Stable Ischemic Heart Disease

Characteristics of Angina (see Chapter 35 )

Angina pectoris is a discomfort in the chest or adjacent areas caused by myocardial ischemia. It is usually precipitated by exertion but may also be initiated by other stressors that increase myocardial O ₂ demand, including emotional distress. Angina that is prolonged, occurs at rest or occurs in an accelerating pattern of increasing frequency and tempo is indicative of unstable angina or acute MI. Heberden’s initial description of angina as conveying a sense of “strangling and anxiety” is still remarkably pertinent. Other adjectives frequently used to describe this distress include constricting, suffocating, crushing, heavy, and squeezing. In other patients, the quality of the sensation can be vague and described as a mild pressure-like discomfort, tightness, an uncomfortable numbness, or a burning sensation. The site of the discomfort is usually retrosternal, but radiation is common and generally occurs down the ulnar surface of the left arm; the right arm and the outer surfaces of both arms may also be involved, as can the neck, back, or jaw ( eFig. 40.1 ). Epigastric discomfort alone or in association with chest pressure may occur and can masquerade as indigestion. Anginal discomfort above the mandible or below the epigastrium is rare. Anginal equivalents (i.e., symptoms of myocardial ischemia other than angina), such as dyspnea, faintness, fatigue, and frequent belching, are more commonly seen in women and older adults. A history of abnormal exertional dyspnea may be an indicator of IHD even when angina is absent. Nocturnal angina may be a manifestation of unstable angina but should also raise suspicion of sleep apnea (see Chapter 89 ). Postprandial angina, presumably caused by redistribution of coronary blood flow to the splanchnic circulation, may be a marker of severe IHD.

The typical episode of angina pectoris usually begins gradually and reaches its maximum intensity over a period of minutes before dissipating. It is unusual for angina pectoris to reach its maximum severity within seconds, and it is characteristic that patients with angina generally prefer to rest, sit, or stop walking during episodes. Chest discomfort while walking in the cold or uphill is suggestive of angina. Features inconsistent with angina pectoris include pain that is pleuritic, sharp, or stabbing in quality or reproduced by movement or palpation of the chest wall or arms (see eFig. 40.1 ) Constant pain lasting many hours or, alternatively, very brief episodes of pain lasting seconds are also unlikely to be due to angina. Typical angina pectoris is relieved within minutes by rest or the use of short-acting nitroglycerin. Response to the latter is often a useful diagnostic tool, although it should be remembered that esophageal pain may also respond to nitroglycerin. A delay of more than 5 to 10 minutes before relief is obtained with rest and nitroglycerin suggests that the symptoms are either not caused by ischemia or are caused by severe ischemia, as with acute MI or unstable angina. The phenomenon of warm-up angina is used to describe the ability of some patients to be able to exercise at higher intensity without angina after an intervening period of rest. This attenuation of myocardial ischemia observed with repeated exertion has been postulated to be caused by ischemic preconditioning (see Chapter 36 ).

Assessment and Classification of Angina Pectoris

A system of grading the severity of angina pectoris proposed by the Canadian Cardiovascular Society (CCS) is widely used (see Table 11.1). The system is a modification of the New York Heart Association (NYHA) functional classification and allows patients to be categorized in more specific terms. Functional estimates based on the CCS criteria have shown a reproducibility that is only moderate and do not correlate well with objective measures of exercise performance.

More objective measures of the impact of angina on quality of life are available, using either general instruments such as the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) or the disease-specific Seattle Angina Questionnaire (SAQ). The SAQ is a validated 19 item self-administered questionnaire that assesses domains of anginal frequency and stability, physical limitation, treatment satisfaction, and disease perception. It can be measured serially to assess the impact of medical therapies and revascularization on angina-related quality of life and has emerged as the preferred instrument for assessment of quality of life in clinical trials.

Although these objective measurements have typically been applied in the research setting, a short seven-question version of the SAQ may be practical for the clinical setting. In the future, embedding simple, objective, patient-centered disease measurements into the clinical encounter is likely to become increasingly important for chronic diseases like SIHD. Understanding the impact of angina on quality of life is a necessary prerequisite for shared decision making, which plays a larger role in SIHD than in many other cardiovascular diseases. Mechanisms of anginal pain are discussed in the online version of this chapter.

Esophageal Disorders

Common disorders that may simulate or coexist with angina pectoris are gastroesophageal reflux and disorders of esophageal motility, including diffuse spasm. To compound the difficulty in distinguishing between angina and esophageal pain, both may be relieved by nitroglycerin. However, esophageal pain is often relieved by milk, antacids, foods, or occasionally warm liquids.

Biliary Colic

Although visceral symptoms are commonly associated with myocardial ischemia (particularly acute inferior MI; see Chapter 37, Chapter 38 ), biliary colic and related hepatobiliary disorders may also mimic ischemia. Biliary pain is steady, usually lasts 2 to 4 hours, and subsides spontaneously, without any symptoms between attacks. It is generally most intense in the right upper abdominal area but may also be felt in the epigastrium or precordium. This discomfort is often referred to the scapula and may radiate around the costal margin to the back.

Costochondritis

In 1921 Tietze first described a syndrome of local pain and tenderness, generally limited to the anterior chest wall and associated with swelling of costal cartilage. The full-blown Tietze syndrome (i.e., pain associated with tender swelling of the costochondral junctions) is uncommon, whereas costochondritis causing tenderness of the costochondral junctions (without swelling) is relatively common. Pain on palpation of these joints is usually well localized and is a useful clinical sign, although deep palpation may elicit pain in the absence of costochondritis. Although palpation of the chest wall often reproduces pain in patients with various musculoskeletal conditions, it should be appreciated that chest wall tenderness does not exclude symptomatic CAD.

Other Neurologic and Musculoskeletal Disorders

Cervical radiculopathy may be confused with angina. This condition may occur as a constant ache, worsened with neck movement, and sometimes results in a sensory deficit. Occasionally, pain mimicking angina can be caused by compression of the brachial plexus by the cervical ribs, and tendinitis or bursitis involving the left shoulder may also cause angina-like pain. Physical examination may also detect pain brought about by movement of an arthritic shoulder or a calcified shoulder tendon. Herpes zoster, caused by recrudescence of the varicella-zoster virus, can manifest by pain across the chest and should be recognized by its dermatomal distribution and associated blistering or crusting rash. Postherpetic neuralgia may persist in the absence of a rash.

Other Causes of Angina-Like Pain

Severe pulmonary hypertension may be associated with exertional chest pain with the characteristics of angina pectoris, and indeed, this pain is thought to be caused by right ventricular ischemia that develops during exertion (see Chapter 88 ). Other associated symptoms include exertional dyspnea, dizziness, and syncope. Related findings are commonly seen on physical examination, such as a parasternal lift, a palpable and loud pulmonary component of the second heart sound, and right ventricular hypertrophy on the ECG.

Pulmonary embolism is initially characterized by dyspnea as the cardinal symptom, but chest pain may also be present (see Chapter 87 ). Pleuritic pain suggests pulmonary infarction, and a history of exacerbation of the pain with inspiration, along with a pleural friction rub, if present, helps distinguish it from angina pectoris.

The pain of acute pericarditis (see Chapter 86 ) may at times be difficult to distinguish from angina pectoris. Recognition of pericarditis may be facilitated by the combination of chest pain not relieved by rest or nitroglycerin and exacerbated by movement, deep inspiration, and lying flat; a pericardial friction rub, which may be evanescent; and changes on the ECG (notably PR-segment depression or diffuse ST elevation).

