{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T07:01:29Z","timestamp":1790060489228,"version":"4.0.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Anti-angiogenic inhibitors (AI) have transformed cancer treatment but are associated with vascular toxicities. The specific association with peripheral artery aneurysm and dissection (PAAD) remains uncharacterized. This study aimed to evaluate the association between AI exposure and PAAD risk and to delineate the temporal patterns of these adverse events across different exposure windows.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This analysis was conducted using the U.S. FDA Adverse Event Reporting System and the Japanese Adverse Drug Event Report databases. Disproportionality analysis using the Reporting Odds Ratio was applied to identify safety signals. Univariate and multivariate logistic regression models were fitted to detect associated factors and quantify the effects of distinct exposure duration windows. Kaplan-Meier analysis and the Weibull distribution were utilized to characterize time-to-onset patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In total, 757,900 FAERS and 136,170 JADER reports were included. Disproportionality analyses identified significantly higher RORs for PAAD (ROR = 3.276 in FAERS; ROR = 8.465 in JADER) and peripheral artery dissection (PAD) (ROR = 6.275 in FAERS; ROR = 9.372 in JADER). The peripheral arterial aneurysm (PAA) signal was marginally non-significant in FAERS but significant in JADER (ROR = 8.113). Subtype-specific analyses showed small-molecule VEGFR-targeted tyrosine kinase inhibitors (SMV-TKIs) were linked to higher reporting of PAAD and PAD, whereas anti-VEGF monoclonal antibodies (anti-VMAs) were associated with elevated reporting across all outcomes. Time-to-onset analyses uncovered temporal heterogeneity: PAAD and PAA occurred early in FAERS (median 29.5 days and 25.0 days, respectively), whereas PAD followed an early- and late-onset pattern. Within JADER, PAA events presented early, while PAD showed delayed onset (median 853.0 days). Multivariable regression supported significant independent associations between AI exposure and both PAAD and PAD, with adjusted Odds Ratios of 4.078 and 7.275 in FAERS and greater effect sizes in JADER. Time-window stratification confirmed dual reporting peaks in the early (0\u201329-day) and long-term (\u2265360-day) windows.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In conclusion, subclass-specific and time-dependent disproportional reporting signals of AI-associated PAAD were identified. Anti-VMAs were associated with elevated signals for PAAD, PAA, and PAD, whereas SMV-TKIs were mainly linked to PAAD and PAD. PAAD and PAA occurred predominantly early after drug initiation, whereas PAD showed prominent delayed onset.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1932218","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:11:35Z","timestamp":1790057495000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Angiogenesis inhibitors and the risk of peripheral artery aneurysm and dissection: a cross-database study"],"prefix":"10.3389","volume":"17","author":[{"given":"Kaixuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Vascular Surgery, Department of General Surgery, Changhai Hospital, Naval Medical University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingsheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, Department of General Surgery, Changhai Hospital, Naval Medical University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1136\/bmj.310.6975.298","article-title":"Statistics notes: the normal distribution","volume":"310","author":"Altman","year":"1995","journal-title":"BMJ Clin. Research ed."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.3390\/diagnostics14192167","article-title":"New insights into the pathophysiology of coronary artery aneurysms","volume":"14","author":"Bararu-Bojan","year":"2024","journal-title":"Diagn. Basel, Switz."},{"key":"B3","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1177\/1358863X211006470","article-title":"Arterial aneurysm and dissection with systemic vascular endothelial growth factor inhibitors: a review of cases reported to the FDA adverse event reporting system and published in the literature","volume":"26","author":"Cheng","year":"2021","journal-title":"Vasc. Medicine Lond. Engl."},{"key":"B4","doi-asserted-by":"publisher","first-page":"867","DOI":"10.3390\/ph16060867","article-title":"Uncovering knowledge gaps in the safety profile of antiangiogenic drugs in cancer patients: insights from spontaneous reporting systems studies","volume":"16","author":"Ciccone","year":"2023","journal-title":"Pharm. Basel, Switz."},{"key":"B5","doi-asserted-by":"publisher","first-page":"176","DOI":"10.4065\/79.2.176","article-title":"Acute aortic dissection: population-based incidence compared with degenerative aortic aneurysm rupture","volume":"79","author":"Clouse","year":"2004","journal-title":"Mayo. Clin. Proc."