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MD Consult: Books: Goldman: Cecil Medicine: Chapter 70 – ANGINA PECTORIS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 70 – ANGINA PECTORIS

Pierre Théroux

Definition

Angina is the most frequent clinical expression of myocardial ischemia. Ischemia, which rapidly develops when a mismatch arises between myocardial oxygen needs and myocardial oxygen supply, can be manifested clinically in many different ways besides angina, from no symptoms (e.g., silent ischemia) to unstable angina ( Chapter 71 ), myocardial infarction (MI; Chapters 69 , 71 , and 72 ), or sudden death ( Chapter 62 ). It may remain stable for a long time or be rapidly progressive. Conversely, atherosclerosis, which is the most common cause of myocardial ischemia, may evolve for years without any manifestations of ischemia.

Chest pain ( Chapter 48 ), which can be caused by various conditions that can originate from the heart or another source, may be ischemic or nonischemic and may or may not be related to coronary artery disease. In almost all instances, the diagnosis of angina is first clinical and then subsequently supported by appropriate diagnostic testing.

Epidemiology

It has been estimated that at least half of the 13 million individuals with coronary artery disease in North America suffer from angina pectoris and that more than 400,000 new cases emerge every year ( Chapter 49 ). An estimated 5.5 million patients come to emergency departments annually for chest pain, and about 1.5 million of them are hospitalized for unstable angina or non–ST segment elevation acute MI ( Chapter 71 ). Half of the 1.2 million patients hospitalized for ST segment elevation MI had prior angina. The annual death rate in patients with stable angina ranges from 1 to 3.2%, depending on the population studied. Although women may have typical angina less frequently than men do, coronary artery disease is the most common cause of death in women, and more women than men die annually of coronary heart disease (CHD) or its complications in the United States. Perhaps because of delayed diagnosis or less optimal therapy, the steady decline in CHD mortality in the United States and other developed countries has been greater in men than in women. It is estimated that the risk of coronary artery disease, MI, and angina among the 10.3 million Americans suffering from obstructive sleep apnea ( Chapter 101 ) is 4.5 times higher than in patients without sleep apnea.

Pathobiology

Atherosclerosis ( Chapter 69 ) by far is the most common anatomic substrate of angina, although angina can also often be evident in the absence of documented atherosclerosis on the angiogram. Ischemia develops when fixed obstructions become severe enough to impede coronary blood flow or when a clot or a spasm is superimposed on a less severe obstruction. Ischemia can further be modulated by hemodynamic status, emotional status, and associated diseases such as anemia ( Chapter 162 ) and hyperthyroidism ( Chapter 244 ). The immediate triggers are consequences of an excessive myocardial oxygen demand or a reduced capacity of supply. In stable angina, the trigger typically is exercise in the presence of a stenosis that reduces the lumen of an epicardial coronary artery by 50% or more, corresponding to a 75% or more reduction in the artery’s cross-sectional diameter.

Angina, which appears after only a few minutes of ischemia, is a complex phenomenon; its mechanisms are only partly explained. Primary angina is initiated by a reduction in oxygen supply, as found, for example, in Prinzmetal’s variant angina and acute MI. In secondary angina, such as effort angina, an increase in demand is the precipitating event. Angina also can be of mixed nature, with elements of both supply and demand. Mental stress, emotions, nycthemeral variations, the postprandial state, exposure to cold, and other personal circumstances may simultaneously reduce coronary flow and increase myocardial oxygen consumption.

Mechanisms for Chest Pain

Ischemia promotes the release of active substances, such as adenosine, bradykinin, lipoxygenase byproducts, and protons, that activate chemosensitive and mechanosensitive receptors and the vanilloid receptor 1 (VR1) widely expressed on capsaicin-sensitive nerves in the cardiovascular system. The signals are transmitted to afferent nerves that connect in the upper fifth sympathetic ganglia and upper thoracic spinal cord to converge with other afferent somatic nerves and descending supraspinal signals to be transmitted to the thalamus and the cortex. These interconnections explain the various facets of the somatic presentation of the anginal pain.

Myocardial Energetics

Myocardial metabolism is essentially aerobic. Free fatty acids and protons accumulate within a few seconds after oxygen deprivation; ST segment changes ensue within minutes, followed by appearance of chest pain. The major determinants of myocardial oxygen consumption associated with heart contraction are, in decreasing order of importance, heart rate, wall tension generated during systole (afterload), inotropic state of the myocardial cell (contractility), and end-diastolic volume (preload) ( Chapter 50 ).

Coronary Circulation

As myocardial oxygen extraction is already high in the basal state (75% at rest, 90% during ischemia), the adaptation of the heart to increasing demand is achieved mainly through vasodilation of coronary resistance vessels. During exercise, coronary blood flow can increase five-fold to six-fold from the resting value of 0.8 mL/g/min by means of the ability of the coronary circulation to autoregulate in response to changes in perfusion pressure and oxygen demand. This autoregulation is modulated by sympathetic and parasympathetic influences; by metabolic factors (primarily adenosine, a potent vasodilator resulting from oxidative phosphorylation of adenosine nucleotides that are produced when adenosine triphosphate use exceeds production); and by many other important vasoactive substances, such as nitric oxide and endothelin.

Coronary perfusion of the left ventricle is mainly during diastole, when wall tension and coronary resistance are lowest. As per Laplace’s law, an intramural gradient in tension—highest in the subendocardium and lowest in the subepicardium—renders subendocardial areas more sensitive to ischemia. The ischemia with both increased demand and decreased supply will therefore be more promptly evident in the subendocardium. More severe ischemia progresses transmurally from the subendocardial to the subepicardial areas. Acute occlusion in the absence of a collateral circulation is directly manifested as ST elevation.

A gradient of pressure across the coronary obstruction builds up as the severity of luminal obstruction increases. The pressure drop through a stenosis is influenced mainly by the cross-sectional area of the stenosis (D pressure × 1/area2 × length of stenosis × flow rate). The reduced distal pressure is associated with vasodilation, which limits the potential coronary reserve (i.e., the potential for any further increase in flow). Diagnostic tests such as the administration of adenosine and dipyridamole and the measure of the fractional flow reserve are based on this phenomenon ( Chapter 54 ).

In the absence of adequate collateralization, stenoses of more than 75% of the cross-sectional area (corresponding to more than 50% lumen diameter by angiography) result in ischemia when the energy requirements are high, as during exercise in stable effort angina. The threshold for ischemia decreases as the severity of the obstruction increases. The extreme is chest pain at rest caused by severe stenoses with inadequate collateral circulation, by thrombus formation in acute coronary syndromes ( Chapter 71 ), or by inappropriate spasm in Prinzmetal’s variant angina. An important contributor to ischemia in acute coronary syndromes is the shedding and distal embolization of plaque and thrombus material, which may occlude the microvasculature and result in cell necrosis and release of troponin.

Endothelium

The endothelium is an extremely active surface that produces potent vasoactive, anticoagulant, procoagulant, and fibrinolytic substances and inflammatory mediators ( Chapter 69 ). Nitric oxide, which is the most potent modulator of endothelial function, increases the intracellular content of cyclic guanosine monophosphate and mediates the vasodilator response to shear rate and a variety of vasoactive products, such as acetylcholine, adenosine diphosphate, bradykinin, and serotonin. The nitric oxide system, although important, is fragile and becomes ineffective in atherosclerotic vessels and when the endothelium is rendered dysfunctional by the presence of risk factors such as smoking, hypercholesterolemia, hypertension, and diabetes mellitus. Prostacyclin derived from the metabolism of arachidonic acid relaxes smooth muscle cells and inhibits platelet aggregation through an increase in the intracellular concentration of cyclic adenosine monophosphate. Endothelin produced by the endothelium is a potent vasoconstrictor with prolonged effect. The so-called syndrome X or microvascular angina relates to microvascular dysfunction in the absence of a detectable coronary occlusion or spasm in the large coronary vessels. It is a frequent and often disturbing cause of chest pain.

Inflammation and Active Plaque

Atherosclerosis is a degenerative process of the vessel wall associated with inflammation and autoimmune processes in response to injury such as oxidative stress and oxidized low-density lipoprotein cholesterol. The early endothelial dysfunction is accompanied by expression of cell adhesion molecules, monocyte-macrophage and lymphocyte infiltration, foam cell formation, cytokine production, and proliferation and migration of smooth muscle cells ( Chapter 69 ). In acute coronary syndromes, the culprit lesion is the site of exaggerated inflammatory reaction accompanied by degeneration of the matrix, rendering the plaque friable and prone to rupture under hemodynamic stress. Rupture exposes tissue factor to the circulating blood, resulting in thrombus formation. Conversely, the plaques in stable angina contain more collagen and a thicker cap, and they are less inflammatory. The elevation of inflammatory markers, particularly C-reactive protein in patients with CHD, is believed to be related to this inflammatory component of atherosclerosis.

