A narrative review of reperfusion therapy in acute ischemic stroke: Emerging advances, current challenges, and future directions

Abstract

Significant advancements over the past decade have transformed reperfusion therapy for acute ischemic stroke. Standard treatments, including intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), offer distinct benefits, with recent innovations expanding their efficacy and applicability. IVT, previously limited by a narrow therapeutic window, has seen enhancement with alternative agents such as tenecteplase, which may deliver comparable or superior outcomes to alteplase in selected cases. Expanding indications for EVT, particularly for large vessel occlusions and in extended time windows, have demonstrated promising results, underscoring its effectiveness beyond conventional time constraints. Recent trials further support the use of EVT for patients with large infarct cores in the anterior circulations, although mortality outcomes remain sensitive to treatment timing. In addition, mobile stroke units (MSUs) and prehospital management strategies have emerged as critical components for minimizing delays and improving clinical outcomes. Future research should focus on optimizing reperfusion therapies to individual patient profiles, investigating neuroprotective adjuncts, and expanding the global availability of MSUs to facilitate timely, accessible stroke care.

Introduction

Ischemic stroke, a sudden disruption of brain function, ranks among the top causes of disability and mortality globally.[1] It involves the ischemic penumbra, a region of brain tissue around the infarct that has the potential to be saved.[2] Timely intervention is critical for preserving the penumbra in acute ischemic stroke patients undergoing reperfusion therapy. Available reperfusion methods include intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), both vital for managing AIS caused by arterial occlusion [Figure 1]. Approved in 1995, IVT remains the standard therapy for AIS, although it is constrained by a short therapeutic window, numerous contraindications, and a modest recanalization success rate.[3] EVT, on the other hand, has gained prominence as a particularly effective option for patients with emergent large vessel occlusions (LVOs).

Figure 1.

Acute management flowchart of ischemic stroke. ^†If IVT is contraindicated, EVT should be the sole procedure performed. AIS: Acute ischemic stroke, CT: Computed tomography, MRI: Magnetic resonance imaging, ICH: Intracranial hemorrhage, IVT: Intravenous thrombolysis, EVT: Endovascular thrombectomy, RCT: Randomized controlled trial

Emerging evidence suggests that combining IVT with EVT, known as bridging therapy, may yield superior outcomes compared to EVT alone.[4,5] In addition, adjunctive therapies, such as tirofiban before EVT, have shown improved outcomes in specific patient populations.[6] Despite expanding reperfusion indications, many AIS patients – particularly those with posterior circulation strokes – remain ineligible due to narrow treatment windows (IVT: within 9 h; EVT: within 24 h from symptom onset) or large ischemic core size. Further research is urgently needed to enhance outcomes for these patients.

This review explores the current state of reperfusion therapy for AIS in prehospital and in-hospital settings, highlights recent advancements, and discusses future perspectives.

Updates on Intravenous Thrombolysis

The ARAMIS trial recently indicated that for patients with minor, nondisabling AIS who presented within 4.5 h of symptom onset, dual antiplatelet therapy was as effective as IVT with alteplase in achieving 90-day excellent functional outcomes.[7] However, a pooled analysis from multiple randomized controlled trials (RCTs) confirms that IVT with alteplase remains an effective reperfusion therapy for AIS patients, regardless of stroke severity.[8] Consequently, most international stroke guidelines recommend IVT with alteplase within 4.5 h from symptom onset, provided brain imaging confirms the absence of intracranial hemorrhage.[9,10] Alteplase, a second-generation tissue plasminogen activator, has shown enhanced 3-month functional outcomes in AIS patients compared to placebo within a defined time window.[11,12]

Recently, neuroimaging-based brain tissue assessment using techniques like MRI and CT perfusion has gained attention, enabling the evaluation of tissue viability beyond conventional time constraints.[13] Given limitations in alteplase accessibility and cost, alternative thrombolytics like tenecteplase are being explored.[14,15,16,17,18,19,20,21,22,23,24,25] Prehospital management strategies aimed at reducing onset-to-treatment time (OTT) are also under investigation to expedite IVT, as timely intervention remains crucial for optimal outcomes.[26]

Prehospital Management

A meta-analysis of nine RCTs emphasizes that early alteplase administration within 4.5 h significantly increases the likelihood of an excellent functional recovery, reinforcing the concept of “time is brain.”[8,27] Mobile stroke units (MSUs) integrated with CT scanners have shown promise in the prehospital setting, enabling thrombolysis administration before hospital arrival. Studies have shown that MSUs reduce OTT by approximately 30 min, increase thrombolysis rates, and improve prehospital triage.[28,29] A prospective, nonrandomized study in Berlin involving 1,543 patients found that deploying MSUs with standard ambulances lowered global disability at 3 months with common odds ratio (OR) for worse mRS at 0.71 (95% confidential interval [CI]: 0.58–0.86; P < 0.001), compared to standard ambulances alone.[30] Another study demonstrated that MSU dispatch improved 3-month functional outcomes across all stroke types, benefiting even those were ineligible for reperfusion therapies.[31] These findings support broader MSU implementation, potentially enhanced by modern communication technologies like 5G, to improve global stroke outcomes.[32]

Despite the advantages of MSUs, their cost can be prohibitive, particularly in developing regions.[33] In resource-limited settings, early AIS identification could enable more timely and informed treatment decisions. Advances in artificial intelligence, telemedicine, and portable imaging technology may replicate some MSU benefits on standard ambulances, especially in underserved areas.[34] In addition, pooled data from two cohort studies evaluating eight prehospital LVO detection scales highlight the utility of tools like the Rapid Arterial Occlusion Evaluation (RACE) scale in optimizing transport decisions for suspected stroke patients, both men and women.[35] Further studies are needed to assess whether implementing these scales in regional transport strategies can improve AIS patient outcomes.

Tenecteplase versus Alteplase

Tenecteplase, a third-generation thrombolytic agent, exhibits superior fibrin specificity and an extended half-life compared to alteplase, offering practical advantages. Unlike alteplase, which requires a 1-h infusion, tenecteplase is delivered as a single bolus over 5–10 s, simplifying administration.[36] Approved for treating ST-segment-elevation myocardial infarction in situations where timely coronary intervention is impractical,[37] tenecteplase has demonstrated similar efficacy to alteplase while offering a reduced risk of systemic bleeding.[38,39] Over the past decade, eleven RCTs have assessed the relative efficacy and safety of tenecteplase compared to alteplase in AIS patients treated within 4.5 h of symptom onset [Table 1].

Table 1.

Randomized trials of intravenous thrombolysis with tenecteplase to alteplase for acute ischemic stroke during the past decade

Study acronym; year published	Trial design	Participants randomized (n)	Time window (h)	NHISS required	Imaging selection	Tenecteplase dose (mg/kg)	Primary outcome	Result	mRS 0–1 of tenecteplase versus alteplase at 90 days
ATTEST; 2015[14]	Phase 2, PROBE	104	0–4.5	1–25	Noncontrast CT, CT perfusion, and CTA	0.25	Percentage of penumbra salvaged at 24–48 h	Mean difference (95% CI): 1.3% (−9.6–12.1)	28% versus 20%
NOR-TEST; 2017[15]	Phase 3, PROBE	1100	0–4.5	≥1	Noncontrast CT, CTA, and brain MRI	0.4	mRS 0–1 at 90 days (superiority)	OR (95% CI): 1.08 (0.84–1.38)	64% versus 63%
EXTEND-IA TNK, part 1; 2018[16]	Phase 2, PROBE	202	0–4.5	No limited	Noncontrast CT, CTA, and partially CT perfusion	0.25	Reperfusion>50% of the involved ischemic territory or absence of retrievable thrombus at the time of the initial angiographic assessment	Adjusted OR (95%CI): 2.6 (1.1–5.9)	49% versus 41%
TRACE; 2021[17]	Phase 2, PROBE	240	0–3	4–25	Noncontrast CT	0.1, 0.25, or 0.32	sICH within 36h	5.0%, 0%, 3.3% versus 1.7%	55%, 63.6%, 62.1% versus 59.3%
AcT; 2022[18]	Phase 3, PROBE	1600	0–4.5	Disabling neurologic deficit	Noncontrast CT and CTA	0.25	mRS 0–1 at 90–120 days (noninferiority)	Unadjusted difference in proportion (95% CI): 2.1% (−2.6–6.9)	36.9% versus 34.8%
TASTE-A; 2022[19]	Phase 2, PROBE	104	0–4.5	No limited	Noncontrast CT and CTA	0.25	Perfusion lesion volume on arrival at hospital	Adjusted incidence rate ratio (95% CI): 0.55 (0.37–0.81)	42% versus 41%
NOR-TEST 2, part A; 2022[20]	Phase 3, PROBE	216	0–4.5	>5	Noncontrast CT and brain MRI	0.4	mRS 0–1 at 90 days (noninferiority)	Unadjusted OR (95% CI): 0.45 (0.25–0.80)	32% versus 51%
TRACE-2; 2023[21]	Phase 3, PROBE	1430	0–4.5	5–25	Noncontrast CT and brain MRI	0.25	mRS 0–1 at 90 days (noninferiority)	RR (95% CI): 1.07 (0.98–1.16)	62% versus 58%
TASTE; 2024[22]	Phase 3, PROBE	680	0–4.5	No limited	CT and CT perfusion	0.25	mRS 0–1 at 90 days (noninferiority)	Standardized risk difference (95% CI): 0.03 (−0.033–0.10)	57% versus 55%
ORIGINAL; 2024[23]	Phase 3, PROBE	1489	0–4.5	1–25	Noncontrast CT	0.25	mRS 0–1 at 90 days (noninferiority)	RR (95% CI): 1.03 (0.97–1.09)	72.7% versus 70.3%
ATTEST-2; 2024[40]	Phase 3, PROBE	1777	0–4.5	No limited	Noncontrast CT	0.25	Distribution of the day 90 mRS score (noninferiority)	Adjusted OR (95%CI): 1.07 (0.90–1.27)	44% versus 42%

