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Toward a Better Understanding of Sex- and Gender-Related Differences in Endovascular Stroke Treatment: A Scientific Statement From the American Heart Association/American Stroke Association

Originally publishedhttps://doi.org/10.1161/STR.0000000000000411Stroke. 2022;53:e396–e406

Abstract

There are many unknowns when it comes to the role of sex in the pathophysiology and management of acute ischemic stroke. This is particularly true for endovascular treatment (EVT). It has only recently been established as standard of care; therefore, data are even more scarce and conflicting compared with other areas of acute stroke. Assessing the role of sex and gender as isolated variables is challenging because they are closely intertwined with each other, as well as with patients’ cultural, ethnic, and social backgrounds. Nevertheless, a better understanding of sex- and gender-related differences in EVT is important to develop strategies that can ultimately improve individualized outcome for both men and women. Disregarding patient sex and gender and pursuing a one-size-fits-all strategy may lead to suboptimal or even harmful treatment practices. This scientific statement is meant to outline knowledge gaps and unmet needs for future research on the role of sex and gender in EVT for acute ischemic stroke. It also provides a pragmatic road map for researchers who aim to investigate sex- and gender-related differences in EVT and for clinicians who wish to improve clinical care of their patients undergoing EVT by accounting for sex- and gender-specific factors. Although most EVT studies, including those that form the basis of this scientific statement, report patient sex rather than gender, open questions on gender-specific EVT differences are also discussed.

Sex is one of the most controversially discussed and politically loaded variables in social and medical research. The scientific community has traditionally dealt with this dilemma with 2 opposite approaches: Sex is either overemphasized or, more frequently, largely ignored. For example, to date, it is not entirely clear whether women with carotid stenosis benefit from carotid endarterectomy to the same extent as men because previous endarterectomy trials failed to include a sufficient number of patients in both sex strata.1–4 When it comes to endovascular stroke treatment (EVT), data are even more scarce because it has been established only recently as the standard of care. Sex may not necessarily play an important role in all aspects of acute ischemic stroke care. For instance, according to everything we know about stroke pathophysiology, the treatment effect of EVT is highly time dependent, and there is no reason to expect substantial differences between men and women in this regard. However, it is beyond doubt that aspects of pre-EVT and post-EVT management are influenced by patients’ sex. For example, stenotic carotid plaques in women show less macrophage infiltration and a more stable phenotype compared with stenotic carotid plaques in men, suggesting that medical management may be more efficient in preventing strokes that necessitate EVT in women than in men.5,6 It is also important to note that most EVT studies, including those that form the basis of this scientific statement, report patient sex rather than gender, although some of the reported differences may be truly related to gender rather than sex. Improving our understanding of sex- and gender-specific differences will help clinicians tailor management strategies better to individual patients and thereby improve their functional outcome.

Disclaimer: Sex Versus Gender

When investigating sex-related differences in medical research, one needs to address the difference between sex and gender. Sex refers to biological factors. In humans, it is categorized as male or female and considered static, that is, does not change over a person’s lifetime.7 Gender, conversely, refers to social roles, behaviors, and expressions7 and includes gender identity but also gender relations, roles, gender institutionalization, and mainstreaming. Gender identity differs from sex in that it is neither binary nor static8; it exists along a continuum and may change over time. That being said, in most patients, particularly older generations, which account for the majority of EVT candidates, there is a large overlap, and gender identity matches sex (The number of transgender individuals in the United States at a population level is estimated to be rather low at 0.3%–0.8%9). Furthermore, in case of an emergency treatment such as EVT, when treatment decisions must be made quickly, usually sex, rather than gender, is reported. As a result, EVT research has focused on sex differences, and there are no robust data on gender-related differences. This scientific statement, therefore, refers mostly to sex differences on the basis of the data that were captured in most EVT studies, and the use of male and female or men and women refers to sex, with the acknowledgment, however, that some of the addressed sex differences may truly be related to gender rather than sex.

What Are Known Sex Differences in EVT?

There are many known important sex-related differences in stroke cause, pathophysiology management, and prognosis between men and women that are relevant for EVT (summarized in detail in Table 1). Most important, women are on average older10 and are more likely to have preexisting disabilities at the time of stroke onset.13–16,39 With regard to EVT use, some studies suggest that there may be undertreatment of women in the acute phase, although others found an increased proportion of women undergoing EVT compared with men.14,15,40 Functional outcomes in women at 90 days and 1 year after EVT are poorer compared with outcomes in men.13,16,30 However, because women survive on average longer after their stroke, their gain in disability-free life expectancy is larger compared with that of men,29 whereas their self-reported poststroke health status is poorer.41

Table 1. Summary of Sex-Related Key Differences in Acute Ischemic Stroke Relevant to EVT

