{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T08:05:40Z","timestamp":1770710740447,"version":"3.49.0"},"reference-count":34,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis Care &amp;amp; Research"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Several observational studies reported that allopurinol, an effective treatment for gout, was associated with important reductions in cardiovascular (CV) events, with calls for large, randomized trials, although some results were conflicting. The present study was undertaken to assess the extent of time\u2010related biases in these observational studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We searched the literature for all observational studies reporting on allopurinol and CV events, focusing on 2 time\u2010related biases. Time\u2010related confounding bias results from studies using cohorts of patients all exposed to allopurinol, with comparisons based on episodes of allopurinol discontinuation, where confounding factors are not updated over follow\u2010up time. Immortal time bias arises from the exposure misclassification of periods of cohort follow\u2010up during which the outcome under study cannot occur.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 12 studies, of which 8 were affected by time\u2010related confounding bias or immortal time bias, while the remaining 4 studies avoided these biases. The studies affected by time\u2010related confounding bias resulted in significant reductions in the incidence of CV events with allopurinol use (pooled hazard ratio [HR] 0.88 [95% confidence interval (95% CI) 0.85\u20130.92]), as did the studies affected by immortal time bias (pooled HR 0.79 [95% CI 0.72\u20130.87]). The 4 studies that avoided these biases resulted in a pooled HR of 1.07 (95% CI 0.91\u20131.25).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Observational studies reporting significantly reduced incidence of CV events with allopurinol use were affected by time\u2010related biases. Overall, studies that avoided these biases did not find a protective effect. The ALL\u2010HEART randomized trial will provide important and accurate evidence on the potential effectiveness of allopurinol on CV outcomes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acr.24713","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T07:41:23Z","timestamp":1622446883000},"page":"858-865","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Allopurinol and Cardiovascular Events: <scp>Time\u2010Related<\/scp> Biases in Observational Studies"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1281-5296","authenticated-orcid":false,"given":"Samy","family":"Suissa","sequence":"first","affiliation":[{"name":"Jewish General Hospital and McGill University  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karine","family":"Suissa","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital Harvard Medical School  Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Hudson","sequence":"additional","affiliation":[{"name":"Jewish General Hospital and McGill University  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/2047487313514895"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-019-01081-5"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0800885"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2761"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.24180"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12872-018-0757-9"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2020.1804551"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2019.11.009"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209707"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex354"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2016-013774"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41710"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.1357"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwm324"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-1111-1"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12883-016-0692-2"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12872-017-0513-6"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex232"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-209008"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.13656"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cger.2009.07.007"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2007.076182"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2017.09.007"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCOUTCOMES.118.004684"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2010.03887.x"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2012.06.528"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.4107"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0099102"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2015.01.013"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2015.11.003"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez576"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-1241.2009.02118.x"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.5083"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2016.04.014"}],"container-title":["Arthritis Care &amp; 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