{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:17:52Z","timestamp":1787735872059,"version":"build-2784847793"},"reference-count":31,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Direct oral factor Xa inhibitors (DOACs) show substantial interindividual exposure variability in real-world practice, yet interpretation of plasma drug concentrations remains challenging because routine monitoring is not standardized. This study evaluated dosing appropriateness, plasma drug exposure measured by chromogenic anti-factor Xa assays, inter-platform comparability, and associations with routine coagulation tests. Methods: This single-center retrospective study included 392 plasma samples from 292 patients with atrial fibrillation treated with apixaban (n = 207), edoxaban (n = 147), or rivaroxaban (n = 38). Post-dose outpatient spot samples were analyzed using Sysmex CS-5100 and CN-6000 analyzers with two chromogenic anti-factor Xa assay systems (BIOPHEN\u2122 DiXaI and BIOPHEN\u2122 Heparin LRT) and drug-specific calibrators. Correlations between routine assays (prothrombin time [PT]\/international normalized ratio [INR], activated partial thromboplastin time [aPTT]) and DOAC concentrations, as well as inter-platform agreement, were assessed using Spearman\u2019s rank correlation and Passing-Bablok regression. Dosing appropriateness was determined according to Food and Drug Administration-approved labeling. Results: Overall dosing appropriateness was 69.2% (edoxaban 73.3%, apixaban 70.5%, rivaroxaban 45.5%), whereas inappropriate underdosing was the predominant prescribing pattern (26.9%), particularly among patients without formal dose-reduction criteria. PT\/INR demonstrated the strongest correlation with edoxaban concentrations (rs = 0.83, p &lt; 0.001). Inter-analyzer correlation between the CS-5100 and CN-6000 was excellent (r = 0.885\u20130.996), with LRT reagents providing highly consistent results across platforms. Conclusions: Real-world outpatient DOAC concentrations demonstrated substantial variability and frequent off-label underdosing. Chromogenic anti-factor Xa assays showed strong inter-platform agreement, particularly with LRT reagents, supporting their analytical reliability for laboratory assessment of DOAC exposure. Because exact dosing times were unavailable, these concentrations should be interpreted as heterogeneous spot samples rather than standardized pharmacokinetic reference intervals; these findings may nonetheless support individualized interpretation of outpatient spot sample DOAC concentrations in selected clinical settings.<\/jats:p>","DOI":"10.3390\/diagnostics16172725","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:11:15Z","timestamp":1787731875000},"page":"2725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Real-World Assessment of Direct Oral Factor Xa Inhibitors: Dosing Appropriateness, Drug Exposure, and Inter-Platform Comparability of Chromogenic Anti-Xa Assays"],"prefix":"10.3390","volume":"16","author":[{"given":"Yoonjung","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6190-1131","authenticated-orcid":false,"given":"Sojin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5668-4120","authenticated-orcid":false,"given":"Yongjung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin 16995, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5320-6705","authenticated-orcid":false,"given":"Kyung-A","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1111\/imj.70103","article-title":"2025 Guidelines for direct oral anticoagulants: A practical guidance on the prescription, laboratory testing, peri-operative and bleeding management","volume":"55","author":"Tran","year":"2025","journal-title":"Intern. Med. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1182\/blood-2018-04-791541","article-title":"Testing and monitoring direct oral anticoagulants","volume":"132","author":"Connors","year":"2018","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.2147\/VHRM.S79065","article-title":"Direct oral anticoagulants: Key considerations for use to prevent stroke in patients with nonvalvular atrial fibrillation","volume":"11","author":"Ment","year":"2015","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1080\/17425255.2023.2287472","article-title":"Pharmacokinetics and pharmacodynamics of direct oral anticoagulants","volume":"19","author":"Hindley","year":"2023","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"euae298","DOI":"10.1093\/europace\/euae298","article-title":"Spotlight on the 2024 ESC\/EACTS management of atrial fibrillation guidelines: 10 novel key aspects","volume":"26","author":"Rienstra","year":"2024","journal-title":"Europace"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/ijlh.13119","article-title":"Evaluation of the Atellica COAG 360 coagulation analyzer in a central laboratory of a maximum care hospital","volume":"42","author":"Lehmann","year":"2020","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1007\/s00277-015-2407-y","article-title":"Anti-coagulation assessment with prothrombin time and anti-Xa assays in real-world patients on treatment with rivaroxaban","volume":"94","author":"Quehenberger","year":"2015","journal-title":"Ann. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1111\/jth.12702","article-title":"Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography\u2014Tandem mass spectrometry (UPLC-MS\/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants","volume":"12","author":"Schmitz","year":"2014","journal-title":"J. Thromb. Haemost."