Abstract
Background:
Endovascular treatment (EVT) for acute large vessel occlusion has proven to be effective in randomized controlled trials. We conducted a prospective cohort study to evaluate the real-world efficacy of EVT in a metropolitan area with a large number of comprehensive stroke centers and to compare it with the results of other registries and randomized controlled trials (RCTs).
Methods:
We analyzed the Kanagawa Intravenous and Endovascular Treatment of Acute Ischemic Stroke registry, a prospective, multicenter observational study of patients treated by EVT and/or intravenous tissue-type plasminogen activator (tPA). Of the 2488 patients enrolled from January 2018 to June 2020, 1764 patients treated with EVT were included. The primary outcome was a good outcome, which was defined as a modified Rankin Scale (mRS) of 0–2 at 90 days. Secondary analysis included predicting a good outcome using multivariate logistic regression analysis.
Results:
The median age was 77 years, and the median National Institute of Health Stroke Scale (NIHSS) score was 18. Pretreatment mRS score 0–2 was 87%, and direct transport was 92%. The rate of occlusion in anterior circulation was 90.3%. Successful recanalization was observed in 88.7%. The median time from onset to recanalization was 193 min. Good outcomes at 90 days were 43.3% in anterior circulation and 41.9% in posterior circulation. Overall mortality was 12.6%. Significant predictors for a good outcome were as follows: age, male, direct transfer, NIHSS score, Alberta Stroke Program Early Computed Tomography Score, intravenous tPA, and successful recanalization.
Conclusion:
EVT in routine clinical use in a metropolitan area showed comparable good outcomes and lower mortality compared to previous studies, despite the high proportion of patients with older age, pretreatment mRS score of >2, posterior circulation occlusion, and higher NIHSS. Those results may have been associated with more direct transport and faster onset-to-recanalization times.
In acute ischemic stroke patients with large vessel occlusion, randomized controlled trials (RCTs) and meta-analysis have reported the safety and efficacy of mechanical thrombectomy.1–3 It has become recommended as a standard treatment in many countries. These developments of mechanical thrombectomy were based on previous RCTs, which had strict inclusion and exclusion criteria in patient selection. However, there were many unknown variables, such as therapeutic time window, diagnostic imaging to evaluate salvageable brain tissue, tissue-type plasminogen activator (tPA) administration, type of device used for endovascular treatment (EVT), and techniques for endovascular procedures; therefore, these trials excluded patients with pre-stroke modified Rankin Scale (mRS) scores ⩾2.
Several prospective registries of EVT in patients with large vessel occlusion that examined real-world outcomes have been reported.4–8 These outcome data were slightly worse than RCTs; however, newer thrombectomy devices, advances in the experience of neurointerventionalists, and improvement of transporting systems for acute stroke patients are expected to improve treatment outcomes and safety in routine clinical practice.
Aims
The Kanagawa Intravenous and Endovascular Treatment of Acute Ischemic Stroke registry (K-NET registry) was established as an open-label, prospective, multicenter, observational registry. This study was conducted in a metropolitan area with a population of 9.2 million, a high population density, and a large number of comprehensive stroke centers. We aimed to provide the initial analysis of real-world outcomes and the aspects associated with good outcome of EVT in patients with acute large vessel occlusion, and to compare with results of other registries and RCTs.
Methods
The K-NET registry is a registry of consecutive patients who received intravenous tPA therapy and/or EVT for acute ischemic stroke (https://www.clinicaltrials.gov; unique identifier: NCT05213533). The first 2488 patients were included between January 2018 and June 2020 at 40 stroke centers in Kanagawa Prefecture, Japan (Supplemental Figure S1). The main inclusion criteria were acute ischemic stroke patients who initiated EVT for large vessel occlusions. Local physicians at each institution decided to perform EVT. There was no time limit from the onset to the start of EVT.
As basic information, the location of onset, transportation method, pretreatment mRS, medical history, the National Institute of Health Stroke Scale (NIHSS) score, imaging findings, and functional outcome were collected. Furthermore, tPA administration, timing of EVT, the device used, number of passes, and the degree of recanalization, perioperative complications, and mRS after 90 days were collected. Intracranial hemorrhage was classified by the Safe Implementation of Thrombolysis in Stroke-monitoring Study criteria. 9 All data were entered into a web-based electronic case report system by the treating physicians. The data underwent standardized quality checks to control for consistency, plausibility, and completeness. Data with unresolved queries were excluded.
