Abstract
Purpose: Optimal dosing of VTE prophylaxis for specific patient populations remains an area of concern as insufficient evidence exists regarding dosing for underweight patients. The purpose of this study is to compare the incidence of major bleeding events in underweight patients given different prophylactic doses of enoxaparin. Methods: This is a retrospective analysis performed at multiple hospitals within a single health care system. Patients with a BMI < 18.5 kg/m2 were divided into 2 groups depending on whether they received at least 1 prophylactic dose of enoxaparin 30 mg subcutaneously once daily or enoxaparin 40 mg subcutaneously once daily. Underweight adult patients were included if they were admitted to an ICU for at least 48 hours and received at least 1 dose of enoxaparin for VTE prophylaxis during their ICU admission. The primary aim was to compare the incidence of clinically significant bleeding between dosing strategies. Secondary aims included the incidence of VTE during admission, ICU length of stay, overall hospital length of stay, and all-cause mortality 30 days post-discharge. Results: A total of 310 patients met inclusion criteria for this study, with 80 patients in the 30 mg group and 230 patients in the 40 mg group. There was no significant difference in major bleeding events between the 2 groups (P = .61). No significant differences in incidence of VTE (P = .455 ), ICU length of stay (P = .466), overall hospital stay (P = .502), or all-cause mortality (P = .925) were found between groups. Conclusions: No difference was found in clinically significant bleeding between underweight critically ill patients receiving VTE prophylaxis with enoxaparin 30 mg once daily or 40 mg once daily. Further studies are needed to evaluate the optimal dosing of VTE prophylaxis with enoxaparin in underweight patients.
Keywords: anticoagulants, critical care, disease management
Introduction
Venous thromboembolism (VTE) can include deep venous thrombosis (DVT), pulmonary embolism (PE) or both. 1 An acute medical illness requiring hospitalization is associated with an 8-fold increased risk of VTE. 1 The American Society of Hematology (ASH) reported that VTE is the third most common cardiovascular diagnosis, with an incidence of about 1 in 1000 patients annually. 2 Hospital acquired VTE is preventable with the proper interventions. These interventions include mechanical measures, such as compression stockings and pneumatic compression devices, or pharmacologic agents. 2 Pharmacologic prophylaxis with anticoagulants in hospitalized patients is a well-established practice that has been shown to reduce the incidence of VTE.1,2
The primary agents utilized for VTE prophylaxis include unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux. 1 The ASH guidelines recommend using UFH or LMWH over no anticoagulation and suggests using LMWH over UFH for pharmacological VTE prophylaxis in critically ill patients. 2 Similar recommendations come from the 2012 CHEST guidelines that state LMWH, UFH, or fondaparinux can be used for thromboprophylaxis in acutely ill hospitalized patients. 1 A systematic review and meta-analysis performed by Fernando and colleges compared the efficacy and safety of agents used for VTE prophylaxis. It was found that when compared to control treatment, LMWH reduced the incidence of DVT (OR: 0.59, 95% CI: 0.33-0.90) and UFH may have reduced the incidence of DVT (OR: 0.82, 95% CI: 0.47-1.37). When compared directly to UFH, it was determined that LMWH probably reduced DVTs (OR: 0.72, 95% CI: 0.46-0.98) to a greater extent. Based on these results, it was hypothesized that LMWH is probably more effective than UFH in reducing incidence of DVT and should be considered the primary pharmacologic agent for thromboprophylaxis. 3
Anticoagulant selection can be challenging in patients with extremes of weight. The enoxaparin package insert states that the safety and efficacy of prophylactic doses in overweight populations have not been fully determined and there is no consensus for dose adjustment in this patient population. 4 Two retrospective studies found that there was a lower incidence of VTE in groups dosed with enoxaparin 40 mg subcutaneous (SC) twice daily and heparin 7500 units SC 3 times a day in patients who weighed > 100 kg.5,6 Scholten et al. 5 looked at 481 patients weighing > 100 kg who underwent bariatric surgery. The patients were split into 2 groups; the first group received LMWH 30 mg SC every twelve hours and the other group received LMWH 40 mg SC every 12 hours. The authors concluded that the higher dose of enoxaparin 40 mg SC every 12 hours may reduce the incidence of DVT complications in patients following bariatric surgery. Wang et al. 6 analyzed the efficacy and safety of high-dose thromboprophylaxis in morbidly obese patients. They evaluated 3928 inpatients with a weight > 100 kg and a body mass index (BMI) > 40 kg/m2. They compared the incidence of VTE in patients who received high-dose thromboprophylaxis (heparin 7500 units 3 times daily or enoxaparin 40 mg twice daily) to those who received standard doses (heparin 5000 units 2 or 3 times daily or enoxaparin 40 mg once daily). They concluded that high-dose prophylaxis reduced the incidence of VTE when compared with the standard-dose group (0.77% vs 1.48%, P = .05) and there was no significant difference in bleeding events. 6
While there is limited data to support dosing strategies in overweight patients, there is even less evidence evaluating VTE prophylaxis dosing in underweight patients. The package insert for enoxaparin recommends clinical monitoring of patients with a body weight < 45 kg for women and <57 kg for men, but does not recommend a specific dose reduction due to lack of evidence. 4 Rojas et al. 7 evaluated anti-Xa activity in patients weighing <55 kg and receiving enoxaparin 40 mg SC once daily for VTE prophylaxis. 8 Anti-Xa levels were supratherapeutic in over half of the total population (60.7% anti-Xa ≥ 0.5 IU/mL, P = .008). The authors concluded that it is reasonable to reduce prophylactic enoxaparin to 30 mg SC once daily in patients who weigh less than 55 kg. Although elevated anti-Xa levels suggest that underweight patients may have an increased bleeding risk, the association between anti-Xa levels and bleeding risk remains controversial. 8 The aforementioned study was designed to provide objective data for enoxaparin VTE prophylaxis dosing in critically ill underweight patients.
