Benefits of beta-Blocker Therapy for Heart Failure

Weighing the Evidence

Author Information
<http://archinte.ama-assn.org/issues/v162n6/rfull/#aainfo>   Sidney
Goldstein, MD
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 beta-adrenergic
receptor blockers (beta-blockers). Based on this knowledge, we can now
appreciate the potential of these drugs for the treatment of heart failure.
Several beta-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 beta-blockers.
Arch Intern Med. 2002;162:641-648
IRA10028
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 beta1-receptors, 1
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r1> , 2
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r2>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r1> , 3
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r3>
The significant reductions in mortality and morbidity recently observed in
large clinical trials of beta1-selective (metoprolol succinate controlled
release/extended release [CR/XL] and bisoprolol) and nonselective
(carvedilol) agents indicate that pharmacologic blockade of beta-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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_t1.html> )
among agents that may be clinically meaningful. The role of beta-adrenergic
receptor blockers (beta-blockers) in the setting of the activated SNS that
occurs in heart failure is the focus of this review.



BASIC RESEARCH EVIDENCE: ADRENERGIC MECHANISMS CONTRIBUTING TO HEART FAILURE



beta-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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r4>
Adrenergic neurohormones (eg, epinephrine and norepinephrine) affect
activity or function of cardiomyocytes via neurohormonal binding at the
beta-receptor. Chronotropic and inotropic effects are regulated primarily by
beta1-adrenoreceptors that bind to norepinephrine with high affinity. In
contrast, beta2-adrenoreceptors bind with higher affinity to epinephrine. 4
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r4>
In the failing heart, enhanced, sustained sympathetic drive down-regulates
beta1-adrenoreceptors and desensitizes the beta-adrenergic system. 2
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r2> , 5
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r5>  Alterations in the
beta-adrenergic system resulting from chronic heart failure include (1)
down-regulation of beta1-adrenergic receptors, (2) uncoupling of downstream
pathways (stimulatory G proteins), and (3) up-regulation of
beta-adrenoreceptor kinase, leading to enhanced phosphorylation of beta1-
and beta2-adrenoreceptors. 6-9
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r6>
Administration of beta1-selective antagonists, such as metoprolol and
bisoprolol, has been shown to (1) up-regulate cardiac beta1-adrenergic
receptors, thereby increasing cardiac responsiveness to exogenously
administered catecholamines, and (2) recouple uncoupled
beta2-adrenoreceptors, thereby restoring normal signal transduction. 6
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r6>  In a comparison of
metoprolol tartrate and carvedilol in 2 concurrent clinical trials, the
beta1-selective agent (metoprolol) increased beta-receptor density in
endomyocardial membranes vs the nonselective beta-blocker (carvedilol),
which did not alter cardiac beta-receptor number ( Figure 1
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_f1.html> ). 10
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r10>  These alterations,
in addition to a possible change in receptor affinity, may explain the
improvement in exercise capacity observed in some patients treated with
beta1-selective agents and not with a nonselective agent such as carvedilol.
11 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r11>  Markers of
myocardial function, such as left ventricular ejection fraction (LVEF),
improved in both the metoprolol and carvedilol groups regardless of
beta-receptor activation. 10
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r10>  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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r12> ,
13 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r13>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r14>
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r15>  The role of
beta-blockade in modulating Ca2+ handling in the cardiomyocyte sarcoplasmic
reticulum has not been fully elucidated. However, it is clear that
beta-blockade–induced bradycardia results in prolonged diastolic filling and
increased Ca2+ loading into the sarcoplasmic reticulum, causing augmentation
of contraction during systole. 5
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r5> , 16
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r16>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r17> , 18
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r18>  In addition to the
positive impact of beta-blockers on Ca2+ mobilization, these agents reduce
myocardial oxygen consumption and may ameliorate the adverse effects of
hypoxia. 5 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r5>
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
alpha1- and beta-adrenoreceptors appear to be involved in this process. 19
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r19> , 20
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r20>
Cardiomyocyte necrosis resulting from chronic catecholamine exposure has
been well documented. 1
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r1>  More recently, the
importance of cell loss due to programmed cell death or apoptosis has been
recognized. 5 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r5> , 21-23
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r21>  Cell death due to
apoptosis occurs without an inflammatory reaction and as a result of
intrinsic changes in intracellular gene-regulated proteins. 24
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r24>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r5>  Incubation of
cardiomyocytes in vitro with norepinephrine induces apoptosis, 5
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r5>  and
beta1-adrenoreceptors appear to play a central role in this effect. 25-27
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r25>
It has been shown that the induction of cardiomyocyte apoptosis by
incubation with norepinephrine can be attenuated with propranolol, a
nonselective beta-blocking agent. 25
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r25>  In canine models of
heart failure, treatment with metoprolol markedly reduces apoptosis in the
myocardium and prevents progression of heart failure ( Figure 2
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_f2.html> ). 23
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r23> , 28
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r28>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r28>  Anti-apoptotic
effects also have been demonstrated with carvedilol. 29
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r29>  However, in vitro
studies using cultured cells recently have shown that although beta1
antagonism inhibits apoptosis, beta2 antagonism increases apoptosis, thus
suggesting a particular importance of beta1 selectivity. 25
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r25>  However, the degree
to which apoptosis plays a role in cardiac remodeling remains uncertain.
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r30> , 31
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r31>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_f3.html> ). 32
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r32>



