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(Circulation. 1999;100:1521-1527.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Long-Term Additive Prognostic Value of Thallium-201 Myocardial Perfusion Imaging Over Clinical and Exercise Stress Test in Low to Intermediate Risk Patients

Study in 1137 Patients With 6-Year Follow-Up

Gérald Vanzetto, MD, PhD; Olivier Ormezzano, MD; Daniel Fagret, MD, PhD; Michel Comet, MD, PhD; Bernard Denis, MD; Jacques Machecourt, MD

From the Departments of Cardiology (G.V., O.O., B.D., J.M.) and Nuclear Medicine (D.F., M.C.), University Hospital, Grenoble, France.

Correspondence to Dr Gérald Vanzetto, Clinique Cardiologique, CHU de Grenoble, BP 217, 38043 Grenoble, Cedex 9, France. E-mail Gerald.Vanzetto{at}ujf-grenoble.fr

	Abstract

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Background—The exercise treadmill test (ETT) and Tl201 single proton emission computed tomography (SPECT) are of short- to medium-term prognostic value in coronary heart disease. We assessed the long-term prognostic value of these tests in a large population of patients with low- to intermediate risk of cardiac events.

Methods and Results—One thousand one hundred thirty-seven patients (857 men, age 55±9 years) referred for typical (62.1%) or atypical (22.4%) chest pain, or suspected silent ischemia (15.5%), were followed up for 72±18 months. Overall mortality was higher after strongly positive (ST depression >2 mm, or >1 mm for a workload 75 W) (2.36%/y) or nondiagnostic ETT (1.63%/y) than after normal (0.85%/y) or positive ETT (1.37%/y) (P=0.002), and after abnormal SPECT than after normal SPECT (1.60%/y versus 0.68%/y, P=0.001). The major cardiac event rate (cardiac death or myocardial infarction [MI]) was 0.88%, 1.59%, 2.10%, and 2.13%/y after negative, positive, strongly positive, and nondiagnostic ETT, respectively (P=0.003), and 0.56%, 1.43%, and 2.05%/y in patients with 0, 1 to 2, and 3 abnormal segments on SPECT, respectively (P<0.002). An abnormal SPECT was predictive of MI (P<0.001), whereas ETT was not. In multivariate analysis, SPECT was of incremental prognostic value over clinical and ETT data for predicting overall mortality and major cardiac events.

Conclusions—The incremental predictive value of SPECT is maintained over 6 years and is particularly relevant after positive, strongly positive, and nondiagnostic ETT.

Key Words: coronary disease • prognosis • exercise • scintigraphy

	Introduction

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The aim of risk stratification in patients with known or suspected coronary artery disease (CAD) is to distinguish patients with a high likelihood of future major cardiac events—who may benefit from invasive strategy¹ —from low-risk patients in whom invasive examination is not useful. Beyond established risk factors and clinical presentation,² exercise treadmill test (ETT)^{3 4 5} and myocardial perfusion imaging^{6 7 8 9 10 11 12 13} are of short- to medium-term prognostic value for the prediction of future cardiac events. Tl201 single photon emission computed tomography (SPECT) has also been demonstrated to add significant information over clinical, ETT, and cardiac catheterization data in this setting.^{14 15 16} Recently, Hachamovitch et al refined the 2-year incremental prognostic value of perfusion imaging in a large cohort of low-¹⁷ and low- to intermediate-risk patients.¹⁸ However, the long-term additive prognostic value of Tl201-SPECT has only been reported in relatively small selected groups of patients.^{19 20 21}

The aim of our study was therefore to assess, in a large cohort of patients with low- to intermediate-likelihood of future cardiac events, whether the prognostic value of Tl201-SPECT was maintained at long-term follow-up and whether myocardial perfusion imaging was of incremental prognostic value over clinical and ETT data.

