Overall, most reports document an improvement in diagnostic accuracy with imaging when compared to a standard exercise ECG,175 although that improvement does not necessarily translate into improved clinical outcomes.147 From a meta- analysis, the diagnostic sensitivity and specificity were 72% and 88% for women undergoing dobutamine stress echocar- diography.149 From a small controlled clinical trial, diagnostic specificity was improved considerably when using gated Tc-99m myocardial perfusion SPECT over Tl-201 myocar- dial perfusion SPECT (92% versus 67%) because of im- proved image quality.1133 Overall, sensitivity and specificity of myocardial perfusion SPECT were reported as 88% and 96% for women.86,175,1134 For CMR, one study reported a diagnostic sensitivity and specificity of 92% and 80% with vasodilator stress magnetic resonance myocardial In part related to differing pathophysiology and clinical presentation, substantial differences in provision of clinical care have been observed between men and women with CAD.1135 Despite increasing recognition of the risks of worsening IHD and attendant complications in women, the frequency with which they are prescribed important risk- modifying therapies such as statins, aspirin, and beta blockers after episodes of ACS remains significantly lower than among men.1136,1137 Among patients with documented SIHD, however, the differences between men and women appear to be much smaller with regard to prescription of these Data from COURAGE suggest that the benefits of GDMT alone in comparison with GDMT plus PCI were similar for men and women.366,1138 Moreover, the outcomes of revascu- larization appear to be less favorable among women than men,1139 1142 although very few women were enrolled in COURAGE. In various risk models, the odds of in-hospital death after PCI have ranged from 25% to 80% higher for women than for men,1143 1147 although this trend might have improved in recent years after the higher incidence of diabetes mellitus and hypertension in women is taken into account.1148 The risk of procedural complications also ap- pears to be significantly higher in women.1149 Although fewer data on the experience of women after CABG are available, in the New York State registry, the odds of in-hospital death for women were 2-fold higher than for men.1149,1150 On the basis of these observations, the initial approach to therapy for women with SIHD should be to prescribe a full regimen of GDMT and to reserve consideration of revascularization for patients who do not obtain a satisfactory response or who experience unacceptable adverse effects. On the basis of the higher risk associated with PCI in women, it might be reasonable to adopt a more conservative approach in under- taking this procedure than in men, although the general principle of using revascularization in patients whose symp- toms are refractory to medical therapy and who are not satisfied with their current level of angina persists. 5.12.2. Older Adults In older adults, often defined as .75 years of age, coronary stenoses are likely to be more diffuse and more severe, with a higher prevalence of 3-vessel and left main disease. Several factors complicate the diagnosis and treatment of SIHD in this age group. Common coexisting conditions of the pulmo- nary, gastrointestinal, and musculoskeletal systems can cause chest pain, making diagnosis more difficult, even in patients with documented IHD. Physiological changes in older adults, including alterations in cardiac output through various mech- anisms, muscle loss and deconditioning, neuropathies, lung disease, and degenerative joint disease, make stress testing more difficult. Thus, many elderly patients are incapable of responding to graded increases in workload as required by standard exercise ECG protocols.118,1151 For patients who are unable to exercise, pharmacological stress imaging is indi- cated. Although the majority of investigations have focused on prognosis by markers of ischemia in the elderly, the results generally reveal a similar accuracy of testing when compared with younger individuals presenting with SIHD.1152 1155 Baseline ECG changes, arrhythmias, and LV hypertrophy, which are more common in older adults who have accumu- lated cardiac comorbidities, also limit the value of stress testing.1156,1157 The higher prevalence of SIHD in older adults results in more tests that are falsely negative, and the prognostic value of the Duke treadmill score in older adults might be limited.1158 Data based on RCTs to guide therapy in older adults are relatively sparse because of the common exclusion of older patients from early clinical trials. Several studies have shown less frequent use of evidence-based therapies in older adults, such as early invasive procedures, anticoagulants, beta block- ers, and glycoprotein IIb/IIIa inhibitors.1156,1159,1160 The find- ings are likely related to several factors. Pharmacotherapy is more difficult in older adults because of changes in drug bioavailability and elimination. Drug drug interactions are more common because of polypharmacy. A more conserva- tive approach to coronary angiography is often appropriate given the higher risk of contrast-induced nephropathy in older adults.1161 Moreover, the risks of morbidity and mortality associated with CABG are increased in older adults. Despite the complexities and concerns related to evaluating and treating elderly patients with SIHD, findings from the COURAGE trial indicated that initial medical therapy was not significantly less effective than medical therapy plus PCI in relieving angina (73% in the GDMT group at 60 months, versus 80% in the medical therapy plus PCI group).1162 Although the mortality rate was 50% higher among patients .65 years of age than among younger patients, there were no significant differences between the 2 treatment groups in either patients younger or older than 65 years. Furthermore, although the incidence of MI and stroke was also higher in older patients, there were no significant differences between treatment groups. In the TIME (Trial of Invasive versus Medical Therapy in the Elderly) trial, 301 patients $75 years of age with chronic angina with CCS Class II or higher despite treatment with $2 antianginal drugs were randomized to GDMT or to an invasive strategy of coronary angiography followed by revascularization with PCI or CABG, if feasi- ble.1163 Patients who were assigned to the early revascular- ization group experienced greater improvement in symptoms at 6 months. This difference disappeared by 12 months, at which time both groups had shown a 2-class improvement in their CCS scores and similar results on other quality-of-life measures. It should be noted that 45% of the group assigned to medical therapy ultimately underwent revascularization because of refractory symptoms. Considerable evidence indicates that elderly patients have higher mortality following PCI and CABG than do younger patients, and the risk appears to rise monotonically when .65 years of age.1144 1147,1164 1166 Compared with patients #65 years of age, adjusted odds of short-term mortality after PCI among patients between the ages of 60 and 80 have ranged from 2.2 to 7.6 in various registries, and the odds of death among those $80 years have ranged from 2.7 to .13. Unfortunately, far fewer data are available on the outcomes of elderly patients undergoing CABG, and much of it could be outdated. On the basis of data from 16 120 patients entered into the New York State registry, the odds of in-hospital mortality rose 8% per year of age .60 years (OR: 1.08; 95% CI: 1.06 to 1.09).1150 On the other hand, in an analysis of 505 645 records from the registry maintained by the STS, age was not found to be a predictor of mortality.1167 In older studies, elderly patients were reported to have favorable results after CABG,1168,1169 and long-term survival rates for elderly pa- tients with SIHD treated medically versus surgically were Older adults constitute a growing proportion of patients with SIHD. On the basis of the available data, it is recom- mended that