Influence of hospital capabilities and prehospital time on outcomes of thrombectomy for stroke in Japan from 2013 to 2016

To determine whether increasing thrombectomy-capable hospitals with moderate comprehensive stroke center (CSC) capabilities is a valid alternative to centralization of those with high CSC capabilities. This retrospective, nationwide, observational study used data from the J-ASPECT database linked to national emergency medical service (EMS) records, captured during 2013–2016. We compared the influence of mechanical thrombectomy (MT) use, the CSC score, and the total EMS response time on the modified Rankin Scale score at discharge among patients with acute ischemic stroke transported by ambulance, in phases I (2013–2014, 1461 patients) and II (2015–2016, 3259 patients). We used ordinal logistic regression analyses to analyze outcomes. From phase I to II, MTs increased from 2.7 to 5.5%, and full-time endovascular physicians per hospital decreased. The CSC score and EMS response time remained unchanged. In phase I, higher CSC scores were associated with better outcomes (1-point increase, odds ratio [95% confidence interval]: 0.951 [0.915–0.989]) and longer EMS response time was associated with worse outcomes (1-min increase, 1.007 [1.001–1.013]). In phase II, neither influenced the outcomes. During the transitional shortage of thrombectomy-capable hospitals, increasing hospitals with moderate CSC scores may increase nationwide access to MT, improving outcomes.

www.nature.com/scientificreports/ ers significantly decreased from 73.9 to 65.2% and from 13.4 to 0.2%, respectively. The proportion of patients who received recombinant tissue-plasminogen activator (rt-PA) administration before MT remained the same between both phases. We observed similar findings for the characteristics of all patients with AIS except for a higher frequency of hypertension, a higher baseline mRS score, and a lower rt-PA administration score in phase I.
Prehospital time of the participating hospitals in each phase. In the MT groups, the total EMS response time remained almost the same between phase I and II, despite a shorter on-scene time in phase II ( Table 2). We observed no clinically meaningful differences in prehospital time metrics in all AIS patients between phases. Notably, the transport time in the MT groups remained the same from phase I to II and comparable with those of all patients with AIS in each phase.
CSC capabilities of the participating hospitals in each phase. The CSC capabilities based on hospital characteristics are summarized in Table 3. In phases I and II, the percentages of missing CSC score data in the MT groups were 6.0% and 14.7%, respectively. Among all participating hospitals, the proportion of thrombectomy-capable hospitals increased from 45.6 to 58.2% from phase I to II. The median CSC scores of all participating hospitals and thrombectomy-capable hospitals remained unchanged between phases. Although there were no between-phase differences in the CSC scores for thrombectomy-capable hospitals, the difference in the median CSC scores between all participating and thrombectomy-capable hospitals in phase II became smaller than that in phase I (17 vs. 18 in phase I, 18 vs. 19 in phase II). Among the 25 items used to assess CSC capabilities, we observed no between-phase differences in availability in all participating hospitals; however, in the thrombectomy-capable hospitals, availability of the items related to endovascular treatment such as fulltime, board-certified endovascular physicians and intra-arterial reperfusion therapy significantly decreased in phase II (p = 0.05, < 0.03) ( Table 3).   (1.003 [0.998-1.007]). The relationships between the total EMS response time and probabilities of an mRS score of 6 at discharge in phases I and II in the MT groups are shown in Fig. 2a, b. Subgroup analyses demonstrated that the effect of total response time on clinical outcomes in phase I was notable for patients aged ≥ 70 years and those who reside in areas with low and intermediate population density (< 300, 300-1000 persons/km 2 ; Fig. 3a). This association was only noted for patients aged < 70 years in phase II (Fig. 3b).

