The phase 3 pediatric anticoagulant era

In this issue of Blood, Brandão et al report the findings of an open-label, single-arm, phase 3 trial of the direct oral thrombin inhibitor dabigatran for extended secondary thromboprophylaxis in children with a history of venous thromboembolism (VTE) (ClinicalTrials.gov identifier: NCT02197416).¹ 

The study population consisted of patients ranging in age from older than 3 months to younger than 18 years with a history of provoked VTE (ie, VTE associated with a clinical trigger such as central venous catheterization, acute illness, or hospitalization) in whom 1 or more prothrombotic risk factors persisted after completion of a conventional therapeutic course of anticoagulation and also patients with recurrent unprovoked VTE. Overall, 18% of the 203 children treated in the trial were being treated for recurrent VTE (provoked or unprovoked) at study entry, and 30% had been diagnosed with inherited protein C or protein S deficiencies or antiphospholipid syndrome (APS). Nearly half the patients had participated in a phase 2B/3, randomized, open-label trial of dabigatran vs standard-of-care (SOC) anticoagulant for 3 months after acute VTE. The preceding course of therapy was low molecular weight heparin in 75% of the patients upon enrollment in the phase 3 trial of extended thromboprophylaxis.

The median duration of dabigatran administration (adjusted for age and body weight) in this study was ∼8 months. The investigators observed primary end points of clinically relevant (ie, major plus clinically relevant nonmajor) bleeding in 2.5% of patients (5 of 203) and recurrent VTE in 1% (2 of 203) with no deaths reported. The primary end point selection and definitions were consistent with recommendations of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH).² 

The findings in this trial of dabigatran for extended secondary VTE prevention are consistent with those of the direct oral anticoagulant (DOAC) factor Xa inhibitor rivaroxaban and SOC arms of the recently reported EINSTEIN Jr (ClinicalTrials.gov identifier: NCT02234843) phase 3 trial³  of acute VTE in children. For patients treated with rivaroxaban, clinically relevant bleeding was found in 3% of patients (10 of 329), and symptomatic recurrent VTE was found in 1% (4 of 335). For SOC, clinically relevant bleeding was found in 2% (3 of 162) patients and recurrent VTE in 3% (5 of 165). The median treatment duration was ∼3 months per arm. The findings of that trial are also consistent with previously published pilot/feasibility phase findings of the National Institutes of Health–sponsored Kids-DOTT (ClinicalTrials.gov identifier: NCT00687882) phase 3 randomized controlled trial⁴  of first-episode acute provoked VTE (outcome-blinded randomization arms of 6 weeks and 12 weeks duration of clinically prescribed anticoagulation [aggregate n = 100]). Clinically relevant bleeding was found in 1% of the patients and symptomatic recurrent VTE in 3%.

The study by Brandão and colleagues provides important new information on the risk of postthrombotic syndrome (PTS, chronic venous insufficiency after deep venous thrombosis) in children receiving extended anticoagulation with a DOAC. They assessed for new-onset PTS (secondary end point) at 6 months and 12 months after enrollment and observed a rate of 1% of patients (2 of 162) with disease. PTS had previously been diagnosed in 17% of the participants. To date, the only other PTS outcome data stemming from a pediatric phase 3 trial of VTE treatment were data from the pilot/feasibility phase of the Kids-DOTT trial, in which 1-year risks of clinically significant and non–clinically significant PTS of 2% (1 of 46) and 13% (6 of 46), respectively, were reported among children treated with a finite course of anticoagulation for acute provoked VTE.⁴  The trial by Brandão et al and the Kids-DOTT trial used different pediatric PTS outcome instruments, each of which is recommended by the ISTH SSC as an option for PTS outcome measurement in VTE clinical trials in children.^5,6 

The low frequency of clinically relevant bleeding observed in the Brandão et al study suggests that dabigatran is safe for extended VTE treatment in children and does not require routine laboratory monitoring. Likewise, the low frequency of clinically relevant bleeding in the EINSTEIN Jr trial³  does not support the use of routine monitoring for rivaroxaban for pediatric VTE treatment. Nevertheless, key issues remain that need additional study such as the optimal duration of anticoagulant therapy for pediatric VTE and the relationship between antiphospholipid antibodies (and APS) and outcomes in young patients treated with DOACs, given evidence of increased risk of recurrent VTE in adult patients with APS in a randomized controlled trial⁷  and individual patient-level meta-analysis.⁸  Other issues include the potential role of DOACs in primary thromboprophylaxis among hospitalized children at increased risk for VTE and the safety and optimal dosing of reversal agents for dabigatran- and other DOAC-associated major bleeding episodes in children. Furthermore, it is a top priority that pediatric drug formulations be made available, particularly when regulatory agency approval is obtained for the pediatric indication(s). When that happens, the potential benefit to children stemming from the brave and generous participation by pediatric patients (and by extension, their parents and/or guardians) in the clinical trials of pediatric DOAC programs will be realized.