Effects of Early Use of Atenolol or Captopril on Infarct Size

and Ventricular Volume

A Double-Blind Comparison in Patients With Anterior Acute
Myocardial Infarction
Jos Galcer-Toms, PhD; Francisco Jos Castillo-Soria, MD; Manuel Villegas-Garca, PhD;
Rafael Florenciano-Snchez, MD; Jos Gins Snchez-Villanueva, MD;
Jos Antonio Nuo de la Rosa, MD; Antonio Martnez-Caballero, PhD;
Jos Antonio Valent-Aldeguer, MD; Pedro Jara-Prez; Manuel Prraga-Ramrez, MD;
Iluminada Lpez-Martnez, MD; Luis Iigo-Garca, MD; Francisco Pic-Aracil, PhD
Background-Blockers and ACE inhibitors reduce early mortality when either one is started in the first hours after
myocardial infarction (MI). Considering the close correlation between morphological changes and prognosis, we aimed
to investigate whether the benefit of both -blockers and ACE inhibitors might reside in a similar protective effect on
infarct size or ventricular volume.
Methods and ResultsIn a randomized, double-blind comparison between early treatment with captopril or atenolol in 121
patients with acute anterior MI, both drugs showed a similar reduction in mean blood pressure. However, only the
atenolol-treated patients showed a significant early reduction in heart rate. Infarct size, obtained from the perfusion
defect in resting single photon emission imaging, was higher in captopril-treated patients than in atenolol-treated
patients: 29.812% versus 20.812% (P0.01) by polar map and 28.313% versus 20.013% (P0.01) by
tomography. Changes from baseline to 1 week and to 3 months in ventricular end-diastolic volume, assessed by
echocardiography, were as follows: 5814 versus 6419 (P0.05) and 6521 mL/m2 (P0.05), respectively, with
captopril, and 5818 versus 6418 (P0.05) and 6930 mL/m2 (P0.05), respectively, with atenolol. Neither group
showed significant changes in end-systolic volume. Among patients with perfusion defect 18% (n51), those treated
with atenolol showed a significant increase of end-systolic and end-diastolic ventricular volumes, whereas captopriltreated patients did not.
ConclusionsAlthough early treatment with atenolol or captopril results in similar overall short- and medium-term
preservation of ventricular function and volumes, in patients with larger infarctions, a -blocker alone does not
adequately protect myocardium from ventricular dilatation. (Circulation. 2001;103:813-819.)
Key Words: myocardial infarction remodeling inhibitors drugs
oth -blockers and ACE inhibitors improve long-term
survival rates in patients when administered after the
acute phase of myocardial infarction (MI),1,2 a benefit mainly
observed in high-risk patients.35 These are not the only links
between -blockers and ACE inhibitors, because both pharmacological agents seem to be able to attenuate underlying
neurohormonal activation in ventricular dysfunction,6 both
reduce the incidence of sudden death,1,5,7 and the antiischemic effect appears not to be a property exclusive to
-blockers.8,9 A further finding common to both ACE inhibitors and -blockers is the reduction in early mortality when
treatment is initiated in the first hours of MI.3,10 Given that
the prognosis of MI depends in great measure on the early

morphological impact,11 it may be that the benefits common

to both drugs are the consequence of a similar preservation
effect on ventricular geometry. The protective effect of ACE
inhibitors on cardiac anatomy has been documented repeatedly in clinical studies,1216 whereas we have experimental
evidence that -blockers increase ventricular dilatation,17,18
and only the reduction of the risk of cardiac rupture attributed
to -blockers 19 suggests a favorable effect on protecting the
ventricular wall. On the other hand, early use of -blockers
seems to limit infarct size, whereas for ACE inhibitors, this
effect has been reported only in experimental models.20
With all this in mind, the present study was designed to
compare the effect of early treatment with atenolol or

Received August 3, 2000; revision received October 4, 2000; accepted October 4, 2000.
From Hospital Universitario Virgen de la Arrixaca de Murcia, Spain.
Correspondence to Jose Galcer-Toms, Profesor asociado, Unidad de Cuidados Coronarios, Hospital Universitario Virgen de la Arrixaca, 30120
Murcia, Spain. E-mail jgalcera@huva.es
2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

813
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captopril on ventricular dilatation and to determine whether

our findings might be explained by each drugs having a
different effect on limiting infarct size.

