Deep Vein Thrombosis, Pulmonary Embolism, Venous Thromboembolic Disease
Conditions
Keywords
venous thromboembolic disease, deep vein thrombosis, pulmonary embolism, trauma, antithrombotic prophylaxis
Brief summary
The rate of venous thromboembolic events in trauma patients at high risk for deep vein thrombosis and pulmonary embolism receiving low dose unfractionated heparin every 8 hours will be equivalent or less than a similar group of patients given a standard every 12 hour dose of low molecular weight heparin.
Detailed description
Venous thromboembolism (VTE) is a common and potentially life threatening complication of major trauma. The risk of developing deep vein thrombosis (DVT) following major trauma exceeds 50% unless adequate chemoprophylaxis is used. Recent national quality improvement initiatives, such as the Surgical Care Improvement Project (SCIP), mandate the risk stratification of hospitalized patients and the use of VTE prophylaxis based on the risk assessment. Low Molecular Weight Heparin (LMWH, enoxaparin) and Low Dose Unfractionated Heparin (LDUH) are commonly used alternatives for VTE chemoprophylaxis following major trauma. LMWH became favored in most trauma centers following a prospective randomized controlled trial comparing the two agents that demonstrated superior efficacy and equivalent safety of LMWH over a twice per day dosing of LDUH. The results of this study were largely responsible for practice guideline recommendation changes favoring the use of LMWH in trauma patients by both the American College of Chest Physicians (ACCP) and the Eastern Association for the Surgery of Trauma (EAST). , This landmark paper did not, however, utilize a three times a day (every 8 hours) dosing of LDUH for prophylaxis, which is the dosing schedule recommended by earlier trials. LDUH administered every 8 hours was demonstrated to have similar efficacy to LMWH in trauma patients in a recent retrospective study. These results call into question the validity of the conclusions of the 1996 study. Because LDUH is less expensive ($0.50/dose) than LMWH (Enoxaparin, $28/dose), similar effectiveness would imply a significant reduction in the cost of prophylaxis and increased value to patients, providers and accountable care organizations and tax-payers. To validate this hypothesis the investigators propose to achieve the following study objectives: 1. Assess the degree of risk for VTE in each patient admitted to the trauma service 2. Determine the rate of VTE events in high risk trauma patients receiving either: * LMWH (30mg enoxaparin) given every twelve hours * LDUH (5000 Units unfractionated Heparin) given every eight hours. 3. Identify and quantify any adverse events associated with either treatment arm. 4. Compare the value of LMWH versus LDUH in the prophylactic treatment of VTE disease in trauma patients.
Interventions
DRUG5000 Units unfractionated Heparin Q 8 hr
Venous thromboembolic prophylaxis medication
DRUG30mg enoxaparin Q12 hr
Venous thromboembolic prophylaxis
Sponsors
Scripps Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Admitted to Scripps Mercy Trauma Service * ≥18 Years old * Stratified to either Significant or Highest risk of VTE by ACCP guidelines
Exclusion criteria
* Estimated Injury Severity Score (ISS) ≤9 * Likely to be discharged before hospital day 7 * Systemic coagulopathy defined with an International Normalized Ratio (INR) of ≥1.2 * Body Mass Index (BMI) \>40 * Likely to Survive for \<7 Days * Pregnancy * Evidence of renal insufficiency (Cr ≥1.3) * Delayed transfer to this facility (\>24 hrs) * Prisoners
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lower Extremity Deep Vein Thrombosis | Within 30 days of hospital admission | Patients will have a bilateral lower extremity duplex ultrasound performed by a registered vascular technologist twice per week if the patient is in the ICU, or once per week if the patient is on the trauma ward. All of the deep veins from the external iliac to and including the calf veins will be interrogated. Diagnosis of deep vein thrombosis (DVT) will be defined as absence of complete vein compressibility, presence of an echogenic thrombus within the vein, absence of color flow characteristics including lack of spontaneity, phasicity, pulsatility and augmentability as noted in the clinical practice guidelines of the American Thoracic Society. The vascular technologist and physician reading the ultrasound study will be blinded to the patient's enrollment status and randomization arm/medication group. |