The classic symptom of aortic dissection is a severe, often sharp pain that radiates to the back (see Chapter 42 ).

Physical Examination

Most patients with SIHD have normal findings on cardiac examination, and thus the single best clue to the diagnosis of angina is the clinical history. Nonetheless, careful examination can exclude other conditions that mimic angina and may reveal atherosclerosis in noncoronary vascular territories, evidence of risk factors for coronary atherosclerosis (i.e., acanthosis nigricans or tendon xanthomas) or the consequences of myocardial ischemia (see Chapter 13 ).

Angina Caused by Increased Myocardial O ₂ Requirements

In this condition, sometimes termed demand angina , the myocardial O ₂ requirement increases in the presence of a constant and usually restricted O ₂ supply. The increased O ₂ requirement commonly stems from a physiologic response to exertion, emotional duress, or mental stress. Of great importance to the myocardial O ₂ requirement is the rate and intensity at which any physical task is carried out. Mental and emotional stress may also precipitate angina, presumably by increased hemodynamic and catecholamine responses to stress, increased adrenergic tone, and reduced vagal activity. The combination of physical exertion and emotion in association with sexual activity may precipitate angina. Other precipitants of angina include physical exertion after a heavy meal and the excessive metabolic demands imposed by fever, thyrotoxicosis, tachycardia from any cause, uncontrolled hypertension, and exposure to the cold.

Angina Caused by Transiently Decreased O ₂ Supply

Like unstable angina, stable angina may be caused by transient reductions in O ₂ supply, a condition sometimes termed supply angina , as a consequence of coronary vasoconstriction that results in dynamic stenosis. In the presence of atherosclerotic stenoses, platelet thrombi and leukocytes may elaborate vasoconstrictor substances such as serotonin and thromboxane A ₂ . In addition, endothelial damage in atherosclerotic coronary arteries decreases production of vasodilator substances such as nitric oxide, resulting in an abnormal vasoconstrictor response to exercise and other stimuli. A variable threshold of myocardial ischemia in patients with chronic stable angina may be caused by dynamic changes in smooth muscle tone and also by constriction of arteries distal to the stenosis. Patients with resulting “variable-threshold angina” may have good days, when they are capable of substantial physical activity, as well as bad days, when even minimal activity can cause clinical and/or electrocardiographic evidence of myocardial ischemia or angina at rest. They often complain of a circadian variation in angina that is more common in the morning. Angina on exertion and sometimes even at rest may be precipitated by cold temperature, emotion, and mental stress. Other factors that reduce myocardial oxygen delivery, such as hypoxemia and anemia, may precipitate angina or lower the anginal threshold.

In rare instances, severe dynamic obstruction may develop in patients without organic obstructing lesions and can cause myocardial ischemia and angina at rest (see Chapter 36, Chapter 37 ). On the other hand, in patients with severe fixed obstruction in one or more epicardial coronary arteries, only a minor increase in dynamic obstruction is necessary for coronary blood flow to fall below a critical level and cause myocardial ischemia.

Importance of Pathophysiologic Considerations in Configuring Therapy

The pathophysiologic and clinical contributions to ischemia in patients with SIHD may have important implications for the selection of anti-ischemic agents, as well as for their timing. The greater the contribution from increased myocardial O ₂ demand associated with tachycardia or increased contractility, the greater the likelihood that beta-blocking agents will be effective; nitrates and calcium channel–blocking agents, at least hypothetically, are more likely to be effective in episodes caused primarily by coronary vasoconstriction. The finding that an increase in myocardial O ₂ requirement precedes episodes of ischemia in most patients with stable angina—that is, that they have demand angina—argues in favor of controlling the heart rate and blood pressure as a primary therapeutic approach.

Biomarkers of Myocyte Injury, Ischemia, and Hemodynamic Stress

Multiple circulating biomarkers reflecting myocardial injury, inflammation, fibrosis, and wall stress demonstrate associations with the risk of major cardiovascular events in patients with SIHD ( Fig. 40.3 ). Blood levels of cardiac troponins T and I are typically used to differentiate patients with acute MI from those with SIHD. However, with the development of high-sensitivity assays, low levels of circulating troponins are now detectable in most patients with SIHD, consistent with chronic myocardial injury, and higher concentrations demonstrate a graded relationship with the subsequent risk for cardiovascular mortality and heart failure. Moreover, patients with SIHD who have increases in high sensitivity troponin levels over time are at increased risk for adverse outcomes, even in the absence of an evident change in clinical status. Although the prognostic importance of chronic myocardial injury is now clear, the therapeutic implications remain an important area for study. Emerging data suggest that more intensive lifestyle and preventive therapies, including higher levels of physical activity and fitness, tighter blood pressure control, and possibly use of sodium-glucose cotransporter 2 (SGLT2) inhibitors among patients with type 2 diabetes mellitus, may attenuate either chronic injury or the risk for adverse events associated with elevated troponin levels. In addition, measuring cardiac troponin may be useful for identifying patients with sufficiently high risk to fall into a population recommended to receive the most intense lipid lowering strategies or patients who don’t meet clinical criteria for blood pressure lowering agents but are sufficiently high risk to warrant antihypertensive therapy. ^{, ,} Moreover, high-intensity statin and intensive blood pressure lowering regimens reduce risk in those with elevated troponin, with absolute risk reductions that are heightened given the high risk status of these patients. ^{, ,}

Biomarkers of neurohormonal activation have also been extensively studied in patients with SIHD. For example, the plasma concentration of brain natriuretic peptide (BNP) increases in response to spontaneous or provoked ischemia. Although BNP and N-terminal pro-BNP (NT-proBNP) do not have sufficient specificity to aid in the diagnosis of SIHD, higher concentrations of these peptides are strongly associated with risk for cardiovascular events in those at risk for and with established CAD. As has been shown with high sensitivity troponin, serial measurements of natriuretic peptides also provide incremental prognostic information in patients with SIHD, suggesting a potential role of outpatient monitoring with these tests. Similar to cardiac troponins, higher levels of NT-proBNP identifies patients with hypertension with greater absolute risk reduction for death and heart failure with more intensive blood pressure lowering, with greatest risk reduction among patients with elevation in both biomarkers. Given the strong association of natriuretic peptides and high-sensitivity troponins with pathologic cardiac remodeling, consideration of echocardiography is reasonable for patients with abnormal levels of these biomarkers, particularly when increasing over time. However, evaluation for ischemia is generally not indicated as these biomarkers are more strongly associated with structural cardiac abnormalities than ischemia. Given the promising results of studies to date, selective measurement of cardiac troponin and natriuretic peptides is emerging as a consideration to guide the intensity of preventive therapies. However, routine measurement of these biomarkers is not yet warranted in patients with SIHD.

Growth differentiation factor-15, ST2, fibroblast growth factor-23, and galectin-3 are also biomarkers that may putatively reflect myocardial ischemia or its consequences and have been associated with cardiovascular outcomes in clinical studies of patients with SIHD. However, insufficient information is available to demonstrate that these measurements provide robust incremental information beyond natriuretic peptide and high-sensitivity troponin measurements, which have emerged as the strongest candidate biomarkers for disease surveillance in patients with SIHD.