Methods
Patients

TABLE 1. Clinical and ECG Characteristics in All

Randomized Patients

Mean age, y
Female sex, n (%)

We conducted a prospective study on consecutive patients admitted

to the Coronary Care Unit of the Hospital Virgen de la Arrixaca,
Murcia, Spain, for suspected large anterior MI 24 hours from the
onset of symptoms, established by the presence of a typical precordial pain lasting 30 minutes and an increase of 0.1 mV in ST
displacement in 3 leads from V1 to V6. Diagnosis of Q-wave MI
was confirmed by both new Q-wave appearance and an increase in
creatine kinase (CK) to more than twice the normal value (190 U/L).
Exclusion criteria were any of the following: informed consent not
given, left bundle-branch block, age 75 years, Killip class II,
myocardiopathy or valvular disease, atrial fibrillation, bradycardia
50 bpm, any degree of AV block, a history of asthma or bronchitis
requiring bronchodilators, systolic blood pressure 95 mm Hg, renal
impairment (serum creatinine 0.2. mmol/L), or any other serious
concomitant disease. Thrombolytic therapy was based on clinical
criteria, and indirect reperfusion criteria were considered, according
to standard protocols,21 in the presence of 2 or more of the following:
(1) CK peak 14 hours from the onset of pain; (2) 50% decrease in
the ST segment 2 hours after the start of thrombolysis compared with
the baseline value; or (3) early relief of pain associated with
reperfusion arrhythmias (thrombolysis-related accelerated idioventricular rhythm or sinus bradycardia). The study protocol was
approved by the Hospital Human Research Committee and by the
Direccin General de Farmacia del Instituto Nacional de la Salud.

Medication Protocol
Randomized, double-blind treatment with captopril or atenolol was
started as soon as possible after informed consent was obtained.
Initially, all patients received a first intravenous dose of 5 mg of
atenolol or placebo administered over 5 minutes, and if this was well
tolerated (no fall of systolic blood pressure below 95 mm Hg or
bradycardia below 45 bpm), another equal dose was given 10
minutes later. Simultaneously with the first intravenous dose of
atenolol or placebo, an oral dose of placebo or 6.25 mg of captopril,
respectively, was given. Subsequent doses were as follows: second
dose, captopril 12.5 mg or atenolol 33 mg 30 minutes after the first
dose; third dose, captopril 25 mg or atenolol 33 mg 4 hours after the
second dose; and thereafter, captopril 25 mg or atenolol 33 mg every
8 hours. To blind this procedure, the Hospital Pharmacy Service
prepared ampoules of atenolol or placebo, first-dose capsules containing 6.25 mg of captopril or placebo, second-dose capsules
containing 12.5 mg of captopril or 33 mg of atenolol, and capsules
for successive doses containing 25 mg of captopril or 33 mg of
atenolol. Target dose was 25 mg of captopril or 33 mg of atenolol
every 8 hours. If hypotension and/or bradycardia occurred, medication was stopped, and after recovery, the next dose was given. Study
medication was discontinued if MI was not confirmed or if the
patient developed any of the following complications: sustained
hypotension (systolic blood pressure 90 mm Hg for 3 hours) or
symptomatic hypotension; heart failure, Killip class II; recurrence
of ischemic pain; or recurrent MI. For the purposes of this study,
post hospital-discharge medication was supplied to each patient by
the Pharmacy Service during follow-up according to group.

