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.


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.


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%.


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).


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).


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.


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.


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.


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.


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).


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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 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.


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.


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.


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.


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.


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.


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. When the data from 2 large multicenter registries, including a total of 3615 symptomatic patients, were com- bined, the estimated diagnostic sensitivity for the CAC score to predict obstructive CAD on invasive angiography was 85%, with a specificity of 75%.218 In a recent meta-analysis of 18 studies, which included 10 355 symptomatic patients, the presence of nonzero CAC score had a pooled sensitivity and specificity of 98% and 40%, respectively, for detection of significant CAD on invasive coronary angiography.174 Although the diagnostic sensitivity of CAC to detect obstructive CAD is fairly high, the frequency of false nega- tive exams (ie, significant CAD in the absence of CAC) is not well established.


When the data from 2 large multicenter registries, including a total of 3615 symptomatic patients, were com- bined, the estimated diagnostic sensitivity for the CAC score to predict obstructive CAD on invasive angiography was 85%, with a specificity of 75%.218 In a recent meta-analysis of 18 studies, which included 10 355 symptomatic patients, the presence of nonzero CAC score had a pooled sensitivity and specificity of 98% and 40%, respectively, for detection of significant CAD on invasive coronary angiography.174 Although the diagnostic sensitivity of CAC to detect obstructive CAD is fairly high, the frequency of false nega- tive exams (ie, significant CAD in the absence of CAC) is not well established. In small single-center studies, perfusion defects on nuclear MPI or high-grade coronary stenosis on coronary angiography can be present in 0% to 39% of symptomatic patients with a calcium score of zero.219 223 In the recent large, multicenter, CONFIRM (Coronary CT An- giography Evaluation For Clinical Outcomes: An Interna- tional Multicenter Registry) registry, CCTA showed mild, nonobstructive CAD in 13%, stenosis $50% in 3.5%, and stenosis $70% in 1.4% of the 10 037 symptomatic patients without known CAD who had a CAC score of zero.214 Documentation of obstructive CAD without CAC occurs more often in younger patients in whom atherosclerotic plaque has not advanced to the stage of calcification. Previous official documents from the AHA and ACCF218 concluded that patients considered to be at low risk of coronary disease by virtue of atypical cardiac symptoms may benefit from CAC testing to help in ruling out the presence of obstructive coronary disease 218 or that coronary calcium assessment may be reasonable for the assessment of symp- tomatic patients, especially in the setting of equivocal tread- mill or functional testing (Class IIb, LOE: B).


Previous official documents from the AHA and ACCF218 concluded that patients considered to be at low risk of coronary disease by virtue of atypical cardiac symptoms may benefit from CAC testing to help in ruling out the presence of obstructive coronary disease 218 or that coronary calcium assessment may be reasonable for the assessment of symp- tomatic patients, especially in the setting of equivocal tread- mill or functional testing (Class IIb, LOE: B). The present writing committee believed that additional evidence in suffi- ciently large cohorts of patients establishing the uncorrected diagnostic accuracy of CAC to rule in or rule out high-grade coronary artery stenosis in symptomatic patients was needed. 2.2.4.3. CMR Angiography Although not widely applied, CMR angiography has been performed for the detection of the extent and severity of obstructive CAD. As a result of small coronary artery size, tortuosity, and motion, the diagnostic accuracy of CMR angiography is reduced as compared with CCTA.224 A multicenter, controlled clinical trial of patients referred to invasive angiography revealed that magnetic resonance an- giography had an 81% negative predictive value for exclud- ing CAD.225 Several meta-analyses that included a total of 59 studies have reported diagnostic sensitivity and specificity ranging from 87% to 88% and 56% to 70%, respec- tively,158,226 with reports of a lower accuracy than that of CCTA.164 Variability in diagnostic accuracy with CMR Fihn et al Stable Ischemic Heart Disease: Full Text e379 angiography has been attributed to a lack of uniformity in pulse sequences and the application of varying analytic CMR have shown comparable abilities to detect CAD as compared with CCTA.228 No recommendations for the use of CMR angiography are included in this guideline. 3. Risk Assessment 3.1. Clinical Assessment 3.1.1.


As a result of small coronary artery size, tortuosity, and motion, the diagnostic accuracy of CMR angiography is reduced as compared with CCTA.224 A multicenter, controlled clinical trial of patients referred to invasive angiography revealed that magnetic resonance an- giography had an 81% negative predictive value for exclud- ing CAD.225 Several meta-analyses that included a total of 59 studies have reported diagnostic sensitivity and specificity ranging from 87% to 88% and 56% to 70%, respec- tively,158,226 with reports of a lower accuracy than that of CCTA.164 Variability in diagnostic accuracy with CMR Fihn et al Stable Ischemic Heart Disease: Full Text e379 angiography has been attributed to a lack of uniformity in pulse sequences and the application of varying analytic CMR have shown comparable abilities to detect CAD as compared with CCTA.228 No recommendations for the use of CMR angiography are included in this guideline. 3. Risk Assessment 3.1. Clinical Assessment 3.1.1. Prognosis of IHD for Death or Nonfatal MI: General Considerations IHD is a chronic disorder with a natural history that spans multiple decades. The disease typically cycles through clini- cally defined phases: asymptomatic, stable angina, accelerat- ing angina, and ACS (UA or AMI), although the progression from one state to another is not necessarily linear. The specific approach to assessing risk of subsequent adverse outcomes varies according to the patient s clinical phase, even though for those with SIHD, there is no universally accepted approach. This represents a key area for future research. The approach recommended in the present guideline is informed by the treatment goals of prolonging survival and optimizing health status and by the concept that the benefits of treatment are often proportional to the patient s underlying risk. From this perspective, it is essential to quantify the patient s prognosis as accurately as possible.


From this perspective, it is essential to quantify the patient s prognosis as accurately as possible. Several ap- proaches to estimating the risk of cardiovascular mortality or events are provided later in this guideline. In the absence of an established prognostic model, the following considerations are highlighted: 1. Sociodemographic characteristics: Age is the single strongest determinant of survival, whereas ethnicity and sex have conflicting and less important effects on risk. Lower socioeconomic status also is associated with 2. Cardiovascular risk factors: Smoking, hypertension, dyslipidemia, family history of premature CAD, obe- sity, and sedentary lifestyle confer a greater risk of complications. 3. Coexisting medical conditions: Diabetes mellitus,230 chronic kidney disease (CKD),231 chronic pulmonary disease, and malignancy are the most important noncar- diac conditions to influence prognosis.232 234 4. Cardiovascular comorbidities: Heart failure, PAD, and cerebrovascular diseases are strong prognostic risk fac- tors for mortality. 5. Psychosocial characteristics: Depression repeatedly has been demonstrated to be strongly and independently associated with worse survival, and anxiety has also been implicated.235 242 Poor social support, poverty, and stress also are associated with adverse 6. Health status: Patients symptoms, functional capacity, and quality of life are associated significantly with survival and the incidence of subsequent ACS.246,247 In a large, prospective cohort of patients in the Veterans Affairs healthcare system, physical limitations due to angina were second only to age in predicting 7. Anginal frequency: Frequency of angina is a very strong predictor of subsequent ACS hospitalizations.246 8. Cardiac disease severity: The degree and distribution of stenoses measured by coronary angiography, findings on exercise testing and stress imaging, and LV function measured with a variety of technologies all provide meaningful prognostic information that supplements more clinical information. 3.1.2.


Cardiac disease severity: The degree and distribution of stenoses measured by coronary angiography, findings on exercise testing and stress imaging, and LV function measured with a variety of technologies all provide meaningful prognostic information that supplements more clinical information. 3.1.2. Risk Assessment Using Clinical Parameters Although there are several models to predict the likelihood of complications and survival in asymptomatic, general popula- tions and in patients with ACS, there is a relative paucity of information about models for assessing the risk of patients with known SIHD that incorporate a broad range of relevant data. Accurate risk assessment according to clinical variables is essential to determining optimal treatment strategies. Lauer and colleagues developed a risk index that incorporates variables from the history and exercise test on the basis of data from .32 000 individuals.248 They found that their index, which can be calculated by using a nomogram (Figure 8), was better able to predict individuals with a low (,3%) risk of death than was the Duke treadmill score. Daly and colleagues reported an index to estimate risk of death or nonfatal AMI derived from data on an international sample of approximately 3000 patients who presented with angina and were followed up for 18 months (Figures 9 and 10). Obstruc- tive CAD was documented in one third, whereas another third had negative evaluations. The c statistic for the model was 0.74, which indicates a relatively high level of accuracy.57 Several risk-assessment schemes have been developed to assist in identifying patients with severe CAD, including left main disease, although several of these studies are up to 2 decades old.


The c statistic for the model was 0.74, which indicates a relatively high level of accuracy.57 Several risk-assessment schemes have been developed to assist in identifying patients with severe CAD, including left main disease, although several of these studies are up to 2 decades old. One study70 identified 8 clinical characteristics that are important in estimating the likelihood of severe IHD: typical angina, previous MI, age, sex, duration of chest pain symptoms, risk factors (hypertension, diabetes mellitus, hy- perlipidemia, and smoking), carotid bruit, and chest pain frequency. A subsequent study71 provided detailed equations to predict both severe IHD and survival on the basis of clinical parameters. One study249 developed a simple risk score for predicting severe (left main or 3-vessel) CAD that was based on 5 clinical variables: age, sex, history of MI, presence of typical angina, and diabetes mellitus with or without insulin use. This same score was validated subse- quently for prognostic purposes.250,251 This score can be easily memorized and calculated (Figure 11) and yields an integer ranging from 0 to 10.57 The score can be applied to determine if a patient is more suitable for stress testing or possibly (in appropriate patients who are at highest risk) for proceeding directly to coronary angiography. Each curve shows the probability of severe IHD as a function of age for a given cardiac risk score. As shown on the Figure 11 graph, some patients have a high likelihood (.50%) of having severe disease for which revascularization might improve survival on the basis of clinical parameters alone.