Dybdahl et al. 8 evaluated the impact of enoxaparin dosing on major and minor bleeding events in low body weight patients weighing <45 kg. They included patients in 3 dosing groups: enoxaparin 30 mg SC once daily, 30 mg SC twice daily, or 40 mg SC once daily. Results were concluded from a total of 173 patients and 210 courses of enoxaparin. There were 37 patients who received 2 different courses of enoxaparin during their hospital stay. Among the 210 courses received by patients, 16.2% were associated with major bleeding and 5.2% with minor bleeding. There was no difference, however, in the incidence of major bleeding by dosing regimen (P = .409). A study conducted by Buckheit and colleagues in 2021 more broadly evaluated thromboprophylaxis dosing with either SC heparin or enoxaparin in patients admitted to medicine or medical stepdown units who weighed ≤45 kg on admission. Patients who received standard dosing, as defined by SC heparin 5000 units 3 times daily or enoxaparin 40 mg daily, were significantly more likely to experience a major bleeding event (OR: 4.73, 95% CI: 1.05-21.34). Roughly 26% of patients who experienced major bleeding were receiving enoxaparin 40 mg daily, and there were no instances of major bleeding in patients who received a reduced dose of enoxaparin 30 mg daily. 9
The studies previously described, which evaluated enoxaparin dosing in underweight patients, utilized an actual body weight-based definition and evaluated only medically ill patients. However, an actual body weight-based definition may not account for all underweight patients. A BMI-based definition for underweight patients accounts for patients who may weigh greater than 45 or 55 kg, but whose body mass is suboptimal for their height. 10 As there is no consensus on recommended dosing strategies in the literature, underweight patients may be receiving different doses for VTE prophylaxis based on pharmacists’ and physicians’ clinical judgement. 8 There is a gap in literature evaluating dosing of enoxaparin in underweight patients as determined by BMI, specifically in the critically ill population. The objective of this study was to evaluate prophylactic enoxaparin dosing for VTE in critically ill underweight patients with a BMI < 18.5 kg/m2. The goal of this study is to provide guidance for safe and effective VTE prophylactic dosing in patients with a low BMI.
Methods
Study Design: This study was a retrospective analysis performed at multiple hospitals within a single health system from August 12, 2015, to August 31, 2023. To be included, patients had to be 18 years of age or older, admitted to an OhioHealth ICU location for ≥48 hours, received at least 1 dose of enoxaparin for VTE prophylaxis (40 mg once daily or 30 mg once daily), and had a BMI < 18.5 kg/m2. Patients were excluded if they were pregnant or breastfeeding, had an indication for enoxaparin other than VTE prophylaxis, had a CrCl < 30 mL/min at time of VTE prophylaxis initiation, or had active bleeding upon admission.
Outcomes: The primary outcome of this study was to compare the incidence of clinically significant bleeding during admission in underweight patients who received at least 1 dose of enoxaparin 40 mg versus 30 mg of prophylaxis. Clinically significant bleeding was defined as having at least one of the following: hemoglobin drop of at least 2 g/dL in 24 hours, transfusion of at least 1 unit of packed red blood cells, bleeding into a critical site (eg, intracranial, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome), or fatal bleeding. Secondary outcomes included the incidence of venous thromboembolism during admission, ICU length of stay, overall hospital length of stay, and all-cause mortality 30 days post-discharge.
