EDITORIAL

Acute radionuclide perfusion imaging for evaluation of chest pain in the emergency department: Need for a large clinical trial

In this era of cost containment and application of practice guidelines to ensure appropriate use of diagnos- tic procedures and therapeutic interventions, there is a need to identify the most optimal diagnostic evaluation of patients who come to the emergency department with chest pain and a nondiagnostic resting electrocardio- gram. The goal is to admit to the hospital only patients with a high probability of an acute ischemic syndrome as a cause of the chest pain and, conversely, not to admit patients deemed at minimal risk of an acute ischemic syndrome on the basis of clinical evaluation and appro- priate selection of laboratory tests.

Nearly 7 million patients are seen each year in the emergency department with chest pain suggestive of acute ischemia. Although chest pain represents 5% of emergency department visits, only 10% to 15% of patients with chest pain are subsequently shown to have experienced an acute myocardial infarction. Also, 5% to 10% of patients with acute myocardial infarction are misdiagnosed and inadvertently sent home. Such pa- tients often have an atypical clinical presentation and a nondiagnostic electrocardiogram and are difficult to distinguish from patients with a noncardiac origin of the chest pain syndrome.

Chest pain evaluation units (CPUs) have been es- tablished in emergency departments throughout the United States. These units are oriented for the compre- hensive evaluation and management strategies deemed appropriate for patients who have chest pain. These units are particularly useful for the workup of patients whose electrocardiograms on admission do not demonstrate ST segment elevation or depression diagnostic of an acute ischemic syndrome and physical examination does not reveal a low systolic blood pressure or pulmonary rales above the bases.' The American College of Emergency Physicians, in a recently published consensus document, states, "The CPU in the emergency department should be designed for the optimal delivery of diagnostic and therapeutic modalities to patients with chest discomfort.

Reprint requests: George A. Beller, MD, Cardiovascular Division, Box 158, University of Virginia Health Sciences Center, Charlottesville, VA 22908.

J Nucl Cardiol 1996;3:546-9. Copyright © 1996 by American Society of Nuclear Cardiology. 1071-3581/96 $5.00+0 43/39/76886

546

The unit should have appropriate diagnostic testing available to identify patients with an acute myocardial infarction and acute ischemic coronary disease, and should be equipped to resuscitate patients who become unstable. ''2 CPUs have emerged because admitting to the hospital all patients "at risk" of having an acute ischemic syndrome cannot be undertaken in a cost- effective manner. The cost of observing a patient in a designated area of the emergency department to rule out an acute ischemic syndrome approximates 20% to 50% of in-hospital costs. One estimate is that the direct cost of unnecessary admissions to an acute coronary unit approximates $3 billion annually?

Two new diagnostic approaches are being evaluated to determine whether they enhance the accuracy of distinguishing patients with chest pain who have an acute coronary syndrome from those with a nonischemic origin of chest pain. The first approach involves the measurement of serum biochemical markers of myocar- dial damage such as CK-MBmass, troponin T, troponin I, and myoglobin. The earliest after the onset of chest pain that these markers provide useful diagnostic information is 6 hours, at which time point myoglobin has an 89% negative predictive value for ruling out acute myocardial damage. 4 After 7 hours after the onset of symptoms, the accuracy of myoglobin as a marker for myocardial necrosis begins to diminish rapidly. Troponin T and CK-MBmass do not achieve their maximum negative predictive value to rule out infarction until 12 hours after the onset of chest pain. 4 Recently data have shown that patients who have acute chest pain have a nondiagnostic electrocardiogram and demonstrate elevation of either troponin T or troponin I have a significantly worse outcome with respect to subsequent cardiac mortality and clinical infarction compared with patients who have no elevation of these serum markers. 5-7 Approximately 30% of patients with unstable angina demonstrate re- lease of myoglobin, troponin T, or troponin I. A limita- tion of this approach is that some patients who arrive at the emergency department more than 8 hours after the onset of chest pain may have had transient elevations of myoglobin, troponin T, or troponin I that disappear before the first blood sample is obtained. These patients with an acute infarction or unstable angina and a non- diagnostic electrocardiogram will still have to be differ- entiated from patients with a noncardiac cause of the

JOURNAL OF NUCLEAR CARDIOLOGY Beller 547 Volume 3, Number 6;546-549 Acute radionuclide peffusion imaging in emergency department

chest pain syndrome. Similarly, patients with unstable angina who never have a release of these biochemical markers still need to be distinguished from patients with no underlying coronary artery disease (CAD) and chest pain of a noncardiac origin.

