DVT Prophylaxis for Total Joint Arthroplasty
Low-Molecular-Weight Heparin

Rajiv Gandhi, M.D., FRCSC
Nizar N Mahomed, M.D., ScD, FRCSC
Division of Orthopaedic Surgery, Toronto Western Hospital, University of Toronto
Toronto, ON

The incidence of asymptomatic deep vein thrombosis (DVT) in joint replacement surgery ranges from 45 to 57% after total hip replacement (THR), and 40 to 84% after total knee replacement (TKR) in the absence of thromboprophylaxis1. Prophylaxis with low-molecular-weight Heparin (LMWH) decreases that incidence to about 15% in THR and 30 % in TKR2-5. The mortality from pulmonary embolism (PE) following joint replacement surgery is estimated at 0.5-2.0 %6-11.

It is generally agreed upon that patients need some sort of prophylactic regime following total joint replacement; however, the selection of a prophylactic regimen involves a balance between efficacy and safety.

The low-molecular-weight Heparins are prepared by either chemical or enzymatic

depolymerization of unfractionated Heparin. The mechanism of action of low-molecular-weight Heparin is through the inhibition of factor Xa12,13.

The low-molecular-weight Heparins have many clinical advantages as compared to unfractionated Heparin. They have a more predictable dose-response than standard Heparin because of reduced binding to plasma proteins and vascular endothelium. They also have a better bioavailability: 90% compared with 30% to 40% for standard Heparin. They also have a longer half-life as compared with standard Heparin14. A fixed consistent dose of LMWH can be used, and there is no need for laboratory monitoring as they don't increase the activated partial thromboplastin time.

Low-molecular-weight Heparin is metabolized in the kidney and therefore should be used with caution in patients with renal insufficiency. Originally, it was thought that LMWH was not associated with the development of thrombocytopenia, but this is not true15. It has been suggested that the platelet count of patients who are receiving low-molecular-weight Heparin for prophylaxis against deep venous thrombosis be checked at least once prior to discharge16.

The efficacy of LMWH has been proven in many studies to decrease the risk of proximal and distal DVT by at least 70% as compared to placebo7,17-19. LMWH has been compared with Warfarin in a number of multi-centre randomized clinical trials using venographically proven DVT as the outcome measure20-23. These studies have all shown that LMWH was more efficacious at preventing clots than Warfarin at the expense of a slightly greater bleeding risk (Table 1).

Table 1. Summary of data from randomized trials comparing LMWH and Warfarin for prevention of VTE

Study

No. Patients

overall DVT Rate(%)

Proximal DVT rate(%)

PE rate(%)

Bleeding
Risk (%)

Hamulyak et al23
Warfarin
Nadroparine


342
330


20.0
17.0


5.8
6.5


NR
NR


2.8
1.5

RD Group21
Warfarin
RD Heparin


218
211


11.0
7.0


6.0
3.0


0
0


4.0
4.0

Hull et al20
Warfarin
Fragmin


388
388


10.7
24


1.0
3.0


NR
NR


4.2
5.1

Francis et al22
Warfarin
Dalteparin


279
271


26.0
15.0


8.0
5.0


NR
NR


1.0
4.0

           

NR- Not Reported

       

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The optimal timing for the first dose of LMWH prophylaxis is controversial. The largest randomized trial addressing this issue is the North American Fragmin Trial (NAFT) which showed that preoperative initiation of Fragmin (2 h preop) increased major bleeding without improved antithrombotic efficacy compared to the early postoperative regimen (mean 6 h postop)25. It is important to note that the first dose of Fragmin, whether started preop or postop, was a half dose at 2500U as compared to the recommended dose of 5000U to decrease the risk of bleeding.

With the increasing use of neuraxial anesthesia, the potential for spinal hematoma with preoperative administration of LMWH remains a concern. In the NAFT study, there were no cases of spinal hematoma among the 482 patients who received neuraxial anesthesia and were administered the modified regimens of Dalteparin (either preoperatively or postoperatively)25.

The recommendations from Chest26 are to begin prophylaxis 6 h after surgery. Starting Heparin 2 h preoperatively or within the first 6 h after surgery only increases the risk of bleeding without any beneficial effect on thromboembolic prophylaxis. Initiation 12-24 hours postoperatively may not be as effective as initiation at 6 h postoperatively. Further randomized trials that directly compare different times of postoperative initiation (eg, 6 h vs 12 h) of the same LMWH are required to establish definitively the timing of the first dose that optimizes the risk-benefit of this prophylaxis.

A literature review by Heit demonstrated that the optimal duration of prophylaxis for most patients should be 7-10 days27. Others have suggested a duration of prophylaxis of 10-14 days28. Prolonged therapy should be considered for those with a history of VTE or other risk factors.

The most effective prophylactic agents for hip and knee replacement patients include low-molecular-weight Heparin, Warfarin, and Fondaparinux, however the optimal prophylactic agent is not yet known. Future studies that stratify patients by risk may help determine the optimal therapeutic agent and the appropriate duration of treatment for each patient.

