Association of Anti–Factor Xa–Guided Dosing of Enoxaparin With Venous Thromboembolism After Trauma

Key Points

Question  Is anti–factor Xa–guided dosing of enoxaparin sodium associated with the rate of venous thromboembolism after trauma?

Findings  In this review of 792 consecutive trauma patients, anti–factor Xa–guided dosing of enoxaparin was no better than a standard fixed dose of enoxaparin in preventing venous thromboembolism. Furthermore, anti–factor Xa levels in the prophylactic range did not prevent venous thromboembolism.

Meaning  If targeting the coagulation cascade does not optimize thromboprophylaxis, other targets, such as platelets, may be necessary.

Importance  The efficacy of anti–factor Xa (anti-Xa)–guided dosing of thromboprophylaxis after trauma remains controversial.

Objective  To assess whether dosing of enoxaparin sodium based on peak anti-Xa levels is associated with the venous thromboembolism (VTE) rate after trauma.

Design, Setting, and Participants  Retrospective review of 950 consecutive adults admitted to a single level I trauma intensive care unit for more than 48 hours from December 1, 2014, through March 31, 2017. Within 24 hours of admission, these trauma patients were screened with the Greenfield Risk Assessment Profile (RAP) (possible score range, 0-46). Patients younger than 18 years and those with VTE on admission were excluded, resulting in a study population of 792 patients.

Exposures  The control group received fixed doses of either heparin sodium, 5000 U 3 times a day, or enoxaparin sodium, 30 mg twice a day. The adjustment cohort initially received enoxaparin sodium, 30 mg twice a day. A peak anti-Xa level was drawn 4 hours after the third dose. If the anti-Xa level was 0.2 IU/mL or higher, no adjustment was made. If the anti-Xa level was less than 0.2 IU/mL, each dose was increased by 10 mg. The process was repeated up to a maximum dose of 60 mg twice a day.

Main Outcomes and Measures  Rates of VTE were measured. Venous duplex ultrasonography and computed tomographic angiography were used for diagnosis.

Results  The study population comprised 792 patients with a mean (SD) age of 46 (19) years and was composed of 598 men (75.5%). The control group comprised 570 patients, was older, and had a longer time to thromboprophylaxis initiation. The adjustment group consisted of 222 patients, was more severely injured, and had a longer hospital length of stay. The mean (SD) RAP scores were 9 (4) for the control group and 9 (5) for the adjustment group (P = .28). The VTE rates were similar for both groups (34 patients [6.0%] vs 15 [6.8%]; P = .68). Prophylactic anti-Xa levels were reached in 119 patients (53.6%) in the adjustment group. No difference in VTE rates was observed between those who became prophylactic and those who did not (7 patients [5.9%] vs 8 [7.8%]; P = .58). To control for confounders, 132 patients receiving standard fixed-dose enoxaparin were propensity matched to 84 patients receiving dose-adjusted enoxaparin. The VTE rates remained similar between the control and adjustment groups (3 patients [2.3%] vs 3 [3.6%]; P = .57).

Conclusions and Relevance  Rates of VTE were not reduced with anti-Xa–guided dosing, and almost half of the patients never reached prophylactic anti-Xa levels; achieving those levels did not decrease VTE rates. Thus, other targets, such as platelets, may be necessary to optimize thromboprophylaxis after trauma.

In 2008, the US Surgeon General declared venous thromboembolism (VTE) a major public health concern, leading to a call to action for VTE prevention.^1,2 Furthermore, many national agencies, including the Centers for Medicare and Medicaid Services, have placed VTE in the category of “reasonably preventable” hospital-acquired conditions.³ In 2012, Thorson et al⁴ showed that, in high-risk trauma patients with a Risk Assessment Profile (RAP) score of 10 or higher, routine screening venous duplex ultrasonography identified a VTE rate of 28%, even with standard thromboprophylaxis (TPX). Most trauma centers have adopted a standard fixed-dose low-molecular-weight (LMW) heparin sodium as TPX, rather than unfractionated (UF) heparin. Despite this TPX regimen, the VTE rate continues to be high in the trauma population.

Current evidence suggests that anti–factor Xa (anti-Xa)–guided dosing of LMW heparin reduces the rate of VTE after trauma compared with the standard fixed dose of enoxaparin sodium. This evidence is based on 2 retrospective studies^5,6 but includes several assumptions that could influence the interpretation of the results, such as small sample sizes, historical rather than contemporary controls, nonstandard TPX in control groups, unmatched groups, and no measurement of delayed TPX (Table 1).

In this study, we reexamined this idea and attempted to control for the multiple confounding variables. We tested the hypothesis that anti-Xa–guided dosing of enoxaparin rather than standard fixed dosing reduces the VTE rate after trauma. To our knowledge, this study is the largest to date on this topic.

