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(Circulation. 1995;91:313-319.)
© 1995 American Heart Association, Inc.

Articles

Myocardial Perfusion Imaging With ^99mTc Tetrofosmin

Comparison to ²⁰¹Tl Imaging and Coronary Angiography in a Phase III Multicenter Trial

Barry L. Zaret, MD; Pierre Rigo, MD; Frans J.T. Wackers, MD; Robert C. Hendel, MD; Simon H. Braat, MD; Ami S. Iskandrian, MD; Bangalore S. Sridhara, MD; Diwakar Jain, MD; Roland Itti, MD; Aldo N. Serafini, MD; Michael L. Goris, MD; Avijit Lahiri, MD; the Tetrofosmin International Trial Study Group

	Abstract

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Background Our objective was to compare the sensitivity and specificity of tetrofosmin, a new ^99mTc-labeled myocardial perfusion imaging agent for the detection of myocardial perfusion abnormalities, with those of ²⁰¹Tl and coronary angiography. Our hypothesis was that same-day stress/rest tetrofosmin imaging could provide data comparable to those of ²⁰¹Tl imaging. Myocardial perfusion imaging plays an important role for the evaluation of coronary artery disease. Newer ^99mTc-labeled agents offer several advantages over ²⁰¹Tl, the conventional myocardial perfusion imaging agent. Tetrofosmin is a new ^99mTc-labeled agent with promising results in preliminary studies.

Methods and Results Two hundred fifty-two patients with suspected coronary artery disease were enrolled in 10 centers in the United States and Europe. All patients underwent exercise and rest myocardial perfusion imaging with ^99mTc-tetrofosmin using two separate injections of the radiotracer 4 hours apart on the same day. Planar images were obtained in three standard views 15 to 60 minutes after radiotracer injection. Patients also underwent standard exercise and redistribution planar ²⁰¹Tl imaging within 2 weeks of tetrofosmin imaging. In addition, 58 healthy subjects with low likelihood of coronary artery disease underwent exercise and rest tetrofosmin imaging. Coronary angiograms were available in 181 patients with suspected coronary artery disease. All radionuclide images were processed in the central core laboratory and interpreted blindly by a panel of four experienced readers. ²⁰¹Tl images and tetrofosmin images were read separately. Discrepancies were resolved by consensus. The workload, peak heart rate, and double products were comparable during exercise for both imaging agents. Technically acceptable paired ²⁰¹Tl and tetrofosmin images were available in 224 of 252 patients. Tetrofosmin images were generally of good quality, with low extracardiac activity, and easy to interpret. Patients were categorized as showing normal, ischemia, infarction, or mixture with each imaging modality. Precise concordance for each of these categories was 59.4% (=0.44; 95% CI, 0.35 to 0.53). When patients were categorized as normal or abnormal, the concordance was 80.4% (=0.55; 95% CI, 0.43 to 0.67). When each of five anatomic territories (septal, anterior, inferior, lateral, and apical) was categorized as normal versus abnormal, the concordance varied from 81% to 90%. When similar comparison was made for the specific category of abnormality, the concordance was 64% to 84%. When coronary angiography was used as the criterion, the sensitivity and positive and negative predictive accuracy of tetrofosmin and ²⁰¹Tl were comparable. The normalcy rate of tetrofosmin images in the healthy subjects with low likelihood of coronary artery disease was 97%.

Conclusions ^99mTc tetrofosmin is a new myocardial imaging agent with favorable imaging characteristics with results comparable to those of ²⁰¹Tl.

Key Words: tetrofosmin • imaging

	Introduction

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Stress radionuclide myocardial perfusion imaging is a well-established modality for the diagnostic and functional evaluation of patients with suspected or known coronary artery disease.¹ This diagnostic entity gained widespread clinical use in 1976 with the introduction of ²⁰¹Tl.² Recently, ^99mTc-labeled myocardial perfusion agents have become available. ^99mTc sestamibi planar and single photon emission computed tomography (SPECT) imaging are now widely used.^{3 99m}Tc teboroxime has had much less clinical utilization, despite its approval for clinical use.⁴