CT: Computed tomography, CTA: CT angiography, NHISS: National Institutes of Health Stroke Scale, mRS: Modified Rankin Scale, PROBE: Prospective, randomized, open-label, blinded end-point, OR: Odds ratio, CI: Confidential interval, RR: Risk ratio, sICH: Symptomatic intracranial hemorrhage, MRI: Magnetic resonance imaging

Several phase 2 and phase 3 RCTs have explored optimal tenecteplase dosages in AIS. The NOR-TEST trial found tenecteplase at 0.4 mg/kg comparable in efficacy and safety to the standard alteplase dose (0.9 mg/kg), though the population had a high prevalence of minor strokes.[15] However, the NOR-TEST 2 trial did not confirm the noninferiority of tenecteplase at 0.4 mg/kg in patients with moderate or severe ischemic stroke when compared to alteplase at 0.9 mg/kg, leading to trial termination due to safety concerns, as patients receiving tenecteplase at 0.4 mg/kg experienced a significantly elevated risk of intracranial hemorrhage (21% vs. 7%; OR: 3.68, 95% CI: 1.49–9.11).[20] Combined analysis of NOR-TEST and NOR-TEST 2 highlighted that the 0.4 mg/kg dose of tenecteplase is unsuitable for moderate-to-severe strokes due to higher mortality and intracranial hemorrhage risks, which escalate with stroke severity.[41]

Another phase 2 trial, TRACE, examined tenecteplase doses ranging from 0.1 to 0.32 mg/kg in Chinese AIS patients, showing no major efficacy or safety differences across doses, with 0.25 mg/kg yielding the best outcomes (63.6% achieving mRS ≤1).[17] The EXTEND-IA TNK Part 2 trial found no improvement in reperfusion or clinical outcomes with tenecteplase at 0.4 mg/kg over 0.25 mg/kg, supporting 0.25 mg/kg as the optimal dose for AIS treatment.[42] Differences in trial design and patient characteristics may contribute to inconsistent findings.

RCTs comparing tenecteplase (0.25 mg/kg) versus alteplase (0.9 mg/kg) in AIS have been published over the past decade. The TASTE trial demonstrated tenecteplase was noninferior to alteplase in the perprotocol analysis; however, this was not confirmed in the intention-to-treat analysis. A meta-analysis incorporating TASTE and other RCT data indicated tenecteplase’s superiority over alteplase with a risk difference of 0.04 (95% CI: 0.01–0.06) and a number-needed-to-treat of 25 to prevent one additional case of disability (mRS 0–1) at 90 days.[22] The ORIGINAL and ATTEST-2 trials confirmed tenecteplase’s non-inferiority in achieving favorable 90-day outcomes with similar safety profiles in Chinese and UK AIS patients within 4.5 h of onset.[23,40] Recently, a meta-analysis pooling data from 11 RCTs with over 7,500 AIS patients found tenecteplase (0.25 mg/kg) associated with higher rates of excellent functional outcomes compared to alteplase, with a risk ratio of 1.05 (95% CI: 1.01–0.10, P = 0.012).[43] These findings support tenecteplase as a superior option to alteplase for selected patients within 4.5 h of symptoms onset. Future meta-analyses using individual patient data from RCTs could offer more robust evidence on tenecteplase’s safety and efficacy in AIS.

