Venous thromboembolism, including deep venous thrombosis and pulmonary embolus, is a major patient safety issue among plastic surgery patients.1–7 Venous thromboembolism kills over 100,000 hospitalized patients every year. Ten percent of patients who present with symptomatic pulmonary embolus will die within 1 hour, and the 3-month mortality of those who survive the acute event approaches 20 percent.8,9 To put this in better context, venous thromboembolism kills more people each year than the combination of breast cancer and motor vehicle accidents.10,11 Surgeons commonly provide mechanical and chemical prophylaxis in an attempt to minimize risk for postoperative venous thromboembolism.
The Plastic Surgery Foundation–funded Venous Thromboembolism Prevention Study showed that a 14-fold variation in venous thromboembolism risk exists among the overall plastic surgery population, and that patients with Caprini scores greater than or equal to 7 receive significant venous thromboembolism risk reduction when postoperative enoxaparin is provided.12–17 However, a substantial proportion of patients in this study had venous thromboembolism events despite this aggressive prophylaxis strategy. Specifically, 4 percent of patients in the highest risk (Caprini score >8) group had a 60-day venous thromboembolism event while receiving daily enoxaparin doses of 40 mg. Although less common, venous thromboembolism occurred in patients at all risk levels of Caprini risk despite enoxaparin prophylaxis. At present, we cannot explain why enoxaparin prophylaxis is ineffective for some patients, and why “breakthrough” events occur despite rigorous compliance with existing guidelines.1,18 This gap in knowledge has important ramifications for patient care and for patient safety after plastic and reconstructive surgery.
The mechanisms of action of enoxaparin is inhibition of factor Xa, a critical downstream component of the clotting cascade. Factor Xa normally converts prothrombin to thrombin, which permits clot to form. Through inhibition of factor Xa, enoxaparin decreases the likelihood of clot formation. The anti–factor Xa level can be used as a marker of enoxaparin activity.19,20 Peak anti–factor Xa level, determined at 4 hours after subcutaneous injection, is the most accurate marker of enoxaparin activity and safety.19,21 Established data from the Venous Thromboembolism Prevention Study and established recommendations from the American Society of Plastic Surgeons and American Association of Plastic Surgeons consensus guidelines support the clinical effectiveness and safety of once-daily enoxaparin dosing.1,12,13,18 However, data from patients with critical illness and thermal injury support that once-daily enoxaparin dosing is insufficient among the overall population,22–24 with only 21 to 35 percent of patients having an acceptable initial steady-state anti–factor Xa level.25–28 This is particularly relevant because, in other surgical populations, inadequate initial peak anti–factor Xa levels have been significantly associated with asymptomatic deep venous thrombosis.19,29,30
We studied the pharmacodynamics of enoxaparin provided at 40 mg/day in a convenience sample of plastic surgery inpatients. We hypothesized that (1) extent of surgical injury, among other patient-level factors, would predict enoxaparin metabolism; (2) inadequate enoxaparin dosing, identified by low anti–factor Xa levels, would predict patients with “breakthrough” venous thromboembolism events; and (3) real-time enoxaparin dose adjustment would substantially increase the proportion of patients with in-range peak anti–factor Xa levels without altering rates of clinically relevant bleeding.
PATIENTS AND METHODS
This study was funded through the Plastic Surgery Foundation’s National Endowment for Plastic Surgery grant mechanism. The study received approval from the University of Utah Institutional Review Board (IRB_00079118). Eligible plastic surgery patients were adults (age 18 years or older) admitted after surgery and placed on enoxaparin prophylaxis dosed at 40 mg/day, started 6 to 12 hours after their procedure. Admission greater than or equal to 3 days postoperatively allowed peak and trough steady-state anti–factor Xa levels to be determined. Prior studies have demonstrated that enoxaparin metabolism and anti–factor Xa levels may be related to extent of injury, and are plausibly independent from baseline venous thromboembolism risk level. Thus, all patients (not just those at high venous thromboembolism risk using the 2005 Caprini score17) were considered for enrollment. Exclusion criteria were contraindication to use of enoxaparin, intracranial bleeding and/or stroke, known bleeding disorder, known heparin-induced thrombocytopenia, creatinine clearance less than or equal to 30 ml/minute, serum creatinine greater than 1.6 mg/dl, or epidural anesthesia. All patients received mechanical prophylaxis with sequential compression devices initiated in the operating room, with the exception of patients undergoing bilateral lower extremity procedures. Sequential compression devices were used after surgery whenever the patient was in bed, and were removed for ambulation. Early ambulation was encouraged. As extent of mobility and ambulation is fluid, we could not reliably quantify postoperative mobility.