Inflammatory Biomarkers

Understanding of the inflammatory contributions to the pathobiology of atherothrombosis (see Chapter 24 ) established interest in inflammatory biomarkers as noninvasive indicators of underlying atherosclerosis and cardiovascular risk. Moreover, demonstration of improved clinical outcomes for patients with SIHD treated with the anti-inflammatory therapies canakinumab and colchicine have provided additional evidence for the importance of chronic inflammation and its potential modification. ^,

The blood concentration of the acute-phase protein high-sensitivity C-reactive protein (hsCRP) correlates with the risk for incident cardiovascular events in patients with SIHD or at risk for its development (see Chapter 25 ). The prognostic value of hsCRP is additive to traditional risk factors, including lipids; however, its incremental clinical value for screening among individuals without known vascular disease continues to be debated. Multiple studies also confirm independent associations of hsCRP with adverse cardiac events among individuals with established SIHD. In addition, hsCRP may be an important biomarker reflecting residual risk among patients following ACS or with established SIHD who are treated to low LDL goals with lipid-lowering therapy. ^, Patients who achieve low LDL cholesterol levels (<70 mg/dL) but with hsCRP levels above 2 mg/L are at higher risk for subsequent ischemic events than patients with low levels of both LDL and hsCRP. Interleukin (IL)-1β, a cytokine that is activated by the Nod-like receptor (NLR)P3 inflammasome, and IL-6, which stimulates hepatic production of CRP, are also both associated with first and recurrent atherothrombotic events. Measurement of their downstream signal manifest by CRP is more practical as CRP is easier to measure and levels are more stable over time; however, with the emerging potential of therapies directed at the IL-1β pathway and other components of NLRP3-inflammasone activation, a rationale for direct measurement of these cytokines may also arise. ^,

Although other biomarkers of inflammation, such as trimethylamine N-oxide, growth factors, cytokines, and metalloproteinases, remain under study as potential biomarkers reflecting inflammatory pathways contributing to atherosclerosis, given their lack of cardiac specificity, they appear unlikely to emerge as clinically useful biomarkers.

Genetic and Transcriptomic Biomarkers

Large-scale genetic mapping programs, utilizing genome-wide association studies (GWAS) and more recently next-generation genome sequencing have identified >50 unique genetic variants contributing to IHD (see Chapter 7 ). These studies have contributed to the identification of many new potential pathogenic targets and have made feasible testing for large numbers of genetic variations simultaneously at relatively low cost. Because the genes contributing to IHD individually explain only a small amount of the variation in disease, combining multiple variants in genetic risk scores is presently thought to be the only viable strategy by which genetic risk prediction could enter clinical practice. Polygenic risk scores can help predict the risk of major adverse cardiovascular event (MACE) in both primary and secondary prevention populations. However, in individuals without known IHD, when compared with conventional predictors, polygenic risk scores appear to only modestly improve discrimination and risk reclassification, if at all. The findings have been similar in patients with previous CAD. As an example, in a study of a genome-wide polygenic risk score for CAD in ∼47,000 individuals, while the top 20% of estimated polygenic risk had a 1.9-fold higher odds of developing CAD, only an additional 4.1% of primary prevention candidates might have qualified for statin therapy if a high risk score were considered to be a risk-enhancing factor. It is possible that continued evolution of larger genetic risk scores, incorporating additional variants identified with finer gene mapping strategies, may improve their performance. It is more likely that genetic testing will enter routine practice as a tool to guide therapeutic drug selection (see Chapter 9 ). Several studies have demonstrated that individuals with high genetic risk scores identifying a genetic predisposition to IHD derive greater reduction in risk with intensive lipid-lowering therapy than do individuals with low genetic risk scores ( Fig. 40.4 ). ^,

Resting Electrocardiogram

Findings on the resting electrocardiogram (ECG) (see Chapter 14 ) are normal in approximately half of patients with SIHD, and even patients with severe CAD may have a normal tracing at rest. A normal resting ECG suggests the presence of normal resting LV function and is an unusual finding in a patient with an extensive previous MI. The most common abnormalities on the ECG in patients with SIHD are nonspecific ST-T wave abnormalities with or without abnormal Q waves. In patients with known CAD, however, the occurrence of ST-T wave abnormalities on the resting ECG (particularly if obtained during an episode of angina) correlate with the severity of the underlying heart disease and are associated with prognosis. In contrast, a normal resting ECG is a more favorable long-term prognostic sign in patients with suspected or definite CAD.

Interval ECGs may reveal the development of Q wave MIs that have gone unrecognized clinically. Various conduction disturbances, most frequently left bundle branch block and left anterior fascicular block, may occur in patients with SIHD. They are often associated with impairment of LV function, reflect multivessel CAD, and are an indicator of a relatively poor prognosis. Various arrhythmias, especially ventricular premature beats, may be present on the ECG, but they too have low sensitivity and specificity for accurately detecting CAD. LV hypertrophy on the ECG is associated with a worse prognosis in patients with chronic stable angina. This finding implies the presence of underlying hypertension, aortic stenosis, hypertrophic cardiomyopathy, or previous MI with remodeling and warrants further evaluation, such as echocardiography to assess LV size, wall thickness, and function.

During an episode of angina pectoris, findings on the ECG become abnormal in 50% or more of patients with normal resting ECGs. The most common finding is ST-segment depression, although ST-segment elevation and normalization of previous resting ST-T wave depression or inversion (pseudonormalization) may develop.

Resting Echocardiography (see Chapter 16 )

Assessment of global LV function is one of the most valuable aspects of echocardiography. Identification of regional wall motion abnormalities may be suggestive of CAD, whereas other findings such as valvular stenosis or pulmonary hypertension may suggest alternative diagnoses. U.S. and European guidelines differ notably regarding recommendations for routine echocardiography in patients with SIHD. European Society of Cardiology (ESC) guidelines recommend routine echocardiography (class I, LOE B) for patients with SIHD whereas U.S. guidelines do not recommend routine echocardiography for all patients with angina pectoris (class III, LOE C); rather echocardiography is recommended for patients with a history of MI, ST-T wave changes, or conduction defects or Q waves on the ECG (class I, LOE B). We also believe echocardiography is appropriate for patients with persistent elevation in cardiac biomarkers such as BNP (or NT-proBNP) or cardiac troponin.

Chest Roentgenography (see Chapter 17 )

The chest roentgenogram is generally within normal limits in patients with SIHD, particularly if they have normal findings on the resting ECG and have not experienced MI. If cardiomegaly is present, it is indicative of severe CAD with previous MI, preexisting hypertension, or an associated nonischemic condition such as concomitant valvular heart disease or cardiomyopathy.

Stress Testing (see Chapter 15 , Chapter 18 )

Noninvasive stress testing can provide useful information to establish the diagnosis and estimate the prognosis in patients with suspected stable angina. However, appropriate application of any noninvasive testing for SIHD requires consideration of Bayesian principles, which state that the negative and positive predictive values of any test are defined not only by its sensitivity and specificity but also by the prevalence of disease (or pretest probability) in the population under study. The value of noninvasive stress testing is greatest when the pretest likelihood is intermediate because the test result is likely to have the greatest effect on the post-test probability of CAD. Moreover, noninvasive testing should be performed only if the incremental information provided by a test is likely to alter the planned management strategy.

A classification scheme developed by Diamond and Forrester over 40 years ago that incorporates age, sex, and whether symptoms are typical, atypical, or nonanginal to estimate the pretest probability of CAD has been replaced by newer algorithms. These newer algorithms for predicting CAD have been developed and calibrated in more modern cohorts. The two CAD Consortium scores, a basic score ( Table 40.1 ) and a more detailed clinical score, are now recommended in the ESC Guidelines on the management of chronic coronary syndromes. A head-to-head comparison of the Diamond-Forrester and CAD Consortium scores demonstrated substantial improvement in the prediction of obstructive CAD with the two newer scores, suggesting that use of these scores could reduce unnecessary referrals for diagnostic testing.

