Assessing the Efficacy of a Single cycle Measurement and Adjustment Strategy for DOACs in Frail Older Patients: rationale and design of the DOAC-FRAIL randomized controlled trial.

Background: Frail older patients are at high risk of both thromboembolism and bleeding, making anticoagulant therapy challenging. Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists because of comparable efficacy and lower bleeding risk. However, evidence supporting their use in frail older patients remains limited. Recent studies have demonstrated that a substantial proportion of frail older patients have DOAC plasma levels outside the expected on-therapy range, which may be associated with an increased risk of bleeding or thromboembolic events. Objectives: The DOAC-FRAIL randomized controlled trial (RCT) aims to determine whether adjustment of DOAC therapy based on peak plasma concentrations improves the safety and efficacy of anticoagulant treatment compared with standard care in frail older patients. Methods: The DOAC-FRAIL study is an international, multicenter, randomized controlled trial including frail older patients aged ≥70 years with a Clinical Frailty Scale score >3 receiving DOAC therapy. Participants are randomized to either a Single Cycle Measurement and Adjustment Strategy based on peak DOAC plasma concentrations or standard care. Patients with a life expectancy of less than 3 months or previous DOAC dose adjustment based on plasma level measurements are excluded. The primary outcome is the composite of bleeding events, including clinically relevant non-major bleeding, and thromboembolic events during 2 years of follow-up. Secondary outcomes include feasibility, determinants of deviant peak DOAC plasma concentrations, quality of life, cost-effectiveness, and all-cause mortality. Results: The DOAC-FRAIL trial is currently ongoing. Participant recruitment has been initiated, and study results are expected after completion of follow-up. Conclusion: The DOAC-FRAIL RCT will provide evidence on whether a plasma concentration-guided DOAC dosing strategy improves clinical outcomes compared with standard care in frail older patients. The findings may contribute to more personalized anticoagulant therapy in this vulnerable population. Trial registration number: EU CT-2025-521362-10-00.