Influencing factors of stroke occurrence and recurrence in hypertensive patients: A prospective follow‐up studies

Abstract Objective To understand the related risk factors of occurrence and recurrence of hypertension and provide scientific basis for relevant departments to better guide prevention and control work. Methods From September 2017 to September 2018, a prospective follow‐up study was performed on patients with hypertension who visited the Second People's Hospital of Wuhu City, Anhui Province. Multivariate Cox regression was used to analyze influencing factors of stroke occurrence and recurrence in follow‐up of hypertensive patients. Results A total of 769 hypertensive patients were enrolled in this study. The average age of hypertensive patients was 65.66 ± 11.70 years old and the BMI index was 24.99 ± 4.17. In this study, 769 patients with hypertension were followed up for 1 year, and the incidence of stroke was 14.69%. This study found that higher levels of blood glucose (RR = 2.027, 95% CI: 1.195–3.438), HCY (RR = 5.928,95% CI: 1.438–24.440), aggravated extent of carotid artery stenosis (RR = 2.620, 95% CI: 1.532–4.481), and drinking (RR = 3.867, 95% CI: 2.038–7.339) were risk factors, and maintaining exercise (RR = 0.325, 95% CI: 0.117–0.907) was a protective factor for stroke occurrence; however, aggravated extent of carotid artery stenosis (RR = 3.158, 95% CI: 1.797–5.550) and smoking (RR = 2.271, 95% CI: 1.142–4.517) were risk factors for stroke recurrence for hypertensive patients. Conclusions For people with high blood pressure, it is necessary to exercise properly, control body weight, avoid obesity, quit smoking, reduce alcohol consumption, and reasonably control blood pressure, blood sugar, and blood lipid.


INTRODUCTION
Stroke is defined as "rapidly developing signs of focal (or global) disturbance of cerebral function lasting >24 h (unless interrupted by surgery or death) with no apparent nonvascular cause" (Hatano, 1976). According to some research results, stroke is the second leading cause of death in the world and is recognized as the major cause of acquired disability for adults in most regions (Lozano et al., 2012;O'Donnell & Yusuf, 2009). Strokes can usually be divided into two subgroups: ischemic stroke and hemorrhagic stroke. Although over the past several decades, age-standardized stroke mortality and morbidity have continued to decline in many developed countries (Kim et al., 2015), stroke burden has increased over the last 30 years in China, and the age-standardized prevalence, incidence and mortality rates were 1114.8 per 100,000 people, 246.8 and 114.8 per 100,000 personyears, respectively .Stroke not only endangers the life and health of patients and reduces their quality of life, but also brings a huge economic and medical burden to the patients' families and society. Stroke accounts for about 2%-4% of total world health care costs, and industrialized countries have shown that stroke accounts for 4% of direct health care costs .
Reducing the burden of stroke in the population requires identifying modifiable risk factors and demonstrating the effectiveness of risk reduction efforts. There are many risk factors for stroke, including both modifiable (e.g., physical exercise, BMI, diet, smoking, drinking, comorbid conditions) and nonmodifiable risk factors (e.g., age, sex, race) (Boehme et al., 2017). Studies have shown that hypertension is the common most and powerful modifiable risk factor for stroke regardless of geographic region and ethnicity, though it contributes to atherosclerotic disease (Boehme et al., 2017;Iadecola & Gorelick, 2004). Evidence from clinical trials shows that controlling of blood pressure can substantially lower risk of stroke (Chobanian et al., 2003).
Early detection, diagnosis, and treatment are critical to prevent and control stroke. Therefore, regular health examination is an important method for early detection of people at risk of stroke. In the present study, we conducted a 1-year follow-up of hypertension patients at the Second People's Hospital of Wuhu City, Anhui Province to reveal the distribution characteristics of risk of stroke among the hypertensive population. The factors related to the occurrence and recurrence risk of stroke were discussed to provide scientific basis and effective data support for better guiding the prevention and treatment of stroke.

Baseline survey
According to the 2017 technical program of screening and intervention project for high-risk groups of stroke, all hypertensive patients enrolled during the study period were comprehensively evaluated and screened by means of questionnaire survey, physical examination, and laboratory examination.

Questionnaire survey
The self-designed questionnaire was used, and the face-to-face survey was conducted by uniformly trained investigators.

