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7: Stable Ischemic Heart Disease Overview This chapter reviews the evaluation and management of stable ischemic heart disease . Risk stratification and application of guideline directed medical therapy are emphasized before consideration of the indications for revascularization. The choice between PCI and CABG surgery is reviewed in light of the SYNTAX trial. There is additional review of the pathophysiology and assessment of myocardial viability and its role in decisionmaking, as recently reported in the STICH trial. The asymptomatic patient and the approach to microvascular angina are also addressed. Authors Patrick T. O'Gara, MD, FACC EditorinChief Thomas M. Bashore, MD, FACC Associate Editor James C. Fang, MD, FACC Associate Editor Glenn A. Hirsch, MD, MHS, FACC Associate Editor Julia H. Indik, MD, PhD, FACC Associate Editor Donna M. Polk, MD, MPH, FACC Associate Editor Sunil V. Rao, MD, FACC Associate Editor 7.1: Risk Stratification Author(s): Benjamin M. Scirica, MD, MPH, FACC Learner Objectives Upon completion of this module, the reader will be able to: 1. Recognize the importance of risk stratification in patients with stable ischemic heart disease (SIHD). 2. Appropriately choose and prioritize the various risk stratification modalities in order to efficiently and costeffectively manage a patient with SIHD. 3. Integrate the results of multiple clinical tests when risk stratifying a patient with SIHD. 4. Recognize the appropriate, and inappropriate, use of different risk stratification techniques. Introduction The diagnosis of SIHD, also termed chronic coronary artery disease (CAD), encompasses a heterogeneous population that varies in terms of comorbidities, symptoms, and risk of future cardiovascular (CV) events. SIHD includes any condition that results in a chronic or repetitive mismatch between myocardial oxygen supply and demand. Typically, SIHD is due to atherosclerotic obstruction of the epicardial coronary arteries; however, it may also arise from microvascular disease and vasospasm, or more rarely, congenital anomalies or nonatherosclerotic vascular injury. Angina, or ischemic chest discomfort, is the classic symptom of SIHD; however, patients may present with dyspnea, heart failure, or arrhythmias as their only symptomatic manifestation. Moreover, many patients with SIHD are free of symptoms, either at the time of diagnosis of SIHD, or after successful medical therapy or revascularization. Due to the diverse nature of SIHD and differences in definitions, estimates vary regarding the actual number of affected people. However, it is estimated that 16.3 million people in the United States alone have CAD, with approximately 9 million reporting symptomatic chest pain and 8 million reporting a prior myocardial infarction (MI).1 The prevalence of SIHD is increasing worldwide as the burden of risk factors—smoking, obesity, diabetes, and hypertension—increases in the large populations of developing nations. Given the variability in this patient population, the evaluation of patients with known or suspected SIHD must incorporate information from multiple clinical modalities to risk stratify effectively, and thereby, deliver appropriate and timely therapy. In general, the goal is to identify patients at the highest risk who will benefit from the most intense therapy, while reassuring and sparing invasive procedures in patients at a lower risk. Many of the tests or techniques reviewed in this chapter are also central to the initial diagnosis of SIHD. This module will review current methods to improve risk stratification among patients with documented SIHD. Diagnosis of SIHD and the risk stratification of asymptomatic patients and of patients with acute coronary syndromes are covered in the module on Asymptomatic CAD in this chapter, Patient Assessment in Chapter 3, and in the module on Initial Management, Risk Assessment, and Risk Stratification of ACS in Chapter 6, respectively. Spectrum of Risk for Future Cardiovascular Disease in Patients With Stable Ischemic Heart Disease In primary prevention (patients without SIHD), risk stratification is typically based on a 10year risk of MI or coronary heart disease death, where a 10year risk is considered low at <10% (or <1% per year), intermediate at 1020%, and high at >20%. Unfortunately, there are no similarly accepted and validated risk categorizations for patients with SIHD, due largely to the fact that different studies included many types of patients at varying risk for CV events. For instance, the 1year rate of death or MI in the PEACE (Prevention of Events With AngiotensinConverting Enzyme Inhibition Trial) study was <2% per year,2 whereas it was more than twice as high among patients in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial3 and the BARI2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial.4 Moreover, many of the landmark studies of SIHD predate widespread utilization of stents, statins, or dualantiplatelet therapy, and therefore, contemporary event rates may be substantially lower. Despite the variability among the data, categorization of patients into low, intermediate, and highrisk categories should be a primary goal in the evaluation of patients with SIHD. Patients with an annual mortality rate of <1% are considered at low risk, 13% are considered at intermediate risk, and >3% are considered at high risk (Table 1). The analogous categories for annual CV death rate would be <1%, 1 2%, and >2%, respectively. Table 1 Noninvasive Risk Stratification Table 1 LV = left ventricle; LVEF = left ventricular ejection fraction. aAlthough the published data are limited, patients with these findings will probably not be at low risk in the presence of either a highrisk treadmill score or severe resting LV dysfunction (LVEF <35%). Adapted with permission from Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACPASIM guidelines for the management of patients with chronic stable anginaexecutive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 1999;99:282948. Overview of Risk Stratification Techniques for Patients With Stable Ischemic Heart Disease (1 of 3) The goal of evaluating a patient with SIHD should be to systematically and efficiently utilize the multiple modalities to maximize the identification of highrisk features without overtesting, but to ensure that critical data that would identify highrisk patients is not missed. There are four broad categories of risk stratification that should be considered5 : 1. 2. 3. 4. Clinical evaluation and assessment of comorbidities Functional capacity/stress test Ventricular function Coronary anatomy Every patient does not require each of these modalities to be evaluated. Nor do they need to be assessed in sequence. A lowrisk patient may only require a clinical evaluation and a stress test or echocardiogram, while a highrisk patient may proceed directly from the clinical evaluation to cardiac catheterization. Risk Stratification Based on Clinical Evaluation Clinical History and Physical Examination The clinical history and physical examination remain cornerstones in the evaluation of patients with SIHD. In general, poorly controlled traditional cardiac risk factors— hypertension, dyslipidemia, smoking, and diabetes—are associated with worse prognosis in patients with SIHD, and given that the overall risk of CV events is higher in patients with SIHD, the absolute risk associated with the presence of diabetes, for example, is even greater than in primary prevention. A history of heart failure, regardless of left ventricular (LV) ejection function, is also a marker of significantly increased risk in almost all SIHD patients. The physical examination should support the history and identify patients with evidence of right sided or leftsided overload or stigmata of noncoronary atherosclerosis. Prior Cardiovascular History A history of a documented severe ischemic event, such as a MI or stroke, substantially increases the risk of subsequent events compared to patients with SIHD who have never had a major ischemic event. In the REACH (Reduction of Atherothrombosis for Continued Health) Registry, patients with a history of MI or stroke (n = 21,890) had a higher 4year rate of CV death, MI, or stroke (18.3%) compared to patients with stable vascular disease but no history of MI or stroke (n = 15,264) (12.2%, p < 0.001) (Figure 1).6 Moreover, the detection of vascular disease in other arterial beds is also important to document as patients with polyvascular disease (concomitant disease of the cerebrovascular or peripheral arterial beds) are at an even higher risk. According to the REACH Registry, the 1year risk of CV death, MI, stroke, or hospitalization for a CV event ranged from 12.6% for patients with an onearterial bed involvement, 21.1% for patients with a twoarterial bed involvement, and 26.3% for patients with a threearterial bed involvement (p < 0.001 for trend).7 Assessing Functional Status and Symptoms of Stable Ischemic Heart Disease All patients with SIHD should be closely questioned regarding their functional status and whether their activities are limited by any potential ischemic symptoms. Simple questions regarding the patient's usual level of activity, such as walking, climbing stairs, carrying grocery bags, or yard work offers invaluable insight into the patient's physical limitations. A careful understanding of the nature of the limiting symptom in patients with low activity may offer insights into potential ischemic burden. Many patients reduce their activities to prevent symptoms of angina and may report a reduction in their pain when it is actually just selflimiting activity. Figure 1 Table 2 Ischemic chest discomfort, or angina, is the classic symptom of SIHD. The diagnosis of angina begins with a careful assessment of clinical symptoms. While there is significant variability in the quality of angina symptoms, angina typically is a thoracic discomfort, often centered in the midsternum that radiates to the neck, jaw, or arm, although some describe it as more epigastric than substernal. It is most commonly described as a pressure, squeezing, or tightness, rather than a sharp pain. Associated symptoms are common and include diaphoresis, dyspnea, nausea, or intense fatigue. In some patients, and, in particular, in women and the elderly, dyspnea or diaphoresis alone, without the "typical" symptoms of substernal pressure, are present and are often ascribed to other causes, delaying diagnosis. The pattern of angina is critical to defining a chronic versus unstable ischemic syndrome. Patients with chronic angina experience symptoms that are predictable, repetitive, and inducible with exertion. Symptoms are typically stable over weeks and months. While exertion (e.g., walking, climbing stairs, cleaning) is the most common precipitant, anxiety and stress can also elicit angina attacks. Chronic angina always resolves with rest or the use of sublingual nitroglycerin. Many patients report the slow onset of angina with exertion that requires them to diminish their level of exertion or even stop. Often, after this initial episode subsides, patients can continue their activities without symptoms. Careful questioning of patients with suspected angina is necessary to determine how their quality of life is affected. Any change in a chronic angina pattern, with either onset at rest or angina with progressively less exertion, requires a more urgent evaluation, as it may indicate a conversion to an unstable ischemic syndrome. Patients can then be appropriately categorized in a different Canadian Cardiovascular Society classification group (Table 2).8 More detailed and sensitive classification can be obtained using more sensitive, patientbased surveys, such as the Seattle Angina Questionnaire. Prevalence and Risk Associated With Angina The reported incidence and prevalence of symptomatic angina is directly related to the population being studied. In populationbased studies, the incidence of angina is closely associated with age and gender. Men between 6585 years old are at the highest risk, with an incidence of >10 cases per 1,000 patientyears. The risk was approximately onehalf in younger men and women of a similar age.1 Among patients with established CAD in the REACH registry, 30% reported a history of stable angina. By design, clinical trial populations are variably enriched for patients with a history of angina, to the extent that the prevalence of a history of angina ranges from 22% in the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial to approximately 55% in the HOPE (Heart Outcomes Prevention Evaluation Study) trial, and to 70% in the PEACE trial. Even among patients who undergo revascularization, angina is common. Almost onethird of the patients in the COURAGE trial9 assigned to percutaneous coronary intervention (PCI), and onehalf of the patients assigned to revascularization in the BARI2D trial,10 had angina at 1 year after randomization. A large clinical database found that 30% of patients who had a PCI still reported angina 1 year later.11 Surprisingly, there is little contemporary data to indicate whether the presence of angina carries any increase in risk compared to patients with no angina, especially when accounting for other comorbidities and LV function. In the Heart and Soul Study of patients with SIHD, 129 patients (14%) had stable angina, but angina alone was not associated with an increased 4year risk of CHD.12 FourYear Risk of Cardiovascular Death, Myocardial Infarction, or Stroke in the REACH Registry Figure 1 Fouryear risk of cardiovascular death, myocardial infarction, or stroke in the REACH Registry according to whether patients had a prior documented ischemic event, stable atherosclerosis, or risk factors only. CV = cardiovascular; MI = myocardial infarction; mo = month; No. = number; REACH Registry = Reduction of Atherothrombosis for Continued Health Registry. Reproduced with permission from Bhatt DL, Eagle KA, Ohman EM, et al, and the REACH Registry Investigators. Comparative determinants of 4 year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;304:13507. Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System Table 2 Reproduced with permission from the Canadian Cardiovascular Society. Grading of Angina Pectoris. 1976. Available at: http://www.ccs.ca. Accessed 02/27/2012. Overview of Risk Stratification Techniques for Patients With Stable Ischemic Heart Disease (2 of 3) Resting 12Lead Electrocardiogram All patients with SIHD should receive baseline and regular 12lead electrocardiograms (ECGs). The presence of pathologic Q waves may indicate an old infarct, therefore identifying a patient at increased risk of future ischemic events or heart failure. Even in the absence of a known MI, pathologic Q waves in the absence of a clear history of MI are common and offer important prognostic information. Silent MI, identified by new Q waves, accounted for 10% and 36.8% of the total number of MIs observed in two recent clinical trials of diabetic patients and were associated with worse outcomes.13,14 Other ECG findings such as atrial fibrillation, fascicular and bundlebranch blocks, and LV hypertrophy have also been associated with worse outcomes in patients with SIHD.15 Smaller infarcts that do not result in persistent Q waves can be identified on a 12lead ECG by analyzing altered RSR' patterns (fragmented QRS), which is associated with increased CV risk.16,17 Established Biomarkers Patients with SIHD should have regular measurements of lipids, fasting blood glucose, glycated hemoglobin, and renal function to ensure that the traditional risk factors are closely monitored at goal levels. Treatment of these risk factors is covered in the module on Prevention in Chapter 4 and the Medical Therapy module in this chapter. Other Biomarkers Many biomarkers, including those that assess myocardial necrosis, inflammation, neurohormonal activation, metabolism, renal function, coagulation, and lipid trafficking have been evaluated with the hope of gaining greater insight into the pathogenesis of atherosclerosis and SIHD. Many biomarkers are elevated in patients with SIHD, and some of them add incremental improvements to other clinical features in terms of discriminating between lowerrisk and higherrisk patients. No biomarker, though, has been shown to provide any clear treatment implications in SIHD. For example, an elevated level of Btype natriuretic peptide (BNP) identifies a patient at an increased risk; however, there are no known treatment therapies that will reduce that risk. The lack of treatment implications has limited the incorporation of biomarkers into current treatment algorithms. The older generations of troponin assays were not sensitive enough to detect elevation in patients with stable cardiac disease. The introduction of more sensitive cardiac troponin assays alters the traditional paradigm of troponin by detecting lower levels of circulating troponin, which are commonly found in patients with SIHD. For example, circulating troponin was detected in >97% of patients in the PEACE trial by using a new highsensitivity assay, and was greater than the 99th percentile, the standard cutpoint for diagnosis of MI, in 11.1% of patients.18 There was a graded stepwise increase in the risk of CV death and heart failure over the 5year followup period that was independent of baseline characteristics, even though these levels are much lower than the older, conventional troponin assays could detect (Figure 2a). Newer troponin assays with even higher sensitivity that can detect small increases during stress tests are now available in some countries, but their role in the evaluation of SIHD remains very much an area of debate. Multiple studies examining the levels of natriuretic peptides in patients with SIHD confirm that elevated levels of hemodynamic stress are independently associated with an increased risk of CV death and heart failure. In one longterm population based study of >1,000 patients with documented CAD, patients in the highest quartile of NTproBNP were at a >2fold increased risk of CV death compared to the lowest quartile (Figure 2b).19 These observations were confirmed in both the HOPE trial and the PEACE trial populations.20,21 In the analyses from the HOPE trial, NT Figure 2a Figure 2b Figure 3 proBNP was the only biomarker that improved the discrimination for the risk of CV death beyond that provided by traditional risk factors. Other studies that evaluated multiple novel biomarkers found that NTproBNP, GDF15, cystatin C, midregional proadrenomedullin (MRproADM), and midregionalproatrial natriuretic peptide (MRproANP) were most strongly related to CV outcomes, although incremental improvement over established risk factors was small, even after combining markers.22 Based on the evidence that biomarkers can offer improved risk stratification, current clinical guidelines give a Class IIa recommendation for the more established markers, such as highsensitivity Creactive protein,23 and Class IIb recommendation for natriuretic peptides in patients with stable CAD.5 The widespread incorporation of these biomarkers is unlikely to occur until there become clear treatment implications, which will require prospective clinical trials. Clinical Risk Scores In contrast to primary prevention and acute coronary syndromes, there are few well validated and accepted integrated clinical risk scores for patients with documented, but stable, CAD. Several scores, including one based on 11 clinical characteristics and another with just five variables—male, presence of typical angina, evidence of an old MI on ECG, diabetes, and insulin use—were shown to be associated with the severity of CAD detected on angiography.15 Another clinical score developed in patients treated with a statin as part of a clinical trial found that a weighted scoring system including age, sex, tobacco use, prior MI, revascularization, hypertension, total cholesterol, and lowdensity lipoprotein cholesterol categorizes patients into a low (<1%), intermediate (13%), and high (>3%) 1year risk of death or MI.24 It is important to note that none of these scores included either exercise tolerance test or LV function, two of the most powerful risk stratification techniques. Assessment of Risk With Functional or Stress Tests Stress testing, both by exercise or pharmacologic stress, provides an enormous amount of prognostic information, and unless contraindicated, should be performed in all patients with suspected or known SIHD to evaluate the presence and burden of ischemia.25 Stress testing should not be performed when urgent catheterization is indicated, or in other tenuous hemodynamic scenarios such as severe aortic stenosis or unstable arrhythmias. Whenever possible, exercise stress testing is preferred to pharmacologic stress testing because exercise capacity and recovery provide significant incremental prognostic information beyond the assessment of ischemia, and because it is the more costefficient option. It is important to remember that while stress tests provide an overall assessment of cardiopulmonary health, they will only identify hemodynamically significant coronary lesions. The understanding that many acute lesions arise from nonobstructive lesions explains why a patient with a "negative" stress test may subsequently present with an acute coronary syndrome. Diseasemodifying therapy, such as blood pressure control, lipidlowering therapy, and antiplatelet drugs, should therefore be based on the overall risk assessment and not just the stress tests results. Exercise Stress Tests Exercise stress testing has been extensively validated in many clinical situations for a variety of indications. One common indication—the diagnosis of CAD in patients without known SIHD—is covered in the module on Asymptomatic CAD in this chapter and in Chapter 3 on Patient Assessment. In general, among patients with known SIHD, the presence of ischemia, as detected by ST segment deviation on exercise testing, may be less important per se than the physiologic parameters assessed during the test. Maximal exercise duration, total exercise capacity, time to symptoms or STsegment deviation, heart rate and blood pressure response to exercise and recovery, and the degree of symptoms are all related to prognosis. Exercise duration and maximal exercise capacity are two of the great integrators of overall health.26 Excellent exercise capacity, even in the presence of documented ischemia, carries a good prognosis, while poor capacity, with or without ischemia, identifies a patient at a higher risk of death. There are several integrated risk scores that combine different exercise test parameters. The Duke Treadmill Score (DTS), which includes exercise duration, maximal ST depression, and the presence and severity of angina, is one of the most wellvalidated and utilized scoring tests (Figure 3). Patients are categorized as low risk (score of >5) with a 1year mortality rate of 0.25%, intermediate risk (score 4 to 10) with a 1year mortality rate of 1.25%, and high risk (score < 11) with a 1year mortality rate of 5.25%.27,28 Other metrics, such as abnormal heart rate recovery pattern, prolonged ST segment depression (>8 minutes into recovery), or abnormal blood pressure response offer further pathophysiologic insight into the overall CV status and identify highrisk patients.25,29 Based on the strength of evidence, cost, and ease, stress testing should, in most cases, be the firstline test for functional capacity among patients who can exercise and have interpretable ECG testing. The indications for additional imaging are reviewed in the next section, but even when imaging is obtained, exercise stress, rather than pharmacologic stress, is preferred whenever possible to obtain functional information. Troponin T and NTproBNP in Stable Ischemic Heart Disease (1 of 2) Figure 2a Elevated levels of highsensitivity troponin T Reproduced with permission from Omland T, de Lemos JA, Sabatine MS, et al, and the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009;361:253847, and Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of BType natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 2007;50:20514. Troponin T and NTproBNP in Stable Ischemic Heart Disease (2 of 2) Figure 2b NTproBNP are shown to be associated with increasing risk of overall mortality in the PEACE trial of patients with documented but stable coronary artery disease. Reproduced with permission from Omland T, de Lemos JA, Sabatine MS, et al, and the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009;361:253847, and Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of BType natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 2007;50:20514. Duke Treadmill Score Figure 3 The Duke Treadmill Score is the most wellvalidated stress testing score that accurately classifies patients into low, intermediate, and high risk based on the time of exercise, extent of ST depressions, and severity of symptoms. In the example, a patient exercises 8 minutes, has a 1 mm STsegment depression, and has nonlimiting angina, which gives a score of 1, placing her in the intermediaterisk category. The same calculations can be performed using a nomogram by drawing a line between 1) “STsegment deviation during exercise” and “Angina during exercise”, and 2) “Ischemiareading line” and “Duration of exercise” to estimate the 1year and 5year mortality risk. Max = maximum; MET = metabolic equivalent; MI = myocardial infarction; min = minutes Overview of Risk Stratification Techniques for Patients With Stable Ischemic Heart Disease (3 of 3) Myocardial Imaging Techniques to Assess Ischemia The presence of ischemia can be detected by radionuclide, echocardiographic, or magnetic resonance imaging (MRI) techniques, and in certain scenarios, is indicated as part of the initial stress test or as a followup test to prior noninvasive studies. The two most clinically relevant parameters obtained from these techniques are: 1) the overall burden and pattern of ischemia, and 2) an assessment of LV function. Consensus practice guidelines recommend that myocardial imaging is appropriate in the following scenarios among patients with known SIHD30: To clarify an equivocal, borderline, or discordant prior stress test where obstructive CAD remains a concern. To evaluate new or worsening symptoms in a patient with known abnormal coronary angiography or prior stress images. To evaluate the physiologic consequence of a coronary stenosis or anatomic abnormality of uncertain significance. For further evaluation of patients with an intermediate or high DTS. The appropriateness of imaging an asymptomatic or stable patient with a history of abnormal coronary angiography or abnormal stress imaging is uncertain if the last stress test was >2 years prior, and inappropriate if the last stress test was within the last 2 years. Repeat radionuclide imaging is considered appropriate in the setting of incomplete revascularization to assess residual ischemia and for recurrent symptoms after revascularization (Figure 4).30 Several findings on stress imaging are important in risk stratification. Evidence of reduced LV function (<35%) at rest or during stress, a large or multiple areas of stressinduced perfusion defect (especially if anterior) or wallmotion abnormalities, and evidence of stressinduced dilation or increased lungupdate of radionuclide tracer identify patients at highest risk (>3% annual mortality rate). Moderate LV function (3549%), moderate stressinduced perfusion defects or wallmotion abnormalities identify intermediaterisk patients (13% annual mortality). Lowrisk patients (<1% annual mortality) include patients with small or no stressinduced perfusion defects or wallmotion abnormalities, although it is important to integrate the imaging results with LV function and the physiologic results from the exercise tests (Table 1).15 Figure 4 Table 1 Figure 5a Figure 5b Figure 5c Figure 5d The indications and prognosis obtained from stress echocardiography or MRI is similar to radionuclide imaging. The choice between the different modalities will depend on local expertise, cost, and if there is additional information that is better assessed with one modality compared to the other. For example, stress echocardiography may be preferred if ischemic mitral regurgitation is suspected. One advantage of stress echocardiography is that exercise testing can be performed, whereas stress MRI requires pharmacologic stress. Figure 6 Assessment of Risk by Left Ventricular Function Regardless of the clinical situation, LV systolic function is not only one of the most powerful predictors of shortterm and longterm outcomes, but it also carries therapeutic implications regarding appropriate medical, revascularization, and devicebased therapies. LV function therefore should be assessed in all patients with SIHD, even without any signs or symptoms of heart failure.31 Figure 7 Echocardiography In most cases, echocardiography will be the modality of choice for assessing LV function, because it is easy to obtain and can also evaluate valvular or other structural heart disease. Most radionuclide studies will also provide accurate measurements of LV function, and if normal, would not require a followup echocardiogram unless there is a clinical suspicion for structural or valvular heart Table 3 disease. The current appropriate use criteria for echocardiography related to the evaluation of patients with SIHD recommend echocardiography in patients with symptoms or conditions related to suspected cardiac etiology, including chest pain. Routine surveillance with repeated echocardiography in patients with known CAD, but no change in symptoms or new signs of any progression is not indicated, however.32 Figure 8 Much of the evidence linking LV function and outcomes comes from older studies such as the CASS (Coronary Artery Surgery Study) trial where over twothirds of the deaths at 5 years were observed in the roughly onethird of patients with reduced LV function. Integration of LV function and the degree of CAD further refines risk stratification. Regardless of the degree of atherosclerosis, worsening ventricular function is associated with increased risk of death (Figures 5a, b, c, d).33 Figure 9 Assessment of Risk According to Coronary Anatomy The decision to define coronary anatomy is one of the key decisionbranch points in the evaluation of patients with SIHD. The decision to proceed to coronary angiography should be based on the results of clinical history and noninvasive risk stratification tools. Many low to intermediaterisk patients with SIHD may not require coronary angiography to appropriately treat their SIHD, while in other patients, catheterization may be the first diagnostic test after the initial clinical evaluation. Defining the coronary anatomy should also be considered as an important tool for risk stratification, and not simply as a diagnostic tool to identify potential lesions for revascularization. It is also important to remember that while coronary angiography is the "goldstandard" for identifying flowlimiting intraluminal obstructions, it is not sensitive to identifying "vulnerable" nonobstructive coronary plaques that may rapidly progress to acute thrombotic lesions. Despite the limitation in identifying the actual lesion that may precipitate an acute coronary syndrome, the extent and burden of atherosclerosis detected on angiography clearly identifies the "vulnerable patient" who is at a higher risk of CV complications. The most simple and widely used classification for risk stratification is based on the number of diseased arteries (i.e., left main or single, double, or triplevessel disease). The prognostic value of this straightforward