Baseline statusAge: Women with stroke are on average 4–5 y older than men with stroke.10
Prestroke disability: Women are more often dependent in their daily activities immediately before the stroke than men, likely attributable in part to older age at onset.11
Nature of stroke symptoms: Women present more often with atypical stroke symptoms than men (eg, pain, fluctuating level of consciousness).12
Symptom severity: Women present with more severe stroke symptoms than men.10,13,14
Social environment: Women are more likely to be in widowhood/live alone or to live in an assisted living arrangement than men.13–16
Stroke typeStroke type: Women present more often with cardioembolic stroke, probably as a result of a higher prevalence of atrial fibrillation, which increases with age, whereas men present more often with small vessel disease.17
Stroke pattern: Because of the differences in stroke cause, women have a higher prevalence of large territorial infarcts compared with men, who have small lacunar strokes more often.17
General stroke care and intravenous thrombolysisHospital admission: Data from Western countries show that women have longer delays in the prehospital phase compared with men, attributable partly to longer onset–to–first medical contact times.14–16,18 In a large Swedish registry, women also have short hospital lengths of stay.16Stroke registry data from Middle Eastern and African countries mostly contain >70% male patients, suggesting a large sex gap in access to acute stroke care on a global level.19,20
Diagnostic workup: Women with AIS symptoms are less likely to see a stroke specialist and to undergo standard diagnostic testing than men.21,22 Vascular imaging is performed less often in women.22
Intravenous thrombolysis: Women are 13% less likely to receive intravenous thrombolysis than men in Western countries.18Underuse and delay in intravenous thrombolysis in women are more pronounced in hospitals without specialized stroke unit care.23
Stroke unit care: Some data suggest that women are less often treated in a stroke unit or intensive care unit than men.24,25
AIS complications: Women have fractures, pulmonary embolism, and deep venous thrombosis more often during the course of AIS treatment, whereas men have pneumonia more often.25
Rehabilitation: Women are less likely to receive acute rehabilitation services,13,16 and a German study suggests that they are less likely to have investigations for secondary stroke prevention measures24 and are more likely to have a palliative care consult.24
EVTAccess to EVT: Available data suggest geographic heterogeneity in sex and gender differences in access to EVT. Data from the United States show similar rates of EVT among men and women with AIS.26 Data from Denmark and Japan suggest lower EVT rates in women.14,15 In a Japanese registry, door–to–arterial puncture times were also longer in women.14 For nonindustrial countries, there is a paucity of data.
Neuroimaging: Women have better collaterals, and infarct growth may be slower in women compared with men.27,28
Technical efficacy: Recanalization success in men and women with EVT is similar.29,30
Treatment effect of EVT: EVT treatment effect on functional outcome (mRS score) does not differ between men and women, but women may have greater gain in disability-free life.29,31
OutcomesFunctional status: Women have worse functional status and are less likely to achieve functional independence than men after AIS in general32 and EVT in particular.14–16,24,30,33
Mortality: Women have higher mortality after AIS than men,34,35 but mortality after EVT is similar in men and women.30
Health-related quality of life: In general, women have poorer health-related quality of life than men,36 but the gain in disability-adjusted life-years after EVT is greater in women than in men.29
Social domain: In general, women are at higher risk for poststroke depression and have reduced mobility compared with men.37 No conclusive evidence exists on sex-/gender-related outcome differences in the social domain after EVT.
Discharge destination: In general, women with AIS are less likely to be discharged home and are more likely to be discharged to long-term care facilities than men, both in general21 and after EVT in particular.38

AIS indicates acute ischemic stroke; EVT, endovascular treatment; and MRS, modified Rankin Scale.

Are Sex Differences in EVT Explained by Differences in Epidemiology and Functional Status?

It is likely that the apparent sex differences in the prestroke functional status and poststroke outcomes in patients undergoing EVT are, in large part, explained by differences in baseline epidemiological variables.32 The key difference in baseline status is patient age, which also has a major impact on post-EVT prognosis. Acute ischemic stroke is a disease that affects primarily older people; thus, the disease burden of acute ischemic stroke is higher for women because their life expectancy is higher.42 Therefore, female patients undergoing EVT are on average older compared with male patients undergoing EVT, which results in poorer overall outcomes. That being said, sex hormones influence cerebrovascular physiology and coagulation profiles.43,44 Thus, it can be expected that differences in baseline epidemiological variables may not be the only reason for sex-related differences in EVT. Of note, pregnancy, hormonal replacement therapies, and treatment with estrogen-containing oral contraceptives are potential risk factors associated with the development of ischemic stroke that are unique to women but are not discussed here because they are outside the scope of this review and the cause of pregnancy-related stroke is less likely to be large vessel occlusion.45

Are Sex and Gender Differences in EVT Explained by Differences in Social and Cultural Roles?

Being male or female can result in different access to health care, employment, financial autonomy, and willingness to participate in research and ultimately differentials in power,43 all of which may affect post-EVT outcomes.

For example, female patients undergoing EVT are more likely to live alone13–16 and to have prestroke disability,38 which results in delays between symptom onset and activation of emergency response compared with men.14–16 Discharge to a nursing home may be more likely in female patients undergoing EVT because they get less help from spouses and available family members compared with their male counterparts.46

Some data from general acute ischemic stroke populations also suggest that women may be less likely to be admitted to a stroke unit or intensive care unit,24,47 possibly because of misdiagnosis of stroke symptoms, delayed presentation, or financial restrictions for female patients with stroke in countries without a publicly funded health care system. However, it is not clear whether this also holds true among patients undergoing EVT.

Furthermore, some evidence suggests that women more often experience poststroke mood disorders, which results in worse modified Rankin Scale (mRS) scores, the most commonly used outcome scale in EVT trials.48,49 Among the risk factors for poststroke mood disorders are low educational level and social isolation,50 which are, again, related to men’s and women’s sociocultural roles.

These data suggest that differences between men and women with respect to sociocultural roles and financial resources may explain a large part of the differences in outcomes of male and female patients undergoing EVT. Of note, much of the sex-focused research in the past has used an oversimplistic approach by assuming that sex (or gender, for that matter) can be analyzed in complete isolation from other sociocultural, epidemiological, and ethnic variables, assuming, for example, that health differences between being male and female can be meaningfully and completely separated from health differences between being poor and wealthy. This is in contradiction to the concept of intersectionality, according to which the influence of epidemiological and social factors such as sex, gender, and social status or ethnicity cannot be completely separated from each other.51 Therefore, it is hard, if not impossible, to isolate the influence of sex on post-EVT outcomes from the influence of the sociocultural aspects outlined above (see Unknown No. 3: How Can the Influence of Sex and Gender Be Differentiated?).

Sex and Gender Differences in EVT: What Are the Unknowns?

For many aspects of EVT care and acute ischemic stroke in general, we currently do not know whether, to what extent, why, and how they are influenced by sex (Table 2).

Table 2. Knowledge Gaps in the Role of Sex in EVT

QuestionExplanationExample
Does the optimal EVT technique differ between men and women?Women have smaller, potentially more fragile cerebral arteries and increased arterial tortuosity, and their collateral circulation seems to be better compared with men, resulting in slower infarct growth.Women may benefit from the use of less traumatic EVT devices that reduce the risk of vessel perforation, even if this comes at the cost of requiring several passes to achieve successful recanalization, which may not be as deleterious as in men given their better collateral circulation.
Women may benefit from femoral artery access as the first-line access route because the radial artery is sometimes too small to harbor the EVT equipment needed to navigate their tortuous arterial anatomy.
How does sex influence post-EVT outcomes?Data suggest that the perception of pain and discomfort and health-related quality of life after EVT are likely to be different between men and women. The mRS, which is the most commonly used outcome scale in EVT research, does not capture these symptoms unless they result in loss of motor function.A man with a poststroke mRS score of 3 may perceive his disability to be either worse or less severe than a woman who has the same disability. The tolerance of disability may also depend on preexisting impairments, which are more likely to be present in women.
How can sex- and gender-related differences be differentiated?Current EVT studies do not distinguish between sex and gender. Thus, it is unclear which differences in EVT between men and women are sex related and which are gender related.It is not clear whether the higher rate of poststroke depression is sex related (eg, attributable to hormonal factors), gender related (eg, attributable to sociocultural factors), or both.
How, to what extent, and why does sex influence access to EVT?Imbalances in power between men and women may lead to restricted access for women and girls to employment, health education, and health care, particularly on a global level.The willingness of the family to pay for EVT for female family members may be lower than that for male family members in some countries because women often do not contribute to the family income.
As a result of poorer health education, women may not recognize the symptoms of stroke, and activation of emergency medical serves may be delayed.

