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Heart Failure

Optimizing Clinical Outcomes in Acute Decompensated Heart Failure

S a b u T h o m a s, M D, A n d r e w J B o y l e, M D a n d G a r y S Fr a n c i s, M D

Division of Cardiology, University of Minnesota

Abstract
Acute decompensated heart failure (ADHF) is a syndrome defined by worsening fatigue, dyspnea, or edema that results from deteriorating
heart function and usually leads to hospital admission or unscheduled medical intervention. It is not a homogenous syndrome, but has
many faces and varying presentations. Although outcomes in stable heart failure have seen improvements in morbidity and mortality, ADHF
continues to portend poor outcomes. Prompt diagnosis and identification of ADHF and its causes are critical to optimising management.
Diagnostic modalities include thorough clinical evaluation, natriuretic peptide assays and, in some cases, invasive hemodynamic
measurements. Optimal evidence-based treatments remain poorly defined despite the high prevalence of this condition and its associated
morbidity and mortality. Complex treatment algorithms have developed, but randomised controlled trials in this area are quite sparse.
Therefore, specific treatment protocols are largely a product of expert consensus and are experiential at best. Pharmacological agents such
as diuretics, vasodilators, natriuretic peptides, and positive inotropes can improve symptoms. Bedside ultrafiltration, non-invasive
ventilation and a host of mechanical circulatory devices have also improved the outlook for heart failure, but their optimal role in ADHF
has yet to be defined. As the number of patients with ADHF increases, further investigation is needed to develop innovative, safer, and
more effective therapies.

Keywords
Heart failure, acute decompensated heart failure, diuretics, natriuresis, ultrafiltration, vasodilators, inotropes, mechanical support

Disclosure: Sabu Thomas, MD, has no conflicts of interest to declare. Andrew Boyle, MD, is an advisor to Thoratec and Medtronic, and receives honoraria from CHF Solutions,
Medtronic, and St Jude Medical. Gary Francis, MD, is an adviser to Merck, ARCA, Gilead, Forest Laboratories, sanofi-aventis, and Boston Scientific.
Received: February 27, 2009 Accepted: March 10, 2009
Correspondence: Gary S Francis, MD, Professor of Medicine, University of Minnesota, Division of Cardiology MMC 508, Minneapolis, MN. E: Franc354@umn.edu

Acute decompensated heart failure (ADHF) is a syndrome defined by
worsening fatigue, dyspnea, or edema that results from deteriorating
heart function and usually leads to hospital admission or unscheduled
medical intervention.1 Among patients over 65 years of age it remains
the leading cause of hospital admission (>1 million admissions per
year in the US alone), has an exceptionally high rate of readmission,
and represents the most costly cardiovascular disorder in developed
countries.2 Despite the many advances in cardiovascular disease,
this syndrome continues to portend a dismal prognosis, with 60-day
mortality rates approaching 20%. 3,4 Furthermore, despite the
development of a number of pharmacological and device-based
therapies that have improved the morbidity and mortality for stable
congestive heart failure, these improvements have not translated into
better survival for ADHF. According to data from the Framingham heart
study, between 1950 and 1969, 30-day and one-year mortality rates for
ADHF were 12 and 28%, respectively, compared with almost identical
30-day and one-year mortality rates of 11 and 28%, respectively,
between 1990 and 1999.5 In contrast, the current average stay (four to
six days) and in-hospital mortality rates (4–5%) for ADHF have
improved significantly.6
The majority of patients with ADHF deteriorate days to weeks after a
period of symptom stability. Most have previously established heart
failure. A multitude of causes exist for acute decompensation of stable
heart failure patients. Medication and dietary non-compliance
as well as diuretic resistance are common causes of acute
decompensation. Important cardiac causes for acute decompensation
of stable heart failure patients include new or worsening myocardial
ischemia, new infarction, atrial fibrillation, and other rhythm disorders.
Other non-cardiac causes include exacerbation of hypertension,
anemia, thyroid disease, ingestion of toxins (cocaine, alcohol),
development of fever, and new/worsening infections. ADHF of both
systolic and diastolic heart failure appear indistinguishable by history
and physical examination. Diastolic heart failure—also referred to as
‘heart failure with preserved ejection fraction’—represents nearly 50%
of cases.7 Once patients with diastolic heart failure are admitted for
ADHF, their subsequent prognosis is similar or worse than that of
patients with ADHF who have a low ejection fraction.8 The absence
of targeted therapies for diastolic dysfunction combined with a narrow
therapeutic window for optimizing volume status makes this subset of
patients a particular challenge.