Captopril
(n59)

Atenolol
(n62)

59.89.6

57.110.1

6 (10)
2

Mean body surface area, m

Previous MI, n (%)

1.810.16

15 (24)
4 (6)

Smokers, n (%)

34 (58)

36 (60)

Diabetes, n (%)

16 (27)

21 (34)

Hypercholesterolemia, n (%)

19 (32)

20 (32)

Hypertension, n (%)

21 (36)

20 (39)

Heart rate, bpm

8016

8115

Mean blood pressure, mm Hg

105 (15)

103 (15)

5 (8)

0.05

1.820.16

7 (12)

Killip class II, n (%)

P
0.06

6 (10)

Mean minutes from symptoms

159197

157209

ST elevation, mm

19.511

Thrombolysis, n (%)

54 (92)

55 (89)

Indirect reperfusion criteria, n (%)

32 (59)

37 (67)

189

perfusion defect (myocardial infarct size), expressed as a percentage

of the total left ventricle, was calculated by tomographic22 and polar
map23 methods. Intraobserver variability for both methods of quantification was 9% and 4%, respectively. Perfusion study imaging was
performed only in those patients who did not develop reinfarction
and who fulfilled the following criteria: confirmation of infarction,
no antecedents of a prior infarction, and no early violation of the
study medication protocol.

Echocardiography
2D echocardiography was performed with Sonos 1000 (HewlettPackard) and a 2.5-MHz transducer. We used apical 4- and
2-chamber views to determine left ventricular ejection fraction and
left ventricular volumes using the biplane summation-of-disks
method recommended by the American Society of Echocardiography.24 Left ventricular ejection fraction and left ventricular volumes
were assessed within the first 24 hours after admission, at 1 week,
and at 3 months. The reproducibility of ventricular volume measurements made by the same observer differed by 8.5% for left
end-diastolic volume and by 6.7% for left end-systolic volume. Left
ventricular end-diastolic volume index and left ventricular endsystolic volume index were derived by means of body surface area.

Coronary Angiography
To compare the extent of coronary disease and infarct-related
coronary artery patency between captopril and atenolol groups, left
catheterization with multiple views of the coronary tree was performed in all surviving patients on day 10. Coronary angiograms
were analyzed by an observer unaware of the patients clinical status.
Significant coronary stenosis was defined as a narrowing of 60%
of the lumen. Vessel patency was established according to TIMI
grades.25

Statistical Analysis
Radionuclide Determinations
Resting single photon emission tomography with 99mTc hexakis
2-methoxyisobutyl isonitrile imaging (MIBI-SPECT) was performed
on the fifth day with a rotating gamma camera (Apex SP4, Elscint)
equipped with a high-resolution collimator. Sixty frames (6464
matrix) were acquired for 25 seconds each over 180 in 3 intervals,
starting in the right anterior oblique position and ending in the
posterior oblique position. The energy window was centered on the
140-keV gamma photopeak. Quantification of the size of the

A descriptive analysis was done on all variables to obtain a

frequency distribution. For the quantitative variables, we also determined the mean, median, SD, and range. The relationship between
categorical variables was assessed by means of contingency tables,
the 2 test, and an analysis of residues to test the trend of associations
or dependence. Between-group comparisons were studied by
ANOVA complemented with means equality contrasts using the
Students t test. Changes from baseline to subsequent measurements
in ventricular volume and ejection fraction were compared by paired

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Galcer-Toms et al

Atenolol vs Captopril: Infarct Size and Remodeling

815

Figure 1. Changes in mean blood pressure and

heart rate. *Significant differences from baseline
values; significant differences between groups
at all times.

t test in the overall population with radionuclide perfusion defect and

in the subgroup of patients with larger infarctions, empirically
defined as the upper and middle tertiles of the perfusion defect. The
level of significance was P0.05. Variables with hypothetical
influence on ventricular dilatation, such as age, sex, history of
diabetes, hypertension, heart rate and blood pressure at admission,
treatment group, baseline and 1-week left ventricular ejection fractions, perfusion defect, and TIMI grade of infarct-related artery, were
introduced into a logistic regression analysis to determine their
independent predictive value for a 15% increase of end-systolic
volume index from baseline to 1 week and from baseline to 3
months. The statistical package used was SPSS.

