The Impact of Sex and Gender on Stroke.

Women face a disproportionate burden of stroke mortality and disability. Biologic sex and sociocultural gender both contribute to differences in stroke risk factors, assessment, treatment, and outcomes. There are substantial differences in the strength of association of stroke risk factors, as well as female-specific risk factors. Moreover, there are differences in presentation, response to treatment, and stroke outcomes in women. This review outlines current knowledge of impact of sex and gender on stroke, as well as delineates research gaps and areas for future inquiry.

Sex and gender publications in brain health: a mapping review of the Asia-Pacific region.

INTRODUCTION: Reporting of sex and gender analysis in medical research has been shown to improve quality of the science and ensures findings are applicable to women and men. There is conflicting evidence on whether efforts by funding agencies and medical journals to encourage reporting of sex and gender analysis has resulted in tangible improvements. This study mapped the inclusion of sex and gender analysis in stroke and dementia research conducted in the Asia-Pacific region. METHODS: A systematic search for Asia-Pacific stroke and dementia research was conducted in PubMed and papers included from the period 2012 to 2022. Eligible studies were reviewed for inclusion of a primary sex or gender focus and categorized by type of sex and gender analysis. Author gender was determined using an algorithm and its associations with inclusion of sex and gender analysis examined. RESULTS: Total Asia-Pacific publications increased from 109 in 2012 to 313 in 2022, but the rate of studies with a primary sex or gender focus did not increase significantly (R2 = 0.06, F(1,9) = 0.59, p = 0.46). Australia, China, India, Japan and South Korea produced the most publications over the study period and were the only countries with at least 50 publications. The impact of author gender was mixed, with female first authorship associated with inclusion of sex or gender analysis and last female authorship associated with studies having a primary sex or gender focus. CONCLUSIONS: In the Asia-Pacific, brain health research is currently centered around high income countries and efforts are needed to ensure research findings are applicable through out the region. While there was a general increase in brain health publications over the last decade, the rate of sex and gender analysis was unchanged. This demonstrates that even with efforts in some countries in place, there is currently a lack of progress in the Asia-Pacific region to produce more research focusing on sex and gender analysis.

The effect of blood pressure lowering medications on the prevention of episodic migraine: A systematic review and meta-analysis.

BACKGROUND: Currently, only a few specific blood pressure-lowering medications are recommended for migraine prevention. Whether benefits extend to other classes or drugs is uncertain. METHODS: Embase, MEDLINE, and the Cochrane Central Registry of Controlled Trials were searched for randomized control trials on the effect of blood pressure-lowering medications compared with placebo in participants with episodic migraine. Data were collected on four outcomes - monthly headache or migraine days, and monthly headache or migraine attacks, with a standardised mean difference calculated for overall. Random effect meta-analysis was performed. RESULTS: In total, 50 trials (70% of which were crossover) were included, comprising 60 comparisons. Overall mean age was 39 years, and 79% were female. Monthly headache days were fewer in all classes compared to placebo, and this was statistically significant for all but one class: alpha-blockers -0.7 (95% CI: -1.2, -0.1), angiotensin-converting enzyme inhibitors -1.3 (95% CI: -2.9, 0.2), angiotensin II receptor blockers -0.9 (-1.6, -0.1), beta-blocker -0.4 (-0.8, -0.0) and calcium channel blockers -1.8 (-3.4, -0.2). Standardised mean difference was significantly reduced for all drug classes and was separately significant for numerous specific drugs: clonidine, candesartan, atenolol, bisoprolol, metoprolol, propranolol, timolol, nicardipine and verapamil. CONCLUSION: Among people with episodic migraine, a broader number of blood pressure-lowering medication classes and drugs reduce headache frequency than those currently included in treatment guidelines.Trial Registration: The study was registered at PROSPERO (CRD42017079176).

Blood Pressure and Stroke: A Review of Sex- and Ethnic/Racial-Specific Attributes to the Epidemiology, Pathophysiology, and Management of Raised Blood Pressure.

