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Abstract
Objectives To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan.
Design Retrospective study.
Setting Six hundred and thirty-one primary care institutions in Japan.
Participants Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database.
Primary and secondary outcome measures Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3–6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1–25 points).
Results In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality.
Conclusions The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.
- Neurosurgery
- VASCULAR SURGERY
Data availability statement
Data may be obtained from a third party and are not publicly available.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
A large-scale, representative hospitals of Japan provided data on national trends in the outcomes of subarachnoid haemorrhage and the prognostic influence of stroke centre capability in Japan for this cross-sectional study.
The Diagnosis Procedure Combination (DPC) database lacks several types of data, such as aneurysm characteristics, cause of death, delayed cerebral ischaemia and treatment of vasospasm.
Not all hospitals agreed to participate in this study, therefore, the results of this study do not reflect the entire situation in Japan.
Inaccuracies in coding may exist within our DPC database.
Introduction
The International Subarachnoid Aneurysm Trial (ISAT), a large randomised controlled trial that compared neurosurgical clipping with endovascular coiling in patients with subarachnoid haemorrhage (SAH), demonstrated the superiority of coiling in 2002.1 After the publication of ISAT, there was a significant increase in endovascular treatment in patients with SAH in the USA and Europe.2–10 In Japan, although clipping remains the mainstay treatment for SAH,11 the number of coiling procedures has increased.12 13
Defining the quality and value of healthcare by reporting processes and outcome measures has received increasing attention. Consequently, the Brain Attack Coalition (BAC) proposed the establishment of Comprehensive Stroke Centers (CSCs) to care for patients who had a stroke, including patients with SAH.14 15 In 2010, we launched the J-ASPECT study, a nationwide survey of acute stroke care capacity, for the proper designation of CSCs in Japan.16–18 Our recent study showed that CSC capabilities were significantly associated with lower in-hospital mortality in clipped, but not coiled, patients with SAH, suggesting that in the modern endovascular era, better outcomes of clipping may be achieved in facilities with high CSC capabilities.19 Notably, we found a significant improvement in the CSC capabilities between 2010 and 2018, which was mainly related to the availability of endovascular treatment and multidisciplinary care.20 Taken together, these studies raise a question regarding the effect of temporal changes in CSC capabilities on the overall clinical outcomes of patients with SAH and the therapeutic choices and outcomes of patients who have undergone clipping and coiling in the modern endovascular era. In Japan, primary stroke centres have been designated by the Japan Stroke Society, but the concept of CSCs has not yet been established. A paradigm shift is needed in the definition of CSCs and the designation of CSCs to include postacute care and outcome follow-up to meet the patients’ and caregivers’ most important requests: better access and improved secondary prevention, stroke rehabilitation, and personalised care.21 However, no previous studies have addressed the important question about the effect of temporal changes in CSC capabilities, on a national level, on the clinical outcomes of patients with SAH who have undergone clipping and coiling.
Here, we sought to examine national, 6-year trends in in-hospital clinical outcomes of patients with SAH and those who underwent clipping or coiling and the prognostic influence of temporal trends in the CSC capabilities on these indicators.
Materials and methods
Diagnosis Procedure Combination database
The J-ASPECT study group used the Diagnosis Procedure Combination (DPC) database to gain new clinical insights on haemorrhagic stroke,11 19 22 an approach we applied again for this cross-sectional survey. The DPC database is a mixed-case patient classification system that was launched in 2002 by the Japanese Ministry of Health, Labour and Welfare, and is linked to a hospital financing system.23 By 2015, the DPC system was adopted by an estimated 1580 acute care hospitals, representing approximately half of all Japanese hospital beds and encompassing a wide variety of centres, including rural, urban, academic, non-academic, small and large hospitals.17 The DPC database includes information on patient demographic characteristics, hospital characteristics, primary diagnoses and procedures based on the International Classification of Diseases and Injuries, 10th revision (ICD-10) procedure codes for discharge.23
Hospital and patient selection
Participation of the hospitals in the J-ASPECT study was voluntary in collaboration with the Japan Neurosurgical Society and Japan Stroke Society.16–18 We identified patients hospitalised for SAH due to a ruptured aneurysm in the deidentified discharge database using the ICD-10 diagnosis codes related to SAH (I60.0–9) (whole cohort). We further selected patients who had been urgently hospitalised between 1 April 2010 and 31 March 2016, and were treated by clipping or coiling (figure 1). We then extracted data on age, sex and comorbidities on admission, including those based on Charlson scores,24 level of consciousness on admission according to the Japan Coma Scale (JCS) (online supplemental appendix S1).11 16 19 22 25 To maximise the accuracy of the DPC data in the mixed-case patient classification system, at least one responsible physician (eg, physicians in charge or residents) was required to record the information regarding diagnoses and therapies received in each patient’s medical chart.26
Supplemental material
Flow chart of inclusion criteria. CSC, Comprehensive Stroke Center; DPC, Diagnosis Procedure Combination; ICD-10, International Classification of Diseases and Injuries, 10th revision; SAH, subarachnoid haemorrhage.
Assessment of CSC capabilities using an institutional survey
The CSC capabilities of the participating hospitals were measured using a validated scoring system (CSC score) in 2010 and 2014.16 We sent out questionnaires with 25 items, which was recommended by the BAC14 to assess the CSC capabilities of facilities to train institutions of the Japan Neurosurgical Society and the Japan Stroke Society that participated in the J-ASPECT study. The analysis was performed by combining the DPC data of patients with SAH admitted between 2010 and 2015 with the CSC score of each participant hospital. The questionnaire items were classified into five categories as follows: personnel, diagnostic, specific expertise, infrastructure and education (online supplemental appendix S2).15 20 One point was assigned to each item, yielding a maximum CSC score of 25. The J-ASPECT study group has examined the effect of CSC scores in patients with SAH, as previously reported.11 16 19
Study outcomes
The study outcomes were the annual number of patients with SAH who were left untreated, those who received clipping or coiling, in-hospital mortality and poor functional outcomes, defined as a modified Rankin Scale (mRS) score of 3–6, at discharge.
Statistical analysis
Treatment procedures were divided into three categories: clipping, coiling and neither clipping nor coiling (untreated group). In Japan, patients with SAH are treated according to the Japan Stroke Society Guideline for the Treatment of Stroke. The specific treatment (clipping, coiling and neither clipping nor coiling) is determined by the surgeons at each institution. We used hierarchical logistic regression models to examine temporal trends in the treatment procedure of patients with SAH in hospitals that agreed to participate in the assessment of CSC capabilities using an institutional survey in 2010 (sub-cohort 1). After excluding patients who were treated by both clipping and coiling in one hospitalisation from sub-cohort 1, we used hierarchical logistic regression models to examine temporal trends in the outcomes of patients with SAH in the hospitals (sub-cohort 2). The model had two levels (hospital and patient): random effects of hospital variation, as well as fixed effects of the CSC score and patient-related factors (age, sex, comorbidity, JCS score and fiscal year of hospitalisation). The interaction of treatment procedure and JCS score was also added to the model.
To examine the prognostic influence of temporal trends in the CSC capabilities on such outcomes, we also assessed the effects of the preceding changes in the CSC capabilities in 2010–2014 (per 1-point increase) by using patients with SAH in hospitals that agreed to participate in the assessment of CSC capabilities in both 2010 and 2014 (sub-cohort 3), similar to the former model. The model had two levels: random effects of hospital variation, as well as fixed effects of the CSC score (CSC score (2010) and the preceding improvement (2010–2014)) and patient-related factors (age, sex, comorbidity and the JCS score).
We also analysed the trend of the treatment procedure and the outcome of patients with SAH of the hospitals that participated every year for 6 years (April 2010–March 2016) (sub-cohort 4). In the above analyses, SAH severity was adjusted by the JCS score as in our previous studies,11 16 17 19 thus minimising its confounding effects. Year trends in patient characteristics were analysed by linear regression for age and Charlson score, probit model for sex, and ordinal probit model for JCS. In untreated patients, patients coded with I60.9 (non-traumatic SAH, unspecified) may be non-aneurysmatic. To address this, we conducted sensitivity analyses by excluding cases with a diagnosis of I60.9. All analyses were performed using SAS V.9.4 (SAS Institute). Patients with missing data were excluded from this study.
