Robert L. Talbert
KEY CONCEPTS
Ischemic heart disease (IHD) is primarily caused by coronary atherosclerotic plaque formation that leads to an imbalance between oxygen supply and demand resulting in myocardial ischemia.
Chest pain is the cardinal symptom of myocardial ischemia due to coronary artery disease (CAD).
Risk factor identification and modification are important interventions for individual patients with known or suspected IHD and as a population-based policy to reduce the impact of this disease.
Major risk factors that can be altered include dyslipidemia (high total and low-density lipoprotein [LDL] cholesterol, low HDL cholesterol, and high triglycerides), smoking, glycemic control in diabetes mellitus, hypertension, and adoption of therapeutic lifestyle changes (exercise, weight reduction, and reduced cholesterol and fat in the diet). Reduction in inflammation may also play an important role.
Most patients with CAD should receive antiplatelet therapy. Chronic stable angina should be managed initially with β-blockers because they provide better symptomatic control at least as well as nitrates or calcium channel blockers and decrease the risk of recurrent myocardial infarction (MI) and CAD mortality.
Nitroglycerin and other nitrate products are useful for prophylaxis of angina when patients are undertaking activities known to provoke angina; however, when angina is occurring on a regular, routine basis, chronic prophylactic therapy should be instituted.
Although calcium channel blockers are effective as monotherapy, they are generally used in combination with β-blockers or as monotherapy if patients are intolerant of β-blockers; most patients with moderate-to-severe angina will require two drugs to control their symptoms. Ranolazine is a second-line drug to be used with β-blockers and certain calcium channel blockers.
Pharmacologic management is as effective as revascularization (percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass grafting [CABG], etc.) if one or two vessels are involved and there are no differences in survival, recurrent MI, or other measures of effectiveness.
Multivessel involvement, especially if the patient has left main CAD or left main equivalent disease, or two- to three-vessel involvement with significant left ventricular dysfunction is best managed with revascularization. With improvements in stent technology, more patients are eligible for this approach compared with CABG.
PTCA and CABG produce similar results overall, but certain patient subsets (e.g., diabetics) should have CABG done.
The clinical performance measures for chronic stable CAD recommended by the American College of Cardiology and the American Heart Association include blood pressure measurement, lipid profile, symptom and activity assessment, smoking cessation, antiplatelet therapy, drug therapy for lowering LDL cholesterol, β-blocker therapy for prior MI, ACE inhibitor therapy, and screening for diabetes.
INTRODUCTION
Atherosclerosis of the epicardial vessels leading to coronary heart disease (CHD) is the main etiology of ischemic heart disease (IHD). This process begins early in life, often not being clinically manifest until the middle-aged years and beyond. IHD may present as an acute coronary syndrome (ACS includes unstable angina, non–ST-segment elevation myocardial infarction [MI] or ST-segment elevation MI—see Chap. 7), chronic stable exertional angina pectoris, and ischemia without clinical symptoms. Coronary artery vasospasm (variant or Prinzmetal’s angina) produces similar symptoms but is not due to atherosclerosis. Microvascular angina that is myocardial ischemia without occlusive CHD is seen more commonly in women than in men. Other manifestations of atherosclerosis include heart failure, arrhythmias, cerebrovascular disease (stroke), and peripheral vascular disease. The American Heart Association (AHA), the American College of Cardiology, and the European Society of Cardiology have published management guidelines for stable and unstable angina.1,2
EPIDEMIOLOGY
The AHA estimates that 83,000,000 American adults have one or more types of cardiovascular disease (CVD) based on data from 2007 to 2010.3 Nearly 2,300 Americans die of CVD each day, or an average of 1 death every 38 seconds. In 2009, the death rates from CVD were 387 (per 100,000) for black males, 281.4 for white males, 269.9 for black females, and 190.4 for white females.3 Mortality data for 2010 show that CVD accounted for 34.3% of 2,468,435 deaths in 2009 or 1 of every ∼4 deaths in the United States. Men die earlier from IHD and AMI than women, and aging of both sexes is associated with a higher incidence of these afflictions. The disparity in mortality from IHD between men and women decreases with aging, being about four to five times more common in men from the age of the mid-30s to a preponderance of female deaths in the very elderly.
The syndrome of angina pectoris is reported to occur with an average annual incidence rate (number of new cases per time period/total number of persons in the population for the same time period) of about 1.5% (range 0.1 to 5/1,000) depending on the patient’s age, gender, and risk factor profile.4 The estimated prevalence of angina in 2010 was 7,800,000 (3.2% of the population), and the incidence of stable angina was 500,000.3 The presenting manifestation in women is more commonly angina, whereas men more frequently have MI as the initial event. Estimates of the incidence and prevalence of angina are not entirely accurate due to waxing and waning of symptoms; angina may disappear in up to 30% of patients with angina that is less severe and of recent onset.
Data from the Framingham study show that the prevalence in a 1970 cohort followed for 10 years was about 1.5% for women and 4.3% for men aged 50 to 59 years at inception.4 The annual rates of new episodes of angina range from 28.3 to 33 per 1,000 population for non-black men, 22.4 to 39.5 for black men, 14.1 to 22.9 for non-black women, and 15.3 to 35.9 for black women in the age range of 65 to 84 years or older.5 AHA estimates that the prevalence of angina was 10.2 million in 2006.5 Between 1980 and 2002, death rates due to CHD among men and women ≥65 years of age fell by 52% in men and 49% in women.5 The risk of developing IHD is not the same worldwide. Countries such as Japan and France are on the low end of the spectrum, whereas Finland, Northern Ireland, Scotland, and South Africa have very high rates of IHD.6,7
Angina may be classified according to symptom severity, disability induced, or a specific activity scale (Tables 6-1 and 6-2). The Specific Activity Scale developed by Goldman et al.8 may be preferable because it has been shown to be equal to or better than the New York Heart Association (NYHA) or Canadian Cardiovascular Society functional classifications for reproducibility and provides better agreement with exercise treadmill testing.
TABLE 6-1 Criteria for Determination of the Specific Activity Scale Functional Class
TABLE 6-2 Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System
An important determinate of outcome for the angina patient is the number of vessels obstructed. Twelve-year survival from the Coronary Artery Surgery Study (CASS) for patients with zero-, one-, two-, and three-vessel disease was 88%, 74%, 59%, and 40%, respectively.9 Other factors that increase the risk of death in medically managed patients include the presence of heart failure (or markers such as poor ventricular wall motion and low ejection fraction), smoking, left main or left main equivalent coronary artery disease (CAD), diabetes, or prior MI. Twelve-year survival for patients with at least one diseased vessel and ejection fractions in the ranges of ≥50% (≥0.50), 35% to 49% (0.35 to 0.49), and 0% to 34% (0 to 0.34) is 73%, 54%, and 21%, respectively. Of particular note, patients with left main CAD (or left main equivalent) are at extremely high risk and constitute a unique group for therapeutic consideration.10 In the CASS, at 15 years of follow-up, 37% of the surgery group and 27% of the medical group are surviving; median survival is 13.3 years versus 6.7 years, respectively (P < 0.0001). It is important to realize that these surgery studies are nearly 20 years old and event rates are now likely lower. Technology advances in coronary artery stent development may now allow more patients to be treated with primary percutaneous intervention (PCI) rather than coronary artery bypass grafting (CABG).11 Indeed, current guidelines provide similar recommendations for PCI and CABG in certain patients.12 If systolic function was normal, then median survival and percent surviving were not different between the surgery and medical groups (median survival of about 15 years). Patients screened but not randomized to CASS had similar survival rates, suggesting that results from randomized patients may be applicable to more generalized populations as a measure of external reliability.
ETIOLOGY AND PATHOPHYSIOLOGY
The pathophysiology that underlies this disease process is dynamic, evolutionary, and complex. An understanding of the determinants of myocardial oxygen demand (MVO2), regulation of coronary blood flow, the effects of ischemia on the mechanical and metabolic function of the myocardium, and how ischemia is recognized is important to understand the rationale for the selection and use of pharmacotherapy for IHD.
Ischemia may be defined as lack of oxygen and decreased or no blood flow in the myocardium. In contrast, anoxia, defined as the absence of oxygen to the myocardium, results in continued perfusion with washout of acid by-products of glycolysis, thereby preserving the mechanical and metabolic status of the heart to a greater extent than does ischemia for short periods of time.
Determinants of Oxygen Demand (MVO2)
The major determinants of MVO2 are (a) heart rate (HR), (b) contractility, and (c) intramyocardial wall tension during systole. Overall, intramyocardial wall tension is thought to be the most important among these three factors. As the consequences of IHD are a result of increased demand in the face of a fixed supply of oxygen in most situations, alterations in MVO2 are critically important in producing ischemia and for interventions intended to alleviate ischemia. MVO2 cannot be directly measured in patients; however, an indirect assessment that correlates reasonably well with MVO2 as determined in experimental animal models is the tension–time index (TTI). This is a measure of the area under the curve of the left ventricular (LV) pressure curve. Tension in the ventricle wall is a function of the radius of the LV and intraventricular pressure. These factors are related through Laplace’s law, which states that wall stress is related directly to the product of intraventricular pressure and internal radius and inversely to wall thickness multiplied by a factor of two. Increasing systemic blood pressure or ventricular dilation would increase wall tension and oxygen demand, whereas ventricular hypertrophy would tend to minimize increasing MVO2. Clinical application of these principles has led to the use of the double product (DP), which is HR multiplied by systolic blood pressure (SBP) (DP = HR × SBP). Although this is a clinically useful indirect estimate of MVO2, it does not consider changes in contractility (an independent variable), and because only changes in pressure are considered with the DP, volume loading of the LV and increased MVO2 related to ventricular dilation are underestimated.
Regulation of Coronary Blood Flow
Coronary blood flow is influenced by multiple factors; however, the caliber of the resistance vessels delivering blood to the myocardium and MVO2 are the prime determinants in the occurrence of ischemia. The anatomy of the vascular bed will affect oxygen supply and, subsequently, myocardial metabolism and mechanical function.
Anatomic Factors
The normal coronary system consists of large epicardial or surface vessels (R1) that normally offer little intrinsic resistance to myocardial flow and intramyocardial arteries and arterioles (R2), which branch into a dense capillary network (about 4,000 capillaries/mm2) to supply basal blood flow of 60 to 90 mL/min per 100 g of myocardium. R1 and R2 are in series and total resistance is the algebraic sum; however, under normal circumstances, the resistance in R2 is much greater. Myocardial blood flow is inversely related to arteriolar resistance and directly related to the coronary driving pressure. The arterioles dynamically alter their intrinsic tone in response to demands for oxygen and other factors, and as a result, myocardial oxygen delivery and MVO2 are tightly coupled in a rapidly responsive system.
Atherosclerotic lesions encroaching on the luminal cross-sectional area of the larger epicardial vessels (R1) transform the relationships among R1, R2, and blood flow. As resistance increases in R1 owing to occlusion, R2 can vasodilate to maintain coronary blood flow. This response is inadequate with greater degrees of obstruction, and the coronary flow reserve afforded by R2 vasodilation is insufficient to meet oxygen demand (also referred to as autoregulation). The extent of functional obstruction is important in the limitation of coronary blood flow, and the presence of relatively severe stenosis (>70%) may provoke ischemia and symptoms at rest, whereas less severe stenosis may allow a reserve of coronary blood flow for exertion.13
The diameter of the lesion impeding blood flow through a vessel is important, but other factors such as length of the lesion and the influence of pressure drop across an area of stenosis also affect coronary blood flow and function of the collateral circulation. Resistance to flow in a vessel is directly related to length of the obstructing lesion, but resistance is inversely related to the diameter of the vessel to the fourth power. Diameter is, therefore, much more important. As blood flows across a stenotic lesion, the pressure drops (energy losses) due to friction between blood and the lesion and due to the abrupt turbulent expansion as blood emerges from the stenosis. This pressure drop is dynamic and directly related to flow giving rise to a resistance that is not fixed, but rather fluctuates, as flow is changed. This relationship can dramatically affect collateral blood flow and its response to exercise, resulting in what has been called coronary steal. A similar situation may also occur when the epicardial or subepicardial vessels steal blood flow from the endocardium in the presence of a stenotic lesion.
Large and small coronary arteries may undergo dynamic changes in coronary vascular resistance and coronary blood flow. Dynamic coronary obstruction can occur in normal vessels and vessels with stenosis in which vasomotion or spasm may be superimposed on a fixed stenosis. Although it is possible that these changes may be active in small coronary arteries, it is also possible that the observed changes may reflect collapse owing to poststenotic intraluminal pressure drop or increased intramyocardial compressive forces associated with inadequate ventricular relaxation.
Collateral blood flow exists to a certain extent from birth as native collaterals, but persisting ischemia may promote collateral growth as developed collaterals. These two types of collaterals differ in anatomy and in their ability to regulate coronary blood flow. Collateral development is dependent on the severity of obstruction, the presence of various growth factors (basic fibroblast growth factor [β-FGF] and vascular endothelial growth factor [VEGF]), endogenous vasodilators (e.g., nitrous oxide, prostacyclin), hormones such as estrogen, and potentially exercise. Collateral development is highly species dependent and this should be considered when reading experimental literature. A recently developed technique called fractional flow reserve (FFR) allows for the measurement of coronary blood flow in the area of stenosis to assess the physiologic significance of stenosis (see Chap. 1 for details).
Metabolic Regulation
Coronary blood flow is closely tied to oxygen needs of the heart. Changes in oxygen balance lead to very rapid changes in coronary blood flow. Although a number of mediators may contribute to these changes, the most important ones are likely to be adenosine, other nucleotides, nitric oxide, prostaglandins, CO2, and H+. Adenosine, which is formed from adenosine triphosphate (ATP) and adenosine monophosphate (AMP) under conditions of ischemia and stress, is a potent vasodilator that links decreased perfusion to metabolically induced vasodilation or reactive hyperemia. The synthesis and release of adenosine into coronary sinus venous effluent occurs within seconds after coronary artery occlusion, and about 30% of the hyperemic response can be blocked by metabolic blockers of adenosine. Coronary reactivity can be used to detect individuals at risk for future events.14
Endothelial Control of Coronary Vascular Tone
The vascular endothelium, a single-cell tissue with an enormous surface area separating the blood from vascular smooth muscle of the artery wall, is capable of a broad range of metabolic functions. The endothelium functions as a protective surface for the artery wall, and as long as it remains intact and functional, it promotes vascular smooth muscle relaxation and inhibits thrombogenesis and atherosclerotic plaque formation; damaged endothelium reacts to numerous stimuli with vasoconstriction, thrombosis, and plaque formation. The vascular endothelium of the coronary arteries synthesizes large molecules such as fibronectin, interleukin-1, tissue plasminogen activator, and various growth factors. Small molecules that are also produced include prostacyclin, platelet-activating factor, endothelin-1, and endothelium-derived relaxing factor (EDRF) that is now characterized as nitric oxide. EDRF is synthesized from L-arginine via nitric oxide synthase and released by shear force on the endothelium as well as through interaction with many biochemical stimuli such as acetylcholine, histamine, arginine, catecholamines, arachidonic acid, ADP, endothelin-1, bradykinin, serotonin, and thrombin. Nitric oxide then causes relaxation of the underlying smooth muscle and may be thought of as a paracrine homeopathic defense mechanism against noxious stimuli. Denudation or loss of the vascular endothelium results in loss of EDRF and this protective mechanism. Loss of the endothelial cell layer and function may occur secondary to physical disruption (percutaneous transluminal coronary angioplasty [PTCA]), factors impinging from the vascular side (cyanide from smoke), or disruption of the intimal–medial layers (oxidized low-density lipoprotein [LDL]). Impaired endothelial function may be related to the development of premature atherosclerosis based on recent family studies. Endothelial function may be improved with angiotensin-converting enzyme inhibitors (ACEIs), statins, and exercise.15
Factors Extrinsic to the Vascular Bed
Blood flow to the coronary arteries arises from orifices located immediately distal to the aorta valve. Perfusion pressure is equal to the difference between the aortic pressure at an instantaneous point in time and the intramyocardial pressure. Coronary vascular resistance is influenced by phasic systolic compression of the vascular bed. The driving force for perfusion is, therefore, not constant throughout the cardiac cycle. Opening of the aortic valve may also lead to a Venturi effect, which can slightly decrease perfusion pressure. If perfusion pressure is elevated for a period of time, coronary vascular resistance declines and blood flow increases; however, continued perfusion pressure increases lead, within limits, to a return of coronary blood flow back toward baseline levels through autoregulation.
Alterations in intramyocardial wall tension throughout the cardiac cycle will also impose significant changes in coronary blood flow. Diastole is the period during which coronary artery filling can occur due to these pressure differences and little or no coronary blood flow occurs to the left ventricle during systole. The extent of pressure development in the ventricle and HR have a major effect on the development of wall tension, time for diastolic coronary artery filling, and MVO2.
Under normal conditions, the average global distribution of blood flow between the epicardial and endocardial layer is about 1:1 at rest and remains approximately even during exercise secondary to autoregulatory changes. Regional disparity of blood flow distribution does exist normally, and these disparities are magnified in the presence of diseased coronary arteries and with increased cardiac work as the vasodilator reserve in the resistance vessels of the subendocardium layers is exhausted. Factors that favor a reduction in subendocardial blood flow include decreased perfusion pressure due to decreased diastolic blood pressure or coronary artery obstruction by atherosclerotic plaques with or without vasomotion, abbreviation of diastole (increased HR), and increased intraventricular diastolic pressure (e.g., valvular obstruction to flow).
Extravascular resistance may decrease coronary blood flow, primarily during systole. This effect is much more pronounced in the LV compared with that in the right ventricle (RV). When the effect of increased contractility is separated from the effect of ventricular pressure, about 75% of extravascular resistance is accounted for by passive stretch in equilibrium with ventricular pressure, whereas only 25% results from active myocardial contraction.
Factors Intrinsic to the Vascular Bed
Metabolic factors, myogenic responses, neural reflexes, and humoral substances within the vascular bed of the coronary circulation function in an orchestrated fashion to maintain relative consistency in blood flow to the myocardium in the face of imposed changes in perfusion pressures. Autoregulation, mediated primarily through the effects of myogenic responses and metabolic factors, is thought to be responsible for maintaining regional blood flow in a narrow range while systemic pressure varies over a range of approximately 50 to 150 mm Hg.
