Orthopedics

Managing the Risk of Thrombosis in the Perioperative Period in Patients Undergoing Orthopedic and Trauma Surgery With Low-Molecular-Weight Heparin: Enoxaparin

Michael R Lassen, MD; Lars C Borris, MD

Abstract

Patients undergoing arthroplastic surgery of the lower limbs and those with multiple injuries have a high risk of thromboembolism. Enoxaparin is a highly effective antithrombotic drug that is well tolerated and without the need for monitoring. Numerous controlled trials in these patient groups have demonstrated enoxaparin to be at least as effective as heparin in reducing the occurrence of deep vein thrombosis while showing a tendency towards lower risk of bleeding complications; therefore, enoxaparin is recommended as thromboprophylaxis in patients undergoing major hip or knee surgery or suffering from multiple trauma.

Abstract

Patients undergoing arthroplastic surgery of the lower limbs and those with multiple injuries have a high risk of thromboembolism. Enoxaparin is a highly effective antithrombotic drug that is well tolerated and without the need for monitoring. Numerous controlled trials in these patient groups have demonstrated enoxaparin to be at least as effective as heparin in reducing the occurrence of deep vein thrombosis while showing a tendency towards lower risk of bleeding complications; therefore, enoxaparin is recommended as thromboprophylaxis in patients undergoing major hip or knee surgery or suffering from multiple trauma.

Enoxaparin is a low-molecular-weight heparin (LMWH) produced by alkaline depolymerization of heparin derived from porcine intestinal mucosa. The average molecular weight of enoxaparin is between 4-5 kD. Enoxaparin has been developed as the sodium salt because this form is associated with more rapid subcutaneous absorption and less inter-individual absorption variability than the calcium salt. Enoxaparin has a higher bioavailability and longer half-life than unfractionated heparin (UFH) which enables it to be administered once daily. Furthermore, animal studies suggest that it has a more favorable safety profile than UFH.

These properties resulted in a dosefinding study showing that 40 mg of enoxaparin administered every 24 hours was effective in preventing deep vein thrombosis (DVT) in patients undergoing total hip replacement in whom the risk of postoperative DVT was high.1 This regimen was chosen on the basis of a good risk:benefit ratio. Injections were started 12 hours before surgery and continued for at least 7 to 14 days after surgery (European regimen). However, in North America (North American regimen), prophylaxis is started 12 to 24 hours after surgery at a dosage of 30 mg every 12 hours to avoid bleeding complications during surgery. This article presents the findings of major clinical studies performed in orthopedic patients during the development of enoxaparin as a thromboprophylactic agent.

ELECTIVE JOINT REPLACEMENT

Patients undergoing hip or knee replacement are at a high risk of developing thromboembolic complications, including DVT or pulmonary embolism (PE) if prophylaxis is not employed.2 Thus, in these patients there is an urgent need for systemic prophylaxis to avoid postoperative death from PE. UFH has been used for many years and has reduced the rate of thromboembolism in clinical trials. In a comprehensive meta-analysis by Collins et al,3 it was shown that both the postoperative DVT rate and the perioperative death rate from PE were reduced by using UFH 5000 IU b.i.d. or t.i.d. compared with no prophylaxis. More recently, enoxaparin has been compared with placebo in patients undergoing total hip or knee replacement.

Total hip replacement. In a placebocontrolled study, enoxaparin (North American regimen) reduced the total DVT and proximal DVT to a highly significant extent without difference in bleeding complications4 (Table 1). In another study comparing the same regimen of enoxaparin with UFH 7500 IU b.i.d. (a dosage that was chosen by titration to match the efficacy of the North American regimen of enoxaparin), an equivalent antithrombotic efficacy was found with both regimens, but the total rate of bleeding complications (major and minor) was significantly higher in the UFH group5 (Table 2). The European regimen of enoxaparin produced a DVT rate of 12.5% compared with a rate of 25% in patients who received UFH 5000 IU t.i.d., and was also associated with a lower bleeding tendency.6 In addition, the rate of proximal DVT was also significantly reduced (Table 2).

Dextran was recommended for prophylaxis in high-risk orthopedic patients in the American consensus report 1986.7 In a comparative study with a standard regimen of Dextran 70, enoxaparin (European regimen) was significantly more antithrombotic and was associated with fewer postoperative blood transfusions as a result of lower perioperative blood loss8 (Table 3).

