Substrate Versus Trigger Ablation for Paroxysmal Atrial Fibrillation

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.

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
- 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