CT and/or magnetic resonance imaging (MRI) were used for diagnostic imaging at admission. The evaluation of ischemic lesions in CT was made with an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 10 of 0–10. The assessment in MRI was made with a Diffusion-weighted Imaging–Alberta Stroke Program Early Computed Tomography Scores (DWI-ASPECTS) 11 of 0–11. The EVT method was determined by neurointerventionalists at each institution based on mechanical thrombectomy, thrombus aspiration, and intra-arterial thrombolysis. There were no restrictions on the selection and frequency of the various devices used for additional treatments such as balloon angioplasty and stenting. The recanalization grade was measured by the modified Thrombolysis in Cerebral Infarction (mTICI) scale. 12 Successful recanalization was defined as an mTICI score of 2b–3.
The primary outcome was the mRS score at 90 days after onset. A good outcome of functional independence was defined as mRS 0–2. The secondary outcome was mTICI grade, symptomatic intracranial hemorrhage within 72 h, and mortality 90 days after onset. In addition, factors related to good outcomes were analyzed. As this study also included patients with pre-stroke mRS 3–5, we defined a favorable outcome as an mRS score of 0–2 at 90 days or no decrease of mRS score, in concordance with the definitions used in previous reports. 13
The study was approved by the Ethics Committee of St. Marianna University School of Medicine (approval no. 3757). According to local regulations, further approval was obtained from local institutional ethics committees or institutional review boards. Written informed consent was obtained from the patient or the surrogate.
Statistical analysis
Baseline characteristics were described using standard statistics. The median and interquartile range (IQR) were used as the baseline parameters for consecutive and ordinal variables. The proportion was used as the baseline parameter for categorical variables. Multivariate logistic regression analysis was performed to examine independent factors that predicted a favorable outcome in patients treated with EVT in anterior circulation occlusion. Related factors include age, sex, onset location, transfer method, baseline NIHSS score, ASPECTS, intravenous tPA, mTICI score, door-to-puncture time, and puncture-to-recanalization time. The odds ratio and confidence interval were derived along with the corresponding p-value. A p-value < 0.05 was significant. All statistical analyses were performed with SPSS (Version 9.4, IBM Corp., Armonk, NY, USA).
Results
There were 1764 patients passing central data quality control evaluated in the primary analyses (Table 1). The median age of 77 years (IQR = 70–84), 42.3% female, and a median baseline NIHSS of 18 (IQR = 12–24). CT was performed on 1021 patients (57.8%), and baseline ASPECTS had a median of 9. MRI was performed on 1311 patients (74.3%), and baseline DWI-ASPECTS had a median of 8. Patients with mRS 0–2 before stroke were 87.0% and direct transport was 92.4%. Most patients had occlusion of middle cerebral artery (45%), followed by internal carotid artery (ICA, 27.6%) and basilar artery (6.3%).
Baseline characteristics in patients with endovascular treatment.
ASPECTS, Alberta Stroke Program Early CT Score; IQR, interquartile range; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; IQR: interquartile range; DWI: diffusion-weighted imaging; ICA: internal carotid artery; MCA: middle cerebral artery; ACA: anterior cerebral artery; BA: basilar artery; VA: vertebral artery; PCA: posterior cerebral artery.
The onset time was confirmed in 907 patients (51.4%) with a median onset-to-the-door time of 61 min (Table 2). The onset time was unknown in 857 patients (48.6%), and the median last-seen-well-to-the-door time was 263 min. The median door-to-puncture time was 63 min, the median puncture-to-recanalization time was 43 min, and the median onset-to-recanalization time was 193 min. Intravenous tPA before EVT was administered in 772 patients (43.7%). Successful recanalization of occluded vessels was observed in 88.7%. Post-treatment symptomatic intracranial hemorrhage was observed in 3.7%.
Procedural results in patients with endovascular treatment.
IQR: interquartile range; mTICI: modified Thrombolysis in Cerebral Infarction
The good outcome after 90 days in total patients was 43.3% (Figure 1). However, when the subjects were limited to pretreatment mRS 0–2 patients in the anterior circulation occlusion, good outcome was 49.3%. Favorable outcome was 47.7%. The relationship between the outcome after 90 days and age or the onset to recanalization time is shown in Supplemental Figure S2. The percentages of good outcomes were 73% in their 50s, 63% in their 60s, 48% in their 70s, 30% in their 80s, and 12% in their 90s. By time from onset to recanalization, the rate of good outcome was the highest at 64% within 120 min and the lowest at 37% at 240–300 min. Time from door to puncture and time from puncture to recanalization were not clearly associated with the outcome at 90 days (Supplemental Figure S3).
