Management of Chronic Stable Angina

Several million Americans suffer from coronary heart disease (CHD), and more than 600,000 die each year from the condition and its complications. Even for patients with chronic stable angina—the form of CHD most commonly encountered in the office setting—the annual risk of cardiovascular death, stroke, or myocardial infarction is high (4% to 5%); adding in hospitalizations for cardiac complications raises the rate to 15%. The array of treatment modalities is extensive, ranging from aspirin, nitrates, beta-blocking agents, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors to angioplasty, stenting, and coronary bypass surgery. These medical and surgical approaches are complemented by exercise, dietary measures, and aggressive treatment of underlying cardiovascular risk factors such as hypercholesterolemia, hypertension, smoking, and diabetes. The goals of therapy include symptom relief, preserved quality of life, improved exercise capacity, prevention of infarction, and, ultimately, improved survival, all of which can often be accomplished by a well-designed medical regimen.

Designing the basic medical regimen of the patient with stable CHD and knowing when referral for consideration of revascularization is indicated are among the important responsibilities of the primary care physician. The popularity of revascularization procedures (i.e., angioplasty and stenting) and the strong economic incentives to perform them necessitate in-depth knowledge by the primary care physician of the indications and limitations of all treatment modalities, as well as a good working relationship with a consulting cardiologist. Patients also appreciate advice on the many heavily promoted diets, vitamins, and other supplements purported to improve outcomes for CHD patients.

PATHOPHYSIOLOGY (1, 2, 3, 4 and 5)

Angina is a symptomatic manifestation of myocardial ischemia (MI), which occurs when oxygen demand exceeds available vascular supply. Symptoms include chest, back, arm, or neck pain, characteristically brought on by exertion, meals, or stress and relieved promptly by nitroglycerin or rest (see Chapter 20). Anginal equivalents include exertional dyspnea (common in women, who may not experience chest pain) and dysrhythmias, also the consequence of MI and resultant left ventricular (LV) dysfunction. There is also a growing appreciation for the frequency and importance of silent MI, defined as objectively documented ischemia occurring in the absence of symptoms. On the basis of results from exercise stress testing and ambulatory monitoring, it is estimated that more than half of patients with chronic stable angina experience episodes of silent ischemia. Contrary to the traditional association of silent ischemia with diabetes, controlled studies find silent ischemia to be no more frequent in diabetics than in nondiabetics. The mechanism(s) remain to be elucidated, but clinical significance is no less important than symptomatic angina.

Atherosclerotic Disease

Most cases of chronic stable angina are related to fixed atherosclerotic lesions narrowing the major coronary vessels. A series of stepwise thrombotic events is believed to account for much of the atherosclerotic occlusion that occurs in the large epicardial arteries. These lesions may develop as a consequence of episodes of acute thrombosis, in which activated platelets and other elements of the clotting system appear to play major roles,
triggered by reactive endothelial injury in areas of cholesterol deposition. The association of thrombotic risk with elevation of C-reactive protein has called attention to the possible role of inflammation and inflammatory mediators. Many, if not most, episodes of acute coronary insufficiency (unstable angina) and infarction are associated with acute thrombosis, often occurring at an ulcerated, eccentrically located, or ruptured plaque, not necessarily at a site of severe stenosis.

Coronary Vasospasm

The restriction of coronary blood supply may also ensue from coronary vasospasm, which is believed to be related to a loss of normal endothelial vasoregulatory activity. The coronary endothelium appears to cease production of vasoactive peptides and prostaglandins, leaving vascular smooth muscle unopposed and susceptible to spasm. It has been documented in patients both with and without underlying atherosclerotic disease and sometimes presents as variant angina (rest pain, ST-segment elevation). Prevalence is about 3% in patients undergoing coronary angiography with ergonovine stimulation, but the true prevalence is estimated to be far greater. Spasm is suspected of playing a role in acute myocardial infarction and triggering anginal episodes. Cigarette smoking and hyperlipidemia appear to interfere with normal endothelial activity, and other precipitants include stress, cold, a-adrenergic stimulation in the setting of beta-blockade, abrupt nitrate withdrawal, ergonovine, cocaine use, and direct mechanical irritation from cardiac catheterization.