EVIDENCE FROM CLINICAL TRIALS



Recent randomized, placebo-controlled clinical trials have evaluated the
survival benefit of beta-blockers added to standard therapy with ACE
inhibitors and diuretics for the treatment of heart failure. We now know
that beta-blockade has beneficial effects on both morbidity and mortality in
patients with heart failure. In fact, the mortality benefit of beta-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 beta-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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r33>  The largest
beta-blocker trial, MERIT-HF, 34
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r34> , 35
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r35>  was reported
shortly after the first 2 trials and was followed by the Beta-Blocker
Evaluation of Survival Trial (BEST). 36
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r36>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r37>  All 4 mortality
trials, CIBIS-II, MERIT-HF, BEST, and COPERNICUS, provided additional
insight into the mortality benefits of beta-blocker use in patients with
heart failure.
Both CIBIS-II and MERIT-HF examined the effect of beta1-selective blockade
using bisoprolol and metoprolol CR/XL, respectively. The CIBIS-II trial 33
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r33>  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 beta1-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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r33>  representing a 34%
risk reduction for all-cause mortality and a 26% risk reduction for death
due to worsening heart failure ( Figure 4
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_f4.html> ). In
MERIT-HF, the use of metoprolol CR/XL (a controlled-release/extended-release
formulation of metoprolol succinate that also provides consistent 24-hour
beta1 blockade) was investigated. At the peak target dose of 200 mg once
daily, beta1-receptor blockade is almost complete and corresponds to 40% to
80% of maximum effect based on exercise heart rate. 38
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r38>  The MERIT-HF trial
34 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r34>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_f5.html> ). 35
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r35>  Sudden death was
the most common cause of mortality, accounting for more than 60% of all
deaths. 34 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r34>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r34>  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.
Two nonselective beta-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
beta-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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r4> , 39
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r39>  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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r39>
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 beta-blocker, the results did
not reach statistical significance and failed to demonstrate a significant
survival benefit. 36 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r36>
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r4>  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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r37>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_f6.html> ). 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.
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r40>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_f7.html> ). 40
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r40>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_f8.html> ). 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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r40>
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_t2.html> . It
can be seen that both studies are similar in regard to their LVEF and annual
placebo mortality rate.
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r33> , 34
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r34> , 36
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r36> , 39
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r39>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r33> , 34
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r34> , 36
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r36> , 39
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r39>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r41>  and 43% of patients
in CIBIS-II had achieved the target dose of 10 mg of bisoprolol per day. 42
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r42>  The dosing
schedules used in these 3 trials are given in Table 3
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_t3.html> .
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ira10028_f8.html> ) 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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r35>  Contrary to
common belief, these trials demonstrate that beta-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 beta-blocker therapy, the
beta-blocker dose should not be up-titrated further and, if necessary, can
be decreased gradually.
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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r2>



COMMENT



It is clear that circulating neurohormones can alter cell contractile
function and that almost all beta-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 beta-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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r13>  These results
provide some mechanistic support for the benefit of beta-blocker use in
suppressing sudden death as observed in the clinical trials MERIT-HF and
CIBIS-II.
Basic research evidence regarding the effects of beta-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 beta1-selective and nonselective
beta-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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r23> , 28
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r28> , 29
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r29>  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
beta1-adrenergic down-regulation and that beta-adrenergic antagonists
counteract this effect set the stage for the evaluation of beta-blocker use
in patients with heart failure. Demonstrated increases in
beta1-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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r10>
The findings of the recent clinical trials have added immensely to our
understanding of the benefits of beta-blocker use in patients with heart
failure. There is now abundant evidence to indicate that beta-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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r43>  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 beta-blockers improves survival after myocardial
infarction from the Beta-Blocker Heart Attack Trial (BHAT) in patients with
heart failure 44 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r44>
and from the recent Carvedilol Post-Infarction in Survival Control in
Left-Ventricular Dysfunction (CAPRICORN) trial in patients with decreased
ejection fraction. 45
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r45>
The MERIT-HF, CIBIS-II, and COPERNICUS trials indicate that beta-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 beta-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 beta-blocker therapy in patients with more
advanced heart failure who are hemodynamically unstable. 46
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r46>  These studies are
important in demonstrating the safety of beta-blocker use in this defined
population with severe heart failure. It is important that the patient
population assessed in these studies be understood because beta-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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r47>
More important, however, beta-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
beta-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 beta-blocker
treatment remains the appropriately designed clinical trial. The BEST study
results indicate that it cannot be assumed that the benefit of beta-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 beta1-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 beta1-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 beta2- and alpha1-receptor blockade provides additional
benefit is not clear. 11
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r11>  There appears to be
little difference in regard to the efficacy of selective vs nonselective
beta-blockers in randomized clinical trials; however, there does appear to
be some difference in their hemodynamic effects. 11
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r11>
Are there other properties that might influence the effectiveness of one
beta-blocker vs another? Carvedilol and bucindolol have been described as
third-generation beta-blockers because they acutely elicit vasodilatation.
For carvedilol, this reduction in afterload is a result of alpha1-receptor
blockade and offsets, to some degree, the early negative inotropic effect of
beta-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 alpha1-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 beta-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 beta-blockersmetoprolol CR/XL, bisoprolol,
and carvedilolhave 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
beta-blockers are prescribed for heart failure. Currently, with fewer than
20% of eligible patients with heart failure receiving a beta-blocker
treatment, the goal of practicing physicians should be to ensure that a
beta-blocker is considered as part of the standard treatment regimen for all
patients with mild to moderate heart failure.



Author/Article Information


From the Division of Cardiovascular Medicine, Henry Ford Heart and Vascular
Institute, Detroit, Mich.

Corresponding author and reprints: Sidney Goldstein, MD, Division of
Cardiovascular Medicine, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI
48202 (e-mail: [log in to unmask] <mailto:[log in to unmask]> ).
Accepted for publication August 7, 2001.




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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.