Gender-related risk factors for perioperative stroke after carotid endarterectomy in symptomatic patients

Results. Perioperative stroke-death rate (within 30 days after the surgery) in women was 6.8% (6/88) and 3.3% (6/181) in men (p > 0.05). In the female group, none of the analyzed risk factors were associated with a higher risk of periprocedural incident, while in men, only hypercholesterolemia was a significant predictor of perioperative stroke (TC > 240 vs 240 vs 200–240: OR = 6.59; 95% CI: 1.12–38.97; p = 0.0375).


Introduction
Carotid endarterectomy (CEA) is a surgical procedure used in ischemic brain stroke prevention in patients with symptomatic and asymptomatic severe carotid artery stenosis.Symptomatic carotid artery stenosis is characterized by amaurosis fugax (AF), transient ischemic attack (TIA) or ischemic stroke.International trials like the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) were independently conducted to assess the safety and efficacy of CEA, compared to the best medical therapy at that time, in patients with recently symptomatic stenosis. 1,2These trials have helped to define the current indications for CEA.The NASCET found that for every 6 patients treated, 1 major stroke would be prevented at 2 years (i.e., the number needed to treat (NNT) out of 6) for symptomatic patients with a 70-99% stenosis. 1CEA should also be considered as a method of stroke prevention before routinely performed coronary artery bypass grafting (CABG) in patients with hemodynamically significant carotid artery stenosis.Moreover, simultaneous CEA-CABG operations are effectively performed in patients at high risk of cardiac and neurologic complications. 3 The guidelines for the management of extracranial artery stenosis are still being discussed in the literature.A post-hoc analysis of the NA-SCET and ECST showed groups of patients who benefitted the most from CEA.][6] The data obtained from the research revealed that, in addition to the degree of stenosis, there were other important factors for the outcome of CEA such as age, gender, neurological symptoms, and others connected with subsequent stroke or surgical risk.It was found that plaque ulceration also increased the risk of stroke.For an ulcerated 95% stenosis, the absolute risk reduction of ipsilateral stroke obtained by CEA was 54%. 1,7In the multicenter NASCET study, it was observed that women have a higher perioperative rate of stroke or death than men, however, these results were not statistically significant, while the ECST detected a significant increase in perioperative stroke and death in women compared with men. 2,80][11] The recently-published CREST (Carotid Revascularization Endarterectomy vs Stenting Trial) results showed that CEA is associ-ated with similar rates of periprocedural stroke in women and men. 12][15] In this paper, we critically analyzed the outcome of surgical treatment of patients with internal carotid artery stenosis in our department.The aim of this research is to compare perioperative stroke or death rate after CEA in male and female patients.Furthermore, it seeks to determine risk factors of perioperative stroke or death in women and men with internal carotid artery stenosis treated with CEA.

Participants
The outcome of surgical treatment of 269 consecutive symptomatic patients with internal carotid artery stenosis was analyzed.The patients were hospitalized from 1 st

Procedure
The patients had carotid artery Doppler ultrasonography performed, during which the degree of stenosis was assessed.All of them were classified to surgical treatment (CEA) -they had 70-84% or 85-99% stenoses according to NASCET criteria. 16Patients with bilateral high-grade stenoses had only the artery with a higher stenosis rating operated on during the 1 hospitalization.During the surgical procedure, an overall superficial assessment of the atherosclerotic plaque was performed by 1 person unaware of the aim of this research, a vascular surgeon specialist (M.Ł).During the assessment procedure, all the plaques were cut open.On the basis of the AHA classification of plaques, the authors divided the examined plaques into 2 groups: type VI or other types by AHA. 17,18Type VI atherosclerotic plaque, according to AHA, is characterized by plaque rupture, intraplaque hemorrhage, thrombus on the plaque surface, large lipid core, and less fibrous tissue. 18ostoperatively, the patient was returned to the intensive care unit for a period of 24 h.All of the patients since the 2 nd day after surgery continued their previous pharmacotherapy (statins, acetylsalicylic acid, anti-hypertensive drugs).
Within 30 days after the surgery, the patients were assessed for early general complications (stroke or death).The adverse outcomes were documented by formal neurological examination by a neurologist in our hospital.Moreover, female and male groups were compared in the aspects of type of atherosclerosis plaque (type VI or other types according to AHA) and concomitant diseases.

Statistical analysis
Women and men were compared across their characteristics using χ 2 test.The statistical comparison included perioperative stroke or death in relation to concomitant diseases and plaque morphology in women and men.As a measure of this correlation, χ 2 test and logistic regression analysis were applied.Uni-and multivariate logistic regression were performed to determine the factors or combination of factors accounting for the occurrence of periprocedural stroke in all patients and in female and male groups separately.P-value p < 0.05 was accepted as the level of significance.Statistical analysis was conducted using the STATA 9 statistical package (StataCorp LLC, College Station, USA).

Results
The characteristics of the groups of women and men are presented in Table 1.Men significantly more frequently than women suffered from ischemic heart disease (p = 0.0359) and peripheral artery occlusive disease (p = 0.0002) while in women, AHA plaque type VI occurred significantly more often than in men (p < 0.0001) (Table 1).
In the female group, none of the analyzed risk factors were associated with a higher risk of periprocedural stroke or death, and none could be included in uni-or multivariate regression (p > 0.1 for all items) (Table 2).

