Applied Radiology

Dr. Mast is a Fellow in Cardiology; Dr. Ravizzini is a Research Associate; and Dr. Borges-Neto is an Associate Professor of Radiology, Assistant Professor of Medicine, and Co-Director of Nuclear Cardiology in the Divisions of Nuclear Medicine and Cardiology at Duke University Medical Center, Durham, NC.

Approximately 5 million patients in the United States come to the emergency department for the evaluation of chest pain each year, and 40% are admitted for further evaluation. ¹ The evaluation of patients presenting to emergency departments (ED) with typical anginal symptoms and diagnostic electrocardiograms (EKGs) showing ST-segment depression or elevation is rarely enigmatic. Typically, these patients are admitted for inpatient care and treated with anticoagulants, anti-platelet agents, nitrates, beta-blockers, or acute reperfusion therapy.

The management and triage of patients presenting with typical or atypical chest pain and normal or non-diagnostic EKGs, however, is often problematic. Clinical and electrocardiographic criteria have relatively poor sensitivity and specificity for determining which patients truly have acute coronary syndromes, and are imperfect predictors of short- and long-term prognosis. ² Thus, many low-risk patients who ultimately prove not to have coronary artery disease (CAD) are admitted for inpatient evaluation and estimates suggest that more than $4 billion are spent annually in the U.S. on the evaluation of low-risk patients presenting with chest pain. ³ Conversely, available information suggests that 2% to 8% of patients who ultimately prove to have myocardial infarction (MI) or unstable angina are mistakenly discharged from the ED. ^4,5 In fact, the failure to treat and diagnose an acute myocardial infarction in the ED accounts for the largest settlements of malpractice lawsuits. ⁶ Chest pain units have been introduced recently in many centers in attempt to reduce cost and streamline management of low-risk patients with acute chest pain. Many such units utilize a rapid "rule-out MI" protocol consisting of serial EKG analysis and cardiac enzymatic markers, including CPK/MB and troponin, followed by early stress testing in attempt to risk stratify patients presenting with acute chest pain. ⁷

Recently, in attempt to risk stratify patients while still in the ED, a number of studies have evaluated acute myocardial perfusion imaging (MPI) using Technetium-99m based agents injected during chest pain or shortly thereafter. Acute MPI in the ED has been demonstrated to have excellent sensitivity and specificity for the diagnosis of myocardial ischemia and infarction, as well providing useful short- and long-term prognostic information. In many cases, acute MPI can guide clinical decision making, as low-risk patients with negative MPI can often be discharged from the ED with timely outpatient follow-up.

This review will address the utility of acute MPI as well as the role of clinical variables and enzymatic markers of myocardial injury in the risk stratification of patients presenting with chest pain and nondiagnostic EKGs. Also, we discuss other potential uses of acute MPI, including estimation of myocardial salvage following reperfusion therapy.

Rationale

Given the limitations of history and physical examination, electrocardiography, and enzymatic markers for the diagnosis of myocardial ischemia or infarction, recently there has been much enthusiasm for the use of acute MPI in the ED for the evaluation and risk stratification of patients presenting with chest pain and non-diagnostic EKGs. The general strategy has been to inject patients, typically with Technetium-99m based radionuclide tracer agents, in the ED during or shortly after the relief of chest pain and perform single-photon computed tomographic (SPECT) myocardial perfusion imaging following stabilization of the patient. Technetium-99m based agents, such as Cardiolyte (DuPont Pharmaceuticals Co., N. Billerica, MA) or Myoview (Nycomed Amersham, Princeton, NJ) are ideally suited for this use, as they can be prepared rapidly without the need for a cyclotron; are taken up by myocardium in proportion to blood flow; and redistribute only minimally, permitting imaging at a later time when the patient has been stabilized. Often, negative acute MPI in low-risk patients with chest pain will permit safe discharge home provided prompt outpatient follow-up and exercise stress testing can be arranged. Those with positive or equivocal perfusion scans are typically admitted with plans for eventual coronary angiography or full stress and rest MPI. Figure 1 illustrates a case recently encountered in our institution in which a middle-aged woman presented to the ED with chest pain suggestive of myocardial ischemia and a non-diagnostic EKG. Initial serum enzymatic markers of myocardial injury were negative, but Tc-99m-sestamibi MPI revealed a large lateral wall perfusion defect. Cardiac catheterization later confirmed the presence of significant coronary artery disease.

