Usefulness of oral dipyridamole suspension for stress thallium imaging without exercise in the detection of coronary artery disease

The American

Journal

of CARDlO UMBER

CORONARY HEART DISEASE

Usefulnessof Oral DipyridamoleSuspension for Stress ThalliumImagingWithout Exercise in the Dete tion of CoronaryArtery Disease SHlJbiICHI HOMMA, MD, RONALD J. CALLAHAN, PhD, BARBARA AMEER, PharmD, KENNETH A. McKUSICK, MD, H. WILLIAM STRAUSS, MD, ROBERT D. OKADA, MD, and CHARLES A. BOUCHER, MD

Stress thallium imaging with intravenous dipyridamole permits assessment of coronary artery disease (CAD). without the need for exercise. However, intravenous dipyridamole is available in the United States only on an experimental basis. To study the use of oral dipyridamole as a clinically available alternative to intravenous dipyridamole for this purpose,. 100 patients underwent thallium imaging with oral dipyridamole. Each patient received 300 mg of pulverized tablets in a 30-ml suspension; Maximal increase in mean heart rate and decrease in mean blood pressure occurred 30 minutes after ingestion. At 45 minutes, 2 mCi of thallium was given intravenously and serial imaging was begun within 7 minutes. The serum dipyridamole level (mean f standard deviation) 45 minutes after 300 mg was administered orally (3.7 f 2.2 pg/ml) was similar to that 5 minutes after 0.56 mg/kg was given intravenously (4.6 f 1.3 pg/ml). Fifty-five patients had some adverse effects between 15 and 75 minutes after oral ingestion, including nausea, headache,

dizziness, chest pain (25 patients) and electrocardiographic changes (14 patients). Intravenous aminophylline was used to resolve these adverse effects in 21 patients. There were no severe arrhythmias, myocardial infarctions or deaths. M the 43 patients with angiographically documented CAD, 39 had an initial perfusion defect that redistributed on the delayed images. When the results in patients who had undergone catheterization were analyzed by individual segment, the presence of thalllum redistribution was associated with normal or hypokinetic contrast left ventriculographic wall motion of that segment, whereas the presence of a persistent defect was associated with akinesia or dyskinesia (Fisher’s standardized Z = 9.14), In conclusion, stress thallium imaging without exercise is feasible with a clinically available form of dipyridamole-the oral suspension. It is safe and may be used for evaluation of CAD to unmask regions of hypoperfused viable myocardium. (Am J Cardiol 1966;57:503-508

From the Cardiac Unit and Division of Nuclear Medicine, Massachusetts General Hospital, Boston, Massachusetts. This study was supported in part by Grants HL 32953, HL 07416 and HL 07535 from the U.S. Public Health Service, National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received May 28, 1985; revised manuscript received July 22, 1985, accepted July 30,1985. Address for reprints: Charles A. Boucher, MD, Cardiac Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.

xercise testing with thallium imaging is widely used for the noninvasive evaluation of patients with suspetted coronary artery disease (CAD1.l Exercise stress testing unmasks CAD that may be compensated and not evident at rest. However, many patients referred for stress testing cannot exercise adequately for either physical or psychologic reasons, and as a result may have nondiagnostic or suboptimal test results. Intrave-