management by GDMT be the initial approach in most patients. Given concerns about higher mortality rate, Fihn et al Stable Ischemic Heart Disease: Full Text e423 particularly in patients .75 or 80 years of age, decisions to recommend revascularization should be undertaken only after careful consideration of patient preferences, functional capac- ity, quality-of-life and end-of-life issues, as well as therapeu- 5.12.3. Diabetes Mellitus Type 1 and type 2 diabetes mellitus are associated with a greater risk of SIHD, and the effects of other risk factors such as hypercholesterolemia are magnified.1170 Cardiovascular mortality rate is 3-fold higher in men with diabetes mellitus and between 2- and 5-fold higher in women with diabetes than in patients without diabetes mellitus.1171,1172 Sudden cardiac death occurs more frequently in patients with diabetes mellitus. Although direct evidence is lacking, asymptomatic ischemia could be more prevalent in patients with diabetes mellitus, possibly because of autonomic neuropathy.1173 The risk of death in a patient with SIHD and diabetes mellitus has been equated to the risk of death in a patient with SIHD and a previous MI.1171,1174 Aggressive management of cardiovascular risk factors, including hypercholesterolemia, hypertension, smoking, low physical activity, and obesity, is essential, along with appropriate glycemic control. Among patients with IHD, the presence of concomitant diabetes mellitus increases the risk of adverse events, irre- spective of whether the patient is treated medically or with revascularization. Two studies have suggested that survival among patients with diabetes mellitus is more favorable after bypass surgery than with medical therapy, although these results are based on subgroup analyses from observational data.991,1175 Of 2 studies comparing PCI and medical therapy in patients with diabetes mellitus, one reported longer sur- vival,1175 but the other did not.991 A subgroup analysis of data from the BARI trial suggested that patients with diabetes mellitus who underwent CABG with 1 arterial conduit had improved survival compared with those who underwent PCI.368 Several retrospective cohort studies have compared outcomes among patients with diabe- tes mellitus undergoing PCI versus CABG. Three observa- tional studies have reported a survival advantage for CABG over PCI, whereas a fourth found no significant difference, and no studies located reported better outcomes after PCI. In the BARI 2D study, 2368 patients with type 2 diabetes mellitus and SIHD were initially selected as candidates for either PCI or CABG on the basis of clinical and angiographic assessment and then were randomly assigned to undergo either prompt revascularization with intensive medical ther- apy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy.408 The study was not designed to compare PCI with CABG. At 5 years, overall survival was similar between the revasculariza- tion and medical-therapy groups (88.3% versus 87.8%), as was the incidence of MACE (77.2% versus 75.9%).409 Pa- tients with the most severe CAD were assigned to the CABG stratum and those with the least severe CAD to the PCI stratum. In the PCI stratum, there was no significant differ- ence in primary endpoints between the revascularization group and the medical-therapy group. In the 763 patients randomized to the CABG stratum, survival was similar but AMI less frequent among those assigned to revascularization plus intensive medical therapy compared with intensive medical therapy (10.0% versus 17.6%; P50.003), and the composite endpoints of all-cause death or MI (21.1% versus 29.2%; P50.010) and cardiac death or MI (P50.03) were also less frequent. Compared with those selected for PCI, patients in the CABG stratum had more 3-vessel disease more proximal LAD stenoses .50% (10% versus 19%), and a significantly higher myocardial jeopardy score.409 One-year follow-up data from the SYNTAX study demon- strated a higher rate of repeat revascularization in patients with diabetes mellitus treated with PCI than in those treated with CABG, driven by a tendency for higher repeat revascu- larization rates in those with higher SYNTAX scores under- A large meta-analysis that included the BARI trial but not BARI 2D failed to identify any significant difference in mortality rate after CABG versus PCI for patients with diabetes mellitus.1079 In a more recent, collaborative analysis that pooled patient-level data from 10 randomized trials (again, not including BARI 2D), Hlatky and colleagues found that of the 1233 patients with diabetes mellitus, 23% of those assigned to CABG died, compared with 29% of those assigned to PCI.1080 By contrast, of the 6561 patients without diabetes mellitus, 13% and 14% died, respectively (P50.014 for interaction). The interaction between diabetes mellitus and treatment remained highly significant after adjustment for multiple patient characteristics and after exclusion of patients enrolled in the BARI 2D trial. Some evidence indicates that the presence of diabetes mellitus adversely affects the outcomes of revascularization. An analysis of the 2009 data on 7812 patients (1233 with diabetes mellitus) in 10 RCTs demonstrated a worse long- term survival rate in patients with diabetes mellitus after balloon angioplasty or BMS implantation than after CABG.1080 Analyses from 3 registries found significantly elevated adjusted ORs for short-term mortality after PCI that ranged from 1.25 to 1.54 in relation to patients without diabetes mellitus.1144,1146,1165 Data from the STS registry indicated that patients with diabetes mellitus on oral therapy had an adjusted OR of 1.15 for death within 30 days (95% CI: 1.09 to 1.21), as well as significantly higher odds of stroke, renal failure, or sternal wound infection than those of patients without diabetes mellitus.1167 For patients on insulin, the adjusted OR for death within 30 days was 1.50 (95% CI: 1.42 to 1.58), and the risks for other complications were also correspondingly higher. In summary, in subjects requiring revascularization for multivessel CAD, current evidence supports diabetes mellitus as an important factor to consider when deciding on a revascularization strategy, particularly when complex or ex- tensive CAD is present (Figure 14). The basis of the currently available data, an intensive approach to reducing cardiovascular risk and symptoms in patients with diabetes mellitus by using GDMT should be the initial approach. For patients whose symptoms are inade- quately managed or who experience intolerable adverse effects, revascularization should be considered. CABG might be associated with lower risk of mortality in patients with diabetes mellitus and multivessel disease than PCI, but this remains uncertain. The ongoing FREEDOM (Future Revas- cularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial could help resolve this question.1177 Obese individuals frequently have reduced physical work capacity and exaggerated dyspnea on exertion. Furthermore, weight limits of exercise and imaging equipment preclude testing the very obese.1178,1179 Because of limitations in exercise testing and challenges with imaging through in- creased breast tissue or chest girth, reduced diagnostic accu- racy has been reported for obese patients.1180 Because of breast tissue artifact, myocardial perfusion PET is more accurate than myocardial perfusion SPECT for the obese patient,191,193,323 although attenuation-correction algorithms or prone imaging can help improve myocardial perfusion SPECT accuracy.187,188 Intravenous contrast enhancement improves image quality in obese patients and results in improved diagnostic certainty for stress echocardiography.181 5.12.5. Chronic Kidney Disease CKD confers greater risk for developing SIHD, for its progression, and for poor outcomes after interventions for AMI.1181 1183 The mortality rate for patients on hemodialysis is .20% per year, and approximately 50% of deaths among these patients are due to a cardiovascular cause.27,1184 To avoid worsening underlying kidney disease, physicians should consider