Elsevier

The Lancet Neurology

Volume 3, Issue 5, May 2004, Pages 305-308
The Lancet Neurology

Rapid Review
Warfarin for atrial fibrillation: the end of an era?

https://doi.org/10.1016/S1474-4422(04)00738-0Get rights and content

Summary

Background

Warfarin 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 developments

New 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.

Section snippets

Current prevention strategies

Although warfarin was introduced into clinical practice during the 1950s, it was not until the late 1980s that level I evidence was provided for its effectiveness in primary and secondary prevention of stroke for patients with non-valvular AF.2, 8, 9 In a recent meta-anlaysis of five primary prevention trials, adjusted dose warfarin was shown to reduce fatal and non-fatal stroke by 62% (95% CI 48–72) with an absolute risk reduction of 2·7% per year.2 Even greater benefits exist for the

Problems with current treatment

There are two major problems associated with the use of warfarin. First, the therapeutic window is very small so that the level of anticoagulation needs to be monitored frequent. The optimal international normalised ratio (INR) for stroke prevention is 2·0–3·0.17 For INR values of 1·7 and 1·5 stroke risk is double or triple, respectively, that for INR 2·0–3·0; INR greater than 3·0 is associated with a higher risk of haemorrhage. Overall, if 1000 patients with non-valvular AF are treated with

New approaches to stroke prevention

After half a century of ad-hoc use of warfarin in non-valvular AF and a decade of its use on the basis of level I evidence (but gross under-use in actual clinical practice), there are, at last, genuine alternative strategies that are in various stages of development. Therapeutic alternatives to warfarin are the nearest to entering clinical practice (table 2) but several interventional and surgical procedures are also being assessed.

Conclusions

Although warfarin is effective in stroke prevention for patients with AF, there are limitations to its use—bleeding side-effects, the need for monitoring, a narrow therapeutic window, etc. Given that AF is such an important risk factor for stroke, particularly in elderly people, the development of oral drugs, such as ximelagatran, that are as safe—should the raised liver enzyme issue be resolved—and effective as warfarin but do not require anticoagulant monitoring is a significant advance. The

Search strategy and selection criteria

References for this review were identified by searches of PubMed using the search terms “atrial fibrillation”, “stroke”, and “prevention”. Other references were identifed from relevant articles and through searches of the authors' files.

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