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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
Arch Intern Med. 2001;161:342-352.
ABSTRACT
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During the past 10 years, the philosophy of heart failure treatment
has evolved from symptom control to a combined prevention and symptom-management
strategy. Recent clinical trials have proved that early detection can delay
progression. Treatment of asymptomatic left ventricular dysfunction is as
important as treatment of symptomatic 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 inhibitors, ß-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 select 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 hydrochloride, and isosorbide dinitrate
are recommended. The data on antiarrhythmic and anticoagulation therapies
are inconclusive.
INTRODUCTION
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 continually improving understanding of
the pathophysiology of heart failure has accelerated the development of new
treatments. However, no single measurement 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 progression.2, 3 Treatment of asymptomatic left ventricular
dysfunction is as important as treatment of symptomatic disease. Because heart
failure specialists are usually referred symptomatic patients, their patients
usually enter the heart failure treatment triangle after the prevention stage
(Figure 1).4
Most patients with asymptomatic left ventricular dysfunction 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, 5, 6
Therefore, despite the inherent complexities of heart failure therapy, it
is important for all physicians to know current management strategies to prevent
end-stage disease.
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Figure 1. The iceberg phenomenon of the
heart failure/left ventricular dysfunction syndrome.
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The treatment of heart failure encompasses pharmacological therapy and
includes surgical approaches such as revascularization of coronary arteries,
mitral valve repair, aortic valve replacement, ventriculectomy, cardiomyoplasty,
and left ventricular assist devices with heart transplant. 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.
DEFINITION
Heart failure is a complex clinical syndrome
that may include fatigue and shortness of breath on exertion (and in advanced
cases, at rest), orthopnea, paroxysmal nocturnal dyspnea, nocturia, mental
status changes, anorexia, and abdominal pain. Patients have different 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 ventricle is systolic
dysfunction, represented by a reduced ejection fraction.1, 7, 8
Ischemic (coronary artery disease [CAD]) and nonischemic conditions (hypertension,
valvular disease, hypertension, thyroid disease, alcohol abuse, myocarditis,
adult congenital heart disease, and cardiomyopathy) may cause systolic dysfunction.1, 9, 10 Coronary artery disease
accounts for approximately 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 efficiently
may be transient, as in a patient with ischemia, or sustained, as in a patient
with concentric myocardial hypertrophy or restrictive cardiomyopathy secondary
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 symptoms on ordinary exertion. Class III patients
have symptoms on minimal exertion, and class IV patients have symptoms at
rest.13 There are 2 major problems with the
classification system, ie, a high degree of interobserver variability to assignment
of class and an inability to detect small changes in clinical status.14 For now, this is the easiest method to group patients,
despite limited ability to predict the degree of physiological systolic dysfunction.
Diagnostic examinations can help expedite appropriate treatment. The
most valuable initial diagnostic examination is the 2-dimensional echocardiogram
coupled with Doppler flow studies. It is easily accessible and inexpensive.
Patients with ejection fractions of no greater than 0.40 are considered to
have systolic dysfunction. The study assesses systolic and diastolic abnormalities
involving the right and left sides of the heart, and it determines the presence
of pericardial, endocardial, valvular, and vascular abnormalities.8 Patients with heart failure often have multiple cardiac
abnormalities causing or contributing to their disease. Radionuclide ventriculography
also reveals biventricular global and regional wall motion abnormalities.
However, it does not permit assessment of other cardiac abnormalities. An
assessment of ventricular function is recommended during the patient's initial
presentation.8
Repeated diagnostic testing is of debatable value. Without a corresponding
clinical change in functional status, there is little value in slight changes
in measured ejection fraction. Most believe that a repeated assessment of
ejection fraction is warranted if there is a significant change in clinical
status, or if the patient has had a recent event.8
Heart failure specialists use exercise testing to better determine functional
capacity. The measurement of peak oxygen consumption is a good measure of
capacity, but it is not clear if exercise testing accurately measures daily
physical stresses encountered by the patient.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 persons have heart failure, with approximately
400 000 to 700 000 new cases each year.17, 18, 19
Heart failure affects approximately 1.5% to 2% of the population.17, 18, 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, 18, 19 Heart failure is
the leading cause of hospitalization,18, 19
and in addition, as many as 20 million patients have an asymptomatic impairment
of cardiac 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 approximately equal.17, 21 Unfortunately, women only account
for approximately 20% of patients in most clinical trials,22
which makes most of the treatment guidelines for women almost speculative.
