Emanuele Spina

Background and Purpose: The timing of anticoagulation resumption in patients who experience ischemic stroke despite ongoing anticoagulation and develop hemorrhagic 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 analyzed data from patients with breakthrough ischemic stroke receiving anticoagulation therapy from the multicenter ASPERA-R registry. Analyses focused on patients with HT. HT was defined according to the Heidelberg Bleeding Classification based on brain imaging within 24 h and categorized as hemorrhagic infarction or parenchymal hematoma. 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 1555 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 (hazard ratio (HR) = 1.42, 95% confidence interval (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 modeling 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 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.

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.

Intravenous thrombolysis (IVT) is the cornerstone of reperfusion therapy for acute ischemic stroke (AIS), yet only a minority of patients achieve functional independence with vessel re-occlusion in up to one-third of cases. IVT targets fibrin but does not inhibit platelet aggregation, providing a rationale for adjunctive early platelet inhibition; so in this context tirofiban, a short-acting glycoprotein IIb/IIIa antagonist, may synergize with thrombolysis, favoring better outcome for AIS patients. We conducted a systematic review and meta-analysis up to August 2025 on MEDLINE (via PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) of RCTs assessing efficacy and safety of early intravenous infusion of tirofiban after thrombolysis in AIS. Outcomes presented as forest plot included functional independence (mRS 0-2), excellent outcome (mRS 0-1), mortality, symptomatic intracranial hemorrhage (sICH), any ICH and early neurological deterioration (END). Risk of Bias was evaluated through Cochrane RoB 2.0 tool. Five RCTs (1,428 patients) were included. At 90 days, functional independence occurred in 78.7% tirofiban-treated versus in 67.8% control patients (RR 1.22, 95% CI 1.05-1.40), with a lower number of END in tirofiban group (RR 0.35, 95% CI 0.15-0.82). Excellent outcome did not significantly differ (RR 2.72, 95% CI 0.26-27.97), as well as mortality (RR 1.07, 95% CI 0.55-2.09), overall ICH rate (RR 1.14, 95% CI 0.75-1.72) and sICH (RR 1.74, 95% CI 0.41-7.42), although an increased number of sICH was observed in tirofiban group. Tirofiban after thrombolysis may be associated with higher rates of functional independence and reduced END. However, given the very low certainty of evidence due to substantial heterogeneity, and imprecision, this meta-analysis should be interpreted as hypothesis-generating, and larger RCTs are required to confirm these findings. PROSPERO: number 1230163.

Recent randomised trials have questioned the benefit of endovascular therapy (EVT) for MeVO stroke, but data from clinical practice are limited. This study aimed to assess the effectiveness and safety of EVT, with or without intravenous thrombolysis (IVT), vs IVT alone in MeVO stroke using registry-based real-world data. This retrospective multicentre study included patients from 82 Italian centres in the Safe Implementation of Treatments in Stroke (SITS) registry (January 2020–December 2023). Adults with acute ischaemic stroke due to MeVO (ACA A1/A2, MCA M2/M3 or more distal or PCA P1/P2), treated with IVT or EVT ± IVT, and with available 90-day mRS scores were included. Patients with tandem occlusions were excluded. Propensity score matching (1:1) was used to balance baseline variables. Primary outcome was functional independence (mRS 0–2) at 90 days. Secondary outcomes included in-hospital mortality, intracranial haemorrhage incidence and recanalisation status. Among 1375 total patients, 780 were included and matched (390 per group) by propensity score. Baseline characteristics were balanced. Functional independence at 90 days was achieved in 60.6% of EVT ± IVT patients vs 60.9% in the IVT-only group (odds ratio [OR] 0.99; 95% CI, 0.73–1.34; P = .939). When restricted to patients with baseline mRS < 2, functional independence rates remained comparable between groups, confirming the primary findings. In-hospital mortality was non-significantly lower in the EVT ± IVT group (5.4% vs 8.7%, P = .069). Symptomatic intracranial haemorrhage rates were comparable between groups, although overall haemorrhagic complications were higher with EVT (18.4% vs 11.2%, P < .0001). Stratified analyses by stroke severity and treatment timing showed consistent lack of benefit across all subgroups (all interaction P-values > .05). The absence of functional benefit from EVT observed in this real-world cohort is consistent with the results of the ESCAPE-MeVO and DISTAL randomized trials. Notably, the higher rate of any intracranial haemorrhage in the EVT group (18.4% vs 11.2%), driven primarily by minor haemorrhagic events, represents a clinically meaningful safety concern that must be weighed against the lack of demonstrated efficacy. A hypothesis-generating signal was observed in patients treated within 180 minutes (OR 2.16, 95% CI 1.06–4.38), warranting prospective investigation. The retrospective design and the limitations inherent to registry-based data, including incomplete procedural data and anatomical heterogeneity in MeVO classification, should be considered when interpreting these findings. Endovascular therapy did not improve long-term functional outcomes compared to IVT alone in MeVO stroke but was associated with higher haemorrhagic risk. These findings support a cautious approach to EVT in this setting, in line with recent trial evidence.

