Delayed treatment of severe stroke: room for thrombectomy?

Abstract

Large vessel occlusion (LVO) stroke is a significant cause of disability and death worldwide. Endovascular therapies to reopen blocked arteries have improved outcomes, reducing disability and mortality. Mechanical thrombectomy (ET) has revolutionized the treatment of acute ischaemic stroke due to LVO. Multiple randomized controlled trials have established the superiority of ET over medical management for patients presenting in the early window. Mechanical thrombectomy is most effective if performed within 6 h of the onset of symptoms of an ischaemic stroke due to LVO.

However, many patients arrive at the hospital beyond this time window. Approximately 70% of stroke patients in the USA arrive at the emergency department more than 6 h after the onset of symptoms, which places them outside the therapeutic window for mechanical thrombectomy. In a study involving a statewide stroke registry, it was reported that 59% of patients arrived at the hospital after 6 h or with unknown onset times.¹

Another study indicated that 74.7% of patients presented more than 4 h after symptom onset, suggesting that a substantial portion of these individuals exceeded the 6 h mark.

Moreover, in Europe, approximately 30–40% of patients with acute ischaemic stroke present to hospitals more than 6 h after symptom onset, which is generally considered outside the standard therapeutic window for mechanical thrombectomy. This statistic reflects the challenges in timely recognition and response to stroke symptoms among the general population.²

In other studies, it has been reported that up to 20% of all stroke presentations might be classified as late presenters, particularly those with wake-up strokes or unclear symptom onset. This group often exceeds the 6 h threshold for ET eligibility.³

This significant delay in presentation is a critical factor that limits treatment options and can adversely affect patient outcomes.

Here, we will present extended treatment indications that include patients presenting after 6 h from symptom onset based on tissue selection and those with large ischaemic cores without advanced imaging techniques.

Tissue-based selection

Several brain imaging techniques can be utilized to assess the condition and guide treatment decisions in patients presenting to the emergency department with ischaemic stroke more than 6 h after symptom onset. The choice of imaging modality often depends on the clinical scenario, available resources, and specific patient characteristics. For patients presenting late (beyond 6 h), magnetic resonance imaging (MRI) may offer advantages over computed tomography (CT) by providing detailed information about ischaemic tissue and potential salvageable areas. However, CT remains a crucial tool due to its speed and accessibility in emergency settings.⁴

Today, multimodal imaging seems to be the most effective opportunity. Combining different imaging modalities (e.g. CT with perfusion and angiography or MRI with perfusion and angiography) provides comprehensive information about brain tissue viability and vascular status. This approach allows for better patient selection for reperfusion therapies beyond traditional time limits.^4,5

Primary modalities include:

1. CT

   • Non-contrast CT (NCCT) is the most widely used initial imaging method. It is fast and readily accessible and effectively rules out haemorrhagic strokes. However, it might not detect early ischaemic changes for several hours after the event.^4,6

   • CT angiography (CTA) visualizes the blood vessels in the brain and can assist in detecting LVOs. It is typically performed in conjunction with NCCT to give a complete picture of both brain tissue and vascular conditions.

   • CT perfusion (CTP) evaluates cerebral blood flow and can aid in distinguishing between the infarct core and the salvageable brain tissue (penumbra). This is especially valuable for identifying patients who could benefit from reperfusion therapies, even if they fall outside the standard timeframes.^7,8

2. MRI

   • Diffusion-weighted imaging (DWI) is particularly effective in detecting acute ischaemic changes, even in small lesions. It accurately delineates the core infarct volume, which is essential for evaluating tissue viability.

   • Fluid-attenuated inversion recovery (FLAIR) imaging is beneficial for spotting lesions that may not appear on DWI or NCCT, mainly when the onset time is unknown.

   • MR angiography (MRA), like CTA, visualizes blood vessels and is used to evaluate occlusions in the cerebral vasculature.

   • MR perfusion (MRP), similar to CTP, assesses cerebral perfusion and can help identify regions at risk of infarction but still salvageable for treatment.

In summary, both CT and MRI techniques play important roles in managing acute ischaemic stroke patients presenting late after symptom onset. Integrating these imaging modalities enhances diagnostic accuracy and treatment efficacy, ultimately improving patient outcomes.^9–11

Trials with tissue-based selection of late candidates

The DAWN trial (Diffusion-Weighted Imaging or CT Perfusion Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) showed strong evidence supporting ET in the 6–24 h window, while the DEFUSE-3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) provided similar support for the 6–16 h window.

• DAWN trial: Patients with significant mismatch between clinical deficit and infarct volume benefited from thrombectomy, with functional independence at 90 days in 49% of treated patients compared to 13% in the control group.

• DEFUSE-3 trial: Similar results were observed for patients in the 6–16 h window, with functional independence in 45% of patients vs. 17% with medical management alone.

