-Blocker Therapy in Heart
Failure
Scientific Review
JAMA. 2002;287:883-889
JoAnne Micale Foody, MD; Michael H. Farrell, MD; Harlan M. Krumholz, MD
Context Care of patients with heart failure has been revolutionized
throughout the past decade. A paradigm shift in the strategy for treating heart
failure caused by systolic dysfunction is in progress. Despite the initial
perception about -blockers' safety,
they are now the most extensively studied class of agents in the treatment of
heart failure and have emerged as an important intervention to improve the
clinical outcomes of heart failure patients.
Objective To provide scientific rationale for the use of -blockers for patients with heart failure.
Data Sources All English-language articles of large, randomized controlled
clinical trials assessing the mortality benefits of -blockers in patients with heart failure were identified to provide
the scientific rationale for the use of -blockers
in heart failure. Basic science studies were reviewed to provide an overview of
the potential physiologic role of -blockers
in heart failure. Finally, clinical guidelines for the treatment of patients
with heart failure were assessed to determine current recommendations for the
use of these agents.
Study Selection and Data
Extraction Randomized controlled clinical
trials of -blockers that
included more than 300 subjects and assessed mortality as a primary end point.
Data Synthesis Of the 4 -blockers tested in
large randomized controlled clinical trials of patients with heart failure, 3
are available in the United States, bisoprolol, carvedilol, and metoprolol; 2
of these, carvedilol and metoprolol, have Food and Drug Administration
indications for the treatment of heart failure. Compared with placebo
treatment, -blocker use is
associated with a consistent 30% reduction in mortality and a 40% reduction in
hospitalizations in patients with class II and III heart failure.
Conclusions Tested in more than 10 000 patients, -blockers reduce morbidity and mortality in class II through IV heart
failure. Along with angiotensin-converting enzyme inhibitors, digoxin, and
diuretics, -blockers have
strengthened the armamentarium to improve clinical outcomes of heart failure
patients. The science supporting -blockers
must be translated into practice safely and rationally if the agents are to
achieve their full potential.
JAMA. 2002;287:883-889
A medication once thought to be dangerous1-3 for patients with
heart failure, -blockers have been
shown to reduce morbidity and mortality4-9 and are strongly supported
by consensus recommendations and clinical guidelines.10-12 Clinicians are now
challenged to translate this important new information into clinical practice.
For half a century, -blockers have been an important therapy for patients with
cardiovascular disease. Originally developed as a drug to treat angina and
hypertension, -blockers have also
become essential therapies for patients with acute myocardial infarction (AMI)
and those with tachyarrhythmias. Even before -blockers
were shown to benefit patients with heart failure, the Nobel Committee declared
James W. Black's development of propranolol as the greatest breakthrough in
pharmaceuticals to treat heart illness since the discovery of digitalis 200
years earlier.13, 14
Enthusiasm for the use of -blockers as a treatment for heart failure emerged slowly.
Conventional wisdom held that heart failure was solely due to a decline in
systolic function and was an absolute contraindication for the prescription of
any medication with negative inotropic action. Initial small studies
demonstrating the significant negative inotropic effects and poor clinical
response to -blockers15, 16 only reinforced this
view. Consequently, early trials of -blockers
in hypertension or AMI excluded patients with heart failure. Until recently,
national guidelines,17-20 the US Food and
Drug Administration, and package inserts stated that -blockers were contraindicated in patients with heart failure.
In 1973, Finn Waagstein et al,21 convinced that the
heart-rate–lowering properties of -blockers
could provide benefit to patients with heart failure, administered practolol to
a 59-year-old woman with heart failure, with dramatic improvement in the
patient's clinical status.22 In another study,23 Waagstein and
colleagues demonstrated that -blockers were well
tolerated by patients with heart failure. Subsequent studies from his group
demonstrated the clinical benefits of -blockers
in patients with heart failure.24, 25 These studies,
however, did not influence mainstream medical culture, and concerns about the
potential adverse effects of -blockers for these
patients remained.
Throughout the next 30 years, experts began to
perceive that heart failure was a complex disorder characterized not only by
declines in systolic function, but also by a maladaptive increase in adrenergic
drive.26, 27 Only after decades of
laboratory science demonstrating biological plausibility,26-35 mechanistic
studies showing direct cardiovascular effects,36-41 and large
randomized clinical trials4-9 demonstrating
mortality benefits did -blockers become
accepted as a treatment for heart failure.
This article reviews the scientific rationale
supporting the use of -blockers for
patients with heart failure and presents current therapy recommendations10-12 based on
guidelines from professional organizations. Our goal is to provide information
for clinicians caring for patients with heart failure to accelerate the
appropriate use of -blockers for their
patients.
