DVT Prophylaxis for Total Joint Arthroplasty
Warfarin

David J. Zukor, M.D., FRCSC
Associate Professor Surgery, McGill University
Chief, Department of Orthopaedic Surgery,
Sir Mortimer B. Davis - Jewish General Hospital,
Montreal, QC

Warfarin (Coumadin) was until recently the most common form of prophylaxis in North America following total hip arthroplasty1. As the gold standard for orthopaedic surgery has been thromboprophylaxis for greater than 15 years, it is reasonable to assume that most orthopaedic surgeons in practice for more than a few years have considerable experience in the use of Warfarin.

Warfarin is a vitamin K antagonist (VKA) which produces its anticoagulant effect by interfering with cyclic interconversion of vitamin K2. Vitamin K is a cofactor for carboxylation of glutamate residues of vitamin K-dependent proteins including coagulation factors II, VII, IX and X. These coagulation factors require carboxylation for their biological activity. Warfarin inhibits the vitamin K conversion cycle thereby causing production of partially carboxylated coagulation factors which have reduced procoagulation activity3.

The time to achieve anticoagulation effect is a minimum of two days. To achieve antithrombotic effect requires five to six days.

Ironically VKAs also inhibit the regulatory anticoagulant proteins C and S4. This is important to consider when initiating Warfarin therapy. A high loading dose (e.g. 10 mg) will not produce a faster anticoagulation effect and in fact by boosting protein C levels may temporarily decrease the overall anticoagulant effect5.

The anticoagulation ability of VKAs is also affected by many medications (inhibition or potentiation)4 and in particular is inhibited by foods rich in vitamin K6 and potentiated by hypermetabolic states including fever.

Advantages of VKAs include: 1) delayed onset allowing for haemostasis following surgery, 2) the ability to be used easily in an out-patient setting and 3) the ability to control and manipulate the intensity of the anticoagulation effect. However, because of the delayed onset (which may allow thrombosis to occur), the variable response, the relatively lower efficacy versus LMWH, the possible drug interactions and the difficulty of the ongoing monitoring, the use of Warfarin has been almost abandoned in Europe and replaced by LMWH and this is occurring in North America as well.

In North America the most authoritative guidelines regarding anticoagulation are those of the American College of Chest Physicians1. Warfarin is one of the anticoagulants considered to be efficacious following elective THR and TKR (Grade 1A evidence) and to a lesser extent for7 hip fracture surgery (Grade 2B evidence). The first dose should be given either the evening before or the evening after surgery. Duration of the therapy should be for a minimum of ten days. INR should be 2.5 (range two to three) for best efficacy and low risk of bleeding.

The article containing the guidelines also reviews all the available, acceptable literature by pooling of multiple carefully screened trials. The evidence is as follows.

THR
Pooled data from five large clinical trials comparing adjusted-dose Warfarin versus LMWH among THR patients7-11. DVT rate 20.7% versus 13.7% (p = .0002) (2,979 patients). Proximal DVT (PVT) 4.8% versus 3.4% NS. Major bleeding 3.3% versus 5.3%. As well a large non-blinded trial of greater than 3,000 THR patients compared Enoxaparin 30 mg s/c bid versus adjusted-dose Warfarin (INR 2-3) noted no significant difference in symptomatic VTE, post-discharge DVT or major bleeds.

TKR
Adjusted-dose VKA was assessed in 12 RCTs with venography end-points7,9, 11-19. Overall there was a high risk of symptomatic DVT (25% - 50%) but a low rate of symptomatic VTE. Two other studies confirm this. One of 257 TKA patients yielded .8% symptomatic DVT by three months whereas the other with 815 patients had a rate of 1.3% of symptomatic DVT and no fatal PE20, 21.

There are six trials comparing VKAs versus LMWH7, 9,11, 15-17. Pooled DVT rates were 48% versus 33% whereas PVT was 10.4% versus 7.1%. In two of these studies the risk of bleeding (but not major bleeding) was higher with LMWH than Warfarin. Two recent meta-analyses7,17 confirmed superior efficacy of LMWH over Warfarin without an increased risk of bleeding.

Overall costs of Warfarin versus LMWH prophylaxis appeared to be similar according to most studies. In one American study of TKRs Warfarin was more cost-effective22. In one Canadian study following THRs Warfarin was approximately ten times more cost-effective23.

Conclusion
Warfarin (Coumadin) is a VKA antagonist previously very commonly used as prophylaxis for venous thromboembolism in orthopaedic surgery.

Two of the most important considerations when choosing an anticoagulant are its efficacy and tendency to cause bleeding. Warfarin is known to be efficacious though relatively less so than LMWH. Warfarin causes less bleeding complications than LMWH (though there are studies showing comparable rates and in general major bleeds are not encountered with either medication).

If using Warfarin, it is important to use it properly - that is aiming for an INR of two to three. The duration of therapy should be a minimum of ten days.

While Warfarin remains an effective anticoagulant, its use appears to be supplanted by LMWH as the latter are slightly more efficacious and easier to use. The search continues for the perfect anticoagulant since the main remaining concern with LMWH is the slightly increased risk of bleeding as compared with other agents. A number of new agents including oral factor Xa inhibitors look promising.

