Nesiritide in Acute Decompensated Heart Failure

Nesiritide in Patients
with Acute Decompensated Heart
Failure

By Sheelendra Shakya
Cardiology Unit II, First Affiliated Hospital, Jiamusi University

Introduction
 Acute decompensated heart failure is a major health
problem that is associated with several million
hospitalizations worldwide each year, poor short-
term outcomes, and high costs.
 Despite the magnitude of the problem, rates of early
death and rehospitalization have not improved over
the past several decades.

Acute Decompensated
Heart Failure
 Majority of patients hospitalized with HF have
evidence of systemic hypertension on admission and
commonly have preserved left ventricular ejection
fraction (LVEF).
 Most hospitalized patients have significant volume
overload, and congestive symptoms predominate.
 Patients with severely impaired systolic function,
reduced blood pressure and symptoms from poor
end-organ perfusion are in the distinct minority.

Journal of Cardiac Failure Vol. 16 No. 6 June 2010

Causes of Decompensation
Precipitating factors No. Percentage (%)
Arrhythmia 7155 13.5

Uncontrolled Hypertension 5220 10.7

Ischemia/ACS 6552 14.7

Worsening renal function 3304 6.8

Pneumonia/Respiratory process 7426 15.3

Nonadherence to medications 4309 8.9

Nonadherence to diet 2504 12.7

Other 6171 12.7
Optimize-HF; Arch Int Med 2008; 168:847-54

No. of precipitating factors No. Percentage (%)
0 18798 38.7
1 20504 42.2
2 6599 13.6
3 2050 4.2
>= 4 661 1.4

Arrhythmias, worsening renal function might be secondary than primary.

Optimize-HF; Arch Int Med 2008; 168:847-54

Diagnosis
 The diagnosis of ADHF should be based primarily on
signs and symptoms.
 When the diagnosis is uncertain, determination of
plasma B-type natriuretic peptide (BNP) or N-terminal
pro-B-type natriuretic peptide (NT-proBNP)
concentration is recommended in patients evaluated for
dyspnea who have signs and symptoms compatible with
HF.
 The natriuretic peptide concentration should not be
interpreted in isolation, but in the context of all
available clinical data bearing on the diagnosis of HF,
and with the knowledge of cardiac and non-cardiac
factors that can raise or lower natriuretic peptide levels.


Treatment Goals
 Improve symptoms, especially congestion and low-output symptoms
 Restore normal oxygenation

 Optimize volume status

 Identify etiology

 Identify and address precipitating factors

 Optimize chronic oral therapy

 Minimize side effects

 Identify patients who might benefit from revascularization

 Identify patients who might benefit from device therapy

 Identify risk of thromboembolism and need for anticoagulant therapy

 Educate patients concerning medications and self management of HF

 Consider and, where possible, initiate a disease management program.


Treatment Strategy
 Fluid Overload:
 Sodium (2g/day) and fluid restriction (<2 L/day)
 Loop diuretics administered at doses needed to produce
a rate of diuresis sufficient to achieve optimal volume
status with relief of signs and symptoms of congestion,
without inducing an excessively rapid reduction in
intravascular volume or serum electrolytes.
 Addition of second type of diuretic (metolazone or
spironolactone) orally or i.v. (cholorothiazide)
 Ultrafiltration


 Supplemental Oxygen
 Routine administration of supplemental Oxygen in
presence of hypoxia only.
 Use of non-invasive positive pressure ventilation may be
considered for severly dyspneic patientswith clinical
evidence of pulmonary edema.

 Venous thromboembolism prophylaxis
 UFH or LMWH to prevent proximal DVT and PE is
recommended for patients who are not already
anticoagulated and have no contraindication to
anticoagulation. If contraindicated, consider
intermittent pneumatic compression devices or graded
compression stockings.


 IV vasodilators
 In absence of symptomatic hypotension, intravenous
nitroglycerin, nitroprusside or nesiritide may be
Nesiritide
considered for rapid improvement of congestive
controversy
symptoms or severe hypertension and for patients who
have persistent severe HF despite aggressive treatment
with diuretics and standard oral therapies.
 Frequent blood monitoring is recommended upon use.
 Decreased in dosage or discontinued if symptomatic
hypotension or worsening renal function develops. Can
be reintroduced once symptoms resolved.


