(Circulation. 1995;91:555-558.)
© 1995 American Heart Association, Inc.
Articles |
The Growing Flood of Technetium-99m Myocardial Perfusion Agents
More Water . . . or More Mud?
From the Department of Internal Medicine (Cardiology), St Louis University Health Sciences Center, St Louis, Mo.
 |
Abstract |
|---|
 Top Abstract IntroductionThe Current Study Questions, Concerns, and...Is Flood Relief in...References |
|---|
"Ol' man river, dat ol' man river,
He must know sumpin', but don't say nothin',
He just keeps rollin', he keeps on rollin' along."
Ol' Man River
—Oscar Hammerstein II
© 1927 T.B. Harms Co. Copyright renewed.
Key Words: Editorials • imaging • perfusion
|
Introduction |
|---|
|
TopAbstractIntroductionThe Current Study Questions, Concerns, and...Is Flood Relief in...References |
|---|
In the wake of a "500-year" flood, we who inhabit the banks of the Mississippi now understand the dark side of Ol' Man River. We learned that once the river came out of its banks, its course would never again be the same. Some victims wondered which was worse, the high water or the muddy sludge it left behind. So it may be in the wake of the confusing flood of newly developed technetium-99m (99mTc)–based myocardial perfusion imaging agents for coronary artery disease detection (Table
). The experienced investigators of the
Multicenter 99mTc
Tetrofosmin Trial1 have piloted us through uncharted
nuclear cardiology waters before, during the inception and validation
of thallium-201 (201TI), 99mTc sestamibi, and
99mTc teboroxime myocardial perfusion
imaging.2 3 4 5 6 7
Their 99mTc tetrofosmin myocardial
imaging results are relatively straightforward and may eventually prove
to be clinically important.8 But while the introduction of
another myocardial perfusion agent can hardly be considered a cause for
alarm, this study raises several important questions and a few concerns
about the current status of cardiovascular radiotracer research and
development and provides an opportunity to consider the future
direction of cardiac radiotracer trials.
|
|
The Current Study |
|---|
|
TopAbstractIntroductionThe Current Study Questions, Concerns, and...Is Flood Relief in...References |
|---|
The Multicenter 99mTc Tetrofosmin Trial has demonstrated that a previously validated8 kit preparation of a new 99mTc-labeled cationic diphosphine compound can be safely used to generate planar myocardial images of quality and diagnostic accuracy similar to the most widely used myocardial perfusion agent, 201TI. In 224 patients with interpretable paired 99mTc tetrofosmin and 201TI studies (90% of patients enrolled), there was a significant concordance (80%) for normal versus abnormal scan comparisons made by a blinded four-expert panel with access to quantitative data for their image analysis. When defect classification (ie, ischemic, infarcted, or mixed) of these same-day symptom-limited exercise stress-rest tetrofosmin results were correlated with comparable stress–3-hour-delay 201TI data, a reduced concordance (59%) was recorded, possibly due to the lack of a "true normal" resting 99mTc tetrofosmin study, as had been observed in prior 99mTc sestamibi studies.9 Of interest, while tetrofosmin-thallium segmental defect concordances were comparable in most vascular territories, inferior wall defect detection was improved but specificity was not enhanced by use of this less-attenuated 99mTc-labeled perfusion agent.
Nonquantitative coronary angiography data, available in approximately
three quarters of the imaged population, were used to derive
99mTc tetrofosmin sensitivity data for relatively severe
coronary stenoses (
75% and 90% luminal diameter reduction).
Sensitivity values and predictive accuracies in patients with and
without myocardial infarction, and normalcy rates in uncatheterized
patients with a low pretest probability of coronary artery disease,
were similar to reported planar 201TI,2 3
99mTc teboroxime,5 and 99mTc
sestamibi7 10 data. Specificity was low with both
agents
(36% to 58%), possibly due to the limited number of angiographically
normal subjects studied, the potential coexistence of microvascular
disease, and the recognized influence of posttest catheterization bias
on false-positive testing rates in this population.
|
Questions, Concerns, and Potential Solutions |
|---|
|
TopAbstractIntroductionThe Current Study Questions, Concerns, and...Is Flood Relief in...References |
|---|
Several issues concerning the study rationale and design of the Multicenter 99mTc Tetrofosmin Trial deserve further comment.
