a b s t r a c t

Background: Acute chest pain is a frequent cause of emergency department (ED) visits. Rest myocardial perfusion imaging (RMPI) during or immediately after an episode of chest pain can provide diagnostic and prognostic information concerning acute coronary syndromes.

Aim: Our purpose was to evaluate the RMPI score in risk stratification of chest pain suspected to be of cardiac ischemic origin and negative troponin assessment.

Methods: Ninety-six patients without an ongoing myocardial infarction or a history of coronary artery disease and in whom RMPI was performed in the ED because of chest pain suspected to be related with acute myocardial ischemia were included.

Follow-up was performed considering the occurrence of death, myocardial infarction, or revascularization in a 12-month period admission.

Results: Fourteen (14.6%) patients had events. According to survival analysis, the variables related with events were a history of angina (hazard ratio [HR], 4.5; P <= .01), an ischemic electrocardiogram (HR, 4.0; P <= .01), the abnormal RMPI (HR, 11.4; P <= .05), and the RMPI score (HR, 1.1; P <= .0001). When the variables of interest were forced into a multivariate model, the ?² associated with the model that includes clinical and electrocardiogram information was 16.3 (P <= .005) and in the model that also includes RMPI score, it was 23.0 (P <= .0005).

Conclusion: In a low- to intermediate-risk group of patients with suspected acute myocardial ischemia, RMPI gives not only diagnostic information but adds prognostic value to the traditional ED risk stratification tools.

(C) 2013

Background

Suspicion of an acute coronary syndrome (ACS) in patients with chest pain is a frequent cause of emergency department (ED) visits. One of the most difficult challenges is to determine whether chest pain is cardiac related and if the patient is at increased risk for a cardiac event [1-3]. High-risk patients can be identified based on clinical history, electro- cardiogram (ECG) changes, and cardiac enzyme elevation [3,4].A larger group of patients presenting, often, with a less urgent clinical scenario and varying the likelihood for coronary disease require additional testing to evaluate their risk [5,6], although sometimes this evaluation results in an unnecessary admission or a missed diagnosis [7,8].

Non-ST-segment elevation ACSs include myocardial infarction and unstable angina. If ischemia is severe enough to cause sufficient myocardial damage and the release of detectable quantities of a marker of myocardial injury, namely, cardiac troponins, the diagnosis of myocardial infarction should be accepted. Unstable angina is recognized by clinical and Electrocardiographic features.

* Corresponding author. Department of Cardiology, Faculty of Medicine, Coimbra University Coimbra Hospital and University Center, 3000-075 Coimbra, Portugal. Tel.: + 351 239 400400×11537; fax: + 351 239 837081.

E-mail address: [email protected] (M.J.V. Ferreira).

Rest myocardial perfusion imaging (RMPI) in the evaluation and risk assessment of acute chest pain was made possible by the availability of technetium-labelED flow agents (sestamibi and tetrofosmin). These radiotracers are taken up by the myocardium in proportion to blood flow. Trapped in the myocardium after administration and with minimal redistribution, image acquisition reflects the blood flow at the time of injection [9-11]. Based on the results of previous studies, the sensitivity of RMPI on the acute setting was high with somehow lower specificity values. A high negative predictive value was also found [12-15]. The information given by the perfusion images is usually looked in a dichotomous manner.

The purpose of the present study was to evaluate the perfusion score in risk stratification of patients with acute chest pain suspected to be of cardiac ischemic origin and negative troponins.

Methods

Population

The hospital where this study was performed is a 1500-bed academic-based care hospital with approximately 140 000 ED visits

0735-6757/$ - see front matter (C) 2013 http://dx.doi.org/10.1016/j.ajem.2013.09.004

per year. There is no dedicated chest pain unit. Percutaneous coronary intervention is available 24 h/d and, since 2002, it is possible to perform RMPI whenever is required by the ED department. Three hundred studies were performed until January of 2011. The patients enrolled in this study were included retrospectively based on their ED medical records, from January 1, 2002, until January 1, 2011, and were followed up for 12 months or until the occurrence of a cardiac event. The inclusion criteria were an emergency admission due to ongoing chest pain or pain within the last 6 hours and suspected ACS. Patients with an ongoing myocardial infarction (ST-elevation myocardial infarction or non-ST-elevation myocardial infarction), a history of myocardial infarction, and myocardial revascularization were exclud- ed from this study.