Myogenic control (also known as the Bayliss effect) of coronary artery tone occurs when the vessel is stretched secondary to an increase in pressure and contracts to return blood flow to normal. It is thought that the myogenic response to stretching in coronary arteries is a modest one and that metabolic factors such as nitric oxide play a much larger role in autoregulation.
There are three well-studied metabolic factors that have the ability to modify coronary artery resistance and blood flow at the local level. Basal coronary blood flow meets oxygen demands of 8 to 10 mL/min per 100 g of myocardium with essentially complete extraction of oxygen from the blood. As cardiac output or mean arterial blood pressure increases, the increased demand for oxygen is met by increasing blood flow because little additional oxygen is available from hemoglobin. Decreased oxygen availability causes vasodilation of vascular smooth muscle and relaxation of precapillary sphincters, which increase tissue oxygen and help maintain blood flow on a regional basis.
At perfusion pressures below 60 mm Hg, as the coronary arteries are maximally dilated and the buffering effect of autoregulation has reached its capacity, further reduction in coronary blood flow will decrease perfusion pressure and tissue oxygenation. It is thought that autoregulation works more efficiently in the epicardial layers than in subendocardial layers, and this may contribute to coronary steal.
Neural components that participate in the regulation of coronary blood flow include the sympathetic nervous system, the parasympathetic nervous system, coronary reflexes, and, possibly, central control of coronary blood flow. Within the sympathetic system, stimulation of the stellate ganglion elicits coronary vasodilation, which is associated with tachycardia and enhanced contractility. This indirect coronary vasodilation is secondary to increased MVO2related to increased HR, contractility, and aortic pressure and occurs following stellate stimulation. The direct effect of the sympathetic system is α1-mediated vasoconstriction at rest and during exercise. Other receptor types, α2 and β1, have little influence on tone, whereas β2 stimulation produces a modest vasodilatory effect. Although coronary atherosclerosis may decrease blood flow secondary to obstruction, severe coronary atherosclerosis and obstruction may also increase the sensitivity of coronary arteries to the effects of β1 stimulation and vasoconstriction.
Vagal stimulation within the parasympathetic system produces a small to moderate increase in coronary blood flow, which involves the coronary efferent and afferent parasympathetic components (Bezold–Jarisch reflex). Indirectly, vasoconstriction may result, with vagal stimulation as the result of bradycardia and decreased contractility reducing MVO2.
Coronary reflexes have an undetermined role in the regulation of coronary blood flow. Based on experimental data, coronary reflexes that may be important include the baroreceptor, the chemoreceptor, Bezold–Jarisch reflex, and the pulmonary inhalation reflex.
FACTORS LIMITING CORONARY PERFUSION
During exercise and pacing, as MVO2 increases, coronary vascular resistance can be reduced to about 25% of basal values, which results in a fourfold to fivefold increase in coronary blood flow. The cross-sectional area can be reduced by about 80% prior to any mechanical or biochemical changes in the myocardium, reflecting a margin of safety for coronary blood flow. The extent of cross-sectional obstruction, the length of the lesion, lesion composition, and the geometry of the obstructing lesion can each affect flow across coronary arteries with atherosclerosis. Bernoulli’s theorem states that the pressure drop across a lesion is directly related to the length of the lesion and inversely related to the radius of the lesion to the fourth power; critical stenosis occurs when the obstructing lesion encroaches on the luminal diameter and exceeds 70%. Lesions creating obstruction of 50% to 70% may reduce blood flow; however, these obstructions are not consistent and vasospasm and thrombosis superimposed on a noncritical lesion may lead to clinical events such as MI.14 If the lesion enlarges from 80% to 90%, resistance in that vessel is tripled. Coronary reserve is diminished at about 85% obstruction owing to vasoconstriction. Exaggerated responsiveness can be seen when coronary stenosis reaches this critical level and the role of vasoactive substances such as prostaglandins, thromboxanes, and serotonin may play more of a role in the regulation of coronary vascular tone and thrombosis.
Little reserve exists for coronary blood flow and a relatively small reduction of 10% to 20% results in decreased myocardial fiber shortening as the first evidence for abnormal function. The subendocardial layers are affected to a greater extent than the epicardium by ischemia, considering changes in fiber shortening, arteriovenous (AV) difference in oxygen saturation, and lactate production. A reduction of 80% gives rise to akinesis and a 95% reduction of coronary blood flow produces dyskinesis during contraction of the ventricles. Although these abnormalities of contraction are associated with transient impaired function, depletion of high-energy phosphate compounds and ultrastructural changes may last for days even after transient ischemia; this has been referred to as stunned myocardium. Chronic hypoperfusion may lead to hibernation, in which ventricular function is impaired over longer time intervals. Hibernating myocardium can be differentiated from necrosis with various techniques (see Chap. 1) and revascularization of hibernating myocardium is useful in improving ventricular function. Regional loss of contractility may impose a burden on the remaining myocardial tissue, resulting in heart failure, increased MVO2, and rapid depletion of blood flow reserve. Consequently, zones of tissue with marginal blood flow may develop in a lateral or transmural fashion; such development puts this tissue at risk for more severe damage if the ischemic episode persists or becomes more severe. Nonischemic areas of myocardium may compensate for the severely ischemic and border zones of ischemia by developing more tension than usual in an attempt to maintain cardiac output. At the cellular level, ischemia and the attendant acidosis are thought to alter calcium release from storage sites such as the sarcolemma and the sarcoplasmic reticulum as well as inhibit the binding of calcium to troponin, thereby impairing the association of actin and myosin. The clinical correlates of these cellular biochemical events leading to the development of LV or RV dysfunction include an S3, dyspnea, orthopnea, tachycardia, fluctuating blood pressure, transient murmurs, and mitral or tricuspid regurgitation.
CLINICAL PRESENTATION AND DIAGNOSIS
General
• Many episodes of ischemia do not cause symptoms of angina (silent ischemia).
• Patients often have a reproducible pattern of pain or other symptoms that appear after specific amount of exertion.
• Increased frequency, severity, duration, or symptoms at rest suggest an unstable angina pattern and the patient should seek help immediately.
Symptoms
• 
Sensation of pressure or burning over the sternum or near it, often but not always radiating to the left jaw, shoulder, and arm; also chest tightness and shortness of breath.
• Pain usually lasts from 0.5 to 30 minutes often with a visceral quality (deep location).
• Precipitating factors include exercise, cold environment, walking after a meal, emotional upset, fright, anger, and coitus.
• Relief occurs with rest and nitroglycerin.
Signs
• Abnormal precordial (over the heart) systolic bulge
• Abnormal heart sounds
Laboratory Tests
• Typically no laboratory tests are abnormal; however, if the patient has intermediate- to high-risk features for unstable angina, electrocardiographic changes and serum troponin, or creatine kinase may become abnormal (Table 6-3).
• Patients are likely to have laboratory test abnormalities for the risk factors for IHD such as elevated total and LDL cholesterol, low HDL cholesterol, impaired fasting glucose or elevated glucose, high blood pressure, elevated C-reactive protein, and abnormal renal function. Hemoglobin should be checked to make sure the patient is not anemic.
Other Diagnostic Tests (see Chap. 1)
• A resting electrocardiogram followed by an exercise tolerance test is usually the first test done in stable patients. A chest x-ray should be done if the patient has heart failure symptoms. Cardiac imaging using radioisotopes to detect ischemic myocardium and measure ventricular function is commonly done when revascularization is being considered. Echocardiography may also be used to assess ventricular wall motion at rest or during stress. Cardiac catheterization and coronary arteriography are used to determine coronary artery anatomy and if the patient would benefit from angioplasty, coronary artery bypass surgery, or other revascularization procedures. Coronary artery calcium (CAC) may be useful in detecting early disease (see Chap. 1).
TABLE 6-3 Short-Term Risk of Death or Nonfatal Myocardial Infarction in Patients with Unstable Angina
Calcium accumulation and overload secondary to ischemia impairs ventricular relaxation as well as contraction. This is apparently a result of impaired calcium uptake after systole from the myofilaments, leading to a less negative decline of the pressure in the ventricle over time. Impaired relaxation is associated with enhanced diastolic stiffness, decreased rate of wall thinning, and slowed pressure decay, producing an upward shift in the ventricular pressure–volume relationship; put more simply, MVO2 is likely to be increased secondary to increased wall tension. Impairment of both diastolic and systolic function leads to elevation of the filling pressure of the left ventricle.
Important aspects of the clinical history for chest pain for patients with angina include the nature or quality of the pain, precipitating factors, duration, pain radiation, and the response to nitroglycerin or rest. Because there can be considerable variation in the manifestations of angina, it is more accurate to refer to these symptoms as an anginal syndrome. For some patients with significant coronary disease, their presenting symptoms may differ from the classical symptoms, yet the symptoms are due to ischemic pain, and these are often referred to as anginal equivalents. Obtaining an accurate and detailed family history is useful in placing symptoms in perspective. Significant positive information includes premature CHD (<55 years in men and <65 years in women) manifested as fatal and nonfatal MI, stroke, peripheral vascular disease, as well as other risk factors such as hypertension, smoking, familial lipid disorders, and diabetes mellitus (considered to be a risk equivalent). Typical pain radiation patterns include anterior chest pain (96%), left upper arm pain (83.7%), left lower arm pain (29.3%), and neck pain at some time (22%). Pain from other areas is less common. Ischemia detected by ECG monitoring is more likely to be detected in the morning hours (6 AM to 12 noon) than other periods throughout the day. Patients suffering from variant or Prinzmetal’s angina secondary to coronary spasm are more likely to experience pain at rest and in the early morning hours. Prinzmetal’s anginal pain is not usually brought on by exertion or emotional stress nor relieved by rest, and the ECG pattern is that of current injury with ST elevation rather than depression. Typical pain that occurs in nonocclusive CAD is referred to as microvascular angina.
It is also important to differentiate the pattern of pain for stable angina from that of unstable angina. Unstable angina may be stratified into categories of risk ranging from high to low (Table 6-3).16 Ischemia may also be painless or silent in 60% to 100% of patients depending on the series cited and the patient population.17 In patients with myocardial ischemia, approximately 70% of the episodes of documented ischemia are painless as determined by ambulatory ECG monitoring, and the ST-segment changes associated with these episodes can be ST elevation or depression. The mechanism of silent ischemia is unclear, but studies have shown that patients not experiencing pain have altered pain perception, with the threshold and tolerance for pain being higher than that of patients who have pain more frequently. Although patients with diabetes tend to have more extensive and microvascular coronary disease than those without diabetes and may suffer from autonomic neuropathy, asymptomatic ischemia is not more prevalent based on the Asymptomatic Cardiac Ischemia Pilot (ACIP) study.18
Lastly, it should be recognized that the threshold for pain due to exertion is fixed in some patients and variable in others and that the amount of exercise or stress necessary to provoke symptoms can change over time. A fixed threshold for the induction of pain or ECG evidence of ischemia means these indicators of ischemia occur at the same, or nearly so, double rate–pressure product (SBP × HR). This is apparently due to at least two factors. Over long periods of time atherosclerosis may progress, leading to more severe stenosis, reduced oxygen supply, and less of an increase in demand to precipitate ischemic symptoms. Once stenotic lesions reach a critical level of about 80% or greater, vasomotion, vasospasm, and thrombotic occlusion become significant factors impairing blood flow to the myocardium. Consequently, anatomic considerations and vasoactive substances may interact to provide an environment amenable to changing thresholds for the production of angina.
There appears to be little relationship between the historical features of angina and the severity or extent of coronary artery vessel involvement. Therefore, one may speculate that severe symptoms might be associated with multivessel disease, but no predictive markers exist on a routine basis.
Chest pain may resemble pain arising from a variety of noncardiac sources and the differential diagnosis of anginal pain from other etiologies may be quite difficult based on history alone. Table 6-4 outlines other common problems that may be present with episodic chest pain. Although much less common, nonatherosclerotic etiologies of CAD do exist and should be excluded with appropriate tests. The clinical classification of chest pain encompasses typical angina including (a) substernal chest pain with a characteristic quality and duration that is (b) provoked by exertion or emotional stress and (c) relieved by rest or nitroglycerin; atypical angina (meets two of the characteristics for typical angina); and noncardiac chest pain (meets ≤1 of the typical angina characteristics).19,20
TABLE 6-4 Differential Diagnosis of Episodic Chest Pain Resembling Angina Pectoris
There are few signs apparent on physical examination to indicate the presence of CAD and usually only the cardiovascular system reveals any useful information. Elevated HR or blood pressure can yield an increased DP and may be associated with angina, and it would be important to correct extreme tachycardia or hypertension if present. Other noncardiac physical findings that suggest that significant CVD may be associated with angina include abdominal aortic aneurysms or peripheral vascular disease. Cardiac examination findings in CAD are noted in Table 6-5. During an angina attack these findings may appear or become more prominent, making them more valuable if present.
TABLE 6-5 Cardiac Exam Findings in Coronary Artery Disease
In addition to screening for CVD risk factors, other recommended tests include hemoglobin, fasting glucose, fasting lipoprotein panel, resting ECG, and chest x-ray in patients with signs or symptoms of heart failure, valvular heart disease, pericardial disease, or aortic dissection/aneurysm.20 Hemoglobin is assessed to insure adequate oxygen-carrying capacity. Fasting glucose determinations to exclude diabetes and glucose monitoring for concurrent diabetes should be performed routinely. Lipids are assessed total, LDL, and HDL cholesterol and triglycerides (see Chap. 11).21 Other risk factors that may be important for some patients include high-sensitivity C-reactive protein, homocysteine level, evidence of chlamydia infection, and elevations in lipoprotein(a), fibrinogen, and plasminogen activator inhibitor.22 Cardiac enzymes should all be normal in stable angina. Troponin T or I, myoglobin, or creatinine phosphokinase-MB isoform may be elevated in patients with unstable angina, and interventions such as anticoagulation or antiplatelet therapy have been shown to reduce cardiac end points when these markers for injury are elevated (Table 6-3).23
Patients presenting with chest pain are stratified into chronic stable angina or having features of intermediate- or high-risk unstable angina (Table 6-3). These features include rest pain lasting >20 minutes, age >65 years, ST- and T-wave changes, and pulmonary edema. Patients with ACS (unstable angina, non–ST-segment elevation AMI, and ST-segment elevation AMI) are managed differently than those with chronic stable angina. For more details on the management of ACS, please refer to Chapter 7.
Diagnostic Tests
See also Chapter 1 and Figure 6-1.
FIGURE 6-1 Diagnosis of patients with suspected ischemic heart disease. Colors correspond to the class of recommendations in the ACCF/AHA Table 6-13. The algorithms do not represent a comprehensive list of recommendations (see text for all recommendations). aSee Table 6-3 for short-term risk of death or nonfatal MI in patients with UA/NSTEMI. bCCTA is reasonable only for patients with intermediate probability of IHD. (CCTA, computed coronary tomography angiography; CMR, cardiac magnetic resonance; ECG, electrocardiogram; Echo, echocardiography; IHD, ischemic heart disease; MI, myocardial infarction; MPI, myocardial perfusion imaging; Pharm, pharmacological; UA/NSTEMI, unstable angina/non–ST-elevation myocardial infarction.)
TREATMENT
Desired Outcome
Important goals in the treatment of IHD are to minimize the likelihood of death and maximize health and function. Objectives of management include:
1. Reduce premature CVD.
2. Prevent complications of IHD, for example, MI.
3. Maintain or restore activity, functional capacity, and quality of life.
4. Completely or nearly completely eliminate ischemic symptoms.
5. Minimize costs of heat care by avoiding unnecessary testing and treatment, preventing hospitalizations, and avoiding complications of testing.
6. Since there is little evidence that revascularization procedures such as angioplasty and coronary artery bypass surgery extend life, the primary focus should be on altering the underlying and ongoing process of atherosclerosis through risk factor modification while providing symptomatic relief through the use of β-blockers, calcium channel blockers, nitrates, and ranolazine for anginal symptoms.
Risk Factor Modification
Primary prevention of IHD through the identification and modification of risk factors prior to the initial morbid event would be the optimal management approach and should result in a significant impact on the prevalence of IHD. However, early recognition of some risk factors may not be possible in all cases, and in others, the patient may not be willing to undertake intervention until overt evidence of coronary disease is apparent. Secondary intervention continues to be more commonly pursued by both healthcare professionals and patients, and it is important to recognize this type of intervention as effective in reducing subsequent morbidity and mortality. The presence of risk factors in individual patients plays a major role in determining the occurrence and severity of IHD.24,25 Risk factors are additive in nature and can be classified as alterable or unalterable (see Table 11-7). Unalterable risk factors include gender; age; family history or genetic composition; environmental influences such as climate, air pollution, and trace metal composition of drinking water; and, to some extent, diabetes mellitus. Improved glycemic control reduces the microvascular complications of diabetes mellitus (see Chap. 57); however, with publication of the ACCORD trial strict control of glucose did not improve the primary outcome.2,26
Risk factors that can be altered include smoking, hypertension, dyslipidemia, obesity, sedentary lifestyle, hyperuricemia, psychosocial factors such as stress and type A behavior patterns, and the use of certain drugs that may be detrimental including progestins, corticosteroids, and calcineurin inhibitors.
