Long-term effects of bisoprolol compared with imidapril on left ventricular remodeling after reperfusion in acute myocardial infarction: An angiographic study in patients with maintained vessel patency☆

Article Outline

• Abstract
• Methods
  • Patient selection
  • Cardiac catheterization and reperfusion therapy
  • Dosing and concomitant therapy
  • Statistical analysis
• Results
  • Patients
  • Baseline characteristics
  • Hemodynamic parameters
  • Ventriculographic data
• Discussion
  • β-Blockade and left ventricular remodeling
  • Previous studies
  • Effects of ACE inhibitors on left ventricular remodeling
  • Study limitations
  • Conclusions
• Acknowledgements
• References
• Copyright

Abstract 

Background Although angiotensin-converting enzyme inhibitor attenuates ventricular enlargement, whether β-blocker therapy induces regression of left ventricular remodeling is not known. The purpose of this study was to compare the effects of bisoprolol therapy with those of imidapril therapy on left ventricular remodeling after acute myocardial infarction (AMI). Methods Sixty patients with AMI who underwent reperfusion therapy were randomly assigned to an imidapril group (20 patients), a bisoprolol group (20 patients), or a control group (20 patients). Administration was started within 24 hours. Left ventricular function on admission and 3 months and 1 year after AMI was investigated. Results Baseline characteristics on admission were similar in the 3 groups except for sex distribution. Mean pulmonary capillary wedge pressure and left ventricular end-diastolic pressure in the bisoprolol group were higher than those in the imidapril group 1 year after admission (pulmonary capillary wedge pressure: 12 ± 7 vs 8 ± 2 mm Hg, left ventricular end-diastolic pressure: 17 ± 8 vs 11 ± 4 mm Hg, P < .01). Left ventricular end-diastolic volume index (EDVI) increased in the bisoprolol group throughout the 1-year period (P < .01), whereas EDVI in the imidapril group decreased (P < .01). The increases in EDVI during 1 year in the bisoprolol group were greater than those of the other 2 groups (bisoprolol: 12 ± 10, imidapril: –9 ± 7, control: 4 ± 11 mL/m², P < .01). Conclusions Early treatment with bisoprolol in AMI cannot prevent left ventricular remodeling, whereas imidapril attenuates left ventricular dilation by decreasing preload. (Am Heart J 2000;140:e27.)

Acute myocardial infarction (AMI) can initiate complex changes in the structural and functional architecture of the left ventricular myocardium, known as left ventricular remodeling; these changes can profoundly affect left ventricular function.¹ It has been reported that early treatment with angiotensin-converting enzyme (ACE) inhibitors improves both the short-term and long-term outcomes in patients with AMI.² Furthermore, an echocardiographic substudy of SAVE confirmed that an ACE inhibitor attenuated time-dependent left ventricular enlargement.³ On the other hand, the effect of early treatment with β-blockers in reducing mortality rates and ischemic events after AMI is well known. Pooled data from trials indicate that mortality rates can be reduced by an average of 21% and reinfarction by 24%.⁴ However, all these trials were conducted several years ago, before the thrombolytic era. It remains unclear whether β-blocker therapy induces regression of left ventricular remodeling.

The major factors involved in left ventricular remodeling are infarct size, patency of the infarct-related artery, and the magnitude of mechanical deformation forces.⁵ Jeremy et al⁶ reported that left ventricular enlargement was more likely to occur in patients with a persistently occluded infarct-related artery than in patients with recanalized arteries. Patent infarct-related arteries appear to attenuate left ventricular enlargement. However, there are few studies that evaluated left ventricular remodeling after AMI in patients with confirmed patency of the infarct-related artery. Therefore, we selected study patients in whom the patency of the infarct-related artery was ascertained during the 1-year period.

The aim of this study was to compare the relative effects of β-blocker therapy with those of ACE inhibitor therapy on left ventricular remodeling after AMI, randomly administered in an early phase.