Patient and public involvement
The data for this study are based on information collected by the J-ASPECT study. Patients and the public were not involved in the development of this study.
Results
National trends in characteristics and proportion of treatment modalities of patients with SAH
In total, 45 011 patients with SAH from 631 hospitals were included in the entire cohort. During the 6-year period, the number of participating hospitals and patients with SAH per year gradually increased from 254 to 374 and 4911 to 8943, respectively. The age significantly increased; however, the proportion of men, comorbidities measured using the Charlson Score Index (CSI) and proportion of comatose (JCS:3-digit code) patients remained stable (table 1).
Characteristic and outcomes of patients with subarachnoid haemorrhage in the J-ASPECT study over 6 years (fiscal year, April 2010 to March 2016)
Trend in the treatment procedure of patients with subarachnoid haemorrhage over 6 years after adjustment for age, sex, level of consciousness on admission (the Japan Coma Scale score), Charlson score, baseline Comprehensive Stroke Center score (in 2010) and years
Trend in outcomes of subarachnoid haemorrhage patients over 6 years after adjustment for age, sex, level of consciousness on admission (the Japan Coma Scale) and Charlson score, baseline Comprehensive Stroke Center score (in 2010) and years
Overall, in all patients with SAH, the proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5% (figure 2), while the proportion of those who received coiling and were left untreated (untreated group) gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively (figure 2) over the study period (table 1). After adjusting for patient-related and hospital-related factors in 36 452 patients from 452 hospitals with the CSC score in 2010 available (sub-cohort 1), trends in decreased use of clipping (year for trend, OR 0.93 (95% CI 0.91 to 0.94)) and increased use of coiling (1.07 (1.05 to 1.09)) were significant (table 2). A similar finding was also observed among 11 763 patients with SAH in 74 facilities that participated consecutively every year during the study period (sub-cohort 4, online supplemental appendix S3).
Trends in treatment usage in hospitals participating in the J-ASPECT study for the 6-year study period (shown according to fiscal year).
We found that the proportion of patients with SAH who remained untreated increased (1.03 (1.01 to 1.05)) (table 2). Patient characteristics of the untreated group are shown in online supplemental appendix S4. The proportion of men, comorbidities and proportion of comatose patients (JCS:3-digit code) remained stable.
National trends in in-hospital outcomes of patients with SAH
Over the 6-year period, in-hospital mortality and poor outcomes of all patients with SAH decreased from 28.2% to 27.1% (figure 3A) and 54.1% to 52.2% (figure 3B), respectively, in the entire cohort (table 1). After adjusting for patient-related and hospital-related factors in 36 452 patients from 452 hospitals with the CSC score available (sub-cohort 1), the in-hospital mortality of all patients with SAH significantly decreased (per year 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)) (table 3). Online supplemental appendices S5 and S6 show the yearly trends of outcomes of JCS 0, 1-digit, 2-digit and 3-digit codes in the untreated, clipping and coiling groups. We found a significant interaction between the treatment procedure (neither clipping nor coiling, clipping, coiling) and the JCS score on both in-hospital mortality and poor outcomes (p for interaction <0.001). Therefore, we analysed the trends in the outcomes of patients with SAH for each treatment procedure. Excluding those who underwent both clipping and coiling in one hospitalisation, sub-cohort 2 included 36 153 patients from 452 hospitals with available CSC scores. The in-hospital mortality of patients with SAH who underwent coiling (0.94 (0.89 to 0.98)) and those who were left untreated (0.93 (0.90 to 0.96)) significantly decreased, while that of those who underwent clipping remained stable (table 3). The proportion of poor outcomes in the untreated group (0.94 (0.90 to 0.98)) significantly decreased, while that of clipped or coiled patients remained unchanged (table 3). A similar finding was observed in patients with SAH in sub-cohort 4, who participated in this study consecutively for 6 years (online supplemental appendix S7). To estimate the reason for the improvement in the outcome of patients with untreated SAH, we examined the characteristics of patients with untreated SAH during these 6 years.
Trends in in-hospital mortality (A) and proportion of patients with modified Rankin scale scores of 3–6 at discharge (B) among patients with subarachnoid haemorrhage for the 6-year study period (year for trend, p<0.001). Outcomes are shown according to fiscal year (eg, 2015 means April 2015 to March 2016).
Effect of temporal changes in CSC capabilities on in-hospital outcomes and use of treatment modalities among patients with SAH
Of the participating hospitals, 335 (53.1%) responded to the two institutional surveys (2010 and 2014), and 31 393 patients with SAH were included in sub-cohort 3. Temporal changes in fulfilment rates of each item on the CSC capabilities from 2010 to 2014 are shown in online supplemental appendix S8. After adjusting for age, sex, CSI, level of consciousness and hospital-related factors, preceding improvement of the CSC score was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)). On the other hand, preceding improvement of the CSC score was not associated with in-hospital mortality and poor functional outcomes, regardless of treatment modality (table 4).
The effect of Comprehensive Stroke Center score preceding improvement (2010–2014) on outcomes (per 1-point increase) after adjustment for age, sex, level of consciousness on admission (the Japan Coma Scale) and Charlson score
Sensitivity analysis
As analysis corresponding to table 2, we investigated trends in the treatment procedure of patients with SAH, excluding cases with a diagnosis of I60.9 over 6 years. We found that the proportion of untreated patients with SAH remained unchanged (1.01 (0.99 to 1.03)).
As analysis corresponding to table 3, we investigated trends in outcomes of patients with SAH excluding cases with a diagnosis of I60.9 over 6 years We found that the in-hospital mortality of untreated SAH patients significantly decreased (0.93 (0.89 to 0.97)) whereas the proportion of mRS 3–6 at discharge remained unchanged (1.00 (0.94 to 1.06)).
As analysis corresponding to table 4, we investigated the effect of the CSC score preceding improvement (2010–2014) on the outcomes (per 1-point increase) of patients with SAH, excluding cases with a diagnosis of I60.9. We found that preceding improvement of the CSC score was not associated with in-hospital mortality (1.00 (0.97 to 1.04)) and discharge mRS 3–6 (0.98 (0.94 to 1.03)).
Discussion
This study demonstrates national, 6-year trends in the characteristics and outcomes of patients with SAH and the effect of the treatment procedure from 2010 to 2015 in Japan. The proportion of patients who underwent coiling and those who were left untreated increased, whereas that of clipped patients decreased. After adjusting for patient-related and hospital-related factors, in-hospital mortality decreased in the coiled and untreated patients, despite unchanged in-hospital mortality in the clipped patients over time. Preceding improvement in CSC capabilities was associated with increased use of coiling but did not influence in-hospital outcomes after clipping or coiling.