The newest ^99mTc-labeled perfusion agent to undergo evaluation has been ^99mTc tetrofosmin.⁵ This novel cat-ionic complex involves [^99mTc(tetrofosmin)₂ O₂]⁺, where tetrofosmin is the ether-functionalized diphosphine ligand 1,2-bis[bis(2-ethoxyethyl)phosphino]ethane. Preliminary studies in experimental preparations have indicated that this new radiopharmaceutical is distributed within the myocardium in proportion to regional myocardial blood flow as measured by the radioactive microsphere technique.⁶ Preliminary clinical studies have also demonstrated the safety of this agent.⁷ In humans, there is relatively rapid clearance of the radioactive tracer from the blood and extracardiac structures after intravenous injection.^{7 8} There appears to be minimal, if any, redistribution from the myocardium over time; 1.2% of the injected dose is taken up by the heart.^{7 8} In preliminary phase I and II clinical studies involving 12 volunteers and 55 patients, respectively, myocardial images obtained with this agent have been reported to be of excellent quality and have encouraged greater exploration of its clinical potential.^{9 10 11}

The purpose of the present study was to evaluate ^99mTc tetrofosmin imaging in a large group of patients in a phase III multicenter trial. In this trial, ^99mTc tetrofosmin imaging data were compared with those of ²⁰¹Tl as well as coronary angiography. Our hypothesis was that ^99mTc tetrofosmin would provide data comparable to those of ²⁰¹Tl imaging. Normalcy rates also were determined in a group of subjects with low likelihood (<3%) of coronary artery disease.¹²

	Methods

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Participating Centers and Protocol Organization
The study was conducted in 10 centers: 6 in the United States (Morton Plant Hospitals, Northwestern University, Philadelphia Heart Institute, Stanford University, University of Miami, and Yale University) and 4 in Europe (Academic Hospital Maastricht, Cardiological Hospital Lyon, Centre Hospitalier Universitaire de Liège, and Northwick Park Hospital) (see "Appendix"). For the purposes of this study, all digital image data were sent to a central core laboratory at Yale University, where images were processed and displayed in a uniform manner suitable for both visual qualitative interpretation and quantitative circumferential profile analysis. All clinical and demographic patient data were collated independently by Amersham International. Statistical analysis was performed independently by "S. Cubed," Sheffield, UK. Before inception of this study, approval was obtained from the institutional review board of each of the participating clinical centers.

Protocol
The protocol involved an open-label phase III multicenter trial designed to assess the safety and diagnostic efficacy of ^99mTc tetrofosmin in patients with known or suspected coronary artery disease. Written informed consent was obtained from each patient. Each patient underwent a tetrofosmin stress/rest imaging study on 1 day. The initial study involved symptom-limited treadmill (8 centers) or bicycle ergometer (2 centers) exercise stress. End points of exercise termination were occurrence of chest pain, fatigue, significant dypsnea, ventricular arrhythmia, or hypotension. Radiotracer (5 to 8 mCi) was injected at peak exercise. Patients were asked to continue exercise for an additional minute after injection. Approximately 4 hours after the initial injection, patients underwent a second tetrofosmin injection (15 to 24 mCi). Imaging was begun between 15 and 60 minutes after each tetrofosmin injection.

Each patient also underwent an exercise ²⁰¹Tl study within 14 days of the tetrofosmin study. For the thallium study, patients received 1.5 to 3.5 mCi at peak exercise. Image acquisition was recommended within 10 minutes after exercise for the stress images and 2 to 4 hours after exercise for the delayed images. In 1 center (Philadelphia Heart Institute), all 26 patients studied received a second injection of ²⁰¹Tl and then underwent a second resting, rather than redistribution, imaging study. Data from both imaging studies were stored on computer disks for transfer to the Core Laboratory.

The low-likelihood subjects entering the protocol underwent only the tetrofosmin exercise/rest study as described above.

Patient Population
Patients were considered eligible for this study on the basis of clinical coronary artery disease if they had clinical symptoms suggestive of coronary disease in association with either an abnormal exercise test, prior abnormal perfusion study, or coronary arteriography demonstrating significant stenosis (>70%) of at least one major vessel. Patients who had experienced a prior myocardial infarction (based on standard clinical definition of at least two of the following: prolonged chest pain, elevation of creatine kinase MB, and transient ECG changes) were also considered eligible. Patients with atypical chest pain were also considered suitable for inclusion. It was required that any oral medications used were administered as a stable dose for at least 2 weeks before study and remained unchanged during the study period.

Patients were excluded from study if they had experienced recent acute myocardial infarction (within 2 months) or manifested unstable coronary artery disease, significant clinical congestive heart failure, valvular disease, left bundle branch block, congenital heart disease, aortic stenosis, or significant intercurrent noncardiac illness.