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Methods 

Patient selection 

The study group comprised 67 consecutive patients who were admitted to our coronary care unit between January 1995 and November 1997 within 4 hours of the onset of chest pain and who met the following criteria: (1) typical ischemic chest pain lasting >30 minutes; (2) electrocardiographic ST-segment elevation of 0.1 mV in 2 contiguous leads; and (3) elevation of serum total creatine kinase (CK) and its MB isoenzyme to at least twice the upper limit of normal. Informed consent was obtained from each patient and/or the patient’s family in the early phase of AMI and was confirmed later by written consent. This study protocol was approved by the hospital ethics committee. Patients with 1 or more of the following conditions were excluded: (1) cardiogenic shock, (2) failed reperfusion therapy, (3) reocclusion of the infarct-related artery during the 1-year follow-up period, and (4) significant valvular heart disease or cardiomyopathy.

Cardiac catheterization and reperfusion therapy 

Right-sided cardiac catheterization, coronary arteriography, and left ventriculography were performed in all patients immediately after they were diagnosed as having AMI. Before coronary arteriography, a Swan-Ganz catheter was inserted into the femoral vein to measure hemodynamic parameters. All patients underwent direct percutaneous transluminal coronary angioplasty, primary stent implantation, or percutaneous transluminal coronary recanalization by means of intracoronary infusion of prourokinase. Patency of the infarct-related artery was graded according to the Thrombolysis in Myocardial Infarction (TIMI) flow criteria.⁷ Successful reperfusion was defined as coronary blood flow improved to TIMI flow grade 3.

Second and third cardiac catheterizations, including a hemodynamic study, coronary arteriography, and left ventriculography, were performed in all patients 3 months and 1 year after admission. Left ventricular end-diastolic volume index (EDVI), end-systolic volume index (ESVI), and ejection fraction (LVEF) were calculated by means of a formula modified by Kennedy et al.⁸ Changes in EDVI and ESVI and hemodynamic parameters were obtained by subtracting respective values on admission from corresponding values at 3 months and at 1 year after myocardial infarction. Two observers unaware of each other’s interpretation and without knowledge of the patients’ clinical data and treatment performed quantitative analysis of recorded images. Intraobserver and interobserver variability of left ventricular volume has been reported previously.⁹

Dosing and concomitant therapy 

Random assignment was performed by means of sealed envelopes. The ACE-inhibiting action of imidapril is 6 to 18 times (inhibition constant of swine kidney and human serum ACE) more potent than either enalapril or captopril.¹⁰, ¹¹ On the other hand, among β₁-selective blockers, bisoprolol not only has the highest β₁ selectivity but is the most potent.¹² In regard to antihypertensive effects, 5 mg/d bisoprolol may be more potent than 5 mg/d imidapril.¹³, ¹⁴ Within 24 hours of chest pain, patients were administered 2.5 mg of bisoprolol or 2.5 mg imidapril. Dose titration was performed on day 3 if blood pressure was >110/80 mm Hg and heart rate >55 beats/min. The target maintenance dosage of the randomized study medication was 5 mg once daily of bisoprolol or imidapril and was continued until 1 year after AMI. All patients were given aspirin and long-acting nitrates. Diuretics were used in 8 patients with congestive heart failure. No patients were treated by intra-aortic balloon pumping after admission.

Statistical analysis 

Results are expressed as mean ± SD. The time course of hemodynamic findings and left ventriculographic data were compared by means of analysis of variance for repeated measures. If changes were significant, a paired or unpaired t test was performed. To test for differences in discrete variables, a χ² test was applied. Correlation coefficients between hemodynamic parameters and ventriculographic parameters were calculated by linear regression analysis. To determine the independent predictive factors for changes in EDVI, ESVI, and LVEF, multivariate linear regression models were used. Covariates examined included clinical characteristics (age, sex, risk factors, site of myocardial infarction, Forrester’s subset, treatment during acute phase, time to recanalization, and maximal level of CK-MB), treatment modality, and changes in hemodynamic parameters during 1 year. A level of P < .05 was regarded as significant.