Computed Tomography (see Chapter 20 )

Coronary artery calcification (CAC) can be detected with a rapid noncontrast CT that utilizes only low doses of ionizing radiation. CAC screening does not have a role in the diagnosis of obstructive CAD among symptomatic patients. However, screening of asymptomatic individuals at intermediate risk for CAD can be useful to guide decisions about initiation and titration of preventive therapies such as statins and aspirin (see Chapter 20 ). ^,

Coronary CTA is a noninvasive method for angiography of the coronary arterial tree and quantification of ventricular function. CT technology has progressed such that high-quality images of the coronary arteries can be obtained in most patients at relatively low overall radiation exposure. Coronary CTA has become a first-line test for evaluation of symptomatic patients with indications for diagnostic testing who do not have known CAD. Sensitivity and specificity of coronary CTA compare favorably to other noninvasive techniques (see Table 40.2 ). Compared with nuclear MPI, a comprehensive anatomic evaluation with coronary CTA offers superior accuracy for the prediction of an abnormal invasive fractional flow reserve (FFR).

The accuracy of coronary CTA for estimating the severity of luminal stenosis is limited in patients with tachycardia unable to be controlled adequately with beta blockers, heavy coronary calcification, or in the region of previously placed coronary stents. For these reasons, stress testing with adjunctive imaging is preferred over CTA for patients with known CAD. In the randomized PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial among 10,003 symptomatic patients without known CAD, coronary CTA was compared with functional testing as an initial evaluation strategy. Clinical outcomes and costs were similar in the CTA and functional testing arms over a median follow-up of 2 years ( Fig. 40.5 ). Patients randomized to coronary CTA underwent more cardiac catheterizations but were less likely to be found to have no obstructive disease on invasive angiography. An important finding from this study was the low rate of cardiovascular events in both treatment arms, highlighting the possibility that deferral of all testing may be reasonable for many lower-risk individuals.

An important advantage of CTA over stress testing is the ability to detect nonobstructive plaque. This capacity has important prognostic and therapeutic implications. In the PROMISE trial, for example, more than half of the coronary events occurred among individuals with <70% stenosis by CTA, many of whom would not be detected with nuclear perfusion imaging. In the SCOT HEART (Scottish Computed Tomography of the Heart) trial, the detection of nonobstructive CAD led to increased administration of preventive therapies in patients undergoing CTA vs patients in the standard of care stress testing arm. ^, It is possible that augmented secondary prevention therapies contributed to the apparent long-term benefit favoring CTA over usual care in SCOT HEART.

Stress myocardial CT perfusion imaging is an emerging technique that provides both anatomic and physiologic information that can be combined with CT angiography in a single protocol with a radiation dose similar to that of nuclear perfusion imaging. In a study of 381 patients across 16 centers, CT perfusion imaging sensitivity and specificity for the diagnosis of CAD (>50% stenosis) were 88% and 55%, respectively, compared with 62% and 67% for SPECT with overall superior accuracy for CT (0.74 versus 0.64, p= 0.001).

In experienced centers with advanced technology, CT has also been used to characterize plaque composition and, when paired with PET in a hybrid PET/CT scanner, can offer an assessment of coronary anatomy concurrent with information regarding myocardial blood flow and metabolism. Nevertheless, the capacity of CT for determination of plaque composition is currently not sufficient for routine application. Fractional flow reserve can also now be estimated from CT angiogram images using complex computational algorithms (CTA-FFR), but these currently require off-line processing using proprietary software. The PLATFORM study compared patient care guided by CTA + CTA-FFR versus usual care and reported a reduction in the probability of finding no obstructive CAD in the group that underwent CTA-FFR before angiography.

Currently, the clinical strength of CT angiography remains its ability to exclude significant CAD with a high negative predictive value and identify low-risk patients with no stenosis and no plaque. In the ISCHEMIA trial, all patients without contraindications underwent a blinded screening CTA before enrollment to ensure significant CAD was present and exclude patients with significant left main CAD. The study, which compared coronary revascularization with initial medical therapy for patients with SIHD and noninvasive evidence of ischemia, did not demonstrate benefit of revascularization despite evidence of substantial ischemia in the study population (see Comparisons between Percutaneous Coronary Intervention and Medical Therapy). Among the many important implications of the ISCHEMIA trial, one is that a strategy using coronary CTA as the initial diagnostic test for patients with angina to exclude severe left main disease before initiating medical therapy for angina can support good outcomes without a need for invasive management. An important corollary is that use of noninvasive stress testing, with or without imaging, is likely to decrease. Since revascularization does not appear to improve outcomes in patients with stable CAD and severe ischemia, the rationale for assessing ischemia before initiating medical therapy for established CAD is questionable.

Cardiac Magnetic Resonance Imaging (see Chapter 19 )

Cardiac magnetic resonance imaging (CMRI) is established as a valuable clinical tool for imaging the aorta and cerebral and peripheral arterial vasculature. It is also a versatile noninvasive cardiac imaging modality that has multiple potential applications in patients with SIHD. CMRI has emerged as highly useful for assessment of myocardial viability because of evidence demonstrating its ability to predict functional recovery after percutaneous or surgical revascularization and good correlation with PET. Pharmacologic stress perfusion imaging with CMRI compares favorably with SPECT (see Table 40.2 ) and also offers accurate characterization of LV function, as well as delineation of patterns of myocardial disease that are often useful in discriminating ischemic from nonischemic myocardial dysfunction. ^, In an unblinded, randomized, clinical-effectiveness trial of CMRI MPI versus invasive FFR among 918 patients with suspected CAD, patients allocated to CMRI were less likely to undergo coronary revascularization (35.7% versus 45.0%; P = 0.005) and CMRI was noninferior compared with invasive FFR for MACE (3.6% versus 3.7%). However, from a viewpoint of practical implementation, availability is limited compared with most other stress imaging modalities.

CMRI coronary angiography in humans has not demonstrated sufficient accuracy to support clinical application. However, it is established as a modality to characterize congenital coronary anomalies (see Chapter 19, Chapter 82 ).

Catheterization and Coronary Angiography

The clinical examination and noninvasive techniques described earlier are extremely valuable in establishing the diagnosis of CAD and are indispensable to the overall assessment of patients with this condition. Currently, however, precise assessment of the anatomic severity of CAD still requires invasive coronary angiography (see Chapter 19, Chapter 82 ). Nevertheless, it should be remembered that myocardial ischemia may occur in the absence of epicardial CAD (see Angina and Ischemia Without Obstructive Epicardial CAD). ^, In a report from the National Cardiovascular Data Registry (NCDR) that included almost 400,000 patients without known CAD, the proportion of individuals who reported angina but had no obstructive disease on coronary angiography approached 50%. In contrast, in a large clinical trial population enrolled on the basis of moderate to severe ischemia on functional testing with or without imaging, after exclusion of patients with left main CAD by coronary CT (1%), 6.4% had no coronary stenoses >50%, 22.3% had single-vessel disease, 31.7% had two-vessel disease, and 39.6% had three-vessel disease. Anatomic findings consistent with high risk are described in the online version of this chapter.

LV function can be assessed by contrast ventriculography (see Chapter 21 ). Global abnormalities in LV systolic function are reflected by elevations in LV end-diastolic and end-systolic volume and depression of the ejection fraction. Abnormalities in regional wall motion (e.g., hypokinesis, akinesis, dyskinesis) may reflect the consequences of CAD.

High-Risk Findings from Coronary Angiography

The independent impact of multivessel CAD and LV dysfunction and their interaction on the prognosis of patients with CAD is well established ( eFig. 40.2 ).

Extent of Coronary Artery Disease

Although several indices have been used to quantify the extent or severity of CAD, the simple classification of disease into single-, double-, or triple-vessel or left main CAD is the most widely used and is effective. Additional prognostic information is provided by the severity of the obstruction and its location, whether proximal or distal. The concept of the gradient of risk is illustrated in eFigure 40.3 . The importance to survival of the quantity of myocardium that is jeopardized is reflected in the observation that an obstructive lesion proximal to the first septal perforating branch of the left anterior descending (LAD) coronary artery was associated with a 5-year survival rate of 90%, as opposed to 98% in patients with more distal lesions. More sophisticated scoring systems, such as the SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score, capture a more detailed assessment of the full extent and severity of epicardial CAD.

High-grade lesions of the left main coronary artery or its equivalent, as defined by severe proximal LAD and proximal left circumflex CAD, are particularly high risk. In natural history studies before the era of aggressive coronary revascularization and modern secondary prevention therapies, mortality without revascularization in patients with severe left main CAD was approximately 15% to 20% per year. Although risk is likely to be lower in the modern era with aggressive secondary prevention medical therapies, no recent data are available, and these anatomic subsets remain strong indications for coronary revascularization.

Advanced Structural Coronary Imaging

Advanced invasive imaging techniques such as intravascular ultrasound (IVUS) provide a more comprehensive evaluation of the coronary wall and have substantially enhanced the detection and quantification of coronary atherosclerosis, as well helping to characterize the vulnerability of coronary atheroma to rupture (see Chapter 21 ). Studies incorporating both coronary angiography and IVUS have demonstrated that IVUS detects the presence of atherosclerosis missed by angiography alone. Although clinical use of IVUS for assessment of borderline stenoses has been largely supplanted by FFR measurement, IVUS continues to have a role in assessing left main coronary stenoses, and bifurcation lesions, and in optimizing stent deployment. Virtual-histology intravascular ultrasound (VH-IVUS) uses IVUS backscatter data to identify plaque components, including calcification, fibrous, and fibrofatty tissue. In several studies, VH-IVUS–defined thin-capped fibroatheroma (VH-TCFA) was associated with future MACE. ^,

Intravascular optical coherence tomography (OCT) is a light-based technology that provides much higher resolution images of the coronary atheroma (10 to 15 microns, versus 100 to 150 microns with IVUS) but penetration is limited to 1 to 3 mm in depth. OCT is particularly useful for measuring fibrous cap thickness and endothelial coverage of stent struts. The major current clinical role for OCT is evaluating patients with acute MI and no evidence of coronary obstruction by angiography, where OCT may detect occult plaque rupture and spontaneous coronary dissection unrecognized on the coronary angiogram.

Functional Assessment

FFR has emerged as the most important invasive tool to complement coronary angiography, providing a functional assessment of the hemodynamic impact of a coronary stenosis. The measurement is simple to perform and highly reproducible. The primary role of FFR is in guiding decisions regarding percutaneous coronary intervention (PCI) for stenoses that appear intermediate in severity by angiography. FFR is determined as the ratio of pressure distal to a stenosis/pressure before the stenosis under conditions of maximal hyperemia, which is usually achieved with adenosine. For practical purposes the proximal pressure measurement is performed in the aorta using the guiding catheter. A stenosis with an FFR value <0.75 is highly likely to be associated with ischemia on nuclear perfusion imaging, whereas stenoses with FFR >0.8 are rarely associated with ischemia; 0.75 to 0.8 represents a “grey zone.”

The iFR has been developed as an alternative to FFR that does not require administration of a vasodilator and thus avoids adverse effects from adenosine and is simpler to perform in the catheterization laboratory. An iFR of >0.89 is commonly used as an analogous threshold to FFR >0.8 as a threshold above which PCI can be deferred. Two large randomized controlled trials comparing PCI guided by iFR versus by FFR show similar outcomes but fewer adverse symptoms and shorter procedural times with iFR (see Fractional Flow Reserve and Chapter 41 ). ^,

Additional options for functional assessment include measurement of coronary flow reserve (maximum hyperemic coronary flow divided by resting flow) and endothelial function; these measurements frequently produce abnormal results in patients with CAD and play an important role in detecting microvascular dysfunction, particularly in those without obstructive epicardial disease. ^, The index of microcirculatory resistance (IMR) is a newer tool to interrogate the coronary microcirculation. These techniques are discussed in Chapter 18, Chapter 20 (see also Patient Selection for Revascularization).

Integrated Invasive Assessment in Patients Without Obstructive CAD

For patients with angina and evidence of ischemia on noninvasive testing, and no obvious epicardial obstructive CAD, symptom burden may be substantial (see Angina and Ischemia Without Obstructive Epicardial CAD). In such patients an integrated functional assessment is possible to identify potential causal pathophysiology. For example, FFR or iFR can be performed to exclude hemodynamically significant diffuse CAD that is underappreciated by angiography. Next, CFR or IMR can be used to interrogate the coronary microcirculation. Finally, acetylcholine can be given at low doses to assess coronary endothelial function and at higher dosages to evaluate for coronary spasm. While such a comprehensive evaluation is currently limited to specialized centers, in a pilot study the CorMicA investigators studied 151 patients with angina and no obstructive CAD with an integrated functional assessment and then randomized them to providing the information to the clinician or blinding the information. The results of the functional assessment were used to stratify patients into endotypes (microvascular angina, coronary spasm, both, or noncardiac pain) with treatment in the randomized group based on the underlying pathophysiology. At 6 months and 1 year, the intervention group had significantly improved SAQ and other health status scores. Additional studies are needed to demonstrate the feasibility of this approach in a broader group of catheterization laboratory practices.

Risk Stratification and Risk Models

Risk stratification is an integral component of the assessment and management of patients with SIHD. Risk assessment should be considered an iterative process, by which the estimation of risk is continually updated as new clinical or test information becomes available or symptoms change. Clinical characteristics, including older age, male sex, diabetes mellitus, previous MI, and the presence of symptoms typical of angina, are predictive of the presence of CAD and associated with a higher risk of major cardiovascular events in patients with SIHD. Left ventricular dysfunction and clinical heart failure are important adverse prognostic indicators in patients with SIHD. The severity of angina, especially the tempo of intensification, and the presence of dyspnea are also important predictors of outcome. Each of the noninvasive and invasive tests that assess the extent of CAD, burden of ischemia, and LV function, also provide powerful prognostic information (see Noninvasive Testing and Invasive Assessment).

