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European Journal of Heart Failure 2002 4(6):765-770; doi:10.1016/S1388-9842(02)00114-9
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© 2002 European Society of Cardiology

Effects of carvedilol on left ventricular remodeling and systolic function in elderly patients with heart failure

A. Palazzuoli*, F. Bruni, L. Puccetti, M. Pastorelli, P. Angori, A.L. Pasqui and A. Auteri

Institute of Internal Medicine, University of Siena Siena, Italy

* Corresponding author. Present address: Istituto di Semeiotica Medica, Ospedale Le Scotte, Viale Bracci, 53100 Siena, Italy; Tel.: +39-577-585451; fax: +39-577-44114. E-mail address: palazzuoli2{at}unisi.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 
Background: Recent studies have shown that carvedilol therapy in patients with heart failure improves clinical outcome and survival, however, the effects of such treatment on left cardiac morphology and function in elderly patients with severe heart failure has not been widely studied.

Aim: The purpose of this study was to establish the effect of carvedilol at short- and long-term on left ventricular size and performance with mono- and two-dimensional echocardiography, in subjects with dilated cardiomyopathy, NYHA III functional class, low LV ejection fraction (EF<35%) and mean age of >70 years.

Methods: We studied 48 patients, previously randomized to treatment with either carvedilol or placebo, and we performed echocardiographic evaluation at the start, and after 3 and 12 months. Left ventricular diameters, LV mass and fractional shortening were calculated by Deveraux formula; left ventricular volumes and ejection fraction were measured by area–length formula; pulmonary pressure was calculated by tricuspid reflow.

Results: After 3 months, only LV end-diastolic diameter was lower in the carvedilol group compared to the placebo group. Nevertheless, after 12 months, patients on carvedilol treatment showed a LV geometric and functional improvement compared to placebo. We found significant differences in: diastolic (P<0.01) and systolic diameters (P<0.001); on LV mass (P<0.002); on LV systolic volume (P<0.03); and on LV ejection fraction (P<0.01). Pulmonary pressure was also reduced in beta-blocker subjects (P<0.001).

Conclusions: Carvedilol therapy for 12 months reduced LV diameters and volumes. Thus, improving cardiac remodeling and LV systolic function in elderly patients with severe heart failure. Several months of therapy are required for these favorable effects to occur, as these changes do not occur in the short term.

Key Words: Carvedilol • Severe heart failure • Echocardiography • LV geometry

Received April 17, 2001; Revised July 4, 2001; Accepted March 20, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 
Heart failure is one of the most common causes of morbidity and mortality in industrialized countries. Although the introduction of angiotensin-converting enzyme (ACE) inhibitors has improved the prognosis in these patients, the mortality rate remains unacceptably high [1,2].

In recent years, the introduction of beta-blockers has generated favorable results in subjects with heart failure through inhibition of sympathetic activity. The effects of antiadrenergic therapy have been extensively reported in a large number of randomized controlled trials, however these studies are different in their design, objectives, duration, selection of patients and beta-blockers tested [3,4].

Carvedilol is the most studied beta-blocker and seems to have more anti-adrenergic activity than others because of unselective beta-1 and beta-2 blockade, alpha blockade and antioxidant properties, this provides a great reduction in cardiac adrenergic drive and work [5,6]. The effects of carvedilol on cardiac performance reveal an improvement in left ventricular systolic function and a slowing down of ventricular chamber enlargement in patients with mild to moderate chronic heart failure. Nevertheless, in advanced classes and in subjects aged over 60 years, these improvements are not so certain. The Heindreich meta-analysis showed that older people treated with beta-blockers did not show a significant reduction in mortality [4]; moreover patients in NYHA class III and IV frequently have complications and poor drug tolerance [7,8]. Currently, there is not enough information regarding efficacy of carvedilol in patients with severe heart failure.

The CIBIS II Trial which recruited subjects with advanced heart failure, showed a higher mortality rate and less cardiac improvements than other studies of patients with less severe clinical conditions [9].

In this study, we investigated the effects of carvedilol on parameters of left ventricular geometry and function, in a group of elderly patients with heart failure due to dilated idiopathic cardiomyopathy with severe systolic dysfunction (EF<35%).


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Study limitations
 References
 
2.1. Study design
This was a double-blind study conducted in forty-eight patients with advanced heart failure due to non-ischemic dilated cardiomyopathy. Patients were randomized to receive either carvedilol or matched placebo after 3-week run-in period with open beta-blocker therapy. After randomization the dose of carvedilol or placebo was titrated up to 12.5–25 mg twice daily over a 7-week period, treatment was then continued for the duration of the study. The initial drug dose was 3125 mg the first week, than 3125 every 12 h, and, if well tolerated it was increased every 2 weeks up to a maximum of 50 mg/day.

