Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: Results of a meta-analysis

doi:10.1067/mhj.2001.115584

American Heart Journal

Volume 141, Issue 6, June 2001, Pages 899-907

https://doi.org/10.1067/mhj.2001.115584 Get rights and content

Abstract

Background Both metoprolol and carvedilol improve cardiac function and prolong survival in patients with heart failure. Carvedilol has broader antiadrenergic effects than metoprolol, but it is not clear whether this characteristic is associated with greater benefits on cardiac function during long-term treatment. Study Design We performed a meta-analysis of all 19 randomized controlled trials of carvedilol or metoprolol that measured left ventricular ejection fraction before and after an average of 8.3 ± 0.1 months of treatment in 2184 patients with chronic heart failure. The mean daily doses were 58 ± 1 mg of carvedilol and the equivalent of 162 ± 1 mg of extended-release metoprolol. In the 15 placebo-controlled trials, the mean ejection fraction increased more in the trials of carvedilol than in the trials of metoprolol (placebo-corrected increases of +0.065 and +0.038, respectively), P = .0002. In the 4 active-controlled trials that compared metoprolol directly with carvedilol, the mean ejection fraction also increased more in the carvedilol groups than in the metoprolol groups (+0.084 on carvedilol and +0.057 on metoprolol, respectively), P = .009. The difference in favor of carvedilol in the active-controlled trials was nearly identical to the difference observed in the placebo-controlled trials and was apparent in patients with and without coronary artery disease. Conclusion Long-term treatment with carvedilol produces greater effects on left ventricular ejection fraction than metoprolol when both drugs are prescribed in doses similar to those that have been shown to prolong life. (Am Heart J 2001;141:899-907.)

Section snippets

Methods

We carried out an extensive search of all controlled trials with metoprolol or carvedilol in heart failure by performing a MEDLINE search with the following key words: β-blockers, congestive heart failure, and human. The search was carried out independently by 2 of the authors (G. V. A. and M. P.). The trials obtained by this search were supplemented by additional information obtained from the reference lists of published articles.

Results

Nineteen clinical trials21, 22, 23, 24, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 with carvedilol or metoprolol (or both) in heart failure met the criteria for inclusion in the current meta-analysis (Table I).

Discussion

The data and analyses summarized in the current article demonstrate that carvedilol produces greater increases in left ventricular ejection fraction than metoprolol does when the 2 drugs are used for the treatment of chronic heart failure. The difference in the effects of the 2 β-blockers was apparent both in placebo-controlled trials (which compared each drug with placebo) and in active-controlled trials (which directly compared the 2 drugs with each other); more than 2000 patients were

References (57)

M Packer
Beta-adrenergic blockade in chronic heart failure: principles, progress, and practice
Prog Cardiovasc Dis
(1998)
EH Ohlstein et al.
Carvedilol inhibits endothelin-1 biosynthesis in cultured human coronary artery endothelial cells
J Mol Cell Cardiol
(1998)
SA Hall et al.
Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade
J Am Coll Cardiol
(1995)
EJ Eichhorn et al.
Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study
J Am Coll Cardiol
(1994)
JN Cohn et al.
Safety and efficacy of carvedilol in severe heart failure
J Card Fail
(1997)
R DerSimonian et al.
Meta-analysis in clinical trials
Controlled Clin Trials
(1986)
HC Bucher et al.
The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials
J Clin Epidemiol
(1997)
M Metra et al.
Effects of short- and long-term carvedilol administration on rest and hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy
J Am Coll Cardiol
(1994)
SL Olsen et al.
Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study
J Am Coll Cardiol
(1995)
M Guazzi et al.
Pulmonary function, cardiac function, and exercise capacity in a follow-up of patients with congestive heart failure treated with carvedilol
Am Heart J
(1999)

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Our understanding of the factors associated with improvement of LVEF and a heart failure with improved EF (HFimpEF) phenotype remains incomplete.
We conducted a retrospective study using a national database of patients followed in the Veterans Affairs (VA) health system with serial assessment of left ventricular ejection fraction (LVEF) by echocardiography. We identified US veterans with a new diagnosis of heart failure with: (i) LVEF of <40 % in the 12 months prior to diagnosis, and (ii) follow-up LVEF assessment at least 6 months after their diagnosis. We defined HFimpEF as a final LVEF of ≥40 %.
Among the 106,414 US veterans with an initial LVEF of <40 % in this analysis, 39,994 (37.6 %) had a final EF of >40 % after a median follow up of 5 years. Multivariate regression analysis identified several factors that were independently associated with LVEF improvement including female sex, younger age, higher BMI, and a history of specific comorbid conditions such as hypertension, valve disease, atrial fibrillation, connective tissue disease, liver disease, and malignancy (p < 0.001). Conversely, a history of ischemic heart disease and peripheral arterial disease, as well as specific racial backgrounds (Black and Hispanic) were associated with lower rates of LVEF improvement. The model c-statistic for predicting LVEF improvement was 0.70.
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Citation Excerpt :
Although many large randomized trials found improved long-term survival for HF patients on β-blockers, the MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure) trial and RESOLVD (Randomized evaluation of strategies for left ventricular dysfunction) pilot study found that treatment with metoprolol for 6 months actually led to decreased LV chamber volumes and increased LVEF. Carvedilol elicits a similar response.15,16 The REVERT (REversal of VEntricular Remodeling with Toprol-XL) trial found that metoprolol’s reverse remodeling effect was most evident in patients with mild LV dilation and no advanced HF symptoms.
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^☆: Reprint requests: James E. Udelson, MD, Division of Cardiology, Tufts University School of Medicine, Boston, MA 02111.

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Congestive Heart FailureComparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: Results of a meta-analysis☆

Abstract

Section snippets

Methods

Results

Discussion

Prog Cardiovasc Dis

J Mol Cell Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Card Fail

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J Clin Epidemiol

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Congestive Heart Failure
Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: Results of a meta-analysis☆

Acute effects of β₁-selective and nonselective β-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure

β₂-Adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis