Understanding delays in acute stroke care: a systematic review of reviews

Understanding delays in acute stroke care: a systematic review of reviews Abstract Background Stroke is the leading cause of adult long-term disability in Western countries. Intravenous thrombolytic therapy with recombinant tissue plasminogen activator is safe and effective within the first 4.5 h after the onset of stroke. Various factors delaying acute stroke care have been identified in the literature. This review aimed to provide an overview of factors delaying acute stroke care and attempted to show how they interact in a synthetic framework. Methods We conducted a systematic review of literature reviews published in Medline and DORIS until 2016 on factors influencing acute stroke pathway timeframe. Results We analyzed 31 reviews that cover all factors of delays from stroke onset to treatment. We identified 27 factors that had a significant impact on acute stroke care and can be categorized into four distinct categories: patient-related factors, training, resources and lack of coordination. We also reported associations between factors observed in both between categories (mainly between patients and organizational/logistical factors) and within categories. Conclusion This review provides a wide overview of factors influencing acute stroke pathway. Since it was observed that the identified factors were interrelated, they needed to be analyzed in a systematic way. We hence created a synthetic framework that combines several categories of factors while assuming that factor weight varies from a study context to another. Better knowledge on underlying mechanisms between factors would provide crucial improvement of the interventions aiming at reducing delays in both pre-hospital and inhospital stages. For future research, we recommend adopting a systemic perspective on factors influencing acute stroke pathway. Introduction Stroke is a primary cause of death and the leading cause of adult long-term disability.1 In an ageing society, the social and economic burden of strokes is increasing and resulting in a public health challenge. For an ischemic stroke, which accounts for about 80% of strokes, intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) administered within 4.5 h of symptom onset is safe, effective and the standard treatment in terms of cost-benefit and the reduction of long-term disability.2 However, the benefits of thrombolytic treatment are deeply time dependent and decline rapidly beyond the first 90 min following symptom onset.3 A meta-analysis conducted on five randomized trials evaluating the efficacy of endovascular thrombectomy (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, EXTEND IA) done by newer generation devices (stent retrievers) showed the benefit on elderly (>80 years), patients not receiving intravenous alteplase, and patients who are treated under 300 min from stroke onset.4 Following this evidence, European and American medical society recommendations and guidelines were amended to integrate endovascular thrombectomy into acute stroke care pathways, providing the treatment to patients up to 6 h after stroke onset. Despite these advances, pre-hospital and inpatient delays remain an important challenge for stroke care management. Indeed, despite a better public awareness of the disease—as well as the proliferation of stroke units (SUs), the improved organization of stroke care pathways and recent advances in telemedicine—only a small minority of stroke patients have access to stroke care in a favorable timeframe, including thrombolytic therapy. In Europe and USA, only one-third of patients with acute stroke arrive at the hospital in adequate time to receive thrombolytic treatment and <7% receive it.5 An important body of literature has emerged presenting factors impacting acute stroke pathway. These factors can have both positive and negative effect on the critical timeframe. The acute stroke timeframe is defined as the time taken from symptom onset to the decision to treat.6 It can be divided into four delay phases: (i) from symptom onset to the decision to seek medical attention (reaction time); (ii) from the decision to seek medical attention to first medical contact (first contact); (iii) from first medical contact to admission (medical evaluation and travel) and (iv) from admission to treatment (inhospital door to needle). A wide variety of factors impact acute stroke pathways at each stage. Some of them like patient stroke knowledge, correct recognition and triage by emergency medical service (EMS) dispatchers or emergency department (ED) physicians, and SU access are leading factors that have already been well studied. In comparison, socioeconomic status, patient psychological factors or structure-level management services are less studied, partly because of the difficulties to capture these factors. The impact of each factor is heterogeneously documented and the knowledge of the underlying mechanisms explaining acute stroke delays remains low.7 One way to explain this is to recognize the growing complexity that sustains the need for system approaches. More than being aware of the distinct factors, it is important to remain aware of the relationship between factors and how they react when those relationships change. To our knowledge, there have been no studies focused on the interaction between factors. We conducted a systematic review of reviews to provide an overview of factors influencing acute stroke care. This approach provides a summary of evidence at different levels, including the combination of different interventions, different outcomes, different conditions, problems or populations. This single synthesis of all relevant evidence also focuses on associations between factors and attempts to demonstrate how they could interact in a synthetic framework that can be adopted to design efficient health care planning interventions. Methods For this review, we adhered to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.8 We searched Medline & DORIS for publications. All searches were carried out in May 2017, not limited by date and restricted to applications in humans. The search was conducted on both resources using a combination of the following terms: (Factors OR Barriers OR Delays) AND (Acute stroke OR Stroke care) AND (Pathways OR Pre-hospital OR Inhospital) AND (Stroke knowledge). Keywords had to be in the title or the abstract of full-length publications. Articles written in English and French were eligible for inclusion and the selected study type was reviewed. Search results initially scanned titles, followed by an abstract assessment for selected publications (see Supplementary appendix S1). We also scanned their reference list. We excluded reviews that did not focus on the acute stroke timeframe (e.g. prevention, rehabilitation and post-acute stroke care) or that focus on risk factors, drug therapy or medical practices, or that aimed only to report stroke delays time. We assessed the methodological quality of the reviews by evaluating the research questions, the methodology with explicit inclusion and exclusion criteria, and analyzing the limitations, although reviews were not rated or excluded based on the overall quality rating. The total articles were first checked by one reviewer (Y.L.), then the abstract selection, performed by one authors (Y.L.), was reviewed by two authors (S.R. and E.M.). The review process is presented in Supplementary appendix S1. Relevant data were extracted from the identified reviews using an abstraction form containing the following elements: (i) search period, (ii) type of review, (iii) number of studies, (iv) geographic coverage, (v) identified factors and related acute stroke phase and (vi) identified links between factors. For the review, the term ‘factor’ designates all positive or negative influence on the acute stroke pathway timeframe. Figure 1 View largeDownload slide Reported associations of factors observed between categories Figure 1 View largeDownload slide Reported associations of factors observed between categories The PRISMA checklist was used to synthesize and report findings, except for items that were not relevant for a systematic review of reviews. Due to the heterogeneity between studies in terms of methodologies and data sources, a statistical analysis or meta-analysis was not possible, so results are presented in a descriptive systematic literature review. Results Study selection The initial search identified 1037 articles. After a review of titles and abstracts, 30 remained for full text examination. Only 4 reviews were added after scanning the reference list and 29 reviews were finally included after the exclusion of 3 reviews that met at least one exclusion criterion (the full list of excluded articles is available from the authors upon request). One review focused on inhospital stroke and two had no indication of the research strategy (one was a special report, and one focused on the epidemiology, pathophysiology, treatment and outcomes of stroke). Of note, 13 of 29 reviews were included even if only a part of the research met our inclusion criteria. Study characteristics Included reviews vary by focus, target population or inclusion criteria. Some reviews focus on one factor (e.g. age-specific,9 sex-specific10,11 or group of factors SES-specific,12–14) while others focused on specific stroke stage (e.g. pre-hospital stage5,15–17) with various stroke stage definitions. Most of the reviews have no countries or regions specified, although one review focused on rural areas18 and another focused on developing countries.19 The result is a wide geographic coverage, even if most of studies were usually conducted in USA and Western Europe. This review covers more than two decades of literature on stroke care management. Earlier reviews mainly focused on inhospital barriers and issues relating to hospital resources. Then, the focus shifted to the pre-hospital stage and the patient stroke knowledge. Eventually, more recent reviews covered the acute stroke pathway focusing on pre- and inhospital coordination. The methodological quality of the included reviews varied considerably (see table 1). Only 5 of 29 reviews were systematic (one included meta-analysis), and 3 of 29 did not precisely describe the search strategy utilized. Some factors were assessed in only one or two reviews with several limitations. For certain factors, the definition of them also varied. This was also the case for SES, which was described by education, income, occupation or socioeconomic index. Table 1 Synthesis of reviews reported association between factors Reference  Review focusa  Search period  Type of reviewb  Pathway  Number of studies  Geographic coverage  Reported links between factorsd  Between categories  Inside categories  Addo et al.13  Partial  2008–11  Overview  Admission to treatment  17  Austria–UK–Denmark–Scotland–USA–Canada–Finland–the Netherlands  Deprivated area -> scan availability and access Income -> scan availability and access/direct access to stroke unit  –  Bouckaert et al.15  Full  1998–08  State-of-the-art review  All acute pathway  47  USA–Sweden–Australia–Israel–Spain–Switzerland–UK–Czech Republic–Germany–Canada–Poland–South Korea–Finland–Norway  Stroke history -> Transport strategy  Coordination services -> scan availability and access  Carter-Jones24  Full  1999–07  Literature review  All acute pathway  9  Australia–USA–UK–Canada–the Netherlands  Leadership -> paramedics and physicians training  Leadership -> coordination services  Donnan et al.35  Full  1998–05  Overview  Admission to treatment  23  USA–Denmark–UK–Canada–Australia  Gender -> rtPA availability and access Gender -> scan availability and access Gender -> services coordination Gender -> transport strategy  Gender -> stroke knowledge Gender -> alone at stroke onset Transport strategy -> scan availability and access Transport strategy -> services coordination  El Khoury et al.25  Full  2000–13  Overview  All acute pathway  19  Germany–USA–South Korea–France–Finland–Canada––Spain–UK–Australia  Training physicians -> weekend/off-hour  –  Fassbender et al.21  Full  1992–12  State-of-the-art review  All care pathway  104  USA–Germany–Taiwan–Sweden–Finland–Denmark–Canada–Japan–Australia–Spain–Austria–South Korea–the Netherlands–France–China  –  Gender -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Johnson et al.36  Full  1999–11  Literature review  First medical contact to admission Admission to treatment  19  Spain–Finland–Australia–USA–Canada–Japan–Italy  Dispatcher’s training -> pre-notification  Coordination services -> scan availability and access  Joubert et al.18  Partial  1993–05  Systematic search and review  Onset to seek help Seek help to first medical contact  7  USA–China–Czech Republic–South Africa–Bulgaria–USA  Rural area -> stroke knowledge  –  Kwan et al.27  Partial  2000–08  Systematic review  First medical contact to admission Admission to treatment  –  USA–Canada–Australia–India–Taiwan–Thailand–Sweden–Germany–Belgium–France–Poland–UK–the Netherlands–Norway–Spain  –  Transport strategy -> coordination services  Lisabeth et al.37  Full  1999–13  Literature review  First medical contact to admission Admission to treatment  14  USA–Germany–Finland  Dispatcher’s training -> pre-notification  Coordination process -> scan availability and access  Marshall et al.14  Partial  2013–15  Systematic search and review  Admission to treatment  7  UK–Sweden–Denmark–USA  Socioeconomic status -> stroke unit direct access Education -> stroke unit direct access Socioeconomic status -> scan availability and access  –  Mazighi et al.16  Full  1994–09  State-of-the-art review  All acute pathway  32  USA–France–UK–Denmark–Spain–Germany–Taiwan  –  Age -> stroke knowledge Gender -> stroke knowledge Ethnic -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Pandian et al.19  Partial  2000–06  State-of-the-art review  All acute pathway  23  Brazil–Argentina–India–China–Thailand–Indonesia–Philippines  Distance -> scan availability and access/stroke unit direct access  –  Stroebele et al.10  Full  1994–08  Systematic review  Onset to seek help Seek help to first medical contact  22  USA–Germany–UK–Spain–Canada–Turkey–Brazil–India–Ireland–Nigeria–Australia–GCC countriesc  –  Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Medical history -> stroke knowledge Ethnic -> stroke knowledge Socioeconomic status -> stroke knowledge Gender -> stroke knowledge  Tai et al.31  Full  1992–10  Literature review  First medical contact to admission Admission to treatment  19  USA–Switzerland–UK–Finland–Australia  Distance -> scan availability and access/stroke unit direct access  –  Teuschl et al.23  Full  1990–09  Systematic search and review  Onset to seek help Seek help to first medical contact  110  USA–GCC countriesc–South Korea–Switzerland–India–Czech Republic–Spain–Brazil–the Netherlands–Germany–Ireland–UK–Australia–Nigeria–Italy–Japan–Norway–Taiwan–Hong Kong–Pakistan  Age -> transport strategy Ethnic -> transport strategy Unemployed -> transport strategy Bystanders -> transport strategy  Gender -> stroke knowledge Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Ethnic -> stroke knowledge Bystanders -> stroke knowledge Stroke history -> stroke knowledge Psychological -> stroke knowledge  Reference  Review focusa  Search period  Type of reviewb  Pathway  Number of studies  Geographic coverage  Reported links between factorsd  Between categories  Inside categories  Addo et al.13  Partial  2008–11  Overview  Admission to treatment  17  Austria–UK–Denmark–Scotland–USA–Canada–Finland–the Netherlands  Deprivated area -> scan availability and access Income -> scan availability and access/direct access to stroke unit  –  Bouckaert et al.15  Full  1998–08  State-of-the-art review  All acute pathway  47  USA–Sweden–Australia–Israel–Spain–Switzerland–UK–Czech Republic–Germany–Canada–Poland–South Korea–Finland–Norway  Stroke history -> Transport strategy  Coordination services -> scan availability and access  Carter-Jones24  Full  1999–07  Literature review  All acute pathway  9  Australia–USA–UK–Canada–the Netherlands  Leadership -> paramedics and physicians training  Leadership -> coordination services  Donnan et al.35  Full  1998–05  Overview  Admission to treatment  23  USA–Denmark–UK–Canada–Australia  Gender -> rtPA availability and access Gender -> scan availability and access Gender -> services coordination Gender -> transport strategy  Gender -> stroke knowledge Gender -> alone at stroke onset Transport strategy -> scan availability and access Transport strategy -> services coordination  El Khoury et al.25  Full  2000–13  Overview  All acute pathway  19  Germany–USA–South Korea–France–Finland–Canada––Spain–UK–Australia  Training physicians -> weekend/off-hour  –  Fassbender et al.21  Full  1992–12  State-of-the-art review  All care pathway  104  USA–Germany–Taiwan–Sweden–Finland–Denmark–Canada–Japan–Australia–Spain–Austria–South Korea–the Netherlands–France–China  –  Gender -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Johnson et al.36  Full  1999–11  Literature review  First medical contact to admission Admission to treatment  19  Spain–Finland–Australia–USA–Canada–Japan–Italy  Dispatcher’s training -> pre-notification  Coordination services -> scan availability and access  Joubert et al.18  Partial  1993–05  Systematic search and review  Onset to seek help Seek help to first medical contact  7  USA–China–Czech Republic–South Africa–Bulgaria–USA  Rural area -> stroke knowledge  –  Kwan et al.27  Partial  2000–08  Systematic review  First medical contact to admission Admission to treatment  –  USA–Canada–Australia–India–Taiwan–Thailand–Sweden–Germany–Belgium–France–Poland–UK–the Netherlands–Norway–Spain  –  Transport strategy -> coordination services  Lisabeth et al.37  Full  1999–13  Literature review  First medical contact to admission Admission to treatment  14  USA–Germany–Finland  Dispatcher’s training -> pre-notification  Coordination process -> scan availability and access  Marshall et al.14  Partial  2013–15  Systematic search and review  Admission to treatment  7  UK–Sweden–Denmark–USA  Socioeconomic status -> stroke unit direct access Education -> stroke unit direct access Socioeconomic status -> scan availability and access  –  Mazighi et al.16  Full  1994–09  State-of-the-art review  All acute pathway  32  USA–France–UK–Denmark–Spain–Germany–Taiwan  –  Age -> stroke knowledge Gender -> stroke knowledge Ethnic -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Pandian et al.19  Partial  2000–06  State-of-the-art review  All acute pathway  23  Brazil–Argentina–India–China–Thailand–Indonesia–Philippines  Distance -> scan availability and access/stroke unit direct access  –  Stroebele et al.10  Full  1994–08  Systematic review  Onset to seek help Seek help to first medical contact  22  USA–Germany–UK–Spain–Canada–Turkey–Brazil–India–Ireland–Nigeria–Australia–GCC countriesc  –  Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Medical history -> stroke knowledge Ethnic -> stroke knowledge Socioeconomic status -> stroke knowledge Gender -> stroke knowledge  Tai et al.31  Full  1992–10  Literature review  First medical contact to admission Admission to treatment  19  USA–Switzerland–UK–Finland–Australia  Distance -> scan availability and access/stroke unit direct access  –  Teuschl et al.23  Full  1990–09  Systematic search and review  Onset to seek help Seek help to first medical contact  110  USA–GCC countriesc–South Korea–Switzerland–India–Czech Republic–Spain–Brazil–the Netherlands–Germany–Ireland–UK–Australia–Nigeria–Italy–Japan–Norway–Taiwan–Hong Kong–Pakistan  Age -> transport strategy Ethnic -> transport strategy Unemployed -> transport strategy Bystanders -> transport strategy  Gender -> stroke knowledge Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Ethnic -> stroke knowledge Bystanders -> stroke knowledge Stroke history -> stroke knowledge Psychological -> stroke knowledge  a Partial means that only a part of the review focused on factors influencing acute stroke pathway; Full means all the review is dedicated to factors influencing acute stroke pathway. b Grant MJ, Booth A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info Libr J 2009;26:91–108. c Gulf Cooperation Council countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates). d [a] -> [b] means significant associations report factor [a] impacting factor [b]. Table 1 Synthesis of reviews reported association between factors Reference  Review focusa  Search period  Type of reviewb  Pathway  Number of studies  Geographic coverage  Reported links between factorsd  Between categories  Inside categories  Addo et al.13  Partial  2008–11  Overview  Admission to treatment  17  Austria–UK–Denmark–Scotland–USA–Canada–Finland–the Netherlands  Deprivated area -> scan availability and access Income -> scan availability and access/direct access to stroke unit  –  Bouckaert et al.15  Full  1998–08  State-of-the-art review  All acute pathway  47  USA–Sweden–Australia–Israel–Spain–Switzerland–UK–Czech Republic–Germany–Canada–Poland–South Korea–Finland–Norway  Stroke history -> Transport strategy  Coordination services -> scan availability and access  Carter-Jones24  Full  1999–07  Literature review  All acute pathway  9  Australia–USA–UK–Canada–the Netherlands  Leadership -> paramedics and physicians training  Leadership -> coordination services  Donnan et al.35  Full  1998–05  Overview  Admission to treatment  23  USA–Denmark–UK–Canada–Australia  Gender -> rtPA availability and access Gender -> scan availability and access Gender -> services coordination Gender -> transport strategy  Gender -> stroke knowledge Gender -> alone at stroke onset Transport strategy -> scan availability and access Transport strategy -> services coordination  El Khoury et al.25  Full  2000–13  Overview  All acute pathway  19  Germany–USA–South Korea–France–Finland–Canada––Spain–UK–Australia  Training physicians -> weekend/off-hour  –  Fassbender et al.21  Full  1992–12  State-of-the-art review  All care pathway  104  USA–Germany–Taiwan–Sweden–Finland–Denmark–Canada–Japan–Australia–Spain–Austria–South Korea–the Netherlands–France–China  –  Gender -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Johnson et al.36  Full  1999–11  Literature review  First medical contact to admission Admission to treatment  19  Spain–Finland–Australia–USA–Canada–Japan–Italy  Dispatcher’s training -> pre-notification  Coordination services -> scan availability and access  Joubert et al.18  Partial  1993–05  Systematic search and review  Onset to seek help Seek help to first medical contact  7  USA–China–Czech Republic–South Africa–Bulgaria–USA  Rural area -> stroke knowledge  –  Kwan et al.27  Partial  2000–08  Systematic review  First medical contact to admission Admission to treatment  –  USA–Canada–Australia–India–Taiwan–Thailand–Sweden–Germany–Belgium–France–Poland–UK–the Netherlands–Norway–Spain  –  Transport strategy -> coordination services  Lisabeth et al.37  Full  1999–13  Literature review  First medical contact to admission Admission to treatment  14  USA–Germany–Finland  Dispatcher’s training -> pre-notification  Coordination process -> scan availability and access  Marshall et al.14  Partial  2013–15  Systematic search and review  Admission to treatment  7  UK–Sweden–Denmark–USA  Socioeconomic status -> stroke unit direct access Education -> stroke unit direct access Socioeconomic status -> scan availability and access  –  Mazighi et al.16  Full  1994–09  State-of-the-art review  All acute pathway  32  USA–France–UK–Denmark–Spain–Germany–Taiwan  –  Age -> stroke knowledge Gender -> stroke knowledge Ethnic -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Pandian et al.19  Partial  2000–06  State-of-the-art review  All acute pathway  23  Brazil–Argentina–India–China–Thailand–Indonesia–Philippines  Distance -> scan availability and access/stroke unit direct access  –  Stroebele et al.10  Full  1994–08  Systematic review  Onset to seek help Seek help to first medical contact  22  USA–Germany–UK–Spain–Canada–Turkey–Brazil–India–Ireland–Nigeria–Australia–GCC countriesc  –  Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Medical history -> stroke knowledge Ethnic -> stroke knowledge Socioeconomic status -> stroke knowledge Gender -> stroke knowledge  Tai et al.31  Full  1992–10  Literature review  First medical contact to admission Admission to treatment  19  USA–Switzerland–UK–Finland–Australia  Distance -> scan availability and access/stroke unit direct access  –  Teuschl et al.23  Full  1990–09  Systematic search and review  Onset to seek help Seek help to first medical contact  110  USA–GCC countriesc–South Korea–Switzerland–India–Czech Republic–Spain–Brazil–the Netherlands–Germany–Ireland–UK–Australia–Nigeria–Italy–Japan–Norway–Taiwan–Hong Kong–Pakistan  Age -> transport strategy Ethnic -> transport strategy Unemployed -> transport strategy Bystanders -> transport strategy  Gender -> stroke knowledge Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Ethnic -> stroke knowledge Bystanders -> stroke knowledge Stroke history -> stroke knowledge Psychological -> stroke knowledge  Reference  Review focusa  Search period  Type of reviewb  Pathway  Number of studies  Geographic coverage  Reported links between factorsd  Between categories  Inside categories  Addo et al.13  Partial  2008–11  Overview  Admission to treatment  17  Austria–UK–Denmark–Scotland–USA–Canada–Finland–the Netherlands  Deprivated area -> scan availability and access Income -> scan availability and access/direct access to stroke unit  –  Bouckaert et al.15  Full  1998–08  State-of-the-art review  All acute pathway  47  USA–Sweden–Australia–Israel–Spain–Switzerland–UK–Czech Republic–Germany–Canada–Poland–South Korea–Finland–Norway  Stroke history -> Transport strategy  Coordination services -> scan availability and access  Carter-Jones24  Full  1999–07  Literature review  All acute pathway  9  Australia–USA–UK–Canada–the Netherlands  Leadership -> paramedics and physicians training  Leadership -> coordination services  Donnan et al.35  Full  1998–05  Overview  Admission to treatment  23  USA–Denmark–UK–Canada–Australia  Gender -> rtPA availability and access Gender -> scan availability and access Gender -> services coordination Gender -> transport strategy  Gender -> stroke knowledge Gender -> alone at stroke onset Transport strategy -> scan availability and access Transport strategy -> services coordination  El Khoury et al.25  Full  2000–13  Overview  All acute pathway  19  Germany–USA–South Korea–France–Finland–Canada––Spain–UK–Australia  Training physicians -> weekend/off-hour  –  Fassbender et al.21  Full  1992–12  State-of-the-art review  All care pathway  104  USA–Germany–Taiwan–Sweden–Finland–Denmark–Canada–Japan–Australia–Spain–Austria–South Korea–the Netherlands–France–China  –  Gender -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Johnson et al.36  Full  1999–11  Literature review  First medical contact to admission Admission to treatment  19  Spain–Finland–Australia–USA–Canada–Japan–Italy  Dispatcher’s training -> pre-notification  Coordination services -> scan availability and access  Joubert et al.18  Partial  1993–05  Systematic search and review  Onset to seek help Seek help to first medical contact  7  USA–China–Czech Republic–South Africa–Bulgaria–USA  Rural area -> stroke knowledge  –  Kwan et al.27  Partial  2000–08  Systematic review  First medical contact to admission Admission to treatment  –  USA–Canada–Australia–India–Taiwan–Thailand–Sweden–Germany–Belgium–France–Poland–UK–the Netherlands–Norway–Spain  –  Transport strategy -> coordination services  Lisabeth et al.37  Full  1999–13  Literature review  First medical contact to admission Admission to treatment  14  USA–Germany–Finland  Dispatcher’s training -> pre-notification  Coordination process -> scan availability and access  Marshall et al.14  Partial  2013–15  Systematic search and review  Admission to treatment  7  UK–Sweden–Denmark–USA  Socioeconomic status -> stroke unit direct access Education -> stroke unit direct access Socioeconomic status -> scan availability and access  –  Mazighi et al.16  Full  1994–09  State-of-the-art review  All acute pathway  32  USA–France–UK–Denmark–Spain–Germany–Taiwan  –  Age -> stroke knowledge Gender -> stroke knowledge Ethnic -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Pandian et al.19  Partial  2000–06  State-of-the-art review  All acute pathway  23  Brazil–Argentina–India–China–Thailand–Indonesia–Philippines  Distance -> scan availability and access/stroke unit direct access  –  Stroebele et al.10  Full  1994–08  Systematic review  Onset to seek help Seek help to first medical contact  22  USA–Germany–UK–Spain–Canada–Turkey–Brazil–India–Ireland–Nigeria–Australia–GCC countriesc  –  Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Medical history -> stroke knowledge Ethnic -> stroke knowledge Socioeconomic status -> stroke knowledge Gender -> stroke knowledge  Tai et al.31  Full  1992–10  Literature review  First medical contact to admission Admission to treatment  19  USA–Switzerland–UK–Finland–Australia  Distance -> scan availability and access/stroke unit direct access  –  Teuschl et al.23  Full  1990–09  Systematic search and review  Onset to seek help Seek help to first medical contact  110  USA–GCC countriesc–South Korea–Switzerland–India–Czech Republic–Spain–Brazil–the Netherlands–Germany–Ireland–UK–Australia–Nigeria–Italy–Japan–Norway–Taiwan–Hong Kong–Pakistan  Age -> transport strategy Ethnic -> transport strategy Unemployed -> transport strategy Bystanders -> transport strategy  Gender -> stroke knowledge Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Ethnic -> stroke knowledge Bystanders -> stroke knowledge Stroke history -> stroke knowledge Psychological -> stroke knowledge  a Partial means that only a part of the review focused on factors influencing acute stroke pathway; Full means all the review is dedicated to factors influencing acute stroke pathway. b Grant MJ, Booth A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info Libr J 2009;26:91–108. c Gulf Cooperation Council countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates). d [a] -> [b] means significant associations report factor [a] impacting factor [b]. Synthesis of results Results are presented in two parts. First, we reported factors and grouped them into four categories: (i) patient, (ii) space, (iii) organizational/logistical and (iv) training. Association between factors are presented in two groups: (i) links observed between categories, and (ii) links observed inside categories. All factors are grouped in table 2, and most cited factors are presented here. Detailed results are available in the Supplementary appendix S2. Table 2 Reported factors influencing acute stroke pathway Factors  References  Patient        Sociodemographic            Age  [9,13,17,23,36]          Gender  [5,11,15,17,23,36,37]          Ethnic  [5,14,15,20,21,23,36]          Alone  [11,15,27,28,35]          Education  [5,14]          Stroke knowledge  [16,19,21,25,27,28,35–39]          Socio economic status  [13]          Income  [5,12,19]          Cognitive  [5,15,17,21,27]          Bystander  [5,11,15,16,21,23,27]      Clinical:            Risk factors  [15]          Symptoms  [5,15,16]          Stroke subtype & severity  [5,15,16,21,23,27,28]          Stroke history  [5,15,16,19,23]  Space            Distance  [5,16,19,23,40]          Deprived area  [12]          Rural/urban  [28,30,40]  Organizational/logistical            Scanner availability and access  [12,15,24,27,29–31]          Pre-notification  [5,15–17,21,29–31,38,40]          Transport strategy  [5,15–17,19,21,25–29,31,36–40]          Coordinated care  [12,16,21,28,30,35,38]          Direct access to SU  [5,24,25]          Off-hours / weekend  [8,15,23,31,38]          Stroke fast track  [17,24,26,31]          Leadership  [24,25]          Beds and stretcher-bearer availability  [27]  Training        Stroke recognition by physicians  [15,16,24,25,27–30,35,38,39]  Factors  References  Patient        Sociodemographic            Age  [9,13,17,23,36]          Gender  [5,11,15,17,23,36,37]          Ethnic  [5,14,15,20,21,23,36]          Alone  [11,15,27,28,35]          Education  [5,14]          Stroke knowledge  [16,19,21,25,27,28,35–39]          Socio economic status  [13]          Income  [5,12,19]          Cognitive  [5,15,17,21,27]          Bystander  [5,11,15,16,21,23,27]      Clinical:            Risk factors  [15]          Symptoms  [5,15,16]          Stroke subtype & severity  [5,15,16,21,23,27,28]          Stroke history  [5,15,16,19,23]  Space            Distance  [5,16,19,23,40]          Deprived area  [12]          Rural/urban  [28,30,40]  Organizational/logistical            Scanner availability and access  [12,15,24,27,29–31]          Pre-notification  [5,15–17,21,29–31,38,40]          Transport strategy  [5,15–17,19,21,25–29,31,36–40]          Coordinated care  [12,16,21,28,30,35,38]          Direct access to SU  [5,24,25]          Off-hours / weekend  [8,15,23,31,38]          Stroke fast track  [17,24,26,31]          Leadership  [24,25]          Beds and stretcher-bearer availability  [27]  Training        Stroke recognition by physicians  [15,16,24,25,27–30,35,38,39]  Table 2 Reported factors influencing acute stroke pathway Factors  References  Patient        Sociodemographic            Age  [9,13,17,23,36]          Gender  [5,11,15,17,23,36,37]          Ethnic  [5,14,15,20,21,23,36]          Alone  [11,15,27,28,35]          Education  [5,14]          Stroke knowledge  [16,19,21,25,27,28,35–39]          Socio economic status  [13]          Income  [5,12,19]          Cognitive  [5,15,17,21,27]          Bystander  [5,11,15,16,21,23,27]      Clinical:            Risk factors  [15]          Symptoms  [5,15,16]          Stroke subtype & severity  [5,15,16,21,23,27,28]          Stroke history  [5,15,16,19,23]  Space            Distance  [5,16,19,23,40]          Deprived area  [12]          Rural/urban  [28,30,40]  Organizational/logistical            Scanner availability and access  [12,15,24,27,29–31]          Pre-notification  [5,15–17,21,29–31,38,40]          Transport strategy  [5,15–17,19,21,25–29,31,36–40]          Coordinated care  [12,16,21,28,30,35,38]          Direct access to SU  [5,24,25]          Off-hours / weekend  [8,15,23,31,38]          Stroke fast track  [17,24,26,31]          Leadership  [24,25]          Beds and stretcher-bearer availability  [27]  Training        Stroke recognition by physicians  [15,16,24,25,27–30,35,38,39]  Factors  References  Patient        Sociodemographic            Age  [9,13,17,23,36]          Gender  [5,11,15,17,23,36,37]          Ethnic  [5,14,15,20,21,23,36]          Alone  [11,15,27,28,35]          Education  [5,14]          Stroke knowledge  [16,19,21,25,27,28,35–39]          Socio economic status  [13]          Income  [5,12,19]          Cognitive  [5,15,17,21,27]          Bystander  [5,11,15,16,21,23,27]      Clinical:            Risk factors  [15]          Symptoms  [5,15,16]          Stroke subtype & severity  [5,15,16,21,23,27,28]          Stroke history  [5,15,16,19,23]  Space            Distance  [5,16,19,23,40]          Deprived area  [12]          Rural/urban  [28,30,40]  Organizational/logistical            Scanner availability and access  [12,15,24,27,29–31]          Pre-notification  [5,15–17,21,29–31,38,40]          Transport strategy  [5,15–17,19,21,25–29,31,36–40]          Coordinated care  [12,16,21,28,30,35,38]          Direct access to SU  [5,24,25]          Off-hours / weekend  [8,15,23,31,38]          Stroke fast track  [17,24,26,31]          Leadership  [24,25]          Beds and stretcher-bearer availability  [27]  Training        Stroke recognition by physicians  [15,16,24,25,27–30,35,38,39]  Factors associated with stroke care delay Patient There are two types of factors related to patient. On the one hand, there are clinical factors relating to strokes and symptoms. On the other hand, are the individual factors, whether demographic, social or cognitive. Among the clinical factors, stroke subtype and associated severity were associated with delays in stroke pathway. Increasing stroke severity is correlated with shorter pre-hospital delay which can be explained by a reduced time from symptoms onset to the first call for medical attention and prior contact for EMS transport. Four studies reviewed by Mazighi et al. demonstrated an association between increasing stroke severity and shorter pre-hospital delay. Specific stroke symptoms like facial droop and language impairment were associated with fast arrival in the emergency room. Patients’ stroke history and specific risk factors (hypertension, atrial fibrillation) were associated with shorter pre-hospital time delay. Among individual factors, stroke knowledge (described as the awareness of risk factors, warning signs and adequate behavior) is well-documented. Most acute stroke delays are attributed to the pre-hospital stage, especially patient stroke knowledge. Poor recognition of stroke symptoms is associated with longer acute stroke pathway. Bystanders at the stroke onset often overcome low patient stroke knowledge or wait-and-see strategy by promptly recognizing the seriousness and emergency of the situation. In a study conducted in North Carolina, USA, the presence of a bystander substantially reduced pre-hospital delay (i.e. median delay 2.0 h vs. 5.8 h).11 Weak associations are reported with age, gender, socioeconomic status (SES) and less-studied factors like psychological and cognitive factors. Interestingly, associations with certain factors are observed among all stroke pathway. Review suggests an association between age and inhospital care9 and reported that age-related differences were not systematically biased against older patients. On a sex-specific review, six studies found gender difference in pre-hospital delays but most of them reported no evidences.11 SES association with the stroke pathway was measured by various factors (patients’ education, income or SES index). Low socioeconomic status was associated with longer pre-hospital delays, inhospital delays and low care quality.14 Ethnic minorities were associated with longer care pathway in few studies. A study conducted in 10 New Jersey, USA, hospitals observed that Hispanic stroke patients wait longer than non-Hispanic white patients to see a physician (OR, 7.95; 95% CI, 1.51–41.6).20 Psychological and cognitive factors mainly affect the response to stroke symptoms with wait-and-see behavior that can partly be explained by a fear of disease or a fear of hospitals.21 Space Space category covers the interrelation of compositional (socio-demographic characteristics of individuals) and contextual (social and physical opportunities)22 factors associated to stroke pathway and explained by the time-critical nature of the disease and observed social health inequalities. Four reviews12,16,23,24 which examined the relationship between socio-spatial factors and stroke pathway suggested that distance to healthcare facilities and neighborhood social level is associated with stroke delay. In England, a study observed disparities of inhospital care against stroke patients from deprived areas and lower thrombolytic treatment rate with patients who travelled the longest distance.5 Organization Organizational and logistical factors associations are well documented. Two main groups are observed: (i) resources strategies covering facilities and staffing and (ii) coordination process referring to organizational dynamics observed to streamlining acute care pathway. Among resources strategies, transport mode and availability of computational tomography (CT) were the most cited factors. Two studies observed increasing alteplase treatment rates and better clinical outcomes with EMS stroke patients compared to private car patients.25 On delay in CT access, a well-known study demonstrated shorter door-to-scan with the relocation of CT scanner to the emergency room.21 Weekend and off-hour admission has been associated with longer door-to-needle times and suboptimal quality of stroke care. Longer inhospital process due to bed unavailability were also reported. Among coordination process, pre-notification was the most cited factor. When applied, interventional studies observed a significant increase of the thrombolysis rate and same observation has been made with the Guidelines stroke program where pre-notification creates shorter door-to-imaging times, door-to-needle times, symptoms-onset-to-needle times and an increase in alteplase treatment within 3 h.21 Pre-notification can be associated with the inhospital stroke code and demonstrated greater impact on onset-to-needle time.26 Reviews observed more broadly the need of coordinated care and agreed on the necessity of a close collaboration between pre-hospital and inhospital staff and services.26 Three reviews gave recommendations for direct admission to SUs and two reviews noticed the importance of leadership. Training Among training factors, which cover especially educational program for both the public and paramedics, stroke recognition by dispatchers and ED physicians is reported as a determinant delay in stroke care pathways. All reviews reported this factor in the pre-hospital stage. Studies observed that only 31–52% of stroke calls are correctly identified by dispatchers. In the inhospital stage, recognition of stroke by ED physician was reported less reported. Studies showed that 24–55% arrive to the ED with their own means. The study reported by Kwan et al. observed inadequate stroke response training for physicians. Links observed between delay’s factors Various associations have been observed between factors. Findings are presented in two groups: (i) association observed between categories, and (ii) association observed inside categories. All reported associations are summarized in the figure 1. Between categories Most associations observed between categories (see figure 1) are reported between patient and organizational/logistical categories. Eight reviews reported four factors that have an impact on transport strategy.5,9,16,23,27–29 These factors are (i) patient age,9 as older patients are likely to arrive by ambulance; (ii) bystander/alone/marital status,16,23,27 as there is a higher probability of EMS use by patients who were not living alone or with a bystander at stroke onset; (iii) stroke severity16,28 as patients with severe stroke were more likely to be transported by EMS16 and (iv) rural/distance,5,28,29 because direct air transport can be considered due to the distance which reduces delays in stroke care pathway. Six reviews reported five factors that have impacted CT access and availability.9,11–14,20 These factors are (i) income,12,14 since the FINMONICA stroke registry observed greater access to CT scan or magnetic resonance imaging for patients from high-income group; (ii) patient age,9 wherein older patients were less likely to receive CT scans; (iii) ethnicity,20 as non-black patients had a greater chance to receive non-invasive carotid imaging; (iv) patient gender,11 since women were less likely to receive brain imaging than men and (v) deprived areas,13 where CT scan was less likely to be performed for stroke patients from deprived areas on the same day of admission. Three reviews reported three factors that were associated with SU direct access.13,14,30 These factors are: (i) income,13 where low-income patients were less likely to receive seven specific processes of care (SU care included); (ii) education,14 e.g. in Sweden a small but significant difference depending on the level of education has been observed14 and (iii) rural/distance,30 noting a study conducted in Australia that observed only 3% of rural patients had access to SU compared to 77% of metropolitan area patients. One review reported association between service coordination and physician stroke knowledge;30 a trained physician has shorter door-to-needle time than a non-trained physician. One review reports the influence of patient education level on the overall stroke care quality.13 In Austria, a study showed that higher educated patients were more likely to benefit from echocardiography and speech therapy during admission. Inside categories We also observed associations inside categories (see figure 2). In patient categories, association with stroke knowledge was well documented. Two extensive reviews10,23 reported numerous associations with the patient’s stroke knowledge. These associations were with age, gender, education, income or SES status, ethnic, alone/married and medical history. To sum up, most of the studies where associations were reported observed better stroke knowledge among women and a decrease of stroke knowledge with age, low education, low-income (or broadly, low socioeconomic status) and non-white patients.10,23 Figure 2 View largeDownload slide Reported associations of factors observed within categories Figure 2 View largeDownload slide Reported associations of factors observed within categories Four factors have been associated with stroke severity. Two reviews reported association between lower socioeconomic status and increasing stroke severity.12,13 One review observed strong evidence for more severe strokes among black patients20 with higher prevalence of coma or ischemic stroke than white patients. Small gender differences in stroke severity was observed in one review.11 In Denmark, a large study observed more severe strokes in women; however, most of the studies of the review reported no gender differences. One review observed more severe strokes in older patients that complicated care decisions.9 Gender differences