eFigure. Flow chart of control and adjustment cohort inclusion patients.
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Ko A, Harada MY, Barmparas G, et al. Association Between Enoxaparin Dosage Adjusted by Anti–Factor Xa Trough Level and Clinically Evident Venous Thromboembolism After Trauma. JAMA Surg. 2016;151(11):1006–1013. doi:https://doi.org/10.1001/jamasurg.2016.1662
Will adjusting the dosage of enoxaparin by prophylactic anti–factor Xa (anti-Xa) trough levels reduce the venous thromboembolism rate in trauma patients?
In this cohort study of 205 trauma patients, those who received enoxaparin adjusted by anti-Xa trough level were compared with those who received enoxaparin sodium at a dosage of 30 mg twice daily without adjustment. Incidence of venous thromboembolism was significantly lower in those whose enoxaparin was adjusted by anti-Xa trough levels.
Enoxaparin dosage adjustment may lead to a reduced rate of venous thromboembolism without an increased risk of bleeding.
Trauma patients are at high risk for developing venous thromboembolism (VTE). The VTE rate when enoxaparin sodium is dosed by anti–factor Xa (anti-Xa) trough level is not well described.
To determine whether targeting a prophylactic anti-Xa trough level by adjusting the enoxaparin dose would reduce the VTE rate in trauma patients.
Design, Setting, and Participants
Single-institution, historic vs prospective cohort comparison study at an urban, academic, level I trauma center. The prospective cohort was enrolled from August 2014 to May 2015 and compared with a historic cohort admitted from August 2013 to May 2014. Trauma patients who received enoxaparin adjusted by anti-Xa trough level (adjustment group) were compared with those who received enoxaparin sodium at a dosage of 30 mg twice daily (control group). Patients were excluded if they were younger than 18 years, had a length of hospital stay less than 2 days, or had preexisting deep vein thrombosis. Patients were excluded from the adjustment group for changes in the choice of thromboprophylaxis (heparin, enoxaparin once-daily dosing, early ambulation), hospital discharge before initial trough levels could be drawn, or incorrect timing of trough levels.
Anti-Xa trough levels were monitored in patients in the adjustment group receiving 3 or more consecutive doses of enoxaparin sodium, 30 mg twice daily. Patients with a trough level of 0.1 IU/mL or lower received enoxaparin sodium increased by 10-mg increments. After providing 3 adjusted doses of enoxaparin, the trough level was redrawn and the dosage was adjusted as necessary. Patients in the control group received enoxaparin sodium at a dosage of 30 mg twice daily without adjustments.
Main Outcomes and Measures
Rates of symptomatic VTE (deep vein thrombosis and pulmonary embolism, confirmed by duplex ultrasonography and chest computed tomographic angiography, respectively) and bleeding risk.
A total of 205 patients (mean [SD] age, 41.3 [18.2] years; 75.1% male) were studied, 87 in the adjustment group and 118 in the control group, with similar baseline characteristics and injury profiles. Subprophylactic anti-Xa troughs were noted in 73 of 87 patients (83.9%) in the adjustment group, and the majority of patients (57 of 87 patients [65.5%]) required dosage adjustment of enoxaparin sodium to 40 mg twice daily. Incidence of VTE was significantly lower in the adjustment group than in the control group (1.1% vs 7.6%, respectively; P = .046). When the adjustment group was compared with the control group, no significant difference was noted in the rate of packed red blood cell transfusion (6.9% vs 12.7%, respectively; P = .18) or mean (SD) hematocrit at discharge (34.5% [6.3%] vs 33.4% [6.8%], respectively [to convert to proportion of 1.0, multiply by 0.01]; P = .19).
Conclusions and Relevance
In this study, subprophylactic anti-Xa trough levels were common in trauma patients. Enoxaparin dosage adjustment may lead to a reduced rate of VTE without an increased risk of bleeding.
