Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company


David D. Waters

Definition and Epidemiology
Acute coronary syndrome (ACS) describes the continuum of myocardial ischemia that ranges from unstable angina at one end of the spectrum to non-ST segment elevation myocardial infarction (MI) at the other end. Unstable angina is distinguished from stable angina ( Chapter 67 ) by the new onset or worsening of symptoms in the previous 60 days or by the development of post-MI angina 24 hours or more after the onset of MI. When the clinical picture of unstable angina is accompanied by elevated markers of myocardial injury, such as troponins or cardiac isoenzymes, non-ST segment elevation MI is diagnosed. The distinction between non-ST segment elevation MI and MI with ST segment elevation ( Chapter 69 ) is clinically important because early recanalization therapy improves the outcome in ST elevation MI but not in non-ST segment elevation MI.
For ACS, whether defined clinically as unstable angina or as non-ST segment elevation MI, the pathophysiologic mechanisms are the same. Most ACS are caused by nonocclusive thrombosis occurring in a native vessel, a vessel that has been the previous site of a coronary angioplasty ( Chapter 70 ), or a coronary artery bypass graft ( Chapter 71 ). In other situations, ACS may be precipitated by coronary spasm or by an increase in myocardial oxygen demand superimposed on preexisting fixed coronary stenoses. From a clinical perspective, the presentation of patients with ACS ranges from that of typical unstable angina to a presentation indistinguishable from ST segment elevation MI. Regardless of the clinical presentation, however, the rapid clinical detection of ACS is key to the institution of appropriate therapy, which is different from that used for stable angina, on the one hand, or ST segment elevation MI, on the other hand.

Approximately 1.5 million patients are hospitalized annually in the United States with unstable angina or non-ST segment elevation MI. These conditions are more common in older people, in people with a history of coronary disease, and in people with atherosclerosis known to be present in other vascular beds or with multiple coronary risk factors.
Several systems have been proposed for classifying unstable angina. Distinguishing primary from secondary unstable angina is of clinical value. Acute worsening of a coronary stenosis causes primary unstable angina by limiting coronary blood flow. Secondary unstable angina arises as a consequence of increased myocardial oxygen demand superimposed on severe underlying coronary disease. The conditions with the potential to provoke secondary unstable angina include tachyarrhythmia, fever, hypoxia, anemia, hypertensive crisis, and thyrotoxicosis. Secondary unstable angina should resolve with successful treatment of the precipitating condition. Patients with non-ST segment elevation ACS should be categorized according to their level of short-term risk because patients at higher risk benefit from more aggressive treatment, whereas low-risk patients do not.
Various classifications have been proposed for primary unstable angina based on presenting symptoms. The most common approach ( Table 68-1 ) includes three levels of severity and three clinical circumstances, to yield nine categories in all. This classification is used frequently to categorize patients for research purposes, but no system is used widely in clinical practice.
The recognition of three specific subtypes of primary unstable angina is worthwhile because their pathophysiology, prognosis, and management are different from those of typical unstable angina. Variant or Prinzmetal’s angina is caused by coronary spasm and usually can be controlled by calcium channel blockers. Unstable angina within 6 months after coronary angioplasty ( Chapter 70 ) almost invariably is caused by restenosis. Because the underlying mechanism is cellular proliferation instead of plaque rupture, antithrombotic drugs are not needed; intravenous nitroglycerin provides effective acute treatment, and repeat revascularization typically is required. Unstable angina in a patient with previous coronary artery bypass graft (CABG) surgery ( Chapter 71 ) often involves advanced atherosclerosis of venous bypass grafts or progression of native vessel disease and portends a lower likelihood of long-term symptomatic relief compared with other patients with unstable angina. For each of these presentations,

Class I
New-onset, severe or accelerated angina. (Angina of <2 mo duration, severe or occurring >3 times/day, or angina that is distinctly more frequent and precipitated by distinctly less exertion. No rest pain within 2 mo)
Class II
Angina at rest, subacute. (Angina at rest within the preceding month but not within the preceding 48 hr)
Class III
Angina at rest, acute. (Angina at rest within the preceding 48 hr)
Class A
Secondary unstable angina. (A clearly identified condition extrinsic to the coronary vascular bed that has intensified myocardial ischemia, e.g., anemia, hypotension, tachyarrhythmia)
Class B
Primary unstable angina
Class C
Postinfarction unstable angina. (Within 2 wk of a documented myocardial infarction)
1. Absence of treatment or minimal treatment
2. Standard therapy for chronic stable angina. (Conventional doses of oral ß-blockers, nitrates, and calcium channel blockers)
3. Maximal therapy. (Maximally tolerated doses of all three categories of oral therapy and intravenous nitroglycerin)
Adapted from Braunwald E: Unstable angina: A classification. Circulation 1989;80:410–414.

unstable angina may progress to non-ST segment elevation MI if adequate treatment is not instituted promptly.
With the exception of ACS caused by the systemic stresses listed previously, plaque rupture or erosion with overlying thrombosis is considered to be the initiating mechanism of ACS, including unstable angina and non-ST segment elevation MI ( Chapter 66 ). Mechanical factors contribute to plaque disruption: A thin fibrous cap is more prone to rupture than a thick one, and plaque rupture occurs commonly where the plaque joins the adjacent vessel wall. Plaque erosion and plaque rupture can initiate an ACS. Erosion usually occurs centrally through a thinning cap rather than at the lateral edge of the plaque.
Inflammation also seems to play a key role in plaque disruption. Macrophages and T lymphocytes accumulate in atherosclerotic plaques because of the expression of adhesion molecules on monocytes, endothelial cells, and leukocytes. These cells release growth factors and chemotactic factors, which lead to local oxidation of low-density lipoprotein cholesterol, proliferation of smooth muscle cells, and production of foam cells.
Increased serum levels of C-reactive protein (CRP) are found in most patients with unstable angina and MI, but not in stable angina, and elevated CRP levels are a strong predictor of subsequent coronary events in patients with coronary disease. Similarly the cytokine interleukin-6, which is the main producer of CRP in the liver, is elevated in unstable angina but not in stable angina.
The stimulus that initiates the acute inflammatory process in ACS has not been identified. Chlamydia pneumoniae, cytomegalovirus, and Helicobacter pylori have been identified within human atherosclerotic lesions, and antibodies against Chlamydia heat-shock proteins can cross-react against heat-shock proteins produced by endothelium, resulting in endothelial damage and accelerated atherosclerosis. Antibodies to Chlamydia, cytomegalovirus, and Helicobacter are found more often in patients with atherosclerosis compared with controls. These associations do not prove causality, however, and clinical trials of antibiotic therapy in patients with ACS have shown no benefit.
Platelet deposition onto the exposed, thrombogenic surface of the ruptured plaque is an important step in the pathogenesis of ACS, yet only a small fraction of disrupted plaques culminate in symptoms. Patients with coronary or peripheral vascular disease have increased platelet reactivity compared with normal controls. Healthy endothelium releases nitric oxide, which inhibits platelet aggregation. This protective mechanism is attenuated in atherosclerosis.
In ACS, platelets are activated and generate thromboxane and prostaglandin metabolites. Severe or persistent unstable angina is associated with the highest thromboxane output, and stabilization of unstable angina is accompanied by a return to normal levels.
Activated platelets and leukocytes interact to stimulate the coagulation system. Monocytes release tissue factor, a small glycoprotein that initiates the extrinsic clotting cascade, leading to an increase in thrombin generation. Transient increases in thrombin-antithrombin III and prothrombin fragment 1 + 2 can be shown in the hour after an ischemic attack in most patients with ACS.
Tissue factor is also present in the lipid-rich core of atherosclerotic plaque and may be one of the major determinants of the thrombogenicity of plaques when they rupture. When tissue factor specifically is inhibited, the deposition of platelets and fibrin onto the ruptured plaque is reduced. Patients with ACS and high circulating levels of tissue factor have unfavorable outcomes.
Overactivity of other components of the coagulation system has been reported in unstable angina, including levels of factor XII, bradykinin precursor, and fibrinogen. Lower tissue-type plasminogen activator and plasminogen activator inhibitor-1 levels indicate that an impairment of the fibrinolytic system also is present.
Culprit lesions in unstable angina and non-ST segment elevation MI exhibit a heightened response to vasoconstrictor stimuli. This response is not present in other coronary segments and is not seen in culprit lesions of patients with stable angina. One explanation for this finding is that endothelin levels are higher in culprit lesions as a result of inflammation. Under experimental conditions, the degree of vasoconstriction varies, however, directly with the amount of platelet deposition. The process of platelet aggregation and thrombus formation releases potent vasoconstrictors, such as thromboxane A2

and serotonin. Vasoconstriction, or the absence of appropriate vasodilation, probably contributes significantly to the development of ischemic episodes in ACS and is a potential target for therapy.
The angiographic aspects of the culprit lesion have been defined from before, to during, to after the episode of unstable angina or non-ST segment elevation MI. If a patient with ACS previously has had a coronary angiogram, the culprit lesion usually can be documented to have progressed markedly since that time. Lesions that progress to cause acute coronary events usually are not severely stenotic; two thirds cause less than a 50% reduction in diameter and would not be targets for revascularization. Angiographic features of a lesion that predict that it will precipitate an acute coronary event include greater asymmetry, greater length, and a steeper outflow angle.
At the time of an episode of unstable angina or a non-ST segment elevation MI, the culprit lesion is more likely to be asymmetrical or eccentric, with a narrow base or neck, compared with control lesions. These angiographic features reflect the underlying plaque disruption with thrombus. Obvious thrombus is visible at angiography in a few patients with unstable angina. Coronary angioscopy reveals plaque rupture with overlying thrombus in most culprit lesions, however.
During the months after an episode of unstable angina or non-ST segment elevation MI, the initial culprit lesion is far more likely to progress and to precipitate another coronary event than are other lesions in the same patient or lesions in stable patients. Lesions with irregular borders, overhanging edges, or obvious thrombus at angiography are more likely to precipitate another event in the ensuing months than are smooth lesions.
Clinical Manifestations
The patient with unstable angina or non-ST segment elevation MI seeks medical attention because he or she has recognized either that new symptoms have appeared or that a previously stable pattern of symptoms has become unstable. Patients with non-ST segment elevation MI also may present with a pattern of increasing anginal episodes at rest or at lower levels of activity, but these patients are more likely to experience a prolonged episode of discomfort at rest. In many patients, the clinical presentation is indistinguishable from acute ST segment elevation MI ( Chapter 69 ), whereas other patients may have nonspecific symptoms ( Chapter 46 ).
The sensation of myocardial ischemia usually is located in the retrosternal area but may be felt only in the epigastrium, back, arms, or jaw. The description may include adjectives such as burning, squeezing, pressure-like, and heavy and, less often, sharp, jabbing, and knife-like. The physician should be cautioned that atypical features do not exclude unstable angina ( Chapter 46 ).
Nausea, sweating, or shortness of breath may accompany episodes of acute myocardial ischemia. In elderly or diabetic patients, these symptoms may be the only indication that myocardial ischemia is present. Women who present with ACS are more likely to have diabetes, hypertension, hyperlipidemia, and heart failure and to be older than men; they are less likely to be smokers and to have had a previous MI or a previous coronary revascularization.
On physical examination, transient signs of left ventricular dysfunction, such as basilar rales or a ventricular gallop, may accompany or follow shortly after an episode of unstable angina. More ominous signs of severe transient left ventricular dysfunction, such as hypotension or peripheral hypoperfusion, are not encountered commonly in the absence of myocardial necrosis. When ACS is manifested as a non-ST segment elevation MI, however, signs and symptoms may be similar to those of ST segment elevation MI ( Chapter 69 ) depending on the size and location of the damage. Physical examination may reveal precipitating causes of or contributing factors to unstable angina, such as pneumonia or uncontrolled hypertension.
The electrocardiogram (ECG) may be entirely normal or show only nonspecific abnormalities in patients with unstable angina or non-ST segment elevation MI. Transient ST segment depression of at least 1 mm that appears during chest pain and disappears with relief is objective evidence of transient myocardial ischemia. When ST segment depression is a persistent feature of ECGs recorded with or without chest pain, the finding commonly represents non-ST segment elevation MI. A common ECG pattern of patients with unstable angina or non-ST segment elevation MI is a persistently negative T wave, which usually indicates that a severe stenosis is present in the corresponding coronary artery. Deeply negative T waves occasionally are seen across all of the precordial leads, a pattern that suggests a severe, proximal stenosis of the left anterior descending coronary artery as the culprit lesion ( Chapter 54 ).
The ECG in ACS may show Q waves from an old MI or left bundle-branch block owing to extensive prior left ventricular damage. Patients with these findings are at increased risk because they are less likely than other patients to be able to tolerate an additional insult to the myocardium. ECG abnormalities may appear or evolve in the absence of new symptoms in patients with ACS. The development of significant Q waves may be the first indicator that the diagnosis is non-ST segment elevation MI, not unstable angina. T wave abnormalities may appear, worsen, or resolve. It is worthwhile to obtain serial ECGs during the first 48 hours and during episodes of chest pain.
Continuous 12-lead ECG monitoring can be performed using new, multiprocessor-controlled, programmable devices. The limited clinical experience with this technology suggests that it can detect episodes of ST segment depression when the presenting ECG is normal and that this information has prognostic and diagnostic value.
According to the traditional paradigm, elevated serum levels of cardiac enzymes or the MB isoenzyme of creatine kinase distinguished between unstable angina and acute MI. The diagnosis of unstable angina could be retained when minor elevations of CK or CK-MB were detected by serial sampling, but it was recognized that these elevations were an adverse prognostic sign. It now is recognized that one fifth to one quarter of patients who otherwise would be diagnosed with unstable angina have elevated levels of troponin T or troponin I on admission or soon thereafter, and most of them have normal levels of CK-MB. In 2000, a Joint European Society of Cardiology/American College of Cardiology committee recommended that these patients be classified as having acute MI, and this change has been widely adopted ( Chapter 69 ). The rationale for this change is that several large studies have shown that elevations of troponin are independent predictors of adverse events.
Troponin measurements may be normal early after the onset of ACS and become positive later, usually by 6 and almost always by 12 hours. Myoglobin, a low-molecular-weight heme protein found in skeletal and cardiac muscle, may be detected 2 hours after the onset of symptoms but is not specific for myocardial damage. CK-MB subforms are usually positive within 6 hours, and troponin T or I is usually positive within 12 hours. Troponin levels remain elevated for 1 week and are useful in making a diagnosis when the patient presents late after a coronary event.
Patients with suspected ACS must be evaluated rapidly and efficiently. A prompt and accurate diagnosis permits the timely initiation of appropriate therapy, which is important because complications are clustered in the early phases of ACS, and appropriate treatment reduces the rate of complications.
Patients with chest pain lasting longer than 20 minutes, hemodynamic instability, or recent syncope or presyncope should be referred to a hospital emergency department. Other patients with suspected unstable angina may be seen initially either in an emergency department or in an outpatient facility where a 12-lead ECG can be obtained quickly.
An ECG must be obtained as soon as possible in the initial evaluation of any patient with suspected ACS. The diagnostic yield is enhanced greatly if a tracing also can be recorded during an episode of chest pain. A normal ECG during chest pain does not exclude unstable angina; however, it does indicate that an ischemic area, if


Figure 68-1 Flow diagram for estimating the risk of acute myocardial infarction (MI) in emergency departments in patients with acute chest pain. For each clinical subset, the numerator is the number of patients with the set of presenting characteristics who developed an MI, whereas the denominator is the total number of patients presenting with that characteristic or set of characteristics. (Adapted from Pearson SD, Goldman L, Garcia TB, et al: Physician response to a prediction rule for the triage of emergency department patients with chest pain. J Gen Intern Med 1994;9:241–247.)
present, is not extensive or severe enough to induce ECG changes, and this finding is a favorable prognostic sign.
The initial assessment should be directed toward determining whether or not the symptoms are caused by myocardial ischemia and, if so, the level of risk. The probability of MI can be estimated from the history, physical examination, and ECG ( Fig. 68-1 ). This information and the assessment of the patient’s clinical features should indicate whether the probability that symptoms are due to myocardial ischemia is high, intermediate, or low ( Table 68-2 ). Based on this information, the patient’s initial triage and management should be determined ( Fig. 68-2 ).
If chest pain and ST segment elevation greater than 1 mm in two contiguous leads are present, the diagnosis is ST segment elevation MI; reperfusion with thrombolytic therapy or primary angioplasty should be considered without delay ( Chapter 69 ). In a patient known to have coronary disease, typical symptoms are highly likely to be caused by myocardial ischemia, particularly if the patient confirms that the symptoms are identical to previous episodes. Conversely, even if chest pain has some typical features, it is unlikely to be related to myocardial ischemia in a young individual known not to have risk factors for coronary disease. In one prospective multicenter study, older age, male sex, and the presence of chest or left arm pain or pressure as the presenting symptom all increased the likelihood that the patient was experiencing acute myocardial ischemia.
When ACS is suspected in a patient younger than age 50 years, it is particularly important to ask about cocaine use, regardless of social class or ethnicity. Cocaine can cause coronary vasospasm and thrombosis in addition to its direct effects on heart rate and arterial pressure, and it has been implicated as a cause of unstable angina and MI ( Chapter 30 ).
Unstable angina may be more difficult to diagnose than stable angina, owing to an absence of some of the distinguishing features. The characteristic relationship between stable angina and physical exertion or other stressful activities is a key diagnostic feature of stable angina that is lacking in unstable angina. ACS may be relieved poorly by nitroglycerin, whereas stable angina almost always responds. The duration of an episode of chest discomfort is usually longer and more variable in unstable angina than in stable angina.


