Ximelagatran effective for preventing blood clots and stroke

Feb 9 2005

A medication that could simplify anticoagulation therapy, ximelagatran, was found to be as effective as other common therapies for preventing stroke and recurrent blood clots, according to studies in the February 9 issue of JAMA. Ximelagatran is currently approved for use in some European countries but it has not been approved in the United States because of concerns about adverse effects.

In the first study, Jean-Noel Fiessinger, M.D., of Hôpital Européen Georges Pompidou, Paris, and colleagues conducted a study of patients with deep vein thrombosis (blood clot in veins of the legs, pelvis or arms) to determine the efficacy and safety of oral ximelagatran compared to standard treatment with the anticoagulants enoxaparin and warfarin.

According to background information in the article, current therapy for patients with acute venous thromboembolism consists of 5 to 7 days of the anticoagulant heparin overlapped with and followed by long-term, oral anticoagulation with a therapy such as warfarin. Heparin must be given parenterally (by injection, usually through the veins) and administration requires considerable health care resources. Warfarin is given orally, but has an unpredictable dose response, interacts with many drugs, and can be affected by changes in diet; thus, continued coagulation monitoring and dose adjustment are necessary. Ximelagatran is administered orally and is rapidly absorbed and quickly converted to its active form.

The trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) included 2,489 patients with deep vein thrombosis. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002. Patients were randomized to receive 6 months of treatment with either oral ximelagatran, twice daily, or subcutaneous enoxaparin, twice daily for 5 to 20 days followed by warfarin.

The researchers found that the primary efficacy end point of recurrent venous thromboembolism occurred in 26 and 24 patients in the ximelagatran and enoxaparin/warfarin groups, respectively, corresponding to estimated cumulative risks of 2.1 percent and 2.0 percent. The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2 percent. This met the prespecified criterion for non-inferiority. The cumulative risk of major bleeding at 6 months in the ximelagatran-treated patients was 1.3 percent compared with 2.2 percent for those receiving enoxaparin/warfarin. All-cause death was not significantly different between the 2 groups.

A total of 9.6 percent of patients in the ximelagatran group had alanine aminotransferase levels (a measurement in the blood used as an indicator of possible liver damage or disease) increase to greater than 3 times the upper limit of normal, vs. 2.0 percent in the enoxaparin/warfarin group. Analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1,240 patients) compared with enoxaparin/warfarin (1/1,249 patients).

"In conclusion, for the initial and prolonged treatment of deep vein thrombosis, direct thrombin inhibition with oral ximelagatran, 36 mg. twice daily, was as effective as enoxaparin/warfarin, without the need for coagulation monitoring or dose adjustment. The mechanism and clinical importance of the increased liver enzyme levels in ximelagatran-treated patients requires further evaluation. Prospective assessment of coronary events in future studies is warranted," the authors write.

In a second study in this week's JAMA, Jonathan L. Halperin, M.D., of Mount Sinai Medical Center, New York, and colleagues compared the efficacy of ximelagatran with warfarin for prevention of stroke in patients with atrial fibrillation.

Non-valvular atrial fibrillation is implicated in nearly15 percent of strokes, according to background information in the article. Research has indicated that warfarin decreases stroke risk by 62 percent, though in practice, the risk of bleeding limits treatment with warfarin, particularly among the elderly. Underuse of warfarin in patients with atrial fibrillation at high risk of bleeding calls for safer, more dependable alternatives. Ximelagatran offers fixed oral dosing without need for coagulation monitoring, rapid onset and offset of action, stable pharmacokinetics with little potential for drug interactions, and no known food interactions.

This trial, SPORTIF V (Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation), was conducted in 2000-2001 at 409 North American sites, involving 3,922 patients with non-valvular atrial fibrillation and additional stroke risk factors. Patients received warfarin or ximelagatran.

The researchers found that the primary event rate (for strokes) with ximelagatran was 1.6 percent per year and with warfarin was 1.2 percent per year. When all-cause death was included in addition to stroke and systemic embolic events, the rate difference was 0.10 percent per year. There was no difference between treatment groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37 percent vs. 47 percent per year). Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal (an indication of liver toxicity) in 6.0 percent of patients treated with ximelagatran, usually within 6 months and typically declined whether or not treatment continued.

"The SPORTIF V trial is the largest yet reported trial involving patients with atrial fibrillation for prevention of stroke and systemic embolism. Low rates of thromboembolism and bleeding occurred when ximelagatran was given in a fixed dose without anticoagulation monitoring. Further investigation is needed to clarify the risk of serious hepatic reactions and identify predictive features to select appropriate patients for treatment with ximelagatran. In the balance are a large number of potentially preventable fatal or disabling strokes that accumulate as a consequence of the limitations and underutilization of warfarin," the authors write.