Trauma patients are at increased risk for venous thromboembolism (VTE), as injury can cause alterations to the coagulation cascade. Traumatic injury leads to direct or indirect endothelial injury, activating tissue factor and platelet aggregation and propagating the coagulation cascade.1 Additionally, injured patients are prone to immobility or may undergo major surgery, further contributing to the risk of VTE.
The incidence of deep vein thrombosis (DVT) in the trauma population ranges from 11.8% to 65%,1-3 with rates of pulmonary embolism (PE) between 1.5% and 2.3% depending on the type and severity of injury.3,4 Venous thromboembolism can be a principal cause of delayed death in trauma patients,5 and proper VTE prophylaxis can be critical in minimizing morbidity and mortality.
Options for thromboprophylaxis in trauma patients include mechanical prophylaxis and chemoprophylaxis. Of the types of chemoprophylaxis, low-molecular-weight heparin is superior to unfractionated heparin at reducing DVT risk (relative risk = 0.68; 95% CI, 0.50-0.94).6 Prophylactic doses of enoxaparin sodium, 30 mg twice daily, are the acceptable standard for DVT prophylaxis.7,8 However, there may be decreased bioavailability of enoxaparin in critically ill trauma patients9,10; consequently, standard prophylactic doses may not be sufficient to achieve optimal therapeutic anti–factor Xa (anti-Xa) trough goals of 0.1 to 0.2 IU/mL in this population.11,12 The risk of VTE when enoxaparin is dosed by anti-Xa trough level is not well described. We sought to investigate the utility of this dosing regimen and hypothesized that targeting a prophylactic anti-Xa trough level by adjusting the enoxaparin dosage would reduce the risk of VTE in trauma patients.
Trauma patients receiving enoxaparin for thromboprophylaxis at an urban, academic, level I trauma center were prospectively enrolled from August 2014 to May 2015, with enoxaparin dosages adjusted according to anti-Xa trough levels (adjustment group). These patients were compared with a historical cohort of trauma patients admitted from August 2013 to May 2014 who received subcutaneous enoxaparin sodium, 30 mg twice daily, for DVT prophylaxis (control group). Clinical characteristics such as age, sex, race, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), body surface area (BSA), creatinine clearance (CrCl), mechanism of injury, types of injuries sustained, regional Abbreviated Injury Scale score, and Injury Severity Score were collected. Start and end dates of enoxaparin administration as well as final dosages in the adjustment cohort were recorded. Outcomes data including hospital length of stay (LOS), intensive care unit LOS, transfusion requirement in milliliters of packed red blood cells (PRBCs), hematocrit at discharge, diagnosis of DVT based on duplex ultrasonographic findings, and diagnosis of PE based on chest computed tomographic angiography (CTA) were extracted and compared. Duplex ultrasonography (upper or lower extremity) and chest CTA were ordered in symptomatic patients on clinical suspicion of DVT or PE. Duplex examinations were performed by certified ultrasonogram technicians, and interpretations of duplex examinations and chest CTA were conducted by board-certified vascular surgeons and radiologists, respectively. Of note, the same vascular laboratory performed duplex examinations throughout the study period, without significant changes in personnel. Proximal lower extremity DVTs included those in the popliteal, femoral, or iliac veins, whereas distal lower extremity DVTs were located below the knee. Enoxaparin was routinely used for DVT prophylaxis at our institution for all trauma patients regardless of injury severity. However, alternative thromboprophylaxis may have been used in cases of renal impairment, heparin-induced thrombocytopenia, severe bleeding risk, or attending preference. This study was approved by the Cedars-Sinai Medical Center Institutional Review Board. The requirement for informed consent was formally waived because the researchers received only deidentified data and had no direct contact with the study participants.
To establish the control group, electronic medical records were queried for all adult trauma patients at Cedars-Sinai Medical Center between August 2013 and May 2014 who received enoxaparin sodium, 30 mg twice daily, at any time during hospitalization. Inclusion criteria required that the patient be administered at least 3 consecutive doses of enoxaparin prophylaxis.