After the discovery of propranolol, laboratory
science laid the groundwork for -blocker
use for patients with heart failure28-35 as it came to be
understood that the pathophysiology of heart failure was related to activation
of the adrenergic nervous system. Early in heart failure, drops in cardiac
output lead to decreased organ perfusion, a compensatory increase in adrenergic
drive, and the subsequent release of neurohormones such as norepinephrine.35, 42 In turn,
norepinephrine stimulates ventricular contraction and increases vascular
resistance, thereby increasing cardiac output and blood pressure. This increase
in the cardiac adrenergic drive, initially a compensatory mechanism for the
failing heart, is one of the earliest measurable responses in heart failure43, 44 occurring while
patients are still asymptomatic.45, 46
This chronic activation of the adrenergic
nervous system leads to several potentially deleterious effects on the heart.47-51 Sustained
adrenergic activation and norepinephrine release raise cardiac output and heart
rate, which then increase myocardial oxygen demand, ischemia, and oxidative
stress. At the same time, peripheral vasoconstriction increases both preload
and afterload, causing additional stress on the failing ventricle. This
long-term mechanical stress in conjunction with cardiac fibrosis52-55 and necrosis28-35 promoted by
norepinephrine contributes to cardiac remodeling and a dilated, less
contractile cardiac chamber. Norepinephrine down-regulates the 1-adrenergic receptor and uncouples the 2-adrenergic
receptor,56-58 leaving the
myocyte less responsive to adrenergic stimuli, and further decreases
contractile function. Thus, prolonged activation of the adrenergic system may
be maladaptive,46, 59-62 causing
progressive deterioration of myocardial function and portending a poor
prognosis.37, 41, 63
As the neurohormonal hypothesis emerged, so too
did a new understanding of the potential role of -blockers in heart failure. Although acute treatment with -blockers decreases
blood pressure and cardiac index, long-term administration of -blockers is associated with significant increases in
ejection fraction64-77 and cardiac index
and a decrease in left ventricular (LV) end diastolic pressure.61, 77-87 -Blockers reverse the deleterious changes associated with LV
remodeling and decrease myocardial mass and LV volume, leading to improved
hemodynamics. Finally, -blockers may also
mediate benefit via regulating heart rate and decreasing cardiac arrhythmias.67 These direct cardiac
effects led to the hypothesis that -blockers
would provide substantial clinical benefits in patients with heart failure.
-Blockers have been
evaluated in more than 10 000 patients with mild, moderate, or severe
heart failure and ejection fractions less than 40% in randomized clinical
trials. Five meta-analyses88-92 have arrived at
the same conclusions: the use of -blockers
was associated with a consistent 30% reduction in mortality and a 40% reduction
in hospitalizations in patients with heart failure. In the most recent of these
meta-analyses,92 it was
estimated that 26 patients would need to be treated to avoid 1 death; 25, to
avoid 1 hospitalization. Despite differences in patient selection, target
doses, methodology, and clinical end points, results were remarkably consistent
across these trials. The evidence suggests that virtually all patients with
heart failure caused by LV systolic dysfunction benefit from -blockers.
Seven mortality trials with more than 300
subjects evaluated the impact of the second- and third-generation -blockers
(metoprolol, bisoprolol, bucindolol, or carvedilol) on patients with
symptomatic LV systolic dysfunction (Table 1).
These trials included the Metoprolol in Dilated Cardiomyopathy (MDC)93, 94 study, the Metoprolol
CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF),6, 9 the Cardiac
Insufficiency Bisoprolol Studies (CIBIS I
and II),4, 5 the Australia, New
Zealand, and United States Carvedilol Clinical Trial8 program, the
Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS),95 and the Beta-Blocker
Evaluation of Survival Trial (BEST)96 (Table 2).
One of the earliest controlled trials of -blockers in heart
failure, MDC,93, 94 was designed to
assess the impact of metoprolol on the combined end point of death or
progression to heart transplantation. In this trial, 383 patients with mild to
moderate heart failure and an ejection fraction less than 40% were randomized
to placebo or metoprolol. Metoprolol initiated at a dose of 5 mg twice daily
and titrated to a high dose of 100 to 150 mg/d was associated with a 34%
decrease in the combined primary end point. Although the improvement was due
entirely to a reduction in the need for cardiac transplantation without a
significant difference in mortality (P
= .12), this study was the first larger-scale trial to add support to the role
of -blockers in heart
failure therapy. Despite its limitations and negative mortality results, the
MDC trial sparked renewed interest in -blockers
as a therapy for heart failure.
