Plitt, Anna (55813399600)Anna (55813399600)PlittRuff, Christian T. (35551858400)Christian T. (35551858400)RuffGoudev, Assen (58395505000)Assen (58395505000)GoudevMorais, Joao (57210400438)Joao (57210400438)MoraisOstojic, Miodrag C. (34572650500)Miodrag C. (34572650500)OstojicGrosso, Michael A. (55885215300)Michael A. (55885215300)GrossoLanz, Hans J. (55931968700)Hans J. (55931968700)LanzPark, Jeong-Gun (57193361505)Jeong-Gun (57193361505)ParkAntman, Elliott M. (7102107511)Elliott M. (7102107511)AntmanBraunwald, Eugene (35375508300)Eugene (35375508300)BraunwaldGiugliano, Robert P. (7005135528)Robert P. (7005135528)Giugliano2025-06-122025-06-122020https://doi.org/10.1016/j.ijcard.2020.01.009https://www.scopus.com/inward/record.uri?eid=2-s2.0-85078825906&doi=10.1016%2fj.ijcard.2020.01.009&partnerID=40&md5=778ac472dce5ed5779900121718db5dehttps://remedy.med.bg.ac.rs/handle/123456789/5014Background: Diabetes mellitus is an independent risk factor for stroke and atrial fibrillation. Therefore, the risk/benefit profile of the oral factor Xa inhibitor edoxaban stratified by diabetes is of clinical interest. Methods: 21,105 patients enrolled in ENGAGE AF-TIMI 48 were stratified into 2 pre-specified groups: without (N = 13,481) and with diabetes (N = 7,624). Results: On average, patients with diabetes were younger, and had a higher body mass index, CHA2DS2-VASc score and baseline endogenous Factor Xa activity. After multivariate adjustments, patients with diabetes had a similar rate of stroke and systemic embolism compared to those without diabetes (adjusted hazard ratio (HRadj) 1.08; 95% confidence interval (CI) 0.94–1.24; p = 0.28). However, the risk of major bleeding was significantly higher in patients with diabetes (HRadj 1.28; 95% CI 1.14–1.44; p < 0.001). The treatment effect of edoxaban (vs warfarin) was not modified by diabetes (all p-interactions > 0.05), a finding supported by the preserved edoxaban concentrations and inhibition of Factor Xa regardless of diabetes. The HRs of stroke and systemic embolism in patients receiving the higher-dose edoxaban regimen vs warfarin were 0.93 and 0.84 (p-interaction = 0.54) in those with and without diabetes respectively. The higher-dose edoxaban regimen reduced major bleeding (by 19–21%) and cardiovascular death (by 7–17%) regardless of diabetes (p-interactions = 0.81 and 0.33 respectively). Conclusion: Patients with diabetes in ENGAGE AF-TIMI 48 had higher bleeding risk, but after adjustment similar stroke risk, compared to those without diabetes. The higher-dose edoxaban regimen had similar efficacy compared to warfarin, while reducing bleeding and cardiovascular mortality, irrespective of diabetes. © 2020 Elsevier B.V.Atrial fibrillationDiabetes mellitusNon-vitamin K antagonist oral anticoagulantsStroke prevention