hours was sufficient to establish the diagnosis of AMI because there was essentially no specific therapy to reverse or prevent the developing myocardial necrosis. The evolution of fibrinolytic therapy and acute mechanical intervention has created significant pressure to identify patients with AMI rapidly.

For patients with a nondiagnostic ECG, early elevation of serum markers of myocardial necrosis confirms a presumptive diagnosis of NSTEMI. Caution is advised, however, when a single serum marker is not elevated. This single test is too insensitive to be used to support a decision that the patient can be discharged or to determine that no acute coronary event has occurred. The patient’s history remains the most vital portion of the diagnostic evaluation of potential ACS. Serial testing substantially improves the sensitiv-ity of these tests (Table 78-6 and Fig. 78-22).71

Troponins

Because of their superior sensitivity and specificity compared with other biochemical markers, cardiac troponins are the best markers for myocardial cell injury. Two myocardium-specific proteins, myocardial troponin I (TnI) and troponin T (TnT), precede the release of creatine kinase (CK-MB) into the serum. The cardiac troponins are genetically distinct from troponin forms found in other muscle tissue, rendering them highly cardiac specific. Mono-clonal antibodies have little cross-reactivity with troponins from skeletal muscle. TnI and TnT are very similar in their diagnostic and prognostic utility as well as their serum kinetics and rates of rise and fall associated with myocardial ischemia, infarction, and ACS.

The biokinetics of troponin release relate to the location of the protein within the cell. Normally, small quantities of troponins are free in the cytosol, and the majority is entwined in the muscle fiber. After injury a biphasic rise in serum troponins corresponds to early release of the free cytoplasmic proteins, followed by a slower and greatly prolonged rise with breakdown of the actual muscle fiber. The slow destruction of the myocardial cell contrac-tile proteins provides a sustained release of the troponins for 5 to 7 days. Serum troponin concentrations begin to rise measurably in the serum at about the same time as CK-MB elevations become detectable, as early as 3 hours after onset, but troponin levels remain elevated for 7 days or more.

The cardiac-specific troponins, determined serially, are highly sensitive for the early detection of myocardial injury. A positive test result is associated with significant risk, and serial negative

elevation and presence of ST segment episodes (defined as ST segment elevation or depression more than 1 mm different from baseline that endured for at least 1 minute) predict cardiac death or MI.65

Measuring QT dispersion may facilitate risk stratification, assessment of therapeutic success, and monitoring of ongoing pharmacotherapy. QT dispersion is the calculated difference between the longest and shortest QT intervals on a 12-lead ECG. Ischemic myocardium has a prolonged repolarization time, and the QT interval measures time from ventricular depolarization to repolarization. Increased variability in measured QT intervals translates to greater QT dispersion, which reflects underlying regional ischemia. Comparing ACS or AMI patients with those found to be free of such disease reveals a difference between popu-lations in QT dispersion values.

Body surface mapping increases the amount of electrocardio-graphic data for processing and decision-making. Whereas serial ECGs and ST segment trend monitoring increase the period of time over which data are collected on a 12-lead ECG, body surface mapping increases the number of electrodes used to gather data and increases the vantage points from which the heart is evaluated. Various devices use 40 to 120 leads. With an 80-electrode device, 64 chest and 16 back electrodes are applied in a vestlike fashion with self-adhering strips. Recording from all electrodes simultane-ously, the body surface map enters ST segment elevation and depression data into a computer, which transforms the data into a color-coded torso image. With red representing ST segment eleva-tion, blue signifying ST segment depression, and green reflecting normal, the degree of disease is also expressed in terms of color intensity.66-68 Body surface mapping may increase sensitivity for MI, especially in areas that are relatively electrically silent on the 12-lead ECG (e.g., posterior and lateral walls of the left ventricle and the right ventricle) and in patients with underlying LBBB.66-68 In the Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction (OCCULT MI) trial, the 80-lead ECG provided an incremental 27.5% increase in STEMI detection as compared with the 12-lead ECG. Patients with 80-lead ECG-only STEMI had adverse outcomes similar to those encoun-tered in the 12-lead STEMI patients, yet these individuals were treated much less aggressively.69

Limitations of Electrocardiography in Acute Coronary Syndrome

The sensitivity and specificity of a single ECG for AMI are approx-imately 60% and 90%, respectively. Serial ECGs in the setting of continued or recurrent pain increase the diagnostic utility.70 The initial ECG is nondiagnostic in approximately half of the patients in the ED who are ultimately diagnosed with AMI. Moreover, nondiagnostic and even normal ECGs do not exclude the diagno-sis for AMI because around 20% of patients ultimately diagnosed with AMI have nondiagnostic ECGs earlier in their course. As time elapses from symptom onset to ECG recording, the ability of the ECG to exclude AMI does not markedly increase.41 Thus a single normal or nondiagnostic ECG does not ensure absence of ACS, even if the ECG was recorded well after the onset of symptoms. In patients being evaluated for ACS, only serial electrocardiogra-phy, combined with serial cardiac marker determinations, can exclude AMI, and even then UA without actual myocardial necro-sis may be present.

Chest Radiography

The chest radiograph provides information concerning the appli-cation of therapies (e.g., an evaluation of mediastinal width in the consideration of fibrinolytic agent use and the determination of pulmonary congestion in the consideration of acute parenteral


Figure 78-21. Chest radiographs in patients with acute coronary syndrome. A, Cardiomegaly. B, Borderline cardiomegaly with pulmonary edema.

A B

TECHNOLOGYDISEASE STUDIED

NO. OF STUDIES (SUBJECTS)

PREVALENCE RANGE OF STUDIES, %

DISEASE SENSITIVITY,* % (95% CI)

DISEASE SPECIFICITY,* % (95% CI)

Creatine kinase (single) AMI 12 (3195) 7-41 37 (31-44) 87 (80-91)

Creatine kinase (serial) AMI 2 (786) 26-43 69-99 68-84

CK-MB (presentation) ACS 1 (1042) 20 23 96AMI 19 (6425) 6-42 42 (36-48) 97 (95-98)

CK-MB (serial) ACS 1 (1042) 20 31 95AMI 14 (11,625) 1-43 79 (71-86) 96 (95-97)

Myoglobin (presentation) AMI 18 (4172) 6-62 49 (43-55) 91 (87-94)

Myoglobin (serial) AMI 10 (1277) 11-41 89 (80-94) 87 (80-92)

Troponin I (presentation) AMI 4 (1149) 6-39 39 (10-78) 93 (88-97)

Troponin I (serial) AMI 2 (1393) 6-9 90-100 83-96

Troponin T (presentation) AMI 6 (1348) 6-78 39 (26-53) 93 (90-96)

Troponin T (serial) AMI 3 (904) 5-78 93 (85-97) 85 (76-91)

CK-MB and myoglobin combination (presentation)

AMI 3 (2283) 9-28 83 (51-96) 82 (68-90)

CK-MB and myoglobin combination (serial) AMI 2 (291) 11-20 100 75-91

Exercise stress ECG ACS 2 (312) 6-10 70-100 82-93

Rest echocardiography ACS 2 (228) 3-30 70 (43-88) 87 (72-94)AMI 3 (397) 3-30 93 (81-91) 66 (43-83)

Stress echocardiography AMI 1 (139) 4 90 89

Sestamibi (rest) ACS 3 (702) 9-17 81 (74-87) 73 (56-85)AMI 3 (702) 92 (78-98) 67 (52-79)

Adapted from Pope JH, Selker HP: Diagnosis of acute cardiac ischemia. Emerg Med Clin North Am 21:217, 2003.ACS, acute coronary syndrome; AMI, acute myocardial infarction; CI, confidence interval; CK-MB, creatine phosphokinase MB fraction; ECG, electrocardiogram.*Point estimate from a single study or a range of reported values; meta-analysis not performed.

Table 78-6Summary of Test Performance Studies of Diagnostic Technologies for Acute Coronary Syndrome in the Emergency Department


Figure 78-22. Serum marker sensitivity relative to the time of onset of chest pain in the patient with acute myocardial infarction. Data obtained from the medical literature. AMI, acute myocardial infarction; CK-MB, creatine phosphokinase MB fraction.

100

80

60

40

20

0

Sen

sitiv

ity fo

r A

MI

Hours from chest pain onsetin the AMI patient

1 2 3 4 5 6 7 8 9 10 11 12

CK-MB

Troponin T

Troponin I

Myoglobin

results predict low risk. A single troponin measurement on pre-sentation, however, has limited utility in excluding AMI and no ability to detect UA without infarction because cell injury is required and because of the time delay in the rise in levels (which may not be detected until 10 hours after symptom onset in some AMI patients).71 Serial measurements, particularly when per-formed at least 6 hours after symptom onset, markedly improve the sensitivity of the cardiac troponins for AMI, and the pattern of rise may assist in determining the acuity of the event. The sensitivity of TnT approaches 50% within 3 to 4 hours of the event. The test result is positive in about 75% of patients at 6 hours after onset of symptoms; at 12 hours, the test is almost 100% sensitive. More recent “highly sensitive troponin assays” produce positive results after AMI reliably within several hours. The newer assays, however, seem to have more false-positive results and are still limited in sensitivity because they do not detect UA.72

Because cardiac troponins are not found in the serum of healthy individuals, an abnormally elevated level is defined as that exceed-ing the 99th percentile in a healthy population. Sensitivity to detect abnormal low troponin levels, however, varies among the multiplicity of existing assays, particularly with respect to TnI. Physicians therefore must be familiar with the sensitivity and limi-tations of the particular assay used at their institution and the cutoff concentrations for clinical decisions.

Data indicate that even very low levels of troponin elevations are associated with significant adverse clinical prognosis.73 In a number of studies, up to 33% of patients diagnosed with UA with normal CK-MB levels had elevated troponin levels, indicating the markers’ improved sensitivity for myocardial cell injury.74 The fact that the risk of these patients for cardiac events and mortality is similar to that of the patients diagnosed with AMI by traditional WHO criteria led to the redefinition of AMI on the basis of bio-chemical markers. On the basis of data from the TIMI-IIIB study, there is almost a linear correlation between increasing troponin levels and risk of cardiac events and mortality, even in patients with a nondiagnostic ECG and normal CK-MB levels.74,75 In a review of more than 7000 NSTEMI patients, troponin levels iden-tified patients at low mortality risk. Small elevations of troponin may be used as an objective measure of “preinfarcts” that charac-terize UA and are associated with increased risk of infarction in the near term. Marked elevations in troponin consistent with AMI

represent further progression along the continuum of ACS toward “traditional” AMI.

Cardiac troponins may also guide ACS treatment. Data from the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy—Thrombolysis in Myo-cardial Infarction (TACTICS–TIMI 18) trial suggest that patients with elevated troponin who are treated with an early invasive interventional strategy within 48 hours have a marked improve-ment in recurrent ischemia, infarction, and mortality, both in the short term and at 6 months. These studies include patients without major ECG criteria for immediate interventional reperfusion strategies.61 The use of glycoprotein IIb/IIIa inhibitors (GPIs) in patients with elevated troponins may prevent early complications in patients with ACS. It is likely that the improved sensitivity of troponin has captured a high-risk ACS population not previously diagnosed or treated. It is important to note that elevated troponin levels identify patients with UA or NSTEMI who stand to gain the greatest benefit from an early invasive strategy with coronary angi-ography and revascularization.73,76

Elevated troponin levels occur in a variety of cardiac and non-cardiac conditions unrelated to the typical ACS and AMI patho-physiology. Cardiac conditions that can result in significant increased troponin levels in patients without evidence of ACS include myocarditis, pericarditis, CHF, LVH, and nonpenetrating cardiac trauma. Although the presence of elevated troponin levels in these conditions might be considered false-positive results, data support the contention that the source of these levels is underlying noninfarction myocyte injury that occurs with these conditions. Moreover, elevated troponin levels in many of these non-ACS cardiac conditions have prognostic significance.77

Troponin elevations can also be seen in noncardiac conditions, including PE, sepsis, and renal insufficiency. Troponin elevation may result from right ventricular dysfunction and myocyte injury in the case of submassive and massive PE and is a significant pre-dictor of adverse outcome. Similar elevated troponin levels are reported in patients with sepsis and critically ill patients with multiple organ system failure.77

Elevated troponin levels are commonly seen in asymptomatic patients with end-stage renal disease. This finding may relate to the high prevalence of cardiac disease in this population rather than any reduced renal clearance, and may still represent evidence of subclinical myocardial damage.78 The TnT isoform is associated


power for AMI and its early rise kinetics compared with other markers. Although some evidence suggests that a normal myoglo-bin value 2 hours after presentation may be used safely to rule out active AMI but not ACS, myoglobin has largely fallen out of favor.

Other Cardiac Markers

Troponin, CK, and myoglobin are all measures of myonecrosis. Biochemical assays for potential new cardiac markers for necrosis are being developed in the hope of finding ones with improved sensitivity, risk determination capability, and prognostic power. One such new cardiac-specific myonecrosis marker is heart-type fatty acid-binding protein. Other potential markers with useful-ness in ACS include those that may detect ischemia before actual necrosis, and plaque instability or inflammation.

Episodes of ischemia can result in biochemical changes before actual irreversible cell necrosis. Ischemic-modified albumin (so-called “cardiac albumin”) is a potentially useful ACS bio-marker that reportedly detects early myocardial ischemia rather than the later myocyte necrosis, and may have even earlier eleva-tion than myoglobin. Other potential ischemia markers include unbound free fatty acids and whole blood choline levels. Markers of hemodynamic status, including the natriuretic peptides, may also be useful in ACS. These markers, such as B-type natriuretic peptide (BNP) and NT-proBNP, are released from cardiac myo-cytes in response to increases in ventricular wall stress. BNP is most commonly used as a marker for CHF but is a useful adjunct to the standard cardiac markers and has good predictive power for recurrent ACS events and cardiac-related deaths, as well as CHF exacerbations, in patients with AMI.80,81 Moreover, the natriuretic peptides are excellent predictors of both short- and long-term mortality in patients with UA, NSTEMI, and STEMI.80,81

Given the underlying pathophysiology of ACS, a variety of bio-chemical markers for inflammation and plaque instability may prove useful in evaluating risk of a cardiac event. Chief among these are the inflammatory markers C-reactive protein (CRP) and high-sensitivity CRP (hsCRP), which have long-term prognostic value for cardiac events in healthy individuals as well as potential short-term prognostic value when combined with other markers for ACS. Other inflammatory markers include interleukin-6 and tumor necrosis factor alpha. Elevated plasma levels of myeloper-oxidase, an abundant leukocyte enzyme found in vulnerable coro-nary plaques that have ruptured, predict short-term risk of adverse cardiac events even with negative cardiac troponin and no evi-dence of myocardial necrosis.82

Multiple Marker Strategies

Diagnostic, risk stratification, and prognostic accuracy might be enhanced by the use of multiple markers for AMI and ACS.83 The combination of CK-MB and myoglobin measurement has a sen-sitivity of 62 to 100% and specificity of 72 to 89% for AMI on presentation. Serial measurements of these markers significantly improve the performance of this combined marker approach. McCord reported on the usefulness of a multimarker strategy involving the early but non–cardiac-specific marker myoglobin with the more specific and prognostic marker TnI. In 817 patients evaluated for ACS in the ED, the combined marker approach had a sensitivity of 96.9% and negative predictive value of 99.6% for AMI when applied at presentation and at 90 minutes.84 Similarly, a three-marker approach (CK-MB, TnI, and myoglobin) in an accelerated critical pathway was reported to have 100% sensitivity and 100% negative predictive power for AMI in 1285 patients assessed for ACS.85 In a large series of ED chest pain patients with an initial nondiagnostic ECG, a 2-hour delta CK-MB combined with a 2-hour delta TnI had a sensitivity of 93% and specificity of

with elevated levels in renal failure more often than TnI, particu-larly in patients undergoing hemodialysis. Elevated troponin levels in the setting of renal failure are associated with increased risk of death and major cardiac and vascular morbidity and should not be ascribed to chronic renal failure unless old records are present to corroborate that the elevated troponin level is actually the patient’s normal baseline level.78

Creatinine Phosphokinase

Creatinine phosphokinase (CK) is found in large quantities not only in cardiac muscle but also in skeletal muscle, brain, kidney, lung, and the gastrointestinal tract. Myocardial cells are by far the most abundant potential sources of CK-MB; thus the appearance of CK-MB in the serum is highly suggestive of MI. The CK-MB fraction remains the best alternative to the troponins as a cardiac marker.79 In the setting of AMI, CK-MB is released and is detect-able in the serum as early as 3 hours after onset of the necrosis. CK-MB characteristically peaks at 20 to 24 hours and becomes normal within 2 to 3 days after injury. Elevated CK-MB values identify a patient at considerable risk for a poor outcome but do not correlate well with infarct size. Unfortunately, skeletal muscle does contain small amounts of CK-MB, particularly the pelvic musculature. Abnormal CK-MB elevations may be seen in patients with trauma, muscular dystrophies, myositis, and rhabdomyolysis and after extremely vigorous exercise.

