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Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


David D. Waters


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 70 ) 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 72 ) is clinically important because acute recanalization therapy is critical for improving the outcome in ST elevation MI but is less urgent in non–ST segment elevation MI.


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 earlier, more aggressive treatment, whereas low-risk patients do not.

Various classifications have been proposed for primary unstable angina on the basis of presenting symptoms. The most common approach ( Table 71-1 ) 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.

TABLE 71-1   — 

Class I New-onset, severe or accelerated angina (angina <2 months in 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 months)
Class II Angina at rest, subacute (angina at rest within the preceding month but not within the preceding 48 hours)
Class III Angina at rest, acute (angina at rest within the preceding 48 hours)
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 Post-infarction unstable angina (within 2 weeks of a documented myocardial infarction)

   1.    Absence of treatment or minimal treatment

   2.    Standard therapy for chronic stable angina (conventional doses of oral β-blockers, nitrates, and calcium-channel blockers)

   3.    Maximal therapy (maximally tolerated doses of all three categories of oral therapy and intravenous nitroglycerin)

Modified from Braunwald E: Unstable angina: A classification. Circulation 1989;80:410–414.

The recognition of three specific subtypes of primary unstable angina is worthwhile because their pathophysiologic processes, 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 to 9 months after percutaneous coronary intervention ( Chapter 73 ) almost invariably is caused by restenosis or stent thrombosis. Unstable angina in a patient with previous coronary artery bypass graft surgery ( Chapter 74 ) 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, unstable angina may progress to non–ST segment elevation MI if adequate treatment is not instituted promptly.


Whether ACS is defined clinically as unstable angina or non–ST segment elevation MI, the pathophysiologic mechanisms are the same. In most instances, ACS is caused by nonocclusive thrombosis in a native vessel, a vessel that has been the previous site of a coronary angioplasty ( Chapter 73 ), or a coronary artery bypass graft ( Chapter 74 ). 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 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.


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 69 ). Mechanical factors contribute to plaque disruption. A thin fibrous cap is more likely to rupture than a thick one is, 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. Most patients with ACS have multiple inflamed coronary lesions.

Increased serum levels of C-reactive protein are found in most patients with unstable angina and MI, but not in stable angina, and elevated C-reactive protein levels are a strong predictor of subsequent coronary events in patients with coronary disease. The cytokine interleukin-6, which is the main producer of C-reactive protein in the liver, similarly 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 than in control subjects. 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 levels of tissue-type plasminogen activator and plasminogen activator inhibitor 1 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 before, during, and after the episode of unstable angina or non–ST segment elevation MI. If a patient with ACS previously has had coronary angiography, 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 predicting that it will precipitate an acute coronary event include greater asymmetry, greater length, and 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 72 ), whereas other patients may have nonspecific symptoms ( Chapter 48 ).

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 knifelike. The physician should be cautioned that atypical features do not exclude unstable angina ( Chapter 48 ).

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.

Physical Examination

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 72 ), 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.


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 12-lead electrocardiography can be performed quickly.

The initial assessment should be directed toward determination of whether 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 electrocardiography ( Fig. 71-1 ). 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 71-2 ). On the basis of this information, the patient’s initial triage and management are determined ( Fig. 71-2 ).

FIGURE 71-1  Flow diagram to estimate 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 had a myocardial infarction; the denominator is the total number of patients presenting with that characteristic or set of characteristics.  (Modified 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.)

TABLE 71-2   — 


   Any of the following features:

   Known coronary disease
   Definite angina in men ≥60 years or women ≥70 years
   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 or women <70 years
   Probable angina in men ≥60 years or women ≥70 years
   Probably not angina in diabetics, or in nondiabetics with ≥2 other risk factors[*]
   Extracardiac vascular disease
   ST depression 0.5–1 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 the following:

   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

Modified from Braunwald E, Jones RH, Mark DB, et al: Diagnosing and managing unstable angina. Circulation 1994;90:613–622.

ECG = electrocardiogram.

* Risk factors include diabetes, smoking, hypertension, and hypercholes-terolemia.

FIGURE 71-2  Initial triage for patients with symptoms suggestive of an acute coronary syndrome (ACS). ECG = electrocardiogram; LV = left ventricular.  (Modified 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. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2000;36:970-1062, with permission.)

