Journal of Cardiac Failure Vol. 19 No.

6 2013

Consensus Statement
Acute Decompensated Heart Failure: Update on New and
Emerging Evidence and Directions for Future Research
MICHAEL M. GIVERTZ, MD,1 JOHN R. TEERLINK, MD,2 NANCY M. ALBERT, RN, PhD,3
CHERYL A. WESTLAKE CANARY, RN, PhD,5 SEAN P. COLLINS, MD, MSc,6 MONICA COLVIN-ADAMS, MD,7
JUSTIN A. EZEKOWITZ, MD,8 JAMES C. FANG, MD,9 ADRIAN F. HERNANDEZ, MD,10 STUART D. KATZ, MD,11
RAJAN KRISHNAMANI, MD,12 WENDY GATTIS STOUGH, PharmD,13 MARY N. WALSH, MD,14 JAVED BUTLER, MD,15
PETER E. CARSON, MD,16 JOHN P. DIMARCO, MD, PhD,17 RAY E. HERSHBERGER, MD,18 JOSEPH G. ROGERS, MD,10
JOHN A. SPERTUS, MD, MPH,19 WILLIAM G. STEVENSON, MD,1 NANCY K. SWEITZER, MD, PhD,20
W.H. WILSON TANG, MD,4 AND RANDALL C. STARLING, MD, MPH4

Boston, Massachusetts; San Francisco, California; Cleveland, Ohio; Azusa, California; Nashville, Tennessee; Minneapolis, Minnesota; Edmonton, Alberta,
Canada; Cleveland, Ohio; Durham, North Carolina; New York, New York; Middletown, Ohio; Buies Creek, North Carolina; Indianapolis, Indiana; Atlanta,
Georgia; Washington, DC; Charlottesville, Virginia; Columbus, Ohio; Kansas City, Missouri; and Madison, Wisconsin

ABSTRACT
Acute decompensated heart failure (ADHF) is a complex clinical event associated with excess morbidity
and mortality. Managing ADHF patients is challenging because of the lack of effective treatments that
both reduce symptoms and improve clinical outcomes. Existing guideline recommendations are largely
based on expert opinion, but several recently published trials have yielded important data to inform
both current clinical practice and future research directions. New insight has been gained regarding vol-
ume management, including dosing strategies for intravenous loop diuretics and the role of ultrafiltration
in patients with heart failure and renal dysfunction. Although the largest ADHF trial to date (ASCEND-
HF, using nesiritide) was neutral, promising results with other investigational agents have been reported. If
these findings are confirmed in phase III trials, novel compounds, such as relaxin, omecamtiv mecarbil,
and ularitide, among others, may become therapeutic options. Translation of research findings into quality
clinical care can not be overemphasized. Although many gaps in knowledge exist, ongoing studies will
address issues around delivery of evidence-based care to achieve the goal of improving the health status
and clinical outcomes of patients with ADHF. (J Cardiac Fail 2013;19:371e389)
Key Words: Heart failure, clinical trials, diuretics, vasodilators, biomarkers, quality of care, ultrafiltration.

From the 1Cardiovascular Division, Brigham and Womens Hospital,
Harvard Medical School, Boston, Massachusetts; 2Department of
Medicine, University of California San Francisco, San Francisco, Califor-
nia; 3Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio;
4
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland,
Ohio; 5School of Nursing, Azusa Pacific University, Azusa, California;
6
Department of Emergency Medicine, Vanderbilt University, Nashville,
Tennessee; 7Cardiovascular Division, University of Minnesota, Minneap-
olis, Minnesota; 8Division of Cardiology, University of Alberta,
Edmonton, Alberta, Canada; 9Division of Cardiovascular Medicine,
Harrington Heart and Vascular Institute, University Hospitals Case
Medical Center, Cleveland, Ohio; 10Division of Cardiology, Department
of Medicine, Duke University Medical Center, Durham, North Carolina;
11
Leon H. Charney Division of Cardiology, New York University School
of Medicine, New York, New York; 12Advanced Cardiovascular Institute,
Middletown, Ohio; 13Department of Clinical Research, Campbell Uni-
versity College of Pharmacy and Health Sciences, Buies Creek, North
Carolina; 14The Care Group, Indianapolis, Indiana; 15Division of Car-
diology, Department of Medicine, Emory University, Atlanta, Georgia;
16
Georgetown University and Washington DC Veterans Affairs Medical
Center, Washington, DC; 17University of Virginia Health System, Char-
lottesville, Virginia; 18Ohio State University, Columbus, Ohio; 19St.
Lukes Mid America Heart Institute, University of MissourieKansas
City, Kansas City, Missouri and 20Department of Medicine, University
of Wisconsin, Madison, Wisconsin.
Manuscript received April 16, 2013; revised manuscript accepted April 17,
2013.
Reprint requests: Michael M. Givertz, MD, Cardiovascular Division,
Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115.
Tel: 617-732-7367; Fax: 617-264-5265. E-mail: mgivertz@partners.org
This paper was reviewed and approved on March 19, 2013 by the Heart
Failure Society of America Executive Council, whose members are listed
in the Acknowledgment.
See page 384 for disclosure information.
1071-9164/$ - see front matter
2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cardfail.2013.04.002

371
372 Journal of Cardiac Failure Vol. 19 No. 6 June 2013
Heart failure is a complex syndrome that involves both
acute and chronic processes. Acute heart failure has various
presentations. It can be characterized by rapidly developing
symptoms of new-onset or de novo heart failure, or it can be
a gradual worsening of chronic heart failure culminating in
acute decompensated heart failure (ADHF), sometimes re-
ferred to as acute on chronic heart failure. Many differ- pitalized for heart failure rather than to a reduction in
ent terms have been used in the literature to describe this
syndrome, including acute heart failure, acute heart failure
syndromes, and ADHF.1 The latter term will be used for
this report.
Despite ongoing and intense efforts, clinical trials have
not yielded therapeutic strategies that improve outcomes
in the ADHF population. Many factors may contribute to
inadequate trial results, including the heterogeneity of the
condition, the likelihood that multiple triggers or patho-
physiologic processes exist and differ among individual
patients, the timing of patient enrollment, and inherent
challenges such as obtaining informed consent and con-
ducting clinical trials in patients who are acutely symptom-
atic and may have high adverse event rates. As a result,
there are limited data to guide patient management. Of
the 44 recommendations relevant to ADHF in the 2010
Heart Failure Society of America (HFSA) heart failure
guidelines, 3 were supported by strength of evidence A, 8
by strength of evidence B, and 33 by strength of evidence
C.2 Similarly, in the American College of Cardiology/
American Heart Association 2009 heart failure guidelines,
only 1 of 25 recommendations related to ADHF was a class
I, level of evidence A recommendation.3
Despite the paucity of evidence, practicing clinicians rou-
tinely seek guidance on the management of patients with
ADHF. Since the publication of the 2010 HFSA heart failure
guidelines, several trials in ADHF have yielded new data. Al-
though these studies advance knowledge and inform clinical
decision making, their results do not warrant a complete revi-
sion of the guidelines. The purpose of the present paper is to
review new data generated in the broad ADHF population in-
volving therapeutic drugs or strategies, biomarkers, and qual-
ity of care initiatives. This paper also highlights gaps in the
current evidence base for the diagnosis, prognosis, risk strati-
fication, management and monitoring of ADHF. Future re-
search efforts should focus on these high-priority areas of
unmet needs. This paper does not address the management
of heart failure in the setting of shock, specific precipitants
(eg, acute myocardial infarction or atrial fibrillation), early
management with bilevel positive airway pressure, or other
agents not approved for use in the United States (eg, levosi-
mendan). Readers interested in these topics should refer to
the 2010 HFSA guidelines for further information.2
Epidemiology
More than 1 million hospitalizations for heart failure
occur annually in the USA.4,5 Heart failure remains a pri-
mary cause of hospitalization among older Americans. An
analysis from the Centers for Medicare and Medicaid
Services (CMS) revealed a risk-adjusted heart failure hospi-
talization rate of w2,000 per 100,000 person-years among
Medicare beneficiaries based on 2008 data.6 A decline in
the relative rate of hospitalization from 1998 to 2008 was
detected in that study, which the authors primarily attrib-
uted to a reduction in the number of unique individuals hos-
repeated hospitalizations. Unfortunately, heart failure is
a progressive disease in most patients, and although some
therapies slow or reverse progression, only cardiac trans-
plantation is curative for patients with irreversible causes.
The prevalence of heart failure is expected to increase in
the USA over the next 20 years.7 Moreover, the risk of hos-
pitalization tends to increase as heart failure progresses, and
ADHF admissions increase the risk of subsequent readmis-
sion and death.
If the expected increase actually occurs, the burden of
heart failure hospitalization will continue to place a major
strain on health care resources. Clinicians, hospital adminis-
trators, and patients now have access to CMS publicly
reported quality metrics for ADHF, including 30-day
mortality and readmission rates (www.cms.gov/Medicare/
Quality-Initiatives-Patient-Assessment-Instruments/Hospital
QualityInits/OutcomeMeasures.html). It remains hotly de-
bated whether the ideal end points have been defined for
ADHF clinical trials and quality metrics.8 Event rates were
lower than predicted in the Acute Effectiveness of Nesiritide
in Decompensated Heart Failure (ASCEND-HF) trial,9 re-
vealing that emerging therapies must have large treatment ef-
fects for an ADHF trial to have the power to detect
a mortality benefit (even with O5,000 patients enrolled).
Therefore, the process to develop new therapies from small
mechanistic trials to large outcome trials will be prolonged
and expensive.
Patient Characteristics
In general, patients hospitalized for ADHF are elderly,
approximately one-half are women, and 25% are non-
white.10 The majority (88% in the OPTIMIZE [Organized
Program to Initiate Lifesaving Treatment in Hospitalized
Patients with Heart Failure] registry)11 have a history of
chronic heart failure rather than a de novo presentation.
These patients typically have multiple comorbidities and
moderately elevated systolic blood pressure, and approxi-
mately one-half have heart failure with preserved ejection
fraction (HF-PEF).10 The majority of patients present
with evidence of congestion or volume overload.10,12 In-
creases in body weight are associated with heart failure
hospitalization and begin at least a week before presenta-
tion.13 Cardiogenic shock during the initial presentation
to the emergency department (ED) is very rare.14,15
ADHF is a heterogeneous syndrome, and more focus on
presenting characteristics may allow for better-targeted
therapies. Clinical characteristics have been proposed to
subcategorize patients with ADHF based on parameters
such as blood pressure, degree of congestion, time course
 Update on Acute Decompensated Heart Failure
of symptoms, presence of cardiogenic shock, or concomi-
tant factors, such as acute coronary syndrome or renal dys-
function.16 In recent trials, patients were selected on the
basis of 1 or more subcategories, such that the known or ex-
pected pharmacologic actions of the drug were matched to
patient characteristics.17,18
Patients with ADHF present in a variety of settings,
and the initial patient assessment and management may dif-
fer depending on the presenting location. Patients may de-
velop acute symptoms in the home environment, prompting
the use of emergency medical services (EMS) personnel as
first responders, or they may present directly to the ED. Pa-
tients routinely managed in heart failure clinics may contact
the heart failure clinical team to notify them of worsening
symptoms. The decision can be made to bring patients in
for urgent clinic evaluations and potential treatment on an
outpatient basis depending on the severity of symptoms.
In this scenario, an ambulatory center or observation unit
may be used for administration of intravenous diuretics
and laboratory monitoring. As health care reimbursement
models change and Accountable Care Organizations and
patient-centered medical home models emerge, a shift
toward initial management of patients with ADHF in outpa-
tient clinics or observation units is likely to occur, particu-
larly in the USA.19,20
Recent data show that subclinical changes in intracardiac
pressures and thoracic impedance occur days before pa-
tients generally seek medical attention owing to escalating
symptoms (typically dyspnea or volume overload).21e23
Therefore, the typical patient with chronic heart failure pre-
senting with symptoms that require hospitalization most
likely has experienced subclinical changes for days, weeks,
or even months. It is anticipated that future treatment strat-
egies will include therapies triggered by monitoring devices
even before symptoms occur.
Clinical Outcomes
Episodes of ADHF are associated with significant short-
and long-term morbidity and mortality. In the Candesartan
in Heart Failure Assessment of Reduction in Mortality and
Morbidity (CHARM) trials, patients hospitalized for heart
failure had a 3-fold greater risk for all-cause mortality
compared with patients who did not have a heart failure
hospitalization after adjustment for known baseline predic-
tors of death.24 The in-hospital mortality reported in major
registries ranges from 4% to 12%, and it may increase to
20%e25% in high-risk subgroups.10,12,14,25e27 It has not
been determined whether the association between an
ADHF event and poor prognosis is related to an underlying
detrimental process that occurs during the episode, as evi-
denced by myocardial necrosis, inflammation, or marked
neurohormonal activation, or if ADHF is a marker of pro-
gressive disease. ADHF episodes are frequent and costly,
and they negatively affect overall health status and quality
of life.
 Givertz et al 373
New Data in Management of ADHF
Standard therapies for managing ADHF (in addition to
background chronic heart failure therapy) primarily include
intravenous loop diuretics for patients with evidence of pul-
monary and/or systemic venous congestion, vasodilators for
patients with acute dyspnea or elevated filling pressures and
evidence of vascular volume redistribution, and positive
inotropes for patients with low cardiac output and
evidence of end-organ dysfunction or damage. However,
robust scientific evidence evaluating the safety and efficacy
of current treatment strategies were lacking before the com-
pletion of several studies designed to address knowledge
gaps. In addition, there have been no new drugs approved
for the treatment of ADHF since 2001.
The management of ADHF requires a multifaceted ap-
proach that involves strategies or methods of delivering
therapy, as well as drug therapies. Recent data will be ex-
amined in the context of these distinctions.
Strategies
Diuretics. The Diuretic Optimization Strategies Eval-
uation (DOSE) trial was designed to test low- versus
high-dose intravenous furosemide administered as a contin-
uous infusion versus intermittent intravenous boluses as the
initial treatment strategy (ie, patients were not treatment re-
sistant).28 This relatively small, prospective, double-blind,
controlled trial randomized a total of 308 patients in
a 1:1:1:1 fashion with the use of a 2
2 factorial design
(Table 1). In the low-dose strategy, the total intravenous fu-
rosemide dose was equal to the total daily oral loop diuretic
dose (in furosemide equivalents). For the high-dose arm,
patients received a dose that was 2.5 times greater than their
total daily oral loop diuretic dose (in furosemide equiva-
lents). The median time to randomization was 14.6 hours.28
No significant difference was observed for efficacy or
safety between the groups (Table 1). Some significant dif-
ferences were noted across secondary end points for the
low versus high dose comparison, including a larger de-
crease in body weight, greater fluid loss, and more dyspnea
relief with higher doses. Length of stay and days alive out
of the hospital did not differ between groups.28 However,
caution should be used in the interpretation of secondary
end points, because the primary efficacy outcome did not
detect significant between-group differences.
The DOSE results suggest that high-dose intravenous fu-
rosemide (median 773 mg over 72 hours) was not associated
with greater increases in serum creatinine compared with
a low-dose strategy (median 358 mg over 72 hours), al-
though more patients experienced an increase in serum cre-
atinine of O0.3 mg/dL at 72 hours in the high-dose (23%)
compared with the low-dose (14%) strategy (P 5 .04).
The difference in creatinine between the 2 groups had
disappeared at 7 days. In earlier retrospective analyses,
high-dose diuretics were associated with a greater risk of
worsening renal function and subsequent mortality.29e32

