CASTLE-HFpEF (Catheter Ablation for Atrial Fibrillation Patients With Heart Failure With Mildly Reduced and Preserved Ejection Fraction)

NCT07254455 | Not Yet Recruiting DMC

• 1 other identifier: 26-0025
• Study Type: interventional
• Target: 900
• Locations: 0 countries
• Sites: N/A

Brief Summary

The clinical equipoise in the treatment of Atrial Fibrillation (AF) in patients with Heart Failure with mildly reduced Ejection Fraction/Heart Failure with Preserved Ejection Fraction (HFmrEF/HFpEF) reflects the scarcity of randomized trials on different treatment modalities. By generating high-quality, evidence-based, randomized data on the impact of treatment on hard outcomes, Catheter Ablation Versus Standard Conventional Treatment in Atrial Fibrillation Patients with Heart Failure with Preserved Ejection Fraction (CASTLE-HFpEF) will provide clinical decision-making guidance and help physicians in the management of patients with HFmrEF/HFpEF and AF. The main hypothesis is that Catheter Ablation (CA) for AF is associated with improved clinical outcomes in patients with HFmrEF/HFpEF and AF compared to medical AF treatment strategies on top of optimal medical HF treatment. CASTLE-HFpEF aims to study these hard clinical outcomes in a randomized cohort of patients with AF and HFmrEF/HFpEF.

Conditions

Atrial Fibrillation; Heart Failure With Preserved Ejection Fraction

Keywords

A-fib; HFpEF; HFmrEF; AF; Catheter ablation

Outcome Measures

Primary Outcomes (1)

• Composite endpoint of all-cause mortality, stroke or transient ischemic attack (TIA), and hospitalizations for worsening HF and clinically relevant decrease of NT proBNP (after 12 months)

  Hierarchical composite endpoint of the hard outcomes all-cause mortality, stroke or TIA, and hospitalizations for worsening HF (all after 36 months), and clinically relevant decrease of NT proBNP (after 12 months), analyzed using the Win Ratio method for each AF treatment arm (PFA-based CA versus conventional therapy). The Win Ratio is a statistical method designed to analyze composite outcomes with hierarchical clinical priorities, such as death, hospitalization, and functional status. Each patient in the treatment group is then compared to each patient in the control group, forming all possible unmatched pairs. Within each pair, the patient who experiences the more favorable outcome at the highest priority level is declared the "winner." The Win Ratio is calculated as the total number of wins in the treatment group divided by the number of wins in the control group, providing a clinically intuitive summary of net benefit.

  Baseline, 12 Months, 36 months

Secondary Outcomes (5)

• Combined hard outcomes (all-cause mortality, stroke or TIA, hospitalizations for worsening HF; time to first event)

  36 months

• Total HF-related events (hospitalization for worsening HF and outpatient worsening HF events)

  36 months

• Kansas City Cardiomyopathy Questionnaire (KCCQ) score

  Baseline, 3 Months, 6 months, 12 months, 24 months, 36 months

• All-cause mortality (time to event)

  36 Months

• Stroke or TIA (time to event)

  36 Months

Study Arms (2)

Standard medical therapy for heart failure with preserved ejection fraction arm

NO INTERVENTION

Participants randomized to receive medical treatment will be treated according to locally applicable guidelines for standard of care. The choice of the specific pharmacological treatment will be left to the discretion of the treating physician whether it is a rate or rhythm control based on the clinical picture, but maintenance of sinus rhythm through anti arrhythmic drugs (AADs) in this study arm will be encouraged. Electrical cardioversion using a defibrillator is allowed in this study arm. Medical therapy for HFmrEF/HFpEF will be continued following standard of care.

Catheter ablation arm

EXPERIMENTAL

Participants assigned to CA will undergo the procedure as soon as possible after baseline evaluation (within 5 weeks), following the Heart Rhythm Society (HRS) consensus statement using pulsed field ablation (PFA). The main aim of the procedure is to achieve isolation of all four pulmonary veins (PVs). In participants with paroxysmal AF, only pulmonary vein isolation (PVI) will be performed. In participants with persistent AF, posterior wall isolation (PWI) in addition to PVI will be applied. Medical therapy for HFmrEF/HFpEF will be continued following standard of care. The physician performing the CA must have performed at least 50 prior AF ablation procedures, comprising PVI and PVI +, with the same approach.

