Project Summary Non-valvular atrial fibrillation (AF) is highly prevalent in older adults and associated with a 5-fold increased risk of cardioembolic stroke. Oral anticoagulants (OACs) can reduce this risk by ~70%, but nearly 50% of such older patients are not anticoagulated, with Alzheimer’s disease and related dementias (ADRD) being among the leading cited reasons, attributed to a higher risk of falls, medication errors, and poor adherence. Since the vast majority of thrombus formation in AF occurs in the left atrial appendage, transcatheter left atrial appendage occlusion (LAAO) has been approved in the US since 2015 as a one-time procedural alternative treatment for stroke prevention in AF patients with high risks of complications from OACs. The uptake of transcatheter LAAO has been growing at a rate of 2 to 3-fold yearly, and it is clearly changing the prescribing pattern of OACs in AF patients. However, our pilot data showed persons living with dementia (PLWDs) are significantly less likely to receive transcatheter LAAO when it is indicated. One likely barrier is that PLWDs and frail older adults were much under-represented in the randomized controlled trials (RCTs) which led to transcatheter LAAO approval. Also, several high-risk characteristics prevalent in PLWDs, including frailty, dementia severity, fall risks, and advanced kidney disease, are risk factors for both the transcatheter LAAO procedure-related complications and bleeding risks from OACs, complicating the prescribing decisions. Thus, there is an urgent need to investigate the net clinical benefit, weighing the benefits of stroke prevention against the major bleeding and procedure complications, comparing transcatheter LAAO with specific OACs in PLWDs. Our objective is to establish a prospective monitoring program in 3 large national healthcare utilization databases (Medicare, IBM Marketscan, and Optum claims data, covering ~15 million lives) from 2015-2025, linked to electronic health records (EHR). We will evaluate treatment outcomes of transcatheter LAAO vs. specific OACs in PLWDs with AF with detailed treatment effect heterogeneity evaluation by frailty, dementia severity, fall risks, advanced kidney disease, and patient-reported and family factors. We will also determine the utilization trends, predictors, and barriers of transcatheter LAAO and OACs in PLWDs, using a novel signal detection tool, TreeScan, developed by the applicant team and adopted by the US Food and Drug Administration for prospective drug safety monitoring. Our central hypothesis is that transcatheter LAAO has a favorable long-term net clinical benefit compared with OACs in PLWDs and the relative benefits vary by specific identifiable clinical factors. This proposal will yield: 1) direct benefit-to-risk data to inform the use of transcatheter LAAO and specific OACs for stroke prevention in PLWDs with AF; 2) a novel and generalizable prospective monitoring program that compares effectiveness and safety o...