ANGINA PECTORIS

Introduction
Background

Angina pectoris is the result of myocardial ischemia caused by an imbalance between myocardial blood supply and oxygen demand. Angina is a common presenting symptom (typically, chest pain) among patients with coronary artery disease. A comprehensive approach to diagnosis and to medical management of angina pectoris is an integral part of the daily responsibilities of health care professionals.
Pathophysiology

Myocardial ischemia develops when coronary blood flow becomes inadequate to meet myocardial oxygen demand. This causes myocardial cells to switch from aerobic to anaerobic metabolism, with a progressive impairment of metabolic, mechanical, and electrical functions. Angina pectoris is the most common clinical manifestation of myocardial ischemia. It is caused by chemical and mechanical stimulation of sensory afferent nerve endings in the coronary vessels and myocardium. These nerve fibers extend from the first to fourth thoracic spinal nerves, ascending via the spinal cord to the thalamus, and from there to the cerebral cortex.

Studies have shown that adenosine may be the main chemical mediator of anginal pain. During ischemia, ATP is degraded to adenosine, which, after diffusion to the extracellular space, causes arteriolar dilation and anginal pain. Adenosine induces angina mainly by stimulating the A1 receptors in cardiac afferent nerve endings.1

Heart rate, myocardial inotropic state, and myocardial wall tension are the major determinants of myocardial metabolic activity and myocardial oxygen demand. Increases in the heart rate and myocardial contractile state result in increased myocardial oxygen demand. Increases in both afterload (ie, aortic pressure) and preload (ie, ventricular end-diastolic volume) result in a proportional elevation of myocardial wall tension and, therefore, increased myocardial oxygen demand. Oxygen supply to any organ system is determined by blood flow and oxygen extraction. Because the resting coronary venous oxygen saturation is already at a relatively low level (approximately 30%), the myocardium has a limited ability to increase its oxygen extraction during episodes of increased demand. Thus, an increase in myocardial oxygen demand (eg, during exercise) must be met by a proportional increase in coronary blood flow.

The ability of the coronary arteries to increase blood flow in response to increased cardiac metabolic demand is referred to as coronary flow reserve (CFR). In healthy people, the maximal coronary blood flow after full dilation of the coronary arteries is roughly 4-6 times the resting coronary blood flow. CFR depends on at least 3 factors: large and small coronary artery resistance, extravascular (ie, myocardial and interstitial) resistance, and blood composition.

Myocardial ischemia can result from (1) a reduction of coronary blood flow caused by fixed and/or dynamic epicardial coronary artery (ie, conductive vessel) stenosis, (2) abnormal constriction or deficient relaxation of coronary microcirculation (ie, resistance vessels), or (3) reduced oxygen-carrying capacity of the blood.

Atherosclerosis is the most common cause of epicardial coronary artery stenosis and, hence, angina pectoris. Patients with a fixed coronary atherosclerotic lesion of at least 50% show myocardial ischemia during increased myocardial metabolic demand as the result of a significant reduction in CFR. These patients are not able to increase their coronary blood flow during stress to match the increased myocardial metabolic demand, thus they experience angina. Fixed atherosclerotic lesions of at least 90% almost completely abolish the flow reserve; patients with these lesions may experience angina at rest.

Coronary spasm can also reduce CFR significantly by causing dynamic stenosis of coronary arteries. Prinzmetal angina is defined as resting angina associated with ST-segment elevation caused by focal coronary artery spasm. Although most patients with Prinzmetal angina have underlying fixed coronary lesions, some have angiographically normal coronary arteries. Several mechanisms have been proposed for Prinzmetal angina: focal deficiency of nitric oxide production,2 hyperinsulinemia, low intracellular magnesium levels, smoking cigarettes, and using cocaine.

Approximately 30% of patients with chest pain referred for cardiac catheterization have normal or minimal atherosclerosis of coronary arteries. A subset of these patients demonstrates reduced CFR that is believed to be caused by functional and structural alterations of small coronary arteries and arterioles (ie, resistance vessels). Under normal conditions, resistance vessels are responsible for as much as 95% of coronary artery resistance, with the remaining 5% being from epicardial coronary arteries (ie, conductive vessels). The former is not visualized during regular coronary catheterization. Angina due to dysfunction of small coronary arteries and arterioles is called microvascular angina. Several diseases, such as diabetes mellitus, hypertension, and systemic collagen vascular diseases (eg, systemic lupus erythematosus, polyarteritis nodosa), are believed to cause microvascular abnormalities with subsequent reduction in CFR.

The syndrome that includes angina pectoris, ischemialike ST-segment changes and/or myocardial perfusion defects during stress testing, and angiographically normal coronary arteries is referred to as syndrome X. Most patients with this syndrome are postmenopausal women, and they usually have an excellent prognosis.3 Syndrome X is believed to be caused by microvascular angina. Multiple mechanisms may be responsible for this syndrome, including (1) impaired endothelial dysfunction,4 (2) increased release of local vasoconstrictors, (3) fibrosis and medial hypertrophy of the microcirculation, (4) abnormal cardiac adrenergic nerve function, and/or (5) estrogen deficiency.5

A number of extravascular forces produced by contraction of adjacent myocardium and intraventricular pressures can influence coronary microcirculation resistance and thus reduce CFR. Extravascular compressive forces are highest in the subendocardium and decrease toward the subepicardium. Left ventricular (LV) hypertrophy together with a higher myocardial oxygen demand (eg, during tachycardia) cause greater susceptibility to ischemia in subendocardial layers.

Myocardial ischemia can also be the result of factors affecting blood composition, such as reduced oxygen-carrying capacity of blood, as is observed with severe anemia (hemoglobin, <8 g/dL), or elevated levels of carboxyhemoglobin. The latter may be the result of inhalation of carbon monoxide in a closed area or of long-term smoking. Ambulatory ECG monitoring has shown that silent ischemia is a common phenomenon among patients with established coronary artery disease. In one study, as many as 75% of episodes of ischemia (defined as transient ST depression of >1 mm persisting for at least 1 min) occurring in patients with stable angina were clinically silent. Silent ischemia occurs most frequently in early morning hours and may result in transient myocardial contractile dysfunction (ie, stunning). The exact mechanism(s) for silent ischemia is not known. However, autonomic dysfunction (especially in patients with diabetes), a higher pain threshold in some individuals, and the production of excessive quantities of endorphins are among the more popular hypotheses.6
Frequency
United States

Approximately 9.8 million Americans are estimated to experience angina annually, with 500,000 new cases of angina occurring every year. In 2009, an estimated 785 000 Americans will have a new coronary attack, and about 470 000 will have a recurrent attack. Only 18% of coronary attacks are preceded by angina. An additional 195,000 silent first myocardial infarctions are estimated to occur each year.7
Mortality/Morbidity

About every 25 seconds, an American will have a coronary event, and about every minute someone will die from one. Coronary heart disease (CHD) caused about 1 of every 5 deaths in the United States in 2005. Final 2005 coronary heart disease mortality in 2005 was 445,687 (232,115 males and 213,572 females). On the basis of 2005 mortality rate data, nearly 2,400 Americans die of cardiovascular disease (CVD) each day—an average of 1 death every 37 seconds. The 2006 overall preliminary death rate from cardiovascular disease was 262.9.7