 IV inotropes
 Milrinone or dobutamine may be considered to relieve
symptoms and improve end-organ function in patients
with advanced HF characterized by LV dilation,
reduced LVEF, and diminished peripheral perfusion or
end-organ dysfunction (low output syndrome),
particularly if SBP <90mmHg, symptomatic
hypotension despite adequate filling pressure, or are
unresponsive to, or intolerant of, intravenous
vasodilators.
 In patients with evidence of fluid overload if they
respond poorly to iv diuretics or manifest diminished or
worsening renal function.


 ACE inhibitors
 ACE inhibitors are recommended for routine administration to
symptomatic and asymptomatic patients with LVEF < 40%.

 Angiotensin Receptor Blockers (ARBs)
 In patients who cannot tolerate ACE inhibitors due to cough,
ARBs are recommended.
 The combination of hydralazine and an oral nitrate may be
considered in such patients not tolerating ARB therapy.
 Individual ARBs may be considered as initial therapy rather than
ACE inhibitors for patients with the following conditions:
 HF post MI
 Chronic HF and reduced LVEF


 Beta blockers
 Beta blockers shown to be effective in clinical trials of patients with HF
are recommended for patients with an LVEF <=40%.
 The combination of a beta blocker and an ACE inhibitor is
recommended as routine therapy for asymptomatic patients with a
LVEF <=40% in both post MI and non post MI.
 Patients with a recent decompensation of HF after optimization of
volume status and successful discontinuation of intravenous diuretics
and vasoactive agents, including inotropic support. Whenever possible,
beta blocker therapy should be initiated in the hospital setting at a low
dose prior to discharge in stable patients.
 Beta blocker therapy is recommended in the great majority of patients
with HF and reduced LVEF, even if there is concomitant diabetes,
chronic obstructive lung disease, or peripheral vascular disease.
 It is recommended that beta blocker therapy be continued in most
patients experiencing a symptomatic exacerbation of HF during chronic
maintenance treatment, unless they develop cardiogenic shock,
refractory volume overload, or symptomatic bradycardia.


 Anticoagulation and Antiplatelet drugs
 Treatment with warfarin (goal international normalized ratio [INR] 2.0-3.0) is
recommended for all patients with HF and chronic or documented
paroxysmal, persistent, or long-standing atrial fibrillation or a history of
systemic or pulmonary emboli, including stroke or transient ischemic attack,
unless contraindicated.
 It is recommended that patients with symptomatic or asymptomatic ischemic
cardiomyopathy and documented recent large anterior MI or recent MI with
documented LV thrombus be treated with warfarin (goal INR 2.0-3.0) for the
initial 3 months post-MI unless contraindicated.
 Long-term treatment with an antiplatelet agent, generally aspirin in doses of
75 to 81 mg, is recommended for patients with HF due to ischemic
cardiomyopathy, whether or not they are receiving ACE inhibitors.
 Warfarin (goal INR 2.0-3.0) and clopidogrel (75 mg) also have prevented
vascular events in post-MI patients and may be considered as alternatives to
aspirin.
 Routine use of aspirin is not recommended in patients with HF without
atherosclerotic vascular disease.


 Digoxin
 Digoxin may be considered to improve symptoms in
patients with reduced LVEF (LVEF <=40%) who have
signs or symptoms of HF while receiving standard therapy,
including ACE inhibitors and beta blockers in NYHA
grade II,III,IV.
 Digoxin should be considered for achieving adequate
control of the ventricular response to atrial fibrillation in
patients with HF.

 Amiodarone
 In patients with HF and an ICD, amiodarone may be
considered to reduce the frequency of recurrent
symptomatic arrhythmias causing ICD shocks.


Discharge Criteria
 Exacerbating factors addressed.
 Near optimal volume status observed.
 Transition from iv to oral diuretic successfully completed.
 Patient and family education completed, including clear
discharge instructions.
 LVEF documented.
 Smoking cessation counseling initiated.
 Near optimal pharmacologic therapy achieved, including
ACEI and beta blocker.
 Follow –up clinic visit scheduled usually for 7-10 days.


Discharge criteria
 Oral medication regimen stable for 24 hours
 No intravenous vasodilator or inotropic agent for 24
hours
 Ambulation before discharge to assess functional
capacity after therapy
 Plans for postdischarge management (scale present in
home, visiting nurse or telephone follow up generally
no longer than 3 days after discharge)
 Referral for disease management, if available.