Statistical Analysis: Study data was collected and managed using REDCap electronic data capture tools hosted at OhioHealth Riverside Methodist Hospital.11,12 Data was analyzed using the statistical software R 4.3.0 and JASP 0.17.1. All analyses were conducted at the 0.05 alpha level. Comparisons in baseline characteristics were made using a Chi-squared test. For the primary outcome, time to event data is reported as a median with 95% CI, and a Mann–Whitney U test was used for comparisons. Secondary outcomes were assessed using a Shapiro–Wilk test, Student’s t-Test, and Mann–Whitney U test.
Results
A total of 782 patients were screened for inclusion and 310 were included in statistical analysis (40 mg group n = 230, 30 mg group n = 80). Of the 472 excluded patients, most were excluded due to not being admitted to an ICU for over 48 hours or not having a BMI < 18.5 kg/m2. Table 1 shows the baseline characteristics of the patients included in the study. Demographics of patients in the 30 mg group compared to those in the 40 mg group were statistically different in regard to gender, height, weight, and BMI. The median age of the total population was 61 years and most of the population was female. The average weight for the 30 mg group was 41.9 kg and the average weight for the 40 mg group was 50.19 kg. The median BMI for the 30 mg group was 16.23 kg/m2 and the median BMI for the 40 mg group was 17.29 kg/m2.
Table 1.
Baseline Characteristics.
| Total population, n = 310 | Daily enoxaparin dose | P-value | ||
|---|---|---|---|---|
| Characteristic | 30 mg, n = 80 | 40 mg, n = 230 | ||
| Age, median (range) | 60 (18-98) | 62.50 (23-98) | 59 (18-92) | .039 |
| Gender, n (%) | ||||
| Female | 159 (51.29) | 65 (81.25) | 94 (40.87) | <.001 |
| Male | 151 (48.71) | 15 (18.75) | 136 (59.13) | |
| Race, n (%) | ||||
| Af. Am. or Black | 42 (13.55) | 8 (10.00) | 34 (14.78) | .090 |
| Asian | 6 (1.94) | 4 (5.00) | 2 (0.87) | |
| Caucasian | 246 (79.35) | 63 (78.75) | 183 (79.57) | |
| Other | 16 (5.16) | 5 (6.25) | 11 (4.78) | |
| Height (cm), median (range) | 167.64 (143.51-205.74) | 162.56 (143.51-187.96) | 172.72 (144.78-205.74) | <.001 |
| Weight (kg), mean (SD) | 48.05 (7.46) | 41.90 (5.39) | 50.19 (6.88) | <.001 |
| BMI (kg/m2), median (range) | 17.00 (12.00-18.50) | 16.23 (12.00-18.34) | 17.29 (12.98-18.50) | <.001 |
| SCr, median (range) | 0.63 (0.20-2.73) | 0.55 (0.20-1.72) | 0.65 (0.20-2.73) | .026 |
| Active cancer diagnosis, n (%) | 57 (18.39) | 16 (20.00) | 41 (17.83) | .665 |
| Antiplatelet use prior to admission, n (%) | 66 (21.29) | 16 (20.00) | 50 (21.74) | .743 |
| Anticoagulant use prior to admission, n (%) | 12 (3.87) | 4 (5.00) | 8 (3.48) | .514 |
| Concomitant antiplatelet during admission, n (%) | 79 (25.48) | 18 (22.50) | 61 (26.52) | .477 |
Clinically significant bleeding occurred in 32.5% of patients who received enoxaparin 30 mg compared to 35.65% of patients who received enoxaparin 40 mg (P = .61) (Table 2). The most frequently met criteria for clinically significant bleeding was a hemoglobin drop of ≥2 g/dL in 24 hours (P = .574), while no patients experienced fatal bleeding. Secondary patient outcomes are listed in Table 3. VTE occurred in 1 patient (1.25%) in the 30 mg group and in 8 patients (3.48%) in the 40 mg group (P = .455). No statistical differences were found in ICU length of stay, hospital length of stay, or all-cause mortality at 30 days.
Table 2.
Clinically Significant Bleeding.
| Total population, n = 310 | Daily enoxaparin dose | P-value | ||
|---|---|---|---|---|
| Variable | 30 mg, n = 80 | 40 mg, n = 230 | ||
| Any major bleeding event, n (%) | 108 (34.84) | 26 (32.50) | 82 (35.65) | .610 |
| Hgb drop ≥ 2g/dL, n (%) | 63 (20.32) | 18 (22.50) | 45 (19.57) | .574 |
| Transfusion, n (%) n = 309 | 56 (18.12) | 12 (15.00) | 44 (19.21) | .400 |
| Critical site bleed, n (%) | 2 (0.65) | 0 (0.00) | 2 (0.87) | 1.000 |
| Fatal bleeding, n (%) | 0 (0.00) | 0 (0.00) | 0 (0.00) | — |
| Death within 30 days of discharge, n (%) | 84 (27.10) | 22 (27.50) | 62 (26.96) | .925 |
Table 3.
