Stopping beta-blockers in people with recovered heart pumping function

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

This trial will try stopping beta-blockers in adults with heart failure whose ejection fraction has recovered to see if stopping them is as safe as continuing them.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 1300 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Assistance Publique - Hôpitaux de Paris (other)
• Locations: 1 site (Paris, IDF)
• Trial ID: NCT06518694 on ClinicalTrials.gov

What this trial studies

BONFIRE is a national, multicenter, randomized, open-label, phase 3 non-inferiority trial with blinded endpoint adjudication enrolling adults who had prior HFrEF but now have normalized LVEF (≥50%), normal indexed LV volumes, and no or mild symptoms. Eligible participants who have been on guideline-directed therapy including a beta-blocker for at least 12 months are randomized 1:1 to either taper off the beta-blocker while keeping other HF medications or to continue usual therapy, with about 650 patients per arm. Major cardiovascular outcomes such as heart-failure hospitalization and death will be tracked and adjudicated by blinded reviewers during follow-up. The trial is designed to test whether withdrawing beta-blockers is not worse than continuing them in this recovered population.

Who should consider this trial

Good fit: Adults (≥18) with a prior LVEF ≤45% who now have LVEF ≥50% for at least 6 months, normal indexed LVEDV, NYHA class I–II, no HF hospitalization in the past 6 months, and on stable guideline-directed therapy including a beta-blocker for ≥12 months.

Not a fit: People with persistent reduced LVEF, recent heart-failure events, moderate-to-severe symptoms (NYHA III–IV), enlarged LV volumes, or not on stable guideline therapy are unlikely to benefit and are excluded.

Why it matters

Potential benefit: If successful, some people with recovered ejection fraction could safely stop beta-blockers and avoid their side effects and pill burden without increasing the risk of heart failure relapse.

How similar studies have performed: Small trials and observational cohorts (for example TRED-HF) have shown that stopping heart-failure therapies can lead to relapse in many patients, so the approach remains unproven and requires larger randomized evidence.

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

Where this trial is running

Paris, IDF

• Hôpital Européen Georges Pompidou — Paris, IDF, France (RECRUITING)

Study contacts

• Study coordinator: Jean Sébastien HULOT, MD, PhD

Conditions: Heart Failure, Heart Failure relapse, Recovered Ejection Fraction, Cardiovascular outcomes, Hospitalization for CV reason, Death, Bisoprolol, Carvedilol