Introduction
Across Europe, stroke remains a leading cause of death and disability, and the absolute number of cases continues to rise despite advances in prevention [1]. The burden is particularly high in Central and Eastern Europe, where age-standardized incidence, mortality, and disability-adjusted life-year rates exceed the European average [2]. This persistent East-West gradient underscores the need for system-level improvements in acute stroke management across the region.
Emergent large-vessel occlusions (LVOs) represent the most severe form of ischemic stroke and are associated with high mortality and long-term disability. Mechanical thrombectomy (MT) has transformed their management. Five pivotal randomized trials (Multicenter Randomized Clinical trial of Endovascular treatment in Acute ischemic stroke in the Netherlands, Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times, EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy, Solitaire With the Intention For Thrombectomy as PRIMary Endovascular treatment for acute ischemic stroke, and Endovascular Revascularization with Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke within 8 Hours) demonstrated its superiority over medical therapy alone [3-7], and the Hyperacute Reperfusion Therapy with Endovascular Mechanical Thrombectomy for Acute Ischemic Stroke individual patient-level meta-analysis confirmed a consistent benefit with a clear time-dependent treatment effect, with each minute of delay reducing the likelihood of functional independence [8].
Observational and pooled analyses have suggested that direct transfer to a comprehensive stroke center (CSC) shortens workflow times and improves outcomes after thrombectomy [9], whereas the underpowered Treatment strategy In Acute larGE vessel occlusion: Prioritize IV or endovascular treatment—A randomized trial (TRIAGE-STROKE) trial and a large meta-analysis appeared to support these findings, thereby favoring the “mothership” strategy [10]. However, the completed RACECAT (Effect of Direct Transportation to Thrombectomy-Capable Center vs Local Stroke Center on Neurological Outcomes in Patients With Suspected Large-Vessel Occlusion Stroke in Nonurban Areas) randomized trial, which used the Rapid Arterial oCclusion Evaluation (RACE) prehospital triage score, found no significant functional advantage for direct transfer, leaving the optimal prehospital pathway for patients with suspected LVO unresolved [11].
Although RACECAT is often cited in support of the “drip-and-ship” approach, the trial was conducted in a predominantly nonurban environment characterized by long transport distances and multiple referral hospitals. Under such conditions, direct transfer did not improve outcomes despite shorter workflow times, reflecting system-level limitations rather than a lack of therapeutic benefit. Extrapolating these findings to densely populated regions with short transfer routes and high procedural capacity may therefore be inappropriate. Whether direct transfer provides additional benefit in urban settings—particularly among patients eligible for both intravenous thrombolysis (IVT) and thrombectomy, who are frequently first directed to primary stroke centers (PSCs)—remains an open question and constitutes a central focus of the present investigation.
Methods
Study setting
This study was based on the Central Hungarian Endovascular Stroke Registry, a prospectively maintained regional database that includes all consecutive patients who underwent MT for acute ischemic stroke. The present analysis covered the period from January 2015 to December 2022, during which a single CSC provided all endovascular services for 11 PSCs in the Central Hungarian region and received additional referrals from neighboring areas.
Emergency medical response and interhospital transfer were coordinated by the National Ambulance Service, a nationwide public agency operating under standardized, stroke-prioritized triage protocols. Hungary’s publicly funded health care system provides universal access and full reimbursement for acute stroke treatment, thereby minimizing socioeconomic bias and ensuring comprehensive case capture.
Decisions regarding direct transfer were made jointly by paramedics and the attending stroke neurologist at the CSC. The RACE score was used by paramedics as a referral tool [12], but no exact cutoff value was predefined, and all patients with debilitating symptoms could be considered for direct transfer. Patients with suspected intracranial hemorrhage (ICH) (e.g., gradual symptom worsening, headache, or contralateral gaze deviation) were preferentially transported to the nearest hospital rather than directly to the CSC.
Ethics approval
The study was reviewed and approved by the Semmelweis University Center of Neurosurgery and Neurointervention Ethics Committee (SE RKEB No. 370/2025). The requirement for individual informed consent was waived.
Geographic coverage
The analysis focused on the urban core of the Central Hungarian region, encompassing approximately 1.7 million inhabitants within a 60-minute ground transport radius of the CSC. The catchment area was delineated using geospatial network analysis in QGIS version 3.34 (QGIS Development Team, Open Source Geospatial Foundation, https://www.qgis.org) and the ETRS89/EOV coordinate reference system (EPSG:23700). Data sources included the Hungarian Central Statistical Office and OpenStreetMap (OpenStreetMap Contributors, https://www.openstreetmap.org). A 60-minute isochrone polygon representing weekday 9:00 a.m. traffic conditions was generated and intersected with administrative boundaries to define the metropolitan service area. The 60-minute radius was selected based on the farthest direct-transfer referral observed during the study period to enable a balanced comparison of transport strategies.
