Dyspnea, Heart Failure
Conditions
Brief summary
The primary objective of this study is to compare the effects of oral Tolvaptan vs. placebo as an adjunct to fixed dose IV furosemide on dyspnea relief in patients with acute decompensated heart failure The primary hypothesis is that the addition of oral Tolvaptan to fixed dose furosemide will be more effective at relieving dyspnea than fixed dose furosemide alone
Detailed description
This study will be a randomized, double blind, placebo controlled, multi-center clinical trial of patients with signs and symptoms consistent with AHF within 24 hours of presentation at Emergency Department. A total of approximately 250 patients will be enrolled in the trial. Patients will be randomized in a 1:1 ratio to either of 2 treatment regimens: * Fixed-dose IV furosemide (1 x total daily oral dose given intravenously in divided doses Q12 hours OR 40 mg IV Q12 hours, whichever is greater) + oral Tolvaptan (given at 0, 24 and 48 hours) * Fixed-dose IV furosemide (1 x total daily oral dose given intravenously in divided doses Q12 hours OR 40 mg IV Q12 hours, whichever is greater) + oral placebo (given at 0, 24 and 48 hours) The study treatment regimen will be administered from randomization through 48 hours, at which point Tolvaptan/placebo will be discontinued and all diuretic treatment will be adjusted at the treating physician's discretion. The primary endpoint will be the proportion of patients with at least moderate improvement in dyspnea by Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours. Patients will be followed daily for the duration of hospitalization or for 7 days (whichever is shortest). All patients will have Day 30 follow up phone contact for assessment of vital status and interval hospitalizations.
Interventions
DRUGTolvaptan
IV furosemide plusTolvaptan (given at 0, 24 and 48 hours)
DRUGPlacebo
IV furosemide plus oral placebo (given at 0, 24 and 48 hours)
Sponsors
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥ 18 years of age * Daily oral dose of furosemide between ≥ 40 mg(or equivalent) * Identified within 24 hours of presentation, defined for purposes of this study as the time of initial dose of intravenous loop diuretic * Prior clinical HF diagnosis that was treated with oral loop diuretics for at least 1 month * Admission for acute decompensated Heart Failure (HF) as determined by * dyspnea at rest or with minimal exertion * Brain Natriuretic Peptide (BNP) \> 400 or NTproBNP \> 2000 pg/mL AND at least one of the following additional signs and symptoms: * Orthopnea * Peripheral edema * Elevated JVP (Jugular Venous Pressure) * Pulmonary rales * Congestion on Chest X-ray * No plan for revascularization, cardiac transplant, of ventricular assist device implantation, or other cardiac surgery within 60 days of randomization * Signed informed consent
Exclusion criteria
* Serum Na \> 140 meq/L * Received IV vasoactive treatment or ultra-filtration therapy for HF since initial presentation * Treatment plan during current hospitalization includes IV vasoactive treatment or ultra-filtration for HF * Systolic Blood Pressure (SBP)\<90mmHg * Serum-Cr\>3.5mg/dl or currently undergoing renal replacement therapy . Known underlying liver disease * Hemodynamically significant arrhythmias * ACS(Acute coronary syndrome) within 4 weeks prior to study entry * Active myocarditis * Hypertrophic obstructive, restrictive, constrictive cardiomyopathy * Severe stenotic valvular disease * Complex congenital heart disease * Constrictive pericarditis * Clinical evidence of digoxin toxicity * Need for mechanical hemodynamic support * Terminal illness (other than heart failure) with expected survival time of less than 1 year * History of adverse reaction to Tolvaptan * Enrollment or planned enrollment in another randomized clinical trial during this hospitalization * Pregnant or breast-feeding * Inability to comply with planned study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours | 8 and 24 hours | The number of patients with at least moderate improvement (as reported by patient) in dyspnea Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function | 0, 24, 48 and 72 hours | Change in Serum creatinine from baseline to 24, 48 and 72 hours |
