The New England Journal o f Me di c i ne
Review Article
Drug Therapy
A L A S T A I R J . J . W O O D , M. D . , Editor
T HE M ANAGEMENT OF C HRONIC
H EART F AILURE
JAY N. COHN, M.D.
H
EART failure is a complex of symptoms —
fatigue, shortness of breath, and congestion
— that are related to the inadequate perfu-
sion of tissue during exertion and often to the reten-
tion of fluid. Its primary cause is an impairment of
the heart’s ability to fill or empty the left ventricle
properly.
The management of heart failure can no longer be
confined to the relief of symptoms. The processes
that contribute to left ventricular dysfunction may
progress independently from the development of
symptoms (Fig. 1). Treatment to prevent or delay
the progression of left ventricular dysfunction may
therefore be quite different from treatment aimed
at relieving symptoms and improving the patient’s
quality of life. Because the symptoms of heart failure
are only weakly related to the severity of left ventric-
ular dysfunction — although the dysfunction itself
is closely linked to mortality — the assessment of a
patient’s risk and the choice of the best therapy re-
quire insight into the mechanisms of both left ven-
tricular dysfunction and the complex of symptoms
we call congestive heart failure.
THE MECHANISMS AND DIAGNOSIS
OF LEFT VENTRICULAR DYSFUNCTION
Ischemic heart disease usually results in a localized
defect in systolic contraction; cardiomyopathy usu-
ally results in global impairment. Hypertension and
valvular disease may produce chronic pressure or vol-
From the Cardiovascular Division, Department of Medicine, University
of Minnesota Medical School, Box 508 UMHC, 420 Delaware St. S.E.,
Minneapolis, MN 55455, where reprint requests should be addressed to
Dr. Cohn.
©1996, Massachusetts Medical Society.
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ume overload that alters the structure and function
of the ventricle. A decrease in diastolic compliance,
manifested as an impediment to the filling of the
left ventricle during diastole, may be part of any
type of left ventricular disease. A decrease in systolic
wall motion is often referred to as systolic dysfunc-
tion. Pure diastolic dysfunction is best defined as an
elevated end-diastolic pressure in a chamber of nor-
mal size.
The reduced ejection fraction that is the hallmark
of chronic systolic dysfunction is closely related to an
increase in the volume of the left ventricular cham-
ber1 (Fig. 1). Structural changes in the myocardium
and vasculature are important contributors to the
progression of left ventricular dysfunction. Myocytes,
vascular smooth-muscle cells, and fibroblasts may
grow or proliferate in response to a variety of stim-
uli.2,3 These structural effects lead to changes in the
caliber or compliance of arteries,4 which augment
the left ventricular load,5 and increases in the vol-
ume and mass of the left ventricle.6 The role of this
process in heart failure is a subject of controversy,
but recent data suggest that such ventricular remod-
eling adversely affects the prognosis of patients who
have had myocardial infarctions.7-9
Enlargement of the left ventricle can usually be
detected during physical examination by careful pal-
pation of the precordial apical impulse with the
patient in the left lateral decubitus position. A lo-
calized, sustained, outward thrust suggests hyper-
trophy; a more diffuse heave indicates dilatation.
Measurement of the left ventricular ejection frac-
tion with echocardiography, radionuclide imaging,
or ventriculography provides the quantification nec-
essary to document the severity of systolic dys-
function. An ejection fraction below 0.45, with or
without symptoms, may be accepted as evidence of
left ventricular dysfunction. In the Studies of Left
Ventricular Dysfunction (SOLVD) Prevention Trial,
asymptomatic left ventricular dysfunction with an
ejection fraction of less than 0.35 was associated
with a 30 percent risk of symptomatic heart failure
during an average follow-up period of three years.10
Although chest radiography is not a sensitive means
of assessing the size or function of the left ventri-
cle,11 the electrocardiogram of a patient with sub-
stantial left ventricular dysfunction is almost always
abnormal.
Diastolic dysfunction is an important contributor
to heart failure, especially in elderly patients or pa-
tients with a history of hypertension.12 Signs of pul-
monary or systemic venous congestion in patients
with a left ventricular chamber of normal size may
 D R UG TH ER A PY

Coronary artery
disease Arrhythmia

Hypertension
Left Low
ventricular Remodeling ejection Death
Cardio- dysfunction fraction
myopathy

Valvular Pump
disease failure

Non- Chronic
cardiac Symptoms heart
factors failure

Figure 1. The Management of Congestive Heart Failure.