Patients were characterized based on the following: age, sex, type of chest pain (typical, atypical or non angina type of pain), history of angina, presence of atherosclerosis risk factors, ECG (ischemic or nonischemic), TIMI risk score, normal or abnormal RMPI, and perfusion score.

TIMI risk score was calculated at patient presentation based on age (>=65 years), 3 or more risk factors for coronary artery disease (CAD), prior coronary stenosis of 50% or more, ST-segment deviation on the ECG, at least 2 anginal events in prior 24 hours, use of aspirin in prior 7 days, and elevated serum cardiac markers [4].

Rest myocardial perfusion imaging

Rest myocardial perfusion imaging was performed by injecting the patient with technetium-99m tetrofosmin (555 mBq). Single-photon emission computed tomography images were acquired using a dual- head gamma camera (Ventri or Millenium VG) in accordance with established guidelines [9]. No attenuation correction was applied. Images were analyzed visually and defined as abnormal whenever a Perfusion defect was noted. A 17-segment scoring system was also used for semiquantification of defects according to standardized myocardial segmentation [16].

Follow-up

Patients were followed up from enrollment to a period of 12 months or until the occurrence of a cardiac ischemic event. Follow-up was performed in all of the included patients by means of the hospital consultative registries and by telephone calls made by a physician to the patient or relatives. End points were cardiac death, myocardial infarction, or myocardial revascularization.

This study was performed according to the national and local ethical standards.

Statistical analysis

Categorical variables were expressed by frequencies and com- pared using the ?² test or Fisher exact test. Continuous variables were expressed as the mean +- SD. Comparison of means was performed using the Student t test or Mann-Whitney U test whenever the distribution was not normal.

The relationship between cardiac events and risk variables was assessed using Cox regression analysis. Univariate analysis was performed by each categorical and continuous variable to predict events during the follow-up period.

To assess the impact of each model (1, clinical; 2, clinical + ECG; 3, clinical + ECG + RMPI score) on risk stratification of patients with chest pain, Cox regression multivariate analysis was used, with variables forced into the model based on the order in which they are acquired in the clinical practice. A series of models were generated with a ?², calculated by the likelihood ratio test, for each model. A P value of .05 or less was considered statistically significant. All

statistical analyses were performed using StatView 5.0.1, version for Macintosh and Windows (SAS Institute, Cary, NC).

Results

Ninety-six patients with ongoing chest pain or a recent episode of chest pain suspected to be of Cardiac origin and negative troponin (cTnI) assessment were included in this study. Table 1 summarizes the baseline characteristics of the population, including age, sex, type of pain, and presence of risk factors and of a previous history of angina relating these features with the occurrence of events. The mean age of the patients was 61.3 +- 12.7 years, 69.8% were men, and 21.9% had typical chest pain. More than (82.3%) of these patients had at least 1 risk factor for CAD. History of angina was present in 26.0% of the patients, and 17.7% had an ECG that could be related with subendocardial ischemia. TIMI score was between 0 and 2 in 82.3% of the studied patients.

Perfusion images were classified as abnormal if the summed rest perfusion score was 1 or higher. An abnormal perfusion image was present in 56.3% of the patients. A score between 1 and 3 was considered slightly abnormal. An analysis considering normal only the studies with a score higher than 3 was also performed, and an abnormal perfusion was, then, apparent in 40.6% of the patients.

In this group, there were 14 events (14.6%) during the 12 months of follow-up, 13 revascularizations, and 1 cardiac death. Rest myocardial perfusion imaging was abnormal (score >= 1) in 13 (92.9%) patients with events. The sensitivity, specificity, and positive and negative predictive value of RMPI considering the occurrence of events were 92.8%, 50%, 24.1%, and 97.6% when the definition of abnormal was an examination with a score different from 0 and were 85.7%, 67.1%, 30.8%, and 96.5% when the definition of abnormal was only the examination with a perfusion score above 3.