Total knee replacement. In a placebo-controlled study, enoxaparin (North American regimen) was effective without any significant difference in safety (Table I).9 Subsequently, in a Danish study, it was found that enoxaparin (European regimen) was as effective and safe as UFH 5000 IU t.i.d.10 This finding contrasted with that of Spiro et al11 who reported a significant reduction in the rate of DVT compared with UFH 5000 IU t.i.d. using the North American regimen of enoxaparin (Table 2). Warfarin has been a preferred prophylactic method for many years in the United States; however, this method requires repeated measurements of the International Normalized Ratio (INR) and for safety reasons the INR should be maintained within a narrow range of 2.0-3.0 to minimize the risk of bleeding complications. Many drug interactions have been described with oral anticoagulants. Because of biological variation in the pharmacodynamics, close monitoring of every patient is necessary. In one study12, enoxaparin (North American regimen) was significantly more antithrombotic than a regimen of warfarin (INR 2.03.0) (Table 4), but there was no difference among the groups in the number of bleeding complications.

Table

TABLE 1Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

TABLE 1

Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

Table

TABLE 2Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

TABLE 2

Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

Table

TABLE 3Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

TABLE 3

Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

Table

TABLE 4Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

TABLE 4

Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

Table

TABLE 5Risk factors for DVT in multiple-injury patients

TABLE 5

Risk factors for DVT in multiple-injury patients

TRAUMA

There is a growing interest in thromboembolic manifestations in traumatized patients. Geerts et al13 published an incidence study of 349 traumatized patients with a mean age of 39 years and a mean severity score of 27. Overall, 201 patients (58%) had phlebographically documented DVT, of whom only 3 developed clinical signs. Moreover, 18% of the patients with thrombosis had proximal DVT. The highest rates were found in patients with lower extremity fractures (69%), spine injury (62%), head injury (54%), and face/chest/abdominal injuries (50%). By employing a multivariate logistic regression analysis, the authors identified five significant risk factors (Table 5).

Another study by the same group14 compared enoxaparin with UFH given prophylactically in a similar group of trauma patients. This study included 344 patients with a mean injury severity score of 23. More than two thirds of the patients had been injured during motor vehicle accidents. One hundred twenty-nine patients received prophylaxis with enoxaparin (North American regimen) and 136 with UFH 5000 IU t.i.d.; both regimens were commenced 14 to 24 hours after injury. Enoxaparin reduced the overall rate of DVT by 30% and the proximal DVT rate by more than 58% (Table 6). In terms of safety, there was a slight trend towards a higher risk of bleeding complications in the enoxaparin group; however, the study was too small to draw any definitive conclusions because the sample size calculation was based on efficacy considerations only.

Patients suffering fractures of the upper third of the femur (femoral neck, inter-, and subtrochanteric femoral fractures) are not only at a high risk of thromboembolic complications because of the fracture itself and the surgical treatment required, but also because of a higher mean age compared with patients undergoing joint replacement.15 The risk of developing DVT in hip fracture patients is between 50% and 70% without prophylaxis. Thromboprophylaxis with oral anticoagulants or UFH has been studied with varying results in these patients. In a Danish study,16 hip fracture patients were randomized to prophylaxis with either enoxaparin (European regimen) or to UFH 5000 IU t.i.d. Both regimens were started as soon as the fracture was radiographically verified. No differences in terms of DVT rate or bleeding complications were detected, but surprisingly there was a statistically significant difference in the postoperative death rate within 3 months after the injury in favor of enoxaparin (Table 7). The mortality in elderly patients with hip fractures is high (about 10% within 1 month of injury) but based on this study, by administering enoxaparin as thromboprophylaxis it seems possible to reduce the mortality in these patients.

CONCLUSION

Patients undergoing joint replacement of the lower extremities or suffering a major trauma have a high risk of developing thromboembolic complications. This risk can be reduced with dextran, UFH, oral anticoagulant or LMWH prophylaxis. Enoxaparin is a LMWH which has been extensively studied in many different categories of orthopedic patients. Enoxaparin has been evaluated against most other pharmacologic regimens and has been found to be effective, well tolerated, and without the need for monitoring. For these reasons, thromboprophylaxis with enoxaparin is recommended in most orthopedic patient categories.