The sensitivity of a single CK-MB determination in diagnosing AMI is dependent on the elapsed time from chest pain onset. Values obtained within 3 hours of onset are poor diagnostic tools, with a sensitivity of only 25 to 50%. CK-MB determinations obtained beyond this 3-hour time period have increasing sensi-tivities for the diagnosis of AMI, ranging from 40% to nearly 100%, particularly when obtained 12 to 16 hours after onset.70 As a result, the use of single determinations of CK-MB is of little value in excluding ACS. Serial sampling, even over relatively short time periods (12 hours), increases sensitivity considerably, par-ticularly when considered with serial electrocardiography and repeated assessments of the patient. Diagnostic utility is also improved by requiring that the CK-MB value not only be ele-vated but also be at least 5% of the total CK value. False-positive elevations can occur with noncoronary conditions, such as peri-carditis, myocarditis, skeletal muscle disease, rhabdomyolysis, trauma, and exercise. In presentations in which dual biomarkers are obtained, the presence of nominal elevations in the CK-MB with simultaneous normal serum troponin value is of less clinical concern.

Myoglobin

Myoglobin, a small protein (17,000 daltons) found in muscle tissue, is rapidly released into the circulation after cellular injury. In cases of myocardial injury, myoglobin rises in the initial 1 to 2 hours, peaks at 5 to 7 hours, and returns to baseline by 24 hours. Because of its rapid rise, myoglobin is attractive as an early indica-tor of myocardial injury. Myocardial myoglobin, however, is not currently distinguishable immunologically from skeletal muscle myoglobin. Thus myoglobin is elevated in any clinical situation involving the skeletal muscle, such as trauma, exercise, and signifi-cant systemic illness. In addition, myoglobin increases are seen in patients with renal failure because of reduced clearance.

The sensitivity of an initial myoglobin at presentation for AMI varies from as low as 21% to as high as 100%.70 Serial testing at 2 to 4 hours after presentation significantly improves the assay’s diagnostic power. A doubling of the level as soon as 1 to 2 hours after the initial measurement greatly increases the sensitivity for the diagnosis of AMI, but this approach is very nonspecific. The value of myoglobin may be in its excellent negative predictive


suggest a role for emergency pharmacologic stress echocardiog-raphy as a provocative test after a period of observation with at least two marker and ECG assessments in a chest pain or ED observation unit.87

Myocardial contrast echocardiography (MCE) uses microbub-ble ultrasonic contrast agents to assess microvascular perfusion and regional function with echocardiography. MCE evaluation of perfusion and regional function allows accurate risk stratification of ED patients with chest pain and nondiagnostic ECGs even before serum markers are available.88 Smaller studies report low rates of adverse cardiac events in chest pain patients with normal MCE findings after a nondiagnostic ECG and negative serum markers.89 The clinical value of MCE in the ED, like that of resting and stress echocardiography, remains uncertain.

Myocardial Scintigraphy

Radionuclide tracer injection and scintigraphy, such as with single-photon emission computed tomography (SPECT), allows real-time assessment of myocardial perfusion and function. Technetium-99 sestamibi has a slow redistribution to ischemic myocardium. This property allows immediate injection and imaging, which detects altered distribution consistent with some form of ischemic heart disease, followed by subsequent scanning, which provides more definitive data regarding the particular subtype of ACS. In patients with a normal initial study, the likeli-hood of ACS is extremely low. In patients with an initial study revealing abnormal distribution (i.e., reduced uptake) of the tracer, some form of ischemic heart disease is likely. Subsequent imaging then reveals one of two patterns: normal redistribution (normal uptake) or continued reduced uptake. The redistribution pattern is consistent with active coronary ischemia, and the con-tinued reduced uptake is found in patients with MI, either remote or recent. Myocardial scintigraphy has promising positive and negative predictive values for cardiac events, with high sensitivity and a good specificity for CAD.90,91

Immediate myocardial scintigraphy is useful in detecting ACS and risk of cardiac events in patients in the ED with atypical chest pain, nondiagnostic ECGs, and low to moderate risk of AMI. Multiple studies find a relatively high incidence of cardiac events, presence of AMI, and need for revascularization in patients with a positive nuclear scan. The probability of a cardiac event is tenfold higher in patients with abnormal scans than in patients with a normal scan. The incidence of cardiac events with a normal scan is lower than 1% for the 30-day period after the index study.92 Myocardial scintigraphy can reduce the number of patients admit-ted from the ED with chest pain who are ultimately determined not to have ACS without reducing appropriate admissions for patients with ACS.93

Myocardial scintigraphy studies are difficult to perform early after the patient’s presentation to the ED. Radioisotopes and the personnel to administer them may not be immediately available, and physician interpretation experience is quite variable. Studies of ED perfusion imaging are resting studies, rather than more provocative stress (exercise or pharmacologically induced) perfu-sion studies.

Computed Tomography

CT imaging is a noninvasive imaging modality to assess for ACS. Electron beam computed tomography (EBCT) was introduced nearly two decades ago to screen for coronary calcium as a marker of underlying atherosclerotic heart disease and risk of ACS.94 Whereas calcium scoring systems exist to assess cardiovascular disease risk, few studies have examined the role of EBCT in the assessment of patients with acute chest pain.95 The few studies that have examined EBCT have demonstrated good sensitivity and

94% for AMI.86 Other multimarker strategies include combining measurement of a conventional marker for myocardial necrosis (troponin) with a marker for inflammation (CRP) and a hemo-dynamic marker (BNP). Many of these multimarker strategies, however, have low specificity. As a result, a positive multimarker test result requires confirmation with later-appearing, more defin-itive cardiac biomarkers.6 Thus the multimarker approach does not offer substantial benefit over the individual biomarker deter-minations and is therefore not recommended.

Echocardiography

Two-dimensional echocardiography detects regional wall motion abnormality associated with ACS. Impaired myocardial contractil-ity can range from hypokinesis to akinesis. Impaired myocardial relaxation during diastole results in decreased ventricular disten-sibility. After AMI, paradoxical wall motion and decreased ejection fraction observed during systole indicates the subsequent loss of muscle tone from necrosis.

Particularly in individuals with nondiagnostic ECGs, the presence of regional systolic wall motion abnormalities in a patient without known CAD is a moderately accurate indicator of acute myocardial ischemia or infarction, with a positive pre-dictive accuracy of about 50%.6 The age of wall motion abnor-malities, however, often cannot be determined without prior echocardiograms.

The absence of segmental abnormalities (presence of either normal wall motion or diffuse abnormalities) has a significant high negative predictive value, as high as 98% for cases of sus-pected MI.6 Moreover, segmental wall motion abnormalities can be seen not only in the zone of acute infarction but also in regions of ischemic stunning. Resting echocardiography provides an assessment of global and regional function, an important pre-dictor of complications and mortality in patients with ACS. Data from the ACC/AHA task force indicate that patients with mild and localized as opposed to extensive wall motion abnormalities, have a low risk of ACS complications.6 In addition, echocardiography can help evaluate other causes of clinical presentations mimicking ACS, including valvular heart disease, aortic dissection, peri-carditis, mitral valve prolapse, and pulmonary embolus. Finally, echocardiography is an important tool to assess for various com-plications of AMI, including acute mitral regurgitation, pericar-dial effusion, ventricular septal and free wall rupture, and intracardiac thrombus formation.

Technical limitations restrict the use of echocardiography in the ED. These limitations include the quality of the study and the expertise of the reader interpreting the study at the patient’s bedside. Injury involving more than 20% of the myocardial wall is required before segmental wall motion abnormalities can be detected echocardiographically.11 In addition, the inability of the two-dimensional echocardiogram to distinguish among ischemia, AMI, or old infarction and the potential absence of wall motion abnormality in nontransmural infarctions can further limit the usefulness of two-dimensional echocardiography.

Stress echocardiography, as opposed to resting echocardiogra-phy, can detect CAD as well as assess cardiac function early after an AMI. This can be performed with graded increases in cardiac workload, either by standardized exercise or pharmacologic adrenergic stimulating agents such as dobutamine. In addition, vasodilating agents, such as dipyridamole and adenosine, induce heterogeneous myocardial perfusion and reveal functional myo-cardial ischemia in susceptible patients. Stress echocardiography is superior to conventional treadmill testing for CAD in women. Graded dobutamine stress echocardiography assesses myocar-dial viability and ventricular function within the first few days after an AMI. Clinical studies of patients with nondiagnostic ECGs, negative markers, and negative rest echocardiography


diagnostic method for the detection of symptomatic CAD in low- to moderate-risk patients.

ACC/AHA guidelines on exercise testing state that such testing can be performed when patients are free of active ischemic or heart failure symptoms for a minimum of 8 to 12 hours.103 Immediate stress testing without the rule-out MI evaluation, however, may be safe and cost-effective in patients with chest pain felt possibly to be of cardiac origin but with low suspicion of ACS. For determination of the safety and value of immediate exercise testing in the ED, 1000 low-risk patients underwent immediate exercise testing with no adverse effects.104 Negative exercise test results were found in 640 patients (64%), all of whom were discharged home from the ED. The rate of CAD diagnosis or cardiac event within 30 days was 29% for the posi-tive stress group, 13% for the nondiagnostic group, and 0.3% for the negative stress group. In total, 30-day follow-up was achieved in 888 (89%) patients and revealed no mortality in any of the three groups.

Graded exercise testing in the ED at most institutions is not available continuously. The mortality rate is extremely low (1 in 2500), but absolute contraindications include recent AMI (within 2 days), high-risk UA, uncontrolled cardiac dysrhythmias causing symptoms or hemodynamic compromise, symptomatic severe aortic stenosis, uncontrolled symptomatic heart failure, acute pul-monary embolus or infarction, acute myocarditis or pericarditis, and acute aortic dissection.103

Patients with a high pretest probability of CAD have a signifi-cant rate of false-negative results, and patients with a low pretest probability have a significant rate of false-positive stress test results. The specificity of the test is decreased in the presence of underlying electrocardiographic abnormalities secondary to med-ications, electrolyte abnormalities, LVH, or artifact. A false-positive test outcome may result from aortic stenosis or insufficiency, hypertrophic cardiomyopathy, hypertension, arteriovenous fistula, anemia, hemoglobinopathies, low cardiac output states, chronic obstructive pulmonary disease, digitalis toxic states, LVH, hyper-ventilation, mitral valve prolapse, and bundle branch blocks. An increase in the rate of false-positive test results in women tends to decrease the usefulness of graded exercise testing in this population.

EMERGENCY DEPARTMENT–BASED CHEST PAIN CENTERS

Specialized units for the lower-risk population are used in 30% of the EDs in the United States The goal of the chest pain center (CPC) is to provide an integrated approach to patients with chest pain or potential ACS that includes rapid triage, early identifica-tion, and treatment of low-risk ACS patients. Guidelines and criti-cal pathways play an essential role in the CPC process. Staff, resources, and space are often dedicated for a CPC, but the unit can be part of an ED observation unit or a “virtual” unit located near or within the ED.

A CPC protocol should rapidly direct patients with possible ACS into a high-level treatment area where an ECG and clinical examination can be performed within the first 10 minutes. Patients with STEMI who require immediate reperfusion therapy or with UA who need further intervention can be identified quickly. This goal can be combined with an efficient ED evaluation of patients with low to moderate risk of ACS. The greatest medical benefit from the CPC is the early identification of patients with AMI and UA; the most significant financial impact is the reduction of low-yield hospital admissions.

The National Heart Attack Alert Program (NHAAP) of the National Heart, Lung, and Blood Institute (NHLBI) challenges clinicians to provide care for ED patients with clear symptoms and

excellent negative predictive value for subsequent cardiac events but have design limitations.

Technical advances in imaging include multidetector computed tomography (MDCT) with multislice 16-, 64-, and 256-slice CT scanning, as well as ECG-gated MDCT. These may revolutionize noninvasive cardiovascular imaging in the setting of ACS. These enhancements allow imaging of the beating heart with minimal motion artifact and accurate resolution to the level of the coronary vessels. Improvements in image reconstruction and reformatting software not only allow direct visualization of the coronary arter-ies, or CT angiography (CTA), but also can provide functional information on perfusion, wall motion, and left ventricular ejec-tion fraction.

The use of MDCT in the ED focuses on two potential proto-cols: a coronary CTA by MDCT and a more global “triple rule-out” thoracic or chest MDCT. Noninvasive coronary CTA by MDCT performs well when compared with standard invasive coronary angiography.96,97 Cardiac CT provides excellent detec-tion of calcified and noncalcified coronary artery plaque and stenosis, indicative of atherosclerosis and risk of ACS.94 CTA may be less useful, however, in a patient with preexisting CAD and extensive coronary calcifications or in those who have undergone prior interventions and have resulting imaging artifacts from coronary stents.97

The triple rule-out or global assessment protocol refers to the use of CT to assess for three life-threatening causes of chest pain, including PE and aortic dissection as well as ACS. The scanning protocol is a compromise between coronary CTA and PE or aortic dissection with larger field-of-view requirements and altera-tions in contrast delivery. A high-resolution, fast MDCT (64-slice or higher) is necessary so that adequate contrast enhancement, imaging, and visualization of the pulmonary vessels, coronary arteries, and aorta can all be obtained.

The literature regarding the use of cardiac CT in patients with acute chest pain is limited. A study of 69 ED patients with chest pain and nondiagnostic ECGs noted that an ECG-gated 16-slice MDCT had a 96% negative predictive value when compared with the final diagnosis of CAD. Three patients were diagnosed by CT with other causes for their chest pain, including pneumonia and PE.98 A study of 64-slice MDCT coronary angiography in 92 ED patients at low risk for ACS reported a sensitivity of 86% and specificity of 92%, which are comparable with values for stress nuclear imaging.99 Another report on use of 64-slice MDCT in 103 patients admitted to the hospital for ACS with nondiagnostic ECGs and negative cardiac markers notes a 100% negative predic-tive power for CTA.100 The greatest benefit of MDCT appears to lie within its powerful negative predictive value, but this occurs at the expense of some false-positive findings that result in further testing, cost, and radiation exposure.101

The clinical indications for and utility of coronary CTA in the ED, as well as global assessment triple rule-out MDCT protocols, require further investigation. Impediments include the limited availability of high-end MDCT technology; the unknown eco-nomic and workflow impact of increased MDCT use; the lack of guidelines for the use of dedicated coronary CTA or the more global assessment, the triple rule-out MDCT, for acute chest pain; and radiation exposure.

Graded Exercise Testing

Exercise stress testing for ED patients is feasible. In more than 1000 patients with low-risk chest pain (5% incidence of CAD) who underwent exercise testing after negative serial markers and 9 hours of ECG monitoring in the ED,102 stress testing had a negative predictive value of 98.7% for the diagnosis of ACS or cardiac event within 30 days. An abbreviated ED-based “rule out MI” protocol followed by mandatory stress testing appears to be an effective


MANAGEMENT OF ACUTE CORONARY SYNDROME

The pathophysiology of an acute coronary event includes (1) endothelial damage through plaque disruption, irregular luminal lesions, and shear injury; (2) platelet aggregation; (3) thrombus formation causing partial or total lumen occlusion; (4) coronary artery vasospasm; and (5) reperfusion injury caused by oxygen free radicals, calcium, and neutrophils. In patients with noninfarc-tion ACS, spontaneous fibrinolysis of the thrombus occurs rapidly, minimizing ischemic insult; persistence of the occlusive thrombus, however, results in MI.

Relationship of Time to Treatment with Outcome

The beneficial effect of reperfusion is a function of the length of ischemic time. In the late 1970s, with the “wavefront phenome-non” of ischemic cell death, it was hypothesized that myocardial necrosis progresses from the subendocardium to the epicardium after coronary occlusion (Fig. 78-23).

Early patency resulting in myocardial salvage is the key benefit of emergent revascularization therapy using either fibrinolysis or primary angioplasty. Timely treatment within the first hours after symptom onset may result in substantial, if not complete, myo-cardial salvage. Delivered later, from 2 to 12 hours after AMI onset,

signs of AMI within 30 minutes of arrival. The NHAAP recom-mends (1) a specific area of the ED equipped for assessing and monitoring patients potentially having ischemia, including stand-ing orders for initial diagnostic and therapeutic actions; (2) a standing protocol with inclusion and exclusion criteria for reper-fusion therapies, including language authorizing the physician to administer fibrinolytic therapy or to mobilize the catheterization laboratory for prespecified cases; (3) a clear demarcation of responsibilities for all members of the reperfusion team; and (4) policies and procedures for the treatment and possible transfer of patients with ST segment elevation AMI who are ineligible for fibrinolytic therapy.

These recommendations highlight the advantages of a target “door-to-drug” time of less than 30 minutes or a door-to-balloon time of less than 90 minutes (where percutaneous procedures are available) for patients with typical and uncomplicated pre-sentations of AMI with ST segment elevation. For example, the CPC can have assigned nursing personnel who rapidly evaluate the patient with chest pain with a 12-lead ECG, as well as screening vital signs and cardiac monitoring, and deliver the ECG directly to a clinician capable of making a decision about activation of the catheterization laboratory or administration of fibrinolytic therapy.

The CPC may also be used as an observation and evaluation unit where patients with chest pain and low to intermediate clini-cal likelihood of ACS can be monitored with electrocardiography, ST segment trending, serial 12-lead ECGs, and sequential serum markers. In addition, many CPCs now use further ACS evaluation with stress testing, echocardiography, or myocardial scintigraphy before disposition.105 Significant cost savings occur, with typical charges and actual costs ranging from 20 to 50% of the costs for the usual inpatient approach.