503

E

504

ORAL DIPYRIDAMOLE

THALLIUM

IMAGING

tar with additional aliquots of the sugar-free suspending solution and brought to a final volume of 30 ml. The suspension was consumed within 2 hours of preparation. Dipyridamole ingestion: On the day of the test the patients fasted, and medications containing methylxanthines were discontinued for 24 hours. An intravenous cannula was placed in an arm vein connected with an infusion of saline solution. At time 0, 30 ml containing 300 mg of the dipyridamole suspension was mixed in 150 ml of water and ingested. Patients then remained supine for the remainder of the study. This is in contrast to an earlier protocol with intravenous dipyridamole in which patients were tilted upright before thallium injection6 Because we occasionally observed severe postural hypotension during the upright phase, we no longer use an upright tilt with either intravenous or oral dipyridamole. Blood pressure, heart rate and a l&lead electrocardiogram were recorded at baseline and at 15-minute intervals during the first 45 minutes of the study. The electrocardiogram was continuously monitored by oscilloscope. If the subject had no chest pain, ST-segment depression or severe ventricular arrhythmia, 2 mCi of Methods thallium-201 was injected intravenously 45 minutes Patients: One hundred patients taken from 2 pa- after oral ingestion of dipyridamole. If a subject had tient groups underwent thallium imaging with oral di- chest pain or showed electrocardiographic changes pyridamole. Group 1 consisted of 53 patients (35 men, before 45 minutes after dipyridamole ingestion, blood 18 women, aged 60 f 10 years [mean f standard devi- pressure and heart rate were monitored every minute. ation]) referred for cardiac catheterization because of Thallium was injected when, in the opinion of the suspected severe CAD. The oral dipyridamole test was cardiologist supervising the test, dipyridamole was performed within 2 weeks of angiography for investi- producing myocardial ischemia (angina or ST-seggative purposes, Group 2 consisted of 47 patients (36 ment depression), and it would be unsafe to allow the men, 11 women, aged 65 f 8 years] referred for stress ischemia to continue to the 45-minute endpoint. In all thallium testing who could not exercise adequately patients with electrocardiographic changes, persistent because of peripheral vascular disease, orthopedic or chest pain or annoying side effects, 75 to 125 mg of arthritic disorders, neurologic deficits or poor condi- aminophylline were injected intravenously when the tioning; they underwent the test for diagnostic pur- imaging began (5 minutes after the thallium injection). poses when intravenous dipyridamole was unavailAll adverse effects were noted and compared with the able. Group 2 patients did not undergo cardiac frequency of those that occurred with intravenous dicatheterization, but were analyzed to increase the pyridamole in previous studies from our laboratory.6 number of patients available to determine the hemoSerum dipyridamole assay: In 10 randomly selectdynamic effects and safety of oral dipyridamole. Pa- ed patients from group 1, 5-ml samples of blood were tients considered to have CAD too severe to permit obtained immediately before thallium injection and exercise testing (those with congestive heart failure or centrifuged within 2 hours for analysis. Blood samples unstable angina, for example] were not included. were also obtained immediately before thallium injecDipyridamole suspension preparation: Dipyridation from 10 randomly selected patients not included mole is distributed in a tablet form. When given as in this study who had undergone intravenous dipytablets, dipyridamole is absorbed variably and results ridamole thallium imaging.* These patients had rein a wide individual variation in peak serum level and ceived a 0.14 mg/kg/min intravenous infusion of ditime required to reach this level.llJz Previous data pyridamole for 4 minutes, and thallium was injected 2 suggest a higher, earlier and more uniform peak serum minutes later.6 level achieved after ingestion of a suspension, with the Dipyridamole serum concentrations were quantipeak levels occurring between 20 and 40 minutes after fied by high-pressure liquid chromatography with uloral ingestion.13 Therefore, to optimize the uniformity traviolet light detection. For the assay, a l-ml serum of absorption, the dipyridamole was administered as a sample was used to which a constant amount of lidofreshly prepared oral suspension rather than in tablet Caine was added as an internal standard. In addition, 6 form. The suspension was prepared by the hospital samples of normal serum had varying known concenpharmacy from tablets on a unit-dose basis. Four 75mg tablets were pulverized in a mortar and pestle and * Intravenous dipyridamole was obtained from Boehringermixed with 5 to 10 ml of standard sugar-free suspend- Ingelheim Ltd., Ridgefield, Connecticut, under investigational ing base. Residual material was rinsed out of the mor- exemption for a new drug (IND) #19,728. nous dipyridamole in conjunction with thallium imaging is an effective alternative method of performing stress thallium imaging, which does not require that the patient exercise. 2-8Dipyridamole causes coronary vasodilation and maximizes regional differences in myocardial perfusion, which are then detected by thallium imaging. As with exercise thallium imaging, the presence of thallium redistribution on delayed images suggestsviable myocardium in a region of relative hypoperfusion.6 However, intravenous dipyridamole is not approved for routine clinical use in the United States and is available only on an experimental basis. Oral dipyridamole is available clinically and is widely used for its platelet inhibiting properties,gJO but it has seldom been used with thallium imaging.2s7The feasibility of oral dipyridamole thallium imaging has not been reported in a large population and no series has analyzed the ability of this method to demonstrate hypoperfusion of viable myocardium [redistribution) in patients with known CAD. This study determines the feasibility and safety of substituting oral for intravenous dipyridamole to perform stress thallium imaging without exercise.

