Prospective evaluation comparing the effects of enalapril and losartan in left ventricular remodeling after acute myocardial infarction

Article Outline

• Abstract
• Methods
  • Population
  • Objectives
  • Design/Randomization/Follow-up
  • Radionuclide ventriculography
    • LVEF calculations
    • Ventricular volume calculations
  • Statistical analysis
• Results
  • Primary end point
  • Secondary end points
    • Mortality and rehospitalization
    • Adverse events
• Discussion
  • Choice of method and timeframes used in the evaluation of ventricular remodeling
  • Choice of the study drugs, doses, and administration route
  • Primary objective
  • Secondary objectives
    • Mortality and morbidity analysis
    • Safety and tolerability
  • Study limitations
  • Conclusions
• References
• Copyright

Abstract 

Background

Previous studies have compared angiotensin receptor blockers and angiotensin-converting enzyme inhibitors in patients with heart failure, but there are few data about the effect of these drugs regarding left ventricular remodeling after myocardial infarction.

Methods

Fifty-two consecutive patients with first anterior wall myocardial infarction within 24 hours of evolution were randomized to receive enalapril (as much as 20 mg; mean, 14.6 mg), or losartan (as much as 50 mg; mean, 48 mg). Left ventricular ejection fraction and ventricular volumes were analyzed in 2 serial radionuclide ventriculograpies, carried out within 4 days after the infarction (mean, 97.4 ± 114.2 hours) and after 6 months (mean, 177.7 ± 16.7 days). Ventriculographies were analyzed by a single blinded observer. Mainly because of the unexpected large SD values obtained, the power of the study to demonstrate equivalence between the groups was only 15.7%.

Results

The differences obtained between the first and the second ventriculographies, for the enalapril and losartan groups, were: for left ventricular ejection fraction, −0.4% ± 6.6% versus −1.1% ± 5.9% (P = . 67; 95% CI, 2.77-4.23); for final systolic volume, 0.07 ± 7.7 mL/m² versus −0.2 ± 6.1mL/m² (P = . 85; 95% CI, −3.57-4.26); for final diastolic volume −0.7 ± 12.1 mL/m² versus −3.6 - 9.9 mL/m² (P = . 34; 95% CI, −3.22-9.17).

Conclusion

This study, although underpowered, suggests that neither enalapril nor losartan was superior as compared with each other for left ventricular remodeling after myocardial infarction; however, powerful evidence of equivalence was not provided.

Although the benefits of angiotensin-converting enzyme inhibitors (ACEI) after acute myocardial infarction (AMI)1, 2, 3, 4, 5, 6, 7, 8, 9 are well known, it has been shown that these agents do not totally block angiotensin II production.10, 11 Moreover, they can produce unfavorable adverse effects12, 13 that contraindicate their use, such as cough (incidence between 0.5% and 37%), angioedema (rarely), and hypotension (incidence between 20% and 30%), probably caused by the accumulation of bradykinin induced by these drugs.14, 15

Angiotensin receptor blockers (AT1 blockers) induce a more complete blockage of angiotensin II and do not cause bradykinin accumulation.16, 17 This may explain, at least partially, the lower incidence of adverse effects observed with these agents.18, 19, 20, 21

Prior studies comparing ACEI and AT1 blocker in heart failure (HF) did not observe differences between enalapril and losartan for ventricular function, New York Heart Association (NYHA) functional class, tolerance to exercise, neurohormones, and quality of life.22, 23 Moreover, in elderly patients, the Evaluation of Losartan in the Elderly (ELITE) study did not find differences in the medications for renal function, in-hospital length of stay because of HF, or functional class (NYHA).18 THE ELITE II study evaluated elderly patients with heart failure and did not find significant differences between captopril and losartan for all-cause mortality.20 Howewer, ELITE II was a superiority trial and not designed to determine equivalence.

More recently, the combination of ACEI and AT1 blocker has been tested in patients with HF.19, 21

So far, only small experimental studies have evaluated the use of AT1 blockers after AMI,24, 25 and 2 ongoing studies in humans (Optimal Trial in Myocardial Infarction With the Angiotensin II Antagonist Losartan [OPTIMAAL]26 and Valsartan in Acute Myocardial Infarction [VALIANT]27) are comparing ACEI and AT1 blockers in this situation.

Thus, the main objective of this study was to compare, in patients with AMI, an ACEI (enalapril) with a well-proven efficacy in this situation12, 13 with an AT1 blocker (losartan).

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Methods 

Population 

From May 1998 to August 2000, 63 consecutive patients (mean age, 57.3 ± 11.6 years; 63.5% men) with a first anterior wall AMI within 24 hours of evolution were randomized to receive losartan or enalapril.

