Mechanism Of Action
Human BNP (hBNP) is secreted by the ventricular
myocardium in response to stretch and exists in several isoforms in the human
body. Elevated levels of BNP have been associated with advanced heart failure
and are considered to be a compensatory mechanism in this disease. Human BNP
binds to the particulate guanylate cyclase receptor of vascular smooth muscle
and endothelial cells, leading to increased intracellular concentrations of
guanosine 3’5’-cyclic monophosphate (cGMP) and smooth muscle cell relaxation.
Cyclic GMP serves as a second messenger to dilate veins and arteries.
Nesiritide has been shown to relax isolated human arterial and venous tissue
preparations that were precontracted with either endothelin-1 or the
alpha-adrenergic agonist, phenylephrine.
In animals, nesiritide had no effects on cardiac
contractility or on measures of cardiac electrophysiology such as atrial and
ventricular effective refractory times or atrioventricular node conduction.
With a dosing regimen of NATRECOR of 2 mcg/kg IV bolus
followed by an intravenous infusion dose of 0.01 mcg/kg/min, Table 4 and Figure
3 summarize the changes in the VMAC trial in PCWP and other measures during the
first 3 hours.
Table 4: Mean Hemodynamic Change from Baseline in the
|Effects at 3 Hours
|Pulmonary capillary wedge pressure (mm Hg)
|Right atrial pressure (mm Hg)
|Cardiac index (L/min/M2)
|Mean pulmonary artery pressure (mm Hg)
|Systemic vascular resistance (dynes•sec•cm-5)
|Systolic blood pressure* (mm Hg)
|* Based on all treated patients: placebo n=142,
nitroglycerin n=143, NATRECOR n=204
†p <0.05 compared to placebo
Figure 3: PCWP through 3 Hours in VMAC
With this dosing regimen, 60% of the 3-hour effect on
PCWP reduction is achieved within 15 minutes after the bolus, reaching 95% of
the 3-hour effect within 1 hour. Approximately 70% of the 3-hour effect on SBP
reduction is reached within 15 minutes. The pharmacodynamic (PD) half-life of
the onset and offset of the hemodynamic effect of NATRECOR is longer than what
the PK half-life of 18 minutes would predict. Longer infusions may exaggerate
the discrepancy from onset and offset effects. For example, in patients who
developed symptomatic hypotension in the VMAC (Vasodilation in the Management
of Acute Congestive Heart Failure) trial, half of the recovery of SBP toward
the baseline value after discontinuation or reduction of the dose of NATRECOR
was observed in about 60 minutes. When higher doses of NATRECOR were infused,
the duration of hypotension was sometimes several hours.
No rebound increase to levels above baseline state was
observed. There was also no evidence of tachyphylaxis to the hemodynamic
effects of NATRECOR in the clinical trials.
In the VMAC trial, in which the use of diuretics was not
restricted, the mean change in volume status (output minus input) during the
first 24 hours in the nitroglycerin and NATRECOR groups was similar: 1279 ±
1455 mL and 1257 ± 1657 mL, respectively.
In patients with heart failure (HF), NATRECOR
administered intravenously by infusion or bolus exhibits biphasic disposition
from the plasma. The mean terminal elimination half-life (t½) of nesiritide
is approximately 18 minutes and was associated with approximately 2/3 of the
area-under-the-curve (AUC). The mean initial elimination phase was estimated to
be approximately 2 minutes. In these patients, the mean volume of distribution
of the central compartment (Vc) of nesiritide was estimated to be 0.073 L/kg,
the mean steady-state volume of distribution (Vss) was 0.19 L/kg, and the mean
clearance (CL) was approximately 9.2 mL/min/kg. At steady state, plasma BNP
levels increase from baseline endogenous levels by approximately 3-fold to
6-fold with NATRECOR infusion doses ranging from 0.01 to 0.03 mcg/kg/min.
Metabolism And Excretion
The mechanism of elimination of nesiritide has not been
studied specifically in humans.
Clinical data suggest that dose adjustment is not
required in patients with renal impairment. The effects of nesiritide on PCWP,
cardiac index (CI), and systolic blood pressure (SBP) were not significantly
different in patients with chronic renal impairment (baseline serum creatinine ranging
from 2 mg/dL to 4.3 mg/dL), and patients with normal renal function.