creatinine clearance in pharmacotherapy and should apply risk scores for predicting the likelihood of contrast-induced nephropathy1161,1185 in conjunction with the use of renal protective strategies such as isosmolar contrast agents during angiography.3,4,4a Unfortunately, studies evaluating the outcomes of revascu- larization in patients with renal disease have not applied a consistent definition of renal disease. Only one study identi- fied by the writing committee used the Kidney Disease Outcome Quality Definition of renal disease grades: Stage 1, mL/min; and Stage 5, ,15 mL/min or ongoing dialysis (1186). Others studies simply described patients as receiving dialysis1187,1188 or defined renal disease as any creatinine clearance ,60 mL/min1189,1190 or any serum creatinine above approximately 2.3 mg/dL.1191,1192 Ongoing studies are begin- ning to use the AKIN (Acute Kidney Injury Network) or RIFLE (Risk, Injury, Failure, Loss, and End-stage) criteria and should ensure more consistency in the study of peripro- cedural complications of percutaneous revascularization. Among patients who were enrolled in the COURAGE trial, the presence of CKD was associated with odds of 1.48 for death, MI, or new heart failure relative to patients without kidney disease.1193 Medical therapy, however, was effective and associated with the same BP and lipid levels as in patients without CKD. Patients with CKD also experience significant and sustained improvement in angina with both PCI and GDMT, and there was no significant interaction between the presence of CKD and treatment assignment in survival rate, incidence of AMI, or improvement in symptoms. To date, randomized comparisons of coronary revascular- ization (with CABG or PCI) and medical therapy in patients with CKD have not been reported. Some, but not all, observational studies or subgroup analyses have demon- strated an improved survival rate with revascularization compared with medical therapy in patients with CKD and multivessel CAD,1191,1193,1194 despite the fact that the inci- dence of periprocedural complications (eg, death, MI, stroke, infection, renal failure) is higher in patients with CKD than in those without renal dysfunction. In 2 cohort studies involving patients with a spectrum of kidney disease ranging from mild to severe, adjusted survival was superior for those who underwent bypass surgery compared with those who received only medical therapy.1191,1194 In 1 study, survival after PCI was improved (compared with medical therapy) in patients with mild, moderate, or severe kidney disease but not in those with end-stage kidney disease. The other study yielded opposite results, with longer survival after PCI in patients with end-stage renal disease but not in those with mild, moderate, or severe kidney disease. Some studies have shown that CABG is associated with a greater survival benefit than PCI among patients with severe renal dysfunction.1187 1192,1194 Five studies have suggested that survival is prolonged among patients with CKD after CABG compared with after PCI,1187,1188,1191,1192,1194 whereas 3 other studies indicated that survival is similar after either of the 2 revascularization strategies, regardless of the severity of underlying renal disease.1189,1190,1192 Figure 14. One-year mortality rates in randomized trials of patients with diabetes and multivessel CAD, comparing PCI (experimental) with CABG (control). An OR .1 suggests an advantage of CABG over PCI. ARTS1 indicates Arterial Revascularization Therapy Study I1033; BARI I, Bypass Angioplasty Revascularization Investigation I1005; CARDia, Coronary Artery Revascularization in Diabetes1176; CI, confidence interval; DM, diabetes mellitus; MASS II, Medicine, Angioplasty, or Surgery Study II1008; OR, odds ratio; SYNTAX, Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery; and W, weighted.1006 Fihn et al Stable Ischemic Heart Disease: Full Text e425 5.12.6. HIV Infection and SIHD HIV infection appears to be associated with an increased risk of premature coronary and cerebrovascular atherosclerosis, which is often accelerated, diffuse, and circumferential, involving whole arteries.1195,1196 AMI is often the initial manifestation.1197 The etiology is likely multifactorial and related to both the underlying infection and antiretroviral therapy. The former appears to promote proliferation of smooth muscle cells and elastin leading to luminal obstruc- tion, although there is poor correlation between CD4 cell counts and severity of CAD. Of the therapeutic agents used to treat HIV infection, protease inhibitors in particular have been epidemiologically linked to dyslipidemia and insulin resistance.1198 1200 The protease inhibitors amprenavir/fosam- prenavir with or without ritonavir and lopinavir with ritonavir have the strongest association with risk of AMI, although saquinavir and nelfinavir do not appear to be associated with MI.1201,1202 The nucleoside reverse-transcriptase inhibitors didanosine and abacavir also are associated with risk of AMI.1202 Other agents, such as nonnucleoside reverse- transcriptase inhibitors (nevirapine and efavirenz), entry in- hibitors, and integrase inhibitors, do not appear to be associ- ated with an increased risk of IHD. Despite the increase in prevalence of IHD among patients with HIV, the absolute increase in incidence of AMI is relatively low, and overall mortality does not appear to be increased.1198,1203 It is likely that this reflects the otherwise enormous benefit conferred by treatment with highly active antiretroviral therapy in the course of HIV infection. None- theless, patients receiving highly active antiretroviral therapy should be assessed for cardiovascular risk factors and moni- tored for signs and symptoms of IHD. It is prudent to recommend a healthy diet, regular physical activity, and avoidance of smoking. Patients with hypercholesterolemia should be managed in a fashion similar to other patients at risk for IHD.1204 5.12.7. Autoimmune Disorders Connective tissue disease represents a less well-studied issue in SIHD. In rheumatoid arthritis, findings from at least one study show increased inflammation in the coronary artery walls, with increased frequency of vulnerable plaques.1205 Accelerated atherosclerosis in systemic lupus erythematosis, due to impaired endothelial function and novel atherogenic and thrombotic risk factors, requires special attention inas- much as the adjusted rate of SIHD in systemic lupus erythematosis is $50-fold higher than in patients without it.1206,1207 A younger population is more frequently affected in systemic lupus erythematosis,1208 and coronary artery spasm is a frequent complication in connective tissue disease.1209 5.12.8. Socioeconomic Factors Low socioeconomic status is highly associated with the risk of cardiovascular disease.1210 Men 30 to 59 years of age with low socioeconomic status are at 55% higher risk of death due to IHD than are those of higher status (RR: 1.55; 95% CI: 1.51 to 1.60), and the risk is .2-fold higher among women In addition to lower socioeconomic status being associated with a higher prevalence of IHD, it has been amply demon- strated that patients of lower socioeconomic status and those who are members of an ethnic or racial minority (in particular African Americans and Hispanics) are less likely to receive a wide variety of diagnostic and therapeutic interventions. These disparities have been observed with regard to cardiac procedures as well as access to cardiologists.1212 Moreover, African Americans and Hispanics are 10% to 40% less likely to receive outpatient secondary prevention therapies for cardiovascular disease.1213 Although lower rates of diagnostic and interventional services have not been adequately ex- plained,1214,1215 it is clear that individuals of lower socioeco- nomic status and ethnic minorities typically have fewer healthcare resources, have worse general health and cardiac risk profiles, and are less knowledgeable about SIHD symp- toms. Healthcare providers and systems should strive to eliminate or ameliorate barriers to care for patients who have SIHD and are of low socioeconomic class or ethnic minorities. 