Inclusion criteria included age ≤75 years and first infarction of the anterior wall occurring within 24 hours of evolution.

Exclusion criteria included being unavailable for follow-up, not agreeing to sign the informed consent form, contraindication for the use of ACEI, AT1 blocker, or both (low blood pressure, creatinine level ≥2.0 mg/dL, pregnancy, hepatic failure, known susceptibility to the study drugs), age >75 years, previous myocardial infarction (MI), chronic atrial fibrillation, previous heart failure, or other causes of heart failure, such as valvular disease, Chagas disease, or congenital heart disease, Forrester class IV according to clinical and radiologic parameters28, 29 and end-stage diseases.

Objectives 

The primary objective of the study was the comparison, in both groups, of the left ventricular remodeling assessed by the global ejection fraction and end-systolic and diastolic volumes, parameters that were obtained with radionuclide ventriculography (RVG).

Pre-specified secondary objectives were the analysis of morbidity and mortality and the evaluation of tolerance and adverse effects of the studied drugs. Adverse effects were defined as the discontinuation of the study drug because of intolerance-, cough-, and hypotension-related symptoms.

Design/Randomization/Follow-up 

This was a prospective, randomized, open study. Analyses of RVGs were done in a blind fashion, by a single observer. Patients were randomized into 2 groups to receive enalapril (at a dose of 2.5 mg twice a day initially, increased to 5 mg twice a day and to 10 mg twice a day) or losartan (at a dose of 6.25 mg twice a day initially, increased to 12.5 mg twice a day and to 25 mg twice a day). The dosage adjustments were made every 24 hours. The target doses were 20 mg/day for enalapril and 50 mg/day for losartan. Patients, including those who discontinued treatment, were observed every 15 days in the first month, then once a month until the sixth month.

The study was approved by the local Research Ethics Committee of the São José do Rio Preto School of Medicine and by the Ethics Committee of Research Projects (CAPPesq) of the University of São Paulo Medical School.

All patients gave informed consent.

Radionuclide ventriculography 

Patients underwent 2 left RVGs to determine left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (ESV), and end-diastolic volume (EDV). The baseline RVG was performed within 4 days after MI (mean, 97.4 ± 114.2 hours), and the follow-up study was performed between 165 and 195 days after MI (mean, 177.7 ± 16.7 days). Autologous red blood cells were labeled with 20 mCi of Technetium 99m-pertechnetate (99mTc), and the in vivo method30 of cell labeling was used.

LVEF calculations 

LVEF was calculated on the basis of the differences in counts between diastole and systole with the following equation:

Ventricular volume calculations 

ESV and EDV were calculated with the method described by Massardo et al.31 This method is based on pixel counts, with the highest activity using the following equation:

in which V is volume, M is pixel area, and R is count rate. Data were processed by the same examiner, who was blinded to patient treatment.

Statistical analysis 

Because ejection fraction is a random variable, the distribution of which may be modeled by the Beta family, the comparison of mean ejection fraction values on the basis of samples from the 2 treatment groups may be carried out by normal approximation (Gaussian). Because this approximation can be assumed as good with sample sizes ≥25, the inclusion of 26 patients in each comparison group was recommended.32 On the basis of this sample size and assuming identical differences in ejection fraction between the first and second ventriculograms in both groups, we obtained a power of 80.3%, for a delta of 5 and alpha of 0.05 to demonstrate equivalence between the groups.33 However, applying the results obtained for ejection fraction, the power was only 7%. For end-systolic volume, with the same assumptions, the expected and obtained powers were 71.1% and 5.4%, respectively. Finally, for end-diastolic volume, the results were 35.4% and 15.7%, respectively.

Variable analysis was conducted on the basis of intention-to-treat, and the t test was used to compare means. Proportions were compared with the normal approximation method for binomial distribution, whenever possible; when this approximation was not valid, the Fisher exact test was used.32

The association of qualitative variables was analyzed with the Pearson χ² test, whenever possible; when it was not possible to use this test because of sample problems, the χ² test was performed according to Cordeiro’s Dependence Analysis.34

A P value ≤.05 (2-tail) was considered to be statistically significant.

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Results 

A total of 63 patients were randomized (32 to the enalapril group and 31 to the losartan group) to replace 8 deaths (5 in the enalapril group and 3 in the losartan group) and 3 cases in which it was not possible to carry out the second RVG (1 in the enalapril group and 2 in the losartan group). One patient withdrew consent to participate in the study, another patient became pregnant, and it was not possible to have ventricular volume analysis for 1 patient, because of technical problems.

