Venous Thromboembolism: Role of Low-Molecular-Weight Heparin in VTE Prophylaxis
Citation: J Trauma. 53(1):142-164, July 2002.
Rogers, Frederick B. MD; Cipolle, Mark D. MD, PhD; Velmahos, George MD, PhD; Rozycki, Grace MD; Luchette, Fred A. MD
From the University of Vermont, Department of Surgery, Fletcher Allen Health Care (F.B.R.), Burlington, Vermont, Department of Surgery, Lehigh Valley Hospital (M.D.C.), Allentown, Pennsylvania, Department of Surgery, Division of Trauma and Critical Care, University of Southern California (G.V.), Los Angeles, California, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, and Department of Surgery, Division of Trauma, Critical Care, and Burns, Loyola University Medical Center (F.A.L.), Maywood, Illinois.
Submitted for publication September 1, 2001.
Accepted for publication March 15, 2002.
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Address for reprints: Frederick B. Rogers, MD, University of Vermont Department of Surgery, Fletcher Allen Health Care, 111 Colchester Avenue, Burlington, VT 05401; email: firstname.lastname@example.org.
Statement of the Problem
The use of LMWH has gained popularity in medical and general surgical patients for reducing the risk of VTE in the past 20 years. LMWH may be better suited than LDH as a prophylaxis against VTE in the trauma patient (which is reviewed in the section The Use of Low-Dose Heparin for DVT/PE Prophylaxis, above). LDH has been shown not to be efficacious. Concerns are ongoing with regard to the potential for LMWH to exacerbate bleeding in the trauma patient with multiple injuries.
A MEDLINE search and review of the literature revealed hundreds of articles examining the use of LMWH in VTE prophylaxis in general surgery. Trauma studies that appeared in the literature were reviewed (Table 5).
A. Level I: A Level I recommendation on this topic cannot be supported because of insufficient data.
B. Level II: LMWH can be used for VTE prophylaxis in trauma patients with the following injury patterns:
E. 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.
F. Level III:
H. 2. LMWH has not been sufficiently studied in the head-injured patient with intracranial bleeding to justify its use at this time.
I. 3. LMWH should not be used when epidural catheters are placed or removed.
The use of LMWH for VTE prophylaxis and treatment has gained popularity in the past 20 years. Three LMWHs are Food and Drug Administration (FDA) approved for VTE prophylaxis or other uses in the United States. Enoxaparin has been approved for use in orthopedic joint replacement surgery and dalteparin has been approved for use in general surgery. Tinzaparin (Innohep, Leo Pharmaceutical Products Ltd., Ballerup, Denmark) has been approved to treat symptomatic DVT with or without PE. Class I data now exist for the use of enoxaparin in trauma patients, but no FDA indication for the use of LMWH in trauma patients has been approved.
LMWHs vary in mass from 2,000 to 9,000 daltons and contain the unique pentasaccharide that is required for specific binding to antithrombin III (ATIII), but in a lower proportion than that contained in the parent unfractionated heparin (UH). LMWHs have proportionally more anti-factor Xa activity compared with anti-factor II activity because they are less able to bind thrombin and ATIII simultaneously to accelerate the inactivation of thrombin by ATIII. However, LMWHs retain their ability to catalyze the inhibition of factor Xa by ATIII. In general, LMWHs have anti-factor Xa/anti-factor II ratios between 4:1 and 2:1. LMWHs have bioavailability superior to that of unfractionated heparin and produce less bleeding for equivalent antithrombotic doses, probably the result of the different effects on platelet function and vascular permeability. However, the relationship between in vitro and in vivo studies has to be carefully examined when looking at LMWHs. Although 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. Overall, LMWHs are clearly superior to placebo for VTE prophylaxis in general surgery, orthopedic surgery, and medical patients with small to minimal bleeding risk.
To give a Level I recommendation for the use of enoxaparin in trauma patients, more studies are needed. However, two studies report good efficacy when enoxaparin was given in moderate- to high-risk trauma patients. In a prospective trial of trauma patients who were considered high-risk for DVT, Knudson et al. randomized 487 consecutive high-risk trauma patients to receive LMWH, PCD, or A-V foot pumps as prophylaxis against DVT. These patients were followed up by serial ultrasounds. The DVT rate was 0.87% for LMWH, 2.5% in the PCD group, and 5.7% in the A-V foot pump group (not statistically significant between groups). Geerts et al.randomized 265 patients to receive LDH or LMWH and followed up with serial venograms. The DVT rate was 44% for LDH and 31% for LMWH (p = 0.014). Quite a disparity existed between the two studies with regard to the incidence of DVT. The study by Geerts et al. used venography as the diagnostic modality, whereas Knudson used serial ultrasound. It is well known that venograms will pick up more DVTs than ultrasound (the clinical significance of an isolated, small calf DVT is open to conjecture). Another issue these studies did not address was bleeding complications. In both studies, bleeding complications were greater with LMWH; in the study by Geerts et al., major bleeding was 0.6% for LDH and 2.9% for LMWH (p = 0.12). In an editorial response to the study by Geerts et al., Osler and Rogers noted that the study was possibly not significantly powered to detect a difference in major bleeding complications despite being able to detect a difference in DVT rates.
