Beta-blOckers discoNtinuation in Patients Presenting Heart FaIlure With REcovered Left Ventricular Ejection Fraction
概览
- 阶段
- 3 期
- 干预措施
- Βeta-Blockers discontinued (with tapering)
- 疾病 / 适应症
- Heart Failure
- 发起方
- Assistance Publique - Hôpitaux de Paris
- 入组人数
- 1300
- 试验地点
- 1
- 主要终点
- death
- 状态
- 招募中
- 最后更新
- 3个月前
概览
简要总结
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.
详细描述
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.
研究者
入排标准
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Group1
Βeta-Blockers therapy will be discontinued (with tapering) while the remaining guideline-directed optimal medical therapy for HF is maintained
干预措施: Βeta-Blockers discontinued (with tapering)
结局指标
主要结局
death
时间窗: Within 1 year minimum after randomization
All-cause death
The primary endpoint of the study will be evaluated with one-year minimum follow-up and will be the composite of:
时间窗: Within 1 year minimum after randomization
\- 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).
Hospitalisation for CV reason
时间窗: Within 1 year minimum after randomization
\- Hospitalisation for CV reason (ACS or need for coronary catheterization +/- revascularization / supra-ventricular arrhythmias / ventricular arrhythmias / Syncope, Pace-Maker implantation / High blood pressure / Stroke).
次要结局
- HF relapse defined by:(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)
- Number of patients hospitalized(At each visit from randomization through study completion, an average of 4 years)
- Changes in NYHA Class(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.(At each visit from randomization through study completion, an average of 4 years)
- Erectile dysfunction (in men only)(At each visit from randomization through study completion, an average of 4 years)
- Evaluation of Side effects: Sensation of cold hands and feet(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)
- Number of patients with a relative increase in LVEDVi(At each visit from randomization through study completion, an average of 4 years)
- Absolute values of NT-pro-BNP concentrations at the different visits(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(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.(At each visit from randomization through study completion, an average of 4 years)
- Evaluation of Side effects : Insomnia(At each visit from randomization through study completion, an average of 4 years)
- Occurrence of Palpitations(At each visit from randomization through study completion, an average of 4 years)
- Evaluation of adherence to therapies evaluated by self-questionnaire(At each visit from randomization through study completion, an average of 4 years)
- Number of patients needing loop diuretics(At each visit from randomization through study completion, an average of 4 years)
- Quality of life (QoL) evaluated by the auto-questionnaire (EQ5D)(At each visit from randomization through study completion, an average of 4 years)
- Evaluation of Side effects: Questionnaire on the Presence of Blury Vision(At each visit from randomization through study completion, an average of 4 years)
- Exercise capacity by 6M walk test (in participating centers)(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(At each visit from randomization through study completion, an average of 4 years)
- Anxiety(At each visit from randomization through study completion, an average of 4 years)
- Syncope / Dizziness requiring a consultation(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(At each visit from randomization through study completion, an average of 4 years)
- Absolute values of heart rate at the different visits(At each visit from randomization through study completion, an average of 4 years)