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NESIRITIDE: USE IN ACUTE
DECOMPENSATED HEART
FAILURE

Jitendra Saraswat, Pharm.D. Candidate



Introduction
Heart failure (HF) is a common clinical syn-
drome, affecting 4.9 million people in the United
States (U.S.) in 2003. There are an additional
550,000 cases diagnosed each year with a mortality
rate of approximately 50% within 5 years.1 Acutely
decompensated heart failure (ADHF) is character-
ized hemodynamically by elevated right and left
ventricular filling pressures, decreased cardiac out-
put, and increased systemic vascular resistance.2 It
is the primary diagnosis for close to one million
hospital admissions annually in the U.S. and a sec-
ondary diagnosis for nearly two million more. The
total cost of HF this year is projected to approach
26 billion dollars.
The in-hospital mortality rate for ADHF is 5 to
8%. This is sobering given that the rate of readmis-
sion is 20% at 30 days and 50% by 6 months.2
While many guidelines exist for the treatment of
different acute cardiovascular conditions including
acute coronary syndromes, ischemic strokes, and
life-threatening arrhythmias, major guidelines for
the treatment of ADHF have not been published.
Guidelines in existence only deal with the treatment
of chronic HF.
Several classes of medications are available


to treat ADHF. Examples include loop diuretics,
such as furosemide (Lasix") and torsemide
(Demadex"), and vasodilators such as nitroglyc-
erin and nesiritide (Natrecor"). Additionally, posi-
tive inotropes are approved for ADHF in patients
with low cardiac output; these include dobutamine
(Dobutrex") and milrinone (Primacor"). (Table 1)
Unfortunately, there is little evidence in the medi-
cal literature to help clinicians select from this list.
This article will discuss the pharmacology, phar-
macokinetics, clinical trials and effects of nesiri-
tide, the latest drug to be approved for ADHF.

Treatment:
ADHF has two physiologic components, central
and peripheral congestion (i.e., volume overload)
and poor cardiac output. Pharmacologic modalities
usually target one or both of these components.
In patients with mild volume overload, intrave-
nous (IV) diuretic therapy with a loop diuretic is
preferred. Monitoring of diuretic efficacy is driven
by urine output tempered by renal function. For pa-
tients with normal renal function, the goal urine
output is > 500 ml in the first 2 hours whereas an
acceptable urine output in patients with serum
creatinine > 2.5 mg/dl is 250 ml.3 If the patient fails
rI,. .fil


mm
PharmaNote Volume 20, Issue 2, November 2004


PharmaNote


VOLUME 20, ISSUE 2 NOVEMBER 2004
Lm __J


INSIDE THIS ISSUE:
NESIRITIDE: USE IN ACUTE
DECOMPENSATED HEART FAILURE



L


PharmaNote


Volume 20, Issue 2, November 2004







Table 1. Dosing recommendations for selected drugs used to treat ADHF.
Drug Dose (start)


Furosemide


Nitroglycerin


Nesiritide


Dobutamine


Milrinone


40 to 180 mg IV bolus


5-10 mcg/min continuous IV infusion


2 mcg/kg IV bolus, followed by 0.01 mcg/kg/min
continuous IV infusion

0.5-1 mcg/kg/min continuous IV infusion

50 mcg/kg continuous IV infusion over 10 min-
utes as loading dose, followed by 0.375 mcg/kg/
min


20-80 mg/hour via continuous infusion
Increase by 5 mcg/min IV every 3-5 min until
clinical response or 20 mcg/min reached. Then, in-
crease by 10-20 mcg/min. Usual range = 5-100
mcg/min.
May be cautiously titrated by 0.005 mcg/kg/min at
intervals no less than 3 hours, if clinically indi-
cated. Maximum dose = 0.03 mcg/kg/min.
Increase every 5 to 15 minutes. Normal effective
range 2-20 mcg/kg/min.

Usual maintenance dose = 0.5 mcg/kg/min. Maxi-
mum recommended dose is 0.75 mcg/kg/min


to attain adequate diuresis after the initial bolus, the
previous dose may be doubled and should be ad-
ministered within 2 to 4 hours of the first dose to
induce more rapid diuresis. Alternatively, a con-
tinuous infusion can be initiated after the initial bo-
lus. Electrolyte deficiencies are often associated
with IV diuretics, and treatment can be complicated
by hypotension, alkalosis, azotemia and renal dys-
function.
In patients with moderate to severe volume
overload, the patient response to intravenous diuret-
ics may be inadequate, especially if renal function
is compromised. In this situation, a more aggressive
pharmacological strategy is required. A diuretic in
combination with a parenteral vasodilator is often
effective in these patients if they have a systolic
blood pressure > 90 mm Hg.4 The addition of ne-
siritide or nitroglycerin to an intravenous diuretic
may elicit a more rapid response. However, hy-
potension is often encountered with this regimen.
In patients with low cardiac output, use of an
inotropic agent can be considered. It may be diffi-
cult to adequately diurese a patient with poor pe-
ripheral perfusion (i.e. low output). The phrase,
"you must warm the patient up before they will dry
out" is often cited, suggesting that peripheral perfu-
sion must be restored before diuresis can be
achieved. There are usually two factors affecting
the selection of an inotrope. Namely, concomitant
therapy with a beta-blocker and baseline blood
pressure. In patients with low cardiac output (CO)
and systolic BP (SBP) < 90 mm Hg the primary
agent should be dobutamine. In patients with low


CO and SBP > 90 mm Hg either dobutamine or the
phosphodiesterase inhibitor, milrinone are reason-
able options. If SBP is less than 90 or the patient is
on a beta-blocker, milrinone is the drug of choice.4
The rationale behind this is that phosphodiesterase
inhibitors, referred to as "inodilators", may signifi-
cantly lower BP, and dobutamine may be less ef-
fective if the Betai receptor is blocked. Routine use
of positive inotropes is discouraged since, despite
symptomatic improvement, they are associated
with decreased survival.

Pharmacology/Pharmacokinetics
Nesiritide is an intravenous, recombinant, puri-
fied preparation of human B-type natriuretic pep-
tide (hBNP). Nesiritide is a naturally-occurring
hormone produced primarily in the ventricles of the
heart in response to increased wall stress that oc-
curs from volume overload. Nesiritide produces
balanced arterial and venous dilation, evidenced by
reductions in systemic vascular resistance, systemic
arterial pressure, pulmonary capillary wedge pres-
sure (PCWP), right atrial pressure, and mean pul-
monary arterial pressure. Nesiritide increases car-
diac output and stroke volume, without increasing
heart rate. It also has natriuretic actions, thereby
promoting diuresis. Following IV administration in
patients with HF, nesiritide exhibits biphasic elimi-
nation from the plasma. The mean initial elimina-
tion phase is approximately 2 minutes. The mean
terminal elimination half-life of nesiritide is ap-
proximately 18 minutes; however, the pharmacody-
namic onset and duration of action is much longer.


PharmaNote Volume 20, Issue 2, November 2004


Titration


PharmaNote


Volume 20, Issue 2, November 2004







Table 2. Trials Comparing Nesiritide to other Agents in ADHF.
Trial Acronym Agents Results
PCWP: At 3 hours, -5.8 vs. -3.8, at 24
nesiritide vs. nitroglycerin vs. pla-
Young, et al. (2002) VMAC eece hours: -8.2 vs. -6.3, both favoring nesiri-
cebo
tide
Dobutamine: VT: 48 + 205 PVBs: 69 +
Burger, et al. (2002)9 PRECEDENT nesiritide vs. dobutamine 214 Nesiritide: Vtach: -5.6 + 17
PVBs: -13 + 83

Peacock, et al. (2003) PROACTION nesiritide vs. standard care Hospital readmission within 30 days re-
duced by 57% vs. Placebo

Silver, et al. (20Hospital readmission. Nesiritide: 4%
Silver, et al. (2002) nesiritide vs. dobutamine Dobutamine: 13
Dobutamine: 13%

Death and hospitalization in high risk.
Nesiritide: 52% Standard care: 78%
Yancy, et al. (2'" 14)1 FUSION I nesiritide vs. standard care N i i ad
Number of days alive and out of hospital
(days). Nesiritide: 83 Standard care: 77


PCWP= Pulmonary capillary wedge pressure. PVB= Premature ventricualr beat. VT= Ventricular tachycardia.


