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Treatment of congestive heart failure: Guidelines for the primary care physician
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 REVIEW ARTICLE

Treatment of Congestive Heart Failure

Guidelines for the Primary Care Physician and the Heart Failure Specialist
Mardi Gomberg-Maitland, MD; David A. Baran, MD; Valentin Fuster, MD, PhD

D
uring the past 10 years, the philosophy of heart failure treatment has evolved from
symptom control to a combined prevention and symptom-management strategy. Re-
cent clinical trials have proved that early detection can delay progression. Treatment
of asymptomatic left ventricular dysfunction is as important as treatment of symp-
tomatic disease. The purpose of this review is to simplify recent guidelines for pharmacological
management of chronic systolic heart failure for the primary care physician and the heart failure
specialist. Early recognition and prevention therapies, combined with lifestyle modification, are
essential in the treatment of heart failure. Therapy with angiotensin-converting enzyme inhibi-
tors, b-blockers, and diuretics is now standard. Digoxin is added to improve clinical symptoms,
especially in patients with atrial fibrillation. Aldosterone antagonists may be recommended in se-
lect patients with stable New York Heart Association class III or IV heart failure. If angiotensin-
converting enzyme inhibitors are not tolerated, angiotensin receptor blockers, hydralazine hydro-
chloride, and isosorbide dinitrate are recommended. The data on antiarrhythmic and anticoagulation
therapies are inconclusive. Arch Intern Med. 2001;161:342-352

During the past 10 years, the philosophy
of heart failure treatment has evolved
from symptom control to a combined
prevention and symptom-management
strategy. Within cardiology, heart failure
specialists have been trained to tackle
this now enormous field. Our continu-
ally improving understanding of the
pathophysiology of heart failure has
accelerated the development of new
treatments. However, no single measure-
ment accurately reflects the effectiveness
of therapy.1 Exhaustive guidelines that
attempt to simplify treatment, written by
various authoritative bodies, make for
intimidating reading.
Recent clinical trials have proved
that early detection can delay progres-
sion.2,3 Treatment of asymptomatic left
ventricular dysfunction is as important
as treatment of symptomatic disease.
Because heart failure specialists are usu-
ally referred symptomatic patients, their
patients usually enter the heart failure
From the Department of Cardiology, The Zena and Michael A. Wiener Cardiovascular
Institute, Mount Sinai Medical Center, New York, NY.
treatment triangle after the prevention
stage (Figure 1).4 Most patients with
asymptomatic left ventricular dysfunc-
tion and early stages of heart failure will
be seen by a general practitioner. The
general practitioner will need to identify
these patients and begin preventive
therapy. Improved prevention and early
intervention should be promoted. 4-6
Therefore, despite the inherent com-
plexities of heart failure therapy, it is
important for all physicians to know cur-
rent management strategies to prevent
end-stage disease.
The treatment of heart failure
encompasses pharmacological therapy
and includes surgical approaches such
as revascularization of coronary arteries,
mitral valve repair, aortic valve replace-
ment, ventriculectomy, cardiomyo-
plasty, and left ventricular assist devices
with heart transplant. The purpose of
this review is to simplify recent guide-
lines for pharmacological management
of chronic systolic heart failure for the
primary care physician and the heart
failure specialist.

(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001 WWW.ARCHINTERNMED.COM
342

©2001 American Medical Association. All rights reserved.

 DEFINITION
Heart failure is a complex clinical
syndrome that may include fatigue
and shortness of breath on exer-
tion (and in advanced cases, at
rest), orthopnea, paroxysmal noc-
turnal dyspnea, nocturia, mental
status changes, anorexia, and
abdominal pain. Patients have dif-
ferent symptoms based on clinical
severity. The syndrome can result
from any cardiac disorder that
impairs the heart’s ability to fill
and/or relax or empty. Inability to
fill and relax the left ventricle is
diastolic dysfunction, defined as an
elevated end-diastolic pressure in a
normal-sized chamber, whereas
difficulty emptying the left ven-
tricle is systolic dysfunction, repre-
sented by a reduced ejection frac-
tion.1,7,8 Ischemic (coronary artery
disease [CAD]) and nonischemic
conditions (hypertension, valvular
disease, hypertension, thyroid dis-
ease, alcohol abuse, myocarditis,
adult congenital heart disease, and
cardiomyopathy) may cause sys-
tolic dysfunction. 1,9,10 Coronary
artery disease accounts for ap-
proximately two thirds of these
cases,8,10,11 whereas “pure” diastolic
dysfunction with preserved systolic
function is seen in patients with
left ventricular hypertrophy,
hypertension, and CAD.12 The left
ventricle’s inability to relax effi-
ciently may be transient, as in a
patient with ischemia, or sus-
tained, as in a patient with concen-
tric myocardial hypertrophy or
restrictive cardiomyopathy second-
ary to infiltrative disorders.7,12
The severity of heart failure is
defined symptomatically, and the
most commonly used system is the
New York Heart Association
(NYHA) functional classification.13
Patients are grouped according to the
degree of effort needed to elicit heart
failure symptoms. Class I patients
exhibit symptoms only at exertion
levels similar to those achieved
readily by healthy individuals,
whereas class II patients have symp-
toms on ordinary exertion. Class III
patients have symptoms on mini-
mal exertion, and class IV patients
have symptoms at rest.13 There are
2 major problems with the classifi-
cation system, ie, a high degree of
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
interobserver variability to assign-
ment of class and an inability to
detect small changes in clinical
status.14 For now, this is the easi-
est method to group patients,
despite limited ability to predict
the degree of physiological systolic
dysfunction.
Diagnostic examinations can
help expedite appropriate treat-
ment. The most valuable initial di-
agnostic examination is the 2-di-
mensional echocardiogram coupled
with Doppler flow studies. It is eas-
ily accessible and inexpensive. Pa-
tients with ejection fractions of no
greater than 0.40 are considered to
have systolic dysfunction. The study
assesses systolic and diastolic ab-
normalities involving the right and
left sides of the heart, and it deter-
mines the presence of pericardial, en-
docardial, valvular, and vascular ab-
normalities.8 Patients with heart
failure often have multiple cardiac
abnormalities causing or contribut-
ing to their disease. Radionuclide
ventriculography also reveals biven-
tricular global and regional wall mo-
tion abnormalities. However, it does
not permit assessment of other car-
diac abnormalities. An assessment of
ventricular function is recom-
mended during the patient’s initial
presentation.8
Repeated diagnostic testing is
of debatable value. Without a cor-
responding clinical change in func-
tional status, there is little value in
slight changes in measured ejec-
tion fraction. Most believe that a re-
peated assessment of ejection frac-
tion is warranted if there is a
significant change in clinical sta-
tus, or if the patient has had a re-
cent event.8
Heart failure specialists use ex-
ercise testing to better determine
functional capacity. The measure-
ment of peak oxygen consumption
is a good measure of capacity, but
it is not clear if exercise testing ac-
curately measures daily physical
stresses encountered by the pa-
tient.15,16 Exercise testing is highly
dependent on the motivation of the
patient and the physician.15,16
EPIDEMIOLOGY
In the United States, 4.8 million per-
sons have heart failure, with ap-
WWW.ARCHINTERNMED.COM
343
Heart Failure Treated
by Specialist
General
Practitioner–Managed
Heart Failure
Unknown
Heart Failure
Asymptomatic
Ventricular
Dysfunction
Figure 1. The iceberg phenomenon of the heart
failure/left ventricular dysfunction syndrome.
proximately 400000 to 700000 new
cases each year.17-19 Heart failure af-
fects approximately 1.5% to 2% of
the population.17-19 At present, the
prevalence in Americans older than
65 years is 6% to 10%, and this
prevalence is expected to rise as the
aged population grows and median
life span increases.17-19 Heart fail-
ure is the leading cause of hospital-
ization,18,19 and in addition, as many
as 20 million patients have an
asymptomatic impairment of car-
diac function, with symptoms likely
to develop in the next 1 to 5 years.20
Despite the higher incidence of heart
failure in men in every age group, the
prevalence in women is approxi-
mately equal.17,21 Unfortunately,
women only account for approxi-
mately 20% of patients in most clini-
cal trials,22 which makes most of the
treatment guidelines for women al-
most speculative.
Heart failure is a progressive, fa-
tal disease. The number of deaths
due to heart failure as a primary or
secondary cause has increased 6-fold
during the last 40 years,19,23,24 de-
spite new advances in treatment. The
risk for death is 5% to 10% annu-
ally in patients with mild symp-
toms and increases to approxi-
mately 30% to 40% annually in
patients with advanced disease.23
With the increasing prevalence, hos-
pital expenditures have escalated.19
Annual direct expenditures, which
include cost of medications, hospi-
talizations, nursing home admis-
sions, and medical follow-up, are
estimated at $20 billion to $40
billion.8,19 Thus, educating all phy-
sicians about treatment guidelines
can have a significant public health
impact.