Trial Study Arms
DOSE 28
Low- vs high-dose furosemide.
n 5 308 Continuous vs intermittent
intravenous bolus.
1:1:1:1 2
2 factorial design.
ASCEND-HF9 Nesiritide 0.01 mg kg1 min1
n 5 7,141 with optional 2 mg/kg bolus
(from 24 h up to 7 d) vs
standard medical therapy
DAD-HF51 Dopamine 5 mg kg1 min1
n 5 60 plus low-dose furosemide
(5 mg/h continuous infusion)
vs high-dose furosemide
(20 mg/h continuous infusion
PROTECT18 Rolofylline 30 mg vs placebo
n 5 2033 for up to 3 d
CARRESS42 Ultrafiltration vs stepped
n 5 188 pharmacologic care
Table 1. Summary of Recently Completed Trials
Population
ADHF presented within previous 24 h, $1 sign
and $1 symptom of HF, history of chronic
HF treated with 80e240 mg/d furosemide
(or equivalent) for $1 mo
Hospitalized for ADHF, dyspnea at rest or with
minimal activity, $1 sign and $1 objective
measure of ADHF, randomized within 24 h
of first IV treatment for ADHF
Hospitalized for ADHF with evidence of
volume overload and eGFR $30 mL min1
1.73 m2
Hospitalized for ADHF, persistent dyspnea
at rest or with minimal activity, estimated
CrCl 20e80 mL/min, BNP $500 pg/mL
or NT-proBNP $2,000 pg/mL, IV loop
diuretic therapy, and enrollment within 24 h
after admission
Patients hospitalized with ADHF who
develop cardiorenal syndrome (defined as
increasing sCr [$0.3 mg/dL] either after
hospitalization (within 7 d from admission
after receiving intravenous diuretics) or before
hospitalization [within 6 wk of the index
hospitalization in the setting of escalating
doses of outpatient loop diuretics]).
Primary End Point
Coprimary:
patient global assessment of symptoms
measured by a VAS and quantified as
the AUC of serial assessments from
baseline to 72 h; change in sCr from
baseline to 72 h
Coprimary: change in self-reported
dyspnea at 6 and 24 h; composite of
HF rehospitalization or all-cause
mortality through day 30
Incidence of worsening renal
function during the first
24 h after randomization,
defined as O0.3 mg/dL rise
in sCr from baseline to 24 h
and O20% decrease in eGFR
from baseline to 24 h
Treatment success (moderate or marked
improvement in dyspnea at both 24
and 48 h), failure (death or
readmission for HF through day 7,
worsening symptoms requiring
intervention by day 7 or discharge, or
persistent worsening renal function),
or no change in patients condition
Combined change in SCr and body
weight at 96 h
374 Journal of Cardiac Failure Vol. 19 No. 6 June 2013
Results
Global assessment of symptoms: bolus
AUC 4,236 6 1,440 vs continuous
AUC 4,373 6 1,404 (P 5 .47); low
dose AUC 4,171 6 1,436 vs high
dose AUC 4,430 6 1,401 (P 5 .06).
Mean change in sCr: bolus 0.05 mg/dL
vs continuous 0.07 mg/dL (P 5 .45);
low dose 0.04 mg/dL vs high dose
0.08 mg/dL (P 5 .21).
Self-reported dyspnea moderately
or markedly better.
At 6 h: placebo 42.1% vs nesiritide
44.5%; P 5 .03.*
At 24 h: placebo 66.1% vs nesiritide
68.2%; P 5 .007.*
Death or rehospitalization for HF at 30 d:
placebo 10.1% vs nesiritide 9.4% (HR
0.93, 95% CI 0.8e1.08; P 5 .31).
sCr increase O0.3 mg/dL: low-dose
dopamine/low-dose furosemide 6.7%
vs high-dose
furosemide 30%; P 5 .042.
O20% decrease in eGFR: low-dose
dopamine/low-dose furosemide
10% vs high-dose furosemide
33.3%; P 5 .057.
Treatment success: placebo 36%
vs rolofylline 40.6%.
No change: placebo 44.2% vs rolofylline
37.5%.
Treatment failure: placebo 19.8%
vs rolofylline 21.8%.
OR for rolofylline: 0.92, 95% CI
0.78e1.09; P 5 .35.
Change in creatinine level: 0.04 6
0.53 mg/dL in the pharmacologic-
therapy group vs 0.23 6 0.70 mg/dL
in the ultrafiltration group; P 5 .003.
Weight loss: 5.5 6 5.1 kg (12.1 6
11.3 lb) in the pharmacologic-therapy
group vs 5.7 6 3.9 kg (12.6 6 8.5 lb)
in the ultrafiltration group; P 5 .58.
Serious adverse events: 72% in the
ultrafiltration group vs 57% in the
pharmacologic-therapy group;
P 5 .03.
 Update on Acute Decompensated Heart Failure  Givertz et al 375

In DOSE, there was no significant difference between the

ADHF, Acute Decompensated Heart Failure; AUC, area under the receiver operating characteristic curve; BNP, B-type natriuretic peptide; CI, confidence interval; CrCl, creatinine clearance; CV, cardiovascular;
eGFR, estimated glomerular filtration rate; HF, heart failure; HR, hazard ratio; IV, intravenous; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; OR, odds ratio; SBP,
CV death or HF hospitalization at 6 mo:
compared with placebo by VAS AUC
Change in dyspnea to day 5: Seralaxin

Proportion of patients with moderately

180-day mortality: placebo 65 deaths

P 5 .41); at 12 mo: aliskiren 35%

low- and high-dose strategies in the clinical composite of
(448 mm
h, 95% CI 120e775);

aliskiren 24.9% vs placebo 26.5%

Days alive out of hospital up to day

vs placebo 37.3% (HR 0.93, 95%

or markedly improved dyspnea at
all 3 early time points: seralaxin
27% vs placebo 26%; P 5 .70.

vs seralaxin 42; HR 0.63 (95%

significantly improved dyspnea

death, rehospitalization, or ED visit within 60 days. How-

(HR 0.92, 95% CI 0.76e1.12;

60: seralaxin 48.3 vs placebo
ever, the numbers of patients and events in DOSE were

CI 0.43e0.93); P 5 .02.

CI 0.79e1.09; P 5 .36)
small. The hazard ratio and 95% confidence interval (CI)
for the high-dose strategy were 0.83, 0.60e1.16.
The findings from DOSE are not likely to substantially
47.7; P 5 .37.
change clinical practice, but they may reduce clinicians
P 5 .007.

concerns regarding the safety of using high-dose diuretics

in ADHF patients, at least up to the doses studied in the
trial. Other recent reports also confirm the safety of
higher-dose diuretics in ADHF.33,34 In addition, there is
2 primary efficacy end points: change in

patient-reported dyspnea at 6, 12, and

no longer a strong rationale for using a continuous infu-

sion of diuretics as an up-front strategy. High-dose ther-
moderately or markedly improved

CV death or HF rehospitalization at
baseline to day 5 (VAS AUC);

apy may be associated with some clinical advantages

patient-reported dyspnea from

regarding response to therapy, but the data are not defin-

24 h (7-point Likert scale)

itive. There was no evidence that continuous infusions

offered an advantage over bolus administration in terms
of efficacy or safety, but the study results may be con-
6 and 12 mo

founded by the rigorous administration of the bolus doses

in the clinical trial context, which may not be represen-
tative of general clinical practice. In a Cochrane review
of earlier studies, a modest benefit of continuous loop di-
uretic infusion regarding urine output and safety was ob-
served,35 but the studies involved were small and
$1,600 pg/mL, and signs/symptoms of fluid
for HF (median 5 d after admission), LVEF
Hemodynamically stable patients hospitalized
$350 ng/L (or NT-proBNP $1,400 ng/L),

#40%, BNP $400 pg/mL or NT-proBNP

Patients with dyspnea at rest or on minimal
exertion, congestion on chest x-ray, BNP

incompletely blinded. Therefore, clinicians should use

eGFR 30e75 mL/min1 1.73 m2, and

their clinical judgment and personal preference when de-

termining mode of administration.
Hypertonic Saline. In small trials, administration of
hypertonic saline (3%) along with high-dose furosemide
and sodium and fluid restriction may be associated with
SBP O125 mm Hg

greater diuretic and clinical response.36e38 In the SMAC-

HF [Sodium Management in Acute and Chronic Heart
Failure] study, 1,927 patients hospitalized for ADHF were
overload

randomized to a single-blind strategy of hypertonic saline

solution plus 250 mg furosemide (intravenous bolus) twice
daily and sodium restriction to 120 mmol (2,760 mg) per
systolic blood pressure; sCr, serum creatinine; VAS, visual analog scale.

day, versus 250 mg furosemide (intravenous bolus) twice

daily (without hypertonic saline) and sodium restriction to
as tolerated) Aliskiren daily
150 mg (increased to 300 mg

80 mmol (1,849 mg) per day. Both groups received fluid re-
Seralaxin 30 mg kg1 d1

*Did not meet USA regulatory requirement of significance.

striction to 1,000 mL/d.39 The primary end point was death

vs placebo for 48 h

or first hospitalization for worsening heart failure during

a mean follow-up of 57 months. A total of 8% of patients
vs placebo

were lost to follow-up. Length of stay was shorter

(3.5 days vs 5.5 days; P ! .0001) and creatinine clearance
was higher at discharge for patients in the hypertonic saline
arm. Readmissions occurred in 18.5% of the hypertonic sa-
line and 120 mmol/d sodium group versus 34.2% of the
n 5 1,639 randomized (n 5 1,615

80 mmol/d sodium group (P ! .0001). Mortality was

also lower in the hypertonic saline group (12.9% vs
in final efficacy analysis)

23.8%; P ! .0001). These data are intriguing, but they

are limited by the lack of blinding, the absence of data
ASTRONAUT162,163

on short-term outcomes, the proportion of patients lost to

RELAX-AHF61

follow-up, and the unknown effect that postdischarge man-

n 5 1,161

agement may have had on the study findings. Additionally,

in usual practice, clinicians and patients may find it ex-
tremely difficult to limit fluid intake to 1,000 mL daily.
376 Journal of Cardiac Failure Vol. 19 No. 6 June 2013

