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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Acute Heart Failure

Intervention / Treatment
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* Drug: Tolvaptan 15 MG


Participation Criteria
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Eligibility Criteria
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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 Exclusion Criteria: Acute coronary syndrome Anuria Sepsis Consciousness impairment Pregnant or breastfeeding women Severe valvular heart diseases (severe valvular stenosis or regurgitation) Admission sodium level > 140 mEq/L Serum total bilirubin > 3 mg/dL Serum potassium > 5.5 mmol/L Allergy or contraindication for tolvaptan Emergency indication for hemodialysis Cardiogenic shock or mechanical circulation support

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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
Interventional 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 days
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Conventional diuretic group<br>The conventional furosemide treatment will follow the modified 2019 Position Statement from the ESC Heart Failure Association | Drug: Tolvaptan 15 MG<br>* vasopressin-2 receptor antagonist 15mg once daily is added-on to the conventional diuretic strategy<br>* Other names: Samsca;|
| Active Comparator: Vasopressin-2 antagonist group<br>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<br>* vasopressin-2 receptor antagonist 15mg once daily is added-on to the conventional diuretic strategy<br>* Other names: Samsca;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative urine volume output at 48h after randomization | Urine volume in mL | Hour 48 | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute heart failure, worsening renal function, loop diuretic resistance, vasopressin-2 receptor antagonist