SI06_Clinician_Cover 10/16/06 10:39 AM Page 1

Vol. 24 No. 2 ISSN 0264-6404 October 2006

SPECIAL EDITION

Challenges in Acute Decompensated

Heart Failure Management:
The Cardiorenal Syndrome

Release Date: October 2006

Jointly sponsored by

and

Supported by an educational grant from Scios Inc.

SI06_Clinician_Cover 10/16/06 10:39 AM Page 2

Duration: Up to 2 hours Detailed Instructions to Access UPENN CME Website

Credit: Up to 2 AMA PRA Category 1 Credit(s) TM
Fee: No charge
Release Date: October 1, 2006
Credit Expiration Date: October 31, 2007
Last Review Date: July 21, 2006
This activity is supported by an educational grant from Scios Inc.
Target Audience
This continuing medical education (CME) activity has been designed to
meet the needs of cardiologists, emergency medicine physicians, and
hospital pharmacists.
Objectives
Upon completion of this CME activity, the reader should be able to:
• Discuss the challenges inherent in selecting therapies for the man-
agement of patients with acute decompensated heart failure (ADHF)
• Describe current treatment strategies implemented in ADHF that
impact the cardiorenal axis
• Identify the risks/benefits of various treatment strategies implemented
in patients with ADHF and their impact on renal function and mortality
• Explain clinical data that address the renal/mortality impact of various
pharmacologic interventions
• Discuss appropriate cardiorenal management of patients with ADHF
Successful Completion
To receive your certificate of credit (certificate of participation for non-
physicians), you must read the entire monograph, then go to the UPENN
CME website to take the posttest (instructions are in the next section).
To pass, you must receive a score of 70% or higher. Next, complete the
evaluation and retrieve or save your certificate.
• Copy the link below into your browser to be directed to the course
page on the University of Pennsylvania CME website:
http://cme-online.med.upenn.edu/adhf
• Create an account (click on “Member Sign-up” at the top of the page);
if you already have an account, log in with your email address and
password
• Register for the course by clicking “Register” in the Course Materials box
• Click “ADHF posttest” in the Course Materials box
• Complete and submit the evaluation instrument, which will appear after
you pass the posttest
• View/print your certificate
• For assistance: cmesupport@mail.med.upenn.edu
Computer Requirements: A 486/66 or Pentium processor (Pentium-class
processor recommended) running Microsoft Windows® 95 or later
(Windows 98, ME, NT 4.0, 2000, XP). A minimum of 16 MB of RAM and
15 MB of free hard disk space is required. A version of Internet Explorer
or Netscape Navigator/Communicator of at least 5.0 is necessary to
successfully use the program.
Accreditation
This activity has been planned and implemented in accordance with the
Essential Areas and policies of the Accreditation Council for Continuing
Medical Education through the joint sponsorship of the University of
Pennsylvania School of Medicine and SynerMed® Communications.
The University of Pennsylvania School of Medicine is accredited by the
ACCME to provide continuing medical education for physicians.
Designation of Credit
The University of Pennsylvania School of Medicine designates this
educational activity for a maximum of 2 AMA PRA Category 1 Credit(s) TM.
Physicians should only claim credit commensurate with the extent of their
participation in the activity.

Course Faculty
Kirkwood F. Adams, Jr, MD Alan S. Maisel, MD, FACC
Associate Professor of Medicine and Radiology Professor of Medicine
Director, Heart Failure Program University of California, San Diego
University of North Carolina at Chapel Hill Director, Coronary Care Unit
Chapel Hill, North Carolina VA San Diego Healthcare System
San Diego, California
Faculty Disclosures
It is policy at the University of Pennsylvania School of Medicine for individuals who are in a position to control the content of an educational activity
to disclose to the learners all relevant financial relationships that they have with any commercial interest that provides products or services that may
be relevant to the content of this CME activity. For this purpose, we consider relationships of the person involved in the CME activity to include
financial relationships of a spouse or partner.
The intent of this policy is not to prevent expert faculty with relevant relationship(s) with commercial interest(s) from involvement in CME, but rather to
ensure that Penn CME-certified activities promote quality and safety, are effective in improving medical practice, are based on valid content, and are
independent of control from commercial interests and free of commercial bias. Peer review of all content was conducted for all faculty presentations
whose disclosure information provided to the Penn Office of CME was found to contain relationships that created a conflict of interest relative to the
topic of their presentation. In addition, all faculty were instructed to provide balanced, scientifically rigorous, and evidence-based presentations.
The staff in the Office of CME at the University of Pennsylvania School of Medicine, Mariell Jessup, MD, the peer reviewer, and the staff at
SynerMed® Communications, our educational partner, have reported no relevant financial relationships with any commercial interests related to the
content of this educational activity.
The following faculty members have reported the listed relevant financial relationships with commercial interests related to the content of this
educational activity.
Faculty Name Name of Commercial Interest Relationship
Kirkwood F. Adams, Jr, MD Amgen, AstraZeneca, Myogen, NitroMed, NovaCardia, Orqis Medical, Grants/Research Support
Otsuka America, Inc., Scios Inc., Vasogen Inc.
Abbott, Amgen, AstraZeneca, Biosite, Bristol-Myers Squibb, GlaxoSmithKline, Consultant
Myogen, Otsuka America, Inc., Pfizer, sanofi-aventis, Scios Inc.
AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Myogen, NitroMed, Novartis, Speakers’ Bureau
Otsuka America, Inc., Scios Inc.
Alan S. Maisel, MD, FACC Abbott, Bayer, Roche, Scios Inc. Grant/Research Support
Biosite Consultant
Biosite, Medtronic, Scios Inc. Speakers’ Bureau

Relevant Financial Relationships: Financial relationships are those relationships in which the individual benefits by receiving a salary, royalty, intellectual property rights, consult-
ing fee, honoraria, ownership interest (eg, stocks, stock options, or other ownership interest, excluding diversified mutual funds), or other financial benefit. Financial benefits are
usually associated with roles such as employment, management position, independent contractor (including contracted research), consulting, speaking and teaching, member-
ship on advisory committees or review panels, board membership, and other activities from which remuneration is received or expected.
Investigational and/or Off-Label Use of Commercial Products and Devices
The University of Pennsylvania School of Medicine requires all faculty to disclose any planned discussion of an investigational and/or off-label use of a pharmaceutical product
or device within their presentation. Participants should note that the use of products outside labeling approved by the US Food and Drug Administration should be considered
experimental and are advised to consult current prescribing information for approved indications.
The investigational agent(s) discussed within this activity include: carperitide, levosimendan, tolvaptan, ularitide and BB9719. These agents have not yet been approved
by the US Food and Drug Administration for the treatment of acute decompensated heart failure.
SI06 Clinician Correx 10/12/06 3:27 PM Page 1
Challenges in Acute Decompensated Heart Failure Management:
The Cardiorenal Syndrome
INTRODUCTION
Heart failure is a chronic and progressive clinical
syndrome and a major and growing public health
problem.1 Worldwide, an estimated 20 million
people are living with some degree of cardiac
dysfunction.2 In the United States, almost 5 million
people are living with the syndrome, with annual
expenditures nearing $30 billion.3 In European
countries, heart failure management accounts
for up to 2% of all healthcare expenses.4
The prevalence of heart failure is reaching epi-
demic proportions,5 with 550,000 new cases
diagnosed annually, and as the elderly population
continues to grow, this important public health
problem seems certain to worsen.2,3 A major part
of the patient burden from heart failure results from
morbidity and mortality related to hospitalization
for acute decompensated heart failure (ADHF).
ADHF is emerging as a major public health prob-
lem within the complex heart failure syndrome.
Between 1979 and 2002, heart failure–related
hospital discharges in the United States increased
by 157%.3 By 2002, there were nearly 1 million
hospital discharges for heart failure each year.3 The
syndrome remains deadly despite recent advances
in treatment. The American Heart Association esti-
mates the 1-year mortality from heart failure in the
first year following diagnosis may be as high as
20% and the mortality rate may be even greater
in the months following admission for ADHF.3
Patients with acute or chronic heart failure are often
intensely ill and elderly individuals suffering from
multiple other diseases including diabetes and
chronic renal insufficiency.6 Population-based stud-
ies indicate a mean patient age of approximately
75 years and that the prevalence of heart failure
increases exponentially with every decade of life.2
Between the ages of 55 and 64 years, the preva-
lence rates among US men and women are 5.8%
and 2.3%, respectively.3 In the population aged 75
years or older, the rates are 9.8% and 10.9%, for
men and women, respectively.3 Hypertension, coro-
nary artery disease, diabetes, renal insufficiency,
anemia, chronic obstructive pulmonary disease,
and other comorbid conditions are all common in
patients with chronic and acute heart failure.6,7
Renal insufficiency, in particular, is prolific, especially
among patients with ADHF, and when combined
with the heterogeneous and complex pathophysio-
logy of the syndrome, its presence can make
patient management an intricate clinical challenge.
A number of new therapies are now well estab-
lished in chronic heart failure, with substantial clinical
trial data supporting the chronic use of angiotensin-
converting enzyme (ACE) inhibitors, ␤-blockers,
angiotensin receptor blockers (ARBs), and aldos-
terone antagonists. Prospective clinical studies have
demonstrated symptomatic improvement, as well
as marked reductions in mortality and morbidity,
and efficacy has been established to be additive
for many agents. These studies have led to strong
recommendations from guideline groups favoring
routine application of therapy among patients with
left ventricular systolic dysfunction.
In contrast, most therapies for acute heart failure
have not undergone rigorous evaluation in
prospective randomized trials. Traditionally, agents
have been administered for short periods with the
goal of symptom relief. The evidence for benefit
is based primarily on observational experience.
Extensive and precise data on safety or the
impact of therapy on short- or long-term out-
comes did not seem as necessary as for chronic
therapy. It was assumed that short-term therapy
would not unfavorably influence outcomes during
follow-up, while adverse effects from brief treat-
ment did not seem problematic for most
therapies. As a result, the great majority of
currently available treatment options have not
undergone rigorous safety and efficacy evalua-
tions in the ADHF population at large or in
high-risk subgroups, such as those with concomi-
tant renal dysfunction. However, mounting
evidence suggests that some of the most widely
used in-hospital treatments may have long-term
adverse effects on renal function, underlying dis-
ease, and, possibly, mortality. When making
treatment decisions, clinicians must necessarily
1
SI06 Clinician 9/15/06 11:42 AM Page 2

consider individual patient profiles, the pathophys-
iology of ADHF with and without renal dysfunction,
as well as what is known and, equally important,
unknown about available treatment options.
Pathophysiology. The heart failure syndrome
cannot be easily reduced to any one cause or
pathophysiologic mechanism. It begins with a struc-
tural or functional abnormality in the heart’s pumping
action, often caused by myocardial ischemia or
uncontrolled hypertension.6 The functional defect
may be systolic or diastolic and typically affects
left ventricular function with secondary loss of right
ventricular function. Commonly, left ventricular
dysfunction will ultimately impair total cardiac func-
Table 1
NEUROHORMONAL ADAPTATIONS
IN PATIENTS WITH ADHF10-19
Hormonal Adaptation Effects in Patients With ADHF
RAAS; activation of • Increases preload and afterload
angiotensin II11,12 • Stimulates release of vasoconstrictors
• Contributes to sodium retention
• Promotes inflammation, vascular smooth-
muscle growth, and endothelial dysfunction
SNS activation10,13 • Increases circulating norepinephrine
• Causes vasoconstriction
• Is toxic to cardiomyocytes
• Increases myocardial inotropy,
chronotropy, and hypertrophy
Endothelin-114 • Induces hypertrophy of cardiac myocytes
• Causes vasoconstriction
• Stimulates and potentiates norepinephrine,
angiotensin II, and aldosterone
• May impair renal function
Arginine vasopressin15 • Contributes to fluid retention
• Stimulates myocardial hypertrophy
• Potentiates effects of angiotensin II
and norepinephrine
Inflammatory cytokines • Contribute to negative inotropy,
(TNF-␣, IL-6)11,16-18 remodeling, thrombotic complications
B-type natriuretic peptide19 • Counteracts many of the negative adaptations
• Promotes diuresis
• Inhibits RAAS, endothelin-1,
and other vasoconstrictors
• May increase GFR
• Enhances sodium excretion
ADHF, acute decompensated heart failure; RAAS, renin-angiotensin-aldosterone system;
SNS, sympathetic nervous system; TNF-␣, tumor necrosis factor-alpha; IL-6, interleukin-6;
GFR, glomerular filtration rate.
tion, producing pulmonary edema, peripheral fluid
overload and congestion, and, in advanced heart
failure, organ hypoperfusion and dysfunction.1,8,9
In the presence of structural and functional impair-
ment in ventricular function, the body initiates a
cascade of neurohormonal and cellular maladapta-
tions that collectively induce adverse myocardial
remodeling and fluid and sodium retention
(Table 1).10-19 These maladaptations may initially
compensate for underlying cardiac dysfunction by
maintaining cardiac output, and allow individuals to
continue a reasonable state of hemodynamic stabil-
ity. However, the maladaptive nature of the body’s
response to cardiac dysfunction ultimately results
in progression to heart failure or sudden death,10
which contributes to the transition from dysfunc-
tional but stable (compensated) to dysfunctional
and unstable (decompensated) heart failure.
Acute Decompensated Heart Failure. Recent
work emphasizes the unique pathophysiology of
ADHF within the spectrum of heart failure. ADHF
often punctuates the continuum of chronic heart
failure and is characterized by periods of subacute
or sudden deterioration with significant worsening
of usual symptoms. ADHF is typically character-
ized by the rapid onset of new heart failure
symptoms or worsening of chronic complaints,
such as dyspnea, fatigue, cough, edema, and
weight gain, which often is not accompanied by
a deterioration of intrinsic cardiac function.20
The underlying catalyst for acute decompensation
is multifactorial and still not completely under-
stood. Decompensation may occur in patients
with existing heart failure receiving inadequate
chronic therapy and in those who do not comply
with medication/dietary recommendations; it may
represent a fundamental functional change or the
progression of underlying cardiovascular disease,
or it may be the result of an acute precipitating
event such as a cardiac arrhythmia, myocardial
infarction, pulmonary embolism, infection, or
uncontrolled hypertension.4,21
Although ADHF can present de novo,4 up to 75%
of patients have a pre-existing heart failure diagno-
sis, and one third (33%) of patients have a history
of previous heart failure–related hospital admis-
sions.7 Like the general heart failure population,
patients with ADHF are elderly and severely ill.

