2052 PART 6 Disorders of the Cardiovascular System

■ LONG-TERM MANAGEMENT

The time of hospital discharge is a “teachable moment” for the patient

with NSTE-ACS, when the caregiver can review and optimize the

medical regimen. Risk factor modification is key, and the importance

of smoking cessation, following an appropriate diet, achieving and

maintaining optimal weight, daily exercise, blood pressure control, and

control of hyperglycemia (in diabetic patients) should be emphasized.

There is evidence of benefit with long-term therapy with several classes

of drugs. Beta blockers, intensive lipid-lowering therapies to achieve an

LDL-C <55 mg/dL, ACE inhibitors or angiotensin receptor blockers,

and sodium-glucose co transport-2 or glucagon-like peptide 1 agonists

in selected patients with type 2 diabetes mellitus (see Chap. 404), are

recommended. The recommended antiplatelet regimen consists of the

combination of low-dose (75–100 mg/d) aspirin and a P2Y12 inhibitor

(clopidogrel, prasugrel, or ticagrelor) for 12 months, unless there is a

high risk of bleeding. Antiplatelet monotherapy should be continued

thereafter, unless long-term full-dose anticoagulation is indicated, in

which case anticoagulant without antiplatelet therapy is recommended

after 1 year (see above). A recent trial in patients (the majority after

NSTE-ACS) who had received DAPT for 3 months after PCI and were

then randomized to aspirin versus placebo on a background of continued ticagrelor for 12 months showed that ticagrelor monotherapy

reduced clinically relevant bleeding without an increase in ischemic

events compared to continuation of DAPT. In selected patients at high

ischemic risk (e.g., those with prior MI, diabetes mellitus, coronary

vein graft, heart failure) who are also at low risk of bleeding and not

on an anticoagulant, continuation of DAPT to 3 years has been shown

to be beneficial. Addition of rivaroxaban 2.5 mg twice daily to DAPT

reduced MI, stent thrombosis, and cardiovascular death, while major

bleeding was increased; however, the net outcome of fatal or irreversible events was reduced with the addition of the low-dose anti–factor

Xa inhibitor.

Registries have shown that women and racial minorities, as well as

patients with NSTE-ACS at high risk, including the elderly and patients

with diabetes or chronic kidney disease, are less likely to receive

evidence-based pharmacologic and interventional therapies with resultant poorer clinical outcomes and quality of life. Special attention

should be directed to these groups.

■ PRINZMETAL’S VARIANT ANGINA

In 1959, Prinzmetal and colleagues described a syndrome of severe

ischemic pain that usually occurs at rest and is associated with STsegment elevation. Prinzmetal’s variant angina (PVA) is caused by

focal spasm of an epicardial coronary artery with resultant transmural

ischemia and abnormalities in left ventricular function that may lead

to acute MI, ventricular tachycardia or fibrillation, and sudden cardiac

death. The cause of the spasm is not well defined, but it may be related

to hypercontractility of coronary arterial smooth muscle due to adrenergic vasoconstrictors, leukotrienes, or serotonin. For reasons that are

not clear, the prevalence of PVA has decreased substantially during the

past few decades, although it remains much more frequent in Japan

than in North America or Western Europe.

Clinical and Angiographic Manifestations Patients with PVA

are generally younger and, with the exception of cigarette smoking,

have fewer coronary risk factors than do patients with NSTE-ACS. Cardiac examination is usually unremarkable in the absence of ischemia.

However, a minority of patients have a generalized vasospastic disorder

associated with migraine and/or Raynaud’s phenomenon. The clinical

diagnosis of PVA is made by the detection of transient ST-segment elevation with rest pain, although many patients may also exhibit episodes

of silent ischemia.

Coronary angiography demonstrates transient coronary spasm

as the diagnostic hallmark of PVA. Atherosclerotic plaques in at

least one proximal coronary artery occur in about half of patients.

Hyperventilation and intracoronary acetylcholine have been used to

provoke focal coronary stenosis on angiography or to provoke rest

angina with ST-segment elevation to establish the diagnosis. In patients

with no obstructive coronary atherosclerosis and suspected coronary

vasomotor abnormalities, a positive provocative test for spasm has

been shown to be safe, identifies a high-risk subgroup, and is endorsed

by guidelines since it permits selection of therapy most appropriate for

the underlying pathophysiology.

TREATMENT

Prinzmetal’s Variant Angina

Nitrates and calcium channel blockers are the main therapeutic

agents. Aspirin may actually increase the severity of ischemic

episodes, possibly as a result of the sensitivity of coronary tone to

modest changes in the synthesis of prostacyclin. Statin therapy has

been shown to reduce the risk of major adverse events, although the

precise mechanism is not established. The response to beta blockers

is variable. Coronary revascularization may be helpful in patients

who also have discrete, flow-limiting, proximal fixed obstructive

lesions. Patients who have had ischemia-associated ventricular

fibrillation despite maximal medical therapy should receive an

implantable cardioverter-defibrillator.

Prognosis Many patients with PVA pass through an acute, active

phase, with frequent episodes of angina and cardiac events during the

first 6 months after presentation, after which there may be a tendency

for symptoms and cardiac events to diminish over time. Survival at

5 years is excellent (~90–95%), but as many as 20% of patients experience an MI. Patients with no or mild fixed coronary obstruction experience a lower incidence of cardiac death or MI compared to patients

with associated severe obstructive lesions. Patients with PVA who

develop serious arrhythmias during spontaneous episodes of pain are at

a higher risk for sudden cardiac death. In most patients who survive an

infarction or the initial 3- to 6-month period of frequent episodes, there

is a tendency for symptoms and cardiac events to diminish over time.

■ GLOBAL CONSIDERATIONS

Ischemic heart disease (IHD), and its most dangerous manifestation,

ACS, remains the most frequent cause of death and disability worldwide. In the mid-twentieth century, these conditions were most common in high-income countries. The elucidation of risk factors leading

to IHD, their management, and the development of therapies to reduce

the deleterious consequences of ACS were responsible for dramatic

reductions in these events that result in cardiovascular mortality. However, these advances have not affected all population groups equally. In

Europe, there remains a northeast to southwest gradient, with higher

prevalence in northern Russia and the Baltic nations and considerably

lower prevalence in France, Italy, and Spain. In the United States,

there remain racial and economic disparities, with poorer outcomes in

minorities and low-income populations.

