Mechanical Thrombectomy Treatment More than 16 h after Last Known Well for Patients with Large Vessel Occlusion

Many clinical trials have shown that mechanical thrombectomy (MT) is effective for stroke patients with large vessel occlusion [1‒5]. However, the efficacy of MT is limited to treatment within a specific time window [1‒6]. The presence of salvageable brain tissue (also known as the penumbra) depends on the interval from stroke onset, degree of collaterals [7, 8], and other factors. Therefore, the penumbra for each patient may not be defined by the time interval from stroke onset alone.

The DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) and DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trials demonstrated the efficacy of MT within 24 h [9] and 16 h [10], respectively, after last known well (LKW), which is defined as the time when the patient was last known to be without stroke signs and symptoms. Moreover, several investigations recently indicated that some patients treated within 24 h after LKW [11] had better outcomes than those administered only standard medical care, such as antiplatelet therapy or anticoagulant therapy. These findings suggest that reperfusion therapy may be effective for patients more than 16 h after LKW. Therefore, we evaluated the efficacy and safety of MT more than 16 h after LKW.

Patients from the Nippon Medical School Hospital (Tokyo, Japan) MT Registry were retrospectively enrolled in this study between April 2011 and August 2022. The Nippon Medical School Hospital MT Registry is a consecutive, prospective registry of patients with acute stroke who were admitted to Nippon Medical School Hospital and underwent MT after they or a legal representative provided consent, which was obtained in writing. The registry and study were approved by the Institutional Review Board of Nippon Medical School (approval number: B-2020-300).

Patients with a prehospital modified Rankin scale (mRS) score of 0–3 and large vessel occlusion in the anterior circulation (internal carotid artery [ICA] occlusion, middle cerebral artery M1 occlusion, and middle cerebral artery M2 occlusion) were enrolled. Patients were selected to undergo MT at the discretion of the operator, and there were no restrictions on the clinical inclusion criteria. Patients who provided consent for treatment themselves or whose families provided it for them and who were considered candidates for thrombectomy by the operator underwent surgery. In accordance with the Japanese guidelines, thrombectomy was performed when there was a mismatch between the ischaemic core volume on computed tomography (CT) perfusion imaging or diffusion-weighted magnetic resonance imaging (DWI MRI) and neurological symptoms or delayed perfusion areas. We use DWI-FLAIR mismatch as well as neurological symptoms to assess the penumbra for MRI. Patients who did not provide consent or who did not meet the aforementioned criteria were excluded from the study.

We divided the eligible patients into the following three groups according to the time from LKW to puncture: early group (LKW <6 h), middle group (LKW 6–16 h), and late group (LKW >16 h). The clinical characteristics and outcomes were compared between the three groups.

The following clinical information was obtained from the Nippon Medical School Hospital MT Registry: sex; age; neurological impairment (National Institutes of Health Stroke Scale [NIHSS] score on admission); mRS score before stroke; vascular risk factors (hypertension, hyperlipidaemia, and diabetes mellitus); atrial fibrillation; Alberta Stroke Program Early CT Score (ASPECTS) according to CT or diffusion-weighted MRI; site of cerebral artery occlusion; clinical pathology; time from LKW to puncture; time from puncture to reperfusion; reperfusion status; symptomatic intracranial haemorrhage (sICH) after MT treatment; and mRS score at 90 days.

Clinical morbidity was determined at discharge using the following Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria: large artery atherosclerosis, cardioembolic stroke, other determined aetiology, and undetermined aetiology [12]. Functional outcomes were estimated using the mRS score. A good outcome was defined as an mRS score of 0–3 at 90 days after stroke onset. The reperfusion status was assessed after MT using the expanded treatment in cerebral ischaemia (eTICI) scale [6], and successful reperfusion was defined as an eTICI score of 2b–3. sICH after MT was defined as local or distant parenchymal haemorrhage type 2 using the Safe Implementation of Thrombolysis in Stroke-Monitoring Study protocol and neurological deterioration from a baseline NIHSS score of ≥4 points [13]. Safety was assessed according to sICH and death (mRS score of 6) after 90 days, whereas efficacy was assessed according to mRS scores of 0–3 after 90 days.

