Newer Imaging Methods for Triaging Patients Presenting to the Emergency Department with Chest Pain

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James McCord, MDa*, Ezra A. Amsterdam, MDb aHenry Ford Health System, Heart & Vascular Institute, 2799 West Grand Boulevard,

K-14, Detroit, MI 48202-2689, USA bDepartment of Internal Medicine, University of California School of Medicine (Davis) and Medical Center, 4860 Y Street, Suite 200, Sacramento, CA 95817, USA

Electron beam computed tomography (EBCT), also known as ultrafast CT, is highly sensitive for detecting and quantifying coronary artery calcium. Coronary artery calcium is absent in the normal vessel and occurs almost exclusively in the arteries with atherosclerosis [1-3]. The degree of coronary calcium is strongly associated with the total atherosclerotic burden [4-6]. Patients who have more coronary artery calcium are more likely to have significant angiographic obstructions and, more importantly, are known to suffer more adverse cardiac events [7-13]. These findings, and the procedure's noninvasive methodology and low cost, have provided the rationale for the use of EBCT for risk stratification of patients in the emergency department (ED) who have possible acute coronary syndrome (ACS) [14-16].

Technology considerations

EBCT involves an electron emitter rather than a standard radiograph that allows for rapid screening times. Transaxial images are obtained at 100 ms with 3-mm to 6-mm slices during one to two breath holds. Scanning is triggered near end-diastole to minimize motion artifact. No intravenous or oral contrast is required and the entire scan can be completed in 10 to 15 minutes. Multislice CT (MSCT) is another CT modality

* Corresponding author.

E-mail address: [email protected] (J. McCord).

that can assess coronary calcium, and studies have shown that this technology correlates well with EBCT for the detection of coronary calcium [17,18]. Many institutions employ MSCT for coronary calcium scoring as this CT modality can also be used for scanning other organs, and EBCT is only useful for coronary calcium quantification. However, most clinical studies have employed EBCT for cardiac risk stratification. The cost of an EBCT is approximately $400.

Histologic studies have shown that tissue densities greater than 130 Hounsfield units (a measurement that characterizes the relative density of a substance) are associated with calcified plaque. A coronary calcium score, also called the Agatston score, is calculated as a product of the area of calcification and a factor based on the maximal calcium density. A composite score to indicate the quantity of calcium detected in the entire coronary artery system is typically used: a score of 0 is considered normal, 1 to 99 is mild, 100 to 400 is moderate, and more than 400 is severe. Coronary calcium scores have also been age- and sex-adjusted as coronary calcium is more extensive in older and male patients [19]. A more recently developed calcium volume score may offer more precision as compared with the traditional Agatston score [20,21].

Coronary calcium score and cardiac risk assessment

Numerous studies have shown that that the coronary calcium score has prognostic value significance in symptomatic and asymptomatic individuals [22-31]. A study of 5365 asymptomatic individuals demonstrated 224 adverse events (death, nonfatal myocardial infarction (MI), coronary bypass surgery, or percutaneous intervention) over 3 years [23]. Individuals who have a score of more than zero had a significantly higher event rate compared with those who do not have calcium (6.1% versus 0.4% in men; 3.3% versus 1.0% in women). The magnitude of cardiac risk is directly related to the extent of calcification [24]. However, controversy has arisen concerning the additional prognostic significance of coronary calcium after accounting for traditional risk factors. In 2000, the American College of Cardiology/American Heart Association published a consensus document concerning EBCT that states, ''Importantly, the incremental value of EBCT over traditional multivariate risk assessment models has yet to be established'' [32].

Some early studies suggest that coronary calcium scores do not offer additional prognostic information after accounting for the Framingham risk score [9], which predicts cardiac risk based on age; sex; low-density lipoprotein and high-density lipoprotein cholesterol; hypertension; cigarette smoking; and diabetes mellitus [33]. The consensus document published in 2000 was written after a literature review through 1998. However, since that time publications have shown that coronary calcium scores give additional independent prognostic information. A recent meta-analysis of four studies demonstrated that an elevated coronary calcium score was associated with an increased risk for adverse cardiac events after accounting for classic cardiac risk factors [26]. Across the categories of the Framingham risk score, a study of 1461 asymptomatic individuals showed at a median of 7 years at follow-up that coronary calcium was predictive of cardiac risk among patients who had a Framingham risk score higher than 10%, but not among patients who had a score less than 10% [34]. Thus, more recent studies suggest that coronary calcium scores are independently predictive of cardiac risk even after accounting for traditional risk factors.

