Paul R. Sutton MD, PHD, FACP1
Stephan D. Fihn MD, MPH, FACP2
1Associate Professor of Medicine, University of Washington School of Medicine
2Professor of Medicine and Health Services, University of Washington School of Medicine, Director, Health Services Research and Development, VA Puget Sound Health Care System
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
December 2004
Definitions
Angina pectoris is the cardinal symptom of myocardial ischemia. Ischemia occurs when the coronary blood supply is inadequate to meet the metabolic demands of the myocardium. This mismatch of coronary blood supply and myocardial metabolic demand usually results from narrowing or occlusion of one or more coronary arteries, but in rare cases, it may be caused by coronary vasospasm or solely by excessive myocardial oxygen demand in the absence of significant coronary atherosclerosis.
Angina is typically a substernal, pressurelike discomfort or pain, but it may also take the form of discomfort in the jaw, shoulder, back, or arm. Usually, it is precipitated by physical exertion or emotional stress, and it is promptly relieved by rest or by taking nitroglycerin. Chronic stable angina refers to a pattern of chest pain or discomfort that does not change appreciably in frequency or severity over 2 months or longer and in which the episodes of pain are provoked by exertions or stresses of similar intensity.1 Unstable angina, by contrast, is defined as rest angina, severe angina of new onset, or an increase in the severity or frequency of previously stable angina. Certain patients with symptoms of unstable angina are at an increased risk for myocardial infarction (MI) or death [see Epidemiology, below]. Chronic stable angina precedes MI in about half of cases and is common afterward. Although angina is a cardinal symptom of ischemic heart disease (IHD), MI or sudden death is the initial presentation of IHD in as many as half of patients.
Epidemiology
IHD is the leading cause of mortality in the United States and the rest of the developed world; it is responsible for more than 20% of deaths.2 In the United States, approximately one million persons suffer an MI, and 500,000 coronary deaths occur each year. IHD is the leading cause of death in the United States for both sexes in both white and black populations.
The prevalence of IHD increases with age and is higher in men than in women in every age group. The American Heart Association (AHA) conservatively estimates that more than six million persons in the United States experience angina.3
In addition to posing an increased risk of MI and premature death, chronic stable angina often limits affected persons' capacity for work and other activities, which, in turn, negatively affects their quality of life. The direct and indirect costs of hospitalization, diagnostic procedures, and revascularization related to angina are substantial. Estimates of direct hospital costs for Medicare patients with a history of chronic stable angina exceed $7 billion annually.1 Of patients with angina who undergo a coronary revascularization procedure, 30% or more never return to work.4
The major modifiable risk factors for IHD are dyslipidemias—in particular, elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol—as well as hypertension, diabetes mellitus, and cigarette smoking.5,6 Other important, but immutable, risk factors are increasing age, a family history of premature coronary disease, and male sex. Obesity, physical inactivity, and atherogenic dietary habits also contribute to cardiovascular risk, although it is difficult to distinguish the risks conferred by these risk factors independently of the risks conferred by the major cardiovascular risk factors because of the potential interaction of these factors. Patients with combinations of risk factors may be at particular risk for developing IHD. Patients with the metabolic syndrome, which consists of obesity (particularly abdominal adiposity), hypertension, dyslipidemia (i.e., elevated triglyceride levels and low HDL levels), and insulin resistance, are at particularly high risk for IHD.7 It is estimated that in the United States, the metabolic syndrome affects nearly 25% of all persons and 43.5% of adults 60 years of age or older.8
Numerous clinical trials have identified important risk factors and effective therapies for coronary artery disease; however, few of these studies have included sufficient numbers of women to draw meaningful conclusions about coronary disease in women.9 Thus, much of the evidence that supports contemporary recommendations for testing, prevention, and treatment of coronary disease in women is extrapolated from studies conducted predominantly in middle-aged men.
Although it has been proposed that 50% or more of patients with IHD lack any of the traditional major risk factors, two studies have challenged this notion; these studies indicate that the vast majority of patients who experience cardiac events (either fatal or nonfatal) have one or more major risk factors.10,11 Nevertheless, interest remains in identifying additional laboratory markers of risk of IHD and, in particular, risk of acute coronary syndromes. In observational studies, several measures of inflammation, including C-reactive protein (CRP) levels, interleukin-6 (IL-6) levels, and levels of soluble cellular adhesion molecules, have been associated with risk of IHD and cardiovascular events.12,13 Measures of fibrinogen, platelet activator inhibitor, and components of the coagulation/fibrinolysis cascade may ultimately be of use in predicting risk of cardiovascular events.12 A number of genetic polymorphisms and candidate genes that may increase the risk of MI have been identified in specific populations. Currently, however, it is uncertain whether these or other laboratory measurements represent truly independent risk factors or whether they will prove useful in clinical practice.14
Pathophysiology and Pathogenesis
Angina occurs as a result of myocardial ischemia, which occurs when cardiac blood supply is insufficient to meet myocardial oxygen demand. Stable angina commonly occurs in the setting of narrowing or partial occlusion of segments of coronary arteries by atherosclerotic plaque. Significant occlusion is defined as a reduction of the diameter of a major coronary artery by 70%, which corresponds to a 50% reduction in vessel lumen surface area; such occlusion is often sufficient to cause angina. Coronary atherosclerosis and angina often progress over time, reflecting both gradual and more abrupt changes in luminal diameter of coronary vessels. Incremental changes in coronary atherosclerosis reflect the progression of existing lesions and the appearance of new stenoses. Abrupt changes in vessel diameter may be associated with sudden changes in anginal symptoms, termed unstable angina. Unstable angina is commonly caused by rupture of vulnerable atherosclerotic plaque with associated platelet thrombosis. Unstable angina may also be caused by endothelial injury, thrombosis of severely stenotic coronary arteries, or coronary artery spasm. Although angina is usually associated with coronary artery disease (CAD), it may also occur in persons with normal or near-normal coronary arteries; in these settings, angina may occur as a result of increased myocardial oxygen demand associated with aortic stenosis, hyperthyroidism, or anemia.
Myocardial ischemia, regardless of cause, is associated with intracardiac release of adenosine. Adenosine release slows atrioventricular conduction and reduces contractility, which are adaptive changes in the setting of myocardial ischemia. Stimulation of adenosine receptors in the chest is believed to be responsible for the sensation of angina.
Angina occurs most often in the setting of coronary atherosclerosis. Atherosclerosis occurs as a result of vascular injury and subsequent responses to injury. Vascular injury may result from the mechanical stress of blood flow or from direct endothelial injury from toxins, such as those in cigarette smoke. Traditional cardiovascular risk factors, such as smoking, hypertension, hyperlipidemia, and diabetes, increase coronary risk, at least in part by potentiating vascular injury or altering the subsequent response to injury. Direct endothelial injury produces a sequence of events similar to chronic inflammation: the endothelium elaborates procoagulants, vasoactive molecules, growth factors, and cytokines. Platelets, inflammatory cells (e.g., monocytes and T cells), and smooth muscle cells are attracted to the site of injury.15 This cascade of events is initially adaptive, resulting in repair of endothelial injury; however, repeated cycles of injury and repair can result in progressive atherosclerosis and luminal narrowing.
Support for the inflammatory hypothesis of atherosclerosis comes from clinical studies that suggest a correlation between the risk of future cardiovascular events and the presence of markers of inflammation, including CRP.12,13 Inflammation may also play a role in acute coronary syndromes (i.e., unstable angina and acute MI). In some studies, levels of CRP during episodes of unstable angina are associated with a greater risk of MI or death,16 although it is not clear whether inflammation (and corresponding elevations of CRP) contributes to the etiology of unstable coronary syndromes or is simply a consequence of myocardial ischemia and injury.17
Histologically, atherosclerotic plaques are composed of a fibrous cap derived from smooth muscle cells; the cap covers a core of oxidized lipids, inflammatory cells, and cellular debris. Immature plaques consist of a necrotic, lipid-rich core surrounded by a thin, fibrous capsule. These so-called vulnerable plaques may not be visible angiographically, but they are prone to disruption and thrombus formation and, thus, are associated with unstable coronary syndromes. In fact, many of the plaques responsible for myocardial infarction may not be associated with significant coronary stenosis.18 Mature atherosclerotic plaques, by contrast, have less necrotic cores and thicker, more stable fibrous caps. These plaques tend to cause greater degrees of coronary stenosis and are the lesions typically identified by coronary angiography; they are generally less susceptible to fracture and are associated less with acute coronary syndromes than are immature plaques. Atherosclerotic lesions may be associated with chronic stable angina, either because of luminal narrowing or because of dysfunctional vascular reactivity.
Clinical Manifestations
A cardinal manifestation of IHD, angina is characterized by substernal pain or discomfort that may radiate to the neck, jaw, epigastrium, back, or arms. Words characteristically used to describe the sensation of angina include “squeezing,” “vicelike,” “heavy,” “griplike,” and “suffocating.” Angina ordinarily lasts only a few minutes. Typical angina has three key characteristics: (1) substernal chest discomfort of characteristic quality and duration that is (2) provoked by exertion or emotional stress and is (3) relieved by rest or nitroglycerin. Atypical angina has two of the three characteristics of typical angina; noncardiac chest pain has one or none of the characteristics of typical angina.
