Louis M. Kwong, Hasan Huseyin Ceylan.
Response/Recommendation: Limited data suggests that weight-adjusted dosing of low-molecular-weight heparin (LMWH) may be of benefit in venous thromboembolism (VTE) prophylaxis for very low body weight and obese patients.
Strength of Recommendation: Limited.
Rationale: While the safety and efficacy of LMWH have been studied extensively in prospective, randomized, control clinical trials, those patients of very low body weight, as well as those of high body weight, were excluded from studies with these agents for prophylaxis following major orthopaedic surgery1–3. Concerns regarding the use of fixed standard dosing include reduced glomerular filtration rate (GFR) and creatinine clearance (CrCL) in patients of low body weight as well as a lower volume distribution (Vd) in these individuals. Because LMWH are primarily renally excreted, increased exposure to the drug due to accumulation may result in over anti-coagulation and a reduction in safety as manifested by an increased bleeding risk in low body weight patients4,5. Conversely, in those of extremely high body weight, a larger Vd may diminish the effectiveness of the antithrombotic agent resulting in a decrease in thromboprophylactic efficacy6,7. Interestingly, obesity is also a risk factor for chronic kidney disease (CKD) and renal insufficiency8. Should this occur, an obese patient with CKD on standard LMWH dosing may experience reduced renal clearance of the drug, increased exposure due to accumulation, and a resultant potential decrease in safety due to increased bleeding risk. Additionally, because LMWHs are hydrophilic in nature and not well distributed in adipose tissue, overdosing may be a risk in those patients whose total bodyweight is represented by a larger proportion of adipose tissue as opposed to an increase in lean body mass9,10.
A meta-regression analysis by Zufferey et al., evaluated the possibility of a dose-effect relationship of LMWH in major orthopedic surgery patients. They reported a correlation between the dose of LMWH administered and the relative risk reduction of asymptomatic total deep venous thrombosis (DVT) observed in each of the dosing studies evaluated11. A preponderance of scientific studies has used the measurement of anti-Xa levels as a surrogate for both efficacy and safety in support of the use of dose-adjusted LMWH for patients at both extremes of body weight12–17. The number of studies in support of weight-adjustment of LMWH administration have increased in the bariatric surgery literature since the introduction of the various LMWH, but limited data exist on the management of obese patients in the trauma and orthopaedic arenas.
In orthopaedic surgery, the literature is unclear as to the effectiveness of standard doses of LMWH for prophylaxis in obese patients18,19. The literature is similarly unclear as to the safety of standard doses of LMWH in patients of very low body weight, although a number of small prospective studies, as well as a trial in healthy volunteers, support a reduction in LMWH dose in patients of low body weight8,20. A number of studies have focused on different dose regimens in support of patients at the extremes of body-weight instead of adjusted dosing calculated based on weight8,21–26. Those few prospective clinical studies were underpowered to show differences in the effectiveness of various dosing regimens on VTE events as well as bleeding events12,24,27,28. While weight-adjustment of LMWH has been demonstrated to be effective in achieving a target anti-Xa level, there is not a consensus on optimum anti-Xa ranges, especially in terms of a clear link between anti-factor Xa levels and bleeding or thrombotic events29. There is also no strong evidence that anti-Xa levels correlate with a reduction in the incidence of clinically important VTE events in patients undergoing orthopaedic procedures30. While many studies support the benefits of weight-adjustment of LMWH administration31–34, no level 1 evidence exists to support the safety and efficacy of weight-adjusted dosing of LMWH for prophylaxis against VTE in orthopaedic surgery. Further trials are needed to confirm the efficacy and safety of weight-adjusted LMWH prophylaxis in orthopaedic surgery for those patients at the extremes of body weight.
1. Colwell CW, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing efficacy and safety. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am. 1994;76(1):3-14. doi:10.2106/00004623-199401000-00002
2. Eriksson BI, Kälebo P, Anthymyr BA, Wadenvik H, Tengborn L, Risberg B. Prevention of deep-vein thrombosis and pulmonary embolism after total hip replacement. Comparison of low-molecular-weight heparin and unfractionated heparin. J Bone Joint Surg Am. 1991;73(4):484-493.
3. Colwell CW, Spiro TE, Trowbridge AA, Stephens JW, Gardiner GA, Ritter MA. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep venous thrombosis after elective knee arthroplasty. Enoxaparin Clinical Trial Group. Clin Orthop Relat Res. 1995;(321):19-27.
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5. DailyMed – LOVENOX- enoxaparin sodium injection. Accessed September 7, 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5017a927-2a24-4f27-89f9-27c805bf7d59#S12.3
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12. Adolf J, Fritsche HM, Haas S, et al. Comparison of 3,000 IU aXa of the low molecular weight heparin certoparin with 5,000 IU aXa in prevention of deep vein thrombosis after total hip replacement. German Thrombosis Study Group. Int Angiol. 1999;18(2):122-126.
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15. Bigos R, Solomon E, Dorfman JD, Ha M. A Weight- and Anti-Xa-Guided Enoxaparin Dosing Protocol for venous thromboembolism Prophylaxis in intensive care unit Trauma Patients. J Surg Res. 2021;265:122-130. doi:10.1016/j.jss.2021.02.034
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18. Jones DL, Jones WA, Fleming KI, et al. Underdosing of Prophylactic Enoxaparin Is Common in Orthopaedic Trauma and Predicts 90-Day Venous Thromboembolism. J Orthop Trauma. 2019;33(11):570-576. doi:10.1097/BOT.0000000000001563
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23. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial. JAMA. 2021;325(16):1620-1630. doi:10.1001/jama.2021.4152
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