Clinical characteristics and outcomes were compared between the patients in the early group (LKW <6 h), middle group (LKW 6–16 h), and late group (LKW >16 h). All statistical analyses were performed using SPSS software (version 27; SPSS Japan, Inc., Tokyo, Japan). The results were considered statistically significant at p < 0.05. Univariate analyses were performed using χ² and Mann-Whitney U tests, as appropriate. Data are presented as medians and interquartile ranges. Categorical variables are presented as frequencies and percentages.

Of the 778 patients registered in the Nippon Medical School Hospital MT Registry, 624 were enrolled in this study. Patients with posterior circulation and those with a prehospital mRS score ≥4 were excluded. The early group (LKW <6 h), middle group (LKW 6–16 h), and late group (LKW >16 h) comprised 432 patients (69.2%), 123 patients (19.7%), and 69 patients (11.1%), respectively (online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000531153).

Regarding the time interval from LKW to puncture, 312 (50.0%) patients underwent puncture 0–4 h (0–240 min) after LKW, 149 (23.9%) patients underwent puncture 4–8 h (241–480 min) after LKW, 47 (7.5%) patients underwent puncture 8–12 h (481–720 min) after LKW, 39 (6.3%) patients underwent puncture 12–16 h (721–960 min) after LKW, 33 (5.3%) patients underwent puncture 16–24 h (961–1,440 min) after LKW, 21 (3.4%) patients underwent puncture 24–48 h (1,441–2,880 min) after LKW, and 15 (2.4%) patients underwent puncture more than 48 h (>2,881 min) after LKW (Fig. 1). Of the patients in the early group (LKW <6 h), middle group (LKW 6–16 h), and late group (LKW >16 h), those in the early group had the shortest onset to puncture time after LKW (188 [133–243] min vs. 559 [442–790] min vs. 1,473 [1,201–2,691] min; p < 0.001). Patients in the early group had the highest baseline NIHSS scores (19 [12–24] vs. 15 [8–20] vs. 12 [7–18]; p < 0.001) and the highest ASPECTS (10 [9–10] vs. 7 [5–8] vs. 7 [6–8]; p = 0.05). M1 occlusion (49.5% vs. 48.0% vs. 23.2%; p < 0.001) and undetermined aetiology (18.8% vs. 10.7% vs. 2.9%; p < 0.001) were most frequently observed in the early group. Hyperlipidaemia (32.2% vs. 36.6% vs. 47.8%; p = 0.04), ICA occlusion (28.7% vs. 24.4% vs. 56.5%; p < 0.001), and large artery atherosclerosis (17.9% vs. 28.7% vs. 44.9%; p < 0.001) were most frequently observed in the late group.

No significant differences in age, sex, hypertension, diabetes mellitus, atrial fibrillation, mRS score before stroke, NIHSS score on admission, use of diffusion-weighted MRI, or time from puncture to reperfusion were observed between the three groups (Table 1). There were no differences in safety and efficacy between the three groups in terms of the following parameters: first-pass successful perfusion (eTICI 2b-3; 54.9% vs. 49.6% vs. 58.0%; p = 0.47), successful perfusion (eTICI 2b-3; 85.4% vs. 92.7% vs. 88.4%; p = 0.10), sICH (6.4% vs. 5.7% vs. 7.2%; p = 0.99), mRS score ≤1 at 90 days (27.5% vs. 30.9% vs. 17.4%; p = 0.12), mRS score ≤2 at 90 days (42.7% vs. 48.0% vs. 36.2%; p = 0.56), mRS score ≤3 at 90 days (52.0% vs. 60.2% vs. 44.9%; p = 0.11), and mRS score of 6 at 90 days (13.8% vs. 10.6% vs. 8.7%; p = 0.37) (Fig. 2; Table 2).