Coronary Artery Disease
Hypertension Left Ventricular
Remodeling
Cardiomyopathy Dysfunction
Valvular Disease
Noncardiac
Factors
Figure 2. The management of congestive heart failure. Left ventricular dysfunction develops through
ventricular remodeling. This leads to arrhythmia, pump failure, and death. Noncardiac factors may be
stimulated by left ventricular dysfunction, but ultimately contribute to cardiac remodeling. Present
pharmacological management is directed at disrupting these pathways.
PATHOPHYSIOLOGY
The philosophy of current treat-
ment can best be understood by re-
viewing the evolution of heart fail-
ure models. From 1940 through
1960, heart failure was thought to re-
sult primarily from renal hypoperfu-
sion.25,26 Standard treatment con-
sisted of digoxin, diuretics, bed rest,
and leg elevation, aimed at improv-
ing renal function and symptoms of
dyspnea and edema. From the 1960s
through the 1980s, physicians
adopted the hemodynamic model,26,27
which suggested that increased ven-
tricular wall stress is the principal
causeoftheheartfailuresyndrome.26,27
An initial injury is thought to initiate
a deleterious feedback cycle by caus-
ing a change in left ventricular geom-
etry of dilation and hypertrophy.28,29
This structural remodeling of the
heart produced by cardiac dysfunc-
tion results in increased preload and
afterload. In turn, the increased size
causes increased wall stress, thus
worsening cardiac performance.30 The
change in geometry also increases mi-
tral regurgitation, worsening ejec-
tion efficiency and further increas-
ing wall stress.8 Treatment was aimed
at vasodilation and improving ven-
tricular contractility to improve car-
diac output and to reduce the wall
stress aggravated by elevated pre-
load and afterload. However, clini-
cal trials of inotropic agents did not
produce long-term mortality ben-
efits, contradicting predictions based
on this model.
The change in focus to the en-
dogenous factors that alter the long-
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
Arrhythmia
Low Ejection
Death
Fraction
Pump
Failure
Symptoms
Chronic
Heart Failure
term structure of the myocardium and
vasculature has revolutionized heart
failure treatment. Activation of neu-
rohormonal systems plays an impor-
tant role in cardiac remodeling (the
alterations in ventricular architec-
ture that occur during the develop-
ment of heart failure).31-34 Many drug
treatments now target the mediators
of the neurohormonal systems acti-
vated in heart failure. Stimulation of
the sympathetic and renin-angioten-
sin systems1,35 lead to elevated levels
of norepinephrine, angiotensin II, al-
dosterone, and vasopressin.1,35 The net
effects of these mediators are vaso-
constriction, increased blood vol-
ume, increased heart rate, and in-
creased contractility.7
Endogenous factors may not
only increase hemodynamic stresses
on the ventricle but also exert direct
toxic effects on the heart.36,37 These
effects may be mediated through vari-
ous cell-signaling pathways that dis-
turb normal myocyte activity, ini-
tiate apoptosis, and promote
fibrosis.37-44 Other neurohormonal
factor levels increased in patients are
endothelin, epinephrine, growth hor-
mome, cortisol, tumor necrosis fac-
tor, prostaglandins, substance P, ad-
renomedullin, and natriuretic
peptides.45 Despite past controversy
about the treatment of ischemic vs
nonischemic heart failure, the pres-
ent consensus is that they should be
treated by the same guidelines.46 This
seems logical because the present
paradigm suggests that they have
similar pathophysiology (Figure 2).1
Heart failure prevention and
treatment now consists of a mul-
WWW.ARCHINTERNMED.COM
344
tidisciplinary approach, including
lifestyle modification to prevent ini-
tial and recurrent injury and phar-
macological intervention to pre-
vent progression in asymptomatic
and symptomatic patients. Coro-
nary artery disease and hyperten-
sion are the 2 most common causes
of heart failure. Two major trials
have demonstrated that the preven-
tion of both factors decreases the risk
for development of heart failure. The
treatment of hypertension in the Sys-
tolic Hypertension in the Elderly
Program (SHEP) trial47 decreased the
risk for development of heart fail-
ure by 81%.48 The treatment of hy-
percholesterolemia in the Scan-
dinavian Simvastatin Survival Study
(4S trial) with a hepatic hydroxy-
methyl glutaryl coenzyme A reduc-
tase inhibitor decreased the risk for
development of heart failure by
20%.49 Modifying lifestyle factors
that contribute to the pathophysi-
ology of hypertension and CAD,
such as smoking, obesity, excess al-
cohol intake, and diabetes, may also
affect heart failure prevention. Iden-
tification and aggressive manage-
ment of potential risk factors for
cardiovascular disease remain im-
portant. However, large-scale clini-
cal trial data have yet to demon-
strate direct effects of adjustment of
these factors on risk for develop-
ment or acceleration of congestive
heart failure (CHF).
GUIDELINES FOR
DRUG THERAPY
Pharmacological intervention con-
tinues to be the mainstay of man-
agement of CHF, and abundant
clinical trial data describe the spe-
cific effects of various agents.
Although sometimes puzzling and
contradictory, the extensive clini-
cal trial database for heart failure
has provided clinicians with
important information, and this
serves as the basis for guidelines
proposed by various expert com-
mittees.
Diuretics
Clinical trials have demonstrated fast
improvement in sodium excretion,
symptoms of fluid overload,50,51 ex-
ercise tolerance, and improvement of
cardiac function52 with diuretics. Most
long-term trials include patients re-
ceiving diuretics, but there are no
long-term studies of diuretics in heart
failure (we refer here to thiazides and
loop diuretics and reserve discus-
sion of spironolactone for a separate
category). Therefore, there is no
proven mortality benefit. Patients
should not be prescribed diuretics as
monotherapy, should start diuretic
therapy for symptoms of fluid reten-
tion, and should continue using these
agents after improvement of symp-
toms.8,52
The practitioner should care-
fully titrate these medications to avoid
excessive volume depletion but al-
low for some decreased renal func-
tion.8,52 Undertitration of primary di-
uretics can diminish the patient’s
response to angiotensin-converting
enzyme (ACE) inhibitors (resulting
from a state of relative volume over-
load) and increase the frequency of
adverse effects of treatment with
b-blockers.53,54 Although ACE inhibi-
tors and digoxin have weak diuretic
properties,53-56 only primary diuret-
ics can control fluid overload ad-
equately. Loop diuretics should be
used as first-line agents, with thia-
zides added for refractory fluid over-
load. Diuretic treatment should be
combined with a low-salt diet,8 a
b-blocker, and an ACE inhibitor.2,3
The practitioner should begin
with oral furosemide, 20 to 40 mg
once daily. Dose titration goals are
maintenance of adequate renal per-
fusion, avoidance of symptomatic
hypotension, and achievement of
stable weight. Hydrochlorothia-
zide, 25 mg, can be added with re-
fractory fluid overload to escalat-
ing furosemide doses. With doses of
oral furosemide of 120 mg twice
daily, 2.5 to 5.0 mg of metolazone
can be added 30 minutes before each
dose for improved diuresis. Adding
metolazone should be approached
with caution because of the poten-
tial for severe hypokalemia and hy-
pomagnesemia. The practitioner
may switch furosemide to bu-
metanide, 2 to 4 mg/d, with 2.5 mg
of metolazone added as needed.
ACE Inhibitors
Angiotensin-converting enzyme in-
hibitors have beneficial effects in the
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
treatment and prevention of heart
failure. Six ACE inhibitors are ap-
proved by the Food and Drug Ad-
ministration for the management of
heart failure, ie, captopril, enalapril
maleate, lisinopril, quinapril hydro-
chloride, trandolapril, and fosino-
pril sodium.20 Ramipril is approved for
the treatment of heart failure after a
myocardial infarction.20 The first
study to demonstrate a clinical ben-
efit in symptoms was the Captopril
Multicenter Study in 1983.57 Many
double-blind placebo-controlled tri-
als with different ACE inhibitors sup-
ported these findings.20 However, 4
major trials of intermediate to long-
term duration established the mor-
bidity and mortality benefit of ACE
inhibitors.
Captopril-Digoxin Multicenter
Trial. The trial studied patients with
mild to moderate heart failure,
(NYHA class II, 81%) of ischemic
and nonischemic origins who were
already receiving diuretics and were
randomized to additional treat-
ment with placebo, digoxin (up to
0.375 mg/d), or captopril (up to 150
mg/d). Captopril decreased emer-
gency care or hospitalization for
worsening heart failure compared
with placebo.58
Studies of Left Ventricular Dys-
function Treatment Trial. The Stud-
ies of Left Ventricular Dysfunction
(SOLVD) Treatment trial also stud-
ied patients with mild to moderate
heart failure (NYHA classes II and
III) with ischemic and nonisch-
emic origins. Patients were random-
ized to receive placebo or enalapril
maleate (up to 20 mg/d) in addi-
tion to conventional therapy. The
combination of enalapril and con-
ventional therapy decreased all-
cause mortality and the risk for
death or hospitalization for heart fail-
ure compared with that for pla-
cebo.59
Vasodilator Heart Failure Trial II.
Patients with NYHA classes II and
III heart failure were randomized to
enalapril maleate (up to 20 mg/d) or
a combination of hydralazine (300
mg/d) plus isosorbide dinitrate (160
mg/d), with both regimens added to
conventional therapy. At 2 years,
enalapril reduced the risk for death
WWW.ARCHINTERNMED.COM
345
28% more than the combination va-
sodilator therapy.60
Cooperative North Scandinavian
Enalapril Survival Study. Patients
with NYHA class IV ischemic and
nonischemic heart failure were ran-
domized to enalapril maleate (up to
40 mg/d) or placebo added to con-
ventional therapy.61 The study dem-
onstrated a 27% reduction in all-
cause mortality at 6 months. Patients
improved functional class and re-
duced their requirement for other
heart failure medications.
Despite copious aggregate evi-
dence of their benefits, ACE inhibi-
tors have been underprescribed in
the United States21 and abroad.6,21,62-64
Angiotensin-converting enzyme in-
hibitors are also given in lower doses
by practitioners than in clinical tri-
als protocols.65 A few recent stud-
ies have addressed the issue of ACE
inhibitor dose effects. The Assess-
ment of Treatment with Lisinopril
and Survival (ATLAS) Study evalu-
ated the difference between high-
(32.5-35.0 mg/d) and low-dose (2.5-
5.0 mg/d) lisinopril in patients with
NYHA classes II through IV heart
failure.9 The study demonstrated no
improvement in mortality, but a de-
creased hospitalization rate for all
causes and heart failure in the high-
dose group.9,20 The Network Study
evaluated different doses of enala-
pril maleate (2.5, 5.0, or 10.0 mg
twice daily) and demonstrated no
difference between high- and low-
dose groups for any end point mea-
sured.66 Finally, the ongoing Accu-
pril Congestive Heart Failure
Investigation and Economic Vari-
able Evaluation (ACHIEVE) trial is
presently evaluating different doses
of quinapril hydrochloride (5-20 mg
twice daily) and mortality.67,68 Al-
though underdosing of ACE inhibi-
tors has been a prominent concern for
many heart failure specialists, avail-
able data have yet to verify subthera-
peutic effects of treatment regimens
involving lower doses than those de-
scribed in the original trials.
Angiotensin-converting en-
zyme inhibitors are recommended
preventive treatment in patients who
have experienced a recent or re-
mote ischemic or nonischemic event
resulting in systolic dysfunction.8
Four major trials supporting this
statement are the Survival and Ven-
tricular Enlargement Trial (SAVE; up
to 150 mg/d),69 the Acute Infarc-
tion Rampiril Efficacy Trial (AIRE;
2.5 or 5.0 mg twice daily),69,70 the
Trandolapril Cardiac Evaluation
Study (TRACE; up to 4 mg/d),71 and
the previously described SOLVD
Trial (evaluating the group of
asymptomatic and symptomatic
patients).72 Post hoc analysis of ACE
inhibitor plus b-blocker therapy in
the SOLVD database73 showed that
the combination of b-blocker and
enalapril was associated with a
greater reduction in mortality than
the use of either agent alone.
Treatment with ACE inhibi-
tors should begin with lower doses,
and, if tolerated, titrated to maxi-
mum. Recommended target doses
are 150 mg/d for captopril, 20 mg/d
for enalapril maleate, 40 mg/d for li-
sinopril, 10 mg/d for ramipiril, 40
mg/d for quinapril hydrochloride,
and 4 mg/d for trandolapril. Renal
function and serum potassium
levels should be assessed within 1 to
2 weeks of initiation8 and every 2 to
3 months thereafter. Tests may need
to be repeated more frequently in
patients with preexisting hypo-
natremia, diabetes, azotemia, or hy-
potension or in patients receiving
potassium supplementation.8 Con-
troversy exists among heart failure
specialists on whether there is sig-
nificant literature documenting the
attenuation of ACE inhibitor ben-
efit with the use of aspirin therapy.8
Most physicians believe that the evi-
dence is not strong, and thus use
both agents.
Titration of ACE inhibitor
therapy combined with diuretics
needs careful clinical and diagnos-
tic monitoring. Serum creatinine
level is expected to increase but may
remain stable, whereas potassium
level, depending on the patient and
diuretic dose, may increase, de-
crease, or remain unchanged. There
is no consensus on the potassium
level that should be tolerated. A level
below 3.8 mmol/L or higher than 5.8
mmol/L is a concern, and potas-
sium supplement therapy should be
reduced or added to achieve safe lev-
els. The goal is to achieve adequate
renal perfusion, to avoid symptom-
atic hypotension, and to insure the
absence of congestion.
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
b-Adrenergic Receptor Blockers
Blockade of b-adrenergic receptors,
previously contraindicated as a heart
failure treatment, is now a pivotal
treatment modality. Early studies of
b-blocker treatment demonstrated
clinically beneficial effects but failed
to prove a reduction in mortal-
ity.74-77 Patients with minimal or mild
symptoms failed to improve NYHA
class,78,79 but decreased their likeli-
hood of clinical exacerbations.78 Se-
lective b1-receptor inhibitors (meto-
prolol succinate and bisoprolol
fumarate) and an agent with a1-, b1-,
and b2-receptor inhibition (carve-
dilol) have improved symptoms and
ejection fraction80 in patients with
moderate to severe symptoms.3,8 The
controversy and fear that b-block-
ers may increase mortality previ-
ously discouraged many physicians
from prescribing these agents. Re-
cent data, however, have lessened
these fears.3,8,80-82
The Cardiac Insufficiency Bisopro-
lol Study. Two thousand six hun-
dred forty-seven patients with mod-
erate to severe heart failure (mostly
NYHA class III) were randomized to
placebo or bisoprolol fumarate, 20
mg, with conventional therapy and
followed up for up to 28 months.
Treatment demonstrated a 34% re-
duction in mortality, a 20% reduc-
tion in risk for any hospitalization,
and a 32% decrease in heart failure
hospitalization.83
The Metoprolol CR/XL Random-
ized Intervention Trial in Heart
Failure. Three thousand nine hun-
dred ninety-one patients in Europe
and the United States were random-
ized to placebo or metoprolol.81,82
Doses were titrated to 100 to 200
mg/d as tolerated by each patient.
The mean age of patients was 64
years, and more than 95% were in
NYHA classes II to III. At 1 year,
there was a 34% reduction in mor-
tality resulting in an early term-
ination of the study. The study
demonstrated a 38% decrease in
cardiovascular mortality, a 41%
decrease in sudden death, a 49%
decrease in death due to progres-
sive heart failure, and a 35% reduc-
tion in the number of patients hos-
pitalized for heart failure.84-87
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346
The US Carvedilol Heart Failure
Trials Program. Four separate mul-
ticenter trials involving 1094 pa-
tients examined patients with mild,
moderate, and severe heart failure
of ischemic and nonischemic ori-
gins. The trials were the Prospective
Randomized Evaluation of Carve-
dilol on Symptoms and Exercise
(PRECISE; up to 25 mg twice daily;
if weight .85 kg, then up to 50 mg
twice daily),88 the Multicenter Oral
Carvedilol Heart Failure Assess-
ment Study (MOCHA; 6.25,12.5, or
25.0 mg twice daily),89 a study of the
safety and efficacy of carvedilol in
severe heart failure (up to 50 mg
twice daily),90 and a study evaluat-
ing carvedilol’s ability to alter the
clinical progression of heart failure in
patients with mild symptoms (up to
100 mg/d).78 A prospective analysis
of the combined data from all 4 stud-
ies evaluated mortality or hospital-
ization during 6 months, or 12
months in the group with mild heart
failure.90 The study demonstrated a
65% decrease in death and resulted
in early termination. There was a
lower risk for worsening heart fail-
ure in the patients with severe heart
failure, but the number of deaths and
hospitalizations was too small for
analysis.
Retrospective Analysis of SOLVD
Data. As mentioned, the SOLVD Trial
demonstrated reduced mortality with
combination therapy of ACE inhibi-
tors and b-blockers.73 Of the pa-
tients in the NYHA class II preven-
tion arm, 24% received a b-blocker,
compared with only 8% in the class
II to III treatment arm. Each agent in-
dividually in both groups demon-
strated a mortality benefit.
Recently, the Beta-Blocker Sur-
vival Trial (BEST),91 a trial of bucin-
dolol hydrochloride (a nonselec-
tive b-blocker) to evaluate mortality
in patients with NYHA classes III and
IV, was terminated early because of
increased mortality.92 This raises
some questions about the use of non-
selective b-blockers in more ad-
vanced disease. The Carvedilol Pro-
spective Randomized Cumulative
Survival Trial (COPERNICUS)
sought to answer the question of
safety and improved mortality in
NYHA class IV patients.68 The trial
was recently stopped because of a
highly significant mortality benefit
in the carvedilol group.93 At pres-
ent, the Carvedilol or Metoprolol Eu-
ropean Study (COMET) is evaluat-
ing the use of carvedilol and
metroprolol for a 4-year period.8
All patients with stable NYHA
class II or III heart failure due to left
ventricular systolic dysfunction are
recommended to receive b-block-
ers 8 ; b-blockers are also recom-
mended in diabetic patients. 9 4
Therapy with b-blockers should not
be started during an acute worsen-
ing of clinical status or evidence of
fluid overload. During acute epi-
sodes for patients already taking
b-blockers, the dose should be de-
creased, or stopped if the patient is in
severe failure.8 If the patient experi-
ences mild to moderate symptoms,
the dose may be halved or contin-
ued with temporary lowering of the
ACE inhibitor dose and increasing
doses of diuretics. Often, the early
fluid retention induced by b-block-
ade lessens with continued therapy.