Low-likelihood coronary subjects were recruited on a voluntary basis.

Imaging Protocol
Before the start of the trial, the imaging protocols were discussed with all investigators, and a consensus was reached with regard to an optimized imaging protocol. For purposes of quality control, images of a resolution phantom and field uniformity were submitted with each study. For thallium studies, imaging was performed first in the left anterior oblique (LAO) position. The angulation of the gamma camera was chosen to provide optimal separation of right and left ventricular activity. On such an image, the septum is vertical and straight. This angulation is not always 45°. The anterior view was taken 45° to the right of the LAO angulation. The left lateral view was obtained with the patient turned on the right side decubitus. The angulation of the gamma camera was the same as for the anterior view. In some of the European centers, an additional steep LAO view was obtained. Delayed ²⁰¹Tl imaging was performed 2 to 4 hours later. The angulation of the gamma camera was carefully reproduced for the same LAO, anterior, and left lateral views. For ²⁰¹Tl planar imaging, the gamma camera was equipped with a general all-purpose parallel-hole collimator. The camera energy window (25%) was symmetrically set on the 80-keV x-ray peak of ²⁰¹Tl. Images were acquired on computer in a 128x128 matrix (word mode) and stored on magnetic disk for processing in the core laboratory.

The position of the gamma camera and positioning of the patient for the tetrofosmin study were identical to those described for ²⁰¹Tl imaging. The angulation of the gamma camera at exercise imaging was carefully reproduced for rest imaging. For tetrofosmin planar imaging, the gamma camera was equipped with a high-resolution parallel-hole collimator. The camera energy window (20%) was symmetrically set on the 140-keV peak of ^99mTc. Images were acquired on computer in 128x128 word mode matrix and stored on magnetic disk for processing in the core laboratory.

Interpretation
All data were processed centrally in the core laboratory. The final data set consisted of the side-by-side stress and either rest or redistribution images for ^99mTc tetrofosmin or ²⁰¹Tl, respectively. Images from the two radiotracer studies were processed and displayed separately. In addition to the raw, unprocessed image data, processed smoothed images as well as circumferential profile quantitative analysis of each patient were available. The thallium and tetrofosmin data were quantitatively processed and displayed in comparison with previously defined normal databases.^{13 14}

Interpretation was made from the initial unprocessed images, with only confirmation or resolution of ambiguity based on the quantitative analysis.

Patient data were interpreted independently by four individual readers without knowledge of clinical data or the results of the corresponding imaging technique. Image sets were read in groups segregated according to radionuclide. Thus, tetrofosmin and thallium studies were always read separately. A final arbitrated consensus (if disagreements were present) was derived from these individual readings. Only after final interpretation had been recorded were comparisons made between thallium and tetrofosmin data sets. Images from the low-likelihood group were interpreted by two readers and were read interspersed with a comparable number of abnormal studies.

The planar image data were evaluated with respect to the five standard anatomic regions: anterior, septal, apical, lateral, and inferior. A separate interpretation was made for each region and for each patient based on one of four possible categories: normal, ischemia (reversible defect), scar (fixed defect), or mixture of ischemia and scar. For purposes of comparisons between imaging techniques, a mixed defect was counted as both scar and ischemia.

Coronary Angiographic Data
Coronary angiographic data were interpreted qualitatively at the clinical sites, with >70% stenosis deemed significant coronary stenosis. No independent core laboratory reading was obtained, and this was a local consensus assessment. Planar image data were related to specific coronary angiographic stenosis in a standard manner used for prior correlative studies involving imaging–coronary anatomic correlations: septal or anterior defects were related to disease of the left anterior descending coronary artery, inferior defects to the right coronary artery, and lateral defects to the circumflex coronary artery. The apex was assigned to either the left anterior descending or right coronary artery, depending on individual arteriographic anatomy.

Radiopharmaceutical Preparation
Tetrofosmin was supplied by Amersham International PLC as a freeze-dried solid in a 10-mL glass vial sealed under an inert nitrogen atmosphere with a rubber closure. Each vial contained 0.23 mg tetrofosmin, 0.32 mg disodium sulfosalicylate, 0.03 mg stannous chloride dehydrate, and 1.00 mg sodium D-gluconate in which the pH had been adjusted with sodium bicarbonate before lyophilization.

