{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:37:56Z","timestamp":1784281076731,"version":"3.55.0"},"reference-count":30,"publisher":"BMJ","issue":"3","funder":[{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Heart"],"accepted":{"date-parts":[[2018,8,2]]},"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Compare the effect of apixaban and warfarin on coagulation and primary haemostasis biomarkers in atrial fibrillation (AF).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The biomarker substudy from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial included 4850 patients with AF randomised to treatment with apixaban or warfarin. Sixty per cent of patients used vitamin K antagonist (VKA) within 7 days before randomisation. Prothrombin fragment 1+2 (F1+2), D-dimer, soluble CD40 ligand (sCD40L) and von Willebrand factor (vWF) antigen were analysed at randomisation and after 2\u2009months of study treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In patients not on VKA treatment at randomisation, F1+2\u2009and D-dimer levels were decreased by 25% and 23%, respectively, with apixaban, and by 59% and 38%, respectively, with warfarin (p&lt;0.0001 for treatment differences for both). In patients on VKA at randomisation, F1+2\u2009and D-dimer levels increased by 41% and 10%, respectively, with apixaban and decreased by 37% and 11%, respectively, with warfarin (p&lt;0.0001 for treatment differences for both). sCD40L levels were slightly increased at 2\u2009months, regardless of VKA or randomised treatment. Apixaban and warfarin also both reduced vWF antigen regardless of VKA treatment. The efficacy (stroke) and safety (bleeding) of apixaban compared with warfarin was similar irrespectively of biomarker levels at 2\u2009months.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Treatment with apixaban compared with warfarin for stroke prevention in patients with AF was associated with less reduction in thrombin generation and fibrin turnover. This effect of apixaban could contribute to the clinical results where apixaban was superior to warfarin both in stroke prevention and in reducing bleeding risk.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"NCT00412984\" ext-link-type=\"clintrialgov\">NCT00412984<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/heartjnl-2018-313351","type":"journal-article","created":{"date-parts":[[2019,2,16]],"date-time":"2019-02-16T10:25:22Z","timestamp":1550312722000},"page":"235-242","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Effect of apixaban compared with warfarin on coagulation markers in atrial fibrillation"],"prefix":"10.1136","volume":"105","clinical-trial-number":[{"clinical-trial-number":"nct00412984","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Christina","family":"Christersson","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Wallentin","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden"},{"name":"Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrika","family":"Andersson","sequence":"additional","affiliation":[{"name":"Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H","family":"Alexander","sequence":"additional","affiliation":[{"name":"Medical Duke Clinical Research Institute, Duke University, Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Alings","sequence":"additional","affiliation":[{"name":"Working Group on Cardiovascular Research, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"De Caterina","sequence":"additional","affiliation":[{"name":"Gabriele d\u2019Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard J","family":"Gersh","sequence":"additional","affiliation":[{"name":"Mayo Clinic College of Medicine, Rochester, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B","family":"Granger","sequence":"additional","affiliation":[{"name":"Medical Duke Clinical Research Institute, Duke University, Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrun","family":"Halvorsen","sequence":"additional","affiliation":[{"name":"Department of Cardiology B, Oslo University Hospital and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hanna","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Huber","sequence":"additional","affiliation":[{"name":"3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, and Sigmund Freud University, Medical School, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine M","family":"Hylek","sequence":"additional","affiliation":[{"name":"Boston University Medical Center, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato D","family":"Lopes","sequence":"additional","affiliation":[{"name":"Medical Duke Clinical Research Institute, Duke University, Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung-Hee","family":"Oh","sequence":"additional","affiliation":[{"name":"Seoul National University Hospital, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agneta","family":"Siegbahn","sequence":"additional","affiliation":[{"name":"Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden"},{"name":"Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2018,9,12]]},"reference":[{"key":"2025100702400057000_105.3.235.1","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.ijcard.2015.03.092","article-title":"Increased prothrombotic profile in the left atrial appendage of atrial fibrillation patients","volume":"185","author":"Breitenstein","year":"2015","journal-title":"Int J Cardiol"},{"key":"2025100702400057000_105.3.235.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(96)00427-5"},{"key":"2025100702400057000_105.3.235.3","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.73.6.527"},{"key":"2025100702400057000_105.3.235.4","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12638"},{"key":"2025100702400057000_105.3.235.