Figure 68-2 Initial triage for patients with symptoms suggestive of an acute coronary syndrome (ACS). ACC/AHA/ACP = American College of Cardiology/American Heart Association/American College of Physicians; ECG = electrocardiogram. (Adapted from Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. J Am Coll Cardiol 2000;36:970–1062, with permission.)
The evaluation of a patient with a possible ACS requires not only establishing the diagnosis, but also assessing the short-term risk of complications requiring intensive care ( Fig. 68-3 ). This risk assessment determines the appropriate intensity of therapy. At the low end of the risk scale, a patient might be discharged home with aspirin and a ß-blocker, to be followed as an outpatient. At the opposite end of the scale, a patient might be hospitalized in a coronary care unit, treated with multiple drugs, and undergo coronary arteriography urgently as a prelude to revascularization.
Troponin levels should be measured when the patient first is seen and again 6 to 12 hours later ( Chapter 69 ). Myocardial perfusion imaging during or shortly after an episode of chest pain can aid in diagnosis and prognosis but is not indicated routinely ( Chapter 52 ). The sensitivity of this test decreases as the interval between chest pain and injection of the nuclear tracer lengthens. Large or multiple reversible perfusion defects indicate increased risk.
Patients with symptoms that suggest ACS can be categorized into low-risk, intermediate-risk, and high-risk groups, based on data available at the time of first assessment ( Table 68-3 ). High-risk patients have ongoing chest pain lasting longer than 20 minutes, reversible ST segment changes of at least 1 mm, or signs of serious left ventricular dysfunction. Low-risk patients have worsening angina without rest pain, are not older than age 65 years, and have a normal or unchanged ECG, without evidence of a previous MI.
The risk assessment should be updated during hospitalization because patients frequently change. Continuing angina with ST segment changes despite medical therapy is an ominous sign that should precipitate urgent coronary arteriography with a view to revascularizations ( Chapter 70 and Chapter 71 ) because the risk of progressing to MI is high ( Fig. 68-4 ). Most episodes of recurrent myocardial


Any of the following features:
Known coronary disease
Definite angina in men =60 years old or women =70 years old
Hemodynamic or ECG changes during pain
Variant angina
ST elevation or depression of at least 1 mm
Marked symmetrical T-wave inversion in multiple precordial leads
Absence of high-likelihood features and any of the following:
Definite angina in men <60 years old or women <70 years old
Probable angina in men =60 years old or women =70 years old
Probably not angina in diabetics, or in nondiabetics with =2 other risk factors*
Extracardiac vascular disease
ST depression 0.05–1 mm
T-wave inversion of at least 1 mm in leads with dominant R waves
Absence of high- or intermediate-likelihood features, but may have:
Chest pain, probably not angina
One risk factor, but not diabetes
T-waves flat or inverted <1 mm in leads with dominant R waves
Normal ECG
ECG = electrocardiogram.
Adapted from Braunwald E, et al: Diagnosing and managing unstable angina. Circulation 1994;90:613–622.

*Risk factors include diabetes, smoking, hypertension, and hypercholesterolemia.

ischemia are silent, and some investigators have reported that ST segment depression as detected by Holter monitoring is a better predictor of an unfavorable outcome.
Troponin measurements should be used in the risk stratification of patients with ACS to supplement the assessment from clinical features and the ECG. Elevated troponin levels strongly predict coronary events over the short-term. A major advantage of troponin measurements is that they contribute to risk independently of most of the other major predictors. In one large study, elevated troponin T, age, hypertension, number of antianginal drugs, and ECG changes at baseline predicted cardiac death or MI. Higher troponin T levels predict higher risk, especially in patients with ST segment depression. Elevated levels of CRP, serum amyloid A, and interleukin-6 also are associated with a poorer prognosis in patients with unstable angina.
The widely used Thrombolysis in Myocardial Infarction (TIMI) risk score, which has been validated in clinical trials, includes seven

Figure 68-3 Derivation and validation of four groups into which patients can be categorized according to risk of major cardiac events within 72 hours after admission for acute chest pain. ECG = electrocardiogram. (From Lee TH, Goldman L: Evaluation of the patient with acute chest pain. N Engl J Med 2000;342:1187–1195.)

At least one of the following features must be present:
Prolonged, ongoing (>20 min) rest pain
Pulmonary edema
Angina with new or worsening mitral regurgitation murmurs
Rest angina with dynamic ST changes of at least 1 mm
Angina with S3 or rales
Angina with hypotension
No high-risk features but must have any of the following:
Rest angina now resolved but not low likelihood of coronary disease
Rest angina (>20 min or relieved with rest or nitroglycerin)
Angina with dynamic T-wave changes
Nocturnal angina
New-onset Canadian Cardiovascular Society class III or IV angina in past 2 weeks but not low likelihood of coronary disease
Q waves or ST depression of at least 1 mm in multiple leads
Age >65 years
No high-risk or intermediate-risk feature but may have any of the following:
Increased angina frequency, severity, or duration
Angina provoked at a lower threshold
New-onset angina within 2 wk to 2 mo
Normal or unchanged ECG
Adapted from Braunwald E, et al: Diagnosing and managing unstable angina. Circulation 1994;90:613–622.

factors: (1) age 65 years or older, (2) at least three of the standard risk factors for coronary disease, (3) a prior coronary stenosis of 50% or more, (4) ST segment deviation on the presenting ECG, (5) at least two anginal episodes in the previous 24 hours, (6) use of aspirin in the previous week, and (7) elevated serum cardiac markers. Among more than 7000 patients with unstable angina or non-ST segment elevation MI in two trials, the event rate over 14 days increased from 4.7% for patients with a score of 0 or 1 to 41% for patients with a score of 6 or 7.
Patients with suspected ACS but with low-risk features often undergo stress testing if the ECGs are nondiagnostic and troponin levels remain normal for 12 hours. The type of test can vary from exercise with ECG monitoring or nuclear imaging to dipyridamole, adenosine, or dobutamine stress with nuclear imaging or echocardiography ( Chapter 46 , Chapter 51 , and Chapter 52 ).


Figure 68-4 Approach to the high-risk patient with an acute coronary syndrome. EF = ejection fraction; GP = glycoprotein. (Adapted from Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. J Am Coll Cardiol 2000;36:970–1062, with permission.)

Prevention and Treatment
The goals of treatment in patients who present with ACS are to control symptoms and either to prevent progression to non-ST segment elevation MI or at least to limit the amount of myocardial damage. Rapid intervention is crucial because the severity of the initial presentation does not inalterably predict the ultimate severity of myocardial damage if effective therapy is instituted.
Nitroglycerin, ß-blockers, and, to a lesser extent, calcium channel blockers reduce the risk of recurrent ischemic attacks. Revascularization ( Chapter 70 and Chapter 71 ) eliminates ischemia entirely in patients with favorable anatomy, and, in some subgroups, CABG surgery has been shown to prolong life. The risk of MI is reduced by antiplatelet and antithrombotic therapy.
Aspirin irreversibly inhibits cyclooxygenase activity in platelets. Consequently the platelet is unable to produce thromboxane A2 , the platelet-specific prostaglandin that induces platelet aggregation ( Chapter 32 ). Aspirin also may influence the pathophysiology of unstable angina through other mechanisms.
Randomized trials have shown conclusively that aspirin reduces the risk of MI by 50 to 67% in patients with unstable angina.[1] The benefit from aspirin begins with the onset of unstable angina and extends for more than 1 year. Because aspirin reduces the risk of MI in patients with stable coronary disease ( Chapter 67 ), the drug should be continued for life after an episode of unstable angina. The dose of aspirin in trials of patients with unstable angina has ranged from 75 to 1300 mg/day. Gastrointestinal side effects increase with increasing dosage. Doses of 325 mg acutely and 81 mg during long-term treatment are sufficient to inhibit maximally the platelet cyclooxygenase pathway.
Although women have been underrepresented in the trials of aspirin, it seems reasonable to assume that the benefit of aspirin extends to women with unstable angina, particularly because aspirin has been shown to reduce coronary events across the broad spectrum of patients with atherosclerosis.
Clopidogrel and ticlopidine are thienopyridines, and their mechanism of action differs from that of aspirin. Both drugs inhibit adenosine diphosphate-mediated platelet activation. Because they act independently from the arachidonic acid pathway, their antiplatelet activities are synergistic with aspirin. Clopidogrel has supplanted ticlopidine because of its more rapid onset of action, lower incidence of serious adverse events, and stronger clinical trial data.
In a trial of more than 12,000 patients with ACS without ST segment elevation, the addition of clopidogrel to aspirin over a 3-to 12-month follow-up period reduced the composite end point of

cardiovascular death, nonfatal MI, or stroke by a relative 20%, representing a 2.1% reduction in absolute risk.[2] This benefit was obtained at the risk of a small increase in the incidence of bleeding. Clopidogrel increases the risk of bleeding during coronary bypass surgery, so this drug usually is not started if the patient is considered to be a surgical candidate.
Platelet membranes contain glycoprotein (GP) receptors. The GP IIb/IIIa receptor changes from its resting to its active state when the platelet is activated by agonists or other platelets and serves as a receptor for fibrinogen and von Willebrand factor. Fibrinogen binding is central to platelet aggregation and thrombus formation in the arterial circulation. In contrast to aspirin or clopidogrel, which do not block thrombin-induced platelet aggregation, GP IIb/IIIa inhibitors block aggregation in response to all potential agonists.
Three GP IIb/IIIa blockers have been approved and are used widely clinically. Abciximab is the Fab fragment of a monoclonal antibody, eptifibatide is a peptide GP IIb/IIIa inhibitor, and tirofiban is a smaller molecule. These drugs must be administered by parenteral infusion; oral GP IIb/IIIa inhibitors failed to reduce events in large clinical trials and have not been approved for use.
Platelet GP IIb/IIIa inhibition at the time of angioplasty reduces ischemic complications in patients with ACS.[3] The benefit with respect to the primary end point of the trials was less with eptifibatide and tirofiban (15 to 20%) than with abciximab (30 to 60%). A trial directly comparing tirofiban and abciximab during angioplasty revealed a lower event rate in the abciximab group.[4]
In addition, five large trials have assessed the value of these drugs in the broader population of patients with unstable angina or non-Q wave MI. Although abciximab was the most successful drug in the angioplasty trials, eptifibatide and tirofiban predominate in the ACS trials.
The value of GP IIb/IIIa inhibitors in patients with unstable angina who are not undergoing intervention is not fully defined. GP IIb/IIIa inhibitors have not been compared with clopidogrel or with low-molecular-weight heparins or studied in patients taking these drugs as background therapy. The current high cost of these drugs makes it tempting to limit their use to high-risk patients. Patients with troponin elevations or other high-risk features seem to benefit from GP IIb/IIIa blockade, but low-risk patients may not benefit.
Current guidelines recommend that eptifibatide or tirofiban should be added to aspirin and heparin in the treatment of patients with high-risk features or with refractory ischemia. These drugs should be continued during coronary angioplasty ( Chapter 70 ) and for 12 to 24 hours after the procedure for tirofiban and for 24 to 72 hours after the procedure for eptifibatide. Abciximab also can be used in patients with unstable angina in whom angioplasty is planned within the following 24 hours. When abciximab is administered before diagnostic coronary angiography, however, the prolonged platelet inhibition it induces may force a delay in the urgent CABG surgery that is needed for some patients. When aspirin and unfractionated heparin are used with GP IIb/IIIa inhibitors, the dose of heparin should be conservative during coronary procedures, and heparin should be discontinued after the procedure if it is uncomplicated.
The principal inhibitory effect of heparin on coagulation is probably via the inhibition of thrombin-induced activation of factor V and factor VIII ( Chapter 33 ). Platelets inhibit the anticoagulant effect of heparin by binding factor Xa and protecting it from inactivation.
The pharmacokinetics of heparin are complex, and the dose-response relationship is nonlinear. Heparin therapy is monitored to maintain the activated partial thromboplastin time ratio within 1.5 to 2.5 times normal. The anticoagulant response to a standard dose of heparin varies widely among patients, such that even when a weight-based nomogram is used in a clinical study, the activated partial thromboplastin time falls outside the therapeutic range more than one third of the time. Results in routine clinical practice are probably much worse. Pooled analyses of randomized trials reveal an average incidence of major bleeding of 6.8% in the continuous infusion groups and 14.2% in the intermittent infusion groups.
The addition of heparin to aspirin reduced the event rate in one trial of patients with unstable angina, and a meta-analysis including several smaller trials concluded that the event reduction conferred by heparin therapy was approximately one third.[5]
Discontinuation of heparin in patients with unstable angina can result in a reactivation of refractory ischemic episodes within hours. Aspirin or warfarin may block this phenomenon. Rebound has been described with other thrombin inhibitors, but the mechanism has not been defined. Mild thrombocytopenia occurs in 10 to 20% of patients treated with unfractionated heparin. In 2 to 10% of patients, a more severe form of thrombocytopenia develops. This antibody-mediated response occurs within 5 to 10 days after initiation of treatment and is associated with thromboembolic sequelae in 30 to 80% of cases. Other adverse effects of heparin include osteoporosis, skin necrosis, alopecia, hypersensitivity reactions, and hypoal-dosteronism.
Low-molecular-weight heparins (LMWH) are fragments of unfractionated heparin produced by enzymatic or chemical depolymerization processes that yield chains with average molecular weights of approximately 5000. Compared with unfractionated heparin, LMWH produce a more predictable anticoagulant response because of their better bioavailability, longer half-life, and dose-independent clearance. The plasma half-life of LMWH after subcutaneous injection ranges from 3 to 6 hours so that once-daily or twice-daily administration is feasible. Monitoring is not required, and LMWH cause less bleeding. The main disadvantage of LMWH is that they currently are far more expensive than unfractionated heparin.
In patients with unstable angina or non-Q wave MI, enoxaparin is superior to unfractionated heparin for the first few days of therapy.[6] [7] The early benefit of LMWH treatment seems to dissipate over the ensuing months, and continuing therapy was not beneficial in most trials. In one trial, treatment from 5 days to 3 months with dalteparin produced an impressive reduction in death or MI at 1 month, with gradual loss of this benefit thereafter.[8]
Heparin is recommended for the acute treatment of all patients with unstable angina except patients determined to be at low risk. Unfractionated heparin should be started with an intravenous bolus of 60 to 70 U/kg followed by a constant infusion of approximately 16 U/kg/hr, adjusted to maintain the activated partial thromboplastin time at 1.5 to 2.5 times control, or 50 to 70 seconds. Subcutaneous administration of enoxaparin or dalteparin may be used instead of unfractionated heparin. The dose of enoxaparin is 1 mg/kg twice daily, and the dose of dalteparin is 120 IU/kg (maximum 10,000 IU) twice daily. Either standard heparin or LMWH should be continued for 2 to 5 days, or until the patient has been stabilized for 24 hours, or until revascularization is performed. The dose of unfractionated heparin should be reduced during coronary angioplasty when aspirin and GP IIb/IIIa inhibitors are being administered concomitantly, and heparin should be discontinued after an uncomplicated procedure. Information is accumulating on the combined use of LMWH and GP IIb/IIIa inhibitors, particularly during coronary interventions; this combination is probably acceptable.
Thrombolytic therapy improves the outcome of patients with ST segment elevation MI ( Chapter 69 ) but is of no benefit in unstable angina or non-ST segment elevation MI. The direct thrombin inhibitor bivalirudin has been recommended as an improvement over heparin during angioplasty and is the agent of choice in patients with heparin-induced thrombocytopenia. Long-term anticoagulation with warfarin is not recommended for patients with unstable angina or non-ST segment elevation MI.
In the only major trial to date that has tested the early effects of cholesterol lowering after ACS, high-dose atorvastatin for 16 weeks in patients with unstable angina for whom revascularization was not planned reduced the composite primary end point.[9] Several other trials showed long-term event reduction in patients with coronary disease; long-term compliance to this therapy is improved if it is begun in the hospital.
An oral ß-blocker at a dose that reduces heart rate and an intravenous nitroglycerin infusion are reasonable treatments to control symptoms in high-risk or intermediate-risk patients with