Simultaneous with these important advances in the high-income

countries, the low- and middle-income countries have moved in the

opposite direction. The improvements in agriculture, nutrition, sanitation, prevention and treatment of infections, and management of

maternal/early childhood disorders, urbanization, and a reduction of

physical labor have, in combination, led to marked increases in coronary risk factors—hypertension, cigarette smoking, obesity, diabetes

mellitus, and elevations of circulating LDL-C. These, in turn, have

been responsible for marked increases in ACS events and cardiovascular mortality. These changes have been most prominent in central

Asia, India, and Pakistan, as well as in the more developed regions of

sub-Saharan Africa.

The current challenge is to apply what was learned in high-income

countries to the large populations in the low- and middle-income

countries that are now at high risk. This will require large educational

efforts directed at both the populations and their caregivers. An additional challenge will be to provide the trained specialized personnel,

facilities, drugs, and devices to deal with these threats. The successful implementation of these measures is now principally a sociopolitico-economic issue. One mitigating factor is that many of the

important drugs to prevent and treat these disorders, such as statins,

ST-Segment Elevation Myocardial Infarction

2053CHAPTER 275

ACE inhibitors, diuretics, beta blockers, and calcium antagonists, are

off patent and are now inexpensive.

■ FURTHER READING

Collet J-P et al: 2020 ESC Guidelines for the management of acute

coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 42:1289, 2021.

Grundy S et al: AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/

AGS/AphA/ASPC/NLA/PCNA: Guidelines on the management of

blood cholesterol. J Am Coll Cardiol 73:e285, 2019.

Januzzi J et al: Recommendations for institutions transitioning to

high-sensitivity troponin testing. J Am Coll Cardiol 73:1059, 2019.

Libby P et al: Reassessing the mechanisms of acute coronary syndromes. Circ Res 124:150, 2019.

Mach F et al: ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart

J 41:111, 2020.

Neumann F-J et al: ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 40:87, 2019.

Thygesen K et al: Fourth universal definition of myocardial infarction.

J Am Coll Cardiol 72:2231, 2018.

Vaglimigli M et al: ESC focused update on dual antiplatelet therapy

coronary artery disease. Eur Heart J 39:213, 2018.

Van Den Berg P, Body R: The HEART score for early rule out of acute

coronary syndromes in the emergency department: A systematic

review and meta-analysis. Eur Heart J Acute Cardiovasc Care 7:111,

2018.

Acute myocardial infarction (AMI) is a common diagnosis in hospitalized patients in industrialized countries. In the United States, ~605,000

patients experience a new AMI, and 200,000 experience a recurrent

AMI each year. About half of AMI-related deaths occur before the

stricken individual reaches the hospital. Of note, the in-hospital mortality rate after admission for AMI has declined from 10 to ~5%. The

1-year mortality rate after AMI is ~15%. Mortality is approximately

fourfold higher in elderly patients (aged >75) as compared with

younger patients.

When patients with prolonged ischemic discomfort at rest are first

seen, the working clinical diagnosis is that they are suffering from an

acute coronary syndrome (Fig. 275-1). The 12-lead electrocardiogram

(ECG) is a pivotal diagnostic and triage tool because it is at the center

of the decision pathway for management, permitting distinction of

those patients presenting with ST-segment elevation from those presenting without ST-segment elevation. Serum cardiac biomarkers are

obtained to distinguish unstable angina (UA) from non-ST-segment

elevation myocardial infarction (NSTEMI) and to assess the magnitude

of an ST-segment elevation myocardial infarction (STEMI). Epidemiologic studies indicate there has been a shift in the pattern of AMI over

the past several decades with more patients with NSTEMI than STEMI.

This chapter focuses on the evaluation and management of patients

with STEMI, while Chap. 274 discusses UA/NSTEMI.

PATHOPHYSIOLOGY: ROLE OF ACUTE

PLAQUE RUPTURE

STEMI usually occurs when coronary blood flow decreases abruptly

after a thrombotic occlusion of a coronary artery previously affected

by atherosclerosis. Slowly developing, high-grade coronary artery

275 ST-Segment Elevation

Myocardial Infarction

Elliott M. Antman, Joseph Loscalzo

Acute coronary syndrome

Presentation

Working Dx

ECG

Biochem.

marker

Final Dx

Myocardial infarction

Unstable angina NQMI Qw MI

No ST elevation

NSTEMI

ST elevation

Ischemic Discomfort

FIGURE 275-1 Acute coronary syndromes. Following disruption of a vulnerable

plaque, patients experience ischemic discomfort resulting from a reduction of

flow through the affected epicardial coronary artery. The flow reduction may be

caused by a completely occlusive thrombus (right) or subtotally occlusive thrombus

(left). Patients with ischemic discomfort may present with or without ST-segment

elevation. Of patients with ST-segment elevation, the majority (wide red arrow)

ultimately develop a Q wave on the ECG (Qw MI), while a minority (thin red arrow)

do not develop Q wave and, in older literature, were said to have sustained a

non-Q-wave MI (NQMI). Patients who present without ST-segment elevation are

suffering from either unstable angina or a non-ST-segment elevation MI (NSTEMI)

(wide green arrows), a distinction that is ultimately made based on the presence

or absence of a serum cardiac biomarker such as CK-MB or a cardiac troponin

detected in the blood. The majority of patients presenting with NSTEMI do not

develop a Q wave on the ECG; a minority develop a Qw MI (thin green arrow). Dx,

diagnosis; ECG, electrocardiogram; MI, myocardial infarction. (Adapted from CW

Hamm et al: Lancet 358:1533, 2001, and MJ Davies: Heart 83:361, 2000; from the BMJ

Publishing Group.)

stenoses do not typically precipitate STEMI because of the development of a rich collateral network over time. Instead, STEMI occurs

when a coronary artery thrombus develops rapidly at a site of vascular

injury. This injury is produced or facilitated by factors such as cigarette smoking, hypertension, and lipid accumulation. In most cases,

STEMI occurs when the surface of an atherosclerotic plaque becomes

disrupted (exposing its contents to the blood) and conditions (local or

systemic) favor thrombogenesis. A mural thrombus forms at the site of

plaque disruption, and the involved coronary artery becomes occluded.

Histologic studies indicate that the coronary plaques prone to disruption are those with a rich lipid core and a thin fibrous cap. After an

initial platelet monolayer forms at the site of the disrupted plaque, various agonists (collagen, ADP, epinephrine, serotonin) promote platelet

activation. After agonist stimulation of platelets, thromboxane A2

 (a

potent local vasoconstrictor) is released, further platelet activation

occurs, and potential resistance to fibrinolysis develops.

In addition to the generation of thromboxane A2

, activation of platelets by agonists promotes a conformational change in the glycoprotein

IIb/IIIa receptor (Chap. 115). Once converted to its functional state,

this receptor develops a high affinity for soluble adhesive proteins (i.e.,

integrins) such as fibrinogen. Since fibrinogen is a multivalent molecule, it can bind to two different platelets simultaneously, resulting in

platelet cross-linking and aggregation.

