Diuretic Effect of Metolazone Pre-dosing Versus Concurrent Dosing

Diuretic Effect of Metolazone Pre-dosing Versus Concurrent Dosing With Furosemide: a Pilot Study

The purpose of this study is to examine whether administering metolazone 60 minutes prior to furosemide increases urine output compared with administering metolazone and furosemide concomitantly. Participants will have equal chance of being assigned to each group.

Study Overview

• Status: Terminated
• Conditions: Fluid Overload; Heart Failure Acute
• Intervention / Treatment: Drug: Metolazone 60 minutes prior to furosemide; Drug: Metolazone concurrently with furosemide

Detailed Description

Diuretic resistance is common among patients with acute decompensated heart failure, and one strategy for overcoming this phenomenon is sequential nephron blockade with loop plus thiazide-type diuretics. Metolazone is an oral thiazide-type diuretic commonly used for this purpose. Due to its delayed absorption, some clinicians suggest that metolazone be given 30-60 minutes prior to the loop diuretic. However, the efficacy and safety of such a strategy has not been investigated despite its added complexity. The purpose of this study is to investigate whether pre-dosing with metolazone confers a difference in efficacy and safety compared to administering it at the same time as furosemide.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 87 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Admission within 48 hours for acute decompensated heart failure with at least one symptom and one sign of volume overload
• Receipt of loop diuretic prior to admission
• Plan to administer furosemide 120 - 160 mg IV bolus twice daily over the next 24 hours with additional diuresis deemed necessary
• If patient is concurrently administered intravenous vasodilator or inotrope, the dose of vasodilator or inotrope must be stable for 6 hours prior to enrollment with a plan to continue the same dose for the 24 hour duration of this study

Exclusion Criteria:

• Metolazone prescribed prior to admission
• Receipt of continuous intravenous infusion of furosemide
• Cirrhosis or end stage renal disease
• Non-English speaking patients

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 Pre-dosing; Metolazone 5 mg by mouth administered 60 minutes prior to furosemide background therapy (120 - 160 mg intravenous bolus, followed by furosemide 120 - 160 mg intravenous bolus 12 - 24 hours after)	Drug: Metolazone 60 minutes prior to furosemide; All patients will receive furosemide background therapy (furosemide 120 - 160 mg IV bolus dosed twice within a twenty four hour period. Patients will be randomized 1:1 to either metolazone 5 mg tablet dosed 60 minutes prior to first dose of furosemide or metolazone dosed concurrently (within ten minute time frame) with the first dose of furosemide.; Other Names: Zaroxolyn
Active Comparator: Metolazone Concurrent Dosing; Metolazone 5 mg by mouth administered at the same time as furosemide background therapy (120 - 160 mg intravenous bolus, followed by furosemide 120 - 160 mg intravenous bolus 12 - 24 hours after)	Drug: Metolazone concurrently with furosemide; All patients will receive furosemide background therapy (furosemide 120 - 160 mg IV bolus dosed twice within a twenty four hour period. Patients will be randomized 1:1 to either metolazone 5 mg tablet dosed 60 minutes prior to first dose of furosemide or metolazone dosed concurrently (within ten minute time frame) with the first dose of furosemide.; Other Names: Zaroxolyn

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-Hour Urine Output	Total measured urine output in milliliters produced after metolazone dose is given	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Total Body Weight	Change in total body weight from baseline value measured prior to metolazone dose to value collected after metolazone dose	Baseline and at 12 to 23 hours after metolazone dose
Change in Serum Creatinine	Change in serum creatinine from baseline value collected prior to metolazone dose to value collected after metolazone dose	Baseline and at 12 to 23 hours after metolazone dose
Acute Kidney Injury	Portion of patients with increase in serum creatinine by ≥ 0.3 mg/dL or ≥ 50% from baseline	Baseline and at 12 to 23 hours after metolazone dose
Hypokalemia	Proportion of patients with potassium level less than 4.0 mEq/L measured after metolazone dose is given	Baseline and at 12 to 23 hours after metolazone dose
Hypomagnesemia	Proportion of patients with magnesium level less than 2.0 mg/dL measured after metolazone dose is given	Baseline and at 12 to 23 hours after metolazone dose
Hyponatremia	Proportion of patients with serum sodium level less than 135 mg/dL measured after metolazone dose is given	Baseline and at 12 to 23 hours after metolazone dose

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Investigators: Principal Investigator: Brent Reed, PharmD, University of Maryland, College Park

Publications and helpful links

General Publications

• Ellison DH, Felker GM. Diuretic Treatment in Heart Failure. N Engl J Med. 2017 Nov 16;377(20):1964-1975. doi: 10.1056/NEJMra1703100. No abstract available. Erratum In: N Engl J Med. 2018 Feb 1;378(5):492.
• Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010 Nov 2;56(19):1527-34. doi: 10.1016/j.jacc.2010.06.034.
• Grosskopf I, Rabinovitz M, Rosenfeld JB. Combination of furosemide and metolazone in the treatment of severe congestive heart failure. Isr J Med Sci. 1986 Nov;22(11):787-90.
• Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med. 1991 May 15;114(10):886-94. doi: 10.7326/0003-4819-114-10-886.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Actual): January 10, 2020
• Study Completion (Actual): January 10, 2020

Study Registration Dates

• First Submitted: November 15, 2018
• First Submitted That Met QC Criteria: November 15, 2018
• First Posted (Actual): November 19, 2018

Study Record Updates

• Last Update Posted (Actual): October 22, 2021
• Last Update Submitted That Met QC Criteria: September 25, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: furosemide; diuretic; metolazone
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Furosemide; Metolazone
• Other Study ID Numbers: HP-00082982

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

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.: Yes