Intravenous Thrombolysis in Extended Time Windows

Following a stroke, the infarct core typically expands over time, though the rate of expansion varies among individuals. Recent research has shifted focus from solely considering onset time to incorporating advanced neuroimaging techniques, such as MRI and perfusion imaging (CT or MRI), to assess brain tissue changes. Accurate evaluation of brain tissue condition in initial scans is essential for identifying AIS patients who might benefit from IVT beyond the standard 4.5-h window.[44]

The 2018 WAKE-UP trial demonstrated that MRI-guided alteplase IVT significantly improved outcomes in AIS patients with uncertain or wake-up stroke onset, based on MRI patterns indicating the stroke likely occurred within the prior 4.5 h.[13] Building on these findings, the EXTEND trial extended the use of alteplase to AIS patients within 9 h of symptom onset, or those presenting with wake-up stroke, provided perfusion imaging showed salvageable tissue.[45] A combined analysis of the EXTEND and EPITHET trials validated that reperfusion therapy offered substantial benefits across all time windows without raising the risk of symptomatic hemorrhage, supporting the efficacy of alteplase for patients with perfusion mismatch within the 4.5–9-h treatment window, including wake-up strokes.[46]

The TIWST trial, which investigated ischemic wake-up stroke patients using non-contrast CT within 4.5 h of symptom discovery, found that tenecteplase did not offer significant benefits over standard care. This suggests that noncontrast CT may be suboptimal for identifying IVT candidates in wake-up strokes.[47]

Recent RCTs have investigated tenecteplase use in AIS patients with LVO and significant penumbral mismatch within an extended time window (4.5–24 h). The phase IIa CHABLIS-T trial found promising reperfusion rates with a lower dose of tenecteplase (0.25 mg/kg), which demonstrated slightly better safety and efficacy compared to the 0.32 mg/kg dose. These findings endorse the potential of tenecteplase as a treatment option in extended timeframes when guided by perfusion imaging.[48] However, the TIMELESS trial, in which 77% of patients received EVT, found no significant functional outcome benefit of tenecteplase over placebo in this extended window, despite higher recanalization rates. This suggests that the benefit of tenecteplase may be limited when combined with thrombectomy, especially for patients who present later.[49]

In contrast, the TRACE-III trial, which included AIS patients with LVO who did not have access to thrombectomy, found tenecteplase to be effective but associated with a higher risk of symptomatic intracranial hemorrhage (sICH). This supports the use of tenecteplase in extended time windows, provided that appropriate imaging is used for patient selection.[50]

While these results are mixed, ongoing trials such as EXIT-BT2 (NCT06010628) and EXTEND-IV (NCT05199662) are expected to clarify the role of tenecteplase in extended treatment windows. A future pooled meta-analysis of relevant RCTs rigorously evaluating tenecteplase in extended-time-window AIS patients is warranted to provide clearer guidance on its use.

Current Status of Endovascular Thrombectomy

In 2015, five RCTs demonstrated that EVT within 6 h of last known well (LKW) using advanced devices and optimized workflows significantly reduced disability in AIS patients with proximal LVO in the anterior circulation and small infarct cores [Table 2].[51,52,53,54,55] The HERMES meta-analysis, which included data from these five RCTs, confirmed EVT’s benefit for large-vessel AIS, showing efficacy across various patients’ subgroups, including differences in age, baseline stroke severity, and prior IVT administration.[71] In 2018, the DAWN and DEFUSE3 trials further extended EVT’s efficacy to patients 6–24 h from LKW, contingent upon CT or MRI perfusion imaging to confirm salvageable brain tissue.[57,58] A pooled analysis of six RCTs (AURORA) showed that EVT resulted in higher functional independence (mRS 0–2) compared to best medical therapy (BMT) alone (45.9% vs. 19.3%; P < 0.0001), with similar safety profiles.[72] The MR CLEAN-LATE trial confirmed EVT benefits in anterior circulation LVO AIS patients presenting 6–24 h from symptom onset, with selection criteria based on collateral flow on CTA, excluding patients meeting DAWN or DEFUSE3 criteria for immediate EVT.[60] These findings emphasize EVT’s critical role in managing reversible cerebral ischemia within 6–24 h.

Table 2.

