High-signal drug assessment for drug-related aortic aneurysm and dissection rupture: Evidence from real-world databases and animal experiments

Xuezhen Xuan; Xuexing Xuan; Jia Li; Xin Guan; Wei Wang; Sichong Qian; Hongjia Zhang; Haiyang Li

doi:10.59717/j.xinn-med.2026.100225

The Innovation Medicine > 2026 Vol. 4 > No. 3 > 100225

Next Article Previous Article

ARTICLE Open Access

Cite PDF

High-signal drug assessment for drug-related aortic aneurysm and dissection rupture: Evidence from real-world databases and animal experiments

1.
Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
2.
Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing 100029, China
3.
College of Basic Medical Sciences, Shandong University, Jinan 250012, China
4.
Department of Cardiovascular Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
5.
Department of Urology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
6.
These authors contributed equally

Show all affliationsShow less

More Information

Corresponding authors: zhanghongjia722@ccmu.edu.cn (H.Z.); drqsc@mail.ccmu.edu.cn (S.Q.); wangweiocean@163.com (W.W.)
Received Date: December 09, 2025

Accepted Date: May 29, 2026

Published Online: May 31, 2026

The Innovation Medicine 4(3), https://doi.org/10.59717/j.xinn-med.2026.100225 | Cite this article

GRAPHICAL ABSTRACT

GRAPHICAL ABSTRACT

DownLoad: Full size image

PUBLIC SUMMARY

PUBLIC SUMMARY
1. Aortic aneurysm and dissection may lead to fatal aortic rupture.
  
  We screened 40 high-signal related drugs from real-world databases and verified the risk with animal models.
  
  These drug signals do not confirm causality, and further research is needed to guide safe clinical medication.

ABSTRACT

ABSTRACT

Background: Aortic rupture represents the most critical complication of aortic aneurysm and dissection (AAD). Identifying and avoiding drugs associated with increased aortic rupture risk may provide immediate clinical benefits. Methods: Data from the FAERS and JADER databases (2004 Q1–2025 Q2) were analyzed. Clinical characteristics associated with adverse events of aortic rupture were summarized. Four disproportionality methods, reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were applied to detect adverse drug reaction signals. Drugs positive in all four methods were classified as high-signal. A time-to-onset analysis was conducted. Rivaroxaban was chosen as a representative drug for further investigation of its impact on aortic rupture risk in an AAD mouse model. Results: FAERS analysis identified 1,313 drug-associated AAD rupture reports involving 333 medications. Antithrombotic agents were most frequently implicated (247 cases, 18.8%), followed by Immunosuppressants (218 cases, 16.6%) and Antineoplastic agents (176 cases, 13.4%). Disproportionality analysis identified 40 drugs with high reporting signals for AAD rupture. Affected individuals were predominantly male (63.8%) and aged ≥65 years (74.0%). Reports and associated fatalities have increased in recent years, although overall mortality has declined. JADER provided 104 reports (17 drugs), consistent with FAERS findings except for the inclusion of SARS-CoV-2 mRNA vaccines. Animal experiments demonstrated that rivaroxaban did not increase AAD incidence but significantly elevated the aortic rupture risk. Conclusion: This study identified 40 high-signal drugs associated with AAD rupture, offering clinical references for safer drug usage. Further studies are necessary to clarify these risks.

FullText(HTML)

