Discussion
In this retrospective study, we found that there were a few clinical characteristics that were correlated with an enoxaparin dosing change for VTE treatment. These characteristics included an age of 2-5.9 months, Native American ethnicity, and critical care status, which was defined as admittance to the pediatric intensive care unit at the start of enoxaparin. Interestingly, factors such as ages of 6-11.9 months, obesity, and AKI did not have statistical significance in terms of the likelihood of having dose changes after starting enoxaparin. Clinically, the non-statistical significance is potentially due to the low number of patients in our study. Over the 9-year period, there were only 68 patients who met inclusion criteria which is a fairly low number of patients treated for VTE, which indicates that the incidence of VTE is uncommon in children. Annually, it is estimated that the incidence of VTE in children is between 0.14 and 0.21 per 10,000 children.16,17
Secondary outcomes focused on enoxaparin monitoring practices. We found that pediatric patients on therapeutic enoxaparin received an average of 7.5 blood draws to check anti-Xa levels, but only received an average of 2 dose changes during a therapeutic course. In children who develop a VTE that has occurred with a clinical risk factor that has resolved, it is suggested to treat for 6-12 weeks.1 Having 7.5 levels checked in that period of time is approximately one blood draw weekly to every other week. Many of these patients start their treatment in the hospital as it has been reported that the incidence of hospital acquired VTE is 30 episodes per 10,000 admissions.18Although costly, monitoring anti-Xa levels in the hospital is convenient. Once a patient is discharged, they must then return for blood draws, which is a painful procedure, therefore disrupting a normal routine and adding to the overall healthcare costs.
In the adult patient population, anti-Xa levels are not commonly checked, mainly due to more predictable pharmacokinetic variables, excluding obese and renal patients. One study examined 99 adult patients on treatment enoxaparin to determine if anti-Xa monitoring was necessary in the obese population.19 It was noted that for safety and potential efficacy purposes, anti-Xa should be monitored in this patient population, although clinical outcomes related to anti-Xa monitoring are controversial. In a case series conducted by Ahuja et al, underweight and renally impaired adult patients were subtherapeutic with their first anti-Xa level and often required dose increases to achieve appropriate levels.20 In these unique adult populations it is necessary to monitor levels while on enoxaparin treatment, but overall in general it is not considered standard of practice. By checking fewer levels, healthcare costs and patient inconvenience is decreased. Although we did not see a statistical significance for obesity or renal impairment leading to dose changes in our population, it is important to note that we strongly recommend continuing to check levels in these patients.
What also makes enoxaparin management difficult in the pediatric population is that dosing is not standardized as it is in adults. Doses are often started at 1 mg/kg twice a day but may vary based on age.1 It is thought that infants up to 6 months require a higher weight based dose than other age groups, while infants 6 months to 12 months are slightly higher than children 1 year to 18 years all start at a standard dose. This variability drives the practice of checking anti-Xa often. Based on the results of our study, there is a possibility that we check levels too often in a population that does not necessarily require it. Standard practice has evolved to checking the first level before the second or third dose, a confirmatory level once stable, a one-week level then a one-month level and so on. Some practices may even check more often, which leads to higher healthcare costs and unnecessary blood draws.
Even with the results of our study, it is important to consider that some patients should still be monitored more frequently while on enoxaparin for safety and potential treatment efficacy. Included in this list are those that met the primary outcome such as critical care status, Native American ethnicity, and younger than 6 months of age. Although not detected in our analysis, we would recommend a conservative approach in frequent monitoring of patients under 10 years old, those with AKI, underweight, obese, or with a clinical judgment by the treating practitioner. That being said, in these sub-populations one could consider decreasing the number of tests drawn, one of which is the confirmatory test. Based on our results, it may be more cost effective and important to test after a week of a therapeutic level since it was found that 37% of our patients required a dose change after a week compared to 13% after the confirmatory level.
The first limitation to this study is the small sample size being evaluated and the lack of standardization of anti-Xa monitoring. If there was a larger sample, there may have been more data to recommend when to test versus not. Due to the infrequent VTE incidence in pediatrics, this could have been more adequate as a multicenter study. Secondly, this is a retrospective study, hence there are many individualized factors that could not be controlled. Although difficult to conduct, future multi-institutional prospective studies could provide beneficial information on dosing, monitoring, and treatment outcomes of enoxaparin use in the pediatric population. Lastly, the pediatric population is so variable with continuously changing kinetics and dynamics plus growth and development play an important role on how medications are dosed and monitored. Future studies should be focused on starting with a well-defined population that share similar characteristics. A focused approach can provide robust details that can eventually be expanded to the greater population.