Catheter Ablation in Atrial Fibrillation Patients With HFpEF (STABLE-SR IV Trial)

• ClinicalTrials.gov Identifier: NCT06125925
• Recruitment Status: Recruiting
• First Posted: November 9, 2023
• Last Update Posted: December 11, 2023
• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Information provided by (Responsible Party): Minglong Chen, The First Affiliated Hospital with Nanjing Medical University

Study Description

Brief Summary:

To investigate whether RFCA is superior to AADs in AF patients with HFpEF on the basis of optimized anti-heart-failure drug therapy regarding their longterm clinical outcomes.

Condition or disease	Intervention/treatment	Phase
Atrial Fibrillation; HFpEF - Heart Failure With Preserved Ejection Fraction	Procedure: Radiofrequency catheter ablation (RFCA); Drug: Medical Therapy	Not Applicable

Detailed Description:

Background: Atrial Fibrillation (AF) is a common cardiac rhythm disorder and radiofrequency catheter ablation (RFCA) has become the first-line therapy in the symptomatic AF patients. Heart failure is often the sister disease with AF. Recently, RFCA was found to be superior to antiarrhythmic drugs (AADs) in heart failure patients with AF and reduced ejection fraction (HFrEF), regarding all-cause mortality and hospitalization for worsening heart failure (HF). However, in heart failure patients with AF and preserved ejection fraction (HFpEF), it remains unknown whether RFCA is superior to AADs in an even larger population, despite several nonrandomized retrospective studies. Thus, this prospective, multi-center, randomized controlled trial aims to investigate whether RFCA could better improve the clinical outcome of AF patients with HFpEF than longterm AADs use.

Aim of this study: To investigate whether RFCA is superior to AADs in AF patients with HFpEF on the basis of optimized anti-heart-failure drug therapy regarding their longterm clinical outcomes.

Design: The STABLE-SR-IV trial is an international, prospective, multi-center, randomized controlled trial. In this trial, physical examination, echocardiogram, NT-proBNP and other blood test would be assessed before enrollment. Those who conform to all the inclusion criteria and absent from any exclusion criteria would enter into a run-in period of 5 weeks (±7 days). Anticoagulation and anti-heart-failure therapy for HFpEF must be optimized according to the current guideline. After the run-in period, inclusion and exclusion criteria would be reassessed. Thereafter, all the subjects enrolled would be randomized into RFCA arm and Medical Therapy arm with a 1:1 manner, namely 218 subjects in each arm. Each arm will follow the protocol of RFCA and medical therapy, respectively. Follow-up duration of this study is up to 2~3 years (12 month enrollment).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 436 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Masking Description: The End Point and Adverse Event Committee is constituted of three experts in the field of heart failure and ablation of atrial fibrillation, but independent of the study. The End Point Adverse Event Committee have received blinded data regarding all serious adverse events, all deaths, all hospitalizations, all outpatient or emergency visits, all cerebrovascular accidents, and all first recurrences of atrial fibrillation, from the Contact Research Organization. The End Point and Adverse Event Committee was responsible for the classification of all received events, for the determination of which events fulfill the end point criteria.
• Primary Purpose: Treatment
• Official Title: Catheter Ablation in Atrial Fibrillation Patients With Heart Failure With Preserved Ejection Fraction: an International, Prospective, Multi-center, Randomized Controlled Study (STABLE-SR IV Trial)
• Actual Study Start Date: November 6, 2023
• Estimated Primary Completion Date: November 2026
• Estimated Study Completion Date: November 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Radiofrequency catheter ablation (RFCA); Radiofrequency ablation is adopted in the study, instead of cryo ablation, surgical ablation or pulsed field ablation. 3-dimensional model is constructed after transseptal puncture. Circumferential pulmonary vein isolation (CPVI) is performed with irrigated contact force catheter. Previously published STABLE-SR approach is recommended as the ablation strategy beyond CPVI.	Procedure: Radiofrequency catheter ablation (RFCA); Radiofrequency ablation is adopted in the study, instead of cryo ablation, surgical ablation or pulsed field ablation. 3-dimensional model is constructed after transseptal puncture. Circumferential pulmonary vein isolation (CPVI) is performed with irrigated contact force catheter. Previously published STABLE-SR approach is recommended as the ablation strategy beyond CPVI.
Active Comparator: Medical therapy; AADs should be prescribed according to the current guidelines, such as amiodarone, dronedarone, or propafenone. In brief, rhythm control is preferred, including electric cardioversion. However, rate control should be considered if rhythm control is contraindicated, intolerated or unpreferred by patients.	Drug: Medical Therapy; AADs should be prescribed according to the current guidelines, such as amiodarone, dronedarone, or propafenone. In brief, rhythm control is preferred, including electric cardioversion. However, rate control should be considered if rhythm control is contraindicated, intolerated or unpreferred by patients.