Race

The annual rates per 1000 population of new episodes of angina are as follows:7

* Age 45-54 years
o 8.5 for nonblack men
o 10.6 for nonblack women
o 11.8 for black men
o 20.8 for black women
* Age 55-64 years
o 11.9 for nonblack men
o 11.2 for nonblack women
o 10.6 for black men
o 19.3 for black women
* Age 65-74 years
o 13.7 for nonblack men
o 13.1 for nonblack women
o 8.8 for black men
o 10.0 for black women

Sex

Angina pectoris is more often the presenting symptom of coronary artery disease in women than in men, with a female-to-male ratio of 1.7:1. It has an estimated prevalence of 4.6 million in women and 3.3 million in men. In one analysis, this female excess was found across countries and was particularly high in the American studies and higher among nonwhite ethnic groups than among whites.8 The frequency of atypical presentations is also more common among women compared with men. Women have a slightly higher rate of mortality from coronary artery disease compared with men, in part because of an older age at presentation and a frequent lack of classic anginal symptoms. The estimated age-adjusted prevalence of angina is greater in women than in men.
Age

The prevalence of angina pectoris increases with age. Age is a strong independent risk factor for mortality. More than 150,000 Americans killed by CVD in 2005 were younger than 65 years. However, in 2005, 32% of deaths from cardiovascular disease occurred before the age of 75 years, which is well before the average life expectancy of 77.9 years.7
Clinical
History

Most patients with angina pectoris report of retrosternal chest discomfort rather than frank pain. The former is usually described as a pressure, heaviness, squeezing, burning, or choking sensation. Anginal pain may be localized primarily in the epigastrium, back, neck, jaw, or shoulders. Typical locations for radiation of pain are arms, shoulders, and neck. Typically, angina is precipitated by exertion, eating, exposure to cold, or emotional stress. It lasts for approximately 1-5 minutes and is relieved by rest or nitroglycerin. Chest pain lasting only a few seconds is not usually angina pectoris. The intensity of angina does not change with respiration, cough, or change in position. Pain above the mandible and below the epigastrium is rarely anginal in nature.

* Ask patients about the frequency of angina, severity of pain, and number of nitroglycerin pills used during angina episodes.
* Angina decubitus is a variant of angina pectoris that occurs at night while the patient is recumbent. Some have suggested that it is induced by an increase in myocardial oxygen demand caused by expansion of the blood volume with increased venous return during recumbency.

Physical

* For most patients with stable angina, physical examination findings are normal. Diagnosing secondary causes of angina, such as aortic stenosis, is important.
* A positive Levine sign (characterized by the patient's fist clenched over the sternum when describing the discomfort) is suggestive of angina pectoris.
* Look for physical signs of abnormal lipid metabolism (eg, xanthelasma, xanthoma) or of diffuse atherosclerosis (eg, absence or diminished peripheral pulses, increased light reflexes or arteriovenous nicking upon ophthalmic examination, carotid bruit).
* Examination of patients during the angina attack may be more helpful. Useful physical findings include third and/or fourth heart sounds due to LV systolic and/or diastolic dysfunction and mitral regurgitation secondary to papillary muscle dysfunction.
* Pain produced by chest wall pressure is usually of chest wall origin.

Causes

* Decrease in myocardial blood supply due to increased coronary resistance in large and small coronary arteries
o Significant coronary atherosclerotic lesion in the large epicardial coronary arteries (ie, conductive vessels) with at least a 50% reduction in arterial diameter
o Coronary spasm (ie, Prinzmetal angina)
o Abnormal constriction or deficient endothelial-dependent relaxation of resistant vessels associated with diffuse vascular disease (ie, microvascular angina)9
o Syndrome X
o Systemic inflammatory or collagen vascular disease, such as scleroderma, systemic lupus erythematous, Kawasaki disease, polyarteritis nodosa, and Takayasu arteritis
* Increased extravascular forces, such as severe LV hypertrophy caused by hypertension, aortic stenosis, or hypertrophic cardiomyopathy, or increased LV diastolic pressures
* Reduction in the oxygen-carrying capacity of blood, such as elevated carboxyhemoglobin or severe anemia (hemoglobin, <8 g/dL) * Congenital anomalies of the origin and/or course of the major epicardial coronary arteries * Structural abnormalities of the coronary arteries o Congenital coronary artery aneurysm or fistula o Coronary artery ectasia o Coronary artery fibrosis after chest radiation o Coronary intimal fibrosis following cardiac transplantation * Risk factors o Major risk factors for atherosclerosis: These include a family history of premature coronary artery disease, cigarette smoking, diabetes mellitus, hypercholesterolemia, or systemic hypertension. o Other risk factors: These include LV hypertrophy, obesity, and elevated serum levels of homocysteine, lipoprotein (a), plasminogen activator inhibitor, fibrinogen, serum triglycerides, or low high-density lipoprotein (HDL). o Metabolic syndrome: This has been characterized by the presence of hyperinsulinemia (fasting glucose level, ≥ 100 mg/dL), abdominal obesity (waist circumference, >40 in for men or >35 in for women), decreased HDL cholesterol levels (<40 mg/dL for men or <50 mg/dL for women), hypertriglyceridemia (>150 mg/dL), and hypertension (≥ 130/85 mm Hg). Based on data from the 2000 US census, an estimated 47 million Americans have the metabolic syndrome. Patients with the metabolic syndrome have a 3-fold increased risk for coronary atherosclerosis and stroke compared with those without this syndrome.7
* Precipitating factors: These include factors such as severe anemia, fever, tachyarrhythmias, catecholamines, emotional stress, and hyperthyroidism, which increase myocardial oxygen demand.
* Preventive factors: Factors associated with reduced risk of atherosclerosis are a high serum HDL cholesterol level, physical activity, estrogen, and moderate alcohol intake (1-2 drinks/d).Differential Diagnoses
Anemia
Isolated Coronary Artery Anomalies
Anxiety Disorders
Kawasaki Disease
Aortic Dissection
Mitral Regurgitation
Aortic Stenosis
Mitral Valve Prolapse
Biliary Colic
Panic Disorder
Cardiomyopathy, Hypertrophic
Pericarditis, Acute
Cholecystitis
Pleurodynia
Coronary Artery Atherosclerosis
Pneumothorax
Coronary Artery Vasospasm
Polyarteritis Nodosa
Diabetes Mellitus, Type 1
Pott Disease (Tuberculous Spondylitis)
Diabetes Mellitus, Type 2
Pulmonary Embolism
Gastric Ulcers
Pulmonary Hypertension, Primary
Gastritis, Acute
Pulmonary Hypertension, Secondary
Gastroesophageal Reflux Disease
Scleroderma
Hiatal Hernia
Systemic Lupus Erythematosus
Hypercholesterolemia, Familial
Takayasu Arteritis
Hypercholesterolemia, Polygenic
Toxicity, Cocaine
Hypertension
Varicella-Zoster Virus
Hyperthyroidism

