Effect of Furosemide Withdraw in Stable Chronic Heart Failure Outpatients

Heart Failure Clinical Trial

— ReBIC-1  

Official title:

Effect of Furosemide Withdraw in Stable Chronic Heart Failure Outpatients With Left Ventricular Dysfunction - the Brazilian Research Network on Heart Failure

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02689180
• Other study ID #: 15-240
• Status: Recruiting
• Phase: Phase 3
• First received: November 25, 2015
• Last updated: February 22, 2016
• Start date: May 2015
• Est. completion date: July 2017

Study information

• Verified date: February 2016
• Source: Hospital de Clinicas de Porto Alegre
• Contact: Luis Eduardo Rohde, PHD
• Phone: 555133598843
• Email: lerohde[@]gmail.com
• Is FDA regulated: No
• Health authority: Brazil: National Committee of Ethics in Research
• Study type: Interventional

Clinical Trial Summary

The ReBIC-1 trial was designed to evaluate the potential clinical risks and benefits of withdrawing furosemide use in stable, apparently euvolemic, chronic HF outpatients in a multicentric double-blinded randomized clinical trial.

Description:

Diuretics play a central role in HF treatment, particularly during episodes of acute decompensation. Furosemide is the prototype of loop diuretics, acting through the inhibition of the Na+K+2Cl- pump at the thick ascending limb of the Henle loop. According to international registries, almost all patients receive a loop diuretic during a hospital stay for acute decompensated HF and the majority are discharged taking a "maintenance dose". Despite the undeniable beneficial hemodynamic effects of improvement of peripheral and central congestion, the net clinical effect of the chronic use of diuretics on HF prognosis is controversial.

Observational studies suggest that use of high doses of diuretics might be related to unfavorable clinical consequences. Undesirable side effects of loop diuretics are not trivial and involve activation of the renin-angiotensin-aldosterone system, elevation of norepinephrine levels, increases in heart rate, detrimental effects on renal function and several electrolyte disturbances.

Few prospective clinical studies, however, directly evaluated the clinical risks and benefits of diuretics. Most of these studies were under-powered, performed more than 2 decades ago, before modern HF therapy with current drugs and devices was completely implemented.

Current clinical guidelines are unanimous to recommend use of diuretics in HF patients with clinical signs and symptoms of congestion, but reinforce the lack of solid clinical scientific evidence for its use, and the potential risks that might be involved. The European Society of Cardiology proposes the administration of the lowest dose necessary to achieve euvolemia, avoiding the unnecessary delay in the use of drugs that modify the natural history of the disease.

Based on these uncertainties about diuretic use in HF, the ReBIC-1 trial was designed to evaluate the potential clinical risks and benefits of withdrawing furosemide use in stable, apparently euvolemic, chronic HF outpatients in a multicentric double-blinded randomized clinical trial.

ReBIC is a Brazilian research network created to develop clinical studies in heart failure and composed predominantly by university tertiary care hospitals. ReBIC and the ReBIC-1 trial were sponsored by the Brazilian National Council for Scientific and Technological Development (CNPq, Brazil), a public governmental institution. Data collection, management, and analysis were performed at the network's data coordinating center at Hospital de Clínicas de Porto Alegre. All the authors reviewed and approved the manuscript and assume full responsibility for the accuracy and completeness of the data and for the fidelity of this report of the study protocol.

ReBIC-1 is a randomized, double-blind, parallel group, placebo-controlled, two-arm trial comparing the short-term efficacy and safety of discontinuation of furosemide in apparently euvolemic outpatients with chronic stable HF and reduced left ventricular ejection fraction (HF-REF).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 230
• Est. completion date: July 2017
• Est. primary completion date: May 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 90 Years

Eligibility

The ReBIC-1 study will enroll HF outpatients that fulfill the following criteria:

1. age equal or greater than 18 year-old;

2. New York Heart Association functional class I or II;

3. Left Ventricular Ejection Fraction = 45% by transthoracic two-dimensional echocardiography performed within 3 months before the screening visit;

4. no previous HF related hospitalization or visit to emergency room within 6 months before the screening visit;

5. treatment with a stable dose of furosemide (40 or 80 mg per day) for at least 6 months before the screening visit;

6. plasma potassium < 5 mg/dl within 3 months before the screening visit;

7. optimal HF treatment with an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and beta-blockers, unless contraindicated or not tolerated.

