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. No coronary stenosis 50% on CCTA *Although the published data are limited; patients with these findings will probably not be at low risk in the presence of either a high-risk treadmill score or severe resting LV dysfunction (LVEF 35%). CAC indicates coronary artery calcium; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; LV, left ventricular; LVEF, left ventricular ejection fraction; and MI, myocardial infarction. Adapted from Gibbons et al.7 Fihn et al Stable Ischemic Heart Disease: Full Text e389 Adapted from Snow et al.377a Reduce premature cardiovascular death; Prevent complications of SIHD that directly or indirectly impair patients functional well-being, including nonfatal AMI and heart failure; Maintain or restore a level of activity, functional capacity, and quality of life that is satisfactory to the patient; Completely, or nearly completely, eliminate ischemic symptoms; and Minimize costs of health care, in particular by eliminating avoidable adverse effects of tests and treatments, by pre- venting hospital admissions, and by eliminating unneces- sary tests and treatments. These goals are pursued with 5 fundamental, complemen- tary, and overlapping strategies: 1. Educate patients about the etiology, clinical manifesta- tions, treatment options, and prognosis of IHD, to support active participation of patients in their treatment decisions. 2. Identify and treat conditions that contribute to, worsen, or complicate IHD. 3. Effectively modify risk factors for IHD by both phar- macological and nonpharmacological methods. 4. Use evidence-based pharmacological treatments to im- prove patients health status and survival, with attention to avoiding drug interactions and side effects. 5. Use revascularization by percutaneous catheter-based techniques or CABG when there is clear evidence of the potential to improve patients health status and survival. 4.2. General Approach to Therapy The writing committee has constructed these guidelines from the perspective that when making decisions about diagnostic tests and therapeutic interventions, their potential effects on improving survival and health status should be considered independently. Although treatment choices often are intended to achieve both goals simultaneously, circumstances exist in which a treatment is administered in pursuit of only one of these goals. For example, when pharmacotherapy such as aspirin or angiotensin-converting enzyme (ACE) inhibitors is prescribed, the goal is to improve survival but not necessarily quality of life. Similarly, revascularization can be performed to improve symptoms, even when there is no expectation of Figure 13. Cumulative incidence of MACE in patients with 3-vessel CAD based on SYNTAX score at 3-year follow-up in the SYNTAX trial treated with either CABG (blue) or PCI (gold). CABG indicates coronary artery bypass graft; CAD, coronary artery disease; MACE, major adverse cardiovascular event; PCI, percutaneous coronary intervention; and SYNTAX, Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery. Adapted from Kappetein.980 Figure 12. Nomogram for prediction of 5-year survival from clinical, physical examination, and cardiac catheterization findings. Asymp indicates asymptomatic; CAD, coronary artery disease; MI, myo- cardial infarction; and Symp, symptom- atic. Reproduced from Califf et al.55 improved survival. Occasionally, treatment recommendations related to achieving these goals can be at odds, such as when a patient is encouraged to take a medication that significantly reduces the risk of death even though it causes mild or moderate adverse side effects. It might also be the case that a patient expresses a preference for a treatment approach (eg, PCI) when the practitioner believes another approach (eg, GDMT) would be preferable. Although practitioners always should engage patients in a detailed discussion about their individual goals and values in order to tailor therapy, this is particularly important when therapeutic goals or the patient s or provid- er s preferences are not aligned. It is essential that these discussions be conducted in a location and atmosphere that permits adequate time for discussion and contemplation. Initiating a discussion about the relative merits of medical therapy versus revascularization while a patient is in the midst of procedure, for example, is not usually consistent with these principles. Reducing the risk of mortality should be pursued as intensively as is sensible for all patients with SIHD. It has been estimated that nearly half of the dramatic decline in cardiovascular mortality observed during the past 40 years is attributable to interventions directed at modifying risk fac- tors. Of this change, 47% can be attributed to treatments, including risk factor reduction after AMI, other guideline- based treatments for UA and heart failure, and revasculariza- tion for chronic angina.391 An additional 44% reduction in age-adjusted death is attributed to population-based changes in risk factors.391 Unfortunately, these changes have been offset somewhat by increases in BMI and type 2 diabetes mellitus, which result in an increased number of deaths.391 The 2011 secondary prevention and risk reduction therapy statement8 summarizes the key interventions known to im- prove survival and prevent subsequent cardiac events. World- wide, it has been estimated that 90% of the risk of MI is attributable to 9 measureable risk factors, including smoking, diabetes mellitus, hypertension, obesity, impaired psycholog- ical well-being, poor diet, lack of exercise, alcohol consump- tion, and dyslipidemia.392 The initial approach to all patients should be focused on eliminating unhealthy behaviors such as smoking and effectively promoting lifestyle changes (eg, maintaining a healthy weight, engaging in physical activity, adopting a healthy diet [Figure 4]). In addition, for most patients, an evidence-based set of pharmacological interven- tions is indicated to reduce the risk of future events. The presumed mechanism by which these interventions work is stabilization of the coronary plaque to prevent rupture and thrombosis.8 These include antiplatelet agents,393 st- atins,394 401 and beta blockers, along with other agents if indicated, to control hypertension.402,403 ACE inhibitors are indicated in many patients with SIHD, especially those with diabetes mellitus or LV dysfunction.296,301,404 Simi- larly, tight glycemic control not only has not been shown to reduce the risk of macrovascular complications in patients with type 2 diabetes mellitus, it also appears