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In a sub-group analysis of the CREST Trial, investigators found that women who underwent carotid stenting had almost double the risk of a periprocedural stroke than those who had carotid endarterectomy. But several independent experts urged caution in interpreting the results.
A new gender-based analysis of data collected as part of a trial that compared carotid artery stenting to carotid endarterectomy has found that women who undergo stenting face almost double the risk of a periprocedural stroke than those who have the surgery.
When the original results of CREST (Carotid Revascularization Endarterectomy versus Stenting Trial) were published in 2010, its overall conclusion was that there was no significant difference between the two procedures in the four-year primary endpoint.
The study designers made a point to recruit a sizable number of women for the trial because the researchers planned to do a sex-specific analysis and wanted large enough numbers. They set a recruitment goal of 40 percent women and ended up slightly short of that at 35 percent.
The follow-up analysis, published online May 6 before the June print edition of The Lancet Neurology, suggests that surgery may be a better option for women because of a higher risk of stroke with stenting in the periprocedural period. The new analysis found that men fared basically the same with either procedure.
In those early days, 6.8 percent of women who had stenting suffered stroke, myocardial infarction or death, compared to 3.8 percent of women who had endarterectomy (p=0.047). No real difference turned up with the men; of those who had stenting, 4.3 suffered a periprocedural event, compared to 4.9 percent of those who had surgery (p=0.64).
The interaction p-value, which looks for a difference between men and women in the events of the periprocedural period was 0.064. (A priori the investigators set the interaction p value level at 0.10 so that anything below this would be considered statistically significant, they said.
“These results suggest that the possibility of an increased periprocedural risk of stroke in women after carotid artery stenting should be taken into account when selecting treatment for carotid artery disease,” the investigators concluded. They noted, however, that additional research is needed to confirm their findings.
Virginia Howard, PhD, associate professor of epidemiology at University of Alabama at Birmingham and lead author for this latest study, told Neurology Today in a telephone interview: “We are not saying that women should have one procedure or women should not have another procedure. You need to look at the individual patient and everything going on.”
DR. VIRGINIA HOWARD: “We are not saying that women should have one procedure or women should not have another procedure. You need to look at the individual patient and everything going on.”
The researchers hypothesized that “women might be at higher risk of periprocedural stroke and death because of technical difficulties related to the fact that they have smaller internal carotid arteries than men: women, on average, have 40 percent smaller internal carotid arteries than men.”
But they also noted that women in the CREST study were more likely than men to be hypertensive and they had a higher mean systolic blood pressure, lower mean diastolic blood pressure, and lower weight than men. And they pointed out that among those patients who got stenting, the lesion length was shorter for women than men.
Dr. Howard said her group is now analyzing angiograms taken as part of the CREST study to see what more might be gleaned from lesion size and anatomical features.
“We need to look at the angiograms of women who had stroke and women who didn't have strokes,” she said. She said the CREST trial underscores the importance of having both men and women well represented in clinical trails.
Several independent stroke experts and an editorial accompanying the study — by Martin M. Brown, MD, professor of stroke medicine at the Institute of Neurology, and Rosalind Raine, MBBS, PhD, professor of health services research, both of the University College London in England — urged caution in jumping to conclusions, however.
Although the investigators did find a significantly higher risk of stroke in women after stenting, they wrote “the test for a treatment-by-sex interaction was not statistically significant for this outcome — i.e., the relative difference in risk between stenting and endarterectomy in women was not statistically different to the relative difference in risk in men.”
They noted that “although the higher rate of periprocedural stroke in women who underwent stenting compared with those who had endarterectomy reached a conventional level of significance (p=0.013), this might still be a chance finding given that many different statistical comparisons were made. Moreover, the result is not consistent with other trial data.”
For instance, the editorialists wrote, in the Carotid Stenting Trialists' Collaboration analysis of individual data from three European-based randomized trials of carotid artery stenting versus carotid endarterectomy, risks of any stroke or death after carotid artery stenting were found to be 8.5 percent in women and 9 percent in men and there was a lower carotid artery stenting to carotid endarterectomy risk ratio in women than men (1.22 versus 1.68).
“We did a meta-analysis of available data on the risk of treatment according to sex from the randomized trials, the findings of which are consistent with there being no real effect of sex on the risks of either treatment,” the editorialists wrote. They added that symptomatic status may be a much more powerful determinant of risk of treatment than sex.
Cheryl Bushnell, MD, associate professor of neurology and director of the Primary Stroke Center at Wake Forest Baptist Medical Center, said she was also surprised by these latest findings. She said they will make her “pause a little bit more and have the discussion with patients that says, ‘This is a large trial and it found that there's a higher rate of early complications for women who get stenting, particularly when it came to stroke.’”
DR. ADNAN I. QURESHI: “Every time you do a subgroup analysis you're always at risk that you have an underpowered study and you might be unable to balance the confounders.”
At the same time, however, she said more research was needed to sort out which patients — whether men or women — would benefit from which approach, including medical management of disease.
“These are high-risk patients, period, and we need to be able to maximize the benefits of therapy,” she told Neurology Today.
Adnan I. Qureshi, MD, professor of neurology, neurosurgery and radiology at the Zeenat Qureshi Stroke Center at the University of Minnesota, who was not involved with the study, said the finding of a sex difference should not be taken simply on face value. He noted that other factors, such as high blood pressure, diabetes, and cholesterol might be at play.
“Every time you do a subgroup analysis you're always at risk that you have an underpowered study and you might be unable to balance the confounders,” he said.
Still, he said it's important to do subgroup analyses to tease out factors such as gender and race that might impact the course of treatment.
The Lancet Neurology study was funded by the NINDS with supplemental funding provided by Abbott Vascular Solutions (formerly Guidant).
The CREST study was carried out at 117 medical centers in the US and Canada between December 2000 and July 2008. It included 2,502 patients who were randomly assigned to carotid endarterectomy or carotid stenting. The study participants included both asymptomatic patients and those who had had a stroke or transient ischemic attack within 180 days of enrolling in the study.
The primary endpoint for the original CREST trial was the composite rate of stroke, myocardial infarction, or death during the periprocedural period; or ipsilateral stroke within four years of randomization. The study was funded by the NINDS with supplemental funding provided by Abbott Vascular Solutions (formerly Guidant).
Howard VJ, Lutsep HL, Brott TG, et al, for the CREST Investigators. Influence of sex on outcomes of stenting versus endarterectomy: A subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). 2011; 10(6):530–537.