REFERENCES

[1]	GBD 2023 Causes of Death Collaborators. (2025). Global burden of 292 causes of death in 204 countries and territories and 660 subnational locations, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023. Lancet (London, England) 406:1811−1872. DOI:10.1016/s0140-6736(25)01917-8 View in Article CrossRef Google Scholar
[2]	Fukui T. (2018). Management of acute aortic dissection and thoracic aortic rupture. J. Intensive Care 6:15. DOI:10.1186/s40560-018-0287-7 View in Article CrossRef Google Scholar
[3]	Pape L. A., Awais M., Woznicki E. M., et al. (2015). Presentation, diagnosis, and outcomes of acute aortic dissection: 17-year trends from the international registry of acute aortic dissection. J. Am. Coll. Cardiol. 66:350−358. DOI:10.1016/j.jacc.2015.05.029 View in Article CrossRef Google Scholar
[4]	Mazzolai L., Teixido-Tura G., Lanzi S., et al. (2024). 2024 ESC Guidelines for the management of peripheral arterial and aortic diseases. Eur. Heart J. 45:3538−3700. DOI:10.1093/eurheartj/ehae179 View in Article CrossRef Google Scholar
[5]	Isselbacher E. M., Preventza O., Hamilton Black Iii J., et al. (2022). 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 80:e223−e393. DOI:10.1016/j.jacc.2022.08.004 View in Article CrossRef Google Scholar
[6]	Peng L., Yang D. and Weng C. (2024). Sintilimab and cardiovascular toxicity. JAMA 331:1333−1334. DOI:10.1001/jama.2024.0673 View in Article CrossRef Google Scholar
[7]	Cirmi S., El Abd A., Letinier L., et al. (2020). Cardiovascular toxicity of tyrosine kinase inhibitors used in chronic myeloid leukemia: An analysis of the FDA adverse event reporting system database (FAERS). Cancers 12:826. DOI:10.3390/cancers12040826 View in Article CrossRef Google Scholar
[8]	Joshi A., Gawey L., Saadi C., et al. (2025). Postmarketing safety surveillance of adalimumab, secukinumab, and infliximab in hidradenitis suppurativa: An analysis of the FDA adverse events reporting system (FAERS) database. J. Am. Acad. Dermatol. 92:1434−1435. DOI:10.1016/j.jaad.2025.02.031 View in Article CrossRef Google Scholar
[9]	Zhu Z., Li Y., Zhu C., et al. (2025). Disproportionality analysis of interstitial lung disease associated with novel antineoplastic agents during breast cancer treatment: A pharmacovigilance study. EClinicalMedicine 82:103160. DOI:10.1016/j.eclinm.2025.103160 View in Article CrossRef Google Scholar
[10]	Tang Y., Zhang J., Fang Y., et al. (2025). Correcting mitochondrial loss mitigates NOTCH1-related aortopathy in mice. Nat. Cardiovasc. Res. 4:235−247. DOI:10.1038/s44161-024-00603-z View in Article CrossRef Google Scholar
[11]	Rochano-Ortiz A., San Sebastián-Jaraba I., Zamora C., et al. (2025). Excessive glycosylation drives thoracic aortic aneurysm formation through integrated stress response. Eur. Heart J. 46:4988−5005. DOI:10.1093/eurheartj/ehaf556 View in Article CrossRef Google Scholar
[12]	Knuuti J., Wijns W., Saraste A., et al. (2020). 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur. Heart J. 41:407−477. DOI:10.1093/eurheartj/ehz425 View in Article CrossRef Google Scholar
[13]	Wolfe R., Broder J. C., Zhou Z., et al. (2025). Aspirin, cardiovascular events, and major bleeding in older adults: Extended follow-up of the ASPREE trial. Eur. Heart J. 46:4410−4422. DOI:10.1093/eurheartj/ehaf514 View in Article CrossRef Google Scholar
[14]	Bowman L., Mafham M., Wallendszus K., et al. (2018). Effects of aspirin for primary prevention in persons with diabetes mellitus. N. Engl. J. Med. 379:1529−1539. DOI:10.1056/NEJMoa1804988 View in Article CrossRef Google Scholar
[15]	Gaziano J. M., Brotons C., Coppolecchia R., et al. (2018). Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): A randomised, double-blind, placebo-controlled trial. Lancet (London, England) 392:1036−1046. DOI:10.1016/s0140-6736(18)31924-x View in Article CrossRef Google Scholar
[16]	Arnett D. K., Blumenthal R. S., Albert M. A., et al. (2019). 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 74:e177−e232. DOI:10.1016/j.jacc.2019.03.010 View in Article CrossRef Google Scholar
