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European Journal of Heart Failure 2001 3(3):335-342; doi:10.1016/S1388-9842(00)00152-5
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© 2001 European Society of Cardiology

Influence of carvedilol on the benefits of physical training in patients with moderate chronic heart failure

J.F. Forissiera,*, P. Vernocheta, P. Bertrandb, B. Charbonnierc and C. Monpèrea

a Centre de réadaptation cardiovasculaire Bois-Gibert 37510 Ballan-Miré, France
b Laboratoire de Biostatistique et d'Informatique médicale, CHU Bretonneau 37044 Tours Cedex 1, France
c Service de Cardiologie D/USCI, CHU Trousseau 37044 Tours Cedex 1, France

* Corresponding author. Tel.: +33-2-47-48-74-75; fax: +33-2-47-53-49-41 E-mail address: bgibert{at}club-internet.fr (J.F. Forissier).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aims: To evaluate prospectively the impact of carvedilol on a short-term physical training program in stable patients with moderate chronic heart failure (CHF), and to analyze parameters predictive of improvement after training.

Methods and results: Thirty-eight patients with CHF were referred for cardiac rehabilitation. Etiology was ischemic in 26 patients, dilated in 12 patients and left ventricular ejection fraction was < 35%. Patients were classified into three groups: group 1 (n = 14) = ACE inhibitors, diuretics and digitalis; group 2 (n = 11) = idem group 1+cardioselective beta-blocker; group 3 (n = 13) = idem group 1+carvedilol. Exercise tests with VO2 measurement were performed before and after a 4-week exercise training program. Patients with carvedilol experienced a 16.6% increase in peak VO2 which was similar to the 13.9% increase in the group with cardioselective beta-blocker and to the 18.5% in the group without beta-blocker. Moreover non-ischemic etiology of CHF was the only parameter predictive of improvement after training (P = 0.02).

Conclusions: Addition of carvedilol did not alter benefits of a short-term physical training program in patients with moderate CHF. No baseline characteristic except for etiology of CHF was predictive of a response to training.

Key Words: Carvedilol • Beta-blocker • Heart failure • Physical training • Cardiac rehabilitation

Received May 9, 2000; Revised September 15, 2000; Accepted November 30, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Despite the beneficial impact of medical treatment in the past decade with extensive use of angiotensin-converting enzyme (ACE) inhibitors [1], chronic heart failure (CHF) remains a major public health problem [2]. Exertional fatigue and dyspnea are usual symptoms and limit physical activity of the patients. These symptoms result both from the cardiopathy and from physical deconditioning with peripheral abnormalities [3].

Beneficial effects of physical training are no longer questionable in these patients affected by CHF, with a significant improvement in functional NYHA class and in exercise performance [4]. This greater exercise tolerance is due primarily to peripheral modifications in skeletal muscular function, vascular tone and autonomic control [3,5] whereas the central resting hemodynamics are poorly modified [6–8].

Carvedilol therapy has been recently demonstrated to have a beneficial impact on morbidity and mortality in patients with stable CHF [9–12]. This non-selective beta-blocker agent with vasodilator properties (alpha 1-) improves functional class and resting hemodynamics [13] and is associated with reduced mortality but does not modify peak oxygen consumption in this population [14,15].

It remains controversial as to whether or not beta-blockers could limit the beneficial effects of physical training in patients with ischemic or non-ischemic stable CHF because of a reduction in chronotropic response or lack of reversibility of peripheral abnormalities [16,17].

Therefore, the aims of this prospective study were to compare the effects of carvedilol, vs. cardioselective beta-blockers or conventional treatment alone (ACE inhibitors and diuretics) on a short-term physical training program in patients with stable CHF and to analyze the influence of the population's baseline characteristics on the prediction of improvement after training.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Population
We prospectively studied 38 patients referred for cardiac rehabilitation because of CHF. All were under stable medical regimen, including ACE inhibitors, diuretics, digitalis±a beta-blocker agent (carvedilol or a beta 1 selective one). No modification of treatment occurred during the last month before enrolment and during the study. All the patients exhibited stable symptoms during the preceding month and were in NYHA functional class II (n=34 patients) or III (n=4 patients).

Criteria for eligibility were history of heart failure, left ventricular ejection fraction<35% assessed by contrast ventriculography or radionucleide angiography, and stable sinus rhythm.

Exclusion criteria were unstable angina, recent myocardial infarction (<2 months), decompensated heart failure, physical limitations due to vascular claudication or orthopedic disease.

