ORIGINAL ARTICLE

The prognosis of patients with congestive heart failure

(CHF) can be significantly improved with drug therapy
targeted at the renin-angiotensin and adrenergic ner-
vous system. β-adrenergic blocking drugs, once con-
traindicated in CHF, have now been shown to improve
survival in CHF.

Congestive heart failure (CHF) is a progressive dis-

Beta-Blockers ease afflicting millions of patients and has become
one of the most common cardiovascular diagnoses

for Congestive for admission to the hospital. Despite advances in

therapy, mortality due to CHF remains high. Recent
understandings of the pathophysiology of the dis-

Heart Failure ease has led to more aggressive medical treatments

MATTHEW J. SORRENTINO, MD
Department of Medicine
Section of Cardiology
University of Chicago,
Pritzker School of Medicine
Chicago, Ill
that have significantly improved the survival of
patients with advanced heart failure.
Congestive heart failure can be defined as the
inability of the heart to meet the metabolic
demands of the peripheral tissues without a signifi-
cant increase in left ventricular filling pressures.
This may occur because of the loss of contractility
of the myocardium as after a myocardial infarction
(systolic dysfunction) or secondary to increased fill-
ing pressures needed to adequately fill a stiffened
myocardium with preserved contractility as seen in
hypertensive heart disease (diastolic dysfunction).
When stroke volume begins to fall, compensatory
mechanisms, such as the release of aldosterone,
angiotensin II, and catecholamines, are stimulated
in an attempt to improve myocardial contractility,
restore stroke volume and preserve blood pressure
and perfusion to vital organs.
The stimulation of these compensatory mecha-
nisms, however, account for many of the symptoms
of CHF. The release of aldosterone leads to salt and
water retention eventually causing the congestive
symptoms of heart failure. The feedback of
angiotensin II and catecholamines on the heart mus-
cle cause further myocyte damage thereby worsen-
ing heart failure. In addition, these hormones may
stimulate ventricular arrhythmias increasing the
risk of sudden cardiac death.
The goal of treatment of CHF is to relieve conges-

REPRINTS
Matthew J. Sorrentino, MD, University of Chicago, Pritzker School of Medicine,
Department of Medicine, Section of Cardiology, 5841 S. Maryland Ave., MC
6080, Chicago, IL 60637 USA
The author has stated that he does not have a significant financial interest or
other relationship with any product manufacturer or provider of services dis-
cussed in this article.
Submitted for publication: December 12, 2002. Accepted: January 28, 2003.