Results
During the period of study, 121 patients were randomized to
receive the study medication; 59 were allocated to receive
captopril and 62 atenolol. Medication with captopril or
atenolol was started at an average of 320 and 310 minutes,
respectively, from the onset of symptoms. The captopriltreated patients were older, almost to statistical significance,
and contained a smaller proportion of women. The remaining
clinical characteristics and details at admission were similar
in the 2 groups (Table 1).
Both captopril- and atenolol-treated patients showed a
similar and significant reduction in mean blood pressure after
15 minutes of their respective first dose. However, only the
atenolol-treated patients showed a significant early reduction
in heart rate (Figure 1). In 10 patients in the atenolol group
and 3 in the captopril group, a systolic blood pressure 90
mm Hg was recorded on at least 1 occasion. Reasons for
withdrawal from medication are listed in Table 2 and include
complications that appeared early, within the first 48 hours,
and during the rest of the hospital stay.

Four patients, 2 in each group of treatment, were excluded

from echocardiographic volume measurements because of
inadequate image quality. Clinical characteristics and details
of admission of patients with radionuclide perfusion defect in
whom changes in ventricular volume were evaluated are
expressed in Table 3.
Among the patients in whom resting MIBI-SPECT was
performed (45 patients treated with captopril and 49 treated
with atenolol), perfusion defect was higher in those who
received captopril: 29.812% versus 20.812% (P0.01)
by polar map and 28.313% versus 20.013% (P0.01) by
tomography. For other indirect indices of infarct size in these
patients, differences reached statistical significance only in
the case of peak CK. There were no significant differences
between groups in subacute catheterization (Table 4).
Subsequent revascularization was performed in 14 patients
in the captopril group, 1 surgically and 13 by angioplasty, and
TABLE 2.

Reasons for Withdrawal During Hospital Treatment

Treatment Groups
Captopril

Atenolol

Violation of protocol, n (early)

1 (1)

1 (1)

Death, n (early)

4 (1)

2 (1)

Post-MI angina, n (early)

1 (0)

1 (1)

Reinfarction, n (early)

2 (0)

1 (0)

Sustained hypotension, n (early)

1 (0)

2 (2)

Heart failure Killip II, n (early)

2 (2)

3 (3)

Ischemic stroke, n (early)

Total, n (early)

1 (1)

(0)

12 (4)

11 (8)

Early indicates within the first 48 hours after randomization.

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TABLE 3. Characteristics of Patients With Perfusion Defect

and Changes in Ventricular Volume

Age, y

Captopril
(n45)

Atenolol
(n49)

5910

5711

4 (9)

9 (18)

1.790.14

1.800.15

Discussion

11 (24)

12 (24)

Considering the close correlation between morphological

changes and prognosis,11 it seems obligatory to investigate
whether the benefit of both -blockers and ACE inhibitors in
early mortality might result from a common protective effect
on ventricular architecture, but although comparative studies
have been called for,14 little has been done to determine to
what extent the similar benefit of -blockers arises from an
equal or from a different effect on ventricular dilatation.
Moreover, if there are no contraindications, simultaneous
early treatment with -blockers and ACE inhibitors is recommended in the case of anterior acute MI,26 although the
clinician frequently questions which of the 2 drugs should
have priority, especially when blood pressure is not elevated.
In the present study, early administration of either captopril
or atenolol was followed by a significant early decrease in
blood pressure. Considering the importance of afterload in the
early expansion of the infarcted wall segment,27 it would be
reasonable to expect from both drugs a similar benefit on
ventricular dilatation in the short-term. However, cardiac
output either does not change15 or increases slightly28 when
captopril is administered early in patients with infarction,
whereas cardiac output usually diminishes with the early
administration of -blockers.29 Therefore, captopril would
seem to reduce to a greater degree the vascular systemic
resistances and consequently the risk of ventricular expansion.30 However, the elongation of the infarcted segment
depends not only on hemodynamic determinants but also on
infarct size. In this respect, a rapid fall in heart rate accom-