Clinical Manifestations

Angina is most often identified by the characteristics of the chest pain (see Table 48-2 ). The pain usually builds up rapidly within 30 seconds and disappears in decrescendo within 5 to 15 minutes, more promptly when nitroglycerin is used. The pain may have visceral, somatic, and cerebral components. It is variably described but typically presents as tightness, squeezing, or constriction; some patients describe an ache, a feeling of dull discomfort, indigestion, or burning pain. The discomfort is most commonly midsternal and classically radiates to the neck, left shoulder, and left arm. It also can be precordial, and it may radiate to the right arm or back, jaw, and teeth (but rarely higher) or to the epigastrium (but rarely lower). The intensity of pain ranges from mild to severe discomfort, and its characteristics and triggers, although variable among patients, are usually reproducible in any given patient. A clenching of the fist over the sternum while describing the pain (Levine’s sign) is a classic representation of a patient with angina.

It is important to recognize angina equivalents in patients who deny pain or discomfort and instead report shortness of breath, dizziness, fatigue, sweating, or gastrointestinal complaints. When these symptoms occur in response to exercise or other stress, patients must be evaluated for possible myocardial ischemia.

Some patterns of angina are of particular interest. First-effort, warm-up, second-wind, or walk-through angina is manifested on first effort, often in the morning, and disappears with continued lighter exercise without reappearing on subsequent equivalent efforts. The mechanism probably is related to the phenomenon of ischemic preconditioning, which is reduced severity of ischemia after repeated short periods of occlusion and ischemia. Nocturnal angina may occur soon after lying down in patients with subclinical heart failure because of an increase in venous return; in the early morning hours, at the time the sympathetic tone is highest in patients with vasospastic disease; or any time in patients with sleep apnea.

Postprandial angina develops during or soon after meals because of an increased oxygen demand in the splanchnic vascular bed. New-onset or de novo angina and progressive angina imply a period of instability that may be defined as unstable angina, especially if the pain occurs at rest or the symptoms are progressive; these patients need close observation until the pattern stabilizes. Silent ischemia is diagnosed when no or minimal symptoms can be evoked despite objective documentation of myocardial ischemia, but in retrospect, subtle symptoms can often be elicited in these patients. At the other extreme, status anginosus is severe class IV angina that has reached a chronic phase and that is refractory to treatment; it is usually associated with extensive atherosclerosis not amenable to reperfusion.

Classifications of Angina

Various classifications have addressed the pathophysiology, diagnosis, severity, and prognosis of angina. The distinction between unstable and stable angina ( Fig. 70-1 ) is based on the pattern of angina: its frequency, triggers, thresholds, severity, duration, accompanying manifestations, and responsiveness to rest or nitroglycerin. Angina is considered stable when symptoms have not been changing recently but rather are precipitated by a degree of effort that is reasonably predictable from day to day and are relieved by rest, more rapidly when nitroglycerin is used. Conversely, a lowering threshold to pain and progression in frequency, severity, or duration of symptoms evoke a diagnosis of unstable angina ( Chapter 71 ).

FIGURE 70-1  Evaluation of chest pain. ACS = acute coronary syndrome; CABG = coronary artery bypass graft; LV = left ventricular; PCI = percutaneous coronary intervention.

Typical angina is defined by an affirmative answer to three simple questions: (1) Is the discomfort substernal? (2) Is it precipitated by exertion? and (3) Is it promptly relieved by rest or nitroglycerin? The interpretation of two affirmative answers is atypical angina, and none or one is noncardiac chest pain. Atypical angina is more frequent in women, who often have a more variable angina threshold as well as a pain that may have an atypical location or description. Elderly patients often complain of dyspnea, weakness, and sweating. Diabetic patients may feel no or subtle symptoms in association with myocardial ischemia. However, unstable angina by definition exhibits atypical features. The prodromal symptoms to an acute coronary syndrome can include fatigue, sleep disturbance, shortness of breath, and poor correlation of symptoms with exercise. Significant coronary artery disease also can often coexist with noncoronary chest pain, so individuals in a susceptible age group with CHD risk factors deserve further evaluation despite atypical pain.

Approximately 80% of individuals with typical symptoms have demonstrable coronary artery disease and evidence of myocardial ischemia; 20% of patients, however, including a higher percentage of younger patients without risk factors, have no evidence of myocardial ischemia despite typical complaints ( Table 70-1 ). In patients with atypical angina, the prevalence of underlying coronary artery disease and myocardial ischemia varies widely from 20% to more than 90%, depending on age and CHD. The Canadian Cardiovascular Society classification, which is the most widely used approach assessing disability due to angina (see Table 48-4 ), helps guide management, even though its predictive value for the extent and severity of coronary artery disease is poor and its prognostic value for subsequent events is weak.


TABLE 70-1   — 
PROBABILITY (%) OF CORONARY ARTERY DISEASE BY AGE, GENDER, AND SYMPTOMS

Gender Age (yr) Definite Angina Atypical Angina Noncardiac Chest pain
Men 30–39 83 46 3
  40–49 88 57 12
  50–59 94 71 18
  60–69 95 78 31
  ≥70 97 94 63
Women 30–39 20 4
  40–49 56 31 4
  50–59 68 30 6
  60–69 81 48 10
  ≥70 96 56

From Chaitman BR, Bourassa MG, Davis K, et al: Angiographic prevalence of high-risk coronary artery disease in patient subsets (CASS). Circulation 1981;64:360–367.

Diagnosis

History

Chest pain can be due to a variety of extracardiac or cardiac causes, and cardiac pain can be ischemic or not ( Table 70-2 ). Ischemic pain is generally related to obstructive coronary atherosclerosis, but it also can be caused by congenital anatomic abnormalities interfering with epicardial flow, such as a congenital abnormality of the coronary circulation, or focal systolic compression of a tunneled epicardial artery by an overlying band of cardiac muscle (termed a myocardial bridge).


TABLE 70-2   — 
DIFFERENTIAL DIAGNOSIS OF CHEST PAIN

   ISCHEMIC PAIN
   Cardiac origin

   Decreased oxygen supply

   Coronary atherosclerosis

   Significant atherosclerosis
   Coronary thrombosis
   Coronary, nonatherosclerotic causes

   Aortic or coronary dissection
   Coronary spasm
   Microvascular spasm
   Cocaine-induced vasoconstriction
   Increased oxygen demand

   Hypertrophic cardiomyopathy
   Aortic stenosis
   Dilated cardiomyopathy
   Increased preload (e.g., aortic or mitral valve regurgitation)
   Tachycardia
   Myocardial bridging
   Congenital abnormality of the coronary circulation
   Noncardiac origin

   Decreased oxygen supply

   Anemia, sickle cell disease
   Hypoxemia (e.g., sleep apnea, pulmonary fibrosis, chronic lung disease, pulmonary embolism)
   Carbon monoxide intoxication
   Hyperviscosity (e.g., polycythemia, hypergammaglobulinemia)
   Increased oxygen demand

   Hyperthyroidism
   Hyperthermia
   High inotropic state (e.g., adrenergic stimulation)
   NONISCHEMIC PAIN
   Cardiac origin

   Pericarditis
   Aortic dissection
   Noncardiac origin

   Gastrointestinal: esophageal (esophagitis, spasm, reflux, rupture, ulcer); biliary (colic, cholecystitis); gastric (peptic ulcer); pancreatitis
   Psychogenic: anxiety disorders (hyperventilation, panic); affective disorders (depression); somatization; cardiac psychosis
   Pulmonary: pulmonary embolism, pneumothorax, pleuritis, pneumonia, pulmonary hypertension
   Neuromuscular: costochondritis, fibrositis, Tietze’s syndrome, rib fracture, herpes zoster, thoracic outlet syndrome, sternoclavicular arthritis

Angina can also result from conditions that increase myocardial oxygen demand beyond supply, including tachyarrhythmias, aortic valve stenosis ( Chapter 75 ), hypertrophic cardiomyopathy ( Chapter 59 ), uncontrolled hypertension ( Chapter 66 ), and cocaine intoxication ( Chapter 32 ), or conditions that limit oxygen delivery, such as anemia and carbon monoxide intoxication. Angina or ischemia that is associated with normal epicardial coronary arteries is commonly related to endothelial dysfunction with failure of normal vasodilation in resistance vessels; a lowered threshold to pain may also contribute in some patients.