Patient population
Patient selection for MT followed contemporary international guidelines applicable at the time of treatment. Before publication of the late-window trials [13,14], patients presenting beyond 6 hours were treated when imaging demonstrated a favorable profile (Alberta Stroke Program Early Computed Tomography Score ≥6). All patients with emergent LVO, a premorbid modified Rankin Scale (mRS) score of 0-2, and an expected life expectancy greater than 6 months were considered eligible. Posterior circulation strokes were treated at the discretion of the neurointerventionalist. Patients with extensive early ischemic changes were rarely selected. Futile transfers were recorded by the CSC in a log containing limited clinical data focused on the reason for thrombectomy deferral. The patient-selection flowchart for this analysis is presented in Supplementary Figure 1.
Thrombectomy procedures
Procedural techniques evolved in parallel with advances in endovascular stroke therapy (EVT). Early cases involved stent-retriever thrombectomy using either the Solitaire AB (Medtronic Neurovascular, Irvine, CA, USA) or Trevo (Stryker Neurovascular, Fremont, CA, USA) devices, combined with proximal balloon-guide catheter aspiration using the Cello Balloon Guide Catheter (Medtronic Neurovascular, Irvine, CA, USA). Following publication of the Contact Aspiration vs Stent Retriever for Successful Revascularization trial [15], direct aspiration as a first-line technique became common and was performed with the Sofia Aspiration Catheter (MicroVention, Aliso Viejo, CA, USA). Combined “Solumbra” approaches—simultaneous aspiration and stent-retriever thrombectomy—were employed at the operator’s discretion according to angiographic findings.
When intracranial atherosclerotic disease or residual stenosis resulted in persistent occlusion, rescue angioplasty or stenting was performed to achieve stable reperfusion. Periprocedural antiplatelet and anticoagulation regimens were tailored to individual risk profiles and institutional safety standards.
Outcome definitions
Symptom-onset-to-admission time was defined as the interval from symptom onset (or last known well) to arrival at the CSC. Reperfusion was assessed on the final angiogram using the modified Thrombolysis in Cerebral Infarction (mTICI) scale, and successful reperfusion was defined as mTICI 2b-3. Functional outcome was evaluated 90 days after treatment using the mRS and was assessed by certified stroke neurologists during outpatient visits or via structured telephone interviews when in-person follow-up was not possible. The mRS is a validated ordinal measure of poststroke disability ranging from 0 (no symptoms) to 6 (death). A score of 0-2 indicates functional independence and was considered a good outcome, consistent with contemporary stroke trials. Mortality was determined through linkage with the National Health Insurance Fund of Hungary (NEAK), which maintains comprehensive national health and mortality data.
Safety assessment
Postprocedural ICHs were categorized according to the Heidelberg Bleeding Classification, differentiating hemorrhagic infarction (HI1-HI2), parenchymal hematoma (PH1-PH2), and remote or extraparenchymal bleeding (intraparenchymal, intraventricular, subarachnoid, or subdural). Symptomatic hemorrhage was defined as PH2 accompanied by neurological deterioration of more than 4 points on the National Institutes of Health Stroke Scale (NIHSS). Classification was performed by expert readers at the CSC based on 24-hour follow-up computed tomography or magnetic resonance imaging scans [16].
Statistical analysis
Continuous variables were summarized as medians (interquartile ranges [IQR[), and categorical variables as counts (percentages). Group differences were evaluated using the Mann-Whitney U test for continuous variables and the χ2 or Fisher’s exact test for categorical variables.
To determine whether primary transfer independently predicted a favorable outcome (mRS ≤2 at 90 days), a multivariable logistic regression model was constructed, including age (≥75 years), NIHSS score (≥6), sex, major comorbidities (hypertension, diabetes, atrial fibrillation, coronary and peripheral artery disease, hyperlipidemia, and malignancy), stroke territory, successful reperfusion (mTICI 2b-3), and IVT use. Transfer mode (primary vs. secondary) was forced into all models as the main exposure variable. Variables were retained if they minimized the Akaike Information Criterion (AIC). Missing covariate data were imputed using subgroup-specific medians.
