ACE-AF is a multicenter randomized study in people aged 78 years and older with symptomatic atrial fibrillation (AF). AF is a common heart rhythm disorder in older adults and can cause reduced quality of life and lead to serious complications such as stroke and heart failure.

The study compares two established treatment strategies:

1. Catheter ablation (an invasive procedure aimed at reducing AF by electrically isolating triggers in the heart, primarily through pulmonary vein isolation), and
2. Optimized medical therapy without AF ablation (medications for rate and/or rhythm control; AV node ablation with pacemaker may be used if clinically indicated according to routine care).

Participants are randomized 1:1 to one of these strategies. All participants will receive an implantable loop recorder (a small heart rhythm monitor placed under the skin) to continuously track heart rhythm and measure AF burden over time.

The study has two co-primary outcomes assessed over 24 months:

1. a composite of major clinical events (all-cause mortality, stroke, major bleeding, cardiac arrest, or hospitalization due to heart failure), and
2. patient-reported health-related quality of life (HRQoL), measured by the SF-36 "General Health" domain.

ACE-AF will provide evidence to guide treatment decisions for very elderly patients with symptomatic AF and help identify which patients benefit most from an ablation-based strategy compared with optimized medical therapy.

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 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 Charlson comorbidity index.

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.

Randomisation (1:1): central, concealed allocation; stratified by sex and Charlson comorbidity index.

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.

ILR implantation for continuous monitoring according to protocol-defined timing/workflow.

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 (co-primary; multiplicity controlled)

Co-primary 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 SF-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 SF-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 co-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). Data are pseudonymised and processed in compliance with GDPR, with data captured in an electronic CRF (REDCap).

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.

Individual participant data (IPD) sharing has not yet been finalised. The steering committee will define an IPD-sharing plan prior to (or in connection with) publication of the primary results, with the intention to enable data access under controlled conditions for qualified researchers.

Open-label due to the nature of the interventions (catheter ablation vs optimized medical therapy). Endpoint definitions and event documentation are standardized per protocol.