World Stroke Organization The Paper of the Month – March
19 Mar 2024Stroke in women: what's new on the horizon?
Stroke in women: what’s new on the horizon?
Author: Prof. Dr. Anita Arsovska – WSA Associate Commissioning Editor
This article is a commentary on the following: Bushnell C. Stroke in Women: Research Accomplishments and Remaining Gaps. Stroke. 2024 Feb;55(2):467-70
Summary of the findings
Since the first guidelines for stroke prevention in women were published in 2014, multiple studieshave shed light onthe relationship between blood pressure (BP) and adverse maternal outcomes.A systematic review and meta-analysis of 12studies concluded that measuring BP at every prenatal visit isessential because there is no BP cutoff that could ruleout adverse pregnancy outcomes (APOs). Only the BPthreshold of ≥140/90 mm Hg can be used to rule in ahigh likelihood of preeclampsia and stroke.A recent scientific statement from the AmericanHeart Association found that APOs with the strongest associationand the highest strength of evidence with mortalityand CVD outcomes are hypertensive disorders of pregnancy,gestational diabetes, preterm delivery, small forgestational age, placental abruption, and miscarriage/stillbirths. The INSTRUCT study (International Stroke Outcomes Study) analyzed stroke outcomes related to differences and showed that the crude pooled mortality was higher for women at 1 year (mortality risk ratio, 1.35[95% CI, 1.24–1.47]) and 5 years (mortality risk ratio,1.24 [95% CI, 1.12–1.38]) compared to men. After adjustment for confounding factors that included age, prestrokefunction, stroke severity, and history of atrial fibrillation,the pooled sex differences reversed for women (mortalityrisk ratios of 0.81 at 1 year and 0.76 at 5 years). The underrepresentation of women in clinical trials of stroke treatment, prevention, and recovery may affect the estimates and eventually the generalizability of the trial results to the population. Understanding the barriers to participation in stroke trials in women and men is critical. Ideally, clinical practice and research on stroke risk factors, prevention, and outcomes will continue to build on the groundwork from these important studies for decades to come.
Commentary
Women are disproportionately and more adversely affected by stroke than men. Stroke is the 5th leading cause of death for men and the 3rd leading cause for women (2). Women live longer than men.By 2030, there will be 72 million people >65 years old (19% of the population), and women will increasingly outnumber men. Lifetime risk of stroke in people aged 55-75 years is higher in women (20%) than men (17%). Women are more likely to live alone and widowed before stroke, more often institutionalized after stroke and have poorer recovery from stroke than men (2). Due to biological characteristics and female-specific risk factors, females not only have a higher risk of stroke, but also a higher chance of experiencing recurrence and higher severity of stroke symptoms than that of males (3, 4, 5).
Recently published papers have highlighted several important issues regarding the specifics in stroke in women.
- Sex differences in traditional and sex specific stroke risk factors
A recent review has focused on addressing sex differences in both traditional and sex-specific stroke risk factors (6). The results showed that women are at increased risk for stroke from both traditional and non-traditional stroke risk factors. On delving deep into risk factors, in the INTERSTROKE study, hypertension (population attributable risk (PAR) = 52.3 %), waist-to-hip ratio (PAR = 25.8 %), and adverse lipid profile (PAR = 29.2 %) were the most impactful risk factors for stroke in women whereas smoking (PAR = 5.3 %) and cardiac causes (PAR = 11.1 %) were not as frequent (7).As women age, they have a higher disease burden of atrial fibrillation, increased risk of stroke related to diabetes, worsening lipid profiles, and higher prevalence of hypertension and obesity compared to men. Further, women carry sex hormone-specific risk factors for stroke, including the age of menarche, menopause, pregnancy, and its complications, as well as hormonal therapy. Men have a higher prevalence of tobacco use and atrial fibrillation, as well as an increased risk for stroke related to hyperlipidemia. Additionally, men have sex-specific risks related to low testosterone levels.
- Acute myocardial infarction and stroke
Another paper prospectively screened consecutive patients with acute ischemic stroke and serial high‐sensitivity cardiac troponin T measurements (8). Of 1067 patients included, 494 were women (46%). Women were older, were more likely to have a higher rate of known atrial fibrillation, to be functionally dependent before admission, have higher stroke severity, and more often had cardioembolic strokes (all P values <0.05). The crude prevalence of acute myocardial injury differed by sex (29% women versus 23% men, P=0.024). Significant associations between acute myocardial injury and outcomes were observed in women (7‐day in‐hospital mortality: adjusted odds ratio [aOR], 3.2 [95% CI, 1.07–9.3]; in‐hospital mortality: aOR, 3.3 [95% CI, 1.4–7.6]; modified Rankin Scale score at discharge: aOR, 1.6 [95% CI, 1.1–2.4]) but not in men. The implementation of sex‐specific cutoffs did not increase the prognostic value of acute myocardial injury for unfavorable outcomes. The authors concluded that the prevalence of acute myocardial injury after ischemic stroke and its association with mortality and greater disability might be sex‐dependent.
