CLINICAL STUDIES
Beta-blockade in heart failure
A comparison of carvedilol with metoprolol
John E. Sanderson, MD, FACC*,
Skiva K. W. Chan, RN*,
Gabriel Yip, MRCP*,
Leata Y. C. Yeung, RN, BSc*,
Kam W. Chan, FRCR ,
Kenneth Raymond, PhD and
Kam S. Woo, MD, FACC*
* Departments of Medicine and Therapeutics, Diagnostic Radiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Department of Organ Imaging, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Department of Pharmacy, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Manuscript received January 5, 1999;
revised manuscript received May 12, 1999,
accepted June 28, 1999.
Reprint requests and correspondence: Dr. J.E. Sanderson, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Clinical Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China.
jesanderson{at}cuhk.edu.hk
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Abstract
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OBJECTIVES
This study was performed to compare the long-term clinical efficacy of treatment with metoprolol versus carvedilol in patients with chronic heart failure.
BACKGROUND
Beta-adrenergic blockade is of proven value in chronic heart failure. Metoprolol, a selective beta-blocker, is widely used, but recent trials suggest carvedilol, a nonselective beta-blocker with alpha-1-receptor antagonist activity and antioxidant activities, is also effective. It is uncertain, however, if these additional properties of carvedilol provide further clinical benefit compared with metoprolol.
METHODS
In this randomized double-blind control trial, 51 patients with chronic heart failure and mean left ventricular (LV) ejection fraction of 26% ± 1.8% were randomly assigned treatment with metoprolol 50 mg twice daily or carvedilol 25 mg twice daily in addition to standard therapy after a four-week dose titration period for a total of 12 weeks. Response was assessed by a quality of life questionnaire, New York Heart Association class, exercise capacity (6-min walk test), radionucleotide ventriculography for LV ejection fraction, two-dimensional echocardiography measurement of LV dimensions and diastolic filling and 24-h electrocardiograph monitoring to assess heart rate variability.
RESULTS
Both carvedilol and metoprolol produced highly significant improvement in symptoms (p < 0.001), exercise capacity (p < 0.05) and LV ejection fraction (p < 0.001), and there were no significant differences between the two drugs. Carvedilol had a significantly greater effect on sitting and standing blood pressure, LV end-diastolic dimension and normalized the mitral E wave deceleration time.
CONCLUSIONS
Both metoprolol and carvedilol were equally effective in improving symptoms, quality of life, exercise capacity and LV ejection fraction, although carvedilol lowers blood pressure more than metoprolol.
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Abbreviations and Acronyms
| | ECG | = electrocardiograph | | LV | = left ventricular |
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There is increasing evidence that beta-adrenergic blockade is useful for patients with chronic heart failure. Several meta-analyses have provided evidence supporting favorable effects of ß-blockade on left ventricular (LV) ejection fraction and the combined risk of death and hospitalization for heart failure (1,2). Metoprolol was the main beta-blocker studied in the original trials (3–6), but a variety of selective and nonselective beta-blockers have been used subsequently (1,2). There are, to date, little data on the relative advantages or disadvantages of different beta-blockers in the treatment of chronic heart failure, although we have previously compared metoprolol with the vasodilating beta-blocker celiprolol (7). Carvedilol is an interesting drug in that it provides nonselective beta-adrenergic receptor antagonism (beta-1 and beta-2) but in addition has a alpha-1 adrenergic blocking action and a documented antioxidant activity (8–12). These additional actions of carvedilol may provide further clinical benefit for the patient. Therefore, we have carried out a randomized double-blind trial to compare carvedilol with metoprolol over a three-month period to determine their relative effectiveness on symptoms, exercise capacity, LV systolic and diastolic function and heart rate variability indices.
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Methods
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Trial design.
This was a randomized double-blind parallel group-controlled trial. Patients with typical symptoms of heart failure and reduced LV ejection fraction (<0.45) were recruited into the study. After baseline measurements, patients were randomized to receive treatment either with metoprolol or carvedilol. Both medications were in identical capsules. There was a four-week dose titration period increasing the dose of carvedilol from 3.125 to 25 mg twice daily and metoprolol from 6.25 to 50 mg twice daily. Doses were increased at weekly intervals. Maintenance of doses was continued for eight weeks (total of 12 weeks of treatment). At the end of 12 weeks, baseline measurements were repeated. Clinical assessment was carried out at 1, 2, 4 and 8 weeks. Compliance was checked by counting the remaining capsules at each visit.
Study objectives.