Larger prospective blinded trials are needed to further eval- Existing Pharmacologic Therapies
uate this therapeutic approach,39 which can not be recom-
Nitrates. Nitrates may be considered for relief of con-
mended for clinical practice at this time.
gestive symptoms in patients with ADHF. Information on
Ultrafiltration. In the Ultrafiltration Versus Intrave-
their use is provided in the full HFSA guidelines, and no
nous Diuretics for Patients Hospitalized for Acute Decom-
new evidence has been generated since the most recent
pensated Heart Failure (UNLOAD) study, ultrafiltration
guidelines publication. Readers are referred to the 2010
reduced body weight and promoted fluid loss to a greater
HFSA guidelines for more information on the role of nitro-
extent than intravenous diuretics in 200 patients hospital-
glycerin and nitroprusside in ADHF, including a detailed
ized for ADHF with signs of volume overload. A reduction
discussion of the Vasodilation in the Management of Acute
in ADHF hospitalizations and unscheduled visits was also
Congestive Heart Failure (VMAC) study.2 Additional com-
observed, but the study was too small to definitively evalu-
parative effectiveness studies of intravenous nitroglycerin
ate the effect of ultrafiltration on outcomes.40 Although the
in ADHF are being planned.
results from UNLOAD and earlier studies were encourag-
Inotropes. As recommended in the 2010 HFSA guide-
ing, 2 recent studies raise concerns about the efficacy and
lines, intravenous inotropes may be considered to relieve
safety of using ultrafiltration as a rescue strategy in high-
symptoms and improve end-organ function in patients
risk patients with ADHF, persistent congestion, and wors-
with advanced heart failure, reduced left ventricular ejec-
ening renal function. In an observational study, Patarroyo
tion fraction (LVEF), and LV dilatation. In particular, pos-
et al examined clinical outcomes of slow continuous ultra-
itive inotropes may be used when patients are hypotensive
filtration (SCUF) in 63 patients with ADHF and refractory
despite adequate filling pressures, are unresponsive or intol-
congestion.41 Although 48 hours of SCUF improved hemo-
erant to intravenous vasodilators, or display diminished or
dynamics and resulted in further weight loss, renal function
worsening peripheral perfusion or renal or other end-
did not improve in this high-risk cohort, and almost 60%
organ dysfunction.2 No new evidence has been generated
required hemodialysis during their hospital course. The
since the most recent guidelines publication. Readers are
Cardiorenal Rescue Study in Acute Decompensated Heart
referred to the 2010 HFSA guidelines for detailed informa-
Failure (CARRESS) randomly assigned (Table 1) 188 pa-
tion on the use of inotropes in ADHF.2
tients with ADHF, worsened renal function, and persistent
Nesiritide. Nesiritide (recombinant human B-type
congestion to a strategy of stepped pharmacologic care
natriuretic peptide [BNP]) was approved to relieve dyspnea
(intravenous diuretics dosed by the investigator to maintain
and to reduce pulmonary capillary wedge pressure in pa-
urine output of 3e5 L/d plus intravenous vasodilators or
tients with ADHF on the basis of the VMAC study, which
inotropes if needed to achieve target urine output) or ultra-
was a short-term trial of 498 patients that was not powered
filtration (target fluid removal rate of 200 mL/h).42 The
to evaluate clinical outcomes.43 Subsequently, 2 meta-
primary end point assessed at 96 hours was the bivariate
analyses brought the safety and efficacy of the drug into
change from baseline in serum creatinine level and weight.
question.44,45 The ASCEND-HF trial was designed to pro-
Ultrafiltration resulted in similar weight loss (w12
spectively answer the questions raised by the meta-analyses
pounds), but it was inferior to pharmacologic care owing
and to respond to the concerns of an expert panel commis-
to an increase in creatinine levels (P 5 .003). In addition,
sioned by the drug sponsor.9,46
more patients in the ultrafiltration group had a serious ad-
The study design and overall results are presented in
verse event (72% vs 57%; P 5 .03). CARRESS enrolled
Table 1. A total of 7,141 patients were randomized 1:1 to
a high-risk population with composite rates of death or
nesiritide (0.01 mg kg1 min1 infusion for 24 hours to
rehospitalization at 60 days of 61% and 48% in the ultrafil-
7 days, with an optional initial 2 mg/kg intravenous bolus),
tration and pharmacologic-therapy groups, respectively
or placebo. In addition, all patients received standard med-
(P 5 .12). An ongoing trial, the Aquapheresis Versus Intra-
ical therapy. The use of loop diuretics, positive inotropes,
venous Diuretics and Hospitalizations for Heart Failure
and vasodilators after randomization were similar between
(AVOID-HF, ClinicalTrials.gov identifier NCT01474200;
groups.9 Self-reported dyspnea improved marginally in the
Table 2) will further evaluate the role of ultrafiltration in
nesiritide group at 6 and 24 hours, but the prespecified cri-
the management of ADHF.
terion for statistical significance (P ! .005) was not met
Ultrafiltration is an option that may be considered instead
(although analyses required by the European Medicines
of diuretics for treating volume overload in the setting of
Agency did achieve significance). Similarly, there was no
ADHF (strength of evidence B, HFSA 2010 guidelines).2
significant difference in the outcome of death or heart fail-
However, major gaps in knowledge remain and include
ure hospitalization between treatment groups. There were
short- and long-term safety, patient impact, and cost-
no between-group differences in the safety end point of
effectiveness of this approach compared with diuretic man-
the proportion of patients with a O25% decrease in esti-
agement. In particular, issues related to venous access,
mated glomerular filtration rate (eGFR) from baseline
systemic anticoagulation and bleeding risks, and acute kid-
(31.4% nesiritide vs 29.5% placebo; odds ratio 1.09, 95%
ney injury need to be explored in larger patient cohorts.
CI 0.98e1.21; P 5 .11). Hypotension was reported more
Patients with ADHF who are truly refractory to diuretic
frequently in the nesiritide group (26.6% vs 15.3%;
therapy also deserve further study.
 Update on Acute Decompensated Heart Failure  Givertz et al 377

P ! .001). The end point findings were consistent across

Estimated Study Completion

Date (ClinicalTrials.gov)
a number of prespecified subgroups.9
What is the current role of nesiritide in light of

December 2012*
September 2013

December 2013
the ASCEND-HF findings? In patients with signs and

August 2013
symptoms of ADHF within 24 hours after the initial presen-
tation, nesiritide did not provide a meaningful incremental
improvement in dyspnea on top of standard therapy at ei-
ther 6 or 24 hours. Therefore, it is not recommended as
an effective therapy in this setting. It is possible that nesiri-
tide may have clinical efficacy in other patient populations

Efficacy: Cumulative urinary volume at 72 h.

544 Time to first rehospitalization or unscheduled

Hospitalized with ADHF and evidence of congestion 450 Mortality or all-cause hospitalization at 1 y

or at even lower doses (ROSE-AHF [Renal Optimization

outpatient or ED visit for ADHF within

Hospitalized with ADHF and evidence of congestion 360 Safety: change in serum cystatin C from

Strategies Evaluation in Acute Heart Failure]: Table 2),

but that hypothesis remains to be tested.
Primary End Point

Dopamine. Dopamine is an adrenergic agonist with

dose-dependent pharmacologic effects. At low doses
(0.5e2.5 mg kg1 min1), dopamine leads primarily to
randomization to 72 h.
90 d after discharge

vasodilation through vascular D1-dopaminergic receptor

stimulation, thereby increasing renal blood flow and GFR.
ATOMIC-AHF Omecamtiv mecarbil infusion for 48 h vs placebo Hospitalized for ADHF within 24 h of initiating loop 600 Dyspnea at 48 h

At medium doses (5e10 mg kg1 min1), dopamine is as-

sociated with positive inotropic and chronotropic effects
through stimulation of b1-adrenergic receptors.47 High
doses of dopamine (O10 to 20 mg kg1 min1) lead to sys-
Table 2. Summary of Select Ongoing Trials

temic vasoconstriction via stimulation of a-receptors. Low-

n

dose or renal-dose dopamine has been used in critical

diuretic, dyspnea at rest or with minimal exertion,

care settings for the prevention or treatment of acute kidney

Aquapheresis therapy (venovenous ultrafiltration) Hospitalized for ADHF with evidence of volume

injury, but the available evidence of efficacy is limited.48,49

Although mechanistic data show beneficial renal effects
overload (estimated excess fluid $10 lb)

of dopamine in chronic heart failure,50 few studies have

evaluated low-dose dopamine specifically in the ADHF
and eGFR 15e60 mL min1 m2

and elevated BNP or NT-proBNP

population.51
Population

The Dopamine in Acute Decompensated Heart Failure

(DAD-HF) trial demonstrated that fewer patients random-
ized to low-dose dopamine (actually 5 mg kg1 min1)
and low-dose furosemide experienced an increase in serum
creatinine O0.3 mg/dL or a O20% decrease in eGFR from
baseline compared with high-dose furosemide, although
the number of patients and absolute numbers of events
in this study was small (Table 1).51 The DAD-HF II
(NCT01060293) and ROSE-AHF (NCT 01132846) trials
ED, emergency department; other abbreviations as in Table 1.

are ongoing (Table 2).

Low-dose dopamine plus low-dose furosemide
vs low-dose furosemide alone vs high-dose

low-dose nesiritide (0.005 mg kg1 min1)

Low-dose dopamine (2 mg kg1 min1) vs

Pharmacologic Agents in Development for ADHF

Treatment Arms

Rolofylline. Rolofylline is an adenosine A1 receptor

antagonist that has been studied in the setting of ADHF
vs intravenous diuretics

and renal impairment. It was hypothesized that A1-receptor

antagonists would preserve GFR, improve the response to
furosemide alone

diuretic therapy, and increase sodium excretion by blocking

the effects of adenosine on the kidney.52e54 In phase II trials,
vs placebo

rolofylline produced greater improvements in dyspnea out-

*Last verified May 2010.

comes, and fewer patients experienced worsening renal

function. A trend toward improved clinical outcome was
also observed.55 However, these findings were not confirmed
NCT01474200

