The purpose of this study is to determine if catheter-based atrial fibrillation (AF) ablation is superior to treatment with antiarrhythmic drugs as a first-line therapy for symptomatic persistent AF.

The burden of atrial fibrillation (AF) on Western countries healthcare systems is steadily increasing, with over 2 million Americans and 4 million Europeans affected by this condition. It is by far the most common sustained arrhythmia encountered in clinical practice, with a striking impact on morbidity and mortality. Achieving a definite cure is highly desirable, as this would have profound social and economic implication. In patients with drug-refractory paroxysmal AF, multiple clinical trials have established the superiority of catheter ablation over further antiarrhythmic drug (AAD) therapy for the long-term maintenance of sinus rhythm, to improve quality of life, and reduce hospitalizations. Recent randomized controlled trials have also demonstrated a beneficial role of catheter ablation as a first-line therapy in patients with paroxysmal AF, with significantly better arrhythmia control and improved quality of life compared to AAD therapy. Patients with symptomatic persistent AF represent a more challenging group to treat, given the overall lower success rate of catheter ablation procedures in this group of patients. Pharmacologic rhythm-control strategies are also less effective in persistent AF, with a substantially increased economic burden given the repeat admissions for electrical cardioversions and AAD initiation/titration. In patients with symptomatic persistent AF who have already failed AADs, catheter ablation has been shown superior to further AAD therapy for sinus rhythm restoration in a recent randomized controlled trial. However, the value of an upstream adoption of catheter ablation for the treatment of symptomatic persistent AF (i.e., before a trial with AADs) is unknown. The purpose of the third Radiofrequency Ablation vs Antiarrhythmic Drugs for Atrial Fibrillation Treatment (RAAFT-3) trial is to determine whether catheter ablation is superior to AAD as a first-line therapy in patients with persistent AF who had not been exposed to antiarrhythmic treatment.

Inclusion Criteria:

Eligible patients have a history of persistent AF with at least 2 episodes in the 9 months prior to enrollment. Persistent AF is defined according to 2014 AHA/ACC/HRS guidelines as continuous AF that is sustained for more than 7 days.Patients are enrolled if they are:

1. Older than 18.
2. Symptomatic with persistent AF.
3. Experienced at least one AF episode that was documented by surface ECG, 6 months before randomization.

Exclusion Criteria:

1. Documented LVEF <40%.
2. Documented left atrial diameter >/=6cm.
3. Moderate to severe LVH (LV wall thickness >1.5cm).
4. Documented severe valvular disease (aortic stenosis, mitral regurgitation, tricuspid regurgitation or presence of mechanical cardiac valves), active coronary artery disease (defined as the presence of >70% stenosis of coronary arteries or documentation of active myocardial ischemia), recent (within 6 months) CABG.
5. Untreated hypothyroidism or hyperthyroidism. Patients who are euthyroid on thyroid hormone replacement therapy are acceptable.
6. Contraindication for the use of all antiarrhythmic drugs including sotalol, dofetilide, amiodarone and 1C antiarrhythmic drugs (liver enzymes and serum creatinine that are outside the upper normal lab values, e.g. > 3 times ULN with 2 abnormal lab values). [Note: Participants will not be excluded if they are able to take any single or combination of drugs without contraindications]
7. Previous left heart ablation procedure, either by surgery or by percutaneous catheter, for atrial fibrillation.
8. Current enrollment in another investigational drug or device study.
9. Presence of any other condition that the investigator feels would be problematic or would restrict or limit the participation of the Patient for the entire study period.
10. Absolute contra-indication to the use of heparin and or oral anticoagulation.
11. Increase risk of bleeding, current peptic ulceration, proliferative diabetic retinopathy, history of severe systemic bleeding, or other history of bleeding diathesis or coagulopathy.
12. Severe pulmonary disease e.g. restrictive pulmonary disease, chronic obstructive disease (COPD).
13. Documented intra-atrial thrombus, tumor, or another abnormality, which precludes left atrial catheter ablation.
14. Previous use of an antiarrhythmic drug, including amiodarone, propafenone, flecainide, sotalol, quinidine, dofetilide, dronedarone (see below for specifications: Antiarrhythmic Drug Group).
15. Women with a positive pregnancy test.
16. Evidence of active cardiac or systemic infection.
17. Medical condition limiting expected survival to less than one year.