{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T05:08:30Z","timestamp":1778389710762,"version":"3.51.4"},"reference-count":45,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Lower limb arterial calcification (LLAC) is a robust imaging biomarker of peripheral artery disease (PAD) severity. Vitamin K antagonists are presumed to accelerate cardiovascular calcification. Direct oral anticoagulants (DOACs) may influence vascular calcification differently, but lower limb data are limited. Methods: We performed a single-center retrospective cross-sectional study comparing LLAC on clinically acquired non-contrast CT between DOAC users and controls without anticoagulation. Patients were propensity score-matched 1:1 (48 DOAC vs. 48 control; n = 96) using baseline clinical covariates. Associations between LLAC scores and perioperative or cardiovascular events were assessed. Segment-specific LLAC was quantified on non-contrast CT and normalized for arterial segment length. A prespecified exposure\u2013duration sensitivity analysis compared the outcomes in patients with \u22655 years of continuous DOAC therapy (n = 22) versus matched controls. Results: In the matched cohort, total LLAC scores did not differ significantly between DOAC and control groups (infrarenal aorta: median 7596.0 vs. 8637.0 (p = 0.487), iliac segment: median 5689.5 vs. 5193.5 (p = 0.602). However, in patients with \u22655 years of DOAC use, LLAC scores were significantly lower in proximal segments: infrarenal aorta median 5593.5 vs. 11,185.0 (p = 0.001997) and iliac arteries 5624.5 vs. 11,501.0 (p = 0.001867)). Higher LLAC was associated with major adverse cardiovascular events (such as myocardial infarction, stroke, or significant bleeding) in controls (p = 0.0023) but not in DOAC-treated patients. Conclusions: In this propensity-matched, cross-sectional CT study, long-term DOAC exposure was associated with lower proximal LLAC scores in a small duration-defined subgroup, while the primary matched analysis showed no overall difference in total LLAC scores. Because baseline (pre-DOAC) imaging was unavailable and residual confounding\/survivor bias is possible, these findings should be considered hypothesis-generating and require prospective validation. The cohort reflected a mixed lower-extremity vascular population rather than exclusively classic chronic atherosclerotic PAD, which may limit biological interpretation and generalizability.<\/jats:p>","DOI":"10.3390\/jcm15093399","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T12:31:56Z","timestamp":1777465916000},"page":"3399","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association Between DOAC Exposure and Lower-Extremity Arterial Calcification: A Propensity-Matched Exploratory CT Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0488-2736","authenticated-orcid":false,"given":"Eniko","family":"Pomozi","sequence":"first","affiliation":[{"name":"Department of Interventional Radiology, Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"},{"name":"Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3774-2214","authenticated-orcid":false,"given":"Dora Zoe","family":"Zatyko","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"},{"name":"Department of Vascular and Endovascular Surgery, Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferenc Imre","family":"Suhai","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"},{"name":"Department of Cardiology, Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0105-1785","authenticated-orcid":false,"given":"Zoltan","family":"Szeberin","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"},{"name":"Department of Vascular and Endovascular Surgery, Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1161\/CIRCRESAHA.116.303849","article-title":"Epidemiology of peripheral artery disease","volume":"116","author":"Criqui","year":"2015","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1313","DOI":"10.1161\/CIR.0000000000001251","article-title":"2024 ACC\/AHA\/AACVPR\/APMA\/ABC\/SCAI\/SVM\/SVN\/SVS\/SIR\/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"149","author":"Gornik","year":"2024","journal-title":"Circulation"},{"key":"ref_3","first-page":"2122","article-title":"Calcium density of peripheral arteries and risk of cardiovascular events: The MESA study","volume":"64","author":"Criqui","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","first-page":"399","article-title":"Lower limb arterial calcification score: A quantitative imaging biomarker for peripheral artery disease","volume":"296","author":"Qanadli","year":"2020","journal-title":"Radiology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1016\/j.jacc.2007.12.058","article-title":"Tibial artery calcification as a marker of amputation risk in patients with peripheral arterial disease","volume":"51","author":"Guzman","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109305","DOI":"10.1016\/j.ejrad.2020.109305","article-title":"Arterial calcification and long-term outcome in chronic limb-threatening ischemia patients","volume":"132","author":"Konijn","year":"2020","journal-title":"Eur. J. Radiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dong, Y., Liu, Y., Cheng, P., Liao, H., Jiang, C., Li, Y., Liu, S., and Xu, X. (2023). Lower limb arterial calcification and its clinical relevance with peripheral arterial disease. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1271100"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kim, T.I., and Guzman, R.J. (2023). Medial artery calcification in peripheral artery disease. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1093355"},{"key":"ref_9","first-page":"1628","article-title":"Warfarin-induced arterial calcification is mediated by inhibition of the vitamin K-dependent matrix Gla protein","volume":"24","author":"Schurgers","year":"2004","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_10","first-page":"52","article-title":"Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans","volume":"114","author":"Rennenberg","year":"2009","journal-title":"Blood"},{"key":"ref_11","first-page":"23","article-title":"Atrial fibrillation patients treated with non\u2013vitamin K antagonist oral anticoagulants have reduced vascular calcification progression","volume":"313","author":"Pastori","year":"2020","journal-title":"Atherosclerosis"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pomozi, E., Nagy, R., Feh\u00e9rv\u00e1ri, P., Hegyi, P., Kiss, B., Dembrovszky, F., Kosztin, A., Nardai, S., Zima, E., and Szeberin, Z. (2023). Direct Oral Anticoagulants as the First Choice of Anticoagulation for Patients with Peripheral Artery Disease to Prevent Adverse Vascular Events: A Systematic Review and Meta-Analysis. J. Cardiovasc. Dev. Dis., 10.","DOI":"10.3390\/jcdd10020065"},{"key":"ref_13","first-page":"847","article-title":"Direct oral anticoagulants and vascular calcification in patients with chronic kidney disease: Results from the VIKI study","volume":"35","author":"Schlieper","year":"2020","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.ijcard.2021.10.025","article-title":"New evidence of direct oral anticoagulation therapy on cardiac valve calcifications, renal preservation and inflammatory modulation","volume":"345","author":"Lavalle","year":"2021","journal-title":"Int. J. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Elango, K., Javaid, A., Khetarpal, B.K., Ramalingam, S., Kolandaivel, K.P., Gunasekaran, K., and Ahsan, C. (2021). The effects of warfarin and direct oral anticoagulants on systemic vascular calcification: A review. Cells, 10.","DOI":"10.3390\/cells10040773"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1021\/acsptsci.3c00307","article-title":"Association of Oral Anticoagulant Therapy with the Prevalence and Severity of Vascular Calcification among Patients with Atrial Fibrillation: A Cohort Study","volume":"7","author":"Wu","year":"2024","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.amjcard.2005.05.014","article-title":"Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography","volume":"96","author":"Koos","year":"2005","journal-title":"Am. J. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chowdhury, M.M., Makris, G.C., Tarkin, J.M., Joshi, F.R., Hayes, P.D., Rudd, J.H.F., and Coughlin, P.A. (2017). Lower limb arterial calcification (LLAC) scores in patients with symptomatic peripheral arterial disease are associated with increased cardiac mortality and morbidity. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182952"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/0735-1097(90)90282-T","article-title":"Quantification of coronary artery calcium using ultrafast computed tomography","volume":"15","author":"Agatston","year":"1990","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"110080","DOI":"10.1016\/j.ejrad.2021.110080","article-title":"Computed tomography-based calcium scoring in cadaver leg arteries: Influence of dose, reader, and reconstruction algorithm","volume":"146","author":"Bleys","year":"2022","journal-title":"Eur. J. Radiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1111\/j.1582-4934.2010.01139.x","article-title":"Arterial calcifications","volume":"14","author":"Rennenberg","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1177\/1358863X251334572","article-title":"Quantification of arterial calcification in peripheral artery disease and its association with amputation and\/or mortality: A systematic review","volume":"30","author":"Woo","year":"2025","journal-title":"Vasc. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"27774","DOI":"10.1038\/s41598-024-79188-3","article-title":"Combined influence of quantum iterative reconstruction level and kernel sharpness on image quality in photon counting CT angiography of the upper leg","volume":"14","author":"Goldbrunner","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6923","DOI":"10.1038\/s41598-025-91239-x","article-title":"Diagnostic limitations in advanced stage peripheral arterial disease in a cadaveric study comparing photon-counting and energy-integrating CT detectors","volume":"15","author":"Hartung","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1097\/RLI.0000000000000808","article-title":"Coronary Artery Calcium Scoring Toward a New Standard","volume":"57","author":"Wang","year":"2022","journal-title":"Investig. Radiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1161\/ATVBAHA.116.306717","article-title":"Medial Arterial Calcification: An Overlooked Player in Peripheral Arterial Disease","volume":"36","author":"Ho","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1093\/aje\/kwr301","article-title":"Bias in observational studies of prevalent users: Lessons for comparative effectiveness research from a meta-analysis of statins","volume":"175","author":"Danaei","year":"2012","journal-title":"Am. J. Epidemiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"999","DOI":"10.7326\/0003-4819-124-11-199606010-00008","article-title":"Survivor treatment selection bias in observational studies: Examples from the AIDS literature","volume":"124","author":"Glesby","year":"1996","journal-title":"Ann. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3231","DOI":"10.1182\/blood-2004-04-1277","article-title":"Oral anticoagulant treatment: Friend or foe in cardiovascular disease?","volume":"104","author":"Schurgers","year":"2004","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1161\/ATVBAHA.121.316252","article-title":"Medial Arterial Calcification: A Significant and Independent Contributor of Peripheral Artery Disease","volume":"42","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.avsg.2023.02.009","article-title":"Evaluation of lower extremity calcium score as a measure of peripheral arterial disease burden and amputation risk","volume":"95","author":"Lee","year":"2023","journal-title":"Ann. Vasc. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yan, H., Chang, Z., and Liu, Z. (2020). The risk factors for calcification vary among the different sections of the lower extremity artery in patients with symptomatic peripheral arterial disease. BMC Cardiovasc. Disord., 20.","DOI":"10.1186\/s12872-020-01615-w"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12964-025-02066-6","article-title":"Protease-activated receptors in vascular smooth muscle cells: A bridge between thrombo-inflammation and vascular remodelling","volume":"23","author":"Habibi","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s43055-020-00176-4","article-title":"Lower extremity arterial calcifications assessed by multislice CT as a correlate to coronary artery disease","volume":"51","author":"Aly","year":"2020","journal-title":"Egypt. J. Radiol. Nucl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e003811","DOI":"10.1136\/bmjdrc-2023-003811","article-title":"Association between lower extremity arterial calcification and coronary arterial calcification in a population at increased risk of cardiovascular disease","volume":"12","author":"Meer","year":"2024","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e33179","DOI":"10.5812\/iranjradiol.33179","article-title":"Lower extremity arterial calcification as a predictor of coronary atherosclerosis in patients with peripheral arterial disease","volume":"13","author":"Shin","year":"2016","journal-title":"Iran. J. Radiol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zwakenberg, S.R., de Jong, P.A., Hendriks, E.J., Westerink, J., Spiering, W., de Borst, G.J., Cramer, M.J., Bartstra, J.W., Doesburg, T., and Rutters, F. (2020). Intimal and medial calcification in relation to cardiovascular risk factors. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0235228"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.avsg.2019.06.043","article-title":"Lower limb arterial calcification and acute thrombosis risk in patients with peripheral artery disease","volume":"63","author":"Chang","year":"2020","journal-title":"Ann. Vasc. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.jvs.2017.06.086","article-title":"Association of arterial calcification with chronic limb ischemia in patients with peripheral artery disease","volume":"67","author":"Zettervall","year":"2018","journal-title":"J. Vasc. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.avsg.2024.11.009","article-title":"Association of iliofemoral calcium score and major vascular complications within the first year after lower limb endovascular revascularization","volume":"111","author":"Derksen","year":"2025","journal-title":"Ann. Vasc. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jvs.2023.02.019","article-title":"Iliac artery calcification score stratifies mortality risk estimation in patients with chronic limb-threatening ischemia undergoing revascularization","volume":"78","author":"Huynh","year":"2023","journal-title":"J. Vasc. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Huang, C.L., Wu, I.H., Wu, Y.W., Hwang, J.J., Wang, S.S., Chen, W.J., Lee, W.J., and Yang, W.S. (2014). Association of lower extremity arterial calcification with amputation and mortality in patients with symptomatic peripheral artery disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090201"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1016\/j.jacc.2015.09.024","article-title":"Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin: ROCKET AF Trial","volume":"66","author":"Sherwood","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"i3189","DOI":"10.1136\/bmj.i3189","article-title":"Comparative effectiveness and safety of non\u2013vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: Propensity weighted nationwide cohort study","volume":"353","author":"Larsen","year":"2016","journal-title":"BMJ"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1053\/j.gastro.2016.12.018","article-title":"Gastrointestinal safety of direct oral anticoagulants: A large population-based study","volume":"152","author":"Abraham","year":"2017","journal-title":"Gastroenterology"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/9\/3399\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T04:12:59Z","timestamp":1778386379000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/9\/3399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":45,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["jcm15093399"],"URL":"https:\/\/doi.org\/10.3390\/jcm15093399","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]}}}