Deep Venous Thrombosis
Conditions
Keywords
child, critical illness, venous thromboembolism, enoxaparin, thrombin generation
Brief summary
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.
Detailed 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.
Interventions
DRUGEnoxaparin
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.
Sponsors
St. Louis Children's Hospital
Dell Children's Medical Center of Central Texas
Children's Hospital and Health System Foundation, Wisconsin
Weill Medical College of Cornell University
Maria Fareri Children's Hospital
University of Rochester
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Eligible subjects will be randomized 1:1 to treatment or control.
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Central Venous Catheter (CVC)- Associated Deep Vein Thrombosis (DVT) | Up to removal of CVC, an average of 6 days | 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 |
| Endogenous Thrombin Potential | Day of, day after and day 4 after insertion of the CVC | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length of Stay in the Hospital | Up to day of discharge from the hospital, an average of 18 days | Duration of stay in the hospital from the day of enrollment |
| Number With Clinically Relevant Bleeding | Up to 30 hours after the last enoxaparin dose | Bleeding that is fatal, associated with a decrease in hemoglobin by ≥2 g/dl in 24 hours, requires medical or surgical intervention to restore hemostasis, or is in the retroperitoneum, pulmonary, intracranial or central nervous system as defined by International Society of Thrombosis and Haemostasis |
| Number With Laboratory Confirmed Heparin-induced Thrombocytopenia | Up to removal of CVC, an average of 6 days | Heparin-induced thrombocytopenia that is diagnosed with a positive serotonin release assay |
| Number of Mortality | Up to day of discharge from the hospital, average of 18 days | In-hospital mortality during the subject's admission |
| Number With Other Thromboembolic Events | Up to removal of CVC, an average of 6 days | 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 to 1st Dose of Enoxaparin | Up to 48 hours after insertion of CVC | Time to first dose of enoxaparin |
| Time to Target Anti-Xa Activity | Up to removal of CVC, an average of 6 days | Time from insertion of the CVC to time that anti-Xa activity was within 0.2-0.5 IU/mL. |
| Number of Missed Doses of Enoxaparin | Up to removal of CVC, an average of 6 days | Number of doses of enoxaparin that were not administered. This outcome measure was only applicable to the enoxaparin arm. |
| Number of Children With Ultrasound | Up to 24 hours after removal of CVC | Number of children in whom ultrasound was not performed. |
| Number of Enrolled Eligible Children | Up to 24 hours after insertion of CVC | Number of eligible children enrolled in the study. |
| Length of Stay in the Pediatric Intensive Care Unit in Days | Up to day of discharge from the pediatric intensive care unit, an average of 10 days | Duration of stay in the pediatric intensive care unit from the day of enrollment |
Countries
United States
Participant flow
Recruitment details
One participant in the enoxaparin group was enrolled during a single arm phase and not included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Prophylaxis With Enoxaparin 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.
Enoxaparin: 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. | 27 |
| Control Arm Participants randomized to the control arm will receive no 'placebo' intervention. | 24 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Parent refused intervention | 2 | 0 |
| Overall Study | Physician Decision | 2 | 0 |
Baseline characteristics
| Characteristic | Prophylaxis With Enoxaparin | Total | Control Arm |
|---|---|---|---|
| Age, Customized 1-13 years old | 13 Participants | 23 Participants | 10 Participants |
| Age, Customized >13 years old | 2 Participants | 4 Participants | 2 Participants |
| Age, Customized <1 year old | 12 Participants | 24 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 41 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of Lumens of CVC 1 | 0 Participants | 2 Participants | 2 Participants |
| Number of Lumens of CVC 2 | 15 Participants | 27 Participants | 12 Participants |
| Number of Lumens of CVC 3 | 12 Participants | 22 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 37 Participants | 17 Participants |
| Sex: Female, Male Female | 16 Participants | 28 Participants | 12 Participants |
| Sex: Female, Male Male | 11 Participants | 23 Participants | 12 Participants |
| Site of Insertion of CVC Left Femoral | 4 Participants | 8 Participants | 4 Participants |
| Site of Insertion of CVC Right Femoral | 8 Participants | 15 Participants | 7 Participants |
| Site of Insertion of CVC Right Internal Jugular | 15 Participants | 28 Participants | 13 Participants |
| Size of Central Venous Catheter (CVC) 3 French (F) | 0 Participants | 2 Participants | 2 Participants |
| Size of Central Venous Catheter (CVC) 4 F | 13 Participants | 24 Participants | 11 Participants |
| Size of Central Venous Catheter (CVC) 5 F | 10 Participants | 20 Participants | 10 Participants |
| Size of Central Venous Catheter (CVC) 7 F | 4 Participants | 5 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 27 | 2 / 24 |
| other Total, other adverse events | 9 / 27 | 6 / 24 |
| serious Total, serious adverse events | 2 / 27 | 0 / 24 |
Outcome results
Primary
