Beta-blOckers discoNtinuation in Patients Presenting Heart FaIlure With REcovered Left Ventricular Ejection Fraction
NCT Number: NCT06518694
Acronym: BONFIRE
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE3
Conditions: Heart Failure
Interventions: DRUG: Βeta-Blockers discontinued (with tapering)
Sponsor: Assistance Publique - Hôpitaux de Paris
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 1300
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: SINGLE (OUTCOMES_ASSESSOR)|Primary Purpose: OTHER
Start Date: 2024-10
Completion Date: 2027-10
Locations: Hôpital Européen Georges Pompidou, Paris, IDF, 75015, France

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.

Primary Outcome Measures: The primary endpoint of the study will be evaluated with one-year minimum follow-up and will be the composite of:, - HF relapse (at any time during the study period):

* drop in LVEF \>10% (expressed as absolute value)
* relative increase in body surface area-indexed left ventricular end-diastolic volume (LVEDVi) \>10%
* increase in NT-proBNP \>2x and ≥ 400 ng/L
* worsening heart failure symptoms requiring hospitalization or out-of-hospital therapeutic management with diuretics (intra-venous or oral)., Within 1 year minimum after randomization|death, All-cause death, Within 1 year minimum after randomization|Hospitalisation for CV reason, - Hospitalisation for CV reason (ACS or need for coronary catheterization +/- revascularization / supra-ventricular arrhythmias / ventricular arrhythmias / Syncope, Pace-Maker implantation / High blood pressure / Stroke)., Within 1 year minimum after randomization
Secondary Outcome Measures: HF relapse defined by:, * Reduction in LVEF by more than 10% (absolute value)
* A relative increase in LVEDVi by more than 10%
* A two-fold rise in baseline NT-pro-BNP concentration and to more than 400 ng/L.
* Clinical evidence of heart failure, based on signs and symptoms as adjudicated by the research team.
* Hospitalization for worsening HF, At each visit from randomization through study completion, an average of 4 years|Death, All-cause Death, At each visit from randomization through study completion, an average of 4 years|All individual reasons for Hospitalisation, as follows:, * ACS or need for coronary catheterisation +/-revascularization
* Recurrent ischemia
* Supra-ventricular or ventricular arrhythmias
* Syncope, PM implantation
* High blood pressure
* Stroke, At each visit from randomization through study completion, an average of 4 years|Cardiovascular death, All-cause cardiovascular death, At each visit from randomization through study completion, an average of 4 years|Number of patients with reduction in LVEF, Number of patients with reduction in LVEF by more than 10% (absolute value) and to less than 50%., At each visit from randomization through study completion, an average of 4 years|Number of patients with a relative increase in LVEDVi, Number of patients with a relative increase in LVEDVi by more than 10% and to higher than the normal range., At each visit from randomization through study completion, an average of 4 years|Number of patients hospitalized, Number of patients hospitalized for worsening HF, At each visit from randomization through study completion, an average of 4 years|Number of patients needing loop diuretics, Number of patients needing loop diuretics for congestive symptoms, during hospitalization and/or in out-of-hospital settings, At each visit from randomization through study completion, an average of 4 years|Changes in NYHA Class, Changes in NYHA Class, At each visit from randomization through study completion, an average of 4 years|Absolute values of NT-pro-BNP concentrations at the different visits, Absolute values of NT-pro-BNP concentrations at the different visits, At each visit from randomization through study completion, an average of 4 years|Proportion of patients with changes in NT-proBNP concentrations to more than 400 ng/L., Proportion of patients with changes in NT-proBNP concentrations to more than 400 ng/L., At each visit from randomization through study completion, an average of 4 years|Number of patients needing beta-blocker re-introduction in the experimental group or beta-blocker discontinuation in the control group, Number of patients needing beta-blocker re-introduction in the experimental group or beta-blocker discontinuation in the control group, At each visit from randomization through study completion, an average of 4 years|Occurrence of arrhythmic events (any types, i.e., supra-ventricular and/or ventricular arrhythmias & requiring hospitalization or not) in all participants, Occurrence of arrhythmic events (any types, i.e., supra-ventricular and/or ventricular arrhythmias \& requiring hospitalization or not) in all participants, At each visit from randomization through study completion, an average of 4 years|Occurrence of infra-clinic supra-ventricular and/or ventricular arrhythmias in patients implanted with ICD before participating the study, Occurrence of infra-clinic supra-ventricular and/or ventricular arrhythmias in patients implanted with ICD before participating the study, At each visit from randomization through study completion, an average of 4 years|Quality of life (QoL) evaluated by the auto-questionnaire (EQ5D), Quality of life (QoL) evaluated by the auto-questionnaire (EQ5D), At each visit from randomization through study completion, an average of 4 years|Quality of life with heart failure, evaluated by the auto-questionnaire KCCQ-12 filled by the patients himself., Quality of life with heart failure, evaluated by the auto-questionnaire KCCQ-12 filled by the patients himself., At each visit from randomization through study completion, an average of 4 years|Anxiety, questionnaire HADS (Hospital Anxiety and Depression Scale), score de 0 à 21, higher scores indicate the presence of anxiety or depression, At each visit from randomization through study completion, an average of 4 years|Erectile dysfunction (in men only), Erectile dysfunction (in men only) by the questionnaire IIEF5 (International Index of Erectile Function)., At each visit from randomization through study completion, an average of 4 years|Absolute values of heart rate at the different visits, Absolute values of heart rate at the different visits and relative change as compared to baseline values (first year), At each visit from randomization through study completion, an average of 4 years|Evaluation of Side effects: Questionnaire on the Presence of Blury Vision, Questionnaire on the Presence of Blury Vision, At each visit from randomization through study completion, an average of 4 years|Evaluation of Side effects: Sensation of cold hands and feet, Sensation of cold hands and feet, At each visit from randomization through study completion, an average of 4 years|Evaluation of Side effects : Insomnia, Insomnia, At each visit from randomization through study completion, an average of 4 years|Occurrence of Palpitations, Occurrence of Palpitations, At each visit from randomization through study completion, an average of 4 years|Syncope / Dizziness requiring a consultation, Syncope / Dizziness requiring a consultation, At each visit from randomization through study completion, an average of 4 years|Evaluation of adherence to therapies evaluated by self-questionnaire, Evaluation of adherence to therapies evaluated by self-questionnaire, At each visit from randomization through study completion, an average of 4 years|Exercise capacity by 6M walk test (in participating centers), Exercise capacity by 6M walk test (in participating centers), At each visit from randomization through study completion, an average of 4 years