Rationale for New Drug Research and Development
The factors
governing pharmaceutical industry research and
development (R&D) are complex and may not be identical for drugs and
diagnostic agents. Business competition has been adequate justification
for the development and testing of many new therapeutic agents and
drug-delivery systems. The unique status of 201TI in the
1980s as the sole commercially available single-photon perfusion agent
may have potentiated 99mTc radiotracer R&D. Quite distinct
from these economic pressures, the new drug approval process that
culminated in Food and Drug Administration approval of
99mTc sestamibi and teboroxime in 1990 also required
compelling scientific evidence of the safety and efficacy of these
agents.
A case could be made on business and scientific grounds for a Phase III international Multicenter 99mTc Tetrofosmin Trial, despite the failure of preliminary institutional studies to demonstrate any significant biokinetic or imaging advantages of this "new" agent in a limited number of patients.11 12 13 It may be less defensible to introduce 99mTc tetrofosmin into what many experts perceive as a shrinking nuclear cardiology marketplace, which has recently witnessed the "indefinite temporary recall" of 99mTc teboroxime. Indeed, the same nuclear imaging community that has failed to universally adopt 99mTc myocardial perfusion imaging may be unwilling to embrace yet another such radiotracer without significant diagnostic or cost advantages.
Defining the `Gold Standard'
While the Food and
Drug Administration has previously used
201TI as its benchmark for regulatory approval of new
perfusion radiotracers, this agent may not represent a true
scientific "gold standard." Its imaging characteristics and
biokinetic profile are not ideal for gamma camera studies, and are
unique from those of the 99mTc perfusion
agents.1 2 3 4 5 6 7
The Figure compares planar myocardial imaging
diagnostic accuracy data from the Phase III multicenter trials of
99mTc tetrofosmin1 and 99mTc
sestamibi (data on file; DuPont-Merck). When blinded expert
interpretations are used, the sensitivity, specificity, and normalcy
rates for these agents are generally comparable to 201TI.
99mTc tetrofosmin appears to offer no significant
diagnostic advantage over 99mTc sestamibi. In light of
these data, a direct comparison of these clinically comparable agents
would be interesting but may not be needed to determine their relative
diagnostic value.
|
Just as pharmacological synergy is a desirable attribute of a new drug, incremental diagnostic value is an advantageous property for a novel imaging agent. Several European and US centers have studied the incremental value of 201TI myocardial scintigraphy in patients with postinfarction14 and stable chest pain.15 16 17 A formal evaluation of these issues is probably warranted for 99mTc tetrofosmin and 99mTc sestamibi. Yet it is difficult to conceive how either of these very similar 99mTc perfusion tracers could diverge significantly on any "relative value scale" or improve significantly upon published 201TI results in this regard.
Future Study Design Considerations
In this ambitious
multicenter study, the carefully blinded core
laboratory interpretation of relatively well-standardized planar
99mTc tetrofosmin imaging data has set a high scientific
standard for future trials. In retrospect, it may be worthwhile to
reexamine why planar 99mTc tetrofosmin imaging protocol was
used when most nuclear laboratories use myocardial tomography. The
authors have successfully demonstrated that a "thrombolysis in
myocardial infarction model" for multicenter drug studies can be
modified and its general design principles applied to the evaluation of
cardiac radiotracers.
As with large therapeutic trials, clinicians and nuclear imagers who see these 99mTc tetrofosmin data may rightfully wonder: "Do the results of this multicenter study apply to my patients?" A four-expert consensus core laboratory reading session does not reflect standard clinical image interpretation in most nuclear imaging laboratories.18 Image quantification can be useful as a "second observer" during clinical reading sessions. However, the Multicenter 99mTc Tetrofosmin Trial investigators did not implement their previous recommendations for core laboratory quantification of data generated at multiple centers.19
One of the significant advantages of 99mTc-labeled radiotracers over 201TI that was not addressed by this or previous multicenter trials is the potential for incremental diagnostic value from gated planar or tomographic imaging and first-pass ventricular function studies compared with static perfusion studies. As distinct from 201TI, 99mTc perfusion agents with prolonged myocardial residence times, when administered in sufficiently high doses (10 to 30 mCi), permit acquisition of ventricular function studies with the capacity to improve test specificity,20 assist in viability assessment,21 and generate a reproducible left ventricular ejection fraction.22 23 24 In 1993, the coding committee of the American Medical Association assigned current procedural terminology codes to facilitate reimbursement for these diagnostic studies, indicating their growing importance in clinical nuclear cardiac imaging. While the availability of functional imaging equipment, reconstruction software, and processing time may be limited in clinical practice, future trial organizers should mandate that the diagnostic accuracy of combined gated functional and perfusion imaging be compared with static 201TI or 99mTc radiotracer studies to determine what (if any) incremental diagnostic value is achieved by this approach.
