RESCUE-Japan LIMIT Trial: Endovascular Therapy for Acute Stroke with a Large Ischemic Region
In patients with acute ischemic stroke and a large ischemic region (ASPECTS 3–5) within 24 hours of onset, does endovascular therapy plus medical care improve 90-day functional outcome compared with medical care alone? This is the index trial that opened large-core EVT as a treatable population.
Yoshimura S et al. (NEJM 2022;386:1303-1313) · doi:10.1056/NEJMoa2118191 · 203 patients
Population
Included
- Age 18 years or older
- NIHSS at admission of 6 or greater
- Pre-stroke modified Rankin scale 0 or 1
- Occlusion of internal carotid artery or M1 segment of MCA on CTA or MRA
- ASPECTS 3 to 5 by CT or DWI-MRI
- Randomization within 6 hours of LKW, or 6 to 24 hours with no signal change on FLAIR (indicating recent infarction)
- Endovascular therapy could be initiated within 60 minutes of randomization
- Acute ischemic stroke
- Age 18 years or older
- A score of at least 6 on the National Institutes of Health Stroke Scale (NIHSS) at admission (scores range from 0 to 42, with higher scores indicating greater neurologic deficit)
- A score of 0 or 1 on the modified Rankin scale before the onset of stroke (scores range from 0 to 6, with 0 indicating no disability and 6 death)
- An occlusion of the internal carotid artery or M1 segment of the middle cerebral artery on computed tomographic angiography (CTA) or magnetic resonance angiography (MRA)
- An Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) value of 3 to 5, as determined with the use of computed tomography (CT) or diffusion-weighted magnetic resonance imaging (MRI)
- Randomization within 6 hours after the time the patient was last known to be well, or within 6 to 24 hours after the time the patient was last known to be well and there was no signal change in the initial image on fluid-attenuated inversion recovery (FLAIR) indicating that the infarction was recent
- Endovascular therapy could be initiated within 60 minutes after randomization
Excluded
- ASPECTS 0 to 2 (extensive infarction, unlikely to regain independence)
- Clinically significant cerebral mass effect with midline shift
- Acute intracranial hemorrhage on CT or MRI
- Investigator-judged high risk of hemorrhage
- A clinically significant cerebral mass effect with midline shift
- An acute intracranial hemorrhage on CT or MRI
- Site investigators considered that there was a high risk of hemorrhage
- Patients with an ASPECTS value of 2 or lower were not evaluated (extensive infarction, unlikely to regain functional independence)
- A full list of exclusion criteria is provided in the trial protocol
Source: Yoshimura S et al., New England Journal of Medicine 2022;386:1303-1313· Retrieved 2026-06-09
Primary Outcome
mRS 0–3 at 90 days (binary)
mRS 0–3 at 90 days
Study Arms
- Agent
- Mechanical thrombectomy or related endovascular therapy. The method was selected by the treating physicians and could include a stent retriever, an aspiration catheter, balloon angioplasty, an intracranial stent, or a carotid-artery stent
- Route
- Endovascular
- Frequency
- Single procedure, with the degree of recanalization measured by the Thrombolysis in Cerebral Infarction (TICI) grading system (TICI grade 2b used as the threshold for successful recanalization)
- Duration
- One-time procedure, initiated within 60 minutes after randomization
- Co-interventions
- Medical care in line with American Heart Association and American Stroke Association guidelines. Alteplase at the Japanese standard dose of 0.6 mg per kilogram of body weight was used when appropriate at the discretion of the treating physician (given to approximately 27% of patients in each group)
Device choice and concomitant care from Yoshimura NEJM 2022 p.1305 (Randomization and Intervention). TICI grade 2b reperfusion was achieved in 86% of EVT patients. Open-label assignment with blinded mRS assessment at 90 days.
- Agent
- Guideline-based medical care without endovascular therapy
- Route
- Medical
- Co-interventions
- Medical care in line with American Heart Association and American Stroke Association guidelines. Alteplase at the Japanese standard dose of 0.6 mg per kilogram of body weight was used when appropriate (29 of 102 medical-care patients, 28.4%)
Control arm received the same guideline-based medical care as the intervention arm, without protocol-mandated endovascular therapy. Source: Yoshimura NEJM 2022 p.1305. The Japanese low-dose alteplase (0.6 mg/kg) is lower than the 0.9 mg/kg standard in US and European guidelines.
Safety
Symptomatic ICH within 48h
9%
4.9%
Symptomatic ICH defined as parenchymal hematoma type 2 (clot in at least 30% of the infarcted area with space-occupying effect) plus worsening of NIHSS by at least 4 points within 48 hours. EVT 9.0% vs medical care 4.9% (RR 1.84, 95% CI 0.64-5.29, P=0.25). Not statistically significant. Source: Yoshimura S et al., NEJM 2022, Table 2 p.1309.
90-day mortality
18%
23.5%
90-day mortality 18.0% EVT vs 23.5% medical care (RR 0.77, 95% CI 0.44-1.32, P=0.33). No significant difference; numerically lower with EVT despite the higher any-ICH rate. Source: Yoshimura S et al., NEJM 2022, Table 2.
Any intracranial hemorrhage within 48h
58%
31.4%
Any intracranial hemorrhage within 48 hours: 58.0% EVT vs 31.4% medical care (RR 1.85, 95% CI 1.33-2.58, P<0.001). The any-ICH signal is the central safety trade-off of large-core EVT. Symptomatic ICH and mortality were not significantly different. Source: Yoshimura S et al., NEJM 2022, Table 2 p.1309.
Trial Design
Type
- Multicenter randomized clinical trial
- Open-label with blinded mRS assessment at 90 days
- 1:1 stochastic minimization (EVT + medical care vs medical care alone)
- Pragmatic enrollment at 45 hospitals in Japan
Timeline
Enrolled November 2018 to September 2021
N
203
Enrollment
203 patients (101 EVT + medical / 102 medical care alone; 1 EVT consent withdrawal → 100 vs 102 ITT) at 45 hospitals in Japan. Pragmatic open-label RCT with blinded mRS adjudication. Enrolled November 2018 to September 2021. Japanese low-dose alteplase (0.6 mg/kg) used in 28.4% of medical-care arm. Published NEJM 2022.
ClinicalTrials.gov
NCT03702413Bedside Pearl
For ASPECTS 3-5 anterior LVO within 6 hours of LKW, or 6-24 hours without FLAIR signal change, EVT improved mRS 0-3 at 90 days from 12.7% to 31.0% (RR 2.43, NNT 5). The trade-off is a near-doubling of any-ICH rate (58% vs 31%, P<0.001), although symptomatic ICH and mortality were not significantly different. Quote both numbers when consenting: 5 patients treated to gain one functional outcome, against the higher hemorrhage rate.