Left Ventricular Outflow Obstruction

Aortic valve disease can lead to angina when hemodynamically significant valvular stenosis or calcific obstruction of coronary ostia results in inadequate coronary perfusion (see Chapter 33). Angina may also be a manifestation of hypertrophic cardiomyopathy, developing as a consequence of significant LV outflow tract obstruction, increased myocardial oxygen demand by a hypertrophied myocardium, and inadequate vascular supply (see Appendix 33-1-30-30).

Microvascular Disease

Coronary microvascular dysfunction, characterized by inappropriately vasoconstrictive responses to autonomic and biochemical stimuli, can increase total resistance and reduce myocardial perfusion. The significance of these findings is unclear, but they have been found with increased frequency among patients with the combination of atypical angina, an ischemic response to exercise stress testing, and a normal coronary angiogram. The terms microvascular angina and syndrome × have been applied to such persons. More study is needed, but the findings suggest a possible explanation for the ischemic chest pain of patients with hypertrophic cardiomyopathy. Diabetics with hyperinsulinism may also be at increased risk for microvascular disease.

Increased Myocardial Oxygen Demand

Regardless of etiology, ischemic episodes are often triggered or aggravated by conditions that increase myocardial oxygen demand (e.g., hyperthyroidism, fever, LV hypertrophy) or decrease oxygen supply (e.g., severe anemia, respiratory insufficiency). A circadian susceptibility to ischemic events has been identified, with the morning hours being the time of greatest risk. Mechanism(s) are unknown, but the phenomenon can be blocked by betablockers or aspirin.

NATURAL HISTORY, PROGNOSIS, AND RISK STRATIFICATION (4, 5, 6, 7, 8, 9, 10 and 11)

Although the clinical course of some patients may extend over 15 to 20 years, most patients with chronic stable angina are at a considerably increased risk of cardiovascular death.

Determinants of Prognosis and Risk

With so many therapeutic options available (including a number that confer considerable risk), it is becoming increasingly important to risk-stratify patients with chronic stable coronary disease. Among the best-established factors affecting prognosis are the number and the location of coronary artery stenoses. Combined angiographic data obtained before the widespread use of bypass surgery reveal that patients with significant disease in one vessel have a mean annual mortality rate of 2.2%. This increases to a rate of 4.5% to 7.0% if the lesion involves the left-main coronary artery. High-grade proximal stenosis of the left anterior descending artery has a prognosis similar to that of left-main disease and is sometimes referred to as a left-main equivalent lesion. With stenosis of two vessels, the mean annual mortality rate is 6.8%; the rate rises to 11.4% for three-vessel disease.

Prognosis also closely correlates with the severity of ischemia, as measured by radionuclide or echocardiographic imaging and by electrocardiographic changes during exercise stress testing (see Chapter 36), regardless of whether the disease is symptomatic or silent. Other major independent determinants of increased risk are LV dysfunction (i.e., reduced ejection fraction; see Chapter 32), LV diastolic dysfunction, LV hypertrophy, ventricular ectopy (see Chapter 29), an intercurrent ischemic event within the last 6 months, and cigarette smoking. The onset of angina in a patient with hemodynamically significant aortic stenosis reduces mean survival to about 2 to 3 years (see Chapter 33).

Many CHD risk factors are powerful independent determinants of prognosis. Smoking, diabetes mellitus, hypertension, hypercholesterolemia, low high-density lipoprotein (HDL) cholesterol, and age (45 years or older in men, 55 years or older in women) are well-documented for their effect on prognosis in patients with stable angina due to atherosclerotic coronary artery disease. However, the fact that these risk factors do not account for all cardiovascular risk has stimulated searches for other determinants of risk and prognosis. Hyperhomocysteinemia emerged from preliminary epidemiologic studies as a potentially important determinant of CHD risk, but subsequent epidemiologic studies and failure of homocysteine-lowering treatment to reduce risk (see Chapters 18, 27, and 31) have tempered enthusiasm for this purported risk factor. Brain (B-type) natriuretic peptides (N-terminal prohormone of BNP [NT-proBNP], which are released from cardiac myocytes in the setting of increased LV myocardial stretch due to LV dysfunction or ischemia and which may also alter vascular smooth muscle function) have been found to have independent predictive value, even in the setting of normal standard measures of LV function and inflammation.

Determining near-term risk is also of value and a source of active study. Preliminary work finds that serum elevations in biomarkers of inflammation (C-reactive protein, amyloid A) and thrombosis (D-dimer) can help predict short-term prognosis (1 to 2 years) in persons with established atherosclerotic disease. There is no significant correlation with longer-term risk (>2 years).