If the patient experiences symptom-
atic hypotension, the doses of
b-blocker and ACE inhibitors should
be separated by at least 1 to 2 hours.
The difficulties in treating
NYHA classes III and IV patients may
best be managed by a heart failure
specialist. For long-term therapy, ti-
tration to the highest dose toler-
ated is recommended for best re-
sults.8 It is still unknown which
agent is the most effective or whether
patients with NYHA class I heart fail-
ure may benefit from treatment.
Aldosterone Antagonists
The guidelines published this year
in the American Journal of Cardiol-
ogy acknowledged that aldosterone
antagonists merit consideration in
heart failure treatment but could not
recommend their use. However, with
the publication of the Randomized
Aldactone Evaluation Study
(RALES),95 most heart failure spe-
cialists are recommending spirono-
lactone in a select group of pa-
tients. The patients studied in the
trial had stable NYHA class III or IV
heart failure, an ejection fraction of
less than 0.35, a serum creatinine
level of less than 221 µmol/L (2.5
mg/dL), and a potassium level of less
than 5.0 mmol/L.8 Patients were
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
treated with an ACE inhibitor and
a loop diuretic but were not al-
lowed potassium-sparing diuretics.
Vasodilators and digitalis were al-
lowed. The double-blind trial ran-
domized 1663 patients to placebo or
25 mg of spironolactone. The trial
terminated early because of the sig-
nificant mortality benefit seen in the
spironolactone group. Patients had
a 30% reduction in the risk for death
and a 31% risk reduction in the risk
for death due to cardiac causes.95
Digoxin
Clinical trials of digoxin have shown
a benefit in symptomatic relief, qual-
ity of life, functional capacity, and ex-
ercise tolerance in patients with mild
to moderate heart failure.8,58,76,96 The
withdrawal of digoxin therapy has re-
sulted in significant clinical deterio-
ration.97 The only trial that has evalu-
ated long-term therapy, the Digitalis
InvestigationGroup(DIG)Trial,dem-
onstrated a decreased risk for all-
cause and heart failure hospitaliza-
tion, but failed to demonstrate a
mortality benefit.98 Digoxin is rec-
ommended for the control of ven-
tricular response in patients with
atrial fibrillation. Digoxin can be
added to therapy consisting of ACE
inhibitors, diuretics, and b-block-
ers in patients with a normal sinus
rhythm to improve clinical symp-
toms and to reduce the number of
heart failure hospitalizations in
NYHA classes II to IV patients. Di-
goxin levels should not be checked
routinely, except to exclude toxic ef-
fects of digitalis (Figure 3).8
NONRECOMMENDED DRUGS
Other drug classes have been stud-
ied and have produced small signifi-
cant morbidity and/or mortality ben-
efit. However, the benefits are not
enough to recommend these thera-
pies for all patients. Other agents
show much promise and are theo-
retically effective but have been in-
adequately studied in human trials
to date.
Angiotensin Receptor Blockers
Long-term studies of angiotensin re-
ceptor blockers have demonstrated
similar hemodynamic and neuro-
WWW.ARCHINTERNMED.COM
347
Assessment of LV Function
(Echocardiogram, Radionuclide
Ventriculogram)
EF ≤0.40
Assessment of Volume Status
Signs and No Signs and
Symptoms of Symptoms of
Fluid Retention Fluid Retention
Diuretic ACE
(Titrate to Inhibitor
Euvolemic State)
Digoxin
β-Blocker
Figure 3. Recommended approach to the
patient with heart failure. LV indicates left
ventricular; EF, ejection fraction; and ACE,
angiotensin-converting enzyme.
hormonal effects as ACE inhibi-
tors, but have not demonstrated con-
sistent effects on symptoms or
exercise tolerance.8 Angiotensin re-
ceptor blockers appear to be safe in
heart failure patients. The Evalua-
tion of Losartan in the Elderly
(ELITE) Study compared captopril
or losartan potassium with conven-
tional therapy in 722 patients aged
at least 65 years.99 There was no dif-
ference in renal function, hospital-
izations for heart failure, or the com-
bined risk of morbidity and mortality
between captopril and losartan
groups. A single-blinded study dem-
onstrated consistent hemodynamic
improvements at 28 days in NYHA
classes II, III, and IV patients given
valsartan in addition to their long-
term ACE inhibitor therapy.68,100
Also, the Randomized Angiotensin
Receptor Antagonist–Angiotensin-
Converting Enzyme Inhibitor Study
(RAAS) is evaluating the safety and
tolerability of combination therapy
(losartan and enalapril) vs standard-
or high-dose enalapril.101 In the Ran-
domized Evaluation of Strategies
for Left Ventricular Dysfunction
(RESOLVD), patients with mild to
moderate symptoms (NYHA classes
II-IV) were randomized to candesar-
tan, enalapril, or both with conven-
tional therapy. There was no signifi-
cant difference in exercise tolerance
or cardiac events among groups.102
It is unclear if the receptor
blockers will have a similar mortal-
ity benefit in heart failure patients.
A trial of more than 3000 patients,
Evaluation of Losartan in the El-
derly II (ELITE II), compared losar-
tan and captopril and reported no
difference in mortality.103 Two large
multicenter trials, Valsartan Heart
Failure Trial (Val-HeFT) and Can-
desartan in Heart Failure Assess-
ment in Reduction of Mortality and
Morbidity (CHARM), are currently
evaluating this issue.8 Angiotensin
receptor blockers are only recom-
mended if ACE inhibitors are not tol-
erated because of angioedema or
cough. Current evidence does not
support combined ACE inhibitor
and angiotensin receptor blocker
therapy.
Hydralazine and Isosorbide
The combination therapy of hydrala-
zine hydrochloride and isosorbide
decreases mortality in heart failure
patients.104 However, in a direct com-
parison with enalapril, enalapril had
a larger mortality benefit.60 Most
physicians first substitute an angio-
tensin receptor blocker if an ACE in-
hibitor is not tolerated. Therefore,
this regimen should only be consid-
ered if ACE inhibitors are not tol-
erated and/or the patient has renal
insufficiency.
Calcium Antagonists
No clinical trials have proven a mor-
tality benefit with calcium antago-
nists. Some have demonstrated no
apparent harm, and that they may
be used if a calcium antagonist is in-
dicated. Amlodipine besylate with
standard therapy in the Prospec-
tive Randomized Amlodipine Sur-
vival Evaluation (PRAISE) demon-
strated no clear benefit on mortality
or major cardiovascular hospitaliza-
tions.105 Although amlodipine did
not affect the combined risk for
death and major cardiovascular hos-
pitalization, it appeared to lower the
risk for death in a retrospective sub-
group analysis of patients with a
nonischemic cardiomyopathy. Al-
though PRAISE-2 hoped to con-
firm this trend, 1 0 6 the attempt
failed.107 In the third Vasodilator
Heart Failure Trial (V-HeFT III),
felodipine with standard therapy had
no effect on exercise tolerance or all-
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
cause mortality.108 Thus, although
these calcium channel blockers do
not have any additional benefits for
heart failure patients, they appar-
ently do not place the patient at in-
creased risk for mortality.
Inotropic Drugs and Vasodilators
Despite the emergence of new ino-
tropic agents, the results do not seem
promising. The recent Vesnari-
none Trial demonstrated an in-
crease in mortality among patients
with severe heart failure.11,109 The use
of intermittent infusion of inotro-
pic agents has no proven mortality
benefit,110,111 and long-term treat-
ment increases mortality.11,109,112
Continuous infusion is often used as
a bridge to cardiac transplantation
and may have some improvement on
the quality of life in patients with ad-
vanced-stage heart failure.110 If pa-
tients require continuous inotropic
agents, they should be referred to a
heart failure specialist.
Additional therapies include
the use of intravenous vasodilators
such as sodium nitroprusside (pure
arterial vasodilator) and nitroglyc-
erin (arterial and venous vasodilator).
Both agents can have adverse ef-
fects. Tolerance develops quickly to
nitroglycerin, and sodium nitro-
prusside administration is associ-
ated with accumulation of toxic me-
tabolites. These drugs are not useful
in the routine management of con-
gestive heart failure.
Antiarrhythmic Agents
Antiarrhythmic agents are recom-
mended if the atrial or ventricular ar-
rhythmia causes a clinical deterio-
ration. Amiodarone reduced the risk
for death and hospitalization for
heart failure in heart failure pa-
tients in the Grupo de Estudio de la
Sobrevidea en la Insuficiencia Car-
diaca en Argentina (GESICA). 113
However, in the Congestive Heart
Failure Survival Trial of Antiarrhyth-
mic Therapy (CHF STAT),114 amio-
darone did not improve all-cause
mortality in patients with asymp-
tomatic arrhythmia. Treatment was
associated with an improved ejec-
tion fraction. Amiodarone thus ap-
pears relatively safe and is pre-
ferred in the treatment of atrial
WWW.ARCHINTERNMED.COM
348
arrhythmias in heart failure pa-
tients.
Other agents have been stud-
ied for treatment of atrial arrhyth-
mias, but are not recommended. Un-
fortunately, D-sotalol hydrochloride
increases risk for death.115 There has
not been a large-scale trial with D,L-
sotalol. Dofetilide, a promising new
drug, increases conversion to nor-
mal sinus rhythm, maintains sinus
rhythm, and reduces the risk for hos-
pitalization in heart failure patients
with atrial fibrillation.116 It does not
alter all-cause mortality.116
Atrial fibrillation is the most
common nonfatal arrhythmia expe-
rienced by the CHF patient. Amio-
darone is recommended for pa-
tients who require lowering of the
heart rate despite use of digoxin and
b-blockers. Amiodarone has numer-
ous adverse effects, most com-
monly thyroid dysfunction, pulmo-
nary fibrosis, gastrointestinal tract
upset, corneal deposits, and prolon-
gation of the QT interval, occasion-
ally leading to ventricular arrhyth-
mias. Amiodarone therapy typically
is started orally at 200 to 400 mg/d.
The practitioner must reduce the di-
goxin dose (to avoid elevation of di-
goxin level with concurrent amio-
darone administration) and
b-blocker dose (to avoid excessive
bradycardia). Patients with signifi-
cant lung disease present a thera-
peutic challenge, as amiodarone and
b-blockers may be contraindi-
cated. This problem is assessed on
a case-by-case basis. Finally, dofeti-
lide represents an intriguing alter-
native, the use of which awaits fur-
ther study.
Treatment of ventricular ar-
rhythmias in patients with end-
stage heart failure is debatable. Treat-
ment with amiodarone at a dose of
200 to 400 mg/d (sometimes with a
loading dose) is useful in selected pa-
tients. It is unclear if implantable car-
dioverter-defibrillators have a mor-
tality benefit in heart failure patients.
The Sudden Cardiac Death in Heart
Failure Trial (SCD-HeFT) is cur-
rently addressing this issue.8
Anticoagulation
Anticoagulation in patients with-
out atrial fibrillation and with di-
minished left ventricular function re-
 Clinical Trials Evaluating Anticoagulation in Congestive Heart Failure*
Acronym Name of Trial
WATCH Warfarin and Antiplatelet Therapy in Chronic Heart Failure
WARCEF Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction
WASH Warfarin Aspirin Study in Heart Failure
*NYHA indicates New York Heart Association; LVEF, left ventricular ejection fraction.
mains controversial. There has been
no double-blind placebo-con-
trolled trial in heart failure pa-
tients. Patients with dilated cardio-
myopathy are predisposed to
thromboembolism because of in-
creased stasis in dilated chambers,
regional wall motion abnormalities
causing asynergy, poor contractil-
ity, and atrial fibrillation.117 In 1981,
Fuster et al118 retrospectively ob-
served an 18% frequency of throm-
boembolism with an incidence of
3.5 per 100 patient-years in pa-
tients with nonischemic dilated car-
diomyopathy.
Verification of this low inci-
dence has been observed in recent
heart failure trials. 5 9 Warfarin
sodium reduced all-cause mortality
and the risk for death or hospital-
ization for heart failure in a recent
SOLVD cohort study.119 It is hoped
that the Warfarin Aspirin Study in
Heart Failure (WASH Trial),120 the
Warfarin and Antiplatelet Ther-
apy in Chronic Heart Failure
(WATCH) Trial,121 and the Warfa-
rin Versus Aspirin in Reduced Car-
diac Ejection Fraction (WARCEF)
Trial121 will answer some of this
uncertainty. The WASH Trial is a
randomized, open, parallel study
comparing warfarin, aspirin, and
no antithrombotic therapy in
NYHA classes II to IV patients.120
The WATCH Trial will compare
aspirin, clopidogrel, and war-
farin in NYHA classes II to IV
patients with an ejection fraction
of no greater than 0.30, and the
WARCEF Trial will compare war-
farin and aspirin in NYHA classes
I to III patients with an ejection
fraction of no greater than 0.30.
The combined data from the
WATCH and WARCEF trials will
have sufficient power to determine
if warfarin reduces stroke risk in
patients with an ejection fraction
of no greater than 0.30 (Table and
Figure 4).
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
NYHA Class
II, III, IV
I, II, III
II, III, IV
NYHA Class
I II
Recommended If Symptoms
of Fluid
Retention
Figure 4. What therapeutic agent to use and when. NYHA indicates New York Heart Association; ACE,
angiotensin-converting enzyme. To convert creatinine level to milligrams per deciliter, divide by 88.4.
POSTHOSPITALIZATION
DISCHARGE GUIDELINES
The inpatient stay for the heart fail-
ure patient is only a small part of his
or her overall long-term treatment.
Patients and caregivers need educa-
tion about salt and fluid restriction
and the importance of checking
weight daily. Depending on their
motivation and ability to comply, se-
lected patients may be taught to use
diuretics on a personalized sliding
scale. Patients should be counseled
to call the practitioner for a net
weight gain of 0.5 to 1.5 kg or clini-
cal signs such as peripheral edema,
change in number of pillows needed
to sleep, or decreasing exercise tol-
erance. Hospital admissions may be
avoided by early intervention by the
practitioner.
CONCLUSIONS
The pharmacological treatment of
heart failure has become a com-
bined symptomatic-preventive man-
agement strategy. Although the
plethora of data on heart failure man-
WWW.ARCHINTERNMED.COM
349
Drugs Compared LVEF for Study Entry
Aspirin, clopidogrel, warfarin #0.30
Warfarin, aspirin #0.30
Warfarin, aspirin, no antiplatelet therapy Not stated
III IV
Diuretic
ACE Inhibitor
β-Blocker
Digoxin
Aldosterone Antagonist
Exercise/Lipid-Lowering
Agents
If Stable While If Symptomatic If Stable,
Receiving While Receiving Creatinine Level
Medication Triple Therapy ≤ 221 µmol/L and
Potassium Level
≤ 5 mmol/L
agement can be overwhelming, it “is
not as complicated as it looks.”122
Therapy with ACE inhibitors,
b-blockers, and diuretics is now stan-
dard. Digoxin is added to improve
clinical symptoms, especially in pa-
tients with atrial fibrillation. Aldoste-
rone antagonists may be recom-
mended in patients with stable NYHA
class III or IV heart failure, an ejec-
tion fraction less than 0.35, a serum
creatinine level of less than 221
µmol/L (2.5 mg/dL), and a potas-
sium level of less than 5.0 mmol/L.
Hydralazine and isosorbide are rec-
ommended if ACE inhibitors are not
tolerated. Angiotensin receptor block-
ers are only recommended if ACE in-
hibitors are not tolerated (cough or
angioedema). Specialists in heart fail-
ure are unsure if a small amount of
ACE inhibitor and b-blocker is bet-
ter than the maximum dose of either
agent alone. Antiarrhythmic agents
are recommended if the atrial or ven-
tricular arrhythmia causes a clinical
deterioration, and anticoagulation is
still a controversial issue.
Early recognition and preven-
tion therapies, combined with life-
style modification, are essential. The
literature is extensive, but the treat-
ment is logical. Apply the guide-
lines to every patient as an indi-
vidual, adjusting the treatment
regimen as indicated by a patient’s
condition and what the growing
medical evidence base deems appro-
priate.
Accepted for publication September 14,
2000.
We acknowledge the assistance
of Michael L. Maitland, MD, PhD, for
careful critique of the manuscript.
Corresponding author and re-
prints: David A. Baran, MD, Box 1030,
The Zena and Michael A. Wiener Car-
diovascular Institute, Mount Sinai
Medical Center, One Gustave L. Levy
Place, New York, NY 10029.
REFERENCES
1. Cohn J. The management of chronic heart fail-
ure. N Engl J Med. 1996;335:490-498.
2. Garg R, Yusuf S, for the Collaborative Group on
ACE Inhibitor Trials. Overview of randomized tri-
als of angiotensin-converting enzyme inhibi-
tors on mortality and morbidity in patients with
heart failure. JAMA. 1995;273:1450-1456.
3. Lechat P, Packer M, Chalon S, Cucherat M, Arab
T, Boissel J-P. Clinical effects of b-adrenergic
blockade in chronic heart failure: a meta-
analysis of double-blind, placebo-controlled, ran-
domized trials. Circulation. 1998;98:1184-
1191.
4. Hoes AW, Mosterd A, Grobbee DE. An epi-
demic of heart failure? recent evidence from Eu-
rope. Eur Heart J. 1998;19(suppl L):L2-L9.
5. Cleland JG. Heart failure: a medical hydra. Lan-
cet. 1998;352(suppl 1):SI1-SI2.
6. Sharpe N. Translation of clinical trial results into
practice. Eur Heart J. 1998;19(suppl L):L28-
L32.
7. Braunwald E, Colucci WS, Grossman W. Clini-
cal aspects of heart failure: high output heart fail-
ure: pulmonary edema. In: Braunwald E, ed. Heart
Disease: A Textbook of Cardiovascular Medi-
cine. Philadelphia, Pa: WB Saunders Co; 1997:
445-456.
8. Packer M, Cohn JN. Consensus recommenda-
tions for the management of chronic heart fail-
ure. Am J Cardiol. 1999;83:1A-38A.
9. Packer M, Poole-Wilson P, Armstrong P, et al.
Comparative effects of low-dose versus high-
dose lisinopril on survival and major events in
chronic heart failure: the Assessment of Treat-
ment with Lisinopril and Survival Study (ATLAS)
[abstract]. Eur Heart J. 1998;19(suppl):142.
10. Parmley W. Pathophysiology of congestive heart
failure. Clin Cardiol. 1992;15:5-12.
11. Cohn J, Goldstein SO, Greenberg BH, et al. A
dose-dependent increase in mortality with ve-
snarinone among patients with severe heart fail-
ure. N Engl J Med. 1998;339:1810-1816.
12. Litwin S, Grossman W. Diastolic dysfunction as
a cause of heart failure. J Am Coll Cardiol. 1993;
22:49A-55A.
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
13. Criteria Committee NYHA, Inc. Diseases of the
Heart and Blood Vessels: Nomenclature and Cri-
teria for Diagnosis. Boston, Mass: Little Brown
& Co Inc; 1964:114.
14. Goldman L, Hashimoto B, Cook EF, Loscalzo A.
Comparative reproducibility and validity of symp-
toms for assessing cardiovascular functional
class: advantages of a new specific activity scale.
Circulation. 1981;64:1227-1234.
15. Guyatt GH, Pugsley SO, Sullivan MJ, et al. Ef-
fect of encouragement on walking test perfor-
mance. Thorax. 1984;39:818-822.
16. Russell SD, McNeer FR, Beere PA, Logan LJ, Hig-
ginbotham MB, for the Duke University Clinical
Cardiology Studies (DUCCS) Exercise Group. Im-
provement in the mechanical efficiency of walk-
ing: an explanation for the “placebo effect” seen
during repeated exercise testing of patients with
heart failure. Am Heart J. 1998;135:107-114.
17. Ho K, Pinsky JL, Kannel WB, Levy D. The epi-
demiology of heart failure: the Framingham
Study. J Am Coll Cardiol. 1993;22:6A-13A.
18. Massie B. Exercise tolerance in congestive heart
failure: role of cardiac function, peripheral blood
flow and muscle metabolism and effect of treat-
ment. Am J Med. 1988;83:75-82.
19. O’Connell J, Bristow MR. Economic impact of
heart failure in the United States: time for a dif-
ferent approach. J Heart Lung Transplant. 1994;
13(suppl):S107-S112.
20. Packer M, Poole-Wilson PA, Armstrong PW, et
al, on behalf of the ATLAS Study Group. Com-
parative effects of low and high doses of the an-
giotensin-converting enzyme inhibitor, lisino-
pril, on morbidity and mortality in chronic heart
failure. Circulation. 1999;100:2312-2318.
21. Editorial Advisory Board. Heart failure: impact and
evolving concepts. Curr Issues Heart Fail. 1999;
1:1-7.
22. Lindenfeld J, Krause-Steinfauf H, Salerno J.
Where are all the women with heart failure?
J Am Coll Cardiol. 1997;30:1417-1419.
23. Massie B, Shah NB. Evolving trends in the epi-
demiologic factors of heart failure: rationale for
preventive strategies and comprehensive dis-
ease management. Am Heart J. 1997;133:703-
710.
24. American Heart Association. 1998 Heart and
Stroke Statistical Update. Dallas, Tex: Ameri-
can Heart Association; 1997.
25. Packer M. How should physicians view heart fail-
ure? the philosophical and physiological evolu-
tion of three conceptual models of the disease.
Am J Cardiol. 1993;71:3C-11C.
26. Pepper G, Lee RW. Sympathetic activation in
heart failure and its treatment with b-blockade.
Arch Intern Med. 1999;159:225-234.
27. Packer M. The neurohormonal hypothesis: a
theory to explain the mechanism of disease pro-
gression in heart failure. J Am Coll Cardiol. 1992;
20:248-254.
28. Pfeffer M, Braunwald E. Ventricular remodeling
after myocardial infarction: experimental obser-
vations and clinical implications. Circulation.
1990;81:1161-1172.
29. Cohn J. Structural basis for heart failure: ven-
tricular remodeling and its pharmacologic inhi-
bition. Circulation. 1995;91:2504-2507.
30. Colucci W, Braunwald E. Pathophysiology of heart
failure. In: Braunwald E, ed. Braunwald Heart Dis-
ease: A Textbook of Cardiovascular Medicine.
Philadelphia, Pa: WB Saunders Co; 1997:394-
420.
31. Pfeffer M, Lamas GA, Vahghan DE, Parisi AF,
Braunwald E. Effect of captopril on progressive
WWW.ARCHINTERNMED.COM
350
ventricular dilation after anterior myocardial in-
farction. N Engl J Med. 1988;319:80-86.
32. Sabbah H, Shimoyana H, Kono T, et al. Effects
of long-term monotherapy with enalapril, meto-
prolol, and digoxin on the progression of left ven-
tricular dysfunction and dilation in dogs with re-
duced ejection fraction. Circulation. 1994;89:
2852-2859.
33. Mulder P, Richard V, Dermeaux G, et al. Role of
endogenous endothelin in chronic heart failure:
effect of long-term treatment with an endothe-
lin antagonist on survival, hemodynamics, and
cardiac remodeling. Circulation. 1997;96:1976-
1982.
34. Eichhorn E, Bristow MR. Medical therapy can im-
prove the biological properties of the chroni-
cally failing heart: a new era in the treatment of
heart failure. Circulation. 1996;94:2285-2296.
35. Pousset F, Isnard R, Lechat P, et al. Prognostic
value of plasma endothelin-1 in patients with
chronic heart failure. Eur Heart J. 1997;18:254-
258.
36. Mann D, Kent RL, Parsons B, Copper G IV. Ad-
renergic effects on the biology of the adult mam-
malian cardiocyte. Circulation. 1992;85:790-
804.
37. Tan L, Jalil JE, Pick R, Janicki JS, Weber KT. Car-
diac myocyte necrosis induced by angiotensin
II. Circ Res. 1991;69:1185-1195.
38. Sabbah H, Sharov VG. Apoptosis in heart fail-
ure. Prog Cardiovasc Dis. 1998;40:549-562.
39. Feuerstein G, Yue TL. Novel mechanisms in the
treatment of heart failure: inhibition of oxygen
radicals and apoptosis by carvedilol. Prog Car-
diovasc Dis. 1998;48:17-24.
40. Goussev A, Sharov VG, Simoyama H, Tanimura
M, Lesch M. Effects of ACE inhibition on cardio-
myocyte apoptosis in dogs with heart failure. Am
J Physiol. 1998;275:H626-H631.
41. Mann D. The effect of tumor necrosis factor-
alpha on cardiac structure and function: a tale
of two cytokines. J Card Fail. 1996;2(suppl):
S165-S172.
42. Liu Y, Cigola, E, Cheng W, et al. Myocyte nuclear
mitotic division and programmed myocyte cell
death characterize the cardiac myopathy in-
duced by rapid ventricular pacing in dogs. Lab
Invest. 1995;73:771-787.
43. Yue P, Massie BM, Simpson PC, Long CS. Cy-
tokine expression increases in nonmyocytes from
rats with postinfarction heart failure. Am
J Physiol. 1998;275:H250-H258.
44. Levine B, Kalman J, Mayer L, Fillit HM, Packer
M. Elevated circulating levels of tumor necrosis
factor in severe chronic heart failure. N Engl
J Med. 1990;323:236-241.
45. Francis G. Congestive heart failure. In: Stein J,
ed. Internal Medicine. 5th ed. St Louis, Mo: Mos-
by–Year Book Inc; 1998:156-175.
46. Abraham W, Singh B. Ischemic and nonisch-
emic heart failure do not require different treat-
ment strategies. J Cardiovasc Pharmacol. 1999;
33(suppl):S1-S7.
47. SHEP Cooperative Research Group. Prevention
of stroke by antihypertensive drug treatment with
isolated systolic hypertension: final results of the
Systolic Hypertension in the Elderly Program
(SHEP). JAMA. 1991;265:3255-3264.
48. Kotsis J, Davis BR, Cutler J, Grimm RH Jr, et
al, for the SHEP Cooperative Research Group.