have been observed with witnessed strokes, because women are more likely to live alone.11 Small gender differences were also observed on the stroke subtype where women had higher frequency of anterior circulation strokes.11 In organizational/logistical category, CT availability and access was associated with three factors. Three reviews reported association with pre-notification.5,24,29 For these reviews, pre-notification permitted the reservation of CT scanners and preparedness of the CT personnel. Five reviews reported that intervention with care coordination can improve CT access and reduce door-to-image times.15,16,24,29,31 One review reported the association of CT access and transport strategy.21 Fassbender et al. reported a study that observed greater access to CT in <25 min for patients transported by EMS. According to four reviews, ED physician training16,30 and leadership24,25 were associated with care coordination. Better coordination and shorter door-to-onset times were observed after implementing a training program. For two reviews, care coordination needs strong leadership to maintain continuing education and resources. Leadership guarantees close collaboration between services and contributes to implementing regional stroke networks.25 One review reports association between weekend/off-hour strokes and transport strategies.23 One study observed that transport times were longer during the weekend. Discussion Principal findings This systematic review provides an exhaustive update on factors influencing acute stroke pathways and better knowledge of the underlying mechanisms by reviewing existing associations between factors. We have found that acute stroke delay can be attributed to patients, space, organizational and training factors. For some of the studies, impact is reported at every stage of the acute stroke pathway. The most cited and consistent factors are patient stroke knowledge, bystanders at stroke onset, transport strategy, pre-notification, regular training, availability and access to CT scan. These multiple factors and interactions form a dynamic framework around the patient and structure the acute stroke pathway. In this framework, the weight of each factor varies according to the context and the scale of the analysis. Studies conducted on a rural setting reported reinforcement between the distance of the patient from the hospital, patient sociodemographic profile (aged, alone) and available resources.18 Similarly, studies conducted in developing countries at state scale reported limited access to adequate resources, poor information and financial costs of the tissue plasminogen activator (tPA).19 Using a systemic approach is consistent with the demonstration of a dynamic framework that could explain increasing complexity and variation in acute stroke care. In this context, the influence of a factor must no longer be interpreted according to the sole impact on the pathway but complemented by its influence on other factors. For example, the rural/urban distinction implies not only a question of travel distance but also the issues of population education, resource optimization and services coordination. By incorporating the interaction between factors, we analyze acute stroke pathway as a complex system. By observing how factors are interrelated within this complex system, we understand the benefit of combined intervention. Multi-factorial interventions like combined educational programs show clear benefits by addressing several barriers at same time.7,15 In Temple, USA, the proportion of patient receiving tPA increased from 1.4 to 5.8% after implementation of a multilevel stroke educational campaign for the public and paramedics. In our review, most studies investigated access to thrombolysis with tPA but our results, in light of recent developments in endovascular therapy, can also apply to patients with large vessel occlusion (LVO). These patients present a worse prognosis and thrombolysis alone had only a small benefit.32 The results of our review showed how factors articulate during all the acute stroke pathway and were consistent with results found for LVO patients. The study reported reduced delays when a triage tool to recognize LVO patients was used at the pre-hospital stage, completed with an educational and training program for EMS personnel. In this case, reduction of delays for identified LVO patients was associated with a significant increase in reaching functional independence after stroke without changing functional independence for patients eligible of IV tPA only.33 Our review has several potential limitations. First, there is inherent weakness in a review of systematic reviews. The quality of reviews may vary in terms of clear inclusion and exclusion criterion and search strategy. Our research only included French and English reviews, which might cause an under representation of non-English and non-French reviews. Some of the included reviews are probably outdated and reviews, published after the search date, are not included. Second, given the heterogeneity of the reviews’ findings in terms of methods, sample size or context, a meta-analysis was not feasible. Because of some reviews have studied similar or overlapping topics, we note that some of the reviews reported the same underling studies. Although some of these studies may represent duplicate cases, each review met our inclusion criteria. Of note for the overall review, the identified stroke factors and the links between factors only imply association but not necessarily causality. The association is relevant when at least one review indicates a significant association. We saw three main implications of this review. First, this review shows the benefit of thematic approach over sequential approach by reporting transversal impact among the stroke pathway of certain factors and association between factors.34 Second, we recognize the understanding of the context as a part of stroke intervention due to the decisive impact among stroke pathway. Last, further research needs to be performed on factors to clarify the synthetic framework by adding causal, feedback and balancing loop. This work is especially true on less-studied factors which can be underestimated by ignoring certain mechanism of the framework. Altogether, this review offers new tools for health care planning and building better strategies to tackle acute stroke care delays. The global and systemic approach provides a comprehensive analysis that is valid in both high- and low-income countries at various scales of interventions. This gathered knowledge is essential for developing effective and equitable acute stroke care pathway. Supplementary data Supplementary data are available at EURPUB online. Funding None. Conflicts of interest: None declared. Key points A wide variety of factors impacts acute stroke pathway at different stages but there is an urgent need of understanding associations between these factors. This systematic review provides an exhaustive framework of factors occurring during the acute stroke pathway. Factors influencing acute stroke pathway varying according to context and scale of the study. References 1 Mozaffarian D, Benjamin EJ, Go AS, et al.   Heart disease and stroke statistics—2016 update. Circulation  2016; 133: e38– 360. Google Scholar CrossRef Search ADS PubMed  2 Lees KR, Bluhmki E, von Kummer R, et al.   Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet  2010; 375: 1695– 703. Google Scholar CrossRef Search ADS PubMed  3 Marler JR, Tilley BC, Lu M, et al.   Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology  2000; 55: 1649– 55. Google Scholar CrossRef Search ADS PubMed  4 Goyal M, Menon BK, van Zwam WH, et al.   Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet  2016; 387: 1723– 31. Google Scholar CrossRef Search ADS PubMed  5 Ragoschke-Schumm a, Walter S, Haass a, et al.   Translation of the “time is brain” concept into clinical practice: focus on prehospital stroke management. Int J Stroke  2014; 9: 333– 40. Google Scholar CrossRef Search ADS PubMed  6 Brice JH, Griswell JK, Delbridge TR, Key CB. Stroke: from recognition by the public to management by emergency medical services. Prehosp Emerg Care  2002; 6: 99– 106. Google Scholar CrossRef Search ADS   7 Churilov L, Fridriksdottir A, Keshtkaran M, et al.   Decision support in pre-hospital stroke care operations: a case of using simulation to improve eligibility of acute stroke patients for thrombolysis treatment. Comput Oper Res  2013; 40: 2208– 18. Google Scholar CrossRef Search ADS   8 Moher D, Liberati A, Tetzlaff J, Altman DG, Group TP, Oxman A, et al.   Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med  2009; 6: e1000097. Google Scholar CrossRef Search ADS PubMed  9 Luker JA, Wall K, Bernhardt J, et al.   Patients’ age as a determinant of care received following acute stroke: a systematic review. BMC Health Serv Res  2011; 11: 161. Google Scholar CrossRef Search ADS PubMed  10 Stroebele N, Müller-Riemenschneider F, Nolte CH, et al.   Knowledge of risk factors, and warning signs of stroke: a systematic review from a gender perspective. Int J Stroke  2011; 6: 60– 6. Google Scholar CrossRef Search ADS PubMed  11 Reeves MJ, Bushnell CD, Howard G, et al.   Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol  2008; 7: 915– 26. Google Scholar CrossRef Search ADS PubMed  12 Cox AM, McKevitt C, Rudd AG, Wolfe CD. Socioeconomic status and stroke. Lancet Neurol  2006; 5: 181– 8. Google Scholar CrossRef Search ADS PubMed  13 Addo J, Ayerbe L, Mohan KM, et al.   Socioeconomic status and stroke: an updated review. Stroke  2012; 43: 1186– 91. Google Scholar CrossRef Search ADS PubMed  14 Marshall IJ, Wang Y, Crichton S, et al.   The effects of socioeconomic status on stroke risk and outcomes. Lancet Neurol  2015; 14: 1206– 18. Google Scholar CrossRef Search ADS PubMed  15 Bouckaert M, Lemmens R, Thijs V. Reducing prehospital delay in acute stroke. Nat Rev Neurol  2009; 5: 477– 83. Google Scholar CrossRef Search ADS PubMed  16 Mazighi M, Derex L, Amarenco P. Prehospital stroke care: potential, pitfalls, and future. Curr Opin Neurol  2010; 23: 31– 5. Google Scholar CrossRef Search ADS PubMed  17 Yperzeele L, Van Hooff R-J, De Smedt A, et al.   Prehospital stroke care: limitations of current interventions and focus on new developments. Cerebrovasc Dis  2014; 38: 1– 9. Google Scholar CrossRef Search ADS PubMed  18 Joubert J, Prentice LF, Moulin T, et al.   Stroke in rural areas and small communities. Stroke  2008; 39: 1920– 8. Google Scholar CrossRef Search ADS PubMed  19 Pandian JD, Padma V, Vijaya P, et al.   Stroke and thrombolysis in developing countries. Int J Stroke  2007; 2: 17– 26. Google Scholar CrossRef Search ADS PubMed  20 Stansbury JP, Jia H, Williams LS, et al.   Ethnic disparities in stroke: epidemiology, acute care, and postacute outcomes. Stroke  2005; 36: 374– 86. Google Scholar CrossRef Search ADS PubMed  21 Fassbender K, Balucani C, Walter S, et al.   Streamlining of prehospital stroke management: the golden hour. Lancet Neurol  2013; 12: 585– 96. Google Scholar CrossRef Search ADS PubMed  22 Macintyre S, Ellaway A, Cummins S. Place effects on health: how can we conceptualise, operationalise and measure them? Soc Sci Med  2002; 55: 125– 39. Google Scholar CrossRef Search ADS PubMed  23 TeuschI Y, Brainin M. Stroke education: discrepancies among factors influencing prehospital delay and stroke knowledge. Int J Stroke  2010; 5: 187– 208. Google Scholar CrossRef Search ADS PubMed  24 Carter-Jones CR. Stroke thrombolysis: barriers to implementation. Int Emerg Nurs  2011; 19: 53– 7. Google Scholar CrossRef Search ADS PubMed  25 El Khoury R, Jung R, Nanda A, et al.   Overview of key factors in improving access to acute stroke care. Neurology  2012; 79: S26– 34. Google Scholar CrossRef Search ADS PubMed  26 Dalloz MA, Bottin L, Muresan IP, et al.   Thrombolysis rate and impact of a stroke code: a French hospital experience and a systematic review. J Neurol Sci  2012; 314: 120– 5. Google Scholar CrossRef Search ADS PubMed  27 Kwan J, Hand P, Sandercock P. A systematic review of barries to delivery of thrombolysis for acute stroke. Age Ageing  2004; 33: 116– 21. Google Scholar CrossRef Search ADS PubMed  28 Crocco TJ. Streamlining stroke care: from symptom onset to emergency department. J Emerg Med  2007; 33: 255– 60. Google Scholar CrossRef Search ADS PubMed  29 Asif KS, Lazzaro MA, Zaidat O. Identifying delays to mechanical thrombectomy for acute stroke: onset to door and door to clot times. J Neurointerv Surg  2014; 6: 505– 10. Google Scholar CrossRef Search ADS PubMed  30 Eissa A, Krass I, Bajorek BV. Optimizing the management of acute ischaemic stroke: a review of the utilization of intravenous recombinant tissue plasminogen activator (tPA). J Clin Pharm Ther  2012; 37: 620– 9. Google Scholar CrossRef Search ADS PubMed  31 Tai YJ, Yan B. Minimising time to treatment: targeted strategies to minimise time to thrombolysis for acute ischaemic stroke. Intern Med J  2013; 43: 1176– 82. Google Scholar CrossRef Search ADS PubMed  32 Smith WS, Lev MH, English JD, et al.   Significance of large vessel intracranial occlusion causing acute ischemic stroke and tia. Stroke  2009; 40: 3834– 40. Google Scholar CrossRef Search ADS PubMed  33 Mohamad NF, Hastrup S, Rasmussen M, et al.   Bypassing primary stroke centre reduces delay and improves outcomes for patients with large vessel occlusion. ESJ  2016; 1: 85– 92. 34 Kimberly J, Minvielle E. The Quality Imperative: Measurement and Management of Quality in Healthcare . London: Imperial College Press, 2000. 35 Donnan GA, Davis SM, Parsons MW, et al.   How to make better use of thrombolytic therapy in acute ischemic stroke. Nat Rev Neurol  2011; 7: 400– 9. Google Scholar CrossRef Search ADS PubMed  36 Johnson M, Bakas T. A review of barriers to thrombolytic therapy: implications for nursing care in the emergency department. J Neurosci Nurs  2010; 42: 88– 94. Google Scholar CrossRef Search ADS PubMed  37 Lisabeth LD, Brown DL, Morgenstern LB. Barriers to intravenous tissue plasminogen activator for acute stroke therapy in women. Gend Med  2006; 3: 270– 8. Google Scholar CrossRef Search ADS PubMed  38 Baldereschi M, Piccardi B, Di Carlo A, et al.   Relevance of prehospital stroke code activation for acute treatment measures in stroke care: a review. Cerebrovasc Dis  2012; 34: 182– 90. Google Scholar CrossRef Search ADS PubMed  39 Ehlers L, Jensen LG, Bech MA, et al.   Organisational barriers to thrombolysis treatment of acute ischaemic stroke. Curr Med Res Opin  2007; 23: 2833– 9. Google Scholar CrossRef Search ADS PubMed  40 Paul CL, Ryan A, Rose S, et al.   How can we improve stroke thrombolysis rates? A review of health system factors and approaches associated with thrombolysis administration rates in acute stroke care. Implement Sci  2015; 11: 51. Google Scholar CrossRef Search ADS   © The Author(s) 2018. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The European Journal of Public Health Oxford University Press

Understanding delays in acute stroke care: a systematic review of reviews

Loading next page...
 
/lp/ou_press/understanding-delays-in-acute-stroke-care-a-systematic-review-of-NbRu60QC1w
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.
