Exercise ECG The exercise ECG has been the cornerstone of diagnostic testing of SIHD patients for several decades. The diagnostic endpoint for an ischemic ECG is $1 mm horizontal or down-sloping (at 80 ms after the J point) ST-segment depression at peak exercise. ST-segment elevation (in a non Q-wave lead and excluding aortic valve replacement) during or after exercise occurs infrequently but represents a high-risk ECG finding consistent with an ACS. The diagnos- tic accuracy of exertional ST-segment depression has been studied extensively in several meta-analyses, systematic re- views, large observational registries, and RCTs.114,145 147,175 The composite diagnostic sensitivity and specificity, unad- justed for referral bias, is 61% and ranges from 70% to 77%, but it is lower in women146,147,175 and lower than that for stress imaging modalities. A similar accuracy has been reported for correlation of ECG ischemia with anatomic CAD by CCTA.176 Diagnostic accuracy is improved when consid- eration is given to additional non-ECG factors, such as exercise duration, chronotropic incompetence, angina, ven- tricular arrhythmias, heart rate recovery, and hemodynamic response to exercise (ie, drop in systolic BP), or when combination scores such as the Duke treadmill or Lauer scores are applied.118,177 180 Multiple factors in addition to the patient s inability to achieve maximal exercise levels influence the accuracy of the ECG during exercise testing to diagnose obstructive CAD. Resting ECG abnormalities preclude accurate interpretation of exercise-induced changes and reduce test accuracy; these include abnormalities affecting the ST segment, such as LV hypertrophy, LBBB, ventricular-paced rhythm, or any resting ST-segment depression $0.5 mm. Although some have proposed calculating the difference from rest to exercise of changes $1 mm for patients with significant resting ST- segment changes, the accuracy of this approach has been less extensively studied and validated. The interpretation of ST- segment changes in patients with right bundle-branch block can be limited, especially in the precordial leads. Certain medications, including digitalis, also influence ST-segment changes and can produce ischemic ECG changes that are frequently false positive findings. In addition, anti-ischemic therapies can reduce heart rate and myocardial workload, and therefore, a lack of ischemic ECG changes can reflect false negative findings when the test is used to diagnose SIHD. It is routine practice to withhold beta-blocker therapy for 24 to 48 hours before testing. Patients who are candidates for an exercise ECG must be able to exercise and must have an interpretable ECG, which is defined as a normal 12-lead ECG or one with minimal resting ST-T-wave abnormalities (,0.5 mm). 2.2.3.2. Exercise and Pharmacological Stress Echocardiography The diagnostic endpoint of exercise and pharmacological stress echocardiography is new or worsening wall motion abnormalities and changes in global LV function during or immediately after stress. In addition to the detection of inducible wall motion abnormalities, most stress echocardi- ography includes screening images to evaluate resting ven- tricular function and valvular abnormalities. This information can be helpful in a symptomatic patient without a proven diagnosis. Pharmacological stress echocardiography in the United States is performed largely by using dobutamine with an endpoint of inducible wall motion abnormalities (Table 11). Vasodilator agents such as adenosine are used rarely in the United States but are used more commonly in Europe. The diagnostic accuracy of exercise and pharmacological stress echocardiography has been studied extensively in multiple meta-analyses, systematic reviews, and large, multicenter, observational registries.91,148 152,154,175 In several contempo- rary meta-analyses, the diagnostic sensitivity (uncorrected for referral bias) ranged from 70% to 85% for exercise and 85% to 90% for pharmacological stress echocardiogra- phy.91,150,152,154 The uncorrected diagnostic specificity ranges Fihn et al Stable Ischemic Heart Disease: Full Text e377 from 77% to 89% and 79% to 90% for exercise and pharmacological stress echocardiography, respectively. The use of intravenous ultrasound contrast agents can improve endocardial border delineation and can result in improved diagnostic accuracy.181 Myocardial contrast echocardiogra- phy also has been examined for determination of rest and stress myocardial perfusion, with the results showing compa- rability to myocardial perfusion SPECT findings in small patient series.182 However, the technique is currently in limited use in the United States. The diagnostic accuracy of all imaging modalities is influenced by technical factors that could be inherent in the technique (ie, variable correlation between perfusion and wall motion abnormalities and CAD extent and severity) or that result from physical characteristics of the patient that reduce image quality. For echocardiography, reduced image quality, defined as reduced LV endocardial visualization, has been reported for obese individuals and those with chronic lung disease, although the use of intravenous contrast enhance- ment results in sizeable improvement in endocardial border delineation. 