Article In Brief
An analysis of more than three dozen studies found that sex is an important variable for clinicians to include in clinical decision-making and study designs.
Sex differences in the severity and composition of carotid atherosclerosis could account for differences in stroke incidence, treatment benefit, and complication rates between men and women, a new study indicates.
All types of plaque features—such as size, composition, and morphology—appeared more frequently or were larger in men than women, according to the systematic review and meta-analysis published in the February issue of Stroke.
The “convincing evidence for sex differences in carotid atherosclerosis” also included the amount of intraplaque hemorrhage, lipid-rich necrotic core, and calcifications within the plaque, the study's authors noted.
“Our results highlight that sex is an important variable to include in both clinical decision-making and study designs,” they wrote. “Further investigation of sex-specific stroke risks with regard to plaque composition is warranted.”
Citing prior research, the authors highlighted that carotid atherosclerosis is believed to be the underlying cause in 10 percent to 15 percent of all ischemic strokes occurring globally.
The authors also pointed out that men incur higher lifetime risks for ischemic stroke and that their strokes are more often related to large-artery atherosclerosis, whereas cardioembolic strokes are more prevalent among women. In addition, trials on carotid endarterectomy reported that perioperative stroke and death risks are higher among women than men and that women benefit less from surgery.
Several studies on sex differences in carotid atherosclerosis in recent decades enrolled a wide range of patients (asymptomatic versus symptomatic patients and mild versus severe atherosclerosis) and assessments of atherosclerotic disease (plaque size, degree of stenosis, or plaque composition). However, those individual studies used variable degrees of adjustments for confounders.
The authors aimed “to systematically review all literature on sex differences in carotid atherosclerosis in order to provide a comprehensive overview of sex differences in carotid plaque composition and morphology.” In addition, they attempted “to meta-analyze previously reported results and to present a roadmap explaining next steps that are needed for implementing this knowledge in clinical practice.”
Dianne van Dam-Nolen, MD, the study's lead author and a PhD candidate, clinical researcher, and physician in the department of neurology at Erasmus University Medical Center in Rotterdam, the Netherlands, told Neurology Today that the “findings are of clinically significant importance” to neurologists because the composition of plaque affects the risk of (recurrent) stroke. For example, intraplaque hemorrhage is considered an important risk factor and is related to both first and recurrent stroke.
“Although the exact mechanisms of sex differences in carotid atherosclerosis are still unclear, we are already able to act on these differences,” Dr. van Dam-Nolen said.
“We can use this knowledge in clinical practice, being aware of differences in likelihood of having a vulnerable carotid plaque which affects patient's stroke risk. Hence, the next step is to investigate the effect of plaque characteristics on stroke per sex separately. This will also allow us to have sex-specific risk scores in order to improve clinical decision-making.”
During stroke workup, the sex differences have implications for the interpretation of carotid atherosclerosis. Ultrasonography and CT angiography are the most commonly used modalities for carotid evaluation, but they cannot reliably identify the presence of intraplaque hemorrhage.
“This underlines the relevance of using magnetic resonance imaging in the diagnostic workup, which is feasible in clinical practice since only one sequence is needed for the detection of intraplaque hemorrhage,” Dr. van Dam-Nolen said.
She noted the lack of studies on sex- specific risks for (recurrent) stroke risk pertaining to carotid plaque composition, likely because they had low power, which emphasizes the importance of including an adequate number of both men and women in clinical trials.
The researchers systematically searched PubMed, Embase, Web of Science, Cochrane Central, and Google Scholar for eligible studies that included male and female participants and documented the prevalence of imaging characteristics of carotid atherosclerosis. Overall, the researchers included 42 articles in their meta-analyses (ranging from two through 23 articles per plaque characteristic).
Men more often had a larger plaque compared to women and, moreover, more frequently had plaques with calcifications (odds ratio=1.57 [95 percent confidence interval, 1.23-2.02]), lipid-rich necrotic core (odds ratio=1.87 [95 percent CI, 1.36-2.57]), and intraplaque hemorrhage (odds ratio=2.52 [95 percent CI, 1.74-3.66]), or an ulcerated plaque (1.81 [95 percent CI, 1.30-2.51]). In addition, there were more notable sex differences for lipid-rich necrotic cores in symptomatic participants than in their asymptomatic counterparts.
Neurologists interviewed by Neurology Today said they found the study to be compelling and relevant to their clinical practice, with potentially concerning implications.
