Risk factors affecting the 1-year outcomes of minor ischemic stroke: results from Xi’an stroke registry study of China[1]


 Background: The incidences of stroke recurrence, disability, and all-cause death of patients with minor ischemic stroke (MIS) remain problematic. The aim of the present was to identify risk factors associated with adverse outcomes at 1-year after MIS in the Xi’an region of China. Methods: The cohort of this prospective cohort study included MIS patients aged 18–97 years with a National Institutes of Health Stroke Scale (NIHSS) score of ≤ 3 who were treated in any of four hospitals in Xi’an region of China between January and December 2015. The 1-year percentage of stroke recurrence, disability, and all-cause death were evaluated. Multivariate logistic regression analysis was performed to assess the association between the identified risk factors and clinical outcomes. Results: Among the 1,121 patients included for analysis, the percentage of stroke recurrence, disability, and all-cause death at 1 year after MIS were 3.4% (38/1121), 9.3% (104/1121), and 3.3% (37/1121), respectively. Multivariate logistic regression analysis identified age, current smoking, and pneumonia as independent risk factors for stroke recurrence. Age, pneumonia, and alkaline phosphatase were independent risk factors for all-cause death. Independent risk factors for disability were age, pneumonia, NIHSS score on admission, and leukocyte count. Conclusions: The 1-year outcomes of MIS is not optimistic in the Xi’an region of China, especially high percentage of disability. In this study, we found the risk factors affecting 1-year stroke recurrence, disability and, all-cause death which need further verification in the subsequent studies.

study, we found the risk factors affecting 1-year stroke recurrence, disability and, all-cause death which need further veri cation in the subsequent studies.

Background
The incidence of stroke has signi cantly increased over the last two decades worldwide [1]. The Global Burden of Disease Study 2010 reported approximately 1.7 million deaths by stroke, which has become the leading cause of death and adult disability in China [2,3]. The high recurrence and disability rates seriously affect the health and quality of life of stroke patients. A minor ischemic stroke (MIS) is de ned as a National Institutes of Health Stroke Scale (NIHSS) score of ≤ 3 [4]. A MIS is typically treated conservatively with antiplatelet agents and general strategies for the prevention of vascular injury. Yet, the rate of recurrent stroke and progression of stroke remain high, as up to one in four of MIS patients is disabled or has died at follow-up [5]. Therefore, it is critical to identify risk factors for stroke recurrence, disability, and death associated with MIS, as most previous studies have focused on long-term risk factors and early detection, while data regarding regional and 1-year risk factors for poor clinical outcomes are relatively limited [6,7]. Moreover, there may be differences in risk factors for poor clinical outcomes of MIS patients among different countries, regions, and ethnicities. In this study, data regarding the incidence and poor clinical outcomes of MIS from January to December 2015 were collected from four level 3 rst-class hospitals in the Xi'an region of China to identify risk factors associated with stroke recurrence,disability, andall-cause death at 1 year after MIS.

Study population
The cohort of this prospective cohort study included MIS patients aged ³18 years old who were treated at any of four hospitals in the Xi'an region of China from January to December 2015. Acute ischemic stroke was diagnosed according to the World Health Organization criteria and con rmed by brain computed tomography (CT) or magnetic resonance imaging (MRI) [8]. The NIHSS score on admission was used to assess the initial neurological severity of the patient [4,9]. MIS is de ned as a NIHSS score at admission ≤ 3 [4]. Patients diagnosed with MIS due to non-vascular causes (primary and meta-static neoplasms, post-seizure paralysis, head trauma, etc.) that led to a brain function de cit or intracerebral hemorrhage, as determined by computed tomography or magnetic resonance imaging, were excluded from analysis, as were those with incomplete follow-up data at 1 year after MIS onset. The diagnostic criteria were consistent across all participating hospitals.

Data collection
Baseline information were collected from the four level 3 rst-class hospitals participating in this study within 24 hours after admission, included patient demographics, vascular risk factors, stroke severity, laboratory data, and complications [10]. Hypertension was defined as the use of any antihypertensive agent, systolic blood pressure (SBP) ≥ 140 mmHg, or diastolic blood pressure (DBP) ≥ 90 mmHg.
Diabetes mellitus (DM) was de ned as a fasting blood glucose (FBG) level ≥ 7 mmol/L or use of any hypoglycemic agent. Dyslipidemia was de ned as the use of any lipid-lowering agent, serum triglyceride ≥ 1.7 mmol/L, low-density lipoprotein cholesterol (LDL-C) ≥ 3.6 mmol/L, or high-density lipoprotein cholesterol (HDL-C) ≤ 1.0 mmol/L. Atrial brillation (AF) was con rmed on at least one electrocardiogram or by the presence of arrhythmia during hospitalization. Peripheral vascular disease (PVD) was de ned as intermittent claudication, an ankle brachial index < 0.9, or history of intermittent claudication with relevant interventional therapy (lower limb artery angioplasty/bypass/other vascular interventional treatment/lower limb amputation). Body mass index (BMI) was de ned as the body mass divided by body height squared, which is universally expressed in units of kg/m2. The NIHSS score was used to assess the severity of neurological impairment within 24 h of admission [11]. The occurrence of pneumonia during hospitalization was also recorded. All fasting blood samples were processed within 2 h of collection. Measurements of quality control specimens were conducted in a blinded manner in a central laboratory.

