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AHCPR Health Technology Reviews. Rockville (MD): Agency for Health Care Policy and Research (US); 1992-1995.

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10Myocardial Perfusion Imaging with Rubidium 82 Positron Emission Tomography

, MD, PhD.

Published: May 1995.

Report

The noninvasive evaluation of patients with known or suspected coronary artery disease (CAD) has helped to identify patients who are at high risk for cardiac events. The information provided by the images of myocardial perfusion by radionuclides complements the anatomical information obtained by coronary arteriography by lending physiologic significance to the visualized coronary stenoses, especially the detection of ischemic myocardium with exercise. Positron emission tomography (PET) with rubidium 82 ((82)Rb) as the radionuclide has been used in some cardiac centers for the imaging of the heart and the detection of ischemic myocardium. Whether this method is superior to the more widely used planar thallium 201 ((201)Tl) scintigraphy or the imaging of (201)Tl distribution by single photon emission computed tomography (SPECT) for the evaluation of cardiac patients and the identification of high-risk patients is the subject of this review.

The noninvasive imaging of the perfusion of the heart was initially done about 20 years ago by planar (201)Tl scintigraphy.(1). By this technique, the distribution of the radiation from the intravenously administered (201)Tl in the myocardium was measured by external detectors and projected as a two-dimensional image of the heart that showed ischemic areas by a decrease or absence of (201)Tl in areas with compromised perfusion. Images obtained after exercise were invaluable in the assessment of the adequacy or inadequacy of the coronary circulation because they revealed ischemic areas that may develop with exertion. The difficulties of underestimating the extent of CAD caused by the unavoidable overlaying of parts of the heart in a two-dimensional projection and the relatively poor quality of the images were addressed to some degree by using a rotational detector and obtaining a three-dimensional image of the myocardial distribution of (201)Tl by the improved method of SPECT. The use of (82)Rb PET represents a further improvement in the three-dimensional imaging of the perfusion of the heart, mainly as the result of the higher energy and characteristic of the radiation that results from the annihilation of the positrons emitted by (82)Rb. The higher energy radiation yields images with higher resolution and more contrast than those obtained with (201)Tl. The directional character of the emitted radiation with (82)Rb allows for making adjustments for the attenuation of the radiation by tissues. The "less accurate" corrections for attenuation with (201)Tl SPECT have led to occasional difficulties in interpreting the images of obese patients, of those with large breasts, or of those having circulatory problems in the posterior-inferior regions of the heart.

Although it is apparent that (201)Tl SPECT imaging has advantages over planar (201)Tl scintigraphy for revealing areas of ischemic myocardium,(2). it is more difficult to determine whether (82)Rb PET is better than (201)Tl SPECT for the evaluation and management of patients with CAD. Data such as those reported in the only two studies where results of (82)Rb PET and (201)Tl SPECT were compared contribute to the uncertainty as to whether there are any real clinically beneficial differences between the two methods.(3,4). In the first study of 202 patients, Go et al(3). showed some difference in the sensitivities and no difference in the specificities, whereas in the second study of 81 patients, Stewart et al(4). showed no difference in the sensitivities but a significant difference in the specificities when the results with (82)Rb were compared with those with (201)Tl.

