Background and Purpose- The sources of emboli in patients with embolic
stroke of undetermined source (ESUS) are multiple and may not respond
uniformly to anticoagulation. In this exploratory subgroup analysis of
patients with carotid atherosclerosis in the NAVIGATE (New Approach
Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to
Prevent Embolism)-ESUS trial, we assessed whether the treatment effect
in this subgroup is consistent with the overall trial population and
investigated the association of carotid atherosclerosis with recurrent
ischemic stroke. Methods- Carotid atherosclerosis was analyzed either as
the presence of mild (ie, 20%-49%) atherosclerotic stenosis or,
separately, as the presence of carotid plaque. Primary efficacy outcome
was ischemic stroke recurrence. Safety outcomes were major bleeding and
symptomatic intracerebral bleeding. Results- Carotid plaque was present
in 40% of participants and mild carotid stenosis in 11%. There was no
significant difference in ischemic stroke recurrence between
rivaroxaban- and aspirin-treated patients among 490 patients with
carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard
ratio [HR], 0.85; 95% CI, 0.39-1.87; P for interaction of treatment
effect with patients without carotid stenosis 0.78) and among 2905
patients with carotid plaques (5.9 versus 4.9/100 patient-years,
respectively, HR, 1.20; 95% CI, 0.86-1.68; P for interaction of
treatment effect with patients without carotid stenosis 0.2). Among
patients with carotid plaque, major bleeding was more frequent in
rivaroxaban-treated patients compared with aspirin-treated (2.0 versus
0.5/100 patient-years, HR, 3.75; 95% CI, 1.63-8.65). Patients with
carotid stenosis had similar rate of ischemic stroke recurrence compared
with those without (5.4 versus 4.9/100 patient-years, respectively, HR,
1.11; 95% CI, 0.73-1.69), but there was a strong trend of higher rate
of ischemic stroke recurrence in patients with carotid plaque compared
with those without (5.4 versus 4.3/100 patient-years, respectively, HR,
1.23; 95% CI, 0.99-1.54). Conclusions- In ESUS patients with carotid
atherosclerosis, we found no difference in efficacy between rivaroxaban
and aspirin for prevention of recurrent stroke, but aspirin was safer,
consistent with the overall trial results. Carotid plaque was much more
often present ipsilateral to the qualifying ischemic stroke than
contralateral, supporting an important etiological role of nonstenotic
carotid disease in ESUS