Major epidemiological features of first‐ever ischemic stroke in Tuzla Canton, Bosnia and Herzegovina

Abstract Background and aims Opacity of data on stroke for Bosnia and Herzegovina (B&H) is mainly due to the lack of a unified national stroke registry. This article aims to present updated epidemiological data on the etiology and risk factors for first‐ever ischemic stroke in Tuzla Canton, B&H. Methods This retrospective hospital‐based study included all first‐ever ischemic stroke patients admitted between January 1, 2018 and December 31, 2018 at the Neurology Department, University Clinical Center Tuzla. Results First‐ever ischemic stroke was diagnosed in 739 patients. Leading risk factors were hypertension (94%), diabetes mellitus (40.7%), and dyslipidemia (38.8%). The most common stroke subtypes were atherothrombotic (36.8%), cardioembolic (21.9%), and stroke of undetermined etiologies (19.2%). Mean NIHSS score at discharge was 13 (IQR 2‐16), and favorable patient outcome (mRs ≤2) was recorded in 26.4% patients. Men (aOR 0.39; 95% CI 0.24‐0.64) and younger patients (aOR 0.96; 95% CI 0.93‐0.98) had significantly higher probability of having a favorable outcome at discharge. Dyslipidemia could be considered as a predictive factor for patient outcome (aOR 0.66; 95% CI 0.43‐1.00). Conclusions More than 92% of our patients had at least one modifiable risk factor, with hypertension and diabetes being at the forefront. One out of four patients had become functionally independent at discharge, while hospital mortality was lower than in other Eastern European countries. The overarching goal should be steered toward the development of a national stroke registry, which should be used as a reference for all further stroke management activities.

costs amounting to over €60 billion. 2 In the same year, stroke was responsible for over 438 000 deaths across the European Continent.
Adjusted stroke-related health and social costs amounted to €3483 per stroke patient. 2 Overpopulation and prolonged life expectancy have significantly increased stroke incidence rates. 3 Substantial geographic and regional differences of stroke incidence have contributed toward increased burden of this disease in low-and middle-income countries, making it a serious public health issue. 4 In 2020, it was estimated that stroke and cardiovascular disease were the leading causes of lost healthy life-years. 5 Opacity of stroke data for Bosnia and Herzegovina [6][7][8] (B&H) is mainly due to a lack of a national stroke registry. The last recorded efforts to present updated stroke data were made in 2014, but again this could not be replicated at the country level. 9 Neighboring countries offer regular updates on stroke incidence and prevalence and plan their public health policies accordingly. [10][11][12][13] Even though lower stroke mortality rates have been observed lately, 14 IS ranks high in both incidence and disability throughout our region. 9,13 This article aims to present an up-to-date overview on the epidemiology, etiology, risk factors, and mortality for first-ever ischemic stroke (FEIS) victims in Tuzla Canton, B&H.

| MATERIALS AND METHODS
World Health Organization's definition was used for the purpose of this study, with IS being defined as "rapidly developing symptoms and/or signs of focal, and at times global, loss of cerebral function, with symptoms lasting more than 24 hours or leading to death with no apparent cause other than that of vascular origin." 15 TOAST criteria have been applied for IS etiology clasification. 1 All patients gave informed consent for their data to be used in this study. In case the patient had a loss, or impairment, of consciousness, consent was obtained from either the accompanying care giver or a family member during patients' stay in the Stroke Unit, following recent recommendations for consent acquirement in acute scenarios. 16 Figure 1. This three-step process ensured better compliance of data reliability because administrative stroke coding alone has proven to be unreliable in some cases. 17

| Study population
Population characteristics were taken from the registry of the Federal Institute for Statistics, 18

| Clinical and laboratory parameters
The following clinical and laboratory parameters were assessed: hypertension, heart disease, atrial fibrillation, diabetes mellitus, dyslipidemia, active smoking status, alcohol overuse, and positive family history.
Hypertension was defined as a systolic blood pressure of >140 mmHg, diastolic blood pressure of >90 mmHg, or previously documented hypertension treatment. 19 Heart disease history included a previously confirmed diagnosis of at least one of the following: angina pectoris, myocardial infarction, cardiomyopathy, heart failure, atrial fibrillation, and other heart rhythm disorders. Diabetes mellitus was present when the fasting blood glucose concentration exceeded 7.0 mmol/L and/or plasma glucose 11 mmol/L at any time of day, or when there was a documented use of a blood-sugar-lowering drug before stroke onset. 20 Dyslipidemia was defined based on the levels of total serum cholesterol (>5.0 mmol/L), low density lipoproteins (>3.0 mmol/L), and triglycerides (>2.0 mmol/L). 21 Active smoking status was noted in case of smoking 10 cigarettes/day 6 months prior to stroke onset, and was considered absent in case the patient had never smoked or had stopped smoking for at least 1 year prior to stroke occurrence. 22,23 Alcohol overuse indicated a consumption of >100 mL alcohol/day during the past 2 months, or acute alcohol intoxication within a 24-hours cycle of stroke onset. 23,24 Positive family history included either of the following: (a) one first-degree relative with early-(<65 years) or late-(≥65 years) IS onset, or (b) at least one second-degree relative with early-or late-IS onset. 25 All data were extracted from the patients' hospital records.

