effects of early use of atenolol and captopril on infarct size and ventricular remodeling

Effects of Early Use of Atenolol or Captopril on Infarct Sizeand Ventricular Volume

A Double-Blind Comparison in Patients With Anterior AcuteMyocardial 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

Backgroundb-Blockers and ACE inhibitors reduce early mortality when either one is started in the first hours aftermyocardial infarction (MI). Considering the close correlation between morphological changes and prognosis, we aimedto investigate whether the benefit of both b-blockers and ACE inhibitors might reside in a similar protective effect oninfarct size or ventricular volume.

Methods and ResultsIn a randomized, double-blind comparison between early treatment with captopril or atenolol in 121patients with acute anterior MI, both drugs showed a similar reduction in mean blood pressure. However, only theatenolol-treated patients showed a significant early reduction in heart rate. Infarct size, obtained from the perfusiondefect in resting single photon emission imaging, was higher in captopril-treated patients than in atenolol-treatedpatients: 29.8612% versus 20.8612% (P,0.01) by polar map and 28.3613% versus 20.0613% (P,0.01) bytomography. Changes from baseline to 1 week and to 3 months in ventricular end-diastolic volume, assessed byechocardiography, were as follows: 58614 versus 64619 (P,0.05) and 65621 mL/m2 (P,0.05), respectively, withcaptopril, and 58618 versus 64618 (P,0.05) and 69630 mL/m2 (P,0.05), respectively, with atenolol. Neither groupshowed significant changes in end-systolic volume. Among patients with perfusion defect .18% (n551), those treatedwith atenolol showed a significant increase of end-systolic and end-diastolic ventricular volumes, whereas captopril-treated patients did not.

ConclusionsAlthough early treatment with atenolol or captopril results in similar overall short- and medium-termpreservation of ventricular function and volumes, in patients with larger infarctions, a b-blocker alone does notadequately protect myocardium from ventricular dilatation. (Circulation. 2001;103:813-819.)

Key Words: myocardial infarction n remodeling n inhibitors n drugs

Both b-blockers and ACE inhibitors improve long-termsurvival rates in patients when administered after theacute phase of myocardial infarction (MI),1,2 a benefit mainlyobserved in high-risk patients.35 These are not the only linksbetween b-blockers and ACE inhibitors, because both phar-macological agents seem to be able to attenuate underlyingneurohormonal activation in ventricular dysfunction,6 bothreduce the incidence of sudden death,1,5,7 and the anti-ischemic effect appears not to be a property exclusive tob-blockers.8,9 A further finding common to both ACE inhib-itors and b-blockers is the reduction in early mortality whentreatment is initiated in the first hours of MI.3,10 Given thatthe prognosis of MI depends in great measure on the early

morphological impact,11 it may be that the benefits commonto both drugs are the consequence of a similar preservationeffect on ventricular geometry. The protective effect of ACEinhibitors on cardiac anatomy has been documented repeat-edly in clinical studies,1216 whereas we have experimentalevidence that b-blockers increase ventricular dilatation,17,18and only the reduction of the risk of cardiac rupture attributedto b-blockers 19 suggests a favorable effect on protecting theventricular wall. On the other hand, early use of b-blockersseems to limit infarct size, whereas for ACE inhibitors, thiseffect has been reported only in experimental models.20

With all this in mind, the present study was designed tocompare 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 [email protected] 2001 American Heart Association, Inc.Circulation is available at http://www.circulationaha.org

813 by guest on April 3, 2015http://circ.ahajournals.org/Downloaded from

captopril on ventricular dilatation and to determine whetherour findings might be explained by each drugs having adifferent effect on limiting infarct size.

MethodsPatientsWe conducted a prospective study on consecutive patients admittedto the Coronary Care Unit of the Hospital Virgen de la Arrixaca,Murcia, Spain, for suspected large anterior MI ,24 hours from theonset of symptoms, established by the presence of a typical precor-dial pain lasting $30 minutes and an increase of .0.1 mV in STdisplacement in .3 leads from V1 to V6. Diagnosis of Q-wave MIwas confirmed by both new Q-wave appearance and an increase increatine kinase (CK) to more than twice the normal value (190 U/L).Exclusion criteria were any of the following: informed consent notgiven, 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 bronchitisrequiring bronchodilators, systolic blood pressure ,95 mm Hg, renalimpairment (serum creatinine .0.2. mmol/L), or any other seriousconcomitant disease. Thrombolytic therapy was based on clinicalcriteria, and indirect reperfusion criteria were considered, accordingto 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 inthe ST segment 2 hours after the start of thrombolysis compared withthe baseline value; or (3) early relief of pain associated withreperfusion arrhythmias (thrombolysis-related accelerated idioven-tricular rhythm or sinus bradycardia). The study protocol wasapproved by the Hospital Human Research Committee and by theDireccin General de Farmacia del Instituto Nacional de la Salud.