As a sensitivity analysis, 1:1 propensity score matching was performed using nearest-neighbor matching without replacement (caliper width of 0.2 standard deviations of the logit). The propensity model included baseline demographic and clinical variables, as well as IVT use. Covariate balance was assessed using standardized mean differences.
Survival time was measured from MT to death or last known follow-up; in surviving patients, follow-up was censored at the time the NEAK database was accessed. Kaplan-Meier curves were used to estimate cumulative survival, and intergroup differences were assessed using the log-rank test. Independent predictors of long-term mortality among patients receiving combined IVT and thrombectomy were evaluated using Cox proportional hazards regression with AIC-based stepwise selection. The proportional hazards assumption was verified graphically and through analysis of Schoenfeld residuals.
Results are reported as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses were performed using Python 3.11 programming language (Python Software Foundation, https://www.python.org) (Statsmodels 0.14; Python Software Foundation, https://www.statsmodels.org. Lifelines 0.28; Collective Innovation, Inc., https://lifelines.readthedocs.io) and were cross-validated in R (R 3.5; R Core Team, https://www.r-project.org) (survival 3.5-5; Therneau T, R Core Team, https://CRAN.R-project.org/package=survival). Figures were generated using GraphPad Prism (version 10.3; GraphPad Software, Inc., San Diego, CA, USA, https://www.graphpad.com). A two-tailed P-value <0.05 was considered statistically significant.
Results
Study population
Between January 2015 and December 2022, a total of 2,795 patients underwent endovascular therapy for emergent LVO within the Central Hungarian Stroke Network. Of these, 778 patients were referred from outside the 60-minute ground transport radius of the CSC and were therefore excluded from further analysis. The remaining 2,017 patients, originating from the densely populated urban inner catchment area, constituted the study population.
Among these, 242 patients (12.0%) were directly transported to the CSC (primary transfer group), whereas 1,775 patients (88.0%) initially presented to another hospital and were subsequently transferred after LVO diagnosis (secondary transfer group).
The median onset-to-admission time was 101 minutes (range, 7-1,071) in the primary transfer group and 240 minutes (range, 40-1,411) in the secondary transfer group (P<0.001) (Figure 1).
The mean estimated travel distance from the referral site to the comprehensive center was 12.6 km (IQR, 7-19 km) for direct transfers and 11.5 km (IQR, 7-16.5 km) for secondary transfers, with no significant difference between transfer strategies (P=0.927).
The number of futile transfers—defined as patients transferred for thrombectomy who ultimately did not undergo the procedure—was significantly higher in the direct transport group (33.0% [119/361]) than in the secondary transfer group (23.6% [549/2,324]; P<0.001). The overall incidence of ICH on CSC admission was 3.4% (23/668), with no difference between transfer strategies. The primary reasons for thrombectomy deferral were spontaneous recanalization of the target vessel (15.7% [105/668]) and distal clot migration (21.3% [142/668]), whereas most of the remaining deferrals were attributable to extensive early ischemic injury in the affected brain territory. In addition, 53 patients in the direct transport subgroup required only IVT upon admission to the CSC.
Baseline patient characteristics
Baseline characteristics of the study population are summarized in Table 1. The primary and secondary transfer groups were largely comparable across demographic, clinical, and angiographic variables. Patients in the primary group were slightly older (median age, 71 years [range, 16-95] vs. 69 years [range, 10-99]; P=0.044), whereas stroke severity at admission was similar (median NIHSS score, 15 in both groups; P=0.698). The proportion of women did not differ significantly between groups (52.1% vs. 48.9%; P=0.373).
The prevalence of vascular risk factors and comorbidities was balanced between groups. Posterior circulation occlusions occurred in 7.9% of primary and 11.3% of secondary transfers (P=0.123), whereas carotid tandem lesions were present in 15.3% and 17.3%, respectively (P=0.467). Successful reperfusion (mTICI 2b-3) was achieved in 88.8% of primary and 87.9% of secondary cases (P=0.751). An important difference was the higher rate of IVT among secondary transfers (55.2% vs. 45.5%; P=0.005).
The 3-month functional follow-up was available for 75.6% of primary and 72.2% of secondary transfers (P=0.283), indicating similar follow-up completeness between groups. One-year mortality follow-up was available for 98.8% and 97.2% of patients in the primary and secondary groups, respectively (P=0.197), ensuring robust long-term survival assessment.
