The algorithms do not represent a comprehensive list of recommendations (see text for all recommendations). See Table 2 for short-term risk of death or nonfatal MI in patients with UA/NSTEMI. CCTA is reasonable only for patients with inter- mediate probability of IHD. CCTA indicates computed coronary tomography angiography; CMR, cardiac magnetic resonance; ECG, electrocardiogram; Echo, echocardiography; IHD, ischemic heart disease; MI, myocardial infarction; MPI, myocardial perfusion imaging; Pharm, pharmacological; UA, unstable angina; and UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction. Fihn et al Stable Ischemic Heart Disease: Full Text e365 informed decision, it is essential to elicit the breadth of their knowledge, values, preferences, and concerns. The healthcare provider has a responsibility to ensure that patients understand and consider both the upside and down- side of available options, in both the near and long terms. All previous guidelines reviewed by the writing committee have recognized the crucial role that patient preferences play in the selection of a treatment strategy.9,10,47 49 It is essential that these discussions be conducted in a location and atmosphere that permits adequate time for discussion and contemplation. Initiating a discussion about the relative merits of PCI or CABG while a patient is in the midst of a procedure, for example, is not usually consistent with these principles. In crafting a diagnostic strategy, the objective is to ascer- tain, as accurately as possible, whether the patient has IHD while minimizing the expense, discomfort, and potential harms of any tests or procedures. This includes avoiding procedures that are likely to yield false positive or false negative results or that are unnecessary or inappropriate. The objective for procedures intended to assess prognosis is similar. Treatment options should be emphasized, especially in cases where there is no substantial advantage of one strategy over others. For most patients, the goal of treatment should be to simultaneously maximize survival and to achieve prompt and complete (or nearly complete) elimination of anginal chest pain with return to normal activities in other words, a functional capacity of Canadian Cardiovascular Society (CCS) Class I angina.50 For example, for an otherwise healthy, active patient, the treatment goal is usually the complete elimination of chest pain and a return to vigorous physical activity. Conversely, an elderly patient with more severe angina and several serious coexisting medical prob- lems might be satisfied with a reduction in symptoms that permits limited activities of daily living. Patients with anat- omy that would ordinarily favor the choice of CABG could have comorbidities that make the risk of surgery unaccept- able, in which case PCI or medical therapy is a more attractive option. In counseling patients, the healthcare provider should be aware of, and help to rectify, common misperceptions. Many patients assume, for example, that opening a partially blocked artery will naturally prevent a heart attack and prolong life irrespective of other anatomic and clinical factors. When there is little expectation of an improvement in survival from revascularization, patients should be so informed. When evidence points to probable benefit from either revascular- ization or medical therapy, it should be quantified to the extent possible, with explicit acknowledgment of uncertain- ties, and should be discussed in the context of what treatment option is best for that particular patient. When possible, the relative time course of response to therapy should be de- scribed for therapeutic choices. Some patients might, for example, initially opt for PCI over medical therapy because relief of symptoms is typically more rapid. However, when informed of the immediate risk of complications of PCI, some Figure 3. Algorithm for risk assessment of patients with SIHD.* *Colors corre- spond to the class of recommendations in the ACCF/AHA Table 1. The algo- rithms do not represent a comprehen- sive list of recommendations (see text for all recommendations). CCTA indi- cates coronary computed tomography angiography; CMR, cardiac magnetic resonance; ECG, electrocardiogram; Echo, echocardiography; LBBB, left bundle-branch block; MPI, myocardial perfusion imaging; and Pharm, pharmacological. patients could prefer conservative therapy. Similarly, many patients choose PCI over CABG because it is less invasive and provides for quicker recovery, despite the fact that repeat revascularization procedures are performed more frequently after PCI. Patients preferences in these circumstances often are influenced by their attitudes toward risk and by the tendency to let immediate smaller benefits outweigh larger future risks, a phenomenon termed temporal discounting. 51 2. Diagnosis of SIHD 2.1. Clinical Evaluation of Patients With Chest Pain 2.1.1. Clinical Evaluation in the Initial Diagnosis of SIHD in Patients With Chest Pain: Recommendations Class I 1. Patients with chest pain should receive a thorough history and physical examination to assess the prob- ability of IHD before additional testing.52 (Level of Evidence: C) 2. Patients who present with acute angina should be categorized as stable or unstable; patients with UA should be further categorized as being at high, moderate, or low risk.4,4a (Level of Evidence: C) The clinical examination is the key first step in evaluating a patient with chest pain and should include a detailed assess- ment of symptoms, including quality, location, severity, and duration of pain; radiation; associated symptoms; provocative factors; and alleviating factors. Adjectives often used to describe anginal pain include squeezing, grip-like, suf- focating, and heavy, but it is rarely sharp or stabbing and typically does not vary with position or respiration. On occasion the patient might demonstrate the classic Levine s sign by placing a clenched fist over the precordium to describe the pain. Many patients do not, however, describe angina as frank pain but as tightness, pressure, or discomfort. Figure 4. Algorithm for guideline-directed medical therapy for patients with SIHD.* *Colors correspond to the class of recommendations in the ACCF/AHA Table 1. The algorithms do not represent a comprehensive list of recommendations (see text for all recommenda- tions). The use of bile acid sequestrant is relatively contraindicated when triglycerides are $200 mg/dL and is contraindicated when triglycerides are $500 mg/dL. Dietary supplement niacin must not be used as a substitute for prescription niacin. ACCF indicates American College of Cardiology Foundation; ACEI, angiotensin-converting enzyme inhibitor; AHA, American Heart Association; ARB, angiotensin-receptor blocker; ASA, aspirin; ATP III, Adult Treatment Panel 3; BP, blood pressure; CCB, calcium channel blocker; CKD, chronic kidney disease; HDL-C, high-density lipoprotein cholesterol; JNC VII, Seventh Report of the Joint National Committee on Pre- vention, Detection, Evaluation, and Treatment of High Blood Pressure; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; MI, myocardial infarction; NHLBI, National Heart, Lung, and Blood Institute; and NTG, nitroglycerin. Fihn et al Stable Ischemic Heart Disease: Full Text e367 Other patients, in particular women and the elderly, can present with atypical symptoms such as nausea, vomiting, midepigastric discomfort, or sharp (atypical) chest pain. In the WISE (Women s Ischemic Syndrome Evaluation) study, 65% of women with ischemia presented with atypical Anginal pain caused by cardiac ischemia typically lasts minutes. The location is usually substernal, and pain can radiate to the neck, jaw, epigastrium, or arms. Pain above the mandible, below the epigastrium, or localized to a small area over the left lateral chest wall is rarely angina. Angina is often precipitated by exertion or emotional stress and relieved by rest. Sublingual nitroglycerin also usually relieves angina, within 30 seconds to several minutes. The history can be used to classify symptoms as typical, atypical, or noncardiac chest pain6 (Table 5). The patient presenting with angina must be categorized as having stable angina or UA.4,4a UA is defined as new onset, increasing (in frequency, intensity, or duration), or occurring at