Catheter Ablation Plus LAAO Versus Anticoagulation in Frail Elderly Patients With Atrial Fibrillation (CLEAR-AF)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Stroke; Hemorrhage; Frailty; Anticoagulants; Atrial Fibrillation (AF); Catheter Ablation; Atrial Appendage
• Intervention / Treatment: Device: catheter ablation combined with LAAO (Left Atrial Appendage Occlusion); Drug: Atrial Fibrillation Radiofrequency Ablation Only

Detailed Description

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
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yumei Xue, M.D.; Phone Number: 086 13570082363; Email: xymgdci@163.com
• Study Contact Backup: Name: Junrong Jiang, M.D.; Phone Number: 086 15817182813; Email: jrkgdci@163.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Guangdong Provincial People's Hospital
      • Contact: Yumei Xue, M.D.; Phone Number: 086 13570082363; Email: xymgdci@163.com
      • Contact: Junrong Jiang, M.D.; Phone Number: 086 15817182813; Email: jrkgdci@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: catheter ablation combined with LAAO; Participants will receive a combined intervention consisting of catheter ablation for rhythm control and percutaneous left atrial appendage occlusion (LAAO) for stroke prevention. These procedures may be performed either during the same operative session (One-Stop) or as separate. This strategy is used as an alternative to long-term oral anticoagulation in elderly patients with a high risk of bleeding.	Device: catheter ablation combined with LAAO (Left Atrial Appendage Occlusion); 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.; 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.
Active Comparator: Atrial Fibrillation Radiofrequency Ablation Only; Participants will receive standard-of-care treatment consisting of catheter ablation followed by long-term oral anticoagulation (OAC) for stroke prevention. This arm follows current clinical guidelines to evaluate baseline efficacy and safety outcomes compared to the device-based strategy.	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 months post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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).	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).	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).	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).	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.	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.	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.	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.	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.	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.	12 months and 24 months post-randomization

Collaborators and Investigators

• Sponsor: Guangdong Provincial People's Hospital
• Collaborators: Abbott (China)

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: January 25, 2026
• First Submitted That Met QC Criteria: February 25, 2026
• First Posted (Actual): March 2, 2026

Study Record Updates

• Last Update Posted (Actual): March 2, 2026
• Last Update Submitted That Met QC Criteria: February 25, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Stroke; Atrial Fibrillation; Catheter Ablation; Randomized Controlled Trial; Hemorrhage; Frailty; Aged; Anticoagulants; Left Atrial Appendage Closure
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Pathological Conditions, Signs and Symptoms; Frailty; Stroke; Atrial Fibrillation; Hemorrhage
• Other Study ID Numbers: 2025161

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in the article, after de-identification, will be shared with researchers whose proposed use of the data has been approved.
• IPD Sharing Time Frame: Beginning 6 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: Data will be available to researchers providing a methodologically sound proposal and with signed data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No