Other Problems to Be Considered

Esophageal spasm
Esophageal rupture
Costochondritis
Herpes zoster
Pneumonia with pleural involvement
Workup
Imaging Studies

* Chest radiograph findings are usually normal in patients with angina pectoris. However, they may show cardiomegaly in patients with previous MI, ischemic cardiomyopathy, pericardial effusion, or acute pulmonary edema. Calcification of coronary arteries frequently correlates with major coronary artery disease.10
* Graded exercise stress testing is the most widely used test for the evaluation of patients presenting with chest pain. In patients with established stable angina pectoris, it also can provide prognostic information about the extent of disease.
o Exercise stress testing can be performed alone and in conjunction with echocardiography or myocardial perfusion scintigraphy tests. Stress echocardiography has an overall sensitivity of 78% and specificity of 86%; myocardial perfusion scintigraphy has an overall sensitivity of 83% and specificity of 77%. Exercise stress testing alone generally has somewhat lower sensitivity and specificity, but it is cheaper and therefore is a reasonable choice in those with a low probability of disease.11
o These test results must be interpreted in the context of the likelihood of the presence of coronary artery disease determined from the patient's history and physical examination findings. In a population with low prevalence, the predictive abilities of these tests are low; however, in patients with a high likelihood of coronary artery disease, the predictive value is much higher.
* Stress echocardiography can be used to evaluate segmental wall motion during exercise. It detects changes in regional wall motion that occur during myocardial ischemia. Normal myocardium becomes hyperdynamic during exercise; ischemic segments become hypokinetic or akinetic.
o Stress echocardiography has the advantage of simultaneous evaluation of LV function, cardiac dimensions, and valvular disease. It is especially useful in patients with baseline ECG abnormalities and those with systolic murmurs suggestive of aortic stenosis or hypertrophic cardiomyopathy.
o It is also helpful for localizing ischemia and evaluating its severity.
o Signs of severe coronary artery disease during exercise stress echocardiography include LV dilation, a decrease in global systolic function, and new or worsening mitral regurgitation. However, with dobutamine stress echocardiography, even in patients with severe coronary artery disease, the LV cavity may not dilate and global systolic function may improve.
o A major problem with stress echocardiography is the technical difficulty with obtaining adequate images in some patients.
* Thallium Tl 201 and technetium Tc 99m sestamibi are the most frequently used myocardial perfusion scintigraphy tests. These tests are especially useful in patients with baseline ECG abnormalities, to localize the region of ischemia, and as prognostic indicators. The presence of increased lung uptake upon thallium imaging is associated with a poor prognosis. Increased lung uptake, together with poststress dilation of the LV and multiple perfusion defects, is suggestive of either left main coronary artery disease or severe 3-vessel disease. The number of affected myocardial segments is predictive of long-term survival. Smaller perfusion defects are usually associated with peripheral coronary artery lesions, which are associated with a better prognosis. The absence of perfusion defects even in the presence of symptoms indicates an excellent prognosis.
* The frequency of infarction or death is 1 case per 10,000 stress tests. Absolute contraindications include symptomatic cardiac arrhythmias, severe aortic stenosis, acute MI within the previous 2 days, acute myocarditis, or pericarditis. Discontinue the exercise stress test in the presence of chest pain, a drop in systolic blood pressure of more than 10 mm Hg, severe shortness of breath, fatigue, dizziness or near syncope, ST depression of more than 2 mm, ST elevation of at least 1 mm without diagnostic Q waves, or development of ventricular tachyarrhythmia.
* In recent years, coronary artery calcium (CAC) scoring by fast computed tomography (CT) has become more popular in clinical practice for risk assessment of patients with chest pain. Currently, electron-beam computed tomography (EBCT) and multi-detector computed tomography (MDCT) are the primary fast CT methods for CAC measurement. However, some controversy exists about the usefulness of this test.12
o In asymptomatic patients, analysis of the data from CAC scoring in patients with an intermediate Framingham risk score reveals that for a score of 400 or more, the patient’s 10-year CAD risk would achieve a risk equivalent status similar to that noted with diabetes or peripheral arterial disease.13 Thus, finding a high CAC score in asymptomatic patients with an intermediate Framingham risk score (10-20% risk of CAD in 10 y) could be useful by resulting in a more aggressive management approach. However, unselected screening is of limited clinical value in asymptomatic patients who have a low Framingham risk score. On the other hand, assessment of CAC in asymptomatic patients with a high Framingham risk score (>20% risk of CAD in 10 y) has limited value since, based on current guidelines, these patients should be treated aggressively irrespective of their CAC scoring.
o In symptomatic patients, exclusion of measurable CAC may be an effective tool before undertaking invasive diagnostic procedures or hospital admission. Patients with CAC scores of less than 100 have a low probability (<2%) of abnormal perfusion on nuclear stress tests, and a low probability (<3%) of obstructive CAD (>50% stenosis) on cardiac catheterization. Studies of large numbers of symptomatic patients demonstrated that the absence of CAC has a high negative predictive value of 96-100%. Thus, an individual with no coronary calcium (score _ 0) can be told with a high level of confidence that he or she has no obstructive angiographic coronary disease.
o In patients with documented CAD, clinical monitoring of CAC progression through serial fast CT scanning to assess progression or regression of CAD is not recommended at this time.
o Since most of current data regarding CAC are collected from patient population of mostly Caucasian men, the guidelines suggest caution in applying these findings to women and ethnic minorities.
o In a 2008 study of 79 patients with stable angina pectoris, all patients underwent both dual-source computed tomography coronary angiography (CTCA) with quantitative computed tomography coronary angiography (QCT) and coronary angiography with intracoronary fractional flow reserve (FFR) measurement of discrete coronary stenoses.14 A total of 89 stenoses were evaluated which demonstrated that correlation between QCT and QCA with FFR measurement was weak (R values of -0.32 and -0.30, respectively). Although correlation between QCT and QCA was statistically significant, this correlation was only moderate (R = 0.53; p < 0.0001). This study demonstrated that anatomical assessment of the hemodynamic significance of coronary stenoses determined by visual CTCA, CCA, or QCT or QCA does not correlate well with the functional assessment of FFR. * Bamberg et al found that, in patients with acute chest pain and an inconclusive initial evaluation (nondiagnostic electrocardiographic findings, negative cardiac biomarkers), age and gender can serve as simple criteria to select patients who would derive the greatest diagnostic benefit from coronary computed tomographic angiography (CTA). In an observational cohort study in 368 low-risk patients, positive findings on 64-slice coronary CTA led to restratification to high risk, and negative findings led to restratification to very low risk, in men younger than 55 years and women younger than 65 years. In contrast, in women older than 65 years and men older than 55 years, a negative result on CTA did not result in restratification to a low-risk category.15 Other Tests * ECG is useful for evaluating persons with angina pectoris; however, findings are variable among patients. o Approximately 50% of patients with angina pectoris have normal findings after a resting ECG. However, abnormalities such as evidence for prior MI, intraventricular conduction delay, various degrees of atrioventricular block, arrhythmias, or ST-T–wave changes may be seen. o During an attack of angina pectoris, 50% of patients with normal findings after resting ECG show abnormalities. A 1-mm or greater depression of the ST segment below the baseline, measured 80 milliseconds from the J point, is the most characteristic change. Reversible ST-segment elevation occurs with Prinzmetal angina. Some patients with coronary artery disease may show pseudonormalization of the resting ECG ST-T–wave abnormalities during episodes of chest pain. * Exercise with ECG monitoring alone is the initial procedure of choice in patients without baseline ST-segment abnormalities or in whom anatomic localization of ischemia is not a consideration. o Horizontal or down-sloping ST-segment depression of at least 1 mm, measured 80 milliseconds from the J point, is considered the characteristic ischemic response. o ST-segment depression of more than 2 mm at a low workload or that persists for more than 5 minutes after termination of exercise and a failure of blood pressure to rise or an actual drop