Abstract

1. INTRODUCTION

The World Health Organization has reported an obesity epidemic affecting many countries, even developing, poor nations.¹ According to the Centers for Disease Control, the prevalence of obesity in the United States in the 12‐19 year age range has already nearly doubled from 10.5% (1988‐1994) to 20.6% (2013‐2014), while extreme obesity (defined as ≥ 120th percentile) has tripled from 2.6% (1988‐1994) to 9.1% (2013‐2014).² Similar to obese adults, obese adolescents have a higher risk of venous thromboembolism (VTE) compared to non‐obese adolescents.³, ⁴, ⁵, ⁶, ⁷ As the global obesity epidemic continues, there will be a greater need to treat overweight and obese adolescents for VTE. This population poses a dosing dilemma when prescribing low‐molecular‐weight heparins (LMWH)—commonly enoxaparin.

There is little data to guide providers on how to dose enoxaparin in overweight and obese adolescents. First, the recommendations by the American College of Chest Physicians (ACCP) for weight‐adjusted dosing of enoxaparin to treat pediatric VTE are based largely on adult studies, despite reduced predictability of the anticoagulant effect in children compared to adults when using weight‐adjusted dosing.⁸, ⁹ Thus, enoxaparin is used off label in children. Second, obesity can affect the pharmacokinetics of enoxaparin, although it is unclear if the net effects warrant dose modifications.¹⁰, ¹¹, ¹², ¹³, ¹⁴ Third, the therapeutic ranges recommended by the College of American Pathologists have not been validated in clinical trials.¹⁵ Finally, the monitoring of enoxaparin utilizing anti‐Xa levels in adults is controversial, and no data exist for adolescents.¹⁶, ¹⁷

Adolescent VTE, most commonly deep vein thrombosis (DVT) and pulmonary embolism (PE), patterns and mortality rates are different compared to adult VTE.¹⁸ For example, PE in adolescents is rarely fatal and likely secondary to fewer comorbidities in the adolescent population.¹⁹ In addition, adult dose‐reduction strategies such as dose‐capping may not apply for an obese adolescent who weighs less.¹², ¹³, ²⁰ Because of these differences, data from obese adolescents is necessary and should not be extrapolated from trials designed for obese adults.

To our knowledge, there has been no study describing dose modifications in obese adolescents diagnosed with VTE. Two case series described enoxaparin prophylaxis in obese adolescents, not treatment.²¹, ²² The small numbers in those studies limit the interpretation of their enoxaparin pharmacokinetic data.

At our institution, the Pediatric Hematology/Oncology (PHO) team is consulted for all adolescent patients diagnosed with VTE. The initial dosing of enoxaparin is determined and ordered at a pediatric hematologist's discretion with some patients receiving doses less than the ACCP's recommendations. After approval by the institution's institutional review board, we performed a retrospective cohort study with the primary goal of describing dosing, anti‐Xa levels, and outcomes of overweight and obese adolescents who received upfront reduced dosing (RD) of enoxaparin. We also compared these patients to overweight and obese adolescents treated at our institution who received standard dosing (SD) to determine if future trials to evaluate the efficacy and safety of dose reduction are warranted.

2. MATERIALS AND METHODS

3. RESULTS AND DISCUSSION

The initial database query resulted in 276 patients. Electronic and written medical record review resulted in 42 patients, 12 of which were excluded for cerebral venous thrombosis (4), recent trauma or surgery (3), or renal disease (5), leaving 30 patients in our study group. Twenty‐seven patients were hospitalized for initial VTE management. Of these 27 hospitalized patients, three were transferred from outside institutions on enoxaparin plus warfarin (2) or heparin infusion (1) at the time of transfer. After 4 weeks of hospitalization, one patient followed up with an outside institution for continued VTE management. Serum creatinine was available in 21 patients (range 0.53‐0.99 mg/dL); the estimated GFR was 97.12 mg/min/1.73 m² (range 69.12‐143.50 mg/min/1.73 m²). Available unconjugated bilirubin levels (n=20), were below 6 mg/dL, the threshold shown to interfere with anti‐Xa level assays.²⁶ Twenty‐nine patients were reportedly negative for antithrombin III deficiency.