Raised blood pressure (BP) is the leading cause of death and disability worldwide, and its particular strong association with stroke is well established. Although systolic BP increases with age in both sexes, raised BP is more prevalent in males in early adulthood, overtaken by females at middle age, consistently across all ethnicities/races. However, there are clear regional differences on when females overtake males. Higher BP among males is observed until the seventh decade of life in high-income countries, compared with almost 3 decades earlier in low- and middle-income countries. Females and males tend to have different cardiovascular disease risk profiles, and many lifestyles also influence BP and cardiovascular disease in a sex-specific manner. Although no hypertension guidelines distinguish between sexes in BP thresholds to define or treat hypertension, observational evidence suggests that in terms of stroke risk, females would benefit from lower BP thresholds to the magnitude of 10 to 20 mm Hg. More randomized evidence is needed to determine if females have greater cardiovascular benefits from lowering BP and whether optimal BP is lower in females. Since 1990, the number of people with hypertension worldwide has doubled, with most of the increase occurring in low- and-middle-income countries where the greatest population growth was also seen. Sub-Saharan Africa, Oceania, and South Asia have the lowest detection, treatment, and control rates. High BP has a more significant effect on the burden of stroke among Black and Asian individuals than Whites, possibly attributable to differences in lifestyle, socioeconomic status, and health system resources. Although pharmacological therapy is recommended differently in local guidelines, recommendations on lifestyle modification are often very similar (salt restriction, increased potassium intake, reducing weight and alcohol, smoking cessation). This overall enhanced understanding of the sex- and ethnic/racial-specific attributes to BP motivates further scientific discovery to develop more effective prevention and treatment strategies to prevent stroke in high-risk populations.

Gender Equity in Leadership and Conferences of the Stroke Society of Australasia.

INTRODUCTION AND AIM: Internationally, women are underrepresented as leaders in major scientific organizations and conferences. We aimed to determine gender differences in leadership roles and annual scientific conferences of the Stroke Society of Australasia (SSA). METHODS: In a retrospective review of SSA data (2014-2019), committee members were obtained through the SSA Web site, and moderators, speakers, and award recipients were identified from SSA annual scientific conference programs. Gender was determined by name inspection and Web search. Absolute numbers and proportions of women and men were recorded for all roles examined, overall and per year. Associations between representation of women in conferences and percentage of women in speaking roles were tested using multinomial regression. RESULTS: Presidential leadership of the SSA was held by men in 2014-2016 and 2019 and women in 2017-2018. SSA committee membership was predominantly women (55%), being lowest (47%) in 2014 and 2019 and highest (65%) in 2017. There was a wide gender variation at scientific conferences, with 41% of keynote speakers being women overall, from 20% in 2016 to 75% in 2015. From 2014 to 2019, 55% of all speakers were women, ranging from 32% (in 2016) to 71% (in 2015). A higher percentage of women as speakers or moderators was associated with a program committee with over a third of its members composed of women (p ≤ 0.044). CONCLUSIONS: Representation of women varied from 2014 to 2019 in the SSA organization and its conferences, although men are more often elected president in the organization and women are less often keynote speakers. When more women were included in the program committee, the representation of women as speakers increased.

Differences in the pre-hospital management of women and men with stroke by emergency medical services in New South Wales.

