Causes of mortality in patients after first‐ever stroke: A retrospective population‐based study

Abstract Background Stroke is the third most common cause of death in developed countries and it is the most common cause of disability in the adult population of Iran. In this study, we aimed to evaluate the effects of age, sex, and other predisposing risk factors on mortality after stroke. Methods We studied 1572 patients with first‐ever stroke during a 7‐year period from January 2008 to December 2014. Patients’ medical records including demographic information, past medical history, physical examination, and laboratory testing were reviewed. We analyzed the correlation of qualitative and quantitative variables with sex and mortality. Results Of all patients, 252 (16%) died during the hospital stay and of the remaining 1320 patients, 453 (34.3%) died during the follow‐up period. There was no significant correlation between mortality and sex (p = .508). Descriptively, the number of women was higher in all age groups except in the age group 55–64 years. No significant correlation was observed between sex and age group (p = .748). We also observed a significant association between age group and mortality (p < .001). Hypertension is the most prevalent disease in both men and women. Higher levels of creatinine, urea, fasting blood sugar, neutrophils, cholesterol, and LDL significantly increase and higher levels of lymphocytes, platelets, RBCs, hemoglobin, and triglyceride significantly decrease the mortality. Conclusion There are no sex differences in mortality after first‐ever stroke. Elderly patients need more support and attention due to greater stroke mortality. Complete blood count, lipid profile and blood levels of urea, creatinine, and fasting blood sugar may be useful in predicting mortality after first‐ever stroke.


BACKGROUND
Stroke is the third most common cause of death after cardiovascular diseases and cancer in developed countries (Lopez et al., 2006;Murray & Lopez, 1997). In the United States, about 75,000 cases of cerebrovascular events occur annually. Almost 88% of these events are cerebral ischemic strokes of which, about 8-12% of them are fatal (Biller et al., 2005). Each year in Iran, 327 out of 100,000 people suffer from stroke, which is the most common cause of disability in the adult population of Iran (Salman et al., 2006). The non-modifiable risk factors for stroke are age, sex, familial history of stroke, and race (Phillips, 2008;Terzis et al., 2003). Some modifiable risk factors for stroke include hypertension, smoking, peripheral vascular disease (PVD), carotid asymptomatic stenosis, atrial fibrillation, congestive heart failure (CHF), coronary artery disease (CAD), diabetes mellitus (DM), dyslipidemia, obesity, and inactivity (Greenberg et al., 2002;Simon et al., 2009). Risk factors for stroke are similar in women and men. However, at stroke onset, hypertension and atrial fibrillation (AF) are more prevalent in women, whereas heart disease, peripheral artery disease, diabetes, smoking, and alcohol consumption are the main risk factors in men (Reeves et al., 2008). Global stroke incidence and prevalence rates are respectively 33% and 41% higher in men than in women (Appelros et al., 2009).
Although the greater prevalence of stroke in men is well known, recent evidence emphasizes the importance of stroke in women (Bousser, 1999). Stroke severity is greater in women than in men, (Lin et al., 1996;Palomeras et al., 2000) and the possibility of hospital discharge after acute stroke is sex-related (Wyller et al., 1997).
In this retrospective study, we examined the effects of age, sex, and other important risk factors on the mortality rate of ischemic stroke.
The results of this study may be helpful in improving preventive strategies and the in-hospital management of stroke patients.

METHODS AND MATERIALS
In this retrospective population-based study, 1572 patients were studied during a 7-year period from January 2008 to December 2014 in Imam Khomeini Hospital, Urmia, Iran. Acute ischemic stroke (AIS) in patients was diagnosed by a neurologist using computed tomography (CT) scan or magnetic resonance imaging (MRI). Stroke was defined as sudden initiation of a focal (or global in case of coma) neurological disturbance of brain function lasting for more than 24 hours or leading to death apparently due to the vascular events (Aho et al., 1980

Statistical analysis
Quantitative variables are given as mean ± standard deviation (SD).
Qualitative data are reported as numbers (percentages). We used a

Ethical approval
All experiments were approved by the Ethics Committee, Urmia University of Medical Sciences, Urmia, Iran and were in accordance with the 1964 Helsinki declaration and its later revisions. F I G U R E 1 Sex and age distribution in patients with first-ever ischemic stroke. No significant correlation was observed between sex and age group (p = .748) F I G U R E 2 Mortality and age distribution in patients with first-ever ischemic stroke. A significant correlation was observed between mortality and age group (p < .001)

Out
Descriptively, Figure 1 demonstrates sex and age distribution and Figure 2 depicts mortality and age distribution in patients with firstever ischemic stroke. According to Figure 1, most of the patients in this study were 75-84 years old. The number of women was higher in all age groups except in the age group 55-64 years. Also, as seen in Figure 2, the highest and the lowest survival rates were observed in age groups <54 and ≥85 years, respectively. Additionally, among the patients younger than 75 years old, the number of survived patients was higher than the number of expired ones. But, among the patients aged greater than or equal to 75, the number of expired patients was higher. No significant correlation was observed between sex and age group (p = 0.748). We also observed a statistically significant association between age groups and mortality (p < .001). Table 1 shows the prevalence of risk factors among the patients and the correlation of each variable with sex. As seen in the table, hypertension (p = .002), DM (p = .001), and smoking (p = .001) are the risk factors with a significant difference between men and women. In Table 2, we have presented the prevalence of risk factors according to mortality. All risk factors except AF (p = .354) were significantly different between the two groups. Tables 3 and 4 demonstrated the quantitative variables including age, blood pressure, and laboratory parameters according to sex and mortality, respectively. Age (p = .729), DBP (p = .282), BS (p = .082), WBC (p = .519) and neutrophil (p = .232) counts, triglyceride (p = .159) and LDL (p = .050) levels were not significantly different between men and women but all other parameters differed significantly between two groups. Also, all of the quantitative variables were different between both expired patients and survived patients except systolic (p = .256) and diastolic (p = .945) blood pressures, WBC count (.346), and HDL level (.092). Finally, the results of univariate logistic regression analysis demonstrated that higher levels of creatinine (p < .001), urea (p < .001), FBS (p < .001), neutrophils (p < .001), cholesterol (p < .001), and LDL (p < .001) significantly increase and higher levels of lymphocytes (p < .001), platelets (p = .044), RBCs (p < .001), hemoglobin (p = .003), and triglyceride (p = .034) significantly decrease the mortality in the patients. Table 5 shows the results of univariate logistic regression analysis for each quantitative variable in survived and expired groups.