The Nesiritide Timeline
 1999:
 Coronary Vasodilatory effects of BNP documented

 2001:
 Approved by FDA for use in ADHF

 2005
 Concerns of worsening renal function and increased death rate

 2010
 Concerns addressed by ASCEND-HF

Nesiritide
 Nesiritide, a recombinant B-type natriuretic peptide
(BNP) with vasodilatory properties, was approved in
2001 for use in patients with acute heart failure on
the basis of studies showing a reduction in
pulmonary-capillary wedge pressure and
improvement in dyspnea at 3 hours.
 Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of
decompensated congestive heart failure. N Engl J Med 2000;343:246-53.
 Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized
controlled trial. JAMA 2002;287:1531-40.
 Zellner C, Protter AA, Ko E, et al. Coronary vasodilator effects of BNP: mechanisms of action in coronary
conductance and resistance arteries. Am J Physiol 1999;276:H1049-57.

 Facilitates cardiovascular fluid homeostasis through counter-regulation of
the renin-angiotensin-aldoesterone system, stimulating cyclic guanosine
monophosphate, leading to smooth muscle cell relaxation.

VMAC trial
 Vasodilation in the Management of Acute
Congestive Heart Failure (VMAC)
 A Study Comparing Blood Flow and Clinical and
Safety Effects of the Addition of Nesiritide, Placebo or
Intravenous Nitroglycerin to Standard Care for the
Treatment of Worsening Congestive Heart Failure.
 Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study
 Study Period from Oct 1999 to August 2000
 N=498

Outcome measures
Primary Outcome Secondary Outcome
 Change from baseline to 3 hours  Effect on PCWP (pulmonary
after the start of study drug in capillary wedge pressure) and
PCWP (pulmonary capillary dyspnea (difficult breathing) 1
wedge pressure) in subjects who hour after the start of study
have right heart catheters; drug;

 Change from baseline in  Onset of effect on PCWP;
dyspnea (difficult breathing) 3
hours after the start study drug  Effect on PCWP 24 hours after
the start of study drug;

 Overall safety profile

Inclusion criteria
 Patients with dyspnea (difficulty breathing and shortness of breath) at rest,
while supine, or immediately upon minimal activity such as talking, eating,
or bathing

 Having evidence of heart disease, rather than pulmonary disease, as the
primary cause for the dyspnea (by demonstrating at least two of the
following: jugular venous distension, paroxysmal nocturnal dyspnea or 2-
pillow orthopnea within 72 hours before the start of study drug, abdominal
discomfort due to hepato-splanchnic congestion, chest x-ray with findings
indicative of heart failure)

 Having elevated cardiac filling pressures either by clinical estimate in non-
catheterized patients, or a measured pulmonary capillary wedge pressure
(PCWP) >= 20 mm Hg in catheterized patients

 Requiring hospitalization and intravenous therapy for at least 24 hours for
the treatment of acutely decompensated heart failure.

Exclusion Criteria
 Patients having systolic blood pressure consistently less than 90 mm Hg

 Having cardiogenic shock (a sudden decrease in blood pressure that results
in decreased perfusion of body tissues and organs), volume depletion, or
any other clinical condition that would contraindicate the administration of
an intravenous agent with potent vasodilating properties

 Having their most recent pulmonary capillary wedge pressure (PCWP) < 20
mm Hg within 24 hours before randomization

 Having a clinical status so acutely unstable that the potential subject could
not tolerate placement of a right heart catheter or the 3-hour placebo period

 Unable to have intravenous nitroglycerin withheld (e.g., intravenous
nitroglycerin for management of an acute coronary syndrome).

Study Drug
Administration
 Nitroglycerin: 216 patients were taking a titrated
dose of nitroglycerin,
 Nesiritide fixed-dose: 211 received 2 mcg/kg bolus
and 0.01 mcg/min infusion of nesiritide and
 Nesiritide adjustable dose: 62 received 2 mcg/kg
bolus and 0.01 mcg/min infusion nesiritide for the
first 3 hours, followed by an adjustable dose that
could be increased up to 0.03 mcg/kg/min.
 Placebo

Outcome
 BNP significantly reduced PCWP and all PA pressures, compared
to NTG and PL, by 15 minutes and through the 3 hour period.

 At 3 hours, dyspnea was improved by BNP compared to PL
(p=0.034); the change in dyspnea with NTG was not statistically
significant (p=0.191).

 By 24 hours, symptomatic hypotension occurred in only 4% of
BNP patients and 5% of NTG patients, whereas more headache
occurred with NTG (20% vs. 8%, p<0.001).

