Clinical trial NCT06518694: Beta-blOckers discoNtinuation in Patients Presenting Heart FaIlure With REcovered Left Ventricular Ejection Fraction
Official title: Beta-blOckers discoNtinuation in Patients Presenting Heart FaIlure With REcovered Left Ventricular Ejection Fraction
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Heart Failure
Keywords: Heart Failure relapse
Recovered Ejection Fraction
Cardiovascular outcomes
Hospitalization for CV reason
Death
Bisoprolol
Carvedilol
Metoprolol
Nebivolol
Randomized
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2024-07-24
Enrollment: 1300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: National, Multicenter, Randomised, Open-label, Non-inferiority, Blinded endpoints prospective trial
Primary purpose: OTHER

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.

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.
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

Primary outcomes:
measure: The primary endpoint of the study will be evaluated with one-year minimum follow-up and will be the composite of:
timeFrame: Within 1 year minimum after randomization
measure: death
timeFrame: Within 1 year minimum after randomization
measure: Hospitalisation for CV reason
timeFrame: Within 1 year minimum after randomization
Secondary outcomes:
measure: HF relapse defined by:
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Death
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: All individual reasons for Hospitalisation, as follows:
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Cardiovascular death
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Number of patients with reduction in LVEF
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Number of patients with a relative increase in LVEDVi
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Number of patients hospitalized
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Number of patients needing loop diuretics
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Changes in NYHA Class
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Absolute values of NT-pro-BNP concentrations at the different visits
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Proportion of patients with changes in NT-proBNP concentrations to more than 400 ng/L.
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Number of patients needing beta-blocker re-introduction in the experimental group or beta-blocker discontinuation in the control group
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Occurrence of arrhythmic events (any types, i.e., supra-ventricular and/or ventricular arrhythmias & requiring hospitalization or not) in all participants
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Occurrence of infra-clinic supra-ventricular and/or ventricular arrhythmias in patients implanted with ICD before participating the study
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Quality of life (QoL) evaluated by the auto-questionnaire (EQ5D)
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Quality of life with heart failure, evaluated by the auto-questionnaire KCCQ-12 filled by the patients himself.
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Anxiety
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Erectile dysfunction (in men only)
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Absolute values of heart rate at the different visits
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Evaluation of Side effects: Questionnaire on the Presence of Blury Vision
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Evaluation of Side effects: Sensation of cold hands and feet
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Evaluation of Side effects : Insomnia
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Occurrence of Palpitations
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Syncope / Dizziness requiring a consultation
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Evaluation of adherence to therapies evaluated by self-questionnaire
timeFrame: At each visit from randomization through study completion, an average of 4 years
measure: Exercise capacity by 6M walk test (in participating centers)
timeFrame: At each visit from randomization through study completion, an average of 4 years
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
state: IDF
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Jean Sébastien HULOT, MD,PhD
role: STUDY_CHAIR
References: