ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Relevance and limitations of clinical follow-up in a pharmacokinetics study on direct oral anticoagulants
Provisionally accepted
- Hôpitaux universitaires de Genève (HUG), Genève, Switzerland
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Introduction: Direct oral anticoagulants (DOACs), including apixaban and rivaroxaban, are widely prescribed for the prevention of cardioembolic stroke and treatment of venous thromboembolism. Although routine therapeutic monitoring is not required, real-world patients often present with multiple comorbidities or drug–drug interactions that may alter exposure. Observational data suggest that high DOAC plasma concentrations may increase bleeding risk, whereas low concentrations may predispose to thromboembolic or ischemic events. This study aimed to investigate the relationship between DOAC plasma concentrations and clinical outcomes in hospitalized patients from the OptimAT cohort. Methods: This prospective study included 200 inpatients from Geneva University Hospitals receiving apixaban (n = 100) or rivaroxaban (n = 100). Pharmacokinetic parameters (AUC 0-8h, C-max, and C-trough) were derived from plasma concentrations measured using validated LC–MS/MS quantification of dried blood spot samples. Clinical follow-up was performed for two years to capture thromboembolic, ischemic, and bleeding events, which were classified according to ISTH criteria. Patients were categorized into percentile-based exposure groups, defined separately for apixaban and rivaroxaban. Kaplan–Meier survival curves and Cox regression models, were used to assess associations between extreme versus moderate plasma concentrations and clinical outcomes. Results: During the two-year follow-up, 27 clinical events were recorded, corresponding to an incidence rate of 9.3 per 100 patient-years for any bleeding (95% CI: 5.57 to 14.44) and 3.9 per 100 patient-years for ischemic or thromboembolic events (95% CI: 1.68 to 7.67). These included one major bleed (0.5%), 18 minor bleeds (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 or low apixaban/rivaroxaban plasma concentration and ischemic/thromboembolic events for any pharmacokinetic parameter. The study power was limited due to a small sample size and a high rate of apixaban and rivaroxaban treatment modifications or discontinuations (41%), which reduced the number of evaluable patients. Conclusion: 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.
Keywords: apixaban, bleeding, direct oral anticoagulants, Ischemic events, pharmacokinetics, plasma concentrations, Real-world study, rivaroxaban
Received: 05 Dec 2025; Accepted: 05 Feb 2026.
Copyright: © 2026 Terrier, Gosselin, Combescure, Fontana, Daali and Reny. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jean Terrier
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