From August 2014 to May 2015, adult patients admitted under the trauma service were prospectively enrolled into the adjustment cohort once enoxaparin was ordered. All patients started with a prophylactic dosage of 30 mg twice daily subcutaneously. Anti-Xa trough levels were obtained 30 minutes to 1 hour before the fourth dose of enoxaparin and were processed at our Cedars-Sinai Medical Center laboratory, at an estimated cost of $43.12 per assay. Plasma samples were analyzed using STA liquid anti-Xa chromogenic reagent via an STA Compact instrument (Diagnostica Stago Inc) calibrated for low-molecular-weight heparin to evaluate anti-Xa activity. Trough levels were followed by the institution’s pharmacy department; if the trough was below the prophylactic level (≤0.1 IU/mL), the dosage of enoxaparin sodium was increased by increments of 10 mg twice daily. After dosage adjustment, another trough level was redrawn after 3 consecutive doses and this process of adjustment was repeated as necessary. Dosages were decreased by increments of 10 mg twice daily for troughs that were higher than acceptable levels (>0.2 IU/mL). The reference goal trough level was based on existing literature,12 including a study describing significantly higher rates of DVT associated with trough levels of 0.1 IU/mL or lower and more wound hematomas associated with trough levels higher than 0.2 IU/mL in patients undergoing hip replacement.13
Patients who were administered at least 3 consecutive doses of enoxaparin prophylaxis were eligible for inclusion. Patients were excluded from the adjustment cohort for changes in thromboprophylaxis (heparin, enoxaparin once-daily dosing, early ambulation), hospital discharge before initial troughs were drawn, or incorrect timing of troughs. Patients were excluded from either cohort if they were younger than 18 years, had a hospital LOS less than 2 days, or had preexisting DVT (eFigure in the Supplement).
Although all injured patients regardless of type of injury (including those with traumatic brain injury and solid-organ injury) were eligible candidates for the dosage adjustment protocol, time to initiation of enoxaparin was at the discretion of the rounding attending physician, with considerations to risk of bleeding, intracranial hemorrhage, and anticipated operations. Once initiated, doses of enoxaparin could be held for operative procedures or suspected bleeding risk based on clinician judgement. Sequential compression devices were used by all patients unless contraindicated by extremity injuries. Volumes of PRBC transfusions were based on any PRBCs administered during hospitalization after enoxaparin initiation, and they included blood transfused for an operative procedure.
Data were analyzed using SPSS version 22 statistical software (SPSS Inc) and are summarized as percentages for categorical variables and as means with standard deviation or medians with interquartile range (IQR) for continuous variables. Comparisons of means were conducted using t test or Mann-Whitney U test, where appropriate. All variables except BSA were noted to be nonparametric. Categorical variables were compared using Pearson χ2 test or Fisher exact test. P < .05 was considered statistically significant.
A total of 205 trauma patients (mean [SD] age, 41.3 [18.2] years; 75.1% male) met inclusion criteria: 87 patients in the adjustment group and 118 in the control group. The 2 cohorts were similar in age, sex, race, BMI, BSA, CrCl, head Abbreviated Injury Scale score, and extremity Abbreviated Injury Scale score (Table 1). The patients in the adjustment group were more severely injured, with a median Injury Severity Score of 17.0 (IQR, 10.0-22.0) compared with 10.0 (IQR, 5.0-20.0) in the control group (P = .01). Between the 2 groups, similar proportions of patients underwent at least 1 major surgery during hospitalization. Aside from the higher percentage of patients in the adjustment group having spine fractures compared with those in the control group (28.7% vs 16.9%, respectively; P = .04), there were no other significant differences in the types of injuries (Table 2). The 2 groups had similar hospital LOS, but the adjustment cohort had longer intensive care unit stays than the control group (median [IQR], 2.0 [0-5.0] vs 1.5 [0-3.0] days, respectively; P = .009). Time to initiation of enoxaparin between the 2 groups was similar, with an overall mean (SD) of 2.6 (3.9) days to first dose (Table 3).