Several risk scores that integrate widely available clinical risk indicators have been developed to aid in prognostication with the aim of directing follow-up and therapeutic decision making. Patients with SIHD and prior MI vary in their risk for recurrent cardiovascular (CV) events. The TIMI Risk Score for Secondary Prevention (TRS 2°P) is a pragmatic integer score based on nine routinely assessed clinical characteristics (age, diabetes, hypertension, smoking, peripheral arterial disease, prior stroke, prior coronary artery bypass grafting (CABG), history of heart failure, and renal dysfunction) that demonstrated a graded relationship with the risk for cardiovascular death, MI, or ischemic stroke in a population of 8598 patients with established coronary or peripheral atherosclerosis ( Fig. 40.6A ). As well, this risk score distinguished a pattern of increasing absolute benefit from treatment with the novel platelet inhibitor vorapaxar. In a second validation cohort in the IMPROVE IT trial of ezetimibe, the TRS 2°P performed similarly for risk stratification and also identified patients with a significantly greater absolute and relative risk reduction with the addition of ezetimibe to simvastatin ( Fig. 40.6B ). Although the discriminatory capacity of the TRS 2°P was only moderate (c-statistic 0.68) in both datasets, the demonstrated role for estimating benefit from more than one specific therapy lends clinical relevance.

In addition, at least three risk scores have been developed for patients who have undergone PCI to aid in decision making regarding the duration of dual antiplatelet therapy. The DAPT risk score estimates net clinical outcome (balancing reductions in ischemia with increases in bleeding) with extending the duration of dual antiplatelet therapy from 12 to 30 months after stenting. The PARIS risk score was developed as a weighted integer score to predict new coronary thrombotic events (MI or stent thrombosis) in patients who had undergone PCI. The PARIS risk variables are similar to those in the TRS 2°P, including PCI for acute coronary syndrome, revascularization before the qualifying PCI, diabetes mellitus, renal dysfunction, and current smoking. Patients are stratified into three bins of coronary thrombotic risk ranging from 1.8% to 10% at 2 years. The PRECISE-DAPT scores a simple five-item risk score, using age, creatinine clearance, hemoglobin, white blood cell count, and previous spontaneous bleeding, that predicts out-of-hospital bleeding during DAPT.

Treatment of Associated Diseases

Several common medical conditions that can increase myocardial O ₂ demand or reduce O ₂ delivery may contribute to the onset of new angina pectoris or exacerbation of previously stable angina. Such conditions include anemia, occult thyrotoxicosis, fever, infections, and tachycardia. Cocaine, which can cause acute coronary spasm and MI, is discussed in Chapter 84 . Heart failure, by causing cardiac dilation, increases in filling pressures or tachyarrhythmias (including sinus tachycardia), can increase myocardial O ₂ need, and increase the frequency and severity of angina in patients with CAD. Identification and treatment of these conditions are critical to the management of SIHD.

Reduction of Coronary Risk Factors

Inflammation (see Chapter 24 , Chapter 25 )

Atherothrombosis has long been thought to be an inflammatory disease. ^, However, only in the past few years have trials of therapeutic interventions established inflammation as a modifiable contributor. Three important trials of pharmacotherapies targeting inflammation alone—without also targeting lipids—have demonstrated clinical benefit in patients with IHD. In Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), three different doses of canakinumab, a monoclonal antibody targeting IL-1β, were tested versus placebo in 10,061 patients with prior MI and hsCRP >2 mg/L. The drug lowered hsCRP and IL-6, but did not affect lipids and significantly reduced rates of the composite outcome of CV death, MI, and stroke. The drug did not lower all-cause mortality and caused a significant excess of fatal infections, highlighting clinical challenges with potent anti-inflammatory agents. Canakinumab will not move forward for clinical development for a cardiovascular indication. A second trial testing low-dose methotrexate did not demonstrate cardiovascular benefit, but conclusions are limited as no effect of the drug at this dose was seen on inflammatory biomarkers.

The most promising agent for current clinical application is low-dose colchicine. After favorable preliminary studies, two large outcome trials have demonstrated clinical benefit of this agent among patients with IHD. The Colchicine Cardiovascular Outcomes Trial (COLCOT) randomized 4745 patients within 30 days of MI to colchicine at a dose of 0.5 mg/day or placebo. The primary ischemic endpoint occurred at approximately 2 years in 7.1% of placebo-treated patients and 5.5% of colchicine-treated patients (HR 0.77; 95% CI, 0.61 to 0.96). The drug was well tolerated but the risk of pneumonia was higher with colchicine and no benefit was seen in all-cause mortality. The Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo)-2 trial enrolled 5522 patients with SIHD, randomizing them to 0.5 mg of colchicine orally once daily versus placebo and treating for an average of approximately 3 years. The primary composite endpoint was significantly reduced in the colchicine arm (HR 0.69; 95% CI, 0.57 to 0.83; P < 0.001; Fig. 40.7 ). Although the drug was well tolerated, an excess in non-CVD deaths was observed (0.7 versus 0.5 events/100 person-years; HR 1.51; 95% CI, 0.99 to 2.31), neutralizing the benefit seen for CVD mortality.

Together, these studies provide compelling evidence that targeting inflammation is a viable strategy for reducing CVD risk. However, to date, none of these anti-inflammatory agents have demonstrated reduction in all-cause mortality and all have reported signals of adverse effects on non-CVD outcomes that may mitigate benefit to some extent. Although colchicine is the most promising agent for current clinical use, additional study is needed to identify patients more likely to suffer infectious or other noncardiac adverse effects from this agent. This area has re-emerged as a priority area for therapeutic development, and additional agents targeting specific inflammatory pathways are being developed and tested.

Pharmacotherapy for Secondary Prevention

Aspirin (see Chapter 24 , Chapter 40 , Chapter 41 )

Aspirin reduces the incidence of major cardiovascular events in men and women with previous MI or stroke and after CABG. Moreover, small studies have supported the benefit of aspirin in patients with chronic stable angina but without a history of MI. Therefore administration of aspirin daily is advisable in patients with SIHD and no contraindications to this drug. Dosing at 75 to 162 mg daily appears to have comparable effects on secondary prevention as dosing at 160 to 325 mg daily and is associated with lower bleeding risk. Even among patients with intracoronary stenting, low-dose aspirin has been showed to be preferable to higher-dose aspirin. Thus aspirin, 75 to 162 mg daily, is preferred for secondary prevention.

P2Y ₁₂ Inhibitors

Other orally acting antiplatelet agents have been studied in patients with SIHD, including patients with or without a prior MI and patients managed with or without prior coronary stenting. Clopidogrel, a thienopyridine derivative, may be substituted for aspirin in patients with aspirin hypersensitivity or in those who cannot tolerate aspirin (see Chapter 41 ). In a randomized comparison between clopidogrel and aspirin in patients with established atherosclerotic vascular disease (the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events [CAPRIE] trial), treatment with clopidogrel resulted in a modest 8.7% relative reduction in the risk for vascular death, ischemic stroke, or MI ( P = 0.043) over a period of 2 years. A meta-analysis of nine randomized trials of aspirin or P2Y ₁₂ inhibitor therapy as monotherapy in patients with atherosclerotic vascular disease was consistent with the results of CAPRIE, demonstrating a relative 19% lower odds of MI.

Studies evaluating the addition of adenosine diphosphate receptor antagonists such as clopidogrel, prasugrel, and ticagrelor, to aspirin in patients with ACS or after PCI have demonstrated important risk reductions. Therefore, dual-antiplatelet therapy (DAPT) combining aspirin with one of these agents is routine in patients with ACS (see Chapter 38, Chapter 39 ). In contrast, the treatment of patients with SIHD with DAPT should be more individualized, as the clinical data suggest important risk/benefit tradeoffs. The selection and duration of antiplatelet therapy after PCI is discussed in Chapter 41 .

