Diagnosis and risk stratification in coronary artery disease: Nuclear cardiology versus stress echocardiography

Diagnosis and risk stratification in coronary artery disease: Nuclear cardiology versus stress echocardiography Robert 0. Bonow, MD Both myocardial perfusion imaging and stress echocardiographic techniques have evolved tremendously during the past decade and now play a major role in the evaluation and management of patients with known or suspected coronary artery disease (CAD). Each method requires clinical experience and technical expertise, and each has potential advantages and disadvantages that, in a given institution or practice setting, may make one or the other perform more accurately, more efficiently, or more cost-effectively. Stress echocardiography offers a relatively cost-effective method for cardiac imaging, and this technique is often viewed as a lower-cost alternative to myocardial perfusion imaging. The available data reported in the literature indicate that stress echocardiography and myocardial perfusion imaging provide comparable results for the diagnosis of CAD. However, in many situations the presence or absence of CAD is less important than determining the extent and severity of disease and identifying patient subgroups at high risk and low risk. From this perspective, myocardial perfusion imaging provides greater sensitivity than stress echocardiography for detecting the presence and extent of ischemic, jeopardized myocardium and for identifying viable yet dysfunctional myocardium. This greater sensitivity translates into more reliable prognostic information than that provided by stress echocardiography. This ability to predict which patients are at risk of subsequent cardiac events, and which are at extremely low risk and can be followed safely without further evaluation, may reduce the long-term costs of treating CAD, even though the short-term costs of stress echocardiography may be lower. (J Nucl Cardiol 1997;4:S172-8.) Key Words: coronary artery disease - echocardiography + myocardial perfusion imaging sestamibi * thallium-201 For more than a decade and a half, exercise and pharmacologic stress myocardial perfusion imaging has been applied to the evaluation of patients with known or suspected coronary artery disease (CAD). The diagnostic utility of perfusion imaging with “‘Tl and, more recently, 99”Tc-labeled perfusion tracers is well established.‘-l3 In recent years, investigation has focused on the prognostic applications of these techniques in patients with known CAD and their ability to stratify patients into low-risk and high-risk subgroups. Nuclear cardiology methods also have profound implications regarding the identification of viable myocardium in patients with CAD and left ventricular (LV) dysftmcFrom the Division of Cardiology, Northwestern University Medical School, Chicago, Ill. Presented in part at the Forty-fourth Annual Scientific Sessions of the American College of Cardiology, Orlando, Fla., March 23, 1996. Reprint requests: Robert 0. Bonow, MD, Division of Cardiology, Northwestern University Medical School, 250 E. Superior St., Suite 524, Chicago, IL 60611. Copyright 0 1997 by American Society of Nuclear Cardiology. 1071-3581/97/$5.00 + 0 4310179773 S172

tion.14-19In such patients, accurate identification, leading to myocardial revascularization, results in significant improvement in LV function. Thus nuclear imaging methods have become firmly integrated into the management strategy of patients with known or suspected CAD. More recently, stress echocardiography has emerged as an alternative means of diagnostic imaging for the noninvasive detection and evaluation of CAD by investigating regional LV wall motion and systolic wall thickening under baseline conditions and during stress. This technique capitalizes on the demonstration of reversible regional LV dysfunction as a sensitive marker of inducible ischemia. A growing body of data indicates that exercise stress echocardiography may achieve diagnostic accuracies similar to those reported with nuclear cardiology methods. 20-29Stress echocardiography offers a relatively cost-effective method for cardiac imaging, and this technique is often viewed as a lower-cost alternative to myocardial perfusion imaging. As a result, stress echocardiography continues to grow and has competed successfully with myocardial perfusion imaging in a number of institutions and practice settings.

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of Echocarcliography

Echocardiography offers several advantages (Table 1). It is a versatile imaging tool for a variety of heart diseases. All cardiac structures are visualized with greater resolution than can be achieved with radiotracer imaging. A standard echocardiographic examination provides information regarding chamber size and function, myocardial wall thickness, and valvular anatomy and function, and Doppler techniques provide additional information regarding pressure gradients and blood flow. All structures are visualized and pump function is assessed. Thus echocardiography is an essential tool for the diagnosis and management of patients with valvular heart disease, congenital heart disease, cardiomyopathies, heart failure, and LV hypertrophy of any origin. It is also used frequently at rest to assess LV function in patients with CAD in addition to a stress myocardial perfusion study; this practice is becoming less possible in a managed-care environment, and practitioners have to choose a single test (or must use the test already chosen by the managed-care organization). Importantly, echocardiography is readily available to the cardiologist and is available in virtually all inpatient and outpatient cardiology facilities. Finally, as noted above, it is a relative low-cost imaging technology. Disadvantages