Go et al(3). reported a prospective comparison of (82)Rb PET and (201)Tl SPECT for myocardial perfusion imaging in 202 consecutive patients who were referred to their PET imaging laboratory. All patients had a coronary arteriogram done within 6 months of the imaging procedure. Approximately three-quarters of the patients were classified as having significant CAD (stenosis equal to or more than 50 percent), 95 (47 percent) had had a previous myocardial infarction (MI), and 70 (35 percent) had had a coronary bypass and/or angioplasty. Each patient had a resting (82)Rb image done and was then given a dose of dipyridamole to induce coronary vasodilation before starting the isometric hand-grip exercise. Stress (82)Rb image data were collected at the height of the exercise, after which, (201)Tl was administered and stress (201)Tl SPECT data were collected. A comparison of the images obtained from all 202 patients showed that the sensitivity and specificity for (82)Rb were 93 percent and 78 percent, respectively, whereas those for (201)Tl were 76 percent and 80 percent, respectively. These findings indicated that the sensitivity of (82)Rb was better than that of (201)Tl, but that the specificities of the two methods were nearly the same. Although 37 (18 percent) were false-negative by (201)Tl, 10 of these were also diagnosed as false-negative by (82)Rb. On the other hand, there were fewer false-positive results with (201)Tl (7 with (201)Tl and 11 with (82)Rb). Of interest was that a comparison of the imaging methods in the 132 patients who did not have either coronary bypass or angioplasty showed that the difference in sensitivities between the two methods was less significant whereas the specificities remained similar and unchanged. These observations that (201)Tl had a relatively high specificity that was similar to that with (82)Rb and had a lower sensitivity might be kept in mind as comparisons of the two methods are considered further.

Stewart et al(4). also compared results obtained with the two imaging techniques in 81 patients selected from those who were referred to their diagnostic coronary angiography center. Patients with prior coronary bypass or angioplasty were excluded. Sixty patients (74 percent) had significant CAD with stenosis equal to or more than 50 percent, and 34 of these patients had a history of MI. All patients underwent dipyridamole infusion in combination with PET imaging, whereas about half of the patients underwent exercise (201)Tl SPECT and the remaining half underwent dipyridamole (201)Tl SPECT. In contrast to the observations of Go et al,(3). these authors found that both (82)Rb and (201)Tl showed the same sensitivity of 84 percent, whereas the specificity with (201)Tl was significantly lower at 53 percent as compared with a specificity of 85 percent with (82)Rb. It is to be noted that some or all of the data for specificity were obtained from patients with a low likelihood of CAD who were selected from patients who were undergoing (201)Tl SPECT scan. Because it is unclear whether posttest bias may have occurred in the selection process and how the results with these patients were used in the determination of the specificity, the significance of the reported low specificity for (201)Tl is not apparent.

A possible clinical benefit of (82)Rb imaging for the management of cardiac patients was discussed in a followup study of the 27 patients(5). who were false-negative for myocardial perfusion abnormalities with (201)Tl imaging, but who were shown to be true positive with (82)Rb imaging in the study of Go et al.(3). MacIntyre et al (5). reported that 17 (63 percent) of these 27 patients went on to have surgical intervention, either coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA), over a period of 2 weeks to 2.5 years after the initial PET-positive imaging. Twelve (71 percent) of the 17 had had prior intervention or MI (5 had CABG, 3 had PTCA, 1 had both CABG and PTCA, and 3 had MI). Although the false-negative rate for (201)Tl SPECT reported by Go et al(3). may have been a little high, it would appear that the continued management of these CAD patients, with careful attention to physical symptoms and other noninvasive tests of cardiac function, may have led to the same appropriate care for these (201)Tl SPECT-negative patients, regardless of the PET results. Because the authors did not discuss the bases for the decisions to proceed with the surgical interventions in the 17 patients, it would be difficult, as the authors state, to determine "what actual weight the PET scan had on the final decision. "

The use of (82)Rb PET in a nonhospital-based center was retrospectively analyzed for 658 (39 percent) of the 1,670 patients who had both a PET scan and a coronary angiogram. Simone et al(6). reported that the sensitivity of 83 percent and the specificity of 91 percent that were found for (82)Rb PET in this setting were comparable to those reported in the above studies. These findings were not particularly surprising, because most of their patients had severe CAD according to prior angiograms and this selection bias could account for the high values in this population. It is, therefore, difficult to interpret the reported results in terms of how useful (82)Rb PET might be, compared with evaluations with (201)Tl scans, in the diagnostic workup and management of cardiac patients before invasive catheterization arteriography is used.