National trends in patient characteristics and treatment of SAH
In this study, the proportion of men among patients with SAH was comparable, but the median age was older than that in studies from Western countries.2 5 6 Trends in the increased use of coiling in this study are consistent with those reported in previous studies on endovascular treatment for SAH in the USA and Europe after ISAT.2–10 The unique finding of the present study is that the increased use of coiling was associated with preceding improvement of the CSC score of the facility. This is supported by our recent study showing trends in an improvement in CSC capabilities of the training institutions of the relevant societies in Japan between 2010 and 2018, which was mainly related to the availability of endovascular treatment (eg, coiling of aneurysms increased from 48.1% in 2010 to 62.4% in 2014) and multidisciplinary care. This result is consistent with that of our previous study showing that preceding improvement of CSC capabilities is associated with increased use of recombinant tissue-plasminogen activator infusion and mechanical thrombectomy for acute ischaemic stroke in Japan.27 Despite such trends in the increased use of coiling, clipping remains the mainstay treatment for SAH in Japan.11 A previous report from the USA demonstrated that coiling is more costly than clipping, which may affect the rapid widespread availability of the procedure.4
The proportion of patients with untreated SAH in this study is consistent with the range (38%–70%) of that in population-based studies of patients with SAH using case ascertainment by chart review28–30 and is lower than that of previous studies using administrative data from the USA.4 The trends in the increased proportion of patients with untreated SAH noted in this study may have several explanations. First, patients with untreated SAH were not considered to be appropriate targets in the included hospitals owing to higher age, comorbidities, severity of SAH, and more widespread recognition of premature withholding or withdrawal of support based on self-fulfilling prophecies. Admittedly, the untreated patients were approximately 3 years older but were more likely to be comatose (the JCS 3-digit 55.5% vs 37.3% in 2015) compared with patients with all SAH in this study. The mean age and Charlson comorbidity score, however, showed no temporal changes, and the proportion of comatose patients decreased over the study period. Taken together, these facts may make this explanation less likely. Further study is necessary to examine the effect of comorbidities such as dementia, congestive heart failure and end-of-life support for patients with severe SAH on such trends in ageing populations such as Japan.31
Second, in patients with mild SAH, measured by the JCS score on admission, a conservative strategy might have been selected because of either an unknown origin of SAH or early deterioration due to rebleeding after admission. Third, interhospital transfer of patients with SAH, especially those with complex cerebral aneurysms and severe comorbidity, to hospitals with higher CSC capabilities may explain such trends. It is important to note that CSC capabilities are associated with better outcomes of clipped, but not coiled, patients with SAH.19 For example, high-flow bypass and reconstructive endovascular treatment for blood blister aneurysms of the internal carotid artery could be performed only at select institutions.32 Fourth, the withdrawal of treatment in patients with SAH owing to advanced age and the need for nursing care might have resulted in transfer to a nursing facility or long-term healthcare facility without curative treatment.
National trends in in-hospital outcomes of patients with SAH
In general, the most common cause of death and poor functional outcomes following SAH is initial bleeding.33 Over time, we found that the severity of SAH and age remained unchanged. The ISAT reported that the probability of death or dependency at 2 months after treatment was higher in the clipping group.1 In the current study, we found trends in improved in-hospital mortality for all SAH patients. The improvement of in-hospital mortality for all SAH patients may be explained by the increased use of coiling, and reduced in-hospital mortality in the coiled and untreated patients.
The trends in improved mortality of the coiled patients may be explained by the steep learning curve of coiling and the rapid development of endovascular technology.19 As for the untreated group, the reduced mortality in this study is consistent with that of a previous study on trends in better clinical outcomes of untreated patients with SAH, using a large administrative database from the USA, suggesting a role for the development of other medical interventions.4 The lack of improvement in in-hospital mortality after clipping, however, in this study was different from that of previous studies from the USA, which showed that in-hospital mortality rates improved for both clipping and coiling.3 7 The presence of unmeasured confounders, such as trends in increased use of clipping for more complex aneurysms, may explain such trends.3 7 Further studies are necessary to answer this question.
A lower proportion of poor functional outcomes was noted only in the untreated group in this study. A previous study demonstrated that the likelihood of an excellent outcome (mRS score 0–a1) is predicted by a good clinical condition after resuscitation, absence of intracerebral haemorrhage on presentation, no evidence of infarction on brain imaging and the absence of blood transfusion during hospitalisation.34 The lack of interval changes in the functional outcomes in either the clipped or coiled patients with SAH in this study is consistent with the findings of a recent study in the USA, showing that the NIS-SOM, a superior proxy for the discharge mRS, did not change for either treatment modality between 2004 and 2014.3 7 Such a lack of improvement in functional outcomes after both modalities may be explained by a change in nationwide discharge protocols, likely secondary to several studies that have advocated for early rehabilitation as a means to improve outcomes in SAH reported in the USA.3 35 In Japan, the Ministry of Health, Labour and Welfare encourages collaboration between regional core hospitals and local medical institutions through a comprehensive community care system.36
Prognostic influence of temporal changes of the CSC capabilities on patient outcomes of SAH
While patient clinical and radiographic phenotypes remain the primary outcome predictors in patients with SAH, interregional and cross-national disparities may also contribute to heterogeneity in patient outcomes.37 38 Such differences may be related to the expertise of the treating physician and the volume of SAH encountered within the institution or may be secondary to discrepancies in treatment protocols for common SAH complications, including hydrocephalus and vasospasm.19 39 Among patients with acute ischaemic stroke, we previously showed that in the same institutions and over the same study period, even a small preceding improvement of the CSC capabilities between 2010 and 2014 (median: 1-point increase, IQR: 1–3 points) was associated with reduced in-hospital mortality and improved outcomes.27 Among patients with SAH in the present study, however, such improvement in CSC capabilities had no effect on short-term clinical outcomes. Although the CSC score consists of heterogeneous items of stroke care expertise, it better reflects the joint effects made by all healthcare professionals, including physicians, nurses and other clinical staff.16–18 In fact, a previous study demonstrated that higher CSC capabilities, categorised into quartiles, were significantly associated with lower in-hospital mortality (eg, Q1 8.5% vs Q4 6.7%) in clipped, but not coiled, patients with SAH,19 suggesting that better outcomes after clipping for patients with SAH may be achieved in facilities with higher CSC capabilities. If referral of patients with SAH with complex aneurysms to facilities with higher CSC capabilities for treatment, especially clipping, increases over time, the effect of such a small increase in the CSC score on the clinical outcomes of patients with SAH may be masked in this analysis because of the presence of unmeasured confounders such as aneurysm size and location and patient comorbidities such as frailty. In addition, the clinical outcomes of patients with SAH may be associated with improvement of quality indicators, such as process indicators including SAH intervention within 72 hours of onset, and administration of fasudil hydrochloride or ozagrel sodium for vasospasm.40 Recently, we developed the Close the Gap-Stroke programme, the first nationwide quality improvement initiative for acute stroke care in Japan.40 Further studies are necessary to examine the effect of adherence to quality indicators on clinical outcomes after SAH.
Relevance and implication of this study
Our previous study showed that better outcomes of patients directly transported who receive clipping, but not coiling, may be achieved in hospitals with the highest baseline (>19 points) CSC capabilities (vs lowest: 6–13).19 In this study, an increased use of coiling, not clipping, was associated with the preceding increase of the CSC capabilities, which was not associated with in-hospital outcomes after clipping. This is in marked contrast to the positive effect of the preceding increase of the CSC capabilities on better outcomes of rt-PA infusion and mechanical thrombectomy in patients with acute ischemic stroke (AIS) in our previous study.25 This may be because interval increase of the CSC capabilities during the study period in Japan is mainly due to increased availability of items related to endovascular surgery and multidisciplinary care (eg, endovascular physicians, stroke unit and interventional coverage 24/7).20 After the publication of the ISAT, in patients with ruptured aneurysms suitable for both treatments, endovascular treatment is increasingly being selected worldwide.1 While there is a consistent increase in the number of endovascular surgeons, those who could treat difficult aneurysms are retiring from emergent neurosurgical care. In addition, the technical standards of clipping had not changed significantly over the study period, decreasing the effect of such small interval improvement of the CSC capabilities on better outcomes of clipped patients.
Training a younger generation of highly skilled cerebrovascular surgeons is mandatory, particularly in facilities with the highest CSC capabilities with high case volume. In response to such unmet needs, the Japanese Society on Surgery for Cerebral Stroke launched in 2016 a skills certification for cerebrovascular surgery. Since the transfer of patients with SAH to the highest CSC capabilities may be associated with better outcomes after clipping,19 further study is required to examine the effect of centralisation of patients of clipping based on implementation of the skills certification system.
