The primary objective of this study is to determine if left atrial appendage closure (LAAC) with the WATCHMAN FLX device is a reasonable alternative to non-vitamin K oral anticoagulants in patients with non-valvular atrial fibrillation.

This study is a prospective, randomized, multi-center global investigation. Subjects will be randomized to either the WATCHMAN FLX Left Atrial Appendage Closure Device ("Device Group") or a commercially available non-vitamin K oral anticoagulant ("Control Group").

Inclusion Criteria:

• The subject is of legal age to participate in the study per the laws of their respective geography
• The subject has documented non-valvular atrial fibrillation (i.e., atrial fibrillation in the absence of moderate or greater mitral stenosis or a mechanical heart valve)
• The subject has a calculated CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack (TIA), vascular disease, age 65 to 74 years, sex category) score of 2 or greater for men and 3 or greater for women
• The subject is deemed to be suitable for the protocol-defined pharmacologic regimens in both the test and control arms
• The subject or legal representative is able to understand and willing to provide written informed consent to participate in the trial
• The subject is able and willing to return for required follow-up visits and examinations

Exclusion Criteria:

• Subjects who are currently enrolled in another investigational study, except when the subject is participating in a mandatory governmental registry, or a purely observational registry with no associated treatments
• The subject requires long-term anticoagulation therapy for reasons other than AF-related stroke risk reduction, for example due to an underlying hypercoagulable state (i.e., even if the device is implanted, the subjects would not be eligible to discontinue OAC due to other medical conditions requiring chronic OAC therapy)
• The subject is contraindicated or allergic to oral anticoagulation medication and/or aspirin
• The subject is indicated for chronic P2Y12 platelet inhibitor therapy
• The subject had or is planning to have any cardiac or non-cardiac intervention or surgical procedure within 30 days prior to or 60 days after implant (including, but not limited to: cardioversion, percutaneous coronary intervention (PCI), cardiac ablation, cataract surgery, etc.)
• The subject had a prior stroke (of any cause, whether ischemic or hemorrhagic) or transient ischemic attack (TIA) within the 30 days prior to enrollment
• The subject had a prior major bleeding event per ISTH definition within the 30 days prior to randomization. Lack of resolution of related clinical sequelae or planned and pending interventions to resolve bleeding/bleeding source, are a further exclusion regardless of timing of the bleeding event
• The subject has an active bleed
• The subject has a reversible cause of AF or transient AF
• The subject is absent of a left atrial appendage (LAA) or the LAA is surgically ligated
• The subject has had a myocardial infarction (MI) documented in the clinical record as either a non-ST elevation MI (NSTEMI) or as an ST-elevation MI (STEMI), with or without intervention, within 30 days prior to enrollment
• The subject has a history of atrial septal repair or has an atrial septal device (ASD)/patent foramen ovale (PFO) device
• The subject has an implanted mechanical valve prosthesis in any position
• The subject has a known contraindication to percutaneous catheterization procedure
• The subject has a known contraindication to transesophageal echo (TEE)
• The subject has a cardiac tumor
• The subject has signs/symptoms of acute or chronic pericarditis.
• The subject has an active infection
• There is evidence of tamponade physiology
• The subject has New York Heart Association Class IV Congestive Heart Failure at the time of enrollment
• The subject is of childbearing potential and is, or plans to become, pregnant during the time of the study (method of assessment upon study physician's discretion)
• The subject has a documented life expectancy of less than 3 years

Transthoracic Echo Exclusion Criteria:

• The subject has left ventricular ejection fraction ( LVEF) < 30%
• The subject has an existing pericardial effusion with a circumferential echo-free space > 5mm
• The subject has a high-risk PFO with an atrial septal aneurysm excursion > 15mm or length > 15mm
• The subject has significant mitral valve (MV) stenosis (i.e., MV area <1.5 cm2)