<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/NCT03296033</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00044503</org_study_id>
    <nct_id>NCT03296033</nct_id>
  </id_info>
  <brief_title>Residual Anti-Xa Activity After Last Treatment Dose of Enoxaparin</brief_title>
  <official_title>Evaluation of Residual Anti-Xa Activity As A Function Of Time Following The Last Treatment Dose of Enoxaparin In Patients Presenting For Elective Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Wake Forest University Health Sciences</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main objective of this study is to determine the time interval following the last&#xD;
      treatment dose of enoxaparin at which the amount of anti-Xa level activity is reliably less&#xD;
      than 0.2IU/mL in patients presenting for elective surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Enoxaparin is a factor Xa inhibitor commonly used for both prophylaxis against and treatment&#xD;
      of thromboembolism. It is also frequently used off-label as a perioperative bridge for&#xD;
      patients that are chronically anticoagulated prior to surgery, such as those taking Warfarin.&#xD;
      It is an attractive option for perioperative use secondary to its predictable pharmacologic&#xD;
      profile and the lack of recommended routine blood monitoring. Therefore, it is common to&#xD;
      encounter a patient who has recently received a treatment dose of Enoxaparin prior to&#xD;
      presenting for surgery. For these patients, and those on other anticoagulant medications,&#xD;
      published guidelines have been developed to help guide clinical decision-making when the&#xD;
      anesthetic/analgesic plan includes regional anesthesia.1 Currently, these guidelines&#xD;
      recommend that a minimum of 24-hours should elapse following the last treatment dose of&#xD;
      Enoxaparin before a neuraxial procedure is performed. However, a recently completed quality&#xD;
      improvement project conducted at Wake Forest Baptist Medical Center found that almost 60% of&#xD;
      patients presenting for surgery while on treatment dose enoxaparin still had significant&#xD;
      anticoagulant activity 24-hours following their last dose, as demonstrated by anti-Xa level&#xD;
      assay testing. Given that the risk of epidural hematoma formation is increased in the setting&#xD;
      of abnormal coagulation parameters2, the significance of this finding is that the risk of&#xD;
      bleeding complications following a neuraxial procedure may still be increased 24-hours after&#xD;
      the last treatment dose of enoxaparin.&#xD;
&#xD;
      While the routine use of anti-Xa level testing may be a viable option to determine when&#xD;
      residual enoxaparin activity is present before proceeding with a neuraxial procedure on a&#xD;
      patient-by-patient basis, it is not universally available at all hospitals. Therefore, it is&#xD;
      important to determine the time interval following the last enoxaparin dose at which the&#xD;
      likelihood that a clinically relevant amount of residual anti-Xa level activity no longer&#xD;
      persists, so that providers can confidently proceed with a neuraxial procedure when anti-Xa&#xD;
      level testing is not available.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    enrollment proved to be a challenge due to the changing of the guidelines for bridging off the&#xD;
    new anticoagulants that are being prescribed&#xD;
  </why_stopped>
  <start_date type="Actual">October 24, 2017</start_date>
  <completion_date type="Actual">January 14, 2022</completion_date>
  <primary_completion_date type="Actual">January 14, 2022</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>
    <intervention_model_description>After consenting to the study, patients will be randomized to one of two groups.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Anti-Xa activity levels following last treatment dose of enoxaparin</measure>
    <time_frame>24 hours or 36 hours (based on randomization) after the last treatment dose of enoxaparin.</time_frame>
    <description>Anti-Xa level activity will be measured in both groups using a chromogenic assay and a hybrid curve calibrated to both heparin and enoxaparin.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time point at which anti-Xa activity is lower than 0.2IU/mL using modeling</measure>
    <time_frame>24 hours or 36 hours after last treatment dose of enoxaparin.</time_frame>
    <description>The randomization of patients to either the 24-hour group or the 36-hour group will allow for modeling, which will generate a prediction of the time point at which the level of anti-Xa activity can reliably be assumed to be lower than 0.2IU/mL.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Anti-Xa activity over time</measure>
    <time_frame>24 hours or 36 hours after last treatment dose of enoxaparin.</time_frame>