to increase the risk of cardiovascular death and complications. Nonetheless, weight loss, aerobic exercise, an AHA Step II diet, and ACE inhibitors in patients with diabetes mellitus with proteinuria all can improve patients risks of microvascular complications and, potentially, cardiac events. For the purposes of this guideline, the writing committee elected to retain the classification for risk of cardiovascular events that has been accepted by consensus over the past 2 decades. Patients with a predicted annual cardiac mortality rate of ,1% per year are considered to be at low risk, those with a predicted rate of 1% to 3% per year are considered to be at intermediate risk, and those with a predicted average .3% per year are considered to be at high risk. For patients at high risk of mortality, the prevalence of severe CAD (eg, left main coronary occlusion) is higher, and coronary angiography can define the coronary anatomy and help to plan further therapy beyond standard GDMT (Figure 5). If the patient is at low or intermediate risk for mortality, therapeutic decisions should be directed toward improving symptoms and function, and catheterization may be deferred if symptoms can be controlled with medical therapy alone. For patients in whom angiography is performed and who are determined to be at low or intermediate risk, evidence reaffirms that it is safe to defer revascularization and institute a program of evidence-based medical therapy, because nei- ther survival nor adverse cardiac events are averted by proceeding immediately to revascularization.366,397,405 409 If a patient in this category has symptoms that are completely or almost completely relieved with medical therapy, it is usually prudent to continue with medical therapy without proceeding to revascularization. If symptoms persist, however, then a discus- sion with the patient to elicit his or her preferences and goals is necessary, along with a frank discussion of the benefits and risks of PCI and CABG, to ascertain whether the symptoms have been ameliorated sufficiently to warrant simply continuing with med- ical therapy alone (Figures 4 and 5). Coronary revascularization generally improves survival among certain subgroups of patients, particularly those with severe left main coronary stenosis. When revascularization is being considered on an elective basis solely for reducing the risk of death, the healthcare provider should engage the patient in an explicit consideration of the estimated improve- ment in survival relative to the potential risks and costs of the procedure and related interventions. Because reliable esti- mates of benefit, such as absolute risk reduction, are fre- quently unavailable for many specific subgroups, the risk for death can be estimated before treatment and the anticipated absolute risk reduction calculated (obtained by multiplying the RR reduction by the pretreatment risk). In the STICH (Surgical Treatment for Ischemic Heart Failure) trial, in which 1212 patients with an LVEF #35% and CAD amena- ble to revascularization were randomized to CABG or med- ical therapy, there was no significant difference in overall mortality rate, but during a median follow-up of 56 months, 28% of those assigned to CABG died of a cardiovascular cause, compared with 33% of those receiving medical ther- apy.410 This information can be converted to a more interpre- table framework, such as the average reduction in risk of events or number needed to treat. In this example, the average reduction in cardiovascular events was 19%, and it would be necessary to perform bypass surgery on about 5 patients with LV dysfunction to prevent 1 cardiovascular death at 5 years Fihn et al Stable Ischemic Heart Disease: Full Text e391 (ie, number needed to treat 5 5, calculated as 1 4 absolute risk reduction, or 1/0.19 [although there would be no effect on overall mortality rate]). This process complies with the Institute of Medicine s goals for transparently sharing evi- dence with patients so that they can control (or more actively participate in) their own decisions.411 In general, a beneficial effect of revascularization on survival has been demonstrated most clearly among patients with the highest cardiovascular risk.412 Although traditional methods of risk stratification have relied on coronary anatomy and LV function, other strategies described in this guideline can be used (Figure 5). The specific anatomic features of the patient and the likelihood of procedural success often influence the approach to a patient for whom revascularization is being considered. For example, a given patient with 1-vessel disease might have coronary anatomic features that would make the risk of PCI high enough and the likelihood of success low enough that CABG or medical therapy would be preferred. In general, complete revascularization leads to better outcomes than incomplete revascularization.413 418 In patients with chronic total occlusion, CABG could be preferable to PCI,419 but this is still controversial. Although the technology and techniques for PCI of chronic total occlusions are improving, there remains no current evidence that survival is improved after successful PCI of a chronic total occlusion. Some patients with diabetes mellitus can have such diffuse disease that neither CABG nor PCI is likely to produce sustained benefits. Other patients can have small-caliber arteries or diffuse disease that is likely to lead to early graft failure. Still others can have long, complex lesions that are very likely to undergo restenosis after PCI, although use of drug-eluting stents (DES) can reduce this risk. The majority of patients with SIHD have clinical features indicating that revascularization is unlikely to improve life expectancy or the risk of subsequent MI. For such patients, antianginal therapy and intensive treatment for risk factors are recommended before consideration of PCI or CABG to relieve symptoms. A broad range of highly effective drugs is available, including beta blockers, calcium channel blockers, long-acting nitrates, and newer agents such as ranolazine. Comparative trials among these medications are relatively few and for the most part small.420 On the basis of the available data, however, all of the classes of agents appear to be relatively similar in antianginal efficacy, and all have very acceptable profiles of safety and tolerability. Beta blockers have been shown to improve survival in patients after AMI and in patients with hypertension; they provide 24-hour coverage and have a long history of clinical use. For these reasons, the writing committee recommends these agents as first-line drugs for treating angina. In patients who do not tolerate or adequately respond to beta blockers, calcium channel blockers and/or long-acting nitrates may be substi- tuted or added. Ranolazine has been shown to inhibit the late sodium current in humans and has demonstrated lusitropic properties.421 Clinical trials have shown that this agent is comparable to other agents in alleviating angina. Although this agent has been approved by the US Food and Drug Administration (FDA) for first-line use in patients with chronic angina, the writing committee recommends that ranolazine be considered in circumstances in which beta blockers, calcium channel blockers, and nitrates are not adequately effective or are not tolerated. 