{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T09:17:02Z","timestamp":1788599822596,"version":"build-2803163510"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T00:00:00Z","timestamp":1565049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Center for Big Data Analytics and Statistics","award":["CLRPG3D0045"],"award-info":[{"award-number":["CLRPG3D0045"]}]},{"DOI":"10.13039\/100007225","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006705","name":"National Taipei University of Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006705","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chang Gung Memorial Hospital Joint Research Programme","award":["NTUT-CGMH-108-07"],"award-info":[{"award-number":["NTUT-CGMH-108-07"]}]},{"name":"NTUT-CGMH Joint Research Programme"},{"DOI":"10.13039\/100012553","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPG3I0091"],"award-info":[{"award-number":["CMRPG3I0091"]}],"id":[{"id":"10.13039\/100012553","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012553","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CORPG3F0561"],"award-info":[{"award-number":["CORPG3F0561"]}],"id":[{"id":"10.13039\/100012553","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology of Taiwan","doi-asserted-by":"publisher","award":["107-2314-B-182A-159-MY2"],"award-info":[{"award-number":["107-2314-B-182A-159-MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>This study compared the risk of major bleeding between atrial fibrillation (AF) patients who took non-vitamin K antagonist oral anticoagulants (NOACs) and antiepileptic drugs (AEDs) concurrently and those who took only NOACs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We performed a retrospective cohort study using Taiwan National Health Insurance database and included AF patients who received NOAC prescriptions from 1 June 2012 to 31 December 2017. The major bleeding risks of person-quarters exposed to NOAC and 11 concurrent AEDs (carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, valproic acid, and zonisamide) were compared with person-quarters exposed to NOAC alone. Adjusted incidence rate differences between NOAC with or without concurrent AEDs were estimated using Poisson regression models weighted by the inverse probability of treatment. Among 104\u00a0319 patients (age 75.0\u2009\u00b1\u200910.3\u2009years; men, 56.2%), 8546 major bleeding events occurred during 731\u00a0723 person-quarters with NOAC prescriptions. Concurrent AED use was found in 15.3% of NOAC-treated patients. Concurrent use of NOAC with valproic acid, phenytoin, or levetiracetam increased adjusted incidence rates per 1000 person-years of major bleeding more significantly than NOAC alone: 153.49 for NOAC plus valproic acid vs. 55.06 for NOAC alone [difference 98.43, 95% confidence interval (CI) 82.37\u2013114.49]; 135.83 for NOAC plus phenytoin vs. 54.43 for NOAC alone (difference 81.4, 95% CI 60.14\u2013102.66); and 132.96 for NOAC plus levetiracetam vs. 53.08 for NOAC alone (difference 79.88, 95% CI 64.47\u201395.30).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>For AF patients, the concurrent use of NOACs and valproic acid, phenytoin, or levetiracetam was associated with a higher risk of major bleeding.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ehjcvp\/pvz035","type":"journal-article","created":{"date-parts":[[2019,8,2]],"date-time":"2019-08-02T08:12:07Z","timestamp":1564733527000},"page":"147-154","source":"Crossref","is-referenced-by-count":49,"title":["Assessing major bleeding risk in atrial fibrillation patients concurrently taking non-vitamin K antagonist oral anticoagulants and antiepileptic drugs"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9437-5350","authenticated-orcid":false,"given":"Chun-Li","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fushin St. Kweishan District, 33305 Taoyuan City, Taiwan"},{"name":"College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Kweishan District, 33302 Taoyuan City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9918-4369","authenticated-orcid":false,"given":"Victor Chien-Chia","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fushin St. Kweishan District, 33305 Taoyuan City, Taiwan"},{"name":"College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Kweishan District, 33302 Taoyuan City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo-Hsuan","family":"Chang","sequence":"additional","affiliation":[{"name":"College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Kweishan District, 33302 Taoyuan City, Taiwan"},{"name":"Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fushin St. Kweishan District, 33305 Taoyuan City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Tzu","family":"Tu","sequence":"additional","affiliation":[{"name":"Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fushin St. Kweishan District, 33305 Taoyuan City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Fu","family":"Kuo","sequence":"additional","affiliation":[{"name":"College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Kweishan District, 33302 Taoyuan City, Taiwan"},{"name":"Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fushin St. Kweishan District, 33305 Taoyuan City, Taiwan"},{"name":"Division of Rheumatology, Orthopaedics and