Prevention of heart failure by antihypertensive
drug treatment in older persons with isolated
systolic hypertension. JAMA. 1997;278:212-
216.
49. Kjekshus J, Pedersen TR, Olsson AG, Gaerge-
 man O, Pyorala K. The effects of simvastatin on
the incidence of heart failure in patients with coro-
nary heart disease. J Card Fail. 1997;3:249-
254.
50. Patterson J, Adams KF Jr, Appelfeld MM, Corder
CN, Masse BR, for the Torsemide Investigators
Group. Oral torsemide in patients with chronic
congestive heart failure: effects on body weight,
edema, and electrolyte excretion. Pharmaco-
therapy. 1994;14:514-521.
51. Sherman L, Liuand CS, Baumgarden S, Charuzi
Y, Chardo F, Kim CS. Pirotanide, a potent di-
uretic with potassium-sparing properties, for the
treatment of congestive heart failure. Clin Phar-
macol Ther. 1986;40:587-594.
52. Wilson JR, Reichek N, Dunkman WB, Goldberg
S. Effect of diuresis on the performance of the
failing left ventricle in man. Am J Med. 1981;70:
234-239.
53. Sackner-Bernstein J, Krum H, Goldsmith RL, et
al. Should worsening heart failure early after ini-
tiation of beta-blocker therapy for chronic heart
failure preclude long-term treatment [ab-
stract]? Circulation. 1995;92:I-395.
54. Cody R, Covit AB, Shaer GL, Laragh JH, Sealey
JE, Feldschuh J. Sodium and water balance in
chronic congestive heart failure. J Clin Invest.
1986;77:1441-1452.
55. el-Ebrashy N, el-Dansoury M, Higazi AM. Effect
of digitalization on urinary excretion of water, so-
dium, potassium and chloride in heart failure.
J Egypt Med Assoc. 1968;51:638-644.
56. Motwani J, Fenwick MK, Morton JJ, Struthers
AD. Furosemide-induced natriuresis is aug-
mented by ultra-low-dose captopril but not by
standard doses of captopril in chronic heart fail-
ure. Circulation. 1992;86:439-445.
57. Captopril Multicenter Research Group. A placebo-
controlled trial of captopril in refractory chronic
congestive heart failure. J Am Coll Cardiol. 1983;
2:755-763.
58. Smith RFJG, Ziesche S, Bhat G, Blankenship K,
Cohn JN, for the V-HeFT VA Cooperative Stud-
ies Group. Functional capacity in heart failure:
comparison of methods of assessment and their
relation to other indexes of heart failure. Circu-
lation. 1993;87(suppl 6):88-93.
59. The SOLVD Investigators. Effect of enalapril on
survival in patients with reduced left ventricular
ejection fractions and congestive heart failure.
N Engl J Med. 1991;325:293-302.
60. Cohn J, Johnson G, Ziesche S, et al. A compari-
son of enalapril with hydralazine-isosorbide di-
nitrate in the treatment of chronic congestive
heart failure. N Engl J Med. 1991;325:303-310.
61. The CONSENSUS Trial Study Group. The effect
of enalapril on mortality in severe congestive heart
failure: results of the Cooperative North Scan-
dinavian Enalapril Survival Study (CONSENSUS).
N Engl J Med. 1987;316:1429-1435.
62. Edep M, Shah NB, Tateo IM, Massie BM. Differ-
ences between primary care physicians and car-
diologists in the management of congestive heart
failure: relation to practice guidelines. J Am Coll
Cardiol. 1997;30:518-526.
63. Clarke K, Gray D, Hampton JR. Evidence of in-
adequate investigation and treatment of pa-
tients with heart failure. Br Heart J. 1994;71:
584-587.
64. McMurray J. Failure to practice evidence-based
medicine: why do physicians not treat patients
with heart failure with angiotensin-converting en-
zyme inhibitors? Eur Heart J. 1998;19:L15-
L21.
65. Packer M. Do angiotensin-converting enzyme in-
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
hibitors prolong life in patients with heart fail-
ure treated in clinical practice? J Am Coll Car-
diol. 1996;28:1323-1327.
66. Poole-Wilson PA. The Network Study: the ef-
fect of dose of ACE-inhibitor on outcome in pa-
tients with heart failure [abstract]. J Am Coll Car-
diol. 1996;27:141A.
67. Davidson N. Hormonal and renal differences be-
tween low dose and high dose angiotensin con-
verting enzyme inhibitor treatment in patients with
chronic heart failure. Heart. 1996;75:576-581.
68. O’Connor C, Gattis WA, Swedberg K. Current and
novel pharmacologic approaches in advanced heart
failure. Am Heart J. 1998;135(suppl):S249-
S263.
69. Pfeffer M, Braunwald E, Moy LA, et al, on behalf
of the SAVE Investigators. Effect of captopril on
mortality and morbidity in patients with left ven-
tricular dysfunction after myocardial infarction:
results of the Survival and Ventricular Enlarge-
ment Trial. N Engl J Med. 1992;327:669-677.
70. The Acute Infarction Rampiril Efficacy (AIRE)
Study. Effect of rampiril on mortality and mor-
bidity of survivors of acute myocardial infarc-
tion with clinical evidence of heart failure. Lan-
cet. 1993;342:821-828.
71. Kober L, Torp-Pedersen C, Carlsen JE, et al, for
the Trandolapril Cardiac Evaluation (TRACE) Study
Group. A clinical trial of the angiotensin-converting–
enzyme inhibitor trandolapril in patients with left
ventricular dysfunction after myocardial infarc-
tion. N Engl J Med. 1995;333:1670-1676.
72. The SOLVD Investigators. Effect of enalapril on
mortality and the development of heart failure in
asymptomatic patients with reduced left ven-
tricular ejection fractions. N Engl J Med. 1992;
327:685-691.
73. Exner D, Dries DL, Waclawiw MA, Shelton B,
Domanski MJ. Beta-adrenergic blocking agent
use and mortality in patients with asymptom-
atic and symptomatic left ventricular systolic dys-
function: a post hoc analysis of the Studies of
Left Ventricular Dysfunction. J Am Coll Cardiol.
1999;33:916-923.
74. Waagstein F, Hjalmarson A, Varnauskas E, Wal-
lentin I. Effect of chronic beta-adrenergic recep-
tor blockade in congestive cardiomyopathy.
Br Heart J. 1975;37:1022-1036.
75. The Metoprolol in Dilated Cardiomyopathy (MDC)
Trial Study Group. 3-Year follow-up of patients
randomized in the Metoprolol in Dilated Cardi-
omyopathy Trial. Lancet. 1998;351:1180-
1181.
76. The Australia and New Zealand Heart Failure Re-
search Collaborative Group. Randomized, pla-
cebo-controlled trial of carvedilol in patients with
congestive heart failure due to ischaemic heart
disease. Lancet. 1997;349:375-380.
77. CIBIS Investigators and Committees. A random-
ized trial of b-blockade in heart failure: the Car-
diac Insufficiency Bisoprolol Study (CIBIS). Cir-
culation. 1994;90:1765-1773.
78. Colucci W, Packer M, Bristow MR, et al, for the
US Carvedilol Heart Failure Study Group. Carve-
dilol inhibits clinical progression in patients with
mild symptoms of heart failure. Circulation. 1996;
94:2800-2806.
79. White M, Rouleau J-L, Pericak D, et al, on be-
half of the RESOLVD Study Group. Effects of
metoprolol-CR in patients with ischaemic and di-
lated cardiomyopathy: the RESOLVD pilot study
(phase II) [abstract]. Eur Heart J. 1998;19:308.
80. Frishman W. Carvedilol. N Engl J Med. 1998;
339:1759-1764.
81. The International Steering Committee. Ratio-
WWW.ARCHINTERNMED.COM
351
nale, design, and organization of the Metopro-
lol CR/XL Randomized Intervention Trial in Heart
Failure (MERIT-HF). Am J Cardiol. 1997;80:54J-
58J.
82. Goldstein S. Clinical studies on beta blockers and
heart failure preceding the MERIT-HF Trial. Am
J Cardiol. 1997;80:50J-53J.
83. CIBIS II Steering Committee. Design of the Car-
diac Insufficiency Bisoprolol Study (CIBIS-II).
Fundam Clin Pharmacol. 1997;11:138-142.
84. Califf R, O’Connor CM. b-Blocker therapy for
heart failure. JAMA. 2000;283:1335-1337.
85. MERIT-HF Group. Effect of metoprolol CR/XL in
chronic heart failure: Metoprolol CR/XL Ran-
domised Intervention Trial in Congestive Heart
Failure (MERIT-HF). Lancet. 1999;353:2001-
2007.
86. Goldstein S, Hjalmarson A. The mortality effect
of metoprolol CR/XL in patients with heart fail-
ure: results of the MERIT-HF Trial. Clin Cardiol.
1999;22(suppl 5):V30-V35.
87. Hjalmarson A, Goldstein S, Fagerberg B, et al,
for the MERIT-HF Study Group. Effects of con-
trolled-release metoprolol on total mortality, hos-
pitalizations, and well-being in patients with heart
failure. JAMA. 2000;283:1295-1302.
