What is the enoxaparin VTE prophylaxis renal dosing recommended for morbidly obese patients with BMI >= 40 and CrCl < 30?

Comment by InpharmD Researcher

There is a general lack of available literature which provides a validated enoxaparin prophylaxis dosing strategy in patients with morbid obesity and renal dysfunction. Evidence is primarily derived from studies examining either renal dysfunction or obesity in isolation, with minimal data evaluating both conditions concurrently. In morbid obesity (BMI ≥40 kg/m²) with normal renal function, enoxaparin prophylaxis is commonly increased to 40 mg twice daily or 0.5 mg/kg twice daily. However, one retrospective study reported administration of 20 mg once daily enoxaparin for thromboprophylaxis in an obese patient with renal dysfunction (CrCl <30 mL/min), though evidence to support this dosing in a broader patient population is lacking.

enoxaparin renal morbid obese

Background

A 2018 review article examined the dosing and monitoring of enoxaparin for venous thromboembolism (VTE) prophylaxis and treatment in patients at extremes of body weight, specifically those with low and high body weights. This review synthesized data from a variety of studies covering literature from 1995 to January 2018. The key studies included in the review investigated the impacts of body weight and body mass index (BMI) on VTE outcomes, bleeding risks, enoxaparin dosing efficacy, and anti-Xa levels, excluding pediatric, and pregnant populations and those with renal dysfunction. The review highlighted that traditional enoxaparin dosing regimens might not be suitable for patients at the extremes of body weight, proposing tailored dosing recommendations based on observed trends despite the lack of definitive clinical trial data. The results emphasized potential dosing adjustments for distinctive patient groups. For patients with low body weight, evidence suggested consideration of a prophylactic dose of 30 mg of enoxaparin subcutaneously once daily, alongside traditional weight-based dosing for VTE treatment. Conversely, in patients with high BMI (≥40 kg/m²), an increased dose of 40 mg subcutaneously twice daily was recommended, with the possibility of 60 mg twice daily for those with a BMI of ≥50 kg/m². Monitoring anti-Xa levels was deemed less routinely beneficial but could be considered in specific situations such as patients with significant bleeding risks or a marked deviation from expected therapeutic outcomes. The review concluded that personalized dosing strategies should consider individual patient risk profiles, including body weight, renal function, and bleeding risk, for optimal enoxaparin management at weight extremes. [1]

Another meta-analysis to evaluate the efficacy and safety of low-molecular-weight heparin (LMWH) in specific patient populations requiring anticoagulation therapy. This comprehensive analysis included data from numerous randomized controlled trials involving patients with varying degrees of renal impairment. The analysis focused on comparing LMWH with other anticoagulants such as unfractionated heparin (UFH) and direct oral anticoagulants (DOACs). Detailed examination of the results highlighted the pharmacokinetic and pharmacodynamic differences between LMWH and other agents, particularly in patients with compromised renal function. The findings of this meta-analysis revealed that LMWH, when administered at prophylactic doses, demonstrated a favorable safety profile with a significantly lower risk of bleeding complications compared to UFH. The study also emphasized the importance of dose adjustment in patients with severe renal dysfunction to mitigate potential adverse effects. In obese patients, it is recommended to increase venous thromboembolism prophylactic doses of LMWHs by 30% in morbidly obese patients with a BMI of >40 kg/m2. Additionally, monitoring of anti-Xa levels is recommended for obesity. These results underscore the role of LMWH in tailored anticoagulation strategies, particularly in high-risk populations with renal insufficiency. [2]

A 2023 review evaluated the safety and efficacy of anti-factor Xa level monitoring for enoxaparin among high-risk patient populations such as those with extremes of weight, renal insufficiency, and pregnancy. The authors included randomized controlled trials and meta-analyses that scrutinized enoxaparin's prophylactic and therapeutic use in patients with significant deviations in body weight, renal function, or who were pregnant. A total of fourteen studies were selected for inclusion in this review. The findings highlighted the presence of subtherapeutic anti-factor Xa levels in patients with extremes of weight or those who were pregnant, indicating potential challenges linked to weight-based dosing protocols of enoxaparin. In patients with renal insufficiency, there was evidence of enoxaparin accumulation, suggesting a potential need for dose reduction. In patients with morbid obesity, an enoxaparin dose of 0.5 mg/kg daily is superior to either fixed-dose enoxaparin (40 mg daily) or a weight-based regimen of 0.4 mg/kg daily when trying to achieve target peak anti-factor Xa levels. The review further elucidated the importance of monitoring anti-factor Xa levels in mitigating adverse events, such as bleeding, associated with enoxaparin, particularly in these high-risk groups. Despite the predictable pharmacokinetic profile of enoxaparin in standard patient populations, this study underscores the necessity of individualized monitoring and dosing adjustments in specific high-risk groups to achieve therapeutic efficacy and safety. More extensive research is warranted involving larger patient cohorts to precisely determine the clinical impact of anti-factor Xa monitoring in managing enoxaparin therapy across these patient populations. [3]

