{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:37:51Z","timestamp":1791221871047,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacoepidemiology and Drug"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Traditional pharmacovigilance systems have limitations in detecting common adverse drug reactions. We investigated whether real\u2010world data (RWD) could have detected rofecoxib's cardiovascular adverse effects earlier using nested case\u2013control (NCC) and case\u2010crossover (CCO) designs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We included adult rofecoxib users from the UK CPRD GOLD (1999\u20132004). In NCC design, cases of a first major adverse cardiovascular event (MACE) were matched with four controls on age, sex, practice and calendar time. Rofecoxib exposure was categorised as current (\u2264\u20093\u2009months), recent (3\u20136), or past use (&gt;\u20096) in NCC, and assessed at the start of each 3\u2010month interval in CCO design. Exposure odds in CCO were compared between a 3\u2010month risk with four reference windows. Conditional logistic regression models estimated adjusted intensity ratio (aIR). To identify the shortest time necessary to detect the association, analyses were conducted in 1\u2010, 2\u2010, 3\u2010, 4\u2010 and 5\u2010years after the drug's market uptake.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Three thousand two hundred and eighteen cases were matched to 10\u2009745 controls (mean age 73.8\u2009years, 66% female). In NCC, current rofecoxib use (42% of cases) was associated with an 18% higher risk of MACE (aIR 1.18, 95% CI 1.08\u20131.29) versus past use. The CCO (3210 risk and 12\u2009737 reference windows) showed an 83% increased risk of MACE (aIR 1.83, 95% CI 1.53\u20132.18). First signal emerged after 2\u2009years with CCO (aIR 3.94, 95% CI 1.88\u20138.25), and after 3\u2009years with NCC design (aIR 1.46, 95% CI 1.18\u20131.81).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Using RWD, cardiovascular adverse effects of rofecoxib could have been detected within 2\u2009years of the market entry in the UK, well before traditional pharmacovigilance methods. This supports incorporating RWD analysis into routine drug safety monitoring.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pds.70343","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T01:24:11Z","timestamp":1773105851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Early Identification of Cardiovascular Adverse Events Associated With Rofecoxib Using Real\u2010World Data From the\n                    <scp>UK<\/scp>\n                    : A Nested Case\u2013Control and Case\u2010Crossover Study"],"prefix":"10.1002","volume":"35","author":[{"given":"Donya","family":"Moslemzadeh","sequence":"first","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences, Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick C.","family":"Souverein","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences, Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana V.","family":"Belitser","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences, Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eibert R.","family":"Heerdink","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences, Utrecht University  Utrecht the Netherlands"},{"name":"Research Group Innovations of Pharmaceutical Care Utrecht University of Applied Sciences  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf H.","family":"Klungel","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences, Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahab","family":"Abtahi","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences, Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"e_1_2_14_2_1","volume-title":"Merck Announces Voluntary Worldwide Withdrawal of VIOXX","author":"Merck","year":"2004"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmp048286"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMOA050493"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(08)61490\u20107"},{"issue":"1","key":"e_1_2_14_6_1","first-page":"e14","article-title":"How Safe Are New Drugs? 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