},{"key":"B6","doi-asserted-by":"publisher","first-page":"S31","DOI":"10.4103\/sja.SJA_543_18","article-title":"The STROBE guidelines","volume":"13","author":"Cuschieri","year":"2019","journal-title":"Saudi J. Anaesth."},{"key":"B7","doi-asserted-by":"publisher","first-page":"485","DOI":"10.3390\/e27050485","article-title":"Bias reduction of modified maximum likelihood estimates for a three-parameter weibull distribution","volume":"27","author":"Da Silva","year":"2025","journal-title":"Entropy"},{"key":"B8","doi-asserted-by":"publisher","first-page":"110714","DOI":"10.1016\/j.intimp.2023.110714","article-title":"The role of PI3K\/AKT signaling pathway in myocardial ischemia-reperfusion injury","volume":"123","author":"Deng","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3127","DOI":"10.1016\/j.ejca.2006.09.015","article-title":"The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review","volume":"42","author":"Eskens","year":"2006","journal-title":"Eur. J. Cancer."},{"key":"B10","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1038\/nature04483","article-title":"Angiogenesis as a therapeutic target","volume":"438","author":"Ferrara","year":"2005","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/nrd1381","article-title":"Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer","volume":"3","author":"Ferrara","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"B12","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/nrd2115","article-title":"Angiogenesis: an organizing principle for drug discovery?","volume":"6","author":"Folkman","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"B13","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1590\/1516-3180.2013.7380002","article-title":"Aortic dissection during antiangiogenic therapy with sunitinib. A case report","volume":"133","author":"Formiga","year":"2015","journal-title":"Sao Paulo Med. J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1545044","DOI":"10.3389\/fphys.2025.1545044","article-title":"Promotion of nitric oxide production: mechanisms, strategies, and possibilities","volume":"16","author":"Gonzalez","year":"2025","journal-title":"Front. Physiol."},{"key":"B15","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1097\/00001648-199901000-00008","article-title":"Causal diagrams for epidemiologic research","volume":"10","author":"Greenland","year":"1999","journal-title":"Epidemiology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1001\/jamaoncol.2021.0210","article-title":"Association between antiangiogenic drugs used for cancer treatment and artery dissections or aneurysms","volume":"7","author":"Guyon","year":"2021","journal-title":"JAMA Oncol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2335","DOI":"10.1056\/NEJMoa032691","article-title":"Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer","volume":"350","author":"Hurwitz","year":"2004","journal-title":"N. Engl. Journal Medicine"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.1002\/cncr.23460","article-title":"Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor","volume":"112","author":"Khakoo","year":"2008","journal-title":"Cancer"},{"key":"B19","doi-asserted-by":"publisher","first-page":"k3532","DOI":"10.1136\/bmj.k3532","article-title":"The reporting of studies conducted using observational routinely collected health data statement for pharmacoepidemiology (RECORD-PE)","volume":"363","author":"Langan","year":"2018","journal-title":"BMJ Clin. Research ed."},{"key":"B20","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1161\/HYPERTENSIONAHA.122.19427","article-title":"VEGF (vascular endothelial growth factor) inhibition and hypertension: does microvascular rarefaction play a role?","volume":"80","author":"le Noble","year":"2023","journal-title":"Hypertens. Dallas, Tex. 1979"},{"key":"B21","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/s41392-025-02249-0","article-title":"Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives","volume":"10","author":"Lee","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1416349","DOI":"10.3389\/fonc.2024.1416349","article-title":"Bevacizumab for the treatment of metastatic colorectal cancer complicated by abdominal aortic aneurysm and mural thrombus: a case report","volume":"14","author":"Li","year":"2024","journal-title":"Front. Oncol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e1060","DOI":"10.1002\/iid3.1060","article-title":"TGF-\u03b2\/Smads signaling pathway, Hippo-YAP\/TAZ signaling pathway, and VEGF: their mechanisms and roles in vascular remodeling related diseases","volume":"11","author":"Liu","year":"2023","journal-title":"Immun. Inflammation Disease"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e011536","DOI":"10.1161\/JAHA.118.011536","article-title":"Impact of treatment modality on vascular function in coarctation of the aorta: the LOVE - COARCT