The treatment of heart failure involves counteracting two related but largely independent processes. Left ventricular
dysfunction, regardless of cause (coronary artery disease, cardiomyopathy, hypertension, or valvular disease), develops
through ventricular remodeling that results in a dilated chamber with a low ejection fraction, leading to episodes of
arrhythmia, progressive pump failure, and premature death. Noncardiac factors (neurohormonal stimulation, endo-
thelial dysfunction, vasoconstriction, and renal sodium retention) may or may not be stimulated by left ventricular dys-
function, but ultimately contribute to the same progressive process of cardiac remodeling; the noncardiac factors in-
dependently cause the dyspnea, fatigue, and edema that are characteristic of the clinical syndrome of congestive heart
failure.

be accepted as adequate evidence that diastolic dys-
function is the predominant mechanism of heart
failure.13 Ventricular arrhythmia is common in pa-
tients with left ventricular dysfunction.11
THE MECHANISMS AND DIAGNOSIS
OF HEART FAILURE
The symptoms of heart failure are predominantly
those of congestion, caused by an elevated ventricu-
lar filling pressure, and of fatigue and organ-system
dysfunction, related to inadequate cardiac output in
response to stress. Vascular and neuroendocrine mech-
anisms5,14-20 are important contributors to the ab-
normalities in regional blood flow, renal retention of
sodium, and pulmonary congestion that lead to
symptoms. Activation of the renin–angiotensin sys-
tem and the sympathetic nervous system may also
contribute to the structural changes in the heart and
peripheral vasculature that mediate the progressive
remodeling of the left ventricle.
Exercise tolerance can be assessed by taking a pa-
tient’s history, but it is better to conduct a maximal-
exercise test, which can be done safely even in pa-
tients with heart failure.21 The analysis of expired air
(respiratory gas exchange) can provide a more pre-
cise quantitative assessment of the disability.22 Circu-
latory congestion can be identified by physical exam-
ination, especially through assessment of the response
of jugular venous pressure to an increase in central
blood volume, which can be induced by abdominal
compression, leg raising, or exercise, and with radi-
ography of the chest.
GOALS OF THERAPY
The short-term goals of therapy for a patient with
heart failure are to relieve symptoms and improve
the quality of life. The achievement of these goals,
which are related primarily to the control of circu-
latory congestion, is best assessed by interviewing
the patient. The long-term goal of therapy should
be to prolong life by slowing, halting, or actually re-
versing the progressive left ventricular dysfunction
that is characteristic of the syndrome. However, we
lack a reliable measure of the effectiveness of therapy
in reaching this goal. Physicians are accustomed to
working with goals for treatment that are measur-
able — for example, the lowering of blood pressure
in hypertension and of the serum cholesterol con-
centration in hyperlipidemia. Heart failure presents
a particular challenge, because no single measure-

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 The New England Journal o f Me di c i ne

ment appears to be a sensitive indicator of the effec-

tiveness of therapy. TABLE 1. DIURETICS USED TO TREAT HEART FAILURE.

RELIEF OF SYMPTOMS
DOSE RANGE
Relieving circulatory congestion and increasing DRUG (mg) FREQUENCY

