{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:21:43Z","timestamp":1777594903057,"version":"3.51.4"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Cardiovascular Quality and Outcomes"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation\u2013Thrombolysis In Myocardial Infarction) compared higher-dose edoxaban regimen (HD-ER) and lower-dose edoxaban regimen with well-managed warfarin in 21\u2009105 patients with atrial fibrillation. The risk factors and clinical impact of gastrointestinal bleeding (GIB) in this trial have not been described in detail.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              This analysis was undertaken to identify risk factors for major GIB (MGIB) and compare the severity and outcomes of GIB with edoxaban and warfarin. During 2.8 years mean follow-up, there were 579 MGIB (1.22% per year), of which 63 were life-threatening or fatal (0.13% per year). Male sex, increased age, prior GIB, concomitant aspirin, lower baseline hemoglobin, renal dysfunction, and higher HAS-BLED and CHADS\n              <jats:sub>2<\/jats:sub>\n              scores were independently associated with the risk of MGIB. Whereas the annual rate of MGIB was higher with HD-ER than with warfarin (1.53% and 1.25%, respectively; hazard ratio, 1.23; 95% confidence interval, 1.02\u20131.48;\n              <jats:italic>P<\/jats:italic>\n              =0.033), the annual rates of life-threatening or fatal GIB were similar (0.15% and 0.18%, respectively). Several indicators of more severe GIB, including hemodynamic instability, hospitalization, \u2265 4 U transfusion, and hemoglobin loss \u22655 g\/dL, were similar with HD-ER and warfarin, whereas surgery required to manage bleeding was less frequent with HD-ER. Lower-dose edoxaban regimen, which achieved 50% lower trough edoxaban levels, was associated with significantly less MGIB than warfarin.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>MGIB occurred more frequently with HD-ER than warfarin. The rates of life-threatening or fatal GIB were low and similar with both HD-ER and warfarin. Clinical outcomes were generally favorable. The correlation between dose, trough edoxaban level, and the risk of GIB risk suggests GIB is exposure-related.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical Trial Registration:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              . Unique identifier: NCT00781391.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circoutcomes.117.003998","type":"journal-article","created":{"date-parts":[[2018,5,10]],"date-time":"2018-05-10T09:10:18Z","timestamp":1525943418000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Gastrointestinal Bleeding With Edoxaban Versus Warfarin"],"prefix":"10.1161","volume":"11","author":[{"given":"James","family":"Aisenberg","sequence":"first","affiliation":[{"name":"Department of Medicine, Icahn School of Medicine, Mount Sinai Medical Center, New York, NY (J.A., P.C.-M.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prapti","family":"Chatterjee-Murphy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Icahn School of Medicine, Mount Sinai Medical Center, New York, NY (J.A., P.C.-M.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn","family":"Friedman Flack","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pennsylvania, Philadelphia (K.F.F.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey I.","family":"Weitz","sequence":"additional","affiliation":[{"name":"McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada (J.I.W.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian T.","family":"Ruff","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Division of Cardiovascular Medicine and Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA (C.T.R., F.N., E.M.A., E.B., R.P.G.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Nordio","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Division of Cardiovascular Medicine and Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA (C.T.R., F.N., E.M.A., E.B., R.P.G.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele F.","family":"Mercuri","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Pharma Development, Basking Ridge, NJ (M.F.M., Y.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youngsook","family":"Choi","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Pharma Development, Basking Ridge, NJ (M.F.M., Y.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elliott M.","family":"Antman","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Division of Cardiovascular Medicine and Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA (C.T.R., F.N., E.M.A., E.B., R.P.G.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugene","family":"Braunwald","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Division of Cardiovascular Medicine and Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA (C.T.R., F.N., E.M.A., E.B., R.P.G.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert P.","family":"Giugliano","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Division of Cardiovascular Medicine and Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA (C.T.R., F.N., E.M.A., E.B., R.P.G.)"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1009638"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1310907"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0905561"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107039"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000041"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.08-0658"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62343-0"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2017.04.031"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH13-02-0150"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.115386"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2014.946"},{"key":"e_1_3_3_13_2","volume-title":"Full Prescribing Information","author":"SAVAYSA\u00ae (edoxaban)","year":"2015","unstructured":"SAVAYSA\u00ae (edoxaban). 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