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Department of
Cardiovascular
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DEFINITION

Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

Outcomes

References

Coronary artery disease is characterized by the presence of atherosclerosis in the epicardial coronary arteries. Atherosclerotic plaques, the hallmark of atherosclerosis, progressively narrow the coronary artery lumen and impair antegrade myocardial blood flow. The reduction in coronary artery flow may be symptomatic or asymptomatic, may occur with exertion or at rest, and may culminate in a myocardial infarction, depending on obstruction severity and the rapidity of development.

This chapter addresses the initial evaluation of patients with suspected coronary artery disease and the management of patients who have established coronary artery disease.

Cardiovascular disease is the leading cause of mortality in the United States among both men and women in every major ethnic group. It accounts for nearly 1 million deaths per year and was responsible for one in five deaths in the United States in 2001.

Approximately 6 million men have a history of a myocardial infarction, angina pectoris, or both. Coronary artery disease is the most common form of cardiovascular disease. In 2001, the death rate from coronary artery disease was 228 per 100,000 white men, 262 per 100,000 black men, 137 per 100,000 white women, and 177 per 100,000 black women. The estimated prevalence of coronary artery disease in men is 6.9%; among women the prevalence is 6.0% (http://www.americanheart.org/statistics/
biostats/index.html).¹

Coronary artery disease is a chronic process that begins during adolescence and slowly progresses throughout life. Independent risk factors include a family history of premature coronary artery disease, cigarette smoking, diabetes mellitus, hypertension, hyperlipidemia, a sedentary lifestyle, and obesity. These risk factors accelerate or modify a complex and chronic inflammatory process that ultimately manifests as fibrous atherosclerotic plaque.

The most widely accepted theory of atherosclerosis holds that the process represents an attempt at healing in response to endothelial injury. The first step in the atherosclerotic process is the development of fatty streaks, which contain atherogenic lipoproteins and macrophage foam cells. These streaks form between the endothelium and the internal elastic lamina. Over time, an intermediate lesion made up of an extracellular lipid core and layers of smooth muscle and connective tissue matrix eventually forms a fibrous cap. The edge of the fibrous cap (the "shoulder" region) plays a critical role in the development of acute coronary syndromes. The shoulder region is the site where most plaques lose their integrity or rupture. Plaque rupture exposes the underlying thrombogenic core of lipid and necrotic material to circulating blood. This exposure results in platelet adherence, aggregation, and progressive luminal narrowing that are associated with acute coronary syndromes (for a detailed description of atherosclerotic plaque, see circ.ahajournals.org/cgi/content/full/92/5/1355).

Inflammation is emerging as a critical component of atherosclerosis genesis, activity, and potential plaque instability. Those patients with established coronary artery disease who possess a confluence of risk factors, the so-called metabolic syndrome, remain at particularly high risk for a future vascular event, such as an acute myocardial infarction and cerebrovascular accident. Biochemical markers such as elevated levels of C-reactive protein signal a higher likelihood of vascular inflammation and portend a higher risk of vascular events such as myocardial infarctions and cerebrovascular accidents. This marker may also signal more rapidly advancing coronary artery disease and the need for aggressive preventive measures.

Patients with coronary artery disease present with stable angina pectoris, unstable angina pectoris, or a myocardial infarction. A patient may seek medical attention with their first symptomatic episode of chest discomfort. Many of these patients possess unbeknownst coronary artery disease and suffer an acute plaque rupture and consequent myocardial infarction. Electrical instability may ensue, including potentially lethal cardiac dysrhythmias. Identifying high-risk individuals prior to their first myocardial event is a multifaceted process that involves both patient and physician education efforts. Screening for coronary artery disease is not sufficient. Risk factor modification, starting at an early age, starts the primary prevention efforts in motion, forestalling the development of symptomatic coronary artery disease. Severe coronary artery disease can be detected before a patient develops symptoms.

Angina pectoris is a perceived symptom resulting from a mismatch of myocardial supply and demand. The compromised myocardial blood flow due to obstructive coronary artery disease is not able to meet the metabolic demands of the myocardial tissue. The anaerobic threshold is crossed and the patient develops symptomatic angina pectoris. Angina pectoris typically initially occurs with exertion or emotional stress, and it subsides within a few minutes with rest or after a coronary artery vasodilator such as sublingual nitroglycerin is administered. It is often predictable, such as when walking up one flight of stairs or taking out the trash on a cold morning. The activity exceeds the anaerobic threshold, whereas rest and/or nitroglycerin sublingually restore aerobic metabolism.

Angina pectoris is most typically described as an uncomfortable sensation such as pressure, tightness, heaviness, burning, squeezing, or choking in the retrosternal area. The sensation can radiate to the neck, arms, back, or epigastrium. It can also be accompanied by nausea, shortness of breath, diaphoresis, or palpitations. Some patients who do not report typical chest discomfort instead describe what is termed an "angina equivalent." The most common angina equivalent is dyspnea; others include discomfort in the jaw, neck, shoulder, arm, epigastrium, or upper back, devoid of any sensation in the chest.

When eliciting the history from a patient, it is important to ask open-ended questions initially. An appropriate line of questioning may include the following:

1. Do you experience any odd feelings in your chest?
   Do you experience chest discomfort, pressure, squeezing, or burning?Do you experience chest pain?Do you experience discomfort or pain in your throat, neck jaw, teeth, or arms?
2. Do you experience undue shortness of breath or fatigue with activity?

Many patients will answer "no" if they are queried solely regarding the presence or absence of chest pain. Chest discomfort is a more all-encompassing question that includes typical angina symptoms coupled with chest pain. It is best to start with a broad line of questioning and then hone in if at first you are not successful.

Angina pectoris is typically categorized according to the Canadian Cardiovascular Society's functional classification system (Table 1).

Stable Angina
Angina pectoris is said to be stable when the pattern of its frequency, intensity, ease of provocation, or duration does not change over a several-week period. Identification of activities that provoke angina and the amount of sublingual nitroglycerin required to relieve symptoms are helpful indicators of stability. A decrease in exercise tolerance or an increase in the need for nitroglycerin suggests that the angina is progressing in severity or is accelerating.