    <description>Determining the relationship of anti-Xa level activity over time, 24 and 36 hours, by using curve fitting or best-fit function.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between anti-Xa levels and patients age</measure>
    <time_frame>24 hours or 36 hours after last treatment dose of enoxaparin.</time_frame>
    <description>Explore clinical predictor (age) for any anti-Xa activity levels &gt; 1 standard deviation over the mean from the above function.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between anti-Xa levels and patients weight</measure>
    <time_frame>24 hours or 36 hours after last treatment dose of enoxaparin.</time_frame>
    <description>Explore clinical predictor (weight) for any anti-Xa activity levels &gt; 1 standard deviation over the mean from the above function.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between anti-Xa levels and patients gender</measure>
    <time_frame>24 hours or 36 hours after last treatment dose of enoxaparin.</time_frame>
    <description>Explore clinical predictor (gender= male or female) for any anti-Xa activity levels &gt; 1 standard deviation over the mean from the above function.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">116</enrollment>
  <condition>Anticoagulants and Bleeding Disorders</condition>
  <condition>Surgery</condition>
  <condition>Regional Anesthesia Morbidity</condition>
  <arm_group>
    <arm_group_label>24 Hours group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Group one will be instructed to administer their last dose of enoxaparin at 07:00 in the morning on the day prior to their scheduled surgery date. This will mean that patients who have their surgery scheduled for 07:00 the following day will be 24-hours removed from their last dose. Patients presenting for surgery later in the day would be slightly farther removed from their last dose, however this is currently considered normal clinical practice.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>36 Hours Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group 2 will be instructed to administer their last dose of enoxaparin at 19:00 in the evening two days prior to their scheduled surgery date. Patients presenting for surgery at 07:00 two days later will be 36-hours removed from their last dose. Patients presenting for surgery later in the day would be slightly farther removed from their last dose, but again this mimics normal clinical practice in which the timing of the last dose of self-administered enoxaparin is not routinely adjusted based on the scheduled surgical start time.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enoxaparin</intervention_name>
    <description>The intervention is the implementation of a 36-hour time period from the last dose of treatment dose Enoxaparin to the blood sampling for anti-Xa testing.</description>
    <arm_group_label>36 Hours Group</arm_group_label>
    <other_name>Lovenox</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enoxaparin</intervention_name>
    <description>This is the historical control arm. 24 hours removed from their last dose (time period from the last dose of treatment dose Enoxaparin to the blood sampling for anti-Xa testing)</description>
    <arm_group_label>24 Hours group</arm_group_label>
    <other_name>Lovenox</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Eligible patients need:&#xD;
&#xD;
          -  to be on treatment dose (1mg/kg twice daily or 1.5mg/kg daily) enoxaparin at the time&#xD;
             of presentation for elective surgery&#xD;
&#xD;
          -  and must be able to accurately report the timing of their last dose and the&#xD;
             administered dosage.&#xD;
&#xD;
          -  Patients must also be between the ages of 18-100 years of age&#xD;
&#xD;
          -  and must be able to give written consent to participate.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with severe renal insufficiency (creatinine clearance &lt;30ml/min) will be&#xD;
             excluded from the study, as the elimination of enoxaparin is known to be affected in&#xD;
             this patient population.&#xD;
&#xD;
          -  Pregnant patients will also be excluded, as the elimination and metabolism of&#xD;
             enoxaparin is known to be altered in this patient population, and dose adjustments are&#xD;
             recommended if treatment dose enoxaparin is used during pregnancy.&#xD;
&#xD;
          -  Patients who are receiving enoxaparin as a bridge from another anti-Xa inhibiting&#xD;
             medication will be excluded as this could unpredictably affect the results of anti-Xa&#xD;
             testing. These medications include: Apixaban, Edoxaban, Fondaparinux, and Xarelto.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Daryl S Henshaw, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wake Forest University Health Sciences</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Wake Forest University Baptist Medical Center</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp SL, Benzon HT, Brown DL, Heit JA, Mulroy MF, Rosenquist RW, Tryba M, Yuan CS. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010 Jan-Feb;35(1):64-101. doi: 10.1097/aap.0b013e3181c15c70.</citation>