NCT01060293

NCT01132846

NCT01300013

in the large 2,033-patient phase III Placebo-Controlled

ROSE-AHF
DAD-HF II
AVOID-HF

Randomized Study of the Selective A1 Adenosine Receptor

Antagonist Rolofylline for Patients Hospitalized With Acute
Trial

Decompensated Heart Failure and Volume Overload to

378 Journal of Cardiac Failure Vol. 19 No. 6 June 2013
Assess Treatment Effect on Congestion and Renal Function
(PROTECT) trial (Table 1).18 No difference in the primary
clinical composite outcome was observed between the rolo-
fylline and placebo groups. Persistent worsening renal func-
tion did not differ between treatment groups,56 and the
incidence of death or readmission for cardiovascular or renal
causes at 60 days also was similar between groups.18
Furthermore, rolofylline was associated with an increased
rate of adverse neurologic events, including seizures and
strokes.57 Based on the data, further development of rolofyl-
line and other adenosine receptor antagonists for ADHF was
discontinued.58
Relaxin. Relaxin is an endogenous peptide initially dis-
covered as a hormone that is active in pregnancy.59,60
Through stimulation of the relaxin receptor, relaxin de-
creases inflammation, decreases fibrosis, increases vasodila-
tion, promotes renal blood flow, and increases vascular
endothelial growth factor and angiogenesis.59 In a variety
of animal models, relaxin prevented ischemia and reperfu-
sion injury, decreased cardiac fibrosis in hypertension and
cardiomyopathy, and reduced cell death and contractile dys-
function in myocardial infarction.60 Relaxin was studied in
a phase II placebo-controlled dose-ranging study of 234 pa-
tients with ADHF, evidence of congestion, mild to moderate
renal impairment, and preserved systolic blood pressure
(O125 mm Hg).17 The Preliminary Study of Relaxin in
Acute Heart Failure (Pre-RELAX-AHF) showed improve-
ments in dyspnea scores for patients treated with relaxin, al-
though hypotension and worsening renal function were
observed at higher doses. The study was too small to draw
conclusions regarding efficacy or clinical outcomes, but
hypothesis-generating observations from the trial suggested
favorable effects on clinical end points including cardiovas-
cular death or hospitalization for heart or renal failure.17 The
larger RELAX-AHF study61 was designed on the basis of
previous data, and enrolled 1,161 ADHF patients within
16 hours of presentation who had dyspnea, congestion,
mild-moderate renal insufficiency, and systolic blood pres-
sure O125 mm Hg (Table 1). Patients were randomly as-
signed to receive an infusion of seralaxin (30 mg kg1 d1)
or placebo for 48 hours with primary efficacy end points be-
ing dyspnea improvement over 5 days with the use of a visual
analog scale (VAS) and over 24 hours with the use of a 7-
point Likert scale. Compared with placebo, seralaxin im-
proved the dyspnea VAS end point (P 5 .007), but it had
no significant effect on the shorter-term end point
(P 5 .70). Seralaxin had no significant effect on the second-
ary end point of death or heart failure readmission at 60 days
(P 5 .89), but it was associated with reduced 180-day mortal-
ity (P 5 .02). More hypotensive events requiring dose reduc-
tion occurred in the seralaxin group (29% vs 18%;
P ! .0001), and more adverse events due to renal impairment
were observed in the placebo group (9% vs 6%; P 5 .03).61
More data are needed to determine the role of seralaxin in pa-
tients with ADHF.
Omecamtiv Mecarbil. The development of positive
inotropic agents for the treatment of ADHF has had
a history marked by early enthusiasm tempered by concerns
for toxicity. Although drugs such as dobutamine, milrinone,
vesnarinone, enoximone, and levosimendan effectively in-
crease cardiac output, they increase the risk of adverse
events, including arrhythmias, ischemia, and hypotension,
and, in some cases, mortality.62e67 Omecamtiv mecarbil
is the first selective cardiac myosin activator to be studied
in humans.68 Through greater binding of myosin to actin
during cardiac systole, omecamtiv mecarbil increases the
force of myocardial contractions without increasing myo-
cardial oxygen consumption.69 In a phase II, dose-ranging
trial in 45 patients with stable heart failure, omecamtiv me-
carbil increased LVEF and stroke volume, and decreased
end-systolic and end-diastolic volumes. Chest pain, tachy-
cardia, and myocardial ischemia were observed at high
plasma concentrations.70 These data were sufficient to pro-
ceed with the Acute Treatment With Omecamtiv Mecarbil
to Increase Contractility-Acute Heart Failure (ATOMIC-
AHF; NCT01300013; Table 2) study to further evaluate
the potential role of omecamtiv mecarbil.
Ularitide. Ularitide is a synthetic form of urodilatin,
a human natriuretic peptide produced in the kidneys. It in-
duces natriuresis and diuresis by binding to specific natri-
uretic peptide receptors (NPR-A, NPR-B, and others),
thereby increasing intracellular cyclic guanosine mono-
phosphate, relaxing smooth muscle cells, and leading to va-
sodilation and increased renal blood flow. Ularitide has
been studied in patients with ADHF in 2 double-blind pla-
cebo-controlled proof-of-concept studies, and it was shown
to exert beneficial effects on symptoms and hemodynam-
ics.71,72 The Trial of Ularitides Efficacy and Safety in
Patients With Acute Heart Failure (TRUE-AHF) is an on-
going phase III randomized clinical trial designed to evalu-
ate the role of ularitide as an intravenous infusion in
addition to conventional therapy in patients with ADHF
(NCT01661634). The primary end point will be a hierarchic
clinical composite variable that includes a patient-centered
assessment of clinical progress, an assessment of lack of
improvement or worsening of HF requiring a prespecified
intervention, and death. The study aims to recruit w2,116
patients with ADHF from 190 centers in North America,
Europe, and Latin America.
Biomarkers
Diagnosis. Natriuretic peptides (plasma BNP or N-
terminal pro-BNP [NT-proBNP]) are recommended in the
current HFSA guidelines to aid in the diagnosis of ADHF
in patients with dyspnea and signs and symptoms of heart
failure.2 The biomarker field is constantly evolving, and
new biomarkers are being investigated. A complete review
of all biomarkers undergoing clinical investigation is out-
side the scope of this paper. In the Biomarkers in Acute
Heart Failure (BACH) trial, midregional proeA-type natri-
uretic peptide (MR-proANP) at a prespecified threshold of
120 pmol/L was noninferior to a BNP level of 100 pg/mL
for the diagnosis of ADHF.73 The use of both BNP and
 Update on Acute Decompensated Heart Failure
MR-proANP slightly, but significantly, enhanced the
diagnostic performance of BNP. Similarly to BNP and
NT-proBNP, MR-proANP levels may be affected by age,
race, sex, body mass index, or comorbidities such as atrial
fibrillation. Confirmatory studies are needed to establish the
role of MR-proANP as a diagnostic tool for ADHF and to
determine its advantages over available biomarkers. Cur-
rently, MR-proANP is not recommended for use.
Prognosis. A number of novel markers predict clinical
outcomes in ADHF. The soluble ST2 receptor is a member
of the interleukin family, and it is up-regulated in response
to myocardial stretch. ST2 levels correlate with New York
Heart Association (NYHA) functional class and predict
1-year mortality in patients with ADHF.74,75 Neutrophil ge-
latinase-associated lipocalin (NGAL) is a marker of acute
kidney injury. When investigated in ADHF, higher levels
strongly predicted all-cause death or hospital readmission
at 30 days,76 although some data indicated that NGAL
more accurately reflects underlying renal function rather
than cardiac disease.77 A more recent study of serum
NGAL found a modest area under the receiver operating
characteristic curve (AUC) of 0.67 for prediction of acute
kidney injury.78 NGAL was not a significant predictor of
acute kidney injury after adjusting for multiple covariates.
Furthermore, measuring urinary NGAL 12e24 hours after
initial therapy may identify patients at risk for acute kidney
injury (P 5 .012) and adverse events at 30 days
(P 5 .02).79 However, another study showed only a small
rise in urinary NGAL in patients with ADHF who devel-
oped acute kidney injury after diuretic therapy.80 A concern
with novel biomarker studies is that creatinine is a poor cri-
terion standard for evaluation of acute kidney injury, damp-
ing the novel biomarkers predictive ability.
Copeptin is the C-terminal fragment of preprovasopres-
sin. In a secondary analysis of the BACH study, elevated
copeptin levels were associated with the highest 90-day
mortality (quartile 4 vs quartile 1). Copeptin was an inde-
pendent predictor of outcome, and it contributed additional
prognostic value to existing markers of outcome in that
analysis.81 The BACH study also suggested that the prog-
nostic ability of midregion proadrenomedullin (MR-
proADM) was limited, with AUC !0.60 for a composite
outcome at 7, 30, and 90 days. Although MR-proADM
had slightly better prognostic ability for survival, even after
adjusting for several clinical confounders, it appears to have
limited clinical utility. Galectin-3 promotes collagen syn-
thesis and cardiac fibrosis, and it has been identified as an
important marker early in the development of heart failure.
The majority of evidence with galectin-3 relates to chronic
heart failure, although galectin-3 was also elevated in pa-
tients with ADHF, and higher levels (O17.8 ng/mL) pre-
dicted short- and long-term mortality.82,83
The emerging data suggest that these and other novel
biomarkers may be clinically useful for the diagnosis and
prognosis of patients with ADHF. For example, a multi-
marker approach may have greater precision in determining
prognosis in chronic heart failure populations84 as well as
 Givertz et al 379
in acute coronary syndromes.85 Further research is needed
to define the specificity and sensitivity of these markers
for ADHF, to determine the influence of demographics
and comorbidities on their diagnostic and prognostic utility,
and to determine the incremental benefit of these markers in
the context of current clinical approaches and costs. There
are no conclusive data on the role of natriuretic peptides or
other biomarkers to guide inpatient heart failure therapy. In
particular, the practice of serial biomarker measurement has
not been shown to improve outcomes in ADHF.
Quality of Care
A major component of the economic burden of heart fail-
ure is related to hospitalizations.5,86 Understanding the
level of quality of health care delivered to patients with
ADHF and how quality affects clinical outcomes is imper-
ative. The rate of hospital adherence to national perfor-
mance measures for patients with heart failure is variable
but improving, and targeted interventions to improve adher-
ence to core measures have been successful.10,87 However,
the degree to which adherence correlates with improved
outcomes has not been well established. Recent mortality
and rehospitalization rates in the Veterans Affairs Health
Care System have trended in opposite directions with de-
creasing mortality and increasing odds for readmission at
30 days.88 Similar trends were observed in the Hospital
Compare database (www.hospitalcompare.hhs.gov), lead-
ing some to question the validity of using readmission
rate as a quality measure.89 Measures associated with
evidence-based drug therapy at the time of discharge (an-
giotensin-converting enzyme [ACE] inhibitor or angioten-
sin receptor blocker [ARB]; or beta-blockade, an
emerging performance measure) have been associated
with a lower risk of 60e90-day postdischarge mortality
or rehospitalization; however, other standard performance
measures were not.90 At 1 year, beta-blocker use at dis-
charge was associated with a lower risk of mortality, but
other standard performance measures were not associated
with mortality or cardiovascular readmission.91 Recent
analyses from the Get With the Guidelines Heart Failure
(GWTG-HF) registry that linked quality measures to Medi-
care claims data showed poor correlations between hospital
ranking and 30-day mortality or readmission.92 Another
study showed that hospitals enrolled in the GWTG-HF
program had greater adherence to the composite CMS
core performance measures than other hospitals, but
CMS-reported 30-day mortality was similar regardless of
participation in GWTG-HF.93 Although the differences in
performance measure adherence rates were statistically sig-
nificant, the absolute differences were small. GWTG-HF
hospitals had statistically lower 30-day all-cause readmis-
sion rates compared with other hospitals. Although the ab-
solute differences again were quite small (24% vs 24.4%;
P 5 .0009), these differences may still translate into sub-
stantial reductions in hospital readmissions and costs
380 Journal of Cardiac Failure Vol. 19 No. 6 June 2013
when applied to the large number of annual ADHF hospi-
talizations within and beyond the USA.93
The evidence is inconclusive to determine the most
effective strategies for improving postdischarge outcomes.
In a systematic review of interventions to reduce 30-day
rehospitalization, interventions centered around the pre-
discharge, postdischarge, and transition phases. A transi-
tional care model may be best.94 In a meta-review of 15
meta-analyses of heart failure disease management
programs (averaging 18.5 studies assessed per meta-
analysis), all-cause mortality tended to be lower in the
intervention group than in the control group.95 Most heart
failure disease management programs in the meta-analysis
included education, self-care, discharge planning, and
medication support; however, interventions were poorly
described and varied between studies. In a large random-
ized study of telemonitoring versus usual care, the addi-
tion of a telephone-activated voice-response system to
postdischarge care did not improve outcomes.96 The
2012 American College of Cardiology/American Heart
Association (ACC/AHA) performance measures were
composed of 9 indicators (3 new and 6 revised),
including LVEF assessment (inpatient and outpatient mea-
sure), symptom and activity measurement, symptom man-
agement, patient self-care education, beta-blocker therapy,
ACE inhibitor or ARB therapy, counseling about implant-
able cardioverter-defibrillator therapy, and postdischarge
follow-up.97 Although a single intervention does not stand
out as being more effective than others, opportunities to
improve care exist beyond reliance on standard perfor-
mance (process or outcome related) measures.92 Some
comprehensive process-of-care strategies that deliver
provider-targeted education and performance feedback
and patient-focused education and self-management strat-
egies were associated with higher rates of rehospitaliza-
tion but a trend toward lower mortality at 1 year.98 In
the Coordinating Study Evaluating Outcomes of Advising
and Counseling in Heart Failure (COACH) study, investi-
gators observed no difference in the primary end point of
death or heart failure rehospitalization for patients ran-
domized to usual care or to additional support provided
by a nurse with specialty training in heart failure.99 Trends
toward decreased mortality and an increase in the number
of short-term hospitalizations were noted.99 The totality of
evidence suggests that heart failure disease management
programs reduce heart failure hospitalization and have
a varying impact on survival and quality of life, but the ef-
fectiveness of specific components of these programs re-
mains to be determined.95,100,101
Early follow-up (within 7 days after discharge) is one
mechanism that was associated with lower rates of all-
cause readmission at 30 days in an observational analysis
of Medicare beneficiaries.102 Focused efforts on treating
cardiac and noncardiac comorbidities and providing com-
prehensive disease management have been proposed to im-
prove postdischarge outcomes in patients with ADHF, but
the effectiveness of bundled or individual interventions
needs to be established through formal evaluation and test-
ing.103 Key components of transition programs that may
promote improved outcomes are: 1) ongoing contact with
a care manager and interactions before and after discharge;
2) education that includes assuring understanding of con-
tent and comprehensive discharge planning, including early
follow-up and medication reconciliation and adherence; 3)
access to community resources; and 4) provider-to-provider
communication and coordination. Rehospitalization rates
may also be influenced more by regional patterns of prac-
tice (ie, underlying use of hospital services) than by patient
factors.104 The number of cardiovascular specialists avail-
able to manage ADHF may play a role in this variation.
Whether or not targeted process-of-care initiatives will
overcome such external factors and beneficially influence
rehospitalization rates remains to be determined. More ev-
idence is required to determine the effectiveness of many
current strategies intended to reduce readmissions.105
Evidence Gaps: Priorities for Future Research
Diagnosis
ADHF is a heterogeneous syndrome that encompasses
new-onset heart failure, worsening chronic heart failure,
heart failure exacerbated by comorbidities,106 nonadher-
ence, or contraindicated drugs or toxins, and reduced
or preserved ejection fraction. This heterogeneity may
cause delays in making the diagnosis of ADHF and insti-
tuting appropriate therapies or processes of care. BNP
and NT-proBNP are useful tools when the diagnosis is
uncertain, but even extremely high or low values do
not always rule in or rule out ADHF and must be inter-
preted with knowledge of the patients clinical picture.
Chest radiography also may be helpful to identify pat-
terns consistent with ADHF, although other objective
measures are needed. Based on preliminary data, limited
bedside echocardiography, combined with ultrasound
measures of lung water, may be helpful to differentiate
ADHF from non-ADHF causes in patients with undiffer-
entiated dyspnea.107e109 Use of thoracic bioimpedance to
determine increases in lung water associated with de-
compensation have produced mixed results,110e112 al-
though newer devices may be helpful to differentiate
hypervolemic and euvolemic patients.113 Most findings,
however, are preliminary, and large-scale studies are
needed to determine the additive value of these tests in
the acute setting. Ongoing studies will determine if other
biomarkers or noninvasive tools will offer advantages to
the existing approach to ADHF diagnosis.
Scores have been developed that use NT-proBNP and
clinical characteristics to diagnose ADHF. The Pro-BNP In-
vestigation of Dyspnea in the Emergency Department
(PRIDE) acute heart failure score had a sensitivity of
96% and a specificity of 84% for the diagnosis of ADHF
at a cutoff of $6 points (Table 3).114 A mathematical model
that included NT-proBNP as a continuous variable, patient

Table 3. PRIDE Score
Predictor
Elevated NT-proBNP (O450 pg/mL for age !50 y
and O900 pg/mL for age $50 y)
Interstitial edema on chest x-ray
Orthopnea
Lack of fever
Current loop diuretic use
Age O75 y
Rales on lung exam
Lack of cough
Total possible points
Adapted from Baggish et al. Am Heart J 2006;151:48e54.114
age, and pretest probability of ADHF also enhanced the di-
agnosis of ADHF, particularly among patients where the
physicians clinical diagnosis was uncertain.115
PrAHF 5 1=1 exp 8 0:011 age  5:9 ptprob
 2:3 lntbnp 0:82 ptprob
lntbnp
where Pr(AHF) is posttest probability for acute heart fail-
ure, ptprob is patients pretest probability, and lntbnp is
log (to base 10) of NT-proBNP value.
Early patient identification is a critical area for future re-
search efforts. Rapid patient identification may facilitate
faster institution of therapies that improve patient symp-
toms and well-being, and it may also allow for more expe-
dient identification of treatable precipitating factors. In an
analysis from ADHERE (Acute Decompensated Heart Fail-
ure National Registry), delayed measurement of natriuretic
peptides and delayed administration of intravenous di-
uretics were strongly associated and linked to a modest in-
crease of in-hospital mortality independently from other
prognostic factors.116 Whether faster or more optimal man-
agement of precipitating factors (ischemia, pulmonary dis-
ease, or arrhythmias) would improve ADHF outcomes has
yet to be determined, and research in this area is warranted.
Pathophysiology
Despite significant clinical research efforts, novel effec-
tive pharmacologic therapies that improve outcomes for pa-
tients with ADHF remain to be identified. Many aspects of
ADHF pathophysiology are poorly understood. Dyspnea,
a patient-centered outcome, has been hard to quantify and
to link to specific objective physiologic or patient out-
comes.117 Multiple pathophysiologic processes are likely to
be present, given the heterogeneity of the syndrome,118 in-
creasing the challenge of identifying therapeutic targets
and treatments that apply to the broad population of patients
with ADHF. There is an inadequate understanding of why pa-
tients with chronic heart failure deteriorate, and more work is
needed to identify these mechanisms. Future research efforts
that focus on patient subsets selected on the basis of sus-
pected pathophysiology may be more successful at identify-
ing targeted treatments more effective than the more
inclusive methods that have traditionally been used.16,118,119
Update on Acute Decompensated Heart Failure  Givertz et al 381
The contribution of cardiorenal syndrome to the patho-
physiology of ADHF has garnered significant interest in
Value
recent years. Many researchers have established that wors-
4 ening renal function (using a variety of definitions) was
a predictor of mortality and morbidity in patients with
2
2 both acute and chronic heart failure.32,120e122 However, ev-
2 idence is lacking to determine the interplay (or interaction)
1 between the kidney and the heart in cardiorenal syndrome,
1
1 ie, whether the kidney contributes to heart failure patho-
1 physiology, poor cardiac function results in renal impair-
14 ment, or it is some combination of both. Two analyses
confirmed the central role that elevated systemic venous
pressure plays in worsening renal function in
ADHF.123,124 Investigators highlighted the important role
of vascular redistribution.125 In additional analyses, wors-
ening renal function was associated with cardiovascular
mortality and heart failure hospitalizations, and it was
also associated with greater reductions in body weight, na-
triuretic peptides, and blood pressure, factors that generally
predict favorable outcomes.126 Furthermore, transient (vs
persistent) worsening renal function during treatment of
ADHF may actually be associated with improved outcomes
when related to aggressive diuresis.34 In addition, several
drug classes that improve survival and reduce morbidity
in chronic heart failure may also increase serum creatinine,
namely, ACE inhibitors, ARBs, and mineralocorticoid re-
ceptor antagonists. These data illustrate the complexity of
cardiorenal interactions. Clearly, more data are needed to
fully characterize the pathophysiologic role of the cardiore-
nal syndrome in ADHF. Ongoing research is examining the
role of dopamine and nesiritide to preserve renal function
when treating ADHF (ROSE-AHF).
Heart failure with preserved ejection fraction accounts
for almost one-half of all ADHF admissions, yet its under-
lying pathophysiology is understood even less than heart
failure with reduced ejection fraction (HF-REF).127 Al-
though limited data exist to characterize patients with
ADHF and preserved ejection fraction, registry data suggest
that postdischarge mortality and rehospitalization rates are
similar to those of patients with reduced ejection frac-
tion,128 although the risk of noncardiac mortality and reho-
spitalization is higher in HF-PEF patients.129 The majority
of completed or ongoing studies of HF-PEF have not been
conducted in the setting of ADHF. Although it is unlikely
that therapies for the acute setting will differ substantially
among HF-PEF and HF-REF patients, achieving a better
understanding of the pathophysiology may allow postdi-
scharge therapies to be specifically tailored to HF-PEF.
For example, systemic or pulmonary arterial hypertension
may play a greater role in decompensation among patients
with HF-PEF and serve as an appropriate target for therapy.
Risk Stratification: Predicting Early Versus Later
Events
Several prognostic models have been developed from
clinical trials or registries in ADHF.130e134 Other scores de-
rived from chronic heart failure (Seattle Heart Failure
382 Journal of Cardiac Failure Vol. 19 No. 6 June 2013
Model)135 or transplant referral populations (Heart Failure
Survival Score)136 were validated in advanced heart failure
populations referred for cardiac transplant,137 though not in
the ADHF setting. A novel model has been developed that
estimates the combined end point of death and failure to
achieve a favorable health status, and it may identify
ADHF patients before discharge who may be good candi-
dates for either advanced therapies or palliative care.138
Risk stratification may be a valuable tool in the setting of
ADHF. Patients identified as high risk for short- or long-
term mortality or rehospitalization may benefit from ag-
gressive optimization of drug or device therapy, focused
disease management initiatives, or therapies targeting co-
morbidities or risk factor modification. A stratified treat-
ment approach for patients with ADHF based on risk
scores has not been tested in clinical trials and is an area
where research is warranted.
Clinical Measures of Patient Improvement
Measures of efficacy should be both clinically relevant
and meaningful to patients. Several outcomes have been
used to evaluate the efficacy of therapeutic agents for
ADHF. In clinical trials, dyspnea is a common end point be-
cause it is generally the symptom that prompts patients to
seek medical attention. Despite this, clinically meaningful
improvements in dyspnea in clinical trials are difficult to
demonstrate, particularly on top of standard diuretic ther-
apy. In secondary analyses of both the Pre-RELAX-AHF
study139 and the PROTECT trial,140 early dyspnea relief
was associated with more favorable outcomes. In the
RELAX-AHF study (Table 1), treatment with serelaxin im-
proved dyspnea at 5 days, but it had no effect on cardiovas-
cular death or heart failure readmission.61 The optimal
method and timing of dyspnea assessment in clinical trials
is controversial,141 although in the clinical setting it is rou-
tinely assessed by physical examination and by querying
patients regarding their degree of breathlessness. Whether
dyspnea is the most relevant end point to judge patient re-
sponse in clinical practice (or in clinical trials) has been
debated.117,142e144 More research is needed to fill the evi-
dence gap that exists between dyspnea improvement, over-
all health status, and clinical outcomes. Functional
measures, such as 6-minute walk or patient-reported health
status measures, or refinements to dyspnea assessment that
include response to exertion also may be informative ways
to judge patient response to ADHF therapies in the clinical
setting.
Monitoring
Devices. The majority of published and ongoing trials
of telemonitoring in heart failure were conducted in pa-
tients with chronic heart failure. The use of existing or sim-
ilar devices to prevent recurrent episodes of heart failure in
the setting of ADHF has not been well studied. When non-
invasive externally applied impedance cardiography (ICG)
was studied in 212 patients in the PREDICT (Prospective
Evaluation and Identification of Cardiac Decompensation
by ICG Test) study, it identified patients at increased
near-term risk for recurrent decompensation.145 Other vari-
ables were also important: patient visual analog scale of
distress, NYHA functional class, and systolic blood pres-
sure. Furthermore, data from other studies indicated that in-
ternally implanted devices that measured intrathoracic
impedance values were not highly sensitive to predict
hospital admissions,146 and they did not reduce heart failure
hospitalizations,147 although studies to date have generally
been underpowered. In contrast, the observational Program
to Access and Review Trending Information and Evaluate
Correlation to Symptoms in Patients With Heart Failure
(PARTNERS-HF) study showed that internal cardiac device
diagnostic data (driven to a large extent by high fluid indi-
ces) independently predicted subsequent heart failure
hospitalization with pulmonary congestion in patients
with NYHA functional class III/IV heart failure who re-
ceived a cardiac resynchronization therapy defibrillator de-
vice with impedance monitoring capabilities (Optivol;
Medtronic).148
Implantable hemodynamic monitoring systems are
currently being investigated for use in heart failure and
are capable of monitoring pulmonary artery pressures (Car-
dioMEMS) or left atrial pressures (Heartpod; St Jude Med-
ical). In the CardioMEMS Heart Sensor Allows Monitoring
of Pressure to Improve Outcomes in NYHA Functional
Class III Heart Failure Patients (CHAMPION) trial, the
270 patients randomized to the CardioMEMS device had
a lower rate of heart failure-related hospitalizations at 6
and 15 months than the 280 patients in the control group.21
The Heartpod device was studied in the Hemodynamically
Guided Home Self-Therapy in Severe Heart Failure
Patients (HOMEOSTASIS) observational pilot trial. The in-
vestigators found that individualized therapy guided by left
atrial pressures was associated with reduced left atrial pres-
sures, improved NYHA functional class, and increased
LVEF and resulted in higher doses of ACE inhibitors/
ARBs and beta-blockers.149 The Left Atrial Pressure Mon-
itoring to Optimize Heart Failure Therapy (LAPTOP-HF)
study is a larger randomized study evaluating the safety
and efficacy (heart failure hospitalization) of the Heartpod
device in patients with NYHA functional class III heart fail-
ure. Although these implantable device studies are not be-
ing conducted specifically in the ADHF population, if the
devices are approved, they will likely be used clinically
in this setting during hospitalization of patients with the de-
vices. Whether used to prevent acute decompensation or in
patients currently undergoing treatment for ADHF, a key el-
ement of improved outcomes will be how aggressively and
thoroughly clinicians respond to data abnormalities. There-
fore, studies in the setting of ADHF are warranted so that
information on how to interpret the data in this setting
can be generated.
Noninvasive monitoring of left ventricular end-diastolic
pressure (LVEDP) has also been studied as a mechanism to
guide treatment and prevent heart failure rehospitalization.
 Update on Acute Decompensated Heart Failure
In a small study of 50 patients hospitalized for ADHF, pa-
tients randomized to daily noninvasive monitoring of
LVEDP with the use of the Vericor monitor (CVP
Diagnostics) had lower estimated LVEDP at discharge and
lower rates of rehospitalizations for heart failure at 1, 3, 6,
and 12 months. However, the study was too small to draw
conclusions regarding clinical outcomes.150 In the future,
noninvasive tools that assess congestion and/or other sensi-
tive factors of decompensation and guide treatment of
ADHF may be most useful to the primary health care pro-
viders of ADHF patients, including emergency physicians,
cardiologists, internists, and hospitalists.151
Biomarkers. The majority of biomarker-guided ther-
apy studies were performed in the chronic heart failure pop-
ulation. The Pro-B-Type Natriuretic Peptide Outpatient
Tailored Chronic Heart Failure Therapy (PROTECT) study
reported a reduction in cardiovascular events among 151
patients with chronic heart failure at a single center who
were randomized to NT-proBNP-guided therapy compared
with standard care.152 Whether or not biomarker-guided
therapy improves outcomes in the setting of ADHF has
not been determined. New evidence evaluating this concept
is lacking, and more studies are critically needed to advance
the field in this area.
Home-based monitoring of biomarkers is another poten-
tial strategy that may be useful to identify and treat epi-
sodes of worsening heart failure before a patients signs
and symptoms progress to the point that hospitalization is
required. The Heart Failure Outpatient Monitoring Evalua-
tion (HOME; NCT01347567) study is enrolling w375 pa-
tients hospitalized or treated as an outpatient with ADHF.
Participants will be randomized into 1 of 3 arms: BNP
home finger-stick monitoring plus health management (in-
vestigator will use BNP data to guide management, along
with weight, signs, and symptoms), health management
alone (BNP levels will be obtained, but results will be
blinded to investigator and subject; investigator will use
weight, signs, and symptoms to manage care), or usual
care. The primary end point is heart failure-related mortal-
ity, heart failure readmission, intravenous diuretic or aug-
mented oral diuretic therapy in the ED, or unplanned
outpatient treatments for ADHF. The Guiding Evidence
Based Therapy Using Biomarker Intensified Treatment
(GUIDE-IT; NCT01685840) study is also enrolling sub-
jects with ADHF to determine the efficacy of a strategy
of NT-proBNP-guided therapy compared with usual care
in high-risk patients with left ventricular systolic dysfunc-
tion. The primary outcome measure is the time to cardio-
vascular death or heart failure hospitalization; all-cause
mortality will also be assessed.
Processes of Care in the Hospital Setting
A wide variation in quality of care for ADHF persists
across the USA.153 Although multiple initiatives that in-
volve processes of care and outcomes in ADHF have
been an intense area of research in recent years, more
 Givertz et al 383