 Fewer adverse events overall occurred in patients treated with
BNP than with NTG (p<0.001).

Conclusion
 When added to standard care, fixed-dose
administration of nesiritide produced a more rapid
and greater improvement in hemodynamics than
NTG titration or standard care alone (PL).
 Nesiritide, but not NTG, was associated with
significant improvements in dyspnea, compared to
standard care alone (PL).

Limitations
 Nesiritide significantly increases the risk of worsening renal
function in patients with ADHF. Whether worsening renal
HR function reflects hemodynamic effect or renal injury is
1.5 unknown, but the prognostic importance of worsening renal
function suggests the need for further investigation in
appropriately powered clinical trials.
 Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with
acutely decompensated heart failure. Circulation 2005;111:1487-91.

 Compared with non inotrope-based control therapy, nesiritide
may be associated with an increased risk of death after
HR treatment for acutely decompensated heart failure. The
1.8 possibility of an increased risk of death should be investigated
in a large-scale, adequately powered, controlled trial before
routine use of nesiritide for acutely decompensated heart
failure.
 Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for
decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005;293:1900-5.

ASCEND-HF
 Acute Study of Clinical Effectiveness of Nesiritide in
Decompensated Heart Failure (ASCEND-HF) trial
was designed to evaluate the effect of nesiritide, in
addition to standard care, on rates of self reported
dyspnea at 6 and 24 hours, rehospitalization for
heart failure or death from any cause at 30 days, and
renal dysfunction.
 Multicentered, Randomized, Double-blind, Placebo-
controlled trial.
 conducted from May 2007 through August 2010 at 398
centers throughout the world.

Study Patients
 Hospitalized for heart failure occurring within 24
hours before they received their first intravenous
treatment for heart failure.
 Diagnosed of acute decompensated heart failure less
than 48 hours after hospitalization for another cause.

Additional Criteria
 Dyspnea at rest or with minimal activity
 One or more accompanying signs
 respiratory rate ≥20 breaths per minute
 pulmonary congestion or edema with rales one third of the way
or more up the lung fields)

 One or more objective measures of heart failure
 evidence of congestion or edema on chest radiography,
 a BNP level ≥400 pg per milliliter
 an N-terminal pro-BNP level ≥1000 pg per milliliter
 pulmonary-capillary wedge pressure >20 mm Hg
 left ventricular ejection fraction <40% in the previous 12
months

Key exclusion criteria
 A high risk of hypotension
 Systolic pressure <100 mm Hg or 110 mm Hg with the use of intravenous nitroglycerin

 Acute coronary syndrome as primary diagnosis

 History of cardiac valvular stenosis, restrictive cardiomyopathy, hypertrophic cardiomyopathy,
or pericardial tamponade

 Persistent, uncontrolled hypertension (SBP [systolic blood pressure] >180 mmHg)

 Previous enrollment in a nesiritide study

 Normal level of BNP or N-terminal pro-BNP

 Severe pulmonary disease

 End-stage renal disease during receipt of renal replacement therapy

 Clinically significant anemia

Study Drug administration
Eligible Patients Management
 All participants received standard
therapies, including diuretics,
morphine, and other vasoactive
medications.
 Study group: Nesiritide infusion
at 0.010 μg per kilogram per
minute (with or without a 2 μg per
kilogram bolus) for 24 hours or
more for up to 7 days.
Nesiritide Placebo  Placebo group: Matching placebo
N = 3496 N = 3511 infusion at 0.010 μg per kilogram
per minute for 24 hours or more
for up to 7 days.

Outcome measures
Primary Endpoint Likert Scale
 Composite of Rehospitalization  7-point ordinal categorical scale
Due to Heart Failure and All-
Cause Mortality
 Markedly better
[ Time Frame: Randomization to Day 30 ]  Moderately better
 Dyspnea Self-Assessment at 6  Minimally better
Hours After Initiation of Study  Unchanged
Drug [ Time Frame: 6 hours after initiation of
study drug ]  Minimally worse
 Dyspnea Self-Assessment at 24  Moderately worse
Hours After Initiation of Study  Markedly worse
Drug [ Time Frame: 24 hours after study drug
initiation ]

