Can enoxaparin be used for DVT prophylaxis in a patient on hemodialysis?

Comment by InpharmD Researcher

Limited data from observational studies (Tables 1-4) demonstrate prophylactic use of enoxaparin in hemodialysis patients to have similar efficacy compared to UFH, along with comparable bleeding and thrombotic outcomes. While an ideal dosing regimen for DVT prophylaxis in patients on hemodialysis has not yet been established, individualized strategies and careful monitoring are recommended while administering enoxaparin in this patient population.

Background

A 2022 systematic review and network meta-analysis assessed the efficacy and safety of anticoagulants for the treatment and prophylaxis of venous thromboembolism (VTE) in patients with renal dysfunction. This comprehensive analysis included 21 randomized controlled trials with a total of 76,574 participants, among whom 8,972 exhibited renal insufficiency, including VTE prophylaxis (N= 7 trials). In the prophylaxis of VTE, desirudin demonstrated a lower risk of VTE occurrence compared to enoxaparin, though it was associated with a higher bleeding risk. Conversely, betrixaban emerged as the most favorable anticoagulant for prophylaxis due to its superior safety and efficacy profile. Among the various anticoagulants studied, enoxaparin was specifically compared concerning its use in patients undergoing hemodialysis. Enoxaparin, when used in such patients, requires careful consideration due to potential challenges in balancing efficacy and the risk of bleeding. The analysis emphasized the necessity of adjusting anticoagulant regimens based on individual renal function to optimize treatment outcomes and minimize adverse effects, especially in high-risk groups such as those receiving hemodialysis. [1]

Data on enoxaparin use, specifically for deep vein thrombosis (DVT) prophylaxis in hemodialysis patients, is limited. Available research mainly investigated the efficacy of enoxaparin in reducing the incidence of recurrent vascular access stenosis in hemodialysis patients. While there are currently no recommendations for an anti-Xa trough level goal in patients with CrCl ≤30 mL/min, trends toward lower thromboembolism incidences and shorter hospital stays have been observed with reduced-dose enoxaparin therapy when compared to unfractionated heparin. Since enoxaparin is excreted predominantly by the kidneys, its half-life increases in patients receiving dialysis. Losses of low molecular weight heparins (LMWH) may occur at the start of high-flux dialysis and hemodiafiltration before the dialyzer membranes become protein-coated. Initially, LMWHs were able to be titrated to achieve a peak anti-Xa activity of 0.4-0.6 IU/ml, and ≤0.2 IU/ml at the end of dialysis; however, research indicates that frequency and duration of dialysis overall will affect LMWH usage. Some studies support the off-label use of enoxaparin, suggesting that prophylactic doses do not significantly increase bleeding risks and can be used without rigorous monitoring. This is in contrast to therapeutic doses, where empirical dose adjustments and biological monitoring are deemed necessary due to challenges in accurately predicting anticoagulation levels with anti-factor Xa, especially in patients with compromised renal function. Overall, tailored anticoagulation strategies are critical in high-risk populations, including those receiving DVT prophylaxis. [2], [3], [4]

A 2004 meta-analysis evaluated 17 randomized trials to compare the efficacy and safety of LMWH, including enoxaparin, with unfractionated heparin (UFH) for patients undergoing hemodialysis. The meta-analysis included data from 11 direct comparisons of LMWH and UFH, revealing no significant differences in bleeding incidents (relative risk [RR] 0.96; 95% confidence interval [CI] 0.27 to 3.43) or extracorporeal circuit thrombosis (RR 1.15; 95% CI 0.70 to 1.91) between the two treatments. While enoxaparin use for DVT prophylaxis was not assessed in the analysis for hemodialysis patients, no evidence of LMWH bioaccumulation with repeated doses was observed, indicating a stable anticoagulant effect without increasing bleeding risks. Despite the theoretical advantages of LMWH, such as predictable anticoagulation and a decreased risk of heparin-induced thrombocytopenia, the meta-analysis emphasized that larger, more rigorous trials are needed to draw definitive conclusions on the most effective anticoagulation strategy for patients with end-stage renal disease undergoing hemodialysis. [5]

