Substrate Versus Trigger Ablation for Paroxysmal Atrial Fibrillation

Study Overview
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Brief Summary
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This is a prospective randomized study to assess the safety and efficacy of FIRM (Focal Impulse and Rotor Modulation)-guided ablation for the treatment of symptomatic atrial fibrillation (AF). The study hypothesis is that the efficacy of AF elimination at 1 year will be higher by ablating patient-specific AF-sustaining rotors and focal sources by Focal Impulse and Rotor Modulation (FIRM) compared to conventional ablation alone (wide-area PV isolation).

Detailed Description
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Pulmonary vein isolation (PVI) is a standard of care therapy for atrial fibrillation (AF). However, it produces suboptimal results, with a single procedure success of 45-55%, and multiple procedure success rates of 65-75% in recent randomized trials. The rationale of PVI is to eliminate triggers from the Pulmonary veins. An alternative strategy is to eliminate the substrates that sustain AF after it has been triggered, as applied to other arrhythmias. However, the relevance of AF substrates - at least in persistent AF - has been questioned with the recent STAR-AF-II trial, in which ablating at additional lines or complex atrial electrograms (CFAE) did not improve the success of PVI alone (Verma et al., 2015) - although success remained at  50% for a single procedure. Because of STAR-AF2, the PVI limb in this trial will be PVI alone (wide area circumferential ablation) with no additional lesions. Focal Impulse and Rotor Modulation (FIRM) is a novel approach to eliminate specific electrical substrates for AF, demonstrated in studies from many laboratories to take the form of localized electrical circuits. These rotors and focal sources lie in patient-specific locations, often away from typical PVI ablation sites and in right atrium, and ablating them has substantially improved the single procedure success rate of PVI in several multi center non-randomized trials (Narayan, J Am Coll Cardiol. 2012; Miller, J Cardiovasc Electrophysiol. 2014). There is therefore equipoise in the literature between PVI alone, with a long-history but suboptimal results, and FIRM only, that is newer with potentially greater efficacy but without randomized trial data. This study will test both strategies in a randomized controlled fashion.

Official Title
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Substrate Ablation (Focal Impulse and Rotor Modulation) Compared to Pulmonary Vein Isolation to Eliminate Paroxysmal Atrial Fibrillation: A Randomized Clinical Trial

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Procedure: FIRM Ablation
* Procedure: Conventional AF ablation with PVI


