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Authors:
Abdullah Alsaeedi MD, FRCPC
Division of internal Medicine
Aljahra Hospital
Kuwait
Dr. Rashed Alhamdan MD, FRCPC
Division of Internal Medicine
Aljahra Hospital
Kuwait
Correspondence:
Dr. R. Alhamdan
Department of Medicine
Aljahra Hospital
Kuwait
E.mail: ralhamdan@yahoo.com
Heart failure is a clinical syndrome characterised
by an inability to provide sufficient cardiac output
to meet tissue demands at normal ventricular filling
pressures (1). The syndrome is a significant health
issue in the United States, where almost 5 million people
have received the diagnosis of heart failure and about
a half million new cases are diagnosed annually. According
to estimates, nearly a half billion dollars are spent
on drugs for treatment of heart failure every year in
the United States (2).
This review focuses on the latest advances
in the management of acute and chronic heart failure
in patients with left ventricular systolic dysfunction.
Acute versus chronic heart failure
Diminished left ventricular systolic function is distinguishable
by an ejection fraction of less than 35% to 40% (1)
and is usually accompanied by an increase in the left
ventricular end systolic and diastolic diameters. In
response, the body activates several compensatory mechanisms
as it attempts to maintain adequate tissue perfusion.
These mechanisms include stimulation of the sympathetic
nervous system, activation of the renin-angiotensin-aldosterone
system, and local vasoregulation (3). Although beneficial
in their initial stages, the mechanisms may have a net
detrimental effect of left ventricular remodeling coupled
with an excessive increase in myocardial oxygen consumption,
which results in further deterioration of cardiac function.
Heart failure can be divided into acute
and chronic forms on the basis of acuity of presentation
and severity of signs and symptoms. In the past, both
acute and chronic types were viewed primarily as haemodynamic
disease and were treated with drugs that improve myocardial
contractility (inotropic agents), optimise volume status
(diuretics), and improve cardiac output through afterload
reduction (vasodilator agents).
Although many of these drugs improved
short-term symptoms in patients with chronic heart failure,
they often failed to produce significant gains in long-term
survival. In contrast, drugs that block neurohormonal
factors, such as angiotensin-converting enzyme (ACE)
inhibitors and beta-blockers, have generally improved
not only the symptoms of chronic heart failure but also
long-term survival.
Treatment of chronic heart failure
To optimally tailor therapy for chronic heart failure
to an individual patient in the outpatient setting,
it is important to categorise the patient's disease
into the appropriate New York Heart Association (NYHA)
class (Table 1). Treatment goals for
chronic heart failure include alleviation of symptoms
and improvement of quality of life, prevention of progression
of myocardial dysfunction, and prolongation of life.
The various drugs used in the treatment of heart failure
contribute differently to these therapeutic end points.
Their differences are outlined in Table
2. A treatment algorithm that integrates the therapeutic
options is shown in Figure
1.
ACE inhibitors
These agents prevent the conversion of angiotensin I
to angiotensin II through inhibition of the angiotensin-converting
enzyme, which results in diminution of the adverse effects
of angiotensin II. Moreover, inhibition of this enzyme
prevents the breakdown of bradykinin and enhances kinin-mediated
prostaglandin synthesis. In the Studies of Left Ventricular
Dysfunction (SOLVD) trial (4), treatment of mild to
moderate heart failure (NYHA classes II and III) with
enalapril (<20 mg/day) was associated with a 16%
reduction in all-cause mortality compared with placebo
(35.2% versus 39.7%; P=.0036). Enalapril use also resulted
in a 26% decrease in risk of death or hospitalisation
for worsening heart failure (P<.0001). Even patients
with reduced cardiac function (ejection fraction, <35%)
who are asymptomatic derive significant benefit from
treatment with ACE inhibitors (i.e. reduction in risk
of heart failure and rate of related hospitalisations)
(5). Thus, it is recommended that all patients with
heart failure and left ventricular systolic dysfunction
receive an ACE inhibitor unless its use is contraindicated.
Beta-blockers
Once a patient's chronic heart failure is stabilised
by an effective dose of ACE inhibitor, beta-blocker
therapy should be initiated. Long-term treatment with
carvedilol (6), bisoprolol fumarate (7), or long-acting
metoprolol (8) has been shown in large randomised clinical
trials to improve the mortality rate in patients who
have NYHA class II or III systolic dysfunction caused
by ischaemic or nonischaemic cardiomyopathy and who
already are taking ACE inhibitors and diuretics.