Heart failure is a progressive, fatal 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
despite new advances in treatment. The risk for death is 5% to 10% annually
in patients with mild symptoms and increases to approximately 30% to 40% annually
in patients with advanced disease.23 With the
increasing prevalence, hospital expenditures have escalated.19
Annual direct expenditures, which include cost of medications, hospitalizations,
nursing home admissions, and medical follow-up, are estimated at $20 billion
to $40 billion.8, 19 Thus, educating
all physicians about treatment guidelines can have a significant public health
impact.
PATHOPHYSIOLOGY
The philosophy of current treatment can best be understood by reviewing
the evolution of heart failure models. From 1940 through 1960, heart failure
was thought to result primarily from renal hypoperfusion.25, 26
Standard treatment consisted of digoxin, diuretics, bed rest, and leg elevation,
aimed at improving 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 ventricular
wall stress is the principal cause of the heart failure syndrome.26, 27 An initial injury is thought to initiate
a deleterious feedback cycle by causing a change in left ventricular geometry
of dilation and hypertrophy.28, 29
This structural remodeling of the heart produced by cardiac dysfunction 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 mitral regurgitation, worsening ejection
efficiency and further increasing wall stress.8
Treatment was aimed at vasodilation and improving ventricular contractility
to improve cardiac output and to reduce the wall stress aggravated by elevated
preload and afterload. However, clinical trials of inotropic agents did not
produce long-term mortality benefits, contradicting predictions based on this
model.
The change in focus to the endogenous factors that alter the long-term
structure of the myocardium and vasculature has revolutionized heart failure
treatment. Activation of neurohormonal systems plays an important role in
cardiac remodeling (the alterations in ventricular architecture that occur
during the development of heart failure).31, 32, 33, 34
Many drug treatments now target the mediators of the neurohormonal systems
activated in heart failure. Stimulation of the sympathetic and renin-angiotensin
systems1, 35 lead to elevated levels
of norepinephrine, angiotensin II, aldosterone, and vasopressin.1, 35
The net effects of these mediators are vasoconstriction, increased blood volume,
increased heart rate, and increased 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 various cell-signaling pathways that
disturb normal myocyte activity, initiate apoptosis, and promote fibrosis.37, 38, 39, 40, 41, 42, 43, 44
Other neurohormonal factor levels increased in patients are endothelin, epinephrine,
growth hormome, cortisol, tumor necrosis factor, prostaglandins, substance
P, adrenomedullin, and natriuretic peptides.45
Despite past controversy about the treatment of ischemic vs nonischemic heart
failure, the present 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
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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.
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Heart failure prevention and treatment now consists of a multidisciplinary
approach, including lifestyle modification to prevent initial and recurrent
injury and pharmacological intervention to prevent progression in asymptomatic
and symptomatic patients. Coronary artery disease and hypertension are the
2 most common causes of heart failure. Two major trials have demonstrated
that the prevention of both factors decreases the risk for development of
heart failure. The treatment of hypertension in the Systolic Hypertension
in the Elderly Program (SHEP) trial47 decreased
the risk for development of heart failure by 81%.48
The treatment of hypercholesterolemia in the Scandinavian Simvastatin Survival
Study (4S trial) with a hepatic hydroxymethyl glutaryl coenzyme A reductase
inhibitor decreased the risk for development of heart failure by 20%.49 Modifying lifestyle factors that contribute to the
pathophysiology of hypertension and CAD, such as smoking, obesity, excess
alcohol intake, and diabetes, may also affect heart failure prevention. Identification
and aggressive management of potential risk factors for cardiovascular disease
remain important. However, large-scale clinical trial data have yet to demonstrate
direct effects of adjustment of these factors on risk for development or acceleration
of congestive heart failure (CHF).
GUIDELINES FOR DRUG THERAPY
Pharmacological intervention continues to be the mainstay of management
of CHF, and abundant clinical trial data describe the specific effects of
various agents. Although sometimes puzzling and contradictory, the extensive
clinical trial database for heart failure has provided clinicians with important
information, and this serves as the basis for guidelines proposed by various
expert committees.