tissue perfusion are major hemodynamic goals relat- Thiazide diuretic

ed to the short-term relief of symptoms. Long-term
relief is dependent on additional factors not neces-
sarily related directly to hemodynamic measurements.
The prudent assessment of patients’ well-being in-
cludes subjective evaluation of the quality of life
(preferably by the patients themselves) and objective
evaluation of the signs of congestion.
Nonpharmacologic Management
Restricting the intake of salt will reduce a patient’s
need for diuretic therapy, and a diet with a daily so-
dium intake of 2 to 3 g can be made quite tolerable
with food additives to improve palatability. Cook-
books that feature low-sodium recipes are useful
source material for doctors and patients. Because
restricting exercise causes deconditioning and regu-
lar exercise can increase peak exercise capacity,23 en-
couraging patients to exercise regularly — and as
strenuously as their symptoms permit — or to enter
into formal rehabilitation programs can enhance
their quality of life. This approach runs contrary to
the traditional recommendation of bed rest,24 but in
neither case have the efficacy and safety been studied
critically. In particular, data are needed on the long-
term effects of regular exercise on left ventricular re-
modeling.
In patients who have recurrent acute episodes of
congestion indicative of ischemic impairment of left
ventricular function, angioplasty or bypass surgery
to induce myocardial reperfusion should be consid-
ered.25 Increasingly severe symptoms in the presence
of correctable valvular disease may also justify sur-
gery, although if there is advanced ventricular dila-
tation the response to surgery may not be good.
Heart transplantation is a dramatically effective form
of therapy, but the limited supply of donors restricts
the procedure to carefully selected patients whose
quality of life and life expectancy without the oper-
ation are so limited that the risk and expense of sur-
gery and subsequent follow-up can be justified.26
Drug Therapy
Drugs for the treatment of symptoms of heart fail-
ure include diuretics, vasodilators, and digoxin.
Diuretics
Diuretics can relieve circulatory congestion and
the accompanying pulmonary and peripheral edema
(Table 1). The induced reduction in atrial and ven-
tricular diastolic pressure may in turn reduce dia-
stolic stress on the ventricular wall and inadequate
subendocardial perfusion, therefore inhibiting the
Hydrochlorothiazide 25–50 Weekly to daily
Chlorthalidone 25–100 Weekly to daily
Loop diuretic
Furosemide 20–200 Daily or twice daily
Bumetanide 0.5–4 Daily or twice daily
Ethacrynic acid 25–100 Daily or twice daily
Torsemide 5–100 Daily
Thiazide-related diuretic
Metolazone 2.5–10 Daily or twice daily
Potassium-sparing diuretic
Triamterene 50–100 Daily or twice daily
Amiloride 5–10 Daily
Spironolactone 25–100 Daily or twice daily
progression of ventricular dysfunction.27 In the ab-
sence of symptoms or signs of congestion, diuretics
have no place in the management of heart failure and
may induce neurohormonal activation that could
have a deleterious effect.
Thiazide diuretics administered intermittently, two
or three times weekly, may be adequate to maintain
normal intravascular volume in mild states of con-
gestion, but the daily administration of a loop di-
uretic, such as furosemide, is necessary when the
congestion is more severe or when impaired renal
function reduces the responsiveness to thiazides. Di-
uretics are generally given in whatever doses are
needed to relieve obvious fluid retention, but a more
precise indicator of therapeutic success is the nor-
malization of ventricular filling pressure, which is
best assessed by measuring the central venous pres-
sure. Elevated pressure in the internal jugular vein or
evidence of hepatojugular reflux (i.e., a sustained in-
crease in blood pressure in the jugular vein during
compression of the right upper quadrant) should
suggest the need for more aggressive diuretic ther-
apy,28 unless there is also symptomatic hypotension
or a progressively rising blood urea nitrogen concen-
tration.
A once-daily dose of a loop diuretic is usually ef-
fective in keeping a patient with heart failure free of
congestion. Those with more persistent fluid reten-
tion may require two doses per day. When venous
blood pressure remains high despite a restricted in-
take of sodium, the administration of a thiazide di-
uretic or a diuretic with similar action, but a differ-
ent site of activity in the renal tubules (e.g., 2.5 to
5 mg of metolazone per day, given one hour before
the administration of the loop diuretic) may be ef-
fective. This diuretic regimen should only be under-
taken with frequent measurements of serum potassi-
um and adequate potassium replacement.
Excessive diuresis can be as harmful to a patient as

