Atrial fibrillation (AF) is the most common arrhythmia, significantly increasing the risk of stroke, heart failure, hospitalization and death in patients. Studies have shown that standardized anticoagulation can effectively reduce the risk of stroke by 64% and the risk of death by 26% in AF patients. Therefore, both European and American guidelines recommend standardized oral anticoagulation (OAC) as an important treatment strategy for stroke prevention in AF patients. However, the use of OAC may also increase the risk of bleeding in patients. Results from large AF anticoagulation randomized trials show that the annual risk of anticoagulation-related bleeding mortality is 2% to 3%. Therefore, according to the guidelines recommendations, assessing the bleeding risk is necessary in patients with anticoagulant indications. Percutaneous left atrial appendage occlusion (LAAO) is a device-based therapy that aims to prevent ischemic stroke in patients with AF. For patients with contraindications to long-term anticoagulation therapy, LAAO can be considered as an alternative strategy to oral anticoagulation (Class II B recommendation) to prevent ischemic stroke and thromboembolism. Multiple studies have shown that LAAO is non-inferior to warfarin and novel oral anticoagulants in stroke prevention for non-valvular AF patients. Age is not only a risk factor for stroke but also an important risk factor for bleeding. In the elderly population, especially those with frailty, the risk factors for both stroke and bleeding are often increased. Currently, there is insufficient evidence to support the use of OAC in frail elderly patients with relative anticoagulant contraindications. Therefore, elderly AF patients may be one of the potential beneficiary groups for LAAO. However, most previous clinical studies on LAAO were based on small sample sizes to analyze their safety and efficacy, and clinical data on the safety and efficacy of LAAO in this high-risk population of elderly AF patients are still limited. To address this, the study aims to conduct a multicenter randomized controlled trial to compare the efficacy and safety of catheter ablation combined with LAAO versus catheter ablation combined with OAC in elderly AF patients with high bleeding risk, filling the gap in this research area. To address these limitations, this multicenter randomized controlled trial is designed to evaluate the efficacy and safety of catheter ablation combined with LAAO versus catheter ablation combined with OAC in elderly AF patients at high risk for bleeding. The primary objective of the study is to compare the 12-month incidence and time-to-occurrence of the composite clinical endpoint. This endpoint includes stroke/TIA, systemic embolism, ISTH-defined major bleeding. By establishing these metrics within the first year, the study aims to fill the current void in clinical evidence and provide a standardized treatment strategy for high-risk elderly patients. In addition to the primary endpoints, the study will conduct a comprehensive long-term evaluation extending to 24 months post-procedure to assess the durability of both treatment strategies. Secondary objectives include the assessment of perioperative safety, specifically focusing on serious intraoperative complications and major adverse events occurring within the first seven days after the LAAO procedure. The trial will also measure long-term rhythm control by tracking the rate of freedom from AF recurrence at the one-year and two-year marks. Furthermore, the study seeks to verify the hypothesized superiority of the ablation-plus-LAAO strategy in reducing the specific burden of anticoagulation-related major bleeding and stroke. Beyond clinical safety and efficacy, the trial will analyze the practical aspects of the two interventions, including procedural success rates, operation duration, fluoroscopy time, and the total duration of hospitalization. A critical component of the research involves identifying specific risk factors associated with complications, with a specialized focus on how frailty scores influence procedural tolerance and long-term prognosis. The study will further explore how different types of AF respond to the LAAO strategy and assess the impact of each treatment on non-major bleeding events. Ultimately, the trial aims to determine which strategy offers a superior improvement in the overall quality of life for elderly patients, thereby optimizing future clinical guidelines.