OBJECTIVES: To examine whether pre-hospital emergency medical service care differs for women and men subsequently admitted to hospital with stroke. DESIGN, SETTING, PARTICIPANTS: Population-based cohort study; analysis of linked Admitted Patient Data Collection and NSW Ambulance data for people admitted to New South Wales hospitals with a principal diagnosis of stroke at separation, 1 July 2005 - 31 December 2018. MAIN OUTCOME MEASURES: Emergency medical service assessments, protocols, and management for patients subsequently diagnosed with stroke, by sex. RESULTS: Of 202 231 people hospitalised with stroke (mean age, 73 [SD, 14] years; 98 599 women [51.0%]), 101 357 were conveyed to hospital by ambulance (50.1%). A larger proportion of women than men travelled by ambulance (52.4% v 47.9%; odds ratio [OR], 1.09; 95% CI, 1.07-1.11), but time between the emergency call and emergency department admission was similar for both sexes. The likelihood of being assessed as having a stroke (adjusted OR [aOR], 0.97; 95% CI, 0.93-1.01) or subarachnoid haemorrhage (aOR, 1.22; 95% CI, 0.73-2.03) was similar for women and men, but women under 70 years of age were less likely than men to be assessed as having a stroke (aOR, 0.89; 95% CI, 0.82-0.97). Women were more likely than men to be assessed by paramedics as having migraine, other headache, anxiety, unconsciousness, hypertension, or nausea. Women were less likely than men to be managed according to the NSW Ambulance pre-hospital stroke care protocol (aOR, 0.95; 95% CI, 0.92-0.97), but the likelihood of basic pre-hospital care was similar for both sexes (aOR, 1.01; 95% CI, 0.99-1.04). CONCLUSION: Our large population-based study identified sex differences in pre-hospital management by emergency medical services of women and men admitted to hospital with stroke. Paramedics should receive training that improves the recognition of stroke symptoms in women.

Stroke care and collaborative academic research in Latin America.

OBJECTIVE: A narrative overview of regional academic research collaborations to address the increasing burden and gaps in care for patients at risk of, and who suffer from, stroke in Latin America (LA). MATERIALS AND METHODS: A summary of experiences and knowledge of the local situation is presented. No systematic literature review was performed. RESULTS: The rapidly increasing burden of stroke poses immense challenges in LA, where prevention and manage-ment strategies are highly uneven and inadequate. Clinical research is increasing through various academic consortia and networks formed to overcome structural, funding and skill barriers. However, strengthening the ability to generate, analyze and interpret randomized evidence is central to further develop effective therapies and healthcare systems in LA. CONCLUSIONS: Regional networks foster the conduct of multicenter studies -particularly randomized controlled trials-, even in resource-poor regions. They also contribute to the external validity of international studies and strengthen systems of care, clinical skills, critical thinking, and international knowledge exchange.

Under-Enrollment of Women in Stroke Clinical Trials: What Are the Causes and What Should Be Done About It?

The under-representation of women in clinical trials is a commonly recognized and seemingly intractable problem in many different areas of clinical medicine. Discrepancies in the enrollment of women in clinical trials raises concerns about the generalizability of trial evidence, as well as the potential for reduced access and utilization of new therapies in women. Recent studies confirm that the problem of under-enrollment of women continues to exist in stroke clinical trials, even after accounting for the sex ratio of stroke cases in the underlying population. The origins of these disparities are complex, and there remains a relative dearth of stroke studies that have examined the causes in detail. Although caution should be used when generalizing research findings from studies conducted in other medical conditions including cardiology trials, factors that contribute to lower enrollment in women include the use of specific trial eligibility criteria (eg, older age, presence of specific comorbidities), patient attitudes and beliefs (resulting in less interest and more refusals in women), and potentially implicit biases among study personnel. Beyond a general call to prioritize stroke research in this area, we also recommend the greater use of trial screening logs, the use of qualitative studies to understand patient attitudes and beliefs towards stroke research, avoiding the use of age-based exclusion criteria (eg, >80 years), and increasing the number of women who lead stroke clinical trials.

Sex matters in stroke: A review of recent evidence on the differences between women and men.

For the most part, stroke is a disease of old age. With the predicted increase in the aged population and longer life expectancies, the number and proportion of people living with stroke is expected to increase, especially among women and the elderly. For those who suffer stroke, there is a high likelihood of experiencing death and severe disability. Therefore, the issue of stroke amongst women (and men) is a key priority in global public health. In this review, we consider sex and gender differences in ischemic and hemorrhagic stroke, and we summarize data that outlines the epidemiology, risk factor, treatment recovery and prevention of stroke. We discuss possible mechanisms for the sex differences, specifically in areas of biology, medical management and social and behavioral context. With evidence showing that women and men experience stroke differently, sex must be taken into account when treating patients and when designing clinical trials.