2
SI06 Clinician 9/15/06 11:42 AM Page 3
In the ADHERE® (Acute Decompensated Heart
Failure National Registry), a national 275-hospital
registry designed to monitor the characteristics
and treatments of patients with ADHF in the com-
munity, mean age was 72.4 years, the median
length of hospital stay was 4.3 days, and the
overall in-hospital mortality rate was 4.0%, which
escalated to 10.6% among patients who required
admission to the intensive care unit.7 Data from
the European Heart Survey—Acute Heart Failure
registry indicate hospital stays of up to 21 days
and in-hospital and 90-day mortality rates of 7%
and 10%, respectively.22
Patients with ADHF have a high risk of morbidity
and mortality, and there are specific ADHF sub-
groups whose risk may be amplified.23 Similar to
those with chronic heart failure, a number of fac-
tors have been associated with increased mortality
in patients hospitalized with ADHF, including age,
coronary artery disease, and diabetes.6 However,
recent large-scale registry studies have identified
that concomitant renal insufficiency is increasingly
recognized as one of the most important, most
common, and most confounding comorbidities,
not only in chronic heart failure but in ADHF as
well.7,23-25 Its prevalence, association with adverse
outcomes, and possible contributions to disease
progression have led to the hypothesis of a dis-
tinct pathophysiologic condition often referred to
as the cardiorenal syndrome.26-28
The cardiorenal syndrome, discussed in detail
below, necessarily influences therapeutic choices
and may limit the efficacy of currently available
treatment options. The immediate symptomatic
treatment and stabilization needed by patients
with ADHF are most often achieved with diuretics
augmented by intravenous (IV) vasodilators and
natriuretic peptides with inotropes reserved for
more selected cases.4,21,29 Such treatments pro-
vide symptomatic relief and restore hemodynamic
stability; however, they may have unforeseen
negative effects on renal function and out-of-
hospital morbidity and mortality, particularly in
patients with the cardiorenal syndrome.28,30
THE CARDIORENAL SYNDROME
Clinical trials to date evaluating therapeutic strate-
gies in patients with ADHF have limited the
enrollment of, or excluded, patients with renal dys-
function,27 and many of the currently available data
on this population are drawn from community-
based samples such as ADHERE. Registries tend
to enroll a greater proportion of women and may
better reflect the at-large ADHF patient population
in this community than do trials.7,28 Registry patients
with ADHF are typically older and sicker than those
enrolled in clinical trials and appear to have a
greater likelihood of renal dysfunction. Thus, an
expanding body of evidence suggests that ADHF
with concomitant renal dysfunction forms its own
unique and deadly pathophysiologic condition.27
The cardiorenal syndrome has been defined in a
variety of ways and continues to be characterized
by ongoing research. The syndrome has been
defined by some researchers as “moderate or
greater renal dysfunction that exists or develops
in a patient with heart failure (either systolic or
with preserved systolic function) during treatment.
Moderate renal dysfunction is defined, in turn,
as a GFR (glomerular filtration rate) of less than
59 mL/min/m2.”28 During an episode of ADHF,
worsening renal function is common and often
defined as an increase in serum creatinine which
has been variously defined. Some observers have
suggested an increase in concentration of even
0.3 mg/dL may be associated with worse prog-
nosis. There is currently no common agreement
on what degree of change in serum creatinine is
needed for the diagnosis of cardiorenal syndrome
in ADHF. Others describe the cardiorenal syndrome
as “a pathophysiological condition in which com-
bined cardiac and renal dysfunction amplifies
progression of failure of the individual organ to lead
to astounding morbidity and mortality…”26 Much
about the syndrome, including the exact underlying
pathophysiology and treatment strategies, remains
a source of debate.27
Prevalence and Prognosis. Renal dysfunction is
a hallmark comorbidity of ADHF, affecting 30% or
more of the overall ADHF patient population.7,26-28,31
As of January 2004, data on 107,362 patients
enrolled in ADHERE were available for analysis, and
30% of patients (more than 32,000 individuals) had
renal insufficiency by history on presentation.7
Serum creatinine concentrations of more than 2.0
mg/dL were evident in 20% of the population, and
9% had serum creatinine concentrations of more
than 3.0 mg/dL.7 Five percent of patients were
3
SI06 Clinician 9/15/06 11:42 AM Page 4
Table 2
STAGES OF CHRONIC KIDNEY DISEASE33
Stage Description mL/min/1.73 m2
1 Kidney damage with normal
or increased GFR
2 Kidney damage with mildly
decreased GFR
3 Moderately decreased GFR
4 Severely decreased GFR
5 Kidney failure <15 or dialysis
GFR, glomerular filtration rate.
Original source: National Kidney Foundation. Am J Kidney Dis. 2002;39
(2 suppl 1): S1-S266.
Adapted with permission from Sarnak MJ et al. Hypertension.
2003;42:1050-1065.
receiving chronic dialysis at the time of admission.7
The average creatinine concentrations in men and
women were 1.9 and 1.6 mg/dL, respectively.28 The
important association of renal function with in-hos-
pital mortality in ADHF is demonstrated by the
increase in death rate to 9.4% in patients with a
serum creatinine concentration of 3.0 mg/dL or
more—more than double the overall in-hospital
mortality rate.28
Although these results are striking enough, serum
creatinine values underestimate the burden of
renal disease in these elderly patients, many of
whom are women. Fully 60% of patients with
ADHF have moderate to severe renal dysfunction.
When considering the prevalence of renal dys-
function in the ADHF community using estimated
GFR, a powerful predictor of mortality,32 the num-
bers are even more alarming. According to the
National Kidney Foundation’s GFR classifications
(Table 2),33 the majority of patients enrolled in
ADHERE had moderate kidney damage. Renal
dysfunction is common, with 46.8% of women
having severe dysfunction or frank renal failure,
and over 60% of men having at least moderate
kidney damage.28 Indeed, an analysis of 88,075
registry patients based on estimated GFR, found
that more than 95% of patients had at least some
degree of renal dysfunction on presentation.31*
Patients with renal insufficiency tend to be male,
older, are more often diabetic, and are more likely to
have myocardial ischemia and a history of myocar-
4 *,**Contains preliminary data from abstract.31,35
dial infarction than are patients with sufficient renal
function (Table 3).34 In general, those with renal
dysfunction are more severely ill, use more hospi-
tal resources, and have worse outcomes than do
GFR, those who have adequate renal function.23,34,35**
The prognosis of patients with the cardiorenal
≥90 syndrome is bleak. It is difficult to overemphasize
the implications of any degree of renal insuffi-
60-89
ciency in ADHF (as well as chronic heart failure):
30-59
15-29
multiple clinical trials and registries have confirmed
that renal dysfunction—either on presentation or
that worsens during hospitalization—confers a
poor prognosis and substantially increases the
risk of in-hospital, intermediate, and long-term
death.23,26,28,36-38
For example, 2 of the 3 noninvasive measures
found to predict in-hospital mortality drawn from
an ADHERE analysis were reflections of kidney
function: baseline blood urea nitrogen (BUN) levels,
systolic blood pressure (BP), and serum creatinine
concentrations.23 Patients with a BUN less than
43 mg/dL had a crude in-hospital mortality rate of
2.8% versus 8.4% among those above the cut-
point. The risk of death was compounded with
cumulative risk factors; patients with an elevated
BUN and systolic BP of less than 115 mm Hg had
an in-hospital death rate of 15.3% versus 5.6%
among those with an elevated BUN and higher BP.
In patients with an elevated BUN, systolic BP less
than 115 mg Hg, and serum creatinine concentra-
tions 2.75 mg/dL or greater, the death rate
escalated to 19.8% versus 13.2% among those
with better kidney function.23
In the randomized VMAC (Vasodilation in the
Management of Acute Congestive Heart Failure)
trial, baseline renal insufficiency and worsening
in-hospital renal function were associated with an
increased risk of 30-day and 6-month mortality.34
The VMAC study was a 489-patient comparison
of nesiritide (a recombinant version of B-type natri-
uretic peptide [BNP]), nitroglycerin, and placebo
in patients with ADHF. Baseline serum creatinine
values were obtained from 481 patients, and renal
insufficiency on presentation, defined as a serum
creatinine concentration of greater than 1.5 mg/dL,
was present in 45% of patients (n=215).34
At 30 days, there was a trend toward increased
mortality among those with renal insufficiency
SI06 Clinician 9/15/06 11:42 AM Page 5

(8.8% vs 5.3%, P=.149). At 6-month follow-up, unclear from the study, but the investigators
the mortality difference between those with and hypothesized that the reduction in uremic toxins
without renal insufficiency was greater and statisti- resulting from the improved kidney function
cally significant (37.4% vs 12.3%, respectively; reduced cardiac stress.39
P<.0001). Patients with renal insufficiency had
significantly longer hospital stays (10.3 vs 8.2 This adverse influence of the cardiorenal connec-
days, respectively; P=.003) and a 59% higher tion is also reflected in the plight of patients with
rate of readmission within 30 days of discharge kidney disease who develop symptomatic cardiac
(27% vs 17%, respectively; P=.016).34 dysfunction. As renal dysfunction radically wors-
ens the prognosis of patients with heart failure,
Worsening in-hospital renal function—an increase heart failure conversely worsens the prognosis of
of greater than 0.5 mg/dL in serum creatinine con- patients receiving dialysis, decreasing the proba-
centration, which was observed in 119 patients— bility of survival by as much as 50%.39,40 In fact,
also adversely affected prognosis. Patients with even mild degrees of renal dysfunction confer
an in-hospital increase in creatinine concentrations an increased risk of developing heart disease.41
had higher 30-day (9.5% vs 6.1%, respectively; Dialysis does not appear to prevent cardiac
P=not significant [NS]) and 6-month (37.9% vs events or cardiac-related mortality in patients
18.8%, respectively; P<.001) mortality rates than with kidney disease.42
did the 361 patients without an increase. Hospital
stays were significantly longer in these patients
(11.8 vs 8.3 days, respectively; P<.001) and
Table 3
rehospitalization within 30 days of discharge more
likely (26% vs 20%, respectively; P=NS).34 BASELINE CHARACTERISTICS OF PATIENTS WITH ADHF
WITH AND WITHOUT RENAL INSUFFICIENCY 34
Pathophysiology. The potential for changes in
cardiac function to adversely affect renal perfusion Serum Creatinine Serum Creatinine
<1.5 mg/dL ≥1.5 mg/dL
and thus renal filtration are well known and pro- Characteristic (n=266) (n=215) P Value
vide an explanation for some aspects of the
Age, y 59 65 <.0001
cardiorenal syndrome. Speculation continues
Men, % 64 75 <.01
regarding the possibility that reduction in renal
Body surface area (m2) 2.0 1.9 .274
function could, in turn, adversely affect cardiac
function. Although not directly applicable to the Sinus rhythm, % 71 63 .063
cardiorenal syndrome, the potential of an associa- Atrial fibrillation, % 12 12 .136
tion between renal dysfunction and cardiac Diabetes mellitus, % 42 53 .027
dysfunction is supported by a recent study of the NYHA class III and IV, % 80 88 .116
effects of renal transplantation on left ventricular Myocardial ischemia, % 48 59 .029
systolic function. Wali and colleagues evaluated LVEF, % 27 27 .904
the effects of kidney or kidney/pancreas transplan- Coronary artery disease, % 61 71 .034
tation in 138 patients with end-stage renal disease Systemic hypertension, % 68 73 .230
(ESRD), left ventricular ejection fraction (LVEF) of Automatic implantable cardiac
40% or less, and diagnosed heart failure.39 At defibrillator/pacemaker, % 20 30 .014
mean 6.6 months posttransplantation, mean LVEF Previous MI, % 41 53 .008
had increased from 32% at baseline to 47%, and Coronary bypass or angioplasty, % 32 44 .010
to 52% at mean 12.5-month follow-up. Mean right atrial pressure, mm Hg* 14 16 <.05
The vast majority of patients (>86%) had an Mean PCWP, mm Hg* 27 28 .280
improvement in LVEF of more than 5%. At Cardiac index, L/min/m * 2
2.2 2.2 .993
long-term follow-up (mean, 36.8 months), 73% of
*In patients who underwent hemodynamic monitoring.
patients were New York Heart Association (NYHA) ADHF, acute decompensated heart failure; NYHA, New York Heart Association; LVEF, left ven-
class I.39 At baseline, 58% were NYHA class IV. tricular ejection fraction; MI, myocardial infarction; PCWP, pulmonary capillary wedge pressure.
Why such dramatic improvements should occur Adapted with permission from Akhter MW et al. Am J Cardiol. 2004;94:957-960.

in patients following kidney transplantation is

5
SI06 Clinician 9/15/06 11:42 AM Page 6

Research into the pathophysiology of the car-
diorenal syndrome has not fully established the
key mechanism operative in this syndrome, but
experimental evidence does provide a more
compelling argument linking renal dysfunction to
cardiac dysfunction by indicating a connection
Figure 1
NEUROHORMONAL CARDIORENAL CONNECTORS26
between neurohormonal activation and cardiac
and renal dysfunction. The neurohormonal and
sympathetic nervous system (SNS) maladapta-
tions that occur with cardiac dysfunction also
occur during periods of suboptimal renal function
(Figure 1).26 Renal dysfunction induces inappropri-
ate activation of the renin-angiotensin-aldosterone
system (RAAS), causing vasoconstriction and fluid
and sodium retention. The RAAS, in turn, acti-
vates the nicotinamide adenine dinucleotide
phosphate–oxidase pathway, resulting in the
excess formation of reactive oxygen species
(ROS).26 Excessive ROS production results in a
nitric oxide (NO)—ROS imbalance that decreases
antioxidants and NO, increases oxidative stress
on both organs, and, ultimately, activates proin-
flammatory cytokines such as interleukin (IL)-1,
IL-6, C reactive protein, and tumor necrosis
factor-␣, which may have negative effects on
inotropy and may cause cardiac remodeling and
worsen atherosclerosis.11,16-18,26 Finally, SNS activity
increases, a phenomenon associated with vaso-
constriction, cardiomyocyte necrosis, and
increased myocardial inotropy, chronotropy,
and hypertrophy.10,13

Such a neurohormonal milieu is evident in patients

identified with the cardiorenal syndrome. A recent
analysis of 48 patients with ADHF with renal dys-
function described a unique neurohormonal profile
that included elevated plasma renin activity,
elevated concentrations of angiotensin II and
aldosterone, and decreased levels of natriuretic
peptides,43* including BNP, which counteracts and
inhibits maladaptive effects of various neurohor-
mones (Table 4).19,43

Cardiac dysfunction and renal dysfunction may

intensify and recede in tandem. Although this
pathophysiologic link has yet to be fully confirmed,27
(A) Angiotensin II affects the other cardiorenal connectors: SNS activation in kidney failure,
generation of ROS, and NF-␬B–mediated proinflammatory gene expression. (B) Imbalance it appears that dysfunction in one organ system is
between NO and ROS is a central event in cardiovascular diseases. In the cardiorenal con- associated with dysfunction in the other.
nection, this balance may influence sympathetic nervous activity, result in release of renin
and angiotensin, and promote inflammation by oxidative modification of substances. (C)
Persistent inflammation has been found in both renal and heart failure. By altering ROS
functioning and promoting ROS and NA formation, inflammation contributes to the positive
IN-HOSPITAL ADHF TREATMENT OPTIONS
feedback loops in the cardiorenal connection. (D) Sympathetic nervous activity is increased AND CARDIORENAL CONSIDERATIONS
in both renal and heart failure. By affecting the other cardiorenal connectors, it can play a
significant role in severe cardiorenal syndrome. It stimulates renin release from the kidneys, Multiple intravenous drugs are now used for the
generates ROS, and induces inflammation. management of patients with ADHF with and
SNS, sympathetic nervous system; ROS, reactive oxygen species; NADPH, nicotinamide
adenine dinucleotide phosphate; NF-␬B, nuclear factor kappa B; NO, nitric oxide; NA, without renal dysfunction (see insert “Currently
noradrenaline; NPY, neuropeptide Y. Used In-Hospital Treatments for the Management
Adapted with permission from Bongartz LG et al. Eur Heart J. 2005;26:11-17. of Acute Decompensated Heart Failure”). Primarily,
these drugs provide symptomatic relief by pro-

6 *Preliminary data from abstract.

SI06 Clinician Correx 10/12/06 3:27 PM Page 7

moting vasodilation and diuresis, which restores

normal hemodynamics, reduces congestion, and Table 4
alleviates dyspnea—one of the main presenting NEUROHORMONAL CHARACTERISTICS OF PATIENTS
ADHF symptoms 30,44 (Table 5 4,45-62)*. However, WITH ADHF WITH THE CARDIORENAL SYNDROME43
some of the most commonly used drugs were
No Cardiorenal Cardiorenal
not developed for an ADHF indication, and their Syndrome* Syndrome*
use is largely empiric.30 As the evidence base for (n=39) (n=9) P Value
the management of ADHF continues to increase Admission creatinine clearance,
and the importance of cardiorenal dysfunction mL/min/1.73 m2 43 ± 15 45 ± 10 .66
begins to emerge, the renal safety of these drugs Systolic blood pressure, mm Hg 130 ± 30 126 ± 23 .65
and their effect on morbidity and mortality have Mean arterial pressure, mm Hg 89 ± 18 79 ± 9 .02
Creatinine, mg/dL -0.02 ± 0.17 0.59 ± 0.30 .0002
come under increasing scrutiny. Obviously, drugs
BL Shionogi† BNP, pg/mL 623 ± 499 312 ± 142 .002
that impair renal function are undesirable, particu-
BL ANP, pg/mL 320 ± 410 116 ± 100 .008
larly in a population with already compromised or
BL NT-proBNP, pg/mL 10,446 ± 10,391 4298 ± 2760 .002
“at-risk” renal function.
BL plasma renin activity,
ng/mL/h 8.3 ± 9.9 23.5 ± 11.8 .004
There is no single, success-guaranteed treatment
BL aldosterone, ng/dL 14 ± 18 32 ± 43 .16
for ADHF. Each patient has a unique medical his-
BL angiotensin II, pg/mL 6.7 ± 7.9 16.0 ± 22.8 .15
tory, combination of comorbidities, risk profile, and 48-hour plasma renin activity,
presentation. Likewise, each treatment option has ng/mL/h 8.3 ± 9.9 23.5 ± 11.8 .004
its own unique cardiorenal safety and efficacy 48-hour angiotensin II, pg/mL 6.0 ± 7.3 27.3 ± 35.2 .009
profile. In the absence of definitive clinical trials, ⌬ weight in 48 hours, kg -3.0 ± 2.8 -0.7 ± 1.5 .003
treatment decisions must be based on a combi-
*Mean ± SD.
nation of individual patient information and an †
Bedside assay for measuring BNP.
understanding of individual treatment options. ADHF, acute decompensated heart failure; ANP, atrial natriuretic peptide; BL, baseline; BNP,
B-type natriuretic peptide; NT, N-terminal; SD, standard deviation.
Treatment must be patient specific, since even
Adapted with permission from Redfield MM et al. Presented at: Heart Failure Society of
drugs within the same class may differently affect America 9th Annual Scientific Sessions; October 20, 2005; Boca Raton, Fla. Abstract 062.
patient outcome.

Table 5
HEMODYNAMIC BENEFITS OF VASOACTIVE AND VASODILATOR AGENTS IN PATIENTS WITH ADHF 4,45-62

PCWP RAP BP PVR SVR CI

Inotropic agents Milrinone Î 4
Î 45
Î 4
Î 4
Î 45
Ï 46

Dobutamine Ï
Î≠ 4
n/a Î 47
ÏÎ≠ 4
Î 4
Ï 46

Dopamine Ï 48
n/a Ï *4,46
Ï *4,46
Ï *4,46
Ï *4,46

Levosimendan Î 4
n/a Î 4
Î 4
Î 4
Ï 4

Toborinone Î 49
Î 50
≠ 51
≠ 50
≠ 50
Ï 49

Vasodilators Nitroglycerin, isosorbide

dinitrate Î 52,53
Î 4,52
Î 52,54
Î 4,52
Î 4,46,52
Ï 52

Nitroprusside Î 55
n/a Î 46
n/a Î 4
Ï 46,56

ACE inhibitors Î 57
n/a Î 57
n/a n/a ≠ 57

Natriuretic peptides Nesiritide Î 57

Î 52
Î 52
Î 52
Î 52
Ï 52

Ularitide Î 58
n/a ≠
59
n/a Î 59
Ï 59

Caperitide Î 60-62
Î 60-62
n/a n/a ≠ 60-62
≠ 60-62

*Increases are dose dependent.

Ï, increase; Î, decrease; ≠, no effect.
ADHF, acute decompensated heart failure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; BP, blood pressure; PVR, pulmonary vascular
resistance; SVR, systemic vascular resistance; CI, cardiac index; n/a, not available; ACE, angiotensin-converting enzyme.

