Pulsed Field Ablation (PFA) vs Anti-Arrhythmic Drug (AAD) Therapy as a First Line Treatment for Persistent Atrial Fibrillation

Inclusion Criteria:

1. Age ≥ 18 years of age, or older if specified by local law

2. Have symptomatic persistent AF, confirmed by both: a. Documentation, within 180 days of randomization, or treatment assignment forroll-in subjects, of either: i. A 24-hour continuous ECG recording (from anyregulatory cleared rhythm monitoring device) confirming continuous AF, OR ii. TwoECGs (from any regulatory cleared rhythm monitoring device) showing continuous AFtaken at least 7 days apart b. Documentation, such as physician note, of persistentcontinuous AF for > 7 days and ≤ 365 days

3. Willing and capable of providing informed consent

4. Willing and capable of participating in all testing associated with this clinicalinvestigation at an approved clinical investigational center

5. Willing to receive LUX-Dx™ insertable cardiac monitor (ICM) during the study oralready has a LUX-Dx™ ICM that was inserted ≤ 6 months(i.e., within 180 days ofconsent

Exclusion Criteria:

1. Treated with AAD (Class I or III) ≤ 6 months (i.e., within 180 days) beforeenrollment,

2. More than 7-day history of therapeutic AAD use (Class I or III), or

3. ≥ 24 hours amiodarone, i Note Pill-in-the-pocket AAD use, is permitted.

4. Treated with AAD ( Class I or III) > 6 months (i.e., more than 180 days) beforeenrollment and experienced AAD failure (adverse drug effects or frequent AFepisodes)

5. Contraindication to, or unwillingness to use, AADs (Class I and III, excludingamiodarone)

6. Contraindication to PFA treatment

7. Contraindication to, or unwillingness to use, systemic anticoagulation, oracceptable alternatives, pre-, intra-, and post-procedure to achieve adequateanticoagulation.

8. Any of the following atrial conditions:

9. Left atrial (LA) anteroposterior diameter ≥ 5.5 cm, or, if LA diameter notavailable, non-indexed volume >100 ml, as documented by physician note orimaging (Note: if both values are available, only the LA diameter will be usedto confirm eligibility criteria)

10. Any prior atrial endocardial, epicardial or surgical ablation procedure forarrhythmia, other than right sided cavotricuspid isthmus ablation or for rightsided supraventricular tachycardia

11. Current atrial myxoma

12. Any PV abnormality, stenosis, or stenting (common and middle PVs areadmissible)

13. Current left atrial thrombus

14. Any of the following cardiovascular conditions:

15. History of sustained ventricular tachycardia or any ventricular fibrillation

16. AF that is secondary to electrolyte imbalance, thyroid disease, alcohol, orother reversible / non-cardiac causes

17. Current or anticipated pacemaker, implantable cardioverter defibrillator orcardiac resynchronization therapy devices, interatrial baffle, atrial septalpatch, atrial septal defect closure device, or patent foramen ovale occluder

18. Valvular disease that is any of the following: i. Symptomatic, ii. Causing orexacerbating congestive heart failure, iii. Associated with abnormal leftventricular (LV) function or hemodynamic measurements

19. Hypertrophic cardiomyopathy

20. Cardiac amyloidosis

21. Any prosthetic heart valve, ring or repair including balloon aorticvalvuloplasty

22. Any inferior vena cava (IVC) filter, known inability to obtain vascular accessor other contraindication to femoral access

23. Rheumatic heart disease

24. Congenital heart disease with any clinically significant residual anatomic orconduction abnormality

25. Awaiting cardiac transplantation or other cardiac surgery within the next 12months

26. Any of the following conditions identified during screening assessments

27. Heart failure associated with New York Heart Association (NYHA) Class IV

28. Left Ventricle Ejection Fraction (LVEF) < 40%

29. Uncontrolled hypertension (Systolic Blood Pressure > 160 mmHg or DiastolicBlood Pressure > 95 mmHg on two (2) BP measurements during screening

30. Any of the following events 90 days prior to randomization (or Index procedure forPFA Assigned or roll-in subjects):

31. Myocardial infarction (MI), unstable angina or coronary intervention

32. Cardiac surgery

33. Heart failure hospitalization

34. Pericarditis or symptomatic pericardial effusion

35. Gastrointestinal bleeding

36. Stroke, TIA, or intracranial bleeding

37. Non-neurologic thromboembolic event

38. Carotid stenting or endarterectomy

39. Known coagulopathy disorder (e.g., von Willbrand's disease, hemophilia)

40. Unwillingness to receive, or unable to tolerate, a subcutaneous, chronicallyinserted LUX-Dx™ ICM device

41. Women of childbearing potential who are pregnant, lactating, not using a reliableform of contraception, or who are planning to become pregnant during the anticipatedstudy period

42. Body Mass Index (BMI) > 45

43. Solid organ or hematologic transplant, or currently being evaluated for a transplant

44. Any prior history or current evidence of hemi-diaphragmatic paralysis or paresis

45. Severe lung disease, or any lung disease involving abnormal blood gases or requiringsupplemental oxygen

46. Severe pulmonary hypertension during screening assessment

47. Renal insufficiency if an estimated glomerular filtration rate (eGFR) is < 30 mL /min / 1.73 m2, or with any history of renal dialysis or renal transplant

48. Active malignancy at enrollment (other than cutaneous basal cell or squamous cellcarcinoma)

49. Clinically significant gastrointestinal problems involving the esophagus or stomachincluding severe or erosive esophagitis, uncontrolled gastric reflux, gastroparesis,esophageal candidiasis or active gastroduodenal ulceration

50. Known active systemic infection

51. Uncontrolled diabetes mellitus or a recorded HgbA1c > 8.0% in the 90 days prior torandomization (or Index procedure for PFA Assigned or roll-in subjects)

52. Untreated diagnosed obstructive sleep apnea with apnea hypopnea index classificationof severe (>30 pauses per hour)

53. Predicted life expectancy less than one (1) year

54. Currently enrolled in another investigational study or registry that would directlyinterfere with this study, except when the subject is participating in a mandatorygovernmental registry, or a purely observational registry with no associatedtreatments; each instance must be brought to the attention of the Sponsor todetermine eligibility

55. Health conditions that, in the investigator's medical opinion, would preventparticipation in the study, interfere with assessment or therapy, significantlyraise the risk of study participation, or modify outcome data or its interpretation

56. Has operational LUX-Dx ICM that was inserted more than 6 months (i.e., >180 days)prior to enrollment

57. Has operational ICM other than a LUX-Dx ICM and does not express a willingness toreceive a LUX-Dx ICM for the study

58. Individuals who may require an ablation, besides the PV and PW, in the left atriumincluding, but not limited to, those with Left-Sided Atrioventricular ReentrantTachycardia (AVRT), Left-Sided Atrial Tachycardia (AT), or Atypical Left-SidedAtrial Flutter.

59. AAD (Class I and III) Drug Naïve Subjects (as defined in criterion #1 and #2), whoare PFA Assigned (Non-Roll-in), PFA randomized, or Roll-in with a CHA2DS2-VASc Score ≥ 4