Real-time anti-Factor Xa measurements in surgical patients to examine enoxaparin metabolism and optimize enoxaparin dose

Principal Investigator: CHRISTOPHER  PANNUCCI
Keywords: Enoxaparin , Anti-Factor Xa , Dose optimization , Thrombosis Department: Plastic & Reconstruct Surgery
IRB Number: 00086103 Co Investigator:  
Specialty: Plastic Surgery
Sub Specialties:
Recruitment Status: Active, not recruiting

Contact Information

Kory Fleming
kory.fleming@hsc.utah.edu
8015816501

Brief Summary

a. SPECIFIC AIMS (Items a-d not to exceed 6 pages)

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 our group and others has shown that 2-10% of highest risk surgical patients have a VTE event despite enoxaparin prophylaxis.  We believe that surgical patients would benefit from an individualized dosing regimen for enoxaparin prophylaxis and that optimized dosing might ultimately decrease observed rates of post-operative VTE.

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.

 

Aim 1: To examine the association between standard enoxaparin dosing and peak and trough steady-state aFXa levels in surgical patients.

Rationale: Current specialty guidelines support a “one size fits all” approach to enoxaparin prophylaxis.  Our preliminary data demonstrate low aFXa peak and trough levels in 50% and 47% of patients, respectively.  This aim will examine the role of dose magnitude and frequency on peak and trough aFXa levels.

Hypothesis: Initial peak and trough aFXa levels will be lower than the accepted prophylactic range in 50% of surgical patients.

Aim 2: To examine response of aFXa levels to a protocol-driven dose adjustment regimen

Rationale: Our preliminary work shows that aFXa levels in response to standard enoxaparin dosing varies widely between patients.  This aim examines whether a clinical protocol for dose adjustment can optimize aFXa levels.

Hypothesis: Protocol-driven enoxaparin dose adjustment in response to aFXa levels will increase the proportion of patients with appropriate aFXa peak levels from 50% to 80% and aFXa trough levels from 47% to 80%.

Aim 3: To examine the association between enoxaparin dose adjustment and risk for bleeding requiring an unplanned operative procedure.

Rationale: Bleeding risk is a major driver in a surgeon’s decision to not provide chemoprophylaxis.  Escalation of dose magnitude for enoxaparin prophylaxis carries a theoretic risk of bleeding due to drug accumulation. 

Hypothesis: Dose adjustment using a clinical algorithm will not be associated with a clinically relevant (>4.0%) increase in re-operative hematoma from the expected baseline rate of 2.1%.

 

Inclusion Criteria

We have assembled a consortium of surgeons at the University of Utah to create a representative and well-rounded cohort of surgical patients.  Surgeons from general surgery, thoracic surgery, vascular surgery, surgical oncology, urologic surgery, plastic and reconstructive surgery, burn surgery, orthopedic surgery and minimally invasive & bariatric surgery will contribute patients to this study.  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, but will identify patients already on enoxaparin and adjust their dose if necessary based on steady-state aFXa levels

Inclusion criteria will include adult (age≥18) patients who have surgery under general anesthesia.  Expected post-operative stay will be ≥2 days to allow for peak and trough aFXa levels to be drawn after the third dose.  Enoxaparin metabolism and aFXa levels are plausibly independent from baseline VTE risk level.  Thus, all patients (not just those at high VTE risk using the 2005 Caprini score) will be eligible for enrollment.

Exclusion Criteria

Exclusion criteria will include contraindication to use of enoxaparin, intracranial bleeding/stroke, hematoma or bleeding disorder, heparin-induced thrombocytopenia positive, creatinine clearance ≤ 30mL/min, serum creatinine >1.6mg/dL, and epidural catheter.