[17]	Visseren F. L. J., Mach F., Smulders Y. M., et al. (2021). 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur. Heart J. 42:3227−3337. DOI:10.1093/eurheartj/ehab484 View in Article CrossRef Google Scholar
[18]	American Diabetes Association Professional Practice Committee. (2022). 10. Cardiovascular disease and risk management: Standards of medical care in diabetes-2022. Diabetes Care 45:S144-s174. DOI:10.2337/dc22-S010. View in Article Google Scholar
[19]	Valgimigli M., Choi K. H., Giacoppo D., et al. (2025). Clopidogrel versus aspirin for secondary prevention of coronary artery disease: A systematic review and individual patient data meta-analysis. Lancet (London, England) 406:1091−1102. DOI:10.1016/s0140-6736(25)01562-4 View in Article CrossRef Google Scholar
[20]	Zhang X., Gong Z., Shen Y., et al. (2025). Author Correction: Alkaline ceramidase 1-mediated platelet ceramide catabolism mitigates vascular inflammation and abdominal aortic aneurysm formation. Nat. Cardiovasc. Res. 4:1206. DOI:10.1038/s44161-025-00720-3 View in Article CrossRef Google Scholar
[21]	Wemmelund H., Jørgensen T. M., Høgh A., et al. (2017). Low-dose aspirin and rupture of abdominal aortic aneurysm. J. Vasc. Surg. 65:616−625.e614. DOI:10.1016/j.jvs.2016.04.061 View in Article CrossRef Google Scholar
[22]	Hariri E., Matta M., Layoun H., et al. (2023). Antiplatelet therapy, abdominal aortic aneurysm progression, and clinical outcomes. JAMA Netw. Open 6:e2347296. DOI:10.1001/jamanetworkopen.2023.47296 View in Article CrossRef Google Scholar
[23]	Lyon A. R., López-Fernández T., Couch L. S., et al. (2022). 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur. Heart J. 43:4229−4361. DOI:10.1093/eurheartj/ehac244 View in Article CrossRef Google Scholar
[24]	Paparella D., Rotunno C., Guida P., et al. (2011). Hemostasis alterations in patients with acute aortic dissection. Ann. Thorac. Surg. 91:1364−1369. DOI:10.1016/j.athoracsur.2011.01.058 View in Article CrossRef Google Scholar
[25]	Guan X., Li J., Gong M., et al. (2016). The hemostatic disturbance in patients with acute aortic dissection: A prospective observational study. Medicine 95:e4710. DOI:10.1097/md.0000000000004710 View in Article CrossRef Google Scholar
[26]	Haller S. J., Crawford J. D., Courchaine K. M., et al. (2018). Intraluminal thrombus is associated with early rupture of abdominal aortic aneurysm. J. Vasc. Surg. 67:1051−1058.e1051. DOI:10.1016/j.jvs.2017.08.069 View in Article CrossRef Google Scholar
[27]	Riveros F., Martufi G., Gasser T. C., et al. (2015). On the impact of intraluminal thrombus mechanical behavior in AAA passive mechanics. Ann. Biomed. Eng. 43:2253−2264. DOI:10.1007/s10439-015-1267-x View in Article CrossRef Google Scholar
[28]	Manils J., Marruecos L. and Soler C. (2022). Exonucleases: Degrading DNA to deal with genome damage, cell death, inflammation and cancer. Cells 11:2157. DOI:10.3390/cells11142157 View in Article CrossRef Google Scholar
[29]	Røed-Undlien H., Schultz N. H., Husebråten I. M., et al. (2024). Apixaban removal during emergency surgery for type A acute aortic dissection: A prospective cohort study. Int. J. Surg. (London, England) 110:7782−7790. DOI:10.1097/js9.0000000000002137 View in Article CrossRef Google Scholar
[30]	Hara T., Fukuda D., Tanaka K., et al. (2018). Inhibition of activated factor X by rivaroxaban attenuates neointima formation after wire-mediated vascular injury. Eur. J. Pharmacol. 820:222−228. DOI:10.1016/j.ejphar.2017.12.037 View in Article CrossRef Google Scholar
[31]	Konstantinides S. V., Meyer G., Becattini C., et al. (2020). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur. Heart J. 41:543−603. DOI:10.1093/eurheartj/ehz405 View in Article CrossRef Google Scholar
[32]	Rao S. V., O'Donoghue M. L., Ruel M., et al. (2025). 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the management of patients with acute coronary syndromes: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 151:e771−e862. DOI:10.1161/cir.0000000000001309 View in Article CrossRef Google Scholar
[33]	Warner J. J., Harrington R. A., Sacco R. L., et al. (2019). Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke. Stroke 50:3331−3332. DOI:10.1161/strokeaha.119.027708 View in Article CrossRef Google Scholar
