Use of oral dipyridamole SPECT thallium-201 imaging in detection of coronary artery disease

PROGRESS IN CARDIOLOGY

Use of oral dipyridamole SPECT thallium-201 imaging in detection of coronary artery disease Sally G. Beer, MD, Jaekyeong Heo, MD, Barbara Kong, MD, Edward Lyons, CNMT, and Abdulmassih S. Iskandrian, MD. Philadelphia, Pa.

Dipyridamole thallium-201 imaging has been studied over the past several years for detection of coronary artery disease (CAD) in multiple clinical settings.r It has been shown to be a useful diagnostic tool in patients who cannot undergo exercise testing,2 as a predictor of subsequent cardiac events following myocardial infarction,3 for risk stratification prior to peripheral vascular surgery,4-6 and in assessment of residual coronary stenosis after angioplasty.7 The majority of these results were obtained by using intravenous dipyridamole, which is not yet commercially available. Oral dipyridamole is widely available, and has a lower incidence of and less severe side effects.8 This study summarizes our experience with oral dipyridamole single photon emission computed tomography (SPECT) with thallium-201 and examines the usefulness of the technique in the detection of CAD and in identifying high-risk patients with multivessel CAD. METHODOLOGY

From February 1987 to March 1989, 241 patients were referred for oral dipyridamole SPECT thallium imaging. Of these, 65 patients also had coronary angiography within 3 months. These patients were not candidates for exercise testing because of physical limitations such as arthritis, claudication, amputation, deconditioning, or neurologic problems. Significant CAD was defined as L 50% diameter narrowing in one or more of the major coronary arteries or their major branches. Coronary angiograms were interpreted without prior knowledge of scintigraphic results. None of the patients had associated significant valvular heart disease or congenital heart disease.

From the Philadelphia. Received Reprint byterian delphia,

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Heart June

Institute, 15, 1989;

requests: AS. Iskandrian. MD, Medical Center of Philadelphia, PA 19104.

Presbyterian accepted

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Philadelphia Heart 39th and Market

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Dipyrldamole imaging. Patients were studied in the supine position during the test, with elevation of the head to less than 45 degrees. The heart rate, blood pressure, and electrocardiogram were recorded at baseline. A maintenance intravenous line with normal saline was started in all patients. A physician was available during the study. Most patients were given an oral dipyridamole dose of 375 mg (five tablets each 75 mg); a few patients weighing less than 100 pounds were given 300 mg. The blood pressure, heart rate, and 12-lead ECG were recorded each 5 minutes for 45 minutes. At 45 minutes (or earlier if symptoms, electrocardiographic changes, or severe side effects occurred), the patients underwent a hand-grip exercise test and then 3.0 mCi of thallium-201 was injected intravenously during the exercise. SPECT images were obtained within 10 minutes and redistribution images were obtained 4 hours after the injection. Intravenous aminophylline (75 to 125 mg) was routinely infused after the initial scans were completed to prevent any side effects of dipyridamole. The ST segment shifts during the monitoring period were described as positive if there was 1 1 mm flat or downsloping ST depression at 80 msec after the J point or if there was L 1.5 mm upsloping depression. SPECT imaging. Images were obtained with a rotating gamma camera (400 AT Starcam; G.E. Medical Systems, Milwaukee, Wise.) in a 180-degree anterior arc extending from the 45-degree right anterior oblique to the 45-degree left posterior oblique projections, acquiring 32 images for 40 seconds each. All images were recorded on a magnetic hard disc system. One pixel thick transaxial tomograms were reconstructed using a conventional filtered back projection algorithm that used Ramp-Hanning filters with a cut-off frequency of 0.84 cycles/cm. The tomograms were aligned to the long axis of the heart and oblique angle tomograms parallel to the long and short axes of the left ventricle were generated from the original transaxial tomograms using a coordinate transformation with commercially available algorithms. Images were evaluated using both gray and color scale

