Phase 4 N=60 Randomized Quadruple-blind Treatment

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

Heart Failure

Bottom Line

View on ClinicalTrials.gov: NCT02606253 ↗

Enrolled (actual)

Serious AEs

3.3%

Results posted

Nov 2019

Primary outcome: Primary: Weight Change Over 48 Hours — -4.6; -5.8; -4.1 kg

Study Design & Population

Study type: Interventional
Phase: Phase 4
Interventions: tolvaptan (Drug); Chlorothiazide (Drug); Metolazone (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: Vanderbilt University
Primary completion: Sep 2018

Outcome Measures

Outcome	Result	p-value
PRIMARY Weight Change Over 48 Hours	-4.6; -5.8; -4.1	—
SECONDARY Net Urine Output	-7.8; -8.8; -9.8	—
SECONDARY Mean Change in Serum Creatinine	0.3; 0.5; 0.03	—
SECONDARY Mean Change in Glomerular Filtration Rate at Discharge	-2; -2; -6	—
SECONDARY Mean Change in Serum Potassium	-0.1; -0.2; 0.1	—
SECONDARY Potassium Supplementation	103; 63; 58	—
SECONDARY Number of Patients With Hypokalemia	3; 2; 2	—
SECONDARY Number of Patients With Escalation of Loop Diuretic Therapy	4; 4; 2	—
SECONDARY Number of Patients With Cardiac Arrhythmias	0; 0; 0	—
SECONDARY Number of Patients With Symptomatic Hypotension	2; 0; 2	—
SECONDARY Change in eGFR From Baseline to 48 Hours	-6; -9; 2	—
SECONDARY Mean Change in Serum Sodium	-1; -1; 4	—

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 145mEq/L or 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

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Data sourced from ClinicalTrials.gov (NCT02606253). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.