ACS. Low-risk and some intermediate-risk patients can be treated with oral or transdermal nitrates and ß-blockers. A patient who develops unstable angina while already taking two or three antianginal drugs should be treated with intravenous nitroglycerin, but symptoms are harder to control compared with a patient who previously took no antianginal drugs.
In patients with unstable angina, sublingual nitroglycerin usually relieves attacks promptly, although it may be less efficacious than in stable angina. Nitroglycerin is a venodilator at low doses and an arteriolar dilator at higher doses; it reduces preload and afterload and myocardial oxygen consumption. The drug directly dilates coronary stenoses and increases oxygen delivery to the ischemic region. Nitroglycerin increases collateral flow and favorably redistributes regional coronary flow. Because of its preferential effect on capacitance as opposed to resistance vessels, it does not induce a coronary steal, in contrast to other vasodilators.
Nitroglycerin and longer acting nitrates act by releasing nitric oxide in vascular smooth muscle through an enzymatic process. Sulfhydryl-donating compounds are necessary for this activity, and their rapid depletion during long-term therapy with nitroglycerin or other nitrate preparations rapidly leads to tolerance to the hemodynamic effects of the drug. This phenomenon is a major problem when nitrates are used as long-term therapy but is less relevant to their use in ACS. Nitroglycerin inhibits platelet aggregation and, in experimental models, reduces platelet thrombus deposition. This effect seems to persist even after tolerance develops for the hemodynamic effects of the drug.
Patients with unstable angina often are treated with an infusion of intravenous nitroglycerin to prevent further attacks. A common starting dose is 10 µg/min. The dose can be increased by 10 µg/min increments until symptoms are controlled or unwanted side effects develop. The most common adverse effects are headache, nausea, dizziness, hypotension, and reflex tachycardia.
The evidence that intravenous nitroglycerin prevents ischemic attacks in unstable angina patients is based on small, uncontrolled studies. No studies of sufficient power have examined whether intravenous nitroglycerin or other nitrate preparations reduce the risk of MI in unstable angina.
Angina episodes usually disappear entirely when patients with unstable angina or non-ST segment elevation MI are hospitalized and given medical therapy. At that point, intravenous nitrates often are replaced with transdermal or oral nitrates.
Although it is accepted widely that ß-blockers are useful to control ischemic episodes in patients with unstable angina or non-ST segment elevation MI, the data to support this claim are mainly inferential or derived from small trials without placebo-treated controls from the early 1980s, an era when patients were not treated routinely with aspirin and heparin. Taken together, these trials indicate that ß-blockers effectively reduce symptoms in patients with unstable angina who are not already taking one of these drugs on admission. Whether or not a ß-blocker also reduces the risk of MI is uncertain because the trials in unstable angina are underpowered to answer this question.
During long-term therapy, a long-acting ß-blocker is preferable to a short-acting one because it can be given once daily. In the context of ACS, it is reasonable to try to achieve ß-blockade within hours, however, and not days. ß-Blockade sometimes is initiated with intravenous boluses titrated to reduce heart rate. Early heart rate control is particularly important in high-risk patients or in patients with tachycardia or a high arterial pressure on admission. A reasonable target heart rate is 50 to 60 beats per minute at rest.
The main contraindications to ß-blockers in unstable angina are reactive airway disease, sinus node dysfunction or atrioventricular block, and severe heart failure. Most patients with chronic obstructive pulmonary disease tolerate a ß-blocker; a ß1 -selective agent (e.g., metoprolol or atenolol) is theoretically less likely to provoke bronchoconstriction. In some patients with conduction system disease, permanent pacing may be indicated in part so that long-term ß-blocker therapy can be given. Mild heart failure that is stable is not a contraindication to ß-blockers in unstable angina. Diltiazem or verapamil should be considered when a ß-blocker cannot be used.
Calcium channel blockers increase coronary blood flow globally and to the ischemic zone. Diltiazem and verapamil slow heart rate, reduce afterload, and reduce myocardial contractility; they reduce myocardial oxygen demand and are useful to control ischemic symptoms. Diltiazem and verapamil have been compared with placebo or a ß-blocker in several small clinical trials in unstable angina, and they seem to be more effective than placebo and equivalent to a ß-blocker in preventing recurrent angina episodes.
Most dihydropyridine calcium channel blockers induce a reflex increase in heart rate in the absence of ß-blockade, a feature that is likely to mitigate any benefit on myocardial ischemia. The rapid absorption and short half-life of the short-acting formulation of nifedipine produce frequent abrupt changes in arterial pressure and heart rate. The calcium channel blocker that has been used most often in the limited number of studies in unstable angina is this formulation of nifedipine. Taken together, these trials provide fairly strong evidence that nifedipine is harmful when used in patients with unstable angina not receiving ß-blockers, but that it may be helpful in controlling angina in patients with an adequate level of ß-blockade. Whether the poor results seen with nifedipine in trials of unstable angina and post-MI patients would have been different with a long-acting formulation or newer dihydropyridines such as amlodipine is open to debate because these drugs have not been evaluated under these conditions.
Diltiazem and verapamil are reasonable choices to treat unstable angina when ß-blockers are contraindicated. The scant evidence suggests that both drugs reduce the frequency of attacks in unstable angina, but there is no evidence that they prevent MI. The combination of either diltiazem or verapamil with a ß-blocker is not generally used in patients with unstable angina because the effect of these calcium channel blockers on heart rate and myocardial contractility are additive to the effects of ß-blockers.
Diltiazem reduced the risk of reinfarction within 14 days in a placebo-controlled trial among patients with non-Q wave MI in the early 1980s. Diltiazem and ß-blockers have not been compared in this situation, and the relevance of this trial to the current management of non-ST segment elevation MI is uncertain.
In most patients hospitalized with unstable angina, symptoms do not recur after institution of antianginal therapy. Patients with refractory unstable angina have a high risk of developing MI. Patients who are labeled as refractory often become asymptomatic when medical therapy is intensified.
Intra-aortic balloon counterpulsation prevents myocardial ischemia effectively in patients whose unstable angina is truly refractory. This mechanical approach improves myocardial blood flow and reduces myocardial oxygen demand by collapsing the resistance to left ventricular ejection in early systole. Intra-aortic balloon counterpulsation is needed for control of symptoms in less than 1% of patients with unstable angina, but it also is used in high-risk cases at the time of coronary angioplasty to provide a margin of safety. Intra-aortic balloon counterpulsation causes lower limb ischemia in approximately 10% of cases, but this complication almost always resolves with removal of the device.
CABG surgery ( Chapter 71 ) and coronary angioplasty ( Chapter 70 ) are performed frequently in patients with unstable angina; however, the precise indications for revascularization, the choice of procedure, and its timing are controversial. CABG surgery relieves angina completely in approximately 90% of patients who undergo the procedure, and symptoms usually do not recur for many years. In patients with lesions amenable to angioplasty, angina also almost always is relieved, but it usually recurs within 6 months in the 20 to 30% of patients who develop restenosis. Whether revascularization prolongs survival and prevents future coronary events in patients at different levels of risk has not been determined adequately from trials.
Randomized trials comparing revascularization with medical therapy in unstable angina first were performed more than 20 years ago. The results of all but the most recent trials are hardly applicable to current clinical decision making because major advances in medical and interventional practices have improved vastly the outcomes with both types of therapy.

An overview of the 10-year results from the clinical trials comparing CABG surgery with medical treatment for stable angina indicates that patients with left main coronary artery stenosis or three-vessel disease obtain the most benefit from surgery. In low-risk groups, such as patients with single-vessel involvement, no survival advantage can be shown with CABG surgery. These conclusions also may be relevant to patients with unstable angina.
Trials of coronary revascularization in unstable angina have compared an “aggressive” approach with a “conservative” approach. The aggressive approach involves early coronary angiography with revascularization by either coronary angioplasty or CABG surgery, depending on the coronary anatomy. Usually, patients with one or two severe stenoses are treated with angioplasty, and patients with more extensive disease undergo CABG surgery. The conservative approach usually limits coronary arteriography to patients who require revascularization to control persistent symptoms and to patients with high-risk features.
Although early trials suggested that the conservative approach was as good as or better than the aggressive approach in patients with ACS, a Scandinavian study of patients with unstable angina showed that the aggressively treated patients had a significantly lower rate of death or nonfatal MI at 6 months.[10] In a more recent study of patients with either unstable angina or non-ST segment elevation MI, the patients randomized to routine catheterization within 4 to 48 hours and revascularization “as appropriate” had a better outcome than patients for whom catheterization was limited to objective evidence of recurrent ischemia or an abnormal stress test.[11] The composite end point of death, nonfatal MI, or rehospitalization for ACS within 6 months was reduced from 19.4 to 15.9%, a 22% relative risk reduction. The degree of benefit was large in high-risk patients (e.g., patients with elevated troponin levels) and marginal or nonexistent in low-risk subgroups.
Patients with non-ST segment elevation MI can develop all of the complications associated with ST segment elevation MI, including arrhythmias, heart failure, and mechanical complications ( Chapter 69 ).
The treatment of unstable angina should be individualized to consider the specific features of the disease and the particular circumstances of the patient. Nevertheless, algorithms provide a useful framework (see Fig. 68-1 ).
Unstable angina is an acute episode related to one active culprit lesion, but the patient has diffuse atherosclerosis. Coronary disease is a chronic condition that usually causes recurrent events spread out over many years. Smoking cessation ( Chapter 14 ), cholesterol lowering ( Chapter 211 ), control of hypertension ( Chapter 63 ) and diabetes ( Chapter 242 ), and other risk factor reductions ( Chapter 67 and Chapter 69 ) may be at least as important long-term as are the specific treatment decisions related to the acute event. An episode of unstable angina may be viewed as an opportunity to improve the patient’s profile with respect to secondary prevention.
Prognosis in unstable angina and non-ST segment elevation MI can be viewed as a composite of the expected prognosis based on the extent of coronary disease and left ventricular function, overlaid with the short-term risk associated with the culprit lesion and the unstable state. The short-term risk is related almost entirely to MI and its complications and to recurrences of unstable angina. Risk is highest in the hours, days, and first month after the onset of symptoms. The incremental risk associated with the unstable state dissipates completely by 1 year. Of unstable angina patients in one series, 11% experienced an MI between hospital discharge and 1 year, but the subsequent annual MI rate was less than 2%.
Published data on prognosis in unstable angina are influenced by patient selection and treatment and can be misleading. The inclusion and exclusion criteria for clinical trials may bias the prognosis by eliminating either low-risk or high-risk patients. If large numbers of younger patients with atypical symptoms and no objective evidence of myocardial ischemia are included, the prognosis of the cohort tends to be better. Conversely, if ECG changes or elevated troponin levels are required, the prognosis tends to be worse.
Prognosis has improved dramatically since the 1980s with the introduction of increasingly more sophisticated medical therapy and revascularization techniques. In a compilation of 10 representative series with a total of nearly 2000 patients with unstable angina, excluding patients with new-onset or post-MI angina, the mortality was 4% in-hospital and 10% at 1 year. Survival without MI was 89% at 1 month and 79% at 1 year. Among 4488 patients with unstable angina in another large study, the mortality rate was 2.4% at 30 days, 5% at 6 months, and 7% at 1 year; the MI rate was 4.8% at 30 days and 6.2% at 6 months. Recurrent ischemia has a major impact on these rates; the 30-day MI rate increases from 2.3 to 7.2 to 21.7% in patients with no ischemia, ischemia, and refractory ischemia. These outcomes represent what can be expected now with modern therapy.

Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company


Jeffrey L. Anderson

Conceptually, myocardial infarction (MI) is myocardial necrosis caused by ischemia. Practically, MI can be diagnosed and evaluated by clinical, electrocardiographic, biochemical, radiologic, and pathologic methods. Technologic advances in detecting much smaller amounts of myocardial necrosis than previously possible (e.g., by troponin determinations) have required a redefinition of MI. Given these developments, the term MI now should be qualified as to size, precipitating circumstance, and timing. This chapter focuses on acute MI associated with ST segment elevation on the electrocardiogram (ECG). This category of acute MI is characterized by profound (“transmural”) acute myocardial ischemia affecting relatively large areas of myocardium. The underlying cause essentially always is complete interruption of regional myocardial blood flow (due to coronary occlusion, usually atherothrombotic) ( Chapter 66 ). This clinical syndrome should be distinguished from the non-ST-elevation MI, in which the blockage of coronary flow is incomplete and for which different acute therapies are appropriate ( Chapter 68 ).
Incidence and Impact
Cardiovascular disease is responsible for almost one half of all deaths in the United States and other developed countries and for one fourth of deaths in the developing world ( Chapter 47 ). By 2020, cardiovascular disease will cause one of every three deaths worldwide. Cardiovascular disease causes about 1 million deaths in the United States each year, accounting for more than 40% of all deaths. Annually, an estimated 1,100,000 Americans suffer a fatal or nonfatal acute MI. Coronary heart disease, the leading cause of cardiovascular death, claims 460,000 lives. Half of coronary heart disease deaths (one quarter million per year) are directly related to acute MI, and at least half of these acute MI-related deaths occur within 1 hour of onset of symptoms and before patients reach a hospital emergency department.
More than 5 million people visit emergency departments in the United States each year for evaluation of chest pain and related symptoms, and almost 1.5 million are hospitalized for an acute coronary syndrome ( Chapter 46 ). The presence of ST-elevation or new left bundle branch block (LBBB) distinguishes patients with acute MI who require consideration of immediate recanalization therapy from other patients with the acute coronary syndrome (non-ST-elevation MI/unstable angina; Chapter 68 ). Changing demographics, lifestyles, and medical therapies have led to a relative decrease in ST-elevation MI. In 1990, ST-elevation MI accounted for 55% of acute MIs, whereas in 1999, the rate had declined to 37%. ST-elevation MI is associated with greater in-hospital (but not post-hospital) mortality than non-ST-elevation MI and is an important contributor to total population mortality.
Pathophysiology and Pathology
Coronary occlusion as a precipitant of acute MI was suggested by the American physician James Herrick in 1912. Concurrently, Obrastzow and Straschesko published cases of “acute coronary thrombosis” in the Russian literature. Full understanding of thrombosis as the mechanism for acute MI did not meet with acceptance until the 1980s. In a seminal study, DeWood and colleagues performed coronary angiography in patients during the early hours of acute MI and found coronary occlusion to be present in 87% of patients studied within 4 hours of onset of symptoms. At emergency coronary bypass surgery, the nature of occlusion was shown to be thrombotic.
In a canine model of coronary occlusion and recanalization, myocardial cell death begins within 15 minutes of occlusion and proceeds rapidly in a wavefront from endocardium to epicardium. Partial myocardial salvage can be achieved by releasing the occlusion within 3 to 6 hours; the degree of salvage is inversely proportional to the duration of ischemia and occurs in a reverse wavefront from epicardium to endocardium. The extent of myocardial necrosis can also be altered by modification of metabolic demands and collateral blood supply. Extensive clinical research over the past two decades has confirmed the promise and defined the limitations of coronary recanalization for human acute MI. Recanalization therapy and advances in adjunctive medical therapy have been associated with progressive declines in 30-day mortality rates from ST-elevation acute MI (from about 30% to 5 to 10%).
Over the past 2 decades, pathologic, angiographic, and angioscopic observations have further refined the pathophysiologic basis of coronary thrombosis. Underlying plaque erosion, fissuring, or rupture of vulnerable atherosclerotic plaques has been determined to be the initiating mechanism of coronary thrombotic occlusion, precipitating intraplaque hemorrhage, coronary spasm, and occlusive luminal thrombosis ( Chapter 66 ).
Further studies have shown that plaque erosion or rupture most frequently occurs in lipid-laden plaques with an endothelial cap weakened by internal collagenase (metalloproteinase) activity derived primarily from macrophages. These macrophages are recruited to the plaque from blood monocytes responding to inflammatory mediators and adhesion molecules.
With plaque rupture, elements of the bloodstream are exposed to the highly thrombogenic lipid-, tissue-factor-, and collagen-containing plaque core and matrix. Platelets adhere, become activated, and aggregate; vasoconstrictive and thrombogenic mediators are secreted; vasospasm occurs; thrombin is generated and fibrin formed; and a partially or totally occlusive platelet- and fibrin-rich thrombus is generated. When coronary flow is occluded, electrocardiographic ST-elevation occurs (ST-elevation acute MI). Partial occlusion, occlusion in the presence of adequate collateral circulation, and/or distal coronary embolization results in unstable angina or non-ST-elevation MI ( Chapter 68 ). Ischemia from impaired myocardial perfusion causes myocardial cell injury or death, ventricular dysfunction, and cardiac arrhythmias.
Although the vast preponderance of MIs are caused by atherosclerosis, occasional patients may develop complete coronary occlusions owing to coronary emboli, in situ thrombosis, vasculitis, primary vasospasm, infiltrative or degenerative diseases, diseases of the aorta, congenital anomalies of a coronary artery, or trauma ( Table 69-1 ).
Clinical Manifestations
Traditionally, the diagnosis of acute MI has rested on the triad of ischemic chest discomfort, ECG abnormalities, and elevated serum cardiac markers. Acute MI was considered present when at least two of the three were present. With their increasing sensitivity and specificity, serum cardiac markers (e.g., troponin I or T) have assumed a dominant role in confirming the diagnosis of acute MI in patients with suggestive clinical and/or ECG features.
Ischemic-type chest discomfort is the most prominent clinical symptom in the majority of patients with acute MI (see Table 46-1 ). The discomfort is characterized by its quality, location, duration, radiation, and precipitating and relieving factors. The discomfort associated with acute MI is qualitatively similar to that of angina pectoris but more severe. It often is perceived as heavy, pressure-like, crushing, squeezing, bandlike, viselike, strangling, constricting, aching, or burning; it is rarely perceived as sharp pain, and generally not as stabbing pain ( Chapter 46 and Chapter 67 ).
The primary location of typical ischemic pain is most consistently retrosternal, but it also may present left parasternally, left precordially, or across the anterior chest ( Chapter 46 ). Occasionally, discomfort is predominantly perceived in the anterior neck, jaw, arms, or epigastrium. It is generally somewhat diffuse; highly localized pain (finger-point) is rarely angina or acute MI. The most characteristic pattern of radiation is to the left arm, but the right or both arms may be involved. The shoulders, neck, jaw, teeth, epigastrium, and interscapular area also are sites of radiation. Discomfort above the jaws or below the umbilicus is not typical of acute MI. Associated symptoms often include nausea, vomiting, diaphoresis, weakness, dyspnea, restlessness, and apprehension.

