CHAPTER 43: THE EVALUATION AND MANAGEMENT OF STABLE ISCHEMIC HEART DISEASE

Stable ischemic heart disease (SIHD) is a major public health concern in most developed nations and has become a leading cause of death and disability in high- as well as low- and middle-resource countries.¹ Thrombosis complicating an atherosclerotic plaque is the proximate cause of acute myocardial infarction (MI) in patients with coronary artery disease (CAD) and represents the leading cause of death for men and women worldwide.² Globally, CAD accounts for 7.4 million deaths annually, and in the United States, it is responsible for one in seven deaths per year, which in 2013 totaled approximately 370,200 fatalities.³ Despite advancements in the identification of atherosclerotic risk factors and effective therapies for primary and secondary prevention, it is estimated that annually 660,000 Americans are hospitalized or die from an initial MI, 305,000 suffer from recurrent MI, and an additional 160,000 individuals develop a clinically silent MI.³ In these patients, the transition from a clinically stable coronary atherosclerotic substrate to an acute life-threatening event remains a focus of intense investigation spanning genetic, basic, translational, and epidemiologic avenues of scientific exploration.⁴ In addition, there is an imprecise temporal and biological boundary on the other end of the clinical spectrum from acute coronary syndrome (ACS) to SIHD. This chapter reviews methods for diagnosing CAD, the clinical profile of patients affected by SIHD, and predictive models for assessing risk to inform treatment. Findings from contemporary landmark clinical trials that have influenced the use of specific medical, percutaneous, surgical, and hybrid treatments will also be discussed.

Etiology and Classification

Myocardial ischemia is mediated by an imbalance between oxygen supply and demand at the cardiomyocyte cellular level (see Chap. 34). Coronary atherosclerosis impairs coronary blood flow (CBF) via a variety of mechanisms and is the dominant cause of angina under conditions of elevated myocardial oxygen demand, such as exercise or emotional stress. However, CBF is impaired even in the absence of epicardial CAD in several other disease states, including severe aortic valve disease with left ventricular hypertrophy (LVH), systemic hypertension, idiopathic dilated cardiomyopathy, and hypertrophic cardiomyopathy. In patients with LVH, ischemia may result from a combination of inadequate capillary density, pathologic changes within small intramyocardial arteries and arterioles, reduced coronary flow reserve (CFR), systolic compressive forces, and markedly elevated diastolic pressures within the vulnerable subendocardium. Nonobstructive epicardial CAD may nevertheless result in endothelial dysfunction and impaired CFR, which is a major mechanism underlying the expression of microvascular angina. A primary reduction in myocardial oxygen supply following intraluminal thrombus formation and/or epicardial constriction underlies the development of ACSs (Table 43–1). There are other, nonatherosclerotic causes of abrupt reductions in CBF, including spontaneous dissection and embolization. Chronic reductions in oxygen supply may also occur with severe, diffuse, and extensive CAD, resulting in myocardial hibernation. Oxygen supply can also be reduced in the setting of severe anemia or hemoglobinopathies, and under these circumstances, the threshold for developing ischemia or myocardial injury can be lowered. The major determinants of myocardial oxygen demand are heart rate, wall stress, and contractility. These factors may act singularly or in combination to trigger an ischemic cascade in a vulnerable patient.

Clinical Features

For over two centuries, it has been recognized that cardiac angina can be diagnosed effectively by a careful patient interview. William Herberden is credited with the initial description of angina in 1772 in his chapter entitled “Pectoris Dolor,” in Commentaries on the History and Cure of Diseases.⁵ Remarkably, several elements from this original characterization of cardiac angina remain pertinent to the management of CAD today. Herberden correctly identified that certain descriptive features of angina, such as the occurrence of chest pain at rest, portend a particularly grave prognosis.

The Canadian Cardiovascular Society (CCS) classification, now four decades old, remains the most commonly used system for grading angina severity (Table 43–2).⁶ Increasing CCS class positively correlates with the number of diseased epicardial coronary arteries discovered at angiography, the presence of impaired left ventricular (LV) function, and need for revascularization with either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery.⁷ The CCS classification system can also be used to predict outcome in patients with chronic CAD: compared with CCS class I status, CCS class IV status is associated a significant increase in all-cause mortality and nonfatal MI 30 months following revascularization.⁷ However, CCS class alone does not necessarily inform clinical decision making in patients with SIHD. Although it has major impact upon quality of life, other factors in addition to symptom severity determine survival and may dictate the therapeutic approach.⁸ In fact, data suggest that qualitative descriptions of symptoms alone may be inaccurate in diagnosing CAD.^8,9 This is particularly the case for patients with who do not report chest pain, but in whom the sole symptom at presentation is jaw, neck, ear, arm, or epigastric discomfort. Among this constellation of cardiac angina equivalent symptoms, exertional dyspnea should be considered a potentially high-risk finding as a result of the association between this symptom and adverse outcome in patients with CAD.⁹ These observations have prompted the consideration of alternative diagnostic strategies that link angina classification with CAD burden directly. For example, a modification of the Diamond-Forrester approach, which considers the likelihood of CAD based on various clinical risk factors, was demonstrated to predict angiographically proven obstructive CAD effectively if age and sex were added to angina type (eg, typical or atypical).¹⁰ This approach may be particularly important given differences in clinical presentation between men and women. Compared to men, women are less likely to present with typical angina symptoms, but more likely to present with throat, jaw, or neck pain, shortness of breath, fatigue, and nonchest discomfort.¹¹ In complimentary work, analyzing levels of high-density lipoprotein, aspartate aminotransferase, and high-sensitivity C-reactive protein (hs-CRP) increased the accuracy of the use of age, sex, and angina type for predicting functionally significant CAD.¹²

Asymptomatic Ischemia

Myocardial ischemia is characterized as asymptomatic, or silent, when it occurs in the absence of angina or an anginal equivalent.¹³ When present, asymptomatic ischemia is correlated positively with incident ischemic heart disease and confers an unfavorable prognosis.¹⁴ The pathophysiology of asymptomatic ischemia remains controversial. Leading contemporary theories emphasize the presence of defective sensory afferent nerve function, which impairs normal sensory conduction from the atria and ventricles to the thoracic sympathetic ganglia and dorsal roots of the spinal cord. Asymptomatic ischemia is frequently observed among patients with diabetes, presumably due to the associated neuropathy. Other patient populations at risk for asymptomatic ischemia include those with a previous MI.¹⁵ Cohn and colleagues¹³ estimate that 50,000 patients per year experience an asymptomatic MI within 30 days of an initial event. Asymptomatic ischemia occurring during the hospital phase of MI is predictive of future cardiovascular events over the next 5 years.¹³ Early repolarization pattern on electrocardiography has also been linked to CAD in asymptomatic populations.¹⁶ In selected patients with SIHD, the prognostic value of asymptomatic ischemia on treadmill exercise stress testing is similar to that associated with symptomatic ischemia, particularly when present at low workloads.^17,18 Ischemia is detected in nearly twice as many asymptomatic patients with diabetes compared to age- and gender-matched patients without diabetes when myocardial perfusion imaging is added to conventional exercise electrocardiogram (ECG) testing,¹⁹ clarifying further the scope of asymptomatic ischemia in at-risk patients.

Although abnormalities in ankle-brachial index, carotid intimal thickness, hs-CRP level, and coronary artery calcification burden may have important implications for the identification of vascular disease, which is strongly associated with myocardial ischemia in asymptomatic patients, the utility of analyzing these factors in asymptomatic populations for the purpose of revascularization remains unresolved.²⁰ This dilemma is reinforced by findings from a small retrospective subgroup analysis of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial in which the addition of PCI to optimal medical therapy (OMT) was not associated with a definitive decrease in nonfatal cardiac events or death compared to OMT alone in patients with silent myocardial ischemia²¹ (see later section on COURAGE trial). Therefore, implementation of clinical management strategies beyond conventional primary and secondary prevention are not recommended currently across the spectrum of asymptomatic patients, although advanced diagnostic and therapeutic measures may be appropriate in selected individuals at intermediate risk (ie, global risk estimate for hard clinical events of ~10%-20% over 10 years).

Heart Failure, Arrhythmias, and Embolic Disease

Impaired LV systolic function is the primary cardiovascular form of end-organ damage in patients with SIHD. Systolic heart failure (HF), or heart failure with reduced ejection fraction (HFrEF), is most likely to occur under conditions in which ≥ 20% of myocardium is injured from chronic ischemia or prior MI(s). Longitudinal remodeling of cardiomyocytes following ischemic injury promotes adverse changes to LV geometry, including elongation and dilation, which together with replacement fibrosis, impair LV systolic function. Diminished contractile performance, stroke volume, and cardiac output result in overactivation of the renin-angiotensin-aldosterone axis and neurohumoral signaling, which, collectively, cause detrimental effects on cardiac and systemic vascular function.²² The aggregate consequences of these changes include an unfavorable hemodynamic profile that promotes increased myocardial oxygen demand and LV afterload, which, in turn, propagate further ischemic injury and clinical HF. The role of medical therapy to attenuate ischemia as a trigger of HF is discussed below. See Chap. 68 for a review of the pathophysiology of HF and Chap. 70 for the broader use of β-adrenergic receptor antagonists, renin- angiotensin-aldosterone inhibitors, nitrates/hydralazine, and diuretics for management of HF with reduced LV systolic function.

Ischemic Mitral Regurgitation

Mitral regurgitation (MR) from ischemia-mediated LV remodeling occurs as a consequence of papillary muscle displacement, leaflet tethering, and/or annular dilatation and is strongly associated with HF and poor long-term outcomes in a graded fashion. The optimal treatment of ischemic MR remains controversial, particularly since this is not primarily a valvular disorder but develops as a consequence of LV dysfunction and adverse remodeling. Restrictive annuloplasty with a downsized rigid ring constitutes the standard surgical approach. Smith and colleagues²³ examined the role of mitral valve repair at the time of CABG surgery. Among 301 patients with moderate ischemic MR (as assessed by an integrative echocardiographic method), the addition of mitral valve repair to CABG surgery did not improve indexed LV end-systolic volume, 1-year mortality, or major adverse cardiac and cerebrovascular events (MACCE) compared to CABG surgery alone, but was associated with a significant increase in cardiopulmonary bypass time, longer postoperative hospital length of stay, and significantly more early neurologic events and supraventricular arrhythmias.²³ Significantly fewer patients who underwent CABG with repair had recurrent moderate or severe MR at 1 year (11%), compared with patients who had CABG alone (30%), yet fully 70% of the latter group had none, trace, or mild MR at 1 year. Two-year outcomes were similar between groups.²⁴ Accurate predictors of the response to CABG alone are needed. For patients with severe ischemic MR, no differences in LV end-systolic volumes or MACCE were reported at 1- and 2-year follow-up among 251 patients randomized to mitral valve replacement or repair.^25,26 Of note, in patients with severe ischemic MR, mitral valve repair resulted in a significantly increased risk of recurrent moderate or severe MR, more HF events and cardiovascular readmissions, and a trend to reduced quality of life. These findings have prompted reevaluation of surgical treatment for ischemic MR late after MI. Device therapy for ischemic MR is under active investigation in the United States.