Diuretics
Clinical trials have demonstrated fast improvement in sodium excretion,
symptoms of fluid overload,50, 51
exercise tolerance, and improvement of cardiac function52
with diuretics. Most long-term trials include patients receiving diuretics,
but there are no long-term studies of diuretics in heart failure (we refer
here to thiazides and loop diuretics and reserve discussion 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 retention, and should continue using these agents
after improvement of symptoms.8, 52
The practitioner should carefully titrate these medications to avoid
excessive volume depletion but allow for some decreased renal function.8, 52 Undertitration of primary diuretics
can diminish the patient's response to angiotensin-converting enzyme (ACE)
inhibitors (resulting from a state of relative volume overload) and increase
the frequency of adverse effects of treatment with ß-blockers.53, 54 Although ACE inhibitors and digoxin
have weak diuretic properties,53, 54, 55, 56
only primary diuretics can control fluid overload adequately. Loop diuretics
should be used as first-line agents, with thiazides added for refractory fluid
overload. Diuretic treatment should be combined with a low-salt diet,8 a ß-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 perfusion, avoidance
of symptomatic hypotension, and achievement of stable weight. Hydrochlorothiazide,
25 mg, can be added with refractory fluid overload to escalating 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 potential
for severe hypokalemia and hypomagnesemia. The practitioner may switch furosemide
to bumetanide, 2 to 4 mg/d, with 2.5 mg of metolazone added as needed.
ACE Inhibitors
Angiotensin-converting enzyme inhibitors have beneficial effects in
the treatment and prevention of heart failure. Six ACE inhibitors are approved
by the Food and Drug Administration for the management of heart failure, ie,
captopril, enalapril maleate, lisinopril, quinapril hydrochloride, trandolapril,
and fosinopril sodium.20 Ramipril is approved
for the treatment of heart failure after a myocardial infarction.20 The first study to demonstrate a clinical benefit
in symptoms was the Captopril Multicenter Study in 1983.57
Many double-blind placebo-controlled trials with different ACE inhibitors
supported these findings.20 However, 4 major
trials of intermediate to long-term duration established the morbidity 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 treatment with placebo, digoxin
(up to 0.375 mg/d), or captopril (up to 150 mg/d). Captopril decreased emergency
care or hospitalization for worsening heart failure compared with placebo.58
Studies of Left Ventricular Dysfunction Treatment Trial
The Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial
also studied patients with mild to moderate heart failure (NYHA classes II
and III) with ischemic and nonischemic origins. Patients were randomized to
receive placebo or enalapril maleate (up to 20 mg/d) in addition to conventional
therapy. The combination of enalapril and conventional therapy decreased all-cause
mortality and the risk for death or hospitalization for heart failure compared
with that for placebo.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 28% more than the
combination vasodilator therapy.60
Cooperative North Scandinavian Enalapril Survival Study
Patients with NYHA class IV ischemic and nonischemic heart failure were
randomized to enalapril maleate (up to 40 mg/d) or placebo added to conventional
therapy.61 The study demonstrated a 27% reduction
in all-cause mortality at 6 months. Patients improved functional class and
reduced their requirement for other heart failure medications.
Despite copious aggregate evidence of their benefits, ACE inhibitors
have been underprescribed in the United States21
and abroad.6, 21, 62, 63, 64
Angiotensin-converting enzyme inhibitors are also given in lower doses by
practitioners than in clinical trials protocols.65
A few recent studies have addressed the issue of ACE inhibitor dose effects.
The Assessment of Treatment with Lisinopril and Survival (ATLAS) Study evaluated
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 decreased hospitalization rate for all causes and heart failure in the
high-dose group.9, 20 The Network
Study evaluated different doses of enalapril 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 measured.66 Finally, the
ongoing Accupril Congestive Heart Failure Investigation and Economic Variable
Evaluation (ACHIEVE) trial is presently evaluating different doses of quinapril
hydrochloride (5-20 mg twice daily) and mortality.67, 68
Although underdosing of ACE inhibitors has been a prominent concern for many
heart failure specialists, available data have yet to verify subtherapeutic
effects of treatment regimens involving lower doses than those described in
the original trials.
