DR-AHF: Tolvaptan add-on Therapy to Overcome Loop Diuretic Resistance in Acute Heart Failure With Renal Dysfunction

Sponsor

Gia Dinh People Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04331132

Collaborator

Otsuka Pharmaceutical Vietnam (Industry)

128

Enrollment

Location

Arms

19.8

Anticipated Duration (Months)

6.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Renal dysfunction, which comprises 10%-40% of acute heart failure patients (AHF), plays an important role in diuretic resistance mechanism. DR-AHF was designed to demonstrate the effectiveness of early tolvaptan (a vasopressin-2 receptor antagonist) add-on therapy in acute heart failure patients with renal dysfunction and clinical evidence of loop diuretic resistance.

Condition or Disease	Intervention/Treatment	Phase
Acute Heart Failure	Drug: Tolvaptan 15 MG	N/A

Detailed Description

This is a single-center, open-label, randomized controlled trial, which will enroll 128 patients hospitalized due to AHF. These patients with wet-warm phenotype whose estimated glomerular filtration rates at admission are above 15 and below 60 mL/min/1.73 m2, and cumulative urine output <300 mL in 2 hours after the first dose of intravenous furosemide will be randomly assigned 1:1 to receive a standard care with uptitrating intravenous furosemide alone or a combination therapy with tolvaptan 15mg once daily for 2 days. The standard furosemide treatment will follow the modified 2019 Position Statement from the ESC Heart Failure Association. The primary endpoint is the cumulative urine output at 48 hour. Key secondary endpoints include the improvement of fractional excretion of sodium at 6 hour, the total dose of furosemide, the changes in the body weights, the net fluid loss, the lessening of diastolic dysfunction parameters on echocardiography, and the incidence of clinically relevant worsening renal function at 48 hour.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

128 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Acute heart failure patients with wet-warm phenotype whose estimated glomerular filtration rates at admission are above 15 and below 60 mL/min/1.73 m2, and cumulative urine output <300 mL in 2 hours after the first dose of intravenous furosemide will be randomly assigned 1:1 to receive a standard care with uptitrating intravenous furosemide alone or a combination therapy with tolvaptan 15mg once daily for 2 daysAcute heart failure patients with wet-warm phenotype whose estimated glomerular filtration rates at admission are above 15 and below 60 mL/min/1.73 m2, and cumulative urine output <300 mL in 2 hours after the first dose of intravenous furosemide will be randomly assigned 1:1 to receive a standard care with uptitrating intravenous furosemide alone or a combination therapy with tolvaptan 15mg once daily for 2 days

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Tolvaptan add-on Therapy to Overcome Loop Diuretic Resistance in Acute Heart Failure With Renal Dysfunction

Actual Study Start Date :

Dec 1, 2021

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jul 26, 2023

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Conventional diuretic group The conventional furosemide treatment will follow the modified 2019 Position Statement from the ESC Heart Failure Association	Drug: Tolvaptan 15 MG vasopressin-2 receptor antagonist 15mg once daily is added-on to the conventional diuretic strategy Other Names: Samsca
Active Comparator: Vasopressin-2 antagonist group Tolvaptan 15mg once daily for 2 days will be added-on the furosemide strategy based on the modified 2019 Position Statement from the ESC Heart Failure Association	Drug: Tolvaptan 15 MG vasopressin-2 receptor antagonist 15mg once daily is added-on to the conventional diuretic strategy Other Names: Samsca

Arm

Intervention/Treatment

Placebo Comparator: Conventional diuretic group

The conventional furosemide treatment will follow the modified 2019 Position Statement from the ESC Heart Failure Association

Drug: Tolvaptan 15 MG

vasopressin-2 receptor antagonist 15mg once daily is added-on to the conventional diuretic strategy

Other Names:

Samsca

Active Comparator: Vasopressin-2 antagonist group

Tolvaptan 15mg once daily for 2 days will be added-on the furosemide strategy based on the modified 2019 Position Statement from the ESC Heart Failure Association

Drug: Tolvaptan 15 MG

vasopressin-2 receptor antagonist 15mg once daily is added-on to the conventional diuretic strategy

Other Names:

Samsca

Outcome Measures

Primary Outcome Measures

Cumulative urine volume output at 48h after randomization [Hour 48]
Urine volume in mL

Secondary Outcome Measures

Cumulative dose of furosemide at 48h after randomization [Hour 48]
Furosemide dose in mg
Symptom of dyspnea by 7-point Likert scale at 24h and 48h after randomization [Hour 24, Hour 48]
3: markedly better, 2: moderately better, 1: minimally better, 0: no change, -1: minimally worse, -2: moderately worse, -3: markedly worse
Changes in body weight at 24h and 48h after randomization [Hour 24, Hour 48]
weight in gram
Incidence of clinically relevant worsening renal function at 24h and 48h after randomization [Hour 24, Hour 48]
An increase in serum creatinine ≥ 0.3 mg/dL within 48 hours accompanying doubling the dose of furosemide according to the diuretic treatment protocol
Changes in serum electrolytes measured at 12h, 24h and 48h after randomization [Hour 12, Hour 24, Hour 48]
Changes in serum sodium (mmol/L), potassium (mmol/L), chloride (mmol/L)
Changes in urine electrolyte excretion at 6h, 24h and 48h [Hour 6, Hour 24, Hour 48]
Increase in sodium (mmol/L), potassium (mmol/L) and chloride (mmol/L) excretion adjusted for urine creatinine (umol/L)
Changes in NT-proBNP at 48h after randomization [Hour 0, Hour 48]
Changes in NT-proBNP (pg/mL)
Changes in mitral e' on echocardiography [Hour 24, Hour 48]
Average of septal e' (cm/s) and lateral e' (cm/s) on tissue doppler imaging in apical 4-chamber view
Changes in E/e' ratio on echocardiography [Hour 24, Hour 48]
The ratio between mitral E (cm/s) and average e' (cm/s)
Changes in left atrial volume on echocardiography [Hour 24, Hour 48]
Average of left atrial volumes (ml) by Simpson's rule in apical 4-chamber and 2-chamber view
Changes in tricuspid regurgitation maximal velocity on echocardiography [Hour 24, Hour 48]
Tricuspid regurgitation maximal velocity (m/s) by continuous wave doppler in apical 4-chamber view
Changes in inferior vena cava maximal diameter on echocardiography [Hour 24, Hour 48]
Inferior vena cava maximal diameter (mm) in subcostal view

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Admitted to hospital with a primary diagnosis of acute heart failure with wet-warm phenotype
Cumulative urine volume output < 300ml within 2 hours after the first dose of intravenous furosemide
eGFR at admission 15-60ml/min/1.73m2