in blood pressure are signs of severe ischemic heart disease and a poor prognosis. o Withhold beta-blockers for approximately 48 hours before the stress test, whenever possible. Patients on digoxin and those with LV hypertrophy with repolarization abnormalities more often show positive results. Exercise stress tests have lower sensitivity and specificity in women and in patients with left bundle-branch block. o Pharmacologic agents (eg, dobutamine, dipyridamole, adenosine) can be used in patients who are unable to exercise. * Ambulatory ECG monitoring can be used for diagnostic purposes in patients with chest pain suggestive of Prinzmetal angina but is primarily used to evaluate the frequency of silent ischemia. Silent ischemia has been shown to be an independent predictor of mortality in patients with angina pectoris. Procedures * Selective coronary angiography is the definitive diagnostic test for evaluating the anatomic extent and severity of coronary artery disease. o Consider coronary angiography in symptomatic patients with inconclusive noninvasive study results, in survivors of sudden cardiac death, in those who are considered to have a poor prognosis based on the results of noninvasive studies, in those with occupational requirements for a definite diagnosis (eg, pilots), or in patients with coronary artery disease who are severely symptomatic despite maximal medical therapy. o In patients in whom Prinzmetal angina is suggested, provocative testing with ergonovine maleate during coronary angiography may be useful. * Intra-aortic balloon counterpulsation can be used in patients who continue to have unstable angina pectoris despite maximal medical treatment. This procedure should be followed promptly by coronary angiography with possible coronary revascularization.16 * In patients whose angina is refractory to medical therapy who are not suitable candidates for either percutaneous or surgical revascularization, enhanced external counterpulsation (EECP) is a safe and noninvasive alternative therapy.17 It increases coronary perfusion and reduces myocardial oxygen demand by diastolic augmentation of the central aortic pressure. Several studies have shown that patients treated with enhanced external counterpulsation have a significantly reduced number of anginal episodes, improved exercise tolerance, and decreased daily use of nitroglycerin tablets. Its therapeutic effects on quality of life are noted to remain at 1-year follow-up.18,19 * EECP also improves systolic blood pressure in patients with refractory angina. In a recent study of 108 consecutive patients undergoing EECP, on average, EECP decreased systolic blood pressure during treatment and follow-up; but in patients with low baseline systolic blood pressure (<110 mm Hg), EECP significantly increased systolic blood pressure.17 Staging The Canadian Cardiovascular Society grading scale is used for classification of angina severity, as follows: * Class I - Angina only during strenuous or prolonged physical activity * Class II - Slight limitation, with angina only during vigorous physical activity * Class III - Symptoms with everyday living activities, ie, moderate limitation * Class IV - Inability to perform any activity without angina or angina at rest, ie, severe limitation The New York Heart Association classification is also used to quantify the functional limitation imposed by patients' symptoms, as follows: * Class I - No limitation of physical activity (Ordinary physical activity does not cause symptoms.) * Class II - Slight limitation of physical activity (Ordinary physical activity does cause symptoms.) * Class III - Moderate limitation of activity (Patient is comfortable at rest, but less than ordinary activities cause symptoms.) * Class IV - Unable to perform any physical activity without discomfort, therefore severe limitation (Patient may be symptomatic even at rest.) Unstable angina is defined as new-onset angina (ie, within 2 mo of initial presentation) of at least class III severity, significant recent increase in frequency and severity of angina, or angina at rest.Treatment Medical Care The main goals of treatment in angina pectoris are to relieve the symptoms, slow the progression of disease, and reduce the possibility of future events, especially MI and premature death. * General measures o Smoking cessation results in a significant reduction of acute adverse effects on the heart and may reverse, or at least slow, atherosclerosis. Strongly encourage patients to quit smoking, and take an active role in helping them to achieve this goal. o Treat risk factors, including hypertension, diabetes mellitus, obesity, and hyperlipidemia. o Several clinical trials have shown that in patients with established coronary artery disease, reduction of low-density lipoprotein (LDL) level with a beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor (ie, statin) is associated with significant reductions in both mortality rate and major cardiac events.20,21,22,23 + These benefits are present even in patients with mild-to-moderate elevations of LDL cholesterol level. + Trials with cholesterol-lowering agents have confirmed the benefits of the therapeutic LDL lowering in older persons. + Angiographic studies demonstrate that a reduction of the LDL level in patients with coronary artery disease could cause slowing of progression, stabilization, or even regression of coronary artery lesions. + One study demonstrated a significant reduction of symptomatic myocardial ischemia in patients with unstable angina or non–Q-wave infarction with the administration of a statin during the early acute phase. + In a study of 10,001 patients with stable coronary artery disease, an aggressive cholesterol-lowering approach with atorvastatin 80 mg daily (mean cholesterol level of 77 mg/dL) compared to a less-aggressive approach with atorvastatin 10 mg daily (mean cholesterol level of 101 mg/dL) resulted in a 2.2% absolute reduction and a 22% relative reduction in the occurrence of a first major cardiovascular event (defined as death from coronary heart disease; nonfatal, non–procedure-related myocardial infarction; resuscitation from cardiac arrest; or fatal or nonfatal stroke).24 This occurred with a greater incidence of elevated aminotransferase levels with the aggressive cholesterol-lowering approach (1.2% vs 0.2%, p <0.001). o Based on several recent studies that have demonstrated the benefits of more aggressive LDL-lowering therapies in high-risk patients with coronary artery disease, the Committee of the National Cholesterol Education Program made the following modifications to the Adult Treatment Panel III (ATP III) guidelines.25 + In high-risk patients, a serum LDL cholesterol level of less than 100 mg/dL is the goal. + In very high-risk patients, an LDL cholesterol level goal of less than 70 mg/dL is a therapeutic option. Patients in the category of very high risk are those with established coronary artery disease with one of the following: multiple major risk factors (especially diabetes), severe and poorly controlled risk factors (especially continued cigarette smoking), multiple risk factors of the metabolic syndrome (especially high triglyceride levels [≥ 200 mg/dL] plus non-HDL cholesterol level [≥ 130 mg/dL] with low HDL cholesterol level [<40 mg/dL]), and patients with acute coronary syndromes. + For moderately high-risk persons (2+ risk factors), the recommended LDL cholesterol level is less than130 mg/dL, but an LDL cholesterol level of 100 mg/dL is a therapeutic option. o Some triglyceride-rich lipoproteins, including partially degraded very LDL levels, are believed to be independent risk factors for coronary artery disease. In daily practice, non-HDL cholesterol level (ie, LDL + very LDL cholesterol [total cholesterol - HDL cholesterol]) is the most readily available measure of the total pool of these atherogenic lipoproteins. Thus, the ATP III has identified non-HDL cholesterol level as a secondary target of therapy in persons with high triglyceride levels (>200 mg/dL). The goal for non-HDL cholesterol level (for persons with serum triglyceride levels >200 mg/dL) is 30 mg/dL higher than the identified LDL cholesterol level goal.
o Patients with established coronary disease and low HDL cholesterol levels are at high risk for recurrent events and should be targeted for aggressive nonpharmacological (ie, dietary modification, weight loss, physical exercise) and pharmacological treatment.
o Several large epidemiologic studies demonstrated that HDL cholesterol levels are inversely related to cardiovascular risk. Thus, developing pharmaceutical agents to increase the HDL level has been an attractive target for prevention and treatment of CAD. Cholesteryl ester transfer protein (CETP) inhibitors have been shown to have the effect of increasing HDL cholesterol levels by blocking this CETP. Torcetrapib has been one of CETP agents that has been used in large randomized trials.26,27
+ Investigation of Lipid level management using coronary UltraSound To assess Reduction of Atherosclerosis by CETP inhibition and HDL Elevation (ILLUSTRATE) was a randomized study that looked at the effect of torcetrapib in 1188 patients with CAD who underwent intravascular ultrasonography at baseline.26 After treatment with atorvastatin to reduce levels of LDL cholesterol to less than 100 mg/dL, patients were randomly assigned to receive atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily.