ISSN
1101-1262
eISSN
1464-360X
D.O.I.
10.1093/eurpub/cky066
Publisher site
See Article on Publisher Site

Abstract

Abstract Background Stroke is the leading cause of adult long-term disability in Western countries. Intravenous thrombolytic therapy with recombinant tissue plasminogen activator is safe and effective within the first 4.5 h after the onset of stroke. Various factors delaying acute stroke care have been identified in the literature. This review aimed to provide an overview of factors delaying acute stroke care and attempted to show how they interact in a synthetic framework. Methods We conducted a systematic review of literature reviews published in Medline and DORIS until 2016 on factors influencing acute stroke pathway timeframe. Results We analyzed 31 reviews that cover all factors of delays from stroke onset to treatment. We identified 27 factors that had a significant impact on acute stroke care and can be categorized into four distinct categories: patient-related factors, training, resources and lack of coordination. We also reported associations between factors observed in both between categories (mainly between patients and organizational/logistical factors) and within categories. Conclusion This review provides a wide overview of factors influencing acute stroke pathway. Since it was observed that the identified factors were interrelated, they needed to be analyzed in a systematic way. We hence created a synthetic framework that combines several categories of factors while assuming that factor weight varies from a study context to another. Better knowledge on underlying mechanisms between factors would provide crucial improvement of the interventions aiming at reducing delays in both pre-hospital and inhospital stages. For future research, we recommend adopting a systemic perspective on factors influencing acute stroke pathway. Introduction Stroke is a primary cause of death and the leading cause of adult long-term disability.1 In an ageing society, the social and economic burden of strokes is increasing and resulting in a public health challenge. For an ischemic stroke, which accounts for about 80% of strokes, intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) administered within 4.5 h of symptom onset is safe, effective and the standard treatment in terms of cost-benefit and the reduction of long-term disability.2 However, the benefits of thrombolytic treatment are deeply time dependent and decline rapidly beyond the first 90 min following symptom onset.3 A meta-analysis conducted on five randomized trials evaluating the efficacy of endovascular thrombectomy (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, EXTEND IA) done by newer generation devices (stent retrievers) showed the benefit on elderly (>80 years), patients not receiving intravenous alteplase, and patients who are treated under 300 min from stroke onset.4 Following this evidence, European and American medical society recommendations and guidelines were amended to integrate endovascular thrombectomy into acute stroke care pathways, providing the treatment to patients up to 6 h after stroke onset. Despite these advances, pre-hospital and inpatient delays remain an important challenge for stroke care management. Indeed, despite a better public awareness of the disease—as well as the proliferation of stroke units (SUs), the improved organization of stroke care pathways and recent advances in telemedicine—only a small minority of stroke patients have access to stroke care in a favorable timeframe, including thrombolytic therapy. In Europe and USA, only one-third of patients with acute stroke arrive at the hospital in adequate time to receive thrombolytic treatment and <7% receive it.5 An important body of literature has emerged presenting factors impacting acute stroke pathway. These factors can have both positive and negative effect on the critical timeframe. The acute stroke timeframe is defined as the time taken from symptom onset to the decision to treat.6 It can be divided into four delay phases: (i) from symptom onset to the decision to seek medical attention (reaction time); (ii) from the decision to seek medical attention to first medical contact (first contact); (iii) from first medical contact to admission (medical evaluation and travel) and (iv) from admission to treatment (inhospital door to needle). A wide variety of factors impact acute stroke pathways at each stage. Some of them like patient stroke knowledge, correct recognition and triage by emergency medical service (EMS) dispatchers or emergency department (ED) physicians, and SU access are leading factors that have already been well studied. In comparison, socioeconomic status, patient psychological factors or structure-level management services are less studied, partly because of the difficulties to capture these factors. The impact of each factor is heterogeneously documented and the knowledge of the underlying mechanisms explaining acute stroke delays remains low.7 One way to explain this is to recognize the growing complexity that sustains the need for system approaches. More than being aware of the distinct factors, it is important to remain aware of the relationship between factors and how they react when those relationships change. To our knowledge, there have been no studies focused on the interaction between factors. We conducted a systematic review of reviews to provide an overview of factors influencing acute stroke care. This approach provides a summary of evidence at different levels, including the combination of different interventions, different outcomes, different conditions, problems or populations. This single synthesis of all relevant evidence also focuses on associations between factors and attempts to demonstrate how they could interact in a synthetic framework that can be adopted to design efficient health care planning interventions. Methods For this review, we adhered to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.8 We searched Medline & DORIS for publications. All searches were carried out in May 2017, not limited by date and restricted to applications in humans. The search was conducted on both resources using a combination of the following terms: (Factors OR Barriers OR Delays) AND (Acute stroke OR Stroke care) AND (Pathways OR Pre-hospital OR Inhospital) AND (Stroke knowledge). Keywords had to be in the title or the abstract of full-length publications. Articles written in English and French were eligible for inclusion and the selected study type was reviewed. Search results initially scanned titles, followed by an abstract assessment for selected publications (see Supplementary appendix S1). We also scanned their reference list. We excluded reviews that did not focus on the acute stroke timeframe (e.g. prevention, rehabilitation and post-acute stroke care) or that focus on risk factors, drug therapy or medical practices, or that aimed only to report stroke delays time. We assessed the methodological quality of the reviews by evaluating the research questions, the methodology with explicit inclusion and exclusion criteria, and analyzing the limitations, although reviews were not rated or excluded based on the overall quality rating. The total articles were first checked by one reviewer (Y.L.), then the abstract selection, performed by one authors (Y.L.), was reviewed by two authors (S.R. and E.M.). The review process is presented in Supplementary appendix S1. Relevant data were extracted from the identified reviews using an abstraction form containing the following elements: (i) search period, (ii) type of review, (iii) number of studies, (iv) geographic coverage, (v) identified factors and related acute stroke phase and (vi) identified links between factors. For the review, the term ‘factor’ designates all positive or negative influence on the acute stroke pathway timeframe. Figure 1 View largeDownload slide Reported associations of factors observed between categories Figure 1 View largeDownload slide Reported associations of factors observed between categories The PRISMA checklist was used to synthesize and report findings, except for items that were not relevant for a systematic review of reviews. Due to the heterogeneity between studies in terms of methodologies and data sources, a statistical analysis or meta-analysis was not possible, so results are presented in a descriptive systematic literature review. Results Study selection The initial search identified 1037 articles. After a review of titles and abstracts, 30 remained for full text examination. Only 4 reviews were added after scanning the reference list and 29 reviews were finally included after the exclusion of 3 reviews that met at least one exclusion criterion (the full list of excluded articles is available from the authors upon request). One review focused on inhospital stroke and two had no indication of the research strategy (one was a special report, and one focused on the epidemiology, pathophysiology, treatment and outcomes of stroke). Of note, 13 of 29 reviews were included even if only a part of the research met our inclusion criteria. Study characteristics Included reviews vary by focus, target population or inclusion criteria. Some reviews focus on one factor (e.g. age-specific,9 sex-specific10,11 or group of factors SES-specific,12–14) while others focused on specific stroke stage (e.g. pre-hospital stage5,15–17) with various stroke stage definitions. Most of the reviews have no countries or regions specified, although one review focused on rural areas18 and another focused on developing countries.19 The result is a wide geographic coverage, even if most of studies were usually conducted in USA and Western Europe. This review covers more than two decades of literature on stroke care management. Earlier reviews mainly focused on inhospital barriers and issues relating to hospital resources. Then, the focus shifted to the pre-hospital stage and the patient stroke knowledge. Eventually, more recent reviews covered the acute stroke pathway focusing on pre- and inhospital coordination. The methodological quality of the included reviews varied considerably (see table 1). Only 5 of 29 reviews were systematic (one included meta-analysis), and 3 of 29 did not precisely describe the search strategy utilized. Some factors were assessed in only one or two reviews with several limitations. For certain factors, the definition of them also varied. This was also the case for SES, which was described by education, income, occupation or socioeconomic index. Table 1 Synthesis of reviews reported association between factors Reference  Review focusa  Search period  Type of reviewb  Pathway  Number of studies  Geographic coverage  Reported links between factorsd  Between categories  Inside categories  Addo et al.13  Partial  2008–11  Overview  Admission to treatment  17  Austria–UK–Denmark–Scotland–USA–Canada–Finland–the Netherlands  Deprivated area -> scan availability and access Income -> scan availability and access/direct access to stroke unit  –  Bouckaert et al.15  Full  1998–08  State-of-the-art review  All acute pathway  47  USA–Sweden–Australia–Israel–Spain–Switzerland–UK–Czech Republic–Germany–Canada–Poland–South Korea–Finland–Norway  Stroke history -> Transport strategy  Coordination services -> scan availability and access  Carter-Jones24  Full  1999–07  Literature review  All acute pathway  9  Australia–USA–UK–Canada–the Netherlands  Leadership -> paramedics and physicians training  Leadership -> coordination services  Donnan et al.35  Full  1998–05  Overview  Admission to treatment  23  USA–Denmark–UK–Canada–Australia  Gender -> rtPA availability and access Gender -> scan availability and access Gender -> services coordination Gender -> transport strategy  Gender -> stroke knowledge Gender -> alone at stroke onset Transport strategy -> scan availability and access Transport strategy -> services coordination  El Khoury et al.25  Full  2000–13  Overview  All acute pathway  19  Germany–USA–South Korea–France–Finland–Canada––Spain–UK–Australia  Training physicians -> weekend/off-hour  –  Fassbender et al.21  Full  1992–12  State-of-the-art review  All care pathway  104  USA–Germany–Taiwan–Sweden–Finland–Denmark–Canada–Japan–Australia–Spain–Austria–South Korea–the Netherlands–France–China  –  Gender -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Johnson et al.36  Full  1999–11  Literature review  First medical contact to admission Admission to treatment  19  Spain–Finland–Australia–USA–Canada–Japan–Italy  Dispatcher’s training -> pre-notification  Coordination services -> scan availability and access  Joubert et al.18  Partial  1993–05  Systematic search and review  Onset to seek help Seek help to first medical contact  7  USA–China–Czech Republic–South Africa–Bulgaria–USA  Rural area -> stroke knowledge  –  Kwan et al.27  Partial  2000–08  Systematic review  First medical contact to admission Admission to treatment  –  USA–Canada–Australia–India–Taiwan–Thailand–Sweden–Germany–Belgium–France–Poland–UK–the Netherlands–Norway–Spain  –  Transport strategy -> coordination services  Lisabeth et al.37  Full  1999–13  Literature review  First medical contact to admission Admission to treatment  14  USA–Germany–Finland  Dispatcher’s training -> pre-notification  Coordination process -> scan availability and access  Marshall et al.14  Partial  2013–15  Systematic search and review  Admission to treatment  7  UK–Sweden–Denmark–USA  Socioeconomic status -> stroke unit direct access Education -> stroke unit direct access Socioeconomic status -> scan availability and access  –  Mazighi et al.16  Full  1994–09  State-of-the-art review  All acute pathway  32  USA–France–UK–Denmark–Spain–Germany–Taiwan  –  Age -> stroke knowledge Gender -> stroke knowledge Ethnic -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Pandian et al.19  Partial  2000–06  State-of-the-art review  All acute pathway  23  Brazil–Argentina–India–China–Thailand–Indonesia–Philippines  Distance -> scan availability and access/stroke unit direct access  –  Stroebele et al.10  Full  1994–08  Systematic review  Onset to seek help Seek help to first medical contact  22  USA–Germany–UK–Spain–Canada–Turkey–Brazil–India–Ireland–Nigeria–Australia–GCC countriesc  –  Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Medical history -> stroke knowledge Ethnic -> stroke knowledge Socioeconomic status -> stroke knowledge Gender -> stroke knowledge  Tai et al.31  Full  1992–10  Literature review  First medical contact to admission Admission to treatment  19  USA–Switzerland–UK–Finland–Australia  Distance -> scan availability and access/stroke unit direct access  –  Teuschl et al.23  Full  1990–09  Systematic search and review  Onset to seek help Seek help to first medical contact  110  USA–GCC countriesc–South Korea–Switzerland–India–Czech Republic–Spain–Brazil–the Netherlands–Germany–Ireland–UK–Australia–Nigeria–Italy–Japan–Norway–Taiwan–Hong Kong–Pakistan  Age -> transport strategy Ethnic -> transport strategy Unemployed -> transport strategy Bystanders -> transport strategy  Gender -> stroke knowledge Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Ethnic -> stroke knowledge Bystanders -> stroke knowledge