5.12.9. Special Occupations Although not recommended for the general population, rou- tine surveillance with functional testing is recommended in a few occupations in which the presence of even asymptomatic cardiac disease could endanger others, such as commercial pilots, police, firefighters, and bus drivers. The general parameters of test performance noted above apply in these circumstances, with the caveat that most of these individuals are at low risk and therefore could be more likely to have false positive results. 6. Patient Follow-Up: Monitoring of Symptoms and Antianginal Therapy The goals of clinical follow-up of patients with SIHD are to maximize function and to minimize long-term mortality and morbidity. In this context, the primary goal of follow-up testing should be to reassess residual or new ischemic burden in the setting of persistent or worsening (but not unstable) symptoms. Thus, follow-up assessment and testing will vary according to the clinical status of the patient and with the evolution of evidence-based practice. Unnecessary testing should be avoided. For patients with SIHD who show no change in symptoms or functional capacity, periodic follow-up serves multiple purposes: Ongoing reassessment of adherence to and effectiveness of the therapeutic regimen, including clinical response, occur- rence of adverse effects, and treatment goals, on the basis of evolving scientific evidence and preferences of the patient. Evaluation of the effectiveness of interventions to modify risk factors such as exertional hypertension. Assessment of the status of coexisting chronic medical conditions that could directly or indirectly affect the management of stable cardiac ischemia. Patients with SIHD who have accelerating symptoms or decreasing functional capacity require prompt reassessment. Patients with SIHD who develop new ACS should be evaluated and treated according to established guidelines.3,4,4a,9,10 Patients who have been treated for an ACS (ie, AMI or UA) within the previous 6 months and who develop chest pain within 30 days of the AMI should be evaluated according to the STEMI or UA/NSTEMI guide- lines as warranted.2 4,4a Patients who have undergone revas- cularization with either PCI or CABG within 6 months should be monitored according to the PCI and CABG guidelines.9,10 Patients with SIHD should be evaluated before elective or emergent surgery according to established perioperative 6.1. Clinical Evaluation, Echocardiography During Routine, Periodic Follow-Up: Recommendations Class I 1. Patients with SIHD should receive periodic follow- up, at least annually, that includes all of the follow- ing (Level of Evidence: C): a. Assessment of symptoms and clinical function; b. Surveillance for complications of SIHD, including heart failure and arrhythmias; c. Monitoring of cardiac risk factors; and d. Assessment of the adequacy of and adherence to recommended lifestyle changes and medical therapy. 2. Assessment of LVEF and segmental wall motion by echocardiography or radionuclide imaging is recom- mended in patients with new or worsening heart failure or evidence of intervening MI by history or ECG. (Level of Evidence: C) Class IIb 1. Periodic screening for important comorbidities that are prevalent in patients with SIHD, including dia- betes mellitus, depression, and CKD, might be rea- sonable. (Level of Evidence: C) 2. A resting 12-lead ECG at 1-year or longer intervals between studies in patients with stable symptoms might be reasonable. (Level of Evidence: C) Class III: No Benefit 1. Measurement of LV function with a technology such as echocardiography or radionuclide imaging is not recommended for routine periodic reassessment of patients who have not had a change in clinical status or who are at low risk of adverse cardiovascular events.117 (Level of Evidence: C) Standard risk-assessment tools that have been developed from clinical and laboratory evaluation of ambulatory popu- lations with suspected CAD, as discussed in detail in Section 2 of this guideline, include patients who have noncardiac causes of presenting symptoms. However, the performance of these same tools in predicting short-term and long-term risk for coronary mortality and coronary events might vary in patients with known SIHD as compared with patients without known disease who present with chest pain syndromes that might or might not represent angina. Although mortality and morbidity rates intuitively might be considered to be higher in patients with documented as opposed to suspected CAD, evidence-based medical management, including adherence to appropriate lifestyle changes, and possibly appropriate revas- cularization in patients with ACS or patients identified as high risk with worsening clinical status or persistent symp- toms despite GDMT, might explain the generally low mor- tality risk that has been found in several studies of patients with established SIHD.57,58,366,1216,1217 The incidence of ad- verse events during longitudinal follow-up of SIHD has declined and can be expected to vary with evolving medical management and with accruing information about the out- comes of revascularization.295,898,1163,1217 1219 Although data on serial testing are limited, one approach to identifying candidates for follow-up testing is to apply prognostic scores for detection of patients with SIHD who are at high risk of MACE. The findings of studies that have examined the prognostic value of testing among patients with known stable CAD who are receiving contemporary GDMT306,1220 1223 could provide clues for identifying candi- dates and appropriate intervals for follow-up testing. In the TIBET (Total Ischemic Burden European Trial) study group, which comprised 682 patients with stable angina and positive exercise ECG tests, adverse outcome was predicted by time to ischemia during exercise, prior infarction or prior CABG, ECG evidence for LV hypertrophy, and LV enlargement by echocardiography.58 Easily available clinical characteristics have been the strongest predictors of risk during follow-up of patients with SIHD in other studies. The Euro Heart Survey found that a score based on the cumulative presence of comorbidity, diabetes mellitus, severity of angina, onset of recurrent symptoms ,6 months previously, abnormal ven- tricular function, and resting ECG repolarization abnormali- ties was associated with an increase in the 1-year risk of death or nonfatal infarction that ranged nearly 100-fold (from 0.5% to 47%) among .3000 outpatients.57 The ACTION (A Coronary Disease Trial Investigating Outcome with Nifedi- pine Gastrointestinal Therapeutic System) trial derived a clinical risk score that separated 5-year risk of death, MI, or stroke from 4% to 35% in .7300 patients with stable angina on the basis of commonly available clinical variables. In order of decreasing importance, the variables included age, LVEF, smoking, white blood cell count, presence of diabetes mellitus, casual (any time of day without regard to time since the last meal) blood glucose concentration, creatinine, prior stroke, frequent angina, findings at coronary angiography, lipid-lowering treatment, QT interval on the resting ECG, systolic hypertension, number of drugs used for angina, prior infarction, and sex.1216 Because the populations enrolled in these studies varied and the results have not been indepen- dently validated, additional prospective studies of patients with established SIHD are required to establish appropriate follow-up evaluation strategies and to establish efficient time intervals for evaluation in stable patients.307,320,1223,1224 6.2. Follow-Up of Patients With SIHD Standard risk assessment tools that have been developed from clinical and laboratory evaluation of ambulatory populations with suspected CAD, as discussed in detail in Section 2 of this guideline, include patients who have noncardiac causes of presenting symptoms. Estimates of the likelihood of future cardiac events using the Framingham score,508,1225 which was Fihn et al Stable Ischemic Heart