The ReBIC-1 study will exclude HF outpatients that fulfill the following criteria:

1. a clinical congestion score (CCS) > 5 points;

2. prior acute coronary syndrome, stroke or myocardial revascularization within 3 months before the screening visit;

3. any severe valve heart disease (aortic, mitral or tricuspid);

4. severe pulmonary disease (asthma, emphysema or fibrosis);

5. severe hepatic failure or cirrhosis;

6. end-stage acute or chronic renal disease (on hemodialysis);

7. malignancy on active treatment;

8. congenital heart disease;

9. participation on any other interventional clinical research;

10. inability to understand and sign informed consent.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• Placebo
Replacement of furosemide by placebo
• Furosemide
Maintenance of furosemide on usual doses

Locations

Country	Name	City	State
Brazil	Cardiovascular Division, Hospital de Clínicas de Porto Alegre	Porto Alegre	RS

Sponsors (2)

Lead Sponsor	Collaborator
Hospital de Clinicas de Porto Alegre	Conselho Nacional de Desenvolvimento Científico e Tecnológico

Country where clinical trial is conducted

Brazil, 

References & Publications (6)

Cowley AJ, Stainer K, Wynne RD, Rowley JM, Hampton JR. Symptomatic assessment of patients with heart failure: double-blind comparison of increasing doses of diuretics and captopril in moderate heart failure. Lancet. 1986 Oct 4;2(8510):770-2. — View Citation

Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol. 2006 Jun 15;97(12):1759-64. Epub 2006 Apr 27. — View Citation

Lip GY, Gibbs CR, Beevers DG. ABC of heart failure: aetiology. BMJ. 2000 Jan 8;320(7227):104-7. Review. — View Citation

McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012 Jul;33(14):1787-847. doi: 10.1093/eurheartj/ehs104. Epub 2012 May 19. Erratum in: Eur Heart J. 2013 Jan;34(2):158. — View Citation

Mielniczuk LM, Tsang SW, Desai AS, Nohria A, Lewis EF, Fang JC, Baughman KL, Stevenson LW, Givertz MM. The association between high-dose diuretics and clinical stability in ambulatory chronic heart failure patients. J Card Fail. 2008 Jun;14(5):388-93. doi: 10.1016/j.cardfail.2008.01.015. Epub 2008 May 27. — View Citation

WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013 Oct 15;128(16):e240-327. doi: 10.1161/CIR.0b013e31829e8776. Epub 2013 Jun 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility of furosemide withdraw - proportion of patients maintained without diuretic during follow-up	Proportion of patients maintained without diuretic during follow-up	90 days	No
Primary	Safety of furosemide withdraw - dyspnea score variation assessed by a visual analog scale	Dyspnea score variation assessed by a visual analog scale after randomization	90 days	Yes
Secondary	Variation of plasmatic levels of natriuretic peptides	Levels of the N-terminal brain natriuretic peptide (NT pro-BNP)	Baseline and 90 days	No
Secondary	Variation in meters walked assessed by the 6 minute walking test		Baseline and 90 days	No
Secondary	Variation in renal function	Change in glomerular filtration rate ( ml/min /1.73 m²) estimated by the Modification of Diet in Renal Disease equation ( MDRD)	Baseline, 15, 45 and 90 days	No
Secondary	Variation on the Clinical Congestion Score	Clinical congestion score assessed by clinical history and physical examination (score from 1 to 22 point)	Baseline, 15, 45 and 90 days	Yes
Secondary	Clinical composite endpoints	Hospital admissions, emergency room visits and death within 90 days	90 days	No