	Methods

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Patients
Between 1987 and 1989, 1693 patients were referred to our institution for an exercise stress Tl201-SPECT. Patients who underwent myocardial revascularization within 3 months before or after the scintigraphy (n=206) or had previous myocardial infarction (MI) <3 months before nuclear testing (n=266), as well as patients >75 years (n=39), were excluded. Of the 1182 remaining patients, 45 (3.8%) were lost to follow-up. Consequently, 1137 patients (96.2%), corresponding to a subset of the patients previously reported at 33 month follow-up,¹³ completed the study.

ETT
Patients performed a symptom-limited ETT on an ergometer bicycle using a standard protocol.¹³ Patients were asked to discontinue anti-ischemic drugs at least 48 hours before the test.

A semi-quantitative treadmill score was derived, with ETT being considered as (1) positive: horizontal or downsloping ST segment depression of 1 to 2 mm measured 0.08 second after the J point, occurring for a workload >75 W, with or without chest pain; (2) strongly positive: ST segment depression >2 mm at any workload, or >1 mm for a workload 75 W, or ST depression post exercise duration >6 minutes; (3) negative: when ST segment remained isoelectric and heart rate achieved 85% of maximum age-predicted heart rate; and (4) nondiagnostic in all other cases.

Tl201-SPECT
Stress-redistribution Tl201-SPECTs were performed according to a standard protocol as previously reported.¹³ After normalization to the pixel with maximum activity, the reconstructed SPECT images were displayed in standard fashion as short axis, horizontal axis, and vertical axis slices using a 256 color scale with normal areas (in red) corresponding to a Tl201 uptake >75% of maximum activity. The left ventricle was divided into 6 segments to enable comparison with the results obtained in our previous report,¹³ and images were visually analyzed by 2 experts. A segment was scored as abnormal in the event of decreased tracer uptake in a surface large enough to be considered significant by the experts. Abnormal segments were defined as reversible (partial or total normalization on redistribution imaging) or fixed.

Data Collection and End Points of the Study
Follow-up was obtained from the patients and their cardiologists using written questionnaires and telephone contacts, when necessary. If no response was obtained, an inquiry was performed with the civil authorities. End points were: (1) overall mortality; (2) cardiac mortality (sudden death or death of demonstrated cardiac origin); (3) occurrence of MI (on the basis of characteristic chest pain, ECG changes, and serum creatinine kinase level > twice the upper limit of normal value); (4) need for myocardial revascularization >3 months after Tl201-SPECT, based on occurrence of severe angina, unstable angina, or acute MI. Major cardiac events were defined by the occurrence of cardiac death or MI.

Statistical Analysis
Variables were expressed as mean value ±1SD or number (%) and compared using Student's unpaired t test or a Pearson ² test. Survival curves were traced on SPSS software using the Kaplan-Meyer method and compared using a log-rank test. When more than 1 event occurred in a patient, only the most severe event was considered in the survival analysis. Annual event rates were calculated by dividing the event rates at the end of follow-up by the mean duration of follow-up. Univariate and multivariate stepwise analyses using a Cox regression model were performed to compare the prognostic value of clinical, ETT, and Tl201-SPECT data. P value <0.05 was considered statistically significant.

	Results

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Baseline Characteristics and Follow-Up
Baseline data are summarized in Table 1. The pretest likelihood of CAD (defined by age, sex, and symptoms, as proposed by Diamond and Forrester² ) was <20% in 335 patients (29.5%), 20% to 80% in 344 patients (30.0%), and >80% in 458 patients (40.5%). The post-test likelihood of CAD (taking into account the combined results of ETT and Tl201-SPECT²² ) was <20% in 497 patients (43.7%), 20% to 80% in 316 patients (27.8%), and >80% in 324 patients (28.5%).

View this table: [in this window] [in a new window]   Table 1. Baseline Data

During follow-up (72±18 months [11 days to 8 years]), 88 patients (7.7%) died, 46 (4%) from a cardiac cause and 42 (3.7%) from a noncardiac cause. MI occurred in 57 patients (5.0%), 7 of whom died from a cardiac cause 8±4 months later. A total of 136 patients (12%) underwent myocardial revascularization (PTCA [n=63] and/or CABG [n=80]) 24±26 months after inclusion in the study.