Electron beam CT in patients who present to the emergency department with chest pain

Between 1999 and 2001, there have been three published studies evaluating the diagnostic usefulness of EBCT in patients evaluated in the ED who had chest pain [14-16]. The first study by

McLaughlin and colleagues [14] evaluated 181 patients who were admitted to the hospital from the ED with chest pain of presumed cardiac origin. Patients were included if they had a normal or nondiagnostic ECG at presentation. Exclusion criteria were history of coronary artery disease (CAD) (MI, coronary bypass surgery, or percutaneous intervention), diagnostic ST changes or Q waves on electrocardiogram, weight more than 250 lb, initial elevated creatine kinase-myocardial band (CK-MB), and known or suspected pregnancy. Among those evaluated, 44 patients did not meet entry criteria and 4 patients did not give consent, yielding 133 patients in the final analysis. An EBCT was considered positive if the score was more than one; the results of the scan were blinded to the responsible clinician.

Patients had 30-day follow-up by phone call for adverse events such as MI (as defined by World Health Organization criteria), coronary artery bypass surgery, percutaneous intervention, or sudden cardiac death. The population was 71% African-American, Hispanic 19%, 19% White, and 1% Asian, and comprised 84 (63%) women and 50 (37%) men. The mean age was 53 + 2 years. There were 86 (64%) patients who had a positive scan and 48 (36%) patients who had a negative scan. In the entire group there were seven (5%) adverse cardiac events, including four MIs, two coronary artery bypass surgeries, and one percutaneous intervention. Among the 48 patients who had normal coronary calcium scores, there was one (2%) adverse event. This patient was a 45-year-old man who suffered a MI after cocaine use. Of the patients who had an abnormal coronary calcium scan, there were six (12%) adverse events. These findings indicated the low event rate associated with the absence of elevated coronary calcium, and the higher adverse event rate in patients who had elevated coronary calcium. However, most patients who had increased coronary calcium did not experience an adverse cardiac event.

The second study by Laudon and colleagues [15] evaluated 105 patients who had chest pain in the ED. Inclusion criteria were women between 40 and 65 years and men between 30 and 55 years; normal initial cardiac marker; and a normal or indeterminate ECG. Exclusion criteria included history of CAD; ECG with ST-segment elevation, Q waves, or left bundle-branch pattern; elevated cardiac marker at presentation, hemodynamic instability; and pregnancy. Patients had follow-up at 4 months and a coronary calcium score more than zero was considered abnormal. The need and type of stress testing was left to the discretion of the physicians who were blinded to the results of the scan.

Of these 105 patients, 54 (51%) were admitted to an inpatient cardiology service and 51 (49%) were admitted to the ED chest pain observation unit. The patient population consisted of 98 Whites, 4 African-Americans, 1 Southeast Asian, 1 Arab, and 1 Hispanic. There were 57 (54%) men and 48 (46%) women. Mean age for men was 45 years and for women 51 years. All patients underwent EBCT and 100 underwent other cardiac testing, including 58 who underwent regular stress testing; 19 who underwent exercise or pharmacologic radionuclide testing; 25 who underwent coronary angiography; and 11 who underwent rest, exercise, or pharmacologic echocardiography. Of the 100 patients who had EBCT and other cardiac testing, 46 patients had an abnormal EBCT and 54 patients had a normal EBCT. There were no patients who had a normal EBCT and abnormal other cardiac test. EBCT had 100% sensitivity, 63% specificity, 100% negative predictive value, and 30% positive predictive value for an abnormal cardiac test. At 4 months there were no adverse events in patients who had a normal EBCT.

The third study by Georgiou and colleagues [16] considered 192 patients who were evaluated in the ED and were believed to require admission to exclude MI. Patients were included if they were aged 30 years or older, had chest pain lasting at least 20 minutes in the last 12 hours, and had a nondiagnostic ECG. Patients were excluded if they had a history of CAD (coronary artery bypass surgery or percutaneous intervention), ECG findings of Q waves, ST-segment elevation more than 1 mm in two consecutive leads, T-wave inversion of 5 mm or more, hemodynamic instability, or pregnancy. There were 221 patients screened. Of these, 13 patients were excluded because of an acute cardiac event at presentation and 16 were excluded because of lack of follow-up data, yielding 192 patients for final analysis.

