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.