EVT indicates endovascular treatment; and MRS, modified Rankin Scale.

Unknown No. 1: Does the Optimal EVT Technique Differ Between Men and Women?

Cerebrovascular anatomy in male is different from that in female individuals. Intracranial internal carotid artery and middle cerebral artery diameters are on average slightly smaller in women compared with men,52 and their arteries are more tortuous.53 Therefore, accessing the target occlusion may be more difficult, and the risk of intracranial vessel perforation is likely to be higher. The smaller arterial caliber of the upper and lower extremities also results in a higher risk of access site complications54,55 and sometimes precludes the use of certain devices such as large sheaths and balloon guide catheters.56 In some women, the radial artery is too small to harbor even the smallest required sheath that is needed to establish access to the target occlusion, and the access route needs to be changed altogether. Furthermore, cerebral hemodynamics, including reactivity to hypercapnia, collateral circulation, and infarct progression rate, seem to differ between men and women27,57 and show menopausal dynamics that are unique to women,57 raising the question of whether EVT selection criteria and techniques could be improved by accounting for sex-specific differences in cerebrovascular pathophysiology. That being said, there currently are no robust data to suggest that patient sex per se influences technical EVT success.29,30

Unknown No. 2: How Does Sex Influence Post-EVT Outcomes?

As mentioned, differences in poststroke outcomes between men and women are influenced by differences in baseline epidemiological variables, but there seems to be an independent influence of sex as well. Evidence suggests that women experience less pain and discomfort compared with men after EVT,58 which is only moderately associated with the mRS score59 because the mRS is heavily weighted on motor function and does not capture discomfort and anxiety. Poststroke depression, on the other hand, is more commonly seen in women.48,49 Sex and gender disparities in nonmotor symptoms that affect quality of life can be missed if only the mRS score is used. Use of patient-reported outcomes can help to capture post-EVT outcomes and the influence of sex in a more comprehensive, multidimensional way.60

Unknown No. 3: How Can the Influence of Sex and Gender Be Differentiated?

Assessing gender effects in EVT requires accurate reporting of gender in EVT studies and clear differentiation of sex and gender, which are currently often used synonymously. Clearly, the greatest value of distinguishing sex versus gender in acute stroke lies mostly in the ability of those variables to help disentangle biological versus socioculturally determined factors contributing to EVT differences, regardless of whether patients are cisgender or transgender. Of note, even if patient gender is not explicitly captured and reported, many studies contain information on gender-related variables such as social support networks, marital status, type of occupation, and education level, and these could be used as a starting point for gender-specific research. Although it would also be interesting to assess the effect of transgender status, this will require a large sample size of transgender patients, and such analyses not only are at high risk of being hampered by investigator biases61 but also allow researchers to capture changes only in the proportions of transgendered individuals who openly identify as such, which may not necessarily reflect the true changes among transgendered individuals.

Unknown No. 4: How Does Sex Influence Access to EVT?

We currently face a relative paucity of data and heterogeneity of data on access to EVT for both sexes, particularly on a global level. From the few available studies on this topic, it seems that EVT rates in men and women in the United States are similar,26 although in some European and Asian countries, EVT rates among women are lower than in men14,15 (Table 1). In many parts of the world, inequality and imbalances in power between men and women persist, leading to restricted access for women and girls to employment, health education, and health care.62 In addition, in some countries, female doctors and nurses are prevented from practicing or are restricted in their practice, which further increases the sociocultural barrier for women to seek medical care. This situation may create a bottleneck in which financial and social dependency, lack of autonomy, and poor health education may prove far more important in determining women’s poststroke outcomes than technological innovations such as EVT, simply because the aforementioned factors prevent women from accessing these technologies. Published data can give us a rough idea about sex-related disparities in treatment access. In 2 large Middle Eastern registries, for example, men accounted for two-thirds of all patients with stroke, indicating severe underdiagnosis and lack of access to stroke care among women.19,63 In addition, in North America and Europe, female patients are less likely to complete investigations for secondary stroke prevention measures during their admission,24 have shorter hospital lengths of stay than men,16 are more likely to receive palliative care consultation,24 and are less likely to be offered acute rehabilitation services.13,16 The exact extent of underdiagnosis and undertreatment with EVT24 and the role that sex plays in this regard are unknown at this time, but according to the few available data, further studies on this topic are highly warranted. It is also important to note that although the above studies refer to patient sex, EVT access may be truly determined by patient gender rather than sex because it is probably more influenced by sociocultural than biological factors.

Assessing Sex- and Gender-Related Differences in EVT: A Road Map for Researchers

A summary of the key suggestions is provided in Table 3. Few studies have systematically assessed the influence of sex in EVT. They are mostly post hoc analyses and thus not sufficiently powered to address the question appropriately. This, along with the fact that women are commonly underrepresented in stroke trials and the included women do not adequately reflect the overall female stroke population, particularly in EVT trials and other interventional trials,64 should be kept in mind in the interpretation of studies that report sex-related differences. Overinterpretation, especially of small, retrospective studies, some of which suggest diminished treatment effect in 1 sex, may unintentionally promote sex biases. During the design of a study, a thoughtful design and choice of inclusion criteria are important to avoid inadequate representation of 1 sex (Figure).

Table 3. Assessing Sex- and Gender-Related Differences in EVT: Suggestions for Researchers

Report stroke type and baseline disability stratified by sex.
Consider eliminating upper age limits or prestroke functional status limit (eg, mRS score <2).
Supplement data on sex-related differences in EVT with prospective registry studies because they are not subject to sex-specific inclusion criteria to the same degree as randomized trials.
Use a primary outcome measure that reflects prestroke/poststroke differences rather than a dichotomized outcome (eg, ΔmRS score or mRS score shift analysis rather than mRS score of 0–2).
Use a diverse set of outcomes, including hard (eg, mortality) and soft (eg, quality-adjusted life-years) outcomes.
Capture sex, gender, or both (depending on the research question) in a systematic way and explicitly say why each was used.
Power trials adequately for sex- and gender-based analysis, and continue enrollment of 1 sex if it is underrepresented after the targeted overall sample size has been achieved.