The mean duration of follow-up was of 314 +- 124 days. Table 2 summarizes the results of the univariate analysis of the various clinical and laboratorial predictors of cardiac events.

The variables related with cardiac events were a history of angina, an ischemic ECG, TIMI risk score, an abnormal perfusion, and the perfusion score.

In this study, Cox multivariate analysis was performed in a stepwise manner entering only clinical variables (Table 3) and clinical and ECG variables (Table 4), and a third analysis was done including clinical, ECG, and perfusion score variables (Table 5). TIMI risk score is also compared with RMPI score in these patients.

In the multivariate analysis, the independent variables related with events were the history of angina, the presence of an ECG suggestive of ischemia, and the RMPI score. When RMPI score was

Table 1

Baseline characteristics of the population according to the occurrence of events

Baseline characteristics	Events (14)	No events (82)	P
Age (y)	63.1 +- 9.5	61.0 +- 13.1	NS
Sex (male)	13 (92.9%)	54 (65.9%)	<=.05
Presence of risk factors for CAD	11 (78.6%)	68 (82.9%)	NS
Diabetes	2 (14.3%)	9 (11.0%)	NS
Hypertension	7 (50%)	54 (65.8%)	NS
Family history of CAD	3 (21.4%)	6 (7.3%)	NS
Smoking habits	4 (28.6%)	19 (23.2%)	NS
Hypercholesterolemia	4 (28.6%)	34 (41.5%)	NS
History of angina	8 (57.1%)	17 (20.7%)	<=.01
Typical chest pain	4 (28.6%)	17 (17.1%)	NS
Ischemic ECG	6 (42.9%)	11 (13.4%)	<=.02
TIMI score >=3	6 (42.9%)	11 (13.4%)	<=.02
Abnormal RMPI (score >= 1)	13 (92.9%)	41 (50%)	<=.005
Abnormal RMPI (score N 3)	12 (85.7%)	27 (32.9%)	<=.0005
RMPI score	11.7 +- 6.2	3.4 +- 5.1	<=.0001

NS, not significant.

Table 2

Cox univariate analysis

	Cox analysis		P
	HR	95% CI
Clinical predictors Age	1.0	0.9-1.0	NS
Male sex	6.0	0.8-46.0	NS
Presence of risk factors	0.8	0.2-2.9	NS
Typical chest pain	1.9	0.6-6.0	NS
History of angina	4.5	1.6-18.0	<=.01
Laboratorial predictors Ischemic ECG	4.0	1.4-11.5	<=.01
TIMI risk score	1.5	1.0-2.0	<=.05
TIMI risk score >=3	4.2	1.5-12.2	<=.01
Abnormal RMPI >=1	11.4	1.5-86.9	<=.05
Abnormal RMPI >=3	10.1	2.3-45.3	<=.005
RMPI (perfusion score)	1.1	1.1-1.2	<=.0001

CI, confidence interval; HR, hazard ratio; NS, not significant.

added to the clinical and ECG model, the prognostic value of the model became stronger (Fig. 1).

TIMI risk score includes clinical, electrocardiographic, and bio- chemical variables, and it has an obvious significance in terms of events. When the information given by the RMPI score was added to the TIMI score, the ?² given by the likelihood ratio test went from 3.8 (P <= .05) to 14.1 (P <= .001; Fig. 2).

Discussion

In the ED, the evaluation of patients with acute chest pain is a challenge and the physician is always balancing between the risk of an unnecessary admission and the risk of a premature discharge of a high-risk patient [2,6,7,17-21].

The enrolled patients in this study were mainly middle-aged men (69.8%) complaining of atypical or noncardiac chest pain (78.1%), referring at least 1 risk factor for CAD (82.3%). There were no significant differences between the group of patients with events and without events regarding to sex, age, and presence of risk factors. The history of angina was referred by a few patients (26.0%), but it was an independent predictor of events, as expected.