This was a retrospective study conducted at the Ryder Trauma Center in the University of Miami/Jackson Memorial Medical Center, Miami, Florida. Adult patients with blunt or penetrating trauma admitted to the trauma intensive care unit (ICU) from December 1, 2014, through March 31, 2017, were prospectively screened for risk and included if they received chemical TPX. In addition to chemical TPX, mechanical TPX was used on the lower extremities of all patients with sequential compression devices unless injury prevented their use. Patients who were younger than 18 years, incarcerated, or pregnant; who died or had an ICU stay of less than 48 hours; or who had VTE on admission were excluded. This study was approved by the University of Miami/Jackson Memorial Medical Center Institutional Review Board; the need for patient consent was waived because this was a retrospective review that met all the standards for waiver of consent.

Risk for VTE was assessed with the RAP within the first 24 hours of admission to the ICU. The RAP score⁴ can range from 0 to 46. Per the ICU protocol, if the RAP score was 8 or higher, the patient was considered to be at high risk and received admission and weekly venous duplex ultrasonography of both lower extremities (inguinal ligament to ankle). Those with a RAP score less than 8 received venous duplex ultrasonography for symptomatic suspicion only. All pulmonary embolisms were diagnosed by computed tomographic angiography of the chest on symptomatic suspicion.

All patients initially received either standard-dose enoxaparin sodium, 30 mg administered subcutaneously twice a day, or standard-dose UF heparin sodium, 5000 U 3 times a day. In the adjustment group, a blood sample was drawn 4 hours after the third dose and the anti-Xa level was determined in the hospital pathology laboratory. According to previous studies, the target peak level considered to be prophylactic was 0.2 to 0.4 IU/mL.^7-9 If the level was within this range, the enoxaparin sodium dose remained at 30 mg twice a day. If the level was subprophylactic, each enoxaparin sodium dose was increased by 10 mg. Another peak level was drawn after the third adjusted dose. If the level was still subprophylactic, enoxaparin doses were each increased by another 10 mg to a maximum of 60 mg twice a day. Patients with no TPX adjustment made up the control cohort.

Patients receiving the standard fixed-dose TPX including both enoxaparin and UF heparin were first compared with those receiving anti-Xa dose-adjusted enoxaparin. Propensity score matching was then used to reduce the confounding factors between those receiving the standard fixed-dose enoxaparin and those receiving dose-adjusted enoxaparin. An approximately 2:1 (control to adjustment) match was made to ensure the groups had the best match with the greatest sample size. Finally, a subgroup analysis was done within the dose-adjustment cohort to compare those with prophylactic anti-Xa levels (0.2-0.4 IU/mL) against those with subprophylactic anti-Xa levels (<0.2 IU/mL).

All statistical analyses were performed using SPSS Statistics, version 22.0 (IBM Corporation). Categorical variables were expressed as frequency (percent) and compared between groups using χ² or Fisher exact test, as appropriate. Parametric data are expressed as mean (SD) and compared using the unpaired, 1-tailed t test for 2 independent samples. Nonparametric data are expressed as median (interquartile range [IQR]) and compared using the Mann-Whitney test. All results were considered statistically significant at 1-sided P ≤ .05.

A total of 950 trauma patients were admitted to the ICU within the study period. After exclusions, the study population comprised 792 patients with the following characteristics: mean (SD) age of 46 (19) years, composed of 598 men (75.5%), mean (SD) RAP score of 9 (4), mean (SD) Injury Severity Score of 20 (12), and median hospital length of stay (LOS) of 15 (IQR, 8-31) days. The overall VTE rate was 6.2% (n = 49), with 4.3% (n = 34) deep venous thrombosis and 2.4% (n = 19) pulmonary embolism. All deep venous thromboses were in the lower extremities, above the knee. Standard fixed-dose TPX was given to 570 patients (control group), and 222 patients (adjustment group) received anti-Xa–guided dosing of enoxaparin. Table 2 shows multiple differences in VTE risk factors, but the overall rates of thrombotic complications—including deep venous thrombosis, and pulmonary embolism—were no different between the control and adjustment groups.

To reduce confounding VTE risk factors, the control group (receiving standard fixed-dose enoxaparin) and the adjustment group (receiving dose-adjusted enoxaparin) were propensity matched. One hundred thirty-two patients receiving enoxaparin sodium, 30 mg twice a day, were matched to 84 patients receiving dose-adjusted enoxaparin based on age, Injury Severity Score, RAP score, LOS, and time to initiation of TPX. Only 2 differences were found after matching (Table 3). The rates of thrombotic complications remained similar between the control and adjustment groups.

Within the adjustment cohort, only 119 (53.6%) reached anti-Xa levels of 0.2 to 0.4 IU/mL at any point during their hospital LOS. Comparing these patients with those who never reached prophylactic levels, we found no factor associated with the inability to reach a prophylactic level. Furthermore, thrombotic complication rates between the groups were not different (Table 4).