Stroke history -> stroke knowledge Psychological -> stroke knowledge  Reference  Review focusa  Search period  Type of reviewb  Pathway  Number of studies  Geographic coverage  Reported links between factorsd  Between categories  Inside categories  Addo et al.13  Partial  2008–11  Overview  Admission to treatment  17  Austria–UK–Denmark–Scotland–USA–Canada–Finland–the Netherlands  Deprivated area -> scan availability and access Income -> scan availability and access/direct access to stroke unit  –  Bouckaert et al.15  Full  1998–08  State-of-the-art review  All acute pathway  47  USA–Sweden–Australia–Israel–Spain–Switzerland–UK–Czech Republic–Germany–Canada–Poland–South Korea–Finland–Norway  Stroke history -> Transport strategy  Coordination services -> scan availability and access  Carter-Jones24  Full  1999–07  Literature review  All acute pathway  9  Australia–USA–UK–Canada–the Netherlands  Leadership -> paramedics and physicians training  Leadership -> coordination services  Donnan et al.35  Full  1998–05  Overview  Admission to treatment  23  USA–Denmark–UK–Canada–Australia  Gender -> rtPA availability and access Gender -> scan availability and access Gender -> services coordination Gender -> transport strategy  Gender -> stroke knowledge Gender -> alone at stroke onset Transport strategy -> scan availability and access Transport strategy -> services coordination  El Khoury et al.25  Full  2000–13  Overview  All acute pathway  19  Germany–USA–South Korea–France–Finland–Canada––Spain–UK–Australia  Training physicians -> weekend/off-hour  –  Fassbender et al.21  Full  1992–12  State-of-the-art review  All care pathway  104  USA–Germany–Taiwan–Sweden–Finland–Denmark–Canada–Japan–Australia–Spain–Austria–South Korea–the Netherlands–France–China  –  Gender -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Johnson et al.36  Full  1999–11  Literature review  First medical contact to admission Admission to treatment  19  Spain–Finland–Australia–USA–Canada–Japan–Italy  Dispatcher’s training -> pre-notification  Coordination services -> scan availability and access  Joubert et al.18  Partial  1993–05  Systematic search and review  Onset to seek help Seek help to first medical contact  7  USA–China–Czech Republic–South Africa–Bulgaria–USA  Rural area -> stroke knowledge  –  Kwan et al.27  Partial  2000–08  Systematic review  First medical contact to admission Admission to treatment  –  USA–Canada–Australia–India–Taiwan–Thailand–Sweden–Germany–Belgium–France–Poland–UK–the Netherlands–Norway–Spain  –  Transport strategy -> coordination services  Lisabeth et al.37  Full  1999–13  Literature review  First medical contact to admission Admission to treatment  14  USA–Germany–Finland  Dispatcher’s training -> pre-notification  Coordination process -> scan availability and access  Marshall et al.14  Partial  2013–15  Systematic search and review  Admission to treatment  7  UK–Sweden–Denmark–USA  Socioeconomic status -> stroke unit direct access Education -> stroke unit direct access Socioeconomic status -> scan availability and access  –  Mazighi et al.16  Full  1994–09  State-of-the-art review  All acute pathway  32  USA–France–UK–Denmark–Spain–Germany–Taiwan  –  Age -> stroke knowledge Gender -> stroke knowledge Ethnic -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Pandian et al.19  Partial  2000–06  State-of-the-art review  All acute pathway  23  Brazil–Argentina–India–China–Thailand–Indonesia–Philippines  Distance -> scan availability and access/stroke unit direct access  –  Stroebele et al.10  Full  1994–08  Systematic review  Onset to seek help Seek help to first medical contact  22  USA–Germany–UK–Spain–Canada–Turkey–Brazil–India–Ireland–Nigeria–Australia–GCC countriesc  –  Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Medical history -> stroke knowledge Ethnic -> stroke knowledge Socioeconomic status -> stroke knowledge Gender -> stroke knowledge  Tai et al.31  Full  1992–10  Literature review  First medical contact to admission Admission to treatment  19  USA–Switzerland–UK–Finland–Australia  Distance -> scan availability and access/stroke unit direct access  –  Teuschl et al.23  Full  1990–09  Systematic search and review  Onset to seek help Seek help to first medical contact  110  USA–GCC countriesc–South Korea–Switzerland–India–Czech Republic–Spain–Brazil–the Netherlands–Germany–Ireland–UK–Australia–Nigeria–Italy–Japan–Norway–Taiwan–Hong Kong–Pakistan  Age -> transport strategy Ethnic -> transport strategy Unemployed -> transport strategy Bystanders -> transport strategy  Gender -> stroke knowledge Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Ethnic -> stroke knowledge Bystanders -> stroke knowledge Stroke history -> stroke knowledge Psychological -> stroke knowledge  a Partial means that only a part of the review focused on factors influencing acute stroke pathway; Full means all the review is dedicated to factors influencing acute stroke pathway. b Grant MJ, Booth A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info Libr J 2009;26:91–108. c Gulf Cooperation Council countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates). d [a] -> [b] means significant associations report factor [a] impacting factor [b]. Table 1 Synthesis of reviews reported association between factors Reference  Review focusa  Search period  Type of reviewb  Pathway  Number of studies  Geographic coverage  Reported links between factorsd  Between categories  Inside categories  Addo et al.13  Partial  2008–11  Overview  Admission to treatment  17  Austria–UK–Denmark–Scotland–USA–Canada–Finland–the Netherlands  Deprivated area -> scan availability and access Income -> scan availability and access/direct access to stroke unit  –  Bouckaert et al.15  Full  1998–08  State-of-the-art review  All acute pathway  47  USA–Sweden–Australia–Israel–Spain–Switzerland–UK–Czech Republic–Germany–Canada–Poland–South Korea–Finland–Norway  Stroke history -> Transport strategy  Coordination services -> scan availability and access  Carter-Jones24  Full  1999–07  Literature review  All acute pathway  9  Australia–USA–UK–Canada–the Netherlands  Leadership -> paramedics and physicians training  Leadership -> coordination services  Donnan et al.35  Full  1998–05  Overview  Admission to treatment  23  USA–Denmark–UK–Canada–Australia  Gender -> rtPA availability and access Gender -> scan availability and access Gender -> services coordination Gender -> transport strategy  Gender -> stroke knowledge Gender -> alone at stroke onset Transport strategy -> scan availability and access Transport strategy -> services coordination  El Khoury et al.25  Full  2000–13  Overview  All acute pathway  19  Germany–USA–South Korea–France–Finland–Canada––Spain–UK–Australia  Training physicians -> weekend/off-hour  –  Fassbender et al.21  Full  1992–12  State-of-the-art review  All care pathway  104  USA–Germany–Taiwan–Sweden–Finland–Denmark–Canada–Japan–Australia–Spain–Austria–South Korea–the Netherlands–France–China  –  Gender -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Johnson et al.36  Full  1999–11  Literature review  First medical contact to admission Admission to treatment  19  Spain–Finland–Australia–USA–Canada–Japan–Italy  Dispatcher’s training -> pre-notification  Coordination services -> scan availability and access  Joubert et al.18  Partial  1993–05  Systematic search and review  Onset to seek help Seek help to first medical contact  7  USA–China–Czech Republic–South Africa–Bulgaria–USA  Rural area -> stroke knowledge  –  Kwan et al.27  Partial  2000–08  Systematic review  First medical contact to admission Admission to treatment  –  USA–Canada–Australia–India–Taiwan–Thailand–Sweden–Germany–Belgium–France–Poland–UK–the Netherlands–Norway–Spain  –  Transport strategy -> coordination services  Lisabeth et al.37  Full  1999–13  Literature review  First medical contact to admission Admission to treatment  14  USA–Germany–Finland  Dispatcher’s training -> pre-notification  Coordination process -> scan availability and access  Marshall et al.14  Partial  2013–15  Systematic search and review  Admission to treatment  7  UK–Sweden–Denmark–USA  Socioeconomic status -> stroke unit direct access Education -> stroke unit direct access Socioeconomic status -> scan availability and access  –  Mazighi et al.16  Full  1994–09  State-of-the-art review  All acute pathway  32  USA–France–UK–Denmark–Spain–Germany–Taiwan  –  Age -> stroke knowledge Gender -> stroke knowledge Ethnic -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Pandian et al.19  Partial  2000–06  State-of-the-art review  All acute pathway  23  Brazil–Argentina–India–China–Thailand–Indonesia–Philippines  Distance -> scan availability and access/stroke unit direct access  –  Stroebele et al.10  Full  1994–08  Systematic review  Onset to seek help Seek help to first medical contact  22  USA–Germany–UK–Spain–Canada–Turkey–Brazil–India–Ireland–Nigeria–Australia–GCC countriesc  –  Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Medical history -> stroke knowledge Ethnic -> stroke knowledge Socioeconomic status -> stroke knowledge Gender -> stroke knowledge  Tai et al.31  Full  1992–10  Literature review  First medical contact to admission Admission to treatment  19  USA–Switzerland–UK–Finland–Australia  Distance -> scan availability and access/stroke unit direct access  –  Teuschl et al.23  Full  1990–09  Systematic search and review  Onset to seek help Seek help to first medical contact  110  USA–GCC countriesc–South Korea–Switzerland–India–Czech Republic–Spain–Brazil–the Netherlands–Germany–Ireland–UK–Australia–Nigeria–Italy–Japan–Norway–Taiwan–Hong Kong–Pakistan  Age -> transport strategy Ethnic -> transport strategy Unemployed -> transport strategy Bystanders -> transport strategy  Gender -> stroke knowledge Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Ethnic -> stroke knowledge Bystanders -> stroke knowledge Stroke history -> stroke knowledge Psychological -> stroke knowledge  Reference  Review focusa  Search period  Type of reviewb  Pathway  Number of studies  Geographic coverage  Reported links between factorsd  Between categories  Inside categories  Addo et al.13  Partial  2008–11  Overview  Admission to treatment  17  Austria–UK–Denmark–Scotland–USA–Canada–Finland–the Netherlands  Deprivated area -> scan availability and access Income -> scan availability and access/direct access to stroke unit  –  Bouckaert et al.15  Full  1998–08  State-of-the-art review  All acute pathway  47  USA–Sweden–Australia–Israel–Spain–Switzerland–UK–Czech Republic–Germany–Canada–Poland–South Korea–Finland–Norway  Stroke history -> Transport strategy  Coordination services -> scan availability and access  Carter-Jones24  Full  1999–07  Literature review  All acute pathway  9  Australia–USA–UK–Canada–the Netherlands  Leadership -> paramedics and physicians training  Leadership -> coordination services  Donnan et al.35  Full  1998–05  Overview  Admission to treatment  23  USA–Denmark–UK–Canada–Australia  Gender -> rtPA availability and access Gender -> scan availability and access Gender -> services coordination Gender -> transport strategy  Gender -> stroke knowledge Gender -> alone at stroke onset Transport strategy -> scan availability and access Transport strategy -> services coordination  El Khoury et al.25  Full  2000–13  Overview  All acute pathway  19  Germany–USA–South Korea–France–Finland–Canada––Spain–UK–Australia  Training physicians -> weekend/off-hour  –  Fassbender et al.21  Full  1992–12  State-of-the-art review  All care pathway  104  USA–Germany–Taiwan–Sweden–Finland–Denmark–Canada–Japan–Australia–Spain–Austria–South Korea–the Netherlands–France–China  –  Gender -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Johnson et al.36  Full  1999–11  Literature review  First medical contact to admission Admission to treatment  19  Spain–Finland–Australia–USA–Canada–Japan–Italy  Dispatcher’s training -> pre-notification  Coordination services -> scan availability and access  Joubert et al.18  Partial  1993–05  Systematic search and review  Onset to seek help Seek help to first medical contact  7  USA–China–Czech Republic–South Africa–Bulgaria–USA  Rural area -> stroke knowledge  –  Kwan et al.27  Partial  2000–08  Systematic review  First medical contact to admission Admission to treatment  –  USA–Canada–Australia–India–Taiwan–Thailand–Sweden–Germany–Belgium–France–Poland–UK–the Netherlands–Norway–Spain  –  Transport strategy -> coordination services  Lisabeth et al.37  Full  1999–13  Literature review  First medical contact to admission Admission to treatment  14  USA–Germany–Finland  Dispatcher’s training -> pre-notification  Coordination process -> scan availability and access  Marshall et al.14  Partial  2013–15  Systematic search and review  Admission to treatment  7  UK–Sweden–Denmark–USA  Socioeconomic status -> stroke unit direct access Education -> stroke unit direct access Socioeconomic status -> scan availability and access  –  Mazighi et al.16  Full  1994–09  State-of-the-art review  All acute pathway  32  USA–France–UK–Denmark–Spain–Germany–Taiwan  –  Age -> stroke knowledge Gender -> stroke knowledge Ethnic -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge  Pandian et al.19  Partial  2000–06  State-of-the-art review  All acute pathway  23  Brazil–Argentina–India–China–Thailand–Indonesia–Philippines  Distance -> scan availability and access/stroke unit direct access  –  Stroebele et al.10  Full  1994–08  Systematic review  Onset to seek help Seek help to first medical contact  22  USA–Germany–UK–Spain–Canada–Turkey–Brazil–India–Ireland–Nigeria–Australia–GCC countriesc  –  Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Medical history -> stroke knowledge Ethnic -> stroke knowledge Socioeconomic status -> stroke knowledge Gender -> stroke knowledge  Tai et al.31  Full  1992–10  Literature review  First medical contact to admission Admission to treatment  19  USA–Switzerland–UK–Finland–Australia  Distance -> scan availability and access/stroke unit direct access  –  Teuschl et al.23  Full  1990–09  Systematic search and review  Onset to seek help Seek help to first medical contact  110  USA–GCC countriesc–South Korea–Switzerland–India–Czech Republic–Spain–Brazil–the Netherlands–Germany–Ireland–UK–Australia–Nigeria–Italy–Japan–Norway–Taiwan–Hong Kong–Pakistan  Age -> transport strategy Ethnic -> transport strategy Unemployed -> transport strategy Bystanders -> transport strategy  Gender -> stroke knowledge Age -> stroke knowledge Education -> stroke knowledge Income -> stroke knowledge Ethnic -> stroke knowledge Bystanders -> stroke knowledge Stroke history -> stroke knowledge Psychological -> stroke knowledge  a Partial means that only a part of the review focused on factors influencing acute stroke pathway; Full means all the review is dedicated to factors influencing acute stroke pathway. b Grant MJ, Booth A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info Libr J 2009;26:91–108. c Gulf Cooperation Council countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates). d [a] -> [b] means significant associations report factor [a] impacting factor [b]. Synthesis of results Results are presented in two parts. First, we reported factors and grouped them