A 2021 prospective cohort study investigated the potential accumulation of enoxaparin during hemodialysis with regional citrate anticoagulation in patients with acute kidney injury, aiming to address concerns about LMWHs accumulating in critically ill patients undergoing continuous renal replacement therapy (CRRT) managed by continuous veno-venous hemodialysis (CVVHD). A total of 29 adult patients from surgical ICUs were included, all receiving enoxaparin subcutaneously for VTE prophylaxis. Anti-Xa levels were measured at baseline and for three consecutive days during CRRT when enoxaparin had reached trough levels. In addition, modified assays of rotational thromboelastometry (ROTEM) were employed to detect subtle changes below the detection limit of conventional anti-Xa testing. Median anti-Xa trough levels remained below the detection limit of the test (<0.1 IU mL-1) throughout the study period, consistent across all four testing points, with interquartile ranges showing minimal variation. Furthermore, the modified ROTEM assays, known to be highly sensitive to LMWHs, did not reveal significant changes in parameters of clot initiation or formation dynamics from baseline to the final day of examination. Consequently, the study concluded that monitoring anti-Xa levels in this specific setting of CRRT with regional citrate anticoagulation may not be necessary, as evidence did not support the accumulation of enoxaparin in the patient cohort. [6]

Finally, a 2022 retrospective chart review examined the safety of enoxaparin for prophylaxis against DVT in patients with chronic kidney disease on hemodialysis. The study compared 200 hospitalized hemodialysis patients divided evenly into two groups: those receiving enoxaparin versus those receiving UFH. Enoxaparin was dosed at 30 mg subcutaneously every 48 hours, while UFH was given at 5,000 units subcutaneously every 8 hours. No statistical differences were observed in incidence of VTE, nor bleeding, between the two groups, including those over 65 years. Notably, there was no development of venous thromboembolism in either group during therapy. Although the overall incidence of bleeding was low, the enoxaparin group exhibited a higher decline in platelet counts compared to the UFH group. The need for packed red cell transfusions was slightly higher in the enoxaparin group (4 versus 2 in the UFH group), but this difference was not statistically significant. The data suggests that enoxaparin may be safe for DVT prophylaxis in hemodialysis patients, warranting further investigation. [7]

References:

[1] Fan G, Wang D, Zhang M, Luo X, Zhai Z, Wu S. Anticoagulant for treatment and prophylaxis of venous thromboembolism patients with renal dysfunction: A systematic review and network meta-analysis. Front Med (Lausanne). 2022;9:979911. Published 2022 Sep 26. doi:10.3389/fmed.2022.979911
[2] Shaikh SA, Regal RE. Dosing of Enoxaparin in Renal Impairment. P T. 2017;42(4):245-249.
[3] Lai S, Coppola B. Use of enoxaparin in end-stage renal disease. Kidney Int. 2013;84(3):433-436. doi:10.1038/ki.2013.163
[4] Davenport A. What are the anticoagulation options for intermittent hemodialysis?. Nat Rev Nephrol. 2011;7(9):499-508. Published 2011 Jul 5. doi:10.1038/nrneph.2011.88
[5] Lim W, Cook DJ, Crowther MA. Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials. J Am Soc Nephrol. 2004;15(12):3192-206.
[6] Wiegele M, Adelmann D, Dibiasi C, Pausch A, Baierl A, Schaden E. Monitoring of Enoxaparin during Hemodialysis Covered by Regional Citrate Anticoagulation in Acute Kidney Injury: A Prospective Cohort Study. J Clin Med. 2021;10(19):4491. Published 2021 Sep 29. doi:10.3390/jcm10194491
[7] Sonali Vadi, Sanjay P. Shah, Kenneth Yim, Ifeanyi Egbunike. Assessment of the Safety of Enoxaparin a Low Molecular Weight Heparin for Prophylaxis against Deep Venous Thrombosis in Patients with Chronic Kidney Disease on Hemodialysis. Archives of Clinical and Biomedical Research 6 (2022): 269-276.

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Can enoxaparin be used for DVT prophylaxis in a patient on hemodialysis?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-4 for your response.


