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.
Name: tolvaptan
Description: Tolvaptan (Samsca) is a vasopressin 2 receptor antagonist that works in the collecting duct of the nephron to cause diuresis.Type: DrugTolvaptan
Name: Chlorothiazide
Description: Chlorothiazide (Diuril) is an intravenous thiazide diuretic that works in the distal convoluted tubule of the nephron to cause diuresis.Type: DrugChlorothiazide
Name: Metolazone
Description: Metolazone (Zaroxolyn) is an oral thiazide diuretic that works in the distal convoluted tubule of the nephron to cause diuresis.Type: DrugMetolazone
Description: 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.
Measure: Weight change Time: 48 hoursDescription: 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.
Measure: Net Urine Output Time: 48 hoursDescription: Mean change in serum creatinine (mg/dl) from enrollment to end of study at 48 hours
Measure: Mean Change in Serum Creatinine Time: 48 hoursDescription: Mean change in serum creatinine (mg/dl) from enrollment to end of study at hospital discharge, an average of 5 days
Measure: Mean Change in Serum Creatinine at discharge Time: hospital discharge an average of 5 daysDescription: Mean change in serum potassium (mEq/L) from enrollment to end of study at 48 hours
Measure: Mean Change in Serum Potassium Time: 48 hoursDescription: Cumulative dose of potassium supplementation (mEq) administered from enrollment to end of study at 48 hours
Measure: Potassium Supplementation Time: 48 hoursDescription: Incidence of severe hypokalemia (serum potassium less than 3.0mEq/L ) from enrollment to end of study
Measure: Severe Hypokalemia Time: 48 hoursDescription: Provider escalation of loop diuretic dosage at 24 hours
Measure: Escalation of Loop diuretic therapy Time: 24 hoursDescription: Incidence of new atrial or ventricular arrhythmias from enrollment to end of study at 48 hours
Measure: Cardiac Arrhythmias Time: 48 hoursDescription: 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.
Measure: Pharmacoeconomic analysis: study drugs Time: 48 hoursDescription: 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
Measure: Pharmacoeconomic analysis: laboratory monitoring Time: 48 hoursDescription: 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)
Measure: Pharmacoeconomic analysis: additional therapies Time: 48 hoursDescription: Mean change in serum sodium (mEq/L) from enrollment to end of study at 48 hours
Measure: Mean change in serum sodium Time: 48 hoursDescription: Incidence of death from study enrollment to hospital discharge, an average of 5 days
Measure: In-hospital mortality Time: Enrollment to hospital discharge an average of 5 daysDescription: Incidence of use of dopamine, dobutamine, or milrinone from enrollment to end of study at 48 hours
Measure: Inotrope utilization Time: 48 hoursDescription: Incidence of Renal replacement therapy utilization (hemodialysis, ultrafiltration) from enrollment to hospital discharge, an average of 5 days
Measure: Renal replacement therapy utilization Time: enrollment to hospital discharge an average of 5 daysDescription: Diuretic Efficiency is calculated as 48hr urine output/ 48hr Furosemide equivalents in milligrams
Measure: Diuretic Efficiency Time: 48 hoursDescription: 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
Measure: Hypotension Time: 48 hoursDescription: Participants will score their congestion on a 10 point scale ranging from "Best" to "Worst"
Measure: Patient Congestion score Time: at enrollment, at 24 hours, and at 48 hoursAllocation: Randomized
Parallel Assignment
There is one SNP
Patients will be randomized to either intravenous chlorothiazide 500mg IV Q12H + an oral placebo capsule Q12H or intravenous placebo infusion Q12H + a capsule containing either oral metolazone 5mg PO Q12H or oral tolvaptan 30mg once daily and placebo capsule in the evening dose. --- Q12H ---
Patients will be randomized to either intravenous chlorothiazide 500mg IV Q12H + an oral placebo capsule Q12H or intravenous placebo infusion Q12H + a capsule containing either oral metolazone 5mg PO Q12H or oral tolvaptan 30mg once daily and placebo capsule in the evening dose. --- Q12H --- --- Q12H ---
Patients will be randomized to either intravenous chlorothiazide 500mg IV Q12H + an oral placebo capsule Q12H or intravenous placebo infusion Q12H + a capsule containing either oral metolazone 5mg PO Q12H or oral tolvaptan 30mg once daily and placebo capsule in the evening dose. --- Q12H --- --- Q12H --- --- Q12H ---
Patients will be randomized to either intravenous chlorothiazide 500mg IV Q12H + an oral placebo capsule Q12H or intravenous placebo infusion Q12H + a capsule containing either oral metolazone 5mg PO Q12H or oral tolvaptan 30mg once daily and placebo capsule in the evening dose. --- Q12H --- --- Q12H --- --- Q12H --- --- Q12H ---