{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T21:09:12Z","timestamp":1776805752196,"version":"3.51.2"},"reference-count":27,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"unspecified","delay-in-days":21,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This work was supported by a research grant from the Jeju National University Hospital in 2018","award":["2018-26"],"award-info":[{"award-number":["2018-26"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2022,5,4]]},"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>The Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout (CARES) trial suggested a higher risk of cardiovascular (CV) death from febuxostat than from allopurinol. However, a significant number of patients died after discontinuation of febuxostat or allopurinol. We investigated whether major adverse cardiovascular events (MACE) and CV death were increased because of discontinuation of febuxostat or allopurinol using the CARES trial data.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We compared the MACE that occurred during administration and after discontinuation in the initial phase after discontinuation, and we compared the CV and non-CV mortality rates in the initial phase after discontinuation to determine the impact of discontinuation of febuxostat or allopurinol.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Among 6190 patients, the incidence rate per 100 person-years for MACE was 3.11 during administration and 6.71 after discontinuation. MACE was significantly increased after discontinuation compared with that during administration within 1\u2009month (HR 7.40; 95% CI 5.38 to 10.17) and 6 months (HR 5.22; 95%\u2009CI 4.26 to 6.39). In the analysis excluding death induced by adverse events that occurred up to 1\u2009day after the last medication, the CV mortality rate was higher than the non-CV mortality rate within 6 months (45.7% vs 27.9%, p=0.0001). In addition, changes in serum uric acid levels from baseline to the last measurement before discontinuation were significantly associated with higher MACE risk after drug discontinuation (HR 1.14; 95% CI 1.04 to 1.26).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>MACE and CV death were increased in the initial stage after discontinuation of febuxostat or allopurinol in patients with gout.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rmdopen-2021-001944","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T11:58:25Z","timestamp":1655899105000},"page":"e001944","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Increased risk of cardiovascular events and death in the initial phase after discontinuation of febuxostat or allopurinol: another story of the CARES trial"],"prefix":"10.1136","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7284-4964","authenticated-orcid":false,"given":"Byeong-zu","family":"Ghang","sequence":"first","affiliation":[{"name":"Rheumatology, Jeju National University College of Medicine and Graduate School of Medicine, Jeju National University Hospital, Jeju, The Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Sung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, The Republic of Korea"},{"name":"Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, The Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihye","family":"Choi","sequence":"additional","affiliation":[{"name":"Rheumatology, Jeju National University College of Medicine and Graduate School of Medicine, Jeju National University Hospital, Jeju, The Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinseok","family":"Kim","sequence":"additional","affiliation":[{"name":"Rheumatology, Jeju National University College of Medicine and Graduate School of Medicine, Jeju National University Hospital, Jeju, The Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Yoo","sequence":"additional","affiliation":[{"name":"Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, The Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"2025090312482283000_8.2.e001944.1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ken457"},{"key":"2025090312482283000_8.2.e001944.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050373"},{"key":"2025090312482283000_8.2.e001944.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710895"},{"key":"2025090312482283000_8.2.e001944.4","doi-asserted-by":"publisher","DOI":"10.1186\/ar2978"},{"key":"2025090312482283000_8.2.e001944.