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 chest or left arm pain or pressure as the presenting symptom increased the likelihood that the patient was experiencing acute myocardial ischemia.

Unstable angina may be more difficult to diagnose than stable angina because of 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.

When ACS is suspected in a patient younger than 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 32 ).


An electrocardiogram (ECG) must be obtained as soon as possible in the initial evaluation of any patient with suspected ACS. The ECG may be entirely normal or show only nonspecific abnormalities in patients with unstable angina or non–ST segment elevation MI. The diagnostic yield is enhanced greatly if a tracing also can be recorded during an episode of chest pain. 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. A normal ECG during chest pain does not exclude unstable angina; however, it does indicate that an ischemic area, if present, is not extensive or severe enough to induce ECG changes, and this finding is a favorable prognostic sign.

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.

The ECG in ACS may show Q waves from an old MI or left bundle branch block due 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 with 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.

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 percutaneous coronary intervention should be considered without delay ( Chapter 72 ).

Cardiac Markers

According to the traditional paradigm, elevated serum levels of cardiac enzymes or the MB isoenzyme of creatine kinase (CK) 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 72 ). The rationale for this change is that several large studies have shown elevations of troponin to be independent predictors of adverse events.

Troponin measurements may be normal early after the onset of ACS and become abnormal 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 detected within 6 hours, and troponin T or I is usually elevated 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.

Risk Assessment and Initial Triage

The evaluation of a patient with a possible ACS requires not only establishment of the diagnosis but also assessment of the short-term risk of complications requiring intensive care ( Fig. 71-3 ). 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 β-blocker, to be observed 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.

FIGURE 71-3  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.)

Troponin levels should be measured when the patient first is seen and again 6 to 12 hours later ( Chapter 72 ). Myocardial perfusion imaging during or shortly after an episode of chest pain can aid in diagnosis and prognosis but is not indicated routinely ( Chapter 54 ). 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 on the basis of data available at the time of first assessment ( Table 71-3 ). 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 65 years, and have a normal or unchanged ECG without evidence of a previous MI.

TABLE 71-3   — 


   At least one of the following features must be present:

   Prolonged, ongoing (>20 minutes) 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 minutes 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 weeks to 2 months
   Normal or unchanged electrocardiogram

Modified from Braunwald E, Jones RH, Mark DB, et al: Diagnosing and managing unstable angina. Circulation 1994;90:613–622.

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 revascularization ( Chapters 73 and 74 ) because the risk of progression to MI is high ( Fig. 71-4 ). Most episodes of recurrent myocardial 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.

FIGURE 71-4  Approach to the high-risk patient with an acute coronary syndrome. EF = ejection fraction; GP = glycoprotein; LV = left ventricular.  (Modified 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. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2000;36:970-1062, with permission.)

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 during 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 level, 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 C-reactive protein, 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 factors: (1) age 65 years or older, (2) at least three of the standard risk factors for coronary disease, (3) 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 thousands of patients with unstable angina or non–ST segment elevation MI, the event rate during 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 ( Chapters 48 , 53 , and 54 ).

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, β-blockers, and, to a lesser extent, calcium-channel blockers reduce the risk of recurrent ischemic attacks. Revascularization ( Chapters 73 and 74 ) eliminates ischemia entirely in patients with favorable anatomy, and coronary artery bypass graft (CABG) surgery has been shown to prolong life in some subgroups. The risk of MI is reduced by antiplatelet and antithrombotic therapy.

Treatments to Reduce Progression to or Size of Myocardial Infarction


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 34 ). Aspirin also may influence the pathophysiologic process 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 70 ), 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 for secondary prevention 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 is a thienopyridine that inhibits adenosine diphosphate–mediated platelet activation ( Chapter 35 ). Because it acts independently from the arachidonic acid pathway, its antiplatelet activity is synergistic with aspirin. The dose is an initial 300 mg loading dose, then 75 mg daily, in combination with aspirin.

In a trial of more than 12,000 patients with ACS without ST segment elevation, the addition of clopidogrel to aspirin during 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 may become a surgical candidate.

Platelet Glycoprotein IIB/IIIA Receptor Inhibitors

Platelet membranes contain glycoprotein (GP) receptors. The GPIIb-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 and clopidogrel, which do not block thrombin-induced platelet aggregation, GPIIb-IIIa inhibitors block aggregation in response to all potential agonists.

