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European Journal of Heart Failure 2003 5(6):803-809; doi:10.1016/S1388-9842(03)00151-X
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© 2003 European Society of Cardiology

Efficacy and tolerability of the long-term administration of carvedilol in patients with chronic heart failure with and without concomitant diabetes mellitus

Savina Nodaria, Marco Metraa,*, Alessandra Dei Casb and Livio Dei Casa

a Cattedra di Cardiologia, Università di Brescia Piazza Spedali Civili, 25100 Brescia, Italy
b Istituto di Clinica Medica Università di Parma, Italy

* Corresponding author. Tel.: +39-030-307221; fax: +39-030-3700359 E-mail address: metramarco{at}libero.it


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Diabetes is frequently associated with heart failure and is an independent risk factor for an increased mortality and morbidity. Beta-blockers are traditionally regarded as relatively contraindicated in patients with diabetes mellitus.

Aim of the study: To assess the efficacy and tolerability of carvedilol administration in patients with heart failure and concomitant diabetes.

Methods and results: One hundred ninety-three patients (68 diabetics, 125 non-diabetics) with chronic heart failure were assessed by radionuclide ventriculography, cardiopulmonary exercise testing and right heart catheterization before and after 12 months of maintenance carvedilol treatment (mean dose, 40±19 mg daily). Diabetic patients were older and with a lower peak VO2, compared with non-diabetics. Long-term carvedilol administration was associated with an improvement in left ventricular function, clinical symptoms, resting and exercise hemodynamic parameters compared to baseline, with no significant difference between the diabetic and the non-diabetic patients. The incidence of adverse effects was also similar between the two groups. Diabetics had higher all-cause mortality with a similar mortality and hospitalization rate, compared to non-diabetics during 33±20 months of follow-up.

Conclusion: Concomitant diabetes does not influence the efficacy and tolerability of carvedilol administration in patients with chronic heart failure.

Key Words: Carvedilol • Chronic heart failure • Concomitant diabetes

Received September 2, 2002; Revised April 28, 2003; Accepted July 17, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Diabetes mellitus is an independent risk factor for heart failure [1–4]. Its prevalence is approximately 20–30% in patients with heart failure [5,6], increasing to 40–45% when glucose abnormalities are systematically assessed [7]. Once heart failure has developed, diabetes is an independent risk factor of increased morbidity and mortality [5–9] acting through multiple mechanisms such as accelerated atherosclerosis, impaired endothelium dependent vasodilatation, increased interstitial myocardial fibrosis, vagal tone reduction, metabolic abnormalities with an increase in fatty acids and a reduction in glucose uptake [6].

Placebo controlled trials have shown the beneficial effects of β-blockers in patients with chronic heart failure [10–12]. As a result, these agents are now recommended to all patients with left ventricular systolic dysfunction and mild to moderate heart failure symptoms [13,14]. However, the administration of β-blockers to patients with concomitant diabetes has been questioned, because they may worsen insulin sensitivity and cause more severe hypoglycemic attacks [15,16]. In contrast to the traditional β-blockers, carvedilol, because of its associated properties, has been shown not to affect plasma glucose levels and insulin sensitivity in hypertensive patients with concomitant diabetes mellitus, [17,18] and in patients with chronic heart failure [19]. In addition, β-blockers might specifically counteract many of the untoward effects of diabetes mellitus, like myocardial ischemia, metabolic abnormalities or reduced vagal drive. Accordingly, their administration has been shown to be associated with a lower mortality rate, compared to placebo, in trials performed in patients with previous myocardial infarction [20–24]. A retrospective analysis of the patients assessed in the Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA) trial also showed greater favorable effects of carvedilol in diabetics, compared to the non-diabetic patients [25]. Thus, the aim of our study was to compare the efficacy and tolerability of the long-term administration of the β-blocker carvedilol in a group of patients with chronic heart failure, with and without concomitant diabetes mellitus, who were assessed both at baseline and after long-term (≥1 year) maintenance therapy.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
The study design was approved by the local ethics committee and all patients gave informed consent to participate. We studied 193 consecutive patients with chronic heart failure caused by idiopathic dilated cardiomyopathy or coronary artery disease, who were in a stable clinical condition, with no hospitalizations for heart failure or change in their drug regimen in the week before initiation of therapy. All patients had symptoms of heart failure for ≥6 months, a left ventricular ejection fraction (LVEF) ≤0.35 by radionuclide ventriculography and a peak VO2≤25 ml kg–1 min–1 by cardiopulmonary exercise testing. All patients were treated with diuretics as required to control fluid retention and an angiotensin converting-enzyme (ACE) inhibitor (or an angiotensin receptor blocker when the ACE inhibitor was not tolerated) unless they had specific contraindications. Patients were excluded if they had unstable angina, an acute myocardial infarction or a coronary revascularization procedure, planned or performed within 3 months; an history of alcohol abuse, active myocarditis, primary valve disease or congenital heart disease; concomitant diseases, which might adversely influence the prognosis and/or impair exercise capacity (e.g. malignancy, musculoskeletal diseases...); contraindications to beta-blocker therapy (asthma, advanced heart block or bradyarrhythmias); and concomitant treatment with other β-blockers, {alpha}-antagonists, calcium antagonists or antiarrhythmic agents, except amiodarone. Patients were subdivided in diabetics and non-diabetics with diabetes diagnosed according to the criteria of the Expert Committee on the Diagnosis and Classification of Diabetes [26].

2.2. Study protocol
Each patient was treated with carvedilol, combined with their usual heart failure treatment. Carvedilol was started at low doses (3.125 mg BID) with gradual increments to the target dose of 25 mg BID (50 mg BID in the patients weighing ≥75 kg) according to a protocol described previously [10,27].

In the week before carvedilol initiation and after 12 months of treatment with the chronic maintenance doses, each patient underwent symptom assessment, using the New York Heart Association (NYHA) functional classification; radionuclide ventriculography, for the measurement of the LVEF and cardiac volumes; maximal cardiopulmonary bicycle exercise testing and right heart catheterization for the measurement of thermodilution cardiac output and intra-cardiac pressures at rest and peak exercise, according to a protocol previously described in detail [27,28]. Peak VO2 was expressed both as an absolute value and as a percentage of the predicted normal value [29].

2.3. Statistical analysis
The primary objective of this study was to assess the effects of carvedilol administration on LVEF, in diabetic compared to non-diabetic patients. The secondary objectives were to assess its tolerance and its effects on the other hemodynamic parameters, clinical symptoms and maximal exercise tolerance in diabetic compared to non-diabetic patients. On the basis of the results of previous studies [27], we calculated that the inclusion of at least 120 patients (60 in each group) would provide 90% power to detect an absolute difference of 5 units in the change from baseline of the LVEF between the diabetic and the non-diabetic patients with the diabetics showing a greater response, compared to the non-diabetics ({alpha}=0.05).

Results are expressed as mean±S.D. Baseline data in the two treatment groups were compared by t-test for continuous variables and by chi-square test for categorical variables. Changes from baseline were evaluated by paired t-test, within each group and by two-way analysis of variance (ANOVA), between the diabetic and the non-diabetic patients. A two-tailed P value <0.05 was considered significant. Cumulative survival estimates were calculated using the Kaplan–Meier method with differences between the survival curves assessed by the log-rank test.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Patient characteristics
Sixty-eight (35%) of the 193 consecutive patients studied had concomitant diabetes mellitus. Diabetes was treated with diet and oral hypoglycemic agents in 44 patients and with insulin (35±23 units/day) in the other 24. Antidiabetic treatment was stable, with no major change in either the agents or doses used in the 3 months before initiation of the beta-blocker treatment. Oral antidiabetic therapy consisted in glibenclamide, 5.3±1.6 mg/day, in 28 patients, gliclazide, 160 mg/day, in seven patients, clorpropamide, 500 mg/day in three patients and metformin+glibenclamide in the other four patients. Baseline characteristics of the patients with and without concomitant diabetes are shown in Table 1. Compared to non-diabetics, diabetics were older and had a lower peak VO2. The prevalence of patients with coronary artery disease tended to be greater among the diabetics, compared to the non-diabetics (46% vs. 34%, P=0.2). All other parameters, including functional class, measurements of left ventricular function, hemodynamic parameters and concomitant treatment were not significantly different between the two groups of patients. During the maintenance phase, non-diabetics and diabetics received mean doses of carvedilol of 40±21 mg daily and 40±13 mg daily, respectively.