*Contain preliminary data from abstracts.58,59 7

SI06 Clinician 9/15/06 11:42 AM Page 8
Diuretics. Despite the absence of large-scale,
randomized, double-blind trials evaluating the
safety and efficacy of diuretics in ADHF and
chronic heart failure, these drugs have long
been considered an essential part of patient
management.46 Use of these agents is ubiquitous
throughout the community, and they remain the
first line of therapy for the great majority of
patients with ADHF. Their importance is illustrated
by data from ADHERE, which revealed that 80.8%
of patients enrolled in this registry were on chronic
diuretic therapy at the time of presentation, and
88% were treated acutely with an IV diuretic
during their admission for ADHF.63* The different
types of diuretics—loop, thiazide, and potassium
sparing—can begin producing rapid diuresis and
natriuresis as quickly as 20 minutes after adminis-
tration.46 This class is supported by practice
guidelines for the reduction of volume overload
in patients with ADHF with symptomatic conges-
tion 4,29 (see insert “Currently Used In-Hospital
Figure 2
SURVIVAL AMONG DIURETIC-TREATED PATIENTS
WITH HEART FAILURE PRIOR TO DECOMPENSATION72
100
90
80
70
60
50
40
30
20
10
0 5 10 15 20 25
Retrospective analysis found that chronic diuretic therapy prior to decompensation
increases incidence of death in a dose-dependent manner. The Kaplan-Meier curve
shows cumulative survival estimates of all-cause mortality at late follow-up among
patients who received no outpatient diuretic therapy (group I), those who received
low-dose outpatient diuretic therapy (<80 mg/d of furosemide) (group II), and those
who received high-dose diuretic therapy (≥80 mg/d of furosemide or the equivalent of
another diuretic) (group III). Group III vs group I: P=.01; group II vs group I: P=.13;
group III vs group II: P=.21.
Adapted with permission from Harjai KJ et al. Int J Cardiol. 1999;71:219-225.
8 *Contains preliminary data from abstract.63,64
Treatments for the Management of Acute
Decompensated Heart Failure”).
Although diuretics are effective at producing short-
term symptomatic relief, there is long-standing
and increasing evidence indicating that they exac-
erbate neurohumoral activity and renal dysfunction
and possibly worsen heart failure outcomes.35,64-70*
In a series of recent studies looking specifically at
patients with ADHF, diuretic therapy was associ-
ated with increases in neurohormonal activity65
and worsening renal function measured by
increases in creatinine concentrations and declin-
ing GFR,35,64,68,69 both of which are established risk
factors for death.23,26,28,36-38 Patients with ADHF who
suffer diuretic-associated renal impairment tend to
be older and have a lower baseline creatinine
clearance at admission than those who do not.69
To date, studies of diuretic therapy in acute heart
failure have not been conducted to assess the
relationship, if any, of maladaptive neurohormonal
activities (such as in the RAAS and SNS) to short-
and long-term outcomes of patients hospitalized
with acute heart failure. In chronic heart failure
studies, diuretic use has been associated with
deterioration in renal function 67,71 and left ventricular
function and increases in systemic vascular
resistance, plasma renin activity, and plasma
levels of maladaptive neurohormones such as
norepinephrine and arginine vasopressin.70
Retrospective analysis suggests that chronic
diuretic therapy prior to decompensation increases
the incidence of death in a dose-dependent
manner (Figure 2).72 Diuretic resistance is also a
common phenomenon in heart failure and associ-
ated with a poor prognosis.4,73 In patients with
acute renal failure, diuretics appear to increase the
risk of mortality,74 and a recent study hypothesized
30
that diuretic use is contributing to the growing
prevalence of ESRD in the United States.75
Despite widespread use and empiric evidence
demonstrating the ability of diuretics to rapidly
reduce fluid congestion, the acute and chronic
findings outlined above raise the possibility that
diuretics may produce symptomatic relief at the
expense of long-term deleterious cardiovascular
effects. Even more importantly, data are very lim-
ited concerning the duration, proper dose, and
method of administration for diuretic therapy.
SI06 Clinician 9/15/06 11:42 AM Page 9
Properly powered and designed trials are needed
to determine the best strategy for the application
of diuretics in the management of ADHF, particu-
larly among the high-risk subgroup of patients
with concomitant renal dysfunction.
Inotropic Agents. Decreased contractile function
is well recognized as the essential aspect and
foundation of the heart failure syndrome. The cen-
tral role of contractile dysfunction has always made
the concept of pharmacologic agents that aug-
ment cardiac systolic function attractive.76
However, despite the development of multiple
inotropic agents and extensive clinical research,
the results of randomized trials and observational
studies have been largely negative and consistently
disappointing for specific inotropic agents, includ-
ing those used to treat acute heart failure.76 In both
acute and chronic heart failure, inotropic drugs,
when compared with placebo and vasodilators,
have been associated with an increased risk of
mortality and other adverse cardiac events.24,76-82*
Milrinone, dobutamine, and dopamine are guide-
line recommended for the management of
low-output ADHF,4,29 which is characterized by the
presence of peripheral hypoperfusion and may or
may not be accompanied by congestion4 (see
insert “Currently Used In-Hospital Treatments for
the Management of Acute Decompensated Heart
Failure”). As a class, inotropic agents cause an
increase in cardiac contractility, thereby raising
cardiac output and increasing cerebral blood
flow.46,76 Each of the agents produces effects that
may relieve ADHF symptoms when low output is
present, while increased diuresis and improved
renal perfusion have also been noted.4 However,
these actions are accompanied by a series of
other effects inherently coupled with positive
inotropy, such as increased heart rate and
myocardial oxygen consumption, proarrhythmia,
and myocardial necrosis, raising considerable
concerns about the safety of this therapy at the
molecular and cellular level.4,46
These worrisome experimental findings have been
seen in the few clinical trials reported to date with
positive inotropic drugs in ADHF. The OPTIME-CHF
(Outcomes of a Prospective Trial of Intravenous
Milrinone for Exacerbations of Chronic Heart Failure)
is considered one of the pivotal studies of inotropic
*Contains preliminary data from abstract.79
management of ADHF.80 This landmark randomized
trial compared milrinone with placebo in 951
severely ill patients with ADHF: at baseline, 92%
were NYHA class III or IV, had a mean LVEF of
23%, and had a mean age of 65 years.
The primary endpoint of the trial was the number
of days hospitalized for cardiovascular causes
within 60 days of randomization. Milrinone-treated
patients spent 6 days in-hospital versus 7 days
for placebo-treated patients, a nonsignificant
difference. There was no difference in in-hospital
or 60-day mortality between treatments or in the
incidence of the composite endpoint of death or
readmission. Milrinone use was associated with
more adverse events, including significantly more
in-hospital atrial fibrillation and symptomatic
hypotension (Table 6, page 12).80 Thus, despite
the use of doses sufficient to produce favorable
hemodynamic effects, no benefit was noted on
symptoms or morbidity, and the proportion of
adverse events was substantially increased.
Studies comparing other inotropic agents with
vasoactive agents have reported similar findings.79,81
In the PRECEDENT (Prospective Randomized
Evaluation of Cardiac Ectopy With Dobutamine or
Natrecor Therapy) study, dobutamine was com-
pared with nesiritide in 255 patients with ADHF
and was associated with significant increases in the
mean number of episodes of ventricular tachycardia
within 24 hours of treatment (P=.001), repetitive
ventricular beats per hour (P=.001), premature
ventricular beats per hour (P=.006), and heart
rate (P<.001).81
Inotropic agents have also been associated with
increased mortality compared with vasodilator ther-
apy in nonrandomized studies.24,79 Observational
data on the in-hospital mortality of inotropic agents
compared with these data on vasodilators from
ADHERE are consistent with the findings and
concerns raised by other clinical studies. Crude
in-hospital mortality rates in ADHERE among
dobutamine- and milrinone-treated patients were
13.9% and 12.3%, respectively, whereas nitro-
glycerin and nesiritide were associated with rates
of 4.7% and 7.1%, respectively.24 Importantly,
even after extensive multivariate adjustment and
propensity matching to help eliminate the concern
that patients treated with inotropic agents were
9
SI06 Clinician 10/12/06 9:39 AM Page 10
COMMENTARY: RENAL FUNCTION AND MORTALITY IN NESIRITIDE-TREATED PATIENTS
The findings of Sackner-Bernstein and colleagues have
generated considerable controversy, since a number of
previous studies have reported either neutral or favorable
effects of nesiritide on renal function.1-8 Indeed, in addition to
the meta-analysis indicating worsening levels,9 nesiritide is
reported to improve8 and/or have no effect on serum creati-
nine concentrations.6 Renal benefits, such as increased
perfusion,4 diuresis, sodium excretion,6,10 and improved
GFR, have been attributed to nesiritide,10 with other studies
reporting decreased bilirubin levels,8 increased urinary vol-
umes,6 and improved BUN levels.3
Careful consideration of the renal meta-analysis and additional
data from the nesiritide clinical database may help clinicians
better understand the effects of this drug on renal function.
Several possible explanations for the conflicting evidence con-
cerning the risk of renal impairment related to nesiritide in these
various analyses must be explored. First, given the potential
implications of the meta-analysis, consideration of its method-
ology is warranted. An important limitation of this analysis
concerns the limited amount of renal data available to the
authors. Analysis of the general relationship of renal function to
drug effect requires repeated measurement of some estimate
of renal function, such as creatinine; however, not a single cut-
point for creatinine change was addressed during the study.
This type of data collection was conducted in the VMAC study,
and a recent analysis demonstrated no difference in
serial serum creatinine measurements conducted at weekly
intervals for 4 weeks between nesiritide- and nitroglycerin-
treated patients over a 30-day period.1
As the authors acknowledge, meta-analyses are inherently lim-
ited because of an inability to analyze patient-level data and
adjust for baseline characteristics.9,11 This is an important
consideration, as the meta-analysis pooled heterogenous
ADHF populations treated with multiple outcome-influencing
medications in addition to nesiritide. The diversity across the
REFERENCES
1. Butler J, Emerman C, Peacock WF, Mathur VS, Young JB, for the VMAC
Study Investigators. The efficacy and safety of B-type natriuretic peptide
(nesiritide) in patients with renal insufficiency and acutely decompensated
congestive heart failure. Nephrol Dial Transplant. 2004;19:391-399.
2. Burger AJ. Clinical predictors of worsening renal function in patients
hospitalized for heart failure. Presented at: Heart Failure Society of America
9th Annual Scientific Sessions; October 19, 2005; Boca Raton, Fla. Abstract
345.
3. Riter HG, Redfield MM, Burnett JC Jr, Chen HH. The effects of low dose
nesiritide with low dose furosemide on renal function in patients with acute
decompensated heart failure and renal dysfunction. Presented at: Heart
Failure Society of America 9th Annual Scientific Sessions; October 19, 2005;
Boca Raton, Fla. Abstract 251.
4. Akhter MW, Singh H, Bourji N, et al. Effects of intravenous nesiritide on renal
hemodynamics in patients with congestive heart failure. Circulation.
2004;110(suppl III):III-556. Abstract.
10
trials may have confounded results. For example, the impact
of concomitant medication use has been demonstrated in at
least one of the trials.12 Following this line of reasoning, recent
analysis of the VMAC database found that neither treatment
with nesiritide nor nitroglycerin were independent predictors of
worsening in-hospital renal function after adjustment for multi-
ple baseline clinical characteristics.2 This null effect of nesiritide
on renal function has been reported in other studies as well.5
Subgroup analysis of the VMAC trial found that renal dysfunc-
tion did not compromise the ability of nesiritide to improve
hemodynamics in ADHF. Nesiritide-treated patients with renal
insufficiency on presentation (serum creatinine >2.0 mg/dL)
had hemodynamic improvements comparable to those pro-
duced in patients with adequate renal function, and renal
function did not worsen with treatment.1
Acknowledging the limitations of the current analyses con-
cerning the renal effects of nesiritide, the data suggest
several factors that are potentially important as modulators
of renal function in patients treated with nesiritide. In VMAC,
increases in serum creatinine concentration to above
0.5 mg/dL among nesiritide-treated patients were associ-
ated with concomitant use of high dosages of diuretics,12 an
observation that may escape detection in the meta-analysis
model. Additionally, the potential dose-dependent effect of
nesiritide on this marker of renal dysfunction is not well
reflected in the Sackner-Bernstein meta-analysis, which
pooled data on nesiritide infusions ranging from 0.015
mcg/kg/min or less to 0.06 mcg/kg/min.13 Upon closer
review of the meta-analysis, only 204 patients included in
the study (from the VMAC trial) received the FDA-approved
dosing regimen (2-mcg/kg bolus plus 0.01 mcg/kg/min infu-
sion).14 Others received dosages that were as much as
0.5-fold to 6-fold higher than that recommended in the cur-
rent prescribing guidelines.15 A recent analysis of the
nesiritide clinical database demonstrated a dose-response
5. Wang DJ, Dowling TC, Meadows D, et al. Nesiritide does not improve renal
function in patients with chronic heart failure and worsening serum creati-
nine. Circulation. 2004;110:1620-1625.
6. Marcus LS, Hart D, Packer M, et al. Hemodynamic and renal excretory effects
of human brain natriuretic peptide infusion in patients with congestive heart
failure: a double-blind, placebo-controlled, randomized crossover trial.
Circulation. 1996;94:3184-3189.
7. Heywood JT. Temporal characteristics of serum creatinine elevations in
patients receiving nesiritide and nitroglycerin. Presented at: Heart Failure
Society of America 9th Annual Scientific Sessions; October 20, 2005;
Boca Raton, Fla. Abstract 255.
8. Zakir RM, Patel RJ, Saric M, Berkowitz RL. Nesiritide is effective for patients
with diastolic dysfunction with and without associated right ventricular failure
and significantly improves renal function. Presented at: Heart Failure Society
of America 9th Annual Scientific Sessions; October 19, 2005; Boca Raton,
Fla. Abstract 395.
SI06 Clinician 10/12/06 9:39 AM Page 11
relationship for worsening renal function with no significant
effect noted at the currently recommended dose, but with
evidence of significant risk of worsening renal function at
higher doses.
Although careful review of the meta-analysis and other data
suggests that there is no convincing evidence for a detri-
mental effect of nesiritide on renal function when initiated at
the currently recommended dose, the possibility of other
explanations for nesiritide-induced increases in serum
creatinine concentrations cannot be fully excluded, and may
include direct nephrotoxicity or an as-yet undiscovered
neurohormonal pathway.
The clinical implications of drug-induced changes in serum
creatinine concentrations also has not been well estab-
lished, and it is unclear what impact, if any, the increases,
determined using an arbitrary cutpoint, have on mortality.11
For example, life-saving agents like ACE inhibitors often
have a modest adverse effect on renal function similar to the
0.5-mg/dL increase in serum creatinine concentrations
observed with nesiritide, but have very-well-documented
beneficial effects on outcomes in chronic heart failure. As
the authors point out, the only way to determine the true
association between renal function and nesiritide use and
the clinical implication of any possible increases in serum
creatinine concentrations is with properly designed and
powered studies to assess these endpoints.9
Like the renal safety data, the mortality data concerning
nesiritide are also difficult to analyze and interpret into a
consistent pattern. The conflicting nature of various analy-
ses to date is not unexpected since there are no adequately
powered and prospective studies on important clinical out-
comes to provide definitive results. In fact, much of the
controversy16 does seem reducible to the absence of large-
scale, prospective randomized mortality and morbidity trial
data. The difficulties related to current data analysis are evi-
dent when the results of another recent meta-analysis are
9. Sackner-Bernstein JD, Skopicki H, Aaronson KD. Risk of worsening renal
function with nesiritide in patients with acute decompensated heart failure.
Circulation. 2005;111:1487-1491.
10. Bhalla V, Willis S, Maisel AS. B-type natriuretic peptide: the level and the
drug-partners in the diagnosis and management of congestive heart failure.
Congest Heart Fail. 2004;10(suppl 1):S3-S27.
11. Teerlink J, Massie BM. Nesiritide and worsening of renal function: the
emperor’s new clothes? Circulation. 2005;111:1459-1461.
12. Heywood JT. Combining nesiritide with high-dose diuretics may increase the
risk of increased serum creatinine. Presented at: Heart Failure Society of
America 9th Annual Scientific Sessions; October 19, 2005; Boca Raton, Fla.
Abstract 240.
13. Sackner-Bernstein JD, Skopicki H, Aaronson KD. Is nesiritide associated
with renal injury in patients with acutely decompensated heart failure?
Circulation. 2004;110(supp III):III-115. Abstract 2413.
considered. This study compared the 30-day mortality rates
of 485 nesiritide-treated patients with ADHF with those of
377 patients randomized to control therapy in 3 double-
blind trials.17 In the analysis, 30-day mortality with nesiritide
was 7.2% versus 4.0% among control patients (P=.059).
The authors of the meta-analysis concluded that nesiritide
may be associated with an increased risk of death.
However, there are several aspects of this meta-analysis
that suggest it may not give an accurate picture of the
effects of nesiritide on mortality in ADHF. First, not all
studies with 30-day mortality data were considered in the
meta-analysis. A pooled analysis of 30-day mortality using
results from all 6 nesiritide trials that evaluated this outcome
measure in patients with ADHF yields a different result.
In these trials, 30-day mortality was 5.9% with nesiritide
compared with 4.4% among controls, a nonsignificant
difference. When results from all 7 nesiritide trials with
30-day mortality data were analyzed, the rates were
5.3% with nesiritide versus 4.3% with controls, a nonsignif-
icant difference. Although a recently published research
letter in JAMA reached a different conclusion and sug-
gested that there was “an association between nesiritide
and increased risk of death within 30 days of use. . .”18 it
should be noted that many of the deaths in the PROAC-
TION study were noncardiac.
As acknowledged by the study authors and common to all
meta-analyses, these studies were unable to control for
baseline patient characteristics and included trials with het-
erogeneous patient populations, nesiritide dosing regimens,
and adjunctive and control treatments. Inotropic therapy,
which is known to increase mortality risk, was used more fre-
quently in nesiritide-treated patients than in control patients
in the 3 trials and may have confounded results.19
Importantly, none of the trials included was powered or
designed to assess mortality as a primary or secondary end-
point.
14. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs
nitroglycerin for treatment of decompensated congestive heart failure: a ran-
domized controlled trial. JAMA. 2002;287:1531-1540.
15. Natrecor® (nesiritide) prescribing information. Freemont, Calif: Scios Inc;
April 2005. Available at: http://www.sciosinc.com/pdf/natrecorpi_final.pdf.
Accessed May 25, 2005.
16. Topol EJ. Nesiritide - not verified. N Engl J Med. 2005;353:113-116.
17. Aaronson K, Sackner-Bernstein JD, Kowalski M, Fox M. Short-term risk
of death after treatment with nesiritide for decompensated heart failure:
a pooled analysis of randomized controlled trials. JAMA.
2005;293:1900-1905.
18. Aaronson KD, Sackner-Bernstein JD. Risk of death associated with nesiritide in
patients with acutely decompensated heart failure. JAMA. 2006;296:1465-1466.
19. Abraham WT. Nesiritide and mortality risk: individual and pooled analyses of
randomized controlled trials. Prev Cardiovasc Med. 2005;6:2.
11
SI06 Clinician 9/15/06 11:42 AM Page 12