At the end of follow-up, 273 patients were receiving ß-blockers, 182 were receiving calcium antagonists, and 682 (60%) had neither of these treatments (547 after normal ETT and normal or mildly abnormal SPECT, 62 after myocardial revascularization, and 73 despite the presence of significant ischemia on initial tests). All patients received advice for optimal eradication of risk factors. Major cardiac events and any cardiac event rates were 1.51% and 3.40%/y, respectively.

Univariate Predictors of Events
Overall Mortality
Age >60 years, previous history of MI, ETT, and Tl201-SPECT were predictors of overall mortality (Figures 1 and 2). The mortality rate was higher after a strongly positive (2.36%/y) or nondiagnostic ETT (1.63%/y) than after a negative (0.85%/y) or positive ETT (1.37%/y) (P=0.002), and after an abnormal (1.60%/y) than after a normal (0.68%/y) Tl201-SPECT (P=0.001). In patients who survived the first 3 years of follow-up, the relationship between the results of the tests and the occurrence of death was maintained for Tl201-SPECT (P=0.01) but not for ETT.

View larger version (26K): [in this window] [in a new window]   Figure 1. Kaplan-Meier overall survival curves according to results of ETT. Number of patients examined each year is indicated. indicates negative ETT; , positive ETT; , strongly positive ETT; and , nondiagnostic ETT.

View larger version (22K): [in this window] [in a new window]   Figure 2. Kaplan-Meier overall survival curves according to results of Tl201-SPECT. Number of patients examined each year is indicated. indicates normal Tl201-SPECT, and •, abnormal Tl201-SPECT.

Major Cardiac Events
Gender, previous history of MI, presence of >1 risk factor, ETT, and Tl201-SPECT were predictors of major cardiac events. The respective major cardiac event rate was 0.88%, 1.59%, 2.10%, and 2.13%/y after normal, positive, strongly positive, and nondiagnostic ETT (P=0.003), and 0.56%, 1.43%, and 2.05%/y in patients with 0, 1 to 2, and 3 abnormal segments, respectively, on Tl201-SPECT (P<0.002) (Figure 3). In patients free of events during the first 3 years, the value of ETT and Tl201-SPECT for the prediction of future major cardiac events was preserved (P=0.009 and 0.002, respectively).

View larger version (25K): [in this window] [in a new window]   Figure 3. Kaplan-Meier major cardiac event–free survival curves according to extent of hypoperfused myocardium on Tl201-SPECT. Number of patients examined each year is indicated. indicates normal Tl201-SPECT; , presence of 1 to 2 abnormal segments; and •, presence of 3 abnormal segments.

Predictors of cardiac death and MI are summarized in Table 2. The cardiac mortality rate was higher after a strongly positive or a nondiagnostic ETT than after a positive or a negative ETT (1.18% and 1.10% versus 0.44% and 0.37%/y, P=0.02), and after an abnormal than after a normal Tl201-SPECT (0.87% versus 0.30%/y, P=0.006), with a significant relationship between the number of abnormal segments and the occurrence of future cardiac death (Figures 4 and 5).

View this table: [in this window] [in a new window]   Table 2. Univariate Predictors of Cardiac Deaths and Nonfatal MI

View larger version (24K): [in this window] [in a new window]   Figure 4. Kaplan-Meier cardiac survival curves according to the number of abnormal segments on Tl201-SPECT. Number of patients examined each year is indicated. indicates normal Tl201-SPECT; , presence of 1 to 2 abnormal segments; and •, presence of 3 abnormal segments.

View larger version (33K): [in this window] [in a new window]   Figure 5. Annual event rates (%) according to the extent of perfusion abnormalities: the larger the defect, the higher the likelihood of events. Mild, moderate, and severely abnormal scans correspond to 1, 2 to 3, and >3 hypoperfused segments, respectively. Revasc. indicates myocardial revascularization.

The MI rate was 0.51%/y after a normal ETT and nonsignificantly higher after a positive, strongly positive, or nondiagnostic ETT (1.33%, 1.05%, and 1.15%/y, respectively, P=0.12). Conversely, Tl201-SPECT was highly predictive of future MI (0.25% and 1.13%/y after normal and abnormal Tl201-SPECT, respectively, P=0.001): the greater the defect, the higher the MI rate (Figure 5).