Sex differences in emergency medical services management of patients with myocardial infarction: analysis of routinely collected data for over 110,000 patients.

Emergency medical services (EMS) activation is an integral component in managing individuals with myocardial infarction (MI). EMS play a crucial role in early MI symptom recognition, prompt transport to percutaneous coronary intervention centres and timely administration of management. The objective of this study was to examine sex differences in prehospital EMS care of patients hospitalized with Ml using data from a retrospective population-based cohort study of linked health administrative data for people with a hospital diagnosis of MI in Australia (2001-18).

Intensive versus guideline-recommended blood pressure reduction in acute lacunar stroke with intravenous thrombolysis therapy: The ENCHANTED trial.

BACKGROUND AND PURPOSE: This was an investigation of the differential effects of early intensive versus guideline-recommended blood pressure (BP) lowering between lacunar and non-lacunar acute ischaemic stroke (AIS) in the BP arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: In 1,632 participants classified as having definite or probable lacunar (n = 454 [27.8%]) or non-lacunar AIS according to pre-specified definitions based upon clinical and adjudicated imaging findings, mean BP changes over days 0-7 were plotted, and systolic BP differences by treatment between subgroups were estimated in generalized linear models. Logistic regression models were used to estimate the BP treatment effects on 90-day outcomes (primary, an ordinal shift of modified Rankin scale scores) across lacunar and non-lacunar AIS after adjustment for baseline covariables. RESULTS: Most baseline characteristics, acute BP and other management differed between lacunar and non-lacunar AIS, but mean systolic BP differences by treatment were comparable at each time point (all pinteraction  > 0.12) and over 24 h post-randomization (-5.5, 95% CI -6.5, -4.4 mmHg in lacunar AIS vs. -5.6, 95% CI -6.3, -4.8 mmHg in non-lacunar AIS, pinteraction  = 0.93). The neutral effect of intensive BP lowering on functional outcome and the beneficial effect on intracranial haemorrhage were similar for the two subgroups (all pinteraction  > 0.19). CONCLUSIONS: There were no differences in the treatment effect of early intensive versus guideline-recommended BP lowering across lacunar and non-lacunar AIS.

Thrombolysis Outcomes in Acute Ischemic Stroke by Fluid-Attenuated Inversion Recovery Hyperintense Arteries.

BACKGROUND AND PURPOSE: To determine factors associated with fluid-attenuated inversion recovery (FLAIR) hyperintense arteries (FLAIR-HAs) on magnetic resonance imaging and their prognostic significance in thrombolysis-treated patients with acute ischemic stroke from the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) trial alteplase-dose arm. METHODS: Patients with acute ischemic stroke (N=293) with brain magnetic resonance imaging (FLAIR and diffusion-weighted imaging sequences) scanned <4.5 hours of symptom onset were assessed for location and extent (score) of FLAIR-HAs, infarct volume, large vessel occlusion (LVO), and other ischemic signs. Logistic regression models were used to determine predictors of FLAIR-HAs and the association of FLAIR-HAs with 90-day outcomes: favorable functional outcome (primary; modified Rankin Scale scores, 0-1), other modified Rankin Scale scores, and intracerebral hemorrhage. RESULTS: Prior atrial fibrillation, LVO, large infarct volume, and anterior circulation infarction were independently associated with FLAIR-HAs. The rate of modified Rankin Scale scores 0 to 1 was numerically lower in patients with FLAIR-HAs versus without (69/152 [45.4%] versus 75/131 [57.3%]), as was the subset of LVO (37/93 [39.8%] versus 9/16 [56.3%]), but not in those without LVO (25/36 [69.4%] versus 60/106 [56.6%]). After adjustment for covariables, FLAIR-HAs were independently associated with increased primary outcome (adjusted odds ratio [95% CI]: overall 4.14 [1.63-10.50]; with LVO 4.92 [0.87-27.86]; no LVO 6.16 [1.57-24.14]) despite an increased risk of hemorrhagic infarct (4.77 [1.12-20.26]). CONCLUSIONS: FLAIR-HAs are more frequent in acute ischemic stroke with cardioembolic features and indicate potential for a favorable prognosis in thrombolysis-treated patients possibly mediated by LVO. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Brain imaging abnormalities and outcome after acute ischaemic stroke: the ENCHANTED trial.