The drug has an onset of action of 15 minutes with
a duration of action of up to an hour or more.5 Af-
ter initiating the recommended dose, 60% of the 3-
hour effect on PCWP reduction is achieved within
15 minutes, reaching 95% of the 3-hour effect
within 1 hour. Approximately 70% of the 3-hour
effect on SBP reduction is reached within 15 min-
utes.9 Human BNP is cleared from the circulation
via the following three independent mechanisms,
listed in order of decreasing importance: 1) binding
to cell surface clearance receptors with subsequent
cellular internalization and lysosomal proteolysis;
2) proteolytic cleavage by endopeptidases, such as
neutral endopeptidase; and 3) renal filtration.5
There is no dose adjustment recommended in renal
insufficiency, though cautious monitoring seems
prudent given its partial renal clearance.
Because the effects of nesiritide are predictable
and sustained at the recommended dosage, it does
not commonly require dose titration or more inva-
sive hemodynamic monitoring.6 In comparison,
tachyphylaxis can occur in patients receiving IV
nitroglycerin, necessitating additional titration and
higher doses. Frequent dose titration and the possi-
bility of hypotension with other ADHF treatments
often mandate that patients be treated in an inten-
sive care unit (ICU). Nesiritide may not require in-
tensive monitoring depending on the clinical situa-
tion; however, this population often require ICU


care for other reasons.

Clinical Trials
The VMAC (Vasodilation in the Management of
Acute Congestive Heart Failure)6 trial evaluated the
use of nesiritide in ADHF. The study was a ran-
domized, double blind, placebo controlled trial
comparing the use of IV nitroglycerin, nesiritide
and placebo in patients suffering from dyspnea due
to ADHF. There were 489 patients enrolled in the
study. The primary end point was the absolute
change in pulmonary capillary wedge pressure
(PCWP) and patient self-evaluation of dyspnea
from baseline to 3 hours after the start of nesiritide
infusion. The secondary outcomes included a com-
parison of hemodynamic and clinical effects of ne-
siritide and nitroglycerin at 24 hours, global clini-
cal status, and the overall safety profile. The study
demonstrated a statistically significant reduction in
PCWP among patients treated with nesiritide com-
pared to nitroglycerin or placebo at 3 and 24 hours.
Nesiritide reduced PCWP by -5.8 mm Hg and -8.2
mm Hg while nitroglycerin reduced it by -3.8 mm
Hg and -6.3 mm Hg at 3 and 24 hours, respectively.
The difference in PCWP was not statistically differ-
ent at 48 hours. Nesiritide was associated with
greater mean reductions in systolic and mean pul-
monary arterial pressure than nitroglycerin at 3
hours. Nesiritide was better tolerated, with fewer


PharmaNote Volume 20, Issue 2, November 2004


PharmaNote


Volume 20, Issue 2, November 2004







Table 3. Adverse Effects of Agents Used in ADHF.


Treatment


Common Adverse Effects


Diuretics electrolyte disturbances (hypokalemia and hypomagnesaemia), hypotension, azotemia, contraction alkalosis

Nitroglycerin dose-dependent hypotension, headache, sinus tahcycardia, nausea, vomiting, tolerance

Nesiritide hypotension, syncope, headache, renal dysfunction, nausea, vomiting

Dobutamine ventricular arrhythmias, tahcycardia, angina, palpitations, hypertension, nausea, vomiting, hypokalemia