The 2018 American Heart Association guidelines recommend ET with Level 1A evidence for patients in the 6–16 h window who meet the DAWN and/or DEFUSE-3 criteria and Level 2A evidence for patients in the 16–24 h window who meet the DAWN criteria. The DAWN and DEFUSE-3 trials demonstrated significant treatment effects, with numbers needed to treat (NNT) of 2.8 and 3.6, respectively. However, strictly adhering to these selective criteria may exclude patients who could benefit from ET, potentially leading to preventable severe disability.^12,13

Large core ischaemic stroke without advanced imaging

Large core ischaemic stroke indicates extensive brain tissue damage due to insufficient blood flow. Although advanced imaging methods such as MRI and CTP are optimal for accurate diagnosis, large core ischaemic strokes can still be recognized and treated even without advanced imaging techniques.

It is essential to understand that without advanced imaging:

• The exact extent of the core infarct is challenging to ascertain.

• The penumbra (salvageable tissue) cannot be evaluated accurately.

• There is an increased risk of misclassifying the stroke’s size or type.

While advanced imaging offers critical insights, the lack of such technology should not hinder proactive stroke management. Clinical expertise, basic CT scans, and diligent patient monitoring are the foundational elements of stroke care, especially in resource-limited environments.

Imaging perfusion and MRI allow precise identification of salvageable tissue (penumbra) and the infarct core. However, NCCT combined with CTA is increasingly used in settings without advanced imaging access. For instance, the MR CLEAN-LATE trial showed comparable outcomes using NCCT and CTA to select patients for thrombectomy. Recent research supports ET in patients with larger ischaemic cores. Trials such as SELECT2 and ANGEL-ASPECT demonstrate positive outcomes for patients with an Alberta Stroke Program Early CT Score (ASPECTS) of 3–5 or large infarct volumes.¹⁴

A multicentre trial indicated that ET significantly improved functional outcomes in patients with acute ischaemic stroke characterized by LVO and an ASPECTS of 3–5. The study found a notable shift towards better outcomes on the modified Rankin scale at 90 days for those receiving ET compared to standard medical treatment alone, with lower mortality rates observed in the ET group.¹⁵

Another trial highlighted that patients with large ischaemic core volumes (ASPECTS 3–5 or core volume ≥50 mL) benefited from ET within 24 h of symptom onset. Despite some associated vascular complications, this study confirmed that ET led to better functional outcomes than medical therapy alone.¹³

A systematic review and meta-analysis of multiple randomized controlled trials demonstrated a significant treatment effect of ET in patients with an ASPECTS of 0–5. The analysis indicated a pooled odds ratio favouring ET for achieving better functional outcomes at 90 days. This suggests that even patients with larger infarct sizes may benefit from ET, challenging previous assumptions and limiting its use to smaller infarcts.^16,17

The safety profile of ET has also been evaluated, with studies reporting low rates of symptomatic intracranial haemorrhage among patients undergoing the procedure. For instance, in trials where ET was applied, rates of symptomatic haemorrhage were comparable between the ET and medical treatment groups.¹⁸

The accumulating evidence supports the use of ET for patients with large infarct volumes due to ischaemic strokes, especially those with ASPECTS as low as 3. However, the efficacy for very low ASPECTS (0–2) remains uncertain and requires further investigation to optimize patient selection criteria and treatment protocols.

Conclusions and future directions

Recent studies have provided compelling evidence regarding the efficacy and safety of ET in this context, even for patients presenting with established large infarcts.

Challenges and ongoing questions remain when treating patients with large cores and delayed treatment. For instance, determining which patients with extensive ischaemic infarcts will gain the most benefit is important. It is also important to tackle complications such as haemorrhagic transformation, which poses a risk—especially in patients with large infarct cores—necessitating careful monitoring and optimized anticoagulation strategies. Additionally, the ‘no-reflow’ phenomenon, where microvascular reperfusion fails despite successful arterial opening, must be addressed.

Another aspect is that the research about the optimal strategies for managing intracranial atherosclerotic disease (ICAD) is under investigation. Studies like RESCUE BT highlight the need for periprocedural antiplatelet therapy tailored to ICAD-related large vessel occlusions.

The future of ET involves integrating mechanical treatments with new pharmacological advances. However, certain studies indicate that the findings do not endorse the use of intravenous tirofiban prior to endovascular thrombectomy in cases of acute ischaemic stroke.¹⁹ Instead, alirocumab 150 mg Q4W can be considered in patients not on statins with inadequately controlled hypercholesterolaemia as a convenient option for lowering LDL cholesterol.²⁰ Additionally, the CHOICE II study evaluates the advantages of intra-arterial thrombolysis post-thrombectomy in improving patient outcomes.

In conclusion, mechanical thrombectomy has emerged as a key treatment for severe strokes. However, determining which patients with significant ischaemic infarcts benefit most from ET remains an unresolved issue. Ongoing research aims to refine patient selection and enhance outcomes further.

Funding

No funding provided.

Data availability

No new data were generated or analysed in support of this research.

Disclaimer

This paper was originally published in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2025” by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper is republished with permission.

References

Author notes