Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Trial

Phase 2TerminatedNCT03003390

Yale University51 enrolled

Overview

The purpose of this phase 2a, multi-center, randomized controlled study, is to explore the efficacy of early prophylaxis against catheter-associated deep venous thrombosis (CADVT) in critically ill children.

Critical illness and the presence of a central venous catheter (CVC) are the most important risk factors for deep venous thrombosis (DVT) in children. Catheter-associated thrombosis (CADVT) is highly prevalent and associated with poor outcomes in critically ill children. Yet, based on underpowered pediatric trials, prophylaxis against CADVT is not recommended in children. The recommendation to provide prophylaxis against thrombosis in critically ill adults should not be applied to children because the hemostatic system and co-morbidities vastly differ between age groups. Pivotal trials are urgently needed to determine whether prophylaxis can prevent CADVT and its complications in critically ill children. However, the timing and extent of reduction in thrombin generation, the biochemical goal of prophylaxis, needed to prevent CADVT in children are unclear. The goal of this application is to explore the efficacy of early prophylaxis against CADVT in critically ill children. Aim 1 is to obtain preliminary evidence on the effect of early prophylaxis on the incidence of CADVT in critically ill children. Based on the natural history of CADVT, we hypothesize that among critically ill children, prophylaxis administered \<24 hours after catheter insertion decreases the incidence of ultrasound-diagnosed CADVT compared with no prophylaxis. In this phase 2a trial, children admitted to the intensive care unit with a newly inserted central venous catheter will receive enoxaparin adjusted according to anti-Xa activity, a control group will not receive enoxaparin adjusted according to anti-Xa activity. Enoxaparin has become the "standard" pediatric anticoagulant for prophylaxis despite the absence of conclusive data. We will use Bayesian approach to determine whether further trials are warranted. Aim 2 is to evaluate the effect of an anti-Xa activity-directed prophylactic strategy on thrombin generation in critically ill children. We hypothesize that among critically ill children, standard prophylactic dose of enoxaparin adjusted by anti-Xa activity reduces thrombin generation to \<700 nanomolar-minute (nM.min), as measured by endogenous thrombin potential (ETP). In non-critically ill adults, prophylactic dose of enoxaparin proven to prevent DVT reduces ETP to \<700 nM.min. Endogenous thrombin potential is the best available measure of thrombin generation. We will measure endogenous thrombin potential and anti-Xa activity at multiple time points then examine their relationship in all children enrolled in the phase 2a trial. The proposed research challenges the current paradigm on prophylaxis against CADVT in children. High quality evidence is needed to prevent CADVT and its complications in this vulnerable population.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

Conditions

Deep Venous Thrombosis

Interventions

EnoxaparinDRUG

The clinical nurse will give enoxaparin subcutaneously every 12 hours at the currently used starting dose of 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 40 mg) for older children. The 1st dose will be given \<24 hours after insertion of the catheter. Doses will be adjusted to target an anti-Xa level of 0.2-0.5 IU/mL.

Eligibility

Sex: ALLMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria 1. Untunneled CVC inserted in the internal jugular or femoral vein within the past 24 hours 2. Child anticipated to stay in the pediatric intensive care unit ≥48 hours 3. CVC anticipated to be required for ≥24 hours 4. \>36 weeks corrected gestational age to \<18 years old Exclusion Criteria 1. Coagulopathy (i.e., international normalized ratio \>2.0, activated partial thromboplastin time \>50 seconds or platelet count \<50,000/mm3) 2. Known bleeding disorder 3. Clinically relevant bleeding as defined by the International Society on Thrombosis and Hemostasis (i.e., Hb decreased ≥2 g/dl in 24 hours, required medical or surgical intervention to restore hemostasis, or in a critical organ system \[i.e., retroperitoneum, pulmonary, intracranial or central nervous system\]) 4. \<60 days from a clinically relevant bleeding as defined above 5. \<7 days after trauma or surgery 6. Anticipated surgery within 48 hours after insertion of the CVC 7. Renal failure (i.e., creatinine clearance \<30 mL/min) 8. Presence of epidural catheter 9. Currently taking an antithrombotic agent (e.g., low molecular weight heparin (LMWH), unfractionated heparin (UFH) at therapeutic doses, Coumadin or aspirin) 10. Radiologically documented DVT at the site of insertion of the CVC in the previous 6 weeks 11. Known hypersensitivity to heparin or its components, including pork products 12. History of heparin-induced thrombocytopenia (HIT) (i.e., positive serotonin release assay) 13. Currently pregnant 14. Currently lactating 15. Prior enrollment in the study 16. Limitation of care

Locations (6)

Yale University Yale New Haven Health

New Haven, Connecticut, United States

Saint Louis Children's Hospital-Washington University School of Medicine-

St Louis, Missouri, United States

Weill Cornell Medicine

New York, New York, United States

University of Rochester Medical Center-Golisano Children's Hospital-

Rochester, New York, United States

Outcomes

Primary Outcomes

Number of Participants With Central Venous Catheter (CVC)- Associated Deep Vein Thrombosis (DVT)

Thrombus in the central vein where the CVC was inserted that is clinically suspected then confirmed radiologically, an incidental radiologic finding, or diagnosed with the study-related active surveillance ultrasound

Time frame: Up to removal of CVC, an average of 6 days

Endogenous Thrombin Potential

An established measure of coagulation status and is the best method to measure thrombin generation. It directly measures the amount of thrombin generation over time capturing the effects of natural (i.e., subject's coagulation status) and pharmacological (e.g., enoxaparin) pro- and anticoagulants. Endogenous thrombin potential is measured using thrombin generation assay.

Time frame: Day of, day after and day 4 after insertion of the CVC

Secondary Outcomes

Number With Other Thromboembolic Events

Thrombus in the deep vein of any extremity or PE that is clinically suspected then confirmed radiologically, an incidental radiologic finding, excluding DVT diagnosed with the study-related active surveillance ultrasound

Time frame: Up to removal of CVC, an average of 6 days

Length of Stay in the Pediatric Intensive Care Unit in Days

Duration of stay in the pediatric intensive care unit from the day of enrollment

Time frame: Up to day of discharge from the pediatric intensive care unit, an average of 10 days

Length of Stay in the Hospital

Duration of stay in the hospital from the day of enrollment

Time frame: Up to day of discharge from the hospital, an average of 18 days

Number With Clinically Relevant Bleeding

Data from ClinicalTrials.gov

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