The natural history of coronary artery spasm is highly variable, reflecting the heterogeneity of patients with this condition. An important variable is the presence of underlying atherosclerotic disease. If spasm occurs in the absence of fixed stenoses, the
prognosis is relatively good (e.g., no mortality, 39% remission over 6 years). Some investigators even suggest that spasm may be a temporary condition; however, myocardial infarction, heart block, and malignant arrhythmias have been documented. The prognosis of patients with spasm in the setting of underlying coronary stenosis is a function of the coronary anatomy; patients with multivessel disease are at greatest risk. Whether the risk is significantly enhanced by the presence of spasm is not yet known.

Risk Stratification

Risk stratification is essential to choosing wisely among the wide range of available treatment modalities. Most patients can be classified clinically into high-, intermediate-, and low-risk categories, supplementing the assessment when there is uncertainty with stress testing and echocardiography (see Tables 30-1 and 30-2; also see Chapters 20 and 36). Refinements using some of the newer biomarkers noted earlier (e.g., D-dimer, high-sensitivity C-reactive protein, NT-proBNP) show promise but need further validation.

Patients suspected of being at high risk need referral for the consideration of coronary bypass surgery. Persons classified as being at intermediate risk may also be candidates for revascularization (bypass vs. angioplasty/stenting) but on an elective basis and predominantly for the improved control of anginal symptoms (there is little evidence of reduced mortality). Lowrisk patients (normal electrocardiogram [ECG], no evidence of heart failure, and no history of MI) with well-controlled symptoms can be followed expectantly and need not be restudied for 3 years. Urgent and full reassessment of risk is indicated when there is a change in clinical status (e.g., change in anginal pattern, development of symptoms suggestive of heart failure).

PRINCIPLES OF MANAGEMENT

The principal goals are to improve functional capacity and quality of life and reduce the risks of adverse cardiac events and death. Measures that control atherosclerotic risk factors, improve oxygen supply, and reduce oxygen demand help to achieve these objectives. The institution of diet and exercise programs (see Chapters 18 and 31), beta-blockade, ACE inhibition, and platelet inhibition are central to this effort, as is aggressive treatment of hypercholesterolemia, hypertension, diabetes, and smoking; revascularization is sometimes necessary. Nitrates and calcium channel blockers can enhance the control of symptoms and improve exercise tolerance. Also critical are attention to exacerbating factors such as heart failure (see Chapter 32), aortic outflow tract obstruction (see Chapter 33), hyperthyroidism (see Chapter 103), anemia (see Chapter 82), and hypoxemic chronic lung diseases (see Chapters 46 and 47).

TABLE 30-1 Risk Stratification for Patients with Stable Angina

Low Risk
	No angina currently or minimal angina
	Normal LV function (normal ejection fraction)
	Small amount of myocardium at risk (probable single-vessel disease)
Moderate Risk
	Moderate angina
	Normal LV function (normal ejection fraction)
	Moderate amount of myocardium at risk (probable two-vessel or proximal left anterior descending artery disease)
High Risk
	Severe angina
	Extensive amount of myocardium at risk (probable three-vessel, left-main, or “left-main equivalent” disease)
	Impaired LV function (ejection fraction <0.40)

TABLE 30-2 Risk Assessment for Patients with Stable Coronary Disease Based on Results of Noninvasive Testing

High Risk (>3% Annual Mortality Rate)
	Severe resting LV dysfunction (LV ejection fraction <0.35)
	High-risk exercise ECG score (Duke treadmill score, ≤-10)
	Severe LV dysfunction during cardiac exercise imaging (LV ejection fraction <0.35)
	Large perfusion defect during stress myocardial perfusion imaging (particularly if anterior)
	Multiple perfusion defects of moderate size during stress myocardial perfusion imaging
	Large, fixed defect with LV dilation or increased lung uptake using rest radionuclide angiography with thallium
	Moderate defect with LV dilation or increased lung uptake during stress myocardial perfusion imaging with thallium
	Defect in more than two segments with a low heart rate (<120 beats/min) or with a low dose of dobutamine (≤10 mg/kg of body weight per minute) during stress echocardiography
	Evidence of extensive ischemia during stress echocardiography
Intermediate Risk (1%-3% Annual Mortality Rate)
	Mild or moderate resting LV dysfunction (LV ejection fraction, 0.35-0.49)
	Intermediate-risk exercise ECG score (Duke treadmill score, -10 to 4)
	Moderate defects without LV dilation or increased lung uptake during stress myocardial perfusion imaging
	Limited defects involving two or fewer segments only at doses of dobutamine >10 mg/kg/min during stress echocardiography
Low Risk (<1% Annual Mortality Rate)
	Low-risk exercise ECG score (Duke treadmill score, ≥5)
	Normal or small defect at rest or during stress with myocardial perfusion imaging
	Normal wall motion or no change in limited wall-motion abnormalities during stress echocardiography
Each test result is an independent predictor of the risk for death. There is little understanding about how to predict risk by combining test results, except that when more than one test result is present, the result predicting a higher risk should be used to guide decisions. Adapted from Williams SV, Fihn SD, Gibbons RJ. Guidelines for the management of patients with chronic stable angina: diagnosis and risk stratification. Ann Intern Med 2001;135:530, with permission.