Outcomeassessment
The patients were followed up at 1, 3, 6 and 12 months after MIS onset. Patients were interviewed face-to-face at 1, 3 months and contacted over the telephone by trained research coordinators at 6, 12 months. The interviewers were trained centrally with a standardized interview protocol and were blinded to a history of MIS for all patients [12]. The collected outcome data included stroke recurrence,disability, and all-cause death. Stroke recurrence during the study follow-up period was de ned as a discrete new neurological de cit consistent with the World Health Organization de nition of occurring within 24 h following a qualifying (entry) event after excluding early deterioration caused by the initial stroke, stroke progression, or some other syndrome [13]. Con rmation of cerebrovascular events were sought from the treating hospital, and suspected recurrent cerebrovascular events without hospitalization were judged by independent endpoint judgement committee. Stroke disability was de ned as a modi ed Rankin scale score of 3-6 at 1 year after MIS onset [14]. All-cause death was de ned as death from any cause, as con rmed by either a death certi cate from the local citizen registry or the medical record of the treating hospital.

Statistical Analysis
Continuous variables are expressed as the mean ± standard deviation or median with interquartile range, while categorical variables are reported as the frequency (percent). Differences between groups were analyzed using the chi-squared test (or Fisher' s exact test, where appropriate) for categorical variables, one-way analysis of variance for normally distributed continuous variables, and the Kruskal-Wallis test for skewed continuous variables. Univariate logistic regression analysis was used to identify baseline differences in clinical variables of patients with vs. without stroke recurrence, disability, and all-cause death. Multivariate logistic regression analysis was performed to analyze the associated affect factor between the clinical outcomes of stroke recurrence, disability, and all-cause death after adjustment for relevant covariates. Sensitive analysis was performed to analyze the in uence between the patients lost to follow-up and the clinical outcomes. All the estimates of parameters were signi cant at p <0.05 level and the clinical signi cance were included in the multivariable logistic regression analysis. A two-tailed probability (p) value of <0.05 was considered statistically signi cant. All analyses were performed with R statistical software (http://www.R-project.org; The R Foundation) and EmpowerStats (http://www.empowerstats.com; X&Y Solutions, Inc., Boston, MA, USA).

Patient recruitment
Of a total of 3,117 patients who were initially enrolled in this study, 416 patients were excluded due a diagnosis of non-acute ischemic stroke in addition to 1,449 with an NIHSS score at admission of > 3. 1252 patients who had experienced minor ischemic stroke. Among these, 131(10.5% 131/1252) were lost to follow-up. Finally, a total of 1,121 patients with MIS (initial NIHSS score ≤ 3) were included for analysis ( Fig. 1).
2.2 Univariate analysis of patients with vs. without stroke recurrence, disability, and all-cause death at 1 year after MIS Among the 1,121 patients included for analysis, the percentage of stroke recurrence, disability, and all-cause death at 1 year after MIS were 3.4% (38/1121), 9.3% (104/1121), and 3.3% (37/1121), respectively (Tables 1, 2, and 3). The results of univariate analysis showed that patients with stroke recurrence at 1 year after MIS were more likely to be older, current smokers, and have a history of previous stroke,PVD, and/or pneumonia than those without. There was no signi cant differences between patients with vs. without stroke recurrence in the sex ratio, BMI on admission, education level, medical insurance type, hypertension, DM, dyslipidemia, AF, moderate to heavy alcohol use, NIHSS score on admission, SBP and DBP on admission, heart rate, total cholesterol, triglycerides, HDL-C, LDL-C, FBG, blood urea nitrogen (BUN), uric acid (UA), alkaline phosphatase (ALP), blood platelet count (BPC), and leukocyte count ( Table 1). Table 2, older patients were more likely to be disabled at 1 year after MIS (p < 0.05) and those with a disability were signi cantly more likely to have a history of previous stroke and/or pneumonia, and a higher NIHSS score on admission, as well as higher BUN measurements and leukocyte counts, as compared to those without. There were no signi cant differences between patients with vs.

