The successful implementation of intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) has greatly reduced disability in patients with acute ischemic stroke (AIS), establishing these therapies as the usual care for re-establishing compromised brain circulation [1-3]. However, the implementation of these therapies varies across regions, especially areas with lower population densities and fewer stroke centers [4,5]. Recent reports from Europe, the United States, and Asia have addressed that such variance is common in these regions and may cause disparities in stroke-related morbidity and mortality [6-8]. Consequently, an urgent imperative has arisen to optimize delivery of reperfusion therapy to AIS patients and elevate regional treatment rates. In fact, reducing disparities in the utilization of reperfusion therapies may be a national goal in some regions [1,2]. In this context, the reperfusion therapy rate (RTR) may be of important clinical significance in AIS patients but is sometimes overlooked [3,9].

Variation in the delivery of reperfusion therapy in AIS may be dependent on hospital characteristics as provision of such therapy requires specialized equipment, coordinated care pathways, and dedicated personnel [10-13]. Furthermore, prior research highlights regional disparities in the quality of stroke care [14], racial differences in door-to-needle time for thrombolysis [15], variation in imaging-to-needle time among hospitals [16], and the impact of these disparities on short-term mortality after AIS [17]. However, the subject of variation in RTR across systems or regional hospitals remains insufficiently explored. Identification of factors responsible for low RTRs can lead to quality initiatives to improve the rates [18,19].

By utilizing data from a comprehensive national stroke audit in South Korea, this study seeks to delineate the overall RTR among stroke patients eligible for reperfusion therapy, examine RTR variations across hospitals, and identify factors influencing hospital RTR at a national level.

The study utilized data from the Acute Stroke Quality Assessment Program (ASQAP), a national audit initiated by the Health Insurance Review and Assessment Service (HIRA) in 2005 pursuant to the National Health Insurance Act and the Medical Aid Act.20 South Korean hospitals were eligible for each assessment if they treated over 10 acute stroke patients within either a 3-month (2013-2014) or 6-month (2016-2018) timeframe.

ASQAP aims to: (1) improve the care quality for hospitalized acute stroke patients, (2) identify and evaluate variation in stroke care services across acute care hospitals, and (3) determine ways to reduce costs related to stroke care.

Every resident in South Korea is a member of the National Health Insurance program [21]. Consequently, all reimbursement claims for medical services, made by healthcare institutions in South Korea, are consolidated and archived by HIRA. Through linkage to the ASQAP database with this claims database, we were able to extract supplementary information pertinent to our study.

The study was approved by the Institutional Review Board of Seoul National University Bundang Hospital (No. X-1704-393-906). With HIRA’s assistance, we accessed hospital- and patient-level data, ensuring all protected health information remained confidential, adhering to the Act on the Protection of Personal Information Maintained by Public Institutions.

Across the 5th to 8th ASQAP assessments, a total of 75,870 patients were admitted to 251 acute care hospitals via the ER for acute stroke. Median hospital NIHSS score documentation rate was 97.5% for all AIS patients. Among them, 56,939 (75.0%) patients had AIS, with 21,804 arriving at the ER within 6 hours from the last-known-normal time. Ultimately, 10,513 patients with an initial NIHSS score of 4 or higher, treated in 247 acute care hospitals, were identified as potentially eligible for reperfusion therapy and included in the study. Four hospitals were excluded due to having no patients eligible for reperfusion therapy.

The average age of the 10,513 patients was 71 years, with 45% being women (Table 1). The median NIHSS score at admission was 9, with a median time of 105 minutes from stroke onset to ER arrival. Approximately one-third of 247 hospitals had a stroke unit and performed at least one IVT and/or EVT monthly. The number of patients eligible for reperfusion therapy in each hospital during the 18-month study period varied widely, ranging from 1 to 341, with a median (IQR) of 20 (4.5-61.5), showing a right-skewed distribution. Notably, around one-third of the hospitals (91 out of 247) had fewer than 10 patients eligible for reperfusion therapy over this period (Supplementary Figure 1).

Reperfusion therapy was administered to 52.9% of the study population, comprising IVT (30.2%), EVT (10.9%), and IVT+EVT (11.8%). The average unadjusted hospital RTR was 34.8% (median [IQR], 37.5% [9.8-56.2]), with a range from 0% to 100%. Approximately 23% of the hospitals (56 out of 247) reported an unadjusted RTR of 0% (Figure 1A and Supplementary Figure 2). Hospitals with lower unadjusted RTRs tended to use EVT less frequently compared with IVT (Figure 1B and C). Additionally, Hospitals with a lower unadjusted hospital RTR typically had smaller stroke volumes (Figure 1D). Hospitals with a 0% unadjusted RTR had an average of 3.1 patients that were eligible for reperfusion therapy over the 18-month study period, compared to an average of 54.1 patients in other hospitals.

