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 (AWARE-2)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation; Radiofrequency Catheter Ablation; Catheter Ablation
• Intervention / Treatment: Procedure: PVI-ONLY, CONTROL ARM; Procedure: PVI-PLUS ARM, INTERVENTIONAL ARM

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.

• Study Type: Interventional
• Enrollment (Estimated): 556
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Girish Nair, MD; Phone Number: 613-696-7272; Email: GNair@ottawaheart.ca
• Study Contact Backup: Name: Sonya Jancar; Phone Number: 19678 613-696-7000; Email: sjancar@ottawaheart.ca

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4W7
      • Recruiting
      • University of Ottawa Heart Institute
      • Contact: Girish Nair, MD; Email: GNair@ottawaheart.ca
      • Principal Investigator: Girish Nair, MD
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
      • Not yet recruiting
      • McGill University Health Center
      • Contact: Vidal Essebag, MD; Email: vidal.essebag@mcgill.ca
      • Principal Investigator: Vidal Essebag, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years on the date of consent for the trial.

2. 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.

3. Subjects must be able to provide informed consent.

Exclusion Criteria:

1. Persistent and permanent AF.
2. History of previous catheter or surgical ablation for AF, AFl, AT, Atrioventricular Nodal Reentrant Tachycardia (AVNRT), Atrioventricular Reentrant Tachycardia (AVRT).
3. Documented AVNRT, AVRT, AT or Atrial Flutter prior to enrolment in the trial.
4. Previous left atrial (LA) ablation or LA surgery.
5. Previous pulmonary vein stenosis or pulmonary vein stent.
6. Pre-existing hemi-diaphragmatic paralysis.
7. Active intracardiac thrombus.
8. Contraindication to systemic oral anticoagulation therapy
9. 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).
10. Reversible causes of AF (e.g., uncontrolled hyperthyroidism, within six months of cardiac surgery).
11. Left ventricular ejection fraction <35%.
12. NYHA Class 4 heart failure.
13. Hypertrophic cardiomyopathy
14. Significant valve disease (moderate or severe mitral/aortic stenosis or regurgitation).
15. Patients with mechanical mitral prosthetic valves
16. Known adverse reaction to adenosine.
17. Chronic Kidney Disease ≥ Stage 4.
18. Significant congenital heart disease (including atrial septal defects or pulmonary vein abnormalities; however, subjects with patent foramen ovale will not be excluded).
19. Pregnant subjects.
20. Cerebral ischemic event (stroke or transient ischemic attack) in the six months prior to consenting for the trial.
21. History of thromboembolic events in the 6 months preceding enrollment.
22. Currently participating or anticipated to participate in interventional clinical trials of drug, device or biologic agents that could affect the results of this trial.
23. Primary pulmonary hypertension
24. Rheumatic heart disease
25. Thrombocytosis, thrombocytopenia and other hypercoagulable states
26. Active systemic infection
27. Patients with life expectancy less than 12 months.
28. Unwilling or unable to comply fully with study procedures and follow-up.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: PVI-ONLY ablation; Pulsed Field Ablation (PFA), control arm	Procedure: PVI-ONLY, CONTROL ARM; PULSED FIELD ABLATION (PFA) PVI-ONLY STRATEGY: CONTROL ARM
Experimental: PVI-PLUS ablation; RADIOFREQUENCY CATHETER ABLATION (RFA), interventional arm	Procedure: PVI-PLUS ARM, INTERVENTIONAL ARM; RADIOFREQUENCY CATHETER ABLATION (RFA) PVI-PLUS : INTERVENTION ARM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Freedom from atrial fibrillation, atrial flutter or atrial tachycardia	AF, AFl or AT, symptomatic or asymptomatic lasting ≥ 30 seconds	61 to 730 days after ablation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ablation procedure duration	Catheter ablation procedure time	On day of ablation
Atrial fibrillation burden	Total duration of AF recorded on ambulatory monitoring/total duration of monitoring	730 days
Long-term rate of documented atrial fibrillation, atrial flutter or atrial tachycardia	Long-term rate of documented AF, AFl or AT lasting ≥ 30 seconds	730 days
Incidence of any ECG/ILR documented atrial fibrillation, atrial flutter or atrial tachycardia	Incidence of any ECG/ILR documented AF, AFl or AT (symptomatic or asymptomatic; lasting ≥ 30 seconds	First 60 days after catheter ablation
Fluoroscopic exposure	Fluoro time in minutes	On day of ablation
Composite Safety outcomes	Procedure Related Complications at any time including Stroke, PV stenosis, pericarditis, phrenic nerve palsy, cardiac perforation, atrio-esophageal fistula, major bleeding and/or death.	730 days
Emergency room visits or hospitalization due to recurrent atrial fibrillation, atrial flutter or atrial tachycardia	Emergency room visits or hospitalization due to recurrent atrial fibrillation, atrial flutter or atrial tachycardia	730 days
Repeat catheter ablation for atrial fibrillation, atrial flutter or atrial tachycardia	Repeat catheter ablation for atrial fibrillation, atrial flutter or atrial tachycardia	730 days
Quality of life scale	EuroQol 5-Dimension questionnaire (EQ-5D), scale of 0-100, higher is better perceived health.	12 and 24 months
Health Economic analyses	Health Economic analyses	730 days
Cumulative duration of Atrial Fibrillation, Atrial Flutter or Atrial Tachycardia (atrial burden)	Cumulative duration of AF, AFL or AT (atrial burden) from day 61 after interventions to end of follow-up	Day 61- Day 730
Comparison of primary outcome events between patients undergoing PVI-ONLY and PVI-PLUS	Comparison of primary outcome events (freedom from atrial fibrillation, atrial flutter or atrial tachycardia) between patients undergoing PVI only (due to lack of additional triggers/substrate) in the PVI-PLUS strategy and those in the PVI-ONLY group.	730 days
Fluoroscopic exposure	Total Air Kerma	On day of ablation
Fluoroscopic exposure	Dose Area Protocol.	On day of ablation
Quality of life scale	Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT), 0-100 score range, 100 - no impairment, and 0-very poor quality of life.	12 and 24 months
Quality of life scale	Canadian Cardiovascular Society Severity of Atrial Fibrillation (CCS-SAF), score range 0-4, higher score being worse symptoms, or greater impairment.	12 and 24 months

Collaborators and Investigators

• Sponsor: Ottawa Heart Institute Research Corporation
• Collaborators: Canadian Institutes of Health Research (CIHR); Abbott
• Investigators: Principal Investigator: Girish Nair, MD, Ottawa Heart Institute Research Corporation

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2030

Study Registration Dates

• First Submitted: March 23, 2021
• First Submitted That Met QC Criteria: March 26, 2021
• First Posted (Actual): March 30, 2021

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Pathological Conditions, Signs and Symptoms; Atrial Fibrillation
• Other Study ID Numbers: v21022021

Drug and device information, study documents

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