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Ximelagatran Promising for Stroke Prevention in Patients with Atrial Fibrillation: Presented at ESC

By Michael J. Worthington

MANNHEIM-HEIDELBERG, GERMANY -- May 14, 2004 -- Ximelagatran is as effective as warfarin for preventing stroke in patients with atrial fibrillation (AF), but causes less bleeding, investigators reported here May 13^th at the 13^th European Stroke Congress.

Prof. Hans-Christoph Diener, MD, Professor of Neurology, Universitat Essen, Germany, reported these findings from the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation III (SPORTIF III), an open-label trial with 3407 subjects, and SPORTIF V, a double blind trial with 3922 subjects.

Both trials compared a 36 mg BID fixed dose of ximelagatran -- an oral direct thrombin inhibitor -- and an adjusted dose of warfarin (target international normalized ratio 2-3) in patients with nonvalvular AF and at least 1 stroke risk factor (prior stroke, advanced age 75 years or greater, left ventricular dysfunction/congestive heart failure, hypertension, or diabetes).

Ximelagatran has several advantages over warfarin, Dr. Diener said, including a wider therapeutic margin, predictable pharmacokinetics, low potential for food, drug and alcohol interactions, fixed oral dosing with no need for adjustment, and no need for patient monitoring.

The aim of the SPORTIF trials was to determine whether ximelagatran was non-inferior to warfarin in the prevention of primary events (all strokes and systemic embolic events), based on intention-to-treat (ITT). The mean treatment period was 17 months in SPORTIF III and 20 months in SPORTIF V with follow-up out to 36 months.

A pre-specified pooled analysis showed no significant difference in primary event rates between ximelagatran and warfarin during 11,346 patient-years of exposure or a mean of 18.5 months (1.62% versus 1.62% per year, respectively; P =.94). Rates of both ischemic and hemorrhagic strokes were similar between groups. In patients with a prior stroke or TIA, the rates of systemic embolic events were not significantly different (2.8% and 3.3% per year; P =.63).

The only significant differences between treatments were in safety outcomes: ximelagatran was associated with a 31.7% incidence of major and minor bleeding compared with 38.7% for warfarin (P <.001). Ximelagatran was associated with a transient increase in serum alanine aminotransferase (ALT) levels >3 times upper limit of normal, which resolved after about 6 months. The incidence of elevated ALT was 6.1% for ximelagatran and 0.8% for warfarin.

In terms of net clinical benefit, use of ximelagatran represented a 16% reduction in the relative risk of primary events plus major bleeding and death over warfarin (P =.038).

"I think that ximelagatran offers a promising treatment option for the prevention of thromboembolism, both in the primary and secondary prevention in people with AF," Prof. Diener said.


[Presentation title: "Stroke prevention with the oral direct thrombin inhibitor ximelagatran in patients with non-valvular atrial fibrillation: pooled analysis of the SPORTIF III and V trials."]

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