This is all because we have NO STROKE LEADERSHIP, thus allowing researchers to willy nilly choose their research topics, rather than following a set stroke strategy. We need survivors in charge, incompetence in stroke has existed for decades, we can't allow it to exist any longer.
Why Stroke Disparities Exist Among Men and Women Here's What Researchers Can Do About It
By Stephanie Cajigal
March 4, 2021
Article In Brief
Research suggests the global burden of stroke disproportionately affects women, but women are far less likely than men to participate in clinical stroke trials. Stroke experts say these data may help neurologists counsel and treat patients, but too many studies produce results that aren't generalizable to women because they lack female participants.
Women tend to have tougher recoveries after stroke and more women than men die from stroke, past research has shown. But experts say a dearth of studies look at why these disparities in outcomes exist.
A collection of papers in a special themed issue on women and stroke in the February issue of the journal Stroke looked at these differences from different perspectives—from the impact of aging on risk, the limitations of findings that don't generalize to women, to the under-enrollment of women in clinical trials.
In one study, researchers who followed more than 9.2 million Canadian adults for a median of 15 years reported that the women had a lower overall hazard of stroke or transient ischemic attack (TIA) than men (HR 0.82, 0.82-0.83), but this risk varied across women's lifespans. Women ages 30 and under, for example, were 26 percent more likely than men to have a stroke (HR 1.26, 1.10-1.45). But for women ages 30 to 39 the risk was similar to that of men (HR 1.00, 0.94-1.06). And between the ages of 40 to 80, the hazard was lower for women. At ages 80 and up, women's stroke risk was again similar to men their age (HR 0.99, 0.98-1.01).
“Women above 80 are a growing portion of the population. It would be a shame to invest in a trial and exclude them. We should remove as many barriers as possible, making trials as diverse as possible.”—DR. SEEMANT CHATURVEDI
These findings may help neurologists counsel and treat patients, stroke neurologists told Neurology Today. But too many studies produce results that aren't generalizable to women because they lack female participants, according to a commentary published in the same issue of Stroke.
The commentary summarized an analysis of stroke clinical trials originally presented at the European Stroke Organization-World Stroke Organization 2020 virtual conference, which found that only 40 percent of trial participants are women. It cited another meta-analysis of 61 stroke trials, which reported that women are under-represented in trials by an average of 7 percentage points.
The study authors, Cheryl Carcel, MD, PhD, of the University of New South Wales in Sydney, Australia, and Mathew Reeves, BVSc, PhD, of Michigan State University in East Lansing, suggest that among strategies to increase enrollment, researchers could conduct qualitative studies to understand why women may not enroll, remove age-based criteria (specifically not excluding patients older than 80), and increase the number of women who are principal investigators.
Another analysis suggests disparities by stroke interventions. The paper combined data from four trials that investigated outcomes for carotid endarterectomy versus stenting. The investigators aimed to look for sex differences in the risk for any stroke or death within 120 days after these procedures as well as the risk for ipsilateral stroke after that period. Individually, the studies showed some difference in outcomes for women versus men, but “the outcome was significantly lower for women compared to men in one trial, nominally lower in another, and nominally higher in the other two,” according to the authors. When researchers pooled the data, they found no significant differences in risk.
Lead author Virginia Howard, PhD, distinguished professor of epidemiology at the University of Alabama at Birmingham School of Public Health, said that if the trials had enrolled more women, they might have had more statistical power to find significant differences in outcomes by sex.
“If we really want to know answers as they relate to comparing results between men and women, we need to power trials to enroll sufficient numbers of men and women and look at exclusion criteria that may contribute to differential enrollment by sex,” she said.
Consider Risk Factors Unique to Women
So, too, neurologists told Neurology Today, should researchers look at the reasons why the outcomes may differ. Numerous studies show women recover less from stroke than men and there may be multiple reasons for this, said Seemant Chaturvedi, MD, FAAN, FAHA, the Stewart J. Greenebaum Endowed Professor of Stroke Neurology and vice-chair for strategic operations within the department of neurology at the University of Maryland School of Medicine.
