Yahnke, Ian

Background Intracranial occlusions in embolic stroke of undetermined source are histopathologically similar to cardiac sources of embolism. Whether patients with embolic stroke of undetermined source and intracranial occlusion benefit from anticoagulation is unknown. Methods A multicenter retrospective cohort of adults with cryptogenic stroke was queried for patients with proximal or medium/distal vessel occlusion. The primary outcome was recurrent ischemic stroke, which was assessed in unadjusted and adjusted Cox proportional hazards models and repeated following 1:1 propensity score matching and biweight kernel density matching. Results Of the 2328 patients who were followed over a median of 1.31 years (interquartile range, 0.34–2.85), 999 (42.6%) had an intracranial occlusion. When compared with patients without an intracranial occlusion, those with an occlusion had fewer atherosclerotic vascular risk factors, more severe symptoms, and less severe cerebral microvascular disease. The rate of recurrent stroke was similar between patients with versus without an intracranial occlusion (6.8%/year [95% CI, 5.7–8.2] versus 7.0%/year [95% CI 6.0–8.1]; adjusted hazard ratio [HR], 1.09 [95% CI, 0.77–1.55]). There was no association between occlusion and recurrent stroke in the adjusted propensity score matching (HR, 1.01 [95% CI, 0.64–1.59]) or kernel density models (HR, 0.95 [95% CI, 0.62–1.45]). There was no interaction between occlusion and treatment with anticoagulation, sex, age, or high‐risk sources of embolism for the primary outcome in the unmatched and matched analyses. Conclusions Intracranial occlusion in patients with embolic stroke of undetermined source is not associated with a greater risk of recurrence when compared with patients without an intracranial occlusion. There was no difference in rate of recurrent stroke with anticoagulation when stratified by presence or absence of occlusion.

Introduction: Four randomized clinical trials have not demonstrated the superiority of anticoagulation over antiplatelet therapy in the prevention of recurrent embolic stroke of undetermined source (ESUS). In this multicenter observational cohort study, we evaluated long-term outcomes associated with various antithrombotic strategies according to potential embolic sources. Methods: A multicenter retrospective observational cohort of consecutive adult patients with ESUS was queried (n=27 sites). Comparisons were made between patients treated with single or combination antiplatelet therapy versus anticoagulation (direct oral anticoagulant, vitamin K antagonist, low molecular weight heparin) with or without antiplatelet therapy initiated within 7 days of stroke. The primary composite outcome of recurrent stroke, major bleeding, or death was assessed using unadjusted and adjusted Cox proportional hazards regression, with clustering by site. Causal inference was assessed using inverse probability of treatment weighted regression adjustment (IPTWRA), accounting for propensity for antiplatelet treatment, with effect estimates summarized as the average treatment effect (ATE) over time (in days). Adjusted models accounted for age, stroke severity, vascular risk factors, and major categories of potential embolic sources. Results: Of the 2201 included patients (n=218 treated with anticoagulation) followed over a median of 564 days (interquartile range [IQR] 154-1124), the median age was 65y (IQR 54-74) and 49.8% were female. Patients treated with anticoagulation were older with more frequent previous stroke, concomitant left ventricular dysfunction, and more severe deficits. Over 4541 person-years of follow-up, the annualized incidence rate of the primary outcome was 14.6% (95% confidence interval [CI], 13.6%-15.8%). Compared to anticoagulation, antiplatelet(s) use was not associated with a lower risk of the primary outcome in the adjusted Cox model (HR 0.91, 95% CI, 0.64-1.29) or in the IPTWRA model (average treatment effect 0.14, 95% CI, -1376.6 to 1376.9). Major bleeding events trended toward significance in the adjusted Cox model (HR 0.51, 95% CI 0.25-1.04) but were no different with IPTWRA (ATE 58.9, 95% CI, -125.4 to 243.2). Conclusions: These results validate the observations of randomized trials indicating a lack of benefit of anticoagulation over antiplatelet therapy in ESUS. A more detailed analysis of heterogeneity of treatment effect is under way.