Catheter Ablation Plus LAAO Versus Anticoagulation in Frail Elderly Patients With Atrial Fibrillation

Официальное название

Randomized Controlled Trial - Catheter Ablation Combined With Left Atrial Appendage Occlusion Versus Catheter Ablation Combined With Oral Anticoagulation for Elderly Frailty Patients With Atrial Fibrillation: Comparison of Efficacy and Safety

Обзор

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.

Подробное описание

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.

Вмешательства

• Устройство catheter ablation combined with LAAO (Left Atrial Appendage Occlusion)
  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 ≥
• Препарат Atrial Fibrillation Radiofrequency Ablation Only
  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.

Первичные конечные точки

• Incidence of Net Adverse Clinical Events (NACE) at 12 Months [Срок оценки: 12 months post-randomization]

Вторичные конечные точки (12)

• Incidence of All-Cause Mortality [Срок оценки: 12 months and 24 months post-randomization]
• Incidence of Cardiovascular Mortality [Срок оценки: 12 months and 24 months post-randomization]
• Incidence of Net Clinical Benefit (NCB) at 24 Months [Срок оценки: 24 months post-randomization]
• Incidence of Unplanned Readmission [Срок оценки: 12 months and 24 months post-randomization]
• Cumulative Incidence of Major Bleeding [Срок оценки: 24 months post-randomization]
• Cumulative Incidence of Thromboembolic Events [Срок оценки: 24 months post-randomization]
• Incidence of Non-major Bleeding [Срок оценки: 24 months post-randomization]
• Procedural Success Rate [Срок оценки: During the procedure and for the duration of the index hospitalization (up to 7 days post-procedure).]
• Total Procedure and Fluoroscopy Duration [Срок оценки: During procedure]
• Length of Index Hospital Stay [Срок оценки: 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 [Срок оценки: Baseline, 6, 12, 18, and 24 months post-randomization.]
• Change in Atrial Fibrillation Effect on Quality-of-Life (AFEQT) Questionnaire Score [Срок оценки: Baseline, 6, 12, 18, and 24 months post-randomization.]

Критерии участия

Inclusion Criteria: (1) Age ≥ 75 years. (2) Confirmed diagnosis of non-valvular atrial fibrillation (paroxysmal or persistent). (3) CHA2DS2-VASc score ≥ 3 (high risk of stroke) . (4) Procedure-related criteria: Sequential Group: Participants who have received catheter ablation for non-valvular AF within 90 to 180 days prior to randomization. One-stop Group: Participants who are scheduled to undergo clinically indicated catheter ablation within 10 days after randomization. (5) Judged by the investigator to be able to tolerate the defined antithrombotic drug regimen. (6) Suitable to undergo Transesophageal Echocardiography (TEE) or Pulmonary Vein Computed Tomography (CT). (7) Able and willing to sign the written informed consent form. (8) Willing to return for all scheduled follow-up visits and examinations. Exclusion Criteria: (1) Presence of thrombus in the left atrium or left atrial appendage identified on preoperative imaging (echocardiogram, pulmonary vein CT, etc). (2) Major bleeding event (per ISTH definition) within 14 days prior to randomization. Participants must be excluded if clinical sequelae persist or if interventions for the bleeding source are planned/pending, regardless of the time elapsed since the event. (3) Requirement for long-term oral anticoagulation (OAC) for reasons other than stroke risk reduction in AF (e.g., underlying hypercoagulable state) that would prevent OAC discontinuation post-device implantation. (4) Any cardiac or major non-cardiac intervention/surgery (excluding AF ablation and cardioversion) performed within 30 days prior to, or scheduled within 60 days after randomization. This includes but is not limited to Percutaneous Coronary Intervention (PCI) or other cardiac ablations. (5) Life expectancy < 2 years, malignancy, infectious endocarditis, uncontrolled infection, or physiological evidence of cardiac tamponade. (6) Clinical Frailty Scale (CFS) score of 1-3 (not frail) or 7-9 (severely frail/terminally ill). (7) Deemed unsuitable for long-term anticoagulation and/or antiplatelet therapy by the investigator due to bleeding risk, allergies, or other reasons. (8) Current participation in another clinical trial that interferes with this study, excluding mandatory government or purely observational registries. (9) Stroke or transient ischemic attack (TIA) within 60 days prior to randomization. (10) Documented myocardial infarction (NSTEMI or STEMI) within 90 days prior to randomization, regardless of intervention. (11) History of atrial septal defect (ASD) repair or presence of an ASD/Patent Foramen Ovale (PFO) occluder. (12) Presence of a mechanical prosthetic valve in any position. (13) Participants of childbearing potential who are pregnant or planning pregnancy during the study period. (14) Medical or anatomical contraindications to percutaneous catheter-based interventions. (15) Documented NYHA Class IV heart failure. (16) History of surgical left atrial appendage (LAA) closure.

Transthoracic Echocardiography (TTE) Specific Exclusions: (1) Low LVEF: Left ventricular ejection fraction (LVEF) < 30%. (2) Presence of pericardial effusion with a circumferential echo-free space > 5mm. (3) Presence of high-risk PFO associated with an atrial septal aneurysm (ASA) with an excursion or length > 15mm. (4) Presence of high-risk PFO with a large shunt (defined as appearance of microbubbles within 3 cardiac cycles and/or a substantial count of microbubbles). (5) Presence of moderate or severe mitral stenosis (mitral valve area < 1.5 cm2).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Guangdong Provincial People's Hospital — Гуанчжоу

Идентификаторы

NCT: NCT07441382 · 2025161

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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