Female gender, n (%)

Body surface area, m

Diabetes, n (%)
Hypertension, n (%)

18 (40)

19 (39)

Heart rate, bpm

7915

8015

Mean blood pressure, mm Hg

10517

10414

ST elevation, mm

18.510

17.47

Thrombolysis, n (%)

42 (93)

45 (92)

Indirect reperfusion criteria, n (%)

30 (71)

35 (78)

P
0.15

in 12 patients in the atenolol group, 2 surgically and 10 by

angioplasty. After hospital discharge, 1 patient in the captopril group was openly treated with -blockers for sinusal
tachycardia.
In both groups, left ventricular ejection fraction was similar
and showed no significant changes from baseline to 1 week.
In both groups, the end-diastolic volume index increased
slightly but significantly. In the medium term, both treatment
groups showed significant improvement of left ventricular
ejection fraction with a similar end-systolic volume, without
significant changes in the end-diastolic volume evaluated at 1
week (Table 5). The patients with perfusion defect imaging in
the middle and upper tertiles (18%; 28 in the captopril
group and 23 in the atenolol group) experienced a different
medium-term evolution in that those treated with atenolol
underwent a significant increase of ventricular volume (Figure 2).
In the logistic regression analysis, left ventricular ejection
fraction at 1 week was the only variable with independent
TABLE 4.

predictive value for an increase of end-systolic ventricular

volume from baseline to 1 week (OR 2.9, 95% CI 1.34 to
6.2), whereas perfusion defect was the only variable with
independent predictive value for an increase of end-systolic
volume from baseline to 3 months (OR 7.9, 95% CI 2.3 to
27.2).

Indices of Infarct Size and Angiographic Data

Captopril
(n45)

Atenolol
(n49)

32001751

24921801

0.05

Polar map

29.812

20.812

0.01

Tomograms

28.313

20.013

0.01

4310

4510

Left ventricular ejection fraction, %

4610

4810

Mean CK peak, U/L

SESTAMIBI-SPECT perfusion defect, %

Radionuclide left ventricular ejection fraction, % at discharge

Catheterization at 10th day
End-diastolic volume index, mL/m

7523

7122

End-systolic volume index, mL/m2

4117

3716

Multivessel, n (%)

14 (31)

14 (29)

41 (91)

43 (88)

Main left coronary artery, n

60% Lesion in left descending artery, n (%)
Infarct-related TIMI grade, n (%)
01

12 (27)

11 (22)

6 (13)

7 (14)

27 (60)

31 (63)

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Galcer-Toms et al
TABLE 5.

Atenolol vs Captopril: Infarct Size and Remodeling

817

Echocardiographic Changes in Left Ventricular Volume and Function

Captopril
(n45)
LVEF, mL/m2

Atenolol
(n49)

LVEDI, mL/m2

LVESI, %

LVEF, %

LVEDI, mL/m2

LVESI, mL/m2

Baseline

428

5814

3411

426

5819

3413

1 Week

439

6419*

3615

448

6418*

3614

3 Months

4510*

6521*

3619

479*

6930*

3721

LVEF indicates left ventricular ejection fraction; LVEDI, left ventricular end-diastolic index; and
LVESI, left ventricular end-systolic index.
*Significant differences from baseline.
Significant differences from 1-week value.

panied the fall in blood pressure only in the case of atenolol,

a combined effect that, in theory, seems ideal to reduce
myocardial oxygen demand and infarct size.29 In accordance
with this presumption, our results showed that patients who

received atenolol showed a lesser MIBI-SPECT perfusion

defect, with no differences between groups with respect to
admission delay, initial ECG, rates of thrombolytic therapy,
indirect reperfusion criteria, initial left ventricular ejection

Figure 2. Changes in ventricular function

and volume in patients with larger infarcts.
*Significant differences from baseline; significant differences from 1-week values;
significant differences between groups.