Dermatology, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3224-7238","authenticated-orcid":false,"given":"Yu-Tung","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fushin St. Kweishan District, 33305 Taoyuan City, Taiwan"},{"name":"Graduate Institute of Nursing, Chang Gung University of Science and Technology, No. 261, Wenhua 1st Road, Kweishan District, 33302 Taoyuan City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0361-6348","authenticated-orcid":false,"given":"Pao-Hsien","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fushin St. Kweishan District, 33305 Taoyuan City, Taiwan"},{"name":"College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Kweishan District, 33302 Taoyuan City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Ching","family":"Kuo","sequence":"additional","affiliation":[{"name":"Institute of Organic and Polymeric Materials, National Taipei University of Technology, No. 1, Section 3, Zhongxiao E Rd, Da-an District, 10607 Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0462-2344","authenticated-orcid":false,"given":"Shang-Hung","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fushin St. Kweishan District, 33305 Taoyuan City, Taiwan"},{"name":"College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Kweishan District, 33302 Taoyuan City, Taiwan"},{"name":"Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fushin St. Kweishan District, 33305 Taoyuan City, Taiwan"},{"name":"Graduate Institute of Nursing, Chang Gung University of Science and Technology, No. 261, Wenhua 1st Road, Kweishan District, 33302 Taoyuan City, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,8,6]]},"reference":[{"key":"2020090710535110500_pvz035-B1","doi-asserted-by":"crossref","first-page":"e7097","DOI":"10.1136\/bmj.e7097","article-title":"Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis","volume":"345","author":"Rasmussen","year":"2012","journal-title":"BMJ"},{"key":"2020090710535110500_pvz035-B2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s11239-016-1446-0","article-title":"Vitamin K antagonists: relative strengths and weaknesses vs. direct oral anticoagulants for stroke prevention in patients with atrial fibrillation","volume":"43","author":"Zirlik","year":"2017","journal-title":"J Thromb Thrombolysis"},{"key":"2020090710535110500_pvz035-B3","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1001\/jama.2017.13883","article-title":"Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation","volume":"318","author":"Chang","year":"2017","journal-title":"JAMA"},{"key":"2020090710535110500_pvz035-B4","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1093\/eurheartj\/ehy136","article-title":"The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation","volume":"39","author":"Steffel","year":"2018","journal-title":"Eur Heart J"},{"key":"2020090710535110500_pvz035-B5","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1111\/head.12781","article-title":"The use of antiepileptics in migraine prophylaxis","volume":"56","author":"Bagnato","year":"2016","journal-title":"Headache"},{"key":"2020090710535110500_pvz035-B6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yebeh.2011.03.011","article-title":"Antiepileptic drugs in the treatment of psychiatric disorders","volume":"21","author":"Kaufman","year":"2011","journal-title":"Epilepsy Behav"},{"key":"2020090710535110500_pvz035-B7","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.eplepsyres.2016.06.003","article-title":"Interactions between non-vitamin K oral anticoagulants and antiepileptic drugs","volume":"126","author":"Stollberger","year":"2016","journal-title":"Epilepsy Res"},{"key":"2020090710535110500_pvz035-B8","doi-asserted-by":"crossref","first-page":"1572.","DOI":"10.1093\/eurheartj\/ehz091","article-title":"Combination of non-vitamin K antagonist oral anticoagulants and antiepileptic drugs","volume":"40","author":"Kurt","year":"2019","journal-title":"Eur Heart J"},{"key":"2020090710535110500_pvz035-B9","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/j.jacc.2016.06.062","article-title":"Thromboembolic, bleeding, and mortality risks of rivaroxaban and dabigatran in Asians with nonvalvular atrial fibrillation","volume":"68","author":"Chan","year":"2016","journal-title":"J Am Coll Cardiol"},{"key":"2020090710535110500_pvz035-B10","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.thromres.2017.10.004","article-title":"Assessment of the coding accuracy of warfarin-related bleeding events","volume":"159","author":"Delate","year":"2017","journal-title":"Thromb Res"},{"key":"2020090710535110500_pvz035-B11","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0021-9681(87)90171-8","article-title":"A new method of classifying prognostic comorbidity in longitudinal studies: development and validation","volume":"40","author":"Charlson","year":"1987","journal-title":"J Chronic Dis"},{"key":"2020090710535110500_pvz035-B12","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1378\/chest.09-1584","article-title":"Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation","volume":"137","author":"Lip","year":"2010","journal-title":"Chest"},{"key":"2020090710535110500_pvz035-B13","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1378\/chest.10-0134","article-title":"A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey","volume":"138","author":"Pisters","year":"2010","journal-title":"Chest"},{"key":"2020090710535110500_pvz035-B14","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1111\/ane.12776","article-title":"Patterns