of Echocarcliography

There are also disadvantages of stress echocardiography that are worth noting. The principal disadvantage of stress echocardiography is the inability to image all of the LV myocardium in a large number of patients. In four studies involving a total of 418 patients, the echocardiography investigators determined that there was inadequate visualization of all myocardial segments in 37% of patients.30”3 In addition, stress echocardiography requires a highly skilled technologist, specialized equipment, and an experienced echocardiographer. Although the same can be argued for nuclear m.yocardial perfusion imaging, the point to be emphasized is that stress echocardiography requires a higher degree of expertise, training, equipment cost, and technical skill than does a standard resting echocardiographic examination. At the present time, stress echocardiography cannot evaluate myocardial perfusion adequately on a routine basis, although new generations of contrast agents and imaging methods are on the horizon that will soon compete with single-photon emission computed tomography (SPECT) for perfusion imaging. Echocarcliography

Versus Nuclear Cardiology

It is clear that both stress echocardiography and myocardial perfusion imaging are technically demanding

Nuclear

Table 1. Advantages of echocardiography

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and disadvantages

Advantages Versatile basic imaging

tool

for

a variety

of heart

diseases All cardiac

structures

visualized

Pump function assessed Often

obtained

at rest

in addition

to stress

nuclear

study

Available

in all inpatient

and

outpatient

carciiology

facilities

Relatively low cost Disadvantages Less

than

100%

success

Requires highly skilled Requires specialized Myocardial

perfusion

rate technician

equipment imaging

not

routinely

available

and require specialized equipment and staff and experienced physicians to achieve excellent results. For a given institution, the better imaging modality is the one that the institution performs more carefully, more accurately, and with greater quality control. Diagnosis of CAD. Assuming equal clinical and technical competence, the debate persists regarding which imaging modality-stress echocardiography or stress myocardial perfusion imaging-is more accurate and efficient for purposes of diagnosis and management of ,CAD. Only a few institutions perform (and interpret) stress echocardiography and nuclear myocardial perfusion with equal levels of skill and experience to report meaningful data, and only one large study comparing the two methods in the same patients has been reported from such an institution. Quinones et a1.2greported that exercise echocardiography and exercise thallium imaging (with exercise stress) provide essentially identical diagnostic information. This is supported by a recent review of the literature involving 11 studies and 808 patients by O’Keefe et a1.,34who reported an overall sensitivity and specificity of stress echocardiography of 78% and 86%, respectively, compared with 83% and 77%, respectively, for myocardial perfusion imaging. Thus the current data would suggest that, if the question is only the presence or absence of CAD, stress echocardiography and myocardial perfusion imaging provide roughly equivalent diagnostic capabilities. Risk Stratification. In the majority of clinical circumstances, the diagnostic issue to be resolved with cardiac stress imaging is not merely the presence or absence of CAD but additional information regarding extent of disease, severity of disease, and prognosis. In this regard, the two techniques are not equivalent, and

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myocardial perfusion imaging appears to have distinct advantages. First, it is generally accepted that stress echocardiography has difficulties in identifying ischemic myocardium within or adjacent to regions of infarcted myocardium and may thus miss patients with the greatest risk of subsequent ischemic events after acute myocardial infarction (MI). This limitation holds true in patients with chronic LV dysfunction, in whom it is often difficult to identify ischemia (i.e., worsening of a wall motion abnormality in a region with abnormal wall motion under basal conditions). It is this particular subgroup of patients, with LV dysfunction and superimposed ischemic, jeopardized myocardium, who are at greatest risk and who benefit the most from accurate detection of inducible ischemia. These two groups of patients, among the highest risk groups with CAD, are evaluated very well with myocardial perfusion imaging. Second, although a number of studies directly comparing stress perfusion imaging with stress echocardiography have reported that the overall diagnostic accuracies regarding the detection of patients with CAD are similar between the two techniques,26~2g~35-3g five of these studies, including the large comparative study of Quinones et a1.2g mentioned previously, also reported that perfusion imaging identifies more ischemic regions (i.e., a greater extent of jeopardized myocardium) than did stress echocardiography.26,2g,36*38,39These studies compared exercise echocardiography with exercise SPECT,26*2gdobutamine echocardiography with dobutamine SPECT,36 dobutamine echocardiography with,dipyridamole SPECT,38 and arbutamine echocardiography with arbutamine SPECT.39 As pointed out by O’Keefe et al 34the reduced sensitivity for the detection of ischemia b;’ stress echocardiography translates directly into more accurate identification of single-vessel CAD with SPECT compared with stress echocardiography (76% vs 67%), more accurate identification of patients with multivessel CAD (72% vs 50%), and more accurate localization of individual coronary artery stenoses (79% vs 65%). In addition, although the available data suggest that a positive stress echocardiographic study confers increased risk in a patient with CAD in a fashion similar to that of a positive nuclear cardiology test result,40-42 the reduced sensitivity for detecting ischemic myocardium with stress echocardiography translates into inaccurate assessment of subsequent ischemic events among those patients with apparently normal stress echocardiograms. It has been well demonstrated that the risk of death or MI after a normal stress myocardial perfusion study is less than 1% per year, based on more than 5500 patients studied with 201T143-45and more than 2000 patients studied with g9mTc-labeled sestamibi.46,47 Although the

