Evaluation of the effect of thrombolytic treatment on infarct size and left ventricular function by enzymatic, scintigraphic, and angiographic methods

American

Heart Journal

Founded in 1925

J u n e 1 9 9 0 Volume 119, Number 6

CLINICAL INVESTIGATIONS

Evaluation of the effect of thrombolytic treatment on infarct size and left ventricular function by enzymatic, scintigraphic, and angiographic methods In a double-blind trial of the European Cooperative Study Group, 721 patients with acute myocardial infarction of less than 5 hours' duration were given either 100 mg recombinant tissue-type plasminogen activator (rt-PA) intravenously over 3 hours or an equivalent placebo infusion. In a subset of 3 1 2 patients, infarct size was assessed by the cumulative myocardial release of a-hydroxybutyrate dehydrogenase (HBDH) during the first 72 hours and by planar thallium scintigraphy (index of hypoperfusion) performed 10 to 22 days after the acute event. Left ventricular ejection fraction (LVEF) was determined by contrast and nuclear angiography. The median values of HBDH during the first 72 hours were 2 0 % lower and the median values of thallium-201 2 8 % smaller in the rt-PA group in comparison with controls. A significant but limited innprovement of anglographic LVEF (2 absolute percentage points) was also shown in the patients treated with rt-PA. A moderate but statistically significant linear association between both measurements of infarct size and LVEF was found. (AM HEART J 1 9 9 0 ; 1 1 9 : 1 2 3 1 . )

Luc Mortelmans, MD, a Johan Vanhaecke, MD, b Emmanuel Lesaffre, PhD, e Alfred Arnold, MD, d Jean-Luc Urbain, MD, a Willem Hermens, MD, e Michel De Roo, MD, a Hilaire De Geest, MD, b Marc Verstraete, MD, f and Frans Van de Werf, MD. b For the European Cooperative Study Group for recombinant tissue type plasminogen activator. Leuven, Belgium, and

Maastricht, The Netherlands It has been demonstrated t h a t early recanalization of the infarct-related coronary artery in a patient with an acute myocardial infarction limits infarct size and preserves left ventricular function. These beneficial effects have been demonstrated with both intracoronary and intravenous streptokinase and more recently with the newer, more fibrin-specific agents, anisolated plasminogen streptokinase activator complex (APSAC) and recombinant tissue-type plasminogen activator (rt-PA). 1-1~ From aDivision of Nuclear Medicine. bDivision of Cardiology, r cal Centre. Department of Epidemiology, fCenter for Thrombosis and Vascular Research. University of Leuven, Belgium: dThorax Centre. Erasmus University, Rotterdam. The Netherlands: eInstitute for Cardiovascular Research. Biomedical Center. University of Limburg, 6200 MD Maastricht. The Netherlands. Received for publication Dec. 12, 1989: accepted Jan. 22. 1990. Reprint requests: Luc Mortelmans, MD, Departmen~ of Nuclear Medicine. U.Z. Gasthuisberg, Herestraat 49. B-3000 Leuven. Belgium. 4/1/19602

The European Cooperative Study Group has recently published the results of a double-blind, placebo-controlled trial of rt-PA in 721 patients who had experienced acute myocardial infarctions of less than 5 hours' duration. 4 Beneficial effects on infarct size, left ventricular function, cardiovascular morbidity and mortality were shown within the same study population. This paper deals with a subset of this trial that comprises 312 patients and pertains to all participating centers in Belgium. The aim of this ancillary study was to confirm the reported reduction of enzymatic infarct size by planar thallium scintigraphy and to compare left ventricular function evaluated by contrast angiography and by radionuclide angiography. METHODS

Study population The population under study is a subset of the 721 patients who were evaluated in a trial of the European Cooperative Study Group. 4 In all of the Belgian 1231

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et al.

