www.thelancet.com/neurology Vol 11 March 2012 225 Articles Lancet Neurol 2012; 11: 225–31 Published Online February 1, 2012 DOI:10.1016/S1474- 4422(12)70017-0 See Comment page 203 *Members listed in webappendix Department of Neurology, University Hospital Essen, Essen, Germany (Prof H-C Diener MD); Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada (Prof S J Connolly MD, Prof J Eikelboom MD, Prof S Yusuf FRCPC, Prof R G Hart MD, O Shestakovska MSc); University of Toronto, Toronto, ON, Canada (Prof C D Joyner MD); University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK (Prof G Y H Lip MD); Health Research Board Clinical Research Facility, Galway, Ireland, (M O’Donnell MD); JW Goethe-University, Frankfurt, Germany (Prof S H Hohnloser MD); and Royal Perth Hospital, Perth, WA, Australia (Prof G J Hankey MD) Correspondence to: Dr Hans-Christoph Diener, Department of Neurology, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany h.diener@uni-essen.de See Online for webappendix Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial Hans-Christoph Diener, John Eikelboom, Stuart J Connolly, Campbell D Joyner, Robert G Hart, Gregory Y H Lip, Martin O’Donnell, Stefan H Hohnloser, Graeme J Hankey, Olga Shestakovska, Salim Yusuf, for the AVERROES steering committee and investigators* Summary Background In the AVERROES study, apixaban, a novel factor Xa inhibitor, reduced the risk of stroke or systemic embolism in patients with atrial fibrillation who were at high risk of stroke but unsuitable for vitamin K antagonist therapy. We aimed to investigate whether the subgroup of patients with previous stroke or transient ischaemic attack (TIA) would show a greater benefit from apixaban compared with aspirin than would patients without previous cerebrovascular events. Methods In AVERROES, 5599 patients (mean age 70 years) with atrial fibrillation who were at increased risk of stroke and unsuitable for vitamin K antagonist therapy were randomly assigned to receive apixaban (5 mg twice daily) or aspirin (81–324 mg per day). The mean follow-up was 1·1 years. The primary efficacy outcome was stroke or systemic embolism; the primary safety outcome was major bleeding. Patients and investigators were masked to study treatment. In this prespecified subgroup analysis, we used Kaplan-Meier estimates of 1-year event risk and Cox proportional hazards regression models to compare the effects of apixaban in patients with and without previous stroke or TIA. AVERROES is registered at ClinicalTrials.gov, number NCT00496769. Findings In patients with previous stroke or TIA, ten events of stroke or systemic embolism occurred in the apixaban group (n=390, cumulative hazard 2·39% per year) compared with 33 in the aspirin group (n=374, 9·16% per year; hazard ratio [HR] 0·29, 95% CI 0·15–0·60). In those without previous stroke or TIA, 41 events occurred in the apixaban group (n=2417, 1·68% per year) compared with 80 in the aspirin group (n=2415, 3·06% per year; HR 0·51, 95% CI 0·35–0·74). The p value for interaction of the effects of aspirin and apixaban with previous cerebrovascular events was 0·17. Major bleeding was more frequent in patients with history of stroke or TIA than in patients without (HR 2·88, 95% CI 1·77–4·55) but risk of this event did not differ between treatment groups. Interpretation In patients with atrial fibrillation, apixaban is similarly effective whether or not patients have had a previous stroke or TIA. Given that those with previous stroke or TIA have a higher risk of stroke, the absolute benefits might be greater in these patients. Funding Bristol-Myers Squibb and Pfizer. Introduction Atrial fibrillation is the most common sustained cardiac arrhythmia. It independently increases the risk of mortality and morbidity by increasing risk of stroke and systemic thromboembolism. 1 The most powerful predictor of stroke in patients with atrial fibrillation is a history of previous stroke or transient ischaemic attack (TIA). 2 Vitamin K antagonist therapy reduces the risk of stroke in atrial fibrillation by two-thirds, 3 and its absolute benefits are greatest in patients at highest risk of stroke, such as those with previous stroke or TIA. 3,4 However, at least a third of patients with atrial fibrillation at risk of stroke are not treated with vitamin K antagonists because of the limitations of vitamin K antagonist therapy, which include various food and drug interactions, a narrow therapeutic window, the need for life-long coagulation monitoring, and a risk of intracranial and systemic bleeding. 5,6 For patients with atrial fibrillation deemed unsuitable for vitamin K antagonist therapy, aspirin is commonly used as a prophylactic drug. Aspirin reduces the risk of stroke by about a fifth compared with placebo 2 and is associated with less bleeding than is vitamin K antagonist therapy. 3,4 However, in patients with atrial fibrillation at high absolute risk of stroke, such as those with previous stroke or TIA and the elderly, a one-fifth reduction in the relative risk of stroke with aspirin, compared with placebo, is suboptimum, and the rate of bleeding with aspirin might not be lower than that with vitamin K antagonist therapy. 7 There is a need for a more effective anticoagulant than aspirin that can be used more widely than vitamin K antagonist therapy in patients with atrial fibrillation who are at high risk of stroke. Apixaban is a new direct and competitive inhibitor of factor Xa. 8 It was compared with aspirin in 5599 patients with atrial fibrillation who were unsuitable for vitamin K antagonist therapy in the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients who have Failed or are Unsuitable for Vitamin K