Evaluation of Conventional Ablation With or Without Focal Impulse and Rotor Modulation to Eliminate Human AF

Randomized Evaluation of Conventional Ablation With or Without Focal Impulse and Rotor Modulation to Eliminate Human Atrial Fibrillation (RECONFIRM): A Randomized Clinical Trial

This prospective randomized study will assess the safety and efficacy of FIRM-guided ablation (FIRM+PVI) compared to pulmonary vein isolation (PVI) without FIRM, for the treatment of symptomatic atrial fibrillation.

Atrial fibrillation (AF) affects over 2 millions Americans. AF may reduce cardiac performance and may result in thrombus formation in the left atrium and thromboembolic events, such as stroke. Ablation to eliminate the causes of this arrhythmia is increasingly performed since pharmacological therapy is suboptimal. Ablation currently targets triggers, by ablating left atrial areas outside the pulmonary veins (pulmonary vein isolation, PVI) in subjects with symptomatic AF who have failed drugs. Unfortunately, this has mixed success with the best outcomes being 50-70% freedom from AF at 1 year post ablation.

A major issue with AF therapy is the lack of knowledge about critical regions of the heart that cause and sustain AF. A recent trial (STAR-AF2) showed that ablating regions empirically - i.e. without defining their role in AF(lines or fractionated electrograms) - did not improve patient outcomes compared to PVI alone (Verma et al, NEJM 2015). However, this leaves us with PVI that had a 50% success rate in that trial and in several other trials even for paroxysmal AF.

We hypothesize that guiding ablation to critical arrhythmia-targeting zones will improve success over PVI alone. Specifically, we hypothesize that computational mapping of AF will find small regions called rotors and focal sources and ablate them, called Focal Impulse and Rotor Modulation (FIRM) ablation, shows promise at eliminating AF substrates. In many single center trials, FIRM improves results from PVI alone. This will be among the first randomized comparisons of FIRM ablation compared to PVI alone, and addresses an important question in the field.

Inclusion Criteria:

1. Age >21 years

2. Reported incidence of at least two documented episodes of symptomatic paroxysmal or persistent atrial fibrillation (AF) during the 3 months preceding trial entry (at least one episode documented by 12-lead ECG or ECG rhythm strip). Ideally, patients will have implanted continuous ECG recorders in place for >30 days prior to the procedure to document AF episodes and percentage of time in AF ("burden") prior to ablation

3. Male -or- Women without childbearing potential (surgically sterile or have been without a period for 12 months), -or- Women of childbearing potential who are not pregnant per a serum HCG lab test

4. Refractory to at least one Class I or III anti-arrhythmic medications. Drug doses must be therapeutic and stable

5. 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)

6. Oral anticoagulation required for those subjects who have a score of two or more based on the following criteria (CHA2DS2VASc)

   • congestive heart failure (1 point)
   • hypertension (1 point)
   • age 75 years or older (2 points)
   • diabetes (1 point)
   • prior stroke or transient ischemic attack (2 points)
   • vascular disease (including coronary artery disease, CAD) (1 point)
   • age 65 years or older (1 point)
   • gender category: female (1 point) Pre-procedural anticoagulation will ideally have been continuous for 3 or more weeks prior to the procedure, as clinically indicated, with INR > 2 in patients taking warfarin.

7. 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 CHA2DS2VASc score >or= 2

8. Signed, informed consent after a full discussion of the risks and benefits of both therapy arms, and the concept of randomization

9. NYHA Class 0, I or II and stable on medical therapy for > 3 months

10. Left atrial diameter <or= 5.5cm (CT or MRI preprocedure, or intracardiac echocardiography, with documented image of largest dimension)

11. LVEF >or= 40%

12. Sustained AF during procedure: If the patient does not experience spontaneous sustained AF (>10 min) during the procedure, typically in paroxysmal AF patients, sustained AF will be induced in routine fashion by burst pacing initially from the coronary sinus, then from other sites, then with isoproterenol infusion. Using intensive AF induction methods (Narayan, J Cardiovasc EP; 2012; 23(5): 447-454) sustained AF is induced in > 90% of paroxysmal AF patients presenting in sinus rhythm. If AF cannot be sustained, the patient does not meet the inclusion criteria for the protocol and the patient will undergo AF ablation per physician direction.

Exclusion Criteria:

1. Reversible Cause of Atrial Fibrillation: Atrial fibrillation from a reversible cause (e.g., surgery, hyperthyroidism, pericarditis); Cardiac or thoracic surgery (e.g., valve repair or coronary artery bypass grafting, CABG) within the last 180 days; AF secondary to electrolyte imbalance, thyroid disease

2. Anti-Coagulation Contraindicated: Contraindication to Heparin; Contraindication to Warfarin or other novel oral anticoagulants (e.g., dabigatran, rivaroxabanm apixaban); History of significant bleeding abnormalities

3. Clotting Diathesis: History of significant blood clotting abnormalities, systemic thrombi or systemic embolization

4. Cardiac Prosthesis: ASD closure device, LAA closure device, prosthetic mitral or tricuspid valve

5. Thrombus or Mass: 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 affect catheter introduction or manipulation; Significant pulmonary embolus within 6 months of enrollment

6. Acute illness or active systemic infection or sepsis that may ordinarily warrant postponement of the procedure

7. History of recent cerebrovascular disease (stroke or TIA) or systemic thromboembolism within < 6 months

8. Severe Heart Failure: NYHA classes III, IV; Heart failure that is not stable on medical therapy; Pulmonary edema that may make planned anesthesia or sedation difficult

9. Non-Stable Coronary Disease: Stable/unstable angina or ongoing myocardial ischemia; Myocardial infarction (MI) within the past 3 months

10. 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 the 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, defined as LA volume index > 60 ml/m2, in whom PVI has low success and 55 mm baskets are too small for the atria

11. Planned Cardiac Surgery: If cardiac transplantation or other cardiac surgery are planned within the 12 months follow period of the trial

12. Life expectancy less than 12 months (the followup period of the trial)

13. Significant pulmonary disease (e.g., COPD) or any other disease that significantly increase risk to the patient from sedation or anesthesia

14. Untreatable allergy to contrast media

15. Electrolyte imbalance: At the time of the 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