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February 13, 2001

fraction, or subacute coronary anatomy. Therefore, although

immediate angiographic reperfusion was not evaluated, it
seems unlikely that the differences found in perfusion defect
would lie in causes found outside the medication under study.
Nevertheless, the fact remains that the difference in the
estimation of infarct size with MIBI-SPECT was surprisingly
marked. In this regard, is possible that the difference observed in the perfusion defect between the 2 treatment groups
does not express the differences in true infarct size and that
atenolol may have brought about a more rapid recuperation of
cellular ischemia and more rapid uptake of 99mTc isonitrile.23
In any case, other indirect indices of infarct size, although
they did not always reach statistical significance, always
favored treatment with atenolol and strongly suggested its
protective effect on myocardium.
Curiously, even in the presence of this difference in
perfusion defect, both treatments resulted in a similar ventricular end-systolic volume in the short term. The similar
influence on ventricular volumes shown by both pharmacological agents in the present study is, in the case of atenolol,
a finding contrary to that documented in a model of MI in the
rat in which treatment with -blockers caused a striking
increase in left ventricular cavity dimensions.17,18 This difference in findings may be explained by the relatively late start
of medication in those models, the second day17 or fifth day18
after coronary ligation, whereby the possible early hemodynamic benefits on infarct size and expansion would be lost.
Moreover, the ventricular dilatation observed in these animal
studies was in part attributed to the blunting of the hypertrophy of the noninfarcted myocardium, and as suggested by our
results, it is probable that the increase in ventricular volume,
conditioned by the treatment with -blockers, is produced
only in relatively large infarctions and might require the 4 or
5 weeks in which ventricular dilatation was documented in
those studies.17,18
Although the protective effect of -blockers on the ventricular morphology in the medium and long term may vary
depending on the experimental model31 or on the vasodilatory
action of some -blockers,32 our results suggest that treatment
with a -blocker alone does not adequately protect patients
with large infarctions from ventricular dilatation in the
medium term.
Finally, our regression analysis points to depressed systolic
function and infarct size as the predictive factors for ventricular dilatation and suggests in which way ACE inhibitors and
-blockers may overlap and result in an additive benefit,33,34
thus supporting the recommendation of the combined use of
both drugs in acute anterior infarction.26
According to the present results, in the absence of contraindications in patients with anterior MI in the first hours of
evolution, toleration of -blockers should be established as a
priority. Given that the benefit of an ACE inhibitor can be
observed in the first few days of evolution,3 its association
with -blockers should not be delayed unnecessarily. In
patients with large infarctions in whom the instigation of
treatment with both drugs results in hypotension, withdrawal
from -blockers must be considered first.

Acknowledgments
We thank Mara Teresa SanMiguel and the Pharmacy Service of the
Hospital Virgen de la Arrixaca for preparing and supplying the study
protocol medication.

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Effects of Early Use of Atenolol or Captopril on Infarct Size and Ventricular Volume: A
Double-Blind Comparison in Patients With Anterior Acute Myocardial Infarction
Jos Galcer-Toms, Francisco Jos Castillo-Soria, Manuel Villegas-Garca, Rafael
Florenciano-Snchez, Jos Gins Snchez-Villanueva, Jos Antonio Nuo de la Rosa, Antonio
Martnez-Caballero, Jos Antonio Valent-Aldeguer, Pedro Jara-Prez, Manuel
Prraga-Ramrez, Iluminada Lpez-Martnez, Luis Iigo-Garca and Francisco Pic-Aracil
Circulation. 2001;103:813-819
doi: 10.1161/01.CIR.103.6.813
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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