{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:23:15Z","timestamp":1792686195854,"version":"4.5.0"},"reference-count":21,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,5,19]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Edoxaban is a direct oral anticoagulant used for stroke prevention in patients with atrial fibrillation (AF) and treatment of venous thromboembolism. We examined the relationship between trough edoxaban concentrations (E\u2010trough) and prothrombin time (PT) and major bleeding in very old Japanese patients with atrial fibrillation and high bleeding risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">In this post hoc analysis of the multicenter, randomized, double\u2010blind, placebo\u2010controlled ELDERCARE\u2010AF (Study of DU\u2010176b Aged 80\u2009Years or Older) trial, patients were randomly assigned 1:1 to edoxaban 15\u2009mg or placebo once daily. After 8\u2009weeks of treatment, E\u2010trough was determined and the incidence of major bleeding examined in each quartile. The incidence of major bleeding by PT was also examined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Data were obtained from 427 patients. E\u2010trough (ng\/mL) was \u22649.24 in the first quartile (107 patients), &gt;9.24 to \u226413.6 in the second (111 patients), &gt;13.6 to \u226421.6 in the third (103 patients), and &gt;21.6 in the fourth (106 patients). Older age, lower body weight, lower creatinine clearance, and the presence of congestive heart failure were independent predictors of higher E\u2010trough. Higher E\u2010trough was associated with greater incidence of major bleeding (0.8%, 1.9%, 3.4%, and 4.7%\/year, respectively,\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.0408). There was a significant positive correlation between E\u2010trough and PT (\n                      <jats:italic toggle=\"no\">r<\/jats:italic>\n                      =0.426,\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      &lt;0.0001). Significantly more major bleeding events occurred in the longer (&gt;13\u2009seconds) versus shorter (\u226413\u2009seconds) PT subgroups (4.61% versus 0.98%\/year,\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.0060).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Several factors were associated with higher E\u2010trough and increased risk of major bleeding events. PT &gt;13 seconds may be a useful predictor of the development of major bleeding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Registration<\/jats:title>\n                    <jats:p xml:lang=\"en\">\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: NCT02801669.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.042950","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T11:06:41Z","timestamp":1778756801000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Association of Edoxaban Pharmacokinetics With Bleeding in Older Patients With Atrial Fibrillation Treated With Low\u2010Dose Edoxaban: A Post Hoc Analysis of a Randomized Controlled Trial"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3202-7203","authenticated-orcid":false,"given":"Ken","family":"Okumura","sequence":"first","affiliation":[{"name":"Saiseikai Kumamoto Hospital","place":["Kumamoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2348-7646","authenticated-orcid":false,"given":"Masaharu","family":"Akao","sequence":"additional","affiliation":[{"name":"National Hospital Organization Kyoto Medical Center","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8723-7489","authenticated-orcid":false,"given":"Masayuki","family":"Fukuzawa","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Igawa","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Global DX, Daiichi Sankyo Co., Ltd.","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2544-8464","authenticated-orcid":false,"given":"Takeshi","family":"Yamashita","sequence":"additional","affiliation":[{"name":"The Cardiovascular Institute","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-25460-9_3"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15026"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.10-0134"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2012883"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2017.08.017"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0044-1785511"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH10-01-0066"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.057190"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.122.024970"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61943-7"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-22-0170"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy807"},{"key":"e_1_3_2_14_2","article-title":"Dose reduction of edoxaban in patients 80\u2009years and older with atrial fibrillation: post hoc analysis of the ENGAGE AF\u2010TIMI 48 randomized clinical trial","volume":"10","author":"Zimerman A","year":"2024","unstructured":"Zimerman A, Braunwald E, Steffel J, et\u00a0al. Dose reduction of edoxaban in patients 80\u2009years and older with atrial fibrillation: post hoc analysis of the ENGAGE AF\u2010TIMI 48 randomized clinical trial. JAMA Cardiol. 2024;10:e241793.","journal-title":"JAMA Cardiol"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1177\/1076029616638506"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11239-020-02326-x"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-14-0942"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-020-02896-y"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12603-017-0982-4"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.033933"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.archger.2009.06.005"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacadv.2025.101757"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.125.042950","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:36:54Z","timestamp":1789713414000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.125.042950"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,19]]},"references-count":21,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,5,19]]}},"alternative-id":["10.1161\/JAHA.125.042950"],"URL":"https:\/\/doi.org\/10.1161\/jaha.125.042950","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,19]]},"assertion":[{"value":"2025-04-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e042950"}}