Heart Failure
Conditions
Brief summary
Hyponatremia is a common finding in acute heart failure (HF) patients and is associated with worse prognosis. In addition to its prognostic value, hyponatremia may have importance during the acute management of HF. We've recently shown that acute or chronic hyponatremia, especially \<130 mEq/L, was associated with higher loop diuretic dose requirements and more frequent need for escalation of the diuretic regimen to achieve the same level of diuresis as normonatremic HF patients. Aquaresis with tolvaptan represents a potentially advantageous approach to the management of volume overload in HF, especially in patients presenting with concomitant hyponatremia. The purpose of the current study is to prospectively evaluate the comparative efficacy and safety of a tolvaptan-based diuretic regimen compared to conventional diuresis with a furosemide-based regimen on short-term clinical and treatment outcomes in hyponatremic acute HF patients. This will be a prospective, open-label, parallel-group, randomized study comparing a tolvaptan-based aquaretic regimen to a conventional continuous infusion loop diuretic-based regimen of furosemide. Up to 55 (target sample size of 50) adult subjects admitted with acute HF and signs of volume overload, and serum sodium less than 135 mEq/L will be randomized to tolvaptan or furosemide treatment arms. The initial 24 hours of study treatment will compare tolvaptan monotherapy to furosemide monotherapy. After the initial 24 hours, treatment regimens may be altered to achieve desired clinical goals. Patients will be followed for up to 96 hours and at discharge for study purposes.
Interventions
DRUGTolvaptan
DRUGFurosemide
Sponsors
Otsuka America Pharmaceutical
University of Southern California
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Acute HF with signs or symptoms of volume overload \[i.e. elevated jugular venous pulsation (JVP), rales, edema\] * Serum sodium \< 135 mEq/L at time of or within first 48 hours of hospitalization * Randomized within 48 hours of presentation to hospital * ≥ 18 years of age * Informed consent
Exclusion criteria
* Severe symptomatic hyponatremia requiring acute treatment * Severe renal impairment upon admission (creatinine clearance \< 20 mL/min) * Renal replacement therapy dependent, or requiring upon admission * Acute coronary syndrome on admission * Requires or has a mechanical circulatory support device * Evidence of cardiogenic shock requiring intravenous vasopressors * Pregnancy * Patient requiring concomitant use of strong CYP3A4 inhibitors (clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, and telithromycin)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Median Urine Output at 24 Hours Post Randomization | 24 hours post randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Change in Serum Creatinine at 24 Hours Post Randomization | 24 hours post randomization | Comparison between baseline and 24 hours post randomization concentrations. |
Other
| Measure | Time frame | Description |
|---|---|---|
| In-hospital Mortality | Participants will be followed for the duration of hospital stay, an expected average of 5 days | — |
| Mean Hourly Urine Output at 24 Hours | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | — |
| Serum Sodium Change | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | Difference assessed at baseline, 8, 24, 48, 72 and 96 hours. |
| Weight Change | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | Difference assessed at baseline, 8, 24, 48, 72 and 96 hours. |
| Cumulative Furosemide Dose | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | — |
| Cumulative Metolazone Use | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | — |
| Change in Self-rated Dyspnea | At baseline, 24 and 96 hours post randomization | — |
| Acute Worsening of Kidney Function (Defined as an Increase in Serum Creatinine 0.3 mg/dL or 25% Above Baseline) | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | — |
| Total Urine Output | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | — |
| Symptomatic Hypotension | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | — |
| Change in Plasma Renin Activity | At baseline, 24 and 96 hours post randomization | — |
| Change in Copeptin | At baseline, 24 and 96 hours post randomization | — |
| Change in N-terminal Pro-B-type Natriuretic Peptide | At baseline, 24 and 96 hours post randomization | — |
| Change in Cystatin C | At baseline, 24 and 96 hours post randomization | — |
| Change in Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL) | At baseline, 24, 48, 72 and 96 hours post randomization | — |