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 D RUG TH ER A PY
inadequate diuresis. Fatigue, hypotension, or azo-
temia in the presence of a normal jugular venous
pressure calls for a reduction in the dose or a discon-
tinuation of diuretic therapy. Since the need for di-
uretics varies depending on the patient’s diet and
level of activity, having patients adjust the dosage
themselves is a useful approach. Patients can be ad-
vised to increase or decrease their diuretic dose to
maintain their weight — as measured each morning
— within a range in which they have few symptoms
of congestion. The ideal body weight should peri-
odically be determined at office visits, during which
the jugular venous pressure can be measured.
An increased intake of potassium may be needed
by patients treated with diuretics in order to maintain
serum potassium concentrations above 4 mmol per
liter. Having patients eat more fruit may sometimes
be sufficient, but potassium-salt supplements are of-
ten required. An alternate strategy is to give patients
a potassium-sparing diuretic along with supplemental
potassium (Table 1). Potassium-sparing diuretics are
not potent natriuretic agents, but they may moderate
the loss of potassium induced by other diuretics.29
Vasodilators
Drugs that relax both arterial and venous smooth
muscle reduce resistance to left ventricular ejection
and increase the total capacity of the venous reser-
voir. In patients with a dilated ventricle this pharma-
codynamic action results in an increase in stroke vol-
ume, a reduction in ventricular filling pressure, and
(at least with some regimens) relief of symptoms and
improved tolerance for exercise.30-33 The intravenous
infusion of sodium nitroprusside34 or, to a lesser ex-
tent, nitroglycerin35 has this hemodynamic effect. It
can also be induced and maintained by the adminis-
tration three or four times daily of either a combi-
nation of hydralazine and isosorbide dinitrate36 or an
angiotensin-converting–enzyme (ACE) inhibitor.37
Patients with persistent symptoms can be given
these last three drugs in combination,38 although
the efficacy of the three-drug combination has not
been demonstrated in controlled trials.
The dosage of these vasodilators needs to be indi-
vidualized on the basis of each patient’s tolerance
and the degree to which symptoms are relieved. Al-
though the target daily dose in clinical trials was 300
mg of hydralazine and 160 mg of isosorbide dini-
trate, these doses were not always achieved, because
of headaches in some patients.36,39,40 Most patients
with heart failure can tolerate moderate doses of
both drugs and are willing to take medication three
or four times daily. An overnight interval of 10
hours between doses of isosorbide dinitrate is desir-
able in order to minimize the likelihood of toler-
ance. The virtues of the combination of hydralazine
and isosorbide dinitrate are that the drugs are rela-
tively inexpensive and the associated risk of hypoten-
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sion or azotemia is low. Other side effects, including
lupus-like syndrome caused by the hydralazine, are
rare.39,40 The long-term efficacy of treatment with hy-
dralazine or isosorbide dinitrate alone is not known,
and combination therapy may prevent the develop-
ment of nitrate tolerance.41,42
Therapy with an ACE inhibitor should always be
initiated in a low dose (e.g., 12.5 mg of captopril or
2.5 mg of enalapril once a day) (Table 2); even lower
initial doses should be given if the patient’s serum so-
dium concentration is less than 135 mmol per liter,
which indicates a high level of plasma renin activity.43
Moderate, asymptomatic hypotension and moderate
azotemia (a serum creatinine concentration of less
than 2.5 mg per deciliter [221 mmol per liter]) are ac-
ceptable side effects of therapy with an ACE inhibitor
and are an indication to reduce the diuretic dose if
the patient’s jugular venous pressure is normal. Symp-
tomatic hypotension, progressive azotemia, or an in-
tolerable cough may, however, occasionally force the
discontinuation of the ACE inhibitor. Other side ef-
fects, including rash and angioedema, are rare.10,40,44
The optimal dose of an ACE inhibitor for the relief
of symptoms has not been established (Table 2).
Other vasodilators have acute hemodynamic ef-
fects but have not yet been proved to relieve symp-
toms. These include alpha-adrenergic antagonists
such as prazosin39 and dihydropyridine calcium-chan-
nel blockers. A unique vasodilator, flosequinan, was
briefly marketed for the treatment of heart failure, on
the basis of its ability to relieve symptoms,45 but was
withdrawn after it was found to reduce survival.46
One advantage of the use of an ACE inhibitor to
relieve symptoms is that it tends to conserve potas-
sium by reducing the secretion of aldosterone. Con-
sequently, hypokalemia induced by diuretics can of-
ten be prevented without the need for supplemental
potassium or a potassium-sparing diuretic.
The use of vasodilators in patients with heart fail-
ure whose systolic function remains good (that is,
patients without remodeling of the ventricular cham-
TABLE 2. ACE INHIBITORS USED TO TREAT HEART FAILURE.
DOSE RANGE TARGET DOSE FOR
DRUG (mg) FREQUENCY SURVIVAL BENEFIT*
Captopril 6.25–150 Three times daily 50 mg three times daily
Enalapril 2.5–20 Twice daily 10 mg twice daily
Lisinopril 2.5–40 Daily —
Ramipril 2.5–10 Once or twice daily 5 mg twice daily
Quinapril 5–20 Twice daily —
Zofenopril† — — 30 mg twice daily
Trandolapril† — — 4 mg daily
*Target doses are those associated with increased survival in clinical trials.
†This drug is not approved in the United States.
Vol ume 335 Numbe r 7  493
 The New England Journal o f Me di c i ne