Discussion
Linking data from the J-ASPECT stroke database from 2013 to 2016 to the national EMS records, we demonstrated the increased use of MT and better clinical outcomes after MT with less initial stroke severity in an increasing number of thrombectomy-capable hospitals following revisions to the clinical practice guidelines for MT in 2015 by the relevant societies in Japan. Although the availability of endovascular physicians in all participating hospitals remained the same during the study period, fewer endovascular physicians were present in thrombectomy-capable hospitals in phase II, probably because of the rapid nationwide increase of such hospitals in response to the abovementioned revisions.
The influence of the CSC capabilities of the thrombectomy-capable hospitals and prehospital time on the clinical outcomes of patients with AIS who received MT in phase I may support the implementation of regional centralization of thrombectomy-capable hospitals 3,5,22 . No such clinical influence was observed in phase II; however, we posit that, in the current transitional period, while there is a relative shortage of thrombectomy-capable Table 3. CSC capabilities based on hospital characteristics in all groups. CSC comprehensive stroke center; * implementation of full-time, board-certified personnel. P-values in bold are significant.  (14,20) 18 (14,20) 0.725 19 (17,21) 19 (17,21)  Temporal changes in patient characteristics. We demonstrated temporal changes in patient characteristics in the MT group, such as a higher age, decreased stroke severity, and better outcomes in phase II, which were consistent with those reported in previous studies of patients with AIS 2,23 . MT use in patients with AIS who were directly transported to a suitable facility via an ambulance in phase I (2.7%) was comparable to the findings from the US hospitals that participated in the Get With The Guidelines-Stroke program (MT use 3.3%) 1 . MT use (5.5%) in patients with AIS in phase II doubled from that in phase I, which may be explained by an increased awareness of the effectiveness of MT and the implementation of thrombectomy-capable hospitals in response to the revised guidelines in Japan 24 .
In contrast, MT use in patients with AIS who were directly transported via an ambulance to a suitable facility in phase II was almost twice the proportion (3.0%) of all patients with AIS who were urgently hospitalized in Japan from April 2010 to March 2016 2 . This is consistent with the findings of previous studies showing that only 60% of urgently hospitalized patients with AIS are transported via an ambulance 7,25 , suggesting the underuse of ambulances for patients with AIS who are possible candidates of MT in Japan.
Influence of the CSC capabilities and total EMS response time of thrombectomy-capable hospitals on clinical outcomes in phases I and II. The observed influence of CSC capabilities of thrombectomy-capable hospitals on clinical outcomes of patients with AIS who received MT in phase I may support the concept of regional centralization of thrombectomy-capable hospitals 3,5,22 . This is consistent with our previous studies using data before 2015. Therein, we demonstrated that hospitals with higher (vs. lower) CSC capabilities were more likely to have lower in-hospital mortality among patients with AIS and to provide timely rt-PA infusion and MT on a 24-h basis 2,7 . Although the CSC score comprises heterogeneous items of stroke care expertise, it reflects the joint effort of multiple healthcare professionals to manage emergencies 7,9,11,12 . One major finding of this study was the lack of association between the CSC capabilities and clinical outcomes of MT in phase II. This unexpected finding may be explained by several observations. First, and most notably, despite the similar CSC scores in phases I and II in the thrombectomy-capable hospitals in this study, Figure 2. Relationships between the total EMS response time or the CSC scores and probabilities of an mRS score of 6 at discharge (stroke outcomes) in the MT group. Panels (a) and (b) show the effects of total EMS response time (minutes) on the probabilities of an mRS score of 6 at discharge in phases I and II, respectively, in the MT group. Panels (c) and (d) show the effects of the CSC scores on the probabilities of an mRS score of 6 at discharge in phases I and II, respectively, in the MT group. EMS emergency medical services; CSC comprehensive stroke center; mRS modified Rankin Scale; MT mechanical thrombectomy. www.nature.com/scientificreports/ the availability of specific items related to endovascular therapy (e.g., full-time availability of board-certified endovascular physicians and intra-arterial reperfusion therapy) decreased. This relative shortage was probably because of the rapid increase in hospitals where MT can be performed. In contrast, in all participating hospitals, the availability of those items remained almost the same from phase I to II, which is consistent with the results in our previous study. Therein, we showed that the implementation of six items, mainly related to endovascular therapy, increased > 20% from 2010 to 2018, especially between 2010 and 2014 12 . Second, even in thrombectomy-capable hospitals with comparable CSC capabilities in phases I and II, there may be a difference in the quality of in-hospital care related to MT, depending on the availability of endovascular physicians [26][27][28][29] . For example, thrombectomy-capable hospitals without sufficient in-house endovascular physicians are more likely to make use of those from neighboring hospitals to perform MT, which may increase the onset-to-reperfusion time and worsen the clinical outcomes 26,30 .
Another key finding of this study was that the total EMS response time was not associated with clinical outcomes of MT in phase II, regardless of the level of urbanization. The influence of the total EMS response time on clinical outcomes in the MT group in phase I is in line with previous studies evaluating the effect of onsetto-treatment time on outcomes of patients who received MT 10 . The total median EMS response time (phase I, 33 min; phase II, 32 min) in the MT group remained unchanged between phase I and II and was shorter than that in a US study (36 min) 31 , suggesting that the total EMS response time may not be an effective target in shortening the onset-to-treatment time. However, this may be characteristic of countries, such as Japan, where a greater proportion of the population lives closer to hospitals than that in more expansive countries 18 . In more expansive countries, driving time exceeding 90 min may be more common. Despite this, we believe that our findings may not be unique to Japan 18 (e.g., 79% of adults in the US reside within 60 min of a hospital that provides acute cardiac therapy 32 ).
The influence of the total EMS response time in phase II may be outweighed by other processes involved in the onset-to-treatment time, such as a delay in EMS activation 33 and the in-hospital workflow before MT 34 . In this study, we did not have information on the time from symptom recognition to the ambulance call or on the www.nature.com/scientificreports/ in-hospital workflow; therefore, we could not quantify the role of those processes on the outcomes of patients with AIS who received MT 26,35 . A recent study suggested that patients with a lower socioeconomic status may be more likely to delay EMS activation than those with a higher status 33 ; however, educational campaigns raising awareness of the signs and symptoms of stroke have had little effect on the actual response to a stroke event 36,37 . In contrast, fast reperfusion is a modifiable factor associated with better clinical outcomes when successful reperfusion is achieved 34,38 . A recent meta-analysis of the pivotal trials that led to the change in guidelines showed that the intermediary outcome, the rate of successful reperfusion, was higher with faster (vs. slower) hospital-arrivalto-groin-puncture time 34 . This nationwide study lends real-world support to the findings of existing literature on the importance of in-hospital workflow to improve clinical outcomes of patients with AIS who receive MT 38,39 .
In the US, AIS care and quality may differ between institutions, with CSCs outperforming primary stroke centers (PSCs) in timely acute reperfusion therapy and risk-adjusted mortality 33 . Recently, we developed the Close The Gap-Stroke (CTGS) program, the first nationwide quality improvement program within the J-ASPECT study; it allows prospective evaluation of the quality of acute stroke care in Japan, using the DPC database and electronic medical records 14,29 . Further studies are necessary to examine the influence of CSC capabilities on performance in terms of quality indicators and clinical outcomes of patients with AIS who received MT after the JSS started to certify PSCs who are able to perform MT.
Our study suggests that equal accessibility to MT remains an urgent unmet need in real-world situations, which may justify the nationwide implementation of thrombectomy-capable hospitals with moderate CSC capabilities since 2015 40 .
In 2019, in Japan, the JSNET started to certify endovascular physicians who are qualified only to perform MT, and the JSS started to certify PSCs that are encouraged to perform MT. Availability of MT in the PSCs is in line with the increasing availability of endovascular treatment at PSCs in the US 40 . The current findings may lend support to this certification policy, as it may assist in equalizing the accessibility to MT.