Eligible patients were approached by the principal investigator (C.J.P.) or the study research coordinator (K.I.F.) and informed consent for participation was obtained. The clinical pathway in Figure 1 was designed in concert with a clinical pharmacist (M.G.), based on our institution’s experience with real-time anti–factor Xa level measurement and dose adjustment.23,25–27 For once-daily enoxaparin dosing, peak anti–factor Xa levels of 0.3 to 0.5 IU/ml and trough levels of 0.1 to 0.2 IU/ml are considered adequate.21,31–33 Anti–factor Xa assay results were available within 2 hours, allowing for real-time dose adjustment. The lower margin of the test’s discrimination is 0.10 IU/ml; levels less than 0.10 IU/ml are reported as zero.
Enrolled patients had peak and trough anti–factor Xa levels determined at 4 and 12 hours after the third enoxaparin dose, respectively. Acceptable levels were determined within a 1-hour range of the planned time point. Patients with out-of-range peak anti–factor Xa levels received real-time enoxaparin dose adjustment based on the pathway in Figure 1. Dose adjustments were made until in-range steady-state peak anti–factor Xa levels were documented or until patients were discharged. Postdischarge enoxaparin was provided at the attending physician’s discretion. However, anti–factor Xa levels were determined during the inpatient stay only.
We prospectively identified patient demographics and comorbid conditions using a chart review and face-to-face patient interviews. Baseline venous thromboembolism risk was quantified using a 2005 Caprini score. The primary surgeon identified the extent of surgical injury, recorded as a percentage of total body surface area with surgical injury, using a Lund Brower chart (Fig. 2). Prior studies in patients with thermal injury have shown a linear correlation between total body surface area burned and enoxaparin metabolism.25
Study outcomes included 90-day symptomatic venous thromboembolism events, including deep venous thrombosis or pulmonary embolus. All events required documentation using duplex ultrasound or pulmonary embolus protocol computed tomographic scan. Patients were not routinely screened for asymptomatic deep venous thrombosis using duplex ultrasound. We tracked 90-day bleeding events requiring alteration in the course of care. These included cessation of enoxaparin prophylaxis, percutaneous drainage procedures, and/or return to the operating room for hematoma evacuation. Study personnel made contact with all patients at 90 days after surgery to identify outcome events that were diagnosed or managed at other institutions. Contact was by means of a direct telephone conversation with the patient or a certified letter.
Data Management and Analysis Plan
Study data were warehoused using the secure, Web-based Research Electronic Data Capture (REDCap) platform hosted at the University of Utah.34 Data were analyzed using the Stata 14 statistical package (StataCorp, College Station, Texas), with assistance from Gregory Stoddard, codirector of the University of Utah Study Design and Biostatistics Center.
We generated descriptive statistics on the proportion of patients with in-range steady-state anti–factor Xa levels at the 4- and 12-hour time points. Bivariate statistics including t test, chi-square test, and Fisher’s exact test were used to examine associations between patient-level factors such as total body surface area with surgical injury and gross weight with in- versus out-of-range levels, with a value of p ≤ 0.05 being considered significant. Linear regression identified independent predictors of peak anti–factor Xa level, when controlling for confounding variables. Ninety-day venous thromboembolism was compared between patients with low and in-range anti–factor Xa. This comparison was performed using a survival time analysis (survival analysis log-rank test), which considered whether patients had an event and when within the 90-day follow-up period this event occurred. Survival time analysis also allowed inclusion of patients who were lost to follow-up. The censoring rate of the survival analysis was 3.6 percent, including three no–venous thromboembolism patients who were lost to follow-up on postoperative days 7, 15, and 20.
