A Comparison of Hydrochlorothiazide and Metolazone in Combination With Furosemide in Congestive Heart Failure Patients - Full Text View

Sponsored by:	University of New Mexico
Information provided by:	University of New Mexico
ClinicalTrials.gov Identifier:	NCT00690521

Purpose

The purpose of this research study is to compare the effectiveness of hydrochlorothiazide or metolazone in combination with furosemide. Patients with heart failure suffer from swelling because of too much fluid in the body. Furosemide, hydrochlorothiazide, and metolazone are all water pills used to treat the swelling. For most patients, taking furosemide alone is successful. However, sometimes patients need to add another water pill. Doctors usually add either metolazone or hydrochlorothiazide. It is not clear which water pill is better when added to furosemide. The purpose of this study is to determine which water pill when added to furosemide is the best at reducing excess fluid in the body.

Condition	Intervention	Phase
Congestive Heart Failure	Drug: metolazone or hydrochlorothiazide	Phase IV

MedlinePlus related topics: Drinking Water Heart Failure

Drug Information available for: Hydrochlorothiazide Furosemide Creatinine Metolazone

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Crossover Assignment, Safety/Efficacy Study
Official Title:	A Comparison of Hydrochlorothiazide and Metolazone in Combination With Furosemide in Congestive Heart Failure Patients

Further study details as provided by University of New Mexico:

Primary Outcome Measures:

The primary endpoint will be change in urinary output. [ Time Frame: 4 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Secondary endpoints will be changes in weight, neurohormones (angiotensin II, catecholamines, brain natriuretic peptide, aldosterone), and electrocardiographic parameters of ventricular instability. [ Time Frame: 4 days ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	13
Study Start Date:	January 2003
Estimated Study Completion Date:	January 2009
Estimated Primary Completion Date:	January 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator Patients will be randomized to receive either metolazone or HCTZ in a randomized, double-blind, placebo controlled crossover trial. The patients will receive the alternative medication if The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.	Drug: metolazone or hydrochlorothiazide The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.
2: Active Comparator Patients will be randomized to receive either metolazone or HCTZ in a randomized, double-blind, placebo controlled crossover trial. The patients will receive the alternative medication if The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.	Drug: metolazone or hydrochlorothiazide The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.

Arms

Assigned Interventions

1: Active Comparator

Patients will be randomized to receive either metolazone or HCTZ in a randomized, double-blind, placebo controlled crossover trial. The patients will receive the alternative medication if The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.

Drug: metolazone or hydrochlorothiazide

The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.

2: Active Comparator

Patients will be randomized to receive either metolazone or HCTZ in a randomized, double-blind, placebo controlled crossover trial. The patients will receive the alternative medication if The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.

Drug: metolazone or hydrochlorothiazide

The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.

Detailed Description:

Objective: To establish which combination of diuretics is the most effective in promoting diuresis in congestive heart failure patients. Secondary Objectives: To determine the duration of action of furosemide as monotherapy and in combination with either hydrochlorothiazide or metolazone. To determine the effect of diuretic combination therapy on neurohormonal activation. Background: Diuretic resistance occurs when a potent diuretic drug, such as furosemide, is given in therapeutic doses and fails to reduce extracellular fluid volume to the desired level in an edematous patient. Studies have shown that metolazone and hydrochlorothiazide have demonstrated a synergistic response when used in combination with furosemide in congestive heart failure patients. The current guidelines for treating diuretic resistance in congestive heart failure patients recommend the metolazone-furosemide combination. However, there is no evidence to conclude that this combination is superior to hydrochlorothiazide-furosemide in increasing diuresis. Methods: Randomized, double-blind, crossover study to compare the efficacy of hydrochlorothiazide and metolazone in combination with stable doses of furosemide in 13 patients with congestive heart failure. The primary endpoint will be change in urinary output. Secondary endpoints will be changes in weight, neurohormones (angiotensin II, catecholamines, brain natriuretic peptide, aldosterone), and electrocardiographic parameters of ventricular instability. Study procedures will be performed at the UNM General Clinical Research Center. Patients will be hospitalized for 2 separate 4-day admissions, separated by a 1-week washout period. At each admission each patient will receive furosemide in combination with either metolazone or hydrochlorothiazide (metolazone for one admission and hydrochlorothiazide for the other). Following administration of combination therapy, blood and urine samples will be collected throughout the day to chart the onset and magnitude of effect of each treatment regimen. Various hemodynamic, renal, endocrine, and neurohormonal parameters will be assesed as will the effect of each combination treatment on ventricular instability using 12-lead electrocardiography. Data will be analyzed using ANOVA to compare changes from baseline and the Student t-test to analyze intertreatment differences.

All statistical analysis will be performed using SAS v6.12.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age >18 years
Diagnosis of chronic congestive heart failure with an ejection fraction ≤45%
Currently on a stable regimen of furosemide consisting of a daily dose of at least 80 mg for at least two weeks.
Patients receiving ACE-inhibitors and/or beta-blockers must be taking these medications for at least two weeks in stable doses.

Exclusion Criteria:

Renal dysfunction (serum creatinine >2 mg/dl or creatinine clearance of <30 ml/min as calculated by the Cockroft and Gault equation)
Hepatic dysfunction (AST and ALT >3 times the upper limit of the normal)
Hypokalemia (<4.0 mg/dl)
Concomitant treatment with any diuretic other than furosemide (with the exception of spironolactone).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00690521

Contacts

Contact: Joe R. Anderson, PharmD	505-272-3664	janderson@salud.unm.edu
Contact: James J Nawarskas, PharmD	505-272-0584	jnawarskas@salud.unm.edu

Locations

United States, New Mexico
University Of New Mexico Hospital	Recruiting
Albququerque, New Mexico, United States, 87120
Contact: Joe R. Anderson, PharmD 505-272-3664 janderson@salud.unm.edu
Contact: James J. Nawarskas, PharmD 505-272-0584 jnawarskas@salud.unm.edu
Principal Investigator: Joe R. Anderson, PharmD

Sponsors and Collaborators

University of New Mexico

More Information

Responsible Party:	University of New Mexico Health Sciences Center College of Pharmacy ( Joe R. Anderson, PharmD )
Study ID Numbers:	HRRC 03-477
Study First Received:	June 2, 2008
Last Updated:	June 3, 2008
ClinicalTrials.gov Identifier:	NCT00690521
Health Authority:	United States: Institutional Review Board

Keywords provided by University of New Mexico:

congestive heart failure
diuretics
combination

Study placed in the following topic categories:

Metolazone
Heart Failure
Heart Diseases
Furosemide
Hydrochlorothiazide

Additional relevant MeSH terms:

Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Therapeutic Uses
Sodium Chloride Symporter Inhibitors
Physiological Effects of Drugs

Diuretics
Cardiovascular Diseases
Cardiovascular Agents
Antihypertensive Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 15, 2009