Patient Specific Ablation Strategy for Atrial Fibrillation (AWARE-2): A Randomized Clinical Trial (AWARE-2)

Ablation Strategy for Paroxysmal Atrial Fibrillation - Trigger and Substrate Guided Wide Area Radiofrequency Ablation Compared to Cryoablation Pulmonary Vein Isolation- Patient Specific Precise Approach to Paroxysmal Atrial Fibrillation Ablation AWARE-2 - Randomized Controlled Trial

Atrial Fibrillation (AF) is a heart rhythm disturbance that affects over a million people in North America. AF can cause strokes, heart failure, poor quality of life and may lead to premature death. Catheter ablation has been shown to be superior to medications for symptoms, prevention of stroke and heart failure. AF recurrence is a problem after catheter ablation. Our research has found that in most cases AF recurrence occurs because the catheter procedure was ineffective. The objective of our clinical trial is to find out if a new method of performing the catheter procedure will be more effective in preventing AF recurrence compared to the current standard of care ablation procedure. Subjects will be randomly allocated to undergo either the standard of care ablation, or the novel patient tailored ablation. The novel method aims to understand the unique factors responsible for AF in each individual and uses this information to perform a patient-tailored catheter ablation procedure. This is expected to improve the results of AF ablation. The effectiveness and safety of the ablation procedure will be specifically evaluated in women to understand the effect of sex on AF ablation.

Study Overview

• Status: Not yet recruiting
• Conditions: Atrial Fibrillation; Radiofrequency Catheter Ablation; Catheter Ablation
• Intervention / Treatment: Procedure: Cryoballoon ablation; Procedure: Radiofrequency catheter ablation +EPS guided trigger and substrate ablation

Detailed Description

Catheter ablation (CA) for paroxysmal atrial fibrillation (AF) is beset by the significant limitation of recurrent AF in one third of subjects. Subjects with recurrence of AF usually require repeat ablation procedures with the attendant risk of potentially serious complications and significant costs to the health care system. We hypothesize that an innovative, a patient specific precise CA strategy will significantly reduce AF recurrence.

This study will determine whether a precise, patient specific ablation strategy (tailored to the patient's triggers and substrate) combining electrophysiological (EPS) testing guided radiofrequency catheter ablation (RFA) for pulmonary vein isolation (PVI) using the wide-area circumferential (WACA) technique along with non-pulmonary vein trigger (NPVT) and low-voltage area (LVA) ablation will improve freedom from recurrent atrial fibrillation (AF) when compared to PVI alone strategy using cryoballoon ablation (CAB).

The PVI-WACA technique has a 'ceiling effect' due to PV reconnection, especially along the posterior wall of the LA as shown in an observational study investigating the pattern of PV reconnection from our institution. Further attempts at improving durable PVI rates with higher energy ablation may not be possible due to concerns regarding esophageal injury and development of atrio-esophageal fistula. It may be possible to improve the results of CA for paroxysmal AF by targeting NPVT and LVA that are not usually targeted during CA using the PVI-WACA only strategy.

This trial is a single-blinded (subjects blinded), prospective, parallel arm RCT. Subjects satisfying the inclusion and exclusion criteria will be randomized (1:1) to either the control arm (cryoballoon ablation) or the experimental arm (RF based WACA ± electrophysiological testing guided ablation of non-PV triggers of AF and low voltage area ablation). Randomization will be conducted after informed consent has been obtained and before catheter ablation. The first 60 days after catheter ablation will be considered a "blanking-period" and atrial tachyarrhythmias (AF, Atrial Flutter [AFl] or Atrial Tachycardia [AT]) occurring during this period will be documented. However, these will not be considered treatment failures. Subject accrual will occur over a 36-month period and each subject will have a minimum follow-up period of 24 months, with a total trial duration of 60-months. Subjects will be followed up at 2,6,12,18 and 24 months after ablation, with an implantable loop recorder (ILR) interrogation. Quality of life questionnaires (EQ-5D, AFEQT questionnaires and CCS-SAF scale) will be administered at baseline,12-months and 24 months post ablation visit. A tool to assist in decision making will be administered to subjects during the consent process.

