One of the most important predictors of prognosis in patients with congestive heart failure(CHF) is the degree of left ventricular (LV) dysfunction (1-4). Since 1975 (5), substantial evidence has been published that β-blockers improve LV dysfunction in patients with CHF.
Recently, Packer et al. (6) were the first to demonstrate that carvedilol reduced the risk for mortality in CHF patients who were treated with the usual background therapy, consisting of angiotensin-converting enzyme (ACE) inhibitors, diuretics, and digoxin. In contrast, previous studies with metoprolol and bisoprolol therapy in patients with idiopathic dilated cardiomyopathy (7,8) failed to demonstrate an improvement of survival by β-blocker therapy.
One of the possible mechanisms of this difference in survival might be a different degree of improvement of LV function by the β-blockers used. Therefore, the objective of our study was to evaluate the available literature on the effect of treatment with different β-blockers on the left ventricular ejection fraction (EF) at rest in patients with CHF.
The available literature was reviewed concerning the relation between the EF and the following β-blockers: metoprolol, carvedilol, bucindolol, atenolol, nebivolol, bisoprolol, and propranolol. The studies were identified using several combined search strategies: (a) conduction of a search from the MEDLINE database (January 1975 through June 1997) using the following key words: heart failure, β-blockers or β-adrenergic receptor blockers, and left ventricular ejection fraction; (b) using the key word combination of heart failure and ejection fraction, with the specific β-blockers as mentioned above; and (c) the reference lists of the articles obtained through the previous searches were screened for additional articles that might have been missed. Only articles in English were considered, and reviews or abstracts were discarded. Moreover, probable duplicates of patient findings by the same research group were also excluded. For inclusion in the analysis, the LVEF should have been tested by echocardiography, radionuclide ventriculography, or angiography.
Of the available studies, the etiology of LV dysfunction was noted and scored as idiopathic dilated cardiomyopathy(IDC) and/or due to coronary artery disease (CAD). Moreover, the duration of follow-up in months, the number of patients included, the baseline EF, and the EF after β-blocker therapy were noted. Finally, the degree of improvement and the statistical significance of this improvement were noted. In studies comparing β-blockers with placebo, the following procedure was applied. The baseline EF and the EF after treatment were given; the in(de)crease in EF in the placebo group was subtracted from the increase in the β-blocker group. Therefore, in these studies, ΔEF as presented in our tables may be different from the difference between EF at baseline and afterβ-blocker treatment. This approach was published previously (9).
Ejection increase by different β-blockers
Forty-one studies were found. Two of our studies using carvedilol in patients with LV dysfunction and hypertension were also included. The following tables show data only for patients receiving active treatment.
Table 1 shows the data for patients treated with metoprolol. Sixteen studies met our criteria. A total of 458 patients were studied. The weighted mean follow-up of the studies was 9.5 months. The weighted mean baseline EF was 24% and increased to 34%. The improvement in EF (after correction for the EF change in possible placebo groups) was 7.4 EF units, with a range of 3-16%.
Table 2 shows the data for patients treated with carvedilol. Fourteen studies met our criteria. A total of 1,030 patients were studied. The weighted mean follow-up of the studies was 7 months. Baseline EF was on average 24% and increased to 32% after treatment with β-blockers. After correction for possible placebo studies, the EF increased 5 EF units. The change in EF in patients with mild LV dysfunction and hypertension was similar to that of the other included studies.
Table 3 shows the data for patients treated with bucindolol. Seven studies met our criteria. A total of 199 patients were studied. The weighted mean follow-up of the studies was 4 months. Baseline EF was similar to studies with otherβ-blockers, 23%, and increased to 29% after treatment. The increase in EF units was on average 4.6%.
Table 4 shows the combined data for patients treated with atenolol, nebivolol, and propranolol. The data were pooled because of the small number of patients and because the increase in EF after treatment was similar to that observed other studies.
In total, 98 patients were studied, with a weighted follow-up of 13 months. Baseline EF was on average 23% and was 32% after treatment. The increase in EF units, after correction for placebo changes, was 8.6%. Figure 1 shows the weighted mean ejection fraction of the several β-blockers.
Idiopathic vs. ischemic cardiomyopathies
Because previous studies (10-12) have shown that with β-blocker therapy the EF increase in patients with idiopathic cardiomyopathy was larger than in patients with ischemic cardiomyopathy, we further analyzed the studies in which only patients with idiopathic or ischemic cardiomyopathy were included.
Eleven studies encompassing 361 patients with idiopathic dilated cardiomyopathy were examined. The weighted mean increase in EF units was 8.5% with a range of 3-16%.
Eleven studies were found for 269 patients with ischemic cardiomyopathy. The mean increase in EF units was 6% with a range of 3-11%. Although no statistics could be performed on the available data, the difference is obviously insignificant.
We also analyzed by linear regression if there was a positive relation between the duration of β-blocker treatment and the increase in EF. No statistical significance was found.
The current analysis shows that (a) in almost all studies a significant increase in the LVEF occurred after treatment with β-blockers, (b) differences among the variousβ-blockers used are small and probably clinically insignificant, and (c) the data suggest that there is only a small difference between patients with idiopathic vs. ischemic cardiomyopathy, which is also probably clinically insignificant.
However, this type of analysis does not allow accurate statistical comparison of the variousβ-blockers. For the latter, a meta-analysis with available data on individual patients is needed. Nevertheless, the differences in improvement are small and, importantly, mean baseline EF values for the different β-blocker studies are almost identical.
Suggested mechanisms of the beneficial effects of β-blocker treatment include blocking the adverse impact of high, possibly cardiotoxic, levels of catecholamines (13-15), and counteracting the shortened diastolic filling time, vasoconstriction by catecholamines, and reninangiotensin-aldosterone system (RAAS) activation (14-16) and increase of metabolic demand, all acting adversely on LV function in the failing heart. Moreover, β-blockers upregulate β-receptors, except for carvedilol (17). Our analysis suggests that the combined effects of these mechanisms on LV function was no different between patients with ischemic and idiopathic dilated cardiomyopathy.
Despite the same improvement in ejection fraction, studies with carvedilol (6) have shown that there is a substantial reduction in mortality. This is in contrast to the mortality studies using metoprolol and bisoprolol (7,8). This suggests that the magnitude of increase in EF by the different β-blockers is unrelated to the improved survival. Possible explanations for the beneficial effect of carvedilol include the additional effects of carvedilol and differences in sample size, as discussed by Packer et al. (6).
Additional effects of carvedilol include α1-blockade and antioxidant effects (6,18-21). In addition, the sample size of the carvedilol study was significantly larger than that of the MDC and CIBIS studies. Ongoing, large-scale, placebo-controlled multicenter mortality studies with metoprolol may provide the answer to the question of whether the specific effects of carvedilol are responsible for the mortality reduction or whether mortality reduction is a general β-blocker effect.
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Proceedings of a symposium held in Apeldoorn, The Netherlands May 31, 1997