Sage Journals: Discover world-class research

Abstract

Background:

The evolution of ischemic stroke is different accordin'g to sex and is one of the main causes of death in women. Previous studies have shown that women are less likely to receive acute treatment, and stroke center type is an important predictor of door-to-needle times. We investigated whether women are attended in a similar way to men in the telestroke network with specialized stroke physicians.

Methods:

A prospective registry of ischemic strokes recorded in the centralized Andalusian telestroke network was analyzed, focusing on sex differences. Demographic data, clinical characteristics, neuroimaging data, treatment intervals, follow-up visits, and clinical outcomes were collected.

Results:

A total of 3009 suspected stroke patients were attended to in the telestroke network from 2019 to 2023, of which 42.74% were women. Women were older (p < 0.001) and less independent upon arrival (p = 0.006) than men. There was no difference in the treatment received or in the treatment time intervals between the groups. Importantly, there was no difference in modified Rankin scale scores at 3 months between sexes. At 3 months post-stroke follow-up, women had fewer imaging tests (p = 0.018) and fewer outpatient visits (p < 0.001) than men.

Conclusions:

No significant difference between men and women has been found in the acute treatment of stroke in a large telestroke network. However, the same is not true for the follow-up and management of patients after the acute phase. This fact supports that strict adherence to protocols and specialization of care lead to equal care that avoids sex differences in stroke treatment and functional outcomes.

Background

Ischemic stroke is a global public health problem and constitutes one of the main causes of disability in adults. The clinical outcome of stroke differs between sexes, representing one of the main causes of death in women globally.¹ Several studies have considered the female sex as an independent predictive factor of disability.² It has not yet been fully clarified whether this difference is because of sex dimorphism or to treatment and management discrepancies. Women have less frequent use of acute stroke medication-based guidelines and are also less likely to receive thrombolysis than men.³

Moreover, women are older than men at stroke onset, a factor that could contribute to their comparatively worse outcome, despite adjustments for age differences.¹ It is generally assumed that strokes of cardioembolic etiology because of atrial fibrillation are more frequent in women, whereas atherothrombotic strokes are more frequent in men.^1,4 The differences in clinical outcomes after reperfusion therapies according to sex remain unclear; age and stroke severity at onset were found to be confounding factors in previous studies.^3,5

Innovation in health care and new technologies offer a great opportunity to reduce health care disparities, particularly in stroke. Telestroke is defined as telemedicine-enabled stroke consultation that allows patients to be treated in their local community hospital by an on-site physician with remote consultation by a specialist.⁶ The use of telestroke is now a class I recommendation by the American Heart Association.⁷ It is believed to have contributed to an overall increase in recombinant tissue plasminogen activator (rtPA) administration and reduced thrombolysis times, addressing geographic disparities in care. In this sense, it remains to be demonstrated whether these networks not only overcome the geographical problem but also inequalities in terms of sex or race. Previous studies have already suggested improving equity; however, findings remain inconclusive,⁸ probably because of the study size or the diversity of the networks analyzed.

In this study, we aimed to explore stroke management and the clinical results according to the sex of patients with suspected strokes managed within a telestroke network.

Methods

A prospective registry of ischemic strokes recorded in the centralized Andalusian telestroke network was analyzed, focusing on sex differences. Andalusia is a region of Spain in southern Europe with an area of 87,597 km² and a population of 8,381,944 inhabitants. The telestroke network has six mechanical thrombectomy nodes. Each node is composed of one hub or comprehensive stroke center (CSC), one stroke unit (SU), and several telestroke spoke centers (THs). A vascular neurologist coordinates the program and provides consultations in the morning shift. A pool of vascular neurologists from the different stroke centers is on call for the remaining shift. In addition to recommending the most appropriate treatment for each patient, the neurologist decides whether the patient should be transferred to an SU or CSC based on the patient’s individual needs and the resources available at each center at that time.

Picture archiving communication systems and medical records are centralized.

Owing to the convenience of having the entire population’s medical records already centralized, network requirements are minimal, consisting mainly of a videoconferencing system (a smartphone with a 4G connection to each center and an on-call neurologist) to allow communication between professionals.⁹

Demographic data, clinical characteristics, type of stroke, and risk factors (including age, diabetes, dyslipidemia, hypertension, smoking, alcohol intake, atrial fibrillation, and personal history of prior stroke/transient ischemic attack and heart disease) were collected for every patient. Neuroimaging evaluation of the current stroke was performed using computed tomography (CT), from which the ASPECTS score and the occluded vessel were determined. All CT are reviewed by the vascular neurologist and the local radiologist on call.

We collected data regarding treatment intervals. They were measured in each phase of the process (door-to-notification/activation time, door and notification-to-brain imaging time, door and notification-to-needle time, door-in-door-out time, door-origin and door-to-puncture femoral time, door-origin, and puncture-to-recanalization time).

Stroke severity was measured using the National Institute of Health Stroke Scale (NIHSS) performed by neurologists by videoconference. The follow-up of patients includes from acute hospitalization to 3 months post-discharge follow-up, adhering to the local protocol of the center where the patient was treated. The 3 months follow-ups were conducted either in person or via telephone, depending on the patient's situation and center protocol. This approach ensured comprehensive monitoring of patient progress and facilitated the collection of data on etiology, neuroimaging results, and the effectiveness of post-stroke interventions. Functional outcomes were evaluated with the modified Rankin Scale (mRS) at 90 days.

The study was approved by the regional ethics committee, PEIBA (Portal de Ética de la Investigación Biomédica de Andalucía) (protocol number: 1818-N-19).

Statistical Analysis

Two-sample t tests or chi-square tests were used to compare the clinical characteristics between men and women (based on sex from birth). Candidate covariates included were age, sex, age-by-sex interaction, NIHSS score at admission, diabetes mellitus, hypertension, atrial fibrillation, heart failure, coronary artery disease, and prior stroke.

Differences between women and men in stroke care in the acute phase (treatment interval times), follow-up, and stroke outcomes (NIHSS score at discharge and mRS at 90 days) were explored using the chi-square test.

All statistical analyses were performed using STATA version 17 (STATA Corp., College Station, TX). All reported p values were based on two-tailed analyses; statistical significance was set at p < 0.05.

Results

A total of 3009 suspected stroke patients were attended to within tele-ictus network from 2019 to 2021, of whom 1286 (42.74%) were women. Women were older than men (69.96 ± 15.77 vs. 68.15 ± 13.15 years, p < 0.001), and a total of 69.54% of the men and 63.85% of the women had been diagnosed with ischemic stroke during their telestroke consult (p = 0.002). Stroke mimics were diagnosed in a higher proportion in women than in men (22.70% vs. 16.34%, p = 0.001). The presence of diabetes mellitus, dyslipidemia, smoking, alcohol intake, previous stroke or TIA, and ischemic heart disease was significantly higher in men. In contrast, atrial fibrillation (31.55% vs. 26.07%, p = 0.038) was more frequent in women than in men. Regarding the ischemic stroke etiology, more cardioembolic strokes were found in women than in men (39.20% vs. 26.75%, p < 0.001). Complete baseline characteristics according to sex are shown in Table 1. Women also had more severe strokes, with higher NIHSS scores (median: 5, interquartile range [IQR] 1–10 vs. 4 IQR 1–9, p = 0.004).

Table 1.