In a review of some studies on myocardial perfusion imaging, Go et al(7). began by stating that "thallium-201 imaging, originally viewed as a screening test, has evolved into a valuable noninvasive diagnostic imaging procedure for coronary artery disease (CAD) and plays a significant role in the management and prognosis of this disease." They cited sensitivities ranging from 76 to 95 percent and specificities ranging from 44 to 62 percent for the diagnosis of CAD with (201)Tl in seven referenced studies, and sensitivities of 94 to 98 percent and specificities of 93 to 100 percent for (82)Rb PET or nitrogen 13 ((13)N) ammonia PET in five referenced studies. They included more detailed discussions of the results from three studies(3,4,8). where (201)Tl SPECT was compared with either (13)N ammonia PET or (82)Rb PET. Those studies included the two discussed above and one by Tamaki et al,(8). who compared the results of (201)Tl SPECT with those of (13)N ammonia PET. Tamaki et al,(8). reported a sensitivity of 96 percent and a specificity of 100 percent for SPECT, which were virtually the same as those (98 percent and 100 percent) reported for PET. In view of these results and the large variations in the values reported in the referenced publications, it is not clear how Go et al(7). accounted for the variations and came to their conclusion that "one cannot deny that PET cardiac imaging is a more accurate test than Tl-201 SPECT for the diagnosis of CAD."

If the data presented by Go et al(7). were representative of the studies that had been done, (82)Rb PET would appear to be the method preferred over (201)Tl SPECT because of the very high specificities for (82)Rb PET and the consistently high sensitivities. However, it should be pointed out that four of the five studies cited by Go et al(7). for PET were done with (13)N ammonia and not (82)Rb. Whether the results with the two radionuclides are the same has not been adequately addressed. Therefore, if the comparison of (82)Rb PET and (201)Tl SPECT is made on the basis of the three studies where (82)Rb was used, the difference in results from the two methods may not be so convincing. This is more evident from the only two studies(3,(4). ) that directly compared the two methods. One study(4). showed that the specificity for (201)Tl SPECT was markedly lower than that for (82)Rb PET, whereas the other(3). reported nearly identical and respectable specificities for the two techniques (similar contradictory findings being reported for the sensitivities). Although (82)Rb PET may have a high sensitivity and a high specificity for diagnosing CAD, similar high values for (201)Tl SPECT have been reported in some studies, such as that by Tamaki et al,(8). which was discussed and dismissed in the review. Other studies,(9-15). besides those cited by Go et al,(7). illustrate that (201)Tl SPECT has yielded sensitivities and specificities that are as high as those reported for (82)Rb PET (Table 1). The sensitivities reported in these studies for (201)Tl SPECT varied from a low of 78 percent to a high of 95 percent, with the majority of the values (four of seven) in the upper end of the range. This range of values is similar to the range of 76 to 95 percent given by Go et al.(7). However, there is a difference in the range of specificities, which was 44 to 94 percent compared to 44 to 71 percent reported by Go et al.(7). It might be noted that, contrary to the many high values (all but one obtained with the use of (13)N ammonia PET) cited by Go et al(7). for PET, there were only two additional studies besides the two comparison studies discussed above that reported on the values obtained with (82)Rb PET. Grover-McKay et al(16). reported a sensitivity of 76 percent and a specificity of 86 percent for (82)Rb PET which are in contrast with the corresponding values of 95 percent and 100 percent reported by Gould et al.(17). The high values obtained by Gould et al(17). were for selected patients with severe CAD (coronary flow reserve of less than 3.0). A lower sensitivity of 31 percent was found for patients with less severe CAD (coronary flow reserve equal to or more that 3.0). The available data illustrate that there are equally wide ranges of values reported for the use of (82)Rb PET and (201)TI SPECT, which do not permit a meaningful comparison, except to conclude that the two methods of appear to yield similar results.

Table 1. Sensitivity and specificity for the diagnosis of coronary artery disease.

Table

Table 1. Sensitivity and specificity for the diagnosis of coronary artery disease.

