- Email: [email protected]
Myocardial perfusion imaging in the acute care setting
Myocardial perfusion imaging in the acute care setting Michael C. Kontos, MD INTRODUCTION Chest pain and other symptoms consistent with myocardial ischemia are a common problem seen in the emergency department (ED). In a recent analysis, conducted in 2003, they were the second most common reason for an ED visit, accounting for approximately 6% of all visits, resulting in an estimated 6.1 million visits per year.1 Despite recent technologic advances, the electrocardiogram (ECG) remains the best tool for rapid triage of these patients. However, ST-segment elevation is present in only about 20% to 30% of patients with myocardial infarction (MI). If other signs of ischemia, such as ST-segment depression and, particularly, T-wave inversion, are used as diagnostic criteria, sensitivity is significantly improved but at a cost of reduced overall specificity. Recent advances in the ability to rapidly measure the myocardial markers of necrosis, such as creatine kinase (CK)–MB, troponin T, and troponin I (TnI), can be used to detect the presence of necrosis in the ED; in some centers point-of-care markers can be used to more rapidly diagnose patients with MI.2 However, although cardiac markers such as troponin are the gold standard for identifying necrosis,3 they are limited by the requirement that a number of hours must pass after the onset of necrosis before they can be detected in the bloodstream. In addition, they are, by definition, negative in patients who only have ischemia. Therefore, after the initial evaluation is performed, most patients require further risk stratification and evaluation for diagnosis. Despite this lowest threshold for evaluating patients, there remains a significant minority of patients with MI or patients who soon progress to MI after discharge who are sent home inadvertently.4 Despite reductions in such discharge rates, estimated to be approximately 8% to 10% in initial studies,5,6 with a decrease to 2% in more recent studies,4 the rates remain From the Department of Internal Medicine, Cardiology Division, and Department of Emergency Medicine and Radiology, Virginia Commonwealth University, Richmond, Va. Reprint requests: Michael C. Kontos, MD, Room 7-074, Heart Station, North Hospital, PO Box 980051, Medical College of Virginia, 1300 E Marshall St, Richmond, VA 23298-0051; [email protected]. J Nucl Cardiol 2007;14:S125-32. 1071-3581/$32.00 Copyright © 2007 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2007.02.009
unacceptably high. An important reason for concern is that these patients do not do well; their morbidity and mortality rate was shown to be 2 to 3 times that of patients with MI who were admitted.6 These medical errors result in a substantial number of lawsuits, comprising an estimated one third of all emergency medicine lawsuits.7 As a risk avoidance strategy, a high rate of admission of patients who do not require hospitalization may occur, thereby further increasing costs. Therefore it is clear that improved means of determining which patients are having myocardial ischemia are important. In the past 10 years a number of strategies have been developed in an effort to more rapidly risk stratify chest pain patients who initially appear to be low risk, in an effort to identify the few high-risk patients among them. In one such strategy, modeled after the chest pain evaluation unit at the University of Cincinnati (Cincinnati, Ohio),8 low-risk patients who present with potential myocardial ischemia undergo an initial ECG. In the absence of ischemic changes and in the presence of other findings suggesting low risk, they are admitted to an observation area, where serial assessment of myocardial markers, and in some cases serial ECGs or continuous ST-segment monitoring, is performed over a 6- to 8-hour period. If any of these tests become positive during this time period, the patient is admitted for further evaluation. If not, stress testing for exclusion of myocardial ischemia is performed, with subsequent patient discharge if negative. BACKGROUND AND INITIAL EXPERIENCE An alternative mechanism is to use acute myocardial perfusion imaging (MPI) to identify high-risk patients. The use of this technique is based on the cascade of events that occur during an acute coronary syndrome (ACS) (Figure 1). An ACS is typically initiated with acute plaque rupture and subsequent intracoronary thrombus development. These events lead to reduced blood flow, which, when severe, results in myocardial ischemia. If this condition is prolonged, myocardial necrosis occurs. Therefore diagnostic techniques that can identify earlier components of this pathway, such as when blood flow reduction occurs, have the potential for allowing earlier identification. Numerous studies have now demonstrated that acute rest MPI is highly accurate for this process. S125
S126
Kontos Myocardial perfusion imaging in the acute care setting
Figure 1. Pathophysiologic sequence of events that occur as a result of plaque rupture, leading to ACS. The precipitating event often is disruption of a vulnerable plaque weakened by inflammation. This event exposes highly thrombogenic subendothelial components, leading to platelet adhesion, activation, and aggregation, which, along with the subsequent initiation of the plasma coagulation cascade, results in thrombus formation. Luminal obstruction resulting from thrombus can range from minimal (asymptomatic) to total occlusion (MI). Frequently, obstruction and flow reduction are in between, resulting in ischemic myocardium with no or minimal permanent damage. Diagnosis of propagating steps can be obtained with a number of currently available diagnostic tools. (Modified with permission from Jesse et al.31)
The potential advantages of using acute rest MPI in the chest pain evaluation process are numerous. It can reduce the delay to diagnosis, therapy, and triage disposition, because decreased blood flow is one of the first events in the ischemic cascade, occurring within seconds after the onset of vessel occlusion. Therefore, as will be discussed later, patients with MI can be identified more quickly than when relying on troponin levels alone. Because MPI is a tomographic imaging technique, ischemia and necrosis that occur in electrocardiographically negative portions of the heart, such as the posterior and lateral walls, can be identified accurately. By better classifying those patients who do or do not have myocardial ischemia, more accurate risk stratification can occur, thus reducing the number of “soft” admissions. Patients who are at low risk for complications can be safely discharged, whereas those who are actually having ongoing ischemia can be more appropriately treated. Through improved, efficient risk stratification, the overall costs can be reduced despite the addition of a relatively costly diagnostic tool. The use of acute MPI to identify ACS in chest pain patients is not a new concept. More than 25 years ago, Wackers et al9 used thallium 201 in intermediate-risk patients admitted to the coronary care unit (CCU) for
Journal of Nuclear Cardiology May/June 2007
Figure 2. Use of acute imaging with Tl-201 in patients admitted to cardiac care unit. Categorization of patients based on whether images were interpreted as having a defect, questionable, or normal. AMI, Acute MI; UA, unstable angina; UA/AMI, unstable angina progressing to acute MI; PMI, previous MI. (Modified with permission from Wackers et al.9)