Disease: Full Text e427 derived from populations that included large numbers of low-risk individuals without disease in their low-risk subsets, are not generally useful when applied to patients with known SIHD. In fact, prediction of risk for coronary mortality and coronary events during short-term and long-term follow-up of patients with SIHD differs from risk stratification in less- ascertained populations with chest pain syndromes. Although mortality and morbidity rates intuitively might be considered to be higher in patients with documented as opposed to suspected IHD, several circumstances serve to confound this assumption. Patients at highest risk, for example, are often identified and aggressively treated during the course of ACS or during initial risk assessment of chest pain. After being treated, asymptomatic patients are typically at low risk for adverse events. Moreover, patients with recognized SIHD could be more likely to receive and adhere to effective therapies than are those whose disease has not been docu- mented. Finally, patients who have been stable for long periods of time could be less prone to development of ACS than are newly ascertained patients with SIHD. Thus, evidence-based medical management, including adherence to appropriate lifestyle changes and possibly appropriate revas- cularization in patients with ACS or patients identified as high risk with worsening clinical status or persistent symp- toms despite GDMT, could explain the generally low mor- tality risk that has been found in several studies of patients with established but stable SIHD.57,58,366,1216,1217 Moreover, large trials conducted during the past decade have shown a declining mortality rate among patients with established SIHD.295,898,1163,1217,1218 Accordingly, risk could change with advances in therapy and patient management, and these advances could alter risk-prediction models. A key component in following up patients with SIHD is to systematically and reproducibly monitor their symptoms and functional status. This should be done, at a minimum, yearly and ideally at each visit. Even though the CCS classification system is the most common metric with which to quantify patients symptoms and function, as noted previously, it is limited by being from the physician s perspective rather than the patient s. Moreover, it has limitations in its reproducibil- ity and interrater reliability. To obtain a valid, reliable, reproducible, and sensitive assessment of patients symp- toms, function, and quality of life from patients perspectives, the SAQ can be used.435,1226 The SAQ is a 19-item, self- reported questionnaire that takes approximately 5 minutes for most patients to complete and explicitly quantifies patients angina frequency, recent changes in their angina, their phys- ical limitations due to angina, their satisfaction with treat- ment, and their perceptions of how their angina limits their quality of life. Scores on the SAQ have been shown to be associated with subsequent survival. ACS admissions and costs246,247,1227 can be integrated into prognostic models to identify patients warranting more aggressive treatment be- cause of an adverse prognosis. In the CADENCE (Coronary Artery Disease in General Practice) study, conducted in 207 primary care clinics throughout Australia,1228 Beltrame and colleagues found wide variation in anginal symptoms accord- ing to the SAQ. Routine use of the SAQ has been endorsed as a performance measure of quality in SIHD.407,436 6.2.1. Focused Follow-Up Visit: Frequency Patients with SIHD should receive regular follow-up to monitor symptoms and progression or complications of dis- ease. Regular visits with a healthcare provider are also necessary to evaluate patients adherence to and effectiveness of therapy as well as occurrence of any adverse effects. Although there are scant data on which to base a definitive recommendation, the writing committee recommends a clin- ical follow-up evaluation every 4 to 12 months. A more precise interval cannot be recommended because many fac- tors influence the length of the follow-up period, including sharing of care by family physicians, internists, and cardiol- ogists, which will vary with regional practice patterns, patient preference, and physician availability. During the first year of therapy, evaluations every 4 to 6 months are recommended. After the first year of therapy, evaluations every 6 to 12 months are recommended if the patient is stable and reliable enough to call or make an appointment when symptoms or functional capacity become worse. Limited data from obser- vational studies indicate that outcomes might be better for patients who receive follow-up from a cardiologist.1229,1230 When patients are managed jointly by their primary care physician and cardiologist, effective communication between physicians is essential. This ultimately will be facilitated by effective implementation of accessible electronic medical records. Periodic office visits can be supplemented by tele- phone, e-mail, or other types of contact between the patient and the healthcare team. 6.2.2. Focused Follow-Up Visit: Interval History and Coexisting Conditions Although follow-up of patients with SIHD often is focused on periodic testing, the most crucial element is a careful interval history. Key elements of the history are: Changes in physical activity or symptoms; Response to therapy, adverse effects, and adherence to recommendations; and Development of relevant, new chronic conditions or changes in existing conditions. Symptomatic change and decreasing functional capacity are important markers for increased risk in patients with SIHD, particularly with increasing age and additional comor- bidities. The evaluation of symptoms should be detailed and directed, as many patients are reluctant to volunteer such information. It should be noted whether patients have reduced their activity, perhaps in an effort to ameliorate anginal symptoms or as a symptom of ventricular dysfunction. The adverse prognostic importance of frequent, typical angina in patients with SIHD is evident in both older and newer studies of risk.57,126,127,1231,1232 Motivation and compliance with risk- reduction measures should be carefully assessed. In particu- lar, assistance with smoking cessation by means of a struc- tured program might be necessary for some patients. Careful attention must be paid to concomitant conditions, such as hypertension, diabetes mellitus, dyslipidemia, heart failure, and depression. 6.2.3. Focused Follow-Up Visit: Physical Examination The physical examination should be directed according to the patient s history. Every patient should have weight, BP, and heart rate measured. BMI and waist circumference can provide signs of additional risk. Signs of heart failure, such as elevated jugular venous pressure, hepatojugular reflux, pul- monary crackles, new murmurs or gallops, or edema, should be sought. The vascular examination should identify any change in peripheral pulses or new bruits. Coexistence of SIHD with extracranial carotid disease makes palpation and auscultation of the carotid arteries particularly important, and examination of the abdomen should include special attention to bruits or abnormally prominent pulsations of the abdomi- nal aorta. 