Randomized trials of endovascular treatment versus best medical treatment alone for acute ischemic stroke with large vessel occlusion during the past decade

Study acronym; year published	Trial design	Participants randomized (n)	Time window (h)	NHISS required	Imaging selection	Primary outcome	Result	mRS 0–3 of EVT versus BMT at 90 days	Mortality of EVT versus BMT at 90 days
Proximal LVO in the anterior circulation and small infarct cores
MR CLEAN; 2015[53]	Phase 3, PROBE	500	0–6	≥2	Noncontrast CT and CTA/MRA/DSA	Ordinal mRS at 90 days	Adjusted common OR (95% CI): 1.67 (1.21–2.30)	51.1% versus 35.6%	21% versus 22%
ESCAPE; 2015[51]	Phase 3, PROBE	316	0–12	>5	Noncontrast CT and CTA	Ordinal mRS at 90 days	Adjusted common OR (95% CI): 3.1 (2.0–4.7)	70% versus 44%	10.4% versus 19.0%
EXTEND-IA; 2015[52]	Phase 2, PROBE	70	0–6	No limited	Noncontrast CT/MRI, CTA/MRA, and significant CT or MR mismatch	Reperfusion at 24 h and early neurologic improvement at 3 days	Adjusted OR (95% CI): 4.7 (2.5–9.0) and 6.0 (2.0–18.0)	89% versus 50%	9% versus 20%
REVASCAT; 2015[54]	Phase 3, PROBE	206	0–8	≥6	Noncontrast CT/MRI/CTP and CTA/MRA/DSA	Ordinal mRS at 90 days	Adjusted OR (95% CI): 1.7 (1.05–2.8)	62.1% versus 47.5%	18.4% versus 15.5%
SWIFT PRIME; 2015[55]	Phase 3, PROBE	196	0–6	8–29	Noncontrast CT/MRI and CTA/MRA	Ordinal mRS at 90 days	Median score (IQR): 2 (1–4) versus 3 (2–5), P<0.001	72% versus 53%	9% versus 12%
PISTE; 2017[56]	PROBE	65	0–5.5	≥6	Noncontrast CT and CTA/MRA	mRS 0–2 at 90 days	Adjusted OR (95% CI): 2.12 (0.65–6.94)	63.6% versus 63.3%	21.2% versus 13.3%
DAWN; 2018[57]	Phase 2/3, PROBE	206	6–24	≥10	Noncontrast CT/MRI, CTP and CTA/MRA	Utility-weighted mRS at 90 days	Adjusted difference (95% CI): 2.0 (1.1–3.0)	61% versus 29%	19% versus 18%
DEFUSE3; 2018[58]	Phase 3, PROBE	182	6–16	≥6	Noncontrast CT/MRI, and CTP/CTA or MR DWI/PWI/MRA	Ordinal mRS at 90 days	OR (95% CI): 2.77 (1.63–4.70)	59% versus 32%	14% versus 26%
RESILIENT; 2020[59]	Phase 3, PROBE	221	0–8	≥8	Noncontrast CT and CTA	Ordinal mRS at 90 days	Adjusted OR (95% CI): 2.28 (1.41–3.69)	57% versus 36%	24.3% versus 30.0%
MR CLEAN LATE; 2023[60]	Phase 3, PROBE	502	6–24	≥2	Noncontrast CT/MRI and CTA/MRA/	Ordinal mRS at 90 days	Adjusted common OR (95% CI): 1.67 (1.20–2.32)	51% versus 42%	24% versus 30%
Proximal LVO in the anterior circulation and large infarct cores
RESCUE-Japan LIMIT; 2022[61]	PROBE	203	0–24	≥6	Noncontrast CT/CTA/CTP or MRI (mainly)/MRA	mRS 0–3 at 90 days	Relative risk (95% CI): 2.43 (1.35–4.37)	31.0% versus 12.7%	18.0% versus 23.5%
SELECT2; 2023[62]	Phase 3, PROBE	352	0–24	≥6	Noncontrast CT, CTA/MRA and CTP/perfusion-diffusion MRI	Ordinal mRS at 90 days	Generalized OR (95% CI): 1.51 (1.20–1.89)	37.9% versus 18.7%	38.4% versus 41.5%
ANGEL-ASPECT; 2023[63]	PROBE	456	0–24	6–30	Noncontrast CT, CTA/MRA and CTP/MRI	Ordinal mRS at 90 days	Generalized OR (95% CI): 1.37 (1.11–1.69)	47.0% versus 33.3%	21.7% versus 20.0%
TENSION; 2023[64]	PROBE	253	0–12	<26	Noncontrast CT (mainly)/MRI and CTA/MRA	Ordinal mRS at 90 days	Adjusted common OR (95% CI): 2.58 (1.60–4.15)	31% versus 13%	40% versus 51%
LASTE; 2024[65]	PROBE	324	0–6.5	No limited	Noncontrast CT/MRI and CTA/MRA	Ordinal mRS at 90 days	Generalized OR (95% CI): 1.63 (1.29–2.06)	33.5% versus 12.2%	36.1% versus 55.5%
TESLA; 2024[66]	Phase 3, PROBE	300	0–24	≥6	Noncontrast CT and CTA	Utility-weighted mRS at 90 days	Absolute risk difference (95% CI): 0.63 (−0.09–1.34)	29.8% versus 19.9%	35.3% versus 33.3%
BAO with small infarct cores
BEST; 2020[67]	PROBE	131	0–8	No limited	Noncontrast CT/MRI and CTA/MRA/DSA	mRS 0–3 at 90 days	Adjusted OR (95% CI): 1.74 (0.81–3.74)	42% versus 32%	33% versus 38%
BASICS; 2021[68]	PROBE	300	0–6	≥10	Noncontrast CT/MRI and CTA/MRA	mRS 0–3 at 90 days	Risk ratio (95% CI): 1.18 (0.92–1.50)	44.2% versus 37.7%	38.3% versus 43.2%
ATTENTION; 2022[69]	PROBE	340	0–12	≥10	Noncontrast CT/MRI and CTA/MRA/DSA	mRS 0–3 at 90 days	Adjusted rate ratio (95% CI): 2.06 (1.46–2.91)	46% versus 23%	37% versus 55%
BAOCHE; 2022[70]	PROBE	217	6–24	≥6	Noncontrast CT/MRI and CTA/MRA/DSA	mRS 0–3 at 90 days	Adjusted rate ratio (95% CI): 1.81 (1.26–2.60)	46% versus 24%	31% versus 42%

