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Background: The prevalence of and outcomes associated with different antithrombotic strategies after left atrial appendage occlusion (LAAO) are not well described., Objectives: This study sought to evaluate patterns of antithrombotic medication strategies at discharge following LAAO with the Watchman FLX device in real-world practice and to compare the risk of adverse events among the different antithrombotic regimens., Methods: The authors evaluated patients in the NCDR (National Cardiovascular Data Registry) LAAO Registry who underwent LAAO with the second-generation LAA closure device between 2020 and 2022. They grouped patients by mutually exclusive discharge antithrombotic strategies and compared the rates of adverse events at 45 days and 6 months using multivariable Cox proportional hazards regression., Results: Among 53,878 patients undergoing successful LAAO with the second-generation LAA closure device, the most common antithrombotic discharge regimens were direct oral anticoagulant (DOAC) plus aspirin (48.3%), DOAC alone (22.6%), dual antiplatelet therapy (8.1%), warfarin plus aspirin (7.7%), and DOAC plus P2Y 12 inhibitor (4.9%). In multivariate analysis, DOAC alone had a lower rate of major adverse events and major bleeding at 45 days of follow-up compared with DOAC plus aspirin (major adverse events: HR: 0.78; 95% CI: 0.68-0.91; major bleeding: HR: 0.69; 95% CI: 0.60-0.80). These differences persisted at 6 months. Warfarin without aspirin also showed lower rates of major bleeding at both time points. No differences were seen in stroke/transient ischemic attack or device-related thrombus., Conclusions: In real-world U.S. practice, discharge on DOAC alone or warfarin alone was associated with a lower rate of adverse events compared with DOAC plus aspirin., Competing Interests: Funding Support and Author Disclosures This analysis was supported by the Boston Scientific Corporation. Although Boston Scientific had no role in the data collection, development of study questions, or analytic approaches, it paid for the statistical analytical work and manuscript support. No authors were compensated for their work on this study. The views expressed here represent those of the authors, and do not necessarily represent the official views of the American College of Cardiology Foundation’s National Cardiovascular Data Registry or its associated professional societies identified at CVQuality.ACC.org/NCDR. Dr Hsu has received honoraria from Medtronic, Abbott, Boston Scientific, Biotronik, Janssen Pharmaceuticals, Bristol Myers Squibb, Pfizer, Sanofi, Zoll Medical, iRhythm, Acutus Medical, Galvanize Therapeutics, and Biosense Webster; has received research grants from Biotronik and Biosense Webster; and has equity in Vektor Medical. Dr Yeh has received research funding and consulting fees from Abbott Vascular, Boston Scientific, and Medtronic; and has received research funding from Bard, Cook, and Philips. Dr Price has received consulting honoraria, speaker fees, and proctoring fees from Abbott Vascular and Boston Scientific; has received consulting honoraria and speaker fees from Medtronic, W.L. Gore, Philips, and Shockwave; and has equity in Indian Wells, Inc. Dr Piccini is supported by grant R01AG074185 from the National Institutes of Aging; receives grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, iRhythm, and Philips; and serves as a consultant to Abbott, Abbvie, ARCA biopharma, Bayer, Boston Scientific, Bristol Myers Squibb (Myokardia), Element Science, Itamar Medical, LivaNova, Medtronic, Milestone, ElectroPhysiology Frontiers, ReCor, Sanofi, Philips, and Up-to-Date. Drs Christen and Allocco are full-time employees and stockholders of Boston Scientific. Dr Freeman has received research funding from the National Institutes of Health/National Heart, Lung, and Blood Institute, and the American College of Cardiology National Cardiovascular Data Registry; has received consulting/advisory board fees from Medtronic, Boston Scientific, Biosense Webster, and PaceMate; and has equity in PaceMate. All other authors have reported that they have no relationships relevant to the contents of this paper., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)