EVT indicates endovascular treatment; and MRS, modified Rankin Scale.

Figure.

Figure. Sex- and gender-specific factors influencing enrollment in endovascular treatment (EVT) trials. Biological (sex-specific) factors are shown in blue; societal (gender-specific) factors are shown in yellow; and investigator-related factors are shown in purple. Currently, there is evidence to suggest underrepresentation of women in EVT trials in terms of the true disease burden, as well as inadequate representation (eg, the women included in EVT trials are on average younger than the women who are, in principle, eligible for EVT). Possible study design solutions tackling these specific factors to mitigate the inadequate representation of sexes in EVT trials are shown in green. Problematic study design solutions with the potential to aggravate inadequate representation of sexes are shown in red. Pts indicates patients.

Sex Versus Gender

Currently, acute stroke research mostly uses sex and gender interchangeably. EVT trials hardly ever differentiate between sex and gender, partly because of the emergency nature of the disease and treatment that precludes clinicians and researchers from taking a detailed social history. This also means that stratifying by gender in randomized trials is not possible. Gender can, however, be assessed in the postacute phase, allowing post hoc analysis of gender-related differences.

Although there is a large overlap between sex and gender, self-identified gender diversity in patients with stroke is expected to increase in the future. We encourage researchers to use the construct that is most relevant for their research question and to clearly state why sex, not gender, is reported and vice versa. Studies examining biological and hormonal factors related to stroke origin or infarct size should consider analysis by sex, although for researchers assessing the impact of stroke on quality of life and social factors (eg, social isolation, poststroke depression), gender may be the more relevant construct and should be systematically captured. Explicit statements on how sex and gender were determined (eg, self-reported versus administrative data, medical records, gender evaluation questionnaires) should be noted in the Methods section.

Stroke Pathogenesis

Many important differences in stroke type and pathophysiology exist between men and women (Table 1). We, therefore, suggest that researchers report stroke cause separately for men and women. Furthermore, pregnant patients have been excluded from most EVT trials, and although pregnancy-related stroke rarely results in a vessel occlusion that can be targeted with EVT,45 categorical exclusion of pregnant patients should be avoided because pregnancy per se is not a contraindication for EVT. Of note, this may not be feasible in randomized trials involving drugs with teratogenic effects.

Baseline Status

The relatively older age and worse prestroke functional status of women have significant implications for clinical trial enrollment (Figure). Simply applying an upper age limit of 80 years results in a disproportionately high exclusion of women from clinical studies.65 This implies a high risk for selection bias: Not only is the proportion of women among EVT trial participants lower than the actual proportion of women having acute ischemic strokes, but also those who are included are not truly representative of the female stroke population. To avoid inadequate representation of women in EVT trials, we suggest refraining from using age and prestroke functional status as exclusion criteria. Because randomized trials often aim to maximize treatment effect within a limited sample size, avoiding age- and disability-based exclusion criteria may, however, not always be possible. In such cases, prospective registry data, in which no such criteria are applied, could provide supplementary evidence.

Neuroimaging and EVT Technique

Cerebral vessels are smaller and potentially more fragile in women than in men,52 and neuroimaging profiles differ.27,57 Thus, studies assessing neuroimaging profiles in EVT candidates and EVT techniques should be sufficiently powered to detect sex-specific differences in neuroimaging profiles and treatment techniques. Imaging variables and treatment complications should be reported for both sex strata, particularly when there is reason to expect sex-specific differences.

Outcomes and Treatment Effect

Clinical trials often use dichotomized outcomes and try to maximize treatment effect by applying strict inclusion criteria. This means that treatment effect in women is often not captured adequately because of baseline disability: A 90-day mRS score of 3 after EVT in a woman with a baseline mRS score of 2 would be considered a treatment failure when the traditional good outcome definition of an mRS score of 0 to 2 is applied, but it can be considered a good outcome if the alternative is an mRS score of 4 with conservative management.

We, therefore, suggest using poststroke/prestroke differences (eg, change in mRS score or accumulated disability) rather than dichotomized outcomes to more accurately reflect treatment effects. The use of additional outcome measures that include both hard (eg, mortality) and soft (eg, mRS score, self-reported health-related quality of life [Neuro-QoL67], ability to return home, and home time) outcomes allows a more comprehensive evaluation of treatment effects in both sexes because the mRS alone does not adequately capture cognition and mood disorders, which may significantly affect patients’ quality of life.68

Of note, the poorer functional outcomes in women are explained largely by their higher age and poorer prestroke functional status rather than being solely a sex-related phenomenon. Researchers should thus clearly distinguish between sex-related differences that can be explained by differences in prognostic baseline variables (eg, premorbid functional status, age, stroke type: spurious sex-related differences) and sex-related differences that cannot be explained by such variables (true sex differences). This applies particularly to nonrandomized studies with less stringent inclusion criteria, in which imbalances in baseline variables between men and women are more likely to occur.

Accounting for Sex-Related Differences to Improve EVT Outcomes: A Road Map for Clinicians

A summary of key suggestions is provided in Table 4. Despite the steep rise in EVT use over the past years,40 some studies suggest that EVT may be underused in women, even in industrialized countries, although these results should be interpreted with caution because the true denominator of EVT-eligible patients for each sex in these studies is unknown.14,15 Being aware of this discrepancy is a first important step for clinicians and should motivate them to thoroughly evaluate female patients with stroke with regard to EVT eligibility.

Table 4. Improving EVT Care by Accounting for Sex- and Gender-Related Differences: Suggestions for Clinicians

Acute phase
 Delay the decision to proceed with palliative care in the first 24 h because it may become a self-fulfilling prophecy.
 Center treatment decisions around treatment effect rather than overall prognosis.
 Determine what the patient considers a desirable outcome as soon as possible from communication with the patient and family members, and center treatment decisions around this goal.
Nonacute phase
 In patients with high stroke risk or past stroke who are living alone, create an action plan about how to activate emergency medical services, and discuss the option of having a life-alert bracelet.
 Encourage patients with high stroke risk or past stroke to explicitly discuss what they consider an acceptable outcome in case of a stroke, and draft a living will that describes these expectations in detail.