BMT: Best medical treatment, CT: Computed tomography, CTA: CT angiography, CTP: CT perfusion, CI: Confidential interval, DSA: Digital subtraction angiography, EVT: Endovascular treatment, IQR: Interquartile range, mRS: Modified Rankin Scale, MRA: MR angiography, NHISS: National Institutes of Health Stroke Scale, OR: Odds ratio, PROBE: Prospective, randomized, open-label, blinded end-point, BAO: Basilar artery occlusion, LVO: Large vessel occlusion, DWI: Diffusion-weighted imaging, PWI: Perfusion-weighted imaging, MRI: Magnetic resonance imaging

For posterior circulation LVO, a condition with high rates of morbidity and mortality, remains particularly challenging. The ATTENTION and BAOCHE trials demonstrated that EVT significantly improved 90-day outcomes in basilar artery occlusion (BAO) within 12 h or the 6–24 h window, despite a higher risk of sICH.[66,67] However, the question of whether EVT alone or in combination with IVT (“bridge therapy”) is superior for LVO-related AIS remains unresolved and warrants further investigation.

Prehospital Management

The HERMES Collaborators analyzed the public health and economic impact of EVT delays for AIS patients, finding that each delay reduces quality-adjusted life years and diminishes the economic value of care provided through EVT.[73] Reducing time delays remains an essential goal. Conventionally, two main strategies provide IVT and EVT access in rural areas: the “drip-and-ship” (DnS) and “mothership” (MS) models. Trials such as RACECAT and TRIAGE-STROKE reported no significant differences in overall functional outcomes between these strategies for rural patients.[74,75] Recently, Henningsen et al. reported that a “parallel dispatch” strategy-simultaneously deploying ground ambulance and helicopter-significantly reduced time to IVT and EVT compared to the DnS and MS models.[76] While this approach offers a more efficient method for rural stroke treatment, it relies on helicopter availability, which can be limited by weather, night-flying capability, and higher costs.

Several prehospital triage tools, such as ACT-FAST, assist paramedics in quickly identifying suspected LVO strokes requiring EVT.[77,78] Studies have demonstrated that ACT-FAST can reduce EVT time by approximately 52 min, improving outcomes by avoiding delays from secondary hospital transfers. However, its primary limitation is a tendency toward false positives, potentially resulting in over-triage and unnecessary bypassing of comprehensive stroke centers (CSCs).[77] Another tool, the Stockholm Stroke Triage System (SSTS), combines severity assessment (moderate-to-severe hemiparesis) with teleconsultation between paramedics and a stroke specialist to decide whether patients should bypass primary stroke centers (PSC) and go directly to a CSC determine if a patient should bypass a local PSC and go directly to a CSC. SSTS reduced onset-to-puncture time by 69 min while maintaining timely IVT administration, improving patient outcomes.[78] The proportion of patients achieving a 3-month mRS score of 0–1 increased from 23.7% to 34.6%, and median NIHSS improvement at 24 h post-EVT increased from 4 to 6 points.[79] However, SSTS has limitations, including potential strain on CSC resources due to PSC bypass and slightly longer in-hospital workflows, as well as unexamined impacts on patients who respond well to IVT before EVT.