4.2.1. Factors That Should Not Influence Treatment Decisions The 2 medical indications for revascularization are to prevent death and cardiovascular complications and to improve symptoms and quality of life. Nonetheless, the use of revas- cularization has risen dramatically in the past 3 decades. Much of this increase appears to be for indications for which benefits in survival or symptoms in comparison with nonin- vasive therapies are unlikely.422 National data suggest that about 12% of PCIs could be inappropriate because they lack evident potential to improve either survival or symptoms.423 Several reasons influence patients and physicians to prefer revascularization when the likelihood of benefit is less than the potential risk of the procedure. An ingrained preference for action (ie, revascularization) over perceived inaction (ie, medical therapy alone) likely often influences the decision making of both patients and physicians.252 Moreover, some healthcare professionals are unduly pessimistic about survival with conservative medical therapy and inaccurately optimis- tic about the survival benefits of revascularization proce- dures.424 As indicated earlier, patients often believe mistak- enly that PCI has the potential to prevent AMI and prolong survival.423,425 In addition, the attendant expense and risk of combined antiplatelet therapy for an uncertain period of time might not be fully considered. Physicians are professionally obligated to provide accurate estimates of the risks, benefits, and costs of various therapeutic options that are based on the best available scientific data. Other factors can induce phy- sicians to recommend revascularization. These include med- icolegal concerns (often exaggerated) and feeling compelled to satisfy the expectations of patients and referring physicians (which are sometimes misinformed or unrealistic).426 Addi- tionally, there are well-documented regional variations in the use and appropriateness of cardiac procedures that appear to reflect local practice styles.427 This might partly reflect a mistaken belief by some physicians that more care is better care. 428 Although successful procedures can be psychologically satisfying to the physician and the patient, this does not justify the attendant economic costs and risk of complications of procedures that offer minimal, if any, genuine benefit.429 431 Although rarely discussed explicitly, financial incentives seem to affect the willingness of a minority of physicians and institutions to recommend certain procedures or drug thera- pies. Strong incentives created by the payment system en- courage overutilization. Also, a small number of physicians might have financial relationships with the manufacturers of devices or drugs that might represent apparent conflicts that ought to be disclosed to patients. At a higher level, those responsible for the payment system, the manufacturers of devices and drugs, and physicians making clinical decisions must commit to supporting guideline-based interventions. Any and all conflicts of interest must be revealed to patients in the process of informed consent before any invasive or noninvasive procedure. 4.2.2. Assessing Patients Quality of Life In addition to interventions undertaken to improve survival and prevent cardiovascular complications, therapy also is prescribed to improve patients health status, a general term that incorporates many facets, including severity of symp- toms, functional limitations, and quality of life. Assessment of health status is often unstructured and exclusively quali- tative, but efforts to standardize this assessment are recom- mended, beginning with a structured inventory of activity, symptoms, and quality of life, supplemented by the use of simple, semiquantitative scales such as the CCS and New York Heart Association classifications.432,433 The CCS and New York Heart Association classifications are limited, however, because they quantify health status from the physicians perspective, rather than directly report- ing patients experiences, and they are known to have limited reproducibility and sensitivity to important clinical changes. Furthermore, even these simple classifications of health status are recorded infrequently in health records.432,434 One ap- proach to directly eliciting perceptions of health status from patients with IHD is to use the self-administered Seattle Angina Questionnaire (SAQ), a valid, sensitive, and prognos- tically important questionnaire, to quantify the symptoms, functional limitations, and quality of life of patients with SIHD.246,247,435 Although such instruments typically are used in research trials, they are readily applicable to clinical practice and can be used serially to assess and monitor the effectiveness of therapy, including antianginal medications and revascularization.434 The formal assessment of a patient s disease-specific health status, through either the CCS or the SAQ, has been endorsed as a performance measure of 4.3. Patient Education: Recommendations Class I 1. Patients with SIHD should have an individualized education plan to optimize care and promote well- ness, including: a. education on the importance of medication adher- ence for managing symptoms and retarding dis- ease progression437 439 (Level of Evidence: C); b. an explanation of medication management and cardiovascular risk reduction strategies in a man- ner that respects the patient s level of under- standing, reading comprehension, and ethnic- ity8,440 444 (Level of Evidence: B); c. a comprehensive review of all therapeutic op- tions8,441 444 (Level of Evidence: B); d. a description of appropriate levels of exercise, with encouragement to maintain recommended levels of daily physical activity8,445 448 (Level of Evidence: C); e. introduction to self-monitoring skills445,447,448 (Level of Evidence: C); and f. information on how