<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01729559</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-12-5973</org_study_id>
    <nct_id>NCT01729559</nct_id>
  </id_info>
  <brief_title>Venous Thromboembolic Prophylaxis After Trauma: Three Times a Day Unfractionated Heparin Versus Twice a Day Enoxaparin</brief_title>
  <official_title>Venous Thromboembolic Prophylaxis After Major Trauma: A Randomized Controlled Trial of Three Times a Day Unfractionated Heparin Versus Twice a Day Enoxaparin</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Scripps Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Scripps Health</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The rate of venous thromboembolic events in trauma patients at high risk for deep vein&#xD;
      thrombosis and pulmonary embolism receiving low dose unfractionated heparin every 8 hours&#xD;
      will be equivalent or less than a similar group of patients given a standard every 12 hour&#xD;
      dose of low molecular weight heparin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Venous thromboembolism (VTE) is a common and potentially life threatening complication of&#xD;
      major trauma. The risk of developing deep vein thrombosis (DVT) following major trauma&#xD;
      exceeds 50% unless adequate chemoprophylaxis is used. Recent national quality improvement&#xD;
      initiatives, such as the Surgical Care Improvement Project (SCIP), mandate the risk&#xD;
      stratification of hospitalized patients and the use of VTE prophylaxis based on the risk&#xD;
      assessment. Low Molecular Weight Heparin (LMWH, enoxaparin) and Low Dose Unfractionated&#xD;
      Heparin (LDUH) are commonly used alternatives for VTE chemoprophylaxis following major&#xD;
      trauma. LMWH became favored in most trauma centers following a prospective randomized&#xD;
      controlled trial comparing the two agents that demonstrated superior efficacy and equivalent&#xD;
      safety of LMWH over a twice per day dosing of LDUH. The results of this study were largely&#xD;
      responsible for practice guideline recommendation changes favoring the use of LMWH in trauma&#xD;
      patients by both the American College of Chest Physicians (ACCP) and the Eastern Association&#xD;
      for the Surgery of Trauma (EAST). , This landmark paper did not, however, utilize a three&#xD;
      times a day (every 8 hours) dosing of LDUH for prophylaxis, which is the dosing schedule&#xD;
      recommended by earlier trials. LDUH administered every 8 hours was demonstrated to have&#xD;
      similar efficacy to LMWH in trauma patients in a recent retrospective study. These results&#xD;
      call into question the validity of the conclusions of the 1996 study. Because LDUH is less&#xD;
      expensive ($0.50/dose) than LMWH (Enoxaparin, $28/dose), similar effectiveness would imply a&#xD;
      significant reduction in the cost of prophylaxis and increased value to patients, providers&#xD;
      and accountable care organizations and tax-payers.&#xD;
&#xD;
      To validate this hypothesis the investigators propose to achieve the following study&#xD;
      objectives:&#xD;
&#xD;
        1. Assess the degree of risk for VTE in each patient admitted to the trauma service&#xD;
&#xD;
        2. Determine the rate of VTE events in high risk trauma patients receiving either:&#xD;
&#xD;
             -  LMWH (30mg enoxaparin) given every twelve hours&#xD;
&#xD;
             -  LDUH (5000 Units unfractionated Heparin) given every eight hours.&#xD;
&#xD;
        3. Identify and quantify any adverse events associated with either treatment arm.&#xD;
&#xD;
        4. Compare the value of LMWH versus LDUH in the prophylactic treatment of VTE disease in&#xD;
           trauma patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">October 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Lower Extremity Deep Vein Thrombosis</measure>
    <time_frame>Within 30 days of hospital admission</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pulmonary Embolus</measure>
    <time_frame>Within 30 days from admission to hospital</time_frame>
    <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 (&lt;92%), onset of pleuritic chest pain without another apparent cause, onset of tachycardia (&gt;100), evidence of hypoxemia, hypocapnia, or respiratory alkalosis on arterial blood gas, or electrocardiographic changes reflecting right ventricular strain.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Bleeding Event</measure>
    <time_frame>Within 30 days of admission to hospital</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heparin Induced Thrombocytopenia</measure>
    <time_frame>Within 30 of admission to hospital</time_frame>
    <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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">495</enrollment>
  <condition>Venous Thromboembolic Disease</condition>
  <condition>Deep Vein Thrombosis</condition>
  <condition>Pulmonary Embolism</condition>
  <arm_group>
    <arm_group_label>5000 Units unfractionated Heparin Q 8 hr</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or &gt;30 days on trauma service.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>30mg enoxaparin Q12 hr</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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 &gt;30 days on trauma service.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5000 Units unfractionated Heparin Q 8 hr</intervention_name>
    <description>Venous thromboembolic prophylaxis medication</description>
    <arm_group_label>5000 Units unfractionated Heparin Q 8 hr</arm_group_label>
    <other_name>LDUH</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>30mg enoxaparin Q12 hr</intervention_name>
    <description>Venous thromboembolic prophylaxis</description>
    <arm_group_label>30mg enoxaparin Q12 hr</arm_group_label>