References: [1] Sebaaly J, Covert K. Enoxaparin Dosing at Extremes of Weight: Literature Review and Dosing Recommendations. Ann Pharmacother. 2018 Sep;52(9):898-909. doi:10.1177/1060028018768449.
[2] Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother. 2009 Jun;43(6):1064-83. doi:10.1345/aph.1L194.
[3] Sikes L, Charles K, Antigua A, Patel R, Imboywa S, Cherian P. Anti-Factor Xa Level Monitoring for Enoxaparin Prophylaxis and Treatment in High-Risk Patient Groups. HCA Healthc J Med. 2023 Apr 28;4(2):105-109. doi:10.36518/2689-0216.1464.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the enoxaparin VTE prophylaxis renal dosing recommended for morbidly obese patients with BMI >= 40 and CrCl < 30?

Level of evidence

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


Please see Tables 1-2 for your response.

Dosing of Enoxaparin in Morbidly Obese Patients: A Retrospective Cohort
Design

Retrospective cohort study

N= 462
Objective To evaluate odds of major bleeding, thrombosis, and ischemic stroke between different enoxaparin dosage strategies in patients weighing ≥120 kg
Study Groups

<90% FDA-approved dose (n= 56)

≥90% FDA-approved dose (n= 406)
Inclusion Criteria Patients weighing ≥120 kg who received therapeutic anticoagulation with enoxaparin for more than 24 hours
Exclusion Criteria Patients without a baseline weight, serum creatinine, a history of heparin-induced thrombocytopenia, or currently pregnant patients
Methods Retrospective chart review conducted from November 1, 2011, through November 1, 2016, at 3 community hospitals. Patients were identified using electronic medical records. Outcomes were compared between patients receiving <90% and ≥90% of the FDA-approved dose of enoxaparin. Subgroup analysis was conducted for patients with CrCL <30 mL/min.
Duration November 1, 2011, through November 1, 2016
Outcome Measures

Primary: Percentage of obese patients who experienced major bleeding within 7 days of discharge or discontinuation of enoxaparin therapy

Secondary: Percentage of patients who experienced minor bleeding, ischemic stroke, VTE, or all-cause death
Baseline Characteristics   <90% FDA-approved dose (n= 56) ≥90% FDA-approved dose (n= 406)
Age, years [IQR] 55.0 [46.5, 63.5] 58.0 [48.0, 67.0]
Female, n (%) 32 (57.1) 178 (43.8)
Caucasian, n (%) 44 (78.6) 336 (82.8)
BMI, kg/m2 [IQR] 48.8 [41.9, 60.9] 43.5 [39.1, 48.8]
Baseline SCr, mg/dL [IQR] 0.82 [0.71, 1.1] 0.91 [0.77, 1.2]
Baseline CrCL, mL/min [IQR] 85.9 [61.1, 104.1] 81.0 [59.3, 102.5]
Baseline platelets, cells/mL [IQR] 242.0 [192.0, 285.5] 211.0 [165.0, 261.0]
Baseline INR [IQR] 1.2 [1.0, 1.4] 1.1 [1.0, 1.2]
Duration of enoxaparin, days) [IQR] 2.5 [2.0, 4.0] 3.0 [2.0, 4.0]
Results   <90% FDA-approved dose (n= 56) ≥90% FDA-approved dose (n= 406) OR (95% CI) p-value
Major bleeding, n (%) 3 (5.4) 8 (2.0) 2.82 (0.7-10.9) 0.12
Minor bleeding, n (%) 0 (0.0) 7 (1.7) — 0.32
Major/minor bleeding, n (%) 3 (5.4) 15 (3.7) 1.48 (0.4-5.3) 0.55
VTE, n (%) 0 (0.0) 3 (0.74) — 0.52
Ischemic stroke, n (%) 0 (0.0) 2 (0.49) — 0.60
All-cause death, n (%) 2 (3.6) 5 (1.2) 2.97 (0.6-15.7) 0.18
Adverse Events No statistically significant difference in major or minor bleeding events between dosage groups. No difference in thrombotic or ischemic events between dosing groups.
Study Author Conclusions Reducing the dose of enoxaparin did not reduce the odds of major bleeding or increase the odds of ischemic stroke or VTE.
Critique The study is limited by its retrospective design and potential underpowering due to low detection of clinical events. The dosing cutoff for comparison may have been too high, and important baseline factors might not have been identified despite propensity matching. More prospective, controlled trials are needed to identify which morbidly obese patients may benefit from an empiric enoxaparin dose reduction.