The pain of the acute MI lasts longer (typically 20 minutes to several hours) than angina and is not reliably relieved by rest or nitroglycerin. The onset of acute MI usually is unrelated to exercise or other apparent precipitating factors. Nevertheless, acute MI begins during physical or emotional stress and within a few hours of arising more frequently than explained by chance.
It is estimated that at least 20% of acute MIs are painless (“silent”) or atypical (unrecognized). Elderly patients and patients with diabetes are particularly prone to painless or atypical MI, which may occur in as many as one third to one half of such patients. Because the prognosis is worse in elderly and diabetic patients, diagnostic vigilance is required. In these patients, acute MI may present as sudden dyspnea (which may progress to pulmonary edema), weakness, light-headedness, nausea, and/or vomiting. Confusional states, sudden loss of consciousness, new rhythm disorders, or an unexplained fall in blood pressure are other, uncommon presentations. The differential diagnosis of ischemic chest pain also should include gastrointestinal disorders (e.g., reflux esophagitis; Chapter 136 ), musculoskeletal pain (e.g. costochondritis), anxiety or panic attacks, pleurisy or pulmonary embolism ( Chapter 94 ), and acute aortic dissection ( Chapter 75 and Table 46-2 ).
There are no physical findings that are diagnostic or pathognomonic of acute MI. The physical examination may be entirely normal or reveal only nonspecific abnormalities. An S4 gallop frequently is found if carefully sought. Blood pressure often is initially elevated, but it may be normal or low. Signs of sympathetic hyperactivity (tachycardia and/or hypertension) may accompany anterior wall MI, whereas parasympathetic hyperactivity (bradycardia and/or hypotension) is more common in inferior wall MI.
The examination is best focused on an overall assessment of cardiac function. Adequacy of vital signs and peripheral perfusion should be noted. Signs of cardiac failure, both left- and right-sided (e.g., S3 gallop, pulmonary congestion, elevated neck veins) should be sought, and observation for arrhythmias and mechanical complications (e.g., new murmurs) is essential. If hypoperfusion is present, determination of its primary cause (e.g., hypovolemia, right heart failure, left heart failure) is critical to management.
Diagnostic Tests
The initial ECG is neither perfectly specific nor perfectly sensitive for all patients who develop acute ST-elevation MI; nevertheless,

Coronary emboli
Causes include aortic or mitral valve lesions, left atrial or ventricular thrombi, prosthetic valves, fat emboli, intracardiac neoplasms, infective endocarditis, and paradoxical emboli
Thrombotic coronary artery disease
May occur with oral contraceptive use, sickle cell anemia and other hemoglobinopathies, polycythemia vera, thrombocytosis, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, antithrombin III deficiency and other hypercoagulable states, macroglobulinemia and other hyperviscosity states, multiple myeloma, leukemia, malaria, and fibrinolytic system shutdown secondary to impaired plasminogen activation or excessive inhibition
Coronary vasculitis
Seen with Takayasu’s disease, Kawasaki’s disease, polyarteritis nodosa, lupus erythematosus, scleroderma, rheumatoid arthritis, and immune-mediated vascular degeneration in cardiac allografts
Coronary vasospasm
May be associated with variant angina, nitrate withdrawal, cocaine or amphetamine abuse, and angina with “normal” coronary arteries
Infiltrative and degenerative coronary vascular disease
May result from amyloidosis, connective tissue disorders (such as pseudoxanthoma elasticum), lipid storage disorders and mucopolysaccharidoses, homocystinuria, diabetes mellitus, collagen vascular disease, muscular dystrophies, and Friedreich’s ataxia
Coronary ostial occlusion
Associated with aortic dissection, luetic aortitis, aortic stenosis, and ankylosing spondylitis syndromes
Congenital coronary anomalies
Including Bland-White-Garland syndrome of anomalous origin of the left coronary artery from the pulmonary artery, left coronary artery origin from the anterior sinus of Valsalva, coronary arteriovenous fistula or aneurysms, and myocardial bridging with secondary vascular degeneration
Associated with and responsible for coronary dissection, laceration, or thrombosis (with endothelial cell injury secondary to trauma such as angioplasty); radiation; and cardiac contusion
Augmented myocardial oxygen requirements exceeding oxyen delivery
Encountered with aortic stenosis, aortic insufficiency, hypertension with severe left ventricular hypertrophy, pheochromocytoma, thyrotoxicosis, methemoglobinemia, carbon monoxide poisoning, shock, and hyperviscosity syndromes

Figure 69-1 Electrocardiographic stratification of chest pain. Size and color of arrow indicate relative frequency of final diagnosis (red = most frequent, blue = less common, green = least common). AMI = Acute myocardial infarction; ECG = electrocardiogram.
it plays a critical role in initial stratification, triage, and management ( Chapter 46 ; Fig. 69-1 ). In an appropriate clinical setting, a pattern of regional ECG ST segment elevation suggests coronary occlusion, causing marked myocardial ischemia; hospital admission is indicated, with triage to the coronary care unit (CCU). An emergent recanalization strategy (thrombolysis or primary angioplasty) should be used

unless contraindicated. Other ECG patterns (ST segment depression, T wave inversion, nonspecific changes, normal ECG) in association with ischemic chest discomfort are consistent with an acute coronary syndrome (non-ST-elevation MI or unstable angina) and are treated with different triage and initial management strategies ( Chapter 68 ).
Serial ECG tracings improve the sensitivity and specificity of the ECG for the diagnosis of acute MI and assist in assessing the outcomes of therapy. When typical ST elevation persists for hours and is followed within hours to days by T wave inversions and Q waves, the diagnosis of acute MI can be made with virtual certainty. The ECG changes in ST-elevation acute MI evolve through three over-lapping phases: (1) hyperacute or early acute, (2) evolved acute, and (3) chronic (stabilized).
Early Acute Phase.
This earliest phase begins within minutes, persists, and evolves over hours. T waves increase in amplitude and widen over the area of injury (hyperacute pattern). ST segments evolve from concave to a straightened to a convex upward pattern (acute pattern). When prominent, the acute injury pattern of blended ST-T waves may take on a “tombstone” appearance ( Fig. 69-2 ). ST segment depressions that occur in leads opposite those with ST elevation are known as “reciprocal changes” and are associated with larger areas of injury and worse prognosis, but also with greater benefits from recanalization therapy.
Other causes of ST elevation must be considered and excluded. These conditions include pericarditis ( Chapter 74 ), left ventricular (LV) hypertrophy with J point elevation, and normal variant early repolarization ( Chapter 50 ). Pericarditis (or perimyocarditis) is of particular concern because it may mimic acute MI clinically, but thrombolytic therapy is not indicated and may be hazardous.
Evolved Acute Phase.
During the second phase, ST elevation begins to regress, T waves in leads with ST elevation become inverted, and pathologic Q or QS waves become fully developed (>0.03 sec duration or >30% of R-wave amplitude).
Chronic Phase.
Resolution of ST elevation is quite variable. It is usually complete within 2 weeks of inferior MI but may be more delayed after anterior MI. Persistent ST elevation, often seen with large anterior MI, is indicative of a large area of akinesis, dyskinesis, or ventricular aneurysm. Symmetric T wave inversions may resolve over weeks to months or persist for an indefinite period of time; hence, the age of an MI in the presence of T wave inversions is often termed “indeterminate.” Q waves usually do not resolve after anterior MI but often disappear after inferior wall MI.
Early recanalization therapy accelerates the time course of ECG changes so that, upon coronary recanalization, the pattern may evolve from acute to chronic over minutes to hours instead of days to weeks. ST segments recede rapidly, T wave inversions and losses of R wave occur earlier, and Q waves may not develop or progress and occasionally may regress. Indeed, failure of ST elevation to resolve by more than 50 to 70% within 1 to 2 hours suggests failure of thrombolysis and may prompt urgent angiography for “rescue angioplasty.”
“True posterior” MI presents a mirror-image pattern of ECG injury in leads V1 to V2 –V4 . The acute phase is characterized by ST depression rather than ST elevation. The evolved and chronic phases show increased R wave amplitude and widening instead of Q waves. Recognition of a true posterior acute MI pattern may lead to an early recanalization strategy. Other

Figure 69-2 Electrocardiographic tracing shows an acute anterior-lateral MI. Note ST elevation in leads I, L, and V1–6 with Q waves in V1–4 . (Courtesy of Dr. Thomas Evans.)
causes of prominent upright anteroseptal forces include RV hypertrophy, ventricular preexcitation variants (Wolff-Parkinson-White syndrome; Chapter 59 ), and normal variants with early R wave progression. New appearance of these changes and/or association with an acute or evolving inferior MI usually allows the diagnosis to be made.
Occlusion of the left circumflex artery, especially when it is nondominant, often is not associated with diagnostic ST elevation and is therefore more difficult to recognize and appropriately triage and manage. Extending the ECG to measure left posterior leads V7 –V9 increases sensitivity for detecting left circumflex-related posterior wall injury patterns with excellent specificity ( Chapter 50 ).
Proximal occlusion of the right coronary artery before the acute marginal branch may cause right ventricular (RV) as well as inferior acute MI in about 30% of cases. Because the prognosis and treatment of inferior acute MI differ in the presence of RV infarction, it is important to make this diagnosis. The diagnosis is assisted by obtaining right precordial ECG leads, which are routinely indicated for inferior acute MI ( Chapter 50 ). Acute ST elevation of at least 1 mm (0.1 mV) in one or more of leads V4R to V6R is both sensitive and specific (>90%) for identifying acute RV injury, and Q or QS waves effectively identify RV infarction.
The presence of LBBB often obscures ST segment analysis in suspected acute MI. The presence of a new (or presumed new) LBBB in association with clinical (and laboratory) findings suggesting acute MI is associated with high mortality; these patients benefit substantially from recanalization therapy and should be triaged and treated in the same way as patients with ST-elevation MI. Certain ECG patterns, although relatively insensitive, suggest acute MI if present in the setting of LBBB: Q waves in two of leads I, aVL, V5 , V6 ; R-wave regression from V1 to V4 ; ST elevation of 1 mm or more in leads with a positive QRS complex; ST depression of 1 mm or more in leads V1 , V2 , or V3 ; and ST elevation of 5 mm or more with a negative QRS complex. The presence of right bundle branch block (RBBB) usually does not mask typical ST-T wave or Q-wave changes except for rare cases of isolated true posterior acute MI, which is characterized by tall right precordial R waves and ST depressions.
The increasing sensitivity and specificity of serum cardiac markers have made them the “gold standard” for detection of myocardial necrosis. However, because there is a delay of from 1 to 12 hours after onset of symptoms before markers become detectable or diagnostic, and given laboratory delays even when markers are positive, the decision to proceed with an urgent recanalization strategy (thrombolysis or primary angioplasty) must be based on the clinical history and initial ECG ( Chapter 46 ; see Fig. 69-1 ).
Candidate serum cardiac markers of acute MI are macromolecules (proteins) released from myocytes undergoing necrosis. Clinically ideal markers are not present normally in serum, become rapidly and markedly elevated during acute MI, and are not released from other injured tissues. In recent years, troponins I and T have emerged as the best markers, although creatine kinase (CK) and its MB isoenzyme continue to be useful. Both myoglobin and CK isoforms have




6 hr
12 hr
Troponin I
2–6 hr
5–10 d
Generally regarded as a test of choice
Troponin T
2–6 hr
5–14 d
A test of choice. Less specific than troponin I (elevated in renal insufficiency)
3–6 hr
2–4 d
Test of choice for recurrent angina once troponin elevated
MB2 Isoform
2–6 hr
1–2 d
Not widely available
1–2 hr
<1 d
Slightly improved sensitivity early in AMI when added to troponin/CK-MB, but not widely used due to low specificity
Adapted from Martin E: ST-Elevation/Q-Wave Myocardial Infarction. In Best Practice of Medicine Praxis Press, 2001; Adams JE III, Abendschein DR, Jaffe AS: Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation 1993;88:750–763.
AMI = acute myocardial infarction; CK = creatine kinase.

a characteristic molecular weight; time of first and maximal detection, peak concentration, and circulatory persistence; and pattern of increase in acute MI ( Table 69-2 ).
Cardiac-derived troponin I (cTnI) and troponin T (cTnT), proteins of the sarcomere, have amino acid sequences distinct from their skeletal muscle isoforms. Cardiac TnI and TnT are not normally present in the blood. With even small acute MIs, troponins increase to 20-fold or more of the lower limits of the assay, and elevations persist for several days. Troponins have progressively replaced routine CK and CK-MB because they are more specific in the setting of injuries to skeletal muscle or other organs that release CK and (to a lesser extent) CK-MB, and they also are more sensitive in the setting of minimal myocardial injury.
The troponins generally are first detectable 2 to 4 hours after the onset of acute MI, are maximally sensitive at 8 to 12 hours, peak at 10 to 24 hours, and persist for 5 to 14 days. Their long persistence has allowed them to replace lactate dehydrogenase (LDH) and LDH isoenzymes for the diagnosis of acute MI in patients presenting late (>1 to 2 days) after symptoms. However, this persistence may obscure the diagnosis of recurrent MI, for which more rapidly cleared markers (i.e., CK-MB) are more useful. Clinically, cTnI and cTnT appear to be of approximately equivalent utility. However, renal failure is more likely to be associated with false-positive elevations of cTnT than cTnI. Although qualitative point-of-service troponin tests can speed the diagnosis of acute MI in the emergency department, serum cardiac markers are often negative within the first few hours after the onset of symptoms.
CK and CK-MB served as the standard cardiac markers for many years, before the advent of cTnI and cTnT. The presence of CK in skeletal muscle and its elevation with even minor skeletal muscle trauma (e.g., intramuscular injections) limits its specificity for acute MI. The MB isoenzyme of CK, although present in lower concentrations than total CK, is much more specific (though not entirely so) for cardiac injury. An increased ratio of CK-MB mass to total CK activity substantially improves the specificity of the diagnosis of acute MI with only a modest reduction in sensitivity. A problem in using the ratio occurs when total CK is markedly elevated (in the presence of skeletal muscle damage, including prolonged cardiac resuscitation) and CK-MB is elevated by units but not ratio. Another clinical dilemma occurs when total CK is within the normal range but the ratio is elevated. Serial measurements of CK and CK-MB are more useful than single measurements in assessing diagnosis, timing, sizing, and success of therapy of acute MI. CK-MB increases within 3 to 4 hours after the onset of acute MI, is maximally sensitive within 8 to 12 hours, peaks at 12 to 24 hours, and returns to normal in 2 to 4 days.
The total quantity of CK/CK-MB protein released correlates with infarct size. Peak concentrations (e.g., for CK/CK-MB) correlate generally but less well with infarct size. Early reperfusion leads to higher and earlier peaks but similar or smaller integrated concentrations over time (consistent with myocardial salvage). The timing of the peak CK-MB may provide useful insight into the success (peak at 10 to 18 hours) or failure (peak at 18 to 30 hours) of recanalization therapy.
The myocardial form (MB-isoform) of CK-MB (designated CK-MB2) undergoes modification (terminal lysine cleavage) by carboxypeptidase to produce the circulating form of MB (CK-MB1). Acute MI disturbs the normal ratio of these two forms, relatively enriching CK-MB2. A ratio of CK-MB2:CK-MB1 of more than 1.5 can detect acute MI as early as 2 hours after the onset of the symptoms and is highly sensitive and specific for diagnosis by 4 to 6 hours. However, the electrophoretic assay is cumbersome, and the test has not been widely adopted because troponin assays are easier to perform.
It does not appear to be cost-effective to measure both a cardiac specific troponin and CK/CK-MB serially over time in every suspected case of acute MI. However, CK/CK-MB still is useful for certain applications, such as to confirm the diagnosis when the troponin level is elevated in a confusing clinical setting, to evaluate possible reinfarction in patients with recurrent chest pain, and, in specific settings, to assess the success of recanalization noninvasively (using time to peak).
Myoglobin is the most rapidly released and cleared serum cardiac marker. It may be detectable within 1 to 2 hours after the onset of acute MI. However, it also is abundant in skeletal muscle and suffers from a lack of specificity. For this reason, it is not commonly used clinically. LDH, aspartate serum transaminase (AST, formerly SGOT), and myosin light chain assays are not recommended because of lower specificity and sensitivity than cTnI, cTnT, and CK-MB.
On admission, routine assessment of complete blood count and platelet count, standard blood chemistries, a lipid panel, and coagulation tests (prothrombin time, partial thromboplastin time) is useful. Results assist in assessing comorbid conditions and prognosis and in guiding therapy. Hematologic tests provide a useful baseline before initiation of antiplatelet, antithrombin, and thrombolytic therapy or coronary angiography/angioplasty. Myocardial injury precipitates a polymorphonuclear leukocytosis, commonly resulting in a white blood cell count of up to 12,000 to 15,000/µL that appears within a few hours and peaks at 2 to 4 days. The metabolic panel provides a useful check on electrolytes, glucose, and renal function. On admission or the next morning, a fasting lipid panel is recommended to assist in decision making for inpatient lipid lowering (i.e., statin therapy if low-density lipoprotein [LDL] is greater than 100 to 130 mg/dL; Chapter 211 ). Unless CO2 retention is suspected, finger oximetry is adequate to titrate oxygen therapy. Systemic acute phase inflammatory markers (e.g., C-reactive protein, erythrocyte sedimentation rate) increase with acute MI, but their incremental value for routine testing remains to be shown.
A chest radiograph is the only imaging test routinely obtained on admission for acute MI. Although the chest radiograph is often normal,