Safety and Efficacy of Tirofiban Used with Endovascular Thrombectomy

Although EVT restores blood flow in over 80% of cases, fewer than half of these patients achieve a favorable prognosis, posing a significant clinical challenge. Tirofiban, a platelet glycoprotein IIb/IIIa receptor inhibitor, may help prevent thrombus formation by blocking platelet aggregation. Its advantages include high receptor affinity, reversible inhibition, and a short half-life.[80] Observational studies suggest that combining tirofiban with EVT may improve vessel recanalization rates and functional outcomes without a corresponding increase in sICH rates among AIS patients.[81,82,83,84] However, the RESCUE BT trial shown no meaningful differences in 90-day functional outcomes between tirofiban and placebo groups, nor did tirofiban reduce reocclusion or improve substantial reperfusion rates, suggesting limited efficacy in AIS of the anterior circulation.[85] Post hoc analysis of the RESCUE BT trial indicated that tirofiban improved functional independence in patients with large artery atherosclerosis and normal renal function. However, in patients with renal insufficiency, the benefits were reduced, and tirofiban significantly increased the risk of sICH in cardioembolic strokes.[86]

A combined analysis of the DEVT and RESCUE BT trials found that tirofiban had functional outcomes and safety comparable to alteplase, with higher reperfusion rates and shorter procedure times, but no significant reduction in 90-day disability.[87] While tirofiban may offer clinical benefits for some AIS patient groups, its effectiveness varies, underscoring the importance of selecting the appropriate dosage and treatment strategy and assessing bleeding risks. Ongoing RCTs (NCT06265051 and NCT05225961) are expected to provide further evidence on this issue.

Endovascular Thrombectomy in Acute Ischemic Stroke with a Large Core

Early RCTs of EVT in AIS excluded patients presenting with LVO and large core infarcts, generally indicated by an Alberta Stroke Program Early CT Scores (ASPECTS) below 6. Recently, six RCTs – RESCUE-Japan-LIMIT, SELECT2, TESLA, ANGEL-ASPECT, TENSION, and LASTE) – examined the safety and efficacy of EVT in this group, specifically in anterior circulation strokes within 24 h of symptom onset. Five of these trials showed significant clinical benefit, with only one trial yielding results that were nearly statistically significant [Table 2].[61,62,63,64,65,66] A meta-analysis of these RCTs revealed that EVT was superior to medical management in terms of enhancing functional outcomes and lowering 90-day mortality in large core infarct patients, especially those with ASPECTS of 3–5 and LVO in critical arteries such as the intracranial internal carotid artery terminus or proximal middle cerebral artery. Recent 1-year follow-up results from SELECT 2 and TENSION further confirmed that EVT’s benefits in survival and functional outcomes are sustained.[88,89] EVT was most effective within 6 h of stroke onset; its benefit decreased when performed beyond 6 h, especially in trials with extended treatment windows. While EVT generally improved functional outcomes, mortality benefits varied, with earlier interventions (e.g., in RESCUE-Japan-LIMIT and TENSION) showing better mortality outcomes.[90] Another meta-analysis pooling data from SELECT2 and ANGEL-ASPECT, involving 82 patients, showed that EVT might still be beneficial for patients with extremely low ASPECTS scores (0–2), though more trials are needed for confirmation.[91]

Observational data from the BASILAR registry in China evaluated EVT versus BMT for patients with BAO and large core infarcts. The study found that EVT improved functional outcomes and decreased mortality in patients with posterior circulation ASPECTS (pc-ASPECTS) scores of ≥5. However, for patients with pc-ASPECTS scores between 0 and 4, outcomes were poor regardless of treatment.[92] Another observational study in Korea showed EVT benefited acute BAO patients with pc-ASPECTS scores ≤6, advocating its consideration in cases with extensive ischemic involvement.[93] Prospective RCTs are needed to refine EVT guidelines for posterior circulation strokes.

Endovascular Thrombectomy in Acute Ischemic Stroke Beyond the Standard Time Window

A post hoc analysis of the DEFUSE 3 trial suggested that some patients with LVO might still exhibit salvageable brain tissue even more than 24 h from their LKW. These “slow progressors,” whose outcomes are shaped by factors such as collateral blood flow and stroke severity, might benefit from EVT even outside the conventional time window.[94] A recent meta-analysis of retrospective studies supports EVT as a viable option for selected AIS patients treated more than 24 h postonset.[95] Another systematic review comparing EVT to BMT for strokes treated beyond 24 h found that EVT significantly improved functional independence (34.6% of EVT patients vs. 15.9% in BMT patients) and lower mortality (24.5% vs. 33.1%).[96] Shifting from a “time clock” to a “tissue clock” approach in patient selection may allow EVT beyond 24 h in certain patients (e.g., NIHSS ≥6, high ASPECTS, favorable imaging profiles).[97,98,99] Prospective studies are essential to validate these criteria and optimize selection based on tissue viability.