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1. Normal dipyridamole thallium tomographic images.Transaxial tomogramsare realigned according to the long axis of the heart producing short-axis, vertical long-axis, and horizontal long-axis slices. Representative slicesfrom each axis show uniform tracer uptake. Fig. 2. Abnormal dipyridamole thallium tomographic images.Initial images(top panels) showextensive perfusion abnormalities involving the anterior wall, septum, and apex. Four-hour delayed images(bottom panels) demonstrate almost complete redistribution compatible with ischemiain the vascular territory of the left anterior descendingcoronary artery. Fig.

as sequential static images, simultaneously comparing immediate and redistribution images. Myocar-

dial segments

and corresponding

coronary

artery

distribution were defined in the short-axis plane. In this representation, the sector between 1:30 and 4:30

o’clock corresponds to the left circumflex distribution, the sector between 430 and 7:30 o’clock corresponds to the right coronary artery distribution, and the sector between 7:30 and 1:30 o’clock correspondsss to the left anterior descending artery distribution. Thallium images were evaluated for abnormalities in regional myocardial uptake. A normal

study was defined as the absence of any perfusion defect in the initial images. A perfusion defect in the initial image that showed complete or partial reperfusion at 4 hours was considered to represent ischemia, while a perfusion defect that remained unchanged in the delayed images was considered to represent scar (Figs. 1 and 2). Statistical analysis. Sensitivity = true positive/(true positive + false negative) X 100; Specificity = true negative/(true negative + false positive) X 100. True positive is a patient with CAD and abnormal images. True negative is a patient with no CAD and normal

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Table I. Pertinent demographics in patients without coronary artery disease by angiography No CAD (n = 17) Age (yr) Male/Female Past history: Diabetes mellitus

Hypertension MI Typical angina Atypical angina Drugs Nitrates $-blockers

Ca++-antagonists Rest electrocardiogram Q wave MI LVH LBBB ST-T wave changes Dipyridamole effect: ST-T depression Chest pain Increased lung thallium uptake

58 -t 12

with

and

CAD (n = 38)

NS NS

13 18 25 21 13

(27) (38) (52) (49) (27)

NS NS 0.04 NS 0.02

34 (21) 12 (25) 32 (62)

0.02 NS NS

6 (35) 1 (6) 0 (0) 9 (53)

23 (48)

NS

11 (23)

NS

2 (4) 25 (52)

NS NS

1 (6) 6 (35) 1 (6)

5 (10) 12 (25) 4 (8)

NS NS NS

5 8 4 5 10

(29) (47) (24) (29) (59)

7 (41) 4 (24) 11 (65)

CAD, Coronary artery disease; LBBB, ventricular hypertrophy; MI, myocardial Numbers inside parentheses represent

branch

block;

_. No CAD (n = 17)

CAD (n = 48)

P

Rest HR (beats/min) HR at peak effect Rest SBP (mm Hg)

73 i 13 89 L 17 133 t 20

75 + 16 82 t 13 128 * 17

NS NS NS

SBP at peak effect Rest DBP (mm Hg) DBP at peak effect

129

128

LVH,

+ 18

86 t 8 79 i

CAD, Coronary artery disease; DPB. rate: SBP, systolic blood pressure.

diastolic

OVD 1VD

MVD artery

NS

20

blood

pressure.

single photon

No. abnormal

Vessel disease by angiography

I

801 11 76 + 14

11

Table Ill. Results of thallium-201 computed tomography (SPECT)

OVD. NO coronary vessel disease. left bundle infarct. percentages.

data before and after oral dipy-

P

63 -t 10 31117

8/9

Table II. Hemodynamic ridamole

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vascular

NS NS HR.

emission

territories

0

1

2,3

11 5 2

5 4 13

1 9 21

disease;

IVD,

single-vessel

heart

disease:

MVD.

multi-

left

images. False positive is a patient with no CAD and abnormal images, and false negative is a patient with CAD and normal images. Data are presented as mean _+ standard deviation (SD) when appropriate. Chi square analysis and Student’s t test were used for comparisons. A probability (p) value of < 0.05 was considered statistically significant. OBSERVATIONS