| Weight Loss | 0, 24, 48, and 72 hours | Change in body weight from baseline to 24, 48, and 72 hours |
| Fluid Loss | 0, 24, 48, and 72 hours | Change from baseline fluid balance at 24, 48, and 72 hours |
| Dyspnea Likert | 48 and 72 hours | Number of patients that experience moderate or greater improvement (patient reported) in dyspnea by 7 point Likert scale at 48 and 72 hours |
| Hospital Stay | 7 days | Total days spent in hospital from baseline until discharge or death |
| Worsening or Persistent Heart Failure or Death | 72 hrs | Number of patients with worsening heart failure or death |
| Serum Sodium | 0, 24, 48, and 72 hours | Change in serum sodium from baseline to 24, 48, and 72 hours |
| Dyspnea 11 Point NRS | 0, 24, 48, and 72 hours | Change in NRS for assessment of dyspnea from baseline to 24, 48, and 72 hours (scale ranges from 0-No difficulty breathing to 10-Difficulty as bad as you can imagine) |
| Freedom From Congestion | 24, 48, and 72 hours | Jugular Venous Pressure (JVP) \< 8 cm, no orthopnea, trace peripheral edema or less, and will be assessed at 24, 48, and 72 hours |
| Development of Worsening Renal Function | 72 hours | increase in serum creatinine ≥ 0.3mg/dl from randomization at any time point during 72 hours after randomization |
| Days Hospitalized or Deceased | 30 days | Total days hospitalized or deceased during the 30 days after randomization |
| All Cause Death or Rehospitalization | 30 days | All cause death or rehospitalization (to include unscheduled clinic visits or ED visits) at 30 days (Kaplan-Meier and 95% confidence interval) |
| Over-diuresis | 72 hours | clinical evidence of volume depletion requiring intervention other than holding diuretics during the 72 hours after randomization |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tolvaptan IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours)
Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours) | 129 |
| Placebo IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours)
Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours) | 128 |
| Total | 257 |
Baseline characteristics
| Characteristic | Tolvaptan | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 66.42 years STANDARD_DEVIATION 12.9 | 62.97 years STANDARD_DEVIATION 15.7 | 64.70 years STANDARD_DEVIATION 14.4 |
| Region of Enrollment United States | 129 Participants | 128 Participants | 257 Participants |
| Sex: Female, Male Female | 44 Participants | 42 Participants | 86 Participants |
| Sex: Female, Male Male | 85 Participants | 86 Participants | 171 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 101 / 129 | 107 / 128 |
| serious Total, serious adverse events | 8 / 129 | 2 / 128 |
Outcome results
Primary
Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours
The number of patients with at least moderate improvement (as reported by patient) in dyspnea Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours.
Time frame: 8 and 24 hours
Population: Baseline population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tolvaptan | Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours | 20 Participants |
| Placebo | Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours | 26 Participants |
p-value: 0.315Chi-squared
Secondary
All Cause Death or Rehospitalization
All cause death or rehospitalization (to include unscheduled clinic visits or ED visits) at 30 days (Kaplan-Meier and 95% confidence interval)
Time frame: 30 days
Population: baseline population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tolvaptan | All Cause Death or Rehospitalization | 0.33 proportion of participants |
