J Thromb Thrombolysis DOI 10.1007/s11239-016-1384-x
The use of anti-factor Xa monitoring in a selection of patients receiving enoxaparin at a large academic medical center Gretchen L. Sacha1 • Katie M. Greenlee1 • Jeffrey M. Ketz1
Springer Science+Business Media New York 2016
Abstract Therapeutic enoxaparin is commonly used over heparin because of its favorable pharmacokinetic profile and ease of administration. Monitoring of the anticoagulant response, if necessary, is done with anti-factor Xa levels. Currently, it is suggested that monitoring may be beneficial in patients who are overweight and those with renal dysfunction. This study aimed to characterize the use of enoxaparin at a large-academic medical center in patients [150 kg, \45 kg and in those with renal dysfunction, and to describe the rate of anti-factor Xa monitoring in these patients. There were 273 patients included in the study: n = 96 for \45 kg arm, n = 111 for [150 kg arm and n = 66 for renal dysfunction arm. Less than 30 % of patients in each arm had low molecular weight heparin anti-factor Xa levels drawn. Of these only half were drawn as peak levels (4 h post dose). Overall rates of anti-factor Xa monitoring was low. It was found that obese patients achieved therapeutic anticoagulation with lower than recommended doses; underweight patients were often subtherapeutic on the recommended doses; and patients with renal dysfunction tended to have therapeutic to subtherapeutic anti-factor Xa levels. Ultimately, this evaluation showed that enoxaparin has unpredictable pharmacokinetics in these three high-risk patient populations and antifactor Xa monitoring may be necessary to ensure therapeutic levels and appropriate dosing.
Electronic supplementary material The online version of this article (doi:10.1007/s11239-016-1384-x) contains supplementary material, which is available to authorized users. & Gretchen L. Sacha
[email protected] 1
Cleveland Clinic, 9500 Euclid Ave/JJN1-200, Cleveland, OH 44195, USA
Keywords Anticoagulation Enoxaparin Low molecular weight heparins Anti-factor Xa Obese Renal dysfunction Underweight
Introduction Enoxaparin is a low molecular weight heparin (LMWH) with a lower protein binding affinity compared to heparin. It also has a more favorable pharmacokinetic profile and thus less need for therapeutic monitoring. However, in patients with significant renal impairment, there are recommendations to monitor enoxaparin’s anticoagulant effect [1]. Other patient populations, such as those at the extremes of weight, may benefit from individualized dosing and monitoring as the pharmacokinetic profile of enoxaparin is not fully understood in these individuals. Currently, pharmacokinetic data is available for the safe use of enoxaparin without the need for therapeutic monitoring in patients up to 144 kilograms (kg) [2]. There are, however, minimal formal evaluations of the safety of enoxaparin when used in patients that are greater than 150 kg. Similarly, there are little published data regarding its use in those under 45 kg, though there is an increased risk of bleeding events when prophylactic doses of enoxaparin are used in females less than 45 kg and males less than 57 kg [1]. Renal dysfunction is associated with decreased enoxaparin clearance, leading to elevations in anti-factor Xa levels and a potential increased risk of bleeding [3]. This has been demonstrated in several published evaluations [2, 4–7]. Manufacturer recommendations are to reduce standard therapeutic enoxaparin doses by 50 % in patients who have a CrCl B 30 mL/min [3]. The manufacturer also recommends to consider monitoring corresponding LMWH anti-factor Xa levels in these patients.
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At this time, there are three high-risk patient populations that are at a potential risk for accumulation of enoxaparin anti-factor Xa levels and subsequent bleeding: renal dysfunction, underweight, and overweight individuals. In these populations, anti-factor Xa levels may aid in the safe dosing of enoxaparin. In this study, investigators aimed to characterize the dosing and monitoring of therapeutic enoxaparin in these populations at a large academic medical center.