To maximize patient safety, the aggressiveness of intervention should be proportional to the patient’s degree of risk (see Table 30-1 and Chapter 20). Often the choices are stated as if they were mutually exclusive, but most of the time they are complementary. Even if revascularization is chosen, medical therapy remains the foundation of management. Surveys of CHD patients in primary care practices often find the underuse of therapies with proven survival benefit (e.g., beta-blockers, ACE inhibitors, aspirin, lipid lowering). A common error is to focus on the relief of angina and revascularization while ignoring aggressive reduction in overall cardiovascular risk.

Treatment of Atherosclerotic Risk Factors and Precipitants of Angina (1, 2, 3, 4 and 5,12, 13, 14, 15, 16 and 17)

Atherosclerotic Risk Factors

The importance of treating atherosclerotic risk factors cannot be overemphasized. Patients with coronary disease have five times the risk of a coronary event. Secondary preventive efforts can improve quality of life, reduce the risk of coronary events, obviate the need for revascularization, and prolong survival. Marked reductions in cardiovascular morbidity and mortality
are achievable with control of hypertension (see Chapter 26), lowering of low-density lipoprotein (LDL) cholesterol (see Chapter 27), and cessation of smoking (see Chapter 54).

Lifestyle modification should be a central component of the treatment program. Key to these efforts is attention to diet and exercise. A dietary program that substitutes polyunsaturates and monounsaturates for saturated and trans fats improves lipid profiles and outcomes (see Chapter 27), as does weight reduction (see Chapter 233) and tightening of glycemic control in patients with diabetes (see Chapter 102). A diet containing oily fish (2 servings a week) remains recommended by such groups as the American Heart Association based on epidemiologic data and other health benefits, but there is no evidence that use of omega-3 fatty acid supplements provides significant secondary prevention, except in the immediate post-MI setting (see later discussion and Chapters 27 and 31). Exercise can significantly improve functional status and cardiac outcomes by enhancing skeletal muscle efficiency, decreasing heart rate and blood pressure, enhancing morale, and fostering an improved sense of well-being (see Chapters 18 and 31).

Reducing elevations in homocysteine, C-reactive protein, and triglycerides and raising HDL cholesterol may also turn out to be helpful, although this is yet to be firmly established by prospective long-term study (see Chapters 27 and 31).

The magnitude of morbidity and mortality reductions from the treatment of atherosclerotic risk factors can approach 30% to 50%, frequently equaling or exceeding that of other measures and mandating that it be a central part of all management programs in persons with coronary disease. A randomized trial of aggressive lipid-lowering therapy compared with angioplasty in patients with mild to moderate stable angina (atorvastatin vs. revascularization treatment) found that lipid lowering was equal to if not better than angioplasty with regard to reducing the frequency of future cardiac events.

Common Precipitants

Attention to precipitants is essential not only for symptomatic relief but also for reducing morbidity and mortality.

Smoking.

Smoking is not only a major CHD risk factor, but it is also a precipitant of angina. The absorbed nicotine increases blood pressure and heart rate, thus increasing myocardial oxygen demand. Nicotine may also cause vasospasm, and the rise in carboxyhemoglobin from smoke inhalation cuts down on oxygen delivery. Even passive smoking (from being in a smokefilled room) can reduce exercise tolerance in patients with stable angina. Cessation of smoking can be psychologically stressful and physically uncomfortable, but the immediate and long-term benefits greatly outweigh the short-term discomfort. The development of symptomatic coronary disease may provide a potent stimulus to smoking cessation; the effort often succeeds when the physician takes a strong interest in achieving it (see Chapter 54).

