Low Dose Intravenous (IV) Infusion of BNP in the Presence and Absence of Acute Type V Phosphodiesterase (PDE V) in Improving Renal Function in Hospitalized Chronic Heart Failure (CHF) Patients With Renal Dysfunction (Aim 3 BNP/PDEV)

Specific Aims 3: Define in Hospitalized Decompensated CHF Patients With Renal Dysfunction, the Renal Actions of Low Dose Intravenous Infusion of BNP in the Presence and Absence of Acute PDE V Inhibition in Improving Renal Function

The purpose of the study is to determine if low doses of BNP can improve renal function in people with chronic heart failure with renal dysfunction, also to determine whether Sildenafil assists with improvement. This study will enroll only hospitalized patients with heart failure.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Renal Dysfunction
• Intervention / Treatment: Drug: BNP and PDE-V; Drug: BNP

Detailed Description

The broad objective of this protocol is to advance our understanding of the pathophysiological mechanisms of human Cardiorenal Syndrome (CRS) with a specific emphasis upon the biological interaction between diuretic therapy, the renin-angiotensin-aldosterone-system (RAAS) and cyclic 3'-5'-guanosine monophosphate (cGMP) pathway.

Chronic heart failure (CHF) as a result of left ventricular systolic dysfunction is a clinical syndrome with high mortality and morbidity. Renal dysfunction is a common and progressive complication of CHF and despite growing recognition of the frequent presentation of combined cardiac and renal dysfunction, or "Cardiorenal Syndrome (CRS)", its underlying pathophysiology is not well understood, with a lack of consensus as to its appropriate management.

The main objective of this study is to extend the findings of the applicant's studies in both human and experimental CHF and determine if low dose intravenous (IV) (0.005/Kg/min) administration of BNP in hospitalized decompensated CHF patients with renal dysfunction would improve the renal function. Furthermore, based on our preliminary data, we also sought to assess if PDE V inhibition potentiated these renal enhancing actions.

Hypothesis: Low dose IV infusion of BNP in hospitalized decompensated CHF patients with CRS will enhance renal and humoral functions as compared to standard therapy, which will be further potentiated by PDEV inhibition as evident by:

Increased sodium excretion, Increased creatinine clearance Decreased plasma creatinine and blood urea nitrogen Suppression of the renin-angiotensin-aldosterone system, Increased renal cGMP generation

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients admitted to St Mary's Hospital, Mayo Clinic Rochester MN with NYHA class III-IV decompensated CHF with renal dysfunction as Calculated creatinine clearance of equal or less than 60 ml/min but greater than 20 ml/min using the Cockcroft-Gault formula.

Exclusion Criteria:

• Cause of acute renal dysfunction can be reasonably ascribed to factors other than heart failure or its treatment
• Known intrinsic renal diseases or renal artery stenosis of =>50%
• Patients taking Nitrates within the previous 24 hours
• Patients needing emergency coronary revascularization or those who may have rapidly changing cardiac function (i.e. patients with acute myocardial infarction or shock)
• Peritoneal or hemodialysis within 90 days or anticipation that dialysis or ultrafiltration of any form will be required during the study period
• Systolic blood pressure < 90 mmHg or cardiogenic shock.
• Requirement of pressors for maintenance of blood pressure.
• Intra-aortic blood pump use.
• History of significant uncorrected renal artery stenosis as defined by >50% stenosis.
• Severe aortic or mitral stenosis or significant LV outflow tract obstruction. Hgb < 10 mg/dL
• Pregnant or nursing women.
• Contraindication to nesiritide.
• Inability to have NSAID dose held for up to 30 hours, if being treated with these medications.
• Administration of radiocontrast medium within 7 days of enrollment or anticipated use of such agents during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: BNP with PDE-V; BNP (Nesiritide) will be infused starting at 0.0025 g/Kg/min IV for 3 hours, if tolerated increased to 0.005 g/kg/min for 45 hours without bolus with PDEV inhibition, they will also receive Sildenafil 12.5 mg at timepoints 0,12, 24 and 36 hours	Drug: BNP and PDE-V; low dose BNP 0.025 u/kg/min for 3 hours then 0.005ug/kg/min 45 hours PDE-V 12.5 mg 4 time points; Other Names: Viagra; nesiritide (Natrecor)
Active Comparator: BNP (Nesiritide) will be infused at 0.005 u/Kg/min IV for 48 h; BNP (Nesiritide) will be infused at 0.025 ug/Kg/min IV for 3 hours then 0.005ug/kg/min 45 hours without bolus. No PDE-V is given.	Drug: BNP; low dose BNP at 0.025 u/kg/min if tolerated then at 0.005 ug/kg/min for 45 hours; Other Names: Nesiritide (Natrecor)
No Intervention: standard care; Patients randomized to this group will continue to receive therapy at the discretion of the heart failure specialist who is managing the patient (with the exception of BNP and low dose dopamine). Blood and Urine will be collected after the patient has been randomized for 48 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary endpoint for this aim will be a comparison of the 3 groups for the percent change in creatinine clearance, and blood urea nitrogen from baseline to 48 hours.	each blood and urine collections 4 time points

Secondary Outcome Measures

Outcome Measure	Time Frame
The secondary endpoints for this aim will be a comparison of the 3 groups for the percent change in plasma, sodium excretion, aldosterone, and renal cGMP generation from baseline line to 48 hours	each blood and urine collection at 4 time points

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Dr Horng H Chen, MD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2009
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: September 3, 2009
• First Submitted That Met QC Criteria: September 4, 2009
• First Posted (Estimate): September 7, 2009

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 15, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: BNP with or without PDE-V in heart failure
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Heart Failure; Renal Insufficiency; Physiological Effects of Drugs; Natriuretic Agents; Natriuretic Peptide, Brain
• Other Study ID Numbers: 09-003303; 1R01HL08415501A2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No