Nineteen patients initially received RD enoxaparin (Table 1). Mean initial anti‐Xa level was within therapeutic range and 14/19 (74%) had initial therapeutic or supra‐therapeutic anti‐Xa levels. Five patients had initial sub‐therapeutic anti‐Xa levels, one of whom tested positive for a lupus anticoagulant and had a thrombus progression. Of the 19 patients, 10 (53%) did not require any dose adjustments during treatment; 23 of 27 (85%) anti‐Xa levels obtained during their treatment were within therapeutic range. The mean initial and final doses were not significantly different (Figure 1). Four RD patients’ final doses were greater than their initial doses (Table 2). Of these four, two patients who were initially dosed at <0.7 mg/kg had thrombus progression despite one patient having an initial supra‐therapeutic anti‐Xa level. Two bleeding events occurred, both of which were minor (Table 1).

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Figure 1

Mean±standard deviation initial (blue) and final dosing (red) for the two study groups. Patients dosed initially at <0.90 mg/kg (RD) did not significantly increase their dose, while patients dosed at ≥0.90 mg/kg (SD) significantly decreased their dose to maintain anti‐Xa levels within therapeutic range (0.5‐1.0 units/mL)

Eleven patients received SD (Table 1). Unlike the RD patients, the SD patients’ mean final dose was significantly lower than their mean initial dose (Figure 1). Notably, in eight patients whose final doses were less than their initial doses, six (75%) were dose reduced secondary to supra‐therapeutic anti‐Xa levels obtained 2‐16 days from initiation of therapy.

Between the two groups, no significant differences were observed in demographics, obesity status, type of VTE, and use of thrombolysis (Table 1). Despite a significantly lower mean initial dose in the RD group compared to the SD group, the mean initial anti‐Xa levels and mean final doses were similar between the groups (Table 1). There were no significant differences in the percentages of patients who had initial sub‐therapeutic, therapeutic, or supra‐therapeutic anti‐Xa levels, the number of anti‐Xa levels obtained during 90 days of treatment, nor in progression or bleeding rates between the two groups (Table 1).

In prior LMWH studies, the reported incidence of progression ranged from 1‐7%²⁷, ²⁸, and the reported incidence of bleeding ranged from 0‐36%.²⁷, ²⁹ Utilizing a mean incidence of approximately 5% for progression, and 20% for minor bleeding, our RD and SD groups did not differ significantly with these mean rates (progression: RD vs 5% P=.25; SD vs 5% P=.43, bleeding: RD vs 20% P=.40, SD vs 20% P=.47).

Ultimately, 83% of all patients were on RD at the end of treatment or at 90 days from diagnosis (n=25, mean dosing 0.73 ± 0.11 mg/kg), with therapeutic or supra‐therapeutic anti‐Xa levels.

These findings suggest that initial doses calculated using actual body weight may be greater than what is needed, which is consistent with some previously published reports.¹², ¹³, ²⁶ Therapeutic or supra‐therapeutic anti‐Xa levels were achieved in 74% of the RD group. However, the degree of dose reduction should be cautiously considered as the two RD progressions occurred in patients who were initially dosed at <0.7 mg/kg.

Though the role of anti‐Xa monitoring for enoxaparin in adult is controversial, monitoring in our SD patients showed supra‐therapeutic levels up to 16 days from the initial dose. The significance of this is unknown as our sample size is small, but may be secondary to the effects that obesity has on enoxaparin pharmacokinetics that have yet to be clearly defined.¹⁰, ¹¹, ¹², ¹³, ¹⁴ Until there are more studies regarding the utility of anti‐Xa levels, overweight individuals should have periodic monitoring, possibly during the first 2 weeks of therapy.¹⁶, ¹⁷

All bleeding events in our study were minor. Compared to the RD group, the SD group had a higher percentage. This is more likely secondary to the small sample size and less likely secondary to overdosing in the SD group; two of the three SD group patients had therapeutic anti‐Xa levels during the bleeding events.

Limitations inherent to retrospective cohort studies at a single institution pertain to this preliminary study. Furthermore, outpatient factors such as injection methods or timing of anti‐Xa level testing are confounding variables. The small sample size precludes any conclusions regarding efficacy and safety. Nonetheless, as obesity rates increase globally, future trials are warranted to evaluate reduced dose enoxaparin in the treatment of overweight and obese adolescents with VTE. The information reported here offers a beginning for that research.

AUTHOR CONTRIBUTIONS

S. Hoffman and C. Braunreiter contributed to the research design, data collection and analysis, and manuscript writing.

RELATIONSHIP DISCLOSURE

The authors have no funding sources or conflicts of interest to disclose.

ACKNOWLEDGMENTS

Notes

Hoffman S, Braunreiter C. Reduced dosing of enoxaparin for venous thromboembolism in overweight and obese adolescents: a single institution retrospective review. Res Pract Thromb Haemost. 2017;1:188–193. 10.1002/rth2.12032 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

REFERENCES