For exploring potential determinants of RTR, we performed bivariate analysis to elucidate a dose-dependent association between all hospital characteristics (total number of beds, monthly stroke volume, stroke unit availability, the number of stroke neurologists, and monthly IVT/EVT case volume) and higher adjusted hospital RTRs (Table 2). Notably, larger hospital size and higher monthly stroke volume strongly correlated with higher adjusted hospital RTRs (Spearman correlation coefficient=0.61 and 0.64, respectively, both P<0.0001) (Figure 2).

Multiple linear regression analysis was conducted to explore the determinants of adjusted hospital RTR. Due to multicollinearity between monthly stroke volume and monthly IVT case volume, two separate models (Model A and Model B) were analyzed, including these variables individually. The analysis identified that stroke unit availability and monthly stroke volume or monthly IVT/EVT case volume were independent determinants of adjusted hospital RTR (Table 3).

An inverse correlation was observed between hospital RTR and 1-year mortality post-stroke, even after adjusting for monthly stroke volume (Figure 3). The adjusted 1-year mortality was 43.5% in hospitals in the lowest quartile of adjusted hospital RTR, in contrast to 37.9% in the highest quartile (Supplementary Table 1).

The main findings of our nationwide study include: (1) a 52.9% overall rate of reperfusion therapy in AIS patients potentially eligible for such treatment; (2) significant variation in unadjusted hospital RTRs, with an average rate of 34.8%; (3) identification of monthly stroke volume, stroke unit availability, and monthly IVT/EVT case volumes as key determinants of RTR; and (4) an inverse correlation between hospital RTR and 1-year post-stroke mortality, independent of stroke volume.

It is noteworthy that approximately 23% of acute care hospitals in our study reported a 0% hospital RTR. These hospitals, on average, treated only 3.1 patients eligible for reperfusion therapy over an 18-month period, compared to 54.1 patients in hospitals with higher RTRs. Accordingly, it may be assumed that poor performance is related to low stroke volume. In the United States, there are 2,446 hospitals, including various kinds of stroke centers such as comprehensive, thrombectomy-capable, or primary stroke centers, and acute stroke ready hospitals, actively involved in acute stroke care [26]. However, there is a paucity of data regarding the distribution of hospital stroke volumes, especially the volume of patients eligible for reperfusion therapy and the corresponding therapy rates. This lack of detailed hospital-level or organizational data on acute stroke care is a common issue in most countries [27]. A recent analysis of ASQAP data on contributing factors for high performance among low-volume suggested a metropolitan location, a greater number of physicians, and the presence of neurologists [28]. The presence of neurologists was also associated with a higher defect-free care rate in these hospitals. Centers with low RTRs may lack the infrastructure or personnel necessary to deliver appropriate reperfusion therapy.

Monthly stroke volume emerged as a key determinant of hospital RTR, showing the highest standardized beta among five potential determinants. When monthly IVT/EVT case volumes were substituted for monthly stroke volume, these two factors—both indicative of patient volume—were identified as influential in determining hospital RTR. Previous studies have indicated that stroke patients treated in low-volume centers tend to experience higher mortality rates compared to those in high-volume centers [29-31]. This disparity may be attributed to the limited resources of low-volume centers, impacting their ability to establish and sustain experienced interdisciplinary stroke teams crucial for delivering high-quality care [32].

Interestingly, a significant inverse correlation between adjusted hospital RTR and 1-year mortality persisted even after adjusting for hospital stroke volume. While this association does not imply causality, it suggests that hospital RTR could serve as a potential quality indicator at the hospital level, irrespective of hospital stroke volume or hospital size.