rest50 (Table 6). However, patients presenting with UA are subdivided by their short-term risk (Table 2). Patients at high or moderate risk often have experienced rupture of coronary artery plaque and have a risk of death higher than that of patients with stable angina but not as great as that of patients with AMI. These patients should be transferred promptly to an emergency department for evalu- ation and treatment. The short-term prognosis of patients with low-risk UA, however, is comparable to those with stable angina, and their evaluation can be conducted safely and expeditiously in an outpatient setting. After thorough characterization of chest pain, the presence of risk factors for IHD55 should be determined. These include smoking, hyperlipidemia, diabetes mellitus, hypertension, obesity or metabolic syndrome, physical inactivity, and a family history of premature IHD (ie, onset in a father, brother, or son before age 55 years or a mother, sister, or daughter before age 65 years). A history of cerebrovascular or periph- eral artery disease (PAD) also increases the likelihood of IHD. 2.1.3. Physical Examination The examination is often normal or nonspecific in patients with stable angina56 but could reveal related conditions such as heart failure, valvular heart disease, or hypertrophic cardiomyopathy. An audible rub suggests pericardial or Potential revascularization procedure warranted based on assessment of coexisting cardiac and noncardiac factors and patient preferences? Perform coronary angiography Yes Heart Team concludes that anatomy and clinical factors indicate revascularization may improve survival (Table 18) Determine optimal method of revascularization based upon patient preferences, anatomy, other clinical factors, and local resources and expertise (Table 18) Yes No No Noninvasive testing suggests high-risk coronary lesion(s) from Figure 2 Continued Guideline- Directed Medical Therapy with ongoing patient education Go to Figure 4 Guideline-Directed Medical Therapy continued in all patients Figure 5. Algorithm for revascularization to improve survival of patients with SIHD.* *Colors correspond to the class of recommendations in the ACCF/AHA Table 1. The algorithms do not represent a comprehensive list of recommenda- tions (see text for all recommendations). pleural disease. Evidence of vascular disease includes carotid or renal artery bruits, a diminished pedal pulse, or a palpable abdominal aneurysm. Elevated blood pressure (BP), xantho- mas, and retinal exudates point to the presence of IHD risk factors. Pain reproduced by pressure on the chest wall suggests a musculoskeletal etiology but does not eliminate the possibility of angina due to IHD. 2.1.4.1. Resting Electrocardiography to Assess Risk: Recommendation Class I 1. A resting ECG is recommended in patients without an obvious, noncardiac cause of chest pain.57 59 (Level of Evidence: B) Patients with SIHD who have the following abnormalities on a resting ECG have a worse prognosis than those with normal ECGs57 59: evidence of prior MI, especially Q waves in multiple leads or an R wave in V1 indicating a posterior infarction60; persistent ST-T-wave inversions, particularly in leads V1 to V361 64; left bundle-branch block (LBBB), bifascicular block, second- or third-degree atrioventricular Figure 6. Algorithm for revascularization to improve symptoms of patients with SIHD.* *Colors correspond to the class of recommendations in the ACCF/AHA Table 1. The algorithms do not represent a comprehensive list of recommenda- tions (see text for all recommendations). CABG indicates coronary artery bypass graft; PCI, percutaneous coronary intervention. Table 5. Clinical Classification of Chest Pain Typical angina (definite) 1) Substernal chest discomfort with a characteristic quality and duration that is 2) provoked by exertion or emotional stress and 3) relieved by rest or nitroglycerin Atypical angina (probable) Meets 2 of the above characteristics Noncardiac chest pain Meets 1 or none of the typical anginal characteristics Adapted from Braunwald et al.6 Fihn et al Stable Ischemic Heart Disease: Full Text e369 (AV) block, or ventricular tachyarrhythmia65; or left ventric- ular (LV) hypertrophy.62,66 2.1.5. Differential Diagnosis Although the symptoms of some patients might be consistent with a very high probability of IHD, in others, the etiology might be less certain, and alternative diagnoses should be considered (Table 7). However, even when angina seems likely to be related to IHD, other coexisting conditions can precipitate symptoms by inducing or exacerbating myocardial ischemia, by either increased myocardial oxygen demand or decreased myocardial oxygen supply (Table 8). When severe, these conditions can cause angina in the absence of signifi- cant anatomic coronary obstruction. Chest pain in women is less often due to IHD than in men, even when the pain is typical. Nevertheless, pain in women can be related to vascular dysfunction in the absence of epicardial CAD. Entities that cause increased oxygen demand include hyper- thermia (particularly if accompanied by volume contrac- tion),67 hyperthyroidism, and cocaine or methamphetamine abuse. Sympathomimetic toxicity, due, for example, to co- caine intoxication, not only increases myocardial oxygen demand but also induces coronary vasospasm and can cause infarction in young patients. Long-term cocaine use can cause premature development of IHD.68,69 Severe uncontrolled hypertension increases LV wall tension, leading to increased myocardial oxygen demand and decreased subendocardial perfusion. Hypertrophic cardiomyopathy and aortic stenosis can induce even more severe LV hypertrophy and resultant wall tension. Ventricular or supraventricular tachycardias are another cause of increased myocardial oxygen demand, but when paroxysmal these are difficult to diagnose. Anemia is the prototype for conditions that limit myocar- dial oxygen supply. Cardiac output rises when the hemoglo- bin drops to ,9 g/dL, and ST-T-wave changes (depression or inversion) can occur at levels ,7 g/dL. Hypoxemia resulting from pulmonary disease (eg, pneu- monia, asthma, chronic obstructive pulmonary disease, pul- monary hypertension, interstitial fibrosis, or obstructive sleep apnea) can also precipitate angina. Polycythemia, leukemia, thrombocytosis, and hypergammaglobulinemia are associated with increased blood viscosity that can decrease coronary artery blood flow and precipitate angina, even in patients without significant coronary stenoses. 2.1.6. Developing the Probability Estimate When the clinical evaluation is complete, the practitioner must determine whether the probability of IHD is sufficient to recommend further testing, which is often a standard exercise test. When the probability of disease is ,5%, further testing is usually not warranted because the likelihood of a false- positive test (ie, positive test in the absence of obstructive CAD) is actually higher than that of a true positive. On the other hand, when the exercise test is negative in a patient who has a very high likelihood of IHD on the basis of the history, there is a substantial chance that in reality the result is falsely negative. Thus, further testing is most useful in patients in whom the cause of chest pain is truly uncertain (ie, the probability of IHD is between 20% and 70%). It is necessary to note, however, that these probabilities relate solely to the presence of obstructive CAD and do not pertain to ischemia due to microvascular disease or other causes. They also do not reflect the likelihood that a nonobstructing plaque could become unstable and cause ischemia. A landmark study52 showed how information about the type of pain and age and sex of the patient can provide a reasonable estimate of the likelihood of IHD. For instance, a 64-year-old man with typical angina has a 94% likelihood of having significant coronary stenosis. A 32-year-old woman with nonanginal chest pain has a 1% chance of coronary stenosis.70 72 Other clinical characteristics that improved the accuracy of prediction include active or recent smoking, Q-wave or ST-T-wave changes on the ECG, hyperlipidemia (defined at the time of study as a total cholesterol level .250 mg/dL), and diabetes mellitus (defined at that time as a fasting glucose level .140 mg/dL). Of these characteristics, Table 