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. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.