(Circulation. 2001;103:813.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
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
From Hospital Universitario Virgen de la Arrixaca de Murcia, Spain.
Correspondence to Jose Galcerá-Tomás, Profesor asociado, Unidad de Cuidados Coronarios, Hospital Universitario Virgen de la Arrixaca, 30120 Murcia, Spain. E-mail jgalcera{at}huva.es
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Abstract |
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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 Results—In 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: 29.8±12% versus 20.8±12% (P<0.01) by polar map and 28.3±13% versus 20.0±13% (P<0.01) by tomography. Changes from baseline to 1 week and to 3 months in ventricular end-diastolic volume, assessed by echocardiography, were as follows: 58±14 versus 64±19 (P<0.05) and 65±21 mL/m2 (P<0.05), respectively, with captopril, and 58±18 versus 64±18 (P<0.05) and 69±30 mL/m2 (P<0.05), respectively, with atenolol. Neither group showed significant changes in end-systolic volume. Among patients with perfusion defect >18% (n=51), those treated with atenolol showed a significant increase of end-systolic and end-diastolic ventricular volumes, whereas captopril-treated patients did not.
Conclusions—Although
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.
Key Words: myocardial infarction • remodeling • inhibitors • drugs
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Both
-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.3 4 5
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 anti-ischemic 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,12 13 14 15 16
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 captopril on ventricular dilatation and to determine whether our findings might be explained by each drug’s having a different effect on limiting infarct size.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patients
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 Dirección 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.
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 (64x64 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 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
(Hewlett-Packard) 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 end-systolic 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
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 Student’s
t test. Changes from baseline
to subsequent measurements in ventricular volume and ejection fraction
were compared by paired 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 P<0.05.
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.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 captopril-treated 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
).
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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.
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significant differences between groups at all times.
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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.
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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: 29.8±12%
versus 20.8±12% (P>0.01) by
polar map and 28.3±13% versus 20.0±13%
(P<0.01) 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).
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Subsequent revascularization was performed in 14 patients in
the captopril group, 1 surgically and 13 by angioplasty, and 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).
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significant differences between groups.In the logistic regression analysis, left ventricular ejection fraction at 1 week was the only variable with independent 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).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 accompanied 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 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.
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Acknowledgments |
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We thank María Teresa SanMiguel and the Pharmacy Service of the Hospital Virgen de la Arrixaca for preparing and supplying the study protocol medication.
Received August 3, 2000; revision received October 4, 2000; accepted October 4, 2000.
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