Each vial was reconstituted according to Kelly et al⁵ with 4 to 8 mL of sterile sodium pertechnetate solution containing no more than 30 mCi/mL. This was prepared by diluting the eluate from a ^99mTc generator with 0.9% saline. Appropriate corrections were made from radioactive decay occurring between reconstitution and injection. The vial was shaken gently to ensure complete dissolution of the lyophilized powder and allowed to stand at room temperature for 15 minutes. The injectate was stored at room temperature and used within 8 hours of reconstitution. Determination of radiochemical purity was performed before use.

Radionuclide Purity and Quality Assurance
A chromatographic system was used to determine the radiochemical purity of each ^99mTc tetrofosmin injection vial. Prepared Gelman ITLC/SG strips (2.0x20 cm) were used. A test sample of 10 to 20 µL was applied by needle to the origin position of the strip. The strip was then placed in an ascending chromatography tank containing a fresh solution of 35:65 acetone/dichloromethane (1-cm depth). The strip was removed once the solvent had eluted to 18 cm. In this system, free pertechnetate runs to the top portion of the strip and ^99mTc tetrofosmin to the middle portion, and reduced hydrolyzed ^99mTc and other hydrophilic complexes remain at the origin. The strip was cut in a predefined manner, and each section was counted in a well counter.

Studies were performed only if % ^99mTc tetrofosmin was >90%.

Statistical Analysis
Data are expressed as mean±SD. Differences between groups were determined by unpaired t tests. Concordance between tetrofosmin and thallium imaging data was expressed both as a percent and as statistics.^{15 16} A value of +1 indicates complete agreement. A value >0.75 indicates excellent agreement beyond chance, 0.40 to 0.75 indicates fair agreement beyond chance, <0.40 indicates poor agreement beyond chance, and 0 indicates chance agreement. Ninety-five percent CIs were given for values. A probability of P<.05 was considered significant.

	Results

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Patient Population
Between November 1991 and April 1992, a total of 252 patients were studied. Their mean age was 61 years (range, 34 to 82 years). Eight-four percent were men. Clinically, 94 patients (37%) had chest pain consistent with angina pectoris, 23 (9%) had experienced a prior myocardial infarction, and 104 (41%) had both a chest pain syndrome and prior infarction. Ten percent of the cohort had experienced a previous coronary artery bypass surgical procedure, and 60 (24%) had prior coronary angioplasty.

Between September and November 1992, an additional group of 58 subjects with low (<3%) likelihood of coronary artery disease was studied. Of this group, 68% were men, and their mean age was 37 years (range, 24 to 58 years).

Exercise Data
The physiological exercise parameters for the ^99mTc tetrofosmin and the ²⁰¹Tl exercise studies were comparable (Table 1). Maximum heart rate achieved was virtually identical. There were physiologically nonrelevant but statistically significant differences between peak systolic blood pressure and rate-pressure product, with both being slightly higher in the ²⁰¹Tl exercise study. The incidence of chest pain and significant ST-segment depression were also comparable. The time between the tetrofosmin and thallium studies was 5.1±4.1 days.

View this table: [in this window] [in a new window]   Table 1. Exercise Data During Tetrofosmin and Thallium Studies

Technical Imaging Data
In this 1-day tetrofosmin imaging protocol, the exercise study was performed initially. The mean injected dose during exercise was 7.7±0.7 mCi. For the resting tetrofosmin study, the dose averaged 22.4±1.7 mCi. The interval between the exercise and rest injections averaged 245±23 minutes. The time between the radionuclide injection and imaging after exercise was 26±16 minutes, and the time between injection and imaging at rest averaged 26±11 minutes.

For the ²⁰¹Tl study, imaging began 13±20 minutes after exercise. Redistribution imaging (or rest/reinjection imaging at one center) began an average of 238±50 minutes after initial injection.

Imaging Results
All patients and normal subjects tolerated the ^99mTc tetrofosmin injections well. There were no major untoward reactions. Two patients reported minor events after administration of tetrofosmin: One reported a burning sensation in the hard palate, and the other complained of an awareness of an unusual smell shortly after injection. Technically acceptable paired imaging data were available in 224 of 252 patients. Of the 28 patients initially recruited but without complete data, 18 did not complete both studies, 6 had poor-quality ²⁰¹Tl studies, 3 poor-quality ^99mTc tetrofosmin studies, and 1 poor-quality studies with both radiopharmaceuticals. Thus, 224 patients form the basis of the comparative study. Of these 224 patients, 111 (49.5%) had no previous myocardial infarction. In general, ^99mTc tetrofosmin images were thought to be of superior technical quality and generally somewhat easier to interpret than ²⁰¹Tl images (Figs 1 and 2). Subdiaphragmatic activity did not present a problem with respect to image interpretation or creation of image artifacts.