with ADHF with an ejection fraction of 35% or less

Table 6 and dyspnea at rest who were unresponsive to IV
MAIN RESULTS OF THE OPTIME-CHF TRIAL80 diuretic therapy were randomized to a 24-hour
infusion of levosimendan or placebo. The primary
Placebo Milrinone endpoint of the trial was a composite measuring
Outcome (n=472) (n=477) P Value
improvement or worsening of patient status by
Hospitalization for cardiac causes evaluating changes in symptoms, worsening heart
within 60 days, d 7 6 .71
failure, and mortality over a 5-day period. Using
In-hospital mortality,% 2.3 3.8 .19
these criteria, levosimendan appeared beneficial.
60-day mortality, % 8.9 10.3 .41
Death or readmission, % 35.3 35.0 .92
At day 5, moderate or marked improvement in
In-hospital adverse events, %
patient global assessment was reported in 76% of
MI 0.4 1.5 .18
levosimendan-treated patients versus 65% in the
New atrial fibrillation or flutter 1.5 4.6 .004
placebo arm (P=.001); however, a propensity
Ventricular tachycardia or fibrillation 1.5 3.4 .06
toward increased adverse events similar to those
Sustained hypotension 3.2 10.7 <.001 seen with other inotropic agents was noted with
60-day adverse events, % levosimendan during the treatment period, includ-
MI 1.1 2.2 .21 ing more frequent hypotension and increased risk
New atrial fibrillation or flutter 3.6 5.6 .14 of ventricular arrhythmia. Although the trial was
Ventricular tachycardia or fibrillation 4.5 5.0 .72 not designed with the power to assess mortality,
the secondary endpoint of 90-day all-cause mor-
OPTIME-CHF, Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of tality was 15.1% in the levosimendan-treated
Chronic Heart Failure; MI, myocardial infarction.
Adapted with permission from Cuffe MS et al. JAMA. 2002;287:1541-1547.
patients and 11.6% in the control group.86

The symptomatic benefits observed in the

simply sicker, these drugs continued to be associ-
ated with an increased risk of death compared
with that of vasodilators, whereas there was no
difference in risk between the vasodilators studied
(nitroglycerin and nesiritide) (Table 7).24
Despite a history of negative findings, the develop-
ment of new inotropic agents—levosimendan and
toborinone—specifically designed for an ADHF
indication was undertaken. Ultimately, develop-
ment of toborinone was suspended because of
a general concern about the safety of agents with
positive inotropic effects mediated by cardiac
phosphodiesterase inhibition. Levosimendan,
on the other hand, has long been used in Europe,
and its development continues.
Preliminary levosimendan studies indicated that
this agent increases cardiac output and stroke
volume, decreases pulmonary capillary wedge
pressure (PCWP), and, in general, improves
hemodynamics.49,50,83-85 The clinical benefits of
levosimendan were investigated in the recently
reported REVIVE-2 (Randomized Evaluations of
Levosimendan) trial.86 In this study, 600 patients
REVIVE-2 trial, however, did not translate into
improved survival in the SURVIVE (Survival of
Patients With Acute Heart Failure in Need of
Intravenous Inotropic Support) trial when
levosimendan was compared with dobutamine.87*
This study randomized 1327 patients with ADHF
requiring hospitalization to IV medication treatment
with levosimendan or dobutamine. Additional
medications, such as IV diuretics and vasodila-
tors, were allowed. The primary endpoint of
180-day mortality was 26% in the levosimendan
group versus 28% in the dobutamine group
(P=.401). The secondary endpoint of 31-day
death was reached by 12% of levosimendan-
treated patients and 14% of dobutamine-treated
patients, also nonsignificant. Hypoperfusion was
more common with levosimendan than with dobu-
tamine (16% vs 14%, respectively), as was the
incidence of atrial fibrillation (9% vs 6%) and ven-
tricular tachycardia (8% vs 7%). However, fewer
levosimendan-treated patients suffered cardiac
failure (12% vs 17%, respectively), but none of
these differences achieved statistical significance.
Given the data from the SURVIVE trial, it appears
that although short-term hemodynamic benefits
may be obtained with levosimendan, these bene-

12 *Contains preliminary data from abstract.

SI06 Clinician 9/15/06 11:42 AM Page 13

fits are accompanied by an increase in adverse
events similar to those observed with other
inotropic therapies, and currently do not translate
into improved survival when compared with stan-
dard inotropic therapy (dobutamine). Further
studies may be warranted to fully elucidate the
safety and therapeutic benefit of this agent.87
Unlike diuretic therapy, inotropic therapy may actu-
ally impart renal benefits or at least does not harm
renal function in the absence of hypotension.
Dopamine and dobutamine are reported to increase
urine flow, creatinine clearance, sodium excretion,
diuresis, GFR, and renal plasma flow in critically ill
patients,4,88-92 whereas milrinone, an inotrope with
vasodilator properties, appears to have a neutral
effect on renal function, although data are limited.93,94
Finally, there is no specific evidence of renal benefit
in patients with ADHF and the cardiorenal syndrome
in the absence of severe low cardiac output.82
Because of the increasing evidence base indicat-
ing an association between inotropic therapy and
death and because of the uncertain renal benefits,
the use of inotropes in the routine management of
ADHF appears to be on the decline.95 In ADHERE,
dobutamine and dopamine were each given to 6%
of patients, and milrinone to 3%.63 Until more data
are available, inotropic therapy should be reserved
for patients with clinical evidence of severe low
cardiac output in whom vasodilator therapy is not
possible because of reduced systemic pressure or
low systemic vascular resistance. Such patients
appear to be very uncommon in ADHF, as is sug-
gested by ADHERE findings.29,76
Vasodilators. Traditional IV vasodilators such as
nitroglycerin, nitroprusside, and isosorbide dini-
trate are important adjuncts in the management
of ADHF. Recent European guidelines recommend
vasodilators be used as first-line therapy in most
patients with ADHF presenting with volume over-
load and adequate BP.4 In general, vasodilators
reduce systemic vascular resistance, which facili-
tates forward blood flow, improves cardiac output,
and produces reliable, predictable, and sustained
reductions in preload and afterload volumes 46
(see insert “Currently Used In-Hospital Treatments

Table 7
MORTALITY ODDS RATIOS IN PAIRWISE TREATMENT COMPARISONS24

NTG (n=6055) NTG (n=5713) NES (n=4663) NES (n=4270) NES (n=4402) DOB (n=3656)
vs vs vs vs vs vs
Analysis* MIL (n=1660) DOB (n=3478) MIL (n=1534) DOB (n=3301) NTG (n=5668) MIL (n=1496)
Unadjusted 0.34 0.24 0.53 0.37 1.64 1.39
(0.28-0.41)† (0.20-0.28)† (0.44-0.64)† (0.32-0.44)† (1.38-1.94)† (1.15-1.68)†
Adjusted for covariates 0.69 0.46 0.59 0.47 0.95 1.27
(0.54-0.88)† (0.38-0.57)† (0.48-0.73)† (0.39-0.56)† (0.78-1.16)‡ (1.04-1.56)§
Adjusted for covariatesII 0.69 0.46 0.59 0.47 0.94 1.24
and propensity score†† (0.53-0.89)† (0.37-0.57)† (0.48-0.73)† (0.39-0.56)† (0.77-1.16)‡ (1.03-1.55)§

Hosmer-Lemeshow goodness-of-fit test not significant at 5% levels for the models adjusted for risk factors and/or propensity, except for covariate-adjusted NTG
vs DOB comparison, where P=.04. Area under the receiver operator curve =0.70 or higher. Because of multiple pairwise comparisons, only P values <.008 were
considered significant using Bonferroni correction.
*Patients taking both medications were excluded from each pairwise analysis.
†
P <.005.
‡
P =.58.
§
P =.021 for covariate adjustment and P=.027 for covariate and propensity score adjustment.
II
Covariates include age, gender, SBP, DBP, BUN, creatinine, sodium, heart rate, and dyspnea.
††
Covariates included in the propensity score by treatment comparison are: NTG vs MIL: SBP, BUN, LVEF, symptom duration, dyspnea, QRS >120 ms, previous
revascularization; NTG vs DOB: SBP, sodium, BUN, heart rate, LVEF, symptom duration; NES vs MIL: SBP, age, LVEF, dyspnea, weight; NES vs DOB: SBP, sodium,
BUN, creatinine, age, weight, LVEF, edema; NES vs NTG: SBP, BUN, creatinine, LVEF, symptom duration, edema, previous HF, QRS >120 ms; DOB vs MIL: SBP,
age, hemoglobin, heart rate, dyspnea, VTF.
NTG, nitroglycerin; MIL, milrinone; DOB, dobutamine; NES, nesiritide; SBP, systolic blood pressure; DBP, diastolic blood pressure; BUN, blood urea nitrogen; LVEF,
left ventricular ejection fraction; HF, heart failure; VTF, ventricular tachycardia/fibrillation.
Adapted with permission from Abraham WT et al. J Am Coll Cardiol. 2005;46:57-64.

13
SI06 Clinician 9/15/06 11:42 AM Page 14
for the Management of Acute Decompensated
Heart Failure”).
In observational studies, vasodilators have com-
pared favorably with placebo and inotropic agents.
However, data are limited in broad populations of
patients with ADHF. In the VMAC trial, nitroglycerin
was associated with reductions in PCWP, sys-
temic vascular resistance, and dyspnea, but, in
general, these parameters were not statistically
significant when compared with placebo.52,96
Tolerance to the effects of nitrate therapy is well
known and has been demonstrated in patients
with acute heart failure.97 The potential for toler-
ance complicates the use of nitrate therapy for
the treatment of patients with ADHF, since in the
absence of hemodynamic monitoring, effects on
wedge pressure are difficult to assess.
In contrast, more data are available concerning
nitrate therapy in patients with acute pulmonary
edema. Isosorbide dinitrate, which produces
venous and arterial dilation,4,46 has been shown by
some, but not others, to improve patient outcome
relative to placebo and bilevel positive airway
pressure (BiPAP).54,98 In patients with pulmonary
edema, isosorbide dinitrate was associated with
a significantly lower combined rate of death,
mechanical ventilation, or myocardial infarction
than was BiPAP (25% vs 85%, respectively;
P=.0003).98 Definitive trials with larger sample
sizes are needed to further elucidate the potential
advantages of nitrate therapy versus noninvasive
ventilatory assistance, but these studies do show
the utility of nitrates in acute pulmonary edema.
Likewise, in a separate study of 110 patients with
pulmonary edema, those receiving moderate-
dose furosemide and IV isosorbide dinitrate in the
prehospital setting had significantly less need for
mechanical ventilation than did those who
received high-dose furosemide plus placebo (13%
vs 40%, respectively; P=.0041).54 Although the
number of events was small, these investigators
found a lower incidence of myocardial infarction
(17% vs 37%, respectively; P=.047) and a lower
overall adverse event rate (25% vs 46%, respec-
tively; P=.041) with moderate-dose furosemide
and IV isosorbide than with high-dose furosemide
plus placebo. The study was not designed to
evaluate outcomes such as mortality, but there
14
was an absolute 4% mortality difference between
the groups that favored isosorbide dinitrate, but
this did not achieve statistical significance (2% vs
6%, respectively; P=.61).54
The use of nitroprusside in ADHF is more restricted
than that of other vasodilators because of concern
about the potential of hypotension and the general
consensus that close monitoring of arterial pres-
sure (often by invasive means) is necessary for safe
application of this therapy. Nitroprusside has been
most often employed in patients with severe heart
failure whose illness is characterized by increased
systemic afterload.4 It quickly and effectively
improves cardiac function in severely ill patients
with ADHF;56 however, high doses may increase
heart rate, exacerbating myocardial ischemia,
therefore making it inappropriate for patients with
ADHF with acute coronary syndromes.46
The renal safety of the traditional vasodilators is
variable (see insert “Currently Used In-Hospital
Treatments for the Management of Acute
Decompensated Heart Failure”). Experimental
data from animal heart failure models suggest
that nitroglycerin and isosorbide dinitrate improve
renal blood flow,99,100 but this has not been corrob-
orated by trial data, which suggest a more neutral
effect.101 Nitroglycerin use is not associated with
worsening renal function,102 and serum creatinine
concentration increases in nitroglycerin-treated
patients with ADHF are reported as predominantly
transient.4,46,102,103* Renal insufficiency is not a con-
traindication to its use,46 although caution is
warranted in such patients.
Conversely, nitroprusside, even though it has
been associated with modest improvements in
creatinine clearance,56 should not be given to
patients with severe renal impairment, as this may
result in the accumulation of toxic levels of thio-
cyanate and cyanide.46,104 It is important to bear in
mind that these agents were not specifically
developed for an ADHF indication, nor were they
studied in robust and properly powered ADHF
clinical trials, leaving their role in ADHF and the
cardiorenal syndrome subject to further study.
Natriuretic Peptides. Natriuretic peptides are
endogenous neurohormones whose production
in the myocardium is increased by structural and
*Contains preliminary data from abstract.102
SI06 Clinician Correx 10/12/06 3:28 PM
functional disease especially involving the left ven-
tricle. These peptides are also released when
ventricular filling pressure is increased, and they
naturally counteract overactivity of the RAAS and
SNS (Table 1, page 2). Recombinant natriuretic
peptides are a relatively new class of drugs used in
the management of ADHF. Two agents in this class
are under development: carperitide (atrial natriuretic
peptide) and ularitide (renally produced urodilatin)
(Table 8).58,60-62 Nesiritide is the only natriuretic
peptide with US Food and Drug Administration
approval. It is specifically indicated for the treatment
of patients with ADHF who have dyspnea at rest
or minimal activity,105 and it is currently prescribed
in approximately 10% of ADHF cases.63
Initial nesiritide efficacy trials focused on the drug’s
ability to improve the hemodynamic profile of
patients with ADHF.52,106,107 In studies conducted by
the Nesiritide Study Group, 2 nesiritide regimens
(0.3-mcg/kg/min infusion and 0.6-mcg/kg/min
infusion) were compared with placebo (efficacy
trial) and active treatments (comparative trial) in
432 patients.106
In the efficacy trial, nesiritide, as compared with
placebo, within 6 hours of treatment produced
significant (P ≤.001) dose-dependent reductions
in PCWP, right atrial pressure, systemic vascular
resistance, and systolic BP, while modestly
increasing the cardiac index. Global clinical
status and dyspnea were also improved. When
EMERGING RECOMBINANT NATRIURETIC PEPTIDES58,60-62
Natriuretic
Peptide Source
Ularitide Renally produced
urodilatin
Carperitide Atria (A-type natriuretic peptide)
ADHF, acute decompensated heart failure; PCWP, pulmonary capillary wedge pressure; SVR, systemic vascular resistance; SIRIUS, Safety and Efficacy of an
Intravenous Placebo-Controlled Randomised Infusion of Ularitide; ESC, European Society of Cardiology.
Page 15
compared with standard care, which included
dobutamine (57%), milrinone (19%), nitroglycerin
(18%), dopamine (6%), and amrinone (1%), global
clinical status, dyspnea, and fatigue were equally
improved with all treatments. In both parts of the
study, hypotension was the most common nesiri-
tide-related adverse event.106
In the randomized, double-blind VMAC trial, the
effects of nesiritide were compared with those of
standard therapy on hemodynamic and sympto-
matic endpoints. Nitroglycerin was included as a
comparator.52 The VMAC study had a complex
design (with several treatment arms) that included
rerandomization of patients assigned to standard
therapy (placebo) after 3 hours. Beneficial acute
hemodynamic effects were observed with nesiri-
tide compared with both standard therapy and
nitroglycerin. Within 15 minutes of the administra-
tion of treatment, nesiritide reduced mean PCWP
to a significantly greater degree than did nitrogly-
cerin or placebo (P<.05), a benefit sustained for at
least 24 hours versus nitroglycerin.52,108 Compared
with placebo, nesiritide produced significant
(P<.05) reductions in right atrial pressure, systemic
vascular resistance, and pulmonary vascular
resistance within 1 hour of treatment. Nitroglycerin
produced similar hemodynamic improvements,
but with the exception of pulmonary vascular
resistance, the changes were not evident until
after 3 hours of treatment, at which time point
Table 8
Potential Benefits in ADHF Status
Reduces dyspnea, PCWP, SVR, Phase 2 (SIRIUS 2) clinical trial results
and 30-day mortality presented at 2005 ESC congress
Neutral effect on renal function
Reduces PCWP, heart rate, right atrial Experimental; tested in limited number of patients
pressure, and aldosterone levels;
no effect on mean arterial pressure,
cardiac index, stroke volume, or SVR
Neutral effect on renal function
15
SI06 Clinician 9/15/06 11:42 AM Page 16

they became comparable to those obtained with sis could not control for baseline imbalances,
nesiritide. Any adverse event was more common such as the higher incidence of previous myocar-
with nitroglycerin than with nesiritide (68% vs dial infarction and ischemia in the dobutamine
51%, respectively; P<.001).52 group.47

