Blanca Fuentes

Background and Purpose.: The timing of anticoagulation resumption in patients who experience ischemic stroke despite ongoing anticoagulation and develop haemorrhagic transformation (HT) remains uncertain. We aimed to describe the characteristics and outcomes of patients with HT after a breakthrough ischemic stroke and to explore the association between anticoagulation resumption timing and the model-predicted balance of recurrent ischemic and bleeding risks in this high-risk population. Methods.: We analysed data from patients with breakthrough ischemic stroke receiving anticoagulation therapy from the multicentre ASPERA-R registry. Analyses focused on patients with HT. HT was defined according to the Heidelberg Bleeding Classification based on brain imaging within 24 hours and categorized as haemorrhagic infarction (HI) or parenchymal hematoma (PH). Anticoagulation resumption and its timing were determined by treating clinicians and were not randomized. Landmark Cox regression models were used to evaluate recurrent ischemic events and moderate-to-severe bleeding after anticoagulation resumption. Restricted cubic spline models and exploratory net clinical benefit analyses integrating ischemic and bleeding risks were used to assess the relationship between anticoagulation resumption timing and model-predicted combined risk, overall and across clinically relevant subgroups. Results.: Among 1,555 patients with breakthrough ischemic stroke, 269 (17.3%) developed HT, of whom 170 (63.2%) resumed anticoagulation and contributed to the restart-timing analyses. At 90 days, patients with HT had higher crude rates of recurrent ischemic events (27.1% vs 13.8%), moderate-to-severe bleeding (7.4% vs 2.8%), and mortality (34.2% vs 17.7%) compared with patients without HT. In landmark analyses, HT was not associated with recurrent ischemic events (HR 1.42, 95% CI 0.85–2.37) but remained strongly associated with moderate-to-severe bleeding (HR 3.39, 95% CI 1.61–7.13). Exploratory net clinical benefit analyses showed that the model-predicted combined risk reached its nadir at approximately 10 days after stroke in the overall HT population, with substantial uncertainty around this estimate. Conclusions.: HT is a marker of poor prognosis in patients with breakthrough ischemic stroke, with an increased risk of bleeding after anticoagulation resumption. Among selected patients who resumed anticoagulation, exploratory modelling suggested that the combined predicted ischemic and bleeding risk reached its nadir at approximately 10 days after stroke. Given the non-randomized treatment timing and potential for treatment-selection bias, this estimate is hypothesis-generating and requires prospective validation.

BACKGROUND: Contrast-associated acute kidney injury (CA-AKI) after endovascular thrombectomy (EVT) worsens outcomes in acute ischemic stroke, but threshold-based definitions do not capture prognostic information from subthreshold changes. We tested whether early creatinine change within 48 hours of EVT conveys graded prognostic information beyond dichotomous CA-AKI. METHODS: We performed a secondary analysis of the CAN-REST registry (Contrast-Associated Nephropathy After Endovascular Stroke Treatment), a retrospective multicenter observational cohort study of 6638 EVT-treated adults with acute ischemic stroke enrolled at 73 centers in 16 countries between January 1 and December 31, 2023. Early creatinine change was quantified as the natural logarithm ratio of 48-hour creatinine to baseline creatinine (ln[48-hour/baseline creatinine]), with CA-AKI defined per Kidney Disease: Improving Global Outcomes criteria (≥0.3 mg/dL or ≥1.5× baseline rise within 48 hours). Multivariable logistic regression adjusted for prespecified baseline and periprocedural covariates examined associations with 90-day modified Rankin Scale shift and in-hospital mortality; linear versus restricted cubic spline specification was selected by likelihood ratio testing, and contrasts were estimated at ±10%, ±25%, and ±50%. RESULTS: Greater creatinine worsening within 48 hours of EVT was independently associated with an unfavorable 90-day modified Rankin Scale shift (adjusted common odds ratio per 1-unit log-ratio increase, 1.48 [95% CI, 1.07–2.04]; linear) and in-hospital mortality (nonlinear dose-response, of larger magnitude). A 10% increase in creatinine at 48 hours—well below Kidney Disease: Improving Global Outcomes threshold—was associated with worse functional outcome (adjusted common odds ratio, 1.04 [95% CI, 1.01–1.07]) and death (adjusted odds ratio, 1.22 [95% CI, 1.13–1.32]); a 10% decrease in creatinine at 48 hours was associated with lower odds of both outcomes (adjusted common odds ratio, 0.96 [95% CI, 0.93–0.99]; adjusted odds ratio, 0.74 [95% CI, 0.65–0.86]). The functional-outcome association concentrated at upper modified Rankin Scale cut-points (severe disability, death); effect modification by baseline renal function was not significant. CONCLUSIONS: Early creatinine change after EVT conveys graded, outcome-specific prognostic information extending below formal CA-AKI thresholds, with a dose-response detectable at changes as modest as ±10%, complementing binary CA-AKI as a framework for post-EVT renal risk assessment. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06596603.