Hypertension.

Hypertension can exacerbate angina by raising myocardial oxygen demand through its effect on afterload. Its treatment can improve the symptomatic control of angina as well as markedly reduce the risks of MI and death (see Chapter 26).

Psychological Stress.

Stress is well-recognized as an important precipitant, but only recently has it been appreciated how common stress-induced ischemia is in patients with coronary artery disease. Episodes of silent ischemia and symptomatic ischemia have been documented in stressful situations. Public speaking and difficult mental tasks can induce as much symptomatic and silent ischemia as exertion in patients with coronary artery disease. High levels of life stress and social isolation are independent predictors of death from coronary disease. The role of personality style, such as so-called type A behavior, remains a subject of debate, although the evidence from studies of mental stress suggests that coronary patients who have a low tolerance for frustrating circumstances might be expected to have an increased likelihood of ischemic stress responses.

Addressing the psychosocial stresses that the anginal patient encounters is critical. An adequate evaluation includes a thorough psychosocial history with emphasis on those factors contributing to stress and social isolation. Urging the hard-driving, impatient person to change personality style is counterproductive, but counseling on means of coping with frustration and introducing simple relaxation techniques (see Appendix 226.1-30-30) may be better appreciated. If acute anxiety or situational stress is known predictably to precipitate severe chest pain or significant silent ischemia, occasional prophylactic use of a minor tranquilizer may be warranted. However, frequent benzodiazepine use in the absence of a true anxiety disorder is strongly discouraged because it can lead to tolerance and even addiction (see Chapter 226); furthermore, tranquilizer use is no substitute for an adequate medical regimen. Beta-blocker therapy can be quite effective in limiting the adverse cardiac effects of anxiety by blocking the attendant adrenergic discharge.

Depression and Anxiety.

Depression and anxiety are common responses to the diagnosis of coronary disease; they can impair not only the patient’s psychological sense of well-being but also the physiologic responses to medical and interventional therapies. Moreover, anxiety is a risk factor for cardiac sudden death, and depression is a more powerful predictor of heart disease than is personality style. After 1 year of proper therapy for angina, any untreated anxiety or depression correlates more closely with exercise capacity and functional status than the severity of the underlying coronary disease. Despite receiving and complying with proper antianginal regimens, patients with these psychological states manifest more physical incapacity than patients free of active depression or anxiety. The close link between these states and functional status makes it imperative to check for and treat anxiety and depression (see Chapters 226 and 227) at the time of initial CHD workup and again during implementation of the antianginal program. Those manifesting mental stress-induced episodes of myocardial ischemia should be considered for SSRI antidepressant/anxiolytic therapy, which can reduce the number of such episodes.

Other Precipitants

One needs to check for and address severe anemia (see Chapter 82), hyperthyroidism (see Chapter 103), heart failure (see Chapter 32), and hypoxemia due to lung disease (see Chapters 46 and 47). All are capable of worsening both symptomatic and silent MI in the context of underlying coronary disease. Neither coffee nor caffeine consumption has been shown to increase the risk of coronary disease, although an oft-quoted epidemiologic study found a minor trend toward increased risk in patients consuming more than four cups of decaffeinated coffee per day. Air pollution and carbon monoxide exposure can trigger angina (see Chapter 20).

Beta-Adrenergic Blocking Agents (18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 and 29)

Beta-blockers can reduce the frequency of angina (especially that induced by exercise) and improve exercise tolerance in persons with stable CHD and reduce the risk of cardiac sudden death and prolong survival in patients surviving myocardial infarction (MI)—45% reductions in sudden death and 20% reductions in all-cause mortality. In patients with stable coronary disease without myocardial infarction, the benefits of beta-blocker therapy with regard to cardiovascular death and nonfatal MI are less evident. Large-scale observational studies fail to confirm a survival benefit in stable outpatients with CHD without prior
infarction, but do find reduced all-cause mortality and reduced cardiovascular morbidity with perioperative beta-blocker use in persons with 2 or more major perioperative cardiovascular risk factors (e.g., high-risk surgery, ischemic heart disease, diabetes mellitus, congestive heart failure, renal insufficiency).