The severity of angina is graded according to the Canadian Cardiovascular Society (CCS) classification [see Table 1].19 Angina grade provides a useful way to evaluate functional limitation, treatment efficacy, and stability of symptoms over time.
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Table 1 Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System18 |
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Anginal chest pain is further characterized as stable or unstable. Unstable angina presents as prolonged angina at rest; new-onset angina that is severe, prolonged, or frequent; and established angina that has become distinctly more frequent, longer in duration, or more easily provoked. Some patients with unstable angina are at increased risk for acute MI and death [see Table 2]; the pathophysiology of unstable angina in these patients is often the result of plaque rupture and thrombosis. Patients with unstable angina and intermediate-risk or high-risk clinical features are best evaluated in the hospital.20
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Table 2 Short-Term Risk of Death or Nonfatal Myocardial Infarction in Patients with Unstable Angina19 |
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Differential Diagnosis
Given the potentially life-threatening sequelae of angina and the availability of effective therapies, it is important to consider angina in all patients presenting with chest pain. One approach to chest pain is to consider the differential diagnosis anatomically [see Table 3]. Various diseases of the heart and pericardium cause chest pain. Arrhythmias and valvular heart disease cause typical angina; pericarditis often causes pleuritic pain (i.e., pain that worsens on inspiration), but it may produce angina that is relieved by sitting up and leaning forward. Dissection of the great vessels can cause a characteristic, sudden, excruciating “tearing” pain in the chest or back. Diseases of the esophagus, such as esophageal spasm and acid reflux, may cause chest pain that is often postprandial or that occurs with recumbence. Esophageal spasm, in particular, can mimic angina and may respond to nitrates or calcium channel blockers. Diseases of lungs and pleura, including pulmonary embolism, pneumonia, pleuritis, and empyema, can cause chest pain that is often pleuritic. Chest wall syndromes, such as costochondritis, can cause substernal chest pain, typically reproduced with palpation. Herpes zoster may cause neuralgia that is localized to the chest; the pain may precede the appearance of the characteristic rash. Patients with panic disorder may describe chest pain or tightness accompanied by shortness of breath, diaphoresis, and other symptoms suggesting cardiac disease.
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Table 3 Differential Diagnosis of Chest Pain |
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Diagnosis and Risk Stratification
PRELIMINARY EVALUATION
The evaluation of patients with chest pain should take into account symptom characteristics and cardiovascular risk factors, because these indicate the probability of angina and IHD [see Patient History and Its Use in Determining Risk for IHD, below]. If the history and physical examination suggest the presence of angina and IHD, patients are further evaluated by noninvasive tests, such as exercise treadmill testing or coronary angiography. Noninvasive testing serves to refine the probability of the diagnosis of IHD and stratify patients according to their risk for near-term cardiovascular events [see Noninvasive Testing, below].21
Patient History and Its Use in Determining Risk for IHD
Determining the pretest probability of significant IHD, which is defined as greater than 70% stenosis of one or more of the major epicardial coronary arteries, is an essential step in the evaluation of patients with suspected IHD. Decisions regarding testing and management are strongly influenced by estimates of the probability of significant IHD [see Figure 1].21
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Figure 1. Approach to Clinical Assessment of Chest Pain An approach to the clinical assessment of patients with chest pain.21 (CABG—coronary artery bypass grafting; IHD—ischemic heart disease; LV—left ventricular; MI—myocardial infarction; PTCA—percutaneous transluminal coronary angioplasty) |
Estimates of the pretest probability of significant IHD can be accurately derived from a description of the chest pain syndrome and the presence or absence of cardiovascular risk factors.22 It is important to characterize suspected angina by location, quality, duration, associated symptoms, and factors that exacerbate or relieve the pain [see Table 4]. Typical angina is substernal, lasts less than 5 minutes, is dull and aching, and is worse with exertion or emotional stress. Atypical angina has some but not all features of anginal chest pain. For example, a patient with aching substernal chest pain that lasts minutes but is unrelated to exertion is considered to have atypical angina. Similarly, a patient with sharp, exertional chest pain may also have atypical angina. Nonanginal pain is chest pain that does not have any features of angina: it is pleuritic or positional, unrelated to exertion, and is fleeting or lasts for many minutes. A detailed chest pain history allows the clinician to classify a patient's chest pain syndrome as typical angina, atypical angina, stable angina, unstable angina, or nonanginal chest pain. Among patients presenting to a clinician with chest pain, the presence of typical angina substantially increases the probability of significant IHD (likelihood ratio, 5.6), whereas the presence of atypical angina does not substantially alter the probability of significant IHD (likelihood ratio, 1.3).23
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Table 4 Recommended Diagnostic Strategies in Patients with Chronic Stable Angina1,2 |
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Once a detailed history of chest pain is obtained, cardiovascular risk factors are assessed; risk factors include increased age, male sex, menopausal status, cigarette smoking, hyperlipidemia, diabetes, hypertension, cerebrovascular disease, peripheral vascular disease, and a family history of premature coronary disease.24 Cardiovascular risk factors greatly affect the pretest probability of significant IHD, particularly for women, younger patients, and patients with atypical chest pain syndromes [see Table 5]. For example, a 55-year-old man with atypical angina and no risk factors has a pretest probability of clinically significant IHD of 45%, whereas a 55-year-old man with typical angina and multiple cardiovascular risk factors has a 95% pretest probability of significant IHD.
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Table 5 Comparison of Pretest Likelihood of IHD in Low-Risk Symptomatic Patients and High-Risk Symptomatic Patients49 |
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Estimating the pretest probability of significant IHD is essential to determine whether further testing is warranted. For example, further diagnostic testing of the patient with a 45% probability of IHD would likely clarify the presence or absence of IHD. On the other hand, further testing of the patient with a 95% probability of IHD would be unlikely to alter the diagnosis of IHD, although further testing might help assess risk of cardiovascular events [see Risk Stratification in Patients with Chronic Stable Angina, below]. In general, further testing is not recommended for patients with a very low pretest probability of significant IHD, as determined by a clinical assessment of patient history and risk factors.
Estimates of the risk of cardiovascular events can also be determined from clinical variables; the Framingham risk equations are commonly used for this purpose [see Figure 2].25 This multivariate model estimates the 10-year risk of developing IHD on the basis of a patient's age; gender; total cholesterol level; and history of diabetes, hypertension, and smoking. This model is widely used, is readily available, and has been validated across a variety of populations.
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Figure 2. Estimates of Cardiovascular Risk Based on Framingham Risk Equations Estimates of major cardiovascular risk for men and women, based on the Framingham risk equations.25 |
The decision to pursue further testing in patients with possible angina appropriately incorporates patient preferences regarding diagnosis or intervention and an assessment of comorbidities [see Patients Warranting Noninvasive Testing, below].
Physical Examination
The physical examination of patients with chronic stable angina is often normal but may indicate the presence of hypertension (e.g., elevated blood pressure, enlarged or laterally displaced point of maximum impulse, S4 gallop, or retinal vascular changes) or coexisting peripheral vascular disease (e.g., diminished pulses or bruits). In younger patients with premature coronary disease, there may be stigmata of genetic dyslipidemia syndromes (e.g., xanthelasma associated with familial hypercholesterolemia). For patients with chest pain, the presence of any of these findings increases the likelihood of significant IHD.
It is particularly helpful to examine a patient during an episode of angina. The presence of an S4 or S3 gallop, a mitral regurgitation murmur, a paradoxically split S2 heart sound, bibasilar crackles, or a chest wall heave makes IHD more likely, particularly if the finding disappears when the pain goes away.26 Physical examination findings that wax and wane with anginal symptoms are of particular significance, because they may indicate significant myocardial dysfunction at low work loads.
Laboratory Tests
A resting 12-lead electrocardiogram should be performed in all patients with suspected angina, although the results are normal in 50% of patients with chronic stable angina.27 The presence of pathologic Q waves is virtually pathognomonic of clinically significant IHD, although isolated Q waves in lead III or a QS pattern in leads V1 and V2 is nonspecific. Several other ECG findings increase the clinical probability of IHD; ST segment depression, T wave inversions, and left ventricular hypertrophy (LVH) favor the diagnosis of angina.28 Arrhythmias, including atrial fibrillation, ventricular tachyarrhythmias, bundle branch blocks, and atrioventricular block, increase the likelihood of IHD somewhat but are nonspecific.
As with the physical examination, an ECG obtained during an episode of pain may be particularly informative. About half of patients with a normal resting ECG will have an abnormality suggestive of ischemia during an episode of chest pain. Suggestive abnormalities include ST segment depression, T wave inversion, or “pseudonormalization” of these abnormalities during pain.29 Abnormalities on a resting ECG that disappear with resolution of pain may indicate severe IHD, because they suggest ischemia at low work loads or unstable coronary syndromes.
Recommended laboratory tests include measurement of hemoglobin and fasting glucose levels and a fasting lipid panel (including measurement of levels of total cholesterol, HDL cholesterol, triglycerides, and calculated LDL cholesterol).1 Hyperlipidemia is an important risk factor for IHD; the risk for IHD increases 1% for each 1 mg/dl increase in serum LDL cholesterol.30 Similarly, patients with impaired glucose tolerance or frank diabetes are at increased risk for IHD. Normal hemoglobin excludes anemia. Thyroid function tests are indicated in patients who have signs or symptoms compatible with hyperthyroidism.
