Highlight
– In a 20-center French cohort (n=584) of patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO) presenting beyond 4.5 hours, administration of IV thrombolysis (IVT) before transfer to a comprehensive stroke center (CSC) was associated with better 90‑day functional outcomes (PSOW-common OR 1.97, 95% CI 1.33–2.92) and markedly higher odds of recanalization during transfer (PSOW-OR 8.69, 95% CI 3.16–23.87) compared with no IVT. Hemorrhagic complication rates were similar between groups.
Background and clinical context
Acute ischemic stroke caused by large vessel occlusion (AIS-LVO) is a leading cause of death and long-term disability. Endovascular therapy (EVT) provides dramatic benefit when performed in appropriately selected patients, including in extended time windows using advanced perfusion imaging (DAWN, DEFUSE‑3). Intravenous thrombolysis (IVT) with alteplase (or increasingly tenecteplase in some systems) is standard within 4.5 hours of symptom onset and in selected patients with unknown onset guided by MRI/CT perfusion criteria. The role of IVT started beyond 4.5 hours in patients with LVO who will undergo EVT has been debated.
Randomized trials have recently questioned routine late-window IVT in patients with LVO who present directly to comprehensive stroke centers with rapid access to EVT: the TIMELESS randomized trial did not demonstrate a benefit of late-window IVT in that specific population. However, many patients with AIS-LVO first present to primary stroke centers (PSCs) without EVT capability and require interhospital transfer. In this logistics‑driven scenario, IVT started at the PSC before transfer might have additional value because it affords more time for systemic thrombolysis to act prior to endovascular reperfusion attempts.
Study design and methods
The OPEN-WINDOW collaborative performed a retrospective, multicenter cohort study across 20 French primary stroke centers between January 2020 and December 2024. Eligible consecutive patients had AIS-LVO, presented to a PSC beyond 4.5 hours from last known well, and were subsequently transferred to a comprehensive stroke center for EVT. The exposure of interest was IVT initiated at the PSC prior to transfer versus no IVT. Advanced brain imaging (MRI or CT with CT perfusion) was performed in 93.2% of patients at the PSC, enabling imaging-based selection in most cases.
Primary outcome was 3‑month functional outcome measured by the modified Rankin Scale (mRS) analyzed with an ordinal shift approach. Secondary outcomes included recanalization observed during transfer and intracerebral hemorrhage (any and symptomatic). To address confounding, investigators used propensity score with overlap weighting (PSOW) to balance baseline covariates between IVT-treated and untreated groups. The cohort included 584 patients; 232 (39.7%) received IVT before transfer.
Key findings
Baseline characteristics: median age was 71 years (IQR 61–81), 52.9% were female, and median baseline NIH Stroke Scale (NIHSS) score was 15 (IQR 10–19). Median time from last known well to PSC imaging was 10.5 hours (IQR 6.9–14.0), reflecting a predominately late/extended time-window population.
Primary outcome — 90‑day functional outcome: After PSOW adjustment, IVT before transfer was associated with a favorable shift in the distribution of mRS scores at 90 days (PSOW common odds ratio 1.97; 95% CI 1.33–2.92; P = .001). This indicates an approximately twofold greater odds of improvement across the ordinal mRS scale for patients treated with IVT prior to transfer than those who were not.
Recanalization during transfer: IVT was strongly associated with documented recanalization while patients were being transferred (PSOW-OR 8.69; 95% CI 3.16–23.87; P < .001). The magnitude of this association suggests that systemic thrombolysis administered before transfer can achieve complete or partial clot dissolution in a meaningful subset of late-window LVO patients, potentially obviating the need for EVT or reducing clot burden prior to endovascular attempts.
Safety: Rates of any intracerebral hemorrhage and symptomatic intracerebral hemorrhage did not differ significantly between the IVT and no‑IVT groups in adjusted analyses. No signal emerged of excess hemorrhagic complications associated with late-window IVT given in the PSC prior to transfer.
Imaging and selection: Nearly all patients underwent advanced imaging at the PSC (MRI or CT perfusion), supporting that treatment decisions were commonly guided by tissue viability (penumbral) imaging — a key factor in selecting candidates for reperfusion therapies beyond conventional time windows.
Interpretation and clinical implications
These observational findings suggest that, in real-world systems where patients with suspected LVO first present to PSCs and require transfer to a CSC, initiating IVT beyond 4.5 hours (guided by advanced imaging) before transfer may increase the probability of early or spontaneous recanalization and improve 90‑day outcomes without increasing hemorrhagic risk.
Mechanistically this is plausible: in selected late-window patients with a favorable penumbral profile, residual flow dynamics and a smaller, distal or partially thrombotic occlusion may permit systemic thrombolytics to lyse thrombus given sufficient time. In the interhospital transfer scenario the additional minutes to hours before EVT provide an opportunity for IVT to act, an interval not available to patients presenting directly to a CSC and undergoing near-immediate EVT — a key distinction from the negative TIMELESS trial.