    <other_name>Lovenox, LMWH, enoxaparin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Admitted to Scripps Mercy Trauma Service&#xD;
&#xD;
          -  ≥18 Years old&#xD;
&#xD;
          -  Stratified to either Significant or Highest risk of VTE by ACCP guidelines&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Estimated Injury Severity Score (ISS) ≤9&#xD;
&#xD;
          -  Likely to be discharged before hospital day 7&#xD;
&#xD;
          -  Systemic coagulopathy defined with an International Normalized Ratio (INR) of ≥1.2&#xD;
&#xD;
          -  Body Mass Index (BMI) &gt;40&#xD;
&#xD;
          -  Likely to Survive for &lt;7 Days&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Evidence of renal insufficiency (Cr ≥1.3)&#xD;
&#xD;
          -  Delayed transfer to this facility (&gt;24 hrs)&#xD;
&#xD;
          -  Prisoners&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Steven R Shackford, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Scripps Mercy Hospital, Department of Trauma Surgery</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Scripps Mercy Hospital</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2016</verification_date>
  <study_first_submitted>November 14, 2012</study_first_submitted>
  <study_first_submitted_qc>November 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 20, 2012</study_first_posted>
  <results_first_submitted>July 29, 2015</results_first_submitted>
  <results_first_submitted_qc>June 7, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">July 18, 2016</results_first_posted>
  <last_update_submitted>June 7, 2016</last_update_submitted>
  <last_update_submitted_qc>June 7, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 18, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>venous thromboembolic disease</keyword>
  <keyword>deep vein thrombosis</keyword>
  <keyword>pulmonary embolism</keyword>
  <keyword>trauma</keyword>
  <keyword>antithrombotic prophylaxis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Embolism</mesh_term>
    <mesh_term>Thrombosis</mesh_term>
    <mesh_term>Embolism</mesh_term>
    <mesh_term>Venous Thrombosis</mesh_term>
    <mesh_term>Thromboembolism</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heparin</mesh_term>
    <mesh_term>Enoxaparin</mesh_term>
    <mesh_term>Calcium heparin</mesh_term>
    <mesh_term>Enoxaparin sodium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>

  <clinical_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.</recruitment_details>
      <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.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>5000 Units Unfractionated Heparin Q 8 Hours</title>
          <description>Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or &gt;30 days on trauma service.&#xD;
5000 Units unfractionated Heparin Q 8 hours: Venous thromboembolic prophylaxis medication. Patients were randomly assigned.</description>
        </group>
        <group group_id="P2">
          <title>30mg Enoxaparin Q12 Hours</title>
          <description>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 &gt;30 days on trauma service.&#xD;
30mg enoxaparin Q12 hours: Venous thromboembolic prophylaxis</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="251"/>
                <participants group_id="P2" count="244"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="220"/>
                <participants group_id="P2" count="216"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="31"/>
                <participants group_id="P2" count="28"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="31"/>
                <participants group_id="P2" count="28"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Basic demographic and clinical characteristics of trauma patients who met all inclusion criteria.</population>
      <group_list>
        <group group_id="B1">
          <title>5000 Units Unfractionated Heparin Q 8 Hours</title>
          <description>Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or &gt;30 days on trauma service.&#xD;
5000 Units unfractionated Heparin Q 8 hours: Venous thromboembolic prophylaxis medication. Patients were randomly assigned.</description>
        </group>
        <group group_id="B2">
          <title>30mg Enoxaparin Q12 Hours</title>
          <description>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 &gt;30 days on trauma service.&#xD;
30mg enoxaparin Q12 hours: Venous thromboembolic prophylaxis</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="220"/>
            <count group_id="B2" value="216"/>
            <count group_id="B3" value="436"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="46.5" spread="21.2"/>
                    <measurement group_id="B2" value="46.4" spread="20.8"/>
                    <measurement group_id="B3" value="46.4" spread="21.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="60"/>
                    <measurement group_id="B2" value="64"/>
                    <measurement group_id="B3" value="124"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="160"/>
                    <measurement group_id="B2" value="152"/>
                    <measurement group_id="B3" value="312"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="220"/>
                    <measurement group_id="B2" value="216"/>
                    <measurement group_id="B3" value="436"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26.1" spread="4.5"/>
                    <measurement group_id="B2" value="26.9" spread="5.2"/>
                    <measurement group_id="B3" value="26.5" spread="4.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Injury Severity Score</title>
          <description>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).</description>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10" lower_limit="1" upper_limit="50"/>
                    <measurement group_id="B2" value="9" lower_limit="1" upper_limit="38"/>
