VTE prophylaxis Dosing in Obesity

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Lauren Igneri
Critical care pharmacist and proud Rutgers University graduate. Enjoys rock climbing, cycling, travel, and lively discussions on the finer points of pharmacokinetics and critical care over a beer with friends.

The Pre-brief

  • In 2017-2018, 42.4% of US adults were obese (BMI ≥30 kg/m2), with 9.2% meeting criteria for severe obesity (BMI ≥40 kg/m2). Women had a higher prevalence of severe obesity (11.5%) than men (6.9%), with adults 40-59 years old having the highest prevalence (11.5%).
    • Obesity increases the risk of venous thromboembolism (VTE). 
  • Dosing of subcutaneous heparin in overweight and obese patients is challenging due to changes in pharmacokinetics and drug distribution compared to non-obese patients. 
    • Obesity is known to increase the volume of distribution of lipophilic medications and clearance of hydrophilic medications.
  • Limited literature exists describing the most optimal VTE prophylaxis dosing strategies for heparin and enoxaparin in obesity.
    • Alternative, increased dosing strategies have been utilized in obesity, but prospective comparative data are lacking.
    • There is significant variability in hospital VTE prophylaxis dosing and monitoring protocols for obese patients.

Which dose to use?

In 2014, a retrospective cohort study by Wang et al. evaluated the incidence of VTE in 3928 obese (weight >100 kg, BMI ≥40 kg/m2), medical/surgical patients who received either high-dose (heparin 7500 units every 8 hours or enoxaparin 40 mg every 12 hours) compared to usual-dose (heparin 5,000 units every 8 hours or enoxaparin 40 mg daily) thromboprophylaxis. High-dose thromboprophylaxis resulted in reduced symptomatic VTE (OR 0.52, 95% CI 0.27-1.00, p=0.050) and did not increase bleeding (OR 0.84, 95% CI 0.66-1.07, p=0.15). Logistic regression analysis indicated high-dose prophylaxis was more effective in patients with higher BMI, p=0.047. An important limitation of this study is that all patients who received high-dose prophylaxis were combined into one group, regardless of whether they received heparin or enoxaparin. 

Subcutaneous heparin 

Currently, there are no prospective studies directly comparing the rate of nosocomial VTE in obese patients treated with conventional heparin 5,000 units every 8 hours versus 7,500 units every 8 hours. Two retrospective studies evaluating low- versus high-dose subcutaneous heparin were published in 2016.

Joy et al. found no significant differences in the incidence of VTE among 1335 obese adults (>100 kg) receiving low-dose heparin 5000 units every 8 hours (3%) versus high-dose heparin 7500 units every 8 hours (1.5%) thromboprophylaxis, p=0.14. However, patients with BMI 35-39.9 or ≥40 kg/m2 had significantly increased bleeding complications (hemoglobin drop ≥2 g/dL) with the use of high-dose vs. low-dose heparin prophylaxis. In a multivariable logistic regression analysis of floor patients with BMI ≥40 kg/m2, heparin 7500 units every 8 hours was associated with an increased incidence of risk of bleeding (hemoglobin drop by 2 g/dL) that required PRBC transfusion), OR 3.4 (95% CI 1.58-7.42), p<0.01.


Similarly, Beall et al. did not find a significant difference in the incidence of VTE in 2,378 obese patients receiving low-dose heparin 5000 units every 8 hours (0.23%) versus high-dose heparin 7500 units every 8 hours (1.02%) thromboprophylaxis, p=0.05. However, no major bleeding occurred in patients. Rates of minor bleeding complications were low (<0.1%) and similar between groups.

Enoxaparin

Pharmacokinetic studies have suggested that standard, fixed-dose VTE prophylaxis regimens are suboptimal in obese patients and result in subtherapeutic anti-factor Xa concentrations. As a result, many hospitals have developed institution-specific dosing recommendations for higher enoxaparin dosing (e.g. 40 mg every 12 hours, 60 mg every 12 hours, 0.5 mg/kg every 24 hours, 0.5 mg/kg every 12 hours, etc.) in obese patients. Few prospective, randomized controlled trials exist evaluating the efficacy of high-dose versus low-dose enoxaparin prophylaxis in obese medical/surgical patients with BMI >40-50 kg/m2

Aside from the previously discussed retrospective study by Wang et al, only one other study evaluated the incidence of VTE with two enoxaparin dosing strategies in obesity. In a bariatric surgery population with an average BMI ~50-51 kg/m2, Scholten et al. found a higher rate of VTE with enoxaparin 30 mg twice daily (5.6%) compared with 40 mg twice daily (0.6%), p<0.001 . These findings suggest that the 40 mg twice daily regimen is more efficacious in an obese patient population.