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.12.049"},{"key":"2025100702400057000_105.3.235.6","doi-asserted-by":"publisher","DOI":"10.1378\/chest.07-2745"},{"key":"2025100702400057000_105.3.235.7","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000077912.12202.FC"},{"key":"2025100702400057000_105.3.235.8","doi-asserted-by":"crossref","first-page":"e215","DOI":"10.1016\/j.jstrokecerebrovasdis.2013.10.011","article-title":"Adenosine diphosphate-induced platelet aggregation might contribute to poor outcomes in atrial fibrillation-related ischemic stroke","volume":"23","author":"Choi","year":"2014","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"2025100702400057000_105.3.235.9","doi-asserted-by":"publisher","DOI":"10.1111\/eci.12140"},{"key":"2025100702400057000_105.3.235.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107039"},{"key":"2025100702400057000_105.3.235.11","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1160\/TH10-06-0393","article-title":"Apixaban decreases coagulation activity in patients with acute deep-vein thrombosis","volume":"105","author":"Barrett","year":"2011","journal-title":"Thromb Haemost"},{"key":"2025100702400057000_105.3.235.12","doi-asserted-by":"publisher","DOI":"10.1160\/TH10-04-0247"},{"key":"2025100702400057000_105.3.235.13","doi-asserted-by":"publisher","DOI":"10.1160\/TH10-02-0097"},{"key":"2025100702400057000_105.3.235.14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2005.01204.x"},{"key":"2025100702400057000_105.3.235.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2009.07.035"},{"key":"2025100702400057000_105.3.235.16","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.thromres.2016.10.011","article-title":"Effect of rivaroxaban on prothrombin fragment 1+2 compared with warfarin in patients with acute cardioembolic stroke: Insight from its serial measurement","volume":"148","author":"Hagii","year":"2016","journal-title":"Thromb Res"},{"key":"2025100702400057000_105.3.235.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2011.12.023"},{"key":"2025100702400057000_105.3.235.18","doi-asserted-by":"publisher","DOI":"10.1253\/circj.68.29"},{"key":"2025100702400057000_105.3.235.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.11.046"},{"key":"2025100702400057000_105.3.235.20","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/s00380-016-0912-0","article-title":"Assessment of trough rivaroxaban concentrations on markers of coagulation activation in nonvalvular atrial fibrillation population","volume":"32","author":"Kitagawa","year":"2017","journal-title":"Heart Vessels"},{"key":"2025100702400057000_105.3.235.21","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1055\/s-0037-1615530","article-title":"D-dimer and factor VIIa in atrial fibrillation - prognostic values for cardiovascular events and effects of anticoagulation therapy. A RE-LY substudy","volume":"115","author":"Siegbahn","year":"2016","journal-title":"Thromb Haemost"},{"key":"2025100702400057000_105.3.235.22","doi-asserted-by":"publisher","DOI":"10.1160\/TH13-01-0032"},{"key":"2025100702400057000_105.3.235.23","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.clinbiochem.2014.03.003","article-title":"D-dimer predicts major bleeding, cardiovascular events and all-cause mortality during warfarin treatment","volume":"47","author":"Lind","year":"2014","journal-title":"Clin Biochem"},{"key":"2025100702400057000_105.3.235.24","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1001\/jamacardio.2016.0199","article-title":"Outcomes in a warfarin-treated population with atrial fibrillation","volume":"1","author":"Bj\u00f6rck","year":"2016","journal-title":"JAMA Cardiol"},{"key":"2025100702400057000_105.3.235.25","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.thromres.2016.02.028","article-title":"Edoxaban, a direct factor Xa inhibitor, suppresses tissue-factor induced human platelet aggregation and clot-bound factor Xa in vitro: comparison with an antithrombin-dependent factor Xa inhibitor, fondaparinux","volume":"141","author":"Honda","year":"2016","journal-title":"Thromb Res"},{"key":"2025100702400057000_105.3.235.26","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/s00392-015-0922-4","article-title":"Monocyte-platelet aggregates and CD11b expression as markers for thrombogenicity in atrial fibrillation","volume":"105","author":"Pfluecke","year":"2016","journal-title":"Clin Res Cardiol"},{"key":"2025100702400057000_105.3.235.27","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.31.4.828"},{"key":"2025100702400057000_105.3.235.28","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0905561"},{"key":"2025100702400057000_105.3.235.29","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1310907"},{"key":"2025100702400057000_105.3.235.30","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1009638"}],"container-title":["Heart"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/heartjnl-2018-313351","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T09:40:08Z","timestamp":1759830008000},"score":1,"resource":{"primary":{"URL":"https:\/\/heart.bmj.com\/lookup\/doi\/10.1136\/heartjnl-2018-313351"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,12]]},"references-count":30,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,1,15]]},"published-print":{"date-parts":[[2019,2]]}},"alternative-id":["10.1136\/heartjnl-2018-313351"],"URL":"https:\/\/doi.org\/10.1136\/heartjnl-2018-313351","relation":{},"ISSN":["1355-6037","1468-201X"],"issn-type":[{"value":"1355-6037","type":"print"},{"value":"1468-201X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,12]]}}}