Methods This was a retrospective, non-interventional, medical chart review conducted at the Cleveland Clinic in Cleveland, Ohio. Patient data was collected from inpatient admissions between January 2010 and October 2015. Patients were categorized into one of three patient arms: weight [150 kg, weight \45 kg, or renal dysfunction [Creatinine Clearance (CrCl) B30 mL/min] at the time of enoxaparin initiation. To prevent overlap of patients between groups, patients with renal dysfunction were included if they weighed between 45 and 150 kg. Patients were included if they were C18 years of age and were receiving therapeutic enoxaparin. Patients receiving prophylactic enoxaparin were excluded. Patients were classified and analyzed as two different occurrences if enoxaparin was discontinued for [48 h during the admission. To ensure that patients were receiving enoxaparin for therapeutic anticoagulation, patients were included if they had a current diagnosis of pulmonary embolism, deep vein thrombosis, venous thromboembolism, or atrial fibrillation, by ICD-9 codes. The following data was collected on each patient: baseline characteristics including demographics such as age, height, body mass index (BMI), renal function and hemoglobin. In addition, initial enoxaparin dose and subsequent dose changes, renal function fluctuations, and all anti-factor Xa levels were collected. This institution utilizes both heparin anti-factor Xa levels and LMWH antifactor Xa levels. These lab values are calibrated for the specific anticoagulant with a therapeutic heparin anti-factor Xa goal range of 0.3–0.7 U/mL and LMWH anti-factor Xa goal range of 0.5–1.0 U/mL. Only peak LMWH anti-factor Xa levels, drawn 3–5 h after the dose, were analyzed. The primary outcome was to determine the rate of LMWH anti-factor Xa monitoring in patients \45 kg, [150 kg and in those with renal dysfunction. Secondary outcomes were to determine the doses that achieved therapeutic levels, determine the timing and assessment of LMWH anti-factor Xa levels, and to determine the rate of major bleeding events that occurred during enoxaparin administration.
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Medians and interquartile ranges or means and standard deviations were analyzed using the Shapiro–Wilk W Test to determine the spread of continuous data. All data was analyzed using JMP Pro 10. This study obtained appropriate IRB approval.
Definitions Renal dysfunction was defined as a CrCl B30 mL/min. CrCl was calculated by the Cockroft-Gault equation using ideal body weight (IBW), or actual body weight (ABW) (if ABW \ IBW) or adjusted body weight (AdjBW) if ABW [120 % of IBW. AdjBW was calculated with the following equation: IBW ? (0.4 (ABW-IBW)). Bleeding events were classified by the TIMI major and minor criteria [8]. Goal therapeutic levels of LMWH anti-factor Xa are 0.5–1.0 U/mL for twice daily or renally adjusted once daily administration, and[1.0 U/mL for once daily 1.5 mg/kg/dose administration. Peak LMWH anti-factor Xa levels were defined as levels drawn 3–5 h after enoxaparin administration. Anti-factor Xa interpretation was assessed based on dose changes as a result of LMWH anti-factor Xa levels and whether or not the dose was continued or discontinued. For example, if a level was subtherapeutic but the dose was not changed, the level was considered to not be correctly interpreted.