Previous studies

Early studies of acute MPI in patients presenting with chest pain evaluated the utility of Thallium-201 and found reasonable sensitivity and specificity for detection of myocardial ischemia and infarction. One such study, in which Thallium-201 was injected following relief of angina in 98 patients, reported sensitivity of 76% with specificity of 67%. ⁵

Imaging with this agent in the acute setting is logistically difficult, however, as significant redistribution of thallium occurs, necessitating prompt SPECT imaging, which is impractical in unstable patients. More recent studies have evaluated the utility of Technetium-99m based agents for acute MPI (Table 1). In an early study, Bilodeau and colleagues ² evaluated 45 patients presenting with suspicion of unstable angina. All patients were injected with Tc-99m-sestamibi during or within 4 hours of chest pain and later underwent SPECT imaging. Cardiac catheterization was later performed in all patients, demonstrating significant CAD in 58%. The sensitivity of MPI for patients injected during acute chest pain was 96% while specificity was 79%. The sensitivity of EKG for significant CAD was only 35% with specificity of 74%. Interestingly, in patients injected while pain free but within 4 hours following relief of chest pain, sensitivity fell to 65% with corresponding specificity of 84%.

In a similar report, Varetto et al ⁹ described 64 patients presenting with chest pain worrisome for myocardial ischemia and non-diagnostic EKGs. All were injected with TC-99m sestamibi during or following relief of chest pain and underwent SPECT MPI. In this study, 30 of 64 patients had perfusion defects, 13 due to myocardial infarction and 14 resulting from unstable angina. False-positive images were seen in only 3 patients. Sensitivity and specificity of MPI in this study were 100% and 92%, respectively. Acute MPI also provided long-term prognostic information in this study, as at 18-month follow-up, no clinical cardiac events occurred in the 34 patients with normal images while 6 events occurred in the 30 patients with perfusion defects.

Kontos and colleagues ¹⁰ published one of the largest studies of acute MPI in ED patients. These investigators studied 532 patients with chest pain and non-diagnostic EKGs who were felt to be at low to moderate risk for acute coronary syndrome. All patients were injected during or within 6 hours of acute chest pain and underwent serial testing with enzymatic markers of myocardial injury. Acute MPI showed perfusion defects in 32% of patients and demonstrated a sensitivity of 93% for detection of MI and a sensitivity of 81% for detecting the combined endpoint of MI or need for coronary revascularization. By multivariate analysis, MPI was the only predictor of MI (P <0.0001) and was the most important predictor of MI or need for revascularization (P <0.0001). The utility of Tc-99m-tetrofosmin (Myoview) in acute MPI has only been studied recently. Heller and et al ¹¹ evaluated 357 patients presenting to 6 centers with chest pain and nondiagnostic EKGs. All patients were injected with Tc-99m-tetrofosmin during or within 6 hours of acute chest pain. Overall, 57% of patients were proven to have significant CAD. In this study, MPI imaging identified 18 of 20 patients with acute MI, for a sensitivity of 90% with a specificity of 60%. By multiple logistic analysis, MPI surpassed other clinical data as the best predictor of MI. Thus, although limited information exists evaluating technetium-99m-tetrofosmin for acute MPI, this agent appears to have similar sensitivity to technetium-99m-sestamibi.

Cost-effectiveness of acute myocardial perfusion imaging

Studies evaluating the cost-effectiveness of acute MPI in the ED have been published recently. It has been hoped that acute MPI could identify low-risk patients and permit early discharge, thus improving resource management. Weissman and coworkers ¹² performed MPI with Tc-99m-sestamibi in 50 patients presenting to the ED with chest pain and nondiagnostic EKGs. All patients were injected with radioisotope during or within 12 hours of acute chest pain. Acute MPI changed management decisions in 68% of patients and 58% were discharged directly from the ED on the basis of normal MPI. No untoward cardiac events occurred in patients with normal MPI. The average cost reduction attributable to this management style was $786 per patient.

In a study comparing 2 hypothetical model strategies for management of patients with chest pain and nondiagnostic EKGs, Radensky et al ¹³ compared hospital costs for patients undergoing acute MPI in the ED with similar patients not undergoing MPI. This model assumed that patients with negative MPI scans would be discharged with outpatient follow-up, while patients with positive or equivocal scans would be admitted. Among patients not undergoing MPI, the decision to admit or discharge was based on clinical criteria and EKG. This model calculated an average cost of $5019 per patient undergoing acute MPI in the ED compared with $6051 per patient not undergoing MPI. Thus, early information suggests that in addition to being safe, MPI appears to be a cost-effective strategy for the management of patients with chest pain and non-diagnostic EKGs.