March 1, 1986

nations of dipyridamole added, ranging from 0 to 15 iug/ml, which is the range of serum dipyridamole concentration anticipated. These were analyzed along with the patient samples for calibration purposes. The drug and its internal standard, lidocaine, were extracted from serum into ethyl acetate, which was evaporated to dryness and reconstituted with 0.1 ml of mobile phase. A 0.02-ml aliquot was injected onto an RCM100,10-p cyano reverse phase column eluted by a mobile phase consisting of 33% acetonitrile and 6% methanol in a 3.4-mM dibutylamine aqueous solution. Absorbance was detected at 254 nm, which generates separate peaks for dipyridamole and lidocaine. Peak height ratios of dipyridamole to lidocaine achieved after injection of patient samples were compared with those achieved after injection of serum samples containing known amounts of dipyridamole. The calibration curve between peak height ratios in the 6 samples of known dipyridamole concentration with the actual serum concentrations was linear (r = 0.99). Thallium myocardial image acquisition and analysis: Myocardial imaging was begun 5 minutes after the thallium injection and repeated in 3 to 4 hours. Images were recorded for 8 minutes each in the anterior, 45’ to 50’ and 70’ left anterior oblique views, as previously reported.6J4J5 The thallium-201 images were interpreted visually from a computer display by 3 independent observers unaware of clinical status or coronary anatomy.15 Computer quantification of thallium uptake and clearance was not used because normal values with dipyridamole thallium imaging have not been firmly established. The left ventricle in each view was separated into 3 segments (anterolateral, apical and inferior on the anterior view; septal, apical and posterior on the 45Oleft anterior oblique view; and anterior, apical and inferior on the 70’ left anterior oblique view). Each segment was judged as showing normal activity, complete redistribution, partial redistribution or persistent defect, as previously described.6J5 Catheterization data: The coronary angiograms were interpreted independently by 2 experienced observers without knowledge of the scan findings. Of the 53 group 1 patients, 43 had significant CAD, defined as at least 50% diameter narrowing of a major coronary artery. One patient had 4-vessel (includes left main), 14 had 3-vessel, 17 had 2-vessel, 11 had l-vessel and 10 had no CAD. If a significant stenosis was pressent, its maximal percent luminal diameter and location were recorded.. For the subsequent analysis anterior, anterolateral and septal thallium myocardial segments were considered to correspond to the territory of the left anterior descending artery, posterior segments to the circumflex artery, and inferior segments to the right coronary artery. The apical segments were not ascribed to any single artery. Contrast left ventriculograms were recorded in all patients in a 30~ right anterior oblique projection. Wall motion in the anterior, apical and inferior segments in this projection was qualitatively graded as normal, hypokinetic, akinetic or dyskinetic; differences of opinion concerning wall motion were resolved by consen-

THE AMERICAN

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SOS

Response to Oral Bipyridamole Minutes After Oral Ingestion

Heart rate Systolic BP Diastolic BP

0

15

30

45

68 f 15” 132 f 20* 76 f 11”

71 f 16” 127 f 20” 74 4 13”

75f 16 123 f 2l+ 72f 13

74f 15 127 f 21 72f 12

* p
sus.16Contrast left ventriculographic segmental wall motion in these segments was compared with thallium distribution in the same segments on the anterior and 70' left anterior oblique images. The presence of normal or hypokinetic wall motion was considered evidence of viable myocardium in that region. Statistical analysis: Hemodynamic changes were evaluated by multivariate analysis of variance with repeated measures. Comparisons between 2 groups of a single numeric variable were performed by t test. Frequency data were compared using chi-square analysis. To evaluate the correlation of the segmental thallium distribution and wall motion, Fisher’s Z test was used. Results are expressed as mean f standard deviation.