Results There were 304 patients identified through the electronic medical record report for evaluation of study inclusion. After exclusion, 273 patients were included: n = 96 for \45 kg arm, n = 111 for [150 kg arm and n = 66 for renal dysfunction arm (Fig. 1). Baseline characteristics for each high-risk patient arm are presented in Table 1. Evaluation of anti-factor Xa Assay monitoring A total of 120 anti-factor Xa levels were drawn for the 273 included patients. If a level was drawn, patients ranged from having 1 to 5 levels ordered. Of the 120 levels, 44 were heparin anti-factor Xa levels and 76 (63 %) were LMWH anti-factor Xa levels. Only 44 of the 76 (58 %) LMWH anti-factor Xa assays were drawn as peak levels. For each arm, median therapeutic, sub- and supratherapeutic LWMH anti-factor Xa levels as well as their associated doses and dose adjustments are presented in Table 2. Patients < 45 kg Of the 96 patients included in the \ 45 kg arm, 28 (29 %) had LWMH anti-factor Xa levels drawn, with a total of 42
The use of anti-factor Xa monitoring in a selection of patients receiving enoxaparin at a… Fig. 1 Patient inclusion diagram
304 Patients Evaluated
< 45 kg Arm n = 105
> 150 kg Arm N = 113
Renal Dysfunction Arm N = 86
Excluded: 8
Excluded: 2
Excluded: 20
Included: 96
Included: 111
Included: 66
Table 1 Baseline characteristics \45 kg (n = 96)
[150 kg (n = 111)
Renal dysfunction (n = 66)
Age
54 (37–54)
49 (42–59)
81.5 (75.8–86.3)
Gender (% female)
93.8 %
50.5 %
69.7 %
Weight, kg
41.7 (39.9–43.5)
159.3 (152.9–170.2)
68.1 (61.2–81.9)
Weight range, kg (min–max)
27.2–44.9
150.1–270.8
48.4–104.1
BMI, kg/m2
16.8 (15.5–18.0)
52.4 (47.0–57.5)
25.1 (21.8–29.2)
Baseline SrCr, mg/dL
0.5 (0.4–0.7)
0.9 (0.7–1.0)
1.7 (1.3–2.0)
Baseline calculated CrCl, mL/min
76.9 (54.1–103.8)
140.9 (116.1–182.3)
27.8 (25.0–30.2)
Initial enoxaparin dose, n (%)
\40 mg/dose: 12 (12.5 %) \150 mg/dose: 27 (24.3 %) \60 mg/dose: 11 (16.7 %) 40 mg/dose: 63 (65.6 %)
150 mg/dose: 83 (74.8 %)
[40 mg/dose: 21 (21.9 %) [150 mg/dose: 1 (0.9 %) Initial frequency of enoxaparin, n (%)
Initial weight based dose of enoxaparin, mg/kg/dose
60 mg/dose: 23 (34.8 %) [60 mg/dose: 32 (48.5 %)
Q24 h—17 (17.7 %) Q12 h—67 (69.8 %)
Q24 h—1 (0 %) Q12 h—94 (84.6 %)
Q24 h—43 (65.1 %) Q12 h—16 (24.4 %)
One time—12 (12.5 %)
One time—16 (14.4 %)
One time—7 (10.6 %)
0.97 (0.92–1.09)
0.91 (0.78–0.97)
0.97 (0.93–1.02)
Data are presented as median [interquartile range (IQR)] unless otherwise specified SrCr serum creatinine, CrCl creatinine clearance, kg kilogram, m meter, mg milligrams
levels overall. Of the 42 levels, only 24 (57.1 %) were peak LMWH anti-factor Xa levels. Within the peak levels, the median LWMH anti-factor Xa level was subtherapeutic at 0.47 (0.31–0.58) U/mL. Patients in this arm primarily had subtherapeutic levels (60.9 % of patients), and the remainder were therapeutic, with one supratherapeutic level, that was not a peak level. The median enoxaparin dose prior to the peak levels evaluated was 1.01 (0.93–1.21) mg/kg/dose.