BACKGROUND: Patients with atrial fibrillation who experience ischemic stroke despite oral anticoagulation (breakthrough stroke) remain at high risk of recurrent vascular events and death. Although inflammation has been associated with thromboembolic risk, its prognostic role in breakthrough stroke remains unclear. We investigated whether a composite inflammatory burden index was associated with adverse outcomes after breakthrough ischemic stroke. METHODS: We conducted a multicenter retrospective cohort study of consecutive patients with breakthrough ischemic stroke from the ASPERA-R registry. Inflammatory burden was assessed using admission neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune–inflammation index, and C-reactive protein. Biomarkers were log-transformed, standardized using Z scores, and combined into a composite inflammatory burden index. Patients were classified as having high (upper tertile) or lower inflammatory burden (lower 2 tertiles). Outcomes included new 90-day ischemic events (recurrent ischemic stroke, transient ischemic attack, or systemic embolism), 24-hour hemorrhagic transformation, and 90-day moderate-to-severe bleeding, intracranial hemorrhage, and mortality. Inverse probability of treatment weighting accounted for center, demographics, vascular risk factors and comorbidities, anticoagulation, competing stroke causes, baseline National Institutes of Health Stroke Scale, prestroke modified Rankin Scale, and time to blood collection. RESULTS: Among 1649 patients enrolled in ASPERA-R, 671 patients from 14 centers had complete biomarker data (median age, 80.1 years [interquartile range, 73.5–85.5]; 52.3% female). Of these, 223 (33.2%) had high inflammatory burden, and 448 (66.8%) had lower inflammatory burden. After weighting, high inflammatory burden was associated with increased risks of ischemic events at 90 days (hazard ratio, 1.53 [95% CI, 1.02–2.30]), all-cause mortality (hazard ratio, 1.70 [95% CI, 1.17–2.47]), moderate-to-severe bleeding (hazard ratio, 2.92 [95% CI, 1.04–8.17]), and hemorrhagic transformation at 24 hours (odds ratio, 2.18 [95% CI, 1.43–3.33]). CONCLUSIONS: In breakthrough ischemic stroke, high inflammatory burden was associated with increased risks of recurrent ischemic events, mortality, hemorrhagic transformation, and major bleeding. A composite of routinely available inflammatory biomarkers may help identify patients with higher residual vascular risk.

Background and Purpose.: Randomized trials support early initiation of direct oral anticoagulants (DOACs) after atrial fibrillation (AF)–related ischemic stroke, but patients with breakthrough ischemic stroke occurring despite ongoing anticoagulation have been largely under-represented. We evaluated the effectiveness and safety of early versus delayed DOAC initiation after breakthrough ischemic stroke. Methods.: We performed a target trial emulation comparing early versus delayed DOAC initiation in patients with breakthrough ischemic stroke. Treatment strategies were prespecified using severity-adapted timing thresholds based on baseline National Institutes of Health Stroke Scale (NIHSS) scores. The study population was drawn from the retrospective arm of the international, multicentre ASPERA study and included patients with AF who experienced an ischemic stroke while receiving continuous anticoagulation. To emulate random assignment and avoid immortal time bias, a cloning–censoring–weighting approach with inverse probability weighting was applied. Primary outcomes were 90-day new ischemic events and moderate-to-severe bleeding. Risk ratios (RRs), absolute risk differences (RDs), and hazard ratios (HRs) were estimated using weighted regression and Cox models. Results.: Among 833 patients (median age 81 years), 336 were assigned to early and 497 to delayed DOAC initiation. At 90 days, early initiation was associated with a lower risk of new ischemic events (RR 0.44, 95% CI 0.21–0.90; RD −3.64%, 95% CI −6.40 to −0.87; HR 0.43, 95% CI 0.21–0.91). Moderate-to-severe bleeding occurred less frequently with early initiation (RR 0.10, 95% CI 0.01–0.76). Early initiation was also associated with lower 90-day all-cause and vascular mortality. A Net Early Benefit Score integrating ischemic and bleeding risks was positive across all NIHSS strata. Conclusions.: In patients with breakthrough ischemic stroke, early severity-adapted DOAC initiation was associated with lower risks of recurrent ischemic events and mortality at 90 days without an increase in major bleeding. These findings support early anticoagulation initiation in this high-risk population.

