Tolvaptan for Advanced or Refractory Heart Failure

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

Detailed Description
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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.

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

Conditions
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Heart Failure, Hyponatremia

Intervention / Treatment
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* Drug: Tolvaptan
* Drug: Standard of care diuretic therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tolvaptan<br>Tolvaptan 15-60 mg, once daily for 4 days or until hospital discharge | Drug: Tolvaptan<br>* 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.<br>* Other names: Samsca;|
| Active Comparator: Standard of care diuretic therapy<br>Usual standard of care diuretic therapy for patients with acute decompensated heart failure | Drug: Standard of care diuretic therapy<br>* Usual standard of care diuretic therapy for patients hospitalized with acute decompensated heart failure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |