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Section Three
CARDIAC SYSTEM
CHAPTER 78 Acute Coronary Syndrome
Michael 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 myocardial infarction (STEMI). ACS and in particular acute myocardial 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 pharmacologic agents provided physicians with effective approaches for
treating life-threatening dysrhythmias. The introduction of selective 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 introduced 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 increasingly important roles, particularly when the diagnosis is not
straightforward.
Fibrinolytic therapy and interventional, catheter-based techniques revolutionized the treatment of patients with STEMI
during the 1980s. Combination therapies with antiplatelet, antithrombotic, 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 timesensitivity 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 evaluation 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. Reduction 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
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998 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
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 fatalities from CAD occur outside the hospital, usually from an ACSrelated 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 constant over time. Physical or psychological stress (physical exertion,
emotional stress, anemia, dysrhythmias, or environmental exposures) may provoke an attack of angina that resolves spontaneously 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 frequency 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 presentation. 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 consistent 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 vasospasm 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
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 necrosis. 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 AMI
Furthermore, regarding an established MI, any one of the following 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,
Chapter 78 / Acute Coronary Syndrome 999
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 transmural 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 pathologic 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 guidelines 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 perfusion most commonly results from coronary arterial vessel stenosis
as a result of atherosclerotic CAD. Usually the reduction of coronary 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 consumption 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 coronary artery blood flow through the fixed, stenotic lesions. Vulnerable 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 activation and thrombus formation. Platelets play a major role in the
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 resulting thrombus can occlude the vessel lumen, leading to myocardial
ischemia, hypoxia, acidosis, and eventually infarction. The consequences of the occlusion depend on the extent of the thrombotic 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 circulation 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 supplied by the affected artery. Angiographic studies demonstrate that
the preceding coronary plaque lesion is often less than 50% stenotic, 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 significant coronary vessel occlusion, local mediators and vasoactive
substances are released, inducing vasospasm, which further compromises 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 inflammatory, thrombotic, and other debris from the occlusive plaque
lesion is released and embolizes into the distal vessel. Such embolization 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 cellular elements into ischemic myocardium can lead to irreversible
myocardial damage that causes reperfusion injury, prolonged ventricular dysfunction (known as myocardial stunning), or reperfusion 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 considerations. 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 presentations. 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 evaluation. 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
1000 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
evaluation over the next several hours then focuses on the detection 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 intravenous morphine sulfate; the acronym MONA summarizes preadmission 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 Preadmission 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 alleviating 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 menopause, and chronic cocaine abuse. Approximately 80% of a population of more than 122,000 patients with known CAD had at least
one of the four conventional risk factors (diabetes mellitus, cigarette 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 Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin 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
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 cardiovascular 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 leftsided 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 exacerbation 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, diaphoresis, 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 gastroesophageal reflux, or reproducible pain on abdominal palpation should
raise suspicion of ACS. Gastroesophageal reflux disease is a
common misdiagnosis in cases of missed ACS.
Table 78-1
Clinical Characteristics of Classic Anginal
Chest Discomfort
CHARACTERISTIC
MORE 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.
Chapter 78 / Acute Coronary Syndrome 1001
Table 78-2
Symptoms of Acute Myocardial Infarction:
Typical and Atypical
BAYER ET AL*†
TINKER‡
URETSKY
ET AL§
PATHY||
515
51
75
75
Dyspnea
118
19
14
77
Syncope
72
4
1
Confusion
46
Stroke
Table 78-3
Key Entities in the Differential Diagnosis
of Chest Pain
Acute myocardial infarction
Unstable angina
Stable angina
Prinzmetal’s angina
Pericarditis
Myocardial or pulmonary contusion
Pneumonia
Pulmonary embolism
Pneumothorax
Pulmonary hypertension
Pleurisy
Aortic dissection
27
Boerhaave’s syndrome
Gastroesophageal reflux
1
51
Peptic ulcer disease
Gastritis or esophagitis
32
6
26
Esophageal spasm
Mallory-Weiss syndrome
Fatigue
36
2
4
10
Cholecystitis or biliary colic
Pancreatitis
Nausea or emesis
28
1
10
Herpes zoster
Musculoskeletal pain
Sudden death
31
SYMPTOM
Typical
Chest pain
Atypical
31
Giddiness
18
Diaphoresis
18
3
22
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.