Limitations
First, selection bias and unmeasured residual confounders may exist 10 . The participating hospitals in the J-ASPECT study were more likely to commit to quality improvement in stroke care than non-participating hospitals; however, the number of MTs performed in phase I corresponded to approximately 74.4% of those reported in the Japanese Registry of Neuroendovascular Therapy-the official registry of the JSNET 41 . Further, the geographical locations of the thrombectomy-capable and all participating hospitals in this study were comparable with those reported in the previous nationwide study on rt-PA use in Japan 18 . This suggests that the findings may represent the real-world situation in Japan. Second, the DPC database lacks data regarding several important factors, including the National Institutes of Health Stroke Scale (NIHSS) score, time metrics, and imaging results 7,8,13,14 . Thus, we used the JCS score, rather than the NIHSS score, as an index of stroke severity. Nationwide implementation of the CTGS program of the J-ASPECT study may solve this issue. Third, the LVO site was not included in the analysis; however, our recent study showed that approximately 86.4% of patients with AIS underwent MT from January 2013 to December 2015 according to the guidelines 29 . Fourth, we did not examine the effect of CSC capabilities on in-hospital care provision 29,39 . The result of the CTGS, an ongoing nationwide quality improvement initiative in Japan, may answer this question 14,29 . Finally, long-term outcomes (≥ 90 days) after AIS were not evaluated. Further studies are necessary to address these issues.

