Prognostic assessment of uncomplicated first myocardial infarction by exercise echocardiography and Tc-99m tetrofosmin gated SPECT

ORIGINAL ARTICLES Prognostic assessment of uncomplicated first myocardial infarction by exercise echocardiography and Tc-99m tetrofosmin gated SPECT Jaume Candell-Riera, MD, PhD, Joan Llevadot, MD, PhD, César Santana, MD, PhD, Joan Castell, MD, PhD, Santiago Aguadé, MD, Lluís Armadans, MD, PhD, Begoña Bermejo, MD, PhD, Guillermo Oller, MD, Herminio García-del-Castillo, MD, Marina Soler-Peter, MD, and Jordi Soler-Soler, MD, PhD Background. We evaluate the prognostic value of stress echo and gated single photon emission computed tomography (SPECT) after a first uncomplicated acute myocardial infarction. Methods and Results. We used predischarge maximal subjective exercise echocardiography and gated SPECT with technetium 99m tetrofosmin to prospectively study 103 patients younger than 70 years with a first acute myocardial infarction. During a 12-month follow-up period, 2 patients died, 9 had heart failure, and 29 had ischemic complications (4 reinfarction and 25 angina). Predictive variables for heart failure in multivariate analysis were ejection fraction evaluated by echocardiography (odds ratio [OR] 8.5, P = .016) or by gated SPECT (OR 10.7, P = .009). Predictive variables for ischemic complications in multivariate analysis were less than 5 metabolic equivalents (METS) in exercise test (OR 5.2, P = .007) and greater than 15% ischemic extent in the polar map (OR 3.6, P = .04) of SPECT. Conclusions. Exercise echocardiography and Tc-99m tetrofosmin gated SPECT were predictive for heart failure, but exercise SPECT was the only test with predictive power for ischemic complications. (J Nucl Cardiol 2001;8:122-8.) Key Words: Myocardial infarction • prognosis • scintigraphy • echocardiography

See related editorial, p 215 Residual myocardial ischemia and left ventricular systolic dysfunction are the major determinants of a patient’s prognosis after myocardial infarction.1,2 In patients who are free from complications during the acute phase (Killip class III or IV, hypotension, ongoing myocardial ischemia, malignant arrhythmias, or evidence of mechanical complications), noninvasive studies provide valuable prognostic information. Residual myocardial ischemia may be assessed with exercise testing3-5 and myocardial perfusion scintigraphy.6-8 Left ventricular systolic function may be evaluated by echocardiography9-11 and radionuclide venFrom Hospital General Universitari Vall d’Hebron, Barcelona, Spain. Received for publication Apr 24, 2000; final revision received July 6, 2000. Reprint requests: Jaume Candell-Riera, MD, Servei de Cardiologia, Hospital General Universitari Vall d’Hebron, Pg Vall d’Hebron 119129, 08035 Barcelona, Spain. Copyright © 2001 by the American Society of Nuclear Cardiology. 1071-3581/2001/$35.00 + 0 43/1/109928 doi:10.1067/mnc.2001.109928 122

triculography.12-14 Any combination of a test detecting residual ischemia or functional capacity and a test assessing ventricular function results in useful prognostic information in patients with uncomplicated first acute myocardial infarction.15,16 Exercise echocardiography17-20 and gated single photon emission computed tomography (SPECT)21-26 can be used to simultaneously evaluate ischemia and left ventricular function, but a comparative study assessing the prognostic value of these tests after acute myocardial infarction has not been performed. Thus we evaluated the prognostic value of predischarge maximal exercise echocardiography and technetium 99m tetrofosmin gated SPECT in a prospective follow-up study of patients with a first uncomplicated myocardial infarction. METHODS Study Population Our study population consisted of 103 patients (aged 56 ± 9 years, 91 men and 12 women) selected from a total of 273 consecutive patients admitted to our coronary care unit between January 1997 and December 1997 with myocardial infarction. One hundred sixty-four patients were excluded because of the