The second diagnostic modality being evaluated for use in the CPU is acute myocardial perfusion imaging with one of the technetium 99m-labeled agents that do not demonstrate significant redistribution over time after intravenous injection. 8 The rationale for acute perfusion imaging is that in the setting of acute myocardial infarction or unstable angina, even with nondiagnostic electrocardiographic changes, a regional decrement in resting myocardial blood flow should be evident in the distribution of one or more stenotic or totally obstructed coronary vessels. Because 99mTc-sestamibi or 99mTc- tetrofosmin do not demonstrate rest redistribution over time, imaging can be delayed up to several hours after tracer administration, which permits mobilization of personnel required for patient transport and a nuclear cardiology laboratory technologist responsible for acqui- sition of scintigraphic data. A short delay in imaging may actually be desirable so that patients can undergo further observation and monitoring in the emergency department for a designated period of time without concern that defect resolution resulting from redistribu- tion will occur. Crucial to the success of this approach is the ability to administer intravenously the imaging agent while chest pain is still present.

To date clinical research studies seeking to validate the use of acute myocardial perfusion imaging in the emergency department for evaluation of chest pain have comprised single-institution studies with rather few numbers of patients. Christian et al. 9 found defects on 99mTc-sestamibi imaging in 13 of 14 patients who had chest pain, a nondiagnostic electrocardiogram, and no evidence of acute infarction determined by any conven- tional criteria. Varetto et al. l° performed 99mTc-sestamibi imaging in 64 patients who came to the emergency department with a suspected acute ischemic syndrome or a nondiagnostic electrocardiogram. Thirty-four patients had a normal scan, and none experienced cardiac events during follow-up or had demonstrable CAD as deter- mined by cardiac catheterization or subsequent stress testing. Thirty patients had a perfusion defect on admis- sion, and of these, 13 developed a myocardial infarction within 12 hours; CAD was diagnosed in another 14 patients, and the remaining three patients were consid- ered to not have CAD. Hilton et al. 1~ performed 99mTc- sestamibi imaging in 102 patients with chest pain sus- pected of having an ischemic origin but associated with a normal or nondiagnostic electrocardiogram. One of the 70 patients with a normal scan had an event, whereas 13% of the 15 patients with equivocal scans and 71% of

the 17 patients with abnormal scans had a cardiac event. At 3 months of follow-up, no patients with a normal scan had experienced an event. 12

Some groups have begun to look at the economic implications of the use of early risk stratification with myocardial perfusion imaging for assessment of chest pain in the emergency department. Stowers et at. ~3 reported that before the use of acute 99~Tc-sestamibi imaging in the emergency department, patients with suspicious chest pain and a nondiagnostic electrocardio- gram had a 96% hospital admission rate. After perfusion imaging was introduced at their institution, the admis- sion rate fell to approximately 60%. Using a "sesta- mibi" strategy, these investigators demonstrated a 17% reduction in hospital costs, with $923 saved per patient in the group undergoing imaging versus the group undergoing evaluation with clinical data and electrocar- diography alone. During follow-up of 180 patients from 3 to 12 months, no events were seen in those discharged from the emergency department with a negative scan. In another study of cost savings, Weissman et al. TM showed that as a result of acute 99mTc-sestamibi imaging in 50 consecutive patients coming to the emergency depart- ment with unexplained chest pain, 68% were triaged to a lower acuity unit and 58% were sent home. A total of 69.37 hospital days were prevented at an absolute cost savings of $785.92 per patient. During a subsequent 10-month follow-up included in this cost-effective analysis, no deaths or myocardial infarction occurred in the 30 patients who had a normal single-photon emis- sion computed tomography (SPECT) 99mTc-sestamibi scan. 15

On the basis of this early data on the use of acute SPECT imaging, algorithms for the use of 99mTc-sesta- mibi for acute chest pain management have been pro- posed. One such algorithm 16 was adapted from a critical pathway algorithm established by the Medical College of Virginia Hospitals Acute Cardiac Team and reprinted by DuPont Pharma with the package insert for 99mTc- sestamibi in 1995. In this algorithm, patients with chest pain with "probable unstable angina" (typical or atypi- cal prolonged symptoms >30 minutes with a normal or nondiagnostic electrocardiogram or new onset of con- gestive heart failure) and "possible unstable angina" (typical or atypical symptoms <30 minutes with a normal or nondiagnostic electrocardiogram) are recom- mended to have a resting perfusion study. Those patients with a negative radionuclide imaging study are either triaged to a lower acuity unit and scheduled for early stress perfusion imaging or sent home with a follow-up stress study performed in the outpatient setting, Those with a positive scan are admitted to the hospital for further evaluation and interventional strategies. Interest- ingly, the dissemination of this algorithm followed the

548 Belier JOURNAL OF NUCLEAI~ CARDIOLOGY Acute radionuclide perfusion imaging in emergency department November/December 1996, Part 1

publication of fewer than five peer-reviewed papers related to this subject, none of which included a large cohort of patients.