classification was most clearly demonstrated in the CASS registry, where there was a stepwise decrease in overall survival according to the number of diseased arteries (Figures 5a, b, c, d).33 This relationship of overall survival to the number of diseased arteries has been confirmed in more recent experiences. In the COURAGE trial, the rate of death or MI after a 4.6year followup period was 12.5% in patients with zero or onevessel disease, approximately 18% in patients with twovessel disease, and approximately 25% in patients with threevessel disease.34 More detailed assessments of the complexity of coronary disease, as calculated by techniques such as the SYNTAX Score, may provide a more complete assessment of atherosclerotic burden and give insight into actual treatment decisions, however, they are not typically calculated in clinical practice. In one study of approximately 1,400 patients with CAD undergoing PCI, the 1year risk of death increased almost twofold with each tertile of SYNTAX score (1.5% vs. 2.1% vs. 5.6%; p = 0.002) (Figures 6, 7).10,35 The American Heart Association/American College of Cardiology Foundation (AHA/ACCF) indications for coronary angiography in patients with SIHD are presented in Table 3.15 Even though they are somewhat dated, these indications remain relevant and are consistent with the recommendations of other professional societies.5 Cardiac Computed Tomography Computed tomography angiography (CTA) has a limited role in the evaluation of patients with known SIHD or in patients with a highsuspicion for CAD.36 In these cases, CTA will potentially delay coronary angiography and expose patients to increased contrast and radiation. However, similar to coronary angiography, the degree of atherosclerosis identified by CTA is associated with worse outcomes. Patients with any luminal abnormalities detected on CTA (who therefore have some degree of atherosclerotic burden) are at a higher risk than patients with no evidence of any luminal obstruction. The risk increases in patients with actual obstructive lesions and, in particular, among patients with left main or left anterior descending artery disease.37 Similar to angiography, the number of diseased arteries identified by CTA is closely associated with CV complications, with the highest risk in patients with left main artery disease (Figure 8).38 CT calcium scanning has no role in the management of patients with SIHD, as these patients are known to have atherosclerosis, and the degree of calcification does not correlate with the degree of stenosis.35 An Integrated Risk Stratification Algorithm Risk stratification in patients with SIHD should proceed in a stepwise and logical progression. The process begins with the clinical history and examination, and the decisions about subsequent testing should build on each additional piece of information (Figure 9). Rarely will one test drive a decision for therapy, but rather the integration of the data from several risk stratification modalities will provide the most complete assessment and, therefore, the most appropriately guided therapeutic decisions. : Appropriate Use Criteria for Cardiac Radionuclide Imaging for Patients With Ischemic Symptoms or Prior Revascularization Figure 4 ACS = acute coronary syndrome; CABG = coronary artery bypass graft; ECG = electrocardiogram; PCI = percutaneous coronary intervention. Reproduced with permission from Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. J Am Coll Cardiol 2009;53:220129. Noninvasive Risk Stratification Table 1 LV = left ventricle; LVEF = left ventricular ejection fraction. aAlthough the published data are limited, patients with these findings will probably not be at low risk in the presence of either a highrisk treadmill score or severe resting LV dysfunction (LVEF <35%). Adapted with permission from Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACPASIM guidelines for the management of patients with chronic stable anginaexecutive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 1999;99:282948. Survival of Medically Treated Patients According to the Number of Diseased Coronary Arteries and Left Ventricular Function (1 of 4) Figure 5a Graphs showing survival for medically treated CASS (Coronary Artery Surgery Study) Registry patients. Panel A: Patients with one, two, or threevessel disease by ejection fraction. EJECFR = ejection fraction. Reproduced with permission from Emond M, Mock MB, Davis KB, et al. Longterm survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1994;90:264557. Survival of Medically Treated Patients According to the Number of Diseased Coronary Arteries and Left Ventricular Function (2 of 4) Figure 5b Graphs showing survival for medically treated CASS (Coronary Artery Surgery Study) Registry patients. Panel B: Patients with onevessel disease by ejection fraction. EJECFR = ejection fraction. Reproduced with permission from Emond M, Mock MB, Davis KB, et al. Longterm survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1994;90:264557. Survival of Medically Treated Patients According to the Number of Diseased Coronary Arteries and Left Ventricular Function (3 of 4) Figure 5c Graphs showing survival for medically treated CASS (Coronary Artery Surgery Study) Registry patients. Panel C: Patients with twovessel disease by ejection fraction. EJECFR = ejection fraction. Reproduced with permission from Emond M, Mock MB, Davis KB, et al. Longterm survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1994;90:264557. Survival of Medically Treated Patients According to the Number of Diseased Coronary Arteries and Left Ventricular Function (4 of 4) Figure 5d Graphs showing survival for medically treated CASS (Coronary Artery Surgery Study) Registry patients. Panel D: Patients with threevessel disease by ejection fraction. EJECFR = ejection fraction. Reproduced with permission from Emond M, Mock MB, Davis KB, et al. Longterm survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1994;90:264557. Rate of Death or MI by Number of Disease Vessels Figure 6 The rate of death or myocardial infarction (MI) according to the number of diseased arteries among patients with stable ischemic heart disease treated with percutaneous coronary intervention (PCI) or optimal medical therapy (OMT). Adapted with permission from Dagenais GR, Lu J, Faxon DP, et al, and the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study Group. Effects of optimal medical treatment with or without coronary revascularization on angina and subsequent revascularizations in patients with type 2 diabetes mellitus and stable ischemic heart disease. Circulation 2011;123:1492500. Rate of Death or MI by SYNTAX Score Figure 7 The rate of death or myocardial infarction (MI) according to the tertile of SYNTAX Score, which quantifies the overall burden and complexity of the disease. Adapted with permission from Wykrzykowska JJ, Garg S, Girasis C, et al. Value of the SYNTAX score for risk assessment in the allcomers population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial. J Am Coll Cardiol 2010;56:2727. Recommendations for Coronary Angiography for Risk Stratification in Patients With Chronic Stable Angina Table 3 Adapted with permission from Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACPASIM guidelines for the management of patients with chronic stable anginaexecutive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 1999;99:282948. Overall Survival by Number of Diseased Arteries Figure 8 Overall survival according to the number of diseased arteries detected by computed tomography angiography. Reproduced with permission from Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic angiography for prediction of allcause mortality. J Am Coll Cardiol 2007;50:116170. Initial Evaluation of Patients With Clinical Symptoms of Angina Figure 9 Algorithm for the initial evaluation of patients with clinical symptoms of angina. ACS = acute coronary syndrome; CABG = coronary artery bypass graft; CAD = coronary artery disease; CV = cardiovascular; CXR = chest X ray; DM = diabetes mellitus; ECG = electrocardiogram; MI = myocardial infarction; MRI = magnetic resonance imaging; PCI = percutaneous coronary intervention. Reproduced with permission from Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: executive summary: the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27:134181. Future Directions Continued research into novel biomarkers such as highsensitivity troponin assays, may further improve the ability to identify patients at the highest risk. The routine incorporation of novel biomarkers into clinical care is unlikely though, until specific treatments based on the results of the tests are identified in clinical trials. Advances in imaging may provide greater insight into which patient may benefit from more intense therapy, including revascularization. For example, more detailed assessments of viability, as detected by cardiac MRI or positron emission tomography (PET) scans may better identify which patients will benefit from revascularization. Advanced imaging techniques are also being evaluated to identify atherosclerotic lesions that are most likely to become unstable prior to becoming symptomatic. Key Points SIHD, also termed CAD, encompasses a heterogeneous population, which varies in terms of comorbidities, symptoms, and risk of future CV events. Risk stratification in patients with SIHD should proceed in a stepwise and logical progression. Categorization of patients into low, intermediate, and highrisk categories should be a primary goal in the evaluation of patients with SIHD. Patients with an annual mortality rate of <1% are considered low risk, an annual rate of 13% as intermediate risk, and >3% as high risk. Four broad categories of risk stratification should be considered: 1) clinical evaluation and assessment of comorbidities, 2) functional capacity/stress rest, 3) ventricular function, and 4) coronary anatomy. Most patients will not need all four domains tested. Based on the strength of evidence, cost, and ease, stress testing should be in most cases the firstline test for functional capacity among patients who can exercise and have an interpretable ECG. Some patients may have an indication for additional imaging, but even when imaging is obtained, exercise stress, rather than pharmacologic, is preferred whenever possible to obtain functional information. Regardless of the clinical situation, LV function is not only one of the most powerful predictors of short and long term outcomes, but also carries therapeutic implications regarding appropriate medical, revascularization, and devicebased therapies. LV function, therefore, should be assessed in all patients with SIHD, even without any signs or symptoms of heart failure. Coronary angiography should be performed based on the results of clinical history and noninvasive risk stratification tools. Many low to intermediaterisk patients with SIHD may not require coronary angiography, whereas in other patients, catheterization may be the first diagnostic test after the initial clinical evaluation. Defining the coronary anatomy, though, should be considered an important tool for risk stratification, and not simply as a diagnostic tool to identify potential lesions for revascularization. References 1. Roger VL, Go AS, LloydJones DM, et al. Heart disease and stroke statistics2011 update: a report from the American Heart Association. Circulation 2011;123:e18e209. 2. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensinconvertingenzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:205868. 3. Boden WE, O'Rourke RA, Teo KK, et al., on behalf of the COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:150316. 4. Frye RL, August P, Brooks MM, et al., on behalf of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:250315. 5. Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: executive summary: the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27:134181. 6. Bhatt DL, Eagle KA, Ohman EM, et al., on behalf of the REACH Registry Investigators. Comparative determinants of 4year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;304:13507. 7. Steg PG, Bhatt DL, Wilson PW, et al., on behalf of the REACH Registry Investigators. Oneyear cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297:1197206. 8. Canadian Cardiovascular Society. Grading of Angina Pectoris. 1976. Available at: http://www.ccs.ca. Accessed 02/27/2012. 9. Weintraub WS, Spertus JA, Kolm P, et al., on behalf of the COURAGE Trial Research Group. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med 2008;359:67787. 10. Dagenais GR, Lu J, Faxon DP, et al., on behalf of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study Group. Effects of optimal medical treatment with or without coronary revascularization on angina and subsequent revascularizations in patients with type 2 diabetes mellitus and stable ischemic heart disease. Circulation 2011;123:1492500. 11. Alexander KP, Cowper PA, Kempf JA, Lytle BL, Peterson ED. Profile of chronic and recurrent angina pectoris in a referral population. Am J Cardiol 2008;102:13016. 12. Gehi AK, Ali S, Na B, Schiller NB, Whooley MA. Inducible ischemia and the risk of recurrent cardiovascular events in outpatients with stable coronary heart disease: the Heart And Soul Study. Arch Intern Med 2008;168:14238. 13. Burgess DC, Hunt D, Li L, et al. Incidence and predictors of silent myocardial infarction in type 2 diabetes and the effect of fenofibrate: an analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Eur Heart J 2010;31:929. 14. Chaitman BR, Hardison RM, Adler D, et al., on behalf of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study Group. The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact of treatment strategy on cardiac mortality and myocardial infarction. Circulation 2009;120:252940. 15. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable anginasummary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 2003;41:15968. 16. Das MK, Saha C, El Masry H, et al. Fragmented QRS on a 12lead ECG: a predictor of mortality and cardiac events in patients with coronary artery disease. Heart Rhythm 2007;4:138592. 17. Das MK, Khan B, Jacob S, Kumar A, Mahenthiran J. Significance of a fragmented QRS complex versus a Q wave in patients with coronary artery disease. Circulation 2006;113:2495501. 18. Omland T, de Lemos JA, Sabatine MS, et al., on behalf of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009;361:253847. 19. Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med 2008;358:210716. 20. Blankenberg S, McQueen MJ, Smieja M, et al., on behalf of the HOPE Study Investigators. Comparative impact of multiple biomarkers and NTerminal probrain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 2006;114:2018. 21. Omland T, Sabatine MS, Jablonski KA, et al., on behalf of the PEACE Investigators. Prognostic value of BType natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 2007;50:20514. 22. Schnabel RB, Schulz A, Messow CM, et al. Multiple marker approach to risk stratification in patients with stable coronary artery disease. Eur Heart J 2010;31:302431. 23. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499511. 24. Marschner IC, Colquhoun D, Simes RJ, et al., on behalf of the LIPID Study Investigators. Longterm risk stratification for survivors of acute coronary syndromes. Results from the Longterm Intervention with Pravastatin in Ischemic Disease (LIPID) Study. J Am Coll Cardiol 2001;38:5663. 25. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol 2002;40:153140. 26. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002;346:793801. 27. Mark DB, Hlatky MA, Harrell FE Jr, Lee KL, Califf RM, Pryor DB. Exercise treadmill score for predicting prognosis in coronary artery disease. Ann Intern Med 1987;106:793800. 28. Mark DB, Shaw L, Harrell FE Jr, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med 1991;325:84953. 29. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heartrate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999;341:13517. 30. Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. J Am Coll Cardiol 2009;53:220129. 31. Davis RC, Hobbs FD, Kenkre JE, et al. Prevalence of left ventricular systolic dysfunction and heart failure in high risk patients: community based epidemiological study. BMJ 2002;325:1156. 32. Douglas PS, Garcia MJ, Haines DE, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. Endorsed by the American College of Chest Physicians. J Am Coll Cardiol 2011;57:112666. 33. Emond M, Mock MB, Davis KB, et al. Longterm survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1994;90:264557. 34. Mancini GB, Bates ER, Maron DJ, et al., on behalf of the COURAGE Trial Investigators. Quantitative results of baseline angiography and percutaneous coronary intervention in the COURAGE trial. Circ Cardiovasc Qual Outcomes 2009;2:3207. 35. Wykrzykowska JJ, Garg S, Girasis C, et al. Value of the SYNTAX score for risk assessment in the allcomers population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial. J Am Coll Cardiol 2010;56:2727. 36. Taylor AJ, Cerqueira M, Hodgson JM, et al. ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography. A report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2010;56:186494. 37. Pundziute G, Schuijf JD, Jukema JW, et al. Prognostic value of multislice computed tomography coronary angiography in patients with known or suspected coronary artery disease. J Am Coll Cardiol 2007;49:6270. 38. Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic angiography for prediction of allcause mortality. J Am Coll Cardiol 2007;50:116170. Printable PDF This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item. 7.2: Medical Therapy Author(s): Richard A. Lange, MD, FACC Learner Objectives Upon completion of this module, the reader will be able to: 1. 2. 3. 4. Apply appropriate secondary prevention measures of coronary heart disease (CHD). Identify antianginal drugs that prevent reinfarction and improve survival in postmyocardial infarction (MI) patients. Identify patients who benefit from angiotensinconverting enzyme (ACE) inhibitors. Describe the goal serum lowdensity lipoprotein cholesterol (LDLC) concentration for patients with stable CHD. Introduction In the patient with chronic coronary artery disease (CAD), the goals of medical therapy are to ameliorate angina and/or prevent recurrent major cardiovascular (CV) events (secondary prevention). The initial approach to all patients should be focused upon eliminating unhealthy behaviors such as smoking and effectively promoting lifestyle changes that reduce CV risk such as maintaining a healthy weight, engaging in physical activity, and adopting a healthy diet. In addition, medical therapies that retard progression (or promote regression) of atherosclerosis, stabilize atherosclerotic plaques, or prevent thrombosis should be administered to decrease the risk of MI and death. Such therapies include antiplatelet agents, ACE inhibitors, and lipidlowering therapy. In the patient with diabetes, tight glycemic control was assumed to be important in secondary CV prevention, but recent studies show that this approach increases the risk of CV death and complications.1 Antiplatelet Therapy Platelet aggregation is a key element of the thrombotic response to plaque disruption. Hence, platelet inhibition is recommended in all patients with chronic CAD unless contraindicated. Aspirin (acetylsalicylic acid) irreversibly acetylates platelet cyclooxygenase, which is required for the production of thromboxane A2 , a powerful promoter of platelet aggregation. By inhibiting thromboxane production and subsequent platelet aggregation, aspirin reduces the risk of thrombotic vascular events. Among 2,920 patients with chronic CAD, the Antiplatelet Trialists' Collaboration metaanalysis showed that aspirin treatment was associated with a 33% reduction in the risk of serious vascular events (nonfatal MI, nonfatal stroke, and vascular death). Over the course of a couple of years of treatment, aspirin would be expected to prevent about 1015 vascular events for every 1,000 people treated.2 Aspirin dose of 75162 mg daily is equally as effective as 325 mg in secondary prevention, but with a lower risk of bleeding. Doses <75 mg have less proven benefit.2,3 The 2007 Chronic Angina Focused Update of the American College of Cardiology/American Heart Association (ACC/AHA) 2002 Guidelines for the Management of Patients With Chronic Stable Angina recommend that all patients with chronic stable angina or those with clinical or laboratory evidence of CAD receive aspirin, 75162 mg daily, indefinitely.3 Although aspirin prevents vascular events, it does not reduce anginal episodes. Aspirin is relatively contraindicated in patients with known allergies to nonsteroidal antiinflammatory drugs, and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Clopidogrel Clopidogrel, a thienopyridine derivative, inhibits platelet aggregation via irreversible inhibition of the adenosine diphosphate P2Y12 receptor. In the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial, which enrolled 19,185 patients with a history of MI, stroke, or peripheral vascular disease, patients who received clopidogrel had 10% fewer serious vascular events than aspirintreated patients.4 Since the magnitude of the difference was small and no additional trials comparing aspirin and clopidogrel in patients with stable CAD have been conducted, clopidogrel is recommended in patients with CAD who are allergic to or cannot tolerate aspirin. The use of dual platelet therapy with aspirin and clopidogrel was no more effective than aspirin alone in reducing vascular events in 15,603 asymptomatic patients with high risk for or with established atherothrombotic disease, including stable CAD, in the CHARISMA (Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization, Management, and Avoidance) study.5 A posthoc analysis showed that patients with documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease appeared to derive significant benefit from dual antiplatelet therapy with clopidogrel plus aspirin.6 Thus, treatment with aspirin 75162 mg daily and clopidogrel 75 mg daily may be reasonable in certain highrisk patients with chronic CAD. BetaBlockers Betablockers are the only antianginal drugs proven to prevent reinfarction and improve survival in patients who have had an MI. Such benefits have not been demonstrated in patients with chronic ischemic heart disease without previous infarction. Nevertheless, betablockers remain firstline therapy in the treatment of chronic ischemic heart disease, particularly effortinduced angina, with the goal to reduce the frequency and severity of angina and to improve exercise capacity. Despite the fact that they differ with regard to cardioselectivity, presence of intrinsic sympathomimetic activity or vasodilating properties, and relative lipid solubility, all betablockers appear to be equally efficacious in stable ischemic heart disease.711 Betablocker dosing should be adjusted to limit the heart rate to 5560 bpm at rest and to not exceed 75% of the exercise heart rate response at the onset of ischemia. Betablockers improve survival, prevent CV hospitalizations, and improve symptoms and exercise tolerance in patients with ischemic cardiomyopathy already receiving treatment with conventional therapy (i.e., diuretics, digoxin, and ACE inhibitors). The CIBIS II (Cardiac Insufficiency Bisoprolol Study II), MERITHF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure), and COPERNICUS (Effect of Carvedilol on Survival in Severe Chronic Heart Failure) trials demonstrated an approximately 35% mortality reduction with bisoprolol, metoprolol, and carvedilol, respectively (Figure 1).1214 This does not appear to be a class effect that extends to all betablockers because the BEST (BetaBlocker Evaluation of Survival Trial) study did not show a reduction in mortality with bucindolol.15 Betablocker therapy should be initiated and continued indefinitely in all patients with prior MI or left ventricular (LV) dysfunction—with or without heart failure symptoms— unless contraindicated.3 Some of the mechanisms responsible for the benefits of betablockers in these patients include increased myocardial betaadrenergic receptor density and sensitivity, and a switch in myocardial substrate utilization from free fatty acids to glucose, which increases myocardial energy efficiency. Although generally well tolerated, betablockers have several notable side effects. Because of their negative inotropic effects, betablocker therapy should be advanced cautiously in patients with impaired LV systolic function. Betablockers may exacerbate coronary vasospasm in patients with variant angina, bronchospasm in patients with reactive airway disease, and limb or digit ischemia in patients with severe peripheral vascular disease or Raynaud's phenomenon. Impotence may also occur with their use. Chronic betablocker therapy leads to an increase in beta receptor density. This can be clinically important, as sudden withdrawal of beta blocker therapy may result in increased sensitivity to endogenous catecholamines, with precipitation of angina pectoris, MI, or death. Figure 1 Mortality Benefit of BetaBlockers in Congestive Heart Failure Figure 1 Annual mortality in four studies of patients with congestive heart failuremost of whom had an ischemic cardiomyopathytreated with a) placebo or b) betablockers in addition to conventional therapy. Those treated with bisoprolol, metoprolol, or carvedilol had improved survival, whereas those treated with bucindolol did not. References: 1. The Cardiac Insufficiency Bisoprolol Study II (CIBISII): A randomised trial. Lancet 1999;353:913. 2. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlledrelease metoprolol on total mortality, hospitalizations, and wellbeing in patients with heart failure: The Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERITHF). MERITHF Study Group. JAMA 2000;283:1295302. 3. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:16518. 4. A trial of the betablocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:165967. Calcium Channel Blockers Calcium channel blockers may be used as effective antianginal agents and for the treatment of hypertension (see Chapter 5: Hypertension), but do not have a direct role for secondary prevention in patients with stable CHD. AngiotensinConverting Enzyme Inhibitors ACE inhibitors reduce mortality and morbidity from CV events in patients who have heart failure due to LV systolic dysfunction, and in those who have acute MI. In addition, "highrisk" patients with CAD or other vascular disease may benefit from an ACE inhibitor in the absence of LV dysfunction or previous MI. In patients with atherosclerotic vascular disease or diabetes and at least one other CAD risk factor, the HOPE (Heart Outcomes Prevention Evaluation) study showed that, compared to placebo, ramipril significantly decreased the primary composite endpoint of CV death, MI, and stroke by 22% over 4.5 years of followup.16 Based on these results, the Food and Drug Administration (FDA) approved the use of ramipril for the reduction of MI, stroke, and death in highrisk patients. Similarly, in the EUROPA (European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease) study, perindopril reduced CV events (CV death, MI, or cardiac arrest) by 20% over 4.2 years of followup in a lowerrisk population with stable CHD and no apparent heart failure.17 Conversely, in the PEACE (Prevention of Events With AngiotensinConverting Enzyme Inhibition) trial, which enrolled >8,000 lowrisk patients with stable CHD and preserved LV function who were receiving intensive current standard therapy, the addition of trandolapril did not reduce CV death, MI, or coronary revascularization (Figure 2).18 The lack of benefit from ACE inhibition in the PEACE trial has been attributed to the fact that the study population was lower risk and more likely to be intensively treated with coronary revascularization and lipidlowering therapy than the patients in the previous studies. Similarly, in the QUIET (Quinapril Ischemic Event Trial)19 and IMAGINE (Ischemia Management With Accupril PostBypass Graft via Inhibition of the Converting Enzyme)20 studies of lowrisk (LV ejection fraction [EF] >0.40) patients who had undergone percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), quinapril did not reduce ischemic events. Based on these studies, the 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina recommend that ACE inhibitors be started and continued indefinitely in all patients with LVEF ≤0.40 and in those with hypertension, diabetes, or chronic kidney disease unless contraindicated.3 Their use is also recommended in patients who are not lower risk (lower risk is defined as those with normal LVEF in whom CV risk factors are well controlled and revascularization has been performed). Finally, it is considered reasonable to use ACE inhibitors among lowerrisk patients with mildly reduced or normal LVEF in whom CV risk factors are well controlled and revascularization has been performed. Figure 2 Lack of Benefit of ACE Inhibitor in "LowRisk" Stable CAD Patients Figure 2 Composite outcome of cardiovascular death, myocardial infarction, or coronary revascularization in “lowrisk” patients with stable coronary artery disease (CAD) and preserved left ventricular function treated with placebo or trandolapril in the PEACE study. Over the 4.8year follow up, the addition of trandolapril to current standard therapy was not beneficial in reducing cardiovascular events. ACE inhibitor = angiotensinconverting enzyme inhibitor. Reproduced with permission from Massachusets Medical Society. The PEACE Trial Investigators. AngiotensinConvertingEnzyme Inhibition in Stable Coronary Artery Disease. N Engl J Med 2004;351:205868. Copyright © 2000, Massachusetts Medical Society. All rights reserved. AngiotensinReceptor Blockers Angiotensinreceptor blockers (ARBs) are recommended for individuals who have indications for an ACE inhibitor (post MI, heart failure due to LV systolic function, or depressed LVEF), but are intolerant of it. The ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) showed that telmisartan was noninferior to ramipril for reducing mortality and CV morbidity over more than 4 years of followup in patients with vascular disease or highrisk diabetes mellitus.21 However, the combination of telmisartan and ramipril was associated with an increased incidence of adverse events without a detectable incremental benefit above either agent alone. Influenza Vaccine An ACC/AHA science advisory recommends annual vaccination with inactivated vaccine (administered intramuscularly) against seasonal influenza to prevent allcause mortality and morbidity in patients with underlying CV conditions.22 A recent cohort study in 1,340 elderly (i.e., 65 years of age or older) patients with congestive heart failure or CAD showed that annual influenza vaccinations reduced the winter period mortality by 37%; the number needed to treat to decrease one death during influenza period is 122 annual vaccinations.23 LowDensity Lipoprotein Cholesterol Lowering Therapy (1 of 2) CV death rates increase with higher serum concentrations of total and LDL cholesterol, and the impact of elevated lipid levels is significantly greater in subjects with preexisting CHD than those without (Figure 3). Even modest elevations in serum cholesterol increase the risk of a cardiac event in patients with CHD or a recent MI. For example, the CARE (Cholesterol and Recurrent Events) trial evaluated the role of pravastatin therapy after MI in patients with average levels of total and LDL cholesterol (209 mg/dl and 139 mg/dl, respectively). In the placebo group, each 25 mg/dl increment in LDLC