Nesiritide has been associated with shorter treat- Whereas renal safety data for traditional vasodila-
ment times and less need for multiple adjunctive tors and inotropes are limited, there is a larger
medications than has the inotropic agent dobuta- body of data concerning the renal safety of nesiri-
mine.47 Dobutamine produces more adverse tide. A recent meta-analysis of 5 randomized
proarrhythmic and chronotropic events than trials involving 1269 patients (by Sackner-
does nesiritide81 and, in unadjusted analysis, was Bernstein and colleagues) has raised questions
associated with a trend toward higher 21-day concerning the potential for worsening renal
readmission rates (20% vs 8% vs 11% with low- function during nesiritide therapy 109 (see
and high-dose nesiritide, respectively) and 6-month “Commentary: Renal Function and Mortality in
mortality rates (31% vs 18% vs 24% with low- Nesiritide Treated Patients” sidebar, page 10).
and high-dose nesiritide, respectively).47 These investigators evaluated the frequency with
which nesiritide-treated patients suffered worsen-
However, these findings were limited by the ing renal function, defined as an increase in
study’s protocol: the open-label design may have serum creatinine concentration of more than 0.5
introduced a selection bias, with sicker patients mg/dL while in-hospital.109 Worsening renal func-
receiving dobutamine, and the unadjusted analy- tion occurred in 22% of nesiritide-treated patients
versus 15% of patients who received non-
Table 9 inotropic-based control therapy (P=.002). When
MEDICATIONS OF PATIENTS WITH ADHF IN ADHERE63
compared with all control therapies used in these
5 trials, the rates were 21% versus 15%, respec-
Chronic Outpatient Medications tively (P<.001). A significantly greater proportion
Prior to Hospitalization Most Common IV Medications of nesiritide-treated patients also required inter-
% % vention for worsening renal function than did
Chronic Medication n=105,388 IV Medication n=105,388
controls (11.1% vs 4.2%, respectively; P=.03).109
ACE inhibitor 41 Diuretic 88
Antiarrhythmic* 11 Dobutamine 6 Likewise, specific reanalysis of outcome data from
ARB 12 Dopamine 6 VMAC found that any perceived mortality increase
Aspirin 38 Milrinone 3 with nesiritide relative to nitroglycerin appeared to
Calcium channel blocker 23 Nesiritide 10 be related to baseline imbalances.110* In the trial,
Cilostazol <1 Nitroglycerin 10 which was not powered for mortality, the 30-day
Digoxin 28 Nitroprusside 1 death rates were 8.1% with nesiritide versus 5.1%
Diuretic 70 with nitroglycerin, and the 6-month rates were
Glitazone 5 25.1% versus 20.8%, respectively, all nonsignifi-
Hydralazine 4
cant differences. After adjustment, the hazard
Lipid-lowering 31
ratios for death for nesiritide versus nitroglycerin
were reduced from 1.56 to 1.17 at 30 days and
Nitrate 26
from 1.22 to 1.06 at 6 months.110 Again, as
NSAID 6
acknowledged by the authors of the meta-analy-
Warfarin 24
sis, the data available to them did not permit this
␤-blocker 48
type of multivariate adjusted analysis. The results
*Antiarrhythmics other than ␤-blockers, calcium channel blockers, or digoxin. from VMAC are consistent with those reported in
ADHF, acute decompensated heart failure; ADHERE, Acute Decompensated Heart Failure ADHERE, where the difference in in-hospital mor-
National Registry; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker;
NSAID, nonsteroidal anti-inflammatory drug; IV, intravenous. tality between nesiritide- and nitroglycerin-treated
Adapted with permission from Acute Decompensated Heart Failure National Registry patients (7.1% vs 4.7%, respectively) was closed
(ADHERE). Available at: http://www.adhereregistry.com/ADHERE_100k.pdf. Accessed
August 27, 2005. by proper adjustment (Table 7, page 13).24

16 *Contains preliminary data from abstract.110

SI06 Clinician 9/15/06 11:42 AM Page 17
The 237-patient PROACTION study (Prospective
Randomized Outcomes Study of Acutely
Decompensated Heart Failure Treated Initially
as Outpatients with Nesiritide), which, like VMAC,
was not powered to assess mortality, reported
similar outcomes. The study compared the use
of nesiritide plus standard care (diuretic, oxygen,
and one or more vasodilators) with placebo plus
standard care among patients with ADHF in the
emergency department. At 30 days, mortality was
5.9% with nesiritide versus 0.9% with placebo
(P=.066). At 180-day follow-up, the perceived,
and nonsignificant, gap in 30-day mortality had
largely disappeared. The rates were 20.6% with
nesiritide versus 17.5% with placebo (P=.479).110,111
The lack of a consistent pattern in the data
concerning the effect of nesiritide on mortality
was also observed when the 30-day outcomes
were compared for nesiritide and control patients.
Using all 6 trials with 30-day mortality reported,
the rates were 6.2% versus 4.4%, respectively,
also a nonsignificant difference. Similarly, among
the 5 trials that reported 6-month mortality, the
rates were 21.5% versus 20.7%, respectively, also
a nonsignificant difference.110-112
The nesiritide mortality data, like the renal safety
data, do not provide convincing evidence of an
adverse effect of the drug. Rather, current infor-
mation is largely inconclusive—and the issue can
be properly evaluated only by conducting addi-
tional prospective and well-designed studies. An
advisory panel, convened after the publication of
the meta-analysis, recommended that nesiritide
continue to be used as recommended on the
label but cited a pressing need for more trials.113
APPROACHES TO THE CARDIORENAL PATIENT
Patients hospitalized with ADHF are urgently ill and
require rapid diagnosis, stabilization, and sympto-
matic relief.4 Most patients—almost 80%—present
to hospital emergency departments,63 an indication
of the acuity of ADHF, and may already be taking
one or more chronic medications (Table 9).63 Acute
treatment strategies that address underlying cata-
lysts, as well as the circulatory crisis, and that do
not conflict with any on-board chronic medications
appear to be most effective when administered
quickly, because early emergency treatment may
*Contains preliminary data from abstract.114
produce better outcomes than does delayed in-
hospital care.63,114* Involvement of the heart failure
specialty staff at the institution is important, and
treatment is most efficient when there is an estab-
lished in-hospital ADHF critical pathway (Figure 3,
page 18).4,115
Current guidelines are vague on whether chronic
medications should be discontinued during acute
care, although they do offer guidance for 2 of the
more common medications taken by patients with
ADHF with existing heart failure: ␤-blockers and
ACE inhibitors. The guidelines recommend that
␤-blocker therapy be continued in patients with
ADHF unless inotropic support is needed.4
␤-Blockers are considered appropriate for patients
treated for decompensated chronic heart failure,
as well as for those who present with a concomi-
tant myocardial infarction, but only after
improvement in congestion and stabilization
(approximately 4 days). ACE inhibitors should
not be added during initiation of acute therapy,
according to current guidelines, since no large-
scale efficacy studies have been conducted in the
ADHF population. ACE inhibitors may reduce GFR,
an undesirable consequence of treatment in a
population with marginal renal function. However,
ACE inhibitors should be initiated prior to discharge
in patients meeting standard guideline criteria once
a stabilized hemodynamic profile is achieved.4
For patients presenting with ADHF and concomi-
tant renal disease, a special consideration of the
source of renal dysfunction is important, as
some causes may be transient and is reversible.
Examination of patients with ADHF with renal dys-
function should begin with an evaluation of the
patient’s fluid status. For example, hypovolemia
resulting in renal hypoperfusion may be the result
of overaggressive diuretic therapy and is reversible
by reducing the diuretic dosage. In cases of euv-
olemia or hypervolemia, renal function should be
evaluated. Pressor therapy is appropriate for
patients who are hypotensive.28
Although uncommon in general populations of
patients with ADHF, low cardiac output may result
in renal hypoperfusion, which may be reversible by
increasing cardiac output with vasodilators.
Patients with normal cardiac output, low systemic
vascular resistance, and worsening renal function
17
SI06 Clinician Correx 10/12/06 3:28 PM Page 18

are in a state sometimes known as “vasodilatory

Figure 3 shock.”28,116 Vasopressin levels are often depleted
ALGORITHM FOR THE MANAGEMENT in such patients, who may benefit from vaso-
OF PATIENTS WITH ADHF115 pressin infusions.28

The last consideration is the presence of intrinsic

renal disease.28 This should be considered after
other possibilities for renal dysfunction have been
ruled out. Intrinsic renal disease may be the result
of diabetes, hypertension, renal vascular disease,
or overuse of diuretics.28 Such patients may be
appropriate candidates for filtration or dialysis
since current medical therapy is unlikely to acutely
reverse intrinsic renal dysfunction.4,28

Finally, novel treatments that may be effective in

patients with the cardiorenal syndrome are under
development. For example, Gottlieb and col-
leagues reported that the A1 adenosine antagonist
BG9719, when administered with furosemide,
increases urinary output while protecting renal
function.68 Others have reported a powerful
aquaretic effect without renal impairment in
patients with ADHF treated with the vasopressin
receptor antagonist tolvaptan.117-119 These drugs,
along with emerging data on existing treatments
and the new natriuretic peptides, may open novel
treatment avenues for ADHF management.

CONCLUSION
ADHF with concomitant renal dysfunction—the
cardiorenal syndrome—is a unique and common
pathophysiologic condition. Any degree of renal
dysfunction in patients with heart failure can
worsen prognosis, and renal dysfunction often
limits treatment options. Indeed, many of the cur-
rently used therapies may worsen renal function
or have indeterminate effects on the kidneys.
How those effects may improve or worsen short-
and long-term outcomes is largely unknown. The
unique presentation and disease pathology of
each patient must be considered, along with the
potential in-hospital and postdischarge risks and
benefits of each drug, before appropriate treat-
ADHF, acute decompensated heart failure; ADHERE, Acute Decompensated Heart Failure ment decisions can be made. Increasing volumes
National Registry; Hx, history; HF, heart failure; CAD, coronary artery disease; DM, diabetes
mellitus; HTN, hypertension; ECG, electrocardiogram; ACS, acute coronary syndromes; CXR, of community-based data on the epidemiology
chest x-ray; CHF, congestive heart failure; BNP, B-type natriuretic peptide; SBP, systolic of the disease and clinical trial data on emerging
blood pressure; AMS, altered mental status; CCU, cardiac care unit; ICU, intensive care unit;
IV, intravenous; ACE, angiotensin-converting enzyme. and existing drugs may eventually help limit the
Adapted with permission from Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 7):S21-S30. morbidity and mortality associated with the car-
diorenal syndrome.