1. Study Framework and Design Rationale: This multicenter randomized controlled trial investigates the efficacy and safety of combining catheter ablation with Left Atrial Appendage Occlusion (LAAO) compared to catheter ablation plus long-term oral anticoagulation (OAC) in a frail elderly population. Given the technical and ethical complexities of blinding invasive surgical procedures and subsequent anticoagulation adjustments, an open-label design is utilized to facilitate individualized post-operative management that reflects real-world clinical practice. 2. Randomization, Enrollment, and Implementation: Following the signing of the written Informed Consent Form (ICF), potential participants enter a rigorous screening phase to ensure compliance with predefined inclusion and exclusion criteria. Eligible subjects (Target N=200) are randomly assigned in a 1:1 ratio to either the Research Group (Ablation + LAAC) or the Control Group (Ablation + OAC) via a centralized Interactive Web Response System (IWRS). The randomization sequence is generated using SPSS 26.0 with stratified block randomization, using the clinical trial institution as the stratification factor. To minimize bias, the interval between randomization and treatment initiation is strictly targeted to be less than 24 hours. The procedures are performed by operators with over 3 years of experience and a minimum of 100 successful AF ablation and LAAC cases to minimize operator-dependent bias. 3. Comprehensive Baseline and Clinical Assessments: A multidimensional baseline assessment is conducted, encompassing demographic data (BMI, lifestyle habits), clinical risk scores (CHA₂DS₂-VASc, HAS-BLED), and comprehensive geriatric assessments, including the Clinical Frailty Scale (CFS), cognitive function (MoCA/MMSE), and Activities of Daily Living (ADL). Detailed medical histories are recorded, including specific definitions for stroke types (TIA, RIND, CS), congestive heart failure (regardless of LVEF), peripheral vascular disease, and chronic kidney disease (eGFR \<60 mL/min/1.73m² per KDIGO guidelines). Laboratory evaluations at baseline include complete blood counts (WBC, Hb, PLT), coagulation markers (INR, PT, APTT), liver/renal functions, thyroid panels (FT3, FT4, TSH), and cardiac biomarkers (NT-ProBNP/BNP). 4. Surgical Procedures and Follow-up Regimen: Surgical parameters for catheter ablation (ablation site, power, temperature, and acute pulmonary vein isolation) and LAAC (device brand/size, stability, and residual shunt) are documented in detail. The structured follow-up schedule occurs at 1, 3, 6, 12, and 24 months post-operation. Efficacy and safety monitoring involve 12/15-lead ECGs at every visit and 24-hour Holter monitoring at months 3, 6, 12, and 24 to quantify AF burden and recurrences (duration ≥30s). Imaging studies including Transthoracic Echocardiography (TTE) are performed at 6, 12, and 24 months, while the Research Group undergoes Transesophageal Echocardiography (TEE) or Cardiac CT (CCT) at 3 and 12 months to assess device stability, residual shunts, and Device-Related Thrombus (DRT), which directly informs antithrombotic therapy adjustments. 5. Statistical Analysis Plan and Sample Size Rationale: As a pilot study, the sample size of 200 subjects (100 per group, including a 10%-15% anticipated dropout rate) is designed to estimate the parameters necessary for a future confirmatory trial rather than to provide definitive statistical power for the composite endpoint (stroke, systemic embolism, and ISTH-defined major bleeding). Statistical analysis will be performed using SPSS 26.0 based on the Intent-to-Treat (ITT) principle, utilizing the Full Analysis Set (FAS), Per-Protocol Set (PPS), and Safety Set (SS). Continuous variables will be compared using independent t-tests or non-parametric tests (Kruskal-Wallis), while categorical data will be analyzed via Chi-square or Fisher's Exact tests. Survival outcomes will be depicted using Kaplan-Meier curves and analyzed through Cox proportional hazard models or Fine-Gray competing risk models to account for non-cardiovascular mortality in the elderly population. Missing data for the primary endpoint will be handled using the Worst Case Carry Forward (WCCF) strategy and Tipping Point sensitivity analysis. 6. Safety Monitoring, Quality Control, and Ethical Oversight: The study adheres to the Declaration of Helsinki and GCP guidelines. An independent Blinded Clinical Endpoint Committee (CEC), composed of cardiologists and neurologists not involved in the study, will perform centralized adjudications of all suspected endpoint events (stroke, systemic embolism, major bleeding, and death) to ensure objectivity. Adverse events (AEs) are classified by severity (Mild, Moderate, Severe) and reported within 24 hours if categorized as Serious Adverse Events (SAEs). Strict quality control measures include Standard Operating Procedures (SOPs), regular site monitoring (CRA) with Source Data Verification (SDV), and independent audits to ensure data traceability and integrity. Protocol Deviations (e.g., visit window violations) and Protocol Violations (e.g., enrollment errors) are systematically recorded and reported to the Ethics Committee. 