The population pharmacokinetic (PK) analyses carried out
to determine the effects of demographics and clinical variables on PK
parameters showed that clearance of nesiritide is proportional to body weight,
supporting the administration of weight-adjusted dosing of nesiritide (i.e.,
administration on a mcg/kg/min basis).
Age, Gender, Race/Ethnicity
Nesiritide clearance was not influenced significantly by
age, gender, or race/ethnicity.
Severity Of HF
Nesiritide clearance was not influenced significantly by
baseline endogenous hBNP concentration, severity of HF (as indicated by
baseline PCWP, baseline CI, or New York Heart Association [NYHA]
Effects Of Concomitant Medications
The co-administration of NATRECOR with enalapril did not
have significant effects on the PK of NATRECOR. The PK effect of
co-administration of NATRECOR with other IV vasodilators such as nitroglycerin,
nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated. During
clinical studies, NATRECOR was administered concomitantly with other medications,
including: diuretics, digoxin, oral ACE inhibitors, anticoagulants, oral
nitrates, statins, class III antiarrhythmic agents, beta-blockers, dobutamine,
calcium channel blockers, angiotensin II receptor antagonists, and dopamine.
Although no PK interactions were specifically assessed, there did not appear to
be evidence suggesting any clinically significant PK interaction.
NATRECOR has been studied in 11 clinical trials including
4505 patients with HF (NYHA class II-III 56%, NYHA class IV 27%; mean age 64
years, women 32%). There were six randomized, multi-center, placebo- or
active-controlled studies (comparative agents included nitroglycerin,
dobutamine, milrinone, nitroprusside, or dopamine) in which 4269 patients with decompensated
HF received continuous infusions of NATRECORat doses ranging from 0.01 to 0.03
mcg/kg/min. Of these patients, the majority (n=3358, 79%) received the NATRECOR
infusion for at least 24 hours; 2182 (51%) received NATRECOR for 24 to 48
hours, and 1176 (28%) received NATRECOR for greater than 48 hours.
In the initial five of these six controlled trials,
NATRECOR was used alone or in conjunction with other standard therapies,
including diuretics (79%), digoxin (62%), oral ACE inhibitors (55%),
anticoagulants (38%), oral nitrates (32%), statins (18%), class III
antiarrhythmic agents (16%), beta-blockers (15%), dobutamine (15%), calcium
channel blockers (11%), angiotensin II receptor antagonists (6%), and dopamine
In the ASCEND-HF trial (Acute Study of Clinical Effectiveness
of Nesiritide in patients with Decompensated Heart Failure), NATRECOR was used
alone or in conjunction with other standard therapies. Most patients (99.4%)
received diuretic medications in conjunction with NATRECOR, with the most
commonly used diuretic being furosemide (55%). The following standard therapies
were used in ≥2% of patients: beta-blockers (72%), aspirin (64%); oral
ACE inhibitors (60%), statins (50%), aldosterone
antagonists (48%), digoxin/digitalis glycoside (39%), oral or topical nitrates
(30%), oral anticoagulants (29%), clopidogrel/thienopyridine (21%), angiotensin
receptor antagonists (19%), antiarrhythmic agents (16%), IV nitroglycerin
(16%); calcium channel blockers (13%), hydralazine (11%), dobutamine (8%),
dopamine (5%), alpha blockers (4%), IV opiates (5%), and NSAIDs (4%). The
following standard therapies were used in <2% of patients: COX2 inhibitors,
milrinone, epinephrine, levosimendan, nitroprusside, norepinephrine,
phenylephrine, and vasopressin.
NATRECOR has been studied in a broad range of patients,
including the elderly (53% >65 years of age), women (33%), minorities (17%
black), and patients with a history of significant morbidities such as
hypertension (71%), previous myocardial infarction (38%), diabetes (43%),
atrial fibrillation/flutter (37%), ventricular tachycardia/fibrillation (10%),
and preserved systolic function (20%). In trials other than the ASCEND-HF
trial, NATRECOR was also studied in patients with nonsustained ventricular
tachycardia (25%) and patients with acute coronary syndromes less than 7 days
before the start of NATRECOR (4%).