6. Three Principal Presentations of UA Rest angina Angina occurring at rest and usually prolonged .20 min, occurring within 1 wk of presentation New-onset angina Angina of at least CCS Class III severity with onset within 2 mo of initial presentation Increasing angina Previously diagnosed angina that is distinctly more frequent, longer in duration, or lower in threshold (ie, increased by $1 CCS class within 2 mo of initial presentation to at least CCS Class III severity) CCS indicates Canadian Cardiovascular Society. Reproduced from Braunwald.50 Table 7. Alternative Diagnoses to Angina for Patients With Chest Pain Nonischemic Cardiovascular Pulmonary Gastrointestinal Chest Wall Psychiatric Aortic dissection Pulmonary embolism Esophageal Esophagitis Spasm Reflux Costochondritis Fibrositis Rib fracture Sternoclavicular arthritis Herpes zoster (before the rash) Anxiety disorders Hyperventilation Panic disorder Primary anxiety Pericarditis Pneumothorax Pneumonia Pleuritis Biliary Colic Cholecystitis Choledocholithiasis Cholangitis Peptic ulcer Pancreatitis Affective disorders (ie, depression) Somatiform disorders Thought disorders (ie, fixed delusions) Reproduced from Gibbons et al.7 diabetes mellitus had the greatest influence on increasing the probability of IHD. The presence of hypertension or a family history of premature IHD did not provide additional predic- tive accuracy. The results of the aforementioned landmark study subsequently were replicated with data from CASS (Coronary Artery Surgery Study)73 and were within 5% of the original estimates for 23 of 24 patient groupings. The single major exception was the category of adults who were #50 years of age with atypical angina, for whom the CASS estimate was 17% higher. On the basis of this high degree of concordance, the data from these studies were merged in the 2002 Chronic Stable Angina guideline7,52,73 (Table 9). Additional validation studies were conducted with data from the Duke Databank for Cardiovascular Disease, which also incorporated electrocardiographic findings (Q waves or ST-T changes) and information about risk factors (smoking, diabetes mellitus, hyperlipidemia).71 Table 10 presents the Duke data for mid-decade patients (35, 45, 55, and 65 years of age). Two probabilities are given. The first is for a low-risk patient with no risk factors and a normal ECG. The second is for a high-risk patient who smokes and has diabetes mellitus and hyperlipidemia but has a normal ECG. A key contribu- tion of the Duke Databank is the value of incorporating data about risk factors into the probability estimate. A limitation of these predictive models, however, is that because they were developed with data from patients referred to university medical centers, they tended to overestimate the likelihood of IHD in patients at lower risk. It is possible to correct this referral (or ascertainment) bias by using the overall prevalence of IHD in the primary-care population,72 although these adjustments are themselves subject to error if the prevalence estimates are flawed. An additional limitation of these models is that they were derived from populations of patients #70 years of age. Yet another drawback is that they perform less well in women, in part because the prevalence of obstructive CAD is lower in women than in men. As shown in Table 9, the Diamond- Forrester model substantially overestimates the likelihood of CAD compared with the prevalence observed in the WISE After integrating data from the clinical evaluation, model predictions, and other relevant factors to develop a probabil- ity estimate, the clinician must then engage the patient in a process of shared decision making, as noted in Section 1.8, to determine whether further testing is warranted. 2.2. Noninvasive Testing for Diagnosis of IHD 2.2.1. Approach to the Selection of Diagnostic Tests to Diagnose SIHD Functional or stress testing to detect inducible ischemia has been the gold standard and is the most common noninva- sive test used to diagnose SIHD. All functional tests are designed to provoke cardiac ischemia by using exercise or pharmacological stress agents either to increase myocardial work and oxygen demand or to induce vasodilation-elicited heterogeneity in induced coronary flow. These techniques Table 8. Conditions Provoking or Exacerbating Ischemia Increased Oxygen Demand Decreased Oxygen Supply Noncardiac Noncardiac Hyperthermia Hyperthyroidism Sympathomimetic toxicity (ie, cocaine use) Hypertension Anxiety Arteriovenous fistulae Anemia Hypoxemia Pneumonia Asthma Chronic obstructive pulmonary disease Pulmonary hypertension Interstitial pulmonary fibrosis Obstructive sleep apnea Sickle cell disease Sympathomimetic toxicity (ie, cocaine use, pheochromocytoma) Hyperviscosity Polycythemia Leukemia Thrombocytosis Hypergammaglobulinemia Cardiac Cardiac Hypertrophic cardiomyopathy Aortic stenosis Dilated cardiomyopathy Tachycardia Ventricular Supraventricular Aortic stenosis Hypertrophic cardiomyopathy Significant coronary obstruction Microvascular disease Modified from Gibbons et al.7 Table 9. Pretest Likelihood of CAD in Symptomatic Patients According to Age and Sex* (Combined Diamond/Forrester and CASS Data) Age, y Nonanginal Chest Pain Atypical Angina Typical Angina Men Women Men Women Men Women CAD indicates coronary artery disease; and CASS, Coronary Artery Surgery Study. * Each value represents the percent with significant CAD on catheterization. Adapted from Forrester and Diamond.52,73 Table 10. Comparing Pretest Likelihood of CAD in Low-Risk Symptomatic Patients With High-Risk Symptomatic Patients (Duke Database) Age, y Nonanginal Chest Pain Atypical Angina Typical Angina Men Women Men Women Men Women Each value represents the percentage with significant CAD. The first is the percentage for a low-risk, mid-decade patient without diabetes mellitus, smoking, or hyperlipidemia. The second is that of a patient of the same age with diabetes mellitus, smoking, and hyperlipidemia. Both high- and low-risk patients have normal resting ECGs. If ST-T-wave changes or Q waves had been present, the likelihood of CAD would be higher in each entry of the table. CAD indicates coronary artery disease; and ECG, electrocardiogram. Reprinted from Pryor et al.71 Fihn et al Stable Ischemic Heart Disease: Full Text e371 rely on the principles embodied within the ischemic cascade (Figure 7), in which graded ischemia of increasing severity and duration produces sequential changes in perfusion, relax- ation and contraction, wall motion, repolarization, and, ulti- mately, symptoms, all of which can be detected by an array of cardiovascular testing modalities.75 The production of ische- mia, however, depends on the severity of stress imposed (ie, submaximal exercise can fail to produce ischemia) and the severity of the flow disturbance. Coronary stenoses ,70% are often undetected by functional testing. Because abnormalities of regional or global ventricular function occur later in the ischemic cascade, they are more likely to indicate severe stenosis and, thus, demonstrate a higher diagnostic specificity for SIHD than do perfusion defects, such as those seen on nuclear MPI. Isolated perfusion defects, on the other hand, can result from stenoses of borderline significance, raising the sensitivity of nuclear MPI for underlying CAD but lowering the specificity for more severe stenosis. The recent availability of multislice CCTA allows for the noninvasive visualization of anatomic CAD with high- resolution images similar to invasive coronary angiography. As would be expected, CCTA and invasive angiography exhibit a high degree of concordance, as they are both anatomic tests, and CCTA is more sensitive in detecting obstructive CAD, especially at diameter stenosis #70%, than is nuclear MPI.76 The accuracy of a CCTA reader in estimating coronary stenosis within a vessel is hindered by the presence of dense coronary calcification and a tendency to overestimate the severity of lesions relative to invasive angiography.77 No direct comparisons of the effectiveness of a functional ap- proach with inducible ischemia or an anatomic approach assessing coronary stenosis have been completed in the noninvasive setting, although several randomized controlled trials (RCTs) are under way, which will directly or indirectly compare test