Nonischemic, noncardiac pain can be caused by pulmonary, gastrointestinal, chest wall, and psychogenic conditions ( Chapter 48 ). In acute situations, aortic dissection ( Chapter 78 ), acute pericarditis ( Chapter 77 ), pulmonary embolism ( Chapter 99 ), or pneumothorax ( Chapter 100 ) must be considered. The clinical picture and differential diagnosis of chest pain can be blurred by the interactions that exist between the different mechanisms of chest pain and the locations of referred pain.

An accurate diagnosis of angina requires an objective documentation of myocardial ischemia associated with the chest pain. No historical evidence, physical examination findings, or other diagnostic tests are perfectly accurate for the diagnosis.

Physical Examination

The physical examination is of limited help in evaluating a patient with chest pain. The examination can occasionally identify cardiac or noncardiac causes of chest discomfort other than CHD, such as aortic stenosis, pericarditis, aortic dissection, costochondritis, and pulmonary disorders (see Tables 48-2 and 70-2 ). The physical examination may also increase the likelihood of CHD by detecting hypertension, xanthomas, xanthelasma, corneal arcus, obesity, diminished pulses, or vascular bruits. Indirect signs of transient myocardial ischemia on the physical examination include pulmonary rales, S4 or S3 gallop, sustained or dyskinetic left ventricular impulse, transient murmur of mitral regurgitation caused by papillary muscle dysfunction, and paradoxical splitting of S2 due to transient left ventricular dysfunction or left bundle branch block.

Diagnostic Tests

Blood Tests

Routine blood tests are not diagnostic in angina but are important to assess risk factors and abnormalities that may precipitate or worsen angina and to distinguish unstable angina from a non–ST elevation acute MI ( Table 70-3 ). The laboratory evaluation should include a complete blood cell count to exclude anemia and thyroid function tests to exclude hyperthyroidism or hypothyroidism, which may precipitate or worsen angina. Creatinine and blood urea nitrogen levels assess the possibility of renal insufficiency as a precipitating or aggravating cause, may influence drug therapy, and help determine prognosis. Patients should also be routinely evaluated for CHD risk factors, including an evaluation for hyperlipidemia ( Chapter 217 ) and diabetes mellitus ( Chapter 247 ). Elevated levels of C-reactive protein identify patients at higher risk for an adverse outcome. Homocysteine levels can also be assessed, although the benefit of treatment has not yet been documented. Markers of myocyte damage (troponin T, troponin I, creatine kinase [CK]-MB) are not routinely indicated except to distinguish unstable angina from a non–ST segment elevation MI ( Chapter 71 ).


TABLE 70-3   — 
OTHER LABORATORY TESTS SUGGESTED IN PATIENTS WITH STABLE ANGINA

   LDL and HDL cholesterol levels (apolipoprotein B, apolipoprotein A-I)
   Triglyceride level
   Fasting glucose concentration
   Creatinine levels
   Homocysteine level in patients with strong family history, especially if not explained by other risk factors
   Hemoglobin, hematocrit
   Test of thyroid function (T4 or TSH level)
   Consider C-reactive protein levels[*]
   Troponin T or troponin I, CK-MB[]

Modified from Braunwald E, Goldman L (eds): Primary Care Cardiology, 2nd ed. Philadelphia, WB Saunders, 2003.

CK-MB = creatine kinase MB; HDL = high-density lipoprotein; LDL = low-density lipoprotein; T4 = thyroxine; TSH = thyroid-stimulating hormone.

* C-reactive protein levels are useful to assess prognosis and may help treatment selection, such as statin therapy.
Should be obtained when a diagnosis of acute coronary syndrome is considered.

Resting Electrocardiogram

A 12-lead electrocardiogram (ECG) recorded in a pain-free state may show arrhythmias, a previous MI, or left ventricular hypertrophy. Obtained during or shortly after an episode of chest pain, the ECG is extremely useful for the diagnosis of ischemia as well as its location, extent, and severity. ST segment shift, most often depression, is the most specific finding, followed by T wave inversion ( Fig. 70-2 ). Pseudonormalization of these anomalies during pain is also a reliable indicator of ischemia. Transient ST segment elevation during pain is indicative of Prinzmetal’s angina or of a severely obstructive lesion with impending MI. Deep T wave inversion in the anterior leads, sometimes more evident in the hours or days that follow an episode of angina, is a marker of significant stenosis of the left anterior descending coronary artery. Diffuse ST changes with an elevation in lead aVR suggest left main disease or multivessel disease.

FIGURE 70-2  Typical electrocardiographic ST segment depression associated with myocardial ischemia. A, Lead V5 at rest. B, Lead V5 at peak exercise. The PQ junction (1) that serves as the baseline reference, the J point (2), and the ST segment at 80 msec past the J point (3) are represented. In this case, the amount of ST segment depression measured 80 msec past the J point is 0.4 mV or 4 mm, and the slope between the J point and 80 msec past the J point is nonexistent since the ST segment is horizontal and not upsloping.

Radiology

A chest radiograph ( Chapter 51 ) is recommended when an intrathoracic disease such as lung disease, pulmonary embolism, or aortic aneurysm is a diagnostic possibility and in patients with suspected heart failure.

Electron beam computed tomography ( Chapter 54 ) permits detection and quantification of coronary artery calcification with a high sensitivity, but calcification alone cannot predict the severity of stenoses. Computed tomography and magnetic resonance angiography are promising tests that are not yet recommended for routine use.

Echocardiography

Echocardiography ( Chapter 53 ) is useful for the evaluation of left ventricular function and valve disease. An echocardiogram should be obtained in patients with a systolic murmur suggestive of aortic stenosis, hypertrophic cardiomyopathy, or mitral regurgitation and to evaluate the severity of ischemic wall motion abnormalities when the test can be obtained during pain or within 30 minutes after its resolution. In patients who have angina and a history of previous MI or symptoms of heart failure, left ventricular function should be assessed quantitatively by echocardiography ( Chapter 53 ) or nuclear techniques ( Chapter 54 ). The combination of significant coronary artery disease and left ventricular dysfunction is associated with a poor prognosis that can often be improved with revascularization (see later). Segmental dysfunction can relate to stunned myocardium (transient dysfunction secondary to acute ischemia) or hibernating myocardium (poorly functioning myocardium secondary to chronic hypoperfusion). These conditions are reversible with appropriate treatment.

Provocative Testing

Standard stressors for provocative testing are exercise on the treadmill or cycle ergometer and pharmacologic stimulation with dobutamine, dipyridamole, or adenosine. Dobutamine produces ischemia by increasing myocardial oxygen needs through chronotropic and inotropic stimulation; adenosine, by potent vasodilation that produces heterogeneous perfusion in the presence of flow-limiting stenoses while the vasodilation in nonobstructed arteries may steal blood away from vessels that already are maximally dilated distal to an occluded vessel; and dipyridamole, by adenosine release. Markers of ischemia during testing are ST segment shifts on the ECG (see Fig. 70-2 ), a perfusion defect on a planar or single-photon emission computed tomography nuclear scan (see Fig. 54-1 ) or on a positron emission tomography scan, and wall motion abnormalities and systolic thinning on an echocardiogram (see Fig. 53-6 ). Combined computed tomography and positron emission tomography allow concomitant studies of coronary anatomy, myocardial perfusion, and metabolism.

Exercise testing with ECG monitoring remains the provocative test recommended for routine use because it mimics physiology and is readily available, inexpensive, and safe. Death or MI occurs in less than one case per 2500 tests if the test is avoided in patients with severe aortic stenosis, severe hypertension, or uncontrolled heart failure. Other contraindications are acute MI, symptomatic arrhythmias, acute pulmonary embolism, pericarditis, and acute aortic dissection. Relative contraindications are hypertension greater than 200 mm Hg systolic or 110 mm Hg diastolic, hypertrophic cardiomyopathy, and high-degree atrioventricular block.

The exercise test protocol is usually adjusted to a patient’s tolerance, aiming for 6 to 12 minutes of exercise time to achieve maximal oxygen consumption. Exercise that is too strenuous with rapid workload increments shortens the duration of the test and may lower the sensitivity for detecting ischemia and estimating exercise capacity; tests that are too easy become measures of endurance. In the commonly used and well-validated Bruce protocol ( Table 70-4 ), the increase in workload between the various stages is relatively large. Less aggressive protocols, such as the Naughton, Weber, and Asymptomatic Cardiac Ischemia Pilot (ACIP) study or a ramp protocol, are preferred in patients with a reduced tolerance.