The benefits of beta-blockade are believed to derive principally from the lowering of myocardial oxygen consumption through reductions in contractility, blood pressure, and heart rate. Beta-blockade also raises the ventricular fibrillatory threshold and, in slowing the heart rate, provides more time for diastolic filling, a key determinant of myocardial perfusion. Coronary plaque regression has been documented. Despite these proven benefits, beta-blockers continue to be underused, especially in the elderly.

Categorization and Preparations

Beta-blockers can be categorized according to their relative cardioselectivity, lipid solubility, intrinsic agonist activity, and alpha-blocking capacity. Available preparations include generic and brand versions, with the latter accounting for many of the sustained-release formulations.

Cardioselectivity refers to the degree of preferential affinity for β₁ receptors, which predominate in the heart and are the principal target of antianginal therapy. Beta-blockers that lack cardioselectivity are more likely at low doses to cause side effects associated with β₂-blockade (bronchospasm, peripheral vasoconstriction, and inhibition of glycogenolysis; see later discussion). Cardioselectivity fades as doses increase. At low to intermediate doses, cardioselectivity is demonstrated by atenolol, metoprolol, acebutolol, betaxolol, and bisoprolol.

Lipid solubility affects absorption, metabolism, serum halflife, and the degree to which an agent crosses the blood-brain barrier. The more lipid soluble an agent is, the more rapid is its absorption, the shorter is its half-life, and the more likely it is to enter the central nervous system (CNS). Lipid-soluble preparations are, for the most part, hepatically metabolized. The most lipid-soluble beta-blockers include propranolol, followed by metoprolol and then pindolol; the least lipid-soluble agents include atenolol and nadolol. Although it was originally believed that lipid solubility predicted the degree of CNS side effects (depression, psychomotor retardation), this has not been confirmed by randomized controlled trials (see later discussion).

Agonist activity is an intrinsic characteristic of pindolol, acebutolol, carvedilol, labetalol, and penbutolol. At low doses, these drugs show some sympatholytic action and tend to cause less reduction in heart rate, contractility, and conduction than other betablockers. Consequently, they are worth considering in patients who develop symptomatic bradycardia with the use of standard beta-blockers. However, as doses increase, these agonist effects are overpowered by the underlying beta-blocking activity.

Alpha-blocking activity is a feature of labetalol and carvedilol. This characteristic makes these agents useful in situations in which potent afterload reduction is desired, as in hypertension and congestive heart failure. Labetalol combines nonselective beta-blockade with agonist activity and alpha-blocking action; it is used predominantly in hypertensive patients. Adverse effects include greater degrees of postural hypotension and sexual dysfunction than seen with most other beta-blockers. Carvedilol offers nonselective beta-blockade in conjunction with alphablockade; in addition, it prevents upregulation of cardiac beta receptors, reduces cardiac norepinephrine, and demonstrates antioxidant effects. The drug is approved by the U.S. Food and Drug Administration for use in heart failure, in which it has been shown to reduce morbidity and mortality (see Chapter 32).

Preparations span the spectrum of duration of action from about 6 hours for generic propranolol to 24 hours for sustainedrelease metoprolol. Most beta-blockers are available generically, having come off patent years ago, which makes for considerable cost savings. Convenience and compliance can be enhanced by the use of a once-daily formulation, but the cost is increased substantially because many of these are brand-name formulations of generic agents.

Adverse Effects

Many side effects are directly attributable to the consequences of beta-blockade on organ systems that require beta stimulation for normal functioning. The risk is greatest when there is underlying organ-system dysfunction. Heart failure, heart block, and severe bronchospasm are among the most worrisome of potential adverse effects, but the risk can be minimized by careful prescribing and monitoring. In most instances, some degree of beta-blockade can be instituted, especially if cardioselective agents are used. Abrupt withdrawal of betablocker therapy can lead to rebound adrenergic stimulation and its attendant adverse consequences.

Heart Failure.

Heart failure may develop or worsen in patients with preexisting LV dysfunction. Not all patients with a reduced ejection fraction necessarily worsen; those with heart failure due to coronary disease may actually improve (see Chapter 32), but careful monitoring is essential. Concurrent use of other negatively inotropic drugs (e.g., verapamil, disopyramide) should be eliminated or at least minimized.

Heart Block.

Patients with underlying conduction system disease may experience symptomatic bradycardia or heart block due to a slowing of the sinoatrial node and atrioventricular conduction; sinus arrest may ensue in such patients. A preparation with some intrinsic beta-agonist activity may be preferred if a betablocker is to be used in the setting of underlying conduction system disease. Close monitoring is critical to safe use in persons with underlying conduction system disease.