increased the risk of a cardiac event (death or nonfatal MI) by 28%.24 Accordingly, patients with known CHD or a CHD equivalent (i.e., diabetes mellitus, symptomatic carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, chronic renal insufficiency, or Framingham 10year risk of CHD >20%) merit aggressive lipid management. The goal serum LDLC concentration for patients with stable CHD or a CHD equivalent is <100 mg/dl.25 When LDLlowering drug therapy is employed in high risk or moderately highrisk persons, it is advised that the intensity of therapy be sufficient to achieve at least a 3040% reduction in LDLC levels. For individuals considered to be at very high risk for CHD, an LDLC goal of <70 mg/dl is a reasonable therapeutic strategy.25 This group would include individuals with established CV disease plus one of the following: 1) multiple major risk factors (especially diabetes), 2) severe and poorly controlled risk factors (especially continued cigarette smoking), and 3) multiple risk factors of the metabolic syndrome (especially high triglycerides >200 mg/dl plus nonhighdensity lipoprotein cholesterol [HDLC] >130 mg/dl with low HDLC [<40 mg/dl]). All patients with high serum LDLC should undergo lifestyle modifications, such as reducing dietary total and saturated fat (to <20% and <10% of caloric intake, respectively), weight loss if overweight, and aerobic exercise. Such changes typically result in <10% reduction in serum total and LDL cholesterol levels. However, in several clinical trials, lifestyle modification alone has been associated with angiographic evidence of slowed progression and modest regression of coronary atherosclerosis and reduced clinical events (angina, MI, coronary revascularization, or death). In these trials, the clinical and angiographic improvement induced by dietary intervention was more likely to occur when it resulted in substantial reductions in LDLC. Unfortunately, dietary modification alone is often unsuccessful in achieving target serum LDLC concentrations. Lipidaltering agents include several classes of drugs: bile acid sequestrants, nicotinic acid, hydroxymethylglutaryl coenzyme A (HMGCoA) reductase inhibitors (statins), fibrates, probucol, and ezetimibe. These drugs differ with respect to mechanism of action and to the degree and type of lipid lowering. Thus, the indications for a particular drug are influenced by the underlying lipid abnormality. Conventional dosing regimens and typical changes in the lipid profile with drug therapy are listed in Table 1. Common side effects are listed in Tables 2a and b. Cessation of therapy because of adverse effects occurs most commonly with bile acid sequestrants and shortacting nicotinic acid, and least commonly with the statins. Statins are the most effective drugs for lowering serum LDLC, with reductions in the range of 2060%. Additionally, they lower serum triglyceride 1535% and raise serum HDLC 515%. Fluvastatin is the least potent, and rosuvastatin is the most potent statin. Adverse reactions occur less frequently with the statins than with the other classes of lipidlowering agents, but patients taking them should be monitored for possible liver or muscle injury. The major effects of the fibrates are to lower serum triglyceride and raise HDLC levels. They are effective for the treatment of hypertriglyceridemia and combined hyperlipidemia with or without lowserum HDLC (hypoalphalipoproteinemia). The benefits of fibrates in the contemporary era of statin use is questionable, since the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial of diabetics Figure 3 Table 1 Table 2a Table 2b with CV disease receiving background statin therapy reported no overall benefit for fenofibrate.26 Bile acid sequestrants are effective in patients with mild to moderate elevations of serum LDLC. They may be used in combination with statins or nicotinic acid in patients with markedly elevated serum levels of LDLC. The use of a bile acid sequestrant is often limited by gastrointestinal side effects. Nicotinic acid is effective in patients with hypercholesterolemia and in combined hyperlipidemia associated with normal or lowserum HDLC levels (hypoalphalipoproteinemia). It raises serum HDL levels with dosages as low as 1 1.5 g/day, but higher doses (>3 g/day) are typically needed to lower serum very LDL (VLDL) and LDL cholesterol. The use of nicotinic acid is often limited by poor tolerability, which can be minimized by taking aspirin beforehand or using a long acting nicotinic acid preparation. In CHD patients who are at increased risk for CV events despite a wellcontrolled LDLC on statin therapy (i.e., those with low HDLC and high triglyceride levels), the addition of highdose, extendedrelease niacin to statin therapy does not reduce the risk of CV events.27 Probucol modestly lowers LDLC, but more prominently reduces HDLC. At present, the use of probucol should be limited to patients with refractory hypercholesterolemia or those with familial hypercholesterolemia and xanthomas. Cholesterol and Death Rate in Patients With and Without CHD Figure 3 Relation between baseline plasma cholesterol measurement and 10year cardiovascular death rate in patients without and with coronary heart disease in the Lipid Research Council Study. Death rates are increased at higher serum cholesterol concentrations in both groups, but the effect is more pronounced in subjects with coronary heart disease. CHD = coronary heart disease Reproduced with permission from Massachusetts Medical Society. Pekkanen J, Linn S, Heiss G, et al. Tenyear mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990;322:17007. Copyright © 1990, Massachusetts Medical Society. All rights reserved. LipidLowering Drug Therapy Table 1 Conventional dosing regimens and typical changes in the lipid profile with drug therapy. HDL = highdensity lipoprotein; LDL = lowdensity lipoprotein. Common Side Effects of LipidLowering Drug Therapy (1 of 2) Table 2a Common Side Effects of LipidLowering Drug Therapy (2 of 2) Table 2b LowDensity Lipoprotein Cholesterol Lowering Therapy (2 of 2) Ezetimibe reduces LDLC by inhibiting absorption of cholesterol by the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in the clearance of cholesterol from the blood. This mechanism is complementary to that of the statins. Hence, ezetimibe is typically used in combination with a statin when cholesterol is not reduced sufficiently by statin therapy alone or it is necessary to reduce the statin dose because of side effects. To date, no longterm clinical outcome studies have been performed with ezetimibe. Several large trials have demonstrated that lipid lowering is beneficial in patients with CHD. There is also ample evidence that elderly patients with CHD who do not have lifelimiting comorbid conditions benefit from lipidlowering therapy.28 A meta analysis of 38 primary and secondary prevention trials found that for each 10% reduction in serum cholesterol, CHD mortality was reduced by 15% and total mortality risk by 11%.29 In addition to the reduction in clinical events, serial angiographic and intravascular ultrasound studies have shown that cholesterol lowering can retard the progression and, in many cases, induce regression of coronary atherosclerosis.30,31 This benefit is most prominent when serum LDLC levels are reduced below 100 mg/dl. The mechanisms of benefit seen with lipid lowering are not completely understood. Regression of coronary atherosclerosis is modest. Furthermore, the magnitude of clinical benefits is disproportionate to the modest degree of regression, and they are seen before significant regression of atherosclerosis could occur. Other factors that may account for the beneficial effects of lipidlowering agents include plaque stabilization, reversal of endothelial dysfunction, antioxidant effects, decreased thrombogenicity, and antiinflammatory effects. CV benefits of cholesterol lowering with statins have been demonstrated in patients with CHD, with or without hyperlipidemia. The 4S (Scandinavian Simvastatin Survival Study) trial of patients with hyperlipidemia (baseline serum total cholesterol levels between 212 and 309 mg/dl) found that simvastatin therapy versus placebo for 5.4 years resulted in statistically significant reductions in total mortality (33% reduction), major coronary events (32% reduction), CV deaths (42% reduction), revascularization procedures (37% reduction), and cerebrovascular events (37% reduction).32 These benefits persisted at the 8year followup period.33 The reduction in major cardiac events was highly correlated with ontreatment serum total cholesterol and LDL concentrations and with changes from baseline. Each additional 1% reduction in LDLC reduced the risk of major cardiac events by 1.7%.34 The LIPID (LongTerm Intervention With Pravastatin in Ischemic Disease Trial) study showed that patients with CHD and a broad range of serum cholesterol concentrations benefit from statin therapy.35 The study randomized patients with serum cholesterol concentrations of 155270 mg/dl to therapy with pravastatin or placebo. After a mean followup of 60 months, the study was terminated prematurely because, compared with placebo, pravastatin therapy lowered morbidity and mortality from CV disease, as well as allcause mortality (Figure 4). The benefit of pravastatin was seen in all predefined subgroups, including those of any age and at any level of total cholesterol, LDLC, HDLC, or triglycerides. The CARE trial showed that statin therapy was beneficial in CHD patients with high normal levels of serum cholesterol.36 In this study, patients with average cholesterol levels (mean serum total cholesterol concentration of 209 mg/dl) were treated with pravastatin (40 mg) or placebo. At 5 years, benefits with pravastatin compared with placebo included significant reductions in the combined incidence of coronary death and nonfatal MI (31% reduction), the need for revascularization (25% reduction), and the frequency of stroke (32% reduction). The benefits were seen only in patients with LDLC levels above 125 mg/dl. Figure 4 The Heart Protection Study (HPS) questioned whether a target LDL goal <100 mg/dl is sufficient in highrisk individuals.37 In this study of >20,000 patients with established CV disease, diabetes, or hypertension, simvastatin (40 mg/day) reduced mortality (13%), cardiovascular mortality (18%), major CV events (24%), and ischemic stroke (25%) compared to placebo over the 5.5year followup. Importantly, subgroup analysis suggested that simvastatin therapy produced similar reductions in relative risk regardless of the baseline levels of LDLC, including subgroups with baseline LDLC levels >135 mg/dl, <116 mg/dl, or <100 mg/dl. The PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial extends the use of statins to the older population.28 Approximately 6,000 subjects ages 70 82 years with a history of vascular disease or CV disease risk factors were randomized to pravastatin (40 mg/day) or placebo and followed for 3.2 years. Major coronary events, defined as nonfatal MI and CHD death, were reduced by 19% and CHD mortality by 24% with pravastatin therapy. Mortality Benefit With Statin Therapy in Patients With a Broad Range of Serum Cholesterol Concentrations Figure 4 KaplanMeier estimates of mortality due to coronary heart disease in the pravastatin and placebo groups in the LIPID Study. CHD = coronary heart disease Reproduced with permission from Massachusetts Medical Society. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The LongTerm Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:134957. Copyright © 1998, Massachusetts Medical Society. All rights reserved. Key Points Unless contraindicated, all patients with evidence of CAD should receive aspirin to prevent MI. Betablockers are the only antianginal drugs proven to prevent reinfarction and improve survival in patients who have had an MI. Stable CAD patients receiving intensive medical therapy who are at low risk for a CV event do not benefit from ACE inhibitor therapy. Conversely, ACE inhibitors reduce CV mortality and morbidity in "highrisk" patients with vascular disease (i.e., those with poorly controlled risk factors or diabetes and other CV risk factors). Statins are the most effective drugs for lowering serum LDLC. The goal serum LDLC concentration for patients with stable CHD or a CHD equivalent is <100 mg/dl, and for those at "very high risk" (i.e., established CHD and multiple risk factors), the LDLC goal is <70 mg/dl. References 1. Gerstein HC, Miller ME, Genuth S, et al., on behalf of the ACCORD Study Group. Longterm effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364:81828. 2. Antithrombotic Trialists' Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:7186. 3. Fraker TD Jr, Fihn SD, Gibbons RJ, et al. 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol 2007;50:226474. 4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:132939. 5. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:170617. 6. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49:19828. 7. Frishman WH, Heiman M, Soberman J, Greenberg S, Eff J. Comparison of celiprolol and propranolol in stable angina pectoris. Celiprolol International Angina Study Group. Am J Cardiol 1991;67:66570. 8. HaufZachariou U, Blackwood RA, Gunawardena KA, O'Donnell JG, Garnham S, Pfarr E. Carvedilol versus verapamil in chronic stable angina: a multicentre trial. Eur J Clin Pharmacol 1997;52:95100. 9. Kardas P. Compliance, clinical outcome, and quality of life of patients with stable angina pectoris receiving once daily betaxolol versus twice daily metoprolol: a randomized controlled trial. Vasc Health Risk Manag 2007;3:235 42. 10. Narahara KA. Doubleblind comparison of once daily betaxolol versus propranolol four times daily in stable angina pectoris. Betaxolol Investigators Group. Am J Cardiol 1990;65:57782. 11. Raftery EB. The preventative effects of vasodilating betablockers in cardiovascular disease. Eur Heart J 1996;17 Suppl B:308. 12. CIBISII Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBISII): a randomised trial. Lancet 1999;353:913. 13. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlledrelease metoprolol on total mortality, hospitalizations, and wellbeing in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERITHF). MERITHF Study Group. JAMA 2000;283:1295302. 14. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:16518. 15. BetaBlocker Evaluation of Survival Trial Investigators. A trial of the betablocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:165967. 16. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensinconvertingenzyme inhibitor, ramipril, on cardiovascular events in highrisk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:14553. 17. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, doubleblind, placebocontrolled, multicentre trial (the EUROPA study). Lancet 2003;362:7828. 18. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensinconvertingenzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:205868. 19. Pitt B, O'Neill B, Feldman R, et al. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol 2001;87:105863. 20. Rouleau JL, Warnica WJ, Baillot R, et al. Effects of angiotensinconverting enzyme inhibition in lowrisk patients early after coronary artery bypass surgery. Circulation 2008;117:2431. 21. Yusuf S, Teo KK, Pogue J, et al., on behalf of the ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:154759. 22. Davis MM, Taubert K, Benin AL, et al. Influenza vaccination as secondary prevention for cardiovascular disease: a science advisory from the American Heart Association/American College of Cardiology. Circulation 2006;114:154953. 23. de Diego C, VilaCorcoles A, Ochoa O, et al. Effects of annual influenza vaccination on winter mortality in elderly people with chronic heart disease. Eur Heart J 2009;30:20916. 24. Pfeffer MA, Sacks FM, Moye LA, et al. Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial. Cholesterol And Recurrent Events. J Am Coll Cardiol 1999;33:12530. 25. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:72032. 26. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:156374. 27. Boden WE, Probstfield JL, Anderson T, et al., on behalf of the AIMHIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med;365:225567. 28. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:162330. 29. Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit: impact of statin trials. Circulation 1998;97:94652. 30. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very highintensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:155665. 31. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipidlowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:107180. 32. [No authors listed]. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:13839. 33. Pedersen TR, Wilhelmsen L, Faergeman O, et al. Followup study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering. Am J Cardiol 2000;86:25762. 34. Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:145360. 35. The LongTerm Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The LongTerm Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:134957. 36. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:10019. 37. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 highrisk individuals: a randomised placebocontrolled trial. Lancet 2002;360:722. Printable PDF This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item. 7.3: Indications for Revascularization Author(s): John McPherson, MD, FACC Learner Objectives Upon completion of this module, the reader will be able to: 1. Utilize appropriate medical therapy in the management of patients with symptomatic obstructive coronary artery disease (CAD). 2. Refer appropriate patients with significant left main or multivessel CAD for surgical or percutaneous revascularization. 3. Compare and contrast the management of patients with stable ischemic heart disease (SIHD) and acute coronary syndromes (ACS) with respect to the need for revascularization. 4. Manage asymptomatic patients with obstructive CAD according to current treatment guidelines. Introduction Despite many advances in the primary prevention of cardiovascular (CV) disease, SIHD continues to be a significant cause of morbidity and disability. It is estimated that 10 million Americans have SIHD, with 500,000 new cases of angina diagnosed each year.1 Unlike patients with ACS, patients with SIHD are primarily managed in the outpatient setting, with a focus on four major aspects of care: 1) identification and treatment of associated diseases that can precipitate angina, 2) reduction of coronary risk factors and modifying lifestyle factors, 3) administering medical therapy (see module on Medical Therapy in this chapter), and 4) revascularization by percutaneous coronary intervention (PCI) or by coronary artery bypass grafting (CABG). Through this comprehensive approach, the prevalence of major CV risk factors, such as tobacco use, hypercholesterolemia, and hypertension, has decreased, and with the use of evidencebased therapies (including antiplatelet agents, beta blockers, angiotensinconverting enzyme [ACE] inhibitors, statins, and myocardial revascularization), mortality from CAD has decreased by nearly 50% over the past several decades.2,3 In 1964, Garrett, Dennis, and DeBakey reported on the first CABG surgery.4 In the following two decades, myocardial revascularization with CABG in patients with SIHD was a major focus of investigation. Studies including the landmark CASS (Coronary Artery Surgery Study)5 and VACS (Veterans Administration Cooperative Study)6 demonstrated a mortality benefit with CABG in specific anatomic subsets of patients, primarily due to the use of the left internal mammary graft to revascularize the left anterior descending (LAD) coronary artery.7 With improvement in surgical techniques and perioperative management, clinical outcomes following elective CABG have continued to improve, with an approximate 2% major adverse event rate and a 1% hospital mortality rate.8 PCI in the form of balloon angioplasty was first performed by Gruentzig in 1977 for the treatment of proximal, noncalcified lesions involving a single coronary artery.9 Refinement of percutaneous techniques has also advanced over the past two decades, allowing for the ability to treat a wide range of patients with significant comorbidities and complex CAD. In addition, advances in adjunctive pharmacological therapy with dual antiplatelet therapy, antithrombotic agents, vascular closure devices, and radial arterial access have also led to a reduction in periprocedural ischemic events and reduced bleeding complications.10 Data from a highvolume PCI center on patients undergoing elective PCI from 20033006 demonstrated a procedural success rate of 96%, a major cardiac adverse event rate of 0.6%, and a mortality rate of 0.1%.11 Along with refinement in revascularization techniques of the past three decades, understanding of the pathogenesis and triggers of adverse CV events in patients with SIHD has advanced in parallel. An important finding is that the majority of ACS are caused by nonobstructive, clinically silent coronary plaques. Several studies, including the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial,12 have demonstrated that successful PCI of severe, clinically stable coronary stenoses does not reduce the rate of death or myocardial infarction compared with optimal medical therapy. In the COURAGE trial, 2,287 patients were randomized to PCI plus optimal medical therapy or optimal medical therapy alone. At 4.6year followup, rates of death and nonfatal myocardial infarction were similar (19.0% and 18.5%, respectively) (Figure 1, panel A). With some exceptions, the primary benefit of revascularization in SIHD patients, therefore, is relief of ischemic symptoms rather than prevention of major cardiac events. In 2009, the American College of Cardiology Foundation, the Society for Cardiovascular Angiography and Intervention, and the Society of Thoracic Surgeons, along with other key specialty and subspecialty societies, published appropriateness criteria for coronary revascularization.13 These criteria and the available evidence guiding the selection of patients who are candidates for revascularization is discussed later in this module. Figure 1 KaplanMeier Survival Curves Figure 1 The estimated 4.6year rate of the composite primary outcome of death from any cause and nonfatal myocardial infarction was 19.0% in the PCI group and 18.5% in the medicaltherapy group. In Panel B, the estimated 4.6year rate of death from any cause was 7.6% in the PCI group and 8.3% in the medicaltherapy group. In Panel C, the estimated 4.6year rate of hospitalization for acute coronary syndrome (ACS) was 12.4% in the PCI group and 11.8% in the medicaltherapy group. In Panel D, the estimated 4.6year rate of acute myocardial infarction was 13.2% in the PCI group and 12.3% in the medicaltherapy group. CI = confidence interval; PCI = percutaneous coronary intervention. Reproduced with permission from Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:150316. Acute Coronary Syndromes The evidence supporting revascularization as the fundamental treatment of patients with ACS and STsegment elevation myocardial infarction (STEMI) is discussed in detail in Chapter 6: Acute Coronary Syndromes. In patients presenting with STEMI, revascularization for primary reperfusion is appropriate unless the presentation is >12 hours from symptom onset and there are no ongoing ischemic symptoms or hemodynamic instability. Following thrombolytic therapy, revascularization is indicated in patients with heart failure or ongoing ischemia and should be considered in patients with STEMI and highrisk features, such as extensive STsegment elevation, new left bundle branch block, anterior infarction, and depressed left ventricular (LV) function.13 Following successful reperfusion therapy, the revascularization of nonculprit arteries before hospital discharge should be performed only in patients with clinical instability, recurrent or provokable ischemia, or depressed LV function. In general, revascularization should be considered in patients presenting with unstable angina or non−STsegment elevation myocardial infarction and highrisk features, as outlined in Chapter 6: Acute Coronary Syndromes. Stable Ischemic Heart Disease There are two principal objectives of revascularization in patients with SIHD: improvement of survival and relief of ischemic symptoms. In general, all patients with SIHD should receive appropriate medical therapy before revascularization is considered. The decision to refer SIHD patients for revascularization generally should be based on five clinical factors: 1) the presence of significant left main disease, 2) noninvasive risk stratification, 3) severity of ischemic symptoms, 4) the anatomical severity of CAD burden, and 5) the intensity of medical therapy. For a discussion regarding the choice of revascularization strategy (i.e., surgical vs. percutaneous) in patients with SIHD, refer to the module on Percutaneous Coronary Intervention versus Coronary Artery Bypass Grafting in this chapter. Table 1 Table 2 Left Main Disease Revascularization in patients with left main coronary stenosis ≥50% was primarily studied in the 1970s and 1980s. Multiple studies from that era, including data from the VACS6 and the CASS registry,5 demonstrated that CABG significantly improved survival compared with medical therapy in patients with significant left main coronary disease. There are currently no randomized studies comparing PCI with medical therapy in left main disease. Based on available surgical data, revascularization is indicated in all patients with significant left main disease, regardless of symptoms or noninvasive findings.14,15 Table 3 Noninvasive Risk Assessment Criteria for noninvasive risk stratification are summarized in Table 1. In patients referred for noninvasive testing, the annual mortality risk is directly related to exercise capacity, severity of ischemic symptoms, the amount of ischemia demonstrated on imaging, and the degree of ventricular dysfunction. In patients with moderatetosevere inducible ischemia (involving ≥10% of total myocardium), patients treated with revascularization have a significantly lower mortality rate compared with those treated medically.16 Thus, revascularization is recommended in nearly all patients with highrisk noninvasive findings; there is uncertainty in asymptomatic or minimally symptomatic patients without proximal LAD coronary disease (Table 2). In patients with intermediate risk on noninvasive testing, nearly all patients with ischemic symptoms despite maximal medical therapy should be referred for revascularization (Table 3). In general, patients with proximal LAD disease or threevessel disease regardless of therapy also benefit from revascularization. Intermediaterisk, asymptomatic patients with a low burden of CAD generally are inappropriate candidates for revascularization. In patients with lowrisk noninvasive findings, only patients with ischemic symptoms despite maximal medical therapy should be referred for revascularization. An exception to this recommendation involves patients with severe symptoms and a large disease burden; therapeutic uncertainty exists regarding patients with no symptoms or with only mild symptoms (Table 4). Severity of Ischemic Symptoms The Canadian Cardiovascular Society (CCS) classification method is most commonly used to evaluate the severity of ischemic symptoms (Table 5). As expected, the severity of anginal symptoms correlates with mortality risk. In patients with class III or IV symptoms, revascularization with CABG has been demonstrated to improve survival compared with medical therapy.5 Although relatively little data are available that compare PCI to medical therapy in these patients, revascularization is recommended in nearly all patients with severe (CCS class III or IV) angina (Table 2). In patients with SIHD who have milder symptoms (CCS class I or II), the decision to revascularize should include consideration of the intensity of medical therapy, noninvasive risk assessment, and the anatomical extent of CAD. Thus, Table 4 Table 5 Table 6 revascularization is indicated in patients who have highrisk noninvasive findings, symptoms despite maximal medical therapy, and significant disease burden (Tables 2, 3). In general, asymptomatic patients should be considered for revascularization only when noninvasive findings are highrisk, or for severe three vessel disease (Table 4). Anatomical Coronary Artery Disease Burden From an anatomical standpoint, it is well established that the extent of CAD predicts outcomes in patients with SIHD. In general, CV risk is associated with the amount of myocardium supplied by the diseased arteries (Table 6). In the CASS study, a mortality benefit was observed with revascularization in patients with the following conditions: Left main coronary artery stenosis or left main equivalent disease Threevessel CAD, particularly with a reduced LV ejection fraction (≤40%) Twovessel CAD including a >75% stenosis in the proximal LAD artery In the absence of the above conditions, the decision to revascularize a patient with SIHD should take into account the degree of CAD in the context of the severity of symptoms on maximal medical therapy, the degree of ischemia present on noninvasive testing, and the amount of myocardium supplied by the diseased vessels. Thus, there is a gradient for the appropriateness of revascularization based on these three factors. For patients with singlevessel CAD not involving the proximal LAD artery, revascularization is only indicated in the presence of class III/IV angina or intermediatetohigh risk findings on noninvasive stress testing (Tables 2, 3). Noninvasive Risk Stratification Table 1 LV = left ventricular; LVEF = left ventricular ejection fraction. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization. J Am Coll Cardiol 2009;53:53053. Appropriateness Ratings by HighRisk Findings on Noninvasive Imaging Study and Severity of Angina Table 2 CTO = chronic total occlusion; LAD = left anterior descending. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization. J Am Coll Cardiol 2009;53:53053. Appropriateness Ratings by IntermediateRisk Findings on Noninvasive Imaging Study and Severity of Angina Table 3 CTO = chronic total occlusion; LAD = left anterior descending. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization. J Am Coll Cardiol 2009;53:53053. Appropriateness Ratings by LowRisk Findings on Noninvasive Imaging Study and Asymptomatic Patients Table 4 CTO = chronic total occlusion; LAD = left anterior descending. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization. J Am Coll Cardiol 2009;53:53053. Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System Table 5 Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization. J Am Coll Cardiol 2009;53:53053. Prognosis by Extent of Anatomical Coronary Artery Disease Table 6 *Assuming medical treatment only. CAD = coronary artery disease; LAD = left anterior descending. Reproduced with permission from Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization. J Am Coll Cardiol 2009;53:53053. Special Patient Subsets Previous Coronary Artery Bypass Grafting In general, the indications for revascularization in patients with prior CABG are the same as for patients without prior CABG; patients with highrisk noninvasive findings or those with obstructive disease subtending a large myocardial territory are expected to derive a mortality benefit with revascularization. By contrast, patients with a patent internal mammary graft to the LAD artery and lowrisk noninvasive findings should be referred for revascularization, primarily for symptomatic relief despite maximal medical therapy. However, with the increased level of complexity of CV disease and limited evidence regarding repeat revascularization in these patients, the threshold for appropriateness is generally lower than for patients without prior CABG.13 Elderly Patients Although increasing age is known to be a strong predictor of adverse events in patients with CAD, it is also clear that elderly patients are at higher risk for adverse events after revascularization from both CABG and PCI.17,18 In addition, most large randomized trials of revascularization excluded elderly patients. With improvements in both surgical and percutaneous revascularization techniques, the risks of revascularization procedures in elderly patients are declining, and data from more recent studies indicate that selected elderly patients derive similar if not more relative benefit from revascularization compared with younger patients.1719 The current practice guidelines for PCI and CABG as well as the Appropriateness Criteria for Revascularization apply to all adult patients with SIHD, regardless of age. However, careful consideration of patientspecific procedural risks and comorbidities is of particular importance in the treatment of elderly patients. Diabetes Patients with diabetes who have SIHD are at increased risk for adverse CV events compared with nondiabetic patients. However, there is no evidence that a more aggressive approach to revascularization in these patients improves outcomes. In the BARI 2D (Bypass Angioplasty Revascularization Investigation) trial, patients with diabetes randomized to revascularization had no improvement in 5year death rate, myocardial infarction, or stroke compared with those treated with optimal medical therapy.20 However, if the decision is made to revascularize a patient with diabetes, there is evidence that outcomes are better with CABG than with PCI. In the era of baremetal stents, a large metaanalysis demonstrated improved longterm survival with CABG compared with PCI.21 Current data on the use of drugeluting stents from the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) study found that patients with diabetes had higher rates of revascularization following PCI than with CABG, particularly in those with more complex disease.22 Chronic Kidney Disease CV disease is the primary cause of mortality in patients with chronic kidney disease. Although data from randomized trials are not available, findings from observational studies suggest an improved survival rate with revascularization in patients with multivessel CAD and chronic kidney disease.23 Left Ventricular Dysfunction Early data from randomized trials demonstrated a survival benefit with CABG compared with medical therapy in patients with mildtomoderate LV systolic dysfunction.5,6 However, more recent data from the STICH (Surgical Treatment for Ischemic Heart Failure) trial did not demonstrate an overall survival benefit with CABG in patients with ischemic cardiomyopathy and LV ejection fraction ≤35%.24 Because multiple secondary endpoints from STICH did indicate improved outcomes with CABG, the study followup has been extended to 10 years to evaluate longterm outcomes. There are currently no randomized data on the use of PCI in this population, and current guidelines state that CABG to improve survival is reasonable in patients with mildtomoderate LV systolic dysfunction and significant CAD with evidence of viable myocardium in the region of intended revascularization.14,15 Hybrid Coronary Revascularization The rationale behind hybrid coronary revascularization is to combine the advantages of CABG (durability of the left internal mammary artery [LIMA] graft) and PCI in patients with multivessel CAD.25 Typically, the LAD artery is surgically bypassed using the LIMA, and PCI is performed of one or more other coronary arteries. Patients particularly suited for the hybrid approach include those with chronic total occlusions or patent vessels unfavorable for PCI and patients with a lack of surgical graft conduit or heavily calcified aortas in which saphenous vein grafting would be difficult. Hybrid procedures may be performed in a suitable hybrid operative suite in one setting, or they may be staged. In a staged procedure, the PCI usually follows the LIMA bypass to minimize perioperative bleeding from antiplatelet therapy and also so that angiographic evaluation of the LIMA graft can be performed. Preoperative Coronary Revascularization In general, decisions on revascularization in patients with SIHD undergoing noncardiac surgery are consistent with those regarding other patients with SIHD. Patients with significant left main or severe threevessel CAD should be treated with revascularization prior to elective noncardiac surgery. In the absence of these indications, there is no evidence that routine preoperative revascularization improves outcomes after noncardiac surgery. If PCI is performed in a patient in whom noncardiac surgery is likely, the operator should consider carefully the timing of the operation, the feasibility of continuing dual antiplatelet therapy during surgery, and the type of stent used in the PCI. Noncardiac surgery performed within 4 weeks of stent implantation is associated with high rates of stent thrombosis and death; in this case, balloon angioplasty is recommended whenever possible. If surgery is anticipated within 112 months following PCI, it recommended that baremetal stents be used, such that dual antiplatelet therapy can be discontinued safely before surgery. If a drugeluting stent is placed, elective surgery should be delayed for at least 12 months, if possible.15 Adjunctive Assessment of the Physiologic Significance of Coronary Artery Stenoses It is wellknown that angiography has limitations in the assessment of coronary stenoses, particularly in the evaluation of intermediate (4070% obstructive) lesions. Fractional flow reserve (FFR) has emerged as a useful tool in the assessment of such lesions. FFR values <0.75 correlate well with ischemia on noninvasive testing, and the findings from the DEFER (Deferral Versus Performance of Balloon Angioplasty in Patients Without Documented Ischemia) study demonstrated that patients with angiographic lesions associated with an FFR >0.75 had better outcomes with medical therapy compared with PCI.26 The evaluation and treatment of patients with multivessel CAD using FFR was studied in the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study.27 In FAME, PCI was deferred in lesions with an FFR of >0.80. Despite lower overall use of stents and revascularization, clinical outcomes were improved in the FFR group compared with the group treated with angiography alone. Intravascular ultrasound (IVUS) can provide significant additional information about coronary lesions, such as luminal diameters, crosssectional area, and plaque size and characteristics. IVUS has been used to assist in the evaluation of angiographically indeterminate coronary lesions. In general, in left main coronary stenoses, a minimal luminal area of <6 mm2 is believed to be consistent with a flow limiting lesion that may benefit from revascularization. In other coronary stenoses, the correlation between minimum luminal area and ischemia is more problematic, as other factors including vessel size, lesion length, and the extent of myocardium subtended by the lesion may influence the ischemic potential and choice of treatment. Summary SIHD is one of the most common manifestations of CV disease, and its prevalence undoubtedly will increase over time. Treatment of patients with SIHD initially should focus on secondary prevention with medical therapy and control of modifiable coronary risk factors. The two fundamental goals of revascularization in SIHD are to improve survival and to provide relief of ischemic symptoms. In SIHD, patients with improved survival with revascularization include those with significant left main disease, a large amount of ischemic myocardium, and severe anginal symptoms despite maximal medical therapy. In stable symptomatic patients, the anatomical degree of CAD burden, the amount of ischemia on noninvasive stress testing, the severity of symptoms, the intensity of medical therapy, and associated comorbidities are all important considerations in determining the clinical benefits of surgical or percutaneous revascularization. Key Points Medical therapy with antiplatelet agents, lipidlowering therapy, and antianginal agents is the mainstay of treatment in patients with SIHD. The goals of revascularization are to improve survival and to provide relief of ischemic symptoms. Revascularization is indicated in patients with significant left main stenosis and in patients with multivessel disease involving the proximal LAD artery, particularly with subnormal LV systolic function. Factors influencing the decision to perform coronary revascularization include the anatomical degree of CAD burden, the amount of provokable ischemia on noninvasive testing, the severity of symptoms, the intensity of medical therapy, and associated comorbidities. References 1. LloydJones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;119:e21 181. 2. Fox CS, Evans JC, Larson MG, Kannel WB, Levy D. Temporal trends in coronary heart disease mortality and sudden cardiac death from 1950 to 1999: the Framingham Heart Study. Circulation 2004;110:5227. 3. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 19802000. N Engl J Med 2007;356:238898. 4. Garrett HE, Dennis EW, DeBakey ME. Aortocoronary bypass with saphenous vein graft. Sevenyear followup. JAMA 1973;223:7924. 5. Alderman EL, Bourassa MG, Cohen LS, et al. Tenyear followup of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation 1990;82:162946. 6. The VA Coronary Artery Bypass Surgery Cooperative Study Group. Eighteenyear followup in the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery for stable angina. Circulation 1992;86:12130. 7. Sabik JF 3rd, Blackstone EH, Gillinov AM, Banbury MK, Smedira NG, Lytle BW. Influence of patient characteristics and arterial grafts on freedom from coronary reoperation. J Thorac Cardiovasc Surg 2006;131:908. 8. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for CardioThoracic Surgery (EACTS). Eur Heart J 2010;31:250155. 9. Gruentzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:618. 10. Marso SP, Amin AP, House JA, et al. Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA 2010;303:2156 64. 11. Hilliard AA, From AM, Lennon RJ, et al. Percutaneous revascularization for stable coronary artery disease. Temporal trends and impact of drugeluting stents. JACC Cardiovasc Interv 2010;3:1729. 12. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:150316. 13. Patel MR, Dehmer, GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AHA/ASNC 2009 Appropriateness Criteria for Coronary Revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology. Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2009;53:53053. 14. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e123210. 15. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44122. 16. Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the shortterm survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:29007. 17. Graham MM, Ghali WA, Faris PD, et al. Survival after coronary revascularization in the elderly. Circulation 2002;105:237884. 18. Singh M, Peterson ED, Roe MT, et al. Trends in the association between age and inhospital mortality after percutaneous coronary intervention: National Cardiovascular Data Registry experience. Circ Cardiovasc Interv 2009;2:206. 19. TIME Investigators. Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary artery disease (TIME): a randomized trial. Lancet 2001;358:9517. 20. Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:250315. 21. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet 2009;373;11907. 22. Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxeleluting stents. J Am Coll Cardiol 2010;55:106775. 23. Hemmelgarn BR, Southern D, Culleton BF, et al. Survival after coronary revascularization among patients with kidney disease. Circulation 2004;110:18905. 24. Velazquez EJ, Lee KL, Deja MA, et al. Coronaryartery bypass surgery in patients with left ventricular dysfunction. N Eng J Med 2011;364:160716. 25. Zhao DX, Leacche M, Balaguer JM, et al. Routine intraoperative completion angiography after coronary artery bypass grafting and 1stop hybrid revascularization: results from a fully integrated hybrid catheterization laboratory/operating room. J Am Coll Cardiol 2009;53:23241. 26. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5year followup of the DEFER study. J Am Coll Cardiol 2007;49:210511. 27. Pijls NH, Fearon WF, Tonino PA, et al., on behalf of the FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2year followup of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol 2010;56:17784. Printable PDF This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item. 7.4: Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting Author(s): John McPherson, MD, FACC Learner Objectives Upon completion of this module, the reader will be able to: 1. Identify patients with coronary artery disease (CAD) in whom revascularization with coronary artery bypass grafting (CABG) confers a survival benefit. 2. Compare the efficacy of percutaneous coronary intervention (PCI) with that of CABG in the treatment of patients with multivessel CAD. 3. Identify patients with specific clinical characteristics who would benefit from surgical revascularization as opposed to percutaneous revascularization. 4. Identify patients with specific clinical characteristics who would benefit from percutaneous revascularization as opposed to surgical revascularization. 5. Review the rationale and possible clinical benefits of hybrid coronary revascularization. Introduction As mentioned in the module on Indications for Revascularization in this chapter, the management of stable ischemic heart disease (SIHD) focuses on reduction of coronary risk factors, aggressive medical therapy, and, when appropriate, revascularization by PCI or with CABG. This module reviews the considerations implicit in the choice of revascularization mode in patients with SIHD. Coronary Artery Bypass Grafting The development of CABG for the treatment of symptomatic CAD occurred in the 1960s.1 In two decades that followed, myocardial revascularization with CABG in patients with SIHD was a major focus of investigation, evaluated in studies including the Coronary Artery Surgery Study (CASS) and registry,2 and the Veterans Administration Cooperative Study.3 In these studies, the major benefit of CABG compared with medical therapy was in relief of anginal symptoms, although there was also a demonstrable mortality benefit with CABG in specific subsets of patients, such as those with left main coronary artery (LMCA) disease, threevessel CAD, and those with left ventricular (LV) dysfunction.4 With improvement in surgical techniques and perioperative management, clinical outcomes following elective CABG have continued to improve, with an approximate 2% major adverse event rate and a 1% hospital mortality rate reported in recent studies.5 Specific refinements to CABG include the use of arterial conduits (left and right internal mammary artery, radial artery), "offpump" (beating heart) CABG, and sternalsparing, minimally invasive techniques. Percutaneous Coronary Intervention Dr. Andreas Gruentzig first performed PCI in the form of balloon angioplasty in 1977 for the treatment of stable angina caused by proximal, noncalcified singlevessel CAD.6 Major advances in percutaneous techniques, including the development of baremetal and drugeluting coronary stents, adjunctive pharmacological therapy with dual antiplatelet therapy and newer antithrombotic agents, vascular closure devices, and radial arterial access have enabled the use of PCI in the treatment of a wide range of patients with significant comorbidities and complex CAD. PCI is now performed in approximately 600,000 patients per year in the United States, in hospitals with and without onsite cardiac surgical capabilities. As with CABG, advances in PCI have also led to a reduction in periprocedural complications despite the treatment of older, higherrisk patients.7 Data from a highvolume PCI center on patients undergoing elective PCI from 20032006 demonstrated a procedural success rate of 96%, a major cardiac adverse event rate of 0.6%, and a mortality rate of 0.1%.8 Recently, a "hybrid" approach to revascularization has been developed, in which the benefits of CABG and PCI are combined to provide patients with a durable, complete revascularization and a minimally invasive procedure. Although longterm data regarding this approach are limited, initial results appear promising, and it is likely that a hybrid approach will emerge as a reasonable therapeutic alternative to traditional CABG and PCI in patients with SIHD.9,10 Regardless of the technique used, it is now clear that coronary revascularization is only one component of a comprehensive strategy in the optimal management of SIHD. The use of longterm antiplatelet agents, control of hypertension and hypercholesterolemia, referral for cardiac rehabilitation, and lifestyle counseling are all important elements in improving outcomes following revascularization. With some exceptions in patients with a high burden of CAD, the primary benefit of revascularization in patients with SIHD is relief of ischemic symptoms rather than prevention of major cardiac events. Given the rapid advancements in both CABG and PCI techniques and postprocedural care, much debate surrounds the choice of surgical versus percutaneous revascularization for any given patient. Several randomized trials comparing CABG and PCI have attempted to answer this question, but progress in this area has been hampered by enrollment of only a small proportion of screened patients and limited generalizability due to the rapid technological advancements in both fields. The available evidence and current recommendations guiding the approach to revascularization in patients with SIHD is discussed in the following sections. Anatomical and Functional Considerations SingleVessel CAD To date, no randomized trial has demonstrated a survival benefit in revascularization of patients with stable, singlevessel CAD not involving the proximal left anterior descending (LAD) coronary artery. Thus, the objective of either CABG or PCI in these patients is relief of ischemic symptoms despite maximal medical therapy. In these cases, PCI is generally the preferred approach because of its lower procedural morbidity, particularly when a more durable internal mammary arterial conduit is not planned or used at time of CABG. A rare exception may be a highly symptomatic, large, chronically occluded artery in which the distal vessel is a reasonable target for surgical grafting and the likelihood of successful PCI is low. Several studies have suggested that CABG for isolated proximal LAD disease is associated with improved survival compared with medical therapy.11 Revascularization for these patients is recommended in the appropriateness criteria for coronary revascularization, published by the American College of Cardiology Foundation (ACCF), the Society for Cardiovascular Angiography and Intervention, and the Society of Thoracic Surgeons, along with other key specialty and subspecialty societies.12 In a large metaanalysis of nine randomized trials, CABG and PCI for proximal LAD disease resulted in similar rates of stroke, myocardial infarction, and 5year survival; CABG was associated with more relief of angina and lower rates of repeat revascularization, whereas PCI was associated with shorter hospital stays and less need for blood transfusion.13 Thus, either approach is considered reasonable in this case. Figure 1 Figure 2 Figure 3 Figure 4a Left Main Coronary Artery Disease Patients with disease of the LMCA (defined as a ≥50% angiographic stenosis) are at particularly high risk of cardiovascular morbidity and mortality. Clearly, CABG for LMCA disease improves survival compared with medical therapy,2,3,11 and revascularization is indicated. Unlike CABG, no randomized data demonstrate a survival benefit in patients with PCI of the LMCA, and currently PCI for LMCA disease is considered inappropriate when CABG is a reasonable option.12,14 However, with the advent of baremetal and drugeluting stents, PCI of the LMCA in patients without prior CABG ("unprotected" LMCA) is increasingly considered a revascularization option. Improved outcomes with contemporary PCI and recent data comparing LMCA PCI with CABG are challenging the standard of care in patients with LMCA disease. Registries comparing PCI and CABG in patients with LMCA disease have shown similar rates of survival, decreased rates of stroke, and increased rates of repeat revascularization with PCI compared with CABG.15 In the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial, a randomized study comparing CABG to PCI with drug eluting stents in patients with multivessel CAD, 40% of the patients had significant LMCA disease.16 In this subgroup, major adverse cardiovascular event rates were similar; the rate of repeat revascularization was significantly higher in the PCI group (11.8% vs. 6.5%) and the stroke rate was significantly higher in the CABG group (2.7% vs. 0.3%). Ongoing large, randomized trials comparing LMCA PCI with CABG will inform the optimal treatment approach for these highrisk patients. Multivessel Disease Improvements in revascularization techniques have allowed both interventional cardiologists and cardiac surgeons to treat effectively more patients with increasing levels of CAD disease burden and comorbidities. Not surprisingly, revascularization with either CABG or PCI is now technically feasible in the vast majority of these patients. In patients with SIHD, PCI of multivessel disease has not been demonstrated to improve survival compared with medical therapy.14 This is in Figure 4b contrast to much older surgical data, in which CABG was shown to improve survival in subsets of patients with multivessel CAD, particularly in patients with threevessel CAD and involvement of the proximal LAD coronary artery, or with LV dysfunction.2,3 Given the significant changes in both surgical techniques and medical therapy, it is unclear whether these results would be replicated in a contemporary setting. With few exceptions, comparing CABG with PCI in randomized trials has been challenging because of inherent difficulties in enrolling typical "realworld" patients, given the necessary study inclusion/exclusion criteria and physician biases. In addition, the data are not always applicable due to the rapid advances in both CABG and PCI techniques (i.e., offpump CABG, drugeluting stents). Thus, many of the currently available data are contained in several large registries and a few randomized trials, with significant variations in techniques. In the New York State Registry, treatment of multivessel CAD was compared in 22,000 patients undergoing PCI using baremetal stents and 15,000 patients treated with CABG.17 Lower mortality with CABG was observed in patients with more complex CAD, including those with threevessel CAD and proximal LAD disease. Similar differences in mortality were reported with the use of drugeluting stents in the same registry.18 Although other registries have not reported differences in survival, findings of increased repeat revascularization following PCI and increased incidence of stroke following CABG have been consistent. In a metaanalysis of 24,000 patients with multivessel CAD treated with drugeluting stents or CABG, rates of myocardial infarction and survival were similar, but rates of repeat revascularization were four times higher in patients treated with PCI.19 In the first randomized trial of PCI versus CABG for the treatment of multivessel CAD, the BARI (Bypass Angioplasty Revascularization Investigation) researchers randomized 1,829 patients with multivessel CAD to balloon angioplasty or CABG.20 At 5 years, infarctfree survival was similar in the two groups (80% vs. 79%), but patients treated with angioplasty had a much higher rate of repeat revascularization (54% vs. 8%). Furthermore, the 5year survival rate was significantly higher in the subgroup of diabetic patients treated with CABG (81% vs. 66%) (Figure 1). Several similar randomized trials compared PCI using baremetal stents with CABG, and Hlatky and colleagues 15 performed a large metaanalysis incorporating these studies along with earlier data. In their analysis, although overall mortality was again similar between the two groups, patients with diabetes and those older than 65 years had improved survival with CABG (Figure 2). The SYNTAX trial was the first large randomized trial to compare treatment with PCI using drugeluting stents to CABG in patients with multivessel CAD.16 In the SYNTAX trial, patients were also stratified according to the presence of LMCA disease and diabetes. The investigators also introduced the "SYNTAX score"21 to objectively evaluate in detail the complexity of CAD. At 3 years, the composite endpoint of death, MI, stroke, and repeat revascularization was higher in the PCI arm (28.0% vs. 20.2%), primarily driven by a difference in repeat revascularization (19.7% vs. 10.7%). Mortality rates were similar in patients treated with CABG and PCI. The SYNTAX study also reaffirmed the notion that clinical outcomes following PCI for multivessel CAD are inversely proportional to the overall burden and complexity of CAD: in patients with low SYNTAX scores (defined as 022) and intermediate SYNTAX scores (2332), event rates were similar in patients treated with PCI or CABG; whereas patients with high SYNTAX scores (≥33) had significantly lower adverse event rates following CABG (Figure 3).22 Previous Coronary Artery Bypass Grafting In patients with previous CABG referred for revascularization, it is important to consider the type and number of remaining functional grafts, the degree of viable myocardium supplied by the diseased vessels, the complexity of the disease in the involved vessels, and patient comorbidities. In patients with a patent internal mammary graft to the LAD coronary artery and poor distal surgical targets, PCI is generally preferred. By contrast, CABG is preferred in patients with extensive disease, reasonable surgical targets, and the availability of an internal mammary conduit to an occluded artery.14 Completeness of Revascularization In the treatment of patients with SIHD, the ability to provide full revascularization may affect patient outcomes. Rates of complete revascularization typically are higher in patients undergoing CABG than in those undergoing PCI, as demonstrated in recent studies including the SYNTAX trial.16 Following PCI, incomplete revascularization has been associated with a slight increase in longterm mortality and increased rates of subsequent CABG (Figures 4a, b).23 Survival Among Patients With and Without Diabetes and Multivessel CAD in the BARI Study Figure 1 Survival among patients who were being treated for diabetes at base line (heavy lines) and all other patients (light lines). Patients assigned to CABG are indicated by solid lines, and those assigned to PTCA by dashed lines. The numbers of patients at risk are shown below the graph at base line, three years, and five years. BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; CAD = coronary artery disease; PTCA = percutaneous transluminal coronary angioplasty. Reproduced with permission from The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335:21725. Mortality in Patients After CABG or Multivessel PCI According to Diabetes Figure 2 *Number of patients available for followup. Data show overall unadjusted mortality rates for patients with diabetes and without diabetes. Panel A includes patients from all ten trials. Panel B excludes patients from the BARI trial. BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention. Reproduced with permission from Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomized trials. Lancet 2009;373;11907. Rates of Major Adverse Cardiac or Cerebrovascular Events According to SYNTAX Score Figure 3 CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention; SYNTAX = Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery. Reproduced with permission from Serruys PW, Morice MC, Kappetein AP, et al., on behalf of the SYNTAX Investigators. Percutaneous coronary intervention versus coronaryartery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:96172. KaplanMeier Survival Curves for Patients With Complete and Incomplete Revascularization After Coronary Stenting (1 of 2) Figure 4a IR = incomplete revascularization. Reproduced with permission from Wu C, Dyer AM, King SB, et al. Impact of incomplete revascularization on longterm mortality after coronary stenting. Circ Cardiovasc Interv 2011;4:41321. KaplanMeier Survival Curves for Patients With Complete and Incomplete Revascularization After Coronary Stenting (2 of 2) Figure 4b IR = incomplete revascularization. Reproduced with permission from Wu C, Dyer AM, King SB, et al. Impact of incomplete revascularization on longterm mortality after coronary stenting. Circ Cardiovasc Interv 2011;4:41321. Special Patient Subsets Diabetes Patients with diabetes and SIHD clearly are at increased risk for adverse cardiovascular events compared with nondiabetic patients. Patients with diabetes referred for revascularization often have more diffuse and complex CAD; achieving complete revascularization with PCI can be more challenging. As mentioned earlier, patients with diabetes enrolled in the BARI trial had a lower mortality rate following CABG when compared with multivessel angioplasty (Figure 1).20 In the era of baremetal stents, a large metaanalysis demonstrated improved long term survival and decreased repeat revascularization in patients with diabetes treated with CABG compared with PCI (Figure 2).15 The most recent available data are from the SYNTAX trial. With the use of drugeluting stents for multivessel PCI, patients with diabetes had higher rates of revascularization following PCI than with CABG, particularly those with more complex disease.16 Overall, rates of death, myocardial infarction, and stroke were similar between the two groups. However, in the subset of diabetics with SYNTAX scores of ≥33, mortality was significantly higher following PCI than after CABG (13.5% vs. 4.1%) (Figure 5). Thus, similar to nondiabetic patients, the decision regarding mode of revascularization should include consideration of CAD complexity and disease burden, which is often greater in patients with diabetes. In patients with extensive disease, CABG is the preferred treatment. Left Ventricular Systolic Dysfunction Data from CASS and other studies established that mortality is improved following revascularization with CABG in patients with LV dysfunction and multivessel CAD.2 Data in the literature are scarce regarding outcomes after contemporary PCI in this patient population, although some studies have demonstrated similar mortality rates in patients treated with PCI and CABG.14 At present, decisions regarding the approach to revascularization in these patients should also be made based on other factors, such as disease complexity, presence of diabetes, and patient preferences.14 Figure 1 Figure 2 Figure 5 Survival Among Patients With and Without Diabetes and Multivessel CAD in the BARI Study Figure 1 Survival among patients who were being treated for diabetes at base line (heavy lines) and all other patients (light lines). Patients assigned to CABG are indicated by solid lines, and those assigned to PTCA by dashed lines. The