Three GPIIb-IIIa blockers have been approved and are used widely clinically. Abciximab is the Fab fragment of a monoclonal antibody, eptifibatide is a peptide GPIIb-IIIa inhibitor, and tirofiban is a smaller molecule. These drugs must be administered by parenteral infusion; oral GPIIb-IIIa inhibitors failed to reduce events in large clinical trials and have not been approved for use.

Platelet GPIIb-IIIa inhibition at the time of percutaneous coronary intervention (PCI) reduces ischemic complications in patients with ACS. The benefit is less with eptifibatide and tirofiban (15 to 20%) than with abciximab (30 to 60%). 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 PCI trials, eptifibatide and tirofiban predominate in the ACS trials.

The value of GPIIb-IIIa inhibitors in patients with unstable angina who are not undergoing intervention is not fully defined. GPIIb-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 benefit from GPIIb-IIIa blockade, but low-risk patients may not.

Current guidelines recommend that eptifibatide or tirofiban be added to aspirin and heparin in the treatment of patients with high-risk features or with refractory ischemia.[3] These drugs should be continued during PCI ( Chapter 73 ) and for 12 to 24 hours after the procedure for tirofiban (0.4 μg/kg/min for 30 minutes, then 0.1 μg/kg/min) and for 24 to 72 hours after the procedure for eptifibatide (180 μg/kg IV bolus, then 2 μg/kg/min until discharge or CABG, up to 72 hours). Abciximab also can be used in patients with unstable angina in whom PCI is planned within the following 24 hours (0.25 g/kg followed by 18- to 24-hour infusion of 10 μg/min, ending 1 hour after the procedure). 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 GPIIb-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 through the inhibition of thrombin-induced activation of factor V and factor VIII ( Chapter 35 ). 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. A meta-analysis including several smaller trials concluded that the event reduction conferred by heparin therapy was approximately one third.[4]

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 hypoaldosteronism.

Low-molecular-weight heparins (LMWHs) 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, LMWHs produce a more predictable anticoagulant response because of their better bioavailability, longer half-life, and dose-independent clearance. The plasma half-life of LMWHs after subcutaneous injection ranges from 3 to 6 hours so that once-daily or twice-daily administration is feasible. Monitoring is not required, and LMWHs cause less bleeding.

In patients with unstable angina or non–Q wave MI, enoxaparin is superior to unfractionated heparin for the first few days of therapy. The early benefit of treatment with LMWHs seems to dissipate in 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.

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.[5] 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 LMWHs should be continued for 2 to 5 days or until the patient has been stabilized for 24 hours or revascularization is performed. The dose of unfractionated heparin should be reduced during coronary angioplasty when aspirin and GPIIb-IIIa inhibitors are being administered concomitantly, and heparin should be discontinued after an uncomplicated procedure. Information is accumulating on the combined use of LMWHs and GPIIb-IIIa inhibitors; in one large randomized trial, enoxaparin was at least equivalent to unfractionated heparin when it was used in combination with tirofiban in patients with unstable angina or non–Q wave MI. More recent data suggest that fondaparinux is superior to enoxaparin.


In one randomized trial of patients with unstable angina or non–Q wave MI for whom early revascularization was not planned, high-dose atorvastatin for 16 weeks reduced the composite primary end point.[6] In another randomized trial comparing atorvastatin (80 mg) with pravastatin (40 mg) begun within 10 days of an episode of ACS, the composite primary end point was significantly reduced during the 2-year follow-up in the atorvastatin group, which achieved a significantly lower low-density lipoprotein cholesterol level.[7] Most of the patients in this trial had undergone PCI for their ACS just before study entry. However, a third randomized trial comparing early aggressive simvastatin therapy with a more conservative simvastatin therapy after ACS showed no early benefit. Nevertheless, several trials have demonstrated long-term reduction in cardiac events with statins in patients with coronary disease ( Chapter 217 ). Long-term compliance is improved if this therapy is begun in the hospital. It is currently recommended that high-dose atorvastatin therapy (80 mg/day) be initiated in the hospital in patients with ACS, with the goal of reducing the low-density lipoprotein cholesterol to 70 mg/dL or lower.

Other Medical Therapy

Thrombolytic therapy improves the outcome of patients with ST segment elevation MI ( Chapter 72 ) but is of no benefit in unstable angina or non–ST segment elevation MI. The direct thrombin inhibitor bivalirudin (1 mg/kg IV bolus followed by 4-hour IV infusion at 2.5 mg/kg/hr, then for 20 hours at 0.2 mg/kg/hr) has been recommended as an improvement over heparin during PCI 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.

