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

Heart Failure Clinical Trial

— REDICAE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05964738
• Other study ID #: REDICAE
• Status: Recruiting
• Phase: Phase 2
• Start date: December 19, 2022
• Est. completion date: June 30, 2024

Study information

• Verified date: July 2023
• Source: Maimónides Biomedical Research Institute of Córdoba
• Contact: Alberto Torres, MD
• Phone: +34620650405
• Email: atorzam.29[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: June 30, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Dyspnea
• Electric Impedance
• Heart Failure
• Safety
• Withdrawal

Intervention

Drug:
• Diuretics withdrawal
Diuretics that not have been demonstrated improve survival in chronic HFrEF are withdrawn
• Diuretics maintenance
Any diuretic could be used

Locations

Country	Name	City	State
Spain	Hospital Universitario Reina Sofía	Córdoba	Córdoba (Andalucía)

Sponsors (2)

Lead Sponsor	Collaborator
Maimónides Biomedical Research Institute of Córdoba	Sociedad Andaluza de Cardiología

Country where clinical trial is conducted

Spain, 

References & Publications (9)

Ekman I, Granger B, Swedberg K, Stenlund H, Boman K. Measuring shortness of breath in heart failure (SOB-HF): development and validation of a new dyspnoea assessment tool. Eur J Heart Fail. 2011 Aug;13(8):838-45. doi: 10.1093/eurjhf/hfr062. — View Citation

Jackson AM, Dewan P, Anand IS, Belohlavek J, Bengtsson O, de Boer RA, Bohm M, Boulton DW, Chopra VK, DeMets DL, Docherty KF, Dukat A, Greasley PJ, Howlett JG, Inzucchi SE, Katova T, Kober L, Kosiborod MN, Langkilde AM, Lindholm D, Ljungman CEA, Martinez F — View Citation

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray — View Citation

McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 1 — View Citation

Nunez J, Bayes-Genis A, Revuelta-Lopez E, Ter Maaten JM, Minana G, Barallat J, Cserkoova A, Bodi V, Fernandez-Cisnal A, Nunez E, Sanchis J, Lang C, Ng LL, Metra M, Voors AA. Clinical Role of CA125 in Worsening Heart Failure: A BIOSTAT-CHF Study Subanalysi — View Citation

Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, Sattar N, Brueckmann M, Jamal W, Cotton D, Iwata T, Zannad F; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, — View Citation

Rohde LE, Rover MM, Figueiredo Neto JA, Danzmann LC, Bertoldi EG, Simoes MV, Silvestre OM, Ribeiro ALP, Moura LZ, Beck-da-Silva L, Prado D, Sant'Anna RT, Bridi LH, Zimerman A, Raupp da Rosa P, Biolo A. Short-term diuretic withdrawal in stable outpatients — View Citation

Romano G, Vitale G, Bellavia D, Agnese V, Clemenza F. Is diuretic withdrawal safe in patients with heart failure and reduced ejection fraction? A retrospective analysis of our outpatient cohort. Eur J Intern Med. 2017 Jul;42:e11-e13. doi: 10.1016/j.ejim.2 — View Citation

Vardeny O, Claggett B, Kachadourian J, Desai AS, Packer M, Rouleau J, Zile MR, Swedberg K, Lefkowitz M, Shi V, McMurray JJV, Solomon SD. Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. Eur — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Tissue fluid overload	Variation of plasmatic levels of antigen carbohydrate 125 (CA-125)	baseline - 30 days - 90 days - 180 days
Secondary	Body Composition Monitor (BCM) of Fresenius Medical Care	Variation of fluid overload assessed by bioelectrical impedance analysis	baseline - 30 days - 90 days - 180 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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