In the US Carvedilol Heart Failure
Study (6), carvedilol use (mean dose, 45 + 27 mg/day)
decreased the mortality rate by 65% compared with placebo
(3.2% versus 7.8%; P<.001), lowered the risk of hospitalisation
for cardiovascular causes by 27% (14.1% versus 19.6%;
P=.036), and decreased the combined risk of death and
hospitalisation by 38% (15.8% versus 24.6%; P<.001).
Similarly, in the Cardiac Insufficiency Bisoprolol Study
II (CIBIS-II) (7), 2,647 patients with NYHA class III
or IV heart failure were randomly assigned to receive
bisoprolol (<10 mg/day) or placebo. Their progress
was followed for a mean of 16 months. Treatment with
bisoprolol was associated with a 34% reduction in mortality
rate compared with placebo (11.8% versus 17.3%; P<.0001)
and a 32% reduction in risk of hospitalisation for heart
failure (P<.0001).
Comparable findings were demonstrated in the Metoprolol
CR/XL Randomised Intervention Trial in Congestive Heart
Failure (MERIT-HF) (8), which randomly assigned 3,991
patients with chronic heart failure to receive either
sustained-release metoprolol (<200 mg/day) or placebo.
The investigators found that treatment with metoprolol
was linked to a 35% reduction in mortality rate compared
with placebo (7.2% versus 11.0%; P=.0062).
The efficacy of beta-blocker use
in patients with severe heart failure was addressed
in the Carvedilol Prospective Randomized Cumulative
Survival (COPERNICUS) trial (9), which randomly assigned
2,289 patients with primarily NYHA class IV heart failure
to receive either carvedilol or placebo. The trial's
findings showed that treatment with carvedilol (mean
dose, 37 mg/day) for a mean period of 10.4 months was
associated with a 35% reduction in risk of death (95%
confidence interval [CI], 19% versus 48%; P=.0014).
However, it is important to note that this trial's criteria
required that participants with severe heart failure
be "clinically stable" and excluded those
who had pulmonary rales, ascites, or significant peripheral
oedema. Other exclusion criteria included acute cardiac
or noncardiac illness that required intensive care or
continued inpatient care, use of intravenous positive
inotropic agents or intravenous vasodilators within
4 days, a systolic blood pressure of less than 85 mm
Hg, a heart rate lower than 68 beats per minute, a serum
creatinine level greater than 2.8 mg/dL (247.5 micromoles/L),
an increase of more than 0.5 mg/dL (44.2 micromoles/L)
in serum creatinine concentration, and a change in body
weight of more than 1.5 kg during the 3- to 14-day screening
period.
On the basis of these trial results,
the latest guidelines recommend initiation of beta-blockers
in all symptomatic patients with left ventricular systolic
dysfunction, provided they are clinically stable and
have no contraindications to the therapy (2).
Diuretics
Thiazide diuretics target fluid overload by preventing
absorption of sodium or chloride at specific sites in
the renal tubules. These agents should not be used alone,
even if symptoms are well controlled, because it has
not been clearly shown that their use reduces mortality
in patients with heart failure (2). Diuretics can provide
rapid symptomatic relief and are crucial in optimising
fluid balance. They should be used with an ACE inhibitor
and a beta-blocker in the management of chronic heart
failure in patients with a propensity for fluid retention.
Spironolactone (Aldactone) inhibits
the neurohormonal axis by directly blocking the effects
of aldosterone in the distal tubule of the kidney. The
Randomized Aldactone Evaluation Study (10) assigned
1,663 patients with severe heart failure (recent or
current symptoms of NYHA class IV heart failure) to
receive either spironolactone (<50 mg/day) or placebo
in addition to conventional therapy with ACE inhibitors
and diuretics. After a mean follow-up period of 24 months,
spironolactone use resulted in a 30% reduction in mortality
rate compared with placebo (35% versus 46%; P<.001)
and a 35% reduction in frequency of hospitalisation
for worsening heart failure (relative risk of hospitalisation,
0.65; 95% CI, 0.54-0.77; P<.001). Important exclusion
criteria of this trial included a serum creatinine level
greater than 2.5 mg/dL (221 micromoles/L) and a serum
potassium level greater than 5.0 mmol/L.
Angiotensin II receptor blockers
Evidence suggests that ACE inhibitors are not completely
effective in suppressing the formation of angiotensin
II. Findings also indicate that alternative local and
systemic pathways (e.g. the chymase pathway) may account
for a significant amount of angiotensin II production.
