Levels, Determinants and Predictive Value of D-Dimer in Patients on Long-Term Direct Oral Anticoagulant for Venous Thrombo-Embolic Disease

Introduction

D-dimer testing plays a crucial role in the diagnostic strategy of venous thromboembolic disease (VTED) and the decision of initiating anticoagulation. It is also used to determine the duration of anticoagulation and to predict recurrent VTED after stopping anticoagulant therapy for unprovoked VTED. Whether the D-dimer (DD) concentration measured during long-term anticoagulant therapy can be used to evaluate the antithrombotic efficacy and possibly predict the risk of recurrence of VTED is currently unknown. The hypothesis is that a low (<250 ng/ml) or normal (< 500 ng/ml) DD concentration on Direct Oral Anticoagulant (DOAC) therapy reflects antithrombotic efficacy and that a high concentration would be associated with an increased risk of recurrence. This study aimed to assess the concentration of DD in patients on long-term anticoagulation (≥12 months) with a DOAC for VTED and identify its determinants and its potential predictive value of recurrent VTED while on treatment.

Methods

All consecutive annually reviewed patients with VTED, aged over 18 with an indication for long-term DOAC therapy, were included. The study took place within the Hemostasis and Thrombosis Unit of the Hematology Division of the Cliniques universitaires Saint-Luc, a tertiary reference center in Brussels, Belgium. Reasons for long-term anticoagulation included repeated VTED events, severe or idiopathic venous thrombo-embolic event(s), and/or severe associated thrombophilia. A total of 267 patients were enrolled, with 30 excluded due to a follow-up period of less than 12 months. Among these 237 patients, 190 with measured DD concentrations while on treatment were included in the statistical analyses. Measured and age-adjusted DD levels (cut-off of age-adjusted DD obtained by age*10 in ng/mL for patients over 50 years old) were analyzed in this cohort considering the potential influence of several variables collected in our electronic health records (EPIC ®) (sex and age, severity and extension of VTED, presence of residual clot and/or post-thrombotic syndrome, concomitant venous insufficiency, family history of VTED, various comorbidities, concomitant thrombophilia and its severity, type, dose and duration of DOAC, compliance to treatment). Logistic regression analysis was used to identify determinants of DD levels and risk factors for recurrent VTED.

Population

The characteristics of the 190 patients with DD levels available are as follows. The median age was 55 years (range 19-90), with 105 males (55,3%). The median duration of DOAC treatment was 41,5 months (range 12-137). Among these patients, 127 were on rivaroxaban (66,8 %), 50 on apixaban (26,3 %), 7 on edoxaban (3,7 %) and 6 on dabigatran (3,2 %). A total of 79 patients (41,6 %) were carriers of at least one thrombophilic trait, with heterozygous Factor V Leiden being the most common. The number of patients with severe thrombophilia was 47. The daily doses of DOAC at the time of analysis were distributed as follows: rivaroxaban 10 mg (86 patients), 15 mg (3 patients), 20 mg (37 patients), 30 mg (1 patient), apixaban 5 mg (39 patients), 10 mg (11 patients), edoxaban 30 mg (5 patients), 60 mg (2 patients), dabigatran 220 mg (2 patients), or 300 mg (4 patients).

Results

Twenty-seven patients (14,2 %) were found to have elevated DD levels (>500 ng/mL), and 18 (9,5 %) when considering age-adjusted DD concentrations. By logistic regression analysis, post-thrombotic syndrome (p=0.016 ; OR=5.396 ; 95% CI [1.368; 21,276]) and apixaban versus rivaroxaban treatment (p=0.013; OR=5.714 ; 95% CI [1.435; 22.61]) were found to be associated with a higher DD concentration. Compliance, comorbidities (cancer, vascular malformation (e.g. aneurysm), chronic inflammatory disease, severe thrombophilia of all types and higher/lower dose of DOAC) were not found to predict a higher DD concentration in patients on DOAC. During the study period, 14 patients experienced recurrent VTED (11 with low/normal and 3 with increased age-adjusted DD levels). The risk of recurrence was found to be independent of the DD concentration as well as the type of DOAC, the compliance to the treatment and the presence of severe thrombophilia.

Conclusions

DD concentration during long-term secondary prevention of VTED by a DOAC is low or normal and does not appear to be predictive of recurrence.