No Difference in Bleeding Risk Between Subcutaneous Enoxaparin and Heparin for Thromboprophylaxis in End-stage Renal Disease

Design

Retrospective non-inferiority and equivalence observational study 

N= 7,021

Objective

To compare the risk of serious bleeding in dialysis patients administered a daily dose of enoxaparin against heparin administered 2 or 3 times per day

Study Groups

Subcutaneous Enoxaparin (n= 2,991)

Subcutaneous Heparin (n= 4,730)

Inclusion Criteria

Enoxaparin or heparin at doses typically prescribed for thromboprophylaxis (≤ 60 mg of subcutaneous enoxaparin injected once/day or ≤ 15,000 units of heparin over 2 to 3 subcutaneous injections/day)

Exclusion Criteria

Concomitant warfarin

Methods

Electronic medical records were screened to identify eligible patients. Baseline characteristics presented were based on risk factors present at screening for bleeding and thrombosis identified by the International Medical Prevention Registry on Venous Thromboembolism Study and the 2008 American College of Chest Physicians Clinical Practice Guidelines for the Prevention of Thromboembolism.

Bleeding was defined as hemorrhagic stroke, gastrointestinal bleeding, postprocedure bleeding, gynecological bleeding, hemorrhage into the abdominal cavity, hemorrhage into the pulmonary cavity, bleeding secondary to a coagulopathy, vascular access bleeding, hematoma, or other (epistaxis, orbital, unspecified bleeding).

Duration

Follow-up: 120 days

Chart review range: April 1993 to January 2012

Outcome Measures

Primary: bleeding resulting in hospitalization or death within 120 days since treatment initiation (measured as rate event per 100-patient years)

Secondary: deep vein thrombosis (DVT) or pulmonary embolism (PE) resulting in hospitalization or death within 120 days since treatment initiation

Baseline Characteristics

 

Enoxaparin (n= 2,991)

Heparin (n= 4,730)

 p-Value

 

Risk Factors for Both Bleeding and Thrombosis

Age ≥ 60 years

67.1% 68.0% Not Significant (NS)  

Male

43.0% 46.3%  0.003  

Caucasian

71.0% 67.0% 0.0002  

Time on dialysis <1 year

49.0% 51.3% 0.04  

Diabetes

41.2%

34.0% <0.0001  

HTN (>130/80 mmHg)

53.4%

53.0% NS  

Average time on intervention drug, days

135

143 NS  

Enoxaparin patients were more likely to be Caucasian, diabetic, and to have undergone orthopedic surgery, whereas heparin patients were more likely to be immobile and prescribed antiplatelet medications. Despite this, later analyses revealed none of the baseline risk factors were associated with an increased risk of bleeding with enoxaparin vs. heparin.

Results

Endpoint

Enoxaparin (Both Regimens) (n= 2,991)

Enoxaparin (Low-dose: 30 mg/day) (n= 1,569)

Enoxaparin (Standard dose: 31-60 mg/day) (n= 1,422)

Heparin (n= 4,730)

Bleeding:

Rate, events per 100 patient-years (95% CI)

RR vs. heparin 

HR vs. heparin 

 

16.9 (12.9 to 22.3)

0.98 (0.78 to 1.23)

--

 

16.3 (11.7 to 22.8)*

0.95 (0.71 to 1.28)

0.89 (CI 0.64 to 1.25)

 

17.6 (12.6 to 24.4)

1.02 (0.76 to 1.38)

0.96 (0.68 to 1.35)

 

17.2 (13.5 to 22.0)

N/A

N/A

Thrombosis:

Rate, events per 100 patient-years

HR vs. heparin

 

--

0.77 (0.49 to 1.22; noninferiority p= 0.04)

 

2.3 (95% CI 1.1 to 4.7) 

--

 

3.0 (95% CI 1.5 to 6.3)

--

 

3.3 (95% CI 1.9 to 5.8)

N/A

Rate of bleeding did not significantly differ between low and standard-dose enoxaparin or between enoxaparin and heparin. Risk of thrombosis was also not significantly worse with enoxaparin versus heparin.