The coagulation cascade is activated on exposure of tissue factor

in damaged endothelial cells at the site of the disrupted plaque. Factors VII and X are activated, ultimately leading to the conversion of

prothrombin to thrombin, which then converts fibrinogen to fibrin

(Chap. 116). Fluid-phase and clot-bound thrombin participate in an

autoamplification reaction leading to further activation of the coagulation cascade. The culprit coronary artery eventually becomes occluded

by a thrombus containing platelet aggregates and fibrin strands

(Fig. 275-2).

In rare cases, STEMI may be due to coronary artery occlusion

caused by coronary emboli, congenital abnormalities, coronary spasm,

and a wide variety of systemic—particularly inflammatory—diseases.

2054 PART 6 Disorders of the Cardiovascular System

time of the day or night, circadian variations have been reported such

that clusters are seen in the morning within a few hours of awakening.

Pain is the most common presenting complaint in patients with

STEMI. The pain is deep and visceral; adjectives commonly used to

describe it are heavy, squeezing, and crushing; although, occasionally,

it is described as stabbing or burning (Chap. 14). It is similar in character to the discomfort of angina pectoris (Chap. 273) but commonly

occurs at rest, is usually more severe, and lasts longer. Typically, the

pain involves the central portion of the chest and/or the epigastrium,

and, on occasion, it radiates to the arms. Less common sites of radiation include the abdomen, back, lower jaw, and neck. The frequent

location of the pain beneath the xiphoid and epigastrium and the

patients’ denial that they may be suffering a heart attack are chiefly

responsible for the common mistaken impression of indigestion. The

pain of STEMI may radiate as high as the occipital area but not below

the umbilicus. It is often accompanied by weakness, sweating, nausea,

vomiting, anxiety, and a sense of impending doom. The pain may commence when the patient is at rest, but when it begins during a period

of exertion, it does not usually subside with cessation of activity, in

contrast to angina pectoris.

The pain of STEMI can simulate pain from acute pericarditis

(Chap. 270), pulmonary embolism (Chap. 279), acute aortic dissection

(Chap. 280), costochondritis, and gastrointestinal disorders. These

conditions should therefore be considered in the differential diagnosis.

Radiation of discomfort to the trapezius is not seen in patients with

STEMI and may be a useful distinguishing feature that suggests pericarditis is the correct diagnosis. However, pain is not uniformly present

in patients with STEMI. The proportion of painless STEMIs is greater

in patients with diabetes mellitus, and it increases with age. In the

elderly, STEMI may present as sudden-onset breathlessness, which may

progress to pulmonary edema. Other less common presentations, with

or without pain, include sudden loss of consciousness, a confusional

state, a sensation of profound weakness, the appearance of an arrhythmia, evidence of peripheral embolism, or merely an unexplained drop

in arterial pressure.

■ PHYSICAL FINDINGS

Most patients are anxious and restless, attempting unsuccessfully to

relieve the pain by moving about in bed, altering their position, and

stretching. Pallor associated with perspiration and coolness of the

extremities occurs commonly. The combination of substernal chest

pain persisting for >30 min and diaphoresis strongly suggests STEMI.

Although many patients have a normal pulse rate and blood pressure

within the first hour of STEMI, patients with anterior infarction may

have manifestations of sympathetic nervous system hyperactivity

(tachycardia and/or hypertension), and those with inferior infarction

may show evidence of parasympathetic hyperactivity (bradycardia

and/or hypotension).

The precordium is usually quiet, and the apical impulse may

be difficult to palpate. In patients with anterior wall infarction, an

abnormal systolic pulsation caused by dyskinetic bulging of infarcted

myocardium may develop in the periapical area within the first days

of the illness and then may resolve. Other physical signs of ventricular

dysfunction include fourth and third heart sounds, decreased intensity

of the first heart sound, and paradoxical splitting of the second heart

sound (Chap. 239). A transient midsystolic or late systolic apical systolic murmur due to dysfunction of the mitral valve apparatus may

be present. A pericardial friction rub may be heard in patients with

transmural STEMI at some time in the course of the illness, if they are

examined frequently. The carotid pulse is often decreased in volume,

reflecting reduced stroke volume. Temperature elevations up to 38°C

may be observed during the first week after STEMI. The arterial pressure is variable; in most patients with transmural infarction, systolic

pressure declines by ~10–15 mmHg from the preinfarction state.

LABORATORY FINDINGS

STEMI progresses through the following temporal stages: (1) acute (first

few hours–7 days), (2) healing (7–28 days), and (3) healed (≥29 days).

The myocardium undergoes a series of cellular responses in the infarct

Cardiomyocyte

swelling

Interstitial

edema

Thrombus

debris

Endothelial

dysfunction

Leukocyte and platelet

activation/interaction

Vulnerable plaque

• inflammation

• extension

• severity

• location

plaque

ion

Thrombogenic blood

• inflammation

• comorbidities

• environmental factors

• genetic background

Vulnerable myocardium

• inflammation

• ischemia duration/extent

• individual susceptibility

FIGURE 275-2 Critical determinants of myocardial infarction injury. The overlapping

of vulnerable plaque and thrombogenic blood are critical determinants for myocardial

infarction occurrence and extension. In addition, myocardial vulnerability, which is

largely due to coronary microvascular dysfunction, contributes to extension and

severity of ischemic injury. In the most severe form (known as no-reflow), structural

and functional impairments sustain vascular obstruction. Endothelial dysfunction

triggers leukocyte and platelet activation/interaction, whereas thrombotic debris

may worsen the obstruction. Furthermore, cardiomyocyte swelling, interstitial

edema, and tissue inflammation promote extravascular compression. (Modified

from F Montecucco, F Carbone, TH Schindler. Pathophysiology of ST-segment

elevation myocardial infarction: Novel mechanisms and treatments. Eur Heart J

37:1268, 2016.)

The amount of myocardial damage caused by coronary occlusion

depends on (1) the territory supplied by the affected vessel, (2) whether

or not the vessel becomes totally occluded, (3) the duration of coronary

occlusion, (4) the quantity of blood supplied by collateral vessels to the

affected tissue, (5) the demand for oxygen of the myocardium whose

blood supply has been suddenly limited, (6) endogenous factors that

can produce early spontaneous lysis of the occlusive thrombus, and (7)

the adequacy of myocardial perfusion in the infarct zone when flow is

restored in the occluded epicardial coronary artery.