findings of pulmonary venous congestion, cardiomegaly, or widened mediastinum may contribute importantly to diagnosis and management decisions. For example, a history of severe, “tearing” chest and back pain in association with a widened mediastinum should raise the question of a dissecting aortic aneurysm ( Chapter 75 ). In such cases, thrombolytic therapy must be withheld pending more definitive diagnostic imaging of the aorta. Other noninvasive imaging (e.g., echocardiography [ Chapter 51 ], cardiac nuclear scans [ Chapter 52 ], and other tests) is performed for evaluation of specific clinical issues, including suspected complications of acute MI. Coronary angiography ( Chapter 54 ) is performed urgently as part of an interventional strategy for acute MI or later for risk-stratification in higher-risk patients managed medically.
Two-dimensional transthoracic echocardiography with color-flow Doppler imaging is the most generally useful noninvasive test obtained on admission or early in the hospital course ( Chapter 51 ). Echocardiography efficiently assesses global and regional cardiac function and evaluates suspected complications of acute MI. The sensitivity and specificity of echocardiography for regional wall motion assessment are high (>90%), although the age of the abnormality (new versus old) must be distinguished clinically or by ECG. Echocardiography is helpful in determining the cause of circulatory failure with hypotension (relative hypovolemia, LV failure, RV failure, or mechanical complication of acute MI). Echocardiography also can differentiate pericarditis and perimyocarditis from acute MI. Doppler echocardiography is indicated to evaluate a new murmur and other suspected mechanical complications of acute MI (papillary muscle dysfunction or rupture, acute ventricular septal defect, LV free wall rupture with tamponade or pseudoaneurysm). Later in the course of acute MI, echocardiography may be used to assess the degree of recovery of stunned myocardium after recanalization therapy, the degree of residual cardiac dysfunction and indications for angiotensin-converting enzyme (ACE) inhibitors and other therapies for heart failure, and the presence of LV aneurysm and mural thrombus (requiring oral anticoagulants).
Radionuclide techniques generally are too time consuming and cumbersome for routine use in the acute setting. More commonly, they are used in predischarge or post-discharge risk stratification to augment exercise or pharmacologic stress testing ( Chapter 52 ). Thallium-201 and technetium-99m-sestamibi alone or together (dual isotope imaging) are currently the most frequently used “cold spot” tracers to assess myocardial perfusion and viability, and infarct size. Infarct avid tracers to identify, locate, and size recent myocardial necrosis are available but rarely required for ST-elevation MI. Computed tomography ( Chapter 52 ) and magnetic resonance imaging ( Chapter 53 ) may be useful to evaluate patients with a suspected dissecting aortic aneurysm and, together with positron-emission tomography, for research purposes and in highly selected clinical applications such as for assessment of myocardial viability.

Prehospital Phase
More than one half of deaths related to acute MI occur within 1 hour of onset of symptoms and before the patient reaches a hospital emergency department. Most of these deaths are caused by ischemia-related ventricular fibrillation (VF) and can be reversed by defibrillation ( Chapter 60 and Chapter 61 ). Rapid defibrillation may allow resuscitation in 60% of patients when delivered by a bystander using an on-site automatic external defibrillator or by a first-responding medical rescuer. Moreover, the first hour represents the best opportunity for myocardial salvage with recanalization therapy. Thus, the three goals of prehospital care are (1) to recognize symptoms promptly and seek medical attention, (2) to deploy an emergency medical system team capable of cardiac monitoring, defibrillation and resuscitation, and emergency medical therapy (e.g., nitroglycerin, lidocaine, atropine), and (3) to transport the patient expeditiously to a medical care facility staffed with personnel capable of providing expert coronary care, including recanalization therapy (thrombolysis or primary angioplasty).
The greatest time lag to recanalization therapy is the patient’s delay in calling for help. Public education efforts have yielded mixed results, and innovative approaches are needed. The feasibility of initiating thrombolytic therapy by highly trained ambulance personnel in coordinated ambulance-emergency department systems has been shown. In coordinated systems and when transportation delays are substantial, initiation of thrombolytic or other antithrombotic therapy in the field may be considered, thereby shortening the time to recanalization.
Hospital Phases
The goals of emergency department care are to identify rapidly patients with acute myocardial ischemia, to stratify them into acute ST-elevation MI as compared with other acute coronary syndromes (see Fig. 68-1 and Fig. 69-1 ), to initiate a recanalization strategy and other appropriate medical care in qualifying patients with acute ST-elevation MI, and to triage rapidly to inpatient (CCU, step-down unit, observation unit) or outpatient care (patients without suspected ischemia) (see Table 68-3 ).
The evaluation of patients with chest pain and other suspected acute coronary syndromes begins with a 12-lead ECG even as the physician is beginning a focused history, including contraindications to thrombolysis, and a targeted physical examination. Continuous ECG monitoring should be started, an intravenous line established, and admission blood tests should be drawn (including cardiac markers such as cTnI or cTnT). As rapidly as possible, the patient should be stratified as having a probable ST-elevation acute MI, non-ST-elevation acute MI, probable or possible unstable angina, or likely noncardiac chest pain.
In patients with presumed ST-elevation acute MI, a recanalization strategy must be selected: alternative choices are thrombolysis (begun immediately in the emergency department with a goal of door-to-needle time of less than 30 minutes) or primary percutaneous coronary intervention (PCI; patient is transferred directly to the cardiac catheterization laboratory with a goal of coronary door-to-angiography time of less than 60 to 90 minutes and door-to-balloon time of less than 90 to 120 minutes; Fig. 69-3 ).
Aspirin should be given to all patients unless contraindicated ( Fig. 69-3 ). Intravenous heparin is appropriate in most patients. Patients with chest pain should be given sublingual nitroglycerin. Persistent ischemic pain may be treated with titrated doses of morphine. Initiation of ß-blocker therapy is usually indicated, especially with hypertension, tachycardia, and ongoing pain. Oxygen should be used in doses sufficient to avoid hypoxemia (fingertip oximetry may be used to monitor). The ideal systolic blood pressure is 100 to 140 mm Hg. Excessive hypertension usually responds to titrated nitroglycerin, ß-blocker therapy, and morphine (for pain). Relative hypotension may require discontinuation of these medications, fluid administration, or other measures as appropriate to the hemodynamic subset (see Table 69-3 ). Atropine should be available to treat symptomatic bradycardia and hypotension related to excessive vagotonia. Transfer to the CCU or catheterization laboratory should occur as expeditiously as possible.
Coronary care for early hospital management of acute MI has reduced in-hospital mortality by more than 50%. The goals of CCU care include (1) continuous ECG monitoring and antiarrhythmic therapy for serious arrhythmias (i.e., rapid defibrillation of VF), (2) initiation or continuation of a coronary recanalization strategy to achieve myocardial reperfusion, (3) initiation or continuation of other acute medical therapies, (4) hemodynamic monitoring and appropriate medical interventions for different hemodynamic subsets of patients, and (5) diagnosis and treatment of mechanical and physiologic complications of acute MI. General care and comfort measures also are instituted. A sample of CCU admission orders is given in Table 69-4 .
General care measures include attention to activity, diet, bowels, education, reassurance, and sedation. Bedrest is encouraged for the first 12 hours. In the absence of complications, dangling and bed-chair and self-care activities can begin within 24 hours. When stabilization has occurred, usually within 1 to 3 days, patients may be


Figure 69-3 Acute ST-elevation myocardial infarction: practical evidence-based guidelines for outcome-effective management. (Original guidelines developed by Kurt Kleinschmidt, M.D., FACEP, for Emergency Medicine Reports, November 2000. Final adaptation and revisions by the CTAP Panel. “Acute Coronary Syndrome [ACS] Pharmacotherapeutic Interventions for UA/NSTEMI—An Evidence-Based Review and Outcome-Optimizing Guidelines for ACS Patients with and without Procedural Coronary Intervention [PCI].”)
transferred to a step-down unit where progressive reambulation occurs. The risk of emesis and aspiration or the anticipation of angiography or other procedures usually dictates nothing by mouth or clear liquids for the first 4 to 12 hours. Thereafter, a heart-healthy diet in small portions is recommended. In patients at high risk for bleeding gastric stress ulcers, a proton pump inhibitor or an H2 -antagonist is recommended for prophylaxis in patients on antithrombotic therapy. Many patients benefit from an analgesic (e.g., morphine sulfate in 2 to 4 mg increments) to relieve ongoing pain and an anxiolytic or sedative during the CCU phase. A benzodiazepine is frequently selected. Sedatives should not be substituted for education and reassurance from concerned caregivers to relieve emotional distress and improve behavior; routine use of anxiolytics is neither necessary nor recommended. Constipation often occurs with bedrest and narcotics; stool softeners and a bedside commode are advised.
The ECG should be monitored continuously in the CCU (and usually in the step-down unit) to detect serious arrhythmias and guide therapy. Measures to limit infarct size (i.e., coronary recanalization) and to optimize hemodynamics also stabilize the heart electrically. Routine antiarrhythmic prophylaxis (e.g., with lidocaine or amiodarone) is not indicated, but specific arrhythmias require treatment (see later text).
Hemodynamic evaluation is helpful in assessing prognosis and guiding therapy (see Table 69-3 ). Clinical and noninvasive evaluation of vital signs is adequate for normotensive patients without pulmonary congestion. Patients with pulmonary venous congestion alone can usually be managed conservatively. Invasive monitoring is appropriate when the cause of circulatory failure is uncertain and when titration of intravenous therapies depends on hemodynamic measurements (e.g., pulmonary capillary wedge pressure and cardiac output). Similarly, an arterial line is not necessary in all patients and may be associated with local bleeding after thrombolysis or potent antiplatelet and antithrombin therapy; arterial catheters are appropriate and useful in unstable, hypotensive patients who do not respond to intravenous fluids to replete or expand intravascular volume (see “Complications”).
Transfer from the CCU to the step-down unit usually occurs within 1 to 3 days, when the cardiac rhythm and hemodynamics are stable. The duration of this late phase of hospital care is usually an additional 2 to 3 days in uncomplicated cases. Activity levels should be increased progressively under continuous ECG monitoring. Medical therapy should progress from parenteral agents to oral medications appropriate for long-term outpatient use.
Risk stratification and functional evaluations are critical to assess prognosis and guide therapy as the time for discharge approaches. Functional evaluation also can be extended to the early postdischarge period. Education must be provided about diet, activity, smoking, and other risk factors (lipids, hypertension).
Early reperfusion of ischemic, infarcting myocardium represents the most important conceptual and practical advance for ST-elevation acute MI and is the primary therapeutic goal. Coronary recanalization is accomplished by using thrombolytic (fibrinolytic) therapy or a primary PCI with angioplasty and, commonly, stenting. Each has relative advantages and disadvantages as the primary recanalization strategy (see Table 69-6 and Table 69-7 ). With broad application of recanalization therapy, 30-day mortality rates from ST-elevation acute MI have progressively declined over the past 3 decades (from 20 to 30% to 5 to 10%).
Thrombolytic Therapy.
During the 1980s and early 1990s, studies demonstrating the ability of thrombolytics to recanalize occluded coronary arteries acutely were followed by controlled trials; an overview of the larger randomized studies, primarily of streptokinase and including a total of 58,600 patients, showed a highly significant 18% reduction in mortality (from 11.5% to 9.8%) at 5 weeks.[1] Patients with anterior ST-elevation benefited more (37 lives saved per 1000) than those with inferior ST-elevation only (8 lives saved per 1000), and younger patients benefited more than the elderly (>75 years). No benefit or a slight adverse trend was observed for patients presenting with normal ECGs or



+/- S4
None required
Normal or high
Control pain, anxiety; ß-blocker; treat SBP to <140 mm Hg
Add fluids to maintain normal pressure. May develop pulmonary edema if hypotension due to unrecognized LV failure
Mild LV failure
Low to high
Rales, +/- S3
Diuresis; nitrates, ACE inhibitor; consider low-dose ß-blocker
Severe LV failure
Low to normal
Above + S3 , +/- ? JVP, +/- edema
Diuresis; nitrates; low-dose ACE inhibitor; avoid ß-blockers. Consider inotropes, urgent revascularization
Cardiogenic shock
Very low
Above + cool, clammy; ? mental, renal function
Avoid hypotensive agents; place intra-aortic balloon pump; urgent revascularization if possible
RV infarct
Very low
? JVP with clear lungs
Give IV fluids. Avoid nitrates and hypotensive agents. Dobutamine if refractory to fluids
Adapted from Forrester JS, Diamond G, Chatterjee K, Swan HJ: Medical therapy of acute myocardial infarction by application of hemodynamic subsets (second of two parts). N Engl J Med 1976;295:1404–1413.
ACE = angiotensin-converting enzyme; IV = intravenous; JVP = jugular venous pressure; LV = left ventricle; PA = pulmonary artery; RV = right ventricle; SBP = systolic blood pressure.

Acute ST-elevation myocardial infarction
CCU with telemetry
Vital signs:
q 1/2h until stable, then q 4h and prn. Pulse oximetry × 24 hr. Notify if heart rate <50 or >100; respiratory rate <8 or >20; SBP <90 or >150; O2 saturation <90%.
Bedrest × 12 hr with bedside commode. Oxygen at 2 L by nasal cannula 3 hr minimum; titrated to O2 saturation >90%
NPO until pain-free, then clear liquids progressing to heart-healthy diet as tolerated, unless on call for catheterization (or other test requiring NPO).
Laboratory* :
Troponin or CK/CK-MB q 8h × 3; comprehensive blood chemistry, CBC with platelets; PT, PTT; lipid profile (fasting in morning). Portable CXR.
D5 W or NS to keep vein open (increase fluids for relative hypovolemia)
Recanalization Therapy* :
Primary coronary angioplasty or thrombolysis (if appropriate)

1. Primary angioplasty (preferred if available within 1–2 hr)

2. Tenecteplase, alteplase, reteplase, or streptokinase (see Table 69-5 for dosing)
1. Nasal O2 at 2 L/min × 3 hr, then by order (per O2 saturation)

2. Aspirin 325 mg chewed on admission, then 162–325 mg PO qd (enteric coated)

3. IV heparin 60 U/kg bolus (max 4000 U) and 12 U/kg/hr (max 1000 U/hr) or enoxaparin 30 mg IV then 1 mg/kg SQ q 12h (maximum SQ doses 100 mg on day 1)

4. Metoprolol 5 mg IV q 5 min up to 3× then 25–50 mg bid or atenolol 5 mg IV q 10 min × 2 then 25–50 mg PO qd (hold for systolic BP <100, pulse <50, asthma, heart failure)

5. Consider nitroglycerin drip × 24–48 hr (titrated to SBP 100–140)

6. Morphine sulfate 2–4 mg IV prn for unrelieved pain

7. Stool softener

8. Anxioluytic or hypnotic if needed

9. ACE inhibitor for hypertension, anterior acute MI, or LV dysfunction, in low oral dose (e.g., captopril 6.25 mg q 8h), begun within 24 hours or when stable (SBP >100) and adjusted upward.

10. Consider: lipid-lowering (i.e., statin if LDL >100 mg/dL), GP IIb/IIIa inhibitor (e.g., eptifibatide or tirofiban) “upstream” for planned PCI, and clopidogrel 300 mg PO, then 75 mg PO qd after PCI (if CABG not planned).