Patients >150 kg Of the 111 patients included in the [150 kg arm, 11 patients (10 %) had LWMH anti-factor Xa levels drawn. A total of 22 levels were drawn in this group, for which only 14 (63.6 %) were peak. The median peak LWMH antifactor Xa level was 0.89 (0.47–0.95) units/mL. Patients primarily had therapeutic levels (64.3 % therapeutic, 21.5 % subtherapeutic, and 14.3 % supratherapeutic). The
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G. L. Sacha et al. Table 2 Results and dose response of LMWH anti-factor Xa levels Median LWMH anti-factor Xa level (U/mL)
Median dose administered at time of level draw (mg/kg/dose)
Median dose after dose adjustment based on level (mg/kg/dose)
Patient arm: \45 kg
n = 23
n = 23
n=6
Subtherapeutic
0.35 (0.23–0.46)
1.04 (0.92–1.23)
1.31 (1.21–1.53)
Therapeutic
n = 14 (60.9 %) 0.59 (0.52–0.66)
n = 14 1.00 (0.93–1.26)
n=4 1.14 (0.90–1.37)
n = 9 (39.1 %)
n=9
n=2
–
–
–
Supratherapeutic
n=0
n=0
n=0
Patient arm: [150 kg
n = 14
n = 14
n=3
Subtherapeutic
0.25 (0.25–0.30)
0.89 (0.79–0.89)
0.94 (0.89–0.99)
n = 3 (21.4 %)
n=3
n=2
0.89 (0.65–0.93)
0.96 (0.67–0.98)
–
n = 9 (64.3 %)
n=9
n=0
1.66 (1.50–1.81)
0.95 (0.89–1.00)
0.53
n = 2 (14.3 %)
n=2
n=1
Patient arm: renal dysfunction
n=5
n=5
n=2
Subtherapeutic
0.41 (0.35–0.47)
0.96 (0.92–1.0)
0.92
n = 2 (40.0 %)
n=2
n=1
Therapeutic
0.55 (0.53–0.82) n = 3 (60.0 %)
0.91 (0.82–1.0) n=3
1.14 n=1
Supratherapeutic
–
–
–
n=0
n=0
n=0
Therapeutic Supratherapeutic
Data are presented as median [interquartile range (IQR)] unless otherwise specified
median enoxaparin dose prior to the levels evaluated was 0.89 (0.77–0.98) mg/kg/dose. Most patients in this arm (74.8 %) received a max dose of 150 mg, lower than the recommended 1 mg/kg/dose. Table 1 in the Supplemental Appendix details the weight, dosing, and LMWH antifactor Xa levels within this group. Patients with renal dysfunction Of the 66 patients included in the renal dysfunction arm, only 7 (11 %) had LWMH anti-factor Xa levels drawn, with 12 levels total overall. Of these, 6 (50 %) were drawn as peak LMWH anti-factor Xa levels. The median peak LWMH anti-factor Xa level was 0.54 (0.44–0.63) units/ mL. Three of the five levels were therapeutic (60 %) and the remainder were subtherapeutic; no levels were supratherapeutic. The median enoxaparin dose prior to the peak levels evaluated was 0.92 (0.89–1.0) mg/kg/dose. Assessment of anti-factor Xa interpretation The assessment of anti-factor Xa interpretation is presented in Table 2 and Figure 1 of the Supplemental Appendix. Overall, 63.6 % of the levels were acted upon accordingly.