6.2.4. Focused Follow-Up Visit: Resting 12-Lead ECG An ECG is necessary when there is a change in anginal pattern, symptoms or findings suggestive of a dysrhythmia or conduction abnormality, and near or frank syncope. It is important to recognize that periodic recording of the standard 12-lead ECG has clinical value that is independent of diag- nostic and prognostic content: It provides a baseline wave- form against which tracings taken during symptoms reason- ably can be compared. Because many patients with SIHD have resting repolarization abnormalities, absence of a timely tracing for comparison with a tracing taken during atypical symptoms can lead to overdiagnosis of acute ische- mia.1233,1234 Conversely, repolarization abnormalities dur- ing symptoms that might be new or significantly more marked can also be consistent with old disease and lead to underdiagnosis or undertreatment of unstable disease.1235 New repolarization abnormalities during serial study have been shown to predict cardiovascular events during the longitudinal study of hypertensive patients in the Framing- ham Heart Study.318 A study of hypertensive patients that included a subgroup with established SIHD also demon- strated an increased risk of cardiovascular endpoints after the development of new repolarization changes during serial evaluation.318,1236 Although there are no prospective randomized data demonstrating that intervention based on routine, periodic evaluation of the ECG alone will alter outcomes in patients with SIHD, pending such evidence, the clinical value of a change in the resting ECG is widely accepted. In patients with established SIHD, a change in a periodically obtained ECG can be the only evidence of intercurrent silent infarction, inadequately treated hyper- tension, or complex arrhythmia that would modify treat- ment. The timing between routine recordings of the 12- lead ECG that would be required and adequate to accomplish these purposes has not been established, but a consensus recommendation based on expert opinion and common practice would be not greater than once yearly for stable patients with SIHD, as well as at the time of any clinical change. 6.2.5. Focused Follow-Up Visit: Laboratory Examination Patients not known to have diabetes mellitus should have a fasting blood glucose measurement every 3 years to detect new-onset diabetes mellitus, and those with established dia- betes mellitus should have glycosylated hemoglobin mea- sured at least annually to assess glycemic control. A lipid profile should be obtained as clinically warranted. Long-term studies (up to 7 years) demonstrate sustained benefit from continued therapy.18,318 Measurement of creatinine kinase also could be appropriate at these times. In circumstances in which the patient is not concurrently followed up by a primary care physician, measurements of hemoglobin, thy- roid function, serum electrolytes, and renal function should be obtained annually, or sooner when prompted by a change in symptoms or signs. 6.3. Noninvasive Testing in Known SIHD For any patients with known SIHD who have recurrent but stable symptoms after having been symptom free for a period of time on GDMT or after revascularization and who do not fall into any of the categories listed in the previous paragraph, the concepts underlying the recommendations for Noninva- sive Testing for Diagnosis of IHD from Section 2.2 gener- ally apply, with the modifications and special consideration discussed below. 6.3.1. Follow-Up Noninvasive Testing in Patients With Known SIHD: New, Recurrent, or Worsening Symptoms Not Consistent With Unstable Angina: Recommendations See Table 20 for a summary of recommendations from this section. 6.3.1.1. Patients Able to Exercise Class I 1. Standard exercise ECG testing is recommended in patients with known SIHD who have new or wors- ening symptoms not consistent with UA and who have a) at least moderate physical functioning and no disabling comorbidity and b) an interpretable ECG.114,145 147 (Level of Evidence: B) 2. Exercise with nuclear MPI or echocardiography is rec- ommended in patients with known SIHD who have new or worsening symptoms not consistent with UA and who have a) at least moderate physical functioning or no disabling comorbidity but b) an uninterpretable ECG.172,276,278,284,306,313,314,320,324,327 329,1237 1240 (Level of Evidence: B) Class IIa 1. Exercise with nuclear MPI or echocardiography is reasonable in patients with known SIHD who have new or worsening symptoms not consistent with UA and who have a) at least moderate physical function- ing and no disabling comorbidity, b) previously required imaging with exercise stress, or c) known multivessel disease or high risk for multivessel dis- ease.1241,1242 (Level of Evidence: B) Class III: No Benefit 1. Pharmacological stress imaging with nuclear MPI, echocardiography, or CMR is not recommended in patients with known SIHD who have new or worsening symptoms not consistent with UA and who are capable of at least moderate physical Fihn et al Stable Ischemic Heart Disease: Full Text e429 functioning or have no disabling comorbidity.333 (Level of Evidence: C) 6.3.1.2. Patients Unable to Exercise Class I 1. Pharmacological stress imaging with nuclear MPI or echocardiography is recommended in patients with known SIHD who have new or worsening symptoms not consistent with UA and 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 imaging with CMR is rea- sonable in patients with known SIHD who have new or worsening symptoms not consistent with UA and who are incapable of at least moderate physical functioning or have disabling comorbidity.280,281,283 (Level of Evidence: B) Class III: No Benefit 1. Standard exercise ECG testing should not be per- formed in patients with known SIHD who have new or worsening symptoms not consistent with UA and who a) are incapable of at least moderate physical functioning or have disabling comorbidity or b) have an uninterpretable ECG. (Level of Evidence: C) 6.3.1.3. Irrespective of Ability to Exercise Class IIb 1. CCTA for assessment of patency of CABG or of coronary stents 3 mm or larger in diameter might be reasonable in patients with known SIHD who have new or worsening symptoms not consistent with UA, irrespective of ability to exercise.1244 1248 (Level of Evidence: B) 2. CCTA might be reasonable in patients with known SIHD who have new or worsening symptoms not consistent with UA, irrespective of ability to exercise, in the absence of known moderate or severe calcifi- Table 20. Follow-Up Noninvasive Testing in Patients With Known SIHD: New, Recurrent, or Worsening Symptoms Not Consistent With UA Test Exercise Status ECG Interpretable COR LOE References Additional Considerations Able Unable Yes No Patients able to exercise* Exercise ECG X X I B (114, 145 147) Exercise with nuclear MPI or Echo X X I B (172, 276, 278, 284, 306, Exercise with nuclear MPI or Echo X Any IIa B (1241, 1242) Prior requirement for imaging with exercise Known or at high risk for multivessel disease Pharmacological stress nuclear MPI/Echo/CMR X X III: No Benefit C (333) Patients unable to exercise Pharmacological stress nuclear MPI or Echo X Any I B (148 150, 152 156) Pharmacological stress CMR X Any IIa B (280, 281, 283) Exercise ECG X X III: No Benefit C N/A Irrespective of ability to exercise CCTA Any Any IIb B (1244 1248) Patency of CABG or coronary stent $3 mm diameter CCTA Any Any IIb B (158, 161, 1244) In the absence of known moderate or severe calcification and intent to assess coronary stent ,3 mm in diameter CCTA Any Any III: No Benefit B (1244 1248) Known moderate or severe native coronary calcification or assessment of coronary stent ,3 mm in diameter in patients who have new or worsening symptoms not consistent with UA *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. CABG indicates coronary artery bypass graft surgery; CCTA, cardiac computed tomography angiography; CMR, cardiac magnetic resonance; COR, class of recommendation; ECG, electrocardiogram; Echo, echocardiography; LOE, level of evidence; MPI, myocardial perfusion imaging; N/A, not available; SIHD, stable ischemic heart disease; and UA, unstable angina. cation or if the CCTA is intended to assess coronary stents less than 3 mm in diameter.158,161,1244 (Level of Evidence: B) Class III: No Benefit 1. CCTA should not be performed for assessment of native coronary arteries with known moderate or severe calcification or with coronary stents less than 3 mm in diameter in patients with known SIHD who have new or worsening symptoms not consistent with UA, irrespective of ability to exercise.1244 1248 (Level of Evidence: B) See Online Data Supplement 1 for additional data on nonin- vasive testing in known SIHD: recurrent or worsening symptoms. Strategies for the selection and use of noninvasive testing in the evaluation of new or worsening symptoms in patients with documented SIHD are similar