modalities: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain; clinicaltrials.gov identifier NCT01174550), RESCUE (Randomized Evalua- tion of Patients With Stable Angina Comparing Diagnostic Examinations; clinicaltrials.gov identifier NCT01262625), and ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; clini- caltrials.gov identifier NCT01471522). In 2010, the United Kingdom s National Institute for Clinical Excellence Guidance for Chest pain of recent onset: Assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin provide, for a health- care system that allocates resources differently from that of the United States, recommendations for an initial assessment of CAD. This Guidance recommends beginning in people without confirmed CAD with a detailed clinical assessment and performing a 12-lead ECG in those in whom stable angina cannot be diagnosed or excluded on the basis of clinical assessment alone. The Guidance suggests that there is no need for further testing in those with an estimated likelihood ,10%. In those with an estimated likelihood of CAD of 10% to 29%, the National Institute for Clinical Excellence document recommends beginning with CT coro- nary artery calcium (CAC) scoring as the first-line diagnostic investigation, whereas the present SIHD guideline provides a Class IIb recommendation for several reasons, as outlined in Section 2.2.4.2. 2.2.1.1. Assessing Diagnostic Test Characteristics A hierarchy of diagnostic test evidence has been proposed by Fryback and Thornbury78 and ranges from evidence on technical quality (level 1) through test accuracy (sensitivity and specificity associated with test interpretation), to changes in diagnostic thinking, effect on patient management, and patient outcomes, to societal costs and benefits (level 6). A similar framework has been proposed for biomarkers by Hlatky et al.79 In practice, although knowledge of the effect of diagnostic testing on outcomes would be highly desirable, the vast majority of available evidence is on diagnostic or prognostic accuracy. Therefore, this information most com- monly is used to compare test performance. Diagnostic accuracy is commonly represented by the terms sensitivity and specificity, which are calculated by comparing test results to the gold standard of the results of invasive coronary angiography. The sensitivity of any noninvasive test to diagnose SIHD expresses the frequency that a patient with angiographic IHD will have a positive test result, whereas the specificity measures the frequency that a patient without IHD will have a negative result. In addition, predictive accuracy represents the frequency that a patient with a positive test does have IHD (positive predictive value) or that a patient with a negative test truly does not have IHD (negative predictive value). The predictive accuracy may be used for both diagnostic and prognostic accuracy analyses; in the latter case, the comparison is to subsequent cardiovascular events. It is important to note that apparent test performance can be altered substantially by the pretest probability of IHD,52,80,81 making the accurate assessment of pretest probability and proper patient selection essential for diagnostic interpretation statements on IHD prevalence by test results. The positive predictive value of a test declines as the disease prevalence decreases in the population under study, whereas the negative predictive accuracy increases.82 Finally, the performance of noninvasive tests also varies in certain patient populations, Figure 7. The Ischemic Cascade. Reproduced with permission from Shaw et al.75 such as obese patients, the elderly, and women (Section 5.12), who often are underrepresented in clinical studies. Estimates of all test characteristics are subject to workup bias, also known as verification or posttest referral bias.81,83,84 This bias occurs when the results of stress testing are used to decide which patients undergo the standard reference proce- dure (invasive coronary angiography) to establish a definitive diagnosis of IHD (ie, patients with positive results on stress testing are referred for coronary angiography, whereas those with negative results are not). This bias has the effect of raising the measured sensitivity and lowering the measured specificity in relation to their true values. Mathematical corrections can be applied to estimate corrected values.84 86 Diagnostic testing is most valuable when the pretest probability of IHD is intermediate for example, when a 50-year-old man has atypical angina, and the probability of IHD is approximately 50% (Table 9). The precise definition of intermediate probability (ie, between 10% and 90%, 20% and 80%, or 30% and 70%) is somewhat arbitrary. In addition to these boundaries, other factors are important in the deci- sion to refer a patient to testing, including the degree of uncertainty acceptable to the physician and patient; the likelihood of an alternative diagnosis; the accuracy of the diagnostic test selected (ie, sensitivity and specificity), test reliability, procedural cost, and the potential risks of further testing; and the benefits and risks of treatment in the absence of additional testing. A definition of 10% and 90%, first advocated in 1980,87 has been applied in several studies.88,89 Although broad, this range still excludes several sizable patient groups (eg, older men with typical angina and younger women with nonanginal pain). When the probability of IHD is high, a positive test result is merely confirmatory, whereas a negative test result might not diminish the probability of disease sufficiently to be clinically useful and could even be misleading because of the possibility that it is a false negative result. When the probability of IHD is very low, however, a negative test result is simply confirmatory, whereas a positive test result might not be clinically useful and could be misleading if falsely positive. The importance of relying on clinical judgment and refraining from testing in very low-risk populations is well illustrated by a thought experiment proposed by Diamond and Kaul in a letter to the editor of The New England Journal of Medicine: As an example, suppose we have a test marker with 80% sensitivity and 80% specificity (typical of car- diac stress tests). Given 100 individuals with a 10% disease prevalence, there will be 8 true positives (10030.130.8) and 18 false positives (10030.930.2). If we refer only these 26 positive responders for angiography, the observed diagnostic yield is only 31% (8/26). Moreover, the test s sensitivity will appear to be 100% (all diseased subjects having a positive test), and its specificity will appear to be 0% (all non-diseased subjects also having a positive test). Hence, the more we rely on a test, the less well it appears to perform. (p. 93)90 The likelihood of CAD proposed above differs substantially from that in the populations from which the estimates of noninvasive test performance were derived; the overall prev- alence of CAD from a meta-analysis was 60%.91 Instead, contemporary age-, sex-, and symptom-based IHD probabil- ity estimates can be gleaned from a multicenter cohort of 14 048 patients with suspected IHD undergoing CCTA.92 2.2.1.2. Safety and Other Considerations Potentially Affecting Test Selection All forms of noninvasive stress testing carry some risk. Maximal exercise testing is associated with a low but finite incidence of cardiac arrest, AMI, and even death. Pharmaco- logical stress agents fall into 2 broad categories: beta-agonists such as dobutamine, which increase heart rate and inotropy, and vasodilators such as adenosine, dipyridamole, or regade- noson, which act to increase blood flow to normal arteries while decreasing perfusion to stenotic vessels. Each of these pharmacological stress agents also carries a very small risk of drug-specific adverse events (dobutamine: ventricular ar- rhythmias; dipyridamole/adenosine: bronchospasm in chronic obstructive pulmonary disease). Nuclear perfusion imaging and CCTA use ionizing radia- tion techniques for visualizing myocardial perfusion and anatomic CAD, respectively. Risk projections are based largely on observations from atomic bomb survivors exposed to higher levels of ionizing radiation. The Linear-No- Threshold hypothesis states that any exposure could result in an increased projected cancer risk and that there is a dose response relationship to elevated cancer risk with higher exposures. Considerable controversy exists surrounding the extrapolation of projected cancer risk to low-level exposure in medical testing, and no reported evidence links low-level exposure to observed cancer risk. Even when the Linear-No- Threshold hypothesis is used, the projected incident cancer is estimated to be very low for nuclear MPI and CCTA.93 95 Nevertheless, general agreement exists that the overriding principle of caution and safety should apply by projecting the Linear-No-Threshold hypothesis. The principle of As Low as Reasonably Achievable (ALARA) should be applied in all patient populations. For CCTA performed with contemporary equipment in accor- dance with the Society of Cardiovascular Computed Tomog- raphy recommendations, average estimated radiation dose ranges from 5 to 10 mSv.96 For stress nuclear MPI, when the American Society of Nuclear Cardiology recommended rest- stress Tc-99m SPECT or Rb-82 positron emission tomogra- phy (PET) protocol97 is used, the estimated radiation dose is approximately 11 or 3 mSV, respectively.97,98 On the basis of American Society of Nuclear Cardiology guidelines, dual- isotope or rest-stress Tl-201 imaging is discouraged for diagnostic procedures because of its high radiation exposure. The use of new high-efficiency nuclear MPI cameras results in a similar or lower effective dose for both dual-isotope and rest-stress Tc-99m imaging.99 101 For both CT and nuclear imaging, the AHA, Society of Cardiovascular Computed Tomography, and American Society of Nuclear Cardiology recommend widespread application of dose-reduction tech- niques whenever possible.96 98 Clinicians should apply the concept of benefit-to-risk ratio when considering testing. When testing is used appropriately, the clinical benefit in Fihn et al Stable Ischemic Heart Disease: Full Text e373 terms of supportive diagnostic or prognostic accuracy ex- ceeds the projected risk such that there is an advantage to testing.13,14 When it is used inappropriately or overused, the benefit of testing is low, and the risk of exposure is unac- ceptably high. Of note, care should be taken when exposing low-risk patients to ionizing radiation. This is particularly of concern in younger patients for whom the projected cancer risk is elevated.102 Use of contrast agents with CCTA can cause allergic reactions. Contrast agents also can affect renal function and therefore should be avoided in patients with chronic kidney disease. CMR might be contraindicated in patients with claustrophobia or implanted devices, and use of gadolinium contrast agents is associated rarely with nephrogenic systemic fibrosis. For this reason, gadolinium is contraindicated in patients with severe renal dysfunction (estimated glomerular ), and the dose should be adjusted for patients with mild to moderate dysfunction (estimated glomerular filtration rates 30 to 60 mL/min per ). As with all safety considerations, the potential risks need to be considered carefully in concert with the potential benefits from the added information obtained to guide care. In addition to pretest likelihood, a variety of clinical factors influence noninvasive test selection.103 105 Chief among these are the patient s ability to exercise, body habitus, cardiac medication use, and ECG interpretability. The decision to add imaging in patients who have an interpretable ECG and are capable of vigorous exercise is important because imaging and nonimaging testing have different diagnostic accuracies, predictive values, and costs. Most, but not all, studies evaluating cohorts of patients undergoing both exercise ECG and stress imaging have shown that the addition of imaging information provides incremental benefit in terms of both diagnostic and prognostic information with an acceptable increase in cost (Section 2.2.1.5).106 117 Other factors affecting test choice include local availability of specific tests, local expertise in test performance and interpretation, the presence of multiple diagnostic or prog- nostic questions better addressed by one form of testing over another, and the existence of prior test results (especially when prior images are available for comparison). Finally, although echocardiographic, radionuclide, and CMR stress imaging can have complementary roles for estimating patient prognosis, there is rarely a reason to perform multiple tests in the same patient, unless the results of the initial imaging test are unsatisfactory for technical reasons or the findings are equivocal or require confirmation. 2.2.1.3. Exercise Versus Pharmacological Testing When a patient is able to perform routine activities of daily living without difficulty, exercise testing to provoke ischemia is preferred because it often can provide a higher physiolog- ical stress than would be achieved by pharmacological testing. This can translate into a superior ability to detect ischemia as well as providing a correlation to a patient s daily symptom burden and physical work capacity not offered by pharmacological stress testing. In addition, exercise capacity alone is a very strong prognostic indicator.118,119 The goal of exercise testing for suspected SIHD patients is 1) to achieve high levels of exercise (ie, maximal exertion), which in the setting of a negative ECG generally and reliably excludes obstructive CAD, or 2) to document the extent and severity of ECG changes and angina at a given workload (ie, demand ischemia) so as to predict the likelihood of underly- ing significant or severe CAD. Thus, candidates for exercise testing must possess sufficient functional capacity to attain maximal, volitional stress levels. Because there is high variability in age-predicted maximal heart rate among sub- jects of identical age,120 achieving 85% of age-predicted maximal heart rate might not indicate sufficient effort during exercise testing and should not be used as a criterion to terminate a stress test.121 Failure to reach peak heart rate (if beta blockers have been held as recommended) or to achieve adequate levels of exercise in the setting of a negative ECG is consistent with functional disability and results in an indeterminate estimation of CAD. Female-specific age- predicted maximal heart rate and functional capacity mea- surements are available.118,122 Standard treadmill protocols initiate exercise at 3.2 to 4.7 metabolic equivalents (METs) of work and increase by several METs every 2 to 3 minutes of exercise (eg, modified or standard Bruce protocol). Most activities of daily living require approximately 4 to 5 METs of physical work to perform. Thus, reported limitations in activities of daily living identify a patient who might be unable to perform maximal exercise. Gentler treadmill protocols, with incre- mental stages of 1 MET, or bicycle stress can help some patients achieve maximal exercise capacity. Optimal candidates with sufficient physical functioning may be identified as those capable of performing at least moderate physical functioning (ie, performing at least mod- erate household, yard, or recreational work and most activi- ties of daily living) and with no disabling comorbidity (including frailty, advanced age, marked obesity, PAD, chronic obstructive pulmonary disease, or orthopedic limita- tions). Patients incapable of at least moderate physical func- tioning or with disabling comorbidity should be referred for pharmacological stress imaging. In the setting of submaximal exercise and a negative stress ECG, consideration should be given to performing additional testing with pharmacological stress imaging to evaluate for inducible ischemia. 