Correspondence

Ximelagatran versus Warfarin after Total Knee Replacement

N Engl J Med 2004; 350:616-617February 5, 2004

Article

To the Editor:

In their study of the prevention of venous thromboembolism after total knee replacement (Oct. 30 issue),1 Francis and colleagues acknowledge that warfarin has a slower onset of action than ximelagatran. They emphasize the fact that about two thirds of the patients who were randomly assigned to warfarin had a therapeutic international normalized ratio (INR) on day 3. It is well known that because of the short half-life of factor VII, the INR during the initial days of warfarin therapy mainly reflects the inhibition of this factor, thus providing a false sense of adequate anticoagulation.

In this study, which involved only 7 to 12 days of anticoagulation, a 3-day period of suboptimal treatment in one group while a drug with a rapid onset of action was used in the other group may explain the findings.

Salomon Banarer, M.D.
University of Louisville, Louisville, KY 40202
s0bana01@louisville.edu

1 References

1. 1

   Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349:1703-1712
   Full Text | Web of Science | Medline

To the Editor:

The EXULT A (Exanta Used to Lessen Thrombosis A) study, reported by Francis et al., demonstrated the superiority of the direct thrombin inhibitor ximelagatran over warfarin for the prevention of venous thromboembolism after total knee replacement. However, despite its widespread clinical use, warfarin should not be considered the best available antithrombotic treatment after total knee replacement. Several double-blind trials1,2 have shown that adjusted-dose warfarin is significantly less effective than low-molecular-weight heparin in reducing the occurrence of venous thromboembolism after total knee replacement. In a meta-analysis carried out by Westrich et al.,3 the overall rate of thromboembolism was 29 percent with low-molecular-weight heparin and 45 percent with warfarin. One possible explanation could be the delayed onset of action of warfarin.

In the EXULT A study, the therapeutic INR range had not been reached in 35 percent of the patients in the warfarin group by postoperative day 3 and in 24 percent of the patients in this group by the day of venography. A direct comparison between ximelagatran and low-molecular-weight heparin is needed to determine the most effective antithrombotic treatment for patients undergoing total knee replacement.

Giuseppe Schillaci, M.D.
Leonella Pasqualini, M.D.
Elmo Mannarino, M.D.
University of Perugia, 06122 Perugia, Italy
skill@unipg.it

3 References

1. 1

   Heit JA, Berkowitz SD, Bona R, 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. Thromb Haemost 1997;77:32-38
   Web of Science | Medline

2. 2

   Leclerc JR, Geerts 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
   Web of Science | Medline

3. 3

   Westrich GH, Haas SB, Mosca P, Peterson M. Meta-analysis of thromboembolic prophylaxis after total knee arthroplasty. J Bone Joint Surg Br 2000;82:795-800
   CrossRef | Web of Science | Medline

To the Editor:

In their study, Francis et al. used a tourniquet in all patients during total knee replacement. However, the use of a pneumatic tourniquet is considered one of the most important risk factors for the occurrence of symptomatic venous thromboembolism. Parmet et al. suggested that the use of a tourniquet during total knee replacement was associated with an increased risk of ultrasound-detected venous thromboembolism,1 and Kato et al. recommended that total knee replacement be performed without a tourniquet to reduce the risk of large venous emboli.2

We believe that the authors should have divided their study groups according to surgical technique — with or without the use of a tourniquet — to evaluate the effects of ximelagatran.

Masahiko Nishiguchi, M.D.
Kawatana National Hospital, Higashi-Sonogi 859-3615, Japan

Noboru Takamura, M.D., Ph.D.
Kiyoshi Aoyagi, M.D., Ph.D.
Nagasaki University, Nagasaki 852-8523, Japan
takamura@net.nagasaki-u.ac.jp

2 References

1. 1

   Parmet JL, Horrow JC, Berman AT, Miller F, Pharo G, Collins L. The incidence of large venous emboli during total knee arthroplasty without pneumatic tourniquet use. Anesth Analg 1998;87:439-444
   CrossRef | Web of Science | Medline

2. 2

   Kato N, Nakanishi K, Yoshino S, Ogawa R. Abnormal echogenic findings detected by transesophageal echocardiography and cardiorespiratory impairment during total knee arthroplasty with tourniquet. Anesthesiology 2002;97:1123-1128
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Banarer cites the delayed onset of anticoagulation after the initiation of warfarin therapy as a possible explanation for the superior efficacy of ximelagatran in our study. The more rapid onset of ximelagatran may have contributed to its effectiveness. Prophylaxis with warfarin is typically initiated on the night before or the evening of surgery. A regimen that is begun earlier results in a stable and low level of anticoagulation at the time of surgery but in a prospective trial was not more effective than warfarin started the night before surgery.1

Dr. Schillaci and colleagues also comment on the delayed action of warfarin. Prior studies of warfarin prophylaxis in orthopedic surgery have not supplied the exact percentage of patients with the INR in the therapeutic range. We believe that the levels of anticoagulation provided in our double-blind, double-dummy study represent the best that can be achieved. We agree that some studies have shown low-molecular-weight heparins to be superior to warfarin for prophylaxis after knee replacement. However, efficacy rates vary widely among reported trials, and warfarin is used by approximately 60 percent of U.S. orthopedic surgeons for prophylaxis after knee replacement.2 Bleeding complications are more common with low-molecular-weight heparins than they are with warfarin,3 and in the single reported study of fondaparinux treatment after total knee replacement, major bleeding was significantly more frequent with fondaparinux than it was with low-molecular-weight heparin.4 The prophylactic benefit relative to the risk of bleeding must be considered.

Dr. Nishiguchi and colleagues highlight the role of tourniquet use as a risk factor for venous thrombosis. We agree that it may be a contributing factor, but tourniquets are currently used in nearly all cases to achieve a bloodless field. Therefore, any approach to prophylaxis must be effective in the setting of tourniquet use, and a study in patients in whom a tourniquet is not used is impractical.

Charles W. Francis, M.D.
University of Rochester, Rochester, NY 14642
charles_francis@urmc.rochester.edu

Scott D. Berkowitz, M.D.
AstraZeneca, Wilmington, DE 19850

Clifford W. Colwell, Jr., M.D.
Scripps Clinic, La Jolla, CA 92037

4 References

1. 1

   Francis CW, Pellegrini VD Jr, Leibert KM, et al. Comparison of two warfarin regimens in the prevention of venous thrombosis following total knee replacement. Thromb Haemost 1996;75:706-711
   Web of Science | Medline

2. 2

   Mesko JW, Brand RA, Iorio R, et al. Venous thromboembolic disease management patterns in total hip arthroplasty and total knee arthroplasty patients: a survey of the AAHKS membership. J Arthroplasty 2001;16:679-688
   CrossRef | Web of Science | Medline

3. 3

   Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001;119:Suppl:132S-175S
   CrossRef | Web of Science | Medline

4. 4

   Bauer KA, Eriksson BI, Lassen MR, Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305-1310
   Full Text | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Masahiko Nishiguchi, Noboru Takamura, Yasuyo Abe, Masafumi Kono, Hiroyuki Shindo, Kiyoshi Aoyagi. (2005) Pilot study on the use of tourniquet: a risk factor for pulmonary thromboembolism after total knee arthroplasty?. Thrombosis Research 115:4, 271-276
   CrossRef