numbers of patients at risk are shown below the graph at base line, three years, and five years. BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; CAD = coronary artery disease; PTCA = percutaneous transluminal coronary angioplasty. Reproduced with permission from The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335:21725. Mortality in Patients After CABG or Multivessel PCI According to Diabetes Figure 2 Number of patients available for followup. Data show overall unadjusted mortality rates for patients with diabetes and without diabetes. Panel A includes patients from all ten trials. Panel B excludes patients from the BARI trial. Reproduced with permission from Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomized trials. Lancet 2009;373;11907. Clinical Outcomes at 1 Year in Patients With Diabetes in the SYNTAX Study Figure 5 CABG = coronary artery bypass grafting; CVA = cerebrovascular accident; MI = myocardial infarction; PES = paclitaxeleluting stents; SYNTAX = Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery. Reproduced with permission from Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxeleluting stents. J Am Coll Cardiol 2010;55:106775. Hybrid Coronary Revascularization Hybrid coronary revascularization typically is characterized by elective revascularization of the LAD coronary artery with a left internal mammary arterial graft and PCI of one or more major epicardial vessels. Other examples include minimally invasive valve surgery combined with PCI to coronary lesions (valve/PCI), to "convert" a highrisk valve/CABG procedure into a lower risk, isolated, minimally invasive valve procedure. Potential benefits of a hybrid procedure include: 1) provides a durable revascularization to the LAD coronary artery; 2) allows for a minimally invasive surgical approach; 3) provides angiographic confirmation of bypass graft patency during hybrid PCI; 4) enables treatment of patients with inadequate graft conduit and/or heavily calcified aortas; and 5) allows effective treatment of patients with multiple comorbidities.14 Emerging data suggest that, in selected patients, outcomes following hybrid coronary revascularization are similar to those following standard CABG.9,10 Depending on the capabilities of the hospital and the needs of the patient, hybrid procedures may be performed in a hybrid operating room or as a staged procedure, with initial CABG or PCI followed by the other within 23 days. In staged hybrid procedures, the CABG component is usually performed first in order to delay the necessary postPCI dual antiplatelet therapy until after the surgery and thus minimize bleeding risk, and also to allow for bypass graft angiography. Heart Team Approach to Revascularization Many patients with SIHD referred for revascularization have complex anatomical CAD and multiple clinical variables that require careful consideration when choosing a revascularization strategy, particularly when both CABG and PCI are technically feasible. Recent randomized trials comparing CABG with PCI, including the SYNTAX study, have mandated the formation of a multidisciplinary Heart Team in the evaluation of patients with complex CAD. The Heart Team, composed of an interventional cardiologist, cardiac surgeon, and occasionally a noninvasive cardiologist, cannot only provide a comprehensive evaluation of the patient's coronary anatomy and suitability for PCI or CABG, but also can assess the patient's comorbidities and treatment preferences. The most recent ACCFendorsed guidelines for both PCI and CABG have recommended a Heart Team approach to revascularization in all patients with unprotected LMCA disease or complex CAD.11,14 Summary Patients with stable, symptomatic CAD should be treated with a comprehensive approach focusing on reduction of coronary risk factors and aggressive medical therapy. The primary goals of revascularization are relief of ischemic symptoms refractory to medical therapy and improvement in survival when extensive CAD is present. Both CABG and PCI have specific advantages: CABG generally is more durable, resulting in more relief of anginal symptoms and fewer repeat revascularization procedures, whereas PCI is associated with less procedural morbidity, shorter hospital stays, and faster recovery. For uncomplicated CAD, CABG and PCI have similar longterm outcomes. As CAD complexity and burden increase, the incidence of continued angina symptoms and need for repeat revascularization increase to a greater extent after PCI compared with CABG. Recent studies have demonstrated similar longterm survival rates after CABG and PCI, even in patients with extensive CAD. However, improved survival after revascularization has only been shown with CABG in these patients, and thus, CABG is currently the preferred approach for patients with significant left main or complex threevessel CAD. Other factors, such as patient age, LV function and the presence of diabetes are important considerations in determining the optimal treatment for individuals with complex CAD, and the involvement of a multidisciplinary Heart Team should be a fundamental component of their care. Future Directions Recently, the National Cardiovascular Disease Registry working group of the ACC was awarded a Grand Opportunities grant by the National Heart, Lung, and Blood Institute to study the comparative effectiveness of PCI and CABG for the treatment of stable CAD.24 In this study, the existing ACC and Society of Thoracic Surgery databases will be used to compare procedural outcomes; in addition, longterm outcomes will be analyzed using the Centers for Medicare & Medicaid Services' 100% denominator file data. It is anticipated that more than 100,000 patients will be included in this study, which undoubtedly will provide valuable information of the optimal approach to revascularization in a wide array of patients. Key Points Revascularization with CABG to improve survival is indicated in patients with significant LMCA disease or severe threevessel CAD involving the proximal LAD coronary artery. In patients with singlevessel CAD, longterm outcomes following successful PCI and CABG are similar. In patients with multivessel CAD without a high level of complexity (e.g., lowtointermediate SYNTAX score), successful revascularization with CABG or PCI results in similar longterm outcomes. In patients with complex multivessel CAD (high SYNTAX score), revascularization with CABG results in fewer repeat revascularization procedures and improved longterm survival compared with multivessel PCI. Patients with significant left main or complex multivessel CAD ideally should be evaluated by a multidisciplinary Heart Team to determine the most appropriate method of revascularization. References 1. Garrett HE, Dennis EW, DeBakey ME. Aortocoronary bypass with saphenous vein graft. Sevenyear followup. JAMA 1973; 223:7924. 2. Alderman EL, Bourassa MG, Cohen LS, et al. Tenyear followup of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation 1990;82:162946. 3. The VA Coronary Artery Bypass Surgery Cooperative Study Group. Eighteenyear followup in the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery for stable angina. Circulation 1992;86:12130. 4. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10year results from randomised trials by the Coronary Artery Bypass Surgery Trialists Collaboration. Lancet 1994;344:56370. 5. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. The Task Force on Myocardial Revascularization of the European Society of Cardiology and the European Association for CardioThoracic Surgery. Eur Heart J 2010;31:250155. 6. Gruentzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:618. 7. Marso SP, Amin AP, House JA, et al. Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA 2010;303:2156 64. 8. Hilliard AA, From AM, Lennon RJ, et al. Percutaneous revascularization for stable coronary artery disease. Temporal trends and impact of drugeluting stents. JACC Cardiovasc Interv 2010;3:1729. 9. Zhao DX, Leacche M, Balaguer JM, et al. Routine intraoperative completion angiography after coronary artery bypass grafting and 1stop hybrid revascularization: results from a fully integrated hybrid catheterization laboratory/operating room. J Am Coll Cardiol 2009;53:23241. 10. Halkos ME, Vassiliades TA, Douglas JS, et al. Hybrid coronary revascularization versus offpump coronary after bypass grafting for the treatment of multivessel coronary artery disease. Ann Thorac Surg 2011;92:1695702. 11. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e123210. 12. Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness Criteria for Coronary Revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology. Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2009;53:53053. 13. Kapoor JR, Gienger AL, Ardehali R, et al. Isolated disease of the proximal left anterior descending artery: comparing the effectiveness of percutaneous coronary interventions and coronary artery bypass surgery. JACC Cardiovasc Interv 2008;1:48391. 14. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44122. 15. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet 2009;373:11907. 16. Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxeleluting stents. J Am Coll Cardiol 2010;55:106775. 17. Hannan EL, Racz MJ, Walford G, et al. Longterm outcomes of coronaryartery bypass grafting versus stent implantation. N Engl J Med 2005;352:217483. 18. Hannan EL, Wu C, Walford G, et al. Drugeluting stents vs. coronaryartery bypass grafting in multivessel coronary disease. N Engl J Med 2008;358:33141. 19. Benedetto U, Melina G, Angeloni E, et al. Coronary artery bypass grafting versus drugeluting stents in multivessel coronary artery disease: a metaanalysis on 24,268 patients. Eur J Cardiothorac Surg 2009;36:6115. 20. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronarybypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335:21725. 21. Sianos G, Morel MA, Kappetein AP, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention 2005;1:21927. 22. Serruys PW, Morice MC, Kappetein AP, et al., on behalf of the SYNTAX Investigators. Percutaneous coronary intervention versus coronaryartery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:96172. 23. Wu C, Dyer AM, King SB 3rd, et al. Impact of incomplete revascularization on longterm mortality after coronary stenting. Circ Cardiovasc Interv 2011;4:41321. 24. Klein LW, Edwards FH, DeLong ER, Ritzenthaler L, Dangas GD, Weintraub WS. ASCERT: the American College of Cardiology FoundationThe Society of Thoracic Surgeons collaboration on the comparative effectiveness of revascularization strategies. JACC Cardiovasc Interv 2010;3:1246. Printable PDF This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item. 7.5: Hibernation, Stunning/Viability Author(s): Anna Lisa Crowley MD, FACC Raymond J. Kim MD, FACC Learner Objectives Upon completion of this module, the reader will be able to: 1. 2. 3. 4. Define myocardial hibernation, stunning, and viability. Identify the techniques currently available to assess myocardial viability. Describe the STICH (Surgical Treatment for Heart Disease) trial. Examine the underlying assumptions in viability testing. Introduction Background The concept that dysfunctional myocardium may be viable has been known for decades. Specific physiologic states that can result in dysfunctional, yet viable myocardium are stunning and hibernation. "Myocardial stunning" describes the state of postischemic myocardial dysfunction in the presence of relatively normal blood flow.1 On light microscopy, stunned myocardium appears normal. However, there is decreased adenosine triphosphate and subtle ultrastructural abnormalities.2 The mechanism underlying stunning is not completely understood. It has been proposed that stunning involves myofilament desensitization to calcium, possibly by initial calcium overload during reperfusion, leading to troponin I proteolysis and/or oxygen radical formation during ischemiareperfusion damaging the contractile cell membranes. In general, stunned myocardium has been shown to recover function within hours to days, and recovery may take longer in cases of longer ischemic episodes prior to revascularization.3 The term "myocardial hibernation" describes the state of chronic myocardial dysfunction at rest that can be partially or completely restored to normal either by improving blood flow and/or by reducing demand.4 This physiology was first noted when ventricular wallmotion abnormalities improved after coronary artery bypass grafting (CABG).57 Biopsy specimens from regions of dysfunctional myocardium that recovered function after CABG showed that 90% of the volume consisted of viable cells.8,9 However, increased glycogen is seen in areas previously occupied by myofilaments, and small mitochondria are present.10 The mechanism underlying hibernating myocardium is not completely understood, but many investigators believe it is due to a chronic reduction in resting coronary blood flow. Others suggest that blood flow is normal in hibernating myocardium, and that the dysfunction results from repetitive episodes of stunning.10 In contrast to the relatively early recovery of function seen with myocardial stunning, recovery of function has been shown to take up to 1 year after revascularization in myocardial hibernation.3 Thus, myocardial stunning and hibernation both represent myocardium that is alive (or viable), rather than dead (or nonviable). Clinical Importance of Viability In patients with coronary artery disease (CAD) and left ventricular (LV) systolic dysfunction, determining which patients may benefit most from revascularization is clinically important. Guidelines for revascularization are provided by the American College of Cardiology Foundation and the American Heart Association (ACCF/AHA), which was last updated in 201111 In patients with poor LV function, surgical revascularization is given a Class I recommendation (evidence/agreement that treatment is useful/efficacious) for patients with the following coronary anatomy: 1) significant left main stenosis or 2) proximal LAD stenosis with two or threevessel disease. These recommendations are based largely on data from older randomized trials that focused primarily on the angiographic appearance of CAD and did not take other factors such as myocardial viability into consideration. While these studies showed benefit in the overall population with severe angiographic disease, from a mechanistic point of view, one would expect that additional information, such as the presence or absence of extensive viable myocardium, could improve patient risk stratification for revascularization. The potential importance of myocardial viability testing in reference to prognosis after revascularization has been evaluated in many small, singlecenter studies, including a metaanalysis demonstrating decreased annual mortality in patients with viability who were undergoing revascularization compared to those who were not undergoing revascularization.12 Allman et al., in a metaanalysis of 24 studies, which included 3,088 patients with a mean LV ejection fraction (EF) of 32%, concluded that, in patients with significant viability (as determined by thallium perfusion imaging, F18 fluorodeoxyglucose metabolic imaging, or dobutamine echocardiography), revascularization was associated with a 79.6% reduction in annual mortality compared with medical treatment (3.2% vs. 16%; p < 0.0001).13 Conversely, in patients without viability, mortality rates were similar for revascularization and medical therapy (7.7% vs. 6.2%; p = not significant). Based on data such as these, the ACCF/AHA guidelines on the diagnosis and management of heart failure from 2009 and CABG surgery from 2011 state that CABG, in addition to those with the coronary anatomy described earlier, may be performed in patients with poor LV function and significant CAD if there is significant viable myocardium (Class IIa recommendation [weight of evidence/opinion is in favor of usefulness/efficacy]).11,14 In contrast, CABG is not recommended in patients without evidence of intermittent ischemia and significant viable myocardium (Class III recommendation [evidence/agreement that treatment is not useful/efficacious or may be harmful]). However, the evidence for these recommendations has limitations. First, studies were small, not randomized, observational, and retrospective, leading to potential patient selection bias. Second, the methodology and criteria for defining viability, as well as the treatment regimens, were not standardized among the different studies. Finally, the success and completeness of myocardial revascularization was not investigated by followup angiography or stress imaging data in most studies.12 Given these flaws, metaanalyses incorporating these data are subject to the same limitations. In part, due to these limitations, the STICH trial was undertaken.15 STICH was a randomized, multicenter, nonblinded trial funded by the National Heart, Lung, and Blood Institute.15 Patients with angiographic documentation of CAD amenable to surgical revascularization and LV systolic dysfunction (EF ≤35%) were eligible for enrollment. Exclusion criteria were left main stenosis >50%, cardiogenic shock, myocardial infarction (MI) within 3 months, and need for aortic valve surgery. In hypothesis 1, enrolled patients were randomly assigned to receive medical therapy alone or medical therapy plus CABG. In hypothesis 2, enrolled patients were randomly assigned to receive medical therapy plus CABG or medical therapy plus CABG and surgical ventricular reconstruction. Between 2002 and 2007, 1,212 patients from 99 centers in 22 countries were enrolled in hypothesis 1. The primary endpoint was death from any cause. In the initial design of the STICH trial, viability testing with singlephoton emission computed tomography (SPECT) was required. However, this requirement proved to be an impediment to study enrollment. Therefore, the protocol was revised in 2004 to make viability testing optional, and the decision to perform the test was left up to the recruiting investigators. In addition, the viability test options were expanded to include SPECT (four separate protocols), dobutamine stress echocardiography (DSE), or both.16 Overall, there was no significant difference between patients with medical therapy alone and medical therapy plus CABG with respect to the primary endpoint of death from any cause at a median of 5.1 years of followup.15 In the 601 patients who received a viability study, there was a significant association between viability and outcome on univariate analysis, but not on multivariate analysis. Surprisingly, the assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone, in contrast with the prior literature.16 The authors point out that conclusions drawn from STICH are limited by a number of factors.16 First, slightly less than half of the 1,212 patients enrolled in the hypothesis 1 comparison underwent viability testing. Second, patients were not randomized to viability testing, and third, testing could have been performed prior to, on the day of, or after study enrollment. These factors may have led to patient selection/enrollment bias and may have influenced subsequent clinical decision making. Additionally, only a small percentage of patients were deemed not to have viable myocardium (19%), which limited the power of the analysis to detect a differential effect of CABG, as compared to medical therapy alone, in patients with myocardial viability as compared to those without myocardial viability. Lastly, the viability analyses were limited to SPECT and DSE imaging. While the results were similar for SPECT and for DSE, caution should be taken to not extrapolate these results to other imaging modalities that were not tested in STICH, such as positron emission tomography (PET), delayedenhancement cardiac magnetic resonance (DECMR), and delayedenhancement multidetector computed tomography (DEMDCT). Despite the study limitations, the STICH trial is a landmark investigation that raises an important question: Is viability assessment important? From a pathophysiologic viewpoint, it would be difficult to interpret the STICH results as concluding that alive myocardium is the same as dead myocardium. On the other hand, from a clinical viewpoint, the STICH results show that using "status quo" viability methods to determine who will benefit from CABG is highly problematic. As a result, there clearly is a need to reassess the underlying mechanisms regarding how viability tests are assumed to work and how they are interpreted. The following sections will focus on the current techniques used to assess myocardial viability and their underlying pathophysiologic basis, and explore what might constitute an "ideal" technique. Given the results from STICH, the numerous small studies published prior to STICH relating viability imaging to functional recovery and prognosis will not be summarized. Instead, fundamental concepts in viability assessment will be examined. Additionally, DECMR as a paradigm will be used to discuss many of the underlying assumptions in viability. Physiological Basis Of Viability Testing Morphology Simple morphological characteristics of the LV may provide useful information about viability. For instance, ventricular wall thinning has been used as a marker for the absence of viability, based on the hypothesis that a thinned region represents scar tissue and chronic MI. Cwajg et al. studied 45 patients with stable CAD and LV dysfunction using echocardiography. and concluded that "a simple measurement of enddiastolic wall thickness ≤6 mm virtually excludes the potential for recovery of function."17 Similarly, Baer et al. studied 43 patients with chronic MI and LV dysfunction with cardiac magnetic resonance (CMR) and concluded that "the depiction of significantly reduced enddiastolic wall thickness (<5.5 mm) excludes a clinically relevant amount of persistent viable myocardium."18 However, there are some limitations with this approach. First, it is not intended to examine viability in the setting of acute MI where wall thickness may be normal or even increased by as much as 50% despite the lack of viable myocytes.19 Second, the time required for acute myocardial necrosis to heal and turn into collagenous scar with resultant wall thinning may be substantial and in the order of 68 weeks. Third, even in the chronic setting, although it is clear that transmural infarction is frequently associated with myocardial thinning, there are less data in the setting of nontransmural infarction, and the transmurality of infarction that is necessary for wall thinning is unknown. Function By definition, the presence of contraction or systolic wall thickening in a region demonstrates substantial viable myocardium. However, the converse may not be true. Absent resting contraction does not necessarily mean that the myocardium is dead. Obvious examples of this include the phenomena of myocardial "stunning" and "hibernation" in which contraction is absent despite preserved viability. Clinically, dysfunctional, but viable, myocardium may be differentiated from infarction by assessing contractile reserve, as only viable myocardium will respond to inotropic stimulation by demonstrating enhanced contraction and systolic thickening. Based on this principle, both DSE and CMR have been used to assess contractile reserve and thus viability. In general, both DSE and CMR demonstrate lower sensitivity than specificity for predicting functional improvement.18,20,21 The observation that contractile reserve may have relatively modest sensitivity for predicting functional improvement highlights the indirect relationship between contractile reserve and viability. Experimental studies of chronic lowflow ischemia have shown that some viable regions are so delicately balanced between reductions in flow and function, with exhausted coronary flow reserve, that any inotropic stimulation merely results in ischemia and precludes the ability to enhance contractility.22 Perfusion Myocardial perfusion is related to myocardial viability in that chronic absence of blood flow, of course, is incompatible with viability. However, it is important to recognize that perfusion does not have a direct onetoone relationship with viability. For example, myocardial ischemia is caused by reduced perfusion, but this pathophysiologic state, by definition, requires viable myocardium. Reperfused acute infarction is another pathophysiologic state where perfusion and viability are dissociated. The entire infarcted region is by definition nonviable; however, tissue perfusion may range from nearly zero in central regions of the infarct with profound microvascular damage to nearly normal in other regions in which the microvasculature is intact.23 The heterogeneity of perfusion in reperfused infarction has been demonstrated in humans using contrast echocardiography,24 and measured in animal models using radioactive microspheres.25 Additionally, the pathophysiology of hibernating Figure 1 myocardium itself suggests a discordance. Although there are some conflicting data, hibernating myocardium, which represents viable tissue, is believed to be due to chronically reduced perfusion. These discrepancies in the relationship between perfusion and viability underscore the potential limitations in utilizing a technique that measures perfusion for assessing viability. Metabolism and Cell Membrane Integrity Techniques that examine the metabolic activity or cell membrane integrity of myocytes should provide, at least theoretically, the most direct means for determining whether myocytes are alive or dead. Scintigraphic techniques using PET or SPECT are examples of such methods.26 Specifically, preserved glucose metabolism can be examined by F18 fluorodeoxyglucose (FDG) PET, cell membrane integrity by thallium201 SPECT, and intact mitochondria by technetium 99m sestamibi SPECT. For the latter two techniques, however, myocardial perfusion probably also affects tracer activity to some degree. Overall, radionuclide techniques demonstrate moderate to good sensitivity (8193%) but poor specificity (5066%) for predicting functional improvement.20 In general, SPECT has lower diagnostic accuracy than PET and is more prone to underestimate viability,27 most likely because of technical limitations, such as lower spatial resolution, use of lower energy tracers, and lack of builtin attenuation correction. The poor specificity of both techniques may also relate to technical limitations; however, the use of functional improvement after revascularization as the truth standard for viability may result in an artificially low specificity. DECMR is another technique that can index cell membrane integrity. Although the gadoliniumbased contrast media used for DECMR is inert, and active transport processes across cell membranes such as for thallium are not present, there appears to be a direct, but inverse relationship between gadolinium concentration and the percentage of viable myocytes within any given region of myocardial tissue. The mechanism is likely based on the following: 1) tissue volume in normal myocardium is predominantly intracellular (7580% of the water space)28; and 2) currently available gadolinium contrast media are "extracellular" agents since they do not cross cell membranes.29 Thus, the volume of distribution of gadolinium contrast in normal myocardium is quite small (approximately 20% of water space), and one can consider viable myocytes as actively excluding contrast media.30 Pathophysiologic states that result in a reduced density of viable myocytes will then have increased volume of distribution of gadolinium and higher concentration.31 Note that this mechanism is independent of the cause or etiology for nonviable myocardium. Whether the tissue consists of contractionband necrosis in the setting of acute MI, collagenous scar in chronic MI, or fibrosis in various nonischemic cardiomyopathies, the region will have increased gadolinium concentration if there is a reduced density of viable myocytes.30 DECMR has been shown to be highly effective in identifying the presence, location, and extent of MI in both the acute and chronic settings in both animal and human studies.3135 Additionally, it has been used to predict reversible myocardial dysfunction in those undergoing revascularization procedures.3638 Recently the delayedenhancement concept has been extended to MDCT. The interpretation of contrastenhancement patterns on MDCT appears quite similar to that for DECMR, and is likely based on the same underlying mechanism because the iodinated contrast media used for MDCT has nearly identical pharmacokinetics as that of "extracellular" gadolinium contrast.39 Likewise, in animal models, DEMDCT assessment of acute and chronic MI has been shown to accurately reflect true infarct size and morphology as determined by histopathology.40 Although currently there are few studies in humans,39,41 these initial studies have demonstrated an excellent agreement between DEMDCT and CMR, albeit with reduced contrasttonoise ratio and image quality for MDCT.39 Figure 1 shows a comparison between DEMDCT and DECMR in three patients. Delayed Enhancement Images From Cardiac Magnetic Resonance and Multidetector Computed Tomography in 3 Different Patients With Acute Myocardial Infarctions Figure 1 Shortaxis delayedenhancement cardiac magnetic resonance (panels a, c, e) and delayedenhancement multidetector computed tomography images (panels b, d, f) in three different patients with acute myocardial infarction attributable to left anterior descending artery (panels a, b), right coronary artery (panels c, d), and left circumflex artery (panels e, f) occlusion after successful revascularization. There is excellent agreement between hyperenhanced regions (arrows) on the two techniques. Adapted with permission from Mahnken AH, Koos R, Katoh M, et al. Assessment of myocardial viability in reperfused acute myocardial infarction using 16slice computed tomography in comparison to magnetic resonance imaging. J Am Coll Cardiol 2005;45:20427. The "Ideal" Technique Knowing How Much Is Alive Is Not Enough A useful exercise is to consider what might constitute an "ideal" technique for assessing viability. Certainly, it would be important for the technique to be fast and safe, and to provide reproducible results. However, what might not be so apparent is that even if a technique were available that could offer precise quantification of viability without technical limitations (e.g., infinite spatial resolution, no artifacts), this would still be insufficient to provide a complete characterization of viability, and thus, would be insufficient to provide the highest accuracy in predicting wallmotion improvement or clinical benefit after coronary revascularization.42 Certainly, there are additional factors that are not related to limitations in noninvasive testing that could reduce accuracy in predicting functional improvement. These have been well described and include perioperative or postoperative occult MI,43 incomplete revascularization as a result of diffuse disease,44 or tethering of regions with extensive scarring adjacent to viable regions.45 For the purposes of this section, these clinical factors will not be considered; instead, it will focus on issues related to the noninvasive assessment of viability and will examine the concept that "knowing how much is alive is not enough." A central tenet of this concept is that a technique that offers even a perfect assessment of what is alive (viable) has substantial and practical limitations compared with a technique that offers both an assessment of what is alive and what is dead (nonviable). This tenet may be counterintuitive, because it would