The Chest Pain Evaluation in the Emergency Room (CHEER) investigators in a prospective, randomized trial compared a CPC with the traditional hospital admission to rule out MI.106 Over a 16-month period, patients with chest pain at intermediate ACS risk on the basis of history, examination findings, and ECG were randomly assigned to either CPC or hospital admission. CPC patients underwent serial serum marker and ECG determinations over a minimum of 6 hours. If investigations were negative and the course uncomplicated, patients were evaluated with an exer-cise stress test, nuclear stress test, or stress echocardiography. If the results of this evaluation were positive, the patient was admitted; if negative, the patient was discharged with cardiology follow-up within 72 hours. In the CPC group, all events occurred in patients with a positive stress test result; no cardiac events occurred in the negative stress test group after ED discharge. Admissions were reduced by 45.8%.

A chest pain–accelerated diagnostic protocol approach to low- to intermediate-risk patients can be feasible, safe, and effective. In a study of comprehensive diagnostic 9-hour evaluation (Heart ER Program) for 1010 patients with possible ACS, patients under-went serial testing with the following: CK-MB at presentation, 3, 6, and 9 hours; continuous 12-lead ECGs; and serial ST segment trend monitoring. Two-dimensional echocardiography and graded exercise testing were performed in the ED after the 9-hour evaluation.

Approximately 80% of patients with chest pain can be safely evaluated in the ED with ultimate discharge to home. The resources required for a successful CPC-based operation in which patients undergo rapid exclusion of ACS through serial testing, continuous monitoring, and immediate provocative stress testing are consid-erable. Although studies suggest that CPCs decrease the number of admissions, they may increase the number of patients seen in the ED for chest pain, and physicians may overuse the CPC accel-erated diagnostic protocol approach in patients whom they would otherwise have discharged.107

Figure 78-23. Relationship between time to reperfusion and benefit in ST segment elevation acute myocardial infarction. This figure depicts combined human and animal data and represents the time-dependent benefit anticipated, depending on the length of the interval between coronary artery occlusion and reperfusion. (Adapted from Tiefenbrunn AJ, Sobel BE: Timing of coronary recanalization. Paradigms, paradoxes, and pertinence. Circulation 85:2311, 1992; Reproduced from U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute [NIH Publication No. 93-3278], September 1993, p 8. Copyright ©1992 American Heart Association.)

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STEMI patients who receive hospital-based reperfusion thera-pies (fibrinolytic agent or PCI) progress through a sequence of steps that can define process time points (Fig. 78-24). Within each interval, various impediments to timely care can occur. Reducing delay times is applicable to all time points in the ED by addressing the four Ds: door (events before arrival at the ED), data (obtaining the ECG), decision (arriving at the AMI diagnosis and deciding on therapy), and drug (administering the fibrinolytic agent or passing the angioplasty catheter across the culprit lesion for PCI candidates).

Preadmission care providers may alert the ED to the impending arrival of a patient with a suspected AMI. A field 12-lead ECG may assist in diagnosis and decrease the reperfusion time by initiating the hospital-based sequence of necessary events to occur in paral-lel as opposed to serially. Self-transported patients with possible ACS should be evaluated by the triage nurse immediately and an ECG acquired within 10 minutes of arrival. Development of hospital-based protocols and system response plans for identify-ing and rapidly treating patients reduces the amount of time to treatment. When using fibrinolysis in uncomplicated cases, the emergency physician should activate the hospital-based system for reperfusion. Checklists of inclusion and exclusion criteria for fibrinolytic therapy should be available, and those fibrinolytic agents should be stored and administered in the ED. In a system in which fibrinolysis is the sole reperfusion therapy, the decision to administer that therapy rests solely with the emergency physi-cian. Nonconsultative communications with family physicians, internists, or cardiologists before administration of the agent may result in unnecessary delays. Only in complicated situations should consultative discussions be required before administration of therapy.

If the hospital offers primary PCI, many hospitals activate “STEMI alert” responses with an ST segment elevation AMI patient. Analogous to the “trauma alert,” the cardiologist and catheterization laboratory personnel are immediately mobilized. Emergency physician activation of the catheterization laboratory demonstrates very high rates of accurate STEMI diagnosis with very low rates of false activation (i.e., the STEMI mimicker) while markedly reducing the time to definitive therapy.112 Inter-hospital transfer of STEMI patients for PCI when they are also candidates for fibrinolysis should be discouraged if definitive therapy (i.e., catheter placement across the culprit lesion) is likely to be delayed beyond 90 minutes, except in cases of hemodynamic

treatment may result in a more modest, but significant benefit. The opening of the occluded artery causes less adverse ventricular modeling, reduces occurrence of ventricular aneurysm, increases blood flow to myocardium, and improves electrophysiologic sta-bility. In the angiographic substudy of GUSTO, preserved left ven-tricular function and mortality at both the 24-hour and the 30-day endpoints were related to angiographic patency at 90 minutes.108 The relationship between rapid revascularization and mortality was demonstrated by De Luca, with each additional 30 minutes of delay to PCI compounding relative mortality risk by 7.5% at 1 year even when adjusted for baseline characteristics.109

Substantial delays often occur between symptom onset and hospital-based initiation of reperfusion therapy.110 In 1991 the NHLBI launched the NHAAP to promote the rapid identification and treatment of AMI. The factors responsible for delay in the care of AMI patients are grouped by the NHAAP into three phases: patient-bystander, preadmission, and hospital. Patient-bystander factors are those that prevent immediate medical care through the EMS system. Median delays range from 2 to 6.5 hours; in fact, 26 to 44% of AMI patients delay more than 4 hours before seeking medical care. In all major studies evaluating patients’ delay, the median time of arrival at the hospital is delayed well beyond the critical first hour during the time period in which half of AMI deaths occur.

Preadmission delay factors occur from the time the patient decides to seek medical attention until the patient arrives at the ED. It is not uncommon for patients to call their primary care physician, which may delay definitive care significantly. For less than half of patients with suspected AMI, the EMS system is the point of first medical contact.111 Many transport themselves or wait for someone other than EMS personnel to take them to the hospital. Further complicating preadmission issues include wide variations in the availability of EMS systems and their integration into systems of care that seek to minimize delays to treatment.

Further delays can occur between the time a patient arrives at the hospital and the initiation of acute revascularization therapy. Overall, the average time to fibrinolysis ranges from 45 to 90 minutes. The GUSTO trial demonstrates a median time from hospital arrival to treatment with fibrinolytic therapy of 70 minutes.108 The AHA recommends that all patients with STEMI receive fibrinolytic therapy within 30 minutes of arrival or undergo primary PCI (i.e., device across culprit artery) no later than 90 minutes after arrival.7

Figure 78-24. The four Ds of emergency department (ED)–based diagnosis and management of the patient with acute myocardial infarction (AMI). Shown are the process time points and intervals through which the patient with AMI passes until treatment in the emergency department. ECG, electrocardiogram. (From U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute [NIH Publication No. 93-3278], September 1993, p 10.)

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increases occurred despite exclusion of patients with obvious contraindications, including preexisting hypotension, bradycar-dia, or heart failure.116 The Clopidogrel and Metoprolol in Myo-cardial Infarction Trial (COMMIT) evaluated approximately 46,000 patients with suspected STEMI, comparing early intrave-nous beta-adrenergic blocking agent use followed by continued oral therapy versus placebo. There was no significant difference between the two groups in terms of mortality. The group receiving beta-adrenergic blocking agents did demonstrate a minimal reduction of reinfarction (2.0 vs. 2.5%) and ventricular fibrillation (2.5 vs. 3.0%) at the expense of a significantly higher rate of car-diogenic shock (5.0 vs. 3.9%). This was more common in patients who were elderly or who had a systolic blood pressure below 120 mm Hg, a heart rate above 110 beats/min, or mild, acute heart failure. Patients receiving the beta-adrenergic blocking agents also had increased rates of development of heart failure requiring treatment, persistent hypotension, and bradycardia.117

The early intravenous use of beta-adrenergic blocking agents, when coupled with contemporary therapy, does not appear to offer significant benefit and is associated with an increased rate of adverse events.118 Oral administration to patients without contra-indication during the first day of management is an appropriate approach to the ACS patient. Empirical therapy in the ED, however, should be reconsidered and reserved for only those patients who have adverse effects from significantly elevated blood pressure despite application of NTG, or significant tachydysrhythmia.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitor agents benefit patients with CHF. ACE inhibitors may also reduce morbidity and mortality after AMI. In particular, patients treated with ACE inhib-itors experience a reduction in cardiovascular mortality, decreased rates of significant CHF, and fewer recurrent AMIs. These benefits increase when ACE inhibitors are used in con junction with other agents, such as aspirin and fibrinolytics. The mechanism of action regarding a reduction in recurrent AMI is unknown but may involve a reduction in plaque rupture related to decreased intra-coronary shear force or neurohumoral influences.

Captopril, enalapril, lisinopril, or ramipril may be used in this setting. The ultimate doses should be maximized after careful titration with these potent agents to avoid hypotension. Therapy should be initiated within the first 24 hours, although ED admin-istration is usually not indicated. In patients with asymptomatic left ventricular dysfunction, therapy should continue for a minimum of 2 to 4 months. In patients with symptomatic CHF, ACE inhibitors should be administered indefinitely. Contraindica-tions to ACE inhibitor therapy include hypotension, volume depletion, and borderline perfusion. Renal function must be mon-itored closely. The angiotensin receptor blockers also inhibit the renin-angiotensin system, so these drugs are possible alterna-tives to ACE inhibitors in patients post-MI with or without heart failure.

HMG–Coenzyme A Reductase Inhibitors (Statins)

A number of investigations have demonstrated a reduction in inflammation and reinfarction, angina, and lethal arrhythmia with the administration of statin drugs in the first few days after an ACS event.119 Initiation of this therapy should occur within the first 24 hours or should continue if patients are already undergo-ing statin therapy, as discontinuation during hospitalization is associated with an increase in near-term mortality and adverse events.120 Administration of statin therapy before elective or urgent PCI for ACS is reasonable to decrease the incidence of periprocedure AMI; however, there are no specific risk or safety data regarding its use in this setting.121

shock as discussed later or in patients in whom fibrinolysis is contraindicated.

Pharmacologic Intervention

Nitroglycerin

Nitrates decrease myocardial preload and, to a lesser extent, after-load. Nitrates increase venous capacitance and induce venous pooling, which decreases preload and myocardial oxygen demand. Direct vasodilation of coronary arteries may increase collateral blood flow to ischemic myocardium. Most studies of intravenous NTG in the setting of AMI are from the prefibrinolytic era. Although a meta-analysis of multiple small trials noted a 35% mortality reduction with intravenous NTG,113 no contemporary evidence supports the routine use of any form of nitrate therapy in patients with AMI.114

Patients with possible ACS and a systolic blood pressure greater than 90 mm Hg should receive a sublingual NTG tablet (0.4 mg or 400 μg) on presentation. If symptoms and pain are not fully relieved with three sublingual tablets, intravenous NTG should be considered. With bradycardia, hypotension, inferior wall AMI, and right ventricular infarction, a sudden decrease in preload associ-ated with NTG can result in profound hypotension. An initial infusion rate of 10 μg/min is titrated to pain symptoms. The clini-cian should increase the infusion at regular intervals, allowing a 10% reduction in the mean arterial pressure if the patient is nor-motensive and a 20 to 30% reduction if hypertensive. Sublingual bolus therapy, the use of additional sublingual NTG in the setting of intravenous NTG infusions, more rapidly increases the serum level of the medication with delivery of 400-μg boluses. Maximal benefit is probably achieved at 200 μg/min, although certain patients may receive additional benefit at higher infusion rates.

Morphine

Morphine is a potent opioid analgesic with weak sympathetic blockade, systemic histamine release, and anxiolysis. If a patient with possible ACS is unresponsive to NTG or has recurrent symp-toms despite maximal anti-ischemic therapy, administration of morphine sulfate is reasonable. The relief of pain and anxiety decreases oxygen consumption and myocardial work. Some vaso-dilatory effects are also noted with preload reduction. Standard doses of morphine sulfate are 2 to 5 mg delivered intravenously, repeated every 5 to 30 minutes as necessary. In addition to allergic reactions, the most significant adverse effect of morphine sulfate administration is hypotension, which is managed with intrave-nous crystalloid in bolus fashion.115

Beta-Adrenergic Blockers

Historically, beta-adrenergic blocking agents have been effective in ameliorating catecholamine-induced tachycardia, including ventricular fibrillation, increased contractility, and heightened myocardial oxygen demand. Although beta-blockade decreases mortality for patients with AMI, these observations occurred when adjunctive therapies were few and beta-adrenergic blockade was essentially monotherapy in AMI. Contemporary management strategies include highly effective reperfusion therapies coupled with potent anticoagulant and antiplatelet agents.

Two large reports suggest that the intravenous use of beta-adrenergic blockade should be reconsidered. The GUSTO-1 trial involved fibrinolytic agents for STEMI followed by early intrave-nous atenolol. The use of the early intravenous beta-adrenergic blocking agents in this study was associated with higher rates of death, heart failure, shock, recurrent ischemia, and pacemaker use than when patients received early oral administration. These


demonstrate benefit in eptifibatide-treated patients with non–ST elevation ACS presentations.133

GPI therapy, in the invasively managed patient, continues to offer improved outcome.134,135 In one large series, patients who received GPIs experienced lower in-hospital mortality (3 vs. 6.2%), which was noted in all STEMI risk groups managed.134 Subsequent analysis of the subgroup of patients receiving stents during PCI noted both a lower mortality rate (10.9 vs. 14.3%) and a lower reinfarction rate (2.3 vs. 5.5%) in the treatment group; also, the composite endpoint (death and reinfarction) occurred much less frequently in the treatment group, with a relative risk reduction of 37%. In a large meta-analysis of similar construction, major bleeding was not significantly different.135

The benefits of GPI therapy were established largely before contemporary invasive strategies, raising questions about the timing (i.e., upstream initiation in the ED) when combined with other antiplatelet therapies. Although small preliminary studies showed promise for upstream GPI administration,123,124 larger trials do not support their routine use in the ED.136,137 Evidence supports a highly selective strategy for use of GPI that balances ACS risk in the treatment of a patient with dual-agent platelet inhibition and planned PCI versus the potential bleeding risk. The glycoprotein IIb/IIIa receptor inhibitors consistently demonstrate benefit in ACS patients treated with urgent mechanical revascu-larization; in other groups of ACS patients, such as medically managed patients, patients receiving a combination fibrinolytic agent, or transferred patients, an invariable positive effect has not been established.

PSY12 Receptor Inhibitor Agents. The thienopyridines—ticlopidine, clopidogrel, and prasugrel—are more potent platelet inhibitors than aspirin. They inhibit the transformation of the PSY12 receptor into its high-affinity ligand-binding state, irrevers-ibly inhibiting platelet aggregation for the duration of the life of the platelet. Ticlopidine has nonlinear kinetics and, with repeated administration, reaches a maximal effect after 8 to 11 days of use. Clopidogrel, a ticlopidine analogue, and prasugrel have the advan-tage of a rapid onset of action.

Clopidogrel and prasugrel are the preferred agents in this class because of their more rapid onset of action and improved safety profile. Prasugrel incurs a higher bleeding risk than clopidogrel, however, in patients older than 75 years, those who weigh more than 60 kg, those who have had a previous transient ischemic attack (TIA) or stroke, and those at high risk for bleeding. Ticlopi-dine is associated with a risk of neutropenia and agranulocytosis; furthermore, it demonstrates a much slower onset of platelet inhi-bition. With clopidogrel, maximal platelet inhibition occurs after 3 to 5 days of clopidogrel therapy with 75 mg daily; an earlier onset of platelet inhibition is seen when a higher loading dose is used (300 to 600 mg). For instance, there is clear benefit to clopi-dogrel administration (300-mg loading dose) at least 6 hours before PCI in patients with STEMI; higher doses (e.g., 600 mg) demonstrate a trend toward improvement at slightly earlier time periods (i.e., 3 to 4 hours).

Ticagrelor, a nucleoside analogue, also acts as a PSY12 receptor inhibitor, however, via a different mechanism not requiring hepatic activation. It is rapidly absorbed reaching peak serum concentration at 2.5 hours. Clinical data from the PLATO trial of 18,624 ACS patients demonstrated that those given ticagrelor were less likely to die from cardiovascular causes, but these improved outcomes are tempered by higher rates of nonprocedure related bleeding, including more frequent fatal intercranial hemmorrage when compared with clopidogrel adminstration.138

In accordance with the 2013 AHA Guidelines for STEMI man-agement, patients should receive a loading dose of clopidogrel, prasugrel, or ticagrelor in addition to standard ACS care (ASA, anticoagulants, and reperfusion therapy) assuming there are no contraindications to its use, prior to PCI.139 For patients with

Calcium Channel Blockade

As with beta-blockade, the primary benefit of calcium channel blockers appears to be with symptom resolution. Unfortunately, these agents may be accompanied by a significant vasodilatory effect resulting in hypotension and potentiation of the coronary ischemic process. Like beta-blocking agents, calcium channel blockers have a substantial negative inotropic effect. AV nodal blockade is also a significant side effect that may be exacerbated in patients previously treated with beta-blockers or with ischemia-related conduction disturbance. Unless specifically used for rate control of supraventricular dysrhythmia in a patient who cannot tolerate beta-blockade, calcium channel blocker agents are not recommended for ACS.

Antiplatelet Therapy

In non-AMI ACS patients, dramatic reductions in the progression to acute infarction are noted with appropriate antiplatelet therapy. The administration of antiplatelet therapy, particularly aspirin, is indicated in the ED for most ACS patients, because in AMI, antiplatelet therapy reduces mortality from 25 to 50%.

Aspirin. Aspirin, the prototypical antiplatelet agent, is the most cost-effective treatment. It irreversibly acetylates platelet cyclooxy-genase, thereby removing all activity for the life span of the platelet (8-10 days). Thus aspirin stops the production of proaggregatory thromboxane A2 and is an indirect antithrombotic agent. Aspirin also has important nonplatelet effects because it inactivates cyclooxygenase in the vascular endothelium, thereby diminishing formation of antiaggregatory prostacyclin.

The Second International Study of Infarct Survival (ISIS-2) trial provides the strongest evidence that aspirin independently reduces the mortality of patients with AMI without fibrinolytic therapy (overall 23% reduction) and is synergistic when used with fibri-nolytic therapy (42% reduction in mortality).122 The usual dose is 324 mg of non–enteric-coated aspirin, chewed and swallowed. Administration of aspirin in the ED is strongly recommended immediately on identification of any patient with suspected ACS, either AMI or UA. It should be administered to all such patients unless significant allergy, hemorrhage, or other issue, such as a potential aortic dissection, contraindicates its use.

Glycoprotein IIb/IIIa Receptor Inhibitors. The GPIs are potent antiplatelet agents and include abciximab, eptifibatide, and tirofi-ban. GPIs, however, demonstrate clinical usefulness in only a subset of ACS patients—those undergoing PCI as a reperfusion strategy. Therefore the primary indication regarding GPI admin-istration is planned mechanical coronary intervention.

Numerous trials demonstrate the effectiveness of these agents in the subset of ACS patients who are managed with PCI with or without an intracoronary stent, consistently showing reduced mortality, need for subsequent revascularization, and recurrent ischemia, although at the cost of an increase in hemorrhagic complications.123-128 A meta-analysis of GPI use in ACS patients concluded that patients who undergo PCI benefit markedly from GPI administration.129 In ACS patients who are managed medi-cally without mechanical revascularization, consistent benefit with GPI therapy is not found with use of either direct outcome measures or secondary markers of successful reperfu-sion, and hemorrhagic complications are increased.130,131 The Inte-grilin to Manage Platelet Aggregation to Combat Thrombus in Acute Myocardial Infarction (IMPACT-AMI) investigators reported the results in AMI patients receiving fibrinolytic agents and varying doses of eptifibatide (i.e., nonmechanical means of reperfusion)132; they noted similar rates of death, recurrent MI, and the need for revascularization procedures but observed an increase in TIMI grade 3 flow at 90 minutes. Furthermore, using troponin values as an estimate of infarct size, investigators did not


emergency physician to reliably predict which patients will require urgent CABG, collaborative multidisciplinary pathways should be developed, with emergency medicine physicians, cardiologists, and cardiovascular surgeons providing input.

Antithrombins

As with antiplatelet therapies in ACS patients, significant reduc-tions in the progression to acute, recurrent, or extensive infarction and death are noted in individuals treated with aggressive anti-thrombin therapy. The antithrombins include unfractionated heparin (UFH), low-molecular-weight (fractionated) heparin (LMWH), and the direct thrombin inhibitors (hirudin and bivali-rudin). Antithrombotic therapy is indicated in ACS patients with recurrent anginal pain, AMI (NSTEMI and STEMI), a positive serum marker, and a dynamic 12-lead ECG.

Heparins. The term heparin refers not to a single structure but rather to a family of mucopolysaccharide chains of varying lengths and composition—hence, unfractionated—with pronounced antithrombotic properties. At standard doses, UFH binds to anti-thrombin III, forming a complex that is able to inactivate factor II (thrombin) and activated factor X. This prevents the conversion of fibrinogen to fibrin, thus preventing clot formation. Heparin by itself has no anticoagulant property. This indirect effect on thrombin inhibits clot propagation; it prevents heparin, however, from having any effect on bound thrombin in a thrombus. UFH also assists in the inactivation of factors XIa and IXa through antithrombin and interacts with platelets.

UFH has a profound synergistic effect with aspirin in prevent-ing death, AMI, and refractory angina in ACS patients, particularly those with AMI and, to a lesser extent, high-risk UA. UFH should be administered early in patients with the following ACS features: recurrent or persistent chest pain, AMI, positive serum marker, and dynamic ECG. In patients undergoing PCI, bleeding and mor-tality were higher in TIMI 14 in patients receiving an 80-unit/kg bolus and 18-unit/kg infusion compared with patients with a lower bolus amount and infusion rate. Therefore the weight-adjusted regimen recommended is an initial bolus of 60 units/kg (maximum 4000 units) and an initial infusion of 12 units/kg/hr with an activated partial thromboplastin time goal of 1.5 to 2.5 times the control value.

LMWHs constitute approximately one third of the molecular weight of heparin and are less heterogeneous in size. The LMWHs inhibit the coagulation system in a fashion similar to that of UFH. Approximately one third of the heparin molecules bind to both antithrombin III and thrombin. The remaining molecules bind only to factor Xa. The variable efficacy found among the LMWHs is attributed to different ratios of antifactor Xa to antifactor IIa. High-ratio preparations have a clear advantage over standard heparin; enoxaparin has the highest ratio of available LMWHs. LMWH was designed on the basis of the hypothesis that inhibi-tion of earlier steps in the blood coagulation system would be associated with a more potent antithrombotic effect than inhibi-tion of subsequent steps. This results from the amplification process inherent in the coagulation cascade—that is, a single factor Xa molecule can lead to the generation of multiple throm-bin molecules.

Potential advantages of LMWH over UFH include easier administration, greater bioavailability, more consistent ther-apeutic response among patients, and longer serum half-life pro-ducing a more manageable administration schedule, albeit at a higher cost. The combination of aspirin, beta-blocker, and LMWH (dalteparin) significantly decreases the rate of nonfatal AMI or death at 1 week of therapy, with a less pronounced effect at 40 to 150 days, but with an increase in minor bleeding epi-sodes.147 Studies comparing outcomes between LMWH and UFH

moderate-to high-risk NSTEMI, the administration of a PSY12 receptor inhibitor should be deferred “downstream” to the attend-ing cardiologist as the best revascularization strategy is determined.140

Another indication is the patient with a high-risk ACS presenta-tion who is truly allergic to ASA (ACC/AHA class I indication)6; this high-risk presentation would be characterized by objective clinical abnormality, including a significantly abnormal serum marker or 12-lead ECG. Considerations include the ultimate treat-ment strategy chosen (i.e., medical vs. invasive) and the time to angiography if an invasive plan is selected. ACS patients managed medically (i.e., noninvasively) or invasively with coronary angiog-raphy deferred to a later time are the most appropriate potential candidates for clopidogrel.141-144 In the patient selected for invasive management, the time to the procedure is a primary issue in considering clopidogrel; patients undergoing early angiography (within 6 hours) are less likely to derive significant benefit, whereas deferred catheterization likely will gain advantage.

In the patient with UA or NSTEMI, clinical benefit is confirmed in UA patients when treated with clopidogrel in a noninvasive strategy scenario, with an increase in major hemorrhage.141 As noted, invasively managed patients receiving the drug with less time to procedure performance do not benefit from such treat-ment. The NSTEMI patient demonstrates improved outcome with clopidogrel therapy when a conservative treatment scenario is ini-tially followed.143 Of note, a large portion of these patients will undergo PCI within the first 24 hours after admission; yet this “delayed” PCI allows for benefit to occur from clopidogrel admin-istered earlier in the course of management.

The STEMI patient who is managed medically (i.e., with a fibri-nolytic agent) will also benefit from clopidogrel use. Clopidogrel therapy in conjunction with fibrinolysis, followed by deferred cardiac catheterization occurring at least 2 days after AMI—clearly beyond the 6-hour window—decreases the rates of death, recur-rent ACS, and urgent coronary revascularization. This improve-ment occurs without a significant increase in hemorrhage.144

The potential need for urgent CABG should also be strongly considered. The higher-risk ACS patient will more likely benefit from PSY12 receptor inhibitor therapy; however, that same patient is also more likely to need urgent CABG. It is not possible, however, to reliably identify ACS patients requiring urgent CABG. Of the 60,000 patients in the CRUSADE registry, 14% underwent CABG, a reasonably frequent rate of surgical intervention145; most centers, however, report a 2 to 5% incidence of coronary surgery. Mehta, in a review of ED ACS patients, was unable to demonstrate a single or combination of clinical features apparent in the ED that reliably identify patients not requiring CABG.146 It is interesting to note that an analysis of the Clopidogrel in Unstable angina to prevent Recent ischemic Events (CURE) data-base suggests that although these CABG patients had a greater incidence of bleeding perioperatively, outcomes were not statisti-cally different in clopidogrel versus placebo groups in this surgi-cal subset.143 It is likely that as the cardiovascular surgeon gains more experience with PSY12 receptor inhibitor administration, this concern will cause less anxiety, as concerns regarding ASA and heparin in years past.

The ACC and AHA suggest—in the form of a class I recommendation—that clopidogrel or ticagrelor should be with-held for at least 24 hours before urgent on-pump CABG if pos-sible.140 If CABG is performed within 5 days of clopidogrel use, patients have an increased incidence of operative and postopera-tive hemorrhage, increased need for transfusions, increased need for reoperation for hemostasis, and increased postoperative mor-tality. Nevertheless, the recommendation suggests that early PSY12 receptor inhibitor therapy be considered in patients who likely will not require CABG.6 In that it does not appear possible for the


hemorrhagic complications in ACS care, this drug may be consid-ered as a reasonable alternative to UFH; however, the increased risk of catheter-associated thrombi during PCI prevents its use without additional UFH administration.155

In the large Optimal Antiplatelet Strategy for Interventions (OASIS) trial, fondaparinux was found to be similar to enoxaparin in the short-term reduction of ischemic events, yet substantially reduced major bleeding and improved long-term outcome.156 The OASIS-6 investigators reviewed the use of fondaparinux in 5436 STEMI patients managed medically with streptokinase. Fondaparinux significantly reduced hemorrhage and the primary study outcome (death or MI) as well as the individual occurrence of these endpoints at 30 days.157

Reperfusion Therapies

Rapidly reestablishing perfusion in the infarct-related coronary artery with the use of fibrinolytic therapy or PCI increases the opportunity for myocardial salvage. Pharmacologic and mechani-cal methods of reperfusion are both effective under specific clinical conditions. The importance of early coronary artery patency was affirmed by the GUSTO investigators in their angiographic sub-study. They demonstrated that 90-minute patency predicts improved rates of survival and preserves left ventricular function.

Fibrinolytic therapy unequivocally improves survival in patients with STEMI and is an ACC/AHA class I recommendation.6 Although fibrinolysis has widespread availability and a proven ability to improve coronary flow, limit infarct size, and improve survival in AMI patients, many individuals with acute infarction are not suitable candidates. Patients with absolute contraindica-tions to fibrinolytic therapy, certain relative contraindications, cardiogenic shock, and UA may not be eligible. The temporal constraints and other limitations of fibrinolytic therapy suggest that rapidly performed PCI is often the treatment of choice in the STEMI patient. To provide the most significant benefit, PCI must be performed as soon as possible after the initial presentation. In other settings and situations, PCI that is delayed is inferior to rapidly administered fibrinolysis.

Fibrinolytic Therapy

Fibrinolytic Agent Selection. Three megatrials compared tissue-type plasminogen activator (t-PA) with streptokinase. The Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI-2) trial and the closely related International Study com-pared a 100-mg infusion of t-PA over 3 hours with streptokinase with or without heparin.158,159 The GISSI-2 study was the first large-scale mortality trial directly comparing t-PA and streptoki-nase in AMI. The investigators found no difference in mortality between the two treatment groups. More strokes occurred with t-PA than with streptokinase (1.3 vs. 1%) in the International Study, yet the frequency of confirmed hemorrhagic stroke was similar for both agents. Similar results were found in the ISIS-3 trial,160 the next fibrinolytic megatrial, which compared t-PA, streptokinase, and anisoylated plasminogen-streptokinase activa-tor complex in approximately 40,000 patients. In contrast to stan-dard practice, the inclusion criteria allowed entry up to 24 hours after symptom onset and did not require diagnostic electrocardio-graphic change. All patients received adjunctive aspirin therapy, and approximately half of the patients were given delayed, unmon-itored subcutaneous heparin. A significant difference in both 35-day mortality and intracranial hemorrhage was not found. The results of the ISIS-3 study proved controversial because of the unmonitored, delayed subcutaneous heparin protocol,160 particu-larly with studies now proving improved infarct artery patency with use of early therapeutic intravenous doses of heparin.

show mixed results; some show better outcomes with LMWH, but others do not.148,149 In summary, the LMWH enoxaparin dem-onstrates some degree of benefit compared with UFH in patients at higher risk for non–ST-segment elevation-ACS who are treated conservatively without immediate PCI (i.e., beyond 24 hours).150 For STEMI patients managed aggressively with rapid PCI, UHF is the preferred over enoxaparin.140

Enoxaparin is administered in a twice-daily regimen subcutane-ously at a dose of 1 mg/kg for all ACS patients. If patients have renal dysfunction with an estimated glomerular filtration rate of less than 30 mL/min, the dose should be reduced to 1 mg/kg in a single daily administration. Few safety data are available for enoxaparin in ACS patients with renal insufficiency, and UFH may be preferable.

Contraindications to heparin therapy include known allergy, active ongoing hemorrhage, and predisposition to such hemor-rhage. Furthermore, patients who have their heparin therapy changed (UFH to LMWH and vice versa) during the active treat-ment phase of their ACS care experience higher rates of bleeding.

The vast majority of patients with AMI require therapy with heparin, whether it is fractionated or unfractionated. Non-AMI ACS, however, is an entirely different issue because UA is a het-erogeneous condition. For example, the stable patient with a classic description of new-onset angina, who is sensation free with a negative serum marker and a normal ECG, is still correctly diagnosed with UA.151 In contrast, an individual with ongoing pain, either intermittent or constant, with a dynamic ECG clearly is experiencing an active, unstable coronary event. The latter patient, who is at higher risk, can benefit from heparin therapy more than the former. Heparin therapy, however, can be a major contributor to morbidity and mortality among hospitalized patients. Major bleeding develops in 1 of every 90 patients treated, and heparin-induced thrombocytopenia in 1 of 34 patients. LMWH is as effective as UFH in patients with non–ST-segment elevation ACS and does not greatly increase the bleeding risk while decreasing the risk of thrombocytopenia.152

Other Antithrombins (Hirudin, Bivalirudin, and Fondaparinux). The direct thrombin inhibitors hirudin and bivalirudin (formerly known as Hirulog) are potent antithrombin anticoagulants pro-viding significant theoretical advantages compared with heparin. Hirudin is a peptide derived from the leech salivary gland but is also synthesized as recombinant hirudin. It binds directly with high affinity to thrombin and can inactivate thrombin already bound to fibrin (clot-bound thrombin) more effectively than UFH. Hirudin does not require endogenous cofactors, such as antithrombin III, for its activity. Also, unlike heparin, hirudin can inhibit thrombin-induced platelet aggregation. Hirudin demon-strates little significant benefit over other anticoagulants in ACS, with a possibly increased rate of hemorrhage; thus it offers little value in the ACS patient.

Bivalirudin is a bifunctional 20–amino acid peptide designed on the basis of the structure of hirudin. It has properties similar to those of hirudin but also interacts with the catalytic site of thrombin. Bivalirudin, however, is more effective than heparin in reducing death or reinfarction in patients with ACS, particularly those patients undergoing very early PCI.153

Bivalirudin, compared with heparin, produces similar rates of ischemia and major bleeding at 1 month. Bivalirudin when used with clopidogrel is comparable to the combination of heparin and GPI before coronary angiography or PCI. When used alone, it is inferior to the combination of heparin and GPI.154 Bivalirudin should be considered an acceptable alternative anticoagulant agent compared with the UFH in the STEMI patient undergoing PCI.140

Fondaparinux is a synthetic oligosaccharide with a structure similar to the heparins. It is the first widely used selective factor Xa inhibitor. With the increased emphasis on the reduction of


in preadmission environments and the ED. At the present time it appears that TNK is marginally more effective, minimally safer, and easier to administer than t-PA and thus is recommended; furthermore, cost differences are minimal and likely will not affect medical decision-making in the ED.