The variations in values from study to study may reflect the effect of some factors that have recognized influences on the sensitivity and specificity of a diagnostic test, such as the prevalence of CAD, the patient selection criteria, and the severity of the CAD (degree of stenosis) in the study population. For instance, a comparison of the results obtained by Go et al(3). with those obtained by Steward et al(5). may illustrate the possible influences of patient selection and the effect of not using a uniform testing protocol for all patients. In the study by Go et al,(3). consecutive patients who came to the clinic were enrolled in the study and were all subjected to the same exercise procedure for PET and SPECT scanning. On the other hand, in the study by Steward et al,(4). patients were selected from those who came to their clinic but they were not subjected to the same exercise procedures for PET and SPECT scanning. Furthermore, Stewart et al(4). enrolled other "normal" individuals for specificity determinations by selecting individuals from a population who had had previous (201)TI SPECT scans, which may have contributed to the low specificity. Other reports, such as that by Mahmarian et al,(10). illustrate that the severity of the stenosis influences the sensitivity of the diagnostic test; sensitivity with (201)TI SPECT increased from 78 percent for stenoses of more than 50 percent to 89 percent for stenoses of more than 70 percent.

The higher pixel count possible with (82)Rb imaging and the truer correction for the attenuation of radiations emanating from the posterior-inferior myocardium or through "excess" tissue may be advantageous for the use of (82)Rb PET over (201)TI SPECT for the noninvasive imaging of the perfusion of the heart. However, appropriate data that demonstrate that (82)Rb PET may be a better diagnostic method than (201)TI SPECT for the detection of myocardial ischemia are not available at this time. As the imaging technology improves and physicians are presented with a clearer image of myocardial perfusion, consideration might be given to the role of noninvasive radionunclide imaging in the diagnosis and therapeutic management (medical treatment, catheterization, and/or revascularization) of cardiac patients and to the extent to which the CAD patients may benefit clinically from these improvements. The true value of cardiac perfusion imaging is the visualization of whether the coronary circulation is adequate to support the function of the heart at rest or with stress in areas that may or may not coincide with stenoses seen by arteriography, which is of major physiologic significance to the patient. Cardiologists have observed that some areas that are supplied by a stenotic coronary vessel may not shown any ischemia with exertion, whereas other areas without arteriographically visible stenosis may show ischemia. These discrepancies between stenosis and ischemia may be the bases for some of the "false-negative" or "false-positive" findings that were reported in studies using arteriography as the "gold standard" for CAD. How frequently this may occur is not known. However, the conservative management of CAD patients who show no sign of myocardial ischemia by radionuclide imaging may not have serios consequences.

Brown and Rowen(18). reported on such patients who had normal (201)TI scintigraphy scans in spite of having severe CAD visible by arteriography. The monitored the outcomes of 176 patients who had come to their clinic for the evaluation of chest pain and who were found to have normal exercise (201)TI scintigraphs for over 2 years. In the group, consisting of 75 patients with significant angiographic CAD (50 percent or more stenosis of at least one major coronary artery), there was one nonfatal MI recorded at 28 months for a cardiac event rate of 0.7 percent/year. In the comparison group, consisting of 101 patients with either angiographically normal coronary arteries or pre-(201)TI test probability of CAD of less than 5 percent on the basis of clinical and exercise electrocardiographic data, there were two cardiac events (one nonfatal MI at 28 months and one cardiac death at 23 months) for a cardiac event rate of 1.0 percent/year. The similarly low cardiac event rates for the two groups suggest that CAD patients with normal stress thallium scans are not at increased risk of having a cardiac event, as summarized in the statement by Brown and Rowen(18). that "even in the presence of angiographically significant CAD, patients with normal exercise thallium-201 studies have a benign prognosis with a very low rate of hard cardiac events" (nonfatal MI or cardiac death). It might be noted that the decision to monitor these patients was made on the basis of normal scans by planar (201)TI scintigraphy. These prognostic results and similar findings by many others, which were summarized in a review by Brown,(19). raise some questions as to whether (201)TI SPECT or (82)Rb PET would have altered the results. On the other hand, these observations suggest that appropriate care for cardiac patients may be available at centers using any of the coronary perfusion imaging methods. It is thus probable that, in the hands of properly experienced users, the use of any of the techniques will continue to provide the necessary information regarding cardiac perfusion for the appropriate management of cardiac patients, without any apparent compromise of the well-being of patients. In this context, the patients with negative (201)TI SPECT scans who were monitored by MacIntyre et al(5). may not have been at increased risk of having a cardiac event without surgical intervention.