CI = confidence interval, RR = relative risk, HR = hazard ratio

Study Author Conclusions

Low doses of enoxaparin appear to be a safe and a more convenient alternative to heparin for thromboprophylaxis in dialysis patients. In a large national comparative effectiveness analysis in the dialysis population, we found that the associated rate of bleeding was not different between patients injected with daily enoxaparin and heparin given two or three times per day for thromboprophylaxis, nor was enoxaparin less effective in preventing venous thromboembolic events.

InpharmD Researcher Critique

Overall, the combined (including both dosage ranges) enoxaparin results demonstrated equivalence to heparin in bleeding risk, and noninferiority to heparin in thrombosis for this patient population. Strengths of the study include thorough baseline risk factor characterization and statistical analyses that adjusted for these potential confounders. One weakness is the potential selection bias conferred by the retrospective observational design, including analysis of baseline characteristics at a single time-point (at enrollment). Other limitations include the lack of characterization of lower vs. higher enoxaparin group baseline characteristics and the lack of presented dose per kg body weight data.

References:

Chan KE, Thadhani RI, Maddux FW. No difference in bleeding risk between subcutaneous enoxaparin and heparin for thromboprophylaxis in end-stage renal disease. Kidney Int. 2013;84(3):555-561. doi:10.1038/ki.2013.152

Safety and Efficacy of Enoxaparin Compared With Unfractionated Heparin for Venous Thromboembolism Prophylaxis in Hemodialysis Patients

Design

Single-center, retrospective, cohort study

N= 225

Objective

To compare the safety and efficacy of enoxaparin with unfractionated heparin (UFH) for deep venous thromboembolism (DVT) prophylaxis in medically ill hemodialysis (HD) patients.

Study Groups

UFH (n= 150)

Enoxaparin (n= 75)

Inclusion Criteria

Patients who received HD with ≥2 consecutive days of concomitant venous thromboembolism (VTE) prophylaxis with enoxaparin 30 mg daily or UFH 5,000 units every 8 hours

Exclusion Criteria

Received therapeutic anticoagulation, UFH 7,500 units every 8 hours, UFH 5,000 units twice daily, > 1 standard dose of enoxaparin for VTE prophylaxis (≥ 40 mg), or if they changed prophylaxis agents during their hospitalization

Methods

Data was collected via retrospective review of electronic medical records. Patients were identified based on patients' International Classification of Diseases (ICD) 9 and 10 codes documented during hospital admission. Patients were given enoxaparin 30 mg daily or UFH 5,000 units every 8 hours.

Bleeding events were categorized as major, clinically relevant nonmajor, or minor based on the International Society on Thrombosis and Haemostasis (ISTH) definitions. Occurrences of DVT or pulmonary embolism (PE) were confirmed with imaging. 

Duration

Patients admitted September 2014 thru December 2016

Outcome Measures

Primary: composite of all bleeding events

Secondary: occurrence of confirmed DVT or PE

Baseline Characteristics

 

UFH (n= 150)

Enoxaparin (n= 75)

p-Value

Age, years

67.8 ± 14.7 67.2 ± 13.8  0.749 

Male

60% 61.3% 0.847 

Race

Caucasian

Black

Asian

 

68%

24.7%

0.7% 

 

62.7%

29.3%

6.7%

N/A 

Body mass index, kg/m2

29.8 ± 6.9 30.5 ± 9.1 0.569

Length of stay, days

7.9 ± 5.5 4.9 ± 2.8 < 0.05

Heparin boluses with HD

86.7% 86.7% 1.000

Concomitant:

Aspirin

Clopidogrel

 

64.7%

24%

 

57.3%

21.3%

 

0.285

0.655

PADUA score for VTE risk

4.2 ± 1.3 3.5 ± 1.4 < 0.05

Results

Endpoint

UFH (n= 150)

Enoxaparin (n= 75)

p-Value

Documented bleed

1 (0.7%) 1 (1.3%)  1

Confirmed VTE

0 0 N/A 

Adverse Events

See results.