The baseline characteristics of the study population are summarized in Table 1. The etiology of heart failure was myocardial ischemia (26 patients) or dilated cardiomyopathy (12 patients). The mean delay between the diagnosis of the disease and the inclusion in the study was 17.8±32.2 months in the ischemic group and 45.1±60.1 months in the non-ischemic one. Patients were classified into 3 groups according to their medical treatment before the beginning of training: group 1=14 patients treated by ACE inhibitors, diuretics and digitalis without beta-blocker; group 2=11 patients treated by ACE inhibitors, diuretics, digitalis and a cardioselective beta-blocker: metoprolol (n=2, mean dose=100 mg/day), bisoprolol (n=2, mean dose=2.5 mg/day) or acebutolol (n=7, mean dose=100 mg/day); group 3=13 patients treated by ACE inhibitors, diuretics, digitalis and carvedilol. Therapy with carvedilol has been initiated in patients >4 months. Nine patients received 25 mg carvedilol BID, three patients received 12.5 mg carvedilol BID and one patient received 6.25 mg carvedilol BID.


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  		Table 1 Baseline characteristics of the study population

 
The physical training protocol was approved by the Ethical Committee of our institution and all of the patients gave informed written consent.

2.2. Exercise protocol and cardiopulmonary assessments
A symptom-limited exercise test was performed on an upright cycle ergometer (Lode Corival 400) using a 10 W/min ramp protocol at a constant rate of 60 rpm. Heart rate was continuously recorded on a 12-lead ECG (Marquette Electronics Inc. Case 15) and blood pressure was measured every 3 min. Exercise test was stopped because of fatigue or excessive dyspnea.

Cardiopulmonary variables (oxygen uptake, carbon dioxide production, and ventilation) were measured breath by breath (Mass Spectrometer Marquette). These data were averaged every 10 s and analyzed by computer. Oxygen uptake per kg body weight (ml/kg min), oxygen pulse (ml/beat) and respiratory exchange ratio were calculated. Oxygen consumption at rest was defined as the mean value of the preceding 2 min before the beginning of exercise.

The ventilatory anaerobic threshold was not determined but the point during exercise at which respiratory exchange ratio equaled unity (RER=1) was assessed and reflected the sub-maximal level of exercise.

At the peak exercise level, blood pressure (BP), heart rate (HR), BPxHR product, exercise duration, peak oxygen consumption (peak VO2), peak ventilation (peak VE) and pulse of O2 (peak VO2/HR) were collected.

During the recovery phase, HR and VO2 after 2 minutes and half-recovery time of peak oxygen consumption (1/2 p VO2), defined as the time needed for peak oxygen consumption to decrease to its half-value, were calculated.

All the patients were familiarized with the cardiopulmonary exercise test before entering the study.

2.3. Physical training program
The training program was prescribed and supervised by a physician at the frequency of 3–5 days per week during 4 weeks. This program comprised:

  • an endurance training session on cycle ergometer, with a target heart rate defined during the first cardiopulmonary exercise test as the heart rate obtained just below the ventilatory anaerobic threshold. Heart rate was controlled and monitored by telemetry at each session. Workload was adjusted according to this target heart rate. The duration of the sessions varied from 20 to 40 min at the end of the rehabilitation and increased by 5 min per week if tolerance was good.
  • a moderate calisthenics exercise session using segmental muscular training (60 min per session, 3–5 sessions per week, for 4 weeks) at a heart rate level<baseline heart rate+10 beats/min.
  • a daily outside walk (mean time=30 min).

An endurance test was performed in the morning and calisthenics exercise in the afternoon.

2.4. Statistical analysis
The statistical analysis consisted of three parts. First, all the quantitative variables of the study were summarized by their means and 95% C.I. Comparisons between the three groups were assessed using an ANOVA test for quantitative baseline variables and using a {chi}2-test for qualitative baseline variables. Then, the comparison before and after training between the three groups was tested with paired t-tests. The relationships between ‘responders’ and ‘non-responders’ and between etiologies of heart failures were assessed with Student's t-test and {chi}2 for the baseline characteristics of the study sample and with paired t-tests for the variations of exercise tests (before and after training). Finally, we performed a stepwise logistic regression including the significant variables from the univariate analysis to assess their relationship with the response to training. The significance level was chosen to be.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Clinical results
The three groups exhibited similar baseline characteristics (Table 1) except for size and heart rate which were lower in group 3 (carvedilol) and duration of CHF which was lower in group 2 (beta-blocker treatment). Size was probably lower because of a higher number of women in this group even though there was no significant difference with other groups. Heart rate was not significantly reduced in group 2 (cardioselective beta-blocker) in comparison with group 1 because Acebutolol, a beta-blocker with agonist activity, was most frequently used at a low dose (100 mg/day). The etiology of CHF was primarily ischemic in groups 1 and 2 and non ischemic in group 3. Baseline peak VO2 was lower in group 1 than in groups 2 and 3 but without a significant difference.

No major adverse training-related side effects occurred during the study.

