The objective of this trial is to evaluate the safety and effectiveness of the Amulet LAA occluder compared to NOAC therapy in patients with non-valvular AF at increased risk for ischemic stroke and who are recommended for long-term NOAC therapy.

The clinical investigation is a prospective, randomized, multicenter active control worldwide trial. Subjects will be randomized in a 1:1 ratio between the Amulet LAA occlusion device ("Device Group") and a commercially available NOAC medication ("Control Group"). The choice of NOAC in the Control Group will be left to study physician discretion.

Inclusion Criteria:

• Documented paroxysmal, persistent, or permanent non-valvular AF (documentation must include an electrocardiogram, Holter, or event recorder)
• At high risk of stroke or systemic embolism, defined as a CHA2DS2-VASc score of ≥ 2 for men and ≥ 3 for women
• Eligible for long-term NOAC therapy
• Able to comply with the required NOAC medication regimen if randomized to the Control Group
• Able to comply with the required medication regimen post-device implant if subject is randomized to the Device Group or subject is a Roll-in
• Able to understand, and is willing to provide, written informed consent to participate in the trial, prior to any clinical investigation related procedure or assessment
• 18 years of age or older, or the age of legal consent
• Able and willing to return for required follow-up visits and assessments

Exclusion Criteria:

• Requires long-term OAC therapy for a condition other than AF
• Planned cardiac intervention or surgery, which is invasive or requires sedation or anesthesia, within 3 months following randomization, other than study-related procedures such as LAAO and cardiac imaging (if applicable)
• Known contraindication to, or allergic to, aspirin, clopidogrel, or OAC medication use
• Indicated for P2Y12 platelet inhibitor for >1 year post-randomization
• In the opinion of the investigator, is considered at high risk for general anesthesia and general anesthesia is planned for the study procedure
• Has undergone atrial septal defect (ASD) repair or has an ASD closure device present
• Has undergone patent foramen ovale (PFO) repair or has a PFO closure device implanted
• Is implanted with a mechanical valve prosthesis
• Is implanted with an inferior vena cava filter
• History of rheumatic or congenital mitral valve heart disease
• Has any of the customary contraindications for a percutaneous catheterization procedure (e.g. subject is too small to accommodate the ICE probe (if planned) or required catheters, or subject has active infection or bleeding disorder)
• Customary contraindications for TEE/TOE (e.g., presence of esophageal varices, esophageal stricture, or history of esophageal cancer)
• Experienced stroke or transient ischemic attack (TIA) within 90 days prior to randomization or implant procedure (as applicable)
• Underwent any cardiac or non-cardiac intervention or surgery within 30 days prior to randomization
• Underwent catheter ablation for AF or atrial flutter within 60 days prior to randomization
• Experienced myocardial infarction within 90 days prior to randomization
• New York Heart Association Class IV Congestive Heart Failure
• Left ventricular ejection fraction ≤ 30% (per most recent assessment)
• Symptomatic carotid disease (defined as > 50% lumen diameter narrowing on CTA, MRA, or TCD with symptoms of ipsilateral transient or visual TIA evidenced by amaurosis fugax, ipsilateral hemispheric TIAs or ipsilateral stroke); if subject has a history of carotid stent or endarterectomy the subject is eligible if there is < 50% lumen diameter narrowing
• Has known intracranial atherosclerosis and/or intracranial small vessel disease (defined as 6 points on the Fazekas Scale)
• Reversible cause of AF (i.e., secondary to thyroid disorders, acute alcohol intoxication, trauma, recent major surgical procedures)
• History of idiopathic or recurrent venous thromboembolism
• LAA is obliterated or surgically ligated
• Thrombocytopenia (defined as < 50,000 platelets per microliter (<50 x 10^9 /L)or anemia (defined as hemoglobin < 10 g/dL) requiring transfusions
• Hypersensitivity to any portion of the device material or individual components of the Amulet LAA occluder device (e.g., nickel allergy)
• Actively enrolled in, or plans to enroll in, a concurrent clinical study in which the active treatment arm may confound the results of this trial
• Is pregnant or breastfeeding, or pregnancy is planned during the course of the investigation
• Active endocarditis or other infection producing bacteremia
• Transient case of AF (i.e., never previously detected, provoked/induced by surgical or catheter manipulations, etc.)
• Severe renal failure (estimated glomerular filtration rate <30 ml/min/1.73m2), but not on dialysis
• Life expectancy is less than 2 years in the opinion of the Investigator
• Presence of other anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the Investigator's opinion, could limit the subject's ability to participate in the clinical investigation or to comply with follow up requirements, or impact the scientific soundness of the clinical investigation results.