{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T19:17:13Z","timestamp":1785611833398,"version":"3.56.0"},"reference-count":45,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>The association of tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR-TKIs) with aneurysm and artery dissection (AAD) has been frequently reported in spontaneous reporting databases.<\/jats:p><\/jats:sec>Objective<\/jats:title>To investigate the risk and incidence of AAD occurrence in patients with cancer treated with oral VEGFR-TKIs, with capecitabine as an active comparator.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This national, historical cohort study was conducted using national claims data from the National Health Insurance Service in Korea from 2007 to 2020, with a 1-year follow-up. Patients with cancer aged 40 years or older prescribed oral VEGFR-TKIs or capecitabine were enrolled. Data were analyzed from September 2022 through April 2023.<\/jats:p><\/jats:sec>Exposure<\/jats:title>Oral VEGFR-TKIs (sorafenib, regorafenib, vandetanib, sunitinib, lenvatinib, axitinib, and pazopanib) or capecitabine as a comparator.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Hazard ratios (HRs) were used to investigate the association between VEGFR-TKI use and AAD after propensity score matching. The primary outcome was AAD, and secondary outcomes were aortic aneurysm and dissection and AAD with rupture. Outcomes were defined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision<\/jats:italic> (ICD-10<\/jats:italic>) diagnosis codes.<\/jats:p><\/jats:sec>Results<\/jats:title>Among 127\u202f710 patients with cancer eligible for the study (80\u202f386 males [62.9%]; mean [SD] age, 62.6 [10.9] years), 37\u202f308 patients received VEGFR-TKIs and 90\u202f402 patients received capecitabine. Among 27\u202f535 matched patients receiving VEGFR-TKIs, the incidence of AAD within 1 year of treatment initiation was 6.0 per 1000 person-years. The median (IQR) time to AAD onset in the matched AAD group was 114 (67-257) days after treatment initiation, with the highest incidence observed during the first 3 months (45 incidents vs 31, 17, and 16 incidents during 3- to 6-month, 6- to 9-month, and 9- to 12-month periods, respectively). Cox regression modeling showed that the risk of AAD occurrence was significantly higher among patients prescribed VEGFR-TKIs than those receiving capecitabine (HR, 1.48; 95% CI, 1.08-2.02); similar results were obtained among females (HR, 2.08; 95% CI, 1.26-3.42), older adults (aged \u226565 years; HR, 1.42; 95% CI, 1.01-1.99), and patients with dyslipidemia (HR, 1.58; 95% CI, 1.11-2.24).<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this study, the use of oral VEGFR-TKIs was associated with an increased risk of AAD occurrence. These findings elucidate vascular toxic effects and may provide a substantial reference for reducing the socioeconomic burden of adverse events associated with VEGFR-TKI use.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.45977","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T16:34:32Z","timestamp":1701275672000},"page":"e2345977","source":"Crossref","is-referenced-by-count":11,"title":["Aneurysm and Artery Dissection After Oral VEGFR-TKI Use in Adults With Cancer"],"prefix":"10.1001","volume":"6","author":[{"given":"Soyoung","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Drug Safety Information, Korea Institute of Drug Safety and Risk Management, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bora","family":"Yeon","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Information, Korea Institute of Drug Safety and Risk Management, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myo-Song","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Information, Korea Institute of Drug Safety and Risk Management, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myungsik","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Information, Korea Institute of Drug Safety and Risk Management, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonggi","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Information, Korea Institute of Drug Safety and Risk Management, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun Mi","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea"},{"name":"Department of Pharmaceutical Medicine and Regulatory Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"zoi231340r2","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.ejphar.2018.07.034","article-title":"Molecular