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: male or female >21 years reported incidence of at least two documented episodes of symptomatic paroxysmal atrial fibrillation (AF) during the three months preceding trial entry (at least 1 episode documented by 12-lead ECG or ECG rhythm strip) women without childbearing potential or women of childbearing potential who are not pregnant per a serum HCG test refractory to at least one Class I or III anti-arrhythmic medications. Drug doses must be therapeutic and stable willingness, ability and commitment to participate in baseline and follow-up evaluations without participation in another clinical trial (unless documented approval received from both sponsors) oral anticoagulation required for those subjects who have a score of two or more based on the following criteria (CHAD score): Congestive heart failure (1 point) hypertention (1 point) age 75 years or older (2 points) diabetes (1 point) prior stroke or transient ischemic attack (2 points) vascular disease (1 point) age 65 years or older (1 point) sex category: female (1 point) patient is willing and able to remain on anti-coagulation therapy for a minimum of 3 months post procedure for all subjects, and potentially indefinitely post procedure if the patient has CHAD score >or=2 signed informed consent after a full discussion of the risks and benefits of both therapy arms, and the concept of randomization NYHA Class 0,I, II stable on medical therapy for > 3months left atrial diameter <or= 5.5cm LVEF >or=40% sustained AF during the procedure EXCLUSION CRITERIA: atrial fibrillation from a reversible cause (e.g., surgery, hyperthyroidism, pericarditis) cardiac or thoracic surgery within the past 180 days AF secondary to electrolyte imbalance, thyroid disease contraindication to Heparin Contraindication to Warfarin or other novel oral anticoagulants history of significant bleeding abnormalities history of significant blood clotting abnormalities, systemic thrombi or systemic embolization ASD closure device, LAA closure device, prosthetic mitral or tricuspid valve atrial clot/thrombus on imaging such as on a trans-esophageal echocardiogram (TEE) within 72 hours of the procedure intramural thrombus or other cardiac mass that may adversely effect catheter introduction or manipulation significant pulmonary embolus within 6 months of enrollment acute illness or active systemic infection or sepsis that may ordinarily warrant postponement of the procedure history of recent cerebrovascular disease (stroke or TIA) or systemic thromboembolism within < 6 months NYHA classes III, IV heart failure that is not stable on medical therapy pulmonary edema, that may make planned anesthesia or sedation difficult stable/unstable angina or ongoing myocardial ischemia myocardial infarction (MI) within the past three months structural heart disease of clinical significance including: congenital heart disease where the abnormality or its correction prohibit or increase the risk of ablation acquired heart disease that may increase risk of ablation, such as significant ventricular septal defect post myocardial infarction rheumatic valve disease, since this produces a unique AF phenotype extreme left atrial enlargement (LA volume index > 60 ml/m2) in whom PVI has low success and 55 mm baskets are too small for the atria cardiac transplantation or other cardiac surgery planned within the 12 month followup period of the trial life expectancy less than 12 months (the followup period of the trial) significant pulmonary disease (e.g., COPD) or any other disease that significantly increase the risk to the patient from sedation or anesthesia untreatable allergy to contrast media at time of ablation procedure, clinically significant abnormalities in serum potassium, sodium, magnesium or other electrolytes that affect the suitability of the patient for ablation at that time

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FIRM ablation<br>These patients will be treated by ablation of patient-specific rotors and focal sources (FIRM) alone. | Procedure: FIRM Ablation<br>* Substrate ablation for AF, via ablation of rotors and focal sources alone.<br>|
| Active Comparator: Conventional AF ablation with PVI<br>These patients will treated by conventional AF ablation by pulmonary vein isolation (PVI) alone. | Procedure: Conventional AF ablation with PVI<br>* Trigger Based Ablation for AF, using Pulmonary Vein Isolation alone.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long term success | Freedom from AF recurrence during 12 months after the initial AF ablation procedure, after an initial 3 month blanking (healing and stabilization) period | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-term freedom from AF/AT | Freedom from AF and atrial tachycardia (AT) during 12 months after the initial AF ablation procedure, after an initial 3 month blanking (healing and stabilization) period. Atrial tachycardias (AT) include those arising from atrial regions where ablation was performed (such as left atrial tachycardia) as well as from regions where ablation was not performed (such as typical cavotricuspid isthmus dependent atrial flutter). | 12 months | 
| Total ablation time | Time from first ablation lesion to the last lesion. Total ablation time will be recorded in all patients, measured as the cumulative application of energy from the first ablation lesion to the last lesion. These values will be compared between the FIRM-guided and conventional ablation groups. If ablation for AT/atrial flutter is pursued, this ablation time will be documented separately. | 1 day | 
| Quality of life (QOL) | Quantitative EuroQol EQ5D scores post-ablation will be compared to those pre-ablation at all time points separately and together (ANOVA). | 12 months | 
| Adverse events | Adverse events will be adjudicated by an independent Data and Safety Monitoring Board, who will determine whether they are or are not related to the procedure. The number and type of adverse events will be compared between FIRM-guided and conventional ablation groups. | 12 months | 
| Consistency of Sources At Repeat Ablation | Any patient with a recurrence who consents to restudy will have an assessment of whether rotors and focal sources lie at the same locations as they did at original study. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rotor, FIRM, Paroxysmal Atrial Fibrillation, Atrial tachyarrhythmia, Ablation, Contact mapping, Clinical trial, Signal processing.