ABC of antithrombotic therapy: Antithrombotic therapy for atrial fibrillation

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Abstract
Evidence from clinical trials It is well established that antithrombotic therapy confers thromboprophylaxis in patients with atrial fibrillation who are at risk of thromboembolism. A recent meta-analysis of antithrombotic therapy in atrial fibrillation showed that adjusted dose warfarin reduced stroke by about 60%, with absolute risk reductions of 3% a year for primary prevention and 8% a year for secondary prevention (numbers needed to treat for one year to prevent one stroke of 33 and 13, respectively). In contrast, aspirin reduced stroke by about 20%, with absolute risk reductions of 1.5% a year for primary prevention and 2.5% a year for secondary prevention (numbers needed to treat of 66 and 40, respectively). Relative to aspirin, adjusted dose warfarin reduced the risk by about 40%, and the relative risk reduction was similar for primary and secondary prevention, and for disabling and non-disabling strokes. However, these data, obtained from well planned clinical trials recruiting patients with relatively stable conditions, are unlikely to be fully extrapolable to all patients in general practice, so that some caution is advised. View larger version: In this window In a new window Meta-analysis of trials comparing warfarin with placebo in reducing the risk of thromboembolism in patients with atrial fibrillation AFASAK=Copenhagen atrial fibrillation, aspirin, and anticoagulation study; BAATAF=Boston area anticoagulation trial for atrial fibrillation; CAFA=Canadian atrial fibrillation anticoagulation study; EAFT=European atrial fibrillation trial; SPAF=Stroke prevention in atrial fibrillation study; SPINAF=Stroke prevention in non-rheumatic atrial fibrillation Overall, warfarin (generally at a dose to maintain an international normalised ratio (INR) of 2-3) is significantly more effective than aspirin in treating atrial fibrillation in patients at high risk of stroke, especially in preventing disabling cardioembolic strokes. The effect of aspirin seems to be on the smaller, non-cardioembolic strokes from which elderly, and often hypertensive, patients with atrial fibrillation are not spared. Recent clinical trials have suggested that there is no role for minidose warfarin (1 mg/day regardless of INR), alone or in combination with antiplatelet agents or aspirin, as thromboprophylaxis in atrial fibrillation. However, the role of other antiplatelet agents (such as indobufen and dipyridamole) in atrial fibrillation is still unclear. One small trial (SIFA) compared treatment with indobufen, a reversible cyclo-oxygenase inhibitor, with full dose warfarin for secondary prevention and found no statistical difference between the two groups, who were well matched for confounding risk factors. Trials of other antiplatelet and antithrombotic drugs (including low molecular weight heparin) have been performed but have generally been too small and underpowered to show significant differences. Large multinational trials comparing a direct thrombin inhibitor (ximelagatran) with adjusted dose warfarin in over 7000 patients at high risk of atrial fibrillation are nearing completion and should be reported in 2003. View larger version: In this window In a new window Meta-analysis of trials comparing aspirin with placebo in reducing risk of thromboembolism in patients with atrial fibrillation AFASAK=Copenhagen atrial fibrillation, aspirin, and anticoagulation study; EAFT=European atrial fibrillation trial; ESPS II= European stroke prevention study II; LASAF=Low-dose aspirin, stroke, and atrial fibrillation pilot study; SPAF=Stroke prevention in atrial fibrillation study; UK-TIA=United Kingdom TIA study The reduction in relative risk with warfarin applies equally to primary and secondary prevention but, as history of stroke confers an increased annual stroke risk (12% v 4.5%), the absolute risk reduction is greater for secondary prevention. The number of patients with atrial fibrillation needing treatment with warfarin to prevent one stroke is therefore about three times greater in primary prevention (37) than in secondary prevention (12). Treatment with full dose anticoagulation carries the potential risk of major bleeding, including intracranial haemorrhage. Meta-analysis of the initial five primary prevention trials plus a further secondary prevention trial suggests the risk of haemorrhagic stroke is only marginally increased from 0.1% to 0.3% a year. Higher rates of major haemorrhage were seen in elderly patients and those with higher intensity anticoagulation. Further recent trials have confirmed an increased bleeding risk in patients with INR >3. View larger version: In this window In a new window Meta-analysis of trials comparing warfarin with aspirin in reducing risk of thromboembolism in patients with atrial fibrillation AFASAK=Copenhagen atrial fibrillation, aspirin, and anticoagulation study; EAFT=European atrial fibrillation trial; PATAF=Prevention of arterial thromboembolism in atrial fibrillation; SPAF=Stroke prevention in atrial fibrillation study Antiplatelet therapy in atrial fibrillation Several clinical trials have studied the effects of aspirin in atrial fibrillation, with doses ranging from 25 mg twice daily to 1200 mg a day. Overall, aspirin reduces the relative risk of stroke by about 20% (a figure which just reaches statistical significance) with no apparent benefit of increasing aspirin dose. Aspirin seems to carry greater benefit in reducing smaller non-disabling strokes than disabling strokes. This may be due to an effect primarily on carotid and cerebral artery platelet thrombus formation, rather than on formation of intra-atrial thrombus. A meta-analysis of trials directly comparing full dose warfarin with aspirin confirmed significant reductions in stroke risk about three times greater with warfarin. The SPAF III trial demonstrates that addition of fixed low doses of warfarin to aspirin treatment is not sufficient to achieve the benefits of full dose warfarin alone....

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