Evaluation of Pharmacological Treatment Withdrawal in Heart Failure Patients with Cardiac Resynchronization Therapy: Eplerenone, Valsartan, Bisoprolol, and Furosemide

The primary objective of this study is to determine the effect of withdrawing **pharmacologic treatment** in patients with cardiac resynchronization therapy who have recovered left ventricular ejection fraction (LVEF). This will be assessed through changes in imaging parameters, specifically LVEF and left ventricular volume, as well as clinical parameters that reflect the worsening of **heart failure**. This is clinically relevant as it may inform treatment strategies for patients who have shown improvement with cardiac resynchronization therapy, potentially reducing medication burden and associated side effects.

Secondary objectives include:

• Determining the safety of withdrawing drug treatment in terms of adverse events during follow-up, including total death, cardiovascular death, hospital admission or emergency room visit for heart failure, and sustained supraventricular or ventricular arrhythmias.
• Assessing changes in other echocardiographic measures, levels of natriuretic peptides, vital signs, and scores in quality of life tests.
• Evaluating the influence of cardiomyopathy genotype on the response to medication withdrawal.

The clinical trial focuses on patients diagnosed with **heart failure** who have undergone cardiac resynchronization therapy. The study population includes both male and female participants, aged 18 years and older, who are in good general health as indicated by their NYHA functional class I-II status and absence of heart failure admissions in the past year. Participants must have a current left ventricular ejection fraction (LVEF) of 50% or higher, with normal volumes confirmed by two consecutive echocardiograms. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include patients with a normally functioning cardiac resynchronization therapy device, who are on pharmacological treatment with beta-blockers, ACEIs/ARA II/ARNI, with or without ARM, and have NT-proBNP levels below specified thresholds. Participants must have given written informed consent. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the effects of withdrawing pharmacological treatment in patients with **heart failure** who have undergone cardiac resynchronization therapy and have shown recovery in left ventricular ejection fraction (LVEF). This is a phase IV, randomized, double-blind, controlled trial. The trial aims to assess both imaging parameters, such as changes in LVEF and left ventricular volume, and clinical parameters that indicate worsening of heart failure. The trial is expected to last until October 2025, with recruitment having started in December 2021.

Participants will be involved in the study for a maximum treatment period of 12 months. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as LVEF, NYHA functional class, and NT-proBNP levels; regular follow-up visits to monitor clinical and imaging parameters; and an end-of-study visit to assess the primary and secondary endpoints. The primary endpoint is the relapse of cardiomyopathy, defined by specific criteria such as a reduction in LVEF or unplanned hospital admissions. Secondary endpoints include total mortality, cardiovascular mortality, and changes in quality of life questionnaires.

Participants are expected to adhere to the study protocol, and any deviation, such as non-compliance with medication or significant adverse events, may lead to early termination from the study. The trial involves the use of several medications, including **eplerenone**, **valsartan**, **bisoprolol fumarate**, and **furosemide**, all administered orally in the form of film-coated tablets. The trial is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants.

The clinical trial involves the administration of several **experimental medications**. The first medication is **eplerenone**, available in two dosages: 50 mg and 25 mg. Both are provided as film-coated tablets under the brand name "eplerenona cinfa" and are manufactured by LABORATORIOS CINFA, S.A. The route of administration is oral, with a maximum daily dose of 50 mg. The treatment period is up to 12 months. Eplerenone is a chemical substance classified under the ATC code C03DA04.

Another medication used in the trial is **valsartan**, available in multiple dosages: 40 mg, 80 mg, 160 mg, and 320 mg. These are also film-coated tablets, marketed under the brand name "Diován" by NOVARTIS FARMACÉUTICA S.A. The oral administration of valsartan allows for a maximum daily dose of 320 mg, with a treatment duration of up to 12 months. Valsartan is a chemical substance with the ATC code C09CA03.

**Bisoprolol fumarate** is included in the trial in dosages of 2.5 mg, 5 mg, and 10 mg, provided as film-coated tablets under the brand "Bisoprolol Cor Aristo" by ARISTO PHARMA GMBH. The administration route is oral, with a maximum daily dose of 10 mg, and the treatment period extends to 12 months. Bisoprolol fumarate is a chemical substance, classified under the ATC code C07AB07.

The trial also includes **furosemide**, available as 40 mg tablets, marketed as "Furosemida KERN PHARMA" by KERN PHARMA, S.L. The administration is oral, with a maximum daily dose of 80 mg, and the treatment period is up to 12 months. Furosemide is a chemical substance with the ATC code C03CA01.

All medications are administered orally, and participant compliance is monitored throughout the trial. The trial aims to evaluate the effects of withdrawing pharmacologic treatment in patients with cardiac resynchronization therapy who have recovered left ventricular ejection fraction (LVEF), focusing on imaging and clinical parameters related to heart failure.

The efficacy of the clinical trial titled "Withdrawal of Pharmacological Treatment in Patients Responding to Cardiac Resynchronization Therapy: (REMOVE)" will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the **relapse of cardiomyopathy** after drug withdrawal, defined by specific criteria such as a reduction in left ventricular ejection fraction (LVEF) of more than 10% if the overall LVEF is less than 50%, or a reduction in LVEF of more than 10% accompanied by a greater than 15% increase in left ventricular end-systolic volume. Additionally, unplanned hospital admissions or visits to the Emergency Department due to decompensated heart failure requiring intravenous diuretics will be considered.

Secondary endpoints include a combination of total mortality, cardiovascular mortality, hospital admissions, or unplanned visits for heart failure, and sustained atrial or ventricular arrhythmias lasting more than 30 seconds. Other secondary measures involve changes from baseline in blood pressure (BP) and heart rate (HR), LVEF, left ventricular total volume variation (LVTVV), left atrial volume indexed by body surface area (VAIi), and left ventricular longitudinal global strain (LSG). Quantitative changes in NT-proBNP levels and changes in quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Minnesota Living With Heart Failure (MLHFQ) scale will also be evaluated.