Discontinuation of Beta-Blockers in Heart Failure Patients with Recovered Left Ventricular Ejection Fraction: A Non-Inferiority Study

The primary objective of the study is to demonstrate the **non-inferiority** of Beta-Blockers therapy discontinuation in patients with **heart failure** (HF) and recovered left ventricular ejection fraction (LVEF), stratified by ischemic versus non-ischemic origin, in terms of HF relapse and adverse cardiovascular outcomes compared to the continuation of Beta-Blockers. This is clinically relevant as it may inform treatment strategies for patients with recovered LVEF, potentially reducing medication burden without compromising safety.

Secondary objectives include:

• Assessing the non-inferiority of Beta-Blockers therapy discontinuation in terms of safety endpoints.
• Evaluating the tolerability of Beta-Blockers therapy discontinuation.
• Assessing patients' compliance with HF therapies.
• Identifying clinical, imaging, or biological predictors of HF relapse or cardiovascular outcomes.

The clinical trial involves participants diagnosed with **heart failure** who have experienced a recovery in left ventricular ejection fraction (LVEF). The study population includes both male and female subjects aged 18 years and older. Participants are required to have an established diagnosis of heart failure for more than 12 months, originating from either ischemic or non-ischemic causes. They must have a documented history of reduced LVEF (≤ 45%), followed by normalization of LVEF (≥ 50% for the last 6 months) as assessed by cardiac echography. The trial includes individuals with a left ventricular end diastolic volume indexed to body surface area within the normal range and exhibiting no or mild symptoms of heart failure, classified as NYHA functional class I or II. Participants should not have had any heart failure-related hospital admissions within the last six months and must currently be receiving a beta-blocker indicated for chronic heart failure for at least 12 months. Additionally, they should be on guideline-directed optimal medical therapy for at least 12 months. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the non-inferiority of discontinuing **beta-blockers** in patients with heart failure and recovered left ventricular ejection fraction (LVEF). The study employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to span a period from June 2024 to June 2028, with participant involvement ranging from a minimum of one year to a maximum of four years, depending on individual follow-up requirements.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, medical history, and current treatment regimen. This visit will ensure that participants have a documented history of heart failure with a previously reduced LVEF that has since normalized. Follow-up visits will occur regularly to monitor the primary endpoint, which includes the first occurrence of heart failure relapse or adverse cardiovascular outcomes. Secondary endpoints will assess various health metrics, including changes in LVEF, NT-proBNP concentrations, and hospitalization rates.

The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of beta-blocker discontinuation. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or choose to withdraw consent. The trial aims to provide valuable insights into the management of heart failure in patients with recovered LVEF, potentially influencing future treatment guidelines.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. The first experimental medication is a combination of **hydrochlorothiazide** and **ramipril**, administered orally in a pharmaceutical form identified as PHF00245MIG. The maximum daily dose is 10 mg, with a total maximum dose of 10,920 mg over a treatment period of 156 days. This medication is classified under the ATC code C09AA05, indicating its role as an ACE inhibitor. Participant compliance will be monitored throughout the trial to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is **perindopril tert-butylamine**, also administered orally in the same pharmaceutical form, PHF00245MIG. The maximum daily dose for this medication is 100 mg, with a total maximum dose of 110 g over the same treatment period. This medication is classified under the ATC code C07AG02, which corresponds to its role as a beta-blocker. Compliance monitoring will be conducted to ensure proper administration.

The trial also includes the use of **valsartan and sacubitril**, administered orally in the pharmaceutical form PHF00082MIG. The maximum daily dose is 100 mg, with a total maximum dose of 110 g over 156 days. This combination is classified under the ATC code C09DX04, indicating its use in cardiovascular treatment. Participant adherence to the dosing schedule will be closely monitored.

**Dapagliflozin propanediol** is another experimental medication in the trial, administered orally in the pharmaceutical form PHF00082MIG. The maximum daily dose is 10 mg, with a total maximum dose of 10.92 g over the treatment period. This medication is classified under the ATC code A10BK01, indicating its role as a sodium-glucose co-transporter 2 (SGLT2) inhibitor. Compliance monitoring will be implemented to ensure proper dosing.

Additionally, the trial includes the use of **losartan potassium and hydrochlorothiazide**, administered orally in the pharmaceutical form PHF00082MIG. The maximum daily dose is 150 mg, with a total maximum dose of 164 g over 156 days. This combination is classified under the ATC code C09CA01, indicating its use as an angiotensin II receptor blocker (ARB). Participant compliance will be monitored throughout the trial.

Non-experimental treatments in the study include standard-of-care therapies such as **ACE inhibitors, plain**, and **Angiotensin II receptor blockers (ARBs), plain**, both administered orally. These treatments serve as comparator treatments to evaluate the efficacy and safety of the experimental medications. The maximum daily dose for ACE inhibitors is 10 mg, with a total maximum dose of 10.92 g, while for ARBs, the maximum daily dose is 150 mg, with a total maximum dose of 164 g over the treatment period. Compliance with these treatments will also be monitored to ensure accurate assessment of outcomes.

Efficacy in the clinical trial titled "BONFIRE - Beta-blockers discontinuation in patients presenting heart failure with recovered left ventricular ejection fraction" will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the first occurrence of events within a composite endpoint during a follow-up period ranging from a minimum of 1 year to a maximum of 4 years. This includes **heart failure (HF) relapse**, characterized by a drop in left ventricular ejection fraction (LVEF) greater than 10%, a relative increase in body surface area-indexed left ventricular end diastolic volume (LVEDVi) greater than 10%, an increase in NT-proBNP levels more than twofold and equal to or greater than 400 ng/L, and worsening HF symptoms requiring hospitalization or out-of-hospital therapy.

Secondary endpoints encompass a variety of measures, including HF relapse defined by specific criteria such as a reduction in LVEF by more than 10%, a relative increase in LVEDVi by more than 10%, and a two-fold rise in baseline NT-proBNP concentration to more than 400 ng/L. Additional secondary endpoints include all-cause death, all individual reasons for hospitalization, all-cause cardiovascular death, and further analyses of HF relapse. Quality of life will be evaluated using the EQ5D and KCCQ-12 questionnaires, while anxiety will be assessed with the HADS questionnaire. Other secondary endpoints include erectile dysfunction in men, side effects, compliance to therapies, and exercise capacity measured by the 6-minute walk test.