Real-time Anti-Factor Xa Measurements in Surgical Patients to Examine Enoxaparin Metabolism and Optimize Enoxaparin Dose

Venous thromboembolism (VTE) encompasses deep venous thrombosis and pulmonary embolus, and is the proximate cause of death in over 100,000 hospitalized patients per year.

This project will critically examine the pharmacokinetics of prophylactic doses of enoxaparin in surgical patients, and will evaluate how alteration of enoxaparin dose magnitude and frequency affects peak and trough aFXa levels as well as risk for re-operative hematoma. If subtherapeutic aFXa levels are observed, the study will design, implement and test a clinical protocol to optimize post-operative aFXa levels. Although not an explicit Aim, this study will also provide important preliminary data on VTE rates in surgical patients with in range and out of range aFXa levels.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism; Deep Venous Thrombosis; Pulmonary Embolus
• Intervention / Treatment: Drug: Standard enoxaparin dose; Drug: Real time enoxaparin dose adjustment

Detailed Description

Venous thromboembolism (VTE) encompasses deep venous thrombosis and pulmonary embolus, and is the proximate cause of death in over 100,000 hospitalized patients per year. To put this in better context, VTE kills more people each year than the annual morbidity from motor vehicle crashes and breast cancer combined. Surgeons commonly provide enoxaparin, a low molecular weight heparin, for VTE prophylaxis. Enoxaparin's activity is quantified by anti-Factor Xa (aFXa) levels. Studies of enoxaparin metabolism in patients with traumatic injury, thermal injury, or those undergoing reconstructive surgery have shown that standard dosing can result in inadequate aFXa levels, likely from the hypermetabolic state associated with significant injury. Small studies have associated subtherapeutic aFXa levels with increased risk for life or limb-threatening VTE events. Prior work from has shown that 2-10% of highest risk surgical patients have a VTE event despite enoxaparin prophylaxis. The investigators believe that surgical patients would benefit from an individualized dosing regimen for enoxaparin prophylaxis and that individualized dosing will decrease observed rates of life or limb-threatening post-operative VTE events.

This project will critically examine the pharmacokinetics of prophylactic doses of enoxaparin in surgical patients, and will evaluate how alteration of enoxaparin dose magnitude and frequency affects peak and trough aFXa levels as well as risk for re-operative hematoma. If subtherapeutic aFXa levels are observed, the study will design, implement and test a clinical protocol to optimize post-operative aFXa levels. Although not an explicit Aim, this study will also provide important preliminary data on VTE rates in surgical patients with in range and out of range aFXa levels.

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults, (age≥18)
• Patients who have had surgery with general anesthesia.
• Post-operative stay will be ≥2 days

Exclusion Criteria:

• Contradiction to use enoxaparin
• History of intracranial bleeding/stroke, hematoma or bleeding disorder, heparin-induced thrombocytopenia positive, and heparin-induced thrombocytopenia positive
• Creatinine clearance ≤ 30mL/min
• Serum creatinine >1.6mg/dL
• Epidural anesthesia
• Patients placed on non-enoxaparin chemoprophylaxis regimens per their surgeon's discretion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard enoxaparin dose; We will identify a convenience sample of surgical patients placed on enoxaparin prophylaxis at their attending surgeon's discretion-the proposed research will not dictate the initial enoxaparin dose magnitude or frequency. However, we will identify patients already on enoxaparin, evaluate peak and trough steady state aFXa levels, and adjust patient's dose if necessary based on steady state aFXa levels. Eligible patients will have enoxaparin prophylaxis started within 36 after surgery at their surgeon's discretion. Steady state peak and trough aFXa levels will be drawn at 4 and 12 hours, respectively, after the third enoxaparin dose. Goal peak aFXa levels will be 0.2-0.4 IU/mL for twice daily dosing and 0.3-0.5 IU/mL for once daily dosing.	Drug: Standard enoxaparin dose; Patients will be placed on enoxaparin prophylaxis per their surgeon's discretion.
Experimental: Real time enoxaparin dose adjustment; Patients with identified out of range levels will receive pharmacist-driven real time enoxaparin dose adjustment and will receive followup steady state peak and trough aFXa levels. aFXa monitoring will be discontinued when in range peak levels are obtained, when enoxaparin prophylaxis is discontinued at surgeon discretion, or when the patient is discharged. Patients may be continued on enoxaparin prophylaxis after discharge per attending surgeon discretion but aFXa levels will not be followed in the outpatient environment.	Drug: Real time enoxaparin dose adjustment; Patients will have steady state peak and trough anti-Xa levels drawn after their third enoxaparin dose. Patients with out of range peak anti-Xa levels will receive real time enoxaparin dose adjustment followed by repeat peak and trough anti-Xa levels.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Venous thromboembolism	Symptomatic 90-day VTE confirmed with imaging	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Re-operative hematoma	Bleeding requiring return to the operating room within 90 days	90 days

Collaborators and Investigators

• Sponsor: University of Utah
• Investigators: Principal Investigator: Christopher Puccini, MD, University of Utah

Publications and helpful links

General Publications

• Pannucci CJ, Fleming KI, Bertolaccini CB, Prazak AM, Huang LC, Pickron TB. Assessment of Anti-Factor Xa Levels of Patients Undergoing Colorectal Surgery Given Once-Daily Enoxaparin Prophylaxis: A Clinical Study Examining Enoxaparin Pharmacokinetics. JAMA Surg. 2019 Aug 1;154(8):697-704. doi: 10.1001/jamasurg.2019.1165.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: March 7, 2016
• First Submitted That Met QC Criteria: March 7, 2016
• First Posted (Estimate): March 9, 2016

Study Record Updates

• Last Update Posted (Actual): May 24, 2019
• Last Update Submitted That Met QC Criteria: May 21, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thrombosis; Venous Thrombosis; Thromboembolism; Venous Thromboembolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin; Enoxaparin sodium
• Other Study ID Numbers: IRB_00086103

Plan for Individual participant data (IPD)

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