Advanced congestive heart failure (CHF) accounts for over one million hospital admissions
yearly in the U.S. and is associated with a 2-year mortality rate of up to 40% - 50%
(according to the American Heart Association 1997 and the CONSENSUS Trial Study Group, 1987).
Inpatient therapy for acutely worsening CHF often includes intravenous (IV) agents to reduce
intracardiac filling pressures and to increase cardiac output. Examples of such agents
include drugs that increase the heart muscle contractility such as dobutamine and
phosphodiesterase inhibitors such as milrinone. While these agents do achieve good blood flow
throughout the body in most patients, several studies suggest that arrhythmias (irregular
heart beats) can be increased in some patients treated with dobutamine or milrinone
(according to Smith TW, et al 1997 and Holmes JR et al 1985; and Anderson JL et al 1986).
Arrhythmias are common in patients with advanced CHF and may contribute to their sudden death
rate of 30% to 70% (according to Stevenson WG, et al 1993).
Holter monitoring of patients with CHF shows 90% have premature ventricular contractions and
non-sustained ventricular tachycardia (rapid beating) show up in 60% of patients (according
to Stevenson WG, et al 1994) and atrial fibrillation in approximately 20% of patients
(according to Smith TW, et al 1997). The occurrence of arrhythmias may be associated with a
decrease in ventricular performance, which may worsen the symptoms of acutely decompensated
CHF and complicate patient management. The ventricle is the heart's pumping chamber that
pumps the oxygen-poor blood returning from the body into the arteries of the lungs, where the
blood picks up oxygen. In atrial fibrillation the heart's two small upper chambers (the
atria) quiver instead of beating effectively. Therefore, it is imperative that new therapies
developed for the treatment of decompensated CHF not be associated with the development or an
increase of arrhythmias. Natrecor® has been studied as an IV treatment for decompensated CHF
in over 500 patients. As interstitial fluid (in the lung tissues) accumulates in advanced CHF
cases, the pulmonary capillary wedge pressure (PCWP) increases. However administration of a
continuous IV infusion of Natrecor® resulted in dose-related decreases in PCWP, right atrial
pressure, and systemic vascular resistance, and an increase in cardiac index which is a
measurement of the volume of blood pumped by the heart, (according to Marcus LS, Hart D,
Packer M, et al 1996; Abraham WT at al 1998; and Mills RM et al 1999 ). Beneficial improved
blood flow throughout the body associated with a decrease in the systolic blood pressure -
heart rate index (the double product), suggests that Natrecor® improves cardiac performance
while not increasing estimated myocardial oxygen consumption.
The primary objective of this study is to compare the effects on heart rate and ventricular
arrhythmias of two doses of Natrecor® to dobutamine, during the first 24 hours of treatment
of decompensated CHF. The primary outcome of the study is an evaluation of: (1) average heart
rate, (2) average hourly premature ventricular beats, and (3) average hourly repetitive
beats, all expressed as a change from baseline, as measured by Holter monitoring (a portable
device that provides continuous monitoring of the electrical activity of the heart).
Additional objectives include exploring the effects of Natrecor® and dobutamine on other
Holter outcomes such as couplets, triplets, and ventricular tachycardia and the evaluation of
ventricular ectopy (seven or more single premature ventricular beats per minute or any run of
more than two ventricular ectopic beats) by the application of specific proarrhythmic
criteria. Clinical symptoms are also measured.
This is a multicenter, randomized, open-label, active-controlled safety study designed to
enroll approximately 240 patients with symptomatic (New York Heart Association [NYHA] Class
III or IV), decompensated CHF for whom treatment with dobutamine or Natrecor® is deemed
appropriate. After a 24-Hour Baseline Holter Monitoring Period, patients are randomized to
dobutamine or Natrecor® (0.015 or 0.03 µg/kg/min). The randomization is stratified by whether
or not the subjects have a known history of Ventricular Tachycardia (non-sustained or
sustained). Treatment assignment is open-label with regard to the study drug (dobutamine or
Natrecor®); assignment to the two Natrecor® dose groups is double-blinded. Dobutamine is to
be administered at a dose of at least 6 µg/kg/min. During the first 24 hours of study drug,
each patient undergoes Holter monitoring. Study drug (dobutamine or Natrecor®) is
administered for at least 24 hours as the single IV vasoactive agent for symptomatic,
decompensated CHF. Other IV vasoactive agents such as milrinone, nitroprusside,
nitroglycerin, and/or any dose of dopamine are not to be added to the study drug during the
first 24 hours of therapy. Dobutamine is not to be added to the Natrecor® infusion during the
first 24 hours of therapy. After 24 hours, the Holter monitor will be removed, and patients
can remain on study drug, if appropriate. Natrecor® patients can continue on their fixed-dose
Natrecor® regimens (still blinded to specific dose group assignment) for up to a maximum of 7
days (with or without the addition of other parenteral agents) or can switch to whatever
treatment is appropriate, at the discretion of the investigator. Patients in the dobutamine
treatment group can continue on study drug as long as appropriate, at the discretion of the
investigator. Systemic hemodynamics (blood pressure and heart rate) are assessed at baseline,
at 15 and 30 minutes, and at 3, 8, 16, and 24 hours following the initiation of study drug.
The study hypothesis is that Natrecor® is not associated with increases in reported
ventricular arrhythmias in patients being treated for symptomatic decompensated CHF.
Continuous IV (intravenous) Infusion for at least 24 hours, and over 24 hours with discretion
of Principal Investigator. Dobutamine starts at 5 mcg/kg/min, may be increased; Natrecor®,
either 0.015 mcg/kg/min or 0.030 mcg/kg/min fixed dose for at least 24 hours, up to a maximum
of 7 days.