2.2.3.3. Exercise and Pharmacological Stress Nuclear Myocardial Perfusion SPECT and Myocardial Perfusion PET Myocardial perfusion SPECT generally is performed with rest and (for exercise or pharmacological stress) with stress Tc-99m agents, with Tl-201 having limited applications (eg, viability) because of its higher radiation exposure.97 Pharma- cological stress generally is used with vasodilator agents administered as a continuous infusion (adenosine, dipyridam- ole) or bolus (regadenoson) injection. The diagnostic end- point of nuclear MPI is reduction in myocardial perfusion after stress. Nonperfusion high-risk markers include a mark- edly abnormal ECG, extensive stress-induced wall motion abnormalities, reduced post-stress left ventricular ejection fraction (LVEF) $5% or global LVEF (rest or post-stress) ,45%, transient ischemic LV dilation, increased lung or right ventricular uptake, or abnormal coronary flow reserve with myocardial perfusion PET.183 186 The diagnostic accuracy for detection of obstructive CAD of exercise and pharmacological stress nuclear MPI has been studied extensively in multiple meta-analyses, systematic reviews, RCTs, and large, multicenter, observational regis- tries.91,114,132,147,148,152,155,156,175 From these reports, the uncor- rected diagnostic sensitivity ranged from 82% to 88% for exercise and 88% to 91% for pharmacological stress nuclear MPI. The uncorrected diagnostic specificity ranged from 70% to 88% and 75% to 90% for exercise and pharmacological stress nuclear MPI, respectively. Diagnostic image quality is affected in obese patients, as well as in women and men with large breasts. Reductions in breast tissue artifact have been reported with the use of the Tc-99m agents as well as with attenuation-correction algo- rithms or prone imaging.187 190 For myocardial perfusion SPECT, global reductions in myocardial perfusion, such as in the setting of left main or 3-vessel CAD, can result in balanced reduction and an underestimation of ischemic burden. Myocardial perfusion PET is characterized by high spatial resolution of the photon attenuation corrected images with Rubidium or 13 N-ammonia used as myocardial blood flow tracers. Although less well studied than myocardial perfusion SPECT, a meta-analysis of 19 studies suggests that PET has a slightly higher (uncorrected) sensitivity for detection of CAD,191,192 including in women and obese patients.193 2.2.3.4. Pharmacological Stress CMR Wall Motion/Perfusion In recent years, more centers have used pharmacological stress CMR in the diagnostic evaluation of SIHD patients. The imaging endpoint depends on the stress agent: develop- ment of a new wall motion abnormality for cine CMR with dobutamine stress or a new perfusion abnormality with vasodilator stress. From a contemporary meta-analysis of 37 studies, the uncorrected diagnostic sensitivity and specificity of dobutamine-induced CMR wall motion imaging were 83% and 86%, whereas the uncorrected diagnostic sensitivity and specificity of vasodilator stress induced CMR MPI were 91% and 81%.153 Several small comparative series have reported accuracy data in relation to stress echocardiography and nuclear imaging. Importantly, normal CMR perfusion has a high negative predictive value for obstructive CAD.194 One multicenter study that enrolled 234 patients demonstrated similar diagnostic accuracy between CMR perfusion and SPECT MPI in detecting obstructive CAD.172 More recently, a randomized study of 752 patients directly compared phar- macological stress CMR with SPECT MPI and reported higher sensitivity by pharmacological stress CMR than SPECT MPI in the detection of angiographically significant dobutamine stress, CMR wall motion had high accuracy for detection of obstructive CAD in patients with suboptimal echocardiographic acoustic window.170 CMR dobutamine wall motion imaging demonstrated higher accuracy than dobutamine echocardiography wall motion.171 Although wall motion and perfusion imaging are used to assess the presence and extent of ischemia, most experienced centers also acquire late gadolinium enhancement (LGE) imaging in the same session to delineate the extent and severity of scarred myocardium. 