The proportion of patients with in-range steady-state anti–factor Xa levels before and after dose adjustment were compared using the chi-square test. Not all patients who had real-time dose adjustment had follow-up anti–factor Xa levels because some patients were discharged before steady state was reached.
Sample Size Calculations
No sample size calculation was performed for the proportion of patients with in- versus out-of-range levels in response to standard dosing, as this portion of the study was observational. Studies in the trauma and burn literature have suggested that 21 to 34 percent of patients treated with standard enoxaparin prophylaxis have appropriate initial peak anti–factor Xa levels, and that protocol-driven dose escalation can double the proportion of in-range patients.24,26 For the dose-adjustment portion of the study, we assumed an initial proportion of in-range patients of 30 percent and a post–dose escalation proportion of in-range patients of 60 percent. With an alpha of 0.05 and beta of 0.9, 26 patients with pre–dose adjustment and post–dose adjustment levels were needed. There are limited data on 12-hour trough levels with daily enoxaparin administration, especially as twice-daily dosing is more common in trauma and burn populations. One study had suggested that 6 percent of patients were in range at 12 hours with daily dosing.35 No sample size calculation was performed for this portion of the study.
One hundred eleven eligible and unique patients were identified and approached between March 15, 2015, and March 14, 2016. One hundred ten of 111 eligible patients (99.1 percent) with whom the study was discussed consented to participate. Sixteen patients were discharged before their third enoxaparin dose and were excluded. Study recruitment was 99.1 percent and study retention was 85.5 percent.
Usable data were available for 94 unique patients. Patients were representative of those commonly cared for at the University of Utah and received a diverse range of surgical procedures (Table 1). Two deaths occurred within 90 days of surgery. One patient died as a result of causes not related to venous thromboembolism on postoperative day 30. A second patient had a deep venous thrombosis diagnosed on postoperative day 4 and died as a result of causes not related to venous thromboembolism on postoperative day 81. Three patients were lost to follow-up. Ninety-day follow-up was available for 94.7 percent of patients.
Enoxaparin Pharmacodynamics and Venous Thromboembolism
Steady-state levels were determined outside the 1-hour window for four peak and six trough anti–factor Xa levels. Two laboratory draws were missed because of patient refusal. Two patients had bleeding events before anti–factor Xa levels were determined. Patients with out-of-range levels or missing levels were dropped from relevant analyses. Of 184 scheduled laboratory draws for initial steady-state levels, 172 (93.4 percent) resulted in usable data.
Eighty-eight patients had appropriately determined peak steady-state anti–factor Xa levels. Among the overall population, 44.3 percent of patients (n = 39) had an in-range peak anti–factor Xa level in response to a dose of 40 mg/day (Fig. 3). Patients with higher gross weight or larger total body surface area with surgical injury were more likely to have low anti–factor Xa levels (Figs. 3 and 4 and Table 2). Linear regression demonstrated that when controlling for age, sex, height, current smoking, Caprini score greater than or equal to 7, and baseline creatinine, gross weight and total body surface area with surgical injury were each independent predictors of peak steady-state anti–factor Xa levels (Table 3).
Five venous thromboembolism events were diagnosed among the overall patient cohort, including four deep venous thromboses and one pulmonary embolus (Table 4). All five events occurred in patients with low peak anti–factor Xa level; 10.2 percent of patients with low anti–factor Xa had a postoperative venous thromboembolism event, as compared to 0 percent of patients with in-range or high anti–factor Xa level. Survival time analysis demonstrated a significant association between low anti–factor Xa level and 90-day venous thromboembolism (p = 0.041) (Fig. 5).
