Influence of Sex Difference on Distribution of Risk Factors and Etiologic Subtypes of Acute Ischemic Stroke: Reality of Facts
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.294553
Source of Support: None, Conflict of Interest: None
Keywords: Acute ischemic stroke, etiologic subtypes, risk factors, women
Approximately, 87% of all strokes are of ischemic type and demand implementation of aggressive and effective preventive and treatment plans. Sex has been recognized to have an influence on presentation, etiology, therapeutic outcome, and prognosis of AIS., Ischemic stroke (IS) is more prevalent in men compared with women in the general population., Women have manifestations of stroke, which are different from men and have worse therapeutic outcome. Conventional risk factors such as hypertension, diabetes mellitus, atrial fibrillation (AF) and inflammation processes are some of the important sex-related considerations. In a recently published study, women were 6.4 years older than men and more likely to have AF and poor functional outcome at three months compared with men. In another study; women were older than men, whereas obesity and hypertension were more prevalent in women than men. In a study from Saudi Arabia (SA), the mean age at onset of IS in men was significantly lesser than women. The difference has not only been observed in risk factors and types of IS but health-related quality of life (HRQoL) and post-stroke depression (PSD) as well. A recent review reporting the sex differences in patient-reported outcome measures after stroke (PROMS) confirmed that women experience worse HRQoL and more PSD and correlated it to advanced age at time of onset of stroke and greater severity of stroke.
Understanding the sex-related complexities of IS are must in proper management care plan of such patients. Nonetheless, the studies describing the influence of sex difference on risk factors and sub-types of acute IS from SA are not available. Stroke is the leading cause of admission under the neurology service in our hospital. This study aims to investigate the influence of sex on distribution of risk factors and etiologic subtype of AIS in patients admitted to our hospital.
The approval from ethical review board committee of Imam Abdulrahman Bin Faisal University was obtained for this study. This study consisted of retrospective data of patients admitted to the hospital between 2010 and 2017 with diagnosis of AIS. Medical record was retrieved through the electronic data bank system of the hospital. Charts of all patients fulfilling the diagnostic criteria for AIS defined by the World Health Organization were reviewed. After excluding the patients with diagnoses other than AIS as hemorrhagic stroke, cerebral venous sinus thrombosis, transient ischemic attack (TIA), subarachnoid hemorrhage, and brain neoplasm based on CT/and MRI brain; a total of 453 patients were included in the study. Data collection method was the same as mentioned in our previous study. AIS was further classified into five major etiologic categories according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification as follows: (1) large artery disease (LAD), (2) small vessel occlusive disease (SVO), (3) cardio embolic (CE), (4) stroke of other determined etiologies (OD), and (5) stroke of undetermined etiology (UD). These patients were separated by sex. Age and vascular risk factors as diabetes mellitus, hypertension, dyslipidemia, current smoking, past history of stroke or TIA, coronary artery disease, valvular heart disease and AF was documented. Patients were identified as having diabetes mellitus if using anti diabetic medications or found to have serum fasting glucose level ≥126 mg/dL or Hb A1c ≥6.5%, hypertension if taking antihypertensive medications or found to have systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg and dyslipidemia if reported to use lipid lowering medications before admission or found to have fasting total cholesterol ≥240 mg/dL (6.2 mmol/L), or Triglyceride ≥200 mg/dL (2.3 mmol/L), or high density lipoprotein ≤40 mg/dL (1 mmol/L) or low density lipoprotein ≥160 mg/dL (4.1 mmol/L). Routine blood sample analysis, as fasting blood sugar, Hb A1c, fasting serum lipid profile were mentioned. Work up for hypercoagulable state and vasculitis was done where needed. EKG Findings, echocardiogram, and Holter monitoring were also mentioned. CT scan/and MRI head and brain was done in all patients. Extracranial duplex, CT angiogram or MRA were done to look for significant extracranial or intracranial LAD. Stenosis ≥50% was considered as significant. Etiologic classification of stroke was done based on these results.