Our study uniquely focused on RTRs among patients potentially eligible for such treatments, diverging from previous research that included the entire stroke population. The latter studies highlighted patient-level predictors of failure to receive thrombolytic therapy, such as ineligibility due to late arrival time to the ER, mild symptoms, and history of prior stroke [33,34]. Assessing the performance of reperfusion therapy specifically within the target group of persons potentially eligible for thrombolytic therapies may offer more precise insights of each hospital’s quality of care relative to AIS. However, accurately defining this group necessitates prerequisites like confirmation of AIS by a stroke specialist, NIHSS score assessment, and calculation of onset-to-arrival time. In the Get With The Guidelines (GWTG)-Stroke program, only 56.1% of patients had documented NIHSS scores [35]. Despite an increase in the average hospital-level documentation rates of NIHSS scores from 27% in 2003 to 70% in 2012, this relatively low NIHSS documentation may hinder precise identification of patients eligible for reperfusion therapy.

In contrast, our study showed a median hospital-level NIHSS documentation rate of 97.5% for all AIS patients, providing a robust basis for studying the potentially eligible group for thrombolytic therapy. Accordingly, we observed a wide variation in hospital RTRs, ranging from 0% to 100%, a phenomenon yet to be explored at a national level. However, it should be noted that there are important determinants of EVT eligibility besides NIHSS, including the occlusion status of major cerebral arteries and the degree of ischemic brain injury on brain imaging. Although NIHSS data provide potential advantages in defining the target group for EVT, NIHSS data alone cannot accurately identify all EVT-eligible patients.

To mitigate disparities in hospital RTRs, several strategies may be considered. One approach involves monitoring, providing feedback, and motivating hospitals with lower performance to improve their metrics. Alternatively, a regionalized approach to stroke systems of care could be considered, whereby AIS patients are directed to higher-volume stroke centers, either by bypassing low-volume centers or facilitating a rapid transfer. However, such strategies might face challenges in rural areas characterized by vast geographic expanses, low population densities, and sparsely located smaller hospitals. While our findings indicate that centralizing stroke systems of care—by strengthening regional stroke networks and supporting low-stroke volume centers through education—may help reduce disparities in hospital RTR and improve stroke outcomes, further research is needed to confirm these observations and guide implementation.

Our study is subject to limitations. First, determining eligibility for reperfusion therapy using national stroke audit data presents challenges. The operational definition used—arrival within 6 hours after the last-known-normal time and an initial NIHSS score of 4 or higher—was intended to be inclusive. However, we may have misclassified participants and inadvertently included patients who should not be considered for reperfusion therapy in clinical practice. For instance, a patient with a lacunar infarction, without major vessel occlusion, arriving 5 hours after stroke onset and with an NIHSS score of 5, would not usually be selected for reperfusion therapy, yet under our criteria, they could be classified as potentially eligible. Moreover, our study could not account for contraindications to reperfusion therapy, possibly leading to underestimation of the true hospital RTR.

However, due to the nature of ASQAP, an external stroke audit program administered by the governmental agency, and the lack of data on EVT eligibility in the ASQAP dataset, we decided not to use IVT exclusion causes of the ASQAP dataset but to adopt an operational definition of IVT/EVT eligibility based solely on NIHSS. The NIHSS cut-off of 4 was determined based on the facts that (1) NIHSS scores of 0-3 have been regarded as minor stroke in pivotal stroke trials such as Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) [36] and Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA (POINT) [37], and (2) NIHSS scores 6 or more are accepted as potential EVT eligibility criteria when analyzing large observational data without angiographic information [1].

Second, our study lacks data on outcomes that are commonly used for evaluating the efficacy of reperfusion therapy, such as immediate NIHSS score improvement, mRS scores at 3 months, and follow-up data on infarct size or cerebral angiographic outcomes. Such detailed clinical information is often unavailable in nationwide datasets, which typically stem from administrative or national stroke audit data, as is the case in our study. Although a meaningful association between the 3-month mRS and 1-year mortality in patients receiving reperfusion therapy has also been reported [38,39], the association between RTR and 1-year mortality should be interpreted cautiously. The relationship between RTR and 1-year mortality might be mediated, at least partly, by environmental or social factors, which are commonly found among typical patients treated in low-volume centers [28].

In conclusion, our nationwide study showed that hospital RTRs for AIS were notably low and exhibited considerable variability, with a clear association observed between hospital RTRs and clinical outcomes post-AIS. These findings imply that hospital RTRs could serve as a valuable metric for assessing the quality of acute stroke care. Furthermore, they highlight the potential of hospital RTR as an important component of a continuous quality improvement initiative in acute stroke care. Future research is warranted to validate the utility of hospital RTR as a metric and to explore its relationship with a broader range of clinical outcomes beyond mortality. Finally, refining the operational definition of potential eligibility for reperfusion therapy may lead to more precise estimates of RTR.