[34]	Cameron S. J., Russell H. M. and Owens A. P., 3rd (2018). Antithrombotic therapy in abdominal aortic aneurysm: Beneficial or detrimental? Blood 132:2619-2628. DOI:10.1182/blood-2017-08-743237 View in Article Google Scholar
[35]	Duarte-Celada W., Rivas K., Suppakitjanusant P., et al. (2025). Safety of thrombolysis in acute ischemic stroke patients with previous aortic abdominal aneurysm repair. J. Stroke Cerebrovasc. Dis. 34:108421. DOI:10.1016/j.jstrokecerebrovasdis.2025.108421 View in Article CrossRef Google Scholar
[36]	Lee C. C., Lee M. T., Chen Y. S., et al. (2015). Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone. JAMA Intern. Med. 175:1839−1847. DOI:10.1001/jamainternmed.2015.5389 View in Article CrossRef Google Scholar
[37]	Daneman N., Lu H. and Redelmeier D. A. (2015). Fluoroquinolones and collagen associated severe adverse events: A longitudinal cohort study. BMJ Open 5:e010077. DOI:10.1136/bmjopen-2015-010077 View in Article CrossRef Google Scholar
[38]	Pasternak B., Inghammar M. and Svanström H. (2018). Fluoroquinolone use and risk of aortic aneurysm and dissection: Nationwide cohort study. BMJ (Clinical research ed.) 360:k678. DOI:10.1136/bmj.k678 View in Article CrossRef Google Scholar
[39]	Bennett A. C., Bennett C. L., Witherspoon B. J., et al. (2019). An evaluation of reports of ciprofloxacin, levofloxacin, and moxifloxacin-association neuropsychiatric toxicities, long-term disability, and aortic aneurysms/dissections disseminated by the Food and Drug Administration and the European Medicines Agency. Expert Opin. Drug Saf. 18:1055−1063. DOI:10.1080/14740338.2019.1665022 View in Article CrossRef Google Scholar
[40]	Liu X. and Li Z. (2025). The role and mechanism of epigenetics in anticancer drug-induced cardiotoxicity. Basic Res. Cardiol. 120:11−24. DOI:10.1007/s00395-024-01054-0 View in Article CrossRef Google Scholar
[41]	Garcia J., Hurwitz H. I., Sandler A. B., et al. (2020). Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat. Rev. 86:102017. DOI:10.1016/j.ctrv.2020.102017 View in Article CrossRef Google Scholar
[42]	Motzer R. J., Escudier B., Gannon A., et al. (2017). Sunitinib: Ten years of successful clinical use and study in advanced renal cell carcinoma. Oncologist 22:41−52. DOI:10.1634/theoncologist.2016-0197 View in Article CrossRef Google Scholar
[43]	Llovet J. M., Ricci S., Mazzaferro V., et al. (2008). Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359:378−390. DOI:10.1056/NEJMoa0708857 View in Article CrossRef Google Scholar
[44]	Roth G. J., Binder R., Colbatzky F., et al. (2015). Nintedanib: From discovery to the clinic. J. Med. Chem. 58:1053−1063. DOI:10.1021/jm501562a View in Article CrossRef Google Scholar
[45]	Wu C. W., Huang H. Y., Lin S. Y., et al. (2024). Vascular endothelial growth factor inhibitors and the risk of aortic aneurysm and aortic dissection. JAMA Netw. Open 7:e240940. DOI:10.1001/jamanetworkopen.2024.0940 View in Article CrossRef Google Scholar
[46]	Guyon J., Gouverneur A., Maumus-Robert S., et al. (2021). Association between antiangiogenic drugs used for cancer treatment and artery dissections or aneurysms. JAMA Oncol. 7:775−778. DOI:10.1001/jamaoncol.2021.0210 View in Article CrossRef Google Scholar
[47]	Oshima Y., Tanimoto T., Yuji K., et al. (2017). Association between aortic dissection and systemic exposure of vascular endothelial growth factor pathway inhibitors in the Japanese adverse drug event report database. Circulation 135:815−817. DOI:10.1161/circulationaha.116.025144 View in Article CrossRef Google Scholar
[48]	Zhang L., Zhou J., Jing Z., et al. (2018). Glucocorticoids regulate the vascular remodeling of aortic dissection via the p38 MAPK-HSP27 pathway mediated by soluble TNF-RII. EBioMedicine 27:247−257. DOI:10.1016/j.ebiom.2017.12.002 View in Article CrossRef Google Scholar
[49]	Tajima Y., Goto H., Ohara M., et al. (2017). Oral steroid use and abdominal aortic aneurysm expansion - positive association. Circ. J. 81:1774−1782. DOI:10.1253/circj.CJ-16-0902 View in Article CrossRef Google Scholar
