Comparison of Oral or Intravenous Thiazides vs Tolvaptan in Diuretic Resistant Decompensated Heart Failure

• Sponsor: Vanderbilt University
• Information provided by (Responsible Party): Zachary L. Cox, Vanderbilt University

Study Description

Brief Summary:

Broad Objectives: To determine the comparative efficacy of commonly employed strategies to overcome loop diuretic resistance when added to concomitant loop diuretics in hospitalized decompensated heart failure patients with hypervolemia

Specific Aims:

1. Compare the 48-hour weight change of either intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when combined with standardized loop diuretic dosing for diuretic resistance in decompensated heart failure
2. Compare the adverse effects of electrolyte depletion and renal function changes between intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when combined with standardized loop diuretic dosing for diuretic resistance in acute heart failure
3. Pharmacoeconomic analysis of the direct costs of intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when combined with standardized loop diuretic dosing for diuretic resistance in acute heart failure

The investigators will conduct a dual center, randomized, double-blind, double-dummy, parallel design trial comparing: oral metolazone, intravenous chlorothiazide, or oral tolvaptan, in combination with loop diuretics in 60 patients hospitalized for hypervolemic decompensated heart failure and displaying loop diuretic resistance.

Condition or disease	Intervention/treatment	Phase
Heart Failure	Drug: tolvaptan; Drug: Chlorothiazide; Drug: Metolazone	Phase 4

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	60 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Comparison of Oral Thiazides vs Intravenous Thiazides vs Tolvaptan in Combination With Loop Diuretics for Diuretic Resistant Decompensated Heart Failure
Study Start Date :	February 2016
Actual Primary Completion Date :	September 27, 2018
Actual Study Completion Date :	October 31, 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Metolazone; Metolazone 5mg tablet orally twice daily for 48 hours.	Drug: Metolazone; Metolazone (Zaroxolyn) is an oral thiazide diuretic that works in the distal convoluted tubule of the nephron to cause diuresis.; Other Name: Zaroxolyn
Experimental: Chlorothiazide; Chlorothiazide 500mg intravenous infusion over 30 minutes twice daily for 48 hours	Drug: Chlorothiazide; Chlorothiazide (Diuril) is an intravenous thiazide diuretic that works in the distal convoluted tubule of the nephron to cause diuresis.; Other Name: Diuril
Experimental: Tolvaptan; Tolvaptan 30mg tablet orally once daily for 48 hours	Drug: tolvaptan; Tolvaptan (Samsca) is a vasopressin 2 receptor antagonist that works in the collecting duct of the nephron to cause diuresis.; Other Name: Samsca

Outcome Measures

Primary Outcome Measures :

1. Weight change [ Time Frame: 48 hours ]
   The primary outcome will be 48-hour standing scale weight change (kg) from enrollment among the metolazone, intravenous chlorothiazide, and tolvaptan arms, using metolazone group as the comparator group for all other groups.

Secondary Outcome Measures :

1. Net Urine Output [ Time Frame: 48 hours ]
   Net urine output from enrollment to the end of study at 48 hours measured in milliliters and collected either by a foley catheter or via a urine collection cup.
2. Mean Change in Serum Creatinine [ Time Frame: 48 hours ]
   Mean change in serum creatinine (mg/dl) from enrollment to end of study at 48 hours
3. Mean Change in Serum Creatinine at discharge [ Time Frame: hospital discharge an average of 5 days ]
   Mean change in serum creatinine (mg/dl) from enrollment to end of study at hospital discharge, an average of 5 days
4. Mean Change in Serum Potassium [ Time Frame: 48 hours ]
   Mean change in serum potassium (mEq/L) from enrollment to end of study at 48 hours
5. Potassium Supplementation [ Time Frame: 48 hours ]
   Cumulative dose of potassium supplementation (mEq) administered from enrollment to end of study at 48 hours
6. Severe Hypokalemia [ Time Frame: 48 hours ]
   Incidence of severe hypokalemia (serum potassium less than 3.0mEq/L ) from enrollment to end of study
7. Escalation of Loop diuretic therapy [ Time Frame: 24 hours ]
   Provider escalation of loop diuretic dosage at 24 hours
8. Cardiac Arrhythmias [ Time Frame: 48 hours ]
   Incidence of new atrial or ventricular arrhythmias from enrollment to end of study at 48 hours
9. Pharmacoeconomic analysis: study drugs [ Time Frame: 48 hours ]
   pharmacoeconomic analysis of the direct costs in U.S. dollars in each arm for the cost of: study medication. All medication and therapy costs will be defined as the Redbook average wholesale price at the time of the trial to reduce inter-institutional price differences and improve external validity of the analysis.
10. Pharmacoeconomic analysis: laboratory monitoring [ Time Frame: 48 hours ]
    pharmacoeconomic analysis of the direct costs in U.S. dollars in each arm for the cost of additional non-trial protocol laboratory analysis cost related to monitoring of electrolytes
11. Pharmacoeconomic analysis: additional therapies [ Time Frame: 48 hours ]
    pharmacoeconomic analysis of the direct costs in U.S. dollars in each arm for the cost of addition of additional therapies for suboptimal diuresis (inotropic therapy, vasodilators)
12. Mean change in serum sodium [ Time Frame: 48 hours ]
    Mean change in serum sodium (mEq/L) from enrollment to end of study at 48 hours