Baseline Characteristics

	Women (n = 1286)	Men (n = 1723)	p
Age, years (mean, SD)	69.96 (15.77)	68.15 (13.16)	<0.001
Medical history, n, %
Atrial fibrillation/flutter	289 (31.56)	311 (26.08)	0.005
Diabetes mellitus	366 (38.73)	574 (44.91)	0.004
Hypertension	829 (75.78)	1058 (73.42)	0.178
Hyperlipidemia	453 (46.70)	664 (51.0)	0.043
Smoker	103 (15.9)	348 (34.87)	<0.001
Alcohol intake	23 (3.79)	263 (29.48)	<0.001
Prior stroke/transient ischemic attack	218 (24.77)	359 (30.02)	0.008
Cardiopathy	152 (17.63)	266 (23.23)	0.002
Clinical characteristics at presentation
NIHSS score at admission, median (IQR)	5 (1–10)	4 (1–9)	0.004
Prestroke mRS score ≤2 (n, %)	1023 (87.06)	1403 (90.40)	0.006
ASPECT ≥6, n, %	1683 (97.68)	1236 (96.11)	0.013
Treatment, n, %
Thrombolysis	104 (10.46)	171 (12.09)	0.215
Thrombectomy	137 (13.78)	164 (11.60)	0.111
Thrombolysis + Thrombectomy	83 (8.35)	120 (8.49)	0.906

Bold values are statistically significant.

SD, standard deviation; NIHSS, National Institute of Health Stroke Scale; IQR, interquartile range; mRS, modified Rankin scale.

Regarding radiological data, a higher percentage of men presented a favorable ASPECT (better than or equal to 6) than women in the initial CT (97.68 vs. 96.11, p = 0.013). The main locations of large vessel occlusion were M1 (37.63%) and M2 (23.48%) in women, while in men they were M1 (25.6%) and carotid internal artery (22.47%; p < 0.001). There was no significant difference in reperfusion treatment (24.25% in women vs. 24.91% in men, p = 0.699). There was also no difference when the treatment was analyzed separately, either in fibrinolytic (13.90% in women vs. 15.98% in men, p = 0.123) or in endovascular treatment (18.76% vs. 17.69%, p = 0.456), between groups. Regarding treatment intervals, there were no differences between the sexes (Table 2).

Table 2.

Differences in Time Intervals between Women and Men

	Women	Men	p
Time (minutes) from symptom onset to arrival at ED (mean, SD)	164.39 (389.07)	187.09 (323.69)	0.190
Time (minutes) from arrival at ED to notification activation (mean, SD)	90.19 (258.02)	87.73 (299.76)	0.829
Notification-to-CT scanner time (minutes) (mean, SD)	59.12 (325.14)	50.55 (113.05)	0.408
Door-to-needle time (minutes) (mean, SD)	89.92 (46.53)	89.99 (107.26)	0.993
Notification-to-needle time (minutes) (mean, SD)	37.63 (2.34)	42.77 (6.78)	0.473
Time (minutes) door-in-out (mean, SD)	159.63 (138.18)	174.46 (199.73)	0.248
Door origin-to-arterial puncture time (minutes) (mean, SD)	253.62 (90.63)	260.12 (126.66)	0.657
Puncture-to-reperfusion time (minutes) (mean, SD)	31.41 (32.49)	44.19 (40.47)	0.009

Bold values are statistically significant.

ED, emergency department; SD, standard deviation CT, computerized tomography.

A total of 90.23% of men and 84.25% of women were admitted to one of the network hospitals (p < 0.001), but there was a difference in the service on admission. Men were admitted more frequently to a neurospecialized service (stroke unit, neurology ward, or neurointensive care) than women (52.34% vs. 60.40%, p = 0.001). Details are shown in Table 3.

Table 3.

Differences on Admission Unit between Women and Men

	Women	Men	p
Stroke unit, n, %	316 (35.59)	482 (37.60)	0.339
Neurology ward, n, %	48 (5.41)	97 (7.57)	0.047
Neurointensive care, n, %	67 (7.55)	123 (9.59)	0.097
Internal medicine, n, %	344 (38.74)	434 (33.85)	0.020

Bold values are statistically significant.

At follow-up, women had fewer neuroimaging tests than men (69.51% vs. 74.05%, p = 0.018). Among patients who had follow-up neuroimaging, CT was performed in a greater number of women (32.61% vs. 26.70%, p = 0.011) and magnetic resonance imaging in a greater number of men (65.22% vs. 71.02%, p = 0.015).

