Double Blind Randomized Placebo Controlled Trial of Natrecor in Acute Decompensated Heart Failure With Normal EF

Overview

Heart failure (HF) is a disease that is caused by a reduced heart muscle function. Reduced heart muscle function can occur as a consequence of reduced pumping activity from a weak heart muscle or because of a stiff heart muscle. This study is looking at the effectiveness of Natrecor (nesiritide) in patients that require hospitalization due to worsening heart failure as a result of a stiff or thickened heart muscle. Natrecor is a man-made version of a protein that my body makes on its own and has been approved for the treatment of patients requiring hospital admission for heart failure and have shortness of breath at rest or with minimal activity. Natrecor has shown to lower the pressures in the heart and decreases the congestion in the lungs. This study is being done to see if the addition of a Natrecor to standard medical therapy for HF will improve symptoms faster or more completely than giving only the standard treatment for CHF.

Despite an increasing number of patients hospitalized with decompensated heart failure in the presence of a normal ejection fraction, there is little clinical trial data to guide clinicians in their acute management . Since the number of patients hospitalized with decompensated heart failure in the presence of normal ejection fraction (\>50%) is increasing, it is imperative to develop effective therapies which are supported by clinical evidence such as randomized clinical trials. The purpose of this study is to evaluate the utility of natriuretic peptide for the specific management of these patients. Loop diuretics (such as Furosemide) are powerful diuretic agents which are used as a first-line therapy in volume overloaded patients with low ejection fraction heart failure. Despite their widespread use, they can cause severe electrolyte and volume abnormalities contributing to increased morbidity and mortality . These adverse effects are exacerbated even further in heart failure patients with normal ejection fraction since these patients are usually older, have worse renal function and are more susceptible to volume depletion and its effects. The FDA approved Natrecor for Acute Decompensated Heart Failure and did not differ between low ejection fraction and normal ejection fraction heart failure. Given however, the low number of patients with normal ejection fraction heart failure in clinical trials and the paucity of outcome data in these patients, we propose to specifically study them. Brief Description of Experimental Approach: Patients who present to the emergency room diagnosed with acute decompensated heart failure requiring the administration of intravenous diuretics and found to have normal contractile function will be eligible for participation in this study. Patients must have pulmonary congestion documented on their admitting chest X-ray and clinical evidence of volume overload such as rales or edema on physical examination at the time of randomization. Patients will have received at least one dose of IV Furosemide either in-route to the emergency room or on presentation to the emergency room. An echocardiogram will be obtained after presentation to the emergency room documenting a normal (\>50%) left ventricular ejection fraction. Patients will be randomized to Natrecor or placebo in addition to a standard medical therapy. Study drug will be administered for 24 hours. Study drug will be initiated with a 2-µg/kg loading bolus followed by .01-µg/kg/min infusion. This may be increased at a rate of .005-µg/kg/min. every 3 hours until maximum dose of .03-µg/kg/min. Any increase in the infusion rate will be preceded by a 1-µg/kg bolus and increases in infusion rates will be permitted only in patients who have a systolic blood pressure \> 100 mmHg. IV Nitroglycerin and IV Milrinone will be prohibited within 2 hours prior to initiating study drug infusion to three hours after completion of study drug infusion. All other intravenous vasoactive medications including other IV inotropes will be avoided within 2 hours prior to initiating study drug infusion to three hours after start of study drug infusion. Oral ACE inhibitors will be avoided from 2 hours prior to initiating study drug infusion to 30 minutes after start of study drug so as to avoid potential hypotension. Concomitant 'standard of care medications' including diuretics (IV or PO), ACE inhibitors, Aldactone, Digoxin etc. will be left to investigator discretion to be administered during the hospital stay as indicated. The primary endpoint of this study will be an absolute reduction in brain natriuretic peptide (BNP) levels three hours after discontinuation of the study drug. BNP is elevated in acute decompensated heart failure and has utility in outcome, severity and prognosis of patients with ADHF . Secondary endpoints will include: all cause in-hospital mortality, physician and patient global score at 24 hours, twenty-four hour urine output after start of study drug infusion, weight change at 24 hours after start of study drug infusion, number of patients with K \< 3.5meq at 24 hours, change in creatinine at 24 hours after start of study drug and at discharge or at 3 days, BNP levels at baseline, 3 hours after discontinuation of the study drug and at discharge or at 3 days, total diuretic dose of IV and PO Lasix at 48 hours and 72 hours after randomization or at discharge, changes in diastolic indices measured by transthoracic echocardiography 24 hours after the start of the study drug and 30 day post-randomization all cause mortality.