Natalia S Rost1, Robert P Giugliano2, Christian T Ruff2, Sabina A Murphy2, Andrea E Crompton2, Andrew D Norden2, Scott Silverman2, Aneesh B Singhal2, José C Nicolau2, Bhupathi SomaRaju2, Michele F Mercuri2, Elliott M Antman2, Eugene Braunwald2. 1. From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.). nrost@partners.org. 2. From the Massachusetts General Hospital, Boston (N.S.R., S.S., A.B.S.); TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Boston MA (R.P.G., C.T.R., S.A.M., A.E.C., A.D.N., E.M.A., E.B.); Heart Institute (InCor), University of São Paulo Medical School, Brazil (J.C.N.); CARE Musheerabad, Hyderabad, India (B.S.); and Daiichi-Sankyo Pharma Development, Edison, NJ (M.F.M.).
Abstract
BACKGROUND AND PURPOSE: Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0-3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin. RESULTS:Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P<0.001; major bleeding 3.03% versus 2.64% per year; P<0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P<0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8-85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36-0.92; P=0.02). No treatment subgroup interactions were found for primary efficacy (P=0.86) or for intracranial hemorrhage (P=0.28). CONCLUSIONS:Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
RCT Entities:
BACKGROUND AND PURPOSE:Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0-3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin. RESULTS: Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P<0.001; major bleeding 3.03% versus 2.64% per year; P<0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P<0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8-85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36-0.92; P=0.02). No treatment subgroup interactions were found for primary efficacy (P=0.86) or for intracranial hemorrhage (P=0.28). CONCLUSIONS:Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
Authors: M Cecilia Bahit; Amit N Vora; Zhuokai Li; Daniel M Wojdyla; Laine Thomas; Shaun G Goodman; Ronald Aronson; J Dedrick Jordan; Brad J Kolls; Keith E Dombrowski; Dragos Vinereanu; Sigrun Halvorsen; Otavio Berwanger; Stephan Windecker; Roxana Mehran; Christopher B Granger; John H Alexander; Renato D Lopes Journal: JAMA Cardiol Date: 2022-07-01 Impact factor: 30.154
Authors: Angela Lowenstern; Sana M Al-Khatib; Lauren Sharan; Ranee Chatterjee; Nancy M Allen LaPointe; Bimal Shah; Ethan D Borre; Giselle Raitz; Adam Goode; Roshini Yapa; J Kelly Davis; Kathryn Lallinger; Robyn Schmidt; Andrzej S Kosinski; Gillian D Sanders Journal: Ann Intern Med Date: 2018-10-30 Impact factor: 51.598