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, diaphoresis, indigestion, syncope). Patients with an ultimate diagnosis of
AMI or UA can have pain that is pleuritic, positional, or reproduced 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 scrutinized 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 unaccompanied 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 atypical symptoms in ACS.25 Compelling data demonstrate a disparity
in treatment approach related to race in patients with acute manifestations 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 findings in patients with symptoms consistent with ACS. Historical
studies using untrained physicians identified chest wall tenderness
1002 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
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 reproducible 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 blockers, 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 associated with misdiagnosis of ACS in medical malpractice closed
claims analysis include physicians with less experience who document 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; conduction 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 fibrillation) or ventricular (e.g., ventricular tachycardia and fibrillation). 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.
Cardiogenic shock is hypotension with end-organ hypoperfusion 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 differential 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 accompanying 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 resistance. Therapeutic measures include vasopressor and inotropic
support, intra-aortic balloon counterpulsation, and early revascularization; fibrinolytic therapy does not decrease mortality in cardiogenic 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 precipitous deterioration in the presence of AMI. Subacute presentations 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 temporizing 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 confirmed 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 counterpulsation, 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 principally 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 ventricular aneurysm development in this population.
Dressler’s syndrome, unlike infarct pericarditis, does not require
transmural involvement. It is a relatively uncommon, late complication 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. Laboratory 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
Chapter 78 / Acute Coronary Syndrome 1003
and can be serous or bloody. Echocardiography assesses pericardial fluid and risk of tamponade. The pericardial reaction is
believed to be immune mediated, and treatment includes antiinflammatory 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 undergoing 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 significant (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 angioplasty group).39
Hyperglycemia in the setting of AMI may be viewed as a complication, as well as a complicating disease process in AMI. Hyperglycemia 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 independent 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 nondiabetics. There is a 4% mortality increase for nondiabetic patients
for every 18-mg/dL elevation in blood glucose level. Hyperglycemia 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 complicating issue. In fact, within a single class of medications, many of
these agents are so similar in efficacy that superiority is determined 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 lowmolecular-weight heparins (LMWHs) cannot be reversed. Fibrinolytic agents also cannot be reversed; rather, therapy including
FFP and packed red blood cell (PRBC) transfusions is most appropriate. 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 hemorrhage related to percutaneous interventions; the most typical is a
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 findings, 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 determines 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 information 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 information 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 pericarditis). 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 variations 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 ventricular walls well.37 In context, a single ECG is neither 100% sensitive 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 diagnosis of the tall T wave includes hyperacute T waves of ischemia,
hyperkalemia, benign early repolarization (BER), LVH, LBBB, and
pericarditis (Fig. 78-1).
1004 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
A
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
B
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.
Table 78-4
Differential Diagnosis of ST Segment
Elevation on the Electrocardiogram
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
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 atypical 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
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 corresponding 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 deviation 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 infarction, repolarization abnormality of ventricular hypertrophy
(the “strain” pattern), bundle branch block, ventricular paced
rhythm (VPR), digoxin effect, hyperkalemia, hypokalemia, PE,
Chapter 78 / Acute Coronary Syndrome 1005
intracranial hemorrhage, myocarditis, rate-related ST segment
depression, postcardioversion of tachydysrhythmias, and pneumothorax (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
A
B
C
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
ST segment elevation AMI, (3) may reflect a “mirror image” of ST
segment elevation from posterior MI when found in the rightsided 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 elevation. 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 frequently 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, intracranial hemorrhage, myocarditis, rate-related ST segment depression, 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).
B
E
Figure 78-3. ST segment depression (STD) in acute coronary
C
D
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.
1006 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
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 morphology, 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 normalappearing 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-ParkinsonWhite syndrome, cerebrovascular accident, hypokalemia, gastrointestinal 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.
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 (inferoposterolateral). 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 localization of some of these lesions, new Q waves appearing in leads
I and aVL (but not V6) indicate a “mid-anterior wall MI,” previously 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
A
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 involvement is reflected by changes in V1 and V2. Extension to the lateral
Table 78-5
Regional ST Segment Changes in Acute
Myocardial Infarction
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
V1 through V3
Elevation
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.
B
C
D
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.
Chapter 78 / Acute Coronary Syndrome 1007
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
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
aVR
V1
V4
II
aVL
V2
V5
Figure 78-6. Anterolateral acute myocardial
III
aVF
V3
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.