When studied in a population that included patients with clinically evident cardiovascular disease ( n = 12,153) or asymptomatic subjects with multiple risk factors ( n = 3284) enrolled in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance) trial, the addition of clopidogrel to aspirin showed no significant benefit with respect to the primary endpoint of cardiovascular death, MI, or stroke over a median of 28 months. However, in the large subgroup of those with established vascular disease, the addition of clopidogrel was associated with a 1% absolute reduction in these events (6.9% versus 7.9%; P = 0.046), thus supporting the hypothesis of a potential benefit from clopidogrel in patients with SIHD taking aspirin. In a subsequent study, patients who had received a coronary stent were randomized to discontinuation of thienopyridine therapy at 12 months or continuation of DAPT through 30 months. Continuation of long-term DAPT reduced the risk of death, MI, or stroke by 13% (absolute difference 1.6%) and stent thrombosis by 72% (absolute 1%) at the cost of a significant increase in bleeding (0.9%). The balance of ischemia reduction and bleeding was more favorable among individuals in this trial who underwent PCI for ACS event than those who underwent elective PCI for SIHD.

Two trials of ticagrelor have demonstrated a reduction of ischemic vascular events in patients with SIHD, but at a cost of increased bleeding. In a randomized placebo-controlled trial of ticagrelor in patients who were 1 to 3 years after a prior MI, whether managed medically or with revascularization, the addition of ticagrelor to aspirin reduced the rate of cardiovascular death, MI, or stroke, balanced against an increased rate of bleeding. Ticagrelor 60 mg twice daily offered similar efficacy with less bleeding than 90 mg twice daily, the dose used in the first year after ACS. A combined analysis of these and other trials of long-term DAPT, predominantly in patients with prior ACS, revealed a significant reduction in cardiovascular mortality. In a subsequent trial among ∼19,000 patients with diabetes mellitus and established SIHD without a prior known MI, ticagrelor added to aspirin reduced the incidence of cardiovascular death, MI, or stroke by a relative 10% (7.7% versus 8.5%; HR 0.90; 95% CI, 0.81 to 0.99). However, major bleeding was increased by more than twofold (2.2% versus 1.0%; HR 2.32; 95% CI, 1.81 to 2.94). As such, treatment with long-term DAPT may be reasonable for selected SIHD patients at high risk of recurrent thrombosis, particularly those with a prior ACS event, provided they have an acceptable risk of bleeding.

Importantly, patients at lower risk for ischemic events, including most patients undergoing PCI for SIHD symptoms who have not had a prior ACS, may not have a favorable balance of risk/benefit with extending the duration of DAPT. Indeed, studies evaluating optimal DAPT duration for elective stenting for SIHD have suggested that shorter durations than 1 year are associated with expectedly lower rates of bleeding than longer durations of treatment. Several studies have examined the discontinuation of aspirin rather than a P2Y ₁₂ inhibitor for longer-term antiplatelet monotherapy. A network meta-analysis of 79,000 patients from 24 trials with different durations of DAPT after PCI with drug eluting stents supports the conclusion that compared with 12-months of DAPT, short-term DAPT followed by P2Y ₁₂ inhibitor monotherapy reduces major bleeding after PCI with drug eluting stents, while extended-term DAPT reduces MI at the cost of more bleeding. As such, the 2016 DAPT guideline from the ACC/AHA recommended that the standard duration of DAPT be at least 6 months for most patients receiving stents for SIHD. Since then, some experts have advocated for even shorter durations of DAPT in some patients post-PCI. Risk scores aimed at weighing these competing risks for ischemic events and bleeding may be useful in decision making (see Risk Stratification and Risk Models). ^{, ,} Patients who are at higher risk of atherothrombotic events with acceptable bleeding risk may be considered for durations of DAPT longer than 6 to 12 months. ^{, ,}

Vorapaxar, an antagonist of the platelet-activating action of thrombin, reduces the risk for recurrent atherothrombosis in patients with SIHD with a prior MI. However, because of a significant increase in the risk for bleeding with vorapaxar, clinical use has been limited and mostly among patients with concomitant peripheral artery disease.

Oral Anticoagulation

Oral anticoagulants (OAC) may be used in patients with SIHD either for secondary prevention of atherothrombosis or because of other indications for chronic anticoagulation, including atrial fibrillation, venous thromboembolic disease, or mechanical heart valves (see also Chapter 95 ). Decisions regarding combined antiplatelet and anticoagulant therapy necessarily take into account the risk of bleeding versus potential antithrombotic benefit. The addition of a single antiplatelet agent to an OAC increases major bleeding rates by >50%, whereas bleeding is more than doubled among those requiring “triple therapy” with OAC, aspirin, and clopidogrel.

Among patients without an indication for OAC for another indication, the addition of a low-dose of the direct OAC rivaroxaban to low-dose aspirin significantly reduced the risk of major cardiovascular events. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, 27395 patients with stable atherosclerotic vascular disease of whom 24824 patients had stable CAD were randomized to receive rivaroxaban 2.5 mg twice daily by mouth plus aspirin or rivaroxaban 5 mg twice daily, or aspirin alone. Patients who qualified for the trial because of CAD who were younger than 65 years of age were also required to have atherosclerosis involving at least two vascular beds or to have at least two additional risk factors for vascular events (current smoking, diabetes mellitus, an eGFR <60 mL per minute, heart failure, or nonlacunar ischemic stroke ≥1 month earlier). Patients receiving a P2Y ₁₂ inhibitor were excluded from participation. In the cohort with SIHD, compared with the aspirin-only group, those allocated to rivaroxaban plus aspirin experienced a 26% relative reduction in the risk of cardiovascular death, MI, or stroke ( P < 0.001). Major bleeding was increased with rivaroxaban-plus-aspirin (3% versus 2%, P < 0.001). In contrast, rivaroxaban 5 mg twice daily without aspirin did not significantly reduce the rate of major cardiovascular events but did increase the risk of bleeding. Rivaroxaban plus aspirin also reduced mortality when compared with aspirin alone (3% versus 4%; HR 0.77; 95% CI, 0.65 to 0.90, p= 0.0012). Based on these results, the ESC guidelines for the management of chronic coronary syndromes (class IIa) recommend considering the addition of a second antithrombotic drug to aspirin for long-term secondary prevention in patients with a high risk of ischemic events and without high bleeding risk. The second antithrombotic drug may be either a P2Y ₁₂ inhibitor or rivaroxaban 2.5 mg twice daily.

For SIHD patients with indications for full -dose OAC who are at relatively low ischemic risk (i.e., no recent MI or stent), it appears reasonable to omit antiplatelet therapy altogether, particularly if bleeding risk is increased. The AFIRE trial randomized patients with atrial fibrillation and stable CAD coronary revascularization >1 year previously) to rivaroxaban monotherapy or rivaroxaban in combination with a single antiplatelet agent. The combination therapy group had higher rates of bleeding, ischemic events, and mortality than the rivaroxaban monotherapy group.