Table

TABLE 6Number (%) of patients developing DVT* in multiple-injury patients prophylactically treated by enoxaparin or UFH

TABLE 6

Number (%) of patients developing DVT* in multiple-injury patients prophylactically treated by enoxaparin or UFH

Table

TABLE 7Rates (%) of DVT* and deaths among 287 patients with hip fractures having thromboprophylaxis by enoxaparin or UFH

TABLE 7

Rates (%) of DVT* and deaths among 287 patients with hip fractures having thromboprophylaxis by enoxaparin or UFH

REFERENCES

1. Planes A, Vochelle N, Ferru J, et al. Enoxaparin, low molecular weight heparin: its use in the prevention of deep venous thrombosis following total hip replacement. Haemostasis. 1986; 16:152-158.

2. Borris LC, Lassen MR. Orthopedic surgery. In: Hull RD, Raskob GE. Pineo GF, eis. Venous Thromboembolism: An evidence-based atlas. Armonk. NY: Futura Publishing Co; 1996: 53-62.

3. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologie surgery. N Engl J Med. 1988; 318:1162-1173.

4. Turpie AGG1 Levine MN, Hirsh J. et al. A randomized controlled trial of a low molecular weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. JV Engl J Med. 1 986; 3 1 5:925-929.

5. Levine MN, Hirsh J, Gent M, et al. Prevention of deep vein thrombosis after elective hip surgery. A randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Intern Med. 1991; 114:545-551.

6. 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. 1988;60:407-410.

7. National Institute of Health. Public Health Service, Prevention of venous thrombosis and pulmonary embolism, consensus development conference statement. JAMA. 1986; 256:744-749.

8. Danish Enoxaparin Study Group. Lowmolecular- weight heparin (enoxaparin) versus dextran 70. The prevention of postoperative deep vein thrombosis after total hip replacement. Arch Intern Med. 1991; 151:1621-1624.

9. Ledere JR, Geerts WH, Desjardins L, et ai. Prevention of deep vein thrombosis after major knee surgery - a randomized, double-blind trial comparing a low molecular weight heparin fragment (enoxaparin) to placebo. Thromb Haemost. 1992; 67:417-43.

10. Fauno P, Suomalainen O, Rehnberg V, et al. Prophylaxis for the prevention of venous thromboembolism after total knee arthroplasty. A comparison between unfractionated and lowmolecular- weight heparin. J Bone Joint Surg. 1994;76:1814-1818.

11. Spiro TE. Colwell CW, Bona RD, et al. Enoxaparin versus unfractionated heparin for prevention of venous thromboembolic disease after knee replacement surgery. Chest. 1994; 106(supp 2):48S.

12. Ledere JR, Feerts WH, Desjardins L et al. Prevention of venous thromboembolism after knee arthroplasty, A randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med. 1996; 124:619-626.

13. Geerts WH, Code KI, Kay RM, Chen E, Szalai JP. A prospective study of venous thromboembolism after major trauma. N Engl J Med. 1994;331:1601-1606.

14. 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;335:701-707.

15. Lassen MR, Borris LC, Trauma. In: Hull RD, Raskob GE, Pineo GF, eds. Venous Thromboembolism: an evidence-based atlas. Armonk, NY: Futura Publishing Co; 1996:70-80.

16. Borris LC, Lassen MR, Poulsen KA, Jensen HP. Thromboembolic complications after hip fracture- prophylaxis with low molecular weight vs. unfractionated heparin [Abstract]. Thromb Haemost. 1995; 73:1104.

TABLE 1

Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

TABLE 2

Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

TABLE 3

Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

TABLE 4

Rates of bleeding complications (minor or major) and DVT, diagnosed by phlebography

TABLE 5

Risk factors for DVT in multiple-injury patients

TABLE 6

Number (%) of patients developing DVT* in multiple-injury patients prophylactically treated by enoxaparin or UFH

TABLE 7

Rates (%) of DVT* and deaths among 287 patients with hip fractures having thromboprophylaxis by enoxaparin or UFH

10.3928/0147-7447-19970202-07

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