{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:00:44Z","timestamp":1790834444233,"version":"4.1.0"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To characterize and compare adverse-event reporting patterns for aspirin without statins, statins without aspirin, and aspirin\u2013statin co-exposure in the FDA Adverse Event Reporting System (FAERS), and to explore statistical reporting-interaction signals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed FAERS reports from 2004 Q1 through 2025 Q1. Active-comparator disproportionality analyses compared aspirin-statin co-exposure with aspirin-without-statin and statin-without-aspirin reports using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM), followed by Benjamini-Hochberg false discovery rate (BH-FDR) correction. Candidate preferred terms (PTs) common to both active-comparator analyses underwent adjusted statistical interaction analyses using four exposure groups, including a neither-drug reference. Primary models retained missing age, sex, and reporter type as explicit Unknown categories, and a complete-case sensitivity analysis excluded reports with missing adjustment covariates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>After deduplication, 18,932,599 unique FAERS reports were retained. The active-comparator analysis included 134,479 aspirin-without-statin reports, 202,565 statin-without-aspirin reports, and 70,806 aspirin\u2013statin co-exposure reports. Among 9,332 and 9,736 PTs tested in the two active-comparator analyses, 119 and 254 PTs remained after prespecified signal-detection criteria and BH-FDR correction, respectively; 42 PTs were common to both comparisons. Adjusted interaction models were reliably estimable for 40 candidates, and 31 PTs met both additive and multiplicative reporting-interaction criteria. Missingness was substantial for age (42.33%), sex (12.12%), and reporter type (4.35%). The complete-case dataset retained 53.83% of reports, and 21 of the 31 primary both-scale-positive PTs remained jointly positive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Aspirin-statin co-exposure showed distinct adverse-event reporting patterns in FAERS. The identified signals are exploratory statistical reporting interactions and do not establish increased incidence, clinical risk, causality, or pharmacological drug-drug interactions. Only 21 of the 31 primary both-scale-positive PTs remained jointly positive in the complete-case sensitivity analysis, reinforcing the need for cautious interpretation and validation in denominator-based pharmacoepidemiologic datasets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1923188","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:41:47Z","timestamp":1790833307000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Disproportionality analysis of adverse event reporting with aspirin, statins, and their co-exposure in FAERS, 2004\u20132025"],"prefix":"10.3389","volume":"13","author":[{"given":"Zuofeng","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baojun","family":"Xie","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]},{"name":"Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University","place":["Ganzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qijian","family":"Wang","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhou","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxuan","family":"Qiu","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinfu","family":"Yan","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayuan","family":"Ling","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]},{"name":"Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University","place":["Ganzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongling","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital of Gannan Medical University, Gannan Medical University","place":["Ganzhou, Jiangxi, China"]},{"name":"Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University","place":["Ganzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1016\/j.jacc.2025.08.015","article-title":"Global, regional, and national burden of cardiovascular diseases and risk factors in 204 countries and territories, 1990\u20132023","volume":"86","author":"Stark","year":"2025","journal-title":"J Am Coll Cardiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1111\/jgs.17038","article-title":"Age-related trajectories of cardiovascular risk and use of aspirin and statin among U.S. adults aged 50 or older, 2011\u20132018","volume":"69","author":"Rhee","year":"2021","journal-title":"J Am Geriatr Soc"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4585","DOI":"10.1038\/s41598-023-31739-w","article-title":"Cardiovascular disease preventive effects of aspirin combined with different statins in the United States general population","volume":"13","author":"Liu","year":"2023","journal-title":"Sci Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1016\/j.amjcard.2020.12.018","article-title":"Overview of aspirin and platelet