work is needed to determine the best approaches. Develop-
ing standard algorithms and processes to rapidly assess, tri-
age, and implement early therapy in patients in prehospital
and ED-based settings (ambulance, ED, or observation
units) is one approach where formal testing is warranted.
Collaborations among prehospital personnel, cardiologists,
hospital-based clinicians, heart failure specialists, and
emergency physicians are needed to ensure a smooth tran-
sition of care. Preliminary data suggest that collaborative
care can result in successful implementation of protocol-
driven therapy.154 Creating networks and integration be-
tween emergency personnel and hospital-based personnel
decreased treatment delays in patients with acute coronary
syndromes.155 Whether similar strategies, such as door-to-
diuretic time or triage of heart failure admissions in the
ED, would be feasible and/or effective to improve out-
comes in ADHF is unknown.
Additional parameters beyond the door-to-diuretic time
(preferably !90 min) could include: 1) clinical assessment
of volume status and readiness for discharge on a twice-
daily basis; 2) assessment of precipitating factors and mea-
surement of electrolytes and renal function at least every
48 hours in patients receiving intravenous diuretics; 3) as-
sessment of LVEF if not done in the past year; and 4) ini-
tiation of an ACE inhibitor (or ARB) and beta-blocker
therapy in patients with HF-REF and no contraindications.
Further studies are needed to determine if these measures
improve quality, reduce length of stay, and favorably affect
longer-term outcomes in ADHF.
The key evidence gap in this arena is in clarifying the
contributions of the individual components of these inter-
ventions to determine which are the most effective. Specific
predischarge strategies are critically important in enhancing
patient knowledge and adherence to postdischarge expecta-
tions. Some examples are education (clinician and patient),
medication optimization and reconciliation, and plans
for postdischarge follow-up. Risk-stratified readmission
models that are widely available and have the potential to
identify high-risk patients who may benefit from aggressive
postdischarge follow-up and management need to be for-
mally evaluated. Examples include the readmission score
(http://readmissionscore.org/heart_failure.php) or the score
developed by Philbin and DiSalvo based on administrative
data.156,157 The optimal method of follow-up (in-home,
heart failure clinic, telephone) for patients may depend on
geography and the availability of clinicians, as well as the
underlying physical, emotional, social (including informed
caregivers and family), and/or economic risk of an individ-
ual patient. New knowledge in these areas would be highly
clinically relevant.
Finally, more work is needed to address palliative care
and end of life issues, particularly as advanced therapies
such as mechanical circulatory support are considered for
broader patient populations.158,159 Although palliative
care should be integrated throughout the course of heart
failure care, an episode of ADHF may act as a trigger for
384 Journal of Cardiac Failure Vol. 19 No. 6 June 2013
clinicians to assess whether or not goals of care have been
addressed and to implement symptom-focused and end of
life care as appropriate.160 A recent study showed that pal-
liative care consultation can be provided in the heart failure
clinic after discharge and can result in reduced symptoms
and improved quality of life.161
Conclusion
Recently completed trials answered questions regarding
the safety and efficacy of diuretic strategies, vasodilator
therapies, and ultrafiltration. Completed trials with neutral
or negative results, though disappointing, contribute to
overall knowledge pertaining to clinical characteristics
and outcomes, and they are informative for the design of fu-
ture trials. The results of ongoing trials of new therapeutic
agents and devices that monitor clinical status will deter-
mine if effective and safe therapies are on the horizon. In
the future, attempts may be made to match patient clinical
characteristics with the expected pharmacologic mecha-
nism of action for new agents or devices, rather than taking
the traditional all comers approach. Successful transla-
tion of this approach into a greater ability to detect effective
therapies remains to be seen. The timing of intervention
will also be tested to determine the optimal pace and loca-
tion of treatment. At present, initiatives to improve pro-
cesses and quality of care may offer the best opportunity
to improve patient outcomes. Although advances have
been realized, many opportunities remain to reduce the
burden of ADHF.
Acknowledgments
The authors acknowledge Bart Galle, PhD, for his contri-
butions to the development of this manuscript, and the
HFSA Executive Committee (Thomas Force, MD, JoAnn
Lindenfeld, MD, John C. Burnett, Jr, MD, John Chin,
MD, Steven R. Houser, PhD, Joseph Hill, MD, PhD, Sharon
A. Hunt, MD, Barry M. Massie, MD, Mandeep R. Mehra,
MD, Sara C. Paul, RN, MSN, Mariann Piano, RN, PhD,
Heather J. Ross, MD, James E. Udelson, MD, and Michael
R. Zile, MD) for their review and critique of this paper.
Disclosures
Michael M. Givertz: consultant or advisory board:
Merck, Cardioxyl. John R. Teerlink: consultant or advisory
board: Amgen, Corthera, Cytokinetics, Novartis, Gambro;
research grants: Amgen, Corthera, Cytokinetics, Novartis,
Affymax, St Jude. Randall C. Starling: sponsored research:
Johnson & Johnson, Scios; stock options: CardioMEMS;
steering committee: Biocontrol INOVATE-HF, NHLBI
Heart Failure Network; advisory board: Medtronic; all de-
tails posted on Cleveland Clinic website. Nancy M. Albert:
honoraria or speakers bureau: BG Medicine, Medtronic;
consultant or advisory board: BG Medicine, Gambro.
Sean P. Collins: consultant or advisory board: The
Medicines Company, Novartis, Radiometer, Trevena; re-
search grants: Medtronic. Justin A. Ezekowitz: research
grants: Amgen, Johnson & Johnson, Alere. James C.
Fang: consultant or advisory board: Medtronic; research
grants: Medtronic. Adrian F. Hernandez: honoraria or
speakers bureau: Corthera, BMS; research grants: Amylin,
Portola, Janssen. Wendy Gattis Stough: consultant: Med-
tronic. Mary N. Walsh: consultant or advisory board:
United Healthcare, Eli Lilly; officer, trustee, or director:
American College of Cardiology. Javed Butler: consultant
of advisory board: Stemira, Medtronic, Trevena, Gambro,
Ono, Bayer, Harvest; research grants: NIH, HRSA, Euro-
pean Union; ethical trial: Medtronic, Otsuka; DSMB or
steering committee: Amgen, Celladon, Corthera, Novatis,
BG Medicine. John P. Dimarco: consultant: Medtronic, St
Jude; speaker: Boston Scientific. John A. Spertus: consul-
tant or advisory board: Genentech, United Healthcare, Jans-
sen, Amgen; equity interests or stock options: Health
Outcomes; royalties or intellectual property rights:
KCCQ, SAQ, PAQ; research grants: Genentech, Lilly, Eva-
Heart, Amorcyte, ACCF. W. H. Wilson Tang: research
grants: NIH, Abbott Laboratories.
References
1. Felker GM, Adams KF Jr, Konstam MA, OConnor CM,
Gheorghiade M. The problem of decompensated heart failure: no-
menclature, classification, and risk stratification. Am Heart J 2003;
145:S18e25.
2. Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA,
Givertz MM, et al. HFSA 2010 comprehensive heart failure practice
guideline. J Card Fail 2010;16:e1e194.
3. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS,
Ganiats TG, et al. 2009 focused update incorporated into the
ACC/AHA 2005 guidelines for the diagnosis and management of
heart failure in adults. A report of the American College of Cardiol-
ogy Foundation/American Heart Association Task Force on Practice
Guidelines developed in collaboration with the International Society
for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53:
e1e90.
4. Hall M, Levant S, DeFrances C. Hospitalization for congestive heart
failure: United States, 2000e2010. NCHS Data Brief 2012;108:1e8.
5. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD,
Borden WB, et al. Heart disease and stroke statisticsd2012 update:
a report from the American Heart Association. Circulation 2012;125:
e2e220.
6. Chen J, Normand SL, Wang Y, Krumholz HM. National and regional
trends in heart failure hospitalization and mortality rates for Medi-
care beneficiaries, 1998e2008. JAMA 2011;306:1669e78.
7. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K,
Ezekowitz MD, et al. Forecasting the future of cardiovascular disease
in the United States: a policy statement from the American Heart As-
sociation. Circulation 2011;123:933e44.
8. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Reho-
spitalization for heart failure: problems and perspectives. J Am Coll
Cardiol 2013;61:391e403.
9. OConnor CM, Starling RC, Hernandez AF, Armstrong PW,
Dickstein K, Hasselblad V, et al. Effect of nesiritide in patients
with acute decompensated heart failure. N Engl J Med 2011;365:
32e43.
10. Fonarow GC, Abraham WT, Albert NM, Gattis Stough W,
Gheorghiade M, Greenberg BH, et al. Influence of a performance-
 Update on Acute Decompensated Heart Failure
improvement initiative on quality of care for patients hospitalized
with heart failure: results of the Organized Program to Initiate Life-
saving Treatment in Hospitalized Patients With Heart Failure (OPTI-
MIZE-HF). Arch Intern Med 2007;167:1493e502.
11. Fonarow GC, Abraham WT, Albert NM, Gattis WA, Gheorghiade M,
Greenberg B, et al. Organized Program to Initiate Lifesaving Treat-
ment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF):
rationale and design. Am Heart J 2004;148:43e51.
12. Follath F, Yilmaz MB, Delgado JF, Parissis JT, Porcher R, Gayat E,
et al. Clinical presentation, management and outcomes in the Acute
Heart Failure Global Survey of Standard Treatment (ALARM-HF).
Intensive Care Med 2011;37:619e26.
13. Chaudhry SI, Wang Y, Concato J, Gill TM, Krumholz HM. Patterns
of weight change preceding hospitalization for heart failure. Circula-
tion 2007;116:1549e54.
14. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F,
Harjola VP, et al. EuroHeart Failure Survey II (EHFS II): a survey
on hospitalized acute heart failure patients: description of population.
Eur Heart J 2006;27:2725e36.
15. Collins SP, Lindsell CJ, Storrow AB, Fermann GJ, Levy PD,
Pang PS, et al. Early changes in clinical characteristics after emer-
gency department therapy for acute heart failure syndromes: identi-
fying patients who do not respond to standard therapy. Heart Fail
Rev 2012;17:387e94.
16. Mebazaa A, Gheorghiade M, Pina IL, Harjola VP, Hollenberg SM,
Follath F, et al. Practical recommendations for prehospital and early
in-hospital management of patients presenting with acute heart fail-
ure syndromes. Crit Care Med 2008;36:S129e39.
17. Teerlink JR, Metra M, Felker GM, Ponikowski P, Voors AA,
Weatherley BD, et al. Relaxin for the treatment of patients with acute
heart failure (Pre-RELAX-AHF): a multicentre, randomised,
placebo-controlled, parallel-group, dose-finding phase IIb study. Lan-
cet 2009;373:1429e39.
18. Massie BM, OConnor CM, Metra M, Ponikowski P, Teerlink JR,
Cotter G, et al. Rolofylline, an adenosine A1-receptor antagonist,
in acute heart failure. N Engl J Med 2010;363:1419e28.
19. Fermann GJ, Collins SP. Observation units in the management
of acute heart failure syndromes. Curr Heart Fail Rep 2010;7:
125e33.
20. Ezekowitz JA, Kaul P, Bakal JA, Quan H, McAlister FA. Trends in
heart failure care: has the incident diagnosis of heart failure shifted
from the hospital to the emergency department and outpatient
clinics? Eur J Heart Fail 2011;13:142e7.
21. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR,
Stevenson LW, et al. Wireless pulmonary artery haemodynamic mon-
itoring in chronic heart failure: a randomised controlled trial. Lancet
2011;377:658e66.
22. Zile MR, Bennett TD, St John SM, Cho YK, Adamson PB,
Aaron MF, et al. Transition from chronic compensated to acute de-
compensated heart failure: pathophysiological insights obtained
from continuous monitoring of intracardiac pressures. Circulation
2008;118:1433e41.
23. Small RS, Wickemeyer W, Germany R, Hoppe B, Andrulli J,
Brady PA, et al. Changes in intrathoracic impedance are associated
with subsequent risk of hospitalizations for acute decompensated
heart failure: clinical utility of implanted device monitoring without
a patient alert. J Card Fail 2009;15:475e81.
24. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ,
Granger CB, et al. Influence of nonfatal hospitalization for heart fail-
ure on subsequent mortality in patients with chronic heart failure.
Circulation 2007;116:1482e7.
25. Cleland JG, Swedberg K, Follath F, Komajda M, Cohen-Solal A,
Aguilar JC, et al. The EuroHeart Failure survey programmeda sur-
vey on the quality of care among patients with heart failure in Eu-
rope. Part 1: patient characteristics and diagnosis. Eur Heart J
2003;24:442e63.
26. Komajda M, Follath F, Swedberg K, Cleland J, Aguilar JC, Cohen-
Solal A, et al. The EuroHeart Failure Survey programmeda survey
 Givertz et al 385
on the quality of care among patients with heart failure in Europe.
Part 2: treatment. Eur Heart J 2003;24:464e74.
27. Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH,
Costanzo MR, Abraham WT, et al. Characteristics and outcomes of
patients hospitalized for heart failure in the United States: rationale,
design, and preliminary observations from the first 100,000 cases in
the Acute Decompensated Heart Failure National Registry (AD-
HERE). Am Heart J 2005;149:209e16.
28. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW,
Goldsmith SR, et al. Diuretic strategies in patients with acute decom-
pensated heart failure. N Engl J Med 2011;364:797e805.
29. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS,
Wigneswaran JR, Wynne J, et al. High prevalence of renal dysfunc-
tion and its impact on outcome in 118,465 patients hospitalized with
acute decompensated heart failure: a report from the ADHERE data-
base. J Card Fail 2007;13:422e30.
30. Peacock WF, Costanzo MR, De Marco T, Lopatin M, Wynne J,
Mills RM, et al. Impact of intravenous loop diuretics on outcomes
of patients hospitalized with acute decompensated heart failure: in-
sights from the ADHERE registry. Cardiology 2009;113:12e9.
31. Hasselblad V, Gattis Stough W, Shah MR, Lokhnygina Y,
OConnor CM, Califf RM, et al. Relation between dose of loop di-
uretics and outcomes in a heart failure population: results of the ES-
CAPE trial. Eur J Heart Fail 2007;9:1064e9.
32. Butler J, Forman DE, Abraham WT, Gottlieb SS, Loh E, Massie BM,
et al. Relationship between heart failure treatment and development
of worsening renal function among hospitalized patients. Am Heart J
2004;147:331e8.
33. Yilmaz MB, Gayat E, Salem R, Lassus J, Nikolaou M, Laribi S, et al.
Impact of diuretic dosing on mortality in acute heart failure using
a propensity-matched analysis. Eur J Heart Fail 2011;13:1244e52.
34. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Poten-
tial effects of aggressive decongestion during the treatment of de-
