{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:12:23Z","timestamp":1792811543405,"version":"4.5.0"},"reference-count":77,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T00:00:00Z","timestamp":1628553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:p>Concomitant use of direct oral anticoagulants (DOACs) and medications with inhibition\/induction effect on P\u2010gp\/CYP3A might increase risk of bleeding\/treatment failure, respectively. We designed a nested case\u2010control study within a Clalit cohort of patients with atrial fibrillation (AF) and a cohort of patients with venous thromboembolism, new users of a DOAC (January 1, 2010 to August 24, 2020). Propensity scores were constructed from demographic\/clinical characteristics, and medications at cohort entry. Each case of: (i) serious bleeding event; (ii) stroke\/systemic emboli (SE) in patients with AF; (iii) recurrent thromboembolism in patients with thromboembolism, was matched by age, sex, length of follow\u2010up, year of cohort entry, DOAC type, and DOAC indication, to up to 20 controls. Within 89,284 patients with AF and venous thromboembolism and 126,302 patient\u2010years of follow\u2010up, there were 1,587 serious bleeding events. Risk of serious bleeding increased in association with concurrent prescription of P\u2010gp\/CYP3A4 inhibitors. Specifically, higher bleeding risk was associated with dabigatran\u2010verapamil, rivaroxaban\u2010verapamil, and rivaroxaban\u2010amiodarone concurrent prescriptions: adjusted odds ratios (ORs) 2.29 (1.13\u20134.60), 2.18 (1.07\u20134.40), and 1.68 (1.14\u20132.49), respectively. There were 1,116 events of stroke\/SE, in 79,302 DOAC\u2010treated patients with AF and 118,124 patient\u2010years of follow\u2010up. Concomitant use of phenytoin, carbamazepine, valproic acid, or levetiracetam was associated with risk for stroke\/SE: adjusted OR 2.18 (1.55\u20133.10). Risk of recurrent venous thromboembolism could not be assessed due to the low number of cases. Concurrent prescriptions of dabigatran or rivaroxaban with verapamil, and of rivaroxaban with amiodarone, are associated with increased risk for serious bleeding. Higher risk for stroke\/SE in patients with AF is associated with concurrent prescriptions of DOACs with phenytoin, carbamazepine, valproic acid, or levetiracetam.<\/jats:p>","DOI":"10.1002\/cpt.2369","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T11:58:35Z","timestamp":1626695915000},"page":"1526-1536","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":100,"title":["Association Between Use of Pharmacokinetic\u2010Interacting Drugs and Effectiveness and Safety of Direct Acting Oral Anticoagulants: Nested Case\u2010Control Study"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4369-6813","authenticated-orcid":false,"given":"Naomi","family":"Gronich","sequence":"first","affiliation":[{"name":"Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center, Clalit Health Services Haifa Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine Technion\u2013Israel Institute of Technology Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nili","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center, Clalit Health Services Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mordechai","family":"Muszkat","sequence":"additional","affiliation":[{"name":"Department of Medicine Hadassah Hebrew University Medical Center Jerusalem Israel"},{"name":"Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,10]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0905561"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107039"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1009638"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-014-7462-0"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2016-309901"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2005.04.017"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3028"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-017-0434-x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.111.180240"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.112.050260"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200342010-00003"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199835050-00003"},{"key":"e_1_2_10_13_1","unstructured":"US Food and Drug Administration.Drug interaction labeling<https:\/\/www.fda.gov\/drugs\/drug\u2010interactions\u2010labeling\/drug\u2010development\u2010and\u2010drug\u2010interactions\u2010table\u2010substrates\u2010inhibitors\u2010and\u2010inducers#table3\u20102>"},{"key":"e_1_2_10_14_1","unstructured":"Flockhart D.A.Drug Interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine <https:\/\/drug\u2010interactions.medicine.iu.edu> (2007). Accessed January 5 2021."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2020.1835"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.150580"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/1060028013504741"},{"key":"e_1_2_10_18_1","volume-title":"Eliquis (Apixaban) [Prescribing Information]","author":"ELIQUIS (apixaban) label (fda.gov)","year":"2012"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-021-00795-z"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.647"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/phar.1698"},{"key":"e_1_2_10_22_1","first-page":"A6568","article-title":"Longembolie door interactie tussen rivaroxaban en carbamazepine [Pulmonary embolism due to interaction between rivaroxaban and carbamazepine]","volume":"157","author":"Risselada A.J.","year":"2013","journal-title":"Ned Tijdschr. Geneeskd"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.4081\/cp.2015.788"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.01067"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy136"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2020.08.016"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.20513"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2101765"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1177\/009127009903900508"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-020-02936-7"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007568811691"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.TP.0000084873.20157.67"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200645110-00002"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2016.06.003"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f880"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.107.019083"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2007.02899.x"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/1477-9560-11-10"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.029694"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.108.023143"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.245993"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12075"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12541"},{"key":"e_1_2_10_44_1","unstructured":"Boehringer Ingelheim International GmbH: PradaxaW (dabigatran etexilate) summary of product characteristics<http:\/\/www.emea.europa.eu\/docs\/en_GB\/document_library\/EPAR_\u2010Product_Information\/human\/000829\/WC500041059.pdf> (2013)."},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-019-06907-8"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.3593"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11239-020-02037-3"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-020-03015-7"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2017.11.047"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.13883"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.03.031"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e3181a819a1"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19325-x"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nucmedbio.2013.05.012"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.116.073411"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.12.072"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.162.4.405"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy566.5075"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1021\/js970316d"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0000000000000644"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics11030133"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2015.03.013"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1040"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2017.05.026"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13419"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2018.08.001"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.04.011"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.2174\/156720208784310196"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706830"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2008.01.071"},{"key":"e_1_2_10_71_1","first-page":"250","article-title":"In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent","volume":"27","author":"Nicolas J.M.","year":"1999","journal-title":"Drug Metab. Dispos."},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(01)00253-4"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40268-014-0045-9"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-019-00677-5"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11239-019-01823-y"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13577"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0218878"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2369","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.2369","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2369","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T08:38:44Z","timestamp":1699346324000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.2369"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,10]]},"references-count":77,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1002\/cpt.2369"],"URL":"https:\/\/doi.org\/10.1002\/cpt.2369","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,10]]},"assertion":[{"value":"2021-04-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}