Main end point assessments included completion of the study, left ventricular systolic function and chamber geometry evaluation; secondary end points were worsening symptoms, suspension therapy and death.

2.2. Patient enrollment
Subjects were eligible if they had: symptomatic but stable heart failure (NYHA class III) due to idiopathic dilated cardiomyopathy without a history of myocardial infarction or angina (all patients had undergone coronary angiography within 1 year of the start of the study); ejection fraction <35%; adequate echocardiographic window for left ventricular diameter and volume analysis; age >65 years. Exclusion criteria were: primitive valvular heart disease; angiographic evidence of coronary disease (diameters plaque of the main artery branches >50%) active myocarditis; a recent history of sustained ventricular tachycardia not controlled with anti-arrhythmic drugs; second or third degree atrio-ventricular or intra-ventricular block; uncontrolled insulin-dependent diabetes mellitus; advanced peripheral artery disease; worsening of bronchial asthma or chronic obstructive lung disease; or hepatic, renal, hematologic, neurologic, or collagen diseases.

All patients continued previous medication with diuretics, angiotensin-converting enzyme inhibitors, digitalis, vasodilating agents, warfarin, or aspirin. Subjects gave written informed consent as approved by the Investigational Human Use Committee.

The total number of subjects recruited was 52, 32 male and 20 female, with age ranging from 71±6 years (mean age 72). Of these 52 patients, 34 were in sinus rhythm and 14 had chronic atrial fibrillation (AF), data from the remaining four patients were excluded as the patients died before the end of the study. Baseline heart rate was 82±12 beats/min, systolic blood pressure (BP) was 135±10 mmHg, diastolic BP was 85±10 mmHg (measured with oscillometric method, Colin Meter, Germany) 28 patients were randomized to carvedilol therapy and 20 to placebo (Table 1).


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  		Table 1 Baseline characteristics of patients

 
2.3. Echocardiographic methods
Mono- and two-dimensional echocardiography was performed at baseline and after 4 and 12 months of treatment. The ultrasound machine used was ATL 3500 HDI, all examinations were recorded on videotape and evaluated by two different specialists. The analysis of the echocardiographic parameters was blinded; intra-observer variability was 9.5% and inter-observer variability was 10.5%. A standard protocol was used, based on apical two and four chamber views according to the recommendations of the American Society of Echocardiography [10]. To determine left ventricular dimension, mass and thickness echocardiography was performed using standard M-mode measurements, LV mass was calculated by parasternal view using the Devereux Formula [11]. Relative wall thickness (RWT) was calculated as the sum of end-diastolic interventricular septum (SIV) and end-diastolic posterior wall (PW) divided by LV end-diastolic diameter (EDD) and was considered low if <30 (eccentric remodeling) [12].

Manual planimetry of the endocardial border was performed including papillary and cord muscles in the chamber area, biplane end-systolic (ESV) and end-diastolic (EDV) volumes were calculated by computer software according to area–length formula [13].

The pulmonary systolic pressure (PAP) was evaluated from the tricuspid valve flow velocity [14].

All results were normalized for the body surface area (m2) calculated from the patient's weight and height during clinical examination. Every measurement was analyzed under electrocardiographic monitoring and expressed as the mean of three different values for patients in sinus rhythm and the mean of five values for patients with atrial fibrillation.

2.4. Statistical analysis
The data (expressed as means±S.D.) was determined for each of the treatment groups at each time point. Repeated measures analysis of variance calculation was performed between 4 and 12 months. Effects were evaluated using the general linear model and mixed model procedures with factors termed Subject Group and Time. In these model the slope was measured by the effects of Time; within analyses the slope was tested by testing Time. Particular interest was devoted to the interaction between Group and Time, to perform between-group comparison of changes.

The data was analyzed for statistically significant differences by two-tailed t-tests for unpaired data and by linear correlation, using the SPSS/PC+4 statistical package (SPSS Inc, Chicago, IL). The significance level was set at P<0.05. Results were considered significant if there was, within or between group analyses, a statistical confidence level of 95%.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Study limitations
 References
 
Of the 52 patients admitted to the study, 31 were randomized to carvedilol therapy and 21 to placebo in a 3:2 ratio, 48 patients completed the study protocol. At the end of the study systolic and diastolic BP were: respectively, 125±10 mmHg in the carvedilol group and 130±5 mmHg in the placebo group; and 75±5 mmHg in carvedilol group and 80±5 in placebo group. Heart rate was 65±5 beats/min in the carvedilol group and 80±10 beats/min in the placebo group (P<0.001). Beta-blocker treatment was stopped in two patients because of clinical worsening, one of these two patients randomized to carvedilol and two to placebo died before 1 year of follow-up. The remaining 48 subjects completed the study; among the patients randomized to carvedilol the mean dosage was 35 mg daily at 4 and 12 months (18 subjects took 25 mg/day and 10 took 50 mg/day).

