Enoxaparin metabolism in reconstructive surgery patients

Principal Investigator: CHRISTOPHER  PANNUCCI
Keywords: Enoxaparin , Deep venous thrombosis , Pulmonary embolus , Venous thromboembolism , Metabolism Department: Plastic & Reconstruct Surgery
IRB Number: 00079118 Co Investigator:  
Specialty: Plastic Surgery, Plastic Surgery, Plastic Surgery, Plastic Surgery, Plastic Surgery, Plastic Surgery, Plastic Surgery, Plastic Surgery, Plastic Surgery, Plastic Surgery
Sub Specialties: Plastic Surgery, Cosmetic, Head and Neck Reconstruction, Microsurgery, Breast Surgery, Plastic Surgery, Hand Upper Extremity and Microvascular Surgery, Plastic Surgery, Facial, Trunk and Extremity Reconstruction, Flap Surgery, Wound Healing
Recruitment Status: Recruiting

Contact Information

CHRISTOPHER  PANNUCCI
christopher.pannucci@hsc.utah.edu
801 581 7719

Brief Summary

Venous thromboembolism (VTE) is an important patient safety issue in plastic and reconstructive surgery.  One in 12 patients characterized as highest risk will have a potentially life or limb-threatening VTE event when no prophylaxis is provided.  Current American Society of Plastic Surgeons recommendations for VTE prophylaxis are based heavily on publications from the Venous Thromboembolism Prevention Study (VTEPS).  VTEPS showed that post-operative, inpatient enoxaparin prophylaxis dosed at 40mg subcutaneously daily can significantly decrease VTE risk among high risk patients.  However, even when provided with this aggressive prophylaxis regimen, one in 25 highest risk patients still had a VTE event. Factors which contribute to this high residual risk remain to be elucidated.

In the clotting cascade, enoxaparin inhibits factor Xa and decreases conversion of prothrombin to thrombin; this, in turn, decreases likelihood that clot will form.  Enoxaparin’s activity is quantified by anti-factor Xa (aFXa) levels.  Studies of enoxaparin metabolism in trauma and burn patients have shown that standard dosing can result in inadequate aFXa levels.  This is believed to be due to the hypermetabolic state associated with significant injury.  Patients at highest VTE risk in plastic surgery include those having cancer and trauma reconstruction, which typically involves multiple-site surgery; this can create a surgical injury equivalent to a moderate size thermal or traumatic injury.  The goal of this project is to examine enoxaparin metabolism in major reconstructive surgery patients.  The data obtained from our study will critically examine the pharmacokinetics of accepted dosing for enoxaparin prophylaxis in the plastic surgery literature.  The proposed research will evaluate peak and trough aFXa levels with standard dosing after major reconstructive surgeries.  If subtherapeutic levels are observed, the study will also design, implement and test a clinical protocol to achieve appropriate post-operative aFXa levels. 

 

This proposal has the following specific aims:

 

Aim 1: To evaluate peak steady-state aFXa levels at four hours after the third dose of enoxaparin 40mg subcutaneously daily.

Rationale: Current plastic surgery literature and ASPS guidelines support enoxaparin doses of 40mg daily.  Literature in the trauma and burn population has shown that standard dosing can result in inadequate peak aFXa levels (<0.3IU/mL).  This aim will examine the role of dose magnitude on aFXa levels.

Hypothesis: Peak aFXa levels will be lower than the accepted range (0.3IU-0.5IU/mL) in 70% of patients at four hours after the third dose.

 

Aim 2: To evaluate aFXa levels at 12 hours after the third dose of enoxaparin 40mg subcutaneous daily

Rationale: Existing guidelines from the American Society of Plastic Surgeons recommend that enoxaparin be dosed at 40mg subcutaneously per day.  Studies in trauma and burn patients have shown unmeasurable aFXa levels at 12 hours in response to once-daily enoxaparin dosing; daily dosing may not provide adequate prophylaxis levels for a 24 hour period.  This aim will examine the effect of dose frequency on aFXa levels.

Hypothesis: Trough aFXa levels will be lower than the accepted range (0.3IU-0.5IU/mL) in 90% of patients at 12 hours after the third dose. 

 

Aim 3: To examine response of aFXa levels to a protocol-driven dose adjustment regimen

Rationale: Previous research has shown that a dose-adjustment algorithm, based on initial aFXa levels, can increase the proportion of patients with appropriate aFXa levels.  This aim will examine whether a clinical protocol for dose escalation can positively affect aFXa levels.

Hypothesis: Protocol-driven enoxaparin dose adjustment in response to initial aFXa levels will increase the proportion of patients with appropriate levels two-fold, from 30% to 60%.

Inclusion Criteria

Inclusion criteria will include adult (age ≥18) patients presenting for reconstructive surgery under general anesthesia.  Expected post-operative stay will be at least three days to allow peak aFXa levels to be drawn.  Eligible patients will include those having major reconstructive surgery involving at least two anatomically distinct sites (e.g. abdominal based breast reconstruction) or trauma patients having major reconstructive procedures (e.g. free flap coverage for a Gustillo 3B tibia fracture).  Enoxaparin metabolism and aFXa levels are likely related to degree of surgical injury, and 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 considered for enrollment.   

Exclusion Criteria

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