View larger version (102K): [in this window] [in a new window]   Figure 1. Stress and redistribution (Redist.) thallium (left) and stress and rest tetrofosmin (right) images in an individual with no coronary artery disease. Left anterior oblique (LAO) images are shown in the upper panels, left lateral (LAT) in the middle panels, and anterior (ANT) in the lower panels.

View larger version (103K): [in this window] [in a new window]   Figure 2. Stress and redistribution (Redist.) thallium images (left) and stress and rest tetrofosmin images (right) in the same patient. Left anterior oblique (LAO) images are shown in the upper panels, left lateral (LAT) in the middle panels, and anterior (ANT) in the lower panels. An inferoapical and anteroapical partially reversible defect is seen with both radionuclide studies.

Each patient was categorized as demonstrating an imaging pattern defined as normal, ischemia, infarction, or mixed (ischemia and infarction). Precise concordance for each of the four categories in each patient was 59.4% (=0.44; 95% CI, 0.35 to 0.53). When patients were categorized as normal versus abnormal, precise concordance was 80.4%, =0.55 (95% CI, 0.43 to 0.67) (Table 2). In the subgroup with no previous infarction, data were comparable. Precise concordance was 56.8% with =0.38 (95% CI, 0.25 to 0.51), and concordance for normal versus abnormal was 74.8% (=0.49; 95% CI, 0.32 to 0.65).

View this table: [in this window] [in a new window]   Table 2. Concordance of Tetrofosmin and Thallium Image Data by Patient

Concordance between thallium and tetrofosmin imaging also was evaluated in each of the five individual anatomic territories (Table 3). Absolute concordance with respect to the four categories in each region ranged from 64% to 84%, with concordance greatest in the anterior, septal, and lateral walls. When images were categorized as abnormal versus normal, regional concordance ranged from 81% to 90%. Regional concordance was somewhat higher for scar (85% to 95%) compared with ischemia (74% to 87%). For each of the five territories, concordance with respect to abnormal versus normal manifested values ranging from 0.56 (95% CI, 0.41 to 0.72) in the lateral wall to 0.73 (95% CI, 0.62 to 0.83) in the septum. Results were comparable for patients without prior infarction (Table 4).

View this table: [in this window] [in a new window]   Table 3. Concordance of Tetrofosmin and Thallium by Territory in All 225 Patients

View this table: [in this window] [in a new window]   Table 4. Concordance of Tetrofosmin and Thallium by Territory: Patients Without Prior Myocardial Infarction

Segmental data were also analyzed from the 1123 available territories pooled together. Although segmental data for each of the five regions may not be totally independent of each other, this analysis has been used routinely in imaging studies. Concordance of the pooled segments for normal versus abnormal was 85.7% (=0.68; 95% CI, 0.63 to 0.72), for ischemia, 82% (=0.49; 95% CI, 0.43 to 0.55), and for scar, 90% (=0.69; 95% CI, 0.64 to 0.75).

Relation to Coronary Angiography
Coronary angiographic data were available in 181 patients. Of these 181 patients, 167 had complete tetrofosmin studies suitable for comparative analysis and 162 had comparably adequate ²⁰¹Tl studies. The sensitivity and positive and negative predictive accuracy of ^99mTc tetrofosmin and ²⁰¹Tl were comparable. Specificity was somewhat higher for tetrofosmin (Table 5). Of note, sensitivity was relatively good but specificity was relatively poor for each agent. In those patients without previous myocardial infarction, sensitivity and specificity data were also comparable (Table 6). Tetrofosmin diagnostic sensitivity was also related to extent of coronary disease, with sensitivities of 74%, 80%, and 90% noted for two- and three-vessel involvement, respectively. When evaluated regionally, sensitivity and specificity for tetrofosmin and thallium were also generally comparable, with the one exception being greater sensitivity for tetrofosmin imaging in defining defects in the inferior wall (73% versus 51%) (Fig 3).

