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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.
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:
Assess the degree of risk for VTE in each patient admitted to the trauma service
Determine the rate of VTE events in high risk trauma patients receiving either:
Identify and quantify any adverse events associated with either treatment arm.
Compare the value of LMWH versus LDUH in the prophylactic treatment of VTE disease in trauma patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 5000 Units unfractionated Heparin Q 8 hr | Experimental | Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or >30 days on trauma service. |
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| 30mg enoxaparin Q12 hr | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 5000 Units unfractionated Heparin Q 8 hr | Drug | Venous thromboembolic prophylaxis medication |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Within 30 days of hospital admission |
| 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. | Within 30 days from admission to hospital |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Steven R Shackford, MD | Scripps Mercy Hospital, Department of Trauma Surgery | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Scripps Mercy Hospital | San Diego | California | 92103 | United States |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| 30mg enoxaparin Q12 hr | Drug | Venous thromboembolic prophylaxis |
|
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| Within 30 days of admission to hospital |
| 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. | Within 30 of admission to hospital |
| 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 |
| COMPLETED |
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| NOT COMPLETED |
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Basic demographic and clinical characteristics of trauma patients who met all inclusion criteria.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
| ||||||||||||||||
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
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| Injury Severity Score | The Injury Severity Score (ISS) is an anatomical scoring system that provides an overall score for patients with multiple injuries. Each injury is assigned an Abbreviated Injury Scale (AIS) score allocated to one of six body regions (Head, Face, Chest, Abdomen, Extremities, External). The highest AIS scores among the three most severely injured body regions are squared and added together to produce the total ISS score. The ISS score ranges from 0 to 75. Each AIS score ranges from 1 to 6 (6 denotes an unsurvivable injury). | Median | Full Range | units on a scale |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Number | percentage of patients | Within 30 days of hospital admission |
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| 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. | Posted | Number | participants | Within 30 days from admission to hospital |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Posted | Number | participants | Within 30 days of admission to hospital |
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| 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. | Posted | Number | participants | Within 30 of admission to hospital |
|
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30 days after admission.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. | 3 | 220 | 3 | 220 | ||
| EG001 | 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 | 1 | 216 | 5 | 216 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Heparin-induced thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment | Same as one of the outcomes. |
| |
| Trauma-related mortality | Injury, poisoning and procedural complications | In-hospital death | Systematic Assessment | Trauma-related in-hospital mortality within 30 days of admission following administration of treatment. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bleeding events | Blood and lymphatic system disorders | Systematic Assessment | Minor or Major bleeding events |
|
The lack of long-term follow-up to identify VTE events among patients who were either transferred or readmitted to other facilities with VTE-related events was not performed. Published risk estimates were inaccurate for our sample size calculation.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Steven R. Shackford, MD | Scripps Mercy Hospital | 619-299-2600 | shackford.steven@scrippshealth.org |
| ID | Term |
|---|---|
| D020246 | Venous Thrombosis |
| D011655 | Pulmonary Embolism |
| D014947 | Wounds and Injuries |
| ID | Term |
|---|---|
| D013927 | Thrombosis |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D004617 | Embolism |
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| ID | Term |
|---|---|
| D017984 | Enoxaparin |
| D006495 | Heparin, Low-Molecular-Weight |
| ID | Term |
|---|---|
| D006493 | Heparin |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |
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| Male |
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A 10% noninferiority margin was selected based on a previous trial showing a difference in the incidence of DVT of 13% with the use of 30 mg of enoxaparin every 12 hours compared to 5,000 U of unfractionated heparin (UFH) every 12 hr. To achieve 90% power using an a priori margin of 10% with a one-sided alpha of 0.025, a total of 182 patients (91 in each arm) was required. |
| Analysis was performed in the total sample of eligible patients and who received their assigned treatment (referred to as the "randomized treated sample") . | Chi-squared, Corrected | 0.025 | One-tailed test of the cumulative VTE incidence between treatment groups. | Risk Difference (RD) | 3.1 | 2-Sided | 95 | -1.6 | 7.7 | Unadjusted cumulative incidence values between the two treatment groups were subtracted to calculate the risk difference for VTE between groups. This difference was compared to the a priori 10% margin of difference using the 95% confidence interval. | Yes | Non-Inferiority or Equivalence | A 10% noninferiority margin was selected based on these data showing a difference in the incidence of DVT of 13% with the use of 30 mg of enoxaparin every 12 hours compared to 5,000 U of UFH every 12 hours. To achieve 90% power using an a priori margin of 10% with a one-sided alpha of 0.025, a total of 182 patients (91 in each arm) was required. This analysis was performed in the entire sample. |
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