to recognize worsening car- diovascular symptoms and take appropriate ac- tion. (Level of Evidence: C) 2. Patients with SIHD should be educated about the following lifestyle elements that could influence prognosis: weight control, maintenance of a BMI of , and maintenance of a waist circumference less than 102 cm (40 inches) in men and less than 88 cm (35 inches) in women (less for certain racial groups)8,440,449 452; lipid manage- ment18; BP control17,453; smoking cessation and avoidance of exposure to secondhand smoke8,454,455; and individualized medical, nutrition, and lifestyle changes for patients with diabetes mellitus to sup- plement diabetes treatment goals and education.456 (Level of Evidence: C) Class IIa 1. It is reasonable to educate patients with SIHD about: a. adherence to a diet that is low in saturated fat, cholesterol, and trans fat; high in fresh fruits, whole grains, and vegetables; and re- duced in sodium intake, with cultural and ethnic preferences incorporated8,17,18,457,458 (Level of Evidence: B); b. common symptoms of stress and depression to minimize stress-related angina symptoms459 (Level of Evidence: C); c. comprehensive behavioral approaches for the management of stress and depression237,460 462 (Level of Evidence: C); and d. evaluation and treatment of major depressive disorder when indicated.237,238,437,461,463,464,467,468 (Level of Evidence: B) Multiple risk factors for heart disease, vascular disease, and stroke are typically present in persons with SIHD, including hypertension, smoking, dyslipidemia, diabetes mel- litus, overweight, and physical inactivity.27,392 At a national level, in 2000, only 5% of individuals without IHD and 7% of those with IHD were fully adherent to recommendations for physical activity, fruit and vegetable consumption, and nonsmoking. The approach to managing risk factors usually requires partnerships among the healthcare team, the patient, their family, and their community. The goal of this partnership is to assure an effective exchange of information, sharing of concerns, and an improved understanding of treatments, with the aim of improving quality of life and health outcomes. The American Academy of Family Physicians defines patient education as the process of influencing patient behavior through the provision of information and counseling that is designed to produce changes in knowledge, attitudes, and skills necessary to maintain or improve health. 469 The Joint Commission mandates patient education as a principal guid- ing policy to improve health outcomes. Effective patient education and counseling are based on a collaborative ap- proach that acknowledges individual patient needs through an understanding of cognitive, behavioral, and sociodemo- graphic factors. Patients actively involved in care decisions are more likely to follow a treatment plan and engage in behaviors that can improve their health. Fihn et al Stable Ischemic Heart Disease: Full Text e393 When educating patients, it is important to communicate an understanding of a specific disease process, the need for laboratory testing, medication management and adherence, reporting of efficacy and side effects, and behavioral lifestyle change.8 Unfortunately, the type, intensity, frequency, and duration of educational programs are not well established for individual risk factors. For example, the Ask, Advise, Assess, Assist, and Arrange algorithm for smoking cessation often is used, although supporting data from RCTs are lacking.470 In addition, who should deliver education programs and how to evaluate efficacy are not well studied. In smoking cessation, the most effective intervention continues to be a physician s recommendation for the patient to quit. However, quit rates for smoking are also dependent on the appropriate use of medical therapies and group support programs.442,471 In dia- betes care, patient education has the potential to be as effective as or more effective than medical therapies.472 The management of hypertension, heart failure, dyslipidemia, type 2 diabetes mellitus, weight loss, and physical activity is enhanced by ongoing health education and support in addi- tion to physician office visits. Factors that complicate effective patient education include low literacy, adverse sociodemographic factors (eg, poverty, social isolation, and emotional disorders such as depression), cultural beliefs and language barriers, environmental factors, advanced age, and the presence of complex comorbidities. These factors and others play an important role in the adoption of healthy lifestyles and adherence to recommended medical therapies. In addition, how to best provide cost- effective educational strategies remains a challenge in today s healthcare environment.473 The lack of payment for these activities remains an important barrier. Clinic-based educa- tion generally consists of the following: 1. Individual counseling. This educational format com- monly is used in the context of a routine clinic visit. It tends to be directive and didactic, generally not inter- active or behaviorally oriented, relatively brief, and sometimes supported with written materials. Follow-up to ascertain effectiveness is not commonly practiced. 2. Group education. Group care or shared office visits have been tested in multispecialty group practices. They offer the benefit of providing education to larger num- bers of patients with similar diagnoses (eg, type 2 diabetes mellitus), combined with an individualized physician visit. They tend to be behaviorally oriented with planned follow-up for effectiveness and outcomes. 3. Self-monitoring. Self-monitoring skills enhance patient education and behavior change. Examples such as home BP and blood glucose monitoring and tracking daily calories and physical activity minutes can support important lifestyle change. Review of self-monitoring logs by patient and provider at subsequent clinic visits supports the continued importance of and attention to behavior change. In some healthcare plans, these data can be entered via web portals for patients.474 4. Internet- and computer-based education. A growing number of health plans provide health information via websites and special programs. This approach is often low in cost to the patient but requires adequate com- puter access and skills, higher reading levels, and self-motivation to change behavior (eg, AHA Choose to 5. Hand-held computer devices, smartphones, and other portable devices. Portable devices have the potential to provide motivational reminders and prompts for life- style change but have not yet been thoroughly tested. Present