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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05964738
Other study ID # REDICAE
Secondary ID
Status Recruiting
Phase Phase 2
First received
Last updated
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
Health authority
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 SofĂ­a 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

Study Design


Related Conditions & MeSH terms


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
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