Eligibility Criteria for Fibrinolytic Agent Therapy The 12-Lead Electrocardiogram. Combined with the patient’s

history and physical examination, the 12-lead ECG is the key determinant of eligibility for fibrinolysis. The electrocardiographic findings include two basic issues: (1) ST segment elevation of 1 mm or more in two or more anatomically contiguous standard limb leads or elevation of 2 mm or more in two or more contigu-ous precordial leads, and (2) new or presumed new LBBB. No evidence of benefit from fibrinolytic therapy is found in patients with ischemic chest pain who lack either appropriate ST segment elevation or the development of a new LBBB.7

Patients with new LBBB and AMI are at an increased risk for a poor outcome and need rapid reperfusion therapy. The new devel-opment of LBBB in the setting of AMI suggests proximal occlusion of the left anterior descending artery and places a significant portion of the left ventricle in ischemic jeopardy. Unfortunately, patients with LBBB receive fibrinolytic agents less often than those with the more electrocardiographically alarming STEMI.

Patients with AMI in anterior, inferior, or lateral anatomic locations benefit from fibrinolytic therapy. The relatively favor-able prognosis associated with inferior infarction without fibri-nolytic therapy requires larger sample sizes to detect a significant survival benefit. The ISIS-2 trial demonstrated a statistically sig-nificant mortality benefit for fibrinolytic therapy in patients with inferior AMI.122 Patients with inferior AMI with coexisting right ventricular infarction, as detected by additional lead ECGs, are likely to benefit because of the large amount of jeopardized myo-cardium. Acute, isolated posterior wall MI, diagnosed by poste-rior leads, may be another electrocardiographic indication for fibrinolysis. Although unproven in large fibrinolytic agent trials, patients with isolated posterior AMI may be considered for reper-fusion therapy.

Fibrinolytic therapy should not be used routinely in patients with only ST segment depression on the 12-lead ECG, and the mortality rate may actually be increased. The TIMI-III trial dem-onstrated a significant difference in outcome in fibrinolytic-treated patients with only ST segment depression—7.4% incidence of death compared with 4.9% in the placebo group.163 These find-ings are further supported in the Fibrinolytic Therapy Trialists’ (FTT) meta-analysis, which demonstrated that the mortality rate among patients with ST segment depression who received fibri-nolytic therapy was 15.2% compared with 13.8% among control subjects.164

Patient’s Age. Past trials do not provide evidence to support withholding fibrinolytic therapy or choosing one particular agent over another on the basis of the patient’s age. In fact, the FTT Collaborative Group concludes that “clearly, age alone should no longer be considered a contraindication to fibrinolytic therapy.”164 Patients older than 75 years do have a higher incidence of hemor-rhagic stroke than younger patients.

Time from Symptom Onset. The generally accepted therapeu-tic time window for administration of a fibrinolytic agent after the onset of ST segment elevation AMI is 12 hours. Patients treated within the first 6 hours of AMI have the best outcome. Later administrations, from 6 to 12 hours after AMI onset, also confer benefit, although of a lesser magnitude. The Late Assessment of Fibrinolytic Efficiency (LATE) trial, which compared fibrinolytic therapy with placebo, found a significant 26% decrease in 35-day mortality in patients treated with t-PA, heparin, and aspirin 6 to 12 hours after the onset of symptoms.165 There was no significant decrease in mortality among patients treated 12 to 24 hours after symptom onset.

Fibrinolytic practice remains highly affected by the results of the GUSTO-I trial. The hypothesis of the GUSTO-I trial was that early and sustained infarct vessel patency is associated with better survival rates in patients with AMI. More than 41,000 patients were randomly assigned to four different fibrinolytic strategies: accelerated t-PA given over 90 minutes plus intravenous heparin, a combination of streptokinase plus a reduced dose of t-PA along with intravenous heparin, and two control groups (streptokinase plus subcutaneous heparin and streptokinase plus intravenous heparin). Unlike in previous trials, t-PA was given in a more aggressive, front-loaded 90-minute infusion (referred to as acceler-ated t-PA). In addition to a primary endpoint of 30-day mortality, the GUSTO investigators explored coronary artery patency and degree of normalization of flow in the angiographic substudy. This portion of the larger trial was designed to determine the relation-ship between early coronary artery patency and outcome. In this trial, accelerated t-PA, administered with intravenous heparin, reduced 30-day mortality significantly by 15% compared with streptokinase with either form of heparin or the combination of t-PA and streptokinase with intravenous heparin. The benefit out to 1-year follow-up was highly consistent across virtually all sub-groups, including elderly patients, AMI location, and time since symptom onset. The angiographic substudy demonstrated a strong relationship between TIMI flow and outcome. Patients with strong forward flow (i.e., TIMI grade 3 flow) at 90 minutes had significantly lower mortality rates than patients with little to no flow. The mechanism for this benefit was found to be earlier, more complete infarct vessel patency with accelerated t-PA; this early t-PA patency advantage over other agents was lost by 180 minutes after symptom onset. As would be expected, the patients with the higher risk derived the most substantial benefit with accelerated t-PA compared with streptokinase in this large study. Patients who received accelerated t-PA did experience more hemorrhagic strokes than those who received streptokinase, but the combined endpoint of death and disabling stroke still favored the accelerated t-PA regimen.

Another important fibrinolytic investigation is GUSTO-III.161 This study compared accelerated t-PA with r-PA; r-PA is a mutant form of t-PA that can be administered in a fixed double-bolus dose with no adjustment required for weight, which simplifies administration. In this very large trial, r-PA was found to be equiv-alent to accelerated t-PA, and the results were nearly identical for the two drugs. The one exception was the patient with presenta-tion more than 4 hours after onset of symptoms—a significant number of patients in many institutions. In this group, acceler-ated t-PA may be superior to r-PA because of its greater fibrin specificity.161

The Assessment of the Safety and Efficacy of a New Thrombo-lytic Agent (ASSENT-2) trial investigated the use of TNK, another mutant of wild-type t-PA. TNK has several potential benefits: (1) its longer half-life allows it to be administered as a single bolus; (2) it is 14 times more fibrin specific than t-PA and even more so than r-PA; and (3) it is 80 times more resistant to plasminogen activator inhibitor type 1 than t-PA. The ASSENT-2 trial ran-domly assigned approximately 17,000 patients with AMI to single-bolus TNK (30-50 mg on the basis of body weight) or accelerated t-PA (100 mg total infusion).162 The investigators found no differences in mortality or intracranial hemorrhage.162 In a subgroup analysis, however, significantly lower 30-day mor-tality was noted among patients with presentation more than 4 hours after onset of symptoms in those treated with TNK. Fur-thermore, fewer nonintracranial major bleeding episodes were encountered in the TNK group. On the basis of these results, it is concluded that TNK is equally or minimally more effective, par-ticularly in late presenters. Concerning adverse reactions, TNK also appears modestly safer than accelerated t-PA. Lastly, because of its single-bolus administration, TNK is markedly easier to use


GISSI-1 trial showed no treatment benefits for patients with previ-ous MIs, the ISIS-2 trial demonstrated a 26% relative mortality rate reduction.122 The FTT meta-analysis further demonstrates that patients with a history of past MI who receive fibrinolytic therapy for recurrent acute infarction have a mortality rate of 12.5% compared with 14.1% among control patients.164

Many studies report successful fibrinolysis in AMI patients with a prior CABG. Complete thrombotic occlusion of the bypass graft is the cause of AMI in approximately 75% of cases as opposed to native vessel occlusion. Because of the large mass of thrombus and absent flow in the graft, conventional fibrinolytic therapy may be inadequate to restore flow. These patients should be preferentially considered for direct angioplasty if immediately available or com-bined fibrinolysis and rescue angioplasty.

Recent Surgery or Trauma. Recent surgery or trauma is con-sidered a relative contraindication to fibrinolytic therapy. The term recent is subject to variable interpretation in fibrinolytic trials. In the GISSI-1 trial,167 patients were excluded if they had had surgery or trauma within the previous 10 days. In the Anglo-Scandinavian Study of Early Thrombolysis (ASSET) trial, patients were excluded for surgery or trauma within the previous 6 weeks.168 Other fibrinolytic therapy trials do not define “recent surgery or trauma.” We recommend avoidance of systemic fibri-nolytic therapy and use of an alternative intervention in patients with AMI within 10 days of surgery or significant trauma.

Menstruation. Because natural estrogen is partially cardiopro-tective, there is little experience with fibrinolysis among premeno-pausal women. Gynecologists indicate that any excessive vaginal bleeding that may occur after receipt of fibrinolytic therapy should be readily controllable by vaginal packing and therefore can be considered as a compressible site of bleeding.

Contraindications. A list of absolute and relative contraindica-tions is shown in Box 78-1.

These studies clearly establish benefit from 0 to 12 hours in patients who are otherwise appropriate candidates for fibrinolytic therapy. Treatment beyond that time is not supported by the lit-erature. The single exception may be a patient with a “stuttering” nature of chest pain 12 to 24 hours after symptom onset, which emphasizes the importance of an adequate history.

Blood Pressure Extremes. Patients with a history of chronic hypertension should not be excluded from fibrinolytic therapy if their blood pressure is under control at the time of presentation or can be lowered to acceptable levels with standard therapy for ischemic chest pain. The admission blood pressure is also an important indicator of risk of intracerebral hemorrhage. The FTT meta-analysis demonstrates that the risk of cerebral hemorrhage increases with systolic blood pressure higher than 150 mm Hg on admission and further increases when systolic blood pressure is 175 mm Hg or higher.164 Despite an increased mortality rate during days 0 and 1, the FTT meta-analysis dem-onstrated an overall long-term benefit of 15 lives saved per 1000 for patients with systolic blood pressures higher than 150 mm Hg and 11 lives saved per 1000 for patients with systolic blood pres-sures of 175 mm Hg or higher.164 Although the FTT meta-analysis appears to indicate an acceptable risk-benefit ratio for patients with substantially increased systolic blood pressure, a persistently elevated blood pressure higher than 200/120 mm Hg is generally considered to be an absolute contraindication to fibrinolytic therapy.

The benefit of fibrinolytic therapy in patients with hypoten-sion is unclear. The GISSI-1 and GISSI-2 trials showed no appar-ent reduction in mortality rate with fibrinolytic therapy among patients classified as Killip class III or IV.158 The FTT meta-analysis, however, demonstrated that patients with an initial sys-tolic blood pressure below 100 mm Hg who were not treated with fibrinolytic therapy had a very high risk of death (35.1%), and those who were treated with fibrinolytic therapy had the largest absolute benefit (60 lives saved per 1000 patients).164 Although cardiogenic shock and CHF are not contraindications to fibrinolysis, PCI is the preferred method of reperfusion if it can be accomplished on site.

Retinopathy. Active diabetic hemorrhagic retinopathy is a strong relative contraindication to fibrinolytic therapy because of the potential for permanent blindness caused by intraocular bleeding. There is no reason, however, to withhold the use of a fibrinolytic agent in a diabetic patient with evidence of simple background retinopathy. Patients with diabetes mellitus who sustain an AMI have an almost doubled incidence of mortality.

Cardiopulmonary Resuscitation. CPR is not a contraindica-tion to fibrinolytic therapy unless CPR is prolonged—more than 10 minutes—or extensive chest trauma from manual com-pression is evident. Although the in-hospital mortality rate is higher in AMI patients who experience cardiac arrest and then receive fibrinolytic agents in the ED, no difference is found in the rates of bleeding complications. Specifically, hemothorax and cardiac tamponade were not diagnosed in those cardiac arrest patients receiving CPR and fibrinolytics who survived to admis-sion. Even CPR prolonged beyond 10 minutes does not appear to be associated with higher rates of complication.166

Previous Stroke or Transient Ischemic Attack. A history of previous stroke or TIA is a major risk factor for hemorrhagic stroke after treatment with fibrinolytic therapy. A history of previ-ous ischemic stroke should remain a strong relative contraindica-tion to fibrinolytic therapy, and previous hemorrhagic stroke an absolute contraindication.

Previous Myocardial Infarction or Past Coronary Artery Bypass Graft. In the setting of AMI, a previous MI should not preclude consideration for treatment with fibrinolytic agents. Without treatment there is a potential for greater loss of function in the newly infarcting region of the myocardium. Although the

Adapted from Physicians’ Desk Reference, 50th ed. Montvale, NJ, Medical Economics, 1996.

BOX 78-1

Recent (within 10 days) major surgery (e.g., coronary artery bypass graft, obstetric delivery, organ biopsy, previous puncture of noncompressible vessels)

Cerebrovascular diseaseRecent gastrointestinal or genitourinary bleeding (within

10 days)Recent trauma (within 10 days)Hypertension: systolic BP 180 mm Hg or diastolic BP

110 mm HgHigh likelihood of left heart thrombus (e.g., mitral stenosis with

atrial fibrillation)Acute pericarditisSubacute bacterial endocarditisHemostatic defects, including those secondary to severe hepatic

or renal diseaseSignificant liver dysfunctionDiabetic hemorrhagic retinopathy or other hemorrhagic

ophthalmic conditionSeptic thrombophlebitis or occluded AV cannula at seriously

infected siteAdvanced age (older than 75 years)Patients currently receiving oral anticoagulants (e.g., warfarin

sodium)Any other condition in which bleeding constitutes a significant

hazard or would be particularly difficult to manage because of its location

Fibrinolysis in Acute Myocardial Infarction: Absolute and Relative Contraindications

AV, atrioventricular; BP, blood pressure.


96% of patients. These additional studies support the findings of the DANAMI-2 trial.169-172

The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) investigators com-pared angioplasty and PCI using coronary stents in STEMI patients undergoing urgent reperfusion therapy; abciximab was added to portions of both treatment groups. At 6 months, the primary endpoint (a composite of death, recurrent infarction, stroke, and urgent revascularization) had occurred in 20% of patients after angioplasty, 17% after PCI with abciximab, 12% after stenting, and 10% after stenting with abciximab.174

The longer-term results with PCI, however, are less clear. Much of the literature comparing the acute reperfusion therapies in AMI does not include the use of coronary stenting during PCI or con-temporary dual-agent platelet therapy. The GUSTO-IIb study showed no overall mortality advantage of PCI at 6 months.171 The issue of long-term outcome in PCI-managed STEMI patients is further complicated by drug-eluting stents (DESs). Early studies used bare metal stents (BMSs), which, in the setting of an acute thrombotic event such as STEMI, raised concern regarding stent thrombosis with obstruction and recurrent AMI.

In comparing BMS and DES with both angiographic and clini-cal outcome variables in STEMI patients treated with PCI using intracoronary stenting, event-free survival at 12 months was sig-nificantly higher in the DES group, with 74% in BMS patients and 86% in DES patients. Furthermore, the target-vessel–failure-free (i.e., correctly functioning culprit artery stent) survival was also significantly greater in the DES patients compared with the BMS group. The rates of death, MI, and stent thrombosis, however, were not significantly different between the groups. Also, a higher rate of stent malposition was noted in the DES group, despite a lower rate of event occurrence in this contingent.175

A meta-analysis of seven randomized trials compared the effects of DES and BMS in 2357 AMI patients. This study reported that DES significantly reduces the need for revascularization without changes in death or MI out to 1-year follow-up; no increased risk of thrombosis was found in the DES group.176 Another group extended the follow-up period of patients managed with coronary stenting. This patient group, undergoing PCI with stenting in an elective setting, extended the period of observation out to 2 years. These investigators found that target vessel revascularization was needed less often in the DES group, yet the rates of AMI and death were similar.177

Thus PCI with stenting appears to be superior to standard angioplasty. The addition of DES to the equation has produced less favorable results, however, with similar rates of MI and death coupled with a lower rate of revascularization in the DES patients to several years postintervention.

Rescue Percutaneous Coronary Intervention. Historically, rescue PCI has been considered advantageous in patients whose infarct-related arteries fail to reperfuse after fibrinolytic therapy.178 These patients are profoundly ill, with a markedly worse outcome. Some centers routinely catheterize patients after fibrinolytic therapy to determine whether successful reperfusion has occurred and to perform angioplasty if feasible. Other centers catheterize patients after fibrinolytic therapy only if there is clinical evidence that the infarct-related artery fails to open, as suggested by continued chest pain or persistent ST segment elevation.179-182

The Middlesbrough Early Revascularization to Limit INfarction (MERLIN) trial compared outcomes after rescue PCI with a con-servative management strategy in STEMI patients in whom fibri-nolysis failed. Rescue PCI was not associated with improved survival at 1 month; furthermore, increased rates of stroke and transfusion were noted in this group. At 1- and 3-year intervals, the lack of survivor benefit persisted.179-181 In a meta-analysis of STEMI patients who did not achieve satisfactory reperfusion after fibrinolysis, rescue PCI was not associated with mortality

Percutaneous Coronary Intervention

Although fibrinolysis has widespread availability and a proven ability to improve coronary flow, limit infarct size, and improve survival in AMI patients, many individuals with acute infarction are not suitable candidates. Patients with absolute contraindica-tions to fibrinolytic therapy, certain relative contraindications, cardiogenic shock, and UA may be ineligible to receive fibrinolytic therapy. The requirement of administering prompt reperfusion therapy to these patients, as well as the other limitations of fibrinolytic therapy, have led many clinicians to advocate for PCI. PCI has many theoretic advantages over fibrinolysis, includ-ing an increased number of eligible patients, a lower risk of intra-cranial bleeding, a significantly higher initial reperfusion rate, an earlier definition of coronary anatomy with rapid triage to surgical intervention, and risk stratification allowing safe, early hospital discharge. Potential disadvantages include lack of opera-tor expertise and numerous catheterization laboratory logistical issues, including limited geographic availability and delay to therapy application.

