Venous Thromboembolism: Low Molecular Weight Heparin (LMWH) in VTE Prophylaxis

Published 1998
Citation: J Trauma. 53(1):142-164, July 2002.

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Authors

EAST Practice Parameter Workgroup for DVT Prophylaxis

Frederick B. Rogers, MD, FACS
University of Vermont Department of Surgery
Director of Trauma and Critical Care
Fletcher Allen Heath Care
Burlington, VT

Mark D. Cipolle, MD, Ph.D.
Surgical Practice Center
Allentown, PA

George Velmahos, MD, Ph.D.
Department of Surgery, Division of Trauma and Critical Care
University of Southern California
Los Angeles, CA

Grace Rozycki, MD
Emory USM, Department of Surgery
Atlanta, GA

I. Statement of the Problem

The use of LMWH has gained popularity for reducing the risk of VTE over the last 20 years. In trauma patients, LMWH has better efficacy than unfractionated heparin (UH) and similar efficacy to sequential compression, with similar bleeding risk when used for VTE prophylaxis.^{[19] [21] [30]} Specifically, in trauma patients with an ISS > 9, LMWH was shown to be more efficacious than unfractionated heparin (UH) in preventing DVT (venogram). However, the LMWH group had more bleeding but this was not statistically significant.In another large study of trauma patients, LMWH was found to have similar efficacy to SCDs in preventing DVT (duplex ultrasound), however, the overall DVT incidence for all groups was only 2%. The orthopedic literature has several studies noting that LMWH outperforms UH for VTE prophylaxis and is more efficacious than oral anticoagulants in knee replacement surgery.^{[11] [24] [34] [39] [41] [49] [52] [56]} The general surgery literature is more variable but two studies show clear efficacy of LMWH over UH for VTE prophylaxis.^{[3] [15]}Except for two recent studies examining one-month prophylaxis in hip replacement surgery, duration of prophylaxis was generally 7 to 14 days while patients were hospitalized.^{[5] [51]}

II. Process

Medline searches and personal review of the literature revealed hundreds of articles examining the use of LMWH in VTE prophylaxis. Two meta-analyses, both published in 1992, regarding the “older” literature on the use of LMWH in general surgery and orthopedic surgery populations were summarized.^{[35] [42]} The important recent Class I studies that have appeared in the English literature were reviewed.

III. Recommendations

A. Level I

There are insufficient data to make Level I recommendations for general use of LMWH as VTE prophylaxis in trauma patients.

B. Level II

Low molecular weight heparin (LMWH) could be used for VTE prophylaxis in trauma patients with the following injury patterns: 1) pelvic fractures requiring operative fixation or prolonged bed rest (>5 days); 2) complex lower extremity fractures (defined as open fractures or multiple fractures in one extremity) requiring operative fixation or prolonged bed rest (> 5 days); 3) spinal cord injury with complete or incomplete motor paralysis. The use of LMWH is predicated on the fact that these patients do not have other injuries that put them at high risk for bleeding.

C. Level III

1. Trauma patients with an ISS >9, who can receive anticoagulants, should receive LMWH as their primary mode of VTE prophylaxis.
2. The use of LMWH or oral anticoagulants for several weeks post-injury should be considered in patients who remain at high risk for VTE (i.e. elderly pelvic fracture patients, spinal cord injury patients, patients who remain at prolonged bed rest (> 5 days), and patients who require prolonged hospitalization or rehabilitation).
3. LMWH has not been sufficiently studied in the head-injured patient with intracranial bleeding to justify its use at this time.
4. LMWH should not be in use when epidural catheters are placed or removed.

IV. Scientific Foundation

The use of LMWH for VTE has gained popularity over the last 10 to 20 years. There are two LMWHs approved for VTE prophylaxis in the US. Enoxaparin is approved for use in orthopedic joint replacement surgery, and dalteparin has been approved for use in general surgery.There is now Class I data in trauma patients for the use of enoxaparin. A landmark study done by Geerts et al. reported in the New England Journal of Medicine,^[19] and the study by Knudson et al. recently published in the Journal of Trauma^[30] advocate for the use of enoxaparin as VTE prophylaxis in trauma patients.