targeted therapy: treating cancer with specificity.","volume":"834","author":"Lee","year":"2018","journal-title":"Eur J Pharmacol"},{"issue":"4","key":"zoi231340r3","doi-asserted-by":"publisher","first-page":"19","DOI":"10.7603\/s40681-015-0019-4","article-title":"An overview of targeted cancer therapy.","volume":"5","author":"Padma","year":"2015","journal-title":"Biomedicine (Taipei)"},{"issue":"3","key":"zoi231340r4","doi-asserted-by":"publisher","first-page":"213","DOI":"10.2147\/vhrm.2006.2.issue-3","article-title":"Angiogenesis in cancer.","volume":"2","author":"Nishida","year":"2006","journal-title":"Vasc Health Risk Manag"},{"issue":"3","key":"zoi231340r5","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1093\/carcin\/21.3.505","article-title":"Tumor angiogenesis: past, present and the near future.","volume":"21","author":"Kerbel","year":"2000","journal-title":"Carcinogenesis"},{"issue":"2","key":"zoi231340r6","doi-asserted-by":"publisher","first-page":"34","DOI":"10.3390\/biomedicines5020034","article-title":"The role of angiogenesis in cancer treatment.","volume":"5","author":"Rajabi","year":"2017","journal-title":"Biomedicines"},{"issue":"3","key":"zoi231340r7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090135","article-title":"Risks of proteinuria associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a systematic review and meta-analysis.","volume":"9","author":"Zhang","year":"2014","journal-title":"PLoS One"},{"issue":"3","key":"zoi231340r8","doi-asserted-by":"publisher","first-page":"R91","DOI":"10.1530\/EJE-14-0198","article-title":"Endocrine side-effects of anti-cancer drugs: thyroid effects of tyrosine kinase inhibitors.","volume":"171","author":"Illouz","year":"2014","journal-title":"Eur J Endocrinol"},{"issue":"3","key":"zoi231340r9","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.beem.2017.04.012","article-title":"Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients.","volume":"31","author":"Resteghini","year":"2017","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"issue":"8","key":"zoi231340r10","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/nrclinonc.2009.94","article-title":"Adverse effects of anticancer agents that target the VEGF pathway.","volume":"6","author":"Chen","year":"2009","journal-title":"Nat Rev Clin Oncol"},{"issue":"4","key":"zoi231340r12","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1007\/s11523-021-00817-2","article-title":"Cardiovascular toxicities of antiangiogenic tyrosine kinase inhibitors: a retrospective, pharmacovigilance study.","volume":"16","author":"Goldman","year":"2021","journal-title":"Target Oncol"},{"key":"zoi231340r13","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.ctrv.2016.12.002","article-title":"Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: a systematic review and meta-analysis.","volume":"53","author":"Abdel-Qadir","year":"2017","journal-title":"Cancer Treat Rev"},{"issue":"8","key":"zoi231340r14","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1161\/CIRCULATIONAHA.116.025144","article-title":"Association between aortic dissection and systemic exposure of vascular endothelial growth factor pathway inhibitors in the Japanese adverse drug event report database.","volume":"135","author":"Oshima","year":"2017","journal-title":"Circulation"},{"issue":"23","key":"zoi231340r15","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.121.020844","article-title":"Aneurysm and artery dissection following the use of vascular endothelial growth factor inhibitor: a real-world analysis using a spontaneous reporting system.","volume":"10","author":"Wang","year":"2021","journal-title":"J Am Heart Assoc"},{"issue":"1","key":"zoi231340r16","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.v9.1","article-title":"Tyrosine kinase inhibitors targeting vascular endothelial growth factor and the risk of aortic dissection\u2014a pharmacovigilance analysis.","volume":"9","author":"D\u00f6rks","year":"2021","journal-title":"Pharmacol Res Perspect"},{"issue":"5","key":"zoi231340r17","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 Med"},{"issue":"5","key":"zoi231340r18","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":"zoi231340r21","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"},{"issue":"5","key":"zoi231340r22","doi-asserted-by":"publisher","first-page":"718","DOI":"10.3346\/jkms.2017.32.5.718","article-title":"Towards