compensated heart failure on renal function and survival.
Circulation 2010;122:265e72.
35. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infu-
sion versus bolus injection of loop diuretics in congestive heart fail-
ure. Cochrane Database Syst Rev 2005:CD003178.
36. Paterna S, Di Pasquale P, Parrinello G, Fornaciari E, Di GF,
Fasullo S, et al. Changes in brain natriuretic peptide levels and bio-
electrical impedance measurements after treatment with high-dose
furosemide and hypertonic saline solution versus high-dose furose-
mide alone in refractory congestive heart failure: a double-blind
study. J Am Coll Cardiol 2005;45:1997e2003.
37. Licata G, Di Pasquale P, Parrinello G, Cardinale A, Scandurra A,
Follone G, et al. Effects of high-dose furosemide and small-volume
hypertonic saline solution infusion in comparison with a high dose
of furosemide as bolus in refractory congestive heart failure: long-
term effects. Am Heart J 2003;145:459e66.
38. Paterna S, Di Pasquale P, Parrinello G, Amato P, Cardinale A,
Follone G, et al. Effects of high-dose furosemide and small-volume
hypertonic saline solution infusion in comparison with a high dose
of furosemide as a bolus, in refractory congestive heart failure. Eur
J Heart Fail 2000;2:305e13.
39. Paterna S, Fasullo S, Parrinello G, Cannizzaro S, Basile I, Vitrano G,
et al. Short-term effects of hypertonic saline solution in acute heart
failure and long-term effects of a moderate sodium restriction in pa-
tients with compensated heart failure with New York Heart Associa-
tion class III (class C) (SMAC-HF study). Am J Med Sci 2011;342:
27e37.
40. Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA,
Teerlink JR, et al. Ultrafiltration versus intravenous diuretics for pa-
tients hospitalized for acute decompensated heart failure. J Am Coll
Cardiol 2007;49:675e83.
41. Patarroyo M, Wehbe E, Hanna M, Taylor DO, Starling RC,
Demirjian S, et al. Cardiorenal outcomes after slow continuous ultra-
filtration therapy in refractory patients with advanced decompensated
heart failure. J Am Coll Cardiol 2012;60:1906e12.
386 Journal of Cardiac Failure Vol. 19 No. 6 June 2013
42. Bart BA, Goldsmith SR, Lee KL, Givertz MM, OConnor CM,
Bull DA, et al. Ultrafiltration in decompensated heart failure with
cardiorenal syndrome. N Engl J Med 2012;367:2296e304.
43. VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treat-
ment of decompensated congestive heart failure: a randomized con-
trolled trial. JAMA 2002;287:1531e40.
44. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsen-
ing renal function with nesiritide in patients with acutely decompen-
sated heart failure. Circulation 2005;111:1487e91.
45. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term
risk of death after treatment with nesiritide for decompensated heart
failure: a pooled analysis of randomized controlled trials. JAMA
2005;293:1900e5.
46. Scios. Panel of cardiology experts provides recommendations
to Scios regarding NATRECOR. 2005. Available at: http://www
sciosinc com/scios/pr_1118721302.
47. Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In:
Brunton LL, Chabner B, Knollman B, editors. Goodman & Oilmans
The Pharmacological Basis of Therapeutics. l2th ed. New York:
McGraw-Hill; 2011. p. 277e334.
48. Kellum JA, Decker M. Use of dopamine in acute renal failure:
a meta-analysis. Crit Care Med 2001;29:1526e31.
49. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J, Austra-
lian and New Zealand Intensive Care Society (ANZICS) Clinical Tri-
als Group. Low-dose dopamine in patients with early renal
dysfunction: a placebo-controlled randomised trial. Lancet 2000;
356:2139e43.
50. Elkayam U, Ng TM, Hatamizadeh P, Janmohamed M, Mehra A. Re-
nal vasodilatory action of dopamine in patients with heart failure:
magnitude of effect and site of action. Circulation 2008;117:200e5.
51. Giamouzis G, Butler J, Starling RC, Karayannis G, Nastas J,
Parisis C, et al. Impact of dopamine infusion on renal function in hos-
pitalized heart failure patients: results of the Dopamine in Acute De-
compensated Heart Failure (DAD-HF) trial. J Card Fail 2010;16:
922e30.
52. Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R,
Goldman S, et al. BG9719 (CVT-124), an A1 adenosine receptor an-
tagonist, protects against the decline in renal function observed with
diuretic therapy. Circulation 2002;105:1348e53.
53. Vallon V, Miracle C, Thomson S. Adenosine and kidney function:
potential implications in patients with heart failure. Eur J Heart
Fail 2008;10:176e87.
54. Slawsky MT, Givertz MM. Rolofylline: a selective adenosine 1 re-
ceptor antagonist for the treatment of heart failure. Expert Opin Phar-
macother 2009;10:311e22.
55. Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM,
OConnor CM, Metra M, et al. The PROTECT pilot study: a random-
ized, placebo-controlled, dose-finding study of the adenosine A1 re-
ceptor antagonist rolofylline in patients with acute heart failure and
renal impairment. J Card Fail 2008;14:631e40.
56. Voors AA, Dittrich HC, Massie BM, DeLucca P, Mansoor GA,
Metra M, et al. Effects of the adenosine A1 receptor antagonist rolo-
fylline on renal function in patients with acute heart failure and renal
dysfunction: results from PROTECT (Placebo-Controlled Random-
ized Study of the Selective Adenosine A1 Receptor Antagonist Rolo-
fylline for Patients Hospitalized With Acute Decompensated Heart
Failure and Volume Overload to Assess Treatment Effect on Conges-
tion and Renal Function). J Am Coll Cardiol 2011;57:1899e907.
57. Teerlink JR, Iragui VJ, Mohr JP, Carson PE, Hauptman PJ,
Lovett DH, et al. The safety of an adenosine A(1)-receptor antago-
nist, rolofylline, in patients with acute heart failure and renal impair-
ment: findings from PROTECT. Drug Saf 2012;35:233e44.
58. Givertz MM. Adenosine A1 receptor antagonists at a fork in the road.
Circ Heart Fail 2009;2:519e22.
59. Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M. Relaxin:
review of biology and potential role in treating heart failure. Curr
Heart Fail Rep 2010;7:75e82.
60. Du XJ, Bathgate RA, Samuel CS, Dart AM, Summers RJ. Cardiovas-
cular effects of relaxin: from basic science to clinical therapy. Nat
Rev Cardiol 2010;7:48e58.
61. Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G,
Greenberg BH, et al. Serelaxin, recombinant human relaxin-2, for
treatment of acute heart failure (RELAX-AHF): a randomised,
placebo-controlled trial. Lancet 2013;381:29e39.
62. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R,
Colucci WS, et al. Short-term intravenous milrinone for acute exac-
erbation of chronic heart failure: a randomized controlled trial.
JAMA 2002;287:1541e7.
63. Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX,
Pocock SJ, et al. Levosimendan vs dobutamine for patients with
acute decompensated heart failure: the SURVIVE randomized trial.
JAMA 2007;297:1883e91.
64. OConnor CM, Gattis WA, Uretsky BF, Adams KF Jr, McNulty SE,
Grossman SH, et al. Continuous intravenous dobutamine is associ-
ated with an increased risk of death in patients with advanced heart
failure: insights from the Flolan International Randomized Survival
Trial (FIRST). Am Heart J 1999;138:78e86.
65. Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC,
Jaski BE, et al, Vesnarinone Trial Investigators. A dose-dependent in-
crease in mortality with vesnarinone among patients with severe
heart failure. N Engl J Med 1998;339:1810e6.
66. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R,
Zeldis SM, et al, PROMISE Study Research Group. Effect of oral
milrinone on mortality in severe chronic heart failure. N Engl J
Med 1991;325:1468e75.
67. Cowley AJ, Skene AM, Enoximone Investigators. Treatment of se-
vere heart failure: quantity or quality of life? A trial of enoximone.
Br Heart J 1994;72:226e30.
68. Teerlink JR, Clarke CP, Saikali KG, Lee JH, Chen MM,
Escandon RD, et al. Dose-dependent augmentation of cardiac sys-
tolic function with the selective cardiac myosin activator, omecamtiv
mecarbil: a first-in-man study. Lancet 2011;378:667e75.
69. Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K,
et al. Cardiac myosin activation: a potential therapeutic approach for
systolic heart failure. Science 2011;331:1439e43.
70. Cleland JG, Teerlink JR, Senior R, Nifontov EM, McMurray JJ,
Lang CC, et al. The effects of the cardiac myosin activator, omecam-
tiv mecarbil, on cardiac function in systolic heart failure: a double-
blind, placebo-controlled, crossover, dose-ranging phase 2 trial.
Lancet 2011;378:676e83.
71. Mitrovic V, Luss H, Nitsche K, Forssmann K, Maronde E, Fricke K,
et al. Effects of the renal natriuretic peptide urodilatin (ularitide) in
patients with decompensated chronic heart failure: a double-blind,
placebo-controlled, ascending-dose trial. Am Heart J 2005;150:
1239.e2ee8.
72. Mitrovic V, Seferovic PM, Simeunovic D, Ristic AD, Miric M,
Moiseyev VS, et al. Haemodynamic and clinical effects of ularitide
in decompensated heart failure. Eur Heart J 2006;27:2823e32.
73. Maisel A, Mueller C, Nowak R, Peacock WF, Landsberg JW,
Ponikowski P, et al. Mid-region pro-hormone markers for diagnosis
and prognosis in acute dyspnea: results from the BACH (Biomarkers
in Acute Heart Failure) trial. J Am Coll Cardiol 2010;55:2062e76.
74. Rehman SU, Mueller T, Januzzi JL Jr. Characteristics of the novel in-
terleukin family biomarker ST2 in patients with acute heart failure. J
Am Coll Cardiol 2008;52:1458e65.
75. Januzzi JL Jr, Peacock WF, Maisel AS, Chae CU, Jesse RL,
Baggish AL, et al. Measurement of the interleukin family member
ST2 in patients with acute dyspnea: results from the PRIDE (Proe
Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency
Department) study. J Am Coll Cardiol 2007;50:607e13.
76. Maisel AS, Mueller C, Fitzgerald R, Brikhan R, Hiestand BC,
Iqbal N, et al. Prognostic utility of plasma neutrophil gelatinase-
associated lipocalin in patients with acute heart failure: the NGAL
Evaluation Along With B-Type Natriuretic Peptide in Acutely
 Update on Acute Decompensated Heart Failure
Decompensated Heart Failure (GALLANT) trial. Eur J Heart Fail
2011;13:846e51.
77. Shrestha K, Borowski AG, Troughton RW, Thomas JD, Klein AL,
Tang WH. Renal dysfunction is a stronger determinant of systemic
neutrophil gelatinase-associated lipocalin levels than myocardial dys-
function in systolic heart failure. J Card Fail 2011;17:472e8.
78. Breidthardt T, Socrates T, Drexler B, Noveanu M, Heinisch C,
Arenja N, et al. Plasma neutrophil gelatinase-associated lipocalin
for the prediction of acute kidney injury in acute heart failure. Crit
Care 2012;16:R2.
79. Collins SP, Hart KW, Lindsell CJ, Fermann GJ, Weintraub NL,
Miller KF, et al. Elevated urinary neutrophil gelatinase-associated
lipocalcin after acute heart failure treatment is associated with wors-
ening renal function and adverse events. Eur J Heart Fail 2012;14:
1020e9.
80. Dupont M, Shrestha K, Singh D, Awad A, Kovach C, Scarcipino M,
et al. Lack of significant renal tubular injury despite acute kidney in-
jury in acute decompensated heart failure. Eur J Heart Fail 2012;14:
597e604.
81. Maisel A, Xue Y, Shah K, Mueller C, Nowak R, Peacock WF,
et al. Increased 90-day mortality in patients with acute heart fail-
ure with elevated copeptin: secondary results from the Biomarkers
in Acute Heart Failure (BACH) study. Circ Heart Fail 2011;4:
613e20.
82. Shah RV, Chen-Tournoux AA, Picard MH, van Kimmenade RR,
Januzzi JL. Galectin-3, cardiac structure and function, and long-
term mortality in patients with acutely decompensated heart failure.
Eur J Heart Fail 2010;12:826e32.
83. van Kimmenade RR, Januzzi JL Jr, Ellinor PT, Sharma UC,
Bakker JA, Low AF, et al. Utility of amino-terminal proebrain natri-
uretic peptide, galectin-3, and apelin for the evaluation of patients
with acute heart failure. J Am Coll Cardiol 2006;48:1217e24.
84. Ky B, French B, Levy WC, Sweitzer NK, Fang JC, Wu AH, et al.
Multiple biomarkers for risk prediction in chronic heart failure.
Circ Heart Fail 2012;5:183e90.
85. Sabatine MS, Morrow DA, de Lemos JA, Gibson CM, Murphy SA,
Rifai N, et al. Multimarker approach to risk stratification in nonST
elevation acute coronary syndromes: simultaneous assessment of tro-
ponin I, C-reactive protein, and B-type natriuretic peptide. Circula-
tion 2002;105:1760e3.
86. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among
patients in the Medicare fee-for-service program. N Engl J Med
2009;360:1418e28.
87. Fonarow GC, Yancy CW, Heywood JT. Adherence to heart failure
quality-of-care indicators in US hospitals: analysis of the ADHERE
registry. Arch Intern Med 2005;165:1469e77.
88. Heidenreich PA, Sahay A, Kapoor JR, Pham MX, Massie B. Diver-
gent trends in survival and readmission following a hospitalization
for heart failure in the Veterans Affairs Health Care System 2002
to 2006. J Am Coll Cardiol 2010;56:362e8.
89. Gorodeski EZ, Starling RC, Blackstone EH. Are all readmissions bad
readmissions? N Engl J Med 2010;363:297e8.
90. Fonarow GC, Abraham WT, Albert NM, Stough WG,
Gheorghiade M, Greenberg BH, et al. Association between perfor-
mance measures and clinical outcomes for patients hospitalized
with heart failure. JAMA 2007;297:61e70.
91. Patterson ME, Hernandez AF, Hammill BG, Fonarow GC,
Peterson ED, Schulman KA, et al. Process of care performance mea-
sures and long-term outcomes in patients hospitalized with heart fail-
ure. Med Care 2010;48:210e6.
92. Hernandez AF, Fonarow GC, Liang L, Heidenreich PA, Yancy C,
Peterson ED. The need for multiple measures of hospital quality: re-
sults from the Get With the GuidelineseHeart Failure Registry of the
American Heart Association. Circulation 2011;124:712e9.
93. Heidenreich PA, Hernandez AF, Yancy CW, Liang L, Peterson ED,
Fonarow GC. Get With the Guidelines program participation, process
of care, and outcome for medicare patients hospitalized with heart
failure. Circ Cardiovasc Qual Outcomes 2012;5:37e43.
 Givertz et al 387
94. Hansen LO, Young RS, Hinami K, Leung A, Williams MV. Interven-
tions to reduce 30-day rehospitalization: a systematic review. Ann In-
tern Med 2011;155:520e8.
95. Savard LA, Thompson DR, Clark AM. A meta-review of evidence on
heart failure disease management programs: the challenges of de-
scribing and synthesizing evidence on complex interventions. Trials
2011;12:194.
96. Chaudhry SI, Mattera JA, Curtis JP, Spertus JA, Herrin J, Lin Z, et al.
Telemonitoring in patients with heart failure. N Engl J Med 2010;
363:2301e9.
97. Bonow RO, Ganiats TG, Beam CT, Blake K, Casey DE Jr,
Goodlin SJ, et al. ACCF/AHA/AMA-PCPI 2011 performance mea-
sures for adults with heart failure: a report of the American College
of Cardiology Foundation/American Heart Association Task Force
on Performance Measures and the American Medical Association-
Physician Consortium for Performance Improvement. J Am Coll Car-
diol 2012;59:1812e32.
98. Mudge A, Denaro C, Scott I, Bennett C, Hickey A, Jones MA. The
paradox of readmission: effect of a quality improvement program in
hospitalized patients with heart failure. J Hosp Med 2010;5:148e53.
99. Jaarsma T, van der Wal MH, Lesman-Leegte I, Luttik ML,
