{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:14:49Z","timestamp":1791850489129,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"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":["Clinical Translational Sci"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In the present study, we aimed to investigate the association between urate\u2010lowering drugs and cardiovascular events, primarily focusing on the risk of febuxostat and topiroxostat when compared with allopurinol in Japan. We conducted an observational study with a cohort design using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, including new urate\u2010lowering drugs users between August 1, 2010, and March 31, 2018. Exposure and control groups were defined based on the first prescription of urate\u2010lowering drugs as follows: febuxostat or topiroxostat for exposure groups, allopurinol for the control group, and benzbromarone for the secondary control group. The primary outcome was cardiovascular events, defined as a composite of acute coronary syndrome, cerebral infarction, and cerebral hemorrhage. Hazard ratios were estimated using a Cox proportional hazards model. The number of patients in each exposure and control group was 1,357,671 in the febuxostat group, 83,683 in the topiroxostat group, 1,273,211 in the allopurinol group, and 258,786 in the benzbromarone group. The adjusted hazard ratios for the cardiovascular risk were 0.97 (95% confidence interval [CI]: 0.95\u20130.98) for febuxostat and 0.84 (95% CI: 0.78\u20130.90) for topiroxostat groups. The benzbromarone group exhibited similar results. No increased cardiovascular risk was observed with febuxostat or topiroxostat when compared with allopurinol in patients with hyperuricemia in Japan. These results provide real\u2010world evidence regarding the cardiovascular risk associated with urate\u2010lowering drugs, indicating that no additional safety\u2010related regulatory actions are warranted in Japan.<\/jats:p>","DOI":"10.1111\/cts.13439","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T07:38:59Z","timestamp":1667288339000},"page":"206-215","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Cardiovascular risk of urate\u2010lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan"],"prefix":"10.1111","volume":"16","author":[{"given":"Sono","family":"Sawada","sequence":"first","affiliation":[{"name":"Office of Medical Informatics and Epidemiology Pharmaceuticals and Medical Devices Agency  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Kajiyama","sequence":"additional","affiliation":[{"name":"Office of Medical Informatics and Epidemiology Pharmaceuticals and Medical Devices Agency  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Shida","sequence":"additional","affiliation":[{"name":"Office of Medical Informatics and Epidemiology Pharmaceuticals and Medical Devices Agency  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Kimura","sequence":"additional","affiliation":[{"name":"Office of Pharmacovigilance I Pharmaceuticals and Medical Devices Agency  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Nakazato","sequence":"additional","affiliation":[{"name":"Office of Pharmacovigilance I Pharmaceuticals and Medical Devices Agency  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toyotaka","family":"Iguchi","sequence":"additional","affiliation":[{"name":"Office of Pharmacovigilance II Pharmaceuticals and Medical Devices Agency  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Oniyama","sequence":"additional","affiliation":[{"name":"Office of Pharmacovigilance I Pharmaceuticals and Medical Devices Agency  Tokyo Japan"},{"name":"Office of Pharmacovigilance II Pharmaceuticals and Medical Devices Agency  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieko","family":"Ishiguro","sequence":"additional","affiliation":[{"name":"Office of Medical Informatics and Epidemiology Pharmaceuticals and Medical Devices Agency  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0430-9887","authenticated-orcid":false,"given":"Yoshiaki","family":"Uyama","sequence":"additional","affiliation":[{"name":"Office of Medical Informatics and Epidemiology Pharmaceuticals and Medical Devices Agency  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208307200"},{"key":"e_1_2_10_3_1","unstructured":"ADENURIC 80 mg film\u2010coated tablets. Product Information.Menarini International Operations Luxembourg S.A.https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/adenuric\u2010epar\u2010product\u2010information_en.pdf. Accessed June 3 2022."},{"key":"e_1_2_10_4_1","unstructured":"ULORIC (febuxostat) tablet for oral use. Label (Highrights of prescribing information).Takeda Pharmaceuticals America Inc.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2019\/021856s013lbl.pdf. Accessed June 3 2022."},{"key":"e_1_2_10_5_1","unstructured":"Feburic\u00ae Tablets 10mg 20mg 40mg. Package insert.Teijin Pharma Limited. [in Japanese].https:\/\/www.pmda.go.jp\/PmdaSearch\/iyakuDetail\/ResultDataSetPDF\/470310_3949003F1023_1_15. Accessed June 3 2022."