of antiepileptic drug prescription in Sweden: a register-based approach","volume":"136","author":"Bolin","year":"2017","journal-title":"Acta Neurol Scand"},{"key":"2020090710535110500_pvz035-B15","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1111\/j.1528-1157.1981.tb04094.x","article-title":"Sodium valproate, platelet dysfunction, and bleeding","volume":"22","author":"Loiseau","year":"1981","journal-title":"Epilepsia"},{"key":"2020090710535110500_pvz035-B16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40268-017-0224-6","article-title":"The risk of thrombocytopenia during valproic acid therapy: a critical summary of available clinical data","volume":"18","author":"Buoli","year":"2018","journal-title":"Drugs R D"},{"key":"2020090710535110500_pvz035-B17","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j.1528-1157.1999.tb00709.x","article-title":"Valproate treatment and platelet function: the role of arachidonate metabolites","volume":"40","author":"Kis","year":"1999","journal-title":"Epilepsia"},{"key":"2020090710535110500_pvz035-B18","doi-asserted-by":"crossref","first-page":"767","DOI":"10.2147\/DDDT.S47718","article-title":"Valproic acid-associated low fibrinogen and delayed intracranial hemorrhage: case report and mini literature review","volume":"7","author":"Chen","year":"2013","journal-title":"Drug Des Devel Ther"},{"key":"2020090710535110500_pvz035-B19","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1055\/s-0037-1617026","article-title":"Acquired von Willebrand syndrome as side effect of valproic acid therapy in children is rare","volume":"29","author":"Eberl","year":"2009","journal-title":"Hamostaseologie"},{"key":"2020090710535110500_pvz035-B20","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1046\/j.0306-5251.2001.01474.x","article-title":"In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)","volume":"52","author":"Wen","year":"2001","journal-title":"Br J Clin Pharmacol"},{"key":"2020090710535110500_pvz035-B21","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1177\/2042098611411127","article-title":"New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?","volume":"2","author":"French","year":"2011","journal-title":"Ther Adv Drug Saf"},{"key":"2020090710535110500_pvz035-B22","first-page":"250","article-title":"In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent","volume":"27","author":"Nicolas","year":"1999","journal-title":"Drug Metab Dispos"},{"key":"2020090710535110500_pvz035-B23","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.eplepsyres.2010.12.013","article-title":"Antiepileptic drugs modulate P-glycoproteins in the brain: a mice study with 11C-desmethylloperamide","volume":"94","author":"Moerman","year":"2011","journal-title":"Epilepsy Res"},{"key":"2020090710535110500_pvz035-B24","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.neuropharm.2006.07.038","article-title":"Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein","volume":"52","author":"Baltes","year":"2007","journal-title":"Neuropharmacology"},{"key":"2020090710535110500_pvz035-B25","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.eplepsyres.2003.12.007","article-title":"Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats","volume":"58","author":"Potschka","year":"2004","journal-title":"Epilepsy Res"},{"key":"2020090710535110500_pvz035-B26","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0920-1211(01)00253-4","article-title":"Repeated administration of the novel antiepileptic agent levetiracetam does not alter digoxin pharmacokinetics and pharmacodynamics in healthy volunteers","volume":"46","author":"Levy","year":"2001","journal-title":"Epilepsy Res"},{"key":"2020090710535110500_pvz035-B27"},{"key":"2020090710535110500_pvz035-B28","doi-asserted-by":"crossref","first-page":"73","DOI":"10.5853\/jos.2014.16.2.73","article-title":"New oral anticoagulants may be particularly useful for Asian stroke patients","volume":"16","author":"Bang","year":"2014","journal-title":"J Stroke"}],"container-title":["European Heart Journal - Cardiovascular Pharmacotherapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/ehjcvp\/advance-article-pdf\/doi\/10.1093\/ehjcvp\/pvz035\/29200886\/pvz035.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/ehjcvp\/article-pdf\/6\/3\/147\/33722685\/pvz035.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/ehjcvp\/article-pdf\/6\/3\/147\/33722685\/pvz035.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,9,7]],"date-time":"2020-09-07T10:54:07Z","timestamp":1599476047000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ehjcvp\/article\/6\/3\/147\/5544109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,6]]},"references-count":28,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,8,6]]},"published-print":{"date-parts":[[2020,5,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ehjcvp\/pvz035","relation":{},"ISSN":["2055-6837","2055-6845"],"issn-type":[{"value":"2055-6837","type":"print"},{"value":"2055-6845","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,5]]},"published":{"date-parts":[[2019,8,6]]}}}