MPI as part of a risk stratification strategy for the chest pain patient

In this era of cost containment and the need for accurate and streamlined diagnostic testing, acute MPI in conjunction with serial enzymatic testing and chest pain units may represent a feasible comprehensive strategy for the management of patients with chest pain. In a recent report, Tatum and colleagues ¹⁴ performed an observational study of 1187 consecutive patients presenting to the ED with chest pain. Within 60 minutes of presentation, each patient was assigned to 1 of 5 acuity levels on the basis of his or her perceived risk of MI. Patients were stratified as level 1 (acute myocardial infarction); level 2 (myocardial infarction or unstable angina); level 3 (probable unstable angina); level 4 (possible unstable angina); and level 5 (non-cardiac chest pain). Those in intermediate risk groups (level 3 and 4) underwent acute MPI. The sensitivity of acute MPI for myocardial infarction was 100% with a specificity of 78%. MPI had a significant effect on management, as 90% of level 4 patients were discharged directly from the ED with outpatient follow-up. At 1-year follow-up, the cardiac event rate was only 3%, with no MI or deaths in those with normal MPI; while the event rate was 42% in those with abnormal MPI. Thus, MPI is an excellent tool for acute risk stratification and also provides long-term prognostic information.

In another study including acute MPI as part of a comprehensive chest pain management strategy, Kontos et al ¹⁵ evaluated 620 low- to moderate-risk patients presenting with chest pain and nondiagnostic EKGs. All patients underwent Tc-99m-sestamibi SPECT imaging and serial enzymatic testing with CPK/MB and troponin I. Of 620 patients, 9% had documented myocardial infarction, while 13% had significant CAD. The sensitivity of MPI for detection of MI was 92% while the sensitivity of troponin I was 90%. The sensitivity for predicting revascularization or significant CAD was higher for MPI than for cardiac enzymes, although specificity of MPI was lower than that of cardiac enzymes. Furthermore, the combination of acute MPI and serial cardiac enzyme analysis proved to be extremely sensitive for detecting MI, as this combination identified all but 1 patient with MI. Furthermore, acute MPI is limited by the inability to differentiate between acute infarction, old infarction, and acute ischemia. In this instance, the use of cardiac enzymatic testing provides complimentary information that is helpful in making this distinction and increases the sensitivity for detection of MI. Thus, the combined use of MPI and cardiac enzymes is likely to provide information that is complimentary and cost-effective as part of a comprehensive strategy for the management of patients presenting with chest pain (figure 2).

Timing of radioisotope injection: Chest pain versus pain resolution

Ideally, injection of radioisotope in patients presenting to the ED with chest pain who are undergoing acute MPI is performed during chest pain, as sensitivity of MPI appears to be highest at that time. The exact time window following cessation of chest pain that allows preservation of reasonable sensitivity of MPI is unknown. Many investigators use the 2-hour time window following relief of chest pain for radioisotope injection, but this practice is based on limited data. In the study by Bidodeau and colleagues, ² patients were included if injection was performed during or up to 4 hours following relief of chest pain. Sensitivity of acute MPI was 96% for patients injected during pain but fell to 65% when injection was performed up to 4 hours following relief of symptoms. A study by Hilton et al, ¹⁶ which evaluated 102 chest pain patients with MPI, injected Tc-99m-sestamibi during chest pain and reported a sensitivity of 94% for occurrence of cardiac events. Other studies have also reported excellent sensitivities for injection of radioisotope performed following relief of symptoms. The large study by Kontos and others ¹⁰ that evaluated 532 patients injected with Tc-99m-sestamibi during or within 6 hours of relief of chest pain reported an overall sensitivity of 93% for detection of MI. In a smaller study involving 64 patients injected with Tc-99m-sestamibi during or following relief of pain (time interval not specified), sensitivity was 100% for detection of MI. ⁶ Finally, the study by Heller et al ¹¹ of 357 patients injected with Tc-99m-tetrofosmin during chest pain or within 6 hours of symptom relief reported a sensitivity of 90%.

The mechanism responsible for persistent myocardial perfusion defects in patients with myocardial ischemia following relief of chest pain is not known with certainly, but is believed to result from myocardial stunning. Jeroudi and colleagues ¹⁷ performed serial echocardiograms in 20 patients presenting with unstable angina. Wall motion abnormalities that persisted following relief of chest pain were seen in 6 patients, some with wall motion abnormalities that continued to be present up to 24 hours following cessation of chest pain. This presumed myocardial stunning, which may occur following severe ischemia, is a likely mechanism responsible for myocardial perfusion defects that persist following relief of chest pain in patients with unstable angina who do not experience MI. Thus, although it is certainly preferable to perform radioisotope injection during chest pain, it appears that excellent sensitivity can be maintained as long as injection is performed within the first few hours following relief of symptoms. In the final report to the referring clinician, many centers make mention of whether or not chest pain was present during injection, and if not, how much time had elapsed since the relief of chest pain. This information can then be considered by the ordering clinician when determining further patient management.