Eighty-five patients had appropriately determined trough steady-state anti–factor Xa levels. Among the overall population, 41.2 percent of patients had a detectable trough anti–factor Xa level at 12 hours after administration (Fig. 6). Thus, with once-daily dosing, 58.8 percent of patients have no detectable effect of chemoprophylaxis for at least 12 hours/day.
Enoxaparin Pharmacodynamics and Bleeding
Three bleeding events occurred among 94 enrolled patients (Table 4). The observed rate of bleeding changing the course of care (including discontinuation of enoxaparin) was 3.2 percent (n = 3). One patient had bleeding at the surgical site requiring percutaneous drainage; this patient had low peak and trough anti–factor Xa levels throughout her hospital stay. One patient had decreased hematocrit and low urine output with presumed presacral bleeding after a combined procedure. No patient was returned to the operating room for hematoma drainage at their plastic surgery site, although one patient required exploratory laparotomy and Graham patch for upper gastrointestinal tract bleeding during their medical intensive care unit stay.
Real-Time Dose Adjustment
Fifty-one patients administered 40 mg of enoxaparin once per day had initial steady-state peak anti–factor Xa levels that were out of range, including 49 patients with low anti–factor Xa levels and two patients with high anti–factor Xa levels. All patients had real-time enoxaparin dose adjustment and 22 patients had at least one repeated peak anti–factor Xa level determined. Fifteen patients had in-range peak anti–factor Xa on enoxaparin 50 mg once daily, two patients had in-range peak anti–factor Xa on enoxaparin 60 mg once daily, and five were discharged before an in-range level occurred. A significantly higher proportion of patients had in-range peak anti–factor Xa during their hospitalization with real-time dose adjustment than with standard dosing alone (67.1 percent versus 44.3 percent; p = 0.002). Among 18 patients who had at least one post–dose adjustment anti–factor Xa trough level determined, four had an in-range anti–factor Xa trough level.
This study directly challenges current dogma surrounding venous thromboembolism prophylaxis—that a “one-size-fits-all” approach using inpatient enoxaparin dosed at 40 mg/day subcutaneously is appropriate for all patients. Prior work from the Venous Thromboembolism Prevention Study showed that one in 25 highest risk patients had a venous thromboembolism event despite receiving fixed-dose enoxaparin prophylaxis. These “breakthrough” events were most common in highest risk patients, as identified by Caprini score. However, it is noteworthy that breakthrough events occurred in patients at all Caprini risk levels. Data from this prospectively conducted clinical trial demonstrate that patient-level factors, including both total body surface area with surgical injury and gross weight, can preemptively identify patients likely to be underdosed using a standard enoxaparin regimen of 40 mg once per day. This is relevant because patients who receive inadequate enoxaparin doses were significantly more likely to have postoperative venous thromboembolism than patients whose dose was adequate (10.2 percent versus 0 percent; p = 0.041).
The utility of real-time anti–factor Xa monitoring and dose adjustment has been shown in the critical care and trauma populations and in patients with thermal injury.24–26 This study is novel because it extrapolates core principles learned in other surgical disciplines—that enoxaparin metabolism depends on patient-level factors, and that metabolism may be altered by injury severity (whether traumatic, thermal, or surgical)—to the plastic surgery population. Three prior studies in orthopedics, trauma, and patients with critical illness have associated low anti–factor Xa levels with deep venous thrombosis.19,29,30 It is noteworthy, however, that all three studies screened asymptomatic patients for deep venous thrombosis using venography or duplex ultrasound. At present, the clinical significance of asymptomatic deep venous thrombosis remains unknown, and current American College of Chest Physicians guidelines do not support screening, even among high-risk patients.36 In contrast, this study associates inadequate enoxaparin dosing with the more clinically relevant outcome of symptomatic venous thromboembolism, identified using patient signs and symptoms instead of screening studies.
