OBJECTIVES: We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) including the comparison of non-vitamin K antagonist oral anticoagulants (NOACs) with warfarin for patients with atrial fibrillation (AF).DESIGN: Network meta-analysis. Two authors independently extracted data. All authors evaluated overall confidence in the evidence.RESULTS: Eighteen RCTs included in our review, a total of 78,796 patients with AF, with sample sizes from 90 to 21,105 patients. Apixaban 5 mg (OR: 0.79, 95% CI: 0.66 to 0.95), dabigatran 110 mg (0.91, 0.74-1.12), dabigatran 150 mg (0.66, 0.53-0.82), edoxaban 60 mg (0.87, 0.74-1.02), and rivaroxaban 20 mg (0.88, 0.74-1.03) reduced the risk of stroke or systemic embolism compared with warfarin. Dabigatran 150 mg had the highest P-score for reducing stroke or systemic embolic events. The risk of haemorhagic stroke and all-cause mortality was lower with all NOACs than with warfarin. Apixaban 5 mg (0.69, 0.60-0.80), dabigatran 110 mg (0.80, 0.69-0.93), dabigatran 150 mg (0.93, 0.80-1.08), edoxaban 30 mg (0.46, 0.40-0.54), and edoxaban 60 mg (0.78, 0.69-0.90) reduced the risk of major bleeding compared with warfarin. Edoxaban 30 mg had the highest P-score for reducing major bleeding. The plots of P-scores rank showed that apixaban offered the most favorable balance of efficacy and safety.CONCLUSIONS: This study adds an attempt for treatment ranking of both efficacy and safety outcomes. Future trials comparing directly NOACs are needed in order to provide conclusive proofs for these results and not only circumstantial evidence offered by a network meta-analysis.