(Circulation. 2001;103:e118.)
© 2001 American Heart Association, Inc.
Correspondence |
ß-Blockade in Chronic Heart Failure
Department of Cardiology, Thoraxcenter, University Hospital Groningen, Groningen, the Netherlands
To the Editor:
We read with great interest the article by Metra et
al1 that was recently
published in the Journal. Although ß-blockade in chronic heart
failure (CHF) emerged as a powerful treatment modality, it remains
unclear whether there is a difference between the various agents, such
as the ß1-selective blockers bisoprolol and
metoprolol and the nonselective ß-blocker carvedilol. The authors
compared response to carvedilol or metoprolol by measuring various
clinical parameters, such as left ventricular
ejection fraction (LVEF) and peak
O2.
They found that both carvedilol and metoprolol improved these
parameters but that carvedilol did so primarily for LVEF
and metoprolol for peak
O2.
This is an interesting but somewhat contradictory finding that suggests
a possible difference in the working profile of these 2
compounds.
There are 2 assertions in this article that are of concern
to us. First, the authors chose LVEF as their primary end point.
Because LVEF increased more with carvedilol, the authors conclude that
carvedilol improves cardiac performance to a greater extent
than metoprolol. However, this may be overstated, because the overall
performance of the patients improved more with metoprolol, as
reflected by a larger increase in peak
O2.
The authors do not discuss this striking paradox. Currently, mortality
is generally considered the most powerful end point in CHF trials. Peak
O2
has been found to be one of the strongest predictors of mortality in
CHF.2 Obviously, serial
measurements of LVEF have additional prognostic value, but it must be
mentioned that in the V-HEFT II
study,3 the treatment
arm that improved LVEF most (hydralazine/isosorbide dinitrate)
was least beneficial with regard to mortality.
Second, the authors repeatedly adduce a difference in the antiadrenergic activity of the 2 drugs to explain the differences they found. Although this may have been established in earlier work,4 no data are presented in the present study to support this statement. In particular, no baseline or follow-up neurohormonal assessments were made that could have confirmed an increased antiadrenergic activity of carvedilol. Moreover, ß-receptor density was restored better by metoprolol,4 indicating that ß1-receptor–specific blockade could be more profound with metoprolol.
In conclusion, although small-scale studies such as the one by Metra et al1 are important, no definite statements on the superiority of either treatment can be made pending the results of large-scale head-to-head comparisons. Thus, we eagerly await the results of the Carvedilol and Metoprolol European Trial (COMET).5
References
-
Metra M,
Giubbini R, Nodari S, et al. Differential effects of ß-blockers in
patients with heart failure: a prospective, randomized, double-blind
comparison of the long-term effects of metoprolol versus carvedilol.
Circulation. 2000;102:546–551.
[Abstract/Free Full Text]
-
Van Den Broek SAJ,
Van Veldhuisen DJ, De Graeff PA, et al. Comparison between New York
Heart Association classification and peak oxygen consumption in the
assessment of functional status and prognosis in patients with chronic
heart failure secondary to ischemic or idiopathic
cardiomyopathy.
Am J Cardiol. 1992;70:359–363.[Medline]
[Order article via Infotrieve]
-
Cintron G, Johnson
G, Francis G, et al. Prognostic significance of serial changes in left
ventricular ejection fraction in patients with congestive
heart failure. Circulation.
1993;87(suppl VI):VI-17–VI-23.
-
Gilbert EM,
Abraham WT, Olsen S, et al. Comparative hemodynamic,
left ventricular functional, and
antiadrenergic effects of chronic treatment with
metoprolol versus carvedilol in the failing heart.
Circulation. 1996;94:2817–2825.
[Abstract/Free Full Text]
-
McGowan J, Murphy
R, Cleland JGF. Carvedilol for heart failure: clinical trials in
progress. Heart Fail Rev. 1999;4:89-95.
Response
Department of Cardiology, University of Brescia, Brescia, Italy
We compared the long-term effects of metoprolol and
carvedilol in patients with chronic heart failure. Carvedilol caused a
larger increase in left ventricular ejection fraction and
exercise stroke volume index, with a greater reduction in mean
pulmonary artery pressure and pulmonary wedge
pressure.R1 In contrast,
metoprolol caused a greater improvement in maximal functional capacity.
However, the 2 ß-blockers improved submaximal functional capacity and
symptoms to a similar degree. The lack of increase in peak
O2
with carvedilol should be ascribed to its greater negative chronotropic
activity, which hindered a sufficient increase in cardiac output and
therefore in peak
O2,
despite the improvement in stroke volume. These data are in accordance
with an analysis showing a significant inverse relationship
between the percent change in peak exercise heart rate and the change
in maximal functional capacity after different ß-blockers in patients
with heart
failure.R2
Peak exercise heart rate is an accurate measure of the cardiac response to sympathetic stimulation. Thus, the greater reduction in peak exercise heart rate with carvedilol is consistent with its greater antiadrenergic activity,R3 and this might explain both the lack of change in maximal functional capacity and the greater improvement in left ventricular function. The lack of ß1-receptor upregulation after carvedilol is caused by its atypical binding characteristicsR4 and should not be regarded as an index of a reduced beneficial effect.
The size of our study population did not allow any inference
regarding the effects of the 2 ß-blockers on prognosis. Left
ventricular ejection fraction and peak
O2
are both important and independent prognostic parameters.
Thus, we agree that the clinical significance of the differences
observed may be shown only by a multicenter trial like the Carvedilol
and Metoprolol European Trial (COMET).
References
-
Metra M,
Giubbini R, Nodari S, et al. Differential effects of ß-blockers in
patients with heart failure: a prospective, randomized, double-blind
comparison of the long-term effects of metoprolol versus carvedilol.
Circulation. 2000;102:546–551.
-
Metra M, Nodari S,
D’Aloia A, et al. Effects of neurohumoral antagonism on symptoms and
quality of life in heart failure. Eur
Heart J. 1998;19(suppl
B):B25–B35.
-
Gilbert EM,
Abraham WT, Olsen S, et al. Comparative hemodynamic,
left ventricular functional, and
antiadrenergic effects of chronic treatment with
metoprolol versus carvedilol in the failing heart.
Circulation. 1996;94:2817–2825.
-
Yoshikawa T, Port
JD, Asano K, et al. Cardiac adrenergic receptor effects of carvedilol.
Eur Heart J. 1996;17(suppl B):8–16.
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