Accelerating Angina
Angina pectoris is said to be accelerating when there is a change in the pattern of stable angina. This may include a greater ease of provocation, more prolonged episodes, and episodes of greater severity, requiring a longer recovery period or more frequent use of sublingual nitroglycerin.

Unstable Angina
Unstable angina pectoris occurs when the pattern of chest pain changes abruptly. Signs of unstable angina are pains at rest, a marked increase in the frequency of attacks, discomfort that occurs with minimal activity, and new-onset angina of incapacitating severity. Unstable angina usually is related to the rupture of an atherosclerotic plaque and the abrupt narrowing or occlusion of a coronary artery, representing a medical emergency.

The initial diagnostic approach for coronary artery disease encompasses a detailed patient history, a complete physical examination, and an electrocardiogram. Once the initial evaluation is performed, laboratory blood tests, stress testing, and a cardiac catheterization may be necessary to obtain further diagnostic insight. The American College of Cardiology (ACC), the American Heart Association (AHA), and the American College of Physicians-American Society of Internal Medicine (ACP-ASIM) have published a position paper on the diagnosis and risk stratification of patients with chronic stable angina pectoris (http://www.annals.org/
issues/v135n7/full/200110020-00014.html).²

History:

The history should include any current symptoms, a complete inventory of co-morbid conditions including cardiac risk factors, and a complete family history. Furthermore, the history should include information about the character and location of discomfort, discomfort radiation, associated symptoms, and precipitating, exacerbating, or alleviating factors. Other important features of the history are the patient's estimate of functional capacity and the presence of additional coronary artery disease risk factors. It is particularly pertinent to establish the presence or absence of coronary artery disease and/or systemic atherosclerosis in any first-degree relative at an age of 55 years or less.

Physical Examination:

The physical examination provides a window of opportunity for the astute clinician. The results of the physical examination of a patient with stable or unstable angina may be entirely normal. Nonetheless, it is important to examine the patient closely for coronary artery disease risk factors and other findings associated with coronary artery disease. The presence of multiple risk factors or atherosclerosis in the carotid or peripheral arteries increases the likelihood that a chest pain syndrome is related to myocardial ischemia. Evaluation should include measurements of blood pressure and the ankle-brachial index,³ and screening for hyperlipidemia and diabetes mellitus. Examination of the carotid arteries should evaluate upstrokes and auscultation for bruits. Examination of the chest wall, neck, and shoulders for deformities and tenderness may be helpful in diagnosing musculoskeletal chest discomfort. Cardiac auscultation may detect murmurs due to aortic stenosis or hypertrophic cardiomyopathy, either of which can cause angina in the absence of coronary artery disease. Assessment of the abdominal aorta for an aneurysm or bruits along with palpation of lower-extremity pulses is necessary to rule out peripheral vascular disease. Careful palpation of all peripheral pulses and assessment of symmetry versus diminution is also a valuable noninvasive approach for assessing the integrity of the arterial circulation. Finally, examination for xanthelasmas, tendon xanthomas, retinal arterial abnormalities, and peripheral neuropathy can be helpful.

Electrocardiogram:

A resting 12-lead electrocardiogram should be performed on all patients with suspected coronary artery disease. Electrocardiographic results are normal in approximately 50% of patients with chronic stable angina,⁴ and can remain normal during an episode of chest discomfort. Importantly, a normal electrocardiogram does not exclude coronary artery disease. The presence of left ventricular hypertrophy, ST-segment changes, T-wave changes, and conduction abnormalities such as complete left bundle branch block increases the likelihood of coronary artery disease. The appearance of diagnostic Q waves in two contiguous electrocardiogram leads greatly increases the probability of coronary artery disease. Arrhythmias also raise the likelihood of coronary artery disease, although atrial fibrillation and flutter are less specific findings and are associated with nonischemic cardiovascular conditions. The electrocardiogram roughly reflects the coronary artery distributions. The right coronary artery is best reflected in leads II, III, and aVF. The left anterior descending coronary artery is most typically reflected in leads V₁ through V₆. Leads I and aVL best represent the left circumflex coronary artery. Anatomic variants including a dominant left circumflex coronary artery and a diminutive right coronary artery display variations to this general scheme. The left circumflex coronary artery territory is the most under-represented coronary artery on the electrocardiogram. An infarction in this territory often demonstrates, at most, subtle ST-T changes, many times devoid of diagnostic Q waves. In a non-ST segment elevation myocardial infarction, patients often will not develop Q waves but instead have alterations in the ST segments and T waves and a reduction in QRS complex amplitude.

Imaging Studies:

Chest Radiograph
The utility of a routine chest radiograph in a patient with chest discomfort has not been established, but it is generally accepted as part of an initial evaluation for coronary artery disease. Calcification of the aortic knob is a common finding in older patients and is a nonspecific indicator of flow-limiting obstructive coronary disease. Infrequently, coronary calcification is present. This establishes the diagnosis of coronary atherosclerosis but does not quantify severity. A chest radiograph can detect findings of congestive heart failure, valvular heart disease, pericardial disease, or aortic aneurysm, some of which may be markers of underlying coronary artery disease.

Ultrafast Electron-beam Computed Tomography
This scan is used to detect coronary calcium, which is associated with coronary artery disease. The specificity of this test is approximately 70% as many scans are false positives.⁵ For this reason, its utility as a screening test for coronary artery disease is controversial. In many respects, this test is most helpful when negative. A negligible coronary calcium score places a patient in a low-risk category for the presence of significant flow-limiting coronary artery disease. A high score establishes the diagnosis but does not provide functionally significant data as to the presence or absence of flow-limiting obstructions. Also, coronary calcium screening may underestimate plaque burden, not detecting so-called soft plaque. Therefore, its use as a screening test is not widely accepted or endorsed.

Echocardiography
Echocardiography is recommended for patients with stable angina and physical findings suggesting concomitant valvular heart disease. It is invaluable for assessing the patient with suspected hypertrophic cardiomyopathy. It is also recommended for the assessment of global and regional left ventricular systolic function in patients who have Q waves on an electrocardiogram, congestive heart failure, complex ventricular arrhythmias, or a history of a past myocardial infarction. Echocardiography also readily assesses the pericardial space, is of no known harm or discomfort, and is readily portable.

Laboratory Studies:

Routine laboratory measurements recommended as a part of the initial evaluation of patients with chronic stable angina should include a serum hemoglobin, fasting glucose, and fasting lipids (total cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, and calculated low-density lipoprotein [LDL] cholesterol). Other markers, such as plasma homocysteine, lipoprotein (a) [Lp(a)], and high-sensitivity C-reactive protein, may be useful in assessing cardiac risk. High-sensitivity C-reactive protein is gaining greater prominence in assessing the inflammatory level of vascular disease and also in predicting future risk of vascular events such as myocardial infarctions and cerebrovascular accidents. It is thought to be the best available surrogate marker of vascular inflammation. Its value can be used to guide both the initiation and intensity of treatment to include better food choices, weight reduction, regular exercise programs, and HMG CoA reductase inhibitor medication commencement and titration.

Once all the foregoing initial evaluations are complete, it is possible to estimate a patient's probability of existing coronary artery disease prior to proceeding with stress testing or coronary angiography (Table 2).

Stress Testing:

Stress testing is a means of further assessing for the presence of flow-limiting, functionally significant coronary artery disease. All stress testing techniques include electrocardiogram and blood pressure monitoring. The American Heart Association has posted a complete review of the indications for exercise stress testing.

The absolute and relative contraindications to exercise stress testing are outlined in Table 3.

Cardiovascular stress testing takes two forms—exercise and pharmacologic administration. The preferred method of cardiovascular stress testing is exercise, utilizing a treadmill or bicycle. Through aerobic exercise, one achieves a greater rate pressure product (the multiplicative of peak systolic blood pressure and peak pulse rate) and therefore greater cardiovascular stress. This permits an assessment of an individual's functional capacity, providing prognostic data utilizing the sole parameter of attained metabolic equivalents or oxygen utilization. Heart rate recovery, the rapidity of the heart rate to decline after exercise cessation, is also an important prognostic parameter. In addition to these variables, the electrocardiogram and specifically the ST segments are carefully analyzed. Unlike pharmacologic data where ST-segment shifts are circumspect, the exercise electrocardiogram is a powerful adjunct and corroborator of abnormal cardiac imaging findings. Exercise-induced arrhythmias are also commonly observed and provide information concerning efficacy of heart dysrhythmia treatment and also may represent the initial manifestation of occult coronary obstructive disease.

The most common pharmacologic agents used for non-exercise stress testing are dobutamine, dipyridamole, and adenosine. Dobutamine is both a beta-receptor 1 and beta-receptor 2 agonist, increasing myocardial contractility, heart rate, and inducing peripheral vasodilation, in sum raising myocardial oxygen demand. It is usually combined with echocardiography, but it can be combined with radionuclide imaging. Dobutamine echocardiography is useful in assessing for the presence of functionally significant obstructive coronary artery disease and also in assessing a post-myocardial infarction patient. Utilizing echocardiography, be it combined with exercise or dobutamine, the physician interpreter is focusing upon the global and regional endocardial response to cardiovascular stress. Under normal circumstances, the end systolic left ventricular volume at peak stress diminishes and endocardial thickening is symmetrically enhanced. When abnormal, a regional decrement of endocardial thickening is observed, supporting inducible myocardial ischemia. In the presence of advanced multivessel coronary artery disease, the left ventricle actually dilates and a marked reduction in global endocardial thickening is observed.

Dobutamine echocardiography is additionally useful for the assessment of myocardial viability in patients with known ischemic left ventricular systolic dysfunction. In this circumstance, when contemplating myocardial revascularization, it is important to determine, pre-procedure, what areas are dysfunctional yet alive versus dysfunctional with irreversible scarring. The key is the so-called biphasic response to dobutamine infusion. When a biphasic response is present, augmentation of endocardial thickening is observed at low-dose dobutamine infusion (5 to 10 µg/kg/min), with a deterioration of endocardial thickening at high-dose infusion (20 to 40 µg/kg/min). The enhanced low-dose response is felt to represent myocardial viability, serving as a positive correlate for sustained left ventricular systolic functional improvement post-revascularization. The decrement in function at high dose reflects myocardial ischemia in the presence of a flow-limiting coronary artery obstruction. This biphasic response is both sensitive and specific for identifying myocardial viability and ischemia. Dobutamine echocardiography can also be safely performed within a few days of an acute myocardial infarction, provided the patient is clinically stable and devoid of symptoms of post-infarction angina, decompensated congestive heart failure, or recurrent dysrhythmias.

Assessing a patient soon after a myocardial infarction serves two purposes. First, the myocardial infarction zones may be transiently dysfunctional, known as myocardial stunning, and demonstrate improved systolic function should a biphasic response to dobutamine be observed. This would support an invasive approach and myocardial revascularization. Second, patients with a myocardial infarction may possess occult coronary artery obstructions in a territory distant from the infarction zone. In patients where a cardiac catheterization is being contemplated, a positive dobutamine echocardiogram for inducible myocardial ischemia removed from the infarct zone often solidifies an invasive approach with coronary arteriography. This is termed "ischemia at a distance."

Nuclear stress testing is an equally important modality for assessing the coronary circulation. Unlike stress echocardiography, where the endocardial thickening response to cardiovascular stress is the marker for inducible myocardial ischemia, nuclear stress testing relies on the concept of coronary flow reserve and differential myocardial blood flow. In the presence of exercise or the administration of a pharmacologic coronary vasodilator, the normal response is hyperemia with a significant increase in myocardial blood flow. If there is no coronary obstructive disease, the pattern of hyperemia and blood flow is reflected as a symmetric increase, with a homogeneous distribution of the blood flow tracer. In the presence of a severe coronary artery stenosis, dipyridamole or adenosine induce coronary macro- and microvascular vasodilation, which results in differential myocardial blood flow that can be detected by radionuclide imaging with thallium-201 or technetium (Tc) 99m-labeled radiopharmaceuticals (Tc 99m sestamibi or Tc 99m tetrofosmin). On nuclear perfusion imaging, functionally significant coronary artery disease is suspected when an area of relative hypoperfusion is detected on peak-stress images when compared with the resting images. Resting nuclear cardiac imaging may also be abnormal. These abnormalities reflect a chronic low blood flow state to the abnormal region of myocardium. This may represent either a chronic low blood flow state to dysfunctional yet viable myocardium versus a completed infarction and non-viable myocardial tissue, best termed myocardial "scar." Admixtures of both findings may occur, including viable and scarred myocardial tissue, supporting the presence of an incomplete infarction and/or ischemic border zone areas in a chronic low blood flow state.