Imaging Studies
Chest radiography is of limited value in most patients with suspected angina31; however, a chest radiograph or other imaging study, such as computed tomography, is indicated in patients with signs or symptoms of congestive heart failure (CHF), valvular heart disease, or pericardial disease or in patients with possible aortic dissection or aneurysm. Echocardiography or multigated equilibrium radionuclide angiography should be obtained in any patient with suspected left ventricular impairment.
Patients Warranting Noninvasive Testing
Noninvasive testing usually has two objectives: to ascertain the probability of clinically important IHD and to estimate the risk of a serious cardiovascular event (e.g., MI or death) in the near future. These two objectives are often pursued concurrently, but it is useful to distinguish between diagnostic testing and testing for purposes of risk stratification.
Noninvasive testing is most likely to influence clinical decision making when the pretest probability of IHD is in the intermediate range. For example, a positive exercise treadmill test in a 55-year-old man with atypical chest pain and no other risk factors (pretest probability of clinically significant IHD, approximately 50%) would significantly increase the suspicion of clinically important IHD (posttest probability, 85%), whereas a negative exercise treadmill test would significantly reduce the suspicion of clinically significant IHD (posttest probability, 15%).
On the other hand, an abnormal exercise treadmill test in a 35-year-old woman with atypical chest pain and no other risk factors (pretest probability of clinically significant IHD, < 5%) would likely be falsely positive and could prompt use of unnecessary medications or potentially invasive diagnostic testing; a negative test would simply support a low clinical suspicion of disease. Therefore, further testing in such a low-risk patient would not be indicated. Similarly, further testing of high-risk patients is not likely to provide information that would alter the diagnosis of IHD. For example, because of the likelihood of significant coronary disease in a 65-year-old man with typical angina (pretest probability, 94%), a positive exercise test would only confirm the high clinical suspicion of IHD; a negative result would only lower the estimate into the moderate range and would not exclude the diagnosis of significant IHD.
Noninvasive testing is commonly obtained in persons with a high clinical probability of having significant IHD. In this setting, however, noninvasive testing is useful to assess risk and establish prognosis but not to establish or refute the diagnosis of coronary disease, as is the case for patients with an intermediate clinical probability of significant IHD.
For purposes of deciding on a course of noninvasive testing, there is no precise definition of the upper and lower boundaries of intermediate probability of IHD; rather, this is a matter of clinical judgment in individual situations. Relevant issues include the degree of uncertainty acceptable to the physician and patient, the probability of an alternative diagnosis, the costs and risks of additional testing, and the benefits and risks of treatment in the absence of additional testing.32 It is reasonable to consider a risk of clinically significant IHD of 10% to 20% or lower as low probability and of 80% to 90% risk or greater as high probability.32
NONINVASIVE TESTING
Patients whose history, physical examination, and ECG results indicate an intermediate or high probability of IHD usually should undergo further diagnostic evaluation [see Figure 3]. Noninvasive testing in patients with an intermediate probability of IHD provides important information about diagnosis (i.e., the presence or absence of coronary disease). In patients with an intermediate or high probability of IHD, noninvasive testing helps to stratify risk for major cardiovascular events. This stratification helps determine treatment strategies.
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Figure 3. Non-invasive Evaluation of Suspected Ischemic Heart Disease Noninvasive testing and angiography in the evaluation of patients suspected of having ischemic heart disease.21 |
Commonly performed noninvasive studies include exercise ECG testing, stress radionuclide myocardial perfusion imaging, and stress echocardiography. The performance characteristics of various noninvasive tests and posttest probabilities of IHD for a range of pretest probabilities are listed [see Table 6].
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Table 6 Posttest Probability of Significant IHD Based on Pretest Probabilities of IHD and Normal or Abnormal Results of Noninvasive Studies |
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ECG Exercise Testing
Guidelines from the American College of Cardiology/American Heart Association/American College of Physicians (ACC/ AHA/ACP) recommend exercise ECG as the first-choice diagnostic test for the average patient with an intermediate pretest probability of IHD and a normal resting ECG.32,33 Exercise testing has imperfect sensitivity and specificity (68% and 77%, respectively), but it is widely available and inexpensive. In addition, it readily identifies patients at high risk for IHD and provides important prognostic information [see Risk Stratification in Patients with Chronic Stable Angina, below]. Exercise testing is generally safe; MI or death occurs with a frequency of less than 1 in 2,500 tests.34 Symptom-limited exercise testing is safe in patients with unstable angina who lack evidence of MI and CHF and who are free of chest pain at the time of testing.32 Specific absolute and relative contraindications for exercise testing can be found in guidelines from the ACC/AHA.1 Other noninvasive tests are preferred in patients who are unable to exercise, in those who previously underwent coronary revascularization, and in those with specific resting ECG abnormalities that would interfere with the interpretation of an exercise ECG (such abnormalities include ST segment depression of greater than 1 mm at rest, preexcitation syndrome, electronically paced rhythm, left bundle branch block, and left ventricular hypertrophy with repolarization abnormalities).32
Interpretation of the exercise test depends on the patient's exercise capacity, symptoms, the reasons for stopping the test, the hemodynamic response, any pertinent findings on physical examination (e.g., exercise-induced S3 heart sound or mitral regurgitation), and any changes in the ECG. Patients who stop the test because of the onset of angina are very likely to have significant IHD. Exercise-induced falls in blood pressure or the development of an exercise-induced S3 heart sound are strongly suggestive of ischemic left ventricular dysfunction. Specific exercise-induced ECG changes suggestive of IHD include a horizontal or downward-sloping ST segment depression or elevation of greater than 1 mm during or after exercise.1 Exercise-induced changes in lead V5 are most reliable for the diagnosis of IHD.1
Stress Radionuclide Myocardial Perfusion Imaging
Although exercise ECG continues to be recommended as the diagnostic test of choice for most patients with suspected angina, stress myocardial perfusion imaging using single-photon emission computed tomography (SPECT) is the most common noninvasive test performed in the United States. SPECT imaging following exercise or pharmacologic stress (e.g., using dipyridamole, adenosine, or dobutamine) has greater sensitivity for IHD than exercise testing, particularly in patients with an abnormal resting ECG; in addition, SPECT can define vascular regions in which stress-induced coronary flow is limited. Furthermore, SPECT imaging allows an estimation of left ventricular (LV) systolic size and function.
Exercise myocardial perfusion SPECT is preferred for patients who have baseline ECG abnormalities that interfere with the interpretation of an exercise ECG. Such abnormalities include a resting ST segment depression greater than 1 mm and LVH; digoxin therapy and ventricular preexcitation can also cause ECG abnormalities.35 Myocardial perfusion SPECT with pharmacologic stress is preferred in the setting of left bundle branch block or ventricular pacing.35 Because of its greater sensitivity, stress myocardial perfusion imaging is an option after a nondiagnostic exercise ECG. Stress myocardial perfusion imaging can also further stratify the risk of IHD in patients with an abnormal exercise ECG.36
Stress Echocardiography
Stress echocardiography (i.e., echocardiography performed after exercise or dobutamine administration) is another option for noninvasive testing to establish the diagnosis of IHD. Stress induces regional wall motion abnormalities in the myocardial regions supplied by stenotic coronary vessels; stress echocardiography defines such regions of the left ventricular wall. Stress echocardiography, like myocardial perfusion imaging, is a good choice for patients with ECG abnormalities that might interfere with the interpretation of an exercise ECG.37The sensitivity of stress echocardiography, as with that of stress myocardial perfusion imaging, is in the range of 80% to 85%. Exercise echocardiography is marginally more specific than other noninvasive diagnostic tests.38
Test Selection
Although exercise ECG remains the recommended initial noninvasive test for most patients with suspected IHD, clinical decision making should also take into account individual patient characteristics, local expertise, and availability. Stress echocardiography and exercise ECG can be performed in a physician's office, whereas radionuclide myocardial perfusion imaging requires a specialized setting. In addition, myocardial perfusion imaging is considerably more expensive than exercise ECG.
Specific noninvasive tests are preferred in certain patient subsets. Patients unable to exercise should undergo some form of pharmacologic noninvasive test. Pharmacologic stress echocardiography using dipyridamole, adenosine, or, less commonly, dobutamine is an option for patients who are unable to exercise. Nonspecific perfusion image defects may be more common with exercise myocardial perfusion imaging in patients with left bundle branch block; pharmacologic stress imaging or echocardiography is preferred in these patients.32 Exercise ECG is less accurate in establishing the diagnosis of IHD in women, and some authors have suggested that SPECT imaging and stress echocardiography are more accurate diagnostic tests for women with an intermediate probability of having IHD.39,40 The ACC/AHA/ACP expert panel concluded, however, that insufficient data are available to recommend stress imaging or echocardiography over standard exercise ECG in women with suspected angina.32
Echocardiography is less sensitive in very obese patients, and examination tables used for SPECT imaging often have weight limitations. Planar scintigraphy, positron-emission tomography, and coronary angiography are testing options for obese patients. Planar scintigraphy is less sensitive than SPECT, and positron emission tomography is less well characterized than other modalities. There is some rationale for performing stress imaging or echocardiography in patients with angina whose histories suggest they are at high risk for major cardiovascular events (e.g., patients who experience angina at low work loads or whose angina is progressive); in such patients, determination of LV systolic function and anatomic distribution of IHD are important considerations in anticipation of a possible need for revascularization. For these patients, it may be appropriate to proceed directly to coronary angiography [see Invasive Testing, below].
