Αρθρογραφία

Introduction
Stroke is the second leading cause of death and the third leading cause of disability-adjusted life-year (DALYs) (1) worldwide, posing considerable socioeconomic burden on
health-care systems. Intravenous thrombolysis is the treatment of choice in patients with acute ischemic stroke who present within 3 or 4.5 h from symptom onset (2). Several
randomized trials support the safety and the beneficial effect on outcome of this intervention (3–7). The time between symptom onset and presentation to the
emergency department (ED) is the fundamental factor for eligibility to undergo intravenous thrombolysis (8). In this regard, it is noteworthy that significant delays exist between symptom
onset and presentation, with a reported range from 2.5 up to 6.3 h (9,10). If these delays were reduced, a considerably larger proportion of patients would be eligible for intravenous thrombolysis, with important implications for their outcome (11,12). A number of studies investigated the factors that affect the interval between stroke symptom onset and ED arrival
(9,10,13–19). It has been reported that using Emerging Medical Services (EMS) and experiencing more severe stroke lead to early presentation at the ED. In contrast, patients who suffer a stroke during the night are more likely to arrive late. However, most of these studies are rather old and were performed before the wide availability and application of intravenous thrombolysis for patients with acute ischemic stroke. The aim of the present study was to evaluate the time to presentation at the ED in patients who suffer an acute ischemic stroke and the factors that affect this time.

We prospectively studied all patients who were admitted in our Department with acute ischemic stroke between September 2010 and March 2016 (n = 922; 42.2% males, age 79.6 ± 6.9 years).
At admission, demographic data (age, sex), history of cardiovascular risk factors [hypertension, type 2 diabetes mellitus (T2DM), atrial fibrillation (AF), smoking, alcohol consumption,
family history of cardiovascular disease (CVD)], history of concomitant CVD (coronary heart disease, previous ischemic stroke, heart failure) and pharmacological treatment
were recorded. Hypertension was defined as a self-reported history of hypertension or intake of antihypertensive medications. T2DM was defined as a self-reported history of T2DM
or intake of antidiabetic medications. AF was defined as a history of AF or the presence of AF at the electrocardiogram recorded at admission. Concomitant CVD was defined as
a self-reported relevant history. Patients were classified intonever smokers, current smokers and past smokers (i.e., those who quitted smoking > 1 year ago). Family history of CVD
was defined as onset of CVD in a male or female first-degree relative <55 or 65 years old, respectively. Anthropometric parameters (weight, height, waist and hip circumference)
and systolic and diastolic blood pressure (BP) were also measured at admission. The body mass index (BMI) was calculated and patients with BMI < 25, 25–30 and >30 kg/m2 were
classified as normal-weight, overweight and obese, respectively. The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Stroke
was categorized as minor, moderate, moderate to severe and severe when the NIHSS at admission was 1–4, 5–15, 16–20 and 21–42, respectively. The time of onset of stroke-related symptoms and the time of arrival at the ED were recorded at admission. The time of onset of symptoms was defined as the time when the first strokerelated symptoms were noticed according to the patients or their relatives. In patients who experienced symptoms during sleep, time of onset of symptoms was defined as the last time when they were without symptoms. The time of arrival at the ED was defined as the time of registration at the EDtriage office. The time to presentation was calculated as the period between the time of onset of stroke-related symptoms and the time of arrival at the ED. When stroke-related symptoms began between 7 am and 7 pm, the stroke was considered to have occurred during daytime. When stroke-related symptoms began between 7 pm and 7 am, the stroke was considered to have occurred during nighttime. Patients with unknown or uncertain time of onset of stroke-related symptoms were excluded from the analyses.
Routine laboratory investigations were performed after overnight fasting at the first day after admission and included serum levels of glucose, total cholesterol, high-density lipoprotein
cholesterol, triglycerides, creatinine, and uric acid. Low-density lipoprotein cholesterol levels were calculated using Friedewald’s formula (20). Glomerular filtration rate was estimated with the Modification of Died in Renal Disease equation (21). The study was approved by the Ethics Committee of the Medical School of the Aristotle University of Thessaloniki.
Statistical analysis
Statistical tests were performed using the R version 3.2.3 of RStudio platform. The distribution of time to presentation was positively skewed and is presented as median and upper and
lower quartiles. The dependent outcome variable was presentation at the ED within 3 h from the onset of stroke-related symptoms and within 4.5 h from the onset of stroke-related symptoms. Explanatory variables were either continuous or categorical. Univariate and multivariate logistic regression analyses were used to calculate the unadjusted and adjusted odds ratio (OR) and confidence intervals (CI), which describe the association between explanatory variables and the dependent variable. Two separate analyses were conducted to identify factors predicting the presentation at the ED within 3 h and within 4.5 h from the onset of symptoms. In the two models, patients who arrived at the ED within 3 h and within 4.5 h from symptoms onset, respectively, were considered as the reference group. The selection of variables that were included in the models was based on clinical experience, literature review and available data.
The selection of variables that were entered in the multivariate model was based on a significance level of 20% (p < .2) in the univariate model, taking into consideration the rule of thumb.
For multivariate analysis, a backward selection model was applied with a significance level of 5% (p < .05).