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Results 

Patients 

Seven patients were excluded from the study for the following reasons: 2 patients had cardiogenic shock, 4 patients had reocclusion of the infarct-related artery during the study period, and 1 patient had cardiomyopathy. Among 4 patients excluded for reocclusion of the infarct-related artery, 1 patient was in the bisoprolol group, 1 patient was in the imidapril group, and 2 patients were in the control group. Therefore the study patients consisted of 60 patients (48 men and 12 women), ranging in age from 30 to 81 years, with a mean age of 61 ± 11 years. The patients were randomly assigned to an imidapril treatment group (20 patients), a bisoprolol treatment group (20 patients), or a control group (20 patients). All patients had successful reperfusion. In the bisoprolol and imidapril groups, no patients had hypotension, bradycardia, or cough. All patients received target doses of 5 mg imidapril or 5 mg bisoprolol. No major adverse cardiac events (AMI, coronary artery bypass surgery, or death) were observed during the follow-up period. The planned 1-year follow-up cardiac catheterization could not be performed because of patient refusal in 1 patient in the bisoprolol group.

Baseline characteristics 

Baseline clinical characteristics were similar in the 3 groups except for sex distribution (Table I).

Table I. Comparison of clinical characteristics in 3 groups

PTCR indicates percutaneous transluminal coronary recanalization; PTCA, percutaneous transluminal coronary angioplasty.

Values are expressed as mean (SD) or number (%) of patients.

*P < .01 vs imidapril and control.

There were no significant differences in the sites of myocardial infarction, median time to recanalization, and maximal level of CK-MB among the 3 groups.

Hemodynamic parameters 

Baseline hemodynamic data on admission were similar in the 3 groups (Table II).

Table II. Hemodynamic characteristics

Values are expressed as mean ± SD.

*P < .01 vs imidapril, ^†P < .05 vs control, ^‡P < .01 vs acute.

Heart rate after 3 months decreased in the bisoprolol group (P < .01). Mean arterial pressure on admission tended to be higher in the bisoprolol group than in the imidapril and control groups, although this difference did not reach statistical significance. Mean arterial pressure was decreased during the follow-up period in the bisoprolol and imidapril groups. However, mean pulmonary capillary wedge pressure (PCWP) and left ventricular end-diastolic pressure (LVEDP) after 1 year were higher in the bisoprolol group than in the imidapril group (P < .01).

Ventriculographic data 

There were significant differences in EDVI (P < .0001) and ESVI (P < .05) during the 1-year period among the 3 groups, but there were no significant differences in LVEF (Figure 1).

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• Fig. 1. 

  Time course of EDVI, ESVI, and LVEF in bisoprolol group (open circles), imidapril group (solid circles), and control group (solid triangle). *P < .01 vs imidapril group, ^†P < .05 vs imidapril group; ^‡P < .01 vs on admission. Values are mean ± SEM.

In the bisoprolol group, EDVI increased and ESVI slightly increased throughout the study. EDVI and ESVI in the imidapril group decreased during the 1-year period. The increase in EDVI during the 1 year in the bisoprolol group was greater than that of the imidapril group (P < .01) (Table III). In addition, the decrease in ESVI during the 1 year in the bisoprolol group was smaller than that of the imidapril group (P < .01) (Table III). The changes in EDVI and ESVI during the 1 year differed between the imidapril group and the control group. In the bisoprolol group, there was no significant difference in EDVI throughout the study between men and women (men vs women: on admission, 73 ± 13 vs 71 ± 8; 3 months, 78 ± 15 vs 79 ± 13; 1 year, 84 ± 17 vs 84 ± 17 mL/m²; not significant). There were significant correlations between mean PCWP or LVEDP after 3 months and the changes in EDVI during the 3-month period (PCWP: r = 0.35, P = .005; LVEDP: r = 0.36, P = .004). In addition, mean PCWP and LVEDP after 1 year showed significant correlations with the changes in ESVI during the 1-year period (PCWP: r = 0.38, P = .006; LVEDP: r = 0.45, P = .0009).