    <PMID>20052816</PMID>
  </reference>
  <results_reference>
    <citation>Henshaw DS, Turner JD, Forest DJ, Thompson GR, Weller RS. Residual Enoxaparin Activity, Anti-Xa Levels, and Concerns About the American Society of Regional Anesthesia and Pain Medicine Anticoagulation Guidelines. Reg Anesth Pain Med. 2017 Jul/Aug;42(4):432-436. doi: 10.1097/AAP.0000000000000617.</citation>
    <PMID>28492441</PMID>
  </results_reference>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>July 6, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 28, 2017</study_first_posted>
  <last_update_submitted>December 4, 2022</last_update_submitted>
  <last_update_submitted_qc>December 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>enoxaparin</keyword>
  <keyword>thromboembolism</keyword>
  <keyword>coagulation</keyword>
  <keyword>factor Xa</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemostatic Disorders</mesh_term>
    <mesh_term>Blood Coagulation Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Enoxaparin</mesh_term>
    <mesh_term>Enoxaparin sodium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 1, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/33/NCT03296033/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <pending_results>
    <submitted>March 9, 2023</submitted>
    <returned>April 6, 2023</returned>
    <submitted>May 8, 2023</submitted>
    <returned>June 6, 2023</returned>
    <submitted>July 17, 2023</submitted>
    <returned>August 3, 2023</returned>
    <submitted>September 8, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03296033
org study id: IRB00044503
nct id: NCT03296033
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The main objective of this study is to determine the time interval following the last
      treatment dose of enoxaparin at which the amount of anti-Xa level activity is reliably less
      than 0.2IU/mL in patients presenting for elective surgery.
Enoxaparin is a factor Xa inhibitor commonly used for both prophylaxis against and treatment
      of thromboembolism. It is also frequently used off-label as a perioperative bridge for
      patients that are chronically anticoagulated prior to surgery, such as those taking Warfarin.
      It is an attractive option for perioperative use secondary to its predictable pharmacologic
      profile and the lack of recommended routine blood monitoring. Therefore, it is common to
      encounter a patient who has recently received a treatment dose of Enoxaparin prior to
      presenting for surgery. For these patients, and those on other anticoagulant medications,
      published guidelines have been developed to help guide clinical decision-making when the
      anesthetic/analgesic plan includes regional anesthesia.1 Currently, these guidelines
      recommend that a minimum of 24-hours should elapse following the last treatment dose of
      Enoxaparin before a neuraxial procedure is performed. However, a recently completed quality
      improvement project conducted at Wake Forest Baptist Medical Center found that almost 60% of
      patients presenting for surgery while on treatment dose enoxaparin still had significant
      anticoagulant activity 24-hours following their last dose, as demonstrated by anti-Xa level
      assay testing. Given that the risk of epidural hematoma formation is increased in the setting
      of abnormal coagulation parameters2, the significance of this finding is that the risk of
      bleeding complications following a neuraxial procedure may still be increased 24-hours after
      the last treatment dose of enoxaparin.

      While the routine use of anti-Xa level testing may be a viable option to determine when
      residual enoxaparin activity is present before proceeding with a neuraxial procedure on a
      patient-by-patient basis, it is not universally available at all hospitals. Therefore, it is
      important to determine the time interval following the last enoxaparin dose at which the
      likelihood that a clinically relevant amount of residual anti-Xa level activity no longer
      persists, so that providers can confidently proceed with a neuraxial procedure when anti-Xa
      level testing is not available.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: After consenting to the study, patients will be randomized to one of two groups.
primary purpose: Basic Science
masking: None (Open Label)
measure: Anti-Xa activity levels following last treatment dose of enoxaparin
time frame: 24 hours or 36 hours (based on randomization) after the last treatment dose of enoxaparin.
description: Anti-Xa level activity will be measured in both groups using a chromogenic assay and a hybrid curve calibrated to both heparin and enoxaparin.