As shown in
without disability in the sex ratio, BMI on admission, education level, medical insurance type, hypertension, DM, dyslipidemia, AF, smoking, moderate to heavy alcohol use, PVD, SBP and DBP on admission, heart rate, total cholesterol, triglyceride, HDL-C, LDL-C, FBG, UA, ALP, and BPC.
Factors associated with all-cause death in patients after MIS are shown in Table 3. The results of univariate analysis showed that the factors associated with death included age, PVD, pneumonia, and ALP (all p < 0.05).
Regardless of whether the patients lost to follow-up were all considered to have no stroke recurrence, disability or death respectively, sensitivity analysis showed that the risk factors between the two groups with or without this part of patients were almost the same. There were only a few differences between the two groups when the patients lost to follow-up were all considered to be stroke recurrence, disability or death, respectively. In addition, by comparing the clinical characteristics of two groups with or without patients lost to followup, only medical insurance type differed between the two groups and there was no statistical difference in other variables(data not shown).

2.3Risk factors for outcomes at 1 year after MIS
Multivariate logistic regression analysis was used to identify independent risk factors for stroke recurrence, disability, and all-cause death  (Table 4).

Discussion
This study is the largest stroke registration study to date in Xi'an, China. The results of the present study showed that a small number of patients with MIS experienced stroke recurrence, disability, and death during the 1-year follow-up period. Nevertheless, these results are not optimistic. Hence, the risk factors associated with poor clinical outcomes at 1 year after MIS were further investigated. The results suggested that the risk factors associated with poor outcomes at 1 year after MIS stroke (i.e., recurrence, disability, and death) are not entirely consistent in Xi'an, China. Therefore, clinicians should apply early prevention strategies on an individual basis.
The results further showed that the percentage of stroke recurrence at 1 year after MIS in the Xi'an region of China was 3.4%, which was lower than the percentage of 13.2% at 1 year and that of 9.8% at 3 months reported by the China National Stroke Registry (CNSR) study [6,15]; lower than the stroke recurrence percentage of 7.6% in the Clopidogrel in high-risk patients with the Acute Non-disabling Cerebrovascular Events (CHANCE) study [16]; also lower than the stroke recurrence percentage of 6.1% by analysis of the Korean Multicenter Stroke Registry [17]; but close to the stroke recurrence percentage of 3.7% recently reported by the TIAregistry.org project [18].
Besides, our data also revealed lower mortality (3.3% vs. 6.3%) and disability (9.3% vs. 17%) at 1 year as compared with the CNSR study [13], butwith a comparable mortality (3.3% vs. 4.1%) to the Korean Multicenter Stroke Registry study at 1 year after MIS [17]. These results suggested that the clinical outcomes of patients with MIS may differ among countries and regions. In addition to the differences in study designs, the percentage of clinical outcomes may also be related to geographical environments, daily habits, economic status, and disease prevention measures, indicating the importance of studies of regional stroke registries.
There are several potential reasons for the lower percentage of stroke recurrence, disability, and all-cause death at 1 year in the present study. First, there were notable differences in the clinical characteristics of previous studies. As compared to the CNSR study [6], patients included in the present study had lower incidences of hypertension (68.5% vs. 73.6%), DM (21.6% vs. 27.3%), dyslipidemia (6.9% vs. 11.8%), atrial brillation (4.8% vs. 5.8%), and previous stroke (26.5% vs. 31.1%), as well as lower NIHSS scores on admission (median, 1 vs. 2). Hence, the percentage of risk factors for clinical outcomes of stroke in this region were relatively lower, which may be related to the better preventive measures and lifestyles in the Xi'an region, as compared with other regions. Second, differences in study designs and regions may have led to the differences in results. The CNSR study was a nationwide survey [6,15] and, thus, does not represent the status quo. The data assessed in the present study were collected from four tertiary grade A hospitals in the Xi'an region, which corresponds to the lower valley of the Wei River in the Guanzhong Plain in northern China. The relatively lower percentage of poor outcomes may be due to more standardized regimens for the diagnosis, treatment, and prevention of secondary stroke than those in the CNSR study, which included primary, secondary, and tertiary hospitals. Other potential reasons for the lower percentage of poor outcomes in the present study could be that most of the patients resided in urban areas of the Xi'an region and more than 90% had medical insurance.
Risk factors affecting the 1-year outcomes (i.e., stroke recurrence, disability, and all-cause death) after MIS in the Xi'an region of China were investigated. In the present and previous studies, age was identi ed as an independent risk factors for stroke recurrence, disability, and allcause death at 1 year after MIS [19,20]. Hence, older patients should be closely monitored for various indicators and early detection and treatment.