Secondary Outcomes.
| Total population, N = 310 | Daily enoxaparin dose | P-value | ||
|---|---|---|---|---|
| Variable | 30 mg, n = 80 | 40 mg, n = 230 | ||
| VTE incidence, n (%) | 9 (2.90) | 1 (1.25) | 8 (3.48) | .455 |
| MICU LOS (days), median (range) | 5 (2-30) | 5 (2-30) | 4 (2-26) | .466 |
| Overall LOS (days), median (range) | 7 (2-76) | 7.50 (2-60) | 7 (2-76) | .502 |
| Disposition at discharge, n (%) | ||||
| AMA | 9 (2.90) | 1 (1.25) | 8 (3.48) | .410 |
| Expired | 48 (15.48) | 8 (10.00) | 40 (17.39) | |
| HHC | 53 (17.10) | 15 (18.75) | 38 (16.52) | |
| Home | 85 (27.42) | 20 (25.00) | 65 (28.26) | |
| Hospice | 46 (14.84) | 17 (21.25) | 29 (12.61) | |
| Long term care | 14 (4.52) | 3 (3.75) | 11 (4.78) | |
| Psychiatric hospital | 5 (1.61) | 1 (1.25) | 4 (1.74) | |
| Short term | 50 (16.13) | 15 (18.75) | 35 (15.22) | |
Discussion
This study is among the first observational cohort analyses to assess the clinical efficacy and safety of VTE prophylaxis dosing of enoxaparin in critically ill underweight patients. Our study aimed to address a knowledge gap in the literature by comparing enoxaparin dosing for VTE prophylaxis in underweight patients defined as a BMI < 18.5 kg/m2. This study found that more clinically significant bleeding occurred in patients who received enoxaparin 40 mg once daily versus patients who received enoxaparin 30 mg once daily. However, this difference was not statistically significant. This study also showed that patients who weighed closer to 40 kg received enoxaparin 30 mg once daily and patients who weighed closer to 50 kg received enoxaparin 40 mg once daily. We theorize that this observation shows providers may be more likely to adjust dosing based on actual body weight than BMI.
Most studies to evaluate enoxaparin dosing in underweight patients have defined their patient cohort based on actual body weight; to our knowledge, this is the first study to evaluate enoxaparin dosing in underweight critically ill patients based on BMI. An abstract published by Lee and colleagues in 2023 sought to determine the safety and efficacy of SC heparin dosing strategies in underweight critically ill patients based on a BMI < 18 kg/m2. 13 A total of 175 patients who received standard dose SC heparin (≥15 000 units/day) were compared to 80 patients who received dose-reduced SC heparin (<15 000 units/day). Similar to our study, no differences were noted in incidence of VTE, ICU length of stay, or hospital mortality. However, the authors found a statistically significant increase in clinically significant bleeding in patients who received standard SC heparin doses (9.14% vs 1.25%, P = .04). 13 Although our study did not find a statistically significant difference in major bleeding between enoxaparin 40 versus 30 mg daily dosing regimens, numerically more bleeding occurred in the standard dose enoxaparin group. The robustness of this finding may have been hindered by our small sample size, and relatively few patients who received a reduced dose of enoxaparin.
Additional limitations to this study include convenience sampling and uneven comparator groups. Due to this study’s retrospective nature, data collection also relied heavily on chart documentation which may have not been accurate for every patient.
Further research is required to determine the most appropriate threshold for reducing the dose of prophylactic enoxaparin in critically ill patients. Educating staff, providing continuing education lectures, and creating an institutionally standardized pharmacist-led dosing protocol may help ensure that underweight ICU patients receive a safe and effective dose of enoxaparin for VTE prophylaxis.
Conclusion
In underweight critically ill patients with a BMI < 18.5 kg/m2 receiving enoxaparin for VTE prophylaxis, patients who received enoxaparin 40 mg once daily versus 30 mg once daily experienced numerically more events of clinically significant bleeding. Although this finding was not statistically significant, it highlights the need for additional studies to evaluate clinically significant bleeding risk between different enoxaparin dosing regimens in underweight ICU patients and to establish evidence-based guidance for dose reductions.
Footnotes
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Elizabeth Curcio 
https://orcid.org/0000-0001-7194-1367
Alyssa S. Meester
https://orcid.org/0000-0002-8071-0226
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