View this table: [in this window] [in a new window]   Table 5. Sensitivity and Specificity of Tetrofosmin and Thallium (Any Defect) in 181 Patients in Relation to Coronary Angiography

View this table: [in this window] [in a new window]   Table 6. Sensitivity and Specificity of Tetrofosmin and Thallium (Any Defect) in Relation to Coronary Angiography in Patients Without Prior Infarction

View larger version (49K): [in this window] [in a new window]   Figure 3. Bar graph showing sensitivity and specificity on a segmental basis for thallium (Tl) and tetrofosmin (Tc-T) imaging in those patients undergoing coronary arteriography. The relation of arteriographic anatomy to site of perfusion defect is defined in the text. Sensitivity data are shown on the left and specificity data on the right. Sensitivities are comparable except in the inferior wall (Inf), where there appears to be greater sensitivity for tetrofosmin without a loss of specificity. Ant/Sept indicates anterior/septal; Lat, lateral.

Normalcy Rates
In contrast to specificity data, the normalcy rate for tetrofosmin imaging in the low-likelihood coronary group was high, with 56 of 58 subjects (97%) demonstrating normal image patterns.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This 10-site multicenter trial study represents the first relatively large clinical experience with ^99mTc tetrofosmin myocardial perfusion imaging. The data indicate that ^99mTc tetrofosmin planar imaging provides high-quality images with a sensitivity for detection of coronary disease comparable to that obtained with ²⁰¹Tl. Although specificity in this selected group of patients was relatively low, normalcy rates were excellent. The low specificity in this study was seen with both ²⁰¹Tl and ^99mTc tetrofosmin imaging. This observation is consistent with several previous studies, indicating that it is currently difficult to determine specificity in a group of highly selected patients who may be referred for catheterization because of an abnormal noninvasive study¹⁷ or who may contain subgroups of patients with microvascular ischemia.¹⁸ For these reasons, defining specificity in terms of normalcy rates in a low-likelihood population is generally recommended.¹²

In the present study, tetrofosmin data were compared primarily with ²⁰¹Tl scintigraphy. When ²⁰¹Tl imaging data were used as a basis, there was fair comparability. Imaging data were also compared with coronary angiographic disease as an additional standard. Sensitivity and specificity for both patient and regional analyses also were generally comparable. Of note, there were comparable data in the patient subset without infarction. This indicates suitability for evaluating patients with chronic stable coronary disease. The one exception was an apparently improved sensitivity for tetrofosmin imaging of the inferior wall, which occurred without a compromise in specificity (Fig 3).

The method of image analysis used in this multicenter trial deserves comment. All data were read in a totally independent and blinded fashion. Four readers each evaluated the data. Thallium and tetrofosmin data were read in separate batches so that there were no immediate direct comparisons between the two radionuclide imaging data sets in individual patients. The final consensus for each study was derived independently. Data were evaluated from the qualitative images. However, quantitative analysis was available for each study and was used primarily to enhance diagnostic certainty. Such an approach is generally consistent with current clinical practice. The efficacy and value of core laboratory central processing of radionuclide data has recently been stressed.¹⁶ In contrast, a core laboratory was not used for coronary angiographic data. However, a relatively significant degree of coronary stenosis was used as the standard in the hope of decreasing the known ambiguity of angiographic analysis in the case of perceived stenosis of intermediate severity.¹⁹

The data of this study support the use of ^99mTc tetrofosmin as a suitable agent for a 1-day imaging protocol involving separate stress and rest radionuclide injections. This may prove to be a significant attribute of this compound. Images were of excellent quality. In our protocol, the stress images were performed initially. This was quite feasible from the standpoint of laboratory throughput and image quality. An advantage of performing the exercise protocol initially involves the possibility of eliminating a subsequent rest study if the initial stress study is normal. This could lead to significant cost savings. However, definition of the optimal 1-day imaging protocol will require performance of appropriate paired prospective studies in which the sequence of study is varied.

The biokinetics of ^99mTc tetrofosmin appear quite suitable for a 1-day protocol.^{7 8} There appears to be little if any redistribution with tetrofosmin.⁸ There is relatively rapid clearance from liver, providing excellent heart-liver ratios for imaging.⁸ Recent data reported by Jain et al⁸ indicate that the heart-liver ratio is 0.7 at 15 minutes after injection at rest and 1.2 at 15 minutes after injection during exercise. There are also excellent ratios of heart activity to that of the lung, gastrointestinal viscera, and spleen under conditions of both stress and rest. These data are consistent with the recently published study by Kelly et al⁵ involving whole-body imaging.

