{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:03:54Z","timestamp":1790831034777,"version":"4.1.0"},"reference-count":33,"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\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Adverse drug reactions (ADRs) represent a significant cause of preventable mortality and continue to pose a major challenge to medication safety. However, national temporal and demographic patterns of deaths in which an ADR was assigned as the underlying cause and cardiovascular disease (CVD) was also listed on the death certificate remain poorly characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a death certificate-based descriptive study using the CDC WONDER Multiple Cause of Death database from 1999 to 2020. Included records were deaths in which an ADR-related ICD-10 code (Y40\u2013Y59) was assigned as the underlying cause of death and a CVD code (I00\u2013I99) was listed among the multiple causes of death. Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated using the 2000 U.S. standard population. Temporal trends were assessed with Joinpoint regression, estimating annual percent change (APC) and average APC (AAPC). Mortality patterns were further analyzed by age, sex, race, region, and urbanization level, and drug categories recorded on the included death certificates were summarized descriptively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      From 1999 to 2020, 3,976 CVD-listed ADR deaths were identified, corresponding to an overall AAMR of 0.057 per 100,000 U.S. population. The AAMR of these deaths increased significantly over the study period (AAPC\u2009=\u20094.755%, 95% CI: 3.513\u20136.428;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;lt;\u20090.001). Mortality burden increased with age, particularly among individuals aged 75 years and older. Males exhibited higher mortality rates than females, and significant disparities were evident by race and geography, with the highest burden observed in Black individuals and rural populations. Drug-specific analysis showed that unspecified drugs were recorded in 1,398 deaths (35.2%). Anticoagulants were the most frequently recorded specified drug category (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009948; 23.8% of all included deaths), particularly among decedents with cerebrovascular disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CVD-listed ADR mortality in the United States rose significantly from 1999 to 2020. The burden was most pronounced in older adults and disproportionately high among males, Black individuals, and rural residents. Anticoagulants were the most frequently recorded specified drug category. These descriptive findings identify population-level patterns that warrant confirmation through studies incorporating medical records, prescribing data, and case-level clinical adjudication.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1857514","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:44:49Z","timestamp":1790829889000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mortality trends in deaths attributed to adverse drug reactions with cardiovascular disease listed among multiple causes in the United States, 1999\u20132020"],"prefix":"10.3389","volume":"13","author":[{"given":"Xing","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The Affiliated Huaian No.1 People\u2019s Hospital of Nanjing Medical University","place":["Huaian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Affiliated Huaian No.1 People\u2019s Hospital of Nanjing Medical University","place":["Huaian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingying","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University","place":["Huaian, Jiangsu, China"]},{"name":"Department of Technology Cooperation and Transformation, The Affiliated Huaian No.1 People\u2019s Hospital of Nanjing Medical University","place":["Huaian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Affiliated Huaian No.1 People\u2019s Hospital of Nanjing Medical University","place":["Huaian, Jiangsu, China"]},{"name":"Department of Technology Cooperation and Transformation, The Affiliated Huaian No.1 People\u2019s Hospital of Nanjing Medical University","place":["Huaian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"afaf231","DOI":"10.1093\/ageing\/afaf231","article-title":"Hospital admissions due to adverse drug reactions and adverse drug events in older adults: a systematic review","volume":"54","author":"Cosgrave","year":"2025","journal-title":"Age Ageing"},{"key":"B2","article-title":"Adverse drug reactions","volume-title":"StatPearls","author":"Kommu","year":"2024"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1002\/cpt.70250","article-title":"NLP in support of pharmacovigilance: QUality adverse drug reaction AcTIve control (QUADRATIC)","volume":"119","author":"Franchini","year":"2026","journal-title":"Clin Pharmacol Ther"},{"key":"B4","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.alit.2026.02.002","article-title":"Is intramuscular adrenaline used promptly against drug-induced anaphylaxis? A perspective from recent analyses of fatal cases in Japan","volume":"75","author":"Yamaguchi","year":"2026","journal-title":"Allergol Int"},{"key":"B5","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1016\/j.cpcardiol.2008.08.002","article-title":"Adverse drug reactions in patients with cardiovascular disease","volume":"33","author":"Faulx","year":"2008","journal-title":"Curr Probl Cardiol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"55","DOI":"10.3390\/diseases9030055","article-title":"Precision medicine and adverse drug reactions related to cardiovascular drugs","volume":"9","author":"Noyes","year":"2021","journal-title":"Diseases"},{"key":"B7","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1093\/ehjcvp\/pvac005","article-title":"Facing the challenge of polypharmacy when prescribing for older people with cardiovascular disease: a review by the European society of cardiology working group on cardiovascular pharmacotherapy","volume":"8","author":"Tamargo","year":"2022","journal-title":"Eur Heart J Cardiovasc Pharmacother"},{"key":"B8","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1093\/ageing\/afr182","article-title":"Frailty in the older surgical patient: a review","volume":"41","author":"Partridge","year":"2012","journal-title":"Age Ageing"},{"key":"B9","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.therap.2023.10.008","article-title":"Drug-induced cardiac toxicity and adverse drug reactions: a narrative review","volume":"79","author":"Destere","year":"2024","journal-title":"Therapie"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1016\/j.jacc.2023.11.007","article-title":"Global burden of cardiovascular diseases and risks, 