seem that by knowing exactly how much is alive, by deductive logic, one should know how much is dead. However, this is an incorrect assumption, and the patient examples in Figure 2 may be illustrative. The left panel in the top row of Figure 3 (Patient A) shows a midventricular, shortaxis DECMR image of a normal heart in diastole. With DECMR, nonviable regions such as infarction appear bright (hyperenhanced), whereas viable regions appear black. First, consider only a "nonviability" or bright region assessment. A quick visual inspection shows no evidence of myocardial bright regions; thus, one rapidly concludes that no infarction is present. In comparison, now consider only a "viability" or black region assessment. One can trace the endocardial and epicardial borders of viable myocardium (center panel), and then plot the transmural extent of viability as a function of position, starting from the anterior wall at 12:00 and moving counterclockwise around the LV (right panel). From the plot, it is obvious that there is marked heterogeneity in the transmural extent of viability, with as much as 12 mm of viable myocardium in the portion of the inferior wall adjacent to the posterior papillary muscle and as little as 7 mm in the anteroseptal wall at the RV insertion site. Concerning this finding, it is important to note that it has been long known that there can be significant variation in diastolic wall thickness at different points around the LV, even if papillary muscles are excluded and healthy volunteers are studied.46 This observation then naturally proceeds to the conclusion that there can be significant variability in the transmural extent of viable myocardium at different locations of the normal LV, as was found in Patient A. The principle that normal hearts can have significant heterogeneity in the extent of viable myocardium has direct clinical implications. For example, in a region with 70%, the viability of the region with the maximum amount of viability may represent either a normal region with 70% the wall thickness of the thickest region or a region with a subendocardial MI. The images from Patient B (Figure 2) underscore this concept. This particular patient had a clinically documented MI due to occlusion of the right coronary artery (RCA), which was reopened during primary angioplasty. Again, consider first only a "nonviability" assessment. From a quick visual perusal (left panel), one can determine that there is a subendocardial bright region in the inferoseptal wall consistent with the patient's prior MI in the RCA perfusion territory. Next, consider only a "viability" assessment, similar to the assessment performed in Figure 2 Figure 3 Figure 4 Figure 5 Patient A. Again, endocardial and epicardial contours are traced (center panel); however, one difference should be noted. The endocardial contour is along the border of viable (black) myocardium, and the infarcted region is not included. The plot showing the extent of viable myocardium (right panel) once more shows marked regional variability, and from this assessment, the presence and/or location of infarction is not evident. Thus, in this patient, the intrinsic variation in the extent of viable myocardium for noninfarcted regions is greater than the reduction in viable myocardium for the region with subendocardial infarction. This renders the subendocardial infarction "invisible" for any technique that can assess only viable myocardium, even if the technique has perfect accuracy and has infinite spatial resolution. These two patient examples highlight the differences between techniques that can visualize only viable myocardium, as opposed to techniques that can visualize viable and nonviable myocardium. Additionally, it is important to recognize that the use of different techniques often lead to differences in the way in which viability is quantified, although the nomenclature used may be the same. For instance, when only viable myocardium can be visualized, the percentage of viability in any given segment is assessed indirectly and generally refers to the amount of viability in the segment normalized to the segment with the maximum amount of viability or to data from a genderspecific database of controls. Conversely, when both viable and nonviable myocardium can be visualized, the percentage of viability can be assessed directly and expressed as the amount of viability in the segment normalized to the amount of viability plus infarction in the same segment (Figure 3). The differences in the way in which viability is measured can alter clinical interpretation. For the normal heart in Patient A, the indirect method would show that there is significant regional variability in the extent of viable myocardium: 60100% of maximum viability; whereas, the direct method would show essentially no variability because all of the segments would be classified as 100% viable. Likewise for Patient B, the indirect method would not be able to identify the region of subendocardial infarction because the extent of viable myocardium in this sector is within the normal variation; whereas, the direct method would clearly identify the region with subendocardial infarction because this region would be the only region with less than 100% viable myocardium. These patient examples also clarify the mechanism by which subendocardial infarcts are routinely missed by techniques such as SPECT and PET (Figure 4).4749 Although it is often reported that limited spatial resolution is the reason, it should be evident that even infinite spatial resolution would not improve the detection of subendocardial infarction by these or other methodologies based on assessing only viable myocardium. Conversely, a methodology with poor spatial resolution (e.g., a single voxel across the LV wall) would still be able to detect subendocardial infarction if it had the ability to assess both alive and dead tissue. Is 'Thinned' Myocardium Always Dead? As discussed earlier in the module, prior studies report that, in patients with coronary disease and LV dysfunction, regions with thinned myocardium represent scar tissue and cannot improve in contractile function after revascularization.17 Some recent observations appear to refute this concept.17,50,51 Figure 5 shows CMR images of two patients (Patient C and Patient D) who have severe CAD and chronic LV dysfunction. The left panels represent longaxis views acquired before coronary revascularization. Two points should be noted on the cine images. First, both patients have severe contractile dysfunction of the anterior wall. Second, Patient D has associated thinning of the anterior wall (diastolic wall thickness, 5.0 mm), whereas Patient C does not (diastolic wall thickness, 8.0 mm). Based on these cine images and the existing literature, one might expect that there is more viable myocardium in the anterior wall of Patient C than in Patient D, and, in fact, question the need for viability testing at all in Patient D because the thinned, akinetic anterior wall must undoubtedly be scar tissue and thus nonviable. The DECMR images acquired before revascularization, however, indicate a different clinical interpretation. In Patient C, there is a bright endocardial rim of hyperenhancement (infarction) that measures, on average, 4.5 mm in thickness. The remaining epicardial rim of tissue, which is black (viable), measures 3.5 mm in thickness (total thickness, 8 mm). In Patient D, there is also an endocardial rim of hyperenhancement; however, it measures on average only 1.5 mm in thickness. The epicardial rim, which is viable measures 3.5 mm in thickness (total thickness, 5 mm). Note that, in both patients, the absolute amount of viable myocardium is the same (3.5 mm), however, when the extent of viability is expressed as a percentage of the total amount of myocardium in the segment, Patient C has less than 50% viable myocardium (3.5 / 8 = 44%), whereas Patient D has >50% viable myocardium (3.5 / 5 = 70%). The rightmost panels represent cine images acquired 2 months after coronary revascularization. Patient C exhibits no improvement in contractile function in the anterior wall and, in fact, develops diastolic wall thinning in this region. Conversely, Patient D exhibits not only significant improvement in anterior wall contractile function, but also recovery of diastolic wall thickness in this region (from 5 mm to 9 mm). Three fundamental points are raised by these patient examples. First, it is apparent that a method that can quantify only viable myocardium, even if technically flawless (e.g., infinite spatial resolution, no artifacts), provides insufficient information to allow a comprehensive assessment of myocardial viability. Because both patients had the same, reduced amount of viable myocardium (3.5 mm thickness), we would have predicted, incorrectly as it turns out, that both patients would not improve in contractile function following revascularization. Second, it is evident that the absolute amount of viable myocardium in a given region is dynamic and can increase or decrease as a result of ventricular remodeling. Whereas it is common knowledge that myocardial viability can decrease, for example due to MI with associated wall thinning, the reverse process in which regions of thin myocardium become thick with an absolute increase in the transmural extent of viability (as in Patient D) has not been described. Third, it appears that quantification of nonviable, in addition to viable, myocardium is important in predicting contractile improvement following revascularization. For instance, incorporating information regarding nonviable myocardium into a ratio of viable to total myocardium (viable plus nonviable) within the same region would lead to the conclusion that the anterior wall of Patient D has a higher percentage of viable myocardium (70%) than Patient C (44%), and thus, is more likely to improve in contractile function. The followup cine images in the figure demonstrate that this prediction is correct. Future investigations are necessary to explore and validate these concepts. Regional Variation in Determining the Extent of Viable Myocardium Figure 2 Left panels show delayedenhancement images of a normal subject (Patient A) and a patient with a subendocardial, inferior wall myocardial infarction (Patient B). The center panels show tracing of the borders of viable myocardium. The right panels plot the extent of viability (thickness) as a function of left ventricular location. Note that there is significant regional variation in the extent of viable myocardium. Adapted with permission from Kim RJ, Shah DJ. Fundamental concepts in myocardial viability assessment revisited: when knowing how much is "alive" is not enough. Heart 2004;90:13740. Differences Between an Indirect and Direct Method of Quantifying Regional Myocardial Viability Figure 3 Cartoon highlighting differences between an indirect and direct method of quantifying regional viability. The indirect method is based on assessment of viable regions only. The direct method is based on assessment of viable and nonviable regions. Viable myocardium is black, and infarct is white. “Remote” zone represents segment with maximum amount of viability. Reproduced with permission from Fuster V, Kim RJ. Frontiers in cardiovascular magnetic resonance. Circulation 2005;112:13544. Short Axis Views From Three Canines With Subendocardial Myocardial Infarctions Figure 4 Comparison of a method that indexes cell membrane integrity and detects only viable myocardium (singlephoton emission computed tomography [SPECT]) and a method that indexes cell membrane integrity and detects both viable and nonviable myocardium (delayedenhancement cardiac magnetic resonance [DECMR]) with histology in three canines with subendocardial infarcts (arrows). Note that the infarcts are not evident on SPECT. Adapted with permission from Wagner A, Mahrholdt H, Holly TA, et al. Contrastenhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet 2003;361:3749. Cardiac Magnetic Resonance in 2 Patients Before and After Revascularization Figure 5 Delayedenhancement cardiac magnetic resonance (CMR) and cine images of two patients (C and D) before coronary revascularization and cine images 2 months after revascularization. Adapted with permission from Kim RJ, Shah DJ. Fundamental concepts in myocardial viability assessment revisited: when knowing how much is "alive" is not enough. Heart 2004;90:13740. Common Assumptions Intermediate Levels of Viability Viability testing is thought to be less helpful when intermediate levels of viability are measured (i.e., levels of viability that result in only approximately 50% of these regions recovering function after revascularization). This view is a result of a common assumption regarding functional recovery. First, it is important to distinguish between what would be desirable clinically from what can actually occur physiologically. While we may ask for an improved technique with better predictive value, perhaps in reality, we are asking for a different physiological relationship—an abrupt threshold of viability, below which there is virtually no chance for functional recovery, and above which nearly all have functional recovery. Figure 6, Panel A demonstrates that, with an abrupt threshold, the problem of predicting an intermediate likelihood for functional recovery is greatly minimized. Unfortunately, this physiological relationship may not exist. Second, it is essential to remember that functional recovery is a continuum (as is viability itself), and not simply a binary—yes or no—function. Thus, part of the problem with intermediate levels of viability is expecting that these regions will or will not have functional recovery in this binary fashion. Because it more closely reflects reality, it may be better to consider most regions with intermediate levels of viability as having a high chance for an intermediate amount of improvement rather than 50% likely to have complete recovery and the other 50% likely to have no improvement whatsoever. Complicating this issue is the belief that a threshold phenomenon exists between the transmural extent of infarction and systolic thickening. This assumption is based primarily on results by Lieberman et al,52 who demonstrated in a canine model of acute infarction that akinesia is expected if infarction involves ≥20% of the wall thickness. However, the animal model involved permanent coronary ligation and likely included effects from myocardial stunning and/or ongoing ischemia. Evaluation in humans with chronic infarction suggests that a threshold phenomenon does not exist.53,54 These data indicate that it is problematic to extrapolate the results of Lieberman's study, which did not consider the effects of stunning and/or ongoing ischemia, to humans following revascularization in whom substantial stunning, ischemia, or hibernation may no longer be present. The finding that two techniques can demonstrate a similar relationship between the amount of viability and the likelihood of functional recovery does not mean that the techniques have the same diagnostic capability. For example, both an accurate and a less accurate technique may show that, for a given intermediate level of viability, on average, 50% of segments recover function. However, part of the problem again is defining functional recovery as a binomial variable. Figure 6, Panel B demonstrates the utility of expressing functional recovery as a continuous variable (e.g., millimeters of improvement in systolic wall thickening). Although the overall relationship is the same, for any given level of viability, the better technique will provide a smaller variability (smaller error bars) in the absolute amount of functional improvement than the worse technique. Functional Recovery as the Standard of Truth The ideal reference standard for evaluating viability imaging techniques would be histopathological examination. However, for the vast majority of clinical studies, this is not feasible, and functional recovery following revascularization has become the de facto standard. This clinical endpoint makes sense for a variety of reasons. Because LV dysfunction portends poor prognosis, one would expect that functional recovery would be an important and beneficial clinical outcome of revascularization. Additionally, if a myocardial region recovers function, then one might confidently assume that the region has a substantial amount of viable myocytes. Indeed, this has been confirmed by histopathological examination. In 33 patients with LAD disease, Maes et al. took transmural needle biopsies from the LV anterior wall during CABG. The biopsies from regions that were dysfunctional prior to Figure 6 revascularization, but recovered afterwards, showed 89% ± 6% of the volume consisted of viable cells.8 Similarly, Dakik et al. reported that among 21 biopsied dyssynergic myocardial segments, the 11 which recovered function after CABG had 93% ± 4% viability by volume.9 However, a common misconception is that, if a region does not have functional improvement, then this region is nonviable. In fact, Maes8 and Dakik9 observed that biopsy specimens from regions that did not improve after revascularization still had 65% ± 25% and 69% ± 21% viability by volume, respectively. There are several reasons why regions that are predominantly viable may not recover function following revascularization. First, revascularization may often be incomplete in patients with extensive atherosclerosis.44 Therefore, there may be persistent areas of hibernating myocardium. Second, viable myocardium may be juxtaposed to regions with extensive scarring and unable to respond to revascularization because of tethering.45 Third, the use of a single evaluation of ventricular function soon after revascularization may lead to an underestimation of the true rate of functional recovery. Bax and colleagues evaluated functional recovery in 26 patients at 3 and 14 months following CABG.3 At 3 months, only 31% of hibernating segments recovered, whereas at 14 months, an additional 61% recovered. Even with these limitations, one could argue that functional recovery is an appropriate truth standard for viability because without recovery there may be no benefit to the patient for undergoing revascularization. On this point, the results by Samady et al. are instructive.55 Of the 104 consecutive patients who underwent pre and postCABG LVEF assessment, 68 patients had improvement in LVEF (>5% increase) and 36 patients had no significant change. Surprisingly, the two groups had similar postoperative improvement in angina and heart failure scores, and there was no difference in CV mortality, with a mean followup period of 32 months. The authors concluded that a lack of improvement in LVEF after CABG is not associated with poorer outcome, and speculated that many patients without improvement in LVEF may nonetheless have substantial viable myocardium that can respond to effective revascularization with beneficial effects on prognosis. Thus, functional recovery is a flawed truth standard for evaluating viability imaging techniques. The primary problem is that regions (or patients) without functional recovery may have substantial viability that may be important to detect clinically. This has implications for the published studies that have used functional recovery as the standard for evaluating tests of viability. Poor specificity (for functional recovery) should be considered less important than poor sensitivity, because for the former, a number of "false positives" (test showed viability but there was no functional recovery) may represent a problem with the truth standard rather than the technique. A future STICH substudy will address whether functional recovery can predict other clinically relevant endpoints such as death (E. Velazquez, personal communication, 2011). The decision for revascularization is dependent on several factors besides the amount of viability, including specifics regarding the coronary anatomy, the presence of angina or ischemia, and patient comorbidities. Additionally, viable myocardium can be in different states (i.e., normal, ischemic, hibernating, cardiomyopathic from a nonischemic process, etc.), and it is likely that differentiating between these states may be important for revascularization decisions in some patients. Assumptions in evaluating viability techniques Figure 6 Panel A: A technique that demonstrates a smooth linear relationship between viability and functional recovery may be considered limited in that intermediate levels of viability predict intermediate likelihood for functional recovery. With an abrupt threshold relationship between viability and functional recovery, the problem of predicting intermediate likelihood for functional recovery is greatly minimized. Panel B: Two techniques with different diagnostic capability may show a similar overall relationship between viability and functional improvement. However, if functional improvement is expressed as a continuous, rather than binomial, variable, the better technique may reduce the variability (smaller error bars) in predicting the absolute amount of functional improvement. Reproduced from Di Carli M and Kwong R (editors). Novel Techniques for Imaging the Heart: Cardiac MR and CT. 1st edition. West Sussex: Wiley Blackwell; 2008. Summary This module provided a review the pathophysiology of myocardial viability and description of its clinical importance. Methods to assess myocardial viability are varied and may only indirectly be related to whether myocytes are alive or dead. There are many assumptions regarding viability testing. Several arise, in part, from considering viability and/or functional recovery as a simple binary—yes or no—function, rather than as a continuum, which better reflects reality. Although an important clinical endpoint, functional recovery after revascularization is a flawed truth standard for evaluating viability techniques, because myocardium that does not recover may be predominantly viable rather than nonviable. Understanding the underlying assumptions in viability testing is important, as the results of the recent STICH trial highlight. In contrast to earlier, smaller studies, STICH found that common clinical methods such as DSE and SPECT have not identified patients with a differential survival benefit from CABG, as compared with medical therapy alone.16 Ultimately, the decision for revascularization still involves many factors besides the amount of viability (and nonviability). Key Points The term "myocardial stunning" describes the state of postischemic myocardial dysfunction in the presence of relatively normal blood flow. The term "myocardial hibernation" describes the state of chronic myocardial dysfunction at rest that can be partially or completely restored to normal either by improving blood flow and/or by reducing demand. Several noninvasive imaging methods are available that assess myocardial viability either indirectly (by measuring morphology or contractile reserve) or directly (by measuring metabolic activity or cell membrane integrity). In the STICH trial, the assessment of myocardial viability with DSE and/or SPECT did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone, in contrast with the prior literature. Understanding the underlying assumptions in current viability assessment methods is important. Suggested Reading 1. Bonow RO, Maurer G, Lee KL, et al, and the STICH Trial Investigators. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med 2011;364:161725. 2. Schinkel AF, Bax JJ, Delgado V, Poldermans D, Rahimtoola SH. Clinical relevance of hibernating myocardium in ischemic left ventricular dysfunction. Am J Med 2010;123:97886. 3. Partington SL, Kwong RY, Dorbala S. Multimodality imaging in the assessment of myocardial viability. Heart Fail Rev 2011;16:38195. References 1. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982;66:11469. 2. Kloner RA, Bolli R, Marban E, Reinlib L, Braunwald E. Medical and cellular implications of stunning, hibernation, and preconditioning: an NHLBI workshop. Circulation 1998;97:184867. 3. Bax JJ, Visser FC, Poldermans D, et al. Time course of functional recovery of stunned and hibernating segments after surgical revascularization. Circulation 2001;104(12 Suppl 1):I3148. 4. Rahimtoola SH. The hibernating myocardium. Am Heart J 1989;117:21121. 5. Rees G, Bristow JD, Kremkau EL, et al. Influence of aortocoronary bypass surgery on left ventricular performance. N Engl J Med 1971;284:111620. 6. Chatterjee K, Swan HJ, Parmley WW, Sustaita H, Marcus HS, Matloff J. Influence of direct myocardial revascularization on left ventricular asynergy and function in patients with coronary heart disease. With and without previous myocardial infarction. Circulation 1973;47:27686. 7. Alderman EL, Fisher LD, Litwin P, et al. Results of coronary artery surgery in patients with poor left ventricular function (CASS). Circulation 1983;68:78595. 8. Maes A, Flameng W, Nuyts J, et al. Histological alterations in chronically hypoperfused myocardium. Correlation with PET findings. Circulation 1994;90:73545. 9. Dakik HA, Howell JF, Lawrie GM, et al. Assessment of myocardial viability with 99mTcsestamibi tomography before coronary bypass graft surgery: correlation with histopathology and postoperative improvement in cardiac function. Circulation 1997;96:28928. 10. Wijns W, Vatner SF, Camici PG. Hibernating myocardium. N Engl J Med 1998;339:17381. 11. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e123210. 12. Bonow RO. Myocardial viability and prognosis in patients with ischemic left ventricular dysfunction. J Am Coll Cardiol 2002;39:115962. 13. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a metaanalysis. J Am Coll Cardiol 2002;39:11518. 14. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53:e1e90. 15. Velazquez EJ, Lee KL, Deja MA, et al. Coronaryartery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364:160716. 16. Bonow RO, Maurer G, Lee KL, et al, and the STICH Trial Investigators. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med 2011;364:161725. 17. Cwajg JM, Cwajg E, Nagueh SF, et al. Enddiastolic wall thickness as a predictor of recovery of function in myocardial hibernation: relation to restredistribution T1201 tomography and dobutamine stress echocardiography. J Am Coll Cardiol 2000;35:115261. 18. Baer FM, Theissen P, Schneider CA, et al. Dobutamine magnetic resonance imaging predicts contractile recovery of chronically dysfunctional myocardium after successful revascularization. J Am Coll Cardiol 1998;31:10408. 19. Haendchen RV, Corday E, Torres M, Maurer G, Fishbein MC, Meerbaum S. Increased regional enddiastolic wall thickness early after reperfusion: a sign of irreversibly damaged myocardium. J Am Coll Cardiol 1984;3:144453. 20. Bax JJ, Poldermans D, Elhendy A, Boersma E, Rahimtoola SH. Sensitivity, specificity, and predictive accuracies of various noninvasive techniques for detecting hibernating myocardium. Curr Probl Cardiol 2001;26:14786. 21. Gunning MG, Anagnostopoulos C, Knight CJ, et al. Comparison of 201Tl, 99mTctetrofosmin, and dobutamine magnetic resonance imaging for identifying hibernating myocardium. Circulation 1998;98:186974. 22. Sansoy V, Glover DK, Watson DD, et al. Comparison of thallium201 resting redistribution with technetium99m sestamibi uptake and functional response to dobutamine for assessment of myocardial viability. Circulation 1995;92:9941004. 23. Ambrosio G, Weisman HF, Mannisi JA, Becker LC. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation 1989;80:184661. 24. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992;85:1699705. 25. Judd RM, LugoOlivieri CH, Arai M, et al. Physiological basis of myocardial contrast enhancement in fast magnetic resonance images of 2dayold reperfused canine infarcts. Circulation 1995;92:190210. 26. Dilsizian V, Bonow RO. Current diagnostic techniques of assessing myocardial viability in patients with hibernating and stunned myocardium. Circulation 1993;87:120. 27. Brunken RC, Mody FV, Hawkins RA, Nienaber C, Phelps ME, Schelbert HR. Positron emission tomography detects metabolic viability in myocardium with persistent 24hour singlephoton emission computed tomography 201Tl defects. Circulation 1992;86:135769. 28. Polimeni PI. Extracellular space and ionic distribution in rat ventricle. Am J Physiol 1974;227:67683. 29. Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadoliniumDTPA complex: a potential NMR contrast agent. AJR Am J Roentgenol 1984;142:61924. 30. Shah DJ, Kim RJ. Magnetic resonance of myocardial viability. In: Edelman RR, ed. Clinical Magnetic Resonance Imaging. 3rd ed. New York: Elsevier; 2005. 31. Rehwald WG, Fieno DS, Chen EL, Kim RJ, Judd RM. Myocardial magnetic resonance imaging contrast agent concentrations after reversible and irreversible ischemic injury. Circulation 2002;105:2249. 32. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999;100:19922002. 33. Fieno DS, Kim RJ, Chen EL, Lomasney JW, Klocke FJ, Judd RM. Contrastenhanced magnetic resonance imaging of myocardium at risk: distinction between reversible and irreversible injury throughout infarct healing. J Am Coll Cardiol 2000;36:198591. 34. Choi KM, Kim RJ, Gubernikoff G, Vargas JD, Parker M, Judd RM. Transmural extent of acute myocardial infarction predicts longterm improvement in contractile function. Circulation 2001;104:11017. 35. Wu E, Judd RM, Vargas JD, Klocke FJ, Bonow RO, Kim RJ. Visualisation of presence, location, and transmural extent of healed Qwave and nonQwave myocardial infarction. Lancet 2001;357:218. 36. Kim RJ, Wu E, Rafael A, et al. The use of contrastenhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000;343:144553. 37. Schvartzman PR, Srichai MB, Grimm RA, et al. Nonstress delayedenhancement magnetic resonance imaging of the myocardium predicts improvement of function after revascularization for chronic ischemic heart disease with left ventricular dysfunction. Am Heart J 2003;146:53541. 38. Wellnhofer E, Olariu A, Klein C, et al. Magnetic resonance lowdose dobutamine test is superior to SCAR quantification for the prediction of functional recovery. Circulation 2004;109:21724. 39. Gerber BL, Belge B, Legros GJ, et al. Characterization of acute and chronic myocardial infarcts by multidetector computed tomography: comparison with contrastenhanced magnetic resonance. Circulation 2006;113:82333. 40. Lardo AC, Cordeiro MA, Silva C, et al. Contrastenhanced multidetector computed tomography viability imaging after myocardial infarction: characterization of myocyte death, microvascular obstruction, and chronic scar. Circulation 2006;113:394404. 41. Mahnken AH, Koos R, Katoh M, et al. Assessment of myocardial viability in reperfused acute myocardial infarction using 16slice computed tomography in comparison to magnetic resonance imaging. J Am Coll Cardiol 2005;45:20427. 42. Kim RJ, Shah DJ. Fundamental concepts in myocardial viability assessment revisited: when knowing how much is "alive" is not enough. Heart 2004;90:13740. 43. Selvanayagam JB, Kardos A, Francis JM, et al. Value of delayedenhancement cardiovascular magnetic resonance imaging in predicting myocardial viability after surgical revascularization. Circulation 2004;110:1535 41. 44. Ragosta M, Beller GA, Watson DD, Kaul S, Gimple LW. Quantitative planar restredistribution 201Tl imaging in detection of myocardial viability and prediction of improvement in left ventricular function after coronary bypass surgery in patients with severely depressed left ventricular function. Circulation 1993;87:163041. 45. Force T, Kemper A, Perkins L, Gilfoil M, Cohen C, Parisi AF. Overestimation of infarct size by quantitative two dimensional echocardiography: the role of tethering and of analytic procedures. Circulation 1986;73:13608. 