Cigarette smoking is common. The Centers for Disease Control and Prevention estimates that ∼42 million people are current smokers (23.1% men; 16.7% women) in this country, and the risk for CHD is increased by about 1.8 in active smokers and by about 1.3 for passive or environmental smoke exposure.3,5 Each year 443,000 Americans die from smoking-related illnesses and 142,000 of the deaths are attributable to CVD.5 Risk due to smoking is related to the number of cigarettes smoked per day and the duration of smoking. Passive smoking in angina pectoris patients has been shown to decrease exercise time.6 Pipe and cigar smokers are at increased risk compared with nonsmokers, but their risk is somewhat less than that of cigarette smokers.27 The direct effects of cigarette smoke that are detrimental to patients with angina include (a) elevated HR and blood pressure from nicotine, which increases MVO2, and impaired myocardial oxygen delivery due to carboxyhemoglobin generation from carbon monoxide inhalation in smoke; (b) the negative inotropic effect of carboxyhemoglobin; (c) increased platelet adhesiveness and promotion of aggregation resulting in thrombotic tendencies due to nicotine and carboxyhemoglobin; (d) lowered threshold for ventricular fibrillation during ischemia due to carboxyhemoglobin; and (e) impaired endothelial function owing to smoking.31 Similar changes have been noted for marihuana smoking as well. Smoking also accelerates the risk for MI, sudden death, cerebrovascular disease, peripheral vascular disease, and hypertension, and it reduces high-density lipoprotein concentrations. Clearly, primary prevention is needed for this risk factor and much of the education effort to discourage initiation of smoking should be targeted for teenagers. Techniques for cessation of smoking that may be useful include aversive conditioning, group programs, self-help programs, hypnosis, cold turkey, and the use of nicotine substitutes (lobeline) or other sources of nicotine replacement products for short-term substitution during withdrawal syndrome. The antidepressant sustained-release buproprion has been shown to be more effective than placebo and best used with smoking cessation counseling. Varenicline, a partial agonist selective for the α4β2 nicotinic acetylcholine receptor subtype, has been shown to improve cessation rates as well.28,29 It may be more cost-effective than other interventions for smoking cessation.30 Cessation of smoking reduces the incidence of coronary events to about 15% to 25% of that associated with continued smoking and these benefits are noted within 2 years of cessation.31 A public ordinance reducing exposure to secondhand smoke was associated with a decrease in AMI hospitalizations in Pueblo, Colorado, by 27% in 2 years.32
Hypertension, whether labile or fixed, borderline or definite, casual or basal, systolic or diastolic, at any age regardless of gender, is the most common and a powerful contributor to atherosclerotic coronary vascular disease.33Morbidity and mortality increase progressively with the degree of blood pressure elevation of either systolic or diastolic pressure and pulse pressure, and no discernible critical value exists (see Chap. 3). Numerous trials have documented the reduction in risk associated with blood pressure lowering; however, most of these studies show that mortality and morbidity reduction is a result of fewer strokes and less renal failure and heart failure. The reduction in CHD end points is significant but not as dramatic. The reasons for this are unclear but perhaps relate to the multifactorial etiology of IHD. Recent guideline changes from the AHA recommend goal blood pressure of <130/80 mm Hg for patients with stable angina, unstable angina, non–ST-segment MI, and ST-segment MI and <120/80 mm Hg in patients with LV dysfunction.33
Hypercholesterolemia is a significant cardiovascular risk factor, and risk is directly related to the degree of cholesterol elevation.24,25 As with hypertension, there is no critical value that defines risk, but rather risk is incrementally related to the degree of elevation and the presence of other risk factors (see Chap. 11 for a detailed discussion). A fasting lipoprotein panel should be obtained in all patients with known CAD. The goals for total, LDL, and HDL cholesterol and triglycerides are discussed in Chapter 11. All patients should undertake therapeutic lifestyle changes. Reductions in LDL cholesterol for primary prevention and secondary intervention have been shown to reduce total and CAD mortality and stroke as well as the need for interventions such as PTCA and CABG. Supplemental vitamin E or other antioxidants reduce the susceptibility of LDL cholesterol to oxidation but clinical trial data have failed to show any benefit with supplementation.34
Overweight and obesity, defined as a body mass index (BMI, weight in kilograms divided by height in meters squared) of ≥25 and ≥30 kg/m2, respectively, are estimated to occur in 68.2% and 34.6% of the U.S. population. BMI is associated with an increased mortality ratio compared with individuals of normal body weight, and the objective for patients with IHD is to maintain or reduce to a normal body weight.3,5 This may be accomplished through dietary modification, exercise, pharmacologic therapy, or surgical therapy. Frequently associated with obesity is a sedentary lifestyle, and inactivity may contribute to higher blood pressure, elevated blood lipid levels, and insulin resistance associated with glucose intolerance in diabetics (insulin resistance or metabolic syndrome). Exercise to the level of about 300 kcal (1,256 kJ) three times a week is useful in improving maximal oxygen uptake, improving cardiorespiratory efficiency, promoting collateral artery formation, and promoting potential alterations in the risk of ventricular fibrillation, coronary thrombosis, and improved tolerance to stress. Epidemiologic studies have found that mortality is directly related to resting HR and a low HR difference between resting and maximal exercise HR, and inversely related to exercise HR. A regular exercise program has been shown to reduce all-cause and cardiac mortality.35,36
Competitiveness, intense striving for achievement, easily provoked hostility, a sense of urgency about doing things quickly and being punctual, impatience, abrupt and rapid speech and gestures, and concentration on self-selected goals to the point of not perceiving and attending to other aspects of the environment are traits that characterize the behavioral pattern known as the type A or coronary prone personality. Although the issue is somewhat controversial, type A individuals may have increased cardiovascular risk with risk ratios ranging from insignificant to three times that of a matched population. Psychological stress and type D personality have been associated with adverse cardiac prognosis, but little is known about their relative effect on the pathogenesis of CHD. “Type D” refers to the tendency to experience negative emotions and to inhibit the expression of these emotions in social interactions. The mechanism by which personality affects the cardiovascular system is not understood, but may reflect the activity of the sympathetic system and enhanced responsiveness of other stress hormones when compared with non–type A personalities.
Alcohol ingestion in small to moderate amounts (<40 g/day of pure ethanol) reduces the risk of CHD; however, consumption of large amounts (>50 g/day) or binge drinking of alcohol is associated with increased mortality from stroke, cancer, vehicular accidents, and cirrhosis.37,38 There appears to be a differential effect depending on race with an inverse relationship between ethanol consumption in whites but a direct relationship between consumption and CAD risk in blacks. The mechanisms for the presumed protective effects of alcohol are not known but the effects may be related to increased high-density lipoprotein levels, impaired platelet function, or associations between the amount of alcohol ingested and personality type. Long-term follow-up studies of alcohol ingestion have found that the beneficial effects on MI are small compared with the overall effects on mortality.39 Whatever the relationship, it is well to remember that alcohol drinking is implicated in over 40% of all fatal automobile accidents and consumption of alcohol predisposes to hepatic cirrhosis, the sixth to seventh most common cause of death in middle age in the United States. With this in mind, it seems illogical to suggest alcohol ingestion as a prophylactic measure for coronary disease but rather advise moderation of alcohol consumption, if it is the preference of the individual.
Thiazide diuretics have been shown to elevate serum cholesterol and triglyceride levels, whereas β-blockers tend to lower HDL and raise LDL slightly; however, a direct association between these drugs and cardiovascular risk is tenuous and based on aggregating results rather than randomized clinical trials. Conjugated equine estrogen alone or in combination with progestin lowers LDL and raises HDL; unfortunately, the HERS trial showed no benefit of hormone replacement therapy for secondary intervention and increased risk for thromboembolism.40 In secondary intervention, HRT or estrogen alone in women after hysterectomy found that hormonal therapy health risks exceeded benefits as well.41,42 Unopposed estrogen is the optimal regimen for elevation of HDL, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, estrogen with cyclic medroxyprogesterone has the most favorable effect on HDL and no excess risk of endometrial hyperplasia. Use of oral contraceptives in women who smoke and are over the age of 35 years increases the risk of MI, stroke, and venous thromboembolism by threefold or higher. Alternative forms of contraception and cessation of smoking should be promoted in these patients. The risk for nonsmoking oral contraceptive users under the age of 35 is very small. The relative risk of breast cancer is increased, but in the absence of risk factors for breast cancer, the relative risk is approximately 1.3 (30% increase). Coffee consumption has also been linked to CHD and caffeine does transiently elevate blood pressure; however, the overall risk, if any, appears to be low and may be related to genetic makeup (CYP1A2 mutation).43,44 Although thiazide diuretics and β-blockers (nonselective without intrinsic sympathomimetic activity) may elevate both cholesterol and triglycerides by approximately 10% to 20%, and these effects may be detrimental, no objective evidence exists from prospective well-controlled studies to support avoiding these drugs at this time. This controversy is most pertinent in the treatment of mild hypertension and it is discussed in greater detail in Chapter 3.
TREATMENT
Stable Ischemic Heart Disease
Table 6-6 contains evidence grading recommendations.
TABLE 6-6 The American College of Cardiology and American Heart Association Evidence Grading System
The guidelines for the management of stable IHD place a strong emphasis on patient education. Class I recommendations include education on the importance of medication adherence, modification of risk, a comprehensive review of all therapeutic options, appropriate levels of exercise, introduction to self-monitoring skills, and recognition of worsening symptoms and steps to take appropriate action if symptoms are changing.12 Patients should be educated about adherence to a diet that is low in saturated fat, cholesterol, and trans fat; high in fresh fruits, whole grains, and vegetables; and reduced in sodium intake (Class IIa). Comprehensive behavioral approaches for the management of stress and depression and evolution and treatment of major depressive disorder are recommended as well (Class IIa, B, C).
Guideline-directed medical therapy (GDMT) provides guidance for risk factor modification in stable IHD. Lifestyle modifications including daily physical activity and weight management are strongly recommended (Class I, B) as well as dietary therapy including reduced saturated fat intake (7% of total calories), trans fat (<1% of total calories), and cholesterol <200 mg/day (Class I, B). In addition to therapeutic lifestyle changes a moderate or high dose of statin therapy is recommended in the absence of contraindications or adverse effects (Class I, A). Patients not tolerating a statin may be given a bile acid sequestrant, niacin, or both (Class IIa, B). The use of niacin has become controversial and more detail can be found in Chapter 11. Under GDMT blood pressure management includes the lifestyle changes described above (Class I, B) with a target blood pressure of 140/90 mm Hg or less in addition to lifestyle modifications (Class I, A). Selection of a particular blood pressure–lowering agent should be based on specific patient characteristics and may include ACEI and/or β-blockers with the addition of other drugs such as thiazide diuretics or calcium channel blockers to achieve a goal blood pressure of <140/90 mm Hg (Class I, B). See Table 6-7 for indications for individual drug classes.
TABLE 6-7 Indications for Individual Drug Classes in SIHD
The goals for diabetes management take into consideration the duration of diabetes and life expectancy. Patients with a short duration of diabetes and long life expectancy have a goal of hemoglobin A1c of ≤7% (≤53 mmol/mol Hb) (Class IIa, B); a goal of 7% to 9% (53 to 75 mmol/mol Hb) is reasonable for certain patients based on age, history of hypoglycemia, presence of microvascular or macrovascular complications, or presence of coexisting medical conditions (Class IIa, C). Pharmacotherapy interventions to achieve the target A1c might be reasonable (Class IIb, A). Therapy with rosiglitazone should not be initiated in patients with SIHD (Class III, C). Another controversy now exists concerning how low to go with A1c. Recent trials described in Chapter 57 point out that lower may not be better.
Physical activity is recommended in all patients with a goal of 30 to 60 minutes of moderate-intensity aerobic activity at least 5 days and preferably 7 days/wk (Class I, B). Risk assessment with a physical activity history and/or an exercise test is recommended to guide prognosis and prescription (Class I, B). Cardiac rehabilitation and physician-directed, home-based programs are recommended for at-risk patient at first diagnosis (Class I, A). Resistance training is also considered to be reasonable at least 2 days/wk (Class IIa, C).
BMI should be assessed at every visit and the goal is to achieve a BMI of 18.5 to 24.9 kg/m2 with a waist circumference of less than 102 cm in men and 88 cm in women (Class I, C). Smoking cessation and avoidance of exposure to environmental tobacco smoke should be encouraged for all patients with follow-up and referral to special programs to aid in cessation through counseling and pharmacologic interventions. The generally accepted approach is the ask, advise, assess, assist, arrange, and avoid approach (Class I, B). See Chapter 16 for more details concerning smoking cessation.
1. Ask each patient about tobacco use at every visit.
2. Advise each smoker to quit.
3. Assess each smoker’s willingness to make a quit attempt.
4. Assist each smoker in making a quit attempt by offering medication and referral for counseling.
5. Arrange for follow-up.
6. Avoid exposure to environmental tobacco smoke.
It is reasonable to consider screening SIHD patients for depression and to refer or treat when indicated (Class IIa, B). Treatment of depression has not been shown to improve CVD outcomes but might be reasonable for its other clinical benefits (Class IIb, C). Alcohol consumption in patients with SIHD should not exceed 4 oz (120 mL) of wine, 12 oz (360 mL) of beer, or 1 oz (30 mL) of spirits a day (Class IIa, C). Patients with SIHD should avoid exposure to increased air pollution to reduce the risk of cardiovascular events (Class IIa, C).
Recommendations for Medical Therapy to Prevent MI and Death
Antiplatelet therapy with aspirin 75 to 162 mg day daily should be continued indefinitely in the absence of contraindications (Class I, A). Clopidogrel is a reasonable alterative when aspirin is contraindicated (Class I, A). Treatment with aspirin 65 to 162 mg daily and clopidogrel 75 mg daily might be reasonable in certain high-risk patients with SIHD (Class IIb, B). The major metabolic pathway for activation of clopidogrel is cytochrome (CYP) P450 2C19, and approximately 30% of whites and African Americans have reduced-function alleles and cannot fully activate clopidogrel, resulting in higher cardiovascular event rates. Asian populations have reduced-function alleles in as many as 60% of individuals. There has been concern over interactions with drugs that can inhibit 2C19 (such as omeprazole), but the clinical significance of these interactions remains uncertain. In certain situations such as placement of drug-eluting stents (DES) and certain valvular disorders this combination may be appropriate. Dipyridamole is not recommended as antiplatelet therapy for patients with SIHD (Class III, B).
β-Blocker therapy should be started and continued for 3 years in all patients with normal LV function after MI or an acute coronary syndrome (Class I, A). Patients with a reduced ejection fraction (≤40% [≤0.40]) with heart failure or prior MI should be started on β-blocker therapy unless contraindicated. Only carvedilol, metoprolol succinate, and bisoprolol have been shown to reduce the risk of death in heart failure patients (Class I, A). β-Blockers should be considered as chronic therapy for all other patients with coronary or other vascular disease (Class IIb, C).
ACEI should be used in all patients with SIHD who also have hypertension, diabetes mellitus, LV ejection fraction (≤40% [≤0.40]), or chronic kidney disease unless contraindicated (Class I, A). ARBs are recommended for patients who cannot tolerate ACEI (Class I, A). ACEIs are reasonable in patients with both SIHD and other vascular disease (Class IIa, B). In a similar vein, ARBs can be substituted for ACEI intolerance (Class IIa, C). Annual influenza vaccine is recommended for patients with SIHD (Class I, B).
Class III recommendations, that is, no benefit, include a number of interventions. Estrogen therapy is not recommended in postmenopausal women with SIHD with the intent of reducing CV risk or improving outcomes (Class III, A). Vitamins C and E and β-carotene supplementation are not recommended since there is no evidence that CV risk is reduced (Class III, A). The use of folate or vitamins B6 and B12 and chelation therapy is not recommended due to the lack of evidence for effectively reducing CVD risk (Class III, A, C). Garlic, coenzyme Q10, selenium, or chromium is not recommended with the intent of reducing CVD risk in patient with SIHD (Class III, C).
Recommendations for Medical Therapy for the Relief of Symptoms
All of the following are Class I recommendations:
1. β-Blockers should be prescribed as initial therapy for relief of symptoms in patients with SIHD (LOE: B).
2. Calcium channel blockers or long-acting nitrates should be prescribed for the relief of symptoms when β-blockers are contraindicated or cause unacceptable adverse effects (LOE: B).
3. Calcium channel blockers or long-acting nitrates, in combination with β-blockers, should be prescribed for relief of symptoms when initial treatment with β-blockers is unsuccessful (LOE: B).
4. Sublingual (SL) nitroglycerin or nitroglycerin spray is recommended for immediate relief of angina in patients with SIHD (LOE: B) 
.
Class IIa recommendations include recommending the use of diltiazem or verapamil instead of a β-blocker as initial therapy for relief of symptoms is reasonable in SIHD (LOE: B). Ranolazine can be useful when prescribed as a substitute for β-blockers when β-blockers cause unacceptable adverse effects or are ineffective or contraindicated (LOE: B). Ranolazine in combination with β-blockers can be used for symptom relief when initial therapy with β-blockers is not successful in SIHD (LOE: A).
There are several interesting agents for the management of SIHD that are not available in the United States. Nicorandil activates ATP-sensitive potassium channels and promotes systemic venous and coronary vasodilation. The efficacy is considered to be similar to oral nitrates, calcium channel blockers, and β-blockers.45 Ivabradine is an inhibitor of the If current of pacemaker cells reducing HR, prolonging diastole, and improving oxygen balance.46Trimetazidine improves the cellular tolerance to ischemia by inhibiting fatty acid metabolism and stimulating glucose metabolism.47
Alternative Therapies for Relief of Symptoms in Patients with Refractory Angina
Class IIb recommendations include enhanced external counterpulsation (LOE: B), spinal cord stimulation (LOE: C), and transmyocardial revascularization (LOE: B). None of these modalities are in common use in the United States. Acupuncture should not be used to improve symptoms or reduce risk of CVD in SIHD (Class III, C).
Recommendations for revascularization to improve survival and to improve symptoms can be found in Tables 6-8 and 6-9.12 Generally speaking, the changes from previous guidelines are more use of PCI in more complex cases. This assumes that the patient has anatomy that can be addressed with PCI and that the SYNTAX (Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) score is ≤22 that represents a high likelihood of a good long-term outcome. Early trials of CABG versus medical therapy found that survival was improved with CABG; however, many of these trials are more than 2 decades old and medical therapy has improved.9,10In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial optimal medical therapy was as good as revascularization with the exception of certain subgroups such as patients with diabetes.26,48 In the COURAGE trial the 4.6-year cumulative primary-event rates (death from any cause and nonfatal MI) were 19% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P = 0.62).48,49 Medicine, Angioplasty, or Surgery Study (MASS II) found medical therapy was associated with an incidence of long-term events and rate of additional revascularization similar to those for PCI. CABG was superior to medical therapy in terms of the primary end points, reaching a significant 44% reduction in primary end points at the 5-year follow-up of patients with stable multivessel CAD.50Addition information is provided later in Revascularization below.
TABLE 6-8 Revascularization to Improve Survival Compared with Medical Therapy
TABLE 6-9 Revascularization to Improve Symptoms with Significant Anatomic (≥50% Left Main or ≥70% Non-Left Main CAD) or Physiologic (FFR ≤0.80) Coronary Artery Stenoses
After assessing and manipulating the alterable risk factors as discussed previously, the next intervention that could be undertaken is the institution of a regular exercise program. Training is possible in many patients with angina and the observed benefits include decreased HR and SBP as well as increased ejection fraction and duration of exercise. Although the mechanism of these effects has been debated, improved overall cardiovascular and muscular condition is probably the most important. Improved production of nitric oxide and coronary vasomotion may account partially for the beneficial effects of exercise. The intensity of exercise influences training and more vigorous programs provide better overall results.35,36 Obviously, an exercise program should be undertaken with caution and in a graded fashion with adequate supervision.
