Catheter Ablation vs Conservative Care in Elderly Patients With Atrial Fibrillation

Background and Rationale

Atrial fibrillation (AF) is highly prevalent in very elderly individuals and is associated with substantial morbidity, including stroke, heart failure (HF), recurrent hospitalisations, polypharmacy, frailty, and impaired health-related quality of life (HRQoL). Catheter ablation is an established rhythm-control therapy in AF, but patients aged ≥78 years have been under-represented in randomised trials, and evidence on comparative effectiveness and safety versus optimised medical therapy in this age group remains limited. ACE-AF is designed to address this knowledge gap using a pragmatic randomised strategy design and continuous rhythm monitoring in both arms.

Study Design

ACE-AF is an investigator-initiated, multicentre, parallel-group, open-label randomised controlled trial conducted at seven Swedish university hospitals and collaborating centres in Denmark, Australia and Greece. Participants aged ≥78 years with symptomatic paroxysmal or persistent AF are randomised 1:1 to an ablation-based strategy or to optimised medical therapy without AF ablation.

Randomisation is performed centrally using an electronic system with allocation concealment until assignment, stratified by sex and age group (78-83 vs >83 years).

Study Arms and Interventions

Arm A: Catheter ablation strategy Catheter ablation is performed according to contemporary clinical practice at experienced centres.

Pulmonary vein isolation (PVI) is prioritised as the primary ablation strategy. Energy source and tools are selected according to local practice and operator discretion, without restriction to a specific technology.

Periprocedural management (imaging, anticoagulation, anaesthesia strategy) follows local standards of care and the study protocol.

Arm B: Optimised medical therapy strategy (no AF ablation) Guideline-directed rate and/or rhythm control tailored to clinical need, including antiarrhythmic drugs and/or cardioversion when appropriate.

AV-node ablation with pacemaker implantation is permitted when clinically indicated, according to standard care.

Treatment optimisation and follow-up adhere to protocol-defined principles and local clinical routines.

Rhythm monitoring (both arms)

All participants receive an implantable loop recorder (ILR) to enable continuous rhythm monitoring, including quantification of AF burden and detection of clinically relevant arrhythmias over time (ILR programming per protocol).

Study Flow and Follow-up

Screening/Baseline (pre-randomisation/visit 1): informed consent; baseline clinical assessment including comorbidity profiling; baseline questionnaires and planned assessments per protocol.

ILR implantation for continuous monitoring will be performed according to protocol-defined timing/workflow between the first and second visit.

Randomisation (1:1): central, concealed allocation; stratified by sex and age group (78-83 vs >83 years).

Intervention phase (visit 2):

Ablation arm: catheter ablation performed as per protocol and site standards. Control arm: initiation/optimisation of medical therapy; AV-node ablation with pacing permitted if clinically indicated.

Follow-up visits: scheduled follow-up visits are performed at approximately 3, 12, 18 and 24 months after randomisation/intervention, with continuous ILR surveillance throughout follow-up. At follow-up, clinical events, adverse events, treatment changes, and patient-reported outcomes are collected according to protocol, and ILR rhythm summaries are reviewed.

Primary Outcomes (two primary endpoints, tested with Holm-Bonferroni multiplicity control.)

The endpoints are evaluated over 24 months after randomisation and controlled for multiplicity using the Holm-Bonferroni procedure:

Composite clinical endpoint: all-cause mortality, stroke, serious bleeding, cardiac arrest, or hospitalisation due to heart failure within 24 months after randomisation.

HRQoL endpoint: effect on HRQoL measured by the RAND-36 "General Health" domain.

Secondary Outcomes

Secondary outcomes include (as specified in the protocol):

AF burden and rhythm outcomes (ILR-derived): AF burden over time, recurrence patterns, and detection of clinically relevant rhythm events.

Healthcare utilisation: hospitalisations and AF/HF-related care contacts.

Patient-reported outcomes: symptom burden and HRQoL using validated instruments (including RAND-36 and additional AF-related questionnaires per protocol).

Safety outcomes: procedure-related and treatment-related complications and serious adverse events.

Treatment pathways: need for cardioversion, medication escalation, AV-node ablation with pacing, and crossover patterns (as applicable).

Exploratory Objectives and Planned Subgroup/Modifier Analyses

Exploratory analyses will examine whether treatment effects differ by baseline characteristics and geriatric domains, including:

Frailty (e.g., Frailty Index and/or Clinical Frailty Scale).

Cognitive status (protocol-defined assessment).

Inflammatory biomarkers and overall comorbidity burden.

Sex (sex-disaggregated reporting and interaction analyses).

AF type (paroxysmal vs persistent).

Imaging substudy (selected Swedish sites): a predefined subgroup (e.g., at Karolinska and Linköping) planned for brain and/or cardiac imaging with MRI and/or CT per protocol to explore mechanistic associations.