Physical examination
Body measurements include height, weight, and blood pressure.
Height measurement requires the subjects to take off their shoes and hats, keep their heels tight and upright, and fix them vertically on the wall with a tape measure. The nurses use a triangular plate to read the right angle side against the wall, and the degree is accurate to 0.5 cm.
The weight measurement requires subjects to take off shoes and coats, wear only single clothing, and the degree is accurate to 0.5 kg.
The body mass index (BMI) was calculated by dividing the weight in kilograms by the squared height in meters (kg/m 2 ). Blood pressure was measured using a mercury sphygmomanometer in a separate room in a quiet environment. The subjects need to sit still for 5 min before measurement and take the average value for 3 consecutive measurements. The interval between any two blood pressure measurements should be more than 30 s. Carotid artery stenosis (CAS) was measured by magnetic resonance imaging (MRI). According to the degree of CAS, the patients were classified into mild, moderate, and severe stenosis group.

Laboratory examination
5 ml of fasting venous blood was taken from the subjects in the morning, and the levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), homocysteine (HCY), and blood glucose were measured.

Research indicators and criteria
Hypertension is defined as any of the following: (1) blood pressure ≥140 and/or 90 mmHg; (2) currently taking antihypertensive drugs; (3) self-report that he/she has been diagnosed with hypertension by doctors. Diabetes was defined as blood glucose ≥ 7.0/11.0 mmol/L (not eating/other time) or currently under medication control.
Dyslipidemia was defined as one or more abnormal indexes (TC  Starting from the date of admission, the patients were followed up for 6 months and 1 year, with a total of 2 times. Follow-up was mainly by telephone, supplemented by outpatient follow-up. Patients who have lost contact for various reasons, such as the mobile phone number change, shutdown, three or more phone calls or refusal to accept follow-up are regarded as shedding cases. The main contents of the follow-up included stroke incidence and death. The endpoint observed was stroke or stroke recurrence during follow-up.

Quality control
Before the investigation, an Expert Symposium was carried out to discuss the specific implementation steps of the project, formulate

Statistical analysis
The SPSS18.0 statistical software program was used for data analysis. Quantitative data and categorical data were expressed by mean with SD and frequency or percentage, respectively. The incidence and recurrence rate of stroke in different group (gender, age, history of stroke, smoking, etc.) were compared by using the chi-squared (χ 2 ) tests and exact probability method of Fisher. The independent variables with statistical significance (p value < .1) in univariate analysis (χ 2 test) were included in multivariate Cox regression to further analyze the risk factors of new onset and recurrence of stroke. p Value < .05 was considered significant.

Univariate analysis of stroke occurrence in hypertensive patients during 1-year follow-up
A total of 769 hypertensive patients were followed up for 1 year, and the incidence rate of stroke occurrence was 14.69%. The results in Table 2 showed that during 1-year follow-up, the increased incidence rates of stroke in hypertensive patients were related to the history of stroke, high age, abnormal index of blood pressure, blood glucose, TC, TG, HDL, HCY, aggravated extent of carotid artery stenosis, smoking, and drinking behavior (p < .05). Keeping exercise behavior decreased the incidence rate of stroke (p < .05). While the incidence rate of stroke has no significant difference between gender, overweight/obesity, and LDL (p > .05).

Multivariate Cox regression analysis of stroke occurrence in hypertensive patients during 1-year follow-up
According to univariate analysis, a total of 12 variables (age, history of stroke, blood pressure, blood glucose, TC, TG, HDL-C, HCY, rate of carotid artery stenosis, smoking, drinking, and exercise) entered the multivariate Cox regression analysis (forward method) in accordance with the inclusion (α = 0.05) and exclusion (β = 0.10) criteria. Table 3 showed that the history of stroke (RR = 2.382, 95% CI: 1.605-3.534), higher levels of blood glucose (RR = 1.632,

Univariate analysis of stroke occurrence in hypertensive patients without history of stroke during 1-year follow-up
A total of 568 hypertensive patients without history of stroke were followed up for 1 year, and the incidence rate of stroke was 10.04%. The results in Table 4 showed that during 1-year follow-up, the increased incidence rate of stroke in hypertensive patients without history of stroke was related to abnormal index of blood glucose, TC, TG, LDL, HCY, aggravated extent of carotid artery stenosis, smoking, and drinking behavior (p < .05). Keeping exercise behavior decreased the incidence of stroke (p < .05). While the incidence rate of stroke has no significant difference between gender, age, overweight/obesity, blood pressure, and HDL (p > .05).

3.6
Univariate analysis of stroke recurrence in hypertensive patients with history of stroke during 1-year follow-up A total of 201 hypertensive patients with history of stroke were followed up for 1 year, and the recurrence rate of stroke was 27.86%. The results in Table 6 showed that during 1-year follow-up, the increased recurrence rate of stroke in hypertensive patients with history of stroke was related to abnormal index of blood pressure, blood glucose, HCY, aggravated extent of carotid artery stenosis, smoking, and drinking behavior (p < .05). Keeping exercise behavior decreased the incidence of stroke (p < .05). While the incidence of stroke has no significant difference between gender, age, overweight/obesity, TC, TG, HDL, and LDL (p > .05).

