(Circulation. 2000;102:484.)
© 2000 American Heart Association, Inc.
Editorial |
What Type of ß-Blocker Should Be Used to Treat Chronic Heart Failure?
From the Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO 80262
Correspondence to Michael R. Bristow, MD, PhD, the Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO 80262.
Key Words: Editorials • heart failure • receptors, adrenergic, beta • hemodynamics
The success of ß-blocking agents in treating mild to
moderate heart failure has generated a debate over whether the salutary
results are strictly a class effect caused by
ß1-adrenergic receptor antagonism or if
additional pharmacological properties of some compounds increase the
efficacy inherent in all agents that block
ß1-receptors. The diverse adrenergic receptor
activities of ß-blocking agents that have been used successfully to
treat chronic heart failure, the emerging role of the various
adrenergic receptor pathways in the mediation of
cardiomyopathic phenotypes in model systems
(recently reviewed in Circulation1 ), and the
vigor of pharmaceutical company scientific marketing all contribute to
the legitimacy and decibel level of the discussion. The original,
largely theoretical arguments2 3 4 have led to increasingly
more rigorous tests of the hypothesis that clinically important
differences exist among these agents. In this issue of
Circulation, Metra et al5 report the
largest of these tests to date. They provide a direct comparison of the
of the ß1-adrenergic-receptor–selective,
"second generation" ß-blocker metoprolol with the nonselective
ß/
-blocker, "third generation" compound carvedilol.
Metra et al5 measured left ventricular (LV) functional and hemodynamic effects in 150 subjects with heart failure who were prospectively randomized 1:1 to the recommended doses of each agent. Previous, smaller studies had reported either subtle differences in favor of carvedilol4 6 or no difference7 between the 2 agents. Their data5 indicate that compared with metoprolol, carvedilol provides, as expected, a greater degree of ß-blockade. Also, as expected and as previously reported in individual clinical trials,8 9 metoprolol produced a greater improvement in maximal exercise than carvedilol, which is likely related to the lower degree of ß-blockade. Most importantly, carvedilol provided a greater degree of improvement in LV function, which was the primary end point of the study.5 Although no differences existed between the 2 agents in the measured clinical end points,5 the sample size was not large enough to detect such differences.
The differences in LV functional improvement in favor of carvedilol in this trial5 included a change in LV ejection fraction (EF) of 10.9 EF units, compared with 7.2 EF units for metoprolol, and greater degrees of improvement in numerous exercise functional indices. Could the difference in LVEF response have been due to the loading condition changes produced by the ß-blocker/vasodilator carvedilol compared with the nonvasodilator compound metoprolol? This is not likely, because systemic vascular resistance and mean arterial pressure did not change in either group, and the slightly greater reduction in pulmonary wedge pressure noted in the carvedilol group would tend to reduce LVEF, not increase it. Moreover, the 2 treatment arms were exceptionally well balanced for baseline factors that can or could influence the effects of ß-blockers on myocardial function, including the percentage of ischemic/nonischemic cardiomyopathy, degree of LV dysfunction, age, sex, and New York Heart association class. Therefore, the data are consistent with improvements in intrinsic systolic LV function by both compounds, with quantitatively greater effects observed in the carvedilol group. Moreover, these quantitatively different effects occurred at respective target or actual administered doses (49 mg/d for carvedilol and 124 mg/d for metoprolol) that are as high or higher than doses that have been used in previous trials and that are, in each case, probably close to the maximum tolerated doses of each agent in heart failure patients.