ber) has not been carefully studied. ACE inhibitors
may improve the survival of these patients,47 but
more focused studies are needed. From a hemody-
namic standpoint, a vasodilator, such as nitrate, that
enhances venous capacity should have a favorable ef-
fect on the congestion resulting from diastolic dys-
function.
Digoxin
The therapeutic efficacy of digoxin in patients with
heart failure and normal sinus rhythm has long been
disputed; recent evidence indicates that withdrawal
of the drug can adversely affect symptoms.48 In most
studies, therapy with digoxin was limited to patients
with dilated hearts and reduced left ventricular sys-
tolic performance. The long-term safety of digoxin
therapy has been questioned on the basis of retro-
spective studies suggesting an adverse effect on sur-
vival.49 A recently completed trial, the Digitalis In-
vestigation Group (DIG) study, sponsored by the
National Institutes of Health and the Department of
Veterans Affairs,50 was conducted in over 7500 pa-
tients with heart failure and noted no significant ef-
fect of digoxin on mortality but a reduction in the
hospitalization rate in the digoxin group as com-
pared with the placebo group.
If it is given to patients with normal sinus rhythm,
digoxin should be used in doses that do not carry a
risk of toxic effects. Serum drug measurements are
usually not necessary to ensure safety. The dosing
scheme followed in the DIG study represents a ra-
tional approach (Table 3).
TABLE 3. DAILY DOSES OF DIGOXIN.*
PROLONGING THE LIVES OF PATIENTS
WITH LEFT VENTRICULAR DYSFUNCTION
A goal in all patients with left ventricular dysfunc-
tion, whether symptomatic or not, is to prevent pro-
gression of the disorder and prolong life. There are
a number of therapeutically modifiable mechanisms
at work in cardiac dysfunction. These include vaso-
constriction due to neural, hormonal, or endothelial
factors that increase the impedance load on the left
ventricle; activation of the sympathetic nervous sys-
tem and the renin–angiotensin system, which can
stimulate the growth of tissue in the myocardium
and the peripheral vasculature; neurohormonal or
tissue-induced mechanisms that have direct toxic ef-
fects on myocytes; progressive enlargement or re-
modeling of the left ventricle; local or circulatory
influences that induce ventricular arrhythmia; and
thromboembolic events.
Nonpharmacologic Management
To avoid aggravating left ventricular dysfunction,
patients should limit their consumption of alcohol
to no more than 2 oz (60 ml) per day; patients with
suspected alcoholic cardiomyopathy should abstain
entirely.51 Isometric exercise places an acute hemo-
dynamic burden on the left ventricle and should be
avoided.52
Coronary reperfusion in ischemic disease can im-
prove contractile function and may also inhibit ven-
tricular dilatation due to the tethering effect of blood
restored to the ventricular wall. Cardiomyoplasty, an
experimental procedure that involves wrapping the
latissimus dorsi muscle around the heart, could have
a favorable effect by limiting further dilatation of the
chamber.53
Drug Therapy
ACE Inhibitors

CORRECTED A number of experimental and clinical studies

CREATININE have found ACE inhibitors to have a favorable effect
CLEARANCE
(ml/min/70 kg)† BODY WEIGHT (kg) on the progression of left ventricular dysfunction.
50 60 70 80 90 100 These studies included research on rats and dogs
dose in mg
with experimentally induced left ventricular dysfunc-
tion54-56 and clinical trials involving both patients
10 0.125 0.125 0.125 0.125 0.250 0.250 with chronic heart failure57,58 and those in the early
20 0.125 0.125 0.125 0.250 0.250 0.250 phase of recovery from acute myocardial infarction.8
30 0.125 0.125 0.250 0.250 0.250 0.250
There is also preliminary evidence suggesting that
40 0.125 0.250 0.250 0.250 0.250 0.250
ACE inhibitors may reduce the risk of coronary is-
50 0.125 0.250 0.250 0.250 0.250 0.250
60 0.250 0.250 0.250 0.250 0.250 0.375
chemic events.59 It is uncertain whether the remark-
70 0.250 0.250 0.250 0.250 0.250 0.375 able response to these drugs in patients with cardio-
80 0.250 0.250 0.250 0.250 0.375 0.375 vascular disease can be attributed to hemodynamic
90 0.250 0.250 0.250 0.250 0.375 0.500 effects, to the reduction in the level of angiotensin
100 0.250 0.250 0.250 0.375 0.375 0.500 II in the plasma or tissue, to increased plasma con-
centrations of bradykinin or nitric oxide, or to inhi-
*Data were adapted from the Digitalis Investigation Group.50
bition of the sympathetic nervous system.
†The corrected creatinine clearance was calculated as 140  (age  serum
creatinine concentration in milligrams per deciliter) for men, and All patients with symptomatic congestive heart
140  (age  serum creatinine concentration)  0.85 for women. failure that is associated with reduced systolic ejec-

