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Vol. 162 No. 6, March 25, 2002 |
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Review Article |
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Benefits of  -Blocker Therapy for Heart Failure
Weighing the Evidence
Sidney Goldstein, MD
Arch Intern Med. 2002;162:641-648.
ABSTRACT
Our understanding of factors contributing to the progression of heart
failure has advanced dramatically over the past 2 decades. We have also gained
considerable insight into the pharmacology of  -adrenergic receptor blockers
(-blockers). Based on this knowledge, we can now appreciate the potential
of these drugs for the treatment of heart failure. Several -blockers
have been shown to be clinically effective in the treatment of heart failure.
Critical evaluation of the evidence from basic research studies, as well as
clinical trials in patients with heart failure, helps to delineate the theoretical
and clinical benefits of -blockers.
INTRODUCTION
Over the past several years, our understanding of the effect of activation
of the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS)
on the pathophysiology of heart failure has resulted in the development of
drugs that have improved morbidity and mortality associated with this chronic
condition. Extensive basic research provided the scientific rationale for
modulation of RAS activation in the treatment of heart failure, and clinical
research has established the importance of angiotensin-converting enzyme (ACE)
inhibitors in the treatment of patients with chronic heart failure. In addition,
it has become clear that blockade of the SNS can have important clinical effects
in patients with heart failure. We also have gained considerable knowledge
of the interaction of the RAS and the SNS in the failing myocardium.
Activation of the SNS initially improves and maintains cardiac function.
However, sustained sympathoadrenergic activation results in chronic elevation
of norepinephrine levels and down-regulation of 1-receptors,1-2 which can be detrimental to cardiac
function. Chronic elevation of plasma norepinephrine levels is also potentially
cardiotoxic and is associated with poor prognosis in patients with heart failure.1, 3
The significant reductions in mortality and morbidity recently observed
in large clinical trials of 1-selective (metoprolol succinate
controlled release/extended release [CR/XL] and bisoprolol) and nonselective
(carvedilol) agents indicate that pharmacologic blockade of -adrenergic
receptors results in considerable clinical improvement in patients with chronic
heart failure. However, there are important differences in pharmacologic or
ancillary properties (Table 1)
among agents that may be clinically meaningful. The role of -adrenergic
receptor blockers (-blockers) in the setting of the activated SNS that
occurs in heart failure is the focus of this review.
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Table 1. Receptor Blockade and Ancillary Properties of -Blockers
Studied in Large Heart Failure Mortality Trials*
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BASIC RESEARCH EVIDENCE: ADRENERGIC MECHANISMS CONTRIBUTING TO HEART
FAILURE
-Adrenergic Receptor Signaling
The SNS is an important regulator of myocardial performance mediated
principally by norepinephrine and its modulation of calcium entry into cardiomyocytes.4 Adrenergic neurohormones (eg, epinephrine and norepinephrine)
affect activity or function of cardiomyocytes via neurohormonal binding at
the -receptor. Chronotropic and inotropic effects are regulated primarily
by 1-adrenoreceptors that bind to norepinephrine with high
affinity. In contrast, 2-adrenoreceptors bind with higher
affinity to epinephrine.4
In the failing heart, enhanced, sustained sympathetic drive down-regulates 1-adrenoreceptors and desensitizes the -adrenergic system.2, 5 Alterations in the -adrenergic
system resulting from chronic heart failure include (1) down-regulation of 1-adrenergic receptors, (2) uncoupling of downstream pathways (stimulatory
G proteins), and (3) up-regulation of -adrenoreceptor kinase, leading
to enhanced phosphorylation of 1- and 2-adrenoreceptors.6-9
Administration of 1-selective antagonists, such as
metoprolol and bisoprolol, has been shown to (1) up-regulate cardiac 1-adrenergic receptors, thereby increasing cardiac responsiveness to
exogenously administered catecholamines, and (2) recouple uncoupled 2-adrenoreceptors, thereby restoring normal signal transduction.6 In a comparison of metoprolol tartrate and carvedilol
in 2 concurrent clinical trials, the 1-selective agent (metoprolol)
increased -receptor density in endomyocardial membranes vs the nonselective -blocker
