"Nov. 19, 2012 -- Unemployment and a history of job loss may raise the risk for heart attack, a new study suggests.
The risk of heart attack may be highest during the first year of unemployment. And the more jobs a person loses, the hi"...
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||Placebo
|Pulmonary capillary wedge pressure (mm Hg)||-2.0||-3.8||-5.8†|
|Right atrial pressure (mm Hg)||0.0||-2.6||-3.1†|
|Cardiac index (L/min/M2)||0.0||0.2||0.1|
|Mean pulmonary artery pressure (mm Hg)||-1.1||-2.5||-5.4†|
|Systemic vascular resistance (dynes§sec§cm-5)||-44||-105||-144|
|* Systolic blood pressure (mm Hg)||-2.5||-5.7†||-5.6†|
|* 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
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 (t1/2) 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] classification).
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 NATRECOR® at 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 (4%).
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 (p=0.034).
In the dose-response study, patients receiving both doses of NATRECOR® reported greater improvement in dyspnea at 6 hours than patients receiving placebo.
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 the ASCEND-HF Study, which was a trial where both arms were administered in addition to standard care, in patients with ADHF. 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 NATRECOR® initiation).
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 NATRECOR® group 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).
Last reviewed on RxList: 9/4/2012
This monograph has been modified to include the generic and brand name in many instances.
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