2.2.3.5. Hybrid Imaging Current imaging is based largely on the use of a single modality, but combined or hybrid applications increasingly are available, which include both PET and CT or SPECT and CT, thus allowing for combined anatomic and functional testing. In addition, newer scanning techniques have allowed assessment of perfusion and FFR by CCTA alone, in addition to coronary anatomy.195 201 Notably, these combined assess- ments allow for a fused image in which the physiological assessment of flow is coupled with the anatomic extent and severity of CAD and also provides information on plaque composition and arterial remodeling. Limited evidence is available on hybrid imaging, although several reports have reported prognostic accuracy for cardiac events with both ischemic and anatomic markers.202 206 Other combinations of imaging modalities also are being developed, including PET/ CMR, which is currently a research application. The strength of combined imaging is the added value of anatomy guiding interpretation of ischemic and scarred myocardium as well as providing information to guide therapeutic decision making. Hybrid imaging also can overcome technical limitations of myocardial perfusion SPECT or myocardial perfusion PET by providing anatomic correlates to guide interpretative accuracy207 and can provide the functional information that an anatomic technique like CCTA or magnetic resonance angiography lacks; however, radiation dose is increased. 2.2.4. Diagnostic Accuracy of Anatomic Testing for the Initial Diagnosis of SIHD 2.2.4.1. Coronary CT Angiography With improvements in temporal and spatial resolution as well as volume coverage, evaluation of coronary arteries with CCTA is now possible with a high degree of image quality.208 The extent and severity of angiographic CAD are 2 of the most important prognostic factors and remain essential for revascularization decision making.209 Five meta-analyses and 3 controlled clinical trials have reported the diagnostic accuracy of CCTA with 64-slice CT, yielding sensitivity values ranging from 93% to 97% and specificity values ranging from 80% to 90%159 166 for detecting obstructive CAD on invasive coronary angiography, unadjusted for referral bias. In a small series of women, the diagnostic accuracy of CCTA was similarly high.210 Prior reports in- cluded subsets of patients who already had been referred for invasive angiography, and as such, test performance would be altered by the biases inherent in a preselected population. Factors related to diminished accuracy include image quality, the extent of coronary calcification, and body mass index A potential advantage of CCTA over standard functional testing is its very high negative predictive value for obstruc- tive CAD, which can reassure caregivers that providing GDMT and deferring consideration of revascularization con- stitute a sensible strategy. In addition to documentation of stenotic lesions, CCTA can qualitatively visualize arterial remodeling and nonobstructive plaque, including calcified, noncalcified, or mixed plaque.211 216 The presence of nonob- structive plaque has been shown to be helpful to guiding risk assessment and can aid in discerning the etiology of patient symptoms.211,215,216 CT information has been correlated with functional stress testing.203,204,215 Not every obstructive lesion produces ischemia, and ischemia can be present in the absence of a significant stenosis in epicardial vessels, which results in discordance between anatomic imaging with CCTA and functional stress testing. Several series have reported the positive predictive value of an anatomic lesion detected on CCTA to range from 29% to 44% when ischemia on a stress study is used as a reference standard.203,204 The evidence on concordance, however, remains incomplete, with current research showing the highest degree of concordance between ischemia and mixed plaque. Because the presence of signif- icant calcification often can preclude the accurate assessment of lesion severity or cause a false positive study, CCTA should not be performed in patients who have known exten- sive calcification or a high risk of CAD. 2.2.4.2. CAC Scoring CT also provides measurement of a CAC score, calculated as the product of the CAC area by maximal plaque density (in Hounsfield units).217 The CAC score frequently has been applied for risk assessment in asymptomatic individuals,5 and it also has been used to predict the presence of high-grade coronary stenosis as the cause of chest pain in symptomatic patients. 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). 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. 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. 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. 