What is the best evidence for pharmacologic VTE prophylaxis in trauma patients?

Is there a preferred agent for VTE prophylaxis in trauma patients?  Is there a superior dosing strategy for these high-risk patients?

The selection and dosing of pharmacologic VTE prophylaxis in trauma patients has a troubled, controversial past.  The literature surrounding the topic is riddled with small, conflicting trials and methodological flaws.

The Beginnings of the Controversy

Although the debate between low-dose unfractionated heparin (LDUH) and low molecular weight heparin (LMWH) has been a long-standing issue within the medical literature as a whole, it primarily made its entrance in the trauma literature in 1996 with an article by Geerts et al in the New England Journal of Medicine.¹

The study by Geerts et al compared heparin 5000 units Q12hr to enoxaparin 30 mg Q12hr among trauma patients with an injury severity score (IIS) of at least 9.  Among 344 patients randomized, the primary endpoint (proximal or distal DVT by day 14) was higher with heparin compared to enoxaparin (44% vs. 31%, p=0.014, RRR 30%, NNT 8).  Although not statistically significant, enoxaparin had a higher rate of major bleeding events (0.6% vs. 2.9%, p=0.12).  As a secondary endpoint, the study also demonstrated a reduction in proximal DVT rates with enoxaparin (14.7% vs. 6.2%, p=0.012, RRR 58%, NNT 12).

Although the findings of the Geerts study were generally accepted and influenced subsequent VTE guidelines, the study results should be interpreted with caution:

• The study was not powered to examine the safety endpoint of major bleeding.  Although not statistically significant, there was a much higher rate of major bleeding with enoxaparin.  The study may have underscored the importance of weighing the risks and benefits of more aggressive pharmacologic VTE prophylaxis.
• The study used a controversial heparin dose (Q12hr vs. Q8hr).  Proponents of heparin argue that Q8hr dosing is the more fair comparator, but heparin opponents will often point to a meta-analysis with low-quality study substrate.²

The Pro-Heparin Counterpunch

In 2010, a study by Arnold et al was published, which is a commonly used counter to the results from Geerts et al.³  The Arnold study retrospectively included 476 trauma patients admitted for more than 72 hours.  Patients were included if they received heparin 5000 units Q8hr (note the higher dose compared to Geerts) or enoxaparin (30 mg Q12hr or 40 mg Q24hr).  The study’s primary endpoint (proximal DVT) was no different between heparin and enoxaparin (7.11% vs. 6.75%, p=0.999).  Additionally, there was no difference in major bleeding events, although enoxaparin was numerically higher (3.8% enoxaparin vs. 1.2% heparin, p=0.09).

Although the retrospective study design by Arnold is less convincing than Geerts’ randomized, double-blind study, it does raise the question regarding whether Geerts used a heparin dose that was an unfair comparison.  Of note, the Arnold study did not distinguish between enoxaparin doses (30 mg Q12hr or 40 mg Q24hr), which is a significant flaw in the study design.

What Say the Guidelines

ACCP Chest 9 Guidelines (2012) ^4,5

The most recent CHEST guidelines offer no preference between LMWH and LDUH in trauma patients.⁴  For major trauma patients, the guidelines provide a grade 2C recommendation equally to both therapies.

Notably, the CHEST guidelines do provide a firm recommendation in patients undergoing orthopedic surgery.⁵  The guidelines have a 2B recommendation supporting LMWH as a preferred therapy over fondaparinux (due to less risk of bleeding) and over LDUH (due to superior efficacy).

EAST Guidelines (2002) ⁶

The EAST (Eastern Association for the Surgery of Trauma) guidelines, having been published in 2002, are now outdated.  Regardless, the guidelines have a strong preference for LMWH over LDUH (primarily due to a lack of high-quality evidence with LDUH).  The guidelines place a stronger recommendation for LMWH in patients with pelvic fractures, complex lower extremity fractures, and spinal cord injury.  On the basis of the Geerts study, the guidelines also provide a level III recommendation for the use of LMWH in patients with an ISS of 9 or more.

Final Conclusions

• Although once a strong recommendation, there is weak evidence supporting the superiority of LMWH over LDUH (heparin) in major trauma patients.
• If heparin is used, a dose of 5000 units subcutaneous Q8hr (not Q12hr) is likely more appropriate, although the evidence is poor.
• If enoxparin is used, a dose of 30 mg subcutaneous Q12hr has been studied more often in trauma patients.  The higher dose may be more appropriate for patients at highest risk for VTE (eg, pelvic, long-bone, or spinal fracture), although the risks and benefits of VTE versus major bleeding need to be considered.

References

1. 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. 1996;335(10):701-7. PMID 8703169.
2. King CS, Holley AB, Jackson JL, Shorr AF, Moores LK. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: A metaanalysis. Chest. 2007;131(2):507-16. PMID 17296655.
3. Arnold JD, Dart BW, Barker DE, et al. Unfractionated heparin three times a day versus enoxaparin in the prevention of deep vein thrombosis in trauma patients. Am Surg. 2010;76(6):563-70. PMID 20583509.
4. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e227S-77S. PMID 22315263.
5. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-325S. PMID 22315265.
6. Rogers FB, Cipolle MD, Velmahos G, Rozycki G, Luchette FA. Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group. J Trauma. 2002;53(1):142-64. PMID 12131409.

Photos by roolrool and Severin Sadjina