Physicians' Academy for Cardiovascular Education

Smaller cerebral infarct size and no increase in microbleeds with NOAC vs. aspirin in AF

O’Donnell M et al., Am Heart J 2016

Effect of Apixaban on Brain Infarction and Microbleeds: AVERROES-MRI Assessment Study

O’Donnell M, Eikelboom J, Yusuf S, et al.
Am Heart J  2016; published online ahead of print


In dementia patients without a clinical history of acute stroke, neuroimaging often identifies the presence of cerebral infarction or hemorrhage, a situation called covert (subclinical) stroke [1,2]. Atrial fibrillation is a well-known risk factor for covert stroke, and in approximately 25% of AF patients covert brain infarction is discovered at routine MRI, often with an ‘embolic’ pattern [3-5]. Moreover, cerebral microbleeds on brain MRI are common in older adults and have been associated with an increased risk of intracerebral bleeding [6,7].
In the AVERROES trial in AF patients, NOAC apixaban reduced the risk of acute clinical ischemic stroke by 63% compared with aspirin, without increasing the risk of intracerebral hemorrhage [8]. However, the effect of apixaban on covert stroke is not known.
In this substudy, brain MRIs in a subgroup of AVERROES participants were done to determine whether apixaban reduced the risk of the composite endpoint of symptomatic ischemic stroke and covert ‘embolic-pattern’ infarction and on microbleeds, as well as to explore the effect of apixaban on the progression of white matter hyperintensities. Mean interval from baseline to follow-up MRI scans was 1.0 year.

Main results

  • Baseline MRI scans revealed brain infarct(s) in 26.2% (n=309/1180), microbleed(s) in 10.5% (n=99/940), covert ischaemic stroke in 20.5% (n=216/1054). Mean periventricular white matter intensity score was 3.0 (SD 2.4), mean subcortical ischaemic volume: 0.76ml (SD 1.9)
  • The rate of the primary outcome was 2.0% in the apixaban group and 3.3% in the aspirin group (HR: 0.55; 95% CI: 0.27-1.14) from baseline to follow-up MRI scan.
  • The rate of new infarction detected on MRI was 2.5% in the apixaban group and 2.2% in the aspirin group (HR: 1.09; 95% CI: 0.47-2.52), and the mean infarct diameter was 1.3cm in the apixaban group compared with 4.1cm in the aspirin group (P=0.03).
  • On follow-up MRI there was no difference between treatment groups in proportion with new (or increase) in microbleeds (HR: 0.94; 95% CI: 0.50-1.76) and reduction in microbleeds (HR: 0.84; 95% CI: 0.56-2.03)(P=0.47 for net change in number of microbleeds between groups)
  • Mean changes in periventricular white matter hyperintensity score were -0.06 (95% CI: 0.01-1.08), subcortical volume: +0.09ml (95% CI: 0.17-1.15ml) with no significant differences between treatment groups (P=0.64 and P=0.82 respectively).


In AF patients, apixaban, compared with aspirin, was associated with a non-significant trend toward reduction in the composite endpoint of clinical ischaemic stroke and covert embolic-pattern infarction. A reduction in the size of cerebral infarcts was seen with apixaban, and it did not increase the number of microbleeds. It should be noted that follow-up was short due to early termination of the AVERROES trial.
Find this article online at Am Heart J


1. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005; 366:2112-7.
2. Longstreth WT, Jr., Dulberg C, Manolio TA, et al. Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 2002; 33:2376-82.
3. Kobayashi A, Iguchi M, Shimizu S, et al. Silent cerebral infarcts and cerebral white matter lesions in patients with nonvalvular atrial fibrillation. J Stroke Cerebrovasc Dis 2012;21:310-7
4. Das RR, Seshadri S, Beiser AS, et al. Prevalence and correlates of silent cerebral infarcts in the Framingham offspring study. Stroke 2008; 39:2929-35.
5. Helgason CM. Cardioembolic stroke: topography and pathogenesis. Cerebrovasc Brain Metab Rev 1992; 4:28-58.
6. Miller VT, Pearce LA, Feinberg WM, et al. Differential effect of aspirin versus warfarin on clinical stroke types in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators. Neurology 1996; 46:238-40.
7. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009; 8:165-74.
8. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806-17.