Clinical trial NCT00982423: The Effects of Decreasing the Lasix Dose on the Cardiorenal System
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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Heart Failure
Kidney Dysfunction
Keywords: heart failure
heart failure with and without kidney dysfunction
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2009-09-23
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Renal Function as Measured by Glomerular Filtration Rate (GFR) at Baseline and in Response to Decreasing Furosemide Dose
timeFrame: 3 weeks, approximately 6 weeks
Secondary outcomes:
measure: Renal Plasma Flow at Baseline and in Response to Decreasing Furosemide Dose
timeFrame: 3 weeks, approximately 6 weeks
measure: Aldosterone at Baseline and in Response to Decreasing Furosemide Dose
timeFrame: 3 weeks, approximately 6 weeks
measure: Plasma Renin Activity at Baseline and in Response to Decreasing Furosemide Dose
timeFrame: 3 weeks, approximately 6 weeks
measure: Angiotensin II at Baseline and in Response to Decreasing Furosemide Dose
timeFrame: 3 weeks, approximately 6 weeks
measure: Plasma Cyclic Guanosine Monophosphate (cGMP) at Baseline and in Response to Decreasing Furosemide Dose
timeFrame: 3 weeks, approximately 6 weeks
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Horng H Chen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. No abstract available.