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1055\/a-1450-8178","article-title":"2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants","volume":"121","author":"Douxfils","year":"2021","journal-title":"Thromb. Haemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1055\/s-0038-1627480","article-title":"International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants","volume":"118","author":"Gosselin","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.cll.2024.04.014","article-title":"Assessing Direct Oral Anticoagulants in the Clinical Laboratory","volume":"44","author":"Gosselin","year":"2024","journal-title":"Clin. Lab. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1056\/NEJMoa1107039","article-title":"Apixaban versus warfarin in patients with atrial fibrillation","volume":"365","author":"Granger","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1056\/NEJMoa1310907","article-title":"Edoxaban versus warfarin in patients with atrial fibrillation","volume":"369","author":"Giugliano","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e335","DOI":"10.3346\/jkms.2022.37.e335","article-title":"Outcomes of On-Label Reduced-Dose Edoxaban in Patients with Atrial Fibrillation: The LEDIOS Registry","volume":"37","author":"Kim","year":"2022","journal-title":"J. Korean Med. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.2215\/CJN.06870909","article-title":"Performance of the Cockcroft-Gault, MDRD, and new CKD-EPI formulas in relation to GFR, age, and body size","volume":"5","author":"Michels","year":"2010","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e014177","DOI":"10.1161\/JAHA.119.014177","article-title":"Label Adherence of Direct Oral Anticoagulants Dosing and Clinical Outcomes in Patients with Atrial Fibrillation","volume":"9","author":"Yu","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1038\/s41598-024-51776-3","article-title":"Edoxaban for stroke prevention in atrial fibrillation and factors associated with dosing: Patient characteristics from the prospective observational ETNA-AF-China registry","volume":"14","author":"Guo","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1016\/j.jtha.2024.12.032","article-title":"Peak and trough concentrations of apixaban and rivaroxaban in adult patients: A systematic review and meta-analysis","volume":"23","author":"Almalbis","year":"2025","journal-title":"J. Thromb. Haemost."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1002\/pds.4268","article-title":"Adherence with direct oral anticoagulants in nonvalvular atrial fibrillation new users and associated factors: A French nationwide cohort study","volume":"26","author":"Maura","year":"2017","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10760296231179439","DOI":"10.1177\/10760296231179439","article-title":"An Updated Pooled Analysis of Off-Label Under and Over-Dosed Direct Oral Anticoagulants in Patients with Atrial Fibrillation","volume":"29","author":"Shen","year":"2023","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.chest.2016.08.1462","article-title":"Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review","volume":"151","author":"Samuelson","year":"2017","journal-title":"Chest"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/jth.15563","article-title":"Inter- and intra-individual concentrations of direct oral anticoagulants: The KIDOAC study","volume":"20","author":"Toorop","year":"2022","journal-title":"J. Thromb. Haemost."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.jacc.2020.07.045","article-title":"Mortality in Patients with Atrial Fibrillation Receiving Nonrecommended Doses of Direct Oral Anticoagulants","volume":"76","author":"Camm","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1002\/clc.23586","article-title":"Effect of non-recommended doses versus recommended doses of direct oral anticoagulants in atrial fibrillation patients: A meta-analysis","volume":"44","author":"Liu","year":"2021","journal-title":"Clin. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1177\/0091270009351883","article-title":"Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers","volume":"50","author":"Ogata","year":"2010","journal-title":"J. Clin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1111\/j.1365-2125.2012.04369.x","article-title":"Apixaban, an oral, direct factor Xa inhibitor: Single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects","volume":"75","author":"Frost","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40262-013-0100-7","article-title":"Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban","volume":"53","author":"Mueck","year":"2014","journal-title":"Clin. Pharmacokinet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/j.1538-7836.2005.01204.x","article-title":"Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients","volume":"3","author":"Schulman","year":"2005","journal-title":"J. Thromb. Haemost."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1111\/jth.13140","article-title":"Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: Communication from the SSC of the ISTH","volume":"13","author":"Kaatz","year":"2015","journal-title":"J. Thromb. Haemost."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1093\/europace\/euab065","article-title":"2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation","volume":"23","author":"Steffel","year":"2021","journal-title":"Europace"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1161\/CIR.0000000000001193","article-title":"2023 ACC\/AHA\/ACCP\/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"149","author":"Joglar","year":"2024","journal-title":"Circulation"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/17\/2725\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:22:07Z","timestamp":1787732527000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/17\/2725"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":31,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["diagnostics16172725"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16172725","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]}}}