Of the 192 patients, 69 (36%) were White, 49 (26%) were Hispanic, 48 (25%) were African-American, and 26 (14%) were Asian-American. Prevalence of coronary calcium was significantly lower in Hispanics compared with Whites (47% versus 73%, P = .004). There were 104 (54%) men and 88 (46%) women. The average follow-up was 50 months G 10. Of the total group, 116 (60%) had some level of calcium detected. There were 58 (30%) patients who had an adverse cardiac event, 30 (16%) who had "hard" events (11 cardiac deaths and 19 nonfatal MIs), and 28 (15%) who had other cardiac events, including nine coronary artery bypass surgeries, four percutaneous interventions, 11 hospitalizations for angina, and four ischemic strokes. Patients who had higher coronary artery calcium scores had significantly more adverse cardiovascular events (Fig. 1). Dividing patients into quartiles of coronary calcium scores, there were no ''hard'' cardiac events in the first quartile, one in the second quartile, ten in the third quartile, and 19 in the fourth quartile. In a multivariate analysis, coronary calcium scores were more predictive of adverse cardiac events as compared with traditional cardiac risk factors.

Considerations regarding the potential role of electron beam CT in the emergency department

Are we ready to start using EBCT in the ED for the routine evaluation of patients who have possible ACS? Use of an ECG, followed by serial cardiac markers and then a rapid, easily performed, and inexpensive EBCT is an attractive strategy for risk stratification in this setting. For many institutions it is a major logistic challenge to provide timely stress tests, which may include imaging modalities, before discharge of low- to intermediate-risk patients from chest pain observation units. However, there are certain patients who should not have an EBCT in this setting. Patients who have known CAD, which was rightly an exclusion criterion for all three studies, are known to have high coronary calcium scores and therefore EBCT would be unlikely to aid in risk stratification. This exception is a relevant issue as

Score

Fig. 1. Patients who have chest pain screened using electron beam tomography in the emergency department. (Adapted from Georgiou D, Budoff MJ, Kaufer E, et al. Screening patients with chest pain in the emergency department using electron beam tomography: a follow-up study. J Am Coll Cardiol 2001;38:105-10; with permission.)

Score

Fig. 1. Patients who have chest pain screened using electron beam tomography in the emergency department. (Adapted from Georgiou D, Budoff MJ, Kaufer E, et al. Screening patients with chest pain in the emergency department using electron beam tomography: a follow-up study. J Am Coll Cardiol 2001;38:105-10; with permission.)

more patients who have atypical symptoms and a history of CAD are being managed in chest pain units [35]. One study demonstrated that 38% of patients evaluated in a chest pain unit had known CAD (history of MI, percutaneous intervention, or coronary artery bypass surgery) [36]. In addition, older patients are known to have a higher degree of coronary calcium even without known coronary disease. Thus, if EBCT is to have some role in risk stratification of patients in the ED who have chest pain, it would likely involve a younger population.

Although the low adverse event rates in patients who have normal EBCT scans in these three studies are impressive (Laudon, 0%; McLaughlin, 0% [excluding the one patient who had cocaine-induced MI]; Georgiou, 0.6% per year), these studies do have some significant limitations. These studies include a small number of patients. More unusual cases of adverse cardiac events, such as the patient who has MI secondary to cocaine, may become apparent if a larger number of patients were studied. Also, all three of these studies only involved a single center. Moreover, in two of the studies, the patients who were entered represented a convenience sample that may have led to selection bias. In the study by Georgiou and colleagues [16], the EBCT scanner was available 5 days per week from 7 am to 11 pm, whereas the study by Laudon and colleagues was ''limited at times in the enrollment of patients by the availability of the EBCT scanner'' [14]. The thought-provoking results of these small studies will hopefully lead the way to a larger multicenter study of consecutive patients.