To date much of the data on the clinical use of acute perfusion imaging for evaluation of chest pain in the emergency department are published only in abstract form. As summarized in a previous editorial by Stowers in this Journal , 13 the logistics of setting up an acute perfusion imaging protocol in the emergency department are formidable. The cost of providing such a service around the clock is not insignificant. Continuous standby doses of the 99mTc-labeled perfusion agent must be available. An acute cardiac triage program must be in place so that emergency department physicians can accurately identify those patients who will benefit most from an acute perfusion imaging strategy. The nuclear cardiology laboratory must be able to easily accommo- date the addition of patients to the schedule with little advance notice. Emergency room nurses or physicians should ideally be trained to rapidly inject patients during acute chest pain. The logistics and costs can escalate if technologists are on call 24 hours a day to come to the CPU to inject patients with doses of the imaging agent and then image them. Finally, trained nuclear cardiolo- gists or nuclear medicine physicians must be available to perform timely interpretations of the myocardial images with many such readings undertaken "off hours."

Traditionally, new clinical applications of stress or resting radionuclide imaging are rarely tested in the milieu of a large multicenter trial. Almost no nuclear cardiology studies have a randomization process in their study design. The diagnostic and prognostic applications of planar and SPECT myocardial perfusion imaging are predominantly evaluated in single-center studies, which only recently made up more than several hundred pa- tients. When multicenter studies have been undertaken, often no more than five or six institutions have partici- pated, and the total number of patients enrolled are often no greater than the number enrolled in single-institution trials.

Acute myocardial perfusion imaging for the assess- ment of patients coming to the emergency department with chest pain and a suspected acute ischemic syn- drome is an exciting new application of SPECT perfu- sion imaging that potentially may be quite cost-effective and enhance quality of care. Conversely, acute perfusion imaging may merely add cost and be no better than observing such patients in a CPU for 8 to 12 hours to obtain serial electrocardiographic tracings and to ex- clude acute myocardial damage by assaying one of the new serum biochemical markers previously described. Patients with evolving new ST segment or T wave abnormalities or elevation of one of these markers would be admitted to the hospital. Patients with no

abnormal elevation of one of these markers (e.g., tropo- nin T troponin I) during the first 12 hours could be triaged directly for elective SPECT perfusion imaging with 99mTc-sestamibi or 99mTc-tetrofosmin during the standard hours of the operation of the nuclear cardiology laboratory. A rest imaging study would be performed first with either 8 mCi of the 99mTc-labeled tracer or 3 mCi of thallium 201 (for dual-isotope imaging). If the resting study is clearly abnormal, the exercise portion of the test would be deferred and the patient admitted with a presumptive diagnosis of unstable angina. If the rest- ing perfusion study is normal, then the exercise portion of the test can be undertaken with 25 to 28 mCi of the 99mTc-labeled agent. If the exercise SPECT study is normal, the patient can then be reassured that underlying CAD is an unlikely cause of the chest pain. If the exercise study shows an inducible defect, then the probability of CAD is high and further diagnostic and management strategies would be undertaken. These may involve coronary angiography or medical management depending on the extent and severity of the perfusion abnormality. This strategy might ultimately be more cost-effective and more convenient for emergency de- partment and nuclear cardiology laboratory personnel than first performing an acute resting 99mTc myocardial perfusion study when such patients first arrive in the emergency department. The Rapid Rule-Out of Myocar- dial Ischemia Observation study used a similar strategy with serum enzyme testing at 0, 3, 6, and 9 hours, serial electrocardiograms with continuous ST segment moni- toring, and graded exercise testing or dobutamine echocardiography if enzyme and electrocardiographic results were negative) 7 This protocol yielded consider- able savings compared with "routine care" ($898 vs $1,522).

A third approach might entail performing exercise electrocardiographic stress testing without radionuclide imaging in clinically low-risk patients with suspected unstable angina who have a normal resting electrocar- diogram and no elevation of one of the biochemical markers and using the SPECT perfusion imaging ap- proach in patients with an intermediate clinical risk of an acute ischemic syndrome.