EVT indicates endovascular treatment.

We also suggest that primary care clinicians proactively ask about the living environments of their patients with known cardiovascular risk factors and discuss what to do in case of an emergency (eg, how to activate emergency medical services, the possibility of using a life-alert bracelet). Because women with stroke are older and more likely to live alone than men with stroke, these precautions will particularly benefit women with high stroke risk.

During their admission, female patients with stroke have a shorter active treatment course16 and are more likely to receive a palliative care regimen24 for ischemic stroke compared with men. Together with their overall poorer post-EVT prognosis, this puts women at a greater risk of withdrawal bias: Clinical experience and scientific literature from female patients undergoing EVT are biased by poorer baseline functional status, frequent undertreatment, and premature withdrawal of care, which may result in a self-fulfilling prophecy. It is, therefore, impossible to judge which outcome could be achieved if all diagnostic and therapeutic options would be leveraged in female patients.69 To prevent withdrawal bias, it may be helpful for physicians to center their therapeutic goals around treatment effect rather than overall prognosis: An elderly female patient with prestroke disability most likely will not achieve a good outcome (mRS score 0–2) with EVT, but her prognosis if EVT is not performed is even worse. It is also important to initiate an open conversation about expected and desirable outcomes with the patients themselves and their family members to prepare them for the range of likely outcomes that can be expected. Because of the poorer baseline functional status of female EVT candidates, these considerations will again affect EVT care in women to a greater degree than in men.

Conclusions

Patients’ sex may influence their stroke risk, acute EVT management, and post-EVT outcomes. Stroke researchers need to be aware of the profound impact of sex on their research; otherwise, they may miss sex-related phenomena in their data and, in the worst case, come to erroneous conclusions. Similarly, clinicians need to understand the importance of sex and sex-related biases in their daily clinical practice in order to tailor their clinical care toward the specific needs of their patients undergoing EVT. Doing so will help to improve diagnosis, treatment, and prevention strategies and thereby improve outcomes for both men and women undergoing EVT. Looking further ahead, the biggest challenge in improving our understanding of sex-related differences in EVT is probably not related to the patients who are treated but rather lies in determining sex-related access barriers to EVT, that is, determining how many men and women who could benefit from EVT lack access to this highly effective treatment in our own hospital, state, and country and on a global scale.

Article Information

Footnotes

The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists.

Endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on April 14, 2022, and the American Heart Association Executive Committee on May 17, 2022. A copy of the document is available at https://professional.heart.org/statements by using either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 215-356-2721 or email .

The American Heart Association requests that this document be cited as follows: Ospel JM, Schaafsma JD, Leslie-Mazwi TM, Amin-Hanjani S, Asdaghi N, Gordon-Perue GL, Couillard P, Hadidi NN, Bushnell C, McCullough LD, Goyal M; on behalf of the American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; and Council on Epidemiology and Prevention. Toward a better understanding of sex- and gender-related differences in endovascular stroke treatment: a scientific statement from the American Heart Association/American Stroke Association. Stroke. 2022;53:e396–e406. doi: 10.1161/STR.0000000000000411