Angiotensin-converting enzyme inhibitors are recommended preventive
treatment in patients who have experienced a recent or remote ischemic or
nonischemic event resulting in systolic dysfunction.8
Four major trials supporting this statement are the Survival and Ventricular
Enlargement Trial (SAVE; up to 150 mg/d),69
the Acute Infarction 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 ß-blocker therapy in the SOLVD database73
showed that the combination of ß-blocker and enalapril was associated
with a greater reduction in mortality than the use of either agent alone.
Treatment with ACE inhibitors should begin with lower doses, and, if
tolerated, titrated to maximum. Recommended target doses are 150 mg/d for
captopril, 20 mg/d for enalapril maleate, 40 mg/d for lisinopril, 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 hyponatremia, diabetes, azotemia, or hypotension or in patients
receiving potassium supplementation.8 Controversy
exists among heart failure specialists on whether there is significant literature
documenting the attenuation of ACE inhibitor benefit with the use of aspirin
therapy.8 Most physicians believe that the
evidence is not strong, and thus use both agents.
Titration of ACE inhibitor therapy combined with diuretics needs careful
clinical and diagnostic monitoring. Serum creatinine level is expected to
increase but may remain stable, whereas potassium level, depending on the
patient and diuretic dose, may increase, decrease, 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 potassium supplement
therapy should be reduced or added to achieve safe levels. The goal is to
achieve adequate renal perfusion, to avoid symptomatic hypotension, and to
insure the absence of congestion.
ß-Adrenergic Receptor Blockers
Blockade of ß-adrenergic receptors, previously contraindicated
as a heart failure treatment, is now a pivotal treatment modality. Early studies
of ß-blocker treatment demonstrated clinically beneficial effects but
failed to prove a reduction in mortality.74, 75, 76, 77
Patients with minimal or mild symptoms failed to improve NYHA class,78, 79 but decreased their likelihood of
clinical exacerbations.78 Selective ß1-receptor inhibitors (metoprolol succinate and bisoprolol fumarate)
and an agent with  1-, ß1-, and ß2-receptor inhibition (carvedilol) have improved symptoms and ejection
fraction80 in patients with moderate to severe
symptoms.3, 8 The controversy and
fear that ß-blockers may increase mortality previously discouraged many
physicians from prescribing these agents. Recent data, however, have lessened
these fears.3, 8, 80, 81, 82
The Cardiac Insufficiency Bisoprolol Study
Two thousand six hundred forty-seven patients with moderate 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% reduction in mortality, a 20% reduction in risk
for any hospitalization, and a 32% decrease in heart failure hospitalization.83
The Metoprolol CR/XL Randomized Intervention Trial in Heart Failure
Three thousand nine hundred ninety-one patients in Europe and the United
States were randomized 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 mortality resulting in an early
termination 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
progressive heart failure, and a 35% reduction in the number of patients hospitalized
for heart failure.84, 85, 86, 87
The US Carvedilol Heart Failure Trials Program
Four separate multicenter trials involving 1094 patients examined patients
with mild, moderate, and severe heart failure of ischemic and nonischemic
origins. The trials were the Prospective Randomized Evaluation of Carvedilol
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 Assessment 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 evaluating 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 studies evaluated mortality or hospitalization 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 failure 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 inhibitors and ß-blockers.73
Of the patients in the NYHA class II prevention arm, 24% received a ß-blocker,
compared with only 8% in the class II to III treatment arm. Each agent individually
in both groups demonstrated a mortality benefit.
Recently, the Beta-Blocker Survival Trial (BEST),91
a trial of bucindolol hydrochloride (a nonselective ß-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 nonselective ß-blockers in more advanced disease.
The Carvedilol Prospective 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 present, the Carvedilol or Metoprolol European
Study (COMET) is evaluating 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 ß-blockers8; ß-blockers are also recommended in diabetic
patients.94 Therapy with ß-blockers should
not be started during an acute worsening of clinical status or evidence of
fluid overload. During acute episodes for patients already taking ß-blockers,
the dose should be decreased, or stopped if the patient is in severe failure.8 If the patient experiences mild to moderate symptoms,
the dose may be halved or continued with temporary lowering of the ACE inhibitor
dose and increasing doses of diuretics. Often, the early fluid retention induced
by ß-blockade lessens with continued therapy. If the patient experiences
symptomatic hypotension, the doses of ß-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, titration
to the highest dose tolerated is recommended for best results.8
It is still unknown which agent is the most effective or whether patients
with NYHA class I heart failure may benefit from treatment.
