By Arzo Hamidi, PharmD, BCCCP
Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago
Prevention of venous thromboembolism (VTE) is important for all hospitalized patients to prevent additional morbidity and costs during hospitalization. Critically ill patients in the intensive care unit (ICU) may have additional risk factors, such as higher illness severity, immobilization, mechanical ventilation, renal failure, and use of central catheters, that predispose them to VTE.1,2 The use of pharmacological and/or mechanical prophylaxis is recommended in hospitalized patients to reduce this risk.
Guideline Recommendations
The American Society of Hematology (ASH) recommends using either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) over no prophylaxis at all and recommends LMWH over UFH, specifically.3 LMWH has a reduced risk of bleeding compared to UFH with similar or superior efficacy.3-6 Most of the data surrounding prophylaxis is in hospitalized, medically ill, not critically ill, patients. The scope of this review will not cover surgical or trauma patients who might have a higher risk of VTE incidence. The purpose of this review is to re-evaluate controversial dosing of enoxaparin in areas of uncertainty, specifically in extremes of body weight and in patients with renal dysfunction, and discuss dosing of UFH.
Enoxaparin for Thromboprophylaxis
Enoxaparin in Low Body Weight
In a study of 56 patients who weighed ≤ 55 kg, patients who received the standard dosing of enoxaparin 40 mg subcutaneously daily had anti-factor Xa levels measured.7 The anti-factor Xa levels were within therapeutic range, instead of prophylactic range, in patients who weighed 50 kg and less. The study did not assess incidence rates of VTE or bleeding. This study highlights the inverse relationship between body weight and anti-factor Xa levels; however, a significant limitation of this study is that it did not include clinical outcomes (thromboembolic or bleeding events). Another study with 210 patients who weighed ≤ 45 kg received LMWH at 30 mg per day, 30 mg twice daily, or 40 mg per day.8 The rate of major bleeding was 16.2% in all of these patients. There was no incidence of VTE in any of the patients. Some limitations of this study were that 86% of patients were women, and doses of enoxaparin were chosen at the discretion of the provider. These studies are summarized in Table 1.
Table 1. Enoxaparin Use in Low Body Weight |
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Study |
Study Design |
Population |
Dose |
Anti-factor Xa (mean) |
VTE Incidence |
Bleeding Incidence |
Rojas7 (n = 56) |
Single-center, prospective of ICU and non-ICU adult patients |
≤ 55 kg |
40 mg/day |
51-55 kg: 0.46 IU/mL 46-50 kg: 0.56 IU/mL ≤ 45 kg: 0.64 IU/mL |
n/a |
n/a |
Dybdahl8 (n = 210) |
Single-center, retrospective cohort of hospitalized patients, including trauma patients |
≤ 45 kg |
30 mg/day or 30 mg BID or 40 mg/day |
n/a |
0 |
16.2% |
ICU: intensive care unit; VTE: venous thromboembolism; BID: twice daily |
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Based on these studies, enoxaparin 40 mg daily may have supratherapeutic anti-factor Xa levels with increased risk of bleeding in patients weighing less than 55 kg. This limited evidence suggests that enoxaparin for prophylaxis should be dosed at 30 mg or an alternative agent should be used in patients with extremely low body weight. While anti-factor Xa levels were used in these studies, they do not have significant clinical utility because these studies did not correlate levels with clinical outcomes. At this time, anti-factor Xa levels are not routinely monitored in patients with low body weight, and future studies may further elucidate this relationship.
Enoxaparin in Obesity
Conversely, standard enoxaparin dosing of 40 mg daily may be insufficient prophylaxis in obese patients. Studies have investigated enoxaparin dosing in patients with varying body mass index (BMI). In a study of 31 patients with BMI > 40 kg/m2, patients received either 40 mg daily, 0.4 mg/kg/day, or 0.5 mg/kg/day.9 Anti-factor Xa levels were measured, but rates of VTE and/or bleeding were not reported. Anti-factor Xa levels were subtherapeutic in 82% of patients who received 40 mg daily, 36% of those who received 0.4 mg/kg/day, and 13% of those who received 0.5 mg/kg/day. In a study of 80 patients with a BMI > 40 kg/m2 who received 0.5 mg/kg/day or 40 mg twice daily, anti-factor Xa levels were measured and were both similar at a mean of 0.28 IU/mL.10 The incidence rates of VTE and major bleeding were negligible in this study.
