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

NCT06518694 | Recruiting Phase 3 DMC

• 2 other identifiers: APHP230833P-PHRC-22-0112
• Study Type: interventional
• Target: 1,300
• Locations: 1 country
• Sites: 1

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.

Conditions

Heart Failure

Keywords

Heart Failure relapse; Recovered Ejection Fraction; Cardiovascular outcomes; Hospitalization for CV reason; Death; Bisoprolol; Carvedilol; Metoprolol; Nebivolol; Randomized

Outcome Measures

Primary Outcomes (3)

• 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 urgent visits 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 Outcomes (26)

• HF relapse defined by:

  At each visit from randomization through study completion, an average of 4 years

• Death

  At each visit from randomization through study completion, an average of 4 years

• All individual reasons for Hospitalisation, as follows:

  At each visit from randomization through study completion, an average of 4 years

• Cardiovascular death

  At each visit from randomization through study completion, an average of 4 years

• Number of patients with reduction in LVEF

  At each visit from randomization through study completion, an average of 4 years

Study Arms (2)

Group1

EXPERIMENTAL

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

Drug: Βeta-Blockers discontinued (with tapering)

Group2

NO INTERVENTION

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

Interventions

Βeta-Blockers discontinued (with tapering) 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.

Group1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Hôpital Européen Georges Pompidou

Paris, IDF, 75015, France

RECRUITING

MeSH Terms

Conditions

Heart Failure; Death

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Jean Sébastien HULOT, MD,PhD

  Assistance Publique - Hôpitaux de Paris

  STUDY CHAIR

Central Study Contacts

Jean Sébastien HULOT, MD, PhD

CONTACT

01 56 09 20 17; jean-sebastien.hulot@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Only outcomes assessor will be blinded to the study arm (Blinded endpoints prospective trial)
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: National, Multicenter, Randomised, Open-label, Non-inferiority, Blinded endpoints prospective trial

Study Record Dates

• First Submitted: June 21, 2024
• First Posted: July 24, 2024
• Study Start: February 11, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027
• Last Updated: January 16, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)