A further concern of these three studies is the large proportion of positive EBCT scans: 49%, 64%, and 60% (Table 1). If an EBCT is positive, what should the next step be in patient management? All of these patients likely would not benefit from coronary angiography, as many patients would not have obstructive coronary disease as a cause of their symptoms. These patients would at least require some form of stress testing, which would make the difficult process of risk stratification even more cumbersome. In addition, the need for ''double-testing'' would likely make the strategy less cost-effective. Instead of using any degree of calcium as defining an abnormal EBCT, certain levels of calcium may be used to assist in risk stratification that may obviate the need for holding the patient for stress testing in the chest pain unit. However, the extent of coronary calcium is affected by age, sex, and race. The optimal degrees of calcium distinguished by age and gender would need to be determined to discriminate a low-risk patient who has chest pain in the ED. The ongoing Multi-Ethnic Study of Atherosclerosis (MESA) is following 6500 individuals over 10 years and will provide additional data concerning EBCT and cardiac risk assessment in a large diverse population.

Finally, although coronary artery calcium is associated with atherosclerosis, EBCT does not detect vulnerable plaques that are the most likely to lead to ACS. In fact, some vulnerable plaques may contain no calcium. A large degree of coronary calcium is associated with more extensive overall atherosclerotic burden, and therefore more stable and unstable plaques. Although more coronary calcium makes developing ACS more likely, the absence of coronary calcium does not preclude the possibility of ACS. In a study of 118 patients who had ACS (101 who had acute MI and 17 who had unstable angina), 12 (10%) had no coronary calcium detected by EBCT [37]. Patients who had ACS and a normal EBCT were significantly younger and more likely to be active

Table 1

Electron beam CT for risk-stratification in patients who have chest pain in the emergency department

Table 1

Electron beam CT for risk-stratification in patients who have chest pain in the emergency department

Number (%)

adverse events in

Number of

Age inclusion

Number (%)

Number (%)

patients who have

Study

patients

criteria in years

positive test

negative test

Follow-up

negative test

Laudon et al

105

Men aged 30-55

51 (49)

54 (51)

4m

0(0)

1999 [14]

Women aged 40-65

McLaughlin et al

134

All ages

86 (64)

48 (36)

30 d

0(0)

1999 [15]

Georgion et al

192

>30

116 (60)

76 (40)

50 m

1 (2)

2001 [16]

cigarette smokers. Thus, there may be certain groups of patients that are more prone to developing ACS in the setting of a normal EBCT.

Cardiac MRI

Cardiac MRI has diagnostic usefulness for myocardial perfusion and regional wall motion abnormalities. Wall motion abnormalities may not only be detected in MI, but transient ischemia in unstable angina may lead to stunning, which in turn can be detected by MRI. An MRI scan may be more sensitive for stunning as compared with radionuclide imaging. Kwong and colleagues [38] studied 161 consecutive patients who were evaluated in the ED for possible ACS. Inclusion criteria were 30 minutes or more of chest pain within 12 hours of presentation, age over 21 years, and weight less than 270 lb. Exclusion criteria were ST-segment elevation MI, pregnancy, significant heart failure such that patient could not lie flat, and metal prosthesis precluding MRI. Of the 161 patients, 25 (16%) had ACS, 10 had NSTEMI, and 15 had unstable angina. The sensitivity and specificity of MRI for ACS were 84% and 85%, respectively. In a multivariate regression analysis, MRI was independently associated with the diagnosis of ACS and was of greater diagnostic usefulness when compared with ECG and peak troponin-I. Considerable research is presently in progress with MRI in identifying coronary atherosclerotic lesions, including vulnerable plaques, which may prove to be of diagnostic value for patients in the ED who have chest pain of unclear origin [39].

CT coronary angiography

Major advances in noninvasive imaging of the coronary arteries by contrast-enhanced CT have stimulated considerable interest in the potential of this technique to rapidly confirm or exclude CAD in low-intermediate risk patients presenting to the ED with chest pain. Contemporary 64 slice CT scanners [40-42] have overcome many of the limitations of earlier 16 slice devices [43], resulting in recently cited gantry rotation times of 330 msec, spatial resolution of 0.4 mm and temporal resolution of 83-165 msec. Although these values are less than those of conventional coronary angiog-raphy (~0.15 mm and 0.33 sec), they are sufficient to yield diagnostic data in a large proportion of patients (Fig. 2). The accuracy of CT coronary an-giography with 64 slice scanners is based on limited comparative studies with invasive coronary angiography in elective patients. In their evaluation of 59 patients, Leber et al reported the following sensitivities of CT angiography for detecting coronary stenoses of various degrees: stenosis <50%, sensitivity 79%; stenosis >50%, sensitivity 73%; stenosis >75%, sensitivity 80% [41]. Specificity was 97%, indicating the utility of the method in identifying absence of CAD. Raff and colleagues compared invasive and CT coronary angiography in 70 patients in whom they analyzed 1,065 coronary artery segments and found a mean difference in percent stenosis of 1.3 + 14.2% [42]. Specificity, sensitivity, positive and negative predictive values of CT angiography for significant stenoses were: 86%, 95%, 66% and 98%, respectively. The latter value again indicates the reliability of a negative CT coronary angiogram in excluding CAD. However, there have been no reports of CT coronary angiography in the ED setting in patients presenting with chest pain.