18
SI06 Clinician 9/15/06 11:42 AM Page 19
REFERENCES
1. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA Guideline Update for the
Diagnosis and Management of Chronic Heart Failure in the Adult. A report of the
American College of Cardiology/American Heart Association Task Force on
Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the
Evaluation and Management of Heart Failure). Available at: http://www.acc.org/
clinical/guidelines/failure/index.pdf. Accessed January 11, 2006.
2. Tendera M. The epidemiology of heart failure. J Renin Angiotensin Aldosterone
Syst. 2004;5(suppl 1):S2-S6.
3. American Heart Association. Heart Disease and Stroke Statistics—2005 Update.
Dallas, Tex: American Heart Association; 2005.
4. Nieminen MS, Bohm M, Cowie MR, et al. Executive summary of the Guidelines on
the Diagnosis and Treatment of Acute Heart Failure: The Task Force on Acute Heart
Failure of the European Society of Cardiology. Eur Heart J. 2005;26:384-416.
5. McCullough PA, Philbin EF, Spertus JA, Kaatz S, Sandberg KR, Weaver WD.
Confirmation of a heart failure epidemic: findings from the Resource Utilization
Among Congestive Heart Failure (REACH) study. J Am Coll Cardiol. 2002;39:60-69.
6. Krum H, Gilbert RE. Demographics and concomitant disorders in heart failure.
Lancet. 2003;362:147-158.
7. Adams KF Jr, Fonarow GC, Emerman CL, 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 (ADHERE). Am Heart J.
2005;149:209-216.
8. Francis GS, Tang WH. Pathophysiology of congestive heart failure. Rev Cardiovasc
Med. 2003;4(suppl 2):S14-S20.
9. Merck. The Merck Manual of Diagnosis and Therapy. Section 16. Cardiovascular dis-
orders. Chapter 203. Heart failure. Available at:
http://www.merck.com/mrkshared/mmanual/section16/chapter203/203a.jsp.
Accessed October 12, 2005.
10. Shah M, Ali V, Lamba S, Abraham WT. Pathophysiology and clinical spectrum of
acute congestive heart failure. Rev Cardiovasc Med. 2001;2(suppl 2):S2-S6.
11. Colucci WS, Braunwald E. Pathophysiology of heart failure. In: Zipes DP, Libby P,
Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease: A Textbook of
Cardiovascular Medicine. Vol 1. 7th ed. Philadelphia, Pa: Elsevier/WB Saunders;
2004:509-538.
12. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II–mediated
cardiovascular and renal diseases. Pharmacol Rev. 2000;52:11-34.
13. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J
Med. 1999;341:577-585.
14. Moe GW, Rouleau JL, Nguyen QT, Cernacek P, Stewart DJ. Role of endothelins in
congestive heart failure. Can J Physiol Pharmacol. 2003;81:588-597.
15. Lee CR, Watkins ML, Patterson JH, et al. Vasopressin: a new target for the treat-
ment of heart failure. Am Heart J. 2003;146:9-18.
16. Chin BS, Conway DS, Chung NA, Blann AD, Gibbs CR, Lip GY. Interleukin-6, tis-
sue factor and von Willebrand factor in acute decompensated heart failure: rela-
tionship to treatment and prognosis. Blood Coagul Fibrinolysis. 2003;14:515-521.
17. Torre-Amione G, Kapadia S, Lee J, Bies RD, Lebovitz R, Mann DL. Expression
and functional significance of tumor necrosis factor receptors in human myocardi-
um. Circulation. 1995;92:1487-1493.
18. Porter KE, Turner NA, O’Regan DJ, Ball SG. Tumor necrosis factor alpha induces
human atrial myofibroblast proliferation, invasion and MMP-9 secretion: inhibition
by simvastatin. Cardiovasc Res. 2004;64:507-515.
19. Bhalla V, Willis S, Maisel AS. B-type natriuretic peptide: the level and the drug-part-
ners in the diagnosis and management of congestive heart failure. Congest Heart
Fail. 2004;10(suppl 1):S3-S27.
20. Schiff GD, Fung S, Speroff T, McNutt RA. Decompensated heart failure: symp-
toms, patterns of onset, and contributing factors. Am J Med. 2003;114:625-630.
21. Tallaj JA, Bourge RC. The management of acute decompensated heart failure -
2003. University of Alabama, Birmingham, Ala. Available at: http://www.fac.org.ar/
tcvc/llave/c038/bourge.PDF. Accessed February 26, 2005.
22. Nieminen MS. Acute heart failure: reality and recommendations. Press release from
the European Society of Cardiology. Available at: http://www.escardio.org/
vpo/ESC_congress_information/ConferenceReleases/CPreleases/Nieminen.htm.
Accessed October 25, 2005.
23. Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ. Risk stratifi-
cation for in-hospital mortality in acutely decompensated heart failure: classification
and regression tree analysis. JAMA. 2005;293:572-580.
24. Abraham WT, Adams KF Jr, Fonarow GC, et al. In-hospital mortality in patients
with acute decompensated heart failure requiring intravenous vasoactive medica-
tions: an analysis from the Acute Decompensated Heart Failure National Registry
(ADHERE). J Am Coll Cardiol. 2005;46:57-64.
25. Cleland JG, Swedberg K, Follath F, et al. The EuroHeart Failure survey programme-
a survey on the quality of care among patients with heart failure in Europe. Part 1:
patient characteristics and diagnosis. Eur Heart J. 2003;24:442-463.
26. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B. The severe car-
diorenal syndrome: ‘Guyton revisited.’ Eur Heart J. 2005;26:11-17.
27. Shlipak MG, Massie BM. The clinical challenge of cardiorenal syndrome.
Circulation. 2004;110:1514-1517.
28. Heywood JT. The cardiorenal syndrome: lessons from the ADHERE database and
treatment options. Heart Fail Rev. 2004;9:195-201.
29. DiDomenico RJ, Park HY, Southworth MR, et al. Guidelines for acute decompen-
sated heart failure treatment. Ann Pharmacother. 2004;38:649-660.
30. Gheorghiade M, Mebazaa A. Introduction to acute heart failure syndromes. Am J
Cardiol. 2005;96(6A):1G-4G.
31. Heywood JT, Fonarow GC, Wynne J. Is heart failure really renal failure?
Observations from 88,705 admissions with decompensated heart failure in the
ADHERE™ Registry. J Am Coll Cardiol. 2005;45(suppl A):173A. Abstract 843-8.
32. Hillege HL, Girbes AR, de Kam PJ, et al. Renal function, neurohormonal activation,
and survival in patients with chronic heart failure. Circulation. 2000;102:203-210.
33. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for
development of cardiovascular disease: a statement from the American Heart
Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure
Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension.
2003;42:1050-1065.
34. Akhter MW, Aronson D, Bitar F, et al. Effect of elevated admission serum creatinine
and its worsening on outcome in hospitalized patients with decompensated heart
failure. Am J Cardiol. 2004;94:957-960.
35. Costanzo MR, Heywood JT, DeMarco T, Fonarow G, Wynne J. Impact of renal
insufficiency and chronic diuretic therapy on outcome and resource utilization in
patients with acute decompensated heart failure. J Am Coll Cardiol. 2004;43
(suppl 1):A180. Abstract 1069-1114.
36. Bibbins-Domingo K, Lin F, Vittinghoff E, Barrett-Connor E, Grady D, Shlipak MG.
Renal insufficiency as an independent predictor of mortality among women with
heart failure. J Am Coll Cardiol. 2004;44:1593-1600.
37. Ezekowitz J, McAlister FA, Humphries KH, et al, for the APPROACH Investigators.
The association among renal insufficiency, pharmacotherapy, and outcomes in
6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol.
2004;44:1587-1592.
38. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The prognostic
implications of renal insufficiency in asymptomatic and symptomatic patients with
left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;35:681-689.
39. Wali RK, Wang GS, Gottlieb SS, et al. Effect of kidney transplantation on left ven-
tricular systolic dysfunction and congestive heart failure in patients with end-stage
renal disease. J Am Coll Cardiol. 2005;45:1051-1060.
40. Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS. Congestive heart
failure in dialysis patients: prevalence, incidence, prognosis and risk factors. Kidney
Int. 1995;47:884-890.
41. Varma R, Garrick R, McClung J, Frishman WH. Chronic renal dysfunction as an
independent risk factor for the development of cardiovascular disease. Cardiol
Rev. 2005;13:98-107.
42. Cheung AK, Sarnak MJ, Yan G, et al. Cardiac diseases in maintenance hemodialy-
sis patients: results of the HEMO study. Kidney Int. 2004;65:2380-2389.
43. Redfield MM, Chen HH, Burnett JC Jr. Unique neurohormonal and renal hemody-
namic profile in patients who develop the cardiorenal syndrome during treatment
of decompensated heart failure. Presented at: Heart Failure Society of America 9th
Annual Scientific Sessions; September 20, 2005; Boca Raton, Fla. Abstract 062.
Available at: http://www.abstracts2view.com/hfsa05/view.php?nu=HFSA5L1_062.
Accessed January 11, 2006.
44. Teerlink JR. Overview of randomized clinical trials in acute heart failure syndromes.
Am J Cardiol. 2005;96(suppl 6A):59G-67G.
45. Nolan J, Sanderson A, Taddei F, Smith S, Muir AL. Acute effects of intravenous
phosphodiesterase inhibition in chronic heart failure: simultaneous pre- and after-
load reduction with a single agent. Int J Cardiol. 1992;35:343-349.
46. Zevitz ME. Heart failure. Available at: http://www.emedicine.com/med/topic3552.htm.
Accessed February 16, 2005.
47. Silver MA, Horton DP, Ghali JK, Elkayam U. Effect of nesiritide versus dobutamine
on short-term outcomes in the treatment of patients with acutely decompensated
heart failure. J Am Coll Cardiol. 2002;39:798-803.
48. Molloy WD, Dobson K, Girling L, Greenberg ID, Prewitt RM. Effects of dopamine
on cardiopulmonary function and left ventricular volumes in patients with acute res-
piratory failure. Am Rev Respir Dis. 1984;130:396-399.
49. Hoit BD, Burwig S, Eppert D, Bhat G, Walsh RA. Effects of a novel inotropic agent
(OPC-18790) on systolic and diastolic function in patients with severe heart failure.
Am Heart J. 1994;128:1156-1163.
50. MacGowan GA, Haber HL, Cowart TD, Tedesco C, Wu C, Feldman MD. Direct
myocardial effects of OPC-18790 in human heart failure: beneficial effects on con-
tractile and diastolic function demonstrated by intracoronary infusion with pres-
sure-volume analysis. J Am Coll Cardiol. 1998;31:1344-1351.
51. Young JB. New therapeutic choices in the management of acute congestive heart
failure. Rev Cardiovasc Med. 2001;2(suppl 2):S19-S24.
52. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitro-
glycerin for treatment of decompensated congestive heart failure: a randomized
controlled trial. JAMA. 2002;287:1531-1540.
53. Leier CV, Huss P, Magorien RD, Unverferth DV. Improved exercise capacity and
differing arterial and venous tolerance during chronic isosorbide dinitrate therapy
for congestive heart failure. Circulation. 1983;67:817-822.
54. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide
dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose
isosorbide dinitrate in severe pulmonary oedema. Lancet. 1998;351:389-393.
55. Breisblatt WM, Navratil DL, Burns MJ, Spaccavento LJ. Comparable effects of
intravenous nitroglycerin and intravenous nitroprusside in acute ischemia. Am
Heart J. 1988;116(2 pt 1):465-472.
56. Khot UN, Novaro GM, Popovic ZB, et al. Nitroprusside in critically ill patients with left
ventricular dysfunction and aortic stenosis. N Engl J Med. 2003;348:1756-1763.
57. Annane D, Bellissant E, Pussard E, et al. Placebo-controlled, randomized, double-
blind study of intravenous enalaprilat efficacy and safety in acute cardiogenic pul-
monary edema. Circulation. 1996;94:1316-1324.
58. Stiles S. SIRIUS 2: ularitide infusion improves hemodynamics, lessens dyspnea in
acute decompensated HF. Available at: http://www.theheart.org/viewArticle.do?
primaryKey=553299&from=/searchLayout.do. Accessed October 13, 2005.
59. Metra M. SIRIUS II. Available at: http://www.escardio.org/knowledge/congress-
es/CongressReports/clinical/2005/metra.htm. Accessed October 20, 2005.
60. Giles TD, Quiroz AC, Roffidal LE, Marder H, Sander GE. Prolonged hemodynamic
benefits from a high-dose bolus injection of human atrial natriuretic factor in con-
gestive heart failure. Clin Pharmacol Ther. 1991;50:557-563.
61. Kikuchi M, Nakamura M, Suzuki T, Sato M, Takino T, Hiramori K. Usefulness of
carperitide for the treatment of refractory heart failure due to severe acute myocar-
dial infarction. Jpn Heart J. 2001;42:271-280.
19
SI06 Clinician Correx 10/12/06 1:14 PM Page 20
62. Suwa M, Seino Y, Nomachi Y, Matsuki S, Funahashi K. Multicenter prospective
investigation on efficacy and safety of carperitide for acute heart failure in the ‘real
world’ of therapy. Circ J. 2005;69:283-290.
63. Acute Decompensated Heart Failure National Registry (ADHERE). Insights from the
ADHERE registry: data from over 100,000 patient cases. Available at:
http://www.adhereregistry.com/ADHERE_100k.pdf. Accessed August 27, 2005.
64. Peacock WF, Emerman CL, Costanzo MR, for the ADHERE Scientific Advisory
Committee. Adverse renal effects of intravenous diuretics in decompensated heart
failure: data from the ADHERE registry. Presented at: Heart Failure Society of
America 9th Annual Scientific Sessions; October 19, 2005; Boca Raton, Fla.
Abstract 291. Available at: http://www.abstracts2view.com/hfsa05/view.php?nu=
HFSA5L1_291. Accessed January 11, 2006.
65. Cataliotti A, Boerrigter G, Costello-Boerrigter LC, et al. Brain natriuretic peptide
enhances renal actions of furosemide and suppresses furosemide-induced aldos-
terone activation in experimental heart failure. Circulation. 2004;109:1680-1685.
66. Butler J, Emerman C, Peacock WF, Mathur VS, Young JB, for the VMAC Study
Investigators. The efficacy and safety of B-type natriuretic peptide (nesiritide) in
patients with renal insufficiency and acutely decompensated congestive heart fail-
ure. Nephrol Dial Transplant. 2004;19:391-399.
67. Tamirisa KP, Aaronson KD, Koelling TM. Spironolactone-induced renal insufficiency
and hyperkalemia in patients with heart failure. Am Heart J. 2004;148:971-978.
68. Gottlieb SS, Brater DC, Thomas I, et al. BG9719 (CVT-124), an A1 adenosine
receptor antagonist, protects against the decline in renal function observed with
diuretic therapy. Circulation. 2002;105:1348-1353.
69. Weinfeld MS, Chertow GM, Stevenson LW. Aggravated renal dysfunction during
intensive therapy for advanced chronic heart failure. Am Heart J. 1999;138:285-290.
70. Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. Acute vaso-
constrictor response to intravenous furosemide in patients with chronic congestive
heart failure. Activation of the neurohumoral axis. Ann Intern Med. 1985;103:1-6.
71. Knight EL, Glynn RJ, McIntyre KM, Mogun H, Avorn J. Predictors of decreased
renal function in patients with heart failure during angiotensin-converting enzyme
inhibitor therapy: results from the Studies of Left Ventricular Dysfunction (SOLVD).
Am Heart J. 1999;138:849-855.
72. Harjai KJ, Dinshaw HK, Nunez E, et al. The prognostic implications of outpatient
diuretic dose in heart failure. Int J Cardiol. 1999;71:219-225.
73. Neuberg GW, Miller AB, O’Connor CM, et al. Diuretic resistance predicts mortality
in patients with advanced heart failure. Am Heart J. 2002;144:31-38.
74. Mehta RL, Pascual MT, Soroko S, Chertow GM, for the PICARD Study Group.
Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA.
2002;288:2547-2553.
75. Hawkins RG, Houston MC. Is population-wide diuretic use directly associated with
the incidence of end-stage renal disease in the United States? A hypothesis. Am J
Hypertens. 2005;18:744-749.
76. Felker GM, O’Connor CM. Inotropic therapy for heart failure: an evidence-based
approach. Am Heart J. 2001;142:393-401.
77. Cohn JN, Goldstein SO, Greenberg BH, et al. A dose-dependent increase in mor-
tality with vesnarinone among patients with severe heart failure. Vesnarinone Trial
Investigators. N Engl J Med. 1998;339:1810-1816.
78. Hampton JR, van Veldhuisen DJ, Kleber FX, et al. Randomised study of effect of
ibopamine on survival in patients with advanced severe heart failure. Second
Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II)
Investigators. Lancet. 1997;349:971-977.
79. Elkayam U, Tassisa G, Binanay C, et al. Use and impact of inotropes and vasodila-
tor therapy during heart failure hospitalization in the ESCAPE trial. Circulation.
2004;110(suppl III):III-515. Abstract 2415.
80. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute
exacerbation of chronic heart failure: a randomized controlled trial. JAMA.
2002;287:1541-1547.
81. Burger AJ, Horton DP, LeJemtel T, et al. Effect of nesiritide (B-type natriuretic pep-
tide) and dobutamine on ventricular arrhythmias in the treatment of patients with
acutely decompensated congestive heart failure: the PRECEDENT study. Am
Heart J. 2002;144:1102-1108.
82. O’Connor CM, Gattis WA, Uretsky BF, et al. Continuous intravenous dobutamine is
associated 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;138:78-86.
83. Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimen-
dan compared with dobutamine in severe low-output heart failure (the LIDO study):
a randomised double-blind trial. Lancet. 2002;360:196-202.
84. Cleland JG, Nikitin N, McGowan J. Levosimendan: first in a new class of inodilator
for acute and chronic severe heart failure. Expert Rev Cardiovasc Ther. 2004;2:9-19.
85. Nieminen MS, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral
effects of continuous infusion of levosimendan in patients with congestive heart
failure. J Am Coll Cardiol. 2000;36:1903-1912.
86. Stiles S. REVIVE-2: levosimendan improves five-day clinical status in acute HF.
Available at: http://www.theheart.org/viewArticle.do?primaryKey=600671&from=
/index.do. Accessed November 28, 2005.
87. Mebazaa A. Survival of patients with acute heart failure in need of intravenous
inotropic support. Presented at: American Heart Association Scientific Sessions;
November 16, 2005; Dallas, Tex. Available at: http://scientificsessions.american-
heart.org/portal/scientificsessions/ss/lbctnewsrelease16. Accessed January 11,
2006.
88. Duke GJ, Briedis JH, Weaver RA. Renal support in critically ill patients: low-dose
dopamine or low-dose dobutamine? Crit Care Med. 1994;22:1919-1925.
89. Ichai C, Passeron C, Carles M, Bouregba M, Grimaud D. Prolonged low-dose
dopamine infusion induces a transient improvement in renal function in hemody-
namically stable, critically ill patients: a single-blind, prospective, controlled study.
Crit Care Med. 2000;28:1329-1335.
90. Pereira CN, Machado FR, Guimaraes HP, Senna AP, do Amaral JL.
Hemodynamics and renal function during administration of low-dose dopamine in
severely ill patients. Sao Paulo Med J. 2004;122:141-146.
20
91. Wimmer A, Stanek B, Kubecova L, et al. Effects of prostaglandin E1, dobutamine
and placebo on hemodynamic, renal and neurohumoral variables in patients with
advanced heart failure. Jpn Heart J. 1999;40:321-334.
92. Varriale P, Mossavi A. The benefit of low-dose dopamine during vigorous diuresis
for congestive heart failure associated with renal insufficiency: does it protect renal
function? Clin Cardiol. 1997;20:627-630.
93. Cody RJ, Kubo SH, Covit AB, et al. Regional blood flow and neurohormonal
responses to milrinone in congestive heart failure. Clin Pharmacol Ther.
1986;39:128-135.
94. Cody RJ. Renal and hormonal effects of phosphodiesterase III inhibition in
congestive heart failure. Am J Cardiol. 1989;63:31A-34A.
95. Dec GW. Acute decompensated heart failure: the shrinking role of inotropic
therapy. J Am Coll Cardiol. 2005;46:65-67.
96. Larsen AI, Goransson L, Aarsland T, Tamby JF, Dickstein K. Comparison of the
degree of hemodynamic tolerance during intravenous infusion of nitroglycerin versus
nicorandil in patients with congestive heart failure. Am Heart J. 1997;134:435-441.
97. Elkayam U. Nitrates in the treatment of congestive heart failure. Am J Cardiol.
1996;77:41C-51C.
98. Sharon A, Shpirer I, Kaluski E, et al. High-dose intravenous isosorbide-dinitrate is
safer and better than Bi-PAP ventilation combined with conventional treatment for
severe pulmonary edema. J Am Coll Cardiol. 2000;36:832-837.
99. Flaim SF, Weitzel RL, Zelis R. Mechanism of action of nitroglycerin during exercise
in a rat model of heart failure. Improvement of blood flow to the renal, splanchnic,
and cutaneous beds. Circ Res. 1981;49:458-468.
100. Wanless RB, Anand IS, Gurden J, Harris P, Poole-Wilson PA. Regional blood flow
and hemodynamics in the rabbit with Adriamycin cardiomyopathy: effects of
isosorbide dinitrate, dobutamine and captopril. J Pharmacol Exp Ther.
1987;243:1101-1106.
101. Elkayam U, Cohen G, Gogia H, Mehra A, Johnson JV, Chandraratna PA. Renal
vasodilatory effect of endothelial stimulation in patients with chronic congestive
heart failure. J Am Coll Cardiol. 1996;28:176-182.
102. Burger AJ. Clinical predictors of worsening renal function in patients hospitalized
for heart failure. Presented at: Heart Failure Society of America 9th Annual
Scientific Sessions; October 19, 2005; Boca Raton, Fla. Abstract 345. Available at:
http://www.abstracts2view.com/hfsa05/view.php?nu=HFSA5L1_345. Accessed
January 11, 2006.
103. Nitroglycerin (glyceryl trinitrate) general monograph. Available at:
http://www.rxmed.com/b.main/b2.pharmaceutical/b2.prescribe.html. Accessed
October 21, 2005.
104. Jain P, Massie BM, Gattis WA, Klein L, Gheorghiade M. Current medical treatment
for the exacerbation of chronic heart failure resulting in hospitalization. Am Heart J.
2003;145(2 suppl):S3-S17.
105. Natrecor® (nesiritide) prescribing information. Freemont, Calif: Scios Inc; April 2005.
Available at: http://www.sciosinc.com/pdf/natrecorpi_final.pdf. Accessed May 25,
2005.
106. Colucci WS, Elkayam U, Horton DP, et al, for the Nesiritide Study Group.
Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated
congestive heart failure. N Engl J Med. 2000;343:246-253.
107. Peacock WF, Emerman CL, Silver MA. Nesiritide added to standard care favorably
reduces systolic blood pressure compared with standard care alone in patients
with acute decompensated heart failure. Am J Emerg Med. 2005;23:327-331.
108. Elkayam U, Akhter MW, Singh H, Khan S, Usman A. Comparison of effects on left
ventricular filling pressure of intravenous nesiritide and high-dose nitroglycerin in
patients with decompensated heart failure. Am J Cardiol. 2004;93:237-240.
109. Sackner-Bernstein JD, Skopicki H, Aaronson KD. Risk of worsening renal function
with nesiritide in patients with acute decompensated heart failure. Circulation.
2005;111:1487-1491.
110. Data on file. Scios Inc. 2006.
111. Peacock WF, et al. Prospective Randomized Outcomes Study of Acute
Decompensated Congestive Heart Failure Treated Initially as Outpatients With
Nesiritide. J Am Coll Cardiol. 2003; 41(suppl A): 336
112. Abraham WT. Nesiritide and mortality risk: individual and pooled analyses of ran-
domized controlled trials. Prev Cardiovasc Med.2005;6:2.
113. Husten L. Braunwald committee recommends more clinical trials, conservative use
of nesiritide. Available at: http://www.theheart.org/viewArticle.do?primaryKey=
506037&from=/searchLayout.do. Accessed October 13, 2005.
114. Emerman CE, Costanzo MR. Early initiation of IV vasoactive therapy improves
heart failure outcomes: an analysis from the ADHERETM registry database.
Ann Emerg Med. 2003;42:S26. Abstract 92.
115. Fonarow GC. The Acute Decompensated Heart Failure National Registry
(ADHERETM): opportunities to improve care of patients hospitalized with acute
decompensated heart failure. Rev Cardiovasc Med. 2003;4(suppl 7):S21-S30.
116. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med.
2001;345:588-595.
117. Gheorghiade M, Orlandi C, Burnett JC, et al. Rationale and design of the multicen-
ter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of
Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVER-
EST). J Card Fail. 2005;11:260-269.
118. Gheorghiade M, Niazi I, Ouyang J, et al. Vasopressin V2-receptor blockade with
tolvaptan in patients with chronic heart failure: results from a double-blind,
randomized trial. Circulation. 2003;107:2690-2696.
119. Gheorghiade M, Gattis WA, O’Connor CM, et al. Effects of tolvaptan, a
vasopressin antagonist, in patients hospitalized with worsening heart failure: a
randomized controlled trial. JAMA. 2004;291:1963-1971.
SI06_Clinician_Cover 10/16/06 10:39 AM Page 3

CLINICIAN® publishes medical data arising out of scientific All correspondence concerning the contents
meetings or submitted as papers forming the theme of a of this publication should be directed to:
monograph on contemporary therapeutics. SynerMed® Editor, CLINICIAN ®
Communications reserves copyright and renewal on all pub- SynerMed® Communications
lished material. Any such material may not be produced in 405 Trimmer Road
any form without the written permission of SynerMed. PO Box 458, Dept. SI06
Califon, NJ 07830
The opinions expressed in CLINICIAN® are those of the con-
tributing faculty and not necessarily those of the sponsors,
the presenter, the grantor, or the producer. Full prescribing
information must be consulted on any of the drugs or proce-
dures discussed herein.
SI06_Clinician_Cover 10/16/06 10:39 AM Page 4

Other CME-sponsored programs addressing the management of patients with acute decompensated heart failure
are offered, including:

• Spotlight: Perspectives on ADHF Panel Discussion: Expert faculty identify distinct ADHF patient types as
they deliberate on the day-to-day management of these patients, available at www.theheart.org under heart fail-
ure/satellite programs (CME).