Medication ProtocolRandomized, double-blind treatment with captopril or atenolol wasstarted as soon as possible after informed consent was obtained.Initially, all patients received a first intravenous dose of 5 mg ofatenolol or placebo administered over 5 minutes, and if this was welltolerated (no fall of systolic blood pressure below 95 mm Hg orbradycardia below 45 bpm), another equal dose was given 10minutes later. Simultaneously with the first intravenous dose ofatenolol or placebo, an oral dose of placebo or 6.25 mg of captopril,respectively, was given. Subsequent doses were as follows: seconddose, captopril 12.5 mg or atenolol 33 mg 30 minutes after the firstdose; third dose, captopril 25 mg or atenolol 33 mg 4 hours after thesecond dose; and thereafter, captopril 25 mg or atenolol 33 mg every8 hours. To blind this procedure, the Hospital Pharmacy Serviceprepared ampoules of atenolol or placebo, first-dose capsules con-taining 6.25 mg of captopril or placebo, second-dose capsulescontaining 12.5 mg of captopril or 33 mg of atenolol, and capsulesfor successive doses containing 25 mg of captopril or 33 mg ofatenolol. Target dose was 25 mg of captopril or 33 mg of atenololevery 8 hours. If hypotension and/or bradycardia occurred, medica-tion was stopped, and after recovery, the next dose was given. Studymedication was discontinued if MI was not confirmed or if thepatient developed any of the following complications: sustainedhypotension (systolic blood pressure ,90 mm Hg for .3 hours) orsymptomatic hypotension; heart failure, Killip class .II; recurrenceof ischemic pain; or recurrent MI. For the purposes of this study,posthospital-discharge medication was supplied to each patient bythe Pharmacy Service during follow-up according to group.

Radionuclide DeterminationsResting single photon emission tomography with 99mTc hexakis2-methoxyisobutyl isonitrile imaging (MIBI-SPECT) was performedon the fifth day with a rotating gamma camera (Apex SP4, Elscint)equipped with a high-resolution collimator. Sixty frames (64364matrix) were acquired for 25 seconds each over 180 in 3 intervals,starting in the right anterior oblique position and ending in theposterior oblique position. The energy window was centered on the140-keV gamma photopeak. Quantification of the size of the

perfusion defect (myocardial infarct size), expressed as a percentageof the total left ventricle, was calculated by tomographic22 and polarmap23 methods. Intraobserver variability for both methods of quan-tification was 9% and 4%, respectively. Perfusion study imaging wasperformed only in those patients who did not develop reinfarctionand who fulfilled the following criteria: confirmation of infarction,no antecedents of a prior infarction, and no early violation of thestudy medication protocol.

Echocardiography2D echocardiography was performed with Sonos 1000 (Hewlett-Packard) and a 2.5-MHz transducer. We used apical 4- and2-chamber views to determine left ventricular ejection fraction andleft ventricular volumes using the biplane summation-of-disksmethod recommended by the American Society of Echocardiogra-phy.24 Left ventricular ejection fraction and left ventricular volumeswere assessed within the first 24 hours after admission, at 1 week,and at 3 months. The reproducibility of ventricular volume measure-ments made by the same observer differed by 8.5% for leftend-diastolic volume and by 6.7% for left end-systolic volume. Leftventricular end-diastolic volume index and left ventricular end-systolic volume index were derived by means of body surface area.

Coronary AngiographyTo compare the extent of coronary disease and infarct-relatedcoronary artery patency between captopril and atenolol groups, leftcatheterization with multiple views of the coronary tree was per-formed in all surviving patients on day 10. Coronary angiogramswere 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 TIMIgrades.25

Statistical AnalysisA descriptive analysis was done on all variables to obtain afrequency distribution. For the quantitative variables, we also deter-mined the mean, median, SD, and range. The relationship betweencategorical variables was assessed by means of contingency tables,the x2 test, and an analysis of residues to test the trend of associationsor dependence. Between-group comparisons were studied byANOVA complemented with means equality contrasts using theStudents t test. Changes from baseline to subsequent measurementsin ventricular volume and ejection fraction were compared by paired

TABLE 1. Clinical and ECG Characteristics in AllRandomized Patients

Captopril(n559)

Atenolol(n562) P

Mean age, y 59.869.6 57.1610.1 0.06

Female sex, n (%) 6 (10) 15 (24) ,0.05

Mean body surface area, m2 1.8160.16 1.8260.16

Previous MI, n (%) 7 (12) 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 80616 81615

Mean blood pressure, mm Hg 105 (15) 103 (15)

Killip class II, n (%) 5 (8) 6 (10)

Mean minutes from symptoms 1596197 1576209

S ST elevation, mm 19.5611 1869

Thrombolysis, n (%) 54 (92) 55 (89)

Indirect reperfusion criteria, n (%) 32 (59) 37 (67)

814 Circulation February 13, 2001

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t test in the overall population with radionuclide perfusion defect andin the subgroup of patients with larger infarctions, empiricallydefined as the upper and middle tertiles of the perfusion defect. Thelevel of significance was P,0.05. Variables with hypotheticalinfluence on ventricular dilatation, such as age, sex, history ofdiabetes, hypertension, heart rate and blood pressure at admission,treatment group, baseline and 1-week left ventricular ejection frac-tions, perfusion defect, and TIMI grade of infarct-related artery, wereintroduced into a logistic regression analysis to determine theirindependent predictive value for a 15% increase of end-systolicvolume index from baseline to 1 week and from baseline to 3months. The statistical package used was SPSS.

ResultsDuring the period of study, 121 patients were randomized toreceive the study medication; 59 were allocated to receivecaptopril and 62 atenolol. Medication with captopril oratenolol 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 remainingclinical characteristics and details at admission were similarin the 2 groups (Table 1).

Both captopril- and atenolol-treated patients showed asimilar and significant reduction in mean blood pressure after15 minutes of their respective first dose. However, only theatenolol-treated patients showed a significant early reductionin heart rate (Figure 1). In 10 patients in the atenolol groupand 3 in the captopril group, a systolic blood pressure ,90mm Hg was recorded on at least 1 occasion. Reasons forwithdrawal from medication are listed in Table 2 and includecomplications 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 excludedfrom echocardiographic volume measurements because ofinadequate image quality. Clinical characteristics and detailsof admission of patients with radionuclide perfusion defect inwhom changes in ventricular volume were evaluated areexpressed in Table 3.

Among the patients in whom resting MIBI-SPECT wasperformed (45 patients treated with captopril and 49 treatedwith atenolol), perfusion defect was higher in those whoreceived captopril: 29.8612% versus 20.8612% (P.0.01)by polar map and 28.3613% versus 20.0613% (P,0.01) bytomography. For other indirect indices of infarct size in thesepatients, differences reached statistical significance only inthe case of peak CK. There were no significant differencesbetween groups in subacute catheterization (Table 4).

Subsequent revascularization was performed in 14 patientsin the captopril group, 1 surgically and 13 by angioplasty, and

Figure 1. Changes in mean blood pressure andheart rate. *Significant differences from baselinevalues; significant differences between groupsat all times.

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) 1 (1) (0)

Total, n (early) 12 (4) 11 (8)

Early indicates within the first 48 hours after randomization.

Galcer-Toms et al Atenolol vs Captopril: Infarct Size and Remodeling 815


in 12 patients in the atenolol group, 2 surgically and 10 byangioplasty. After hospital discharge, 1 patient in the capto-pril group was openly treated with b-blockers for sinusaltachycardia.

In both groups, left ventricular ejection fraction was similarand showed no significant changes from baseline to 1 week.In both groups, the end-diastolic volume index increasedslightly but significantly. In the medium term, both treatmentgroups showed significant improvement of left ventricularejection fraction with a similar end-systolic volume, withoutsignificant changes in the end-diastolic volume evaluated at 1week (Table 5). The patients with perfusion defect imaging inthe middle and upper tertiles ($18%; 28 in the captoprilgroup and 23 in the atenolol group) experienced a differentmedium-term evolution in that those treated with atenololunderwent a significant increase of ventricular volume (Fig-ure 2).