to those in suspected SIHD. As always, in patients with interpretable rest ECGs who are capable of exercise, treadmill exercise ECG testing remains the first choice. Whenever possible, initial and follow-up testing should be performed with the same stress and imaging techniques so that any interval change can be attributed more reliably to alterations in clinical status rather than mere differences in technique. Loss of the ability to exercise on follow-up testing, in and of itself, suggests deterioration in functional and clinical status. In general, the diagnostic accuracy of stress testing is similar in patients with and without known SIHD (Section 2.2.3). A few meta-analyses examining the effect of prior MI on diagnostic accuracy have found that the specificity of exercise ECG was higher in mixed popula- tions,145 whereas the diagnostic performance of exercise echocardiography was reduced. In contrast, the specificity of exercise SPECT was increased because of the predictive value of total stress perfusion abnormalities, which in- cludes both the risk of ischemia plus infarcted myocardi- um.91 Although CMR LGE imaging detects MI, current evidence indicates that assessment of myocardial ischemia provides incremental diagnostic1249 and prognostic value above LGE detection of infarction284 in patients with or without known SIHD. In contrast to stress testing, the diagnostic value of CCTA differs in patients with and without known CAD. Limitations of image quality relating to coronary calcifi- cation, coronary stents, or vascular clips can reduce diagnostic accuracy, and revascularization also affects results. The large caliber of venous conduits facilitates the assessment of patients who have undergone CABG with CCTA and has sensitivities of 89% to 98% and specifici- ties of 89% to 97% for the identification of .50% diameter stenoses in grafts on invasive coronary angiog- raphy.1244 1246 The accurate evaluation of coronary stents with CCTA depends on the material and diameter of the stent, with image artifacts related to the stents metallic structure preventing assessment of 9% to 11% of stents.1247,1248 Typically, stents .3 mm in diameter can be assessed,1248 with sensitivities for detecting a .50% di- ameter in-stent restenosis on invasive coronary angiogra- phy of 86% to 94% and specificities of 91% to 93%. 6.3.2. Noninvasive Testing in Known SIHD Asymptomatic (or Stable Symptoms): Recommendations See Table 21 for a summary of recommendations from this section. Table 21. Noninvasive Testing in Known SIHD: Asymptomatic (or Stable Symptoms) Test Exercise Status ECG Interpretable Pretest Probability of Ischemia COR LOE References Additional Considerations Able* Unable Yes No Exercise or pharmacological stress with nuclear MPI, Echo, or CMR at $2-y intervals X X Prior evidence of silent ischemia or high risk for recurrent cardiac event. Meets criteria listed in additional considerations. IIa C (10, 12, 15) a) Unable to exercise to adequate workload or b) Uninterpretable ECG or c) History of incomplete coronary revascularization Exercise ECG at $1-y intervals X X Any IIb C N/A a) Prior evidence of silent ischemia OR b) At high risk for recurrent cardiac event Exercise ECG X X No prior evidence of silent ischemia and not at high risk of recurrent cardiac event. IIb C N/A For annual surveillance Exercise or pharmacological stress with nuclear MPI, Echo, or CMR or CCTA Any Any Any III: No Benefit C (10, 12, 15) a) ,5-y intervals after CABG, or b) ,2-y intervals after PCI *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. CABG indicates coronary artery bypass graft surgery; CCTA, cardiac computed tomography angiography; CMR, coronary magnetic resonance; COR, class of recommendation; CCTA, computed tomography angiography; CMR, cardiac magnetic resonance; ECG, electrocardiogram; Echo, echocardiography; LOE, level of evidence; MPI, myocardial perfusion imaging; N/A, not available; PCI, percutaneous coronary intervention; and SIHD, stable ischemic heart disease. Fihn et al Stable Ischemic Heart Disease: Full Text e431 Class IIa 1. Nuclear MPI, echocardiography, or CMR with ei- ther exercise or pharmacological stress can be useful for follow-up assessment at 2-year or longer inter- vals in patients with SIHD with prior evidence of silent ischemia or who are at high risk for a recur- rent cardiac event and a) are unable to exercise to an adequate workload, b) have an uninterpretable ECG, or c) have a history of incomplete coronary revascularization.10,12,15 (Level of Evidence: C) Class IIb 1. Standard exercise ECG testing performed at 1-year or longer intervals might be considered for follow-up assessment in patients with SIHD who have had prior evidence of silent ischemia or are at high risk for a recurrent cardiac event and are able to exercise to an adequate workload and have an interpretable ECG. (Level of Evidence: C) 2. In patients who have no new or worsening symptoms or no prior evidence of silent ischemia and are not at high risk for a recurrent cardiac event, the useful- ness of annual surveillance exercise ECG testing is not well established. (Level of Evidence: C) Class III: No Benefit 1. Nuclear MPI, echocardiography, or CMR, with ei- ther exercise or pharmacological stress or CCTA, is not recommended for follow-up assessment in pa- tients with SIHD, if performed more frequently than at a) 5-year intervals after CABG or b) 2-year intervals after PCI.10,12,15 (Level of Evidence: C) See Online Data Supplement 1 for additional data on nonin- vasive testing in known SIHD: asymptomatic (or stable symptoms). 6.3.3. Factors Influencing the Use of Follow-Up Testing The appropriateness of performing noninvasive testing in patients who either are asymptomatic or have stable symp- toms (ie, routine surveillance testing) depends on factors related to the likelihood of significant findings, such as the patient s risk for rapidly advancing disease, propensity to have silent ischemia, and length of time since revasculariza- tion. The data supporting follow-up testing are sparse and insufficient to support routine, repeat testing in asymptomatic individuals. However, evidence exists that persistent ische- mia on testing is a prognostically poor finding. Exploratory data from a small cohort of 314 patients with SIHD enrolled in the COURAGE trial nuclear substudy revealed that a reduction in the ischemic myocardium is associated with an (unadjusted) reduction in the incidence of death or MI combined.306 In the BARI 2D trial, at 1 year of follow-up, more extensive and severe stress myocardial perfusion SPECT abnormalities were associated with higher rates of death or MI.276 There are, however, several circumstances in which a decision to perform follow-up testing is thought to be warranted in the absence of a change in clinical status, although data supporting this approach are limited. These circumstances include, but are not limited to, evaluation of incomplete revascularization, assessment of the adequacy of medical therapy by provocative exercise testing, a substantial change in risk profile, or the need to reevaluate coronary status in anticipation of major noncardiovascular surgery when the patient s exercise capacity is limited or unknown (although revascularization in this circumstance has not been shown to reduce the risk of perioperative cardiovascular complications), as detailed in the ACCF/AHA Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery Guideline.1250 Care should be taken when interpreting paired testing results to incorporate not only the change in the extent and severity of ischemia but also the workload at onset and total exercise capacity achieved, as these factors relate to the patient s symptom burden and functional correlates in daily life. Outside of such special circumstances, routine periodic testing is not recommended in patients who are at low risk for progression or had overt symptoms on initial presentation (ie, those without known silent ischemia) or very early after revascularization. In addition to a lack of evidence for testing to detect ischemia, currently there is also little research to support exercise stress testing for risk assessment in asymp- tomatic patients with known CAD, except for cardiac reha- bilitation and exercise prescription purposes (Section 4.4.1.4.). 