Fixed defects were associated with a higher risk of future cardiac death (6.7% versus 2.6% in patients without fixed defects, P=0.03) whereas reversible defects were more predictive of future MI (6.9% versus 4.0% in patients without reversible defects, P=0.03).

Myocardial Revascularization
The revascularization rate was 1.21%, 4.28%, 3.02%, and 2.01%/y after normal, positive, strongly positive, and nondiagnostic ETT, respectively (P<0.001). Similarly, revascularization was more frequent after abnormal than after normal Tl201-SPECT (2.65% versus 0.60%/y, P<0.0001), especially in the presence of 1 reversible defect (2.86% versus 1.51%/y, P<0.0001) or of a large defect (Figure 5).

Multivariate Predictors of Events
Age (P=0.04), ETT (P=0.03), and Tl201-SPECT (P=0.003) were independent predictors of overall mortality. Multivariate predictors of major cardiac events are summarized in Table 3: Tl201-SPECT and ETT were independent predictors of cardiac death. Tl201-SPECT was also predictive of future MI, whereas ETT was not. Figure 6 depicts the incremental prognostic value of clinical, ETT, and Tl201-SPECT data considered in hierarchical order.

View this table: [in this window] [in a new window]   Table 3. Cox-Multivariate Predictors of Cardiac Deaths and Nonfatal MI

View larger version (39K): [in this window] [in a new window]   Figure 6. Incremental prognostic value of clinical, ETT, and SPECT data, considered in hierarchical order, for prediction of major cardiac events. Clinical presentation (ie, typical or atypical chest pain, or no symptom [third bar]) provides additive prognostic information over age (first bar) and sex (second bar). Results of ETT (ie, negative, positive, strongly positive, or nondiagnostic [fourth bar]) are of additive prognostic value over clinical data. Similarly, the results of SPECT (ie, normal or abnormal [fifth bar]) or the number of abnormal segments on SPECT (sixth bar) add significant prognostic information to that provided by clinical and ETT data. Clinical indicates clinical presentation, and # defects, number of abnormal segments on SPECT.

	Discussion

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Our main finding is that the incremental prognostic value of Tl201-SPECT over clinical and ETT data for the prediction of major cardiac events, already demonstrated at short- to medium-term follow-up, was maintained at long-term follow-up in patients with low- to intermediate likelihood of CAD.

Long-Term Prognostic Value of Myocardial Perfusion Imaging
The short- to medium-term prognostic value of myocardial perfusion imaging is established: after normal scan, the major cardiac event rate is <1%/y during the 1 to 3 years following examination.^{6 7 8 13} Conversely, the greater the perfusion defect, the higher the likelihood of future events.^{6 7 13} Fixed defects reflect the amount of irreversibly injured myocardium and left ventricular dysfunction and are more predictive of future deaths, whereas reversible defects reflect the amount of jeopardized myocardium and are more predictive of future ischemic events.^{11 17} Furthermore, a large perfusion defect (>40% of the myocardium) is a powerful predictor of mortality, whereas patients with mild to moderate defect size (15% to 35% of the myocardium) have a higher likelihood of future MI.¹⁸ These conclusions, however, have been drawn from medium-term follow-up studies (21 to 44 months)^{6 11 13 15 18} or from long-term follow-up studies (6 to 10 years) on relatively small populations (217 to 309 patients) of selected patients with normal perfusion scans¹⁹ or documented CAD.^{20 21}

In this study, the prognostic value of Tl201-SPECT was maintained over a 6-year period in a population of 1137 patients with relatively low likelihood of events, extending the conclusions drawn from our 33-month follow-up study¹³ and from other short- to medium-term studies^{6 7 8 9 10 11 12} : the major cardiac event rate remained remarkably low after normal perfusion scan and was 3.3 times higher after an abnormal scan, with a close relationship between the extent of perfusion abnormalities and the occurrence of events.