exclusion of MI. They demonstrated a very high sensitivity for identifying not only patients with MI but also those who had unstable angina as well. Images were abnormal in all 34 patients who had acute MI (Figure 2), as well as in 27 of the 47 patients (58%) who had unstable angina. In contrast, none of the 98 patients diagnosed with stable angina or atypical chest pain had abnormal studies. Other groups have also reported similar results.10 Despite promising results from this and other studies, acute MPI never came into widespread use because of important limitations. The intrinsic properties of thallium make it a less-than-optimal imaging tracer. It is subject to attenuation, and its rapid redistribution means that imaging must be performed soon after injection. In addition, it is not generator-produced, and patient doses have to be ordered from a vendor in advance. This latter requirement is impractical and too costly given the unpredictable number of patients presenting with chest pain over a given period of time. Finally, because only planar imaging was available at the time of these studies, sensitivity was suboptimal for identifying patients who had a lesser degree of myocardial ischemia. The development of the technetium agents, specifically sestamibi and tetrofosmin, led to a renewed interest in using acute MPI for identifying ED patients with ACS. The technetium isotopes have important advantages compared with thallium. They do not redistribute,11 so patients can be injected in the ED while having symptoms and undergo imaging after clinical stabilization. The images obtained subsequently provide a snapshot of the blood flow at the time of injection. In addition, the isotope characteristics allow gating so that simultaneous assessment of wall motion and thickening,12 in addition to perfusion, is obtained, allowing the differentiation of
Journal of Nuclear Cardiology Volume 14, Number 3;S125-32
perfusion defects resulting from attenuation and those from ischemia.13 By applying specific computer algorithms, accurate quantification of ejection fraction also can be obtained. In one of the first studies to evaluate the use of technetium sestamibi in patients with potential myocardial ischemia, sestamibi imaging was performed in 64 patients who had been admitted to the CCU and had a nondiagnostic ECG.14 Of these patients, 34 had no perfusion defects, and no cardiac events were detected on subsequent follow-up of this group. In contrast, of the 30 patients who did have perfusion defects, MI was present in 13 and unstable angina was diagnosed in 14. In the first study demonstrating that acute MPI could be used as an accurate risk stratification technique in an ED setting, 102 patients who had a nonischemic ECG underwent acute imaging.15 Adverse events occurred in 12 of 17 patients (71%) who had abnormal images and in 2 of 15 (13%) who had equivocal images but in only 1 of 70 (1.4%) who had a normal scan. The only significant predictors of adverse events included 3 or more cardiac risk factors and abnormal perfusion imaging, whereas on multivariate analysis, the only independent predictor was found to be abnormal MPI findings. In a follow-up study there were no events at 90 days in patients who had normal scans.16 CLINICAL STUDIES AND TRIALS Until this point, all studies had been conducted at a single center with relatively small numbers of patients. This limitation was addressed in a multicenter study that investigated acute MPI with tetrofosmin in 357 patients with nondiagnostic ECGs who presented to 6 different medical centers.17 Overall, MI was present in 20 patients, of whom 18 (90%) had abnormal MPI findings. Revascularization was performed in 21 patients, of whom 16 had abnormal MPI findings. The sensitivity for MI was 90%, with a specificity of 60%, but more importantly, the negative predictive value was very high, at 99%. Consistent with prior results, acute MPI had significant incremental diagnostic value over clinical variables alone, with a stepwise increase in diagnostic value when added to age, gender, cardiac risk factors, chest pain characteristics, and the ECG (Figure 3). It was estimated that discharging patients who had negative MPI findings would result in an estimated cost savings of more than $4200 per patient. Although observational data demonstrated the utility of acute MPI in the chest pain evaluation process, the ultimate test is the ability of any particular technique to demonstrate its utility in a randomized controlled trial. Such utility was demonstrated by the Emergency Room Assessment of Sestamibi for Evaluation of Chest Pain
Kontos Myocardial perfusion imaging in the acute care setting
S127
Figure 3. Incremental prognostic value of rest tetrofosmin single photon emission computed tomography (SPECT) imaging over clinical variables. Model A, Clinical variables; model B, model A plus 3 or more risk factors (RF); model C, model B plus admission ECG and chest pain (CP) at time of tetrofosmin injection. (Modified with permission from Heller et al.17)
(ERASE) trial, which was a prospective, randomized, multicenter trial of 2475 patients who presented to the ED with chest pain and had either normal or nondiagnostic ECGs.18 Patients then were randomized to receive usual care or to undergo usual care with the addition of acute MPI. The primary outcome of this trial was appropriateness of the initial triage decision. Overall, the sensitivities of the 2 diagnostic strategies for identifying MI and acute ischemia were similar and not significantly different. With both treatment strategies, 1 patient with MI was missed, resulting in sensitivities of 96% and 97%, respectively. However, patients in the acute MPI arm had a significantly lower hospitalization rate, which translated into an estimated cost savings of $70 per patient. This trial demonstrated that despite the addition of expensive technology, overall costs could be reduced through more efficient care of patients with myocardial ischemia. USE OF ACUTE REST MPI IN A CHEST PAIN EVALUATION PROCESS On the basis of its successful use in multiple studies, a chest pain evaluation process that is risk-based and goal-driven was developed by the Acute Cardiac Team at the Medical College of Virginia (Virginia Commonwealth University, Richmond, Va).19 In contrast to other studies in which acute MPI was applied to low-risk patients, this chest pain evaluation protocol encompasses the entirety of the chest pain presentation, from the highest to the lowest risk. As part of this evaluation process, acute MPI is used as part of a strategy to further define risk in the group of patients for whom there is no objective evidence of ACS at the time of presentation. The initial triage level is based on the initial presentation, chest pain characteristics, initial ECG, and history
S128
Kontos Myocardial perfusion imaging in the acute care setting
Journal of Nuclear Cardiology May/June 2007
Table 1. Triage strategy based on initial presentation, chest pain characteristics, initial ECG, and history of coronary disease
Primary Probability risk Probability of assignment of AMI ischemia
Diagnostic criteria
Secondary risk Disposition stratification
Admit to CCU Serial ECGs, Ischemic ST cardiac elevation, acute markers every posterior MI 6–8 h until peak Serial ECGs; Admit to Moderate High Ischemic ECG, Level 2: cardiac CCU, fast (10%–50%) (20%–50%) acute CHF, Definite or markers at 0, track rule-in known CAD highly 3, 6, and 8 h; protocol with typical probable if rule-in for symptoms ACS AMI (markers positive), continue every 6–8 h until peak MPI; cardiac Level 3: Low Moderate Nonischemic ECG Observation: markers at 0, Fast track Probable (1%–10%) (5%–20%) and either 3, 6, and 8 h; rule-in ACS typical serial ECGs protocol symptoms ⬎30 min and no CAD or atypical symptoms ⬎30 min and known CAD Level 4: Very low Low (⬍5%) Nonischemic ECG ED evaluation MPI Possible UA (⬍1%) and either typical symptoms ⬍30 min or atypical symptoms Level 1: AMI
Level 5: Very low suspicion for AMI or UA
Very high (⬎95%)
Very low (⬍1%)
Very high (⬎95%)
Very low (⬍1%)
Evaluation must clearly document noncardiac etiology for symptoms
ED evaluation as deemed necessary
As appropriate for clinical condition
Treatment strategy Fibrinolytics within 30 min, primary PCI within 90 min
ASA, IV UFH or SC LMWH, IV and/or topical NTG, IV and/or PO -blocker, clopidogrel, GP IIb/IIIa inhibitor if TnI positive, catheterization/PCI ASA; if cardiac markers or MPI positive, treat per level 2 protocol; if negative, stress
If MPI positive, admit to level 2 treatment protocol; if MPI negative, discharge and schedule outpatient stress As appropriate for clinical condition
AMI, Acute MI; PCI, percutaneous intervention; CHF, congestive heart failure; CAD, coronary artery disease; ASA, aspirin; IV, intravenous; UFH, unfractionated heparin; SC, subcutaneous; LMWH, low–molecular weight heparin; NTG, nitroglycerin; PO, oral; GP, glycoprotein; UA, unstable angina.
