A Study Comparing Blood Flow and Clinical and Safety Effects of the Addition of Natrecor (Nesiritide), Placebo or Intravenous Nitroglycerin to Standard Care for the Treatment of Worsening Congestive Heart Failure.
A Study Comparing Blood Flow and Clinical and Safety Effects of the Addition of Natrecor (Nesiritide), Placebo or Intravenous Nitroglycerin to Standard Care for the Treatment of Worsening Congestive Heart Failure.
The purpose of this study is to compare the hemodynamic (blood flow) and clinical effects of
 the study drug, Natrecor (nesiritide, a recombinant form of the natural human peptide
 normally secreted by the heart in response to heart failure) to those of intravenous
 nitroglycerin or placebo, when added to the standard care therapy that is usually
 administered in the treatment of patients with worsening congestive heart failure.
Advanced congestive heart failure (CHF) accounts for over 1 million hospital admissions
 yearly in the U.S. and is also associated with a high rate of readmission to the hospital
 within a short turn-around time period following discharge. CHF is associated with a
 relatively high death rate, up to 40 or 50% in 2 years. The risk of sudden cardiac death in
 patients with CHF is 6 to 9 times greater than that of the general population. Despite
 medical advances, some patients are unresponsive to the oral medications used to treat CHF
 and require added therapy. Such patients are typically New York Heart Association (NYHA)
 Class III and IV, and require intravenous (IV) therapy with inotropic agents. Inotropic
 agents are drugs that influence muscular contractility. IV administration with inotropic
 drugs requires careful patient selection and close monitoring to ensure safe and effective
 therapy.

 There are many medical conditions that lead to worsening CHF and these underlying conditions
 contribute to a significant and potentially life-threatening loss of cardiac function. Some
 of these are conditions that lead to abnormal cardiac contraction and/or relaxation (e.g.,
 coronary arterial disease, hypertension, diabetes, drug or alcohol toxicity); conditions that
 lead to volume or pressure overload (mitral or tricuspid valve regurgitation,
 hyperthyroidism); and conditions that limit ventricle filling (e.g., mitral or tricuspid
 valve stenosis). However, many patients have a condition of dilated cardiomyopathy, an
 abnormality of the heart muscle wall in which the walls of the heart become stretched and
 weakened, with no easily identifiable cause. Any risk factor may cause CHF, but combinations
 dramatically increase the risk of developing CHF.

 Natriuretic peptides ANP and BNP are small molecules and are the group of naturally-occuring
 substances that act in the body to oppose the activity of the renin-angiotensin-aldosterone
 (RAA) system. They serve as counter-regulatory hormones and are secreted in response to the
 increased atrial and ventricular stretching that occurs in secondary increased blood volume.
 Natrecor (nesiritide) is the proprietary name for the IV formulation of human B-type
 natriuretic peptide (hBNP).

 In-patient treatment for acutely decompensated CHF with intravenous vasodilator therapy (such
 as nitroglycerin or nitroprusside) is useful for a number of reasons. Vasodilators reduce
 ventricular filling pressure and volume, decreasing pulmonary congestion and the resulting
 symptoms of breathlessness. Intravenous vasodilators may also achieve afterload reduction
 leading to decreased mitral regurgitation and increased forward stroke volume. IV
 administration of externally produced hBNP leads to vasodilation, antagonism of the
 renin-aldosterone system and an increase in diuresis. hBNP may be a potent agent for the
 treatment of CHF, with a unique combination of desirable blood flow throughout the body,
 hormones secreted by the sympathetic nervous system, and renal effects not possessed by
 currently available therapies. In a 6-hour placebo-controlled comparison in patients with
 acutely decompensated CHF, Natrecor® was associated with significant improvements in the
 symptoms of CHF (including dyspnea and fatigue), a decrease in aldosterone, and an increase
 in urine output. (According to LeJemtel et al 1998) The VMAC trial (Vasodilation in the
 Management of Acute CHF) is a double-blinded, randomized, active-controlled and
 placebo-controlled study in which the study drug would be added to standard care therapies
 such as diuretics, dobutamine, or dopamine. This study compares the effects of the addition
 of Natrecor®, nitroglycerin, or placebo to standard care (diuretics, dobutamine, dopamine, or
 other long-term cardiac therapies) in patients requiring hospitalization for the treatment of
 dyspnea at rest due to acutely decompensated CHF. Based on the cumulative experience with
 Natrecor, the dose of Natrecor was modified for the VMAC trial to a 2-µg/kg bolus followed by
 a 0.01-µg/kg/min infusion.

 The primary objective of the VMAC study is to compare the blood flow and observe treatment
 and safety effects of the new dose of Natrecor to placebo, when added to standard care, in
 the treatment of acutely worsening CHF. The primary overall outcome that the study plan is
 based upon are the changes from the beginning of a study to 3 hours after the start of study
 drug, in pulmonary capillary wedge pressure (PCWP) (in subjects who have right heart
 catheters only) and the subject's self-evaluation of their breathing difficulties. The
 secondary objective is to compare the hemodynamic, (blood flow throughout the body) and
 clinical effects of Natrecor® with IV nitroglycerin and placebo. Additional objectives
 include a comparison of the use of other IV vasoactive agents and/or IV diuretics and the
 effects on other hemodynamic variables. The hypothesis of this study is that using the
 modified dose of Natrecor, (a 2-µg/kg bolus followed by a 0.01-µg/kg/min infusion) will
 achieve peak effects sooner than with previously studied doses, to sustain effects for at
 least 48 hours, and minimize excessive effects on blood pressure. Natrecor or placebo,
 administered as an intravenous 2-µg/kg bolus, followed by a fixed-dose infusion of
 0.01-µg/kg/min.
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 hepatosplanchnic 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:

 -  NPatients 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).