| Pulmonary Embolus | Within 30 days from admission to hospital | Patients with any or all of the following signs and symptoms suggestive of pulmonary embolism will have a CT angiogram (CTA) performed for diagnosis: Sudden onset of dyspnea, deterioration of existing dyspnea, decreased oxygen saturation (\<92%), onset of pleuritic chest pain without another apparent cause, onset of tachycardia (\>100), evidence of hypoxemia, hypocapnia, or respiratory alkalosis on arterial blood gas, or electrocardiographic changes reflecting right ventricular strain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bleeding Event | Within 30 days of admission to hospital | Bleeding events will be classified by the Graafsma et al. severity of bleeding criteria (Major, Minor or No Bleeding). A major bleeding event will be defined as any overt bleeding following initiation of chemoprophylaxis associated with one or more of the following; a decrease in hemoglobin of ≥2 g/dL, bleeding leading to a transfusion of ≥2 units of packed red blood cells, a new retroperitoneal or intracranial bleed, or bleeding that warranted cessation of chemoprophylaxis treatment. Minor bleeding is defined as clinically evident bleeding not meeting criteria for major bleeding. |
| Heparin Induced Thrombocytopenia | Within 30 of admission to hospital | The possible occurrence of heparin induced thrombocytopenia (HIT) was investigated when any patient (in either low molecular weight heparin \[LMWH\] or low dose unfractionated heparin \[LDUH\] study arm) had a platelet count drop of ≥50% (from a baseline value at the time of initiation of VTE prophylaxis) between day 5 and 14 following initiation of chemoprophylaxis per American College of Chest Physicians (ACCP) guidelines. |
Countries
United States
Participant flow
Recruitment details
From November 15, 2012 through September 15, 2014, consecutively admitted adult trauma patients were evaluated for eligibility for the study. Patients aged 18 years and older and at risk for Venous thromboembolic event (VTE) based on the American College of Chest Physicians guidelines were included.
Pre-assignment details
Those with an estimated Injury Severity Score (ISS) equal to or less than 9, those expected to have a hospital length of stay less than seven days by reason of discharge or death, and prisoners were excluded.
Participants by arm
| Arm | Count |
|---|---|
| 5000 Units Unfractionated Heparin Q 8 Hours Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or \>30 days on trauma service.
5000 Units unfractionated Heparin Q 8 hours: Venous thromboembolic prophylaxis medication. Patients were randomly assigned. | 220 |
| 30mg Enoxaparin Q12 Hours Randomly assigned trauma patients to receive Low Molecular Weight Heparin (30mg enoxaparin) given subcutaneously every twelve hours until primary or secondary outcome measure reached, discharge, or \>30 days on trauma service.
30mg enoxaparin Q12 hours: Venous thromboembolic prophylaxis | 216 |
| Total | 436 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 31 | 28 |
Baseline characteristics
| Characteristic | 30mg Enoxaparin Q12 Hours | Total | 5000 Units Unfractionated Heparin Q 8 Hours |
|---|---|---|---|
| Age, Continuous | 46.4 years STANDARD_DEVIATION 20.8 | 46.4 years STANDARD_DEVIATION 21 | 46.5 years STANDARD_DEVIATION 21.2 |
| Body Mass Index | 26.9 kg/m^2 STANDARD_DEVIATION 5.2 | 26.5 kg/m^2 STANDARD_DEVIATION 4.9 | 26.1 kg/m^2 STANDARD_DEVIATION 4.5 |
| Injury Severity Score | 9 units on a scale | 9 units on a scale | 10 units on a scale |
| Region of Enrollment United States | 216 participants | 436 participants | 220 participants |
| Sex: Female, Male Female | 64 Participants | 124 Participants | 60 Participants |
| Sex: Female, Male Male | 152 Participants | 312 Participants | 160 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 220 | 5 / 216 |
| serious Total, serious adverse events | 3 / 220 | 1 / 216 |
Outcome results
Primary
Lower Extremity Deep Vein Thrombosis
Patients will have a bilateral lower extremity duplex ultrasound performed by a registered vascular technologist twice per week if the patient is in the ICU, or once per week if the patient is on the trauma ward. All of the deep veins from the external iliac to and including the calf veins will be interrogated. Diagnosis of deep vein thrombosis (DVT) will be defined as absence of complete vein compressibility, presence of an echogenic thrombus within the vein, absence of color flow characteristics including lack of spontaneity, phasicity, pulsatility and augmentability as noted in the clinical practice guidelines of the American Thoracic Society. The vascular technologist and physician reading the ultrasound study will be blinded to the patient's enrollment status and randomization arm/medication group.