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 D R UG TH ER A PY
tion or left ventricular remodeling should be treated
with ACE inhibitors. These drugs improved the sur-
vival of patients with chronic heart failure and an
ejection fraction of less than 0.35 in the SOLVD tri-
al,44 and those with an ejection fraction of less than
0.45, together with reduced exercise capacity, in the
Veterans Affairs Cooperative Vasodilator–Heart Fail-
ure Trial II.40 In patients with an acute myocardial
infarction who have an ejection fraction of less than
0.40,60 symptoms or signs of acute heart failure,61 or
anterior infarction not treated with thrombolytic
drugs,62 ACE inhibitors have prevented heart failure
and reduced mortality. Ideally, these drugs should
be given in the dosage found in clinical trials to in-
crease survival (Table 2). The various ACE inhibitors
have not been compared directly.
Hydralazine and Isosorbide Dinitrate
The combination of hydralazine and isosorbide
dinitrate has been demonstrated to prolong life in
clinical trials involving patients with congestive heart
failure who were also given diuretics and digoxin.39,40
The vasodilative combination did not have as favor-
able an effect on survival as did enalapril, but its ef-
fect on left ventricular function and exercise capacity
was more favorable than that of enalapril. This must
be kept in mind if the combination (in the dosage
scheme recommended above) is used as a substitute
for an ACE inhibitor.
Antiarrhythmic Drugs
Antiarrhythmic drugs are not currently recom-
mended to suppress ventricular arrhythmias except
in the event of ventricular fibrillation in a patient in
whom careful monitoring, with electrophysiologic
testing if possible, demonstrates the effectiveness and
safety of the chosen drug. Amiodarone is used more
often in patients with heart failure than other anti-
arrhythmic drugs because of the lower risk of pro-
arrhythmia,63,64 but antiarrhythmic drugs have not
been proved to prolong life in these patients. One
recent trial found that amiodarone reduced mortal-
ity, but another found no significant effect.65,66 Im-
planted defibrillators may be a more effective thera-
py for patients at particularly high risk for recurrent
cardiac arrest.67,68
Anticoagulant Therapy
Since thromboembolism is a potential complica-
tion in patients with heart failure, some experts rec-
ommend routine prophylactic anticoagulation. Al-
though no prospective trial of anticoagulation has
been conducted in such patients, recent retrospec-
tive analyses of large-scale trials indicate that the rate
of thromboembolic events is so low (2 to 3 per 100
patient-years) that the rationale for routine antico-
agulation is questionable.69,70 Aspirin is frequently
given as a substitute for warfarin. Patients with heart
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failure who are at particularly high risk for throm-
boembolism — for example, those with a history of
embolism or those with atrial fibrillation — should
probably receive maintenance anticoagulant therapy,
even though the benefits have not yet been docu-
mented.
COMMON ERRORS IN THE MANAGEMENT
OF HEART FAILURE
The complexity of heart failure and the wide array
of available treatments burden the physician with
difficult decisions. Moreover, a number of common
errors can deprive the patient of some of the benefits
of treatment.
Not Recognizing Heart Failure
A normal-sized heart, as seen radiographically,
and an absence of edema or pulmonary rales do not
exclude the diagnosis of heart failure. Careful assess-
ment of jugular venous pressure, particularly in re-
sponse to exercise or to pressure on the right upper
quadrant, and echocardiographic quantification of
the size of the left ventricle and of its systolic and
diastolic function may reveal abnormalities that sug-
gest a cardiac cause for fatigue or dyspnea.
Improper Dosage of Diuretics
Insufficient doses of diuretics fail to restrain the
persistent cardiac distention that harms both myo-
cardial metabolism and function. On the other hand,
too much diuretic medication can cause hypovole-
mia, prerenal azotemia, and an unnecessarily low car-
diac output. Carefully adjusting the dosage to opti-
mize intravascular volume can result in long-term
benefits.
Failure to Assess the Quality of Life
Physicians too often rely only on objective find-
ings (e.g., edema or pulmonary congestion) to mon-
itor the effectiveness of therapy and disregard more
subtle, subjective observations. The restoration of an
adequate quality of life can be judged only through
an in-depth interview. Therapy whose only long-
term goal is relief of congestion is inadequate.
Failure to Consider Long-Term Therapeutic Goals
Because heart failure worsens over time and is
usually accompanied by progressive dilatation and
remodeling of the left ventricle, an important goal
of therapy is to halt or delay this progression. The
short-term relief of symptoms may have little rela-
tion to the progression of the syndrome over time.
The results of the SOLVD Prevention Trial10 provide
strong support for the administration of enalapril to
prevent symptomatic heart failure and reduce the
need for hospitalization in patients who have low
ejection fractions without symptoms of heart failure.
Vol ume 335 Numbe r 7  495
 The New England Journal of Me di c i ne
Inadequate Dosage of ACE Inhibitors
Physicians frequently prescribe ACE inhibitors in
doses well below those demonstrated in clinical trials
of enalapril, captopril, and ramipril to improve prog-