OBJECTIVE: To test the hypothesis that imaging signs of 'brain frailty' and acute ischaemia predict clinical outcomes and symptomatic intracranial haemorrhage (sICH) after thrombolysis for acute ischaemic stroke (AIS) in the alteplase dose arm of ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED). METHODS: Blinded assessors coded baseline images for acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions; and hyperattenuated arteries) and pre-existing changes (atrophy, leucoaraiosis and old ischaemic lesions). Logistic regression models assessed associations between imaging features and death at 7 and 90 days; good recovery (modified Rankin Scale scores 0-2 at 90 days) and sICH. Data are reported with adjusted ORs and 95% CIs. RESULTS: 2916 patients (67±13 years, National Institutes of Health Stroke Scale 8 (5-14)) were included. Visible ischaemic lesions, severe hypoattenuation, large ischaemic lesion, swelling and hyperattenuated arteries were associated with 7-day death (OR (95% CI): 1.52 (1.06 to 2.18); 1.51 (1.01 to 2.18); 2.67 (1.52 to 4.71); 1.49 (1.03 to 2.14) and 2.17 (1.48 to 3.18)) and inversely with good outcome. Severe atrophy was inversely associated with 7-day death (0.52 (0.29 to 0.96)). Atrophy (1.52 (1.08 to 2.15)) and severe leucoaraiosis (1.74 (1.20 to 2.54)) were associated with 90-day death. Hyperattenuated arteries were associated with sICH (1.71 (1.01 to 2.89)). No imaging features modified the effect of alteplase dose. CONCLUSIONS: Non-expert-defined brain imaging signs of brain frailty and acute ischaemia contribute to the prognosis of thrombolysis-treated AIS patients for sICH and mortality. However, these imaging features showed no interaction with alteplase dose.

Brain Imaging Signs and Health-Related Quality of Life after Acute Ischemic Stroke: Analysis of ENCHANTED Alteplase Dose Arm.

BACKGROUND AND PURPOSE: The influence of specific brain lesions on health-related quality of life (HRQoL) after acute ischemic stroke (AIS) is uncertain. We aimed to identify imaging predictors of poor HRQoL in alteplase-treated participants of the alteplase dose arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: ENCHANTED was an international trial of low- versus standard-dose intravenous alteplase in AIS patients, with functional outcome (modified Rankin scale [mRS]) and HRQoL on the 5-dimension European Quality of Life Scale (EQ-5D) assessed at 90 days post-randomization. Brain images were analyzed centrally by trained assessors. Multivariable logistic regression was undertaken in the study population randomly divided (2:1) into training (development) and validation (performance) groups, with age (per 10-year increase), ethnicity, baseline National Institutes of Health Stroke Scale (NIHSS) score, diabetes mellitus, premorbid function (mRS score 0 or 1), and proxy respondent, forced into all models. Data are presented with odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Eight prediction models were developed and validated in 2,526 AIS patients (median age 67.5 years; 38.4% female; 61.7% Asian) with complete brain imaging and 90-day EQ-5D utility score data. The best performance model included acute ischemic changes in the right (OR 1.69, 95% CI: 1.24-2.29) and deep (OR 1.50, 95% CI: 1.03-2.19) middle cerebral artery (MCA) regions. Several background features of brain frailty - atrophy, white matter change, and old infarcts - were significantly associated with adverse physical but not emotional HRQoL domains. CONCLUSIONS: In thrombolysed AIS patients, right-sided and deep ischemia within the MCA territory predict poor overall HRQoL, whilst features of old cerebral ischemia are associated with reduced physical HRQoL.