V6
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
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.
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
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) suggests concomitant right ventricular infarction. Coexistent reciprocal change with inferior STEMI is associated with larger infarct
size and increased mortality. Occlusion of the left circumflex
1008 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
RIGHT PRECORDIAL LEADS
A
A
B
C
V1
V2
B
POSTERIOR LEADS
V8
V9
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.
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 accessory leads V7 through V9).6 The culprit lesion may be in the right
coronary artery, its posterior descending branch, or the left circumflex 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 precordial 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 detection 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 isolated 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 consensus 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 infarction 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 features 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 tamponade. 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 precordial 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, demonstrate 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 ventricular 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 consideration 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 coronary artery disease; alternatively, this finding in lead aVR may
represent multivessel disease, acute proximal left anterior descending occlusion, or (less commonly) left circumflex or right coronary 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, particularly 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 amplitude; (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. Isolated BER in the limb leads is quite rare and should prompt
Chapter 78 / Acute Coronary Syndrome 1009
I
aVR
RV1
RV4
II
aVL
RV2
RV5
III
aVF
RV3
RV6
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.
A
B
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).
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 insensitive yet specific associated electrocardiographic finding in pericarditis, 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 pericardium 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 myocardium paradoxically bulges outward during systole, has characteristic 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 morphology (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 clinical presentation. Preexisting LBBB, however, shares many similarities 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 frequent 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
1010 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
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
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
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
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
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.)
Chapter 78 / Acute Coronary Syndrome 1011
I
aVR
V1
V4
II
aVL
V2
V5
V3
V6
III
aVF
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.
obtain a population of patients with LBBB and enzymatic evidence of AMI.58 Three independent electrocardiographic predictors 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 diagnosis, 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 recommended 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 measurement) 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 manifestations 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 predominantly 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 oriented 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 evaluation 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
(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 abnormality (or strain pattern), with ST segment depression and asymmetrically 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 evidence of obstructive CAD. Positive serum markers for cardiac
ischemia may be present, as well as hemodynamic compromise. It
occurs principally in postmenopausal women and characteristically 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 terminology 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 captured 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
1012 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
II
A
II
aVL
V2
V5
III
aVF
V3
V6
B
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.
Chapter 78 / Acute Coronary Syndrome 1013
I
1653
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
A
I
1723
B
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.
1014 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
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
aVR
V1
V4
RV4
II
III
aVL
V1
aVF
V1
V5
V8
V6
V9
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.
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 depression 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 elevation on the 12-lead ECG.
Electrocardiographic Adjuncts in the Diagnosis
of Acute Coronary Syndrome
Additional lead ECGs can increase sensitivity for AMI by evaluating 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 paraspinal area, at the same level as leads V4 to V6. Morphologic
Chapter 78 / Acute Coronary Syndrome 1015
changes in the posterior leads may be subtle, principally because
of the increased distance between these electrodes and the posterior 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.
Anterior
Posterior
V9
V1
Isolated acute
posterior wall MI
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.
0713
0726
0739
Use of the 15-lead ECG may improve diagnostic precision but
does not appear to affect the rate of AMI diagnosis, use of reperfusion 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 detection 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 additional 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 potentially 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 specificity 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 coronary care unit setting revealed that only serum cardiac marker
0756
Lead V3
Lead III
A
1315
1321
1332
C
0456
0516
0642
Lead V2
Lead III
D
2315
2329
2347
2358
0008
B
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.
1016 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
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 populations in QT dispersion values.
Body surface mapping increases the amount of electrocardiographic 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 simultaneously, 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 elevation, 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 encountered 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 approximately 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 diagnosis 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 electrocardiography, combined with serial cardiac marker determinations, can
exclude AMI, and even then UA without actual myocardial necrosis may be present.
Chest Radiography
The chest radiograph provides information concerning the application 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
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 sensitivity 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. Monoclonal 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 contractile 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
Chapter 78 / Acute Coronary Syndrome 1017
A
B
Figure 78-21. Chest radiographs in patients with acute coronary syndrome. A, Cardiomegaly. B, Borderline cardiomegaly with pulmonary edema.