TABLE 70-4   — 
COMMON EXERCISE TEST PROTOCOLS

Protocol Stage Duration (min) Grade (%) Rate (mph) Metabolic Equivalents at Completion Functional Class
Modified Bruce protocol[*] 1 3 0 1.7 2.5 III
  2 3 10 1.7 5 II
  3 3 12 2.5 7 I
  4 3 14 3.4 10 I
  5 3 16 4.2 13 I
Naughton protocol[] 0 2 0 2 2 III
  1 2 3.5 2 3 III
  2 2 7 2 4 III
  3 2 10.5 2 5 II
  4 2 14 2 6 II
  5 2 17.5 2 7 I

Modified from Braunwald E, Goldman L (eds): Primary Cardiology, 2nd ed. Philadelphia, WB Saunders, 2003.

Ramp protocols in which the workload is gradually increased on the basis of the patient’s estimated functional capacity to achieve maximal effort in approximately 10 minutes are also useful.

* Commonly used in ambulatory patients.
Commonly used in patients with recent myocardial infarction, unstable angina, or other conditions that are expected to limit exercise.

An issue with exercise testing is its predictive value. On the basis of Bayes’ theorem ( Chapter 9 ), ST segment shifts on exercise testing in patients with a low probability of angina will most often be false-positives, whereas the same changes in patients with a higher clinical probability of the disease will almost always represent true-positives. It can be argued that a positive test result only confirms a diagnosis when the probability of CHD is high, whereas a negative test result is not discriminatory enough for diagnosis, and that a negative test result is only confirmatory when the probability is low, whereas a positive test result has little effect on the probability ( Fig. 70-3 ). As a result, the strongest indication for diagnostic exercise testing is in patients with an intermediate (10% and 90%) pretest probability of CHD (see Table 70-1 ). The test is less useful for diagnosis in patients with a high or a low pretest probability, and it is not recommended for patients with an abnormal baseline ECG (e.g., left bundle branch block, resting ST segment elevation or depression, use of digitalis, Wolff-Parkinson-White syndrome, electrolyte abnormalities) that precludes the interpretation of ST segment change. However, exercise testing can be helpful for purposes other than the diagnosis of CHD, such as the evaluation of exercise tolerance and functional capacity, arrhythmias, and prognosis. An exercise test also may be appropriate in asymptomatic individuals with diabetes or other CHD risk factors before they undertake an exercise program or in individuals with calcifications on electron beam computed tomography ( Chapter 54 ). A negative test result in asymptomatic persons or in individuals with noncardiac chest pain (probability of coronary artery disease less than 15%) virtually excludes ischemic heart disease.

FIGURE 70-3  A, Approximate probability of coronary artery disease before and after noninvasive testing in a patient with typical angina pectoris. These percentages demonstrate how the sequential use of an ECG and an exercise thallium test may affect the probability of coronary artery disease in a patient with typical angina pectoris. B, Approximate probability of coronary artery disease before and after noninvasive testing in a patient with atypical angina symptoms. C, Approximate probability of coronary artery disease before and after noninvasive testing in an asymptomatic subject in the coronary artery disease age range.  (Redrawn from Branch WB Jr [ed]: Office Practice of Medicine, 3rd ed. Philadelphia, WB Saunders, 1994, p 45.)

In many patients, the standard exercise ECG can be complemented with perfusion imaging for more precise diagnosis (see Fig. 70-3 ) or should be replaced by an alternative diagnostic approach ( Table 70-5 ). Exercise perfusion or echocardiography is preferred to an exercise ECG in patients with resting ST segment abnormalities secondary to left ventricular hypertrophy, intraventricular conduction defect, preexcitation, electrolyte abnormalities, or digitalis use. Imaging is also indicated in patients with an abnormal ECG after a previous MI or coronary artery bypass grafting.


TABLE 70-5   — 
SUGGESTED NONINVASIVE TESTS IN DIFFERENT TYPES OF PATIENTS WITH STABLE ANGINA

Exertional angina, mixed angina, walk-through angina, postprandial angina with or without prior myocardial infarction  
Normal resting ECG Treadmill exercise ECG test
Abnormal, uninterpretable resting ECG Exercise myocardial perfusion scintigraphy (201Tl, 99mTc-sestamibi) or exercise echocardiography
Unsuitable for exercise Dipyridamole or adenosine myocardial perfusion scintigraphy, dobutamine stress echocardiography
Atypical chest pain with normal or borderline abnormal resting ECG or with nondiagnostic stress ECG, particularly in women Exercise myocardial perfusion scintigraphy, exercise echocardiography
Vasospastic angina ECG during chest pain, ST segment ambulatory ECG, exercise test
Dilated ischemic cardiomyopathy with typical angina or for assessment of hibernating or stunned myocardium Regional and global ejection fraction by radionuclide ventriculography or two-dimensional echocardiography, radionuclide myocardial perfusion scintigraphy; in selected patients, flow and metabolic studies with positron emission tomography
Syndrome X Treadmill exercise stress ECG, coronary blood flow by positron emission tomography, Doppler probe
Known severe aortic stenosis or severe hypertrophic cardiomyopathy with stable angina Exercise stress tests contraindicated; dipyridamole or adenosine myocardial perfusion scintigraphy in selected patients; coronary angiography preferred
Mild aortic valvar disease or hypertrophic cardiomyopathy with typical exertional angina “Prudent” treadmill myocardial perfusion scintigraphy, dipyridamole or adenosine myocardial perfusion scintigraphy

Modified from Braunwald E, Goldman L (eds): Primary Care Cardiology, 2nd ed. Philadelphia, WB Saunders, 2003.

ECG = 12-lead electrocardiogram.

Pharmacologic stress testing with dipyridamole or adenosine is preferred to exercise in patients who cannot exercise adequately; ischemia is then assessed by perfusion scintigraphy with thallium Tl-201 or technetium Tc-99m–sestamibi ( Chapter 54 ) or by echocardiography ( Chapter 53 ). Fixed perfusion deficits usually represent previous MI, whereas reversible deficits present only after exercise represent transient ischemia. Alternatively, reversible wall motion abnormalities and systolic wall thinning on echocardiography are indicators of reversible ischemia.

The overall sensitivity of exercise ECG for detecting coronary artery disease is about 70%, and its specificity for excluding coronary artery disease is about 75% ( Table 70-6 ). ECG abnormalities most likely to indicate significant ischemia are horizontal or downsloping ST segment depression of more than 1 mV (see Fig. 70-2 ) and occurrence of symptoms consistent with angina. Many other specific and nonspecific features, such as dyspnea and a low tolerance, are of prognostic significance.


TABLE 70-6   — 
APPROXIMATE SENSITIVITY AND SPECIFICITY OF COMMON TESTS TO DIAGNOSE CORONARY ARTERY DISEASE

    Sensitivity Specificity
Exercise electrocardiography
  >1 mV ST depression 0.70 0.75
  >2 mV ST depression 0.33 0.97
  >3 mV ST depression 0.20 0.99
Perfusion scintigraphy
  Exercise SPECT 0.88 0.72
  Pharmacologic SPECT 0.90 0.82
Echocardiography
  Exercise 0.85 0.81
  Pharmacologic stress 0.81 0.79
PET 0.95 0.95

From Gibbons RJ, Abrams J, Chatterjee K, et al: ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation 2003;107:149–158.

PET = positron emission tomography; SPECT = single-photon emission computed tomography.

The sensitivity and specificity of imaging approaches are, in general, higher than those of the ECG, although they are also influenced by the pretest likelihood of the disease (see Table 70-6 ). False-negative perfusion scans occur in patients with three-vessel disease and global left ventricular ischemia because low flow is diffuse rather than focal. The positron emission tomography scan provides high-quality imaging corrected for soft tissue attenuation and is the “gold standard” for assessing viability in areas of dysfunction. The choice among stress perfusion imaging, stress echocardiography, and positron emission tomography is largely a matter of local expertise, although a patient’s individual characteristics occasionally can be compelling (see Table 70-5 ).

Continuous ECG monitoring allows detection of otherwise clinically silent ischemia. Many patients with symptomatic angina also experience multiple additional episodes of asymptomatic ischemia with a total ischemic burden higher than clinically suspected. Control of asymptomatic ischemia by approaches that reduce ischemic burden rather than focus on symptoms may improve prognosis in some patients with episodes of silent ischemia.

Coronary Angiography

Coronary angiography ( Chapter 56 ) remains the current standard for assessing the presence and severity of CHD and is required for guiding revascularization procedures ( Table 70-7 ). Indeed, some patients may be incorrectly diagnosed with CHD for years until angiography shows no disease, whereas other patients may be treated symptomatically for noncardiac diseases until angiography documents CHD.