11. Specific treatments for hemodynamic subgroups (see Table 69-3 ).
Adapted from Ryan TJ, Antman EM, Brooks NH, et al: 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1999;34:890–911.
ACE = angiotensin-converting enzyme; CABG = coronary artery bypass graft; CCU = coronary care unit; CK = creatine kinase; CBC = complete blood count; CXR = chest radiograph; GP = glycoprotein; IV = intravenous; LDL = low density lipoprotein; LV = left ventricle; MI = myocardial infarction; NPO = nothing by mouth; NS = normal saline; PCI = percutaneous coronary intervention; PT = prothrombin time; PTT = partial thromboplastin time; SBP = systemic blood pressure; SQ = subcutaneous.

*If not ordered in emergency department.

ST-depression alone. Benefit was time-dependent, declining from about 40 lives saved per 1000 within the first hour, to 20 to 30 lives saved per 1000 for hours 2 to 12, to a nonsignificant 7 lives saved per 1000 for hours 13 to 24. Even greater relative and absolute benefit within the first 1 to 2 hours was demonstrated in another overview that also included smaller studies.[2]
The additional recanalization benefit of tissue plasminogen activator (tPA) compared with streptokinase was best shown in a randomized international study of 41,021 patients with ST-elevation acute MI. Mortality at 30 days was significantly lower (by 14%) with an accelerated tPA regimen plus intravenous heparin (6.3%) than with streptokinase (7.3%).[3] In an angiographic substudy, the patency rate of the infarct-related artery at 90 minutes varied inversely with mortality, being higher for tPA (81%) than with the streptokinase regimens (53 to 60%). Differences in mortality were accounted for by differences in complete restoration of flow (54% versus 29 to



1.5 MU in 30–60 min
30 U in 5 min
100 mg in 90 min*
10 U + 10 U, 30 min apart
30–50 mg† over 5 sec
Circulating half-life (min)





Allergic reactions
Systemic fibrinogen depletion
Intracerebral hemorrhage





Patency (TIMI-2/3) rate, 90 min‡





Lives saved per 100 treated




Cost per dose (approx U.S. dollars)

*Accelerated tPA given as follows: 15-mg bolus, then 0.75 mg/kg over 30 min (maximum, 50 mg), then 0.50 mg/kg over 60 min (maximum 35 mg).
†TNK-tPA is dosed by weight (supplied in 5 mg/mL vials): <60 kg = 6 mL; 61–70 kg = 7 mL; 71–80 kg = 8 mL; 81–90 kg = 9 mL; >90 kg = 10 mL.
‡Based on: Granger CB, Califf RM, Topol EJ: Thrombolytic therapy for acute myocardial infarction. A review. Drugs 1992;44:293–325; Bode C, Smalling RW, Berg G, et al: Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. The RAPID II Investigators. Circulation 1996;94:891–898.
§Patients with ST elevation or bundle branch block, treated <6 hr.
?Based on the finding from the GUSTO trial that tPA saves one more additional life per 100 treated than does SK. (From an international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 1993;329:673–682; and Simes RJ, Topol EJ, Holmes DR Jr, et al: Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation 1995;91:1923–1928.)

Ischemic-type chest discomfort or equivalent for 30 min to 12 hr with new or presumed new ST-segment elevation in two contiguous leads of =2 mm (=0.2 mV) in leads V1 , V2 , or V3 or =1 mm in other leads
New or presumed new left bundle branch block with symptoms consistent with myocardial infarction
Absence of contraindications
Active bleeding or bleeding diathesis (menses excluded)
Prior hemorrhagic stroke, other strokes within 1 year
Intracranial or spinal cord neoplasm
Suspected or known aortic dissection
Severe, uncontrolled hypertension (>180/110 mm Hg)
Anticoagulation with therapeutic or elevated INR (>2–3)
Old ischemic stroke; intracerebral pathology other than above
Recent major trauma/surgery (<2–4 wk)
Recent noncompressible vascular punctures
Recent retinal laser therapy
Cardiogenic shock when revascularization is available
Adapted from Ryan TJ, Antman EM, Brooks NH, et al: 1999 update: ACC/AHA Guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1999;34:890–911.
INR = international normalized ratio.

33%). Longer-acting variants of tPA, given by single (tenecteplase) or double bolus (reteplase) injections, have been developed and approved for clinical use; these agents are more convenient to give but have not further improved survival.
The major risk of thrombolytic therapy is bleeding. Intracerebral hemorrhage is the most serious and frequently fatal complication; its incidence rate is 0.5 to 1% with currently approved regimens. Older age (>70 to 75 years), female gender, hypertension, and higher relative doses of tPA and heparin increase the risk of intracranial hemorrhage. The risk:benefit ratio should be assessed in each patient when thrombolysis is being considered and specific regimens are being selected.
The characteristics of currently approved intravenous thrombolytics are summarized in Table 69-5 ; current indications for and contraindications to thrombolytic therapy are summarized

Alternative recanalization strategy for ST-elevation or LBBB acute MI within 12 hr of symptom onset (or >12 hr if symptoms persist)
Cardiogenic shock developing within 36 hr of ST-elevation/Q-wave acute MI or LBBB acute MI in patients <75 years old who can be revascularized within 18 hr of shock onset
Recommended only at centers performing >200 PCI/yr with backup cardiac surgery and for operators performing >75 PCI/yr
Higher initial recanalization rates
Reduced risk of intracerebral hemorrhage
Less residual stenosis; less recurrent ischemia/infarction
Useful when thrombolysis contraindicated
Improves outcomes with cardiogenic shock
Access, advantages restricted to high-volume centers, operators
Longer average time to treatment
Results more operator dependent
Higher system complexity, costs
Adapted from Ryan TJ, Antman EM, Brooks NH, et al: 1999 update: ACC/AHA Guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1999;34:890–911.
LBBB = left bundle branch block; MI = myocardial infarction; PCI = percutaneous coronary intervention (includes balloon angioplasty, stenting).

in Table 69-6 . Patients with ST-elevation or new/presumed new LBBB presenting within 12 hours of the onset of symptoms and without contraindications are candidates for thrombolytic therapy.
Primary Percutaneous Coronary Intervention.
PCI has emerged as an alternative, usually as the preferred, recanalization strategy ( Table 69-7 ). PCI achieves mechanical recanalization by inflation of a catheter-based balloon centered within the thrombotic occlusion ( Chapter 70 ). Percutaneous transluminal coronary angioplasty (PTCA) is generally augmented by placing a stent at the site of occlusion as a scaffold to enlarge the lumen and retain optimal postangioplasty expansion.
The relative benefits of primary PTCA or PCI over thrombolysis have been established through moderate-sized comparative studies, registry data, and indirect evidence. A meta-analysis of ten randomized trials found a significantly lower mortality rate (4.4%

vs. 6.5%, odds ratio [OR] 0.66) and lower rates of nonfatal reinfarction (2.9% vs. 5.3%, OR 0.53) and intracerebral hemorrhage with primary PTCA compared with thrombolysis. [4] In recent registry studies, PCI yielded better outcomes across all age groups than thrombolysis when performed within 1 to 2 hours of presentation.
Currently, a primary PCI strategy may begin with initiation of a GP IIb/IIIa inhibitor in the emergency department, together with aspirin and heparin, followed by rapid application of coronary angioplasty with stenting. Whether the addition of a reduced dose of a plasminogen activator to a GP IIb/IIIa therapy in the emergency department could further improve outcomes with early PCI without compromising safety is under investigation.
Operator and institutional experience is an issue more important to outcomes with primary PCI than thrombolysis and has been incorporated into current recommendations ( Table 69-7 ). Primary PCI is feasible in community hospitals without surgical capability, but concerns about timing and safety remain, and this approach is not yet advocated in current guidelines.
Patients with ST-elevation or new/presumed new LBBB presenting within 12 hours are candidates for primary PCI. An additional important indication is cardiogenic shock occurring within 36 hours of the onset of acute MI and treated within 18 hours of the onset of shock. However, benefit was not established for patients older than 75 years of age, and benefit was greater with earlier PCI.[5]
Selecting a Recanalization Regimen.
Whether to use PCI or thrombolytic therapy depends on local resources and experience, as well as on patient factors. Outcomes appear to be determined more by the care with which a strategy is developed and implemented than whether thrombolytic therapy or primary PCI forms the preferred approach to recanalization. In general, in experienced facilities (>200 PCIs/center; surgical capability; >75 PCIs/operator annually; frequent primary PCI, e.g., >16/year/center; >4/operator/year) able to mobilize and treat quickly (<60 to 120 minutes to angiography and balloon inflation), primary PCI is generally considered the preferred strategy, with stenting preferred over balloon PTCA.[6] PCI is particularly preferred for patients at higher risk for mortality (including shock), for later presentations (>4 hours), and for patients with greater risk of intracerebral hemorrhage (age older than 70 years, female gender, therapy with hypertensives). Ancillary antithrombotic therapy with primary PCI includes aspirin, unfractionated heparin or a low-molecular-weight heparin, and a GP IIb/IIIa inhibitor (preferably initiated on admission before catheterization). Clopidogrel is begun directly after PCI and continued after discharge.
For other situations, thrombolytic therapy becomes the recommended recanalization strategy. The selection of a specific thrombolytic regimen is based on the risk of complications of the acute MI, the risk of intracerebral hemorrhage, and a consideration of economic constraints. Using these factors, longer-acting variants of tPA (i.e., tenecteplase and reteplase) have become dominant in the United States market; in Europe and elsewhere, less costly streptokinase is still widely used. A nonimmunogenic thrombolytic is preferred for patients with a history of prior streptokinase use. Streptokinase has a lower risk of intracerebral hemorrhage if excessive heparin is avoided. Tenecteplase combined with enoxaparin was more effective than tenecteplase with standard heparin or with a GP IIb/IIIa inhibitor (abciximab) plus heparin in a recent large trial.[7] Reteplase with abciximab also showed no mortality advantage when combined (in half-dose) with abciximab than with heparin alone; ischemic events decreased but intracerebral hemorrhage increased, especially in the elderly. In hospitals with long ambulance transport times (>60 to 90 minutes), a strategy for initiating prehospital thrombolysis may be considered.
Over the past decade, the application of recanalization therapy has remained relatively constant in the United States at 70 to 75% of “eligible” acute MI patients. Primary PCI use has increased (24% of eligible patients), although thrombolytic therapy continues to be more commonly applied (48% of eligible patients).
Antiplatelet Therapy
Platelets form a critical component of coronary thrombi. Aspirin inhibits platelet aggregation by irreversibly blocking cyclooxygenase-1 (COX-1) activity by selective acetylation of serine at position 530. COX-1 catalyzes the conversion of arachidonic acid to thromboxane-1, a potent platelet aggregator ( Chapter 32 ).
Aspirin has been extensively tested to prevent coronary heart disease ( Chapter 33 ). Aspirin trials in ST-elevation acute MI have been more limited but positive. The most important trial of aspirin in ST-elevation acute MI randomized over 17,000 patients with “suspected acute MI” (representing mostly but not entirely ST-elevation acute MI) to aspirin or control and to intravenous streptokinase or control. At 5 weeks, the relative risk of vascular death was reduced 21% by aspirin alone, 25% by streptokinase alone, and 40% by aspirin plus streptokinase.[8] Since that time, aspirin has been included as standard therapy in most ST-elevation acute MI treatment regimens.
Current guidelines strongly recommend aspirin (class I indication) on admission in a dose of 162 to 325 mg, preferably chewed. Aspirin is continued in the same dose throughout hospitalization and then indefinitely in a dose of 81 to 325 mg daily as an outpatient (enteric-coated forms are popular).
Clopidogrel and ticlopidine exert potent antiplatelet effects by blocking the platelet membrane adenosine diphosphate (ADP) receptor ( Chapter 33 ). Because of its lower hematologic (neutropenic) toxic potential, clopidogrel has become the preferred agent in this class. For aspirin-allergic patients, clopidogrel has become the alternative of choice for acute and chronic therapy of ST-elevation acute MI. A loading dose of 300 mg/day followed by 75 mg/day provides effective antiplatelet activity.
The efficacy of clopidogrel has been demonstrated for secondary prevention, for post-PCI patients, and for non-ST-elevation acute coronary syndromes, but limited data are available for acute therapy of ST-elevation acute MI. Begun on admission for non-ST-elevation acute MI or unstable angina, clopidogrel added to aspirin reduced vascular events (by 22%) at 3 to 12 months compared with aspirin alone. Extrapolation has led to the recommendation that clopidogrel be used as an alternative antiplatelet for ST-elevation acute MI patients when aspirin is contraindicated and be considered routinely (in addition to aspirin) in patients after primary PCI. Therapy for longer than 1 month might specifically be considered for higher-risk patients with more vascular disease or with complications of PCI.
Inhibitors of the platelet membrane glycoprotein IIb/IIIa receptor, a fibrinogen receptor, have been shown to benefit high-risk patients with non-ST-elevation acute coronary syndrome ( Chapter 33 and Chapter 68 ) on admission or after PCI. The benefit in ST-elevation MI is smaller when route stenting is used and if GP IIb/IIIa therapy is administered only in the catheterization laboratory. Earlier GP inhibition in the emergency department or pre-catheterization may be more effective to improve coronary patency at the time of angiography and event-free survival at 6 months. If early coronary artery bypass graft (CABG) surgery is a possibility after angiography, a shorter-acting inhibitor (eptifibatide, tirofiban) may impart a lower perioperative risk of bleeding than abciximab. For ST-elevation acute MI patients treated with thrombolysis, GP IIb/IIIa inhibitors added to reduced-dose tPA (e.g., half-dose tPA) improves early coronary patency. However, larger trials have not shown improved survival, and serious bleeding risks (including intracerebral hemorrhage) are increased. Whether such regimens are appropriate for specific subgroups, such as younger patients with large ST-elevation acute MIs scheduled with some delay for PCI remains to be determined.
Antithrombin Therapy
Upon injection, heparin complexes with antithrombin (AT)-III. The heparin-AT-III complex inactivates circulating thrombin and, less effectively, factor X. Clot-bound thrombin is resistant. Evidence for the contribution of heparin to antithrombotic regimens is mostly observational, indirect, or inferential ( Chapter 33 ).
Heparin is recommended with primary PCI and for patients receiving thrombolysis with tPA (see Fig. 69-3 and Table 69-4 ). It also is recommended intravenously with streptokinase or anistreplase for patients at high risk for systemic emboli (e.g., large or anterior acute MI with LV thrombus, atrial fibrillation [AF]). Low-dose