To our knowledge, this is the largest trauma study population to date, and the major findings are as follows: (1) VTE rates were similar with anti-Xa–guided dosing or standard fixed-dose TPX after trauma; (2) almost half the patients never achieved an anti-Xa level of 0.2 IU/mL or higher during their hospital LOS despite progressively increasing doses of enoxaparin; and (3) VTE rates were similar regardless of the anti-Xa level. This third finding supports the interpretation that, at least in trauma patients with moderate to high risk for VTE, anti-Xa levels may not be as useful as previously suspected for titrating TPX. Furthermore, given that increasing doses of enoxaparin did not reduce VTE rates, other targets, such as platelets, may be necessary to optimize TPX.^10,11

Rates of VTE after trauma remain high despite multiple strategies for optimizing TPX.¹² Current guidelines recommend LMW heparin for TPX,¹³ but VTE rates can still range from 3% to 44% depending on risk factors.^14-18 To address refractory VTE, at least 3 strategies can be used for dosing LMW heparin: thromboelastography¹⁹ weight-based^20,21 or anti-Xa–based^5,6,22-24 methods. Each has its proponents and has shown promise in specific conditions, but there is still no consensus on which strategy is best.

Several studies have focused on the use of anti-Xa level for TPX. Several studies have focused on anti-Xa to optimize TPX. Because LMW heparin binds to antithrombin III (ATIII), it initiates a conformational change and ultimately leads to the acceleration of factor Xa inhibition.^23,25 Although ATIII is the major molecule that interacts with LMW heparin to affect the coagulation cascade, many downstream coagulation factors are also inactivated through this mechanism.²² Measurement of anti-Xa involves a chromogenic response from the cleavage of a tagged substrate by unbound factor Xa.²³ This result reflects the level of anticoagulation and can thus be used to guide TPX.

Singer et al⁶ performed one of the first studies to investigate anti-Xa–guided dosing of enoxaparin. Those researchers initiated a dose adjustment protocol on the basis of peak anti-Xa levels over a 12-month period. Comparing their results with those of a historical cohort, Singer et al concluded that the deep venous thrombosis rate was significantly reduced with the dosing protocol. Ko et al reached a similar conclusion; the VTE rate was reduced compared with the rate of a historical cohort.⁵

One problem with the study by Singer et al⁶ is the comparison with a historical cohort receiving UF heparin. In 1996, a randomized clinical trial found that LMW heparin prevented more VTEs than did UF heparin after trauma, effectively making LMW heparin the recommended TPX. Many studies since, including 2 large multicenter analyses, have similarly found that LMW heparin is superior to UF heparin for preventing VTE after trauma.^26,27 Inherently, these findings undermine the comparison of dosing regimens with a less effective control group receiving UF heparin.

Table 1 highlights another issue addressed with our analysis—delayed TPX initiation. Both delayed initiation and missed doses of TPX have been associated with higher VTE rates after trauma.^28,29 This risk factor is frequently overlooked. We attempted in our analysis to ameliorate the impact of delayed prophylaxis by using propensity score matching; previous studies did not consider this variable.

First, we compared the dose-adjustment cohort with standard TPX of either enoxaparin sodium, 30 mg twice a day, or UF heparin sodium, 5000 U 3 times a day. Although this comparison has the same inherent bias as that stated in previous studies, it allowed for any baseline differences between the groups to emerge. There were several risk factor differences between the cohorts that could affect the thrombotic complication rates of either group (Table 2). Second, we isolated all the patients receiving only enoxaparin and matched the groups according to differences in age, Injury Severity Score, RAP score, time to initiation of TPX, and LOS (Table 3). This approach allowed a comparison of anti-Xa–guided dosing with the accepted standard-dose TPX (enoxaparin sodium, 30 mg twice a day) among appropriately matched cohorts.

We recognize that absence of proof is not proof of absence; thus, our failure to find a VTE difference with anti-Xa–guided enoxaparin dosing does not necessarily mean that a dose less than 60 mg twice a day would not reduce the VTE rates. The risk of bleeding must be balanced with the risk of VTE. Our main goal, however, was to evaluate the process of using a peak anti-Xa level as a surrogate for adequate prophylaxis. Perhaps failure to reduce the VTE incidence may be associated with failure to reach the anti-Xa prophylactic range of 0.2 to 0.4 IU/mL. In fact, only 53.6% of our patients reached this range, which is consistent with other reports.^5,6,20,22-24 By comparing the group achieving a prophylactic range with the group remaining at a subprophylactic level, we derived 2 conclusions. First, no variable evaluated was associated with the inability to reach the prophylactic anti-Xa level. Second, reaching a prophylactic anti-Xa level did not reduce the VTE rate, indicating that the range may not truly be prophylactic (Table 4).

