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Background An optimal antithrombotic strategy for patients aged 80 years or older with atrial fibrillation (AF) remains elusive. Objective Using a systematic review with traditional and network meta-analysis, we investigated outcomes in AF patients ≥80 years treated with different antithrombotic strategies. Methods We searched eligible randomised controlled trials (RCTs) and observational studies from MEDLINE, EMBASE, Cochrane Library and Web of Science databases from inception to 16 December 2021. Research comparing treatment outcomes of novel oral anticoagulants (NOACs), aspirin, vitamin K antagonists (VKAs) or no oral anticoagulant/placebo therapy in patients ≥80 years with AF were included. Outcomes were stroke or systemic embolism (SSE), major bleeding, all-cause mortality, intracranial bleeding (ICH) and gastrointestinal bleeding. Traditional and network meta-analyses were performed. Net clinical benefit integrating SSE and major bleeding was calculated. Results Fifty-three studies were identified for analysis. In the meta-analysis of RCTs, risk of SSE (risk ratio [RR]: 0.82; 95% confidence interval [CI]: 0.73–0.99) and ICH (RR: 0.38; 95% CI: 0.28–0.52) was significantly reduced when NOACs were compared with VKAs. Network meta-analysis of RCTs demonstrated that edoxaban (P -score: 0.8976) and apixaban (P -score: 0.8528) outperformed other antithrombotic therapies by showing a lower major bleeding risk and better net clinical benefit. Both traditional and network meta-analyses from RCTs combining with observational studies showed consistent results. Conclusions In patients aged 80 years or older with AF, NOACs have better outcomes than VKAs regarding efficacy and safety profiles. Edoxaban and apixaban may be preferred treatment options since they are safer than other antithrombotic strategies. [ABSTRACT FROM AUTHOR]