Beta blockade reduces the sensitivity of all noninvasive tests, particularly exercise ECG41; it is recommended that, whenever possible, beta blockers be withheld for four half-lives (approximately 48 hours) before noninvasive testing is undertaken. Digoxin causes resting ST segment depression and reduces the specificity of exercise ECG.
In general, it is cost-effective to perform exercise ECG as the initial test in most patients, followed by additional imaging for patients in whom further diagnostic or prognostic testing is warranted.42 Noninvasive testing is not generally recommended as a screening test in asymptomatic persons. Specific exceptions include patients whose occupation requires periodic stress testing (e.g., pilots, firefighters, competitive athletes, and police).
Imaging Studies under Investigation
Several CT and magnetic resonance imaging techniques are currently under study for use in diagnosing patients with suspected angina or in stratifying such patients for risk of cardiac events. Of these techniques, the most widely used is electron-beam computed tomography (EBCT), which detects coronary artery calcification. Although the sensitivity of EBCT for the diagnosis of significant coronary artery stenosis is high, the specificity of EBCT for significant coronary artery stenoses ranges from only 41% to 76%, yielding many false positive results. Some studies suggest that the “calcium score” derived from EBCT predicts the extent of angiographically detected CAD.43 Studies that correlate calcium scores with risk of future cardiac events have been fraught with methodologic problems44,45; it is not clear whether EBCT adds significantly to clinical risk assessment using validated tools such as the Framingham risk score.46 To date, no prospective, population-based studies have investigated a potential association between calcium score derived from EBCT and risk of future coronary events; likewise, no studies have shown that screening for IHD with EBCT reduces mortality.
Asymptomatic patients identified as being at potentially high risk for cardiac events on the basis of EBCT may suffer anxiety and undergo unnecessary procedures as a result of the study. Estimates of the cost efficacy of EBCT relative to current strategies for diagnosis and risk stratification are varied and are sensitive to the prevalence of disease in a screened population; currently, the clinical benefits of screening asymptomatic patients are uncertain.47 The ACC/AHA guidelines do not recommend EBCT and other imaging procedures, such as MRI angiography, in asymptomatic patients.48 Although EBCT testing is currently not recommended as a screening test, it is reasonable to evaluate patients who have undergone EBCT and who have been found to have severe coronary calcification with some form of noninvasive testing.
INVASIVE TESTING
Coronary angiography provides unequaled detail of coronary anatomy, including detail sufficient to enable evaluation for possible revascularization; however, angiography is invasive and expensive compared with noninvasive testing. In addition, although angiography identifies the degree and distribution of coronary stenoses, it provides inconsistent assessment of the functional significance and stability of a particular coronary lesion32; for example, plaques that can possibly rupture and thereby cause acute coronary syndromes are commonly angiographically insignificant.18 Moreover, studies have called into question the reliability of angiographic measurements of coronary stenosis in some settings.49
The decision to pursue angiography should be based on preferences of the patient and provider, coexisting illnesses, estimates of the probability of high-risk IHD, and the urgency to confirm or refute a possible diagnosis of IHD.
Direct referral for coronary angiography is recommended for patients who have survived sudden death, because of the high probability of multivessel IHD in these patients.32 Other patients for whom angiography is recommended as a diagnostic test include those for whom the diagnosis of IHD remains uncertain despite noninvasive testing, provided the benefit of a more certain diagnosis outweighs the risk and cost of angiography; patients who cannot undergo noninvasive testing because of disability, illness, or morbid obesity; patients with suspected non atherosclerotic angina (e.g., coronary dissection, coronary anomaly, Kawasaki disease, and coronary artery spasm); and patients with a high pretest probability of disease of the left main coronary artery or three-vessel IHD [see Prognostic Value of Coronary Angiography,below].32
DIAGNOSIS OF CHRONIC STABLE ANGINA
The presence of clinically stable, typical angina for a period of 2 or more months is adequate to establish the diagnosis of chronic stable angina. As mentioned [see Preliminary Evaluation, above], an accurate estimate of the likelihood of significant IHD can be established from simple clinical criteria (i.e., characteristics of chest pain and cardiovascular risk factors). For patients with an uncertain diagnosis after undergoing clinical assessment, particularly patients with some cardiovascular risk factors and an atypical angina syndrome, noninvasive testing is valuable for establishing the diagnosis of IHD. IHD can be confirmed by coronary angiography, which is also helpful in defining the severity of coronary atherosclerosis [see Risk Stratification in Patients with Chronic Stable Angina, below].
RISK STRATIFICATION IN PATIENTS WITH CHRONIC STABLE ANGINA
Risk stratification that determines the prognosis for MI or death is essential in determining treatment recommendations for patients with chronic stable angina. In general, a patient's coronary risk is determined by the interplay of four factors32: (1) left ventricular systolic function; (2) the extent and severity of atherosclerotic occlusion of the coronary tree (i.e., ischemic burden); (3) plaque stability (i.e., risk of plaque rupture); and (4) coexisting medical conditions. Clinical parameters, results of noninvasive testing, and coronary angiography provide important prognostic and diagnostic information.
Clinical Parameters Indicating High Risk
Although noninvasive testing and coronary angiography are the mainstays of risk stratification, clinical parameters alone are sufficient to identify some patients as having a high probability of severe IHD (i.e., three-vessel disease or left main CAD). Hubbard and colleagues developed a simplified algorithm for predicting the probability of severe IHD on the basis of six clinical parameters: age, gender, presence of typical angina, presence of diabetes, insulin use, and prior MI (as indicated by history or ECG) [see Figure 4].50 Older patients with multiple risk factors have a greater than 50% chance of having severe IHD and should be considered for direct referral for coronary angiography. In one study, a previous history of MI and the presence of a carotid bruit (a marker for peripheral vascular disease) more than doubled the probability of severe IHD.51 Direct referral for coronary angiography is estimated to be cost-effective when the pretest probability of severe IHD is high.52
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Figure 4. Probability of Severe Coronary Disease Nomogram showing the probability of severe coronary disease (i.e., three-vessel disease or left main coronary artery disease) on a five-point score. One point is awarded for each of the following variables: male gender; typical angina; history or electrocardiographic evidence of myocardial infarction; diabetes; and use of insulin. Each curve shows the probability of severe coronary disease as a function of age.50 |
Follow-up Noninvasive Testing
Noninvasive testing is a sensible approach for the majority of patients without high-risk characteristics. Available diagnostic modalities predict death more accurately than cardiovascular events such as MI. Patients with IHD are stratified according to their risk of death into three categories: those at low risk (< 1% mortality a year); those at intermediate risk (1% to 3% mortality a year); and those at high risk (> 3% mortality a year). Persons estimated to be at low risk for death generally may be managed medically without further diagnostic testing unless their condition deteriorates.32 Persons estimated to be at intermediate or high risk after initial noninvasive testing may need to undergo additional studies for the purpose of further risk stratification.
Left ventricular systolic function
Declining left ventricular systolic function is the strongest single predictor of long-term mortality in patients with IHD.53 Patients with an ejection fraction of less than 35% have a mortality in excess of 3% a year. Left ventricular function can be assessed by echocardiography, stress myocardial perfusion imaging with SPECT, angiographic ventriculography, or gated nuclear medicine studies. As noted, not all patients with angina require evaluation of left ventricular function. Patients with a normal resting ECG and no history of MI or CHF are very likely to have normal left ventricular systolic function (92% to 95% probability).54 Patients with a history of CHF, MI, or ECG evidence of prior MI should undergo evaluation of left ventricular function.
Exercise treadmill ECG
In addition to the diagnostic information it provides, exercise treadmill ECG testing supplies useful prognostic information. Exercise capacity during a treadmill test is one of the strongest predictors of cardiovascular risk. Exercise capacity is influenced, in part, by LV function, both at rest and with exercise. Several measures of exercise capacity are used: exercise duration, maximum heart rate, exercise duration A5 heart rate, and estimates of work measured in metabolic equivalents (METs). Other important variables include ECG measures of exercise-induced ischemia, as reflected in ST segment depression or elevation, and the duration of ST segment deviation during the recovery phase of the exercise protocol.
The Duke treadmill score (DTS) combines these exercise test variables and is the most widely used prognostic treadmill score.55 The DTS is calculated as follows:
The angina index equals 2 when angina is the reason for stopping the exercise test; it equals 1 when angina occurs during the test or the recovery period; and it equals 0 if no angina occurs. In patients with a low-risk DTS (i.e., ≥ +5), the 4-year survival is 99% (average annual mortality, 0.25%) [see Table 7]. Patients with a high-risk DTS (< -10) have a 4-year survival rate of 79% (average annual mortality, 5%). In one study, more than two thirds of outpatients with suspected IHD had low-risk scores, and only 4% of patients had high-risk scores.55 Available data suggest that patients with frequent ventricular ectopy or a slow heart rate recovery time following exercise testing are also at increased risk for death during subsequent follow-up,56 although it remains uncertain how best to incorporate this information into the stratification of risk.