TABLE 70-7   — 
CORONARY ANGIOGRAPHY FOR DIAGNOSIS AND RISK STRATIFICATION IN PATIENTS WITH ANGINA

FOR DIAGNOSTIC PURPOSE
Recommended on the basis of evidence or general consensus
Patients with suspect angina or with a changing angina pattern surviving sudden cardiac death
Weight of evidence or opinion is in favor
Uncertain diagnosis after noninvasive testing, and the benefit of a more certain diagnosis outweighs the risk and cost of coronary angiography
Inability to undergo noninvasive testing because of disability, illness, or morbid obesity
Occupational requirement for a definitive diagnosis
Suspected nonatherosclerotic cause of myocardial ischemia
Suspicion of a coronary spasm
High pretest probability of left main or three-vessel disease
Recurrent hospitalization for chest pain in the absence of definitive diagnosis
Overriding desire for a definitive diagnosis and a greater than low probability of CAD
Not recommended
Significant comorbidity in patients in whom the risk of coronary arteriography outweighs the benefit of the procedure
Overriding personal desire for a definitive diagnosis and a low probability of CAD
FOR RISK STRATIFICATION OR TREATMENT
Recommended on the basis of evidence or general consensus
With disabling (CCS class III and class IV) chronic stable angina despite medical therapy
With high-risk criteria on noninvasive testing regardless of anginal severity
Patients with angina who have survived sudden cardiac death or serious ventricular arrhythmia
Angina and symptoms and signs of congestive heart failure
Clinical characteristics that indicate a high likelihood of severe CAD
Weight of evidence or opinion is in favor
Significant left ventricular dysfunction (EF <45%), CCS class I or class II angina, and demonstrable ischemia but less than high-risk criteria on noninvasive testing
High-risk criteria suggesting ischemia on noninvasive testing
Inadequate prognostic information after noninvasive testing
Clinical characteristics that indicate a high likelihood of severe
CAD
CCS class I or class II angina, preserved left ventricular function (EF >45%), and less than high-risk criteria on noninvasive testing
CCS class III or class IV angina that improves to class I or class II with medical therapy
CCS class I or class II angina but intolerance (unacceptable side effects) to adequate medical therapy
Not recommended
CCS class I or class II angina in patients who respond to medical therapy and who have no evidence of ischemia on noninvasive testing
Patients who prefer to avoid revascularization after adequate explanation

Modified from Gibbons RJ, Abrams J, Chatterjee K, et al: ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation 2003;107:149–158.

CAD = coronary artery disease; CCS = Canadian Cardiovascular Society; CHD = coronary heart disease; EF = ejection fraction.

Fractional Flow Reserve Coronary Angiography

Fractional flow reserve (FFR) can be measured only in the catheterization laboratory. A pressure guidewire positioned distal to the stenosis provides the distal pressure (Pd); the aortic pressure (Pa) is measured through the guiding catheter. Maximal hyperemia is induced by the administration of a potent vasodilator such as adenosine, adenosine triphosphate, or papaverine and measured as the ratio of mean distal pressure to mean aortic pressure (FFR = Pd/Pa). A cutoff value of 0.75 permits accurate discrimination between coronary obstructive lesions that induce ischemia and those that do not. Although it is simple and helpful to evaluate the prognosis of patients and to establish the indication for revascularization of stenoses of doubtful significance, its application has been limited because of the hardware required.

Other Anginal Syndromes

Variant Angina or Prinzmetal’s Angina

The diagnosis is based on the documentation of transient ST segment elevation during an episode of chest pain in the absence of a focal, severe, fixed coronary stenosis. The chest pain occurs predominantly at rest, although approximately one third of patients may also experience the pain during exercise. There is a predilection for the pain to wake the patient in the early morning hours when sympathetic activity is increasing. The syndrome is often cyclical, with periods of exacerbation with repetitive episodes of chest pain that may persist only for seconds or be more prolonged and severe, alternating with periods with few or no symptoms. The pain is typically relieved by nitroglycerin. The ST segment elevation accompanying the pain signifies transmural ischemia due to total abrupt occlusion of a nonsignificant stenosis in the absence of a collateral circulation. The subsequent rapid reperfusion may explain the high prevalence of severe life-threatening arrhythmias.

Prinzmetal’s variant angina typically is caused by an occlusive spasm superimposed on a nonsevere coronary artery stenosis; however, at times, no underlying stenoses are seen, or the underlying stenosis may be severe. Because of these uncertainties, it is mandatory to perform coronary angiography in all patients with vasospastic disease. Associated Raynaud’s phenomenon and migraine headache have been described in some patients, suggesting that the syndrome may be part of a more generalized vasospastic disorder. A provocative test for spasm with acetylcholine or ergonovine is useful to establish the diagnosis and to assess the response to therapy in patients with normal or nearly normal coronary angiograms, in whom the diagnosis is otherwise unclear.

Angina with Normal Coronary Angiography

The chest pain in this syndrome occurs most frequently at rest, often in relation to emotional stress; periods of exacerbation commonly alternate with symptom-free periods. It is more frequent in women, and an important component is altered perception of pain or hypersensitivity to certain stimuli. The diagnosis requires objective documentation of ischemia with ST-T segment changes, of a metabolic abnormality, of transient regional perfusion defect, or of endothelial dysfunction that limits blood flow reserve. β-Blockers may be useful, particularly when a relative tachycardia, hypertension, or decreased heart rate variability on Holter monitoring is present. Nitroglycerin can relieve symptoms in approximately 50% of patients, and long-acting nitrates or calcium antagonists are sometimes helpful. Prognosis in general is favorable and not different from that of a general age-matched population in the absence of coronary artery disease.

Risk Stratification

Risk stratification incorporates demographic data (e.g., age, sex), risk factors, findings on physical examination, and diagnostic testing ( Fig. 70-4 ). Abnormal blood lipids and cigarette smoking are the two most important risk factors, and these two plus high blood pressure, diabetes, abdominal obesity, stress, lack of daily consumption of fruits and vegetables, lack of daily exercise, and absence of regular consumption of small amounts of alcohol predict more than 90% of the risk of an MI worldwide.

FIGURE 70-4  Approach to the use of stress testing and angiography for the evaluation of chronic stable angina. ECG = electrocardiogram.  (Modified from American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Management of Patients with Chronic Stable Angina. ACC/AHA/ACP-ASIM Pocket Guidelines. Elsevier Science, 2000.)

High-risk findings on an exercise test include ST segment depression of 2 mm or more, ST segment depression of 1 mm or more in the first stage of the Bruce protocol, sustained ST segment depression of 5 minutes or more after cessation of exercise, blood pressure decrease of 10 mm Hg or more, severe ventricular arrhythmias during or after exercise at a heart rate of 120 beats per minute, and inability to complete the equivalent of 6 minutes of the Bruce protocol. Less specific symptoms, such as dyspnea, are also important for prognosis.

High-risk features on the nuclear scan are ischemia of more than 15% of the left ventricle, multiple perfusion defects in more than one vascular bed, large and severe perfusion defects, left ventricular dilation, uptake of the tracer in the lung with exercise, and postexercise left ventricular dilation. High-risk stress echocardiographic criteria are multiple reversible wall motion abnormalities and more severe and extensive abnormalities (see Table 70-8 ).


TABLE 70-8   — 
USING THE RESULTS OF NONINVASIVE TESTING FOR RISK STRATIFICATION

HIGH RISK (>3% ANNUAL MORTALITY RATE)
Severe resting left ventricular dysfunction (LVEF <35%)
High-risk treadmill score (score ≤- 11)[*]
Severe exercise left ventricular dysfunction (exercise LVEF <35%)
Stress-induced large perfusion defect (particularly if anterior)
Stress-induced multiple perfusion defects of moderate size
Large, fixed perfusion defect with left ventricular dilation or increased lung uptake (201Tl)
Stress-induced moderate perfusion defect with left ventricular dilation or increased lung uptake (201Tl)
Echocardiographic wall motion abnormality (involving more than two segments) developing at low dose of dobutamine or at a low heart rate (<120 beats/min)
Stress echocardiographic evidence of extensive ischemia
INTERMEDIATE RISK (1–3% ANNUAL MORTALITY RATE)
Mild to moderate resting left ventricular dysfunction (LVEF = 35–49%)
Intermediate-risk treadmill score (- 11 < score < 5)[*]
Stress-induced moderate perfusion defect without left ventricular dilation or increased lung intake (201Tl)
Limited stress echocardiographic ischemia with a wall motion abnormality only at higher doses of dobutamine involving two segments or less
LOW RISK (<1% ANNUAL MORTALITY RATE)
Low-risk treadmill score (score ≥5)[*]
Normal or small myocardial perfusion defect at rest or with stress[]
Normal stress echocardiographic wall motion or no change of limited resting wall motion abnormalities during stress[]

From Gibbons RJ, Abrams J, Chatterjee K, et al: ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients with Chronic Stable Angina). J Am Coll Cardiol 2003;41:159–168.