46. Helak JW, Reichek N. Quantitation of human left ventricular mass and volume by twodimensional echocardiography: in vitro anatomic validation. Circulation 1981;63:1398407. 47. Wagner A, Mahrholdt H, Holly TA, et al. Contrastenhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet 2003;361:3749. 48. Klein C, Nekolla SG, Bengel FM, et al. Assessment of myocardial viability with contrastenhanced magnetic resonance imaging: comparison with positron emission tomography. Circulation 2002;105:1627. 49. Ibrahim T, Bulow HP, Hackl T, et al. Diagnostic value of contrastenhanced magnetic resonance imaging and singlephoton emission computed tomography for detection of myocardial necrosis early after acute myocardial infarction. J Am Coll Cardiol 2007;49:20816. 50. John AS, Dreyfus GD, Pennell DJ. Images in cardiovascular medicine. Reversible wall thinning in hibernation predicted by cardiovascular magnetic resonance. Circulation 2005;111:e245. 51. Shah DJ, Kim HW, Elliott M, et al. Contrast MRI predicts reverse remodeling and contractile improvement in akinetic thinned myocardium. Circulation 2003;108(17 Suppl):IV697. 52. Lieberman AN, Weiss JL, Jugdutt BI, et al. Twodimensional echocardiography and infarct size: relationship of regional wall motion and thickening to the extent of myocardial infarction in the dog. Circulation 1981;63:73946. 53. Mahrholdt H, Wagner A, Parker M, et al. Relationship of contractile function to transmural extent of infarction in patients with chronic coronary artery disease. J Am Coll Cardiol 2003;42:50512. 54. Nelson C, McCrohon J, Khafagi F, Rose S, Leano R, Marwick TH. Impact of scar thickness on the assessment of viability using dobutamine echocardiography and thallium singlephoton emission computed tomography: a comparison with contrastenhanced magnetic resonance imaging. J Am Coll Cardiol 2004;43:124856. 55. Samady H, Elefteriades JA, Abbott BG, Mattera JA, McPherson CA, Wackers FJ. Failure to improve left ventricular function after coronary revascularization for ischemic cardiomyopathy is not associated with worse outcome. Circulation 1999;100:1298304. Printable PDF This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item. 7.6: Microvascular Angina Author(s): Ashish Gupta, MD, PhD C. Noel Bairey Merz, MD, FACC Carl J. Pepine, MD, MACC Learner Objectives Upon completion of this module, the reader will be able to: 1. Review new data regarding the prevalence of microvascular coronary dysfunction. 2. Discuss emerging data regarding pathophysiological mechanisms of microvascular coronary dysfunction. 3. Evaluate diagnostic strategies for microvascular coronary dysfunction. Background and Prevalence of Microvascular Coronary Dysfunction The exact prevalence of microvascular coronary dysfunction as the basis for angina and other findings suggesting ischemic heart disease (IHD) is unknown. But it is estimated that over 9 million Americans have angina pectoris, which significantly impacts quality of life, ability to work, and costs to society.1 Among patients undergoing coronary angiography for evaluation of chest pain thought to represent angina pectoris, a significant proportion has angiographically "normal" epicardial vessels or insufficient obstructive disease to explain ischemia. The CASS (Coronary Artery Surgery Study) registry found that among 25,000 patients undergoing coronary angiography, 39% of females and 11% of men had what appeared to be "normal" epicardial arteries.2 The American College of Cardiology (ACC)National Cardiovascular Data Registry (NCDR) database of >375,886 patients found that "nonobstructive coronary artery disease (CAD)" was considerably more frequent than that reported from the CASS, and the frequency was significantly higher among women (51%) versus men (32%).3 The WISE (Women's Ischemia Syndrome Evaluation) prospective cohort found that 62% of females referred to angiography for angina had nonobstructive CAD,4 and approximately onehalf of these patients who had coronary flow measured had evidence of microvascular dysfunction (reduced flow reserve to adenosine). Among patients presenting with biomarker confirmed acute coronary syndrome in multiple clinical trials, women were found to have a higher prevalence of nonobstructive disease versus men (Figure 1).5 Angina, in general, also appears to be more prevalent in women than men, based on comparisons from 31 countries: 6.7% in women versus 5.6% in men.6 Historical Considerations, Definitions, and Nomenclature In their classical report on the relationship between clinical manifestations and pathologic findings, Blumgart and colleagues7 noted that uncomplicated angina pectoris was usually associated with occlusions of at least two of the main epicardial coronary arteries. With the introduction of coronary angiography, this concept was reinforced by multiple reports. Using this background in 1967, Likoff and colleagues8 first called attention to the "paradox of angina with unmistakable normal coronary angiograms" in a group of 15 women with ischemic electrocardiogram (ECG) abnormalities without diabetes or hypertension. They also suggested the possibility of microvascular abnormalities. Referring to a group of patients with normal coronary angiograms plus ECG and transmyocardial lactate evidence of myocardial ischemia reported by Arbogast and Bourassa, Kemp and colleagues coined the descriptor "syndrome X" in 1973.9,10 Cannon and colleagues11 introduced the term "microvascular angina" in 1983 after documenting evidence for microvascular dysfunction as an inappropriate coronary flow response to various stimuli, despite angiographically normal epicardial vessels. However, in subsequent studies they questioned the presence of ischemia when they could not detect left ventricular (LV) wall motion abnormalities by echocardiography. In 1991, Maseri and colleagues proposed that focal ischemia, in small regions scattered throughout the myocardium caused by prearteriolar dysfunction, could explain the absence of LV wall motion changes.12 Using cardiac magnetic resonance imaging, which provides superior resolution to evaluate perfusion, Panting, Pennell, and colleagues then documented a relative failure of subendocardial perfusion to increase with adenosine infusion in these patients that could also account for an absence of major changes in LV wall motion.13 More recently, Camici and Crea14 further refined the definition of coronary microvascular dysfunction as "a dysregulation of coronary blood flow, not attributable to obstructive CAD, that results from either structural or functional mechanisms in the coronary microvasculature." They also developed a clinical classification (Table 1), and summarized the possible pathogenetic mechanisms based on alterations observed and their possible causes (Table 2). Figure 1 Table 1 Table 2 Prevalence of “Normal” or Nonobstructive Coronary Arteries in Acute Coronary Syndrome Trials Reporting Results of “Early Angiography Figure 1 Reproduced with permission from Anderson RD, Pepine CJ. How to manage angina with normal coronary arteries (update). In: Fauci A, Braunwald E, Kasper D, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw Hill Professional; 2009. Clinical Classification of Coronary Microvascular Dysfunction Table 1 Adapted with permission from Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:83040. Pathogenetic Mechanisms of Coronary Microvascular Dysfunction Table 2 ACS = acute coronary syndrome. Adapted with permission from Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:83040. Clinical Findings Clinically, the syndrome of microvascular angina is characterized by predominantly effort or stressrelated chest symptoms (discomfort, dyspnea) that often are indistinguishable from symptoms attributable to angina pectoris associated obstructive CAD. While microvascular angina may occur in men, most patients with this syndrome are women. The exam is usually normal, as is the ECG, other than occasional minor STT wave alterations. These patients often have some ST segment depression and/or perfusion studies suggestive of myocardial ischemia during spontaneous or provoked angina that is not attributable to obstructive CAD. These abnormalities, however, are widely variable in their reproducibility on repeated testing, but this finding is also not unusual for many patients with obstructive CAD. Although testing for epicardial coronary artery spasm is important, because it can be specifically treated, the overwhelming majority of patients with microvascular angina have no evidence for spontaneous or provoked coronary artery spasm or cardiac (e.g., hypertrophic or dilated cardiomyopathy, transplant vasculopathy) or systemic (e.g., amyloidosis) diseases known to be associated with microvascular coronary dysfunction. The WISE cohort identified a high prevalence of atherosclerosis risk conditions (e.g., hypertension, diabetes, and obesity), and except in patients with left bundle branch block, LV systolic function is usually normal or may even be hyperdynamic. Nevertheless, while there is usually important functional disability, this syndrome was believed to be rarely associated with sudden death or myocardial infarction (MI), until the more recent WISE findings discussed in the next section. Pathophysiology Atherosclerosis Risk Factors Numerous small studies initially suggested that women with atherosclerosis risk factors were usually postmenopausal, while larger consecutive cohorts, including the WISE study, suggested that these women tend to be younger and frequently premenopausal compared with those with obstructive CAD.4 Traditional risk factors like hypertension, obesity, hypertriglyceridemia, and diabetes, as well as the Framingham risk score tend to underestimate the risk for adverse outcomes. Several conditions found only in females, including early menopause, gestational diabetes, peripartum vascular dissection, preeclampsia and eclampsia, polycystic ovarian syndrome, low birth weight children, and hypothalamic hypoestrogenemia, carry increased risk for CAD later in life,15 but it is unknown if such conditions portend microvascular angina before these women develop clinically manifest CAD. Data from the WISE study demonstrated that coronary microvascular dysfunction is present in at least 50% of women with chest pain in the absence of obstructive CAD and cannot be completely explained by risk factors for atherosclerosis, hormone levels, or inflammatory markers. The diagnosis of microvascular dysfunction should be considered in patients with chronic chest pain syndromes resembling angina, who do not have evidence of obstructive CAD. Women also suffer disproportionately from a variety of generalized vascular disorders that are known to be associated with CAD, as well as microvascular disease, including systemic lupus erythematosus (SLE), rheumatoid arthritis, migraine, Raynaud's phenomenon, and autoimmune arthritis. These observations support the influence of lifelong, varying reproductive hormone levels related to ovarian cycling, pregnancy, peripartum, and menopause that are likely to influence vascular function. The role that abnormal coronary reactivity plays in ischemia among women without obstructive CAD has been described, but the relative importance of endothelial and microvascular dysfunction has been insufficiently explored. An integrated working understanding of the cascade of mechanisms and manifestations of ischemia impacting IHD risk in women is reviewed in Figure 2.16 It has been proposed that microvascular coronary dysfunction leading to chronic stable angina (e.g., microvascular angina) is more prevalent in women than men as a result of risk factor clustering, vascular inflammation and remodeling, and hormonal alterations.1518 Abnormal coronary reactivity occurs in the setting of atherosclerosis risk factors and is usually associated with underlying atheroma vulnerable to clinical instability and more progressive disease states. It is for this reason that identifying nonobstructive atheroma may provide greater risk stratification in women. An overarching working model of this proposed female specific IHD pathophysiology is depicted in Figure 3.16 Although the relationship between microvascular dysfunction and epicardial atherosclerosis is not fully understood, a leading hypothesis is that it is a single disease process. This is based on observations from animal models documenting that most atherosclerosis risk conditions (e.g., increased lowdensity lipoprotein cholesterol [LDLC], glucose) injure the microvessels. The response to vascular wall injury may vary related to sex differences in vascular remodeling and vascular reactivity. Figure 2 Figure 3 Cascade of Mechanisms and Manifestations of Ischemia Having an Impact on Ischemic Heart Disease Risk in Women Figure 2 Adapted with permission from Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol 2009;54:156175. Overarching Model of Ischemic Heart Disease Pathophysiology in Women Figure 3 CAD = coronary artery disease; PCOS = polycystic ovarian syndrome. Adapted with permission from Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol 2009;54:156175. Regulation of the Microvascular Coronary Circulation Various regulatory mechanisms of the microvascular coronary circulation and experimental evidence supporting these mechanisms have been reviewed in detail by Patel and Fisher.19 The complex interplay of these regulatory pathways is outlined in Figure 4, and a brief synopsis of key regulatory mechanisms follows. Metabolic Factors Broadly speaking, coronary flow is linearly related to myocardial oxygen requirements. An increase in myocardial metabolism must be balanced by an increased supply of nutrients and oxygen from blood, otherwise ischemia results. The supply increase is primarily a result of microvascular endotheliummediated dilation via nitric oxide, adenosine, and adenosine triphosphate sensitive K+ channels. Myogenic Factors Maintenance of intraluminal pressure within fine limits in the microcirculation is necessary to ensure adequate transport of substances across the vascular lumen to the tissues. With elevated intraluminal pressure, there is a risk of tissue damage due to edema. In the medium sized arterioles, the main mechanism involved in regulation of the microvascular circulation is alteration of smooth muscle tone in response to changes in intraluminal pressure, and this is independent of endothelial function. These myogenic responses are reduced in the subendocardium compared with the subepicardium, which may also explain why the subendocardium is more prone to ischemic injury, particularly given the increased physical stresses in the subendocardium during the cardiac cycle. Endothelial Factors Three major mediators include nitric oxide, endothelialderived hyperpolarizing factor, and prostacyclin. Production and release of these mediators is triggered by shear stress detected at the endothelial cell surface receptor. In addition, endothelial cells are responsible for production of potent vasoconstrictors including thromboxane A2, some prostaglandins, angiotensin II, and endothelin 1. Maintenance of smooth muscle tone is dependent on a fine balance between endothelialderived vasoconstrictors and vasodilators. Other Factors Many other factors play a role in control of the microcirculation. These include the autonomic nervous system and extravascular physical forces of the beating heart. Subendocardial perfusion, in particular, is reduced by physical forces related to the contracting heart muscle, which explains why the subendocardium is most prone to ischemic injury. Figure 4 Mechanisms Responsible for Regulation of Myocardial Microvascular Resistance Figure 4 Factors involved in regulating tone of the microcirculation. Endothelialdependent regulation, mediated by release of mediators from endothelial cells in response to stimuli such as shear stress and platelet derived factors, is the dominant mechanism in larger arterioles. Myogenic regulation utilizes smooth muscle cell stretch receptors in activation of membrane bound ionic channels to respond to changes in intraluminal pressure and is dominant in medium sized microvessels. Metabolic factors (e.g., change in PCO2, pH, and adenosine) contribute to dilation in response to increasing metabolic activity, and this is most prominent in the smallest microvessels. In addition, neurally mediated factors and extravascular mechanical forces are involved in regulation of myocardial microvascular resistance. ACh = acetylcholine; EDHF = endothelialderived hyperpolarizing factor; K+ATP = adenosine triphosphate sensitive K+ channel; LVEDP = left ventricular enddiastolic pressure; NO = nitric oxide; PKC = protein kinase C; PLC = phospholipase C; RVEDP = right ventricular enddiastolic pressure. Adapted with permission from Patel B, Fisher M. Therapeutic advances in myocardial microvascular resistance: unraveling the enigma. Pharmacol Ther 2010;127:13147 Pathogenetic Mechanisms of Microvascular Coronary Dysfunction On the basis of the clinical settings in which it occurs, microvascular coronary dysfunction can be classified into four types: 1) dysfunction occurring in the absence of CAD and myocardial diseases, 2) dysfunction in the presence of myocardial diseases, 3) dysfunction in the presence of obstructive epicardial CAD, and 4) iatrogenic dysfunction. Various clinical scenarios have been reviewed by Camici and Crea,14 and are summarized in Table 2. Several pathophysiologic mechanisms including structural and functional aberrations of the coronary microvasculature, as well as the extravascular changes, may account for microvascular coronary dysfunction. Pathogenetic Mechanisms of Coronary Microvascular Dysfunction Table 2 ACS = acute coronary syndrome. Adapted with permission from Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:83040. Table 2 Assessment of Microvascular Function As a result of the small size of the coronary microcirculation and limited resolution of available imaging techniques, direct visualization and morphologic assessment of human coronary microvasculature in vivo is not possible with current techniques. Therefore, assessment is usually based on evaluating physiologic and functional properties.20 Both noninvasive and invasive methods are available (Table 3). In general, these techniques may be grouped into three categories: 1) techniques for assessment of inducible myocardial ischemia (e.g., magnetic resonance imaging [MRI] perfusion, position emission tomography [PET], singlephoton emission computed tomography [SPECT]), 2) myocardial perfusion abnormality, and 3) assessment of coronary flow response to maximal hyperaemia. Table 3 In the absence of obstructive CAD, inducible myocardial ischemia or myocardial perfusion defect or impaired coronary flow reserve (CFR) may be used as indicators of coronary microvascular dysfunction. The ability to quantify microvascular blood flow in resting and stress states allows for the determination of CFR, the ratio of maximal hyperemic to resting flow rates. Mild variations in a normal cutoff exist between different quantification methods, such that a CFR <2.0 and 2.5 is generally considered abnormal.21 CFR is typically decreased when measured in a vessel with epicardial stenosis, but in the absence of this, decreased CFR is representative of microvascular coronary dysfunction. Available Methods to Assess Coronary Microvascular Function Table 3 CFR = coronary flow reserve; CT = computed tomography; FFR = fractional flow reserve; IMR = index of microcirculatory resistance; MRI = magnetic resonance imaging; PET = position emission tomography; SPECT = singlephoton emission computed tomography; TIMI = Thrombolysis in Myocardial Infarction. Adapted with permission from Leung DY, Leung M. Noninvasive/invasive imaging: significance and assessment of coronary microvascular dysfunction. Heart 2011;97:58795. Management Considerations Chronic angina in a patient with microvascular coronary dysfunction is associated with diverse spectra of clinical disorders and involves multiple mechanisms with various clinical consequences. In approaching a patient with chronic angina, the following specific conditions need to be considered for appropriate management after obstructive CAD and coronary spasm have been excluded with reasonable certainty: Insulin resistance states (e.g., diabetes, metabolic syndrome). Associated myocardial disorders (e.g., primary cardiomyopathies [e.g., dilated and hypertrophic] and secondary cardiomyopathies [e.g., long standing hypertension, severe valvular disease]). Inflammatory/immune/connective tissue disorder (e.g., SLE, rheumatoid arthritis, progressive systemic sclerosis, giant cell arteritis). Known diseases of the myocardium (e.g., myocarditis). Early infiltrative heart disease (e.g., amyloidosis, hemochromatosis). If none of the preceding structural mechanisms for coronary microvasculature are likely, the patient should be considered to have a functional disorder to explain "microvascular angina" and other manifestations of myocardial ischemia. Although large outcome studies are needed, some treatments have been shown to be effective in small trials for reduction of symptoms and even improvement in microvascular coronary function. Therapeutic approaches to patients with chronic stable angina in patients with normal epicardial coronary arteries for the improvement of function, angina, and quality of life are outlined in Table 4.19,22 Whether these treatments modify the intermediate to longterm course or reduce the frequency of adverse outcomes is unknown at this time. Table 4 Therapeutic Approaches to Patients With Angina and Normal Coronary Arteries Table 4 ACE = angiotensinconverting enzyme; ARB = angiotensinreceptor blocker; CAD = coronary artery disease; EECP = enhanced external counterpulsation; VSMC = vascular smooth muscle cell. Key Points Chronic stable angina, even among patients with normal appearing coronary angiography, carries a significant burden in terms of morbidity and overall adverse outcome. Microvascular coronary dysfunction is an important prognostic factor in a wide range of diseases. Microvascular coronary dysfunction may be present in the absence of overt obstructive disease in conduit and epicardial arteries. Microvascular coronary dysfunction can be detected in the presence of vascular risk factors and may be reversible with lifestyle modification and treatment of risk factors. Microvascular coronary dysfunction may lead to myocardial ischemia, as seen in patients with microvascular angina. Assessment of coronary microcirculation depends on evaluation of its functional aspects. Both invasive and noninvasive methods are available to assess microvascular coronary function. Most available methods do not assess microvascular coronary function in isolation. They assess the total impact of both epicardial coronary disease and microvascular dysfunction on coronary flow or myocardial perfusion reserve. A CFR <2.5 is generally considered abnormal. Decreased CFR in the setting of normal epicardial vessels is representative of microvascular coronary dysfunction. Assessment of microvascular coronary function may allow early identification of at risk patients, monitoring of treatment, or open new therapeutic intervention. Management includes traditional antianginal drugs and novel therapies including potassium channel openers, metabolic agents, ρkinase inhibitors, angiotensinconverting enzyme inhibitors, late sodium channel modifiers, and statins. References and Suggested Reading References 1. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117:e25 146. 2. Davis KB, Chaitman B, Ryan T, Bittner V, Kennedy JW. Comparison of 15year survival for men and women after initial medical or surgical treatment for coronary artery disease: a CASS registry study. Coronary Artery Surgery Study. J Am Coll Cardiol 1995;25:10009. 3. Shaw LJ, Shaw RE, Merz CN, et al. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and inhospital mortality in the American College of CardiologyNational Cardiovascular Data Registry. Circulation 2008;117:1787801. 4. Shaw LJ, Merz CN, Pepine CJ, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of HealthNational Heart, Lung, and Blood Institutesponsored Women's Ischemia Syndrome Evaluation. Circulation 2006;114:894904. 5. Anderson RD, Pepine CJ. How to manage angina with normal coronary arteries (update). In: Fauci A, Braunwald E, Kasper D, et al. Harrison's Principles of Internal Medicine. 17th ed. New York: McGrawHill Professional; 2009. 6. Hemingway H, Langenberg C, Damant J, Frost C, Pyörälä K, BarrettConnor E. Prevalence of angina in women versus men: a systematic review and metaanalysis of international variations across 31 countries. Circulation 2008;117:152636. 7. Blumgart HL, Schlesinger MJ, Davis D. Studies on the relation of the clinical manifestations of angina pectoris, coronary thrombosis, and myocardial infarction to the pathologic findings. With particular reference to the significance of the collateral circulation. Am Heart J 1940;19:190. 8. Likoff W, Segal BL, Kasparian H. Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med 1967;276:10636. 9. Arbogast R, Bourassa MG. Myocardial function during atrial pacing in patients with angina pectoris and normal arteriograms. Comparison with patients having significant coronary artery disease. Am J Cardiol 1973;32:25763. 10. Kemp HG Jr, Vokonas PS, Cohn PF, Gorlin R. The anginal syndrome with normal coronary arteriograms. Report of a six year experience. Am J Med 1973;54:73542. 11. Cannon RO 3rd, Watson RM, Rosing DR, Epstein SE. Angina caused by reduced coronary vasodilator reserve of the small coronary arteries. J Am Coll Cardiol 1983;1:135973. 12. Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coll Cardiol 1991;17:499506. 13. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med 2002;346:194853. 14. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:83040. 15. Pepine CJ, Kerensky RA, Lambert CR, et al. Some thoughts on the vasculopathy of women with ischemic heart disease. J Am Coll Cardiol 2006;47(3 Suppl):S305. 16. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol 2009;54:156175. 17. Robinson JG, Wallace R, Limacher M, et al. Cardiovascular risk in women with nonspecific chest pain (from the Women's Health Initiative Hormone Trials) Am J Cardiol 2008;102:6939. 18. Gulati M, CooperDeHoff RM, McClure C, et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med 2009;169:84350. 19. Patel B, Fisher M. Therapeutic advances in myocardial microvascular resistance: unraveling the enigma. Pharmacol Ther 2010;127:13147. 20. Leung DY, Leung M. Noninvasive/invasive imaging: significance and assessment of coronary microvascular dysfunction. Heart 2011;97:58795. 21. Kern MJ, de Bruyne B, Pijls NH. From research to clinical practice: current role of intracoronary physiologically based decision making in the cardiac catheterization laboratory. J Am Coll Cardiol 1997;30:61320. 22. Beltrame JF, Crea F, Camici P. Advances in coronary microvascular dysfunction. Heart Lung Circ 2009;18:1927. Suggested Reading 1. Shimokawa H, Yasuda S. Myocardial ischemia: current concepts and future perspectives. J Cardiol 2008;52:67 78. 2. Camici PG. Is the chest pain in cardiac syndrome X due to subendocardial ischemia? Eur Heart J 2007;28:1539 40. 3. Pries AR, Habazettl H, Ambrosio G, et al. A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings. Cardiovasc Res 2008;80:16574. 4. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction. Circulation 2007;115:128595. 5. Pauly DF, Johnson BD, Anderson RD, et al. In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensinconverting enzyme inhibition is associated with improved microvascular function: a doubleblind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE). Am Heart J 2011;162:67884. 6. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2011;Sep 11:[Epub ahead of print]. Printable PDF This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item. 7.7: Asymptomatic Coronary Artery Disease Author(s): Michael S. Lauer, MD, FACC Learner Objectives Upon completion of this module, the reader will be able to: 1. Cite criteria for valid screening tests for chronic disease so that physicians can work with their patients to make informed decisions about whether to undergo testing. 2. Appraise the value of novel risk markers of asymptomatic disease, appreciating that statistical independence alone is inadequate evidence. 3. Describe assessments that should be undertaken in all asymptomatic adults, assessments that should not be undertaken in any asymptomatic adult, and assessments that might be reasonable in intermediaterisk asymptomatic adults. Introduction Perhaps no other type of medical technology better captures the public imagination than screening. “Catch it early,” the thinking goes, because by catching it early, one can “nip it in the bud,” literally stopping potentially deadly disease in its tracks before it even has a chance to strike. There is no question that screening for asymptomatic disease can, when properly applied, save lives. Largescale randomized trials have shown, for example, that screening can lower death rates related to certain cancers (e.g., breast, colon, and lung) and related to abdominal aortic aneurysm.1 However, in other cases, screening has not worked, and has instead led to probable harm, with many patients subject to unneeded and in some cases dangerous downstream tests and procedures.25 Coronary artery disease (CAD) potentially lends itself well to screening. It has long been known that there is an extended asymptomatic latent period, a period that can last for decades. One half of all major coronary events, including fatal events, come without warning. Despite improvements in medical therapy and prevention, there continues to be a high prevalence of atherosclerotic risk factors in the United States. The combination of new and potentially powerful screening tests, along with effective treatments for risk factors, gives credence to routine CAD screening among adults deemed to be at intermediate risk.6 Screening for Chronic Disease: General Considerations The United States Preventive Services Task Force (USPSTF) has listed four criteria for when screening is valuable (Table 1): two related to disease and two related to a candidate test.7 For a disease to be worthwhile screening, it must be common and serious, and it must have a prolonged asymptomatic phase; both of these criteria are clearly met for CAD. For a screening test to have value, it must have a low falsepositive rate, and its use must lead to improved clinical outcomes. When examining these two criteria, screening tests for CAD fall short. For example, even among adults who were enrolled in the MESA (MultiEthnic Study of Atherosclerosis) and who had high coronary calcium scores, well over 90% experienced no coronary events during a median 3.8 years of followup.8 To date, no randomized trials have definitively shown a link between use of a screening test and reduced risk of myocardial infarction (MI) or coronary death. Of note, none of the four USPSTF criteria mention prediction. The literature linking various noninvasive tests to clinical events is extensive, but it is important to keep in mind that prediction does not necessarily imply prevention. It is tempting to use observational data to show that patients who undergo screening tests have better clinical outcomes. However, it is important for clinicians to recognize serious biases that cloud interpretation of observational analyses, and to be able to explain them to their colleagues and patients, who may be overly influenced by aggressive directtoconsumer advertising.3 Three major biases in observational screening studies are9 : 1. Leadtime bias: Disease is detected at an earlier stage, but death (or a major clinical event) occurs whenever it was destined to occur, leading to an increase in apparent survival. 