of coronary disease (Table 1).19 Patients are then subsequently triaged in an initial diagnostic and treatment strategy based on these variables. High-risk patients are treated in accordance with American College of Cardiology/American Heart Association–recommended guidelines for the management of ST-elevation MI and non–ST-elevation ACS.20 Lower-risk patients are separated into 2 different
diagnostic categories, or levels, and acute MPI is used to further restratify patients. Level 3 patients are those who are estimated to have a low to moderate risk of myocardial ischemia at the time of presentation, based on having a nonischemic ECG and typical symptoms that were prolonged and no history of coronary disease, or those who have a history of coronary disease but atypical
Journal of Nuclear Cardiology Volume 14, Number 3;S125-32
Kontos Myocardial perfusion imaging in the acute care setting
S129
Table 2. Comparison of event rates based on initial triage level and on MPI results
Level 2 Level 3 Level 4 Negative MPI findings Positive MPI findings
No. of patients
MI (%)
Revascularization (%)
MI/revascularization (%)
191 160 282 338 100
25 (13) 5 (3.0) 2 (0.7) 0 (0) 7 (7)
56 (29) 27 (17) 7 (2.5) 7 (2.1) 30 (30)
64 (34) 28 (18) 8 (2.8) 7 (2.1) 32 (32)
There was a stepwise increase in MI and revascularization, as well as the combination, as risk increased from level 4 to level 2 (all significantly different [P ⬍ .05]). Patients who had positive MPI findings had an event rate similar to and not significantly different from the high-risk level 2 patients. Conversely, patients with negative MPI findings had an event rate similar to the low-risk level 4 patients. (Modified from Tatum et al.19)
symptoms. All patients undergo acute MPI with subsequent serial marker sampling as part of a rapid rule-in protocol. Patients who have positive MPI findings are retriaged to coronary angiography, whereas negative MPI findings and markers lead to stress MPI for further risk stratification. The lowest-risk patients, who have an estimated risk of myocardial ischemia of less than 5% and are similar in risk to those typically evaluated in chest pain observation units,8 are level 4 patients. They are defined by the presence of a nonischemic ECG and either short-lived typical symptoms or more prolonged atypical symptoms. In contrast to the handling of level 3 patients, the evaluation process for level 4 patients is ED-based. Patients are subsequently discharged home if images are negative, whereas those who have positive images are admitted to the CCU with increased treatment based on the higher risk. It is important to recognize that the role of acute perfusion imaging is different for these 2 different levels. For level 3 patients, a higher-risk group based on their presentation but without objective evidence of ACS, acute MPI provides an intermediate diagnostic and triage step. Positive MPI findings effectively rule in ACS, such that early invasive intervention is warranted, whereas negative MPI findings in this intermediate-risk group provide reassurance that ACS is unlikely and that early stress testing and discharge are safe. In contrast, for level 4 patients, who have a low risk for ACS, the goal of acute MPI in the ED is to identify those with unsuspected ACS to prevent inadvertent discharge, thus effectively preventing missed MI. Utilization of this strategy has been demonstrated subsequently to be an accurate and effective way of identifying high-risk patients. As demonstrated in Table 2, as the triage risk level decreased from level 2 to 4, so did the incidence of MI and the incidence of the combination of MI and revascularization.19 Patients who had positive MPI findings had outcomes similar to those of the level 2 patients, a group considered to be at high
risk for ACS. More importantly, the risk in patients with negative acute MPI findings was very low. COMPARISON WITH MARKERS OF NECROSIS One potential limitation of most of these studies is that because they appropriately included lower-risk chest pain patients, most had MI excluded, and no individual study had more than 20 patients with MI. As a result, sensitivity estimates have relatively broad confidence intervals. To address this, outcomes in 141 patients diagnosed with MI after undergoing acute MPI were analyzed.21 The sensitivity was 89% (95% confidence interval, 83%-94%), consistent with prior studies, with 125 patients having abnormal images. Patients who had MI but negative acute MPI findings had significantly lower peak CK and CK-MB values. Most studies performed via acute MPI used CK-MB as the gold standard for diagnosing MI. However, troponin is now recognized as the gold standard for identifying myocardial necrosis. Despite its high diagnostic sensitivity, cardiac markers and MPI should be considered complementary, rather than competitive, diagnostic tools for identifying ACS patients. In a study of 620 patients the diagnostic utility of these 2 tests was compared.22 By use of a CK-MB definition of MI that was the standard at the time of the study, the sensitivity was nonsignificantly higher for TnI (Figure 4). However, MPI had a significantly higher sensitivity for identifying those patients who subsequently underwent revascularization. Importantly, when compared with TnI at the time of presentation, MPI had a substantially higher sensitivity for identifying both MI and revascularization, as well as the combination of these 2 variables. An important aspect of using acute MPI in patients with myocardial ischemia is not only the ability to qualitatively identify patients who have ischemia (positive or negative) but also the ability to quantitate the overall ischemic risk area. The most important determi-
S130
Kontos Myocardial perfusion imaging in the acute care setting
Figure 4. Sensitivity of MPI (dark gray bars), initial TnI (white bars), and serial TnI (light gray bars) for identifying endpoints. Asterisk, P ⬍ .001 compared with MPI. Pound sign, P ⬍ .001 compared with serial TnI. Rev, Revascularization; Sig, significant disease (⬎70% stenosis). (Modified with permission from Kontos et al.22)
nant of infarct size is the ischemic risk zone.23 In studies in which myocardial perfusion deficit at discharge was measured with MPI, perfusion defect size correlated well with other outcome predictors, including left ventricular ejection fraction.24 The size of myocardial perfusion abnormalities is of significant clinical importance, because patients with larger defects have a worse long-term prognosis.25,26 Rest MPI results in earlier, better risk stratification than biomarkers alone. For example, 2 patients with similar low peak TnI values, one resulting from occlusion of a small branch vessel and the other resulting from brief occlusion of the proximal portion of a major vessel, would have markedly different areas at risk and the potential for markedly different outcomes. The size of the risk area also varies dramatically among those patients initially considered to be at low risk but ultimately diagnosed with MI. In a study of 141 patients who had acute rest MPI and were subsequently diagnosed with acute MI, the ischemic area at risk ranged from 0% to 62% of the left ventricle, with a mean risk area of 16% ⫾ 10% (median, 16%).27 Interestingly, the risk area in patients with normal ECGs was found to be similar to that in patients with abnormal ECGs (16% ⫾ 12% vs 19% ⫾ 12%, P ⫽ .25),27 providing a partial explanation for the high in-hospital mortality rate found in one recent large study of patients with MI who initially had a normal or nondiagnostic ECG.28 These data indicate that despite the absence of ischemic electrocardiographic changes, many patients are at a very high risk for having large areas of myocardial necrosis if not treated appropriately. Although selected subgroups of patients with known coronary artery disease are not normally considered candidates for acute MPI because of their higher pretest likelihood of ischemia, rest MPI can provide additional
Journal of Nuclear Cardiology May/June 2007