210 COMP THER. 2003; 29(4):210–214

tive symptoms, improve exercise tolerance and the
quality of life, prevent further progression of heart
failure and prolong life. Diuretics are used to elimi-
nate congestion. Digoxin can improve exercise time
and decrease hospitalizations for heart failure exac-
erbations. Inhibition of the renin-angiotensin sys-
tem and catecholamines can further improve
symptoms, prevent ongoing cardiac decompensation
and prolong life.
ACE INHIBITORS
The renin-angiotensin system is stimulated in heart
failure when the fall in perfusion pressure to the
kidney from a low cardiac output stimulates the
juxtaglomerular cells of the kidney to release renin.
Renin begins the metabolic cascade that leads to the
synthesis of angiotensin II, a hormone that is a
potent vasoconstrictor thereby maintaining blood
pressure. In addition, feedback of angiotensin II on
the heart improves myocardial contractility, both
directly and indirectly through the stimulation of
the release of norepinephrine, and works as a
potent growth factor leading to left ventricular
hypertrophy. The production of angiotensin II also
stimulates the release of the salt and water retaining
hormone aldosterone. These hormones are elevated
early in CHF before the onset of symptoms. With
time, however, feedback of these hormones on the
myocardium can increase cardiac fibrosis, worsen
myocardial function and increase the risk of cardiac
arrhythmias and sudden death.
Angiotensin converting enzyme (ACE) inhibitors
can improve cardiac performance by decreasing sys-
temic vascular resistance (afterload reduction) and
decrease the effects of angiotensin II on the
myocardium. Clinical studies have shown that ACE
inhibitors improve the quality of life and mortality
in patients with systolic dysfunction. In the Cooper-
ative North Scandinavian Enalapril Survival Study
(CONSENSUS),1 enalapril compared to placebo in
NYHA Class IV CHF patients showed a significant
improvement in survival and the quality of life. The
Studies of Left Ventricular Dysfuction (SOLVD)
group2 extended these results to symptomatic and
asymptomatic heart failure patients with ejection
fractions less than 35%. These studies suggest that
the early treatment of systolic dysfunction even
before the onset of symptoms can improve the qual-
ity of life by reducing hospitalizations, the onset of
symptoms and lead to fewer deaths due to cardio-
vascular disease. These studies and others have led
to the recommendation that ACE inhibitors are
drugs of first choice in patients with left ventricular
dysfunction even in the absence of symptoms.
NEUROHORMONAL ACTIVATION
In addition to the early production of angiotensin II,
an early change in CHF patients is the activation of
the sympathetic nervous system. Norepinephrine
levels are elevated in patients with heart failure and
are predictive of mortality.3 Chronic activation of
the sympathetic nervous system improves contrac-
tility of the myocardium and enhances cardiac out-
put and perfusion. There are deleterious effects of
chronic sympathetic activation as well. Elevated
catecholamine levels lead to increased heart rate,
increased systemic and pulmonary vascular resis-
tance, and decreased renal blood flow. This can lead
to worsening myocardial ischemia, myocyte necro-
sis and fibrosis, and arrhythmias. Catecholamines,
in addition to angiotensin II and aldosterone, are
responsible for deleterious cardiac remodeling and a
progressive decline in cardiac function.
As it became clear that the progression of heart
failure is due to over activation of compensatory
mechanisms, treatments designed to blunt these
responses were studied. The ACE inhibitor trials
showed clear symptomatic and mortality benefit by
inhibition of the production of angiotensin II. Inhi-
bition of the sympathetic nervous system with β-
adrenergic blocking drugs has now been shown to
give clear benefits as well.
H O W β- A D R E N E R G I C B L O C K I N G D R U G S
WORK
Catecholamines mediate their actions through the
action of adrenergic receptors. There are three
adrenergic receptors present in cardiac tissue. The
biologic responses mediated by these receptors are
listed in Table 1. The major catecholamine stimulat-
ing the heart is norepinephrine released primarily
from local sympathetic nerve endings in the heart.4
Initially, norepinephrine will improve cardiac per-
formance but over time will lead to progressive
heart failure by producing cardiac myocyte injury
TABLE 1
Biologic Responses Mediated by Adrenergic Receptors
in the Human Heart (Adapted from 5)
Biologic Response Adrenergic Receptor
Cardiac myocyte hrowth β1, β2, α1
Positive inotropic
tesponse β1, β2, minimal α1
Positive chronotropic
response β1, β2