Angiotensin II receptor blockers
(ARBs) inhibit the neurohormonal system by blocking
the action of angiotensin II at the receptor level,
thereby inhibiting the actions of both ACE and non-ACE
mechanisms. Unlike ACE inhibitors, ARBs do not inhibit
the breakdown of bradykinin, and the lack of accumulation
of kinins is thought to be the reason for the lower
incidence of cough seen with use of these agents compared
with ACE inhibitors.
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Results of long-term treatment have
been similar with ARBs and with ACE inhibitors in terms
of reduction of symptoms and mortality in patients with
chronic heart failure (11).
Investigators in the Valsartan Heart
Failure Trial (12) randomly assigned 5,010 patients
with NYHA class II, III, or IV heart failure to receive
either valsartan (<160 mg twice daily) or placebo
in addition to standard therapy with ACE inhibitors,
beta-blockers, digoxin, and diuretics. In this trial,
the mortality rate was equivalent between the two groups
and the combined end point of mortality and morbidity
was 13.2% lower with valsartan compared with placebo
(P=.009), mainly due to a 24% reduction in the risk
of hospitalisation for heart failure (13.8% versus 18.2%;
P<.001). However, subgroup analysis showed an adverse
effect on morbidity and mortality in the subgroup that
received valsartan, an ACE inhibitor, and a beta-blocker
(12). These findings raised concern about the safety
potential of this triple-drug regimen.
Digitalis
Digitalis inhibits the sodium ion-potassium ion ratio
in adenosine triphosphatase, resulting in increased
cardiac contractility. Recent data suggest that digoxin
(Digitek, Lanoxicaps, Lanoxin) also may attenuate the
activation of the neurohormonal system by decreasing
sympathetic outflow and renin suppression.
The Digitalis Investigation Group
trial (13) randomly assigned 6,800 patients with mild
to moderate heart failure to receive either digoxin
or placebo. After a mean follow-up period of 37 months,
treatment with digoxin did not affect survival (P=.80)
but did decrease the risk of hospitalisation for heart
failure by 28% compared with placebo (26.8% versus 34.7%;
P<.001).
Digoxin is recommended in patients
with chronic heart failure who remain symptomatic despite
treatment with ACE inhibitors and beta-blockers and
in patients with both heart failure and atrial fibrillation
who require control of the ventricular rate (2).
Hydralazine and nitrates
Long-term vasodilator therapy also has been shown to improve
symptoms in patients with heart failure and, when given
in addition to a standard regimen of digoxin and diuretics,
to improve the mortality rate compared with placebo (14).
However, vasodilators do not reduce mortality as much
as ACE inhibitors.
The Vasodilator-Heart Failure Trial
II (15) randomly assigned 804 men with chronic heart
failure to receive either the combination of hydralazine
hydrochloride (75 mg four times daily) and isosorbide
dinitrate (40 mg four times daily) or enalapril (10
mg twice daily). The 2-year mortality rate was lower
in the enalapril arm of the trial than in the hydralazine-nitrate
arm (18% versus 25%; P=.016).
Thus, treatment with hydralazine
(Apresoline) and oral nitrates is reserved mainly for
patients with heart failure who are unable to tolerate
ACE inhibitors or ARBs, primarily because of renal insufficiency,
hyperkalaemia, hypotension, or cough (2).
Therapy for acute heart failure
Patients with decompensated heart failure should receive
aggressive medical care, and their therapy needs to
be aimed predominantly at improving haemodynamic and
end-organ function (16). Acute exacerbation of heart
failure should prompt a complete assessment of current
haemodynamic and volume status and should initiate a
search for any reversible exacerbating or inciting factors.
Clinically, it is useful to divide
patients with acute exacerbations of heart failure into
four broad groups: (1) patients with elevated volume
and normal cardiac output, (2) those with elevated volume
and low cardiac output, (3) those who have low volume
and low cardiac output, and (4) those with normal volume
and low cardiac output. Treatment options for the four
subsets are outlined in Table3.
A combination of these constellations
of clinical findings is often present in patients who
present with acute heart failure. In addition, patients
may shift from one subset to another and thus require
vigilant monitoring and adjustment of therapy. Insertion
of a pulmonary artery catheter may help with the assessment
of haemodynamic parameters.
Volume status of patients with acute
heart failure should be optimised with diuretics, if
needed, and stable haemodynamics must be demonstrated
satisfactorily before initiation of therapy with neurohormonal
blocking agents. Nitroprusside sodium (Nitropress),
given intravenously, may be preferred in critically
ill patients who require afterload reduction with an
agent that allows rapid adjustment of response. An intra-aortic
balloon pump can provide rapid afterload reduction in
patients with severe heart failure and may serve as
a temporising measure before more definitive therapy.
Use of a short-acting oral ACE inhibitor
is a reasonable approach in patients whose condition
is more stable and, compared with long-acting agents,
allows more precise titration of dose. Initiation of
beta-blocker therapy in a patient with acute decompensated
heart failure is contraindicated because it initially
may result in transient worsening of left ventricular
function. If the patient already takes beta-blockers
as an outpatient, therapeutic options include continuing
beta-blockers and adding aggressive intravenous diuretic
therapy, cutting the outpatient beta-blocker dose to
half, and temporarily discontinuing beta-blocker therapy.
Choice among these options depends on the severity of
clinical presentation.
Current recommendations discourage
use of beta-blockers in acutely ill patients in the
intensive care unit who have one or both of the following:
marked fluid retention or refractory heart failure requiring
intravenous inotropic support. Once the patient's condition
is stable from the perspectives of haemodynamics and
volume, beta-blocker therapy may be started gradually.
Severe heart failure refractory
to maximal medical management
Despite the improvement in both cardiac contractility
and peripheral vasodilatation seen with use of positive
inotropic agents, long-term oral therapy (17) and intermittent
intravenous infusions (18) have been associated with
potentially deleterious effects on survival. Nevertheless,
in a highly select patient with severe symptoms who
cannot be weaned from continuous inotropic support and
who is not a candidate for other devices or transplantation,
inotropic agents given by continuous infusion may provide
measurable improvement in quality of life. After proper
discussion with the patient about the benefits and risks
of such treatment, therapy with these agents may be
considered.
B-type natriuretic peptide (BNP)
is a hormone synthesised by the ventricle in response
to volume expansion and wall stress. Elevated levels
of plasma BNP have been associated with worse morbidity
and mortality rates in patients with chronic heart failure
(19). Nesiritide (Natrecor), a vasodilator that is a
human recombinant form of BNP, is administered as a
continuous infusion in patients with acute heart failure.
It has been shown to lower pulmonary capillary wedge
pressure more effectively than intravenous nitroglycerin
or placebo during acute exacerbations of heart failure
(20). Guidelines for its use continue to evolve.
Biventricular pacing resynchronises
ventricular contraction in a failing heart and is gaining
acceptance as a therapeutic option for patients with
symptomatic heart failure and a widened QRS interval
on electrocardiography. The Multicenter InSync Randomized
Clinical Evaluation trial (21) included 453 patients
with moderate to severe heart failure, an ejection fraction
of 35% or less, and an intraventricular conduction delay
(>130 milliseconds) who were receiving optimal medical
management. In this study, atrial synchronised biventricular
pacing (i.e. leads in one atrium and both ventricles)
significantly improved exercise tolerance, functional
class, and quality of life.
Left ventricular assist devices
are currently used as mechanical "bridge"
devices to cardiac transplantation in patients with
severe heart failure that is refractory to maximal supportive
therapy. These devices divert blood out of the left
ventricle through a large inflow conduit inserted in
the left ventricular apex, into a pump-driven system,
back into a large outflow conduit, and into the ascending
aorta.
Investigators in the Randomized
Evaluation of Mechanical Assistance for the Treatment
of Congestive Heart Failure trial (22) randomly assigned
129 patients with end-stage heart failure who were ineligible
for cardiac transplantation to receive a left ventricular
assist device or optimal medical management. Use of
the device resulted in significant benefit to survival
compared with optimal medical management at 1 year (52%
versus 25%; P=.002) and at 2 years (23% versus 8%; P=.09).
However, effectiveness was limited by a 28% to 42% incidence
of infection, bleeding, and device failure.
Conclusion
The management of acute and chronic heart failure continues
to evolve rapidly. In patients with chronic heart failure,
inhibition of the neurohormonal axis with agents such
as ACE inhibitors and beta-blockers has improved morbidity
and mortality rates significantly. In contrast, patients
with acute exacerbation of decompensated heart failure
require an aggressive approach targeted at improving
haemodynamics and end-organ function.
The cornerstones of the management
of acute heart failure are identification of potentially
reversible causes and immediate initiation of supportive
therapy to optimise volume status and cardiac output.
Administration of positive inotropic agents and placement
of an intra-aortic balloon pump when clinically indicated
may provide significant haemodynamic benefits while
awaiting definitive therapy. Patients whose heart failure
is refractory to conventional measures should be considered
for referral to a heart transplantation center, where
they can be evaluated for possible transplantation and,
if necessary, initiation of mechanical circulatory support
with a ventricular assist device.
Care of patients with severe heart
failure will continue to be a challenge that requires
proper selection from the pharmacologic, interventional,
and mechanical options available.
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