useful diagnostic information. This procedure should be limited to patients with a nonischemic ECG who have atypical symptoms, particularly if the symptoms are different from their typical angina, or to those with coronary disease who have had a recent negative cardiac evaluation. However, patients with prior MI, especially those with Q waves on the ECG, are likely to have perfusion defects, and subsequent repeat rest imaging after a pain-free period is required to differentiate new ischemia from old infarction. In recognition of the high diagnostic utility of acute radionuclide imaging, the American College of Cardiology/American Heart Association/American Society of Nuclear Cardiology guidelines for clinical utility published in 2003 have indicated that acute perfusion imaging is a class 1 indication for evaluating patients with a negative nonischemic ECG.29 Ideal candidates for acute MPI include those with symptoms suggestive of ACS and a nonischemic ECG in the absence of a prior history of MI.30 Importantly, the ability to obtain and report the results rapidly requires coordination among nuclear cardiologists, ED physicians, and other support personnel who make this technique work. LIMITATIONS OF ACUTE TECHNETIUM IMAGING: POTENTIAL ROLE FOR METABOLIC IMAGING Though a highly useful technique for evaluating patients with chest pain, acute MPI has some important limitations. The presence of a perfusion defect can indicate the presence of acute ischemia, acute infarction, or old infarction. However, differentiating these 3 in the acute setting is not always necessary, as all 3 identify a higher-risk patient. Both patients with acute ischemia and those with infarction require admission, whereas those with unsuspected prior MI are also at increased risk. If differentiation from acute ischemia is deemed important, repeat imaging in a pain-free state can be used. Resolution of a perfusion defect would indicate that the initial defect found on imaging in the ED was a result of acute ischemia; if unchanged, then prior MI is the likely etiology. Finally, sensitivity is not perfect, and in patients who have a small ischemic risk area (typically ⬍5% of the left ventricle), a defect often will not be visible. An important limitation of acute MPI is its utilization in symptom-free patients. To obtain a high sensitivity, patients should be injected while having symptoms or shortly after their cessation. However, up to 50% of patients may become pain-free shortly after presentation. In addition, sensitivity may be low in those patients who have brief, intermittent symptoms. One potential alternative strategy to deal with those who are pain-free at the time of presentation is to perfuse Tl-201 and image them
Journal of Nuclear Cardiology Volume 14, Number 3;S125-32
immediately. This procedure can be combined with a single set of markers sampled at the time of presentation. If findings of both serum markers and thallium imaging are normal, immediate stress MPI with a technetium 99m–labeled agent can be performed. However, MPI is likely to be logistically difficult in many cases, and alternative imaging strategies or isotopes would be useful for assessing this large population. Therefore an imaging agent that could detect the metabolic changes occurring as a result of ischemia would have significant utility in these patients. In conclusion, chest pain patients are a high-volume, high-risk, and high-cost population. MPI is an important technology that can identify the high-risk patients among those who have a low-risk presentation. Decreased sensitivity in the absence of symptoms indicates a need for alternative imaging techniques. Acknowledgment The author has received research funding from BristolMyers Squibb.
References 1. Xie J, Zheng ZJ, Mensah GA, et al. Emergency department visits due to chest pain in the United States [abstract]. Circulation 2006;113:E331 (p99). 2. Newby LK, Storrow AB, Gibler WB, et al. Bedside multimarker testing for risk stratification in chest pain units: the Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin, and Troponin I (CHECKMATE) study. Circulation 2001;103:1832-7. 3. Alpert JS, Thygesen K, Bassand JP, et al. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol 2000; 36:959-69. 4. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 2000;342:1163-70. 5. Schor S, Behar S, Modan B, Barell V, Drory J, Kariv I. Disposition of presumed coronary patients from an emergency room. A follow-up study. JAMA 1976;236:941-3. 6. Lee TH, Rouan GW, Weisberg MC, et al. Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room. Am J Cardiol 1987;60: 219-24. 7. Karcz A, Holbrook J, Burke MC, et al. Massachusetts emergency medicine closed malpractice claims: 1988-1990. Ann Emerg Med 1993;22:553-9. 8. Gibler WB, Runyon JP, Levy RC, et al. A rapid diagnostic and treatment center for patients with chest pain in the emergency department. Ann Emerg Med 1995;25:1-8. 9. Wackers FJ, Lie KI, Liem KL, et al. Potential value of thallium201 scintigraphy as a means of selecting patients for the coronary care unit. Br Heart J 1979;41:111-7. 10. van der Wieken LR, Kan G, Belfer AJ, et al. Thallium-201 scanning to decide CCU admission in patients with non-diagnostic electrocardiograms. Int J Cardiol 1983;4:285-99.
Kontos Myocardial perfusion imaging in the acute care setting
S131
11. Okada RD, Glover D, Gaffney T, Williams S. Myocardial kinetics of technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile. Circulation 1988;77:491-8. 12. Mannting F, Morgan-Mannting MG. Gated SPECT with technetium-99m-sestamibi for assessment of myocardial perfusion abnormalities. J Nucl Med 1993;34:601-8. 13. Kontos MC, Haney A, Jesse RL, Ornato JP, Tatum J. Perfusion defects in the absence of abnormal wall motion and thickening are not clinically significant in chest pain patients undergoing acute rest myocardial perfusion imaging [abstract]. J Am Coll Cardiol 2006;47:108A. 14. Varetto T, Cantalupi D, Altieri A, Orlandi C. Emergency room technetium-99m sestamibi imaging to rule out acute myocardial ischemic events in patients with nondiagnostic electrocardiograms. J Am Coll Cardiol 1993;22:1804-8. 15. 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. 16. Hilton TC, Fulmer H, Abuan T, et al. Ninety-day follow-up of patients in the emergency department with chest pain who undergo initial single-photon emission computed tomography perfusion scintigraphy with technetium 99m-labeled sestamibi. J Nucl Cardiol 1996;3:308-11. 17. Heller GV, Stowers SA, Hendel RC, et al. Clinical value of acute rest technetium-99m tetrofosmin tomographic myocardial perfusion imaging in patients with acute chest pain and nondiagnostic electrocardiograms. J Am Coll Cardiol 1998;31:1011-7. 18. Udelson JE, Beshansky JR, Ballin DS, et al. Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia: a randomized controlled trial. JAMA 2002;288: 2693-700. 19. Tatum JL, Jesse RL, Kontos MC, et al. Comprehensive strategy for the evaluation and triage of the chest pain patient. Ann Emerg Med 1997;29:116-25. 20. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non–STsegment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970-1062. 21. Kontos MC, Kurdziel K, McQueen R, et al. Comparison of 2-dimensional echocardiography and myocardial perfusion imaging for diagnosing myocardial infarction in emergency department patients. Am Heart J 2002;143:659-67. 22. Kontos MC, Jesse RL, Anderson FP, et al. Comparison of myocardial perfusion imaging and cardiac troponin I in patients admitted to the emergency department with chest pain. Circulation 1999;99:2073-8. 23. Reimer KA, Jennings RB, Cobb FR, et al. Animal models for protecting ischemic myocardium: results of the NHLBI Cooperative Study. Comparison of unconscious and conscious dog models. Circ Res 1985;56:651-65. 24. Christian TF, Behrenbeck T, Gersh BJ, et al. Relation of left ventricular volume and function over one year after acute myocardial infarction to infarct size determined by technetium-99m sestamibi. Am J Cardiol 1991;68:21-6. 25. Miller TD, Christian TF, Hopfenspirger MR, et al. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation 1995;92:334-41. 26. Miller TD, Hodge DO, Sutton JM, et al. Usefulness of technetium-99m sestamibi infarct size in predicting posthospital
S132
Kontos Myocardial perfusion imaging in the acute care setting
mortality following acute myocardial infarction. Am J Cardiol 1998;81:1491-3. 27. Kontos MC, Kurdziel KA, Ornato JP, et al. A nonischemic electrocardiogram does not always predict a small myocardial infarction: results with acute myocardial perfusion imaging. Am Heart J 2001;141:360-6. 28. Welch RD, Zalenski RJ, Frederick PD, et al. Prognostic value of a normal or nonspecific initial electrocardiogram in acute myocardial infarction. JAMA 2001;286:1977-84. 29. Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imagingexecutive summary: a report of the American College of
Journal of Nuclear Cardiology May/June 2007
Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). Circulation 2003;108:1404-18. 30. Wackers FJ, Brown K, Heller G, et al. American Society of Nuclear Cardiology position statement on radionuclide imaging in patients with suspected acute ischemic syndromes in the emergency department or chest pain center. J Nucl Cardiol 2002;9: 246-50. 31. Jesse RL, Kontos MC, Roberts CS. Diagnostic strategies for the evaluation of the patient presenting with chest pain. Prog Cardiovasc Dis 2004;46:417-37.
