Benefits of -Blocker
Therapy for Heart Failure
Weighing the Evidence
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 -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.
Arch Intern Med.
2002;162:641-648
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.
-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
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.
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
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.
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.
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.
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.
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
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.
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 -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 -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/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]).
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.