Nonvalvular
atrial fibrillation (AF) is an independent risk factor for
stroke that becomes increasingly prevalent as populations age. More than half a dozen clinical trials have demonstrated that anticoagulation with the
vitamin K antagonist
warfarin is the most effective
therapy for
stroke prophylaxis in AF. The narrow therapeutic index of
warfarin requires that the intensity of anticoagulation be maintained within the international normalized ratio (INR) range of 2.0 to 3.0 to optimize efficacy while minimizing
bleeding risk. The pharmacokinetics of
warfarin are subject to variability due to interactions with multiple drugs and foods, making maintenance of the INR within this range difficult to achieve in clinical practice without close coagulation monitoring and frequent dose adjustments. Current guidelines recommend oral anticoagulation for high-risk individuals with AF but these inherent limitations lead to substantial underprescribing, particularly in elderly patients at greatest risk. This has stimulated the development of new agents with improved benefit-risk profiles, such as
ximelagatran, the first of the oral
direct thrombin inhibitors, which has a wider therapeutic margin and low potential for drug interactions, allowing fixed dosing without anticoagulation monitoring.
Ximelagatran has been evaluated for
stroke prevention in AF in the
Stroke Prevention using an Oral
Direct Thrombin Inhibitor in
Atrial Fibrillation (SPORTIF) program, the largest clinical trials of antithrombotic
therapy for
stroke prevention in AF to date. The phase III trials of
ximelagatran in AF, SPORTIF III and V, found a fixed oral dose of
ximelagatran (36 mg twice daily) comparable to dose-adjusted
warfarin (INR 2.0 to 3.0) in preventing
stroke and systemic thromboembolic complications among high-risk patients with AF. Results from the population of over 7000 patients in SPORTIF III and V demonstrate noninferiority of
ximelagatran compared with
warfarin. Data from SPORTIF III show an absolute reduction in
stroke and systemic embolic events with
ximelagatran compared with
warfarin of 1.6% per year versus 2.3% per year, respectively ( P = 0.10). SPORTIF V further supports noninferiority between the two agents with an absolute risk reduction of 0.45%, well within the predefined noninferiority margin (95% confidence interval -0.13, 1.03; P = 0.13). Although event rates for major
bleeding did not differ significantly with
ximelagatran versus
warfarin in either study, combined rates for major and minor
bleeding were significantly reduced with
ximelagatran. The overall net clinical benefit, taking into account effects on
stroke or systemic embolic events, major
bleeding, and death, was also greater with
ximelagatran compared with
warfarin in both studies. Elevated serum
transaminase enzymes were observed in approximately 6% of patients given
ximelagatran in these trials. These typically occurred 1 to 6 months after initiating treatment and usually abated without clinical sequelae whether or not treatment was continued. Given the consistency of response, the favorable overall benefit-risk ratio and the convenience of fixed oral dosing,
ximelagatran may increase the number of patients with AF eligible for anticoagulation and amplify the potential for prophylaxis against
stroke.