Procedure: Catheter ablation

Interventions

Catheter ablation PROCEDURE

A catheter ablation (CA) is a minimally invasive medical procedure for treatment of cardiac arrhythmias. Rhythm control of AF is attempted by pulmonary vein isolation (PVI) and posterior wall isolation (PWI). During the procedure, a catheter is guided to the heart through a blood vessel, which is either the femoral vein or a central vein, in order to ablate abnormal conductive heart tissue that causes the arrhythmias. Ablation is achieved either by thermal (cauterization by radiofrequency (RF) ablation / freezing by cryoballoon) or non-thermal mechanisms (primarily irreversible electroporation (IRE) through pulsed field ablation (PFA)). In case of successful ablation, a normal heart rhythm (sinus rhythm) can be restored.

Catheter ablation arm

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥18 years of age at screening visit.
• Clinical signs and symptoms of HF (26).
• Left ventricular ejection fraction (LVEF) \>40% within the past 12 months (most recent LVEF measurement)
• Elevated NT-proBNP levels during screening or within 12 months prior to screening (most recent value; blood test):
• For patients in normal sinus rhythm (NSR) at the time of blood sampling: NT proBNP ≥300 pg/mL
• For patients in AF at the time of blood sampling: NT-proBNP ≥600 pg/mL
• Echocardiographic evidence of HFmrEF/HFpEF, with at least one of the following during screening or within the 12 months prior to screening:
• Left atrial volume index (LAVI) ≥34 mL/m2 for patients in NSR, or LAVI ≥40 mL/m2 for patients in AF.
• Tricuspid regurgitation (TR) peak velocity \>2.8 m/s.
• Mitral E/e' ratio at rest ≥9.
• Left ventricular mass index (LVMI) ≥115 g/m2 for men and ≥95 g/m2 for women.
• Septal thickness or posterior wall thickness ≥1.1 cm.
• Patients previously diagnosed with persistent AF since ≤4 months prior to screening with an indication for anticoagulation, OR Patients previously diagnosed with paroxysmal AF since ≤4 months prior to screening with an already known AF burden of ≥1% and/or an AF episode of ≥24 hours, with an indication for anticoagulation OR Patients with paroxysmal AF without known AF burden (diagnosed since ≤4 months prior to screening) or no previously diagnosed AF who are subsequently diagnosed with AF after receiving a single-lead electrocardiography (ECG) patch for 30 days. These patients should have an AF burden of ≥1% and/or an AF episode of ≥24 hours on the ECG patch (more details down below in section 8.1.1) and an indication for anticoagulation.
• Stable optimal medical therapy for HFmrEF/HFpEF for at least 4 weeks (diuretics \& SGLT2 inhibitors unless contraindicated; angiotensin receptor-neprilysin inhibitors \& mineralocorticoid receptor antagonists as deemed appropriate by the treating physician; Amiodarone and Beta-blockers are not considered for defining heart failure therapy).
• Signed written informed consent obtained from the participant or participant's legal representative and ability for participant to comply with the requirements of the study.

You may not qualify if:

• Participants will be excluded from the study for any of the following reasons:
• Previous catheter ablation for AF.
• Known infiltrative cardiomyopathy, hypertrophic cardiomyopathy and amyloidosis.
• Documented left atrial diameter \>6cm.
• Any contraindication for chronic anticoagulation therapy or heparin, including hypersensitivity to any of the components.
• Acute coronary syndrome, cardiac surgery, angioplasty, or cerebrovascular accident within 2 months prior to enrollment.
• Planned cardiovascular intervention during the follow-up period.
• Patients with severe valvular disease
• Life expectancy ≤12 months.
• Untreated hypothyroidism or hyperthyroidism (blood test).
• Requirement for dialysis due to end-stage chronic kidney disease.
• Mental or physical inability to participate in the study.
• Women currently pregnant (blood test) or breastfeeding or not using reliable contraceptive measures during fertility age.
• Enrollment in another investigational drug or device study within the last 30 days before registration.
• Medical or psychological conditions that would not permit the participant to complete the study or sign informed consent.

Sponsors & Collaborators

• Tulane University: lead
• Boston Scientific Corporation: collaborator
• Johnson & Johnson: collaborator

MeSH Terms

Conditions

Atrial Fibrillation

Interventions

Catheter Ablation

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Radiofrequency Ablation; Radiofrequency Therapy; Therapeutics; Ablation Techniques; Surgical Procedures, Operative

Study Officials

• Nassir Marrouche, MD

  Tulane University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kunal Sameer, MD, MHA

CONTACT

504-988-3062; ksameer@tulane.edu

Han Feng, PhD

CONTACT

310-666-7248; hfeng6@tulane.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2025
• First Posted: November 28, 2025
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): October 1, 2030
• Last Updated: May 20, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share