As shown on the Figure 11 graph, some patients have a high likelihood (.50%) of having severe disease for which revascularization might improve survival on the basis of clinical parameters alone. For example, a 50-year-old male patient who has diabetes melli- tus, is taking insulin, and has typical angina and a history of previous MI has a likelihood of severe coronary stenosis .60% and thus might proceed directly to angiography if warranted by his preferences and other clinical factors, although in most circumstances stress testing will assist in planning further tests and treatments.87,252 Creation of valid, quantitative models on the basis of data from current regis- tries and trials to accurately identify patients with anatomic distributions of CAD for which revascularization has been shown to improve survival, such as left main disease, should be a research priority. Studies have suggested that addition of levels of novel biomarkers such as C-reactive protein and brain natriuretic peptide can improve prediction of mortality and cardiovas- cular events.5,57 Considerable controversy remains; however, as to whether these tests truly provide incremental informa- tion beyond more well-accepted risk factors, and few of the studies have focused on patients with SIHD.253 255 Inflamma- tory biomarkers, such as myeloperoxidase,256 biochemical markers of lipid-related atherogenic processes [lipoprotein(a), apolipoprotein B, small dense LDL, and lipoprotein- associated phospholipase A2],257,258 and low levels of circu- lating troponin detected by high-sensitivity assays259 also are under investigation as indices of risk in patients with SIHD. 3.2. Advanced Testing: Resting and Stress Noninvasive Testing 3.2.1. Resting Imaging to Assess Cardiac Structure and Function: Recommendations Class I 1.


Resting Imaging to Assess Cardiac Structure and Function: Recommendations Class I 1. Assessment of resting LV systolic and diastolic ven- tricular function and evaluation for abnormalities of myocardium, heart valves, or pericardium are rec- ommended with the use of Doppler echocardiogra- phy in patients with known or suspected IHD and a prior MI, pathological Q waves, symptoms or signs suggestive of heart failure, complex ventricular ar- Figure 8. Nomogram to predict risk of death based on clinical data and results of exercise testing. To determine risk, draw a vertical line from each risk marker to the top line, labeled POINTS, to calculate points for each risk marker. The sum of all these points is then marked on the line labeled TOTAL POINTS. Drop vertical lines from there to yield the 3- and 5-year sur- vival probabilities. For binary variables, 1 means yes and 0 means no. MET indi- cates metabolic equivalent. Reproduced from Lauer et al.248 Fihn et al Stable Ischemic Heart Disease: Full Text e381 rhythmias, or an undiagnosed heart mur- mur.21,57,58,260,261 (Level of Evidence: B) Class IIb 1. Assessment of cardiac structure and function with resting echocardiography may be considered in pa- tients with hypertension or diabetes mellitus and an abnormal ECG. (Level of Evidence: C) 2. Measurement of LV function with radionuclide im- aging may be considered in patients with a prior MI or pathological Q waves, provided there is no need to evaluate symptoms or signs suggestive of heart fail- ure, complex ventricular arrhythmias, or an undi- agnosed heart murmur. (Level of Evidence: C) Class III: No Benefit 1. Echocardiography, radionuclide imaging, CMR, and cardiac CT are not recommended for routine Figure 9. Euro heart score sheet to calculate risk score for patients presenting with stable angina (derived from 3779 patients with newly diagnosed SIHD).


Euro heart score sheet to calculate risk score for patients presenting with stable angina (derived from 3779 patients with newly diagnosed SIHD). *$1 of previous cerebrovascular event; hepatic disease defined as chronic hepatitis or cirrhosis, or other hepatic disease causing elevation of transaminases $3 times upper limit of normal; PVD defined as claudication either at rest or on exertion, amputation for arterial vascular insufficiency, vascular surgery (reconstruction or bypass) or angioplasty to the extremities, documented aortic aneurysm, or noninvasive evidence of impaired arterial flow; chronic renal failure defined as chronic dialysis or renal transplantation or serum creatinine .200 mmol/L; chronic respiratory disease defined as a diagnosis previously made by physician or patient receiving bronchodilators or FEV1 ,75%, arterial PO2 ,60%, or arterial PCO2 .50% predicted in previous studies; chronic inflammatory conditions defined as a diagnosis of rheumatoid arthritis, systemic lupus erythematosus or other connective tissue dis- ease, polymyalgia rheumatica, and so on; malignancy defined as a diagnosis of malignancy within a year of active malignancy. FEV1 indicates forced expiratory volume; PO2, partial pressure of oxygen; PCO2, partial pressure of carbon dioxide; and PVD, peripheral vas- cular disease. Reproduced from Daly et al.57 Figure 10. Risk of death or MI over 1 year after diagnosis of SIHD according to Euro heart score. Plot to assign estimated probability of death or nonfatal MI within 1 year of presentation according to combination of clinical and investigative features in patients with stable angina. MI indicates myocardial infarction. Reproduced from Daly et al.57 Figure 11. Nomogram showing the probability of severe (3-vessel or left main) coronary disease based on a 5-point score. One point is awarded for each of the following variables: male sex, typical angina, history and electrocardiographic evi- dence of MI, and diabetes mellitus and use of insulin.