Outcome Measures

Primary Outcome Measures :

1. Composite endpoint of worsening heart failure requiring unplanned hospitalizations or urgent visits, and cardiovascular death (Time-to-first event analysis) [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]

Secondary Outcome Measures :

1. Time to hospitalization or urgent visits for heart failure [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]
   Worsening heart failure includes worsening heart failure requiring unplanned hospitalization and worsening heart failure requiring urgent visits.
2. Time to hospitalization for heart failure [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]

   In addition to signs and symptoms of HF, the patient should also receive treatment specifically directed at HF, including at least 1 of the following: 1) significant augmentation in oral diuretic therapy; 2) initiation of intravenous diuretic (even a single dose) or vasoactive agent (eg, vasodilator, vasopressor, or inotropic therapy); or 3) mechanical circulatory support or fluid removal.

   Unplanned hospitalization is defined as any unscheduled hospital admission with a length of stay that either exceeds 24 h or crosses a calendar day, and not planned by the investigators. In case the hospitalization is classified as planned by the Investigator and the time interval between the decision to admit and the admission is less than 24 hours, the End Point and Adverse Event Committee will give final classification concerning planned or unplanned.

3. Time to urgent visits for heart failure [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]
   Worsening of Heart Failure Requiring Unplanned Urgent Visits Patients have an urgent, unscheduled office or emergency visit for HF with signs, symptoms, and diagnostic testing results identical to those already described for an HF hospitalization. The patient must also (with the exception of significant augmentation in oral diuretic therapy) require therapy similar to that previously described for an HF hospitalization.
4. Time to cardiovascular death [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]
   All deaths due to cardiovascular reasons and all heart transplants because of terminal HF. Deaths due to worsening of HF, acute coronary syndrome, cerebrovascular accident.
5. Time to all-cause death [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]
   All deaths were reviewed and adjudicated by the Clinical Events Committee
6. Time to cardiovascular hospitalization [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]
   Unplanned Hospitalization due to Cardiovascular Reasons Any in-hospital stay over one date change due to cardiovascular reason, which includes worsening of HF, acute coronary syndrome, cerebrovascular accidents, or other cardiovascular events, and not planned by the investigator. In case the hospitalization is classified as planned by the investigator, and the time interval between the decision to hospitalize and the hospitalization is less than 24 hours, the End Point and Adverse Event Committee will give final classification concerning planned or unplanned.
7. Total number of worsening heart failure events and cardiovascular deaths [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]
8. Change in quality of life - KCCQ score [ Time Frame: Baseline, 3 months, 12 months ]
   KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ Total Symptom Score incorporates the symptom domains into a single score. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
9. Change in quality of life - MLWHFQ [ Time Frame: Baseline, 3 months, 12 months ]
   The Mayo AF-Specific Symptom Inventory (MAFSI) is a questionnaire comprised of a 10-item AF symptom checklist that asked about both the frequency and severity of each symptom. MAFSI frequency of symptoms over the past month was recorded as 0 (never), 1 (rarely), 2 (sometimes), 3 (often), and 4 (always) for each of the 10 items listed in the questionnaire. The 10 item responses were summed for a total Frequency Score that ranged from 0 (no AF symptoms) to 40 (worst score).
10. Change in 6-minute walk test from baseline to Month 3 and Month 12 [ Time Frame: Baseline, 3months, 12 months ]
    The 6-minute walk test is a sub-maximal exercise test used to assess aerobic capacity and endurance.
11. Change in H2FPEF score from baseline to Month 3 and Month 12 [ Time Frame: Baseline, 3 months, 12 months ]
    The H2FPEF score is a clinical scoring system used to assess the likelihood of heart failure with preserved ejection fraction (HFpEF) in patients with suspected heart failure. It helps in differentiating HFpEF from other causes of dyspnea. The total score ranges from 0 to 5, with higher scores indicating a greater likelihood of HFpEF.
12. Change in N-terminal pro-B type natriuretic peptide (NT-proBNP) from baseline to Month 3 and Month 12 [ Time Frame: Baseline, 3 months, 12 months ]
    Elevated levels of NT-pro BNP are indicative of increased cardiac stress and can help in the diagnosis, assessment, and monitoring of heart failure.
13. Change in NYHA class from baseline to Month 3, 6 and 12 [ Time Frame: Baseline, 3 months, 12 months ]
    NYHA class is a widely used system for assessing the functional status and severity of heart failure symptoms in patients, with NYHA class IV being the worst.
14. Time to change of diuretics [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]

    Based on status of baseline diuretics, the intention to treat population will be divided into patients with baseline diuretics and patients without.

    For patients without the usage of baseline diuretics, the outcome of changes in diuretics is the initiation of diuretics during the follow-up period.

    For patients without the usage of baseline diuretics, the outcomes including:

    1. permanent discontinuation;
    2. escalation defined as increased dosage, iv fused diuretic or combination with another diuretic;
    3. de-escalation (including permanent discontinuation or decrease in dosage); Changes in diuretic therapy are analyzed in a time-to-first event fashion using a multivariable Cox regression model to obtain hazard ratios (HRs) and 95% confidence intervals (CIs).
15. Change in atrial fibrillation burden [ Time Frame: Baseline, 12 months ]
    Atrial fibrillation burden refers to the amount of time that a person with atrial fibrillation spends in an irregular heart rhythm over a specific period, using a Holter monitor.
16. Time to Atrial Fibrillation recurrence (RFCA arm) [ Time Frame: From randomization until completion of the planned follow-up, up to 36 months ]
    A 30-second episode of AF in ablation group following the 90 day blanking period, confirmed through blinded review by an ECG Core Lab Committee was used for defining the endpoint of recurrent AF.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Symptomatic paroxysmal or persistent atrial fibrillation
• CHADS2-VASc score≥ 2

• Conform to the diagnosis of HFpEF

  1. NYHA II-IV level;
  2. Left ventricular ejection fraction (LVEF)≥ 50%;
  3. NT-proBNP≥ 300 pg/mL under sinus rhythm or NT-proBNP≥ 600 pg/mL under atrial fibrillation or flutter;
  4. Evidence of left ventricular diastolic dysfunction/raised left ventricular filling pressure on echocardiogram.
• Sign informed consent

Exclusion Criteria:

• A life expectancy below 2 years due to any non-cardiovascular condition
• Reversible atrial fibrillation, such as hyperthyroidism or hypokalemia-related atrial fibrillation
• Prior atrial fibrillation ablation
• Left atrial size≥ 55 mm
• Heart failure due to any of the following: known genetic hypertrophic cardiomyopathy, infiltrative cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, constrictive pericarditis, active myocarditis, cardiac tamponade, or uncorrected primary valvular disease
• Previous cardiac transplantation, complex congenital heart disease, rheumatic heart disease
• Any contraindication for radiofrequency catheter ablation, antiarrhythmic drugs or anticoagulation
• Acute coronary syndrome, cardiac surgery, angioplasty or cerebrovascular accident within 12 weeks before enrollment
• Severe hepatic and renal dysfunction
• Body mass index> 50 kg/m2
• Female in period of pregnancy or breast-feeding
• Any conditions that, in the opinion of the investigator, may render the patient unable to complete the study
• Involved in other studies

The inclusion and exclusion criteria would be reassessed after run-in period and the cut-off of NT-proBNP would be set as >125 pg/ml under sinus rhythm or >365 pg/ml under AF/atrial flutter (AFL).

Contacts and Locations

Contacts

Contact: Hailei Liu, PhD; +86-18094226858; liuhailei@njmu.edu.cn

Contact: Nan Wu, MD; +86-18351977986; wunannjmu@163.com

Locations

China

the First Affiliated Hospital of Nanjing Medical University; Recruiting

Nanjing, China

Contact: Hailei Liu

Sponsors and Collaborators

The First Affiliated Hospital with Nanjing Medical University

More Information

• Responsible Party: Minglong Chen, Director of Heart Center, The First Affiliated Hospital with Nanjing Medical University
• ClinicalTrials.gov Identifier: NCT06125925
• Other Study ID Numbers: 2023-SR-659
• First Posted: November 9, 2023
• Last Update Posted: December 11, 2023
• Last Verified: December 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Minglong Chen, The First Affiliated Hospital with Nanjing Medical University:

atrial fibrillation; HFpEF; radiofrequency catheter ablation; drug therapy

Additional relevant MeSH terms:

Heart Failure; Atrial Fibrillation; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Pathologic Processes