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Optimizing Clinical Outcomes in Acute Decompensated Heart Failure
Given the scope of ADHF, significant effort has been directed toward the
management of this syndrome. The purpose of this article is to summarize
the available treatments and outline the evidence for their efficacy.
Particular attention will be devoted to informing clinicians of the optimal
utilization of existing strategies. The reader is encouraged to use this article
in combination with the more comprehensive practice guidelines provided
by the Heart Failure Society of America (HFSA)9 and the European Society
of Cardiology (ESC),10 from which the majority of the recommendations of
this article are derived.
Diagnosis
The diagnosis of ADHF is always a clinical diagnosis. The initial
assessment should include a focused history and physical
examination. Patients most commonly present with cough, dyspnea,
and fatigue, which rapidly become more severe and may be
associated with chest pain or pressure. However, the signs and
symptoms of ADHF can overlap with those of many other medical
conditions; common mimickers of ADHF include asthma and
exacerbations of chronic obstructive pulmonary disease (COPD).
ADHF can develop gradually or precipitously (acute pulmonary
edema). Laboratory testing is undertaken to verify the diagnosis when
uncertainty exists. Echocardiography is performed to reveal specific
features of cardiac geometry, valvular function, and chamber size and
function. Nevertheless, the onus lies with the clinician to rapidly
identify patients with ADHF in order to avoid a need for ventilatory
support, a delay in hospital discharge, a need for hospital
readmission, and an increase in overall resource utilization. 11,12
On presentation, patients are typically tachypneic and may be using
accessory respiratory muscles to breathe. Chest auscultation usually
reveals crackles from pulmonary edema and up to one-third of patients
have wheezing referred to as ‘cardiac asthma.’ If present, hypotension
may indicate cardiogenic shock from severe ventricular dysfunction.
Examination of the heart may reveal the presence of an S3 or S4 gallop.
Of the many symptoms that occur during ADHF, dyspnea on minimal
exertion is the most sensitive, whereas paroxysmal nocturnal dyspnea
remains the most specific.13 Elevated internal jugular vein pressure is the
most important physical finding of ADHF.13 In terms of diagnostic tests,
interstitial edema and pulmonary venous congestion on chest
radiography significantly increase the likelihood of ADHF.13 Assays for
B-type natriuretic peptide (BNP) or N-terminal BNP are useful
in ruling out ADHF when normal, but are not required in cases of ADHF
that are obvious based on clinical criteria alone. In patients recruited to
the Breathing Not-Properly study, BNP values >100pg/ml were 90%
sensitive and 76% specific for the diagnosis of ADHF.14 More recently
N-terminal B-type natriuretic peptide has been used. Its values
are roughly five- to eight-fold higher than standard BNP assays.
Natriuretic peptides are also useful in long-term risk stratification in
patients with ADHF.15
On admission to hospital, clinicians should routinely obtain an
electrocardiogram, a transthoracic echocardiogram (with Doppler), a
complete blood count, a basic metabolic profile, arterial blood gases,
cardiac enzymes (if ongoing ischemia is suspected), and thyroid
function tests. Finally, although central venous lines and pulmonary
artery catheterization can provide useful information regarding
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intracardiac hemodynamics in selected patients, their routine use is
not recommended.16
Treatment
There are many options based on clinical trials for treating
patients with stable, chronic heart failure. These treatments include
angiotensin-converting enzyme (ACE) inhibitors,17,18 angiotensin-II receptor
The short-term goals of treatment for
acute decompensated heart failure
include hemodynamic stabilization,
support of oxygenation and ventilation,
and relief of symptoms.
blockers (ARBs),19,20 β-blockers21,22 aldosterone antagonists,23 and nitrates/
hydralazine.18 Device therapies include implantable cardioverter
defibrillators,24 cardiac resynchronization therapy,25 and ventricular assist
devices (VADs).26 However, the existing therapies for ADHF have not been
subjected to randomized controlled trials to the same extent and are
therefore subject to bias and the imprecision of non-scientific experiential
observation. Large clinical trials in patients with ADHF are challenging to
perform because the short-term hospital mortality rate is low (4–5%), and
symptom improvement and non-fatal clinical events have proved difficult
to measure in a robustly quantitative manner. The short-term goals
of treatment for ADHF include hemodynamic stabilization, support of
oxygenation and ventilation, and relief of symptoms.