subcutaneous heparin (7500 U twice daily) has been recommended for patients with acute MI to prevent deep vein thrombosis in the absence of intravenous heparin; however, current early reambulation after acute MI and routine use of aspirin may make routine subcutaneous heparin unnecessary.
Excessive bleeding when heparin is used in combination with antithrombotic regimens has led to reductions in heparin doses with improved safety. When given with a thrombolytic, intravenous heparin is begun concurrently and given for 48 hours. Currently recommended doses include a 60 U/kg bolus (maximum 4000 U) followed initially with a 12 U/kg per hour infusion (maximum 1000 U/hour) with adjustment after 3 hours based on aPTT (target of 50 to 70 seconds, 1.5 to 2 times control). Experimental regimens including a GP IIb/IIIa inhibitor and a thrombolytic have used even lower heparin doses. During primary PCI, high-dose heparin is used (Activated Clotting Time [ACT] 300 to 350 seconds). Given together with a GP IIb/IIIa inhibitor during PCI, heparin is dosed to a lower ACT range (150 to 300 seconds).
Low-molecular-weight heparins (LMWHs) have enhanced inhibitory activity for factor Xa ( Chapter 33 ). They also have more reliable bioavailability and longer durations of action, permitting once or twice daily subcutaneous administration in fixed (weight-adjusted) doses. LMWHs have been extensively tested for the non-ST-elevation acute coronary syndrome and for prophylaxis of deep vein thrombosis. The LMWH enoxaparin combined with tenecteplase was more effective than tenecteplase combined with standard heparin or with a GP IIb/IIIa inhibitor (abciximab) plus heparin in ST-elevation acute MI.[9]
Direct acting thrombins, such as hirudin and its analogues, do not require AT-III for activity; they inhibit clot-bound heparin and are not neutralized by plasma proteins ( Chapter 33 ). Unlike heparin, hirudins do not induce thrombocytopenia. Early trials using surrogate end points were promising. However, bleeding can be problematic, and clinical trials to date have not shown a survival advantage.
Nitroglycerin and other organic nitrates (isosorbide dinitrate and isosorbide mononitrate) induce vascular smooth muscle relaxation by generating vascular endothelial nitric oxide. The resulting vasodilation of veins and peripheral and coronary arteries may beneficially reduce excessive cardiac preload and afterload, increase coronary caliber in responsive areas of stenosis, reverse distal small coronary arterial vasoconstriction, improve coronary collateral flow to ischemic myocardium, and inhibit platelet aggregation in acute MI ( Chapter 67 ). The result is improved oxygen delivery and reduced oxygen consumption. Potential clinical benefits include relief of ischemia, limitation of infarct size, prevention of dilative remodeling, control of hypertension (afterload), and relief of congestion (preload).
In the pre-reperfusion era, nitrates appeared to confer a mortality benefit in acute MI. In the context of thrombolytic therapy and aspirin, however, mortality benefits are modest, with a relative mortality reduction of about four lives saved per 1000 treated.[9] Nitroglycerin is definitely recommended for the first 24 to 48 hours for patients with acute MI and heart failure, large anterior MI, persistent ischemia, or hypertension. For other patients without contraindications, nitrates are possibly useful.
When nitrates are clearly indicated early in acute MI, intravenous nitroglycerin is preferred. Intravenous nitroglycerin may begin with a bolus injection of 12.5 to 25 µg followed by an infusion of 10 to 20 µg/min. Infusion dose is increased by 5 to 10 µg every 5 to 10 minutes up to about 200 µg/min during hemodynamic monitoring until clinical symptoms are controlled or blood pressures targets are reached (decreased by 10% in normotensives, decreased by 30% in hypertensives, but not below 80 mm Hg mean or 90 mm Hg systolic).
ß-Blocker Therapy.
ß-Adrenoceptor blockers reduce heart rate, blood pressure, and myocardial contractility, and they stabilize the heart electrically. These actions provide clinical benefit to most patients with acute MI by limiting myocardial oxygen consumption, relieving ischemia, reducing infarct size, and preventing serious arrhythmias.
In the prethrombolysis era, a meta-analysis of 28 randomized trials involving 27,500 patients found a modest early benefit on mortality (14% odds reduction), cardiac arrest (16% reduction), and nonfatal reinfarction (19% reduction). In acute MI subjects receiving thrombolytic therapy, immediate (intravenous then oral) metoprolol reduced recurrent ischemic events and reinfarction compared with deferred oral therapy. [10] Experience has shown that moderate to severe heart failure should preclude early intravenous ß-blocker use but not predischarge and outpatient oral therapy, initiated in small doses and carefully adjusted once stability is achieved.
Early ß-blockade is generally recommended (class I) for acute MI patients without severe LV failure or other contraindications (asthma, hypotension, severe bradycardia) who can be treated within 12 hours, regardless of concomitant thrombolysis or PCI, in those with ongoing or recurrent ischemic pain, and in those with tachyarrhythmias. Long-term ß-blocker therapy is recommended for all MI survivors without uncompensated heart failure, if not otherwise contraindicated. Therapy is begun within a few days (if not acutely) and continued indefinitely.
Angiotensin-Converting Enzyme Inhibitor Therapy.
The reninangiotensin system is activated in acute MI and heart failure. Inhibition of ACE has been shown to improve remodeling after acute MI (especially after large anterior acute MI). ACE inhibitors also have demonstrated efficacy in heart failure, wherein they prevent disease progression, hospitalization, and death ( Chapter 56 ). A meta-analysis of three major trials and 11 smaller ones involving more than 100,000 patients showed an overall mortality reduction of 6.5%, representing about five lives saved per 1000 patients treated.[9] Benefit was concentrated in higher-risk patients with large or anterior acute MIs and with LV dysfunction or failure.
ACE inhibitor therapy should begin within the first 24 hours (in the absence of hypotension—systolic pressure less than 100 mm Hg—or other contraindications). Patients with anterior injury and clinical heart failure should be particularly targeted (class I indication), although other patients also are candidates (class IIa). Long-term therapy should be given to patients with depressed ejection fraction or clinical heart failure and probably to all patients who tolerate these drugs.[11]
ACE inhibitor therapy should begin with low oral doses and be progressively adjusted to full dose as tolerated. For example, the short-acting agent captopril may be started in a dose of 6.25 mg or less and adjusted over 1 to 2 days to 50 mg twice daily. Before discharge, therapy may be transitioned to longer-acting agents such as ramipril, lisinopril, zofenopril, enalapril, or quinapril.
Antiarrhythmic therapy is reserved for treatment of, or short-term prevention after, symptomatic or life-threatening ventricular arrhythmias, together with other appropriate measures (cardioversion, treatment of ischemia and metabolic disturbances). Patients with severe left ventricular dysfunction (ejection fraction less than 30%) with or without nonsustained ventricular tachycardia (VT) more than a few days after acute MI may be considered for an implantable cardioverter defibrillator (ICD) ( Chapter 61 ).[12]
Digitalis and intravenous inotropes may increase oxygen demand, provoke serious arrhythmias, and extend infarction. Current recommendations support the use of digoxin in selected patients recovering from acute MI who develop supraventricular tachyarrhythmias (e.g., AF) or heart failure refractory to ACE inhibitors and diuretics. Intravenous inotropes (e.g., dobutamine, dopamine, milrinone, and norepinephrine) are reserved for temporary support of patients with hypotension and circulatory failure unresponsive to volume replacement ( Chapter 56 and Chapter 103 ). Other treatment measures for these patients (e.g., intra-aortic balloon pump, early revascularization) are discussed herein.
Lipid-Lowering Therapy.
Lipid lowering, particularly with HMG-CoA-reductase inhibitors (statins), has been progressively validated for secondary (and primary) prevention in large clinical trials over the past decade ( Chapter 211 ). Statins also have been shown to have anti-inflammatory effects, and inflammation now is known to play a prominent role in progression and destabilization of atherosclerotic plaques, leading to acute MI. Studies on non-ST-elevation acute coronary syndromes show early benefits from lipid lowering begun during hospitalization ( Chapter 68 ), and randomized studies are underway in patients with ST-elevation acute MI.

A fasting lipid profile should be obtained on admission. An LDL cholesterol greater than 100 mg/dL should lead to in-hospital initiation of lipid-lowering therapy, usually with a statin. Statin therapy also appears to benefit post-MI patients whose LDL is less than 100 mg/dL.
Other Medical Therapies
Calcium channel blockers, although anti-ischemic, also are negatively inotropic and have not been shown to reduce mortality after ST-elevation acute MI. With certain agents and patient groups, harm has been suggested. For example, short-acting nifedipine has been reported to cause reflex sympathetic activation, tachycardia, hypotension, and increased mortality. Verapamil or diltiazem (heart-rate slowing drugs) may be given to patients in whom ß-blockers are ineffective or contraindicated for control of rapid ventricular response with AF or relief of ongoing ischemia in the absence of heart failure, left ventricular dysfunction, or atrioventricular (AV) block.
Magnesium is protective for myocytes against calcium overload under conditions of experimental ischemia and recanalization, but magnesium, given 1 hour after thrombolysis was of no benefit in a large randomized trial of patients with acute MI. Magnesium currently is not recommended in acute MI unless levels are below normal or for patients with torsades de pointes-type VT associated with a prolonged QT interval.
Glucose-insulin-potassium (GIK) infusion was proposed as a beneficial metabolic therapy for acute MI in 1962 and subsequently has been tested in several small- to moderate-sized trials. Although intriguing, GIK requires further testing in the context of contemporary therapy.
Complications and Their Treatment
When chest pain recurs after acute MI, the diagnostic possibilities include postinfarct ischemia, pericarditis, infarct extension, and infarct expansion. Characterization of the pain, physical examination, ECG, echocardiography, and cardiac marker determinations assist in differential diagnosis. CK-MB often discriminates reinfarction better than cTnI or cTnT.
Postinfarction angina developing spontaneously during hospitalization for acute MI despite medical therapy usually merits coronary angiography. ß-Blockers (intravenously, then orally) and nitroglycerin (intravenously then orally or topically) are recommended medical therapies. Pain with recurrent ST elevation or re-elevation of cardiac markers may be treated with (re)administration of a tPA or, possibly, a GP IIb/IIIa inhibitor, together with nitroglycerin, ß-blockade, and heparin. Streptokinase, which induces neutralizing antibodies, generally should not be reutilized after the first few days. If facilities for angiography, PCI, and surgery are available, an invasive approach is recommended for discomfort occurring hours to days after acute MI and associated with objective signs of ischemia. Radionuclide testing (e.g., adenosine thallium) may be helpful in patients with discomfort that is transient or of uncertain ischemic etiology.
Infarct expansion implies circumferential slippage with thinning of the infarcted myocardium. Infarct expansion may be associated with chest pain but without re-elevation of cardiac markers. Expansive remodeling may lead to an LV aneurysm. The risk of remodeling is reduced with early recanalization therapy and administration of ACE inhibitors.
Acute pericarditis most commonly presents on days 2 to 4 in association with large, “transmural” infarctions causing pericardial inflammation. Occasionally, hemorrhagic effusion with tamponade develops; thus, overanticoagulation should be avoided. Pericarditis developing later (2 to 10 weeks) after acute MI may represent Dressler’s syndrome, which is believed to be immune-mediated. The incidence of this post-MI syndrome has decreased dramatically in the modern era. Pericardial pain is treated with aspirin (preferred, especially in the acute setting) or other nonsteroidal agents (indomethacin); severe symptoms may require corticosteroids.
Ventricular Arrhythmias ( Chapter 60 )
Acute MI is associated with a proarrhythmic environment that includes heterogeneous myocardial ischemia, heightened adrenergic tone, intracellular electrolyte disturbance, lipolysis and free fatty acid production, and oxygen free radical production on recanalization. Arrhythmias thus are common early during acute MI. Micro-reentry is likely the most common electrophysiologic mechanism of early phase arrhythmias, although enhanced automaticity and triggered activity also are observed in experimental models.
Primary VF is the most serious MI-related arrhythmia and contributes importantly to mortality within the first 24 hours. It occurs with an incidence of 3 to 5% during the first 4 hours and then declines rapidly over 24 to 48 hours. Polymorphic VT, and less commonly monomorphic VT, are associated life-threatening arrhythmias that may occur in this setting. Clinical features (including warning arrhythmias) are not adequately specific or sensitive to identify those at risk for sustained ventricular tachyarrhythmias, so all patients should be continuously monitored. Prophylactic lidocaine reduces primary VF but may increase mortality and is not recommended. Primary VF is associated with higher in-hospital mortality, but long-term prognosis is unaffected in survivors.
Accelerated idioventricular rhythm (AIVR) (60 to 100 beats/min) frequently occurs within the first 12 hours and is generally benign (i.e., is not a risk factor for VF). Indeed, AIVR frequently heralds recanalization after thrombolytic therapy. Antiarrhythmic therapy is not indicated except for sustained, hemodynamically compromising AIVR.
Late VF develops more than 48 hours after the onset of acute MI, often in patients with larger MIs or heart failure, portends a worse prognosis for survival, and may require aggressive measures (e.g., consideration of an ICD). Monomorphic VT resulting from reentry in the context of an MI or scar also may appear later after MI and require long-term therapy (e.g., ICD, antiarrhythmic medications).
Electrical cardioversion is required for VF and sustained polymorphic VT (synchronized shock) and sustained monomorphic VT that causes hemodynamic compromise (unsynchronized shock) ( Chapter 60 and Chapter 61 ). Brief intravenous sedation is given to conscious, “stable” patients. For slower, stable VT and nonsustained VT requiring therapy, intravenous amiodarone, intravenous lidocaine, or intravenous procainamide are commonly recommended. After episodes of VT/VF, infusions of antiarrhythmic drugs may be given for 6 to 24 hours; the ongoing risk of arrhythmia then is reassessed. Electrolyte and acid-base imbalance and hypoxia should be corrected. ß-Blockade is useful for frequently recurring polymorphic VT associated with adrenergic activation (“electrical storm”). Additional, aggressive measures should be considered to reduce cardiac ischemia (e.g., emergent PCI or CABG) and left ventricular dysfunction (intra-aortic balloon pump) in patients with recurrent polymorphic VT despite ß-blockers and/or amiodarone.
Patients with sustained VT or VF occurring late in the hospital course should be considered for long-term prevention and therapy. An ICD provides greater survival benefit than antiarrhythmic drugs (i.e., amiodarone or sotalol) alone in patients with ventricular arrhythmias and can improve survival after acute MI for patients with an ejection fraction less than 30% regardless of their rhythm status.[12]
Atrial Fibrillation and Other Supraventricular Tachyarrhythmias ( Chapter 59 )
AF occurs in up to 10 to 15% of patients after an acute MI, usually appearing within the first 24 hours. The incidence of atrial flutter or another supraventricular tachycardia is much lower. The risk of AF increases with age, larger MIs, heart failure, pericarditis, atrial infarction, hypokalemia, hypomagnesemia, hypoxia, pulmonary disease, and hyperadrenergic states. The incidence of AF is reduced by effective early recanalization. Hemodynamic compromise with rapid rates and systemic embolism (in ?2%) are adverse consequences of AF. Systemic embolism may occur on the first day, so prompt anticoagulation with heparin is indicated.
Recommendations for management of AF include electrical cardioversion for patients with severe hemodynamic compromise or ischemia; rate control with intravenous digitalis for patients with

ventricular dysfunction (i.e., give 0.6 to 1.0 mg; one half initially and one half in 4 hours), with an intravenous ß-blocker in those without clinical ventricular dysfunction, or with intravenous diltiazem or verapamil and compensated patients with a contraindication to ß-blockers; and anticoagulation with heparin (or LMWH). Class I or III antiarrhythmic drugs are generally reserved for patients with or at high risk for recurrence and may be continued for 6 weeks if sinus rhythm is restored and maintained. Amiodarone is currently the most popular choice for this indication.
Sinus and AV nodal dysfunction are common during acute MI. Sinus bradycardia, a result of increased parasympathetic tone often in association with inferior acute MI, occurs in 30 to 40% of patients. Sinus bradycardia is particularly common during the first hour of acute MI and with recanalization of the right coronary artery (Bezold-Jarisch reflex). Vagally mediated AV block also may occur in this setting. Anticholinergic therapy (atropine) is indicated for symptomatic sinus bradycardia (heart rate generally less than 50 beats/minute associated with hypotension, ischemia, or escape ventricular arrhythmia), including ventricular asystole, and symptomatic second-degree (Wenckebach) or third-degree block at the AV nodal level (narrow QRS complex escape rhythm). Atropine is not indicated and may worsen infranodal AV block (anterior MI, wide complex escape rhythm).
New-onset infranodal AV block and intraventricular conduction delays or bundle branch blocks (BBBs) predict substantially increased in-hospital mortality. Fortunately, their incidence has declined in the recanalization era (from 10 to 20% to about 4%). Mortality is more related to extensive myocardial damage than to heart block itself, so cardiac pacing only modestly improves survival. Prevention and treatment are accomplished by transcutaneous (standby or active) pacing, temporary intravenous pacing, and/or permanent pacing, applied in decreasing frequency.
Prophylactic placement of multifunctional patch electrodes in high-risk patients allows for immediate pacing (and defibrillation) if needed. Application is indicated for symptomatic sinus bradycardia refractory to drug therapy, infranodal second-degree (Mobitz II) or third-degree AV block, and new or indeterminate-age bifascicular (LBBB; RBBB with left anterior or left posterior fascicular block) or trifascicular block (bilateral or alternating BBB [any age], BBB with first-degree AV block). Transcutaneous pacing ( Chapter 61 ) is uncomfortable and intended for prophylactic and temporary use only. In patients requiring pacing, a transvenous pacing electrode is inserted as soon as possible. Pacing electrode insertion also is indicated (prophylactically) in patients at very high risk (>30%) of requiring pacing, including patients with bilateral (alternating) BBB, with new/indeterminate age bifascicular block with first-degree AV block, and with infranodal second-degree AV block.
Indications for permanent pacing after acute MI depend on the prognosis of the AV block and not solely on symptoms. Class I indications include even transient second- or third-degree AV block in association with BBB, and symptomatic AV block at any level. Advanced block at the AV nodal level (“Wenckebach”) rarely is persistent or symptomatic enough to warrant permanent pacing.
Cardiac pump failure is the leading cause of circulatory failure and in-hospital death from acute MI. Manifestations of circulatory failure may include a weak pulse, low blood pressure, cool extremities, a third heart sound, pulmonary congestion, oliguria, and obtundation. However, several distinct mechanisms, hemodynamic patterns, and clinical syndromes characterize the spectrum of circulatory failure in acute MI. Each requires a specific approach to diagnosis, monitoring, and therapy (see Table 69-3 ).
Left Ventricular Dysfunction
The degree of LV dysfunction correlates well with the extent of acute ischemia/infarction. Hemodynamic compromise becomes evident when impairment involves 20 to 25% of the left ventricle, and cardiogenic shock or death occurs with involvement of 40% or more ( Chapter 103 ). Pulmonary congestion and S3 and S4 gallops are the most common physical findings. Early recanalization (via thrombolytics, PCI, or CABG) is the most effective therapy to reduce infarct size, ventricular dysfunction, and associated heart failure. Medical treatment of heart failure related to the ventricular dysfunction of acute MI is otherwise generally similar to that of heart failure in other settings ( Chapter 56 ) and includes adequate oxygenation and diuresis (begun early, blood pressure permitting, and continued long-term if needed). Intravenous vasodilator therapy (for preload and afterload reduction), inotropic support, and intra-aortic balloon counterpulsation are indicated in cardiogenic shock ( Chapter 103 ). Nitrates (nitroglycerin) reduce preload and effectively relieve congestive symptoms.
Volume Depletion
Relative or absolute hypovolemia is a frequent cause of hypotension and circulatory failure and is easily corrected if recognized and treated promptly. Poor hydration, vomiting, diuresis, and disease-or drug-induced peripheral vasodilation may contribute. Hypovolemia should be identified and corrected with intravenous fluids before more aggressive therapies are considered. An empirical fluid challenge may be tried in the appropriate clinical setting (e.g., hypotension in absence of congestion; inferior or RV infarction; hypervagotonia). If filling pressures are measured, cautious fluid administration to a pulmonary capillary wedge pressure of up to about 18 mm Hg may optimize cardiac output and blood pressure without impairing oxygenation.
Right Ventricular Infarction
RV ischemia and infarction occur with proximal occlusion of the right coronary artery (before the takeoff of the RV branches). Ten to 15% of inferior acute ST-elevation MIs show classic hemodynamic features, and these patients form the highest risk subgroup for morbidity and mortality (25 to 30% vs. <6% hospital mortality). Improvement in RV function commonly occurs over time, suggesting reversal of ischemic stunning and other favorable accommodations, if short-term management is successful.
Hypotension with clear lung fields and elevated jugular venous pressure in the setting of inferior or inferoposterior acute MI should raise the suspicion of RV infarction. Kussmaul’s sign (distention of the jugular vein on inspiration) is relatively specific and sensitive in this setting. Right-sided ECG leads show ST-elevation, particularly in V4R , in the first 24 hours of RV infarction. Echocardiography is helpful in confirming the diagnosis (RV dilation and dysfunction are observed). If right heart pressures are measured, a right atrial pressure of =10 mm Hg and =80% of the pulmonary capillary wedge pressure is relatively sensitive and specific for RV ischemic dysfunction.
Management of RV infarction consists of early maintenance of RV preload, reduction of RV afterload, early recanalization, short-term inotropic support if needed, and avoidance of vasodilators (e.g., nitrates) and diuretics used for left ventricular failure (which may cause marked hypotension). Volume loading with normal saline alone is often effective. If the cardiac output fails to improve after 0.5 to 1 liter of fluid, inotropic support with dobutamine is recommended. High-grade AV block is common, and restoration of AV synchrony with temporary AV sequential pacing may lead to substantial improvement in cardiac output. The onset of AF (in up to one third of RV infarcts) may cause severe hemodynamic compromise requiring prompt cardioversion. Early coronary recanalization with thrombolysis or PCI markedly improves outcomes.
Cardiogenic Shock
Cardiogenic shock ( Chapter 103 ) is a form of severe LV failure characterized by marked hypotension (systolic pressures less than 80 mm Hg) and reductions in cardiac index (<1.8 L/min/m2 ) despite high LV filling pressure (pulmonary capillary wedge pressure greater than 18 mm Hg). The cause is loss of a critical functional mass (>40%) of the left ventricle. Cardiogenic shock is associated with mortality rates of more than 70 to 80% despite aggressive medical therapy. Risk factors include age, large (usually anterior) acute MI, previous MI, and diabetes. In patients with suspected shock, hemodynamic monitoring and intra-aortic balloon counterpulsation (IABP) are indicated. Intubation often is necessary. With early application, urgent mechanical revascularization (PCI or CABG) affords the best chance for survival, especially in patients younger than 75 years old.[5]