LMWHs vary in size from 2000 to 9000 Daltons. They contain the unique pentasaccharide which is required for specific binding to antithrombin III but in a lower proportion than that contained in the parent UH.LMWHs have proportionally more anti-factor Xa activity compared to anti-factor II activity because they are less able to bind thrombin and ATIII simultaneously to accelerate the inactivation of thrombin by ATIII.However, they retain their ability to catalyze the inhibition of factor Xa by ATIII. In general, LMWHs have anti-factor Xa to anti-factor II ratios between 4:1 and 2:1.LMWHs have superior bioavailability to unfractionated heparin and produce less bleeding for equivalent antithrombotic doses. This is probably the result of the different effects on platelet function and vascular permeability.^[25] However, the relationship between in vitro and in vivo studies has to be carefully examined when looking at LMWHs.While their in vitro anti-factor IIa activity is less than that of UH, the superior bioavailability of LMWHs results in their anti-IIa activity being proportionally greater in vivo.^[54] Overall, LMWHs are clearly superior to placebo for VTE prophylaxis in general surgery, orthopedic surgery, and medical patients with small to minimal bleeding risk.

More studies are needed in trauma patients to give a Level I recommendation for the use of enoxaparin. However, three of these studies report good efficacy when enoxaparin was given bid in moderate to high risk trauma patients (Table 6). In a prospective trial of trauma patients who were considered high risk for DVT, Knudson et al. showed that enoxaparin resulted in a DVT rate of only 0.8%, though it was not significantly less than sequential compression or AV impulse pumps.^[30]Geerts et al. showed that, in trauma patients with an ISS>9, enoxaparin was superior to UH and resulted in less overall and proximal DVT rates. There were more bleeding incidents in the enoxaparin group but this was not statistically significant. This landmark study showed that enoxaparin was more effective than low-dose heparin in preventing VTE after major trauma and that both interventions were safe.^[19] A pilot study has been done comparing three modes of prophylaxis: enoxaparin vs UH vs sequential compression in patients with ISS>9 considered to be at high risk for DVT.^[21] The DVT rate in the enoxaprin group was lower than that in both the UH and se quential compression group, however, this did not reach statistical significance because of sample size. These studies would support the use of enoxaparin in trauma patients at moderate to high risk for VTE with an acceptable bleeding risk.

There is one study that clearly shows Logiparin 3500 units q8 hr is superior to UH 5000 units q8 hr in spinal cord injury patients. Event rates (DVT and bleeding) were 0/20 in the Logiparin group and 7/21 in SH group. ^[20]

There have been three studies which have examined the cost-effectiveness of using a relatively expensive therapy, ie LMWH, in hip replacement surgery. Taking into account the reduction in DVT with similar or lower bleeding risk and the ability to administer LMWH without following coagulation, it has been shown to be more cost-effective than SH.^{[1] [39] [44]}

In their meta-analysis on the prevention of venous thromboembolism after injury, Velmahos et al^[61]showed that there was no difference in PE rate when LMWH was compared to SCH (OR 3.010:9% CI: 0.585, 15,485).However, the confidence intervals were wide and the authors concluded that a significant difference cannot be excluded.

V. Summary

There is a wealth of Class I data supporting the use of LMWH as VTE prophylaxis in orthopedic surgery. This literature is derived primarily fromtotal hip and knee replacement patients. Overall, LMWH appears to be equivalent or superior to UH for prophylaxis in general surgery patients. There is now Class I data inferring that LMWH is superior to UH for prophylaxis in moderate to high-risk trauma patients.However, selection of VTE prophylaxis in trauma patients can be a challenging balance between VTE risk and bleeding risk. Most data in many different types of patients confirm improved efficacy of LMWH with the same or even less bleeding risk compared to UH prophylaxis. LMWH should be the standard form of VTE prophylaxis in trauma patients with complex pelvic and lower extremity injuries as well as spinal cord injuries. The Class I data would imply that LMWH should be strongly considered for use in all high risk trauma patients when their bleeding risk is acceptable.

VI. Future Investigation

There are many unresolved issues concerning VTE prophylaxis of trauma patients that need to be studied in a multicenter fashion.There is one multicenter trial being formulated at this time, which will address the use of LMWH in trauma patients and address not only efficacy of LMWH but also bleeding complications. This Class I data will more clearly define the role of LMWH in VTE prophylaxis in trauma patients. When these studies are completed, the Class I data will more clearly define the role of LMWH in VTE prophylaxis in trauma patients. Hopefully, the multicenter trials will also establish a risk factor scoring tool for clinicians to better quantify VTE risk in their patient population. Until prospectively validated risk assessment tools are available, we urge that each institution adopt local guidelines for VTE risk and establish guidelines among the trauma, orthopedic, and neurological surgeons for bleeding risk after trauma.