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References

  • 1. Endarterectomy for asymptomatic carotid artery stenosis: executive committee for the asymptomatic carotid atherosclerosis study.JAMA. 1995; 273:1421–1428CrossrefMedlineGoogle Scholar
  • 2. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).Lancet. 1998; 351:1379–1387CrossrefMedlineGoogle Scholar
  • 3. Halliday A, Mansfield A, Marro J, Peto C, Peto R, Potter J, Thomas D; MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial.Lancet. 2004; 363:1491–1502. doi: 10.1016/S0140-6736(04)16146-1CrossrefMedlineGoogle Scholar
  • 4. Brott TG, Hobson RW, Howard G, Roubin GS, Clark WM, Brooks W, Mackey A, Hill MD, Leimgruber PP, Sheffet AJ, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis.N Engl J Med. 2010; 363:11–23. doi: 10.1056/NEJMoa0912321CrossrefMedlineGoogle Scholar
  • 5. Bushnell CD, Chaturvedi S, Gage KR, Herson PS, Hurn PD, Jiménez MC, Kittner SJ, Madsen TE, McCullough LD, McDermott M, et al. Sex differences in stroke: challenges and opportunities.J Cereb Blood Flow Metab. 2018; 38:2179–2191. doi: 10.1177/0271678X18793324CrossrefMedlineGoogle Scholar
  • 6. Hellings WE, Pasterkamp G, Verhoeven BA, De Kleijn DP, De Vries JP, Seldenrijk KA, van den Broek T, Moll FL. Gender-associated differences in plaque phenotype of patients undergoing carotid endarterectomy.J Vasc Surg. 2007; 45:289–296. doi: 10.1016/j.jvs.2006.09.051CrossrefMedlineGoogle Scholar
  • 7. Moleiro C, Pinto N. Sexual orientation and gender identity: review of concepts, controversies and their relation to psychopathology classification systems.Front Psychol. 2015; 6:1511. doi: 10.3389/fpsyg.2015.01511Google Scholar
  • 8. Day S, Mason R, Lagosky S, Rochon PA. Integrating and evaluating sex and gender in health research.Health Res Policy Syst. 2016; 14:75. doi: 10.1186/s12961-016-0147-7Google Scholar
  • 9. Chan PS. Invisible gender in medical research.Circ Cardiovasc Qual Outcomes. 2019; 12:e005694. doi: 10.1161/CIRCOUTCOMES.119.005694LinkGoogle Scholar
  • 10. Appelros P, Stegmayr B, Terént A. Sex differences in stroke epidemiology: a systematic review.Stroke. 2009; 40:1082–1090. doi: 10.1161/STROKEAHA.108.540781LinkGoogle Scholar
  • 11. Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA. Gender differences in stroke incidence and poststroke disability in the Framingham Heart Study.Stroke. 2009; 40:1032–1037. doi: 10.1161/STROKEAHA.108.542894LinkGoogle Scholar
  • 12. Labiche LA, Chan W, Saldin KR, Morgenstern LB. Sex and acute stroke presentation.Ann Emerg Med. 2002; 40:453–460. doi: 10.1067/mem.2002.128682CrossrefMedlineGoogle Scholar
  • 13. Madsen TE, DeCroce-Movson E, Hemendinger M, McTaggart RA, Yaghi S, Cutting S, Furie KL, Saad A, Siket MS, Jayaraman MV. Sex differences in 90-day outcomes after mechanical thrombectomy for acute ischemic stroke.J Neurointerv Surg. 2019; 11:221–225. doi: 10.1136/neurintsurg-2018-014050CrossrefGoogle Scholar
  • 14. Uchida K, Yoshimura S, Sakai N, Yamagami H, Morimoto T. Sex differences in management and outcomes of acute ischemic stroke with large vessel occlusion.Stroke. 2019; 50:1915–1918. doi: 10.1161/STROKEAHA.119.025344LinkGoogle Scholar
  • 15. Mainz J, Andersen G, Valentin JB, Gude MF, Johnsen SP. Disentangling sex differences in use of reperfusion therapy in patients with acute ischemic stroke.Stroke. 2020; 51:2332–2338. doi: 10.1161/STROKEAHA.119.028589LinkGoogle Scholar
  • 16. Willers C, Lekander I, Ekstrand E, Lilja M, Pessah-Rasmussen H, Sunnerhagen KS, von Euler M. Sex as predictor for achieved health outcomes and received care in ischemic stroke and intracerebral hemorrhage: a register-based study.Biol Sex Differ. 2018; 9:11. doi: 10.1186/s13293-018-0170-1CrossrefMedlineGoogle Scholar
  • 17. Förster A, Gass A, Kern R, Wolf ME, Ottomeyer C, Zohsel K, Hennerici M, Szabo K. Gender differences in acute ischemic stroke: etiology, stroke patterns and response to thrombolysis.Stroke. 2009; 40:2428–2432. doi: 10.1161/STROKEAHA.109.548750LinkGoogle Scholar
  • 18. Foerch C, Misselwitz B, Humpich M, Steinmetz H, Neumann-Haefelin T, Sitzer M; Arbeitsgruppe Schlaganfall Hessen. Sex disparity in the access of elderly patients to acute stroke care.Stroke. 2007; 38:2123–2126. doi: 10.1161/STROKEAHA.106.478495LinkGoogle Scholar
  • 19. Al-Rukn S, Mazya M, Akhtar N, Hashim H, Mansouri B, Faouzi B, Aref H, Abdulrahman H, Kesraoui S, Hentati F, et al. Stroke in the Middle-East and North Africa: a 2-year prospective observational study of intravenous thrombolysis treatment in the region: results from the SITS-MENA Registry.Int J Stroke. 2020; 15:980–987. doi: 10.1177/1747493019874729CrossrefGoogle Scholar
  • 20. Akhtar N, Kate M, Kamran S, Singh R, Bhutta Z, Saqqur M, Elzouki AN, Babu B, Bourke P, Morgan D, et al. Sex-specific differences in short-term and long-term outcomes in acute stroke patients from Qatar.Eur Neurol. 2020; 83:154–161. doi: 10.1159/000507193CrossrefGoogle Scholar
  • 21. Turtzo LC, McCullough LD. Sex differences in stroke.Cerebrovasc Dis. 2008; 26:462–474. doi: 10.1159/000155983CrossrefMedlineGoogle Scholar
  • 22. Bruce SS, Merkler AE, Bassi M, Chen ML, Salehi Omran S, Navi BB, Kamel H. Differences in diagnostic evaluation in women and men after acute ischemic stroke.J Am Heart Assoc. 2020; 9:e015625. doi: 10.1161/JAHA.119.015625LinkGoogle Scholar
  • 23. Pérez-Sánchez S, Barragán-Prieto A, Ortega-Quintanilla J, Domínguez-Mayoral A, Gamero-García MÁ, Zapata-Arriaza E, Torres-Chacón R, de Albóniga-Chindurza A, Zapata-Hidalgo M, Moniche F, et al. Sex differences by hospital-level in performance and outcomes of endovascular treatment for acute ischemic stroke.J Stroke. 2020; 22:258–261. doi: 10.5853/jos.2019.03223CrossrefGoogle Scholar
  • 24. Weber R, Krogias C, Eyding J, Bartig D, Meves SH, Katsanos AH, Caso V, Hacke W. Age and sex differences in ischemic stroke treatment in a nationwide analysis of 1.11 million hospitalized cases.Stroke. 2019; 50:3494–3502. doi: 10.1161/STROKEAHA.119.026723LinkGoogle Scholar