                    <measurement group_id="B3" value="9" lower_limit="1" upper_limit="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Lower Extremity Deep Vein Thrombosis</title>
        <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.</description>
        <time_frame>Within 30 days of hospital admission</time_frame>
        <group_list>
          <group group_id="O1">
            <title>5000 Units Unfractionated Heparin Q 8 Hours</title>
            <description>Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or &gt;30 days on trauma service.&#xD;
5000 Units unfractionated Heparin Q 8 hours: Venous thromboembolic prophylaxis medication. Patients were randomly assigned.</description>
          </group>
          <group group_id="O2">
            <title>30mg Enoxaparin Q12 Hours</title>
            <description>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 &gt;30 days on trauma service.&#xD;
30mg enoxaparin Q12 hours: Venous thromboembolic prophylaxis</description>
          </group>
        </group_list>
        <measure>
          <title>Lower Extremity Deep Vein Thrombosis</title>
          <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.</description>
          <units>percentage of patients</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="105"/>
                <count group_id="O2" value="103"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.8"/>
                    <measurement group_id="O2" value="2.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Analysis was performed in a subset of patients who received at least one follow-up venous duplex ultrasound of the lower extremities.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>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.</non_inferiority_desc>
            <p_value>0.025</p_value>
            <p_value_desc>One-tailed test of the cumulative VTE incidence between treatment groups.</p_value_desc>
            <method>Chi-squared, Corrected</method>
            <param_type>Risk Difference (RD)</param_type>
            <param_value>6.5</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.9</ci_lower_limit>
            <ci_upper_limit>15.8</ci_upper_limit>
            <estimate_desc>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.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Analysis was performed in the total sample of eligible patients and who received their assigned treatment (referred to as the &quot;randomized treated sample&quot;) .</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>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.</non_inferiority_desc>
            <p_value>0.025</p_value>
            <p_value_desc>One-tailed test of the cumulative VTE incidence between treatment groups.</p_value_desc>
            <method>Chi-squared, Corrected</method>
            <param_type>Risk Difference (RD)</param_type>
            <param_value>3.1</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.6</ci_lower_limit>
            <ci_upper_limit>7.7</ci_upper_limit>
            <estimate_desc>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.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Pulmonary Embolus</title>
        <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 (&lt;92%), onset of pleuritic chest pain without another apparent cause, onset of tachycardia (&gt;100), evidence of hypoxemia, hypocapnia, or respiratory alkalosis on arterial blood gas, or electrocardiographic changes reflecting right ventricular strain.</description>
        <time_frame>Within 30 days from admission to hospital</time_frame>
        <group_list>
          <group group_id="O1">
            <title>5000 Units Unfractionated Heparin Q 8 Hours</title>
            <description>Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or &gt;30 days on trauma service.&#xD;
5000 Units unfractionated Heparin Q 8 hours: Venous thromboembolic prophylaxis medication. Patients were randomly assigned.</description>
          </group>
          <group group_id="O2">
            <title>30mg Enoxaparin Q12 Hours</title>
            <description>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 &gt;30 days on trauma service.&#xD;
30mg enoxaparin Q12 hours: Venous thromboembolic prophylaxis</description>
          </group>
        </group_list>
        <measure>
          <title>Pulmonary Embolus</title>
          <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 (&lt;92%), onset of pleuritic chest pain without another apparent cause, onset of tachycardia (&gt;100), evidence of hypoxemia, hypocapnia, or respiratory alkalosis on arterial blood gas, or electrocardiographic changes reflecting right ventricular strain.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="105"/>
                <count group_id="O2" value="103"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Bleeding Event</title>
        <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.</description>
        <time_frame>Within 30 days of admission to hospital</time_frame>
        <group_list>
          <group group_id="O1">
            <title>5000 Units Unfractionated Heparin Q 8 Hours</title>
            <description>Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or &gt;30 days on trauma service.&#xD;
5000 Units unfractionated Heparin Q 8 hours: Venous thromboembolic prophylaxis medication. Patients were randomly assigned.</description>
          </group>
          <group group_id="O2">
            <title>30mg Enoxaparin Q12 Hours</title>
            <description>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 &gt;30 days on trauma service.&#xD;
30mg enoxaparin Q12 hours: Venous thromboembolic prophylaxis</description>
          </group>
        </group_list>
        <measure>
          <title>Bleeding Event</title>
          <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.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="105"/>
