Clinical Question: Is ximelagatran as effective as warfarin in preventing stroke in patients with nonvalvular atrial fibrillation?
Study Design: Randomized controlled trial (nonblinded)
Synopsis: Patients with atrial fibrillation were recruited from hospitals, physician offices, and health care clinics to participate in this manufacturer-sponsored, open-label study comparing fixed dosages of ximelagatran (n = 1,704 patients) with dosages of warfarin to maintain an International Normalized Ratio between 2.0 and 3.0 (n = 1,703 patients). To be included in the study, patients had to have at least one additional risk factor, such as hypertension, age older than 75 years, previous thromboembolic phenomena, left ventricular ejection fraction less than 40 percent, symptomatic congestive heart failure, or age older than 65 years plus coronary artery disease or diabetes mellitus. The large number of exclusion criteria included recent stroke, transient ischemic attack, acute coronary syndrome, conditions associated with increased risk of bleeding, endocarditis, planned major surgery, or cardioversion. Allocation to treatment group was masked.
The primary outcome, all stroke (ischemic or hemorrhagic) and systemic embolic events, was assessed via intention to treat. The secondary end points, also assessed by intention to treat, included bleeding, treatment discontinuation, ischemic stroke, transient ischemic attack, systemic embolism, death, stroke, and acute myocardial infarction. The study was designed to have 90 percent power, a minimum of 12 months of follow-up per patient, and an aggregate of 80 primary events. The primary outcomes were assessed by local study-affiliated neurologists or stroke specialists who were masked to treatment. The authors had data on all but 10 patients who never took the study drug. Slightly more patients receiving warfarin completed the study (86 versus 82 percent receiving ximelagatran).
The total mortality was approximately the same in each group (4.6 percent). The mean length of follow-up was 17 months. In the group treated with warfarin, 56 patients had primary events during 2,440 patient-years (yearly rate = 2.3 percent) compared with 40 patients in the ximelagatran group during 2,446 patient-years (yearly rate = 1.6 percent). This difference was not significant. The rate of secondary events in each group was similar, with the exception of bleeding complications, which occurred less often in the ximelagatran group (26 percent per year) than in the warfarin group (30 percent per year).
Bottom Line: In this manufacturer-sponsored, open-label study, patients with atrial fibrillation who were at increased risk of stroke and were treated with ximelagatran or warfarin had comparable outcomes. If these results are confirmed independently, ximelagatran may become the preferred treatment, because it does not require monitoring and may cause fewer bleeding complications. (Level of Evidence: 2b)