For patients with atrial fibrillation who have indications for DAPT due to recent ACS or coronary stenting, reassessment of the risks and benefits of OAC should be performed after considering the increased bleeding risk associated with combination therapy. For example, among patients at lower stroke risk it may be preferable to defer OAC after MI and/or stenting, and re-initiate OAC once the patient can safely be withdrawn from DAPT. When triple therapy is necessary, recommendations include (1) limiting exposure to triple therapy to the shortest possible duration, (2) targeting the lower range of international normalized ratio (INR) for warfarin, (3) avoiding the more potent P2Y ₁₂ antagonism of prasugrel and ticagrelor (i.e., clopidogrel is preferred in combination with OAC), and (4) routinely administering proton pump inhibitors to prevent GI bleeding. Multiple studies have assessed withdrawal of aspirin from triple therapy and demonstrated a favorable effect on the incidence of bleeding without significant loss of efficacy on stroke and systemic embolism and stent thrombosis/MI compared with triple therapy. However, it should be acknowledged that none of the key trials were adequately powered to detect small to moderate increases in ischemic events. The possible regimens and timing of withdrawal of aspirin after PCI in patients with CAD and atrial fibrillation are discussed in Chapter 41 . In general, for patients with atrial fibrillation and indications for DAPT, current evidence supports shortening the course of aspirin, continuing clopidogrel and using a DOAC instead of warfarin.

Beta-Blocking Agents

Beta adrenoceptor–blocking drugs (beta-blocking agents) reduce death and recurrent MI in patients who have experienced MI (see Chapter 38, Chapter 39 ) and are useful for managing angina. However, the optimal duration of treatment after MI is not clear, particularly for patients without LV dysfunction. Moreover, whether these drugs are also of value in preventing MI and sudden death in patients with SIHD without previous MI is less certain, and there have been no prospective controlled trials involving placebo. Findings from observational studies are mixed, with one of the largest studies reporting no reduction in mortality in patients with SIHD receiving beta-blocking agents ( Fig. 40.8 ). However, such observational studies are limited by the high potential for uncontrolled confounding. Moreover, it is plausible that the favorable effects of beta blockers on ischemia and arrhythmias evident in randomized trials among patients with prior MI or reduced LVEF may extend to other patients with SIHD. Therefore, although the use of beta blockers as first-line therapy for uncomplicated hypertension has been questioned, it is sensible to use these drugs when angina, hypertension, or both are present in patients with SIHD and when these drugs are well tolerated. ^{, ,}

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

Although inhibitors of the renin-angiotensin-aldosterone system are not indicated for the treatment of angina, these drugs appear to have important benefits in reducing the risk for future ischemic events in some patients with cardiovascular disease. ^{, ,} Potentially beneficial effects of ACE inhibitors include reductions in LV hypertrophy, progression of atherosclerosis, plaque rupture, and thrombosis, in addition to a potentially favorable influence on myocardial O ₂ supply-and-demand relationships, cardiac hemodynamics, sympathetic activity, and coronary endothelial function.

Two trials provided strong evidence supporting the therapeutic benefit of ACE inhibitors in patients with normal LV function and absence of heart failure. In the HOPE (Heart Outcomes Prevention Evaluation) study, ramipril significantly decreased the risk for major vascular events by a relative 22% in 9297 patients with atherosclerotic vascular disease or diabetes mellitus. EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable CAD) similarly showed a 20% relative reduction in the risk for cardiovascular death, MI, or cardiac arrest in 13,655 patients with stable CAD in the absence of heart failure. In contrast, in the PEACE (Prevention of Events with Angiotensin Converting Enzyme Inhibition) trial, trandolapril showed no effect on the risk for cardiovascular death, MI, or coronary revascularization or all-cause mortality alone in 8290 patients with stable CAD and preserved LV function receiving intensive preventive therapy (see Fig. 40.9 ). ^{, ,} ACE inhibitors are recommended for all patients with CAD and LV dysfunction and for those with hypertension, diabetes, or chronic kidney disease. ACE inhibitors may be considered for optional use in all other patients with SIHD, including those with a normal LV ejection fraction and well-controlled cardiovascular risk factors. ^, In patients with established vascular disease or high-risk diabetes, angiotensin receptor blockers (ARBs) appear to provide similar secondary prevention benefits as ACE inhibitors, and thus are suitable alternatives for patients intolerant to ACE inhibitors. However, they should generally not be used in combination with ACE inhibitors as the combination provides no additional benefit over the individual agents and results in an increased rate of complications.

Antioxidants and Vitamins (see Chapter 25 )

Oxidized LDL particles are strongly linked to the pathophysiology of atherogenesis, and observational studies have suggested that high dietary intake of antioxidant vitamins (A, C, and beta-carotene) and flavonoids (polyphenolic antioxidants), naturally present in vegetables, fruits, tea, and wine, is associated with a decrease in CAD events. However, in multiple large randomized trials of antioxidant supplements, including vitamin E, vitamin C, beta-carotene, folic acid, and vitamins B ₆ and B ₁₂ , the risk for major cardiovascular events was not reduced. Similarly, despite multiple observational studies suggesting that low levels of vitamin D are associated with increased CV risk, randomized trials have failed to show reduction in cardiovascular disease with vitamin D supplementation. ^, Thus, there is no basis for recommending that individuals with IHD take supplemental folate, vitamins C, D, or E, or beta-carotene for the purpose of improving cardiovascular outcomes.

Counseling and Changes in Lifestyle (see Chapter 25 )

The psychosocial issues faced by patients with angina are similar to, although usually less intense than, those experienced by patients with acute MI. Depressive symptoms are strongly associated with health status as reported by the patient, including the burden of symptoms and overall quality of life, independent of LV function, and the presence of ischemia. In addition, the association between depressive symptoms and IHD may reflect a causal relationship between the former and atherothrombosis inasmuch as depressive symptoms are associated with higher levels of circulating biomarkers of inflammation. Moreover, a genetic predisposition to depression has been associated with risk for CAD. In conjunction with counseling, treatment with a selective serotonin reuptake inhibitor appears to be safe and effective in managing depression in patients with IHD. Thus, effort to evaluate and treat depression in patients with SIHD is an important element of the overall management of such patients. Moreover, psychosocial stress at work, home, or both is associated with an increased risk for MI and may be a target for preventive interventions. Physical exercise may complement antidepressant pharmacotherapy in reducing depressive symptoms.

An important aspect of the physician’s role is to counsel patients with respect to dietary habits, goals for physical activity, the types of work that they can do, and their leisure activities. ^, Certain changes in lifestyle may be helpful, such as modifying strenuous activities if they produce angina. A history of stable angina should not preclude physical exertion, either for recreational activities and lifestyle or when physical exertion is required in employment. However, isometric activities such as weightlifting and other activities such as snow shoveling, which involves an energy expenditure of between 60% and 65% of peak O ₂ consumption, and cross-country skiing may be undesirable. In addition, these latter activities expose the individual to the detrimental effects of cold on the O ₂ supply-and-demand relationship.

Eliminating or reducing the factors that precipitate anginal episodes is of obvious importance. Patients learn their usual threshold by trial and error. Patients should avoid sudden bursts of activity, particularly after long periods of rest or inactivity, after meals, and in cold weather. Both chronic angina and unstable angina exhibit a circadian rhythm characterized by a peak shortly after arising. The stress of sexual intercourse is approximately equal to that of climbing one flight of stairs at a normal pace or any activity that induces a heart rate of approximately 120 beats/min. Most patients with stable angina are able to continue satisfactory sexual activity. Patients with SIHD may use sildenafil and other phosphodiesterase inhibitors to treat organic impotence, but these agents cannot be used in conjunction with nitrates as this combination may promote life-threatening hypotension.

Although from a perspective of both quality of life and avoiding prolonged ischemia, it is desirable to minimize the number of bouts of angina, occasional angina is not to be feared. If there is a clear pattern of effort angina, prophylactic use of short-acting nitrates several minutes before engaging in the offending activity may provide sufficient vasodilation to prevent an anginal episode.