Abstract Body (Do not enter title and authors here):
Background
A growing body of observational data suggests an important link between atrial fibrillation (AF) and cognitive decline. It remains unknown whether oral anticoagulation (OAC) effectively prevents cognitive decline in patients with AF and no conventional risk factor for stroke.

Hypothesis
We hypothesize that OAC will be superior to placebo in the prevention of stroke, transient ischemic attack (TIA) or cognitive decline in subjects with non-valvular AF and a low risk of stroke.

Methods
In the BRAIN-AF trial (NCT02387229), patients with AF and no CHADS-65 indication for OAC were randomized 1:1 in a double-blinded fashion to rivaroxaban 15 mg daily versus placebo. For patients with vascular disease, a double-dummy design was incorporated to ensure that they received either rivaroxaban or aspirin. Cognitive testing with MoCA was performed yearly and at the final visit, MMSE was repeated at the final visit. The composite primary efficacy outcome consisted of stroke, TIA (with a motor deficit or aphasia) or cognitive decline (reduction in MoCA score ≥2 points). The study drug was discontinued if a patient developed a CHADS-65 indication for OAC. The primary efficacy analysis was by intention-to-treat.

Results
A total of 1235 patients, mean age 53.4±7.3 years, 25.6% women, were randomized between April 2015 and November 2023 across 53 centers in Canada. AF was paroxysmal, persistent, and permanent in 78.5%, 11.2%, and 10.4% of patients, respectively. At the interim analysis, the data safety and monitoring board (DSMB) recommended early termination for futility. During a median follow-up of 3.7 years (interquartile range 1.9 – 6.0) and based on the intention-to-treat principle, the primary outcome occurred in 130 patients (7.0% per year) randomized to rivaroxaban vs. 126 (6.4% per year) randomized to placebo [hazard ratio 1.10, 95% confidence interval (0.86-1.40); P=0.46]. Major bleeding occurred in 2 patients (0.09% per year) on rivaroxaban and 5 (0.21% per year) on placebo (P=0.27).

Conclusions
In patients with AF and no CHADS-65 indication for OAC, rivaroxaban does not reduce the incidence of cognitive decline, stroke, or TIA.
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