Patients at increased risk for developing STEMI include those with

multiple coronary risk factors and those with UA (Chap. 274). Less

common underlying medical conditions predisposing patients to STEMI

include hypercoagulability, collagen vascular disease, cocaine abuse, and

intracardiac thrombi or masses that produce coronary emboli.

There have been major advances in the management of STEMI with

recognition that the “chain of survival” involves a highly integrated

system starting with prehospital care and extending to early hospital

management so as to provide expeditious implementation of a reperfusion strategy.

CLINICAL PRESENTATION

In up to one-half of cases, a precipitating factor appears to be present

before STEMI, such as vigorous physical exercise, emotional stress, or

a medical or surgical illness. Although STEMI may commence at any

ST-Segment Elevation Myocardial Infarction

2055CHAPTER 275

Zone of necrosing

myocardium

Troponin free

in cytoplasm

Cardiomyocyte

Myosin Actin Troponin complex

bound to actin filament

Lymphatic system

Venous system

0

0

1

2

5

10

20

50

1 2 3

Myoglobin and

CK isoforms

Troponin

(large MI)

Troponin

(small MI)

10% CV/99th percentile

CKMB

Days after onset of AMI

Multiples of the AMI cutoff limit

456789

FIGURE 275-3 The zone of necrosing myocardium is shown at the top of the figure,

followed in the middle portion of the figure by a diagram of a cardiomyocyte that

is in the process of releasing biomarkers. The biomarkers that are released into

the interstitium are first cleared by lymphatics followed subsequently by spillover

into the venous system. After disruption of the sarcolemmal membrane of the

cardiomyocyte, the cytoplasmic pool of biomarkers is released first (left-most arrow

in bottom portion of figure). Markers such as myoglobin and CK isoforms are rapidly

released, and blood levels rise quickly above the cutoff limit; this is then followed

by a more protracted release of biomarkers from the disintegrating myofilaments

that may continue for several days. Cardiac troponin levels rise to about 20–50

times the upper reference limit (the 99th percentile of values in a reference control

group) in patients who have a “classic” acute myocardial infarction (MI) and

sustain sufficient myocardial necrosis to result in abnormally elevated levels of the

MB fraction of creatine kinase (CK-MB). Clinicians can now diagnose episodes of

microinfarction by sensitive assays that detect cardiac troponin elevations above

the upper reference limit, even though CK-MB levels may still be in the normal

reference range (not shown). CV, coefficient of variation. (Modified from EM

Antman: Decision making with cardiac troponin tests. N Engl J Med 346:2079, 2002,

and; bottom image: Reproduced with permission from AS Jaffe: Biomarkers in acute

cardiac disease: The present and the future. J Am Coll Cardiol 48:1, 2006.)

zone, beginning with recruitment of polymorphonuclear leukocytes

(for removal of dead cells and clearance of extracellular macromolecules) followed by proinflammatory monocytes (that recruit fibroblasts) and ultimately reparative monocytes (that promote angiogenesis

and interstitial collagen production).

When evaluating the results of diagnostic tests for STEMI, the temporal phase of the infarction must be considered. The laboratory tests

of value in confirming the diagnosis may be divided into four groups:

(1) ECG, (2) serum cardiac biomarkers, (3) cardiac imaging, and (4)

nonspecific indices of tissue necrosis and inflammation.

■ ELECTROCARDIOGRAM

The electrocardiographic manifestations of STEMI are described in

Chap. 240. During the initial stage, total occlusion of an epicardial

coronary artery produces ST-segment elevation. Most patients initially

presenting with ST-segment elevation ultimately evolve Q waves on

the ECG. However, Q waves in the leads overlying the infarct zone

may vary in magnitude and appear only transiently, depending on the

reperfusion status of the ischemic myocardium and restoration of transmembrane potentials over time. A small proportion of patients initially

presenting with ST-segment elevation will not develop Q waves when

the obstructing thrombus is not totally occlusive, obstruction is transient, or a rich collateral network is present. Among patients presenting

with ischemic discomfort but without ST-segment elevation, if a serum

cardiac biomarker of necrosis (see below) is detected, the diagnosis of

NSTEMI is ultimately made (Fig. 275-1). A minority of patients who

present initially without ST-segment elevation may develop a Q-wave

myocardial infarction (MI). Previously, it was believed that transmural

MI is present if the ECG demonstrates Q waves or loss of R waves, and

nontransmural MI may be present if the ECG shows only transient

ST-segment and T-wave changes. However, electrocardiographicpathologic correlations are far from perfect, and terms such as Q-wave

MI, non-Q-wave MI, transmural MI, and nontransmural MI have been

replaced by STEMI and NSTEMI (Fig. 275-1). Contemporary studies

using magnetic resonance imaging (MRI) suggest that the development

of a Q wave on the ECG is more dependent on the volume of infarcted

tissue rather than the transmurality of infarction.

■ SERUM CARDIAC BIOMARKERS

Certain proteins, referred to as serum cardiac biomarkers, are released

from necrotic heart muscle after STEMI. The rate of liberation of specific proteins differs depending on their intracellular location, their

molecular weight, and the local blood and lymphatic flow. Cardiac

biomarkers become detectable in the peripheral blood once the capacity of the cardiac lymphatics to clear the interstitium of the infarct

zone is exceeded and spillover into the venous circulation occurs. The

temporal pattern of protein release is of diagnostic importance. The

criteria for AMI require a rise and/or fall in cardiac biomarker values

with at least one value above the 99th percentile of the upper reference

limit for normal individuals.

Cardiac-specific troponin T (cTnT) and cardiac-specific troponin I

(cTnI) have amino-acid sequences that differ from those of the skeletal

muscle forms of these proteins. These differences permitted the development of quantitative assays for cTnT and cTnI using highly specific

monoclonal antibodies. cTnT and cTnI may increase after STEMI to

levels many times higher than the upper reference limit (the highest

value seen in 99% of a reference population not suffering from MI),

the measurement of cTnT or cTnI is of considerable diagnostic usefulness, and they are now the preferred biochemical markers for MI

(Fig. 275-3). With improvements in the assays for the cardiac-specific

troponins, it is now possible to detect concentrations <1 ng/L in

patients without ischemic-type chest discomfort. The cardiac troponins are particularly valuable when there is clinical suspicion of either

skeletal muscle injury or a small MI that may be below the detection

limit for creatine phosphokinase (CK) and its MB isoenzyme (CKMB), and they are, therefore, of particular value in distinguishing UA

from NSTEMI. In practical terms, the high-sensitivity troponin assays

are of less immediate value in patients with STEMI. Contemporary

urgent reperfusion strategies necessitate making a decision (based

2056 PART 6 Disorders of the Cardiovascular System

largely on a combination of clinical and ECG findings) before the

results of blood tests have returned from the laboratory. Levels of cTnI

and cTnT may remain elevated for 7–10 days after STEMI.