Only with well-designed, prospective clinical stud- ies in large numbers of patients, using sophisticated outcomes and economic analyses, will the precise role of acute myocardial perfusion imaging be ascertained for application in patients who come to the emergency department with chest pain and a suspected acute is- chemic syndrome. This is an exciting area of investiga- tion in which ideally a randomized study made up of a large number of patients from multiple participating institutions and a core imaging interpretation laboratory appears warranted. Perhaps the trial can be named EDIT

/

JOURNAL OF NUCLEAR CARDIOLOGY Beller 549 Volume 3, Number 6;546-549 Acute radionuclide perfusion imaging in emergency department

(Emergency D e p a r t m e n t Imag ing Trial) in recogni t ion

o f this edi torial!

George A. Beller, MD

R e f e r e n c e s

1. Goldman L, Cook EF, Johnson PA, Brand DA, Rouan GW, Lee TH. Prediction of the need for intensive care in patients who come to the emergency departments with acute chest pain. N Engl J Med 1996;334:1498-504.

2. Graft L, Joseph T, Andelman R, et al. American College of Emergency Physicians information paper: chest pain units in emergency departments--a report from the Short-Term Observa- tion Services Section. Am J Cardiol 1995;76:1036-9.

3. Fineberg HV, Scadden D, Goldman L. Care of patients with a low probability of acute myocardial infarction: cost effectiveness of alternatives to coronary-care-unit admission. N Engl J Med 1984; 310:1301-7.

4. de Winter RJ, Koster RW, Sturk A, Sanders GT. Value of myoglobin, troponin T, and CK-MBm,~ in ruling out an acute myocardial infarction in the emergency room. Circulation 1995; 92:3401-7.

5. Lindahl B, Venge R Wallentin L, for the FRISC study group. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease. Circulation 1996;93: 1651-7.

6. Wu AHB, Abbas SA, Green S, et al. Prognostic value of cardiac troponin T in unstable angina pectoris. Am J Cardiol 1995;76: 970-2.

7. Ravkilde J, Nissen H, Horder M, Thygesen K. Independent prognostic value of serum creatine kinase isoenzyme MB mass, cardiac troponin T and myosin light chain levels in suspected acute myocardial infarction: analysis of 28 months of follow-up in 196 patients. J Am Coll Cardiol 1995;25:574-81.

8. Beller GA, Kaul S. Evaluation of chest pain in the emergency department: potential role of active radionuclide perfusion imag-

ing. ACC Curt J Rev 1996;5:68-71. 9. Christian TF, Clements IR Gibbons RJ. Noninvasive identification

of myocardium at risk in patients with acute myocardial infarction and nondiagnostic electrocardiograms with technetium-99m ses- tamibi. Circulation 1991;83:1615-20.

10. Varetto T, Cantalupi D, Altieri A, Orlandi C. Emergency room technetium-99m sestarnibi imaging to rule out acute myocardial ischemic events in patients with nondiagnostic electrocardio- grams. J Am Coll Cardiol 1993;22:1804-8.

11. Hilton TC, Thompson RC, Williams HJ, Saylors R, Fulmer H, Stowers SA. Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain. J Am Coll Cardiol 1994;23:1016-22.

12. Hilton TC, Fulmer H, Abuan T, Thompson RC, Stowers SA. Ninety-day follow-up of patients in the emergency department with chest pain who undergo initial single-photon emission com- puted tomographic perfusion scintigraphy with technetium 99m- labeled sestamibi. J Nucl Cardiol 1996;3:308-11.

13. Stowers SA. Myocardial perfusion scintigraphy for assessment of acute ischemic syndromes: can we seize the moment? J Nucl Cardiol 1995;3:274-7.

14. Weissman IA, Dickinson CZ, Dworkin HJ, O'Neill WW, Juni JE. Cost-effectiveness of myocardial perfusion imaging with SPECT in the emergency department evaluation of patients with unex- plained chest pain. Radiology 1996;199:353-7.

15. Weissman IA, Dickinson C, Dworkin H, et al. Emergency center myocardial perfusion SPECT--long-term follow-up: cost-effec- tive imaging providing diagnostic and prognostic information [Abstract], J Nucl Med 1995;36:88E

16. Tatum JL, Ornato JE Jesse RL, Peberdy MA, Katta SR. A diagnostic strategy using Tc-99m sestamibi for evaluation of pa- tients with chest pain in the emergency department [Abstract]. Circulation 1994;90:I-367.

17. Gomez MA, Anderson JL, Karagounis LA, Muhlestein JB, Mooers FB, for the ROMIO Study Group. An emergency department-based protocol for rapidly ruling out myocardial ischemia reduces hospital time and expense: results of a ran- domized study (ROMIO). J Am Coll Cardiol 1996;28:25-33.