2.2.1.4. Concomitant Diagnosis of SIHD and Assessment of Risk Although the primary goal of testing among patients with new onset of symptoms suggesting SIHD is to diagnose or exclude obstructive CAD, the various modalities also can provide additional information about long-term risk (Section 3.3.2), and this prognostic ability may influence the selection of an initial test. Exercise capacity remains one of the strongest indicators of long-term risk (including death) for men and women with suspected and known CAD.118,123 125 In addition, information derived from treadmill exercise (eg, Duke treadmill score126,127 and heart rate recovery) provides incremental diagnostic and prognostic information. For this reason, it is preferable to perform exercise stress if the patient is able to achieve a maximal workload. For the exercise- capable patient with a normal baseline ECG, the decision to perform imaging with nuclear or echocardiographic tech- niques along with stress ECG should be based on many factors, including the likelihood of garnering substantial incremental prognostic information that is likely to alter clinical and therapeutic management. Estimates of cost-effectiveness of various testing strategies in symptomatic patients have been used to inform responses to rising healthcare costs. However, to be of value, estimates of cost-effectiveness must use contemporary estimates of effec- tiveness that incorporate considerations of disease prevalence and test accuracy. Furthermore, costs must reflect not only the index test but also the episode of care and the longer-term induced costs and outcomes of diagnosed and undiagnosed SIHD. Ideally, these data would be derived from RCTs or registries designed to compare the effectiveness of testing strategies and observed associated costs. However, in the interim until such evidence is available, mixed methods and decision analytic models provide general estimates of the cost-effectiveness of various forms of testing. Mixed methods use observational evidence of index and downstream proce- dures, hospitalization, and drug costs and apply cost weights to estimate cumulative costs,128 130 whereas decision analytic models simulate clinical and financial data.131 137 Regardless of the approach, inherent assumptions and uncertainties with regard to the data and incomplete consideration of risks and benefits require that such calculations be considered as In most studies, stress imaging is estimated to provide a benefit over exercise ECG at a reasonable cost, commensu- rate with accepted values for cost effectiveness (ie, at the threshold for economic efficiency of ,$50 000 per added year of life), a result driven primarily by more frequent angiography and adverse cardiovascular events for those with a negative exercise ECG. Results of decision analytic and mixed modeling approaches comparing stress echocardiogra- phy with myocardial perfusion SPECT vary, with some favoring exercise echocardiography and others favoring ex- ercise nuclear MPI.128,133 The patient s pretest likelihood of CAD also influences cost-effectiveness such that exercise echocardiography is more cost-effective in lower-risk patients (with annual risk of death or MI ,2%) than in higher-risk patients, in whom nuclear MPI is more cost-effective. Use of invasive coronary angiography as a first test is not cost-effective in patients with a pretest probability ,75%.139,140 Finally, it is important to note that as the reimbursement for stress imaging decreases (it is now less than half the value used in older studies), the relative cost-effectiveness (dollars/quality-adjusted life-year saved) of stress imaging is more favorable than that of exercise ECG, and the comparative advantage of lower- to higher-cost imaging procedures is minimized. The cost-efficiency of CCTA is less well studied but also depends on disease prevalence.139,140 Data conflict as to whether patients undergoing CCTA as initial imaging modal- ity are less or more likely to undergo invasive coronary angiography or revascularization, although it appears that they have similar or lower rates of adverse cardiovascular events.128,130,141,142 As a result, CCTA performed alone or in combination with functional testing minimizes adverse car- diac events, maximizes quality-adjusted life-years,140,143 and is estimated to be cost-effective. Although data on cost-effectiveness and patient satisfac- tion for CMR are limited, evidence suggests that CMR can improve patient management. The German Pilot/European Cardiovascular Magnetic Resonance (EuroCMR) registry of 11 040 consecutive patients evaluated for cardiomyopathy, ischemia, and myocardial viability found that CMR satisfied all requested imaging needs in 86% of patients so that no further imaging was required.144 In the 3351 stress CMR cases, invasive angiography was avoided in 45%, compared with 18% in patients who underwent nuclear imaging. 2.2.2. Stress Testing and Advanced Imaging for Initial Diagnosis in Patients With Suspected SIHD Who Require Noninvasive Testing: Recommendations See Table 11 for a summary of recommendations from this section. 2.2.2.1. Able to Exercise Class I 1. Standard exercise ECG testing is recommended for patients with an intermediate pretest probability of IHD who have an interpretable ECG and at least moderate physical functioning or no disabling co- morbidity.114,145 147 (Level of Evidence: A) 2. Exercise stress with nuclear MPI or echocardiogra- phy is recommended for patients with an intermedi- ate to high pretest probability of IHD who have an uninterpretable ECG and at least moderate physical functioning or no disabling comorbidity.91,132,148 156 (Level of Evidence: B) Class IIa 1. For patients with a low pretest probability of ob- structive IHD who do require testing, standard exercise ECG testing can be useful, provided the patient has an interpretable ECG and at least mod- erate physical functioning or no disabling comorbid- ity. (Level of Evidence: C) 2. Exercise stress with nuclear MPI or echocardiogra- phy is reasonable for patients with an intermediate to high pretest probability of obstructive IHD who have an interpretable ECG and at least moderate physical functioning or no disabling comorbid- ity.91,132,148 156 (Level of Evidence: B) 3. Pharmacological stress with CMR can be useful for patients with an intermediate to high pretest prob- ability of obstructive IHD who have an uninterpre- table ECG and at least moderate physical function- ing or no disabling comorbidity.153,157,158 (Level of Evidence: B) Class IIb 1. CCTA might be reasonable for patients with an intermediate pretest probability of IHD who have at Fihn et al Stable Ischemic Heart Disease: Full Text e375 least moderate physical functioning or no disabling comorbidity.158 166 (Level of Evidence: B) 2. For patients with a low pretest probability of ob- structive IHD who do require testing, standard exercise stress echocardiography might be reason- able, provided the patient has an interpretable ECG and at least moderate physical functioning or no disabling comorbidity. (Level of Evidence: C) Class III: No Benefit 1. Pharmacological stress with nuclear MPI, echocar- diography, or CMR is not recommended for patients who have an interpretable ECG and at least moder- ate physical functioning or no disabling comorbid- ity.155,167,168 (Level of Evidence: C) 2. Exercise stress with nuclear MPI is not recom- mended as an initial test in low-risk patients who have an interpretable ECG and at least moderate physical functioning or no disabling comorbidity. (Level of Evidence: C) 2.2.2.2. Unable to Exercise Class I 1. Pharmacological stress with nuclear MPI or echo- cardiography is recommended for patients with an intermediate to high pretest probability of IHD who are incapable of at least moderate physical function- ing or have disabling comorbidity.148 150,152 156 (Level of Evidence: B) Class IIa 1. Pharmacological stress echocardiography is reason- able for patients with a low pretest probability of Table 11. Stress Testing and Advanced Imaging for Initial Diagnosis in Patients With Suspected SIHD Who Require Noninvasive Testing Test Exercise Status ECG Interpretable Pretest Probability of IHD COR LOE References Able Unable Yes No Low Intermediate High Patients able to exercise* Exercise ECG X X X I A (114, 145 147) Exercise with nuclear MPI or Echo X X X X I B (91, 132, 148 156) Exercise ECG X X X IIa C N/A Exercise with nuclear MPI or Echo X X X X IIa B (91, 132, 148 156) Pharmacological stress CMR X X X X IIa B (153, 157, 158) CCTA X Any X IIb B (158 166) Exercise Echo X X X IIb C N/A Pharmacological stress with nuclear MPI, Echo, or CMR X X Any III: No Benefit C (155, 167, 168) Exercise stress with nuclear MPI X X X III: No Benefit C N/A Patients unable to exercise Pharmacological stress with nuclear MPI or Echo X Any X X I B (148 150, 152 156) Pharmacological stress Echo X Any X IIa C N/A CCTA X Any X X IIa B (158 166) Pharmacological stress CMR X Any X X IIa B (153, 157, 158, 169 172) Exercise ECG X X Any III: No Benefit C (91, 132, 148 156, 161) Other CCTA If patient has any of the following: a) Continued symptoms with prior normal test, or b) Inconclusive exercise or pharmacological stress, or c) Unable to undergo stress with MPI or Echo Any Any X IIa C (173) CAC score Any Any X IIb C (174) CAC indicates coronary artery calcium; CCTA, cardiac computed tomography angiography; CMR, cardiac magnetic resonance imaging; COR, class of recommendation; ECG, electrocardiogram; Echo, echocardiography; IHD, ischemic heart disease; LOE, level of evidence; MPI, myocardial perfusion imaging; N/A, not available; and SIHD, stable ischemic heart disease. *Patients are candidates for exercise testing if they are capable of performing at least moderate physical functioning (ie, moderate household, yard, or recreational work and most activities of daily living) and have no disabling comorbidity. Patients should be able to achieve 85% of age-predicted maximum heart rate. IHD who require testing and are incapable of at least moderate physical functioning or have disabling comorbidity. (Level of Evidence: C) 2. CCTA is reasonable for patients with a low to intermediate pretest probability of IHD who are incapable of at least moderate physical functioning or have disabling comorbidity.158 166 (Level of Evi- dence: B) 3. Pharmacological stress CMR is reasonable for pa- tients with an intermediate to high pretest probabil- ity of IHD who are incapable of at least moderate physical functioning or have disabling comorbid- ity.153,157,158,169 172 (Level of Evidence: B) Class III: No Benefit 1. Standard exercise ECG testing is not recommended for patients who have an uninterpretable ECG or are incapable of at least moderate physical function- ing or have disabling comorbidity.91,132,148 156,161 (Level of Evidence: C) Class IIa 1. CCTA is reasonable for patients with an intermedi- ate pretest probability of IHD who a) have continued symptoms with prior normal test findings, or b) have inconclusive results from prior exercise or pharma- cological stress testing, or c) are unable to undergo stress with nuclear MPI or echocardiography.173 (Level of Evidence: C) Class IIb 1. For patients with a low to intermediate pretest probability of obstructive IHD, noncontrast cardiac CT to determine the CAC score may be consid- ered.174 (Level of Evidence: C) See Online Data Supplement 1 for additional data on diag- nostic accuracy of stress testing and advanced imaging for the diagnosis of suspected SIHD. 2.2.3. Diagnostic Accuracy of Nonimaging and Imaging Stress Testing for the Initial Diagnosis of Suspected SIHD 2.2.3.1. Exercise ECG The exercise ECG has been the cornerstone of diagnostic testing of SIHD patients for several decades. The diagnostic endpoint for an ischemic ECG is $1 mm horizontal or down-sloping (at 80 ms after the J point) ST-segment depression at peak exercise. ST-segment elevation (in a non Q-wave lead and excluding aortic valve replacement) during or after exercise occurs infrequently but represents a high-risk ECG finding consistent with an ACS. The diagnos- tic accuracy of exertional ST-segment depression has been studied extensively in several meta-analyses, systematic re- views, large observational registries, and RCTs.114,145 147,175 The composite diagnostic sensitivity and specificity, unad- justed for referral bias, is 61% and ranges from 70% to 77%, but it is lower in women146,147,175 and lower than that for stress imaging modalities. A similar accuracy has been reported for correlation of ECG ischemia with anatomic CAD by CCTA.176 Diagnostic accuracy is improved when consid- eration is given to additional non-ECG factors, such as exercise duration, chronotropic incompetence, angina, ven- tricular arrhythmias, heart rate recovery, and hemodynamic response to exercise (ie, drop in systolic BP), or when combination scores such as the Duke treadmill or Lauer scores are applied.118,177 180 Multiple factors in addition to the patient s inability to achieve maximal exercise levels influence the accuracy of the ECG during exercise testing to diagnose obstructive CAD. Resting ECG abnormalities preclude accurate interpretation of exercise-induced changes and reduce test accuracy; these include abnormalities affecting the ST segment, such as LV hypertrophy, LBBB, ventricular-paced rhythm, or any resting ST-segment depression $0.5 mm. Although some have proposed calculating the difference from rest to exercise of changes $1 mm for patients with significant resting ST- segment changes, the accuracy of this approach has been less extensively studied and validated. The interpretation of ST- segment changes in patients with right bundle-branch block can be limited, especially in the precordial leads. Certain medications, including digitalis, also influence ST-segment changes and can produce ischemic ECG changes that are frequently false positive findings. In addition, anti-ischemic therapies can reduce heart rate and myocardial workload, and therefore, a lack of ischemic ECG changes can reflect false negative findings when the test is used to diagnose SIHD. It is routine practice to withhold beta-blocker therapy for 24 to 48 hours before testing. Patients who are candidates for an exercise ECG must be able to exercise and must have an interpretable ECG, which is defined as a normal 12-lead ECG or one with minimal resting ST-T-wave abnormalities (,0.5 mm). 2.2.3.2. Exercise and Pharmacological Stress Echocardiography The diagnostic endpoint of exercise and pharmacological stress echocardiography is new or worsening wall motion abnormalities and changes in global LV function during or immediately after stress. In addition to the detection of inducible wall motion abnormalities, most stress echocardi- ography includes screening images to evaluate resting ven- tricular function and valvular abnormalities. This information can be helpful in a symptomatic patient without a proven diagnosis. Pharmacological stress echocardiography in the United States is performed largely by using dobutamine with an endpoint of inducible wall motion abnormalities (Table 11). Vasodilator agents such as adenosine are used rarely in the United States but are used more commonly in Europe. The diagnostic accuracy of exercise and pharmacological stress echocardiography has been studied extensively in multiple meta-analyses, systematic reviews, and large, multicenter, observational registries.91,148 152,154,175 In several contempo- rary meta-analyses, the diagnostic sensitivity (uncorrected for referral bias) ranged from 70% to 85% for exercise and 85% to 90% for pharmacological stress echocardiogra- phy.91,150,152,154 The uncorrected diagnostic specificity ranges Fihn et al Stable Ischemic Heart Disease: Full Text e377 from 77% to 89% and 79% to 90% for exercise and pharmacological stress echocardiography, respectively. The use of intravenous ultrasound contrast agents can improve endocardial border delineation and can result in improved diagnostic accuracy.181 Myocardial contrast echocardiogra- phy also has been examined for determination of rest and stress myocardial perfusion, with the results showing compa- rability to myocardial perfusion SPECT findings in small patient series.182 However, the technique is currently in limited use in the United States. The diagnostic accuracy of all imaging modalities is influenced by technical factors that could be inherent in the technique (ie, variable correlation between perfusion and wall motion abnormalities and CAD extent and severity) or that result from physical characteristics of the patient that reduce image quality. For echocardiography, reduced image quality, defined as reduced LV endocardial visualization, has been reported for obese individuals and those with chronic lung disease, although the use of intravenous contrast enhance- ment results in sizeable improvement in endocardial border delineation. 