Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: A phase 2 dose-finding study

J. A. Heit, C. W. Colwell, C. W. Francis, J. S. Ginsberg, S. D. Berkowitz, J. Whipple, G. Peters

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Abstract

Background: Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular-weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and clot-bound thrombin. Methods: We performed a randomized, parallel, dose-finding study of 600 adults undergoing elective total knee replacement at 68 North American hospitals to determine the optimum dose of ximelagatran to use as prophylaxis against venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venographic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding. Results: A total of 594 patients received at least 1 dose of the study drug; 443 patients were evaluable for efficacy. Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4.2%; P=.3). There was no major bleeding with administration of 24 mg of ximelagatran twice daily. Conclusion: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.

Original languageEnglish (US)
Pages (from-to)2215-2221
Number of pages7
JournalArchives of Internal Medicine
Volume161
Issue number18
StatePublished - Oct 8 2001

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Enoxaparin
Knee Replacement Arthroplasties
Antithrombins
Venous Thromboembolism
Venous Thrombosis
Pulmonary Embolism
Hemorrhage
Low Molecular Weight Heparin
ximelagatran
Thrombin
Mouth
Sodium
Confidence Intervals
Incidence
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Internal Medicine

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Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement : A phase 2 dose-finding study. / Heit, J. A.; Colwell, C. W.; Francis, C. W.; Ginsberg, J. S.; Berkowitz, S. D.; Whipple, J.; Peters, G.

In: Archives of Internal Medicine, Vol. 161, No. 18, 08.10.2001, p. 2215-2221.

Research output: Contribution to journalArticle

Heit, J. A. ; Colwell, C. W. ; Francis, C. W. ; Ginsberg, J. S. ; Berkowitz, S. D. ; Whipple, J. ; Peters, G. / Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement : A phase 2 dose-finding study. In: Archives of Internal Medicine. 2001 ; Vol. 161, No. 18. pp. 2215-2221.
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abstract = "Background: Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular-weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and clot-bound thrombin. Methods: We performed a randomized, parallel, dose-finding study of 600 adults undergoing elective total knee replacement at 68 North American hospitals to determine the optimum dose of ximelagatran to use as prophylaxis against venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venographic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding. Results: A total of 594 patients received at least 1 dose of the study drug; 443 patients were evaluable for efficacy. Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27{\%} (6.6{\%}), 19.8{\%} (2.0{\%}), 28.7{\%} (5.8{\%}), and 15.8{\%} (3.2{\%}), respectively. Rates of overall venous thromboembolism (22.7{\%}) and proximal deep vein thrombosis or pulmonary embolism (3.1{\%}) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9{\%}; 95{\%} confidence interval, -18.0{\%} to 4.2{\%}; P=.3). There was no major bleeding with administration of 24 mg of ximelagatran twice daily. Conclusion: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.",
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AU - Francis, C. W.

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