Table 78-6
Summary of Test Performance Studies of Diagnostic Technologies for Acute Coronary Syndrome
in the Emergency Department
TECHNOLOGY
DISEASE
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
AMI
1 (1042)
19 (6425)
20
6-42
23
42 (36-48)
96
97 (95-98)
CK-MB (serial)
ACS
AMI
1 (1042)
14 (11,625)
20
1-43
31
79 (71-86)
95
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
AMI
2 (228)
3 (397)
3-30
3-30
70 (43-88)
93 (81-91)
87 (72-94)
66 (43-83)
Stress echocardiography
AMI
1 (139)
4
90
89
Sestamibi (rest)
ACS
AMI
3 (702)
3 (702)
9-17
92 (78-98)
81 (74-87)
67 (52-79)
73 (56-85)
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.
1018 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
Sensitivity for AMI
100
80
60
40
20
0
1
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.
results predict low risk. A single troponin measurement on presentation, 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 performed 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 exceeding 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 limitations 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 biochemical 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 identified patients at low mortality risk. Small elevations of troponin
may be used as an objective measure of “preinfarcts” that characterize UA and are associated with increased risk of infarction in
the near term. Marked elevations in troponin consistent with AMI
2
3
4
5
6
7
8
9
10
11
12
Hours from chest pain onset
in the AMI patient
CK-MB
Troponin I
Troponin T
Myoglobin
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 Myocardial 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 improvement 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 angiography and revascularization.73,76
Elevated troponin levels occur in a variety of cardiac and noncardiac conditions unrelated to the typical ACS and AMI pathophysiology. 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 predictor 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
Chapter 78 / Acute Coronary Syndrome 1019
with elevated levels in renal failure more often than TnI, particularly 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
power for AMI and its early rise kinetics compared with other
markers. Although some evidence suggests that a normal myoglobin 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
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 detectable 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 sensitivities 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, particularly 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 elevated but also be at least 5% of the total CK value. False-positive
elevations can occur with noncoronary conditions, such as pericarditis, 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.
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 usefulness 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 biomarker that reportedly detects early myocardial ischemia rather
than the later myocyte necrosis, and may have even earlier elevation 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 myocytes 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 shortand long-term mortality in patients with UA, NSTEMI, and
STEMI.80,81
Given the underlying pathophysiology of ACS, a variety of biochemical 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 myeloperoxidase, an abundant leukocyte enzyme found in vulnerable coronary plaques that have ruptured, predict short-term risk of adverse
cardiac events even with negative cardiac troponin and no evidence of myocardial necrosis.82
Myoglobin
Multiple Marker Strategies
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 indicator 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 significant 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
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 sensitivity 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
Creatinine Phosphokinase
1020 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
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 hemodynamic 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 definitive cardiac biomarkers.6 Thus the multimarker approach does
not offer substantial benefit over the individual biomarker determinations and is therefore not recommended.
Echocardiography
Two-dimensional echocardiography detects regional wall motion
abnormality associated with ACS. Impaired myocardial contractility can range from hypokinesis to akinesis. Impaired myocardial
relaxation during diastole results in decreased ventricular distensibility. 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 abnormalities, 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 suspected 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 predictor 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 complications of AMI, including acute mitral regurgitation, pericardial 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 echocardiography, 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 myocardial ischemia in susceptible patients. Stress echocardiography
is superior to conventional treadmill testing for CAD in women.
Graded dobutamine stress echocardiography assesses myocardial 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
suggest a role for emergency pharmacologic stress echocardiography 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 microbubble 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 likelihood 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 continued 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 admitted 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) perfusion 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
Chapter 78 / Acute Coronary Syndrome 1021
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 arteries, or CT angiography (CTA), but also can provide functional
information on perfusion, wall motion, and left ventricular ejection fraction.