2.2.3.3. Exercise and Pharmacological Stress Nuclear Myocardial Perfusion SPECT and Myocardial Perfusion PET Myocardial perfusion SPECT generally is performed with rest and (for exercise or pharmacological stress) with stress Tc-99m agents, with Tl-201 having limited applications (eg, viability) because of its higher radiation exposure.97 Pharma- cological stress generally is used with vasodilator agents administered as a continuous infusion (adenosine, dipyridam- ole) or bolus (regadenoson) injection. The diagnostic end- point of nuclear MPI is reduction in myocardial perfusion after stress. Nonperfusion high-risk markers include a mark- edly abnormal ECG, extensive stress-induced wall motion abnormalities, reduced post-stress left ventricular ejection fraction (LVEF) $5% or global LVEF (rest or post-stress) ,45%, transient ischemic LV dilation, increased lung or right ventricular uptake, or abnormal coronary flow reserve with myocardial perfusion PET.183 186 The diagnostic accuracy for detection of obstructive CAD of exercise and pharmacological stress nuclear MPI has been studied extensively in multiple meta-analyses, systematic reviews, RCTs, and large, multicenter, observational regis- tries.91,114,132,147,148,152,155,156,175 From these reports, the uncor- rected diagnostic sensitivity ranged from 82% to 88% for exercise and 88% to 91% for pharmacological stress nuclear MPI. The uncorrected diagnostic specificity ranged from 70% to 88% and 75% to 90% for exercise and pharmacological stress nuclear MPI, respectively. Diagnostic image quality is affected in obese patients, as well as in women and men with large breasts. Reductions in breast tissue artifact have been reported with the use of the Tc-99m agents as well as with attenuation-correction algo- rithms or prone imaging.187 190 For myocardial perfusion SPECT, global reductions in myocardial perfusion, such as in the setting of left main or 3-vessel CAD, can result in balanced reduction and an underestimation of ischemic burden. Myocardial perfusion PET is characterized by high spatial resolution of the photon attenuation corrected images with Rubidium or 13 N-ammonia used as myocardial blood flow tracers. Although less well studied than myocardial perfusion SPECT, a meta-analysis of 19 studies suggests that PET has a slightly higher (uncorrected) sensitivity for detection of CAD,191,192 including in women and obese patients.193 2.2.3.4. Pharmacological Stress CMR Wall Motion/Perfusion In recent years, more centers have used pharmacological stress CMR in the diagnostic evaluation of SIHD patients. The imaging endpoint depends on the stress agent: develop- ment of a new wall motion abnormality for cine CMR with dobutamine stress or a new perfusion abnormality with vasodilator stress. From a contemporary meta-analysis of 37 studies, the uncorrected diagnostic sensitivity and specificity of dobutamine-induced CMR wall motion imaging were 83% and 86%, whereas the uncorrected diagnostic sensitivity and specificity of vasodilator stress induced CMR MPI were 91% and 81%.153 Several small comparative series have reported accuracy data in relation to stress echocardiography and nuclear imaging. Importantly, normal CMR perfusion has a high negative predictive value for obstructive CAD.194 One multicenter study that enrolled 234 patients demonstrated similar diagnostic accuracy between CMR perfusion and SPECT MPI in detecting obstructive CAD.172 More recently, a randomized study of 752 patients directly compared phar- macological stress CMR with SPECT MPI and reported higher sensitivity by pharmacological stress CMR than SPECT MPI in the detection of angiographically significant dobutamine stress, CMR wall motion had high accuracy for detection of obstructive CAD in patients with suboptimal echocardiographic acoustic window.170 CMR dobutamine wall motion imaging demonstrated higher accuracy than dobutamine echocardiography wall motion.171 Although wall motion and perfusion imaging are used to assess the presence and extent of ischemia, most experienced centers also acquire late gadolinium enhancement (LGE) imaging in the same session to delineate the extent and severity of scarred myocardium. 2.2.3.5. Hybrid Imaging Current imaging is based largely on the use of a single modality, but combined or hybrid applications increasingly are available, which include both PET and CT or SPECT and CT, thus allowing for combined anatomic and functional testing. In addition, newer scanning techniques have allowed assessment of perfusion and FFR by CCTA alone, in addition to coronary anatomy.195 201 Notably, these combined assess- ments allow for a fused image in which the physiological assessment of flow is coupled with the anatomic extent and severity of CAD and also provides information on plaque composition and arterial remodeling. Limited evidence is available on hybrid imaging, although several reports have reported prognostic accuracy for cardiac events with both ischemic and anatomic markers.202 206 Other combinations of imaging modalities also are being developed, including PET/ CMR, which is currently a research application. The strength of combined imaging is the added value of anatomy guiding interpretation of ischemic and scarred myocardium as well as providing information to guide therapeutic decision making. Hybrid imaging also can overcome technical limitations of myocardial perfusion SPECT or myocardial perfusion PET by providing anatomic correlates to guide interpretative accuracy207 and can provide the functional information that an anatomic technique like CCTA or magnetic resonance angiography lacks; however, radiation dose is increased. 2.2.4. Diagnostic Accuracy of Anatomic Testing for the Initial Diagnosis of SIHD 2.2.4.1. Coronary CT Angiography With improvements in temporal and spatial resolution as well as volume coverage, evaluation of coronary arteries with CCTA is now possible with a high degree of image quality.208 The extent and severity of angiographic CAD are 2 of the most important prognostic factors and remain essential for revascularization decision making.209 Five meta-analyses and 3 controlled clinical trials have reported the diagnostic accuracy of CCTA with 64-slice CT, yielding sensitivity values ranging from 93% to 97% and specificity values ranging from 80% to 90%159 166 for detecting obstructive CAD on invasive coronary angiography, unadjusted for referral bias. In a small series of women, the diagnostic accuracy of CCTA was similarly high.210 Prior reports in- cluded subsets of patients who already had been referred for invasive angiography, and as such, test performance would be altered by the biases inherent in a preselected population. Factors related to diminished accuracy include image quality, the extent of coronary calcification, and body mass index A potential advantage of CCTA over standard functional testing is its very high negative predictive value for obstruc- tive CAD, which can reassure caregivers that providing GDMT and deferring consideration of revascularization con- stitute a sensible strategy. In addition to documentation of stenotic lesions, CCTA can qualitatively visualize arterial remodeling and nonobstructive plaque, including calcified, noncalcified, or mixed plaque.211 216 The presence of nonob- structive plaque has been shown to be helpful to guiding risk assessment and can aid in discerning the etiology of patient symptoms.211,215,216 CT information has been correlated with functional stress testing.203,204,215 Not every obstructive lesion produces ischemia, and ischemia can be present in the absence of a significant stenosis in epicardial vessels, which results in discordance between anatomic imaging with CCTA and functional stress testing. Several series have reported the positive predictive value of an anatomic lesion detected on CCTA to range from 29% to 44% when ischemia on a stress study is used as a reference standard.203,204 The evidence on concordance, however, remains incomplete, with current research showing the highest degree of concordance between ischemia and mixed plaque. Because the presence of signif- icant calcification often can preclude the accurate assessment of lesion severity or cause a false positive study, CCTA should not be performed in patients who have known exten- sive calcification or a high risk of CAD. 2.2.4.2. CAC Scoring CT also provides measurement of a CAC score, calculated as the product of the CAC area by maximal plaque density (in Hounsfield units).217 The CAC score frequently has been applied for risk assessment in asymptomatic individuals,5 and it also has been used to predict the presence of high-grade coronary stenosis as the cause of chest pain in symptomatic patients. 