Intravascular ultrasonography was repeated in 910 of these patients (77%) after 24 months of treatment to evaluate the disease progression. Compared with atorvastatin monotherapy, torcetrapib–atorvastatin therapy was associated with an impressive 61% relative increase in HDL levels and a 20% relative decrease in LDL levels resulting in an LDL to HDL ratio of less than 1.0 in this group of patients. Despite this favorable change in the HDL and LDL levels, among patients who underwent repeat intravascular ultrasonography, the percent atheroma volume between the 2 groups was not different. Torcetrapib did not result in significant decrease in the progression of coronary atherosclerosis, but it was associated with an increase in blood pressure.
+ Rating Atherosclerotic Disease change by Imaging with A New Cholesteryl-Ester-transfer protein inhibitor (RADIANCE) 2, a trial reported in 2007, looked into the effect of torcetrapib on carotid atherosclerosis progression in patients with mixed dyslipidaemia.27 Although similar to the ILLUSTRATE trial, torcetrapib also substantially raised HDL levels and lowered LDL levels in this study; it did not affect the progression of carotid atherosclerosis. Similar to the ILLUSTRATE trial, torcetrapib also significantly increased systolic blood pressure.
+ Investigation of Lipid level management to Understand its iMpact IN ATherosclerotic Events (ILLUMINATE), an international phase 3 study of 15,000 patients, was terminated early because it had already recorded 82 deaths in the patients taking torcetrapib-atorvastatin compared with 51 deaths in patients taking atorvastatin alone. In addition, the rates of MI, revascularization, angina, and heart failure were higher in the torcetrapib-atorvastatin arm. Due to the disappointing results of these studies, torcetrapib will not be developed further. Whether this failure represents a problem unique to torcetrapib or is common among the entire class of CETP inhibitors remains to be determined.
o A recent study demonstrated that in patients with established coronary artery disease who have low HDL levels and low-risk LDL levels, drug therapy with medications that raise HDL levels and lower triglyceride levels but have no effect on LDL levels (eg, gemfibrozil) could significantly reduce the risk of major cardiac events.
o Currently, the accepted approach to the management of patients with coronary artery disease and low HDL levels is as follows:
+ In all persons with low HDL cholesterol levels, the primary target of therapy is to achieve the ATP III guideline LDL cholesterol level goals with diet, exercise, and drug therapy as needed.
+ After reaching the targeted LDL level goal, emphasis shifts to other issues. That is, in patients with low HDL cholesterol levels who have associated high triglyceride levels (>200 mg/dL), the secondary priority is to achieve the non-HDL cholesterol level goal of 30 mg/dL higher than the identified LDL cholesterol level goal. In patients with isolated low HDL cholesterol levels (triglycerides <200 mg/dL), drugs to raise the HDL cholesterol level (eg, gemfibrozil, nicotinic acid) can be considered. o Exercise training results in improvement of symptoms, increase in the threshold of ischemia, and improvement of patients' sense of well-being. However, before enrolling a patient in an exercise-training program, perform an exercise tolerance test to establish the safety of such a program. o Consider enteric-coated aspirin at a dose of 80-325 mg/d for all patients with stable angina who have no contraindications to its use.28,29 In patients in whom aspirin cannot be used because of allergy or gastrointestinal complications, consider clopidogrel.30 o Although early observational studies suggested a cardiovascular protective effect with the use of hormone replacement therapy, recent large randomized trials failed to demonstrate any benefit with hormone replacement therapy in the primary or secondary prevention of cardiovascular disease.31 + In fact, these studies even demonstrated an increased risk of coronary artery disease and stroke in patients on hormone replacement therapy. + The Women's Health Initiative study demonstrated that the use of hormone replacement therapy for 1 year in 10,000 healthy postmenopausal women is associated with 7 more instances of coronary artery disease, 8 more strokes, 8 more pulmonary emboli, 8 more invasive breast cancers, 5 fewer hip fractures, and 6 fewer colorectal cancers. + Based on these data, the risks and benefits of hormone replacement therapy must be assessed on an individual basis for each patient. * Sublingual nitroglycerin has been the mainstay of treatment for angina pectoris. Sublingual nitroglycerin can be used for acute relief of angina and prophylactically before activities that may precipitate angina. No evidence indicates that long-acting nitrates improve survival in patients with coronary artery disease.32 * Beta-blockers are also used for symptomatic relief of angina and prevention of ischemic events. They work by reducing myocardial oxygen demand and by decreasing the heart rate and myocardial contractility. Beta-blockers have been shown to reduce the rates of mortality and morbidity following acute MI.33 * Long-acting heart rate–slowing calcium channel blockers can be used to control anginal symptoms in patients with a contraindication to beta-blockers and in those in whom symptomatic relief of angina cannot be achieved with the use of beta-blockers, nitrates, or both. Avoid short-acting dihydropyridine calcium channel blockers because they have been shown to increase the risk of adverse cardiac events. * Anginal symptoms in patients with Prinzmetal angina can be treated with calcium channel blockers with or without nitrates. In one study, supplemental vitamin E added to a calcium channel blocker significantly reduced anginal symptoms among such patients.34 * In patients with syndrome X and hypertension, ACE inhibitors may normalize thallium perfusion defects and increase exercise capacity.35 Surgical Care * Revascularization therapy (ie, coronary revascularization) can be considered in patients with left main artery stenosis greater than 50%, 2- or 3-vessel disease and LV dysfunction (ejection fraction, <45%), poor prognostic signs during noninvasive studies, or severe symptoms despite maximum medical therapy. The 2 main coronary revascularization procedures are percutaneous transluminal coronary angioplasty, with or without coronary stenting, and coronary artery bypass grafting. * Patients with 1- or 2-vessel disease and normal LV function who have anatomically suitable lesions are candidates for percutaneous transluminal coronary angioplasty and coronary stenting. Restenosis is the major complication, with symptomatic restenosis occurring in 20-25% of patients. Restenosis mostly occurs during the first 6 months after the procedure and can be managed by repeat angioplasty. Several trials have demonstrated that the use of drug-eluting stents (eg, sirolimus-eluting stents, paclitaxel-coated stents) can remarkably reduce the rate of in-stent restenosis. With the introduction of these drug-coated stents, patients with multivessel coronary artery disease are more frequently treated with percutaneous revascularization as opposed to the surgical revascularization.36,37 More recently, some concerns have arisen that instead of improving the long-term prognosis, drug-eluting stents might actually worsen it. In addition, stent thrombosis is a major concern with the use of drug-eluting stents. A meta-analysis of individual data on 4,958 patients enrolled in 14 randomized trials comparing sirolimus-eluting stents with bare-metal stents looked at the long-term effect of these stents.37 The mean follow-up interval was 12.1-58.9 months. The primary end point was death from any cause. The secondary end points were stent thrombosis, the composite end point of death or myocardial infarction, and the composite of death, MI, or a revascularization. The overall risk of death