In follow-up to the MDC trial, the MERIT-HF6, 9 was designed to
determine whether therapy with the long-acting metoprolol CR/XL was associated
with a reduction in all-cause mortality. Larger than the MDC trial, this study
randomized 3991 patients with stable New York Heart Association class II
through IV heart failure and already receiving standard medical treatment
(including angiotensin-converting enzyme [ACE] inhibitors, diuretics, and
digitalis) to increasing doses of metoprolol CR/XL or placebo. The MERIT-HF
trial featured a 2-week placebo run-in period to assess clinical stability. The
starting dosage of metoprolol CR/XL was 12.5 or 25 mg/d and was gradually
increased every 2 weeks to the target dose of 200 mg/d. At the conclusion of
the study, 64% of the patients were receiving 200 mg of metoprolol per day.
Planned follow-up was 2 years, but the study was stopped early because of a
significant decrease in all-cause mortality in the metoprolol treatment arm.
Treatment with metoprolol was associated with a 34% decrease in all-cause
mortality, a 38% decrease in cardiovascular mortality, a 41% decrease in sudden
death, a 49% decrease in death caused by progressive heart failure, and a 35%
reduction in hospitalizations caused by heart failure. Treatment of 27 patients
with metoprolol for 1 year could prevent 1 death.
At approximately the same time, the CIBIS-I4 sought to determine
whether bisoprolol therapy was associated with an improvement in survival and
functional status in patients with moderate heart failure and already receiving
diuretics and ACE inhibitors. Although patients treated with bisoprolol had
marked improvements in functional class and reduced readmissions, the observed
difference in mortality between groups did not reach statistical significance (P = .22; relative risk [RR], 0.80; 95%
confidence interval [CI], 0.56-1.15). In general, CIBIS-I demonstrated the
safety of bisoprolol in patients with moderate heart failure and its efficacy
in improving functional class and decreasing hospitalizations.
The CIBIS-II,5 with greater
statistical power than its predecessor, CIBIS-I, was designed to determine
whether bisoprolol at optimal target doses of 10 mg/d would be associated with
improved survival. The trial was stopped early after treatment with bisoprolol
was found to have a significant mortality benefit: 156 (11.8%) vs 228 (17.3%)
deaths with an RR reduction of 0.66 (95% CI, 0.54-0.81; P<.001) noted in the -blocker group. There were significantly fewer sudden deaths
among patients receiving bisoprolol than among those receiving placebo (48
[3.6%] vs 83 [6.3%] deaths), with an RR reduction of 0.56 (95% CI, 0.39-0.80; P = .001). In addition, all-cause hospital
admission was reduced in the treatment group (hazard ratio, 0.80 [95% CI,
0.71-0.91]; P<.001). Treatment
effects were independent of the severity or cause of heart failure. Of note,
CIBIS-II did not have a run-in period and thus may be more representative of -blocker use in
clinical practice. According to these findings, treating 23 patients with
bisoprolol would prevent 1 death.
Carvedilol, a third-generation -blocker with 1, 1, and 2
blocking properties as well as antioxidant activity, was extensively tested in
the US Carvedilol Heart Failure Program, which consisted of different
multicenter trials,8, 81, 97 each with a run-in
period and including 1094 patients with chronic heart failure. Within each of
the trial protocols, patients with mild, moderate, or severe heart failure and
LV ejection fractions of 35% were randomized to carvedilol (n = 696) or placebo
(n = 398). Carvedilol therapy was associated with a significant reduction in
overall mortality rate (3.2% vs 7.8% in the placebo group). The reduction in
mortality was 65% (95% CI, 39%-80%; P<.001).
Carvedilol therapy was associated with a 27% reduction in hospitalizations for
cardiovascular causes (P = .04)
and a 38% reduction in the combined end point of hospitalization or death (P<.001).
In the COPERNICUS,95 the first study to
target New York Heart Association IIIB to IV patients with heart failure
despite optimal medical therapy, there was a significant 35% decrease in
all-cause mortality in patients treated with carvedilol. In order to address
concerns over the safety of these agents in patients with advanced disease,
outcome data were analyzed by high-risk subsets. Even in patients who had fluid
retention, used intravenous inotropes or vasodilators within 2 weeks, or had 3
heart failure admissions within 1 year, carvedilol use was associated with a
50% RR reduction in all-cause mortality (95% CI, 27%-90%). Carvedilol was well
tolerated at 12 months, with 13% of the carvedilol-treated patients and 16% of
the placebo-treated patients withdrawing from therapy. According to these
results, administering carvedilol to just 14 patients with severe heart failure
would save 1 life.
