Discussion
We analyzed that patients with TBI received enoxaparin approximately 7.5 days after admission due in part to a high percentage of these patients receiving unfractionated heparin, and approximately 11 days after admission were required before patients with TBI reached the target prophylactic enoxaparin dose of 40 mg two times per day. After enoxaparin was started the median time required to reach a dose within the target anti-Xa range was 3.5 days for both patients with and without TBI. This delay was in part due to the need to increase the enoxaparin dose multiple times, as well as the time required between troughs. These findings provide guidance that a substantial delay exists between when pharmacological prophylaxis is initiated and when adequate prophylaxis is received.
Our result highlight two challenges in pharmacologic prophylaxis after TBI: (1) timely and (2) effective dosing. A subanalysis in a related study23 that we performed demonstrated that 48.9% did not receive enoxaparin, of which 26.4% received unfractionated heparin, whereas the remainder did not receive any thromboprophylactic agent. Approximately 1.1% were not started on an agent due to bleeding, whereas 61.8% were either discharged or had an in-hospital mortality before one could be initiated. In this same study, we found that of the patients that were placed on enoxaparin; 75.0% did not achieve adequate anti-Xa levels; 6.4% died, whereas the remainder were discharged before attaining an adequate level. These data provide more insight into the delays that result in adequate dosing.
Although there was no statistical difference as to when a VTE was first diagnosed in this study, diagnosis in the TBI cohort appeared to occur later. This trend may be due to altered mental status secondary to TBI or ventilator dependence, which may impact a clinician’s ability to detect a symptomatic VTE, thus leading to later diagnosis. VTE may occur even earlier in patients with TBI. Given that the inclusion criteria for this study required patients who remained hospitalized until they reached target anti-Xa trough levels, this cohort represents a subset of patients that were inherently more complex than typical trauma patients. Our data demonstrate that many of these patients had additional injuries and required interventions which may have precluded early pharmacological thromboprophylaxis.
The concern for ICH progression is one reason for delay in timely dosing, although 46.3% of the patients were started on unfractionated heparin prior to receiving enoxaparin, suggesting that many patients were able to receive pharmacological prophylaxis. Fear of ICH progression often delays the initiation of enoxaparin, although increasingly it is administered early after brain trauma.23–32 Prospective data established that enoxaparin 24 hours after admission was safe for some patients with TBI.24 25 Subsequently, the decision to initiate pharmacological prophylaxis was based on whether or not ICH progression was observed on the follow-up CT.26 31 32 If ICH progression was noted, exposure to pharmacological prophylaxis predicted further progression. If no ICH progression was observed, then pharmacological prophylaxis was encouraged.26 31 32 The rate of ICH progression was about 10% whether or not pharmacological prophylaxis was initiated.26 When early pharmacological prophylaxis is initiated after TBI, there is a lower VTE rate with no difference in rate of late neurosurgical intervention.27 31 32
Since approximately half of the patients with TBI studied were initiated first on unfractionated heparin prophylaxis, the belief that unfractionated heparin is somehow safer than enoxaparin persists despite evidence that the opposite may be true as unfractionated heparin is associated with a higher rate of ICH progression.3 As enoxaparin has increased bioavailability, longer plasma half life, more predictable pharmacokinetics and pharmacodynamics,8 interacts less with platelets, and has a lower incidence of heparin-induced thrombocytopenia compared with unfractionated heparin33 the belief that unfractionated heparin is safer is unfounded.
Unfractionated heparin at 5000 U three times a day continues to be proposed as ‘non-inferior’ to enoxaparin in part due to a trial that concluded the two medication may have similar VTE rates.12 This trial was underpowered to demonstrate the actual difference in the VTE rate as it predicted a VTE rate of 44% for unfractionated heparin and 31% for enoxaparin instead of the observed rate of 8.2% for unfractionated heparin and 5.1% for enoxaparin (p=0.2).8 12 In addition, the trial was not powered to detect a difference in the rate of PE or HIT, both of which impact the complication rate and healthcare costs.8 10 More recently, enoxaparin 30 mg two times per day was established as superior to unfractionated heparin 5000 U three times a day at reducing VTE.8 10 11
The optimal dose for many patients in this study was 40 mg two times per day. At our institution, all trauma patients are started on enoxaparin 40 mg two times per day unless one or more of the following exclusions apply: TBI, spinal cord injury, suspicion for ongoing bleeding, evidence of acute or chronic kidney disease, or 65 years of age or older. Our data demonstrate that the majority of patients with TBI require enoxaparin 40 mg two times per day or higher. The decision to initiate patients with TBI with enoxaparin 40 mg two times per day, in an effort to minimize the time to achieve adequate thromboprophylaxis, will require further investigation. Customized dosing using the patient’s creatinine dosing may result in better optimized initial enoxaparin dosing.34 35
This study was limited by its small size and lack of randomization. At times, disagreement occurred between the trauma and neurosurgical services regarding appropriate pharmacological prophylaxis for patients with TBI. This study could not capture the reasons for missed enoxaparin doses. As noted, the two cohorts were not similar with regard to injury severity so the higher VTE rate in patients with TBI could be attributable to reasons other than delayed or inadequate pharmacological prophylaxis. Importantly, the objective of this article was to characterize the delay until an adequate dose of enoxaparin was received in patients with and without brain trauma and not to compare the VTE rates between these cohorts. Despite these limitations, we demonstrated that unfractionated heparin and low enoxaparin doses could be reasons for higher VTE rates in patients with TBI. Although the Brain Trauma Foundation established that there is insufficient evidence to support recommendations regarding the preferred agent, dose, or timing of pharmacological prophylaxis, these recommendations may be outdated.36 Partly due to the findings of this study, we have collaborated with our neurointensivist and neurosurgical colleagues at our institution to implement earlier initiation of enoxaparin.
In conclusion, based on anti-Xa levels 11 days after admission were required before patients with TBI received an adequate enoxaparin dose for pharmacological prophylaxis due to delays in its initiation and because unfractionated heparin was frequently used as an intermediate agent. The median enoxaparin dose required to reach target anti-Xa levels for both patients with TBI and patients without TBI was 40 mg two times per day. The early administration of enoxaparin titrated by anti-Xa trough levels should be strongly considered for patients with TBI. A prospective randomized clinical trial with a larger TBI cohort is recommended to improve VTE prophylaxis for this population.