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Table 7 Survival According to Risk Groups Based on Duke Treadmill Score (DTS) |
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Stress testing
Stress myocardial perfusion imaging and stress echocardiography are commonly used in risk stratification of patients with IHD, although their prognostic value is less known than that of exercise ECG.57 In patients with an intermediate-risk exercise ECG (DTS < +5 and ≥ -10), annual mortality is between 1% and 3%; these patients are usually referred for additional diagnostic testing, either stress imaging or coronary angiography. In patients with a high-risk exercise ECG result (DTS < -10), annual cardiac mortality is estimated to exceed 3%; these patients are generally referred for coronary angiography. Patients with a low-risk exercise ECG (DTS ≥ +5) require no further testing and may be medically managed. It is also appropriate to obtain a stress imaging study for purposes of risk stratification for patients who are unable to exercise and for patients with uninterpretable rest ECGs. Stress imaging studies are preferred over exercise ECG for evaluating ischemia in symptomatic patients who have previously undergone revascularization.
A normal poststress myocardial perfusion imaging study, as with a low-risk exercise ECG, indicates an excellent prognosis, even among patients with chronic stable angina.58 The number, size, and location of abnormalities on stress myocardial perfusion studies indicate the distribution and severity of coronary artery stenoses; larger and more numerous perfusion defects are associated with more severe CAD. Stress-induced LV dysfunction—a marker of severe multivessel IHD—is indicated by LV dilatation or lung uptake of radionuclide tracer.59,60Patients with two or more moderate to large stress-induced perfusion defects or evidence of stress-induced LV dysfunction are considered to have a high probability of severe IHD; these patients are candidates for referral for coronary angiography.
A negative stress echocardiogram also indicates a good prognosis.61 In the presence of significant IHD, stress induces regional wall motion abnormalities in the myocardial regions supplied by the stenotic coronary vessel. Stress-induced wall motion abnormalities involving two or more segments at lower levels of stress predict high-risk IHD. As with stress myocardial perfusion imaging, stress-induced LV dilatation suggests multivessel IHD. Abnormal stress echocardiography provides diagnostic and prognostic information that is incremental to that obtained by exercise ECG,62 although there are relatively fewer follow-up data for this test than for myocardial perfusion studies.
Prognostic Value of Coronary Angiography
The anatomic extent of IHD is a powerful indicator of prognosis. Referral for coronary angiography should be considered for patients with a high-risk exercise ECG (DTS < -10), a high-risk stress myocardial perfusion imaging study, or a high-risk stress echocardiogram, provided the patient is a candidate for revascularization.
In the Coronary Artery Surgery Study database of patients with suspected IHD who were referred for coronary angiography, the 12-year survival rate for patients with normal coronary arteries was 91%, compared with 74% for patients with one-vessel disease, 59% for patients with two-vessel disease, and 40% for patients with three-vessel disease.63 Proximal lesions are associated with greater risk than more distal lesions.64 LV function remains crucially important. For example, the 5-year survival of a 65-year-old man with stable angina, three-vessel coronary stenoses, and normal LV function is 93%, compared with 5-year survival of only 58% in a similar patient with an LV ejection fraction of 30%.64 Although angiography provides detailed information about the extent and severity of stenoses, it does not define which ones are actually responsible for anginal symptoms. Furthermore, the atherosclerotic plaques most likely to rupture and to thereby cause acute coronary syndromes, including MI and death, are often missed by coronary angiography.18
In summary, for patients with IHD, the strongest predictor of long-term survival is LV systolic function. A second determinant of survival is the severity and distribution of coronary lesions. A third determinant is the stability of coronary plaques; plaque instability and rupture increase the short-term risk of unstable coronary syndromes and death. Currently, there is no satisfactory means to measure this third determinant.
Treatment
The two overarching goals of the treatment of patients with chronic stable angina are to reduce the likelihood of untoward clinical events (i.e., acute coronary syndromes and sudden death) and to improve quality of life by reducing anginal symptoms and enhancing function. Treatment options include lifestyle modifications, medications, and revascularization. Evidence-based guidelines have been published, and a general approach to the treatment of patients with chronic stable angina is outlined below. However, management should be individualized in accordance with a patient's risk of adverse outcomes, coexisting conditions, and preferences, as well as in consideration of the cost and effectiveness of therapeutic alternatives. An ACC/AHA/ACP expert panel developed an mnemonic for the treatment of patients with chronic stable angina [see Table 8].21
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Table 8 The “ABCDEs” of Treatment for Patients with Chronic Stable Angina20 |
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LIFESTYLE MODIFICATION
Smoking Cessation
Among nonpharmacologic interventions, smoking cessation has the greatest impact on total mortality and cardiovascular risk. A systematic review of prospective cohort studies of smokers with IHD found a striking 29% to 36% relative risk reduction in all-cause mortality for patients who were able to quit smoking.65 Most patients in these cohort studies had previous MI, angioplasty, or coronary artery bypass grafting (CABG) at the time of entry into the study. The magnitude of the risk reduction for smoking cessation was as great as or greater than that expected to result from use of aspirin, statins, beta blockers, or angiotensin-converting enzyme (ACE) inhibitors. Smoking cessation should be strongly and repeatedly recommended to all patients with known or suspected IHD who smoke. Physicians should become accustomed to applying effective techniques for counseling patients and using effective medications such as nicotine replacement and bupropion. Patients' efforts to quit are often more effective in the setting of a formal smoking-cessation program; therefore, internists should be familiar with local smoking-cessation resources and programs.
Physical Activity and Dietary Modifications
Physical activity
Regular physical activity and dietary modifications also reduce cardiovascular risk. Physical fitness during middle age is associated with lower long-term cardiovascular mortality66; in addition, self-reported increases in physical activity is associated with reduced all-cause and cardiovascular mortality in elderly men.67 In the Health Professionals Follow-up Study, half an hour or more of brisk walking each day was associated with an 18% relative risk reduction in cardiovascular events; in addition, greater duration and intensity of exercise were associated with greater reductions in risk.68 This study also suggested that weight training was associated with a decreased cardiovascular risk. Although these observational studies are potentially subject to bias, the preponderance of evidence strongly supports recommending regular physical activity to patients.
Patients with chronic stable angina should be encouraged to include moderate aerobic activity in their daily lives.21 Moderate physical activity consists of walking briskly for 30 minutes or more five to seven times a week or the equivalent. Unresolved questions include whether more vigorous physical activity provides greater risk reduction than moderate exercise; whether sustained aerobic exercise of 30 or more minutes is necessary for cardiovascular benefit or whether an accumulation of 30 or more minutes of physical activity during the day is sufficient; and to what extent physical activity provides reductions in risk above and beyond those achieved simply through modification of specific risk factors, such as dyslipidemia, hypertension, and diabetes.
Dietary modification
Diet also has the potential to modify multiple coronary risk factors—namely, lipid levels, obesity, insulin resistance, and hypertension. Although trials assessing the effects of dietary modification on stable IHD have not uniformly demonstrated benefit, several trials have shown reductions in cardiac mortality. In the Lyon Diet Heart Study, patients who had had an MI were randomized either to adopt a Mediterranean diet rich in fresh fruits and vegetables, whole grains, olive oil, fish, and relatively little meat or to adopt a prudent Western diet low in saturated fats. At 4 years' follow-up, patients randomized to the Mediterranean diet enjoyed a 2.5% to 3% per year reduction in cardiac death and nonfatal MI.69 Another trial randomized patients with IHD (about half of whom had a history of MI) either to adopt an Indo-Mediterranean diet rich in fresh fruits, vegetables, legumes, nuts, and whole grains and supplemented with omega-3 fatty acids or to adopt a prudent Indian diet low in saturated fats. Moderate exercise was recommended for all patients. Patients randomized to the Indo-Mediterranean diet had a 7.4% absolute reduction in the risk of MI or cardiac death at 2 years' follow-up.70 Patients randomized to the intervention diet had significant reductions in daily intake of calories, protein, fat (mostly saturated), cholesterol, and salt; they ingested significantly more complex carbohydrates, fiber, monounsaturated and polyunsaturated fats, fruits, vegetables, legumes, nuts, and omega-3 polyunsaturated oils.
Other studies demonstrate evidence of the protective benefit of fresh fruits and vegetables. The Nurses' Health Study and Health Professionals Follow-up Study found that persons in the highest quintile of fruit and vegetable intake had a 20% relative risk reduction for nonfatal MI or cardiac death compared with the lowest quintile.71 A review of diet and IHD concluded that three dietary strategies are effective at reducing the risk of IHD: (1) substituting unsaturated fats (particularly polyunsaturated fats) for saturated fats (e.g., animal fats) and trans-fatty acids (e.g., stick margarine, vegetable shortenings, many commercially prepared baked goods, and deep-fried foods); (2) increasing consumption of omega-3 fatty acids (e.g., oily fish, canola oil, soybean oil, and flaxseed oils); and (3) consuming a diet high in fruits, vegetables, nuts, and whole grains and low in refined grains.72
MEDICAL THERAPY TO REDUCE CARDIOVASCULAR RISK
Antiplatelet Agents
Aspirin
Acute coronary events commonly result from rupture of an atherosclerotic plaque and subsequent platelet aggregation and thrombosis. Aspirin inhibits cyclooxygenase and the synthesis of prothrombotic platelet thromboxane A2. In studies of more than 3,000 patients with chronic stable angina that compared treatment with aspirin to placebo, the use of aspirin reduced the risk of adverse cardiovascular events by 33% over 6 months.73,74 This reduction in relative risk corresponds to a reduction in absolute risk of approximately 5%. In other words, five cardiovascular events would be prevented for every 100 persons with known cardiovascular disease treated with aspirin for 6 months.73In the Swedish Angina Pectoris Aspirin Trial, which involved patients with stable angina, the addition of aspirin (75 mg daily) to a regimen of sotalol resulted in a 34% decrease in MI and sudden death75; most of this decrease involved reductions in the incidence of first MI. In the Physician's Health Study, which involved asymptomatic middle-aged men, the use of aspirin (325 mg every other day) was associated with a decrease in the incidence of MI.76 Doses ranging from 75 to 325 mg daily were found to offer equivalent benefit,77 although the incidence of gastrointestinal toxicity was dose-dependent. All patients with chronic stable angina should be treated with aspirin unless there is a history of documented aspirin allergy or life-threatening gastrointestinal hemorrhage.