Coronary Vasoconstriction.

Coronary vasoconstriction is a theoretical concern in patients with coronary disease, especially in those with atherosclerotic disease complicated by vasospasm and in those with purely vasospastic disease. Clinically, it is rarely a problem. In fact, beta-blockers have actually been proved to be useful in patients with variant angina, although they are usually prescribed in conjunction with coronary vasodilators such as nitrates or calcium channel blockers. The observed benefit of beta-blockers in settings of suspected coronary vasoconstriction is believed to be related to their favorable effects on platelet aggregation, oxygen demand, and other factors contributing to vasospasm or angina.

Peripheral Vasoconstriction.

Peripheral vasoconstriction can occur with beta-blocker therapy, particularly in patients who suffer from vasospastic Raynaud’s disease. However, as long as a low-dose cardioselective program is used, the Raynaud’s patient can usually tolerate beta-blocker treatment. Similarly, patients with peripheral atherosclerotic arterial disease rarely suffer a compromise in limb perfusion when taking a beta-blocker (see Chapter 34).

Bronchospasm.

By blocking β₂-receptors, nonselective betablockers (and all preparations when used in full doses) may trigger bronchospasm, the most serious side effect of beta-blocker use. Bronchospasm may occur in any patient with a history of bronchospastic disease, even if the patient is asymptomatic at the time of initiating therapy. Many regard asthma as a relative contraindication to beta-blocker use, but careful use is possible in patients with inactive or well-controlled bronchospastic disease, so long as doses are kept low and a cardioselective agent is used. Nonetheless, caution and careful monitoring of flow rates are advised because even low doses of a relatively cardioselective agent can worsen bronchospasm in a patient with asthma.

Blunted Response to Hypoglycemia.

Beta-blockers blunt the adrenergic response to hypoglycemia. This may impair patient recognition of a hypoglycemic episode in patients taking insulin
or potent oral agents and, in theory, prolong the duration of hypoglycemia by inhibiting catecholamine-induced glycogenolysis and glucose mobilization. In practice, prolongation of hypoglycemia is rare, and diabetics have a very high risk of cardiovascular morbidity and mortality that is markedly reduced by beta-blocker therapy. Consequently, beta-blocker use is not contraindicated in diabetics, even in those taking insulin, but careful dosing and cardioselectivity are required, as are detailed patient education and careful program design (see Chapter 102).

CNS Side Effects and Depression.

Early anecdotal reports described cognitive problems, depression, sexual dysfunction, altered sleep, nightmares, and fatigue associated with betablocker use. These problems appeared particularly frequently with the use of propranolol (the first beta-blocker to become available) and in the elderly; however, randomized controlled trials found no increase in the risk for depression and revealed only a very small absolute risk for fatigue or sexual dysfunction (<1%). Although it was hypothesized that risk was related to use of lipid-soluble preparations such as propranolol, no such association has been confirmed. Concern about these potential side effects appears overstated and should not be used as a basis for denying a trial of carefully monitored beta-blocker therapy.

Rebound.

Abrupt withdrawal of beta-blockade can precipitate an exacerbation of angina, acute coronary insufficiency, or even infarction. It has been hypothesized that an up-regulation of betaadrenergic receptors results from long-term blockade and makes these patients more sensitive to unopposed beta-adrenergic stimulation. Onset is characteristically within 2 to 6 days after the abrupt cessation of therapy. Concern about withdrawal often occurs in the perioperative setting, in which medications might have been held for surgery. About 10% of stable anginal patients experience a serious rebound in symptoms when betablockade is suddenly terminated. Infarction and death may occur. Those at greatest risk are patients on large doses who have achieved much benefit from beta-blockade. Withholding beta-blockers for up to 48 hours can be done without risking any increase in angina. Patients who experience an exacerbation usually do so 2 to 6 days after the abrupt discontinuation of therapy. Tapering therapy over the course of 1 to 2 weeks can minimize a withdrawal reaction.

Lipids.

Although beta-blocker use (especially of nonselective agents) may cause a modest increase in serum triglycerides and a small reduction in serum HDL cholesterol, there is no evidence that these effects are clinically significant. Moreover, both animal and human studies demonstrate beta-blocker inhibition of serum factors and vessel wall stresses important to atherogenesis.

