Diuretic Effect of Metolazone Pre-dosing Versus Concurrent Dosing

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Fluid Overload, Heart Failure Acute

Intervention / Treatment
-----------------
* Drug: Metolazone 60 minutes prior to furosemide
* Drug: Metolazone concurrently with furosemide


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 89 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, open-label, active control pilot study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metolazone Pre-dosing<br>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<br>* 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.<br>* Other names: Zaroxolyn;|
| Active Comparator: Metolazone Concurrent Dosing<br>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<br>* 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.<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
diuretic, metolazone, furosemide