1990\u20132022","volume":"82","author":"Mensah","year":"2023","journal-title":"J Am Coll Cardiol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1779819","DOI":"10.3389\/fonc.2026.1779819","article-title":"National trends and disparities in non-cancer mortality among older adults with oral cancer in the United States, 1999\u20132020","volume":"16","author":"Jing","year":"2026","journal-title":"Front Oncol"},{"key":"B12","first-page":"1","article-title":"2013 NCHS urban\u2013rural classification scheme for counties","volume":"166","author":"Ingram","year":"2014","journal-title":"Vital Health Stat 2"},{"key":"B13","first-page":"172","article-title":"Individualized dosing of vancomycin in geriatric patients","volume":"69","author":"Such\u00e1nkov\u00e1","year":"2020","journal-title":"Epidemiol Mikrobiol Imunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1007\/s00508-020-01801-y","article-title":"Clinical pharmacist interventions in cardiovascular disease pharmacotherapy in elderly patients on excessive polypharmacy: a retrospective pre-post observational multicentric study","volume":"133","author":"Stuhec","year":"2021","journal-title":"Wien Klin Wochenschr"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1096366","DOI":"10.3389\/fphar.2023.1096366","article-title":"A systematic review on sex differences in adverse drug reactions related to psychotropic, cardiovascular, and analgesic medications","volume":"14","author":"Shan","year":"2023","journal-title":"Front Pharmacol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"100188","DOI":"10.1016\/j.eclinm.2019.10.001","article-title":"Reported adverse drug reactions in women and men: aggregated evidence from globally collected individual case reports during half a century","volume":"17","author":"Watson","year":"2019","journal-title":"EClinicalMedicine"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1283132","DOI":"10.3389\/fcvm.2024.1283132","article-title":"Gender differences in all-cause and cardiovascular mortality among US adults: from NHANES 2005\u20132018","volume":"11","author":"Lv","year":"2024","journal-title":"Front Cardiovasc Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1161\/HYPERTENSIONAHA.124.22870","article-title":"Sex-related disparities in cardiovascular outcomes among older adults with late-onset hypertension","volume":"81","author":"Bugeja","year":"2024","journal-title":"Hypertension"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e022883","DOI":"10.1161\/JAHA.121.022883","article-title":"Sex differences in cardiovascular outcomes of older adults after myocardial infarction","volume":"10","author":"Kerola","year":"2021","journal-title":"J Am Heart Assoc"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e70000","DOI":"10.1002\/inm3.70000","article-title":"Risk factors for cardiovascular and metabolic disease: integrating traditional and novel paradigms","volume":"1","author":"Wang","year":"2025","journal-title":"iNew Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1007\/s40615-015-0101-3","article-title":"Racial and ethnic disparities in adverse drug events: a systematic review of the literature","volume":"2","author":"Baehr","year":"2015","journal-title":"J Racial Ethn Health Disparities"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e249465","DOI":"10.1001\/jamanetworkopen.2024.9465","article-title":"Racial and ethnic disparities in initiation of direct oral anticoagulants among medicare beneficiaries","volume":"7","author":"Reynolds","year":"2024","journal-title":"JAMA Netw Open"},{"key":"B23","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.jnma.2019.10.003","article-title":"Race\/ethnicity- and sex-related differences in direct oral anticoagulant initiation in newly diagnosed atrial fibrillation: a retrospective study of medicare data","volume":"112","author":"Essien","year":"2020","journal-title":"J Natl Med Assoc"},{"key":"B24","doi-asserted-by":"publisher","first-page":"7769","DOI":"10.22605\/RRH7769","article-title":"Barriers to rural health care from the provider perspective","volume":"23","author":"Maganty","year":"2023","journal-title":"Rural Remote Health"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.1056\/NEJMsa1103053","article-title":"Emergency hospitalizations for adverse drug events in older Americans","volume":"365","author":"Budnitz","year":"2011","journal-title":"N Engl J Med"},{"key":"B26","year":""},{"key":"B27","doi-asserted-by":"publisher","first-page":"e333","DOI":"10.1093\/ehjci\/jeac106","article-title":"2022 ESC guidelines on cardio-oncology developed in collaboration with the European hematology association, the European society for therapeutic radiology and oncology and the international cardio-oncology society","volume":"23","author":"Lyon","year":"2022","journal-title":"Eur Heart J Cardiovasc Imaging"},{"key":"B28","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1093\/eurheartj\/ehab674","article-title":"Defining cardiovascular toxicities of cancer therapies: an international cardio-oncology society consensus statement","volume":"43","author":"Herrmann","year":"2022","journal-title":"Eur Heart J"},{"key":"B29","doi-asserted-by":"publisher","first-page":"981838","DOI":"10.3389\/fcvm.2022.981838","article-title":"Cardiovascular effects of immunosuppression agents","volume":"9","author":"Elezaby","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"112066","DOI":"10.1016\/j.ejrad.2025.112066","article-title":"Very rare adverse reactions to intravascular contrast media: from Kounis to sweet syndrome","volume":"187","author":"Van Der Molen","year":"2025","journal-title":"Eur J Radiol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.ejro.2019.02.004","article-title":"Kounis syndrome induced by contrast media: a case report and review of literature","volume":"6","author":"Shibuya","year":"2019","journal-title":"Eur J Radiol Open"},{"key":"B32","doi-asserted-by":"publisher","first-page":"533","DOI":"10.2165\/00002018-200730060-00007","article-title":"Surveillance of prescription drug-related mortality using death certificate data","volume":"30","author":"Wysowski","year":"2007","journal-title":"Drug Saf"},{"key":"B33","doi-asserted-by":"publisher","first-page":"C40","DOI":"10.1016\/S0149-2918(98)80007-6","article-title":"Limitations and strengths of spontaneous reports data","volume":"20","author":"Goldman","year":"1998","journal-title":"Clin Ther"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1857514\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:44:57Z","timestamp":1790829897000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1857514\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":33,"alternative-id":["10.3389\/fcvm.2026.1857514"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2026.1857514","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"1857514"}}