- Vascular risk factors and stroke
Remfry et al. examined sex-based differences in associations of vascular risk factors with incident cardiovascular events in the UK Biobank (9). Among the 363 313 participants (53.5% women), 8470 experienced MI (29.9% women) and 7705 experienced stroke (40.1% women) over 12.66 [11.93, 13.38] years of prospective follow-up. Men had greater risk factor burden and higher arterial stiffness index at baseline. Women had greater age-related decline in aortic distensibility. Older age [RHR: 1.02 (1.01–1.03)], greater deprivation [RHR: 1.02 (1.00–1.03)], hypertension [RHR: 1.14 (1.02–1.27)], and current smoking [RHR: 1.45 (1.27–1.66)] were associated with a greater excess risk of MI in women than men. Low-density lipoprotein cholesterol was associated with excess MI risk in men [RHR: 0.90 (0.84–0.95)] and apolipoprotein A (ApoA) was less protective for MI in women [RHR: 1.65 (1.01–2.71)]. Older age was associated with excess risk of stroke [RHR: 1.01 (1.00–1.02)] and ApoA was less protective for stroke in women [RHR: 2.55 (1.58–4.14)].The conclusion was that older age, hypertension, and smoking appeared stronger drivers of cardiovascular disease in women, whereas lipid metrics appeared stronger risk determinants for men.
Buhari et al. described the sex differences in age and cardiovascular care to examine their relationship with stroke hazard in AF (10). Their cohort consisted of 354 254 individuals with AF (median age 78 years, 49.2% female). Females were more likely to be diagnosed in emergency departments and less likely to receive cardiologist assessments, statins, or LDL-C testing, with higher LDL-C levels among females than males. The adjusted HR for stroke associated with female sex was 1.27 (95% confidence interval 1.21–1.32). A significant age–sex interaction was revealed, such that female sex was only associated with increased stroke hazard at age >70 years. Adjusting for markers of cardiovascular care and multimorbidity further decreased the HR, so that female sex was not associated with increased stroke hazard at age ≤80 years. They concluded that older age and inequities in cardiovascular care may partly explain higher stroke rates in females with AF.
- Endometriosis and stroke
A recently published paper hypothesized that the expression level of Tissue Factor (TF) and microRNA126 (miR-126) may play a role in the susceptibility of women with endometriosis to develop a stroke (11) Women with laparoscopically confirmed endometriosis had a 34 % greater risk of stroke than those without endometriosis (11). Of the total association of endometriosis with risk of stroke, the largest proportion has been related to hysterectomy/oophorectomy (11)). No differences were observed in the association between endometriosis and stroke by age, infertility, history, body mass index, or menopausal status. The author hypothesized that women with endometriosis may be at a higher risk of stroke than those without endometriosis as a result of TF upregulation and miR-126 downregulation, both conditions connected with endometriosis pathogenesis (11). The risk of stroke may become more strident after hysterectomy/oophorectomy occurrence, because surgery appears to further increase TF expression.
- Sexual dysfunction in female individuals living with stroke
Latella et al. conducted a scoping review to better investigate the hot topic of sexual functioning of female stroke survivors (12). Current data indicated substantial connections between stroke and female sexual dysfunction (SD), including factors like desire/libido, sexual satisfaction, and sexual intercourse. Some intervention programs have been created to provide specific guidance to healthcare professionals in addressing patients’ requirements for sexual recovery, although their adequacy remains uncertain. However, to date, there are neither specific rehabilitation programs for post-stroke female SD nor healthcare personnel trained to deal with post-stroke sexual issues adequately and efficiently. The incorporation of sexual rehabilitation into the overall rehabilitation process for stroke patients is crucial, ideally within an interdisciplinary framework. Despite being a fundamental aspect of post-stroke women’s lives, sexuality remains underinvestigated and underdisclosed.
- American Heart Association and Go Red for Women month
For many years, the American Heart Association has emphasized the importance of understanding sex‐related differences in cardiovascular disease and stroke (13). During Go Red for Women month, the goal is to increase public awareness and knowledge of the impact of cardiovascular disease among women as well as highlight important scientific findings regarding sex‐specific epidemiology, risk factors, and outcomes in cardiovascular disease and stroke. In this issue of the Journal of the American Heart Association (JAHA), 15 articles, including 12 original research articles, 1 systematic review, and 2 editorials are featured.
Conclusion
Women across the life span have been underrepresented or excluded fromstroke clinical trials and research, not only because of age and comorbidities but also due to pregnancy/puerperium/breasfeeding. Systematic study of stroke risk and outcomes in women is paramount, and publications are starting to provide some insights into the complexities of preventing stroke and optimizing outcomes in this population. These advances could be used to improve trial design and participation of women, thereby enhancing the generalizability of studies focused on stroke treatment, prevention, and recovery (1).
References
- Bushnell C. Stroke in Women: Research Accomplishments and Remaining Gaps. Stroke. 2024 Feb;55(2):467-70.
- Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL, Howard VJ, Lichtman JH, Lisabeth LD, Piña IL, et al; American Heart Association Stroke Council. Guidelines for the prevention of stroke in women:a statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2014;45:1545–1588. doi:10.1161/01.str.0000442009.06663.48
- Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, De Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. circulation. 2017 Mar 7;135(10):e146-603.
