Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children

Abstract

This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved. Primary end points included VTE recurrence, bleeding events, and mortality at 6 and 12 months. Overall, 203 children received dabigatran, with median exposure being 36.3 weeks (range, 0-57 weeks); 171 of 203 (84.2%) and 32 of 203 (15.8%) took capsules and pellets, respectively. Overall, 2 of 203 children (1.0%) experienced on-treatment VTE recurrence, and 3 of 203 (1.5%) experienced major bleeding events, with 2 (1.0%) reporting clinically relevant nonmajor bleeding events, and 37 (18.2%) minor bleeding events. There were no on-treatment deaths. On-treatment postthrombotic syndrome was reported for 2 of 162 children (1.2%) who had deep vein thrombosis or central-line thrombosis as their most recent VTE. Pharmacokinetic/pharmacodynamic relationships of dabigatran were similar to those in adult VTE patients. In summary, dabigatran showed a favorable safety profile for secondary VTE prevention in children aged from >3 months to <18 years with persistent VTE risk factor(s). This trial was registered at www.clinicaltrials.gov as #NCT02197416.

Graphical abstract

Figure 1.

Disposition of patients.

Figure 2.

Kaplan-Meier curves for all age strata. Combined (on-treatment) for time to recurrent VTE (A) and postthrombotic syndrome (adjudicated data from the treated set) (B).

Figure 3.

Pharmacokinetic-pharmacodynamic relationship curves at trough sampling times. For dabigatran PK and dTT (A, overall; B, aged 12 to <18 years; C, aged 2 to <12 years; D, aged from >3 months to <2 years), aPTT (E, overall; F, aged 12 to <18 years; G, aged 2 to <12 years; H, aged from >3 months to <2 years), and ECT (I, overall; J, aged 12 to <18 years; K, aged 2 to <12 years; L, aged from >3 months to <2 years) by age group. aPTT, activated partial thrombin time; Dabititrn, dabigatran titration; EEOT, early end of treatment; UNS, unscheduled.