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
Population: The numbers analyzed on the day after CVC insertion and four days after CVC insertion differ from the overall number of participants. Participants were excluded if the CVC was removed or if blood was not drawn.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prophylaxis With Enoxaparin | Endogenous Thrombin Potential | Day of CVC Insertion | 919.7 Nanomolar-minute (nM.min) |
| Prophylaxis With Enoxaparin | Endogenous Thrombin Potential | Day After CVC Insertion | 851.19 Nanomolar-minute (nM.min) |
| Prophylaxis With Enoxaparin | Endogenous Thrombin Potential | Day 4 After CVC Insertion | 826.97 Nanomolar-minute (nM.min) |
| Control Arm | Endogenous Thrombin Potential | Day of CVC Insertion | 1035.6 Nanomolar-minute (nM.min) |
| Control Arm | Endogenous Thrombin Potential | Day After CVC Insertion | 896.58 Nanomolar-minute (nM.min) |
| Control Arm | Endogenous Thrombin Potential | Day 4 After CVC Insertion | 969.89 Nanomolar-minute (nM.min) |
p-value: 0.22Linear mixed effects model
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prophylaxis With Enoxaparin | Number of Participants With Central Venous Catheter (CVC)- Associated Deep Vein Thrombosis (DVT) | 7 Participants |
| Control Arm | Number of Participants With Central Venous Catheter (CVC)- Associated Deep Vein Thrombosis (DVT) | 13 Participants |
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prophylaxis With Enoxaparin | Length of Stay in the Hospital | 16 days |
| Control Arm | Length of Stay in the Hospital | 16 days |
p-value: 0.58Wilcoxon (Mann-Whitney)
Secondary
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prophylaxis With Enoxaparin | Length of Stay in the Pediatric Intensive Care Unit in Days | 12 days |
| Control Arm | Length of Stay in the Pediatric Intensive Care Unit in Days | 8 days |
p-value: 0.31Wilcoxon (Mann-Whitney)
Secondary
Number of Children With Ultrasound
Number of children in whom ultrasound was not performed.
Time frame: Up to 24 hours after removal of CVC
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prophylaxis With Enoxaparin | Number of Children With Ultrasound | 47 Participants |
Secondary
Number of Enrolled Eligible Children
Number of eligible children enrolled in the study.
Time frame: Up to 24 hours after insertion of CVC
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prophylaxis With Enoxaparin | Number of Enrolled Eligible Children | 51 Participants |
Secondary
Number of Missed Doses of Enoxaparin
Number of doses of enoxaparin that were not administered. This outcome measure was only applicable to the enoxaparin arm.
Time frame: Up to removal of CVC, an average of 6 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis With Enoxaparin | Number of Missed Doses of Enoxaparin | 8 Doses of enoxaparin |
Secondary
Number of Mortality
In-hospital mortality during the subject's admission
Time frame: Up to day of discharge from the hospital, average of 18 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prophylaxis With Enoxaparin | Number of Mortality | 5 Participants |
| Control Arm | Number of Mortality | 2 Participants |
p-value: 0.43Fisher Exact
Secondary
Number With Clinically Relevant Bleeding
Bleeding that is fatal, associated with a decrease in hemoglobin by ≥2 g/dl in 24 hours, requires medical or surgical intervention to restore hemostasis, or is in the retroperitoneum, pulmonary, intracranial or central nervous system as defined by International Society of Thrombosis and Haemostasis
Time frame: Up to 30 hours after the last enoxaparin dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prophylaxis With Enoxaparin | Number With Clinically Relevant Bleeding | 1 Participants |
| Control Arm | Number With Clinically Relevant Bleeding | 0 Participants |
p-value: 1Fisher Exact
Secondary
Number With Laboratory Confirmed Heparin-induced Thrombocytopenia
Heparin-induced thrombocytopenia that is diagnosed with a positive serotonin release assay
Time frame: Up to removal of CVC, an average of 6 days
Population: None of the participants experienced this outcome; hence, a statistical analysis was not performed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prophylaxis With Enoxaparin | Number With Laboratory Confirmed Heparin-induced Thrombocytopenia | 0 Participants |
| Control Arm | Number With Laboratory Confirmed Heparin-induced Thrombocytopenia | 0 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prophylaxis With Enoxaparin | Number With Other Thromboembolic Events | 1 Participants |
| Control Arm | Number With Other Thromboembolic Events | 1 Participants |
p-value: 1Fisher Exact
Secondary
Time to 1st Dose of Enoxaparin
Time to first dose of enoxaparin
Time frame: Up to 48 hours after insertion of CVC
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prophylaxis With Enoxaparin | Time to 1st Dose of Enoxaparin | 21.1 hours from insertion of CVC |
Secondary
Time to Target Anti-Xa Activity
Time from insertion of the CVC to time that anti-Xa activity was within 0.2-0.5 IU/mL.
Time frame: Up to removal of CVC, an average of 6 days
Population: This outcome measure is only applicable to subjects in the enoxaparin arm because the control arm did not receive enoxaparin for which anti-Xa activity is used to titrate the dose. Only 12 participants in the enoxaparin arm achieved the target anti-Xa activity.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prophylaxis With Enoxaparin | Time to Target Anti-Xa Activity | 70.4 hours from insertion of CVC |