Multicenter dose-finding and efficacy and safety outcomes in neonates and children treated with dalteparin for acute venous thromboembolism

Background: Low molecular weight heparins (LMWHs) constitute the mainstay of anticoagulant therapy for pediatric venous thromboembolism (VTE). The safety and effectiveness of dalteparin, an LMWH, has not been established in children, and pediatric data on dalteparin for VTE are limited to one single-center experience. Objective: To establish dose-finding (primary endpoint) and efficacy/safety outcomes (secondary endpoints) in children treated with dalteparin in a substudy of the Kids-DOTT trial. Patients and methods: A prospective multicenter trial using dalteparin subcutaneously twice daily for acute VTE in children aged ≤ 21 years was conducted under an investigator-held Investigational New Drug application registered with the US Food and Drug Administration. Initial weight-based dosing per protocol was as follows: infants (< 12 months), 150 IU kg^-1; children (1-12 years), 125 IU kg^-1; and adolescents (13-18 years), 100 IU kg^-1. Bleeding events were categorized according to ISTH criteria. Descriptive non-parametric statistics were employed for all analyses. Results: Eighteen patients (67% male) were enrolled from January 2010 to October 2013 across four centers. No supratherapeutic levels were observed. Median (range) therapeutic doses by age group were as follows: infants (n = 3), 180 IU kg^-1 (146-181 IU kg^-1); children (n = 7), 125 IU kg^-1 (101-175 IU kg^-1); and adolescents (n = 8), 100 IU kg^-1 (91-163 IU kg^-1). The median duration of dalteparin use was 48 days (range: 2-169 days), and the median follow-up was 10.5 months (range: 2-35 months). There were no related serious adverse events, no clinically relevant bleeding events, and no symptomatic recurrent VTEs. Conclusion: Dalteparin successfully achieved targeted anti-factor Xa levels in 18 children and young adults with acute VTE with a standardized age-based dosing regimen, with a favorable safety and efficacy profile.