Study Author Conclusions

The current study utilized standard doses of enoxaparin based on package insert recommendations for patients with a creatinine clearance < 30 mL/min. The results suggest that the bleeding and thrombotic risk between enoxaparin 30 mg daily and UFH 5,000 units every 8 hours cohorts may be similar. Future randomized, controlled trials are needed to confirm these findings.

InpharmD Researcher Critique

This was a single-center study with a limited sample size. The included patients were given enoxaparin 30 mg/day for VTE prophylaxis, and lower doses were not investigated. 

References:

Green MS, Tellor KB, Buckallew AR. Safety and Efficacy of Enoxaparin Compared With Unfractionated Heparin for Venous Thromboembolism Prophylaxis in Hemodialysis Patients. Hosp Pharm. 2017;52(9):623-627. doi:10.1177/0018578717724799

Evaluation of Enoxaparin for Inpatient Venous Thromboembolism Prophylaxis in End-Stage Renal Disease Patients on Hemodialysis
Design

Single-center, retrospective cohort study

N= 332

Objective To compare the risks of bleeding of enoxaparin and unfractionated heparin (UFH) in hospitalized, hemodialysis (HD)-dependent patients
Study Groups

Enoxaparin (n= 322)

UFH (n= 10)

Inclusion Criteria Patients at least 18 years of age with ESRD on HD, admitted inpatient for at least 48 hours, and received at least 1 subcutaneous (SQ) dose of either enoxaparin 30 mg or UFH 5000 units during admission
Exclusion Criteria Not ESRD, previously on therapeutic anticoagulation before initiating prophylactic doses, pregnant, prisoners, and/or received both enoxaparin and UFH for VTE prophylaxis
Methods Retrospective chart review of ESRD on HD patients receiving enoxaparin 30 mg SQ daily or UFH 5000 units SQ for VTE prophylaxis. Data collected included baseline characteristics and outcomes. Major bleeding or CRNMB was the primary outcome, defined by ISTH criteria
Duration January 2017 to August 2019
Outcome Measures

Primary: Major bleeding or clinically relevant non-major bleeding (CRNMB)

Secondary: Major bleeding alone, new-onset thromboembolic events

Baseline Characteristics   Enoxaparin (n= 322) UFH (n= 10) p-value
Age (y), median (interquartile range [IQR]) 63 (56-69) 61.5 (52-71) 0.918
Weight (kg), median (IQR) 75 (65.5-90.9) 82.6 (73.5-90.9) 0.378
Female 168 (52.2%) 5 (50) 0.892
Black 250 (77.6%) 10 (100) 0.582
Length of stay (day), median (IQR) 7.8 (4.5-14.9) 8.4 (4.2-11.4) 0.286
Thrombocytopenia during admission 138 (42.9%) 4 (40%) 0.562
Results   Enoxaparin (n= 322) UFH (n= 10) p-value
Major bleeding or CRNMB 22 (6.8%) 0.498
Major bleeding alone 14 (4.3%) 0.646

New onset thromboembolic event

Deep vein thrombosis (DVT) alone

Pulmonary embolism (PE) alone

DVT and PE

8 (2.5%)

5 (1.6%)

1 (0.3%)

1 (0.3%)

1 (10%)

0

1 (10%)

0

0.973

-

-

-

Adverse Events Three enoxaparin patients suffered fatal hemorrhages. Thrombocytopenia was associated with increased bleeding risk (odds ratio 4.23, p= 0.004)
Study Author Conclusions The difference in major or CRNMB rates between both anticoagulants was not statistically significant. However, the 6.8% bleed rate is concerning for inpatient enoxaparin usage, and caution should be applied when considering this drug for VTE prophylaxis in the ESRD on HD population.
Critique

The study's retrospective design and small UFH group limit the ability to draw definitive conclusions. The single-center nature and exclusion of peritoneal dialysis patients may affect generalizability. The study highlights the need for prospective research to better understand enoxaparin's safety and efficacy in this population.