Michelle Leppert, MD, MBA, assistant professor of neurology at the University of Colorado Denver–Anschutz Medical Campus, said it is not surprising that among the overall and asymptomatic patient cohorts, men had more worrisome and advanced features of carotid plaques.
“Endogenous estrogen is thought to serve a protective role in the development of atherosclerosis in premenopausal women. In addition, there is a higher prevalence of atherosclerotic risk factors among men,” Dr. Leppert said, citing smoking hypertension, diabetes, and hyperlipidemia as examples.
However, she pointed out that in the symptomatic cohort—patients with a stroke or transient ischemic attack (TIA)—men still had higher rates of stenosis, more often containing lipid-rich necrotic core and intraplaque hemorrhage. As a result, the threshold for women to develop strokes or TIAs from carotid plaques may be lower than in men.
“This conclusion, if true, could have far-reaching implications, including how we select women for carotid interventions,” she said.
While prior clinical trials demonstrated that women derive less benefit from carotid artery surgical revascularization, this study highlights that plaque characteristics may have been driving those sex differences, said Bharti Manwani, MD, PhD, assistant professor of vascular neurology with McGovern Medical School at UTHealth Houston.
“This information is helpful for neurologists, as now they can be more aware of the increased probability of an unstable, high-risk plaque in men,” Dr. Manwani said. These results, she added, suggest that men in particular may be more likely to benefit from surgery than medical management alone.
“These studies need to examine other clinical and lifestyle risk factors in these individuals and prospectively follow the study participants for stroke events, first or recurrent, as well as changes in plaque features.”—DR. VIRGINIA J. HOWARD
The design of the systematic review and meta-analysis was rigorous, Dr. Manwani noted. For instance, the researchers excluded studies with selection, information, or outcome bias.
Another strength of the study is the inclusion of results from both CT and MRI, said Seemant Chaturvedi, MD, FAAN, FAHA, Stewart J. Greenebaum Endowed Professor of Stroke Neurology and director of the comprehensive stroke program at the University of Maryland School of Medicine.
Dr. Manwani said the high heterogeneity in the studies included in this analysis was a limitation, however. The authors did not have access to patient demographics such as age, ethnicity, vascular risk factors, and smoking status—all of which affect carotid atherosclerosis. Adjustments should be made for these factors, she said, in order “to understand and interpret these results more meaningfully.
“Women may respond better to what's called intensive medical therapy,” such as strict control of cholesterol and blood pressure and increased physical activity, said Dr. Chaturvedi, the principal investigator of the Symptomatic Carotid Outcomes Registry (SCORE).
SCORE aims to build upon the trials conducted more than 30 years ago, which did not include statins, new antiplatelet agents, and newer antihypertensive medications. It aims to evaluate that clinical care with intensive medical therapy alone and assess whether the one-year stroke rate in patients with symptomatic carotid stenosis and low risk clinical features will be less than 5 percent.
“The goal of the (SCORE) study,” Dr. Chaturvedi said, “is to establish that women who receive intensive medical therapy have a low stroke risk.”
Additional cohort studies are needed involving more thorough workup of carotid atherosclerosis to examine plaque characteristics, beyond the use of only ultrasonography, said Virginia J. Howard, PhD, FAHA, FSCT, distinguished professor of epidemiology in the School of Public Health at the University of Alabama at Birmingham.
“These studies need to examine other clinical and lifestyle risk factors in these individuals and prospectively follow the study participants for stroke events, first or recurrent, as well as changes in plaque features,” Dr. Howard said.
In addition to enrolling sufficient numbers of women and men, the studies should include participants from various racial and ethnic groups—an important additional consideration not mentioned in the systematic review and meta-analysis, she said.
“Endogenous estrogen is thought to serve a protective role in the development of atherosclerosis in premenopausal women. In addition, there is a higher prevalence of atherosclerotic risk factors among men.”—DR. MICHELLE LEPPERT
While the authors stated that men have higher lifetime risks for ischemic stroke, Dr. Howard noted that women actually have a higher lifetime risk of any stroke, partially explained by the fact that women live longer than men.
“Despite lower age-specific rates of stroke in women compared to men, stroke has a disproportionate impact on the lives of women,” she said. “Women are older than men by an average of four to five years when they have a stroke event, and as a consequence of aging populations, more stroke events in total occur in women than in men. Studies show that women have worse recovery, poorer function, and lower quality of life following stroke.”
Drs. Van Dam-Nolen, Manwani, and Howard had no disclosures. Dr. Chaturvedi previously was a consultant for Astra Zeneca but is not currently consulting with the company.