At the end of the study, the recommended sample size of 52 patients (26 patients per group) carried out the 2 RVGs, and they comprised the population included in the primary end point analysis.

The mean patient age was 57.3 ± 11.6 years (56.1 ± 11.9 in the enalapril group and 57.3 ± 9.9 in the losartan group; P = not significant [NS]), and 63.5% of patients were men (65.3% in the enalapril group and 69.2% in the losartan group, P = NS). No statistically significant differences were found between the groups in rates of hypertension, diabetes mellitus, smoking habit, or previous angina pectoris; time between AMI beginning and hospitalization or randomization; at hospital arrival, Forrester class I, heart rate, or systolic and diastolic blood pressures; or the use of thrombolytics, aspirin, β-blockers, and nitroglicerin. As shown in Table I, taking into account only the patients submitted to both RVGs (52 patients), the enalapril and losartan groups were also demonstrated to be similar.

Table I. Baseline characteristics*

* Only patients with both ventriculographies-see text.

Primary end point 

As shown in Table II, left ventricular remodeling, taking into account LVEF, ESV, and EDV, was similar in both groups.

Table II. Left ventricular remodeling analysis by radionuclide ventriculography and comparison between the 2 ventriculographies for each group

LVEF, Left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVEDV, left ventricular end-diastolic volume; diff, difference between the values obtained in both ventriculographies.

Analyzing each group separately, no statistically significant differences were found when comparing the baseline and the 6-month after MI RVGs (Table II).

Secondary end points 

Mortality and rehospitalization 

There were 5 deaths (15.6%) in the enalapril group and 3 deaths in the losartan group (9.6%; P = . 47; 95% CI, −0.10-0.22). Excluding the in-hospital deaths, 9 patients in the enalapril group (33.3%) and 6 patients in the losartan group (21.4%) were rehospitalized during the follow-up period (P = . 37; 95% CI, −0.11-0.35). The composite end point of all-cause mortality and all-cause hospitalization was observed in 14 patients in the enalapril group (43.7%) and 9 patients in the losartan group (29%; P = .29; 95% CI, −0.09-0.38).

Adverse events 

The incidence of adverse events in the whole population was significantly higher in the enalapril group (34.6% vs 7.6%, P = .01; 95% CI, 0.05-0.47). Cough leading to the discontinuation of treatment was also significantly higher in the enalapril group (19.2% vs 0%, P = .01; 95% CI, 0.04-0.34). A significantly higher number of patients in the losartan group who completed the 6-month follow-up were taking the target dose than patients in the enalapril group (92.3% vs 65.3%, P = .01; 95% CI 95%, −0.47-0.05).

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Discussion 

It has been shown that long-term therapy with ACEI may prevent or attenuate left ventricular remodeling by blocking angiotensin II, which plays an important role in this process.1, 2

Recent studies suggested that AT1 blockers promote a more complete inhibition of the renin-angiotensin system (RAS) when compared with ACEI.16, 17 So far, only 2 studies carried out in patients with HF have evaluated whether this more effective inhibition, induced by AT1 blockers, results in greater benefits in left ventricular remodeling.

This study is the first to evaluate the role of an AT1 blocker compared with an ACEI in ventricular remodeling after MI.

Choice of method and timeframes used in the evaluation of ventricular remodeling 

RVG was the method chosen to evaluate ventricular remodeling in this study, because it has higher reproducibility and accuracy than the methods commonly used in this kind of evaluation.35 The nuclear method does not depend on geometric changes to calculate volumes.35 In radionuclide methods, volume is calculated on the basis of the amount of radioactive material (counts) present in the ventricular chamber. These counts are linearly related to ventricular volume and indicate the exact volume in the cardiac chamber throughout the cardiac cycle. This characteristic is the major advantage of RVG, especially after MI, when ventricular remodeling changes the geometry of the heart. However, few studies have used serial RVG to evaluate ventricular remodeling after AMI.36

Ventricular remodeling after MI starts right after the occlusion of the coronary artery and, depending on the species, progresses for weeks or months.37 Therefore, this process should be evaluated with serial tests to provide a reliable time analysis. There are no conclusive data to allow an accurate estimate of the period taken for the remodeling process; however, it is known that the most significant changes in ventricular geometry take place within 6 months after AMI, and the impact of the changes after this period is small.38, 39

Therefore, time points established to perform baseline and follow-up RVGs were 4 days and 6 months, respectively.