Choice of Beta-Blocker

The choice of agent should be based predominantly on cost, the need for cardioselectivity, and the duration of action. Generically available formulations (e.g., propranolol, metoprolol, atenolol) are 1/10 to 1/30 the cost of brand-name beta-blockers. Cardioselectivity deserves consideration in patients with asthma, peripheral vascular disease, or neuropsychiatric problems. The duration of action becomes important for maximizing compliance, which is facilitated by the use of agents that can be administered on a once-daily or twice-daily basis. The combination of low cost, cardioselectivity, and prolonged duration of action makes generic preparations of metoprolol and atenolol the preferred beta-blockers for most patients with coronary disease. An agent with some intrinsic beta-agonist activity (e.g., generic pindolol) may be worth considering in anginal patients with conduction system disease or sinus node dysfunction bothered by symptomatic bradycardia when taking a beta-blocker without such activity. The presence of heart failure does not need to be a contraindication to beta-blocker use; both long-acting metoprolol and carvedilol have demonstrated the ability to improve survival in patients with heart failure (see Chapter 32).

Titration of Dose

Beta-blocker therapy requires the titration of dose against the resting and exercise heart rates. Lowering the resting heart rate to about 60 beats/min is usually considered evidence of sufficient beta-blockade but may not be a reliable indicator in elderly patients. A subset of patients do not achieve adequate control of their angina at this level of beta-blockade. Further increases in dose (and a slower resting heart rate) may be necessary to prevent chest pain. Such bradycardia is often well-tolerated hemodynamically. Typical target heart rates are 50 to 60 beats/min at rest, with an increase to 70 to 80 beats/min with moderate exercise and to no more than 100 beats/min with vigorous exercise. The true measures of adequate therapy remain the suppression of angina and the improvement of exercise tolerance. Times of maximum diurnal adrenergic activity (early morning and early evening) are the ones most important to cover with beta-blockade because they are times when risks of cardiac events are greatest.

Angiotensin-Converting Enzyme Inhibitors (30, 31, 32, 33, 34 and 35)

Angiotensin-converting enzyme inhibitors (ACEIs) have emerged as a cornerstone of CHD management, demonstrating significant reductions in cardiovascular morbidity and mortality in persons with high CHD event risk, including those with stable angina and normal ejection fractions, independent of effects on heart failure and blood pressure.

Effect on CHD Morbidity and Mortality

Reductions of 20% to 30% in the risk of cardiac death, infarction, and stroke were observed in the Heart Outcomes Prevention Evaluation (HOPE) trial in high-risk persons with preserved LV function, half of whom had stable angina; similar and confirmatory findings were provided by the European Trial on the Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease in persons at lower risk for adverse CHD events. The observed benefits appear independent of blood pressure reduction, aspirin use, beta-blockers, lipidlowering agents, and antihypertensive drugs, suggesting a unique mode of action beyond the inhibition of angiotensininduced vasoconstriction. One explanatory hypothesis links the observed benefits to drug-stimulated increases in vascular tissue kinins and their effects on endothelial physiology, including vasodilation, tissue thromboplastin production, nitric oxide levels, prostacyclin synthesis, and oxidative stress. ACE inhibitors have shown the ability to limit vascular smooth muscle proliferation, plaque rupture, and LV hypertrophy and to improve vascular endothelial function and fibrinolysis. The accumulating evidence of survival benefit recommends ACE inhibition to all patients with CHD, irrespective of LV function. Combination with beta-blockade appears to enhance benefit and limit risk even further.

Adverse Effects

The most common adverse effect is dry cough, which is believed to be related to the drug-induced increase in tissue bradykinins, triggering a nagging dry cough in about 5% to 10% of patients. Angioedema is also seen and may have a similar mechanism. Renal dysfunction may occur in the context of bilateral
renal artery stenosis (see Chapters 26 and 32) but is usually not a concern. The potential for an adverse drug-drug interaction with aspirin has been a concern. Post hoc analyses of studies performed for other reasons suggest a possible reduction in cardiovascular benefit when the two drugs are taken together. Speculation centers on aspirin-induced inhibition of prostaglandin synthesis blunting the beneficial kinin-triggered effects on blood vessels. Even with blunting of the ACEI’s effect, the net benefit of taking the two agents together still exceeds that of not using them, leading most experts to believe that it would be premature to withhold aspirin in the context of ACE inhibitor therapy. The literature should be followed closely.

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