Results Heart rate and blood pressure response to oral dipyridamole suspension: Heart rate increased and systolic and diastolic blood pressure decreased from baseline 15, 30 and 45 minutes after dipyridamole ingestion (p
508

ORAL DIPYRIDAMOLE

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had chest pain during the protocol. Chest pain occurred 20 to 45 minutes after administration of oral Group ldipyridamole, occurring between 20 and 29 minutes in Catheterized 3 patients (20%), between 30 and 39 minutes in 7 paGroup 2Total CAD No CAD Not Catheterized tients (47%) and between 40 to 45 minutes in 5 patients (n=iOO) (n=43) (n=lO) (n = 47) (33%) The development and time of onset of chest pain was unrelated to the number of vessels with CAD. Any adverse effect 55 (55%) 25 (58%) 5 (50%) 25 (53 %) Eleven of the 15 patients received aminophylline. SevNon-cardiac Nausea 20 (20%) 4 (9%) 2 (20%) 14 (30%) en of the 15 patients with chest pain who underwent Headache 13 (13%) 4 (9%) 4(40%) 5 (11%) catheterization also had ST-segment depression and Dizziness 10 (10%) 6 (14%) 2 (20%) 2 (4%) all received aminophylline. Two other patients with Facial flash a (8%) 2 (5%) 2 (20%) 4 (9%) CAD (1 of whom also had ST-segment depression] had Vomiting 6 (6%) 1(2%) i(lO%) 4 (9%) no chest pain, but had more than 10 premature ventricCardiac Angina 25 (25%) 14(33%) 1 (10%) 10(21%) ular beats per minute; these 2 patients also received ST depression 14(14%) 8 (19%) 0 6 (13%) aminophylline and their arrhythmias resolved. Ventricular arrhythmia 2 (2%) 2(5%) 0 0 Serum dipyridamole concentration: The mean serum dipyridamole concentration after oral ingestion CAD = coronary artery disease. was 3.7 f 2.2 pg/ml in 10 patients (Fig. 1). Two of these patients had angina. Their levels, 2.5 and 4.7 pg/ml, were not different from those in the 8 patients without of pain in 24 of the 25 patients was 13 f 5 minutes from the onset to its complete resolution. In the 17 patients angina. The heart rate and blood pressure responses who received aminophylline, the chest pain and elec- were similar in the 5 patients with serum levels higher trocardiographic changes began to subside within 4 than 3 pg/ml compared with those in the 5 patients minutes after the injection and was resolved in 12 f 5 with serum levels lower than 3 pg/ml after oral dipyminutes. No patient had recurrence of pain that could ridamole was given. The serum concentration in 10 be attributed to dipyridamole ingestion, One patient other patients given intravenous dipyridamole was 4.6 who had not undergone catheterization had chest pain f 1.3 kg/ml. There was no significant difference bethat did not resolve after treatment with 200 mg of tween the mean serum concentration achieved after aminophylline and required morphine for relief. This oral vs intravenous dipyridamole. Nine of the 10 valpatient’s pain persisted for 2 hours and was atypical for myocardial ischemia. There was no myocardial infarction, severe arrhythmias or deaths from oral dipyridaINITIAL DELAYED mole treatment. In the 53 patients who had undergone catheterization, the occurrence of chest pain was compared with coronary angiographic findings. Fifteen patients (28%)

TABLE II

Adverse Effects of Oral Dipyridamole

ANT

10 .

* = Anglna

5O”LAO

01

‘70” LAO Ora I

Intravenous

FIGURE 1. lndlvidual serum dipyridamole level values after oral vs intravenous dipyridamole administration at the time of thallium injection in 10 randomly selected patients. Nine of 10 patients who received oral dipyridamole had levels higher than the P-standard deviation lower limit (2 pg/ml) seen in the patients who received intravenous dipyridamole. However, the range of serum levels with dipyridamole appeared to be wider with oral than with intravenous administration. There was no relation between the serum level and heart rate and blood pressure response or occurrence of adverse effects.

FIGURE 2. Example of serial thallium images afler oral dipyridamole was given to a patient. There is an extensive perfusion defect that Is most marked in the anterior (ANT) wall, septum and apex. These segments showed complete redistribution. Right ventricular redistribution is also present. This patient had an occluded left anterior descending and severely stenosed dominant right coronary artery with normal left ventricular contraction. LAO = left anterior oblique.

