|Principal Investigator: CHRISTOPHER PANNUCCI|
|Keywords: Enoxaparin , Metabolism , Plastic Surgery , Clot , Embolism , Anti-factor Xa||Department: Plastic & Reconstruct Surgery|
|IRB Number: 00086052|
|Specialty: Plastic Surgery|
|Recruitment Status: Recruiting|
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 trauma and burn patients 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. Patients at highest VTE risk in reconstructive surgery include those having cancer and trauma reconstruction, which typically involves multiple-site surgery; this creates a surgical injury equivalent to a moderate size thermal or traumatic injury. Our prior work has demonstrated that one in 25 highest risk reconstructive surgery patients have a VTE event despite enoxaparin prophylaxis. We believe that reconstructive surgery patients, particularly those with large total body surface area injured, are more similar to trauma and burn patients than previously recognized.
This project will critically examine the pharmacokinetics of prophylactic doses of enoxaparin after major reconstructive surgery, 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.
Aim 1: To examine the association between twice-daily enoxaparin dosing and peak and trough steady-state aFXa levels in reconstructive surgery patients.
Rationale: Current plastic surgery literature and American Society of Plastic Surgeons guidelines support enoxaparin doses of 40mg daily. Our preliminary data demonstrate low aFXa peak and trough levels in 74% and 68% of patients, respectively. This aim will examine the role of dose frequency on peak and trough aFXa levels.
Hypothesis: Twice-daily enoxaparin dosing will increase the proportion of in-range initial peak aFXa levels from 26% to 50%, and the proportion of in-range initial trough aFXa levels from 32% to 50%.
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 50% to 80%.
Aim 3: To examine the association between twice-daily enoxaparin dosing 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 frequency for enoxaparin prophylaxis carries a theoretic risk of bleeding due to drug accumulation.
Hypothesis: Twice-daily enoxaparin dosing will not be associated with a clinically relevant (>5.0%) increase in re-operative hematoma from the expected baseline rate of 3.4%.
Inclusion criteria will include adult (age≥18) patients who have reconstructive surgery. 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 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 eligible for enrollment.
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, or epidural anesthesia.