unacceptably high. An important reason for concern is that these patients do not do well; their morbidity and mortality rate was shown to be 2 to 3 times that of patients with MI who were admitted.6 These medical errors result in a substantial number of lawsuits, comprising an estimated one third of all emergency medicine lawsuits.7 As a risk avoidance strategy, a high rate of admission of patients who do not require hospitalization may occur, thereby further increasing costs. Therefore it is clear that improved means of determining which patients are having myocardial ischemia are important. In the past 10 years a number of strategies have been developed in an effort to more rapidly risk stratify chest pain patients who initially appear to be low risk, in an effort to identify the few high-risk patients among them. In one such strategy, modeled after the chest pain evaluation unit at the University of Cincinnati (Cincinnati, Ohio),8 low-risk patients who present with potential myocardial ischemia undergo an initial ECG. In the absence of ischemic changes and in the presence of other findings suggesting low risk, they are admitted to an observation area, where serial assessment of myocardial markers, and in some cases serial ECGs or continuous ST-segment monitoring, is performed over a 6- to 8-hour period. If any of these tests become positive during this time period, the patient is admitted for further evaluation. If not, stress testing for exclusion of myocardial ischemia is performed, with subsequent patient discharge if negative. BACKGROUND AND INITIAL EXPERIENCE An alternative mechanism is to use acute myocardial perfusion imaging (MPI) to identify high-risk patients. The use of this technique is based on the cascade of events that occur during an acute coronary syndrome (ACS) (Figure 1). An ACS is typically initiated with acute plaque rupture and subsequent intracoronary thrombus development. These events lead to reduced blood flow, which, when severe, results in myocardial ischemia. If this condition is prolonged, myocardial necrosis occurs. Therefore diagnostic techniques that can identify earlier components of this pathway, such as when blood flow reduction occurs, have the potential for allowing earlier identification. Numerous studies have now demonstrated that acute rest MPI is highly accurate for this process. S125
S126
Kontos Myocardial perfusion imaging in the acute care setting
Figure 1. Pathophysiologic sequence of events that occur as a result of plaque rupture, leading to ACS. The precipitating event often is disruption of a vulnerable plaque weakened by inflammation. This event exposes highly thrombogenic subendothelial components, leading to platelet adhesion, activation, and aggregation, which, along with the subsequent initiation of the plasma coagulation cascade, results in thrombus formation. Luminal obstruction resulting from thrombus can range from minimal (asymptomatic) to total occlusion (MI). Frequently, obstruction and flow reduction are in between, resulting in ischemic myocardium with no or minimal permanent damage. Diagnosis of propagating steps can be obtained with a number of currently available diagnostic tools. (Modified with permission from Jesse et al.31)
The potential advantages of using acute rest MPI in the chest pain evaluation process are numerous. It can reduce the delay to diagnosis, therapy, and triage disposition, because decreased blood flow is one of the first events in the ischemic cascade, occurring within seconds after the onset of vessel occlusion. Therefore, as will be discussed later, patients with MI can be identified more quickly than when relying on troponin levels alone. Because MPI is a tomographic imaging technique, ischemia and necrosis that occur in electrocardiographically negative portions of the heart, such as the posterior and lateral walls, can be identified accurately. By better classifying those patients who do or do not have myocardial ischemia, more accurate risk stratification can occur, thus reducing the number of “soft” admissions. Patients who are at low risk for complications can be safely discharged, whereas those who are actually having ongoing ischemia can be more appropriately treated. Through improved, efficient risk stratification, the overall costs can be reduced despite the addition of a relatively costly diagnostic tool. The use of acute MPI to identify ACS in chest pain patients is not a new concept. More than 25 years ago, Wackers et al9 used thallium 201 in intermediate-risk patients admitted to the coronary care unit (CCU) for
Journal of Nuclear Cardiology May/June 2007
Figure 2. Use of acute imaging with Tl-201 in patients admitted to cardiac care unit. Categorization of patients based on whether images were interpreted as having a defect, questionable, or normal. AMI, Acute MI; UA, unstable angina; UA/AMI, unstable angina progressing to acute MI; PMI, previous MI. (Modified with permission from Wackers et al.9)
exclusion of MI. They demonstrated a very high sensitivity for identifying not only patients with MI but also those who had unstable angina as well. Images were abnormal in all 34 patients who had acute MI (Figure 2), as well as in 27 of the 47 patients (58%) who had unstable angina. In contrast, none of the 98 patients diagnosed with stable angina or atypical chest pain had abnormal studies. Other groups have also reported similar results.10 Despite promising results from this and other studies, acute MPI never came into widespread use because of important limitations. The intrinsic properties of thallium make it a less-than-optimal imaging tracer. It is subject to attenuation, and its rapid redistribution means that imaging must be performed soon after injection. In addition, it is not generator-produced, and patient doses have to be ordered from a vendor in advance. This latter requirement is impractical and too costly given the unpredictable number of patients presenting with chest pain over a given period of time. Finally, because only planar imaging was available at the time of these studies, sensitivity was suboptimal for identifying patients who had a lesser degree of myocardial ischemia. The development of the technetium agents, specifically sestamibi and tetrofosmin, led to a renewed interest in using acute MPI for identifying ED patients with ACS. The technetium isotopes have important advantages compared with thallium. They do not redistribute,11 so patients can be injected in the ED while having symptoms and undergo imaging after clinical stabilization. The images obtained subsequently provide a snapshot of the blood flow at the time of injection. In addition, the isotope characteristics allow gating so that simultaneous assessment of wall motion and thickening,12 in addition to perfusion, is obtained, allowing the differentiation of
Journal of Nuclear Cardiology Volume 14, Number 3;S125-32