American Heart

Journal

T a b l e I. P a t i e n t c h a r a c t e r i s t i c s a t a d m i s s i o n

Age (yr) Male subjects (%) Time from onset of symptoms to start of therapy (hours) Patients with ant. infarction (ECG) Patients in Killip Class III or IV (%) Patients with angina pectoris for less than 4 weeks (%) Patients with previous infarction (%) Sum of ST (ECG) J-point 60 msec after J-point

r t - P A (n = 149)

Placebo (n = 145)

57.6 (33.6-70.9) 89.2 2.86 _+ 0.97

57.6 (32.8-70.3) 85.5 2.83 _+ 1.03

NS NS NS

31.9

p < 0.05

4.1

5.6

NS

32.7

36.5

NS

4.7

5.5

NS

45

19.3 (6.3-41.3) 14.8 (5.0-32.7)

15.9 (6.4-40.2) 12.9 (5.5-29.4)

NS NS

The age of the patients (mean and the full range) and the gender (percent of male subjects) is indicated. The mean delay and its standard deviation between the onset of symptoms and the start of treatment is given in hours. The percentage of patients in each treatment group with anterior infarction, with overt left heart failure or shock (Killip III, IV) and with a previous myocardial infarction is mentioned. The median value of the Sum of ST elevation (at J-point and 60 msec thereafter) measured on the ECG at admission were equally distributed. The equal distribution of the patient characteristics between both treatment groups was checked by the chi square test and by the two-tailed Fisher exasct test. NS, not significant.

T a b l e II. A n g i o g r a p h i c d a t a (10 t o 14 d a y s a f t e r a d m i s s i o n ) rt-PA

Placebo

Infarct-related vessel LAD 51 (39.1%) 51 (36%) RCA 68 (51.1%) 75 (52.8%) CX 13 (9.8%) 16 (11.2%) Patency of infarct-related vessel (TIMI grades) Grade 0, no 14 (9.6%) 24 (16.8%) per fusion Grade 1, minimal 11 (7.5%) 8 (5.6%} perfusion Grade 2, partial 9 (6.2%) 16 (11.2%) perfusion Grade 3, complete 112 (76.7%) 95 (86.4%) perfusion Number (%) of diseased coronary vessels No disease 12 (9.7%) 4 (3.2%) 1-Vessel 54 (43.6%) 55 144.7%} 2-Vessel 35 (29.0%) 35 (28.5%) 3-Vessel 22 (17.7%) 29 (23.6%)

NS

NS

NS

The actual numbers of patients are given. Percentages of the total number of patients in each treatment group are shown in parentheses. TIMI grades of perfusion: 0, no-perfusion; 1, penetration with minimal perfusion qcontrast fails to opacify entire coronary bed distal to the stenosis for the duration of the cine run); 2, partial perfusion ~contrast opacities the entire coronary bed distal to the stenosis; however, the rate of entry and/or clearance is slower in the coronary bed distal to the obstruction than in comparable areas not perfused by the infarct-related vesselh 3, complete perfusion (filling and clearance of contrast is as rapid in the coronary bed distal to the stenosis as in the other coronary bed). NS, not significant: LAD. left anterior descending coronary artery; RCA, right coronary artery; CX. circumflex coronary artery. The same statistical tests as in table I were used. A chi square analysis of contingency tables was performed.

c e n t e r s 312 p a t i e n t s b e t w e e n 20 a n d 71 years of age w h o h a d e x p e r i e n c e d a c u t e m y o c a r d i a l i n f a r c t i o n s of less t h a n 5 h o u r s ' d u r a t i o n were s e l e c t e d a n d r a n d o m i z e d o n t h e b a s i s of s t r i c t E C G c r i t e r i a a n d w h e n n o c o n t r a i n d i c a t i o n s to