(carvedilol), which did not alter cardiac -receptor number (Figure 1).10
These alterations, in addition to a possible change in receptor affinity,
may explain the improvement in exercise capacity observed in some patients
treated with 1-selective agents and not with a nonselective
agent such as carvedilol.11 Markers of myocardial
function, such as left ventricular ejection fraction (LVEF), improved in both
the metoprolol and carvedilol groups regardless of -receptor activation.10 In a randomized, placebo-controlled study, metoprolol
CR/XL significantly increased LVEF and left ventricular end-diastolic and
end-systolic volumes relative to placebo after 24 weeks of therapy in patients
with ischemic and dilated cardiomyopathy.12-13
This was also demonstrated in a subset of patients (n = 41) with chronic heart
failure enrolled in the Metoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure (MERIT-HF); treatment with metoprolol CR/XL for 6
months resulted in significant increases in LVEF as well as significant decreases
in left ventricular end-diastolic volume index and left ventricular end-systolic
volume index compared with baseline.14
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Figure 1. Comparison of the effect of metoprolol
vs carvedilol on cardiac 1-receptor density. Data are mean
± SEM. Adapted with permission from Gilbert et al.10
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Calcium Handling
Contraction and relaxation of cardiac muscle are regulated by the concentration
of intracellular free calcium (Ca2+), which is controlled by release
or uptake of Ca2+ by the sarcoplasmic reticulum.15
The role of -blockade in modulating Ca2+ handling in the
cardiomyocyte sarcoplasmic reticulum has not been fully elucidated. However,
it is clear that -blockade–induced bradycardia results in prolonged
diastolic filling and increased Ca2+ loading into the sarcoplasmic
reticulum, causing augmentation of contraction during systole.5, 16
Metoprolol also has been shown to reduce carnitine palmitoyl transferase I
(CPT-I) activity in dogs with heart failure by redirecting substrate utilization,
which may contribute to an increased rate of Ca2+ uptake in the
sarcoplasmic reticulum and improvement in cardiac contractility.17-18
In addition to the positive impact of -blockers on Ca2+ mobilization,
these agents reduce myocardial oxygen consumption and may ameliorate the adverse
effects of hypoxia.5
Cardiac Remodeling
A feature of myocardial dysfunction and progressive heart failure is
cardiac remodeling with dilatation of the left ventricle. This process involves
both cardiac hypertrophy and apoptosis or programmed cell death. The loss
of cardiomyocytes and the development of fibrotic interstitial tissue result
in compromised cardiac performance. Many factors have been identified that
mediate hypertrophy, including adrenergic stimulation. In cultured cardiomyocytes,
norepinephrine induces DNA and protein synthesis without compensatory cell
division, leading to increased cardiomyocyte size. Both  1-
and -adrenoreceptors appear to be involved in this process.19-20
Cardiomyocyte necrosis resulting from chronic catecholamine exposure
has been well documented.1 More recently, the
importance of cell loss due to programmed cell death or apoptosis has been
recognized.5, 21-23
Cell death due to apoptosis occurs without an inflammatory reaction and as
a result of intrinsic changes in intracellular gene-regulated proteins.24 Cellular triggers that may lead to apoptosis are
dominant features of the failing heart, including increased cytosolic calcium
concentration, exposure of cardiac myocytes to hypoxia, and excess levels
of norepinephrine.5 Incubation of cardiomyocytes
in vitro with norepinephrine induces apoptosis,5
and 1-adrenoreceptors appear to play a central role in this
effect.25-27
It has been shown that the induction of cardiomyocyte apoptosis by incubation
with norepinephrine can be attenuated with propranolol, a nonselective -blocking
agent.25 In canine models of heart failure,
treatment with metoprolol markedly reduces apoptosis in the myocardium and
prevents progression of heart failure (Figure
2).23, 28 The specific
mechanisms of this anti-apoptotic effect are not fully understood, although
there is evidence that metoprolol leads to enhanced expression of Bcl-2, a
cellular oncoprotein that inhibits apoptosis.28
Anti-apoptotic effects also have been demonstrated with carvedilol.29 However, in vitro studies using cultured cells recently
have shown that although 1 antagonism inhibits apoptosis, 2 antagonism increases apoptosis, thus suggesting a particular importance
of 1 selectivity.25 However,
the degree to which apoptosis plays a role in cardiac remodeling remains uncertain.