• Study Type: Interventional
• Enrollment (Estimated): 390
• 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 6139797000; Email: sjancar@ottawaheart.ca

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4W7
      • University of Ottawa Heart Institute
      • Contact: Girish Nair, MD; Email: GNair@ottawaheart.ca
      • Principal Investigator: Girish Nair, MD
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
      • 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 two episodes of AF over the past 12 months; Early Persistent AF- at least two episodes of AF.
3. At least one episode of AF documented on 12-lead ECG, Holter monitor, Trans- telephonic monitor (TTM) or Loop Recorder.
4. 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, AVNRT, 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 or radiocontrast materials.
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 (eg. uncontrolled hyperthyroidism, within six months of cardiac surgery).
11. Left ventricular ejection fraction <35%.
12. NYHA Class 3-4 heart failure.
13. Hypertrophic cardiomyopathy with septal or posterior LV wall thickness of >1.8 cm.
14. Significant valve disease (moderate or severe mitral/aortic stenosis or regurgitation).
15. Known adverse reaction to adenosine.
16. Significant chronic kidney disease (eGFR <30ml/min/1.73m2).
17. Significant congenital heart disease (including atrial septal defects or pulmonary vein abnormalities; however, subjects with patent foramen ovale will not be excluded).
18. Pregnant subjects.
19. Cerebral ischemic event (stroke or transient ischemic attack) in the six months prior to consenting for the trial.
20. Life expectancy less than one-year.
21. Currently participating or anticipated to participate in clinical trials of drug, device or biologic agents that could affect the results of this trial.
22. 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: Cryoballoon ablation; Cryoballoon Pulmonary Vein Isolation-Wide area circumferential ablation (WACA)	Procedure: Cryoballoon ablation; Cryoballoon pulmonary vein isolation ablation
Experimental: RF based WACA ± EP testing guided ablation of non-PV triggers of AF and low voltage area ablation; Radiofrequency wide area circumferential ablation (WACA) ± electrophysiological testing guided ablation of non-pulmonary vein triggers of AF and low voltage area ablation	Procedure: Radiofrequency catheter ablation +EPS guided trigger and substrate ablation; RF based WACA ± electrophysiological testing guided ablation of non-PV triggers of AF and low voltage area ablation

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 365 days after ablation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Atrial fibrillation burden	Total duration of AF recorded on ambulatory monitoring/total duration of monitoring	760 days
Long-term rate of documented AF, AFl or AT	Long-term rate of documented AF, AFl or AT lasting ≥ 30 seconds	760 days
Incidence of any ECG/ILR documented AF, AFl or AT	Incidence of any ECG/ILR documented AF, AFl or AT (symptomatic or asymptomatic; lasting ≥ 30 seconds	First 60 days after catheter ablation
Ablation procedure duration	Catheter ablation procedure time	On day of ablation
Fluoroscopic exposure	Total Air Kerma (mGy)	On day of ablation
Fluoroscopic exposure dose	Dose Area Protocol (Gy.cm2)	On day of ablation
Procedure Related Complications	Stroke, PV stenosis, pericarditis, phrenic nerve palsy, cardiac perforation, atrio-esophageal fistula, major bleeding and/or death.	760 days
Emergency room visits or hospitalization due to recurrent AF, AFl or AT	Emergency room visits or hospitalization due to recurrent AF, AFl or AT	760 days
Repeat catheter ablation for AF, AFl or AT	Repeat catheter ablation for AF, AFl or AT	760 days
Quality of life scale	EQ-5D	12 and 24 months
Quality of life questionnaire	AFEQT questionnaire	12 and 24 months
Quality of life SAF scale	CCS-SAF scale	12 and 24 months

Collaborators and Investigators

• Sponsor: Ottawa Heart Institute Research Corporation
• Collaborators: University of British Columbia; McGill University
• Investigators: Principal Investigator: Girish Nair, MD, Ottawa Heart Institute Research Corporation

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

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): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; 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