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Background and Purpose— Aortic arch atherosclerosis (AAA) is a possible source of embolism in patients with embolic stroke of undetermined source. Previous studies reported high rates of embolic events in patients with AAA, especially those with high-risk AAA. This exploratory analysis of NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) focused on patients with AAA and assessed their characteristics, stroke recurrence rates, and response to treatment. Methods— The detection of AAA and the assessment of its features were based on transesophageal echocardiography that was done in 19% of participants. AAA plaques were considered to have complex features when reported as complex or ulcerated or were ≥4 mm in thickness or had a mobile thrombus present. Results— Among 1382 participants who had transesophageal echocardiography, 397 (29%) had AAA and 112 (8%) had complex AAA. Mean (SD) age (63 [10] versus 67 [9] versus 69 [9]; P <0.001), prevalence of diabetes mellitus (19% versus 26%, versus 32%; P =0.002), and aortic valvulopathy (10 versus 20 versus 20; P <0.001) increased across no versus noncomplex versus complex AAA, respectively. In multivariable analyses, increasing age, diabetes mellitus, aortic valvulopathy, statin use before randomization, chronic infarcts on imaging, and region were independently associated with any AAA versus no AAA and also with complex AAA versus no AAA. Multiterritorial qualifying infarcts rather than single-territory infarcts were observed in 21% with complex AAA versus 17% noncomplex versus 13% no AAA ( P =0.07). Annualized rates of ischemic stroke recurrence were 7.2% versus 4.2% versus 5.6% for complex versus noncomplex versus no AAA, respectively. While prevalence of complex AAA increased with increasing risk score, after adjusting for risk score, we did not observe increased risk of recurrent stroke for patients with complex AAA (hazard ratio, 1.1; 95% CI, 0.53–2.4), although the number of outcomes was limited. In patients with complex AAA, 4 strokes occurred among rivaroxaban-assigned patients and 4 strokes among aspirin-assigned patients. Conclusions— Complex AAA is prevalent in embolic stroke of undetermined source patients and is associated with atherosclerotic burden. Whether complex AAA independently increases recurrent stroke risk and whether a non-vitamin-K oral anticoagulant as compared with aspirin may be effective for reducing recurrent stroke requires additional study. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02313909.

Background and Purpose— Emboli in embolic stroke of undetermined source (ESUS) may originate from various potential embolic sources (PES), some of which may respond better to anticoagulation, whereas others to antiplatelets. We analyzed whether rivaroxaban is associated with reduction of recurrent stroke compared with aspirin in patients with ESUS across different PES and by number of PES. Methods— We assessed the presence/absence of each PES (atrial cardiopathy, atrial fibrillation, arterial atherosclerosis, left ventricular dysfunction, cardiac valvulopathy, patent foramen ovale, cancer) in NAVIGATE-ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) participants. Prevalence of each PES, as well as treatment effect and risk of event for each PES were determined. Results by number of PES were also determined. The outcomes were ischemic stroke, all-cause mortality, cardiovascular mortality, and myocardial infarction. Results— In 7213 patients (38% women, mean age 67years) followed for a median of 11 months, the 3 most prevalent PES were atrial cardiopathy (37%), left ventricular disease (36%), and arterial atherosclerosis (29%). Forty-one percent of all patients had multiple PES, with 15% having ≥3 PES. None or a single PES was present in 23% and 36%, respectively. Recurrent ischemic stroke risk was similar for rivaroxaban- and aspirin-assigned patients for each PES, except for those with cardiac valvular disease which was marginally higher in rivaroxaban-assigned patients (hazard ratio, 1.8 [95% CI, 1.0–3.0]). All-cause mortality risks were similar across treatment groups for each PES while too few myocardial infarctions and cardiovascular deaths occurred for meaningful assessment. Increasing number of PES was not associated with increased stroke recurrence nor all-cause mortality, and outcomes did not vary between rivaroxaban- and aspirin-assigned patients by number of PES. Conclusions— A large proportion of patients with ESUS had multiple PES which could explain the neutral results of NAVIGATE-ESUS. Recurrence rates between rivaroxaban- and aspirin-assigned patients were similar across the spectrum of PES. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.

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Background and Purpose Inflammatory biomarkers predict incident and recurrent cardiac events, but their relationship to stroke prognosis is uncertain. We hypothesized that high-sensitivity C-reactive protein (hsCRP) predicts recurrent ischemic stroke after recent lacunar stroke. Methods Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within Secondary Prevention of Small Subcortical Strokes (SPS3), a Phase III trial in patients with recent lacunar stroke. Patients were assigned in factorial design to aspirin versus aspirin plus clopidogrel, and higher versus lower blood pressure targets. Patients had blood samples collected at enrollment, and hsCRP measured using nephelometry at a central laboratory. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (HR, 95%CI) for recurrence risks before and after adjusting for demographics, comorbidities, and statin use. Results Among 1244 lacunar stroke patients (mean 63.3 ± 10.8 years), median hsCRP was 2.16 mg/L. There were 83 recurrent ischemic strokes (including 45 lacunes), and 115 major vascular events (stroke, myocardial infarction, vascular death). Compared with the bottom quartile, those in the top quartile (hsCRP >4.86 mg/L) were at increased risk of recurrent ischemic stroke (unadjusted HR 2.54, 95%CI 1.30–4.96), even after adjusting for demographics and risk factors (adjusted HR 2.32, 95%CI 1.15–4.68). HsCRP predicted increased risk of major vascular events (top quartile adjusted HR 2.04, 95%CI 1.14–3.67). There was no interaction with randomized antiplatelet treatment. Conclusions Among recent lacunar stroke patients, hsCRP levels predict risk of recurrent strokes and other vascular events. HsCRP did not predict response to dual antiplatelets.

The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS. OBJECTIVE To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke. DESIGN, SETTING, AND PARTICIPANTS The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019. INTERVENTIONS Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d. MAIN OUTCOMES AND MEASURES Association of recurrent ESUS with stroke characteristics. RESULTS A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively). CONCLUSIONS AND RELEVANCE In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy.

IMPORTANCEIt is uncertain whether anticoagulation is superior to aspirin at reducing recurrent stroke in patients with recent embolic strokes of undetermined source (ESUS) and left ventricular (LV) dysfunction.OBJECTIVE To determine whether anticoagulation is superior to aspirin in reducing recurrent stroke in patients with ESUS and LV dysfunction. DESIGN, SETTING, AND PARTICIPANTS Post hoc exploratory analysis of data from the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) trial, a randomized, phase 3 clinical trial with enrollment from December 2014 to September 2017. The study setting included 459 stroke recruitment centers in 31 countries. Patients 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of the 7213 NAVIGATE ESUS participants, 7107 (98.5%) had a documented assessment of LV function at study entry and were included in the present analysis. Data were analyzed in January 2021. INTERVENTIONS Participants were randomized to receive either 15 mg of rivaroxaban or 100 mg of aspirin once daily. MAIN OUTCOMES AND MEASURESThe study examined whether rivaroxaban was superior to aspirin at reducing the risk of (1) the trial primary outcome of recurrent stroke or systemic embolism and (2) the trial secondary outcome of recurrent stroke, systemic embolism, myocardial infarction, or cardiovascular mortality during a median follow-up of 10.4 months. LV dysfunction was identified locally through echocardiography and defined as moderate to severe global impairment in LV contractility and/or a regional wall motion abnormality. A Cox proportional hazards model was used to assess for treatment interaction and to estimate the hazard ratios for those randomized to rivaroxaban vs aspirin by LV dysfunction status.RESULTS LV dysfunction was present in 502 participants (7.1%). Of participants with LV dysfunction, the mean (SD) age was 67 (10) years, and 130 (26%) were women. Among participants with LV dysfunction, annualized primary event rates were 2.4% (95% CI, 1.1-5.4) in those assigned to rivaroxaban vs 6.5% (95% CI, 4.0-11.0) in those assigned aspirin. Among the 6605 participants without LV dysfunction, rates were similar between those assigned to rivaroxaban (5.3%; 95% CI, 4.5-6.2) vs aspirin (4.5%; 95% CI, 3.8-5.3). Participants with LV dysfunction assigned to rivaroxaban vs aspirin had a lower risk of the primary outcome (hazard ratio, 0.36; 95% CI, 0.14-0.93), unlike those without LV dysfunction (hazard ratio, 1.16; 95% CI, 0.93-1.46) (P for treatment interaction = .03). Results were similar for the secondary outcome. CONCLUSIONS AND RELEVANCEIn this post hoc exploratory analysis, rivaroxaban was superior to aspirin in reducing the risk of recurrent stroke or systemic embolism among NAVIGATE ESUS participants with LV dysfunction.

Background and Purpose: Optimal secondary prevention for patients with embolic stroke of undetermined source (ESUS) remains unknown. We aimed to assess whether high-sensitivity cardiac troponin T (hs-cTnT) levels are associated with major vascular events and whether hs-cTnT may identify patients who benefit from anticoagulation following ESUS. Methods: Data were obtained from the biomarker substudy of the NAVIGATE ESUS trial, a randomized controlled trial testing the efficacy of rivaroxaban versus aspirin for secondary stroke prevention in ESUS. Patients were dichotomized at the hs-cTnT upper reference limit (14 ng/L, Gen V, Roche Diagnostics). Cox proportional hazard models were computed to explore the association between hs-cTnT, the combined cardiovascular end point (recurrent stroke, myocardial infarction, systemic embolism, cardiovascular death), and recurrent ischemic stroke. Results: Among 1337 patients enrolled at 111 participating centers in 18 countries (mean age 67±9 years, 61% male), hs-cTnT was detectable in 95% and at/above the upper reference limit in 21%. During a median follow-up of 11 months, the combined cardiovascular end point occurred in 68 patients (5.0%/y, rivaroxaban 28 events, aspirin 40 events; hazard ratio, 0.67 [95% CI, 0.41–1.1]), and recurrent ischemic stroke occurred in 50 patients (4.0%/y, rivaroxaban 16 events, aspirin 34 events, hazard ratio 0.45 [95% CI, 0.25–0.81]). Annualized combined cardiovascular end point rates were 8.2% (9.5% rivaroxaban, 7.0% aspirin) for those above hs-cTnT upper reference limit and 4.8% (3.1% rivaroxaban, 6.6% aspirin) below with a significant treatment modification ( P =0.04). Annualized ischemic stroke rates were 4.7% above hs-cTnT upper reference limit and 3.9% below, with no suggestion of an interaction between hs-cTnT and treatment ( P =0.3). Conclusions: In patients with ESUS, hs-cTnT was associated with increased cardiovascular event rates. While fewer recurrent strokes occurred in patients receiving rivaroxaban, outcomes were not stratified by hs-cTn results. Our findings support using hs-cTnT for cardiovascular risk stratification but not for decision-making regarding anticoagulation therapy in patients with ESUS. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02313909.