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following: age above 70 years (77), previous diagnosis of myocardial infarction (41), severe associated diseases (9), complications during hospitalization (34), impossibility of calculating ejection fraction (EF) by echocardiography or gated SPECT (6), and inability to perform exercise testing (3). On the basis of echocardiographic criteria, 54 patients had inferior infarction, lateral infarction, or both; 35 had anterior infarction; and 14 had non–Q-wave infarction. Of these, 13 had inferior infarction, lateral infarction, or both, and 1 had anterior infarction as shown by rest Tc-99m tetrofosmin SPECT. Forty-three patients (42%) received thrombolytic therapy within 6 hours after the onset of symptoms. There were no significant differences in clinical features, results of tests, or follow-up data between patients with or without thrombolysis. At the time of exercise testing before hospital discharge, the patients were receiving β-blockers (85 [82%]), calcium antagonists (15 [14%]), and nitrates (15 [14%]).

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obtained. Rest images were acquired 15 to 30 minutes after administration of the radiopharmaceutical dose. The left ventricle was divided into 20 segments (6 in vertical long-axis view, 6 in horizontal long-axis view, 4 in basal short-axis view, and 4 in mid short-axis view) that were assigned a score depending on the activity (1, normal; 2, mild defect; 3, moderate defect; 4, severe defect).28 All studies were evaluated by consensus between 2 experienced observers. A segment was considered necrotic if a mild, moderate, or severe defect was observed at rest. A segment was considered ischemic if reversibility was observed between exercise and rest images. The total extent of ischemia was quantified in the polar maps by use of the difference between the polar rest and polar exercise images with a 10% cutoff value.29 Automatic quantification of EF from gated myocardial perfusion SPECT was calculated with an algorithm that operates in 3-dimensional space and uses gated short-axis image cavity volumes.30

Diagnostic Tests Before hospital discharge (6-8 days after admission), maximal subjective exercise echocardiography and Tc-99m tetrofosmin SPECT were performed. Exercise test. Exercise testing was performed on a bicycle ergometer with the patient in the sitting position. The initial workload was 50 W, with 25-W increments every 3 minutes. The test was stopped when the patient had symptoms or hypotension or when ST segment depression exceeded 0.2 mV. Stress echocardiography. Left ventricular EF at rest was calculated by Simpson’s method, which permits the quantification of end-diastolic and end-systolic volumes in the apical 4-chamber view. Images were digitized on-line with a Cine View Rwave–triggered acquisition system both at rest and less than 2 minutes after exercise was stopped; they were stored in a quadscreen, continuous-loop format on 3.5-inch floppy disks. The digitized images were evaluated by consensus between 2 experienced readers. The left ventricle was evaluated with a previously described scoring system (1, normal; 2, hypokinesia; 3, akinesia; 4, dyskinesia) of the American Society of Echocardiography27 divided according to a 16-segment model. On the basis of the known distribution of the segments to vascular territory, segments were divided into subgroups according to infarction and noninfarction zone location. The criterion for ischemia was the presence of a new inducible wall motion abnormality or worsening of a resting wall motion abnormality. The criterion for necrosis was the presence of wall motion abnormalities at rest. Gated SPECT. All patients received an intravenous dose of Tc-99m tetrofosmin (8 mCi) 30 to 60 seconds before the end of exercise. Fifteen to 30 minutes after the administration of the radiopharmaceutical dose, stress images were acquired with a scintillation camera with a high-resolution collimator and a semicircular orbit starting at a 30° right anterior oblique position, with detection being carried out every 3°. Reconstruction was performed (Butterworth filter, order 5, section frequency 0.4), and short-axis, horizontal long-axis, and vertical long-axis sections were obtained. A 24-mCi dose of Tc-99m tetrofosmin was administered immediately after stress images were

Follow-up Follow-up ranged from the time of hospital discharge to the development of complications. In the patients without complications, follow-up was 12 months. Patients were included in the ischemic complications group when reinfarction or angina developed (Canadian Cardiovascular Society classes II, III, and IV).31 Patients in New York Heart Association functional classes III and IV32 were included in the heart failure group. The need for revascularization (coronary angioplasty or stent or cardiac surgery) was not considered a complication.