• The Pulse on ADHF Management: ADHF management pathways are discussed by expert faculty, providing
a foundation that is key to treatment decisions, available at www.theheart.org under heart failure/satellite
programs (CME).

• Perspectives on ADHF Management: Thresholds for Pharmacotherapy: A useful reference guide that
summarizes each therapeutic drug category used in ADHF management, including dosing guidelines. Available
at www.medcme.org under Cardiovascular: Heart Failure.

• Clinical Courier ® Newsletter: Managing Patients With ADHF: (Due to be released in October 2006)
This newsletter provides highlights from the recent Steering Committee on ADHF and includes 2 case studies
that further emphasize evidence-based intervention strategies in ADHF. This publication will be available at
www.medcme.org under Cardiovascular: Heart Failure.

All of these programs are available at no cost.

Developed and Produced by

© 2006 SynerMed® Communications All rights reserved (06SI06) Printed in USA

SI06_Envelope 9/15/06 1:15 PM Page 1

Editor, CLINICIAN ®
PRSRT STD
SynerMed® Communications US POSTAGE
405 Trimmer Road PAID
PO Box 458, Dept. SI06 PERMIT NO. 22
Califon, NJ 07830 MIDLAND, MI

ta nt CME
Impor Enclosed
als
Materi

Jointly Sponsored by

and

Supported by an educational grant from Scios Inc.

SPECIAL EDITION

Vol. 24 No. 2

Challenges in Acute Decompensated Heart

Failure Management: The Cardiorenal Syndrome
SI06_Poster.qxd 9/15/06 1:17 PM Page 1