One likely explanation why reaching a prophylactic level of anti-Xa may not be sufficient is related to an ATIII deficiency after trauma.^19,30 Both UF heparin and LMW heparin, bind to ATIII, forming a complex that leads to the deactivation of clotting factors—mainly, factor Xa.²⁵ This typically seen deficiency would logically decrease the impact of the heparin-based anticoagulation, thus producing a higher VTE rate.

Furthermore, in the past 2 decades, optimizing TPX in the trauma population has focused on controlling the coagulation cascade. Despite various TPX strategies, refractory VTE persists. Evidence from this study suggests that we may be exhausting our efforts to alter the consequences of coagulation factors. Evolving evidence shows that new targets, including platelets and fibrinolysis, may be the next step toward optimal TPX. Both heparin and LMW heparin induce platelet aggregation.³¹ Furthermore, heparinoids interact with the platelet surface,³² changing platelet morphology,³³ and promote the expression of P-selectin.^31,34,35 By activating platelets in this way, crosslinking of fibrinogen to αIIbβ3 is upregulated, ultimately supporting platelet aggregation.^34-36 This basic mechanism has been confirmed in the clinical setting by Harr et al,¹⁰ who showed that thromboelastography-guided increases in heparin dose amplified platelet contribution to clot strength. Harr et al also noticed a 2-fold increase in LMW heparin had no influence on thromboelastography reaction time, showing that hypercoagulability may be resistant to standard heparin-based TPX. Connelly et al¹⁹ showed similar results with thromboelastography reaction times. These results suggest a possible explanation for why VTE is not eliminated with increasing doses of LMW heparin and why other factors, such as platelets, may participate.

The results and interpretations of the present study must be considered in the context of its limitations. This study was a retrospective review and thus was not randomized. We attempted to address this issue by propensity score matching, but even though the patients were ultimately well matched, matching introduces a selection bias into the study. The ideal evaluation would include prospective, randomized cohorts, but in the absence of such, propensity score matching allows for the comparison of similar groups to avoid the inherent bias of nonrandomized, unmatched cohorts. Furthermore, because negative results were the main finding, we can only conclude that there was a failure to find a reduction in VTE rate. Despite this failure, we have conducted the largest and longest study to date (to our knowledge) that evaluated patients who were adequately matched regarding anti-Xa dosing of TPX.

Venous thromboembolism rates did not decrease over a 27-month period with anti-Xa–guided dosing of enoxaparin. Furthermore, about half of the trauma patients in the study were unable to reach a prophylactic anti-Xa level during their hospital stay despite repeated increases in dosing. Even the patients who achieved prophylactic anti-Xa levels did not see a reduced VTE rate. Based on these results, we are skeptical of the clinical use of anti-Xa to guide TPX after trauma, especially considering increased surveillance, time, and cost for testing and higher doses of medication. At this point, we believe that we may not be able to optimize TPX by targeting only the coagulation factors. Our results, along with other emerging evidence,^10,19 suggest that other additional targets—such as platelets—could hold great promise for decreasing VTE after trauma.

Corresponding Author: Kenneth G. Proctor, PhD, Ryder Trauma Center, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, 1800 NW 10th Ave, Ste T-215 (D40), Miami, FL 33136 (kproctor@miami.edu).

Accepted for Publication: June 25, 2017.

Published Online: October 25, 2017. doi:10.1001/jamasurg.2017.3787

Author Contributions: Dr Proctor had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Karcutskie, Eidelson, Lineen, Namias, Proctor.

Acquisition, analysis, or interpretation of data: Karcutskie, Dharmaraja, Patel, Eidelson, Padiadpu, Martin, Lama, Lineen, Schulman, Proctor.

Drafting of the manuscript: Karcutskie, Dharmaraja, Patel, Eidelson, Padiadpu, Martin, Lama, Proctor.

Critical revision of the manuscript for important intellectual content: Karcutskie, Dharmaraja, Patel, Eidelson, Padiadpu, Lama, Lineen, Namias, Schulman, Proctor.

Statistical analysis: Karcutskie, Eidelson, Martin, Proctor.

Obtained funding: Proctor.

Administrative, technical, or material support: Karcutskie, Eidelson, Padiadpu, Lineen, Proctor.

Study supervision: Namias, Schulman, Proctor.

Conflict of Interest Disclosures: None reported.

Meeting Presentation: This study was presented in part at the Association of Veterans Affairs Surgeons 41st Annual Surgical Symposium; May 7, 2017; Houston, Texas.

Additional Contributions: The trauma intensive care unit staff, including residents and ancillary staff, at Ryder Trauma Center assisted with patient care. Ron Manning, ARNP, MSPH, Ryder Trauma Center, University of Miami, was the manager and coordinator for this study. These contributors were not compensated for their work.