Limitations
Our study has several limitations. First, the DPC database lacks several types of data, such as aneurysm characteristics,38 cause of death, delayed cerebral ischaemia and treatment of vasospasm. However, similar limitations pertain to all previous database studies using ICD coding that examined the relationship between trends and outcomes after aneurysm treatment.3–7 9 10 Second, not all hospitals agreed to participate in this study. The institutions participating in the J-ASPECT study were self-selected; therefore, the results of this study do not reflect the entire situation in Japan. In a previous J-ASPECT study,16 we investigated the characteristic differences between centres that did not participate in that study and those that did. We found that the institutions that participated in this study tended to have more beds and more stroke cases than the non-participating institutions. This suggests that the institutions that were more active in stroke care and potentially eligible for the CSC participated in that study and were likely motivated to improve stroke care quality.16 This could be a potential source of bias in this study. However, the results of the present study could encourage improvement in the treatment outcomes of non-participating institutions. We believe that this study will contribute to the improvement of treatment outcomes in Japan. Third, inaccuracies in coding may exist within our DPC database.41 Especially, in untreated patients, the patients coded with I60.9 (non-traumatic SAH, unspecified) may be non-aneurysmatic cases. Overall, the sensitivity analysis showed comparable findings with the original analysis except for trends in proportion of untreated SAH patients and trends in proportion of mRS 3–6 in untreated patients. The part of different results of sensitivity analyses suggested that the patients coded with I60.9 have increased the proportion of untreated SAH patients and decreased the proportion of mRS 3–6 in untreated patients. The comparison of the characteristics and outcomes between the patients with a diagnosis of I60.9 and those excluding a diagnosis of I60.9 (online supplemental appendix S9) showed the patients with a diagnosis of I60.9 were more likely to be comatose than those excluding a diagnosis of I60.9 (the JCS 3-digit 47.8% vs 34.6%, p<0.001), and show higher proportion of untreated patients (75.9% vs 24.8%, p<0.001). The results suggest that, in this study, the patients coded with I60.9 was likely to include a large number of severe SAH cases that were not considered as appropriate targets of curative procedures (coiling or clipping) at the time of admission. Although we investigated the characteristics of the patients coded with I60.9, the study based on ICD-10 have limitation in the terms of accurate diagnosis. Previously, we performed a validation study on patients with SAH in our analysis of the J-ASPECT study11 using a two-stage sampling method. In that study, we confirmed the high accuracy of diagnoses, treatment modalities and outcomes. In 2017, the Japan Neurosurgical Society established the Japan Neurosurgical Database (JND), which is a nationwide, prospective, observational study registry.42 In the near future, collaboration studies using other nationwide registries such as the JND may reveal new insights about patients with SAH and may overcome the above limitations of the J-ASPECT study. Fourth, because the DPC database contains medical information only during hospitalisation, long-term follow-up data were not included in this study. The ISAT reported that the probability of death or dependency at 2 months, 1 year and 10 years after treatment was higher in the clipped patients.1 43 We believe that short-term outcomes regarding mRS scores and mortality may be helpful as reasonable predictive markers for long-term outcomes. Further research is necessary to investigate long-term patient outcomes after SAH.
Conclusions
This nationwide study showed 6-year trends in overall better outcomes of patients with SAH, which may be attributable to the increased use of coiling and multidisciplinary care for untreated patients. Improvement of CSC capabilities during the study period is associated with increased use of coiling, but not with short-term clinical outcomes after both treatments. Further study is required to examine the effect of centralisation of clipping based on implementation of the skills certification system on outcomes of SAH patients after clipping.
Supplemental material
Supplemental material
Data availability statement
Data may be obtained from a third party and are not publicly available.
Ethics statements
Patient consent for publication
Acknowledgments
We thank the Japan Neurosurgical Society and the Japan Stroke Society for their collaboration.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Collaborators J-ASPECT Study Collaborators: Hidekazu Takahashi (Ageo Central General Hospital), Isao Sasaki (Ainomiyako Neurosurgery Hospital), Kazuo Kitazawa (Aizawa Hospital), Minoru Saitoh (Akashi City Hospital), Hitoshi Saito (Akita City Hospital), Hiroaki Shimizu (Akita University Hospital), Minoru Asahi (Ako City Hospital), Makoto Goda (Almeida Memorial Hospital), Atsuhito Takemura (Aomori City Hospital), Tatsuya Sasaki (Aomori Prefectural Central Hospital), Masaaki Shibukawa (Araki Neurosurgical Hospital), Isao Fuwa (Arao Municipal Hospital), Saburo Watanabe (Asahi General Hospital; Ashikaga Red Cross Hospital), Seiko Kataoka (Ashiya Municipal Hospital), Koji Takasaki (Atsuchi Neurosurgical Hospital), Kouji Shiga (Ayabe City Hospital), Kensuke Hayashida (Azumi General Hospital), Hidefuku Gi (Baba Memorial Hospital), Ryunosuke Uranishi (Bellland General Hospital), Toshihiko Iuchi (Chiba Cancer Center), Junichi Ono (Chiba Cerebral and Cardiovascular Center), Chiaki Ito (Chiba Children's Hospital), Kenji Wakui (Chiba Neurosurgical Clinic), Takashi Saegusa (Chiba Rosai Hospital), Isao Kitahara (Chiba Tokushukai Hospital), Yasushi Ejima (Chidoribashi Hospital), Hiroshi Tanaka (Chigasaki Municipal Hospital), Satoru Hayashi (Chikamori Hospital), Kazuyoshi Hattori (Chubu Rousai Hospital), Shinji Okita (Chugoku Rosai Hospital), Toshikazu Ichihashi (Chutoen General Medical Center), Tsugumichi Ichioka (Daiichitowakai Hospital), Shinichi Shirakami (Daiyukai General Hospital), Takeshi Matsuoka (Date Red Cross Hospital), Akio Hyodo (Dokkyo Medical University Koshigaya Hospital), Teruo Kimura (Doutou Neurosurgical Hospital), Tomonori Kobayashi (Ebina General Hospital), Kanehisa Kohno (Ehime Prefectural Central Hospital), Kazunori Yamanaka (Fuchu Hospital), Akira Morooka (Fuji City General Hospital), Nozomi Mori (Fujii Masao Memorial Hospital), Hideo Kunimine (Fujii Neurosurgical