{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:21:15Z","timestamp":1791562875376,"version":"4.3.4"},"reference-count":25,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T00:00:00Z","timestamp":1659657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate whether serum urate levels, number of gout flares, and tophi burden are related to death from cardiovascular (CV) causes after treatment with febuxostat or allopurinol in patients with gout from the Cardiovascular Safety of Febuxostat or Allopurinol in Patients With Gout and Cardiovascular Comorbidities (CARES) trial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients were randomly assigned to receive febuxostat (40 mg or 80 mg once daily, according to serum urate levels at week 2) or allopurinol titrated in 100\u2010mg increments from 200\u2013400 mg or 300\u2013600 mg (with dose determined according to kidney function). Changes from baseline in serum urate level, gout flares, and tophus resolution were key exploratory efficacy parameters in the overall population and in subgroups of patients who died and those who did not die from a CV\u2010related cause. The latter subgroup included patients who died due to non\u2010CV causes and those who did not die due to any cause.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients received treatment with febuxostat (n\u00a0=\u00a03,098) or allopurinol (n\u00a0=\u00a03,092) for a median follow\u2010up period of 32 months (for a maximum of 85 months). In the overall population, mean serum urate levels were lower in those receiving febuxostat compared with those receiving allopurinol at most study visits. There were no associations between serum urate levels and death from CV causes with febuxostat. The number of gout flares requiring treatment was higher within 1 year of treatment with febuxostat compared with allopurinol (mean incidence of gout flares per patient\u2010years of exposure 1.33 versus 1.20), but was comparable thereafter and decreased overall throughout the study period (mean incidence of gout flares per patient\u2010years of exposure 0.35 versus 0.34 after 1 year of treatment; overall mean incidence 0.68 versus 0.63) irrespective of whether the patient died from a CV\u2010related cause. Overall, 20.8% of patients had \u22651 tophus at baseline; tophus resolution rates were similar between treatment groups, with cumulative resolution rates of &gt;50%.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In the CARES trial, febuxostat and allopurinol (\u2264600 mg doses) had comparable efficacy in patients with gout and CV disease, and there was no evidence of a relationship between death from CV causes and serum urate levels, number of gout flares, or tophus resolution among the patients receiving febuxostat.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42160","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T13:10:10Z","timestamp":1652188210000},"page":"1593-1601","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Evaluation of the Relationship Between Serum Urate Levels, Clinical Manifestations of Gout, and Death From Cardiovascular Causes in Patients Receiving Febuxostat or Allopurinol in an Outcomes Trial"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6189-8078","authenticated-orcid":false,"given":"Kenneth G.","family":"Saag","sequence":"first","affiliation":[{"name":"University of Alabama at Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Becker","sequence":"additional","affiliation":[{"name":"University of Chicago Pritzker School of Medicine  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B.","family":"White","sequence":"additional","affiliation":[{"name":"Cardiology Center University of Connecticut School of Medicine  Farmington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Whelton","sequence":"additional","affiliation":[{"name":"Johns Hopkins University  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey S.","family":"Borer","sequence":"additional","affiliation":[{"name":"State University of New York Downstate University of the Health Sciences  Brooklyn New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip B.","family":"Gorelick","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology Northwestern University Feinberg School of Medicine  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Hunt","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc.  Lexington Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majin","family":"Castillo","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc.  Lexington Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2232-8931","authenticated-orcid":false,"given":"Lhanoo","family":"Gunawardhana","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc.  Lexington Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"CARES Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40807"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3199"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3810\/pgm.2012.09.2600"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050046"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2011.09.033"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.703389"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.168.10.1104"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hct083"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23121"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.10.086"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014070660"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex432"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k2893"},{"key":"e_1_2_8_15_1","first-page":"983","article-title":"Urate lowering therapies in the treatment of gout: a systematic review and meta\u2010analysis","volume":"20","author":"Borghi C","year":"2016","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2015.997213"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.21772"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710895"},{"key":"e_1_2_8_19_1","first-page":"e1144","article-title":"Cardiovascular risk of nonsteroidal anti\u2010inflammatory drugs: an under\u2010recognized public health issue [review]","volume":"9","author":"Varga Z","year":"2017","journal-title":"Cureus"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2012.04.011"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780200320"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32234-0"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.21773"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-247148"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2010.03887.x"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209213"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.42160","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.42160","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.42160","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T20:25:56Z","timestamp":1759955156000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.42160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,5]]},"references-count":25,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["10.1002\/art.42160"],"URL":"https:\/\/doi.org\/10.1002\/art.42160","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,5]]},"assertion":[{"value":"2021-05-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}