perfusion defects resulting from attenuation and those from ischemia.13 By applying specific computer algorithms, accurate quantification of ejection fraction also can be obtained. In one of the first studies to evaluate the use of technetium sestamibi in patients with potential myocardial ischemia, sestamibi imaging was performed in 64 patients who had been admitted to the CCU and had a nondiagnostic ECG.14 Of these patients, 34 had no perfusion defects, and no cardiac events were detected on subsequent follow-up of this group. In contrast, of the 30 patients who did have perfusion defects, MI was present in 13 and unstable angina was diagnosed in 14. In the first study demonstrating that acute MPI could be used as an accurate risk stratification technique in an ED setting, 102 patients who had a nonischemic ECG underwent acute imaging.15 Adverse events occurred in 12 of 17 patients (71%) who had abnormal images and in 2 of 15 (13%) who had equivocal images but in only 1 of 70 (1.4%) who had a normal scan. The only significant predictors of adverse events included 3 or more cardiac risk factors and abnormal perfusion imaging, whereas on multivariate analysis, the only independent predictor was found to be abnormal MPI findings. In a follow-up study there were no events at 90 days in patients who had normal scans.16 CLINICAL STUDIES AND TRIALS Until this point, all studies had been conducted at a single center with relatively small numbers of patients. This limitation was addressed in a multicenter study that investigated acute MPI with tetrofosmin in 357 patients with nondiagnostic ECGs who presented to 6 different medical centers.17 Overall, MI was present in 20 patients, of whom 18 (90%) had abnormal MPI findings. Revascularization was performed in 21 patients, of whom 16 had abnormal MPI findings. The sensitivity for MI was 90%, with a specificity of 60%, but more importantly, the negative predictive value was very high, at 99%. Consistent with prior results, acute MPI had significant incremental diagnostic value over clinical variables alone, with a stepwise increase in diagnostic value when added to age, gender, cardiac risk factors, chest pain characteristics, and the ECG (Figure 3). It was estimated that discharging patients who had negative MPI findings would result in an estimated cost savings of more than $4200 per patient. Although observational data demonstrated the utility of acute MPI in the chest pain evaluation process, the ultimate test is the ability of any particular technique to demonstrate its utility in a randomized controlled trial. Such utility was demonstrated by the Emergency Room Assessment of Sestamibi for Evaluation of Chest Pain
Kontos Myocardial perfusion imaging in the acute care setting
S127
Figure 3. Incremental prognostic value of rest tetrofosmin single photon emission computed tomography (SPECT) imaging over clinical variables. Model A, Clinical variables; model B, model A plus 3 or more risk factors (RF); model C, model B plus admission ECG and chest pain (CP) at time of tetrofosmin injection. (Modified with permission from Heller et al.17)
(ERASE) trial, which was a prospective, randomized, multicenter trial of 2475 patients who presented to the ED with chest pain and had either normal or nondiagnostic ECGs.18 Patients then were randomized to receive usual care or to undergo usual care with the addition of acute MPI. The primary outcome of this trial was appropriateness of the initial triage decision. Overall, the sensitivities of the 2 diagnostic strategies for identifying MI and acute ischemia were similar and not significantly different. With both treatment strategies, 1 patient with MI was missed, resulting in sensitivities of 96% and 97%, respectively. However, patients in the acute MPI arm had a significantly lower hospitalization rate, which translated into an estimated cost savings of $70 per patient. This trial demonstrated that despite the addition of expensive technology, overall costs could be reduced through more efficient care of patients with myocardial ischemia. USE OF ACUTE REST MPI IN A CHEST PAIN EVALUATION PROCESS On the basis of its successful use in multiple studies, a chest pain evaluation process that is risk-based and goal-driven was developed by the Acute Cardiac Team at the Medical College of Virginia (Virginia Commonwealth University, Richmond, Va).19 In contrast to other studies in which acute MPI was applied to low-risk patients, this chest pain evaluation protocol encompasses the entirety of the chest pain presentation, from the highest to the lowest risk. As part of this evaluation process, acute MPI is used as part of a strategy to further define risk in the group of patients for whom there is no objective evidence of ACS at the time of presentation. The initial triage level is based on the initial presentation, chest pain characteristics, initial ECG, and history
S128
Kontos Myocardial perfusion imaging in the acute care setting
Journal of Nuclear Cardiology May/June 2007
Table 1. Triage strategy based on initial presentation, chest pain characteristics, initial ECG, and history of coronary disease
Primary Probability risk Probability of assignment of AMI ischemia
Diagnostic criteria
Secondary risk Disposition stratification
Admit to CCU Serial ECGs, Ischemic ST cardiac elevation, acute markers every posterior MI 6–8 h until peak Serial ECGs; Admit to Moderate High Ischemic ECG, Level 2: cardiac CCU, fast (10%–50%) (20%–50%) acute CHF, Definite or markers at 0, track rule-in known CAD highly 3, 6, and 8 h; protocol with typical probable if rule-in for symptoms ACS AMI (markers positive), continue every 6–8 h until peak MPI; cardiac Level 3: Low Moderate Nonischemic ECG Observation: markers at 0, Fast track Probable (1%–10%) (5%–20%) and either 3, 6, and 8 h; rule-in ACS typical serial ECGs protocol symptoms ⬎30 min and no CAD or atypical symptoms ⬎30 min and known CAD Level 4: Very low Low (⬍5%) Nonischemic ECG ED evaluation MPI Possible UA (⬍1%) and either typical symptoms ⬍30 min or atypical symptoms Level 1: AMI
Level 5: Very low suspicion for AMI or UA
Very high (⬎95%)
Very low (⬍1%)
Very high (⬎95%)
Very low (⬍1%)
Evaluation must clearly document noncardiac etiology for symptoms
ED evaluation as deemed necessary
As appropriate for clinical condition
Treatment strategy Fibrinolytics within 30 min, primary PCI within 90 min
ASA, IV UFH or SC LMWH, IV and/or topical NTG, IV and/or PO -blocker, clopidogrel, GP IIb/IIIa inhibitor if TnI positive, catheterization/PCI ASA; if cardiac markers or MPI positive, treat per level 2 protocol; if negative, stress
If MPI positive, admit to level 2 treatment protocol; if MPI negative, discharge and schedule outpatient stress As appropriate for clinical condition
AMI, Acute MI; PCI, percutaneous intervention; CHF, congestive heart failure; CAD, coronary artery disease; ASA, aspirin; IV, intravenous; UFH, unfractionated heparin; SC, subcutaneous; LMWH, low–molecular weight heparin; NTG, nitroglycerin; PO, oral; GP, glycoprotein; UA, unstable angina.
