Organizational Factors Determining Access to Reperfusion Therapies in Ischemic Stroke-Systematic Literature Review

Background: After onset of acute ischemic stroke (AIS), there is a limited time window for delivering acute reperfusion therapies (ART) aiming to restore normal brain circulation. Despite its unequivocal benefits, the proportion of AIS patients receiving both types of ART, thrombolysis and thrombectomy, remains very low. The organization of a stroke care pathway is one of the main factors that determine timely access to ART. The knowledge on organizational factors influencing access to ART is sparce. Hence, we sought to systematize the existing data on the type and frequency of pre-hospital and in-hospital organizational factors that determine timely access to ART in patients with AIS. Methodology: Literature review on the frequency and type of organizational factors that determine access to ART after AIS. Pubmed and Scopus databases were the primary source of data. OpenGrey and Google Scholar were used for searching grey literature. Study quality analysis was based on the Newcastle-Ottawa Scale. Results: A total of 128 studies were included. The main pre-hospital factors associated with delay or access to ART were medical emergency activation practices, pre-notification routines, ambulance use and existence of local/regional-specific strategies to mitigate the impact of geographic distance between patient locations and Stroke Unit (SU). The most common intra-hospital factors studied were specific location of SU and brain imaging room within the hospital, and the existence and promotion of specific stroke treatment protocols. Most frequent factors associated with increased access ART were periodic public education, promotion of hospital pre-notification and specific pre- and intra-hospital stroke pathways. In specific urban areas, mobile stroke units were found to be valid options to increase timely access to ART. Conclusions: Implementation of different organizational factors and strategies can reduce time delays and increase the number of AIS patients receiving ART, with most of them being replicable in any context, and some in only very specific contexts.


Introduction
Stroke is a major public health problem worldwide causing approximately 6.2 million deaths per year [1]. Of all acute ischemic stroke (AIS) types, those resulting from proximal occlusion of cervical or intracranial large vessels have the worst prognosis. Timely delivery of acute reperfusion therapies (ART) with thrombolysis in the first 4.5 h and/or thrombectomy up to 24 h is essential to restore normal brain circulation and prevent death and disability [2]. The odds ratio (OR) of an excellent outcome (free of disability) with thrombolysis compared with placebo decreases with treatment delays, from 2.8 when patients are treated between 0 and 90 min, to 1.6 for 91 to 180 min, 1.4 for 181 to 270 min, Despite its critical importance to public health planification, systematic analysis of these factors has never been performed. Therefore, we decided to review the literature to gather information on organizational factors that determine timely access to ART.

Materials and Methods
Search Strategy: Pubmed and Scopus databases were used to search for relevant publications addressing organizational factors and strategies associated with timely access to ART using the following term associations: "ischemic stroke", thrombolysis, thrombectomy, "endovascular treatment" with "access" and "delay". We complemented this search by examining reference lists of the most relevant studies and the Open grey database (http://www.opengrey.eu/, accessed on 1 January 2021).
Criteria for Inclusion and Exclusion of Studies: Prospective and retrospective studies published after endovascular treatment approval for AIS (2015), excluding studies after 31 December 2020 to minimize the contribution of the COVID-19 pandemic containing information on one of the following domains under analysis: pre-hospital organizational (population education, emergency stuff training, emergency activation, ambulance use, existence of specific stroke code protocols, mobile stroke unit, and telemedicine/telestroke), intra-hospital (hospital pre-notification, stroke unit, protocols, specific imaging protocols, pre-notification of the neuroradiology team, telemedicine/telestroke), and inter-hospital (transport). Conference or seminar's abstracts Despite its critical importance to public health planification, systematic analysis of these factors has never been performed. Therefore, we decided to review the literature to gather information on organizational factors that determine timely access to ART.

Materials and Methods
Search Strategy: Pubmed and Scopus databases were used to search for relevant publications addressing organizational factors and strategies associated with timely access to ART using the following term associations: "ischemic stroke", thrombolysis, thrombectomy, "endovascular treatment" with "access" and "delay". We complemented this search by examining reference lists of the most relevant studies and the Open grey database (http://www.opengrey.eu/, accessed on 1 January 2021).
Criteria for Inclusion and Exclusion of Studies: Prospective and retrospective studies published after endovascular treatment approval for AIS (2015), excluding studies after 31 December 2020 to minimize the contribution of the COVID-19 pandemic containing information on one of the following domains under analysis: pre-hospital organizational (population education, emergency stuff training, emergency activation, ambulance use, existence of specific stroke code protocols, mobile stroke unit, and telemedicine/telestroke), intra-hospital (hospital pre-notification, stroke unit, protocols, specific imaging protocols, pre-notification of the neuroradiology team, telemedicine/telestroke), and inter-hospital (transport). Conference or seminar's abstracts and/or studies with unclear inclusion criteria, studies based on selective or convenience sampling and non-English publications were excluded.
Data Extraction: Titles and abstracts were independently verified by 2 investigators (AB, JS). Disagreements regarding the inclusion of specific studies were resolved by a third investigator. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist for systematic reviews was used to guide data extraction. The verification of the duplication of studies was performed automatically using the Mendeley bibliographic reference management system. and/or studies with unclear inclusion criteria, studies based on selective or convenience sampling and non-English publications were excluded.
Data Extraction: Titles and abstracts were independently verified by 2 investigators (AB, JS). Disagreements regarding the inclusion of specific studies were resolved by a third investigator. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist for systematic reviews was used to guide data extraction. The verification of the duplication of studies was performed automatically using the Mendeley bibliographic reference management system.
The identified and rejected studies were recorded in a separate database, documenting the main reason for their exclusion (Appendix A- Table A1).
Data Synthesis: The data were analyzed descriptively. No meta-analysis was anticipated or performed due to the expected and marked heterogeneity and methodological variability of the studies. Study quality was assessed using "The Newcastle-Ottawa Scale (NOS)" instrument [7] (Appendix A- Table A2).