In addition, pneumonia was identi ed as an independent risk factor for stroke recurrence, disability, and all-cause death at 1 year after MIS in the Xi'an region, similar with the ndings of previous studies [21,22]. Pneumonia is closely related to dysphagia caused by stroke [22], suggesting that treatment for swallowing di culties after stroke must be improved in the Xi'an region. So, clinicians should promptly evaluate patients with dysphagia and initiate swallowing rehabilitation, dietary guidance, and education of dysphagia in order to reduce the percentage of pneumonia after MIS and improve treatment outcomes.
Similar to previous studies [23][24][25], current smoking was found to be an independent risk factor associated with 1-year stroke recurrence after MIS. After stroke, persistent smoking increases the risk of stroke recurrence. There exists a dose-response relationship between smoking quantity and the risk of stroke recurrence [24,25] because smoking increases the short-term risk of stroke by promoting thrombosis and reducing cerebral blood flow via arterial vasoconstriction [26,27]. Therefore, it is important to control smoking among MIS patients.
In this study, an elevation in ALP levels was an independent risk factor for all-cause death, in accordance with the ndings of previous studies [28][29][30]. Elevated ALP was related with an increased risk of all-cause death in patients with end-stage renal disease [28,29] and as an independent predictor of poor outcomes of patients with preserved kidney function in the CNSR study [30]. As a possible explanation, serum ALP has been implicated in the pathogenesis of vascular calcification and subclinical atherosclerosis [31,32]. Vascular calcification plays a significant role in the process of atherosclerosis and also leads to increased vascular stiffness and reduced vascular compliance. So, clinicians should pay more attention to ALP levels in patients with MIS, as early detection and intervention may reduce the risk of death within 1 year after stroke.
In the present study, the NIHSS score and leukocyte count on admission were identi ed as risk factors for stroke disability at 1 year after MIS, consistent with the ndings of previous results [33][34][35][36]. A higher NIHSS score indicates severe neurological impairment. Because there is no speci c treatment for cerebral function injury caused by stroke, the outcomes of the majority of patients with severe neurological impairment were generally poor. Previous studies have reported that a high leukocyte count in the early stages of stroke is closely related to the severity of stroke and co-infection, which leads to aggravation of stroke and subsequent disability [37,38]. However, an elevated leukocyte count in the early stage after stroke may not necessarily be caused by infection, thus the clinician should assess the presence of co-infections. For non-infectious stroke, the patient' s family members should be informed of a potentially poor outcome as early as possible. Early prevention and treatment of digestive tract ulcers and acute brain-heart syndrome may be hampered by a state of stress.
In addition, multivariate analysis showed that alcohol seemed to be a protective factor. The possible explanation is that we only record whether the alcohol used or not, but did not record the amount of alcohol consumed. However, based on the clinical characteristics, the mean age was higher in the patients with MIS who had adverse outcomes (include stroke recurrence, disability, all-cause death) at 1 year follow up. This may due to the fact that most of the patients were in good health before the onset, more patients may have previous drunk alcohol. This phenomenon may lead to the tendency of alcohol consumption to be a protective factor in our multivariate analysis, but the results were not statistically signi cant.
There were some limitations to this study that should be addressed. First, the four hospitals participating in this study were not selected at random, thus there was potential for selection bias when evaluating the real burden of disease in the Xi'an region of China. In addition, all the participating hospitals were level 3 rst-class hospitals that may not necessarily represent the status quo of MIS treatment in community hospitals. Second, the focus of this study was the in uence of risk factors on admission and during hospitalization on 1-year outcomes, so potential factors after discharge were not analyzed. Third, the data obtained from cerebrovascular and neurological imaging in this study were incomplete, so there was a lack of image-related risk factors, such as infarct volume and infarct location. Forth, in this study, 131 cases (10.5%) patients were lost to follow-up at 1 year after MIS. However, the sensitivity analysis showed that the patients lost to follow-up in this study was close to randomizing, which did not affect the result.

Conclusions
In conclusion, The 1-year outcomes of MIS is not optimistic in the Xi'an region of China, especially high percentage of disability. In this study, we found the risk factors affecting 1-year stroke recurrence, disability and all-cause death, which need further veri cation in the subsequent studies.

Declarations
Ethics approval and consent to participate The study protocol was approved by the ethics committees of the First Hospital of Xi'an and conducted in accordance with the ethical principles for medical research involving human subjects as described in the Declaration of Helsinki. Written informed consent was obtained from all patients participating in this study.

Consent for publication
All authors of this study agreed to publish.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors have no competing interests to declare.    Stroke disability was defined as modified Rankin Scale≥3. "−" not included in the multivariate analysis.