Aspirin alternatives
Two thienopyridine derivatives, clopidogrel and ticlopidine, inhibit adenosine diphosphate—mediated activation of platelet glycoprotein IIb/IIIa. These agents, particularly clopidogrel, are reasonable alternatives for aspirin-intolerant patients with chronic stable angina. In a randomized, controlled trial of patients with symptomatic vascular disease (including patients with chronic stable angina), clopidogrel was slightly more effective than aspirin in reducing the risk of MI, vascular death, and ischemic stroke.78 Clopidogrel is much more expensive than aspirin; in addition, approximately 200 more patients would need to be treated with clopidogrel than with aspirin for 2 years to prevent one major vascular event.79 There are no studies demonstrating that ticlopidine reduces cardiovascular events in outpatients with chronic stable angina. Ticlopidine can cause cytopenia, and there is a reported rare association with thrombotic thrombocytopenic purpura.
Lipid-Lowering Agents
There are abundant data showing the beneficial effects of lipid-lowering therapy in patients with chronic stable angina. Each 1% reduction in total cholesterol is associated with an approximately 2% reduction in coronary events.80 In the Scandinavian Simvastatin Survival Study, patients with documented ischemic heart disease (including chronic stable angina) and elevated total cholesterol levels (i.e., levels of 212 to 308 mg/dl) were randomized to receive either a statin or placebo.81 A 30% to 35% reduction in mortality and major coronary events was observed in patients receiving a statin. In the Cholesterol and Recurrent Events Trial, patients with prior MI and somewhat lower cholesterol levels (i.e., mean total cholesterol and LDL cholesterol of 209 mg/dl and 139 mg/dl, respectively) had a 25% relative risk reduction in the composite outcome of fatal or nonfatal MI when treated with a statin.82 In the Heart Protection Study, patients with IHD or conditions that confer a similarly high risk of MI or coronary death (e.g., peripheral vascular disease, cerebrovascular disease, or diabetes) were randomized to receive either simvastatin (40 mg) or placebo, irrespective of baseline LDL level.83 Statin therapy reduced total mortality; the incidence of first MI, coronary death, and stroke; and the use of revascularization procedures among all groups of patients, including those with LDL cholesterol levels of less than 116 mg/dl at entry (3.0 mmol/L). From this study, it may be concluded that all patients with chronic stable angina should be treated with a statin, barring specific allergy. Detailed recommendations for lipid-lowering therapy are provided by the National Cholesterol Education Program Adult Treatment Program III (NCEP ATP III).30
The target for therapy for patients with known IHD, including patients with chronic stable angina, is a serum LDL cholesterol level of less than 100 mg/dl. Patients with diabetes, peripheral vascular disease, and cerebrovascular disease are regarded as having a risk of cardiovascular events equivalent to patients with established IHD; the target for therapy in these patients is an LDL cholesterol level of less than 100 mg/dl, which is the same as in patients with known IHD. For other patients, including patients with possible IHD (e.g., a patient with atypical angina and a nondiagnostic exercise treadmill test) or two or more cardiovascular risk factors, the aggressiveness of lipid-lowering therapy is determined by calculating cardiovascular risk from the Framingham risk calculator30 and the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm) [see Figure 2].
Available data suggest a potential benefit for more aggressive lowering of LDL cholesterol. In one study, low-risk patients with stable, mild to moderate angina were randomized to receive either atorvastatin, 80 mg daily, or percutaneous coronary intervention (PCI) followed by usual care (including lipid-lowering treatment). Patients receiving atorvastatin required fewer revascularization procedures or admissions for worsening angina with objective evidence of ischemia (13.4% versus 20.9%).84 Patients in the atorvastatin-treated group reached an average LDL cholesterol level of 77 mg/dl, as compared with 119 mg/dl in the PCI group. A second study compared the effects of intensive lipid-lowering therapy using atorvastatin (80 mg/day) with mod erate lipid-lowering therapy using pravastatin (40 mg/day).85 Patients treated with atorvastatin (80 mg/day) achieved an average LDL cholesterol level of 79 mg/dl (2.05 mmol/L) and show ed less progression of coronary atherosclerosis than patients treated with pravastatin (40 mg/day), who achieved an average LDL cholesterol level of 110 mg/dl (2.85 mmol/L).
Statin therapy is associated with several important potential adverse reactions. Elevations of liver transaminase levels have been described in patients taking statin drugs, although elevations to levels greater than three times the upper limit of normal (necessitating discontinuance) occur in fewer than 0.3% to 0.5% of patients.86
Rhabdomyolysis from statins is an uncommon dose-related phenomenon that usually occurs within the first few weeks of therapy, but it may occur at any time; rhabdomyolysis resolves after withdrawal of the offending drug. Clinically significant myopathy with 10-fold elevations of creatine kinase (CK) occurs in about 0.5% of patients treated with statins.86 Massive rhabdomyolysis usually occurs only with concomitant use of clofibrate, niacin, or gemfibrozil. The incidence appears to be higher with drugs that interfere with the cytochrome P-450 system (e.g., simvastatin, lovastatin, and atorvastatin) and lower with less potent agents (e.g., pravastatin and fluvastatin). Predispositions to this adverse effect include certain P-450 polymorphisms (CYP3A4), renal failure, liver disease, hypothryoidism, concomitant medications (e.g, macrolides, azole antifungals, cyclosporine, protease inhibitors, selective serotonin reuptake inhibitors, nefazodone, verapamil, diltiazem, and amiodarone), and ingestion of grapefruit juice in quantity.87 Myopathy can also occur without elevation of CK.88
Niacin, fibric acid derivatives (e.g., gemfibrozil and clofibrate), and bile acid sequestrants (e.g., cholestyramine and colestipol) reduce cholesterol an average of 6% to 15%. Niacin raises the HDL cholesterol, lowers the LDL cholesterol, and reduces the level of triglycerides. A meta-analysis of 37 studies suggests that the lipid-lowering effect of these agents is associated with reduced coronary mortality and total mortality.89 In high-risk patients with a low HDL cholesterol level or hypertriglyceridemia, it is reasonable to consider the use of niacin or a fibric acid derivative, alone or in combination with a statin.90,91,92 In the Veterans Affairs HDL Intervention Trial (VA-HIT), patients with established IHD and low HDL cholesterol levels who were randomized to receive gemfibrozil experienced a significant reduction in major cardiovascular events and cardiovascular mortality, as compared with patients who received placebo.90 In another study, patients with established IHD and low levels of HDL cholesterol who were randomized to receive simvastatin plus niacin had fewer first cardiovascular events, as compared with patients who received placebo or simvastatin alone.91
Ezetimibe represents a new class of agent that inhibits intestinal absorption of cholesterol and produces moderate reductions in LDL cholesterol. Its principal indication at this time, as with the bile-acid sequestrants, is to augment the lipid-lowering efficacy of a statin.93Ezetimibe is associated with fewer gastroinstestinal side effects than bile-acid sequestrants. Niacin commonly causes flushing, a side effect that can be mitigated by gradual titration toward a target dose and by pretreatment with aspirin. Extended-release preparations of niacin are associated with less flushing. Niacin modestly increases glucose intolerance and can cause hyperuricemia. As with statins, niacin and fibric acid derivatives are associated with a risk of elevations in transaminase levels, as well as with infrequent hepatitis and rare myositis. Although the manufacturers of these drugs recommend routine laboratory evaluation of liver function, routine monitoring was shown to have a low yield in a primary care practice.94
Reduction of non-LDL cholesterol lipid fractions may also reduce cardiovascular risk, particularly in patients who have the metabolic syndrome. Although definitions vary, the metabolic syndrome is a constellation of cardiovascular risk factors, including insulin resistance, obesity, hypertension, and dyslipidemia.95 The dyslipidemia characteristic of the metabolic syndrome consists of elevated triglycerides, a low HDL cholesterol level, and a normal (or near-normal) LDL cholesterol level. Retrospective analysis of the VA-HIT, which studied patients with established coronary disease and low HDL cholesterol levels, suggested that the benefits of treatment with gemfibrozil are most pronounced in patients with insulin resistance (whose fasting plasma insulin levels were comparable to those found in patients with the metabolic syndrome).96 Because patients with the metabolic syndrome have elevated cardiovascular risk despite often having unremarkable LDL cholesterol levels, NCEP ATP III recommends measuring non-HDL cholesterol in patients with elevated triglyceride levels (i.e., triglyceride levels ≥ 200 mg/dl or 2.25 mmol/L) through use of the following formula:
The level of non-HDL cholesterol determined by this formula corresponds to the sum of LDL cholesterol and atherogenic remnant lipoproteins containing apolipoprotein B (very low density lipoprotein cholesterol). Among patients with hypertriglyceridemia, the target level for non-HDL cholesterol is less than 130 mg/dl for patients with IHD or IHD equivalent conditions, as well as for patients with two or more cardiovascular risk factors and a 10-year risk of cardiovascular events greater than 20%, as determined by the Framingham risk estimates [see Figure 2].30
In summary, numerous studies demonstrate that patients with IHD benefit from treatment with statins; this includes IHD patients with relatively normal LDL cholesterol levels. The vast majority of patients with chronic stable angina should be treated with a statin. Treatment with niacin or fibric acid derivatives should be considered in patients with a low HDL cholesterol level or an elevated triglyceride level. In view of the consistent benefits of statins across many patient subsets, it would be most reasonable to consider adding niacin or fibric acid derivatives to statin therapy.