|
Is Flood Relief in Sight? |
|---|
|
TopAbstractIntroductionThe Current Study Questions, Concerns, and...Is Flood Relief in...References |
|---|
The positive impact of multicenter clinical research on cardiovascular medicine cannot be refuted. The controversies noted above do not devalue previous institutional or multicenter studies performed to evaluate new radiopharmaceuticals. However, a rationale and model for the rational development of new cardiac imaging agents must emerge. New radiotracers must offer patient dosimetry advantages, improved spatial or temporal image resolution, or provide diagnostic information on a previously unmeasurable but clinically relevant biological parameter. Absent obvious toxicity or bioavailability advantages or detection of a previously undiagnosable "orphan" disease, new radiotracers must meet or exceed this scientific standard. The Multicenter 99mTc Tetrofosmin Trial has demonstrated that this chemically distinctive radiotracer is biokinetically and diagnostically comparable to existing myocardial perfusion imaging agents. But this agent's apparent lack of clinical or imaging advantages should signal caution among investigators and clinicians.
While the introduction of 99mTc tetrofosmin may eventually create a market niche that drives down the cost of all myocardial imaging agents, the radiopharmaceutical industry must adapt its ongoing research efforts in response to data such as those reported by the Multicenter 99mTc Tetrofosmin Study. In this broader context, the lack of any identifiable advantage would be anticipated to significantly limit a "novel" imaging agent's chances for future clinical or marketing success. Although the Multicenter Tetrofosmin Trial represents a high-water mark in the 10-year history of 99mTc perfusion tracer investigation,25 it may now be time to temporarily close the floodgates on 99mTc-labeled myocardial imaging agent development and to proceed with greater restraint, lest "ol' man river . . . jus' keeps rollin' along," further muddying the waters of clinical nuclear cardiology.
|
Footnotes |
|---|
Reprint requests and correspondence to D. Douglas Miller, MD, Associate Professor of Medicine, St Louis University Health Sciences Center, Division of Cardiology, 14th floor, 3635 Vista Ave at Grand Blvd, PO Box 15250, St Louis, MO 63110-0250.
The opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopAbstractIntroductionThe Current Study Questions, Concerns, and...Is Flood Relief in...References |
|---|
1. Zaret BL, Rigo P, Wackers FJT, Hendel RC, Braat SH, Iskandrian AS, et al for the Tetrofosmin International Trial Study Group. Myocardial perfusion imaging with technetium-99m tetrofosmin: comparison with thallium-201 imaging and coronary angiography in a phase III multicenter trial. Circulation. 1994;90:313-319.
2.
Zaret BL, Wackers FJ. Nuclear cardiology—Medical Progress.
Parts 1-2. N Engl J Med. 1993;329:775-783 and 855-863.
3. Wackers FJ, Fetterman RC, Mattera JA, Clements JP. Quantitative planar thallium-201 stress scintigraphy: a critical evaluation of the method. Semin Nucl Med. 1985;15:46-66.[Medline] [Order article via Infotrieve]
4.
Koster K, Wackers FJ, Mattera JA, Fetterman RC. Quantitative
analysis of planar technetium-99m inonitrile myocardial perfusion
images using modified background subtraction. J Nucl Med. 1990;31:1400-1408.
5.
Dahlberg ST, Weinstein H, Hendel RC, McSherry B, Leppo JA.
Planar myocardial perfusion imaging with technetium-99m teboroxime:
comparison by vascular territory with thallium-201 and coronary
angiography. J Nucl Med. 1992;33:1783-1788.
6. Hendel RC, McSherry B, Karimeddini M, Leppo JA. Diagnostic value of a new myocardial perfusion agent, teboroxime (SQ 30217), utilizing a rapid planar imaging protocol: preliminary results. J Am Coll Cardiol. 1990;16:855-861.
7. Iskandrian AS, Heo J, Kong B, et al. Use of technetium-99m isonitrile (RP-30A) in assessing left ventricular perfusion and function at rest and during exercise in coronary artery disease, and comparison with coronary arteriography and exercise thallium-201 SPECT. Am J Cardiol. 1989;64:270-275. [Medline] [Order article via Infotrieve]
8.
Kelly JD, Forster AM, Higley B, Archer CM, Booker FS, Canning
LR, et al. Technetium-99m tetrofosmin as a new radiopharmaceutical for
myocardial imaging. J Nucl Med. 1993;34:222-227.
