{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:54:48Z","timestamp":1790394888500,"version":"4.1.0"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020971","name":"Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Gen\u00e8ve","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Direct oral anticoagulants (DOACs), including apixaban and rivaroxaban, are widely prescribed for the prevention of cardioembolic stroke and the treatment of venous thromboembolism. Although routine therapeutic monitoring is not required, real-world patients often present with multiple comorbidities or drug\u2013drug interactions that may alter drug exposure. Observational data indicate that high DOAC plasma concentrations may increase bleeding risk, whereas low concentrations may predispose individuals to thromboembolic or ischemic events. In this study, we aimed to analyze the relationship between DOAC plasma concentrations and clinical outcomes in hospitalized patients from the OptimAT cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This prospective study included 200 inpatients from Geneva University Hospitals receiving apixaban (n = 100) or rivaroxaban (n = 100). Pharmacokinetic parameters (AUC 0\u00a0h\u20138\u00a0h, C-max, and C-trough) were derived from plasma concentrations measured using validated LC\u2013MS\/MS quantification of dried blood spot samples. Clinical follow-up was performed for 2\u00a0years to record thromboembolic, ischemic, and bleeding events, which were classified according to the ISTH criteria. Patients were categorized into percentile-based exposure groups, defined separately for apixaban and rivaroxaban. Kaplan\u2013Meier survival curves and Cox regression models were used to assess associations between extreme versus moderate plasma concentrations and clinical outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>During the 2-year follow-up, 27 clinical events were recorded, corresponding to an incidence rate of 9.3 per 100 patient\u2013years for any bleeding event (95% CI: 5.57\u201314.44) and 3.9 per 100 patient\u2013years for ischemic or thromboembolic events (95% CI: 1.68\u20137.67). These included one major bleeding event (0.5%), eighteen minor bleeding events (9%), six arterial ischemic events (3%), and two venous thromboembolic events (1%). No significant association was found between high apixaban\/rivaroxaban plasma concentrations and bleeding events or between low apixaban\/rivaroxaban plasma concentrations and ischemic\/thromboembolic events for any pharmacokinetic parameter. The study power was limited by the small sample size and a high rate of apixaban and rivaroxaban treatment modifications or discontinuations (41%), which reduced the number of evaluable patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this real-world cohort, apixaban and rivaroxaban plasma concentrations were not associated with clinical outcomes. While highlighting the limitations of analyzing clinical outcomes within the framework of a pharmacokinetic study, these data are informative for future meta-analyses aimed at minimizing publication bias from neutral results.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1761151","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T06:36:23Z","timestamp":1772433383000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Relevance and limitations of clinical follow-up in a pharmacokinetic study on direct oral anticoagulants"],"prefix":"10.3389","volume":"17","author":[{"given":"Jean","family":"Terrier","sequence":"first","affiliation":[{"name":"Division of General Internal Medicine, Geneva University Hospitals","place":["Geneva, Switzerland"]},{"name":"Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals","place":["Geneva, Switzerland"]},{"name":"Geneva Platelet Group, Faculty of Medicine, University of Geneva","place":["Geneva, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Gosselin","sequence":"additional","affiliation":[{"name":"Division of General Internal Medicine, Geneva University Hospitals","place":["Geneva, Switzerland"]},{"name":"Geneva Platelet Group, Faculty of Medicine, University of Geneva","place":["Geneva, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Combescure","sequence":"additional","affiliation":[{"name":"Center of Clinical Research, Geneva University Hospital","place":["Geneva, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Fontana","sequence":"additional","affiliation":[{"name":"Geneva Platelet Group, Faculty of Medicine, University of Geneva","place":["Geneva, Switzerland"]},{"name":"Division of Angiology and Hemostasis, Geneva University Hospitals","place":["Geneva, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youssef","family":"Daali","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals","place":["Geneva, Switzerland"]},{"name":"Geneva Platelet Group, Faculty of Medicine, University of Geneva","place":["Geneva, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Luc","family":"Reny","sequence":"additional","affiliation":[{"name":"Division of General Internal Medicine, Geneva University Hospitals","place":["Geneva, Switzerland"]},{"name":"Geneva Platelet Group, Faculty of Medicine, University of Geneva","place":["Geneva, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.3390\/medicina60101712","article-title":"Bleeding events associated with rivaroxaban therapy in naive patients with nonvalvular atrial fibrillation: a longitudinal study from a genetic perspective with INR Follow-Up","volume":"60","author":"Ain","year":"2024","journal-title":"Med. 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