of coronary disease (Table 1).19 Patients are then subsequently triaged in an initial diagnostic and treatment strategy based on these variables. High-risk patients are treated in accordance with American College of Cardiology/American Heart Association–recommended guidelines for the management of ST-elevation MI and non–ST-elevation ACS.20 Lower-risk patients are separated into 2 different
diagnostic categories, or levels, and acute MPI is used to further restratify patients. Level 3 patients are those who are estimated to have a low to moderate risk of myocardial ischemia at the time of presentation, based on having a nonischemic ECG and typical symptoms that were prolonged and no history of coronary disease, or those who have a history of coronary disease but atypical
Journal of Nuclear Cardiology Volume 14, Number 3;S125-32
Kontos Myocardial perfusion imaging in the acute care setting
S129
Table 2. Comparison of event rates based on initial triage level and on MPI results
Level 2 Level 3 Level 4 Negative MPI findings Positive MPI findings
No. of patients
MI (%)
Revascularization (%)
MI/revascularization (%)
191 160 282 338 100
25 (13) 5 (3.0) 2 (0.7) 0 (0) 7 (7)
56 (29) 27 (17) 7 (2.5) 7 (2.1) 30 (30)
64 (34) 28 (18) 8 (2.8) 7 (2.1) 32 (32)
There was a stepwise increase in MI and revascularization, as well as the combination, as risk increased from level 4 to level 2 (all significantly different [P ⬍ .05]). Patients who had positive MPI findings had an event rate similar to and not significantly different from the high-risk level 2 patients. Conversely, patients with negative MPI findings had an event rate similar to the low-risk level 4 patients. (Modified from Tatum et al.19)
symptoms. All patients undergo acute MPI with subsequent serial marker sampling as part of a rapid rule-in protocol. Patients who have positive MPI findings are retriaged to coronary angiography, whereas negative MPI findings and markers lead to stress MPI for further risk stratification. The lowest-risk patients, who have an estimated risk of myocardial ischemia of less than 5% and are similar in risk to those typically evaluated in chest pain observation units,8 are level 4 patients. They are defined by the presence of a nonischemic ECG and either short-lived typical symptoms or more prolonged atypical symptoms. In contrast to the handling of level 3 patients, the evaluation process for level 4 patients is ED-based. Patients are subsequently discharged home if images are negative, whereas those who have positive images are admitted to the CCU with increased treatment based on the higher risk. It is important to recognize that the role of acute perfusion imaging is different for these 2 different levels. For level 3 patients, a higher-risk group based on their presentation but without objective evidence of ACS, acute MPI provides an intermediate diagnostic and triage step. Positive MPI findings effectively rule in ACS, such that early invasive intervention is warranted, whereas negative MPI findings in this intermediate-risk group provide reassurance that ACS is unlikely and that early stress testing and discharge are safe. In contrast, for level 4 patients, who have a low risk for ACS, the goal of acute MPI in the ED is to identify those with unsuspected ACS to prevent inadvertent discharge, thus effectively preventing missed MI. Utilization of this strategy has been demonstrated subsequently to be an accurate and effective way of identifying high-risk patients. As demonstrated in Table 2, as the triage risk level decreased from level 2 to 4, so did the incidence of MI and the incidence of the combination of MI and revascularization.19 Patients who had positive MPI findings had outcomes similar to those of the level 2 patients, a group considered to be at high
risk for ACS. More importantly, the risk in patients with negative acute MPI findings was very low. COMPARISON WITH MARKERS OF NECROSIS One potential limitation of most of these studies is that because they appropriately included lower-risk chest pain patients, most had MI excluded, and no individual study had more than 20 patients with MI. As a result, sensitivity estimates have relatively broad confidence intervals. To address this, outcomes in 141 patients diagnosed with MI after undergoing acute MPI were analyzed.21 The sensitivity was 89% (95% confidence interval, 83%-94%), consistent with prior studies, with 125 patients having abnormal images. Patients who had MI but negative acute MPI findings had significantly lower peak CK and CK-MB values. Most studies performed via acute MPI used CK-MB as the gold standard for diagnosing MI. However, troponin is now recognized as the gold standard for identifying myocardial necrosis. Despite its high diagnostic sensitivity, cardiac markers and MPI should be considered complementary, rather than competitive, diagnostic tools for identifying ACS patients. In a study of 620 patients the diagnostic utility of these 2 tests was compared.22 By use of a CK-MB definition of MI that was the standard at the time of the study, the sensitivity was nonsignificantly higher for TnI (Figure 4). However, MPI had a significantly higher sensitivity for identifying those patients who subsequently underwent revascularization. Importantly, when compared with TnI at the time of presentation, MPI had a substantially higher sensitivity for identifying both MI and revascularization, as well as the combination of these 2 variables. An important aspect of using acute MPI in patients with myocardial ischemia is not only the ability to qualitatively identify patients who have ischemia (positive or negative) but also the ability to quantitate the overall ischemic risk area. The most important determi-
S130
Kontos Myocardial perfusion imaging in the acute care setting
Figure 4. Sensitivity of MPI (dark gray bars), initial TnI (white bars), and serial TnI (light gray bars) for identifying endpoints. Asterisk, P ⬍ .001 compared with MPI. Pound sign, P ⬍ .001 compared with serial TnI. Rev, Revascularization; Sig, significant disease (⬎70% stenosis). (Modified with permission from Kontos et al.22)
nant of infarct size is the ischemic risk zone.23 In studies in which myocardial perfusion deficit at discharge was measured with MPI, perfusion defect size correlated well with other outcome predictors, including left ventricular ejection fraction.24 The size of myocardial perfusion abnormalities is of significant clinical importance, because patients with larger defects have a worse long-term prognosis.25,26 Rest MPI results in earlier, better risk stratification than biomarkers alone. For example, 2 patients with similar low peak TnI values, one resulting from occlusion of a small branch vessel and the other resulting from brief occlusion of the proximal portion of a major vessel, would have markedly different areas at risk and the potential for markedly different outcomes. The size of the risk area also varies dramatically among those patients initially considered to be at low risk but ultimately diagnosed with MI. In a study of 141 patients who had acute rest MPI and were subsequently diagnosed with acute MI, the ischemic area at risk ranged from 0% to 62% of the left ventricle, with a mean risk area of 16% ⫾ 10% (median, 16%).27 Interestingly, the risk area in patients with normal ECGs was found to be similar to that in patients with abnormal ECGs (16% ⫾ 12% vs 19% ⫾ 12%, P ⫽ .25),27 providing a partial explanation for the high in-hospital mortality rate found in one recent large study of patients with MI who initially had a normal or nondiagnostic ECG.28 These data indicate that despite the absence of ischemic electrocardiographic changes, many patients are at a very high risk for having large areas of myocardial necrosis if not treated appropriately. Although selected subgroups of patients with known coronary artery disease are not normally considered candidates for acute MPI because of their higher pretest likelihood of ischemia, rest MPI can provide additional
Journal of Nuclear Cardiology May/June 2007
useful diagnostic information. This procedure should be limited to patients with a nonischemic ECG who have atypical symptoms, particularly if the symptoms are different from their typical angina, or to those with coronary disease who have had a recent negative cardiac evaluation. However, patients with prior MI, especially those with Q waves on the ECG, are likely to have perfusion defects, and subsequent repeat rest imaging after a pain-free period is required to differentiate new ischemia from old infarction. In recognition of the high diagnostic utility of acute radionuclide imaging, the American College of Cardiology/American Heart Association/American Society of Nuclear Cardiology guidelines for clinical utility published in 2003 have indicated that acute perfusion imaging is a class 1 indication for evaluating patients with a negative nonischemic ECG.29 Ideal candidates for acute MPI include those with symptoms suggestive of ACS and a nonischemic ECG in the absence of a prior history of MI.30 Importantly, the ability to obtain and report the results rapidly requires coordination among nuclear cardiologists, ED physicians, and other support personnel who make this technique work. LIMITATIONS OF ACUTE TECHNETIUM IMAGING: POTENTIAL ROLE FOR METABOLIC IMAGING Though a highly useful technique for evaluating patients with chest pain, acute MPI has some important limitations. The presence of a perfusion defect can indicate the presence of acute ischemia, acute infarction, or old infarction. However, differentiating these 3 in the acute setting is not always necessary, as all 3 identify a higher-risk patient. Both patients with acute ischemia and those with infarction require admission, whereas those with unsuspected prior MI are also at increased risk. If differentiation from acute ischemia is deemed important, repeat imaging in a pain-free state can be used. Resolution of a perfusion defect would indicate that the initial defect found on imaging in the ED was a result of acute ischemia; if unchanged, then prior MI is the likely etiology. Finally, sensitivity is not perfect, and in patients who have a small ischemic risk area (typically ⬍5% of the left ventricle), a defect often will not be visible. An important limitation of acute MPI is its utilization in symptom-free patients. To obtain a high sensitivity, patients should be injected while having symptoms or shortly after their cessation. However, up to 50% of patients may become pain-free shortly after presentation. In addition, sensitivity may be low in those patients who have brief, intermittent symptoms. One potential alternative strategy to deal with those who are pain-free at the time of presentation is to perfuse Tl-201 and image them
Journal of Nuclear Cardiology Volume 14, Number 3;S125-32
immediately. This procedure can be combined with a single set of markers sampled at the time of presentation. If findings of both serum markers and thallium imaging are normal, immediate stress MPI with a technetium 99m–labeled agent can be performed. However, MPI is likely to be logistically difficult in many cases, and alternative imaging strategies or isotopes would be useful for assessing this large population. Therefore an imaging agent that could detect the metabolic changes occurring as a result of ischemia would have significant utility in these patients. In conclusion, chest pain patients are a high-volume, high-risk, and high-cost population. MPI is an important technology that can identify the high-risk patients among those who have a low-risk presentation. Decreased sensitivity in the absence of symptoms indicates a need for alternative imaging techniques. Acknowledgment The author has received research funding from BristolMyers Squibb.