Perspectives on Optimizing Stroke Treatment Approaches

Optimal thrombolytic methods

IVT within 4.5 h remains the primary treatment for AIS. While alteplase is the standard, other agents such as tenecteplase, reteplase, nonimmunogenic staphylokinase, and recombinant human prourokinase show promise within this window. Tenecteplase at a dose of 0.25 mg/kg, for example, has demonstrated similar safety to alteplase with better outcomes.[43] The RAISE trial found reteplase to be effective in patients with NIHSS scores of 4–25, showing superior outcomes compared to alteplase without elevating the risk of intracranial hemorrhage.[24] In Russia, the FRIDA trial found that nonimmunogenic staphylokinase was safe and easier to administer.[100] Similarly, recombinant human prourokinase showed comparable efficacy and safety to alteplase in the phase 3 PROST trial.[25] Additional researches are required to evaluate each agent’s safety and efficacy across various patient populations.

Expanding eligibility for endovascular thrombectomy in large vessel occlusion

Although numerous RCTs have explored EVT for AIS with LVO, current trials have limited eligibility to patients treated within 24 h. The ongoing LATE-MT (NCT05326932) and BAOCHE-2 (NCT06560203) trials in China aim to assess EVT efficacy in the extended 24–72 h window for anterior circulation LVO and BAO, respectively. Moreover, evidence on EVT benefits for patients typically excluded from trials (e.g., those with pre-existing disabilities, NIHSS scores under 6, and elderly patients) remains limited. Studies have shown EVT to be safe for elderly patients, with favorable outcomes, particularly with modified approaches such as thromboaspiration over stent retrievers.[101,102] Tailoring EVT protocols to factors like age, premorbid function, and specific EVT techniques may improve outcomes in these populations.[103] Further trials focused on these groups are needed to broaden EVT indications for AIS patients with LVO.

Reperfusion Strategies with Neuroprotection

Despite the benefits of IVT and EVT, many AIS patients, especially those with BAO or large core infarcts, continue to have poor outcomes, underscoring the need for adjunctive neuroprotection strategies. Nonpharmacological approaches like normobaric hyperoxia (NBO), remote ischemic conditioning (RIC), and hypothermic neuroprotection may enhance brain protection and reduce treatment complications. NBO, for instance, shows promise in AIS patients through enhanced oxygen supply to the penumbra and blood–brain barrier protection.[104,105,106,107,108,109,110,111] However, RIC, though low-cost and noninvasive, showed mixed efficacy in AIS, with a recent meta-analysis suggesting secondary prevention benefits but little impact on functional outcomes.[112] Hypothermic neuroprotection may benefit selected AIS patients with malignant stroke traits (e.g., large infarct size, ASPECTS <6).[113] Further, RCTs are needed to determine optimal cooling techniques and timing for maximizing neuroprotection.

Conclusion and Future Directions

Advances in AIS reperfusion therapy have broadened treatment options, with EVT and alternative thrombolytics offering improved outcomes for many patients. Imaging-based selection criteria are shifting focus from rigid time limits to tissue viability, potentially expanding treatment windows. Future research should prioritize refining patient selection, developing neuroprotective adjuncts, and exploring prehospital innovations, such as MSUs, to improve care access. Expanding EVT indications for patients with large core infarcts or posterior circulation strokes could benefit a larger patient population. Prospective studies are essential to validate the safety and efficacy of these evolving approaches and establish protocols that enhance functional outcomes while minimizing risks.

Author contributions

Chuanhui Li, Qiuting Wang, and Na Liu contributed to the study design and concept. Qiuting Wang drafted the manuscript. Na Liu, Leticia Simo, and Qingfeng Ma critically revised the manuscript. All authors have 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.

Conflicts of interest

Dr. Chuanhui Li is an Editorial Board member of Brain Circulation. The article was subject to the journal’s standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

Funding Statement

This study was funded by Beijing Hospitals Authority Youth Programme (NO. QML20230805), The Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (NO. 2023-JKCS-08), National Natural Science Foundation of China (NO. 82171278), and Capital’s Funds for Health Improvement and Research (NO. 2024-2-2017).