Statistical Analysis Two dependent variables (congestive heart failure and ischemic complications) were selected for analysis. The following predictive variables were also used for analysis. For exercise testing we used peak oxygen consumption (metabolic equivalents [METS]), development of angina during exercise, and ST segment depression of 0.1 mV or greater 0.08 seconds after the J point. For stress echocardiography we used resting left ventricular EF, overall number of necrotic segments, difference in score between rest and early postexercise scans, and number of patients with at least 1 ischemic segment. For gated SPECT we used resting left ventricular EF, overall number of necrotic segments, difference in score between late and early postexercise scans, number of patients with at least 1 ischemic segment, and extent of ischemia in the polar map (difference between rest uptake and exercise uptake greater than 10%). To assess the association between categorical predictive variables and complications, we used the χ2 test (or Fisher exact test when the expected cell values were <5 in ≥1 cell). To assess the association between numerical predictive variables and complications, we used the Student t test and nonparametric Mann-Whitney U test (if there were <30 patients in a category). The risk odds ratio was used to estimate the risk of heart failure or ischemic complications according to predictive variables. Multiple logistic regression analysis was used to identify the main predictors of ischemic complications among exercise testing and

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Table 2. Risk of heart failure according to its predictors

Table 1. Distribution of patients according to predictors of heart failure

Heart failure

Heart failure Yes (n = 9) Exercise test METS Median 5 P25-P75 4.4-6.2 Range 0-7 Echocardiography EF (%) Median 38 P25-P75 30-51.5 Range 29-56 Necrotic segments Median 4 P25-P75 1-6.5 Range 0-10 SPECT EF (%) Median 34 P25-P75 25.5-40 Range 14-54 Necrotic segments Median 9 P25-P75 8-13.5 Range 7-15

No (n = 94)

6.3 5.8-7 0-127

P

.008

58.5 49-65 35-79

.001

0 0-1.3 0-8

<.001

Present (n) Exercise test METS >5 METS ≤5 Echocardiography EF ≥40% EF <40% Gated SPECT EF ≥40% EF <40%

Absent (n)

Odds ratio

P

3 6

75 19

8.0

.006

4 5

88 6

18.3

.001

2 7

79 15

18.7

<.001

Table 3. Risk of heart failure according to multiple logistic regression analysis

EF

Odds ratio

95% CI

P

8.5 10.7

1.5-47.9 1.8-63.4

.016 .009

49.5 43-55 20-75

.001

Echocardiography <40% Gated SPECT <40%

5 4-8 0-12

.001

tion. The patients with complications were not significantly different from the patients without complications with respect to age, sex, smoking habits, previous angina, diabetes, hypertension, enlarged heart on chest radiograph, creatine kinase levels, or localization of infarction. Mean ± SD values in exercise test variables were as follows: 100 ± 26 W, 7.9 ± 1.3 METS, 64% ± 12% of peak heart rate, and 160 ± 27 mm Hg peak systolic blood pressure. Seven patients had angina, and 23 had depression of the ST segment of 0.1 mV or greater during exercise testing. Although no patient was excluded from the echocardiographic motion analysis because of poor image quality, 21 studies were considered suboptimal. The mean number of ischemic segments observed in stress echocardiography in patients with ischemic complications (0.4 ± 0.8) was not significantly different from that obtained in patients without complications (0.3 ± 0.7). The mean number of ischemic segments observed in SPECT in patients with ischemic complications (5 ± 3.8) was significantly higher than that obtained in patients without complications (2.4 ± 2.7, P = .0008). Twenty percent of patients had 1 or more ischemic segments in stress echocardiography, and 49% of patients had 1 or more ischemic segments in SPECT. Mean EF obtained by echocardiography (55% ± 11%) was higher than that obtained by gated SPECT (47% ± 11%). A substantial correlation (r = 0.735,