Hospital), Kazutaka Yatsushiro (Fujimoto General Hospital), Masahiro Satoh (Fujita General Hospital), Ichiro Nakahara (Fujita Health University Hospital), Syougo Imae (Fujiyoshida Municipal Hospital), Hirochiyo Wada (Fukaya Red Cross Hospital), Mamoru Murakami (Fukuchiyama City Hospital), Masanori Kabuto (Fukui Katsuyama General Hospital), Katsuyuki Hirakawa (Fukuoka City Hospital), Isao Inoue (Fukuoka Seisyukai Hospital), Hidenori Yoshida (Fukuoka Tokushukai Medical Center), Kiyoshi Kazekawa (Fukuoka University Chikushi Hospital), Masani Nonaka (Fukuoka University Hospital), Kouzou Fukuyama (Fukuoka Wajiro Hospital), Shigenari Kin (Fukuokashinmizumaki Hospiral), Kiyoshi Saito (Fukushima Medical University Hospital), Yoichi Watanabe (Fukushima Red Cross Hospital), Tadashi Arisawa (Fukuyama City Hospital), Kou Takahashi (Furukawaseiryou Hospital), Tetsuya Tanigawara (Gifu Municipal Hospital), Junki Ito (Gifu Prefectural Tajimi Hospital), Toru Iwama (Gifu University Hospital), Kei Hisada (Hachisuga Hospital), Makoto Takeda (Hakodate Central General Hospital), Jun Niwa (Hakodate Municipal Hospital), Mikio Nishiya (Hakodate Neurosurgical Hospital), Shuji Hayashi (Hakujyuji Hospital), Ichiro Fujishima (Hamamatsu City Rehabilitation Hospital), Teiji Nakayama (Hamamatsu Medical Center), Yoshihiko Watanabe (Hamamatsu Rosai Hospital), Koichirou Matsukado (Hamanomachi Hospital), Takamichi Yuguchi (Hanwa Memorial Hospital), Tadahisa Shono (Harasanshin Hospital), Hiroyuki Nishimura (Hata Kenmin Hospital), Jyunya Hayashi (Hayashi Hospital) (Hekinan Municipal Hospital), Keisuke Migita (Higashihiroshima Medical Center), Kazuhiro Yokoyama (Higashiosaka City Medical Center), Naofumi Isono (Higashisumiyoshi Morimoto Hospital), Satoshi Utsuki (Higashitotsuka Memorial Hospital), Hirotoshi Ohtaka (Higashiyamato Hospital), Takata Hisashi (Himi Municipal Hospital), Takamitsu Uchizawa (Hirosaki Stroke and Rehabilitation Center), Hiroki Ohkuma (Hirosaki University Hospital), Shigeki Nishino (Hiroshima City Hiroshima Citizens Hospital), Atsushi Tominaga (Hiroshima Prefectural Hospital), Masayuki Sumida (Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital), Kaoru Kurisu (Hiroshima University Hospital), Naoki Shinohara (HITO Medical Center), Kiyohiro Houkin (Hokkaido University Hospital), Mitsunobu Kaijima (Hokushikai Megumino Hospital), Kazumi Nitta (Hokuto Hospital), Junkoh Yamamoto (Hospital of the University of Occupational and Environmental Health), Shinichi Yoshimura (Hyogo College of Medicine), Yoshio Sakagami (Hyogo Prefectural Awaji Medical Center), Hideo Aihara (Hyogo Prefectural Kakogawa Medical Center), Takayuki Sakaki (Hyogo Prefectural Nishinomiya Hospital), Hiroko Oyama (Ibaraki Prefectural Central Hospital), Keishi Fujita (Ibaraki Seinan Medical Center Hospital), Sumio Kobayashi (Iida Municipal Hospital), Nobuaki Momozaki (Imari Arita Kyoritsu Hospital), Atsushi Sato (Ina Central Hospital), Hideki Murakami (Inagi Municipal Hospital), Masahito Hara (Inazawa Municipal Hospital), Akazi Kazunori (Institute of Brain and Blood Vessels Mihara Memorial Hospital), Fumitaka Miya (Ise Red Cross Hospital), Hisato Minamide (Ishikawa Prefectural Central Hospital), Tsuyoshi Inoue (Ishikiriseiki Hospital), Shinichiro Kurokawa (Ishinkai Yao General Hospital), Syuichi Ishikawa (Ishinomaki Red Cross Hospital), Naohisa Miura (Itabashi Chuo Medical Center), Shinya Noda (Itami Kousei Neurosurgical Hospital), Shoji Mashiyama (Iwaki Kyoritsu General Hospital), Shinji Amano (Iwata Municipal General Hospital), Kuniaki Ogasawara (Iwate Medical University Hospital), Takayuki Sugawara (Iwate Prefectural Central Hospital), Yukihiko Shimizu (Iwate Prefectural Isawa Hospital), Keiichi Saito (Iwate Prefectural Iwai Hospital), Kazuyuki Miura (Iwate Prefectural Kuji Hospital), Akinori Yabuta (Iwate Prefectural Ninohe Hospital), Tatumi Yamanome (Iwate Prefectural Oofunato Hospital), Hiroshi Seto (Izumi General Medical Center), Makoto Hasebe (Izumi Hospital), Hikaru Mizobuchi (Izumino Hospital), Junkoh Sasaki (JA Akita Kouseiren Oomagarikousei Medical center), Shin Tsuruoka (JA Toride Medical Center), Keiichi Nishimaki (Japanese Red Cross Akita Hospital), Katsumi Takizawa (Japanese Red Cross Asahikawa Hospital), Hiroki Toda (Japanese Red Cross Fukui Hospital), Hitoshi Tsugu (Japanese Red Cross Fukuoka Hospital), Nozomi Suzuki (Japanese Red Cross Kitami Hospital), Takeshi Kohno (Japanese Red Cross Kochi Hospital), Shu Hasegawa (Japanese Red Cross Kumamoto Hospital), Ken Asakura (Japanese Red Cross Maebashi Hospital), Ichiro Suzuki (Japanese Red Cross Medical Center), Masaki Miyatake (Japanese Red Cross Society Azumino Hospital), Hiromu Konno (Japanese Red Cross Society Hachinohe Hospital), Katsunobu Takenaka (Japanese Red Cross Takayama Hospital), Akira Ikeda (JCHO Chukyo Hospital), Keizou Yamamoto (JCHO Hitoyoshi Medical Center), Yoshihiro Nishiura (JCHO Isahaya General Hospital), Keigo Matsumoto (JCHO Kobe Central Hospital), Kazunari Koga (JCHO Kumamoto General Hospital), Satoshi Inoha (JCHO Kyushu Hospital), Masaki Morisige (JCHO Nankai Medical Center), Kunihiko Harada (JCHO Tokuyama Central Hospital), Hirofumi Hiyama (JCHO Tokyo Takanawa Hospital), Yasuaki Takeda (JCHO Tokyo Yamate Medical Center), Taturou Mori (JCHO Yokohama Chuo Hospital), Takekazu Akiyama (Jinmeikai Akiyama Neurosurgical Hospital), Osamu Okuda (Juntendo Tokyo Koto Geriatric Medical Center), Hajime Arai (Juntendo University Hospital); (Juntendo University Nerima Hospital); (Juzenkai Hospital), Kazuaki Awamori (Kaetsu Hospital), Naoki Shirasaki (Kaga Medical Center), Kimihiro Yoshino (Kagawa Rosai Hospital), Atsushi Shindo (Kagawa University Hospital), Kazuho Hirahara (Kagoshima City Hospital), Shunichi Tanaka (Kagoshima Prefectural Kanoya Medical Center), Teruaki Kawano (Kagoshima Tokushukai Hospital), Kazunori Arita (Kagoshima University Hospital); (Kainan Hospital), Hiroaki Sawaura (Kamagaya General Hospital), Hiromu Hadeishi (Kameda Medical Center), Yoichi Uozumi (Kamiiida Daiichi General Hospital), Masahiko Tanaka (Kan-Etsu Hospital), Shunsuke Shiraga (Kanazawa Medical University Hospital), Shuji Sato (Kanazawa Neurosurgical Hospital), Mitsutoshi Nakada (Kanazawa University Hospital), Kimihisa Kinoshita (Kaneda Hospital), Nakazawa Kazutomo (Kano Hospital), Yasuhiro Fujimoto (Kansai Electric Power Hospital), Kunikazu Yoshimura (Kansai Medical University Hospital), Masaaki Iwase (Kansai Medical University Takii Hospital), Shinichi Yagi (Kanto Neurosurgical Hospital), Atsushi Tsuchiya (Kanto Rosai Hospital), Junichi Harashina (Kasai Shoikai Hospital), Akira Watanabe (Kasaoka Daiichi Hospital), Sadao Kaneko (Kashiwaba Neurosurgical Hospital), Naoto Kuwayama (Kasugai Municipal Hospital), Junya Hayashi (Kawasaki Hospital), Masaaki Uno (Kawasaki Medical School Hospital), Masayuki Sasou (Kazuno Kosei Hospital), Sotaro Higashi (Keiju Medical Center), Kazunari Yoshida (Keio University Hospital), Masakazu Kitahara (Kenwakai Hospital), Kenwakai Otemati Hospital (Kenwakai Otemati Hospital), Satoshi Suzuki (Kieikai Hospital), Sumio Suda (Kimitsu Chuo Hospital), Amami Kato (Kindai University Hospital), Yusaku Nakamura (Kindai University Sakai Hospital), Satoshi Magarisawa (Kiryu Kosei General Hospital), Kenji Hashimoto (Kishiwada City Hospital), Hiroyuki Matsumoto (Kishiwada Tokushukai Hospital), Hirotoshi Hamaguchi (Kita-Harima Medical Center), Tomohiko Satou (Kitakami Saiseikai Hospital), Masaru Idei (Kitakyushu General Hospital), Haruhisa Tsukamoto (Kitakyushu Municipal Medical Center), Eiichiro Kamatsuka (Kitamurayama Hospital), Toshihiro Kumabe (Kitasato University Hospital), Naoaki Sato (Kobari General Hospital), Yasuyuki Toba (Kobayashi Neurosurgical Neurological Hospital), Nobuyuki Sakai (Kobe City Medical Center General Hospital), Takashi Tominaga (Kobe Ekisaikai Hospital), Haruo Yamashita (Kobe Red Cross Hospital), Eiji Kohmura (Kobe University Hospital), Masanori Morimoto (Kochi Health Sciences Center), Tetsuya Ueba (Kochi Medical School Hospital), Toyoaki Shinohara (Kofu Neurosurgical Hospital), Kazuyoshi Watanabe (Kohka Public Hospital), Hidenori Endo (Kohnan Hospital), Kenjirou Hujiwara (Kohsei General Hospital), Ichiro Nakahara (Kokura Memorial Hospital), Toshinori Hasegawa (Komaki City Hospital), Hisashi Nitta (Komatsu Municipal Hospital), Kuroyanagi Takayuki (Komoro Kosei General Hospital), Nobuhiko Mizutani (Konan Kosei Hospital), Akira Tsunoda (Koshigaya Municipal Hospital), Fumio Suzuki (Koto Memorial Hospital), Tetsuya Morimoto (Kouseikai Takai Hospital), Takuya Kawai (Koyama Memorial Hospital), Mitsuyuki Fujitsuka (Kugayama Hospital), Akira Takada (Kumamoto City Hospital), Hiromasa Tsuiki (Kumamoto Rousai Hospital), Junichi Kuratsu (Kumamoto University Hospital), Masaki Chin (Kurashiki Central Hospital), Hidemichi Sasayama (Kurashiki Heisei Hospital), Shigehiro Ohmori (Kurosawa Hospital), Seiko Hasegawa (Kurosishi General Hospital), Kazuhiro Kikuchi (Kurosu Hospital), Motohiro Morioka (Kurume University Hospital), Masanori Isobe (Kushiro Rosai Hospital), Hiroki Yoshida (Kyorin University Hospital), Masayuki Yokota (Kyoritsu Hospital), Nozomu Murai (Kyoto City Hospital), Yasumasa Yamamoto (Kyoto Katsura Hospital), Nobuhito Mori (Kyoto Min-Iren Chuo Hospital), Minoru Kidooka (Kyoto Okamoto Memorial Hospital), Hiroshi Tenjin (Kyoto Second Red Cross Hospital), Susumu Miyamoto (Kyoto University Hospital), Yoshihiro Iwamoto (Kyoto Yamashiro General Medical Center), Hitonori Takaba (Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers), Sei Haga (Kyushu Rosai Hospital), Koji Iihara (Kyushu University Hospital), Yoshinori Arai (Makita General Hospital), Toshiyuki Tsukada (Maruko Central Hospital), Hirohide Karasudani (Matsudo City Hospital), Kenji Hashimoto (Matsushita Memorial Hospital), Masakazu Suga (Matsuyama Shimin Hospital), Kawamoto Yukihiko (Mazda Hospital), Hiroaki Fujiwara (Meisei Hospital), Naoto Izumi (Meiseikai Abashiri Neurosurgical Rehabilitation Hospital), Youtarou Takeuchi (Meitetsu Hospital), Motohiro Arai (Midorigaoka Hospital), Hidenori Suzuki (Mie University Hospital), Shinji Okumura (Mimihara General Hospital), Hiromasa Tsuiki (Minamata City General Hospital and Medical Center), Tomoyoshi Oikawa (Minamisoma City General Hospital), Hisashi Tanaka (Minato Medical Coop-Kyoritsu General Hospital), Yasushi Shibata (Mito Kyodo General Hospital), Tetsuya Masaoka (Mitoyo General Hospital), Takashi Matsuoka (Mitsugi General Hospital), Masahiko Kasai (Mitsuwadai General Hospital), Hitoshi Miyake (Miyake Neurosurgical Hospital), Hajime Ohta (Miyakonojo Medical Association Hospital), Osamu Hamasaki (Miyoshi Central Hospital), Misao Nishikawa (Moriguchi-Ikuno Memorial Hospital), Naohiko Kubo (Morioka Red Cross Hospital), Yosimasa Kinosita (Munakata Suikokai General Hospital), Hiroshi Ooyama (Muroran City General Hospital), Hiroyuki Kaidu (Musashino General Hospital), Tarou Komuro (Nagahama City Hospital), Hiroaki Shigeta (Nagano Children's Hospital), Yoshikazu Kusano (Nagano Municipal Hospital), Shigekazu Takeuchi (Nagaoka Chuo General Hospital), Takayuki Matsuo (Nagasaki University Hospital), Yoshiharu Tokunaga (Nagasakiken Shimabara Hospital), Norimoto Nakahara (Nagoya Central Hospital), Nobukazu Hashimoto (Nagoya City East Medical Center), Mitsuhito Mase (Nagoya City University Hospital), Keizo Yasui (Nagoya Daini Red Cross Hospital), Junpei Yoshimoto (Nagoya Memorial Hospital), Toshihiko Wakabayashi (Nagoya University Hospital), Jin Momoji (Naha City Hospital), Kenji Kamiyama (Nakamura Memorial Hospital), Koji Oka (Nakamura Memorial South Hospital), Hiromichi Koga (Nakatsu Municipal Hospital), Kazuya Morimoto (Nakatsu Neurosurgical Hospital), Tsutomu Kadekaru (Nanbu Tokushukai Hospital), Hiroyuki Nakase (Nara Medical University Hospital), Junichi Iida (Nara Prefectural Nara Hospital), Michio Nakamura (Narita Red Cross Hospital), Hiroharu Kataoka (National Cerebral and Cardiovascular Center), Naoki Tokumitsu (Nayoro City Hospital), Yasuyuki Nagai (NHO Beppu Medical Center), Hirokazu Tanno (NHO Chiba Medical Center), Hiroyuki Masaoka (NHO Disaster Medical Center), Hiroshi Nakane (NHO Fukuoka Higashi Medical Center), Takato Kagawa (NHO Hamada Medical Center), Masaaki Saiki (NHO Himeji Medical Center), Satoshi Ushikoshi (NHO Hokkaido Medical Center), Kotaro Ogihara (NHO Iwakuni Clinical Center), Junichi Imamura (NHO Kagoshima Medical Center), Katsuhiro Yamashita (NHO Kanmon Medical Center), Akira Nakamizo (NHO Kyushu Medical Center), Yoshinari Nakamura (NHO Minami Wakayama Medical Center), Ei-Ichirou Urasaki (NHO Nagasaki Kawatana Medical Center), Noriyuki Suzaki (NHO Nagoya Medical Center), Hidehiro Hirabayashi (NHO Nara Medical Center), Chiaki Takahashi (NHO Niigata Hospital), Youichirou Namba (NHO Okayama Medical Center), Kazuo Hashikawa (NHO Osaka National Hospital), Tomonori Yamada (NHO Osakaminami Medical Center), Masayuki Ezura (NHO Sendai Medical Center), Kazuyuki Kuwayama (NHO Shikoku Medical Center for Children and Adults), Keiichi Sakai (NHO Shinshu Ueda Medical Center), Katsuhiro Kuroda (NHO Shizuoka Medical Center), Hideyuki Kurihara (NHO Takasaki General Medical Center), Masayuki Ishihara (NHO Tochigi Medical Center), Hideki Sakai (NHO Toyohashi Medical Center), Masayuki Miyazono (NHO Ureshino Medical Center), Kosuke Miyahara (NHO Yokohama Medical Center), Atsuo Yoshino (Nihon University Itabashi Hospital), Hideaki Takahashi (Niigata Cancer Center Hospital), Akihiko Saito (Niigata City General