Pharmacological therapies that have been used to treat ADHF
patients include intravenous (IV) diuretics, IV nitroglycerin, nitroprusside,
nesiritide, vasodilating inotropes (dobutamine, milrinone), and,
occasionally, vasopressor-type inotropes (dopamine and norepinephrine).
Morphine sulfate, tourniquets, and phlebotomy are no longer routinely
used. Non-pharmacological modalities used in patients with ADHF
include ultrafiltration, positive pressure ventilation, and mechanical
circulatory support devices.
Diuretic Therapy
Under most circumstances, the relief of tissue congestion is the primary
goal of ADHF therapy, as volume overload is central to its pathophysiology.
The clinical goal is to relieve dyspnea. Most patients who present with
severe ADHF have pulmonary capillary wedge pressures that exceed
25mmHg.16 Patients whose filling pressures are reduced by diuretics will
nearly always experience improvement in symptoms.27 Diuretic-induced
reductions in BNP levels between admission and discharge, when
observed, is comforting to physicians and can mean that such patients are
less likely to fall victim to quick repeat hospitalizations—an important
quality control measure in heart failure therapy.28 However, sequential
measurements of plasma natriuretic pepide levels are not routinely
recommended, as day-to-day variance can be substantial.29
Clinicians rely heavily on diuretic therapy with loop diuretics, in part
because thiazide diuretics alone are ineffective when the glomerular
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Heart Failure
filtration rate (GFR) is reduced.30 There is some evidence that continuous
infusions of loop diuretics are superior to bolus infusions because of
reduced activation of the renin–angiotensin–aldosterone system and
more consistent tissue levels of diuretic in the kidney.31 When blood
pressure is stable, loop diuretics can be combined with vasodilator
therapy such as nitroprusside to quickly reduce filling pressure and
improve cardiac output.
Non-loop diuretics such as metolazone and aldosterone antagonists can
be used together with loop diuretics in patients who fail to respond
to IV loop diuretics alone. More natriuresis is achieved when
metolazone is combined with furosemide than with either drug used
alone. Spironolactone can be added to reduce edema and preserve
potassium, but larger doses in the range of 100mg/day may be
required. Aldosterone antagonists should be avoided in patients with
renal insufficiency (Cr ≥2mg/dl) and hyperkalemia.
In a meta-analysis of small randomized controlled trials, mortality rates are
lower among stable heart failure patients receiving diuretics compared
with placebo; however, the mortality benefits of loop diuretics in ADHF are
uncertain.32 Thus, there is some degree of caution regarding their routine
use in ADHF, as some studies, albeit mostly observational, report worsening
mortality with increasing diuretic dose.28,33,34 Loop diuretics can directly
worsen outcomes by further reducing GFR, exacerbating electrolyte
abnormalities, and activating the renin–angiotensin–aldosterone system. In
a small trial of 104 patients presenting to the emergency department with
ADHF and respiratory distress, patients were randomized to receive either
high-dose furosemide (80mg IV every 15 minutes) combined with low-dose
IV isosorbide dinitrate (1mg/hour doubled every 10 minutes) or high-dose
isosorbide dinitrate (3mg IV every five minutes) alone. Mechanical
ventilation was required more in patients in the high-dose furosemide
group compared with the isosorbide group alone (40 versus 13%;
p<0.004).35 No one doubts the value of IV loop diuretics in the setting of
ADHF, but it should be noted that their use can further reduce GFR, and
some patients remain essentially unresponsive. Adding IV thiazide (Diuril)
500–1,000mg or oral metolazone can sometimes prompt a diuresis when
loop diuretics alone are ineffective. Occasionally, ultrafiltration or even
hemodialysis is necessary. Some investigators believe that ultrafiltration
should be more widely used as an adjunct or even a substitute for high-
dose continuous-loop diuretic drip.
Studies have prompted investigators to evaluate alternative strategies,
such as adenosine-1 receptor blockers, for reducing congestion.34
Neveretheless, until such therapies are widely tested, loop diuretics will
likely continue to be a cornerstone of ADHF therapy.
Ultrafiltration
Bedside ultrafiltration performed by cardiologists is a relatively novel
approach for the treatment of ADHF. Although this therapy is costly, if
patients can be kept out of the hospital for longer, it may prove
cost-effective. In the Ultrafiltration versus IV Diuretics for Patients
Hospitalized for Acute Decompensated Heart Failure Trial (UNLOAD), 200
ADHF patients were randomized to ultrafiltration versus diruetics alone.
The UNLOAD trial demonstrated that ultrafiltration improved weight loss
and dyspnea, decreased the need for vasoactive drugs, and reduced
readmission rates with serum creatinine levels that were similar to
52
levels seen in the diuretic group.36 Smaller clinical trials comparing
ultrafiltration with IV diuretics also showed greater volume removal,
more BNP reduction, shorter hospital stays, and less need for
rehospitalization.34,37,38 The UNLOAD trial indicated that ultrafiltration
could keep patients out of hospital longer. Ultrafiltration and
adenosine-1 receptor blockers are undergoing additional study.
Vasodilators
IV vasodilators reduce congestion and improve cardiac index without
increasing myocardial oxygen consumption. Randomized controlled trials
in ADHF have demonstrated that IV nitrate therapy resulted in acute
improvement of dyspnea.33,39 Although its use has waned in recent years,
IV morphine sulfate 2–4mg acts centrally to inhibit sympathetic drive to the
periphery, thus reducing symptoms of dyspnea and alleviating anxiety and
air-hunger. It is most commonly used as first-line therapy for acute
pulmonary edema in the emergency department setting.
As the majority of patients with ADHF have increased or normal blood
pressure, reducing impedance to ejection remains important to improving
forward flow.14 Short-term nitroprusside is particularly useful in patients
with ADHF when blood pressure is normal or increased, particularly
24 hours after an acute myocardial infarction.40 ACE inhibitors, ARBs, and
β-adrenergic blockers should be continued if tolerated and blood
pressure remains satisfactory. Low blood pressures (~90–100mHg
systolic) may not necessarily preclude the use of these agents if there are
no symptoms and careful monitoring is ensured.41 The mean aortic
pressure should be kept at 65–70mmHg. As with stable heart failure
patients, renal function and potassium should be carefully monitored. The
combined use of oral isosorbide dinitrate and hydralazine is an
under-utilized treatment method and should be used when switching
from nitroprusside to oral agents.42
Nesiritide
The atrial natriuretic peptides (ANPs) and BNPs are endogenously
released in response to increased stretching of the atria and ventricle,
respectively. They act to counteract increased neurohormonal activity by
promoting natriuresis and vasodilation. The Vasodilation in the
Management of Acute Congestive Heart Failure Trial (VMAC) randomized
498 patients with New York Heart Association (NYHA) class IV heart
failure to nesiritide, IV nitoglycerin, or placebo. The results demonstrated
that pulmonary capillary wedge pressure was marginally reduced at
three hours (-5.8mmHg for nesiritide versus placebo; p<0.001) and
dyspnea was reduced at three hours. The 30-day readmission rate was
20% among patients in the nesiritide group compared with 23% in the
nitroglycerin group. Although nesiritide was rapidly accepted as a
therapy for ADHF after US Food and Drug Administraton (FDA) approval,
it has recently come under scrutiny because of fears regarding potential
adverse effects.43 Furthermore, a meta-analysis of randomized controlled
trials of nesiritide versus placebo that looked at 30-day survival revealed
a non-significant trend toward increased mortality in the nesiritide group
(7.2 versus 4%; p=0.059).44 However, more recent data from the
Follow-Up Serial Infusions of Nesiritide in Advanced Heart Failure
(FUSION-II) study suggests that nesiritide is safe.45 It is a reasonable, albeit
expensive, IV vasodilator to be used in the setting of ADHF, but lower
doses may be safer and more efficacious. A large randomized controlled
mortality trial of nesiritide is currently under way.
