American Heart Journal
Volume 150, Issue 4 , Pages 689.e11-689.e16, October 2005

Enalapril suppresses ventricular remodeling more effectively than losartan in patients with acute myocardial infarction

Second Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan

Received 10 July 2004; accepted 26 March 2005.

Article Outline

Background

Ventricular remodeling after acute myocardial infarction (AMI) is associated with increased morbidity and mortality. ELITE II study showed that losartan, an angiotensin receptor blocker, shows a survival benefit to the same degree as captopril, an angiotensin-converting enzyme inhibitor, does in patients with heart failure. However, recent OPTIMAAL study showed that clinical outcomes after losartan are not superior to those after captopril in patients with AMI. We examined the effect of losartan on ventricular remodeling after AMI comparatively with that of enalapril.

Methods

We enrolled 203 consecutive patients with AMI (mean age 62 ± 11 years). All patients underwent primary percutaneous coronary intervention and were randomly assigned to losartan (25-50 mg, n = 101) or enalapril (2.5-10 mg, n = 102) treatment. Biplane left ventriculography was performed just after primary percutaneous transluminal coronary angioplasty (acute phase) and 6 months after the onset of AMI.

Results

Any of the maximal creatine kinase level, left ventricular end-diastolic volume index, end-systolic volume index, and ejection fraction measured at acute phase was not different between losartan and enalapril groups. However, changes in left ventricular end-diastolic index (18 ± 25 vs 8 ± 24 mL/m2) and left ventricular end-systolic volume index (10 ± 20 vs 2 ± 18 mL/m2) from acute phase to 6 months were significantly greater in losartan than in enalapril group. Change in left ventricular ejection fraction (0.2% ± 10.3% vs 3.4% ± 11.6%) from acute phase to 6 months was significantly smaller in losartan than in enalapril group. The plasma level of brain natriuretic peptide at 6 months was significantly higher in losartan than in enalapril group (all P < .05).

Conclusion

These indicate that enalapril suppresses ventricular remodeling after AMI more effectively than losartan.

 

The progressive left ventricular enlargement after acute myocardial infarction (AMI), that is, ventricular remodeling, causes pump dysfunction and increases incidences of mortality and morbidity.1, 2, 3 It has been reported that cardiac renin-angiotensin system is activated after AMI and is involved in the pathophysiology of ventricular remodeling.4, 5 Many clinical studies demonstrated that angiotensin-converting enzyme (ACE) inhibitors (ACEIs) attenuate ventricular remodeling and decrease the mortality and morbidity of patients with AMI.1, 2, 3 Angiotensin type 1 receptor blockers (ARBs), another type of inhibitor of renin-angiotensin system, induce a more complete blockage of angiotensin II produced by ACE and chymase.6, 7 The validity of ARB in patients with heart failure was shown in the Val-HeFT and the CHARM studies.8, 9 However, these studies were designed to compare between ARB and placebo treatments, or between ARB plus ACEI treatment and ACEI treatment. The ELITE II study, which compared ACEI and ARB in heart failure, did not reveal significant difference in all-cause mortality between captopril and losartan.10 More recently, the OPTIMAAL showed that the incidence of cardiovascular death was greater in losartan group than in captopril group.11 Consequently, it is not concluded which drug, ARB or ACEI, is beneficial for the treatment in patients with AMI. We hypothesized that there is a difference in the effect on the development of ventricular remodeling after AMI between ARB and ACEI treatments. To test this, we examined comparatively the effects of losartan and enalapril on left ventricular remodeling and plasma BNP level after AMI.

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Methods 

Study patients 

All patients gave their written informed consent. The study was approved by the ethical committee on human research at our institution.

Consecutive 257 patients with AMI transferred to our institution between April 1999 and December 2002 who underwent primary percutaneous coronary intervention (PCI) and agreed to be involved to the study were initially enrolled. There were 206 men and 51 women, and their mean age was 63 ± 11 years. The diagnosis of AMI was made by the presence of typical prolonged chest pain accompanied by ST elevation on the 12-lead electrocardiogram and significant increase in MB fraction of creatine kinase (CK). After the coronary intervention, the patients were randomly divided into 2 groups by an envelope method; 137 patients were treated with enalapril (2.5 mg/d in 19 patients, 5 mg/d in 114, and 10 mg/d in the other 4), and the other 120 were treated with losartan (25 mg/d in 22, 50 mg/d in 96, and 100 mg/d in 2). All patients also were administered aspirin (200 mg) and ticlopidin (200 mg) just after admission. Aspirin (200 mg) was continued, whereas ticlopidin was withdrawn at 2 weeks after the onset of AMI.