Ischemic Cardiomyopathy

The role of surgical revascularization in patients with ischemic cardiomyopathy has also been addressed. The Surgical Treatment for Ischemic Heart Failure (STICH) trial evaluated the role of CABG surgery in patients with decreased LV systolic function (LV ejection fraction [LVEF] ≤ 35%) and CAD.²⁷ In this study, 127 clinical sites from 26 countries contributed a total of 1212 patients (median LVEF = 28%) who were largely CCS class II/III and New York Heart Association (NYHA) functional class II/III. Compared to OMT, the primary end point of death from any cause at a median follow-up of 56 months was not significantly different in patients randomized to CABG surgery plus OMT (41% vs 36%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.72-1.04; P = .12), although the combined end point of death from any cause or hospitalization for cardiovascular causes occurred significantly less often in the CABG group (HR, 0.74; 95% CI, 0.64-0.85; P < .001). At a median follow-up of 9.8 years, however, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower among patients who underwent CABG.²⁸ In a nonrandomized substudy of the STICH trial, the role of preoperative viability testing assessed by single-photon emission computed tomography (SPECT) or dobutamine stress echocardiography was assessed. The presence of viability as defined in this study did not identify a group of patients who had a differential response to CABG.²⁹ Identifying specific subgroups of ischemic cardiomyopathy patients for whom surgical revascularization may be beneficial remains an important topic for future clinical trial investigations.

Ischemic heart Failure, Pulmonary Hypertension, and Thromboembolism

Pulmonary hypertension (PH), defined currently³⁰ as a mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, is an independent risk factor for death in patients with HF as a result of ischemic heart disease. In this scenario, left atrial hypertension due to impaired LV systolic function induces pulmonary vascular congestion and is linked to right HF.³¹ Atrial fibrillation is the most common arrhythmia among patients with ischemic HF; ventricular tachycardia is of greatest clinical concern. Sustained monomorphic ventricular tachycardia may arise in or near an area of myocardial scar formation, whereas polymorphic ventricular tachycardia or ventricular fibrillation may occur as a consequence of acute ischemia, electrolyte imbalance, or drug effect. Indeed, unstable ventricular arrhythmias may occur in SIHD patients even in the absence of significant changes in clinical status. Patients with atrial fibrillation (see Chap. 83) or those with specific, acquired forms of structural heart disease (eg, LV aneurysm or LV apical akinesis) are at increased risk for systemic thromboembolism. Anticoagulant therapy is indicated for stroke prevention according to the patient’s individualized risk profile and in alignment with published clinical management guidelines.

Coronary atherosclerotic plaque formation occurs as a consequence of aberrant molecular signaling pathways that increase vascular inflammation, induce injury to blood vessel wall cellular components, and promote adverse vascular remodeling.³² An understanding of the cellular mechanisms that contribute to atherogenesis has helped focus efforts on imaging modalities for detection and characterization of CAD. Cardiac computed tomography (CT) is very sensitive for the detection of coronary artery calcifications, the imaging signature of chronic atherosclerosis.³³ Molecular imaging techniques for quantitative evaluation of plaque inflammation may help identify at-risk lesions in vulnerable patients, but are not used in routine practice. Progress in catheter-based infrared fluorescence, plaque thermography, contrast-enhanced magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (PET) suggests that clinical applicability of these modalities for real-time diagnosis and enhanced characterization of CAD may be realized.^34,35 For example, ¹⁸F-sodium fluoride PET, which localizes to osteogenic (ie, calcific) activity, has been used to delineate culprit from nonculprit coronary lesions in small clinical studies.³⁶ Coupling intravascular ultrasound with high-resolution optical coherence tomography in a single device has also been used in vivo and paves the way for simultaneous near-field assessment of vascular wall contour and plaque penetration depth.³⁷

The Vulnerable Plaque/Vulnerable Patient

Predicting future cardiovascular events in patients with CAD remains a difficult task. The identification of specific patients who are at elevated risk for acute MI as a result of the presence of certain atherosclerotic lesion characteristics and/or clinical factors is a central focus of evaluation and management strategies in clinical practice. Ongoing research is focused on discriminating at-risk atherosclerotic lesions based on propensity for rupture, rapid progression in size, or the expression of other features that suggest a high likelihood for future thrombotic complications.³⁴ Collectively, these characteristics describe a vulnerable plaque; the attributes of such a lesion predict a higher likelihood of thrombosis, MI, and/or ventricular arrhythmias (see Chap. 37 for detailed discussion of myocardial ischemia and MI). Active inflammation, large lipid core and thin fibrous cap, and luminal stenosis of > 90% are some of the key criteria used to identify the vulnerable plaque (Table 43–3). Although plaque risk stratification remains within the preclinical domain, there is accumulating evidence to suggest that cutting-edge diagnostic methods may be able to discern plaque stability in patients in the future. In one study of 203 patients undergoing coronary angiography, an increased lipid plaque burden index detected by near-infrared spectroscopy was independently associated with future major adverse cardiac events.³⁸ Similar findings are reported for cardiac CT coronary angiography, in which the relationship between certain plaque features (eg, luminal stenosis, positive remodeling, low-attenuation plaques) and adverse clinical events has been demonstrated in studies involving over 21,000 CAD patients.³⁹

In the current era, widespread use of statin therapy has attenuated the inflammatory burden of atherosclerotic lesions, which has led some to emphasize other mechanisms, particularly factors promoting superficial erosion leading to fibrous remodeling, for defining the vulnerable plaque. This proposed shift may provide a pathobiological correlate to trends suggesting a recent decrease in the prevalence of ST-segment elevation MI (STEMI), (ie, plaque rupture) with a corresponding relative increase in the prevalence of non–ST-segment elevation MI (NSTEMI) in which culprit lesions tend to be fibrous (see Chap. 37 for pathobiology of MI).³² In addition, the vulnerable plaque concept has been expanded in recent years to include vulnerable patients at risk for an ACS or sudden cardiac death (SCD) based on their metabolic, atherogenic, hematologic, and/or myocardial substrate. Examples include patients with metabolic syndrome, CAD, and hypercoagulable disorders, and patients with certain forms of cardiomyopathy that predispose to electrical-mechanical instability and unstable arrhythmias.^32,34

Conventional Risk Factors

There is a great deal of overlap between conventional risk factors associated with the de novo development of atherosclerosis and those that promote progression of existing disease. Identifying treatable risk factors in patients with chronic CAD should be accomplished as recommended by the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for secondary prevention and cardiac rehabilitation.⁴⁰ These guidelines call for a nine-point strategy focused on specific biochemical, psychosocial, and exercise training–associated goals to decrease the progression of chronic CAD and its manifestations (Table 43–4). Interventions that decrease the incidence of ischemic events include those that lead to reductions in cigarette smoking, low-density lipoprotein (LDL) cholesterol, systemic hypertension, LVH, and factors that promote thrombosis.

Numerous observational studies have demonstrated a positive, continuous, and graded relationship between systemic blood pressure and cardiovascular disease risk.^41,42 In SIHD patients, hypertension is a risk factor for recurrent MI, an observation that is likely a consequence of the associated endothelial dysfunction and the adverse effects of persistently elevated afterload on myocardial function and oxygen demand. In patients with diabetes, uncontrolled hypertension is a strong predictor of premature death, cardiovascular morbidity, and progressive nephropathy. The Systolic Blood Pressure Intervention Trial (SPRINT) tested whether the conventional systolic blood pressure (SBP) goal of 140 mm Hg is sufficient to reduce cardiovascular events in nondiabetic, nonstroke patients at increased cardiovascular risk. Compared to a standard treatment goal SBP < 140 mm Hg, patients randomized to intensive therapy (SBP < 120 mm Hg) had lower risk for the composite end point of MI, other ACSs, stroke, HF, or death from cardiovascular causes at 1 year (HR, 0.75; 95% CI, 0.64-0.89; P < .001). Directionally similar findings were observed for all-cause mortality, although the beneficial effects of intensive therapy were associated with an attendant increase in the number of medications prescribed, systemic hypotension, syncope, electrolyte abnormalities, and acute kidney injury.⁴³

The presence of LVH or increased LV mass confers an increased risk for incident MI, HF, and SCD in patients with SIHD, as well as in community-based populations of adults free of known CAD.^44,45 It has been proposed that the risk imposed by LVH may be reversible. For example, ECG evidence of LVH regression in treated hypertensive patients is associated with a significant reduction in cardiovascular disease event rates.⁴⁶

Socioeconomic, Environmental, and Iatrogenic Factors

Early Life Programming and Ischemic Heart Disease

In addition to the conventional risk factors associated with coronary heart disease events discussed earlier, novel associations between environmental risk factors and the progression of ischemic heart disease have been identified. Barker and Osmond⁴⁷ first proposed that perinatal factors such as low birth weight or intrauterine growth restriction increased the risk for chronic cardiovascular disease in adulthood. These findings are supported further by recent data suggesting, more specifically, that birth weight < 2500 g or > 3500 g forecasts subclinical atherosclerosis in adulthood, as assessed by abnormal carotid intima medial thickness.⁴⁸

Socioeconomic Factors, Geography, Environmental Exposures, and Ischemic Heart Disease

An inverse association between income status or education level and revascularization has been reported in the United States,⁴⁹ whereas Gerber and colleagues⁵⁰ demonstrated that low socioeconomic status and limited access to health care confer a significantly elevated risk for adverse long-term (~10 years) outcome in post-MI patients.⁵¹ Chronic exposure to air pollution (ie, fine particulate pollution) is also associated with an increased risk of coronary heart disease mortality that is believed to occur as a consequence of increased vascular inflammation or dysregulation of cardiovascular autonomic function. Conversely, SIHD patients in rural geographic locations appear to demonstrate lower rates of cholesterol assessment and statin use and register fewer ambulatory physician visits as compared to urban patients,⁵² although it is not known whether this accounts for differential trends in CAD prevalence across these settings.