DISCUSSION
In the current population-based study, we assessed the risk factors of mortality in patients after the first-ever stroke. The most common age range of the first-ever stroke was 75-84 years and only in the age group 55-64 years, the number of men was dominant. We did not assess the correlation between sex and incidence of first-ever stroke because all of the patients in this retrospective study had stroke and we did not have control group to assess the correlation between sex and stroke incidence. Also, no significant correlation was found between age and sex. According to studies, sex differences highly depend on the patient's age in stroke incidence. In middle-aged people, the rate of ischemic stroke in females begins to increase due to the onset of menopause and loss of sex hormones (Towfighi et al., 2007), and it stays high in elderly women (age >85 years) compared with elderly men (Bots et al., 2017). The population-based study in Sweden reported a 60% lower incidence for stroke in women than in men at ages 55-64 years and a 50% higher incidence by the age of 75 years in women (Löfmark & Hammarström, 2007). Similarly, the Oxford Vascular Study found lower stroke incidence in women than in men aged 55-74 years, but the higher probability for women aged 85 years and older (Kissela et al., 2004). The WHO MONICA Project (18 European and Asian populations) surveyed 28-day stroke mortality which was equivalent or higher in women than in men (Thorvaldsen et al., 1995). Sealy-Jefferson et al. (2012) demonstrated that women are protected from stroke until almost 80 years of age in comparison with men and no sex differences in stroke risk were shown in their study. In the study of Rural Tianjin, China from 1992 to 2012 revealed that the incidence of stroke was lower in women than in men for all age groups, and the male/female incidence ratios decreased over time, especially in those aged ≥65 years (from 2.6 to 1.6 to 1.3). However, the incidence of stroke, annually, was greater in women than in men (8.0% versus 5.8%) from 1992 to 2012. Also, no significant sex difference in 30day mortality was observed in their study (Wang et al., 2014 (Asplund et al., 1988;Gillum et al., 1984;Reeves et al., 2008).
In this study, we did not find any significant correlation between mortality and sex. We also observed a statistically significant association between age groups and mortality.
According to this study, risk factors vary depending on sex and Furthermore, Nationwide Danish Study (Andersen et al., 2010) demonstrated that before the age of 70-80 years, stroke risk factors were mostly more prevalent in men except for hypertension and AF, both being more prevalent in women. A recent review on sex differences in stroke also has demonstrated that women with stroke are more likely to have hypertension and AF, whereas, heart disease, MI, peripheral arterial disease, DM, and alcohol and tobacco use are more prevalent in men (Reeves et al., 2008). In the current study, the most common cause of death after the first-ever stroke was hypertension. Among cardiac causes, only AF was not significantly related to mortality and this finding is in contrast with previous studies (Broderick et al., 1992;Ghatnekar & Glader, 2008;Kimura et al., 2005;Lamassa et al., 2001).
In the study of Hannon et al. (2010) et al. (2018) has shown that higher levels of HDL are associated with decreased risk of stroke, but some studies have suggested that higher levels of total cholesterol, HDL, LDL, and non-HDL cholesterol significantly decrease the incidence of stroke. They have also explained that higher levels of non-HDL cholesterol can be a significant risk factor for the cardiac disease but not necessarily for stroke (Gordon et al., 1977;Sughrue et al., 2016). This can describe that cardiac disease could cause a higher mortality rate in patients with stroke. As most of the studies have evaluated the relationship between laboratory results and the risk of stroke, and since there are not many studies assessing the association of lab results with mortality after the first-ever stroke, we recommend further studies in order to evaluate the correlation between laboratory findings and mortality after the first-ever stroke.
Also, follow-up of the patients with regard to the mortality was performed using phone calls in most of the cases. Thus, we were not able to detect the causes of mortality after stroke during follow-up period and this was one of the limitations of our study. Further studies especially cohort ones are recommended to be conducted in order to assess the causes of mortality in patients after first-ever stroke. Also, parameters such as history of rehabilitation which could alter the patients' prognosis were incomplete among the medical files, so we were unable to analyze them in the study. This was another limitation of the current study. Thus, we recommend considering these parameters in the future studies.
In conclusion, this study shows that there are no sex differences in mortality after first-ever stroke. Also, we concluded that age groups determine important differences in patients suffering from first-ever strokes and elderly patients need more support and attention because of greater stroke mortality. Furthermore, complete blood count, lipid profile, and blood levels of urea, creatinine, and FBS may be useful in predicting mortality after first-ever stroke.

CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.

FUNDING
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

AUTHOR CONTRIBUTIONS
All authors have read and approved the manuscript, and ensure that this is the case.

DATA AVAILABILITY STATEMENT
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.