CURRENTLY USED IN-HOSPITAL TREATMENTS FOR THE MANAGEMENT OF ACUTE DECOMPENSATED HEART FAILURE
Class Drug Dosage
Diuretics* Furosemide • Range of doses is typical once or twice daily from
Loop 20-160 mg given PO/IV1
• Titrate up to 600 mg/d as needed for severe or persistent
edema1
• Dose is typically titrated in increments of 20 to 80 mg,
usually 6-8 hours after previous dose1
• Resistance often necessitates escalating doses 2,3
Bumetanide • 0.5-2 mg PO 1-2 times/d1
• 0.5-1 mg IV/IM1
• Titrate upward until desired diuretic effect is achieved;
do not exceed 10 mg/d with any administrative route1
Torsemide • 10-20 mg/d PO/IV 1
• Do not exceed 200 mg/d; titrate upward by doubling dose
until desired diuretic effect is achieved 1
Natriuretic Nesiritide • Recommended dose as established by the VMAC trial:
peptides 2-mcg/kg IV bolus followed by IV infusion of
0.01 mcg/kg/min 18
• Omission of the bolus has been the practice of some
clinicians when there is concern about inducing
hypotension because of low baseline blood pressure or
uncertain volume status
• Maintenance doses above 0.01 mcg/kg/min have been
used to improve cardiac index and further reduce filling
pressures
• When necessary, the infusion dose of nesiritide can be
increased. In the VMAC trial there was limited experience
with increasing the doses in patients who had central
hemodynamic monitoring as follows: 0.005 mcg/kg/min
(preceded by a bolus of 1 mcg/kg), no more frequently
than every 3 hours up to a maximum dose of 0.03
mcg/kg/min. Nesiritide should not be titrated at frequent
intervals as is done with other IV agents that have a
shorter half-life19
Vasodilators Nitroglycerin • 0.2-10 mcg/kg/min IV infusion1
• Titrate by 10-20 mcg/kg/min increments until desired
effect or maximally tolerated dose reached 40
Sodium • Begin infusion at 0.3-0.5 mcg/kg/min IV1
nitroprusside • Increase by 0.5-mcg/kg/min increments and titrate to
desired effect; average dose is 1-6 mcg/kg/min47
• Infusion rates of >10 mcg/mL/min may cause cyanide
toxicity47
Inotropes Dobutamine • 2 to 5 mcg/kg/min infusion 47
• May be titrated until desired therapeutic effect achieved51
• Tolerance may develop even within 48 hours of use and
require further up-titration2,51
Milrinone
• Continuous infusion of 0.25-1.0 mcg/kg/min47
• 50-mcg/kg IV loading dose over 10 minutes may be used
when rapid hemodynamic effects are desired as in
cardiogenic shock, but otherwise treatment is usually
initiated without a bolus, as onset of hemodynamic effects
will occur in 30 minutes and effects will be similar at 2 to
3 hours 63
• Titrate to maintain adequate systolic BP and cardiac
output 63
Dopamine • May be given as low dose regimen (typically
< 2.5 mcg/kg/min) or 2.5- to 5-mcg/kg/min continuous IV
infusion for systemic hemodynamic effects 49
• Titrated to desired hemodynamic effect
• Not to exceed 20 mcg/kg/min
Medications for Treatment of Acute Pulmonary Edema
Class Drug Dosage Applications
Vasodilators Isosorbide • Begin with 1 mg/h; increase to • ADHF with pulmonary edema • Documented
dinitrate 10 mg/h2 and adequate BP 2
Other Morphine • 2-5 mg IV every 5-30 minutes 78 • Early management of ADHF,
particularly for restless and
dyspneic patients2
Although multiple ACE inhibitors are available, only IV enalaprilat and sublingual captopril have been formally evaluated for patients with ADHF. ARBs are considered alternatives to ACE inhibitors,80 but have not been evaluated for patients with ADHF. Current guidelines do not endorse the routine use of ACE inhibitors during the acute phase of heart failure.2
*Multiple oral and parenteral diuretics are currently available in the United States. This primer focuses on the 3 IV diuretics most frequently used by the more than 100,000 patients enrolled in ADHERE. Experimental nesiritide regimen of 0.3 mcg/kg IV bolus followed by 0.015 mcg/kg/min infusion. CI, confidence interval; HR, heart rate; OR, odds ratio.
Adapted with permission from Adams KF Jr, Naccarelli GV. Perspectives on Acute Decompensated Heart Failure Management: Thresholds for Pharmacotherapy. Califon, NJ: SynerMed® Communications; 2005.
Applications Main Contraindications Benefits in ADHF Main Adverse Reactions Renal Actions Mortality Data REFERENCES
• Edema and congestion • Documented • Alleviation of edema and congestion 2,9 Physiological • No large-scale prospective trials to evaluate effects on renal function in patients • No prospective studies of the mortality effects of loop diuretics have been conducted in 1. Zevitz ME. Heart failure. Available at: http://www.emedicine.com/med/topic3552.htm. Accessed
associated with hypersensitivity 1 • Symptomatic relief of dyspnea and symptoms of • May increase RAAS and SNS activity 2 with ADHF patients with ADHF February 16, 2005.
ADHF 2,4-6 • Anuria 1 edema2 • Potassium/magnesium loss8 • Increase SCr levels5,10,11 • Retrospective analysis of data from the ESCAPE trial suggests a dose-related increase in 2. Nieminen MS, Bohm M, Cowie MR, et al. Eur Heart J. 2005;26:384-416.
• Low cardiac output • Electrolyte depletion 1 • Decrease in GFR12,13 6-month mortality15 3. Neuberg GW, Miller AB, O’Connor CM, et al. Am Heart J. 2002;144:31-38.
Clinical 4. LASIX® (furosemide) prescribing information. Bridgewater, NJ: Aventis Pharmaceuticals, Inc.; January
syndrome complicated • Reversible increases in BUN4-6
• Skin reactions8 Chronic Heart Failure 2004. Available at: http://www.aventispharma-us.com/PIs/lasix.pdf. Accessed September 21, 2005.
by congestion 7 • Epidemiological data suggest a possible association between chronic diuretic 5. Bumex® (bumetanide tablets) prescribing information. Nutley, NJ: Roche Laboratories Inc.; March
• Ototoxicity8 • Retrospective analysis of results from PRAISE study in outpatients showed that diuretic
• Hepatic and renal use and increased prevalence of ESRD14 2003. Available at: http://www.rocheusa.com/products/bumex/pi.pdf. Accessed September 21, 2005.
• Gynecomastia8 use was associated with a dose-dependent increase in the risk of death after adjusting for
disease with 6. DEMADEX® (torsemide tablets and injection) prescribing information. Nutley, NJ: Roche Laboratories
• Fluid/electrolyte imbalance8 many baseline clinical characteristics3
associated edema8 Inc.; March 2003. Available at: http://www.rocheusa.com/products/demadex/pi.pdf. Accessed
• Gastrointestinal upset 4 • Baseline diuretic therapy in patients with CHF and systolic dysfunction was associated with September 21, 2005.
• Neurologic events (eg, dizziness, increased mortality16 7. DiDomenico RJ, Park HY, Southworth MR, et al. Ann Pharmacother. 2004;38:649-660.
headache)6 • Associated with increased risk of death/nonrecovery for patients with acute renal failure17 8. Brater DC. N Engl J Med. 1998;339:387-395.
9. Brater DC. Am J Med Sci. 2000;319:38-50.
10. Weinfeld MS, Chertow GM, Stevenson LW. Am Heart J. 1999;138:285-290.
11. Peacock WF, Emerman CL, Costanzo MR, for the ADHERE Scientific Advisory Committee.
Presented at: Heart Failure Society of America 9th Annual Scientific Sessions; September 19, 2005;
Boca Raton, Fla. Abstract 291.
• ADHF patients with • Documented • At currently indicated dose, the drug reduces • Hypotension21 • Increases in SCr may occur during administration of nesiritide. The extent to • No prospective adequately designed studies of the effects of nesiritide on mortality and 12. Cataliotti A, Boerrigter G, Costello-Boerrigter LC, et al. Circulation. 2004;109:1680-1685.
13. Gottlieb SS, Brater DC, Thomas I, et al. Circulation. 2002;105:1348-1353.
dyspnea at rest or with hypersensitivity 19 PCWP, PAP, right atrial pressure, SVR, • Bradycardia21 which changes in renal function depend on concomitant medications or other morbidity in patients with ADHF have been conducted to date
14. Hawkins RG, Houston MC. Am J Hypertens. 2005;18:744-749.
minimal activity 19
• Cardiogenic shock 19 systolic BP 19-21 • Headache19 factors has not been established. As indicated below, renal function has also • Retrospective review of the data from drug development studies conducted to date have 15. Hasselblad V, Stough WG, Shah MR, et al. Presented at: Heart Failure Society of America 9th
• Systolic BP • At currently indicated dose, the drug reduces • Nausea/vomiting19 been noted to improve with nesiritide typically when cardiac index is increased not provided convincing evidence on the effects of nesiritide on mortality or morbidity. The Annual Scientific Sessions; September 19, 2005; Boca Raton, Fla. Abstract 250.
<90 mm Hg 19 PCWP, PAP, right atrial pressure, systolic BP 19-21 in patients with ADHF and “low output” syndrome studies analyzed have had small sample sizes with low event rates, enrolled different 16. Harjai KJ, Dinshaw HK, Nunez E, et al. Int J Cardiol. 1999;71:219-225.
• Low cardiac filling • Increases cardiac index without changing heart rate • Retrospective analysis has identified risk factors for increases in SCr with patient populations, and used different dosing regimens35 17. Mehta RL, Pascual MT, Soroko S, Chertow GM, for the PICARD Study Group. JAMA.
pressures 19 typically at doses above 0.01 mcg/kg/min, but nesiritide, including starting doses above 0.01 mcg/kg/min and the concomitant • Overall 30-day mortality rate from 6 randomized trials with nesiritide to date were 6.2% 2002;288:2547-2553.
individual variation is common 18,21 use of high-dose diuretics23,24 vs. 4.4% with control, a nonsignificant difference.35 18. Adams KF Jr, Mathur VS, Gheorghiade M. Am Heart J. 2003;145(2 suppl):S34-S46.
• Reduces symptomatic dyspnea when added to • Retrospective meta-analysis of various starting doses of nesiritide found SCr • Retrospective meta-analysis of 3 of the 6 ADHF randomized, double-blind studies (N=862) 19. Natrecor® (nesiritide) prescribing information. Freemont, Calif: Scios Inc; April 2005. Available at:
http://www.sciosinc.com/pdf/natrecorpi_final.pdf. Accessed May 25, 2005.
standard therapy (consisting mainly of diuretics)20,21 increases of >0.5 mg/dL in 21% of nesiritide-treated patients vs 15% of controls suggested trend toward increased 30-day mortality (7.2% vs 4.0%, P=.059)36 20. Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531-1540.
• May reduce plasma aldosterone levels 21 (P=.001) and greater need for intervention for WRF (11% vs 4%, P=.03) 25 • Trials used in this meta-analysis were small, had short follow-up periods, and few deaths; 21. Colucci WS, Elkayam U, Horton DP, et al, for the Nesiritide Study Group. N Engl J Med.
• Does not have proarrhythmic effect 22 • Other studies suggest neutral effect on renal function26-28 inotrope use at baseline was greater with nesiritide, possibly increasing mortality; the analysis 2000;343:246-253.
• In addition, several studies report improvements in renal function and included intention to treat, and some deaths occurred before nesiritide was administered35 22. Burger AJ, Horton DP, LeJemtel T, et al. Am Heart J. 2002;144:1102-1108.
blood flow 29-31 • Among the 5 trials that reported 6-month mortality, the rates were 21.5% vs 20.7% with 23. Abraham WT. Circulation. 2005;112(17 supp II):II-589. Abstract 2789.
• May improve diuresis, sodium excretion, and GFR32 control, a nonsignificant difference.19 24. Heywood JT. Circulation. 2005;112(17 supp II):II–451-II–452. Abstract 2180.
• No correlation between nesiritide and WRF in VMAC33 • Baseline differences in mortality risk factors may significantly influence mortality rates in 25. Sackner-Bernstein JD, Skopicki H, Aaronson KD. Circulation. 2005;111:1487-1491.
• 89% of SCr increases in nesiritide-treated patients in VMAC were transient32 clinical trials not powered to assess mortality. Of the variables with baseline differences, 26. Butler J, Emerman C, Peacock WF, Mathur VS, Young JB, for the VMAC Study Investigators.
Nephrol Dial Transplant. 2004;19:391-399.
• In the VMAC trial through day 30, the incidence of elevations in creatinine to creatinine clearance ≤60 mL/min, SBP ≤100 mm Hg, prior dopamine or dobutamine use, 27. Redfield MM, Chen HH, Miller WL, Karon BL, Frantz RP, Burnett JC Jr. Presented at: Heart Failure
>0.5 mg/dL above baseline was 28% and 21% in the nesiritide (2 mcg/kg bolus and history of ventricular tachycardia were significant predictors of mortality, using Society of America 9th Annual Scientific Sessions; September 19, 2005; Boca Raton, Fla. Abstract
followed by 0.01 mcg/kg/min) and nitroglycerin groups, respectively19 univariate Cox regression models. These baseline covariates may account for the excess 221.
• Nesiritide may affect renal function in susceptible individuals. In patients mortality observed in subjects receiving nesiritide in VMAC37 28. Wang DJ, Dowling TC, Meadows D, et al. Circulation. 2004;110:1620-1625.
with severe heart failure whose renal function may depend on activity of the • The 237-patient PROACTION study (Prospective Randomized Outcomes Study of Acutely 29. Riter HG, Redfield MM, Burnett JC Jr, Chen HH. Presented at: Heart Failure Society of America 9th
RAAS, treatment with nesiritide may be associated with azotemia. When Decompensated Heart Failure Treated Initially as Outpatients with Nesiritide), which, like Annual Scientific Sessions; September 19, 2005; Boca Raton, Fla. Abstract 251.
nesiritide was initiated at doses higher than 0.01 mcg/kg/min (0.015 and VMAC, was not powered to access mortality, reported similar outcomes. The study compared 30. Zakir RM, Patel RJ, Saric M, Berkowitz RL. Presented at: Heart Failure Society of America 9th
Annual Scientific Sessions; September 19, 2005; Boca Raton, Fla. Abstract 395.
0.03 mcg/kg/min), there was an increased rate of elevated SCr over baseline the use of nesiritide plus standard care (diuretic, oxygen, and one of more vasodilators) with 31. Akhter MW, Singh H, Bourji N, et al. Circulation. 2004;110(suppl III):III-556. Abstract.
compared with standard therapies, although the rate of acute renal failure and placebo plus standard care among ADHF patients in the emergency department. At 30 days, 32. Bhalla V, Willis S, Maisel AS. Congest Heart Fail. 2004;10(suppl 1):S3-S27.
need for dialysis was not increased. In the 30-day follow-up period in the VMAC mortality was 5.9% with nesiritide versus 0.9% with placebo (P =.066). At 180-day follow-up, 33. Burger AJ. Presented at: Heart Failure Society of America 9th Annual Scientific Sessions;
trial, 5 patients in the nitroglycerin group (2%) and 9 patients in the nesiritide the perceived, and nonsignificant, gap in 30-day mortality had largely disappeared. The rates September 19, 2005; Boca Raton, Fla. Abstract 345.
group (3%) required first-time dialysis (P=NS)19 were 20.6% with nesiritide versus 17.5% with placebo (P =.479).38 34. Elkayam U. Circulation. 2005;112(17 supp II):II-676. Abstract 3168.
• SCr increases in patients treated with nesiritide were not associated with an • In a retrospective analysis of the ADHERE registry, cases in which patients received 35. Abraham WT. Previews in Cardiovasc Med. 2005;6:2.
increased risk of acute mortality when compared with control 34 nitroglycerin, nesiritide, milrinone, or dobutamine (N=15,230) were reviewed and risk 36. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. JAMA. 2005;293:1900-1905.
37. Abraham WT. Circulation. 2005;112(17 supp II):II-589. Abstract 2790.
factor and propensity score-adjusted ORs for in-hospital mortality were calculated.
38. Abraham WT. Circulation. 2005;112(17 supp II):II-676. Abstract 3169.
Patients who received IV nitroglycerin or nesiritide had lower in-hospital mortality than 39. Abraham WT, Adams KF Jr, Fonarow GC, et al. J Am Coll Cardiol. 2005;46:57-64.
those treated with dobutamine or milrinone. The adjusted OR for nesiritide compared with 40. Elkayam U, Bitar F, Akhter MW, Khan S, Patrus S, Derakhshani M. J Cardiovasc Pharmacol Ther.
nitroglycerin was 0.94 (95% CI, 0.77 to 1.16, P=.58), reflecting a similar in-hospital 2004;9:227-241.
mortality for nitroglycerin and nesiritide39 41. Elkayam U, Akhter MW, Singh H, Khan S, Usman A. Am J Cardiol. 2004;93:237-240.
42. Larsen AI, Goransson L, Aarsland T, Tamby JF, Dickstein K. Am Heart J. 1997;134:435-441.
• ADHF with symptoms • Documented sensitivity • Dose-related acute veno- and arterial dilation well • Tolerance to hemodynamic effects, • No prospective trials on renal safety in patients with ADHF • No prospective mortality trials to date 43. Nitroglycerin (glyceryl trinitrate) general monograph. Available at:
http://www.rxmed.com/b.main/b2.pharmaceutical/b2.prescribe.html. Accessed September 21,
of volume overload • Hypotension 40 documented in patients with chronic heart failure 2 including reduction in filling pressures • Excreted through renal pathway43 • Retrospective analysis of data from the VMAC study demonstrated 7-day and 6-month
2005.
and adequate BP 2,7 • Shock 40 • Rapid dose-related reduction in preload and are common within 12 to 24 hours of • Caution is advised when administering to patients with severe renal or hepatic mortality rates of 0.5% and 20.8%, respectively20 44. Heywood JT. Presented at: Heart Failure Society of America 9th Annual Scientific Sessions;
afterload well documented in patients with chronic administration, more so at higher doses 2 disease43 • In a retrospective analysis of the ADHERE registry, cases in which patients received September 20, 2005; Boca Raton, Fla. Abstract 255.
heart failure40 • Hypotension 2,20 • No correlation between nitroglycerin and WRF in VMAC33 nitroglycerin, nesiritide, milrinone, or dobutamine (N=15,230) were reviewed and risk 45. Flaim SF, Weitzel RL, Zelis R. Circ Res. 1981;49:458-468.
• High doses acutely reduced filling pressures in • Headache 2,20 • 92% of SCr increases in nitroglycerin-treated patients in VMAC were transient 44 factor and propensity score-adjusted ORs for in-hospital mortality were calculated. 46. Elkayam U, Cohen G, Gogia H, Mehra A, Johnson JV, Chandraratna PA. J Am Coll Cardiol.
ADHF (but not lower doses), but rapid development • Experimental data suggest increased renal blood flow, but human data Patients who received IV nitroglycerin or nesiritide had lower in-hospital mortality than 1996;28:176-182.
of hemodynamic tolerance was documented as do not 45,46 those treated with dobutamine or milrinone. The adjusted OR for nesiritide compared with 47. Jain P, Massie BM, Gattis WA, Klein L, Gheorghiade M. Am Heart J. 2003;145(2 suppl):S3-S17.
well 41 • May have neutral effect on renal vascular resistance and blood flow 46 nitroglycerin was 0.94 (95% CI, 0.77 to 1.16, P=.58), reflecting a similar in-hospital 48. Khot UN, Novaro GM, Popovic ZB, et al. N Engl J Med. 2003;348:1756-1763.
• Higher doses generally necessary to reduces SVR42 mortality for nitroglycerin and nesiritide 39 49. Cohn JN. Cardiovasc Drugs Ther. 1994;8:119-122.
50. Teerlink JR. Am J Cardiol. 2005;96(6a):59G-67G.
51. Leier CV. Am J Med. 1986;81(4c):40-45.
• Severe low output • Documented • Reduces preload and afterload with fall in central • Excessive hypotension, close monitoring • Not studied in broad populations of patients with ADHF • No prospective mortality trials in patients with ADHF2
52. Leier CV, Binkley PF. Prog Cardiovasc Dis. 1998;41:207-224.
heart failure2 hypersensitivity1 venous and systemic pressures47 of blood pressure recommended1 • Only use for patients with adequate renal function47 • Results in acute MI equivocal2 53. Bayram M, De Luca L, Massie MB, Gheorghiade M. Am J Cardiol. 2005;96(6a):47G-58G.
• Increased afterload • Hypotension 49 • Increases cardiac index and reduces filling • May increase heart rate50 • Thiocyanate and cyanide levels may become toxic in patients with insufficient • May increase mortality in MI patients without heart failure42 54. Leier CV. In: Leier CV, ed. Cardiotonic Drugs: A Clinical Survey. New York, NY: Marcel Dekker;
(eg, hypertensive heart • Arteriovenous shunt or pressure49 • “Coronary steal syndrome” in ADHF renal function 47 1986:49-84.
failure or mitral coarctation of aorta1 caused by ACS 2,47
55. Dobutrex® (dobutamine HCl) prescribing information. Indianapolis, Ind: Eli Lilly and Company; July
regurgitation)2 • Atrial fibrillation/flutter, • May increase thiocyanate and 1998. Available at: http://www.rxmed.com/b.main/b2.pharmaceutical/b2.prescribe.html. Accessed
• Severe aortic stenosis especially when cyanide levels47 September 21, 2005.
with hemodynamic ventricular rate is rapid • Methemoglobeminia (rare) 47 56. Wimmer A, Stanek B, Kubecova L, et al. Jpn Heart J. 1999;40:321-334.
compromise 48 (relative)1 57. Duke GJ, Briedis JH, Weaver RA. Crit Care Med. 1994;22:1919-1925.
58. O’Connor CM, Gattis WA, Uretsky BF, et al. Am Heart J. 1999;138:78-86.
59. Elkayam U, Tassisa G, Binanay C, et al. Circulation. 2004;110(suppl III):III-515. Abstract 2415.
• ADHF with cardiogenic • Documented • Increased stroke volume and cardiac output due to • Atrial and ventricular arrhythmia, which • No direct effect on renal vasculature reported55 • No controlled trials of the effect of dobutamine plus standard therapy vs standard therapy 60. Adams KF Jr, De Marco T, Berkowitz RL, Chang S. Circulation. 2003;108(suppl IV):IV-695. Abstract
shock and/or signs or hypersensitivity1 positive inotropy 53 may be severe, such as rapid atrial • No consistent effect on renal function alone on mortality in patients with ADHF2 3158.
symptoms of • Idiopathic hypertrophic • Reduces left ventricular filling pressures 53 fibrillation or ventricular tachycardia • May, however, improve renal perfusion in patients with low-output syndrome, 61. Felker GM, O’Connor CM. Am Heart J. 2001;142:393-401.
Observational data
peripheral subaortic stenosis 51 • Reduces systemic afterload2 fibrillation 2
which increases GFR, reduces SCr, and increases diuresis 2,56,57 62. Silver MA, Horton DP, Ghali JK, Elkayam U. J Am Coll Cardiol. 2002;39:798-803.
• Adjusted in-hospital mortality in ADHERE: 13.9% vs 12.3% with milrinone; 4.7% with
hypoperfusion 2,52 • Atrial fibrillation or • May improve diuresis 2 • Excessive tachycardia 54,55
63. Baruch L, Patacsil P, Hameed A, Pina I, Loh E. Am Heart J. 2001;141:266-273.
nitroglycerin; and 7.1% with nesiritide39
flutter51 • Vasoconstriction at high doses 2 64. PRIMACOR® (milrinone lactate injection) prescribing information. North Chicago, Ill: Sanofi-
• In the FIRST study, use of dobutamine at entry into the trial was associated with higher Synthelabo Inc.; January 2003. Available at: http://www.sanofisynthelabo.us/products/pi_primacor/
• May cause ischemia and induce
mortality after 6 months of follow-up58 pi_primacor.html. Accessed September 21, 2005.
chest pain2
• Preliminary data from the ESCAPE study found that inotrope but not vasodilator use was 65. Anderson JL, Baim DS, Fein SA, Goldstein RA, LeJemtel TH, Likoff MJ, for the Milrinone
• Weaning may result in renal insufficiency Investigators and their associates. J Am Coll Cardiol. 1987;9:711-722.
associated with increased 6-month mortality vs other therapies which persisted when
or hypotension, especially if done 66. Cody RJ. Am J Cardiol. 1989;63:31A-34A.
outcomes were adjusted for renal function and blood pressure59
abruptly 2 67. Cody RJ, Kubo SH, Covit AB, et al. Clin Pharmacol Ther. 1986;39:128-135.
• Preliminary unadjusted analysis from the ADHERE registry suggests that use of inotropes
68. Cuffe MS, Califf RM, Adams KF Jr, et al. JAMA. 2002;287:1541-1547.
was associated with a marked increase in mortality in patients with ADHF and preserved 69. Intropin® (dopamine HCl) prescribing information. Wilmington, Del: DuPont Pharma; August 1992.
systolic function (19% vs 2% in untreated, P<.0001)60 Available at: http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Mono
• Systematic review of the use of inotropes in acute and chronic HF suggests a negative graphs/CPS-%20(General%20Monographs-%20I)/INTROPIN.html. Accessed September 21, 2005.
impact on survival except in the very limited number of patients that present with severe 70. Friedrich JO, Adhikari N, Herridge MS, Beyene J. Ann Intern Med. 2005;142:510-524.
“low output failure” who are candidates for bridge to more definitive therapy (assist device 71. Kellum JA, J MD. Crit Care Med. 2001;29:1526-1531.
or transplantation)61 72. Cotter G, Metzkor E, Kaluski E, et al. Lancet. 1998;351:389-393.
• Trend towards higher 6-month mortality vs low-dose nesiritide (31% vs 18%, P<.05)†62 73. Sharon A, Shpirer I, Kaluski E, et al. J Am Coll Cardiol. 2000;36:832-837.
74. Masip J, Betbese AJ, Paez J, et al. Lancet. 2000;356:2126-2132.
75. Isordil® Titradose® (isosorbide dinitrate tablets) prescribing information. Philadelphia, Pa: Wyeth
• Mild to moderate low • Documented • Increases cardiac output 63 • Ventricular arrhythmias, including • Effects not well studied in clinical trials to date • Associated with increased risk of death with patients with CHF64
Laboratories; July 2001. Available at: http://www.biovail.com/local/files/IsordilPI.pdf. Accessed
cardiac output 7 hypersensitivity64 • Reduces preload and afterload 65 sustained and nonsustained ventricular • May have neutral effect on GFR, renal blood flow, and renal vascular • The OPTIME study, which was a prospective placebo-controlled (standard therapy), September 21, 2005.
• ADHF with peripheral • Atrial fibrillation • Decreases PAP and PCWP2 tachycardia and ventricular fibrillation64 resistance66,67 randomized trial, showed trend toward increased in-hospital (3.8% vs 2.3%, P=.19) and 76. Wanless RB, Anand IS, Gurden J, Harris P, Poole-Wilson PA. J Pharmacol Exp Ther.
hypoperfusion 2 especially when • Atrial fibrillation64 • Patients with low cardiac output syndrome may have improvement in renal 60-day death (10.3% vs 8.9%, P=.41) among patients with ADHF 68 1987;243:1101-1106.
ventricular response is • Hypotension64 blood flow and GFR from increasing cardiac output 61 • ADHERE unadjusted in-hospital mortality: 12.3% vs 13.9% with dobutamine*; 7.1% with 77. Mantle JA, Russell RO, Tauxe WN, Dustan HP, Rogers WJ, Rackley CE. Nouv Presse Med.
not well controlled53 • Angina/chest pain64 nesiritide*; and 4.7% with nitroglycerin39 1980;9(34 suppl):2399-2403.
• Headache64 78. Fonarow GC. Rev Cardiovasc Med. 2002;3(suppl 4):S18-S27.
79. Meine TJ, Roe MT, Chen AY, et al. Am Heart J. 2005;149:1043-1049.
80. Jong P, Demers C, McKelvie RS, Liu PP. J Am Coll Cardiol. 2002;39:463-470.
81. Acute Decompensated Heart Failure National Registry (ADHERE). Acute Decompensated Heart
Failure National Registry: 4th quarter 2004 national benchmark report. Available at:
• Same as dobutamine • Documented • Selective vasodilation in renal, splanchnic, • Ectopic beats69 • Angina69 • May improve renal perfusion and GFR with improvement in natriuresis and • No prospective randomized controlled trials evaluating effect on morbidity and mortality in http://www.adhereregistry.com. Accessed October 28, 2005.
hypersensitivity69 coronary, and cerebral vascular beds at doses • Nausea69 • Palpitations69 diuresis2 ADHF
• Pheochromocytoma69 <2 mcg/kg/min 2 • Vomiting69 • Headache69 • However, available overview data do not clearly support favorable effects on • Inotropic properties cause similar general concern about the potential for an adverse effect
• Ventricular fibrillation 69 • May enhance diuresis and sodium excretion 2 • Tachycardia69 • kidney function. Increases in urine output are short-lived 70 on survival consistent with a class effect
• Increases myocardial contractility and output 2 Vasoconstriction69 • Meta-analysis of ARF patients suggests no mortality benefit 71 ABBREVIATIONS
ACE angiotensin-converting enzyme OPTIME-CHF Outcomes of a Prospective
ACS acute coronary syndrome Trial of Intravenous
Main Contraindications Benefits in Acute Pulmonary Edema Main Adverse Reactions Renal Actions Mortality Data
ADHERE Acute Decompensated Heart Milrinone for Exacerbations
• Venous and arterial dilation 50 • Hypotension2 • No dedicated trials in patients with acute pulmonary edema • No prospectively conducted mortality trials in acute Failure National Registry of Chronic Heart Failure
hypersensitivity 50 • Reduces arterial BP 72 • Headache2 • Experimental data suggest possible increase in renal pulmonary edema ADHF acute decompensated heart failure PAP pulmonary artery pressure
• Allergy to organic nitrates 47 • Some reports show it may be safer than BiPAP. For patients with severe pulmonary edema, • Tolerance75 blood flow 76 • For patients admitted with severe pulmonary edema In ARB angiotensin receptor blocker PCWP pulmonary capillary wedge
lower incidence of death, need for mechanical ventilation within 24 hours of hospital • May improve renal plasma flow 77 randomized comparison with furosemide, mortality was 2% ARF acute renal failure pressure
admission than with BiPAP (25% vs 85%, P=.0003).73 But others find positive pressure vs 6% with the diuretic (P=.61) 72 BiPAP bilevel positive airway ventilation PO orally
support superior.74 BP blood pressure PRAISE Prospective Randomized
• Compared with high dose furosemide, combination of low dose furosemide and ISDN BUN blood urea nitrogen Amlodipine Survival
resulted in less need for mechanical ventilation (13% vs 40%, P=.0041) and lower CHF chronic heart failure Evaluation
incidence of MI than with furosemide (17% vs 37%, P=.047)72 ESCAPE The Evaluation Study of PVR pulmonary vascular
Congestive Heart Failure and resistance
• Documented hypersensitivity • Reduces preload and afterload 78
• Central nervous system suppression 78 • Not established; no randomized trials in ADHF patients to • Not established; no randomized trials in ADHF patients to Pulmonary Artery Catheterization RAAS renin-angiotensin-
• Venodilation78 • Ventilatory depression 78 determine risks and benefits 78 determine risks and benefits78 Effectiveness aldosterone-system
• Decreases dyspnea78 • Nausea/vomiting1 • Compared with placebo and nitroglycerin, morphine increases
ESRD end-stage renal disease SCr serum creatinine
• Reduces SNS activation 78 • Associated with increased risk of death, MI, cardiogenic risk of death and other adverse outcomes for ACS patients79
FIRST The FGF-2 Initiating SNS sympathetic nervous system
shock, and CHF in patients with ACS 79
Revascularization Support Trial SVR systemic vascular resistance
GFR glomerular filtration rate VMAC Vasodilation in the
IM intramuscular Management of Acute
81 † ‡
IV intravenous Congestive Heart Failure
MI myocardial infarction WRF worsening renal function