Forward thinking in reperfusion therapy for acute ischemic stroke

Acute ischemic stroke (AIS), the most common subtype of stroke, and results primarily from the sudden interruption of cerebral blood flow due to arterial occlusion, initiating a cascade of ischemia, energy failure, and neuronal injury. The therapeutic priority is to achieve rapid and effective reperfusion, thereby salvaging penumbral tissue at risk of infarction. Over the past three decades, intravenous thrombolysis (IVT), endovascular thrombectomy, and their combination have become the standard reperfusion therapies.[1-3] Large clinical trials have confirmed their effectiveness in reducing morbidity and mortality. However, despite these advances, major challenges persist. A critical appraisal of these challenges, together with a forward-looking vision, is essential to guide the next stage of innovation in reperfusion therapy. Further Improving the Efficacy of Reperfusion Therapy IVT with tissue plasminogen activator has long been the cornerstone of AIS treatment. However, its modest efficacy, narrow therapeutic window, and risk of bleeding limit its overall impact. In recent years, the advent of endovascular thrombectomy has dramatically transformed the treatment landscape, achieving high rates of large-vessel recanalization. However, the paradox of “futile recanalization” persists: Despite angiographic success in over 80% of cases, more than half of patients remain disabled or die.[4] This mismatch between high rates of large-vessel recanalization and poor functional outcomes is attributable to multiple factors, including distal embolism, microvascular no-reflow, early re-occlusion, poor collateral circulation, procedure-related injury, and suboptimal patient selection. Thus, in AIS, recanalization of the occluded artery is crucial but not sufficient; other therapeutic strategies are equally important, including achieving durable tissue-level reperfusion, refining patient selection, and protecting the brain against secondary injury. Future advances in reperfusion therapy will rely on a multidimensional strategy that overcomes the limitations observed in current practice. Ultra-early intervention, facilitated by advanced imaging and streamlined workflows, remains the most effective strategy for preserving the ischemic penumbra. Concurrently, refinement of thrombectomy devices and procedural techniques should prioritize achieving rapid and durable first-pass reperfusion, minimizing distal embolization, and shortening procedure duration. Particular attention should be directed to postthrombectomy hypoperfusion, an underexplored phenomenon that requires methods for immediate detection and targeted intervention to translate angiographic success into genuine tissue reperfusion. In parallel, combining reperfusion with adjunctive neuroprotective strategies holds promise when coupled with effective recanalization. Furthermore, the nonpharmacological therapies proposed by Dr. Wu’s group, which target the major imbalanced states occurring both before and after reperfusion therapy, may represent a milestone strategy for brain cytoprotection after stroke.[5] Equally critical is precision peri-procedural management, in which individualized control of blood pressure and glucose, alongside optimized antithrombotic regimens, can profoundly influence the long-term outcomes and may be as decisive as the intervention itself. It is noteworthy that a substantial proportion of poor outcomes after ischemic stroke are due to microcirculatory dysfunction or distal embolization that occur despite successful reperfusion. These mechanisms represent major contributors to incomplete tissue reperfusion. Recent randomized trials suggest that adjunctive intra-arterial thrombolysis following thrombectomy may enhance functional recovery without increasing hemorrhagic risk. A meta-analysis further indicated that this benefit was mainly observed in patients with postthrombectomy expanded Thrombolysis in Cerebral Infarction (eTICI) 2b reperfusion, with no significant effect in those achieving eTICI 2c–3.[6] Patient-level pooled analyses are warranted to refine patient selection, optimize thrombolytic strategies, and clarify the influence of prior IVT. Incorporating perfusion imaging before the completion of the endovascular procedure may further help identify patients most likely to benefit from this approach. Recent randomized controlled trials have confirmed that endovascular thrombectomy improves functional outcomes even in patients with large infarct cores, although outcomes remain poorer than in small-core strokes due to extensive baseline injury.[7] These findings underscore the need to optimize tissue salvage and mitigate reperfusion injury through refined imaging-based patient selection and adjunctive therapies. Meanwhile, endovascular thrombectomy for medium-vessel occlusions represents an emerging frontier. Current evidence remains heterogeneous, reflecting technical challenges related to smaller vessel caliber and distal access.[8] Continued innovation in device design and standardized imaging criteria may be essential to define patient subgroups most likely to benefit and to safely extend endovascular thrombectomy indications to these populations. Mobile stroke units (MSUs) epitomize the principle of “time is brain,” delivering imaging and thrombolysis directly to the patient’s doorstep and reducing treatment delays by up to an hour. These time savings translate into tangible clinical benefits, expanding eligibility for reperfusion therapy and improving outcomes.