Randomized Controlled Trial- Ablation Strategy for Paroxysmal Atrial Fibrillation - Trigger and Substrate Guided Wide Area Radiofrequency Ablation Compared to Pulsed Field Ablation Pulmonary Vein Isolation

Official title

AWARE-2 - Randomized Controlled Trial Ablation Strategy for Paroxysmal Atrial Fibrillation - Trigger and Substrate Guided Wide Area Radiofrequency Ablation Compared to Pulsed Field Ablation Pulmonary Vein Isolation

Overview

Atrial fibrillation (AF) is a common heart rhythm disorder affecting over a million people in North America and is associated with serious complications including stroke, heart failure, reduced quality of life, and premature death. Catheter ablation has been shown to be more effective than medications for controlling symptoms and reducing the risk of these complications; however, recurrence of AF after ablation remains a significant challenge, often due to incomplete or ineffective initial procedures. This clinical trial aims to determine whether a novel, patient-tailored ablation strategy can improve outcomes compared to the current standard-of-care approach. Participants will be randomly assigned to undergo either standard pulmonary vein isolation or a more individualized ablation procedure that identifies and targets patient-specific sources of AF. All participants will undergo the ablation procedure, receive continuous heart rhythm monitoring, and be followed over time to assess recurrence and safety outcomes.

Detailed description

This study is a randomized controlled trial evaluating two different catheter ablation strategies for patients with paroxysmal atrial fibrillation (AF). Participants are randomly assigned in a 1:1 ratio to either the control arm or the experimental arm prior to undergoing their ablation procedure. In the control arm, patients receive a pulmonary vein isolation (PVI)-only strategy using pulsed field ablation (PFA). This approach targets only the pulmonary veins, which are the most common source of AF triggers, and does not include additional ablation beyond isolating these veins. In contrast, the experimental arm uses a more comprehensive PVI-PLUS strategy with radiofrequency ablation (RFA). In addition to standard pulmonary vein isolation, this strategy includes patient-specific ablation of non-pulmonary vein triggers and abnormal atrial substrate, such as low-voltage areas identified during electrophysiologic testing. This individualized approach aims to reduce arrhythmia recurrence by addressing additional sources of AF beyond the pulmonary veins.

All participants undergo their assigned catheter ablation procedure as part of routine clinical care, with procedural details tailored according to the randomized strategy. Following the ablation, patients receive an implantable loop recorder (ILR), which is a small device placed under the skin that continuously monitors heart rhythm. The ILR allows for continuous, long-term detection of atrial arrhythmias, including both symptomatic and asymptomatic episodes, ensuring accurate assessment of treatment outcomes throughout the study period.

Participants are followed closely for a total of 24 months after the ablation procedure. During this follow-up period, patients attend scheduled visits at 2, 6, 12, 18, and 24 months, where ILR data are reviewed and clinical assessments are performed. The continuous monitoring provided by the ILR is central to evaluating the study's primary and secondary outcomes, including recurrence of atrial fibrillation, atrial flutter, or atrial tachycardia. In addition to rhythm monitoring, patients complete quality-of-life questionnaires at baseline and at 24 months, and any repeat procedures, hospital visits, or complications are recorded. This structured follow-up ensures comprehensive evaluation of both the effectiveness and safety of the two ablation strategies over time.

Interventions

• Procedure PVI-ONLY, CONTROL ARM
  PULSED FIELD ABLATION (PFA) PVI-ONLY STRATEGY: CONTROL ARM
• Procedure PVI-PLUS ARM, INTERVENTIONAL ARM
  RADIOFREQUENCY CATHETER ABLATION (RFA) PVI-PLUS : INTERVENTION ARM

Primary outcome measures

• Freedom from atrial fibrillation, atrial flutter or atrial tachycardia [Time frame: 61 to 730 days after ablation]

Secondary outcome measures (12)

• Atrial fibrillation burden [Time frame: 730 days]
• Long-term rate of documented atrial fibrillation, atrial flutter or atrial tachycardia [Time frame: 730 days]
• Incidence of any ECG/ILR documented atrial fibrillation, atrial flutter or atrial tachycardia [Time frame: First 60 days after catheter ablation]
• Ablation procedure duration [Time frame: On day of ablation]
• Fluoroscopic exposure [Time frame: On day of ablation]
• Composite Safety outcomes [Time frame: 730 days]
• Emergency room visits or hospitalization due to recurrent atrial fibrillation, atrial flutter or atrial tachycardia [Time frame: 730 days]
• Repeat catheter ablation for atrial fibrillation, atrial flutter or atrial tachycardia [Time frame: 730 days]
• Quality of life scale [Time frame: 12 and 24 months]
• Health Economic analyses [Time frame: 730 days]
• Cumulative duration of Atrial Fibrillation, Atrial Flutter or Atrial Tachycardia (atrial burden) [Time frame: Day 61- Day 730]
• Comparison of primary outcome events between patients undergoing PVI-ONLY and PVI-PLUS [Time frame: 730 days]

Eligibility criteria

Inclusion criteria

• Age ≥18 years on the date of consent for the trial.
• Subjects must have paroxysmal AF with at least one episode of AF over the past 12 months (patients on antiarrhythmic medications do not need to satisfy this criterion).

At least one episode of AF documented on 12-lead ECG, Holter monitor, Trans-telephonic monitor (TTM) or Loop Recorder.

• Subjects must be able to provide informed consent.

Exclusion criteria

• Persistent and permanent AF.
• History of previous catheter or surgical ablation for AF, AFl, AT, Atrioventricular Nodal Reentrant Tachycardia (AVNRT), Atrioventricular Reentrant Tachycardia (AVRT).
• Documented AVNRT, AVRT, AT or Atrial Flutter prior to enrolment in the trial.
• Previous left atrial (LA) ablation or LA surgery.
• Previous pulmonary vein stenosis or pulmonary vein stent.
• Pre-existing hemi-diaphragmatic paralysis.
• Active intracardiac thrombus.
• Contraindication to systemic oral anticoagulation therapy
• Current immunosuppressant therapy (corticosteroids, biologic immunomodulators; such patients may be considered if they can safely discontinue immunosuppressants for three months prior to and for three months following catheter ablation).
• Reversible causes of AF (e.g., uncontrolled hyperthyroidism, within six months of cardiac surgery).
• Left ventricular ejection fraction <35%.
• NYHA Class 4 heart failure.
• Hypertrophic cardiomyopathy
• Significant valve disease (moderate or severe mitral/aortic stenosis or regurgitation).
• Patients with mechanical mitral prosthetic valves
• Known adverse reaction to adenosine.
• Chronic Kidney Disease ≥ Stage 4.
• Significant congenital heart disease (including atrial septal defects or pulmonary vein abnormalities; however, subjects with patent foramen ovale will not be excluded).
• Pregnant subjects.
• Cerebral ischemic event (stroke or transient ischemic attack) in the six months prior to consenting for the trial.
• History of thromboembolic events in the 6 months preceding enrollment.
• Currently participating or anticipated to participate in interventional clinical trials of drug, device or biologic agents that could affect the results of this trial.
• Primary pulmonary hypertension
• Rheumatic heart disease
• Thrombocytosis, thrombocytopenia and other hypercoagulable states
• Active systemic infection
• Patients with life expectancy less than 12 months.
• Unwilling or unable to comply fully with study procedures and follow-up.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Canada · 2 centers

• University of Ottawa Heart Institute — Ottawa
• McGill University Health Center — Montreal

Identifiers

NCT: NCT04823299 · v21022021

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