Time frame: Within 30 days of hospital admission
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5000 Units Unfractionated Heparin Q 8 Hours | Lower Extremity Deep Vein Thrombosis | 4.8 percentage of patients |
| 30mg Enoxaparin Q12 Hours | Lower Extremity Deep Vein Thrombosis | 2.9 percentage of patients |
Comparison: Analysis was performed in a subset of patients who received at least one follow-up venous duplex ultrasound of the lower extremities.p-value: 0.02595% CI: [-2.9, 15.8]Chi-squared, Corrected
Comparison: Analysis was performed in the total sample of eligible patients and who received their assigned treatment (referred to as the randomized treated sample) .p-value: 0.02595% CI: [-1.6, 7.7]Chi-squared, Corrected
Primary
Pulmonary Embolus
Patients with any or all of the following signs and symptoms suggestive of pulmonary embolism will have a CT angiogram (CTA) performed for diagnosis: Sudden onset of dyspnea, deterioration of existing dyspnea, decreased oxygen saturation (\<92%), onset of pleuritic chest pain without another apparent cause, onset of tachycardia (\>100), evidence of hypoxemia, hypocapnia, or respiratory alkalosis on arterial blood gas, or electrocardiographic changes reflecting right ventricular strain.
Time frame: Within 30 days from admission to hospital
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5000 Units Unfractionated Heparin Q 8 Hours | Pulmonary Embolus | 1 participants |
| 30mg Enoxaparin Q12 Hours | Pulmonary Embolus | 0 participants |
Secondary
Bleeding Event
Bleeding events will be classified by the Graafsma et al. severity of bleeding criteria (Major, Minor or No Bleeding). A major bleeding event will be defined as any overt bleeding following initiation of chemoprophylaxis associated with one or more of the following; a decrease in hemoglobin of ≥2 g/dL, bleeding leading to a transfusion of ≥2 units of packed red blood cells, a new retroperitoneal or intracranial bleed, or bleeding that warranted cessation of chemoprophylaxis treatment. Minor bleeding is defined as clinically evident bleeding not meeting criteria for major bleeding.
Time frame: Within 30 days of admission to hospital
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5000 Units Unfractionated Heparin Q 8 Hours | Bleeding Event | 2 participants |
| 30mg Enoxaparin Q12 Hours | Bleeding Event | 3 participants |
Secondary
Heparin Induced Thrombocytopenia
The possible occurrence of heparin induced thrombocytopenia (HIT) was investigated when any patient (in either low molecular weight heparin \[LMWH\] or low dose unfractionated heparin \[LDUH\] study arm) had a platelet count drop of ≥50% (from a baseline value at the time of initiation of VTE prophylaxis) between day 5 and 14 following initiation of chemoprophylaxis per American College of Chest Physicians (ACCP) guidelines.
Time frame: Within 30 of admission to hospital
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5000 Units Unfractionated Heparin Q 8 Hours | Heparin Induced Thrombocytopenia | 1 participants |
| 30mg Enoxaparin Q12 Hours | Heparin Induced Thrombocytopenia | 0 participants |