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. 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. 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. 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). *$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. 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). 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. A normal stress CMR study with either vasodilator myocardial perfusion or inotropic stress cine imaging is associated with a low annual rate of cardiac death or MI, ranging from 0.01% to 0.6%,280,283 and provides accu- rate risk assessment in patients of either sex.281,343 2. Detection of myocardial ischemia (by either perfusion or cine imaging) and LGE imaging of infarction appear to provide complementary information. 3. An abnormal stress CMR with evidence of ischemia is associated with elevated likelihood of cardiac death or MI, with hazard ratios ranging from 2.2 to 12.279,282 The current evidence related to CMR for risk assessment of patients is limited by the predominance of data collection from tertiary care centers with high experience in CMR, heterogeneity of imaging techniques and equipment, and evolution of interpretative standards. 3.2.2.8. Special Patient Group: Risk Assessment in Patients Who Have an Uninterpretable ECG Because of LBBB or Ventricular Pacing Isolated false-positive reversible perfusion defects of the septum on nuclear MPI due to abnormal septal motion causing a reduction in diastolic filling time have been reported in patients with LBBB without significant coronary stenosis. Compared to patients without LBBB, use of exercise stress in patients with LBBB or ventricular pacing substan- tially reduced diagnostic specificity.289,292 Although a normal nuclear perfusion scan in this clinical setting is highly accurate in indicating the absence of a significant coronary stenosis and a low risk of subsequent cardiac events,288 an abnormal study can be nondiagnostic.148,287 In patients with LBBB on a rest ECG, dobutamine stress echocardiography is less sensitive but more specific than nuclear MPI in detecting coronary stenosis and provides prognostic information that is incremental to clinical findings.344 One meta-analysis dem- onstrated that abnormal stress nuclear MPI and stress echo- cardiography each confer an up to 7-fold increased risk of adverse cardiovascular events.148 3.2.3. Prognostic Accuracy of Anatomic Testing to Assess Risk in Patients With Known CAD 3.2.3.1. Coronary CT Angiography Given the high accuracy in detecting angiographically signif- icant coronary stenosis, estimates of cardiovascular risk according to the Duke CAD index with data obtained via CCTA appear to be as accurate as those obtained from cardiac catheterization. However, the actual event rates in patients undergoing CCTA have been substantially lower because of differences in the underlying risk profiles of patient groups that have been referred for these 2 procedures.345 Further- more, data from CONFIRM suggest that the finding of nonobstructive CAD on CCTA supplements clinical informa- tion in predicting risk of mortality.286 For example, 20% to 25% of patients with an intermediate pretest likelihood of risk (1% to 3% annual mortality rate) based on clinical informa- tion (without EF) were reassigned to a different risk category according to information from CCTA. Given that failed bypass grafts can result in unprotected CAD, which confers a higher risk, the assessment of the extent of graft patency by CCTA is also of prognostic value.346,347 Although exercise stress testing in general is preferred in risk assessment, for patients unlikely to achieve conclusive results, consensus opinion suggests that it is reasonable to proceed with a CCTA for risk-assessment purposes. Several ongoing trials are comparing the prognostic values of CCTA and functional imaging modalities such as nuclear MPI and stress echocardiography.348 At present, there are no prospectively gathered trial data demonstrating that CCTA leads to better patient selection for medical or invasive intervention or to better clinical outcomes. 3.3. Coronary Angiography 3.3.1. Coronary Angiography as an Initial Testing Strategy to Assess Risk: Recommendations Class I 1. Patients with SIHD who have survived sudden car- diac death or potentially life-threatening ventricular arrhythmia should undergo coronary angiography to assess cardiac risk.349 351 (Level of Evidence: B) 2. Patients with SIHD who develop symptoms and signs of heart failure should be evaluated to determine whether coronary angiography should be performed for risk assessment.352 355 (Level of Evidence: B) 3.3.2. Coronary Angiography to Assess Risk After Initial Workup With Noninvasive Testing: Recommendations Class I 1. Coronary arteriography is recommended for pa- tients with SIHD whose clinical characteristics and results of noninvasive testing indicate a high likeli- hood of severe IHD and when the benefits are deemed to exceed risk.59,126,260,310,356 362 (Level of Evidence: C) Class IIa 1. Coronary angiography is reasonable to further as- sess risk in patients with SIHD who have depressed LV function (EF <50%) and moderate risk criteria on noninvasive testing with demonstrable ische- mia.363 365 (Level of Evidence: C) 2. Coronary angiography is reasonable to further as- sess risk in patients with SIHD and inconclusive prognostic information after noninvasive testing or in patients for whom noninvasive testing is contra- indicated or inadequate. (Level of Evidence: C) 3. Coronary angiography for risk assessment is reason- able for patients with SIHD who have unsatisfactory quality of life due to angina, have preserved LV function (EF >50%), and have intermediate risk criteria on noninvasive testing.306,366 (Level of Evidence: C) Class III: No Benefit 1. Coronary angiography for risk assessment is not recommended in patients with SIHD who elect not to undergo revascularization or who are not candidates for revascularization because of comorbidities or individual preferences.306,366 (Level of Evidence: B) 2. Coronary angiography is not recommended to fur- ther assess risk in patients with SIHD who have preserved LV function (EF >50%) and low-risk criteria on noninvasive testing.306,366 (Level of Evidence: B) 3. Coronary angiography is not recommended to assess risk in patients who are at low risk according to clinical criteria and who have not undergone nonin- vasive risk testing. (Level of Evidence: C) 4. Coronary angiography is not recommended to assess risk in asymptomatic patients with no evi- dence of ischemia on noninvasive testing. (Level of Evidence: C) Coronary angiography defines coronary anatomy, including the location, length, diameter, and contour of the epicardial coronary arteries; the presence and severity of coronary luminal obstruction(s); the nature of the obstruction; the presence and extent of angiographically visible collateral flow; and coronary blood flow. Despite the ability of newer noninvasive imaging modalities such as CT angiography to visualize and characterize the coronary tree, invasive coro- nary angiography currently remains the gold standard. Coronary angiography has 2 clinical goals: 1) to assess a patient s risk of death and future cardiovascular events through characterization of the presence and extent of ob- structive CAD and 2) to ascertain the feasibility of percuta- neous or surgical revascularization. The likelihood that re- vascularization might decrease angina and improve a patient s quality of life should be considered when a patient deems his or her quality of life unsatisfactory despite a conscientious program of evidence-based medical therapy. Fihn et al Stable Ischemic Heart Disease: Full Text e387 The most commonly used nomenclature for defining cor- onary anatomy is that which was developed for CASS367 and further modified by the BARI study group.368 This scheme is based on the assumption that there are 3 major coronary arteries: the LAD, the circumflex, and the right coronary artery, with a right-dominant, left-dominant, or codominant circulation. The extent of disease is defined as 1-vessel, 2-vessel, 3-vessel, or left main disease, with a significant stenosis $70% diameter reduction. Left main disease, how- ever, also has been defined as a stenosis $50%. Despite being recognized as the traditional gold standard for clinical assessment of coronary atherosclerosis, coronary angiography is not without limitations. First, the technical quality of angiograms in many settings can make accurate interpretation difficult or impossible. In a random sample of .300 coronary angiograms performed in New York State during the 1990s, 4% were of unacceptable quality, and 48% exhibited technical deficiencies that could interfere with accurate interpretation.369 Although more modern techniques and equipment likely have eliminated some of these deficien- cies, few studies have addressed this issue, particularly in patients who present technical challenges, such as those who are obese. Second, problems also exist with interobserver reliability. These investigators also found only 70% overall agreement among readers with regard to the severity of stenosis, and this was reduced to 51% when restricted to coronary vessels rated as having some stenosis by any reader. Third, angiography in isolation provides only anatomic data and is not a reliable indicator of the functional significance of a given coronary stenosis unless a technique such as FFR (discussed below) is used to provide information about the physiological significance of an anatomic stenosis. Lastly, coronary angiography does not distinguish between a vulner- able plaque, with a large lipid core, thin fibrous cap, and increased macrophages, and a stable plaque that does not exhibit these features. Serial angiographic studies performed before and after acute events and early after MI suggest that plaques resulting in UA and MI commonly were found to be ,50% obstructive before the acute event and were therefore angiographically silent. 