References:

Sacks J, Luc SA. Evaluation of Enoxaparin for Inpatient Venous Thromboembolism Prophylaxis in End-Stage Renal Disease Patients on Hemodialysis. Hosp Pharm. 2021;56(6):718-724. doi:10.1177/0018578720954151

The Impact of Continuous Veno-Venous Hemodiafiltration on the Efficacy of Administration of Prophylactic Doses of Enoxaparin: A Prospective Observational Study
Design

Prospective observational study

N= 40

Objective To determine if patients receiving prophylactic doses of enoxaparin and treated with continuous veno-venous hemodiafiltration (CVVHDF) reach prophylactic values of anti-Xa factor activity
Study Groups

CVVHDF group (n= 20)

Control group (n= 20)

Inclusion Criteria

Adult ICU patients between 18 and 80 years old; at least 72 h treatment with CVVHDF before enrollment (for the CVVHDF group); indications for anticoagulant prophylaxis with enoxaparin 40 mg sc. once daily

Exclusion Criteria

Indications for LMWH use other than anticoagulant prophylaxis; intracranial hemorrhage; serious bleeding within a week before admission to ICU, if not managed; disseminated intravascular coagulopathy; heparin induced-thrombocytopenia; hypersensitivity or allergic reaction to enoxaparin or fondaparinux; thrombocytopenia < 50 G L−1; prothrombin time > 20 s or INR > 1.7; use of antiplatelet drugs; presence of congenital coagulopathy

Methods

Included patients received prophylactic doses of 40 mg of enoxaparin subcutaneously. Anti-Xa factor activity was determined on the third day of receiving enoxaparin. Blood samples were taken just before administration and at 3 hours, 6 hours, and 9 hours after administration. CVVHDF was performed at a dose of 30 mL/kg/hour. 

Duration August 2021 to August 2022
Outcome Measures

Primary: Anti-Xa factor activity levels

Secondary: Number of patients with anti-Xa factor activity within the prophylactic range

Baseline Characteristics Characteristic CVVHDF Group (n = 20) Control Group (n = 20)
Female 7 (35%) 11 (55%)
Age, years  59 ± 10.9 65.5 ± 17.5
BMI, kg/m2 30.6 ± 6.1 26.1 ± 4.9
Time since admission to ICU, days (range) 4.5 (4–7) 7.5 (6.3–11.5)
Mechanically ventilated 7 (35%) 9 (45%)
Vasopressors administration 10 (50%) 10 (50%)
SAPS II score at admission 45 ± 10 37 ± 13
APCHE II score at admission 20 ± 9 15 ± 7
SOFA score at study day 9 ± 4 6 ± 3
Results Endpoint Anti-Xa Factor activity, IU/mL p-Value
CVVHDF Group (n= 20) Control Group (n= 20)

Time since enoxaparin administration

0h

+3h

+6h

+9h

 

0.07 (±0.05)

0.26 (±0.09)

N/A

N/A

 

0.08 (±0.06)

0.39 (±0.16)

N/A

N/A

 

>0.99

0.0092

0.3893

0.8614

No significant differences in anti-Xa factor activity were noted between the groups except for after 3 hours of enoxaparin administration.

Additionally, there were no significant differences in the numbers of patients who had anti-Xa factor activity within the prophylactic range (0.2–0.4 IU/mL) between the CVVHDF and control groups. 

Results were presented as graphs, thus, full data points were not available for 6 and 9 hours. 

Adverse Events N/A
Study Author Conclusions CVVHDF has only a mild effect on the enoxaparin prophylactic effect measured by anti-Xa factor activity. There is no need to increase the dose of enoxaparin for patients requiring CVVHDF.
Critique The study provides valuable insights into the impact of CVVHDF on enoxaparin efficacy, but the small sample size and single-center design may limit generalizability. The heterogeneous patient population and lack of randomization could introduce bias. Further research with larger, randomized studies is needed to confirm these findings.
References:

Aszkiełowicz A, Steckiewicz KP, Okrągły M, Wujtewicz MA, Owczuk R. The Impact of Continuous Veno-Venous Hemodiafiltration on the Efficacy of Administration of Prophylactic Doses of Enoxaparin: A Prospective Observational Study. Pharmaceuticals (Basel). 2023;16(8):1166. Published 2023 Aug 16. doi:10.3390/ph16081166