  • 25. Eriksson M, Glader EL, Norrving B, Terént A, Stegmayr B. Sex differences in stroke care and outcome in the Swedish national quality register for stroke care.Stroke. 2009; 40:909–914. doi: 10.1161/STROKEAHA.108.517581LinkGoogle Scholar
  • 26. Lekoubou A, Bishu KG, Ovbiagele B. Stroke thrombectomy utilization rates by sex: what were things like before 2015?J Stroke Cerebrovasc Dis. 2020; 29:104587. doi: 10.1016/j.jstrokecerebrovasdis.2019.104587CrossrefGoogle Scholar
  • 27. Dula AN, Luby M, King BT, Sheth SA, Magadán A, Davis LA, Gealogo GA, Merino JG, Hsia AW, Latour LL, et al; LESION Investigators. Neuroimaging evolution of ischemia in men and women: an observational study.Ann Clin Transl Neurol. 2019; 6:575–585. doi: 10.1002/acn3.733CrossrefGoogle Scholar
  • 28. Dula AN, Mlynash M, Zuck ND, Albers GW, Warach SJ; DEFUSE 3 Investigators. Neuroimaging in ischemic stroke is different between men and women in the DEFUSE 3 cohort.Stroke. 2020; 51:481–488. doi: 10.1161/STROKEAHA.119.028205LinkGoogle Scholar
  • 29. Sheth SA, Lee S, Warach SJ, Gralla J, Jahan R, Goyal M, Nogueira RG, Zaidat OO, Pereira VM, Siddiqui A, et al. Sex differences in outcome after endovascular stroke therapy for acute ischemic stroke.Stroke. 2019; 50:2420–2427. doi: 10.1161/STROKEAHA.118.023867LinkGoogle Scholar
  • 30. Dmytriw AA, Ku JC, Yang VXD, Hui N, Uchida K, Morimoto T, Spears J, Marotta TR, Diestro JDB. Do outcomes between women and men differ after endovascular thrombectomy? A meta-analysis.AJNR Am J Neuroradiol. 2021; 42:910–915. doi: 10.3174/ajnr.A7075CrossrefGoogle Scholar
  • 31. Chalos V, de Ridder IR, Lingsma HF, Brown S, van Oostenbrugge RJ, Goyal M, Campbell BCV, Muir KW, Guillemin F, Bracard S, et al; HERMES Collaborators. Does sex modify the effect of endovascular treatment for ischemic stroke?Stroke. 2019; 50:2413–2419. doi: 10.1161/STROKEAHA.118.023743LinkGoogle Scholar
  • 32. Lisabeth LD, Reeves MJ, Baek J, Skolarus LE, Brown DL, Zahuranec DB, Smith MA, Morgenstern LB. Factors influencing sex differences in poststroke functional outcome.Stroke. 2015; 46:860–863. doi: 10.1161/STROKEAHA.114.007985LinkGoogle Scholar
  • 33. Rinaldo L, Rabinstein AA, Cloft H, Knudsen JM, Castilla LR, Brinjikji W. Racial and ethnic disparities in the utilization of thrombectomy for acute stroke.Stroke. 2019; 50:2428–2432. doi: 10.1161/STROKEAHA.118.024651LinkGoogle Scholar
  • 34. Phan HT, Blizzard CL, Reeves MJ, Thrift AG, Cadilhac D, Sturm J, Heeley E, Otahal P, Konstantinos V, Anderson C, et al. Sex differences in long-term mortality after stroke in the INSTRUCT (INternational STRoke oUtComes sTudy): a meta-analysis of individual participant data.Circ Cardiovasc Qual Outcomes. 2017; 10:e003436. doi: 10.1161/CIRCOUTCOMES.116.003436LinkGoogle Scholar
  • 35. Phan HT, Gall S, Blizzard CL, Lannin NA, Thrift AG, Anderson CS, Kim J, Grimley R, Castley HC, Kilkenny MF, et al. Sex differences in causes of death after stroke: evidence from a national, prospective registry.J Womens Health (Larchmt). 2021; 30:314–323. doi: 10.1089/jwh.2020.8391CrossrefMedlineGoogle Scholar
  • 36. Phan HT, Blizzard CL, Reeves MJ, Thrift AG, Cadilhac DA, Sturm J, Heeley E, Otahal P, Rothwell P, Anderson CS, et al. Sex differences in long-term quality of life among survivors after stroke in the INSTRUCT.Stroke. 2019; 50:2299–2306. doi: 10.1161/STROKEAHA.118.024437LinkGoogle Scholar
  • 37. Bushnell CD, Reeves MJ, Zhao X, Pan W, Prvu-Bettger J, Zimmer L, Olson D, Peterson E. Sex differences in quality of life after ischemic stroke.Neurology. 2014; 82:922–931. doi: 10.1212/WNL.0000000000000208CrossrefMedlineGoogle Scholar
  • 38. Deb-Chatterji M, Schlemm E, Flottmann F, Meyer L, Alegiani A, Brekenfeld C, Fiehler J, Gerloff C, Thomalla G; GSR-ET Investigators. Sex differences in outcome after thrombectomy for acute ischemic stroke are explained by confounding factors.Clin Neuroradiol. 2021; 31:1101–1109. doi: 10.1007/s00062-020-00983-2CrossrefGoogle Scholar
  • 39. Caso V, Paciaroni M, Agnelli G, Corea F, Ageno W, Alberti A, Lanari A, Micheli S, Bertolani L, Venti M, et al. Gender differences in patients with acute ischemic stroke.Womens Health (Lond). 2010; 6:51–57. doi: 10.2217/whe.09.82CrossrefMedlineGoogle Scholar
  • 40. Smith EE, Saver JL, Cox M, Liang L, Matsouaka R, Xian Y, Bhatt DL, Fonarow GC, Schwamm LH. Increase in endovascular therapy in Get With The Guidelines–Stroke after the publication of pivotal trials.Circulation. 2017; 136:2303–2310. doi: 10.1161/CIRCULATIONAHA.117.031097LinkGoogle Scholar
  • 41. Caroli E, Weber-Baghdiguian L. Self-reported health and gender: the role of social norms.Soc Sci Med. 2016; 153:220–229. doi: 10.1016/j.socscimed.2016.02.023Google Scholar
  • 42. Arnao V, Acciarresi M, Cittadini E, Caso V. Stroke incidence, prevalence and mortality in women worldwide.Int J Stroke. 2016; 11:287–301. doi: 10.1177/1747493016632245CrossrefMedlineGoogle Scholar
  • 43. Cislaghi B, Weber AM, Gupta GR, Darmstadt GL. Gender equality and global health: intersecting political challenges.J Glob Health. 2020; 10:010701. doi: 10.7189/jogh.10.010701Google Scholar
  • 44. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, Khatiwoda A, Lisabeth L. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes.Lancet Neurol. 2008; 7:915–926. doi: 10.1016/S1474-4422(08)70193-5CrossrefMedlineGoogle Scholar
  • 45. Liu S, Chan W-S, Ray Joel G, Kramer Michael S, Joseph KS. Stroke and cerebrovascular disease in pregnancy: incidence, temporal trends, and risk factors.Stroke. 2019; 50:13–20. doi: 10.1161/STROKEAHA.118.023118LinkGoogle Scholar
  • 46. Nagaraja N, Olasoji EB, Patel UK. Sex and racial disparity in utilization and outcomes of t-PA and thrombectomy in acute ischemic stroke.J Stroke Cerebrovasc Dis. 2020; 29:104954. doi: 10.1016/j.jstrokecerebrovasdis.2020.104954CrossrefGoogle Scholar
