Age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against catheter-associated thrombosis in critically ill children

PROJECT SUMMARY Pediatric venous thromboembolism (VTE), which is predominantly deep venous thrombosis (DVT), is a top contributor to harm in hospitalized children. Critical illness and central venous catheter (CVC) are the most important risk factors for VTE in children. Among critically ill children, the risk of CVC-associated DVT (CADVT) is as high as 54% with 72% of cases in infants <1-year old. Given that VTE is generally preventable in adults with pharmacologic prophylaxis, national initiatives are ongoing to prevent VTE in children. However, the incidence of pediatric VTE has not decreased in 2 decades. Due to paucity of age-appropriate evidence on its efficacy against CADVT, pharmacologic prophylaxis is uncommon in children. Extrapolation of evidence from adults is not appropriate because the coagulation system changes significantly with age. We recently completed a Bayesian phase 2b randomized clinical trial funded by NICHD. In this trial, we randomized critically ill children to early administration of prophylactic dose of enoxaparin, the most commonly used anticoagulant for prophylaxis, or usual care. Prophylaxis with enoxaparin appeared to reduce the risk of CADVT by half. In post hoc analyses, the reduction was limited to older children ≥1-year old. The goal of the proposed Catheter-Related Early Thromboprophylaxis with Enoxaparin (CRETE) Studies is to investigate this newly identified age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of CADVT in critically ill children. To achieve this goal, we aim (1) to confirm the efficacy and safety of early administration of prophylactic dose of enoxaparin in reducing the risk of CADVT in critically ill older children; (2) to determine the efficacy and safety of early administration of therapeutic dose of enoxaparin in reducing the risk of CADVT in critically ill infants; and, (3) to probe the mechanisms that underly the age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of CADVT in critically ill children. We will conduct 2 multicenter Bayesian explanatory randomized clinical trials in parallel to address Specific Aims 1 and 2. Depending on age, subjects will be randomized to different doses of enoxaparin vs usual care. Subjects will be systematically assessed for the development of CADVT using ultrasonography and clinically for bleeding. Using plasma obtained from subjects in the 2 trials, we will conduct an exploratory mechanistic nested case-control study to address Specific Aim 3. Biomarkers of the different mechanisms underlying CVC-associated thrombus formation, particularly thrombin generation, will be compared between subjects with and without CADVT. We will use Bayesian methods to improve the efficiency in the conduct and analyses of these studies. The proposed CRETE Studies address NICHD’s research priorities on child development, critical illness, therapeutics and innovative clinical trial design. They will provide high-quality age-appropriate evidence that will inform preventive strategies against CADVT and decrease harm in hospitalized children.