actualizing the value potential of Korea health insurance review and assessment (HIRA) data as a resource for health research: strengths, limitations, applications, and strategies for optimal use of HIRA data.","volume":"32","author":"Kim","year":"2017","journal-title":"J Korean Med Sci"},{"issue":"6","key":"zoi231340r24","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/j.ejcts.2008.02.029","article-title":"Ascending aortic curvature as an independent risk factor for type A dissection, and ascending aortic aneurysm formation: a mathematical model.","volume":"33","author":"Poullis","year":"2008","journal-title":"Eur J Cardiothorac Surg"},{"issue":"5","key":"zoi231340r25","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/s41569-020-00472-6","article-title":"Epidemiology and management of aortic disease: aortic aneurysms and acute aortic syndromes.","volume":"18","author":"Bossone","year":"2021","journal-title":"Nat Rev Cardiol"},{"issue":"6","key":"zoi231340r26","doi-asserted-by":"publisher","first-page":"398","DOI":"10.7326\/M18-3079","article-title":"Graphical depiction of longitudinal study designs in health care databases.","volume":"170","author":"Schneeweiss","year":"2019","journal-title":"Ann Intern Med"},{"key":"zoi231340r27","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/1471-2261-14-174","article-title":"Population risk factor estimates for abdominal aortic aneurysm from electronic medical records: a case control study.","volume":"14","author":"Smelser","year":"2014","journal-title":"BMC Cardiovasc Disord"},{"issue":"3","key":"zoi231340r28","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1111\/bcp.2013.76.issue-3","article-title":"Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis.","volume":"76","author":"Qi","year":"2013","journal-title":"Br J Clin Pharmacol"},{"issue":"2","key":"zoi231340r29","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1111\/ajco.12473","article-title":"A study on the association between hyperlipidemia and hypothyroidism and the response to TKIs in metastatic renal cell carcinoma.","volume":"12","author":"Song","year":"2016","journal-title":"Asia Pac J Clin Oncol"},{"key":"zoi231340r30","doi-asserted-by":"publisher","first-page":"k678","DOI":"10.1136\/bmj.k678","article-title":"Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study.","volume":"360","author":"Pasternak","year":"2018","journal-title":"BMJ"},{"issue":"6","key":"zoi231340r31","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1093\/ejcts\/ezy167","article-title":"Statistical primer: propensity score matching and its alternatives.","volume":"53","author":"Benedetto","year":"2018","journal-title":"Eur J Cardiothorac Surg"},{"issue":"2","key":"zoi231340r32","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1002\/pst.v10.2","article-title":"Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies.","volume":"10","author":"Austin","year":"2011","journal-title":"Pharm Stat"},{"issue":"1","key":"zoi231340r33","doi-asserted-by":"publisher","first-page":"16","DOI":"10.21037\/atm","article-title":"Balance diagnostics after propensity score matching.","volume":"7","author":"Zhang","year":"2019","journal-title":"Ann Transl Med"},{"issue":"15","key":"zoi231340r34","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1002\/sim.v14:15","article-title":"Graphical methods for assessing violations of the proportional hazards assumption in Cox regression.","volume":"14","author":"Hess","year":"1995","journal-title":"Stat Med"},{"issue":"3","key":"zoi231340r35","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1093\/aje\/154.3.236","article-title":"Prevalence of and risk factors for abdominal aortic aneurysms in a population-based study: the Troms\u00f8 Study.","volume":"154","author":"Singh","year":"2001","journal-title":"Am J Epidemiol"},{"issue":"8","key":"zoi231340r36","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.115.001926","article-title":"Population-based study of incidence of acute abdominal aortic aneurysms with projected impact of screening strategy.","volume":"4","author":"Howard","year":"2015","journal-title":"J Am Heart Assoc"},{"issue":"9","key":"zoi231340r37","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1161\/CIRCULATIONAHA.121.056546","article-title":"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.","volume":"145","author":"Hibino","year":"2022","journal-title":"Circulation"},{"issue":"4","key":"zoi231340r38","doi-asserted-by":"publisher","first-page":"268","DOI":"10.7326\/M16-2607","article-title":"Sensitivity