Reduced-dose direct oral anticoagulation vs antiplatelet strategies after left atrial appendage occlusion in atrial fibrillation. a triple target trial emulation from a federated research network

Background Optimal antithrombotic therapy after left atrial appendage occlusion (LAAO) in patients with atrial fibrillation (AF) remains uncertain. Reduced-dose direct oral anticoagulants (DOACs) are increasingly used in clinical practice as alternatives to antiplatelet-based strategies, but comparative outcome data are limited. We aimed to compare clinical outcomes associated with low-dose DOAC therapy versus dual antiplatelet therapy (DAPT) and versus single antiplatelet therapy (SAPT) after LAAO. Methods This study was conducted using the TriNetX Global Collaborative Network, a federated research platform aggregating de-identified electronic health records from 169 healthcare organizations worldwide, comprising more than 150 million patients. We identified adult patients with AF undergoing percutaneous LAAO between 2010 and 2025. Three parallel propensity score–matched analyses were conducted: reduced-dose DOAC versus dual antiplatelet therapy (DAPT), single antiplatelet therapy (SAPT) versus DAPT, and reduced-dose DOAC versus SAPT. Outcomes included all-cause death, thromboembolic events, device-related thrombosis, bleeding events, and net clinical benefit (NCB). Results After matching, 1,773 patients were included in each group for the reduced-dose DOAC versus DAPT comparison (mean follow-up 1.4±1.0 years). Reduced-dose DOAC was associated with lower risks of all-cause death (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.65–0.96) and major bleeding (HR 0.87, 95%CI 0.77–0.98), with no significant differences in ischemic stroke, thromboembolism, or device-related thrombosis. NCB favored reduced-dose DOAC (HR 0.87, 95%CI 0.78–0.96). SAPT was also associated with fewer bleeding events and favorable outcomes compared with DAPT (Figure). In the reduced-dose DOAC versus SAPT comparison (1,582 matched patients per group), reduced-dose DOAC showed a borderline higher risk of major bleeding (HR 1.14, 95%CI 1.00–1.30; p=0.06), while mortality, thromboembolic outcomes, and NCB did not differ significantly. Clinical outcomes did not differ significantly in an additional matched analysis between reduced-dose apixaban and rivaroxaban after LAAO, although a numerical trend toward lower event rates with rivaroxaban was observed. In sensitivity analyses limited to early post-implant period (follow-up beginning 1 day after the index date and administratively censored at 90 days), findings were directionally consistent with the primary analyses. Conclusions In contemporary practice after LAAO, reduced-dose DOAC therapy was associated with more favorable outcomes than DAPT but showed no clear advantage over SAPT, supporting simplified and individualized post-implant antithrombotic strategies.