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

NCT02606253 | Completed Phase 4 Results

• 1 other identifier: VU-IRB-TBD
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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. 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. 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. 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

Conditions

Heart Failure

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Weight Change Over 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.

  48 hours

Secondary Outcomes (11)

• Net Urine Output

  48 hours

• Mean Change in Serum Creatinine

  48 hours

• Mean Change in Glomerular Filtration Rate at Discharge

  hospital discharge an average of 5 days

• Mean Change in Serum Potassium

  48 hours

• Potassium Supplementation

  48 hours

Other Outcomes (6)

• Number of Patients With In-hospital Mortality

  Enrollment to hospital discharge an average of 5 days

• Number of Patients With New Inotrope Utilization

  48 hours

• Number of Patients With Renal Replacement Therapy Utilization

  enrollment to hospital discharge an average of 5 days

Study Arms (3)

Metolazone

ACTIVE COMPARATOR

Metolazone 5mg tablet orally twice daily for 48 hours.

Drug: Metolazone

Chlorothiazide

EXPERIMENTAL

Chlorothiazide 500mg intravenous infusion over 30 minutes twice daily for 48 hours

Drug: Chlorothiazide

Tolvaptan

EXPERIMENTAL

Tolvaptan 30mg tablet orally once daily for 48 hours

Drug: tolvaptan

Interventions

tolvaptan DRUG

Tolvaptan (Samsca) is a vasopressin 2 receptor antagonist that works in the collecting duct of the nephron to cause diuresis.

Also known as: Samsca

Tolvaptan

Chlorothiazide DRUG

Chlorothiazide (Diuril) is an intravenous thiazide diuretic that works in the distal convoluted tubule of the nephron to cause diuresis.

Also known as: Diuril

Chlorothiazide

Metolazone DRUG

Metolazone (Zaroxolyn) is an oral thiazide diuretic that works in the distal convoluted tubule of the nephron to cause diuresis.

Also known as: Zaroxolyn

Metolazone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• age of 18 years or older
• hospital admission for hypervolemic decompensated heart failure complicated by loop diuretic resistance
• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37204, United States

Location

Related Publications (1)

• Cox ZL, Hung R, Lenihan DJ, Testani JM. Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial. JACC Heart Fail. 2020 Mar;8(3):157-168. doi: 10.1016/j.jchf.2019.09.012. Epub 2019 Dec 11.

  PMID: 31838029 DERIVED

MeSH Terms

Conditions

Heart Failure

Interventions

Tolvaptan; Chlorothiazide; Metolazone

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Amides; Quinazolinones; Quinazolines

Limitations and Caveats

We conducted a single-center trial. We were not powered for non-inferiority. The observed weight loss standard deviation exceeded the expected standard deviation, reducing power. Outcomes at discharge were influenced by open-label diuretic therapy

Results Point of Contact

• Title: Dr. Zachary Cox, Associate Professor
• Organization: Lipscomb University College of Pharmacy

zac.cox@lipscomb.edu

6159667163

Study Officials

• Zachary L Cox, PharmD

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Lipscomb University College of Pharmacy

Study Record Dates

• First Submitted: November 11, 2015
• First Posted: November 17, 2015
• Study Start: February 1, 2016
• Primary Completion: September 27, 2018
• Study Completion: October 31, 2018
• Last Updated: November 8, 2019
• Results First Posted: November 8, 2019

Record last verified: 2019-10

Locations

US (1)