Treatment of Ischemic Signs and Symptoms

An oral β-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 β-blockers. A patient who develops unstable angina while already taking two or three antianginal drugs should be treated with intravenous nitroglycerin, but symptoms are more difficult to control than in a patient who previously took no antianginal drugs.

Nitroglycerin and Nitrate Therapy

In patients with unstable angina, sublingual nitroglycerin (0.4 mg every 5 minutes ≤3 doses/15 minutes) 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 increments of 10 μg/min 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 patients with unstable angina 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 β-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 β-blockers effectively reduce symptoms in patients with unstable angina who are not already taking one of these drugs on admission. Whether a β-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 β-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 β-blockade within hours, however, and not days. One approach is to begin metoprolol at an oral dose of 50 mg every 6 to 8 hours and to increase the dose as necessary to control heart rate, blood pressure, and symptoms. β-Blockade sometimes is initiated with intravenous boluses titrated to reduce heart rate. Early heart rate control is particularly important in high-risk patients and 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 β-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 β-blocker; a β1-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 β-blocker therapy can be given. Mild heart failure that is stable is not a contraindication to β-blockers in unstable angina. Diltiazem or verapamil should be considered when a β-blocker cannot be used.

Calcium-Channel Blockers

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 β-blocker in several small clinical trials in unstable angina, and they seem to be more effective than placebo and equivalent to a β-blocker in preventing recurrent angina episodes.

Most dihydropyridine calcium-channel blockers induce a reflex increase in heart rate in the absence of β-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 (10 mg three times daily up to 30 mg four times daily) 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 it is used in patients with unstable angina not receiving β-blockers but that it may be helpful in controlling angina in patients with an adequate level of β-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 (180 to 360 mg/day) and verapamil (240 to 480 mg/day) are reasonable choices for treatment of unstable angina when β-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 β-blocker is not generally used in patients with unstable angina because the effects of these calcium-channel blockers on heart rate and myocardial contractility are additive to the effects of β-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 β-blockers have not been compared in this situation, and the relevance of this old trial to the current management of non–ST segment elevation MI is uncertain.

Recurrent or Refractory Unstable Angina

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 for development of MI. Patients whose angina is labeled 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 PCI 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.

Coronary Revascularization

CABG surgery ( Chapter 74 ) and PCI ( Chapter 73 ) 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 PCI, angina also almost always is relieved, but repeated procedures are more common during follow-up than in CABG patients. The introduction of drug-eluting stents has almost totally eliminated restenosis, and the incidence of stent thrombosis is low. Whether revascularization prolongs survival and prevents future coronary events in patients at different levels of risk has not been determined adequately from trials.

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 PCI or CABG surgery, depending on the coronary anatomy. Formerly, patients with one or two severe stenoses were treated with PCI, and patients with more extensive disease underwent CABG surgery. More recently, the near elimination of restenosis with drug-eluting stents has increased the use of PCI and decreased the use of CABG surgery in patients with multivessel disease. 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, more recent studies of patients with either unstable angina or non–ST segment elevation MI tend to show that patients randomized to routine catheterization within 4 to 48 hours and revascularization “as appropriate” have a better outcome than do patients for whom catheterization is limited to objective evidence of recurrent ischemia or an abnormality on stress testing. In one study, for example, the composite end point of death, nonfatal MI, or rehospitalization for ACS within 6 months was reduced by about 20%, with the benefit restricted almost entirely to high-risk patients (e.g., patients with elevated troponin levels).[8]


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 72 ). However, with the exception of recurrent ischemia, complications are less common in non–ST segment elevation MI because the amount of myocardial damage tends to be less.

Integrated Approach to Treatment

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. 71-1 ).

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 during many years. Smoking cessation ( Chapter 30 ), cholesterol lowering ( Chapter 217 ), control of hypertension ( Chapter 66 ) and diabetes ( Chapter 248 ), and other risk factor reductions ( Chapters 70 and 72 ) are more important long term than are the specific treatment decisions related to the acute event. Maintaining compliance long term with medical therapy appears to reduce the risk of a future coronary event by up to 80%. 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 selection of patients 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 the 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.

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