Saliva sampling (optional subgroup): in a predefined subgroup, saliva is collected for exploratory biomarker/genetic analyses relevant to ageing and treatment response (separate consent; optional participation).

If subgroup analyses are underpowered, results will be reported as exploratory.

Sample Size and Statistical Considerations

The planned sample size is 282 participants, providing adequate power to detect clinically meaningful differences over 24 months, accounting for crossover and loss to follow-up. Primary analyses are performed according to the intention-to-treat principle. Multiplicity across the two primary endpoints is addressed using a pre-specified Holm-Bonferroni approach.

Safety Oversight

Participant safety is overseen by an independent Data Monitoring Committee (DMC), comprising senior cardiology researchers independent of the study (Professor Eva Swahn, Professor Lars Lund, and Professor Johan Engdahl). Safety monitoring and adverse event reporting are conducted throughout the study according to the protocol.

Ethics, Regulatory, and Data Protection

The study has been approved by the Swedish Ethical Review Authority (Dnr 2025-02305-01; decision date 12 May 2025); amendment approved 19 May 2026 (Dnr 2026-02894-02). Data are pseudonymised and processed in compliance with GDPR, with data captured in an electronic CRF (REDCap).

• Catheter Ablation for Atrial Fibrillation (Procedure), also known as catheter ablation, pulmonary vein isolation: Catheter ablation for symptomatic atrial fibrillation with pulmonary vein isolation (PVI) prioritized as the primary lesion set. Energy source and tools are selected according to local practice and operator discretion (no restriction to a specific technology), performed under routine standards of care at experienced centres.
• Optimized Medical Therapy for Atrial Fibrillation (Drug), also known as Guideline-directed medical therapy, Rate control, Rhythm control: Guideline-directed rate and/or rhythm control tailored to the participant's clinical condition, including rate-control medications and/or antiarrhythmic drugs and cardioversion when clinically appropriate. AF ablation is not performed as part of this strategy.
• Implantable Loop Recorder (ILR) (Device): Subcutaneous implantable loop recorder used for continuous rhythm monitoring and quantification of atrial fibrillation burden throughout follow-up. Implanted in all participants according to protocol-defined workflow.
• AV Node Ablation With Pacemaker implantation (Procedure): AV node ablation with permanent pacing may be performed when clinically indicated according to routine care, as part of the optimized medical therapy strategy.

Primary outcomes

• Composite clinical endpoint (all-cause mortality, stroke, serious bleeding, cardiac arrest, or heart failure hospitalization) [24 months after intervention (visit 2)]: First part of the co-primary outcome: Proportion of participants with ≥1 of the following events within 24 months after intervention (visit 2): all-cause death, stroke, serious bleeding, cardiac arrest, or hospitalization for heart failure. Events will be adjudicated per protocol.
• Change in RAND-36 General Health score [Baseline to 24 months after intervention (visit 2)]: Second part of the co-primary outcome: Change from baseline in the RAND-36 "General Health" domain score at 24 months after the intervention (visit 2). Scores range 0-100; higher scores indicate better perceived health. Intention-to-treat. Because HRQoL is undefined after death, scores are not imputed for participants who die before the 24-month assessment; instead, deceased participants are assigned the worst rank (worst-rank / composite estimand, ICH E9(R1)) and the primary comparison uses a rank-based test. Missing data other than death are handled under a missing-at-random assumption with pre-specified sensitivity analyses.