One point is awarded for each of the following variables: male sex, typical angina, history and electrocardiographic evi- dence of MI, and diabetes mellitus and use of insulin. Each curve shows the probability of severe coronary disease as a function of age. Reproduced from Hubbard et al.249 assessment of LV function in patients with a normal ECG, no history of MI, no symptoms or signs suggestive of heart failure, and no complex ventric- ular arrhythmias. (Level of Evidence: C) 2. Routine reassessment (<1 year) of LV function with technologies such as echocardiography radionuclide imaging, CMR, or cardiac CT is not recommended in patients with no change in clinical status and for whom no change in therapy is contemplated. (Level of Evidence: C) See Online Data Supplement 2 for additional data on using resting imaging to assess cardiac structure and function. In the presence of signs or symptoms suggestive of heart failure, it is imperative to obtain an objective measure of LV function if a prognosis-altering change in therapy could be based on the findings. For example, a rest ejection fraction (EF) ,35% is associated with an annual mortality rate .3% per year.260 Resting 2-dimensional echocardiography with Doppler echocardiography is the preferred approach because it provides a thorough assessment of all aspects of cardiac structure and function, including identifying the mechanism of heart failure and differentiating systolic LV from diastolic dysfunction. Rest imaging also can provide valuable therapeutic guidance and prognostic information in patients without symptoms or signs of ventricular dysfunction or changing clinical status, especially in those with evidence of other forms of heart disease (eg, hypertensive, valvular).


Rest imaging also can provide valuable therapeutic guidance and prognostic information in patients without symptoms or signs of ventricular dysfunction or changing clinical status, especially in those with evidence of other forms of heart disease (eg, hypertensive, valvular). For example, echocardiography can identify LV or left atrial dilation; identify aortic stenosis (a potential non-CAD mechanism for angina-like chest pain); measure pulmo- nary artery pressure; quantify mitral regurgitation; identify a LV aneurysm; identify a LV thrombus, which increases the risk of death262; and measure LV mass and the ratio of wall thickness to chamber radius all of which predict cardiac events and mortality.20,117,263 267 Although nuclear imaging accurately measures EF, it does not provide additional information on valvular or pericardial disease and requires exposure to ionizing radiation.21,268 Although CMR is applied less widely, it also accurately measures LV performance and provides insight into myocar- dial and valvular structures.269 Use of delayed hyperenhance- ment techniques can identify otherwise undetected scarred as well as viable myocardium. Cardiac CT also provides high- resolution detection of cardiac structures and EF. Neverthe- less, all 3 tests generally are more expensive than a resting echocardiogram. Although the amount of ionizing radiation required in cardiac CT and nuclear MPI has been lowered over the years and will continue to reduce, the use of these tests for risk assessment is discouraged in patients with low pretest probability of CAD and in young patients. 3.2.2. Stress Testing and Advanced Imaging in Patients With Known SIHD Who Require Noninvasive Testing for Risk Assessment: Recommendations See Table 12 for a summary of recommendations from this section. 3.2.2.1. Risk Assessment in Patients Able to Exercise Class I 1.


Risk Assessment in Patients Able to Exercise Class I 1. Standard exercise ECG testing is recommended for risk assessment in patients with SIHD who are able to exercise to an adequate workload and have an interpretable ECG.106 110,112 114,132 134 (Level of Evi- dence: B) 2. The addition of either nuclear MPI or echocardiog- raphy to standard exercise ECG testing is recom- mended for risk assessment in patients with SIHD who are able to exercise to an adequate workload but have an uninterpretable ECG not due to LBBB or ventricular pacing.7,111,264 266,270,299,300 (Level of Evidence: B) Class IIa 1. The addition of either nuclear MPI or echocardi- ography to standard exercise ECG testing is rea- sonable for risk assessment in patients with SIHD who are able to exercise to an adequate workload and have an interpretable ECG.271 279 (Level of Evidence: B) 2. CMR with pharmacological stress is reasonable for risk assessment in patients with SIHD who are able to exercise to an adequate workload but have an uninterpretable ECG.279 284 (Level of Evidence: B) Class IIb 1. CCTA may be reasonable for risk assessment in patients with SIHD who are able to exercise to an adequate workload but have an uninterpretable ECG.285,286 (Level of Evidence: B) Class III: No Benefit 1. Pharmacological stress imaging (nuclear MPI, echocardiography, or CMR) or CCTA is not rec- ommended for risk assessment in patients with SIHD who are able to exercise to an adequate workload and have an interpretable ECG. (Level of Evidence: C) 3.2.2.2. Risk Assessment in Patients Unable to Exercise Class I 1.