Outcome measures
Secondary Endpoints Persistent/Worsening HF
 Overall Well-Being Self-Assessment at 6  Clinical manifestations of worsening or
Hours After Initiation of Study Drug persistent decompensated heart failure
[ Time Frame: 6 hours after study drug initiation ] were defined by at least one of the
following:
 Overall Well-Being Self-Assessment at 24  New, persistent or worsening:
Hours After Initiation of Study Drug
[ Time Frame: 24 hours after study drug initiation ] dyspnea, orthopnea, paroxysmal
nocturnal dyspnea, edema,
 Composite of Persistent or Worsening Heart pulmonary basilar rales/crackles,
Failure and All-Cause Mortality jugular venous distension, renal
[ Time Frame: Randomization to hospital discharge (up to Day 30) ] hypoperfusion with no other apparent
cause, or
 Number of Days Alive and Outside the  Radiologic evidence of worsening
Hospital [ Time Frame: Randomization to Day 30 ] heart failure.
 A new therapy specifically for the
 Composite of Cardiovascular
Rehospitalization and Cardiovascular treatment of worsening or persistent
Mortality [ Time Frame: Randomization to Day 30 ] decompensated heart failure.

Results
Primary Endpoint
 Although a small increase in the
number of patients reporting
improvement in dyspnea was observed
at both the 6- and 24-hour time points,
this finding did not meet the
prespecified criteria for significance.

 Rehospitalization for heart failure or
death from any cause at 30 days
occurred in 321 patients in the
nesiritide group (9.4%) as compared
with 345 patients in the placebo group
(10.1%) (absolute difference, −0.7
percentage points; 95% confidence
interval [CI], −2.1 to 0.7;P = 0.31)

Conclusion
 The use of nesiritide in patients with acute
decompensated heart failure neither increased nor
decreased the incidence of death or rehospitalization for
heart failure at 30 days.
 Self reported dyspnea at 6 and 24 hours was marginally
improved when nesiritide was added to conventional
therapy, but this finding did not meet prespecified
criteria for statistical significance.
 Nesiritide thus cannot be recommended in the broad
population of patients with acute decompensated heart
failure represented by the study population in this trial.

Addressing the concern
 There was no significant difference between the
groups with respect to the rate of death from any
cause at 30 days.
 There was no significant difference between the
nesiritide group and the placebo group with respect
to the proportion of patients with renal impairment
at any time from randomization through day 30
regardless of the degree of baseline renal
insufficiency.

 The incidence of renal injury was not different
between nesiritide- and nitroglycerin-treated patients
with acute heart failure; however, nitroglycerin was
associated with a decline in glomerular filtration rate
and increase in blood urea nitrogen despite higher
baseline and on treatment blood pressures.
 Ng, T. M.; Ackerbauer, K. A.; Hyderi, A. F., et al., Comparative
effects of nesiritide and nitroglycerin on renal function, and
incidence of renal injury by traditional and RIFLE criteria in acute
heart failure. J Cardiovasc Pharmacol Ther 2012, 17 (1), 79-85.

 Nesiritide can be administered safely without
negatively impacting long-term renal function in
patients admitted with Decompensated Heart Failure
with preserved Ejection Fraction.
 Kelesidis, I.; Mazurek, J.; Khullar, P., et al., The effect of nesiritide on
renal function and other clinical parameters in patients with
decompensated heart failure and preserved ejection fraction. Congest
Heart Fail 2012, 18 (3), 158-64.

 Nesiritide resulted in improvements in dyspnea and
edema, and similar adverse effects compared with
conventional treatment. In spite of no reduction on
short-term mortality and a reversible influence on
renal function, nesiritide was still an important
chioce for the elderly (>/=75 years) with AHF.
 Fu, S.; Yi, S.; Zhu, B., et al., Efficacy and safety of a modified
dosage regimen of nesiritide in patients older than 75 years with
acute heart failure. Aging Clin Exp Res 2012.

Summary
 Nesiritide neither increases nor decreases the rate of death and
rehospitalization.
 The observed effect of nesiritide on dyspnea is small (and not
significant) with the coadministration of other therapies that
relieve congestion.
 Nesiritide is not associated with worsened renal function, but it is
associated with an increase in the rate of hypotension.
Thank you
 Nesiritide results in improvements in dyspnea and edema and can
still benefit patients admitted with Decompensated Heart Failure
with preserved Ejection Fraction or the elderly.
 Nesiritide cannot be recommended for routine use in the broad
population of patients with acute heart failure. The decision to use
Nesiritide must be based on an individual patient basis.

Nesiritide in Acute Decompensated Heart Failure

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