Aldosterone Antagonists
The guidelines published this year in the American
Journal of Cardiology 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 specialists are
recommending spironolactone in a select group of patients. 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 treated with an ACE inhibitor and a loop diuretic but were not
allowed potassium-sparing diuretics. Vasodilators and digitalis were allowed.
The double-blind trial randomized 1663 patients to placebo or 25 mg of spironolactone.
The trial terminated early because of the significant 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,
quality of life, functional capacity, and exercise tolerance in patients with
mild to moderate heart failure.8, 58, 76, 96
The withdrawal of digoxin therapy has resulted in significant clinical deterioration.97 The only trial that has evaluated long-term therapy,
the Digitalis Investigation Group (DIG) Trial, demonstrated a decreased risk
for all-cause and heart failure hospitalization, but failed to demonstrate
a mortality benefit.98 Digoxin is recommended
for the control of ventricular response in patients with atrial fibrillation.
Digoxin can be added to therapy consisting of ACE inhibitors, diuretics, and ß-blockers
in patients with a normal sinus rhythm to improve clinical symptoms and to
reduce the number of heart failure hospitalizations in NYHA classes II to
IV patients. Digoxin levels should not be checked routinely, except to exclude
toxic effects of digitalis (Figure 3). 8
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Figure 3. Recommended approach to the patient
with heart failure. LV indicates left ventricular; EF, ejection fraction;
and ACE, angiotensin-converting enzyme.
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NONRECOMMENDED DRUGS
Other drug classes have been studied and have produced small significant
morbidity and/or mortality benefit. However, the benefits are not enough to
recommend these therapies for all patients. Other agents show much promise
and are theoretically effective but have been inadequately studied in human
trials to date.
Angiotensin Receptor Blockers
Long-term studies of angiotensin receptor blockers have demonstrated
similar hemodynamic and neurohormonal effects as ACE inhibitors, but have
not demonstrated consistent effects on symptoms or exercise tolerance.8 Angiotensin receptor blockers appear to be safe in
heart failure patients. The Evaluation of Losartan in the Elderly (ELITE)
Study compared captopril or losartan potassium with conventional therapy in
722 patients aged at least 65 years.99 There
was no difference in renal function, hospitalizations for heart failure, or
the combined risk of morbidity and mortality between captopril and losartan
groups. A single-blinded study demonstrated 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 Randomized Evaluation of Strategies for Left
Ventricular Dysfunction (RESOLVD), patients with mild to moderate symptoms
(NYHA classes II-IV) were randomized to candesartan, enalapril, or both with
conventional therapy. There was no significant difference in exercise tolerance
or cardiac events among groups.102
It is unclear if the receptor blockers will have a similar mortality
benefit in heart failure patients. A trial of more than 3000 patients, Evaluation
of Losartan in the Elderly II (ELITE II), compared losartan and captopril
and reported no difference in mortality.103
Two large multicenter trials, Valsartan Heart Failure Trial (Val-HeFT) and
Candesartan in Heart Failure Assessment in Reduction of Mortality and Morbidity
(CHARM), are currently evaluating this issue.8
Angiotensin receptor blockers are only recommended if ACE inhibitors are not
tolerated 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 hydralazine hydrochloride and isosorbide
decreases mortality in heart failure patients.104
However, in a direct comparison with enalapril, enalapril had a larger mortality
benefit.60 Most physicians first substitute
an angiotensin receptor blocker if an ACE inhibitor is not tolerated. Therefore,
this regimen should only be considered if ACE inhibitors are not tolerated
and/or the patient has renal insufficiency.
Calcium Antagonists
No clinical trials have proven a mortality benefit with calcium antagonists.
Some have demonstrated no apparent harm, and that they may be used if a calcium
antagonist is indicated. Amlodipine besylate with standard therapy in the
Prospective Randomized Amlodipine Survival Evaluation (PRAISE) demonstrated
no clear benefit on mortality or major cardiovascular hospitalizations.105 Although amlodipine did not affect the combined
risk for death and major cardiovascular hospitalization, it appeared to lower
the risk for death in a retrospective subgroup analysis of patients with a
nonischemic cardiomyopathy. Although PRAISE-2 hoped to confirm this trend,106 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-cause mortality.108 Thus, although these calcium channel blockers do
not have any additional benefits for heart failure patients, they apparently
do not place the patient at increased risk for mortality.