Journal of Nuclear Cardiology March/April 1997, Part 2

patient numbers are smaller in the literature on stress echocardiography, it appears that the risk of death or MI is considerably higher in patients with a normal stress echocardiogram. In three recent studies,40,48,49the rate of death or MI during 1 year in patients with a negative stress echocardiogram was 2.5%. Thus a negative stress echocardiogram has a poorer negative predictive value than a negative nuclear test, and the reduced sensitivity in detecting jeopardized myocardium with stress echocardiography26,29,36,38,39 may result in the failure to detect some patients at risk of important cardiac events during the subsequent year. The reason for the reduced ability of stress echocardiography to detect ischemic myocardium compared with myocardial perfusion imaging may relate to the concept that regional perfusion defects occur earlier in the process of myocardial ischemia than do abnormalities of regional LV function. However, another reason for this reduced sensitivity is undoubtedly related to the technical difficulties, mentioned earlier, in the adequate imaging of substantial regions of LV myocardium in a large number of patients. Hoffmann et al.33 recently demonstrated that 55 (37%) of 150 patients had stress echocardiograms in which there was inadequate visualization of three or more of 16 myocardial segments for analysis of baseline or stress regional function, in keeping with three other studies in which the same average of inadequate studies (37%) has been reported.30-32 Hoffman et al. also reported an additional 35 patients (23% of the total) in whom studies were considered “adequate” but in whom there was inadequate visualization of two myocardial segments, which represents one eighth of the total LV myocardium. The inadequate visualization of substantial amounts of the left ventricle in a large number of patients could contribute importantly to the underestimation of ischemic myocardium. This concept is supported by recent data in which both transthoracic stress echocardiography and transesophageal stress echocardiography were performed during the same dobutamine infusion in 42 patients.32 With transthoracic imaging, 26% of all myocardial segments demonstrated ischemic changes with dobutamine, whereas 39% of myocardial segments demonstrated ischemic changes with the transesophageal approach. The one-third lower number of ischemic myocardial segments with transthoracic stress echocardiography compared with transesophageal stress echocardiography is similar to the lower number of ischemic segments reported for transthoracic stress echocardiography compared with stress myocardial perfusion imaging in the same patients.26,29,36,38,39 Ischemia will not be detected if the ischemic myocardium cannot be visualized satisfactorily. In contrast, the proportion of myocardial SPFCT perfusion images that is judged inadequate is much less

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than that reported for stress echocardiography. According to the multicenter tetrofosmin data comparing 201T1 with 99mTc-labeled tetrofosmin, inadequate studies occurred in less than 5% of patients with each tracer.5o Specificity of Stress-induced Regional Wall Motion Abnormalities. In addition to the lower sensitivity in detecting ischemic myocardium, it is conceivable that indexes of regional function (and relative changes in function with stress) by echocardiography will prove to be less specific for CAD than perfusion defects by nuclear imaging. In the last decade, the experience with radionuclide angiography has clearly shown that the functional response to exercise is influenced importantly by factors such as age, sex, blood pressure responses, and LV hypertrophy.’ These factors will undoubtedly affect the perceived diagnostic accuracy of echocardiography as it is employed more liberally in unselected patient populations.s1 Identifying Viable but Dysfunctional Myocarpiurn. Markers for viable myocardium in patients with CAD and LV dysfunction include intact metabolic activity (which can be assessed with positron emission tomographic imaging), cell membrane integrity (which can be assessed with SPECT imaging and thallium and possibly 99”Tc-based perfusion tracers), and inotropic reserve (which can be assessed with low-dose dobutamine echocardiography). Dobutamine stress echocardiography is now an accepted technique for assessing myocardial viability, with 15 studies involving a total of 405 patients s2-66demonstrating an average 83% positive predictive value and 81% negative predictive value for recovery of regional wall motion after myocardial revascularization.67 These predictive values are equivalent to those reported with positron emission tomographic techniques. 68,69Compared with thallium SPECT, dobutamine echocardiography has a higher specificity and positive predictive value but a lower sensitivity and negative predictive value.67 Thus similar to the detection of myocardial ischemia, thallium imaging detects viable myocardium with greater sensitivity than dobutamine echocardiography, yielding a greater negative predictive value. The lower sensitivity of dobutamine echocardiography in detecting viable myocardium may arise from the lack of inotropic reserve in some dysfunctional myocardial regions that are so delicately balanced between the reductions in flow and function, with exhausted coronary flow reserve, that any catecholamine stimulation to increase oxygen demands will merely result in ischemia. In addition, the cellular dedifferentiation at the ultrastructural level with dropout of myofibrillar units that occurs with the more chronic stages of hibernation in humans70-72 may