Table III. Left ventriculographic data

Values are expressed as mean (SD).

*P < .01 vs imidapril, ^†P < .01 vs control, ^‡P < .05 vs control, ^§P = .001 vs 3 months.

The changes in LVEF during 1 year were more closely correlated with the changes in ESVI during 1 year than the changes in EDVI during 1 year (ESVI: P = –.74, P < .0001; EDVI: P = –.26, P = .07). Treatment modality and the changes in mean PCWP and LVEDP were independent predictors of the changes in EDVI during 1 year, whereas the changes in heart rate during 1 year was not (Table IV).

Table IV. Univariate and multivariate predictors of changes in EDVI during 1 year

Treatment modality was the best predictor of the changes in EDVI during 1 year (P = .001). On the other hand, there were no predictors of changes in ESVI and LVEF during 1 year.

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Discussion 

The findings in the current study indicate that progressive left ventricular dilation occurs as a result of β-blocker therapy after AMI in patients with successful reperfusion. To the best of our knowledge, this is the first report to demonstrate effect of β-blocker therapy for left ventricular remodeling after AMI in comparison with ACE inhibitor therapy in human beings.

β-Blockade and left ventricular remodeling 

Because β-blockers increase EDVI through heart rate effects alone, a careful analysis of the results is needed. This negative chronotropic effect may account for the increase in left ventricular volume indexes. However, EDVI continued to increase without heart rate changes between 3 months and 1 year in the bisoprolol group. The changes in heart rate were not related to the changes in EDVI during 1 year by multivariate linear regression models. Early bisoprolol therapy in rats after myocardial infarction showed additional increase in left ventricular volume in comparison with sham-operated rats treated with bisoprolol.¹⁵ The increase in EDVI in the bisoprolol group is not solely an effect of heart rate slowing.

Clinical epidemiologic studies have demonstrated a favorable effect of β-blockers on the morbidity and mortality rates of patients with AMI.⁴ On the other hand, experimental studies showed that β-blocker therapy could have a damaging effect on the left ventricular remodeling process in rats subjected to permanent coronary occlusion or reperfusion.¹⁶, ¹⁷ However, the effects of β-blockers on left ventricular remodeling have not been estimated in human beings. In this study, imidapril reduced LVEDP, whereas bisoprolol did not reduce this pressure. Modulation of afterload as well as preload affects left ventricular dilation after AMI.¹⁸ β-Blockers increased the preload, such as LVEDP, by its negative inotropic and chronotropic effects in rats.¹⁹ An increase in preload leads to an increase in wall stress.²⁰ Therefore, preload reduction or the combination of preload and afterload reduction is necessary to reduce left ventricular remodeling after AMI. The patency of the infarct-related artery attenuates left ventricular remodeling.⁶ Although the patency was confirmed during the study period, left ventricular remodeling occurred in the bisoprolol group. In this group, the increased preload appears to override the effects of the patency of the infarct-related artery.

Ejection fraction, an indicator of global left ventricular function, increased during 1 year in the imidapril and bisoprolol groups. The mechanism of such improvement remains unclear. Our data in the imidapril group are in agreement with those reported by Sharpe et al.²¹ The CIBIS trial,²² with bisoprolol, showed that heart rate reduction is related to improvement of left ventricular function. However, we did not observe such a relation. Heart rate reduction will lead to an increase in end-diastolic volume through longer diastolic filling. The increase in left ventricular end-diastolic volume causes improvement of ejection fraction according to the Frank-Starling law. On the other hand, left ventricular contraction will be suppressed by the negative inotropic effect of β-blockers. Under the circumstances of β-blocker therapy, ejection fraction appears to be determined by the balance of the preload-increasing and negative inotropic effects. Which of these two effects is more predominant may depend on the condition of the patients. The severity of myocardial infarction, patency of infarct-related arteries, and background of patients may differ between our study and the CIBIS trial. The negative inotropic effect appears to have predominated in our study.

