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

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.

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).