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Long-term carvedilol treatment is more effective than metoprolol for improving the cardiac function of people with heart failure
TREATMENT
Long-term carvedilol treatment is more effective than metoprolol for improving the cardiac function of people with heart failure Abstracted from: Packer M, Antonopoulos GV, Berlin JA, Chittans J, Konstam MA, Udelson JE. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis. Am Heart J. 2001;141:899^907.
BACKGROUND Di¡erent beta-blockers may have varying e¡ects on heart failure prognosis. Metoprolol and carvedilol both improve cardiac function and prolong survival in people with heart failure. Carvedilol has broader antiadrenergic e¡ects but it is not clear whether this is associated with di¡erent long-term e¡ects on cardiac function. OBJECTIVE To compare the long-term e¡ects of carvedilol and metoprolol treatment on the left ventricular ejection fraction of those with chronic heart failure. DESIGN Meta-analysis. SEARCH STRATEGY MEDLINE search and scanning of bibliographies. There was no attempt to include unpublished literature. INCLUSION/EXCLUSION CRITERIA Randomized controlled trials of carvedilol or metoprolol vs placebo; or carvedilol vs metoprolol for people with
heart failure. Studies were excluded if they did not provide left ventricular ejection fraction measurements before and after intervention or had treatment periods shorter than 3 months. Nineteen studies were included, four directly comparing carvedilol and metoprolol.
DATA SYNTHESIS 2184 people with chronic heart failure (most NYHA class II or III symptoms) were treated for an average of 8.3 months. Mean daily dose was 58 mg carvedilol or 162 mg extended release metoprolol.
MAIN RESULTS In both placebo-controlled and direct comparison trials the mean ejection fraction increased more with carvedilol than metoprolol (both po0.009) (seeTable 1).
AUTHORS’ CONCLUSIONS Compared to metoprolol, carvedilol is associated with greater increases in cardiac function (ejection fraction) for people with chronic heart failure.
Table 1 Mean ejection fraction increase in heart failure patients treated with placebo, metoprolol or carvedilol Placebo
Carvedilol
Metoprolol
Adjusted increase attributable to carvedilol compared with metoprolol or placebo
Four trials comparing carvedilol vs metoprolol
F
0.08970.002
0.05570.002
Nine trials comparing placebo vs carvedilol Six trials comparing placebo vs metoprolol
0.01270.001 0.02570.001
0.07970.001 F
F 0.06370.002
0.02970.011 (P=0.009) 0.02870.007 F
Note:Figures represent mean 7 standard deviation.
1361-2611/02/$ - see front matter & 2002 Elsevier Science Ltd. All rights reserved doi:10.1054/ebcm.457, available online at http://www.idealibrary.com.on
Evidence-based Cardiovascular Medicine (2002) 6, 75^76
75
Commentary Three beta-blockers have been found to reduce mortality in people with chronic heart failure: metoprolol, bisoprolol and carvedilol. Metoprolol and bisoprolol are b1 selective receptor antagonists, while carvedilol blocks all three adrenergic receptors (a1, b1, and b2). It is unknown whether the additional blocking actions of carvedilol make a difference. Packer and colleagues try to answer this question, with respect to left ventricular ejection fraction. They found that carvedilol improves ejection fraction marginally more than metoprolol, by about 3%. The studies measured ejection fraction in a variety of ways. The most accurate method is magnetic resonance imaging. One recent study (not included in the meta-analysis) used this technique to measure the effect of metoprolol on left ventricular size and function.1 Metoprolol produced an absolute increase in left ventricular ejection fraction of 7% above placebo.This compares to a 3.8 % increase in the meta-analysis of the placebo-controlled trials and 5.5% in the direct comparison trials. It is possible that all previous trials have slightly underestimated the real increase in ejection fraction. The next, and perhaps more important, question is whether the observed increase in ejection fraction will translate into reduced mortality. There may be a dissociation between improvements in ejection fraction and mortality since the time sequence of improvement in