Risk Assessment in Patients Unable to Exercise Class I 1. Pharmacological stress with either nuclear MPI or echocardiography is recommended for risk assess- ment in patients with SIHD who are unable to exercise to an adequate workload regardless of interpretability of ECG.7,264 266,287 290 (Level of Evidence: B) Class IIa 1. Pharmacological stress CMR is reasonable for risk assessment in patients with SIHD who are unable to exercise to an adequate workload re- gardless of interpretability of ECG.280 284,291 (Level of Evidence: B) 2. CCTA can be useful as a first-line test for risk assessment in patients with SIHD who are unable to Fihn et al Stable Ischemic Heart Disease: Full Text e383 exercise to an adequate workload regardless of interpretability of ECG.286 (Level of Evidence: C) 3.2.2.3. Risk Assessment Regardless of Patients Ability to Exercise Class I 1. Pharmacological stress with either nuclear MPI or echocardiography is recommended for risk assess- ment in patients with SIHD who have LBBB on ECG, regardless of ability to exercise to an adequate workload.287 290,292 (Level of Evidence: B) 2. Either exercise or pharmacological stress with imag- ing (nuclear MPI, echocardiography, or CMR) is recommended for risk assessment in patients with SIHD who are being considered for revasculariza- tion of known coronary stenosis of unclear physio- logical significance.266,278,293,294 (Level of Evidence: B) Class IIa 1. CCTA can be useful for risk assessment in patients with SIHD who have an indeterminate result from functional testing.286 (Level of Evidence: C) Class IIb 1. CCTA might be considered for risk assessment in patients with SIHD unable to undergo stress imaging or as an alternative to invasive coronary angiogra- phy when functional testing indicates a moderate- to Table 12.


CCTA might be considered for risk assessment in patients with SIHD unable to undergo stress imaging or as an alternative to invasive coronary angiogra- phy when functional testing indicates a moderate- to Table 12. Using Stress Testing and Advanced Imaging for Patients With Known SIHD Who Require Noninvasive Testing for Risk Assessment Test Exercise Status ECG Interpretable COR LOE References Additional Considerations Able Unable Yes No Patients able to exercise* Exercise ECG X X I B (106 110, 112 114, 132 134) Exercise with nuclear MPI or Echo X X I B (7, 111, 264 266, 270, 299, 300) Abnormalities other than LBBB or ventricular pacing Exercise with nuclear MPI or Echo X X IIa B (271 279) Pharmacological stress CMR X X IIa B (279 284) CCTA X X IIb B (285, 286) Pharmacological stress imaging (nuclear MPI, Echo, CMR) or CCTA X X III: No Benefit C N/A Patients unable to exercise Pharmacological stress with nuclear MPI or Echo Pharmacological stress CMR X Any IIa B (280 284, 291) CCTA X Any IIa C (286) Without prior stress test Regardless of patient s ability to exercise Pharmacological stress with nuclear MPI or Echo Any X I B (287 290, 292) LBBB present Exercise/pharmacological stress with nuclear MPI, Echo, or CMR Any Any I B (266, 278, 293, 294) Known coronary stenosis of unclear physiological significance being considered for revascularization CCTA Any Any IIa C N/A Indeterminate result from functional testing CCTA Any Any IIb C N/A Unable to undergo stress imaging or as alternative to coronary catheterization when functional testing indicates moderate to high risk and angiographic coronary anatomy is unknown Requests to perform multiple cardiac imaging or stress studies at the same time Any Any III: No Benefit C N/A *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.


Using Stress Testing and Advanced Imaging for Patients With Known SIHD Who Require Noninvasive Testing for Risk Assessment Test Exercise Status ECG Interpretable COR LOE References Additional Considerations Able Unable Yes No Patients able to exercise* Exercise ECG X X I B (106 110, 112 114, 132 134) Exercise with nuclear MPI or Echo X X I B (7, 111, 264 266, 270, 299, 300) Abnormalities other than LBBB or ventricular pacing Exercise with nuclear MPI or Echo X X IIa B (271 279) Pharmacological stress CMR X X IIa B (279 284) CCTA X X IIb B (285, 286) Pharmacological stress imaging (nuclear MPI, Echo, CMR) or CCTA X X III: No Benefit C N/A Patients unable to exercise Pharmacological stress with nuclear MPI or Echo Pharmacological stress CMR X Any IIa B (280 284, 291) CCTA X Any IIa C (286) Without prior stress test Regardless of patient s ability to exercise Pharmacological stress with nuclear MPI or Echo Any X I B (287 290, 292) LBBB present Exercise/pharmacological stress with nuclear MPI, Echo, or CMR Any Any I B (266, 278, 293, 294) Known coronary stenosis of unclear physiological significance being considered for revascularization CCTA Any Any IIa C N/A Indeterminate result from functional testing CCTA Any Any IIb C N/A Unable to undergo stress imaging or as alternative to coronary catheterization when functional testing indicates moderate to high risk and angiographic coronary anatomy is unknown Requests to perform multiple cardiac imaging or stress studies at the same time Any Any III: No Benefit C N/A *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.