analysis in observational research: introducing the E-value.","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann Intern Med"},{"issue":"8","key":"zoi231340r39","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1016\/j.avsg.2014.07.008","article-title":"Sex differences in abdominal aortic aneurysm: the role of sex hormones.","volume":"28","author":"Makrygiannis","year":"2014","journal-title":"Ann Vasc Surg"},{"issue":"2","key":"zoi231340r40","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1007\/s11523-023-00951-z","article-title":"Analysis of anti-angiogenesis-related adverse events associated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma.","volume":"18","author":"Lee","year":"2023","journal-title":"Target Oncol"},{"issue":"5","key":"zoi231340r41","doi-asserted-by":"publisher","DOI":"10.1111\/ijcp.2019.73.issue-5","article-title":"Assessing fluoroquinolone-associated aortic aneurysm and dissection: data mining of the public version of the FDA adverse event reporting system.","volume":"73","author":"Meng","year":"2019","journal-title":"Int J Clin Pract"},{"issue":"9","key":"zoi231340r42","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1586\/14737140.2014.929501","article-title":"Risk of thyroid dysfunction in patients with solid tumors treated with VEGF receptor tyrosine kinase inhibitors: a critical literature review and meta analysis.","volume":"14","author":"Abdel-Rahman","year":"2014","journal-title":"Expert Rev Anticancer Ther"},{"issue":"2","key":"zoi231340r43","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1634\/theoncologist.2016-0233","article-title":"Pharmacoepidemiology of clinically relevant hypothyroidism and hypertension from sunitinib and sorafenib.","volume":"22","author":"Walko","year":"2017","journal-title":"Oncologist"},{"issue":"5","key":"zoi231340r44","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1536\/ihj.17-461","article-title":"Aortic dissection and cardiac dysfunction emerged coincidentally during the long-term treatment with angiogenesis inhibitors for metastatic renal cell carcinoma.","volume":"59","author":"Takada","year":"2018","journal-title":"Int Heart J"},{"issue":"8","key":"zoi231340r45","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1161\/ATVBAHA.119.312497","article-title":"Inhibition of VEGF (vascular endothelial growth factor)-A or its receptor activity suppresses experimental aneurysm progression in the aortic elastase infusion model.","volume":"39","author":"Xu","year":"2019","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"zoi231340r1","volume-title":"Pharmacotherapy: A Pathophysiologic Approach","author":"DiPiro","year":"2017","edition":"10th ed"},{"key":"zoi231340r23","first-page":"1","volume-title":"Etiology, Pathogenesis and Pathophysiology of Aortic Aneurysms and Aneurysm Rupture","author":"Spigset","year":"2011"},{"key":"zoi231340r11","unstructured":"Choueiri? TK, Sonpavde? GP. Toxicity of molecularly targeted antiangiogenic agents: cardiovascular effects. Accessed April 25, 2023. https:\/\/www.uptodate.com\/contents\/toxicity-of-molecularly-targeted-antiangiogenic-agents-cardiovascular-effects"},{"key":"zoi231340r19","unstructured":"Medicines and Healthcare Products Regulatory Agency. Systemically administered VEGF pathway inhibitors: risk of aneurysm and artery dissection. Accessed April 28, 2023. https:\/\/www.gov.uk\/drug-safety-update\/systemically-administered-vegf-pathway-inhibitors-risk-of-aneurysm-and-artery-dissection"},{"key":"zoi231340r20","unstructured":"Food and Drug Administration. January - March 2020: potential signals of serious risks\/new safety information identified by the FDA Adverse Event Reporting System (FAERS). Accessed April 28, 2023. https:\/\/www.fda.gov\/drugs\/questions-and-answers-fdas-adverse-event-reporting-system-faers\/january-march-2020-potential-signals-serious-risksnew-safety-information-identified-fda-adverse"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2812356\/kang_2023_oi_231340_1700172700.11574.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T16:34:36Z","timestamp":1701275676000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2812356"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,29]]},"references-count":45,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2023.45977","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,29]]}}}