Most studies evaluating enoxaparin in obese patients utilized peak anti-factor Xa levels taken 4-6 hours post-dose as surrogates for efficacy. A peak anti-factor Xa level between 0.2 to 0.5 IU/mL is a suggested target for thromboprophylaxis dosing. A number of studies demonstrated that patients with higher BMIs (e.g. >50 kg/m2) were more likely to achieve therapeutic peak anti-factor Xa levels with the use of higher enoxaparin dosing regimens. It is unknown whether this translates to a reduced incidence of nosocomial VTE.  A review by Sebaaly et al. suggests that enoxaparin 40 mg twice daily is appropriate for patients with BMI >40 kg/m2 as it results in reduced incidence of VTE and generally achieves anti-factor Xa targets. However, enoxaparin 60 mg twice daily may be considered for those with BMI >50 kg/m2

Although anti-factor Xa monitoring is not routinely recommended to guide dose adjustments for VTE prophylaxis, it may be reasonable to target peaks of 0.2 to 0.5 IU/mL after the third or fourth prophylactic dose in obese patients at higher risk of bleeding or thrombotic complications. When anti-factor Xa levels are either above or below the target range, adjust total daily dose by 10-20% and re-check peak anti-factor Xa once at steady state.

De-brief

  • Appropriate VTE prophylaxis dosing in obesity is challenging due to pharmacokinetic and drug distribution changes that occur from increased adipose tissue and increased total drug clearance compared to non-obese patients.
    • There is limited literature supporting higher VTE prophylaxis dosing regimens in obese patients reduce the risk of nosocomial VTE.
  • For patients with BMI >40 kg/m2 who require subcutaneous heparin for VTE prophylaxis (e.g. impaired renal function), high-dose heparin (7500 units every 8 hours) was shown to reduce the incidence of nosocomial VTE compared with usual-dose heparin (5000 units every 8 hours).
    • Other studies have failed to show a reduction in VTE with high-dose.
    • There is conflicting evidence on whether high-dose heparin increases the risk of major bleeding.
  • For obese patients able to receive enoxaparin VTE prophylaxis, higher than usual dosing regimens reduce the risk of VTE and increase the likelihood of peak anti-factor Xa target attainment (0.2 to 0.5 IU/mL).
    • BMI ≥40 kg/m2: enoxaparin 40 mg twice daily
    • BMI ≥50 kg/m2: enoxaparin 60 mg twice daily
    • Peak anti-factor Xa levels may be monitored 4-6 hours after the third or fourth dose of enoxaparin. Adjust total daily dose by 10-20% when anti-factor Xa levels are either above or below the target range. 

References

  1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity among adults and youth: United States, 2017-2018. NCHS Data Brief No. 360. https://www.cdc.gov/nchs/products/databriefs/db360.htm. Accessed December 14, 2021.
  2. Ageno W, Becattini C, Brighton T, et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation. 2008; 117:93-102. 
  3. Wang TF, Milligan PE, Wong CA, et al. Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients. Thromb Haemost. 2014;111(1):88–93.
  4. Joy M, Tharp E, Hartman H, et al. Safety and efficacy of high-dose unfractionated heparin for prevention of venous thromboembolism in overweight and obese patients. Pharmacotherapy. 2016;36(7):740–748.
  5. Beall J, Woodruff A, Hempel C, Wovkulich M, Zammit K. Efficacy and safety of high-dose subcutaneous unfractionated heparin prophylaxis for the prevention of venous thromboembolism in obese hospitalized patients. Hosp Pharm. 2016;51(5):376–381.
  6. Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg. 2002 Feb;12(1):19-24.
  7. Sebaaly J, Covert K. Enoxaparin dosing at extremes of weight: literature review and dosing recommendations. Ann Pharmacother. 2018; 52(9):898-909.

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