Forty-eight patients (31 men and 17 women) had CAD by angiography. Of these patients, 36 (76%) had multivessel CAD and 12 (24% ) had one-vessel CAD. There were 10 patients with left main coronary artery disease. There were 17 patients without CAD by angiography (eight men and nine women). The pertinent demographic data are shown in Table I. Side effects. ECG changes consistent with ischemia after administration of dipyridamole were noted in one patient with no CAD and in five patients with CAD. Chest pain was reported in 18 patients-6 with no CAD and 12 with CAD (p = NS). There were no serious side effects such as death, acute myocardial infarction, severe angina pectoris, severe hypotension, or significant arrhythmia. On the other hand, headaches, flushes, and mild nausea were experienced by approximately 50% of the patients. Hemodynamic response. The heart rate increased

from 74 -t 15 beats/min at rest to 84 -I- 4 beats/min at peak effect (p = 0.001). The systolic blood pressure was 130 t- 18 and 128 -t 20 mm Hg, respectively (p = NS) (Table II). SPECT thallium-201 in CAD. The overall results are shown in Table III. Thus 41 of the 48 patients with CAD had abnormal perfusion patterns (sensitivity = 85 % ). Of the seven patients with CAD and false negative SPECT thallium images, two had disease involving the diagonal branch of the left anterior descending artery alone, one had a 90% stenosis of a diagonal branch and a 50% stenosis of the left anterior descending artery, one had 80 % stenosis of a diagonal branch and a 60% right coronary artery stenosis, one had isolated left anterior descending stenosis, one had isolated right coronary stenosis, and one had right coronary and circumflex stenoses. As seen in Table III, the SPECT results suggested multivessel CAD in 21 of the 36 patients (58%) with angiographic evidence of multivessel CAD, while this pattern was seen less often in patients with angiographic evidence of one-vessel CAD (3 of 12 [25 % 1, p < 0.05).

Of the 25 patients with thallium perfusion defects in more than one vascular territory, 21 (84% ) had multivessel CAD by angiography compared with 13 of 22 patients (59%) with perfusion abnormality in one vascular territory and 2 of 18 patients (11% ) with no CAD (p < 0.001). Further, most patients with

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Table IV. Perfusion abnormalities asassessed by thallium-

201 single photon emission computed tomography (SPECT) Type Vessel disease by angiography

Normal

Scar

11 5 2

3 3 6

OVD IVD MVD Abbreviations

of perfusion

abnormality

SPECT thallium-201 imaging

dipyridamole

V. Perfusion patterns as assessed by thallium-201 single photon emissioncomputed tomography (SPECT) Table

Perfusion

as in Table III.

pattern

Angiographic assessment

Normal

Abnormal

No CAD CAD

11 7

6 38

Ischemia 3 4 28

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Abbreviations

as in Table I.

Table VI. Published reports on oral dipyridamole thallium

imaging multivessel CAD had reversible defects (28 of 36 [78%], while only 4 of 12 patients (33%) with

one-vessel CAD had an ischemic type perfusion abnormality (p = 0.005) (Table IV). Increased lung thallium uptake was seen in only four patients (8 % ) (Table I). Patients with no CAD. These patients could by no means be considered as normal subjects; they were symptomatic and had coronary risk factors and some even had a history of previous myocardial infarction. It therefore was not unexpected to find that 6 of these 17 patients (35 % ) had an abnormal perfusion pattern (specificity = 65%) Table V). The defects were in the vascular territory of one vessel in five of the six patients with abnormal scans and were consistent with scar in three of the six patients (Tables III and IV). The coronary vessels showed <50 % stenosis in three of these six patients. Further, four patients had a history of hypertension, one had diabetes mellitus, one had had previous myocardial infarction, and three had abnormal Q waves on the electrocardiogram. COMMENTS

Previous studiesg-l’ show that intravenous dipyridamole thallium imaging is as sensitive and specific as exercise thallium-201 imaging in the detection of CAD. Recent studies12 show that the traditional dose of intravenous dipyridamole (0.56 mg/kg) may not produce maximal coronary vasodilation in all patients, and the addition of hand-grip exercise does not necessarily increase the magnitude of augmentation of coronary blood flow. Intravenous dipyridamole, however, remains an investigational agent. Taillefer et aL8 compared the results of oral and in-

travenous dipyridamole thallium-201 myocardial imaging. They found that coronary vasodilation with a 400 mg oral dose of dipyridamole offered increased sensitivity and specificity in detecting CAD compared with an oral dose of 200 mg. The results with the higher oral dose of dipyridamole were comparable to those with intravenous dipyridamole and the

No. of patients Study (Ref. no.)