Several trials of varying sizes comparing primary PCI with fibri-nolysis have been reported. Interventions in the early trials were performed before the widespread adoption of coronary stents with GPI. Despite a clear and consistent benefit of PCI in restoring patency of the infarct-related artery, differences in mortality in the individual trials were difficult to evaluate because of the smaller sample sizes. The Primary Angioplasty in Myocardial Infarction (PAMI) trial enrolled 395 patients randomly assigned to undergo PCI or to receive t-PA.169 Compared with standard-dose t-PA, PCI reduced the combined occurrence of nonfatal reinfarction or death, was associated with a lower rate of intracranial hemorrhage, and resulted in a similar left ventricular function. The results of the Netherlands trial indicate that primary angioplasty is associ-ated with a higher rate of patency of the infarct-related artery, a less severe residual stenotic lesion, better left ventricular function, and less recurrent myocardial ischemia and infarction than in patients receiving streptokinase.170

In a substudy of the GUSTO-IIb trial,171 the investigators ran-domly assigned 1138 patients with AMI to either PCI or acceler-ated t-PA. The composite 30-day endpoint included death, nonfatal reinfarction, and nonfatal disabling stroke. Of the patients assigned to PCI therapy, 83% were candidates for such treatment and underwent angioplasty 1.9 hours after ED arrival for a total elapsed time from chest pain onset to therapy of 3.8 hours. Ninety-eight percent of the patients assigned to fibrinolytic therapy received t-PA 1.2 hours after hospital arrival. The composite end-point was encountered significantly less often in the PCI group (9.6%) than in the t-PA group (13.7%) at 30 days. When the individual components of the composite endpoint at 30 days were considered separately, death, infarction, and stroke occurred at statistically similar rates for both treatment groups. A meta-analysis reviewed 10 major studies comparing fibrinolysis with primary PCI in more than 2600 patients. The 30-day mor tality and stroke occurrence were significantly lower in the PCI group.172

The second Danish Acute Myocardial Infarction (DANAMI-2) trial comprehensively investigated the PCI strategy.173 Investiga-tors randomly assigned AMI patients to receive either PCI or accelerated treatment with alteplase (t-PA). Patients arrived at hospitals without invasive capabilities (totaling 24) or with angioplasty capability (totaling 5). Stents and GPI were available and were used at the discretion of the treating physicians. For angioplasty-managed patients at noninvasive centers, transfer to PCI-capable institutions had to occur within a 3-hour time period. Significant differences were observed in a composite endpoint of death, reinfarction, or disabling stroke at 30 days between the groups, with rates of 8.5% in the PCI group versus 14.2% in the fibrinolytic group. Transfer for PCI occurred within 2 hours in


If the time required to mobilize staff and arrange for PCI is prolonged or if delays in transfer are anticipated, fibrinolysis is preferred. Prior agreement between the ED and the cardiovascular physicians at institutions with invasive capability must be obtained so that PCI consideration does not introduce further delays in fibrinolytic drug administration. Consensus clinical pathways limit additional delays in the administration of fibrinolytic agents in patients who are considered for PCI in AMI.187

An elegant analysis of the “PCI versus fibrinolysis” consider-ation in the STEMI patient asks: How long should the practitioner wait for PCI in a patient who is fibrinolytic eligible? Consider-ations include the important time-to-therapy question and also factors such as the time from onset to presentation, patient age, and infarct location. Time recommendations are also provided with respect to patient age, infarct duration, and MI anatomic location. The maximal elapsed times one should wait for PCI (the actual time to balloon inflation), at which point the survival benefit of the invasive strategy is lost and the patient should receive a fibrinolytic agent, are discussed here.188

In a complex analysis of 192,509 patients in a national STEMI registry,188 acceptable PCI “waiting times” range broadly from approximately 40 to 180 minutes. For instance, the relatively younger patient who is experiencing an anterior STEMI and is seen within 2 hours of symptom onset should be in the catheter-ization laboratory with the catheter across the lesion within 40 minutes or should receive a fibrinolytic agent. Conversely, the older patient with an inferior or lateral STEMI who is seen more than 2 hours after symptom onset could wait up to 179 minutes (almost 3 hours) before any PCI survival benefit is lost. Patient presentations with the “maximal allowable” time to catheter place-ment across the lesion are as follows:

• Within 2 hours of symptom onset—94 min• Beyond 2 hours of symptom onset—190 min• Younger than 65 years—71 min• Older than 65 years—155 min• Anterior STEMI—115 min• Nonanterior STEMI—112 minFurther analysis combined commonly encountered clinical

variables in typical STEMI presentations:• Patient presentation within 2 hours of symptom onset and:

• Anterior STEMI with age younger than 65 years—40 min• Anterior STEMI with age older than 65 years—107 min• Nonanterior STEMI with age younger than 65

years—58 min• Nonanterior STEMI with age older than 65

years—168 min• Patient presentation beyond 2 hours of symptom onset and:

• Anterior STEMI with age younger than 65 years—43 min• Anterior STEMI with age older than 65 years—148 min• Nonanterior STEMI with age younger than 65

years—103 min• Nonanterior STEMI with age older than 65

years—179 minSymptom duration as well as patient age and infarct location affects reperfusion therapy decisions. Patients who are not able to rapidly reach the PCI suite should receive fibrinolysis. This analysis does not represent the standard for treatment comparisons.188

Delays to reperfusion therapy have negative consequences, as noted in a subset of patients in the GRACE database. The investi-gators examined the outcome impact of treatment delays on STEMI patients receiving reperfusion therapy. This study involved 3959 patients from 106 hospitals in 14 countries with presentation within 6 hours of chest pain onset who underwent either PCI (55%) or fibrinolysis (45%). Delays in reperfusion were associated with increased mortality for both treatment strategies and were more pronounced in those patients receiving fibrinolysis.189

reductions. In this very ill group, however, the incidence of heart failure and recurrent infarction was reduced. Repeat fibrinolysis was not associated with significant improvements in mortality or recurrent infarction.182 Although the decision to offer rescue PCI in the patient in whom fibrinolytic therapy has failed remains controversial, evidence favors rescue PCI and does not support the use of repeat fibrinolysis.

Facilitated Percutaneous Coronary Intervention. Facilitated percu-taneous coronary intervention refers to combination therapy involving fibrinolysis coupled with emergent PCI. This concept originally was developed to maximize therapy in STEMI patients who would be transferred urgently for PCI; the patient would receive the additive benefit of medical therapy (a fibrinolytic agent) before transfer, optimizing the culprit artery for the benefit of mechanical therapy before arrival at the PCI-capable institu-tion. Unfortunately, outcomes from this facilitated approach are less optimal than either fibrinolysis or standard PCI alone. The ASSENT-4 PCI investigators considered this approach with tenecteplase in a facilitated PCI protocol for STEMI patients. The tenecteplase group had a higher rate of the primary endpoint (death, acute CHF, or shock) within 90 days as well as increased occurrences of stroke, ischemic cardiac complications, and need for repeat revascularization.183 A larger meta-analysis of 17 trials compared facilitated PCI with standard PCI in the STEMI patient. Patients undergoing facilitated PCI experienced higher rates of poor outcome and complication than patients in the standard PCI group. The facilitated PCI group fared less well, with a higher rate of nonfatal recurrent infarction, urgent need for revascularization, major bleeding, and stroke.184 The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial, though stopped early, clearly supported this conclusion.185 In light of these results, the continued use of a facilitated PCI approach is unclear outside of a scientific investigation.186

Choice of Reperfusion Therapy

The principal choices for reperfusion therapy in the STEMI patient include fibrinolysis and PCI, although numerous recom-mendations exist. Regardless of the strategy selected, “the systems goal should be a first medical contact–to-[therapy] time within 90 minutes.”7 The following recommendations should be considered by the emergency physician and other involved clinicians in deter-mining the most appropriate reperfusion therapy for the STEMI patient. A fibrin-specific fibrinolytic agent is the preferred strategy in the patient without contraindication to such therapy who is seen early in the time course of the infarction (i.e., within 3 hours). In this fibrinolytic-preferred strategy, PCI either is not available (i.e., a noninvasive center) or is delayed (transfer or other logistical problems). The system goal for fibrinolytic therapy is to deliver the drug within 30 minutes of patient presentation.7

PCI is the preferred reperfusion strategy in the STEMI patient who can arrive in the catheterization laboratory with placement of the catheter adjacent to the culprit artery lesion within 90 minutes of initial hospital arrival.7 High-risk STEMI patients, “late present-ers” (i.e., more than 3 hours since the onset of STEMI symptoms), and individuals with contraindication to fibrinolysis are also can-didates for PCI. When the diagnosis of STEMI is in doubt, PCI is the most appropriate diagnostic and therapeutic strategy.

If applied early and without delay, PCI provides improved outcome over fibrinolysis in the STEMI patient. It should be initi-ated within 90 minutes of arrival at the initial hospital ED.7 As noted in the DANAMI-2 study,173 PCI initiated within 3 hours of initial hospital arrival is also superior to fibrinolysis. Because many hospital systems do not have the capability of meeting the time goal for primary PCI, fibrinolytic therapy is preferred because of the critical importance of time to treatment from onset of symp-toms of STEMI in reducing morbidity and mortality.7


at the time of PCI, invasive therapy restored coronary perfusion in 96% of cases, and all of these patients survived without neuro-logic deficit. The outcome in the comatose patient subgroup was less favorable, with approximately a 50% survival rate and good neurologic outcome.197

Therapeutic hypothermia, when combined with PCI, in resus-citated cardiac arrest STEMI patients demonstrates an impressive rate of survival with good neurologic outcome. In a series of 40 such patients, therapeutic hypothermia coupled with PCI demon-strated a significantly improved rate of survival.198

It is reasonable to include PCI as part of a standard postresus-citation care program, including therapeutic hypothermia, as almost 50% of cardiac arrest survivors have an acute occlusion or culprit lesion amenable to intervention.199 Furthermore, PCI need not preclude or delay the initiation of therapeutic hypothermia, as many methods may be used concurrently in the catheterization laboratory.

Another study compared reperfusion strategies in cardiac arrest survivors who experienced STEMI in the immediate postresusci-tation period. Regardless of the reperfusion method, approxi-mately 65% of patients survived to 6 months, with 53% demonstrating good neurologic function. The rate of an adverse event, such as significant hemorrhage in patients who received more than 10 minutes of CPR, was similar in those patients who did and did not receive a fibrinolytic agent.166

Transfer of a Patient with Acute Coronary Syndrome

There are several indications for the transfer of a patient with ACS to a facility with PCI capability. These include rapid access to PCI (catheter across the lesion within 90 minutes of arrival to the initial hospital), persistent hemodynamic instability or ventricular dysrhythmias, and postinfarction or postreperfusion ischemia. Hospital transfer for PCI is also suggested for patients with fibri-nolytic contraindications who may benefit from PCI or CABG.

The urgent transfer of a fibrinolytic-eligible STEMI patient to another institution for PCI is not recommended until fibrinolytic therapy has been initiated if a delay in PCI application is antici-pated.174 In fact, the ACC/AHA guidelines note that in hospitals without PCI capability, immediate transfer for primary PCI is a treatment option when it can be accomplished within 120 minutes of first medical contact.140 If delays in PCI performance are antici-pated and the patient is an acceptable candidate for fibrinolysis, the fibrinolytic should be started before or during transport to the receiving hospital.

Many institutions are not PCI capable. Thus the decision for the emergency physician involves not only the relatively simple “lytic versus PCI” issue but also the potential need for urgent transfer to a larger center. The PRimary Angioplasty in patients transferred from General community hospitals to specialized per-cutaneous coronary angioplasty (PTCA) Units with or without Emergency thrombolysis (PRAGUE) investigators explored the potential benefit of PCI over fibrinolysis and the all-important impact of transfer of the STEMI patient in a noninterventional hospital over a multiyear follow-up study. At the end of the 5-year period, the cumulative incidence of composite endpoint (death from any cause, recurrent infarction, stroke, and/or revasculariza-tion) was 53% in fibrinolytic patients compared with 40% in the PCI group. The investigators concluded that the early benefit from a transfer-related invasive strategy was sustained over the 5-year follow-up period. The benefit was largely a result of a lower event rate in the first 30 days after presentation.200

The potential need to transfer the STEMI patient over long distances can also affect reperfusion therapy decisions. In a study of patients in rural hospitals in central Illinois, a standard treat-ment protocol initiated by the emergency physician included rapid

A cooperative effort among all providers and units can reduce markedly the door-to-therapy time in STEMI patients.190 A “STEMI alert” system, analogous to the “trauma alert” approach, mobilizes hospital-based resources, optimizing the approach to the AMI patient. This system, whether activated by data gathered in the ED or in the field, has the potential to offer time-sensitive therapies in a rapid fashion. In fact, emergency physician activa-tion of the catheterization laboratory demonstrates very high rates of accurate STEMI diagnosis while markedly reducing the time to definitive therapy with very low rates of inappropriate activation (i.e., the STEMI mimicker).112,191,192 The ACC and AHA recognize the numerous challenges and potential difficulties in achieving these reperfusion therapy time goals.7

Reperfusion Therapy in Cardiogenic Shock

Patients with AMI with cardiogenic shock, which occurs in up to 10% of cases, demand special consideration because of a mortality rate approaching 80%. Fibrinolysis is not effective in these patients owing to a significantly lower coronary perfusion pressure. In shock, the occlusive thrombus is not exposed to the fibrinolytic agent, resulting in clinical failure of the drug. In large fibrinolytic trials such as GISSI-1 and ISIS-2,163,168 AMI patients in cardiogenic shock do not benefit from fibrinolysis. Conversely, primary PCI has been investigated in more than 600 patients in several small studies. A cumulative analysis revealed a significantly lower mor-tality rate (45%) compared with placebo or historical controls.193 The SHould we emergently revascularize Occluded Coronaries in cardiogenic shocK? (SHOCK) trial compared the outcomes of AMI patients in cardiogenic shock.194 Patients were randomly assigned to emergency revascularization (PCI or emergent CABG) or initial medical stabilization, including fibrinolysis. The primary endpoint was mortality from all causes at 30 days; 6-month sur-vival was the secondary endpoint. Overall mortality at 30 days did not differ significantly between the revascularization and medical therapy groups. Six-month mortality was lower in the revascularization group than in the medical therapy group. The investigators conclude that in AMI patients with cardiogenic shock, emergency revascularization does not significantly reduce overall mortality at 30 days. After 6 months, however, there is a significant survival benefit. Thus, emergency revascularization with PCI or CABG is preferred in patients with STEMI compli-cated by cardiogenic shock irrespective of the delay to treatment (i.e., more than 120 minutes first medical contact to PCI time usually measured for transferring these patients). Fibrinolytic therapy should be given to eligible patients who are otherwise unsuitable candidates for PCI or CABG.140

Resuscitated Cardiac Arrest with ST Segment Elevation Myocardial Infarction

The management of the STEMI patient resuscitated from cardiac arrest includes: (1) rapid revascularization with PCI, (2) strict hemodynamic monitoring, (3) serum glucose control, (4) oxygen and volume-limiting ventilation, and (5) immediate application of therapeutic hypothermia for those patients whose cardiac arrest was caused by ventricular fibrillation or pulseless ventricular tachycardia.195 A clinical presentation of coma after cardiac arrest should not be considered a contraindication to reperfusion therapy, as such findings are commonly present. In a series of 186 patients who underwent immediate PCI after successful resuscita-tion for cardiac arrest complicating STEMI, PCI was successful in almost 90%, restoring adequate coronary perfusion. It is interest-ing to note that 54% survived beyond 6 months, with a large proportion having intact neurologic function.196 A second inves-tigation reviewed 135 patients with resuscitated cardiac arrest complicated by STEMI. Among those patients who were conscious


hospital transfer for PCI. Fibrinolysis was used at the discretion of the treating emergency physician when either unanticipated delays occurred or the physician felt such therapy was necessary. In this study, the median initial hospital arrival to transfer initia-tion time was 46 minutes; a large portion of this delay was a to the transport vehicle. The transferring and accepting hospitals’ arrival to catheter median placement times were 29 minutes and 35 minutes, respectively. Overall, the initial hospital arrival to catheter placement time was 117 minutes. No transfer-related complications occurred. Sixty percent of STEMI patients received some form of reperfusion therapy in this rural system within 120 minutes.201 This prolonged transport issue was also explored in an established treatment system involving 30 hospitals ranging up to 210 miles from the PCI center. Over a 2.5-year period, 1345 con-secutive STEMI patients were managed, including 1048 patients transferred from non-PCI hospitals.202 These two investigations suggest that rapid transfer for PCI in the STEMI patient can occur in the rural setting with acceptable time to therapy.

Potential Pharmacologic Management Approach

The patient with stable chest pain with a normal to minimally abnormal ECG and a negative serum marker is best managed initially with NTG sublingually or topically in combination with aspirin. Resolution of the discomfort with continued stability probably does not warrant further ED pharmacologic manage-ment. Continued or recurrent pain in the ED may be treated with parenteral morphine sulfate. Continued pain may ultimately require intravenous NTG and heparinization with UFH or LMWH, with additional antiplatelet therapy with either a thieno-pyridine or GPI. The patient with “stable” UA (i.e., new-onset or altered pattern but now symptom free and lacking abnormal serum markers and ECG) does not require heparin or other more aggressive platelet inhibition therapy in most cases.