Background: The relevance of prior antithrombotic and thrombolytic treatment for decision‐making regarding endovascular thrombectomy (EVT) for acute ischemic stroke due to large vessel occlusion with established large infarcts is uncertain. This study investigates associations of prior antithrombotic medication and thrombolysis with the efficacy and safety of EVT for acute ischemic stroke due to large vessel occlusion with established large infarct. Methods: TENSION (Efficacy and Safety of Thrombectomy in Stroke With Extended Lesion and Extended Time Window) was a prospective randomized open‐label blinded–end point clinical trial. Patients with acute ischemic stroke due to large vessel occlusion and established large infarct were randomized to EVT with medical therapy or medical therapy alone. Exposures were preadmission antithrombotic treatment with antiplatelet agents or anticoagulants and intravenous thrombolysis. The primary efficacy end point was functional outcome at 90 days. Safety outcomes included death and symptomatic intracranial hemorrhage. Results: The study included 246 patients (median age, 74 years; interquartile range, 65 to 80 years; 49% women); 124 (50%) were assigned to EVT. Of 176 patients (72%) with prior antithrombotic therapy, 75 (31%) received antiplatelets, 56 (23%) anticoagulants, and 89 (36%) intravenous thrombolysis. EVT was associated with better functional outcome in patients with (common odds ratio [cOR], 2.40 [95% CI, 1.22–4.99]) and without (cOR, 2.29 [95% CI, 1.53–3.46]) antiplatelet therapy; with (cOR, 2.45 [95% CI, 1.17–5.28]) and without (cOR, 2.12 [95% CI, 1.44–3.15]) anticoagulation; as well as receiving (cOR, 1.46 [95% CI, 0.83–2.61]) and not receiving (cOR, 2.89 [95% CI, 1.87–4.51]) thrombolysis. Interaction analyses were consistent with similar treatment effects across subgroups. Mortality and rates of symptomatic intracranial hemorrhage were similar between groups. Conclusions: Benefit and safety of EVT were not modified by prior antithrombotic/thrombolytic therapy. Preadmission exposure to antiplatelets or anticoagulants or use of intravenous thrombolysis should not exclude eligible patients with stroke from EVT. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT03094715.

Purpose: Several recent trials have shown improved functional outcomes with endovascular thrombectomy (EVT) in patients presenting with large ischaemic lesions, yet the impact of reperfusion on lesion pathophysiology in this population remains incompletely understood. We hypothesised that EVT reduces ischaemic oedema formation and that attenuation of oedema mediates functional outcome improvement beyond changes in lesion extent. Methods: We performed a secondary analysis of the randomised TENSION trial, which enrolled patients with anterior circulation ischaemic stroke and baseline ASPECTS 3–5. Oedema progression was quantified as the change in CT-based net water uptake between baseline and follow-up non-contrast CT (ΔNWU), derived from relative hypoattenuation within the infarct. Lesion extent change was assessed by the difference in ASPECTS between baseline and follow-up imaging (ΔASPECTS). Associations of ΔNWU and ΔASPECTS with 90-day modified Rankin Scale (mRS) were tested using ordinal logistic regression. Mediation analyses estimated the proportion of EVT’s treatment effect on functional outcome explained by ΔNWU and ΔASPECTS. Results: Among 177 patients, median follow-up NWU was 28.5% (IQR: 19.2–36.6) and follow-up ASPECTS was 2 (IQR: 1–3). EVT was associated with substantially lower oedema progression (ΔNWU 4.7% vs 15.9% without EVT; P < .001). Mediation analysis suggested that a model-estimated 34% of EVT-related improvement in mRS was associated with reduced oedema formation (ΔNWU), whereas 14% was associated with lesion extent change (ΔASPECTS). In a sensitivity analysis using nonparametric bootstrap with 5000 resamples, the mediation signal remained robust for ΔNWU but was substantially weaker for ΔASPECTS. Conclusion: In large-core stroke, EVT was associated with significantly attenuated oedema progression between baseline and follow-up imaging. Reduced ischaemic water uptake was strongly associated with EVT benefit on 90-day functional outcome in mediation models, supporting oedema attenuation as a plausible mechanistic pathway of EVT benefit.