Returning to Unpaid Work after Stroke: The Psychosocial Outcomes in Stroke Cohort Study.

BACKGROUND: While returning to paid work is a crucial marker of stroke recovery, little is known about the differences in unpaid work by sex following stroke. We aimed to determine the sex differences in participation in unpaid work 12 months after stroke. METHODS: Psychosocial outcomes in stroke were a prospective, multicentre observational study that recruited individuals, 18-64 years, within 28 days of stroke from New South Wales, Australia. Unpaid work was defined as ≥5 h per week of one or more of: unpaid domestic work for the household; unpaid care of others; looking after own children without pay or looking after someone else's children without pay. Data was collected before stroke, 28 days (baseline), 6 and 12 months follow-up. RESULTS: Eighty per cent of women and 52% of men engaged in ≥5 h per week of unpaid work before stroke. At 12 months after, 69% of women and 53% of men completed ≥5 h of unpaid work per week. For women, there was a significant association between participation in unpaid work at 12 months and having financially dependent children (OR 2.67; 95% CI 1.08-6.59). A return to unpaid work in men was associated with participation in unpaid work before stroke (OR 3.74; 95% CI 2.14-6.53). CONCLUSIONS: More women are engaged in unpaid work before and at 12 months after stroke, but there is a reduction in the proportion of women returning to unpaid work at 12 months not seen in men. Consideration may need to be given to the development of rehabilitation strategies targeted at the specific needs of stroke survivors.

Clinical Utility of Electronic Alberta Stroke Program Early Computed Tomography Score Software in the ENCHANTED Trial Database.

BACKGROUND AND PURPOSE: Clinical utility of electronic Alberta Stroke Program Early CT Score (e-ASPECTS), an automated system for quantifying signs of infarction, was evaluated in a large database of thrombolyzed patients with acute ischemic stroke. METHODS: All baseline noncontrast computed tomographic scans of patients with anterior circulation acute ischemic stroke who participated in the alteplase dose arm of the randomized controlled trial ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) were reviewed; poor quality and large (>6 mm) slice thickness were excluded. Included scans had e-ASPECTS scores correlated with baseline neurological severity (National Institutes of Health Stroke Scale scores) and 90-day disability outcomes (modified Rankin Scale scores). Multivariable logistic regression models were used to determine the predictive ability of e-ASPECTS for disability outcomes and symptomatic intracranial hemorrhage. RESULTS: Of 2426 available computed tomographic images, 1480 (61%) were included in analyses of e-ASPECTS scores (median 9 [interquartile range, 8-10], 77% with good [range, 8-10] scores). Lower e-ASPECTS scores (per 1-point decrease) were significantly associated with increasing baseline National Institutes of Health Stroke Scale scores (r, -0.31; P<0.0001) and 90-day poor outcome (modified Rankin Scale scores, 2-6; r, -0.27; P<0.001). Adjusted odds ratios and 95% confidence intervals for 90-day outcomes were death or disability (modified Rankin Scale scores, 2-6; 0.91 [0.85-0.97]), death and major disability (modified Rankin Scale scores, 3-6; 0.89 [0.83-0.95]), and death (0.86 [0.79-0.95]); and for symptomatic intracranial hemorrhage, according to the Implementation of Thrombolysis in Stroke-Monitoring Study criteria was 0.87 (0.72-1.05). CONCLUSIONS: e-ASPECT scores from thin computed tomographic slices (≤6 mm) were highly correlated with baseline neurological severity and independently predict functional recovery and adverse outcomes in acute ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01422616.