Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia

Abstract

In the phase 2b/3 DIVERSITY trial (NCT01895777), 3 months' treatment with dabigatran was non-inferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm phase 3 secondary VTE prevention study (NCT02197416), up to 12 months' dabigatran was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in DIVERSITY and safety in both studies. Thrombophilia types were similar between DIVERSITY (total population) and secondary prevention studies: factor-V-Leiden, 42% vs 33%; prothrombin mutation G20210A, 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; antiphospholipid antibodies, 18% vs 20% patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary endpoint (Mantel-Haenszel-weighted rate difference -0.135 [95% CI-0.36, 0.08], non-inferiority P = .0014); comparable to the total DIVERSITY population (46% vs 42%) showing dabigatran non-inferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran-treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia.

How I treat pediatric venous thromboembolism in the DOAC era

“…There are no studies that can address this issue with respect to long-term anticoagulation resulting in challenges in decision-making. 8 , 23 For this patient (and similar ones), we suggest continuing anticoagulation indefinitely and reevaluating the need to continue anticoagulation annually. So long as the patient is not experiencing bleeding side effects, it is reasonable to continue anticoagulation indefinitely given the potential benefit of preventing a VTE (the next one could be life-threatening pulmonary embolism) vs the risk of serious bleeding.…”

“…It is important to note that both the Diversity and Einstein Jr studies continued treatment for secondary prevention of VTE in children beyond the initial 3-month treatment phase, but the dosing regimen was not changed. 23 The UNIVERSE study used a body weight–adjusted rivaroxaban regimen in a 10 mg equivalent dose as post-Fontan prophylaxis for children with hypoplastic left heart syndrome as opposed to the 20 mg equivalent in the VTE studies. 17 One could consider lowering the dose in a similar ratio to maintain the quality of life, although there are no data to support this.…”

“…One could also consider continuing treatment dosing, given the low bleeding rate in clinical trials and the available data on efficacy. 16 , 22 , 23 …”

“…There are no published studies of children using secondary thromboprophylaxis with DOACs beyond 15 months. 8 , 23 Furthermore, after 6 months, one could consider lowering the DOAC dose in a similar ratio to that for adults, 88 however, there are no data to support this plan.…”

“…In addition to VTE treatment, DOACs have been evaluated for VTE prevention in children with congenital and acquired heart disease and cancer, thereby adding to the growing number of children enrolled in clinical trials ( Table 1 ). 16 , 17 , 18 , 22 , 23 , 24 , 25 …”