Milrinone ventricular arrhythmias, sudden cardiac death, angina, palpitations, atrial tachycardias, hypotension


patients reporting adverse events, primarily head-
ache. The incidence of hypotension was similar;
however, the duration of hypotension was longer
with nesiritide due to a longer duration of action.
Studies evaluating patients with ADHF have re-
ported a nonsignificant trend towards reduced read-
mission in patients treated with nesiritide compared
with nitroglycerin or positive inotropes, including
dobutamine.6'7 In the VMAC trial,6 the authors note
that the 6 month readmission rate was 13% for ni-
troglycerin and 7% for nesiritide; however, VMAC
was not powered to show statistical difference for
this outcome. Similar results have been reported
with nesiritide compared to dobutamine. Silver et
al.3, found a non-significant trend towards fewer
rehospitalizations related to heart failure in patients
treated with nesiritide (4% vs. 13%, p = 0.081). In
the PROACTION (Prospective Randomized Out-
comesStudy of Acutely Decompensated Conges-
tive Heart Failure Treated Initially as Outpatients
with Natrecor) study, nesiritide reduced the rate of
hospital readmission at 30 days by 57% compared
with placebo; the change did not achieve statistical
significance (p=0.058).8
Nesiritide may be safer than positive inotropes
with respect to arrhythmogenicity.9 The PRECE-
DENT (Prospective Randomized Evaluation of
Cardiac Ectopy with Dobutamine or Nesiritide
Therapy)9 study demonstrated that dobutamine in-
creases the incidence of ventricular tachycardia
(VT) and ventricular ectopy when compared with
nesiritide. (Table 2) On the other hand, the inci-
dence of hypotension was lower with dobutamine.
This multi-center, randomized, open-label, active-
control trial compared the safety of low dose dobu-
tamine (L 5 mcg/kg/min) with 2 fixed doses of ne-


mm
PharmaNote Volume 20, Issue 2, November 2004


siritide (0.015 and 0.030 mcg/kg/min) in 255 pa-
tients. End points included mean heart rate, number
of premature ventricular beats (PVBs) per hour,
and repetitive beats per hour. Dobutamine signifi-
cantly increased all measures of ventricular ectopy,
while nesiritide reduced the rate of VT compared
with baseline. Dobutamine increased the mean
number of VT episodes per 24 hours by 48 + 205
(P=0.001), repetitive ventricular beats by 15 + 53
(P=0.001) and PVBs by 69 + 214 (P=0.006). Dobu-
tamine increased the heart rate by 5.1 + 7.7 bpm
(P<0.001). Nesiritide had significantly smaller ef-
fect on these parameters. Both agents resulted in
similar improvements in signs and symptoms of
HF. The adverse effects of positive inotropes and
evidence of reduced survival have prompted the
American Heart Association and American College
of Cardiology to discourage the routine use of inter-
mittent outpatient inotropic support in patients with
severe HF (Class III recommendation).10
Results from FUSION I (Follow Up Serial Infu-
sions Of Natrecor), a pilot trial designed to evaluate
the safety and tolerability of weekly infusions of
nesiritide when administered in the outpatient set-
ting to patients with advanced HF who are at high
risk for hospitalization, were recently pubished.11'12
FUSION I was a multi-center (46 U.S. sites), ran-
domized, open-label pilot study with three treat-
ment arms enrolling a total of 210 patients. Pa-
tients were randomized to receive either standard
care (usual long-term cardiac medications with or
without IV inotropes) or serial infusions of either
0.005 or 0.01 [tg/kg/min of nesiritide in addition to
their usual long-term cardiac medications, exclud-
ing IV inotropes. Patients were further classified as
low- or high-risk based on seven criteria (patients


PharmaNote


Volume 20, Issue 2, November 2004







with four or more of these criteria were considered
high risk). All patients had weekly outpatient visits
for 12 weeks. Nesiritide patients received a four- to
six- hour infusion at each weekly visit. At the end
of follow-up, the primary endpoint, the incidence
of investigator-reported adverse events, was similar
in all treatment arms. A subgroup analysis showed
that patients in the higher risk stratum experienced
a statistically significant reduction in death and
hospitalization with nesiritide (52% vs. 78%;
p=0.038). The number of days that patients were
alive and out of the hospital also improved (67 vs.
77 days; p=0.027). Through week 12, 5% of nesiri-
tide patients and 17% of standard care patients had
died (p=0.079) at 12 weeks. While the results of
this pilot study are encouraging, a larger trial dem-
onstrating similar benefits in this population is nec-
essary.