efforts to improve the effectiveness of patient education and lifestyle interventions integrate key constructs related to behavior change theory. A summary of the most common models is provided below: 1. Motivational interviewing, a social learning theory, promotes behavioral change through empathetic and reflective listening, encouraging patients to determine their reasons for change, helping healthcare profession- als deal with resistance, and supporting self-efficacy.476 2. Self-efficacy theory posits that the ability to change behavior depends upon one s self-confidence to per- form a specific action (such as walking 30 minutes daily) and the belief that one can persist with this action. Low self-efficacy predicts poor ability to achieve a specified lifestyle change. Improving one s self- efficacy will improve the ability to change a particular 3. The Transtheoretical Model of behavior change is based on stages of change. The theory relies on the obser- vation that many individuals traverse 5 distinct temporal processes in achieving permanent change. These in- clude precontemplation, contemplation, preparation, ac- tion, and maintenance. Application of this model of change entails categorizing an individual s progress in the process of change and recognizing that cycling through phases is common in the process of achieving The interventions described above should be provided within a medical environment that provides coordinated, team-based care. Data accumulating from interventions that incorporate principles of the chronic care model,479 such as the patient-centered medical home, have demonstrated bene- ficial effects not only on intermediate outcomes such as glycemic and BP but also on cost, utilization, and mortality rate.480,481 This approach depends on the active participation of an engaged, informed patient, which in turn relies on the patient s understanding of his or her condition, ability to adhere safely to complex medical therapies, and willingness to communicate on a regular basis with the healthcare team. In addition to counseling about the approach to management of SIHD and risk reduction, patients often seek information about other aspects of their health, particularly issues that are often not directly addressed by healthcare providers. One such topic that commonly arises is possible restric- tions on sexual activity. Regrettably, there are relatively limited scientific data on the cardiovascular demands and potential risks of sexual activity in patients with heart disease, some of it dating back 3 or 4 decades and nearly all of it dealing with men. In general, sexual activity is equivalent to mild to moderate physical activity requiring 3 to 5 METs (ie, the equivalent of climbing 2 flights of stairs or walking briskly).482 The few available studies suggest that AMI within 1 to 2 hours of sexual activity is associated with an average RR of 2.7 among middle-aged men, with the greatest risk among those who are sedentary.483 486 Because the overall incidence of AMI is low in the population and periods of exposure relatively infrequent, it has been postulated that the absolute risk is exceedingly low for any individual.487 How- ever, ECG monitoring during sexual activity in 1 study of men with IHD revealed that nearly a third developed ST depression and nearly half developed arrhythmias. It ap- peared, however, that these findings also were found during similarly stressful activities that did not involve sex, and the arrhythmias were largely benign. Moreover, these patients were not initially on anti-ischemic medications, and it was reported that the ischemic changes on ECG resolved when subjects took beta blockers. Thus, it seems that sexual activity should not necessarily be regarded as appreciably different from other types of physical activity that impose equivalent metabolic demands. Needless to say, patients should be treated to maximize their capacity for physical activity, as described subsequently in this guideline. Patients often express concerns that medications given to treat symptoms or reduce cardiovascular risk could cause erectile dysfunction. Although these perceptions are often firmly and widely held, studies and reviews have not delin- eated a clear association between these drugs, including beta blockers, and sexual dysfunction.488 492 A related issue that could arise is use of phosphodiesterase 5 inhibitors, such as sildenafil, vardenafil, or tadalafil, to improve erectile function. Although, as discussed in the section on treatment of SIHD, current evidence has shown that these drugs do not raise the risk of adverse cardiovascular events in men with SIHD,493,494 there is a clear risk of serious hypotension when they are taken in conjunction with nitrates, and the combination is absolutely contraindicated. There are also potential drug drug interactions with alpha-blockers that are sometimes used to treat hypertension.495 4.4. Guideline-Directed Medical Therapy 4.4.1. Risk Factor Modification: Recommendations 4.4.1.1. Lipid Management Class I 1. Lifestyle modifications, including daily physical ac- tivity and weight management, are strongly recom- mended for all patients with SIHD.18,496 (Level of Evidence: B) 2. Dietary therapy for all patients should include re- duced intake of saturated fats (to <7% of total calories), trans fatty acids (to <1% of total calories), and cholesterol (to <200 mg/d).18,497 500 (Level of Evidence: B) 3. In addition to therapeutic lifestyle changes, a mod- erate or high dose of a statin therapy should be prescribed, in the absence of contraindications or documented adverse effects.18,398,400,458,501 (Level of Evidence: A) Class IIa 1. For patients who do not tolerate statins, LDL cho- lesterol lowering therapy with bile acid seques- trants,* niacin, or both is reasonable.502,504,505 (Level of Evidence: B) Epidemiological studies have established serum cholesterol as an important coronary heart disease risk factor. The Framingham Heart Study, Multiple Risk Factor Intervention trial, and the Lipid Research Clinics trials all found a continuous, graded increase in coronary events with increas- ing LDL cholesterol in men and women who were initially free of IHD.502,506 508 A similar relationship has been ob- served among patients with SIHD.509 511 The association between LDL cholesterol and cardiovascular risk is curvilin- ear, or log-linear, meaning that the decrease in RR for a given 1-mg/dL decrease in LDL cholesterol seems to be the same at any level of baseline LDL cholesterol. The principal lipid modification strategy recommended by the NCEP ATP-III (National