Conclusion
In the current transitional period, while there is a relative shortage of thrombectomy-capable hospitals, increasing the number of hospitals with moderate CSC scores may benefit the general Japanese population by equalizing access to MT in response to AIS. Certification of endovascular physicians qualified to perform MT may also promote such accessibility in thrombectomy-capable hospitals.

Data availability
We have documented the data, methods, and materials used to conduct the research in this report. The individual patient data are not publicly available owing to the memorandum signed by the directors of the participating hospitals and the principal investigator of the J-ASPECT Study group.

Funding
This study was supported by the Practical Research Project for lifestyle-related diseases, including cardiovascular diseases and diabetes mellitus, managed by the Japan Agency for Medical Research and Development (JP19ek0210088, JP20ek0210129, JP20ek0210147, JP21ek0210147); Grants-in-Aid from the Japanese Ministry of Health, Labour and Welfare (H28-Shinkin-Ippan-011, 19AC1003); KAKENHI grants (25293314, 18H02914) from the Japan Society for the Promotion of Science; and Intramural Research Fund (20-4-10) for Cardiovascular Diseases of National Cerebral and Cardiovascular Center.

Competing interests
Dr. Iihara is the principal investigator. Dr. Kada  and Daiichi Sankyo Co., Ltd.; and personal fees from Biomedical Solutions Co., Ltd., Johnson and Johnson Co., Ltd., Medtronic Co., Ltd., Penumbra Co., Ltd., Stryker Co., Ltd., and Terumo Co., Ltd., outside of the submitted work. Dr. Higashi reports receiving grants from the Japan Agency for Medical Research and Development and a KAKENHI grant from the Japan Society for the Promotion of Science during the conduct of the study. Dr. Sakamoto reports receiving grants from the Japan Agency for Medical Research and Development during the conduct of the study; personal fees from Boehringer Ingelheim Japan, Inc.; and grants from Asahi Kasei Pharma Corporation, Japan Blood Products Organization, and the Japanese Ministry of Health, Labour and Welfare, outside the submitted work. Dr. Iihara reports receiving grants from the Japanese Ministry of Health, Labour and Welfare, the Japan Agency for Medical Research and Development, and a KAKENHI grant from the Japan Society for the Promotion of Science during the conduct of the study; as well as grants from Otsuka Pharmaceutical Co., Ltd., Kaneka Medix Corporation, Eisai Co., Ltd., and Mitsubishi Tanabe Pharma Co., outside the submitted work. All other authors have nothing to disclose.
Correspondence and requests for materials should be addressed to K.I.
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