Secondary outcomes

• Differences of atrial fibrillation and atrial tachycardia burden (ILR-derived) between groups [From date of ILR implantation (intervention day, visit 2) up to 30 months after implantation.]: Differences in percentage of time in atrial fibrillation and atrial tachycardia ("AF/AT burden") measured by continuous monitoring using an implantable loop recorder (ILR) between randomization groups.
• Hospitalizations (all-cause and cardiovascular) [Up to 24 months after intervention]: Number of hospital admissions, including cardiovascular/AF-related hospitalizations, collected from clinical records.
• Serious adverse events and treatment-related complications [Up to 24 months after intervention]: Serious adverse events (SAEs) and procedure-/treatment-related complications, including ablation-related and device-related complications, recorded and classified per protocol.
• Additional patient-reported outcomes (AF symptoms / disease-specific HRQoL) [Baseline and follow-up (3, 12, 18) through 24 months after intervention]: Symptom burden and AF-related quality of life assessed using validated questionnaires specified in the protocol (e.g., ASTA and/or AFEQT, as applicable).
• Changes in Left atrial reservoir strain (LASr) [Up to 12 months after intervention (visit 2)]: Left atrial function assessed as reservoir strain (LASr) by deformation imaging (speckle-tracking / deformation tracking, as per protocol). Reported as change from baseline to follow-up. Unit of measure: %
• Cognitive function measured by Montreal Cognitive Assessment (MoCA) [MoCA scores will be collected and assessed at baseline, 12, 18, and 24 months after intervention (visit 2).]: MoCA total score assessed at follow-up visits. Reported as change from baseline
• Frailty score assessed by e-Frailty index [Up to 24 months after intervention; visit 2 ( 12, 18, and 24 months)]: Frailty will be assessed using the e-Frailty index at baseline and follow-up. The outcome will be reported as a change in score from baseline to each follow-up time point.
• Discrimination of a prediction model for the ACE-AF primary composite outcome [From baseline up to 24 months after intervention (visit 2).]: A multivariable prediction model (using baseline clinical variables and AI-derived features) will be developed to predict the time to first occurrence of the ACE-AF primary composite clinical outcome.
• Predictors of differential treatment effect on AF/AT burden [From implantation (visit 2) up to 30 months after intervention]: Baseline clinical variables (and AI-derived features, as available) will be evaluated as predictors of differential treatment effect on ILR-derived atrial fibrillation and atrial tachycardia (AF/AT) burden over follow-up.
• Participants with at least one event in the composite neurological endpoint (dementia, stroke, intracranial hemorrhage) [Up to 24 months after intervention (visit 2).]: Composite neurological endpoint defined as the first occurrence of any of the following during follow-up: 1. Incident dementia 2. Stroke (ischemic or hemorrhagic) 3. Intracranial hemorrhage (including intracerebral hemorrhage and subarachnoid hemorrhage, per protocol definition) Results will be reported as number and percentage of participants with ≥1 composite event during follow-up.
• Total healthcare costs per participant [Up to 24 months after intervention (visit 2)]: Total direct healthcare costs per participant from intervention through follow-up, derived from healthcare utilization data (e.g., hospital inpatient/outpatient visits, procedures, emergency visits) and valued using standard regional/national tariffs per the health-economic analysis plan. Reported as mean/median cost per participant by group.
• All-cause mortality, stroke/TIA, serious bleeding, cardiac arrest, hospitalization due to heart failure analyzed separately [Up to 24 months after intervention]
• Incident dementia [Up to 24 months after intervention (visit 2)]: Proportion of participants with a new diagnosis of dementia during follow-up, based on predefined diagnostic criteria and/or registry/medical record confirmation.

Other outcomes

• Discrimination of an inflammation proteomics-based prediction model for the ACE-AF primary composite outcome [Up to 24 months after intervention (visit 2).]: A predefined subgroup of patients included in the County of Stockholm and Östergotland will be analyzed using a targeted inflammation proteomics panel. A prespecified inflammation proteomics score will be computed from the panel. The score combined with baseline clinical covariates will be used to develop a prediction model for time to first occurrence of the ACE-AF primary composite outcome event.
• Correlation between change in Epicardial fat and the combined AF/AT burden [From implantation (visit 2) up to 24 months after the intervention]: Correlation between CT-derived Epicardial fat volume around LA the combined AF/AT burden measured by ILR through follow-up.
• Discrimination of a saliva proteomics-based prediction model for the primary composite outcome [Baseline through 24 months after intervention]: In a predefined subgroup providing separate consent, saliva samples will be analyzed using a proteomics platform. A prespecified salivary proteomics score will be used to develop a prediction model for the first occurrence of the study primary composite outcome event from baseline.
• Change from baseline in oral health-related quality of life (OHIP-14 total score) [Up to 12 months after baseline visit]: Patient-reported oral health-related quality of life measured using the Swedish version of the Oral Health Impact Profile (OHIP-14). The outcome will be reported as change from baseline in OHIP-14 total score.

Sex: All, ages: 78 Years to any

Inclusion Criteria:

1. Age ≥78 years.
2. ECG-documented atrial fibrillation.
3. AF type: paroxysmal, persistent, or longstanding persistent AF.
4. Suitable candidate for catheter ablation according to ESC guidelines.
5. Charlson's comorbidity index ≤7.

Exclusion Criteria:

1. Left atrial (LA) dimension >55 mm, based on echocardiography within the previous year.
2. Acute coronary syndrome or coronary artery bypass surgery within the last 12 weeks.
3. Severe valvular heart disease (per ESC definitions) or congenital heart disease.
4. Prior surgical or catheter AF ablation procedure, or prior AV-node (atrioventricular nodal) ablation.
5. Contraindication to oral anticoagulation.
6. AF due to a reversible cause.
7. Medical condition likely to limit survival to <12 months.
8. Unable or unwilling to provide informed consent.
9. History of non-compliance with medical therapy.
10. BMI <18 or >37 kg/m².

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• Emmanouil Charitakis, MD, PhD, Principal investigator, Karolinska University Hospital

NIH grants: 2025