Myocyte toxicity β1 predominantly, β2
Myocyte apoptosis β1
COMP THER. 2003; 29(4) 211
and cell death. In patients with CHF, chronic sym-
pathetic stimulation causes the down regulation of
β1-adrenergic receptors. This may be an adaptive
change in the failing heart but substantial signaling
capacity remains to allow ongoing myocardial toxic-
ity from chronic overactivity of the sympathetic
nervous system.5 The rationale behind β-adrenergic
blocking drug therapy is to enhance this endoge-
nous anti-adrenergic strategy by further inhibition
of the effects of the sympathetic nervous system.
β- A D R E N E R G I C B L O C K I N G D R U G
CLASSIFICATION
There are three classes of β-adrenergic blocking
drugs commonly used clinically. Nonselective
β-adrenergic blocking drugs, such as propranolol,
have equal affinities for blocking both β 1 - and
β2-adrenergic receptors. The cardioselective β-adren-
ergic blocking drugs, such as metoprolol and biso-
prolol, selectively block β 1 adrenergic receptors
compared with β2 adrenergic receptors. Metoprolol
is about 75-fold selective for β1- versus β2-adrenergic
receptors while bisoprolol is about 120-fold selec-
tive.5 The third class of agents are the α-β-adrenergic
blocking drugs such as carvedilol. These agents are
nonselective β-adrenergic blocking drugs as well as
α-adrenergic blocking drugs leading to further
peripheral vasodilatation. They are commonly used
as effective antihypertensive agents. Both the selec-
tive β-adrenergic blocking drugs and the α-β-adren-
ergic blocking drugs have been studied in heart
failure. There is still debate whether a strategy to
antagonize only the β1-adrenergic receptors respon-
sible for cardiac toxicity with the selective β-adren-
ergic blocking drugs will offer more advantage to
patients than a more global adrenergic blockade as
offered by the nonselective α-β-adrenergic blocking
drugs. The recently completed Carvedilol or Meto-
prolol European Trial (COMET) comparing these
Selected Mortality Trials with β-Adrenergic Blocking Drugs in Heart Failure11
Functional
No. of Class II/III/IV
Trial Pts. (% per group)
US Carvedilol Heart Failure 1,094
Study
Cardiac Insufficiency 2,647
Bisoprolol Study-II
Metoprolol CR/XL 3,991
Randomized Intervention Trial
212 COMP THER. 2003; 29(4)
two agents in heart failure showed an absolute 5.7%
benefit in survival with carvedilol although the
metoprolol dose used in this trial was substantially
lower than the dose used in previous trials.6
CLINICAL TRIALS
A Swedish group first reported in 1975 in an uncon-
trolled study that long-term β-adrenergic blockade
improved symptoms in dilated cardiomyopathy
patients.7 Swedberg and collegues reported a series of
heart failure patients that had an improvement in
survival with β-adrenergic blocking drugs when com-
pared with age-matched controls.8 This was followed
by a randomized multicenter trial that showed that
metoprolol improved exercise time, raised ejection
fractions and lowered pulmonary capillary wedge
pressures in patients with dilated cardiomyopathy
compared to placebo.9 A small study performed in
this country showed an improvement in exercise
capacity and functional class in dilated cardiomyopa-
thy patients referred to a heart transplant center.10
Despite these intriguing results, most experts felt that
β-adrenergic blocking drugs were contraindicated in
heart failure because of the observed worsening of
symptoms that would occasionally occur in patients
with left ventricular dysfunction.
Three major mortality studies using β-adrenergic
blocking drugs in heart failure have been completed
and have shown a striking mortality benefit when β-
adrenergic blocking drugs were added to standard
heart failure therapy (usually diuretics, digoxin, and
ACE inhibitors),11 Table 2. Both selective β-adrener-
gic blocking drugs and α-β-adrenergic blocking
drugs have been used in these trials.
The US Carvedilol trials were the first mortality
trials to be completed. Carvedilol is a nonspecific α-
β-adrenergic blocking drug. The carvedilol program
consisted of four separate protocols in patients with
ejection fractions less than 35% entering the trials
TABLE 2
Ejection Mortality Medication/
Fraction Reduction Target Dose
53/44/3 23% 65% Carvedilol,
25–50 mg b.i.d.
0/83/17 28% 34% Bisoprolol,
10 mg q.d.
41/55/4 28% 34% Metoprolol CR/XL
200 mg q.d.
based on a 6-minute exercise test dividing the group
into mild, moderate or severe heart failure.12 The
pooled data of all four studies showed a dramatic
improvement in morbidity and mortality prompting
the data monitoring committee to prematurely end
the study. The overall mortality rate was 7.8% in the
placebo group and 3.2% in the carvedilol group (65%