[9,10] Nevertheless, implementation remains uneven. High costs, resource constraints, and limited diagnostic accuracy in the prehospital setting continue to hinder widespread adoption of MSUs. For countries with developing prehospital systems, the future will depend on strategic deployment of MSUs in high-incidence regions, coupled with artificial intelligence-driven triage tools to enhance prehospital stroke recognition. In addition, blood-based biomarkers reflecting blood–brain barrier disruption and mobile diagnostic tools that capable of distinguishing ischemic from hemorrhagic stroke or stroke mimics may provide a more affordable and widely deployable diagnostic approach. The integration of such biomarkers with prehospital thrombolysis strategies represents a promising avenue to further improve prehospital stroke triage and expand timely reperfusion on a population scale. Thrombolytic Regimens and Antithrombotic Therapy after Thrombolysis The range of pharmacological options for thrombolysis remains limited. Alteplase, tenecteplase, and urokinase[11] dominate current practice, each with distinct strengths and limitations. Tenecteplase provides ease of administration and favorable pharmacodynamic properties, but its optimal dosing across diverse populations remains to be established. Urokinase, although inexpensive, is constrained by rigid dosing regimens and limited efficacy. Importantly, at the global level, many countries and regions still face economic barriers that limit access to IVT, underscoring the need for more affordable and widely deployable therapies. The next frontier involves novel thrombolytics characterized by enhanced fibrin specificity, improved pharmacokinetics, and a lower risk of hemorrhage. Recombinant prourokinase and recombinant human urokinase precursor have emerged as promising candidates. Future strategies may also include combination approaches, such as pairing thrombolysis with neuroprotective or anti-inflammatory agents, or precision dosing tailored to genetic and imaging biomarkers. Such innovations hold the potential not only to enhance recanalization rates but also to reshape the therapeutic landscape of thrombolysis. Neurological deterioration after IVT remains a major clinical challenge, affecting up to one-third of patients.[12] While hemorrhagic transformation accounts for some cases, the majority result from hypercoagulability, re-occlusion, or thrombus extension.[13] Current guidelines, which recommend delaying antiplatelet therapy for 24 h postthrombolysis, are designed to minimize bleeding risk but may inadvertently allow prothrombotic complications to unfold unchecked.[1] The 24-h antithrombotic prohibition originated from the NINDS (tissue plasminogen activator for AIS) trial 30 years ago,[14] this conservative approach was rooted in prudence rather than robust randomized evidence to minimize the potential additive risk of intracerebral hemorrhage. Paradoxically, thrombolysis itself activates platelets, leading to platelet-rich thrombus formation and vessel re-occlusion; this prothrombotic state peaks within 2 h and persists for over 12 h, significantly influencing functional outcomes.[15-17] The absence of antithrombotic therapy during this vulnerable window thus created a clinically significant “gray zone” of high-risk neurological deterioration. An emerging paradigm is risk-adapted early antithrombotic therapy. Current evidence allows the identification of high-risk patients mainly based on vascular pathology and baseline stroke severity, including those with large artery atherosclerosis, small vessel occlusion, severe initial neurological deficits, or no prior antiplatelet therapy.[18-22] For these patients, rigid adherence to the 24-h antiplatelet delay may forgo meaningful functional benefits. The challenge remains balancing ischemic prevention with hemorrhagic safety, requiring careful selection of agents and optimal timing. More recently, the Advancing Stroke Safety and Efficacy through Early Tirofiban Administration after Intravenous Thrombolysis (ASSET-IT) trial, a multicenter randomized controlled trial conducted in China and published in The New England Journal of Medicine, demonstrated that the early administration of tirofiban following IVT did not increase the risk of symptomatic intracranial hemorrhage and improved the proportion of patients achieving favorable functional outcomes.[23] This long-awaited finding represents a pivotal step forward for clinicians, signaling the potential closure of a long-standing therapeutic gap. It is imperative to conduct high-quality, mechanism-informed, and precisely targeted trials to refine patient selection, optimize therapeutic agents and timing, and integrate early antithrombotic therapy within comprehensive stroke care, including bridging to endovascular therapy. These advances mark the beginning of a new era in early postthrombolysis management, offering the potential to substantially improve the outcomes in patients treated with IVT. Extended Time Windows of Reperfusion Therapy The strict 4.5 h time window for IVT excludes a substantial proportion of patients who may still retain salvageable brain tissue. Trials such as Efficacy and safety of MRI-based thrombolysis in wake-up stroke (WAKE-UP), Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND), DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention (DAWN), and Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE-3) have demonstrated that imaging-based “tissue window” selection can safely extend the benefit of reperfusion therapy well beyond conventional limits.