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

Acute Heart Failure Clinical Trial

— DR-AHF  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04331132
• Other study ID #: 92/CN-HÐÐÐ
• Status: Recruiting
• Phase: N/A
• Start date: December 1, 2021
• Est. completion date: July 26, 2023

Study information

• Verified date: September 2021
• Source: Gia Dinh People Hospital
• Contact: Nhat M. Giang, M.D
• Phone: +84919963999
• Email: minhnhat_210189[@]yahoo.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 128
• Est. completion date: July 26, 2023
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Heart Failure
• Heart Failure
• Renal Insufficiency

Intervention

Drug:
• Tolvaptan 15 MG
vasopressin-2 receptor antagonist 15mg once daily is added-on to the conventional diuretic strategy

Locations

Country	Name	City	State
Vietnam	Cardiology Department	Ho Chi Minh City

Sponsors (2)

Lead Sponsor	Collaborator
Gia Dinh People Hospital	Otsuka Pharmaceutical Vietnam

Country where clinical trial is conducted

Vietnam, 

References & Publications (3)

Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM. Diuretic Therapy for Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Mar 17;75(10):1178-1195. doi: 10.1016/j.jacc.2019.12.059. Review. — View Citation

Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner-La Rocca HP, Martens P, Testani JM, Tang WHW, Orso F, Rossignol P, Metra M, Filippatos G, Seferovic PM, Ruschitzka F, Coats AJ. The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019 Feb;21(2):137-155. doi: 10.1002/ejhf.1369. Epub 2019 Jan 1. Review. — View Citation

Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 Jul 14;37(27):2129-2200. doi: 10.1093/eurheartj/ehw128. Epub 2016 May 20. Erratum in: Eur Heart J. 2016 Dec 30;:. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cumulative urine volume output at 48h after randomization	Urine volume in mL	Hour 48
Secondary	Cumulative dose of furosemide at 48h after randomization	Furosemide dose in mg	Hour 48
Secondary	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
Secondary	Changes in body weight at 24h and 48h after randomization	weight in gram	Hour 24, Hour 48
Secondary	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
Secondary	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
Secondary	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
Secondary	Changes in NT-proBNP at 48h after randomization	Changes in NT-proBNP (pg/mL)	Hour 0, Hour 48
Secondary	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
Secondary	Changes in E/e' ratio on echocardiography	The ratio between mitral E (cm/s) and average e' (cm/s)	Hour 24, Hour 48
Secondary	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
Secondary	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
Secondary	Changes in inferior vena cava maximal diameter on echocardiography	Inferior vena cava maximal diameter (mm) in subcostal view	Hour 24, Hour 48