Hogenhuis J, Veeger NJ, et al. Effect of moderate or intensive disease
management program on outcome in patients with heart failure: Co-
ordinating Study Evaluating Outcomes of Advising and Counseling
in Heart Failure (COACH). Arch Intern Med 2008;168:316e24.
100. McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary
strategies for the management of heart failure patients at high risk
for admission: a systematic review of randomized trials. J Am Coll
Cardiol 2004;44:810e9.
101. Whellan DJ, Hasselblad V, Peterson E, OConnor CM,
Schulman KA. Metaanalysis and review of heart failure disease man-
agement randomized controlled clinical trials. Am Heart J 2005;149:
722e9.
102. Hernandez AF, Greiner MA, Fonarow GC, Hammill BG,
Heidenreich PA, Yancy CW, et al. Relationship between early physi-
cian follow-up and 30-day readmission among Medicare beneficia-
ries hospitalized for heart failure. JAMA 2010;303:1716e22.
103. Gheorghiade M, Peterson ED. Improving postdischarge outcomes in
patients hospitalized for acute heart failure syndromes. JAMA 2011;
305:2456e7.
104. Epstein AM, Jha AK, Orav EJ. The relationship between hospital
admission rates and rehospitalizations. N Engl J Med 2011;365:
2287e95.
105. Bradley EH, Curry L, Horwitz LI, Sipsma H, Thompson JW,
Elma M, et al. Contemporary evidence about hospital strategies for
reducing 30-day readmissions: a national study. J Am Coll Cardiol
2012;60:607e14.
106. Fonarow GC, Abraham WT, Albert NM, Stough WG,
Gheorghiade M, Greenberg BH, et al. Factors identified as precipitat-
ing hospital admissions for heart failure and clinical outcomes: find-
ings from OPTIMIZE-HF. Arch Intern Med 2008;168:847e54.
107. Secko MA, Lazar JM, Salciccioli LA, Stone MB. Can junior emer-
gency physicians use E-point septal separation to accurately estimate
left ventricular function in acutely dyspneic patients? Acad Emerg
Med 2011;18:1223e6.
108. Nazerian P, Vanni S, Zanobetti M, Polidori G, Pepe G, Federico R,
et al. Diagnostic accuracy of emergency Doppler echocardiography
for identification of acute left ventricular heart failure in patients
with acute dyspnea: comparison with Boston criteria and N-terminal
prohormone brain natriuretic peptide. Acad Emerg Med 2010;17:
18e26.
109. Volpicelli G, Caramello V, Cardinale L, Mussa A, Bar F,
Frascisco MF. Bedside ultrasound of the lung for the monitoring of
acute decompensated heart failure. Am J Emerg Med 2008;26:
585e91.
110. Kamath SA, Drazner MH, Tasissa G, Rogers JG, Stevenson LW,
Yancy CW. Correlation of impedance cardiography with invasive he-
modynamic measurements in patients with advanced heart failure:
388 Journal of Cardiac Failure Vol. 19 No. 6 June 2013
the Bioimpedance Cardiography (BIG) substudy of the Evaluation
Study of Congestive Heart Failure and Pulmonary Artery Catheteri-
zation Effectiveness (ESCAPE) trial. Am Heart J 2009;158:217e23.
111. Tanino Y, Shite J, Paredes OL, Shinke T, Ogasawara D, Sawada T,
et al. Whole body bioimpedance monitoring for outpatient chronic
heart failure follow up. Circ J 2009;73:1074e9.
112. Wang DJ, Gottlieb SS. Impedance cardiography: more questions than
answers. Curr Cardiol Rep 2006;8:180e6.
113. Piccoli A, Codognotto M, Cianci V, Vettore G, Zaninotto M,
Plebani M, et al. Differentiation of cardiac and noncardiac dyspnea
using bioelectrical impedance vector analysis (BIVA). J Card Fail
2012;18:226e32.
114. Baggish AL, Siebert U, Lainchbury JG, Cameron R, Anwaruddin S,
Chen A, et al. A validated clinical and biochemical score for the di-
agnosis of acute heart failure: the ProBNP Investigation of Dyspnea
in the Emergency Department (PRIDE) Acute Heart Failure Score.
Am Heart J 2006;151:48e54.
115. Steinhart B, Thorpe KE, Bayoumi AM, Moe G, Januzzi JL Jr,
Mazer CD. Improving the diagnosis of acute heart failure using
a validated prediction model. J Am Coll Cardiol 2009;54:
1515e21.
116. Maisel AS, Peacock WF, McMullin N, Jessie R, Fonarow GC,
Wynne J, et al. Timing of immunoreactive B-type natriuretic peptide
levels and treatment delay in acute decompensated heart failure: an
ADHERE (Acute Decompensated Heart Failure National Registry)
analysis. J Am Coll Cardiol 2008;52:534e40.
117. West RL, Hernandez AF, OConnor CM, Starling RC, Califf RM.
A review of dyspnea in acute heart failure syndromes. Am Heart J
2010;160:209e14.
118. Felker GM, Pang PS, Adams KF, Cleland JG, Cotter G, Dickstein K,
et al. Clinical trials of pharmacological therapies in acute heart fail-
ure syndromes: lessons learned and directions forward. Circ Heart
Fail 2010;3:314e25.
119. Metra M, Felker GM, Zaca V, Bugatti S, Lombardi C, Bettari L, et al.
Acute heart failure: multiple clinical profiles and mechanisms require
tailored therapy. Int J Cardiol 2010;144:175e9.
120. Forman DE, Butler J, Wang Y, Abraham WT, OConnor CM,
Gottlieb SS, et al. Incidence, predictors at admission, and impact
of worsening renal function among patients hospitalized with heart
failure. J Am Coll Cardiol 2004;43:61e7.
121. Klein L, Massie BM, Leimberger JD, OConnor CM, Pina IL,
Adams KF Jr, et al. Admission or changes in renal function during
hospitalization for worsening heart failure predict postdischarge sur-
vival: results from the Outcomes of a Prospective Trial of Intrave-
nous Milrinone for Exacerbations of Chronic Heart Failure
(OPTIME-CHF). Circ Heart Fail 2008;1:25e33.
122. Metra M, Nodari S, Parrinello G, Bordonali T, Bugatti S, Danesi R,
et al. Worsening renal function in patients hospitalised for acute heart
failure: clinical implications and prognostic significance. Eur J Heart
Fail 2008;10:188e95.
123. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO,
Starling RC, et al. Importance of venous congestion for worsening
of renal function in advanced decompensated heart failure. J Am
Coll Cardiol 2009;53:589e96.
124. Damman K, van Deursen VM, Navis G, Voors AA, van
Veldhuisen DJ, Hillege HL. Increased central venous pressure is as-
sociated with impaired renal function and mortality in a broad spec-
trum of patients with cardiovascular disease. J Am Coll Cardiol 2009;
53:582e8.
125. Fallick C, Sobotka PA, Dunlap ME. Sympathetically mediated
changes in capacitance: redistribution of the venous reservoir as
a cause of decompensation. Circ Heart Fail 2011;4:669e75.
126. Blair JE, Pang PS, Schrier RW, Metra M, Traver B, Cook T, et al.
Changes in renal function during hospitalization and soon after dis-
charge in patients admitted for worsening heart failure in the placebo
group of the EVEREST trial. Eur Heart J 2011;32:2563e72.
127. Udelson JE. Heart failure with preserved ejection fraction. Circula-
tion 2011;124:e540e3.
128. Fonarow GC, Stough WG, Abraham WT, Albert NM,
Gheorghiade M, Greenberg BH, et al. Characteristics, treatments,
and outcomes of patients with preserved systolic function hospital-
ized for heart failure: a report from the OPTIMIZE-HF Registry. J
Am Coll Cardiol 2007;50:768e77.
129. Zile MR, Gaasch WH, Anand IS, Haass M, Little WC, Miller AB,
et al. Mode of death in patients with heart failure and a preserved
ejection fraction: results from the Irbesartan in Heart Failure With
Preserved Ejection Fraction Study (I-Preserve) trial. Circulation
2010;121:1393e405.
130. Felker GM, Leimberger JD, Califf RM, Cuffe MS, Massie BM,
Adams KF Jr, et al. Risk stratification after hospitalization for de-
compensated heart failure. J Card Fail 2004;10:460e6.
131. OConnor CM, Abraham WT, Albert NM, Clare R, Gattis Stough W,
Gheorghiade M, et al. Predictors of mortality after discharge in pa-
tients hospitalized with heart failure: an analysis from the Organized
Program to Initiate Lifesaving Treatment in Hospitalized Patients
With Heart Failure (OPTIMIZE-HF). Am Heart J 2008;156:662e73.
132. OConnor CM, Hasselblad V, Mehta RH, Tasissa G, Califf RM,
Fiuzat M, et al. Triage after hospitalization with advanced heart fail-
ure: the ESCAPE (Evaluation Study of Congestive Heart Failure and
Pulmonary Artery Catheterization Effectiveness) risk model and dis-
charge score. J Am Coll Cardiol 2010;55:872e8.
133. Peterson PN, Rumsfeld JS, Liang L, Albert NM, Hernandez AF,
Peterson ED, et al. A validated risk score for in-hospital mortality
in patients with heart failure from the American Heart Association
Get With the Guidelines program. Circ Cardiovasc Qual Outcomes
2010;3:25e32.
134. Hsieh M, Auble TE, Yealy DM. Validation of the Acute Heart Failure
Index. Ann Emerg Med 2008;51:37e44.
135. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD,
Cropp AB, et al. The Seattle Heart Failure Model: prediction of sur-
vival in heart failure. Circulation 2006;113:1424e33.
136. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE,
Mancini DM. Development and prospective validation of a clinical
index to predict survival in ambulatory patients referred for cardiac
transplant evaluation. Circulation 1997;95:2660e7.
137. Goda A, Williams P, Mancini D, Lund LH. Selecting patients for
heart transplantation: comparison of the Heart Failure Survival Score
(HFSS) and the Seattle Heart Failure Model (SHFM). J Heart Lung
Transpl 2011;30:1236e43.
138. Allen LA, Gheorghiade M, Reid KJ, Dunlay SM, Chan PS,
Hauptman PJ, et al. Identifying patients hospitalized with heart fail-
ure at risk for unfavorable future quality of life. Circ Cardiovasc Qual
Outcomes 2011;4:389e98.
139. Metra M, Teerlink JR, Felker GM, Greenberg BH, Filippatos G,
Ponikowski P, et al. Dyspnoea and worsening heart failure in patients
with acute heart failure: results from the Pre-RELAX-AHF study.
Eur J Heart Fail 2010;12:1130e9.
140. Metra M, OConnor CM, Davison BA, Cleland JG, Ponikowski P,
Teerlink JR, et al. Early dyspnoea relief in acute heart failure: prev-
alence, association with mortality, and effect of rolofylline in the
PROTECT study. Eur Heart J 2011;32:1519e34.
141. Ezekowitz JA, Hernandez AF, OConnor CM, Starling RC, Proulx G,
Weiss MH, et al. Assessment of dyspnea in acute decompensated
heart failure: insights from ASCEND-HF (Acute Study of Clinical
Effectiveness of Nesiritide in Decompensated Heart Failure) on the
contributions of peak expiratory flow. J Am Coll Cardiol 2012;59:
1441e8.
142. Allen LA, Hernandez AF, OConnor CM, Felker GM. End points for
clinical trials in acute heart failure syndromes. J Am Coll Cardiol
2009;53:2248e58.
143. Gheorghiade M, Ruschitzka F. Beyond dyspnoea as an endpoint in
acute heart failure trials. Eur Heart J 2011;32:1442e5.
144. Teerlink JR. Dyspnea as an end point in clinical trials of therapies for
acute decompensated heart failure. Am Heart J 2003;145:S26e33.
145. Packer M, Abraham WT, Mehra MR, Yancy CW, Lawless CE,
Mitchell JE, et al. Utility of impedance cardiography for the
 Update on Acute Decompensated Heart Failure
identification of short-term risk of clinical decompensation in stable
patients with chronic heart failure. J Am Coll Cardiol 2006;47:
2245e52.
146. Conraads VM, Tavazzi L, Santini M, Oliva F, Gerritse B, Yu CM,
et al. Sensitivity and positive predictive value of implantable intra-
thoracic impedance monitoring as a predictor of heart failure hospi-
talizations: the SENSE-HF trial. Eur Heart J 2011;32:2266e73.
147. van Veldhuisen DJ, Braunschweig F, Conraads V, Ford I, Cowie MR,
Jondeau G, et al. Intrathoracic impedance monitoring, audible patient
alerts, and outcome in patients with heart failure. Circulation 2011;
124:1719e26.
148. Whellan DJ, Ousdigian KT, Al-Khatib SM, Pu W, Sarkar S,
Porter CB, et al. Combined heart failure device diagnostics identify
patients at higher risk of subsequent heart failure hospitalizations: re-
sults from PARTNERS HF (Program to Access and Review Trending
Information and Evaluate Correlation to Symptoms in Patients With
Heart Failure) study. J Am Coll Cardiol 2010;55:1803e10.
149. Ritzema J, Troughton R, Melton I, Crozier I, Doughty R, Krum H,
et al. Physician-directed patient self-management of left atrial pressure
in advanced chronic heart failure. Circulation 2010;121:1086e95.
150. Sharma GV, Woods PA, Lindsey N, OConnell C, Connolly L,
Joseph J, et al. Noninvasive monitoring of left ventricular end-
diastolic pressure reduces rehospitalization rates in patients hospital-
ized for heart failure: a randomized controlled trial. J Card Fail 2011;
17:718e25.
151. Givertz MM. Hemodynamic monitoring to guide treatment of acute
heart failure. J Card Fail 2011;17:726e8.
152. Januzzi JL Jr, Rehman SU, Mohammed AA, Bhardwaj A, Barajas L,
Barajas J, et al. Use of amino-terminal proeB-type natriuretic pep-
tide to guide outpatient therapy of patients with chronic left ventric-
ular systolic dysfunction. J Am Coll Cardiol 2011;58:1881e9.
153. Bernheim SM, Grady JN, Lin Z, Wang Y, Wang Y, Savage SV, et al.
National patterns of risk-standardized mortality and readmission for
acute myocardial infarction and heart failure. Update on publicly re-
ported outcomes measures based on the 2010 release. Circ Cardio-
vasc Qual Outcomes 2010;3:459e67.
154. Storrow AB, Collins SP, Lyons MS, Wagoner LE, Gibler WB,
Lindsell CJ. Emergency department observation of heart failure:
 Givertz et al 389
preliminary analysis of safety and cost. Congest Heart Fail 2005;
11:68e72.
155. Rokos IC, French WJ, Koenig WJ, Stratton SJ, Nighswonger B,
Strunk B, et al. Integration of pre-hospital electrocardiograms and
ST-elevation myocardial infarction receiving center (SRC) networks:
impact on Door-to-balloon times across 10 independent regions.
JACC Cardiovasc Interv 2009;2:339e46.
156. Keenan PS, Normand SL, Lin Z, Drye EE, Bhat KR, Ross JS, et al.
An administrative claims measure suitable for profiling hospital per-
formance on the basis of 30-day all-cause readmission rates among
patients with heart failure. Circ Cardiovasc Qual Outcomes 2008;1:
29e37.
157. Philbin EF, DiSalvo TG. Prediction of hospital readmission for heart
failure: development of a simple risk score based on administrative
data. J Am Coll Cardiol 1999;33:1560e6.
158. Petrucci RJ, Benish LA, Carrow BL, Prato L, Hankins SR, Eisen HJ,
et al. Ethical considerations for ventricular assist device support:
a 10-point model. ASAIO J 2011;57:268e73.
159. Entwistle JW, Sade RM, Petrucci RJ. The ethics of mechanical sup-
port: the need for new guidelines. Ann Thorac Surg 2011;92:
1939e42.
160. Goodlin SJ. Palliative care in congestive heart failure. J Am Coll Car-
diol 2009;54:386e96.
161. Evangelista LS, Lombardo D, Malik S, Ballard-Hernandez J,
Motie M, Liao S. Examining the effects of an outpatient palliative
care consultation on symptom burden, depression, and quality of
life in patients with symptomatic heart failure. J Card Fail 2012;
18:894e9.
162. Gheorghiade M, Albaghdadi M, Zannad F, Fonarow GC, Bohm M,
Gimpelewicz C, et al. Rationale and design of the multicentre, ran-
domized, double-blind, placebo-controlled Aliskiren Trial on Acute
Heart Failure Outcomes (ASTRONAUT). Eur J Heart Fail 2011;13:
100e6.
163. Gheorghiade M, Bohm M, Greene SJ, Fonarow GC, Lewis EF,
Zannad F, et al. Effect of aliskiren on postdischarge mortality
and heart failure readmissions among patients hospitalized for
heart failure: the ASTRONAUT randomized trial. JAMA 2013;
309:1125e35.