Results
Among the 922 consecutive patients who were admitted in our Department with acute ischemic stroke between September 2010 and March 2016, time of onset of strokerelated symptoms was certain in 682 patients (73.9%) and these patients were included in the analyses. Themedian time fromthe onset of stroke-related symptoms to ED presentation was 2.1 h (range, 0.15 to 168 h). Regarding the outcome variables, 68.8% of the patients arrived within 4.5 h from the onset of symptoms and 56.5% of the patients arrived within 3 h fromthe onset of symptoms. Baseline characteristics of patients who arrived at the ED within 4.5 h from the onset of stroke symptoms and of patients who arrived later are presented in Table 1. Baseline characteristics of patients who arrived at the ED within 3 h from the onset of stroke symptoms and of patients who arrived later are presented in Table 2. In univariate analysis, variableswhich predicted presentation at
the ED within 4.5 h from the onset of stroke-related symptoms were smoking status and the means of transportation to the hospital. The following variables were entered in the multivariate
model: atrial fibrillation, family history of CVD, smoking status, serum glucose levels, means of transportation to the hospital and whether stroke-related symptoms started during daytime or nighttime (Table 3). In multivariate analysis, independent predictors of presentation within 4.5 h were the use ofEMSfor transportation to the hospital (OR 2.61, 95% CI 1.38–4.94, p = .003), family history of CVD (OR 4.00, 95% CI 1.61–12.23, p = .006) and the absence of history of smoking (OR 2.49, 95% CI 1.13–5.42, p = .021). In univariate analysis, variables which predicted presentation at the ED within 3 h from the onset of stroke-related symptoms were atrial fibrillation, family history of CVD, smoking status, whether stroke-related symptoms started during daytime or nighttime and the means of transportation to the hospital. The following variables were entered in the multivariate model: T2DM, atrial fibrillation, family history of CVD, smoking status, HbA1c, the means of transportation to the hospital, whether the symptoms had started during daytime or nighttime and stroke severity at admission (Table 4). In multivariate analysis, independent predictors of presentation within 3 h were the use of EMS for transportation to the hospital (OR 6.24, 95% CI 2.52–16.63, p = .0001), family history of CVD (OR 3.07, 95%
CI 1.14–9.43, p = .03), and a moderately severe stroke at admission (OR vs. minor stroke 0.38, 95% CI 0.16–0.87, p = .02).
Discussion
An important finding of the present study is that a considerable proportion of patients with acute ischemic stroke arrives at the ED more than 3–4.5 h after the onset of stroke-related symptoms, i.e., outside the window for performing intravenous thrombolysis. More specifically, 31.2% and 43.5% of patients arrived after 4.5 and 3 h from symptom onset, respectively. These rates and the median time to presentation at the ED (2.1 h) in our population are in agreement with the findings of previous studies (9,10,13,15,16,22). Therefore, there is a great need to shorten
these delays in order to perform intravenous thrombolysis in more patients with acute ischemic stroke, which was shown to substantially improve their functional outcome. This reduction is
even more important in our country, where thrombolytic therapy is performed very rarely (19). In the present study, the use of EMS was a strong predictor for timely arrival at the ED. Patients who used the EMS had 2.61 higher odds for arriving at the ED within 4.5 h after the onset of symptoms and 6.24 higher odds for arriving within 3 h. Several previous studies (9,15,16,19,22–24) also showed the importance of using the EMS and this association is consistent across different countries, populations, and cultures. Consequently, the use of EMS must be promoted by the national health systems as one of the crucial factors for the timely presentation at the ED of patients with acute ischemic stroke. We also found that family history of CVD was also an independent predictor of arrival at the ED within 4.5 h (OR 4.00) and for 3 h (OR 3.07) from symptoms’ onset. Previous studies showed that patients with a personal history of stroke or transient ischemic attach are more likely to arrive at the ED on time (9,22). However, this is the first study that evaluated the associationbetween family history of CVD and the delay in presentation after ischemic stroke. This association might be due to the patients’ or their relatives’ ability to identify the symptoms of stroke, which allows faster transportation to the hospital.
Patients who never smoked were also more likely (OR 2.49) to arrive at the hospital within 4.5 h from the onset of symptoms compared with current smokers. Also, a trend for an association with arrival within 3 h was observed but was marginally non-significant in multivariate analysis (OR 2.40, 95% CI 0.87–6.70, p = .09). In contrast to our results, a previous study found no association between smoking status and pre-hospital delay in patients with acute ischemic stroke (9). Our findings that current smokers are less likely to arrive on time at the ED after an acute ischemic stroke have potentially important public health implications, since smoking increases the risk of ischemic stroke (25). Therefore, smokers might represent a target group for educational campaigns, e.g., by placing “FAST” warning labels on cigarette packets (8). Patients with moderately severe stroke (NIHSS at admission between 5 and 15) were more likely to arrive beyond the 3-h window from the onset of symptoms than patients with a minor stroke (NIHSS at admission between 1 and 4). In contrast, previous studies reported that more severe stroke is
associated with less delays in presentation (9,10,13,19,22). These discrepant findings might be explained by the availability of EMS and the attitude of patients towards EMS across different countries. Indeed, patients with more severe stroke are less likely to be able to use their own car to arrive at the hospital. Therefore, in countries where EMS is less widely available or patients prefer to use their own car to go to the hospital, patients with more severe stroke are less likely to arrive on time after the event. In this context, we previously reported that the majority of the general population in Northern Greece reported that they would prefer to use their private car to go to the hospital in case of a stroke instead of calling the EMS (26). We also observed a trend for patients with stroke occurring during daytime (7 am to 7 pm) to arrive earlier at the ED, although this association did not persist in multivariate analysis. Previous studies also showed that patients who experience stroke-related symptoms during the night are more likely to arrive late at the hospital (13,19). In conclusion, a considerable proportion of patients with acute ischemic stroke arrives at the ED after the 4.5-h threshold for performing intravenous thrombolysis. Non-smokers, patients with a family history of CVD, with moderately severe stroke and those who use the EMS to arrive at the hospital are more likely to arrive on time to undergo this life-saving intervention. Therefore, educational programs and stroke campaigns must focus on the promotion of the use of EMS in all patients with acute ischemic stroke and also educate the general population about the symptoms of stroke and the importance of timely arrival at the hospital.