Antihypertensive Therapy
Hypertension contributes to cardiovascular risk by increasing myocardial wall stress, oxygen demand, and endothelial injury. Treatment of hypertension in patients with IHD reduces the risk of future cardiovascular events.97 A reduction in systolic blood pressure of 2 mm Hg is associated with a 7% reduction in mortality from IHD.98 By lowering myocardial oxygen demand, treatment of hypertension may also improve anginal symptoms. The therapeutic target for patients with IHD is to maintain blood pressure at levels below 140/90 mm Hg.99
Two groups of patients with hypertension and chronic stable angina warrant particular consideration: patients with specific coexisting chronic conditions (e.g., diabetes, heart failure, or renal insufficiency) and patients with LVH. Guidelines from the Joint National Committee for the Diagnosis, Evaluation, and Treatment of Hypertension (JNC) recommend a lower therapeutic target blood pressure for hypertensive patients who have diabetes, heart failure, or renal insufficiency—namely, a level below 130/85 mm Hg.99 Although no specific target has been promulgated for therapy for hypertension and LVH, the latter is a marker for the severity and chronicity of hypertension and is a risk factor for MI, CHF, and cardiac sudden death.100 Treatment of hypertension results in the regression of LVH; ECG evidence of LVH regression is associated with a significantly reduced risk of cardiovascular events.101 Patients with LVH should therefore be targeted for aggressive antihypertensive therapy.
Two classes of antihypertensives—beta-adrenergic receptor antagonists (i.e., beta blockers) and calcium channel blockers—are also effective antianginal medications. Beta blockers confer mortality benefit in patients after MI102 and are recommended as first-line therapy for most patients with chronic stable angina.32 Calcium channel blockers (e.g., diltiazem, verapamil, and long-acting dihydropyridines) are also effective antihypertensive and antianginal medications. Current ACC/AHA/ACP guidelines recommend beta blockers as first-line antihypertensive therapy in patients with chronic stable angina. Long-acting calcium channel blockers are an acceptable alternative, particularly in patients without a history of MI.102
ACE Inhibitors
Results of the Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that ACE inhibitors reduced MI, stroke, and cardiovascular death in patients at high cardiovascular risk. In this study, patients with a history of IHD, diabetes, stroke, or peripheral vascular disease and at least one additional cardiovascular risk factor (e.g., hypertension, dyslipidemia, cigarette smoking, or microalbuminuria) were randomized to receive either ramipril (10 mg daily) or placebo; patients were followed for an average of 4 years. Total mortality was reduced 1.8% in the ramipril-treated group; in terms of numbers needed to treat (NNT), this means that 56 patients would need to be treated for 4 years to prevent one death. The primary outcome of MI, stroke, or cardiovascular death was reduced by 3.8% (NNT of 26). This study indicated that a broad range of patients at high risk for IHD who had normal left ventricular function obtained an impressive survival benefit from the use of ACE inhibitors. The magnitude of benefit was greater than might have been expected for the small decrement in average blood pressure observed in the study, suggesting a mechanism at work other than reduction in blood pressure.103 In the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), patients with stable coronary disease and no known congestive heart failure or uncontrolled hypertension were randomized to receive either the ACE inhibitor perindopril or placebo.104 Combined cardiovascular end points were significantly reduced in the perindopril group; in addition, there was a nonsignificant reduction in total mortality. On the basis of the HOPE and EUROPA trials, it can be concluded that most patients with chronic stable angina should be treated with an ACE inhibitor, barring renal insufficiency, hyperkalemia, or an allergy to ACE inhibitors. Angiotensin receptor blockers may offer a similar benefit, but these agents have not been extensively studied in this regard.
MEDICAL THERAPY FOR ANGINAL SYMPTOMS
The major classes of medications for the treatment of angina include beta blockers, calcium channel blockers, and nitroglycerin/nitrates. Randomized trials demonstrate that beta blockers and calcium channel blockers are equally effective in relieving angina and improving exercise tolerance.105,106 Current guidelines, however, recommend beta blockers as first-line therapy32,33 because they improve survival and reduce cardiac events in patients who have had a previous acute MI107 and in elderly patients with systolic hypertension108; no similar benefits have been demonstrated for calcium channel blockers or nitrates. In addition, beta blockers improve survival and reduce the risk of stroke and congestive heart failure in patients with hypertension.109 Beta blockers should be considered as initial antianginal therapy in patients with chronic stable angina.
Beta Blockers
Beta blockers decrease heart rate, myocardial contractility, blood pressure, and myocardial oxygen demand by inhibiting cardiac and peripheral beta-adrenergic receptors. Beta blockers delay the onset of angina and increase exercise capacity in patients with exertional angina.110,111 They are titrated to a dose adequate to reduce the resting heart rate to 55 to 60 beats/min. Titration to lower heart rates may be necessary in patients with more severe angina, provided patients do not develop heart block or symptoms of severe bradycardia.
Beta blockers are generally well tolerated by patients with chronic obstructive pulmonary disease; however, they may exacerbate bronchospasm in patients with severe asthma. Beta blockers are well tolerated in patients with diabetes, and in these patients, they can reduce macrovascular events112; theoretically, however, beta blockers can mask the adrenergically mediated symptoms of hypoglycemia insulin (e.g., tachycardia).
Beta blockers are contraindicated in the presence of severe bradycardia, high-degree atrioventricular block, sinus node dysfunction, and uncompensated congestive heart failure. Patients with extensive peripheral vascular disease and claudication may experience worsening of their symptoms. Beta blockers are also contraindicated in the small subset of patients with pure variant or vasospastic angina (i.e., angina occurring in the absence of fixed obstruction of the coronary arteries), in whom beta blockade is unlikely to alleviate symptoms. In these patients, beta blockers may actually worsen angina as a result of unopposed alpha-adrenergic effects. Calcium channel blockers are the preferred first-line agent in this patient group [see Calcium Channel Blockers, below].
Calcium Channel Blockers
Calcium channel blockers reduce smooth muscle tone and cause coronary and peripheral vasodilatation, improving coronary blood flow and reducing peripheral vascular resistance. Calcium channel blockers can be used as monotherapy in the treatment of chronic stable angina, although combinations of beta blockers and calcium channel blockers relieve angina more effectively than either agent alone. Combination therapy with a beta blocker may blunt the reflex tachycardia that can occur with dihydropyridine calcium channel antagonists. All calcium channel blockers exert some negative inotropic effect, although this effect is typically most significant clinically with the nondihydropyridine agents verapamil and diltiazem. Calcium channel blockers are contraindicated in the presence of decompensated congestive heart failure, although the vasoselective dihydropyridine agents amlodipine and felodipine are tolerated in patients with clinically stable LV dysfunction.113Verapamil and diltiazem have a pronounced effect on heart rate and conduction; they should be used with caution in combination with beta blockers because of the increased risk of heart block associated with the combined use of these agents. Constipation and peripheral edema are common side effects of calcium channel blockers.
Nitrates and Nitroglycerin
Nitrates and nitroglycerin dilate coronary arteries and their collateral vessels, directly improve myocardial perfusion, diminish afterload, and increase venous capacitance. These agents exert antianginal effects by improving coronary blood flow and by reducing myocardial oxygen demand. Long-acting nitrate preparations, in tablet or patch form, reduce the severity and frequency of angina and improve exercise tolerance; however, they often induce a reflexive increase in sympathetic tone and increase heart rate. Therefore, long-acting nitrates are often used in combination with beta blockers or calcium channel blockers. Short-acting nitroglycerin tablets or spray is appropriate for the immediate relief of exercise-induced or rest angina. They may also prevent angina when taken several minutes before exertion sufficient to cause angina.
Nitroglycerin and nitrates should not be used within 24 hours of taking sildenafil (Viagra) or other phosphodiesterase inhibitors used in the treatment of erectile dysfunction, because of the potential for life-threatening hypotension.114 It is important to discuss this interaction with patients taking nitrates or sildenafil. Nitroglycerin and nitrates are relatively contraindicated in patients with severe aortic stenosis or hypertrophic obstructive cardiomyopathy because of an increased risk of syncope resulting from diminished cardiac output. Continued use of long-acting nitrates results in tachyphylaxis; the mechanism of this is unclear. An adequate nitrate-free period (8 to 12 hours each day) is necessary to minimize this effect. Headaches are common and often limit nitroglycerin and nitrate therapy; with continued use, headaches will diminish in up to 80% of patients. Hypotension may occur, particularly in hypovolemic patients.
