Evaluation of Residual Anti-Xa Activity As A Function Of Time Following The Last Treatment Dose of Enoxaparin In Patients Presenting For Elective Surgery
Phase: PHASE4
Conditions: Anticoagulants and Bleeding Disorders, Surgery, Regional Anesthesia Morbidity
Sponsor: Wake Forest University Health Sciences

Protocol version: 
Template updated 9.24.14 
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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 
 
NCT03296033 
 
Date  Document was IRB-Approved:   4/6/2020

Protocol version: 
Template updated 9.24.14 
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Study 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 
 
Principal Investigator: Daryl S. Henshaw, MD; Co-investigator(s): James Turner, MD; Dan Forest, 
MD; Robert S. Weller, MD;  
 
Sponsor or funding source: Department of Anesthesiology, Wake Forest University School of Medicine 
 
Background, Rationale and Context 
 
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.   
 
Objectives 
 
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.    
 
Methods and Measures 
 
Design 
• 
This is a randomized prospective observation trial.   
 
Setting 
• 
This study will be conducted at a single institution (Wake Forest Baptist Medical Center), 
which is an academic level-1 trauma center. 
 
Subjects selection criteria 

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Patients presenting for elective surgery who are either chronically on treatment-dose enoxaparin or 
who are being bridged with treatment-dose enoxaparin from another anticoagulant will be potentially 
recruited for this investigation.  
   
• 
Inclusion Criteria 
Eligible patients need to be on treatment dose (1mg/kg twice daily or 1.5mg/kg daily) 
enoxaparin at the time of presentation for elective surgery and must be able to accurately 
report the timing of their last dose and the administered dosage.  Patients must also be 
between the ages of 18-100 years of age and must be able to give written consent to 
participate.  Patients who are bridged with enoxaparin from one of the currently available oral 
Anti-Xa inhibitors (Abixaban [Eliquis], Edoxaban [Sayvasa], and Rivaroxaban [Xarelto]) will 
be eligible as long as the duration from their last oral Anti-Xa inhibitor dose to their date of 
surgery is at least 5 days (120-hours).   
• 
Exclusion Criteria 
Patients with severe renal insufficiency (creatinine clearance <30ml/min) will be excluded 
from the study, as the elimination of enoxaparin is known to be affected in this patient 
population.  Pregnant patients will also be excluded, as the elimination and metabolism of 
enoxaparin is known to be altered in this patient population, and dose adjustments are 
recommended if treatment dose enoxaparin is used during pregnancy.  Patients who are 
receiving enoxaparin as a bridge from another intravenous anti-Xa inhibiting medication will 
be excluded as this could unpredictably affect the results of anti-Xa testing.  These 
medications include: Fondaparinux. Patients who are on an oral Anti-Xa inhibitor (Abixaban 
[Eliquis], Edoxaban [Sayvasa], and Rivaroxaban [Xarelto]) will be excluded if the duration of 
time from their last dose to the date of surgery (i.e., the duration that they are bridged with 
enoxaparin) is less than 5 full days (120 hours).   .  
• 
Sample Size 
Historical data from a previous publication (which showed that at 24-hours 58% of patients 
had an anti-Xa level ≥ 0.2IU/mL) was used to conduct a power analysis. In this prior study, 
data points were collected between 23.25-hours and 32-hours, and anti-Xa levels ranged 
between 0 and 0.54IU/mL. Assuming a similar relationship between anti-Xa activity levels 
and time observed in the original study pertains to later times, simulations using a sample size 
of 150 patients resulted in a threshold of approximately 29-hours with 95% confidence limits 
of approximately 28-hours and 33-hours.  It was felt that a 5-hour window of the 95% 
confidence limit would provide acceptable guidance for clinical care. We expect some drop 
out and patient loss since some patients may have their surgical procedure cancelled 
following enrollment/randomization. In addition, occasionally the decision regarding the use 
of bridging therapy changes following a patient’s visit to the preoperative assessment clinic.  
Therefore, we plan to enroll upwards of 180 patients until 150 patients have completed the 
study and have their data available for analysis.  
 