This study further demonstrates that a one-size-fits-all approach to venous thromboembolism prevention is probably not in the best interest of plastic surgery patients. Prior work14 has identified a 14-fold variation in venous thromboembolism risk among the overall population of plastic surgery patients, and current guidelines from both the American Society of Plastic Surgeons and the American Association of Plastic Surgeons recommend a risk-stratified approach to venous thromboembolism prophylaxis using the 2005 Caprini score. Data from this study show that patient-level factors can be used to identify patients likely to receive inadequate prophylaxis with standard enoxaparin doses. These data, considered as a whole, provide reasonable evidence that a “group” approach to venous thromboembolism prevention is not best for our patients—consideration of the patient as an individual, instead of part of the aggregate, should guide our decision-making process as we consider both baseline risk and the optimal venous thromboembolism prevention strategy. Current American Society of Plastic Surgeons guidelines recommend consideration of venous thromboembolism chemoprophylaxis for high-risk patients, identified using procedure type or Caprini score, and current American Association of Plastic Surgeons guidelines recommend consideration of venous thromboembolism chemoprophylaxis for patients with Caprini scores greater than 8. When surgeons choose to provide enoxaparin chemoprophylaxis to these high-risk patient groups, real-time anti–factor Xa level monitoring and enoxaparin dose adjustment may provide augmented venous thromboembolism risk reduction when compared to a fixed-dose regimen.
Care individualization is not unique to plastic surgery, nor are we the only group studying this phenomenon—the White House recently announced the Precision Medicine Initiative, a $215 million project administered by means of the National Institutes of Health’s Precision Medicine Initiative Cohort Program. This study will enroll a cohort of 1 million people to study patient-level variation as a predictor of outcomes.37,38 A precision approach, guided by the individual instead of the aggregate, will tailor treatment to the individual and will ultimately optimize the patient’s risk-to-benefit relationship.
This study was designed prospectively and free of commercial bias from industry funding. However, this study does have limitations worth mentioning. These data demonstrate a significant association between inadequate enoxaparin dosing and downstream venous thromboembolism events. Venous thromboembolism rates were high (5.6 percent), but the number of observed events was low (five). Thus, we cannot rigorously control for identified confounders using regression analysis. Bivariate statistics showed that patients with low anti–factor Xa had significantly higher Caprini scores. This clinically makes sense—factors such as sepsis, recent operative procedure, long bone fracture, and traumatic injury are risk factors in the Caprini score and also promote a systemic inflammatory response that increases enoxaparin metabolism.25,26 Caprini score was not an independent predictor of peak anti–factor Xa level in a linear regression model. All but three patients had 90-day follow-up or were known to have died as a result of non–venous thromboembolism causes within 90 days. Three patients did not respond to phone calls or certified letters and their outcomes are unknown. Time-series analysis allowed us to incorporate these patients’ data into the final analysis, recognizing their limited follow-up.
Steady-state levels of enoxaparin are achieved after the third dose, and this study provided patients with once-daily dosing. Thus, pharmacodynamic data from this study were derived from plastic surgery inpatients admitted for 3 or more days after surgery. In addition, patients who had real-time dose adjustment and repeated steady-state anti–factor Xa levels determined were admitted for at least 6 days. Our patient population is skewed toward trauma patients and major oncologic reconstructions, as these patients were typically admitted long enough for anti–factor Xa levels to be determined. This may decrease generalizability of our data to the overall population.
We have shown that patient-level variation in enoxaparin metabolism exists in the plastic and reconstructive surgery population. Among the overall population, 44 percent and 41 percent of patients had appropriate in-range peak and trough anti–factor Xa levels, respectively, based on fixed-dose prophylaxis provided at 40 mg/day. Patients with inadequate anti–factor Xa levels were significantly more likely to have a postoperative venous thromboembolism event (10.2 percent versus 0 percent; p = 0.041). Real-time anti–factor Xa level monitoring is feasible in an academic medical center, and real-time enoxaparin dose adjustment can significantly increase the proportion of patients with in range peak anti–factor Xa levels. Enoxaparin dose escalation does not produce an increased number of 90-day bleeding events.
This study was funded by a Plastic Surgery Foundation National Endowment for Plastic Surgery grant to Christopher J. Pannucci, M.D., M.S.
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