References 1. Xie J, Zheng ZJ, Mensah GA, et al. Emergency department visits due to chest pain in the United States [abstract]. Circulation 2006;113:E331 (p99). 2. Newby LK, Storrow AB, Gibler WB, et al. Bedside multimarker testing for risk stratification in chest pain units: the Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin, and Troponin I (CHECKMATE) study. Circulation 2001;103:1832-7. 3. Alpert JS, Thygesen K, Bassand JP, et al. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol 2000; 36:959-69. 4. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 2000;342:1163-70. 5. Schor S, Behar S, Modan B, Barell V, Drory J, Kariv I. Disposition of presumed coronary patients from an emergency room. A follow-up study. JAMA 1976;236:941-3. 6. Lee TH, Rouan GW, Weisberg MC, et al. Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room. Am J Cardiol 1987;60: 219-24. 7. Karcz A, Holbrook J, Burke MC, et al. Massachusetts emergency medicine closed malpractice claims: 1988-1990. Ann Emerg Med 1993;22:553-9. 8. Gibler WB, Runyon JP, Levy RC, et al. A rapid diagnostic and treatment center for patients with chest pain in the emergency department. Ann Emerg Med 1995;25:1-8. 9. Wackers FJ, Lie KI, Liem KL, et al. Potential value of thallium201 scintigraphy as a means of selecting patients for the coronary care unit. Br Heart J 1979;41:111-7. 10. van der Wieken LR, Kan G, Belfer AJ, et al. Thallium-201 scanning to decide CCU admission in patients with non-diagnostic electrocardiograms. Int J Cardiol 1983;4:285-99.
Kontos Myocardial perfusion imaging in the acute care setting
S131
11. Okada RD, Glover D, Gaffney T, Williams S. Myocardial kinetics of technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile. Circulation 1988;77:491-8. 12. Mannting F, Morgan-Mannting MG. Gated SPECT with technetium-99m-sestamibi for assessment of myocardial perfusion abnormalities. J Nucl Med 1993;34:601-8. 13. Kontos MC, Haney A, Jesse RL, Ornato JP, Tatum J. Perfusion defects in the absence of abnormal wall motion and thickening are not clinically significant in chest pain patients undergoing acute rest myocardial perfusion imaging [abstract]. J Am Coll Cardiol 2006;47:108A. 14. Varetto T, Cantalupi D, Altieri A, Orlandi C. Emergency room technetium-99m sestamibi imaging to rule out acute myocardial ischemic events in patients with nondiagnostic electrocardiograms. J Am Coll Cardiol 1993;22:1804-8. 15. 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. 16. Hilton TC, Fulmer H, Abuan T, et al. Ninety-day follow-up of patients in the emergency department with chest pain who undergo initial single-photon emission computed tomography perfusion scintigraphy with technetium 99m-labeled sestamibi. J Nucl Cardiol 1996;3:308-11. 17. Heller GV, Stowers SA, Hendel RC, et al. Clinical value of acute rest technetium-99m tetrofosmin tomographic myocardial perfusion imaging in patients with acute chest pain and nondiagnostic electrocardiograms. J Am Coll Cardiol 1998;31:1011-7. 18. Udelson JE, Beshansky JR, Ballin DS, et al. Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia: a randomized controlled trial. JAMA 2002;288: 2693-700. 19. Tatum JL, Jesse RL, Kontos MC, et al. Comprehensive strategy for the evaluation and triage of the chest pain patient. Ann Emerg Med 1997;29:116-25. 20. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non–STsegment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970-1062. 21. Kontos MC, Kurdziel K, McQueen R, et al. Comparison of 2-dimensional echocardiography and myocardial perfusion imaging for diagnosing myocardial infarction in emergency department patients. Am Heart J 2002;143:659-67. 22. Kontos MC, Jesse RL, Anderson FP, et al. Comparison of myocardial perfusion imaging and cardiac troponin I in patients admitted to the emergency department with chest pain. Circulation 1999;99:2073-8. 23. Reimer KA, Jennings RB, Cobb FR, et al. Animal models for protecting ischemic myocardium: results of the NHLBI Cooperative Study. Comparison of unconscious and conscious dog models. Circ Res 1985;56:651-65. 24. Christian TF, Behrenbeck T, Gersh BJ, et al. Relation of left ventricular volume and function over one year after acute myocardial infarction to infarct size determined by technetium-99m sestamibi. Am J Cardiol 1991;68:21-6. 25. Miller TD, Christian TF, Hopfenspirger MR, et al. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation 1995;92:334-41. 26. Miller TD, Hodge DO, Sutton JM, et al. Usefulness of technetium-99m sestamibi infarct size in predicting posthospital
S132
Kontos Myocardial perfusion imaging in the acute care setting
mortality following acute myocardial infarction. Am J Cardiol 1998;81:1491-3. 27. Kontos MC, Kurdziel KA, Ornato JP, et al. A nonischemic electrocardiogram does not always predict a small myocardial infarction: results with acute myocardial perfusion imaging. Am Heart J 2001;141:360-6. 28. Welch RD, Zalenski RJ, Frederick PD, et al. Prognostic value of a normal or nonspecific initial electrocardiogram in acute myocardial infarction. JAMA 2001;286:1977-84. 29. Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imagingexecutive summary: a report of the American College of
Journal of Nuclear Cardiology May/June 2007
Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). Circulation 2003;108:1404-18. 30. Wackers FJ, Brown K, Heller G, et al. American Society of Nuclear Cardiology position statement on radionuclide imaging in patients with suspected acute ischemic syndromes in the emergency department or chest pain center. J Nucl Cardiol 2002;9: 246-50. 31. Jesse RL, Kontos MC, Roberts CS. Diagnostic strategies for the evaluation of the patient presenting with chest pain. Prog Cardiovasc Dis 2004;46:417-37.