Results
We identified a total of 1464 (Pubmed) and 1101 (Scopus) publications using the predefined searching criteria. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart diagram ( Figure 2) resumes the selection and inclusion process.  The number of studies after deduplication was 658. A total of 286 papers were selected as relevant for complete text evaluation, after which, a further 158 studies were excluded (Appendix A- Table A3). The three main reasons for exclusion were no data (n = 142/89.8%), very specific population (n = 14/8.86%) and language (n = 2/1.26%). Figure 3 summarizes the organizational factors identified in the systematic review.
The number of studies after deduplication was 658. A total of 286 papers were selected as relevant for complete text evaluation, after which, a further 158 studies were excluded (Appendix A- Table A3). The three main reasons for exclusion were no data (n = 142/89.8%), very specific population (n = 14/8.86%) and language (n = 2/1.26%). Figure 3 summarizes the organizational factors identified in the systematic review.

Pre-Hospital Organizational Factors
We identified 67 studies addressing pre-hospital organizational factors associated with delay or access to ART (Appendix A- Table A3). Activation of stroke code, pre-hospital notification and use of pre-hospital emergency services , mobile stroke units [24][25][26][27][28][29][30][31][32], implementation of specific electronic apps to insert and share clinical data with

Quality Assessment of the Studies
The majority of studies were classified as being of good quality (Appendix A- Table A2). Only three studies were assessed as poor quality. The grey literature search identified 36 articles, none related to the topic of this review.
Contribution of organizational or management factors must always be contextualized. For instance, in remote areas, protocols for patients with possible stroke should consider the clinical status (severity) and the distance from a center with thrombectomy capability [22,37,56]. This triage would direct patients with a high probability of large vessel occlusion to distant centers with such capability (motherboard model) but only if the patient would arrive within the time window for the treatment. Another example of organizational strategies useful in a specific context is the use of mobile SUs. Past studies show that mobile SUs are cost-effective only when intensive use is anticipated such as in urban areas with high population density [25,[27][28][29][30][31][32]. Monitoring of stroke pathways protocols to guarantee consistent performance [76,78] and having the best information available such as the population density and distribution, specific location of the human and material resources [54,76] involved is central for optimizing the chain of stroke care. In order to improve access to ART, priority should be given to the discussion of organizational factors and models of stroke care with the integration of national and regional health facilities. Introduction of advanced imaging techniques in more peripheral regions could lead to more AIS receiving ART. Implementation of mixed prehospital approaches of care, for instance combining mothership with drip-and-ship models for mechanical thrombectomy may be complex, but in some regions would be the sole alternative to increase the number of patients with AIS receiving the best indicated treatment.

Conclusions
This systematic review identified several organizational factors that determine access to ART. Most of them, for instance population education, promotion of protocols, and training of stroke teams, are mandatory and applicable in any context. There are, however, specific interventions whose application is dependent on the specific population and geographical characteristics.   (2) (10)         RIHT: development of the stroke protocol, training of all professionals in the hospital for stroke recognition (single stroke scales); use of posters in the hospital; publication in the newspaper/website of the institution of relevant information RIHT: rapid patient registration on admission, thrombolysis bag, direct transport to the imaging room, thrombolysis in the imaging room
RIHT (thrombectomy): total priority of the imaging room for the stroke patient, introduction of a protocol for the elaboration and quick readings of the images. RPHT: "mobile stroke unit" (in urban contexts).
Wolters FJ, Paul NL, Li L, Rothwell PM; Oxford Vascular Study. Sustained impact of UK FAST-test public education on response to stroke: a population-based time-series study. Int J Stroke. 2015 Oct; 10 (7): 1108-14. RTPH: mass education campaign * Gray-marked cells correspond to studies that derive from interventions deliberately made to reduce pre-or in-hospital delay times, or to increase the number of patients benefiting from acute reperfusion therapies.