Tolvaptan for Advanced or Refractory Heart Failure

Tolvaptan for the Management of Acute Decompensated Heart Failure in Patients With Advanced or Refractory Heart Failure

This study will clarify the clinical usefulness of Tolvaptan therapy in patients with complicated acute decompensated heart failure and hyponatremia (low blood sodium).

Study Overview

• Status: Terminated
• Conditions: Heart Failure; Hyponatremia
• Intervention / Treatment: Drug: Tolvaptan; Drug: Standard of care diuretic therapy

Detailed Description

Despite its demonstrated efficacy and tolerability, Tolvaptan remains underutilized for the treatment of acute decompensated heart failure (ADHF) in many centers. Post-hoc analysis suggests that Tolvaptan may provide optimal outcomes in patients with more advanced heart failure (HF) including those with cardiorenal syndrome, marked hyponatremia and severe congestion, or a combination of those conditions. The efficacy of Tolvaptan in HF patients with loop diuretic resistance and in those requiring inotropic support remains uncertain.

The purpose of this study is to examine the benefit of Tolvaptan versus the current standard of care diuretic therapy for patients hospitalized with ADHF and evidence of advanced or complex HF with severe hyponatremia. Patients with advanced or complex disease are defined as those with suboptimal diuretic response over a 48 hour period.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Hospital admission for ADHF with volume overload as evidenced by ≥ 2 of the following: Elevated JVP, peripheral edema, ascites, pulmonary rales, congestion on chest X-ray, elevated NT-pro-BNP > 2000 pg/ml
• Inadequate clinical response indicated by body weight loss < 1.0 kg/day over 48 hours despite adequate doses of IV loop diuretic (at least 40 mg furosemide daily) and fluid restriction 2 L/24 hours.
• ≥1 of the following over the preceding 48 hours: Potential need for inotropic support to improve urine output, and/or renal insufficiency (estimated glomerular filtration rate <45 mL/min/1.73 m2)
• Serum sodium ≤134 mmol/L
• ≥18 years-old

Exclusion Criteria:

• Cardiac surgery within 60 days of enrollment
• Planned cardiac mechanical support or transplant; subjects with previously implanted ventricular assist device (VAD) will not be excluded
• Need for intravenous pressor support for symptomatic hypotension
• Biventricular pacemaker placement within the last 60 days
• Hemofiltration or dialysis
• Known cirrhosis
• Supine systolic arterial blood pressure less than 85 mmHg
• Refusal or inability to sign informed consent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tolvaptan; Tolvaptan 15-60 mg, once daily for 4 days or until hospital discharge	Drug: Tolvaptan; Tolvaptan is a selective vasopressin receptor antagonist that inhibits activation of the V2 receptor and synthesis and insertion of the aquaporin2 channel into the apical membrane of the renal collecting duct. Tolvaptan inhibits the reabsorption of free water, inducing free water diuresis and increasing serum sodium levels without adversely influencing electrolyte levels or stimulating the sympathetic nervous system or renin-angiotensin system.; Other Names: Samsca
Active Comparator: Standard of care diuretic therapy; Usual standard of care diuretic therapy for patients with acute decompensated heart failure	Drug: Standard of care diuretic therapy; Usual standard of care diuretic therapy for patients hospitalized with acute decompensated heart failure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in body weight	From randomization to 96 hours after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total 96 hour urine output	Measured in ml urine	From randomization to 96 hours post randomization
Subjective change in shortness of breath	As assessed by a 5 point Likert scale	48 hours after randomization and 96 hours post randomization
Change in renal function	Measured by estimated glomerular filtration rate	From randomization to 7 days post randomization
Proportion of patients developing worsening renal function (WRF)	Categorical measure- need for renal replacement therapy or ultrafiltration or increase in serum creatinine by > 26 umol/L	From randomization to 7 days post randomization
Change in serum sodium	Measured in mmol/L	From randomization to 7 days post randomization
Length of hospitalization	Number of days in hospital	From hospital admission to 30 days post randomization
Need for intensive care unit admission	Categorical measure (yes/no)	From hospital admission to 30 days post randomization
Need for positive inotropic agent use	Categorical measure (yes/no)	From randomization to 7 days post randomization
Composite of Worsening Renal Function or need for inotropic agent	Worsening Renal Function defined as increase from serum creatinine at randomization of more than 30 umol/L at any time from randomization to 7 days. This is a categorical outcome (yes/no)	From randomization to 7 days post randomization
30 day cardiovascular death and/or hospitalization	Categorical outcome (yes/no)	From Randomization to 30 days post randomization
Clinical markers of congestion	Described as total number of the presence of Jugular venous pressure (JVP) level, edema, rales, orthopnea, 3rd heart sound	From randomization to 96 hours after randomization
Change in N-terminal brain natriuretic peptide (NT-pro BNP)	Measurement calculated in absolute value of NT-pro-BNP	From randomization to 96 hours post randomization compared to baseline

Collaborators and Investigators

• Sponsor: University of Calgary
• Investigators: Principal Investigator: Jonathan Howlett, MD, University of Calgary

Study record dates

Study Major Dates

• Study Start: October 1, 2016
• Primary Completion (Actual): June 30, 2020
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: October 17, 2016
• First Submitted That Met QC Criteria: November 6, 2016
• First Posted (Estimate): November 9, 2016

Study Record Updates

• Last Update Posted (Actual): July 27, 2020
• Last Update Submitted That Met QC Criteria: July 23, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Water-Electrolyte Imbalance; Heart Failure; Hyponatremia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Diuretics; Tolvaptan
• Other Study ID Numbers: REB16-0064

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No