Clinical trial NCT04331132: Tolvaptan add-on Therapy to Overcome Loop Diuretic Resistance in Acute Heart Failure With Renal Dysfunction
Official title: Tolvaptan add-on Therapy to Overcome Loop Diuretic Resistance in Acute Heart Failure With Renal Dysfunction
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Acute Heart Failure
Keywords: acute heart failure
worsening renal function
loop diuretic resistance
vasopressin-2 receptor antagonist
Lead sponsor: Gia Dinh People Hospital
Sponsor class: OTHER
Collaborators: name: Otsuka Pharmaceutical Vietnam
First posted: 2020-04-02
Enrollment: 128
Sex: ALL
Minimum age (years): 20
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 days
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Cumulative urine volume output at 48h after randomization
timeFrame: Hour 48
Secondary outcomes:
measure: Cumulative dose of furosemide at 48h after randomization
timeFrame: Hour 48
measure: Symptom of dyspnea by 7-point Likert scale at 24h and 48h after randomization
timeFrame: Hour 24, Hour 48
measure: Changes in body weight at 24h and 48h after randomization
timeFrame: Hour 24, Hour 48
measure: Incidence of clinically relevant worsening renal function at 24h and 48h after randomization
timeFrame: Hour 24, Hour 48
measure: Changes in serum electrolytes measured at 12h, 24h and 48h after randomization
timeFrame: Hour 12, Hour 24, Hour 48
measure: Changes in urine electrolyte excretion at 6h, 24h and 48h
timeFrame: Hour 6, Hour 24, Hour 48
measure: Changes in NT-proBNP at 48h after randomization
timeFrame: Hour 0, Hour 48
measure: Changes in mitral e' on echocardiography
timeFrame: Hour 24, Hour 48
measure: Changes in E/e' ratio on echocardiography
timeFrame: Hour 24, Hour 48
measure: Changes in left atrial volume on echocardiography
timeFrame: Hour 24, Hour 48
measure: Changes in tricuspid regurgitation maximal velocity on echocardiography
timeFrame: Hour 24, Hour 48
measure: Changes in inferior vena cava maximal diameter on echocardiography
timeFrame: Hour 24, Hour 48
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: Cardiology Department
Study officials:
affiliation: Cardiology Department
name: Hai H. Nguyen, Ph.D
role: STUDY_CHAIR
References:
citation: Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-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. No abstract available.
citation: 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.
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.
citation: Minh NG, Hoang HN, Maeda D, Matsue Y. Tolvaptan Add-on Therapy to Overcome Loop Diuretic Resistance in Acute Heart Failure With Renal Dysfunction (DR-AHF): Design and Rationale. Front Cardiovasc Med. 2022 Jan 27;8:783181. doi: 10.3389/fcvm.2021.783181. eCollection 2021.