The Use of Tolvaptan to Prevent Renal Dysfunction in High Risk Patients With Heart Failure-Pilot Study

The Use of Tolvaptan to Prevent Renal Dysfunction in High Risk Patients With Acute Decompensated Heart Failure-Pilot Study

It is well known that the use of loop diuretics in acute setting may decrease glomerular filtration rate (GFR) and increase serum creatinine leading to renal dysfunction. Loop diuretic induced elevation in serum creatinine can lead to increase in length of hospital stay and possibly morbidity. Previous studies have suggested that tolvaptan unlike aggressive loop diuretic therapy may not activate neurohormonal system nor decrease renal blood flow. These properties may make tolvaptan a useful addition to diuretic therapy to prevent renal dysfunction in high-risk patients. Therefore the primary objective of this study is to determine if the use of tolvaptan in combination with diuretic therapy may prevent development of renal dysfunction in high risk patients with heart failure.

Hypothesis: Administration of tolvaptan in combination with continuous loop diuretic therapy in acutely decompensated heart failure patients at high risk for developing diuretic induced renal dysfunction will have a lower proportion of patients increasing their serum creatinine > 0.3 mg/dL within a 96 hour time frame as compared to patients just receiving standard of care continuous infusion diuretic.

Study Overview

• Status: Withdrawn
• Conditions: Heart Failure
• Intervention / Treatment: Drug: placebo; Drug: Tolvaptan

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health Systems

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ≥ 18 years old
• Prior clinical diagnosis of systolic heart failure (EF < 40% within the past 18 months) with daily home use of oral loop diuretic for at least one month.
• Daily oral dose of furosemide ≥ 40 mg and ≤ 240 mg (or equivalent)
• Identified within 24 hours of hospital admission
• Heart failure defined by at least 1 symptom (dyspnea, orthopnea, or edema) AND 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest radiography)
• Anticipated need for IV loop diuretics for at least 48 hours
• Likely requires daily net urine output in the range of 1-3 L/day for over a 72-96 hour time period.
• Albumin level < 3.5 g/dL
• Willingness to provide informed consent

Exclusion Criteria:

• Received or planned IV vasoactive treatment (inotropes, vasodilators) or ultra-filtration therapy for heart failure
• BNP < 250 ng/ml or NT-proBNP < 1000 mg/ml (if drawn for clinical purposes)
• Systolic BP < 90 mmHg
• Serum creatinine > 3.0 mg/dl at baseline or renal replacement therapy or creatinine clearances < 10 mL/min
• Serum sodium > 145 mEq/L
• Acute coronary syndrome within 4 weeks
• Anticipated need for coronary angiography or other procedures requiring IV contrast.
• Patients receiving any of the following drugs: clarithromycin, ketoconazole, itraconazole,ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, telithromycin, erythromycin, fluconazole, aprepitant, diltiazem, verapamil, cyclosporine, and grapefruit juice.
• Pregnant or nursing patients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tolvaptan Arm; Tolvaptan 30 mg qd x 3 days and Low Dose Loop Continuous Infusion - Initial Dosing: Furosemide - 10 mg/hr Bumentanide - 0.25 mg/hr Torsemide - 5 mg/hr	Drug: Tolvaptan
Placebo Comparator: Placebo; Placebo x 3 days and standard of care continuous infusion diuretic	Drug: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal dysfunction	Increase in serum creatinine > 0.3 mg/dL within a 96 hours from enrollment	96 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight	Change in weight over 24, 48, 72, and 96 hours	24, 78, 72, 96
Urine output	Net urine output over 24, 48, 72, and 96 hours	24, 48, 72, 96
Hospitalization length of stay		10

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Failure	Need to increase diuretic dose in tolvaptan study group prior to 72 hr time point	72hr

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: Otsuka Pharmaceuticals
• Investigators: Principal Investigator: Barry E Bleske, Pharm. D., University of Michigan

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: August 8, 2012
• First Submitted That Met QC Criteria: August 10, 2012
• First Posted (Estimate): August 13, 2012

Study Record Updates

• Last Update Posted (Estimate): December 11, 2015
• Last Update Submitted That Met QC Criteria: December 10, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Heart Failure; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: 11-PAF06621