The role of substance abuse in the development and progression of CAD is increasingly recognized. The adverse effects of tobacco use, including exposure to second-hand smoke, on the cardiovascular system are well established.⁵³ It is estimated that tobacco use alone is responsible for approximately 467,000, or 20%, of all deaths in the United States annually.⁵⁴ Perhaps equally important is the prevalence of recreational cocaine use and its contribution to coronary heart disease. Nearly 34 million people in the United States have reported a history of cocaine use, of whom approximately 1% report use within the last month.⁵⁵ Cocaine can accelerate coronary atherosclerosis, enhance platelet aggregation, induce coronary vasospasm, and increase myocardial oxygen demand via its effects on heart rate and blood pressure.⁵⁶

Risk factors for CAD unique to low- and middle-resource countries include psychosocial stress associated with migration, massive pollution, inadequate sanitation, persistently elevated rates of tobacco use and second-hand tobacco exposure, and limited opportunities to exercise. In addition, other factors, such as body weight, should be considered when considering coronary heart disease risk in patients from low- and middle-resource countries.⁵⁷

Malignancy, Human Immunodeficiency Virus, and Ischemic Heart Disease

Treatment of several noncardiac medical conditions, such as various malignancies, may also predispose to coronary heart disease events in vulnerable populations. Mantle radiation for the treatment of Hodgkin lymphoma is associated with a significantly increased incidence of proximal CAD, higher coronary artery calcification scores (see Coronary Artery Calcification Score in Ischemic Heart Disease section), and an elevated likelihood of the need for revascularization therapy.⁵⁸ Several chemotherapeutic agents, particularly 5-fluorouracil, capecitabine, nilotinib, ponatinib, temsirolimus, thalidomide, and lenalidomide, are linked to the development of angina from epicardial or microvascular abnormalities.⁵⁹ Although patients with orthotropic heart transplantations may develop epicardial CAD, graft failure long term is most commonly a result of a diffuse, small-vessel arteriopathy that is immune mediated.⁶⁰ Patients infected with the human immunodeficiency virus (HIV) appear to be at increased risk for a wide range of inflammatory vascular diseases, including CAD. This may occur as a manifestation of HIV itself; low CD4⁺ T-cell count has been associated with the presence of coronary artery stenotic lesions > 50% of luminal diameter.⁶¹ Alternatively, CAD in HIV-infected individuals could occur as a consequence of highly active antiretroviral therapy (HAART) use.⁶² Compared to HIV-negative patients, the prevalence of noncalcified coronary plaques is approximately three-fold higher in HIV-positive patients on HAART therapy (odds ratio [OR], 3.26; 95% CI, 1.30-8.18),⁶³ which may account for parallel findings in similar patients suggesting that the risk of incident MI is increased approximately four-fold.⁶⁴ The mechanistic link between HAART and CAD remains speculative but may involve cross-reactivity between protease inhibitors and lipid metabolism–regulating proteins that results in dyslipidemia, insulin resistance, central adiposity, and lipodystrophy.^62,65 In selected HIV patients at elevated risk for cardiovascular disease, protease inhibitors may be inappropriate; under these circumstances, consultation with an infectious disease specialist to determine optimal HIV therapy is advised, as is the early institution of aggressive risk factor control (eg, statin therapy).

Technologic advances in the past two decades have expanded the noninvasive options available for diagnosis and risk stratification of patients with chronic CAD. Although guidelines and appropriate use criteria have been published, practice patterns vary widely in the application of testing to the individual patient. Noninvasive testing, with or without imaging as dictated by specific patient attributes, is appropriate for the vast majority of patients. There are high-risk clinical features, however, that would substantiate the use of invasive coronary angiography as the first step (Fig. 43–1).

Exercise Electrocardiogram Stress Testing

Numerous studies involving thousands of patients have validated the prognostic utility of ECG treadmill testing. Data from patients with medically managed SIHD enrolled in the Coronary Artery Surgery Study (CASS) demonstrated that failure to complete stage 1 of a standard Bruce protocol was associated with a markedly elevated mortality 4 years after testing.¹⁷ Others have shown that the presence of exercise-induced ST-segment depression, an abnormal blood pressure response to exercise, and poor functional capacity on stress testing are associated with early mortality from cardiovascular disease.⁶⁶

The Duke Treadmill Score (DTS) is commonly used in clinical practice for predicting the probability of a future MI or cardiovascular death in patients with CAD, and is widely available at point of care, including via the use of the DTS smartphone mobile application. In this model, a numeric score is generated that reflects patient exercise time, extent of ST-segment depression, and presence of anginal symptoms. The DTS correlates with future cardiovascular mortality; is valid in the era of diuretics, renin-angiotensin-aldosterone axis inhibitors, and β-adrenergic receptor antagonists; and is predictive in both men and women.⁶⁷ The DTS and other similar models that use functional capacity and ECG findings as the chief performance measures may be confounded by baseline ECG abnormalities and limitations to exercise from noncardiovascular causes. These scoring systems do not include information regarding the anatomic distribution, extent, and severity of ischemia, nor do they involve an assessment of LV function during exercise stress. Access to these data often enhances the prognostic valve of stress testing and provides the clinician with a more informed understanding of ischemic burden from which to guide treatment decisions in specific patients.⁶⁸ Importantly, cardiopulmonary exercise testing, which is being used increasingly to evaluate patients with unexplained dyspnea, does not use a standardized protocol for provoking ischemia. Instead, this method identifies ischemia as a cause of symptoms occurring during exercise, and clinicians intending to assess inducible ischemia should rely on standardized exercise protocols (eg, Bruce protocol) validated for this purpose.

Rest and Stress Echocardiography

Resting transthoracic echocardiography is useful to characterize LV systolic and diastolic function in patients with SIHD, especially in those with prior MI and HF. Reduced LVEF is strongly associated with an increased risk for incident ventricular tachycardia and SCD. In select patients following MI, low ejection fraction (EF) alone (≤ 0.30) is sufficient to warrant certain forms of device therapy, such as an implantable cardioverter-defibrillator (ICD). In ischemic cardiomyopathy patients (EF ≤ 0.35) with HF symptoms, ICD therapy for primary prevention of SCD is also indicated. Stress echocardiography is more sensitive and specific than ECG stress for the detection of CAD. In patients with chronic CAD, the presence of LVH, diminution in systolic wall thickening in one or more segments during stress, or compensatory hyperkinesis in nonischemic segments portends increased risk for future cardiovascular events.^69,70

Myocardial Perfusion Imaging

Myocardial perfusion imaging (MPI) typically involves SPECT with visual and quantitative analysis. There is increasing experience with PET. Attenuation correction algorithms improve SPECT test performance. ECG gating is used for analysis of global and regional LV performance. Table 43–5 summarizes the comparative advantages of stress SPECT MPI and stress echocardiography for CAD diagnosis. A normal stress MPI study in a patient with an ischemic ECG response to exercise defines a favorable prognosis for which an invasive treatment strategy is usually not justified, especially if an adequate workload was achieved during the study.⁷¹

Abnormal stress MPI in patients with established CAD is predictive of cardiac death and nonfatal MI.⁷² Transient, stress-induced LV dilation and a decrease in EF of > 5% are independent predictors of cardiac death and are useful in risk stratification of patients with chronic CAD.⁷³ Stress cardiac MRI is sensitive, predicts territorial ischemia accurately, and is not subject to breast or gastrointestinal signal attenuation that may confound the interpretation of SPECT imaging results in women.⁷⁴ Provocable ischemia on stress MRI enhances the discriminatory value of conventional risk stratification methods by up to seven-fold and, in one study, resulted in reclassification of 91% of patients at moderate risk (65.7% to low risk; 25.8% to high risk).⁷⁵ Abnormal CFR on MPI can be a prognostic marker in patients without overt CAD. In a cohort of 761 patients undergoing evaluation for CAD in whom a prior positive cardiac biomarker was known, decreased CFR was associated with major cardiovascular events over a 2.8-year period compared to patients with normal CFR (HR, 2.25; 95% CI, 1.31-3.86; P = .003).⁷⁶ Converging data suggest that CFR may be useful in place of diagnostic angiography for quantifying ischemic burden in patients without significant epicardial coronary stenoses for whom small-vessel CAD is believed to be responsible for cardiovascular events.⁷⁷

The Clinical Implication of High Ischemic Burden on Myocardial Perfusion Imaging Testing

MPI data are useful for identifying high-risk chronic stable CAD patients for whom revascularization therapy may be appropriate.⁷⁸ Table 43–6 summarizes criteria for high, intermediate, and low risk based on noninvasive diagnostic testing. Referral for angiography to search for CAD extensive enough to warrant surgical revascularization is reasonable for patients with high-risk features. A subset analysis of 314 patients from the COURAGE trial suggested that adding PCI to OMT may be more efficacious than OMT alone for the treatment of SIHD patients when a quantitative ischemic burden exceeding 10% of the myocardium is established.^78,79,80 Furthermore, a decrease in ischemic burden by ≥ 5% with either PCI plus OMT or OMT alone resulted in a significant increase in event-free survival over 5 years (Fig. 43–2). These data suggest that a large myocardial ischemic burden on MPI testing may be a useful metric for the consideration of PCI as an initial treatment strategy. These subgroup analyses should be considered hypothesis generating and await prospective validation in larger numbers of patients with multivessel CAD (see later section on ISCHEMIA Trial).

Coronary Computed Tomographic Angiography

Coronary CT angiography (CCTA) provides an anatomic assessment of the epicardial coronary arteries. Because of its high spatial resolution and negative predictive value, CCTA is especially helpful to exclude important CAD in patients with a low pretest likelihood of disease. CCTA is also well suited to visualize suspected congenital coronary artery anomalies and great vessel anatomy. Appropriate use criteria for advanced testing, including CCTA and stress imaging, are provided in Table 43–7. The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) study evaluated CCTA as an initial diagnostic strategy for symptomatic patients with CAD (n = 10,003). Compared to exercise stress testing, CCTA did not result in a reduction in the composite end point of death, MI, hospitalization for unstable angina, or major procedural complications at 25 months (3.3% vs 3.0%; adjusted HR, 1.04; 95% CI, 0.83-1.29; P = .75), although patients in the CCTA arm underwent fewer diagnostic coronary angiograms indicating no obstructive CAD (3.4% vs 4.3%; P = .02).⁸¹ Overall, routine use of this technology in those with SIHD is not recommended.⁸²

Coronary Artery Calcification Score in Ischemic Heart Disease

Coronary artery calcification observed on cardiac CT strongly correlates with the presence of established atherosclerosis.⁸³ The coronary artery calcification score is a quantitative measure of overall vascular calcium burden. The presence of calcium in the vessel wall does not correlate with the degree of luminal obstruction, although the overall burden may predict future coronary heart disease events.⁸⁴ Serial coronary artery calcification scoring to assess the rate of disease progression is not recommended.⁸⁵

Invasive Coronary Angiography

Referral for invasive coronary angiography in patients with SIHD is most often indicated for refractory symptoms or high-risk features on noninvasive testing and serves as a prelude to revascularization. In individuals with symptoms suggestive but not diagnostic of CAD, invasive angiography may be appropriate if their occupations constitute a risk to themselves or others (eg, airline pilots, firefighters, others).⁸⁶ In certain patients for whom the diagnosis of CAD on clinical grounds may be elusive as a result of atypical chest pain characteristics or asymptomatic ischemia (eg, patients with diabetes), a lower threshold for coronary angiography may be appropriate. As a result of atypical symptomatology and relatively lower diagnostic accuracy rates on conventional stress testing, women are more frequently considered for invasive angiography in the setting of an ambiguous presentation and/or inconsistent noninvasive data, but consideration of this approach should be weighed against the low, but finite, risks of the procedure. Moreover, findings from population studies suggest that in the United States, coronary angiography may be overused as an initial diagnostic test for CAD.⁸⁷ In fact, invasive angiography should not be considered as the first diagnostic strategy in women patients presenting with atypical chest pain or who are at low risk for CAD. Additional indications for invasive angiography include the evaluation of CAD in patients with reduced EF (< 0.40), patients surviving SCD, or patients with ventricular arrhythmias and a high or intermediate likelihood of CAD.⁸⁶

Goal-directed therapy in the management of SIHD is focused on (1) prevention of death and MI and (2) reducing symptoms and signs of myocardial ischemia. The intensity of treatment is dictated by the magnitude of risk and the severity of the ischemic burden. The decision to initiate medical, percutaneous, surgical, or hybrid treatment is developed in the context of a patient’s specific clinical, coronary angiographic, and LV functional profiles. Patient values and preferences should also be taken into account.