Future Directions
This study indicates the potential of ^99mTc tetrofosmin as a new myocardial perfusion imaging agent suitable for 1-day studies. However, the study does have limitations. It should be noted that these data were obtained with planar imaging techniques. Further studies are necessary to evaluate imaging potential using tomographic SPECT techniques. It would be anticipated that, as with ^99mTc sestamibi, imaging will be more optimal with the SPECT than with the planar technique.

Patients in this study were evaluated exclusively with exercise. Further studies are required to assess the clinical utility of pharmacological stress imaging with dipyridamole, adenosine, and/or dobutamine.²⁰ In addition, the utility of this imaging agent for assessing myocardial viability will also require further study and comparison to thallium reinjection techniques.

The relatively simple kit formulation and the possibility of imaging within 30 minutes after injection suggest a potential role for imaging in acute coronary disease. Such a role could involve imaging of acute infarction, resting ischemia in the coronary care unit, assessment of thrombosis, and early emergency department diagnosis of infarction, as has been suggested for ^99mTc sestamibi.²¹

Finally, tetrofosmin imaging data were compared initially with those of ²⁰¹Tl. Additional clinical studies comparing ^99mTc tetrofosmin and ^99mTc sestamibi imaging directly in various types of exercise and pharmacological stress would also be of interest.

	Acknowledgments

 
This study was supported by a grant to individual institutions by Amersham International. The assistance of Astrid Swanson in the preparation and typing of the manuscript is greatly appreciated.

	Footnotes

 
Reprint requests to Barry L. Zaret, MD, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St, New Haven, CT 05420-8017.

Dr Zaret is a consultant to Amersham International PLC. He owns no stock in the company.

Tetrofosmin International Trial Study Group
Academic Hospital Maastricht, Maastricht, The Netherlands: Simon H. Braat, MD, Serve Halders, MD, Levinus Koppejans, Irene Cajob, Piet Willems.

Cardiological Hospital, Lyon, France: Roland Itti, MD, Laurence Bontemps, MD, Pascale Egroizard, MD, Yehia Sayegh, Marc Fraysse.

Centre Hospitalier Universitaire de Liège, Liège, Belgium: P. Rigo, MD, T.R. Benoit, MD, B. Lellerlo, J. Foulon.

Morton Plant Hospital, Clearwater, Florida: Robert Kline, MD, Gerard Morrissette, MD, Lewis Price, MD, Rhonwen Jackson.

Northwestern University Hospital, Chicago, Ill: Robert C. Hendel, MD, Stewart Spies, MD, Steven Bellow, MD, Scott Leonard, Caryn Bull.

Northwick Park Hospital, Harrow, UK: Avijit Lahiri, MD, Bangalore Sridhara, MD, Usha Raval, John Crawley, Terry Smith.

Philadelphia Heart Institute, Philadelphia, Pa: Ami Iskandrian, MD, Jaekyeong Heo, MD, William Unteeker, MD, Norman Feinsmith, Virginia Cave, Valerie Wasserleben.

Stanford University, Palo Alto, Calif: Michael L. Goris, MD, Ross McDougall, MD, Louis Blake, Nora Gurevich, Chris Fujii.

University of Miami, Miami, Fl: Aldo N. Serafini, MD, Shabbir Ezuddin, Rafael Sequeira, Maureen Lowery.

Yale University, New Haven, Conn: Diwakar Jain, MD, Barry L. Zaret, MD, Frans J. Wackers, MD, Jennifer Mattera, Michael McMahon, Mark Saari.

Central Core Laboratory, Yale University, New Haven, Conn: Barry L. Zaret, MD, Frans J. Wackers, MD, Diwakar Jain, MD, Michael McMahon, Patricia Atkinson.

Received November 28, 1994; accepted November 30, 1994.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Zaret BL, Wackers FJ. Nuclear cardiology (medical progress). N Engl J Med. 1993;329:775-783, 855-863. [Free Full Text]

2. Strauss HW, Harrison K, Langan JK, Lebowitz E, Pitt B. Thallium-201 for myocardial imaging: relation of thallium-201 to regional myocardial perfusion. Circulation. 1975;51:641-645. [Abstract/Free Full Text]

3. Wackers FJ, Berman DS, Maddahi J, et al. Technetium-99m hexakis 2-methoxyisobutyl isonitrile: human biodistribution, dosimetry, safety and preliminary comparison to thallium-201 for myocardial perfusion imaging. J Nucl Med. 1989;30:301-311. [Abstract/Free Full Text]

4. Kiat H, Maddahi J, Roy LT, et al. Comparison of technetium 99m methoxy isonitrile and thallium 201 for evaluation of coronary artery disease by planar and tomographic methods. Am Heart J. 1989;17:1-11.

