The Role of Low Molecular Weight Heparin (LMWH) in Venous Thromboembolism (VTE) Prophylaxis in Trauma Patients

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 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) should 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 requiring operative fixation or prolonged bed rest; 3) spinal cord injury with complete or incomplete motor paralysis.

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, and patients who require prolonged hospitalization or rehabilitation).

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.

Meta-analyses in 1992 by Nurmohamed et al.⁴² and Leizorovicz et al.³⁵ compared LMWH to UH for postoperative prophylaxis. Nurmohamed et al. examined 17 studies with 6878 patients in general surgery and six orthopedic studies with 1294 patients. There was a reduction in occurrence of DVT and PE in both general surgery and orthopedic surgery patients. There did appear to be some increased bleeding in the general surgery patients when the studies with only strong methodology were considered. Overall, this analysis did not show the expected major improvements in thrombosis prevention. If more weight is given to the studies with "strong" methodology, LMWH conferred little additional thromboprophylactic effect and may be associated with more bleeding in general surgery patients. The study by Leizorovicz et al. analyzed 52 randomized trials, 29 in general surgery and 23 in orthopedic surgery. They compared LMWH to: placebo, UH, and dextran. This analysis showed that LMWH is more efficacious than placebo for VTE prophylaxis and also suggested that LMWHs are more efficacious than UH with no difference in the incidence of major hemorrhage. They concluded that LMWH seemed to have a higher benefit to risk ratio than UH in preventing perioperative thrombosis. Another meta-analysis sub0jected 42 published, randomized, controlled studies in general surgery and orthopedic surgery to analysis using typical odds ratio with 95% CI. It concluded that, in surgery for hip fracture, LMWH is more effective than placebo but the studies comparing LMWH and low-dose heparin were too small to show any clinically relevant difference although there was a trend toward better efficacy with LMWH. ³²

There is a multicenter trial underway designed to recruit a cohort of 4500 patients which will involve 150 medical centers in the US. The final conclusion and definitive data of the incidence of DVT and PE when comparing enoxaparin with warfarin will be available after the full complement of 4500 patients is recruited. The study is intended to demonstrate the incidence of thromboembolic disease during the acute hospital phase and the medium term phase for the patient undergoing elective hip replacement.¹⁰

The literature is replete with studies comparing LMWH to either placebo, UH, or oral anticoagulants in the prevention of VTE in hip surgery patients. ^{2,5,14,17,26,28,33,36,39,41,46-52,55,57,59} LMWH is superior to both placebo and UH in prevention of DVT with similar or even less bleeding occurrence.^{11,28,39,41,49,58,59} LMWH appears to be similar to low dose warfarin in VTE prophylaxis in hip replacement patients. ^23,26 These studies are all prospective and randomized trials. Most use fibrinogen uptake scanning as a screen for DVT with subsequent confirmation by venography. Dose-ranging studies have been performed extensively with enoxaparin and have shown that this drug given either 30 mg bid or 40 mg daily show relative equivalent efficacy with acceptable bleeding rates. ^39,47,55 Dalteparin also appears to be superior to UH in preventing proximal DVT with the advantage that it only needs to be given once daily in hip replacement surgery.¹⁴ There have been two recent articles showing that patients remain at significant DVT risk for at least one month after hip surgery and that continued prophylaxis with enoxaparin for a full month postoperatively reduced the risk of DVT when compared to patients who had enoxaparin only while they were in the hospital.^5,51 Another recent study has shown enoxaparin just given in the immediate perioperative period tended to reduce venogram proven DVT (42% to 28%) in hip replacement surgery patients.⁵⁹

Total knee arthroplasty patients appear to behave somewhat differently than hip replacement patients in that they have an overall higher DVT incidence and appear to respond better to LMWH when compared to oral anticoagulation (Table 2).^24,34,52,56 The advantage of LMWH over oral anticoagulation appears to be lost when hip and knee replacement patients are examined together (Table 3).^23,26,52 Enoxaparin appears to outperform UH in VTE prophylaxis in knee replacement surgery with similar bleeding risks.^17,33,56 Most importantly, LMWH appears to outperform low-dose warfarin adjusted to an INR of 2 to 3 in preventing VTE in knee replacement surgery^24,34,52,56 (see Table 2). These studies have resulted in enoxaparin being recommended as the prophylaxis regimen of choice after knee replacement surgery by the Chest Consensus Conference.

Prospective studies comparing LMWH to UH in general surgery patients yield more variable results than those in orthopedics (Table 4). Dalteparin given at 2500 anti-factor Xa units daily out-performed placebo.⁴⁵ However, when compared to UH, the studies are variable. Caen⁸ showed dalteparin 5000 units daily was similar to 5000 units UH bid in preventing DVT in general surgery patients. A multicenter trial from Scandinavia showed that DVT was significantly reduced among patients given dalteparin 2500 units daily compared to UH. However, there were more bleeding complications in the dalteparin group.³ A prospective randomized multicenter trial conducted in Germany³¹ showed that the LMWH MonoEmbolex was similar to 5000 units tid of UH tid with similar bleeding risks. One large, multicenter, randomized trial conducted in England comparing dalteparin 2500 units qd to UH (5000 units bid) again showed similar efficacy between both drugs in VTE prophylaxis with similar bleeding risks. However, this study only tracked clinically evident DVT and was severely criticized for this obvious drawback. Dose ranging studies using enoxaparin at 20, 40, and 60 mg, have been unable to find a once daily dose that is more efficacious than UH 5000 units given tid.⁵³ However, more bleeding was encountered when enoxaparin was given at 60 mg daily. Enoxaparin was shown to be better than dextran for VTE prophylaxis in cancer surgery patients.⁶⁰ Bergqvist et al. have shown efficacy using the LMWH Tanzaparin in emergency abdominal surgery.⁶ Two studies show clear efficacy of LMWH over UH in DVT prevention in general surgery patients.^3,15 Dalteparin has an indication for VTE prophylaxis for abdominal surgery in the United States based on its once daily dosage and superior bioavailability compared to UH. However, two studies indicate there are more bleeding complications with dalteparin (2500 units) use in general surgery patients compared to UH.^4,29

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 5). 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 sequential 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

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 from total 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 are two multicenter trials being formulated at this time, both of which will address the use of LMWH in trauma patients and answer the question of synergy between anticoagulation and sequential compression. 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.

VI.   References

Reference Conclusions