Study of Low Dose Nesiritide With or Without Sildenafil in Congestive Heart Failure Patients With Renal Dysfunction

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to show that low dose recombinant BNP coupled with phosphodiesterase V inhibition will improve renal dysfunction and promote relief of volume overload in patinets with acute decompensated heart failure complicated by the cardiorenal syndrome.

Detailed Description
-----------------
Renal dysfunction is a common comorbidity, as well as a common and progressive complication, of heart failure (HF). Increasingly, the clinical syndrome of HF is one of cardiorenal failure owing to the frequent presentation of combined cardiac and renal dysfunction. Recent studies have established the prognostic importance of renal dysfunction in patients with chronic HF. An analysis of the patients in the second prospective randomized study of Ibopamine on mortality and efficacy (PRIME) by Hillege et al1 demonstrated that estimated glomerular filtration rate (GFR) is the most powerful predictor of mortality, exceeding functional status and ejection fraction (EF). In an ongoing prospective study, we are assessing the neurohumoral and renal hemodynamic profile of hospitalized patients with ADHF who do or do not develop the CRS. Our preliminary findings suggest that indeed the combination of pronounced activation of renin-angiotensin-aldosterone system (RAAS), decreased renal perfusion pressure and importantly, a relative deficiency of the natriuretic peptides (despite marked volume overload) predisposes to the development of CRS.

Official Title
-----------------
A Randomized, Double Blinded Placebo Controlled Cross-over Study of Low Dose B-type Natriuretic Peptide (Nesiritide) With or Without Concomitant Phosphodiesterase V (PDE V) Inhibition(Sildenafil) in Congestive Heart Failure Patients With Renal Dysfunction

Conditions
-----------------
Congestive Heart Failure, Renal Dysfunction

Intervention / Treatment
-----------------
* Drug: low dose Nesiritide
* Drug: nesiritide, Sildenafil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Left ventricular ejection fraction 35% assessed by echocardiography, nuclear scan or left ventriculogram within the past 2 years Stable (NYHA) class II and III symptoms as defined by: no change in NYHA symptoms over the past 3 months; on stable doses of ACE inhibitor and beta blocker for one month; no episode of decompensated CHF over the past 3 months. Calculated creatinine clearance of equal or less than 60 ml/min and greater than 30 ml/min, using the Cockcroft-Gault formula assessed within the past 12 months Exclusion Criteria: Nitrates or alpha blockers Prior diagnosis of intrinsic renal diseases including renal artery stenosis of > 50% Peritoneal or hemodialysis within 90 days or anticipation that dialysis or ultrafiltration of any form will be required during the study period Hospitalization for decompensated CHF during the past 3 months Myocardial infarction within 3 months of screening Unstable angina within 3 months of screening or any evidence of myocardial ischemia Significant valvular stenosis, hypertrophic, restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis Severe congenital heart diseases Sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening Second or third degree heart block without a permanent cardiac pacemaker Stroke within 3 months of screening or other evidence of significantly compromised CNS perfusion Serum sodium of < 125 mEq/dL or > 150 mEq/dL Serum potassium of < 3.5 mEq/dL or > 5.7 mEq/dL Hemoglobin < 10 gm/dl Other acute or chronic medical conditions or laboratory abnormality which may increase the risks associated with study participation or may interfere with interpretation of the data Received an investigational drug within 1 month prior to dosing Patients with an allergy to iodine. Female subject who is pregnant or breastfeeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1: low dose BNP alone<br>low dose BNP with placebo | Drug: low dose Nesiritide<br>* Nesiritide infusion 0.005ug/kg/min<br>* Other names: Natracor;|
| Active Comparator: 2: low dose BNP + PDEVI<br>low dose BNpo + PDEVI | Drug: nesiritide, Sildenafil<br>* Nesiritide 0.005ug/kg/min Sildenafil 50 mg<br>* Other names: Viagra;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the efficacy of low dose BNP alone vs low dose BNP + PDE V inhibition in improving renal function in patients with CHF and renal dysfunction. (Calculated creatinine clearance = or < than 60 ml/min and > 30 ml/min, within 12 months.) |  | prospective | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| We also want to characterize both plasma and urinary humoral profile in these patients. |  | prospective | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Congestive Heart Failure, Congestive Heart Failure with a NYHF Class 2-3, Ejection Fraction of 35 or less