into four categories: (i) patient, (ii) space, (iii) organizational/logistical and (iv) training. Association between factors are presented in two groups: (i) links observed between categories, and (ii) links observed inside categories. All factors are grouped in table 2, and most cited factors are presented here. Detailed results are available in the Supplementary appendix S2. Table 2 Reported factors influencing acute stroke pathway Factors  References  Patient        Sociodemographic            Age  [9,13,17,23,36]          Gender  [5,11,15,17,23,36,37]          Ethnic  [5,14,15,20,21,23,36]          Alone  [11,15,27,28,35]          Education  [5,14]          Stroke knowledge  [16,19,21,25,27,28,35–39]          Socio economic status  [13]          Income  [5,12,19]          Cognitive  [5,15,17,21,27]          Bystander  [5,11,15,16,21,23,27]      Clinical:            Risk factors  [15]          Symptoms  [5,15,16]          Stroke subtype & severity  [5,15,16,21,23,27,28]          Stroke history  [5,15,16,19,23]  Space            Distance  [5,16,19,23,40]          Deprived area  [12]          Rural/urban  [28,30,40]  Organizational/logistical            Scanner availability and access  [12,15,24,27,29–31]          Pre-notification  [5,15–17,21,29–31,38,40]          Transport strategy  [5,15–17,19,21,25–29,31,36–40]          Coordinated care  [12,16,21,28,30,35,38]          Direct access to SU  [5,24,25]          Off-hours / weekend  [8,15,23,31,38]          Stroke fast track  [17,24,26,31]          Leadership  [24,25]          Beds and stretcher-bearer availability  [27]  Training        Stroke recognition by physicians  [15,16,24,25,27–30,35,38,39]  Factors  References  Patient        Sociodemographic            Age  [9,13,17,23,36]          Gender  [5,11,15,17,23,36,37]          Ethnic  [5,14,15,20,21,23,36]          Alone  [11,15,27,28,35]          Education  [5,14]          Stroke knowledge  [16,19,21,25,27,28,35–39]          Socio economic status  [13]          Income  [5,12,19]          Cognitive  [5,15,17,21,27]          Bystander  [5,11,15,16,21,23,27]      Clinical:            Risk factors  [15]          Symptoms  [5,15,16]          Stroke subtype & severity  [5,15,16,21,23,27,28]          Stroke history  [5,15,16,19,23]  Space            Distance  [5,16,19,23,40]          Deprived area  [12]          Rural/urban  [28,30,40]  Organizational/logistical            Scanner availability and access  [12,15,24,27,29–31]          Pre-notification  [5,15–17,21,29–31,38,40]          Transport strategy  [5,15–17,19,21,25–29,31,36–40]          Coordinated care  [12,16,21,28,30,35,38]          Direct access to SU  [5,24,25]          Off-hours / weekend  [8,15,23,31,38]          Stroke fast track  [17,24,26,31]          Leadership  [24,25]          Beds and stretcher-bearer availability  [27]  Training        Stroke recognition by physicians  [15,16,24,25,27–30,35,38,39]  Table 2 Reported factors influencing acute stroke pathway Factors  References  Patient        Sociodemographic            Age  [9,13,17,23,36]          Gender  [5,11,15,17,23,36,37]          Ethnic  [5,14,15,20,21,23,36]          Alone  [11,15,27,28,35]          Education  [5,14]          Stroke knowledge  [16,19,21,25,27,28,35–39]          Socio economic status  [13]          Income  [5,12,19]          Cognitive  [5,15,17,21,27]          Bystander  [5,11,15,16,21,23,27]      Clinical:            Risk factors  [15]          Symptoms  [5,15,16]          Stroke subtype & severity  [5,15,16,21,23,27,28]          Stroke history  [5,15,16,19,23]  Space            Distance  [5,16,19,23,40]          Deprived area  [12]          Rural/urban  [28,30,40]  Organizational/logistical            Scanner availability and access  [12,15,24,27,29–31]          Pre-notification  [5,15–17,21,29–31,38,40]          Transport strategy  [5,15–17,19,21,25–29,31,36–40]          Coordinated care  [12,16,21,28,30,35,38]          Direct access to SU  [5,24,25]          Off-hours / weekend  [8,15,23,31,38]          Stroke fast track  [17,24,26,31]          Leadership  [24,25]          Beds and stretcher-bearer availability  [27]  Training        Stroke recognition by physicians  [15,16,24,25,27–30,35,38,39]  Factors  References  Patient        Sociodemographic            Age  [9,13,17,23,36]          Gender  [5,11,15,17,23,36,37]          Ethnic  [5,14,15,20,21,23,36]          Alone  [11,15,27,28,35]          Education  [5,14]          Stroke knowledge  [16,19,21,25,27,28,35–39]          Socio economic status  [13]          Income  [5,12,19]          Cognitive  [5,15,17,21,27]          Bystander  [5,11,15,16,21,23,27]      Clinical:            Risk factors  [15]          Symptoms  [5,15,16]          Stroke subtype & severity  [5,15,16,21,23,27,28]          Stroke history  [5,15,16,19,23]  Space            Distance  [5,16,19,23,40]          Deprived area  [12]          Rural/urban  [28,30,40]  Organizational/logistical            Scanner availability and access  [12,15,24,27,29–31]          Pre-notification  [5,15–17,21,29–31,38,40]          Transport strategy  [5,15–17,19,21,25–29,31,36–40]          Coordinated care  [12,16,21,28,30,35,38]          Direct access to SU  [5,24,25]          Off-hours / weekend  [8,15,23,31,38]          Stroke fast track  [17,24,26,31]          Leadership  [24,25]          Beds and stretcher-bearer availability  [27]  Training        Stroke recognition by physicians  [15,16,24,25,27–30,35,38,39]  Factors associated with stroke care delay Patient There are two types of factors related to patient. On the one hand, there are clinical factors relating to strokes and symptoms. On the other hand, are the individual factors, whether demographic, social or cognitive. Among the clinical factors, stroke subtype and associated severity were associated with delays in stroke pathway. Increasing stroke severity is correlated with shorter pre-hospital delay which can be explained by a reduced time from symptoms onset to the first call for medical attention and prior contact for EMS transport. Four studies reviewed by Mazighi et al. demonstrated an association between increasing stroke severity and shorter pre-hospital delay. Specific stroke symptoms like facial droop and language impairment were associated with fast arrival in the emergency room. Patients’ stroke history and specific risk factors (hypertension, atrial fibrillation) were associated with shorter pre-hospital time delay. Among individual factors, stroke knowledge (described as the awareness of risk factors, warning signs and adequate behavior) is well-documented. Most acute stroke delays are attributed to the pre-hospital stage, especially patient stroke knowledge. Poor recognition of stroke symptoms is associated with longer acute stroke pathway. Bystanders at the stroke onset often overcome low patient stroke knowledge or wait-and-see strategy by promptly recognizing the seriousness and emergency of the situation. In a study conducted in North Carolina, USA, the presence of a bystander substantially reduced pre-hospital delay (i.e. median delay 2.0 h vs. 5.8 h).11 Weak associations are reported with age, gender, socioeconomic status (SES) and less-studied factors like psychological and cognitive factors. Interestingly, associations with certain factors are observed among all stroke pathway. Review suggests an association between age and inhospital care9 and reported that age-related differences were not systematically biased against older patients. On a sex-specific review, six studies found gender difference in pre-hospital delays but most of them reported no evidences.11 SES association with the stroke pathway was measured by various factors (patients’ education, income or SES index). Low socioeconomic status was associated with longer pre-hospital delays, inhospital delays and low care quality.14 Ethnic minorities were associated with longer care pathway in few studies. A study conducted in 10 New Jersey, USA, hospitals observed that Hispanic stroke patients wait longer than non-Hispanic white patients to see a physician (OR, 7.95; 95% CI, 1.51–41.6).20 Psychological and cognitive factors mainly affect the response to stroke symptoms with wait-and-see behavior that can partly be explained by a fear of disease or a fear of hospitals.21 Space Space category covers the interrelation of compositional (socio-demographic characteristics of individuals) and contextual (social and physical opportunities)22 factors associated to stroke pathway and explained by the time-critical nature of the disease and observed social health inequalities. Four reviews12,16,23,24 which examined the relationship between socio-spatial factors and stroke pathway suggested that distance to healthcare facilities and neighborhood social level is associated with stroke delay. In England, a study observed disparities of inhospital care against stroke patients from deprived areas and lower thrombolytic treatment rate with patients who travelled the longest distance.5 Organization Organizational and logistical factors associations are well documented. Two main groups are observed: (i) resources strategies covering facilities and staffing and (ii) coordination process referring to organizational dynamics observed to streamlining acute care pathway. Among resources strategies, transport mode and availability of computational tomography (CT) were the most cited factors. Two studies observed increasing alteplase treatment rates and better clinical outcomes with EMS stroke patients compared to private car patients.25 On delay in CT access, a well-known study demonstrated shorter door-to-scan with the relocation of CT scanner to the emergency room.21 Weekend and off-hour admission has been associated with longer door-to-needle times and suboptimal quality of stroke care. Longer inhospital process due to bed unavailability were also reported. Among coordination process, pre-notification was the most cited factor. When applied, interventional studies observed a significant increase of the thrombolysis rate and same observation has been made with the Guidelines stroke program where pre-notification creates shorter door-to-imaging times, door-to-needle times, symptoms-onset-to-needle times and an increase in alteplase treatment within 3 h.21 Pre-notification can be associated with the inhospital stroke code and demonstrated greater impact on onset-to-needle time.26 Reviews observed more broadly the need of coordinated care and agreed on the necessity of a close collaboration between pre-hospital and inhospital staff and services.26 Three reviews gave recommendations for direct admission to SUs and two reviews noticed the importance of leadership. Training Among training factors, which cover especially educational program for both the public and paramedics, stroke recognition by dispatchers and ED physicians is reported as a determinant delay in stroke care pathways. All reviews reported this factor in the pre-hospital stage. Studies observed that only 31–52% of stroke calls are correctly identified by dispatchers. In the inhospital stage, recognition of stroke by ED physician was reported less reported. Studies showed that 24–55% arrive to the ED with their own means. The study reported by Kwan et al. observed inadequate stroke response training for physicians. Links observed between delay’s factors Various associations have been observed between factors. Findings are presented in two groups: (i) association observed between categories, and (ii) association observed inside categories. All reported associations are summarized in the figure 1. Between categories Most associations observed between categories (see figure 1) are reported between patient and organizational/logistical categories. Eight reviews reported four factors that have an impact on transport strategy.5,9,16,23,27–29 These factors are (i) patient age,9 as older patients are likely to arrive by ambulance; (ii) bystander/alone/marital status,16,23,27 as there is a higher probability of EMS use by patients who were not living alone or with a bystander at stroke onset; (iii) stroke severity16,28 as patients with severe stroke were more likely to be transported by EMS16 and (iv) rural/distance,5,28,29 because direct air transport can be considered due to the distance which reduces delays in stroke care pathway. Six reviews reported five factors that have impacted CT access and availability.9,11–14,20 These factors are (i) income,12,14 since the FINMONICA stroke registry observed greater access to CT scan or magnetic resonance imaging for patients from high-income group; (ii) patient age,9 wherein older patients were less likely to receive CT scans; (iii) ethnicity,20 as non-black patients had a greater chance to receive non-invasive carotid imaging; (iv) patient gender,11 since women were less likely to receive brain imaging than men and (v) deprived areas,13 where CT scan was less likely to be performed for stroke patients from deprived areas on the same day of admission. Three reviews reported three factors that were associated with SU direct access.13,14,30 These factors are: (i) income,13 where low-income patients were less likely to receive seven specific processes of care (SU care included); (ii) education,14 e.g. in Sweden a small but significant difference depending on the level of education has been observed14 and (iii) rural/distance,30 noting a study conducted in Australia that observed only 3% of rural patients had access to SU compared to 77% of metropolitan area patients. One review reported association between service coordination and physician stroke knowledge;30 a trained physician has shorter door-to-needle time than a non-trained physician. One review reports the influence of patient education level on the overall stroke care quality.13 In Austria, a study showed that higher educated patients were more likely to benefit from echocardiography and speech therapy during admission. Inside categories We also observed associations inside categories (see figure 2). In patient categories, association with stroke knowledge was well documented. Two extensive reviews10,23 reported numerous associations with the patient’s stroke knowledge. These associations were with age, gender, education, income or SES status, ethnic, alone/married and medical history. To sum up, most of the studies where associations were reported observed better stroke knowledge among women and a decrease of stroke knowledge with age, low education, low-income (or broadly, low socioeconomic status) and non-white patients.10,23 Figure 2 View largeDownload slide Reported associations of factors observed within categories Figure 2 View largeDownload slide Reported associations of factors observed within categories Four factors have been associated with stroke severity. Two reviews reported association between lower socioeconomic status and increasing stroke severity.12,13 One review observed strong evidence for more severe strokes among black patients20 with higher prevalence of coma or ischemic stroke than white patients. Small gender differences in stroke severity was observed in one review.11 In Denmark, a large study observed more severe strokes in women; however, most of the studies of the review reported no