Dosage and Administration
The approved dose is 2 mcg/kg administered as
an IV bolus, followed by a continuous IV infusion
of 0.01 mcg/kg/min.5 The dose can be slowly ti-
trated, based on clinical response, to the maximum
dose of 0.03 mcg/kg/min, although experience with
doses greater than 0.01 mcg/kg/min is limited.
Blood pressure must be monitored closely. If hy-
potension occurs, the dose should be reduced or
discontinued. Once the patient is stabilized, the in-
fusion should be restarted at a dose that is reduced
by 30% (with no bolus administration). Hypoten-
sion can be prolonged, therefore, at higher doses a
period of observation may be required even after
drug discontinuation. The prolonged half-life also
necessitates close attention to titration guidelines
since rapid titration may provoke profound hy-
potension and renal failure.

Contraindications
Nesiritide is not recommended for patients in
whom vasodilating agents are not appropriate, such
as patients with significant valvular stenosis (aortic
stenosis, mitral stenosis, idiopathic hypertrophic
subaortic stenosis, valvular heart disease), restric-
tive or obstructive cardiomyopathy, constrictive
pericarditis, pericardial tamponade or pericardial
effusion, or other conditions in which cardiac out-
put is dependent upon venous return, or for patients
suspected to have low cardiac filling pressures.


Adverse Effects
Side effects of nesiritide are a direct result
of its mechanism of action. In separate clinical tri-
als, the side-effect profile of nesiritide was lower
than nitroglycerin and dobutamine. In VMAC,6 the
overall adverse event rate was lower for nesiritide
than nitroglycerin (20% vs. 5%). The incidence of
hypotension was similar in both groups (8%) with a
longer duration of hypotension in the nesiritide
group. PRECEDENT9 compared the incidence of
adverse effects between nesiritide and dobutamine.
There was a statistically significant increase in the
incidence of arrhythmias in patients receiving
dobutamine. Nesiritide caused hypotension more
often. Table 3 lists common adverse effects with
ADHF treatments.
There is a lack of information about drug-
interactions with nesiritide. No studies have been
conducted in this area. Based on the mechanism of
action, it is recommended that nesiritide not be
given within 24 hours of the phosphodiesterase in-
hibitors, sildenafil, vardenafil, or tadalafil, since the
risk of hypotension may be increased. Pharmacody-
namic drug interactions are possible with any other
treatment that lowers blood pressure. Nesiritide
should be used cautiously in patients receiving anti-
hypertensives, inodilators, or nitrates.

Cost
The retail cost of nesiritide is approximately 500
dollars for every 1.5 mg vial. The cost for a 70 kg



The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D.


PharmaNote Volume 20, Issue 2, November 2004


PharmaNote


Volume 20, Issue 2, November 2004








patient would be 47 dollars for a loading dose of 2
mcg/kg and 336 dollars for a 24 hour infusion with
an infusion rate of 0.010 mcg/kg/min. The acquisi-
tion cost of other medical treatments is considera-
bly less than that of nesiritide. Many institutions
reserve nesiritide for patients who fail to respond to
conventional therapy with diuretics, inotropes, or
nitroglycerin. Others suggest that the increased ac-
quisition cost is offset by nesiritide's efficacy,
which may permit early discharge and increased
time to rehospitalization. However, this has not
been clearly validated. In fact a recent analysis of
the available data suggests that nesiritide is not
more cost-effective than dobutamine in the acute
setting. (Gerhard T, et al. Abstract #244E, Ameri-
can College of Clinical Pharmacy (ACCP), 2004
Annual Meeting, Dallas, TX) It is not clear whether
nesiritide will be cost-effective in the outpatient
setting, though the the data from FUSION suggest-
ing that hospitalizations might be reduced is excit-
ing.