CAD

No CAD

Imaging

Gould14 Homma13 Taillefer8 Borges-Neto17 Present study

48 43 19 84 48

10 10 6 16 17

Planar Planar Planar SPECT SPECT

Abbreviations

Sensitivity 48 91 84 92 85

Specificity 90 80 100 76 65

as in Tables I and III.

side effects were less. Homma et al.13 showed equally good results with a suspension of oral dipyridamole (300 mg). Earlier studies by Gould et al.14 suggested a slight decrease in sensitivity of oral dipyridamole as compared with exercise thallium imaging. All of the above studies, however, used planar thallium imaging. SPECT offers improved imaging results over planar imaging because of improved contrast and lack of overlap and superimposition.15 Thus at ideal doses, intravenous dipyridamole may produce better results than an oral dose. We and others are currently investigating the use of thallium imaging with intravenous adenosine as a coronary vasodilator, and the preliminary results are encouraging. All our patients underwent hand-grip exercise in addition to receiving oral dipyridamole during thallium injection. A major problem with oral dipyridamole is that the absorption rate is variable and hence peak blood levels are unpredictable and cannot be determined by observation of changes in heart rate, blood pressure, electrocardiographic changes, or quality of thallium images.16 We and others have, however, elected to inject thallium 45 minutes after the oral dose and the results as shown have been acceptable. Borges-Neto et al.,17 who used SPECT thallium imaging in conjunction with oral dipyridamole, found a sensitivity of 92 % in detecting CAD and a sensitivity of 63% in detecting multivessel CAD. Our data with oral dipyridamole-SPECT thallium imaging agree with these results and show a sensitivity of 85 % in detecting CAD and a sensitivity of 58% in detect-

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Fig. 3. Forty-second anterior view imageswith oral dipyridamole (left two images) and with exercise (right image). The dipyridamole thallium imagesare of good quality becauseof high counts in the heart. Note that the subdiaphragmaticactivity is not suppressed(left panel). There is markedly increasedlung thallium upake in addition to subdiaphragmaticactivity in the middle panel. This patient had extensive coronary artery disease.In contrast, post-exerciseimages(right panel) showvirtually no subdiaphragmatic

activity.

ing multivessel CAD (Tables III and IV). The presence of thallium perfusion defects in more than one vascular territory was highly consistent with multivessel CAD assessed by angiography (84% ). We did not expect and neither did we find a one-to-one relationship between the presence of disease as determined by angiography and corresponding thallium defects. The reasons are (1) variation in anatomic distribution of coronary arteries and (2) inability to predict hemodynamic severity of stenosis based on percent diameter stenosis.18 Comparison of our data with the data of other studies is noted in Table VI. Most patients with multivessel CAD assessed by angiography in our study had reversible defects consistent with ischemia (Table IV), even though only a few had chest pains or ST segment depression. Most of our patients were taking antianginal medication, which in previous studies has also been shown not to influence the coronary vasodilation and hence the imaging results. The images were uniformly of high quality because of increased counts in target organ and hence in the target-to-background ratio, and in our experience they could easily be differentiated from rest images (Fig. 3). Another consideration in dipyridamole thallium images in addition to availability is related to the cost; oral dipyridamole is inexpensive while intravenous dipyridamole, when released, is likely to be considerably more expensive. This issue is an important one in the current era of cost containment. There were six patients with abnormal thallium201 SPECT images who were found to have no significant CAD by angiography. The precise reason for this discrepancy is not clear, but some of these patients had coronary risk factors or mild CAD (or both) and therefore they were not normal subjects. The role of abnormal coronary vasomotor tone and

