The Effects of Decreasing the Lasix Dose on the Cardiorenal System

Heart Failure Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00982423
• Other study ID #: 09-003210
• Secondary ID: R01HL084155P01HL
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: September 18, 2009
• Last updated: June 22, 2015
• Start date: July 2009
• Est. completion date: July 2014

Study information

• Verified date: June 2015
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 90 Years

Eligibility

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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Failure
• Kidney Dysfunction
• Renal Insufficiency

Intervention

Drug:
• Furosemide
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.

Locations

Country	Name	City	State
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Mayo Clinic	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

McKie PM, Schirger JA, Benike SL, Harstad LK, Chen HH. The effects of dose reduction of furosemide on glomerular filtration rate in stable systolic heart failure. JACC Heart Fail. 2014 Dec;2(6):675-7. doi: 10.1016/j.jchf.2014.05.014. Epub 2014 Sep 24. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	3 weeks, approximately 6 weeks	Yes
Secondary	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.	3 weeks, approximately 6 weeks	Yes
Secondary	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.	3 weeks, approximately 6 weeks	No
Secondary	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.	3 weeks, approximately 6 weeks	No
Secondary	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.	3 weeks, approximately 6 weeks	No
Secondary	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.	3 weeks, approximately 6 weeks	No