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Optimizing Clinical Outcomes in Acute Decompensated Heart Failure
Positive Inotropes
Although positive inotropes are necessary for some patients with ADHF
presenting with shock or inadequate cardiac output, their routine use for
symptomatic and hemodynamic optimization is not recommended. These
agents can be arrythmogenic and are associated with increased mortality.3
Dobutamine with its β-1 and mild β-2 activity is considered a positive
inotrope with mild vasodilator activity. Its role in ADHF has been
primarily to increase cardiac index in patients with inadequate
forward flow. Older studies looking at infusions of dobutamine for up
to five days in ADHF patients has shown improved symptoms for
up to one month. 46,47 However, more contemporary data in the
ambulatory setting indicate that intermittent dobutamine therapy is
associated with worse outcomes.48 The Acute Decompensated Heart
Failure National Registry (ADHERE) registry revealed a higher mortality
rate for IV positive inotropes, including dobutamine, compared with
nesiritide or nitroglycerin.49 Dobutamine can also instigate myocardial
ischemia and can worsen mitral regurgitation. However, in low-output
states dobutamine can be life-saving and should be tried prior to the
insertion of an intra-aortic balloon pump (IABP). Norepinephrine,
vasopressin, and/or epinephrine are used to restore blood pressure if
cardiogenic shock is present, usually prior to the insertion of an
intra-aortic balloon pump.
Milrinone is a phosphodiesterase III inhibitor and increases myocardial
contractility and peripheral vasodilation via elevated levels of cyclic
adenosine monophosphate (cAMP). Unlike dobutamine, it can be
added to β-antagonists. The Outcomes of a Prospective Trial of IV
Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF)
studied 951 patients admitted with ADHF with stable blood pressure.
Patients were randomized to either milrinone infusion or placebo. At
60 days post-infusion, no difference was found for the primary end-
point of total hospital days. There was a trend toward increased
mortality in the milrinone group. There were more atrial arrhythmias
and hypotensive episodes in the milrinone group.3 Milrinone is now
used mainly when ADHF is associated with severe pulmonary
hypertension and/or right-sided heart failure as it is a pulmonary-
artery-pressure-lowering agent.
Despite the weight of evidence in favor of using positive inotropic
agents sparingly, these drugs continue to be widely used in ADHF. In our
opinion, these agents should be reserved for short-term or palliative
settings, especially when there is a very low cardiac index (we favor
dobutamine) or severe pulmonary hypertension (we favor milrinone).
Respiratory Therapies
In addition to supplemental oxygen therapy for hypoxia and
pulmonary edema, short-term positive pressure ventilation may be
considered for ADHF patients. Although previous studies have shown
that continuous positive airway pressure (CPAP) improves mortality
and reduces the need for mechanical ventilation,50–53 a more recent
study did not demonstrate a mortality benefit.54 We do not routinely
use CPAP in ADHF patients. Although not rigorously compared in
randomized controlled trials, bi-level positive airway pressure (BIPAP)
is probably similar in terms of these outcomes, but it does carry the
additional risk of aspiration pneumonia. Among patients with central
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sleep apnea, CPAP improves many secondary outcomes, but the
primary study was probably not sufficiently powered to demonstrate
a mortality benefit. 52 In ADHF associated with acute myocardial
infarction and/or cardiogenic shock, mechanical ventilation with
intubation is recommended over non-invasive ventilation, although
the complete indications for endotracheal intubation are beyond the
scope of this article.
Mechanical Circulatory Support
Patients with ADHF who remain in cardiogenic shock should be
considered for mechanically-assisted circulatory support with one of
the following devices: intra-aortic balloon pump (IABP), cardiopulmonary
assist device, or implantable left VADs. These patients typically are
severely ill, intubated, on a ventilator, and have poor urine output. They
often have low cardiac indices (<2l/minute per m2), systolic blood
As the population of patients with acute
decompensated heart failure continues to
grow, it will drive the development of more
innovative and, hopefully, safer and more
effective therapies.
pressures less than 90mmHg, and significantly elevated pulmonary
capillary wedge pressures and hypoxemia with metabolic acidosis
despite adequate medical therapy. The mortality rate is exceptionally
high despite any therapy.