3.2. Exercise tests and cardiopulmonary measurements
3.2.1. Resting and submaximal parameters
Resting heart rate significantly decreased after training in group 1 without beta-blocker (training effect) but was not modified in other groups. Systolic blood pressure at rest was not significantly modified (Table 2).


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  		Table 2 Cardiopulmonary exercise tests before and after training in the study population

 
In groups 1, 2, 3, the point at which RER=1 occurred for higher workload and VO2 measurements. The HR level at which RER=1 was not significantly different from baseline (Table 2). This improvement occurred after training in the patients with or without a cardioselective beta-blocker or carvedilol (Table 3).


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  		Table 3 Comparison of the variations of exercise tests before and after training between groups

 
3.2.2. Maximal performances
Peak VO2 after training increased from 18.1±4.1 to 21.2±3.7 ml/min per kg in group 1 without beta-blocker, from 21.5±5.7 to 24.3±6.2 ml/min per kg in group 2 with a cardioselective one and from 20±8.8 to 23.4±10.7 in group 3 with carvedilol (P<0.05 for baseline vs. training in each group). In groups 1, 2, 3, variation of peak VO2 was respectively: +18.5%; +13.9%; +16.6% (P=NS between groups).

Peak heart rate significantly increased in the group with carvedilol and increased slightly in groups 1 and 2. However, comparison between the 3 groups showed no significant difference. Ventilation (peak VE) increased significantly in each group after training without significant difference between groups.

3.2.3. Recovery parameters
There was no significant modification concerning the parameters of recovery in each group. VO2 at 2 min recuperation/peak VO2, HR at 2 min recuperation/peak HR and 1/2 pVO2 decreased slightly in group 3 (P=NS) and were not modified in groups 1 and 2.

3.3. Baseline characteristics of ‘responders’ and ‘non-responders’
Twenty-two patients (58%) were considered as ‘responders’, i.e. more than 10% increase in peak VO2 after training. Analysis of baseline characteristics of ‘responder’ and ‘non-responder’ patients found no discriminant parameter except for resting heart rate and cause of CHF. A higher resting HR (P=0.05) and the non-ischemic etiology (P=0.01) seemed to be associated in our population with an increase in peak VO2>10%. There was no significant difference in univariate analysis in terms of therapy, pre-training left ventricular ejection fraction and peak VO2, delta peak HR and in the number of ergometry sessions (Table 4).


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  		Table 4 Baseline characteristics of ‘responder’ (>10% increase in peak VO2) and ‘non responder’ patients (<10% increase in peak VO2)

 
In multivariate analysis, the only factor predictive of a response to training was the non-ischemic cause of CHF (P=0.02). A higher resting HR (P=0.07) and a lower peak VO2 (P=0.06) tended to be associated with the ‘responder’ group without significant difference.

Similarly analysis of correlation between delta peak VO2 and baseline characteristics of the population showed that non-ischemic etiology of CHF was the only parameter significantly correlated with an improvement of peak VO2 after training (P<0.008).

3.4. Effects of exercise training and etiology of heart failure
Patients with ischemic and non ischemic CHF were not different except for sex-ratio and size which were probably linked (P<0.05) (Table 5).


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  		Table 5 Baseline characteristics and results of exercise tests in ischemic and non ischemic cardiomyopathies

 
Improvement of VO2 at AT was not different between groups. Increase of exercise duration and peak HR after training was similar in the 2 groups. However, peak of VO2 increased much higher in patients with non-ischemic CHF (+5.1±3.7 ml/min per kg) than in patients with ischemic CHF (+2.2±2.3 ml/min per kg) (P<0.01). Concerning the recovery parameters, {Delta}1/2 pVO2 was significantly different between the two groups (+11±31 s in ischemic patients vs. –24±36 s in non-ischemic patients, P=0.01).

The major effects of training in ischemic and non-ischemic cardiomyopathies are summarized in Table 5.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
In our study, patients with CHF with or without carvedilol exhibited a similar increase in peak VO2 after 4 weeks of exercise training. Patients who were treated with carvedilol experienced a 16.6% increase in peak VO2 which did not differ significantly with the 13.9% increase in the group treated with a cardioselective beta-blocker and with the 18.5% increase in the group without beta-blocker.