Overall, the two study groups were well matched in baseline clinical and angiographic characteristics, and the completeness of follow-up supported the validity of subsequent outcome comparisons.
Clinical outcomes
At 90 days, 50.3% of patients in the primary transfer group achieved a good functional outcome compared with 40.5% in the secondary transfer group (P=0.015). This favorable shift across the full mRS distribution reflects a consistent reduction in poststroke disability among patients directly transported to the CSC (Figure 2).
In multivariable logistic regression adjusting for age ≥75 years, baseline NIHSS score ≥6, IVT use, posterior circulation stroke, and major comorbidities, primary transfer remained an independent predictor of good functional outcome (OR: 1.74; 95% CI 1.25-2.42; P=0.001).
In a sensitivity analysis using 1:1 propensity score matching, all 242 directly transported EVT patients were successfully matched to 242 secondary-transfer patients, resulting in substantially improved baseline balance. In the matched cohort, direct transfer remained significantly associated with higher odds of good functional outcome at 90 days (OR: 1.72; 95% CI 1.12-2.63; P=0.013), confirming the robustness of the primary analysis.
Among patients receiving IVT, a good functional outcome occurred significantly more often following primary transfer (P=0.046).
Hemorrhagic complications
According to the Heidelberg classification, hemorrhagic transformation patterns were broadly similar between transfer groups (Table 2). HI1-HI2 occurred in 11.2% of primary and 14.7% of secondary transfers (P=0.169), reflecting the natural evolution of LVO strokes rather than true treatment-related complications. Parenchymal hematoma was uncommon, with PH1 occurring in 2.9% versus 5.0% and PH2 in 3.3% versus 3.7% (P=0.196 and P>0.999, respectively). Subarachnoid hemorrhage, typically representing a small angiographically evident but clinically minor consequence of mechanical reperfusion, occurred in 7.9% versus 8.2% of cases (P>0.999). Other bleeding types—including remote parenchymal, intraventricular, and subdural hemorrhage—were rare and evenly distributed.
A modest excess of any ICH was observed after secondary transfer (28.3% vs. 21.9%, P=0.038), paralleling the higher use of IVT in this group (55.2% vs. 45.5%). Among patients who received both IVT and thrombectomy, the rates of any ICH and its subtypes were no longer significantly different, indicating that the observed excess reflected differences in treatment exposure rather than transfer strategy (Figure 3).
Survival following combined reperfusion therapy
Because of differences in IVT use and the associated variation in ICH rates, the effect of transfer strategy on survival was evaluated in a data-driven subgroup analysis of patients who received both IVT and thrombectomy (n=1,110). In this cohort, Kaplan-Meier analysis demonstrated significantly higher survival after primary transfer compared with secondary transfer (log-rank P=0.026). The median follow-up time for mortality assessment was 12.2 months (IQR, 7.8-18.4 months). In multivariable Cox regression adjusted for age ≥75 years, baseline NIHSS score ≥6, successful reperfusion (mTICI 2b-3), and major comorbidities, primary transfer remained an independent predictor of improved survival (HR: 0.67; 95% CI 0.47-0.95; P=0.026). After stepwise AIC-based variable selection, the association persisted (HR: 0.69; 95% CI 0.49-0.97; P=0.034). Adverse predictors included advanced age, higher baseline NIHSS score, diabetes, hypertension, and coronary artery disease (Figure 4).
Discussion
This study provides the first comprehensive data from the Eastern-Central European region, a historically and economically homogeneous area representing a substantial share of the European population. The principal finding is that direct transfer for MT may be associated with significant functional and survival benefits, most pronounced among patients receiving combined IVT and thrombectomy. To our knowledge, this represents the first observation of a potential mortality advantage linked to prehospital transfer strategy in a large real-world endovascular stroke cohort. In addition, direct transfer independently predicted better 90-day functional outcomes after adjustment for age, stroke severity, and comorbidities.
The two transport groups were comparable in demographics, comorbidities, and reperfusion success, enabling a clear assessment of routing effects. Importantly, the TRIAGE-STROKE trial likewise reported balanced baseline characteristics and demonstrated a substantial time advantage for direct CSC transport, reducing onset-to-groin puncture time by approximately 35 minutes, whereas PSC-first routing primarily accelerated thrombolysis. Despite being underpowered because of funding limitations, TRIAGE-STROKE observed a nonsignificant trend toward improved functional outcomes with direct transport. Our results mirror this pattern: the time gained by bypassing PSCs translated into more favorable 90-day outcomes, reinforcing that streamlined prehospital routing—particularly faster access to thrombectomy—can meaningfully influence recovery.