Data was entered and analyzed using Statistical Package for the Social Sciences software program, version 22.0 (SPSS, Chicago, Illinois). Mean and standard deviation (M ± SD) were computed for age and scaled data. Relevant descriptive statistics, frequency, and percentage were computed for vascular risk factors as diabetes mellitus, hypertension, IHD, dyslipidemia, AF, smoking, and previous history of stroke and TIA. Descriptive data were analyzed using either t tests, the rank-sum test, or χ2-based tests as appropriate. Age was compared among the stroke subtypes using one-way analysis of variance. Chi-square test was used to check proportion between men and women for qualitative variables and the limit of statistical significance was set at P value less than 0.05.
Data of 453 patients were included. Of these, 300 (66.2%) were men and 153 (33.7%) women with M: F of nearly 2:1. The mean ± SD age of all patients was 61.5 ± 14.5 years. The mean age of women was greater than that of men (65.9 ± 15.5 vs. 59.2 ± 13.4; P = 0.00). Women outnumbered men significantly in higher age groups. Sex distribution in different age groups has been shown in [Figure 1]. Distribution of different risk factors for AIS was analyzed according to the sex. Demographic characteristics, vascular risk factors and etiologic subtypes of acute ischemic stroke in males and females are detailed in [Table 1]. The predominant risk factors for AIS in women were the hypertension, found in 87.2% compared to 73.6% men (P = 0.00) and AF; 40% in women compared with 20.3% in men (P = 0.00; odds ratio [OR], 1.96; 95% CI, 1.27–3.04). Past history of stroke was statistically more frequent in women than men (P = 0.03). Current smoking was also significantly different in both sexes as it was found in nearly 10% of men compared with only 1.9% women (P = 0.00) No significant difference was found in prevalence of diabetes mellitus, history of coronary artery disease, and dyslipidemia in both sexes. On multivariate analysis; arterial hypertension, AF, previous history of stroke, previous history of TIA and current smoking were different in both sexes. Women were less likely to have previous history of TIA than men (OR, 1.02, 95% CI, 1.00–1.04). Baseline biochemical values for fasting glucose, lipid profiles and other relevant investigations in males and females are detailed in [Table 2]. Mean values for LDL and TG were higher whereas HDL were lesser in men compared with women. Echocardiogram and Carotid Doppler studies were carried out less frequently in women compared with men (P = 0.001 and 0.00 respectively).
Etiologic subtypes of AIS varied significantly according to the sex as shown in [Figure 2]. There were more UD strokes in women than in men (33.3% vs. 28.3%). Women suffered CE strokes (26.1% vs. 17.7%; P = 0.024; OR, 1.48; 95% CI, 1.03–2.12) statistically more frequently than men. Other etiologic subtypes, that is, LAD (10.5% vs. 16.3%; P = 0.05; OR, 0.64; 95% CI, 0.37–1.08) and SVO (23.5% vs. 31.0%; P = 0.05; OR, 0.75; 95% CI, 0.54–1.05) were less frequent in women compared with men. Possible causes for cardioembolic sources were AF either isolated or in combination with valve disease or cardiomyopathy in 64; valvular heart disease, 13; clot, 19; akinetic left ventricular segment, 2; dilated cardiomyopathy, 5; and patent foramen ovale, 3.
In this study, men (66.2%) outnumbered the women and this is similar to previous studies.,,,, Although men have the higher age specific rate for IS, women have the higher life time risk for stroke. Stroke is more common among men than women although the difference seems to decrease with increasing age. The positive effect of estrogen on cerebral vasculature might be one of the reasons for women to have lower incidence for stroke than men, which may protect them against IS excluding the CE etiology. An incidence rate of 8.84 for men and 13.24 for women per 100,000 population has been reported from SA. Men were more common than women in age group less than 71 years, the difference declined in 71–80 years and women outnumbered the men above 80 years of age group in our cohort of patients. Age is an important non-adjustable risk factor which plays a key role in determining sex-related differences observed in epidemiology of IS. Life expectancy is greater in women, and more of women than men live in ages known to have increased risk for IS. Appelros et al. have reported the mean age of first IS 68.6 years for men and 72.9 years for women. Studies from SA have reported that stroke is most frequent in the 61–70 years age group., We found it more frequently between 51 and 60 years of age and this finding reflects that younger age group is now getting affected more by stroke than observed in the past. The mean age for women was 65.8 ± 5.3 years at onset of stroke and this is lesser than studies from Japan (75.0 ± 11.7 years) and Sweden; 80.4 years (Lund, Sweden) but comparable to Brazil (65.3 ± 12.1). Studies from Eastern Europe (Novosibirsk, Tartu, Uzhgorod, Tblisi) for stroke in women average at 69.1 years, from Western Europe 76.0 years, and from North America and Australasia average 73.3 years. In a systematic review including epidemiological studies, mainly based on Western European surveys; the mean age at first-ever stroke was 68.6 years among men, compared to 72.9 years among women. Authors stated that women get first stroke on an average at age nearly four and a half years later than men. Women were on average approximately seven years older than men at the time of onset of stroke in our study which is nearly similar to studies from Spain and Japan.,
Significant sex difference has been observed in stroke evaluation as well in studies. In an American study; 71% of men with IS compared with 62% of women had their carotid arteries evaluation, and 57% of men had echocardiography vs. 48% of women. No difference was observed in MRI utilization rates. Similar observation was made in an European study; Carotid duplex imaging, echocardiography, and angiography were done less frequently in women with stroke than men. Carotid Doppler studies and echocardiogram were done less frequently in women than men in our study as well.