“On the whole, women tend to be older at the time of stroke, and because of that have an increasing number of comorbidities,” he said. “In some studies, women have shown to have higher rates of cognitive impairment at the time of stroke. Another factor relates to social support. If a woman is older, her spouse may have passed away and may have less social support when recovering from stroke.”
Louise D. McCullough, MD, PhD, the Roy M. And Phyllis Gough Huffington Distinguished Chair of Neurology at the University of Texas McGovern Medical School in Houston, Texas, agrees that because women tend to be older when they have a stroke, they experience more stroke-related disability. In addition, many women ages 75 and up have strokes related to atrial fibrillation and these strokes tend to be larger than strokes related to atherosclerosis, she explained. Clinical trials should carefully record women's pre-stroke functional status to better measure their outcomes, said Dr. McCullough.
“It's really difficult to assess sex differences in stroke unless you look at the entire picture. If a woman is 95, she is going to have more comorbidities, be frailer, and have worse outcomes. Women are also more socially isolated and have higher rates of depression. Once we correct for age, depression, pre-stroke disability, and living environment, women may even have better outcomes than men,” she said.
Certain drugs may benefit women more than men, Dr. McCullough said, citing a study showing a therapy for heart failure only benefited women and had no effect on men. “We have to look at sex differences in biology and ischemic pathways to make sure we are targeting the right thing. We may need to develop therapies that have different targets based on age or sex,” she said.
Dr. Chaturvedi said more studies should be devoted to studying treatments in women. “Some primary care physicians hesitate to use anticoagulants in older women because of fear of bleeding. It would be good to know how using a low-dose anticoagulant [in this population] compares to using a higher dose anticoagulant,” he said. The field also needs more data on how women with carotid stenosis do with surgery versus intensive medical treatment, he said.
Steven R. Messé, MD, FAAN, FAHA, professor of neurology at the Hospital of the University of Pennsylvania, some evidence, including a study published in 2016 that he authored, showed that women who present with acute ischemic stroke are slightly less likely than men to get IV tissue plasminogen activator (tPA).
“The toughest questions are why there are differences in treatment? Is it due to implicit biases that doctors carry with them when they talk to women as opposed to men? Is it that women don't present the same way? Is it because they refuse treatment more? Many of those things if not all of them may be involved,” he said.
According to Dr. Chaturvedi, researchers should also scrutinize exclusion criteria and consider whether turning away stroke patients who are 80 or older is necessary. “Women above 80 are a growing portion of the population,” he said. “It would be a shame to invest in a trial and exclude them. We should remove as many barriers as possible, making trials as diverse as possible.”
Focus on Recruitment
Are women underrepresented in clinical trials because of their reluctance to participate or because of systemic issues? Neurologists say it could be a little bit of both.
“One of the innovations was to use home visits to bring the study to people in the community if they had difficulty coming to our offices during customary work hours.”DR. PHILIP B. GORELICK
“We should do focus groups to understand why women who were offered enrollment didnt choose to participate. Some of this may be due to trial design, like excluding patients over 80, but some of it may be women themselves. These are two different things requiring different approaches: One is patient education and one is physician education. Both can be hard.”—DR. LOUISE D. MCCULLOUGH
Dr. Chaturvedi, for example, said some studies show women are more likely to decline treatments that are invasive. “I've been involved in trials comparing surgery to treatment. If given the choice, women would prefer medical treatment rather than invasive procedures,” Dr. Chaturvedi said.
When recruiting women for an invasive arm of a study, Dr. Chaturvedi makes the extra effort to provide them with information about the study, including explanatory videos. Having other study participants speak with potential study patients and explain what it's like to be part of the study may be helpful, he said.
“It gives them an understanding of what is involved with the study visits and the burden of being in the study. In some cases, it may not feel like not a burden because they may have closer monitoring of their blood pressure, cholesterol, and other risk factors,” Dr. Chaturvedi said.