The ECG is a readily available diagnostic tool that provides an immediate identification of patients with a myocardial infarction with ST elevation. Establishing the correct diagnose in patients with chest pain without ST changes is much more challenging.

When the ECG shows ST-segment changes or T-wave abnormal- ities, the risk of an ACS is high. The prevalence of myocardial infarction is 80% among patients with new ST elevation and 20% among those with ST depression or T-wave inversion not known to be old [6]. In this study, 17.7% of the patients had an ECG suggestive of ischemia (T- wave changes not known to be new). The presence of ECG changes was also a predictor of events. Clinical, ECG, and biochemical variables (information about biochemical markers of injury), assessed in a dichotomous interpretation, present or absent, can be combined in scores of risk as the one used in this study-TIMI risk score.

According to TIMI risk score, this was a group of patients of low to intermediate risk. Almost all patients in this study had a TIMI risk

Table 3

Multivariate analysis: clinical model

HR CI P

Sex (male)	6.6	0.9-50.6	NS
Age	1.0	0.9-1.0	NS
History of angina	4.9	1.5-16.2	<=.01

Likelihood test: ?² = 13.2; P <= .005.

CI, confidence interval; HR, hazard ratio; NS, not significant.

Table 4

Multivariate analysis: clinical model and ECG model

	HR	CI	P
Sex (male)	5.7	0.7-44.3	NS
Age	1.0	0.8-1.0	NS
History of angina	4.8	1.5-15.8	<=.01
Ischemic ECG	2.7	0.9-8.1	NS (.07)

?² = 16.3; P <= .005.

CI, confidence interval; HR, hazard ratio; NS, not significant.

score between 0 and 2 (82.3%). A TIMI risk score of 3 or 4 was found more frequently among patients with cardiac events. TIMI risk score has proved to be a valuable scoring tool, ready to use at ED admission. According to some authors, it seems to underestimate the risk of events for patients classified with a low risk [4,22,23]. In fact, according to our results, almost all the patients had a score inferior to 3, a low-risk population, although events occurred in 14.6% of the patients.

Rest myocardial perfusion imaging has been studied extensively and found to be useful for risk stratification of patients with chest pain in the ED. Previous studies demonstrated a low risk of cardiac events in patients with chest pain and normal RMPI. The sensitivity to diagnose an evolving infarction or the presence of CAD was high with a somewhat lower specificity [12-15,24,25].

Our study was performed in the ED on patients with chest pain or an episode of pain in the last 6 hours (the last episode of pain must allow the injection of the tracer in the 6-hour interval), without a history of myocardial infarction or myocardial revascularization. Patients with an ongoing myocardial infarction were excluded from this analysis.

In patients like these, sometimes, it is not easy to identify those with a higher risk of events. Usually, a careful surveillance in a chest pain unit or even in the ED with Clinical monitoring, serial, or continuous ECG recording, institution of therapy, and selected cases, a stress test after clinical stabilization is the normal procedure. Rest myocardial perfusion imaging, in this context, can be helpful. From previous studies, this procedure is cost-effective, avoiding unneces- sary admissions and a long permanence in the hospital [26-29]. Considering unstable angina, ideally, the isotope injection should be done during ongoing chest pain or within 2 hours after chest pain relief [9]. In the present study, it was allowed an interval of 6 hours, taking into account that it is very difficult to respect the 2-hour interval in the ED, and the results of studies, as those performed with unstable angina patients or with an angioplasty model, found perfusion abnormalities several hours after the ischemic episode [30,31].

The follow-up begun immediately after enrollment, and none of the included patients had an evolving myocardial infarction defined by the established criteria for this study.

The operative characteristics of the test, considering the occur- rence of events, changed according to the definition of abnormal (cutoff >= 1 vs N 3), as expected. However, in both cases, high sensitivity and negative predictive values were found. Overall, RMPI

Table 5

Multivariate analysis: clinical model, ECG, and perfusion model

	HR	CI	P
Sex (male)	3.7	0.5-30.4	NS
Age	1.0	0.9-1.0	NS
History of angina	3.8	1.1-12.7	<=.05
Ischemic ECG	3.3	1.1-10.0	<=.05
RMPI score	1.1	1.0-1.1	<=.005

Likelihood test: ?² = 23.0; P <= .0005.