                <count group_id="O2" value="103"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Heparin Induced Thrombocytopenia</title>
        <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.</description>
        <time_frame>Within 30 of admission to hospital</time_frame>
        <group_list>
          <group group_id="O1">
            <title>5000 Units Unfractionated Heparin Q 8 Hours</title>
            <description>Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or &gt;30 days on trauma service.&#xD;
5000 Units unfractionated Heparin Q 8 hours: Venous thromboembolic prophylaxis medication. Patients were randomly assigned.</description>
          </group>
          <group group_id="O2">
            <title>30mg Enoxaparin Q12 Hours</title>
            <description>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 &gt;30 days on trauma service.&#xD;
30mg enoxaparin Q12 hours: Venous thromboembolic prophylaxis</description>
          </group>
        </group_list>
        <measure>
          <title>Heparin Induced Thrombocytopenia</title>
          <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.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="105"/>
                <count group_id="O2" value="103"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>30 days after admission.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>5000 Units Unfractionated Heparin Q 8 Hours</title>
          <description>Low Dose Unfractionated Heparin (5000 Units) given every eight hours until primary or secondary outcome measure reached, discharge, or &gt;30 days on trauma service.&#xD;
5000 Units unfractionated Heparin Q 8 hours: Venous thromboembolic prophylaxis medication. Patients were randomly assigned.</description>
        </group>
        <group group_id="E2">
          <title>30mg Enoxaparin Q12 Hours</title>
          <description>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 &gt;30 days on trauma service.&#xD;
30mg enoxaparin Q12 hours: Venous thromboembolic prophylaxis</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>In-hospital death</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="220"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="216"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Heparin-induced thrombocytopenia</sub_title>
                <description>Same as one of the outcomes.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="220"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="216"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Trauma-related mortality</sub_title>
                <description>Trauma-related in-hospital mortality within 30 days of admission following administration of treatment.</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="220"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="216"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="220"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="216"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Bleeding events</sub_title>
                <description>Minor or Major bleeding events</description>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="220"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="216"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>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. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_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.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Steven R. Shackford, MD</name_or_title>
      <organization>Scripps Mercy Hospital</organization>
      <phone>619-299-2600</phone>
      <email>shackford.steven@scrippshealth.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01729559
org study id: IRB-12-5973
nct id: NCT01729559
lead sponsor: 
has dmc: Yes
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:

        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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Outcomes Assessor)
measure: Lower Extremity Deep Vein Thrombosis
time frame: Within 30 days of hospital admission
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.
measure: Pulmonary Embolus
time frame: Within 30 days from admission to hospital
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.
measure: Bleeding Event
time frame: Within 30 days of admission to hospital
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.
measure: Heparin Induced Thrombocytopenia
time frame: Within 30 of admission to hospital
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.
arm group label: 5000 Units unfractionated Heparin Q 8 hr
arm group type: Experimental
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.
arm group label: 30mg enoxaparin Q12 hr
arm group type: Active Comparator
description: 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.
intervention type: Drug
intervention name: 5000 Units unfractionated Heparin Q 8 hr
description: Venous thromboembolic prophylaxis medication
arm group label: 5000 Units unfractionated Heparin Q 8 hr
other name: LDUH
intervention type: Drug
intervention name: 30mg enoxaparin Q12 hr
description: Venous thromboembolic prophylaxis
arm group label: 30mg enoxaparin Q12 hr
other name: Lovenox, LMWH, enoxaparin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Steven R Shackford, MD
role: Principal Investigator
affiliation: Scripps Mercy Hospital, Department of Trauma Surgery
facility: 
country: United States
responsible party type: Sponsor
mesh term: Pulmonary Embolism
mesh term: Thrombosis
mesh term: Embolism
mesh term: Venous Thrombosis
mesh term: Thromboembolism
mesh term: Heparin
mesh term: Enoxaparin
mesh term: Calcium heparin
mesh term: Enoxaparin sodium
sharing ipd: Undecided
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and 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.
point of contact: 