CK rises within 4–8 h and generally returns to normal by 48–72 h

(Fig. 275-3). An important drawback of total CK measurement is its

lack of specificity for STEMI, as CK may be elevated with skeletal

muscle disease or trauma, including intramuscular injection. The MB

isoenzyme of CK has the advantage over total CK that it is not present

in significant concentrations in extracardiac tissue and, therefore, is

considerably more specific. However, cardiac surgery, myocarditis, and

electrical cardioversion often result in elevated serum levels of the MB

isoenzyme. A ratio (relative index) of CK-MB mass to CK activity ≥2.5

suggests but is not diagnostic of a myocardial rather than a skeletal

muscle source for the CK-MB elevation.

Many hospitals are using cTnT or cTnI rather than CK-MB as the

routine serum cardiac marker for diagnosis of STEMI, although any

of these analytes remains clinically acceptable. It is not cost-effective to

measure both a cardiac-specific troponin and CK-MB at all time points

in every patient.

While it has long been recognized that the total quantity of protein

released correlates with the size of the infarct, the peak protein concentration correlates only weakly with infarct size. Recanalization of

a coronary artery occlusion (either spontaneously or by mechanical

or pharmacologic means) in the early hours of STEMI causes earlier

peaking of biomarker measurements (Fig. 275-3) because of a rapid

washout from the interstitium of the infarct zone, quickly overwhelming lymphatic clearance of the proteins.

The nonspecific reaction to myocardial injury is associated with

polymorphonuclear leukocytosis, which appears within a few hours

after the onset of pain and persists for 3–7 days; the white blood

cell count often reaches levels of 12,000–15,000/μL. The erythrocyte

sedimentation rate rises more slowly than the white blood cell count,

peaking during the first week and sometimes remaining elevated for 1

or 2 weeks.

■ CARDIAC IMAGING

Abnormalities of wall motion on two-dimensional echocardiography

(Chap. 241) are almost universally present. Although acute STEMI

cannot be distinguished from an old myocardial scar or from acute

severe ischemia by echocardiography, the ease and safety of the procedure make its use appealing as a screening tool in the emergency

department setting. When the ECG is not diagnostic of STEMI, early

detection of the presence or absence of wall motion abnormalities by

echocardiography can aid in management decisions, such as whether

the patient should receive reperfusion therapy (e.g., fibrinolysis or a

percutaneous coronary intervention [PCI]). Echocardiographic estimation of left ventricular (LV) function is useful prognostically; detection of reduced function serves as an indication for therapy with an

inhibitor of the renin-angiotensin-aldosterone system. Echocardiography may also identify the presence of right ventricular (RV) infarction, ventricular aneurysm, pericardial effusion, and LV thrombus.

In addition, Doppler echocardiography is useful in the detection and

quantitation of a ventricular septal defect and mitral regurgitation, two

serious complications of STEMI.

Several radionuclide imaging techniques (Chap. 241) are available

for evaluating patients with suspected STEMI. However, these imaging

modalities are used less often than echocardiography because they are

more cumbersome and lack sensitivity and specificity in many clinical

circumstances. Myocardial perfusion imaging with [201Tl] or [99mTc]-

sestamibi, which are distributed in proportion to myocardial blood

flow and concentrated by viable myocardium (Chap. 273), reveals a

defect (“cold spot”) in most patients during the first few hours after

development of a transmural infarct. Although perfusion scanning is

extremely sensitive, it cannot distinguish acute infarcts from chronic

scars and, thus, is not specific for the diagnosis of acute MI. Radionuclide ventriculography, carried out with [99mTc]-labeled red blood cells,

frequently demonstrates wall motion disorders and reduction in the

ventricular ejection fraction in patients with STEMI. While of value in

assessing the hemodynamic consequences of infarction and in aiding

in the diagnosis of RV infarction when the RV ejection fraction is

depressed, this technique is nonspecific, as many cardiac abnormalities

other than MI alter the radionuclide ventriculogram.

MI can be detected accurately with high-resolution cardiac MRI

(Chap. 241) using a technique referred to as late enhancement. A

standard imaging agent (gadolinium) is administered and images are

obtained after a 10-min delay. Since little gadolinium enters normal

myocardium, where there are tightly packed myocytes, but does percolate into the intercellular region of the infarct zone, there is a bright

signal in areas of infarction that appears in stark contrast to the dark

areas of normal myocardium.

An Expert Consensus Task Force for the Universal Definition of

Myocardial Infarction has provided a comprehensive set of criteria for

the definition of MI that integrates the clinical and laboratory findings

discussed earlier (Table 275-1) as well as a classification of MI into

five types that reflect the clinical circumstances in which it may occur

(Fig. 275-4).

INITIAL MANAGEMENT

■ PREHOSPITAL CARE

The prognosis in STEMI is largely related to the occurrence of two

general classes of complications: (1) electrical complications (arrhythmias) and (2) mechanical complications (“pump failure”). Most out-ofhospital deaths from STEMI result from the sudden development of

ventricular fibrillation. The vast majority of deaths due to ventricular

fibrillation occur within the first 24 h of the onset of symptoms, and of

these, over half occur in the first hour. Therefore, the major elements

of prehospital care of patients with suspected STEMI include (1) recognition of symptoms by the patient and prompt seeking of medical

attention; (2) rapid deployment of an emergency medical team capable of performing resuscitative maneuvers, including defibrillation;

(3) expeditious transportation of the patient to a hospital facility that

is continuously staffed by physicians and nurses skilled in managing arrhythmias and providing advanced cardiac life support; and

(4) expeditious implementation of reperfusion therapy. The greatest

delay usually occurs not during transportation to the hospital but,

rather, between the onset of pain and the patient’s decision to call for

help. This delay can best be reduced by health care professionals educating the public concerning the significance of chest discomfort and

the importance of seeking early medical attention. Regular office visits

with patients having a history of, or who are at risk for, ischemic heart

disease are important “teachable moments” for clinicians to review the

symptoms of STEMI and the appropriate action plan.

Increasingly, monitoring and treatment are carried out by trained

personnel in the ambulance, further shortening the time between the

onset of the infarction and appropriate treatment. General guidelines

for initiation of fibrinolysis in the prehospital setting include the ability

to transmit 12-lead ECGs to confirm the diagnosis, the presence of paramedics in the ambulance, training of paramedics in the interpretation of

ECGs and management of STEMI, and online medical command and

control that can authorize the initiation of treatment in the field.