The initial clinical evaluation and social conditions were similar in the carvedilol treated group and in the placebo group. Table 2 shows baseline mono and two-echocardiographic parameters in both groups: level of LV systolic dysfunction; LV mass; LV enlargement and geometry; and pulmonary pressure did not exhibit significant differences.


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  		Table 2 Baseline echocardiographic parameters in carvedilol and placebo groups

 
At 4 months, comparison between the two groups revealed significant lowering of LV end-diastolic diameter (EDD) in the carvedilol group (37.7±3.5 mm/m2 vs. 40.1±3.1 P<0.04) other values did not change.

The comparison of the treated and placebo groups at the start and at 4 months did not show any significant differences. Comparison of the carvedilol group at 4 and at 12 months showed an increase in EF (28.0±7.3 vs. 34.9±7.7 P<0.01) and shortening fraction (SF) (18.5±4.9 vs. 25.3±5.4 P<0.01) and a significant decrease in LV ESV (81.2±25.8 vs. 68.0±19.8 ml/m2 P<0.01) and pulmonary pressure (28.6±4.1 vs. 26.3±4.3 mmHg P<0.05). No change was found in the control group. Comparison of the carvedilol group at baseline and at 12 months showed more significant results: LV end-systolic diameter (EDS) decreased from 31.7±3.9 to 28.3±4.6 mm/m2 (P<0.01); SF increased from 16.7±5.2 to 25.3±5.4; LV ESV decreased from 83.9±18.3 to 68.0±19.8 ml/m2 (P<0.01); LV mass decreased from 210.7±32.6 to 186.6±35.4 g/m2 (P<0.05); EF increased from 25.0±7.4 to 34.9±7.7 (P<0.01); systolic PAP decreased from 31.3±7.3 to 26.3±4.6 mmHg (P<0.01). The placebo group at the same time only showed a decrease in systolic PAP from 31.4±2.3 to 29.1±3.2 mmHg (P<0.05) (Figs. 1 and 2).


Figure 1
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  		Fig. 1 Carvedilol decreases average LV mass after 12 months of treatment but not after 4 months. The P value refers to difference of slopes.

 


Figure 2
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  		Fig. 2 Carvedilol decreases average Relative Wall Thickness (RWT) after 12 months of treatment but not after 4 months. The P value refers to difference of slopes.

 
Analysis between the two groups after 12 months showed a significant reduction in the carvedilol group compared to the placebo group for LV EDD (36.6±3.7 vs. 40.7±3.6 P<0.001) and LV end-systolic diameters (27.7±4.1 vs. 31.0±3.5 P<0.01). LV ESV decreased in the carvedilol group (67.5±18 vs. 75.7±5.5 ml/m2 P<0.03); and similar effects were seen for LV myocardial mass (183.5±20 vs. 199.2±13 g/m2 P<0.002) and for RWT (0.29±0.02 vs. 0.27±0.02 P<0.001) (Figs. 1 and 2). LV EF increased in the carvedilol group (34.6±6.6 vs. 30.1±6.2 P<0.01); and finally systolic PAP showed a decrease in the carvedilol group (26.3±4.5 vs. 31.2±4.3 mmHg P<0.001) (Figs. 3 and 4).


Figure 3
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  		Fig. 3 Carvedilol improves hemodynamic conditions: LV ejection fraction (EF) calculated with area–length formula increases after 12 months. The P value refers to difference of slopes.

 


Figure 4
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  		Fig. 4 Carvedilol improves hemodynamic conditions: Systolic Pulmonary Pressure calculated by tricuspid flow reduces at the same time of therapy. The P value refers to difference of slopes.

 
No significant differences were found after 4 and 12 months between patients with AF and the non-AF group.

After 12 months, we found a mean improvement in LV EF of 5%, a mean decrease in LV mass of 16 g/m2 and systolic PAP of 5 mmHg in the carvedilol group, compared to the placebo group.

Comparison between groups over time did not show any morphological or functional changes at 4 months, however, after 12 months we found significant differences in geometrical and systolic parameters (Table 3).


