Abstract 41: Cerebral Microbleeds and the Effect of Anticoagulation on Outcomes in 3699 Patients With Embolic Strokes of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial

Abstract

Background: Cerebral microbleeds (CMBs) are reported to predict recurrent stroke and antithrombotic-related intracerebral hemorrhage (ICH). We characterize CMBs in a well-defined population of embolic strokes of undetermined source (ESUS). Notably, we report for the first time interactions between CMBs and effects of random assignment to anticoagulant therapy. Methods: Subgroup analyses of the NAVIGATE ESUS randomized trial comparing rivaroxaban 15 mg vs. aspirin 100 mg daily were performed. CMBs were rated on T2*-GRE sequences obtained at baseline MRI in 3699 participants (mean age 67y). Multivariable regression analyses were used to identify variables independently associated with CMBs. Cox proportional hazards models were used to estimate the contribution of CMBs to risk of recurrent stroke, ischemic stroke, ICH and all-cause mortality. Analyses followed the intent-to-treat paradigm. Results: CMBs were present in 11% of participants. CMBs were strictly deep in 55%, lobar in 26%, and mixed in 19% of cases. Most (68%) had 1-2 CMBs, 27% had 3-10, and 5% >10. Advancing age (OR per yr 1.0, 95% CI 1.01-1.04), East Asian ethnicity (1.6, 1.0-2.4), hypertension (2.2, 1.5-3.2), multi-territorial ESUS (2.0, 1.4-2.7), chronic infarcts (1.8, 1.4-2.2), and occult ICH (5.2, 2.8-9.9) were independently associated with CMBs. During a median follow-up of 11 months, 5.1% of participants had recurrent stroke (4.8% ischemic stroke; 0.3% ICH) and 1.3% died. The presence of CMBs was associated with a 50% increased risk of recurrent stroke (HR 1.5, 95% CI 1.0-2.3), four-fold risk of ICH (4.2, 1.3-13.9), and two-fold risk of all-cause mortality (2.1, 1.1-4.3), and strictly lobar CMBs with a ~2.5-fold risk of ischemic stroke (2.3, 1.3-4.3). There were no interactions between CMBs and treatment assignments for recurrent stroke (p-value for interaction=0.2), ischemic stroke (p=0.3), or all-cause mortality (p=0.6). The hazard ratio (HR) of ICH on rivaroxaban was similar between persons with CMBs (HR 3.1, 95% CI 0.3 - 30.0) and persons without CMBs (HR 3.0, 95% CI 0.6 - 14.7; interaction p=1.0). Conclusions: CMBs mark an increased risk of recurrent ischemic stroke, ICH and mortality in ESUS, but do not appear to influence effects of rivaroxaban, particularly on the outcome of ICH.