Discussion
In this prospective study, we have shown that the implementation of a pharmacist-driven, weight-based protocol with anti-Xa monitoring for enoxaparin dose titration is both safe and feasible in a critically ill trauma population. Using anti-Xa levels for dose monitoring, ICU pharmacists were able to increase enoxaparin doses with confidence. Despite these dose increases, only three patients (1.1%) experienced a major bleeding event. Furthermore, the protocol was adhered to in 91% of patients, suggesting that it is practical and easy to follow. Interestingly, 69% of patients had a target anti-Xa level measured during their time in the ICU of which only 59% achieved a target level on the lowest dose of 30 mg two times per day. These results suggest that nearly half of critically ill patients with trauma will require at least one dose titration during their hospitalization to reach an enoxaparin dose that achieves adequate prophylactic anti-Xa levels.
Perhaps most importantly, these results demonstrate that this protocol is safe to use in a critically ill trauma population. Several studies have shown that this population has altered drug metabolism and pharmacokinetics, making it difficult to know what the optimal enoxaparin dose should be.22 23 As a result, many clinicians opt to keep the enoxaparin dose at either 30 mg or 40 mg to prevent major bleeding episodes in patients who are often high risk for ongoing or subsequent hemorrhage. In one of the largest studies that examined outcomes following implementation of a similar dose titration protocol with anti-Xa levels, Gates et al reported that 11.9% of patients required a blood transfusion, which was not significantly different than in patients who were maintained at 30 mg two times per day.18 In a study of their institutional anti-Xa level-based dose titration enoxaparin protocol, Taylor et al observed clinically significant bleeding in 5.3% of patients.24 In this study, only 1.1% of patients experienced a major bleeding event and no patient died because of bleeding. This is likely an underestimate as we only studied patients admitted to the ICU. These results add to a body of literature supporting the safety of higher doses of enoxaparin in the trauma population and reinforce the most recent guidelines from the American Association for the Surgery of Trauma, American College of Surgeons Committee on Trauma and the Western Trauma Association, which all recommend starting enoxaparin at a dose of 40 mg two times per day.25 26
Pharmacist-driven protocols exist for many inpatient anticoagulant therapies and VTE prophylaxis.27 28 Prior results in VTE prophylaxis implementation in hospitalized patients suggest that when pharmacists lead anticoagulation management services, patients experience lower bleeding and mortality rates.28 We believe that this is the first report of such a protocol in which ICU pharmacists have been given autonomy outside of the timing of the first dose of enoxaparin in the trauma population. We demonstrate that the protocol was adhered to 91% of the time, which suggests that it has the support of the staff and is easy to follow. Furthermore, we had excellent buy-in from the trauma and critical care staff as we did not find any evidence of physician opposition to a dose increase in the setting of a sub-target anti-Xa level.
Though 70% of patients in this study had documented target anti-Xa levels prior to hospital discharge, nearly a third of patients did not achieve a target level. This was likely a result of the application of the protocol to critical care patients only, as patients who reached target levels had significantly longer lengths of hospital and ICU lengths of stay compared with those who did not reach target anti-Xa levels. There will always be a number of patients whose length of stay is too short for them to achieve on-target anti-Xa levels, however with the expansion of this protocol to those admitted to non-critical care units, we hope that the percentage of patients who achieve a target anti-Xa prior to discharge increases. Notably, we did not observe a difference in VTE rates when comparing those who did and did not achieve a target anti-Xa level. Though several studies have observed decreased VTE rates with target anti-Xa levels,21 29 30 the data remain mixed with others reporting trends towards decreased VTE rates without statistical significance.31–33 We suspect that if all patients admitted to the trauma service had been included, we may have seen a difference in VTE rates in those with target anti-Xa levels.
Our study is not without limitations. First, this is a prospective cohort study from a single institution that relied heavily on medical record review. As such, this may not be an accurate representation of all critically injured patients. As we only included patients who received enoxaparin, we were unable to compare rates of VTE or bleeding to patients who received a different type of VTE prophylaxis or no VTE prophylaxis. Additionally, as the current protocol has only been applied to patients admitted to the ICU, we were not able to examine the efficacy or safety of this protocol in the general trauma population. In the future, we hope to expand this protocol to all patients admitted to the hospital, including those admitted outside the ICU. Finally, the actual target anti-Xa level for enoxaparin prophylaxis was based on prior studies that showed a decrease in DVT rates with higher anti-Xa levels. Furthermore, this study only examined peak anti-Xa values and did not track anti-Xa trough levels. As more work is completed on this topic, it becomes clear that the true anti-Xa level at which patients receive a true prophylactic benefit remains somewhat unknown.19–21
In conclusion, VTE remains a significant cause of morbidity in the critically ill trauma population. Though enoxaparin has been shown to be the superior agent for VTE prophylaxis in the trauma population, the ideal dose and titration regimen have not yet been settled on. Here, we have demonstrated that a pharmacist-driven, dose titration regimen based on anti-Xa level monitoring in trauma patients admitted to the ICU is safe and feasible. However, there remains room for improvement as 30% of patients did not achieve a target anti-Xa level prior to discharge from the hospital. In the future, we hope to expand this quality improvement project to include all admitted patients with trauma, not just those admitted to the ICU. Additionally, we plan to study our institutional rates of VTE in patients with trauma before and after implementation of this new protocol.