Concerning the risk factors for acute stroke, women were found to have hypertension more commonly and smoking less commonly than men, which is in agreement with other studies.,, Hypertension and dyslipidemia were more common in women vs in men in a study by Maeda et al. as well. Other studies have reported women to have diabetes mellitus, and past history of stroke less commonly than men. We did not find any statistically significant difference on univariate analysis for diabetes mellitus which is similar to finding by Rodrguez-Castro et al. Previous history of stroke was more frequent in women than men in our patients and this could be explained by the fact that the women have higher life time risk of stroke in comparison with men and are therefore more likely to suffer from recurrent stroke events. AF is found more frequently in women compared to men with IS,, and has been identified as an independent predictor for worse outcome after stroke., Despite knowing the fact about poor outcome after stroke in women with AF, oral anticoagulation is not prescribed regularly in women which further increases the risk of CE events in them. AF was found significantly more commonly in women compared with men (P = 0.00) in our patients as well. Regarding stroke etiology; statistically significant difference was identified between both sexes (P = 0.02). CE was observed more frequently, whereas SVO and LAD subtypes less frequently in women than men. Higher frequency of AF in women is the likely reason for increased prevalence of CE stroke in women. Other studies have also reported women having higher frequency of CE and lesser frequency of SVO subtype., Patients with stroke due to AF not only have poor prognosis, but an increased rate of complications and a higher in-hospital mortality than patients with stroke not having AF. Greater number of women were categorized as Stroke of UD than men. This could be explained by fewer echocardiogram and carotid Doppler studies in women than men leading to incomplete diagnostic work up. The higher frequency of LAD etiologic subtype observed in men compared with women is similar to other studies.,, Higher frequency of active smoking in men can be the possible explanation which is a recognized risk factor for atherothrombotic stroke.
The major limitation of our study is its retrospective data collection. The difference in clinical presentations, given treatment, and outcome could not be studied because of deficiencies in documentation. Despite its limitations, significant differences in risk factors distribution and types of stroke between men and women have been highlighted in our study population. We have compared our findings with literature from other parts of the world and shown our data in detail as literature from SA on this important aspect of stroke is deficient. Furthermore, as the difference in outcome after IS has also been reported worse in women than men, future studies are required in relevance to this subject including multicenter and population based studies.
Significant sex-related differences were observed in risk factor distribution and etiologic subtypes of AIS. Women were older and had higher frequency of hypertension, AF, and past history of stroke than men. Women were more likely to have CE etiologic subtypes of IS than men. SVO and LAD etiologic subtypes were observed less frequently in women than men. This study from KSA has highlighted the importance of sex-related difference in AIS as a primary objective. The effect of sex difference on AIS in our region from KSA is not different from the rest of world despite having different culture.
There is a need to design further studies including multicenter and population-based studies addressing the differences in clinical features, offered treatment (including thrombolysis, anticoagulation and intervention) and outcome between women and men with AIS.
This research made use of the computational resources and technical services provided by the Scientific and High Performance Computing Center at Imam Abdulrahman Bin Faisal University.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2]