OBJECTIVES: Edoxaban and rivaroxaban are both once daily oral anticoagulants that have shown non-inferiority in terms of safety and efficacy versus warfarin without the need for regular INR control. This study aims to compare both drugs correcting for differences in study design and patient characteristics. METHODS: The EINSTEIN trial studied rivaroxaban, with results for DVT and PE published separately. Patient level data was available from the Hokusai in VTE trial comparing edoxaban with warfarin, which was subject to explorative analyses of both safety and efficacy concentrating on age, creatinine clearance, weight, planned duration of treatment and – for the warfarin arm - the percentage of time that the INR was in the therapeutic range. Subsequently, the data from Hokusai were truncated to match the follow up in Einstein and a matched adjusted indirect comparison was carried out. Results are compared with and without adjustments. RESULTS: : The explorative analyses versus warfarin show significant interactions between efficacy and age and efficacy and creatinine level. When estimating the efficacy from Hokusai as if with a follow up as in Einstein estimated odds ratio’s decrease from, 1.02 (0.70-1.33) to 0.90 (0.62-1.35) for the DVT population and from 0.88 (0.67-1.10) to 0.87 (0.60-1.13) for the PE population. For safety the odds-ratio increases from 0.75 (0.55-0.95) to 0.77 (0.51-1,04) in the DVT population and decreases from 0.89 (0.66,1.11) to 0.87 (0.61-1.13) for DVT patients. While not achieving any statistical significance all point estimates, except for DVT efficacy, trended in favor of edoxaban when compared to rivaroxaban. CONCLUSIONS: The indirect comparison with rivaroxaban shows favorable results of edoxaban albeit non-significant. The patient level data in comparison to warfarin suggests that tailored use of edoxaban may lead to significant improvements in outcomes.