[2,24-26] In more recent years, studies in the field of IVT, such as The Treatment With Intravenous Alteplase in Ischemic Stroke Patients With Onset Time Between 4.5 and 24 Hours (HOPE), Tenecteplase Reperfusion Therapy in Acute Ischemic Stroke for China – Phase III Trial (TRACE-III), Extending the Time Window for Thrombolysis Using Advanced Imaging Selection Study (EXPECTS), and other trials have also explored the use of advanced imaging to select patients suitable for thrombolysis, with promising results.[27-29] More recently, the concept of a “molecule window” has been proposed as a potential landmark strategy, pointing to a new direction for functional outcome–oriented recanalization therapies.[30] In contrast to the “tissue window,” which identifies patients likely to benefit from recanalization based on imaging of the ischemic penumbra, the “molecule window” focuses on molecular markers to guide treatment selection. Because infarct core progression varies widely among patients with AIS, using time alone as the eligibility criterion for reperfusion therapy is inadequate.[31] Imaging represents only one major selection strategy. With the expanding application of artificial intelligence in medicine, integrating AI to synthesize multimodal patient information for identifying candidates for reperfusion therapy is a promising direction that warrants further investigation. This paradigm shift underscores that treatment eligibility should be guided not by clock time, but by the biological state of the brain as revealed by advanced imaging. In the coming decade, expanding access to advanced imaging and refining tissue-based criteria will be essential for implementing this approach worldwide. Current evidence indicates that, with appropriate screening and assessment, patients treated more than 24 h after onset may still benefit from reperfusion therapy. Notably, some studies have explored recanalization for chronic cerebral artery occlusion and reported potential benefits, although further research is required to confirm its safety and efficacy. Although these studies require further confirmation, they nonetheless suggest that tissue-window–based selection and treatment may represent a more rational approach. The ischemic penumbra is a dynamic region defined by reversible cellular dysfunction, providing a critical target for functional outcome-oriented therapy. Building on this concept, the “molecular window” has been proposed to guide treatment selection using biomarkers that reflect salvageable tissue.[30] Promising candidates include phosphatidylserine, which labels early apoptotic yet potentially recoverable cells, extracellular mitochondrial particles, and molecules involved in neuroinflammatory signaling. These modifiable biomarkers may allow more precise identification of patients likely to benefit from reperfusion and adjunctive therapies, complementing traditional imaging-based selection. Advances in spatial omics and artificial intelligence-driven analyses could further enable integration of molecular information into clinical decision-making, offering a novel, biology-centered strategy for outcome-directed stroke therapy. In summary, reperfusion therapy for AIS has made remarkable progress, but its full potential has yet to be realized. The challenge is no longer simply reopening the artery, but ensuring reperfusion that is durable, safe, and tissue-effective. The field now stands at a critical inflection point. By embracing forward-looking strategies that integrate biology, technology, and systems of care, the field can move closer to the ultimate goal – not merely recanalization, but functional recovery. Author contributions Wenbo Zhao conceived the article, drafted the initial manuscript, and revised the mansucript. Marc Fisher provided critical intellectual input and revised the manuscript for important scientific content. Xunming Ji contributed to the conceptual framework, provided senior oversight, and critically revised the manuscript. All authors reviewed and approved the final version of the manuscript. Ethical policy and institutional review board statement Not applicable. Data availability statement Data sharing is not applicable to this article as no datasets were generated and/or analyzed during the current study. Financial support and sponsorship The study was supported by the National Natural Science Foundation of China (82422024) and the Beijing Natural Science Foundation for Outstanding Young Scholars (JQ22020). Conflicts of interest Prof. Xunming Ji is the Editor-in-Chief, Dr. Wenbo Zhao is an Associate Editor, Dr. Marc Fisher is an Editorial Board member of Brain Circulation. The article was subject to the journal’s standard procedures, with peer review handled independently of them and their research groups.