,%arch 1, 1986

ues achieved after the oral dosage were higher than 2.0 pg/ml, the 2 standard deviation lower limit achieved with intravenous dipyridamole. The 1 value below the 2.0 pg/ml serum level after oral ingestion (1.5 pg/ml) occurred in a patient whose thallium study subsequently demonstrated redistribution. Thallium imaging analysis: A representative scan in a patient with CAD is shown in Figure 2. The scans in all 100 patients were judged to be of good quality and comparable to those achieved in other patients who received intravenous dipyridamole. Among the 43 patients with CAD who had undergone catheterization, 42 had 1 or more thallium perfusion defects on the initial images. The patient with a false-negative result had 3-vessel CAD. Of 42 CAD patients with abnormal initial scans, 39 (91%) demonstrated redistribution, which was partial in 8, complete in 14, and partial and complete in different regions in 17. Eighty percent of redistributing segments were considered to be in a perfusion bed of a stenosed coronary artery. Figure 3 shows the relation between regional wall motion by contrast left ventriculography and the presence of thallium-201 redistribution on serial images in 318 segments in the 53 patients who underwent catheterization. A normal segment or a segment with complete redistribution was usually associated with normal wall motion. Partial redistribution was usually associated with normal or hypokinetic wall motion, whereas a persistent defect tended to be associated with akinesia or dyskinesia. Overall, the correlation of thallium distribution to wall motion was significant with a Fisher’s standardized Z value of 9.14. Eight of 10 patients (80%) with no significant CAD on angiography had a normal thallium scan.

Discussion This study demonstrates that dipyridamole thallium imaging can be performed with an oral suspension, a form that is clinically available. The serum concentration achieved after oral vs intravenous dipyridamole administrations were comparable, although there appeared to be a greater range of values after oral administration. Blood pressure decreases and heart rate increases were maximal at 30 minutes after oral ingestion of dipyridamole and these persisted for 45 minutes, most likely reflecting the achievement of adequate blood levels during the time interval. In a previously reported series of 60 patients from our laboratory, mean heart rate increased 10 beats/min and mean systolic blood pressure decreased 10 mm Hg with the patient in the supine position after intravenous dipyridamole.6 These changes were not significantly different from those with oral dipyridamole. In a series from another laboratory, the mean heart rate increase after intravenous dipyridamole appeared to be greater (15 beats/min) than ours, but the decrease in mean blood pressure was similar (5 mm Hg).l7 Fifty-five percent of our patients experienced some adverse effects, including headache, dizziness, nausea and chest pain. This number is comparable to the 43% previously reported for intravenous dipyridamole.”

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Although the difference did not reach statistical significance, nausea appeared to occur more frequently with oral than with intravenous dipyridamole (20% vs lo%, p = 0.09).6In most patients, the noncardiac adverse effects were mild and well tolerated. Only 4 patients required aminophylline for severe nausea or headache. However, in these 4 patients, the symptoms did not appear to resolve as promptly as did angina and ST-segment depression. Only 33% of the patients with documented CAD who had undergone catheterization had chest pain, When chest pain occurred, it developed 32 f 10 minutes after oral ingestion, and in no patient did the pain begin more than 45 minutes after oral ingestion, Intravenous aminophylline promptly eliminated the chest pain. Once aminophylline was given, there was no late recurrence of pain that could be attributed to myocardial ischemia secondary to dipyridamole ingestion. However, because aminophylline reverses the dipyridamole effect, we attempted to delay its administration until at least 5 minutes after the thallium injection, ST-segment depression was observed in 14% of all patients, which is similar to that which occurred in patients with intravenous dipyridamole.6 There were no severe ischemic episodes (i.e., ventricular tachycardia/fibrillation, myocardial infarction or death) as a result of oral dipyridamole administration. Dipyridamole thallium imaging seeks to unmask redistribution indicating hypoperfusion of viable myocardium. In this study, redistribution occurred in 91% of the patients with CAD. Of myocardial segments with partial or complete redistribution, 80% were in regions corresponding to significant stenoses on coronary angiography and 90% demonstrated normal or hypokinetic wall motion in the corresponding regions on left ventriculography. Th.us, as shown in previous studies, redistribution with oral dipyridamole thallium imaging signifies relative lhypoperfusion of viable myocardium.6 The presence and extent of thallium redistribution has been shown to be useful in predicting future cardiac events with exercise thallium imag-

