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Extended prevention of venous thromboembolism following an initial six month period of warfarin therapy

An article from the e-journal of the ESC Council for Cardiology Practice

Oral ximelagatran is superior to placebo for extended prevention of venous thromboembolism in patients initially treated with warfarin (INR 2.0-3.0) for six months.

Venous Thromboembolism

Idiopathic venous thromboembolism is associated with a 5-7 % increased risk of recurrence after an initial six months of anticoagulation with conventional-intensity warfarin (INR 2.0-3.0), but can be reduced with the use of extended warfarin therapy (1). However, this effect might be outweighed by an annual risk of major bleeding of 3 to 4 percent. Treatment with low-intensity warfarin therapy for a longer period may reduce the risk of bleeding (2), but this approach is still controversial (3).

Recently, Schulman and co-workers assessed a new treatment option, namely the effects of the oral direct thrombin inhibitor ximelagatran 24 mg twice daily or placebo in patients who had completed 6 months of anticoagulant therapy for an episode of venous thromboembolism. The extended prevention was given for approximately 18 months. The double-blinded randomised study comprised 1233 patients from 142 centers worldwide (4). The frequency of symptomatic venous thromboembolism was 2.8 percent among those receiving ximelagatran, a rate that was 78 percent lower than in the placebo group. Death for any cause occurred in 6 patients in the ximelagatran group and in 7 patients in the placebo group. Bleeding occurred in 134 patients - 6 major bleeding and in 111 patients 5 major bleeding -, respectively. As evident from other trials of oral ximelagatran, an elevation of alanine aminotransferase (ALAT) level to more than three times the upper limit of the normal level was seen in 6.4 % of the patients compared to 1.2 % in the placebo group, indicating that the measurement of ALAT so far is necessary in patients treated with ximelagatran.

Treatment with the new direct thrombin inhibitor ximelagatran is an attractive new concept of oral anticoagulation, that does not require monitoring of the coagulation system. This drug and the new very low molecular weight heparins – the pentasaccharides - are currently being evaluated in patients with ischaemic heart disease, atrial fibrillation and as prophylaxis and treatment of venous thromboembolism.

Schulman et al showed that oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism and that there was no significant increase in the frequencies of bleeding complications (4). However, a direct comparison of ximelagatran and warfarin based on efficacy of the drugs, inconveniences in laboratory monitoring (INR, ALAT) and costs, is warranted, before any conclusion can be drawn as to the drug of choice in long-term prevention of venous thromboembolism. While waiting for such comparisons, extended prevention of venous thromboembolism with oral ximelagatran might be an option in some patients.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.


1) Hirsh J, Dalen JE, Anderson DR et al. Oral anticoagulants: mechanism of action, clinical effectiveness and optimal therapeutic range. Chest 2001; 119: Suppl: 8S-21S.

2) Ridker PM, Goldhaber SZ, Danielson E et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thrombo-embolism. N Engl J Med 2003; 348: 1425-34.

3) Kearon C, Ginsberg JS, Kovacs M et al. Comparison of Low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349: 631-9.

4) Schulman S, Wåhlander K, Lundström T, Clason S B, Erikson H, for the THRIVE III Investigators: Secondary prevention of venous thromboembolism with oral direct thrombin inhibitor Ximelagatran. N Engl J Med 2003;349:1713-21.

Notes to editor

Assoc. Prof. J. F. Lassen and Dr S. D. Kristensen
Aarhus, Denmark
Vice-Chairman of the Working Group on Thrombosis

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.