measure: Time point at which anti-Xa activity is lower than 0.2IU/mL using modeling
time frame: 24 hours or 36 hours after last treatment dose of enoxaparin.
description: The randomization of patients to either the 24-hour group or the 36-hour group will allow for modeling, which will generate a prediction of the time point at which the level of anti-Xa activity can reliably be assumed to be lower than 0.2IU/mL.
measure: Anti-Xa activity over time
time frame: 24 hours or 36 hours after last treatment dose of enoxaparin.
description: Determining the relationship of anti-Xa level activity over time, 24 and 36 hours, by using curve fitting or best-fit function.
measure: Relationship between anti-Xa levels and patients age
time frame: 24 hours or 36 hours after last treatment dose of enoxaparin.
description: Explore clinical predictor (age) for any anti-Xa activity levels > 1 standard deviation over the mean from the above function.
measure: Relationship between anti-Xa levels and patients weight
time frame: 24 hours or 36 hours after last treatment dose of enoxaparin.
description: Explore clinical predictor (weight) for any anti-Xa activity levels > 1 standard deviation over the mean from the above function.
measure: Relationship between anti-Xa levels and patients gender
time frame: 24 hours or 36 hours after last treatment dose of enoxaparin.
description: Explore clinical predictor (gender= male or female) for any anti-Xa activity levels > 1 standard deviation over the mean from the above function.
arm group label: 24 Hours group
arm group type: Active Comparator
description: Group one will be instructed to administer their last dose of enoxaparin at 07:00 in the morning on the day prior to their scheduled surgery date. This will mean that patients who have their surgery scheduled for 07:00 the following day will be 24-hours removed from their last dose. Patients presenting for surgery later in the day would be slightly farther removed from their last dose, however this is currently considered normal clinical practice.
arm group label: 36 Hours Group
arm group type: Experimental
description: Group 2 will be instructed to administer their last dose of enoxaparin at 19:00 in the evening two days prior to their scheduled surgery date. Patients presenting for surgery at 07:00 two days later will be 36-hours removed from their last dose. Patients presenting for surgery later in the day would be slightly farther removed from their last dose, but again this mimics normal clinical practice in which the timing of the last dose of self-administered enoxaparin is not routinely adjusted based on the scheduled surgical start time.
intervention type: Drug
intervention name: Enoxaparin
description: The intervention is the implementation of a 36-hour time period from the last dose of treatment dose Enoxaparin to the blood sampling for anti-Xa testing.
arm group label: 36 Hours Group
other name: Lovenox
intervention type: Drug
intervention name: Enoxaparin
description: This is the historical control arm. 24 hours removed from their last dose (time period from the last dose of treatment dose Enoxaparin to the blood sampling for anti-Xa testing)
arm group label: 24 Hours group
other name: Lovenox
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
last name: Daryl S Henshaw, MD
role: Principal Investigator
affiliation: Wake Forest University Health Sciences
facility: 
country: United States
citation: Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp SL, Benzon HT, Brown DL, Heit JA, Mulroy MF, Rosenquist RW, Tryba M, Yuan CS. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010 Jan-Feb;35(1):64-101. doi: 10.1097/aap.0b013e3181c15c70.
PMID: 20052816
citation: Henshaw DS, Turner JD, Forest DJ, Thompson GR, Weller RS. Residual Enoxaparin Activity, Anti-Xa Levels, and Concerns About the American Society of Regional Anesthesia and Pain Medicine Anticoagulation Guidelines. Reg Anesth Pain Med. 2017 Jul/Aug;42(4):432-436. doi: 10.1097/AAP.0000000000000617.
PMID: 28492441
responsible party type: Sponsor
mesh term: Hemostatic Disorders
mesh term: Blood Coagulation Disorders
mesh term: Enoxaparin
mesh term: Enoxaparin sodium
sharing ipd: No
provided document: 
submitted: March 9, 2023
returned: April 6, 2023
submitted: May 8, 2023
returned: June 6, 2023
submitted: July 17, 2023
returned: August 3, 2023
submitted: September 8, 2023