Effect of Diuretics Withdrawal in Chronic Heart Failure With Reduced Ejection Fraction

Study Overview
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Brief Summary
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REDICAE trial was designed to evaluate the safety and tolerability of diuretics withdrawal in stable, euvolemic chronic outpatients with heart failure with reduced ejection fraction. It is a single-center, randomized, open-label, phase II clinical trial.

Detailed Description
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Treatment of heart failure with reduced ejection fraction (HFrEF) has improved patient survival in recent decades. Diuretics are essentials in acute decompensated heart failure, specially furosemide. However, when patients are stable and euvolemic diuretics (loop diuretics, thiazide diuretics or acetazolamide) might increase adverse effects: renin-angiotensin-aldosterone system activation, renal function impairment or electrolyte disturbances. The 2021 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure recommend angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA) and sodium-glucose co-transporter 2 inhibitors (iSTLT2) as first-line therapy for HFrEF. A significant proportion of patients take a maintenance diuretics dose despite the clinical benefits and prognosis are controversial. Current clinical guidelines suggest that diuretic use can be reduced or discontinued in selected euvolemic or hypovolemic patients. This statement is based on the results of the ReBIC-1 trial published in 2019, which showed a neutral effect of furosemide discontinuation in stable chronic outpatients with HFrEF treated according to the 2016 ESC heart failure guidelines standards of care. REDICAE trial was designed to evaluate the safety and tolerability of diuretics withdrawal, not just furosemide, in stable euvolemic chronic outpatients with HFrEF. It is a single-center, randomized, open-label phase II clinical trial. The pathophysiology of congestion in heart failure is complex and multifactorial. In the REDICAE trial, volume status will be determined by biomarkers, echocardiography and bioelectrical impedance analysis. The patients enrolled in the study will be under contemporary guideline-directed medical therapy, including SGLT2 inhibitors. This trial is the largest prospective trial evaluating the clinical effects of diuretic discontinuation in HFrEF patients under contemporary pharmacological therapy for heart failure. REDICAE trial develops in Hospital Universitario Reina Sofía in Cordoba (Spain)

Official Title
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Safety and Tolerability of Diuretics Withdrawal in Heart Failure With Reduced Ejection Fraction. REDICAE Trial.

Conditions
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Heart Failure, Electric Impedance, Dyspnea, Safety, Withdrawal

Intervention / Treatment
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* Drug: Diuretics withdrawal
* Drug: Diuretics maintenance


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Outpatients diagnosed of chronic HFrEF by criteria of ESC Guidelines of 2021 Age equal or greater than 18 year-old Stable and euvolemic outpatients determined by clinical criteria, biomarkers (CA-125 < 23 U/mL) and bioelectrical impedance analysis Left Ventricular Ejection Fraction less than 50% by echocardiography or cardiovascular magnetic resonance performed within 6 months before the screening visit New York Heart Association functional class I or II No episodes of acute decompensated heart failure within 2 months before the screening visit Treatment with a stable dose of diuretic for at least 1 month before the screening visit Optimal medical therapy with ACEI/ARNI, BB, MRA and iSGLT2 must be started to titration unless any of them were contraindicated or not tolerated Plasma potassium < 5 mg/dl in the screening visit EXCLUSION CRITERIA: Acute coronary syndrome within 3 months before screening visit Awaiting cardiac resynchronization therapy Any severe valve heart disease not yet treated Pulmonary hypertension or any severe pulmonary disease End-stage chronic kidney disease (on hemodialysis). Acute kidney injury Severe hepatic failure or cirrhosis Malignancy on active treatment Congenital heart disease Awaiting cardiac transplantation Inability to understand and sign the informed consent Participation in any other interventional clinical research

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diuretics withdrawal<br> | Drug: Diuretics withdrawal<br>* Diuretics that not have been demonstrated improve survival in chronic HFrEF are withdrawn<br>|
| Active Comparator: Diuretics maintenance<br> | Drug: Diuretics maintenance<br>* Any diuretic could be used<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Dyspnea assessed by a visual analogue scale (VAS) | VAS scores are scaled from 0 to 100 millimeters (mm). Higher scores mean a worse outcome. | baseline - 30 days - 90 days - 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute decompensated heart failure events | Number of Hospital admissions, emergency department visits or unscheduled medical appointments requiring intravenous diuretic treatment, and increase in diuretic dose or reintroduction of an oral diuretic. | 180 days | 
| Variation of plasmatic levels of natriuretic peptides | Levels of the N-terminal pro b-type natriuretic peptide (NT-proBNP) | baseline - 30 days - 90 days - 180 days | 
| Tissue fluid overload | Variation of plasmatic levels of antigen carbohydrate 125 (CA-125) | baseline - 30 days - 90 days - 180 days | 
| Body Composition Monitor (BCM) of Fresenius Medical Care | Variation of fluid overload assessed by bioelectrical impedance analysis | baseline - 30 days - 90 days - 180 days | 
| Inferior vena cava (IVC) diameter | IVC diameter measured in its intra-hepatic portion at 2 cm of the junction with the hepatic veins using a longitudinal view from a sub-xiphoid position. IVC is dilated when its diameter is more than 20 mm. | baseline - 30 days - 90 days - 180 days | 
| Hepatic vein Doppler | Pulsed wave Doppler shows a systolic (S) and diastolic (D) components. Normal pattern (S > D), mildly abnormal pattern (S < D) and severely abnormal pattern (S reverses) | baseline - 30 days - 90 days - 180 days | 
| Portal vein Doppler | Pulsed wave Doppler shows a continuous nonpulsatile flow. Using the pulsatility fraction (PF=100*[(Vmax - Vmin)/Vmax)]) are three patterns: normal PF < 30%, mildly abnormal PF 30-50% and severely abnormal PF >50%. | baseline - 30 days - 90 days - 180 days | 
| Intra-renal venous Doppler | Pulsed wave Doppler shows a normal pattern when flow is continuous. Mildly abnormal pattern shows a biphasic flow (S and D). Severely abnormal pattern shows a monophasic flow (D) | baseline - 30 days - 90 days - 180 days | 
| Ultrasound congestion parameters by Venous Excess Ultrasound (VExUS) protocol | IVC diameter, hepatic vein Doppler, portal vein Doppler and intra-renal venous Doppler patterns are combined to report VExUS grades: Grade 0 (no congestion): IVC < 20 mm Grade 1 (mild congestion): IVC ≥ 20 mm and any combination of normal or mildly abnormal pattern Grade 2 (moderate congestion): IVC ≥ 20 mm + ≥ 1 severely abnormal pattern Grado 4 (severe congestion): IVC ≥ 20 mm + ≥ 2 severely abnormal pattern | baseline - 30 days - 90 days - 180 days | 
| Congestion assessed by lung ultrasound | Pleural effusion or pathological B lines. More than two B lines are considered as pathological. | baseline - 30 days - 90 days - 180 days | 
| Quality of life status | Change From Baseline in the Kansas City Cardiomyopathy Questionnaire 12 (KCCQ-12) score. KCCQ-12 scores are scaled from 0 to 100. Higher scores mean a better outcome. | baseline - 30 days - 90 days - 180 days | 
| 6 minute walk test | Change From Baseline in meters walked, as assessed by the 6 minute walk test | baseline - 30 days - 90 days - 180 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Diuretics, Dyspnea, Safety, Fluid overload, Withdraw, Electric Impedance