To compare the efficacy and tolerability of metoprolol and carvedilol by assessment of symptoms (using the Minnesota Quality of Life Heart Failure Questionnaire), exercise capacity (6-min walking test), LV ejection fraction (measured by radionucleotide ventriculography and echocardiography), LV diastolic function (by Doppler echocardiography) and heart rate variability by 24-h ambulatory electrocardiograph (ECG) monitoring. The primary end points were symptom score, exercise time and LV ejection fraction. The study had a 90% power to detect a 55% reduction in symptom score, a 20% increase in the 6-min walking time and a 12% increase in LV ejection fraction from baseline for each drug group, all of which would be considered clinically significant.
Study patients.
Patients with a clinical diagnosis of chronic heart failure who were on standard therapy with diuretics, digoxin and angiotensin-converting enzyme inhibitors and with a LV ejection fraction of <0.45 (by radionucleotide ventriculography) were recruited. Patients were excluded if they had significant valvular heart disease as the etiology of LV dysfunction, active myocarditis, unstable angina, a documented history of sustained ventricular tachycardia or symptomatic nonsustained ventricular tachycardia or second- or third-degree atrioventricular block. Patients with chronic obstructive lung diseases, asthma, long-term alcohol or drug abuse or chronic renal failure (serum creatine >200 µmol/liter), hepatic hematological, neurological or collagen vascular disease were excluded. All subjects gave written informed consent, and the study was approved by the Ethics Committee of the Faculty of Medicine, the Chinese University of Hong Kong.
Study measurements.
Baseline measurements included assessment of symptoms using the Minnesota Heart Failure Symptom Questionnaire, New York Heart Association (NYHA) class and routine clinical examination (pulse, heart rate, sitting and standing blood pressure, examination of jugular venous pressure, position of the apex beat and presence or absence of a heart murmur or lung rales). A 6-min corridor walk test was carried out. Two baseline walk tests were carried out and the results averaged. Routine two-dimensional Doppler echocardiography was performed with measurement of LV dimensions. Pulse-wave Doppler echocardiography was performed to assess mitral inflow velocities. The usual variables were measured: peak early mitral filling velocity (E wave), peak atrial filling velocity (A wave), ratio of the peak early and atrial filling velocities (E/A), deceleration time of the E wave (DT) and isovolumic relaxation time (IVRT), as previously described (13). Radionucleotide ventriculography was used to assess LV ejection fraction in the usual way. A 24-h ambulatory ECG monitoring was performed at baseline and at 12 weeks. Analysis was undertaken using the Marquette (Milwaukee, Wisconsin) MARS 8000 analyzer. Standard measurements of heart rate variability by spectral and time domain analyses were undertaken (14). Routine blood laboratory tests were performed at baseline, and at four and eight weeks.
Statistical analysis.
Differences between the treatment groups were carried out by repeated-measures analysis of variance for continuous variables (ANOVA) with Bartlets test with homogeneity variances and Tukey-Kramer multiple comparison test if p < 0.05, Friedman’s test for nonparametric data and Fisher exact test for differences between proportions. Differences between baseline and week 12 within groups were tested by paired t tests, and Wilcoxon matched pairs signed ranks test for nonparametric data. The results are expressed as mean ± SEM. Differences were considered significant if p < 0.05.
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Results
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Subjects.
Fifty-one patients with a mean LV ejection fraction of 26 ± 1.8% were recruited in the study, 26 receiving metoprolol and 25 receiving carvedilol. There were no significant differences in age, gender or other baseline characteristics (Table 1). The majority had idiopathic dilated cardiomyopathy (45%) with ischemic cardiomyopathy on the etiology in 22% and hypertensive heart disease in 33%. All but one patient were taking an angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist. The average daily dose of frusemide was similar in both groups. There were no significant differences between the two groups at baseline.
Withdrawals.
In the carvedilol group, five patients did not complete the study. Four patients were withdrawn because of worsening symptoms, in particular, weakness and dizziness. One patient was withdrawn because of the development of angioneurotic edema. In the metoprolol group, three patients were withdrawn, one because of increased breathlessness, who subsequently died. There were no differences between carvedilol and metoprolol (p = 0.46, Fisher exact test).
Symptoms.
The results of the symptom (quality of life) questionnaire score and assessment of NYHA functional class are shown in Table 2. Both drugs were associated with a highly significant reduction in symptom questionnaire score and NYHA class. However, there were no significant differences between metoprolol and carvedilol.
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Table 2 Effects of Metoprolol or Carvedilol on Symptoms, Exercise Capacity, Blood Pressure and Heart Rate (Mean ± SEM)
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Blood pressure and heart rate (table 2).
At 12 weeks, carvedilol produced a highly significant (p < 0.001) reduction in sitting and standing systolic and diastolic blood pressures compared with baseline. Metoprolol had no significant effect on sitting systolic or diastolic blood pressure or standing systolic blood pressure but had a mild effect on standing diastolic blood pressure. The differing effects on diastolic blood pressure between the two drugs were significant (p = 0.01). Both drugs had a highly significant effect on heart rate reducing the mean resting heart rate from 85 ± 2.52 to 64 ± 2 beats/min for metoprolol and 83 ± 2.7 to 65 ± 2.2 beats/min for carvedilol (both p < 0.001).