Table 2 Low Molecular Weight Heparin in Trauma

VII. References

1. Bergqvist D, Burmark US, Frisell J, et al: Thromboprophylactic effect of low molecular weight heparin started in the evening before elective general abdominal surgery: A comparison with low-dose heparin. Semin Thromb Hemost 16 Suppl:19-24, 1990
2. Bergqvist D, Benoni G, Björgell O, et al: Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med335:696-700, 1996
3. Colwell CW, Spiro TE. Efficacy and safety of enoxaparin to prevent deep vein thrombosis after hip arthroplasty. Clin Orthop 319:215-22, 1995
4. The European Fraxiparin Study (EFS) Group. Comparison of a low molecular weight heparin and unfractionated heparin for the prevention of deep vein thrombosis in patients undergoing abdominal surgery. Br J Surg 75:1058-63, 1988
5. Geerts WH, Jay RM, Code KI, et al: A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 335:701-7, 1996
6. Green D, Lee MY, Lim AC, et al: Prevention of thromboembolism after spinal cord injury using low­molecular-weight heparin. Ann Intern Med 113:571-4, 1990
7. Greenfield LJ, Proctor MC, Rodriguez JL, et al: Posttrauma thromboembolism prophylaxis. J Trauma 42:100-3, 1997
8. Heit J. Efficacy and safety of ardeparin compared to warfarin for prevention of venous thromboembolism following total knee replacement: A double-blind dose ranging [Abstract]. Thromb Haemost 73:978, 1995
9. Hirsh J, Levine MN. Low molecular weight heparin: Laboratory properties and clinical evaluation: A review. Eur J Surg Suppl 571:9 -22, 1994
10. Knudson MM, Morabito D, Paiement GD, et al: Use of low molecular weight heparin in preventing thromboembolism in trauma patients. J Trauma 41:446-59, 1996
11. Leclerc JR, Geerts, Desjardins L, et al: Prevention of venous thromboembolism after knee arthroplasty. A randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med 124:619-26, 1996
12. Leizorovicz A, Haugh MC, Chapuis FR, et al: Low molecular weight heparin in prevention of perioperative thrombosis. BMJ 305:913-20, 1992
13. Menzin J, Richner R, Huse D, et al: Prevention of deep-vein thrombosis following total hip replacement surgery with enoxaparin versus unfractionated heparin: A pharmacoeconomic evaluation. Ann Pharmacother 28:271-5, 1994
14. Monreal M, Lafoz E, Navarro A, et al: A prospective double-blind trial of a low molecular weight heparin once daily compared with conventional low-dose heparin three times daily to prevent pulmonary embolism and venous thrombosis in patients with hip fracture. J Trauma 29:873-5, 1989
15. Nurmohamed MT, Rosendaal FR, Büller HR, et al: Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: A meta-analysis. Lancet 340:152-6, 1992
16. Planes A, Vochelle N, Mazas F, et al: Prevention of postoperative venous thrombosis: A randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemost 60:407-10, 1988
17. Planes A, Vochelle N, Darmon JY, et al: Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: Double-blind randomised comparison of enoxaparin versus placebo. Lancet 348:224-8, 1996
18. RD Heparin Arthroplasty Group. RD heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. J Bone Joint Surg 76-A:1174-85, 1994
19. Samama MM, Bara L, Gerotziafas GT. Mechanisms for the antithrombotic activity in man of low molecular weight heparins. Haemostasis 24:105-17, 1994
20. Spiro TE, Fitzgerald RH, Trowbridge AA, et al: Enoxaparin a low molecular weight heparin and warfarin for the prevention of venous thromboembolic disease after elective knee replacement surgery [Abstract]. Blood 84 (10 Suppl 1):26a, 1994
21. Velmahos GC, Kern J, Chan LS, Oder D, Murray JA, Shekelle P. Prevention of venous thromboembolism after injury: an evidence-based report-Part I: analysis of risk factor and evaluation of the role of vena cava filters. J Trauma 2000;49:132-139.

Table

Low Molecular Weight Heparin

Trauma

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