News Author: Laurie Barclay, MD

April 28, 2006 — Ximelagatran is associated with less bleeding then warfarin for patients with nonvalvular atrial fibrillation, according to the results of a pooled analysis of the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V participants reported in the April 24 issue of the Archives of Internal Medicine.

"Ximelagatran is a novel direct thrombin inhibitor that can be administered as a fixed oral dose, without the need for anticoagulant monitoring," write James D. Douketis, MD, from McMaster University in Hamilton, Ontario, and colleagues. "Managing warfarin therapy is problematic because of the need for anticoagulant monitoring, with INR [International Normalized Ratio] testing required every 1 to 4 weeks for dose adjustments. Warfarin also interacts with other drugs, food, genetic polymorphisms, and acute illness, with the potential to cause excessive anticoagulation and bleeding."

This pooled analysis included 7329 patients with nonvalvular atrial fibrillation enrolled in the SPORTIF III and V trials to compare bleeding outcomes in patients who received ximelagatran, 36 mg twice daily, or warfarin sodium (target INR, 2.0 - 3.0). Outcome measures included annual risk of any and major bleeding, case-fatality rate, time course and anatomic sites of major bleeding, and risk factors for major bleeding with ximelagatran and warfarin treatment.

The annual incidence of any bleeding was 31.75% for ximelagatran and 38.82% for warfarin (relative risk reduction, 18.2%; 95% confidence interval [CI], 13.0 - 23.1; P < .001); and incidence of major bleeding was 2.01% vs 2.68% (relative risk reduction, 25.1%; 95% CI, 3.2 - 42.1; P = .03). The case-fatality rate of bleeding was similar with ximelagatran and warfarin (8.16% vs 8.09%; P = .98). After 24 months of treatment, the cumulative incidence of major bleeding was higher with warfarin than with ximelagatran (4.7% vs 3.7%; P = .04). Both treatments were similar in terms of anatomic sites of bleeding.

Risk factors for bleeding with ximelagatran treatment were diabetes mellitus (hazard ratio [HR], 1.81; 95% CI, 1.19 - 2.77; P = .006), previous stroke or transient ischemic attack (HR, 1.78; 95% CI, 1.16 - 2.73; P = .008), age 75 years or older (HR, 1.70; 95% CI, 1.33 - 2.18; P < .001), and aspirin use (HR, 1.68; 95% CI, 1.08 - 2.59; P = .02). In warfarin-treated patients, risk factors for bleeding were previous liver disease (HR, 4.88; 95% CI, 1.55 - 15.39; P = .007); aspirin use (HR, 2.41; 95% CI, 1.69 - 3.43; P < .001); and age 75 years or older (HR, 1.26; 95% CI, 1.03 - 1.52; P = .02).

Study limitations include pooling of the study sample from 2 studies of different design; the inclusion of intracerebral bleeding episodes as major episodes, which might have exaggerated the number of major bleeding episodes if some intracerebral episodes initially were ischemic strokes with subsequent hemorrhagic transformation; and lack of evidence of causality.

"Treatment with ximelagatran, 36 mg twice daily, is associated with a lower risk of bleeding than warfarin in patients with nonvalvular atrial fibrillation," the authors write. "Aspirin use and increasing age were associated with an increased risk of bleeding in ximelagatran- and warfarin-treated patients.... These potential benefits of ximelagatran therapy should be weighed against potential risks of treatment, which include elevated serum liver enzyme levels in approximately 6% of patients with atrial fibrillation and, rarely, severe and possibly fatal hepatitis."

AstraZeneca, the maker of ximelagatran, employs one of the authors. The other authors have disclosed no relevant financial relationships.