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Figure 2. Apoptosis in heart failure (HF).
TUNEL indicates TdT-mediated dUTP nick-end labeling.28
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Oxidative Stress
Oxidative stress is thought to enhance the generation of oxygen-free
radicals and may result in myocardiocyte damage and apoptosis. An association
between heart failure and increased free radicals has been demonstrated in
animal models and in patients with heart failure.30-31
The nonselective agent carvedilol has been shown to inhibit the formation
of free radicals, block lipid peroxidation, and prevent oxygen radical–induced
cell death in vitro; such effects have not been reported with metoprolol use.
However, in a recent study comparing carvedilol with metoprolol treatment
in heart failure patients, both agents reduced the level of oxidative stress
to the same degree, which is most likely related to the improvement in heart
failure status, indicating no additional antioxidant benefit with carvedilol
(Figure 3).32
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Figure 3. Mean ± SEM thiobarbituric
acid–reactive substance (TBARS) values for patients who completed the
protocol at baseline, month 4, and month 6 for metoprolol and carvedilol,
respectively. Differences between baseline and month 6 were significant for
both metoprolol (P<.001) and carvedilol (P = .02)
as indicated by within-group paired t tests. The overall analysis
of variance performed between groups for all time points was not significant
(NS). Adapted with permission from Kukin et al.32
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EVIDENCE FROM CLINICAL TRIALS
Recent randomized, placebo-controlled clinical trials have evaluated
the survival benefit of -blockers added to standard therapy with ACE
inhibitors and diuretics for the treatment of heart failure. We now know that -blockade
has beneficial effects on both morbidity and mortality in patients with heart
failure. In fact, the mortality benefit of -blockade in addition to
standard therapies exceeds that of any other current pharmacologic intervention
in similar patient populations, including available clinical trial data with
ACE inhibitor therapy. These drugs provide an added effect beyond that achieved
with ACE inhibitors.
Randomized Clinical Trials: New York Heart Association Class II to
IV
Four large trials have been completed in the last 5 years and, in general,
they support the concept that -adrenergic blockade is beneficial in
heart failure. The initial US Carvedilol Heart Failure Trials Program, which
was not designed to assess mortality, was followed by the Cardiac Insufficiency
Bisoprolol Study-II (CIBIS-II), a trial powered to study the mortality benefit
of bisoprolol use in patients with heart failure.33
The largest -blocker trial, MERIT-HF,34-35
was reported shortly after the first 2 trials and was followed by the Beta-Blocker
Evaluation of Survival Trial (BEST).36 The
most recent mortality trial, the Carvedilol Prospective Randomized Cumulative
Survival (COPERNICUS) trial, was the last of the randomized mortality trials
completed, and it focused on patients with severe heart failure.37
All 4 mortality trials, CIBIS-II, MERIT-HF, BEST, and COPERNICUS, provided
additional insight into the mortality benefits of -blocker use in patients
with heart failure.
Both CIBIS-II and MERIT-HF examined the effect of 1-selective
blockade using bisoprolol and metoprolol CR/XL, respectively. The CIBIS-II
trial33 included 2647 symptomatic patients,
limited to those with New York Heart Association (NYHA) class III or IV heart
failure with LVEF of 35% or less. Bisoprolol is a long-acting, once-daily 1-blocker. Patients with class IV disease accounted for 17% of the population.