Choice of the study drugs, doses, and administration route 

In this study, an active control was used to make sure that none of the patients would be restricted to the clinical benefits of RAS inhibition. Enalapril was chosen because its efficacy, dosage, and safety are well documented in several well-conducted studies.12, 13

Enalapril was tested against an AT1 blocker (losartan), a drug with a proven safety and efficacy profile.16, 18, 20, 22, 23

Losartan and enalapril were given twice a day to try to reach the maximum inhibition of the RAS system, and the target dose for both drugs was tested in previous studies.12, 13, 20

Primary objective 

Losartan was similar to enalapril for LV ventricular remodeling after a first left ventricular anterior wall infarction, as demonstrated in Table II.

As shown inTable II, the non-significant differences that occurred in the ventriculograms, for both groups, were very mild. These data suggest that there was attenuation in the process of ventricular remodeling and that this effect was similar for both losartan and enalapril. We cannot exclude the possibility that concomitant medication, such as aspirin, β-blockers, and fibrinolytics, may have some role in this attenuation.

So far, only the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study21 and the ELITE substudy40 evaluated the effects of AT1 blockers on LV ventricular remodeling. In the RESOLVD pilot study,21 768 patients with NYHA functional class II to IV received candesartan, enalapril, or a combination of both for 43 weeks. There were no significant differences in LVEF and ventricular volumes when candesartan and enalapril were compared, but when the drugs were combined, a significant decrease was observed in systolic and diastolic ventricular volumes. The ELITE substudy40 included 29 elderly patients with HF and compared losartan and captopril in LV ventricular remodeling after 48 weeks of therapy and 5 days after therapy discontinuation. A significant decrease in systolic ventricular volumes was observed in both groups. Diastolic ventricular volume decreased in both groups, but this reduction was only significant in the captopril group. After treatment discontinuation, the EDV remained significantly lower than baseline only in the captopril group.

However, these studies were carried out in patients with HF, and the authors emphasize that the results obtained may not be extrapolated for other populations, such as patients who have had an AMI. To the best of our knowledge, there are no published data for patients after MI.

Secondary objectives 

Mortality and morbidity analysis 

The mortality rates found in the losartan group (3 deaths, 4.76%) was lower than in the enalapril group (5 deaths, 7.93%). However, the small sample size does not allow any conclusion on this issue.

There were no significant differences when the end points mortality due to any cause and rehospitalizations due to any cause were combined. The same was observed in the ELITE I18 and II20 and the RESOLVD21 studies, which evaluated patients with HF. However, it is important that none of these studies were designed or had adequate power to show a true equivalence.

The Valsartan Heart Failure Trial (Val-HeFT) study,41 in which patients with HF who had been using ACEI were randomized to receive valsartan or placebo, failed to demonstrate a decrease in mortality rate, despite the significant benefit obtained when the variables all-cause mortality and morbidity were combined. This difference was mostly a result of the difference in the hospitalization rate between the 2 groups and the improvement in ejection fraction and quality-of-life scores. Subgroup analysis showed interesting data; the main benefit was obtained in the small percentage of patients who did not receive ACEI (7% of the total), and the subgroup receiving ACEI, a AT1 blocker, and a β-blocker did not had any benefit.

Safety and tolerability 

Similar to other studies comparing AT1 blocker and ACEI, in this study tolerability to losartan was higher than tolerability to enalapril.18, 19, 20, 21 None of the patients assigned to received losartan had a cough, and treatment discontinuation because of cough was significantly higher in patients assigned to receive enalapril. Moreover, a significantly higher number of patients in the losartan group completed the study taking the target dose than patients in the enalapril group.

However, there were no significant differences between the 2 groups for hypotension, as opposed to other studies.18, 20 This was probably related to the low incidence of hypotension in our patients and also to the small sample size.

Study limitations 

The first limitation of this study is related to its open design. However, the primary objective of the study was to evaluate ventricular remodeling established with serial ventriculographies, analyzed by a single blinded investigator, which certainly attenuates any eventual biases.

Second, because the obtained results were different from the expected, mainly because of the large SD values (different from literature2), the power of the study to demonstrate equivalence between the groups was only 15.7%. So, our results should not be regarded as evidence one way or another, but a piece of additive information for more definitive results.

Conclusions 

This study, although underpowered, suggests that neither enalapril nor losartan was superior for left ventricular remodeling after MI. However, powerful evidence of equivalence was not provided.

We thank Maria Angélica Lemos, MD, Mauricio de Nassau Machado, MD, and Eleuses V de Paiva, MD, for their cooperation in the study; Christopher Granger, MD, for his suggestions on the manuscript; and Biossintética and Biolab Pharmaceuticals for providing the study drugs.

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