Another single-center, prospective study of 91 patients with a BMI of > 30 kg/m2 who received enoxaparin 40 mg/day or 60 mg/day found that anti-factor Xa levels were 0.25 IU/mL and 0.35 IU/mL, respectively.11 Again, incidence rates of VTE and/or bleeding were not measured in this study. These studies are summarized in Table 2.
Table 2. Enoxaparin Use in Obesity |
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Study |
Study Design |
Population |
Dose |
Anti-factor Xa (mean) |
VTE Incidence |
Bleeding Incidence |
Freeman9 (n = 31) |
Single-center, prospective group of general medicine patients |
> 40 kg/m2 |
40 mg/day 0.4 mg/kg/day 0.5 mg/kg/day |
< 0.2 IU/mL in: 82% of 40 mg/day 36% of 0.4 mg/kg/day 13% of 0.5 mg/kg/day |
n/a |
n/a |
Miranda10 (n = 91) |
Single-center, prospective group of hospitalized patients |
> 30 kg/m2 |
40 mg/day 60 mg/day |
0.25 IU/mL 0.35 IU/mL |
n/a |
n/a |
Gibson11 (n = 80) |
Multicenter, prospective group of hospitalized patients |
> 40 kg/m2 |
0.5 mg/kg/day 40 mg BID |
0.28 IU/mL 0.28 IU/mL |
0 |
0 |
ICU: intensive care unit; VTE: venous thromboembolism; BID: twice daily |
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Similar to low body weight patients, there is limited evidence to suggest ideal dosing in obesity, since many studies measuring anti-factor Xa levels did not report clinical outcomes. The current recommendation for enoxaparin dosing for deep vein thrombosis (DVT) prophylaxis would be 40 mg twice daily or a weight-based dose of 0.5 mg/kg daily divided into two doses.
Renal Impairment
A single-center, retrospective study of 460 critically ill patients with renal impairment studied prophylactic dosing with enoxaparin or UFH.12 Renal dysfunction was most commonly an acute kidney injury, but the study also included severely decreased renal function and end-stage renal disease. The average daily dose of enoxaparin was 39 ± 4 mg. After an adjusted analysis, there was a significant difference in major bleeding events with enoxaparin compared to UFH (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.11-3.04; P = 0.02). There was no difference in rates of VTE. As expected with an agent that is dependent on renal clearance, there may be an increased risk of bleeding in the setting of renal impairment. Further studies should investigate if reduced doses may be safe and tolerable for these patients.
Unfractionated Heparin
Since enoxaparin may not be the appropriate agent for every patient for VTE prophylaxis, UFH may be used as an alternative agent. Similarly, UFH often is chosen in patients who may have a higher bleeding risk. UFH is dosed at 5,000 units three times daily or twice daily. The choice for frequency often is determined by thrombosis risk vs. bleeding risk.
A pharmacoepidemiologic study included more than 30,000 ICU patients who received 5,000 units either twice daily or three times daily.13 The incidence rates of VTE or major bleeding in these patients were not statistically significantly different between either dosing frequency. Other studies with mixed ICU and non-ICU patients showed similar results regarding incidence of VTE or major bleeding.14,15 When choosing UFH frequency, several factors may be taken into consideration: risk-benefit evaluation, practical and operational considerations such as patient comfort surrounding a subcutaneous injection, nursing resources, pharmacy resources, sleep hygiene related to medication administration, time, and drug cost. These studies are summarized in Table 3.