Chronic prophylactic therapy for patients with more than one angina episode per day may also be instituted with β-adrenergic blocking agents, and in many instances, β-blockers may be preferable because of less frequent dosing and other properties inherent in β-blockade (e.g., potential cardioprotective effects, antiarrhythmic effects, lack of tolerance, and antihypertensive effects), as well as their antianginal effects and documented protective effects in post-MI patients.19,51 β-Blockers may also slow the progression of plaque volume.52 Patients who continue to smoke have reduced antianginal efficacy of β-blockers. This may be due to enhanced hepatic metabolism of drugs that are eliminated through this route or related to the effects of smoking on MVO2 and oxygenation.53 The one characteristic that is relevant is the duration of effect on the DP. β-Blockers with longer half-lives (e.g., nadolol) are more likely to affect the DP for a longer period of time and require fewer doses per day. The choice of β-blocker for angina rests on choosing the appropriate dose to achieve the goals outlined for HR and DP, and choosing an agent that is well tolerated by individual patients and cost. Selective use may incorporate ancillary properties, but these are secondary considerations in overall drug product selection. Patients most likely to respond well to β-blockade are those who have a high resting HR and those having a relatively fixed anginal threshold. In other words, their symptoms appear at the same level of exercise or workload on a consistent basis. Symptoms appearing with variable workloads suggest fluctuations in myocardial oxygen supply, perhaps due to coronary artery vasomotion, and these patients are more likely to respond to calcium channel antagonists.
Nitrate therapy should be the first step in managing acute attacks for patients with chronic stable angina if the attacks are infrequent (i.e., a few times per month) or for prophylaxis of symptoms when undertaking activities known to precipitate attacks. In general, if angina occurs no more often than once every few days, then SL nitroglycerin tablets or spray or buccal products may be sufficient to allow the patient to maintain an adequate lifestyle. For episodes of first-effort angina occurring in a predictable fashion, nitroglycerin may be used in a prophylactic manner with the patient taking 0.3 to 0.4 mg SL about 5 minutes prior to the anticipated time of activity. Nitroglycerin spray may be useful when inadequate saliva is produced to rapidly dissolve SL nitroglycerin or if a patient has difficulty opening the container. Most patients have a response that lasts about 30 minutes or so, but this is subject to interindividual variability. When angina occurs more frequently than once a day, a chronic prophylactic regimen using β-blockers as the first line of therapy should be considered (see Fig. 6-2 for the SIHD algorithm). Chronic prophylactic therapy with long-acting forms of nitroglycerin (oral or transdermal), isosorbide dinitrate (ISDN), 5-mononitrate, and pentaerythritol trinitrate may be effective; however, the development of tolerance is a major limiting step in their continued effectiveness. Since long-acting nitrates are not as effective as β-blockers and do not have beneficial effects, monotherapy with nitrates should not be first-line therapy unless β-blockers and calcium channel blockers are contraindicated or not tolerated. As described previously, providing a nitrate-free interval of 8 hours/day or longer appears to be the most promising approach to maintaining the efficacy of chronic nitrate therapy. Recent investigations into the mechanisms of nitrate tolerance in normal volunteers have shown that treatment with isosorbide mononitrate (ISMN) for 7 days resulted in not only tolerance but also endothelial dysfunction that is thought to be due to reactive oxygen species generated during bioactivation of high-potency nitrates.54,55 Chronic nitrate use may be associated with ACS presentation changes with a preponderance of unstable angina and NSTEMI over STEMI.56 Oral administration of nitrates is susceptible to a saturable first-pass effect; therefore, larger doses can produce a measurable hemodynamic effect and dose titration should be based on these changes in the DP. There are few well-controlled studies comparing oral or SL nitrate efficacy, and the choice among these products should be based on familiarity with the preparation, cost, and patient acceptance.
FIGURE 6-2 Algorithm for risk assessment in patients with SIHD.
Calcium channel antagonists have the potential advantage of improving coronary blood flow through coronary artery vasodilation as well as decreasing MVO2 and may be used instead of β-blockers for chronic prophylactic therapy; however, in chronic stable angina comparative trials of long-acting calcium channel blockers with β-blockers do not show significant differences in response.57,58 They are as effective as β-blockers and are most useful in patients who have a variable threshold for exertional angina. Calcium antagonists may provide better skeletal muscle oxygenation, resulting in decreased fatigue and better exercise tolerance. Additionally, if contraindications exist to β-blocker therapy, calcium antagonists can be safely used in many patients. The available calcium channel blockers appear to have similar efficacy in the management of chronic stable angina. Differences in their electrophysiology, peripheral and central hemodynamic effects, and adverse effect profiles are useful in selecting the appropriate agent. Patients with conduction abnormalities and moderate to severe LV dysfunction (ejection fraction <35% [<0.35]) should not be treated with verapamil or diltiazem, whereas amlodipine may be safely used in many of these patients. Diltiazem has significant effects on the AV node and can produce heart block in patients with preexisting conduction disease or when other drugs, such as digoxin or β-blockers, with effects on conduction are used concurrently. Nifedipine may cause excessive HR elevation, especially if the patient is not receiving a β-blocker, and this may offset the beneficial effect it has on MVO2. Gingival hyperplasia has also been reported with nifedipine, and some dental authorities say this may be seen in as many as 20% of patients on nifedipine. Case–control studies with calcium blockers suggest an increased risk for MI and cancer.59,60 The relationship to cancer appears to be weak to nonexistent, whereas the risk for MI is probably real and related to the type of drug used and relationship to recent MI. Immediate-release formulations of calcium blockers can activate the sympathetic nervous system and, in patients with recent MI or significant coronary disease, may induce ischemia. This effect has not been shown for longer-acting products. The hemodynamic effect of calcium antagonists is complementary to β-blockade, and, consequently, combination therapy is rational, but clinical trial data do not support the notion that combination therapy is always more effective.57,61
Nonpharmacologic Therapy 
Revascularization The decision to undertake PCI or CABG for revascularization is based on the extent of coronary disease (number of vessels and location/amount of stenosis) and ventricular function. The recommended mode of coronary revascularization is outlined in Table 6-8.62,63
The largest randomized trial of PCI versus CABG is the Bypass Angioplasty Revascularization (BARI) trial conducted in 1,829 patients with two- or three-vessel disease; 64% of these patients had an admitting diagnosis of UA and 19% were diabetic.64 The 10-year survival was 71% for PTCA and 73.5% for CABG (P = 0.18). At 10 years, the PTCA group had substantially higher subsequent revascularization rates than the CABG group (76.8% vs. 20.3%, P < 0.001), but angina rates for the two groups were similar. In the subgroup of patients with no treated diabetes, survival rates were nearly identical by randomization (PTCA 77% vs. CABG 77.3%, P = 0.59).65 Insulin-requiring diabetics and chronic kidney disease seem to be at the highest risk and CABG is the revascularization procedure of choice for this population.49 In a large observational study by Hannan et al., patients with proximal LAD lesions and multivessel disease had higher survival rates with CABG than with PTCA.64,66,67 High-risk patients who should be considered for CABG over PCI are those with LV systolic dysfunction, patients with diabetes, and those with two-vessel disease with severe proximal LAD involvement or severe three-vessel or left main disease62 (Table 6-8). Angina with Extremely Serious Operative Mortality (AWESOME) found that patients who were older than 70 years of age support the trial conclusions that either bypass or PCI effectively relieves medically refractory ischemia among high-risk unstable angina patients whose age was greater than 70 years.68
PCI has been used successfully in the management of unstable angina.69 PTCA involves the insertion of a guidewire and inflatable balloon into the affected coronary artery and enlarging the lumen of the artery by stretching the vessel wall. This frequently causes atheroma plaque fracture by stretching inelastic components and denudation of the endothelium resulting in loss of nitric oxide and other vasodilators and exposure of plaque contents to the vascular compartment. Consequently, immediate vascular recoil, platelet adhesion and aggregation, mural thrombus formation, smooth muscle proliferation, and synthesis of extracellular matrix may give rise to acute occlusion and early or late restenosis.70–72 The presence of coronary artery spasm and intraluminal thrombus, common occurrences in unstable angina, increases the hazard of these complications. The advent of combination therapy with ASA, UFH, or LMWH and IIb/IIIa receptor antagonists and coronary artery stents has dramatically reduced the occurrence of early reocclusion and late restenosis.73,74 Patients best suited for PTCA are those with recent onset of worsening of angina without a long history of symptoms. Angiographic characteristics associated with these clinical findings that allow the greatest probability of success for PTCA are severe, discrete, proximal lesions found in a large epicardial vessel subtending a moderate or large area of viable myocardium and have high risk. Patients with focal saphenous vein graft lesions who are poor candidates for reoperation have a Class IIa recommendation for PCI. Class IIb indications include patients with one or more lesions to be dilated in vessels subtending a less than moderate area of viable myocardium and patients with multivessel disease and proximal LAD lesions, diabetes, or abnormal LV function.63 Previously, candidates for PTCA must also be suited for CABG because a small percentage of procedures results in emergency CABG. Improvements in PCI and stent technology have led to some institutions performing procedures without surgical backup.75 Success of PCI may be defined as angiographic success (TIMI 3 flow and <20% residual stenosis), procedural success (lack of in-hospital clinical complications), and clinical success (anatomic and procedural success with relief of ischemic pain for at least 6 months). In trials of invasive versus conservative strategies (medical management) using PCI, death or MI is less frequent in some trials but not all.48,76,77 Numerous studies support the use of IIb/IIIa receptor antagonists in addition to ASA and UFH or LMWH and, as described previously, abciximab was superior to tirofiban in the only comparative study available.78,79 The initial success rate for PTCA in unstable angina is ∼80% to 90%, but these patients are at risk for more complications than are those with stable angina because of the underlying pathophysiology.
In the event of prolonged chest pain and ischemic ECG changes unrelieved by nitrate therapy or calcium channel antagonists, one may assume total occlusion of a coronary vessel and steps should be taken to restore blood flow with either PCI or CABG.
Coronary Artery Bypass Grafting Following the introduction of saphenous vein graft replacement for the severely occluded coronary arteries by Favorolo and Garrett in 1967, CABG became an accepted and commonly used approach for the management of IHD.80 The objectives in performing CABG are twofold: (a) reduce the number of symptomatic anginal attacks not controlled with medical management or PCI and improve the lifestyle of the patient and (b) reduce the mortality associated with CAD. Surgery is effective in providing pain relief in large numbers of patients, with about 70% to 95% being pain-free at 1 year and 46% to 55% being pain-free at 5 years. This compares favorably with medical management, with which only about 30% are free of symptoms at 5 years. Mortality at 10 years from the largest published studies is 26.4% with CABG and 30.5% with medical management (P = 0.03), but there are significant differences based on subgroup analysis (e.g., left main disease vs. one-vessel disease without a proximal LAD lesion).80 The second objective is met in certain patients and this has been addressed in three large, well-controlled trials of bypass surgery. These three studies, the Veterans Administration (VA), European Cooperative Surgery Study (ECSS), and the CASS, are not directly comparable because the inclusion and exclusion criteria for entry into each study were different and patients were followed for different periods of time. They have also been criticized for not being representative of the population that may be candidates for surgery, lacking women or late-middle-aged or elderly patients, and crossover of medically managed patients to the surgical group. A major change in medical practice that influences the interpretation of these older studies is the common procedure of stent placement at the time of angioplasty.11,81,83 There are about 20 different types of stents available and their use is associated with greater luminal diameter after angioplasty, fewer acute reocclusions, and less restenosis after stent placement.84 Consequently, the validity of generalizing the results from these studies to routine practice has been questioned, but these studies are useful for providing a basis for decisions concerning surgery. Current Class I recommendations for CABG in asymptomatic or mild angina patient include significant (>50%) left main coronary artery stenosis, left main equivalent (≥70% stenosis of the proximal LAD and proximal left circumflex artery), and three-vessel disease, especially in patients with LV ejection fraction <50% (<0.50).80 Class IIa recommendations for CABG are proximal LAD stenosis with one- or two-vessel disease and Class IIb one- or two-vessel disease not involving the proximal LAD. In stable angina, Class I recommendations are the same as for mild angina with the following additions: one- or two-vessel disease without significant proximal LAD stenosis, but with a large area of viable myocardium and high-risk criteria in noninvasive testing; disabling angina despite maximal medical therapy, when surgery can be performed with acceptable risk. Class IIb recommendations in stable angina include proximal LAD stenosis with one-vessel disease and one- or two-vessel disease without significant proximal LAD stenosis but with a moderate area of viable myocardium and ischemia on noninvasive testing. The indications for CABG in UA/NSTEMI are described previously. In ST-segment MI CABG is indicated for ongoing ischemia/infarction not responsive to maximal medical therapy (Class IIb).
In patients with poor LV function CABG is indicated for the same indications as in mild angina for Class I. Class IIa recommendations include poor LV function with significant viable, noncontracting, revascularizable myocardium without any of the aforementioned anatomic patterns (e.g., left main disease). CABG is useful in patients with life-threatening ventricular arrhythmia in the presence of left main disease and three-vessel disease (Class I) and in bypassable one- or two-vessel disease causing life-threatening ventricular arrhythmias and proximal LAD disease with one- or two-vessel disease (Class IIa).
CABG may also be used for patients who have failed PTCA if there is ongoing ischemia or threatened occlusion with significant myocardium at risk and in patients with hemodynamic compromise (Class I). Class IIa recommendations for failed PTCA include a foreign body in a crucial anatomic position and hemodynamic compromise in patient with impairment of the coagulation system and without a previous sternotomy. CABG may be repeated in patients with a previous CABG if disabling angina exists despite maximal noninvasive therapy (Class I) and if a large area of myocardium is threatened and is subtended by bypassable distal vessels (Class IIa).
The need for nitrates and β-blockers is clearly reduced by surgery, with only 30% of CABG patients requiring chronic medication, whereas 70% of their medical counterparts received anginal drugs. Employment status after surgery has been shown in CASS to be more dependent on the pretreatment status than an effect induced by the treatment arm, and about 70% of patients are employed before and after surgery. Recent follow-up analyses of these studies suggest that patients who have diabetes or peripheral vascular disease, who are African Americans, or who continued to smoke are at high risk for CAD events, and diabetics, in particular, are more likely to have a better outcome with CABG than with PTCA.64,76 The overall benefit noted after CABG is similar in men and women, and elderly patients appear to have outcomes similar to younger patients.
Operative mortality is reported to range from 1% to 3% and is related to the number of vessels involved and preoperative ventricular function. Patients in CASS with one-, two-, or three-vessel disease had operative mortalities of 1.4%, 2.1%, and 2.8%, respectively. The relationship to LV ejection fraction follows a similar trend with ejection fractions of greater than 50% (0.50), 20% to 40% (0.20 to 0.40), and less than 20% (0.20) having operative mortality rates of 1.9%, 4.4%, and 6.7%, respectively. Perioperative infarction averages 5% depending on the sensitivity of the method for assessment, and the occurrence of an infarct reduces long-term survival. Neurologic dysfunction is relatively common postoperatively in CABG patients (∼6%), but many of the deficits are clinically insignificant and resolve with time. Fatal brain damage occurs in 0.3% to 0.7%, stroke in about 5%, and ophthalmologic defects occur in 25%, but only 3% have clinically apparent field defects. Peripheral nerve lesions (12%) and brachial plexopathy (7%) are also reported to occur. Other complications include constrictive pericarditis (0.2%), cellulitis at the site of vein graft, and mediastinal infections (1% to 4%).
Graft patency influences the success for symptom control, and survival and the mechanism for early graft occlusion is probably different from that associated with late closure. Early occlusion is related to platelet adhesion and aggregation, whereas late occlusion may be related to endothelial proliferation and progression of atherosclerosis. Patency of grafts early on after the CABG is reported to range from 88% to 97% in at least one graft and 58% to 81% in all grafts at 1 year. Long-term patency based on the CASS Montreal Heart Institute experience suggests that 60% to 67% of all grafts remain patent at 5 to 11 years. Antiplatelet therapy has been demonstrated to improve early and late patency rates and should probably be used in all patients who do not have any contraindications.78,79,82 Aspirin with or without other antiplatelet agents reduces the late development of vein graft occlusions. At the current time, prasugrel, a new antiplatelet drug, is only indicated for patients with ACS who are going to undergo PCI.83Late graft closure is related to elevated lipid levels and the progression of atherosclerosis in the grafted vessels as well as the native circulation. Elevation of very-low-density lipoprotein (VLDL), LDL, and LDL apolipoprotein B is correlated to disease progression and graft closure. Aggressive lipid lowering can stabilize the progression of CAD and may induce regression in selected coronary artery segments within a patient following CABG. Cessation of smoking is an important preoperative and postoperative objective as well as in the management of other coronary risk factors (e.g., hypertension) and institution of a supervised, daily exercise program is recommended. Internal mammary artery grafts should be used for revascularizing the left anterior descending artery system when possible owing to better graft survival and clinical outcomes.
Valvular heart disease can coexist with CHD, although this is relatively uncommon with rheumatic valve disease, usually the mitral valve, and more common with aortic stenosis and regurgitation. Angina may occur in 35% to 65% of patients with aortic stenosis or regurgitation, and, if severe, may be the cause of angina in the absence of CAD. Patients being evaluated for possible CABG should also be evaluated for valvular disease to determine if valve replacement needs to be performed along with bypass grafting.
Percutaneous Transluminal Coronary Angioplasty Since the introduction into clinical cardiology of PTCA by Gruentzig in 1977, this procedure has gained rapid acceptance as a safe and effective means of managing CAD.69 It is estimated that more than 750,000 PCI procedures are done each year in this country and 525,000 of them are PTCA. The proposed mechanisms of reduced stenosis with PTCA include (a) compression and redistribution of the atherosclerotic plaque; (b) embolization of plaque contents; (c) aneurysm formation; and (d) disruption of the plaque and arterial wall with distortion and tearing of the intima and media, which leads to denudation of the endothelium, platelet adhesion and aggregation, thrombus formation, and smooth muscle proliferation. Of these mechanisms, the last one is felt to be the most important, but the others may contribute to opening of the lesions in some situations.
