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

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.

Inclusion criteria

• Age ≥ 18 years-old
• Established diagnosis of HF for more than 12 months, from an ischemic or a non-ischemic origin
• 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.
• 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)
• No or mild symptoms of HF (defined as NYHA functional class I or II)
• No heart failure-related hospital admission within the last six months
• 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
• 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.

• With or without ICD
• Ability to provide written informed consent to participate to the study
• Patient affiliated to Social Security

Exclusion criteria

• Atrial, supra-ventricular, or ventricular arrhythmias, in the last 12 months and/or requiring beta-blockers according to investigator.
• Uncontrolled arterial hypertension according to investigator decision.
• Symptomatic angina or evidence of infra-clinic myocardial ischemia requiring beta-blockers according to investigator decision.
• Cardiac resynchronization therapy
• 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.
• History of severe outcomes at beta-blockers interruption: HF relapse, occurrence of arrythmias
• Severe valvulopathy, restrictive, infiltrative or hypertrophic cardiomyopathy, constrictive pericarditis, or acute myocarditis within 3 months prior to inclusion Visit.
• Planned coronary, carotid, or peripheral artery revascularization known at the day of inclusion
• Chronic renal failure with eGFR <20mL/Min per 1.73m² (CKD-Epi) at inclusion
• Hepatic insufficiency classified as Child-Pugh B or C at the inclusion Visit.
• Any past solid organ transplantation or planned organ transplantation within 12 months
• Any condition other than HF that could limit survival to less than one year
• Pregnancy or breastfeeding women or women of childbearing potential without adequate contraceptive method
• Current participation in another interventional trial.
• Patient under legal protection (protection of the court, or in curatorship or guardianship).
• Any disorder, unwillingness or inability, which in investigator's opinion, might jeopardise the patient's safety or compliance with the protocol