Follow-up visits were conducted for 29.61% of patients with differences by sex (25.93% in women vs. 32.57% in men, p < 0.001). The global mortality rate was 14.86% without a difference between women and men (15.37% vs. 14.47%, p = 0.508), even after adjustment for confounders (mRS score, age, atrial fibrillation, previous TIA/stroke) (OR: 0.81; CI95%: 0.61–1.07). There was no significant difference by sex in good functional outcomes (mRS ≤ 2) at discharge (72.80% vs. 72.91%, p = 0.965) and 90 days (71.58% vs. 76.97%, p = 0.179) among surviving patients. After adjustment for confounders (age, diabetes, dyslipidemia, and ischemic heart disease), these data were maintained (OR: 0.93, CI95%: 0.59–1.47).

Discussion

Women have a higher burden of stroke mortality and disability than men.¹⁰ However, it is not clear whether this is because of purely biological differences in the response to brain ischemia and ischemic risk or to a disparity in health care provision.¹ Andalusia has been called the “Spanish Stroke Belt” on account of its high stroke mortality rate. A telestroke network was created to improve this statistic by reorganizing and improving stroke care in the region. In this way, inequalities between areas have been reduced since it has been achieved that almost the entire population is less than an hour away from a center where stroke treatment can be performed.¹¹

Regarding the acute phase and differences in health care provision between sexes, our data show that there are no important differences in the management of stroke in the acute phase with similar rates of treatments and interval times to treatment. Previous studies have shown that women are less likely to receive endovascular treatment or rtPA than men, even after adjusting for functional status before onset and the time from onset to the hospital door.^12,13 Stroke center type was also an important hospital-level predictor of tPA utilization and times to treatment in previous studies, with differences in patients treated in a rural/smaller hospital and those treated in metropolitan/larger hospitals.^14,15 Hospitals without specialized stroke care have longer delays, which is pronounced for women.⁵ One of the causes of treatment delays in women is the difficulty of diagnosis and presentation (stroke mimics are also more frequent in women in our study). However, this issue has been overcome with telestroke networks and specialized physicians. We also found longer times to reperfusion in men, probably related to proximal occlusions (internal carotid artery [ICA] and M1), which are more frequent in men and are usually of atheromatous origin that make the procedure more difficult.

Most studies have found that strokes are more severe in women than in men, although age may be a confounding factor. Although severity increases with age, previous studies have shown poor outcomes, even after adjusting for risk factor profile and age.¹⁶ The differences in the risk factor profile found in men and women seem to be one of the main points of interest. In general, most modifiable risk factors are found more frequently in men; however, women with modifiable risk factors have a greater likelihood of developing a stroke.¹⁷ Moreover, atrial fibrillation and ischemic strokes are more frequent in women.^18,19 These profiles are also met in our study.

Although functional outcomes after stroke usually differ according to sex, our study demonstrates that with proper management in the acute phase following established protocols by vascular neurologists, these outcomes can be balanced. Thus, the mRS at 3 months in our study was similar between both sexes. However, although there are no differences in acute management, there are differences in patient follow-up. In this case, this follow-up is not guided by neurologists and is performed according to the center. Men are admitted to the neurology service more frequently than women. Reasons for this finding may be that women are older at the onset of stroke or their previous functional grade, which, although not statistically significant, the trend is toward a higher previous mRS in women. It is known that admission to stroke units and treatment by specialized physicians reduces mortality and dependency and is recommended by the main management guidelines. Even for hemorrhagic strokes with high dependency and subsidiary mortality, admission to the stroke unit is better than admission to intensive care.²⁰ This different management may influence outcomes, and perhaps, the degree of dependence and mortality could be lower in women if they were treated the same as men.