Table 3. Unfractionated Heparin Frequency |
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Study |
Study Design |
UFH Dose |
VTE Incidence(BID vs. TID) |
Bleeding Incidence(BID vs. TID) |
Reynolds13 (n = 30,800) |
Retrospective epidemiological study of ICU patients |
5,000 units BID vs. TID |
6.23% vs. 6.16%, P = 0.8 |
Major bleed: 0.33% vs. 0.23%, P = 0.084 |
Sorgi14 (n = 4,188) |
Single-center, retrospective cohort of mixed patients |
5,000 units BID vs. TID |
1.2% vs. 1.9%, P = 0.14 |
Major bleed: 0.71% vs. 0.77%, P = 0.85 |
Wiethorn15 (n = 787) |
Single-center, retrospective cohort of mixed patients |
5,000 units BID vs. TID |
4% vs. 3%, P = 0.635 |
Major and non-major bleed: 10% vs. 8%, P = 0.31 |
UFH: unfractionated heparin; VTE: venous thromboembolism; BID: twice daily; TID: three times daily; ICU: intensive care unit |
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Conclusion
The use of pharmacological DVT prophylaxis is recommended unless contraindicated to prevent VTE in hospitalized patients. Enoxaparin is recommended over UFH; however, weight and renal function always should be considered. In instances where providers may interpret an increased bleeding risk due to patient comorbidity or renal function, UFH may be used. UFH is dosed at either twice or thrice daily in terms of frequency, with similar clinical outcomes.
References
- Samuel S, Li W, Dunn K, et al. Unfractionated heparin versus enoxaparin for venous thromboembolism prophylaxis in intensive care units: A propensity score adjusted analysis. J Thromb Thrombolysis 2023;55:617-625.
- Eck RJ, Hulshof L, Wiersema R, et al. Incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients: Data from two prospective cohort studies. Crit Care 2021;25:27.
- Schünemann HJ, Cushman M, Burnett AE, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018;2:3198-3225.
- Beitland S, Sandven I, Kjaervik LK, et al. Thromboprophylaxis with low molecular weight heparin versus unfractionated heparin in intensive care patients: A systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 2015;41:1209-1219.
- Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients. Chest 2012;141(2 Suppl):e195s-e226s.
- Alikhan R, Bedenis R, Cohen AT. Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction). Cochrane Database Syst Rev 2014;5:CD003747.
- Rojas L, Aizman A, Ernst D, et al. Anti-Xa activity after enoxaparin prophylaxis in hospitalized patients weighing less than fifty-five kilograms. Thromb Res 2013;132:761-764.
- Dybdahl D, Walliser G, Pershing M, et al. Enoxaparin dosing for venous thromboembolism prophylaxis in low body weight patients. Clin Med Insights Blood Disord 2019;12:1-7.
- Freeman A, Horner T, Pendleton RC, Rondina MT. Prospective comparison of three enoxaparin dosing regimens to achieve target anti-factor Xa levels in hospitalized, medically ill patients with extreme obesity. Am J Hematol 2012;87:740-743.
- Miranda S, Cam-Duchez VL, Benichou J, et al. Adjusted value of thromboprophylaxis in hospitalized obese patients: A comparative study of two regimens of enoxaparin: The ITOHENOX study. Thromb Res 2017;155:1-5.
- Gibson CM, Hall C, Davis S, Schillig JM. Comparison of two escalated enoxaparin dosing regimens for venous thromboembolism prophylaxis in obese hospitalized patients. J Thromb Thrombolysis 2021;52:577-583.
- DeBiase C, Giuliano CA, Doshi M, et al. Enoxaparin versus unfractionated heparin for venous thromboembolism prophylaxis in renally impaired ICU patients. Pharmacotherapy 2021;41:424-429.
- Reynolds PM, Van Matre ET, Wright GC, et al. Evaluation of prophylactic heparin dosage strategies and risk factors for venous thromboembolism in the critically ill patient. Pharmacotherapy 2019;39:232-241.
- Sorgi MW, Bauer SR, Bauer SR, et al. Effectiveness and safety of twice daily versus thrice daily subcutaneous unfractionated heparin for venous thromboembolism prophylaxis at a tertiary medical center. J Pharm Pract 2022;35:190-196.
- Wiethorn EE, Harrison S, Weeda ER, Bell CM. Effectiveness and safety of twice- versus thrice-daily subcutaneous heparin for venous thromboembolism prophylaxis at a large academic medical center. Ann Pharmacother 2022;56:541-547.
Prevention of venous thromboembolism (VTE) is important for all hospitalized patients to prevent additional morbidity and costs during hospitalization. Critically ill patients in the intensive care unit (ICU) may have additional risk factors that predispose them to VTE.
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