References

  1. Geerts W.H., Pineo G.F., Heit J.A., Bergqvist D., Lassen M.R., Colwell C.W., et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338S-400S.
  2. Friedman P.A., Rosenberg R.D., Hauschka P.V., Fitz-James A. A spectrum of partially carboxylated prothrombins in the plasmas of coumarin-treated patients. Biochimica et biophysica acta 1977;494:271-6.
  3. Nelsestuen G.L., Zytkovicz T.H., Howard J.B. The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin. The Journal of biological chemistry 1974;249:6347-50.
  4. Hirsh J., Dalen J., Anderson D.R., Poller L., Bussey H., Ansell J., et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:8S-21S.
  5. Harrison L., Johnston M., Massicotte M.P., Crowther M., Moffat K., Hirsh J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Annals of internal medicine 1997;126:133-6.
  6. Rohde L.E., de Assis M.C., Rabelo E.R. Dietary vitamin K intake and anticoagulation in elderly patients. Current opinion in clinical nutrition and metabolic care 2007;10:1-5.
  7. Hull R., Raskob G., Pineo G., Rosenbloom D., Evans W., Mallory T., et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. The New England journal of medicine 1993;329:1370-6.
  8. Hull R.D., Pineo G.F., Francis C., Bergqvist D., Fellenius C., Soderberg K., 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. The North American Fragmin Trial Investigators. Archives of internal medicine 2000;160:2199-207.
  9. 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. Thrombosis and haemostasis 1995;74:1428-31.
  10. Francis C.W., Pellegrini V.D., Jr., Totterman S., Boyd A.D., Jr., Marder V.J., Liebert K.M., et al. Prevention of deep-vein thrombosis after total hip arthroplasty. Comparison of warfarin and dalteparin. The Journal of bone and joint surgery 1997;79:1365-72.
  11. RD Heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. RD Heparin Arthroplasty Group. The Journal of bone and joint surgery 1994;76:1174-85.
  12. Lotke P.A., Palevsky H., Keenan A.M., Meranze S., Steinberg M.E., Ecker M.L., et al. Aspirin and warfarin for thromboembolic disease after total joint arthroplasty. Clinical orthopaedics and related research 1996:251-8.
  13. Kaempffe F.A., Lifeso R.M., Meinking C. Intermittent pneumatic compression versus coumadin. Prevention of deep vein thrombosis in lower-extremity total joint arthroplasty. Clinical orthopaedics and related research 1991:89-97.
  14. Francis C.W., Pellegrini V.D., Jr., Leibert K.M., Totterman S., Azodo M.V., Harris C.M., et al. Comparison of two warfarin regimens in the prevention of venous thrombosis following total knee replacement. Thrombosis and haemostasis 1996;75:706-11.
  15. Leclerc J.R., Geerts W.H., Desjardins L., Laflamme G.H., L'Esperance B., Demers C., et al. Prevention of venous thromboembolism after knee arthroplasty. A randomized, double-blind trial comparing enoxaparin with warfarin. Annals of internal medicine 1996;124:619-26.
  16. Heit J.A., Berkowitz S.D., Bona R., Cabanas V., Corson J.D., Elliott C.G., et al. Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind, dose-ranging study. Ardeparin Arthroplasty Study Group. Thrombosis and haemostasis 1997;77:32-8.
  17. Fitzgerald R.H., Jr., Spiro T.E., Trowbridge A.A., Gardiner G.A., Jr., Whitsett T.L., O'Connell M.B., et al. Prevention of venous thromboembolic disease following primary total knee arthroplasty. A randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin. The Journal of bone and joint surgery 2001;83-A:900-6.
  18. Francis C.W., Davidson B.L. Berkowitz S.D., Lotke P.A., Ginsberg J.S., Lieberman J.R., et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial. Annals of internal medicine 2002;137:648-55.
  19. Francis C.W., Berkowitz S.D., Comp P.C., Lieberman J.R., Ginsberg J.S., Paiement G., et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. The New England journal of medicine 2003;349:1703-12.
  20. Lieberman J.R., Sung R., Dorey F., Thomas B.J., Kilgus D.J., Finerman G.A. Low-dose warfarin prophylaxis to prevent symptomatic pulmonary embolism after total knee arthroplasty. The Journal of arthroplasty 1997;12:180-4.
  21. Robinson K.S., Anderson D.R., Gross M. Petrie D., Leighton R., Stanish W., et al. Ultrasonographic screening before hospital discharge for deep venous thrombosis after arthroplasty: the post-arthroplasty screening study. A randomized, controlled trial. Annals of internal medicine 1997;127:439-45.
  22. Hull R.D., Raskob G.E., Pineo G.F., Feldstein W., Rosenbloom D., Gafni A., et al. Subcutaneous low-molecular-weight heparin vs warfarin for prophylaxis of deep vein thrombosis after hip or knee implantation. An economic perspective. Archives of internal medicine 1997;157:298-303.
  23. Skedgel C., Goeree R., Pleasance S., Thompson K. O'Brien B., Anderson D. The cost-effectiveness of extended-duration antithrombotic prophylaxis after total hip arthroplasty. The Journal of bone and joint surgery 2007;89:819-28.

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