- Basu E, Salehi Omran S, Kamel H, Parikh NS. Sex differences in the risk of recurrent ischemic stroke after ischemic stroke and transient ischemic attack. European Stroke Journal. 2021 Dec;6(4):367-73.
- Ekker MS, de Leeuw FE. Higher incidence of ischemic stroke in young women than in young men: mind the gap. Stroke. 2020 Nov;51(11):3195-6.
- Hanna M, Wabnitz A, Grewal P. Sex and Stroke Risk Factors: A Review of Differences and Impact. Journal of Stroke and Cerebrovascular Diseases. 2024 Feb 3:107624.
- O’Donnell MJ, Chin SL, Rangarajan S, Xavier D, Liu L, Zhang H, Rao-Melacini P, Zhang X, Pais P, Agapay S, Lopez-Jaramillo P. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. The lancet. 2016 Aug 20;388(10046):761-75.
- Sur NB, Kozberg M, Desvigne-Nickens P, Silversides C, Bushnell C. Improving stroke risk factor management focusing on health disparities and knowledge gaps. Stroke. 2024 Jan;55(1):248-58.
- Remfry E, Ardissino M, McCracken C, Szabo L, Neubauer S, Harvey NC, Mamas MA, Robson J, Petersen SE, Raisi-Estabragh Z. Sex-based differences in risk factors for incident myocardial infarction and stroke in the UK Biobank. European Heart Journal-Quality of Care and Clinical Outcomes. 2024 Mar;10(2):132-42.
- Buhari H, Fang J, Han L, Austin PC, Dorian P, Jackevicius CA, Yu AY, Kapral MK, Singh SM, Tu K, Ko DT. Stroke risk in women with atrial fibrillation. European Heart Journal. 2024 Jan 7;45(2):104-13.
- Mormile R. Potential hypothesis for the increased risk of stroke in women with endometriosis. European Journal of Obstetrics and Gynecology and Reproductive Biology. 2024 Jan 1;292:270.
- Latella D, Grimaldi A, Calabrò RS. Sexual Functioning and Sexual Health in Female Patients following Stroke: A Scoping Review with Implications for Rehabilitation. Journal of Personalized Medicine. 2024 Feb 29;14(3):267.
- Mujahid MS, Peterson PN. JAHA Go Red for Women Spotlight on Women and Cardiovascular Disease and Stroke. Journal of the American Heart Association. 2024 Feb 27:e035104.
Interview to Prof. Cheryl Bushnell
1. What did you set out to study?
I was asked to write a review for the Centennial issue of Stroke, and summarize the most important updates in the past 10 years.
2. Why this topic?
As the Stroke Section Co-editor for Stroke in Women, this is a topic I know well and try to keep up with the literature. I decided to focus on 1) a summary of the Women’s Health Initiative (WHI) trial results because this drives many of the meta-analyses cumulative results related to hormone therapy and stroke risk; 2) comorbidities that drive stroke outcomes in women, and 3) stroke clinical trials and how women have been historically under-represented.
3. What were the key findings?
To summarize the WHI trial outcomes from on-study and post-intervention, it is important to understand that differences in outcomes exist for women taking estrogen alone (conjugated equine estrogen or CEE for women post-hysterectomy/oophorectomy) or estrogen plus medroxyprogesterone (CEE/MPA for women with a uterus). There were differences in the comorbidities of women in each trial which could have impacted the outcomes. For example, women in the CEE-alone trial had worse cardiovascular profiles and were more racially diverse. Interestingly, the CEE-alone trial was stopped early because of the stroke incidence whereas the CEE/MPA trial was stopped because of increased risk of breast cancer and the overall risk/benefit profile for all outcomes. I also summarized a decade worth of data on stroke risk and adverse pregnancy outcomes, which has provided a wealth of information for practitioners to consider in their daily practices for their women patients. Women also need to be educated so they can manage their own risks. Lastly, much needs to be done to increase representation of women in clinical trials, including examining screening logs to determine the characteristics of women who decline, but also adapt study designs and protocols to allow more women to participate. One example is to increase the age cutoff for participation, since women are older at the time of stroke.
4. Why is it important? Or how might these results impact clinical practice?
These results have already impacted clinical practice, especially the results of the WHI. However, hopefully, the message for women with adverse pregnancy outcomes and the need to mitigate cardiovascular risk will become incorporated into primary care, cardiology, neurology, and Ob/Gyn practices. Women need to understand their risk and once child bearing years are over, many may not realize the early events that can impact long-term risk of stroke.
5. What surprised you most?
This field is evolving quickly, with an explosion of literature on the topic of stroke in women and sex differences. We need to continue to study these areas and sift through a lot of information to keep up.
6. What’s next for this research?
Many brilliant neurologists, internists cardiologists, and epidemiologists are studying these issues in women. I also believe scientific statements and guidelines are providing and will continue to provide practical changes to best practices that can improve the care of women and prevent future stroke, as well as improve outcomes.
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