In CIBIS-II, 384 deaths were reported, 156 (11.8%) in the bisoprolol group
and 228 (17.3%) in the placebo group,33 representing
a 34% risk reduction for all-cause mortality and a 26% risk reduction for
death due to worsening heart failure (Figure
4). In MERIT-HF, the use of metoprolol CR/XL (a controlled-release/extended-release
formulation of metoprolol succinate that also provides consistent 24-hour 1 blockade) was investigated. At the peak target dose of 200 mg once
daily, 1-receptor blockade is almost complete and corresponds
to 40% to 80% of maximum effect based on exercise heart rate.38
The MERIT-HF trial34 included 3991 ambulatory
patients with NYHA class II, III, or IV heart failure with LVEF of 40% or
less, who were stabilized on standard heart failure therapy, including ACE
inhibitors and diuretics. Most patients (96.4%) had NYHA class II or III heart
failure; 145 patients (3.6%) had class IV failure. In addition, half of the
patients were older than 65 years, and one third had LVEF less than 25%. Overall,
a 34% risk reduction for all-cause mortality was reported in MERIT-HF, with
a 49% risk reduction for death due to worsening heart failure and a 41% decrease
in sudden death (Figure 5).35 Sudden death was the most common cause of mortality,
accounting for more than 60% of all deaths.34
In addition to its mortality benefit, metoprolol CR/XL use decreased the combined
event rate of all-cause mortality and heart failure hospitalizations by 31%.34 Results of subgroup analyses based on a variety of
patient characteristics including age, sex, race, and etiology of heart disease
are consistent with results observed in the primary study group.
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Figure 4. Survival curve from the Cardiac
Insufficiency Bisoprolol Study-II (CIBIS-II) trial (P<.001).
Reprinted with permission from CIBIS-II Investigators.33
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Figure 5. Kaplan-Meier curve of cumulative
percentage of total mortality (P = .006, adjusted for interim
analyses; P<.001, nominal), sudden death (P<.001),
and worsening heart failure (P = .002) in the Metoprolol Controlled
Release/Extended Release (CR/XL) Randomized Intervention Trial in Congestive
Heart Failure (MERIT-HF). Reprinted with permission from MERIT-HF Study Group.34
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Two nonselective -blockers, carvedilol and bucindolol, have also
been evaluated in clinical trials of heart failure. The US Carvedilol Heart
Failure Trials Program included 1094 patients and evaluated a nonselective -blocker
for the treatment of heart failure due to systolic dysfunction. The US Carvedilol
Heart Failure Trials Program was designed as 4 separate protocols and was
not designed to assess mortality; however, safety analyses unexpectedly demonstrated
a mortality benefit.4, 39 Consequently,
the program was terminated prematurely with a limited number of mortality
events (31 placebo-treated patients [7.8%] died compared with 22 carvedilol-treated
patients [3.2%]).39
The observations from the recently reported BEST are more difficult
to interpret. Patients with more advanced heart failure and ejection fractions
of 35% or less were included in BEST. Although a beneficial trend was observed
with bucindolol use, a nonselective -blocker, the results did not reach
statistical significance and failed to demonstrate a significant survival
benefit.36 There were 411 deaths (14.9%) in
the bucindolol group and 449 deaths (16.6%) in the placebo group during approximately
2 years of follow-up. It is not clear why no significant survival effect was
observed with bucindolol use. However, possible explanations may include differences
in the study population, the specific pharmacologic properties of bucindolol,
or both.
The question regarding comparative efficacy of immediate-release metoprolol
and carvedilol is currently under investigation in the Carvedilol or Metoprolol
European Trial (COMET). This study is comparing metoprolol tartrate (rather
than metoprolol succinate CR/XL) with carvedilol in approximately 3000 patients
with heart failure in Europe.4 Because this
trial is not a direct comparison of carvedilol with metoprolol CR/XL, the
agent used in MERIT-HF, the usefulness of the results will be somewhat limited.
Results in Patients With Severe Heart Failure
The COPERNICUS trial was designed specifically to examine the mortality
effect of carvedilol in patients with severe heart failure with LVEF less
than 25%.37 The study enrolled 2289 patients
with severe heart failure characterized as having symptoms at rest or with
minimal exertion and demonstrated a 35% decrease in mortality (95% confidence
interval, 19%-48%; P<.001) (Figure 6). The placebo population had an annual mortality rate of
18.5% and a mean LVEF of 20%. The results were consistent across all predetermined
prespecified characteristics, and treatment was well tolerated.