I 0 &B

in = 203)

(n=53)

Normal Wall Mol~on Hypokinesis Akinws or Dvskinesis

In =24)

(n=381

FIGURE 3. Percentage of segments with normal, hypokinetic or akinetic/dyskinetic wall motion on the contrast left ventriculogram relative to thallium scan findings: normal, complete redistribution, partial redistribution or persistent defect are on the abscissa. In contrast to a persistent defect, a perfusion defect demonstrating redistribution was associated with viable myocardium, as assessed by the adequacy of rest left ventricular wall motion.

508

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lit6 et specificit& respective de la scintigraphie myocardique reolide apres and with intravenous dipyridamole thallium injection de 201 TI au tours de l’effort, apres injection de dipyridamole et au imaging.l7*20 Although not proved in our study, one repos: comparison chez 70 sujets coronarographies. Arch Ma1 Coeur 19m;74:147-155. would anticinate similar uroanostic value in the find5. Josephson MA, Brown BG, Hecht HS, Hopkins J. Pierce CD, Petersen RB. ing of redistribution with oral dipyridamole thallium Noninvasive detection and localization of coronary stenoses in patients: comimaging, as has been shown with other stress thallium parison of resting dipyridamole and exercise thallium-261 myocardial perfusion imaging. Am Heart J 2982;103:1008-1018. imaging procedures. 8. Leppo J, Boucher CA, Okada RD, Newell JB, Strauss WH, Pohost GM. The main limitation of oral dipyridamole thallium Serial thallium-301 myocardial imaging after dipyridamole infusion: diagnosimaging is that the oral form takes longer to produce tic utility in detecting coronary stenoses and relationship to regional wall coronary vasodilation than the intravenous form and motion. Circulation 1982;66:649-657. Wilde P, Walker P, Watt I, Rees JR, Davies ER. Thallium myocardial the dilation may persist for 30 to 60 minutes. As a 7. imaging: recent experience using a coronary vasodilator. Clin Radio1 1982; result, use of oral dipyridamole requires a longer peri- 33:43-50. Boucher CA, Okada RD. Thallium-201 myocardial perfusion imaging withod of physician supervision than the intravenous ap- 8. out exercise. Rest and dipyridamole studies. Chest 1984;86:159-161. proach. This may cause a patient undergoing oral 9. Schafer AI, Handin RI. The role of platelets in thrombotic and vascular dipyridamole thallium imaging to require more physi- disease. Prog Cardiovasc Dis 1979;22:31-52. Chesbro JH, Fuster V, Elveback LR, Clements IP, Smith IC, Holmes DR, cian and laboratory time than one undergoing an exer- 10. Bardsley WT. Effect of dipyridamole and aspirin on late vein-graft patency cise or intravenous dipyridamole thallium study. One after coronary bypass operations. N Engl J Med 1984;310:209-214. may consider injecting the thallium earlier [such as at 11. Bjornson TJJ, Mahony C. Clinical Pharmakokinetics of dipyridamole. Res [SuppI] 1983;IV:93-103. 30 minutes), but this point may not represent peak Thromb 12. Nielsen-Kudsk F, Pedersen AK. Pharmacokinetics of dipyridamole. Acta effect in all patients, as evidenced by 5 of the 15 group Pharmacol et Toxicol 1979;44:391-399. 12. Mellinger TJ, Bohorfoush JG. Blood levels of dipyridamole in humans. 1 patients who had angina between 40 and 45 minutes Arch Int Pharmacodyn 1966;163:471-480, after oral dipyridamole. Another limitation is that oral 14. Brown KA, Boucher CA, Okada RD, Strauss HW, Pohost GM. Quantification of pulmonary thallium-361 activity after upright exercise in normal subdipyridamole may affect thallium kinetics differently importance of peak heart rate and propranolol usagein defining normal from the shorter-acting intravenous form.21,22This sus- jects: v&es. Am J Cardiol 1984;53:1678-1682. tained effect may increase washout and alter the imag- 15. Okada RD. Boucher CA, Kirshenbaum HK, Kusbner FG, Strauss HW, ing findings, but we have not examined this issue. On Block PC, McKusick KA, Pohost GH. Improved diagnostic accuracy of thallium-201 stress test using multipIe observers and criteria derived from interobthe other hand, new myocardial perfusion imaging server analysis of variance. Am J Cardiol 1980;46:619-624. agents other than thallium, which do not distribute in 18. Okada RD. Kushner FG, Kirshenbaum HD, Strauss HW, Dinsmore RE, the myocardium or clear from the blood as rapidly as Newell JB, Boucher CA, Pohost GM. Observer variance in the qualitative evaluation of left ventricular wail motion and the quantitation of left ventricuthallium,23 may require an agent such as oral dipyridalar ejection fraction using rest and exercise multigated blood pool image. mole that produces a more prolonged “stress.” These CircuIation 1980;61:128-136.. 17. Leppo JA, O’Brien J, Rothendler JA. Getchell JD, Lee VW. Dipyridamole issues are subjects for future investigations. thallium 201 scintigraphy in the prediction of future cardiac events after acute ingl%lg

