Plasma Levels Measurement of the Four Direct Oral Anticoagulants in Patients with Atrial Fibrillation at the Time of Acute Thromboembolic and Bleeding Events.

Background: Direct oral anticoagulants (DOACs) are standard therapy to prevent thromboembolic events in non-valvular atrial fibrillation (NVAF) and are generally used without routine monitoring of plasma anti-Xa or anti-IIa levels.

Objectives: To assess whether plasma levels of anti-Xa or anti-IIa at the time of presentation are associated with acute thromboembolic or bleeding events in DOAC-treated NVAF patients.

Methods: This prospective case-control study included consecutive long-term DOAC-treated NVAF patients presenting to a European emergency department with acute thromboembolic or bleeding events (cases), or for other medical reasons (controls). DOAC plasma levels were measured using drug-specific chromogenic anti-Xa assays (rivaroxaban, apixaban, edoxaban) or diluted thrombin time (dabigatran), categorized into quartiles, and analyzed according to event type.

Results: Among 1,794 patients (mean age 82 years, 49% female), 8% had thromboembolic events, 15% bleeding events, and 77% other presentations. DOAC treatment included apixaban (45%), dabigatran (17%), rivaroxaban (17%), and edoxaban (21%). Thromboembolic events were more common in patients with DOAC plasma levels in the first quartile (Q1: 50% vs. 26%; p<0.001), while bleeding events were more common in the fourth quartile (Q4: 46% vs. 23%; p<0.001). Q1 levels were associated with increased odds of thromboembolic events (OR 2.04, 95% CI: 1.36-3.08), and Q4 levels with bleeding events (OR 2.05, 95% CI: 1.49-2.82).

Conclusion: DOAC plasma levels show substantial interindividual variability and are associated with acute thromboembolic and bleeding events. These observations may help generate hypotheses for future studies aimed at better defining the role of DOAC plasma monitoring in clinical practice.