Antiplatelet Therapy

Aspirin exerts an antithrombotic effect by irreversibly inhibiting cyclooxygenase-1 and the downstream synthesis of platelet thromboxane A₂. In the Physicians’ Health Study, aspirin given on alternative days to asymptomatic men was associated with a decreased incidence of MI.⁸⁸ In the Swedish Angina Pectoris Aspirin Trial, SIHD patients receiving 75 mg of aspirin demonstrated an approximately 33% reduction in MI, sudden death, and vascular events compared with placebo.⁸⁹ In 2009, the Antithrombotic Trialists’ Collaboration Group published a meta-analysis of 16 randomized placebo-controlled trials evaluating the effect of aspirin on future vascular events (eg, MI, stroke, or vascular death) in approximately 17,000 patients with established CAD.⁹⁰ Treatment with aspirin significantly decreased the rate of major vascular events, particularly MI (4.3% vs 5.3% per year; rate ratio [RR], 0.69; 95% CI, 0.60-0.80) and stroke (2.08% vs 2.54% per year; RR, 0.81; 95% CI, 0.71-0.92), without inducing a significant increase in the risk of hemorrhagic stroke. Daily use of aspirin (75-162 mg/d) for secondary prevention of MI in both men and women with SIHD is an AHA/ACC Class I recommendation.⁸⁶ Low-dose aspirin (75 or 81 mg) is recommended for maintenance therapy in combination with P2Y₁₂ inhibitors for patients who undergo PCI.

Clopidogrel is used in combination with aspirin as part of a strategy of dual antiplatelet therapy (DAPT) following PCI in patients with SIHD or ACS (including unstable angina, NSTEMI, and STEMI). The recommended minimal duration of DAPT after PCI with non–first-generation drug-eluting stents (DESs) is 6 months for patients with SIHD and 12 months for patients with ACS, but this remains a “moving target” with the introduction of newer generation stents. Minimal DAPT duration differs for patients treated with bare metal stents (30 days). Based on the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) study, clopidogrel is also provided for up to 1 year in patients with non–ST-segment elevation ACS managed medically.⁹¹ Clopidogrel is a Class I recommendation for STEMI patients treated with fibrinolysis or not receiving reperfusion therapy, with an intended 1-year course of treatment.⁹² Because of their superior efficacy, prasugrel and ticagrelor, two other P2Y₁₂ inhibitors, are preferred over clopidogrel for maintenance therapy (in combination with low-dose aspirin) after PCI for ACS, provided there are no contraindications to their use. Neither prasugrel nor ticagrelor has been studied in the setting of PCI for SIHD, and thus, only clopidogrel is approved for this indication. Prasugrel should not be used in patients with prior stroke or transient ischemic attack and is generally avoided in patients aged over 75 years or of low body weight (< 60 kg) because of a lack of net clinical benefit.

Interest in extended-duration DAPT stems in part from a subgroup analysis of post-MI patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial that demonstrated nearly a 25% reduction in a composite end point of cardiovascular death, MI, and stroke with clopidogrel plus aspirin compared with aspirin alone.⁹³ Several underpowered trials have examined the utility of long-term DAPT in patients after PCI across a spectrum of clinical indications (reviewed in Wang et al⁹⁴ and Keach et al⁹⁵). The DES arm of the Dual Antiplatelet Therapy (DAPT)⁹⁶ study randomized 9961 patients who were clinically stable and without bleeding complications 12 months after PCI (38% for stable angina) to an additional 18 months of aspirin plus a thienopyridine (clopidogrel or prasugrel) or aspirin alone. Prolonged DAPT was associated with a significant reduction in stent thrombosis and MACCE, at the expense of an increased risk of bleeding. The treatment benefit was driven by a reduction in MI related to both stent thrombosis and de novo events in other locations. There was an increased rate of ischemic events over the 3 months after cessation of thienopyridine therapy at completion of the trial. The small absolute increase (0.5%) in total mortality for patients treated with DAPT in this study has not been observed in other studies of DAPT for both cardiac and neurologic indications. The US Food and Drug Administration performed a separate meta-analysis and concluded that there is not an incremental mortality risk with DAPT.

The Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial assessed the effects of DAPT on cardiovascular death, MI, and stroke in patients 1 to 3 years after MI.⁹⁷ A total of 21,612 post-MI patients were randomized to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, in addition to aspirin. At a median follow-up of 33 months, there were small but significant reductions in the composite primary end point in both ticagrelor arms (HR, 0.85 for ticagrelor 90 mg; 95% CI, 0.75-0.96; P = .008; HR, 0.84 for ticagrelor 60 mg; 95% CI, 0.74-0.95; P = .004) compared to placebo (Fig. 43–3). For every 10,000 patients treated with ticagrelor 90 mg twice daily, 40 primary end points would be prevented at the expense of 41 Thrombolysis in Myocardial Infarction (TIMI) major bleeds; for every 10,000 patients treated with ticagrelor 60 mg twice daily, 42 primary end points would be averted at the expense of 31 TIMI major bleeds. The US Food and Drug Administration has approved the 60-mg ticagrelor dose in combination with aspirin (81 mg) for secondary prevention. Follow-up analyses of the PEGASUS-TIMI 54 trial suggested that the benefit of adding ticagrelor to aspirin for long-term secondary prevention is more marked for post-MI patients continuing on or restarting P2Y₁₂ inhibition after only a brief interruption, especially when compared with patients who have declared themselves stable for 2 or more years after MI and off P2Y₁₂ inhibitor therapy for more than 1 year.⁹⁸ Data assessing the role of prasugrel under similar clinical circumstances are lacking.

Protease-activated receptor (PAR)-1 antagonism with vorapaxar inhibits thrombin-induced activation of platelets. Morrow and colleagues⁹⁹ tested the effect of vorapaxar on outcomes in a 26,449 patients with SIHD, defined in this study as prior history of MI, ischemic stroke, or peripheral artery disease. At 2 years of follow-up, patients randomized to treatment with vorapaxar 2.5 mg daily had a significant decrease in the risk of cardiovascular death, MI, stroke, or ischemia requiring revascularization compared to placebo (HR, 0.88; 95% CI, 0.82-0.95; P = .001). However, the risk for moderate or severe bleeding was also increased significantly in the treatment arm (HR, 1.66; 95% CI, 1.43-1.93; P < .001), and the study was discontinued early for patients with a history of intracranial hemorrhage. When considering bleeding risk as part of the overall study outcome, there was no difference between groups for the prespecified composite end point of cardiovascular death, MI, stroke, or moderate/severe bleeding (HR, 0.97; 95% CI, 0.90-1.04; P = .40). Decisions regarding long-term DAPT with P2Y₁₂ inhibitors or use of vorapaxar must be individualized, taking into account ischemic risk versus bleeding hazard.

Anticoagulant Therapy

Oral anticoagulant therapy with a vitamin K antagonist such as warfarin is an effective strategy to prevent recurrent MI when the dose is titrated to a target international normalized ratio (INR) of 2.0 to 3.0.¹⁰⁰ Hurlen and colleagues¹⁰¹ randomized 3630 post-MI patients to warfarin, aspirin, or combination warfarin plus aspirin for 4 years. Compared with aspirin alone, warfarin or combination warfarin plus aspirin conferred an approximate 19% relative risk reduction for the primary composite end point of death, nonfatal recurrent MI, or stroke. However, warfarin was associated with an elevated rate of major (nonfatal) bleeding complications. Under most circumstances, long-term treatment with aspirin is favored over vitamin K antagonist therapy for the secondary prevention of MI in patients with SIHD, unless an independent indication for warfarin use is present (such as atrial fibrillation).¹⁰²

Direct oral anticoagulants are used for stroke prevention in patients with atrial fibrillation and elevated CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) scores and for the management of venous thromboembolism. Early studies with dabigatran showed an increased risk with this agent for MI compared with warfarin.¹⁰³ Low-dose rivaroxaban has been used in combination with DAPT in patients with ACS and is associated with decreased rates of hard clinical end points but with increased bleeding risk.¹⁰⁴ Management of patients who require long-term anticoagulation (eg, mechanical valve, atrial fibrillation with CHA₂DS₂-VASc score > 2) and DAPT after ACS must be individualized to strike the appropriate balance between the risks of stent thrombosis and bleeding. Consideration of bare metal stent use to shorten the duration of DAPT and use of warfarin targeted to a lower therapeutic INR range (2.0-2.5) have been recommended.¹⁰⁵ There is limited experience with both direct oral anticoagulants and P2Y₁₂ inhibitors other than clopidogrel in this context. The What Is the Optimal Antiplatelet and Anticoagulation Therapy in Patients With Oral Anticoagulation Trial (WOEST) was an open-label, multicenter, clinical study in Belgium and the Netherlands testing the effect on outcome of clopidogrel alone or combination therapy with clopidogrel plus aspirin in PCI patients on standing anticoagulant therapy with warfarin (n = 573). There was significantly less bleeding in patients assigned to double therapy (warfarin plus clopidogrel) compared to patients assigned to aspirin, clopidogrel, and warfarin (HR, 0.36; 95% CI, 0.26-0.50; P < .0001) without an attendant increase in MI, cardiac death, stroke, or stent thrombosis at 1 year of follow-up.¹⁰⁶ Additional studies are in progress.