Distribution of modified Rankin Scale scores at 90 days for patients with endovascular treatment; for patients with anterior and posterior circulation occlusion; for patients with pretreatment mRS 0–2.
Logistic regression analysis was performed on the factors related to good outcome after 90 days (Supplemental Table S1). The following factors were significantly associated with good outcome in 1592 patients treated with EVT in anterior circulation occlusion: age (p < 0.0001), male (p = 0.0342), direct transfer (p = 0.0034), NIHSS score at admission (p < 0.0001), ASPECTS (p < 0.0001), intravenous tPA (p = 0.0213), higher mTICI grade (p = 0.0043), and short door-to-puncture time (p = 0.0166).
A comparison of this study with the Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke (HERMES) trials 3 and other registered studies is shown in Table 3. In this study, the median age (77 years) and NIHSS on admission (median = 18) were higher, and the pre-stroke mRS 0–2 ratio was lower than previous studies. Furthermore, direct transport was higher (92.4%) than previous studies. The onset-to-door time was 64 min (median), which was faster than previous studies, and the onset-to-recanalization time was also faster (194 min). The rate of good outcomes in this study was lower (43.3%) than those of the HERMES trial 3 (46%) and Safe Implementation of Treatments in Stroke–International Stroke Thrombectomy Registry (SITS-ISTR) 5 (45.5%); however, it was higher than the rates of other registries.8,10,12 Furthermore, 49.3% of patients with anterior circulation obstruction who had pre-stroke mRS 0–2 had good outcome, which was higher than the HERMES trial. 3 The mortality rate at 90 days in this study was 12.8%, which was lower than other studies.
Comparison among the current data of the K-NET and the published data from the HERMES and other registries.
HERMES, Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials; MR CLEAN, Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; GSR-ET, German Stroke Registry–Endovascular Treatment; ETIS, Endovascular Treatment in Ischemic Stroke; SITS-ISTR, Safe Implementation of Treatment in Stroke–International Stroke Thrombectomy Registry; ICA: internal carotid artery; K-NET: Kanagawa Intravenous and Endovascular Treatment of Acute Ischemic Stroke; NIHSS: National Institute of Health Stroke Scale; IQR: interquartile range; mRS: modified Rankin Scale; IV tPA: intravenous tissue-type plasminogen activator; ASPECTS: Alberta Stroke Program Early Computed Tomography Score; DWI: diffusion-weighted imaging.
Discussion
K-NET is a regional stroke registry of EVT for acute ischemic stroke, which includes 40 stroke centers and most stroke centers are currently implementing EVT. This study investigated the transport status of acute stroke patients in a large metropolitan area, the implementation status of recanalization therapy, treatment results, and factors related to good outcomes. Despite a large number of enrolled patients with poor conditions, the treatment results of this study were comparable good outcomes and lower mortality to previous registries, which may be related to more direct transport and faster onset-to-recanalization times.
This study had the following advantages for achieving a good outcome over other studies: (1) direct transportation was exceptionally high at 92.4%, (2) a faster time from onset to visit (median 64 min), (3) the recanalization rate was higher (88.7%), and (4) symptomatic intracranial hemorrhage was lower (3.7%). The high direct transport rate was because the primary stroke centers (PSCs) are densely packed in the metropolitan areas of Japan; thus, EVT can be performed in many PSCs, and interhospital transfer is not actively performed.
Because most of the patients in this study were transported directly, it was difficult to evaluate treatment outcomes relative to interhospital transfer. Recent reviews reported that the mothership model patients may have better functional outcome than the drip-and-ship model patients. 14 , 15 However, most studies were retrospective with selection bias, and this issue is still controversial. Multicenter randomized controlled trials are needed to resolve this question.
The enrolled patients in this study had more conditions associated with poor outcomes than in the previous studies: (1) the patients were older (median 77 years), (2) baseline NIHSS was higher, (3) pre-stroke mRS 0–2 was lower, (4) it included patients with posterior circulation occlusion, (5) a high rate of ICA occlusion, and (6) no time limit from onset to admission in the inclusion criteria. In addition, the proportion of patients with unknown onset time (48.7%) was extremely high compared with the German Stroke Registry–Endovascular Treatment (GSR-ET) study (28.2%). 6 The lower rate of intravenous tPA infusion (43.6%) compared to other studies was due to a large number of patients outside the tPA indication time.
The onset-to-recanalization time was faster than previous registries and HERMES. However, it was not a significant factor for good outcome in multivariate analysis. The percentage of good outcome was best within 120 min of onset-to-recanalization time (64%) and worst between 240 and 300 min (37%). This may be because the optimal time to a good outcome is different for patients with an early window and those with a late window. 16 Our results indicated that the earlier the time, the better the outcome for patients who recanalized within 6 h of onset, whereas there was no relationship between time and outcome for patients who recanalized after 6 h.