Comparison with echocardiography

Other investigators have evaluated chest pain patients with transthoracic echocardiography in attempt to detect acute ischemia or infarction. Peels and colleagues ¹⁸ performed echocardiography on 43 patients presenting to the ED with chest pain and nondiagnostic EKGs. All patients were imaged during active chest pain and eventually underwent cardiac catheterization for determination of presence or absence of CAD. In this study, sensitivity of echocardiography for detection of myocardial ischemia was 88% with specificity of 78%. For detection of MI, sensitivity was 92% with specificity of 53%. As with acute MPI, echocardiography can not distinguish between acute MI, old infarction, or acute ischemia. Thus, although available data is limited, rapid echocardiography may hold promise in the evaluation of the ED patient with chest pain.

Acute MPI for estimation of myocardial salvage

Other investigators have utilized acute MPI for estimation of myocardium at risk and eventual myocardial salvage in patients presenting with acute MI ^16-18 (figure 3). Radioisotope injection with Tc-99m agents can be performed during the acute coronary event prior to thrombolytic therapy or percutaneous coronary intervention. Following reperfusion, SPECT MPI is performed, followed by repeat radioisotope injection and follow-up imaging prior to discharge, in attempt to quantify how much myocardium was initially jeopardized and how successful reperfusion therapy was in salvaging myocardium at risk. Although rarely used clinically at present, this strategy is a useful research tool and has been used in establishing efficacy of drug and mechanical reperfusion techniques for acute MI.

Acute MPI in the management of patients with chest pain

The initial management of patients with ischemic chest pain and diagnostic EKG changes is usually straightforward, as these patients are typically admitted to hospital, stabilized with medical therapy, and referred for coronary angiography or stress testing. Similarly, those presenting with clearly non-cardiac chest pain are easy to triage and are generally discharged home with outpatient follow-up to explore potential non-cardiac sources of chest pain. Conversely, those patients at low to intermediate risk for an acute coronary syndrome and nondiagnostic EKGs often prove more difficult to triage toward inpatient or outpatient evaluation. These low to intermediate risk patients, who consume a sizable proportion of healthcare resources, are excellent candidates for acute MPI in the ED. Many of these low-risk patients who undergo acute MPI can be discharged safely from the ED with outpatient follow-up for full stress testing to be performed within 72 hours. Follow-up stress testing is important because it will likely increase the sensitivity for detection of CAD, especially in patients injected with radioisotopes in the ED following relief of chest pain.

Other clinical variables are also important in the management of patients presenting with acute chest pain. Serum cardiac enzymes (CPK with MB, troponin) continue to be useful in diagnosing MI, but will not be positive in ischemia. Thus, the combination of acute MPI with cardiac enzymes is often helpful in determining whether a perfusion defect is due to an acute myocardial infarction or due to ischemia or old infarction. Furthermore, as described by Kontos and colleagues, ¹³ the combination of acute MPI and cardiac enzyme testing provides excellent sensitivity for excluding myocardial infarction. It must be remembered that neither acute MPI nor cardiac enzyme testing possesses perfect sensitivity for detection of myocardial ischemia or infarction. Thus, hospital admission may still be indicated for a subset of patients having negative acute MPI scans and negative cardiac enzymes who are felt to have a high likelihood of significant CAD.

Conclusion

Acute myocardial perfusion imaging is becoming an important adjunct in the ED management of patients with chest pain and nondiagnostic EKGs. A number of studies have shown excellent sensitivity and reasonable specificity of acute MPI for detection of myocardial ischemia or infarction. Radioisotopes with minimal redistribution, such as Tc-99m-sestamibi or Tc-99m-tetrofosmin, are ideal agents as imaging can be performed when the patient has been stabilized. Preferably, patients are injected during the episode of chest pain, however, a number of studies have demonstrated preserved sensitivity in patients injected within hours of pain relief. Acute MPI also appears to be cost-effective and it is hoped that it can enhance efficacious resource utilization in low- to moderate-risk patients with chest pain. The use of acute MPI can be combined with the enzymatic markers of cardiac injury to provide complimentary information regarding the likelihood of MI or ischemia. Further studies will provide more information about the role of acute MPI in the management of patients with chest pain in the ED. AR

References

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