3.7
Multivariate Cox regression analysis of stroke recurrence in hypertensive patients with history of stroke during 1-year follow-up According to univariate analysis, a total of 10 variables (blood pressure, blood glucose, TG, HDL-C, HCY, rate of carotid artery stenosis, smoking, drinking, and exercise) entered the multivariate Cox regression analysis (forward method) in accordance with the inclusion (α = 0.05) and exclusion (β = 0.10) criteria. Results in Table 7 showed that aggravated extent of carotid artery stenosis (RR = 3.158, 95% CI: in hypertensive people. Studies have shown that hypertension is a major risk factor for stroke, followed by dyslipidemia, diabetes, physical inactivity, smoking, and overweight/obesity (Guan et al., 2017), while epidemiological studies have demonstrated a positive relationship between heavy alcohol use and hypertension (Stranges et al., 2004).
In this study, 769 patients with hypertension were followed up for 1 year, and the incidence of stroke was 14.69%. Data from the national stroke screening survey show that the standardized prevalence rate of survival stroke patients in study population aged 60 and older was 4.94% in total (Xia et al., 2019). Because hypertension was the most prevalent risk factor for stroke, people with high blood pressure have a higher stroke rate than the general population.
Multivariate Cox regression analysis of influencing factors of stroke  (Kvitkina et al., 2020), the incidence of acute ischemic stroke was significantly increased when there were low levels of TG and TG/HDL-C (Deng et al., 2019), patients with hyperhomocysteinemia (HHcy) have a higher risk of developing ischemic stroke , carotid stenosis is a known independent risk factor for perioperative stroke (Klarin et al., 2020), smoking increases the risk of stroke in the general population, there is evidence of a doseresponse relationship between the number of cigarettes and the risk of stroke (Matsuo et al., 2020), and increases in physical activity levels may improve function and health status for stroke survivors (Aguiar et al., 2017).
In this study, hypertensive patients were divided into those with no history of stroke and those with history of stroke, and multivariate Cox regression analysis of influencing factors of stroke was conducted respectively. The 568 hypertensive patients without history of stroke were followed up for 1 year, and the incidence of stroke was 10.04%, while the rate of recurrent stroke in 201 patients with history of stroke was 27.86%. Another study from China shows that the rate of recurrent stroke after the first-ever stroke was 5.7% (Han et al., 2020), and a meta-analysis suggested that the cumulative risk of recurrence 1 year after initial stroke was 11.1% (Mohan et al., 2011); all of them were lower than the incidence of stroke in this study, probably because the subjects in this study were people with hypertension.
The study also found that higher levels of blood glucose, HCY, aggravated extent of carotid artery stenosis, and drinking were risk factors, and maintaining exercise was a protective factor for stroke occurrence; however, aggravated extent of carotid artery stenosis and smoking were risk factors for stroke recurrence for hypertensive patients.
These risk factors were partly confirmed by other investigators. For instance, diabetes, smoking, dyslipidemia, and alcohol intake were recognized as important risk factors for the occurrence and recurrence of ischemic stroke in America and dyslipidemia and smoking were among the risk factors in Arab countries (Benamer & Grosset, 2009).
Hypertensive patients without history of stroke had more risk factors than those with history of stroke, possibly because people with history of stroke have improved their bad behaviors, such as eating habits, drinking, and exercise.
From what has been discussed above, for people with high blood pressure, it is necessary to exercise properly, control body weight, avoid obesity, quit smoking, reduce alcohol consumption, and reasonably control blood pressure, blood sugar, and blood lipid.
Although this study is a prospective study, there are still some deficiencies. First, the main disadvantage of cohort study design is the existence of bias and confounding factors, which may affect the reliability of the study results. The patients with hypertension included in this study are from one hospital, which may have bias in admission rate. In addition, although this study has taken some measures to control potential confounding factors, we cannot completely rule out the interference of other unpredictable factors affecting the prognosis of patients. Second, this study only collected the physiological and biochemical indexes of patients at admission, and lacked the collection information during follow-up.

ACKNOWLEDGMENTS
This study was reviewed and approved by the Ethics Committee of The Second People's Hospital of Wuhu. The patients/participants provided their written informed consent to participate in this study. We are very grateful to all the doctors and graduate students of Department of Neurology in the Second People's Hospital of Wuhu who participated in this survey.

DATA AVAILABILITY STATEMENT
The data sets generated and analyzed during the current study are available from the corresponding author on reasonable request.