Adding imaging to the electrocardiographic stress test adds approximately 15 percentage points to both the sensitivity and specificity. In certain circumstances, electrocardiographic stress testing is of borderline help, particularly in the presence of an abnormal resting electrocardiogram (Table 4).

Cardiac stress imaging is useful for determining the extent, severity, and location of ischemia. The exercise portion of the test also provides prognostic information. Among the prognostic markers are the Duke treadmill score,⁶ the heart-rate recovery (HRR) score,⁷ and the chronotropic response index (CRI).⁸ The Duke treadmill scoring system is summarized in Table 5.

The Duke treadmill score is calculated according to the following formula: the exercise time in minutes minus five times the maximal ST-segment deviation in mm (during or after exercise) minus the angina score (0 if there is no angina, 4 if angina occurs, and 8 if angina is the reason for stopping the test).

The HRR score is calculated according to the following formula: the heart rate in beats per minute (bpm) at peak exercise minus the heart rate at 1 minute postexercise. A normal HRR score (>12 bpm) is associated with a low risk of death, while a low HRR score (<8 bpm) is associated with a high risk. HRR scores from 8 bpm through 12 bpm indicate an intermediate risk. The CRI is calculated according to the following formula: the peak heart rate in bpm minus the resting heart rate divided by ([220 minus patient's age] minus resting heart rate). A normal CRI (>0.8) is associated with a decreased probability of coronary artery disease and a lower risk of death. A low CRI (<0.8) in a patient who is not on beta-blocker therapy is associated with an increased likelihood of coronary artery disease and a higher risk of death.

Coronary Arteriography:

Cardiac catheterization is currently the "gold standard" for determining the presence of obstructive coronary artery disease. A cardiac catheterization yields a two-dimensional rendering of the coronary artery circulation. To assist in circumventing the limitations of a two-dimensional depiction of three-dimensional anatomy, multiple views from varying angles are obtained as a standard. It is exceedingly important to visualize each coronary artery segment from at least two orthogonal views. Coronary artery plaque formation is usually eccentric in location, not a smooth cylindrical encroachment upon the coronary artery lumen, and variable in appearance from different vantage points. This eccentricity can lead to both under- and overestimation of coronary artery disease severity, necessitating a methodical approach to view acquisition.

A more accurate assessment of coronary arterial lumen compromise is by assessing the cross-sectional area of the coronary artery, expressed as a percentage obstruction. This requires the direct visualization of the coronary artery from within the lumen. This limitation has proved the catalyst for the development of intravascular ultrasound. During this procedure, a small flexible ultrasound probe is threaded down the coronary artery. The images are obtained in real time, with a percentage lumen diameter readily calculated. For coronary artery lesions not well seen on routine coronary artery arteriography, this has been an extremely helpful technique providing clarification as to disease severity. Additionally, intravascular ultrasound can help guide the interventional cardiologist as to device selection prior to performing percutaneous coronary artery revascularization. A subset of patients where intravascular ultrasound has proven extremely helpful is the cardiac transplantation population. These patients develop a coronary arteriopathy where compromise of the coronary arterial lumen is smooth, cylindrical, and diffuse throughout the coronary arterial tree. A routine cardiac catheterization may demonstrate the somewhat smaller coronary arteries with a distal, tapered appearance. Without a normal reference segment, it is not possible to accurately ascribe a percentage of lumen compromise. Intravascular ultrasound is able to identify the internal elastic membrane and therefore define the expected coronary arterial lumen size and compare it to the actual lumen size. This can have important implications in terms of assessing for allograft arteriopathy and the adjustment of the immunosuppressive medication regimen.

The indications for cardiac catheterization in patients with chronic stable angina have been outlined by the ACC/AHA Task Force on Practice Guidelines.

Once a cardiac catheterization has been performed, the three most common therapeutic options are medical therapy, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). Medical therapy for patients with documented cardiovascular disease involves the aggressive management of cardiovascular risk factors through lifestyle modification and drug treatment. The American Heart Association and the American College of Cardiology have recently updated their joint management guidelines for patients with atherosclerotic cardiovascular disease. The previously mentioned ACC/AHA/ACP-ASIM position paper includes recommendations for the treatment of chronic stable angina (http://www.annals.org/issues/
v135n8/full/200110160-00014.html).

Lifestyle Modification:

Patients with documented coronary artery disease should actively pursue lifestyle modifications that reduce the risk of future cardiovascular events. These modifications alone, with the guidance and strong encouragement of the physician-led healthcare team, can make a significant positive impact on future cardiovascular and vascular event rates.

Smoking
Tobacco use is one of the most important contributors to recurrent cardiovascular events. Tobacco use induces endothelial dysfunction, reduces coronary vasoreactivity, increases circulating carbon monoxide levels, impairs functional status, and raises blood pressure. Smoking cessation is imperative, and it is more likely to be successful for those patients who are counseled by a physician or who enroll in a formal smoking cessation program that can be multifaceted to include addictive therapy, behavioral therapy, hypnosis, and acupuncture. Nicotine replacement therapy (Nicorette, Nicotrol, Nicotrol NS, Habitrol, NicoDermCQ, ProStep) and bupropion (Zyban) are the pharmacologic agents of choice. It has been documented that the physician can play an active role in smoking cessation success. Repeated counseling and encouragement from the physician is important at each physician patient encounter. A supportive atmosphere is best.