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LWMH anti-factor Xa levels >1.0 U/mL Overall, there were three patients with LWMH anti-factor Xa levels [1 U/mL. The patient characteristics are detailed in Table 3. The highest LWMH anti-factor Xa levels seen in this evaluation was a 4.5 h level of 1.81 U/mL seen in one patient weighing 151.7 kg. None of these three patients experienced obvious or notable bleeding events. Bleeding There were 8 bleeding events that occurred throughout the evaluated enoxaparin therapy. All classified bleeding events met TIMI minor criteria; no events met TIMI major criteria. Six events occurred in the\45 kg group, one in the [150 kg group and one in the renal dysfunction group. Five of the patients had anti-factor Xa levels drawn during therapy, three levels were subtherapeutic and one was therapeutic. The remaining level, in a patient \45 kg, was a 16 h trough of 0.59 U/mL and was likely a supratherapeutic peak level with subsequent therapeutic levels. Only two patients had enoxaparin discontinued due to the suspected bleeding event, one in the [150 kg arm and one in the renal dysfunction arm. The rest remained on and were
The use of anti-factor Xa monitoring in a selection of patients receiving enoxaparin at a…
Table 3 Characteristics of patients with LMWH anti-factor Xa levels above 1 U/mL Patient 1
Patient 2
Patient 3
Patient arm
\45
[150
[150
Age, years
63
47
68
Gender
Female
Female
Female
Weight, kg
41.1
150.2
151.7
BMI, kg/m2
15.5
54.8
54.0
Baseline CrCl, mL/min
58.3
182.2
73.7
Anti-factor Xa level, U/mL
1.14
1.50
1.81
Dose that achieved this level, mg
40 every 12 h
150 every 12 h
135 every 12 h
Time post enoxaparin administration, h
6.0
3.5
4.5
Dose adjustment
Dose decreased to 30 mg every 12 h
Enoxaparin D/C
Dose decreased to 80 mg every 12 h
Enoxaparin disposition
Discharged with enoxaparin
Enoxaparin D/C due to therapeutic INR
Enoxaparin D/C due to therapeutic INR
Subsequent antifactor Xa levels
Subsequent therapeutic peak level = 0.51 U/mL; dose was not changed and no additional levels were drawn.
No additional levels drawn
Subsequent 7 h level = 0.97 U/mL; dose was decreased again to 70 mg Q12 h. No additional levels drawn.
LMWH low molecular weight heparin, kg kilograms, mL milliliters, min minutes, mg milligrams, D/C discontinued, enox enoxaparin
discharged on enoxaparin with no further documented or objective bleeding episodes.
Discussion This study has shown that in patients\45 kg,[150 kg and patients with renal dysfunction, our institution is conservative initiating, continuing, and monitoring enoxaparin therapy, indicated by the small number of patients included over a four year period. In addition, we found that of 120 anti-factor Xa levels, 44 (36.7 %) were drawn as LMWH levels and appropriately timed as peak levels. In patients that it has been recommended by CHEST guidelines to consider monitoring anticoagulant effects, this is being done infrequently at this institution. Overall, monitored patients \45 kg were often subtherapeutic on doses of 1 mg/kg, patients [150 kg tended to be therapeutic but received doses \1 mg/kg, and patients with renally adjusted enoxaparin more often than not reached therapeutic LMWH anti-Xa levels. A meta-analysis by Lim et al. published in 2006 [7] showed that patients with a CrCl \30 mL/min, receiving standard 1 mg/kg every 12 h dosing of enoxaparin had higher anti-factor Xa levels compared to those with normal renal function. This was associated with a 3.8 fold increase
in the risk of major bleeding. When enoxaparin was renally adjusted to doses of 1 mg/kg daily, there was no statistically significant difference in anti-factor Xa levels between individuals with and without renal dysfunction [7]. The present study correlates with these findings as the patients in the renal dysfunction arm tended to have therapeutic levels when receiving renally adjusted enoxaparin doses and no patients in this arm had supratherapeutic levels. There are few studies evaluating the use of enoxaparin and anti-factor Xa monitoring in patients [150 kg. Deal et al. [9]. conducted a retrospective case series and found that in 26 patients with a BMI C40 kg/m2, the median dose of therapeutic enoxaparin was 0.8 mg/kg dosed every 12 h (capped at 150 mg/dose). In those evaluated, the median dose of enoxaparin that achieved therapeutic anti-factor Xa levels was 0.74 mg/kg dosed every 12 h [9]. Based on these results, Lalama et el [10]. developed an enoxaparin pharmacy dosing protocol, in which patients with a BMI C40 kg/m2 were dosed with 0.75 mg/kg enoxaparin every 12 h (every 24 h if CrCl B30 mL/min). After implementation, the authors evaluated 31 patients with a median weight of 138 kg (105–197 kg). The authors found that 48 % of patients had an initial anti-factor Xa level within therapeutic range, 36 % had supratherapeutic levels and 16 % had subtherapeutic levels. The mean dose needed to
