Beta-blOckers discoNtinuation in Patients Presenting Heart FaIlure With REcovered Left Ventricular Ejection Fraction

NCT ID: NCT06518694

Last Updated: 2026-01-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 1300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-02-11
• Study Completion Date: 2027-10-31

Brief Summary

A significant proportion of patients initially diagnosed with heart failure and a reduced left ventricular ejection fraction (LVEF<40%, HFrEF) presents a substantial improvement in response to evidence-based medical and device therapies. Some of these patients (estimated from 20 to 30%) even display a complete normalization of LVEF (i.e., >50%) and are now recognized as a specific sub-group of patients named Heart Failure with recovered Ejection Fraction (HFrecovEF). Different studies have shown that reverse remodeling with recovery of cardiac function and stabilization of HF symptoms are associated with improved clinical outcomes over the long-term. Whether these patients present a stable remission of HF and could benefit a therapeutic de-escalation is however unclear. Until novel data are provided, medical therapies are thus continued indefinitely in these stable patients with HFrecovEF. Current guidelines for the management of patients with heart failure and a reduced left ventricular ejection fraction recommends a comprehensive therapy, including 5 different therapeutic classes (RAAS blockers (with a preference for ARNi) + Beta-Blockers + SGLT2i + Mineraloreceptors Antagonists + or - Diuretics ).

None of these therapies (with the recent exception of one SGLT2i, i.e. Dapagliflozin) have been tested in patients with HFrecovEF. In addition, it is unclear whether the benefit of older therapies (notably beta-blockers) remains in patients receiving modern comprehensive therapy as newer drugs were tested as add-on therapies. This polypharmacy is lowering adherence and is creating a challenge for physicians and patients. Betablockers are notably associated with frequent side effects, a limited tolerance and a significant reduction of quality of life. Their efficacy on outcomes is not established in patients with normal LVEF. Pilot studies have suggested that Beta-blockers interruption in patients with HF and normal EF was associated with functional improvement.

Detailed Description

BONFIRE is a National, Multicenter, Randomised, Open-label, Non-inferiority, Blinded endpoints prospective trial.

The study concerns HF patients with a history of reduced left ventricular ejection fraction (45% or below), but with a normalized LVEF (currently ≥ 50 % on cardiac echography) under an optimal medical therapy as recommended in European guidelines (including beta-blockers, RAAS blockade with ARNI or ACE-I or ARBs, SGLT2 inhibitors, MRA, + or - loop diuretics) AND with no or mild symptoms and no heart failure-related events within the last six months.

The patients fulfilling the full inclusion criteria and without exclusion criteria, that agree to participate the protocol and that have signed the informed consent will be randomized (1:1) into two groups:

• Experimental group (N=650): Βeta-Blockers therapy will be discontinued (with tapering) while the remaining guideline-directed optimal medical therapy for HF is maintained.
• Control group (N=650): The patients will continue their usual guideline-directed optimal medical therapy for HF, including Βeta-Blockers therapy, without modification.

Conditions

Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: SINGLE

Study Groups

Group1

Βeta-Blockers therapy will be discontinued (with tapering) while the remaining guideline-directed optimal medical therapy for HF is maintained

Group Type: EXPERIMENTAL

Βeta-Blockers discontinued (with tapering)

Intervention Type: DRUG

The experimental group will undergo discontinuation of their beta-blockers treatment during the study period.

The tapering of beta-blocker will start on the day after randomisation and is based on a reduction by half-dose every 48 hours (1/2 maximally recommended dose for 48 hours, then ¼ maximally recommended dose for 48 hours) until reaching the minimal recommended dosage (1/8 maximally recommended dose) for 48 hours before complete interruption of treatment. Consequently, the tapering will not be needed in patients already receiving the minimal recommended dosage (i.e., 1/8 dose) at inclusion, and these patients will be instructed to stop taking beta-blockers the day after randomisation.

Group2

The patients will continue their usual guideline-directed optimal medical therapy for HF, including Βeta-Blockers therapy, without modification.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Βeta-Blockers discontinued (with tapering)

The experimental group will undergo discontinuation of their beta-blockers treatment during the study period.