relative risk reduction) during an average follow-up
of 6.5 months. In addition, hospitalizations for heart
failure were reduced in the carvedilol group.
The initial US carvedilol trials did not evaluate a
large number of patients with advanced severe
heart failure. The Carvedilol Prospective Random-
ized Cumulative Survival (COPERNICUS) trial eval-
uated carvedilol in over 2000 patients with NYHA
Class IV heart failure and an ejection fraction less
than 25%.13 Cavedilol was started in the hospital at
3.125 mg b.i.d. after patients were stabilized out of
the intensive care unit and off inotropic drugs for
four days. Patients in the carvedilol group had a
35% risk reduction in total mortality. This study
showed that it was safe to start β-adrenergic block-
ing drugs in patients with severe heart failure once
they had been treated for pulmonary congestion.
Treatment with β-adrenergic blocking drugs is rec-
ommended to begin in the hospital with slow titra-
tion of the dose to full dose as an outpatient.
There have been two major β-adrenergic blocking
drug trials using selective β1-adrenergic receptor
antagonists. The Cardiac Insufficiency Bisoprolol
Study II (CIBIS-II) studied the highly-selective β1-
adrenergic receptor antagonist bisoprolol in 2647
symptomatic NYHA Class III–IV CHF patients with
ejections fractions of 35% or less.14 The study was
stopped early with a significant 34% decrease in all
cause mortality in patients taking the β-adrenergic
blocking drug.
The Metoprolol CR/XL Randomised Intervention
Trial in Congestive Heart Failure (MERIT-HF)
enrolled 3,991 patients with NYHA Class II–IV
heart failure and an ejection fraction of 40% or
less.15 Extended-release metoprolol was used at a
starting dose of 12.5 to 25 mg/d. The dose was dou-
bled every two weeks to a maximum dose of 200
mg/d. The mean daily dose of metoprolol achieved
at the end of the study was 159 mg/d with 64% of
patients receiving the target dose of 200 mg/d. Simi-
lar to the CIBIS-II trial, there was a 34% risk reduc-
tion in total mortality in the metoprolol group.
Are all β-adrenergic blocking drugs the same?
Carvedilol, an α-β-adrenergic blocking drug, and the
cardiac selective β-adrenergic blocking drugs have
shown mortality reductions in patients with CHF.
Could this experience be extrapolated to all β-adren-
ergic blocking drugs? The Beta-Blocker Evaluation
of Survival Trial Investigators (BEST) studied bucin-
dolol, a nonselective β-adrenergic blocking drug, in
patients with severe heart failure.16 The study was
stopped after two years because no significant dif-
ferences were observed for the primary endpoint of
all cause mortality although cardiovascular deaths
were decreased with the β-adrenergic blocking
drug. This result suggests that the mortality benefits
of β-adrenergic blocking drugs cannot be considered
a class effect given the neutral results of this study.
H O W T O U S E β- A D R E N E R G I C B L O C K I N G
DRUGS IN HEART FAILURE.
All patients with CHF are potential candidates for β-
adrenergic blocking drug therapy. Table 3 lists the
relative contraindications for β-adrenergic blocking
drug use. Care should be taken in patients who
experience sudden worsening of their heart failure
symptoms. β-adrenergic blocking drugs should be
held if patients are admitted to the hospital in pul-
monary edema until the congestion is relieved and
inotropic support is no longer required. Patients
presenting with tachycardia and hypotension may
experience complications with β-adrenergic block-
ing drug therapy. These individuals are hyperadren-
ergic and require catecholamine stimulation to
maintain an adequate cardiac output and blood
pressure. β-adrenergic blockade can lead to hemo-
dynamic collapse. In addition, asthma is a relative
contraindication to β-adrenergic blocking drugs
since these agents can worsen bronchospasm. β-
adrenergic blocking drugs can be safely used in dia-
betics without undue concern that patients will be
unable to recognize hypoglycemic reactions.
The data from the β-adrenergic blocking drug tri-
als strongly support the use of these drugs in
patients with NYHA Class II, III and stabilized
NYHA Class IV heart failure. A treatment benefit is
less certain in asymptomatic or NYHA Class I heart
failure. Certain groups of patients do have a clear
TABLE 3
Relative Contraindications to β-Adrenergic Blocking Drugs
• Reactive Airway Disease sensitive to
β-adrenergic blocking drugs
• Bradycardia (heart rate < 50 bpm)
• Hypotension (systolic blood pressure
< 90 mm Hg)
• Second or third degree heart block
• Significant CHF exacerbation (pulmonary edema,
need for inotropic agents, tachycardia and
hypotension suggesting hyperadrenergic state)
COMP THER. 2003; 29(4) 213

