Clinical Question: Is ximelagatran effective for stroke prevention in patients with non-valvular atrial fibrillation?

Setting: Outpatient (any)

Study Design: Randomized controlled trial (double-blinded)

Allocation: Concealed

Synopsis: Ximelagatran offers fixed oral dosing without the need for coagulation monitoring in the prevention of stroke in patients with nonvalvular atrial fibrillation. Investigators enrolled 3,922 patients with nonvalvular atrial fibrillation and additional established stroke risk factors. Eligible patients were randomized to treatment with ximelagatran in a dosage of 36 mg twice daily or warfarin adjusted to an International Normalized Ratio of 2.0 to 3.0. Persons assessing outcomes were blinded to treatment group assignment. All enrolled patients were followed for a mean of 20 months.

Using intention-to-treat analysis, recurrent stroke events occurred with equal frequency in the ximelagatran and warfarin treatment groups (1.6 versus 1.2 percent per year, respectively). Major bleeding events and all-cause mortality were similar between the two treatment groups. Elevated serum alanine transaminase levels were three times greater than normal in 6 percent of patients in the ximelagatran group—almost all returned to normal regardless of whether treatment was continued. One case of fatal liver disease was documented. The study was 90 percent powered to detect a 2 percent difference in stroke prevention rates between the two treatment groups. Another article in the same journal (O’Brien CL, Gage BF. Costs and effectiveness of ximelagatran for stroke prophylaxis in chronic atrial fibrillation. JAMA 2005;293:699–706) reported that ximelagatran is unlikely to be cost-effective in patients with atrial fibrillation unless they already have a high risk of intracranial hemorrhage or an established low quality of life with warfarin.

Bottom Line: Fixed-dose ximelagatran appears to be as effective as warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. Concerns about cost effectiveness, the potential for increasing the risk of myocardial ischemia, and the rare but potentially serious risk of liver toxicity should limit its use to patients intolerant to warfarin or who are at a high risk of intracranial hemorrhage. (Level of Evidence: 1b)