Oral Metolazone and Intermittent Intravenous Furosemide Versus Continuous Infusion Furosemide in Acute Heart Failure

Addition of Oral Metolazone to Intermittent Intravenous Furosemide Versus Transition to Continuous Infusion Furosemide in Acute Decompensated Heart Failure Patients Experiencing an Inadequate Response to Therapy

The purpose of this prospective, randomized, open-label study is to compare two diuretic strategies in patients with acute decompensated heart failure (ADHF): the addition of an oral thiazide diuretic to intravenous bolus (IVB) loop diuretic will be compared to transition from IVB to continuous infusion (CI) loop diuretic.

Study Overview

• Status: Terminated
• Conditions: Acute Decompensated Heart Failure
• Intervention / Treatment: Drug: Addition of oral Metolazone; Drug: Furosemide dose escalation

Detailed Description

Patients hospitalized for ADHF secondary to fluid overload and who are experiencing an inadequate response to IVB furosemide and require additional diuresis will be enrolled. Patients will be randomized to one of two treatment arms: the addition of oral metolazone to continued IVB furosemide versus transition from IVB to CI furosemide. A suggested algorithm for initial dosing and titration of these two diuretic strategies will be provided. Baseline and daily data collection will include various efficacy and safety endpoints including daily net urine output and weight, patient and physician global assessment scale, length of stay, 30-day death or rehospitalization, vital signs, electrolytes, and renal function. Clinically meaningful efficacy and safety endpoints will be compared.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC_Chapel Hill

Participation Criteria

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:

1. Greater than or equal to 18 years of age

2. Hospitalized for acute decompensated heart failure (ADHF) secondary to fluid overload as defined by the presence of at least

   • 1 symptom (e.g. dyspnea, orthopnea, paroxysmal nocturnal dyspnea) AND
   • 1 sign (e.g. rales on auscultation, > 2+ peripheral or presacral> edema, hepatomegaly, ascites, jugular vein distension > 7 cm, pulmonary vascular congestion on chest radiography)
3. Inadequate response to IV diuretics and requiring additional diuresis as determined by primary medical team
4. Received less than six doses of IV furosemide OR enrolled within 72 hours of hospital admission
5. Anticipated need for intravenous diuretic therapy for at least 48 hours
6. Able to provide informed consent

Exclusion Criteria:

1. Receiving a continuous infusion loop diuretic during current hospital visit
2. Substantial diuretic response to pre-randomization diuretic dosing such that higher doses of diuretic would be contraindicated (based on judgement of patient's primary team)
3. Planned or ongoing intravenous vasoactive therapy (e.g. inotrope, vasodilator) or mechanical support (e.g. intra-aortic balloon pump, ventricular assist device) for ADHF during this hospitalization
4. Planned elective admission for elective placement/revision of a cardiovascular device (e.g. defibrillator, biventricular pacemaker) during this hospitalization or such within the preceding 7 days
5. Systolic blood pressure < 90 mmHg
6. Serum creatinine > 3 mg/dL at baseline or renal replacement therapy including ultrafiltration
7. Serum potassium < 3.5 mEq/L (3.0 - 3.4 mEq/L allowed if supplemental potassium is being administered)
8. Serum magnesium < 1.6 mg/dL (1.4 - 1.5 mg/dL allowed if supplemental magnesium is being administered)
9. Acute coronary syndrome or hemodynamically significant arrhythmias causing worsening HF
10. Severe, uncorrected primary cardiac valvular disease, acute myocarditis, constrictive pericarditis, hypertrophic obstructive cardiomyopathy, restrictive or constrictive cardiomyopathy, complex congenital heart disease
11. Primary pulmonary hypertension with right sided heart failure
12. Use of iodinated radiocontrast material in prior 72 hours or planned within the next 48 hours
13. Enrollment or planned enrollment in another randomized clinical trial during hospitalization

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: Addition of PO Thiazide Diuretic; Addition of oral metolazone 5 mg daily to current intravenous bolus furosemide. All subjects will continue their current dose of intravenous bolus furosemide.	Drug: Addition of oral Metolazone; Addition of oral metolazone 5 mg daily to continued current dose of intravenous bolus furosemide; Other Names: Zaroxolyn
Active Comparator: IV furosemide dose escalation; Current IV furosemide dose will be escalated to 2-2.5 x current dose, given as either IV bolus or continuous infusion over 24 hours.	Drug: Furosemide dose escalation; Furosemide dose escalation via either IV bolus (2-2.5 x current dose) or continuous infusion (2-2.5 x current dose administered over previous 24 hours); Other Names: Lasix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily Net Fluid Output on Day 2 (24-48 Hours After Randomization)	Net fluid output = fluid output during 24-48 hours after randomization - fluid intake during 24-48 hours after randomization. A negative value means that daily fluid intake was less than the daily fluid output.	24-48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily Net Fluid Output on Days 1, 3, and 4	Daily net fluid output = daily fluid output - daily intake. A negative value means that daily fluid intake was less than the daily fluid output.	0-24, 48-72, 72-96 hrs
Daily Urine Output (mL Urine Out Per mg Furosemide (IV Equivalent) Received)		0-24, 24-48, 48-72, 72-96 hrs
Daily Weight		Baseline (Dry), Baseline, 0-24, 24-48, 48-72, 72-96 hrs
Patient Global Assessment Scale	Scale range: 1-5 Which of the following best describes your overall health state today?; = markedly worse; = worse; = neither better nor worse; = better; = markedly better	Baseline, 24, 48, 72, 96 hrs
Physician Global Assessment Scale	Scale range: 1-5 Which of the following best describes the patient's overall health state today?; = markedly worse; = worse; = neither better nor worse; = better; = markedly better	Baseline, 24, 48, 72, 96 hours
Need for Additional or Alternative Diuretic (Crossover) or Other Vasoactive Therapy (Study Failure)	Patients will be considered a treatment failure if they require additional diuretic (including crossover to the alternative study arm) or require IV vasoactive drug therapy (e.g. vasodilators including nitroglycerin or inotropes) as deemed appropriate/necessary by their medical team.	0-96 hours
Time to Return to Baseline Weight		0-96 hours
Length of Hospitalization		Assessed till hospital discharge, an average of 1 week (longest 29 days)
30-day All-cause Mortality		30 days
Rehospitalization at 30 Days		30 days
Unscheduled Heart Failure Visits to Emergency Department or Outpatient Clinic		30 days
Blood Urea Nitrogen (BUN)		Baseline, 24, 48, 72, 96 hours

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: University of Illinois at Chicago; Virginia Commonwealth University
• Investigators: Principal Investigator: Jo E. Rodgers, PharmD, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2008
• Primary Completion (Actual): May 28, 2016
• Study Completion (Actual): November 14, 2017

Study Registration Dates

• First Submitted: May 17, 2009
• First Submitted That Met QC Criteria: May 18, 2009
• First Posted (Estimate): May 19, 2009

Study Record Updates

• Last Update Posted (Actual): March 13, 2018
• Last Update Submitted That Met QC Criteria: February 13, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Diuretics; Acute Decompensated Heart Failure
• 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: 08-1292