| Placebo | All Cause Death or Rehospitalization | 0.29 proportion of participants |
p-value: 0.70995% CI: [0.21, 0.32]Log Rank
Secondary
Days Hospitalized or Deceased
Total days hospitalized or deceased during the 30 days after randomization
Time frame: 30 days
Population: baseline population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Days Hospitalized or Deceased | 10.19 days | Standard Deviation 10.9 |
| Placebo | Days Hospitalized or Deceased | 11.69 days | Standard Deviation 11.7 |
p-value: 0.373Wilcoxon (Mann-Whitney)
Secondary
Development of Worsening Renal Function
increase in serum creatinine ≥ 0.3mg/dl from randomization at any time point during 72 hours after randomization
Time frame: 72 hours
Population: baseline population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tolvaptan | Development of Worsening Renal Function | 50 Participants |
| Placebo | Development of Worsening Renal Function | 34 Participants |
p-value: 0.037Chi-squared
Secondary
Dyspnea 11 Point NRS
Change in NRS for assessment of dyspnea from baseline to 24, 48, and 72 hours (scale ranges from 0-No difficulty breathing to 10-Difficulty as bad as you can imagine)
Time frame: 0, 24, 48, and 72 hours
Population: baseline population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Dyspnea 11 Point NRS | 24 hours | -2.20 units on a scale | Standard Deviation 2.5 |
| Tolvaptan | Dyspnea 11 Point NRS | 48 hours | -2.85 units on a scale | Standard Deviation 2.7 |
| Tolvaptan | Dyspnea 11 Point NRS | 72 hours | -3.07 units on a scale | Standard Deviation 3 |
| Placebo | Dyspnea 11 Point NRS | 24 hours | -1.84 units on a scale | Standard Deviation 2.1 |
| Placebo | Dyspnea 11 Point NRS | 48 hours | -2.29 units on a scale | Standard Deviation 2.3 |
| Placebo | Dyspnea 11 Point NRS | 72 hours | -2.42 units on a scale | Standard Deviation 2.4 |
Comparison: This is a repeated measures analysis so all rows (visits) are taken into account.p-value: 0.30395% CI: [-0.26, 0.82]Mixed Models Analysis
Secondary
Dyspnea Likert
Number of patients that experience moderate or greater improvement (patient reported) in dyspnea by 7 point Likert scale at 48 and 72 hours
Time frame: 48 and 72 hours
Population: baseline population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tolvaptan | Dyspnea Likert | 48 hours | 88 Participants |
| Tolvaptan | Dyspnea Likert | 72 hours | 69 Participants |
| Placebo | Dyspnea Likert | 48 hours | 74 Participants |
| Placebo | Dyspnea Likert | 72 hours | 48 Participants |
Comparison: This is a repeated measures analysis so all rows (visits) are taken into account.p-value: 0.206Chi-squared
Secondary
Fluid Loss
Change from baseline fluid balance at 24, 48, and 72 hours
Time frame: 0, 24, 48, and 72 hours
Population: baseline population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Fluid Loss | 24 hours | -2182.25 mL | Standard Deviation 1844.4 |
| Tolvaptan | Fluid Loss | 48 hours | -1948.01 mL | Standard Deviation 1635.6 |
| Tolvaptan | Fluid Loss | 72 hours | -1757.09 mL | Standard Deviation 1670.4 |
| Placebo | Fluid Loss | 24 hours | -1541.48 mL | Standard Deviation 1524.5 |
| Placebo | Fluid Loss | 48 hours | -1419.09 mL | Standard Deviation 1378.6 |
| Placebo | Fluid Loss | 72 hours | -1401.24 mL | Standard Deviation 1386.5 |
Comparison: This is a repeated measures analysis so all rows (visits) are taken into account.p-value: 0.15795% CI: [-1176.96, 190.55]Mixed Models Analysis
Secondary
Freedom From Congestion
Jugular Venous Pressure (JVP) \< 8 cm, no orthopnea, trace peripheral edema or less, and will be assessed at 24, 48, and 72 hours
Time frame: 24, 48, and 72 hours
Population: baseline population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tolvaptan | Freedom From Congestion | 24 hours | 9 Participants |
| Tolvaptan | Freedom From Congestion | 48 hours | 24 Participants |