Lipid-Lowering Therapy

Previous secondary prevention recommendations emphasized aggressive lipid management to a target LDL cholesterol < 100 mg/dL for all ischemic heart disease patients or < 70 mg/dL if it can be safely achieved in high-risk patients.⁴⁰ Current guideline recommendations emphasize use of moderate- or high-intensity statin therapy for four patient groups, including those with SIHD. Specifically, in patients aged ≤ 75 years with a history of a prior cardiovascular event, high-intensity statin therapy (eg, rosuvastatin 20-40 mg daily or atorvastatin 40-80 mg daily) is recommended; moderate-intensity statin therapy (eg, rosuvastatin 10-20 mg daily or atorvastatin 20-40 mg daily) is recommended for SIHD patients > 75 years of age. Contraindications to drug therapy, including drug-drug interactions or drug intolerance, should be used to influence dose selection. The Scandinavian Simvastatin Survival Study (4S) demonstrated that treatment with simvastatin in patients with SIHD and a baseline total cholesterol > 210 mg/dL was associated with an approximate 35% reduction in mortality and major coronary event rates.¹⁰⁷ In the Cholesterol and Recurrent Events (CARE) study, men and women with previous MI, total cholesterol levels < 240 mg/dL, and LDL cholesterol levels of 115 to 174 mg/dL treated with pravastatin demonstrated a 24% reduction in the risk of future MI compared with placebo.¹⁰⁸ LaRosa and colleagues¹⁰⁹ tested the hypothesis that high-dose statin therapy is superior to low-dose statin therapy for the secondary prevention of cardiovascular events in patients with SIHD. In the randomized, prospective Treating to New Targets (TNT) trial, 10,001 such patients (enrollment LDL < 130 mg/dL) were randomized to receive 80 or 10 mg of atorvastatin daily over 6 years. Patients treated with 80 mg of atorvastatin achieved a mean LDL cholesterol level of 77 mg/dL versus 101 mg/dL for those allocated to 10 mg of atorvastatin. High-dose atorvastatin therapy was associated with a 22% relative risk reduction for the combined primary end point of death from ischemic heart disease, nonfatal MI, or stroke.¹⁰⁹ The lowest optimal level of LDL cholesterol for primary or secondary prevention has not been established.

Stitziel and colleagues in collaboration with the Myocardial Infarction Genetics Consortium Investigators sequenced exons of the NPC1L1 protein in a large cohort of patients with coronary heart disease and in normal controls and reported that carriers of inactivating mutations had LDL cholesterol levels that were 12 mg/dL lower than in noncarriers (P = .04). Carrier status was associated with a relative reduction in risk for coronary heart disease events of 53% (OR, 0.47; 95% CI, 0.25-0.87; P = .008).¹¹⁰ These findings coincided with clinical trial data from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) suggesting that simvastatin (40 mg daily) in combination with ezetimibe (10 mg daily), which targets the NPC1L1 gene, was more effective than simvastatin alone for decreasing LDL levels and cardiovascular events at 6 years after ACS.¹¹¹ Alirocumab and evolocumab are monoclonal antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9), which degrades hepatic LDL receptors. These therapies have been approved for the treatment of patients who are heterozygous for familial hypercholesterolemia and in patients with clinical atherosclerotic disease who require additional LDL cholesterol lowering or are unable to tolerate guideline-recommended doses of statins plus ezetimibe.

β-Adrenergic Receptor Antagonists

β-Adrenergic receptor antagonists (when administered orally) are associated with increased short- and long-term survival rates in post-MI patients.^112,113,114 The use of these agents in the acute phase of MI has been influenced by the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) results.¹¹⁵ Numerous long-term trials of β-adrenergic receptor antagonists attest to their efficacy for secondary prevention of recurrent MI and cardiac death, but to date, no trial has tested whether β-blockers reduce mortality in patients with SIHD, years after or without antecedent MI. In general, their effectiveness is relatively greater among higher risk patients, particularly among those with reduced EF, HF, or ventricular arrhythmias. In lower risk patients, however, β-adrenergic receptor antagonists are recommended only for up to 3 years after uncomplicated MI without other relative indications (eg, atrial fibrillation, reduced EF). In patients with SIHD and HF, treatment should be restricted to the use of carvedilol, long-acting metoprolol, or bisoprolol, agents shown to reduce adverse outcomes in this population.^116,117,118 On a physiologic level, β-adrenergic receptor antagonists favorably influence myocardial oxygen supply-demand balance by reducing heart rate, myocardial contractility, systemic arterial pressure, and LV wall stress. The reduction in heart rate may also allow for enhanced CBF as a result of longer diastolic filling times, and anginal frequency and nitroglycerin use are decreased.¹¹⁹

The therapeutic benefit of β-adrenergic receptor antagonists appears to be a class effect with the exception of agents that express intrinsic sympathomimetic activity. In patients with severe angina (ie, CCS class III/IV), full drug efficacy depends largely on dose titration to achieve a heart rate ≤ 60 bpm at rest or ≤ 75 bpm with exertion (or ≤ 75% of the heart rate at which angina occurs). Ambulatory monitoring may be necessary to ensure that severe bradycardia (ie, ≤ 40 bpm) or advanced atrioventricular (AV) block does not occur.

Recent registry data affirm earlier findings that the benefit of β-adrenergic receptor antagonists is observed principally in the post-MI period. Observational data from the Reduction of Atherothrombosis for Continued Health (REACH) registry, for example, demonstrated that among a total cohort of 44,708 patients, rates for the composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke did not differ relative to β-adrenergic receptor antagonist use in patients with CAD without prior MI, with remote history of MI, or with only risk factors for CAD.¹²⁰ The initiation of β-adrenergic receptor antagonists following MI and continuing for 3 years is a Class I indication in patients with normal LV function. Use of β-adrenergic receptor antagonists is also a Class I indication in patients with LV systolic dysfunction and HF or prior MI, unless contraindicated.¹²¹

Fatigue, lethargy, insomnia, nightmares, worsening claudication, and impotence are potential adverse effects and may adversely affect medication adherence. Absolute contraindications to the use of β-adrenergic receptor antagonists include severe bradycardia (heart rate < 60 bpm at rest), preexisting AV block (PR interval > 0.24 seconds, second- or third-degree AV block), sick sinus syndrome, or acutely decompensated HF. Asthma, severe depression, brittle diabetes, and peripheral vascular disease are relative contraindications that require cautious use, but β-adrenergic receptor antagonists may be an important part of medical management strategies in patients with these disorders and as a rule tend to be underused in patients with chronic obstructive pulmonary disease in particular.

β-Adrenergic receptor antagonists are frequently used in combination with other antianginal medications for maximum benefit and symptom control. Adding a β-adrenergic receptor antagonist to nitrates, for example, appears more effective in controlling anginal symptoms than monotherapy with either agent alone.¹²² Similar observations have been made with combination calcium channel blockers (CCBs); long-acting dihydropyridine derivatives are preferred to avoid excessive bradycardia in this setting.^86,122

Calcium Channel Blockers

CCBs decrease vascular smooth muscle cell and cardiac myocyte transmembrane calcium flux. They induce vasodilatation of epicardial coronary arteries to improve CBF and attenuate vasospastic and exertional angina. CCBs also improve angina by lowering systemic vascular resistance and mean arterial blood pressure to decrease LV afterload, thereby decreasing myocardial oxygen demand. The negative inotropic effects of these agents also favorably influences myocardial oxygen supply-demand balance, but may affect cardiac function adversely in patients with significantly impaired LV function. In patients with normal LV systolic function, CCBs may result in increased myocardial contractility as a compensatory response to lowered systemic vascular resistance.

Antianginal efficacy with CCBs is comparable to that obtained with β-adrenergic receptor antagonists.⁴² However, the efficacy of CCB monotherapy for reducing MI or cardiac death in patients with SIHD has not been demonstrated convincingly. The primary indications for CCB therapy include blood pressure or heart rate control and alleviation of anginal symptoms after optimization of β-adrenergic receptor, nitrate, and angiotensin-converting enzyme inhibitor therapy.

Renin-Angiotensin-Aldosterone System Inhibitors

Several randomized controlled trials in support of long-term angiotensin-converting enzyme (ACE) inhibition for the reduction of cardiovascular death, recurrent MI, and stroke in intermediate- and high-risk patients with SIHD have been reported. The Heart Outcomes Prevention Evaluation (HOPE) study tested the efficacy of ramipril (10 mg/d) on cardiovascular outcomes in a large cohort of patients with CAD, stroke, peripheral vascular disease, or diabetes plus at least one other cardiovascular risk factor.¹²³ Patients with comorbid HF were excluded, and participants were not known to a have a decreased LVEF. Compared with placebo, ramipril therapy resulted in a significant reduction in the rate of death from cardiovascular causes, MI, stroke over 5 years (14.0% vs 17.8%; RR, 0.78; 95% CI, 0.70-0.86). ACE inhibitor therapy also reduced incident diabetes. In the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), a trial that enrolled patients with chronic CAD and relatively lower risk profiles, perindopril therapy was associated with a directionally similar reduction in cardiovascular disease outcomes.¹²⁴ The consequences of adding perindopril to standing β-adrenergic receptor antagonist therapy were analyzed in a retrospective analysis of the EUROPA trial. This subgroup study showed that combination therapy reduced the relative risk of the primary end point of cardiovascular death, nonfatal MI, or resuscitated cardiac arrest by 24% compared with placebo plus β-adrenergic receptor antagonist therapy (HR, 0.76; 95% CI, 0.64-0.91; P = .02).¹²⁵ The salutary effects of ACE inhibitors were not as firmly established among lower risk patients enrolled in the Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy (PEACE) trial, especially among patients with normal LV function, optimal lipid profiles, and prior revascularization.¹²⁶ ACE inhibitors are a Class I recommendation for all SIHD patients with LV dysfunction (EF < 0.40), hypertension, diabetes, or chronic kidney disease and a Class IIa recommendation for patients with both SIHD and other vascular disease.¹²⁶ Angiotensin receptor blockers (ARBs) are an appropriate alternative for patients who cannot tolerate ACE inhibitors.^121,127 They should not be used in combination with ACE inhibitors. The mineralocorticoid receptor antagonists spironolactone and eplerenone have been demonstrated to be beneficial for patients with both advanced (NYHA Class III/IV and EF < 0.35) and lesser degrees of HF.^128,129,130 Initiation of eplerenone, in addition to the use of β-adrenergic receptor antagonist and ACE inhibitor therapy, is a class I recommendation for treatment of patients after MI with reduced EF (< 0.40), HF, or diabetes.¹³¹ Use of these agents must be considered in the context of renal function and potassium homeostasis. Indications for the use of combination sacubitril/valsartan, in preference to an ACE inhibitor or ARB, are reviewed in Chap. 70.