At first glance, our results may appear to be at odds with the RACECAT trial, which found no significant difference between transfer strategies. However, that study was conducted predominantly in rural regions, where long transfer distances and heterogeneous access to CSCs limit the potential benefit of direct routing. Moreover, a major contributor to RACECAT’s neutral outcome was the futile long-distance transfer of patients with undiagnosed ICH, an issue that would be unlikely to cause comparable clinical deterioration over short urban distances [11]. Our system, based on the joint online triage of stroke patients by paramedics in consultation with attending neurologists, demonstrates that the clinical signs of hemorrhage can often be identified in the field and that the rate of transferred ICH cases can be kept reasonably low.
Subgroup analyses of the RACECAT trial showed that outcomes after secondary transfer were strongly influenced by hospital performance, particularly door-in-door-out times at primary centers [17], underscoring the importance of monitoring and optimizing this critical workflow interval. As a potential alternative in settings with primary centers of modest performance, mobile stroke units have been shown to expedite diagnosis and treatment, thereby shortening time to reperfusion and reducing unnecessary long-distance transfers of patients with hemorrhagic stroke [18].
In our registry, patients receiving combined IVT and thrombectomy typically presented within the early therapeutic window, when rapid and complete reperfusion is most critical. The survival benefit associated with primary transfer likely stems from more timely and effective reperfusion of fast progressors, who in the secondary transfer group were frequently diverted to thrombolysis-only centers. Although this approach reflects current European Stroke Organisation, European Society of Minimally Invasive Neurological Therapy recommendations prioritizing thrombolysis at the nearest stroke unit [19], such detours may delay definitive endovascular treatment and reduce the overall therapeutic effect. Notably, the most recent American stroke guidelines acknowledge the ongoing challenges of prehospital destination triage and, in contrast to earlier recommendations favoring transport to the nearest thrombolysis-capable center, now endorse consideration of local system characteristics and direct transport to the closest endovascular thrombectomy-capable hospital when rapid interhospital transfer processes are not well established [20]. Our findings are consistent with this updated perspective. Our observation of more frequent ICH in the secondary transfer group aligns with a recent individual participant data meta-analysis of the “mothership” trials, which demonstrated increased hemorrhage with uncertain functional benefit from combined thrombolysis and thrombectomy [21]. Together, these data suggest that upfront thrombolysis may offer limited advantage in urban settings with rapid access to thrombectomy, particularly if it prolongs transfer times. In such environments, a selective or “rescue” thrombolysis approach—administering fibrinolytics only when angiographic or clinical evidence indicates incomplete reperfusion—may be preferable. This concept is supported by the CHemical OptImization of Cerebral Embolectomy trial, which demonstrated improved 90-day outcomes with intra-arterial alteplase after successful thrombectomy, without an increased risk of bleeding [22]. Thus, in metropolitan stroke networks, a thrombectomy-first strategy with selective adjunctive thrombolysis may achieve an optimal balance between efficacy and safety; however, this strategy has yet to be tested in large randomized trials.
Limitations
This single-center observational study is subject to residual confounding, and the lack of randomization represents a key limitation of our conclusions. Patients with early recanalization at a PSC were not included in the EVT cohort, which may have introduced selection bias and potentially influenced the estimated treatment effect; however, the observed rate of such cases was low. Follow-up for functional outcomes was incomplete, which may have introduced bias. Nevertheless, completeness was similar between groups, and one-year mortality follow-up was nearly complete, allowing valid comparisons and a robust assessment of survival outcomes. Detailed in-hospital time metrics from the PSCs were not available for analysis. Our findings are most applicable to urban stroke networks but are likely generalizable to countries with comparable population structures and health care organization. Although the COVID-19 pandemic overlapped with the study period, its impact on severe stroke management appeared minimal in previous comprehensive studies [23].
Conclusions
We found that bypassing PSCs within 60 minutes of a thrombectomy-capable CSC may improve functional recovery and survival among patients with LVO. Our data support the recently guideline-endorsed, system-adapted direct transport strategy and, as the first large observational cohort from a fully publicly funded, resource-limited health care system in Eastern-Central Europe, suggest that this paradigm is generalizable beyond the United States to diverse health care settings. Nevertheless, high-performing PSCs and mobile stroke units remain essential in less densely populated regions, and the integration of complementary strategies is key to building effective nationwide stroke networks.
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