Catheter-Related Early Thromboprophylaxis With Enoxaparin Studies
Purpose
The goal of the CRETE Studies is to investigate the newly identified age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of central venous catheter-associated deep venous thrombosis in critically ill children.
Condition
- Deep Venous Thrombosis
Eligibility
- Eligible Ages
- Under 17 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- >36 weeks corrected gestational to <17 years old 2. <24 hours after insertion of an untunneled CVC 3. CVC inserted in the internal jugular or femoral vein
Exclusion Criteria
- Radiologic diagnosis of CADVT in the site of insertion in prior 6 weeks 2. Currently receiving an antithrombotic agent, e.g., LMWH, UFH, warfarin and aspirin, but not UFH at dose to maintain patency of a vascular catheter 3. Presence of clinically relevant bleeding, i.e., hemoglobin decreased ≥2 g/dl in 24 hours, required medical or surgical intervention to restore hemostasis, or in the retroperitoneum, pulmonary, intracranial or central nervous system, in the prior 60 days 4. Surgery in the prior 7 days 5. Major trauma in the prior 7 days 6. Presence of coagulopathy, i.e., INR >2.0, aPTT >50 seconds or platelet count <50 x 10^3/mcL 7. Presence of renal failure, i.e., creatinine clearance <30 mL/min/1.73 m2 8. Known hypersensitivity to heparin or pork products 9. Laboratory confirmed HIT 10. Current pregnancy or lactation 11. Presence of an epidural catheter 12. Limitation of care 13. Previous enrollment in the CRETE Studies
Study Design
- Phase
- Phase 2/Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Intervention Model Description
- Older children 1-17 years old and infants <1 year old will be randomized separately. Older children will be randomized 2:1 to prophylactic dose of enoxaparin or control stratified by age. Infants will be randomized 1:1:1 to therapeutic dose of enoxaparin with high or low anti-Xa target or control stratified by age.
- Primary Purpose
- Prevention
- Masking
- Single (Outcomes Assessor)
- Masking Description
- The CRETE Studies are open-label with blinded endpoint. Systematic ultrasonographic assessment will be performed with the images blindly and centrally adjudicated.
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Enoxaparin (Older Children Prophylactic) |
Prophylactic dose of enoxaparin for older children 1-17 years old. |
|
|
No Intervention Control (Older Children) |
Usual care without placebo for older children 1-17 years old. |
|
|
Experimental Enoxaparin (Infants Therapeutic High Anti-Xa Target) |
Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of >0.5-1 IU/mL. |
|
|
Experimental Enoxaparin (Infants Therapeutic Low Anti-Xa Target) |
Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of 0.2-0.5 IU/mL. |
|
|
No Intervention Control (Infants) |
Usual care without placebo for infants <1 year old. |
|
Recruiting Locations
More Details
- Status
- Recruiting
- Sponsor
- Yale University
Detailed Description
Pediatric venous thromboembolism (VTE), which is predominantly deep venous thrombosis (DVT), is a top contributor to harm in hospitalized children. Its incidence increased by >300% in the past 2 decades. 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. Pharmacologic prophylaxis is the most effective strategy against VTE in adults. However, 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 hemostatic system changes significantly with age. The investigators recently completed a Bayesian phase 2b randomized clinical trial. In this trial, the investigators 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, reduction was limited to older children 1-17 years old. The goal of the 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, the investigators 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. The investigators 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, the investigators will conduct an exploratory mechanistic nested case-control study to address Specific Aim 3. Biomarkers of selected mechanisms underlying CVC-associated thrombus formation, particularly thrombin generation, will be compared between subjects with and without CADVT. The investigators will use Bayesian methods to improve the efficiency in the conduct and analyses of these studies. The CRETE Studies will provide high-quality age-appropriate evidence that will inform preventive strategies against CADVT and decrease harm in hospitalized children.