Current guidelines for the cardioversion of paroxysmal Atrial Fibrillation at the Emergency Department do not prioritize between antiarrhythmic agents and do not consider the time taken for successful cardioversion. Furthermore, the use of flecainide -a class 1C antiarrhythmic agent- is contraindicated for the cardioversion of patients with revascularized coronary artery disease, as well as patients with ischemic cardiomyopathy and preserved ejection fraction. These recommendations stem from insufficient data, mainly from the CAST study.

The present study is a prospective, multicentre, randomized clinical trial. The primary goals of this clinical trial are to prove the superiority of flecainide over amiodarone in the successful cardioversion of paroxysmal atrial fibrillation at the Emergency Department, and to prove that the safety of flecainide is non-inferior to amiodarone, in patients with coronary artery disease without residual ischemia and ejection fraction over 35%. The secondary goals of the study are to prove the superiority of flecainide over amiodarone in the reduction of hospitalizations from the Emergency Department due to atrial fibrillation, in the time taken to achieve cardioversion, and to the reduction of the need to conduct electrical cardioversion.

The study population will be all consecutive new-comers to the Emergency Department with primary diagnosis of paroxysmal atrial fibrillation and history of coronary artery disease without angina, without residual ischemia and with ejection fraction > 35%. The sample size will be 200 patients, who will be monitored for 30 days. At the Emergency Department, all patients will be under continuous ECG monitoring, and a 24-hour ECG device will also be placed (Holter). The patients will be randomized to the treatment group (flecainide) and the control group (amiodarone).

Patients in both arms will stay at the ED for a total of 6 hours after therapy initiation. If no adverse events occur in this time, the patient will be discharged from the ED. Otherwise, the patient will be admitted to the hospital. At 24 hours, the patients will visit the study centre for physical examination, ECG, cardiac ultrasound, 24-hour ECG removal and adverse events evaluation. At 30 days, follow-up via phone calls will be conducted for the evaluation of the study outcomes and adverse events.

As of June 2025, an interim analysis has been completed, and preliminary study results have been submitted for presentation at the European Society of Cardiology (ESC) Congress. Based on the interim findings, the study's target sample size has been revised to a total of 80 patients.

Inclusion Criteria:

1. Age: 18-85 years old

2. Paroxysmal Atrial Fibrillation, documented by 12-lead ECG, with one of the following:

   1. Atrial Fibrillation onset less than 48 hours from the time of presentation to the Emergency Department

   2. Atrial Fibrillation onset between 48 hours and 7 days from the time of presentation to the Emergency Department, and patient has been on anticoagulation for at least 30 days

   3. History of Coronary Artery Disease without residual ischemia, defined by one of the following criteria:

      • PCI <= 1 year, or

      • CABG <= 3 years, or

      • Negative imaging-based stress testing within 1 year, and:

        • History of known coronary artery stenosis > 60% without revascularization, or
        • PCI >= 1 year, or
        • CABG >= 3 years

3. Ejection Fraction > 35% (documented by cardiac ultrasound at the Emergency Department, or within 1 year)

4. Signed informed consent from the patient or legal representative.

Exclusion Criteria:

1. Based on ECG at the Emergency Department:

   1. Atrial Flutter
   2. Newly documented Left Bundle Branch Block (LBBB)
   3. Newly documented Right Bundle Branch Block (RBBB) with QRS duration > 150ms

2. Previously documented 24-hour ECG holter monitoring with > 720 poly PVCs/24hours, or non sustained ventricular tachycardia

3. No history of coronary artery disease

4. ST-Segment Elevation Myocardial Infarction (STEMI)

5. Non-ST-Segment Elevation Myocardial Infarction (NSTEMI), according to ESC 2020 guidelines on NSTEMI:

   1. If troponin at t0h is over the "low" criterion on table of the cutoff values
   2. If the change of troponin (Δtroponin) at t1h is over the respective cutoff value at the table for the cutoff values

6. Unstable angina, defined as myocardial ischemia at rest or at minimum effort, in the absence of acute injury/necrosis of myocardial cells

7. Known residual ischemia:

   1. Positive imaging-based stress testing

   2. Negative imaging-based stress testing >= 1 year, and:

      • History of known coronary artery stenosis > 60% without revascularization, or
      • PCI >= 1 year, or
      • CABG >= 3 years

8. History of acute coronary syndrome within 1 year

9. Severe Aortic Valve Stenosis (mean pressure gradient > 40mmHg, AVA < 1cm/m^2)

10. Severe Chronic Kidney Disease (stage >= 4)

11. Severe systematic disease, including neoplasmatic disease under any antineoplasmatic treatment, liver failure, infection with fever

12. Use of strategy "pill in the pocket", by taking flecainide (max 200mg) or propafenone (max 600mg) within 6 hours prior to Emergency Department visit

13. Known dysanexia or allergy to flecainide or amiodarone

14. Pregnancy or/and breastfeeding

15. Participation in any other clinical trial

16. Life expectancy less than 1 year

17. Inappropriate, unfit, or unwilling to follow the desingated protocol procedures.