• Geoffrey A Donnan, Helen M Dewey, and Brian R Chambers.
• National Stroke Research Institute, Department of Neurology, Austin Health, Department of Medicine, University of Melbourne, Heidelberg Heights, Victoria, Australia. gdonnan@unimelb.edu.au
• Lancet Neurol. 2004 May 1;3(5):305-8.

BackgroundWarfarin has been in routine clinical use for more than 50 years; however, it was not proven to be of benefit in both primary and secondary prevention of stroke for patients with non-valvular atrial fibrillation (AF) until about a decade ago. Despite its efficacy in reducing the risk of stroke in patients with AF by about 60%, with an absolute reduction of about 3% per year, there have always been barriers to its use. These barriers have included the need for monitoring the degree of anticoagulation with blood tests to measure the international normalised ratio, frequent dose adjustments to maintain this ratio within quite a narrow therapeutic range, and the risk of bleeding should the upper limits of this range be exceeded. Aspirin has also been used but is less effective.Recent DevelopmentsNew oral drugs are being tested; these may be as effective at reducing stroke risk as warfarin in patients with AF. Direct thrombin inhibitors such as ximelagatran are not inferior to warfarin and, based on results from the SPORTIF III and V trials, are perhaps safer, with no need for long-term monitoring and dose adjustment. However, the side-effect of raised amounts of the liver enzyme alanine amino-transferase in 6% of patients needs to be resolved. In the ACTIVE trial, the efficacy of a combination of antiplatelet drugs (aspirin plus clopidogrel) is being tested against dose-adjusted warfarin; and in AMADEUS, the factor-Xa inhibitor and pentasaccharide idraparinux is being assessed in a similar way. Several surgical procedures and devices are also being developed to control AF rhythm and prevent stroke. WHERE NEXT?: The place of these new drugs in the management of AF needs to be established. In the short term, it seems that ximelagatran will replace warfarin in patients for whom there is evidence of a favourable risk-to-benefit ratio. The SPORTIF population consists of patients with AF plus at least one risk factor. More information about the effect of raised liver enzymes will probably not be available until phase IV studies are completed. Combination antiplatelet drugs need to be tested further--perhaps even triple therapy with aspirin, clopidogrel, and dipyridamole--if the results of ACTIVE are encouraging. The place of surgical procedures and devices to control rhythm and prevent stroke is unclear. Whatever happens, there is a high probability that the days of warfarin are numbered.

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