Other Outcome Measures:

1. In-hospital mortality [ Time Frame: Enrollment to hospital discharge an average of 5 days ]
   Incidence of death from study enrollment to hospital discharge, an average of 5 days
2. Inotrope utilization [ Time Frame: 48 hours ]
   Incidence of use of dopamine, dobutamine, or milrinone from enrollment to end of study at 48 hours
3. Renal replacement therapy utilization [ Time Frame: enrollment to hospital discharge an average of 5 days ]
   Incidence of Renal replacement therapy utilization (hemodialysis, ultrafiltration) from enrollment to hospital discharge, an average of 5 days
4. Diuretic Efficiency [ Time Frame: 48 hours ]
   Diuretic Efficiency is calculated as 48hr urine output/ 48hr Furosemide equivalents in milligrams
5. Hypotension [ Time Frame: 48 hours ]
   Incidence of hypotension (defined as a systolic blood pressure less than 85mmHg for 2 repeated measurements within 30 minutes or lasting at least 30 minutes or symptomatic hypotension necessitating clinical intervention) from enrollment to 48 hours end of study
6. Patient Congestion score [ Time Frame: at enrollment, at 24 hours, and at 48 hours ]
   Participants will score their congestion on a 10 point scale ranging from "Best" to "Worst"

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• age of 18 years or older
• hospital admission for hypervolemic decompensated heart failure complicated by loop diuretic resistance
• 24 hour telemetry monitoring on an inpatient ward
• basic metabolic panel laboratory assessment twice daily during the study period

Hypervolemia will be diagnosed by the admitting provider as either (i) pulmonary artery catheterization with a pulmonary capillary wedge pressure greater than 19mmHg plus a systemic physical exam finding of hypervolemia (peripheral edema, ascites, or pulmonary edema on auscultation) or (ii) in the absence of pulmonary artery catheterization data 2 of the following signs or symptoms: peripheral edema ascites, jugular venous pressure > 10mmHg, or pulmonary edema on chest x-ray.

Loop diuretic resistance is defined as a provider decision to pursue combination diuretic therapy because of failure to reach provider defined adequate diuresis (can not exceed urine output of 2 L in past 12 hours) despite receipt of an intravenous loop diuretic dose of a furosemide equivalent of at least 240mg/day over at least the past 12 hours (40mg furosemide = 20mg torsemide = 1mg bumetanide).

Exclusion Criteria:

• decision to pursue hemodialysis by a nephrologist
• estimated glomerular filtration rate by the MDRD equation < 15ml/min/m2
• systolic blood pressure < 85mmHg
• pregnancy
• serum potassium < 3.0mEq/L
• serum sodium > 145mEq/L or < 130mEq/L
• severe malnutrition
• advanced liver disease
• inability to perform standing weights
• inability to collect and measure urine with either a foley catheter or urine collection containers
• concomitant therapy with strong CYP3A4 inhibitors/inducers (systemic ketoconazole, clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir, nefazodone, rifampin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, St. John's Wort)
• concomitant therapy with p-glycoprotein inhibitors (cyclosporine, erythromycin, tacrolimus, dronedarone, quinidine, or verapamil)
• non-study diuretics (spironolactone doses >75mg/day, eplerenone > 75mg/day, non-study thiazides or loop diuretics, or systemic acetazolamide, triamterene, or amiloride therapy)
• thiazides administration in the previous 24 hours prior to randomization

Contacts and Locations

Locations

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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37204

Sponsors and Collaborators

Vanderbilt University

Investigators

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Principal Investigator:	Zachary L Cox, PharmD	Vanderbilt University

More Information

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Responsible Party:	Zachary L. Cox, Associate Professor, Lipscomb University College of Pharmacy, Vanderbilt University
ClinicalTrials.gov Identifier:	NCT02606253 History of Changes
Other Study ID Numbers:	VU-IRB-TBD
First Posted:	November 17, 2015
Last Update Posted:	January 10, 2019
Last Verified:	January 2019

Keywords provided by Zachary L. Cox, Vanderbilt University:

loop diuretics; thiazide diuretics; vasopressin antagonists; diuretic resistance; heart failure

Additional relevant MeSH terms:

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Heart Failure; Heart Diseases; Cardiovascular Diseases; Diuretics; Metolazone; Chlorothiazide; Vasopressins; Tolvaptan; Sodium Potassium Chloride Symporter Inhibitors; Sodium Chloride Symporter Inhibitors	Natriuretic Agents; Physiological Effects of Drugs; Hemostatics; Coagulants; Vasoconstrictor Agents; Antidiuretic Agents; Antidiuretic Hormone Receptor Antagonists; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Antihypertensive Agents