Venous Thromboembolism
Conditions
Keywords
deep vein thrombosis, venous thromboembolism, pulmonary embolism
Brief summary
Trauma patients are at high risk of developing deep vein thrombosis (DVT) and pulmonary embolism (PE). The incidence of DVT varies greatly from 5-63% among studies depending on patient's individual risk factors, modality of prophylaxis, and methods of detection. The incidence of PE may be as low (0.3-4.3%) but carries a mortality of 20-50% which makes prevention of DVT of the utmost importance. The current standard of care for DVT prophylaxis in the trauma patient with high risk of DVT is enoxaparin, a low molecular weight heparin, administered twice a day as long as anticoagulation in not contraindicated. Many studies have demonstrated its efficacy when compared to mechanical compression and to unfractionated heparin, however one of the most robust of these studies still reported an DVT incidence of 35% in patients treated with enoxaparin. Another drug, fondaparinux, is a selective factor Xa inhibitor that could offer added benefits over enoxaparin such as once daily dosing and a drastically reduced risk of heparin induced thrombocytopenia (HIT). Fondaparinux has been already be widely used in post-operative hip surgery and major knee surgery patients with good results. It has also been shown to be effective in DVT prophylaxis in patients who have had major abdominal surgery and also in acute medical patients. Fondaparinux has yet to be used in trauma patients. Trauma patients are a diverse and distinct population given the acuity of their injuries and their increased risk of bleeding who at this time still do not have a perfect method for DVT prophylaxis. We hypothesize that fondaparinux will be effective in decreasing the risk of DVT when used in the trauma patient population. This is a non randomized prospective cohort study designed to test the efficacy of fondaparinux in the prophylaxis of DVT and PE in trauma patients.
Detailed description
Patients with trauma admitted to San Francisco General Hospital and qualify for the study will be assigned to +fondaparinux and no fondaparinux arms based on guidelines that were developed for and are considered the standard of care for the use of low molecular weight heparin in the same group of patients for the same indication. These guidelines will separate patients at risk for DVT into those that are high risk and very high risk. The primary efficacy outcome measures will be DVT and PE. Presence of DVT will be assessed with serial color flow duplex ultrasound during the patients in hospital stay at weekly intervals up to 3 weeks and when the patient has symptoms of DVT. PE will be diagnosed according to clinical suspicion by the patients treating physicians and subsequent imaging by CT. We plan on enrolling approximately 100 patients in the +fondaparinux and 100 patients in the no fondaparinux arm. We will compare both the incidence of DVT and PE in these groups and to the incidences in the literature and historical controls. A second aim of the study is to evaluate the adverse outcomes such as increased bleeding in patients who receive fondaparinux. A third and final aim of the study is to describe the effect of fondaparinux on antifactor Xa levels in trauma patients.
Interventions
fondaparinux 2.5mg SubQ daily for DVT prophylaxis to be started by treating physicians once deemed safe and to be discontinued once patient in discharged from the hospital or at discretion of treating physicians.
Sequential compression devices at all times during the patient's hospital admission will be used in patients who have a contraindication to pharmacologic DVT prophylaxis. This is already the current standard of care.
Sponsors
GlaxoSmithKline
Mary Knudson, M.D.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients age ≥ 18 years old admitted to San Francisco General Hospital for injury with at least one risk factor for venous thromboembolism (VTE). Risk factors are: Age ≥ 40 years, pelvic fracture, lower extremity fracture, spinal cord injury, shock or head injury, major operative procedure, mechanical ventilation \> 3 days, venous injury
Exclusion criteria
* prisoners * pregnant patients * patients who are anticipated to have a \< 5 day length of stay as determined by the admitting trauma surgeon * patients who decline to participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Presence of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE) | within 3 weeks post injury | Color-flow duplex venous ultrasonography examinations of upper and lower extremities were performed within 48 hours of injury, and then weekly until discharge or 3 weeks. DVT was defined as any clot occurring in the subclavian, iliac, femoral, or popliteal location. Patients were examined daily for clinical signs and symptoms of venous thromboembolism (VTE) and PE. Small, nonocclusive clots discovered in other locations were observed for progression on sequential ultrasonography examinations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Normal Trough and Peak Fondaparinux Concentration | Day 3 | Serum samples were collected 30 minutes before (trough) and 2 hours after (peak) the third dose of fondaparinux. Normative data plots comparing study participants with healthy volunteers were supplied by the company outsourced to analyze samples. |
| Increased Bleeding Attributed to Fondaparinux | 3 weeks post injury | Coagulopathic bleeding due to fondaparinux was suspected in patients requiring packed red cell transfusions after initiation of fondaparinux therapy only if the change in hematocrit prompting transfusion was not clinically commensurate with the degree of injuries that the patient had sustained (primarily orthopaedic) and/or the hematocrit did not respond appropriately post-transfusion. |
Countries
United States
Participant flow
Recruitment details
During a 6-month period, consecutive adults presenting to one Level I urban trauma center were screened for eligibility, enrolled and assigned to a treatment category using previously-developed clinical guidelines.