Exercise
Functional capacity is a strong predictor of major adverse cardiac events.⁹ Functional capacity can be improved by following an exercise program that entails at least 30 minutes of exercise 3 or 4 days per week; a daily regimen is optimal. Moderate and high-risk patients should be enrolled in a medically supervised exercise program. This is especially important for those patients who have either suffered a myocardial infarction or underwent a coronary artery revascularization procedure. A cardiac rehabilitation program that includes formal supervision and encouragement in the form of vital sign monitoring, exercise technique and duration instruction, and dietary education helps set a program of optimal cardiovascular health. This is the critical time period when a patient is most apt to listen, learn, and cultivate sustained motivation for the future. It also exposes the patient to individuals with similar diagnoses, helping mitigate the "why me" philosophy.

Weight Control
The best weight management strategy is diet and exercise. Ideal benchmarks are a body mass index between 19 kg/m² and 25 kg/m² and a waist circumference of no more than 40 inches for men and 35 inches for women. Weight loss has a favorable metabolic syndrome impact on many cardiac risk factors, including hypertension, a high LDL level, a low HDL level, and glucose intolerance. The success to any program is discipline. Again, the physician-led healthcare team including a dietitian is invaluable, constructing an attainable and sustainable dietary and exercise plan. This is not an overnight fix and this needs to be emphasized. Conversely, this is a change for life where a goal weight may not be obtained for 12 months. What is important is that sustained positive change transpires and small steps toward achieving personal goals are being realized. Success will breed success. The American Heart Association has posted recommendations for weight management and diet for patients with coronary artery disease on two web sites (http://www.americanheart.org/scientific/
statements/1994/079402.html and http://circ.ahajournals.org/cgi/
content/full/102/18/2284).

Pharmacologic Therapy:

Pharmacologic therapy should be a part of the treatment plan for every patient with documented coronary artery disease. Antiplatelet therapy should be prescribed for every patient, and an antianginal agent should be provided to those who remain symptomatic. Unless contraindicated, an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker are recommended for all patients who have a history of a myocardial infarction and left ventricular systolic dysfunction.

Antiplatelet Therapy
Aspirin is the mainstay of antiplatelet therapy for patients who have known coronary artery disease or symptoms suggestive of coronary artery disease. Aspirin inhibits both cyclo-oxygenase and the synthesis of thromboxane A2. For patients who have known vascular disease (eg, myocardial infarction, cerebrovascular accident, or claudication), aspirin at 75 mg/d to 325 mg/d reduces the incidence of a myocardial infarction, cerebrovascular accident, and vascular death by approximately 33%.¹⁰ The American Heart Association (http://www.americanheart.org/scientific/
statements/1997/109702.html) reviews the role of aspirin in the management of cardiovascular disease.

Clopidogrel (Plavix), a thienopyridine derivative, blocks adenosine diphosphate-induced platelet activation. Clopidogrel is indicated as an alternative for patients who cannot take aspirin. In fact, the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial demonstrated the superiority of clopidogrel over aspirin in patients with documented atherosclerotic vascular disease.¹¹ Compared with aspirin, clopidogrel treatment produced a statistically significant 0.53% reduction in the absolute risk of stroke, myocardial infarction, or death (5.30% for clopidogrel v 5.83% for aspirin; p = 0.043). The marked cost difference between aspirin and clopidogrel is the likely reason that clopidogrel is not used more widely.

The combination of aspirin and clopidogrel versus aspirin alone for preventing death, myocardial infarction, cerebrovascular accident, or refractory ischemia in patients with unstable angina or non-Q-wave MI was compared recently in the CURE trial.¹² Patients who received combination therapy had a 20% lower relative risk than did those in the aspirin-only group.

Anti-anginals
Beta-blockers, calcium channel blockers, and nitrates are the mainstays of antianginal therapy. Unless contraindications exist, all patients who have a history of angina pectoris should carry sublingual nitroglycerin. Beta-blockers are recommended as first-line therapy for the management of stable angina in all patients with established coronary artery disease (Table 6).

Contraindications to beta blockade include severe bradycardia, high-degree atrioventricular block, and sick sinus syndrome. Depression, severe asthma, diabetes with a tendency towards profound hypoglycemia, and peripheral vascular disease with severe claudication are relative contraindications. The initial target heart rate should be 55 bpm to 60 bpm at rest, although some patients may require more aggressive beta blockade for adequate angina control. Dose-limiting symptoms include lethargy, fatigue, sexual dysfunction, insomnia, nightmares, worsening asthma, or worsening claudication.

Patients who have a history suggestive of vasospastic angina should be treated with a calcium channel blocker or a long-acting nitrate as an initial therapy. Either treatment option can also serve as a substitute for a beta-blocker in the presence of traditional angina when intolerable beta-blocker effects ensue.

All calcium channel blockers exert some degree of negative inotropic effect, so they should be used cautiously in patients with left ventricular systolic dysfunction. Some patients with impaired systolic function, particularly those with a nonischemic cardiomyopathy, may tolerate the more arterial dilating, vaso-selective dihydropyridine calcium channel blockers (eg, amlodipine).¹³ The use of calcium antagonists for angina control in patients who have ischemic cardiomyopathy remains controversial, and therefore they should be considered only after beta-blocker and long-acting nitrate therapy have been given an adequate trial. Adverse effects associated with the calcium antagonists include peripheral edema, hypotension, constipation, and worsening heart failure. Verapamil and diltiazem may cause bradycardia and heart block, particularly if they are combined with a beta-blocker. The short- and intermediate-acting dihydropyridines may raise the risk of myocardial infarction but lower the risk of stroke, although the data are controversial.¹⁴ In general, these agents should be avoided in the management of angina and hypertension because there are many excellent alternatives that are known to be safe. Table 7 reviews the dosing of the calcium antagonists indicated for managing angina pectoris.

Nitrates improve exercise tolerance and prolong the time to onset of angina in patients with exertional angina. They are contraindicated in patients who have severe aortic stenosis or hypertrophic cardiomyopathy because they may adversely alter hemodynamics and exacerbate symptoms. In order for these medications to exert their maximum effect, patients must observe a nitrate-free period of 8 to 12 hours every day; otherwise tolerance in the form of tachyphylaxis is likely to develop. The most common side effect of nitrates is headache; it typically remits without the need to discontinue therapy. Less common side effects are lightheadedness, syncope, and pre-syncope.