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32234-0"},{"key":"2025090312482283000_8.2.e001944.6","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1093\/rheumatology\/kez189","article-title":"Comparative cardiovascular risk of allopurinol versus febuxostat in patients with gout: a nation-wide cohort study","volume":"58","author":"Kang","year":"2019","journal-title":"Rheumatology"},{"key":"2025090312482283000_8.2.e001944.7","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1161\/CIRCULATIONAHA.118.033992","article-title":"Assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol: population-based cohort study","volume":"138","author":"Zhang","year":"2018","journal-title":"Circulation"},{"key":"2025090312482283000_8.2.e001944.8","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1002\/art.40583","article-title":"New perspectives in rheumatology: implications of the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities trial and the associated food and drug administration public safety alert","volume":"70","author":"Choi","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"2025090312482283000_8.2.e001944.9","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1093\/rheumatology\/kez552","article-title":"Discontinuing febuxostat might cause more deaths than continuing febuxostat: the untold story from the CARES trial","volume":"59","author":"Ghang","year":"2020","journal-title":"Rheumatology"},{"key":"2025090312482283000_8.2.e001944.10","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu364"},{"key":"2025090312482283000_8.2.e001944.11","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwm070"},{"key":"2025090312482283000_8.2.e001944.12","first-page":"287","article-title":"Relationship between high cost sharing and adverse outcomes: a truism that's tough to prove","volume":"16","author":"Choudhry","year":"2010","journal-title":"Am J Manag Care"},{"key":"2025090312482283000_8.2.e001944.13","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1214\/aos\/1176345976","article-title":"Cox\u2019s Regression Model for Counting Processes: A Large Sample Study","volume":"10","author":"Andersen","year":"1982","journal-title":"The Annals of Statistics"},{"key":"2025090312482283000_8.2.e001944.14","article-title":"Detection of uric acid crystals in the vasculature of patients with gout using dual-energy computed tomography","volume":"138","author":"Barazani SH","year":"2018","journal-title":"Circulation"},{"key":"2025090312482283000_8.2.e001944.15","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1001\/jamacardio.2019.3201","article-title":"Dual-Energy computed tomography detection of cardiovascular monosodium urate deposits in patients with gout","volume":"4","author":"Klauser","year":"2019","journal-title":"JAMA Cardiol"},{"key":"2025090312482283000_8.2.e001944.16","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2014-005308","article-title":"Prevalence of birefringent crystals in cardiac and prostatic tissues, an observational study","volume":"4","author":"Park","year":"2014","journal-title":"BMJ Open"},{"key":"2025090312482283000_8.2.e001944.17","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12406"},{"key":"2025090312482283000_8.2.e001944.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra043430"},{"key":"2025090312482283000_8.2.e001944.19","doi-asserted-by":"crossref","unstructured":"Keenan RT KS , Pillinger MH . chapter 94 Etiology and Pathogenesis of Hyperuricemia and Gout. In: Kelley\u2019s Textbook of Rheumatology. 9th edn. Elsevier, 2017: 1597\u2013619.","DOI":"10.1016\/B978-0-323-31696-5.00094-2"},{"key":"2025090312482283000_8.2.e001944.20","doi-asserted-by":"crossref","DOI":"10.1136\/annrheumdis-2020-eular.1909","article-title":"OP0168\u2005cardiovascular event associated with initiating allopurinol and febuxostat - acute gout attack and cardiovascular gout","volume":"79","author":"Kim","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"2025090312482283000_8.2.e001944.21","doi-asserted-by":"publisher","DOI":"10.1136\/ard.33.4.304"},{"key":"2025090312482283000_8.2.e001944.22","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.semarthrit.2021.06.009","article-title":"Identification and characterization of peripheral vascular color-coded DECT lesions in gout and non-gout patients: the VASCURATE study","volume":"51","author":"Pascart","year":"2021","journal-title":"Semin Arthritis Rheum"},{"key":"2025090312482283000_8.2.e001944.23","doi-asserted-by":"crossref","first-page":"184","DOI":"10.4329\/wjr.v12.i8.184","article-title":"Quantification of uric acid in vasculature of patients with gout using dual-energy computed tomography","volume":"12","author":"Barazani","year":"2020","journal-title":"World J Radiol"},{"key":"2025090312482283000_8.2.e001944.24","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021372"},{"key":"2025090312482283000_8.2.e001944.25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1912388"},{"key":"2025090312482283000_8.2.e001944.26","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1809798"},{"key":"2025090312482283000_8.2.e001944.27","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1093\/rheumatology\/kez552","article-title":"Discontinuing febuxostat might cause more deaths than continuing febuxostat: the untold story from the cares trial","volume":"59","author":"Ghang","year":"2020","journal-title":"Rheumatology"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2021-001944","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T19:48:28Z","timestamp":1756928908000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2021-001944"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6]]},"references-count":27,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,6,22]]},"published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1136\/rmdopen-2021-001944"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2021-001944","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6]]}}}