Invasive hemodynamic monitoring is not indicated routinely for acute MI but should be used selectively for high-risk patients. Indeed, routine use of balloon catheters in intensive care patients may cause net hazard. Hence, class I recommendations for balloon flotation right-heart catheter monitoring are limited to severe or progressive heart failure or pulmonary edema, progressive hypotension and cardiogenic shock, and suspected mechanical complications (e.g., papillary muscle rupture or acute ventricular septal defect). Intra-arterial pressure monitoring is recommended for patients with severe hypotension and/or cardiogenic shock, those receiving vasopressors and (class IIa) potent vasodilators (e.g., nitroprusside). Intravenous nitroglycerin and intravenous inotropes often can be safely given with noninvasive blood pressure monitoring.
Introduced more than 30 years ago, IABP has been frequently used for medically refractory unstable ischemic syndromes and cardiogenic shock. The deflated balloon catheter is introduced into the femoral artery and advanced to the aorta. Balloon inflation is triggered by the ECG during early diastole, augmenting coronary blood flow, and deflated in early systole, reducing LV afterload. Primary IABP therapy for cardiogenic shock associated with acute MI provides temporary stabilization, but it has not reduced in-hospital mortality (>80%). Its greatest utility has proved to be for temporary hemodynamic support in patients whose ventricular dysfunction is spontaneously or surgically reversible. IABP is currently recommended in the setting of acute MI as a stabilizing measure for patients undergoing angiography and subsequent PCI or surgery for (1) cardiogenic shock, (2) mechanical complications (acute mitral regurgitation, acute ventricular septal defect), (3) refractory post-MI ischemia, and (4) recurrent intractable VT or VF associated with hemodynamic instability. IABP is not useful in patients with significant aortic insufficiency or severe peripheral vascular disease.
MI may result in mechanical complications associated with substantial morbidity and mortality. These occur usually within the first week and account for about 15% of acute MI-related deaths. Complications include acute mitral valve regurgitation, ventricular septal defect, free wall rupture, and LV aneurysm. Suspicion and investigation of a mechanical defect should be raised by a new murmur and/or sudden, progressive hemodynamic deterioration with pulmonary edema and/or a low output state. Transthoracic or transesophageal echocardiography/Doppler usually establishes the diagnosis. A balloon flotation catheter may be helpful in confirming the diagnosis and monitoring therapy. Arteriography to identify correctable coronary artery disease is warranted in most cases. Surgical consultation should be requested promptly, and urgent repair is usually indicated.
Acute mitral valve regurgitation ( Chapter 72 ) results from infarct-related rupture or dysfunction of a papillary muscle. Total rupture leads to death in 75% of cases within 24 hours. Medical therapy is begun with nitroprusside to lower preload and improve peripheral perfusion. Emergent surgical repair (if possible) or replacement is then undertaken. Surgery is associated with high mortality (up to 25 to 50%) but leads to better functional and survival outcomes than medical therapy alone.
Postinfarction septal rupture with ventricular septal defect, which occurs with increased frequency in the elderly, in hypertensive patients, and possibly after thrombolysis, also warrants emergent surgical repair. Because a small ventricular septal defect may suddenly enlarge and cause rapid hemodynamic collapse, all septal perforations should be repaired. Upon diagnosis, an IABP should be inserted, a surgical consultation obtained, and surgical repair undertaken as soon as feasible.
LV free wall rupture usually causes acute tamponade with sudden death, but in a small percentage of cases, resealing or localized containment (“pseudoaneurysm”) may allow medical stabilization, usually with inotropic support and/or IABP followed by emergent surgical repair.
A left ventricular aneurysm may develop after a large, usually anterior, acute MI. When refractory heart failure, VT, or systemic embolization occurs despite medical therapy, surgical repair is indicated. Current techniques better preserve LV integrity and geometry, with improved outcomes.
Thromboembolism has been described in about 10% of clinical series and 20% of autopsy series, suggesting a high rate of undiagnosed events. Thromboembolism contributes to 25% of hospital deaths from acute MI. The incidence appears to be declining in the “recanalization era” in association with greater use of antithrombotics, reductions of infarct size, and earlier ambulation. Systemic arterial emboli (including cerebrovascular emboli) arise typically from an LV mural thrombus, whereas pulmonary emboli commonly arise from thrombi in leg veins. Arterial embolism may cause dramatic clinical events, such as hemiparesis, loss of a pulse, ischemic bowel, or sudden hypertension, depending on the regional circulation involved.
Mural thrombosis with embolism typically occurs in the setting of large (especially anterior) ST-elevation acute MI and heart failure. The risk of embolism is particularly high when a mural thrombus is detected by echocardiography (up to one third of anterior ST-elevation acute MI patients). Thus, in anterior ST-elevation acute MI and other high-risk patients, echocardiography should be performed during hospitalization; if positive, anticoagulation should be started (with an antithrombin), if not already initiated, and continued (with warfarin) for 6 months.
Deep vein thrombosis may be prevented by lower extremity compression therapy, by limiting the duration of bedrest, and by subcutaneous unfractionated heparin or LMWH (in those not receiving intravenous heparin) until fully ambulatory ( Chapter 78 ). Pulmonary embolism is treated with intravenous heparin, then oral anticoagulation for 6 months ( Chapter 94 ).
Post-MI Risk Stratification
The goal of risk stratification before and early after discharge for acute MI is to assess ventricular and clinical function, latent ischemia, and arrhythmic risk, and to use this information for patient education and prognostic assessment and to guide therapeutic strategies.
Risk stratification generally involves functional assessment by one of three strategies: cardiac catheterization, submaximal exercise stress ECG before discharge (at 4 to 6 days), or symptom-limited stress testing at 2 to 6 weeks after discharge. Many patients with ST elevation-acute MI undergo invasive evaluation for primary PCI or after thrombolytic therapy. Catheterization generally is performed during hospitalization for patients at high risk. In others, predischarge submaximal exercise testing (to peak heart rate of 120 to 130 beats/min or 70% of the predicted maximum) appears safe when performed in patients who are ambulating without symptoms; it should be avoided within 2 to 3 days of acute MI and in patients with unstable post-MI angina, uncompensated heart failure, or serious cardiac arrhythmias. Alternatively or in addition, patients may undergo symptom-limited stress testing at 2 to 6 weeks before returning to work or other increased physical activities. Abnormal test results include not only ST-depression but also low functional capacity, exertional hypotension, and serious arrhythmias. Patients with positive tests are considered for coronary angiography.
The sensitivity of stress testing can be augmented with radionuclide perfusion imaging (thallium-201 and/or technetium-99m-sestamibi; Chapter 52 ) or echocardiography ( Chapter 51 ). Supplemental imaging also can quantify the LV ejection fraction and size the area of infarct and/or ischemia. For patients on digoxin or with ST-segment changes that preclude accurate ECG interpretation (e.g., baseline LBBB or LV hypertrophy), an imaging study is recommended with initial stress testing. In others, an imaging study may be performed selectively for those in whom the exercise ECG test is positive or equivocal. For patients unable to exercise, pharmacologic stress testing can be performed using adenosine or dipyridamole scintigraphy or dobutamine echocardiography.
Routine 24- to 48-hour predischarge or postdischarge ambulatory ECG (Holter) monitoring is not currently recommended. Modern telemetry systems capture complete rhythm information during hospital observations and allow for identification of those with serious arrhythmias. Sustained VT or VF occurring late during hospitalization or provoked at electrophysiologic study in patients with nonsustained VT are candidates for an ICD (especially if ejection fraction is less than 40%) or antiarrhythmic drug therapy (amiodarone or, possibly, sotalol). The utility of other tests


Aspirin (81–325 mg qd)
High bleeding risk
Reduces mortality, reinfarction, and stroke
Clopidogrel (75 mg qd)
High bleeding risk
Indicated after PCI for 1 mo-1 yr. Also, reduces vascular events when added to aspirin in non-ST-elevation acute MI (not yet tested for routine use after ST-elevation acute MI)
Asthma, bradycardia, severe CHF
Reduces mortality, reinfarction, sudden death, arrhythmia, hypertension, angina, atherosclerosis progression
ACE inhibitor
Hypotension, allergy, hyperkalemia
Reduces mortality, reinfarction, stroke, heart failure, diabetes, atherosclerosis progression
Lipid lowering (e.g., a statin)
Myopathy, rhabdomyolysis, hepatitis
Goal = LDL < 100 (Statins also may benefit patients with lower LDL.* ) Consider addition of niacin or fibrate for high non-HDL cholesterol, low HDL
Nitroglycerin sublingual
Aortic stenosis; sildenafil (Viagra) use
Instruct on prn use and appropriate need for medical attention
Medications given at hospital discharge improve long-term compliance.
CHF = congestive heart failure; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MI = myocardial infarction; PCI = percutaneous coronary intervention.
See also Ryan TJ, Antman EM, Brooks NH, et al: 1999 update: ACC/AHA Guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1999;34:890–911.

*Heart Protection Study, 2002 (Lancet 2002;360:7–22).

of arrhythmia vulnerability (signal-averaged ECG, heart rate variability, baroreflex sensitivity, T-wave alternans) has not yet been established ( Chapter 58 ). Prophylactic ICD placement prevents sudden death after acute MI for patients with severely depressed function (ejection fraction less than 30%) regardless of rhythm status.[12]
Advances in secondary prevention have resulted in increasingly effective measures to reduce recurrent MI and cardiovascular death. Secondary prevention should be conscientiously applied after acute MI ( Table 69-8 ).
A fasting lipid profile is recommended on admission, and lipid lowering (statin preferred) is begun in-hospital if LDL exceeds 100 mg/dL ( Chapter 211 ). Recent data show statins are effective in secondary prevention regardless of age or baseline lipids levels, even when the LDL is less than 100[13] ; thus, near universal application after acute MI may be recommended in the near future.
Continued smoking doubles subsequent mortality risk after acute MI, and smoking cessation reduces risk of reinfarction and death within 1 year. Because the risks of continued smoking or early relapse after quitting are high, smoking cessation measures should receive the highest priority ( Chapter 14 ). An individualized cessation plan should be formulated including pharmacologic aids (nicotine gum and patches, bupropion).
Antiplatelet therapy ( Chapter 33 ) should consist of aspirin, given long-term to all patients without contraindications (usual dose, 81 to 325 mg/day). Clopidogrel (75 mg/day) also is given after PCI and may be appropriate for others at higher risk for recurrent vascular events. Duration of therapy should be at least 1 month, but a study of patients with non-ST-elevation acute coronary syndrome supports a 3- to 12-month treatment course. Anticoagulant therapy (i.e., warfarin) is indicated after acute MI for patients unable to take antiplatelet therapy (aspirin or clopidogrel), those with persistent or paroxysmal AF, those with LV thrombus, and those who have suffered a systemic or pulmonary embolism. Anticoagulants also may be considered for patients with extensive wall motion abnormalities and markedly depressed ejection fraction with or without heart failure (class II indication). Data on the benefit of warfarin instead of or in addition to aspirin are inconclusive.
ACE inhibitor therapy may prevent adverse myocardial remodeling after acute MI and reduce heart failure and death; it is clearly indicated for long-term use in patients with anterior acute MI or LV ejection fraction less than 40%. There is increasing evidence that ACE inhibitors also may reduce atherosclerosis progression and acute MI recurrence regardless of ejection fraction.[9] These data provide adequate rationale to use ACE inhibitors routinely in patients without hypotension or other contraindications. Other physicians are awaiting the results of additional ongoing trials in lower risk secondary prevention groups. At the very least, patients with other indications for therapy (hypertension, mild renal insufficiency, intermediate glucose tolerance) should be strongly considered for long-term therapy.
ß-blockers are strongly recommended for long-term therapy in all post-MI patients without contraindications. Even those with moderately severe but compensated LV dysfunction may tolerate and benefit from ß-blockers if begun in small, slowly adjusted doses. ß-blockers are continued indefinitely if tolerated.
Nitroglycerin is prescribed routinely for sublingual or buccal administration for acute anginal attacks. Longer-acting oral (isosorbide mononitrate or dinitrate) or topical nitrates may be added to treatment regimens for angina or heart failure in selected patients. Calcium channel blockers are negatively inotropic and are not routinely given; however, they may be given to selected patients without LV dysfunction (ejection fraction greater than 40%) who are intolerant of ß-blockers and require these drugs for antianginal therapy or control of heart rate in AF. Short-acting nifedipine should be avoided.
Hormone replacement therapy is not begun after an acute MI because it increases thromboembolic risk during the first year and does not prevent reinfarction. Continuing therapy in those already on hormone replacement is individualized.
Hypertension ( Chapter 63 ) and diabetes mellitus ( Chapter 242 ) must be assessed and controlled compulsively in patients after acute MI. ACE inhibitors or ß-blockers as described earlier are usually the first choice therapies for hypertension, with angiotensin receptor blockers (ARBs) indicated when ACE inhibitors are not tolerated. ACE inhibitors and ARBs may also reduce the long-term complications of diabetes.
Despite theoretical rationale and promising early reports, antioxidant supplementation (e.g., vitamin E, vitamin C) has not been demonstrated to benefit patients after acute MI in large, controlled trials, and is not generally recommended. Folate therapy is recommended in patients with elevated homocysteine levels.
Antiarrhythmic drugs are not generally recommended after acute MI, and class I antiarrhythmics may increase the risk of sudden death. Class III drugs (amiodarone, sotalol, dofetilide) may be used as part of the management strategy for specific arrhythmias (e.g., AF, VT).
The hospital stay provides an important opportunity to educate patients about their MI and its treatment, coronary risk factors, and behavioral modification. Education should begin on admission and continue after discharge. However, the time before discharge is particularly opportune. Many hospitals use case managers and prevention specialists to augment physicians and nurses, provide educational materials, review important concepts, assist in formulating and actualizing individual risk-reduction plans, and ensure proper and timely outpatient follow-up. The latter should include early return appointments with the patient’s physician (within a few weeks). Instructions on activities also should be given

before discharge. Many hospitals have cardiac rehabilitation programs that provide supervised, progressive exercise.



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