Patients should be able to achieve 85% of age-predicted maximum heart rate. CCTA indicates cardiac computed tomography angiography; CMR, cardiac magnetic resonance imaging; COR, class of recommendation; ECG, electrocardiogram; Echo, echocardiography; LBBB, left bundle-branch block; LOE, level of evidence; MPI, myocardial perfusion imaging; and N/A, not available. Exercise Echo or pharmacological stress with MPI or Echo 1. Exercise echo or pharmacological stress with either nuclear MPI or echocardiography is recommended for risk assessment in patients with SIHD who have LBBB on ECG, regardless of ability to exercise to an (Level of Evidence: B) high-risk result and knowledge of angiographic cor- onary anatomy is unknown. (Level of Evidence: C) Class III: No Benefit 1. A request to perform either a) more than 1 stress imaging study or b) a stress imaging study and a CCTA at the same time is not recommended for risk assessment in patients with SIHD. (Level of Evidence: C) See Online Data Supplement 2 for additional data on risk assessment. 3.2.2.4. Exercise ECG To assess the risk of cardiovascular events in patients who are able to exercise to an adequate workload and have an interpretable resting ECG, exercise is the preferred stressor because it provides an objective assessment of functional capacity and correlative information with activities of daily living.


Exercise ECG To assess the risk of cardiovascular events in patients who are able to exercise to an adequate workload and have an interpretable resting ECG, exercise is the preferred stressor because it provides an objective assessment of functional capacity and correlative information with activities of daily living. The occurrence of ST-segment depression at a reduced workload or persisting into recovery coupled with exertional symptoms is associated with a high risk of cardiovascular mortality.302 Other risk markers for mortality include low exercise capacity (generally defined as less than stage II of the Bruce protocol or #20% age- and sex-predicted val- ues),118 failure to increase systolic BP to .120 mm Hg or a sustained .10 mm Hg decrease from resting values during exercise, complex ventricular ectopy or arrhythmias during stress or recovery, and delayed heart rate recovery (eg, ,10- or 12-beats-per-minute reduction in the first minute).303 The Duke treadmill score and the Lauer nomogram score are validated predictive instruments that incorporate parameters from an exercise ECG test. The Duke treadmill score includes duration of exercise, severity of ST-depression or elevation, and angina (limiting and nonlimiting); has been demonstrated to be highly predictive across an array of patient populations, including women and men with suspected and known SIHD; and has been shown to provide independent risk information beyond clinical data, coronary anatomy, and LVEF.126,177 It stratifies patients into risk groups that could prove useful for patient management, as follows: no further testing for low- risk patients, consideration for invasive testing for high-risk patients, and stress imaging for the intermediate-risk patients. By comparison, the Lauer score incorporates clinical vari- ables, which results in more effective classification of low- risk (,1% annual mortality rate) patients.248 3.2.2.5.


By comparison, the Lauer score incorporates clinical vari- ables, which results in more effective classification of low- risk (,1% annual mortality rate) patients.248 3.2.2.5. Exercise Echocardiography and Exercise Nuclear MPI Evidence from thousands of patients evaluated in multiple large registries and clinical trials and meta-analyses confirm that a normal exercise echocardiogram or exercise nuclear MPI is associated with a very low risk of death due to cardiovascular causes or AMI.111,265,304 The extent and sever- ity of inducible abnormalities in wall motion or perfusion are directly correlated with the degree of risk. For nuclear MPI, reversible perfusion defects encompassing 10% of the myo- cardium (determined either semiquantitatively with summed scores or quantitatively) to assess defect extent and severity are considered moderately abnormal, and reversible perfusion defects encompassing $15% of the myocardium are consid- ered severely abnormal.277,305,306 Other findings also indica- tive of elevated risk include a reduction in reduced post-stress LVEF $5% or a global LVEF ,45%, transient ischemic LV dilation, increased lung or right ventricular uptake, or abnor- mal coronary reserve (detected on myocardial perfusion PET). For echocardiography, a wall motion abnormality extending beyond 2 to 3 segments as well as the presence of change in .1 coronary territory are suggestive of higher risk. For both tests, multiple defects in different coronary territo- ries with either moderately reduced perfusion (or $10% of the myocardium) or inducible wall motion abnormalities with transient ischemic dilatation are suggestive of severe CAD. Currently, the National Institutes of Health National Heart, Lung, and Blood Institute sponsored ISCHEMIA trial is under way and is comparing the effectiveness of a conserva- tive versus catheterization-based initial management strategy for patients with moderate severe ischemia.


Currently, the National Institutes of Health National Heart, Lung, and Blood Institute sponsored ISCHEMIA trial is under way and is comparing the effectiveness of a conserva- tive versus catheterization-based initial management strategy for patients with moderate severe ischemia. Several large single-center and multicenter registries have demonstrated consistently that both stress nuclear MPI and stress echocardiography provide incremental prognostic value beyond that provided by a standard ECG.115,272,299,305,307 315 The addition of imaging is manda- tory for patients who have an uninterpretable baseline ECG (including the presence of LBBB or ventricular pacing, LV hypertrophy, use of digitalis or electrolyte abnormalities, coexisting resting ST-segment abnormality, or preexcitation syndromes) and might be of value in patients with equivocal stress-induced316 ECG ST changes317 or an intermediate Duke treadmill score.316 Poornima et al, demonstrated that nuclear MPI has independent prognostic value even in pa- tients with low-risk Duke treadmill scores, but only if there is increased clinical risk, such as a history of typical angina, MI, diabetes mellitus, and advanced age.318,319 Similarly, infor- mation from exercise echocardiography appears to provide improved prediction of mortality among patients with low- risk Duke treadmill scores.311,318 From a large registry, the extent of ischemic myocardium as quantified by summed difference score by nuclear MPI has been shown to form an effective prognostic score for the prediction of cardiac mor- tality.320 Results from exercise nuclear MPI and exercise stress echocardiography appear to provide accurate estimates of the likelihood of death among men and women with suspected and known SIHD and for patients from different From a review of large single- and multicenter registries and meta-analyses,111,115,272 the following conclusions can be made: 1.


Several large single-center and multicenter registries have demonstrated consistently that both stress nuclear MPI and stress echocardiography provide incremental prognostic value beyond that provided by a standard ECG.115,272,299,305,307 315 The addition of imaging is manda- tory for patients who have an uninterpretable baseline ECG (including the presence of LBBB or ventricular pacing, LV hypertrophy, use of digitalis or electrolyte abnormalities, coexisting resting ST-segment abnormality, or preexcitation syndromes) and might be of value in patients with equivocal stress-induced316 ECG ST changes317 or an intermediate Duke treadmill score.316 Poornima et al, demonstrated that nuclear MPI has independent prognostic value even in pa- tients with low-risk Duke treadmill scores, but only if there is increased clinical risk, such as a history of typical angina, MI, diabetes mellitus, and advanced age.318,319 Similarly, infor- mation from exercise echocardiography appears to provide improved prediction of mortality among patients with low- risk Duke treadmill scores.311,318 From a large registry, the extent of ischemic myocardium as quantified by summed difference score by nuclear MPI has been shown to form an effective prognostic score for the prediction of cardiac mor- tality.320 Results from exercise nuclear MPI and exercise stress echocardiography appear to provide accurate estimates of the likelihood of death among men and women with suspected and known SIHD and for patients from different From a review of large single- and multicenter registries and meta-analyses,111,115,272 the following conclusions can be made: 1. A normal exercise nuclear MPI study or a normal exercise stress echocardiogram during which the age- predicted target heart rate is achieved is associated with a very low annual risk of cardiac death and AMI (generally ,1%) in both men and women. 2.


A normal exercise nuclear MPI study or a normal exercise stress echocardiogram during which the age- predicted target heart rate is achieved is associated with a very low annual risk of cardiac death and AMI (generally ,1%) in both men and women. 2. Normal and mildly abnormal nuclear MPI or exercise stress echocardiography is associated with a low fre- quency of referral for coronary revascularization or worsening clinical status and UA admission (1.3% and Fihn et al Stable Ischemic Heart Disease: Full Text e385 3. Rates of cardiac ischemic events increase in proportion to the degree of abnormalities on stress nuclear MPI or echocardiography, with moderate to severe abnormali- ties associated with an annual risk of cardiovascular death or MI $5%.115,278,279,284,305,306,310,313,314,323 330 4. For patients with mild abnormalities, coronary angiog- raphy might be considered if the patient exhibits other features that might indicate the likelihood of high-risk CAD, including low EF on gated nuclear MPI or echocardiographic imaging331 or transient ischemic dil- atation of the left ventricle.332 5. Moderate to severe abnormalities, such as abnormal wall motion in $4 segments or multivessel abnormali- ties, indicate an increased risk (range: 6- to 10-fold) over that of patients with a normal stress imaging Nonetheless, the current literature with regard to exercise nuclear MPI or exercise echocardiography should be clarified in several ways.