Hospital), Hiroyuki Arai (Niigata Neurosurgical Hospital), Igarashi Michitoku (Niigata Prefectural Central Hospital), Mitsuo Kouno (Niigata Tokamachi Hospital), Osamu Onodera (Niigata University Medical & Dental Hospital), Shiro Kobayashi (Nippon Medical School Chiba Hokusoh Hospital), Shunichi Yoneda (Nipponbashi Hospital), Hiroshi Kusunoki (Nishiagatsuma Welfare Hospital), Naoya Takeda (Nishikobe Medical Center), Hiroji Miyake (Nishinomiya Kyoritsu Neurosurgical Hospital), Toshio Yokoe (Nishio Municipal Hospital), Tatsuya Nakamura (Nishitokyo Central General Hospital); (Nishiwaki Municipal Hospital), Takayuki Kubodera (Nissan Tamagawa Hospital), Mitsuhiko Hokari (Nitobe Memorial Nakano General Hospital), Yasunari Otawara (Noshiro Kosei Medical Center), Cheho Park (Noto General Hospital), Hidemitu Nakagawa (Nozaki Tokushukai Hospital), Kensuke Kawai (NTT Medical Center Tokyo), Souichi Obara (Obara Hospital), Haruki Takahashi (Obase Hospital), Masafumi Ohtaki (Obihiro Kosei General Hospital), Atsuya Okubo (Odate Municipal General Hospital), Katsuhiko Hayashi (Ogaki Tokushukai Hospital), Hideyuki Ohnishi (Ohnishi Neurological Center), Masahisa Kawakami (Ohta Nishinouchi Hospital), Yu Takeda (Oita Prefectural Hospital), Akihiko Kaga (Oitaken Koseiren Tsurumi Hospital), Yutaka Yamaguchi (Oitaoka Hospital), Ryoichi Hayashi (Okaya City Hospital), Koji Tokunaga (Okayama City Hospital), Hiroyuki Nakashima (Okayama Kyokuto Hospital); (Okayama Kyoritsu General Hospital), Yasuyuki Miyoshi (Okayama Saiseikai General Hospital), Isao Date (Okayama University Hospital), Atusi Kimoto (Okinawa Kyodo Hospital), Satoshi Yamamoto (Okinawa Miyako Hospital), Toshimitsu Uchihara (Okinawa Prefectural Hokubu Hospital), Tomoaki Nagamine (Okinawa Prefectural Nanbu Medical Center / Nanbu Child Medical Center), Masahiro Noha (Okinawa Red Cross Hospital), Hiromichi Sadashima (Okinawatokushuukai Uwajimatokushukai Hospital), Toshihiko Kinjo (Okitama Public General Hospital), Osamu Tao (Ome Municipal General Hospital), Masayuki Nakajima (Omihachiman Community Medical Center), Akira Isoshima (Omori Red Cross Hospital), Kouichi Kuramoto (Omuta City Hospital), Shigeru Daido (Onomichi Municipal Hospital), Yoshiyasu Iwai (Osaka City General Hospital), Kenji Ohata (Osaka City University Hospital); (Osaka Kouseinenkin Hospital), Manabu Kinoshita (Osaka Medical Center for Cancer and Cardiovascular Diseases), Toshihiko Kuroiwa (Osaka Medical College Hospital), Akatsuki Wakayama (Osaka Neurological Institute), Naoki Hayashi (Osaka Neurosurgical Hospital), Kohsuke Yamashita (Osaka Red Cross Hospital), Yasunobu Gotou (Osaka Saiseikai Ibaraki Hospital), Kouich Iwatsuki (Osaka University Hospital), Yoshida Masahiro (Osaki Citizen Hospital); (Ota Memorial Hospital), Nobuaki Kobayasi (Otaru Chuo Hospital), Yoshimasa Niiya (Otaru General Hospital), Syouji Mabuchi (Otaru Municipal Medical Center for Brain Cardiovascular and Mental disorders), Motohiro Takayama (Otsu City Hospital), Masaaki Saiki (Otsu Red Cross Hospital), Kazuo Yamamoto (Rakuwakai Otowa Hospital), Junta Moroi (Research Institute for Brain and Blood Vessels-Akita), Susumu Suzuki (Rinku General Medical Center); (Rumoi Central Clinic), Tatsuya Abe (Saga University Hospital), Hiroshi Sugimori (Saga-Ken Medical Centre Koseikan), Masato Sugitani (Sagamihara Kyodo Hospital), Akio Ookura (Saiseikai Fukuoka General Hospital), Naoko Fujimura (Saiseikai Futsukaichi Hospital); (Saiseikai Gose Hospital), Osamu Nishizaki (Saiseikai Imabari Hospital), Sumio Isimaru (Saiseikai Kawaguchi General Hospital), Toru Nishi (Saiseikai Kumamoto Hospital), Hiroshi Wanihuchi (Saiseikai Kurihashi Hospital), Nobukuni Murakami (Saiseikai Kyoto Hospital), Hiroto Murata (Saiseikai Matsusaka General Hospital), Naoki Kitagawa (Saiseikai Nagasaki Hospital), Katsuhiko Kono (Saiseikai Noe Hospital), Michiya Kubo (Saiseikai Toyama Hospital), Masashi Nakatsukasa (Saiseikai Ustunomiya Hospital), Yuji Okamoto (Saiseikai Yahata General Hospital), Makoto Inaba (Saiseikai Yokohamashi Tobu Hospital), Hidetoshi Ooigawa (Saitama Cardiovascular and Respiratory Center), Atsuhiro Kojima (Saitama City Hospital), Kyoichi Nomura (Saitama Medical Center), Takamitsu Fujimaki (Saitama Medical University Hospital), Kenji Yamamoto (Saitama Red Cross Hospital), Osamu Fukuda (Saito Memorial Hospital), Yoshikazu Nakajima (Sakai City Medical Center), Kazuyuki Kouno (Saku Central Hospital), Takaaki Yoshida (Saku Central Hospital Advanced Care Center), Reizou Kanemaru (Sanseikai Kanemaru Neurosurgery Hospitai), Yohei Kudoh (Sanyudo Hospital), Toshitaka Nakamura (Sapporo Azabu Neurosurgical Hospital), Masayoshi Takigami (Sapporo City General Hospital), Shogo Nishi (Sapporo Higashi Tokushukai Hospital), Nobuhiro Mikuni (Sapporo Medical University Hospital), Akira Takahashi (Sapporo Shiroishi Memorial Hospital), Rokuya Tanikawa (Sapporoteishinkai Hospital), Seisaburo Sakamoto (Sasebo Chuo Hospital), Makio Kaminogo (Sasebo City General Hospital), Seiichiro Hoshi (Secomedic Hospital), Yoshinari Okumura (Seikeikai Hospital), Shinichi Okabe (Seirei Memorial Hospital), Haruhiko Sato (Seirei Mikatahara General Hospital), Shiro Miyata (Seiwakai Wada Hospital), Kotaro Tsumura (Sekishinkai Kawasakisaiwai Hospital), Hiroshi Karibe (Sendai City Hospital), Noriaki Watabe (Sendai East Neurosurgical Hospital), Kazuhiko Nozaki (Shiga University of Medical Science Hospital), Fusao Ikawa (Shimane Prefectural Central Hospital), Takashi Yoshida (Shimizu Hospital), Ryuji Nakamura (Shimonoseki City Hospital), Norifumi Shimoeda (Shimotsuga General Hospital), Tsutomu Hitotsumatsu (Shin Koga Hospital), Tomoaki Kameda (Shin-Oyama City Hospital), Hiroshi Ishiguchi (Shingu Municipal Medical Center), Atsuo Shinoda (Shinoda General Hospital), Masanobu Hokama (Shinonoi General Hospital), Akinori Yamamura (Shinsapporo Neurosurgical Hospital); (Shinseikai Toyama Hospital), Kazuhiro Hongo (Shinshu University Hospital), Takeshi Kondoh (Shinsuma General Hospital), Makoto Ichinose (Shintakeo Hospital), Takashi Inoue (Shinwakai Yachiyo Hospital), Kenichi Murao (Shiroyama Hospital), Takafumi Wataya (Shizuoka Children's Hospital), Seiji Fukazawa (Shizuoka City Shizuoka Hospital), Takahisa Mori (Shonan Kamakura General Hospital), Shinsuke Muraoka (Showa Inan General Hospital), Tomoaki Terada (Showa University Fujigaoka Hospital), Hirosuke Fujisawa (Shuto General Hospital), Tsuneo Shishido (Shuuwa General Hospital), Mayumi Mori (Souseikai Shin Yoshizuka Hospital), Arai Hiroaki (South Miyagi Medical Center), Shinjitsu Nishimura (Southern Tohoku General Hospital), Zenichiro Watanabe (Southern Tohoku Hospital), Yuichiro Tanaka (St. Marianna University School of Medicine), Yasunari Niimi (St. Lukes International Hospital), Susumu