Among 257 patients, 54 patients (35 in enalapril and 19 in losartan group) were subsequently excluded from the analysis because they did not agree to undergo cardiac catheterization at 6 months after the onset of AMI or could not continue enalapril or losartan mainly as a result of side effects. Therefore, this study included 102 patients in enalapril group and 101 patients in losartan group.

Measurements of left ventricular volume and function 

All patients underwent cardiac catheterization including coronary angiography and biplane left ventriculography (LVG) at acute phase and 6 months after the onset of AMI. Two cardiologists who were unaware of the treatment assignment (enalapril or losartan) analyzed the LVG. Ventricular silhouettes in the 30° right anterior oblique and 60° left anterior oblique projections were digitized with an LVG analysis system (Cardio 500, Kontron Instruments, Eching, Germany), and left ventricular end-diastolic volume index (LVEDVI), end-systolic volume index (LVESVI), and left ventricular ejection fraction (LVEF) were determined. Changes in LVEDVI, LVESVI, and LVEF were calculated by subtracting the respective value measured at acute stage from the corresponding value at 6 months.

Measurement of BNP 

BNP is an objective biochemical marker for the severity of cardiac function in patients with heart failure.12 Therefore, we also analyzed the plasma level of BNP at 6 months after the onset of AMI with the commercially available EIA kits (Shionogi, Japan).

Statistical analysis 

All results are expressed as mean ± SD. Comparisons between losartan and enalapril groups were performed using unpaired Student t test and χ2 test. A P value <.05 was regarded as significant.

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Results 

Profiles of the study patients 

Table I shows patient profiles for 2 groups. None of age, sex, culprit lesion for AMI, maximum CK level, cardiac index (CI), and pulmonary capillary wedge pressure (PCWP) at admission (acute phase) was different between losartan and enalapril groups. None of total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and blood sugar was also different between the 2 groups.

Table I. Patients profiles in each treatment group
Losartan (n = 101)Enalapril (n = 102)
Age62 ± 1162 ± 11
Sex (female/male)18/8319/83
Culprit (LAD/LCX/RCA)59/13/2943/18/41
CK max, U/mL3933 ± 28323662 ± 2373
At admission (acute phase)
mBP, mm Hg96 ± 1493 ± 13
HR, beat/min84 ± 1482 ± 16
CI, L/m2 per min2.6 ± 0.62.6 ± 0.7
PCWP, mm Hg13 ± 612 ± 5
Blood chemistry
Total cholesterol, mg/dL178 ± 33179 ± 44
Triglyceride, mg/dL82 ± 4375 ± 42
HDL cholesterol, mg/dL48 ± 1145 ± 12
Blood sugar, mg/dL142 ± 43144 ± 67
At 6 m (chronic phase)
mBP, mm Hg99 ± 1497 ± 15
HR, beat/min68 ± 1266 ± 11
CI, L/m2 per min2.5 ± 0.52.6 ± 0.6
PCWP, mm Hg9 ± 49 ± 4
Blood chemistry
Total cholesterol, mg/dL183 ± 34188 ± 46
Triglyceride, mg/dL136 ± 72131 ± 73
HDL cholesterol, mg/dL49 ± 1549 ± 14
Blood sugar, mg/dL115 ± 39116 ± 54
Drugs during f/u period
β-Blocker (+/−)62/3970/32
Calcium-channel antagonist (+/−)9/9211/91
Statin (+/−)30/7142/60
Diuretics (+/−)14/8710/92

Values are presented as means ± SD. mBP, Mean blood pressure; HR, heart rate; f/u, follow-up; LCX, left circumflex artery.

Changes in LV volume and function after AMI 

Figure 1 shows LVEDVI, LVESVI, and LVEF at acute phase and 6 months after the onset of AMI for all patients. None of LVEDVI, LVESVI, and LVEF was different between losartan and enalapril groups at acute phase. However, at 6 months, LVESVI (55 ± 24 vs 48 ± 21 mL/m2) was significantly greater, and LVEF (48% ± 12% vs 52% ± 10%) was significantly smaller in losartan than in enalapril group (Figure 1, A and B). The changes in LVEDVI and LVESVI from acute phase to 6 months were also significantly greater, and the change in LVEF was significantly smaller in losartan group than in enalapril group (all P < .05) (Figure 1, C).