Cholesterol Education Program Adult Treatment Panel III) in patients with SIHD is the reduction of LDL cholesterol.18,24 This should start with therapeutic lifestyle changes, including dietary therapy, daily physical activity, and weight management. Most patients also will benefit from cholesterol-lowering drug therapy, preferably with a statin. Effective dietary approaches to lowering LDL cholesterol include replacing saturated and trans fatty acids with dietary carbohydrates or unsaturated fatty acids and reducing dietary cholesterol. Although the response to dietary interventions is variable, a diet low in saturated fat and cholesterol typically lowers LDL cholesterol by 10% to 15%.497 500 Other benefi- cial dietary interventions can include addition of plant sta- nols/sterols (2 g/d), which trials suggest lower LDL choles- terol by 5% to 15%, and addition of viscous fiber (.10 g/d), which reduces LDL cholesterol by 3% to 5%.512 515 A 10-lb weight loss reduces LDL cholesterol by 5% to 8%.496 Regular physical activity is also a key component of therapeutic lifestyle modification. Although exercise does not reliably lower LDL cholesterol, it facilitates weight loss and has other beneficial effects on the lipid profile.516 518 Controlled clinical trials of lipid-lowering drug therapy have demonstrated that lowering of LDL cholesterol is associated with a reduced risk of adverse cardiovascular events. Earlier trials used bile acid sequestrants (cholesty- ramine), fibric acid derivatives (gemfibrozil and clofibrate), or niacin. More contemporary studies have convincingly established the efficacy of statins in the primary and second- ary prevention of coronary events.394 396,398,400,501,519 522 In a prospective meta-analysis published by the Cholesterol Treat- ment Trialist Collaborators in 2010 that examined data from 26 randomized trials of statin therapy (comparing higher- to lower-dose statin therapy or statin therapy to a control regimen), the mean difference in LDL cholesterol was 31 mg/dL, ranging from 12 to 68 mg/dL. Each 40-mg/dL reduction in LDL cholesterol was associated with a 10% reduction in all-cause mortality and a 20% reduction in coronary mortality, with corresponding reductions in nonfatal MI, need for coronary revascularization, and first nonfatal ischemic stroke.458 The absolute benefit of therapy was a *The use of bile acid sequestrant is relatively contraindicated when triglycerides are $200 mg/dL and is contraindicated when triglycerides are $500 mg/dL. Dietary supplement niacin must not be used as a substitute for prescription niacin. Fihn et al Stable Ischemic Heart Disease: Full Text e395 function of an individual s absolute risk of fatal MI.458 In trials comparing higher- to lower-dose statin therapy, the average, weighted reduction in LDL cholesterol at 1 year was 20 mg/dL among those receiving higher-dose regimens. Among patients assigned to more intensive regimens, there was a 15% lower incidence of major vascular events (95% CI: 11 to 18; P,0.0001), which reflected a 13% lower risk of coronary death or nonfatal MI (95% CI: 7 to 19; P,0.0001), a 19% lower risk of undergoing coronary revascularization ischemic stroke (95% CI: 5 to 26; P50.005). The reductions in serum LDL cholesterol and in cardiovascular risk were similar in magnitude to those observed in trials comparing statin therapy to a control regimen. The absolute benefit of therapy was defined chiefly by an individual s absolute risk of death due to coronary occlusion.458 Appropriate treatment goals for patients with SIHD have been informed by several trials of intensive lipid-lowering therapy. The HPS (Heart Protection Study) compared simvastatin 40 mg daily to placebo in patients with IHD, other occlusive vascular dis- ease, or diabetes mellitus. On-treatment LDL cholesterol levels averaged 88 mg/dL in those allocated to simvastatin and 127 mg/dL in those randomized to placebo. A consistent and early benefit of therapy was demonstrated, with a 13% reduction in mortality rate and an 18% reduction in coronary death rate.398 Similar reductions in RR were observed regard- less of baseline levels of LDL cholesterol, including in those with initial levels ,116 mg/dL or ,97 mg/dL. (Of note, LDL cholesterol levels in the HPS were not drawn with patients in the fasting state and were measured values rather than the calculated values used in clinical practice and in most trials; measured LDL cholesterol is generally about 15% higher than calculated LDL cholesterol.)398 In the TNT (Treating to New Targets) trial, patients with clinically apparent IHD and LDL cholesterol .130 mg/dL were randomly assigned to either 10 mg or 80 mg of atorvastatin per day. The mean LDL cholesterols were 77 mg/dL during treatment with 80 mg of atorvastatin and 101 mg/dL during treatment with 10 mg of atorvastatin. There was a 22% reduction in a composite cardiovascular endpoint and a 20% reduction in cardiac deaths with more intensive therapy but no reduction in all-cause mortality.400 In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) study patients with a past history of MI were randomly assigned to intensive lipid-lowering therapy with atorvastatin 80 mg daily or simvastatin 20 mg daily. During treatment, mean LDL cholesterol levels were 104 mg/dL in the simvastatin group and 80 mg/dL in the atorvastatin group. The results showed a nonsignificant trend toward reduction of the primary com- posite endpoint of coronary death, nonfatal MI, or cardiac arrest (hazard ratio: 0.89; 95% CI: 0.78 to 1.01); significant reductions in some secondary endpoints such as nonfatal MI and coronary revascularization; and no effect on all-cause mortality.501 It should be noted that both these trials com- pared 2 drug regimens and did not directly test the benefit of achieving a given level of LDL cholesterol and that, to date, there is no clear evidence that treating to a specific target, as opposed to treating with a higher dose of a higher-potency statin, is beneficial. The mean achieved LDL cholesterol levels among patients treated in the high-dose atorvastatin arms of the TNT and IDEAL studies were 77 and 81 mg/dL, respectively. These data support intensive LDL cholesterol lowering with statins in patients with SIHD. An update of the ATP-III report18,24 recommends treatment to an LDL cholesterol level ,100 mg/dL in patients with established CAD or other high-risk features, with an LDL cholesterol goal of ,70 mg/dL as a therapeutic option in patients at very high risk. However, as discussed above, although the presence of data confirming the use of a specific, numeric target LDL cholesterol