Effect of Furosemide Withdraw in Stable Chronic Heart Failure Outpatients

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Placebo
* Drug: Furosemide


Participation Criteria
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Eligibility Criteria
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The ReBIC-1 study will enroll HF outpatients that fulfill the following criteria: age equal or greater than 18 year-old; New York Heart Association functional class I or II; Left Ventricular Ejection Fraction ≤ 45% by transthoracic two-dimensional echocardiography performed within 3 months before the screening visit; no previous HF related hospitalization or visit to emergency room within 6 months before the screening visit; treatment with a stable dose of furosemide (40 or 80 mg per day) for at least 6 months before the screening visit; plasma potassium < 5 mg/dl within 3 months before the screening visit; 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: a clinical congestion score (CCS) > 5 points; prior acute coronary syndrome, stroke or myocardial revascularization within 3 months before the screening visit; any severe valve heart disease (aortic, mitral or tricuspid); severe pulmonary disease (asthma, emphysema or fibrosis); severe hepatic failure or cirrhosis; end-stage acute or chronic renal disease (on hemodialysis); malignancy on active treatment; congenital heart disease; participation on any other interventional clinical research; inability to understand and sign informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Withdraw of furosemide<br>Withdraw of of 40 or 80 mg of furosemide per day | Drug: Placebo<br>* Replacement of furosemide by placebo<br>|
| Active Comparator: Maintenance of furosemide<br>Maintenance of 40 or 80 mg of furosemide per day | Drug: Furosemide<br>* Maintenance of furosemide on usual doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of furosemide withdraw - proportion of patients maintained without diuretic during follow-up | Proportion of patients maintained without diuretic during follow-up | 90 days | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variation of plasmatic levels of natriuretic peptides | Levels of the N-terminal brain natriuretic peptide (NT pro-BNP) | Baseline and 90 days | 
| Variation in meters walked assessed by the 6 minute walking test |  | Baseline and 90 days | 
| 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 | 
| 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 | 
| Clinical composite endpoints | Hospital admissions, emergency room visits and death within 90 days | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, diuretics, furosemide