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The Effects of Decreasing the Lasix Dose on the Cardiorenal System (Aim1)

Primary Purpose

Heart Failure, Kidney Dysfunction

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Furosemide

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring heart failure, heart failure with and without kidney dysfunction

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria for Subjects with Compensated CHF without Renal Dysfunction:

Left ventricular ejection fraction of equal or less than 40% assessed by echocardiography, nuclear scan, MRI, or left ventriculogram within the past 36 months.
Stable New York Heart Association (NYHA) class II and III symptoms as defined by: a) no change in NYHA symptoms over the past 3 months; b) on stable doses of ACE inhibitor or beta blocker or digoxin or furosemide or angiotensin II receptor, type 1 (AT1) blocker over the past 3 months; c) no episode of decompensated CHF over the past 6 months.
Calculated creatinine clearance of equal or less than 80 ml/min, using the Cockcroft-Gault formula assessed within the past 36 months and a confirmatory calculated creatinine clearance equal or less than 80 ml/min at the time of enrollment.

Inclusion Criteria for Subjects with Compensated CHF with Renal Dysfunction:

Left ventricular ejection fraction of equal or less than 40% assessed by echocardiography, nuclear scan or left ventriculogram within the past 36 months.
Stable New York Heart Association (NYHA) class II and III symptoms as defined by: a) no change in NYHA symptoms over the past 3 months; b) on stable doses of ACE inhibitor or beta blocker or digoxin or furosemide or AT1 blocker over the past 3 months; c) no episode of decompensated CHF over the past 6 months.
Calculated creatinine clearance of equal or less than 60 ml/min and greater than 20 ml/min, using the Cockcroft-Gault formula assessed within the past 36 months and a confirmatory calculated creatinine clearance equal or less than 60 ml/min and greater than 20 ml/min at the time of enrollment.

Exclusion Criteria for both groups:

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
Patients who are taking aldosterone antagonist
Hospitalization for decompensated CHF during the past 6 months
Subjects on other diuretics besides furosemide
Myocardial infarction within 6 months of screening
Unstable angina within 6 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 central nervous system (CNS) perfusion
Alanine Aminotransferase (ALT) result >1.5 times the upper limit of normal
Serum sodium of < 125 milliequivalent (mEq)/dL or > 150 mEq/dL
Serum potassium of < 3.5 mEq/dL or > 5.5 mEq/dL
Serum digoxin level of > 2.0 ng/ml
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
In the opinion of the investigator is unlikely to comply with the study protocol or is unsuitable for any reason.

Sites / Locations

Mayo Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Furosemide

Arm Description

Subjects received their clinically prescribed dose of furosemide for a 3 week stabilization period, then were assessed for cardiorenal and humoral function. Subjects then had a 50% reduction of the furosemide dose for a 3 week stabilization period, and were assessed for cardiorenal and humoral function again.

Outcomes

Primary Outcome Measures

Renal Function as Measured by Glomerular Filtration Rate (GFR) at Baseline and in Response to Decreasing Furosemide Dose

Kidney function was measured by GFR determined by iothalamate clearance. GFR describes the flow rate of filtered fluid through the kidney measured in milliliters per minute per 1.73 m^2 of body surface area. A lower GFR means the kidney is not filtering normally. An estimated GFR of less than 60 mg/min/1.73 m^2 of body surface area is considered to be impaired kidney function.

Secondary Outcome Measures

Renal Plasma Flow at Baseline and in Response to Decreasing Furosemide Dose

Effective renal plasma flow (eRPF) is a measure used to calculate renal plasma flow (RPF) and hence estimate renal function. Renal plasma flow is the volume of blood plasma that flows through the kidneys per unit time, measured as ml/min.

Aldosterone at Baseline and in Response to Decreasing Furosemide Dose

Aldosterone is part of the renin-angiotensin-aldosterone system (RAAS). Drugs that interfere with the secretion or action of aldosterone are in use as antihypertensives, like lisinopril, which lowers blood pressure by blocking the angiotensin-converting enzyme (ACE), leading to lower aldosterone secretion. The net effect of these drugs is to reduce sodium and water retention but increase retention of potassium.

Plasma Renin Activity at Baseline and in Response to Decreasing Furosemide Dose

Plasma renin activity is a measure of the activity of the plasma enzyme renin, which plays a major role in the body's regulation of blood pressure, thirst, and urine output. Renin is an enzyme that hydrolyses angiotensinogen secreted from the liver into the peptide angiotensin I. Renin's primary function is to cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.

Angiotensin II at Baseline and in Response to Decreasing Furosemide Dose

Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by the angiotensin-converting enzyme (ACE) primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of antidiuretic hormone (ADH) and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood pressure.

Plasma Cyclic Guanosine Monophosphate (cGMP) at Baseline and in Response to Decreasing Furosemide Dose

Any change in atrial filling pressures leads to the release of atrial natriuretic peptides (ANP) from the heart. Once released, atrial peptides exert potent direct vasodilator and natriuretic actions by virtue of the ability to increase their intracellular second messenger, cGMP. Plasma cGMP correlates closely with the severity of congestive heart failure.

Full Information

NCT ID

NCT00982423

First Posted

September 18, 2009

Last Updated

June 22, 2015

Sponsor

Mayo Clinic

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT00982423

Brief Title

The Effects of Decreasing the Lasix Dose on the Cardiorenal System

Acronym

Aim1

Official Title

To Define the Effects of Decreasing the Furosemide Dose on Cardiorenal and Humoral Function in Humans With Compensated Chronic Heart Failure (CHF) With and Without Renal Dysfunction

Study Type

Interventional

2. Study Status

Record Verification Date

June 2015

Overall Recruitment Status

Completed

Study Start Date

July 2009 (undefined)

Primary Completion Date

July 2014 (Actual)

Study Completion Date

July 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Mayo Clinic

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The investigators' objective is to define the effects of decreasing the furosemide dose on heart, kidney and humoral function in people with compensated heart failure and kidney dysfunction and also in people with compensated heart failure without kidney dysfunction. Secondly, to define the humoral activation in both groups.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure, Kidney Dysfunction

Keywords

heart failure, heart failure with and without kidney dysfunction

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

41 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Furosemide

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Furosemide

Other Intervention Name(s)

Lasix

Intervention Description

Primary Outcome Measure Information:

Title

Renal Function as Measured by Glomerular Filtration Rate (GFR) at Baseline and in Response to Decreasing Furosemide Dose

Description

Time Frame