study","volume":"8","author":"Martins","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"B25","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1056\/NEJMoa065044","article-title":"Sunitinib versus interferon alfa in metastatic renal-cell carcinoma","volume":"356","author":"Motzer","year":"2007","journal-title":"N. Engl. Journal Medicine"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1001\/jama.2008.656","article-title":"Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis","volume":"300","author":"Nalluri","year":"2008","journal-title":"JAMA"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1748445","DOI":"10.3389\/fcvm.2026.1748445","article-title":"Onco-hypertension: hypertension induced by VEGF pathway inhibition","volume":"13","author":"Palaskas","year":"2026","journal-title":"Front. Cardiovasc. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/s41580-023-00631-w","article-title":"Biology and therapeutic targeting of vascular endothelial growth factor A","volume":"24","author":"P\u00e9rez-Guti\u00e9rrez","year":"2023","journal-title":"Nat. Reviews. Mol. Cell Biology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"8321400","DOI":"10.1155\/2021\/8321400","article-title":"Inhibition of vascular smooth muscle and cancer cell proliferation by new VEGFR inhibitors and their immunomodulator effect: design, synthesis, and biological evaluation. Oxidative med","volume":"2021","author":"Ran","year":"2021","journal-title":"Cell. Longev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1002\/pds.1001","article-title":"The reporting odds ratio and its advantages over the proportional reporting ratio","volume":"13","author":"Rothman","year":"2004","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"B31","doi-asserted-by":"publisher","first-page":"796","DOI":"10.7150\/ijms.6048","article-title":"Data mining of the public version of the FDA adverse event reporting system","volume":"10","author":"Sakaeda","year":"2013","journal-title":"Int. J. Med. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S0140-6736(05)66459-8","article-title":"Abdominal aortic aneurysm","volume":"365","author":"Sakalihasan","year":"2005","journal-title":"Lancet London, Engl."},{"key":"B33","first-page":"453","article-title":"Role of angiogenesis and vascular remodeling in chronic obstructive pulmonary disease","volume":"2","author":"Siafakas","year":"2007","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e2546960","DOI":"10.1001\/jamanetworkopen.2025.46960","article-title":"Angiogenesis inhibitors and arterial dissection or aneurysm in patients with metastatic colorectal cancer","volume":"8","author":"Singier","year":"2025","journal-title":"JAMA Netw. Open"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1001\/jamaoncol.2022.3511","article-title":"Efficacy and safety of telaglenastat plus cabozantinib vs placebo plus cabozantinib in patients with advanced renal cell carcinoma: the CANTATA randomized clinical trial","volume":"8","author":"Tannir","year":"2022","journal-title":"JAMA Oncol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e87776","DOI":"10.7759\/cureus.87776","article-title":"Rupture of abdominal aortic aneurysm after Bevacizumab treatment for colorectal cancer","volume":"17","author":"Uemura","year":"2025","journal-title":"Cureus"},{"key":"B37","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.apsb.2021.07.023","article-title":"Targeting PI3K\/AKT signaling for treatment of idiopathic pulmonary fibrosis","volume":"12","author":"Wang","year":"2022","journal-title":"Acta Pharmaceutica Sin. B"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e240940","DOI":"10.1001\/jamanetworkopen.2024.0940","article-title":"Vascular endothelial growth factor inhibitors and the risk of aortic aneurysm and aortic dissection","volume":"7","author":"Wu","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"B39","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1161\/01.HYP.0000138688.78906.6b","article-title":"Essential role of vascular endothelial growth factor in angiotensin II-induced vascular inflammation and remodeling","volume":"44","author":"Zhao","year":"2004","journal-title":"Hypertens. (Dallas, Tex. 1979)"},{"key":"B40","doi-asserted-by":"publisher","first-page":"109759","DOI":"10.1016\/j.intimp.2023.109759","article-title":"Cordycepin suppresses vascular inflammation, apoptosis and oxidative stress of arterial smooth muscle cell in thoracic aortic aneurysm with VEGF inhibition","volume":"116","author":"Zhou","year":"2023","journal-title":"Int. Immunopharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1932218\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:11:36Z","timestamp":1790057496000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1932218\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":40,"alternative-id":["10.3389\/fphar.2026.1932218"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1932218","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"article-number":"1932218"}}