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Figure 6. Kaplan-Meier analysis of survival
from the Carvedilol Prospective Randomized Cumulative Survival trial (P<.001, adjusted). Reprinted with permission from Packer et al.37
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Subgroup analysis of similar patients included in MERIT-HF with NYHA
class III or IV and LVEF less than 25% (n = 795) confirmed these findings.40 In the MERIT-HF severe heart failure subgroup, not
only did metoprolol CR/XL use result in a 39% risk reduction for total mortality,
it also resulted in a 55% risk reduction for death due to worsening heart
failure and a 45% risk reduction for sudden death (Figure 7).40 In addition, metoprolol
CR/XL use decreased the combined end point of all-cause mortality plus all-cause
hospitalization by 29%. The drug was well tolerated, with 31% fewer all-cause
withdrawals and 45% fewer withdrawals due to worsening heart failure in the
metoprolol CR/XL group compared with the placebo population (Figure 8). In this severe heart failure subgroup of MERIT-HF, metoprolol
CR/XL therapy also resulted in an improvement in NYHA functional class (P = .003) compared with placebo.40
Subgroup analysis of NYHA class III and IV patients with LVEF less than 25%
in MERIT-HF and COPERNICUS data is given in Table 2. It can be seen that both studies are similar in regard
to their LVEF and annual placebo mortality rate.
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Figure 7. Mortality curve from post hoc
subgroup analysis of patients with severe heart failure in the Metoprolol
Controlled Release/Extended Release (CR/XL) Randomized Intervention Trial
in Congestive Heart Failure (MERIT-HF). Adapted with permission from Goldstein
et al.40
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Figure 8. Reasons for withdrawal of study
medication in the Metoprolol Controlled Relase/Extended Release (CR/XL) Randomized
Intervention Trial in Congestive Heart Failure.34
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Table 2. Subgroup Analysis for NYHA Class III-IV Patients With LVEF
Less Than 25% in COPERNICUS and MERIT-HF Trials
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Dosing and Tolerability
The trials discussed in the present review generally included ambulatory
patients who were stable on the accepted contemporary therapy for heart failure
(ACE inhibitors, digitalis, and diuretics).33-34,36, 39
Patients with heart rates below 60 to 68 beats per minute and systolic blood
pressures below 90 to 100 mm Hg were excluded from the studies. With the exception
of the US Carvedilol Heart Failure Trials Program, which had an active run-in
period, the trials were initiated after a period of stabilization on standard
therapy followed by a placebo run-in period. Patients completing the run-in
periods were randomized in their respective trials and were gradually up-titrated
over a 6- to 8-week period to a total maximum target dose (10 mg of bisoprolol
daily, 50 mg [<75 kg] or 100 mg [>75 kg] of bucindolol hydrochloride twice
daily, or 200 mg of metoprolol CR/XL daily; maximum target doses of carvedilol
varied among the 4 protocols, ranging from 6.25 mg twice daily to 50 mg twice
daily).33-34,36, 39
These drugs were well tolerated; most patients were titrated to maximum or
near maximum doses. For example, at completion of MERIT-HF, 64% of patients
had achieved the maximum target dose of 200 mg of metoprolol CR/XL per day,
87% had achieved a dose of 100 mg or more of metoprolol CR/XL per day,41 and 43% of patients in CIBIS-II had achieved the
target dose of 10 mg of bisoprolol per day.42
The dosing schedules used in these 3 trials are given in Table 3. There were no differences in discontinuations between the
active and placebo arms of these trials, although assessment of both adverse
events and discontinuations in the US Carvedilol Heart Failure Trials Program
is confounded because of the open-label run-in phase. Because of this, patients
who died during the run-in phase or did not tolerate carvedilol were excluded.
In MERIT-HF, compared with the placebo group, withdrawal of the study drug
from all causes was 10% lower (Figure 8)
and withdrawal due to worsening heart failure was 25% lower in the metoprolol
CR/XL group, although this finding did not reach statistical significance.35 Contrary to common belief, these trials demonstrate
that -blockers are well tolerated in patients with heart failure; with
initiation at low doses and careful titration, most patients can achieve a
maximum therapeutic dose. In the setting of worsening failure during -blocker
therapy, the -blocker dose should not be up-titrated further and, if
necessary, can be decreased gradually.
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Table 3. Recommended Doses of -Blockers for Patients With Chronic
Heart Failure
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Both carvedilol and metoprolol are highly lipophilic compounds and are
metabolized and cleared by the liver. In the setting of hepatic congestion,
dosage reduction may be required. Bisoprolol is less lipophilic and exhibits
both hepatic and renal clearance. There does not appear to be any significant
interaction with other cardiac drugs, including warfarin and digoxin.2
COMMENT
It is clear that circulating neurohormones can alter cell contractile
function and that almost all -blocking agents have the ability to improve
cell function, resulting in increased ejection fraction, improved diastolic
relaxation and myocardial energetics, and decreased end-diastolic pressures.
The mechanism by which -blockers alter the electrophysiologic properties
of the ventricle to decrease the occurrence of sudden death is, however, still
uncertain. In the pilot study for MERIT-HF, metoprolol CR/XL decreased ventricular
ectopy and the frequency of nonsustained ventricular tachycardia associated
with an increase in LVEF.13 These results provide
some mechanistic support for the benefit of -blocker use in suppressing
sudden death as observed in the clinical trials MERIT-HF and CIBIS-II.
Basic research evidence regarding the effects of -blockers on
apoptosis and oxidative stress also suggests little difference between agents.
Evidence that catecholamines, particularly norepinephrine, can cause apoptosis
in isolated myocytes supports the potential lethality of these neurohormones
to these cells. Both 1-selective and nonselective -blockers
have been shown to reduce apoptosis in animal models of heart failure; however,
there is no evidence linking a reduction in apoptosis with improved clinical
outcomes in patients with heart failure.23, 28-29
Similarly, treatments with carvedilol and metoprolol have been shown to reduce
oxidative stress in patients with heart failure; however, this is more likely
a result of improved heart failure status rather than a direct effect of either
agent.
The evidence that catecholamines, particularly norepinephrine, cause 1-adrenergic down-regulation and that -adrenergic antagonists
counteract this effect set the stage for the evaluation of -blocker
use in patients with heart failure. Demonstrated increases in 1-adrenoreceptor density following metoprolol treatment appear to correlate
with enhanced exercise capacity. However, improvement in ejection fraction
appears to be independent of receptor up-regulation because a positive effect
has been observed with the cardioselective agent metoprolol, which up-regulates
receptors, and the nonselective agent carvedilol, both of which appear to
have no effect on receptor density.10
The findings of the recent clinical trials have added immensely to our
understanding of the benefits of -blocker use in patients with heart
failure. There is now abundant evidence to indicate that -blockers have
a significant effect on the failing ventricle and that these benefits are
translated into improved survival and decreased hospitalization of patients
with heart failure. It is also clear from these studies that they have an
incremental effect on mortality when added to ACE inhibitor therapy.
The question of whether conclusions drawn from randomized clinical trials
can be generalized to patients in the overall population is frequently, and
quite appropriately, raised. It is imperative that clinical trials include
patients who are representative of the general population. The patients included
in these trials are symptomatic, and many of them have severe exercise limitation.
However, both ends of the clinical spectrum have not been included in these
trials.
None of the studies described above recruited patients with NYHA class
I heart failure. However, some extrapolations can be made from the Australia/New
Zealand carvedilol trial.43 In that study,
investigators recruited asymptomatic, post–myocardial infarction patients
with decreased ejection fractions and observed a significant benefit on combined
mortality and hospitalization. Further, there is additional evidence that
use of -blockers improves survival after myocardial infarction from
the Beta-Blocker Heart Attack Trial (BHAT) in patients with heart failure44 and from the recent Carvedilol Post-Infarction in
Survival Control in Left-Ventricular Dysfunction (CAPRICORN) trial in patients
with decreased ejection fraction.45
The MERIT-HF, CIBIS-II, and COPERNICUS trials indicate that -blockers
are not only safe for the treatment of severe heart failure, they are also
extremely effective in decreasing mortality and the need for hospitalization.
It must be emphasized, however, that although some patients enrolled in these
trials were classified as experiencing severe heart failure, they were generally
stable on therapy with ACE inhibitors and diuretics without severe fluid overload.