Nakashima (St. Mary’s Hospital), Akira Nakamizo (Steel Memorial Yawata Hospital), Shinichi Wakabayashi (Suiseikai Kajikawa Hospital), Kazuhito Nakamura (Suisyoukai Murata Hospital), Hiroki Sato (Suwa Central Hospital), Yukinari Kakizawa (Suwa Red Cross Hospital), Hiroki Takano (Tachikawa General Hospital), Norihito Shirakawa (Takamatsu Municipal Hospital), Masahiro Kagawa (Takamatsu Red Cross Hospital), Eiichiro Mabuchi (Takarazuka City Hospital), No (Takarazuka Daiichi Hospital), Kazusige Maeno (Takatsuki General Hospital), Takayuki Koizumi (Takeda General Hospital), Warou Taki (Takeda Hospital), Yusuke Nakagaki (Takikawa Neurosurgical Hospital), Kazuyuki Tane (Tane General Hospital); (Tannan regional medical center), Hiromichi Ooishi (Tanushimaru Central Hospital), Katsuyuki Asaoka (Teinekeijinkai Hospital), Yoshinori Akiyama (Tenri Hospital), Tadao Kawamura (Tenshindo Hetsugi Hospital), Atumi Takenobu (Teraoka Memorial Hospital), Masayuki Yokota (The Veritas Hospital), Takehisa Tuji (Tobata Kyoritsu Hospital), Teiji Tominaga (Tohoku University Hospital), Masami Shimoda (Tokai University Hachioji Hospital), Mitsunori Matsumae (Tokai University Hospital), Shinji Noda (Toki General Hospital), Koiti Moroki (Tokuda Neurosurgical Hospital), Hirofumi Oka (Tokushima Prefectural Kaifu Hospital), Masahito Agawa (Tokushima Prefecture Naruto Hospital), Hajimu Miyake (Tokushima Red Cross Hospital), Junichiro Satomi (Tokushima University Hospital), Masateru Katayama (Tokyo Dental College Ichikawa General Hospital), Shinichi Numazawa (Tokyo General Hospital), Taketoshi Maehara (Tokyo Medical and Dental University Hospital), Hiroyuki Jimbo (Tokyo Medical University Hachioji Medical Center), Michihiro Kohno (Tokyo Medical University Hospital), Satoshi Ihara (Tokyo Metropolitan Children's Medical Center), Koji Matuoka (Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology), Oikawa Akihiro (Tokyo Metropolitan Health and Medical Treatment Corporation Ohkubo Hospital), Kensaku Yoshida (Tokyo Metropolitan Hiroo Hospital), Takahiro Oota (Tokyo Metropolitan Tama Medical Center), Haruhiko Hoshino (Tokyo Saiseikai Central Hospital), Makoto Noguchi (Tokyo Teisin Hospital), Takakazu Kawamata (Tokyo Women's Medical University Hosptal), Youichi Hashimoto (Tomakomaihigashi Hospital), Keiichirou Onitsuka (Tomei Atsugi Hospital), Masahiko Kitano (Tominaga Hospital), Jae-Hyun Son (Tomishiro Central Hospital), Toru Masuoka (Tonami General Hospital), Naoki Koketsu (Tosei General Hospital), Keiichi Akatsuka (Tottori Municipal Hospital), Masamichi Kurosaki (Tottori University Hospital), Miyamori Tadao (Toyama City Hospital), Hiroaki Hondo (Toyama Prefectural Central Hospital), Kazumasa Yamatani (Toyama Red Cross Hospital), Satoshi Kuroda (Toyama University Hospital), Hirofumi Oyama (Toyohashi Municipal Hospital), Takashi Matsumoto (Toyokawa City Hospital), Junji Koyama (Toyooka Hospital), Ogura Koichiro (Toyota Kosei Hospital), Shinji Yamamoto (Tsuchiura Kyodo General Hospital), Hitoshi Tabata (Tsuchiura Kyodo Hospital Namegata District Medical Center); (Tsukazaki Hospital), Kazuya Uemura (Tsukuba Medical Center Hospital), Kazuhiko Sato (Tsuruoka Municipal Shonai Hospital), Hideyuki Yoshida (Tsuyama Chuo Hospital), Takafumi Nishizaki (Ube-Kohsan Central Hospital), Hiroshi Egami (Uki General Hospital), Osamu Yamamura (University of Fukui Hospital), Hideo Takeshima (University of Miyazaki Hospital), Shogo Ishiuchi (University of the Ryukyus Hospital), Akira Matsumura (University of Tsukuba Hospital), Hiroyuki Kinouchi (University of Yamanashi Hospital), Susumu Mekaru (Urasoe General Hospital), Mikihiko Takeshita (Ushiku Aiwa General Hospital), Hitoshi Ozawa (Ushioda General Hospital); (Usuikai Tano Hospital), Kiichiro Zenke (Uwajima City Hospital), Takeshi Matsuyama (Wakakusa Daiichi Hospital), Naoyuki Nakao (Wakayama Medical University Hospital), Toshikazu Kuwata (Wakayama Rosai Hospital), Teruyuki Habu (Wakayama-Seikyo Hospital), Tomoyoshi Okumura (Wakkanai Teishinkai Hospital), Seiya Takehara (Yaizu City Hospital), Rei Kondo (Yamagata City Hospital Saiseikan), Takashi Kumagai (Yamagata Prefectural Central Hospital), Keiten So (Yamagata Prefectural Shinjo Hospital), Sunao Takemura (Yamagata Saisei Hospital), Sonoda Yukihiko (Yamagata University Hospital), Manabu Urakawa (Yamaguchi Prefectural Grand Medical Center), Yasuhiro Hamada (Yamaguchi Red Cross Hospital), Michiyasu Suzuki (Yamaguchi University Hospital), Mikito Uchida (Yamanashi Kosei Hospital), Hidehito Koizumi (Yamanashi Prefectural Central Hospital), Hiroshi Ozawa (Yamanashi Red Cross Hospital), Masaru Yamada (Yamato Municipal Hospital), Takashi Tsuruno (Yao Tokushukai General Hospital), Gen Ishida (Yasugi Municipal Hospital), Ryouichi Masuda (Yatsuo General Hospital), Makoto Kimura (Yawata Medical Center), Shinichirou Ishihara (Yayoigaoka Kage Hospital), Masashi Morikawa (Yodogawa Christian Hospital); (Yokkaichi Municipal Hospital), Sachio Suzuki (Yokohama Asahi Chuo General Hospital), Hiroaki Tanaka (Yokohama City Minato Red Cross Hospital), Hidetoshi Murata (Yokohama City University Hospital), Katsumi Sakata (Yokohama City University Medical Center); (Yokohama Rosai Hospital), Motohiro Nomura (Yokohama Sakae Kyosai Hospital), Akihiro Nemoto (Yokohamashintoshi Neurosurgecal Hospital), Sumio Endou (Yokohamasinmidori Hospital), Nobuo Hirota (Yokosuka City Uwamachi Hospital), Kennji Itou (Yonezawa City Hospital), Hiroaki Minami (Yoshida Hospital), Yoshihumi Teramoto (Yuaikai Hospital).
Contributors RK and KI drafted the manuscript. KI was involved in obtaining funding. AKada, KN and KI were involved in study concept, design and the analysis of data. KO, TK, TI, YM, NSakai, YS, SM, SK, HS, SY, TOsato, NH, IN, KN, ID, YH, HH, HN, HK, TOhta, HF, NT, AKurogi, NR, AN, KA, TS, KY, DO, SO, AH, NSaito, HA, SM and TT were involved in the acquisition of data. All authors reviewed the study report, made comments or suggestions on the manuscript drafts and approved the final version. KI is the guarantor.
Funding This work 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, JP22ek0210147); Grants-in-Aid from the Japanese Ministry of Health, Labour and Welfare (H28-Shinkin-Ippan-011, 19AC1003, 21FA1010, 22FA1015); KAKENHI grants (25293314, 18H02914, 22H03191, principal investigator: Koji Iihara) 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. The funding sources had no role in the study design, data collection and analysis, manuscript preparation or decision to publish.
Competing interests KI reports grant support from Idorsia Pharmaceuticals Japan Limited. The other authors report no conflicts of interest.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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