 

References:
[1] [1] Czupryn MJ, Exline C. Dosing of Enoxaparin in Morbidly Obese Patients: A Retrospective Cohort. Hosp Pharm. 2018 Oct;53(5):331-337. doi:10.1177/0018578718757518.

 

108 (31.5%)​

Enoxaparin for thromboprophylaxis in overweight and obese patients: a prescribing audit at a tertiary hospital

Design

Retrospective observational audit

N= 343

Objective

To describe prescribing patterns for enoxaparin at the Royal Perth Hospital in the absence of specific prescribing guidelines for overweight or obese patients.

Study Groups

Normal weight (n= 143)

Overweight (n= 108)

Obese (n= 92)

Inclusion Criteria

 Patients who received enoxaparin in one of three wards at Royal Perth Hospital from September to December 2016. 

Exclusion Criteria

Patients without available medical records, documented weight, height or BMI, and patients receiving therapeutic anticoagulation therapy. 

Methods

Data collection was from inpatient medication charts and medical notes. Enoxaparin dosing was assessed in relation to BMI and renal function. The reference dose for non-obese patients was 40 mg daily. Analysis was descriptive and exploratory. 

Duration

September to December 2016

Outcome Measures

Primary: Percentage of obese patients receiving dose-adjusted enoxaparin

Secondary: Prescribing patterns in relation to BMI and renal function

Baseline Characteristics

  

All patients (n= 343)

Age (years)

 50 ± 22   

Male sex

 200 (58%)

BMI (kg/m2)

 26.5 ± 5.9

Normal weight

 143 (41.7%)

Overweight

 108 (31.5%)

Obese

 92 (26.8%)

Weight (kg)

 81.3 ± 24.4     

Severe renal impairment

 6 (1.7%)

Length of hospital stay (days)

 8.9 ± 7.3

Duration of enoxaparin administration (days)

 5.6 ± 3.9

Results

Endpoint 

Total

 20 mg daily (CrCl <30)

40 mg daily (CrCl <30)

  60 mg daily (CrCl <30)  40 mg twice daily (CrCl <30)

BMI (kg/m2) 18-25

  143  3  8 --  --

BMI (kg/m2) 25-30

 108  -- 0 -- --

BMI (kg/m2) ≥30

 92   1 3 --  --

Of the 326 patients prescribed enoxaparin and with available CrCl data, the regimens were 40 mg daily (95.7%; n = 312), 20 mg daily (3.7%; n = 12), 40 mg twice daily (0.3%; n = 1) or 60 mg daily (0.3%; n = 1). Some underdosing of enoxaparin (20 mg/day) was observed among patients with normal renal function, for whom a 40-mg/day dose would be warranted.

Adverse Events

Not reported

Study Author Conclusions

 Patient weight appears insufficiently considered in the prescribing of prophylactic enoxaparin, likely due to inadequate awareness of evidence regarding enoxaparin thromboprophylaxis in obesity. Local prescribing guidelines are warranted, and their effect should be monitored. 

InpharmD Researcher Critique

The study highlights the lack of specific guidelines for enoxaparin dosing in overweight and obese patients, which may lead to underdosing. However, the study is limited by its retrospective design, single-center setting, and lack of clinical outcome data such as VTE or bleeding events. Additionally, the documentation of patients' weight and height was inconsistent, which could affect the accuracy of BMI calculations. 



References:
[1] [1] Masoum MS, Emmerton LM. Enoxaparin for thromboprophylaxis in overweight and obese patients: a prescribing audit at a tertiary hospital. J Pharm Prac Res. 2019;49:376-379. doi:10.1002/jppr.1524