Prospective Comparison of Metolazone Versus Chlorothiazide for Acute Decompensated Heart Failure With Diuretic Resistance

The primary objective of the study is to compare efficacy of metolazone and chlorothiazide as add-on therapy in patients refractory to loop diuretics with heart failure with a reduced ejection fraction (HFrEF). This will be a single-center randomized pilot study.

Study Overview

• Status: Terminated
• Conditions: Cardiovascular Diseases; Heart Failure; Heart Failure With Reduced Ejection Fraction; Heart Failure Acute
• Intervention / Treatment: Drug: Metolazone Oral Tablet; Drug: Chlorothiazide Injection

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 18 years old
• Admitted for acute decompensated HF with left ventricular ejection fraction (LVEF) <40%
• Refractory fluid overload:
• Unresponsive (<500 mL net negative over previous 24 hours) AND ineffective diuresis (determined by HF team) to moderate intensity push or low intensity continuous infusion loop diuretic (80 mg IV furosemide or equivalent bumetanide dose of 4 mg)
• English or Spanish-speaking subjects
• Willing and able to comply with study procedures

Exclusion Criteria:

• Baseline thiazide use prior to admission or prior to study enrollment
• Renal replacement therapies (RRT) or glomerular filtration rate (GFR) <30 mL/min at the time of enrollment
• Pregnant women
• Cognitive impairment
• Prisoners
• Left ventricular assist devices (LVAD) or temporary mechanical circulatory support devices
• History of cardiac transplant
• Reported allergy to thiazides
• No enteral access or unable to take medications enterally
• Palliative diuretics
• Systolic blood pressure (SBP) <90 mm Hg prior to randomization
• Patients receiving concomitant lithium therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metolazone; Metolazone 5 mg by mouth once daily for 2 days	Drug: Metolazone Oral Tablet; Day 1: Metolazone 5 mg PO Day 2: Metolazone 5 mg PO; Other Names: Zaroxolyn
Active Comparator: Chlorothiazide; Chlorothiazide 500 mg IV once daily for 2 days	Drug: Chlorothiazide Injection; Day 1: Chlorothiazide 500 mg IV Day 2: Chlorothiazide 500 mg IV; Other Names: Diuril

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Net urine output at 24 hours	Milliliters of urine output minus the oral plus intravenous intake	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Net urine output at 48 hours	Milliliters of urine output minus the oral plus IV intake	48 hours
Net fluid balance over 12 hours	the net fluid balance over 12 and 24 hours prior to the addition of metolazone or chlorothiazide compared to the 12 hours after addition of the study drug	24 hours
Net fluid balance over 24 hours	Net fluid balance over 24 hours prior to the addition of metolazone or chlorothiazide compared to the 24 hours after addition of the study drug	48 hours
Weight change	Change in documented weight in kg at 48 hours after starting metolazone or chlorothiazide	48 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electrolyte disturbances	Frequency of hypokalemia, hypomagnesemia, hyponatremia	48 hours
Worsening renal function	increase in serum creatinine greater that 0.5 mg/dL from the patient's baseline value on the day of the first dose of chlorothiazide or metolazone	48 hours
Hospital length of stay	Number of days hospitalized	Assessed until hospital discharge, an average of 7 days
ICU length of stay	Number of days patient is located in an ICU	Assessed until hospital discharge, an average of 7 days
In-hospital mortality	Incidence of in-hospital mortality	Assessed until hospital discharge, an average of 7 days

Collaborators and Investigators

• Sponsor: University of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2018
• Primary Completion (Actual): January 1, 2021
• Study Completion (Actual): January 1, 2021

Study Registration Dates

• First Submitted: April 16, 2018
• First Submitted That Met QC Criteria: June 20, 2018
• First Posted (Actual): July 2, 2018

Study Record Updates

• Last Update Posted (Actual): February 16, 2021
• Last Update Submitted That Met QC Criteria: February 10, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Heart failure; Diuretic resistance; Loop diuretics; Thiazide diuretics
• Additional Relevant MeSH Terms: Heart Diseases; Heart Failure; Cardiovascular Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Chloride Symporter Inhibitors; Metolazone; Chlorothiazide
• Other Study ID Numbers: 20455

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No