thrombolytic therapy were present. A complete description of i n c l u s i o n a n d e x c l u s i o n c r i t e r i a h a s b e e n p u b l i s h e d . 4 S u r v i v i n g p a t i e n t s (n = 296) were r e f e r r e d to t h e U n i v e r sity H o s p i t a l of L e u v e n 10 to 14 d a y s a f t e r t h e a c u t e e v e n t for f u r t h e r d i a g n o s t i c e v a l u a t i o n , i n c l u d i n g t h a l l i u m scintigraphy, equilibrium gated nuclear angiography at rest a n d c o r o n a r y a n d left v e n t r i c u l a r a n g i o g r a p h y . All p a t i e n t s r e c e i v e d 250 m g a s p i r i n orally a n d a b o l u s i n j e c t i o n of 5000 I U h e p a r i n i m m e d i a t e l y before t h e s t a r t of t r i a l m e d i c a t i o n . P a t i e n t s a l l o c a t e d to t h e r t - P A g r o u p r e c e i v e d a 10 m g i n t r a v e n o u s b o l u s of r t - P A followed b y 50 m g o v e r 1 h o u r a n d 40 m g over t h e n e x t 2 h o u r s . C o n t r o l p a t i e n t s r e c e i v e d a s i m i l a r i n f u s i o n of placebo. A f t e r t h e s t a r t of t h e i n f u s i o n , all p a t i e n t s were t r e a t e d w i t h h e p a r i n {1000 I U / h I a n d a s p i r i n (75 to 125 mg) e v e r y o t h e r d a y u n til a n g i o g r a p h y was p e r f o r m e d . O t h e r t r e a t m e n t was given o n l y if clinically i n d i c a t e d . R a n d o m i z a t i o n was b a l a n c e d for e a c h p a r t i c i p a t i n g h o s p i t a l . Diagnostic P r o c e d u r e s B l o o d s a m p l e s for e n z y m e a n a l ysis were collected i n t h e r e f e r r i n g h o s p i t a l s o n a d m i s sion a n d a f t e r 12, 24, 36, 48, 72 a n d 96 h o u r s (7 s a m p l e s per patient). Plasma a-hydroxybutyrate dehydrogenase ( H B D H ) a c t i v i t i e s were d e t e r m i n e d c e n t r a l l y as d e s c r i b e d p r e v i o u s l y , n T h e c u m u l a t i v e release o f H B D H in p l a s m a over 72 h o u r s , e x p r e s s e d in i n t e r n a t i o n a l u n i t s p e r l i t e r of p l a s m a , was c a l c u l a t e d as a n i n d e x of i n f a r c t size. T h a l l i u m s c i n t i g r a p h y was p e r f o r m e d a t r e s t 5 m i n u t e s a f t e r i n j e c t i o n of 2 m C i of t h a l l i u m 201, a n d t h r e e p l a n a r p r o j e c t i o n s were a c q u i r e d ( a n t e r i o r , 4 5 - d e g r e e left a n t e r i o r o b l i q u e [LAO], 7 0 - d e g r e e LAO). F i v e h u n d r e d k c o u n t s were c o l l e c t e d in e a c h view w i t h t h e use of a 20% w i n d o w c e n t e r e d o n t h e 80 k e V m e r c u r y x - r a y p e a k a n d o n t h e 167 k e V g a m m a - r a y p e a k . A g e n e r a l a l l - p u r p o s e c o l l i m a t o r was f i t t e d t o a small-field g a m m a c a m e r a ( P H O g a m m a V, Sie m e n s M e d i c a l S y s t e m s , Inc., Iselin, N.J.) a n d c o n n e c t e d t o a d e d i c a t e d c o m p u t e r s y s t e m ( S i m i s III, I n f o r m a t e k , P a r i s . F r a n c e ) . A q u a n t i t a t i v e a n a l y s i s of p e r f u s i o n d e f e c t s

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was performed with the use of thallium and a circumferential profile method, as previously described by Goris and Briandet. 12After a preprocessing step the maximum count, the average count, and the mean of the four largest values along each of the 256 radii were individually calculated. The means and the standard deviations of these parameters in a normal population were also determined. For each radius, the "magnitude" or "thallium hypoperfusion index" was calculated as the ratio of the difference of the lower limit of normality (the mean minus 1.5 SD) and the value from the patient under study divided by the local SD of the normal values. The total scintigraphic thallium index was defined as the sum of the positive "magnitudes" on all the radii. Ten minutes after the injection of human serum albumin labeled with 20 mCi of technetium-99m, an equilibrium gated nuclear angiography (EGNA) was acquired over 10 minutes in the 45-degree LAO position and the left ventricular ejection fraction (LVEF) was calculated by an automatic software program. 12 Coronary and left ventricular angiograms were obtained with the Sones technique and recorded on 35 mm films. The films were read by a central angiography assessment group blinded to patient identity and treatment assignment. This group identified the infarct-related vessel with the assistance of the electrocardiogram, scored the patency of the infarct-related vessel, and evaluated the technical quality of the angiogram. 4 The members of the core laboratory for quantitative angiography measured LVEF from the 30-degree right anterior oblique projection by using the arealength method. Statistical analysis of the influence of therapy on the thallium index, enzymatic infarct size, and scintigraphic and angiographic LVEF was performed with the use of nonparametric tests (Wilcoxon signed rank sum test). The results were expressed as the median value and their 90% range. The level of significance was set at a p value of 0.05. The association between both measurements of infarct size and LVEF was evaluated by linear regression. To determine whether the same relationship exists in both treatment groups, an extra term that expressed the code was added to the linear model. The percentage of variance due to regression and the confidence limits of the regression coefficient and the intercept were calculated. The regression model was checked by testing for normality of the residuals. The correspondence between the scintigraphic and angiographic determination of LVEF was illustrated by a paired t test. A Spearman's rank correlation coefficient between both estimates of infarct size was determined. All calculations were done with the Statistical Analysis System (SAS) package (Statistical Analysis System Institute, Cary, N.C.). 13 RESULTS