level for all patients with SIHD has been challenged, the benefit of therapy with moderate- to high-dose statin therapy is well established.458 For this reason, the recommendations in this guideline stress the importance of prescribing a statin in at least a moderate dose. The ATP-IV report is anticipated later in 2012 and is expected to provide guidance for the treatment of LDL cholesterol levels on the basis of the results of an extensive systematic review. Factors that identify patients at very high risk in the ATP-III update include the presence of established coronary vascular disease, plus 1) multiple major risk factors, especially diabetes mellitus; 2) severe and poorly controlled risk factors, especially continued tobacco use; and 3) multiple risk factors for the metabolic syndrome. Again, it should be acknowledged that no studies have assessed the benefits of titrating lipid- lowering drugs to achieve a specific LDL cholesterol target. In addition, trials of intensive lipid lowering for secondary prevention have used statins alone. Although the addition of other agents could lower LDL cholesterol in patients in whom a target level cannot be achieved with a statin, the utility of this approach in reducing risk of cardiovascular morbidity and mortality has not been firmly established. A secondary target of therapy introduced by ATP-III is non HDL cholesterol in patients with elevated triglycer- ides.18,24 Non HDL cholesterol is defined as the difference between total cholesterol and HDL cholesterol. It includes all cholesterol and lipoprotein particles that are considered atherogenic, including LDL cholesterol, lipoprotein, intermediate-density lipoprotein, and very-low-density lipo- protein, and is a predictor of cardiovascular death.523 Because statins lower LDL cholesterol and non HDL cholesterol to a similar extent, the relative benefits of lowering these 2 lipid measures cannot be distinguished from recent clinical trials. Fibrates could reduce the risk of coronary events in patients with high triglycerides and low HDL cholesterol levels and could have an adjunctive role in these patients in combination with statins.503,524 Nicotinic acid raises HDL cholesterol, and several trials support the efficacy of niacin when used alone or in combination with statins.504,505,525 Observational studies and treatment trials suggest that consumption of omega-3 fatty acids reduces cardiovascular risk. Cohort and case control studies have found an RR reduction of about 15% for fish consumption versus little or no fish consumption.526 In the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico) Preven- tion study in patients with prior MI, 1 g daily of fish oil supplement resulted in a 20% reduction in mortality at 42 months.527 Pharmacological treatment with fish oil at higher doses (2 to 4 g daily) is effective in reducing triglyceride 4.4.1.2. Blood Pressure Management Class I 1. All patients should be counseled about the need for lifestyle modification: weight control; increased physical activity; alcohol moderation; sodium reduc- tion; and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy prod- ucts.17,529 537 (Level of Evidence: B) 2. In patients with SIHD with BP 140/90 mm Hg or higher, antihypertensive drug therapy should be instituted in addition to or after a trial of lifestyle modifications.538 543 (Level of Evidence: A) 3. The specific medications used for treatment of high BP should be based on specific patient characteris- tics and may include ACE inhibitors and/or beta blockers, with addition of other drugs, such as thiazide diuretics or calcium channel blockers, if needed to achieve a goal BP of less than 140/ 90 mm Hg.544,545 (Level of Evidence: B) Hypertension is an important independent risk factor for ischemic cardiovascular events. Observational studies have demonstrated a continuous and graded relationship between BP and cardiovascular risk. In a collaborative meta-analysis of prospective studies of nearly 1 million adults without preexisting vascular disease, the risk of a vascular death increased linearly over the BP range of 115/75 mm Hg to 185/115 mm Hg, without a threshold effect. Each increment of 20 mm Hg in systolic BP or 10 mm Hg in diastolic BP was associated with a doubling of risk.546 RCTs indicate that treatment results in a reduction of cardiovascular risk consistent with predictions Treatment of high BP should begin with lifestyle measures. Maintenance of an appropriate body weight (BMI ,25 ) is a key element of the nonpharmacological strategies recommended to improve BP control; weight loss of 10 kg typically results in a decrease in BP of 5 to 20 mm Hg.529 531,548,549 Consumption of a diet rich in fruits, vegeta- bles, and low-fat dairy products532,533; reduction of dietary sodium intake529,531,533,534,550; regular physical activity535; and moderation of alcohol consumption536 also result in signifi- cant lowering of BP. In many patients with SIHD, therapy with medications will be required to lower BP to the desired level. Treatment trials have definitively demonstrated a beneficial effect of antihy- pertensive drug therapy on cardiovascular disease risk. An overview of 17 placebo-controlled trials, most of which focused on lowering diastolic BP, showed that reducing diastolic BP 5 to 6 mm Hg (or an estimated 10 to 20 mm Hg in systolic BP) within a population was associated with a significant reduction in vascular mortality, with approxi- mately 40% reduction in stroke and 20% reduction in coronary events.547 This benefit of treatment also has been observed in studies of older adult patients with isolated Despite the plethora of clinical studies, the appropriate BP threshold for initiating medical therapy and specific treatment goals for patients with chronic IHD remain controversial. RCTs have demonstrated a benefit from antihypertensive therapy in patients with a diastolic BP .90 mm Hg547 and also in patients with isolated systolic hypertension and a systolic BP .160 mm Hg.539,551,552 The Seventh Report of the Joint National Committee on Prevention, Detection, Evalua- tion, and Treatment of High Blood Pressure recommends a target BP of ,140/90 mm Hg in patients with uncomplicated hypertension and of ,130/80 mm Hg in patients with diabetes mellitus or CKD.17 Observations from epidemiolog- ical studies and the relatively high absolute risk of cardiovas- cular events in patients with vascular disease have led some to suggest that a lower BP target might also be appropriate in individuals with SIHD.553 On the other hand, excessive reduction in diastolic BP could compromise coronary perfusion