The use of MDCT in the ED focuses on two potential protocols: a coronary CTA by MDCT and a more global “triple ruleout” thoracic or chest MDCT. Noninvasive coronary CTA by
MDCT performs well when compared with standard invasive
coronary angiography.96,97 Cardiac CT provides excellent detection 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 alterations 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 predictive 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 economic 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
diagnostic method for the detection of symptomatic CAD in lowto 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 positive 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 pulmonary embolus or infarction, acute myocarditis or pericarditis,
and acute aortic dissection.103
Patients with a high pretest probability of CAD have a significant 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 medications, 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, hyperventilation, 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 identification, and treatment of low-risk ACS patients. Guidelines and critical 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 lowyield 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
1022 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
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 noninfarction 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 phenomenon” 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, myocardial salvage. Delivered later, from 2 to 12 hours after AMI onset,
TIME TO REPERFUSION VERSUS DEGREE OF BENEFIT
Maximal
benefit
Definite benefit
Timedependent
through
myocardial
salvage
Time-independent,
possibly through open artery
and collateral development
100
80
Benefit (%)
signs of AMI within 30 minutes of arrival. The NHAAP recommends (1) a specific area of the ED equipped for assessing and
monitoring patients potentially having ischemia, including standing orders for initial diagnostic and therapeutic actions; (2) a
standing protocol with inclusion and exclusion criteria for reperfusion 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 clinical 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 exercise 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 lowto 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 underwent 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 considerable. 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 accelerated diagnostic protocol approach in patients whom they would
otherwise have discharged.107
60
40
20
0
0
1
2
4
6
8
10
12
Time to treatment reperfusion agent (hr)
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.)
Time interval I
(from the arrival
at the emergency
department to
the initial ECG)
ED
t
(infu ime 4:
age sion of drug
nt s
tarte thromb
olyt
d)
ic
ED
t
(dec ime 3:
trea ision to decisio
t
thro ment, admin n
is
mbo sign
ifie ter th
lytic
age d by o rombo
rder
nt)
ly
ing tic
ED
t
(init ime 2:
ial E
d
CG ata
)
ED
t
(arr ime 1:
iv
dep al at th door
artm
e
ent) emerg
enc
y
Tim
e
(ons 0: on
s
et o
f sy et
mpt
oms
)
Chapter 78 / Acute Coronary Syndrome 1023
Time interval II
Time interval III
(from the initial
(from the decision
ECG to the
to treat with
decision to treat thrombolytic therapy
with thrombolytic
to the start of
therapy)
drug infusion)
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 stability. In the angiographic substudy of GUSTO, preserved left ventricular 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.)
STEMI patients who receive hospital-based reperfusion therapies (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 parallel 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 identifying 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 physician. 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 Interhospital 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
1024 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
shock as discussed later or in patients in whom fibrinolysis is
contraindicated.
Pharmacologic Intervention
Nitroglycerin
Nitrates decrease myocardial preload and, to a lesser extent, afterload. 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 associated with NTG can result in profound hypotension. An initial
infusion rate of 10 µg/min is titrated to pain symptoms. The clinician should increase the infusion at regular intervals, allowing a
10% reduction in the mean arterial pressure if the patient is normotensive 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 symptoms despite maximal anti-ischemic therapy, administration of
morphine sulfate is reasonable. The relief of pain and anxiety
decreases oxygen consumption and myocardial work. Some vasodilatory 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 intravenous 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 betaadrenergic blockade should be reconsidered. The GUSTO-1 trial
involved fibrinolytic agents for STEMI followed by early intravenous 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
increases occurred despite exclusion of patients with obvious
contraindications, including preexisting hypotension, bradycardia, or heart failure.116 The Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) evaluated approximately
46,000 patients with suspected STEMI, comparing early intravenous 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 cardiogenic 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 contraindication 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 inhibitors experience a reduction in cardiovascular mortality, decreased
rates of significant CHF, and fewer recurrent AMIs. These benefits
increase when ACE inhibitors are used in con­junction 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 intracoronary 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 administration 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. Contraindications to ACE inhibitor therapy include hypotension, volume
depletion, and borderline perfusion. Renal function must be monitored closely. The angiotensin receptor blockers also inhibit
the renin-angiotensin system, so these drugs are possible alternatives 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 undergoing 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
Chapter 78 / Acute Coronary Syndrome 1025
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 ischemiarelated 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 cyclooxygenase, 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 fibrinolytic 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 tirofiban. 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 administration 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 medically without mechanical revascularization, consistent benefit
with GPI therapy is not found with use of either direct
outcome measures or secondary markers of successful reperfusion, and hemorrhagic complications are increased.130,131 The Integrilin 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
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 revascularization; 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, irreversibly 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 advantage 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. Ticlopidine is associated with a risk of neutropenia and agranulocytosis;
furthermore, it demonstrates a much slower onset of platelet inhibition. 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 clopidogrel 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 management, 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
1026 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
moderate-to high-risk NSTEMI, the administration of a PSY12
receptor inhibitor should be deferred “downstream” to the attending cardiologist as the best revascularization strategy is
determined.140
Another indication is the patient with a high-risk ACS presentation 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 treatment 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 angiography 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 treatment. The NSTEMI patient demonstrates improved outcome with
clopidogrel therapy when a conservative treatment scenario is initially 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 administered earlier in the course of management.