nosis. In most studies examining the relief of symp-
toms or improvement in the ability to exercise, the
drugs were given in the highest tolerated conven-
tional doses. Furthermore, even high doses of capto-
pril (300 mg per day) have been found to improve
exercise tolerance in controlled trials.33
Failure to Use Hydralazine and Isosorbide Dinitrate
Despite the evidence that the combination of hy-
dralazine and isosorbide dinitrate improves exercise
tolerance and survival in patients with heart failure,
this combination is not widely used to treat heart
failure. It should be given to patients who cannot
tolerate ACE inhibitors and to patients who remain
symptomatic even while taking an ACE inhibitor, al-
though no controlled trials with this second group
of patients have been done.
Use of Potentially Harmful Drugs
Some commonly used drugs may adversely affect
cardiac function, counteract the favorable effects of
other drugs, or increase the risk of sudden death in
patients with heart failure. Antiarrhythmic drugs,
nonsteroidal antiinflammatory drugs, and first-gen-
eration calcium antagonists such as verapamil, dil-
tiazem, and nifedipine should be used only with great
caution.
NEW APPROACHES TO MANAGEMENT
Evidence of the steady progression of heart fail-
ure, as well as the high mortality rate (about 40
percent in the first four years after diagnosis, as seen
in large trials40,44) among patients being given the
best currently available therapy has stimulated the
search for new and better drugs. Several drugs are
now being studied, predominantly in patients who
are already receiving diuretics, ACE inhibitors, and
digoxin.
Beta-Adrenergic Antagonists
Studies in Sweden,71,72 small, short-term studies
using metoprolol,73,74 and recently completed long-
term trials of metoprolol75 and bisoprolol76 provide
evidence that beta-adrenergic antagonists may have
a favorable effect on the course and prognosis of
at least some cases of heart failure. However, the
achieved reductions in morbidity and mortality did
not reach statistical significance in these studies, and
the use of these drugs is therefore still viewed as ex-
perimental. The potential acute adverse effect of
beta-adrenergic antagonists on left ventricular func-
tion requires that they be started in low doses with
gradual upward titration.
496  Aug u s t 1 5 , 1 9 9 6
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Beta-Adrenergic Antagonists with Vasodilative Action
Trials are currently under way of second-genera-
tion beta-adrenergic antagonists that also have vaso-
dilative action or additional cardiac effects.77,78 A se-
ries of recently completed six-month trials of about
1000 patients treated with carvedilol, a beta-adre-
nergic antagonist with a1-blocking and antioxidant
effects, revealed a consistent 65 percent reduction in
mortality.79 These studies suggest that drugs of this
type may delay or prevent the progression of heart
failure and may protect against sudden death. A trial
of bucindolol, a drug with properties similar to
carvedilol, is currently under way.
Vesnarinone
Vesnarinone has inotropic and possibly antiar-
rhythmic properties. In patients with severe heart
failure, a single daily dose of 60 mg reduced mortal-
ity.80 However, the increased mortality associated
with a dose of 120 mg, along with the small size and
short duration of the trial, led the Food and Drug
Administration to recommend a larger, longer trial,
which is now under way.
Calcium Antagonists
Although the negative inotropic effects of first-
generation calcium antagonists have led to a strong
recommendation against their use in heart failure,81
the action of felodipine and amlodipine is consider-
ably more restricted to the vascular walls. The ad-
ministration of these two drugs to augment vasodi-
lation induced by ACE inhibitors has been studied
in two multicenter trials.82,83 Preliminary reports sug-
gest that there was no adverse effect on the long-
term progression of disease or on survival.
Neurohormonal Inhibitors
Drugs that inhibit the sympathetic nervous sys-
tem or the renin–angiotensin system, including ibo-
pamine, imidazoline-receptor agonists, a2-adrenergic–
receptor agonists, angiotensin II–receptor antagonists,
and endopeptidase inhibitors, are in various stages
of evaluation as possible therapy for heart failure.
Their value will need to be assessed by evaluations
of mortality in very large trials or adequate sur-
rogates for progression of heart failure in smaller
studies.
Other Drugs with Cardiac Action
Although potent inotropic drugs lost their luster
after milrinone and xamoterol were found to have an
adverse effect on mortality,84,85 drugs in this class
(e.g., pimobendan)86 continue to be studied.
OPTIMAL MANAGEMENT
The complexity of heart failure and the physiolog-
ic and pharmacologic insight required for its treat-
 D R UG TH ER A PY
ment have led to the development of guidelines to
assist the primary care physician. One such set of
guidelines has recently been developed by the Agen-
cy for Health Care Policy and Research,87 and an-
other by a joint task force of the American Heart As-
sociation and the American College of Cardiology.88
These guidelines emphasize the importance of doc-
umenting the presence of heart disease, with special
attention to imaging the left ventricle for its size and
function. They stress the importance of identifying
the symptoms and signs of expanded ventricular vol-
ume, of early intervention with ACE inhibitors, and
of diagnosing correctable ischemia and valve dys-
function. They also point out the critical importance
of educating patients and of maintaining close fol-
low-up to minimize decompensation that requires
intensive and expensive intervention. Whether such
guidelines will be followed by primary care physi-
cians and thus have an impact on the treatment they
give patients is not yet known.89
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 New England Journal of Medicine
CORRECTION
The Management of Chronic Heart Failure
To the Editor: In his discussion of diuretic therapy in his excellent re-
1 and ejection fraction, subserve this physiologic goal. The therapies for
view of congestive heart failure (Aug. 15 issue), Dr. Cohn did not
mention that resistance to diuretics frequently develops in patients
with severe refractory heart failure. The underlying mechanisms in-
clude decreased drug delivery to the nephron due to reduced renal
blood flow, competition with organic acids for active secretion, com-
pensatory sodium retention, hypochloremia, and decreased absorp-
tion of sodium due to edema of the gastrointestinal tract. Resistance
can often be overcome by administering large intravenous doses or
continuous infusions of diuretics. For example, furosemide, in doses
of up to 4000 mg daily, is well tolerated and can cause a diuresis of
2 To the Editor: I agree with Drs. Howard and Dunn, who stress the im-
3 to 10 kg of body weight per day. In a group of patients with con-
gestive heart failure who were resistant to 250-mg intravenous bolus
doses of furosemide, continuous infusions at rates as high as 168 mg
per hour were effective.3 Most patients required oral doses of up to
1000 mg daily to prevent recurrent edema.
Congestive heart failure is the most common diagnosis-related group
among patients over 65 years of age, with annual hospitalization costs
4
estimated at $8 billion. Aggressive diuresis is essential in order to
avoid prolonged hospitalization and excessive costs.
Patricia A. Howard, Pharm.D.
Marvin I. Dunn, M.D.
University of Kansas Medical Center
Kansas City, KS 66160-7231
References
1. Cohn JN. The management of chronic heart failure. N Engl J Med
1996;335:490-498.
2. Gerlag PGG, van Meijel JJ. High-dose furosemide in the treat-
ment of refractory congestive heart failure. Arch Intern Med
1988;148:286-291.
3. van Meyel JJ, Smits P, Dormans T, Gerlag PG, Russel FG, Grib-
nau FW. Continuous infusion of furosemide in the treatment of
patients with congestive heart failure and diuretic resistance. J
Intern Med 1994;235:329-334.
4. Garg R, Packer M, Pitt B, Yusuf S. Heart failure in the 1990s: evo-
lution of a major public health problem in cardiovascular medicine.
J Am Coll Cardiol 1993;22:Suppl A:3A-5A.
To the Editor: In his review of the management of heart failure, Dr.
Cohn failed to mention that the fundamental pathophysiologic mech-
anism responsible for the clinical features and the eventual outcome
of heart failure is the imbalance between the delivery of oxygen and
Downloaded from www.nejm.org on August 27, 2009 . Copyright © 1996 Massachusetts Medical Society. All rights reserved.
the oxygen requirements in various tissues and organs. Heart failure
can be defined, in essence, as the inability of the cardiac output to
sustain the level of oxygen delivery necessary for the preservation of
aerobic metabolism. The different mechanisms and indicators of car-
diac function, such as preload, afterload, contractility, cardiac output,
heart failure outlined in the article will fail if adequate oxygen delivery
is not maintained. It is therefore puzzling that terms such as oxygena-
tion, oxygen delivery, aerobic metabolism, and oxygen therapy were
not mentioned.
Hamid Sahebjami, M.D.
Veterans Affairs Medical Center
Cincinnati, OH 45220
Dr. Cohn replies:
portance of adequate diuresis in treating patients with intense sodium
retention. Maintenance of normovolemia is a key to avoiding recurrent
hospitalization. I prefer to use a second diuretic (metolazone, as out-
lined in my review) instead of massive doses of furosemide to achieve
the desired effect. In most patients this therapy delivers enough so-
lute to the ascending limb to render the loop diuretic more effective.
Clearly, when this approach is not successful, the intravenous or oral
high-dose regimens of furosemide that Howard and Dunn describe
may be necessary.
Dr. Sahebjami’s concept that heart failure is fundamentally a defi-
ciency in tissue oxygen delivery is a simple, traditional view that prob-
ably can no longer be defended. In states of cardiogenic shock inade-
quate tissue oxygenation leads to organ system failure. In chronic
heart failure the neurohormonal stimulation, cardiac and vascular
structural remodeling, sodium retention, and exercise intolerance are
not easily attributable to oxygen debt. Therapies that probably do
not directly affect oxygen delivery appear to have long-term favorable
effects, whereas some therapies that augment oxygen delivery may
have a deleterious effect. Although hemodynamic abnormalities re-
sulting in impaired oxygen delivery may be fundamental to the gen-
esis of heart failure, they do not appear to account for the clinical
manifestations that characterize the chronic disease.
There was an error in the second footnote of Table 3. The correct
formula for creatinine clearance is as follows: (140 - age) ÷ serum
creatinine concentration.
Jay N. Cohn, M.D.
University of Minnesota Medical School
Minneapolis, MN 55455
N Engl J Med 1997;336:295