Visualization of the coronary arteries by CT has important advantages that include its non-invasive methodology, rapidity, reliability in excluding severe CAD and simultaneous acquisition of other chest structures such as the aorta and pulmonary arteries. However, limitations of the technique are significant. A low heart rate (optimally, <70/min) is required to avert blurring of the images of the moving coronary arteries. Administration of a beta blocker or rate-limiting calcium channel blocker is often necessary for this purpose. Regular rhythm is also necessary precluding CT angiography in patients with atrial fibrillation or frequent ectopic beats. Even with the currently enhanced resolution, the method cannot precisely assess the severity of coronary stenoses, which has resulted in diagnostic categories such as no CAD, < 50% stenosis, > 50% stenosis and uninterpretable due to calcification or artifact. A dose of 60-100 cc of iodinated contrast is required, which may be a relative contraindication in patients with renal insufficieny. Finally, the radiation dose is higher than that with invasive coronary angiography and has led to methods for reducing the exposure of the patient [43].

Summary

Three small single-center studies using EBCT in the ED to risk stratify patients who have chest pain and nondiagnostic ECGs show promising results, but limitations of this approach are apparent. Although patients who did not have

Fig. 2. Noninvasive visualization of coronary artery anatomy by 64-slice multislice computed tomography (CT). (A ,B) Volume rendering technique depicts a severe stenosis of the right coronary artery (RCA) distal to the marginal branch, nodular coronary calcifications mainly extrinsic to the RCA lumen and normal left coronary artery. (C,D) Maximum-intensity projection demonstrates severe soft plaque of the RCA and superficial calcific plaques of the RCA and proximal left circumflex artery. (E,F) Invasive coronary angiography confirms the major stenosis of the RCA and absence of significant lesions in the left coronary artery. (From Raff GL, Gallagher MJ, O'Neill WW, et al. Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral computed tomography. J Am Coll Cardiol 2005;46:552-7; with permission.)

Fig. 2. Noninvasive visualization of coronary artery anatomy by 64-slice multislice computed tomography (CT). (A ,B) Volume rendering technique depicts a severe stenosis of the right coronary artery (RCA) distal to the marginal branch, nodular coronary calcifications mainly extrinsic to the RCA lumen and normal left coronary artery. (C,D) Maximum-intensity projection demonstrates severe soft plaque of the RCA and superficial calcific plaques of the RCA and proximal left circumflex artery. (E,F) Invasive coronary angiography confirms the major stenosis of the RCA and absence of significant lesions in the left coronary artery. (From Raff GL, Gallagher MJ, O'Neill WW, et al. Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral computed tomography. J Am Coll Cardiol 2005;46:552-7; with permission.)

coronary calcium detected by EBCT had very low adverse event rates, EBCT in this setting can be associated with poor positive predictive value that would lead to at least the need for another cardiac test, such as stress testing, or even unnecessary hospital admission. Before EBCT is adopted as routine practice in this patient population, a large multicenter study of consecutive patients is required to better ascertain for which subset of patients this would be an effective strategy. This subset would likely include a younger population that does not have a history of CAD. Ideally this would lead to a randomized diagnostic trial comparing EBCT in this population with some form of stress testing. Other imaging technologies, including cardiac MRI and MSCT, are even less well studied in this patient population, but may prove to be of value in this setting in the future.

Limited data with 64 slice scanners indicate diagnostic quality coronary imaging in many patients and a high degree of reliability of a negative study. However, although the technique has important potential, significant limitations remain and there are currently no reported studies of its utility in the ED setting.

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ELSEVIER saunders

Cardiol Clin 23 (2005) 549-557

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