[50]	Pujades-Rodriguez M., Morgan A. W., Cubbon R. M., et al. (2020). Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study. PLoS Med. 17:e1003432. DOI:10.1371/journal.pmed.1003432 View in Article CrossRef Google Scholar
[51]	Jang Y. H., Choi E. Y., Lee H., et al. (2024). Long-term use of oral corticosteroids and safety outcomes for patients with atopic dermatitis. JAMA Netw. Open 7:e2423563. DOI:10.1001/jamanetworkopen.2024.23563 View in Article CrossRef Google Scholar
[52]	Ko Y. H., Tsai M. S., Lee P. H., et al. (2013). Methylprednisolone stiffens aortas in lipopolysaccharide-induced chronic inflammation in rats. PloS One 8:e69636. DOI:10.1371/journal.pone.0069636 View in Article CrossRef Google Scholar
[53]	Hibino M., Otaki Y., Kobeissi E., et al. (2022). Blood pressure, hypertension, and the risk of aortic dissection incidence and mortality: Results from the J-SCH study, the UK biobank study, and a meta-analysis of cohort studies. Circulation 145:633−644. DOI:10.1161/circulationaha.121.056546 View in Article CrossRef Google Scholar
[54]	Bardou F. N., Guillaud O., Erard-Poinsot D., et al. (2019). Tacrolimus exposure after liver transplantation for alcohol-related liver disease: Impact on complications. Transpl. Immunol. 56:101227. DOI:10.1016/j.trim.2019.101227 View in Article CrossRef Google Scholar
[55]	Chen C. H., Shyue S. K., Hsu C. P., et al. (2018). Atypical antipsychotic drug olanzapine deregulates hepatic lipid metabolism and aortic inflammation and aggravates atherosclerosis. Cell. Physiol. Biochem. 50:1216−1229. DOI:10.1159/000494573 View in Article CrossRef Google Scholar
[56]	Rodrigues-Diez R., González-Guerrero C., Ocaña-Salceda C., et al. (2016). Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling. Sci. Rep. 6:27915. DOI:10.1038/srep27915 View in Article CrossRef Google Scholar
[57]	Fanti S., Dyer C., Ingimarsdóttir I. J., et al. (2025). Combined adaptive immune mechanisms mediate cardiac injury after COVID-19 vaccination. Circulation 152:1485−1500. DOI:10.1161/circulationaha.125.074644 View in Article CrossRef Google Scholar
[58]	Witberg G., Barda N., Hoss S., et al. (2021). Myocarditis after Covid-19 Vaccination in a Large Health Care Organization. N. Engl. J. Med. 385:2132−2139. DOI:10.1056/NEJMoa2110737 View in Article CrossRef Google Scholar
[59]	Satyam S. M., El-Tanani M., Bairy L. K., et al. (2025). Unraveling cardiovascular risks and benefits of COVID-19 vaccines: A systematic review. Cardiovasc. Toxicol. 25:306−323. DOI:10.1007/s12012-024-09954-2 View in Article CrossRef Google Scholar
[60]	Meylan S., Livio F., Foerster M., et al. (2021). Stage III hypertension in patients after mRNA-based SARS-CoV-2 vaccination. Hypertension (Dallas, Tex. : 1979) 77:e56-e57. DOI:10.1161/hypertensionaha.121.17316 View in Article Google Scholar
[61]	Takahashi M., Kondo T., Yamasaki G., et al. (2022). An autopsy case report of aortic dissection complicated with histiolymphocytic pericarditis and aortic inflammation after mRNA COVID-19 vaccination. Leg. Med. (Tokyo) 59:102154. DOI:10.1016/j.legalmed.2022.102154 View in Article CrossRef Google Scholar

Cited by

ABOUT THIS ARTICLE

Cite this article:

Xuan X., Xuan X., Li J., et al. (2026). High-signal drug assessment for drug-related aortic aneurysm and dissection rupture: Evidence from real-world databases and animal experiments. The Innovation Medicine 4:100225. https://doi.org/10.59717/j.xinn-med.2026.100225

Xuan X., Xuan X., Li J., et al. (2026). High-signal drug assessment for drug-related aortic aneurysm and dissection rupture: Evidence from real-world databases and animal experiments. The Innovation Medicine 4:100225. https://doi.org/10.59717/j.xinn-med.2026.100225

Welcome!

To request copyright permission to republish or share portions of our works, please visit Copyright Clearance Center's (CCC) Marketplace website at marketplace.copyright.com.

PDF

Figures(6) Tables(1)

Supplementary Information

download_supplementary
SI-Extended-TIME-DOI-225

Article Metrics

Article views(555) PDF downloads(122)

High-signal drug assessment for drug-related aortic aneurysm and dissection rupture: Evidence from real-world databases and animal experiments

GRAPHICAL ABSTRACT

PUBLIC SUMMARY

ABSTRACT