ejection fraction is not known. None of the studies reviewed looked at sequential changes in ejection fraction between 3 months and12 months.The duration of treatment and the period of assessment in these trials varied considerably from 3 months to 14 months. It is possible that there is early improvement of the ejection fraction, which then levels off. In contrast, mortality curves from the large-scale trials have found gradual separation of the treatment and placebo groups. If the observed effects of carvedilol on ejection fraction reflect a true difference, how is it related to the additional properties of carvedilol? The simplest explanation is that cardevilol antagonises the a-receptor and reduces afterload compared with meto-
76
Evidence-based Cardiovascular Medicine (2002) 6, 75^76
prolol. Intrinsic actions on the myocardium are a less likely possibility, although carvedilol does have anti-oxidant and antiproliferative actions.2 The clinical significance of the a-blocking effect remains uncertain. It is likely that b1 receptor blockade is more important because of its impact on heart rate and norepinephrine-induced cell death. This meta-analysis only assessed ejection fraction. Effects on functional outcomes such as exercise capacity have not been examined. In a study by Metra and colleagues metoprolol improved exercise capacity more than carvedilol.3 A similar trend was found in a study conducted by our team.4 The results of the ongoing COMET trial, a European study that examines effects on mortality of cardevilol vs metoprolol, are also awaited with interest. John E Sanderson The Chinese University of Hong Kong Prince of Wales Hospital Hong Kong
Literature cited 1. Groenning BA, Nilsson JC, Sondergaard L, et al. Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol 2000; 36: 2072^2080. 2. Wei S, Chow LTC, Sanderson JE. Effect of carvedilol in comparison with metoprolol on myocardial collagen postinfarction. J Am Coll Cardiol 2000; 36: 276 ^281. 3. Metra M, Giubbini R, Nodari S, et al. Differential effects of b-blockers in patients with heart failure. A prospective randomised double blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation 2000; 102: 546 ^551. 4. Sanderson JE, Chan SKW, Yip G, et al. Beta-blockade in heart failure. A comparison of carvedilol with metoprolol. J Am Coll Cardiol 1999; 34: 1522^1528.
Long-term carvedilol treatment is more effective than metoprolol for improving the cardiac function of people with heart failure Abstracted from: Packer M, Antonopoulos GV, Berlin JA, Chittans J, Konstam MA, Udelson JE. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis. Am Heart J. 2001;141:899^907.
BACKGROUND Di¡erent beta-blockers may have varying e¡ects on heart failure prognosis. Metoprolol and carvedilol both improve cardiac function and prolong survival in people with heart failure. Carvedilol has broader antiadrenergic e¡ects but it is not clear whether this is associated with di¡erent long-term e¡ects on cardiac function. OBJECTIVE To compare the long-term e¡ects of carvedilol and metoprolol treatment on the left ventricular ejection fraction of those with chronic heart failure. DESIGN Meta-analysis. SEARCH STRATEGY MEDLINE search and scanning of bibliographies. There was no attempt to include unpublished literature. INCLUSION/EXCLUSION CRITERIA Randomized controlled trials of carvedilol or metoprolol vs placebo; or carvedilol vs metoprolol for people with
heart failure. Studies were excluded if they did not provide left ventricular ejection fraction measurements before and after intervention or had treatment periods shorter than 3 months. Nineteen studies were included, four directly comparing carvedilol and metoprolol.
DATA SYNTHESIS 2184 people with chronic heart failure (most NYHA class II or III symptoms) were treated for an average of 8.3 months. Mean daily dose was 58 mg carvedilol or 162 mg extended release metoprolol.
MAIN RESULTS In both placebo-controlled and direct comparison trials the mean ejection fraction increased more with carvedilol than metoprolol (both po0.009) (seeTable 1).
AUTHORS’ CONCLUSIONS Compared to metoprolol, carvedilol is associated with greater increases in cardiac function (ejection fraction) for people with chronic heart failure.