6.3.4. Patient Risk and Testing By using clinical, noninvasive, and invasive data acquired during the initial evaluation and subsequently, recommenda- tions about stress testing in patients with known SIHD can be formulated on the basis of the following considerations: In the absence of a change in clinical status, patients with a low projected annual mortality rate (,1%) are those with low-risk Duke treadmill scores, either without imaging or with nega- tive imaging findings, whose 4-year cardiovascular survival rate approximates 99%. The low-risk category also includes patients with normal stress imaging who lack adverse prog- nostic characteristics, such as diabetes mellitus or prior MI. Younger women without diabetes mellitus or a prior MI who have normal stress nuclear MPI remain at very low risk for as long as 7 to 9 years,307 depending on specific clinical characteristics, and probably do not require repeat stress imaging during that period in the absence of changes in Data are more limited with regard to the value of serial testing strategies in patients at intermediate risk of cardiac mortality (1% to 3% per year). Follow-up testing probably should be performed only if decisions about a change in pharmacological management, level of exercise, or revascu- larization will be influenced directly by the test result or if the patient has persistent symptoms despite adequate GDMT. Thus, in the patient with known SIHD, the goal of repeat testing is the assessment of residual ischemic burden after optimization of GDMT or the consideration of revasculariza- tion as a result of failed optimal medical management. Furthermore, to be considered significant, findings should be outside the expected range of variability of test results, which is approximately 5% for stress nuclear MPI,306,366 such that patients move into a higher or lower risk category. Even for high-risk patients, the value of annual exercise testing (or serial exercise testing at alternative intervals) in the absence of a change in symptoms has not been studied adequately. Yearly exercise testing could be useful in patients with SIHD who have .3% risk of mortality per year, because a marked decrease in exercise capacity or a marked increase in ischemic burden can warrant reevaluation of the medical regimen or interventional plan. Examples of such patients are those with a high-risk Duke treadmill score, patients with an EF ,50% and significant CAD in .1 major vessel, patients with diabetes mellitus, and those with multivessel disease who have not undergone CABG. Some data also suggest that ischemic burden might be useful in targeting ischemia-guided revascularization. In a substudy of the COURAGE trial, the overall event-free survival rate was 86.6% in patients with $5% reduction in ischemic myocardium versus 75.3% in those without significant reduction in ischemic burden after 6 Although this trial substudy was not powered to examine differences in clinical outcomes, the results are similar to the BARI 2D trial, in which patients with high myocardial jeopardy scores randomized to CABG had fewer cardiovas- cular events (AMI and composite endpoint of all-cause mortality or MI and cardiac death or MI) than those with high scores who received only medical therapy.276,409 6.3.5. Stability of Results After Normal Stress Testing in Patients With Known SIHD The durability of information gained from a stress test over time varies widely according to the characteristics of the patients and the type of test performed. Among patients with several clinical risk factors and negative stress imaging studies, the relative hazard for cardiac death or MI can increase after a 2-year follow-up time period, whereas among other groups, the risk remains low through 2 years and can be safely assumed to remain low for an extended period of time. In 1 large single-site study, the factors associated with an earlier increase in risk included diabetes mellitus, male sex, increased age (ie, $70 years), a history of previous MI or revascularization, and having undergone a pharmacological stress test rather than an exercise test327 (Figure 15). The relationships were, however, complex and covarying. Impor- tantly, among patients who were younger and female and did not have diabetes mellitus or a history of MI or revascular- ization, the annual risk of adverse cardiovascular events was predicted to remain ,1% for as long as 9 years, on the basis of hard events observed during the 2-year follow-up period. In contrast, in an 80-year-old man with a normal pharmaco- logical stress study, the risk of an adverse event rose to .1% in ,1 year after an index-negative perfusion evaluation. 6.3.6. Utility of Repeat Stress Testing in Patients With Known CAD The interpretation of repeat testing should be based on a threshold change value that exceeds the expected variability in test results, even in patients at high risk for recurrent events, and especially in those with no interval clinical change.1244 Although the variability of exercise and stress testing results is not well established,306,1251 factors such as differences in day-to-day operations in the same laboratory, interobserver variability, and differences between practices in different imaging laboratories are important contributory factors in observed differences in serial testing. A 5% change in the percent of ischemic myocardium (based on extent and severity) has been suggested by some investigators as a threshold that indicates clinically significant change for stress nuclear MPI.306,1251 The findings from different exercise or stress imaging modalities (echocardiography versus nuclear MPI) can be even more difficult to compare, such that clinicians should use the same imaging modality over time whenever possible. Despite these concerns, significant changes in risk category (such as shifting to a lower- or higher-risk patient subset) may be used to guide interpretabil- ity of interval change in repeat testing,306,333 and the presence of significant interval change can alter risk assessment. For example, in the ACME (Angioplasty Compared to Medicine) trial, patients whose exercise nuclear MPI normalized after 6 months of randomized treatment had an improved survival Figure 15. Incidence of cardiac death or nonfatal MI during follow-up after a nor- mal stress MPI. Adapted with permission from Hachamovitch et al.327 MI indicates myocardial infarction; MPI, myocardial perfusion imaging. Fihn et al Stable Ischemic Heart Disease: Full Text e433 rate (92%) compared with those with persistent ischemia (82%, P50.02).333 The ongoing technical evolution within imaging modalities is, in part, aimed at minimizing intraob- server, interobserver, and intertest variability. 6.3.7. Future Developments Numerous opportunities to improve the diagnosis and man- agement of SIHD remain. Large registries have the potential to improve the diagnosis of IHD and to assess risk according to clinical information and results from noninvasive testing. Risk-assessment strategies from older databases should be updated with modern information and statistical techniques. Technical development across all cardiac imaging modalities continues to evolve rapidly, often outpacing the ability to perform rigorous clinical validation and application. Current and anticipated technical developments of CT scanners and software are intended to improve the spatial and temporal resolution of cardiac CT images while reducing the radiation dose received from a typical examination. They include wider detector arrays that allow higher numbers of simultaneously acquired image slices, faster x-ray tube rotation times, and the use of alternative image reconstruction techniques that target image noise, all of which could improve the diagnostic value of CCTA in currently challenging scenarios, such as calcified coronary arteries and coronary stents. 