In contrast to the other recent large trials,
the BEST96 failed to
demonstrate that bucindolol improved overall survival in patients with New York
Heart Association class III to IV heart failure. The data and safety monitoring
board halted this study, which randomized 2708 patients. Patients receiving
bucindolol, a nonselective -blocker with
vasodilatory properties, showed a significant decrease in cardiovascular
mortality as well as significant decreases in norepinephrine levels and
significant increases in LV function. Subgroup analysis suggested that black
patients may have fared worse with bucindolol. This result raised questions
regarding efficacy of bucindolol in patients with heart failure as well as
concerns that -blockers may not
be an effective therapy for black patients with advanced heart failure.
Heart failure patients with recent AMI have also
not been extensively studied. Patients with heart failure were generally
excluded from post-AMI -blocker trials,
and heart failure patients with recent AMI were excluded from heart failure -blocker trials.
The CAPRICORN study98 was the first large
mortality trial to specifically randomize patients with LV dysfunction
following AMI to assess whether carvedilol in addition to ACE inhibition would
improve all-cause mortality in an era of aggressive reperfusion therapy.
Patients with LV dysfunction (ejection fraction <40%) with or without heart
failure were randomized to carvedilol or placebo early after an AMI. Patients
receiving carvedilol had a lower rate of all-cause mortality (12% vs 15%), with
a hazard ratio of 0.77. The original primary end point for this study was
all-cause mortality. However, because of a lower-than-anticipated overall
mortality in the study sample, a new combined end point of all-cause mortality
or hospital admission for cardiovascular events was adopted. Although there was
no difference in the new primary end point (35% carvedilol vs 37% placebo),
all-cause mortality was lower in patients receiving carvedilol than in those
receiving placebo (12% vs 15%; P
= .03). Although nominally significant for the outcome of all-cause mortality, P = .03 does not meet the higher level of
significance (.005) established when the primary end point was changed from
all-cause mortality to a combined end point of all-cause mortality and
cardiovascular hospitalizations. In practical terms, however, the observed 23%
reduction in mortality represents a clinically important outcome.
With the emergence of strong new evidence
demonstrating that -blockers decrease
morbidity and mortality in a broad range of patients with heart failure,
guidelines from the American College of Cardiology and the American Heart
Association,12 the European
Society of Cardiology,11 and the Heart Failure
Society of America10 all strongly support
the use of -blockers in
patients with heart failure. The recently published, revised heart failure
guidelines of the American College of Cardiology–American Heart Association12 and the European
Society of Cardiology clinical practice guidelines11 recommend use of -blockers in a
broader range of heart failure patients, including those with asymptomatic LV
systolic dysfunction and those with severe symptomatic disease.
These guidelines emphasize that the majority of
patients with heart failure are candidates for -blockers,
with few exceptions. Currently, only patients with absolute contraindications
to these drugs or patients with severe heart failure requiring intravenous
inotropes or mechanical support should not receive these agents. Not only are
these agents beneficial in patients with mild to moderate symptomatic heart
failure caused by systolic dysfunction, but also they improve survival in
patients with severe symptomatic heart failure.
Developed nearly half a century ago by Sir James
Black, -blockers have
become the most extensively scrutinized treatment for heart failure. Basic
science, mechanistic studies, and large, randomized controlled clinical trials
support the value of -blockers for
patients with heart failure caused by systolic dysfunction. Tested in more than
10 000 patients, they reduce morbidity and mortality in class II through
IV heart failure. Along with ACE inhibitors, digoxin, and diuretics, -blockers have
strengthened the armamentarium to improve clinical outcomes of heart failure
patients. The science supporting -blockers
must be translated into practice safely and rationally if the agents are to
achieve their full potential.
Author/Article Information
Author Affiliations: Department of
Internal Medicine, Sections of Cardiovascular Medicine (Drs Foody and Krumholz)
and General Medicine (Dr Farrell), and the Section of Health Policy and
Administration, Department of Epidemiology and Public Health (Dr Krumholz),
Yale University School of Medicine, New Haven, Conn; and the Center for
Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, Conn (Dr
Krumholz).
Corresponding Author: Harlan M.
Krumholz, MD, Yale University School of Medicine, 333 Cedar St, PO Box 208025,
New Haven, CT 06520-8025.
Acknowledgment: We wish to acknowledge the helpful comments of Stephen Gottlieb,
MD, William Abraham, MD, Ed Havranek, MD, Fred Masoudi, MD, and Javed Butler,
MD. We also wish to acknowledge the outstanding editorial assistance of Ms
Maria Johnson.
Financial Disclosure: Dr Krumholz has provided consultation to AstraZeneca and CV
Therapeutics. He has received grant support from Pfizer, Merck, Sanofi, Biogen,
and Bristol-Myers Squibb.
Scientific Review and Clinical Applications
Section Editor: Wendy Levinson, MD, Contributing Editor.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.