In all, 312 Belgian p a t i e n t s e n t e r e d t h e study. Five p a t i e n t s of t h e r t - P A g r o u p a n d 11 control p a t i e n t s died during the first 2 weeks after acute m y o c a r d i a l infarction. Of t h e 294 surviving p a t i e n t s r e f e r r e d to our hospital, 149 were allocated to the r t - P A t r e a t m e n t group a n d 145 to the placebo t r e a t m e n t group.

Thrombolysis effect on AMI and L V [unction

1233

III. Influence of therapy on infarct size and global ejection fraction

Table

rt-PA

Placebo

A. I n f a r c t Size ( m e d i a n value; 90% range) H B D H Q72 636 (41-2017) 791 (91-2016) p = 0.024 (IU/l) (n = 113) (n = 130) T h a l l i u m i n d e x 2356 (256-9761) 3381 (384-9105) p = 0.017 (n = 113) (n = 105) B. Global Ejection F r a c t i o n ( m e d i a n value %; 90% range) EGNA 54.5 (23-77) 52.0 (22.1-74.9) p = 0.48 (n = 144) (n = 140) Anglo 53.0 (32-69.2) 51.0 (31-65) p = 0.024 (n = 136) (n = 128) ANGIO, contrast angiography; EGNA, equilibrium gated nuclear angiography; HBDH Q72, cumulative release during 72 hours of a-hydroxybutyrate dehydrogenase. Nonparametric Wilcoxon test was used for all parameters.

P a t i e n t characteristics at a d m i s s i o n are s u m m a r i z e d in T a b l e I. T h e r e were no significant differences between t h e two t r e a t m e n t groups at randomization. T h e angiographic d a t a are s u m m a r i z e d in T a b l e II. T h e left a n t e r i o r descending c o r o n a r y a r t e r y (LAD) was the i n f a r c t - r e l a t e d vessel in 37 % of the p a t i e n t s (39% in the r t - P A g r o u p a n d 36% in the control group). T h e right c o r o n a r y a r t e r y (RCA) was the inf a r c t - r e l a t e d vessel in 51% of the p a t i e n t s (51% in the r t - P A g r o u p a n d 52 % in t h e control group) a n d the circumflex c o r o n a r y a r t e r y (CX) was t h e infarctrelated vessel in 10% of t h e t o t a l studied p o p u l a t i o n (10% in t h e r t - P A g r o u p a n d 11% in the control group). A high grade of p a t e n c y ( T I M I grades 2 a n d 3) was f o u n d in b o t h groups (83 % in the t h r o m b o lysis g r o u p a n d 78% in t h e control group). 14 T h e results of the e n z y m a t i c ( H B D H during the first 72 hours) a n d scintigraphic (total thallium index) evaluations of infarct size are s u m m a r i z e d in T a b l e III. W i t h b o t h m e t h o d s , a significantly smaller infarct size was f o u n d in t h e t h r o m b o l y s i s group as c o m p a r e d to the control group: 636 U/1 versus 791 U / 1 (p = 0.024) for the e n z y m a t i c index a n d 2356 versus 3281 for t h e scintigraphic index (p = 0.017). T h e d a t a of the two m e t h o d s used to evaluate the L V E F indicate an i m p r o v e m e n t of left ventricular function in p a t i e n t s t r e a t e d with rt-PA. Angiographic L V E F was 53.0% versus 51.0% (p = 0.024), whereas scintigraphic L V E F was 54.5% versus 52.0% (p = 0.48) in the t h r o m b o l y s i s a n d in the control group, respectively. T h e difference in scintigraphic L V E F did not reach t h e level of significance because of t h e large v a r i a t i o n in ejection f r a c t i o n as d e t e r m i n e d b y this t e c h n i q u e (Figs. 1 a n d 2). T h e r e l a t i o n s h i p b e t w e e n infarct size a n d residual L V E F is shown in a s c a t t e r d i a g r a m in which the t h a l l i u m index is indicated on the x axis and the scintigraphic a n d angiographic L V E F is indicated on