The VMAC (Vasodilation in the Management of Acute
Congestive Heart Failure) trial was a randomized, double-blind study of 489
patients (246 patients requiring a right heart catheter, 243 patients without a
right heart catheter) who required hospitalization for management of shortness
of breath at rest due to acutely decompensated HF. The study compared the
effects of NATRECOR, placebo, and IV nitroglycerin when added to background
therapy (IV and oral diuretics, non-IV cardiac medications, dobutamine, and
dopamine). Patients with acute coronary syndrome, preserved systolic function,
arrhythmia, and renal impairment were not excluded. The primary endpoints of
the study were the change from baseline in PCWP and the change from baseline in
patients' dyspnea, evaluated after three hours. Close attention was also paid
to the occurrence and persistence of hypotension, given nesiritide's relatively
long (compared to nitroglycerin) PK and PD half-life.
NATRECOR was administered as a 2 mcg/kg bolus over
approximately 60 seconds, followed by a continuous fixed dose infusion of 0.01 mcg/kg/min.
After the 3-hour placebo-controlled period, patients receiving placebo crossed
over to double-blinded active therapy with either NATRECOR or nitroglycerin.
The nitroglycerin dose was titrated at the physician's discretion. A subset of
patients in the VMAC trial with central hemodynamic monitoring who were treated
with NATRECOR (62 of 124 patients) were allowed dose increases of NATRECOR after
the first 3 hours of treatment if the PCWP was ≥20 mm Hg and the SBP was ≥100
mm Hg. Dose increases of a 1 mcg/kg bolus followed by an increase of the
infusion dose by 0.005 mcg/kg/min were allowed every 3 hours, up to a maximum
dose of 0.03 mcg/kg/min. Overall, 23 patients in this subset had the dose of
NATRECOR increased in the VMAC trial.
In the VMAC study, patients receiving NATRECOR reported
greater improvement in their dyspnea at 3 hours than patients receiving placebo
In the dose-response study, patients receiving both doses
of NATRECOR reported greater improvement in dyspnea at 6 hours than patients
NATRECOR was also studied in a randomized, double-blind,
placebo-controlled, parallel-group, multicenter trial evaluating the efficacy
and safety of NATRECOR compared with placebo in patients with ADHF, the
ASCEND-HF Study. The study was divided into a screening phase, a double-blind
treatment phase, and a follow-up phase, including a Day 30 visit and a
telephone contact at Day 180. Patients who qualified for the study were ≥18
years of age, hospitalized for the management of ADHF or diagnosed with ADHF
within 48 hours after being hospitalized for another reason. They were
randomized to receive either NATRECOR as a continuous IV infusion at 0.010
mcg/kg/min with or without an initial 2 mcg/kg bolus (at the discretion of the
physician) or a matching placebo bolus and infusion.
The primary objective of ASCEND-HF was to evaluate
whether treatment with NATRECOR compared to placebo improved patient outcomes
(as measured by a reduction in the composite of HF rehospitalization and
all-cause mortality from randomization through Day 30) or HF symptoms (as
measured by patient self-assessed Likert dyspnea scale which included Markedly
Better, Moderately Better, Minimally Better, No Change, Minimally Worse, Moderately
Worse and Markedly Worse at 6 hours and 24 hours after NATRECORinitiation).
A total of 7141 patients were randomized of which 7007
patients took at least one dose of study medication (modified intent-to-treat
population) and received treatment for 24 to 168 hours (7 days), if the
patient's clinical condition warranted continued treatment for dyspnea or
pulmonary congestion, at the physician's discretion. The median treatment duration
was 42.9 hours for the placebo group and 40.8 hours for the NATRECOR group. The
patients' mean age was 65.5 years. The patient population was 65.8% male, 55.9%
Caucasian, 24.7% Asian and 15.1% Black or African American.
The incidence rate for the composite of HF
rehospitalization and all-cause mortality from randomization through Day 30 was
9.4% in the NATRECORgroup compared with 10.1% in the placebo group. The
difference was not statistically significant (p=0.313). The self-assessed dyspnea
results did not meet the pre-specified criteria for statistical significance (p
≤0.005 for both or p ≤0.0025 for either) at either time point.
A total of 273 deaths were reported during the first 30
days after therapy and 876 (12.5%) deaths were reported from randomization
through Day 180, 429 (12.3%) patients in the NATRECOR group and 447 (12.7%)
patients in the placebo group. Approximately 65% of the deaths at 180 days were
cardiovascular (mostly worsening heart failure). There was no statistically
significant difference between treatment groups (p=0.5).