  • View full-size image.
  • Figure 1. 

    LV volume and function after AMI in all patients. A, LVEDVI, LVESVI, and LVEF at admission (acute phase) in losartan (open bar) and enalapril groups (closed bar). B, LVEDVI, LVESVI, and LVEF at 6 months after the onset of AMI in losartan (open bar) and enalapril groups (closed bar). C, Changes in LVEDVI, LVESVI, and LVEF from acute phase to 6 months after the onset of AMI in losartan (open bar) and enalapril groups (closed bar). *P < .05 versus losartan group.

Changes in LV volume and function in patients with culprit lesion in left anterior descending coronary artery 

There were a larger number of patients with culprit lesion in the right coronary artery (RCA) in enalapril group. In addition, the maximal CK level was smaller in losartan group compared with that in enalapril group, although not significantly different. The patients with culprit lesion in the left anterior descending (LAD) coronary artery and anterior myocardial infarction seem to have a larger infarction area than those with culprit in RCA and inferior infarction. Therefore, we analyzed the data in patients with anterior myocardial infarction to exclude the bias with the infarction area. In patients with anterior myocardial infarction, the maximal CK level was 3957 ± 3049 U/mL in losartan group and 4289 ± 2921 U/mL in enalapril group (P = .559). None of LVEDVI, LVESVI, and LVEF was statistically different between losartan and enalapril groups at acute phase and 6 months after the onset of AMI (Figure 2, A and B). However, the changes in LVEDVI and LVESVI from acute phase to 6 months were significantly greater, and the change in LVEF was significantly smaller in losartan group than in enalapril group (Figure 2, C).

  • View full-size image.
  • Figure 2. 

    LV volume and function after AMI in the patients with anterior myocardial infarction and culprit lesion in LAD. A, LVEDVI, LVESVI, and LVEF at admission in losartan (open bar) and enalapril groups (closed bar). B, LVEDVI, LVESVI, and LVEF at 6 months after the onset of AMI in losartan (open bar) and enalapril groups (closed bar). C, Changes in LVEDVI, LVESVI, and LVEF from acute phase to 6 months after the onset of AMI in losartan (open bar) and enalapril groups (closed bar). *P < .05 versus losartan group.

Comparison of plasma level of BNP 

The plasma level of BNP at 6 months after the onset of AMI was higher in losartan group than in enalapril group (P < .05, Figure 3, A). In patients with anterior myocardial infarction, the plasma level of BNP was also higher in losartan group than in enalapril group (P < .05, Figure 3, B).

  • View full-size image.
  • Figure 3. 

    Plasma level of BNP at 6 months after the onset of AMI in losartan (open bar) and enalapril groups (closed bar) in all patients (A) and patients with anterior myocardial infarction (MI) and culprit lesion in LAD (B). *P < .05 versus control group.

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Discussion 

Role of renin-angiotensin system in ventricular remodeling 

The progression of ventricular remodeling after AMI deteriorates cardiac function and increases the incidence in mortality and morbidity. It is known that cardiac renin-angiotensin system is activated after AMI and is involved in the development of ventricular remodeling.4, 5 Many clinical studies demonstrated that ACEIs attenuate ventricular remodeling and decrease the mortality and morbidity of patients with AMI.1, 2, 3 The mechanisms for the prevention of ventricular remodeling with ACEI are explained by the inhibition of interstitial fibrosis and hypertrophy.13

On the other hand, experimental and clinical studies indicate that matrix metalloproteinases (MMPs) contribute to ventricular remodeling after AMI.14, 15 We recently reported that the pericardial level of MMP activity, especially MMP-2 activity, is well correlated with LVEDVI in patients with coronary artery disease.16 It is known that angiotensin II is involved in MMP-2 activation.17, 18 Furthermore, Wang et al19 reported that MMP-2 is colocalized with angiotensin II and ACE in age-associated, remodeled, large artery of nonhuman primates. These studies suggest that ACEI inhibits MMP-2 activity by diminishing the generation of angiotensin II and prevents ventricular remodeling in patients with AMI. Recently, Lods et al17 reported that ACEI reduced the serum levels of MMP-2 and MMP-9, but ARB did not show any effect in patients with glomerulonephritis. Their report implicates that the effects of ARB on cardiovascular system are not always equivalent to those of ACEI.