June 1990

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1234

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1. Relationship between infarct size, measured by a

thallium (T1.) index and the left ventricular ejection fraction (LVEF) estimated by scintigraphic (Egna) and angiographic (Angio) techniques. Both measurements were taken 10 to 14 days after myocardial infarction (0 = patients treated with placebo; * = patients treated with rt-PA). The linear regression lines are also shown: LVEF (Angio)= 6 0 . 0 3 - 0.0024 *T1. index and LVEF ( E g n a ) = 6 3 . 8 1 0.0035 *T1. index.

the y axis (Fig. 1). Similar plots of enzymatic totals (x axis) versus scintigraphic LVEF are shown in Fig. 2. The regression coefficients and the intercepts with their confidence limits and the percentage of variance due to regression are shown in Table IV. The residuals showed no major deviations from the linear model. No significant difference in the regression model was found when the code of therapy was included. The correlation between the two measures of infarct size is shown on the scatter diagram of Fig. 3. (Spearman's rank correlation coefficient was 0.57.) A comparison between the measurement of LVEF by the scintigraphic and angiographic method is presented in Fig. 4. A paired t test of the differences of

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Enz. I. S. Fig. 2. Relationship between infarct size measured by the cumulative sum ofa-hydroxybutyrate dehydrogenase (Enz. I.S.) and LVEF (same symbols as in Fig. 1). The equations of the linear regressions are: LVEF (Angio) = 60.94 - 0.011 *Enz. I.S. and LVEF (Egna) = 63.13 - 0.015 *Enz. I.S.

LVEF showed a mean difference of -0.98% (95% confidence limits were -2.92, 0.94) with a standard deviation of 11.23%. The Spearman's rank correlation coefficient was 0.71. DISCUSSION

The purposes of this study were to confirm the reported effect of intravenous thrombolytic therapy with rt-PA therapy on enzymatic infarct size by the results of thallium scintigraphy and to compare left ventricular function assessed by contrast and radionuclide ventriculography in all Belgian patients in an international multicentral trial. 4 Scintigraphic imaging of infarct size can be performed either with infarct-avid tracers such as technetium 99m-labeled pyrophosphate, 15 and indiumlabeled antimyosine,16 or with perfusion tracers such as thallium 20117 2-methoxyisobutylisonitrile18 and

Volume 119 Number

6

Thrombolysis effect on A M I and L V function

1235

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Fig. 3. Scatter diagram showing the correlation between two independent measures of infarct size. The Spearman correlation coefficient is 0.57; p < 0.0001. Symbols are the same as in Figs. 1 and 2.

t e c h n e t i u m - l a b e l e d macroaggregates} 9 T h e infarctavid tracers have the advantage of not accumulating in old infarcts. However, we were unable to use t h e m because of the delay between the onset of s y m p t o m s and the scintigraphic evaluation. For this reason, thallium 201 was selected in this s t u d y to measure hypoperfusion. Besides visual interpretation, a semiq u a n t i t a t i v e or q u a n t i t a t i v e m e t h o d can be used. Q u a n t i t a t i v e scintigraphic m e t h o d s for evaluation of infarct size have been applied in both e x p e r i m e n t a l and clinical studies. 15, 2o-22 Two main types of quantification m e t h o d s can be distinguished: thresholding t e c h n i q u e s with an a r b i t r a r y cut-off value between normal and pathologic pixel values 23, 24 and circumferential profile techniques t h a t compare the count rate variation within the ventricle wall with the m e a n of a n o r m a l d a t a base. 25, 26 T h e relevance of myocardial perfusion scintigraphy in the assessment of t h r o m b o l y t i c t h e r a p y in acute myocardial infarction has recently been reviewed by G. Beller} 7 P a t i e n t s in our s t u d y u n d e r w e n t planar thallium scintigraphy at rest, and the h y p o p e r f u s i o n index was calculated with a circumferential profile method. T h e total thallium h y p o p e r f u s i o n index was calculated as the sum of the deviations of perfusion in the segments from all three projections versus the thallium u p t a k e in a n o r m a l d a t a base. With this parameter, a statistically significant reduction of 28% in infarct size was n o t e d in the group t r e a t e d with r t - P A (Table III). This value is very similar to the 20 % reduction f o u n d b y the cumulative release of H B D H . T h e correlation coefficient between the thallium index and H B D H during the first 72 hours was d e t e r m i n e d to be 0.57, which is similar to the corre-

4.0

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LVEF(Angio) Fig. 4. Scatter diagram showing the correlation of the LVEF measured by radionuclide (Egna) and angiographic (Angio) techniques. A paired t test of the differences (LVEF Angio minus LVEF Egna) illustrates that both methods result in the same LVEF for the whole group (mean difference equals -0.98%; 95% confidence limits: -2.29%, 0.94%), but that there is a clear variation in individual patients (SD = 11.23).