Summary
ADHF is treated based on the severity of symp-
toms and other patient-specific considerations, such
as concomitant illness, background therapy, and
clinical parameters. In patients experiencing moder-
ate to severe symptoms or those who are not re-
sponsive to IV diuretics, nesiritide represents an al-
ternative to conventional vasodilators and positive
inotropes. Nesiritide is administered as a fixed dose
and with minimal titration. It relieves central con-
gestion better than nitroglycerin, though sympto-
matic and clinical improvement was not different at
48 hours. Nesiritide is better tolerated than conven-
tional therapies. It appears to cause less ventricular
ectopy compared with inotropes, though the clinical
significance of this observation has not been vali-
dated. The American College of Cardiology/
American Heart Association will release an up-
dated HF guideline this fall that will, for the first
time, devote a section to ADHF. Ongoing studies
will further help clinicians identify the role of ne-
siritide in the acute and outpatient setting.11

References
1. Heart disease and stroke statistics-2004 update. American
Heart Association. Available at www.americanheart.org.
2. Fonarow GC. Pharmacologic Therapies for Acutely De-
compensated Heart Failure. Reviews in Cardiovascular


Medicine. Rev Cardiovasc Med 2002;3 Suppl 4:S18-27.
3. Peacock WF 4th, Albert NM. Observation unit manage-
ment of heart failure. Emerg Med Clin North Am
2001;19:209-32.
4. DiDomenico RJ, Park HY, Southworth MR, et al. Guide-
lines for Acute Decompensated Heart Failure Treatment.
Ann of Pharmacother 2004; 38:649-660.
5. Clinical Pharmacol. Gold Standard Media; Aug. 2004.
6. VMAC Investigators. Intravenous nesiritide vs. nitro-
glycerin for treatment of decompensated congestive heart
failure: a randomized controlled trial. JAMA
2002;287:1531-40.
7. Silver MA, Horton DP, Ghali JK, et al. Effect of nesiri-
tide versus dobutamine on short-term outcomes in the
treatment of patients with acutely decompensated heart
failure. J Am Coll Cardiol 2002;39:798-803.
8. Peacock WF, Emerman CL. Safety and efficacy of nesiri-
tide in the treatment of decompensated heart failure in
observation patients: the PROACTION trial (abstract). J
Am Coll Cardiol 2003;41:336A.
9. Burger AJ, Horton DP, LeJemtel T, Ghali JK, Torre G,
Dennish G, et al. Effect of nesiritide (B-type natriuretic
peptide) and dobutamine on ventricular arrhythmias in
the treatment of patients with acutely decompensated
congestive heart failure: the PRECEDENT study. Am
Heart J 2002;144:1102-8.
10. ACC/AHA guidelines for the evaluation and manage-
ment of chronic heart failure in the adult: a report of the
American College of Cardiology/American Heart Asso-
ciation Task Force on Practice Guidelines. J Am Coll
Cardiol 2001;38:2101-13.
11. Press Release -- SCIOS. Las Vegas, NV and Fremont, CA -
September 23, 2003.
12. Yancy CW, Saltzberg MT, Berkowitz RL, et al. Safety
and feasibility of using serial infusions of nesiritide for
heart failure in an outpatient setting (from the FUSION I
trial). Am J Cardiol 2004;94:595-601.




New Drug Approvals

Trospium chloride tablets (Sanctura, Indevus) is an
antimuscarinic (i.e., antispasmodic) agent indicated
for the treatment of overactive bladder in patients with
urinary incontinence, urgency, and urinary frequency.
Like other antimuscarinics, it is contraindicated in
patients with or at risk for urinary or gastric retention,
uncontrolled narrow-angle glaucoma, or a
hypersensitivity to its ingredients, including lactose.
The recommended dosage is 20 mg twice daily, with
each dose taken at least one hour before meals or on
an empty stomach. Patients with a creatinine clearance
<30 mL/min should receive a dosage of 20 mg once
daily at bedtime; patients age 75 years or older may
need to take 20 mg once daily. Sanctum is available as
20-mg tablets.


a
PharmaNote Volume 20, Issue 2, November 2004


PharmaNote


Volume 20, Issue 2, November 2004




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