gender differences. One review observed more severe strokes in older patients that complicated care decisions.9 Gender differences have been observed with witnessed strokes, because women are more likely to live alone.11 Small gender differences were also observed on the stroke subtype where women had higher frequency of anterior circulation strokes.11 In organizational/logistical category, CT availability and access was associated with three factors. Three reviews reported association with pre-notification.5,24,29 For these reviews, pre-notification permitted the reservation of CT scanners and preparedness of the CT personnel. Five reviews reported that intervention with care coordination can improve CT access and reduce door-to-image times.15,16,24,29,31 One review reported the association of CT access and transport strategy.21 Fassbender et al. reported a study that observed greater access to CT in <25 min for patients transported by EMS. According to four reviews, ED physician training16,30 and leadership24,25 were associated with care coordination. Better coordination and shorter door-to-onset times were observed after implementing a training program. For two reviews, care coordination needs strong leadership to maintain continuing education and resources. Leadership guarantees close collaboration between services and contributes to implementing regional stroke networks.25 One review reports association between weekend/off-hour strokes and transport strategies.23 One study observed that transport times were longer during the weekend. Discussion Principal findings This systematic review provides an exhaustive update on factors influencing acute stroke pathways and better knowledge of the underlying mechanisms by reviewing existing associations between factors. We have found that acute stroke delay can be attributed to patients, space, organizational and training factors. For some of the studies, impact is reported at every stage of the acute stroke pathway. The most cited and consistent factors are patient stroke knowledge, bystanders at stroke onset, transport strategy, pre-notification, regular training, availability and access to CT scan. These multiple factors and interactions form a dynamic framework around the patient and structure the acute stroke pathway. In this framework, the weight of each factor varies according to the context and the scale of the analysis. Studies conducted on a rural setting reported reinforcement between the distance of the patient from the hospital, patient sociodemographic profile (aged, alone) and available resources.18 Similarly, studies conducted in developing countries at state scale reported limited access to adequate resources, poor information and financial costs of the tissue plasminogen activator (tPA).19 Using a systemic approach is consistent with the demonstration of a dynamic framework that could explain increasing complexity and variation in acute stroke care. In this context, the influence of a factor must no longer be interpreted according to the sole impact on the pathway but complemented by its influence on other factors. For example, the rural/urban distinction implies not only a question of travel distance but also the issues of population education, resource optimization and services coordination. By incorporating the interaction between factors, we analyze acute stroke pathway as a complex system. By observing how factors are interrelated within this complex system, we understand the benefit of combined intervention. Multi-factorial interventions like combined educational programs show clear benefits by addressing several barriers at same time.7,15 In Temple, USA, the proportion of patient receiving tPA increased from 1.4 to 5.8% after implementation of a multilevel stroke educational campaign for the public and paramedics. In our review, most studies investigated access to thrombolysis with tPA but our results, in light of recent developments in endovascular therapy, can also apply to patients with large vessel occlusion (LVO). These patients present a worse prognosis and thrombolysis alone had only a small benefit.32 The results of our review showed how factors articulate during all the acute stroke pathway and were consistent with results found for LVO patients. The study reported reduced delays when a triage tool to recognize LVO patients was used at the pre-hospital stage, completed with an educational and training program for EMS personnel. In this case, reduction of delays for identified LVO patients was associated with a significant increase in reaching functional independence after stroke without changing functional independence for patients eligible of IV tPA only.33 Our review has several potential limitations. First, there is inherent weakness in a review of systematic reviews. The quality of reviews may vary in terms of clear inclusion and exclusion criterion and search strategy. Our research only included French and English reviews, which might cause an under representation of non-English and non-French reviews. Some of the included reviews are probably outdated and reviews, published after the search date, are not included. Second, given the heterogeneity of the reviews’ findings in terms of methods, sample size or context, a meta-analysis was not feasible. Because of some reviews have studied similar or overlapping topics, we note that some of the reviews reported the same underling studies. Although some of these studies may represent duplicate cases, each review met our inclusion criteria. Of note for the overall review, the identified stroke factors and the links between factors only imply association but not necessarily causality. The association is relevant when at least one review indicates a significant association. We saw three main implications of this review. First, this review shows the benefit of thematic approach over sequential approach by reporting transversal impact among the stroke pathway of certain factors and association between factors.34 Second, we recognize the understanding of the context as a part of stroke intervention due to the decisive impact among stroke pathway. Last, further research needs to be performed on factors to clarify the synthetic framework by adding causal, feedback and balancing loop. This work is especially true on less-studied factors which can be underestimated by ignoring certain mechanism of the framework. Altogether, this review offers new tools for health care planning and building better strategies to tackle acute stroke care delays. The global and systemic approach provides a comprehensive analysis that is valid in both high- and low-income countries at various scales of interventions. This gathered knowledge is essential for developing effective and equitable acute stroke care pathway. Supplementary data Supplementary data are available at EURPUB online. Funding None. Conflicts of interest: None declared. Key points A wide variety of factors impacts acute stroke pathway at different stages but there is an urgent need of understanding associations between these factors. This systematic review provides an exhaustive framework of factors occurring during the acute stroke pathway. Factors influencing acute stroke pathway varying according to context and scale of the study. References 1 Mozaffarian D, Benjamin EJ, Go AS, et al.   Heart disease and stroke statistics—2016 update. Circulation  2016; 133: e38– 360. Google Scholar CrossRef Search ADS PubMed  2 Lees KR, Bluhmki E, von Kummer R, et al.   Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet  2010; 375: 1695– 703. Google Scholar CrossRef Search ADS PubMed  3 Marler JR, Tilley BC, Lu M, et al.   Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology  2000; 55: 1649– 55. Google Scholar CrossRef Search ADS PubMed  4 Goyal M, Menon BK, van Zwam WH, et al.   Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet  2016; 387: 1723– 31. Google Scholar CrossRef Search ADS PubMed  5 Ragoschke-Schumm a, Walter S, Haass a, et al.   Translation of the “time is brain” concept into clinical practice: focus on prehospital stroke management. Int J Stroke  2014; 9: 333– 40. Google Scholar CrossRef Search ADS PubMed  6 Brice JH, Griswell JK, Delbridge TR, Key CB. Stroke: from recognition by the public to management by emergency medical services. Prehosp Emerg Care  2002; 6: 99– 106. Google Scholar CrossRef Search ADS   7 Churilov L, Fridriksdottir A, Keshtkaran M, et al.   Decision support in pre-hospital stroke care operations: a case of using simulation to improve eligibility of acute stroke patients for thrombolysis treatment. Comput Oper Res  2013; 40: 2208– 18. Google Scholar CrossRef Search ADS   8 Moher D, Liberati A, Tetzlaff J, Altman DG, Group TP, Oxman A, et al.   Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med  2009; 6: e1000097. Google Scholar CrossRef Search ADS PubMed  9 Luker JA, Wall K, Bernhardt J, et al.   Patients’ age as a determinant of care received following acute stroke: a systematic review. BMC Health Serv Res  2011; 11: 161. Google Scholar CrossRef Search ADS PubMed  10 Stroebele N, Müller-Riemenschneider F, Nolte CH, et al.   Knowledge of risk factors, and warning signs of stroke: a systematic review from a gender perspective. Int J Stroke  2011; 6: 60– 6. Google Scholar CrossRef Search ADS PubMed  11 Reeves MJ, Bushnell CD, Howard G, et al.   Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol  2008; 7: 915– 26. Google Scholar CrossRef Search ADS PubMed  12 Cox AM, McKevitt C, Rudd AG, Wolfe CD. Socioeconomic status and stroke. Lancet Neurol  2006; 5: 181– 8. Google Scholar CrossRef Search ADS PubMed  13 Addo J, Ayerbe L, Mohan KM, et al.   Socioeconomic status and stroke: an updated review. Stroke  2012; 43: 1186– 91. Google Scholar CrossRef Search ADS PubMed  14 Marshall IJ, Wang Y, Crichton S, et al.   The effects of socioeconomic status on stroke risk and outcomes. Lancet Neurol  2015; 14: 1206– 18. Google Scholar CrossRef Search ADS PubMed  15 Bouckaert M, Lemmens R, Thijs V. Reducing prehospital delay in acute stroke. Nat Rev Neurol  2009; 5: 477– 83. Google Scholar CrossRef Search ADS PubMed  16 Mazighi M, Derex L, Amarenco P. Prehospital stroke care: potential, pitfalls, and future. Curr Opin Neurol  2010; 23: 31– 5. Google Scholar CrossRef Search ADS PubMed  17 Yperzeele L, Van Hooff R-J, De Smedt A, et al.   Prehospital stroke care: limitations of current interventions and focus on new developments. Cerebrovasc Dis  2014; 38: 1– 9. Google Scholar CrossRef Search ADS PubMed  18 Joubert J, Prentice LF, Moulin T, et al.   Stroke in rural areas and small communities. Stroke  2008; 39: 1920– 8. Google Scholar CrossRef Search ADS PubMed  19 Pandian JD, Padma V, Vijaya P, et al.   Stroke and thrombolysis in developing countries. Int J Stroke  2007; 2: 17– 26. Google Scholar CrossRef Search ADS PubMed  20 Stansbury JP, Jia H, Williams LS, et al.   Ethnic disparities in stroke: epidemiology, acute care, and postacute outcomes. Stroke  2005; 36: 374– 86. Google Scholar CrossRef Search ADS PubMed  21 Fassbender K, Balucani C, Walter S, et al.   Streamlining of prehospital stroke management: the golden hour. Lancet Neurol  2013; 12: 585– 96. Google Scholar CrossRef Search ADS PubMed  22 Macintyre S, Ellaway A, Cummins S. Place effects on health: how can we conceptualise, operationalise and measure them? Soc Sci Med  2002; 55: 125– 39. Google Scholar CrossRef Search ADS PubMed  23 TeuschI Y, Brainin M. Stroke education: discrepancies among factors influencing prehospital delay and stroke knowledge. Int J Stroke  2010; 5: 187– 208. Google Scholar CrossRef Search ADS PubMed  24 Carter-Jones CR. Stroke thrombolysis: barriers to implementation. Int Emerg Nurs  2011; 19: 53– 7. Google Scholar CrossRef Search ADS PubMed  25 El Khoury R, Jung R, Nanda A, et al.   Overview of key factors in improving access to acute stroke care. Neurology  2012; 79: S26– 34. Google Scholar CrossRef Search ADS PubMed  26 Dalloz MA, Bottin L, Muresan IP, et al.   Thrombolysis rate and impact of a stroke code: a French hospital experience and a systematic review. J Neurol Sci  2012; 314: 120– 5. Google Scholar CrossRef Search ADS PubMed  27 Kwan J, Hand P, Sandercock P. A systematic review of barries to delivery of thrombolysis for acute stroke. Age Ageing  2004; 33: 116– 21. Google Scholar CrossRef Search ADS PubMed  28 Crocco TJ. Streamlining stroke care: from symptom onset to emergency department. J Emerg Med  2007; 33: 255– 60. Google Scholar CrossRef Search ADS PubMed  29 Asif KS, Lazzaro MA, Zaidat O. Identifying delays to mechanical thrombectomy for acute stroke: onset to door and door to clot times. J Neurointerv Surg  2014; 6: 505– 10. Google Scholar CrossRef Search ADS PubMed  30 Eissa A, Krass I, Bajorek BV. Optimizing the management of acute ischaemic stroke: a review of the utilization of intravenous recombinant tissue plasminogen activator (tPA). J Clin Pharm Ther  2012; 37: 620– 9. Google Scholar CrossRef Search ADS PubMed  31 Tai YJ, Yan B. Minimising time to treatment: targeted strategies to minimise time to thrombolysis for acute ischaemic stroke. Intern Med J  2013; 43: 1176– 82. Google Scholar CrossRef Search ADS PubMed  32 Smith WS, Lev MH, English JD, et al.   Significance of large vessel intracranial occlusion causing acute ischemic stroke and tia. Stroke  2009; 40: 3834– 40. Google Scholar CrossRef Search ADS PubMed  33 Mohamad NF, Hastrup S, Rasmussen M, et al.   Bypassing primary stroke centre reduces delay and improves outcomes for patients with large vessel occlusion. ESJ  2016; 1: 85– 92. 34 Kimberly J, Minvielle E. The Quality Imperative: Measurement and Management of Quality in Healthcare . London: Imperial College Press, 2000. 35 Donnan GA, Davis SM, Parsons MW, et al.   How to make better use of thrombolytic therapy in acute ischemic stroke. Nat Rev Neurol  2011; 7: 400– 9. Google Scholar CrossRef Search ADS PubMed  36 Johnson M, Bakas T. A review of barriers to thrombolytic therapy: implications for nursing care in the emergency department. J Neurosci Nurs  2010; 42: 88– 94. Google Scholar CrossRef Search ADS PubMed  37 Lisabeth LD, Brown DL, Morgenstern LB. Barriers to intravenous tissue plasminogen activator for acute stroke therapy in women. Gend Med  2006; 3: 270– 8. Google Scholar CrossRef Search ADS PubMed  38 Baldereschi M, Piccardi B, Di Carlo A, et al.   Relevance of prehospital stroke code activation for acute treatment measures in stroke care: a review. Cerebrovasc Dis  2012; 34: 182– 90. Google Scholar CrossRef Search ADS PubMed  39 Ehlers L, Jensen LG, Bech MA, et al.   Organisational barriers to thrombolysis treatment of acute ischaemic stroke. Curr Med Res Opin  2007; 23: 2833– 9. Google Scholar CrossRef Search ADS PubMed  40 Paul CL, Ryan A, Rose S, et al.   How can we improve stroke thrombolysis rates? A review of health system factors and approaches associated with thrombolysis administration rates in acute stroke care. Implement Sci  2015; 11: 51. Google Scholar CrossRef Search ADS   © The Author(s) 2018. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

The European Journal of Public HealthOxford University Press

Published: Apr 20, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off