Underdosing of Prophylactic Enoxaparin Is Common in Orthopaedic Trauma and Predicts 90-Day Venous Thromboembolism

Abstract

Objectives: To determine the feasibility and impact of real-time anti-factor Xa (aFXa) level monitoring and enoxaparin dose adjustment in orthopaedic trauma. To examine the adequacy of standard fixed-dose enoxaparin chemoprophylaxis and to examine whether patient-specific factors influence enoxaparin metabolism. Design: Prospective cohort. Setting: Academic Level-I trauma center. Patients: Postoperative adult orthopaedic trauma patients undergoing acute fracture or nonunion surgery of the pelvis, acetabulum, or lower extremity placed on 30 mg of enoxaparin twice daily. Intervention: Peak steady-state aFXa levels were drawn with a goal range of 0.2–0.4 IU/mL. Patients with out-of-range levels underwent a 10-mg dose adjustment followed by repeat aFXa draws. Main Outcome Measures: Peak and trough aFXa levels, 90-day venous thromboembolism, and bleed events. Results: Of 109 enrolled patients, 43% had inadequate initial peak aFXa levels (aFXa < 0.2 IU/mL) with standard dosing. Higher gross weight, acetabular surgery, and operation length predicted low aFXa levels (P < 0.001, 0.006, 0.004, respectively). Dose adjustment increased the proportion of patients with in-range aFXa levels from 53.2% to 87.8% (P < 0.001). Patients with low aFXa levels during hospitalization or at discharge had significantly higher 90-day deep vein thrombosis and pulmonary embolism rates compared to those with adequate aFXa levels (deep vein thrombosis 12% vs. 1.36%; P = 0.023, pulmonary embolism 8% vs. 0%; P = 0.027). There were no major bleed events. Conclusions: Patients receiving inadequate enoxaparin chemoprophylaxis were at significantly increased risk of 90-day venous thromboembolism. Standard fixed-dose enoxaparin provided inadequate chemoprophylaxis in 43% of postoperative orthopaedic trauma patients, which significantly improved with dose adjustment. Weight, acetabular surgery, and operation length predicted inadequate enoxaparin prophylaxis. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Enoxaparin titrated by anti-Xa levels reduces venous thromboembolism in trauma patients

“…Similar to this study, it is likely that the majority of the literature examining differences in VTE rate based on chemoprophylaxis regimen is heterogenous due to underpowering of studies. 16,18,[20][21][22] This study has some additional noteworthy limitations. First, it is a single site, retrospective study which may limit generalizability.…”

“…Overall, the results support that using anti-Xa levels to guide LMWH dosing is effective in reducing the overall rate of VTE, consistent with much of the existing literature. 4,[16][17][18][19] Although this study involved thousands of patients, it was still limited by sample size. Because of the low incidence of PE events in the population, the sample size must be exceedingly large to detect small but potentially clinically significant differences.…”

Standard Fixed Enoxaparin Dosing for Venous Thromboembolism Prophylaxis Leads to Low Peak Anti-Factor Xa Levels in Both Head and Neck and Breast Free Flap Patients

“…Subtherapeutic afXa levels have been reported in various patient populations with fixed-dose enoxaparin regimens, calling for real-time adjustments. 25 27 Another strategy is the implementation of a weight-based approach to improve outcomes. In our study, TBW, or alternatively BMI, was found to be a significant predictor of afXa level after controlling for case type (H&N vs. breast), enoxaparin regimen, gender, comorbidities, and surgery time; in short, the greater the TBW or BMI, the lower the afXa level.…”

Optimal Dosing of Prophylactic Enoxaparin after Surgical Procedures: Results of the Double-Blind, Randomized, Controlled FIxed or Variable Enoxaparin (FIVE) Trial

“…We found that weight-based enoxaparin (0.5 mg/kg twice daily) was not inferior to fixed-dose enoxaparin (40 mg twice daily) for avoidance of underanticoagulation, and that weight-based enoxaparin was superior to fixed-dose enoxaparin for avoidance of overanticoagulation. FIVE trial data have relevance beyond pharmacokinetic optimization, because studies in plastic surgery, 16 orthopedic surgery, 25,33 trauma surgery, 19,20,29 and surgical patients in general 34 have shown that inadequate anticoagulation significantly increases postoperative venous thromboembolism risk, and studies in orthopedic surgery have correlated high anti-factor Xa levels with increased risk for bleeding. 25 Our data are consistent with prior nonrandomized studies suggesting that weight-based enoxaparin dosing is pharmacokinetically superior to fixed-dose enoxaparin in surgical patients.…”

“…19 Our group's aggregate data from 577 surgical patients receiving twice-daily enoxaparin clearly show a significant increased risk for 90-day symptomatic venous thromboembolism in patients with low versus adequate peak anti-factor Xa levels (6.2 percent versus 1.5 percent; p = 0.003). 17,33,34,43 Whether these data are generalizable to all surgical patients is unknown. Arguably, the plastic and reconstructive surgery population is the ideal population on which to test concepts for surgical patients in general, as plastic surgery inpatients represent a cross-section of surgical patients.…”