Elsevier

American Heart Journal

Volume 178, August 2016, Pages 145-150
American Heart Journal

Clinical Investigation
Effect of apixaban on brain infarction and microbleeds: AVERROES-MRI assessment study

https://doi.org/10.1016/j.ahj.2016.03.019Get rights and content

Background

Clinical and subclinical (covert) stroke is a cause of cognitive loss and functional impairment. In the AVERROES trial, we performed serial brain magnetic resonance imaging (MRI) scans in a subgroup to explore the effect of apixaban, compared with aspirin, on clinical and covert brain infarction and on microbleeds in patients with atrial fibrillation.

Methods

We performed brain MRI (T1, T2, fluid-attenuated inversion recovery, and T2* gradient echo sequences) in 1,180 at baseline and in 931 participants at follow-up. Mean interval from baseline to follow-up MRI scans was 1.0 year. The primary outcome was a composite of clinical ischemic stroke and covert embolic pattern infarction (defined as infarction >1.5 cm, cortical-based infarction, or new multiterritory infarction). Secondary outcomes included new MRI-detected brain infarcts and microbleeds and change in white matter hyperintensities.

Results

Baseline MRI scans revealed brain infarct(s) in 26.2% and microbleed(s) in 10.5%. The rate of the primary outcomes was 2.0% in the apixaban group and 3.3% in the aspirin group (hazard ratio [HR] 0.55; 0.27-1.14) from baseline to follow-up MRI scan (mean duration of follow-up: 1 year). In those who completed baseline and follow-up MRI scans, 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; 0.47-2.52), but new infarcts were smaller in the apixaban group (P = .03). There was no difference in proportion with new microbleeds on follow-up MRI (HR 0.92; 0.53-1.60) between treatment groups.

Conclusions

Apixaban treatment was associated with a nonsignificant trend toward reduction in the composite of clinical ischemic stroke and covert embolic-pattern infarction and did not increase the number of microbleeds in patients with atrial fibrillation compared with aspirin.

Section snippets

AVERROES trial

The study design and the main study methods and results have been previously reported.8,9 Patients were eligible if they had atrial fibrillation and at least 1 additional risk factor for stroke. Patients were required to be unsuitable for VKA therapy based on prior exposure (~50%), expectation of high bleeding risk or poor anticoagulant control, or patients’ preference. Patients were randomized to receive in blinded fashion apixaban 5 mg bid (2.5 mg bid in patients meeting 2 of the following 3

Sample size

Our original sample size was calculated based on the following considerations: (1) a proposed minimal risk reduction of approximately 50% for all “embolic” strokes (clinical stroke and embolic pattern on MRI) with apixaban compared with aspirin; (2) control event rate of symptomatic ischemic stroke of 4.2% per year in the aspirin group (based on recruitment of participants with CHADS2 score of ≥2) and a covert infarction rate of 11.7% per year, of which we anticipated that one-third would have

Results

In total, 1,185 participants were included in the MRI assessment study, and baseline MRI scans were received for 1,180 (99.6%), 601 participants in the apixaban group and 579 participants in the aspirin group. During follow-up, 29 participants died. Follow-up MRI scans were received for 931 (80.9%), and interpretable for analysis in 925 (80.4%) participants with baseline MRI scans and alive at time of final follow-up. In the entire cohort, follow-up MRI scans were completed in 79.8% in the

Discussion

Compared with aspirin, apixaban was associated with a trend toward a reduced risk of the composite of clinical stroke and covert “embolic” ischemic stroke. Although apixaban did not reduce the risk of any new infarction detected on routine MRI of brain, the size of infarcts was significantly smaller in the apixaban group compared with the aspirin group. Compared with aspirin, apixaban did not increase the burden of microbleeds on follow-up MRI. However, the event rate for new MRI-detected

References (24)

  • V.T. Miller 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)
  • S.J. Connolly et al.

    Apixaban in patients with atrial fibrillation

    N Engl J Med

    (2011)
  • Cited by (50)

    • Mechanisms and Clinical Manifestations of Cognitive Decline in Atrial Fibrillation Patients: Potential Implications for Preventing Dementia

      2023, Canadian Journal of Cardiology
      Citation Excerpt :

      In the Rotterdam Study, patients treated with coumarin had a higher burden of CMB (OR, 1.70; 95% CI, 1.24-2.34) but no statistically significant greater risk for development of new CMB during follow-up (OR, 1.44; 95% CI, 0.89-2.32).78 In a randomized trial, there was no difference in the proportion of new CMB in patients who received apixaban compared with aspirin after a mean follow-up of 1 year (HR, 0.92; 95% CI, 0.53-1.60),79 and among patient with embolic strokes of undetermined source the HR of intracerebral hemorrhage of those who received rivaroxaban was similar in persons with and without CMB (P for interaction = 0.97).80 In a systematic review and meta-analysis of stroke patients there was an excess of CMB among those treated with warfarin in patients with hemorrhagic strokes, but not among those with ischemic strokes or transient ischemic attacks.81

    • Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial

      2021, The Lancet Neurology
      Citation Excerpt :

      For this approach, the MRI substudy16 of the International Carotid Stenting Study served as a role model, because the comparative analysis of MRI outcomes in both treatment groups (ie, stenting versus carotid endarterectomy) resulted in nearly identical results to those in the main study based on purely clinical outcomes, with less than 10% of the patients from the main study. More recently, the MRI substudies of the AVERROES17 and the COMPASS18 randomised trials found that clinical and MRI outcomes were concordant and thus their combined use has been advocated. In line with this recommendation, the REDUCE trial19 implemented clinical and MRI outcomes as a co-primary outcome and showed the usefulness of this combination in a stroke-prevention randomised trial testing patent foramen ovale closure.

    • Relationships of Overt and Silent Brain Lesions With Cognitive Function in Patients With Atrial Fibrillation

      2019, Journal of the American College of Cardiology
      Citation Excerpt :

      Anticoagulation use was not associated with a higher microbleed count, and microbleed count was not associated with cognitive function. This finding is in agreement with data showing that aspirin and apixaban had a similar impact on the incidence of microbleeds (27). Currently available data therefore suggest that anticoagulation is safe in most patients with microbleeds, although it remains controversial whether there is a subgroup of patients with a high microbleed burden who should not be started on anticoagulation despite their high stroke risk (28,29).

    View all citing articles on Scopus
    View full text