Inotropic Drugs and Vasodilators
Despite the emergence of new inotropic agents, the results do not seem
promising. The recent Vesnarinone Trial demonstrated an increase in mortality
among patients with severe heart failure.11, 109
The use of intermittent infusion of inotropic agents has no proven mortality
benefit,110, 111 and long-term
treatment 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 advanced-stage
heart failure.110 If patients 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 nitroglycerin (arterial
and venous vasodilator). Both agents can have adverse effects. Tolerance develops
quickly to nitroglycerin, and sodium nitroprusside administration is associated
with accumulation of toxic metabolites. These drugs are not useful in the
routine management of congestive heart failure.
Antiarrhythmic Agents
Antiarrhythmic agents are recommended if the atrial or ventricular arrhythmia
causes a clinical deterioration. Amiodarone reduced the risk for death and
hospitalization for heart failure in heart failure patients in the Grupo de
Estudio de la Sobrevidea en la Insuficiencia Cardiaca en Argentina (GESICA).113 However, in the Congestive Heart Failure Survival
Trial of Antiarrhythmic Therapy (CHF STAT),114
amiodarone did not improve all-cause mortality in patients with asymptomatic
arrhythmia. Treatment was associated with an improved ejection fraction. Amiodarone
thus appears relatively safe and is preferred in the treatment of atrial arrhythmias
in heart failure patients.
Other agents have been studied for treatment of atrial arrhythmias,
but are not recommended. Unfortunately, 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 normal sinus rhythm, maintains sinus rhythm, and reduces the risk for hospitalization
in heart failure patients with atrial fibrillation.116
It does not alter all-cause mortality.116
Atrial fibrillation is the most common nonfatal arrhythmia experienced
by the CHF patient. Amiodarone is recommended for patients who require lowering
of the heart rate despite use of digoxin and ß-blockers. Amiodarone has
numerous adverse effects, most commonly thyroid dysfunction, pulmonary fibrosis,
gastrointestinal tract upset, corneal deposits, and prolongation of the QT
interval, occasionally leading to ventricular arrhythmias. Amiodarone therapy
typically is started orally at 200 to 400 mg/d. The practitioner must reduce
the digoxin dose (to avoid elevation of digoxin level with concurrent amiodarone
administration) and ß-blocker dose (to avoid excessive bradycardia).
Patients with significant lung disease present a therapeutic challenge, as
amiodarone and ß-blockers may be contraindicated. This problem is assessed
on a case-by-case basis. Finally, dofetilide represents an intriguing alternative,
the use of which awaits further study.
Treatment of ventricular arrhythmias in patients with end-stage heart
failure is debatable. Treatment with amiodarone at a dose of 200 to 400 mg/d
(sometimes with a loading dose) is useful in selected patients. It is unclear
if implantable cardioverter-defibrillators have a mortality benefit in heart
failure patients. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)
is currently addressing this issue.8
Anticoagulation
Anticoagulation in patients without atrial fibrillation and with diminished
left ventricular function remains controversial. There has been no double-blind
placebo-controlled trial in heart failure patients. Patients with dilated
cardiomyopathy are predisposed to thromboembolism because of increased stasis
in dilated chambers, regional wall motion abnormalities causing asynergy,
poor contractility, and atrial fibrillation.117
In 1981, Fuster et al118 retrospectively observed
an 18% frequency of thromboembolism with an incidence of 3.5 per 100 patient-years
in patients with nonischemic dilated cardiomyopathy.
Verification of this low incidence has been observed in recent heart
failure trials.59 Warfarin sodium reduced all-cause
mortality and the risk for death or hospitalization 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 Therapy in Chronic Heart Failure (WATCH) Trial,121 and the Warfarin Versus Aspirin in Reduced Cardiac
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 warfarin in NYHA classes II to IV patients
with an ejection fraction of no greater than 0.30, and the WARCEF Trial will
compare warfarin 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 1 and Figure 4).
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Clinical Trials Evaluating Anticoagulation in Congestive Heart Failure*
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