Previous studies 

Experimental studies suggested that β-blockers had no influence on volume or shape of the left ventricle in myocardial dysfunction with microembolization or DC shock in dogs.²³, ²⁴ However, in these studies, treatment with β-blockers was begun 3 to 11 weeks after acute myocardial damage. It is now clear that remodeling begins early during infarction, with infarct expansion or stretching over a period of 6 weeks.²⁵, ²⁶ A recent study suggested that early bisoprolol treatment increases diastolic wall stress and left ventricular volume in rats after myocardial infarction.¹⁵ It is probable that early remodeling is promoted by early treatment with β-blockers. A large part of the benefit from β-blocker therapy appears to have stemmed from the prevention of sudden deaths, reduction of reinfarction, and prevention of atherosclerotic plaque tears.²⁷

Previous clinical studies suggested that β-blocker therapy (carvedilol) has an effect on attenuation of left ventricular remodeling by decreasing left ventricular size in patients with ejection fraction <45% after AMI.²⁸ Carvedilol is a unique multiple-action drug, a nonselective β-blocker with additional vasodilating properties caused by α₁ blockade. If we had chosen carvedilol, different results might be observed. Our study patients had preserved left ventricular function on admission; 63% of patients had LVEF >50%. The difference between our data and previous findings may be ascribed to starting left ventricular function.

Effects of ACE inhibitors on left ventricular remodeling 

In 1992, with the publication of the SAVE trial, ACE inhibitors were established as an important additional treatment for AMI.²⁹ Our results were similar to the previous reports.³, ¹⁸, ²¹ A longer-term follow-up study of patients with AMI indicated that the process of left ventricular enlargement continues for even more than 1 year after AMI.³⁰ Long-term ACE inhibitor therapy may be needed for preventing progression in left ventricular dilation by sustaining reduction in preload and afterload.

Study limitations 

Despite the randomized, prospective trial, the number of patients was small. Moreover, our study was not designed to assess the effects of early treatment with ACE inhibitors or β-blockers on long-term mortality or morbidity rates after AMI. Long-term treatment with β-blockers in patients surviving AMI reduced mortality rates and the rate of reinfarction.³¹ Further large-cohort studies are required to compare the benefits of ACE inhibitors and β-blockers on cardiovascular death after AMI.

This study used β-blocker monotherapy in comparison with ACE inhibitor monotherapy. If a combination group of β-blockers and ACE inhibitors had been included in this study, different results may have been found. Recently, retrospective subanalysis of the SAVE study suggested that the beneficial effects of β-blocker use in patients with LVEF ≤40% after myocardial infarction appear to be additive to those of ACE inhibitors, known to improve prognosis.³²

Sex distribution differed in the 3 groups. Previous studies have shown that women who have myocardial infarction are at increased risk for death and congestive heart failure.³³, ³⁴ However, the TAMI trial suggested that sex differences do not affect salvage of left ventricular function.³⁵ There was no difference in the infarct zone regional response of myocardium during hospitalization between women and men after thrombolysis.³⁵, ³⁶ Sex differences were not observed in left ventricular remodeling in our bisoprolol group.

Conclusions 

Early treatment with β-blockers shows less decline in the indexes of preload and increases left ventricular volume in AMI. This treatment cannot prevent left ventricular remodeling. Early treatment with ACE inhibitors attenuates left ventricular remodeling.

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Acknowledgements 

We are indebted to the nurses and physicians who helped us in this study and to Ms Hiromi Hosaka for secretarial assistance.

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