CI, confidence interval; HR, hazard ratio; NS, not significant.

Fig. 1. Comparison of predictive models of risk: clinical, clinical + ECG, and clinical + ECG + RMPI score.

identified most patients with events, and in this context, a normal examination produces a low risk of events. These results are similar to those obtained by other authors [13,32-34].

The low specificity of perfusion images could be explained, partially, by attenuation artifacts. The gated study was not performed, and so wall motion analysis could not be used to differentiate true and false small perfusion defects. The use of gating can add specificity but can also decrease sensitivity because we are dealing with a group of patients without myocardial infarction and where the contractility abnormalities are even more transient than the perfusion abnormal- ities [35].

On patients with events, larger perfusion defects were noted, and this fact leads to the conclusion that rest perfusion score could be used in risk stratification of patients with chest pain. The main objective of this study was to investigate the use of rest myocardial perfusion score in risk stratification of patients with chest pain in the ED. For that purpose, a period of 1 year was selected for follow-up. The end points were myocardial infarction, myocardial revascularization, and cardiac death. A low incidence of events was seen among patients with a normal perfusion imaging: 2.4% to 3.5%, depending on the considered cutoff of 1 or 3. Other authors had similar results [34].

Using Cox proportional hazards analysis, the influence of clinical and laboratorial variables in predicting the risk of Ischemic events was evaluated. The presence of angina, an ischemic ECG, and abnormal perfusion images had the highest hazard ratio. As categorical variables, they only allow to differentiate 2 levels of risk. Both TIMI and the perfusion scores were also independent risk variables. In a multivariate analysis, including in the model, successively, clinical, ECG, and RMPI score, the difference in ?² values proves the relationship between RMPI and cardiac events and its incremental value compared with clinical and ECG evaluation at admission level alone. Rest myocardial perfusion imaging adds also prognostic information to TIMI risk score.

Fig. 2. Comparison of prognostic value of TIMI score and TIMI score combined with RMPI score.

The incremental value of RMPI was, therefore, testified in a group of patients with chest pain and negative troponins. Swinburn et al [25] had similar results with a heterogeneous group of patients regarding ECG features and diagnose including patients with evolving myocar- dial infarction or a history of myocardial infarction.

Clinical implications

Risk stratification of patients with chest pain is a difficult task, and the tools routinely used in the ED are not always sufficient, if our goal is a prompt and safe decision.

In this study, a relationship was found between the extension of perfusion defects in RMPI and the occurrence of cardiac ischemic events. The number of abnormal examinations was a concern. A follow-up study was, by this reason, essential. A normal perfusion was associated with lower event rate.

Rest myocardial perfusion imaging seems to be useful in the evaluation of patients with chest pain, particularly on those negative troponins.

Beyond the results of the present study, we should emphasize that the cost-effectiveness of the perfusion examination in the evaluation of chest pain is associated with a reduction of unnecessary admissions, lower angiography rate, and shorter length of stay [26-28].

There are a few practical problems in the implementation of this method and its widespread adoption in the ED. These problems are caused by the cost of the radiotracer and the almost absence of active nuclear medicine laboratories 24 hours a day and 7 days a week, although whenever the possibility of performing a nuclear study exists, in particular, rest myocardial perfusion study, its results seemed to be helpful in risk stratification and therapeutic decision of patients with chest pain.

Limitations

This was an observational cohort single-center study with the limitations inherent to this kind of analysis. Coronary angiography was not performed in all of the included patients to assess the presence of CAD. To overcome this limitation, besides myocardial infarction and death, revascularization was considered an end point in patient follow-up.

Wall motion analysis, using gated acquisition, or attenuation correction was not performed, and this could contribute for a larger number of positive results of the perfusion study and lower specificity of the test.

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