Effect of Furosemide Withdraw in Stable Chronic Heart Failure Outpatients (ReBIC-1)

Hospital de Clinicas de Porto Alegre

Status and phase: Unknown; Phase 3

Conditions: Heart Failure

Treatments: Drug: Furosemide; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02689180

15-240

Details and patient eligibility

About

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.

Full 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).

Enrollment: 230 estimated patients

Sex: All

Ages: 18 to 90 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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230 participants in 2 patient groups, including a placebo group

Withdraw of furosemide

Placebo Comparator group

Description:

Withdraw of of 40 or 80 mg of furosemide per day

Treatment:

Drug: Placebo

Maintenance of furosemide

Active Comparator group

Description:

Maintenance of 40 or 80 mg of furosemide per day

Treatment:

Drug: Furosemide