IABPs have two major hemodynamic mechanisms: displacement
of blood to the proximal aorta during diastole with improved coronary
blood flow and afterload reduction during systole via rapid balloon
deflation. The expected hemodynamic effects seen with IABPs include a
decrease in systolic pressure with an increase in mean and diastolic
pressure, a reduction of the heart rate, a decrease in the mean pulmonary
capillary wedge pressure, and an elevation in the cardiac output.53 By
reducing left ventricular (LV) wall tension, an IABP also reduces
myocardial oxygen demand. IABP alone is sometimes occasionally
hemodynamically effective in patients with cardiogenic shock resulting
from an acute myocardial infarction54 A large non-randomized multicenter
trial demonstrated that IABP reversed end-organ hypoperfusion in acute
myocardial infarction and cardiogenic shock when vasopressor therapy
was ineffective.51 The mortality rate nevertheless is dismal and exceeds
80% in cardiogenic shock when IABP is not combined with coronary
reperfusion or revascularization strategies.55,56
Cardiopulmonary assist devices are rapidly emerging as life-saving
temporary treatment in patients with severe ADHF. They have important
roles to play in acute cardiogenic shock, cardiopulmonary arrest,
high-risk percutaneous coronary interventions (PCIs), and fulminant
myocarditis presenting with shock.57 Cannulae are placed in the aorta
and right atrium. Blood from the venous catheter is fed into an
oxygenator and heat exchanger and returned to the arterial circuit.
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Heart Failure

There role is now rapidly expanding, but they require a team approach
that includes cardiac surgeons, cardiologists, and dedicated nurses.
There are three broad categories of short-term VADs used today for
ADHF: centrifugal, axial flow, and left atrial-to-femoral-arterial pumps.
Long-term VADs used as a bridge-to-transplant or as destination
therapy are beyond the scope of this article and will not be
discussed here.
Centrifugal pumps use rotating impellers that serve as a short-term
bypass pump. The Bio-Medicus™ (Bio-Medicus Inc, Minneapolis, MN)
and Sarns™ device (Sarns/3M, Ann Arbor, MI) are currently available for
clinical use. The pumps can also be used as a right ventricular assist
device (RVAD) or provide bi-ventricular (BiVAD) support in addition to its
traditional left VAD role. These devices can be placed percutaneously or
via median sternotomy. Despite their versatility, centrifugal pumps do
have several drawbacks that include non-pulsatile flow that can lead to
poor end-organ perfusion and, depending on pump design, can
contribute to significant hemolysis.
Axial flow pumps are placed in a retrograde fashion across the aortic
valve into the LV. Here they draw blood out of the left ventricle into
the aorta in a non-pulsatile fashion with relatively low rates of
hemolysis. The Impella™ device (Abiomed Inc., Danvers, MA) was
implanted in 24 patients with post-cardiotomy heart failure. The
mortality rate of 54%, which was non-inferior compared with patients on
IABP support alone.58
Finally, left-atrial-to-femoral-arterial pumps such as the
TandemHeart™ (Cardiac Assist Inc., Pittsburgh) have a venous
catheter placed in the left atrium across the interatrial septum and an
arterial line placed in the iliac artery. These can be placed in the
catheterization laboratory in under 30 minutes and will allow
stabilization of the patient in ADHF until more definitive therapies are
available. The role of this device for short-term stabilization was
evaluated in 18 patients with cardiogenic shock due to a myocardial
infarction. After a mean of four days, the cardiac index improved from
1.7 to 2.4l/minutes/m2 and there was a significant increase in mean
blood pressure and reduction in pulmonary artery, pulmonary
capillary wedge, and central venous pressures. 59 However, compared
with IABP there was no difference in mortality. 60
Conclusions
ADHF is a complex medical problem that is growing in magnitude and
scope. The treatment options are increasingly complex and this has
resulted in some consolidation of heart failure specialists in large
tertiary referral centers. Older treatments such as diuretics and
vasodilation are still widely used, but newer approaches including
ultrafiltration and various circulatory mechanical assist devices are
rapidly emerging. Complex treatment algorithms have developed, but
randomized controlled trials are quite sparse. Judgment regarding
specific treatment protocols is largely a product of expert consensus
or experiential at best. As the population of patients with ADHF
continues to grow, it will drive the development of more innovative
and, hopefully, safer and more effective therapies. ■

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