Atrial fibrillation (AF) is the most common cardiac risk factor for
stroke. Oral
anticoagulants such as the
vitamin K antagonist
warfarin have been proven effective in reducing the risk of
stroke in AF.
Warfarin, however, has many disadvantages including the need for coagulation monitoring, a narrow therapeutic index, inter-/intra-patient variability and food-drug interactions. As a result,
warfarin is underused in clinical practice and a viable alternative is needed.
Ximelagatran, the first oral
direct thrombin inhibitor, is given as a fixed dose, does not have a narrow therapeutic index, has low potential for drug interactions, has no significant food interactions and does not require coagulation monitoring.
Ximelagatran has been evaluated in the
Stroke Prevention using an ORal
direct Thrombin Inhibitor in
atrial Fibrillation (SPORTIF) trial programme, the largest clinical trials of antithrombotic
therapy for
stroke prevention in AF to date. The phase III trials, SPORTIF III and V, compared
ximelagatran (36 mg twice daily) with well-controlled
warfarin (international normalized ratio 2.0-3.0) in a combined population of more than 7,000 moderate- to high-risk AF patients. Data from SPORTIF III show an absolute reduction in
stroke and systemic embolic events with
ximelagatran compared with
warfarin at 21 months (1.6 vs. 2.3% per year, respectively; p = 0.10). Preliminary data from SPORTIF V appear to further support non-inferiority between the two agents. On-treatment analysis of the rate of major
bleeding events shows an absolute, nonsignificant reduction in the event rate per year with
ximelagatran versus
warfarin in both studies. The results of SPORTIF III and V demonstrate that a fixed oral dose of
ximelagatran, without coagulation monitoring, is comparable to dose-adjusted
warfarin in preventing
stroke and other thromboembolic complications among moderate- to high-risk AF patients and has a lower rate of both major and minor
bleeding. With its positive benefit-risk ratio,
ximelagatran may increase the population of eligible patients for anticoagulation with AF and maximize the potential of anticoagulation in the prevention of
stroke.