In the logistic regression analysis, left ventricular ejectionfraction at 1 week was the only variable with independent

predictive value for an increase of end-systolic ventricularvolume from baseline to 1 week (OR 2.9, 95% CI 1.34 to6.2), whereas perfusion defect was the only variable withindependent predictive value for an increase of end-systolicvolume from baseline to 3 months (OR 7.9, 95% CI 2.3 to27.2).

DiscussionConsidering the close correlation between morphologicalchanges and prognosis,11 it seems obligatory to investigatewhether the benefit of both b-blockers and ACE inhibitors inearly mortality might result from a common protective effecton ventricular architecture, but although comparative studieshave been called for,14 little has been done to determine towhat extent the similar benefit of b-blockers arises from anequal or from a different effect on ventricular dilatation.Moreover, if there are no contraindications, simultaneousearly treatment with b-blockers and ACE inhibitors is rec-ommended in the case of anterior acute MI,26 although theclinician frequently questions which of the 2 drugs shouldhave priority, especially when blood pressure is not elevated.

In the present study, early administration of either captoprilor atenolol was followed by a significant early decrease inblood pressure. Considering the importance of afterload in theearly expansion of the infarcted wall segment,27 it would bereasonable to expect from both drugs a similar benefit onventricular dilatation in the short-term. However, cardiacoutput either does not change15 or increases slightly28 whencaptopril is administered early in patients with infarction,whereas cardiac output usually diminishes with the earlyadministration of b-blockers.29 Therefore, captopril wouldseem to reduce to a greater degree the vascular systemicresistances and consequently the risk of ventricular expan-sion.30 However, the elongation of the infarcted segmentdepends not only on hemodynamic determinants but also oninfarct size. In this respect, a rapid fall in heart rate accom-

TABLE 4. Indices of Infarct Size and Angiographic Data

Captopril(n545)

Atenolol(n549) P

Mean CK peak, U/L 320061751 249261801 ,0.05

SESTAMIBI-SPECT perfusion defect, %

Polar map 29.8612 20.8612 ,0.01

Tomograms 28.3613 20.0613 ,0.01

Radionuclide left ventricular ejection fraction, % at discharge 43610 45610

Catheterization at 10th day

Left ventricular ejection fraction, % 46610 48610

End-diastolic volume index, mL/m2 75623 71622

End-systolic volume index, mL/m2 41617 37616

Multivessel, n (%) 14 (31) 14 (29)

Main left coronary artery, n 1 2

$60% Lesion in left descending artery, n (%) 41 (91) 43 (88)

Infarct-related TIMI grade, n (%)

01 12 (27) 11 (22)

2 6 (13) 7 (14)

3 27 (60) 31 (63)

TABLE 3. Characteristics of Patients With Perfusion Defectand Changes in Ventricular Volume

Captopril(n545)

Atenolol(n549) P

Age, y 59610 57611

Female gender, n (%) 4 (9) 9 (18) 0.15

Body surface area, m2 1.7960.14 1.8060.15

Diabetes, n (%) 11 (24) 12 (24)

Hypertension, n (%) 18 (40) 19 (39)

Heart rate, bpm 79615 80615

Mean blood pressure, mm Hg 105617 104614

S ST elevation, mm 18.5610 17.467

Thrombolysis, n (%) 42 (93) 45 (92)

Indirect reperfusion criteria, n (%) 30 (71) 35 (78)



panied the fall in blood pressure only in the case of atenolol,a combined effect that, in theory, seems ideal to reducemyocardial oxygen demand and infarct size.29 In accordancewith this presumption, our results showed that patients who

received atenolol showed a lesser MIBI-SPECT perfusiondefect, with no differences between groups with respect toadmission delay, initial ECG, rates of thrombolytic therapy,indirect reperfusion criteria, initial left ventricular ejection

TABLE 5. Echocardiographic Changes in Left Ventricular Volume and Function

Captopril(n545)

Atenolol(n549)

LVEF, mL/m2 LVEDI, mL/m2 LVESI, % LVEF, % LVEDI, mL/m2 LVESI, mL/m2

Baseline 4268 58614 34611 4266 58619 34613

1 Week 4369 64619* 36615 4468 64618* 36614

3 Months 45610* 65621* 36619 4769* 69630* 37621

LVEF indicates left ventricular ejection fraction; LVEDI, left ventricular end-diastolic index; andLVESI, left ventricular end-systolic index.

