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A Phase 2 Dose-Finding Study

John A. Heit, MD; Clifford W. Colwell, MD; Charles W. Francis, MD; Jeffrey S. Ginsberg, MD; Scott D. Berkowitz, MD; James Whipple, MS; Gary Peters, MD; for the AstraZeneca Arthroplasty Study Group

Arch Intern Med. 2001;161:2215-2221.

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.

From the Division of Cardiovascular Diseases, Mayo Clinic and Mayo Foundation, Rochester, Minn (Dr Heit); the Department of Orthopedic Surgery, Scripps Clinic, La Jolla, Calif (Dr Colwell); the Department of Medicine, University of Rochester Medical Center, Rochester, NY (Dr Francis); the Division of Hematology, McMaster University, Hamilton, Ontario (Dr Ginsberg); and AstraZeneca LP, Wayne, Pa (Drs Berkowitz and Peters and Mr Whipple).

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