| Tolvaptan | Freedom From Congestion | 72 hours | 27 Participants |
| Placebo | Freedom From Congestion | 24 hours | 12 Participants |
| Placebo | Freedom From Congestion | 48 hours | 20 Participants |
| Placebo | Freedom From Congestion | 72 hours | 17 Participants |
p-value: 0.471Chi-squared
p-value: 0.585Chi-squared
p-value: 0.12Chi-squared
Secondary
Hospital Stay
Total days spent in hospital from baseline until discharge or death
Time frame: 7 days
Population: baseline population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Hospital Stay | 6.46 days | Standard Deviation 5.9 |
| Placebo | Hospital Stay | 7.35 days | Standard Deviation 7 |
p-value: 0.33495% CI: [0.96, 0.99]Log Rank
Secondary
Over-diuresis
clinical evidence of volume depletion requiring intervention other than holding diuretics during the 72 hours after randomization
Time frame: 72 hours
Population: baseline population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tolvaptan | Over-diuresis | 7 Participants |
| Placebo | Over-diuresis | 3 Participants |
p-value: 0.334Chi-squared
Secondary
Renal Function
Change in Serum creatinine from baseline to 24, 48 and 72 hours
Time frame: 0, 24, 48 and 72 hours
Population: Baseline population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Renal Function | 24 hours | 0.13 mg/dL | Standard Deviation 0.4 |
| Tolvaptan | Renal Function | 48 hours | 0.10 mg/dL | Standard Deviation 0.4 |
| Tolvaptan | Renal Function | 72 hours | 0.03 mg/dL | Standard Deviation 0.6 |
| Placebo | Renal Function | 24 hours | 0.04 mg/dL | Standard Deviation 0.3 |
| Placebo | Renal Function | 48 hours | 0.05 mg/dL | Standard Deviation 0.4 |
| Placebo | Renal Function | 72 hours | 0.06 mg/dL | Standard Deviation 0.4 |
Comparison: This is a repeated measures analysis so all rows (visits) are taken into account.p-value: 0.02195% CI: [0.03, 0.34]Mixed Models Analysis
Secondary
Serum Sodium
Change in serum sodium from baseline to 24, 48, and 72 hours
Time frame: 0, 24, 48, and 72 hours
Population: baseline population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Serum Sodium | 24 hours | 3.18 mmol/L | Standard Deviation 3.3 |
| Tolvaptan | Serum Sodium | 48 hours | 3.34 mmol/L | Standard Deviation 3.7 |
| Tolvaptan | Serum Sodium | 72 hours | 2.84 mmol/L | Standard Deviation 3.9 |
| Placebo | Serum Sodium | 24 hours | 0.23 mmol/L | Standard Deviation 2.5 |
| Placebo | Serum Sodium | 48 hours | -0.24 mmol/L | Standard Deviation 2.8 |
| Placebo | Serum Sodium | 72 hours | -0.44 mmol/L | Standard Deviation 2.9 |
Comparison: This is a repeated measures analysis so all rows (visits) are taken into account.p-value: 0.24195% CI: [-1.79, 0.45]Mixed Models Analysis
Secondary
Weight Loss
Change in body weight from baseline to 24, 48, and 72 hours
Time frame: 0, 24, 48, and 72 hours
Population: Baseline population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Weight Loss | 24 hours | -4.41 lbs | Standard Deviation 6.6 |
| Tolvaptan | Weight Loss | 48 hours | -6.11 lbs | Standard Deviation 7.4 |
| Tolvaptan | Weight Loss | 72 hours | -8.19 lbs | Standard Deviation 9.7 |
| Placebo | Weight Loss | 24 hours | -1.16 lbs | Standard Deviation 13.2 |
| Placebo | Weight Loss | 48 hours | -3.46 lbs | Standard Deviation 6.3 |
| Placebo | Weight Loss | 72 hours | -5.53 lbs | Standard Deviation 7 |
Comparison: This a repeated measure analysis so all rows (visits) are taken into account.p-value: 0.4395% CI: [-1.47, 3.44]Mixed Models Analysis
Secondary
Worsening or Persistent Heart Failure or Death
Number of patients with worsening heart failure or death
Time frame: 72 hrs
Population: baseline population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tolvaptan | Worsening or Persistent Heart Failure or Death | 54 Participants |
| Placebo | Worsening or Persistent Heart Failure or Death | 60 Participants |
p-value: 0.148Chi-squared