370,371 Diagnostic test- ing to determine vulnerable plaque, and therefore the subsequent risk for MI, remains intensely studied, but no gold standard yet has emerged.372 Despite these limita- tions of coronary angiography, the extent and severity of CAD remain very significant predictors of long-term patient outcomes (Table 13).55,70,71,373,374 For patients who are found to be at high risk of coronary events or death on the basis of clinical data and noninvasive testing, coronary angiography is often warranted to provide a more complete risk assessment even though cardiac symp- toms might not be severe. Certain clinical characteristics, though relatively infrequent in patients with IHD, have been associated with a high likelihood of severe disease, including the following: chest pain leading to pulmonary edema, chest pain associated with lightheadedness, syncope or hypoten- sion, exertional syncope, and an exercise-induced gallop sound on cardiac auscultation. In addition to clinical signs and symptoms, findings on noninvasive studies could also suggest that certain patients are at high risk of serious cardiac events. These findings include abnormal physiological re- sponse to exercise or imaging studies that suggest extensive myocardial ischemia (Table 14). Some examples from Table 14 (high-risk category) which may suggest somewhat less extensive myocardial ischemia: CCTA 2-vessel disease, CAC score .400 Agatston units, severe resting LV dysfunction (LVEF ,35%) not readily explained by noncoronary causes, stress defects at 10% level, 2 coronary beds wall motion abnormality on stress echocardiography but only 2 segments. Coronary angiography helps to quantify risk on the basis of an anatomic prognostic index; the simplest and most widely used is the classification of disease into 1-, 2-, or 3-vessel or left main CAD.358,375 377 In the CASS registry364 of medically treated patients, the 12-year survival rate of patients with normal coronary arteries was 91%, compared with 74% for those with 1-vessel disease, 59% for those with 2-vessel disease, and 40% for those with 3-vessel disease. The probability of survival declines progressively with the num- ber of coronary arteries that are occluded. The presence of severe proximal LAD artery disease significantly reduces the survival rate. The 5-year survival rate with 3-vessel disease plus .95% proximal LAD stenosis was reported to be 59%, as compared with a rate of 79% for 3-vessel disease without LAD stenosis (Table 13). With the use of data accumulated in the 1980s, a nomogram was developed to predict 5-year survival rate on the basis of clinical history, physical examination, coronary angiography, and LVEF (Figure 12). The importance of considering clinical factors and especially LV function in estimating the risk of a given coronary angiographic finding is illustrated by comparing the predicted 5-year survival rate of a 65-year-old man with stable angina, 3-vessel disease, and normal ventricular function with that of a 65-year-old man with stable angina, 3-vessel disease, heart failure, and an EF of 30%. The 5-year survival rate for the former was estimated to be 93%, whereas patients with the same characteristics but with heart failure and reduced EF had a predicted survival rate of only 58%. Because of advances Table 13. CAD Prognostic Index Extent of CAD Prognostic Weight Survival Rate (%)* *Assuming medical treatment only. CAD indicates coronary artery disease; LAD, left anterior descending. Reproduced from Califf et al.55 in treatment, it is almost certain that the survival rate has improved since these studies were conducted, but the relative differences in survival likely persist. The development of symptomatic LV failure in a patient with SIHD is often an indication of severe, obstructive CAD and demands expeditious evaluation for the presence of active ischemia. Depending on the acuity and severity of symptoms, angiography or evaluation for ischemia with noninvasive testing is warranted. An additional, but less quantifiable, benefit of coronary angiography and LV function assessment derives from the ability of experienced angiographers to integrate the findings on coronary angiography