LVEF = left ventricular ejection fraction.

* Score = (duration of exercise in minutes) – (5 × mm of ST segment depression) – (4 × angina score), where 0 = no angina, 1 = nonlimiting angina, and 2 = angina that causes discontinuation of the test.
Although the published data are limited, patients with these findings will probably not be at low risk in the presence of either a high-risk treadmill score or severe resting left ventricular dysfunction (LVEF <35%).

The extent of disease evaluated by the number of diseased vessels (>50% lumen diameter reduction) is the traditional angiographic marker of risk. In this assessment, left main disease is considered a separate high-risk entity or the equivalent of two-vessel disease, and specific attention is paid to proximal left anterior artery disease ( Table 70-9 ).


TABLE 70-9   — 
CORONARY ARTERY DISEASE PROGNOSTIC INDEX

Extent of Coronary Artery Disease 5-Year Mortality Rate (%)[*]
1-vessel disease, 75% 7
>1-vessel disease, 50–74% 7
1-vessel disease, ≥95% 9
2-vessel disease 12
2-vessel disease, both ≥95% 14
1-vessel disease, ≥95% proximal LAD 17
2-vessel disease, ≥95% LAD 17
2-vessel disease, ≥95% proximal LAD 21
3-vessel disease 21
3-vessel disease, ≥95% in at least 1 27
3-vessel disease, 75% proximal LAD 33
3-vessel disease, ≥95% proximal LAD 41

From Califf RM, Armstrong PW, Carver JR, et al: Task Force 5: Stratification of patients into high, medium and low risk subgroups for purposes of risk factor management. J Am Coll Cardiol 1996;27:1007–1019.

LAD = left anterior descending coronary artery.

* Assuming medical treatment only.

Treatment

The management of angina pectoris aims to prevent death and MI, reducing ischemic episodes to improve quality of life and slowing or even reversing the process of atherosclerosis. Success requires physicians and often a team of health care professionals with programs that address individual patients’ needs with information, counseling, lifestyle adjustments, medications, and judicious use of interventions ( Table 70-10 and Fig. 70-5 ).


TABLE 70-10   — 
TREATMENT OF PATIENTS WITH STABLE ANGINA

GENERAL MEASURES

   Rule out and control aggravating conditions

   Associated noncardiac diseases
   Associated cardiac disease
   Use of drugs aggravating angina
   Smoking cessation
   Dietary counseling for body weight and lipids control
   Exercise prescription
   Treat to targets

   Hypertension
   Blood lipids
   Diabetes
PHARMACOLOGIC THERAPY: RECOMMENDATIONS FOR PHARMACOTHERAPY TO PREVENT MI AND DEATH AND TO REDUCE SYMPTOMS

   Recommended on the basis of evidence or general consensus
   Aspirin in the absence of contraindications
   β-Blockers as initial therapy in the absence of contraindications in patients with prior MI or without prior MI
   Angiotensin-converting enzyme inhibitor in all patients with CAD who also have diabetes or left ventricular systolic dysfunction
   Low-density lipoprotein–lowering therapy in patients with documented or suspected CAD and LDL cholesterol greater than 130 mg/dL, with a target LDL of less than 100 mg/dL
   Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina
   Calcium-channel antagonists or long-acting nitrates as initial therapy for reduction of symptoms when β-blockers are contraindicated
   Calcium-channel antagonists or long-acting nitrates in combination with β-blockers when initial treatment with β-blockers is not successful
   Calcium-channel antagonists and long-acting nitrates as a substitute for β-blockers if initial treatment with β-blockers leads to unacceptable side effects
   Weight of evidence or opinion is in favor
   Clopidogrel when aspirin is contraindicated
   Long-acting non-dihydropyridine calcium-channel antagonists instead of β-blockers as initial therapy
   In patients with documented or suspected CAD and LDL cholesterol level of 100 to 129 mg/dL, several therapeutic options are available (Level of Evidence: B)
   Lifestyle and/or drug therapies to lower LDL to less than 100 mg/dL
   Weight reduction and increased physical activity in persons with the metabolic syndrome
   Institution of treatment of other lipid or nonlipid risk factors; consider use of nicotinic acid or fibric acid for elevated triglycerides or low HDL cholesterol
   Angiotensin-converting enzyme inhibitor in patients with CAD or other vascular disease
   Usefulness unclear
   Low-intensity anticoagulation with warfarin in addition to aspirin
   Not recommended
Dipyridamole
Chelation therapy

From Gibbons RJ, Abrams J, Chatterjee K, et al: ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients with Chronic Stable Angina). J Am Coll Cardiol 2003;41:159–168.

CAD = coronary artery disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MI = myocardial infarction.

FIGURE 70-5  Algorithm for the treatment of stable angina. AS = aortic stenosis; CABG = coronary artery bypass graft; CAD = coronary artery disease; MI = myocardial infarction; NTG = nitroglycerin; PTCA = percutaneous transluminal coronary angioplasty.  (Modified from American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Management of Patients with Chronic Stable Angina. ACC/AHA/ACP-ASIM Pocket Guidelines. Elsevier Science, 2000.)

Cardiovascular Health

Control of Risk Factors and General Status

Control of risk factors is the cornerstone of primary and secondary prevention. Lifestyle interventions should address smoking cessation, weight reduction, physical fitness, and diet. Drugs that clearly improve outcomes (e.g., aspirin, statins, and medications to control blood pressure) are routinely indicated. Associated diseases that can worsen CHD or precipitate ischemia, such as anemia, thyrotoxicosis, fever, infection, chronic lung disease, sleep apnea, diabetes, renal failure, and depression, must be recognized and addressed. The physician must also diagnose and treat associated cardiac conditions, such as valvar heart disease, bradyarrhythmias and tachyarrhythmias, and heart failure.

Prevention of Death and Myocardial Infarction

Death and MI can be prevented by antithrombotic and statin therapy and, in many patients, by β-blockers and angiotensin-converting enzyme inhibitors. Revascularization with coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) can also prolong life and prevent MI in patients with critical coronary artery stenoses.

Antithrombotic Therapy

Aspirin

Aspirin, which is a cornerstone of treatment in cardiovascular disease, should be used by all CHD patients who do not have a contraindication ( Chapter 35 ). Aspirin’s effect is fully achieved with an initial dose of 300 mg, which inhibits the pretreatment platelet pool, followed by doses of 80 to 160 mg daily to inhibit the 10% of the platelet pool that is regenerated every day. In these doses, secondary prevention with use of aspirin reduces the risk of MI, stroke, or vascular death by 22%; of death by 15%; of nonfatal MI by 35%; and of nonfatal stroke by 25%.[1]

In six primary prevention trials in patients without CHD, the benefit of aspirin in women is a reduction in cardiovascular events (by 12%) and stroke (by 17%) but not in MI or cardiovascular mortality. By comparison, the benefit in men is a reduction in cardiovascular events (by 14%) and MI (by 32%) but not in stroke or cardiovascular mortality ( Chapter 35 ).[2]

Clopidogrel

Clopidogrel is a thienopyridine that irreversibly inhibits the adenosine diphosphate PY12 receptor ( Chapter 35 ). At a dose of 75 mg/day, it is slightly more effective than aspirin for the secondary prevention of cardiovascular events in patients with a recent stroke or MI or with symptomatic peripheral vascular disease, with no increase in adverse effects. The combination of aspirin plus clopidogrel (loading dose of 300 mg followed by 75 mg/day) reduces the risk of cardiovascular death, nonfatal MI, or stroke by 20% (P < .0001) during an average follow-up of 9 months.[3] However, clopidogrel plus aspirin was no better than aspirin alone in a large study of patients with clinical cardiovascular disease or multiple risk factors, with a suggestion of benefit in the former group and harm in the latter group.[4] The general recommendation is to use aspirin as a first-line agent for primary and secondary prevention, clopidogrel as an alternative in patients who are intolerant of aspirin or develop an ischemic event while taking aspirin, and the combination of aspirin and clopidogrel after stent implantation ( Chapter 72 ) and for 9 to 12 months after an acute coronary syndrome ( Chapter 71 ).

Anticoagulant Therapy

Warfarin is as effective as aspirin for secondary prevention but is associated with a higher risk of bleeding. Combination therapy with warfarin plus aspirin is superior to aspirin alone, provided the international normalized ratio is maintained above 2.0, but the benefit of the combination needs to be weighed against a risk of bleeding in 1 of 100 patient years of treatment, mainly when the international normalized ratio is higher than 3.[5] Anticoagulants are used more liberally in Europe than in America. Atrial fibrillation ( Chapter 63 ) is a strong indication for warfarin; aspirin should be added in patients with CHD unless a contraindication is present.