In general, patients who are found to be at low or moderate risk for cardiovascular complications during risk stratification should be treated aggressively with medical therapy. Medical therapy should not be considered to have failed until the patient has been treated with full therapeutic doses of a beta blocker, a calcium channel blocker, and a long-acting nitrate and continues to experience angina or develops unacceptable adverse effects.
PATIENTS WITH DIABETES MELLITUS
IHD therapy for patients with diabetes merits special consideration. Cardiovascular events are the leading cause of death in patients with diabetes, and this patient group is at particularly high risk for MI. Middle-aged persons with diabetes and no history of MI have a risk of MI and cardiac death equivalent to that of nondiabetic patients with a history of MI.115 A substudy of the Heart Protection Study demonstrated that treatment with statins reduced major coronary and major vascular events, even among diabetic patients without a prior diagnosis of ischemic heart disease and among diabetic patients with LDL cholesterol levels lower than 116 mg/dl (3 mmol/L).116 Treatment with statins resulted in a relative risk reduction for major coronary events (nonfatal MI and coronary death [27%]), stroke (25%), and first revascularization procedures (17%). A HOPE substudy demonstrated the benefits of ACE inhibitors in patients with diabetes and one or more cardiovascular risk factors.117 Treatment with an ACE inhibitor resulted in a 25% reduction in MI, stroke, or cardiovascular death. Total mortality was reduced 24%; progression to overt nephropathy was reduced by 24%. In the United Kingdom Prospective Diabetes Study, beta blockers were found to be equivalent to ACE inhibitors in reducing the risk of macrovascular complications.112 Another study found that cardiovascular events were more common in patients with type 2 diabetes mellitus and hypertension who were randomized to receive a dihydropyridine calcium channel blocker, as compared with patients who received an ACE inhibitor.118 It remains uncertain whether to attribute this result to a higher risk of cardiovascular events among the group taking the calcium channel blocker amlodipine or to a reduced risk of cardiovascular events among the group taking the ACE inhibitor fosinopril. Nevertheless, most experts consider calcium channel blockers to be third-line agents for patients with diabetes and hypertension. Results of the Hypertension Optimal Treatment (HOT) study support aggressive blood pressure reduction in patients with diabetes; the target blood pressure for these patients is 135/80 mm Hg or lower.119
Although it remains uncertain when to initiate antiplatelet therapy in diabetic patients, it is reasonable to treat diabetic patients who have any additional cardiovascular risk factor with aspirin or an equivalent antiplatelet therapy.120 The American Diabetes Association and the NCEP recommend a target LDL cholesterol level of 100 mg/dl (2.59 mmol/L) or lower.31,121
REVASCULARIZATION
Techniques for revascularization include PCI, using catheter-based methods with or without placement of intracoronary stents, and CABG. For most patients with angina, survival with optimal medical therapy is equivalent to that resulting from revascularization; in addition, CABG results in excellent symptom relief. For a select few patients with chronic stable angina, revascularization is associated with improved survival, as compared with that achieved with medical therapy.122 Among 2,649 patients with left main coronary stenoses or multivessel coronary artery disease and reduced LV systolic function, those who were treated with CABG in randomized trials had an absolute mortality at 5 years that was more than 5% lower than that of patients assigned to medical management (10.2% versus 15.8%).123 This benefit persisted at 10 years' follow-up. There is much weaker evidence to suggest that patients with proximal stenoses of the left anterior descending coronary artery and normal LV function also experience lower mortality with CABG. One randomized trial showed no difference in mortality among patients assigned to CABG, PCI, or medical management.124 In two trials comparing CABG with PCI, survival was equivalent; however, the patients who underwent surgery had fewer symptoms and required fewer antianginal medications and subsequent revascularization procedures.125,126 Initial costs and short-term (procedure-related) mortality were higher in patients who underwent CABG. Most of the patients enrolled had two-vessel CAD and normal LV systolic function. In one study, survival was improved in patients with diabetes who underwent CABG, as compared with patients who underwent PCI.125
Randomized trials comparing PCI with medical management in patients with one- or two-vessel CAD and normal LV systolic function have demonstrated equivalent survival.127,128 Relief of symptoms was generally greater with PCI than that seen with medical therapy, although PCI was associated with an increased risk of procedure-related MI and death127,128 and substantially greater cost.129
On the basis of a limited number of randomized trials, it appears that only the subgroup of patients with severe coronary disease (defined as two- or three-vessel disease) and impaired LV function can confidently expect improved average survival after revascularization and that improvement is seen only with CABG. Thus, evaluation for revascularization is generally recommended for patients who are at moderate or high risk of death and who are willing to undergo a revascularization procedure.32 Patients meeting these criteria who are found to have either extensive areas of ischemia on noninvasive testing or reduced LV systolic function should then be considered candidates for angiography. It should be recognized, however, that the results of currently available studies comparing PCI, CABG, and medical therapy do not reflect recent advancements in all three forms of treatment. For example, restenosis rates with PCI using stents, drug-eluting stents, and platelet inhibitors are lower than previously reported rates with angioplasty techniques.
In general, medical therapy is preferred in patients who are determined through risk stratification by noninvasive testing to be at low risk for death. There is no evidence that revascularization improves survival in such patients. For this reason, currently available evidence suggests that many revascularization procedures conducted in the United States may not be warranted.
COMPLICATIONS
Chronic stable angina, as the name suggests, is a long-standing stable or progressive condition caused, in most instances, by atherosclerotic narrowing of the coronary vessels. Coronary atherosclerosis, however, is a risk factor for acute coronary syndromes, including MI and sudden cardiac death. Much of the diagnostic evaluation of patients with chronic stable angina is undertaken to determine the intermediate-term risk of acute coronary events. Much of the treatment of patients with chronic stable angina is intended to reduce the risk of acute coronary complications, principally MI and sudden cardiac death. Another major complication of chronic stable angina is CHF. Major causes of CHF include MI and hypertension—common conditions in patients with IHD.130 Finally, patients with IHD are at risk for other vascular diseases, namely stroke and peripheral vascular disease.
It is also important to consider complications of conditions that predispose patients to IHD. For example, diabetes is a major risk factor for IHD and is often complicated by peripheral vascular disease, renal insufficiency, neuropathy, and retinopathy. In addition to increasing the risk of IHD, cigarette smoking confers a significant risk of chronic pulmonary disease, cancer, and peripheral vascular disease.
FOLLOW-UP
Patients with chronic stable angina should be regularly followed in a primary care setting. There is little evidence to recommend a particular frequency of follow-up visits, although ACC/AHA/ACP guidelines suggest regular visits at 4- to 12-month intervals for patients with chronic stable angina.21 The expert panel recommends addressing the following questions at each visit21:
It is important to inquire about changes in anginal symptoms or activity levels to identify patients who require increased intensity of antianginal therapy or further risk stratification. For example, it would be reasonable to repeat noninvasive testing in a patient with stable class II angina who developed new class III anginal symptoms since the last clinic visit. Similarly, in a patient with new symptoms of CHF, it would be appropriate to perform echocardiography and consider referral for coronary angiography; multiple-vessel CAD with reduced left ventricular function would be an indication for CABG.
Medical therapy should be reviewed at each visit to assess adherence to recommended therapy, knowledge about doses and indications, and potential side effects. In addition, it is worth considering whether recent evidence for benefit from new therapies or new indications for existing therapies support a modification of IHD management. Patients with chronic stable angina should be encouraged to quit smoking, to eat a prudent diet, and to regularly engage in moderate exercise. Successful adoption of these interventions is challenging, but repeated encouragement from a personal physician enhances success.131
Vital signs (i.e., heart rate, blood pressure, and weight) should be regularly followed. The physical examination is focused on the heart, lungs, and vasculature. Findings of particular note include signs of CHF, new or changing heart murmurs, arrhythmias, or evidence of carotid or peripheral vascular disease.
Laboratory assessment should include periodic measurements of fasting lipid levels. Regular measurements of liver transaminase and CK levels are not recommended in the absence of symptoms. Other laboratory testing is indicated by comorbid conditions or changes in the patient's history and physical examination.
There is no evidence showing that regular ECG studies are helpful in the management of patients with chronic stable angina in the absence of changes in history or physical examination. ECGs are indicated when new medications are introduced that may affect cardiac conduction. Changes in anginal or syncopal symptoms and findings suggestive of dysrhythmia or conduction abnormalities should also prompt a repeat ECG.
There is little evidence to guide the use of repeat stress testing in patients with chronic stable angina. Recommendations for follow-up stress testing vary according to initial assessments of a patient's cardiovascular risk.21 For example, patients with class II angina whose exercise treadmill test places them at low risk have an annual risk of mortality of less than 1%; these patients do not require follow-up stress testing for a period of 3 to 4 years in the absence of new and concerning symptoms or signs. Similarly, patients who underwent PCI more than 6 months earlier and who have minimal residual stenosis are unlikely to benefit from regular stress testing. It is not known whether patients at intermediate or high cardiovascular risk benefit from periodic stress testing.
Follow-up noninvasive tests are selected according to the approach outlined (see above). When possible, the same form of stress (exercise or pharmacologic) and testing (ECG or imaging) should be repeated, because this permits the most valid comparison with the original study.21
Patients should be referred to a cardiologist when appropriate for consideration of revascularization. Candidates for referral include patients with valvular disorders that require repair, patients with angina that is refractory to maximal medical therapy, and patients with comorbidities that complicate therapy.
References
Editors: Dale, David C.; Federman, Daniel D.