Prior studies have shown that women are less likely than men to be investigated with standard diagnostic tests and that women admitted to hospitals with stroke are less likely to receive defect-free care.¹¹ In our study, women had fewer neuroimaging tests after stroke. This fact causes women to have a higher percentage of misdiagnoses. This could be related to admissions to nonspecialized units, internal medicine in most cases, which also results in poor follow-up. Only one-third of patients have any follow-up visits in the months after acute treatment, and most of these patients are men. This may affect our results since we do not have complete data for all patients. However, this indicates the need for specialized physicians with adequate training who can guarantee a complete study of all patients to ensure adequate secondary prevention.

On the one hand, one of the limitations of the study is that it is observational, and some data might be missing. On the other hand, its great strength is the large number of patients included and its prospective nature. The large number and the fact that they reflect routine clinical practice make the results very reliable.

Much effort has been made to reduce sex-based differences in the acute management of stroke, but there is still a significant gap in subacute management. These differences could be overcome with a comprehensive strategy that addresses the existing issues, including further education of physicians and written protocols, remote support from tertiary care institutions, and implementation of future subacute clinical trials that test rural/urban strategies for stroke care.

Footnotes

Acknowledgments

The preprint of the article (doi: https://doi.org/10.1101/2023.03.07.23286961) and has been posted on medRxiv: . Some data were presented as a poster at the 9th European Stroke Organisation Conference in Munich in 2023.

Data Availability

The present study is compliant with the journal’s data availability standards, and any data not provided in the article may be shared by request of other qualified investigators. The authors have full access to all the data in the study and take responsibility for its integrity and data analysis.

Authors’ Contributions

S.P.-S.: Conceptualization (lead); methodology (lead); writing—original draft (lead); formal analysis, writing and editing. A.B.-P.: Methodology, formal analysis (lead), supervision, writing—review and editing (equal). J.B.L.: Investigation, data management, review, and editing (equal). J.A.C.R.: Data collection, review and editing (equal). E.Z.-A.: Data collection, review, and editing. L.A.P.: Data collection, review. A.H.G.: Data management, review, and editing. M.Á.G.G.: Data collection, review, and editing. B.G.: review and editing. J.F.: Data collection, review, and editing. B.P.G.: Review and editing. A.D.M.: Data management, review, and editing. L.A.G.: Data management, review, and editing. J.F.N.: Data management, review, and editing. C.T.: Data management, review, and editing. M.M.: Data management, review, and editing. R.T.: Data management, review, and editing. P.B.: Data management, review, and editing. F.M.: Data management, review, and editing. R.V.M.: Data management, review, and editing. P.M.: Data management, review, and editing. A.G.: Conceptualization; methodology, review, and editing. J.M.: Conceptualization (lead); methodology, supervision, validation, review, and editing.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Abbreviations Used

References

Giralt

, Domingues-Montanari

, Mendioroz

, et al. The gender gap in stroke: A meta-analysis. Acta Neurol Scand, 2012; 125(2):83–90; doi: 10.1111/j.1600-0404.2011.01514.x

Hung

, Lai

, Hsu

, et al. Gender gap and risk factors for poor stroke outcomes: A single hospital-based prospective cohort study. J Stroke Cerebrovasc Dis, 2018; 27(8):2250–2258; doi: 10.1016/j.jstrokecerebrovasdis.2018.04.014

Liu

, Li

, Tang

, et al. The influence of sex in stroke thrombolysis: A systematic review and meta-analysis. J Clin Neurol, 2018; 14(2):141–152; doi: 10.3988/jcn.2018.14.2.141

Bushnell

, Howard

, Lisabeth

, et al. Sex differences in the evaluation and treatment of acute ischaemic stroke. Lancet Neurol, 2018; 17(7):641–650; doi: 10.1016/S1474-4422(18)30201-1

Pérez-Sánchez

, Barragán-Prieto

, Ortega-Quintanilla

, et al. Sex differences by hospital-level in performance and outcomes of endovascular treatment for acute ischemic stroke. J Stroke, 2020; 22(2):258–261; doi: 10.5853/jos.2019.03223

Verma

, Towfighi

, Brown

, et al. Moving towards equity with digital health innovations for stroke care. Stroke, 2022; 53(3):689–697; doi: 10.1161/STROKEAHA.121.035307

