ABSTRACT/SUMMARY The number of patients with atrial fibrillation, the most common sustained cardiac arrhythmia, is projected to double to 8-12 million by 2050. Because more than 80% of patients are 65 years of age or older, there will be a corresponding increase in Medicare expenditures for this disease, which now total $8 billion annually. Atrial fibrillation increases stroke risk five-fold and is thought to cause 15% of all strokes; thus, anticoagulation to prevent ischemic strokes is a primary component of treatment. In recent years the non-vitamin K antagonist oral anticoagulants (NOACs)?dabigatran, rivaroxaban, apixaban, and edoxaban ?have replaced warfarin as the recommended anticoagulant for most patients. Several lines of evidence indicate clinically important differences in NOAC efficacy and safety. Factors that alter plasma concentrations, which determine the anticoagulant effect, and differ between the NOACs could affect relative efficacy and safety. Although the NOACs have comparable half-lives, rivaroxaban and edoxaban are taken once daily, resulting in more than a 10-fold variation in steady-state plasma concentrations, whereas for apixaban and dabigatran, taken twice daily, this variation is less than 2-fold. Proton-pump inhibitors reduce concentrations of dabigatran, which requires gastric acidity for absorption, and confer a substantially greater reduction in major upper gastrointestinal (GI) bleeds for dabigatran than for other NOACs, suggesting reduced anticoagulant activity. Preliminary data from atrial fibrillation patients in a GI bleeding study indicate better outcomes for apixaban than for dabigatran or rivaroxaban, underscoring the need for reliable data on NOAC relative efficacy and safety. However, the available/in- progress RCTs and observational studies cannot provide the needed data. Concurrent inhibitors of NOAC elimination potentially increase the risk of major bleeding. For some infrequently prescribed inhibitors, the FDA recommends NOAC dose reduction. However, guidelines do not recommend changed practice for the most commonly prescribed inhibitors which increase mean plasma concentrations 1.3 to 2.2-fold and are prescribed for at least one-fourth of patients with NOAC treatment. The clinical effects of these potential interactions are unknown. Thus, we will conduct a rigorous Medicare cohort study to provide the data on NOAC relative efficacy and safety urgently needed to inform practice for the growing number of patients with atrial fibrillation. We will test the hypotheses that: Aim 1: In patients with non-valvular atrial fibrillation, the incidence of any stroke/systemic embolus (efficacy endpoint) and hemorrhagic stroke/fatal bleed (safety endpoint) differs between the NOACs. Aim 2: Concurrent use of NOACs with moderate inhibitors of PGP/CYP3A4 that have potential clinical alternatives increases the risk of hemorrhagic stroke/fatal bleed.