in SIHD patients, and some studies have demonstrated a J-shaped relationship between diastolic BP and coronary events.554 The ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial,555 which enrolled patients with type 2 diabetes mellitus at high risk of cardiovascular events, found no benefit of targeting a systolic BP of 120 mm Hg compared with a systolic BP of 140 mm Hg in reducing a composite endpoint of MI, stroke, or death from cardiovascular causes. In a related vein, in AASK (African-American Study of Kidney Diseases and Hypertension),556 1094 black patients with hypertensive kidney disease (diastolic pressure .95 mm Hg and glomerular filtration rate of 20 to 60 mL/min) and no diabetes mellitus were randomly assigned to achieve a mean arterial pressure target #92 mm Hg (corresponding to 130/ 80 mm Hg) or to a target of 102 to 107 mm Hg (correspond- ing to 140/90 mm Hg). Overall, there was no advantage to more intensive BP control with regard to progression to end-stage kidney disease or death.556 Although in patients with uncomplicated hypertension there are a variety of considerations in selecting a medication, effective BP lowering is the most important factor in prevent- ing stroke and MI. Clinical trials have failed to convincingly demonstrate superiority of any single antihypertensive drug class in preventing cardiovascular events.544,545 In many patients with SIHD, the choice of medications is guided by compelling indications for specific classes of drugs, as discussed elsewhere in this guideline (Table 15).557 ACE inhibitors improve outcomes in most patients with CAD, especially those with a history of MI, LV dysfunction and heart failure, or CKD or diabetes mellitus.295,296,301,558 562 Angiotensin-receptor blockers (ARBs) are beneficial in the same spectrum of patients.563 566 Beta blockers are recom- mended in patients with angina pectoris, a history of MI, or LV dysfunction.567 571 Aldosterone antagonists improve prognosis in patients with LV dysfunction and heart fail- ure.572,573 Calcium antagonists are useful in the treatment of angina. Many patients with SIHD will require a combination of drugs, including a diuretic, to achieve optimal BP control. Fihn et al Stable Ischemic Heart Disease: Full Text e397 The role of emotional stress in relationship to hypertension has yet to be fully elucidated. It might be important to acknowledge the potential relationship of stress to many of the cardiovascular risk factors, particularly hypertension, when counseling patients. 4.4.1.3. Diabetes Management Class IIa 1. For selected individual patients, such as those with a short duration of diabetes mellitus and a long life expectancy, a goal hemoglobin A1c (HbA1c) of 7% or less is reasonable.574 576 (Level of Evidence: B) 2. A goal HbA1c between 7% and 9% is reasonable for certain patients according to age, history of hypo- glycemia, presence of microvascular or macrovascu- lar complications, or presence of coexisting medical conditions.577,578 (Level of Evidence: C) Class IIb 1. Initiation of pharmacotherapy interventions to achieve target HbA1c might be reasonable.456,579 588 (Level of Evidence: A) Class III: Harm 1. Therapy with rosiglitazone should not be initiated in patients with SIHD.589,590 (Level of Evidence: C) Diabetes mellitus is an important independent risk factor for cardiovascular disease. Type 1 diabetes mellitus is associated with at least a 10-fold increase in cardiovascular events,591,592 and patients with type 2 diabetes mellitus have a risk of death from cardiovascular causes that is 2 to 6 times that of persons without diabetes mellitus.593 595 The complications of athero- sclerosis account for 80% of deaths among patients with diabetes mellitus, and IHD is responsible for the majority of deaths.574,596 Diabetes mellitus is associated with a poor outcome in patients with SIHD, even after the extent of disease and other clinical characteristics are taken into ac- count. In the CASS registry, for example, patients with diabetes mellitus had a 57% greater risk of death after adjustment for other risk factors.597 Clinical trials have demonstrated a salutary effect of intensive glycemic control on the development of microvas- cular complications of diabetes mellitus, such as retinopathy, nephropathy, and peripheral and autonomic neuropa- thy,574,575,598 with secondary analyses suggesting a benefit extending into the normal range of HbA1c. However, the efficacy of intensive diabetes therapy in reducing cardiovas- cular disease is less well established. In the DCCT (Diabetes Control and Complications Trial), patients with type 1 dia- betes mellitus were randomized to intensive (mean achieved therapy. During the mean 6.5 years of observation, fewer cardiovascular events occurred in the intensive-treatment group, but the number of events was small, and the difference between groups did not reach statistical significance.574 In a long-term follow-up study of this population, however, inten- sive therapy reduced the risk of cardiovascular events by 42%.579 Intensive glycemic controlled to a reduction in microvascular complications (primarily the need for retinal laser photocoagulation) but not cardiovascular events in the patients with type 2 diabetes mellitus who participated in the UKPDS (UK Prospective Diabetes Study).575 In a secondary analysis, treatment with metformin seemed to confer most of the benefit, whereas treatment with a sulfonylurea was not associated with a significant improvement in any endpoint.599 Patients in UKPDS treated with metformin had a lower median HbA1c (7.4% versus 8.0%) and a 37% reduction in $1 diabetes endpoints compared with those in the conven- tional therapy (diet alone) group.580 In the PROactive (Pros- pective Pioglitazone Clinical Trial in Macrovascular Events) study, patients with type 2 diabetes mellitus and evidence of vascular disease were randomized to pioglitazone or placebo. HbA1c averaged 7.8% at baseline and decreased by 0.3% in the placebo group and by 0.8% in those on active therapy. There was no significant difference between treatment groups in the primary study endpoint, although pioglitazone resulted in a statistically significant 16% relative reduction in a secondary endpoint of mortality, nonfatal MI, and stroke.581 Three studies in patients with type 2 diabetes mellitus suggest that even more intensive glucose lowering fails to reduce the incidence of cardiovascular events and could cause harm.576,578,600 The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial tested a strategy of intensive glucose control with a target HbA1c of 6.5%, with the Table 15. 