Interventions and Interactions 
• 
Patients on treatment dose enoxaparin will be identified at the time of their preoperative 
anesthesia consultation.  These patients will be seen in the preoperative assessment clinic by a 
study team member and the study will be discussed with them at that time. 
• 
Patients may elect to consent during their preoperative anesthesia consultation visit, or if they 
would like to think it over and talk with family/friends, a study team member will follow-up 
with them by phone to answer further questions.  
• 
After consenting to the study, patients will be randomized to one of two groups.   
o 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 

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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.   
o 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.   
• 
All patients consented for the study will be called by a study team member or study 
coordinator two days before their surgical date to ensure they understand when they are 
supposed to self-administer their last dose of enoxaparin.  
• 
Upon arrival for surgery, all consented patients will have demographic information recorded 
(age, weight, gender) as well as the enoxaparin dosage and the timing of their last 
administration.   
• 
All patients in the study will have a blood sample drawn.  Two laboratory tests will be sent.  
1). Anti-Xa level assay (Heparin Assay) 
2). Basic Metabolic Panel (BMP) (for evaluation of creatinine). 
• 
When feasible, blood sampling will be performed at the same time that intravenous access for 
fluid/medication administration is obtained to minimize patient discomfort.   
• 
Anti-Xa level testing will be performed using a chromogenic assay and a hybrid 
heparin/enoxaparin curve (Biophen Heparin 6 kit). 
• 
The results of both of these tests will be collected from the electronic medical record after the 
results are posted.   
• 
Following collection of the blood samples, the patient’s participation in the study will be 
concluded.   
• 
The results of the anti-Xa level test will be shared with the patient and the risk-benefit 
decision of proceeding with neuraxial block (if indicated) will be left to the anesthesiologist 
of record.  
 
Outcome Measure(s) 
The primary outcome of the study is the measurement of anti-Xa activity levels following the last 
treatment dose of enoxaparin in patients presenting for elective surgery. Anti-Xa level activity will be 
measured using a chromogenic assay and a hybrid curve calibrated to both heparin and enoxaparin.  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.   
 
Secondary outcomes will include determining the relationship of anti-Xa level activity over time (by 
using curve fitting or best-fit function) as well as attempting to determine if there are any patient 
conditions or characteristics that can predict delayed clearance of enoxaparin (elevated anti-Xa levels).  
 
 
Analytical Plan 
For the primary analysis, logistic regression of success criterion (anti-Xa activity level < 0.2 IU/mL) and 
95% confidence limits at a success level (<0.2) of 95% likelihood will be utilized.  For secondary 
analyses we plan to describe the best-fit function for anti-Xa activity levels over time.  We also plan to 
explore clinical predictors for any anti-Xa activity levels > 1 standard deviation over the mean from the 
above function.   

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Human Subjects Protection 
 
Subject Recruitment Methods 
Patients on treatment dose enoxaparin will be identified at the time of their preoperative anesthesia 
consultation.  These patients will be seen in the preoperative assessment clinic by a study team member 
and the study will be discussed with them.  They will be given information related to the study (consent 
form). Patients may elect to consent to participation that day, or a study team member will follow-up with 
them by phone two days before their surgery to answer questions.  If they choose to participate at that 
time the consent paperwork will be completed the day of surgery, but they will be randomized and 
instructed on when to self-administer their last treatment dose of enoxaparin prior to surgery. 
 
Informed Consent 
Signed informed consent will be obtained from each subject.  Only providers listed as a primary or co-
investigator, study team member or study coordinator will obtain written informed consent.   
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy 
and confidentiality, only a unique study identifier will appear on the data collection form.  Any 
collected patient identifying information corresponding to the unique study identifier will be 
maintained on a linkage file, store separately from the data.  The linkage file will be kept secure, with 
access limited to designated study personnel.  Following data collection subject identifying 
information will be destroyed 3 years after closure of the study by shredding the documentation, 
consistent with data validation and study design, producing an anonymous analytical data set.  Data 
access will be limited to study staff.  Data and records will be kept locked and secured, with any 
computer data password protected.  No reference to any individual participant will appear in reports, 
presentations, or publications that may arise from the study. 
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study staff. 
 
The cost of both laboratory tests (anti-Xa level and BMP) will not be billed to the patient.  These 
costs will be covered by the study sponsor (Department of Anesthesiology).   
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB and sponsor or appropriate government agency if appropriate. 
 
References 
1. Horlocker T, et al.  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; 35:64-101. 
 
2. Gulur P, Tsui B, Pathak R, Koury M, Lee H. Restrospective analysis of the incidence of epidural 
haematoma in patients with epidural catheters and abnormal coagulation parameters.  Br J of 
Anaesth 2015; 114 (5): 808-11.   
 

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Appendix 
1. Data collection form 
2. Consent form