The STEMI patient who is managed medically (i.e., with a fibrinolytic 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, recurrent ACS, and urgent coronary revascularization. This improvement 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) database suggests that although these CABG patients had a greater
incidence of bleeding perioperatively, outcomes were not statistically different in clopidogrel versus placebo groups in this surgical 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 withheld for at least 24 hours before urgent on-pump CABG if possible.140 If CABG is performed within 5 days of clopidogrel use,
patients have an increased incidence of operative and postoperative hemorrhage, increased need for transfusions, increased need
for reoperation for hemostasis, and increased postoperative mortality. 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
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 reductions in the progression to acute, recurrent, or extensive infarction
and death are noted in individuals treated with aggressive antithrombin therapy. The antithrombins include unfractionated
heparin (UFH), low-molecular-weight (fractionated) heparin
(LMWH), and the direct thrombin inhibitors (hirudin and bivalirudin). 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 antithrombin 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 preventing 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 mortality 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 weightadjusted 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 inhibition of earlier steps in the blood coagulation system would be
associated with a more potent antithrombotic effect than inhibition 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 thrombin molecules.
Potential advantages of LMWH over UFH include easier
administration, greater bioavailability, more consistent ther­
apeutic response among patients, and longer serum half-life producing 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 episodes.147 Studies comparing outcomes between LMWH and UFH
Chapter 78 / Acute Coronary Syndrome 1027
show mixed results; some show better outcomes with LMWH,
but others do not.148,149 In summary, the LMWH enoxaparin demonstrates 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 subcutaneously 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 hemorrhage. Furthermore, patients who have their heparin therapy
changed (UFH to LMWH and vice versa) during the active treatment 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 heterogeneous 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 providing 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 demonstrates 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
hemorrhagic complications in ACS care, this drug may be considered 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 mechanical 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 substudy. 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 contraindications 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 tissuetype 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 compared 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 streptokinase 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 activator complex in approximately 40,000 patients. In contrast to standard practice, the inclusion criteria allowed entry up to 24 hours
after symptom onset and did not require diagnostic electrocardiographic change. All patients received adjunctive aspirin therapy,
and approximately half of the patients were given delayed, unmonitored 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 particularly with studies now proving improved infarct artery patency
with use of early therapeutic intravenous doses of heparin.
1028 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
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 accelerated 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 relationship 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 subgroups, 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 equivalent to accelerated t-PA, and the results were nearly identical for
the two drugs. The one exception was the patient with presentation more than 4 hours after onset of symptoms—a significant
number of patients in many institutions. In this group, accelerated 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 Thrombolytic 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 randomly 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 mortality was noted among patients with presentation more than 4
hours after onset of symptoms in those treated with TNK. Furthermore, 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, particularly 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
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 contiguous 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 development 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 favorable prognosis associated with inferior infarction without fibrinolytic therapy requires larger sample sizes to detect a significant
survival benefit. The ISIS-2 trial demonstrated a statistically significant 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 myocardium. Acute, isolated posterior wall MI, diagnosed by posterior leads, may be another electrocardiographic indication for
fibrinolysis. Although unproven in large fibrinolytic agent trials,
patients with isolated posterior AMI may be considered for reperfusion 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 demonstrated a significant difference in outcome in fibrinolytictreated patients with only ST segment depression—7.4% incidence
of death compared with 4.9% in the placebo group.163 These findings 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 fibrinolytic 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 hemorrhagic stroke than younger patients.
Time from Symptom Onset. The generally accepted therapeutic 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.
Chapter 78 / Acute Coronary Syndrome 1029
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 literature. 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 demonstrated 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 pressures 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 hypotension is unclear. The GISSI-1 and GISSI-2 trials showed no apparent reduction in mortality rate with fibrinolytic therapy among
patients classified as Killip class III or IV.158 The FTT metaanalysis, however, demonstrated that patients with an initial systolic 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 contraindication to fibrinolytic therapy unless CPR is prolonged—more
than 10 minutes—or extensive chest trauma from manual compression 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 admission. 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 previous ischemic stroke should remain a strong relative contraindication 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
GISSI-1 trial showed no treatment benefits for patients with previous 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 combined fibrinolysis and rescue angioplasty.