Exercise capacity (table 2).
Both drugs were associated with a significant improvement in exercise capacity as measured by the 6-min walk test. This effect appeared to be slightly greater with metoprolol than carvedilol, but the differences between the two drugs were not significant.
LV systolic function (table 3).
Both drugs produced a highly significant increase in LV ejection fraction (metoprolol 7 ± 1.9% and carvedilol 8 ± 2.1%), but there was no significant difference between the drugs. Carvedilol, but not metoprolol, reduced LV end-diastolic dimension significantly.
LV diastolic function (table 3).
Neither drug produced a significant change of peak mitral E wave velocity. Both carvedilol and metoprolol prolonged the deceleration time of the mitral E value towards normal, but this reached statistical significance only in the carvedilol group (p < 0.001) in whom the deceleration time was normalized. There was also a reduction in the E/A ratio, which was significant for both metoprolol and carvedilol.
Heart rate variability indices (table 4).
Apart from the predictable changes on average, minimum and maximum heart rate and NN, there were no significant changes in any of the time domain or spectral heart rate variability indices between baseline and week 12 for either metoprolol or carvedilol.
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Discussion
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In this three-month study comparing metoprolol and carvedilol in patients with chronic heart failure, we have demonstrated that both agents significantly improved symptoms (as judged by a Quality of Life Questionnaire and NYHA class), exercise capacity and LV ejection fraction. Carvedilol lowered resting and sitting blood pressure more than metoprolol and also reversed the shortening of the deceleration time of the mitral E wave more than metoprolol. However, apart from these differences, there were no other apparent advantages of carvedilol over metoprolol. Both drugs have been shown previously to improve symptoms and LV ejection fraction (1–11). However, the effect on exercise capacity has been variable. Most previous studies with metoprolol have shown an improvement in exercise capacity in the long term, but improvement in exercise capacity has not been a consistent feature in the larger trials of carvedilol (8). It has been suggested that improvement in exercise capacity may be greater with selective beta-1 receptor antagonists because the beta-2-adrenoreceptor-mediated vasodilatation on exercise is preserved. Although the increase in exercise capacity in our study was slightly greater with metoprolol, the difference was not significant, and both drugs significantly increased exercise capacity. Previous studies have used a variety of methods of assessing exercise capacity. The robustness of the 6-min walk test is improved if two baseline measurements are performed, as was done in this study (15).
Our results differ slightly from those of Gilbert et al. (16). In that study, the authors suggest that compared with metoprolol, carvedilol was associated with greater improvement in NYHA functional class, and there was a trend (all not significant) for carvedilol to produce a relatively greater improvement in LV ejection fraction, stroke volume and stroke work. However, that study, unlike ours, was not a randomized trial comparison of metoprolol against carvedilol but a comparison of two substudies from two different placebo-controlled trials, allowing for the possibility of considerable patient heterogeneity and bias.
Effect on blood pressure.
The greater effect on blood pressure by carvedilol is probably due to its alpha-adrenergic receptor antagonism properties. This effect on blood pressure was still apparent at 12 weeks, indicating that alpha receptor blockade is still operative after three-month therapy. In previous studies with alpha-blockers in heart failure, the benefits have not been sustained, due to the development of tolerance. Kukin et al. (17) were unable to demonstrate any benefit of combined therapy with doxazosin and metoprolol compared with metoprolol alone after three months of continuous treatment. However, in hypertension, Weber et al. (18) demonstrated that there was a chronic difference between carvedilol and metoprolol, and their results suggest that carvedilol’s vasodilatory action is not subject to the development of tolerance. Our study would support this view.
Diastolic function.
The reduction in E/A ratio by both metoprolol and carvedilol suggests that over the long term, both reduce the early filling pressure gradient across the mitral valve and hence velocity, that is, the filling pattern is less restrictive, although the fall in peak E wave velocity alone was not significant for either drug. The increased A wave velocity seen particularly with metoprolol suggests either an increased atrial contribution due to the prolongation of diastole consequent on the bradycardia, or improved atrial contractile function. Our result with metoprolol is similar to those of Andersson et al. (19), who also found that therapy with metoprolol was associated with a decrease in E-wave deceleration time, implying a less restrictive filling pattern. In contrast, Quaife et al. (20) found that carvedilol did not change various radionucleotide parameters of LV diastolic function, including peak filling rate and time to peak filling in patients with idiopathic or ischemic cardiomyopathy. It is difficult to explain the difference between these and our results. However, it is well known that the Doppler mitral flow parameters are influenced by changes in loading conditions (21,22), and the larger changes we detected with carvedilol are probably due to its greater effect on afterload and preload. This may explain carvedilol’s greater effect on the mitral deceleration time, although the differences were small, and there was also a trend for improvement with metoprolol. However, these changes in the mitral diastolic filling patterns may have clinical relevance in light of previous studies showing that a short deceleration time (a restrictive filling pattern) is associated with a worse prognosis (23–25). Furthermore, Little et al. (26) demonstrated that the deceleration time predicts LV chamber stiffness. In addition, carvedilol may, because of its alpha-antagonism, exert a greater effect on the extracellular matrix and chamber stiffness than metoprolol. Recent studies have shown that norepinephrine increases extracellular matrix via alpha-adrenoceptor stimulation in human vascular smooth muscle (27). The greater effect of carvedilol on the mitral deceleration time may reflect a greater effect on diastolic function and possibly, therefore, on mortality. Our study, of course, is too small to test a mortality effect of the two drugs, and this is currently being prospectively evaluated in the Carvedilol or Metoprolol European Trial (COMET).