Acknowledgment: We acknowledge the technical assistance of Wendy Kowalker, Gerard Cotter, George Desko, Maureen McCarthy and William Shea, and the secretarial assistance of Janice Cahill. We also appreciate the support of Dupont/NEN Medical Products for this research study.

References 1. Beller GA, Watson DD, Gibson RS. Assessment of myocardial perfusion. In: Come PC, ed. Diagnostic Radiology. Philadelphia: J.B. Lippincott, 1985: 125-149. 2. Albro PC, Gould KL, Westcott RJ, Hamilton GW, Ritchie JL, Williams DL. Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic coronary vasodilatation. III. Clinical trial. Am J Cardiol 1978;42:751-760. 3. Narita M, Kurihara T, Usami M. Noninvasive detection of coronary artery disease by myocardial imaging with thallium-361: the significance of pharmacologic interventions. Jpn Circ J 1981;45:127-146. 4. Machecourt J, Denis B, Wolf JE, Comet M, Pellet J, Martin-Noel P. Sensibi-

myocardial infarction. N EngI J Med 1984;310:1014-1018. 18. Brown KA, Boucher CA, Okada RD, Guiney TE. Newell JB. Strauss HW, Pohost GM. Prognostic value of exercise thallium-261 imaging in patients presenting for evaluation of chest pain. JACC 1983;1:994-1001. 19. Gibson RS, Watson DD, Craddock GB, Crampton RS, Kaiser DL, Denny MJ, Beller GA. Prediction of cardiac events after uncomplicated myocardial infarction: a prospective study comparing predischarge exercise thallium-361 scintigraphy and coronary angiography. Circulation 1983;68:321-326. 20. Boucher CA, Brewster DC, Darling RC, Okada RD. Strauss HW, Pohost GM. Determination of cardiac risk before peripheral vascular surgery: use of dipyridamole thallium imaging to select patients for consideration of preoperative coronary angiography and myocardial revascularization. N EngI J Med 1985;312:389-394. 21. Okada RD, Leppo JA, Boucher CA, Pohost GM. Myocardial kinetics of thallium-261 after dipyridamole infusion in normal canine myocardium and in myocardium distal to a stenosis. J CIin Invest 1982;9:199-209. 22. Belier GA, Holzgrefe HH, Watson DD. Intrinsic washout rates of thalhum201 in normal and ischemic myocardium after dipyridamole-induced vasodiIation. CircuIation 1985;71:378-386. 23. Holman BL, Jones AG, Lister-James J, Davison A, Abrams MJ, Kirshenbaum JM, Tumeh SS, English RJ. A new Tc-QQm-labeled myocardial imaging agent, HexakisJt-ButyIisonitriJe]-Technetium(I)-99m TBI: Initial experience in the human. J NucJ Med 1984;25:1350-1355.