β-Adrenergic Blocking Drug Starting and Target Doses
Medication
Carvedilol
Bisoprolol
Metoprolol CR/XL
benefit from β-adrenergic blocking drugs. For exam-
ple, β-adrenergic blocking drugs are indicated in
post myocardial infarction patients with asympto-
matic left ventricular dysfunction.
The agents that should be used for CHF are the
medications shown to give benefit in the large ran-
domized clinical trials. β-adrenergic blocking drug
treatment is started after the patient’s clinical status
is stabilized on appropriate doses of diuretics and
ACE inhibitors. β-adrenergic blocking drug treat-
ment is started at a low dose with every two week
titration to the target levels established in the clinical
trials (Table 4). Patients may experience some side
effects early in the titration. If patients experience
dizziness or low blood pressure, diuretic doses can
be reduced with improvement in symptoms. Symp-
tomatic improvement with β-adrenergic blocking
drug therapy may not be noticed by the patient for
two to three months after starting therapy. In addi-
tion, therapy may improve survival without bringing
about an improvement in symptoms. For this rea-
son, patients should be encouraged to remain on the
drug even if no symptomatic relief is obtained.
SUMMARY
The treatment of CHF has evolved with an
improved understanding of the causes of the pro-
gression of heart failure. Several large clinical trials
with strategies inhibiting the renin-angiotensin-
aldosterone and adrenergic systems have shown sig-
nificant improvements in morbidity and mortality.
Current guidelines for the treatment of CHF indi-
cate the use of β-adrenergic blocking drugs for
patients with symptomatic left ventricular systolic
dysfunction and ejection fractions less than 40%.
Despite these recommendations, large numbers of
patients with CHF are either not being treated or
are on subtherapeutic doses of β-adrenergic block-
ing drugs. Our challenge as health care providers is
to identify patients who can benefit from further
therapy and ensure that the proper dose of β-adren-
ergic blocking drugs are used to improve the mor-
bidity and mortality of CHF patients. CT
214 COMP THER. 2003; 29(4)
TABLE 4
Starting Dose Target Dose
3.125 mg b.i.d. 25–50 mg b.i.d.
1.25 mg daily 10 mg daily
12.5–25 mg daily 200 mg daily
REFERENCES
1. The CONSENSUS Trial Study Group. The effects of
enalapril on mortality in severe congestive heart failure. N
Engl J Med. 1987;316:1429–1435.
2. The SOLVD Investigators. Effect of enalapril on mortality
and the development of heart failure in asymptomatic
patients with reduced left ventricular ejection fractions. N
Engl J Med. 1992;327:685–691.
3. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepineph-
rine as a guide to prognosis in patients with chronic conges-
tive heart failure. N Engl J Med. 1984;311:819–823.
4. Carson PE. Beta blocker treatment in heart failure. Prog
Cardiovasc Dis. 1999;41:301–322.
5. Bristow MR. β-Adrenergic receptor blockade in chronic
heart failure. Circulation. 2000;101:558–569.
6. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Compari-
son of carvedilol and metoprolol on clinical outcomes in
patients with chronic heart failure in the Carvedilol Or
Metoprolol European Trial (COMET): randomized con-
trolled trial. Lancet. 2003;362:7–13.
7. Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I.
Effect of chronic beta-adrenergic receptor blockade in con-
gestive cardiomyopathy. Br Heart J. 1975;37:1022–1036.
8. Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Pro-
longation of survival in congestive cardiomyopathy by beta-
receptor blockade. Lancet. 1979;1:1264–1266.
9. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial
effects of metoprolol in idiopathic dilated cardiomyopathy.
Lancet. 1993;342:1441–1446.
10. Engelmeier RS, O’Connell JB, Walsh R, Rad N, Scanlon PJ,
Gunnar RM. Improvement in symptoms and exercise toler-
ance by metoprolol in patients with dilated cardiomyopa-
thy: A double-blind, randomized, placebo-controlled trial.
Circulation. 1985;72:536–546.
11. Garg RK, Sorrentino MJ. Beta blockers for CHF: Adrenergic
blockade dramatically reduces morbidity and mortality.
Postgrad Med. 2001;109:49–56.
12. Packer M, Bristow MR, Cohn JN, et al. The effect of
carvedilol on morbidity and mortality in patients with
chronic heart failure. N Engl J Med. 1996;334:1349–1355.
13. Packer M, Coats AJ, Fowler MB, et al. Carvedilol Prospec-
tive Randomized Cumulative Survival Study Group. Effect
of carvedilol on survival in severe chronic heart failure. N
Engl J Med. 2001;344:1651–1658.
14. CIBIS-II Investigators and Committees. The Cardiac Insuffi-
ciency Bisoprolol Study-II (CIBIS-II): A randomized trial.
Lancet. 1999;353:9–13.
15. MERIT-HF Study Group. Effect of metoprolol CR/XL in
chronic heart failure: Metoprolol CR/XL Randomised Inter-
vention Trial in Congestive Heart Failure (MERIT-HF).
Lancet. 1999;353:2001–2007.
16. Beta-Blocker Evaluation of Survival Trial Investigators. A
trial of the beta-blocker bucindolol in patients with advanced
chronic heart failure. N Engl J Med. 2001;344:1659–67.