The indications for PTCA have been provided by the ACC/AHA and now span single-vessel or multivessel disease as well as asymptomatic and symptomatic patients (see Table 6-9).69 In addition to providing recommendations for which type of patients are appropriate for PTCA, the guidelines also provide recommendations for the volume of procedures, the use of intravascular ultrasound, and surgery backup when PTCA is being considered. 
PTCA generally is not useful if only a small area of viable myocardium is at risk, when ischemia cannot be demonstrated, when borderline (<50%) stenosis or lesions are difficult to dilate, or when patients are at high risk for morbidity or mortality or both (e.g., left main or equivalent disease or three-vessel disease). PTCA alone or when used in conjunction or sequentially with thrombolysis for acute MI is discussed in Chapter 7. Stent placement accompanies balloon angioplasty in about 80% of cases in the United States. The current recommendations for PCI are provided in Table 6-10 based on class of angina.
TABLE 6-10 Pharmacologic Management of Percutaneous Coronary Intervention
Assessment of outcome with PCI can be based on several angiographic, procedural, and clinical outcomes as discussed previously. The success of PCI is dependent on the experience of the operator (high volume, better outcome), on complicating factors for the patient (including the number of vessels to be dilated), and on technical advances in the equipment used (e.g., steerable and low-profile catheters). The acute success rate for opening of uncomplicated stenotic lesions ranges from 96% to 99% with the combined balloon/device/pharmacologic approach in experienced hands, and angina is decreased or eliminated in about 80% of cases. The success rate for totally occluded lesions is somewhat less (∼65%). Mortality at 1 year is 1% and 2.5% for single-vessel disease and multiple-vessel involvement, respectively, reflecting the good prognosis associated with this degree of CAD. At 10 years, survival is 95% and 81% for single and multiple disease, respectively.69 Most patients remain event-free (no death, MI, or CABG) for an extended period. Symptomatic status, as measured by the NYHA classification, is improved in many patients. Restenosis is noted in 32% to 40% after balloon angioplasty at 6 months, and half of these patients will have symptoms associated with restenosis.69 A few late restenotic events occur, but most restenosis occurs within the first 6 months. Anatomic factors that predict restenosis include lesions >20 mm in length, excessive tortuosity of the proximal segment, extremely angulated segments (>90°), total occlusions >3 months old and/or bridging collaterals, and inability to protect major side branches and degenerated vein grafts with friable lesions. Clinical factors that predict worse outcome include diabetes, advanced age, female gender, unstable angina, heart failure, and multivessel disease. A four-variable scoring system that predicts cardiovascular collapse for failed PTCA includes percentage of myocardium at risk (e.g., >50% viable myocardium at risk and LV ejection fraction <25% [<0.25]), pre-angioplasty percent diameter stenosis, multivessel CAD, and diffuse disease in the dilated segment or a high myocardial jeopardy score.69 Strut thickness of the stent influences restenosis as well and thicker struts are associated with angiographic and clinical restenosis.84,85 With the development of DES, early reocclusion has been reduced dramatically but late in-stent thrombosis has been a problem. As stent technology has evolved, due to better polymers, better strut design, and better antiproliferative agents (e.g., everolimus), stent thrombosis has dropped to as low as 0.3%, MI to 1.9%, and target lesion revascularization to 2.5%.84
The overall complication rate ranges from 2% to 21% depending on the lesion type. Coronary occlusion, dissection, or spasm occurs in 4% to 8% of patients, whereas ST-segment elevation MI occurs in 1.6% to 4.8%.69Prolonged angina and ventricular tachycardia or fibrillation occurs in 6.9% and 2.3%, respectively. In-hospital mortality ranges from 0.7% to 2.5% overall and high-risk events for mortality included ventricular arrhythmias and MI. The frequency of urgent CABG because of complications ranges from 0.4% to 5.8%.69
Current AHA/ACC recommendations for antithrombotic therapy in PCI are outlined in Table 6-10.69,82 Antiplatelet therapy with ASA 80 to 325 mg/day given at least 2 hours prior to angioplasty is currently recommended. If patients are sensitive to ASA, clopidogrel or prasugrel is an acceptable alternative. In elective settings, clopidogrel should be started at least 72 hours in advance of the procedure to allow for maximal antiplatelet effects. Alternatively, a loading dose of clopidogrel (300 to 600 mg) or prasugrel 60 mg may be given to achieve a more rapid antiplatelet effect.86–88 The combination of ASA plus clopidogrel or prasugrel is currently recommended for patients undergoing angioplasty and stenting and this combination is safer and superior to antiplatelet therapy plus anticoagulation with warfarin-like drugs.82 Follow-up for up to 4 years from the Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial shows that the benefit of combined antiplatelet therapy evident after 30 days is maintained after 4 years.89 Aspirin is an incomplete inhibitor of platelet aggregation and combination therapy of ASA plus a GP IIb/IIIa receptor antagonist for PCI has shown a relative risk reduction of 37.5% for death and nonfatal MI at 30 days favoring GP IIb/IIIa receptor antagonists over placebo (absolute rates of 5.5% vs. 8.9% based on PCI trials of EPIC, IMPACT-II, EPILOG, CAPTURE, RESTORE, and EPISTENT).69As discussed in Revascularization above, high-risk patients and those having a stent placed are most likely to benefit from GP IIb/IIIa receptor antagonist use. Patients presenting with elevated cardiac biomarkers are also more likely to receive benefit from GP IIb/IIIa receptor antagonists than patients with normal levels of biomarkers.90 In the only comparative trial (TARGET), abciximab was superior to tirofiban.91
During PTCA patients are usually heparinized to prevent immediate thrombus formation at the site of arterial injury and on coronary guidewires and catheters; anticoagulation is continued for up to 24 hours. The intensity of anticoagulation is monitored using the activated clotting time (ACT) and the targeted range for ACT is 250 to 300 seconds (HemoTec device) in the absence of GP IIb/IIIa receptor antagonist use.69 When GP IIb/IIIa receptor antagonists are not used, UFH is given as an IV bolus of 70 to 100 international units/kg to achieve a target ACT of 200 seconds. The loading dose is lowered to 50 to 70 international units/kg when GP IIb/IIIa receptor antagonists are given. Target ACT for eptifibatide and tirofiban is <300 seconds during angioplasty; postprocedural UFH infusions are not recommended during GP IIb/IIIa receptor antagonist therapy. Mechanisms that result in restenosis include acute lumen loss owing to recoil, mural thrombosis formation, and smooth muscle cell proliferation with synthesis of extracellular matrix.71 Approaches to prevent restenosis may be aimed at altering the underlying mechanisms. Recoil and loss of luminal diameter may be reduced by the use of stent placement; however, this beneficial effect is offset by an increased number of vascular complications. Cracking of the plaque leads to severe damage to the arterial wall, exposure of collagen, and endothelial dysfunction. These factors promote mural thrombi, and the propensity for thrombus formation is related, in part, to the composition of the plaque as well as the depth of injury. Combination therapy with ASA, heparin, and IIb/IIIa receptor antagonists is recommended to minimize acute occlusion and numerous clinical trials document the efficacy of this combined approach.69,79,92 Bivalirudin is a specific and reversible direct thrombin inhibitor that is indicated for use as an anticoagulant in patients with unstable angina undergoing PTCA. Based on the REPLACE-2 and ACUITY studies, bivalirudin is comparable to heparin in preventing thrombosis and may be associated with less bleeding.93,94 A more complete discussion of antithrombotic therapy can be found in Chapter 7.
When medical therapy, PTCA, and CABG have been compared, low-risk patients with single-vessel CAD and normal LV function had greater alleviation of symptoms with PTCA than with medical treatment; mortality rates and rates of MI were unchanged. In high-risk patients (risk was defined by severity of ischemia, number of diseased vessels, and presence of LV dysfunction), improvement of survival was greater with CABG than with medical therapy. In moderate-risk patients with multivessel CAD (most had two-vessel disease and normal LV function), PTCA and CABG produced equivalent mortality rates and rates of MI.
The development of DES has changed the natural course of stent thrombosis when compared with bare-metal stents (BMS) that have existed for a longer period of time. Currently there are three types of DES available (sirolimus [Cypher™], paclitaxel [Taxus™], and everolimus [Zortress™]). Soon after the introduction of BMS, it became apparent that early stent thrombosis (≤30 days) was an uncommon but serious complication of therapy.71,84,85,95 Stent thrombosis is an infrequent but severe complication of both BMS and DES, but there is no apparent difference in overall stent thrombosis frequency at 4 years of follow-up, although the time course appears to be different. There is a relative numeric excess of stent thrombosis late after DES implantation; however, no differences in death or death and infarction have been observed. Target lesion revascularization is needed less often with DES compared with BMS. Implantation of DES stents outside of approved indications and lack of proper positioning of the stent are related to the occurrence of late stent thrombosis. Longer-term follow-up with larger subsets of patients (i.e., lesion number, type, and location and patient comorbidities) is needed to fully understand this issue and the evolution of newer platforms for drug delivery will likely alter the natural history of DES stent thrombosis.96 A very important consideration is the use of combination antiplatelet therapy (aspirin + clopidogrel or prasugrel) for at least a year following implantation.78,79,82 Patients who are unable to activate clopidogrel due to a reduced-function allele for CYP2C19 may be treated with 150 mg/day rather than 75 mg/day or switched to prasugrel.97 Drugs that inhibit CYP2C19 should probably be avoided, although there is conflicting evidence in the literature.98–100
Pharmacologic Therapy
Historically, about 30% of anginal syndrome symptoms have responded regardless of which therapy was instituted. These observations stem from two problems inherent in clinical trials undertaken to assess the efficacy of any therapy for angina: (a) adequate trial design incorporating appropriate controls and washout periods, and (b) assessment of treatment effects using objective measures of efficacy including improvement in exercise performance, resting and ambulatory ECG improvement in ischemic changes, or other objective tests to address other aspects of myocardial function or metabolism. The use of pain episode frequency and nitroglycerin consumption is subjective, and their use as sole measures of efficacy should be avoided. Objective assessment using ETT has shown that placebo does not provide improvement in patients with exertional angina, substantiating this as a valid means to assess efficacy.
β-Adrenergic Blocking Agents Decreased HR, decreased contractility, and a slight to moderate decrease in blood pressure with β-adrenergic receptor antagonism reduce MVO2.101,102 The predominant receptor type in the heart is the β1-receptor, and competitive blockade minimizes the influence of endogenous catecholamines on the chronotropic and inotropic state of the myocardium. These beneficial effects may be countered to some degree with increased ventricular volume and ejection time seen with β-blockade; however, the overall effect of β-blockers in patients with effort-induced angina is a reduction in oxygen demand (Table 6-11). The β-blockers do not improve oxygen supply, and in certain instances, unopposed α-adrenergic stimulation following the use of β-blockers may lead to coronary vasoconstriction. For patients with chronic exertional stable angina, β-blockers improve symptoms about 80% of the time and objective measures of efficacy demonstrate improved exercise duration and delay in the time at which ST-segment changes and initial or limiting symptoms occur. β-Blockers do not alter the rate–pressure product (DP) for maximal exercise, therefore substantiating reduced demand rather than improved supply as the major consequence of their actions. Reflex tachycardia from nitrate therapy can be blunted with β-blocker therapy, making this a common and useful combination. Although β-blockade may decrease exercise capacity in healthy individuals or in patients with hypertension, it may allow angina patients previously limited by symptoms to perform more exercise and ultimately improve overall cardiovascular performance through a training effect. Ideal candidates for β-blockers include patients in whom physical activity figures prominently in their anginal attacks, those who have coexistent hypertension, those with a history of supraventricular arrhythmias or post-MI angina, and those who have a component of anxiety associated with angina.3 β-Blockers may also be safely used in angina and heart failure as described in Chapter 4. Pertinent pharmacokinetics for the β-blockers includes half-life and route elimination, which are reviewed in Chapter 3. Drugs with longer half-lives need to be dosed less frequently than ones with shorter half-lives; however, disparity exists between half-life and duration of action for several β-blockers (e.g., metoprolol) and this may reflect attenuation of the central nervous system–mediated effects on the sympathetic system as well as the direct effects of this category on HR and contractility. Renal and hepatic dysfunction can affect the disposition of β-blockers, but these agents are dosed to effect, either hemodynamic or symptomatic, and route of elimination is not a major consideration in drug selection.
TABLE 6-11 Effect of Drug Therapy on Myocardial Oxygen Demand a
Guidelines for the use of β-blockers in treating angina include the objective of lowering resting HR to 50 to 60 beats/min and limiting maximal exercise HR to about 100 beats/min or less. It has also been suggested that exercise HR should be no more than about 20 beats/min or a 10% increment over resting HR with modest exercise. Because β-blockade is competitive and circulating catecholamine concentrations vary depending on the intensity of exercise and other factors, and cholinergic tone may be important in controlling HR in some patients, these guidelines are general in nature. These effects are generally dose and plasma concentration related, and for propranolol, plasma concentrations of 30 ng/mL (30 mcg/L; 115 nmol/L) are needed for a 25% reduction of anginal frequency. Initial doses of β-blockers should be at the lower end of the usual dosing range and titrated to response as indicated above.
There is little evidence to suggest superiority of any β-blocker; however, the duration of β-blockade is dependent partially on the half-life of the agent used, and those with longer half-lives may be dosed less frequently. Of note, propranolol may be dosed twice a day in most patients with angina and the efficacy is similar to that seen with more frequent dosing. The ancillary property of membrane-stabilizing activity is irrelevant in the treatment of angina, and intrinsic sympathomimetic activity appears to be detrimental in rest or severe angina because the reduction in HR would be minimized, therefore limiting a reduction in MVO2. Cardioselective β-blockers may be used in some patients to minimize adverse effects such as bronchospasm in asthma, intermittent claudication, and sexual dysfunction. A common misunderstanding is that β-blockers are not well tolerated in peripheral arterial disease, but, in fact, their use is associated with a reduction in death and improved quality of life.103 It should be remembered that cardioselectivity is a relative property and the use of larger doses (e.g., metoprolol 200 mg/day) is associated with the loss of selectivity and with adverse effects. Post–acute-MI patients with angina are particularly good candidates for β-blockade both because anginal symptoms may be treated as well as reducing the risk of post-MI reinfarction and because mortality has been demonstrated with timolol, propranolol, and metoprolol (see Chap. 4). Combined β-blockade (nonselective) and α-blockade with labetalol may be useful in some patients with marginal LV reserve, and fewer deleterious effects on coronary blood flow are seen when compared with other β-blockers.
Extension of pharmacologic effect is the underlying reason for many of the adverse effects seen with β-blockade. Hypotension, decompensated heart failure, bradycardia and heart block, bronchospasm, and altered glucose metabolism are directly related to β-adrenoreceptor antagonism. Patients with preexisting LV systolic and decompensated heart failure and the use of other negative inotropic agents are most prone to developing overt heart failure, and in the absence of these, heart failure is uncommon (less than 5%). Other drugs that depress conduction are additive to β-blockade, and intrinsic conduction system disease predisposes the patient to conduction abnormalities. Altered glucose metabolism is most likely to be seen in insulin-dependent diabetics, and β-blockade obscures the symptoms of hypoglycemia except for sweating. β-Blockers may also aggravate the lipid abnormalities seen in patients with diabetes; however, these changes are dose related, are more common with normal baseline lipids than dyslipidemia, and may be of short-term significance only. One of the more common reasons for discontinuation of β-blocker therapy is related to central nervous system adverse effects of fatigue, malaise, and depression. Cognition changes seen with β-blockers are usually minimal and comparable to other categories of drugs based on studies done in hypertension.104 Abrupt withdrawal of β-blocker therapy in patients with angina has been associated with increased severity and number of pain episodes and MI. The mechanism of this effect is unknown but may be related to increased receptor sensitivity or disease progression during therapy, which becomes apparent following discontinuation of β-blockade. In any event, tapering of β-blocker therapy over about 2 days should minimize the risk of withdrawal reactions for those patients in whom therapy is being discontinued.
β-Adrenoreceptor blockade is effective in chronic exertional angina as monotherapy and in combination with nitrates and/or calcium channel antagonists. β-Blockers should be the first-line drug in chronic angina requiring daily maintenance therapy because β-blockers are more effective in reducing episodes of silent ischemia, reducing early morning peak of ischemic activity, and improving mortality after Q-wave MI than nitrates or calcium channel blockers (Fig. 6-3).1 If β-blockers are ineffective or not tolerated, then monotherapy with a calcium channel blocker or combination therapy if monotherapy is ineffective for either alone may be instituted. Patients with severe angina, rest angina, or variant angina (i.e., a component of coronary artery spasm) may be better treated with calcium channel blockers or long-acting nitrates.
FIGURE 6-3 Algorithm for guideline-directed medical therapy for patients with SIHD. Colors correspond to the class of recommendations in the ACCF/AHA Table 6-13. The algorithms do not represent a comprehensive list of recommendations (see text for all recommendations). aThe use of bile acid sequestrant is relatively contraindicated when triglycerides are 200 mg/dL and is contraindicated when triglycerides are 500 mg/dL. bDietary supplement niacin must not be used as a substitute for prescription niacin. (ACCF, American College of Cardiology Foundation; ACEI, angiotensin-converting enzyme inhibitor; AHA, American Heart Association; ARB, angiotensin receptor blocker; ASA, aspirin; ATP III, Adult Treatment Panel 3; BP, blood pressure; CCB, calcium channel blocker; CKD, chronic kidney disease; HDL-C, high-density lipoprotein cholesterol; JNC VII, Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; MI, myocardial infarction; NHLBI, National Heart, Lung, and Blood Institute; NTG, nitroglycerin.)