The ACS patient with an abnormal ECG, particularly ST segment and T wave abnormalities, or elevated serum markers may warrant numerous therapies, including ASA, heparin, and other antiplatelet agents. NTG may be administered by the topical or intravenous route. The patient with recurrent angina may also benefit from such an approach. Heparin therapy is generally indi-cated in this instance.

The AMI patient without ST segment elevation requires aspirin, NTG, heparin, and morphine sulfate. Depending on hospital

■ Anginal equivalent symptoms that are not characteristically associated with ACS vary widely and often distract from the diagnosis. The patient’s age, diabetes status, ethnicity, and gender are considered with an atypical history.

■ Limitations of the 12-lead ECG in ACS include initial nondiagnostic findings, evolving fluctuations with ongoing symptoms, anatomic myocardial “blind spots,” and confounding or obscuring patterns, such as LBBB.

■ Patients with proximal left anterior descending artery stenosis (Wellens syndrome) may have deeply inverted or biphasic T waves in the anterior precordial leads.

■ ST segment elevation in lead aVR over 0.5 mV suggests left main coronary artery disease.

■ Functional testing strategies for ACS include graded exercise testing, echocardiography, myocardial scintigraphy, and coronary CT. Graded exercise testing with or without nuclear scintigraphy can be used in the patient with low to moderate likelihood of CAD who is able to exercise. Myocardial scintigraphy with pharmacologic stress can be used in the debilitated or older patient (i.e., unable to exercise). Echocardiography with pharmacologic stress is appropriate for the woman older than 45 years, the patient with diabetes mellitus, and patients with other forms of organic heart disease (valvular dysfunction and low cardiac output states). The use of coronary CT is most appropriate in the younger patient, yet its widespread application cannot be advised.

■ Fibrinolysis is not effective in patients with AMI in cardiogenic shock.

■ Advancements in other noninvasive imaging modalities to assess ACS include coronary CTA and triple rule-out MDCT protocols; their role in the ED remains undefined.

■ Unless used for rate control of supraventricular dysrhythmia in a patient who cannot tolerate beta-blockade, calcium channel blockade is not recommended for ACS.

KEY CONCEPTS

protocols and the type of ACS, a thienopyridine can be adminis-tered in the ED or in the coronary care area. The patient with ST segment elevation AMI is treated with the preceding medications and is considered for urgent revascularization, achieved by fibri-nolytic agents, PCI, or, in the rare case, CABG.

The references for this chapter can be found online by accessing the accompanying Expert Consult website.

CHAPTER 78 / Acute Coronary Syndrome 1033.e1

References

1. Mackay J, Mensah G, eds. The Atlas of Heart Disease and Stroke. Geneva: World Health Organization; 2004.

2. Hunink MG, et al: The recent decline in mortality from coronary heart disease, 1980-1990: The effect of secular trends in risk factors and treatment. JAMA 1997; 227:535.

3. McCaig LF, Burt CW: National Hospital Ambulatory Medical Care Survey: 2001 emergency department summary. Adv Data 2003; 335:1.

4. Nawar EW, Niska RW, Xu J: National hospital ambulatory medical care survey: 2005 emergency department summary. Adv Data 2007; 386:1.

5. Rosamond W, et al: Heart disease and stroke statistics—2007 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115:e69.

6. Anderson JL, et al: ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007; 50:e1.

7. Antman EM, et al: 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction. Circulation 2008; 117:296.

8. Ryan TJ, Melduni RM: Highlights of latest American College of Cardiology and American Heart Association Guidelines for Management of Patients with Acute Myocardial Infarction. Cardiol Rev 2002; 10:35.

9. Spertus JA, et al: Challenges and opportunities in quantifying the quality of care for acute myocardial infarction. J Am Coll Cardiol 2003; 41:1653.

10. Weinstein MD, Stason WB: Cost-effectiveness of interventions to prevent or treat coronary heart disease. Annu Rev Public Health 1985; 6:41.

11. Thygesen K, et al: Universal definition of myocardial infarction. Circulation 2007; 116:2634.

12. Antman EM, et al: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). J Am Coll Cardiol 2004; 44:E1.

13. Diop D, Aghababian RV: Definition, classification, and pathophysiology of acute coronary ischemic syndromes. Emerg Med Clin North Am 2001; 19:259.

14. Badimon L, Badimon JJ, Vilahur G, Segalés E, Llorente V: Pathogenesis of the acute coronary syndromes and therapeutic implications. Pathophysiol Haemost Thromb 2002; 32:225.

15. Hargarten KM, et al: Limitations of prehospital predictors of acute myocardial infarction and unstable angina. Ann Emerg Med 1987; 16:1325.

16. Khot UN, et al: Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003; 290:898.

17. Han JH, et al: The role of cardiac risk factor burden in diagnosing acute coronary syndromes in the emergency department setting. Ann Emerg Med 2007; 49:145.

18. Body R, McDowell G, Carley S, Mackway-Jones K: Do risk factors for chronic coronary heart disease help diagnose acute myocardial infarction in the emergency department? Resuscitation 2008; 79:41-45.

19. Currier JS, et al: Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr 2003; 33:506-512.

20. Shoenfeld Y, et al: Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 2005; 112:3337.

21. Mattu A, Petrini J, Swencki S, Chaudhari C, Brady WJ: Premature atherosclerosis and acute coronary syndrome in systemic lupus erythematosus. Am J Emerg Med 2005; 23:696-703.

22. Swap CJ, Nagurney JT: Value and limitations of chest pain history in the evaluation of patients with suspected acute coronary syndromes. JAMA 2005; 294:2623.

23. Body R, et al: The value of symptoms and signs in the emergent diagnosis of acute coronary syndromes. Resuscitation 2010; 81:281-286.

24. Tierney WM, et al: Physicians’ estimates of the probability of myocardial infarction in emergency room patients with chest pain. Med Decis Making 1986; 6:12.

25. Canto JG, et al: Prevalence, clinical characteristics, and mortality among patients with myocardial infarction without chest pain. JAMA 2000; 283:3223.

26. Canto JG, et al: Atypical presentations among Medicare beneficiaries with unstable angina pectoris. Am J Cardiol 2002; 90:248.

27. Grossman SA, et al: Predictors of delay in presentation to the ED in patients with suspected acute coronary syndromes. Am J Emerg Med 2003; 21:425.

28. Alexander KP, et al: Acute coronary care in the elderly. Part I: Non-ST segment elevation acute coronary syndromes. Circulation 2007; 115:2549.

29. Jacoby RM, Nesto RW: Acute myocardial infarction in the diabetic patient: Pathophysiology, clinical course, and prognosis. J Am Coll Cardiol 1992; 20:736.

30. McSweeney JC, et al: Women’s early warning symptoms of acute myocardial infarction. Circulation 2003; 108:2619.

31. Venkat A, et al: The impact of race on the acute management of chest pain. Acad Emerg Med 2002; 10:1199.

32. Pope JH, et al: Missed diagnosis of acute cardiac ischemia in the emergency department. N Engl J Med 2000; 342:1163.

33. McCarthy BD, Beshansky JR, D’Agostino RB, Selker HP: Missed diagnoses of acute myocardial infarction in the emergency department: Results from a multicenter study. Ann Emerg Med 1993; 22:579.

34. Brady WJ, Perron A: Acute cardiovascular complications in ED patients with AMI. Ann Emerg Med 2000; 36:S33.

35. Brady WJ, Swart G, DeBehnke DJ, Ma OJ, Aufderheide TP: The efficacy of atropine in the treatment of hemodynamically unstable bradycardia and atrioventricular block: Prehospital and emergency department considerations. Resuscitation 1999; 41:47.

36. Swart G, Brady WJ Jr, DeBehnke DJ, Ma OJ, Aufderheide TP: Acute myocardial infarction complicated by hemodynamically unstable bradyarrhythmia: Prehospital and emergency department treatment with atropine. Am J Emerg Med 1999; 17:647.

37. Zimetbaum PJ, Josephson ME: Use of the electrocardiogram in acute myocardial infarction. N Engl J Med 2003; 348:933.

38. Mooe T, Eriksson P, Stegmayr B: Ischemic stroke after acute myocardial infarction: A population-based study. Stroke 1997; 28:762.

39. Tiefenbrunn AJ, Chandra NC, French WJ, Gore JM, Rogers WJ: Clinical experience with primary percutaneous transluminal coronary angioplasty compared with alteplase (recombinant tissue-type plasminogen activator) in patients with acute myocardial infarction: A report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol 1998; 31:1240.

40. Zarich W, Nesto RW: Implications and treatment of acute hyperglycemia in the setting of acute myocardial infarction. Circulation 2007; 115:e436.

41. Singer AJ, et al: Effect of duration from symptom onset on the negative predictive value of a normal ECG for exclusion of acute myocardial infarction. Ann Emerg Med 1997; 29:575.

42. Smith SW: Upwardly concave ST segment morphology is common in acute left anterior descending coronary artery occlusion. Acad Emerg Med 2003; 10:516.

43. Brady WJ, et al: Electrocardiographic ST segment elevation: The diagnosis of AMI by morphologic analysis of the ST segment. Acad Emerg Med 2001; 8:961.

44. Wang K, Asinger RW, Marriott HJ: ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med 2003; 349:2128.

45. Otto LA, Aufderheide TP: Evaluation of ST segment elevation criteria for the prehospital electrocardiographic diagnosis of acute myocardial infarction. Ann Emerg Med 1994; 23:17.

46. Brady WJ, et al: Reciprocal ST segment depression: Impact on the electrocardiographic diagnosis of ST segment elevation acute myocardial infarction. Am J Emerg Med 2002; 20:35.

47. Brady WJ, et al: Electrocardiographic ST segment elevation in emergency department chest pain center patients: Etiology responsible for the ST segment abnormality. Am J Emerg Med 2001; 9:25.

48. Doevendans PA, et al: Electrocardiographic diagnosis of reperfusion during thrombolytic therapy in acute myocardial infarction. Am J Cardiol 1995; 75:1206-1210.

49. Wehrens XH, Doevendans PA, Ophuis TJ, Wellens H: A comparison of electrocardiographic changes during reperfusion of acute myocardial infarction by thrombolysis or percutaneous transluminal coronary angioplasty. Am Heart J 2000; 139:430.

50. Szymanski FM, et al: Electrocardiographic features and prognosis in acute diagonal or marginal branch occlusion. Am J Emerg Med 2007; 25:170.

51. Saw J, Davies C, Fung A, Spinelli JJ, Jue J: Value of ST elevation in lead III greater than lead II in inferior wall acute myocardial infarction for predicting in-hospital mortality and diagnosing right ventricular infarction. Am J Cardiol 2001; 87:4481.

52. Zehmer U, et al: Effects of fibrinolytic therapy in acute myocardial infarction with or without right ventricular involvement. J Am Coll Cardiol 1998; 2:876.

1033.e2 PART III ◆ Medicine and Surgery / Section Three • Cardiac System

53. Rostoff P, et al: Electrocardiographic prediction of acute left main coronary artery occlusion. Am J Emerg Med 2007; 25:852.

54. Yamaji H, et al: Prediction of acute left main coronary artery obstruction by 12-lead electrocardiography. ST segment elevation in lead aVR with less ST segment elevation in lead V1. J Am Coll Cardiol 2001; 38:1348.

55. Sharkey SW, Berger CR, Brunette DD, Henry TD: Impact of the electrocardiogram on the delivery of thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1994; 73:550-553.

56. Haissaguerre M, et al: Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008; 358:2016-2023.

57. Smith S, Nolan M: Ratio of T amplitude to QRS amplitude best distinguishes acute anterior MI from anterior left ventricular aneurysm. Acad Emerg Med 2003; 10:516.

58. Sgarbossa EB, et al: Electrocardiographic diagnosis of evolving acute myocardial infarction in the presence of left bundle-branch block: GUSTO-1 (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) Investigators. N Engl J Med 1996; 334:481.

59. Edhouse JA, Sakr M, Angus J, Morris FP: Suspected myocardial infarction and left bundle branch block: Electrocardiographic indicators of acute ischaemia. J Accid Emerg Med 1999; 16:331.

60. Sgarbossa EB, Pinski SL, Gates KB, Wagner GS: Early electrocardiographic diagnosis of acute myocardial infarction in the presence of ventricular paced rhythm: GUSTO-1 Investigators. Am J Cardiol 1996; 77:423.

61. Pitta SR, et al: ST segment depression on the initial electrocardiogram in acute myocardial infarction: Prognostic significance and its effect on short-term mortality: A report from the National Registry of Myocardial Infarction (NRMI-2, 3, 4). Am J Cardiol 2005; 95:843.

62. Brady WJ, et al: A comparison of the 12-lead ECG to the 15-lead ECG in emergency department chest pain patients: Impact on diagnosis, therapy, and disposition. Am J Emerg Med 2000; 18:239.

63. Zalenski RJ, Cooke D, Rydman R, Sloan EP, Murphy DG: Assessing the diagnostic value of an ECG containing leads V4R, V8, and V9: The 15-lead ECG. Ann Emerg Med 1993; 22:786.

64. Fesmire FM, Percy RF, Bardoner JB, Wharton DR, Calhoun FB: Usefulness of automated serial 12-lead ECG monitoring during the initial emergency department evaluation of patients with chest pain. Ann Emerg Med 1998; 31:3.

65. Jernberg T, Lindahl B, Wallentin L: ST-segment monitoring with continuous 12-lead ECG improves early risk stratification in patients with chest pain and ECG nondiagnostic of acute myocardial infarction. J Am Coll Cardiol 1999; 34:1413.

66. Ornato J: Electrocardiographic body surface mapping. In: Chan TC, et al, eds. The ECG in Emergency Medicine and Acute Care. Philadelphia: Elsevier; 2004.

67. Ornato JP, et al: 80-lead body map detects acute ST-elevation myocardial infarction missed by standard 12-lead electrocardiography. J Am Coll Cardiol 2002; 39:L332A.

68. Self WH, et al: Body surface mapping in the emergency department evaluation of the chest pain patient: Use of the 80-lead ECG system. Am J Emerg Med 2006; 24:87.

69. Hoekstra JW, et al: Acute detection of ST-elevation myocardial infarction missed on standard 12-lead ECG with a novel 80-lead real-time digital body surface map: Primary results from the multicenter OCCULT MI trial. Ann Emerg Med 2009; 54:779.

70. Menown IB, Mackenzie G, Adgey AA: Optimizing the initial 12-lead electrocardiographic diagnosis of acute myocardial infarction. Eur Heart J 2000; 21:275.

71. Balk EM, Ioannidis JP, Salem D, Chew PW, Lau J: Accuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department. Ann Emerg Med 2001; 37:478.

72. Reichlin T, et al: Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009; 361:858.

73. Kontos MC, et al: Implication of different cardiac troponin I levels for clinical outcomes and prognosis of acute chest pain patients. J Am Coll Cardiol 2004; 43:958.

74. Ohman EM, et al: Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996; 335:1333.

75. James S, et al: Troponin T levels and risk for 30-day outcomes in patients with acute coronary syndrome: Prospective verification in the GUSTO-IV trial. Am J Med 2003; 115:178.

76. Fromm RE: Cardiac troponins in the intensive care unit: Common causes of increased levels and interpretation. Crit Care Med 2007; 35:584.

77. Agewall S, Giannitsis E, Jernberg T, Katus H: Troponin elevation in coronary vs. non-coronary disease. Eur Heart J 2011; 32:404-411.

78. Khan NA, Hemmelgarn BR, Tonelli M, Thompson CR, Levin A: Prognostic value of troponin T and I among asymptomatic patients with end-stage renal disease: A meta-analysis. Circulation 2005; 112:3088.

79. Fesmire FM, Christenson RH, Fody EP, Feintuch TA: Delta creatine kinase-MB outperforms myoglobin at two hours during the emergency department identification and exclusion of troponin positive non-ST segment elevation acute coronary syndromes. Ann Emerg Med 2004; 44:12.

80. Bassan R, et al: B-type natriuretic peptide: A novel early blood marker of acute myocardial infarction in patients with chest pain and no ST-segment elevation. Eur Heart J 2005; 26:234.

81. Galvani M, et al: N-terminal pro-brain natriuretic peptide on admission has prognostic value across the whole spectrum of acute coronary syndromes. Circulation 2004; 110:128.

82. Brennan ML, et al: Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003; 349:1595.

83. Morrow DA, Braunwald E: Future of biomarkers in acute coronary syndromes: Moving toward a multimarker strategy. Circulation 2002; 108:250.

84. McCord J, et al: Ninety-minute exclusion of acute myocardial infarction by use of quantitative point-of-care testing of myoglobin and troponin I. Circulation 2001; 104:1483.

85. Ng SM, et al: Ninety-minute accelerated critical pathway for chest pain evaluation. Am J Cardiol 2001; 88:403.

86. Fesmire FM, et al: The Erlanger chest pain evaluation protocol: A one-year experience with serial 12-lead ECG monitoring, two-hour delta serum marker measurements, and selective nuclear stress testing to identify and exclude acute coronary syndromes. Ann Emerg Med 2002; 40:584.