| Examination and imaging
IS was confirmed by neurological examination, neuroimaging methods, and laboratory tests. Final stroke diagnosis was always re-evaluated by a stroke neurologist or an attending senior neurologist. Neurological examination focused on initial screening of vital functions (airway, breathing, circulation monitoring), as well as on the consciousness level, head and gaze deviation, and presence of movement lateralization.
Neurological deficit severity on admission and discharge were assessed by the National Institutes of Health Stroke Scale (NIHSS). 26 Vital status and independent functional outcomes were assessed by the modified Rankin Scale (mRS) across two different time points: upon admission, and 1 month after stroke onset. 27 Primary neuroimaging method was a non-contrast head computed tomography (CT) scan, due to its sensitivity and time effectiveness for hemorrhagic stroke exclusion. Magnetic resonance imaging (MRI) was rarely used because of its limited availability, time-saving measures, and MRI eligibility criteria. 28 Table 3. Mean mRS score at admission was 4 (IQR 3-5) and at discharge 3 (IQR 2-5). In 20.9% (n = 155/739) of patients, a fatal outcome was registered. Although mortality was higher among women, the difference in mortality between the sexes was not statically significant.  10 Similarly, in Serbia stroke is the primary cause of mortality in women and secondary cause among men. 12 Our results of age at stroke onset correspond to regional findings by the Croatian and Serbian study group. 11,13 This is also in accordance with several global studies which have confirmed the relationship between stroke onset and age and its impact on global stroke burden both in regard to high mortality and disability. 29 Most stroke risk factors are alterable, providing the possibility of stroke-risk management. Hypertension, diabetes, and dyslipidemia have all been previously reported as important factors for stroke onset. 30 The risk factors most accountable for stroke incidence in Serbia were smoking, physical inactivity, hypertension, and obesity. 13 We observed similar effects with hypertension and diabetes. High prevalence of hypertension in our study group might be due to unhealthy lifestyle choices, dietary regiments, obesity, lack of physical activity, active smoking status, and constant stress exposure. This is further supported by the latest hypertension study in B&H. 31 While the presence of hypertension and atrial fibrillation was insignificant between men and women, the Croatian study group conversely reported statistically more frequent presence of these factors in women. 11 Otherwise, the presented stroke risk factors in our study cohort conform to the reports by other European study groups 32,33 and fit with the delineated cardiovascular risk in middle-income countries. 14 Active smoker status was higher in the Croatian study group when compared to ours (32.3% vs 25.6%, respectively), while alcohol overuse was lower (8.6% vs 10.7%, respectively), 11 given smoking and alcohol overuse were significantly more associated with men in both studies. 11 General stress often accounts for hypertension, especially considering the already established link between anxiety and hypertension occurence. 34 Moreover, IS events are increasingly affecting younger people, with a predicted twofold incidence increase during the coming years. 35 This may be due to poor diet, obesity, hyperlipidemia, and sedentary lifestyle, all of which may lead to increased morbidity of several vascular diseases besides stroke. More than 92%

| Statistical analysis
(n = 680/739) of our patients had at least one modifiable stroke risk factor, which further places emphasizes on primary prevention not only for IS but also for other cardiovascular diseases. Developing healthy nutritional behaviors and habits should be one of the aims of future public educational campaigns. Additionally, health benefits of regular physical activity and exercise should not be neglected because of their role in prevention, or even reduction, of chronic noncommunicable diseases. 36 Conversely, factors such as age, sex, race, and genetic makeup cannot be changed, warranting high-risk patients to have regular checkups and consultations with their attending physicians. Systemic control of modifiable stroke risk factors, accompanied by established dietary and exercise habits, can be crucial for these high-risk subgroups.
IS subtype analysis showed no significant statistical adherence between the sexes. Even so, atherothrombotic subtype was more common in men, both in the Croatian study group and ours. 11 This finding is also consistent with previous studies carried out in this Department. 37 Inversely, we have found that women are affected more by the lacunar subtype, instead of the cardioembolic ones, as has been previously reported. 38

| CONCLUSION
More than 92% of our patients had at least one modifiable risk factor, with hypertension and diabetes being at the forefront. One out of four patients has become functionally independent at discharge, while hospital mortality was lower than in other Eastern European countries. This indicates an urgent need for targeted risk factor management, acute-care development, and post-stroke therapeutic coordination. This analysis provides the most recent data on stroke epidemiological features in Tuzla Canton, B&H. Epidemiological studies, conjoined by other data-acquisition techniques on stroke patterns and features, will provide a more comprehensive understanding of stroke occurrence, together with its specificities across different subgroups. The overarching goal should be steered toward the development of a national stroke registry, which should be used as a reference for all further stroke management activities.

ACKNOWLEDGMENTS
We would like to thank Prof. Urs Fischer (University of Bern) for his support and comments during the writing of this manuscript.

FUNDING
The author(s) received no financial support for the research, authorship, and/or publication of this article.

CONFLICT OF INTEREST
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Adnan Mujanovic had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

TRANSPARENCY STATEMENT
Adnan Mujanovic affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

DATA AVAILABILITY STATEMENT
The datasets generated and analyzed for the current study are not publicly available due to ethical concerns, but are available from the corresponding author upon reasonable request and after clearance from the ethics committee.