Background and Aims: Rituximab has been proposed as a potential treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but formal evidence regarding its clinical effectiveness is weak. The CIDPRIT trial found no clinical benefit in comparison with placebo, but secondary analyses suggested some beneficial effect. Analysis of serum neurofilament light chain (sNfL) may provide evidence to support rituximab's effect on CIDP patients. Methods: We performed a post hoc analysis of sNfL levels from the CIDPRIT trial participants. Blood samples were collected at baseline, month 6, and 12. sNfL was measured using Simoa technology. Geometric means and z‐scores were compared across groups. Linear mixed‐effects models and survival analyses were used to evaluate treatment effects and clinical correlations. Results: 33 participants were included (18 rituximab, 15 placebo). Baseline sNfL was significantly higher in the rituximab group (11.51 vs. 6.67 pg/mL, p = 0.019). While between‐group differences over time were not statistically significant, rituximab‐treated patients showed stable sNfL levels at month 6 and a slight decrease at month 12, contrasting with modest increases in the placebo group. Among rituximab‐treated patients who remained clinically stable at month 12, sNfL showed a non‐significant decline by 31%. No significant associations were found between baseline sNfL and clinical worsening. NfL levels correlated with neurophysiological parameters of axonal damage. Interpretation: The analysis did not demonstrate biomarker‐based evidence of rituximab efficacy in CIDP. However, observed trends suggest a possible biological effect in reducing axonal injury in a subset of patients. Further studies are needed to clarify the role of sNfL in treatment monitoring and patient stratification.

Background The optimal timing for initiating direct oral anticoagulants (DOACs) after acute ischemic stroke or transient ischemic attack (TIA) in patients with nonvalvular atrial fibrillation (NVAF) remains uncertain. Objective To determine whether early initiation of DOACs is superior to delayed initiation in preventing new vascular events. Methods This guideline was developed using the GRADE approach and includes a systematic review and meta-analysis of four randomized controlled trials (TIMING, ELAN, OPTIMAS, START) enrolling 6,664 patients. Outcomes were selected via Delphi consensus. Meta-analyses used random-effects models, with certainty of evidence rated per GRADE methodology. Results Early DOAC initiation was associated with a trend toward fewer recurrent ischemic events (RR 0.77, 95% CI 0.52–1.14) and thromboembolic events (RR 0.73, 95% CI 0.50–1.06), with no increase in symptomatic intracranial hemorrhage (RR 0.93, 95% CI 0.44–1.97) or major extracranial bleeding (RR 0.84, 95% CI 0.42–1.69). Certainty of evidence was low due to imprecision. An individual patient data meta-analysis from CATALYST collaboration further supported early treatment in patients with minor to moderate stroke. Recommendations We recommend early DOAC initiation within 4 days in patients with minor to moderate stroke to prevent new vascular events. Early DOAC initiation over delayed treatment is indicated in patients with severe acute ischemic stroke to prevent new vascular events. Conclusion Early DOAC initiation appears safe and potentially more effective than delayed treatment, supporting a shift toward earlier anticoagulation in selected patients with NVAF and recent ischemic stroke.