Organic Nitrates

Organic nitrates (eg, nitroglycerin, isosorbide dinitrate) are nitric oxide donors that activate soluble guanylyl cyclase in vascular smooth muscle cells to increase intracellular cyclic guanosine monophosphate and induce blood vessel relaxation. These medications treat ischemia by (1) inducing venodilation of capacitance vessels to decrease preload, thus decreasing LV wall stress and myocardial oxygen demand; (2) dilating epicardial coronary arteries to improve CBF; and (3) recruiting coronary collaterals. In patients with CAD, use of nitrates is associated with lower angina frequency and increased time to ischemic ECG findings on treadmill testing.⁸⁶ Nitroglycerin also expresses antithrombotic properties, predominately via attenuation of platelet aggregation. Monotherapy with nitrates does not influence survival or decrease cardiovascular death rates in SIHD patients.

Tachyphylaxis to organic nitrate use is common in clinical practice, although the precise mechanisms remain unclear. Pentaerithrityl tetranitrate (PETN) has been shown in preclinical studies to exert properties that delay nitrate tolerance. However, a randomized, controlled study of 655 patients demonstrated that PETN did not affect exercise duration significantly compared to placebo in patients with SIHD. There was a signal of possible benefit in a prespecified subgroup of patients with low exercise tolerance at baseline.¹³² Nevertheless, in the absence of available nitrate derivatives for which drug tolerance is not a concern, integrating a nitrate-free interval (8-12 hours) or longer drug holidays has been suggested (ie, intermittent drug cessation for 2- to 3-day periods). Co-administration of nitrates with sildenafil greatly increases the risk of potentially life-threatening hypotension because both agents increase cyclic guanosine monophosphate bioactivity to potentiate vasodilatation.¹³³

Ranolazine

Ranolazine is a selective inhibitor of late sodium influx into myocytes, which in turn leads to decreased myocardial contractility.¹³⁴ Early clinical trials established that ranolazine monotherapy is effective in improving exercise tolerance in patients with SIHD.¹³⁵ In the prospective, randomized, placebo-controlled Combination Assessment of Ranolazine in Stable Angina (CARISA) trial, ranolazine (750-1000 mg twice daily) in combination with standard doses of atenolol, amlodipine, or diltiazem, significantly increased time to onset of angina and exercise performance compared with placebo.¹³⁶ Additionally, ranolazine significantly reduced the frequency of angina and nitroglycerin requirements during the 12-week period following randomization. Findings from a meta-analysis of seven randomized controlled trials (including CARISA) comparing ranolazine with placebo or usual care support a benefit with ranolazine on exercise tolerance and angina frequency.¹³⁷ Adverse effects include dizziness and constipation; discontinuation rates in large trials have been approximately 1%.¹³⁸ Although rare, QT interval prolongation has been seen with ranolazine therapy but not yet linked to clinically important arrhythmias. Drug interactions may be important, however, and the use of ranolazine is not recommended in patients receiving nondihydropyridine CCBs, quinolones, or azole antifungal medications, among others. Ranolazine is best reserved for patients with persistent symptoms despite maximal medical therapy or for patients unable to tolerate other antianginal therapies because of adverse effects.

Background, Major Trials, and Observational Studies

Intensive lifestyle modification and evidence-based drug therapy remain the cornerstones of treatment for patients with SIHD.¹³⁹ Patients with refractory symptoms despite OMT and/or elevated clinical or angiographic risk profiles and suitable coronary anatomy can benefit from revascularization with PCI or CABG surgery. Considerations regarding revascularization in the SIHD patient are distinctly different from those in the ACS patient. Quality-of-life and cost-effectiveness analyses support the concept of a staged approach in most instances, although it remains to be determined whether the medication and lifestyle adherence rates achieved in clinical trials can be realistically duplicated in routine contemporary clinical practice.

Indications for coronary artery revascularization in patients with SIHD can be considered in terms of those that prolong life and those that are targeted to symptom relief and/or ischemia reduction (Table 43–8). The choice of revascularization strategy (ie, PCI vs CABG) relates to coronary artery anatomy, LV systolic function, systemic factors (eg, diabetes), and patient values and preferences. The benefits of surgical revascularization are generally greater for patients with extensive and complex CAD, as well as when LV systolic dysfunction or diabetes is present. A heart team approach to patient-centered shared decision making is recommended with left main or multivessel CAD, especially with reduced EF. The ACC/AHA appropriate use criteria for coronary revascularization include 155 specific clinical scenarios for which PCI or CABG surgery may be considered.⁷⁹

Percutaneous Coronary Intervention Versus Optimal Medical Therapy

COURAGE Trial

Boden and colleagues⁸⁰ conducted a prospective, randomized controlled trial involving 2287 SIHD patients recruited between 1999 and 2004. Participants with symptomatic but stabilized angina (CCS class < IV), at least one ≥ 70% flow-obstructing lesion in at least one proximal epicardial coronary artery, and objective evidence of myocardial ischemia were included in the trial. Exclusion criteria were nonstabilized CCS class IV angina, a markedly positive (high-risk) stress test result, refractory HF, and prior revascularization ≤ 6 months before study.⁸⁰ Patients were randomized to receive OMT alone or in combination with PCI. For PCI, a strategy of target lesion revascularization was used, whereas OMT included aspirin or clopidogrel, long-acting metoprolol, amlodipine, and isosorbide dinitrate, alone or in combination with an ACE inhibitor or ARB, and a lipid-lowering agent. These medications were provided to study participants free of charge, and patients were assigned a nurse manager to track their individual progress and adherence to assigned treatments. All patients were instructed in smoking cessation, diet, and expectations for physical activity. Median follow-up was 4.6 years. There were no statistically significant baseline clinical differences between treatment groups, other than an excess of proximal left anterior descending artery (LAD) disease among patients allocated to OMT. PCI relieved anginal symptoms more effectively than OMT alone over the first 36 months of the trial, after which freedom from angina rates were comparable. There was no significant difference in overall survival, survival free of MI, and survival free of ACS. Extended survival data on a subgroup of 1211 COURAGE trial patients demonstrated no significant mortality difference between PCI and OMT groups at a mean of 6.2 years (25% vs 24%; HR, 1.03; 95% CI, 0.83-1.21; P = .76; Fig. 43–4).¹⁴⁰ These observations were directionally similar to those reported in a meta-analysis of > 50,000 patients.¹⁴¹ In the COURAGE trial, 238 patients (21%) crossed over from OMT to the PCI group over the course of the study, a fact that illustrates the dynamic nature of the disease substrate and the importance of individualized care.

Cost-effectiveness and quality-of-life measures in patients undergoing an initial OMT or PCI strategy for the treatment of SIHD were also evaluated in the COURAGE trial. Both treatment groups demonstrated significant improvement in standardized measures to assess angina-specific health status (using the Seattle Angina Questionnaire) and overall physical and mental well-being (using the RAND 36-item health study). Although the OMT plus PCI group was more likely to report freedom from angina and improved quality of life early after randomization, there were no significant differences between groups 24 months following treatment assignment.¹⁴² Furthermore, the additional financial cost of PCI was not offset by gains in life-years or quality-adjusted life-years.

ISCHEMIA Trial

Subgroup data from the COURAGE trial suggest that PCI plus OMT may be preferred over OMT alone in patients with SIHD and high residual ischemic burden on MPI (see earlier section on MPI). However, the question of whether moderate or severe ischemia is a sufficient determinant of treatment strategy in this population has not been subjected to sufficiently powered prospective clinical studies.¹⁴³ In clinical practice, proponents in favor of OMT are matched by those in favor of revascularization for patients with this clinical profile. There is strong agreement, therefore, that additional trials are needed to address this clinical equipoise and guide management of this sizeable and potentially vulnerable patient population.¹⁴⁴ The International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial aims to address this issue by studying patients with SIHD, defined by ≥ 10% ischemic myocardium by MPI, ≥ 3 of 16 segments with stress-induced severe hypokinesis or akinesis by echocardiography, ≥ 12% ischemic myocardium by stress cardiac MRI, or ST-segment depression > 2.0 mm observed at a low exercise workload in patients with typical angina during an exercise treadmill testing (NCT01471522 at ClinicalTrials.gov). Investigators anticipate involving approximately 300 participating sites from 30 countries. Subjects with normal renal function undergo CCTA upon enrollment to exclude anatomic left main disease or the absence of obstructive epicardial CAD. Patients are then randomized to an invasive strategy (OMT plus revascularization) or a conservative strategy (OMT alone). Over an average follow-up time of 3 years, differences between groups for the composite primary end point of cardiovascular death and nonfatal MI will be assessed, as well as various secondary end points.¹⁴⁵

FAME Trials

Assessing fractional flow reserve (FFR) involves measuring the pressure gradient across a fixed coronary stenosis at the time of maximal coronary vasodilation, usually after adenosine infusion. Findings from the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial demonstrated that stenting atherosclerotic lesions defined by FFR < 0.75 was associated with a decrease in cardiovascular end points.¹⁴⁶ These data shifted the approach to lesion selection for PCI from an anatomic basis to one determined by physiology. By assessing the functional relevance of atherosclerotic lesions, particularly 50% to 70% occlusions, FFR analysis provides a point-of-care diagnostic opportunity to determine the functional significance of lesions that may appear otherwise equivocal on two-dimensional angiography. To determine whether FFR could be used in a manner akin to high ischemic burden on MPI for guiding appropriateness of PCI in SIHD, the FAME-2 trial¹⁴⁷ measured outcomes in this patient population when referred for angiography and randomized to FFR-guided PCI plus OMT or OMT alone. Findings from the study suggested a benefit in the FFR-guided PCI plus OMT group, in which the composite end point of death, MI, or urgent revascularization was significantly reduced compared to OMT alone (4.3% vs 12.7%; HR, 0.32; 95% CI, 0.19-.053; P < .0001; Fig. 43–5). The composite end point reduction was driven by a decrease in the need for urgent revascularization; the individual end points of death and MI did not differ between groups. Directionally similar findings have been reported in other large clinical trials.^148,149 Although findings from FAME-2 are encouraging and provide an additional framework for the application of FFR in clinical practice, additional data to substantiate these findings will be forthcoming.

BARI 2D Trial

The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial established that an initial revascularization strategy with either PCI or CABG surgery offered no significant survival advantage over OMT alone in patients with type 2 diabetes and SIHD.^150,151 In this trial, 2368 type 2 diabetic patients with SIHD were selected for revascularization with either PCI or CABG surgery at the discretion of the managing physician. Approximately 13% of those enrolled had proximal LAD disease, whereas nearly one-third had three-vessel CAD. Patients were randomized to receive either prompt revascularization (within 4 weeks) or OMT, unless their angina progressed and required more urgent revascularization. Patients were subsequently randomized in a 2×2 factorial design to receive either insulin provision or insulin-sensitization therapy. Among patients undergoing PCI, 34.7% received a DES, 56.0% received a bare metal stent, and 9.3% did not receive a stent.¹⁵⁰ At 5 years, rates of survival and freedom from major adverse cardiovascular events did not differ between the medical and revascularization arms or between those allocated to insulin provision versus insulin sensitization (Fig. 43–6). Patients for whom CABG was the intended method of revascularization (CABG stratus) and who were assigned to revascularization had significantly fewer major cardiovascular events than did patients in the CABG stratum who were assigned to the medical therapy group. Forty-two percent of patients assigned to medical therapy crossed over to revascularization over the course of the study. It should be emphasized that BARI 2D was not a study of PCI versus CABG among patients with diabetes and chronic CAD.