Statins

Statins inhibit 3-hydroxy-3-methylglutaryl–coenzyme A reductase in the liver, thereby leading to enhanced expression of the low-density lipoprotein receptors that capture blood cholesterol ( Chapter 217 ). Clinical trials and meta-analyses of primary and secondary prevention trials with statins have consistently documented reductions of 30% in low-density lipoprotein cholesterol levels, 30% in the risk of a major coronary event, and 21% in the risk of death.[6] Statins also reduce the risk of MI and stroke and of the need for revascularization procedures. These risk reductions are generally similar in men and women and in older and younger individuals. More recent trials have shown added benefit when low-density lipoprotein cholesterol levels are lowered to 70 mg/dL rather than to 100 mg/dL, the current official goal of the National Cholesterol Education Program (Adult Treatment Panel III) guideline recommendations.[7] On the basis of these results, several agencies and groups now endorse a target of 70 mg/dL for high-risk patients, such as patients with established CHD. By comparison, raising HDL, either via direct infusion or the CTEP inhibitor torcetrapib, does not reduce the progression of atherosclerosis.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme inhibitors are indicated in all patients who have CHD and who also have diabetes, left ventricular systolic dysfunction, or hypertension. Although their benefit largely relates to a reduction in blood pressure, part of their benefit may be related to pleiotropic effects on the endothelium and on inflammation. In three large randomized trials, the risk of an adverse cardiovascular outcome has been reduced by 14% (P < .001) with use of the equivalent of ramipril at 10 mg/day.[8]

β-Blockers

β-Blockers reduce mortality in patients with a previous MI, hypertension, or left ventricular dysfunction and are effective in controlling ischemia. On the basis of these effects, their routine use is recommended in patients with angina, although a benefit on survival has not been convincingly documented in patients who have angina alone without these other risk factors.

Revascularization Procedures

Revascularization with PCI or CABG is indicated to improve survival in patients with left main vessel disease, two- or three-vessel disease and moderate to severe left ventricular dysfunction, two-vessel disease with involvement of the proximal left anterior descending coronary artery independently of left ventricular function, left ventricular dysfunction regardless of symptoms, proximal left anterior disease when ischemia is documented, and class III or class IV angina with medical therapy ( Chapters 73 and 74 ). The presence of a large ischemic zone on noninvasive testing is also an indicator of better survival with revascularization. In the absence of these criteria, coronary revascularization can still be useful for the control of angina, but medical therapy offers equivalent outcomes in terms of subsequent MI and death. [9] [10]

Control of Symptoms

Medical Management

β-Blockers, nitrates, and calcium antagonists reduce myocardial oxygen demand. Nitrates and calcium antagonists also increase coronary blood flow.

Nitroglycerin and nitrates produce immediate venous and arteriolar vasodilation, thereby reducing preload and afterload, respectively; the benefit is a decrease in wall tension, myocardial work, and myocardial oxygen needs. The drugs further increase oxygen delivery by vasodilating epicardial arteries and relieving the vasoconstriction secondary to endothelial dysfunction ( Table 70-11 ). These vasodilator effects are endothelium independent because nitrates are converted into nitric oxide, which activates guanylate cyclase to produce cyclic guanosine monophosphate, which in turn is a potent vasodilator with antiplatelet activity. Sublingual nitroglycerin or oral spray can terminate an angina attack and can be used for the prophylaxis of predictable pain. Long-acting nitrates administered orally or transdermally are used to prevent angina and to improve exercise tolerance. They are routinely used in the morning but also can be used during the night in patients with nocturnal angina. For avoidance of nitrate tolerance, 8 to 12 hours free of exposure daily is recommended. Nitroglycerin and nitrates can cause vasodilation-induced headache, a decrease in blood pressure, and, more rarely, severe hypotension with bradycardia due to activation of the vagal Bezold-Jarisch reflex. Because the vasodilation by nitroglycerin is markedly exaggerated and prolonged in the presence of the phosphodiesterase inhibitors sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), these drugs and nitrates should not be used within 24 hours of each other.

β-Blockers

β-Blockers decrease myocardial oxygen consumption by reducing heart rate, the inotropic state, and blood pressure at rest and during exercise ( Table 70-12 ). They also enhance left ventricular perfusion by prolonging the diastolic filling time. An additional gain is a reduction of the degree of hemodynamic stress imposed on fragile coronary lesions, thereby preventing their rupture. Although different β-blockers have different pharmacokinetic and pharmacodynamic properties, they all are effective in delaying or avoiding the ischemic threshold by reducing the heart rate–blood pressure product during exercise. Doses are usually titrated to reduce the resting heart rate to 55 to 60 beats per minute, and even to less than 50 beats per minute if there are no associated symptoms or ECG abnormalities. It is sometimes useful to adjust the dose by monitoring the heart rate during exercise so that it goes no higher than approximately 75% of the heart rate that is associated with the onset of ischemia.

All β-blockers block β1-receptors. Some agents, such as metoprolol, atenolol, and carvedilol, are more selective, at least at low doses, whereas others also act on the β2-receptors that dilate bronchi and induce glycogenolysis in liver and muscles. A selective agent is therefore advantageous in bronchospastic disease. Some agents, such as acebutolol and pindolol, possess intrinsic sympathomimetic activity effects; others, such as labetalol and carvedilol, also have α-adrenergic blocking. The property of intrinsic sympathomimetic activity is useful in patients with significant bradycardia at rest, in whom such drugs mainly prevent the acceleration of heart during exercise, and in patients with peripheral vasospasm. Agents without intrinsic sympathetic activity may increase triglyceride levels and reduce high-density lipoprotein cholesterol levels. Sotalol also possesses class III amiodarone-like antiarrhythmic activity, which makes it useful in patients with arrhythmias. Lipid solubility tends to be associated with more central nervous system side effects, more rapid absorption, and metabolism by the liver. Contraindications to β-blockers are significant bradyarrhythmias, acute but not chronic heart failure, and active asthma. Relative contraindications are Raynaud’s phenomenon, severe claudication, severe depression, and diabetes with labile blood glucose levels. A few reports have described an exaggeration of angina in patients with Prinzmetal’s angina. The most frequent side effects are fatigue, nightmares, asthma, and erectile dysfunction, but the increased risk of these side effects is low in placebo-controlled trials.

Calcium-Channel Antagonists

These drugs reduce calcium flux through the voltage-sensitive L-type calcium channels. All calcium-channel antagonists are potent coronary vasodilators that can relieve coronary artery spasm. These drugs also decrease myocardial oxygen needs by slowing heart rate and by reducing blood pressure and contractility. Significant differences exist between drugs in the in vivo expression of these properties ( Table 70-13 ). The dihydropyridines are more potent vasodilators, resulting in reflex adrenergic stimulation that masks the negative chronotropic effects. Short-acting nifedipine and other dihydropyridines may be associated with poorer outcomes in unstable angina and should be avoided unless the patient is also effectively treated with β-blockers. Verapamil has potent effects on cardiac conduction and contractility. The heart rate and vasodilator properties of diltiazem are intermediate between those of the dihydropyridines and verapamil, often resulting in a more favorable side effect profile. The dihydropyridines are advantageous when a bradyarrhythmia is present, and the new dihydropyridines are a better choice in heart failure. Verapamil and diltiazem are contraindicated in sinus node disease, in atrioventricular nodal block, and in patients with left ventricular dysfunction after MI; they are better choices in patients with atrial tachyarrhythmias. Calcium-channel antagonists are as effective as β-blockers for improving effort angina and are better in rest angina, particularly Prinzmetal’s angina. Side effects related to vasodilation include hypotension, headache, and peripheral edema. Worsening of heart failure can occur with all drugs, whereas bradycardia and atrioventricular dissociation can occur with verapamil and diltiazem, particularly in combination with β-blockers. Constipation is common with verapamil.

Ranolazine was recently approved in the United States for the treatment of chronic angina in patients who do not respond to amlodipine, β-blockers, and sublingual nitrates. It improves exercise tolerance without decreasing blood pressure or heart rate, although its mechanism of action is not fully understood. The most frequent side effects are dizziness, headache, constipation, and nausea. The drug prolongs the QT interval and is contraindicated in patients with preexisting QT interval prolongation, in patients receiving drugs that prolong the QTc interval (such as class Ia or class III antiarrhythmic agents, macrolide antibiotics, and certain antipsychotics), and in patients taking medications that inhibit the metabolic enzyme cytochrome P-450 3A (CYP3A).

