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

• ClinicalTrials.gov Identifier: NCT00904488
• Recruitment Status: Terminated
• First Posted: May 19, 2009
• Results First Posted: February 13, 2018
• Last Update Posted: March 13, 2018
• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: University of Illinois at Chicago; Virginia Commonwealth University
• Information provided by (Responsible Party): University of North Carolina, Chapel Hill

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Decompensated Heart Failure	Drug: Addition of oral Metolazone; Drug: Furosemide dose escalation	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 11 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 2008
• Actual Primary Completion Date: May 28, 2016
• Actual Study Completion Date: November 14, 2017

Arms and Interventions

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 Name: 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 Name: Lasix

Outcome Measures

Primary Outcome Measures :

1. Daily Net Fluid Output on Day 2 (24-48 Hours After Randomization) [ Time Frame: 24-48 hours ]
   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.

Secondary Outcome Measures :

1. Daily Net Fluid Output on Days 1, 3, and 4 [ Time Frame: 0-24, 48-72, 72-96 hrs ]
   Daily net fluid output = daily fluid output - daily intake. A negative value means that daily fluid intake was less than the daily fluid output.
2. Daily Urine Output (mL Urine Out Per mg Furosemide (IV Equivalent) Received) [ Time Frame: 0-24, 24-48, 48-72, 72-96 hrs ]
3. Daily Weight [ Time Frame: Baseline (Dry), Baseline, 0-24, 24-48, 48-72, 72-96 hrs ]
4. Patient Global Assessment Scale [ Time Frame: Baseline, 24, 48, 72, 96 hrs ]

   Scale range: 1-5 Which of the following best describes your overall health state today?

   1. = markedly worse
   2. = worse
   3. = neither better nor worse
   4. = better
   5. = markedly better
5. Physician Global Assessment Scale [ Time Frame: Baseline, 24, 48, 72, 96 hours ]

   Scale range: 1-5 Which of the following best describes the patient's overall health state today?

   1. = markedly worse
   2. = worse
   3. = neither better nor worse
   4. = better
   5. = markedly better
6. Need for Additional or Alternative Diuretic (Crossover) or Other Vasoactive Therapy (Study Failure) [ Time Frame: 0-96 hours ]
   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.
7. Time to Return to Baseline Weight [ Time Frame: 0-96 hours ]
8. Length of Hospitalization [ Time Frame: Assessed till hospital discharge, an average of 1 week (longest 29 days) ]
9. 30-day All-cause Mortality [ Time Frame: 30 days ]
10. Rehospitalization at 30 Days [ Time Frame: 30 days ]
11. Unscheduled Heart Failure Visits to Emergency Department or Outpatient Clinic [ Time Frame: 30 days ]
12. Blood Urea Nitrogen (BUN) [ Time Frame: Baseline, 24, 48, 72, 96 hours ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, North Carolina

UNC_Chapel Hill

Chapel Hill, North Carolina, United States, 27599

Sponsors and Collaborators

University of North Carolina, Chapel Hill

University of Illinois at Chicago

Virginia Commonwealth University

Investigators

• Principal Investigator: Jo E. Rodgers, PharmD; University of North Carolina, Chapel Hill

More Information

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT00904488
• Other Study ID Numbers: 08-1292
• First Posted: May 19, 2009
• Results First Posted: February 13, 2018
• Last Update Posted: March 13, 2018
• Last Verified: January 2018

Keywords provided by University of North Carolina, Chapel Hill:

Acute Decompensated Heart Failure; Diuretics

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; Metolazone; Furosemide; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Sodium Potassium Chloride Symporter Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Sodium Chloride Symporter Inhibitors