and the combined risk of death or MI were not significantly different for patients receiving sirolimus-eluting stents versus bare-metal stents. A sustained reduction in the need for revascularization occurred after the use of sirolimus-eluting stents compared with bare-metal stents. The overall risk of stent thrombosis with sirolimus-eluting stents was not significantly higher than bare-metal stents. However, evidence showed an increase in the risk of stent thrombosis associated with sirolimus-eluting stents after the first year. * Patients with single-vessel disease and normal ventricular function treated with percutaneous transluminal coronary angioplasty show improved exercise tolerance and fewer episodes of angina compared with those who receive medical treatment. However, no difference in the frequency of MI or death has been shown between these two groups. * The Clinical Outcomes Utilizing Revascularization and AGgressive Drug Evaluation (COURAGE) trial looked at the benefits of PCI as an initial management strategy in patients with stable CAD. This trial was a randomized and involved 2287 patients who had objective evidence of myocardial ischemia and significant CAD.38 Of these, 1149 patients were randomized to undergo PCI with optimal medical therapy (PCI group) and 1138 were to receive optimal medical therapy alone (medical-therapy group). They were observed for 2.5-7 years (median, 4.6 y). During the follow-up, no difference was reported in the primary outcome of death from any cause and nonfatal MI between the PCI group and the medical-therapy group. In addition, no significant differences were noted between the 2 groups in the secondary end points of the composite of death, MI, and stroke; hospitalization for acute coronary syndrome; or MI. * Patients with significant left main coronary artery disease, 2- or 3-vessel disease and LV dysfunction, diabetes mellitus, or lesions anatomically unsuitable for percutaneous transluminal coronary angioplasty have better results with coronary artery bypass grafting. The overall operative mortality rate for coronary artery bypass grafting is approximately 1.3%. The rate of graft patency 10 years after surgery is less than 50% for vein grafting, although more than 90% of grafts using internal mammary arteries are patent at 10 years. In recent years, interest has increased regarding surgery without cardiopulmonary bypass (ie, off-pump) in an attempt to avoid the morbidity associated with cardiopulmonary bypass. A recent randomized study demonstrated that off-pump coronary surgery was as safe as on-pump surgery and caused less myocardial damage. However, the graft-patency rate was lower at 3 months in the off-pump group than in the on-pump group. * Laser transmyocardial revascularization has been used as an experimental therapy for the treatment of severe, chronic, stable angina refractory to medical or other therapies.39 This technique has been performed with either an epicardial surgical technique or by a percutaneous approach. In both approaches, a series of transmural endomyocardial channels are created to improve myocardial perfusion. The surgical transmyocardial revascularization technique has been associated with symptomatic relief for end-stage chronic angina in the short term. However, no published data address the long-term efficacy of surgical transmyocardial revascularization. Nonetheless, this technique appears to provide at least symptomatic relief for end-stage chronic angina in the short term.40 * A subgroup of patients with coronary artery disease experiences angina that is not amenable to revascularization and is refractory to medical therapy. Some studies have indicated that human CD34+ stem cells induce neovascularization in ischemic myocardium enhancing perfusion and function. The feasibility and safety of this treatment was tested in a recent phase I/IIa double-blind, randomized controlled trial of 24 patients (19 men and 5 women aged 48-84 y) with Canadian Cardiovascular Society class 3 or 4 angina who were undergoing optimal medical treatment and who were not candidates for mechanical revascularization.41 Patients received granulocyte colony-stimulating factor 5 microg x kg(-1) x d(-1) for 5 days with leukapheresis on the fifth day. Electromechanical mapping was performed to identify ischemic but viable regions of myocardium for injection of cells in the active treatment group versus saline injection in the placebo group. The total dose of cells was divided in 10 intramyocardial and transendocardial injections. There was no incidence of myocardial infarction, elevation of cardiac enzymes, perforation, or pericardial effusion. Also, there was no incidence of ventricular tachycardia or ventricular fibrillation during the administration of granulocyte colony-stimulating factor or intramyocardial injections. Serious adverse events were evenly distributed between the therapy and the control groups. A trend was demonstrated in frequency of angina, nitroglycerine usage, exercise time, and Canadian Cardiovascular Society class that favored CD34+ cell-treated patients versus control subjects given saline injections. Based on the results of this study a larger phase IIb study is currently under way to further evaluate this novel therapy. * Increased coronary sinus pressure has been suggested to reduce myocardial ischemia by redistribution of blood from nonischemic to ischemic areas. The Coronary Sinus Reducer (Neovasc Medical, Inc, Or Yehuda, Israel) is a percutaneous implantable device designed to establish coronary sinus narrowing and to elevate coronary sinus pressure. In a 2007 study, the safety and feasibility of the Coronary Sinus Reducer was evaluated in 15 patients with coronary artery disease and refractory angina who were not candidates for revascularization.42 All procedures were completed successfully and no procedure-related adverse events occurred during the periprocedural and the follow-up periods. Angina score improved in 12 of 14 patients. Also, the extent and severity of myocardial ischemia measured by dobutamine echocardiography and by thallium single-photon emission computed tomography was reduced significantly (p = 0.004 [n = 13] and p = 0.042 [n = 10], respectively). This study demonstrated that the implantable Coronary Sinus Reducers may be a feasible and safe treatment for patients with refractory angina. Further large clinical studies are needed before the use of these devices become an accepted treatment. Diet A diet low in saturated fat and dietary cholesterol is the mainstay of the Step I and Step II diet from the American Heart Association. Activity The level of activity that aggravates anginal symptoms is different for each patient. However, most patients with stable angina can avoid symptoms during daily activities simply by reducing the speed of activity. Medication The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Antiplatelet agents Prevent thrombus formation by inhibiting platelet aggregation. Aspirin is proven beneficial in primary and secondary prevention of coronary artery disease. In patients with aspirin intolerance, use clopidogrel. Clopidogrel is also used in combination with aspirin after coronary stent placement. Recently, clopidogrel use in addition to aspirin has been shown to be significantly superior to aspirin alone in patients with acute coronary syndrome without ST-segment elevation MI. Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin) Prevents platelet aggregation by irreversible cyclooxygenase inhibition with subsequent suppression of thromboxane A2. Antiplatelet effect can last as long as 7 d. * Dosing * Interactions * Contraindications * Precautions Adult 81-325 mg PO qd Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease salicylate serum levels; anticoagulants may cause additive hypoprothrombinemic effects and increased bleeding time; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; because of association with Reye syndrome, do not use in children ( <16 y) with flu