References

  1. Geerts W.H., Heit J.A., Clagett P., et al. Prevention of venous thromboembolism. Chest 2001; 119(suppl):S132-S175
  2. Leclerc J.R., Gent M., Hirsch J., et al. The incidence of symptomatic venous thromboembolism after enoxaparin prophylaxis in lower extremity arthroplasty: a cohort study of 1984 patients. Canadian Collaborative Group. Chest 1998; 114(suppl):115S-118S
  3. Dahl O.E., Gudmundsen T.E., Haukeland L. Late occurring clinical deep vein thrombosis in joint operated patients. Acta Orthop Scand 2000; 71:47-50
  4. Colwell C.W., Collis D.K., Paulson R., et al. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty: evaluation during hospitalization and three months after discharge. J Bone Joint Surg 1999; 81-A:932-940
  5. Goodman L.R. CT diagnosis of pulmonary embolism and deep venous thrombosis. RadioGraphics 2000; 20:1201-1205.
  6. Lieberman J.R., Geerts W.H. Prevention of venous thromboembolism after total hip and knee arthroplasty. J Bone Joint Surg Am. 1994;76:1239-50.
  7. Clagett G.P., Anderson F.A. Jr, Levine M.N., Salzman E.W., Wheeler H.B. Prevention of venous thromboembolism. Chest. 1992;102(4 Suppl):391S-407S.
  8. Kakkar V.V., Howe C.T., Flanc C., Clarke M.B. Natural history of postoperative deep-vein thrombosis. Lancet. 1969;2:230-2.
  9. Leyvraz P.E., Bachmann F., Hoek J., Buller H.R., Postel M., Samama M., Vandenbroek M.D. Prevention of deep vein thrombosis after hip replacement: randomized comparison between unfractionated heparin and low molecular weight heparin. Br Med J. 1991;303:543-8. Erratum in: BMJ. 1991;303:1243.
  10. Wroblewski B.M., Siney P.D., White R. Fatal pulmonary embolism after total hip arthroplasty. Seasonal variation. Clin Orthop Relat Res. 1992;276:222-4.
  11. Wolf L.D., Hozack W.J., Rothman R.H. Pulmonary embolism in total joint arthroplasty. Clin Orthop Relat Res. 1993;288:219-33.
  12. Hirsh J., Dalen J.E., Deykin D., Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest. 1992; 102(4 Suppl):S337-51.
  13. Hirsh J., Levine M.N. Low molecular weight heparin. Blood. 1992;79:1-17.
  14. Whang P.G., Lieberman J.R. Low-molecular-weight heparin. J Am Acad Orthop Surg. 2002;10:299-302.
  15. Warkentin T.E., Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126 (3 Suppl):311S-37S.
  16. Lieberman J., Hsu W.K. Prevention of Venous Thromboembolic Disease after total hip and knee arthroplasty. J Bone J Surg 2005. 87-A . 2097-2112
  17. Hoek J.A., Nurmohamed M.T., Hamelynck K.J., Marti R.K., Knipscheer H.C., ten Cate H., Buller H.R., Magnani H.N., ten Cate J.W. Prevention of deep vein thrombosis following total hip replacement by low molecular weight heparinoid. Thromb Haemost. 1992;67:28-32.
  18. Mohr D.N., Silverstein M.D. Murtaugh P.A., Harrison J.M. Prophylactic agents for venous thrombosis in elective hip surgery. Meta-analysis of studies using venographic assessment. Arch Intern Med. 1993;153:2221-8.
  19. Nurmohamed M.T., Rosendaal F.R., Buller H.R., Dekker E., Hommes D.W., Vandenbroucke J.P., Briet E. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet. 1992;340:152-6.
  20. Hull R.D., Raskob G.E., Pineo G., Rosenbloom D., Evans W., Mallory T., Anquist K., Smith F., Hughes G., Green D., Elliott C.G., Panju A., Brant R. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med. 1993;329:1370-6.
  21. 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 Am. 1994;76:1174-85
  22. Francis C.W., Pellegrini V.D. Jr, Totterman S., Boyd A.D. Jr, Marder V.J., Liebert K.M., Stulberg B.N., Ayers D.C., Rosenberg A., Kessler C., Johanson N.A. Prevention of deep-vein thrombosis after total hip arthroplasty. Comparison of warfarin and dalteparin. J Bone Joint Surg Am. 1997;79:1365-72.
  23. Hamulyak K., Lensing A.W., van der Meer J., Smid W.M., van Ooy A., Hoek J.A. Subcutaneous low-molecular weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement? Fraxiparine Oral Anticoagulant Study Group. Thromb Haemost. 1995;74:1428-31.
  24. Freedman K.B., Brookenthal K.R., Fitzgerald R.H. Jr, Williams S., Lonner J.H. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg Am. 2000;82:929-38.
  25. Hull R., Pineo G., Francis C., et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double blind, randomized comparison: North American Fragmin Trial Investigators. Arch Intern Med 2000; 160:2199-2207
  26. Raskob G., Hirsh J. Controversies in Timing of the First Dose of Anticoagulant Prophylaxis Against Venous Thromboembolism After Major Orthopedic Surgery Chest 2003;124;379-385
  27. Heit J.A.. Low-Molecular-Weight Heparin: The Optimal Duration of Prophylaxis Against Postoperative Venous Thromboembolism After Total Hip or KneeReplacement. Thrombosis Research 2001 101 V163 - V173
  28. Geerts W.H., Pineo G.F., Heit J.A., Bergqvist D., Lassen M.R., Colwell C.W., Ray J.G. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):338S-400S.

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