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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Βeta-Blockers discontinued (with tapering)
  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 n

Первичные конечные точки

• The primary endpoint of the study will be evaluated with one-year minimum follow-up and will be the composite of: [Срок оценки: Within 1 year minimum after randomization]
• death [Срок оценки: Within 1 year minimum after randomization]
• Hospitalisation for CV reason [Срок оценки: Within 1 year minimum after randomization]

Вторичные конечные точки (12)

• HF relapse defined by: [Срок оценки: At each visit from randomization through study completion, an average of 4 years]
• Death [Срок оценки: At each visit from randomization through study completion, an average of 4 years]
• All individual reasons for Hospitalisation, as follows: [Срок оценки: At each visit from randomization through study completion, an average of 4 years]
• Cardiovascular death [Срок оценки: At each visit from randomization through study completion, an average of 4 years]
• Number of patients with reduction in LVEF [Срок оценки: At each visit from randomization through study completion, an average of 4 years]
• Number of patients with a relative increase in LVEDVi [Срок оценки: At each visit from randomization through study completion, an average of 4 years]
• Number of patients hospitalized [Срок оценки: At each visit from randomization through study completion, an average of 4 years]
• Number of patients needing loop diuretics [Срок оценки: At each visit from randomization through study completion, an average of 4 years]
• Changes in NYHA Class [Срок оценки: At each visit from randomization through study completion, an average of 4 years]
• Absolute values of NT-pro-BNP concentrations at the different visits [Срок оценки: 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. [Срок оценки: 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 [Срок оценки: At each visit from randomization through study completion, an average of 4 years]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Другое

Центры проведения

Франция · 1 центр

• Hôpital Européen Georges Pompidou — Paris

Идентификаторы

NCT: NCT06518694 · APHP230833 · P-PHRC-22-0112

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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