gated SPECT predictive variables. A forward stepwise modeling strategy was used (ie, variables were included sequentially in the model according to its log-likelihood ratio χ2 test, provided it was significant). Multiple logistic regression analysis was not used to identify the main predictors of heart failure because few patients had this complication. Heart failure– and ischemic complication–free intervals were estimated according to the standard method of Kaplan-Meier.33 The log rank test was used to compare these intervals according to predictive variables. The statistical significance level was established at 5%. SPSS for Windows (Release 6.0, SPSS Inc) was used for the analysis.

RESULTS Of the 103 patients included in the study, 2 died, 9 had heart failure, and 29 had ischemic complications (4 reinfarction and 25 angina) during the 12 follow-up months. Sixteen patients underwent revascularization but were not included in the ischemic complications group because they did not have previous angina or reinfarction. Eighty percent of the severe complications, including 2 deaths and 2 of 4 infarctions, developed during the first month after infarc-

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Table 4. Distribution of patients according to predictors of ischemic complications

Ischemic complications Yes (n = 29)

No (n = 58)

Exercise test METS Median 6.0 P25-P75 4.9-6.4 Range 0-7.7 SPECT Exercise uptake–rest uptake Median 5 P25-P75 2-7.5 Range 0-14 Ischemic area at polar map Median 14 P25-P75 6.1-26.5 Range 0.4-49

P

6.3 6.0-7 0-127

.02

2 0-4 0-12

<.001

6.8 2.1-14 0-56

.014

Table 5. Risk of ischemic complications according to their predictors

Ischemic complications Present (n = 29) Exercise test METS >5 17 ≤5 12 Gated SPECT Ischemic segments 0 2 ≥1 27 Ischemic area at polar map <15% 15 ≥15% 14

Absent (n = 58)

Odds ratio

P

48 10

3.4

.02

17 41

5.6

.035

49 13

3.2

.027

P < .001) was observed between both methods. The area under the receiver operating characteristic curves of echocardiography EF and gated SPECT EF were identical (0.84) for the diagnosis of heart failure, and the best cutoff level to discriminate between patients in whom heart failure developed and those in whom it did not was EF less than 40% for both techniques. Eleven percent of patients had echocardiography EFs less than 40%, and 20% of patients had gated SPECT EFs less than 40%.

Figure 1. Kaplan-Meier curves showing interval free from heart failure as a function of METS, echocardiographic EF (ECHO EF), and gated SPECT EF (G-SPECT EF).

In bivariate analysis, predictive variables of heart failure (Tables 1 and 2) were METS for exercise test, EF, and number of necrotic segments for echocardiography and gated SPECT. Table 3 shows the results of multivariate analysis for prediction of heart failure with echocardiography and gated SPECT. Predictive variables were EF less than 40% for both techniques. Kaplan-Meier curves depicting the heart failure–free interval for these variables are shown in Figure 1. Tables 4 and 5 show the results of bivariate analysis for ischemic complications. Among variables from exercise testing, fewer than 5 METS was the only variable predictive of complications. There were no significant

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Figure 2. Kaplan-Meier curves showing interval free from ischemic complications as a function of METS, ischemic segments (isch segm) at echocardiography (ECHO) and at SPECT, and ischemic extent in a polar map of SPECT.

Table 6. Risk of ischemic complications according to multiple logistic regression analysis

Odds ratio

95% CI

P

1.6-17.2 1.3-10.3

.007 .04

ischemic complication–free interval for echocardiography and SPECT variables are shown in Figure 2.

DISCUSSION METS ≤5 Ischemic area at polar map ≥15%

5.2 3.6

differences between the presence of angina and ST during exercise testing between patients with ischemic complications and the remaining patients (26% vs 13%, P = .07, and 26% vs 12%, P = .2, respectively). No echocardiographic variable was predictive of ischemic complications. One or more SPECT ischemic segments and ischemia extent of 15% or more of the polar map were predictive variables of ischemic complications. Table 6 shows the results of multivariate analysis of ischemic complications for exercise testing and SPECT. Predictive variables of ischemic complications were 5 METS or fewer and 15% or greater ischemic extent of the polar map in SPECT. Kaplan-Meier curves depicting the

Although some authors34 have recommended routine cardiac catheterization and coronary arteriography in all patients after acute myocardial infarction, reports that have compared outcomes of patients assigned to routine coronary arteriography with those of patients assigned to conservative management without routine coronary arteriography have not found differences in the rates of death, nonfatal infarction, or myocardial revascularization procedures.35-38 In Europe, the proportion of patients having coronary angiography within 6 months of acute myocardial infarction varied between countries from 8% to 61%.39 In our hospital, cardiac catheterization is not routinely performed after a first uncomplicated myocardial infarction.15,16 In this series cardiac catheterization was carried out in only 35% of cases. Remarkable features of our series are the low mortality rate (1.8%) and the considerable incidence of

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ischemic complications (28%). Most of the complications after an uncomplicated myocardial infarction developed during the first month. Eighty-one percent of the severe complications, including 2 deaths and 2 of 4 infarctions, developed during the first month. These data demonstrate the importance of establishing the risk stratification before hospital discharge. In this series 2 techniques were performed to simultaneously evaluate the ventricular function and residual ischemia: exercise echocardiography and Tc-99m tetrofosmin gated SPECT. The detection of residual ischemia is the most relevant prognostic factor after a first uncomplicated myocardial infarction in the thrombolytic era. However, the number of patients with silent ischemia, detected by either exercise echocardiography, stress echocardiography, or SPECT, is lower at this time. In our series none of the stress-echocardiographic parameters was predictive of ischemic complications. This fact is discordant with the results of other series in which ischemia detected by exercise echocardiography was predictive of ischemic complications,17-20 but it confirms the opinion of Brown40 that, after a revision of the 2 largest studies41,42 of postmyocardial risk stratification with stress echocardiography, echocardiographically defined ischemia has no significant prognostic value. Other studies have observed a higher sensitivity of radionuclide techniques for the detection of multivessel disease43,44 and postinfarction complications45; in our series gated SPECT was more sensitive for the detection of residual ischemia. Only in 20% of patients were new contractility alterations detected with echocardiography after exercise stress testing, whereas reversible defects were observed in 48% of the patients with SPECT. Low peak heart rate in exercise testing, attributed to treatment with β-blockers, could accentuate the lower sensitivity of exercise echocardiography. Therefore it is not surprising that SPECT was more predictive of ischemic complications during follow-up. The incorporation of new methods (such as the second harmonic and contrast administration, as well as dobutamine administration46,47) may improve the sensitivity of the test to detect residual ischemia. On the other hand, the EF and the extent of necrosis, together with the number of METS achieved during exercise, are the most predictive variables of heart failure. In our study we confirmed a good correlation between the EF determined by 2-dimensional echocardiography and that of the gated SPECT. The EF and the extent of necrosis quantified both by echocardiography and by gated SPECT were predictive of heart failure, results comparable to those already described.43,48 Although the significance of these variables appears to be lower in a first uncomplicated myocardial infarction, the EF is still the most important prognostic variable of mortality in the stratification of any

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patient after an infarction, regardless of whether it is the first infarction or whether it is complicated.49 We conclude that exercise echocardiography and Tc99m tetrofosmin gated SPECT in a first uncomplicated myocardial infarction may provide important prognostic information. echocardiography and gated SPECT were predictive of heart failure, and SPECT was the only test with predictive power for ischemic complications. We are grateful to Gaietà Permanyer-Miralda, MD, for his revision of the manuscript and to Josep Vaqué, MD, for help in statistical analysis.

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35.

36.

37.

38.

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40.

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42.

43.

44.

45.

46.

47.

48.

49.