The value of the noninvasive imaging of myocardial perfusion is high for the evaluation of patients who have chest pains and who may or may not have exertional angina and electrocardiographic changes with exercise. These methods have helped to identify some CAD patients who may need to be evaluated further by catheterization and arteriography for possible revascularization. As more correlative data are accumulated, it may be possible to use the various diagnostic tests to identify reliably those patients who may benefit from surgical intervention and those who could confidently be managed by medical therapy. Currently, there are insufficient data to accomplish this differentiation in all cases. As a result, questions have been raised regarding the appropriateness of some of the revascularizations.(20-23). Consistent with these questions are the findings of some large, multicenter studies(24-26). that showed that revascularization may not be needed by nor be survival benefit for all CAD patients. These studies provided data that indicated that CABG may have survival benefits for only those CAD patients who had severe stenosis (more than 70 percent) of the left main coronary artery or multiple-vessel CAD and had evidence of abnormal left ventricular function. Even these indications may need to be investigated further in view of a later, 10-year followup report of the coronary artery surgery study.(27). The data in that report suggest that, although the survival of patients with abnormal left ventricular function (ejection fraction less than 0.50) may have been better with initial surgical treatment, there was no difference in the cumulative survival between the medically treated and the surgically treated groups at 10 years, nor was there a difference in the percentage of patients who remained alive and free of nonfatal MI between the two groups. However, there are clinical benefits of revascularization, besides survival benefits, for patients who need relief from anginal pains and diminished capacity as the result of symptoms that do not respond to intensive medical therapy. Therefore, with the possible exception of patients with left main coronary artery or multiple vessel disease and diminished left ventricular function, the decision to proceed with revascularization may depend on the response of the patient to medical therapy.

If normal planar (201)Tl scintigraphy can identify most of those cardiac patients who are not at increased risk of having cardiac events, the better visualization of myocardial perfusion by (201)Tl SPECT and/or (82)Rb PET may be needed only for the further evaluation of those with positive or ambiguous images on planar (201)Tl scans. It is likely that there will always be some situations when a clearer and more precise image would be helpful for making decisions to proceed with appropriate diagnostic or management procedures. Currently, there are few data to suggest how prevalent this need might be among patients being seen at the cardiac centers. Keeping in mind that there is no argument against the use of adequate tests to ensure that the well-being of the patient is not jeopardized, it may be of interest to note the charges for the following diagnostic cardiac test: planar (201)Tl scintigraphy, $700 to $900; (201)Tl SPECT , $1,100 to $1,400; (82)Rb, PET, $1,100 to $2,800; echocardiography, $750 to $1,100; catheterization and angiography, $3,200 to $6,500. Wheather the use of a more expensive technology is necessary in particular situations might be considered when making management and therapeutic decisions as cardiac patients are evaluated.

In summary, the image of cardiac perfusion produced with (82)Rb PET is clearer than that with (201)Tl SPECT as the result of the higher pixel counts and corrections for the attenuation of the radiations. Whether these improved images lead to higher sensitivity and specificity for detecting myocardial ischemia, compared to those obtained with (201)Tl SPECT, is not apparent from the available data because the reported sensitivities and specificities with both methods vary over the same wide range which includes values that are acceptable and some that are not acceptable. It would appear that all three methods (planar (201)Tl scintigraphy, (201)Tl SPECT, and (82)Rb PET) may be used to evaluate myocardial perfusion noninvasively in most patients who are referred to a cardiac center. Patients with negative scans by any of the methods may not be at increased risk of having a cardiac event and might be conservatively managed as dictated by their clinical condition and symptoms.

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