Data from a recent multicenter, longitudinal, cross-sectional analysis of 2.7 million PCI procedures between 2009 and 2014 revealed important trends in nonacute PCI use that may reflect practice changes in response to data reported in the COURAGE and BARI-2D trials. From this study, nonacute PCI volume was observed to decrease from 89,704 in 2010 to 59,375 in 2014. Furthermore, patients undergoing nonacute PCI had higher angina severity levels, had greater use of antianginal medication, and were more likely to have high-risk findings on MPI in 2014 as compared to 2010.¹⁵² Additional factors other than clinical trial data that may have influenced these trends include Appropriate Use Criteria for Coronary Revascularization¹⁵³ or other factors not yet studied. Among these may be the integration of certain clinical variables that assist in identifying patients who are likely to benefit from early CABG surgery. In one substudy of the BARI-2D trial, increase in myocardial jeopardy index (is, the ratio of myocardial territories supplied by diseased coronary arteries or their branches) and total number of coronary lesions, as well as prior coronary revascularization and decreased LVEF, identified a group of patients treated with CABG for whom the 5-year rate of death, MI, or stroke was substantially decreased compared to OMT. An increase in the magnitude of this effect was observed when considering patients with worrisome angiographic findings and increased Framingham risk score.¹⁵⁴

Percutaneous Coronary Intervention Versus Coronary Artery Bypass Graft Surgery

The conventional approach to patients with high-risk multivessel CAD has favored surgical revascularization. This strategy is an outgrowth of results from older randomized trials, including the CASS study, which demonstrated a long-term survival benefit for patients undergoing initial therapy with CABG surgery in whom isolated left main CAD, left main equivalent CAD, or three-vessel CAD with LV systolic dysfunction was known.¹⁵⁵ Importantly, the efficacy of surgery in these studies was greatest in patients with impaired LV systolic function and/or severe symptoms.

Numerous comparisons between PCI and CABG surgery for patients with multivessel CAD have been conducted. Evolving technologic advances in stent design, antiplatelet therapies, techniques for chronic total occlusion, and lipid-lowering drugs; improvement in myocardial preservation techniques; and use of arterial conduits at surgery have confounded the application of these older data to contemporary practice.

As a result of increased utilization of angioplasty as an initial revascularization strategy for patients with symptomatic CAD in the early 1990s, the Bypass Angioplasty Revascularization Investigation 1 (BARI-1) trial was conducted to test the hypothesis that balloon angioplasty and CABG surgery are equally effective strategies for patients with multivessel CAD and angina.¹⁵⁶ In BARI-1, 1829 multivessel CAD patients were randomly assigned to undergo percutaneous transluminal coronary angioplasty (PTCA) or CABG surgery and were followed for > 5 years. No long-term survival advantage was seen for CABG surgery versus PTCA, although a subset of patients with treated diabetes demonstrated improved survival with surgery when the left internal thoracic artery was used for LAD bypass. Importantly, patients with anatomically significant left main CAD (> 50% stenosis) or a history of unsuccessful PTCA or stent placement were excluded from trial entry. Only 43 subjects had disease of the proximal LAD, and the mean EF was 56%. Many experts have argued that the BARI-1 patients were not representative of those thought to benefit most from surgical revascularization. The BARI-1 trial was conducted prior to the DES era.

To investigate the influence of DES use on PCI versus CABG outcomes in patients with chronic CAD, Hannan and colleagues¹⁵⁷ performed an observational study using 2003 to 2004 data from the Cardiac Surgery Reporting System (CSRS) and the Percutaneous Coronary Intervention Reporting System (PCIRS) of the New York State Department of Health. Patients with a history of revascularization, left main CAD, or MI < 24 hours after treatment were excluded. Surgical revascularization for three- or two-vessel CAD was associated with lower rates of death and death or MI compared with PCI with DES over 18 months of follow-up. The survival rates of patients with diabetes were significantly higher in the surgical revascularization group; a subset analysis showed lower rates of death and MI in patients with EF ≤ 0.40 treated with surgery. The results from this study were akin to previous observations in the pre-DES era, as consolidated in a meta-analysis, suggesting that CABG surgery for the treatment of multivessel CAD is associated with lower long-term mortality than PCI in a real-world setting.¹⁵⁸ Directionally similar findings were reported in the ASCERT 1 observational study, which retrospectively analyzed outcome data from 189,793 patients with two- or three-vessel CAD without acute MI undergoing CABG surgery (n = 86,244) or PCI (n = 103,549). Although at 1 year of follow-up there was no significant difference between groups for outcome, the adjusted mortality at 4 years was lower for CABG patients compared to PCI patients (RR, 0.79; 95% CI, 0.76-0.82).^{159,160,161,162}

SYNTAX Trial

The Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) trial was designed to demonstrate noninferiority between multivessel PCI (with a first-generation paclitaxel-eluting stent) and CABG surgery for patients with multivessel CAD for the primary composite end point of death from any cause, stroke, MI, or repeat revascularization during the 12 months following treatment.¹⁶³ The SYNTAX trial differed from previous studies by virtue of DES use, inclusion of patients with significant left main CAD in both treatment arms, and joint involvement of interventional cardiologists and cardiac surgeons in the assessment of CAD severity and treatment allocation. The results suggested that surgical revascularization resulted in a significantly lower rate of the combined primary end point. This effect was largely driven by the reduced need for revascularization after surgery versus PCI. Surgery resulted in an increased likelihood of periprocedural stroke, although there was no difference between treatment groups for the combined end point of death from any cause, stroke, or MI.

Among the strengths of the SYNTAX trial was the use of a numerical score for the objective evaluation of coronary disease severity and likelihood of revascularization success. The SYNTAX score is generated by summarizing various qualitative plaque features and stenosis locations and serves as an objective measure of coronary disease severity that can be used to stratify anticipated patient outcomes (Table 43–9; also see syntaxscore.com).¹⁶³ Patients with high (≥ 33) and intermediate (23-32) SYNTAX scores had lower rates of MACCE with surgery compared with PCI out to 5 years (high SYNTAX score: 26.8% surgery vs 44.0% PCI; P < .0001; intermediate SYNTAX score: 25.8% surgery vs 36.0% PCI). Event rates were similar for patients with low (≤ 22) SYNTAX scores. The trial also established that PCI is noninferior to bypass surgery for treatment of left main CAD (31.0% MACCE rate in the CABG surgery group vs 36.9% in the PCI group; P = .12).¹⁶⁴

SYNTAX Score II

One limitation to the original SYNTAX score was that patient-specific clinical variables were not used to inform decision-making with respect to the choice between CABG or PCI (Fig. 43–7). The SYNTAX II score was developed to account for baseline clinical/demographic features. The SYNTAX II score, which predicted a difference in outcome according to CABG or PCI therapy, is composed of the following eight variables: anatomic SYNTAX score, age, creatinine clearance, LVEF, presence of unprotected left main CAD, peripheral vascular disease, female sex, and chronic obstructive pulmonary disease. Results from this analysis suggested that patients who are older with unprotected left main CAD and chronic obstructive pulmonary disease require a higher SYNTAX score (more complex coronary artery anatomy) to favor treatment with CABG (Fig. 43–8). Overall, this study provides evidence in support of individual-specific algorithms for determining risk and optimal treatment strategy for complex CAD patients.¹⁶⁵

Revascularization and Clinical Decision Making in Stable Ischemic Heart Disease

Progress in Coronary Stent Technology

Sufficient long-term follow-up data have been accrued for patients undergoing PCI with conventional bare metal stent, cobalt-chromium everolimus-eluting stent (EES), paclitaxel-eluting stent (PES), and sirolimus-eluting stent (SES), as well as bioabsorbable polymer-based biolimus-eluting stent (BES).¹⁶⁶ Based on data from 51 randomized clinical trials (n = 52,158 patients), Palmerini and colleagues¹⁶⁷ reported that EES therapy was superior to other stents at a median follow-up of 3.8 years for decreasing mortality, stent thrombosis, and MI. They further distinguish zotarolimus-eluting stents as having lower rates of stent thrombosis than SESs and lower rates of MI than bare metal stent or PESs. These findings are in concert with clinical trial data suggesting incremental benefit in outcome according to technologic iteration of stents. For example, the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System (SPIRIT IV) trial randomized 3687 patients with inducible angina or ischemia undergoing PCI and found that patients receiving EESs had improved outcome compared to patients receiving PESs based on lower rates of the primary end point of target lesion failure (4.2 vs 6.8%; RR, 0.62; 95% CI, 0.46-0.82; P = .001), as well as the secondary end points of MI and stent thrombosis.¹⁶⁸ Other factors that influence PCI efficacy include optimal stent placement (apposition), concomitant use of intravascular ultrasound or optical coherence tomography, and measurement of FFR.

Progress in Off-Pump Coronary Artery Bypass Graft Surgery

Traditional CABG surgical strategy is associated with stroke or cognitive impairment (ie, postperfusion syndrome) as a result of microemboli formation in the cardiopulmonary bypass filter, instrumentation of the aorta, and adverse changes in arteriolar tone/permeability of the central nervous system circulation.¹⁶⁹ By contrast, off-pump CABG surgery, in which graft anastomosis is performed on the beating heart to avoid cardiopulmonary bypass, has been proposed as an alternative strategy to conventional CABG surgery that is safer. Indeed, a number of meta-analyses suggest a decrease in risk for death, stroke, renal failure, blood transfusion requirement, inotropic support, or hemodynamic support among patients undergoing off-pump versus conventional CABG surgery.^170,171 However, head-to-head trials comparing these approaches are limited, although availability of these data would seem to be important given the technical difficulty of performing vascular grafting on the beating heart. In the German Off-Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) study, patients > 75 years of age referred for first-time CABG surgery (n = 2539) were randomized to the off-pump or conventional surgical approach. There was no difference between groups for the composite end point of death, stroke, MI, or repeat revascularization at 30 days or 1 year, calling into question the advantage of the off-pump approach even in a patient cohort at increased risk based on age at enrollment.¹⁷²

Hybrid Revascularization

CABG surgery remains the favored revascularization strategy for patients with multivessel CAD and high SYNTAX scores, particularly in the presence of LV systolic dysfunction or diabetes. However, the principal driver of clinical benefit in this patient group appears to be based on the efficacy of internal mammary artery anastomosis to the LAD.¹⁷³ By contrast, vein graft occlusion may occur in up to 30% of patients within 1 post-operative year, whereas DES patency rates in non-LAD coronary arteries are on par or better than that reported for vein grafts.¹⁷⁴ This raises the possibility that a hybrid approach involving left internal mammary artery–LAD graft placement surgery and PCI using DES to atherosclerotic non-LAD lesions, or hybrid coronary revascularization (HCR), may be an optimal revascularization approach in patients with multivessel CAD. Although definitive outcome data for HCR remain lacking, this approach appears safe and technically feasible but at present is markedly underused.¹⁷⁴ In one study of 147 patients with multivessel CAD treated with HCR and case matched to a cohort of patients undergoing off-pump CABG surgery with sternotomy, no difference between groups was observed for 5-year survival (86.6% vs 84.3%; P = .61), although the need for repeat revascularization or blood transfusion was higher and lower, respectively, in the HCR group.¹⁷⁵ A number of prospective clinical trials examining the role of HCR in multivessel CAD patients and accounting for high-risk subphenotypes, such as diabetes, are ongoing (eg, NCT02504762, NCT02293928 at ClinicalTrials.gov).