5. Kelly JD, Forster AM, Higley B, et al. Technetium-99m tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging. J Nucl Med. 1993;34:222-227. [Abstract/Free Full Text]

6. Sinusas AJ, Shi QX, Saltzberg MT, et al. Technetium-99m tetrofosmin to assess myocardial blood flow: experimental validation in an intact canine model of ischemia. J Nucl Med. 1994;35:664-667.

7. Higley B, Smith FW, Smith T, et al. Technetium-99m-1,2{bis(2-ethoxyethyl)phosphine}ethane: human biodistribution, dosimetry and safety of a new myocardial perfusion imaging agent. J Nucl Med. 1993;34:30-38. [Abstract/Free Full Text]

8. Jain D, Wackers FJ, Mattera J, McMahon M, Sinusas AJ, Zaret BL. Biokinetics of 99m Tc-tetrofosmin, myocardial perfusion imaging agent: implications for a one day imaging protocol. J Nucl Med. 1993;34:1254-1259. [Abstract/Free Full Text]

9. Sridhara BS, Braat S, Itti R, Rigo P, Cload P, Lahiri A. Early and late myocardial imaging with a new technetium-99m diphosphine (PPN 1011) in coronary artery disease. J Am Coll Cardiol. 1992;19:202A. Abstract.

10. Sridhara B, Sochor H, Rigo P, et al. Myocardial single-photon emission computed tomographic imaging with technetium 99m tetrofosmin: stress-rest imaging with same-day and separate-day rest imaging. J Nucl Cardiol. 1994;1:138-143. [Medline] [Order article via Infotrieve]

11. Takahashi N, Tamaki N, Tadamura E, et al. Combined assessment of regional perfusion and wall motion in patients with coronary artery disease with technetium 99m tetrofosmin. J Nucl Cardiol. 1994;1:29-38. [Medline] [Order article via Infotrieve]

12. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med. 1979;300:1350-1358. [Abstract]

13. Sigal SL, Soufer R, Fetterman RC, Mattera JA, Wackers FJ. Reproducibility of quantitative planar thallium-201 scintigraphy: quantitative criteria for reversibility of myocardial perfusion defects. J Nucl Med. 1991;32:759-765. [Abstract/Free Full Text]

14. Wackers FJ, Gibbons RJ, Verani MS, et al. Serial quantitative planar technetium-99m isonitrile imaging in acute myocardial infarction: efficacy for noninvasive assessment of thrombolytic therapy. J Am Coll Cardiol. 1989;14:861-873. [Abstract]

15. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159-174. [Medline] [Order article via Infotrieve]

16. Wackers FJ, Bodenheimer M, Fleiss JL, Brown M, and the Multicenter Study on Silent Myocardial Ischemia (MSSMI) Thallium-201 Investigators. Factors affecting uniformity in interpretation of planar thallium-201 imaging in a multicenter trial. J Am Coll Cardiol. 1993;21:1064-1074. [Abstract]

17. Rozansky A, Diamond GA, Berman D, Forrester JS, Morris D, Swan HJC. The declining specificity of exercise radionuclide ventriculography. N Engl J Med. 1983;309:518-522. [Abstract]

18. Brush JE, Cannon RO, Schenke BA, et al. Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med. 1988;319:1302-1307. [Abstract]

19. Fleming RM, Kirkeeide RL, Smalling RW, Gould KL. Patterns in visual interpretation of coronary arteriograms as detected by coronary arteriography. J Am Coll Cardiol. 1991;18:945-951. [Abstract]

20. Iskandrian AS, Heo J. Pharmacologic stress testing. In: Zaret BL, Beller GA, eds. Nuclear Cardiology: State of the Art and Future Directions. St Louis, Mo: Mosby; 1993:170-180.

21. Christian TF, Schwartz RS, Gibbons RJ. Determinants of infarct size in reperfusion therapy for acute myocardial infarction. Circulation. 1992;86:81-90.[Abstract/Free Full Text]

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