Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis

Abstract

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.

Data‐driven machine‐learning analysis of potential embolic sources in embolic stroke of undetermined source

“…Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) trial [27] as well as several other studies [28][29][30][31][32][33][34][35][36][37][38][39][40] showed that the prevalence of carotid plaques is higher ipsilateral to the infarct than contralateral in patients with ESUS. In addition, the AF-ESUS (Prediction of Atrial Fibrillation after Embolic Stroke of Undetermined Source) study showed that new incident AF is less frequently detected in patients with ESUS and carotid plaques compared to those without [18].…”

It's Time to Say Goodbye to the ESUS Construct

“…Recently published data from the NAVIGATE trial have shown that up to 40% of the patients included in that trial had carotid plaques, this being clearly more frequent on the ipsilateral side to the qualifying stroke. Interestingly, the group of patients with carotid plaques showed a strong tendency to higher frequency of stroke recurrences compared with those without carotid plaques ( 18 ).…”

Non-stenosing Carotid Atherosclerosis and Arterial Stiffness in Embolic Stroke of Undetermined Source

“…The association between this subtype of ESUS and arterial stiffness is particularly important in order to explain some possible collateral effects of anticoagulant therapy in these patients. Indeed, in NSA-ESUS, a recent study showed that aspirin was safer than rivaroxaban, determining lower rates of major bleeding (19). Since previous studies showed that arterial stiffness may promote the occurrence of cerebral hemorrhage (17) and hemorrhagic transformation after ischemic stroke (14), it is possible that in NSA-ESUS this factor may favor hemorrhagic complications.…”