Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Trial

Yale University

Status and phase: Terminated; Phase 2

Conditions: Deep Venous Thrombosis

Treatments: Drug: Enoxaparin

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03003390

1302011506

1R21HD089131-01A1 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 51 patients

Sex: All

Ages: Under 17 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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51 participants in 2 patient groups

Prophylaxis with enoxaparin

Experimental group

Description:

A clinical nurse will administer enoxaparin subcutaneously \<24 hours after insertion of the central venous catheter and then give enoxaparin subcutaneously every 12 hours until the removal of the catheter.

Treatment:

Drug: Enoxaparin

Control arm

No Intervention group

Description:

Participants randomized to the control arm will receive no 'placebo' intervention.