In addition, most patients were ambulatory with stable blood pressure. Whether -blocker
therapy has a role in patients with more compromised heart failure with fluid
overload and hypotension remains to be studied. At the present, a series of
studies are under way to evaluate the role of temporary intravenous support
with inotropic agents as a bridge to -blocker therapy in patients with
more advanced heart failure who are hemodynamically unstable.46
These studies are important in demonstrating the safety of -blocker
use in this defined population with severe heart failure. It is important
that the patient population assessed in these studies be understood because -blocker
therapy has not been shown as yet to provide acute improvement and should
not be viewed as lifesaving therapy in a patient whose condition is progressively
deteriorating. Improvements in LVEF take place over a number of weeks.47
More important, however, -blocker therapy has a greater public
health benefit potential in the larger population of patients with mild to
moderate heart failure. Although these patients have a lower mortality rate,
they represent most patients with heart failure. The relative benefit of -blocker
use in mild to moderate heart failure is similar to that in patients at higher
risk, but the absolute benefit is much greater in the high-risk patients.
The true test of the efficacy and benefit of a specific -blocker
treatment remains the appropriately designed clinical trial. The BEST study
results indicate that it cannot be assumed that the benefit of -blocker
use in patients with heart failure is a class effect. Persuasive clinical
trial evidence in large numbers of patients with class II to IV stable heart
failure demonstrates that mortality and morbidity are improved with use of
the 1-selective agents metoprolol CR/XL and bisoprolol and
with the nonselective agent carvedilol. Moreover, the clinical outcome results
of these trials are remarkably similar. Blockade of the 1-receptor
appears to be the common denominator, and therefore a critical element responsible
for the morbidity and mortality benefits observed with the use of these agents.
Whether 2- and 1-receptor blockade provides
additional benefit is not clear.11 There appears
to be little difference in regard to the efficacy of selective vs nonselective -blockers
in randomized clinical trials; however, there does appear to be some difference
in their hemodynamic effects.11
Are there other properties that might influence the effectiveness of
one -blocker vs another? Carvedilol and bucindolol have been described
as third-generation -blockers because they acutely elicit vasodilatation.
For carvedilol, this reduction in afterload is a result of 1-receptor
blockade and offsets, to some degree, the early negative inotropic effect
of -blockade, potentially improving tolerability. However, this vasodilator
effect can result in orthostasis during initiation and titration; thus patients
must be monitored closely during this time. Over the long term, studies have
demonstrated that tolerance develops, and the hemodynamic effects of 1-blockade with carvedilol are no longer apparent. Convenient once-daily
dosing also is important in patients with heart failure. Both bisoprolol and
metoprolol CR/XL are administered once daily and may improve compliance in
some patients; however, of these 2 agents, only metoprolol CR/XL (and carvedilol,
which requires twice-daily dosing) are approved for the treatment of heart
failure in the United States.
CONCLUSIONS
The primary criterion for selection of a -blocker treatment should
be proven effectiveness in reducing mortality and morbidity in patients with
heart failure in a large prospective randomized trial. We now have abundant
information to indicate that 3 -blockers—metoprolol CR/XL, bisoprolol,
and carvedilol—have been proven to be effective in this regard. Secondary
criteria are those that encourage compliance, including tolerability (particularly
during the titration phase), dosing frequency (daily vs twice daily), and
medication cost. These factors should be considered when -blockers are
prescribed for heart failure. Currently, with fewer than 20% of eligible patients
with heart failure receiving a -blocker treatment, the goal of practicing
physicians should be to ensure that a -blocker is considered as part
of the standard treatment regimen for all patients with mild to moderate heart
failure.
AUTHOR INFORMATION
Accepted for publication August 7, 2001.
Corresponding author and reprints: Sidney Goldstein, MD, Division
of Cardiovascular Medicine, Henry Ford Hospital, 2799 W Grand Blvd, Detroit,
MI 48202 (e-mail: sgoldst1{at}hfhs.org).
From the Division of Cardiovascular Medicine, Henry Ford Heart and
Vascular Institute, Detroit, Mich.
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congestive heart failure. N Engl J Med. 1984;311:819-823.
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