7. Data Management and Confidentiality: Data are captured via Electronic Case Report Forms (eCRFs) with double-entry verification. A detailed Data Management Plan (DMP) governs external data, query resolution, and database locking procedures. All subject information is treated as strictly confidential, identifiable only by subject codes, and accessible only to authorized researchers, ethics committees, and regulatory authorities. Data backups are performed weekly on secure cloud servers, and records will be preserved for at least 5 years following the conclusion of the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
200
1. Ablation: CPVI will be performed using the EnSite X system and HD Grid catheter. Additional linear ablation (e.g., mitral isthmus or roof lines) may be added based on the patient's atrial substrate if sinus rhythm is not restored. LAAO: An LAA closure device (Watchman FLX, LAmbre, or LACbes) will be implanted under TEE or ICE guidance. 2. Antithrombotic Regimen: Days 0-90: Participants receive OAC (NOAC or Warfarin). Day 90 to 12 Months: If imaging confirms no DRT and no residual leak ≥ 5 mm, therapy will be de-escalated (e.g., to aspirin monotherapy) at the investigator's discretion.
Atrial Fibrillation Radiofrequency Ablation: Procedures will be performed using the EnSite X 3D mapping system with an HD Grid high-density mapping catheter for atrial modeling, followed by pulmonary vein isolation using any approved ablation catheter. Linear ablation may be added if necessary. Guideline-directed oral anticoagulation (e.g., NOACs or warfarin) will be continued post-procedure.
Guangdong Provincial People's Hospital
Guangzhou, Guangdong, China
Incidence of Net Adverse Clinical Events (NACE) at 12 Months
NACE is defined as a composite endpoint consisting of stroke, systemic embolism, and major bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) criteria. The analysis will measure the time from randomization to the first occurrence of any event within this composite endpoint.
Time frame: 12 months post-randomization
Incidence of All-Cause Mortality
The percentage of participants who died from any cause during the follow-up period. All-cause mortality includes both cardiovascular and non-cardiovascular deaths.
Time frame: 12 months and 24 months post-randomization
Incidence of Cardiovascular Mortality
Death due to cardiovascular causes, including myocardial infarction, sudden cardiac death, heart failure, stroke, or other vascular causes. Any death for which a non-cardiovascular cause cannot be identified will also be classified as cardiovascular death.
Time frame: 12 months and 24 months post-randomization
Incidence of Net Clinical Benefit (NCB) at 24 Months
NCB is defined as a composite endpoint consisting of stroke, systemic embolism, major bleeding (according to ISTH criteria), and all-cause mortality. The analysis will measure the time from randomization to the first occurrence of any event within this composite endpoint at 24 months.
Time frame: 24 months post-randomization
Incidence of Unplanned Readmission
The incidence of unplanned rehospitalization, including cardiovascular-related hospitalizations (e.g., heart failure, arrhythmia) and bleeding-related hospitalizations.
Time frame: 12 months and 24 months post-randomization
Cumulative Incidence of Major Bleeding
The cumulative incidence of major bleeding events related to antithrombotic therapy, defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria. This includes fatal bleeding, symptomatic bleeding in a critical area or organ, and bleeding causing a fall in hemoglobin level of 20 g/L or more.
Time frame: 24 months post-randomization
Cumulative Incidence of Thromboembolic Events
The cumulative incidence of thromboembolic events, including ischemic stroke, systemic embolism, and device-related thrombosis (DRT) as confirmed by imaging.
Time frame: 24 months post-randomization
Incidence of Non-major Bleeding
The percentage of participants experiencing non-major bleeding events, defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria, which do not meet the definition of major bleeding but require medical intervention or clinical attention.
Time frame: 24 months post-randomization
Procedural Success Rate
The percentage of participants who successfully undergo both atrial fibrillation ablation and left atrial appendage closure (LAAC) device implantation. Success is defined as stable device position with no major complications and no residual peridevice leak (or leak \< 5mm) confirmed by imaging.
Time frame: During the procedure and for the duration of the index hospitalization (up to 7 days post-procedure).
Total Procedure and Fluoroscopy Duration
The total time from initial vascular access (puncture) to the removal of all catheters from the body, as well as the total duration of X-ray fluoroscopy exposure during the intervention.
Time frame: During procedure
Length of Index Hospital Stay
The total number of days the participant remains hospitalized from the date of admission for the index procedure until the date of discharge.
Time frame: From the day of admission for the index procedure through the day of discharge, assessed up to 24 months .
Change in Clinical Frailty Scale (CFS) Score
Assessment of global frailty using the Clinical Frailty Scale (CFS). This judgment-based tool uses descriptions and icons to categorize frailty. The score ranges from 1 (Very Fit) to 9 (Terminally Ill). Higher scores indicate a worse clinical outcome (greater frailty).
Time frame: Baseline, 6, 12, 18, and 24 months post-randomization.
Change in Atrial Fibrillation Effect on Quality-of-Life (AFEQT) Questionnaire Score
The change in the AFEQT total score from baseline to 12 months and 24 months. The AFEQT is a 20-item validated instrument used to assess health-related quality of life in patients with atrial fibrillation. The score ranges from 0 (worst) to 100 (best).
Time frame: Baseline, 6, 12, 18, and 24 months post-randomization.
Change in Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) Scores
Assessment of functional independence using the Barthel Index for ADL (Basic Activities) and the Lawton Scale for IADL (Instrumental Activities). The Barthel Index ranges from 0 to 100, and the Lawton IADL typically ranges from 0 to 8. For both scales, higher scores indicate a better clinical outcome (greater independence).
Time frame: Baseline, 6, 12, 18, and 24 months post-randomization.
Change in Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA) Score
Assessment of cognitive impairment using the Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA). The MMSE total score ranges from 0 to 30, and the MoCA total score ranges from 0 to 30. For both instruments, higher scores indicate a better clinical outcome (better cognitive function).
Time frame: Baseline, 6, 12, 18, and 24 months post-randomization.
Modified Rankin Scale (mRS) Score Following Stroke Event
Assessment of disability or dependence in participants who experience a stroke during the study. The scale ranges from 0 (no symptoms) to 6 (dead). Higher scores indicate greater disability.
Time frame: At stroke occurrence (up to 2 years)
National Institutes of Health Stroke Scale (NIHSS) Score Following Stroke Event
A tool to measure stroke-related neurological impairment in participants who experience a stroke event. Total score ranges from 0 to 42, with higher scores indicating more severe impairment.
Time frame: At stroke occurrence (up to 2 years)
Days Alive and Out of Hospital (DAOH) within 12 Months
DAOH represents a composite measure of mortality and morbidity. It is calculated as the total number of days a participant is alive and not hospitalized during the first 12 months (365 days) after randomization. Any day spent in a hospital or a skilled nursing facility, or any day after death, is excluded from DAOH.
Time frame: From randomization up to 12 months
Incidence of Major Adverse Cardiovascular Events (MACE) by Atrial Fibrillation Subtypes
Comparison of MACE incidence between participants with paroxysmal atrial fibrillation (pAF) and persistent atrial fibrillation (perAF). MACE is defined as a composite of cardiovascular death, stroke, and systemic embolism.
Time frame: From randomization up to 24 months
Incidence of Acute Major Adverse Events (MAE)
The incidence of serious intraoperative complications and MAE within 7 days post-procedure. MAE includes, but is not limited to, symptomatic pericardial effusion/tamponade, stroke, systemic embolism, major bleeding (per ISTH criteria), or procedure-related death.
Time frame: From the index procedure up to 7 days
Incidence of Atrial Arrhythmia Recurrence
Recurrence is defined as any documented episode of atrial fibrillation (AF), atrial flutter (AFL), or atrial tachycardia (AT) lasting more than 30 seconds. These episodes must be confirmed by electrocardiogram (ECG) or Holter monitoring following a 3-month blanking period post-ablation. The 3-month blanking period allows for post-procedural healing and stabilization, and arrhythmias occurring during this time are not counted as recurrences.
Time frame: 12 months and 24 months post-randomization
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