Table 1 Mean ejection fraction increase in heart failure patients treated with placebo, metoprolol or carvedilol Placebo
Carvedilol
Metoprolol
Adjusted increase attributable to carvedilol compared with metoprolol or placebo
Four trials comparing carvedilol vs metoprolol
F
0.08970.002
0.05570.002
Nine trials comparing placebo vs carvedilol Six trials comparing placebo vs metoprolol
0.01270.001 0.02570.001
0.07970.001 F
F 0.06370.002
0.02970.011 (P=0.009) 0.02870.007 F
Note:Figures represent mean 7 standard deviation.
1361-2611/02/$ - see front matter & 2002 Elsevier Science Ltd. All rights reserved doi:10.1054/ebcm.457, available online at http://www.idealibrary.com.on
Evidence-based Cardiovascular Medicine (2002) 6, 75^76
75
Commentary Three beta-blockers have been found to reduce mortality in people with chronic heart failure: metoprolol, bisoprolol and carvedilol. Metoprolol and bisoprolol are b1 selective receptor antagonists, while carvedilol blocks all three adrenergic receptors (a1, b1, and b2). It is unknown whether the additional blocking actions of carvedilol make a difference. Packer and colleagues try to answer this question, with respect to left ventricular ejection fraction. They found that carvedilol improves ejection fraction marginally more than metoprolol, by about 3%. The studies measured ejection fraction in a variety of ways. The most accurate method is magnetic resonance imaging. One recent study (not included in the meta-analysis) used this technique to measure the effect of metoprolol on left ventricular size and function.1 Metoprolol produced an absolute increase in left ventricular ejection fraction of 7% above placebo.This compares to a 3.8 % increase in the meta-analysis of the placebo-controlled trials and 5.5% in the direct comparison trials. It is possible that all previous trials have slightly underestimated the real increase in ejection fraction. The next, and perhaps more important, question is whether the observed increase in ejection fraction will translate into reduced mortality. There may be a dissociation between improvements in ejection fraction and mortality since the time sequence of improvement in ejection fraction is not known. None of the studies reviewed looked at sequential changes in ejection fraction between 3 months and12 months.The duration of treatment and the period of assessment in these trials varied considerably from 3 months to 14 months. It is possible that there is early improvement of the ejection fraction, which then levels off. In contrast, mortality curves from the large-scale trials have found gradual separation of the treatment and placebo groups. If the observed effects of carvedilol on ejection fraction reflect a true difference, how is it related to the additional properties of carvedilol? The simplest explanation is that cardevilol antagonises the a-receptor and reduces afterload compared with meto-
76
Evidence-based Cardiovascular Medicine (2002) 6, 75^76
prolol. Intrinsic actions on the myocardium are a less likely possibility, although carvedilol does have anti-oxidant and antiproliferative actions.2 The clinical significance of the a-blocking effect remains uncertain. It is likely that b1 receptor blockade is more important because of its impact on heart rate and norepinephrine-induced cell death. This meta-analysis only assessed ejection fraction. Effects on functional outcomes such as exercise capacity have not been examined. In a study by Metra and colleagues metoprolol improved exercise capacity more than carvedilol.3 A similar trend was found in a study conducted by our team.4 The results of the ongoing COMET trial, a European study that examines effects on mortality of cardevilol vs metoprolol, are also awaited with interest. John E Sanderson The Chinese University of Hong Kong Prince of Wales Hospital Hong Kong
Literature cited 1. Groenning BA, Nilsson JC, Sondergaard L, et al. Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol 2000; 36: 2072^2080. 2. Wei S, Chow LTC, Sanderson JE. Effect of carvedilol in comparison with metoprolol on myocardial collagen postinfarction. J Am Coll Cardiol 2000; 36: 276 ^281. 3. Metra M, Giubbini R, Nodari S, et al. Differential effects of b-blockers in patients with heart failure. A prospective randomised double blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation 2000; 102: 546 ^551. 4. Sanderson JE, Chan SKW, Yip G, et al. Beta-blockade in heart failure. A comparison of carvedilol with metoprolol. J Am Coll Cardiol 1999; 34: 1522^1528.