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result in reduced or absent responsiveness to catecholamine stimulation. The lower specificity of SPECT imaging compared with dobutamine echocardiography regarding recovery of regional wall motion may be interpreted as an indication that thallium imaging overestimates the potential for recovery of wall motion after revascularization. There may be regions in which viable myocardial cells retain thallium but are intermixed with fibrosis and will not improve in function after revascularization. The recruitment of contractile reserve by dobutamine may indicate which of these viable segments with thallium uptake has the potential for improved function after revascularization. This is certainly the case in myocardial regions in which thallium uptake is at the lower end of the viability range, such as thallium activities measuring 50% to 60% of the activity in normal zones, in which the likelihood of functional recovery may depend on whether the magnitude and distribution of viable cells are sufficient to maintain contractile responsiveness. The interpretation that thallium overestimates the likelihood of functional recovery may be countered by the argument that recovery of regional LV function after revascularization may not be the only, or even the most important, benefit of revascularization of viable but dysfunctional myocardium. Even in the absence of improved LV systolic function, revascularization of viable myocardium downstream from a critical coronary artery stenosis may attenuate LV dilation and remodeling, reduce the propensity to develop ventricular arrhythmias, and reduce the risk of subsequent fatal ischemic events. Thus the lower specificity of thallium imaging for predicting recovery of systolic function may be unimportant in the context of a broader view of the benefits of revascularization of viable but dysfunctional myocardium. It should also be noted that comparative studies have the potential for anatomic misalignment between the SPECT and echocardiographic studies, because the orientation of the heart is inherently different between the techniques. The standard used for functional recovery in most studies is the echocardiographic determination of improved wall motion, such that correct registration of myocardial segments between the dobutamine stress echocardiogram and the follow-up echocardiogram is virtually guaranteed. In contrast, substantial assumptions must be made regarding the location of perfusion abnormalities on SPECT imaging relative to echocardiographic landmarks. Thus the finding that a dobutamine echocardiogram predicts recovery of echocardiographic wall motion with greater accuracy than SPECT imaging is not totally unexpected.

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Table 2. Advantages perfusion imaging

vs stress echo

of myocardial

Advantages Optimal studies more frequent More accurate identification of jeopardized myocardium More accurate for prognosis (especially negative predictive value) Cost-effectiveness regarding clinical outcomes

Conclusion There are a number of advantages of stress myocardial perfusion imaging that should be considered in view of the preceding discussion (Table 2). Nuclear perfusion imaging results in a greater likelihood of optimal studies for assessment of myocardial ischemia and viability compared with dobutamine echocardiography. This results in greater accuracy in identifying the presence and extent of jeopardized myocardium. Hence perfusion imaging is more accurate for assessing prognosis and, in particular, has a greater negative predictive value in identifying low-risk subgroups of patients. This ability of perfusion imaging to predict which patients are at risk of subsequent cardiac events and which are at extremely low risk and can be followed safely without further evaluation may reduce the long-term costs of treating CAD, although the short-term costs of perfusion imaging may be higher than those of stress echocardiography. On the other hand, the majority of the available studies indicate that the overall diagnostic accuracy for the detection of CAD by stress echocardiography is similar to that achieved by nuclear stress testing. Dobutamine echocardiography is at least as accurate as SPECT methods for identifying viable myocardium in patients with LV dysfunction. Echocardiography is also both less expensive and more readily available to the referring cardiologist. With these latter considerations in mind, it is reasonable to anticipate that the use of stress echocardiography will continue to grow in the future. The continued viability of nuclear cardiology in the competitive environment of diagnostic imaging will require greater attention to combined assessment of myocardial perfusion and LV function, which can now be achieved with gated SPECT, greater emphasis on cost and costeffectiveness, and continued emphasis on convincing outcome data in patients with known or suspected CAD.

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