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, history of blood coagulation defects, or taking anticoagulants; adverse effects include prolonged bleeding time, rhinitis, asthma, urticaria, and exacerbation of gout; monitor BP, BUN, and uric acid level; consider discontinuing 7 d before surgery

Clopidogrel (Plavix)

Selectively inhibits ADP binding to platelet receptor and subsequent ADP-mediated activation of GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Consider in patients with contraindication to aspirin.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

75 mg PO qd
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Naproxen associated with increased occult GI blood loss; prolongs bleeding time; safety of coadministration with warfarin not established

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active pathological bleeding

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution in patients at increased risk of bleeding from trauma, surgery, or other pathological conditions; caution in patients with lesions with propensity to bleed (eg, ulcers); adverse effects include rash, diarrhea, purpura, GI ulcers, neutropenia, and rare cases of agranulocytosis; consider discontinuing 7 d before surgery
Beta-adrenergic blocking agents

Work by competing with endogenous catecholamines for beta-adrenergic receptors. Reduce myocardial oxygen consumption via several effects, including decrease in resting and exercise heart rates and reductions in myocardial contractility and afterload. Classified as nonselective, beta-1 selective, and having intrinsic sympathomimetic effects.

Metoprolol (Lopressor, Toprol XL)

Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. Is lipophilic and penetrates CNS.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

50-200 mg PO bid
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effects; sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives may increase toxicity; may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; uncompensated CHF; bradycardia; asthma; cardiogenic shock; AV conduction abnormalities

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Beta-adrenergic blockade may mask signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; monitor patient closely and withdraw drug slowly; during IV administration, carefully monitor BP, heart rate, and ECG; adverse effects include hypotension, decreased libido, impotence, lethargy, depression, and decreased HDL; may cause less bronchial tree and arterial smooth muscle constriction

Atenolol (Tenormin)

Selectively blocks beta-1 receptors with little or no effect on beta-2 receptors. Is hydrophilic and does not penetrate CNS.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

50-200 mg PO qd
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Aluminum salts, barbiturates, calcium salts, cholestyramine, NSAIDs, penicillins, and rifampin may decrease effects; haloperidol, hydralazine, loop diuretics, and MAOIs may increase toxicity

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; CHF; pulmonary edema; cardiogenic shock; AV conduction abnormalities; heart block (without pacemaker)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Beta-adrenergic blockade may hide symptoms of acute hypoglycemia and mask signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism and cause thyroid storm; monitor patients closely and withdraw drug slowly; adverse effects include bradycardia, hypotension, decreased libido, impotence, and decreased HDL; beta1-selective blockers may cause less bronchial tree and arterial smooth muscle constriction; titrate dose carefully to level of patient tolerance and effectiveness

Propranolol (Inderal)

Nonselective beta-blocker that is lipophilic (penetrates CNS). Although generally short-acting agent, long-acting preparations also available.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

IR: 40-160 mg PO bid
SR: 60-320 mg PO qd
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity; may increase toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; history of bronchospasm; uncompensated CHF; bradycardia; cardiogenic shock; AV conduction abnormalities

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Beta-adrenergic blockade may mask signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly and monitor closely; adverse effects include bronchial constriction, Raynaud phenomenon, hypotension, decreased libido, impotence, lethargy, depression, and decreased HDL; caution in Wolff-Parkinson-White syndrome and renal or hepatic dysfunction
Calcium channel blockers

Reduce transmembrane flux of calcium via calcium channels. Cause smooth muscle relaxation, resulting in peripheral arterial vasodilation and afterload reduction. Indicated when symptoms persist despite treatment with beta-blockers or when beta-blockers are contraindicated. Also indicated in patients with Prinzmetal angina with or without nitrates.

Amlodipine (Norvasc)

During depolarization, inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

5-10 mg PO qd
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Fentanyl may increase hypotensive effects; may increase cyclosporine levels; H2 blockers (eg, cimetidine) may increase toxic effects

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90 mm Hg systolic)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Severe aortic stenosis, CHF, hepatic dysfunction; adverse effects include headache, edema, flushing, palpitation, drowsiness, and fatigue

Diltiazem (Cardizem CD, Dilacor)

During depolarization, inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

IR: 120-360 mg PO divided tid/qid
SR: 120-480 mg PO qd
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

May increase carbamazepine, digoxin, cyclosporine, and theophylline levels; when administered with amiodarone, may cause bradycardia and decrease in cardiac output; when given with beta-blockers may increase cardiac depression; cimetidine may increase levels

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90 mm Hg systolic)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution in impaired renal or hepatic function; may increase LFT levels, and hepatic injury may occur; adverse effects include constipation, AV conduction block, worsening of heart failure, peripheral edema, bradycardia, and AV dissociation

Verapamil (Calan, Covera)

During depolarization, inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

IR: 80-120 mg PO tid/qid
SR: 120-240 mg PO qd/bid
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

May increase carbamazepine, digoxin, theophylline, and cyclosporine levels; amiodarone can cause bradycardia and decrease in cardiac output; when administered concurrently with beta-blockers may increase cardiac depression; cimetidine may increase levels

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90 mm Hg systolic)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Hepatocellular injury may occur; transient elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have occurred (elevations have been transient and may disappear with continued treatment); monitor liver function periodically; adverse effects include constipation, AV dissociation, worsening heart failure, bradycardia, negative inotropism, and hypotension
Short-acting nitroglycerins

Suitable for immediate relief of exertional or rest angina. Can also be used for prophylaxis several minutes before planned exercise to avoid angina. Reduce myocardial oxygen demand by reduction of LV and arterial pressure, primarily by reducing preload.