Risk Factor Management:

If lifestyle modification alone has failed to adequately treat the most serious of the modifiable risk factors-hypertension, diabetes, and hyperlipidemia-aggressive pharmacologic therapy is warranted. The ACC/AHA/ACP-ASIM guidelines cover this important topic (http://circ.ahajournals.org/cgi/content/full/99/21/2829).

Hypertension
The management of hypertension in patients with coronary artery disease is exceedingly important. Not only does control of blood pressure reduce myocardial oxygen consumption and thereby reduce angina, it also lowers the incidence of cardiovascular events.

Beta-blockers devoid of intrinsic sympathomimetic activity represent first-line antihypertensive therapy for patients who have a history of myocardial infarction or coronary artery disease with angina. ACE inhibitors are indicated for all patients with diabetes mellitus or a history of myocardial infarction, particularly those with impaired left ventricular systolic function. In the recently published Heart Outcomes Prevention Evaluation (HOPE) study, high-risk patients without a history of a myocardial infarction who were treated with the ACE inhibitor ramipril experienced a significant reduction in major cardiac events.¹⁵ Therefore, in the presence of coronary artery disease, selecting antihypertensive medications should be undertaken strategically. For instance, in a patient who has known coronary artery disease and a prior myocardial infarction with residual left ventricular systolic dysfunction, choosing an antihypertensive regimen to include both a beta-blocker and ACE inhibitor is indicated. If the blood pressure is still not adequately controlled on these medications, often a low-dose diuretic can provide synergistic blood pressure lowering effects.

Calcium channel blockers are useful for patients with hypertension and angina despite maximum tolerable beta blockade administration. The long-acting dihydropyridines are preferred; short-acting preparations should be avoided because they might increase the risk of cardiac events via precipitous blood pressure reduction and inducing the coronary steal phenomenon, diverting coronary arterial blood flow from flow-limited myocardial regions. A more complete review of hypertension management is available in the Hypertension Chapter. The full text of the recommendations contained in the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) can be viewed online (http://www.nhlbi.nih.gov/guidelines/hypertension).

Hyperlipidemia
The management of elevated lipids is an important part of the comprehensive care program for every patient with atherosclerotic disease. The Hyperlipidemia Chapter reviews the current management guidelines. A diet in which a patient obtains less than 30% of total calories from fat, less than 7% of total calories from saturated fat, and less than 200 mg/d of cholesterol is appropriate for all at-risk patients.

The current guidelines of the National Cholesterol Education Program (NCEP) recommends an LDL level of less than 70 mg/dl for all patients with coronary artery disease or other atherosclerotic disease.. Patients whose LDL levels are higher than 100 mg/dl should start diet therapy. Those whose LDL levels are higher than 130 mg/dl should be started on lipid-lowering drug therapy.

The HMG-CoA reductase inhibitors (statins) are the recommended first-line agents for patients who have coronary artery disease, elevated total and LDL cholesterol levels, and triglyceride levels less than 400 mg/dl (Table 8). Following an acute coronary event, these agents should be started in the hospital in order to provide maximum benefit.

The NCEP does not yet recommend statins for all patients with coronary artery disease irrespective of lipid values. However, the results of the Heart Protection Study (HPS) may alter future recommendations regarding the use of statins in patients who are at high risk for coronary artery disease but whose lipid levels are normal.¹⁶ In that trial, investigators gave 40 mg/d of simvastatin to patients at high risk for coronary artery disease who had no history of coronary artery disease and whose cholesterol levels were normal or even low. After 5 years, these patients experienced a 12% reduction in total mortality and a 24% reduction in cardiac events. In light of these findings, future guidelines may recommend statin therapy for all patients at high risk for coronary artery disease including patients with type 2 diabetes or established vascular disease, regardless of their cholesterol levels.

The NCEP also recommends a target HDL level of more than 45 mg/dl for men with coronary artery disease and more than 55 mg/dl for women. Those patients who have metabolic syndrome (obesity, hypertension, and insulin resistance) often have HDL levels lower than 35 mg/dl. These patients are at especially high risk for arterial vascular disease. Their recommended lifestyle changes include regular exercise and weight loss, which are two of the most effective ways to raise HDL levels. If lifestyle changes fail to increase HDL levels to their target, drug treatment with a fibrate or niacin should be considered, particularly in patients whose triglyceride levels are greater than 200 mg/dl. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) reported that gemfibrozil lowered the risk of myocardial infarction and cardiovascular death by 22% over 5 years. This was in a group of patients who had a history of myocardial infarction, low HDL levels (<40 mg/dl), LDL levels less that 140 mg/dl, and a mean triglyceride level of 160 mg/dl.¹⁷ HDL levels rose 6% and triglyceride levels fell 31% in the treatment group, while LDL levels did not change significantly.

VA-HIT emphasized the importance of triglycerides in the overall management of lipid disorders.¹⁷ Patients with elevated triglyceride levels must aggressively pursue lifestyle modifications. Exercise, weight loss, smoking cessation, reduction of alcohol intake, and aggressive diabetes control all lower triglyceride levels. In patients whose fasting triglyceride levels are greater than 500 mg/dl, fibrate or niacin therapy should be considered before LDL-lowering therapy is started. Triglyceride levels between 200 mg/dl and 499 mg/dl should be addressed after LDL-lowering therapy is started.

The management of serum lipid abnormalities is presently changing. The threshold for prescribing a statin medication is being lowered. Many physicians, in the presence of documented arterial vascular disease, are prescribing a statin irrespective of absolute lipid values. Many are guiding therapy based on ultra-sensitive C-reactive protein values, titrating the statin dose upwards in those patients with elevated CRP values, even in the presence of normal lipid parameters. Scientific validation of this approach is yet to be confirmed.

