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

February 22, 2016 updated by: Hospital de Clinicas de Porto Alegre

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

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed 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).

Study Type

Interventional

Enrollment (Anticipated)

230

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Brazil
    • RS
      • Porto Alegre, RS, Brazil, 90035-903
        • Recruiting
        • Cardiovascular Division, Hospital de Clínicas de Porto Alegre
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Priscila Raupp da Rosa, MD
        • Principal Investigator:
          • Luis E. Rohde, MD
        • Principal Investigator:
          • Andreia Biolo, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Feasibility of furosemide withdraw - proportion of patients maintained without diuretic during follow-up
Time Frame: 90 days
Proportion of patients maintained without diuretic during follow-up
90 days
Safety of furosemide withdraw - dyspnea score variation assessed by a visual analog scale
Time Frame: 90 days
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
Time Frame: Baseline and 90 days
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
Time Frame: Baseline and 90 days
Baseline and 90 days
Variation in renal function
Time Frame: Baseline, 15, 45 and 90 days
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
Time Frame: Baseline, 15, 45 and 90 days
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
Time Frame: 90 days
Hospital admissions, emergency room visits and death within 90 days
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospital de Clinicas de Porto Alegre

Collaborators

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Investigators

  • Study Chair: Luis Eduardo Rohde, PHD, Hospital de Clínicas de Porto Alegre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2015

Primary Completion (Anticipated)

May 1, 2017

Study Completion (Anticipated)

July 1, 2017

Study Registration Dates

First Submitted

November 25, 2015

First Submitted That Met QC Criteria

February 22, 2016

First Posted (Estimate)

February 23, 2016

Study Record Updates

Last Update Posted (Estimate)

February 23, 2016

Last Update Submitted That Met QC Criteria

February 22, 2016

Last Verified

February 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 15-240

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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