MANAGEMENT IN THE EMERGENCY

DEPARTMENT

In the emergency department, the goals for the management of

patients with suspected STEMI include control of cardiac discomfort,

rapid identification of patients who are candidates for urgent reperfusion therapy, triage of lower-risk patients to the appropriate location

in the hospital, and avoidance of inappropriate discharge of patients

with STEMI. Many aspects of the treatment of STEMI are initiated in

the emergency department and then continued during the in-hospital

phase of management (Fig. 275-5). The overarching goal is to minimize the time from first medical contact to initiation of reperfusion

therapy. This may involve transfer from a non-PCI hospital to one that

is PCI capable, with a goal of initiating PCI within 120 min of first

medical contact (Fig. 275-5).

Aspirin is essential in the management of patients with suspected

STEMI and is effective across the entire spectrum of acute coronary

ST-Segment Elevation Myocardial Infarction

2057CHAPTER 275

syndromes (Fig. 275-5). Rapid inhibition of cyclooxygenase-1 in platelets followed by a reduction of thromboxane A2

 levels is achieved by

buccal absorption of a chewed 160–325-mg tablet in the emergency

department. This measure should be followed by daily oral administration of aspirin in a dose of 75–162 mg.

In patients whose arterial oxygen (O2

) saturation is normal, supplemental O2

 is of limited if any clinical benefit and therefore is not

cost-effective. However, when hypoxemia is present, O2

 should be

administered by nasal prongs or face mask (2–4 L/min) for the first

6–12 h after infarction; the patient should then be reassessed to determine if there is a continued need for such treatment.

CONTROL OF DISCOMFORT

Sublingual nitroglycerin can be given safely to most patients with

STEMI. Up to three doses of 0.4 mg should be administered at about

5-min intervals. In addition to diminishing or abolishing chest discomfort, nitroglycerin may be capable of both decreasing myocardial oxygen

demand (by lowering preload) and increasing myocardial oxygen supply

(by dilating infarct-related coronary vessels or collateral vessels). In

patients whose initially favorable response to sublingual nitroglycerin is

followed by the return of chest discomfort, particularly if accompanied

by other evidence of ongoing ischemia such as further ST-segment or

T-wave shifts, the use of intravenous nitroglycerin should be considered. Therapy with nitrates should be avoided in patients who present

with low systolic arterial pressure (<90 mmHg) or in whom there is

clinical suspicion of RV infarction (inferior infarction on ECG, elevated jugular venous pressure, clear lungs, and hypotension). Nitrates

should not be administered to patients who have taken a phosphodiesterase-5 inhibitor for erectile dysfunction within the preceding 24 h,

because it may potentiate the hypotensive effects of nitrates. An idiosyncratic reaction to nitrates, consisting of sudden marked hypotension, sometimes occurs but can usually be reversed promptly by the

rapid administration of intravenous atropine.

Morphine is a very effective analgesic for the pain associated with

STEMI. However, it may reduce sympathetically mediated arteriolar

and venous constriction, and the resulting venous pooling may reduce

cardiac output and arterial pressure. These hemodynamic disturbances

usually respond promptly to elevation of the legs, but in some patients,

volume expansion with intravenous saline is required. The patient

may experience diaphoresis and nausea, but these events usually pass

and are replaced by a feeling of well-being associated with the relief of

pain. Morphine also has a vagotonic effect and may cause bradycardia

or advanced degrees of heart block, particularly in patients with inferior infarction. These side effects usually respond to atropine (0.5 mg

intravenously). Morphine is routinely administered by repetitive (every

5 min) intravenous injection of small doses (2–4 mg), rather than by

the subcutaneous administration of a larger quantity, because absorption may be unpredictable by the latter route.

Intravenous beta blockers are also useful in the control of the pain of

STEMI. These drugs control pain effectively in some patients, presumably by diminishing myocardial O2

 demand and hence ischemia. More

important, there is evidence that intravenous beta blockers reduce the

risks of reinfarction and ventricular fibrillation (see “Beta-Adrenoceptor

Blockers” below). A commonly employed regimen is metoprolol, 5 mg

every 2–5 min for a total of three doses, provided the patient has a heart

rate >60 beats/min, systolic pressure >100 mmHg, a PR interval <0.24 s,

and rales that are no higher than 10 cm up from the diaphragm. Fifteen

minutes after the last intravenous dose, an oral regimen is initiated of

50 mg every 6 h for 48 h, followed by 100 mg every 12 h.

Patient selection is important when considering beta blockers

for STEMI. Oral beta blocker therapy should be initiated in the first

24 h for patients who do not have any of the following: (1) signs of

heart failure, (2) evidence of a low-output state, (3) increased risk for

cardiogenic shock, or (4) other relative contraindications to beta blockade (PR interval >0.24 s, second- or third-degree heart block, active

asthma, or reactive airway disease).

Unlike beta blockers, calcium antagonists are of little value in the

acute setting, and there is evidence that short-acting dihydropyridines

may be associated with an increased mortality risk.

MANAGEMENT STRATEGIES

The primary tool for screening patients and making triage decisions is

the initial 12-lead ECG. When ST-segment elevation of at least 2 mm in

two contiguous precordial leads and 1 mm in two adjacent limb leads

is present, a patient should be considered a candidate for reperfusion

therapy (Figs. 275-1 and 275-5). The process of selecting patients for

TABLE 275-1 Definitions of Myocardial Injury and Infarction

Criteria for Myocardial Injury

The term myocardial injury should be used when there is evidence of elevated

cardiac troponin (cTn) levels with at least one value above the 99th percentile

upper reference limit (URL). The myocardial injury is considered acute if there is

a rise and/or fall of cTn values.

Criteria for Acute Myocardial Infarction (types 1, 2, and 3 MI)

The term acute myocardial infarction (MI) should be used when there is acute

myocardial injury with clinical evidence of acute myocardial ischemia and with

detection of a rise and/or fall of cTn values with at least one value above the 99th

percentile URL and at least one of the following:

• Symptoms of myocardial ischemia

• New ischemic electrocardiographic (ECG) changes

• Development of pathologic Q waves

• Imaging evidence of new loss of viable myocardium or new regional wall

motion abnormality in a pattern consistent with an ischemic etiology

• Identification of a coronary thrombus by angiography or autopsy (not for types

2 or 3 MIs)

Postmortem demonstration of acute atherothrombosis in the artery supplying

the infarcted myocardium meets criteria for type 1 MI. Evidence of an

imbalance between myocardial oxygen supply and demand unrelated to acute

atherothrombosis meets criteria for type 2 MI. Cardiac death in patients with

symptoms suggestive of myocardial ischemia and presumed new ischemic ECG

changes before cTn values became available or abnormal meets criteria for

type 3 MI.

Criteria for Coronary Procedure–Related MI (types 4 and 5 MI)

Percutaneous coronary intervention (PCI)–related MI is termed type 4a MI.

Coronary artery bypass grafting (CABG)–related MI is termed type 5 MI.

Coronary procedure–related MI <48 h after the index procedure is arbitrarily

defined by an elevation of cTn values >5 times for type 4a MI and >10 times for

type 5 MI of the 99th percentile URL in patients with normal baseline values.

Patients with elevated preprocedural cTn values, in whom the preprocedural

cTn levels are stable (<20% variation) or falling, must meet the criteria for a >5-

or >10-fold increase and manifest a change from the baseline value of >20%. In

addition, they must have at least one of the following:

• New ischemic ECG changes (this criterion is related to type 4a MI only)

• Development of new pathologic Q waves

• Imaging evidence of loss of viable myocardium that is presumed to be new

and in a pattern consistent with an ischemic etiology

• Angiographic findings consistent with a procedural flow-limiting complication

such as coronary dissection, occlusion of a major epicardial artery or graft,

side-branch occlusion-thrombus, disruption of collateral flow, or distal

embolization

Isolated development of new pathologic Q waves meets the type 4a MI or type 5

MI criteria with either revascularization procedure if cTn levels are elevated and

rising, but less than the prespecified thresholds for PCI and CABG.

Other types of type 4 MI include type 4B MI stent thrombosis and type 4C MI

restenosis that both meet type 1 MI criteria.

Postmortem demonstration of a procedure-related thrombus meets the type 4a

MI and type 5 MI criteria if associated with a stent.

Criteria for Prior or Silent/Unrecognized MI

Any one of the following criteria meets the diagnosis for prior or silent/

unrecognized MI:

• Abnormal Q waves with or without symptoms in the absence of nonischemic

causes

• Imaging evidence of loss of viable myocardium in a pattern consistent with

ischemic etiology

• Pathoanatomical findings of a prior MI

Source: Reproduced with permission from K Thygesen et al: Fourth universal

definition of myocardial infarction (2018). Circulation 138:e618, 2018.

2058 PART 6 Disorders of the Cardiovascular System

Myocardial Infarction Type 1 Myocardial Infarction Type 2

Atherosclerosis and oxygen

supply/demand imbalance

Vasospasm or coronary

microvascular dysfunction

Non-atherosclerotic

coronary dissection

Oxygen supply/demand

imbalance alone

Plaque rupture/erosion with

occlusive thrombus

Plaque rupture/erosion with

non-occlusive thrombus

Damaged

heart tissue

Occluded

cardiac vessel

FIGURE 275-4 Distinction between type 1 and type 2 myocardial infarction (MI). A. Type 1 MIs are caused by atherothrombotic coronary artery disease (CAD) and usually

precipitated by atherosclerotic plaque disruption (rupture or erosion). The relative burden of atherosclerosis and thrombosis in the culprit lesion varies greatly. B. The

pathophysiologic mechanism leading to ischemic myocardial injury in the context of a mismatch between oxygen supply and demand has been classified as type 2 MI, while

the infarct-related coronary artery is typically occluded in Type 1 MI’s, subtotal occlusion may be present in Type II Mi’s. (Adapted from K Thygesen: Circulation 138:e618, 2018.)

STEMI patient who is a

candidate for reperfusion

Diagnostic angiogram

Medical

therapy only

*Patients with cardiogenic shock or severe heart failure initially seen at a non–PCI-capable hospital should be transferred for cardiac

catheterization and revascularization as soon as possible, irrespective of time delay from myocardial infarction (MI) onset (Class I, LOE: B).

†Angiography and revascularization should not be performed within the first 2–3 h after administration of fibrinolytic therapy.

PCI CABG

Initially seen at a

PCI-capable

hospital

Initially seen at a

non–PCI-capable

hospital*

Send to cath lab

for primary PCI

FMC-device time

≤90 min

(Class I, LOE: A)

Transfer for

angiography and

revascularization

within 3–24 h for

other patients as

part of an

invasive strategy†

(Class IIa, LOE: B)

Transfer for

primary PCI

FMC-device

time as soon as

possible and

≤120 min

(Class I, LOE: B)

Administer fibrinolytic

agent within 30 min of

arrival when

anticipated FMCdevice >120 min

(Class I, LOE: B)

Urgent transfer for

PCI for patients

with evidence of

failed reperfusion

or reocclusion

(Class IIa, LOE: B)

DIDO time ≤30 min

FIGURE 275-5 Reperfusion therapy for patients with ST-segment elevation myocardial infarction (STEMI). The bold arrows and boxes are the preferred strategies.

Performance of percutaneous coronary intervention (PCI) is dictated by an anatomically appropriate culprit stenosis. CABG, coronary artery bypass graft; DIDO, door-in–

door-out; FMC, first medical contact; LOE, level of evidence. Colors correspond to the class of recommendation in the guideline. While the infarct-related coronary artery

is typically occluded in Type I MI’s, subtotal occlusion may be present in Type II MI’s. (Reproduced with permission from PT O’Gara: 2013 ACCF/AHA guideline for the

management of st-elevation myocardial infarction. Circulation 127:e362, 2013.)

ST-Segment Elevation Myocardial Infarction

2059CHAPTER 275

fibrinolysis versus primary PCI (angioplasty or stenting; Chap. 276) is

discussed below. In the absence of ST-segment elevation, fibrinolysis

is not helpful, and evidence exists suggesting that it may be harmful.

LIMITATION OF INFARCT SIZE

The quantity of myocardium that becomes necrotic as a consequence of

a coronary artery occlusion is determined by factors other than just the

site of occlusion. While the central zone of the infarct contains necrotic

tissue that is irretrievably lost, the fate of the surrounding ischemic

myocardium (ischemic penumbra) may be improved by timely restoration of coronary perfusion, reduction of myocardial O2

 demands,

prevention of the accumulation of noxious metabolites, and blunting

of the impact of mediators of reperfusion injury (e.g., calcium overload

and oxygen-derived free radicals). Up to one-third of patients with

STEMI may achieve spontaneous reperfusion of the infarct-related coronary artery within 24 h and experience improved healing of infarcted

tissue. Reperfusion, either pharmacologically (by fibrinolysis) or by

PCI, accelerates the opening of infarct-related arteries in those patients

in whom spontaneous fibrinolysis ultimately would have occurred and

also greatly increases the number of patients in whom restoration of

flow in the infarct-related artery is accomplished. Timely restoration of

flow in the epicardial infarct–related artery combined with improved

perfusion of the downstream zone of infarcted myocardium results in

a limitation of infarct size. Protection of the ischemic myocardium by

the maintenance of an optimal balance between myocardial O2

 supply

and demand through pain control, treatment of congestive heart failure

(CHF), and minimization of tachycardia and hypertension extends

the “window” of time for the salvage of myocardium by reperfusion

strategies.