9. Taillefer R, Gagnon A, Laflamme L, Gregriore J, Leveille J, Phaneuf DC. Same day injections of Tc-99m methoxy isobutyl isonitrile (Hexamibi) for myocardial tomographic imaging: comparison between rest-stress and stress-rest injection sequences. Eur J Nucl Med. 1989;15:113-117. [Medline] [Order article via Infotrieve]
10.
Taillefer R, Lambert R, Essiambre R, Phaneuf DC, Leveille J.
Comparison between thallium-201, technetium-99m sestamibi and
technetium-99m teboroxime planar myocardial perfusion imaging in
detection of coronary artery disease. J Nucl Med. 1992;33:1091-1098.
11.
Jain D, Wackers FJ, Mattera J, McMahon M, Sinusas AJ, Zaret
BL. Biokinetics of technetium-99m tetrofosmin: myocardial perfusion
imaging agent: implications for a one-day imaging protocol. J
Nucl Med. 1993;34:1254-1259.
12.
Higley B, Smith FW, Smith T, Gemmell HG, Das Gupta P,
Gvozdanovic DV, et al.
Technetium-99m-1,2-bis[bis(2-ethoxyethyl)phosphino] ethane:
human biodistribution, dosimetry and safety of a new myocardial
perfusion imaging agent. J Nucl Med. 1993;34:30-38.
13.
Nakajima K, Taki J, Shuke N, Bunko H, Takata S, Hisada K.
Myocardial perfusion imaging and dynamic analysis with
technetium-99m tetrofosmin. J Nucl Med. 1993;34:1478-1484.
14. Candell-Riera J, Permanyer-Miralda G, Castell J, Ruis-Davi A, Domingo E, Alvarez-Aunon E, et al. Uncomplicated first myocardial infarction: strategy for comprehensive prognostic studies. J Am Coll Cardiol. 1991;18:1207-1219. [Abstract]
15.
Oosterhuis WP, Niemeyer MG, Kuijper AFM, Zwinderman AH,
Breeman A, Ascoop APL, et al. Evaluation of the incremental diagnostic
value and impact on patient treatment of thallium scintigraphy. J
Nucl Med. 1992;33:1727-1734.
16.
Steingart RM, Wassertheil-Smoller S, Tobin JN, Wexler J,
Budner N. Nuclear exercise testing and the management of coronary
artery disease. J Nucl Med. 1991;32:753-758.
17.
Pollock SG, Abbott RD, Boucher CA, Beller GA, Kaul S.
Independent and incremental prognostic value of tests performed in
hierarchical order to evaluate patients with suspected coronary artery
disease: validation in models based on the tests.
Circulation. 1992;85:237-248.
18.
Watson DD, Smith WH, Beller GA, Vinson EL, Taillefer R.
Blinded evaluation of planar technetium-99m sestamibi myocardial
perfusion studies. J Nucl Med. 1992;33:668-675.
19. 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]
20. DePuey EG, Rozanski A. Gated Tc-99m sestamibi SPECT to characterize fixed defects as infarct or artifact. J Nucl Med. 1992;33:927. Abstract.
21. Chua T, Kiat H, Germano G, Maurer G, van Train K, Friedman J, Berman D. Gated technetium-99m sestamibi for simultaneous assessment of stress myocardial perfusion, post-exercise regional ventricular function and myocardial viability. J Am Coll Cardiol. 1994;23:1107-1114. [Abstract]
22.
DePuey EG, Nichols K, Dobrinsky C. Left ventricular ejection
fraction assessed from gated technetium-99m sestamibi SPECT. J
Nucl Med. 1993;34:1871-1876.
23. Jones RH, Borges-Neto S, Potts JM. Simultaneous measurement of myocardial perfusion and ventricular function during exercise from a single injection of technetium-99m sestamibi in coronary artery disease. Am J Cardiol. 1990;66:68E-71E. [Medline] [Order article via Infotrieve]
24.
Borges-Neto S, Coleman RE, Jones RH. Perfusion and function at
rest and treadmill exercise using technetium-99m sestamibi: comparison
of one- and two-day protocols in normal volunteers. J Nucl
Med. 1990;31:1128-1132.
25. Jones AG, Davison A, Abrams MJ, Brodack JW, Toothaker AK, Adelstein SJ, Kassis AI. Biological studies of a new class of technetium complexes: the hexakis (alkylisonitrile) technetium (I) cations. Int J Nucl Biol. 1984;11:225-234.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||