Exercise training is well known to improve significantly functional capacities in coronary artery disease patients with no or moderate ventricular dysfunction, whatever the pathology or age [18,19]. In those patients, beta-blocker therapy does not seem to alter the expected enhancement of cardiorespiratory fitness, despite the reduction of chronotropic reserve [20]. Moreover, effects of rehabilitation and beta-blockers are synergic on heart rate variability, inducing a more favorable sympathovagal balance [21] and exercise training may offset adverse effects in lipoprotein metabolism induced by beta-blockers [20]. More recently indications of physical training have been extended to stable CHF patients with a beneficial impact on exercise capacities [22,23]. The European Heart Failure Training Group (EHFTG) reported the positive training effect in 134 stable CHF patients after 16 weeks of exercise (+13% in peak O2 consumption,+17% in exercise duration) [4]. After 4 weeks of ergometer and calisthenic training, the increase in peak VO2 and in exercise duration in our study were, respectively, +16.4% and +21%. This greater improvement was probably in part explained by the characteristics of our population which was younger (mean age=54.4±14 years) than the population of the EHFTG (mean age=60.5±8.6 years). Moreover these results outlined the beneficial impact of physical training in a short-term period in patients with stable CHF and confirmed previous studies: Minotti et al. [24] studied patients who performed single-arm training for 28 days and found a significant improvement in oxydative metabolism. In the same way, Jetté et al. [25] recruited 10 patients with CHF who trained 55 min in the morning and 30–60 min in the afternoon 5 days/week for 4 weeks: a significant improvement in peak oxygen uptake from 1.0 to 1.2 liters/min was observed after training.

Little is known about the influence of beta-blocker therapy on the potential benefits of physical training in CHF patients. Demopoulos et al. [16] studied 23 patients with CHF who were treated with carvedilol or propranolol and found a similar increase in peak VO2 after 12 weeks training in the 2 groups (propranolol: +27%, carvedilol: +24%). Furthermore, Curnier et al. [26] found a similar increase in VO2 at anaerobic threshold and at peak exercise in two groups of 34 CHF patients with or without a beta-blocker after a 4-week training program. Our study strengthened this conclusion with an increase in peak VO2 of 13.9% in the group treated with a cardioselective beta-blocker and of 16.6% in the group carvedilol, even after a shorter training period. However, our training program was more intensive and was performed in paucisymptomatic patients. It associated cycle ergometer, calisthenic exercise and daily walk, whose combination is known to be more beneficial than cycle ergometer training alone [4]. This beneficial impact of carvedilol did not seem to be due to its vasodilator properties because a similar increase was reported in the cardioselective beta-blocker group. It could be explained partly by a significant higher peak heart rate level.

The pronostic value of patient characteristics on training effects remains still controversial. In our study no baseline characteristic except for etiology of CHF was predictive of response after training. A higher heart rate was predictive of a response to training in univariate analysis but this result was not confirmed by the multivariate analysis. Moreover contrary to other studies a lower baseline peak VO2 was not a predictive parameter. Only the non-ischemic etiology seemed to be associated in univariate and multivariate analysis with a response to exercise: patients with non-ischemic heart failure showed more of an improvement in peak VO2 in comparison with ischemic patients (+5.1±3.7 vs. 2.2±2.3 ml/min per kg, P<0.01). In the EHFTG study the same result was observed. No baseline patient parameter was significantly correlated with outcome and only the non-ischemic etiology seemed to be in relation with a higher improvement in peak VO2 (non ischemic: +3.1±5.2 vs. ischemic:+1.5±2.3 ml/min per kg, P<0.05). However, the ischemic/non-ischemic groups were heterogeneous in terms of age, symptoms and baseline exercise tolerance and ischemic patients exhibited a more severe disease in this latest study. Keteyan et al. [27] observed the same tendency among CHF patients in the exercise group: increase in peak VO2 tended to be greater in those with idiopathic dilated cardiomyopathy (305±60 ml/min) than in those with ischemic cardiomyopathy (121±67 ml/min) (P=0.07).

The reason why non-ischemic patients seemed to benefit more from physical training is unclear. Ischemic and non-ischemic groups exhibited similar baseline characteristics except for the sex-ratio (M/F) which was significantly higher in the ischemic group but probably did not explain the result. Moreover patients with CAD did not have to stop exercise prematurely because of ischemia or another adverse effect. One possible explanation could be a more important physical deconditioning in non-ischemic patients even though baseline peak VO2 was similar in the two groups. However, peak VO2 reflects only partially peripheral skeletal muscle abnormalities and could have missed subtle differences in a young population affected by CHF without severe symptoms. Furthermore, delay between beginning of disease and training was longer in non-ischemic patients (17.8±32.2 months in ischemic patients vs. 45.1±60.1 months in non-ischemic patients, P=0.07) and was associated with a higher but non-significant resting heart rate. This longer delay strengthened hypothesis of more pronounced deconditioning state in those non-ischemic patients.

4.1. Limitations
This study included a small number of patients without randomization before beginning of training. However, this prospective work concerned homogeneous and comparable groups and allowed us to confirm and strengthen results of previous studies.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
A short-term 4-week exercise training program increased submaximal tolerance and peak VO2 in patients with moderate CHF. Addition of carvedilol or cardioselective beta-blockers to the usual treatment did not alter benefits of rehabilitation. This training program was intensive and safe under a strict medical supervision. Moreover the non-ischemic etiology of CHF seemed to be significantly correlated with a greater improvement in peak VO2 after training.


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

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