*Significant differences from baseline.Significant differences from 1-week value.

Figure 2. Changes in ventricular functionand volume in patients with larger infarcts.*Significant differences from baseline; sig-nificant differences from 1-week values;significant differences between groups.



fraction, or subacute coronary anatomy. Therefore, althoughimmediate angiographic reperfusion was not evaluated, itseems unlikely that the differences found in perfusion defectwould lie in causes found outside the medication under study.Nevertheless, the fact remains that the difference in theestimation of infarct size with MIBI-SPECT was surprisinglymarked. In this regard, is possible that the difference ob-served in the perfusion defect between the 2 treatment groupsdoes not express the differences in true infarct size and thatatenolol may have brought about a more rapid recuperation ofcellular ischemia and more rapid uptake of 99mTc isonitrile.23In any case, other indirect indices of infarct size, althoughthey did not always reach statistical significance, alwaysfavored treatment with atenolol and strongly suggested itsprotective effect on myocardium.

Curiously, even in the presence of this difference inperfusion defect, both treatments resulted in a similar ven-tricular end-systolic volume in the short term. The similarinfluence on ventricular volumes shown by both pharmaco-logical agents in the present study is, in the case of atenolol,a finding contrary to that documented in a model of MI in therat in which treatment with b-blockers caused a strikingincrease in left ventricular cavity dimensions.17,18 This differ-ence in findings may be explained by the relatively late startof medication in those models, the second day17 or fifth day18after coronary ligation, whereby the possible early hemody-namic benefits on infarct size and expansion would be lost.Moreover, the ventricular dilatation observed in these animalstudies was in part attributed to the blunting of the hypertro-phy of the noninfarcted myocardium, and as suggested by ourresults, it is probable that the increase in ventricular volume,conditioned by the treatment with b-blockers, is producedonly in relatively large infarctions and might require the 4 or5 weeks in which ventricular dilatation was documented inthose studies.17,18

Although the protective effect of b-blockers on the ven-tricular morphology in the medium and long term may varydepending on the experimental model31 or on the vasodilatoryaction of some b-blockers,32 our results suggest that treatmentwith a b-blocker alone does not adequately protect patientswith large infarctions from ventricular dilatation in themedium term.

Finally, our regression analysis points to depressed systolicfunction and infarct size as the predictive factors for ventric-ular dilatation and suggests in which way ACE inhibitors andb-blockers may overlap and result in an additive benefit,33,34thus supporting the recommendation of the combined use ofboth drugs in acute anterior infarction.26

According to the present results, in the absence of contra-indications in patients with anterior MI in the first hours ofevolution, toleration of b-blockers should be established as apriority. Given that the benefit of an ACE inhibitor can beobserved in the first few days of evolution,3 its associationwith b-blockers should not be delayed unnecessarily. Inpatients with large infarctions in whom the instigation oftreatment with both drugs results in hypotension, withdrawalfrom b-blockers must be considered first.

AcknowledgmentsWe thank Mara Teresa SanMiguel and the Pharmacy Service of theHospital Virgen de la Arrixaca for preparing and supplying the studyprotocol medication.

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Prraga-Ramrez, Iluminada Lpez-Martnez, Luis Iigo-Garca and Francisco Pic-AracilMartnez-Caballero, Jos Antonio Valent-Aldeguer, Pedro Jara-Prez, Manuel

Florenciano-Snchez, Jos Gins Snchez-Villanueva, Jos Antonio Nuo de la Rosa, Antonio Jos Galcer-Toms, Francisco Jos Castillo-Soria, Manuel Villegas-Garca, Rafael

Double-Blind Comparison in Patients With Anterior Acute Myocardial InfarctionEffects of Early Use of Atenolol or Captopril on Infarct Size and Ventricular Volume: A

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effects of early use of atenolol and captopril on infarct size and ventricular remodeling

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