Table IV. Regression analysis between infarct size and left ventricular ejection fraction

EGNA/T]Sndex Angio/Tl.index EGNA/Enz+I.S. Angio/Enz.I.S.

Regression coefficient

Intercept

R2

-0.0035 (-0.0025; -0.0043) -0.0024 (-0.0020; - 0 . 0 0 2 8 ) -0.015 (-0.0012; - 0 . 0 1 8 ) -0.011 (-0.0096; - 0 . 0 1 3 )

63.81 (66.61-61.02) 60.03 (59.16-61.90) 63.13 (60.22-66.05) 60.94 (58.93-62.95)

0.33 0.36 0.26 0.35

The regression coefficient and the intercept (with their confidence limits between brackets) of a linear relationship are indicated, showing the relationship between infarct size, measured by scintigraphy (T1, Index) and enzymes (Enz,I+S.), and LVEF, measured by radionuelide and contrast angiography. The coefficient of variance due to regression (R 2) is shown in the last column.

lation coefficient of 0.65 found by Morrision et al. 21 It should be n o t e d t h a t these two p a r a m e t e r s measure different p h e n o m e n a at different times. H B D H estimates the a m o u n t of necrotic tissue in the first 72 hours, whereas the thallium index reflects the grade of h y p o p e r f u s i o n at rest 10 to 14 days after the onset of symptoms. In addition, because of the superposition of myocardial tissue, a planar technique has definite shortcomings in contrast to a tomographic technique, which has the q u a n t i t a t i v e potential to calculate infarct volume and the additional advan-

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tage of providing information about the localization and the extent of the defect. This advantage is emphasized by the fact that a better correlation coefficient was found in the case of anterior infarcts in which superposition plays a lesser role. Finally, this correlation can be disturbed by previous myocardial infarction (seven patients in the rt-PA group and eight patients in the placebo group), right ventricular, and nontransmural infarction that cannot be detected by thallium scintigraphy. In this trial the influence of thrombolysis on left ventricular function measured by radionuclide and contrast angiograms was studied after 10 to 14 days, and a significant difference in left ventricular function was only found by means of contrast angiography (LVEF of 53.0% versus 51.0%). This difference in global ejection fraction is very similar to the 2.2 % absolute difference found in the total study population. 4 The 2.5% difference in radionuclide LVEF between the two treatment groups was not statistically significant. This can be explained by a fairly extensive variation of the scintigraphic LVEF in comparison to the angiographic LVEF. A statistical analysis of the differences in LVEF determined by both methods resulted in a mean difference nearly equal to zero but with a high standard deviation, which may be explained by our technique of using human serum albumin instead of red blood cells as the intravascular tracer for scintigraphic LVEF determination. This compound is easy to use but diffuses rapidly out of the blood vessels in a short period of time. There was a moderate, but nevertheless significant, correlation between infarct size and LVEF as shown in Figs. 1 and 2. The percentage of variance that was due to linear regression ranges from 0.26 to 0.36. The linear model fits better when angiographic methods for LVEF measurement and enzymatic methods for infarct size measurements are used. The limited relationship is possibly due to a varying suppression of ventricular function because of some residual myocardial stunning and to an overestimation of infarct size measured with thallium scintigraphy in patients with a recurrent myocardial infarction or by the effect of ischemic, but viable and contracting, myocardial tissue. It can be concluded that the intravenous infusion of 100 mg of rt-PA, administered over 3 hours in combination with heparin and aspirin and started within 5 hours after the onset of myocardial infarction, significantly reduces infarct size as assessed by two independent methods: a 20% reduction was shown by an enzymatic method, and a 28 % reduction

American Heart Journal

was shown by thallium scintigraphy. As in many other placebo-controlled trials, 2s the resulting preservation of global left ventricular function in the thrombolysis group was small and could only be demonstrated with contrast ventriculography. A significant but moderate correlation between infarct size and preservation of ventricular function was demonstrated. We thank Mrs. V. Van den Maegdenbergh, Mr. E. Van de Gaer, P. Drent, L. Verhaegen and Mr. Janssens for their technical assistance. We also thank Mrs. M. J. Vangoetsenhoven for her assistance in the preparation of the manuscript. REFERENCES

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