A Comparison of Hydrochlorothiazide and Metolazone in Combination With Furosemide in Congestive Heart Failure Patients

June 3, 2008 updated by: University of New Mexico
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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

13

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • New Mexico
      • Albququerque, New Mexico, United States, 87120
        • Recruiting
        • University of New Mexico Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Joe R. Anderson, PharmD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • 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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 1
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.
Active Comparator: 2
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The primary endpoint will be change in urinary output.
Time Frame: 4 days
4 days

Secondary Outcome Measures

Outcome Measure
Time Frame
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
4 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of New Mexico

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2003

Primary Completion (Anticipated)

January 1, 2009

Study Completion (Anticipated)

January 1, 2009

Study Registration Dates

First Submitted

June 2, 2008

First Submitted That Met QC Criteria

June 3, 2008

First Posted (Estimate)

June 4, 2008

Study Record Updates

Last Update Posted (Estimate)

June 4, 2008

Last Update Submitted That Met QC Criteria

June 3, 2008

Last Verified

June 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HRRC 03-477

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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