Nitrates Nitroglycerin has a well-documented role in the alleviation of acute anginal attacks when used as rapidly absorbed and readily available preparations by the oral and IV routes (see Table 6-12 and Fig. 6-3).105 SL, buccal, or spray products are the products of choice for this indication. Prevention of symptoms may be accomplished by the prophylactic use of oral or transdermal products; however, recent concern has been expressed over the long-term efficacy of many of these preparations and the development of tolerance.106–108
TABLE 6-12 Nitrate Products
Nitrates have multiple potential mechanisms of action, and for a given patient it is not always clear which of these is most important. In general, the major action appears to be indirectly mediated through a reduction of MVO2secondary to venodilation and arterial–arteriolar dilation, leading to a reduction in wall stress from reduced ventricular volume and pressure (see Table 6-11). Systemic venodilation also promotes increased flow to deep myocardial muscle by reducing the gradient between intraventricular pressure and coronary arteriolar (R2) pressure. Direct actions on the coronary circulation include dilation of large and small intramural coronary arteries, collateral dilation, coronary artery stenosis dilation, abolition of normal tone in narrowed vessels, and relief of spasm; these actions occur even if the endothelium is denuded or dysfunctional. It is likely that depending on the underlying pathophysiology, different mechanisms become operative. For example, in the presence of a 60% to 70% stenosis, venodilation with MVO2 reduction is most important; however, with higher-grade lesions, direct effects on the coronary circulation and vessel tone are the predominant effects. Nitroglycerin and pentaerythritol tetranitrate (PETN) in low doses are bioactivated by mitochondrial aldehyde dehydrogenase (ALDH-2) to nitrite or denitrated metabolites that require further activation by cytochrome oxidase or acidic disproportionation in the inner membrane space finally yielding nitric oxide. Nitric oxide activates soluble guanylate cyclase to increase intracellular concentrations of cyclic GMP resulting in vasorelaxation.108 In contrast, ISDN and ISMN are bioactivated via P450 enzymes to nitric oxide. At higher concentrations, nitroglycerin and PETN may also be bioactivated to nitric oxide via P450 enzymes. Increased cyclic GMP induces a sequence of protein phosphorylation associated with reduced intracellular calcium release from the sarcoplasmic reticulum or reduced permeability to extracellular calcium and, consequently, smooth muscle relaxation. Oxidative stress within the mitochondria causes inactivation of ALDH-2 leading to impaired bioactivation of nitroglycerin during prolonged treatment.109 Thomas et al. performed a study in normal volunteers to evaluate the effect of ISMN 120 mg/day given for 7 days on endothelial function. They found that ISMN impaired endothelial function suggesting a role for oxygen free radicals and nitrate-induced abnormalities in endothelial-dependent vasomotor responses that were reversed with a vitamin C infusion of 24 mg/min given for 15 minutes.106 Furthermore, ISDN has been shown to impair flow-mediated dilation and carotid intimal–medial thickness after 3 months of treatment.110 These deleterious changes in endothelial function, intima–media thickness, and the occurrence of tolerance suggest that the role of nitrates in IHD may be changing.
Pharmacokinetic characteristics common to the organic nitrates used for angina include a large first-pass effect of hepatic metabolism, short to very short half-lives (except for ISMN), large volumes of distribution, high clearance rates, and large interindividual variations in plasma or blood concentrations. Pharmacodynamic–pharmacokinetic relationships for the entire class remain poorly defined, presumably due to methodologic difficulty in characterizing the parent drug and metabolite concentrations at or within vascular smooth muscle and secondary to counterregulatory or adaptive mechanisms from the drug’s effects as well as the occurrence of tolerance. Nitroglycerin is extracted by a variety of tissues and metabolized locally; differential extraction and metabolite generation occur depending on the tissue site. There are also numerous technical problems limiting the generation of reliable pharmacokinetic parameter estimates including the following: assay sensitivity, arterial–venous extraction gradients and therefore extrahepatic metabolism, in vitro degradation, drug adsorption to polyvinyl chloride tubing and syringes, potentially saturable metabolism, accumulation of metabolites (some of which are active) with multiple doses, postural and exercise-induced changes in pharmacokinetics, a variety of variables associated with transdermal delivery including the delivery system (matrix, membrane-limited, ointment), vehicle used, the surface area and thickness of application, the site application, and other skin variables (temperature, moisture content).
Nitroglycerin concentrations are affected by the route of administration, with the highest concentrations usually obtained with IV administration, the lowest seen with lower oral doses. Peak concentrations with SL nitroglycerin appear within 2 to 4 minutes, with the oral route producing peaks at about 15 to 30 minutes and by the transdermal route at 1 to 2 hours. The half-life of nitroglycerin is 1 to 5 minutes regardless of route, hence the potential advantage of sustained-release and transdermal products. Transdermal nitroglycerin does produce sufficient concentrations for acute hemodynamic effects to occur and these concentrations are maintained for long intervals; however, the hemodynamic and antianginal effects are minimal after 1 week or less with chronic, continuous (24 hours/day) therapy.
ISDN is metabolized to isosorbide 2-mononitrate and 5-mononitrate (ISMN). ISMN is well absorbed and has a half-life of about 5 hours and may be given once or twice daily depending on the product chosen. Multiple, larger doses of ISDN lead to disproportionate increases in the area under the plasma time profile, suggesting that metabolic pathways are being saturated or that metabolite accumulation may influence the disposition of ISDN. Little pharmacokinetic information is available for other nitrate compounds.
Nitrate therapy may be used to terminate an acute anginal attack, to prevent effort or stress-induced attacks, or for long-term prophylaxis, usually in combination with β-blockers or calcium channel blockers. SL nitroglycerin 0.3 to 0.4 mg will relieve pain in about 75% of patients within 3 minutes, with another 15% becoming pain-free in 5 to 15 minutes. Pain persisting beyond about 20 to 30 minutes following the use of two or three nitroglycerin tablets is suggestive of ACS and the patient should be instructed to seek emergency aid. Patients should be instructed to keep nitroglycerin in the original, tightly closed glass container and to avoid mixing with other medication, because mixing may increase nitroglycerin adsorption and vaporization. Additional counseling should include the facts that nitroglycerin is not an analgesic but rather it partially corrects the underlying problem and that repeated use is not harmful or addicting. Patients should also be aware that enhanced venous pooling in the sitting or standing positions may improve the effect as well as the symptoms of postural hypotension, and that inadequate saliva may slow or prevent tablet disintegration and dissolution. An acceptable albeit expensive alternative is lingual spray, which may be more convenient and has a shelf life of 3 years compared with 6 months or so for some forms of nitroglycerin tablets.
Chewable, oral, and transdermal products are acceptable for the long-term prophylaxis of angina; however, considerable controversy surrounds their use and it appears that the development of tolerance or adaptive mechanisms limits the efficacy of all chronic nitrate therapies regardless of route. Dosing of the longer-acting preparations should be adjusted to provide a hemodynamic response, and as an example, this may require doses of oral ISDN ranging from 10 to 60 mg as often as every 3 to 4 hours owing to tolerance or first-pass metabolism, and similar large doses are required for other products. Nitroglycerin ointment has a duration of up to 6 hours, but it is difficult to apply in a cosmetically acceptable fashion over a consistent surface area, and response varies depending on the epidermal thickness, vascularity, and amount of hair. Percutaneous adsorption of nitroglycerin ointment may occur unintentionally if someone other than the patient applies the ointment, and limiting exposure through the use of gloves or some other means is advisable. Peripheral edema may also impair the response to nitroglycerin because venodilation cannot increase capacitance to a maximum and pooling may be reduced. Transdermal patch delivery systems were approved on the basis of sustained and equivalent plasma concentrations to other forms of therapy. Trials required by the Food and Drug Administration using transdermal patches as a continuous 24-hour delivery system revealed a lack of efficacy for improved exercise tolerance. Subsequently, large, randomized, double-blind, placebo-controlled trials of intermittent (10 to 12 hours on; 12 to 14 hours off) transdermal nitroglycerin therapy in chronic stable angina demonstrated modest but significant improvement in exercise time after 4 weeks for the highest doses at 8 to 12 hours after patch placement.111 Subjective assessment methods for nitrate effects include reduction in the number of painful episodes and the amount of nitroglycerin consumed. Objective assessment includes the resolution of ECG changes at rest, during exercise, or with ambulatory ECG monitoring. Because nitrates work primarily through a reduction in MVO2, the DP can be used to optimize the dose of SL and oral nitrate products. It is important to realize that reflex tachycardia may offset the beneficial reduction in SBP and calculation of the observed changes is necessary. The DP is best assessed in the sitting position and at intervals of 5 to 10 and 30 to 60 minutes following SL and oral therapy, respectively. Owing to the placebo effect, unpredictable and variable course of angina, numerous pharmacologic effects of nitroglycerin, diurnal variation in pain patterns, stringent investigative protocols, and interindividual sensitivity to nitroglycerin, assessment with transdermal and sustained-release products is difficult. ETT provides valuable information concerning efficacy and mechanism of action for nitrates, but its use is usually reserved for clinical investigation rather than for routine patient care. Most ETT studies have shown nitrates to delay the onset of ischemia (ST-segment changes or initial chest discomfort) at submaximal exercise, but the threshold for maximal exercise is unaltered, suggesting a reduction in oxygen demand rather than an improved oxygen supply. More sophisticated studies of myocardial function such as wall motion abnormalities and myocardial metabolism could be used to document efficacy; however, these studies are generally only for investigative purposes.
Adverse effects of nitrates are related most commonly to an extension of their pharmacologic effects and include postural hypotension with associated central nervous system symptoms, headaches and flushing secondary to vasodilation, and occasional nausea from smooth muscle relaxation. If hypotension is excessive, coronary and cerebral filling may be compromised leading to MI and stroke. While reflex tachycardia is most common, bradycardia with nitroglycerin has been reported. Other noncardiovascular adverse effects include rash with all products but particularly with transdermal nitroglycerin, the production of methemoglobinemia with high doses given for extended periods, and measurable concentrations of ethanol (intoxication has been reported) and propylene glycol (found in the diluent) with IV nitroglycerin.
Tolerance with nitrate therapy was first described in 1867 with the initial experience using amyl nitrate for angina and later widely recognized in munitions workers who underwent withdrawal reactions during periods of absence from exposure. Tolerance to nitrates is associated with a reduction in tissue cyclic GMP, which results from decreased production (guanylate cyclase) and increased breakdown via cyclic GMP-phosphodiesterase and increased superoxide levels. One proposed mechanism for the lack of cyclic GMP is lack of conversion of organic nitrates to nitric oxide as described previously.105
Most of the published information is from controlled trials examining nitrate tolerance that have been done with either ISDN or transdermal nitroglycerin, and these studies demonstrate the development of tolerance within as little as 24 hours of therapy. While the onset of tolerance is rapid, the offset may be just as rapid, and one alternative dosing strategy to circumvent or minimize tolerance is to provide a daily nitrate-free interval of 6 to 8 hours. Studies with a variety of nitrate preparations and dosing schedules demonstrate that this approach is useful and the nitrate-free interval should be a minimum of 8 hours and perhaps 12 hours for even better effects.105 Another concern for intermittent transdermal nitrate therapy is the occurrence of rebound ischemia during the nitrate-free interval. Freedman et al. found more silent ischemia during the patch-free interval during a randomized, double-blind, placebo-controlled trial than during the placebo patch phase, although others have not noted this effect.112 ISDN, for example, should not be used more often than three times per day if tolerance is to be avoided. Interestingly, hemodynamic tolerance does not always coincide with antianginal efficacy, but this is not well studied.
Nitrates may be combined with other drugs for anginal therapy including β-adrenergic blocking agents and calcium channel antagonists. These combinations are usually instituted for chronic prophylactic therapy based on complementary or offsetting mechanisms of action (Table 6-12). Combination therapy is generally used in patients with more frequent or symptoms not responding to β-blockers alone (nitrates plus β-blockers or calcium blockers), in patients intolerant of β-blockers or calcium channel blockers, and in patients having an element of vasospasm leading to decreased supply (nitrates plus calcium blockers).113 Modulation of calcium entry into vascular smooth muscle and myocardium as well as a variety of other tissues is the principal action of the calcium antagonists. The cellular mechanism of these drugs is not completely understood and it differs among the available classes of the phenylalkylamines (verapamil-like), dihydropyridines (nifedipine-like), benzothiazepines (diltiazem-like), bepridil, and a recent class referred to as T-channel blockers. Receptor-operated channels stimulated by norepinephrine and other neurotransmitters, and potential-dependent channels activated by membrane depolarization, control the entry of calcium, and consequently the cytosolic concentration of calcium responsible for activation of actin–myosin complex leading to contraction of vascular smooth muscle and myocardium. In the myocardium, calcium entry triggers the release of intracellular stores of calcium to increase cytosolic calcium, whereas in smooth muscle calcium derived from the extracellular fluid may do this directly. Binding proteins within the cell, calmodulin and troponin, after binding with calcium, participate in phosphorylation reactions leading to contraction. Decreased calcium availability, through the actions of calcium antagonists, inhibits these reactions. Direct actions of the calcium antagonists include vasodilation of systemic arterioles and coronary arteries, leading to a reduction of arterial pressure and coronary vascular resistance as well as depression of the myocardial contractility and conduction velocity of the sinoatrial and atrioventricular nodes (see Chap. 8). Reflex β-adrenergic stimulation overcomes much of the negative inotropic effect, and depression of contractility becomes clinically apparent only in the presence of LV dysfunction and when other negative inotropic drugs are used concurrently. Verapamil and diltiazem cause less peripheral vasodilation than nifedipine, and, consequently, the risk of myocardial depression is greater with these two agents. Conduction through the AV node is predictably depressed with verapamil and diltiazem, and they must be used with caution in patients with preexisting conduction abnormalities or in the presence of other drugs with negative chronotropic properties. MVO2 is reduced with all of the calcium channel antagonists because of reduced wall tension secondary to reduced arterial pressure and, to a minor extent, depressed contractility (Table 6-11). HR changes are dependent on the drug used and the state of the conduction system. Nifedipine generally increases HR or causes no change, whereas either no change or decreased HR is seen with verapamil and diltiazem because of the interaction of these direct and indirect effects. In contrast to the β-blockers, calcium channel antagonists have the potential to improve coronary blood flow through areas of fixed coronary obstruction and by inhibiting coronary artery vasomotion and vasospasm. Beneficial redistribution of blood flow from well-perfused myocardium to ischemic areas and from epicardium to endocardium may also contribute to improvement in ischemic symptoms. Overall, the benefit provided by calcium channel antagonists is related to reduced MVO2 rather than improved oxygen supply based on lack of alteration in the rate pressure product at maximal exercise in most studies performed to date. However, as CAD progresses and vasospasm becomes superimposed on critical stenotic lesions, improved oxygen supply through coronary vasodilation may become more important.
Absorption of the calcium channel antagonists is characterized by excellent absorption and large, variable first-pass metabolism resulting in oral bioavailability ranging from about 20% to 50% or greater for diltiazem, nicardipine, nifedipine, verapamil, felodipine, and isradipine. Amlodipine has a range of bioavailability of ∼60% to 80%. Saturation of this effect may occur with verapamil and diltiazem, resulting in greater amounts of drug being absorbed with chronic dosing. Nifedipine may have slow or fast absorption patterns, and the ingestion of food delays and impairs its absorption as well as potential enhanced absorption in elderly patients. This variability in absorption produces fluctuation in the hemodynamic response with nifedipine. SL nifedipine is frequently used to provide a more rapid response; however, the rationale for this application is suspect because little nifedipine is absorbed from the buccal mucosa and the swallowed drug is responsible for the observed plasma concentrations. Absorption of verapamil in sustained-release products may be influenced by food, and when used in the fasted state, dose dumping may occur, resulting in high peak concentrations with some products. The approved sustained-release products for nifedipine, verapamil, and diltiazem are approved primarily for the treatment of hypertension (see Chap. 3). The presence of severe liver disease (e.g., alcoholic liver disease with cirrhosis) has been shown to reduce the first-pass metabolism of verapamil, and this shunting of drug around the liver gives rise to higher plasma concentrations and lower dose requirements in these patients. Interestingly, this effect appears to be stereoselective for the more active isomer of verapamil. Verapamil may also reduce liver blood flow; however, evidence for this reduction is based primarily on animal experiments. Few data are available regarding the influence of liver disease on the kinetics of calcium blockers; however, these drugs undergo extensive hepatic metabolism with little unchanged drug being renally excreted, and liver disease can be expected to alter the pharmacokinetics. Nifedipine has no active metabolites, whereas norverapamil possesses 20% or less activity of the parent compound. Desacetyldiltiazem has not been studied in humans, but canine studies suggest its potency ranges from 100% to 40% of the parent compound for various cardiovascular effects; the clinical importance of these observations remains to be determined. With chronic dosing of verapamil and diltiazem, apparent saturation of metabolism occurs, producing higher plasma concentrations of each drug than those seen with single-dose administration. Consequently, the elimination half-life for verapamil is prolonged, and less frequent dosing intervals may be used in some patients. The elimination half-life for diltiazem is also somewhat prolonged and the half-life of desacetyldiltiazem is longer than that of the parent drug, but it is not clear if less frequent dosing may be used. Bepridil also undergoes hepatic elimination and an active metabolite, 4-hydroxyphenyl bepridil, is produced; the parent compound has a long half-life of 30 to 40 hours. Nifedipine does not accumulate with chronic dosing; however, it is eliminated via oxidative pathways that may be polymorphic, and slow and fast metabolizers have been described for nifedipine. Most of the calcium channel blockers are eliminated via CYP3A4 and other CYP isoenzymes and many inhibit CYP3A4 activity as well. Renal insufficiency has little or no effect on the pharmacokinetics of these three drugs. Although disease alterations in kinetics have been described, the most important quantitative alteration is the influence of liver disease on bioavailability and elimination that reduce the clearance of verapamil and diltiazem, and dosing in this population should be done with caution. Altered protein binding due to renal disease, decreased protein concentration, or increased α1-acid glycoprotein has been noted, but the clinical import of these changes is unknown.
Good candidates for calcium channel blockers in angina include patients with contraindications or intolerance of β-blockers, coexisting conduction system disease (except for verapamil and diltiazem), patients with Prinzmetal’s angina (vasospastic or variable threshold angina), the presence of peripheral vascular disease, severe ventricular dysfunction (amlodipine is probably calcium channel blocker of choice and others need to be used with caution if the ejection fraction is <40% [<0.40]), and concurrent hypertension.
Ranolazine is a new drug for angina that has a unique mechanism of action unlike any other drugs used to alter the relationship between oxygen supply and demand. It reduces calcium overload in the ischemic myocyte through inhibition of the late sodium current (INa). Myocardial ischemia produces a cascade of complex ionic exchanges that can result in intracellular acidosis, excess cytosolic Ca2+, myocardial cellular dysfunction, and, if sustained, cell injury and death. Activation of the ATP-dependent K+ current during ischemia results in a strong efflux of K+ ions from myocytes. Sodium channels are activated on depolarization, leading to a rapid influx of sodium into the cells. The inactivation of INa has a fast component lasting a few milliseconds and a slowly inactivating component that can last hundreds of milliseconds.114 Ranolazine is a relatively selective inhibitor for late INa. In isolated ventricular myocytes in which the late INa was pathologically augmented, ranolazine prevented or reversed the induced mechanical dysfunction, as well as ameliorated abnormalities of ventricular repolarization. Ranolazine does not affect HR, inotropic state, or hemodynamic state or increase coronary blood flow.