biology","volume":"144","author":"Santos-Gallego","year":"2021","journal-title":"Am J Cardiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.atherosclerosis.2022.07.004","article-title":"Statin therapy for the primary prevention of cardiovascular disease: Pros","volume":"356","author":"Razavi","year":"2022","journal-title":"Atherosclerosis"},{"key":"B6","doi-asserted-by":"publisher","first-page":"100197","DOI":"10.1016\/j.jacadv.2022.100197","article-title":"Aspirin with or without statin in individuals without atherosclerotic cardiovascular disease across risk categories","volume":"2","author":"Khan","year":"2023","journal-title":"JACC Adv"},{"key":"B7","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1001\/jama.2018.20578","article-title":"Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis","volume":"321","author":"Zheng","year":"2019","journal-title":"JAMA"},{"key":"B8","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.pharmthera.2018.10.004","article-title":"Statins: adverse reactions, oxidative stress and metabolic interactions","volume":"195","author":"Liu","year":"2019","journal-title":"Pharmacol Ther"},{"key":"B9","doi-asserted-by":"publisher","first-page":"12808","DOI":"10.3390\/ijms222312808","article-title":"Cytochrome P450 enzymes and drug metabolism in humans","volume":"22","author":"Zhao","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1136\/heartjnl-2021-320154","article-title":"Aspirin and statin therapy for primary prevention of cardiovascular disease in older adults","volume":"108","author":"Montgomery","year":"2022","journal-title":"Heart"},{"key":"B11","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1007\/s40264-024-01423-7","article-title":"The REporting of A disproportionality analysis for DrUg safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV): explanation and elaboration","volume":"47","author":"Fusaroli","year":"2024","journal-title":"Drug Saf"},{"key":"B12","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1007\/s11095-020-02801-3","article-title":"Comparison of signal detection algorithms based on frequency statistical model for drug-drug interaction using spontaneous reporting systems","volume":"37","author":"Noguchi","year":"2020","journal-title":"Pharm Res"},{"key":"B13","first-page":"281","article-title":"Statistical mining of potential drug interaction adverse effects in FDA\u2019s spontaneous reporting system","volume":"2010","author":"Harpaz","year":"2010","journal-title":"AMIA Annu Symp Proc"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e15337","DOI":"10.1111\/1756-185X.15337","article-title":"Statin-associated muscle symptoms: a comprehensive exploration of epidemiology, pathophysiology, diagnosis, and clinical management strategies","volume":"27","author":"Shah","year":"2024","journal-title":"Int J Rheum Dis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1016\/j.amjmed.2023.08.010","article-title":"Trends in upper gastrointestinal bleeding in patients on primary prevention aspirin: a nationwide emergency department sample analysis, 2016\u20132020","volume":"136","author":"Li","year":"2023","journal-title":"Am J Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2261264","DOI":"10.1080\/2162402X.2023.2261264","article-title":"Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases","volume":"12","author":"Reid","year":"2023","journal-title":"OncoImmunology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1002\/pst.2148","article-title":"Assessing safety at the end of clinical trials using system organ classes: a case and comparative study","volume":"20","author":"Carragher","year":"2021","journal-title":"Pharm Stat"},{"key":"B18","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.pcad.2022.11.002","article-title":"Clinical conundrums involving statin drug-drug interactions","volume":"75","author":"Lamprecht","year":"2022","journal-title":"Prog Cardiovasc Dis"},{"key":"B19","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1055\/s-0039-1678527","article-title":"Management of patients with asymptomatic and symptomatic carotid artery disease: update on anti-thrombotic therapy","volume":"119","author":"Pastori","year":"2019","journal-title":"Thromb Haemost"},{"key":"B20","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.amjmed.2021.09.027","article-title":"Management of atherosclerotic carotid artery disease: a brief overview and update","volume":"135","author":"Hassani","year":"2022","journal-title":"Am J Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1056\/NEJMra1712125","article-title":"Aspirin-exacerbated respiratory disease","volume":"379","author":"White","year":"2018","journal-title":"N Engl J Med"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1923188\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:41:48Z","timestamp":1790833308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1923188\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":21,"alternative-id":["10.3389\/fmed.2026.1923188"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1923188","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"1923188"}}