Correspondence

Recombinant Hirudin Compared with Low-Molecular-Weight Heparin to Prevent Thromboembolic Complications after Total Hip Replacement

N Engl J Med 1998; 338:920-921March 26, 1998

Article

To the Editor:

Eriksson et al. (Nov. 6 issue),1 in comparing desirudin (Revasc) with enoxaparin (Lovenox) for the prevention of thromboembolic complications after total hip replacement, administered a standard European dosage of enoxaparin (40 mg subcutaneously once daily). In the United States, enoxaparin is approved for this indication at a dosage of 30 mg subcutaneously twice daily. A regimen of 30 mg twice daily is also the current recommendation set forth by the American College of Chest Physicians.2

In the study by Eriksson et al., proximal deep-vein thrombosis was the primary end point. The studies by Colwell et al.3 and Spiro et al.4 have shown that 30 mg of enoxaparin given subcutaneously twice daily is more efficacious than 40 mg administered once daily in preventing thromboembolic complications after total hip-replacement surgery.

A major limitation of these studies is their small samples. Colwell et al. reported an absolute reduction in venographic deep-vein thrombosis of 15 percent among patients who could be evaluated (6 percent in the twice-daily group, as compared with 21 percent in the once-daily group; P<0.001).3 The rates of proximal deep-vein thrombosis were 3 percent in the twice-daily group and 6 percent in the once-daily group. Spiro et al. reported similar results, though not as conclusive.4 Twice-daily enoxaparin was associated with a 3 percent absolute reduction in venographic deep-vein thrombosis among patients who could be evaluated as compared with once-daily enoxaparin (11 percent vs. 14 percent). The rates of proximal deep-vein thrombosis were 6 percent in each group.

When one is comparing a new or experimental therapy with an established therapy, bias should be avoided by using the most efficacious regimen studied to date as the basis for comparison. If desirudin had been compared with a regimen of 30 mg of enoxaparin twice daily, would the conclusions of Eriksson et al. have been different? The authors should have at least discussed the limitations of their study to explain why the once-daily enoxaparin regimen was used rather than twice-daily enoxaparin.

Jon Robb, Pharm.D.
St. Mary's Medical Center, Evansville, IN 47750

4 References

1
Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997;337:1329-1335
Full Text | Web of Science | Medline

2
Clagett GP, Anderson FA Jr, Heit J, Levine MN, Wheeler HB. Prevention of venous thromboembolism. Chest 1995;108:Suppl:312S-334S
CrossRef | Web of Science | Medline

3
Colwell CW Jr, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement: a clin-ical trial comparing efficacy and safety. J Bone Joint Surg Am 1994;76:3-14
Web of Science | Medline

4
Spiro TE, Johnson GJ, Christie MJ, et al. Efficacy and safety of enoxaparin to prevent deep vein thrombosis after hip replacement surgery. Ann Intern Med 1994;121:81-89
Web of Science | Medline

Author/Editor Response

Dr. Eriksson replies:

To the Editor: My colleagues and I welcome the question from Dr. Robb regarding the choice of dose of low-molecular-weight heparin. There is a slight difference in European and North American practices, which is reflected in the labeling of low-molecular-weight heparins such as enoxaparin. In Europe the drug is approved for preoperative treatment and once-daily administration at a dose of 40 mg. In the United States, prophylactic treatment with enoxaparin is started within 24 hours postoperatively at a dosage of 30 mg twice daily.

Surgery triggers the coagulation process, and thrombi may be initiated perioperatively when stasis is present.1,2 Leaving patients without protection against coagulation during this period may be detrimental, although a total daily dose of 60 mg of enoxaparin might compensate for this. Until now there has been no evidence of a difference in efficacy between the two enoxaparin regimens in Europe and the United States. Clinical trials comparing the efficacy and safety of starting treatment with low-molecular-weight heparins before or after surgery are required to answer Dr. Robb's questions. A regimen including a preoperative dose of enoxaparin and a 30-mg dose twice daily postoperatively may be effective and safe, but such a regimen is not approved for general use.

The results of the studies by Colwell et al.3 and Spiro et al.,4 referred to by Dr. Robb, were incongruous, possibly because of small samples, varying treatment periods, low power, wide confidence intervals, and the fact that the study by Colwell et al. was open-label. In their double-blind trial, Spiro et al. found no difference between a 40-mg dose of enoxaparin administered once daily and a 30-mg dose given twice daily. It must be remembered that treatment in these two studies was started within 24 hours after surgery.

Our study may still attract clinical and scientific interest, since it included more than 2000 patients monitored with a standardized venographic technique and was one of three pivotal studies on desirudin showing that direct inhibition of thrombin is effective in the prevention of deep-vein thrombosis after elective orthopedic surgery.5,6 Desirudin is the first drug to show superiority over low-molecular-weight heparin. The pharmacokinetic profile of the drug, allowing its administration in close relation to the start of surgery, after the induction of cerebrospinal anesthesia, might also contribute to a beneficial effect.

Bengt I. Eriksson, M.D., Ph.D.
Sahlgrenska–Östra University Hospital, S-416 85 Göteborg, Sweden

6 References

1
Planes A, Vochelle N, Fagola M. Total hip replacement and deep vein thrombosis: a venographic and necropsy study. J Bone Joint Surg Br 1990;72:9-13
Web of Science | Medline

2
Stamatakis JD, Kakkar VV, Sagar S, Lawrence D, Nairn D, Bentley PG. Femoral vein thrombosis and total hip replacement. BMJ 1977;2:223-225
CrossRef | Web of Science | Medline

3
Colwell CW Jr, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement: a clinical trial comparing efficacy and safety. J Bone Joint Surg Am 1994;76:3-14
Web of Science | Medline

4
Spiro TE, Johnson GJ, Christie MJ, et al. Efficacy and safety of enoxaparin to prevent deep vein thrombosis after hip replacement surgery. Ann Intern Med 1994;121:81-89
Web of Science | Medline

5
Eriksson BI, Ekman S, Kalebo P, Zachrisson B, Bach D, Close P. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996;347:635-639
CrossRef | Web of Science | Medline

6
Eriksson BI, Ekman S, Lindbratt S, et al. Prevention of thromboembolism with use of recombinant hirudin -- results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am 1997;79:326-333
Web of Science | Medline

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