Heart rate variability.
Neither carvedilol nor metoprolol significantly improved heart rate variability. In a previous study, we demonstrated that metoprolol did improve high-frequency power and baroreceptor function (28). However, in that study, the measurements were done over short 5- to 7-min recording periods during controlled respiration. In the UK-Heart Study (29), heart failure patients with SDNN <50-ms mortality had a significantly higher mortality. The majority of our patients had an SDNN of about 80 ms. However, we were unable to demonstrate any improvement in this value after treatment with either metoprolol or carvedilol.
Study limitations.
This study had a relatively small number of patients, and there is a possibility of a type II error. It was not powered to detect any differences in mortality and was designed to determine if there were any obvious or major differences in clinical efficacy, especially in terms of symptoms, quality of life and exercise capacity between the two drugs. To this extent, we used a wide range of well-validated techniques including the Minnesota Heart Failure Symptom Questionnaire and the 6-min walk test. Several studies have now demonstrated a clear independent inverse relation between the 6-min walk test and both mortality and morbidity (15). We did not have a placebo group in the study. At the time of planning this study, several larger scale studies had already confirmed the benefit of beta-blockade in chronic heart failure compared with placebo. Furthermore, in our previous study (7), there were no significant changes in symptoms or exercise capacity on LV ejection fraction over the 12-week study period in the placebo group. There was a nonsignificant trend for improvement of symptoms, but LV ejection fraction fell in direct contrast to the beta-blockade groups.
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Conclusions
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In this study, we have confirmed the beneficial effects of metoprolol and carvedilol in patients with chronic heart failure. We were unable to show any differences between carvedilol and metoprolol on symptoms, quality of life, exercise capacity or LV ejection fraction. Carvedilol did lower both systolic and diastolic blood pressure significantly more than metoprolol and normalized the mitral E wave deceleration time. It is possible that these additional effects on blood pressure and diastolic function, which may be mediated by alpha receptor blockade, will be translated into improved mortality and morbility in the longer term, but in terms of improving symptoms, exercise capacity or LV ejection fraction, the additional actions of carvedilol do not appear to provide any extra benefit compared with metoprolol.
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Footnotes
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This work was supported in part by a Research grant from Boehringer Mannheim (Mannheim, Germany).
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C. Maack, T. Elter, G. Nickenig, K. LaRosee, M. Crivaro, A. Stablein, H. Wuttke, and M. Bohm
Prospective crossover comparison of carvedilol and metoprolol in patients with chronic heart failure
J. Am. Coll. Cardiol.,
October 1, 2001;
38(4):
939 - 946.
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T. Ohtsuka, M. Hamada, G. Hiasa, O. Sasaki, M. Suzuki, Y. Hara, Y. Shigematsu, and K. Hiwada
Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy
J. Am. Coll. Cardiol.,
February 1, 2001;
37(2):
412 - 417.
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J. G. F. Cleland, M. L. Kukin, J. Kalman, R. H. Charney, D. K. Levy, C. Buchholz-Varley, O. N. Ocampo, and C. Eng
Are All {beta}-Blockers for Heart Failure the Same? Response
Circulation,
August 8, 2000;
102
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e41 - e42.
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M. Metra, R. Giubbini, S. Nodari, E. Boldi, M. G. Modena, and L. D. Cas
Differential Effects of {beta}-Blockers in Patients With Heart Failure : A Prospective, Randomized, Double-Blind Comparison of the Long-Term Effects of Metoprolol Versus Carvedilol
Circulation,
August 1, 2000;
102(5):
546 - 551.
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S. Wei, L. T. C. Chow, and J. E. Sanderson
Effect of carvedilol in comparison with metoprolol on myocardial collagen postinfarction
J. Am. Coll. Cardiol.,
July 1, 2000;
36(1):
276 - 281.
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Abstract
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