Recent Surgery or Trauma. Recent surgery or trauma is considered 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 AngloScandinavian 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 fibrinolytic 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 cardioprotective, there is little experience with fibrinolysis among premenopausal 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 contraindications is shown in Box 78-1.
Fibrinolysis in Acute Myocardial Infarction:
BOX 78-1 Absolute and Relative Contraindications
Recent (within 10 days) major surgery (e.g., coronary artery
bypass graft, obstetric delivery, organ biopsy, previous
puncture of noncompressible vessels)
Cerebrovascular disease
Recent gastrointestinal or genitourinary bleeding (within 10 days)
Recent trauma (within 10 days)
Hypertension: systolic BP 180 mm Hg or diastolic BP
110 mm Hg
High likelihood of left heart thrombus (e.g., mitral stenosis with
atrial fibrillation)
Acute pericarditis
Subacute bacterial endocarditis
Hemostatic defects, including those secondary to severe hepatic
or renal disease
Significant liver dysfunction
Diabetic hemorrhagic retinopathy or other hemorrhagic
ophthalmic condition
Septic thrombophlebitis or occluded AV cannula at seriously
infected site
Advanced 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
Adapted from Physicians’ Desk Reference, 50th ed. Montvale, NJ, Medical
Economics, 1996.
AV, atrioventricular; BP, blood pressure.
1030 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
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 contraindications 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, including an increased number of eligible patients, a lower risk of intracranial 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 operator 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 fibrinolysis 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 associated 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 randomly assigned 1138 patients with AMI to either PCI or accelerated 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. Ninetyeight percent of the patients assigned to fibrinolytic therapy
received t-PA 1.2 hours after hospital arrival. The composite endpoint 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 metaanalysis reviewed 10 major studies comparing fibrinolysis with
primary PCI in more than 2600 patients. The 30-day mor­tality
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 Investigators 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
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 compared 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 contemporary 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 clinical outcome variables in STEMI patients treated with PCI using
intracoronary stenting, event-free survival at 12 months was significantly 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 infarctrelated 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 conservative management strategy in STEMI patients in whom fibrinolysis 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
Chapter 78 / Acute Coronary Syndrome 1031
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 percutaneous 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 institution. 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 recommendations 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 determining 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 presenters” (i.e., more than 3 hours since the onset of STEMI symptoms),
and individuals with contraindication to fibrinolysis are also candidates 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 initiated 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 symptoms of STEMI in reducing morbidity and mortality.7
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” consideration in the STEMI patient asks: How long should the practitioner
wait for PCI in a patient who is fibrinolytic eligible? Considerations 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 catheterization 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 placement 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 min
Further 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 min
Symptom 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 investigators 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
1032 PART III ◆ Medicine and Surgery / Section Three • Cardiac System
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 activation 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 mortality 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 survival 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 complicated 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 resuscitation for cardiac arrest complicating STEMI, PCI was successful in
almost 90%, restoring adequate coronary perfusion. It is interesting to note that 54% survived beyond 6 months, with a large
proportion having intact neurologic function.196 A second investigation reviewed 135 patients with resuscitated cardiac arrest
complicated by STEMI. Among those patients who were conscious
at the time of PCI, invasive therapy restored coronary perfusion
in 96% of cases, and all of these patients survived without neurologic 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 resuscitated 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 demonstrated a significantly improved rate of survival.198
It is reasonable to include PCI as part of a standard postresuscitation 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 postresuscitation period. Regardless of the reperfusion method, approximately 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 fibrinolytic 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 anticipated.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 anticipated 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 percutaneous 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 revascularization) 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 treatment protocol initiated by the emergency physician included rapid
Chapter 78 / Acute Coronary Syndrome 1033
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 initiation 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 consecutive 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 management. 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 thienopyridine 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 indicated in this instance.
The AMI patient without ST segment elevation requires aspirin,
NTG, heparin, and morphine sulfate. Depending on hospital
protocols and the type of ACS, a thienopyridine can be administered 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 fibrinolytic agents, PCI, or, in the rare case, CABG.
KEY CONCEPTS
■ 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.
The references for this chapter can be found online by
accessing the accompanying Expert Consult website.
Chapter 78 / Acute Coronary Syndrome 1033.e1
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