Initial subprophylactic anti-Xa troughs were noted in 73 of 87 patients (83.9%) in the adjustment group, and the majority of patients (57 of 87 patients [65.5%]) required dosage adjustment of enoxaparin sodium to 40 mg twice daily (Figure). Risk factors were compared between those whose initial anti-Xa trough levels were subprophylactic (n = 73) vs prophylactic (n = 14); the subprophylactic group had a higher CrCl than the prophylactic group (median [IQR], 117.1 [87.6-155.6] vs 92.8 [70.2-122.3] mL/min, respectively; P = .046) (Table 4).
The incidence of VTE was significantly greater in the control group compared with the adjustment group (7.6% vs 1.1%, respectively; P = .046). There was no significant difference in the rate of patients in whom duplex ultrasonography was performed for suspected DVT between the 2 groups (28.8% in the control group vs 26.4% in the adjustment group; P = .71). One patient in the control group was diagnosed as having a PE, and the remainder of patients were diagnosed as having lower extremity DVTs (Table 3). No patient was diagnosed as having an upper extremity DVT. One patient in the adjustment group had a right lower extremity distal DVT (posterior tibial and peroneal veins) with a subprophylactic anti-Xa trough level of 0.1 IU/mL and was in the process of dosage adjustment, with the most recent dosage of enoxaparin sodium being 40 mg twice daily. This patient continued prophylactic enoxaparin, achieving an anti-Xa trough level of 0.21 IU/mL, and had follow-up surveillance with ultrasonography that did not show propagation of the clot. Of all patients included in the study, there was 1 non-VTE– and nonbleeding-related mortality in the adjustment cohort. There were no significant differences between the 2 cohorts in terms of the percentage of patients requiring PRBC transfusions, mean volume of PRBCs received in each group, or discharge hematocrit (Table 3). When the adjustment group was compared with the control group, no significant difference was noted in the rate of PRBC transfusion (6.9% vs 12.7%, respectively; P = .18) or mean (SD) hematocrit at discharge (34.5% [6.3%] vs 33.4% [6.8%], respectively [to convert to proportion of 1.0, multiply by 0.01]; P = .19).
Injured patients are at increased risk for VTE, which can lead to delayed mortality and morbidity after initial successful resuscitation. Although enoxaparin sodium, 30 mg twice daily, is considered standard for VTE prophylaxis,7,8 this may be insufficient in preventing thromboembolic events in critically ill patients as there may be decreased enoxaparin bioavailability in this population.9-12,14 Consistent with the literature, our study found that 83.9% of trauma patients had subprophylactic anti-Xa trough levels at enoxaparin sodium dosages of 30 mg twice daily. Because standard pharmacologic administration has proven suboptimal, alternative methods of dosing enoxaparin to achieve adequate prophylaxis have been proposed, including weight-based dosing and dosage adjustments based on peak anti-Xa levels.10,15-20 To our knowledge, this study is the first to demonstrate that when enoxaparin is dosed to achieve a target anti-Xa trough level in trauma patients, there is a decreased rate of VTE without an increased risk of bleeding.
Ideal enoxaparin dosing and monitoring for thromboprophylaxis have been debatable. Enoxaparin sodium dosing in obese trauma patients is possible by weight-based administration at 0.5 mg/kg twice daily with subsequent dosage adjustments aimed at a prophylactic peak range of 0.2 to 0.6 IU/mL.16 Nunez et al10 conducted a prospective study comparing weight-based enoxaparin sodium dosages at 0.6 mg/kg twice daily in 37 critically ill trauma patients, with a historical cohort (n = 26) receiving standard prophylactic enoxaparin. Instead of recording peak anti-Xa levels, Nunez and colleagues measured anti-Xa trough levels. The patients who had weight-based dosing achieved increased rates of goal trough levels (61%) compared with those who received the standard prophylactic dosage (8%). Rather than adjusting enoxaparin dosage by weight, our study adjusted dosing by anti-Xa trough levels in the trauma population and demonstrates decreased rates of VTE.