For patients with angina refractory to conventional medical or revascularization therapies, palliative treatment with spinal cord stimulation, enhanced external counterpulsation (EECP), or surgical transmyocardial laser revascularization (TMLR) may be considered.⁸⁶

Spinal Cord Stimulation

The efficacy of spinal cord stimulation depends on the accurate placement of the stimulating electrode in the dorsal epidural space, usually at the C7 to T1 level. Data in favor of spinal cord stimulation as a useful treatment for refractory angina are mainly limited to case series and small clinical trials. The Electrical Stimulation Versus Coronary Artery Bypass Surgery in Severe Angina Pectoris (ESBY) study randomized 104 patients with end-stage ischemic heart disease to spinal cord stimulation or CABG surgery.¹⁷⁶ Participants in the ESBY trial were at elevated surgical risk and had preoperative clinical profiles that did not predict a clear prognostic benefit from surgery. Compared with surgery, spinal cord stimulation resulted in lower 6-month mortality with similar improvement in angina frequency and severity.¹⁷⁶ Subsequent trials have been underpowered or have not shown a compelling benefit with respect to angina, quality of life score, or improvement in exercise tolerance with spinal cord stimulation in patients with severe, refractory angina.¹⁷⁷ Nonetheless, spinal cord stimulation appears safe, and speculation remains that this intervention favorably influences sympathetically and parasympathetically mediated neurovascular tone, improves CBF, and exerts anti-ischemic effects in some patients.¹⁷⁸

Enhanced External Counterpulsation

EECP uses cuff inflation for the application of compressed air-induced pressure to the lower extremities that is synchronized with the cardiac cycle. Specifically, in early diastole, positive pressure is applied sequentially from the lower legs to the lower and upper thighs for the facilitation of increased retrograde aortic blood flow and increased coronary diastolic perfusion pressure. In patients with refractory angina, EECP (~35 hours of treatment time) is associated with a reduction in angina frequency and nitrate use, increased exercise tolerance, and improved quality of life.^179,180 Patients with severely limiting angina and without a smoking history are most likely to benefit.¹⁸¹ Certain forms of valvular heart disease (eg, aortic regurgitation), recent revascularization, and severe hypertension are contraindications to this form of therapy. Nevertheless, the favorable response to EECP observed in select patients with refractory angina has raised speculation that it should be implemented earlier in the treatment course. Sufficiently powered randomized clinical trials of EECP versus OMT are lacking.

Transmyocardial Laser Revascularization

TMLR has been performed in the operating room (using a carbon dioxide or holmium:YAG laser) or catheterization laboratory by percutaneous approach with a specialized (holmium:YAG laser) catheter. Early uncontrolled studies suggested that percutaneous TMLR may provide symptomatic relief in patients with angina refractory to maximal medical therapy.¹⁸² However, subsequent randomized, placebo-controlled trials were unable to substantiate these findings and demonstrated no benefit for percutaneous TMLR beyond that of a sham procedure when patients were blinded to treatment status.¹⁸³ Findings from prospective randomized controlled trials support surgical TMLR beyond medical therapy alone for symptom relief and decreased hospitalization frequency. Furthermore, in a multicenter randomized trial comparing surgical TMLR with medical therapy in 192 patients with angina refractory to maximal medical therapy, Frazier and colleagues correlated improvements in CCS class from surgical TMLR with a decrease in the number of fixed or reversible perfusion defects evaluated by MPI.¹⁸⁵ These findings have not been widely replicated. The mechanism by which TMLR reduces angina is also not resolved. As a result of discrepancies among reports on efficacy and concern for increased rates of iatrogenic morbidity following surgical or percutaneous TMLR, including ventricular perforation, cardiac tamponade, stroke, and MI, the use of this strategy is controversial.¹²¹

Chelation Therapy

Sodium ethylenediamine tetra acetic acid (EDTA) has long been recognized for its capacity to bind di- or trivalent cations, including some implicated in the pathobiology of atherosclerotic CAD, such as calcium (Ca²⁺). On the heels of promising data from small, uncontrolled trials suggesting a potential benefit with chelation therapy in patients with CAD, the Trial to Assess Chelation Therapy (TACT) was completed and serves as the first sufficiently powered trial studying EDTA therapy in CAD. In this double-blind placebo-controlled 2 × 2 factorial multicenter randomized trial, 1708 patients (> 50 years old, > 6 weeks post-MI, serum creatinine < 2.0 mg/dL) were randomized to receive 40 infusions of 500 mL of chelation solution fortified with B vitamins versus placebo and to an oral vitamin regimen or placebo. A favorable effect on the primary end point of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for recurrent angina was observed in patients randomized to chelation compared to placebo (HR, 0.82; 95% CI, 0.69-0.99; P = .035), which did not appear to hinge on randomization to the oral vitamin therapy stratum.¹⁸⁶ The effect of chelation was most pronounced in patients with diabetes or prior anterior MI, setting the framework for the forthcoming TACT-2 trial that aims to assess the benefit of combination chelation plus oral vitamin and mineral therapy in diabetic CAD patients specifically.¹⁸⁷ A pathophysiologic mechanism accounting for the benefits of chelation therapy in the original TACT study remains unclear, however, and additional data are necessary to clarify indications, timing, and duration of the chelation therapy.

Following initiation and titration of OMT, reevaluation every 4 to 6 months is recommended. A general assessment of functional capacity, response to treatment, changes in quality of life, and any adverse medication effects is advised. Patients should be screened for depression, social isolation, chronic kidney disease, peripheral vascular disease, sexual dysfunction, and obstructive sleep apnea.^188,189,190

An assessment of LVEF and segmental wall motion by echocardiography or MPI is recommended in patients with a change in symptoms or evidence of MI by history or ECG,¹⁹¹ but not routinely in the absence of these clinical indications. Laboratory assessment of fasting lipids and glucose should be performed in accordance with current guideline recommendations.¹⁹² In the stable patient without weight change or dietary modification, lipids can be assessed every 6 to 12 months.

Guidelines are imprecise regarding the frequency with which routine noninvasive testing should be repeated in patients with SIHD. Echocardiography, SPECT MPI, CCTA, or cardiac MRI is not recommended in SIHD patients when performed more frequently than at 5-year intervals after CABG or 2-year intervals after PCI.¹⁹¹ Patients at relatively low risk for future cardiovascular events (eg, those with stable CCS class, preserved LV function, unchanged functional capacity) do not require annual stress testing.⁸⁶ Routine follow-up stress testing at 3- to 5-year intervals may be useful in selected patients, including those with diabetes or known incomplete revascularization. Table 43–10 provides the ACC/AHA indications for performing echocardiography, exercise treadmill testing, stress MPI, and coronary angiography in the follow-up setting.

Microvascular Circulatory Disease

Angina with normal-appearing epicardial coronary arteries may reflect microvascular circulatory dysfunction and impaired intramyocardial perfusion. Formerly termed cardiac syndrome X, recent investigations have defined more clearly the pathophysiology of microvascular circulatory dysfunction (Table 43–11).^193,194 The original epidemiologic observations that reported a clustering of patient characteristics associated with this clinical phenomenon (eg, female predominance, hypertension, obesity) have been redefined to emphasize the histologic and pathophysiologic processes that increase the probability of disease expression (Table 43–12). Abnormal coronary vascular reactivity from impaired endothelial-dependent and -independent signaling likely explains decreased CFR associated with most forms of this condition.¹⁹⁵

Microvascular ischemia is often difficult to diagnose. Comparison of myocardial blood flow under basal conditions and after intracoronary infusion of adenosine with a Doppler flow wire can be performed once obstructive epicardial CAD has been excluded at angiography.¹⁹³ Assessment of CFR or myocardial perfusion reserve using PET or cardiac MRI is the most common and reliable noninvasive method for diagnosing microvascular circulatory dysfunction. Many investigators and clinicians use a cutoff of < 3.0 mL/min/g myocardial tissue (quantified at peak hyperemia relative to rest) to diagnose microvascular circulatory disease provided the patient has cardiac angina and that no epicardial coronary stenosis > 50% is present.¹⁹⁶

Data from the Women’s Ischemia Syndrome Evaluation (WISE) study demonstrated a positive association between impaired coronary microvascular reactivity and abnormal functional capacity.¹⁹⁷ In this analysis, 190 women (18% with epicardial coronary luminal stenosis > 50%) underwent invasive assessment of coronary flow velocity in response to intracoronary adenosine injection. Women with a decreased coronary flow velocity response were significantly more likely to have reduced exercise tolerance compared with women with normal vascular reactivity. Treatment of patients with microvascular disease should focus on pathophysiologic mechanisms that contribute to endothelial dysfunction, with emphasis on smoking cessation, lipid and glycemic management, and blood pressure control. Conventional anti-ischemic therapy may control symptoms in some patients, but overall results are usually mixed.¹⁹⁸ Microvascular disease was not previously thought to confer an elevated risk of future adverse cardiovascular events or early mortality.^199,200 Up to 30% of women diagnosed with microvascular circulatory disease will develop clinically evident CAD within 10 years, and women with this condition experience 5-year cardiovascular disease event rates of approximately 8%.²⁰¹ In women with non–flow-limiting epicardial CAD who experience ACS, 30-day mortality of 2% has been reported.²⁰² As a result of persistent variability in treatment responsiveness to β-adrenergic receptor antagonists, CCBs, ACE inhibitors, and nitrate therapy in this patient population, comprehensive longitudinal studies of novel therapies designed to characterize patient outcome are needed.