The major cardiac event rate in our population was relatively low (1.51%/y), compared with 3.0%/y in a population with a higher rate of previous MI or ischemic events,¹⁸ and 1.19%/y in a population of patients without known CAD.¹⁷ Although a high number of patients were studied for angina, 70% of our patients had no previous serious ischemic events and none had a history of recent MI. Our patients were also 8 years younger than those in the previous studies.^{17 18} Furthermore, the major cardiac event rate in middle-aged Frenchmen has been reported to be 1.56 to 2.24 times lower than in the US population.²³ Nevertheless, we confirmed in this setting that (1) the occurrence of major cardiac events was dramatically increased in patients with a large perfusion defect; (2) a mild to moderate defect was a predictor of future MI¹⁸ ; (3) a fixed defect was a long-term predictor of death; and (4) a reversible defect predicted further ischemic events.

Survival curves continued to diverge over time, suggesting that the predictive value of Tl201-SPECT was maintained over 6 years: patients with abnormal scans who survived the first 3 years had an impaired long-term prognosis, whereas there was no inflection in the survival curve of patients with normal tests.

Additive Value of Tl201 Perfusion Imaging Over Clinical and ETT Data
Several studies have demonstrated the medium-term additive value of perfusion imaging over clinical and ETT data in populations with high,¹⁴ intermediate,^{15 16 18} low,¹⁷ or very low²⁴ likelihood of CAD. At long-term follow-up, we found that a negative ETT conferred a better prognosis than a strongly positive or nondiagnostic ETT and that ETT was of incremental value over clinical data despite its suboptimal negative predictive value. Tl201 scan provided long-term incremental value over clinical and ETT data (Figure 7), consistent with the study by Nallamothu et al, demonstrating that SPECT was superior to ETT for identifying patients with extensive CAD.²⁵ Because perfusion imaging better reflects the extension of CAD than does ETT, it is logical that the long-term prognostic information provided by Tl201-SPECT will be of incremental value over that afforded by ETT.

View larger version (33K): [in this window] [in a new window]   Figure 7. Flow chart illustrating additive prognostic value of Tl-201 imaging over ETT for prediction of major cardiac events. When performed after ETT, SPECT accurately identifies higher and lower risk patients, whatever the results of ETT. The additive value of SPECT is particularly relevant after positive, strongly positive, and nondiagnostic ETT; the prognosis for patients with a normal scan are particularly good in this setting. OR indicates odds ratio.

Limitations of the Study
A quantitative treadmill score was not used in our study, as its value was not clearly demonstrated at the start of our survey.⁴ However, we used a semiquantitative 4-grade score, taking into account parameters acknowledged to be of prognostic value.²⁶ Another possible limitation is the absence of quantitative analysis for SPECT scans. However, expert visual analysis has recently been demonstrated to be similar to automatic quantitative analysis for prognostic stratification.²⁷ Finally, the Tl-201 heart to lung uptake ratio was not available for our patients.

Myocardial revascularization was performed in 102 patients without subsequent events: the prognostic accuracy of ETT and Tl201-SPECT might therefore have been underestimated rather than overestimated in these patients. A posthoc analysis excluding these patients did not, however, alter our results. Furthermore, revascularization was performed less frequently in our series than in more recent studies,¹⁸ because guidelines now recommend that patients with a large perfusion defect undergo myocardial revascularization.²⁸ Similarly, the use of ß-blockers might have improved the prognosis of patients with abnormal tests but these biases would have affected both ETT and Tl201-SPECT to the same extent.

Conclusions and Clinical Implications
Myocardial perfusion imaging is of long-term prognostic value in patients with low-to intermediate likelihood of CAD, patients with normal Tl201-SPECT having a very low probability of future major cardiac events. The incremental prognostic value of Tl201-SPECT over clinical and ETT data are particularly relevant, after positive, strongly positive, and nondiagnostic ETT, our results suggesting that, in this setting, patients with normal scans do not require further explorations for the 6 years following initial examination.

Received March 5, 1999; revision received June 18, 1999; accepted June 28, 1999.

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