88. Packer M, Colucci WS, Sackner-Bernstein JD, et
al, for the PRECISE Study Group. Double-blind,
placebo-controlled study of the effects of carve-
dilol in patients with moderate to severe heart
failure. Circulation. 1996;94:2793-2799.
89. Bristow M, Gilbert EM, Abraham WT, et al, for
the MOCHA Investigators. Carvedilol produces
dose-related improvements in left ventricular
function and survival in subjects with chronic
heart failure. Circulation. 1996;94:2807-2816.
90. Packer M, Bristow MR, Cohn JN, et al, for the
US Carvedilol Heart Failure Study Group. The ef-
fect of carvedilol on morbidity and mortality in
patients with chronic heart failure. N Engl J Med.
1996;334:1349-1355.
91. The BEST Steering Committee. Design of the
Beta-Blocker Evaluation Survival Trial (BEST). Am
J Cardiol. 1995;75:1220-1223.
92. Domanaski M, for The BEST Steering Commit-
tee. BEST (Beta-Blocker Evaluation Survival Trial).
Paper presented at: 1999 Scientific Sessions of
the American Heart Association; November 7-10,
1999; Atlanta, Ga.
93. Julian D. Clinical Trials Registry. Available at:
http://www.cardiosource.com. Accessed May 1,
2000.
94. Bristow M, Gilbert EM, Abraham WT, et al.
Effect of carvedilol on LV function and mortal-
ity in diabetic versus non–diabetic patients
with ischemic or nonischemic dilated cardio-
myopathy [abstract]. Circulation. 1996;94:I-
644.
95. Pitt B, Zannad F, Remme WJ, et al, for the Ran-
domized Aldactone Evaluation Study Investiga-
tors. The effect of spironolactone on morbidity
and mortality in patients with severe heart fail-
ure. N Engl J Med. 1999;341:709-717.
96. Guyatt G, Sullivan MJ, Fallen EL, et al. A con-
trolled trial of digoxin in congestive heart fail-
ure. Am J Cardiol. 1988;61:371-375.
97. Uretsky BFYJ, Shahidi FE, Yellen LG, Harrison
MC, Jolly MK, on behalf of the PROVED Inves-
tigative Group. Randomized study assessing the
effect of digoxin withdrawal in patients with mild
to moderate chronic congestive heart failure: re-
sults of the PROVED trial. J Am Coll Cardiol. 1993;
22:955-962.
98. The Digitalis Investigators Group. The effect of
digoxin on mortality and morbidity in patients
 with heart failure. N Engl J Med. 1997;336:525-
533.
99. Pitt B, Segal R, Martinez FA, et al, on behalf of
ELITE Study Investigators. Randomized trial of
losartan versus captopril in patients over 65 with
heart failure (Evaluation of Losartan in the El-
derly Study, ELITE). Lancet. 1997;349:747-
752.
100. Baruch L, Anand I, Cohen IS, Ziesche S, Judd
D, Cohn JN, for the Vasodilator Heart Failure Trial
(V-HeFT) Study Group. Augmented short- and
long-term hemodynamic and hormonal effects
of an angiotensin receptor blocker added to an-
giotensin-converting enzyme inhibitor therapy in
patients with heart failure. Circulation. 1999;99:
2658-2664.
101. Pitt B, Chang P, Grossman W, Dunlay M, Tim-
mermans PB. Rationale, background, and de-
sign of the Randomized Angiotensin Receptor
Antagonist–Angiotensin-Converting Enzyme In-
hibitor Study (RAAS). Am J Cardiol. 1996;78:
1129-1131.
102. McKelvie R, Yusuf S, Pericaf D, Held P. Com-
parison of candesartan, enalapril, and their com-
bination in congestive heart failure: Random-
ized Evaluation of Strategies for Left Ventricular
Dysfunction (RESOLVD pilot study) [abstract].
Eur Heart J. 1998;19:188A.
103. Poole-Wilson P, Pitt B. ELITE II (Evaluation of
Losartan in the Elderly) Study: the Losartan Heart
Failure Survival Study. Paper presented at: 1999
Scientific Sessions of the American Heart Asso-
ciation; November 7-10, 1999; Atlanta, Ga.
104. Cohn J, Archibald DG, Xiesche S, et al. Effect of
vasodilator therapy on mortality in chronic con-
gestive heart failure: results of a Veterans Ad-
ministration Cooperative Study. N Engl J Med.
1986;314:1547-1552.
105. Packer M, O’Conner CM, Ghali JK, et al, for the
Prospective Randomized Amlodipine Survival
(REPRINTED) ARCH INTERN MED/ VOL 161, FEB 12, 2001
©2001 American Medical Association. All rights reserved.
View publication stats
Evaluation Study Group. Effect of amlodipine on
morbidity and mortality in severe chronic heart
failure. N Engl J Med. 1996;335:1107-1114.
106. Oparil S. Long-term morbidity and mortality tri-
als with amlodipine. J Cardiovasc Pharmacol.
1999;33(suppl):S1-S6.
107. Packer M. PRAISE-2: Prospective Randomized
Amlodipine Survival Evaluation. Paper pre-
sented at: 49th Scientific Sessions of the Ameri-
can College of Cardiology; March 12-15, 2000;
Anaheim, Calif.
108. Cohn J, Ziesche S, Smith R, et al, for the Vaso-
dilator-Heart Failure Trial (V-HeFT) Study Group.
Effect of calcium antagonist felodipine as supple-
mentary vasodilator therapy in patients with
chronic heart failure treated with enalapril: V-
HeFT III. Circulation. 1997;96:856-863.
109. Cohn J, Goldstein SO, Greenberg BH, et al, for
the Vesnarinone Trial Investigators. A dose-
dependent increase in mortality with vesnari-
none among patients with severe heart failure.
N Engl J Med. 1999;339:1810-1816.
110. Elis A, Bental T, Kimchi O, Ravid M, Lishner M.
Intermittent dobutamine treatment in patients
with chronic refractory congestive heart failure:
a ra ndom ize d, double -blind, pla c e bo-
controlled study. Clin Pharmacol Ther. 1998;63:
682-685.
111. Dies F, Krell MJ, Whitlow P, et al. Intermittent
dobutamine in ambulatory outpatients with
chronic cardiac failure [abstract]. Circulation.
1986;74:II-138.
112. Feldman A, Bristow MR, Parmley WW, et al, for
the Vesnarinone Study Group. Effects of vesna-
rinone on morbidity and mortality in patients with
heart failure. N Engl J Med. 1993;329:149-155.
113. Dovel HC, Nul DR, Grancelli HO, Perrone SV,
Bortman GR, Curiel R, for Grupo de Estudio de
la Sobrevida en la Insuficiencia Cardiaca en Ar-
gentina (GESICA). Randomized trial of low-
WWW.ARCHINTERNMED.COM
352
dose amiodarone in severe congestive heart fail-
ure. Lancet. 1994;344:493-498.
114. Singh S, Fletcher RD, Fisher SG, et al, for the Sur-
vivial Trial of Antiarrhythmic Therapy in Conges-
tive Heart Failure. Amiodarone in patients with con-
gestive heart failure and asymptomatic ventricular
arrhythmias. N Engl J Med. 1995;333:72-82.
115. Waldo A, Camm AJ, DeRuyter H, et al, for the
SWORD Investigators. Effect of D-sotalol on mor-
tality in patients with left ventricular dysfunc-
tion after recent and remote myocardial infarc-
tion. Lancet. 1996;348:7-12.
116. Torp-Pedersen C, Moller M, Bloch-Thomsen PE,
et al, for the Danish Investigators of Arrhythmia
and Mortality on Dofetilide Study Group. Dofeti-
lide in patients with congestive heart failure and
left ventricular dysfunction. N Engl J Med. 1999;
341:857-865.
117. Koniaris L, Goldhaber SZ. Anticoagulation in di-
lated cardiomyopathy. J Am Coll Cardiol. 1998;
31:745-748.
118. Fuster V, Gersh BH, Giuliani ER, Tajik AJ, Bran-
denberg RO, Frye RI. The natural history of id-
iopathic dilated cardiomyopathy. Am J Cardiol.
1981;47:525-531.
119. Al-Khadra A, Salem DN, Rand WM, Udelson JE,
Smith JJ, Konstam MA. Warfarin anticoagula-
tion and survival: a cohort analysis from the Stud-
ies of Left Ventricular Dysfunction. J Am Coll Car-
diol. 1998;31:749-753.
120. Cardiosource. The Warfarin Aspirin Study in Heart
Failure (WASH Trial). Available at: http://
www.cardiosource.com. Accessed May 1, 2000.
121. Pullicino PM, Halperin JL, Thompson JL. Stroke
in patients with heart failure and reduced left ven-
tricular ejection fraction. Neurology. 2000;54:
288-294.
122. Mills R, Young JB. Heart failure therapy: not as
complicated as it looks [editorial]. Clin Cardiol.
1999;22:333.