},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710895"},{"key":"e_1_2_10_7_1","unstructured":"FDA adds Boxed Warning for increased risk of death with gout medicine Uloric (febuxostat).FDA Drug Safety Communication. Food and Drug Administration.https:\/\/www.fda.gov\/drugs\/drug\u2010safety\u2010and\u2010availability\/fda\u2010adds\u2010boxed\u2010warning\u2010increased\u2010risk\u2010death\u2010gout\u2010medicine\u2010uloric\u2010febuxostat. Accessed April 27 2022."},{"key":"e_1_2_10_8_1","unstructured":"Adenuric.Procedural steps taken and scientific information after the authorisation.European Medicine Agency.https:\/\/www.ema.europa.eu\/en\/documents\/procedural\u2010steps\u2010after\/adenuric\u2010epar\u2010procedural\u2010steps\u2010taken\u2010scientific\u2010information\u2010after\u2010authorisation_en.pdf. Accessed April 27 2022."},{"key":"e_1_2_10_9_1","unstructured":"Febuxostat.Revision of precautions.Pharmaceuticals and Medical Devices Agency.https:\/\/www.pmda.go.jp\/files\/000230437.pdf. Accessed April 27 2022."},{"key":"e_1_2_10_10_1","unstructured":"Report on investigation results.Pharmaceuticals and Medical Devices Agency.https:\/\/www.pmda.go.jp\/files\/000230432.pdf. Accessed April 27 2022."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz119"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.033992"},{"key":"e_1_2_10_13_1","first-page":"393","article-title":"Major cardiovascular events in patients with gout and associated cardiovascular disease or heart failure and chronic kidney disease initiating a xanthine oxidase inhibitor","volume":"10","author":"Foody J","year":"2017","journal-title":"Am Health Drug Benefits"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex065"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12872-018-0757-9"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/1076189"},{"key":"e_1_2_10_17_1","volume-title":"Clinical Guidelines for the Management of Hyperuricemia and Gout"},{"key":"e_1_2_10_18_1","volume-title":"Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Failure (2017 Revision)"},{"key":"e_1_2_10_19_1","volume-title":"JCS 2018 Guideline on Diagnosis of Chronic Coronary Heart Disease"},{"key":"e_1_2_10_20_1","volume-title":"Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017"},{"key":"e_1_2_10_21_1","first-page":"1","article-title":"Trends in mortality and morbidity of cardiovascular disease in Japan (Wagakoku ni okeru shinshikkan no shibouritsu\/rikanritsu no doukou) [in Japanese]","volume":"53","author":"Hisamatsu T","year":"2018","journal-title":"Jpn J Cardiovasc Dis Prevent"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2018.06.028"},{"key":"e_1_2_10_23_1","volume-title":"Guideline of National Database of Health Insurance Claims and Specific Health Checkups of Japan"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2014-006450"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.4847"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.115.06344"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.13656"},{"key":"e_1_2_10_28_1","unstructured":"Research group on characterization and methods of extraction and analysis of MID\u2010NET data under the research on regulatory science of pharmaceuticals and medical devices supported by Japan Agency for Medical Research and Development Grant No. 17mk0101088h0001: FY2017\u2010FY2019 [in Japanese].https:\/\/amedfind.amed.go.jp\/amed\/index?now=Thu+Nov+03+16%3A14%3A25+JST+2022. Accessed April 27 2022."},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.5423"},{"key":"e_1_2_10_30_1","unstructured":"Act on the Pharmaceuticals and Medical Devices Agency (Act No. 192 of 2002) [in Japanese].https:\/\/elaws.e\u2010gov.go.jp\/document?lawid=414AC0000000192. Accessed April 27 2022."},{"key":"e_1_2_10_31_1","unstructured":"Pharmaceuticals and Medical Devices Agency.MIHARI Project [in Japanese].https:\/\/www.pmda.go.jp\/safety\/surveillance\u2010analysis\/0045.html. Accessed April 27 2022."},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32234-0"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/futurepharmacol2020011"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0066116"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13439","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.13439","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13439","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T18:00:57Z","timestamp":1692295257000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13439"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,11]]},"references-count":33,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1111\/cts.13439"],"URL":"https:\/\/doi.org\/10.1111\/cts.13439","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,11]]},"assertion":[{"value":"2022-07-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}