Diabetes Mellitus
Diabetics with coronary artery disease have a particularly high risk for recurrent cardiovascular events, and they should be targeted for aggressive risk-factor modification. Although randomized controlled trials have not shown that aggressive control of diabetes leads to any statistically significant reduction in macrovascular events, it does reduce the incidence of microvascular complications, including nephropathy and retinopathy. The risk of macrovascular complications may be reduced by the use of the newer antidiabetic agents (eg, the insulin-sensitizing agents pioglitazone, rosiglitazone, and metformin) because they may confer more favorable metabolic changes than do the sulfonylureas. The American Diabetes Association recommends Hemoglobin A1c level of less than 7%.

Other Considerations
Hormone replacement therapy for postmenopausal women with coronary artery disease is not recommended. The Heart and Estrogen/Progestin Replacement Study (HERS) did not find hormone replacement therapy providing secondary prevention benefit.¹⁸ On the other hand, the Multiple Outcomes of Raloxifene Evaluation (MORE) study showed that the estrogen receptor modulator raloxifene did lower the risk of cardiovascular events in a subset of patients with established coronary artery disease.¹⁹ However, the MORE study was not designed to evaluate cardiovascular outcomes, so its results should not be used to draw broad conclusions.

Several other independent risk factors have been identified over the past several years: lipoprotein (a) [Lp(a)] and homocysteine.^20-22 No prospective, randomized trial has yet been completed to evaluate the effects of Lp(a) lowering, but elevated Lp(a) levels are known to be associated with an increased risk of cardiovascular events. Likewise, elevated plasma homocysteine levels are associated with an increased risk of cardiovascular events. Treatment with folic acid and vitamins B6 and B12 does lower homocysteine levels, but trials are still needed to determine if lowering these levels results in a corresponding reduction in cardiovascular events.

Treatment with vitamin E does not lower cardiovascular event rates, and it is not recommended.²³ Antioxidants such as vitamin C, beta-carotene, and probucol are promising, but they are not recommended for routine use.

Revascularization
The primary revascularization options are percutaneous coronary intervention and coronary artery bypass grafting surgery. Other procedures-laser, rotational, and directional atherectomy-are used occasionally. Adjunctive beta or gamma radiation can be administered for in-stent restenosis.

The most common percutaneous coronary intervention techniques are percutaneous transluminal coronary angioplasty and coronary stenting. A major limitation of percutaneous coronary intervention is restenosis at the intervention site. This represents the body's response to local injury with an exaggerated neointimal proliferative response. The use of stents, aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors lowers the rate of restenosis to less than 10% at 6 months in optimal circumstances.²⁴ Recent studies of stents coated with antiproliferative agents such as sirolimus have shown promise in lowering the restenosis rate after stenting.²⁵ Folic acid supplementation following stenting has been shown to lower the restenosis rate.²⁶ These advances are likely to continue to increase the frequency of stenting procedures in the United States. The reduction in restenosis rates has also permitted addressing previously prohibitive lesions such as an unprotected left main coronary artery stenosis. In patients where traditional bypass surgery may be high risk, primary stenting of a left main coronary artery stenosis is now feasible.

The most common conduits for coronary artery bypass surgery are the saphenous vein and the internal thoracic (mammary) artery. Radial artery grafts are also used, but their long-term patency rates remain under question. Their long-term patency rates seem highly dependent upon surgical skill and technique. The long-term patency rates of internal thoracic artery grafts are superior to those of venous grafts. Over the past several years, more coronary artery bypass surgeries have been performed without cardiopulmonary bypass. This procedure (off-pump CABG) confers several putative benefits, including a lower risk of neurological and renal impairment.

Many clinical trials have been performed over the past two decades to compare outcomes following medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting in patients with symptomatic coronary artery disease. However, many of these trials were limited in their design, and may not apply to the contemporary management of coronary artery disease because none capitalized on the most recent treatment advances. Nonetheless, these studies represent the only available data to assist the physician in making often-difficult management decisions. In general, invasive procedures have not been shown to improve survival in most groups of patients with chronic angina; however, they are effective for managing symptomatic angina pectoris. The American College of Cardiology and the American Heart Association have jointly published guidelines for the use of both percutaneous coronary intervention and coronary artery bypass grafting surgery.

Percutaneous Coronary Intervention
versus Medical Therapy
Percutaneous coronary intervention is more effective than medical therapy in relieving angina, but it confers no greater survival benefit.²⁷ Aggressive lipid-lowering therapy appears to be as effective as both percutaneous coronary intervention and usual medical care for preventing ischemic events.²⁸

Coronary Artery Bypass Grafting
versus Medical Therapy
Coronary artery bypass grafting produces better survival rates compared to medical therapy, and it is recommended for symptomatic patients with left main coronary artery disease, three-vessel coronary artery disease, or two-vessel coronary artery disease marked by stenosis of the proximal left anterior descending artery.^29-31 Some studies suggest coronary artery bypass grafting improves survival in patients who have severe stenosis of the proximal left anterior descending artery, regardless of ventricular function.³² Coronary artery bypass grafting is more effective than medical therapy for the relief of angina, although this benefit narrows after 5 to 10 years.

Percutaneous Coronary Intervention
versus Coronary Artery Bypass Grafting
Outcomes following percutaneous coronary intervention and coronary artery bypass grafting have been compared in high-risk patients. The two largest studies in the United States were the Emory Angioplasty versus Surgery Trial (EAST)³³ and the Bypass Angioplasty Revascularization Investigation (BARI).³⁴ In both trials, percutaneous coronary intervention was limited solely to angioplasty, thus the findings do not apply to the current commonplace practice of intracoronary stenting. Likewise, current coronary artery bypass grafting techniques, including the more frequent use of arterial conduits and off-pump coronary artery bypass grafting, were not included in either trial. Nonetheless, the major findings of these two trials have been incorporated into practice guidelines. EAST demonstrated that the long-term survival rate following percutaneous coronary intervention and coronary artery bypass grafting was comparable. BARI found that coronary artery bypass grafting produced better long-term survival rates than did percutaneous coronary intervention. However, the benefit of coronary artery bypass grafting in BARI was not apparent until seven years postoperatively, and it was largely attributable to the significantly greater survival rate in the subgroup of patients who had diabetes mellitus.³⁵ Both trials showed that coronary artery bypass grafting was superior to percutaneous coronary intervention in relieving angina and in obviating the need for repeat revascularization procedures. New large-scale randomized trials are needed to compare the effectiveness of aggressive medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting in the management of coronary artery disease, but given the rapid rate of discovery and technologic development, any such trial will likely be outdated by the time it is completed. The treatment of cardiac disorders including coronary artery disease is shifting to a less percutaneous and less surgical approach. With the introduction of drug-eluting stents, restenosis rates have been lowered and acute thrombotic complications are rare given the advances in anti-platelet therapy.