Ranolazine is extensively metabolized via CYP450 3A and potent inhibitors of 3A increase the plasma concentration by a factor of about three. Ketoconazole, diltiazem, and verapamil should not be coadministered with ranolazine. Absorption from the gut is quite variable and the apparent half-life is 7 hours. Steady state is reached 3 days of twice-daily dosing. Ranolazine is indicated for the treatment of chronic angina and because it prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal agents. Contraindications include preexisting QT interval prolongation, hepatic impairment, concurrent QT interval prolonging drugs, and moderately potent to potent concurrent 3A inhibitors. QT prolongation occurs in a dose-dependent fashion with ranolazine with an average increase of 6 milliseconds, but 5% of the population has QTc prolongation of 15 milliseconds. Baseline and follow-up ECGs should be obtained to evaluate effects of the QT interval. In controlled trials, the most common adverse reactions are dizziness, headache, constipation, and nausea. Ranolazine should be started at 500 mg twice daily and increased to 1,000 mg twice daily as needed based on symptoms.115
Based on randomized, placebo-controlled trials, the improvement in exercise time is a modest increase of 15 to about 45 seconds compared with placebo.116–118 In a large ACS trial, ranolazine reduced recurrent ischemia but did not improve the primary efficacy end point of the composite of cardiovascular death, MI, or recurrent ischemia.119 Ranolazine may have antiarrhythmic effects as assessed by continuous ECG monitoring of patients in the first week after admission for acute coronary syndrome.120 In a trial of non–ST-elevation acute coronary syndrome, ranolazine, compared with placebo, was not associated with increased risk for sudden cardiac death in patients with prolonged QTc.121 It may also be cost-effective in patients not controlled well on otherwise optimal medical therapy.122
Coronary Artery Spasm and Variant Angina Pectoris (Prinzmetal’s Angina)
Prinzmetal, in his original description of variant angina pectoris, noted the waxing and waning course of this syndrome associated with ST-segment elevation and most commonly resolves without progression to MI. Patients who develop variant angina are usually younger and have fewer coronary risk factors but more commonly smoke than patients with chronic stable angina. Hyperventilation, exercise, and exposure to cold may precipitate variant angina attacks or there may be no apparent precipitating cause. The onset of chest discomfort is usually in the early morning hours. The exact cause of variant angina is not well understood, but may be an imbalance between endothelium-produced vasodilator factors (prostacyclin, nitric oxide) and vasoconstrictor factors (e.g., endothelin, angiotensin II) as well as an imbalance of autonomic control characterized by parasympathetic dominance or inflammation may also play a role.123,124 More recently there have been a number of potential common adrenoreceptor polymorphisms that may predispose patients to developing vasospasm.118,119,125 Another possible explanation is a recently discovered genetic mutation. The eNOS T-786C mutation appears to be a reversible etiology of Prinzmetal’s variant angina in white Americans whose angina might be ameliorated by L-arginine.126
The diagnosis of variant angina is based on ST-segment elevation during transient chest discomfort (usually at rest) that resolves when the chest discomfort diminishes in patients who have normal or nonobstructive coronary lesions. In the absence of ST-segment elevation, provocative test using ergonovine, acetylcholine, or methacholine may be used to precipitate coronary artery spasm, ST-segment elevation, and typical symptoms. Nitrates and calcium antagonists should be withdrawn prior to provocative testing. Provocative testing should not be used in patients with high-grade lesions. Hyperventilation may also be used to provoke spasm and patients who have a positive hyperventilation test are more likely to have higher frequency of attacks, multivessel disease, and a high degree of AV block or ventricular tachycardia.
Optimization of therapy includes dose titration using sufficiently high doses to obtain clinical efficacy without unacceptable adverse effects in individual patients. All patients should be treated for acute attacks and maintained on prophylactic treatment for 6 to 12 months following the initial episode. The occurrence of serious arrhythmias during attacks is associated with a greater risk of sudden death, and these patients should be treated more aggressively and for prolonged periods. For patients without arrhythmias who become asymptomatic and remain so for several months after treatment has been instituted, withdrawal of therapy may be safe after first ascertaining that disease activity is quiescent. Aggravating factors such as alcohol or cocaine use or cigarette smoking should be eliminated when instituting treatment.
Nitrates have been the mainstay of therapy for the acute attacks of variant angina and coronary artery spasm for many years. Most patients respond rapidly to SL nitroglycerin or ISDN; however, IV and intracoronary nitroglycerin may be very useful for patients not responding to SL preparations. In particular, vasospasm provoked by ergonovine may require intracoronary nitroglycerin. Although studies with nitrates generally show them to be efficacious, high doses are often required and it is unclear if they reduce mortality. Because calcium antagonists may be more effective, have few serious adverse effects in effective doses, and can be given less frequently than nitrates, some consider them the agents of choice for variant angina.
Nifedipine, verapamil, and diltiazem are all equally effective as single agents for the initial management of variant angina and coronary artery spasm. Dose titration is important to maximize the response with calcium antagonists. Comparative trials are few in number and do not reveal significant differences among these three drugs for variant angina. Patients unresponsive to calcium antagonists alone may have nitrates added. Combination therapy with nifedipine–diltiazem or nifedipine–verapamil has been reported useful for patients unresponsive to single-drug regimens. This is probably rational because, at the cellular level, the drugs have different receptors, but the combination of verapamil–diltiazem should be used cautiously owing to their potential additive effects on contractility and conduction.
β-Adrenergic blockade has little or no role in the management of variant angina according to most authorities.127 Although not all studies report increased painful episodes of variant angina with the addition of β-blockers, they may induce coronary vasoconstriction and prolong ischemia, as documented by continuous ECG monitoring. Other approaches to therapy attempting to modify sympathetic/parasympathetic tone include α-antagonists, anticholinergics, plexectomy, surgical interruption of the sympathetic innervation of the heart, thromboxane receptor antagonism, prostacyclin, lipoxygenase inhibition, and ticlopidine, but these drugs or procedures do not occupy a major place in therapy at the present time. One interesting case report found that the likely cause of MI was coronary artery spasm in a woman with migraine headaches because of the possible increased serotonergic activity secondary to concomitant use of zolmitriptan and citalopram.128
Silent Ischemia
The objective in the treatment of silent myocardial ischemia is to reduce the total number of ischemic episodes, both symptomatic and asymptomatic, regardless of the direction of ST-segment shift.17 The incidence of silent ischemia in the general, asymptomatic population is not known.129–132 Significant day-to-day variability in the number of episodes, the duration of ischemia, and the amount of ST-segment deviation complicate both the understanding of this process and the utility of various therapeutic interventions. Silent ischemia in patients with known CAD is common (∼80% of all ischemic episodes) and associated with the extent of disease as well as a high risk for MI and sudden death when compared with symptomatic episodes of ischemia. Although the underlying mechanisms for silent ischemia are continuing to be defined, increased physical activity, activation of the sympathetic nervous system, increased cortisol secretion, increased coronary artery tone, and enhanced platelet aggregation due to endothelia dysfunction leading to intermittent coronary obstruction may be additive in lowering the threshold for ischemia. Platelet aggregability is increased in the morning hours (7 to 11 AM), corresponding to circadian rhythms noted for the peak frequency of ischemia, acute MI, and sudden death. Silent ischemia is associated with ST-segment elevation or depression and frequently occurs without antecedent changes in HR or blood pressure, suggesting that this form of ischemia is a result of primary reduction in oxygen supply. Silent ischemia is classified into Class I, patients who do not experience angina at any time, and Class II, patients who have both asymptomatic and symptomatic ischemia. Patients with silent ischemia have a defective warning system for angina pain that may encourage excessive myocardial demand. Regardless of the exact mechanism, there is increasing concern that painless ischemia carries considerable risk for myocardial perfusion defects, detrimental hemodynamic changes, arrhythmogenesis, and sudden death.129 Silent ischemia is associated with reduced survival and increased need for PTCA and CABG as well as increased risk of AMI.133 Because it is apparently very common in some settings, major emphasis should be placed on its management. A consensus has not been reached for the most appropriate method of detecting and quantifying the magnitude of silent ischemia; however, ambulatory electrocardiogram monitoring is felt by many to be the most useful tool at the present time.
The initial step in management is to modify the major risk factors for IHD, hypertension, hypercholesterolemia, and smoking, and data from the Multiple Risk Factor Intervention Trial (MRFIT) show these interventions to be useful in patients with silent ischemia. In a subset of the study population who had abnormal baseline exercise ECG responses, the special intervention group had a 57% reduction in CHD death (22.2/1,000 vs. 51.8/1,000) and a reduction in sudden death resulting from cessation of smoking and lowering of blood pressure and cholesterol when compared with the usual-care group.
ACIP, a randomized trial of medical therapy versus revascularization (PTCA or CABG), at the 2-year follow-up demonstrates that total mortality was 6.6% in the angina-guided strategy (i.e., therapy based on symptoms), 4.4% in the ischemia-guided strategy (based on ECG changes), and 1.1% in the revascularization strategy (P < 0.02). The rate of death or MI was 12.1% in the angina-guided strategy, 8.8% in the ischemia-guided strategy, and 4.7% in the revascularization strategy (P < 0.04).133 The rate of death, MI, or recurrent cardiac hospitalization was 41.8% in the angina-guided strategy, 38.5% in the ischemia-guided strategy, and 23.1% in the revascularization strategy (P < 0.001). Post-MI patients and those with a high level of sympathetic nervous system activity are perhaps the best candidates for β-blocker therapy.
Calcium channel antagonists alone and in combination have been shown to be effective in reducing symptomatic and asymptomatic ischemia; however, they do not interrupt the diurnal surge in ischemia observed on ambulatory monitoring and, in general, they are somewhat less effective than β-blockers for silent ischemia.130,131 Nifedipine in particular seems to provide less protection and provides wide fluctuations in response with approximate reductions in the number of episodes ranging from 0% to 93% and in duration from 23% to 65% unless combined with β-blockers. Fewer studies are available with other calcium blockers and comparative trials are uncommon. Earlier studies have shown that combination therapy with calcium and β-blockers provides a better response than calcium blockers and nitrates or monotherapy.132,133
A randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]) of PCI in patients with silent ischemia after AMI found that PCI compared with antiischemic drug therapy reduced the long-term risk of major cardiac events with better preservation of ventricular function than with medical therapy.134,135
PHARMACOECONOMIC CONSIDERATIONS
Pharmacoeconomic studies have been performed primarily in patients with acute coronary syndromes and only with low-molecular-weight heparins, glycoprotein IIb/IIIa receptor antagonists, and statins.136Most of the studies on LMWHs have been cost-minimization analyses and have focused on enoxaparin sodium, because this is the only LMWH proven to be superior to UFH. Several analyses show that, compared with UFH plus aspirin, enoxaparin sodium provides cost savings during both hospitalization (30 days) and 1-year follow-up. These cost savings are mainly attributable to fewer cardiac interventions, shorter hospital stays, and lower administrative costs. Indeed, the clinical and economic advantages of enoxaparin sodium have led to its recommendation in recent guidelines as the antithrombotic agent of choice for CAD. Most of the economic analyses of GP IIb/IIIa inhibitors have been cost-effectiveness analyses.137 Such analyses indicate that the high acquisition costs of these drugs may be at least partially offset by reductions in other costs if a noninvasive approach to risk stratification is used. Furthermore, use of GP IIb/IIIa inhibitors appears to give favorable cost-effectiveness ratios compared with other accepted therapies, such as fibrin-specific thrombolytic therapy, in the cardiovascular field, particularly in high-risk patients and those undergoing percutaneous coronary intervention. However, more comprehensive economic data on the GP IIb/IIIa inhibitors are needed. Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors appears to be an acceptable alternative to the standard of care and is superior to UFH alone in PCI and is considered to be cost-effective.138
Atorvastatin when used in ACS has been shown to reduce events and this offsets the upfront acquisition costs.139 The total expected cost was (British) £784.05 per patient in the placebo cohort and £851.59 per patient in the atorvastatin cohort, resulting in an incremental cost of £67.54 per patient in the atorvastatin group. The cost per event avoided was £1,762.04. One third of the cost of atorvastatin treatment was offset within 16 weeks by the cost savings resulting from the reduction in the number of events in the atorvastatin cohort compared with the placebo cohort. Other analyses of statins have found this class to be cost-effective especially in patients at higher risk.139
Aspirin and clopidogrel have been evaluated for secondary prevention of CHD and while aspirin is very cost-effective, clopidogrel is only cost-effective for patients who cannot take aspirin.
Clinical Controversy…
Once patients with angina develop symptoms sufficient for pharmacologic therapy on a daily basis, the initial prophylactic therapy recommended is a β-blocker. There is a paucity of comparative, long-term clinical trials of β-blockade versus calcium channel blockers to determine which is superior for survival benefit. β-Blockers are recommended first-line therapy because of their efficacy in post-MI patients and favorable adverse effect profile.
Recent developments in the understanding of bioactivation of organic nitrates have given rise to concern over endothelial dysfunction induced by nitrates when administered long term. Not all nitrate products are activated via the same mechanisms and this may impact how effective individual drugs are in long-term treatment.
In stable CAD, medical management has been reported for outcomes similar to revascularization and these findings may have a significant impact on how healthcare resources are utilized in the future.
EVALUATION OF THERAPEUTIC OUTCOMES
Improved symptoms of angina, improved cardiac performance, and improvement in risk factors may all be used to assess the outcome of treatment of IHD and angina. Symptomatic improvement in exercise capacity (longer duration) or fewer symptoms at the same level of exercise is subjective evidence that therapy is working. Once patients have been optimized on medical therapy, symptoms should improve over 2 to 4 weeks and remain stable until their disease progresses. There are several instruments (e.g., Seattle Angina Questionnaire, Specific Activity Scale [Table 6-1], Canadian Classification System [Table 6-2]) that could be used to improve the reproducibility of symptom assessment.2 If the patient is doing well, then no other assessment may be necessary. Objective assessment is obtained through increase in exercise duration on ETT and the absence of ischemic changes on ECG or deleterious hemodynamic changes. Echocardiography and cardiac imaging may also be used; however, due to their expense, they are only used if a patient is not doing well to determine if revascularization or other measures should be undertaken. Coronary angiography may be used to assess the extent of stenosis or restenosis after angioplasty or CABG. 
The performance measurement set recommended by the ACC/AHA is provided in Table 6-13.
TABLE 6-13 American College of Cardiology, American Heart Association, and Physician Consortium for Performance Improvement Chronic Stable Coronary Artery Disease Core Physician Performance Measurement Seta
ABBREVIATIONS
REFERENCES
1. Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: Executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27:1341–1381.
2. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44–e164.
3. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: A report from the American Heart Association. Circulation 2013;127:e6–e245.
4. Sytkowski PA, D’Agostino RB, Belanger A, Kannel WB. Sex and time trends in cardiovascular disease incidence and mortality: The Framingham Heart Study, 1950-1989. Am J Epidemiol 1996;143:338–350.
5. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics—2010 update: A report from the American Heart Association. Circulation 2010;121:e46–e215.
6. Menotti A, Keys A, Blackburn H, et al. Comparison of multivariate predictive power of major risk factors for coronary heart diseases in different countries: Results from eight nations of the Seven Countries Study, 25-year follow-up. J Cardiovasc Risk 1996;3:69–75.
7. Keys A. Mediterranean diet and public health: Personal reflections. Am J Clin Nutr 1995;61:1321S–1323S.
8. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new specific activity scale. Circulation 1981;64:1227–1234.
9. Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1994;90:2645–2657.
10. Caracciolo EA, Davis KB, Sopko G, et al. Comparison of surgical and medical group survival in patients with left main coronary artery disease. Long-term CASS experience. Circulation 1995;91:2325–2334.
11. Park SJ, Park DW. Percutaneous coronary intervention with stent implantation versus coronary artery bypass surgery for treatment of left main coronary artery disease: Is it time to change guidelines? Circ Cardiovasc Interv 2009;2:59–68.
12. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;126:3097–3137.
13. Epstein SE, Cannon RO 3rd, Talbot TL. Hemodynamic principles in the control of coronary blood flow. Am J Cardiol 1985;56:4E–10E.
14. von Mering GO, Arant CB, Wessel TR, et al. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: Results from the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 2004;109:722–725.
15. Ferrari R, Fox K. Insight into the mode of action of ACE inhibition in coronary artery disease: The ultimate ‘EUROPA’ story. Drugs 2009;69:265–277.
16. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non ST-Elevation Myocardial Infarction): Developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148–e304.
17. Cohn PF. A new look at benefits of drug therapy in silent myocardial ischaemia. Eur Heart J 2007;28:2053–2054.
18. Caracciolo EA, Chaitman BR, Forman SA, et al. Diabetics with coronary disease have a prevalence of asymptomatic ischemia during exercise treadmill testing and ambulatory ischemia monitoring similar to that of nondiabetic patients. An ACIP database study. ACIP Investigators. Asymptomatic Cardiac Ischemia Pilot Investigators. Circulation 1996;93:2097–2105.
19. Fraker TD Jr, Fihn SD, Gibbons RJ, et al. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol 2007;50:2264–2274.
20. 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.
21. Panel E. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015–3023.
22. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: Exploratory analysis of a randomized trial. Ann Intern Med 2010;152:488–496, W174.
23. Crowe E, Lovibond K, Gray H, Henderson R, Krause T, Camm J. Early management of unstable angina and non-ST segment elevation myocardial infarction: Summary of NICE guidance. BMJ 2010;340:c1134.
24. Panel E. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
25. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. J Am Coll Cardiol 2004;44:720–732.
26. Group BDS, Frye RL, August P, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–2515.
27. Wald NJ, Watt HC. Prospective study of effect of switching from cigarettes to pipes or cigars on mortality from three smoking related diseases. BMJ 1997;314:1860–1863.
28. Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: A randomized trial. Circulation 2010;121:221–229.
29. Swan GE, McClure JB, Jack LM, et al. Behavioral counseling and varenicline treatment for smoking cessation. Am J Prev Med 2010;38:482–490.
30. Keating GM, Lyseng-Williamson KA. Varenicline: A pharmacoeconomic review of its use as an aid to smoking cessation. Pharmacoeconomics 2010;28:231–254.