Moderate to severe abnormalities, such as abnormal wall motion in $4 segments or multivessel abnormali- ties, indicate an increased risk (range: 6- to 10-fold) over that of patients with a normal stress imaging Nonetheless, the current literature with regard to exercise nuclear MPI or exercise echocardiography should be clarified in several ways. Although a normal exercise nuclear MPI or exercise echocardiogram usually is associated with a low annual risk of cardiac death or AMI, the negative predictive value is reduced among patients with a higher pretest likeli- hood of CAD.111,115,279,284,305,306,310,313,314,323 328,330 Further- more, although trials have shown that imaging is useful to detect ischemia and guide intervention in patients with SIHD and that a reduction in ischemia by stress nuclear MPI is associated with an observed (unadjusted) event-free sur- vival,306,333 there is no trial evidence comparing the effective- ness of a strategy of imaging testing for risk stratification versus a strategy of nontesting in patients with SIHD. 3.2.2.6. Dobutamine Stress Echocardiography and Pharmacological Stress Nuclear MPI In one third to one half of patients who undergo risk assessment, exercise stress is not recommended because of an inability to exercise or an abnormal ECG. Similar to exercise echocardiography, multiple large single-center reports have shown that dobutamine stress echocardiography accurately classifies patients into high-risk and very-low-risk groups.


Similar to exercise echocardiography, multiple large single-center reports have shown that dobutamine stress echocardiography accurately classifies patients into high-risk and very-low-risk groups. A normal dobutamine echocardiogram is associated with a risk of an adverse cardiac event of 1% to 2%.312,334 Classification as high risk by dobutamine stress echocardiography is most reliable when ischemia is detected in the territory of the LAD and is somewhat less reliable in patients with diabetes mellitus.335 In specialized centers, either quantification of strain rate or myocardial contrast enhancement on dobuta- mine echocardiography has been shown to provide informa- tion that supplements the wall motion score alone in predict- ing cardiac mortality.336 Dobutamine echocardiography also has been used extensively in risk-stratifying patients with SIHD undergoing noncardiac vascular surgery.


A normal dobutamine echocardiogram is associated with a risk of an adverse cardiac event of 1% to 2%.312,334 Classification as high risk by dobutamine stress echocardiography is most reliable when ischemia is detected in the territory of the LAD and is somewhat less reliable in patients with diabetes mellitus.335 In specialized centers, either quantification of strain rate or myocardial contrast enhancement on dobuta- mine echocardiography has been shown to provide informa- tion that supplements the wall motion score alone in predict- ing cardiac mortality.336 Dobutamine echocardiography also has been used extensively in risk-stratifying patients with SIHD undergoing noncardiac vascular surgery. Because the risk of a cardiac event in the perioperative period is quite low, the positive predictive value of dobutamine echocardiography is also low, although the negative predictive value of a normal result is very high and is associated with a very low likelihood of a perioperative event.337,338 Similar to exercise SPECT, vasodilator stress nuclear MPI has been shown to effectively assess risk of subsequent events in patients with SIHD, with a low annualized event rate of 1.6% observed in patients with a normal adenosine SPECT versus 10.6% in patients with a severely abnormal study (summed stress score .13).339 This event rate also was observed in elderly patients with normal pharmacological SPECT.340,341 Because of greater comorbidity in patients who cannot exercise, the annualized event rate of patients who had a normal pharmacological stress nuclear MPI increase the event rate nearly 2-fold higher than that of exercising patients who had a normal nuclear MPI, after adjustment for age and comorbidity.342 Additional nonperfusion risk markers can be derived from pharmacological stress, including an abnormal ECG, high resting heart rate, and low peak/rest heart rate ratio.276,332 To facilitate clinical risk assessment, a nomogram based on robust risk markers, including LV function and extent of myocardial ischemia by SPECT, has been devel- oped and validated (Appendix 4).276 3.2.2.7.


Because the risk of a cardiac event in the perioperative period is quite low, the positive predictive value of dobutamine echocardiography is also low, although the negative predictive value of a normal result is very high and is associated with a very low likelihood of a perioperative event.337,338 Similar to exercise SPECT, vasodilator stress nuclear MPI has been shown to effectively assess risk of subsequent events in patients with SIHD, with a low annualized event rate of 1.6% observed in patients with a normal adenosine SPECT versus 10.6% in patients with a severely abnormal study (summed stress score .13).339 This event rate also was observed in elderly patients with normal pharmacological SPECT.340,341 Because of greater comorbidity in patients who cannot exercise, the annualized event rate of patients who had a normal pharmacological stress nuclear MPI increase the event rate nearly 2-fold higher than that of exercising patients who had a normal nuclear MPI, after adjustment for age and comorbidity.342 Additional nonperfusion risk markers can be derived from pharmacological stress, including an abnormal ECG, high resting heart rate, and low peak/rest heart rate ratio.276,332 To facilitate clinical risk assessment, a nomogram based on robust risk markers, including LV function and extent of myocardial ischemia by SPECT, has been devel- oped and validated (Appendix 4).276 3.2.2.7. Pharmacological Stress CMR Imaging Although clinical experience with using stress CMR for risk assessment is substantially less than with stress echocardiog- raphy and nuclear MPI, available evidence indicates that stress CMR can provide highly accurate prognostic informa- tion. On the basis of 16 single-site studies providing data from 7200 patients283 (8 of these studies used vasodilator stress perfusion imaging, 6 dobutamine stress CMR cine imaging, and 2 combined stress perfusion and cine imaging), the following general conclusions can be drawn: 1.