and left ventriculography to estimate the potential benefit of revascularization strategies discussed below. The characteristics of coronary lesions (eg, stenosis severity, length, complexity, and presence of thrombus), the number of lesions posing jeopardy to regions of contracting myocardium, the possible role of collaterals, and the mass of jeopardized viable myocardium also can afford some insight into the conse- quences of subsequent vessel occlusion. For example, a patient with a noncontracting inferior or lateral wall and severe proxi- mal stenosis of a very large LAD artery is presumably at substantial risk of developing cardiogenic shock if the LAD artery were to become occluded. In view of the importance of proximal versus distal coronary stenoses, a jeopardy score has been developed, which takes the prognostic significance of a lesion s location into consider- ation.378 Angiographic studies indicate that a direct correlation also exists between the angiographic severity of CAD and the amount of angiographically insignificant plaque buildup else- where in the coronary tree. These studies suggest that the higher mortality rate of patients with multivessel disease could occur because they have more mildly stenotic or nonstenotic plaques that are potential sites for acute coronary events than do patients For many years, it has been known that patients with severe stenosis of the left main coronary artery have a poor progno- sis when treated medically. A gradation of worsening risk also has been found with increasing degrees of stenosis of the left main in medically managed patients.380 382 Angiographic determination of the significance of left main disease can be difficult, with suboptimal intraobserver agreement with re- gard to the degree of severity of any given stenosis.381,383,384 However, multiple other modalities are available to the angiographer to assist in accurately determining the signifi- cance of a left main lesion (ie, FFR and intravascular ultrasound). Despite the challenges posed by angiographic determination of left main disease, it remains the best option for the diagnosis and reevaluation of left main disease if concern exists about progression of previously diagnosed disease because of the inability to consistently detect and evaluate this condition with noninvasive testing or clinical 4.1. Definition of Successful Treatment The paramount goals of treating patients with SIHD are to minimize the likelihood of death while maximizing health and function. The more specific objectives are to: Table 14. Noninvasive Risk Stratification High risk (3% annual death or MI) 1. Severe resting LV dysfunction (LVEF 35%) not readily explained by noncoronary causes 2. Resting perfusion abnormalities 10% of the myocardium in patients without prior history or evidence of MI 3. Stress ECG findings including 2 mm of ST-segment depression at low workload or persisting into recovery, exercise-induced ST-segment elevation, or exercise-induced VT/VF 4. Severe stress-induced LV dysfunction (peak exercise LVEF drop in LVEF with stress 10%) 5. Stress-induced perfusion abnormalities encumbering 10% myocardium or stress segmental scores indicating multiple vascular territories with abnormalities 6. Stress-induced LV dilation 7. Inducible wall motion abnormality (involving 2 segments or 2 coronary beds) 8. Wall motion abnormality developing at low dose of dobutamine ( 10 mg/kg/min) or at a low heart rate ( 9. CAC score 400 Agatston units 10. Multivessel obstructive CAD (70% stenosis) or left main stenosis (50% stenosis) on CCTA Intermediate risk (1% to 3% annual death or MI) 1. Mild/moderate resting LV dysfunction (LVEF 35% to 49%) not readily explained by noncoronary causes 2. Resting perfusion abnormalities in 5% to 9.9% of the myocardium in patients without a history or prior evidence of MI 3. 1 mm of ST-segment depression occurring with exertional symptoms 4. Stress-induced perfusion abnormalities encumbering 5% to 9.9% of the myocardium or stress segmental scores (in multiple segments) indicating 1 vascular territory with abnormalities but without LV dilation 5. Small wall motion abnormality involving 1 to 2 segments and only 1 coronary bed 6. CAC score 100 to 399 Agatston units 7. One vessel CAD with 70% stenosis or moderate CAD stenosis (50% to 69% stenosis) in 2 arteries on CCTA Low risk ( 1% annual death or MI) 1. Low-risk treadmill score (score 5) or no new ST segment changes or exercise-induced chest pain symptoms; when achieving maximal levels of exercise 2. Normal or small myocardial perfusion defect at rest or with stress encumbering 5% of the myocardium* 3. Normal stress or no change of limited resting wall motion abnormalities during stress 4. CAC score 100 Agatston units 5. 