Residual Anti-Xa Activity After Last Treatment Dose of Enoxaparin

Evaluation of Residual Anti-Xa Activity As A Function Of Time Following The Last Treatment Dose of Enoxaparin In Patients Presenting For Elective Surgery

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 0.2 international unit per milliliter (IU/mL) in patients presenting for elective surgery.

Study Overview

• Status: Terminated
• Conditions: Surgery; Regional Anesthesia Morbidity; Anticoagulants and Bleeding Disorders
• Intervention / Treatment: Drug: Enoxaparin; Drug: Enoxaparin

Detailed Description

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 parameters, 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.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

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 anti-Xa inhibiting medication will be excluded as this could unpredictably affect the results of anti-Xa testing. These medications include: Apixaban, Edoxaban, Fondaparinux, and Xarelto.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 24 Hours group; 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.	Drug: Enoxaparin; 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.; Other Names: Lovenox; Drug: Enoxaparin; 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); Other Names: Lovenox
Experimental: 36 Hours Group; 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.	Drug: Enoxaparin; 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.; Other Names: Lovenox; Drug: Enoxaparin; 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); Other Names: Lovenox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Residual Anti-Xa Activity Levels Following Last Treatment Dose of Enoxaparin	Anti-Xa level activity will be measured in both groups using a chromogenic assay and a hybrid curve calibrated to both heparin and enoxaparin.	Time Frame: 24 hours or 36 hours (based on randomization) after the last treatment dose of enoxaparin. Actual lab draw will vary, as planned, given surgical arrival time.
Time Point at Which Anti-Xa Activity is Lower Than 0.2 International Unit Per Milliliter (IU/mL) Using Modeling	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 0.2 IU/mL.	Time Frame: 24 hours or 36 hours (based on randomization) after the last treatment dose of enoxaparin. Actual lab draw will vary, as planned, given surgical arrival time.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relationship Between Anti-Xa Levels and Patient Age	Analyze and determine the best-fit function (beta and standard error) for anti-Xa activity level activity (IU/mL) to determine if there is a significant association between anti-Xa activity at the time of presentation and patient age (years). Individual patient characteristics were assessed to determine their impact on the odds of success, defined as an anti-Xa level of <0.2IU/mL. Patient characteristics assessed included age, sex, renal function (calculated by Cockcroft-Gault and modified Cockcroft-Gault formulae), and body mass index (BMI), the latter of which was assessed post-hoc. Odds ratios were calculated with both groups combined, as time from last dose varied and even overlapped between groups, which was expected/anticipated as part of the study design. All patient characteristics were analyzed using three separate time intervals from last dose (<24-hours, 24-hours through 35.9-hours, and >36-hours).	Anti-Xa levels were measured at the time of presentation for surgery. Age was collected at the time of enrollment.
Relationship Between Anti-Xa Levels and Patients Gender (Sex)	Analyze and determine the best-fit function (beta and standard error) for anti-Xa activity level activity (IU/mL) to determine if there is a significant association between anti-Xa activity at the time of presentation and (gender= male or female). Individual patient characteristics were assessed to determine their impact on the odds of success, defined as an anti-Xa level of <0.2IU/mL. Patient characteristics assessed included age, sex, renal function (calculated by Cockcroft-Gault and modified Cockcroft-Gault formulae), and body mass index (BMI), the latter of which was assessed post-hoc. Odds ratios were calculated with both groups combined, as time from last dose varied and even overlapped between groups, which was expected/anticipated as part of the study design. All patient characteristics were analyzed using three separate time intervals from last dose (<24-hours, 24-hours through 35.9-hours, and >36-hours).	Anti-Xa levels were measured at the time of presentation for surgery. Gender was collected at the time of enrollment.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relationship Between Anti-Xa Levels and Patient Renal Function	Analyze and determine the best-fit function (beta and standard error) for anti-Xa activity level activity (IU/mL) to determine if there is a significant association between anti-Xa activity at the time of presentation and renal function. Individual patient characteristics were assessed to determine their impact on the odds of success, defined as an anti-Xa level of <0.2IU/mL. Patient characteristics assessed included age, sex, renal function (calculated by Cockcroft-Gault and modified Cockcroft-Gault formulae), and body mass index (BMI), the latter of which was assessed post-hoc. Odds ratios were calculated with both groups combined, as time from last dose varied and even overlapped between groups, which was expected/anticipated as part of the study design. All patient characteristics were analyzed using three separate time intervals from last dose (<24-hours, 24-hours through 35.9-hours, and >36-hours).	Anti-Xa levels were measured at the time of presentation for surgery as was glomerular filtration rates, which were used to calculate creatinine clearance.

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Investigators: Principal Investigator: Daryl S Henshaw, MD, Wake Forest University Health Sciences

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2017
• Primary Completion (Actual): January 14, 2022
• Study Completion (Actual): January 14, 2022

Study Registration Dates

• First Submitted: July 6, 2017
• First Submitted That Met QC Criteria: September 26, 2017
• First Posted (Actual): September 28, 2017

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: September 8, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: thromboembolism; coagulation; enoxaparin; factor Xa
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Blood Coagulation Disorders; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin; Enoxaparin sodium
• Other Study ID Numbers: IRB00044503

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No