Comparison of Oral or Intravenous Thiazides vs Tolvaptan in Diuretic Resistant Decompensated Heart Failure
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: tolvaptan; Chlorothiazide; Metolazone
Intervention description: Tolvaptan (Samsca) is a vasopressin 2 receptor antagonist that works in the collecting duct of the nephron to cause diuresis.; Chlorothiazide (Diuril) is an intravenous thiazide diuretic that works in the distal convoluted tubule of the nephron to cause diuresis.; Metolazone (Zaroxolyn) is an oral thiazide diuretic that works in the distal convoluted tubule of the nephron to cause diuresis.
Intervention MeSH terms: Metolazone; Chlorothiazide; Tolvaptan
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: loop diuretics; thiazide diuretics; vasopressin antagonists; diuretic resistance; heart failure

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.
    

Eligibility 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