It is possible women are not asked to participate in trials as often as are men. Dr. Messé and colleagues conducted a study published in 2009 that surveyed patients with acute stroke or their proxy decision-makers about their willingness to participate in a treatment trial. Overall, 57 percent of respondents said they would participate in the trial described to them. The researchers didn't find any differences in responses with respect to sex.
Dr. McCullough said she agrees with Drs. Carcel and Reeves, the authors of the Stroke commentary, that qualitative studies would shed light on why women are under-enrolled in trials.
“We should do focus groups to understand why women who were offered enrollment didn't choose to participate. Some of this may be due to trial design, like excluding patients over 80, but some of it may be women themselves. These are two different things requiring different approaches: One is patient education and one is physician education. Both can be hard,” she said.
Dr. Chaturvedi contends that researchers should monitor the percentage of women enrolled as a trial is progressing and try different tactics to boost their enrollment as needed. Primary care providers, for example, could help with recruitment.
“Primary care providers can try to make some extra effort to know about some of the key trials that are applicable to their patient population and refer them to those studies,” he said.
Philip B. Gorelick, MD, MPH, FAAN, adjunct professor of neurology at Northwestern University Feinberg School of Medicine, said he sees parallels between what Drs. Carcel and Reeves propose in their commentary and how he and colleagues recruited patients for the African-American Antiplatelet Stroke Prevention Study published in 2003. The trial involved more than 60 sites that compared the efficacy and safety of ticlopidine versus aspirin in preventing recurrent stroke, myocardial infarction, and vascular death in African-Americans with recent, noncardioembolic ischemic stroke. Slightly more than half of the 1,809 participants were women.
Dr. Gorelick said that prior to the study, researchers conducted a survey to learn why people would or would not participate in the trial if asked. Respondents lacked awareness of clinical trials and indicated there were economic factors that made it difficult for them to participate. The survey also uncovered communication barriers and a general mistrust of clinicians and researchers.
Dr. Gorelick said he and his team spent months building support from organizations within Chicago and elsewhere, including churches, health associations, and women's organizations, which in turn helped with recruitment.
“One of the innovations was to use home visits to bring the study to people in the community if they had difficulty coming to our offices during customary work hours,” Dr. Gorelick explained. Going forward, he suggested investigators consider making it easier for women or anyone, to participate in trials by replacing some in-person check ins with virtual visits.
“If we really want to know answers as they relate to comparing results between men and women, we need to power trials to enroll sufficient numbers of men and women and look at exclusion criteria that may contribute to differential enrollment by sex.”—DR. VIRGINIA HOWARD
“I think a big take-home point is to ensure that we are as aggressive in treating women as men because there is now overwhelming data showing that women benefit from revascularization strategies as much, if not more, than men.”—DR. STACIE DEMEL
What Clinicians Can Do
“Women may have unique risk factors because of biological reasons, but there is one thing we can do: Be more proactive in identifying atrial fibrillation and treating it. Anticoagulant medications are very effective in preventing stroke in patients with A-fib,” said Dr. Chaturvedi. He noted that some studies show only 40 percent of patients who would be good candidates for anticoagulants are actually receiving them.
And while neurologists can't do anything about the fact that women are older at the time of stroke, they can help women access services to maximize their recovery. “Social isolation is not good for stroke survivors. Refer them to stroke support groups,” Dr. Chaturvedi said.
Dr. Gorelick recommends setting up a good rehabilitation support system for stroke survivors and connecting them with organizations such as the American Heart Association and AAN for additional education and resources.
“I think a big take-home point is to ensure that we are as aggressive in treating women as men because there is now overwhelming data showing that women benefit from revascularization strategies as much, if not more, than men,” said Stacie Demel, DO, PhD, assistant professor of neurology at the University of Cincinnati College of Medicine. Recent studies show women with acute ischemic stroke enter hospitals with higher baseline disability but have lower in-hospital mortality as compared with men, she said.
“It's sex and age. Those two concepts can't be completely disentangled, and there is a lot of implicit bias even among providers,” Dr. McCullough said. It doesn't help that many trials exclude patients with pre-stroke Modified Rankin scores of three or greater, which disqualifies many elderly women.
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