31. Russell LB, Carson JL, Taylor WC, Milan E, Dey A, Jagannathan R. Modeling all-cause mortality: Projections of the impact of smoking cessation based on the NHEFS. NHANES I Epidemiologic Follow-Up Study. Am J Public Health 1998;88:630–636.
32. Bartecchi C, Alsever RN, Nevin-Woods C, et al. Reduction in the incidence of acute myocardial infarction associated with a citywide smoking ordinance. Circulation 2006;114:1490–1496.
33. Rosendorff C. Hypertension and coronary artery disease: A summary of the American Heart Association scientific statement. J Clin Hypertens (Greenwich) 2007;9:790–795.
34. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 2012;3:CD007176.
35. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: Updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation 2007;116:1081–1093.
36. Williams MA, Haskell WL, Ades PA, et al. Resistance exercise in individuals with and without cardiovascular disease: 2007 update: A scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2007;116:572–584.
37. Fuchs FD, Chambless LE, Folsom AR, et al. Association between alcoholic beverage consumption and incidence of coronary heart disease in whites and blacks: The Atherosclerosis Risk in Communities Study. Am J Epidemiol 2004;160:466–474.
38. Britton A, Marmot MG, Shipley MJ. How does variability in alcohol consumption over time affect the relationship with mortality and coronary heart disease? Addiction 2010;105:639–645.
39. Romelsjo A, Allebeck P, Andreasson S, Leifman A. Alcohol, mortality and cardiovascular events in a 35 year follow-up of a nationwide representative cohort of 50,000 Swedish conscripts up to age 55. Alcohol Alcohol 2012;47:322–327.
40. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–613.
41. Rossouw JE, Cushman M, Greenland P, et al. Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women’s health initiative trials of hormone therapy. Arch Intern Med 2008;168:2245–2253.
42. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2012;7:CD004143.
43. El-Sohemy A, Cornelis MC, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype and risk of myocardial infarction. Genes Nutr 2007;2:155–156.
44. Celik T, Iyisoy A, Amasyali B. The effects of coffee intake on coronary heart disease: Ongoing controversy. Int J Cardiol 2010;144:118.
45. Group IS. Effect of nicorandil on coronary events in patients with stable angina: The Impact of Nicorandil in Angina (IONA) randomised trial. Lancet 2002;359:1269–1275.
46. Fox K, Ford I, Steg PG, Tendera M, Ferrari R, BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A randomised, double-blind, placebo-controlled trial. Lancet 2008;372:807–816.
47. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86:580–588.
48. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–1516.
49. Maron DJ, Boden WE, O’Rourke RA, et al. Intensive multifactorial intervention for stable coronary artery disease: Optimal medical therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial. J Am Coll Cardiol 2010;55:1348–1358.
50. Hueb W, Lopes NH, Gersh BJ, et al. Five-year follow-up of the Medicine, Angioplasty, or Surgery Study (MASS II): A randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2007;115:1082–1089.
51. 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). Circulation 2003;107:149–158.
52. Sipahi I, Tuzcu EM, Wolski KE, et al. Beta-blockers and progression of coronary atherosclerosis: Pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med 2007;147:10–18.
53. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm 2007;64:1917–1921.
54. Munzel T, Daiber A, Mulsch A. Explaining the phenomenon of nitrate tolerance. Circ Res 2005;97:618–628.
55. Daiber A, Munzel T. Characterization of the antioxidant properties of pentaerithrityl tetranitrate (PETN)-induction of the intrinsic antioxidative system heme oxygenase-1 (HO-1). Methods Mol Biol 2010;594:311–326.
56. Ambrosio G, Del Pinto M, Tritto I, et al. Chronic nitrate therapy is associated with different presentation and evolution of acute coronary syndromes: Insights from 52,693 patients in the Global Registry of Acute Coronary Events. Eur Heart J 2009;31:430–438.
57. Pehrsson SK, Ringqvist I, Ekdahl S, Karlson BW, Ulvenstam G, Persson S. Monotherapy with amlodipine or atenolol versus their combination in stable angina pectoris. Clin Cardiol 2000;23:763–770.
58. Verdecchia P, Reboldi G, Angeli F, et al. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension 2005;46:386–392.
59. Opie LH, Yusuf S, Kubler W. Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: A critical analysis based on 100 studies. Prog Cardiovasc Dis 2000;43:171–196.
60. Howes LG, Edwards CT. Calcium antagonists and cancer. Is there really a link? Drug Saf 1998;18:1–7.
61. Knight CJ, Fox KM. Amlodipine versus diltiazem as additional antianginal treatment to atenolol. Centralised European Studies in Angina Research (CESAR) Investigators. Am J Cardiol 1998;81:133–136.
62. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—2002: 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 Unstable Angina). Circulation 2002;106:1893–1900.
63. King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation 2008;117:261–295.
64. Sobel BE. Coronary revascularization in patients with type 2 diabetes and results of the BARI 2D trial. Coron Artery Dis 2010;21:189–198.
65. BARI Investigators. The final 10-year follow-up results from the BARI randomized trial. J Am Coll Cardiol 2007;49:1600–1606.
66. Hannan EL, Racz MJ, Gold J, et al. Adherence of catheterization laboratory cardiologists to American College of Cardiology/American Heart Association guidelines for percutaneous coronary interventions and coronary artery bypass graft surgery: What happens in actual practice? Circulation 2010;121:267–275.
67. Simoons ML, Windecker S. Controversies in cardiovascular medicine: Chronic stable coronary artery disease: Drugs vs. revascularization. Eur Heart J 2010;31:530–541.
68. Ramanathan KB, Weiman DS, Sacks J, et al. Percutaneous intervention versus coronary bypass surgery for patients older than 70 years of age with high-risk unstable angina. Ann Thorac Surg 2005;80:1340–1346.
69. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006;113:e166–e286.
70. Rathore S, Kinoshita Y, Terashima M, et al. A comparison of clinical presentations, angiographic patterns and outcomes of in-stent restenosis between bare metal stents and drug eluting stents. EuroIntervention 2010;5:841–846.
71. Lemesle G, Maluenda G, Collins SD, Waksman R. Drug-eluting stents: Issues of late stent thrombosis. Cardiol Clin 2010;28:97–105.
72. Onuma Y, Serruys PW, Kukreja N, et al. Randomized comparison of everolimus- and paclitaxel-eluting stents: Pooled analysis of the 2-year clinical follow-up from the SPIRIT II and III trials. Eur Heart J 2010;31:1071–1078.
73. Coons JC, Battistone S. 2007 guideline update for unstable angina/non-ST-segment elevation myocardial infarction: Focus on antiplatelet and anticoagulant therapies. Ann Pharmacother 2008;42:989–1001.
74. Vermeer NS, Bajorek BV. Utilization of evidence-based therapy for the secondary prevention of acute coronary syndromes in Australian practice. J Clin Pharm Ther 2008;33:591–601.
75. Tebbe U, Hochadel M, Bramlage P, et al. In-hospital outcomes after elective and non-elective percutaneous coronary interventions in hospitals with and without on-site cardiac surgery backup. Clin Res Cardiol 2009;98:701–707.
76. Chaitman BR, Hardison RM, Adler D, et al. The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: Impact of treatment strategy on cardiac mortality and myocardial infarction. Circulation 2009;120:2529–2540.
77. Curzen NP. Is there evidence for prognostic benefit following PCI in stable patients? COURAGE and its implications: An interventionalist’s view. Heart 2009;96:103–105.
78. Bottorff MB, Nutescu EA, Spinler S. Antiplatelet therapy in patients with unstable angina and non-ST-segment-elevation myocardial infarction: Findings from the CRUSADE national quality improvement initiative. Pharmacotherapy 2007;27:1145–1162.
79. Levine GN, Berger PB, Cohen DJ, et al. Newer pharmacotherapy in patients undergoing percutaneous coronary interventions: A guide for pharmacists and other health care professionals. Pharmacotherapy 2006;26:1537–1556.
80. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation 2004;110:e340–e437.
81. King SB 3rd, Marshall JJ, Tummala PE. Revascularization for coronary artery disease: Stents versus bypass surgery. Annu Rev Med 2009;61:199–213.
82. Spinler SA. Managing acute coronary syndrome: Evidence-based approaches. Am J Health Syst Pharm 2007;64:S14–S24.
83. Toth PP. The potential role of prasugrel in secondary prevention of ischemic events in patients with acute coronary syndromes. Postgrad Med 2009;121:59–72.
84. Lange RA, Hillis LD. Second-generation drug-eluting coronary stents. N Engl J Med 2010;362:1728–1730.
85. Doostzadeh J, Clark LN, Bezenek S, Pierson W, Sood PR, Sudhir K. Recent progress in percutaneous coronary intervention: Evolution of the drug-eluting stents, focus on the XIENCE V drug-eluting stent. Coron Artery Dis 2010;21:46–56.
86. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624–629.
87. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–2015.
88. Mahoney EM, Wang K, Arnold SV, et al. Cost-effectiveness of prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention: Results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel-Thrombolysis in Myocardial Infarction TRITON-TIMI 38. Circulation 2010;121:71–79.
89. Schuhlen H, Kastrati A, Pache J, Dirschinger J, Schomig A. Sustained benefit over four years from an initial combined antiplatelet regimen after coronary stent placement in the ISAR trial. Intracoronary Stenting and Antithrombotic Regimen. Am J Cardiol 2001;87:397–400.
90. Takakuwa KM, Ou FS, Peterson ED, et al. The usage patterns of cardiac bedside markers employing point-of-care testing for troponin in non-ST-segment elevation acute coronary syndrome: Results from CRUSADE. Clin Cardiol 2009;32:498–505.
91. Topol EJ, Moliterno DJ, Herrmann HC, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001;344:1888–1894.
92. Spinler SA, Rees C. Review of prasugrel for the secondary prevention of atherothrombosis. J Manag Care Pharm 2009;15:383–395.
93. Stone GW, Ware JH, Bertrand ME, et al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: One-year results from the ACUITY trial. JAMA 2007;298:2497–2506.
94. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004;292:696–703.
95. Canan T, Lee MS. Drug-eluting stent fracture: Incidence, contributing factors, and clinical implications. Catheter Cardiovasc Interv 2010;75:237–245.
96. Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med 2010;362:1663–1674.
97. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354–362.
98. Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: A cohort study. Ann Intern Med 2010;152:337–345.
99. Zairis MN, Tsiaousis GZ, Patsourakos NG, et al. The impact of treatment with omeprazole on the effectiveness of clopidogrel drug therapy during the first year after successful coronary stenting. Can J Cardiol 2010;26:e54–e57.
100. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713–718.
101. Hall SL, Lorenc T. Secondary prevention of coronary artery disease. Am Fam Physician 2010;81:289–296.
102. Messerli FH, Bangalore S, Yao SS, Steinberg JS. Cardioprotection with beta-blockers: Myths, facts and Pascal’s wager. J Intern Med 2009;266:232–241.
103. Feringa HH, van Waning VH, Bax JJ, et al. Cardioprotective medication is associated with improved survival in patients with peripheral arterial disease. J Am Coll Cardiol 2006;47:1182–1187.
104. Prince MJ, Bird AS, Blizard RA, Mann AH. Is the cognitive function of older patients affected by antihypertensive treatment? Results from 54 months of the Medical Research Council’s trial of hypertension in older adults. BMJ 1996;312:801–805.
105. Abrams J, Thadani U. Therapy of stable angina pectoris: The uncomplicated patient. Circulation 2005;112:e255–e259.
106. Thomas GR, DiFabio JM, Gori T, Parker JD. Once daily therapy with isosorbide-5-mononitrate causes endothelial dysfunction in humans: Evidence of a free-radical-mediated mechanism. J Am Coll Cardiol 2007;49:1289–1295.
107. Schuhmacher S, Wenzel P, Schulz E, et al. Pentaerythritol tetranitrate improves angiotensin II-induced vascular dysfunction via induction of heme oxygenase-1. Hypertension 2010;55:897–904.
108. Daiber A, Oelze M, Wenzel P, et al. Nitrate tolerance as a model of vascular dysfunction: Roles for mitochondrial aldehyde dehydrogenase and mitochondrial oxidative stress. Pharmacol Rep 2009;61:33–48.
109. Gori T, Daiber A, Di Stolfo G, et al. Nitroglycerine causes mitochondrial reactive oxygen species production: In vitro mechanistic insights. Can J Cardiol 2007;23:990–992.
110. Sekiya M, Sato M, Funada J, Ohtani T, Akutsu H, Watanabe K. Effects of the long-term administration of nicorandil on vascular endothelial function and the progression of arteriosclerosis. J Cardiovasc Pharmacol 2005;46:63–67.
111. Parker JO, Amies MH, Hawkinson RW, et al. Intermittent transdermal nitroglycerin therapy in angina pectoris. Clinically effective without tolerance or rebound. Minitran Efficacy Study Group. Circulation 1995;91:1368–1374.
112. Freedman SB, Daxini BV, Noyce D, Kelly DT. Intermittent transdermal nitrates do not improve ischemia in patients taking beta-blockers or calcium antagonists: Potential role of rebound ischemia during the nitrate-free period. J Am Coll Cardiol 1995;25:349–355.
113. Ajani AE, Yan BP. The mystery of coronary artery spasm. Heart Lung Circ 2007;16:10–15.
114. Reffelmann T, Kloner RA. Ranolazine: An anti-anginal drug with further therapeutic potential. Expert Rev Cardiovasc Ther 2010;8:319–329.
115. Fernandez SF, Tandar A, Boden WE. Emerging medical treatment for angina pectoris. Expert Opin Emerg Drugs 2010;15:283–298.
116. Chaitman BR. Efficacy and safety of a metabolic modulator drug in chronic stable angina: Review of evidence from clinical trials. J Cardiovasc Pharmacol Ther 2004;9(Suppl 1):S47–S64.
117. Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375–1382.
118. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: A randomized controlled trial. JAMA 2004;291:309–316.
119. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: The MERLIN-TIMI 36 randomized trial. JAMA 2007;297:1775–1783.
120. Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: Results from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007;116:1647–1652.
121. Karwatowska-Prokopczuk E, Wang W, Cheng ML, Zeng D, Schwartz PJ, Belardinelli L. The risk of sudden cardiac death in patients with non-ST elevation acute coronary syndrome and prolonged QTc interval: Effect of ranolazine. Europace 2013;15:429–436.
122. Phelps CE, Buysman EK, Gomez Rey G. Costs and clinical outcomes associated with use of ranolazine for treatment of angina. Clin Ther 2012;34:1395–1407.e4.
123. Sakata K, Miura F, Sugino H, et al. Assessment of regional sympathetic nerve activity in vasospastic angina: Analysis of iodine 123-labeled metaiodobenzylguanidine scintigraphy. Am Heart J 1997;133:484–489.
124. Hung MJ, Cherng WJ, Yang NI, Cheng CW, Li LF. Relation of high-sensitivity C-reactive protein level with coronary vasospastic angina pectoris in patients without hemodynamically significant coronary artery disease. Am J Cardiol 2005;96:1484–1490.
125. Park JS, Zhang SY, Jo SH, et al. Common adrenergic receptor polymorphisms as novel risk factors for vasospastic angina. Am Heart J 2006;151:864–869.
126. Glueck CJ, Munjal J, Khan A, Umar M, Wang P. Endothelial nitric oxide synthase T-786C mutation, a reversible etiology of Prinzmetal’s angina pectoris. Am J Cardiol 2010;105:792–796.
127. Lanza GA, Pedrotti P, Pasceri V, Lucente M, Crea F, Maseri A. Autonomic changes associated with spontaneous coronary spasm in patients with variant angina. J Am Coll Cardiol 1996;28:1249–1256.
128. Acikel S, Dogan M, Sari M, Kilic H, Akdemir R. Prinzmetal-variant angina in a patient using zolmitriptan and citalopram. Am J Emerg Med 2010;28:257.e3–257.e6.
129. Schoenenberger AW, Kobza R, Jamshidi P, et al. Sudden cardiac death in patients with silent myocardial ischemia after myocardial infarction (from the Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]). Am J Cardiol 2009;104:158–163.
130. Singh N, Mironov D, Goodman S, Morgan CD, Langer A. Treatment of silent ischemia in unstable angina: A randomized comparison of sustained-release verapamil versus metoprolol. Clin Cardiol 1995;18:653–658.
131. Dwivedi SK, Saran RK, Mittal S, Gupta R, Narain VS, Puri VK. Silent ischemic interval on exercise test is a predictor of response to drug therapy: A randomized crossover trial of metoprolol versus diltiazem in stable angina. Clin Cardiol 2001;24:45–49.
132. Pratt CM, McMahon RP, Goldstein S, et al. Comparison of subgroups assigned to medical regimens used to suppress cardiac ischemia (the Asymptomatic Cardiac Ischemia Pilot [ACIP] Study). Am J Cardiol 1996;77:1302–1309.
133. Davies RF, Goldberg AD, Forman S, et al. Asymptomatic Cardiac Ischemia Pilot (ACIP) study two-year follow-up: Outcomes of patients randomized to initial strategies of medical therapy versus revascularization. Circulation 1997;95:2037–2043.
134. Erne P, Schoenenberger AW, Burckhardt D, et al. Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: The SWISSI II randomized controlled trial. JAMA 2007;297:1985–1991.
135. Erne P, Schoenenberger AW, Zuber M, et al. Effects of anti-ischaemic drug therapy in silent myocardial ischaemia type I: The Swiss Interventional Study on Silent Ischaemia type I (SWISSI I): A randomized, controlled pilot study. Eur Heart J 2007;28:2110–2117.
136. Bosanquet N, Jonsson B, Fox KA. Costs and cost effectiveness of low molecular weight heparins and platelet glycoprotein IIb/IIIa inhibitors: In the management of acute coronary syndromes. Pharmacoeconomics 2003;21:1135–1152.
137. Plosker GL, Ibbotson T. Eptifibatide: A pharmacoeconomic review of its use in percutaneous coronary intervention and acute coronary syndromes. Pharmacoeconomics 2003;21:885–912.
138. Caron MF, McKendall GR. Bivalirudin in percutaneous coronary intervention. Am J Health Syst Pharm 2003;60:1841–1849.
139. Hay JW, Yu WM, Ashraf T. Pharmacoeconomics of lipid-lowering agents for primary and secondary prevention of coronary artery disease. Pharmacoeconomics 1999;15:47–74.