This study included a higher number (13.0%) of patients with mRS 3 or higher who already had pre-existing disabling deficits before onset than other studies.4–6,8 Therefore, we defined a favorable outcome as a good outcome even if there was no deterioration after treatment in patients with pre-stroke mRS 3 or higher. We showed that a favorable outcome was 48%. A previous study reported that pre-stroke-dependent patients benefit from EVT and should not be routinely excluded from this treatment. 13
Previous studies reported that age, baseline NIHSS, ASPECTS, mothership, time to recanalization, recanalization rate, and symptomatic intracranial hemorrhage were associated with good outcomes.6,17 In this study, as in previous reports, younger age, direct transfer, low baseline NIHSS, higher ASPECTS, intravenous tPA, successful recanalization, no symptomatic intracranial hemorrhage, no subarachnoid hemorrhage, and door-to-puncture time were independent factors associated with good outcomes.
There were several limitations to this study. First, this study used a registry with prospective enrollment without a control arm. As we could not establish the external validation of the completeness of consecutive enrollment, there was a selection bias for each institution regarding the indications for treatment. Second, there were no data available on the total number of EVT procedures performed in Kanagawa Prefecture. Third, there was no central imaging core laboratory for imaging in this study, and it was not possible to check the image evaluation of each institution. Fourth, mRS at 90 days was assessed by local physicians, which may have introduced bias, even though the assessment of mRS was conducted by independent physicians other than the treating physicians.
Conclusion
The K-NET registry indicated real-world outcomes of EVT in a metropolitan area with a high population density and a large number of comprehensive stroke centers. The current EVT in routine clinical use showed comparable good outcomes and lower mortality compared to previous registries and RCTs, despite the high proportion of patients with older age, pretreatment mRS score >2, posterior circulation occlusion, and higher NIHSS. Those results may have been associated with more direct transport and faster onset-to-recanalization times.
Supplemental Material
sj-docx-1-wso-10.1177_17474930221138014 – Supplemental material for Primary results of mechanical thrombectomy for acute ischemic stroke: The K-NET registry in the Japanese metropolitan area
Supplemental material, sj-docx-1-wso-10.1177_17474930221138014 for Primary results of mechanical thrombectomy for acute ischemic stroke: The K-NET registry in the Japanese metropolitan area by Toshihiro Ueda, Yasuhiro Hasegawa, Masataka Takeuchi, Masafumi Morimoto, Yoshifumi Tsuboi, Ryoo Yamamoto, Shogo Kaku, Junichi Ayabe, Takekazu Akiyama, Daisuke Ishima, Kentaro Mori, Hiroshi Kagami, Hidemichi Ito, Hidetaka Onodera, Hiroshi Doi, Tomoyuki Tsumoto, Shunsuke Hataoka, Masayuki Noda, Nagatsuki Tomura, Osamu Masuo, Yoichi Yoshida, Yasuyuki Kaga, Kentaro Tatsuno, Tomohide Yoshie, Satoshi Takaishi and Yoshihisa Yamano in International Journal of Stroke
Footnotes
Acknowledgements
The authors are grateful to Ms Tomomi Shibuya and Mr Satoshi Muta (Department of Practical Management of Medical Information, St. Marianna University School of Medicine) for collecting and checking data.
Author contributions
T.U. contributed to the study concept/design, study supervision, data acquisition, statistical analysis/interpretation of data, and drafting/revising the manuscript. Y.H. contributed to the study concept/design, study supervision, and drafting the manuscript. M.T., M.M., Y.T., R.Y., S.K., J.A., T.A., D.I., K.M., H.K., H.I., H.O., H.D., T.T., S.H., M.N., N.T., O.M., and Y.Y. contributed to data acquisition. Y.K. contributed to the statistical analysis/interpretation of data. K.T., T.Y., S.T., and Y.Y. contributed to the acquisition, analysis, and interpretation of data.
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr T.U. reports consulting fees from Kaneka Medix. Dr Y.H. reports consulting fees from Bayer Pharmaceutical and Nippon Boehringer Ingelheim. Dr M.T. reports consulting and lecture fees from Johnson and Johnson and Stryker. Dr T.T. reports consulting and lecture fees from Stryker and Terumo.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The K-NET registry was partially supported by a grant from the Japanese Society of Neuroendovascular Therapy.
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References
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