Prophylactic enoxaparin monitoring may be based on anti-Xa peak or trough levels. A retrospective review by Kopelman et al21 compared trauma patients receiving enoxaparin sodium at a dosage of 30 mg twice daily with those receiving a dosage of 40 mg twice daily. They monitored peak anti-Xa levels and found that although the group who received the higher dosage had improved peak levels, this did not translate to a statistically significant decrease in VTEs. Lin et al22 also monitored peak anti-Xa levels in 38 acute burn patients who received enoxaparin sodium at a dosage of 30 mg twice daily for chemoprophylaxis and found that 30 of these patients (79%) had initial anti-Xa peak levels less than 0.2 IU/mL. By dosing enoxaparin according to an anti-Xa peak level goal of 0.2 to 0.4 IU/mL, they found that burn patients required a median dosage of 50 mg twice daily to achieve the goal. In a follow-up study of a larger cohort, Lin et al20 found that 64 of their 84 patients (76.2%) had low initial peak levels. If peaks were low, then the dosage of enoxaparin was increased by 20% and a level was redrawn at 4 hours after the third postadjustment dose. Despite these adjustments, adequate peak levels were never achieved in 18% of the patients and 2 patients still had VTE episodes. The only patient who developed a DVT in the adjustment cohort of our study was in the process of undergoing dosage adjustment after an enoxaparin sodium dosage of 40 mg twice daily was inadequate.
Rather than monitoring peak levels, we chose to adjust the enoxaparin dosage to target anti-Xa trough levels, as some studies suggest that troughs may better correlate with rates of DVT after trauma.12,23 One prospective study of 54 critically ill surgical and trauma patients demonstrated that standard prophylactic dosages of enoxaparin sodium, 30 mg twice daily, often resulted in low anti-Xa levels and higher rates of DVT.12 The investigators found that 27 of the patients (50%) had low trough levels (≤0.1 IU/mL) and 37% of those with subprophylactic levels had DVTs, while 11% of those with adequate levels had DVTs. There was no difference in peak levels between those who had DVTs compared with those who did not. Van et al24 also demonstrated that while peak anti-Xa level was not predictive of low anticoagulant activity and DVT formation, thromboelastography findings were. Additionally, Costantini et al17 conducted a prospective study with 61 trauma patients, adjusting the dosage of enoxaparin according to goal peak anti-Xa levels of 0.2 to 0.4 IU/mL. Despite aggressive dosage adjustments, there was still a 4.9% VTE rate. In their study, trough levels did not correlate well with peaks, with only 5 patients achieving both therapeutic peak and trough levels; 2 of the 3 patients with DVTs had adequate peak levels. No patient in the subtherapeutic peak group had a therapeutic trough. In light of these findings, we chose to dose enoxaparin by targeting prophylactic anti-Xa trough levels (goal >0.1 IU/mL) rather than peak levels and observed a decreased rate of VTEs when doing so.
There are limited data on the correlation between bleeding risk and anti-Xa trough levels in existing literature. Levine et al13 monitored anti-Xa levels drawn 12 hours after enoxaparin administration in patients undergoing hip replacement and receiving the once-daily regimen. They found that anti-Xa trough levels higher than 0.2 IU/mL correlated with an increased rate of wound hematoma (24.5%) compared with 5.3% when levels were 0.2 IU/mL or lower. In our study, patients undergoing dosage adjustment based on trough goals demonstrated no significant difference in PRBC transfusion rate or predischarge hematocrit compared with patients receiving the standard enoxaparin sodium dosage of 30 mg twice daily. This suggests that our protocol of dosing enoxaparin does not increase the risk of bleeding-related complications and is safe in trauma patients.
Prior studies describe factors associated with low anti-Xa levels, including male sex, weight, BMI, BSA, CrCl, vasopressor use, multiple organ dysfunction, peripheral edema, and critical illness.12,17 In our study, analysis of the adjustment cohort suggested that higher CrCl may be associated with subprophylactic anti-Xa troughs (Table 4), consistent with data in existing literature.25 Critically ill trauma patients may experience increased CrCl due to a hyperdynamic state. We propose that this translates to faster drug clearance and elimination, which could result in lower levels of enoxaparin and anti-Xa activity. However, as identifying risk factors associated with low anti-Xa levels was not the primary aim of our study, these findings warrant further substantiation by a larger sample size and additional regression analysis.