Nitroglycerin (Nitrostat, Nitro-bid, Nitrol)

Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic GMP production. Result is decrease in BP.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

0.3-0.6 mg SL prn
0.4 mg metered-dose spray PO prn
0.1-0.8 mg/h patch TD qd
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Concurrent sildenafil (Viagra) may cause severe hypotension and death; aspirin may increase serum concentrations; calcium channel blockers may cause markedly symptomatic orthostatic hypotension (dose adjustment of either agent may be necessary)

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe anemia; shock; postural hypotension; head trauma; closed-angle glaucoma; cerebral hemorrhage; hypertrophic obstructive cardiomyopathy

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution in coronary artery disease and low systolic BP; adverse effects include hypotension, flushing, headache, light-headedness, and tolerance (8- to 12-h nitrate-free interval is most effective method to prevent development of tolerance); high IV doses may cause methemoglobinemia, heparin resistance, and ethanol intoxication; ischemia may worsen upon withdrawal
Long-acting nitroglycerins

Reduce LV preload and afterload by venous and arterial dilation, which subsequently reduces myocardial oxygen consumption and relieves angina. Also cause dilation of epicardial coronary arteries, which is beneficial in patients with coronary spasm. In addition, nitroglycerin has antithrombotic and antiplatelet effects in patients with angina pectoris. No evidence suggests that nitrates improve survival or slow progression of coronary artery disease.

Isosorbide (Isordil, ISMO)

Relaxes vascular smooth muscle by stimulating intracellular cyclic GMP. Decreases LV pressure (ie, preload) and arterial resistance (ie, afterload). Reduces cardiac oxygen demand by decreasing LV pressure and dilating arteries.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Isosorbide dinitrate:
2.5-10 mg SL prn IR
10-30 mg PO bid/tid SR
80-120 mg PO qd IR
Isosorbide mononitrate:
10-20 mg PO bid SR
30-120 mg PO qd
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Alcohol may cause severe hypotension and cardiovascular collapse; aspirin may increase serum concentrations and actions; calcium channel blockers may increase symptomatic orthostatic hypotension (adjust dose of either agent); may decrease effects of heparin

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severe anemia; closed-angle glaucoma; postural hypotension; head trauma; cerebral hemorrhage

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Tolerance to vascular and antianginal effects of nitrates may develop; minimize tolerance by using smallest effective dose or pulse therapy (intermittent dosing) or by alternating with other coronary vasodilators (take last daily dose of short-acting agent no later than 7 pm); caution when administering to patients with glaucoma
Angiotensin-converting enzyme inhibitors

Angiotensin-converting enzyme (ACE) Inhibitors have been shown to reduce rates of death, MI, stroke, and need for revascularization procedures in patients with coronary artery disease or diabetes mellitus and at least one43 other cardiovascular risk factor, irrespective of the presence of hypertension or heart failure. The 2009 Canadian Hypertension Education Program recommends beta-blockers and ACE inhibitors as first-line therapy that patients with angina, recent myocardial infarction or heart failure.44


Ramipril (Altace)

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

2.5-5 mg PO qd; not to exceed 20 mg/d
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

May increase digoxin, lithium, and allopurinol levels; probenecid may increase levels; coadministration with diuretics increases hypotensive effects; NSAIDs may reduce hypotensive effects

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; history of angioedema

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Adverse effects include persistent cough, angioedema, hypotension, and prerenal azotemia; caution in renal impairment, valvular stenosis, or severe CHF
Anti-ischemic agents, miscellaneous

Ranolazine elicits action unlike beta-blockers, calcium antagonists, or nitrates. It does not affect hemodynamics or contractile and conduction parameters.

Ranolazine (Ranexa)

Cardioselective anti-ischemic agent (piperazine derivative) that partially inhibits fatty acid oxidation. Also inhibits late sodium current into myocardial cells and prolongs QTc interval. Indicated for chronic angina unresponsive to other antianginal treatments. Used in combination with amlodipine, beta-blockers, or nitrates. Unlike beta-blockers, calcium channel blockers, and nitrates, does not reduce blood pressure or heart rate. Effect on angina rate or exercise tolerance appears to be smaller in women than in men. Absorption is highly variable but unaffected by food.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

500 mg PO bid initially; if necessary, may increase to 1000 mg PO bid
Pediatric

Not established.Follow-up

Deterrence/Prevention:

* Coronary atherosclerosis is the main preventable cause of mortality in the United States. A rigorous effort to address correctable risk factors is the mainstay of preventive cardiovascular medicine.
* Smoking cessation is the single most effective preventive intervention to reduce coronary atherosclerosis prevalence. It has been associated with a coronary artery disease reduction of 7-47% in primary prevention settings.
* Aggressive treatment of diabetes mellitus, hypertension, LV hypertrophy, hyperlipidemia, and obesity has an important role in the prevention of coronary artery disease.
* The most important recent development in coronary atherosclerosis risk modification is the introduction of inhibitors of beta-hydroxy-beta-methylglutaryl coenzyme A reductase. Reductions of total and LDL cholesterol levels by 25% and 35%, respectively, can achieve a similar reduction in rates of total and coronary mortality, MI, and need for coronary revascularization.

Complications:

* Complications of angina pectoris include unstable angina, MI, and death.

Prognosis:

* Important prognostic indicators in patients with angina pectoris include LV function, severity and location of atherosclerotic lesions, and response of symptoms to medical treatment.
o LV function is the strongest predictor of long-term survival. Elevated LV end-diastolic pressure and volume along with reduced LV ejection fraction ( <40%) are poor prognostic signs.
o Critical lesions of left main and proximal left anterior descending coronary arteries are associated with a greater risk. Mortality rates are also directly associated with the number of epicardial arteries involved.
o Unstable angina, recent MI, or both is a sign of atherosclerotic plaque instability, which is a strong predictor of increased risk of short-term coronary events.
* A number of signs during noninvasive testing are predictive of a higher risk of coronary events, including ST-segment depression of more than 2 mm at a low workload, ST-segment depression that persists for more than 5 minutes after termination of exercise, and failure of blood pressure to rise or an actual drop in blood pressure.
* Patients who continue to smoke after an MI have a 22-47% increased risk of reinfarction and death.
* In general, Prinzmetal angina and syndrome X are associated with excellent long-term prognoses.

Patient Education:

* Educating patients about the benefits of smoking cessation, a low-cholesterol diet, physical activity, and periodic screening for diabetes mellitus and hypertension is the prime component of a long-term management plan.
* For excellent patient education resources, visit eMedicine's Circulatory Problems Center, Cholesterol Center, Heart Center, and Statins Center. Also, see eMedicine's patient education articles Angina Pectoris, High Cholesterol, Understanding Your Cholesterol Level, Lifestyle Cholesterol Management, Understanding Cholesterol-Lowering Medications, Chest Pain, Coronary Heart Disease, and Heart Attack.

Miscellaneous
Medicolegal Pitfalls

* In patients with stable angina pectoris, even the most carefully performed history and physical examination have limitations. Classification of these patients solely on the basis of history and physical examination findings may lead to serious mistakes. Some type of stress testing is usually indicated to confirm the diagnosis and quantitate the severity of ischemia.
* In women, elderly persons, and diabetic patients, coronary artery disease may manifest with atypical presentations other than angina pectoris, such as silent ischemia or infarction. Clinicians should use a careful approach when evaluating these patients.