The tapering of beta-blocker will start on the day after randomisation and is based on a reduction by half-dose every 48 hours (1/2 maximally recommended dose for 48 hours, then ¼ maximally recommended dose for 48 hours) until reaching the minimal recommended dosage (1/8 maximally recommended dose) for 48 hours before complete interruption of treatment. Consequently, the tapering will not be needed in patients already receiving the minimal recommended dosage (i.e., 1/8 dose) at inclusion, and these patients will be instructed to stop taking beta-blockers the day after randomisation.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age ≥ 18 years-old

2. Established diagnosis of HF for more than 12 months, from an ischemic or a non-ischemic origin

3. With a documented history of reduced left ventricular ejection fraction (LVEF ≤ 45%), followed by a normalisation of LVEF (≥ 50 % for the last 6 months) assessed by cardiac echography.

4. With a left ventricular end diastolic volume indexed to body surface area (LVEDVi) within the normal range (≤74ml/m2 in men and ≤61 ml/m2 in women)

5. No or mild symptoms of HF (defined as NYHA functional class I or II)

6. No heart failure-related hospital admission within the last six months

7. Currently receiving a beta-blocker indicated for chronic heart failure (i.e. bisoprolol or carvedilol or metoprolol or nebivolol) whatever the dose used, for at least 12 months

8. And receiving the guideline-directed optimal medical therapy for at least 12 months (i.e., maximal tolerated dose of SGLT2 inhibitors, and of RAAS blocker (Angiotensin receptor neprilysin inhibitor OR Angiotensin-converting-enzyme-inhibitors OR Angiotensin II receptors blockers), and MRA if tolerated). Loop diuretics use is adjusted to congestive signs according to physicians' decision.

No initiation or major adjustment in heart failure therapies should have occurred during the 3 months prior to study inclusion.

9. With or without ICD

10. Ability to provide written informed consent to participate to the study

11. Patient affiliated to Social Security

Exclusion Criteria

1. Atrial, supra-ventricular, or ventricular arrhythmias, in the last 12 months and/or requiring beta-blockers according to investigator.

2. Uncontrolled arterial hypertension according to investigator decision.

3. Symptomatic angina or evidence of infra-clinic myocardial ischemia requiring beta-blockers according to investigator decision.

4. Cardiac resynchronization therapy

5. Extra-cardiac conditions requiring beta-blockers (migraine, essential tremor, prevention of bleeding from esophageal varices in patients with liver cirrhosis, adrenergic symptoms of hyperthyroidism…) according to investigator decision.

6. History of severe outcomes at beta-blockers interruption: HF relapse, occurrence of arrythmias

7. Severe valvulopathy, restrictive, infiltrative or hypertrophic cardiomyopathy, constrictive pericarditis, or acute myocarditis within 3 months prior to inclusion Visit.

8. Planned coronary, carotid, or peripheral artery revascularization known at the day of inclusion

9. Chronic renal failure with eGFR <20mL/Min per 1.73m² (CKD-Epi) at inclusion

10. Hepatic insufficiency classified as Child-Pugh B or C at the inclusion Visit.

11. Any past solid organ transplantation or planned organ transplantation within 12 months

12. Any condition other than HF that could limit survival to less than one year

13. Pregnancy or breastfeeding women or women of childbearing potential without adequate contraceptive method

14. Current participation in another interventional trial.

15. Patient under legal protection (protection of the court, or in curatorship or guardianship).

16. Any disorder, unwillingness or inability, which in investigator's opinion, might jeopardise the patient's safety or compliance with the protocol

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jean Sébastien HULOT, MD,PhD

Role: STUDY_CHAIR

Assistance Publique - Hôpitaux de Paris

Locations

Hôpital Européen Georges Pompidou

Paris, IDF, France

Site Status: RECRUITING

Countries

France

Central Contacts

Jean Sébastien HULOT, MD, PhD

Role: CONTACT

jean-sebastien.hulot@aphp.fr

01 56 09 20 17

Facility Contacts

Jean Sébastien HULOT, MD, PhD

Role: primary

jean-sebastien.hulot@aphp.fr

01 56 09 20 17

Other Identifiers

P-PHRC-22-0112

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

APHP230833

Identifier Type: -

Identifier Source: org_study_id