Effects of ACEI and ARB on ventricular remodeling 

ARB theoretically causes a more complete blockade of angiotensin II because angiotensin II is also produced via chymase pathway, which is especially important in human heart and is not inhibited by ACEI.6, 7 On the other hand, it is reported that at least or part of the effect of ACEI is dependent on bradykinin–nitric oxide pathway, which is not involved in the effect of ARB, and ACEI improves endothelium-dependent vasodilation in patients with heart failure.20, 21, 22 Therefore, it is controversial which drug, ACEI or ARB, is beneficial for the treatment of heart failure and AMI. Some clinical trials of the comparison between ACEI and ARB were reported. ELITE II study did not show any difference between captopril and losartan for all-cause mortality in patients with heart failure.10 More recently, OPTIMAAL study showed that cardiovascular death was higher in losartan group than captopril group in patients with AMI, although all-cause mortality was not different between captopril and losartan groups.11 Considering the results from OPTIMAAL study, it seems that captopril is superior to losartan in patients with AMI.

In the present study, we administered losartan or enalapril just after the onset of AMI, and enalapril was found to suppress more effectively ventricular enlargement after AMI compared with losartan. Moreover, plasma BNP level, which was an objective marker for the severity of heart failure,12 was lower in enalapril group compared with that in losartan group. Maia et al23 reported that enalapril was not superior to losartan in the suppression of ventricular remodeling after AMI, being inconsistent with our present results. However, the number of the patients in this previous study was small, and more importantly, reperfusion therapy was not done at an acute phase of AMI. Recently, direct PCI and stenting became a standard therapy for AMI, and it is unquestionable that early reperfusion therapy is the most important strategy for the reduction of infarct size and inhibition of the development of ventricular remodeling at chronic phase.24, 25 In the present study, all patients underwent PCI and stenting at an acute phase. Thus, our results are suitable for understanding the effect of each drug on ventricular remodeling after reperfusion therapy against AMI at acute phase.

Study limitation 

We evaluated LV volume and function just after primary PCI and 6 months after the onset of AMI. It is well known that the ischemic and noninfarcted myocardium within the risk area is still under residual stunning during acute phase of AMI, which may have affected the measurements of LV volume and function at acute phase and therefore the results of the study. However, this study clearly demonstrated that the plasma level of BNP at 6 months was significantly higher in losartan group than in enalapril group, being consistent with the results of the changes in LV volume and function from acute stage to 6 months.

It may be pointed out that the doses of the drugs used in this study were small compared with those used in the previous multicenter clinical studies such as OPTIMAAL and ELITE II. In Japan, 50 mg is widely accepted as a common dose for losartan and 5 mg for enalapril. A low dose (8 mg) of candesartan, another angiotensin receptor blocker, was found to be effective in the treatment of congestive heart failure in Japan,26 whereas a higher dose (32 mg) was used in CHARM study.9 We believe that lower dosages were effective also against ventricular remodeling after AMI in Japanese population.

Angiotensin II combines with several types of receptor. Particularly, angiotensin type I (AT1) and type II (AT2) are important in the cardiovascular system.27 It is shown that angiotensin II–AT1 promotes the atherosclerosis and remodeling, but angiotensin II–AT2 protects against atherosclerosis and remodeling in experimental studies. Each ARB has a different affinity and strength against AT1 and AT2. Furthermore, each ARB is different in antagonistic profiles.28 Losartan dissociates quickly from the receptor, valsartan and irbesartan bind for a longer period, and candesartan exhibits a noncompetitive binding profile. Because it is reported that tissue and plasma levels of renin concentration is increased after ARB treatment,28, 29 it is thought that a noncompetitive binding ARB is suitable for the suppression of angiotensin II–AT1 at tissue level against the increase in tissue levels of angiotensin. In the present study, enalapril was superior to losartan about ventricular remodeling after AMI. However, it is unknown whether the result is applied to another ARB such as valsartan or candesartan. Further studies are recommended.

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References 

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PII: S0002-8703(05)00337-6

doi:10.1016/j.ahj.2005.03.038

American Heart Journal
Volume 150, Issue 4 , Pages 689.e11-689.e16, October 2005

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