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Background Evidence to guide the optimal timing of antiplatelet and oral anticoagulants (OACs) therapy after hemorrhagic infarction (HI) versus parenchymal hematoma (PH) is limited and inconsistent, leading to substantial variation in practice. This study's goal was to study the practice pattern and compare clinical outcomes associated with early‐versus‐delayed initiation of antiplatelet/OACs after hemorrhagic transformation (HT). Methods This multicenter, retrospective, cross‐sectional study included patients with acute ischemic stroke and HT. Patients with an HI or PH were categorized by HT to antithrombotic initiation time, and their outcomes—30‐day HT exacerbation, composite outcomes of recurrent stroke/systemic emboli, 90‐day vascular death, and functional outcomes—were compared. Results Of 748 patients, 496 received antiplatelets, and 252 received OACs after HT. The median HT‐to‐antiplatelet time was significantly shorter after HI than PH (1 [interquartile range, 0–2] versus 3 [interquartile range, 1–5] days; P <0.001). There were no statistically significant differences in HT exacerbation and composite outcomes (30‐day), as well as vascular death and unfavorable functional outcomes (90‐day), between patients who received same‐day, early (HI, <1 day; PH, <3 days), or late (HI, >1 day; PH, >3 days) antiplatelets after either HI or PH. Among patients on OACs, those with HI had shorter median HT‐to‐OAC time than PH (7 [interquartile range, 2–15] versus 15 [interquartile range, 7–32] days; P <0.001). Although HT exacerbation rates (30‐day) were comparable between early (HI, <7 days; PH, <15 days) and late (HI, >7 days; PH, >15 days) OAC initiation after either HI or PH, late initiation after PH was accompanied by higher rates of composite outcomes (30‐day) than early initiation (20.7% versus 3%; P =0.044). Regression models adjusted for demographics, National Institutes of Health Stroke Scale, and stroke severity showed no statistically significant association between early initiation of antiplatelets or OACs with HT exacerbation risk. Conclusions Our study found no statistically significant difference in HT exacerbation between early and late initiation of antiplatelets or OACs among patients with HI/PH, while prolonged delay among patients with PH were accompanied by increased systemic thromboembolic events. Although these findings offer preliminary clinical insight, prospective studies are needed.

BACKGROUND: Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. METHODS: We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. RESULTS: Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21–1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97–1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10–0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83–1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04–0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15–0.73]). CONCLUSIONS: After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06398366.

Introduction: Embolic stroke of undetermined source (ESUS) is a clinical construct encompassing heterogenous possible mechanisms of incident stroke, potentially with variable responsiveness to anticoagulation and antiplatelet treatment. This study aims to identify differences in recurrent stroke risk based on phenotypic clusters in an ESUS population, and whether some clusters may benefit relatively more from anticoagulation over antiplatelet therapy. Methods: We identified patient phenotypes from a multicenter, retrospective cohort study of 1909 ESUS patients by dividing them into groups using Partitioning Around Medoids (PAM) with correlation-weighted Gower distance over 23 baseline demographic, clinical, laboratory, radiographic, and cardiac features. We confirmed optimal clustering at 3 groups. We assessed cluster associations with time to recurrent stroke using Kaplan-Meier survival analysis. We then employed a causal survival forest to estimate conditional average treatment effects (CATE) of anticoagulation versus antiplatelet therapy using the same baseline features as predictors with a 365-day horizon for restricted mean survival time differences. Finally, we used best linear projection to identify baseline features predictive of treatment effect and assessed whether effects differed significantly by cluster. Results: Cluster 1 (n=542) identified a low-risk, younger sample with minimal baseline disability and comorbidity burden. Cluster 2 (n=743) comprised a moderate-risk phenotype with intermediate comorbidity. Cluster 3 (n=626) represented the oldest and highest-risk phenotype. Kaplan-Meier analysis demonstrated significant differences in stroke-free survival across patient clusters (p < 0.001), where Cluster 1 experienced the lowest recurrent stroke rate and Cluster 3 had the highest. The clustering algorithm successfully identified clinically meaningful phenotypes with distinct risk profiles. While CATE varied across clusters, the differences were not statistically significant. Conclusion: In a multicenter ESUS population, we identified 3 distinct phenotypic clusters, each comprising nearly one-third of the sample and with a differential risk of recurrent stroke. Although cluster was not a significant effect modifier, substantial CATE variability by cluster was observed. Future clinical trials may consider evaluating secondary stroke prevention therapies among phenotypically similar patients who may respond differentially to novel therapies.

Background: Embolic stroke of undetermined source (ESUS) comprises infarct mechanisms presumed to be embolic and non-lacunar. One explanation for the lack of superiority of anticoagulation over aspirin is the inclusion of subcortical infarcts with white matter disease (WMD), reflecting small vessel pathology. We hypothesized that WMD is associated with recurrent ischemic stroke (RIS) in ESUS and this risk is not lessened by anticoagulation. Methods: We conducted a secondary analysis of the multicenter Cardiac Abnormalities in Stroke Prevention and Recurrence (CASPR) registry, including ESUS patients from 27 U.S. centers (2015–2024). WMD severity was graded using the Fazekas scale from MRI and dichotomized as mild (0–1) vs. moderate-to-severe (2–3). The primary outcome was RIS. Secondary outcomes were major bleeding and all-cause mortality. Inverse probability of treatment weighting (IPTW) adjusted for baseline differences. Cox proportional hazards models assessed associations between WMD and outcomes. Subgroup analyses explored effect modification by age, risk factors, and treatment type. Results: Among 1,890 ESUS patients with MRI data, 684 (36.2%) had Fazekas 2–3. These patients were older with more vascular risk factors, but IPTW achieved covariate balance. In the weighted cohort, RIS occurred more frequently in Fazekas 2–3 vs. 0–1 (7.1% vs. 4.6%/year; HR 1.56, 95% CI 1.10–2.22, p = 0.01). Major bleeding and mortality were similar (bleeding: 1.7% vs. 1.8%/yr, HR 0.96, p = 0.92; death: 7.0% vs. 6.7%/yr, HR 1.04, p = 0.81). Subgroup analyses showed no interaction between WMD and age, vascular risk factors, or treatment type (antiplatelet vs. anticoagulation), suggesting consistent RIS risk in those with higher WMD. Discussion: Moderate-to-severe WMD identifies ESUS patients at higher risk of ischemic stroke recurrence, with no mitigation by anticoagulation. These findings suggest that WMD may indicate non-embolic mechanisms and support the use of imaging-based risk stratification in ESUS.