BACKGROUND: Intravenous thrombolysis (IVT) in patients with recent ingestion of direct oral anticoagulants (DOACs) is a frequent challenge and remains controversial. The benefit of DOAC reversal before IVT is uncertain. METHODS: Using target trial methodology, we analyzed data from 28 comprehensive stroke centers. Patients on DOACs were included if they met IVT criteria, had a National Institutes of Health Stroke Scale score of ≥2, and last DOAC intake within 48 hours or was undeterminable. Safety and efficacy outcomes (symptomatic intracerebral hemorrhage, any intracerebral hemorrhage, major bleeding, 90-day mortality, and good functional outcome [modified Rankin Scale score of 0–2 or return to baseline]) were compared between those receiving IVT versus no IVT and IVT with versus without reversal. In addition, a comparison was made with patients from the New Zealand stroke registry, all of whom underwent reversal with idarucizumab. We adjusted for covariates known to be associated with safety and efficacy outcomes, including age, stroke severity, intended thrombectomy, blood glucose, blood pressure, DOAC reversal, and time from last intake. RESULTS: Overall, 1342 patients fulfilled the target trial criteria. The median age was 80 (interquartile range, 73–86) years, median National Institutes of Health Stroke Scale score was 11, 50% were female, and 52% of patients received endovascular therapy. IVT was given in 342 of 1342 (25%) patients. Of these, 141 (41.2%) had verified DOAC intake <12 hours before admission, and 92 (26.9%) within 12 to 24 hours. Symptomatic intracerebral hemorrhage occurred in 10 of 328 (3.0%) of patients receiving IVT and 54 of 921 (5.9%) patients not receiving IVT (adjusted difference, −2.1% [95% CI, −5.3% to +1.2]). Patients receiving IVT were more likely to have good functional outcomes (adjusted difference, +14.4% [95% CI, +7.1% to +21.8%]). Comparing 289 patients with reversal (from the additional New Zealand registry) and 283 patients without reversal before IVT (from the target trial population), there was no significant difference in symptomatic intracerebral hemorrhage, major bleeding, or efficacy outcomes. CONCLUSIONS: This target trial confirms previous observational data regarding the safety of off-label IVT in patients with recent DOAC intake. More data and dedicated trials are needed for patients with confirmed high DOAC plasma levels and regarding the efficacy and safety of DOAC reversal before IVT.

Background: Recent randomized trials have questioned the benefit of endovascular therapy (EVT) for medium vessel occlusion (MeVO) stroke, but data from clinical practice are limited. This study aimed to assess the effectiveness and safety of EVT, with or without intravenous thrombolysis (IVT), versus IVT alone in MeVO stroke using registry-based real-world data. Methods: This retrospective multicenter study included patients from 82 Italian centers in the SITS registry (January 2020–December 2023). Adults with acute ischemic stroke due to MeVO (ACA A1/A2, MCA M2/M3 or more distal, or PCA P1/P2), treated with IVT or EVT±IVT, and with available 90-day modified Rankin Scale (mRS) scores were included. Patients with tandem occlusions were excluded. Propensity score matching (1:1) was used to balance baseline variables. Primary outcome was functional independence (mRS 0–2) at 90 days. Secondary outcomes included in-hospital mortality, intracranial hemorrhage incidence, and recanalization status. Results: Among 1375 total patients, 780 were included and matched (390 per group) by propensity score. Baseline characteristics were balanced. Functional independence at 90 days was achieved in 57.7% of EVT±IVT patients versus 59.2% in the IVT-only group (OR 0.939, 95% CI 0.706–1.248, p=0.663). In-hospital mortality was non significantly lower in the EVT±IVT group (5.4% vs 8.7%, p=0.069). Symptomatic intracranial hemorrhage rates were comparable between groups, although overall hemorrhagic complications were higher with EVT (18.4% vs 11.2%, p0.05). Conclusions: EVT did not improve long-term functional outcomes compared to IVT alone in MeVO stroke but was associated with higher hemorrhagic risk. These findings support a cautious approach to EVT in this setting, in line with recent trial evidence.