Background/Objectives: Although comprehensive transthoracic echocardiography (TTE) is part of the diagnostic workup in acute ischemic stroke, it is not cost-effective to use it for all patients. Guidelines recommend using it only for selected patients to guide secondary prevention. Neurologist-led, stroke-focused cardiac ultrasound (S-FoCUS) is an emerging bedside screening tool that optimizes cardiac evaluation in acute stroke care. We hypothesize that the implementation of S-FoCUS screening may reduce resource utilization in terms of hospital stay and TTE procedures. Methods: We conducted a retrospective before-and-after cohort study of patients with suspected acute ischemic stroke or TIA admitted to our comprehensive stroke center. We compared two 6-month periods: the pre-S-FoCUS period, during which patients underwent TTE as the initial cardiac imaging modality; and the post-S-FoCUS period, during which patients initially underwent S-FoCUS, with subsequent TTE performed only in the presence of abnormal findings or at the clinician’s discretion. We compared the time from admission to first cardiac ultrasound assessment, length of stay, relative reduction in TTE procedures and estimated in-hospital costs. Results: The pre-S-FoCUS period included 224 patients, and the post-S-FoCUS period included 229 patients. The S-FoCUS protocol reduced the median time to first cardiac ultrasound assessment by two days (median [IQR] 3 [2–5] vs. 1 [1–2], p < 0.001) and the median length of stay by one day (6 [4–9] vs. 5 [3–10], p = 0.014). Implementing the S-FoCUS protocol was associated with an exploratory estimate of lower in-hospital costs (approximately €716 per screened patient) driven mainly by a shorter length of stay. The distribution of the frequency of predefined cardioembolic sources was similar between both periods. There was a high agreement rate between the S-FoCUS and TTE findings in patients who underwent both tests: mitral stenosis (κ = 0.78), left atrial severe enlargement (κ = 0.74), left ventricular hypokinesia/akinesia (κ = 0.84), and depressed LVEF (κ = 0.88). Conclusions: Neurologist-led S-FoCUS is a feasible triage strategy to improve efficiency in the acute stroke pathway.