Despite favorable findings, we acknowledge that there are several limitations to our study. By using a retrospective control cohort, we noted that some patients may have had subcutaneous administration of heparin prior to initiation of enoxaparin as DVT prophylaxis. Also, although sequential compression devices are routinely ordered for all trauma patients unless contraindicated by extremity fractures, the retrospective nature of data collection made it difficult to accurately capture the number of patients who actually received sequential compression devices. In addition, the anti-Xa assay may currently be an uncommon test in clinical laboratories; thus, the generalizability of our findings may be limited to hospitals with access to this assay. The relatively small size of the cohorts limits the power of our study, and a larger sample population may offer more robust conclusions.
Because surveillance DVT ultrasonography and chest CTA are not routinely performed at our institution, these studies were ordered only when there was clinical suspicion of an acute DVT or PE. We acknowledge the possibility of a surveillance bias because higher rates of imaging could result in higher rates of diagnosis. As such, the VTE rate may be underestimated in our study population compared with prior studies. However, in our study, DVT duplex ultrasonography was performed at comparable rates in the adjustment and control groups, but more VTEs were diagnosed in the control group.
Although our prospective cohort was followed up until hospital discharge or death, our data may be limited by follow-up and patients may have developed VTE after discharge home or transfer to another facility. Many patients were discharged from the hospital before repeated troughs confirming adequate levels could be drawn. Lin et al20 conducted 30-day postdischarge telephone interviews to follow up their acute burn patients who received enoxaparin dosage adjustments targeted to peak levels while hospitalized, reporting that no additional episodes of VTE were noted. Although we did not follow up patients after discharge, patients would no longer be receiving enoxaparin dosage adjustments; therefore, we believe that VTEs in this setting would not reflect results of the dosage adjustment protocol.
In our study, most patients in the adjustment cohort (57 of 87 patients [65.5%]) required dosage adjustment of enoxaparin sodium to 40 mg twice daily (Figure) and only 1 occurrence of VTE was noted. It is unclear whether this is an adequate dosage for most trauma patients, as there has been evidence of unpredictable anti-Xa levels in patients with the previously mentioned risk factors. We therefore suggest that trauma patients may initially begin treatment with enoxaparin sodium at a dosage of 40 mg twice daily, but we advocate subsequent dosing based on trough goals. Similar trough-based protocols for dosing enoxaparin may be beneficial in other critically ill or high-risk patients with less predictable trough levels and would be an opportunity for further study.
We found that subprophylactic anti-Xa trough levels are common in trauma patients and that enoxaparin dosage adjustments based on trough levels may lead to a reduced rate of VTE without increasing bleeding risk. A prospective randomized clinical trial with a larger cohort is recommended to establish this enoxaparin dosing protocol in trauma patients.
Corresponding Author: Eric J. Ley, MD, Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Ste 8215N, Los Angeles, CA 90048 (email@example.com).
Accepted for Publication: April 24, 2016.
Published Online: July 6, 2016. doi:10.1001/jamasurg.2016.1662.
Author Contributions: Drs Ko and Ley had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Ko, Chung, Mason, Margulies, Ley.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Ko, Chung, Yim, Gewertz, Ley.
Critical revision of the manuscript for important intellectual content: Ko, Harada, Barmparas, Chung, Mason, Dhillon, Margulies, Gewertz, Ley.
Statistical analysis: Ko, Harada, Barmparas, Chung, Ley.
Administrative, technical, or material support: Mason.
Study supervision: Barmparas, Chung, Margulies, Gewertz.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the nursing staff and pharmacy department at Cedars-Sinai Medical Center for their care of the patients in this study as well as Sogol Ashrafian, BS, and Beatrice J. Sun, BS, Department of Surgery, Division of Trauma and Critical Care, Cedars-Sinai Medical Center, Los Angeles, California, who assisted with data acquisition; they received no compensation.
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