87. Bedetti G, et al: Stress echo in chest pain unit: The SPEED trial. Int J Cardiol 2005; 102:41.

88. Tong KL, et al: Myocardial contrast echocardiography versus thrombolysis in myocardial infarction score in patients presenting to the emergency department with chest pain and a nondiagnostic electrocardiogram. J Am Coll Cardiol 2005; 46:920.

89. Jeetley P, Burden L, Greaves K, Senior R: Prognostic value of myocardial contrast echocardiography in patients presenting to hospital with acute chest pain and negative troponin. Am J Cardiol 2007; 99:1369.

90. Hilton TC, et al: Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain. J Am Coll Cardiol 1994; 23:1016.

91. Kontos MC, Jesse RL, Schmidt KL, Ornato JP, Tatum JL: Value of acute rest sestamibi perfusion imaging for evaluation of patients admitted to the emergency department with chest pain. J Am Coll Cardiol 1997; 30:976.

92. Kontos MC, Wackers FJ: Acute rest myocardial perfusion imaging for chest pain. J Nucl Cardiol 2004; 11:470.

93. Udelson JE, Beshansky JR, Ballin DS: Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia: A randomized controlled trial. JAMA 2002; 288:2693.

94. Budoff MJ, et al: Assessment of coronary artery disease by cardiac computed tomography: A scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 2006; 114:1761.

95. Stillman AE, et al: Use of multidetector computed tomography for the assessment of acute chest pain: A consensus statement of the North American Society of Cardiac Imaging and the European Society of Cardiac Radiology. Eur Radiol 2007; 17:2196.

96. Hoffman MH, et al: Noninvasive coronary angiography with multislice computed tomography. JAMA 2005; 293:2471.

97. Gallagher MJ, Raff GL: Use of multislice CT for the evaluation of emergency room patients with chest pain: The so-called “triple rule-out”. Catheter Cardiovasc Interv 2008; 71:92.

98. White CS, et al: Chest pain evaluation in the emergency department: Can MDCT provide a comprehensive evaluation? AJR Am J Roentgenol 2005; 185:533.

99. Gallagher MJ, et al: The diagnostic accuracy of 64-slice computed tomography coronary angiography compared with stress nuclear imaging in emergency department low-risk chest pain patients. Ann Emerg Med 2007; 49:125.

100. Hoffman U, et al: Coronary multidetector computed tomography in the assessment of patients with acute chest pain. Circulation 2006; 114:2251.

CHAPTER 78 / Acute Coronary Syndrome 1033.e3101. Newman DH: Computed tomographic angiography for low risk chest

pain: Seeking passage. Ann Emerg Med 2009; 53:305.102. Gibler WB, et al: A rapid diagnostic and treatment center for patients

with chest pain in the emergency department. Ann Emerg Med 1995; 25:1.

103. Gibbons RJ, et al: ACC/AHA 2002 guideline update for exercise testing: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol 2002; 40:1531-1540.

104. Amsterdam EA, Kirk JD, Diercks DB, Lewis WR, Turnipseed SD: Immediate exercise testing to evaluate low-risk patients presenting to the emergency department with chest pain. J Am Coll Cardiol 2002; 40:251.

105. Amsterdam EA, Kirk JD, Diercks DB, Lewis WR, Turnipseed SD: Exercise testing in chest pain units: Rationale, implementation, and results. Cardiol Clin 2005; 23:503.

106. Farkouh ME, et al: A clinical trial of a chest-pain observation unit for patients with unstable angina: Chest Pain Evaluation in the Emergency Room (CHEER) Investigators. N Engl J Med 1998; 339:1882.

107. Goodacre S, et al: Effectiveness and safety of chest pain assessment to prevent emergency admissions: ESCAPE cluster randomized trial. BMJ 2007; 335:659.

108. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. The GUSTO Angiographic Investigators. N Engl J Med 1993; 329:1615.

109. De Luca G, Suryapranata H, Ottervanger JP, Antman EM: Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction. Circulation 2004; 109:1223-1225.

110. Weaver WD, et al: Prehospital-initiated vs. hospital-initiated thrombolytic therapy. The Myocardial Infarction Triage and Intervention Trial. JAMA 1993; 270:1211.

111. O’Connor RE, et al: Part 10: Acute Coronary Syndromes: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S787-S817.

112. Kurz MC, Babcock C, Sinha S, Tupesis JP, Allegretti J: The impact of emergency physician–initiated primary percutaneous coronary intervention on mean door-to-balloon time in patients with ST-segment–elevation myocardial infarction. Ann Emerg Med 2007; 50:527-534.

113. Yusuf S, Collins R, MacMahon S, Peto R: Effect of intravenous nitrates on mortality in acute myocardial infarction: An overview of the randomised trials. Lancet 1988; 1:1088.

114. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet 1995; 345:669-685.

115. Meine TJ, et al: Association of intravenous morphine use and outcomes in acute coronary syndromes: Results from the CRUSADE Quality Improvement Initiative. Am Heart J 2005; 149:1043.

116. Pfisterer M, et al: Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: The GUSTO-I experience: Global utilization of streptokinase and TPA (alteplase) for occluded coronary arteries. J Am Coll Cardiol 1998; 32:634.

117. Chen ZM, et al: Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: Randomized placebo-controlled trial. Lancet 2005; 366:1622.

118. Bates ER: Role of intravenous beta-blockers in the treatment of ST-elevation myocardial infarction. Circulation 2007; 115:2904.

119. Kinlay S, et al: High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation 2003; 108:1560-1566.

120. Heeschen C, et al: Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 2002; 105:1446-1452.

121. Patti G, et al: Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: Results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007; 49:1272-1278.

122. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 2:349.

123. Bellandi F, Maioli M, Leoncini M, Toso A, Dabizzi RP: Early abciximab administration in acute myocardial infarction treated with primary coronary intervention. Int J Cardiol 2006; 108:36.

124. Rakowski T, et al: Early abciximab administration before primary percutaneous coronary intervention improves infarct-related artery patency and left ventricular function in high-risk patients with anterior wall myocardial infarction: A randomized study. Am Heart J 2007; 153:360.

125. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty: The EPIC Investigation. N Engl J Med 1994; 330:956.

126. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The EPILOG investigators. N Engl J Med 1997; 336:1689.

127. van den Merkhof LF, et al: Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty. Results of the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study. J Am Coll Cardiol 1999; 33:1528.

128. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT II. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis–II. Lancet 1997; 349:1422.

129. Boersma E, et al: Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta-analysis of all major randomised clinical trials. Lancet 2002; 359:189.

130. Simoons ML, GUSTO IV-ACS Investigators: Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: The GUSTO IV-ACS randomised trial. Lancet 2001; 357:1915.

131. Zhao XQ, Theroux P, Snapinn SM, Sax FL: Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non–Q-wave myocardial infarction: Angiographic results from the PRISM-PLUS trial (Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms): PRISM-PLUS Investigators. Circulation 1999; 100:1609.

132. Ohman EM, et al: Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction: Results of a randomized, placebo-controlled, dose-ranging trial: IMPACT-AMI Investigators. Circulation 1997; 95:846.

133. Roe MT, et al: A randomized, placebo-controlled trial of early eptifibatide for non–ST-segment elevation acute coronary syndromes. Am Heart J 2003; 146:993.

134. Srinivas VS, et al: Effectiveness of glycoprotein IIb/IIIa inhibitor use during primary coronary angioplasty: Results of propensity analysis using the New York State Percutaneous Coronary Intervention Reporting System. Am J Cardiol 2007; 99:482.

135. Montalescot G, et al: Abciximab in primary coronary stenting of ST-elevation myocardial infarction: A European meta-analysis on individual patients’ data with long-term follow-up. Eur Heart J 2007; 28:443.

136. Stone GW, et al: Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: One-year results from the ACUITY trial. JAMA 2007; 298:2497-2506.

137. Giugliano RP, et al: Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009; 360:2176-2190.

138. Wallentin L, et al: Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045-1057.

139. O’Gara PT, et al: 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127:529-555.

140. Wright RS, et al: 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011: 123:2022-2060.

141. Yusuf S, et al: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494 [erratum, N Engl J Med 2001; 345:1506, 1716].

142. Bromberg-Marin G, et al: Effectiveness and safety of glycoprotein IIb/IIIa inhibitors and clopidogrel alone and in combination in non–ST-segment elevation myocardial infarction (from the National Registry of Myocardial Infarction–4). Am J Cardiol 2006; 98:1125.

143. Fox KA, et al: Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for

1033.e4 PART III ◆ Medicine and Surgery / Section Three • Cardiac System

non–ST-elevation acute coronary syndrome: The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial. Circulation 2004; 110:1202.

144. Sabatine MS, et al: Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352:1179.

145. Hoekstra JW, et al: Improving care of patients with non–ST-elevation acute coronary syndromes in the emergency department: The CRUSADE initiative. Acad Emerg Med 2002; 9:1146.

146. Mehta RH, et al: Challenges in predicting the need for coronary artery bypass grafting at presentation in patients with non–ST-segment elevation acute coronary syndromes. Am J Cardiol 2006; 98:624.

147. Low-molecular-weight heparin during instability in coronary artery disease: Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group. Lancet 1996; 347:561.

148. Cohen M, et al: A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease: Efficacy and safety of subcutaneous enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997; 337:447.

149. Klein W, et al: Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: Fragmin in Unstable Coronary Artery Disease Study (FRIC). Circulation 1997; 96:61.

150. Petersen JL, et al: Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non–ST-segment elevation acute coronary syndromes: A systematic overview. JAMA 2004; 292:89.

151. Brewster GS, Herbert ME: Medical myth: Heparin should be administered to every patient admitted to the hospital with possible unstable angina. West J Med 2000; 173:138.

152. Ferguson JJ, et al: Enoxaparin vs. unfractionated heparin in high-risk patients with non–ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: Primary results of the SYNERGY randomized trial. JAMA 2004; 292:45.

153. Sinnaeve PR, et al: Direct thrombin inhibitors in acute coronary syndromes: Effect in patients undergoing early percutaneous coronary intervention. Eur Heart J 2005; 26:2396.

154. Stone GW, et al: Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355:2203.

155. Yusuf S, et al: Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006; 295:1519-1530.

156. The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators: Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354:1464.

157. Peters RJ, et al: The role of fondaparinux as an adjunct to thrombolytic therapy in acute myocardial infarction: A subgroup analysis of the OASIS-6 trial. Eur Heart J 2008; 29:324.

158. GISSI-2: A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. Lancet 1990; 336:65.

159. In-hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomised between alteplase and streptokinase with or without heparin. The International Study Group. Lancet 1990; 336:71.

160. ISIS-3: A randomised comparison of streptokinase vs. tissue plasminogen activator vs. anistreplase and or aspirin plus heparin vs. aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. Lancet 1992; 339:753.

161. A comparison of reteplase with alteplase for acute myocardial infarction: The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. N Engl J Med 1997; 337:1118.

162. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: The ASSENT-2 double-blind randomised trial. Lancet 1999; 354:716.

163. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation 1994; 89:1545.

164. Indications for fibrinolytic therapy in suspected acute myocardial infarction: Collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients: Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Lancet 1994; 343:311.

165. Late Assessment of Thrombolytic Efficacy (LATE) study with alteplase 6-24 hours after onset of acute myocardial infarction. Lancet 1993; 342:759.

166. Richling N, et al: Thrombolytic therapy vs. primary percutaneous intervention after ventricular fibrillation cardiac arrest due to acute ST-segment elevation myocardial infarction and its effect on outcome. Am J Emerg Med 2007; 25:545.

167. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Lancet 1986; 1:397.

168. Wilcox RG, et al: Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; 2:525.

169. Grines CL, et al: A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction: The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1993; 328:673.

170. Zijlstra F, et al: A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993; 328:680.

171. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction: The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. N Engl J Med 1997; 336:1621.

172. Weaver WD, et al: Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review. JAMA 1997; 278:2093.

173. Andersen HR, et al: A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003; 349:733.

174. Stone GW, et al: Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002; 346:957.

175. van der Hoeven BL, et al: Sirolimus-eluting stents versus bare-metal stents in patients with ST-segment elevation myocardial infarction: 9-month angiographic and intravascular ultrasound results and 12-month clinical outcome results from the MISSION! Intervention Study. J Am Coll Cardiol 2008; 51:618.

176. Pasceri V, et al: Meta-analysis of clinical trials on use of drug-eluting stents for treatment of acute myocardial infarction. Am Heart J 2007; 153:749.

177. Marzocchi A, et al: Long-term safety and efficacy of drug-eluting stents: Two-year results of the REAL (REgistro AngiopLastiche dell’Emilia Romagna) multicenter registry. Circulation 2007; 115:3181.

178. Califf RM, et al: Evaluation of combination thrombolytic therapy and timing of cardiac catheterization in acute myocardial infarction: Results of thrombolysis and angioplasty in myocardial infarction phase 5 randomized trial. Circulation 1991; 83:1543.

179. Sutton AG, et al: A randomized trial of rescue angioplasty versus a conservative approach for failed fibrinolysis in ST-segment elevation myocardial infarction: The Middlesbrough Early Revascularization to Limit INfarction (MERLIN) trial. J Am Coll Cardiol 2004; 44:287.

180. Sutton AG, et al: One-year results of the Middlesbrough Early Revascularisation to Limit INfarction (MERLIN) trial. Heart 2005; 91:13305.

181. Kunadian B, et al: Early invasive versus conservative treatment in patients with failed fibrinolysis—no late survival benefit: The final analysis of the Middlesbrough Early Revascularisation to Limit INfarction (MERLIN) randomized trial. Am Heart J 2007; 153:763.

182. Wijeysundera HC, et al: Rescue angioplasty or repeat fibrinolysis after failed fibrinolytic therapy for ST-segment myocardial infarction: A meta-analysis of randomized trials. J Am Coll Cardiol 2007; 49:422.

183. Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) Investigators: Primary vs. tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): Randomised trial. Lancet 2006; 367:569.

184. Keeley EC, Boura JA, Grines CL: Comparison of primary and facilitated percutaneous coronary interventions for ST-elevation myocardial infarction: Quantitative review of randomised trials. Lancet 2006; 367:579.

185. Leopold JA: Does thrombolytic therapy facilitate or foil primary PCI? N Engl J Med 2008; 358:2277-2279.

186. Boden WB, Faxon DP: Facilitated percutaneous coronary intervention. J Am Coll Cardiol 2006; 48:1120-1128.

CHAPTER 78 / Acute Coronary Syndrome 1033.e5187. Brady WJ, Esterowitz D, Syverud SA: Consideration for primary

angioplasty: Impact on the door-to-drug time in AMI patients ultimately treated with thrombolytic agent. Am J Emerg Med 2001; 19:15.

188. Pinto DS, et al: Hospital delays in reperfusion for ST-elevation myocardial infarction: Implications when selecting a reperfusion strategy. Circulation 2006; 114:2019.

189. Nallamothu B, et al: Relationship of treatment delays and mortality in patients undergoing fibrinolysis and primary percutaneous coronary intervention: The Global Registry of Acute Coronary Events. Heart 2007; 93:1552.

190. Camp-Rogers T, Kurz MC, Brady WJ: Hospital-based strategies contributing to percutaneous coronary intervention time reduction in the patient with ST-segment elevation myocardial infarction: A review of the “system-of-care” approach. Am J Emerg Med 2012; 30:491.

191. Kraft PL, Newman S, Hanson D, Anderson W, Bastani A: Emergency physician discretion to activate the cardiac catheterization team decreases door-to-balloon time for acute ST-elevation myocardial infarction. Ann Emerg Med 2007; 50:520.

192. Singer AJ, et al: Emergency department activation of an interventional cardiology team reduces door-to-balloon times in ST-segment elevation myocardial infarction. Ann Emerg Med 2007; 50:538.

193. Goldberg RJ, et al: Cardiogenic shock after acute myocardial infarction: Incidence and mortality from a community-wide perspective, 1975 to 1988. N Engl J Med 1991; 325:1117.

194. Hochman JS, et al: Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999; 341:625.

195. Sunde K, et al: Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 2007; 73:29-39.

196. Garot P, et al: Six-month outcome of emergency percutaneous coronary intervention in resuscitated patients after cardiac arrest complicating ST-elevation myocardial infarction. Circulation 2007; 115:1354.

197. Gorjup V, Radsel P, Kocjancic ST, Erzen D, Noc M: Acute ST-elevation myocardial infarction after successful cardiopulmonary resuscitation. Resuscitation 2007; 72:379.

198. Knafelj R, Radsel P, Ploj T, Noc M: Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial infarction. Resuscitation 2007; 74:227.

199. Spaulding CM, et al: Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med 1997; 336:1629-1633.

200. Widimsky P, et al: Long-term outcomes of patients with acute myocardial infarction presenting to hospitals without catheterization laboratory and randomized to immediate thrombolysis or interhospital transport for primary percutaneous coronary intervention: Five years’ follow-up of the PRAGUE-2 Trial. Eur Heart J 2007; 28:679.

201. Aguirre FV, et al: Rural interhospital transfer of ST-elevation myocardial infarction patients for percutaneous coronary revascularization: The Stat Heart Program. Circulation 2008; 117:1145.

202. Henry TD, et al: A regional system to provide timely access to percutaneous coronary intervention for ST-elevation myocardial infarction. Circulation 2007; 116:721.

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