Discussion
We examined the outcomes of CEA in the aspect of potential risk factors for perioperative stroke or death in a male and female group of 269 patients.We found that plaque type VI according to AHA was significantly more common in women, however none of the analyzed factors were associated with a higher risk of periprocedural stroke or death in this group.The risk of periprocedural incident was influenced in a statistically significant fashion by hypercholesterolemia in men.
Several studies have confirmed a difference in outcome after carotid surgical treatment of carotid arteries stenoses between men and women.Hayes et al. observed that plaque on angiograms and timing of the surgery relative to the time of the qualifying ischemic event.None of the risk factors like diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, intermittent claudication or smoking significantly increased the perioperative risk, nor the age or sex of the patient. 33Type of anesthesia (general vs local) also does not affect perioperative mortality and morbidity in patients undergoing CEA. 34n the basis of the ECST results, 4 statistically significant risk factors were determined: ocular vs cerebral presenting symptoms; systolic hypertension ≥180 mm Hg; peripheral vascular disease; and female sex. 35It was also shown that in patients with intracranial occlusions and stenoses, perioperative and late strokes or vascular deaths appear more frequently in comparison to those without intracranial lesions. 36In contrast, some authors emphasize that contralateral stenosis ≥50% and previous symptoms of cerebral vascular accidents or intraoperative shunt insertion and postoperative high blood pressure may not be risk factors for increased complications after CEA. 37ur study revealed that female sex is connected with AHA plaque type VI presence (in gross eye view assessment in women undergoing CEA).Moreover, we found that the risk factors for perioperative stroke or death after CEA differ between women and men.Sex differences have been recognized in atherosclerotic plaque formation, cerebral stroke risk and occurrence of cardiovascular events. 23Some studies in relation to the hormone level in women and the occurrence of cardiovascular events proved that estrogens have a protective effect on atherogenesis, and, as a consequence, on clinical manifestations of atherogenesis. 38A literature review leads to the conclusion that carotid plaque type VI according to AHA occurs more often in symptomatic women with ICA stenosis than in men.However, carotid artery plaques obtained from asymptomatic women are more stable and less inflammatory compared to men. 23Irregular, ulcerated atherosclerotic plaques have important clinical significance.Such lesions have a tendency for disruptions that are often a source of distal emboli as well as occlusion, resulting in transient cerebral symptoms.Plaque type VI, in which disruptions of the lesion surface, hematoma or hemorrhage, and thrombotic deposits have developed, are largely responsible for morbidity and mortality from atherosclerosis. 39More studies focusing on specific factors affecting different outcomes between men and women after CEA simultaneously assessed in both symptomatic and asymptomatic patients are needed to draw clinically relevant conclusions.
In conclusion, the results of our research demonstrate that periprocedural complications after CEA did not differ between women and men.The fact that AHA plaque type VI was more frequent in women and men more frequently were suffering from ischemic heart disease and peripheral artery occlusive disease, appeared not to influence significantly the outcome of CEA.However, multivariate analysis women developed more than a 2-fold increase in the number of emboli in the postoperative period.The authors found that a possible explanation for the increased rate of complications after CEA was the increased thromboembolic potential of women. 19Laman et al. and Stork et al. described a higher level of microembolic signals in women in the postoperative period, which were associated with earlier cerebrovascular complications. 20,21n the basis of a literature review concerning the etiological factors responsible for different outcomes between women and men after CEA, several ones were distinguished: vessel diameter, plaque morphology, sex hormones, microembolic potential and restenosis.][21][22][23][24][25][26][27][28][29] However, the overall evidence for outcome differences by gender-specific characteristics in the literature is limited. 30Mantese et al. found that sex did not modify the treatment effect. 31Some authors emphasize that female sex alone is not an adjunctive risk factor for poor outcome after CEA in comparison to male patients, however subgroups of female patients at ahigher surgical risk can be distinguished -with contralateral occlusion or diabetes. 326][7] The risk factor profiles obtained from the NASCET database included the presence of a hemispheric vs retinal TIA, leftsided procedure, contralateral carotid occlusion, ipsilateral ischemic lesion on CT scans, irregular or ulcerated including all patients, regardless of their sex, showed that those with ischemic heart disease and AHA type VI carotid atherosclerotic plaque are at a higher risk for periprocedural stroke.In men, contrary to women, hypercholesterolemia significantly increases the risk of the incident.Therefore, we believe that many different factors, not only the degree of stenosis, radiological characteristics, like regularity of atherosclerotic plaque and presence of intracranial disease, but also sex of the patient, should be taken into consideration when balancing the benefits and harms of ICA revascularization.In addition, further work is needed to develop the risk assessment tools specific to patients undergoing CEA.

Table 1 .
Comparison of characteristics of the women's and men's groups LDL) of the examined group were collected from medical documentation, which was prepared in accordance with the aim of this research.

Table 2 .
Risk factors and plaque types in the group of women examined a -based on 3 separate blood pressure analyses.

Table 3 .
Risk factors and plaque types in the group of men examined a -based on 3 separate blood pressure analyses.

Table 4 .
Uni-and multivariate logistic regression analysis of risk factors in men

Table 5 .
Uni-and multivariate logistic regression analysis of risk factors in total group