Background: Studies have suggested that administering antithrombotics—oral anticoagulants (OACs) and antiplatelets (APLT)—after acute ischemic stroke(AIS) with hemorrhagic transformation (HT) is safe and can reduce ischemic recurrence. However, the safety of their early initiation after HT remains unclear. Method: This study utilized data from nine centers across several countries. The study population included patients with AIS who subsequently experienced HT. Patients with a specific HT type—hemorrhagic infarction(HI) or parenchymal hematoma(PH)—were categorized based on the time between HT and antithrombotic initiation, and their outcomes were compared. Outcomes included 30-day HT exacerbation and composite outcomes of recurrent stroke and systemic emboli, as well as 90-day vascular death and functional outcome. Results: Of 748 patients,496 received APLT, and 252 were prescribed OACs after HT. The median HT-to-APLT time was significantly shorter among HI patients than PH patients(1[IQR:0-2] vs. 3[IQR:1-5] days,p<0.001). The rates of 30-day HT exacerbation and composite outcomes, as well as 90-day vascular death and unfavorable functional outcomes, did not significantly differ between patients who received same-day, early (HI:<1day;PH:<3days), or late (HI:>1day;PH:>3days) APLTs after either HI or PH. Among patients who received OACs, those with HI had a significantly shorter median HT-to-OAC time than PH (7[IQR:2-15] vs. 15[IQR:7-32] days,p<0.001). However, 30-day HT exacerbation rates were comparable between early (HI:<7days;PH:<15days) and late (HI:>7days;PH:>15days) OAC initiation among patients with either HI or PH, late initiation among patients with PH was associated with higher rates of 30-day composite outcomes than early initiation(20.7% vs. 3%,p=0.044). Based on regression models adjusted for NIHSS and stroke severity, early initiation of APLTs or OACs was not associated with increased risk of HT exacerbation. Conclusion: Findings suggest that the same-day initiation of APLTs after HI or PH-1, and within 1-3days following PH-2, might not be associated with HT exacerbation or worsening outcomes. Similarly, OACs initiated 2-7days after HI and 7-15days after PH may not be associated with worsened patients' outcomes, whereas delays beyond these timeframes can be associated with higher thromboembolic risk.

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.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45–1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28–2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35–5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53–20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18–0.88]; P interaction =0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

BACKGROUND: Patients presenting with cervical artery dissection (CAD) are at risk for subsequent ischemic events. We aimed to identify characteristics that are associated with increased risk of ischemic stroke after initial presentation of CAD and to evaluate the differential impact of anticoagulant versus antiplatelet therapy in these high-risk individuals. METHODS: This was a preplanned secondary analysis of the STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection), a multicenter international retrospective observational study (63 sites from 16 countries in North America, South America, Europe, Asia, and Africa) that included patients with CAD predominantly between January 2015 and June 2022. The primary outcome was subsequent ischemic stroke by day 180 after diagnosis. Clinical and imaging variables were compared between those with versus without subsequent ischemic stroke. Significant factors associated with subsequent stroke risk were identified using stepwise Cox regression. Associations between subsequent ischemic stroke risk and antithrombotic therapy type (anticoagulation versus antiplatelets) among patients with identified risk factors were explored using adjusted Cox regression. RESULTS: In all, 4023 patients (mean age was 47.4 years; 44.5% were women) were included. By day 180, subsequent ischemic stroke occurred in 5.3% of the cohort. In adjusted Cox regression, factors associated with increased risk of subsequent ischemic stroke were prior history of ischemic stroke (adjusted hazard ratio [aHR], 7.31 [95% CI, 1.61–33.13]; P =0.010), presentation within 7 days from first symptoms (aHR, 3.04 [95% CI, 1.04–8.91]; P =0.043), infarct on baseline imaging (aHR, 9.85 [95% CI, 3.65–26.58]; P <0.001), and occlusive dissection (aHR, 2.34 [95% CI, 1.03–5.34]; P =0.043). Only patients with occlusive dissection demonstrated a reduced risk of subsequent ischemic stroke when treated with anticoagulation versus antiplatelets (aHR, 0.36 [95% CI, 0.16–0.80]; P =0.01). CONCLUSIONS: In this post hoc analysis of the STOP-CAD study, several factors associated with subsequent ischemic stroke were identified among patients with CAD. Furthermore, we identified a potential benefit of anticoagulation in patients with CAD with occlusive dissection. These findings require validation by meta-analyses of prior studies to formulate optimal treatment strategies for specific high-risk CAD subgroups.

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.