Comparison of Oral or Intravenous Thiazides vs Tolvaptan in Diuretic Resistant Decompensated Heart Failure
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ClinicalTrials.gov Identifier: NCT02606253 |
Recruitment Status :
Completed
First Posted : November 17, 2015
Results First Posted : November 8, 2019
Last Update Posted : November 8, 2019
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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:
- 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
- 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
- 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 |
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Heart Failure | Drug: tolvaptan Drug: Chlorothiazide Drug: Metolazone | Phase 4 |

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 |

Arm | Intervention/treatment |
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Active Comparator: Metolazone
Metolazone 5mg tablet orally twice daily for 48 hours.
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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
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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
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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 |
- Weight Change Over 48 Hours [ 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.
- Net Urine Output [ Time Frame: 48 hours ]Net urine output from enrollment to the end of study at 48 hours measured in liters
- 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
- Mean Change in Glomerular Filtration Rate at Discharge [ Time Frame: hospital discharge an average of 5 days ]Mean change in glomerular filtration rate from enrollment to end of study at hospital discharge, an average of 5 days
- 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
- Potassium Supplementation [ Time Frame: 48 hours ]Cumulative dose of potassium supplementation (mEq) administered from enrollment to end of study at 48 hours
- Number of Patients With Hypokalemia [ Time Frame: 48 hours ]Incidence of hypokalemia (serum potassium less than 3.5mEq/L ) from enrollment to end of study
- Number of Patients With Escalation of Loop Diuretic Therapy [ Time Frame: 24 hours ]Provider escalation of loop diuretic dosage at 24 hours for urine output less than 3 L at 24 hours
- Number of Patients With Cardiac Arrhythmias [ Time Frame: 48 hours ]Incidence of new atrial or ventricular arrhythmias from enrollment to end of study at 48 hours
- Number of Patients With Symptomatic Hypotension [ Time Frame: 48 hours ]SBP < 85 mmHg plus medical intervention for symptomatic hypotension
- Change in eGFR From Baseline to 48 Hours [ Time Frame: 48 hours ]Change in estimated glomerular filtration rate (ml/min/m2) from baseline to 48 hours
- 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
- Number of Patients With 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
- Number of Patients With New Inotrope Utilization [ Time Frame: 48 hours ]Incidence of new initiation of dopamine, dobutamine, or milrinone from enrollment to end of study at 48 hours
- Number of Patients With 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
- Diuretic Efficiency [ Time Frame: 48 hours ]Diuretic Efficiency is calculated as 48hr urine output/ 48hr Furosemide equivalents in milligrams
- Change in Serum Chloride From Baseline [ Time Frame: 48 hours ]Change in serum chloride (mEq/L) from baseline to 48 hrs
- Change in Patient Congestion Score [ Time Frame: 48 hours ]Participants will score their congestion on a 10cm scale ranging from "Best" (10cm) to "Worst" (0cm). Change in score (units in centimeters) from baseline to 48 hours.

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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02606253
United States, Tennessee | |
Vanderbilt University Medical Center | |
Nashville, Tennessee, United States, 37204 |
Principal Investigator: | Zachary L Cox, PharmD | Vanderbilt University |
Documents provided by Zachary L. Cox, Vanderbilt University:
Responsible Party: | Zachary L. Cox, Associate Professor, Lipscomb University College of Pharmacy, Vanderbilt University |
ClinicalTrials.gov Identifier: | NCT02606253 |
Other Study ID Numbers: |
VU-IRB-TBD |
First Posted: | November 17, 2015 Key Record Dates |
Results First Posted: | November 8, 2019 |
Last Update Posted: | November 8, 2019 |
Last Verified: | October 2019 |
loop diuretics thiazide diuretics vasopressin antagonists diuretic resistance heart failure |
Heart Failure Heart Diseases Cardiovascular Diseases Metolazone Chlorothiazide Tolvaptan Antidiuretic Hormone Receptor Antagonists |
Molecular Mechanisms of Pharmacological Action Natriuretic Agents Physiological Effects of Drugs Antihypertensive Agents Diuretics Sodium Chloride Symporter Inhibitors Membrane Transport Modulators |