Venous Thromboembolic Prophylaxis After Trauma: Three Times a Day Unfractionated Heparin Versus Twice a Day Enoxaparin

• Sponsor: Scripps Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT01729559
• Collaborator: (none)
• Enrollment: 495
• Location: 1
• Arms: 2
• Duration (Months): 23
• Patients Per Site Per Month: 21.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Venous Thromboembolic Disease; Deep Vein Thrombosis; Pulmonary Embolism	Drug: 5000 Units unfractionated Heparin Q 8 hr; Drug: 30mg enoxaparin Q12 hr	Phase 4

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.

1. Identify and quantify any adverse events associated with either treatment arm.

2. Compare the value of LMWH versus LDUH in the prophylactic treatment of VTE disease in trauma patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 495 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Venous Thromboembolic Prophylaxis After Major Trauma: A Randomized Controlled Trial of Three Times a Day Unfractionated Heparin Versus Twice a Day Enoxaparin
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 5000 Units unfractionated Heparin Q 8 hr Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or >30 days on trauma service.	Drug: 5000 Units unfractionated Heparin Q 8 hr; Venous thromboembolic prophylaxis medication; Other Names: LDUH
Active Comparator: 30mg enoxaparin Q12 hr 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.	Drug: 30mg enoxaparin Q12 hr; Venous thromboembolic prophylaxis; Other Names: Lovenox, LMWH, enoxaparin

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Scripps Mercy Hospital	San Diego	California	United States	92103

Sponsors and Collaborators

• Scripps Health

Investigators

• Principal Investigator: Steven R Shackford, MD, Scripps Mercy Hospital, Department of Trauma Surgery

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Scripps Health
• ClinicalTrials.gov Identifier: NCT01729559
• Other Study ID Numbers: IRB-12-5973
• First Posted: Nov 20, 2012
• Last Update Posted: Jul 18, 2016
• Last Verified: Jun 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Scripps Health: venous thromboembolic disease; deep vein thrombosis; pulmonary embolism; trauma; antithrombotic prophylaxis
• Additional relevant MeSH terms: Pulmonary Embolism; Thrombosis; Embolism; Venous Thrombosis; Thromboembolism; Heparin; Enoxaparin; Calcium heparin; Enoxaparin sodium

Study Results

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 Detail	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.

Arm/Group Title	5000 Units Unfractionated Heparin Q 8 Hours	30mg Enoxaparin Q12 Hours
Arm/Group Description	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.	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
Period Title: Overall Study
STARTED	251	244
COMPLETED	220	216
NOT COMPLETED	31	28

Baseline Characteristics

Arm/Group Title	5000 Units Unfractionated Heparin Q 8 Hours	30mg Enoxaparin Q12 Hours	Total
Arm/Group Description	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.	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	Total of all reporting groups
Overall Participants	220	216	436
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.5 (21.2)	46.4 (20.8)	46.4 (21.0)
Sex: Female, Male (Count of Participants)
Female	60 27.3%	64 29.6%	124 28.4%
Male	160 72.7%	152 70.4%	312 71.6%
Region of Enrollment (participants) [Number]
United States	220 100%	216 100%	436 100%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.1 (4.5)	26.9 (5.2)	26.5 (4.9)
Injury Severity Score (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	10	9	9

Outcome Measures

1. Primary Outcome

Title	Lower Extremity Deep Vein Thrombosis
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	5000 Units Unfractionated Heparin Q 8 Hours	30mg Enoxaparin Q12 Hours
Arm/Group Description	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.	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
Measure Participants	105	103
Number [percentage of patients]	4.8	2.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5000 Units Unfractionated Heparin Q 8 Hours, 30mg Enoxaparin Q12 Hours
	Comments	Analysis was performed in a subset of patients who received at least one follow-up venous duplex ultrasound of the lower extremities.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.025
	Comments	One-tailed test of the cumulative VTE incidence between treatment groups.
	Method	Chi-squared, Corrected
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	6.5
	Confidence Interval	(2-Sided) 95%; -2.9 to 15.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	5000 Units Unfractionated Heparin Q 8 Hours, 30mg Enoxaparin Q12 Hours
	Comments	Analysis was performed in the total sample of eligible patients and who received their assigned treatment (referred to as the "randomized treated sample") .
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.025
	Comments	One-tailed test of the cumulative VTE incidence between treatment groups.
	Method	Chi-squared, Corrected
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; -1.6 to 7.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

2. Primary Outcome

Title	Pulmonary Embolus
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	5000 Units Unfractionated Heparin Q 8 Hours	30mg Enoxaparin Q12 Hours
Arm/Group Description	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.	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
Measure Participants	105	103
Number [participants]	1 0.5%	0 0%

3. Secondary Outcome

Title	Bleeding Event
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	5000 Units Unfractionated Heparin Q 8 Hours	30mg Enoxaparin Q12 Hours
Arm/Group Description	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.	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
Measure Participants	105	103
Number [participants]	2 0.9%	3 1.4%

4. Secondary Outcome

Title	Heparin Induced Thrombocytopenia
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	5000 Units Unfractionated Heparin Q 8 Hours	30mg Enoxaparin Q12 Hours
Arm/Group Description	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.	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
Measure Participants	105	103
Number [participants]	1 0.5%	0 0%

Adverse Events

Time Frame	30 days after admission.
Arm/Group Title	5000 Units Unfractionated Heparin Q 8 Hours		30mg Enoxaparin Q12 Hours
Arm/Group Description	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.		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
All Cause Mortality
	5000 Units Unfractionated Heparin Q 8 Hours		30mg Enoxaparin Q12 Hours
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	5000 Units Unfractionated Heparin Q 8 Hours		30mg Enoxaparin Q12 Hours
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/220 (1.4%)		1/216 (0.5%)
Blood and lymphatic system disorders
Heparin-induced thrombocytopenia	1/220 (0.5%)	1	0/216 (0%)	0
Injury, poisoning and procedural complications
Trauma-related mortality	2/220 (0.9%)	2	1/216 (0.5%)	1
Other (Not Including Serious) Adverse Events
	5000 Units Unfractionated Heparin Q 8 Hours		30mg Enoxaparin Q12 Hours
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/220 (1.4%)		5/216 (2.3%)
Blood and lymphatic system disorders
Bleeding events	3/220 (1.4%)	3	5/216 (2.3%)	5

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.