Critically ill adolescents are at greatest risk for developing hospital-acquired venous thromboembolism. To date, no phase 3 randomized controlled trials have been conducted for pharmacological thromboprophylaxis as primary venous thromboembolism prevention in children. The investigators will perform a United States definitive multicenter phase 3 randomized controlled trial of the low molecular weight heparin enoxaparin as primary venous thromboembolism prophylaxis among critically ill adolescents who are classified a priori as high risk based upon the investigators validated risk prediction models.
Admission Age between 12- 18 years of age
Within 24 hours of pediatric intensive care unit (PICU) admission for enrollment
Presence of a Central Venous Catheter
Presumed or confirmed infection or systemic inflammatory condition
Active treatment for VTE or known VTE present prior to or on pediatric intensive care unit (PICU) admission
Current receipt of an antithrombotic agent excluding unfractionated heparin for vascular catheter patency
Active ISTH-defined clinically relevant bleeding
Surgery in the last 7-days
Parallel
Enoxaparin
DrugEnoxaparin thromboprophylaxis administered subcutaneously twice daily (every 12 hours) from enrollment through pediatric intensive care unit discharge
Risk (i.e., cumulative incidence) of Symptomatic venous thromboembolism
International Society on Thrombosis and Haemostasis (ISTH) defined symptomatic venous thromboembolism
Risk (i.e., cumulative incidence) of Clinically relevant bleeding
International Society on Thrombosis and Haemostasis (ISTH) defined clinically relevant bleeding (Major bleeding + Clinically relevant Non-major bleeding)
Net Clinical Benefit - Modelled Attributable Risk Difference in HA-VTE (Efficacy) by Attributable Risk Difference in clinically relevant bleeding (Safety)
Net clinical benefit is a bivariate endpoint analysis (i.e., trade-off of venous thromboembolism and bleeding risks as described below). One-year risks and corresponding 95% confidence intervals (CI) of hospital-acquired venous thromboembolism and clinically relevant bleeding for each study arm will be calculated from weighted Kaplan-Meier curves. A bivariate decision curve will be specified using the 12-month absolute risk difference for venous thromboembolism and bleeding outcomes. Bivariate outcomes for enoxaparin and no pharmacological thromboprophylaxis will be compared under a hypothesis of superiority using the superiority boundary of a bivariate endpoint analysis, with inference based on the 95% confidence rectangle (i.e., the rectangle defined by the 95% CI for hospital-acquired venous thromboembolism absolute risk difference and the 95% CI for bleeding absolute risk difference). Superiority will be decided if the 95% confidence rectangle rules out the superiority curve.
Risk (i.e. cumulative incidence) of symptomatic venous thromboembolism
International Society on Thrombosis and Haemostasis-defined symptomatic venous thromboembolism
Risk (i.e. cumulative incidence) of clinically relevant bleeding
International Society on Thrombosis and Haemostasis-defined clinically relevant bleeding (Major Bleeding + Clinically Relevant Non-Major Bleeding)
Serious adverse events
As federally defined.
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Johns Hopkins All Children's Hospital
Lead sponsor
University of California, San Diego
Collaborator
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