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  		Table 1 Baseline characteristics

 
3.2. Effects of long-term carvedilol administration
Among the 193 patients studied, 22 (14 non-diabetics and eight diabetics) did not undergo the hemodynamic and clinical reassessment, due to death or cardiac transplantation (18 patients, 10 non-diabetics and eight diabetics), lack of compliance with the study protocol (3 non-diabetics) and withdrawal of β-blockade for bronchial asthma (one non-diabetic). The remaining 171 patients (111 non-diabetics and 60 diabetics) were reevaluated after 12 months of carvedilol treatment with maintenance doses.

The clinical laboratory, exercise, left ventricular function and hemodynamic parameters of the patients with and without concomitant diabetes, reassessed after long-term β-blocker therapy are shown in Tables 2–4. Compared to non-diabetics, diabetics had higher plasma glucose levels, a greater impairment of maximal exercise capacity and higher resting mean pulmonary artery pressure and pulmonary wedge pressure at baseline. These differences between the two groups persisted after long-term β-blockade.


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  		Table 2 Effects on laboratory data, left ventricular function, clinical status and exercise parameters

 


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  		Table 3 Hemodynamic responses at rest

 


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  		Table 4 Hemodynamic responses at peak exercise

 
Long-term carvedilol administration was associated with a significant improvement in LVEF and volumes, NYHA functional class and 6 min walk distance (Table 2), an increase in both the resting and peak exercise cardiac index, stroke volume index, stroke work index and a decline in heart rate, mean artery pulmonary pressure and pulmonary wedge pressure (all P<0.05 vs. baseline) (Tables 3 and 4). These changes were significant in both the non-diabetic and the diabetic patients, with the exception of the decline in the left ventricular end diastolic volume, which did not reach statistical significance in the diabetics. No significant difference in the magnitude of the changes caused by carvedilol was observed between non-diabetics and diabetics.

3.3. Adverse reactions
The dose of oral hypoglycemic agent or of insulin was increased during the first months of carvedilol treatment in eight diabetic patients (12%). However, only one patient (1.5%) had to be hospitalized for hyperglycemia. In all the cases, the insulin dose was adjusted with progressive normalization of the metabolic control without any change in concomitant β-blocker therapy. Hypoglycemic episodes were reported in five diabetic patients (7.3%). They were always well tolerated and never caused patient hospitalization.

The most common adverse reactions occurring during up-titration of carvedilol were worsening heart failure, which was observed in four non-diabetic (3%) and two diabetic (3%) patients and dizziness and/or symptomatic hypotension, which were observed in nine non-diabetic (7.2%) and four diabetic (5.9%) patients. Other side effects included symptomatic bradycardia, requiring pacemaker implantation in four non-diabetic (3.2%) and three diabetic (4.4%) patients, bronchial asthma in one (0.8%) non-diabetic patient and Raynaud's phenomenon in another non-diabetic patient (0.8%). Side effects led to permanent discontinuation of carvedilol in five patients, four for worsening heart failure and one for bronchial asthma. The four patients in whom β-blockade was discontinued for worsening heart failure had NYHA class IV symptoms at baseline and subsequently died. No significant difference in the incidence of any side effects was observed between non-diabetic and diabetic patients.

3.4. Follow-up
The duration of follow-up was 33±20 months. Overall, 21 non-diabetic patients (17%) and 21 diabetic patients (31%) died or underwent urgent transplantation. The cause of death was worsening heart failure in eight diabetic (12%) and nine non-diabetic (7%) patients and sudden death in eight diabetic (12%) and 12 non-diabetic (10%) patients. Urgent transplantation occurred in two diabetic patients (3%). Non-cardiac death occurred in three diabetic patients (4%) and in one patient after elective transplantation. Cumulative survival analysis showed a higher incidence of all-cause mortality in the diabetic patients, compared to the non-diabetics with 6 months, 1 year and 2 years mortality of 85, 79 and 76% in the diabetic patients and 96%, 92% and of 87% in the non-diabetic patients, respectively (P=0.01). The incidence of all-cause death and hospitalization did not reach statistical significance between the diabetics and the non-diabetics, although, there was a greater event rate in the diabetics (cumulative event free survival of 65%, 56% and 46% in the diabetics and of 80%, 70% and 60% in the non-diabetics, respectively).


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Diabetes mellitus is frequently associated with heart failure and is an independent risk factor for increased morbidity and mortality [3–7]. Although β-blockers may favorably counteract many of the untoward effects of diabetes [6], they may also worsen insulin sensitivity and hypoglycemic reactions [15,16]. In our study, we have shown that long-term carvedilol administration has a similar efficacy and tolerability in diabetic and non-diabetic patients. Our results are consistent with the results in the post-infarction trials [20–24] and with recent post-hoc analyses of placebo controlled trials in patients with chronic heart failure [25,30–32]. In our study, we did not include a placebo group for ethical reasons and thus, we could only compare the change from baseline between our patients with and without concomitant diabetes. However, the tolerability and the effects of carvedilol on the measurements of left ventricular function and functional capacity were studied more thoroughly in our study, compared to the multicenter trials. We have thus been able to show a similar tolerability and efficacy of carvedilol in patients with and without concomitant diabetes.

In our study, carvedilol administration was well tolerated, with no significant difference in the incidence of side effects in the diabetic compared to the non-diabetic patients. These results are consistent with previous studies [32,33] and may be ascribed to the ancillary properties of carvedilol, which unlike the traditional β-blockers has no untoward effects on insulin sensitivity and glycemic control [17–19]. However, it should also be noted that administration of the β1-selective agents metoprolol and bisoprolol has not been associated with any increase in the incidence of side effects in diabetic compared to non-diabetic patients [30,31]. It may be therefore concluded that diabetes mellitus should no longer be regarded as an absolute or relative contraindication to β-blocker therapy in patients with chronic heart failure.

In our study, the diabetic patients had a greater all-cause mortality with a similar incidence of death and hospitalizations, compared to the non-diabetic patients. These results are consistent with previous studies showing that diabetes is an independent risk factor of increased mortality in patients with heart failure [5–9]. The lack of a placebo group does not allow us to draw any conclusion regarding the effects of carvedilol on the prognosis of the diabetic, compared to the non-diabetic patients. In a re-analysis of the COPERNICUS trial, carvedilol has been associated with a similar risk reduction of all-cause mortality and mortality or hospitalization in the diabetic compared to the non-diabetic patients [32].

In conclusion, our study shows that carvedilol administration has similar beneficial effects on left ventricular function, resting and exercise hemodynamics and clinical conditions, with a similar good tolerability in patients with heart failure, with and without concomitant diabetes mellitus. Diabetes should not, therefore, be regarded as a relative contraindication to long-term carvedilol therapy in patients with chronic heart failure.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
{star} This paper was partially supported by CARIPLO funds from ‘Centro per lo studio del trattamento dello scompenso cardiaco’ of the University of Brescia.


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

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