  • 47. McKevitt C, Coshall C, Tilling K, Wolfe C. Are there inequalities in the provision of stroke care? Analysis of an inner-city stroke register.Stroke. 2005; 36:315–320. doi: 10.1161/01.STR.0000152332.32267.19LinkGoogle Scholar
  • 48. Gall S, Phan H, Madsen TE, Reeves M, Rist P, Jimenez M, Lichtman J, Dong L, Lisabeth LD. Focused update of sex differences in patient reported outcome measures after stroke.Stroke. 2018; 49:531–535. doi: 10.1161/STROKEAHA.117.018417LinkGoogle Scholar
  • 49. Towfighi A, Ovbiagele B, El Husseini N, Hackett ML, Jorge RE, Kissela BM, Mitchell PH, Skolarus LE, Whooley MA, Williams LS; on behalf of the American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Poststroke depression: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2017; 48:e30–e43. doi: 10.1161/STR.0000000000000113LinkGoogle Scholar
  • 50. Park EY, Kim JH. An analysis of depressive symptoms in stroke survivors: verification of a moderating effect of demographic characteristics.BMC Psychiatry. 2017; 17:132. doi: 10.1186/s12888-017-1292-4Google Scholar
  • 51. Labovitz DL. Stroke epidemiology and intersectionality: understanding stroke outcomes in Mexican Americans in Corpus Christi.Stroke. 2020; 51:2886–2887. doi: 10.1161/STROKEAHA.120.031848LinkGoogle Scholar
  • 52. Davison MA, Ouyang B, Keppetipola KM, Chen M. Arterial diameter and the gender disparity in stroke thrombectomy outcomes.J Neurointerv Surg. 2018; 10:949–952. doi: 10.1136/neurintsurg-2017-013697CrossrefGoogle Scholar
  • 53. Ciurică S, Lopez-Sublet M, Loeys BL, Radhouani I, Natarajan N, Vikkula M, Maas AHEM, Adlam D, Persu A. Arterial tortuosity.Hypertension. 2019; 73:951–960. doi: 10.1161/HYPERTENSIONAHA.118.11647LinkGoogle Scholar
  • 54. Kotowycz MA, Johnston KW, Ivanov J, Asif N, Almoghairi AM, Choudhury A, Nagy CD, Sibbald M, Chan W, Seidelin PH, et al. Predictors of radial artery size in patients undergoing cardiac catheterization: insights from the Good Radial Artery Size Prediction (GRASP) study.Can J Cardiol. 2014; 30:211–216. doi: 10.1016/j.cjca.2013.11.021CrossrefMedlineGoogle Scholar
  • 55. Pandie S, Mehta SR, Cantor WJ, Cheema AN, Gao P, Madan M, Niemela K, Rao SV, Schwalm JD, Valentin V, et al. Radial versus femoral access for coronary angiography/intervention in women with acute coronary syndromes: insights from the RIVAL trial (RadIal Vs femorAL access for coronary intervention).JACC Cardiovasc Interv. 2015; 8:505–512. doi: 10.1016/j.jcin.2014.11.017CrossrefMedlineGoogle Scholar
  • 56. Al-Khatib WK, Zayed MA, Harris EJ, Dalman RL, Lee JT. Selective use of percutaneous endovascular aneurysm repair in women leads to fewer groin complications.Ann Vasc Surg. 2012; 26:476–482. doi: 10.1016/j.avsg.2011.11.026CrossrefMedlineGoogle Scholar
  • 57. Matteis M, Troisi E, Monaldo BC, Caltagirone C, Silvestrini M. Age and sex differences in cerebral hemodynamics: a transcranial Doppler study.Stroke. 1998; 29:963–967. doi: 10.1161/01.str.29.5.963LinkGoogle Scholar
  • 58. Joundi RA, Rebchuk AD, Field TS, Smith EE, Goyal M, Demchuk AM, Dowlatshahi D, Poppe AY, Williams DJ, Mandzia JL, et al. Health-related quality of life among patients with acute ischemic stroke and large vessel occlusion in the ESCAPE trial.Stroke. 2021; 52:1636–1642. doi: 10.1161/STROKEAHA.120.033872LinkGoogle Scholar
  • 59. Deb-Chatterji M, Konnopka A, Flottmann F, Leischner H, Fiehler J, Gerloff C, Thomalla G. Patient-reported, health-related, quality of life after stroke thrombectomy in clinical practice.Neurology. 2020; 95:e1724–e1732. doi: 10.1212/WNL.0000000000010356CrossrefMedlineGoogle Scholar
  • 60. Reeves M, Lisabeth L, Williams L, Katzan I, Kapral M, Deutsch A, Prvu-Bettger J. Patient-reported outcome measures (PROMs) for acute stroke: rationale, methods and future directions.Stroke. 2018; 49:1549–1556. doi: 10.1161/STROKEAHA.117.018912LinkGoogle Scholar
  • 61. Lloyd BB, Archer J. Problems and issues in research on gender differences.Curr Psychol Rev. 1981; 1:287–304Google Scholar
  • 62. World Medical Association. World Medical Association statement on access of women and children to health care.Accessed February 4, 2022. https://www.wma.net/policies-post/wma-resolution-on-access-of-women-and-children-to-health-care-and-the-role-of-women-in-the-medical-profession/Google Scholar
  • 63. al-Rajeh S, Larbi EB, Bademosi O, Awada A, Yousef A, al-Freihi H, Miniawi H. Stroke register: experience from the eastern province of Saudi Arabia.Cerebrovasc Dis. 1998; 8:86–89. doi: 10.1159/000015823Google Scholar
  • 64. Carcel C, Reeves M. Under-enrollment of women in stroke clinical trials: what are the causes and what should be done about it?Stroke. 2021; 52:452–457. doi: 10.1161/STROKEAHA.120.033227LinkGoogle Scholar
  • 65. Foerch C, Czapowski D, Misselwitz B, Steinmetz H, Neumann-Haefelin T; Arbeitsgruppe Schlaganfall Hessen (ASH). Gender imbalances induced by age limits in stroke trials.Neuroepidemiology. 2010; 35:226–230. doi: 10.1159/000319457Google Scholar
  • 66. Deleted in proofGoogle Scholar
  • 67. Cella D, Lai JS, Nowinski CJ, Victorson D, Peterman A, Miller D, Bethoux F, Heinemann A, Rubin S, Cavazos JE, et al. Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology.Neurology. 2012; 78:1860–1867. doi: 10.1212/WNL.0b013e318258f744CrossrefMedlineGoogle Scholar
  • 68. Polding LC, Tate WJ, Mlynash M, Marks MP, Heit JJ, Christensen S, Kemp S, Albers GW, Lansberg MG; DEFUSE 3 Investigators. Quality of life in physical, social, and cognitive domains improves with endovascular therapy in the DEFUSE 3 trial.Stroke. 2021; 52:1185–1191. doi: 10.1161/STROKEAHA.120.031490LinkGoogle Scholar
  • 69. Holloway RG, Arnold RM, Creutzfeldt CJ, Lewis EF, Lutz BJ, McCann RM, Rabinstein AA, Saposnik G, Sheth KN, Zahuranec DB, et al; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, and Council on Clinical Cardiology. Palliative and end-of-life care in stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2014; 45:1887–1916. doi: 10.1161/STR.0000000000000015LinkGoogle Scholar

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