This study demonstrated that the efficacy and safety of MT performed for patients more than 16 h after LKW were similar to those of MT performed for patients less than 6 h after LKW and 6–16 h after LKW. The current guidelines recommend MT for patients who meet strict neuroimaging criteria within 16 h (grade A) and 24 h (grade B) after LKW [14], based on the results of the DEFUSE-3 trial [8] and DAWN trial [7]. However, several previous case series and retrospective studies [15‒18], including the DAWN trial, have reported a small sample size of cases for which MT was performed more than 16 h after LKW. Therefore, the efficacy of MT performed more than 16–24 h after LKW has not yet been clarified.

In this study, in terms of successful reperfusion rates, good functional outcomes, and mortality at 3 months, the efficacy of MT performed for patients more than 16 h after LKW was similar to that of MT performed less than 6 h after LKW and 6–16 h after LKW. The proportion of patients with functional independence (mRS score ≤3) in the before 16 h group was consistent with the proportions of patients with functional independence in the endovascular groups of the DAWN trial and DEFUSE-3 trial (60%, 57%, and 64%, respectively).

Regarding safety outcomes, the proportion of patients with sICH (7%) in our study in the after 16 h group was similar to the proportions of patients with sICH in the endovascular groups of the DAWN trial (6%) and DEFUSE-3 trial (7%). In contrast, mortality at 3 months (9%) in the late group was less frequent compared to that in the endovascular groups of the DAWN trial (19%) and DEFUSE-3 trial (14%). As a result, the safety and efficacy of MT more than 16 h after LKW may be similar to those of the less than 16 h group. Therefore, these results suggest that performing MT more than 16 h after LKW is safe and effective.

Several previous studies using RAPID software (iSchemaView, Mountain View, CA, USA) have reported treatment for patients who met strict neuroimaging criteria. However, in practice, not all centres, especially those in Japan, have this software. In this study, the ASPECTS based on MRI results and neurological symptoms was used for MT decision-making. Previous studies of treatment based on perfusion imaging have been limited by strict patient selection [2‒4, 9, 10], thus limiting the patients who can be treated. However, the safety and efficacy of MT in this study were similar to those of the RAPID system reported previously [3, 9, 10], which showed that MT may be effective when performed based on MRI results and clinical information alone.

Regarding the TOAST classification and occlusion site of the cerebral artery, more patients with large artery atherosclerosis and ICA occlusion were observed in the more than 16 h group. This indicated that large artery atherosclerosis is more likely to cause the development of collateral blood vessels attributable to long-term vascular changes [19, 20]. Collateral blood vessels via the anterior communicating artery and arterial ring of Willis were more prone to atherosclerotic ICA occlusion, thus suggesting more residual penumbra. Therefore, patients with large artery atherosclerotic ICA occlusion may be candidates for MT, even more than 16 h after LKW.

This study had several limitations. Firstly, it was a retrospective analysis of a prospectively enrolled registry. To ensure the generalisability of the study findings, they must be verified by a randomised controlled trial. Secondly, endovascular treatment performed more than 16 h after LKW was not in compliance with Japanese clinical guidelines; however, consent was obtained from the patient or the patient’s family. Thirdly, the number of cases was small, but our sample size was larger than those of previous studies. Fourth, the data in this study were obtained from a single centre. However, the treatment was based on essentially the same ideas, particularly the classification of ischaemic stroke subtypes and the evaluation of the cerebral ischaemia scale (eTICI) for reperfusion on digital subtraction angiography. Therefore, the data did not show any bias.

MT for patients more than 16 h after LKW was safe and resulted in outcomes similar to those of MT for patients within 16 h after LKW. These results support the feasibility of MT for patients with anterior circulation more than 16 h after LKW. Randomised controlled studies are required to validate these findings.

This study protocol was reviewed and approved by Nippon Medical School Hospital, approval number 228003. We obtained written informed and signed consent from the participant/the participant’s representative and from parents/legal guardians for all participants aged under 18.

The authors have no conflicts of interest to declare.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Takehiro Katano conceived and designed the study and drafted the manuscript; Kentaro Suzuki, Ryutaro Kimura, and Tomonari Saito collected the data; Yasuhiro Nishiyama did the statistical analysis; and Kazumi Kimura critically revised the manuscript.

All data generated or analysed during this study are included in this article and its online supplementary material. Further enquiries can be directed to the corresponding author.