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.

Use of Direct Oral Anticoagulants in Children and Adolescents

“…Few children developed recurrent VTE and few children experienced major bleeding events and/or clinically relevant nonmajor bleeding. 21 In both studies, dabigatran PK/PD relationships were comparable to previous adult data (►Table 2). 20,21 Further studies on dabigatran in the pediatric population are depicted in ►Table 2.…”

“…18 Interim results of two phase III trials on dabigatran in children were presented at the Annual Meeting of the International Society on Thrombosis and Haemostasis (ISTH), July 6 to 19, 2019, in Melbourne. 20,21 In the open-label, randomized, active-controlled, multicenter, phase IIb/III trial (DIVERSITY study), 234 children aged 12 to < 18, 2 to < 12, and 0 to < 2 years with confirmed diagnosis of VTE and initially treated with UFH or LMWH were randomized (2:1) to dabigatran (capsules, pellets, or oral liquid solution) twice a day or SOC and treated for 3 months. Results of this study indicate that dabigatran is noninferior to SOC in terms of efficacy and safety, and demonstrate the appropriateness of the age-and bodyweight-adjusted dosing algorithm for dabigatran to use in children aged between 0 and < 18 years (►Table 2).…”

Heavy menstrual bleeding on direct factor Xa inhibitors: Rationale and design of the MEDEA study

“…The standard anticoagulation. 37,38 Furthermore, the net benefit of dose reduction in women with HMB while on factor Xa inhibitor treatment requires additional investigation, possibly in an extension of the current trial.…”

Treatment of Venous Thromboembolism in Special Populations with Direct Oral Anticoagulants

“…75 In addition, an interim analysis of a single-arm, prospective cohort, phase III study demonstrated a favorable safety profile of dabigatran used for up to 12 months in approximately 200 children aged 0 to <18 years who required anticoagulation for the secondary prevention of VTE and with a persistent risk factor for VTE. 76,77 The phase III EINSTEIN Junior trial evaluated rivaroxaban (20 mg o.d. equivalent adjusted according to body weight following at least 5 days of initial heparin therapy) versus standard of care anticoagulation therapy for the treatment of acute VTE in approximately 500 children and neonates.…”