Schwamm

, Holloway

, Amarenco

, et al. A review of the evidence for the use of telemedicine within stroke systems of care: A scientific statement from the American Heart Association/American Stroke Association. Stroke, 2009; 40(7):2616–2634; doi: 10.1161/STROKEAHA.109.192360

Reddy

, Wu

, Zhang

, et al. Lack of racial, ethnic, and sex disparities in ischemic stroke care metrics within a tele-stroke network. J Stroke Cerebrovasc Dis, 2021; 30(1):105418; doi: 10.1016/j.jstrokecerebrovasdis.2020.105418

Barragán-Prieto

, Pérez-Sánchez

, Moniche

, et al. Express improvement of acute stroke care accessibility in large regions using a centralized telestroke network. Eur Stroke J, 2022; 7(3):259–266; doi: 10.1177/23969873221101282

10.

Rexrode

, Madsen

, Yu

AYX

, et al. The impact of sex and gender on stroke. Circ Res, 2022; 130(4):512–528; doi: 10.1161/CIRCRESAHA.121.319915

11.

Montaner

, Jiménez-Hernández

, López-Barneo

. How to unfasten the Spanish stroke belt? Andalusia chooses research. Int J Stroke, 2014; 9(7):946–949; doi: 10.1111/ijs.12332

12.

Uchida

, Yoshimura

, Sakai

, et al. Sex differences in management and outcomes of acute ischemic stroke with large vessel occlusion. Stroke., 2019; 50(7):1915–1918; doi: 10.1161/STROKEAHA.119.025344

13.

Lorenzano

, Ahmed

, Falcou

, et al. Does sex influence the response to intravenous thrombolysis in ischemic stroke? Answers from safe implementation of treatments in stroke—international stroke trombolysis register. Stroke, 2013; 44(12):3401–3406; doi: 10.1161/STROKEAHA.113.002908

14.

Leira

, Hess

, Torner

, et al. Rural-urban differences in acute stroke management practices: A modifiable disparity. Arch Neurol, 2008; 65(7):887–891; doi: 10.1001/archneur.65.7.887

15.

Read

, Levy

. Differences in stroke care practices between regional and metropolitan hospitals. Intern Med J, 2005; 35(8):447–450; doi: 10.1111/j.1445-5994.2005.00882.x

16.

Madsen

, Howard

, Jimenez

, et al. Impact of conventional stroke risk factors on stroke in women: An update. Stroke., 2018; 49(3):536–542; doi: 10.1161/STROKEAHA.117.018418

17.

Fang

, Singer

, Chang

, et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: The AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study. Circulation., 2005; 112(12):1687–1691; doi: 10.1161/CIRCULATIONAHA.105.553438

18.

Nielsen

, Skjoth

, Overvad

, et al. Female sex is a risk modifier rather than a risk factor for stroke in atrial fibrillation. Should we use CHA₂-DS₂-VA rather than CHA₂-DS₂-VASc? Circulation, 2018; 137(8):832–840; doi: 10.1161/CIRCULATIONAHA.117.029081

19.

Shantsila

, Wolff

, Lip

, et al. Gender differences in stroke prevention in atrial fibrillation in general practice: Using the GRASP-AF audit tool. Int J Clin Pract, 2015; 69(8):840–845; doi: 10.1111/ijcp.12625

20.

Ungerer

, Ringleb

, Reuter

, et al. Stroke unit admission is associated with better outcome and lower mortality in patients with intracerebral hemorrhage. Eur J Neurol, 2020; 27(5):825–832; doi: 10.1111/ene.14164

Closing the Sex-Based Differences in Stroke Care: Insights from a Large Telestroke Network on Treatment and Postacute Management

Abstract

Background:

Methods:

Results:

Conclusions:

Background

Methods

Statistical Analysis

Results

Discussion

Footnotes

Acknowledgments

Data Availability

Authors’ Contributions

Author Disclosure Statement

Funding Information

Abbreviations Used

References