Revascularization

Successful PCI ( Chapter 73 ) and CABG surgery ( Chapter 74 ) immediately relieve the obstruction to blood flow and angina. The option of revascularization should be investigated by coronary angiography ( Chapter 56 ) in patients with stable angina whenever symptoms are not satisfactorily controlled ( Table 70-14 ). Angiography also should be performed in high-risk patients, including patients with left ventricular dysfunction, unless it is contraindicated.

Coronary Artery Bypass Graft versus Percutaneous Coronary Intervention

Factors to be weighed in selecting PCI compared with CABG include number of diseased vessels, location and characteristics of the obstructive lesions, left ventricular function, age, comorbidities, diabetes, local expertise, and preference of the patient. Symptomatic and angiographic improvement is expected in more than 90% of patients undergoing PCI, with a complication rate less than 5%. Elective CABG surgery is associated with a mortality rate of 0.2%. The risk of CABG surgery is affected by many factors, including age, comorbid diseases, left ventricular function, and extent of coronary artery disease. Internal thoracic artery grafts are associated with a better short-term and long-term outcome.

Observational studies and clinical trials have generally showed that PCI and CABG have a similar benefit for survival and for preventing MI. Patients with left ventricular dysfunction, proximal left anterior descending coronary artery disease, and diabetes[11] usually fare better with CABG. PCI is generally preferred in patients with single-vessel disease. In patients with multivessel disease, PCI allows a more prompt return to normal life, but CABG often permits a more complete revascularization, with better long-term control of angina and less need for subsequent revascularization procedures. [12] [13] To the extent to which the advantages of CABG are related to restenosis at the site of a PCI, drug-eluting stents may narrow the advantage; however, CABG retains the benefit of providing an alternative conduit as native disease progresses in segments of an artery that initially were not appropriate for PCI. PCI is preferred in patients who have associated valve disease that is not yet severe enough to require surgery, whereas CABG is preferred if concurrent valve surgery is indicated. Other considerations include coronary anatomy, local expertise, comorbid conditions, and preferences of the patient. PCI and CABG surgery are constantly evolving, so choices between the two are likely to continue to evolve.


TABLE 70-11   — 
CLINICAL USE OF NITROGLYCERIN AND NITRATES

    Dose Duration of Action Indication
Nitroglycerin
  Sublingual or buccal spray 0.15–1.5 mg Relief of angina Before or at onset of pain
  Ointment 7.5–40 mg 8–12 hr Prophylaxis of angina
  Transdermal 0.2–0.8 mg/hr 8–16 hr Prophylaxis of angina
  Intravenous 5–1000 mg/hr Ongoing; increasing doses as needed Recurrent chest pain, systemic hypertension, left-sided heart failure
Isosorbide dinitrate
  Oral 5–40 mg tid 6–8 hr Prophylaxis of angina
Isosorbide-5-mononitrate
  Oral 20 mg bid 8–12 hr Prophylaxis of angina
  Oral, slow release 30–240 mg/day 12–20 hr Prophylaxis of angina

TABLE 70-12   — 
CLINICAL USE OF β-BLOCKERS

Compound by Receptor Activity Intrinsic Sympathomimetic Activity[*] Membrane Stability Effect Half-life (hr) Excretion Use
β1 AND β2
Propranolol ++ 1–6 Hepatic 20–80 mg bid-tid
Propranolol long-acting ++ 8–11 Hepatic 80–360 mg od
Nadolol 40–80 Renal 40–80 mg od
Pindolol + + 3–4 Renal 2.5–7.5 mg tid
Sotalol 7–18 Renal 40–160 mg bid
Timolol 4–5 Hepatic-renal 10–15 mg bid
β1 SELECTIVE
Acebutolol + + 3–4 Hepatic 200–600 mg bid
Atenolol 6–9 Renal 50–200 mg od
Bisoprolol 9–12 50% renal 5–20 mg od
Metoprolol 3–7 Hepatic 50–200 mg bid
Metoprolol long-acting 14–25 Hepatic 100–400 mg
Esmolol 4.5 min Esterases in red cells Bolus 500 μg/kg
          50–300 μg/kg/min IV
β1, β2, α2
Labetalol + 6 Hepatic 200–600 mg bid
Carvedilol + 6–10 Hepatic 200–600 mg bid

* Presence commonly associated with maintenance of or increase in heart rate; absence associated with decrease in heart rate.


TABLE 70-13   — 
PROPERTIES OF CALCIUM-CHANNEL BLOCKING DRUGS IN CLINICAL USE

      Hemodynamic Effect  
Drugs Usual Dose Elimination Half-life (hr) HR PVR Side Effects
DIHYDROPYRIDINES
Nifedipine PA[*] 10–40 mg bid 10 ↑↑ ↓↓↓ Hypotension, dizziness, flushing, edema, constipation
Nifedipine XL[*] 30–180 mg od 24 ↓↓  
Amlodipine 2.5–10 mg od 30–50 = ↓↓↓ Headache, edema
Felodipine 2.5–10 mg od 11–16 ↓↓↓ Headache, dizziness
Isradipine 2.5–10 mg bid 8 = ↓↓↓ Headache, fatigue
Nicardipine 20–40 mg tid 2–4 ↓↓↓  
Nicardipine SR[*] 30–60 mg bid 8–10 ↓↓ Headache, dizziness, flushing, edema
Nisoldipine 10–40 mg od 7–12 = ↓↓↓ As for nifedipine
Nitrendipine 20 mg od-bid 5–12 ↓↓↓ As for nifedipine
OTHERS
Bepridil 200–400 mg od 24–40 Arrhythmias, dizziness, nausea
Diltiazem 30–90 mg tid 4–6 Hypotension, dizziness, bradycardia, edema
Diltiazem CD[*] 120–440 mg od  
Verapamil 80–160 mg tid 3–8 ↓↓  
Verapamil SR[*] 120–480 mg od ↓↓ Hypotension, heart failure, edema, bradycardia

HR = heart rate; PVR = peripheral vascular resistance.

* PA, XL, SR, CD: long acting.


TABLE 70-14   — 
CURRENT RECOMMENDATIONS FOR MYOCARDIAL REVASCULARIZATION IN PATIENTS WITH CHRONIC STABLE ANGINA

CABG SURGERY VERSUS MEDICAL THERAPY
Among patients with medically refractory angina pectoris, CABG surgery is indicated for symptom improvement.[9]
Among patients with medically stable angina pectoris, CABG surgery is indicated to prolong life in left main coronary artery disease or three-vessel disease (regardless of left ventricular function) and, possibly, help symptoms.
CABG surgery may be indicated for prolongation of life if the proximal left anterior descending coronary artery is involved (regardless of the number of diseased vessels).
PCI VERSUS MEDICAL THERAPY
Among patients with medically refractory angina pectoris, PCI is indicated for symptom improvement. [9] [10]
PCI may be indicated in the presence of severe myocardial ischemia, regardless of symptoms. PCI does not appear to improve survival compared with medical treatment among patients with one- or two-vessel disease.[10]
In the absence of symptoms or myocardial ischemia, PCI is not indicated (merely for the presence of an anatomic stenosis).
PCI VERSUS CABG SURGERY
For single-vessel disease, PCI and CABG surgery provide excellent symptom relief, but repeated revascularization procedures are required more frequently after PCI. Intracoronary stenting is preferred to regular PCI, but direct comparison with CABG surgery is limited. [9] [11] [12] [13]
For treated diabetics with two- or three-vessel disease, CABG surgery is the treatment of choice.[11]
For nondiabetics, multivessel PCI and CABG surgery are acceptable alternatives. The choice of PCI or CABG surgery for initial treatment depends primarily on local expertise and the patient’s and physician’s preferences.[9]
In general, PCI is preferred for patients at low risk and CABG surgery for patients at high risk.
Large differences in mortality are unlikely, but smaller, potentially important differences in mortality cannot be excluded by the available data.
CABG surgery is associated with more complete revascularization and superior early relief of angina, but these differences diminish after 3–5 years.
No significant differences in rates of myocardial infarction have been shown.
Repeated revascularization procedures are required significantly more often after PCI; this problem is reduced with drug-eluting stents.
Initial costs, quality of life, and return to work are initially more favorable with PCI than with CABG surgery, but these outcomes roughly equalize during 3–5 years.

Modified from Rihal CS, Gersh BJ, Yusuf S: Chronic coronary artery disease: Coronary artery bypass surgery vs. percutaneous transluminal coronary angio-plasty vs. reduced therapy. Reproduced from Braunwald E, Goldman L (eds): Primary Care Cardiology, 2nd ed. Philadelphia, WB Saunders, 2003.

CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention.

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