| Hospital Length of Stay | Participants will be followed for the duration of hospital stay, an expected average of 5 days | — |
| Incidence of Electrolyte Abnormalities | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | Hypo- and hyperkalemia defined as outside the range of 3.5 to 5.0 mEq/L Hypo- and hypermagnesemia defined as outside the range of 1.5-2.4 mEq/L |
| Glomerular Filtration Rate (Estimated) | Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tolvaptan Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone)
Tolvaptan | 18 |
| Furosemide Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)
Furosemide | 15 |
| Total | 33 |
Baseline characteristics
| Characteristic | Tolvaptan | Furosemide | Total |
|---|---|---|---|
| Age, Continuous | 53 years STANDARD_DEVIATION 11.7 | 59 years STANDARD_DEVIATION 8.9 | 56 years STANDARD_DEVIATION 10.8 |
| Home Loop Diuretic Dose (Furosemide equivalents) | 93 mg STANDARD_DEVIATION 63.5 | 108 mg STANDARD_DEVIATION 77.5 | 100 mg STANDARD_DEVIATION 68.5 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 18 participants | 15 participants | 33 participants |
| Sex: Female, Male Female | 7 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 11 Participants | 14 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 15 |
| other Total, other adverse events | 0 / 18 | 0 / 15 |
| serious Total, serious adverse events | 0 / 18 | 0 / 15 |
Outcome results
Primary
Median Urine Output at 24 Hours Post Randomization
Time frame: 24 hours post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tolvaptan | Median Urine Output at 24 Hours Post Randomization | 2910 mL |
| Furosemide | Median Urine Output at 24 Hours Post Randomization | 3150 mL |
Secondary
Median Change in Serum Creatinine at 24 Hours Post Randomization
Comparison between baseline and 24 hours post randomization concentrations.
Time frame: 24 hours post randomization
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tolvaptan | Median Change in Serum Creatinine at 24 Hours Post Randomization | Median Scr at Baseline | 1.15 mg/dL |
| Tolvaptan | Median Change in Serum Creatinine at 24 Hours Post Randomization | Median Scr at 24h | 1.06 mg/dL |
| Tolvaptan | Median Change in Serum Creatinine at 24 Hours Post Randomization | Median 24h Change | -0.08 mg/dL |
| Furosemide | Median Change in Serum Creatinine at 24 Hours Post Randomization | Median 24h Change | -0.01 mg/dL |
| Furosemide | Median Change in Serum Creatinine at 24 Hours Post Randomization | Median Scr at Baseline | 0.87 mg/dL |
| Furosemide | Median Change in Serum Creatinine at 24 Hours Post Randomization | Median Scr at 24h | 0.96 mg/dL |
Other Pre-specified
Acute Worsening of Kidney Function (Defined as an Increase in Serum Creatinine 0.3 mg/dL or 25% Above Baseline)
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Change in Copeptin
Time frame: At baseline, 24 and 96 hours post randomization
Other Pre-specified
Change in Cystatin C
Time frame: At baseline, 24 and 96 hours post randomization
Other Pre-specified
Change in N-terminal Pro-B-type Natriuretic Peptide
Time frame: At baseline, 24 and 96 hours post randomization
Other Pre-specified
Change in Plasma Renin Activity
Time frame: At baseline, 24 and 96 hours post randomization
Other Pre-specified
Change in Self-rated Dyspnea
Time frame: At baseline, 24 and 96 hours post randomization
Other Pre-specified
Change in Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL)
Time frame: At baseline, 24, 48, 72 and 96 hours post randomization
Other Pre-specified
Cumulative Furosemide Dose
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Cumulative Metolazone Use
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Glomerular Filtration Rate (Estimated)
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Hospital Length of Stay
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Incidence of Electrolyte Abnormalities
Hypo- and hyperkalemia defined as outside the range of 3.5 to 5.0 mEq/L Hypo- and hypermagnesemia defined as outside the range of 1.5-2.4 mEq/L
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
In-hospital Mortality
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Mean Hourly Urine Output at 24 Hours
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Serum Sodium Change
Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Symptomatic Hypotension
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Total Urine Output
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
Other Pre-specified
Weight Change
Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.
Time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days