Comparative bleeding risks among NOAC users for nonvalvular atrial fibrillation aged <65 years in the Sentinel System

Background: Nonvitamin K antagonist oral anticoagulants (NOACs) are alternatives to warfarin for treatment of nonvalvular atrial fibrillation (NVAF). Randomized trials compared NOACs with warfarin, but not the safety of individual NOACs against each other. An FDA study using Medicare data concluded that among patients aged ≥65 years rivaroxaban had a less favorable safety profile compared to other NOACs; however, it is unclear if this safety profile persists in younger users.

Objectives: To compare major extracranial bleeding (MEB), gastrointestinal (GI) bleeding, and intracranial hemorrhage (ICH) in NOAC users for NVAF aged < 65 years in the FDA Sentinel System.

Methods: A retrospective new user cohort study was conducted among standard dose NOAC users with NVAF, aged ≤65 years between October, 2010, and February, 2022. New users of standard dose apixaban, dabigatran and rivaroxaban with a diagnosis of NVAF in the prior 183 days were identified. Those with kidney replacement, deep vein thrombosis, pulmonary embolism, joint replacement, mitral stenosis, valve replacement or repair, or receiving dialysis were excluded. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for each outcome (MEB, GI bleed, and ICH) in inverse probability of treatment weighted pairwise comparisons: rivaroxaban vs. apixaban, rivaroxaban vs. dabigatran, dabigatran vs. apixaban.

Results: Comparing rivaroxaban and apixaban, 57,932 and 96,057 users were identified, respectively, of whom 28% were female with an average age 56 years. Comparing rivaroxaban and dabigatran, 57,399 and 20,188 users were identified respectively, of whom 25% were female with an average age of 56. Comparing dabigatran and apixaban 20,163 and 96,668 users were identified respectively, of whom 28% were female with an average age of 56. Rivaroxaban use compared to apixaban use was associated with an increased risk of MEB (HR 1.92, 95% CI [1.54, 2.39]), GI bleed (HR 1.91, 95% CI [1.56, 2.34]), and ICH (HR 1.63, 95% CI [0.99, 2.70]). Comparing rivaroxaban to dabigatran, there was a suggestion of increased risk of MEB (HR 1.42, 95% CI [0.98, 2.07]), GI bleed (HR 1.32, 95% CI [0.89, 1.96]), and ICH (HR 1.18, 95% CI [0.52, 2.67]), but statistical significance was not achieved. Similarly, a suggested increase was seen comparing dabigatran to apixaban: MEB (HR 1.34, 95% CI [0.88, 2.05]), GI bleed (HR 1.22, 95% CI [0.82, 1.81]), and ICH (HR 1.43, 95% CI [0.58, 3.52]).

Conclusions: Among patients aged < 65 years treated with standard-dose NOACs for NVAF, and notwithstanding other considerations (e.g., effectiveness or dosing schedules), rivaroxaban and dabigatran were associated with a less favorable safety profile than apixaban. These findings align with previous studies in older adults.