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  		Table 3 Functional and morphological differences between the two groups after 12 months of treatment

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Study limitations
 References
 
The most important result of this study is that carvedilol is able to partially reverse eccentric remodeling, (LV mass and LV volumes) in patients with advanced heart failure due to idiopathic cardiomyopathy. These changes occurred in subjects in a stable clinical condition. Other studies have reported similar results in patients with mild to moderate heart failure, but there is no agreement on beta-blocker efficacy in more severe stages [8,15,16].

The positive effects occurred in subjects treated formerly with ACE-inhibitors at maximum dosage and diuretics, against a placebo group treated in the same way, and who did not show any evidence of LV enlargement regression. The functional and morphological improvement was not apparent in the short term but only after many months of carvedilol therapy. Several other authors have shown evidence of an improvement in systolic and diastolic function after a few weeks of beta-blocker treatment [16,17]. This could be due to a lower mean drug dosage in our study.

Analysis of beta-blocker trial results demonstrates a consistent beneficial effect on cardiovascular mortality in chronic heart failure, the positive effect has been seen with various drugs but it seems to be most pronounced with carvedilol [4,18,19]. Previous studies have also shown an improvement in LV mass and chamber geometry even after short-term (3 months) carvedilol treatment [20]. Nevertheless, Krum et al. reported that subjects with more advanced NYHA class did not obtain a beneficial effect with carvedilol and 37% developed worsening heart failure [8].

The precise mechanism of the improved long-term outcome remains unclear, although the reduction in non-sudden death seems to be more marked than the decrease in sudden death, this could suggest that beta-blockade exerts major effects on the progression of heart failure. The present study is in accordance with this hypothesis, as it has demonstrated how carvedilol is able to reduce LV volumes and to increase EF in advanced NYHA class [20,21].

Although the reduction of LV remodeling shown in the current study confirms the beneficial action of carvedilol on LV systolic function, the exact mechanism cannot be explained on the basis of positive geometrical reverse. The failing heart is submitted to continuous adrenergic activation to maintain adequate performance by increasing heart rate and contractility [22], beta-blocker action reveal not only with slowing of heart rate that could partially determine an improvement of systolic function, but also by metabolic and neuro-endocrine actions [23–25].

Carvedilol reduces renin activity and possibly levels of circulating catecholamines protecting cardiac myocytes. It also improves vagal capacity and decreases stimulation of vasoconstrictive substances like endothelin, angiotensin and vasopressin [26,27]. This neuro-hormonal blockade provides other beneficial effects on inhibition of muscle cell growth, slowing cardiac hypertrophy, decreasing hibernating myocardium and on reduction of ventricular arrhythmias [28–30].

The initial inotropic reduction caused by beta-blockers, can in the early period cause a mild temporary worsening of clinical condition and impairment of LV function, but in the long term, regression of volumes and mass occur. These salutary changes of reverse remodeling would be expected to decrease metabolic demand and parietal wall stress [30,31].

Even if elderly patients with advanced NYHA class are more susceptible to adverse effects during beta-blocker initiation, carvedilol showed a good tolerability and positive action on left ventricular size and function. In older patients, it is necessary to have close observation during titration of the drugs, starting with low doses and increasing the dosage slowly compared to younger patients: thus, more patience is required to produce structural and hemodynamic results, but this will improve long-term outcomes in these subjects [32–35]. To prevent the negative inotropic effect of carvedilol it is advised to maintain low doses during the starting period.

Our study confirms that carvedilol in the long-term treatment of heart failure produces a positive inotropic effect and reduces eccentric remodeling after a year, even in older patients with severe systolic dysfunction and advanced NYHA class [36–38]. These anti-remodeling actions provide further evidence of the beneficial effects of carvedilol in addition to standard therapy.


   5. Study limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
References
 
This study has some limitations linked to non-invasive assessment of left ventricular measures and systolic function. Left ventricular volumes and ejection fraction have been measured with area–length formula that has demonstrated a good correlation with ventriculography. Nevertheless, our results could be partially due to afterload reduction and heart rate slowing. The method used is especially limited for patients with atrial fibrillation (n=14), we have tried to minimize these problems by taking a mean of five measures. All measurements were performed in apical four chamber projection; therefore, the kinesis of the anterior and posterior walls was not evaluated, even if in dilated non-ischemic cardiomyopathy the alteration of contractility should involve in the same way all LV parietal segments.


   Acknowledgements
 
We are grateful to Roche Italia S.P.A. for the supply of carvedilol and for financial support. We thank Dr Duranti and Dr Colombi for technical assistance.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 

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