2. Lengthtime bias: Patients with indolent disease that occurs over a prolonged period without manifesting symptoms are more likely to be detected when undergoing a screening test, because aggressive disease strikes before the test is performed. Detecting less aggressive disease by screening tests leads to an apparent increase in survival in this group. 3. Overdiagnosis bias: This is related to lengthtime bias. “Disease” is detected by screening tests, but the “disease” never would have clinically manifested had it never been found. This is sometimes called “pseudodisease.” Sometimes disease regresses spontaneously; other times it progresses so slowly that another pathological process kills the patient first.10 Table 1 United States Preventive Services Task Force Criteria for a Valid Screening Test Table 1 Reproduced with permissino from U.S. Preventive Services Task Force. Guide to Clinical Preventive Services (2nd Edition): Report of the U.S. Preventive Services Task Force. McLean, VA: International Medical Publishing; 2009. Assessing the Value of Novel Prognostic Tests In the absence of randomized trials, most data on novel prognostic tests are based on cohort studies in which investigators have attempted to show that tests are “independently” predictive of risk after accounting for known predictors. Typically, investigators use regression models (e.g., Cox regression) and pronounce a test to be independently predictive if the “adjusted” pvalue is <0.05. An American Heart Association (AHA) Scientific Statement on evaluation of novel markers of cardiovascular risk describes more stringent criteria.11 These include the following: Statistical independence over and above existing data (e.g., age, gender, standard risk factors). Discrimination: The ability to distinguish between people who develop disease and those who do not. This is typically assessed by calculating a “c statistic,” or “cindex,” which is analogous to the area under a receiver operating characteristic (ROC) curve. A value of 1.0 implies perfect discrimination, whereas a value of 0.5 implies no discriminative ability any better than chance. Reclassification: The ability of a test to accurately reclassify people from one risk category to another. For example, if a person who ultimately develops disease is reclassified from intermediate to high risk, the test reclassifies correctly; conversely, if a person who ultimately develops disease is reclassified from high to intermediate risk, the test has yielded misleading information. Measures to assess reclassification include the “Net Reclassification Improvement.” Other important test characteristics to consider include: Accuracy and reproducibility: Does the test correctly measure what it claims to measure, and will it do so in a consistent manner? Costs: When a physician orders a test, he or she can cause the patient and society to incur a variety of costs, including those of the test itself as well as the costs of downstream tests, procedures, and complications. Test impact: Beyond costs and procedures, tests can lead to lifestyle changes and pharmacological interventions. These may be reasonable, but only if they lead to improved clinical outcomes. In the absence of randomized trials, one often cannot determine whether a test has a salutary impact.12 The preceding criteria and characteristics are summarized in Table 2. Table 2 Characteristics by Which Novel RiskStratification Tests Are Assessed Table 2 References: 1. Hlatky MA, Greenland P, Arnett DK, et al.; on behalf of the American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation 2009;119:240816. 2. Lord SJ, Irwig L, Simes RJ. When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need randomized trials? Ann Intern Med 2006;144:8505. Current Guidelines: General Approach and Recommendations on Specific Tests The American College of Cardiology Foundation and the AHA (ACCF/AHA) recently released guidelines on assessment of cardiovascular risk in asymptomatic adults.6 The guidelines recommend the following approach. First, clinicians should calculate a global risk score for all adults (Class IB). A variety of risk scores are available (Table 3); all use multiple traditional cardiovascular risk factors. The scores are useful for deriving a single quantitative estimate to classify subjects as being low risk (<10% risk/10 years), intermediate risk (1020%/10 years), or high risk (>20%/10 years) for experiencing major coronary events. To further modify risk, the guidelines recommend obtaining family history for premature atherothrombotic cardiovascular disease (Class IB). For subjects who are deemed to be at low or high risk, no further testing is needed. Second, clinicians can consider performing further tests in adults who, based on global risk scores and family history, are at intermediate risk (1020% 10year risk). Among the tests that clinicians might consider (Class IIA) in this intermediaterisk group are: Highsensitivity Creactive protein (hsCRP): In adults who meet the inclusion and exclusion criteria of the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial,13 (i.e., men ages >50 years; women ages >60 years; lowdensity lipoprotein cholesterol <130 mg/dl; not on lipidlowering, hormone replacement, or immunosuppressant therapy; without clinical coronary heart disease, diabetes, chronic kidney disease, severe inflammatory conditions, or contraindications to statins) to detect elevated levels. Urine analysis: In adults with hypertension or diabetes, to detect microalbuminuria. Resting electrocardiogram (ECG): In adults with hypertension or diabetes, to detect left ventricular hypertrophy, silent Q waves, intraventricular conduction delays, and STT abnormalities. Carotid intimamedia thickness: Published recommendations on required equipment, technical approach, and operator training and experience for performance of the test must be carefully followed to achieve highquality results. Anklebrachial index: Reasonable for asymptomatic adults. Coronary calcium: Reasonable for asymptomatic adults. The guidelines list a group of tests that may be reasonable (Class IIB). These include hsCRP in younger adults than those enrolled in the JUPITER trial, urine analysis in the absence of hypertension or diabetes, lipoproteinassociated phospholipase A2, resting ECGs in the absence of hypertension or diabetes, echocardiography in the absence of hypertension, exercise ECG (e.g., in sedentary adults considering starting a vigorous exercise program) with particular attention to nonECG markers such as exercise capacity, and stress myocardial perfusion imaging (MPI) in people with diabetes, a strong family history, and high coronary calcium score. Finally, the guidelines delineate tests that should NOT be done (Class III): genotypes, lipid measures beyond those provided by a standard profile, natriuretic peptide, arterial flow dilatation, arterial stiffness, stress echocardiography, stress MPI (except as noted earlier), computed tomography (CT) angiography, and magnetic resonance (MR) angiography. Table 3 Global Risk Scores Table 3 CHD = coronary heart disease; CVD = cardiovascular disease; HDL = highdensity lipoprotein; hsCRP = highsensitivity Creactive protein; LDL = lowdensity lipoprotein; MI = myocardial infarction. Reproduced with permission from: Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50103. Special Circumstances The ACCF/AHA guidelines address specific approaches to asymptomatic adults with diabetes and approaches to women.6 For people with diabetes, it is reasonable (Class IIA) to measure coronary calcium, while it may be considered (Class IIB) to obtain glycosylated hemoglobin and stress MPI. It is noteworthy that investigators have performed a randomized trial of MPI in diabetes and found that, although MPI abnormalities predicted coronary events, the use of MPI did not reduce risk.14 This trial, known as DIAD (Detection of Ischemia in Asymptomatic Diabetics), demonstrates the principle that prediction does not necessarily imply prevention. The guidelines recommend that a global risk score and family history be obtained in all asymptomatic women (Class IB for both). Unmet Needs It is noteworthy that the ACCF/AHA guidelines do not give any Class IA recommendation for clinicians assessing cardiovascular risk in asymptomatic adults. This is because it is not known whether any measurement or test (including global risk scores) improves outcomes. One might think that risk assessment and screening tests could lead to improved adherence and motivation to interventions that treat risk factors, but at least one randomized US Army trial of coronary artery calcium scoring was negative.15 Similarly, it is not known whether acquisition of global risk scores, family history, or findings from screening tests guide therapy or longterm monitoring in such a way as to improve health outcomes, mainly because randomized trials on this topic are few.12,16 The recently completed NLST (National Lung Screening Trial) serves as an example.17 Key Points It cannot be automatically assumed that diagnosing disease in an early, asymptomatic state prevents clinical disease or improves health. It cannot be automatically assumed that if a test predicts clinical events, its routine use will prevent events. Although a test may “independently” predict events by standard statistical criteria, it may fail to improve clinicians’ ability to discriminate patients who will develop disease from those who will not, and to properly reclassify patients’ risk. More importantly, although a test may predict events, it may not predict response to preventive interventions. All asymptomatic adults should be checked for global risk based on standard cardiovascular risk factors, and for family history of premature CAD. Physicians may refer intermediaterisk patients for a number of tests, but they should inform their patients that it is not known whether obtaining information from additional tests will lead to better health. These tests include hs CRP (for those meeting JUPITER criteria), urine analysis and resting ECG (in people with hypertension or diabetes), carotid intimamedia thickness, anklebrachial index, and coronary calcium scores. Randomized trials are needed to improve physicians’ ability to work with patients and make informed evidence based decisions about screening for CAD in asymptomatic adults. References 1. Ashton HA, Buxton MJ, Day NE, et al.; on behalf of the Multicentre Aneurysm Screening Study Group. The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial. Lancet 2002;360:15319. 2. Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet 2002;359:8814. 3. Lee TH, Brennan TA. Directtoconsumer marketing of hightechnology screening tests. N Engl J Med 2002;346:52931. 4. Lauer MS. Screening for coronary heart disease: has the time for universal imaging arrived? Cleve Clin J Med 2007;74:64550, 6534, 656 5. Andriole GL, Crawford ED, Grubb RL 3rd, et al.; on behalf of the PLCO Project Team. Mortality results from a randomized prostatecancer screening trial. N Engl J Med 2009;360:13109. 6. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50103. 7. U.S. Preventive Services Task Force. Guide to Clinical Preventive Services (2nd Edition): Report of the U.S. Preventive Services Task Force. McLean, VA: International Medical Publishing; 2009. 8. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358:133645. 9. Patz EF, Jr., Goodman PC, Bepler G. Screening for lung cancer. N Engl J Med 2000;343:162733. 10. Black WC, Czum JM. Screening coronary CT angiography: no time soon. J Am Coll Radiol 2007;4:2959. 11. Hlatky MA, Greenland P, Arnett DK, et al.; on behalf of the American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation 2009;119:240816. 12. Lord SJ, Irwig L, Simes RJ. When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need randomized trials? Ann Intern Med 2006;144:8505. 13. Ridker PM, Danielson E, Fonseca FA, et al.; on behalf of the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated Creactive protein. N Engl J Med 2008;359:2195207. 14. Young LH, Wackers FJ, Chyun DA, et al.; on behalf of the DIAD Investigators. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 2009;301:154755. 15. O'Malley PG, Feuerstein IM, Taylor AJ. Impact of electron beam tomography, with or without case management, on motivation, behavioral change, and cardiovascular risk profile: a randomized controlled trial. JAMA 2003;289:2215 23. 16. Bonow RO. Clinical practice. Should coronary calcium screening be used in cardiovascular prevention strategies? N Engl J Med 2009;361:9907. 17. The National Lung Screening Trial Research Team. Reduced lungcancer mortality with lowdose computed tomographic screening. N Engl J Med 2011;Jun 30:[Epub ahead of print]. Printable PDF This portion of the activity is not conducive to printing. Please visit the online version of this product to see this item. Chapter 7 Exam Visit the online version of the product to see the correct answer and commentary. 1. A paper in a medical journal reports on a new diagnostic screening test that is a “statistically significant independent predictor” of major cardiovascular events in asymptomatic adults, even after accounting for standard risk factors. The authors argue that clinicians should use the test. Which of the following is the most important reason why the authors’ argument is not valid? A. Failure to account for discrimination. B. Failure to account for impact on outcome. C. Failure to account for reclassification. D. Failure to account for calibration. 2. Which of the following statements is TRUE regarding the treatment of multivessel CAD? A. Routine revascularization in patients with ischemic cardiomyopathy and LV ejection fraction below 35% improves survival. B. Percutaneous revascularization guided by FFR is associated with similar numbers of stents per procedure but improved outcomes at 2 years compared with revascularization guided by angiography. C. Patients with diabetes and multivessel CAD have improved survival with CABG compared with PCI using baremetal stents; mortality data comparing surgery with drugeluting stents in patients with diabetes are inconclusive. D. A patient with severe stenoses in the proximal LAD artery and proximal right coronary artery should be treated with maximal medical therapy and referred for revascularization only for relief of anginal symptoms. 3. In which of the following situations is revascularization associated with improved survival? A. Chronic occlusion of a large dominant circumflex artery; intermediate risk on noninvasive testing; class II angina. B. Severe stenoses of the midLAD and proximal circumflex arteries; intermediate risk on noninvasive testing; asymptomatic on metoprolol. C. Chronic occlusion of a dominant right coronary artery; severe stenosis of the midcircumflex; class II angina on maximal medical therapy. D. 80% stenoses of the proximal LAD and proximal circumflex arteries; normal ventricular function; class I angina. 4. Which of the following tests is LEAST likely to provide any incremental prognostic information in patients with established SIHD? A. Echocardiography. B. Cardiac MRI. C. NTproBNP or BNP. D. Computed tomography calcium score. 5. When evaluating patients with SIHD and categorizing them into an appropriate risk group, which of the following are the corresponding 1year mortality rates for low, intermediate, or high risk? A. <5% (low), 58% (intermediate), >8% (high). B. <1% (low), 13% (intermediate), >3% (high). C. <3% (low), 34% (intermediate), >5% (high). D. <10% (low), 1020% (intermediate), >20% (high). 6. Which of the following statements is TRUE regarding revascularization? A. Compared with stenting, CABG for isolated proximal LAD disease is associated with improved 1year survival. B. In patients with multivessel CAD, 1year mortality rates are similar following PCI with drugeluting stents compared with CABG. C. In patients with multivessel CAD, 1year repeat revascularization rates are similar following PCI with drugeluting stents compared with CABG. D. In the SYNTAX study, patients with significant LMCA disease had similar 1 year rates of survival and repeat revascularization after PCI compared with CABG. 7. A 45yearold man with diabetes is evaluated for chronic Canadian Cardiovascular Society class III angina despite treatment with aspirin, metoprolol, ranolazine, and atorvastatin. On cardiac catheterization, his ventricular function is normal, and he has focal 90% stenoses in his midLAD coronary artery, midright coronary artery, and a large first obtuse marginal branch. Which of the following statements is TRUE regarding this patient’s treatment? A. Continued medical therapy with addition of a longacting nitrate is indicated, given his normal LV function. B. Multivessel PCI with drugeluting stents is associated with an increased risk of mortality at 1 year compared with CABG, regardless of his SYNTAX score. C. In patients with diabetes, multivessel PCI with drugeluting stents is associated with an increased risk of repeat revascularization at 1 year compared with CABG. D. The patient should be further evaluated with myocardial perfusion imaging and undergo revascularization if moderate or highrisk findings are demonstrated. 8. A 64yearold man with angiographic documentation of CAD amenable to surgical revascularization and a LVEF of 30% is being evaluated in the clinic for routine followup. His most recent MI was 6 months ago. He does not have left main or aortic valve disease and has never had cardiogenic shock. You are considering whether or not a viability study will help you to determine if this patient will benefit from surgical revascularization. Which of the following statements is TRUE regarding the prognostic value of a viability study in this patient? A. Viability assessment by SPECT and/or DSE will identify patients with a greater likelihood of survival, independent of other baseline prognostic variables. B. Viability assessment by SPECT is superior to DSE in identifying patients with a differential survival benefit from CABG. C. Viability assessment by SPECT and/or DSE will identify patients with a differential survival benefit from CABG. D. Viability assessment by DSE is superior to SPECT in identifying patients with a differential survival benefit from CABG. E. Viability assessment by SPECT and/or DSE will not identify patients with a differential survival benefit from CABG. 9. A 62yearold woman presents to your office complaining of chest discomfort, which has been increasing in frequency over the past 2 years. At first she noticed the discomfort with extreme exertion, while running with her grandchildren. The discomfort began in her substernal region and radiated to her back and left shoulder, and resolved with rest. She attributed these symptoms to getting old and being out of shape. About 9 months ago, she noticed that these episodes were occurring about once a week and now were precipitated by either physical activity (walking up or down the stairs, doing household chores with her arms) or emotional stress related to her job as a teacher of autistic children. Although these episodes continue to resolve with rest, she is concerned about whether she should retire. She has a 50 packyear smoking history and quit 2 years ago when these episodes first started. She admits to poor dietary habits, history of hypertension, and infrequent migraine both diagnosed in her late 40s and currently treated with enalapril 10 mg daily and hydrochlorothiazide 12.5 mg daily. She has dyslipidemia treated with lovastatin 20 mg daily for 2 years with total cholesterol of 215 mg/dl, lowdensity lipoprotein (LDL) of 125 mg/dl, highdensity lipoprotein of 32 mg/dl, and triglycerides of 178 mg/dl. She does not have diabetes. She has never seen a cardiologist and has never had an ECG or any other cardiovascular testing. Her father died of a fatal myocardial infarction at the age of 62, and her mother died of lung cancer at the age of 58. Her older brother has had coronary artery bypass grafting, and her younger sister has dyslipidemia and diabetes. Other than being overweight (5 feet 3 inches, 174 lbs) with a blood pressure today of 162/89 mm Hg, her exam is unremarkable. Her cardiologist determines that she has stable angina, and that her blood pressure and LDL need better control. Before addressing her retirement question and per ACC/American Heart Association (AHA) guidelines, the cardiologist discusses the need for additional noninvasive cardiac risk stratification. Her resting ECG was normal, and enalapril was increased to 20 mg, hydrochlorothiazide to 25 mg daily, and lovastin to 40 mg daily. After a lengthy discussion, the patient was not interested in taking a longacting nitrate, fearing that it would provoke her migraine. Likewise, she did not want to take a betablocker or calcium antagonist because she had experienced fatigue and edema when she had been prescribed these agents over the previous years for hypertension. The patient returns to the office nurse for blood pressure checks over the next 3 weeks. Then an exercise stress test was done using the Bruce protocol with Duke treadmill scoring. Her stress test results are as follows: Resting heart rate: 80 bpm; resting blood pressure 128/78 mm Hg. Time on treadmill: 9 minutes and 30 seconds without chest discomfort. Peak heart rate: 142 bpm; peak blood pressure 185/92 mm Hg. At peak exercise, she exhibits a 1.5 mm horizontal to downsloping ST depression in inferior leads, consistent with ischemia with fairly high workload. She did not have any symptoms. An immediate postexercise echocardiogram reveals an ejection fraction of 65% and no wall motion abnormalities. Her STsegment depression resolved completely in 1 minute. Which of the following is NOT a primary goal of therapy for patients with chronic stable angina? A. Reduce coronary perfusion pressure. B. Increase quality of life by reducing ischemia and preventing symptoms. C. Increase quantity of life by disease modification and prevention of myocardial infarction and death. Please visit the online version to engage in this Exam. 1. The correct answer is B. For a screening test to be of value, its use must lead to an improvement in clinical outcome. 2. The correct answer is C. In a large metaanalysis of studies comparing coronary artery bypass surgery with multivessel PCI, lower mortality was observed in patients with diabetes who were treated with surgery.1 These studies were conducted before the advent of drugeluting stents. The SYNTAX study compared multivessel PCI with drugeluting stents to surgery.2 In SYNTAX, although there was no difference in mortality in the diabetic subgroup, the patients treated with PCI had increased rates of repeat revascularization at followup. The STICH trial compared routine revascularization to optimal medical therapy in patients with ischemic cardiomyopathy and severe LV dysfunction (defined as a LV ejection fraction below 35%).3 In STICH, overall mortality was no different between the two groups, although secondary endpoints were improved in the surgical arm. The followup in STICH will be extended to examine the effect of revascularization on longterm mortality. In the FAME study, the use of FFR in guiding percutaneous revascularization in patients with multivessel CAD resulted in lower rates of stent use and improved outcomes at 2 years.4 Patients with multivessel CAD including severe disease of the proximal LAD artery should be considered for revascularization to improve survival. This recommendation is based on the CASS study.5 References 1. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomized trials. Lancet 1990;373;11907. 2. Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3 vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxeleluting stents. J Am Coll Cardiol 2010;55:106775. 3. Velazquez EJ, Lee KL, Deja MA, et al. Coronary artery bypass surgery in patients with left ventricular dysfunction. N Eng J Med 2011;364:160716. 4. Pijls NH, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2year followup of the FAME study. J Am Coll Cardiol 2010;56:17784. 5. Alderman EL, Bourassa MG, Cohen LS, et al. Tenyear followup of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation 1990;82:162946. 3. The correct answer is D. Data on the mortality benefit of revascularization in patients with multivessel CAD is primarily from the studies from three decades ago comparing CABG with medical therapy. In the CASS study,1 a mortality benefit was observed with revascularization in patients with the following conditions: Left main coronary artery stenosis or left main equivalent disease Threevessel CAD, particularly with a reduced LV ejection fraction (≤40%) Twovessel CAD including >75% stenosis in the proximal LAD There is no evidence that survival is improved in patients with singlevessel CAD not involving the proximal LAD. Patients with mildtomoderate angina from multivessel CAD not involving the proximal LAD may derive symptomatic relief from revascularization, but there is no evidence that survival is improved. References 1. Alderman EL, Bourassa MG, Cohen LS et al. Tenyear followup of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation 1990;82:162946. 4. The correct answer is D. Assessment of LV function is critical in the evaluation of patients with SIHD, and thus, echocardiography provides important information regarding prognosis. Cardiac MRI is also a reasonable test in patients with SIHD. In addition to providing quantifiable data regarding LV function, it may offer insight into myocardial viability, which may help guide therapy. NTproBNP or BNP have been shown to identify patients at greater risk of death and heart failure among patients with SIHD, and therefore, do add incremental prognostic information. Calcium scoring, as assessed with CT, has no role in the management of patients with SIHD, as these patients are known to have atherosclerosis and the degree of calcification does not correlate with the degree of stenosis. References 1. Douglas PS, Garcia MJ, Haines DE, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 Appropriate use criteria for echocardiography. a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance Endorsed by the American College of Chest Physicians. J Am Coll Cardiol 2011;57:112666. 2. Omland T, Sabatine MS, Jablonski KA, et al, and the PEACE Investigators. Prognostic value of BType natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 2007;50:20514. 3. Taylor AJ, Cerqueira M, Hodgson JM, et al. ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography. A report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2010;56:186494. 5. The correct answer is B. While the risk categories in SIHD are not as well validated and accepted as in primary prevention, in SIHD, low risk is considered a 1year mortality rate of <1%, intermediate risk is considered a 1year mortality rate of 13%, and high risk is considered a 1 year mortality rate of >3%. In primary prevention, the rates are much lower, with a 10year risk of death and MI of <10% (or <1% per year) in lowrisk patients, 1020% in intermediaterisk patients, and >20% in highrisk patients. References 1. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable anginasummary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 2003;41:15968. 6. The correct answer is B. The SYNTAX study was the first randomized trial to compare treatment with PCI using drugeluting stents with CABG in patients with multivessel CAD. Overall rates of mortality at 12 months were similar in the two groups, whereas repeat revascularization procedures were increased in patients treated with PCI. In SYNTAX, the 40% of patients with significant LMCA disease were stratified at randomization to PCI or CABG. In this group, mortality rates were similar, and repeat revascularization rates were increased following PCI. In a large metaanalysis, CABG and PCI for proximal LAD disease resulted in similar rates of stroke, myocardial infarction, and 5year survival; CABG was associated with more relief of angina and lower rates of repeat revascularization, whereas PCI was associated with shorter hospital stays and less need for blood transfusion. References 1. Serruys PW, Morice MC, Kappetein AP, et al., on behalf of the SYNTAX Investigators. Percutaneous coronary intervention versus coronaryartery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:96172. 2. Kapoor JR, Gienger AL, Ardehali R, et al. Isolated disease of the proximal left anterior descending artery: comparing the effectiveness of percutaneous coronary interventions and coronary artery bypass surgery. JACC Cardiovasc Interv 2008;1:48391. 7. The correct answer is C. The SYNTAX study was the first randomized trial to compare treatment with PCI using drugeluting stents versus CABG in patients with multivessel CAD. In SYNTAX, patients with diabetes were stratified at randomization to PCI or CABG. In this group, mortality rates were similar, whereas repeat revascularization rates were increased following multivessel PCI. However, in the subset of patients with diabetes with SYNTAX scores of ≥33, mortality was significantly higher following PCI than with CABG (13.5% vs. 4.1%). Revascularization is indicated in this patient, given his severe anginal symptoms despite medical therapy in the presence of significant CAD. References 1. Banning AP, Westaby S, Morice MC, et al. Diabetic and nondiabetic patients with left main and/or 3 vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxeleluting stents. J Am Coll Cardiol 2010;55:106775. 2. Serruys PW, Morice MC, Kappetein AP, et al., on behalf of the SYNTAX Investigators. Percutaneous coronary intervention versus coronaryartery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:96172. 3. Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness Criteria for Coronary Revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology. Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2009;53:53053. 8. The correct answer is E. Option C is incorrect because SPECT and DSE will NOT identify patients with a differential survival benefit from CABG, based on the STICH viability trial results. Options B and D are incorrect because there is no significant difference between DSE and SPECT in terms of lack of identifying patients with a differential survival benefit from CABG, based on the STICH viability trial results. Option A is incorrect because viability status is not significantly associated with the rate of death after adjustment for other significant baseline variables such as LVEF, enddiastolic volume, and endsystolic volume index.1 References 1. Bonow RO, Maurer G, Lee KL, et al, and the STICH Trial Investigators. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med 2011;364:161725. 9. The correct answer is A. There are two primary objectives in managing patients with chronic stable angina: 1) increase quantity of life by disease modification to prevent myocardial infarction and death, and 2) increase quality of life by reducing ischemia and preventing angina and related symptoms. See the 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina. Treating her high blood pressure to the 120130 mm Hg systolic and 6085 mm Hg diastolic level will not impair coronary perfusion, but will reduce myocardial oxygen demand to lessen the possibility of ischemia. References 1. Fraker TD Jr, Fihn SD; 2002 Chronic Stable Angina Writing Committee; American College of Cardiology; American Heart Association; Gibbons RJ, Abrams J, Chatterjee K, et al. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol 2007;50:226474.