left ventricular hypertrophy cannot be addressed from this small sample size. There were seven patients with CAD in whom no perfusion defects were appreciated with dipyridamole imaging. Four of these patients had mild CAD (less than 70% stenosis of major vessels), a branch disease (or both); two patients had one-vessel CAD with >70% stenosis and only one had two-vessel CAD. In conclusion, our data show that oral dipyridamole SPECT thallium-201 imaging is useful in identifying patients with CAD. The presence of perfusion defects in more than one vascular territory is very suggestive of multivessel CAD assessed by angiography. The test is inexpensive compared with intravenous dipyridamole imaging and yields results comparable to submaximal stress thallium imaging.ig Thus oral dipyridamole SPECT thallium imaging is useful in detecting CAD and multivessel CAD in patients who are not candidates for exercise testing. SUMMARY

This study examined the merits of oral dipyridamole SPECT thallium-201 imaging in detecting CAD and multivessel CAD. The 65 patients included in this study (aged 62 t- 11 years) were not candidates for exercise testing (for the usual reasons). Coronary arteriography revealed no significant CAD in 17 patients and 250 % narrowing of one or more vessels in 48 patients; 12 had one-vessel and 36 had multivesse1 CAD (high-risk group). Thallium-201 was injected intravenously 45 minutes after an oral dose of 375 mg of dipyridamole, and SPECT imaging was performed within 10 minutes and 4 hours after injection. There were no serious side effects; only six patients (8% ) had ST segment depression and 18 patients (28%) had chest pain. The heart rate in-

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creased from 74 + 15 beats/min at rest to 84 & 14 beats/min at peak effect @ = 0.001); the systolic blood pressure did not change (130 f 18 and 128 k 20 mm Hg, respectively, p = NS). The thallium images were abnormal in 6 of 17 patients (35 % ) with no CAD, in 7 of 12 patients with one-vessel disease (58 % ), and in 34 of 36 patients with multivessel CAD (94%) (p = 0.001). Twenty-one of 25 patients (84 % ) with a perfusion abnormality in more than one vascular territory had multivessel CAD assessed by angiography. Thus oral dipyridamole SPECT thallium-201 imaging is a safe and inexpenive method for the detection of CAD in patients who are otherwise not candidates for exercise testing. Patients with perfusion defects in more than one vascular territory are highly likely to have multivessel CAD assessed by angiography. In our experience, these results are not different from those achieved with submaximal exercise SPECT thallium-201 imaging. The authors wish to thank Crescida Cox for secretarial assistance in preparing this report. REFERENCES

1. Iskandrian AS, Heo J, Askenase A, Segal BL, Auerbach N. Dipyridamole cardiac imaging. AM HEART J 1988;115:432-43. 2. Homma S, Gilliland Y, Guiney TE, Strauss HW, Boucher CA. Safety of intravenous dipyridamole for stress testing with thallium imaging. Am J Cardiol 1987;59:152-4. 3. Leppo JA, O’Brien J, Rothendler JA, Getchell JD, Lee VW. Dipyridamole-thallium-201 scintigraphy in the prediction of future cardiac events after acute myocardial infarction. N Engl J Med 1984;310:1014-18. 4. Boucher CA, Brewster DC, Darling RC, Okada RD, Strauss HW, Pohost GM. Determination of cardiac risk by dipyridamole-thallium imaging before peripheral vascular surgery. N Engl J Med 1985;312:389-94. 5. Eagle KA, Singer DE, Brewster DC, Darling RC, Mulley AG, Boucher CA. Dipyridamole-thallium scanning in patients undergoing vascular surgery. JAMA 1987;257:2185-9. 6. Leppo J, Plaja J, Gionet M, Tumolo J, Paraskos JA, Cutler BS. Noninvasive evaluation of cardiac risk before elective vascular surgery. J Am Co11 Cardiol 1987;9:269-76. 7. Jain A, Mahmarian JJ, Borges-Neto S, Johnston DL, Cashion WR, Lewis JM, Raizner AE. Clinical significance of perfusion

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Iskandrian AS, Heo J, Kong B, Lyons E. The effect of exercise level on the ability of thallium-201 tomographic imaging in detecting coronary artery disease: analysis of 461 patients. J Am Co11Cardiol (In press)