Glucocorticoids and nonsteroidal anti-inflammatory agents, with

the exception of aspirin, should be avoided in patients with STEMI.

They can impair infarct healing and increase the risk of myocardial

rupture, and their use may result in a larger infarct scar. In addition,

they can increase coronary vascular resistance, thereby potentially

reducing flow to ischemic myocardium.

■ PRIMARY PERCUTANEOUS CORONARY

INTERVENTION

(See also Chap. 276) PCI, usually angioplasty and/or stenting without

preceding fibrinolysis, referred to as primary PCI, is effective in restoring perfusion in STEMI when carried out on an emergency basis in

the first few hours of MI. It has the advantage of being applicable to

patients who have contraindications to fibrinolytic therapy (see below)

but otherwise are considered appropriate candidates for reperfusion.

It appears to be more effective than fibrinolysis in opening occluded

coronary arteries and, when performed by experienced operators in

dedicated medical centers, is associated with better short-term and

long-term clinical outcomes. Compared with fibrinolysis, primary

PCI is generally preferred when the diagnosis is in doubt, cardiogenic

shock is present, bleeding risk is increased, or symptoms have been

present for at least 2–3 h when the clot is more mature and less easily

lysed by fibrinolytic drugs. However, PCI is expensive in terms of personnel and facilities, and its applicability is limited by its availability,

around the clock, in only a minority of hospitals (Fig. 275-5). Whereas

prior trials suggested that the only vessel upon which an intervention

should be performed is the infarct-related artery, more contemporary

studies (PRAMI, CvLPRIT, COMPLETE) provide evidence that performing PCI on nonculprit coronary vessels results in a lower rate of

cardiovascular events and a lower need for subsequent ischemia-driven

revascularization.

■ FIBRINOLYSIS

If no contraindications are present (see below), fibrinolytic therapy

should ideally be initiated within 30 min of presentation (i.e., door-toneedle time ≤30 min). The principal goal of fibrinolysis is prompt restoration of full coronary arterial patency. The fibrinolytic agents tissue

plasminogen activator (tPA), streptokinase, tenecteplase (TNK), and

reteplase (rPA) have been approved by the U.S. Food and Drug Administration for intravenous use in patients with STEMI. These drugs all

act by promoting the conversion of plasminogen to plasmin, which

subsequently lyses fibrin thrombi. Although considerable emphasis

was first placed on a distinction between more fibrin-specific agents,

such as tPA, and non-fibrin-specific agents, such as streptokinase, it is

now recognized that these differences are only relative, as some degree

of systemic fibrinolysis occurs with the former agents. TNK and rPA

are referred to as bolus fibrinolytics since their administration does not

require a prolonged intravenous infusion.

When assessed angiographically, flow in the culprit coronary artery

is described by a simple qualitative scale called the Thrombolysis in

Myocardial Infarction (TIMI) grading system: grade 0 indicates complete occlusion of the infarct-related artery; grade 1 indicates some

penetration of the contrast material beyond the point of obstruction,

but without perfusion of the distal coronary bed; grade 2 indicates perfusion of the entire infarct vessel into the distal bed, but with flow that

is delayed compared with that of a normal artery; and grade 3 indicates

full perfusion of the infarct vessel with normal flow. The latter is the

goal of reperfusion therapy, because full perfusion of the infarct-related

coronary artery yields far better results in terms of limiting infarct size,

maintenance of LV function, and reduction of both short- and longterm mortality rates. Additional methods of angiographic assessment

of the efficacy of fibrinolysis include counting the number of frames

on the cine film required for dye to flow from the origin of the infarctrelated artery to a landmark in the distal vascular bed (TIMI frame

count) and determining the rate of entry and exit of contrast dye from

the microvasculature in the myocardial infarct zone (TIMI myocardial

perfusion grade). These methods have an even tighter correlation with

outcomes after STEMI than the more commonly employed TIMI flow

grade.

tPA and the other relatively fibrin-specific plasminogen activators,

rPA and TNK, are more effective than streptokinase at restoring full

perfusion—i.e., TIMI grade 3 coronary flow—and have a small edge in

improving survival as well. The current recommended regimen of tPA

consists of a 15-mg bolus followed by 50 mg intravenously over the

first 30 min, followed by 35 mg over the next 60 min. Streptokinase is

administered as 1.5 million units (MU) intravenously over 1 h. rPA is

administered in a double-bolus regimen consisting of a 10-MU bolus

given over 2–3 min, followed by a second 10-MU bolus 30 min later.

TNK is given as a single weight-based intravenous bolus of 0.53 mg/

kg over 10 s. In addition to the fibrinolytic agents discussed earlier,

pharmacologic reperfusion typically involves adjunctive antiplatelet

and antithrombotic drugs, as discussed subsequently.

Clear contraindications to the use of fibrinolytic agents include

a history of cerebrovascular hemorrhage at any time, a nonhemorrhagic stroke or other cerebrovascular event within the past year,

marked hypertension (a reliably determined systolic arterial pressure

>180 mmHg and/or a diastolic pressure >110 mmHg) at any time

during the acute presentation, suspicion of aortic dissection, and active

internal bleeding (excluding menses). While advanced age is associated

with an increase in hemorrhagic complications, the benefit of fibrinolytic therapy in the elderly appears to justify its use if no other contraindications are present and the amount of myocardium in jeopardy

appears to be substantial.

Relative contraindications to fibrinolytic therapy, which require

assessment of the risk-to-benefit ratio, include current use of anticoagulants (international normalized ratio ≥2), a recent (<2 weeks) invasive

or surgical procedure or prolonged (>10 min) cardiopulmonary resuscitation, known bleeding diathesis, pregnancy, a hemorrhagic ophthalmic condition (e.g., hemorrhagic diabetic retinopathy), active peptic

ulcer disease, and a history of severe hypertension that is currently adequately controlled. Because of the risk of an allergic reaction, patients

should not receive streptokinase if that agent had been received within

the preceding 5 days to 2 years.

Allergic reactions to streptokinase occur in ~2% of patients who

receive it. While a minor degree of hypotension occurs in 4–10% of

patients given this agent, marked hypotension occurs, although rarely,

in association with severe allergic reactions.

Hemorrhage is the most frequent and potentially the most serious

complication. Because bleeding episodes that require transfusion are