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achieve therapeutic anti-factor Xa levels was 0.71 mg/kg twice daily [10]. Finally, Thompson-Moore et al. [11]. published a pharmacokinetic study evaluating appropriate enoxaparin dosing in patients with a BMI[40 kg/m2 or ABW[140 kg. In the 41 included patients, the median enoxaparin dose was 0.9 mg/kg every 12 h and 87.7 % of patients had peak, steady-state, anti-factor Xa levels drawn. Of these, 38.9 % were therapeutic, 50 % were supratherapeutic, and 11.1 % were subtherapeutic. The median dose to achieve therapeutic and supratherapeutic levels was 0.83 and 0.98 mg/ kg, respectively. Doses based on ABW were an independent predictor of supratherapeutic anti-factor Xa levels. The above studies correlate with the findings of the current study indicating that in obese individuals, [150 kg or with BMI [40 kg/m2, dose requirements may be less than the recommended 1 mg/kg/dose to achieve therapeutic anti-factor Xa levels. Overall, doses of 1 mg/kg do not appear to provide therapeutic levels consistently and often, doses less than 1 mg/kg produce therapeutic anti-factor Xa levels. In this study, bleeding events were minimal and occurred in only 8 patients. Only one of these patients had a supratherapeutic anti-factor Xa level, however, the timing of the onset of the bleeding event and this level is unknown. Historically, it has been shown that higher antifactor Xa levels is a risk factor for bleeding events [2, 4, 12]. It may be theorized from these findings, that antifactor Xa level monitoring is reasonable in patients at a high risk of bleeding and in those with unpredictable pharmacokinetics, to prevent the occurrence of bleeding complications. This evaluation included anti-factor Xa levels that were drawn as peak levels based on the recommendations of the enoxaparin product package labeling [1] and the CHEST guideline recommendations [3]. The range of 3–5 h was used for this study to allow for variation in blood draws and to represent the peak time of 4 h, as recommended [3]. However, the association between anti-factor Xa activity and efficacy and safety of enoxaparin is controversial and the most appropriate method of monitoring anti-factor Xa levels (i.e. peak or trough) remains to be determined. Limitations of this study include the small patient population. The goal number of patients was met, but the number of patients receiving monitoring was less than originally anticipated. Due to the retrospective nature of this evaluation, this study did not evaluate the risk of developing thrombosis to determine the effectiveness of targeting peak anti-factor Xa levels. Although only peak levels were evaluated, it is not definitive that these levels were drawn at steady state, but the importance and implication of steady state levels of enoxaparin is still not currently known.
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Conclusion This retrospective analysis characterized the use of enoxaparin in three groups of potentially high-risk patient arms, those \45 kg, [150 kg and those with renal dysfunction. It was found that levels are seldom being checked, and levels are rarely drawn as peaks. Educating providers regarding proper draw time and ordering the proper assay is imperative for the appropriate monitoring of this agent. It may be possible to utilize the benefits of the electronic medical record to provide alerts to prompt the provider to the correct anti-factor Xa assay as well as the appropriate timing of the level. Our results indicate that the recommended doses for those \45 or [150 kg do not provide consistently therapeutic levels and anti-factor Xa monitoring may be warranted. Obese patients achieved therapeutic anticoagulation with lower than recommended doses; underweight patients were often subtherapeutic on the recommended doses; and patients with renal dysfunction tended to have therapeutic to subtherapeutic anti-factor Xa levels. Bleeding events were minimal, but most often occurred in patients \45 kg, even though this group most often had subtherapeutic levels. In this evaluation, albeit a small sample size and low number of anti-factor Xa levels to evaluate, bleeding did not seem to be associated with anti-factor Xa levels. This has been found in previous evaluations and may need to be further studied. These high-risk patient populations have unpredictable pharmacokinetics and anti-factor Xa monitoring may be necessary to ensure therapeutic levels and appropriate dosing.
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