Assessment of plasma levels of D-dimer and prothrombin fragment 1+2 in patients on direct oral anticoagulants versus vitamin K antagonists

Introduction: A central question regarding treatment of venous thromboembolism (VTE) is how long maintenance anticoagulation therapy should be continued. Current decision algorithms are based on D-dimer (DD) measurements before and/or after discontinuation of anticoagulation. However, recent clinical data questioned the validity of this approach in patients taking direct oral anticoagulants (DOACs). One reason for this may be generally higher DD levels in patients on DOACs than in those on vitamin K antagonists (VKAs). The aim of our study was to comparatively assess DD levels in a large cohort of patients on either DOAC or VKA therapy. Prothrombin fragment 1+2 (F1.2) was additionally measured to monitor thrombin formation rates.

Method: The study population consisted of patients with VTE who received maintenance anticoagulation therapy. DD and F1.2 measurements performed during visits in our outpatient thrombophilia clinic were retrospectively assessed. Samples not drawn at peak or trough post-dose intervals, as well as duplicate peak and trough samples were excluded from analysis. The final DOAC cohort included 419/249 (peak/trough) samples from patients on rivaroxaban, 353/138 samples on apixaban, and 60/26 samples on edoxaban treatment. Patients on VKAs with an INR within the therapeutic range of 2 to 3 (n=228) served as the reference cohort.

Results: DOAC plasma levels were in line with expectations regarding peak and trough levels ([Fig. 1A]). In the VKA cohort, median (IQR) DD and F1.2 levels were<0.19 (<0.19-0.27) mg/L and 32 (24-49) pM, respectively. Biomarker concentrations at peak and trough sampling intervals did not differ statistically from each other within the DOAC subgroups ([Fig. 1B/C]). Levels of both markers were significantly higher (p<0.001) in the DOAC than in the VKA cohort(s), with overall DD levels of 0.24 (<0.19-0.45) mg/L for rivaroxaban, 0.30 (<0.19-0.51) mg/L for apixaban, and 0.35 (<0.19-0.60) mg/L for edoxaban. Overall F1.2 levels were 114 (86-160) pM for rivaroxaban, 129 (97-181) pM for apixaban, and 134 (103-178) pM for edoxaban. The proportion of patients showing DD levels above age-adjusted cut-off (DD+) was lower in the VKA cohort than in patients on either DOAC (p<0.006; [Fig. 1D]). In comparison to DD+, the relative number of patients showing F1.2 levels above the upper reference limit (307 pM, F1.2+) was lower in all groups whereat overall F1.2+and combined F1.2+/DD+were significantly lower in the VKA vs. the rivaroxaban und apixaban cohorts (p<0.015, [Fig. 1D]).

Fig. 1 Drug- and biomarker plasma levels in the VKA and DOAC patient cohorts A) DOAC trough and peak drug levels. B) Levels of D-Dimer. C) Levels of F1.2. D) Proportion (%) of D-Dimer and F1.2 levels above cut-off or upper limit of reference interval. A-C) Values shown excluding outliers (Tukey&apos;s Fences).

Conclusion: Comparable DD and F1.2 levels at peak and trough post-dose intervals indicate that both biomarkers reach a steady-state level in patients on DOACs. Thus, both markers principally appear to be applicable to assess and guide anticoagulation therapy. Higher levels of DD and F1.2 in patients on DOACs may warrant establishment or reconsideration of threshold values and corresponding validation of clinical decision algorithms.