Patients with atrial fibrillation (AF) who experience an ischemic stroke despite oral anticoagulation (OAC) face a high risk of recurrence and bleeding. We aimed to compare 90-day outcomes between patients with and without competing stroke etiologies after a breakthrough ischemic stroke while on OAC for AF. ASPERA-R retrospectively enrolled adults (>18 years) with AF who experienced a breakthrough ischemic stroke, defined as either first or recurrent event, occurring on continuous OAC (last intake ≤48 hours), across 35 centers from February 2020 to February 2025. Patients' eligibility required imaging-confirmed ischemic stroke, baseline vessel imaging, and a standardized 90-day follow-up. Patients with inadequate anticoagulant dosing or poor adherence were excluded. Competing etiologies were defined as any additional mechanism coexisting with cardioembolism and plausibly contributing to the index stroke. The primary outcome was 90-day recurrent ischemic stroke; secondary outcomes included modified Rankin Scale shift, myocardial infarction, and vascular and all-cause death. Bleedings were also evaluated. We performed inverse probability weighting to balance baseline covariates and applied Cox or regression models to compare outcomes. Among 1,649 patients (mean age 78 years, 47.8% male), 24.3% had competing etiologies, most commonly large artery atherosclerosis (59.9%). Considering the weighted population, 90-day recurrent ischemic stroke occurred more often in those with competing etiologies (6.0% vs 2.7%; adjusted hazard ratio [aHR] 2.62, 95% CI 2.01-3.42; p < 0.001). Risk was greatest for large artery atherosclerosis and other determined causes. Competing etiologies also had worse disability distribution (adjusted odds ratio 1.30, 95% CI 1.08-1.55; p = 0.005) and higher all-cause mortality (aHR 1.58, 95% CI 1.18-2.12; p = 0.002). Moderate-to-severe bleeding was higher with competing etiologies (aHR 1.82, 95% CI 1.08-3.09; p = 0.026), whereas 24-hour hemorrhagic transformation was less frequent (adjusted risk difference -4.3%, 95% CI -7.8% to -0.7%; p = 0.020). Other outcomes did not differ. One in 4 patients with AF and breakthrough ischemic stroke on OAC had competing etiologies, most often large artery atherosclerosis. These patients showed higher risk of recurrent stroke, functional dependence, mortality, and bleeding, highlighting the need for development of individualized secondary prevention. Main study limitations include observational retrospective design and incomplete data on on-treatment anticoagulation quality. ClinicalTrials.gov NCT06823466.

Contrast-associated acute kidney injury (CA-AKI) is a potentially preventable complication after exposure to iodinated contrast media. In patients undergoing endovascular thrombectomy (EVT) for acute ischemic stroke (AIS), the incidence and clinical impact are poorly characterized, and no validated prediction tool is currently available. The aim of this study was to assess the incidence and prognostic significance of CA-AKI in EVT-treated patients with AIS and to develop and validate a predictive score. A retrospective, multicenter cohort study was conducted involving EVT-treated patients across 73 centers in 16 countries (January-December 2023). Inclusion criteria were age ≥18 years, absence of dialysis, availability of preprocedural and 48-hour postprocedural creatinine levels, and available 90-day follow-up (modified Rankin Scale [mRS] score). The primary outcome was CA-AKI, defined by KDIGO (Kidney Disease: Improving Global Outcomes criteria;creatinine increase ≥0.3 mg/dL or ≥1.5 times baseline, within 48 hours). Secondary outcomes were (1) in-hospital mortality, (2) 90-day mRS score, and (3) 90-day severe disability or death (mRS score >3). Logistic models assessing associations with outcomes accounted for within-center clustering by applying robust standard errors. CA-AKI prediction models were developed across imputed data sets using univariable selection (p < 0.20), backward elimination (p < 0.05), and coefficient-based scoring after categorization of continuous predictors, with internal validation by bootstrap to obtain optimism-adjusted estimates. Among 6,638 patients (median age 74 years; 48.7% male), CA-AKI occurred in 326 (4.9%) and was independently associated with in-hospital mortality (adjusted odds ratio [aOR] 2.269; 95% CI 1.615-3.190), higher 90-day mRS scores (adjusted common odds ratio 1.584; 95% CI 1.110-2.258), and 90-day severe disability or death (aOR 1.530; 95% CI 1.057-2.216). A preprocedural risk model including 12 routine clinical variables-sex, ethnicity, arterial hypertension, dyslipidemia, chronic kidney disease, antiplatelet therapy, NIH Stroke Scale score at admission, serum glucose, estimated glomerular filtration rate, hemoglobin, mean arterial pressure, and IV thrombolysis-demonstrated acceptable discrimination (area under the receiver operating characteristic curve 0.710 [95% CI 0.682-0.738]; precision-recall area under the curve 0.13 [95% CI 0.10-0.16]), good calibration (slope 0.870 [95% CI 0.759-0.928]), good overall performance (Brier score 0.045 [95% CI 0.042-0.049]). A second model that included EVT-related variables (e.g., contrast volume) showed similar performances. In this large, international cohort, CA-AKI occurred in approximately 1 in 20 EVT-treated patients with AIS and was independently associated with poor outcomes. A simple preprocedural risk score enables early identification of high-risk individuals and may support preventive strategies.