The greater degree of ß-blockade produced by carvedilol, as assessed
by a greater inhibition of exercise heart rate,5 is not
surprising. This could be predicted from the differences in the
pharmacology of the 2 agents1 and from previously reported
comparisons of the relative degree of ß-blockade conferred by each
agent using dobutamine dose-response curves.10
In addition to being a potent ß1-adrenergic
receptor blocking agent with an 
12-fold higher affinity than
metoprolol for ß1-receptors, carvedilol at
target doses blocks ß2- and
1-receptors and mildly lowers cardiac
adrenergic drive.1 4 Carvedilol also has the additional
unique property of not up-regulating3 4 down-regulated
ß1-adrenergic receptors, as does
metoprolol.3 4 11 12 The result is a "more
comprehensive" degree of adrenergic inhibition.1 This
explains why in Metra et al’s study5 and in previous
trials,8 9 13 14 15 subjects treated with metoprolol tend to
have better maximal exercise responses than subjects treated with
carvedilol or bucindolol, because the maximal exercise response in
heart failure subjects is heart rate–dependent. However, as again
demonstrated in the Metra et al trial,5 the greater degree
of ß-blockade delivered by the standard target doses of carvedilol
does not seem to compromise quality of life or submaximal exercise
responses, both of which tend to improve13 14 16 or are at
least not worsened,17 18 which is similar to the effects
of metoprolol.19
On the basis of the "adrenergic hypothesis"2 20 21 of
the progression of myocardial failure and remodeling, it has been
argued that a more comprehensive degree of adrenergic blockade is a
desirable property of an antiadrenergic agent used
to treat chronic heart failure.21 This hypothesis is
directly supported by dose-response studies in patients with mild to
moderate heart failure, in whom larger doses of ß-blockers have
produced greater improvements in LV function than smaller
doses.15 18 This general concept is also supported by work
in transgenic mouse models that overexpress adrenergic receptors in the
heart. In these cardiac overexpressor models, heightened and sustained
myocardial signaling through the human
ß1,22 23
ß2,24 and
125 receptor pathways produces a
pathological phenotype on a background of normal myocardial
structure and function. Although in these models, evidence exists that
the ß1-receptor pathway is more pathogenic than the
ß2-receptor pathway,1 22 23 24
crosses of the ß2-cardiac overexpressor mouse
with other genetic models of cardiomyopathy result
in an acceleration of myocardial failure and
remodeling.26 27 Thus, if the general mechanism of action
of ß-blocker therapy in chronic heart failure is prevention and
partial reversal of adrenergically-mediated myocardial dysfunction and
remodeling,21 28 it would make sense to block the full
cytotoxic and growth-promoting effects of norepinephrine
(and potentially epinephrine), which can theoretically be
mediated by all 3 of the aforementioned receptors. Therefore, the data
reported by Metra et al5 are consistent with the
pharmacological effects of each agent, work in model systems, and the
current conceptual framework of how antiadrenergic
treatment improves the natural history of heart failure.
What about the relative clinical effects of metoprolol and carvedilol
or, more generally, second versus third generation ß-blocking agents?
The comparison trials, including Metra et al’s,5 have not
been large enough to reach conclusions regarding clinical end points,
and so one is left comparing the results of different trials conducted
with each type of agent. Because of differences in the patient
populations of these trials (recently reviewed in
Circulation1 ), a comparison of clinical effects
between individual trials is not particularly useful. What may be
generally concluded is that both second- and third-generation compounds
reduce mortality and morbidity in mild to moderate chronic heart
failure.1 This is also not surprising in view of the
apparently greater pathogenic consequences of
ß1-compared with
ß2-receptor signaling, the approximate 2:1:1
dominance of
ß1:ß2:1
receptors in the failing human heart,29 and the
understanding that the major source of increased adrenergic activity is
cardiac neuronal-derived norepinephrine.
Norepinephrine is a ß1-selective
agonist that is 20-fold more selective for human
ß1- versus ß2-receptors
and 10-fold more selective for ß1-receptors
versus human myocardial
1-receptors.30 Thus, in the
failing human heart, the majority of the adverse biological effects of
increased cardiac adrenergic drive is mediated by
ß1-adrenergic receptors and, on the basis of
this reality, it would be predicted that large differences would not
exist between the myocardial or clinical effects of second generation,
ß1-selective versus third generation,
comprehensive antiadrenergic agents. The LV
functional differences between metoprolol and carvedilol reported in
the Metra et al study5 are consistent with such a
small but measurable incremental effect of adding
ß2- and 1-receptor
blockade to ß1-blockade. Whether comparable
clinical differences exist will have to be determined from large direct
comparison trials, such as the Carvedilol and Metoprolol European Trial
(COMET). Until these data are available, the answer to the question of
what type of ß-blocker to be used in mild to moderate heart failure
is still either a second generation,
ß1-selective compound such as metoprolol or
bisoprolol or the third generation, nonselective ß/ blocker
carvedilol.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
(Circulation. 2000;102:484-486.)
References
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