Dabigatran Etexilate in the Treatment of Acute Thromboembolic Disease in Children
Until now, standard anticoagulants such as low-molecular-weight heparin or unfractionated heparin and others have been used in pediatric patients for the treatment of thromboembolism. The study presented below aimed to determine whether dabigatran could be the drug of the future in the treatment of pediatric patients with thromboembolism.
Introduction
Dabigatran etexilate is an oral anticoagulant that acts as a direct thrombin inhibitor (DOAC). This drug has the potential to overcome the current limitations of standard care for children with venous thromboembolism in the future.
The aim of the presented clinical study was to determine the suitability of the dabigatran dosing algorithm in the pediatric population and to compare the efficacy and safety of dabigatran dosing according to this algorithm with the efficacy of standard care for children with venous thromboembolic disease (VTE).
Methodology and course of the study
DIVERSITY was a phase IIb/III randomized controlled open-label study conducted in 65 centers in 26 countries. Standard care for pediatric patients with thromboembolism includes low-molecular-weight heparins (LMWH), unfractionated heparin, vitamin K antagonists (VKA), or fondaparinux. This treatment was compared with a pediatric dosing regimen of oral dabigatran in children younger than 18 years according to age and weight nomograms. Dabigatran was administered to children with acute VTE who were initially treated with parenteral anticoagulants (5-21 days) and required anticoagulant therapy for at least 3 months.
Patients were randomized in a 1:2 ratio (standard care: dabigatran) and stratified by age (12 to < 18 years; 2 to < 12 years; neonates to < 2 years). The primary composite efficacy endpoint (intention-to-treat analysis) was the proportion of children with complete thrombus resolution, prevention of venous thromboembolism recurrence, and prevention of death related to venous thromboembolism. Secondary study endpoints included safety (determined by serious bleeding events) and evaluation of pharmacokinetics and pharmacodynamics.
Results
A total of 328 children were enrolled in the study from February 2014 to November 2019, with 267 randomly assigned to receive either standard care (n = 90; 34%) or dabigatran (n = 177; 66%). The median duration of standard anticoagulant therapy was 85 days, while dabigatran administration was 84.5 days. Similar numbers of patients in both groups achieved the primary endpoint: 38 of 90 (42%) and 81 of 177 (46%), respectively (p < 0.0001). During therapy, bleeding events occurred in 22 of 90 children in the standard care group (24%) and in 38 of 176 children in the dabigatran group (22%) (hazard ratio [HR] 1.15; 95% confidence interval [CI] 0.68-1.94; p = 0.61), with serious bleeding events occurring in 2% of both groups (HR 0.94; 95% CI 0.17-5.16; p = 0.95).
Regarding pharmacokinetics and pharmacodynamics, a linear relationship was demonstrated between total dabigatran concentration in plasma and dilute thrombin time and ecarin clotting time values. A non-linear relationship was observed with activated partial thromboplastin time values; these curves were similar to those for adults.
Serious adverse events were reported in 20% of children receiving standard care and in 13% receiving dabigatran. The most common serious adverse events included vascular disorders (3% vs. 1%) and gastrointestinal issues (2% vs. 3%). One patient with standard care died due to retroperitoneal bleeding; however, this was not considered treatment-related.
Discussion and conclusion
The study demonstrated that dabigatran administration in a dosage regimen adjusted according to age and weight in patients under 18 years old is a suitable solution for venous thromboembolic disease. Dabigatran also achieves comparable results to the standard care currently used in terms of efficacy and has similar pharmacodynamic and pharmacokinetic effects to those observed in adult patients. Dabigatran is thus a viable alternative to currently used anticoagulants in children with venous VTE.
Source:
Halton J., Brandão L. R., Luciani M. et al.; DIVERSITY Trial Investigators. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomized, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol 2021 Jan; 8 (1): e22-e33, doi: 10.1016/S2352-3026(20)30368-9.
Did you like this article? Would you like to comment on it? Write to us. We are interested in your opinion. We will not publish it, but we will gladly answer you.