Clinical relevance depends on context. For PSCs that can obtain perfusion or diffusion imaging to identify tissue at risk and are not directly linked to immediate EVT, the data support considering IVT in selected late-window patients with LVO who lack contraindications. This strategy may be especially important where transfer times are substantial.
Comparison with prior randomized evidence
Large randomized trials established EVT benefit in extended windows (DAWN, DEFUSE‑3) using imaging selection for salvageable tissue. Randomized evidence for IVT in unknown or extended windows is more limited and mixed: MRI-guided thrombolysis in unknown onset (WAKE‑UP) showed benefit in selected patients; more recent RCT evidence (TIMELESS) did not demonstrate benefit of late-window IVT in patients directly admitted to CSCs with fast access to EVT. The present study addresses a different operational question — whether IVT started at PSCs before transfer confers benefit. Observational data here suggest it might, but randomized testing is needed to establish causality.
Strengths
– Multicenter, pragmatic dataset reflecting routine practice across 20 PSCs with high use of advanced imaging.
– Consecutive patient inclusion likely reduced selection bias at the enrollment stage.
– Use of propensity score overlap weighting reduced measured confounding and improved comparability between treatment groups.
– Clinically meaningful outcomes (90‑day mRS) and safety endpoints were reported.
Limitations and cautions
– Retrospective design: residual confounding and unmeasured selection biases (physicians likely selected IVT recipients based on factors not fully captured in the dataset).
– Heterogeneity in thrombolytic agent and dosing: the report does not fully detail agent choice (alteplase vs tenecteplase) or dose variations across centers, which may affect generalizability.
– Transfer systems: the cohort reflects a French network with specific imaging and transfer patterns; findings may not generalize to systems with different transfer times, imaging capacity, or EVT availability.
– Imaging selection: high use of perfusion/MR selection in this cohort may have enriched for patients more likely to benefit, limiting applicability where advanced imaging is less available.
– Possibility of informative censoring: patients recanalized before arrival to the CSC may have different downstream care pathways affecting outcome ascertainment.
– Observational results should be seen as hypothesis‑generating; randomized confirmation is needed before changing guideline recommendations.
Expert perspective and practice implications
For clinicians working in PSCs without on-site EVT, this study supports a pragmatic approach: when advanced imaging shows a favorable penumbral pattern and no contraindications to thrombolysis, consideration of IVT before transfer is reasonable and may increase the chance of recanalization and better functional outcome. Shared decision-making and careful documentation of contraindications remain essential. Systems-level considerations include protocols for rapid imaging, clear transfer pathways, and feedback loops to monitor outcomes and bleeding complications.
For policymakers and stroke network designers, the results underscore the importance of tailored protocols: one-size-fits-all recommendations (e.g., never give late-window IVT) may not be optimal across diverse systems. Prospective randomized trials testing IVT before transfer in late-window, imaging-selected AIS-LVO patients are warranted and would clarify whether the observed associations represent causal benefit.
Conclusion
In this large multicenter retrospective cohort, initiating IV thrombolysis beyond 4.5 hours at primary stroke centers before interhospital transfer for EVT was associated with higher rates of recanalization during transfer and improved 90‑day functional outcomes without increased hemorrhagic complications. These results are hypothesis‑generating and support the rationale for randomized trials evaluating late-window IVT specifically in the interhospital transfer setting. Clinicians should balance potential benefits against local system variables, imaging availability, and individual patient risks when considering late-window thrombolysis before transfer.
Funding and registration
As a retrospective cohort, clinicaltrial.gov registration was not applicable. Funding sources and detailed disclosures are reported in the original publication (Seners et al., JAMA Neurol. 2025).
Selected references
1. Seners P, Nehme N, Ter Schiphorst A, et al; OPEN-WINDOW collaborators. Intravenous Thrombolysis Use in the Late Time Window Before Interhospital Transfer for Thrombectomy. JAMA Neurol. 2025 Dec 1:e254712. doi:10.1001/jamaneurol.2025.4712.
2. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018;378(1):11-21. (DAWN trial)
3. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018;378(8):708-718. (DEFUSE‑3)
4. Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018;379(7):611-622. (WAKE‑UP)
5. Saver JL, Goyal M, Bonafe A, et al. Stent‑retriever thrombectomy after intravenous t‑PA vs. t‑PA alone in stroke. N Engl J Med. 2015;372(24):2285-2295. (MR CLEAN and related thrombectomy trials)
Suggested next steps for research
– Randomized controlled trials testing late-window IVT initiated at PSCs prior to transfer versus no IVT (or placebo) in imaging-selected AIS-LVO patients with clinically relevant endpoints (mRS at 90 days, recanalization, hemorrhage).
– Subgroup analyses by thrombolytic agent (alteplase vs tenecteplase), transfer time intervals, and specific perfusion/MR-selection criteria.
– Health‑systems research to quantify trade-offs in resource use, transfer logistics, and outcomes under varied protocols.