Pre-assignment details
Of 105 enrolled participants, 18 were excluded from analysis (13 discharged or transferred prior to second venous ultrasonography; 4 received non-study DVT prophylaxis; 1 had a known protein-C deficiency).
Participants by arm
| Arm | Count |
|---|---|
| Fondaparinux Sodium Patients at high risk or very high risk for venous thromboembolism received fondaparinux 2.5mg SubQ daily, with (very high risk) or without (high risk) mechanical compression upon admission or by 3rd day after injury. | 81 |
| No Fondaparinux Patients at high risk or very high risk for venous thromboembolism AND contraindication to anticoagulant administration received mechanical compression, with (very high risk) or without (high risk) possible temporary IVC filter (prn as determined by caregiver). | 6 |
| Total | 87 |
Baseline characteristics
| Characteristic | Fondaparinux Sodium | No Fondaparinux | Total |
|---|---|---|---|
| Age Continuous | 43.1 years STANDARD_DEVIATION 19.3 | 56.8 years STANDARD_DEVIATION 20.9 | 44.3 years STANDARD_DEVIATION 19.7 |
| Region of Enrollment United States | 81 participants | 6 participants | 87 participants |
| Sex: Female, Male Female | 21 Participants | 1 Participants | 22 Participants |
| Sex: Female, Male Male | 60 Participants | 5 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 81 | 2 / 6 |
| serious Total, serious adverse events | 0 / 81 | 0 / 6 |
Outcome results
Primary
Presence of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE)
Color-flow duplex venous ultrasonography examinations of upper and lower extremities were performed within 48 hours of injury, and then weekly until discharge or 3 weeks. DVT was defined as any clot occurring in the subclavian, iliac, femoral, or popliteal location. Patients were examined daily for clinical signs and symptoms of venous thromboembolism (VTE) and PE. Small, nonocclusive clots discovered in other locations were observed for progression on sequential ultrasonography examinations.
Time frame: within 3 weeks post injury
Population: Of 11 patients with initial contraindication to anticoagulation, 5 were cleared by the treating physicians to receive fondaparinux within 3 days of injury, and 6 were not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux Sodium | Presence of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE) | DVT | 2 participants |
| Fondaparinux Sodium | Presence of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE) | DVT after fondaparinux | 1 participants |
| Fondaparinux Sodium | Presence of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE) | PE | 0 participants |
| No Fondaparinux | Presence of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE) | DVT | 2 participants |
| No Fondaparinux | Presence of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE) | DVT after fondaparinux | NA participants |
| No Fondaparinux | Presence of Deep Vein Thrombosis (DVT) or Pulmonary Embolus (PE) | PE | 0 participants |
Secondary
Increased Bleeding Attributed to Fondaparinux
Coagulopathic bleeding due to fondaparinux was suspected in patients requiring packed red cell transfusions after initiation of fondaparinux therapy only if the change in hematocrit prompting transfusion was not clinically commensurate with the degree of injuries that the patient had sustained (primarily orthopaedic) and/or the hematocrit did not respond appropriately post-transfusion.
Time frame: 3 weeks post injury
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fondaparinux Sodium | Increased Bleeding Attributed to Fondaparinux | 0 participants |
Secondary
Normal Trough and Peak Fondaparinux Concentration
Serum samples were collected 30 minutes before (trough) and 2 hours after (peak) the third dose of fondaparinux. Normative data plots comparing study participants with healthy volunteers were supplied by the company outsourced to analyze samples.
Time frame: Day 3
Population: Serum samples were obtained from 63 representative patients from our study who received Fondaparinux and compared against normative values from normal volunteers supplied by our sponsor.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux Sodium | Normal Trough and Peak Fondaparinux Concentration | Trough values outside normative range | 0 Participants |
| Fondaparinux Sodium | Normal Trough and Peak Fondaparinux Concentration | Peak values outside normative range | 0 Participants |