The diagnostic and treatment options for coronary artery disease are changing rapidly. New pharmaceuticals are being developed and introduced into the treatment armamentarium. Biologic markers are now used to track coronary artery disease activity at the vascular level, guiding medication selection and dose titration. Procedures are less invasive and offer percutaneous treatment options such as drug-eluting stents, previously unavailable. Despite these advances, coronary artery disease and its deleterious manifestations represent the number one killer in the United States. This is in large part due to poor dietary choices, sedentary lifestyles, and continuance of tobacco use. Efforts at both primary and secondary prevention of obstructive coronary artery disease among the general public are still lacking. Public awareness campaigns are a partial success. It is imperative for the physician to allocate time to address the importance of lifestyle modification efforts.

Furthermore, the genetic basis of coronary artery disease is slowly being unraveled. In the future, a genetic assessment of an individual's risk for the development of atherosclerotic vascular disease may be possible at a young age. These findings may guide both lifestyle modification prescription and also the choice and dosage of selected pharmaceuticals. One thing is clear—a preemptive approach is the best way to tackle the enormity of coronary artery disease. We must erase the myth that medications, stenting, and bypass surgery are curative approaches. Instead, the patient must meet the healthcare team at least half way to achieve a successful health outcome.

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1. American Heart Association. 2004 Heart and Stroke Statistical Update. Dallas, Texas: American Heart Association; 2004.
   
   
2. Williams SV, Fihn SD, Gibbons RJ. Guidelines for the management of patients with chronic stable angina: diagnosis and risk stratification. Ann Intern Med. 2001;135:530-547.
   
   
3. Zheng ZJ, Sharrett AR, Chambless LE, et al. Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. 1997;131:115-125.
   
   
4. Connolly DC, Elveback LR, Oxman HA. Coronary heart disease in residents of Rochester, Minnesota: IV. Prognostic value of the resting electrocardiogram at the time of initial diagnosis of angina pectoris. Mayo Clin Proc. 1984;59:247-250.
   
   
5. Bielak LF, Rumberger JA, Sheedy PF 2nd, Schwartz RS, Peyser PA. Probabilistic model for prediction of angiographically defined obstructive coronary artery disease using electron beam computed tomography calcium score strata. Circulation. 2000;102:380-385.
   
   
6. Mark DB, Shaw L, Harrell FE Jr, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med. 1991;325:849-853.
   
   
7. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med. 1999;341:1351-1357.
   
   
8. Lauer MS, Okin PM, Larson MG, Evans JC, Levy D. Impaired heart rate response to graded exercise. Prognostic implications of chronotropic incompetence in the Framingham Heart Study [see comments]. Circulation. 1996;93:1520-1526.
   
   
9. Snader CE, Marwick TH, Pashkow FJ, Harvey SA, Thomas JD, Lauer MS. Importance of estimated functional capacity as a predictor of all-cause mortality among patients referred for exercise thallium single-photon emission computed tomography: report of 3,400 patients from a single center. J Am Coll Cardiol. 1997;30:641-648.
   
   
10. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy-I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81-106.
    
    
11. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339.
    
    
12. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrence Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502.
    
    
13. Packer M, O'Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med. 1996;335:1107-1114.
    
    
14. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995;274:620-625.
    
    
15. Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation. 2001;104:522-526.
    
    
16. Collins R. Peto R. Armitage J. The MRC/BHF Heart Protection Study: preliminary results. International J Clin Practice. 2002;56:53-56.
    
    
17. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-418.
    
    
18. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605-613.
    
    
19. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002;287:847-857.
    
20. Genest J Jr, Jenner JL, McNamara JR, et al. Prevalence of lipoprotein (a) [Lp(a)] excess in coronary artery disease. Am J Cardiol. 1991;67:1039-1045.
    
    
21. Ariyo AA, Thach C, Tracy R; Cardiovascular Health Study Investigators. Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med. 2003; 349:2108-2115.
    
    
22. Stampfer MJ, Malinow MR, Willet WC, et al. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA. 1992;268:877-881.
    
    
23. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153.
    
    
24. The EPISTENT Investigators. Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet. 1998;352:87-92.
    
    
25. Rensing BJ, Vos J, Smits PC, et al. Coronary restenosis elimination with a sirolimus eluting stent: first European human experience with 6-month angiographic and intravascular ultrasonic follow-up. Eur Heart J. 2001;22:2125-2130.
    
    
26. Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med. 2001;345:1593-1600.
    
    
27. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med. 1992;326:10-16.
    
    
28. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med. 1999;341:70-76.
    
    
29. The VA Coronary Artery Bypass Surgery Cooperative Study Group. Eighteen-year follow-up in the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery for stable angina. Circulation. 1992;86:121-130.
    
    
30. Varnauskas E. Twelve-year follow-up of survival in the randomized European Coronary Surgery Study. N Engl J Med. 1988;319:332-337.
    
    
31. Passamani E, Davis KB, Gillespie MJ, Killip T. A randomized trial of coronary artery bypass surgery. Survival of patients with a low ejection fraction. N Engl J Med. 1985;312:1665-1671.
    
    
32. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet. 1994;344:563-570.
    
    
33. King SB 3rd, Lembo NJ, Weintraub WS, et al. A randomized trial comparing coronary angioplasty with coronary bypass surgery. Emory Angioplasty versus Surgery Trial (EAST). N Engl J Med. 1994;331:1044-1050.
    
    
34. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med. 1996;335:217-225.
    
    
35. No authors listed. Seven-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI) by treatment and diabetic status. J Am Coll Cardiol. 2000;35:1122-1129.

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