One study clearly showed Logiparin (Novo/Nordisk Pharmaceuticals, Inc., Princeton, NJ) 3,500 units every 8 hours is superior to LDH 5,000 units every 8 hours in spinal cord-injured patients. Event rates (DVT and bleeding) were 0 of 20 in the Logiparin group and 7 of 21 in LDH group.
In a meta-analysis on the prevention of venous thromboembolism after injury, Velmahos et al. showed no difference in PE rates when LMWH was compared with LDH (OR, 3.010; 9% CI, 0.585-15.485). However, the confidence intervals were wide and the authors concluded that a significant difference could not be excluded.
Class I data that now exist infer that LMWH is superior to LDH 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. Data in many different types of patients confirm improved efficacy of LMWH with the same or less bleeding risk compared with LDH prophylaxis. The Class I data would imply that LMWH should be strongly considered for use in all high-risk trauma patients (except those with head injuries) when their bleeding risk is acceptable.
Many unresolved issues remain concerning VTE prophylaxis of trauma patients that need to be studied in a multicenter fashion. Further studies on the efficacy of LMWH, not only on DVT but also on PE, need to be implemented in a multi-institutional format. The risk of major bleeding needs to be addressed in high-risk trauma patients. This is especially true in the head-injured patients when LMWHs are safe. Finally, new synthetic pentasaccharides that specifically activate factor Xa have been shown in elective orthopedic surgery to be even more efficacious against DVT than LMWH. What role these synthetic pentasaccharides would have as a prophylaxis against VTE needs to be established.
We thank Jody Ciano for her help in the preparation of this article.
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Prevention of thromboembolism after spinal cord injury using low-molecular-weight heparin. Ann Intern Med. 113:571–574
Compared Logiparin 3,500 units daily for 8 wk (n = 20) vs. SH 5,000 units tid q8h for 8 wk (n = 21) in spinal cord injury patients. DVT and bleeding rates were 0/20 in Logiparin group and 7/21 in SH group. LMWH is safe and effective for VTE prevention in selected patients with spinal cord injury and complete motor paralysis, and is superior to SH.
A comparison of low-dose heparin with lowmolecular- weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 335:701–707
Landmark study of trauma patients with ISS ≥ 9 who could receive anticoagulants. 173 had low-dose heparin and 171 had enoxaparin 30 mg bid. DVT rate: 31% enoxaparin vs. 44% heparin group (p = 0.014). Proximal DVT rate lowered 15% to 6% (p = 0.012) in enoxaparin group compared with heparin group. 5 bleeding cases in enoxaparin group and 1 in heparin group (p = 0.12). LMWH was more effective than low-dose heparin to prevent VTE after major trauma.
Use of low molecular weight heparin in preventing thromboembolism in trauma patients. J Trauma. 41:446–459
Prospective trial in trauma patients with AIS ≥ 3, major head injury, spine, pelvic or lower extremity fractures, acute venous injury, or age > 50 years assigned to heparin vs. no heparin, depending on injury. Heparin patients were randomized to receive LMWH (enoxaparin 30 mg bid) or mechanical compression with PCDs or AVIs. Enoxaparin was safe and effective for preventing DVT in high-risk trauma patients. When heparin is contraindicated, mechanical compression is warranted.
Posttrauma thromboembolism prophylaxis. J Trauma. 42:100–103
II (pilot study)
Small pilot study of 53 patients compared enoxaparin vs. SH vs. PCDs in high-risk trauma patients with ISS ≥ 9 and in patients considered to be at high-risk for DVT. Overall DVT rate was 43%. Enoxaparin group had half the DVTs of either SH or PCD groups, though not statistically significant because of sample size.
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. 49:132–139
SH vs. LMWH meta-analysis (for PE) revealed 3 studies (2 RCT and 1 non-RCT); showed no difference in PE (OR, 3.01; 95% CI, 0.585–15.485). However, CIs were wide and a significant difference could not be excluded.
SH, subcutaneous heparin; AIS, Abbreviated Injury Scale; RCT, randomized controlled trial.