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Oral Anticoagulant, Ximelagatran, Studied as Alternative to Warfarin for Stroke Prevention
In SPORTIF III (Stroke Prevention by ORal Thrombin Inhibitor in atrial Fibrillation), an open-label, randomized, non-inferiority trial, patients treated with EXANTA (n=1,704) had 40 strokes and systemic embolic events compared to 56 strokes and systemic embolic events in patients treated with warfarin (n=1,703). For those patients remaining on treatment throughout the trial (on treatment analysis), patients receiving EXANTA had 29 strokes and systemic embolic events compared to 52 events for patients on warfarin, a statistically significant relative risk reduction of 41 percent (p=0.018).
SPORTIF III was conducted in 3,407 patients in 23 countries in Europe, Asia, Australia and New Zealand. In SPORTIF III, 1,704 patients with NVAF and at least one additional stroke risk factor received fixed-dose EXANTA (36 mg bid) and 1,703 patients received warfarin (dose-adjusted to an INR of 2-3). The SPORTIF program enrolled both newly-treated patients and patients that were already on warfarin therapy. Patients were treated for between 12 and 26 months. Warfarin was well controlled in the study with 66 percent of INR measurements between 2.0 and 3.0.
In SPORTIF III, there were 29 major (requiring hospitalization) bleeding events in the group receiving EXANTA compared to 41 in the warfarin arm (p=ns). In the trial, 6.5 percent of patients treated with EXANTA experienced an increase to greater than three times the upper limit of normal of a liver enzyme called ALT, compared to 0.7 percent of patients in the warfarin group. Nearly all enzyme changes occurred within the first six months of treatment and decreased with or without drug discontinuation. These results, together with those from previous and future studies in the clinical program for EXANTA, will form the overall benefit-risk profile for the product.
EXANTA is the first oral direct thrombin inhibitor under Phase III investigation and the first investigational oral anticoagulant agent to reach Phase III in more than 50 years. The intended mechanism of action of EXANTA is to inhibit the activity of an enzyme called thrombin, which is critical to the final step in the formation of blood clots. Ongoing clinical studies with EXANTA utilize a fixed dose without coagulation monitoring.
SPORTIF III is one of two Phase III trials of the SPORTIF program. The SPORTIF program includes 7,320 patients. Results of the North American part of the program, SPORTIF V, which includes 3,913 patients at 409 sites, are expected in late 2003.
According to the American Heart Association, atrial fibrillation (AF) is found in about two million Americans and is a major risk factor for stroke. AF increases the risk of stroke five-fold, accounting for about 15 percent of all strokes nationally.
The stroke rate among patients with AF averages about 5 percent per year, rising to almost 25 percent for those over the age of 80. Older patients with risk factors such as hypertension or diabetes are at increased risk. Patients with AF tend to have more serious first strokes compared to those without AF. The number of patients with AF is likely to increase by two and half times during the next 50 years, reflecting the growing population of the elderly.
In AF, the two small upper chambers of the heart, called the atria, quiver instead of beating effectively. Blood in these quivering chambers can pool and clot. If a section of the blood clot travels to an artery in the brain and becomes lodged, a stroke may result.
The results of several prospective randomized stroke prevention trials show that the relative risk of stroke in AF patients can be reduced by 62 percent using oral anticoagulant therapy. However, many eligible patients are not receiving oral anticoagulant therapy.
Treatment guidelines from the American College of Chest Physicians as well as the combined guidelines of the American College of Cardiology, American Heart Association and the European Society of Cardiology recommend the use of warfarin for most AF patients. However, warfarin is significantly underutilized.