Front. Neurol. Frontiers in Neurology Front. Neurol. 1664-2295 Frontiers Media S.A. 10.3389/fneur.2024.1341423 Neurology Brief Research Report Sex differences in functional outcomes of intravenous thrombolysis among patients with lacunar stroke Wueger Patrizia 1 † Noseda Roberta 2 † Pagnamenta Alberto 3 4 5 Bianco Giovanni 6 Seiffge David 7 Michel Patrik 8 Nedeltchev Krassen 9 Bonati Leo 10 Kägi Georg 11 Niederhauser Julien 12 Nyffeler Thomas 13 Luft Andreas 14 Wegener Susanne 14 Schelosky Ludwig 15 Medlin Friedrich 16 Rodic Biljana 17 Peters Nils 18 Renaud Susanne 19 Mono Marie Luise 20 Carrera Emmanuel 21 Fischer Urs 7 10 De Marchis Gian Marco 11 Cereda Carlo W. 1 6 * 1Faculty of Biomedical Sciences, Università Della Svizzera Italiana, Lugano, Switzerland 2Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland 3Clinical Trial Unit, Ente Ospedaliero Cantonale, Lugano, Switzerland 4Department of Intensive Care, Ente Ospedaliero Cantonale, Lugano, Switzerland 5Division of Pneumology, University of Geneva, Geneva, Switzerland 6Neurocentre of Southern Switzerland, Ospedale Regionale di Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland 7Department of Neurology, University Hospital Bern, Bern, Switzerland 8Stroke Center, Neurology Service, Lausanne University Hospital, Lausanne, Switzerland 9Department of Neurology, Kantonsspital Aarau, Aarau, Switzerland 10Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland 11Department of Neurology, Kantonsspital St. Gallen, St. Gallen, Switzerland 12Stroke Unit, Hopital Nyon, Nyon, Switzerland 13Center of Neurology and Neurorehabilitation, Luzerner Kantonsspital, Luzern, Switzerland 14Department of Neurology, Universitätsspital Zürich, Zürich, Switzerland 15Division of Neurology, Kantonsspital Münsterlingen, Münsterlingen, Switzerland 16Division of Neurology, HFR Fribourg, Stroke Unit, Fribourg, Switzerland 17Department of Neurology, Kantonsspital Winterthur, Winterthur, Switzerland 18Department of Neurology and Stroke Center, Hirslanden Hospital, Zurich, Switzerland 19Division of Neurology, Pourtalès Hospital, Neuchatel, Switzerland 20Stroke Unit, Stadtspital Waid und Triemli, Zürich, Switzerland 21Department of Neurology, Hôpitaux Universitaires de Genève, Geneva, Switzerland

Edited by: Francesco Corea, Azienda USL Umbria 2, Italy

Reviewed by: Marialuisa Zedde, IRCCS Local Health Authority of Reggio Emilia, Italy

Massimo Del Sette, Ente Ospedaliero Ospedali Galliera, Italy

Ana Isabel Fumagalli, Sanatorio Parque Rosario Argentina, Argentina

 *Correspondence: Carlo W. Cereda, carlo.cereda@eoc.ch

†These authors share first authorship

 13 02 2024 2024 15 1341423 20 11 2023 24 01 2024 Copyright © 2024 Wueger, Noseda, Pagnamenta, Bianco, Seiffge, Michel, Nedeltchev, Bonati, Kägi, Niederhauser, Nyffeler, Luft, Wegener, Schelosky, Medlin, Rodic, Peters, Renaud, Mono, Carrera, Fischer, De Marchis and Cereda. 2024 Wueger, Noseda, Pagnamenta, Bianco, Seiffge, Michel, Nedeltchev, Bonati, Kägi, Niederhauser, Nyffeler, Luft, Wegener, Schelosky, Medlin, Rodic, Peters, Renaud, Mono, Carrera, Fischer, De Marchis and Cereda

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 Background

This study aimed to assess if there are sex differences in the functional outcome of intravenous thrombolysis (IVT) among patients with lacunar stroke (LS).

 Methods

Consecutive patients admitted from 1 January 2014 to 31 January 2020 to hospitals participating in the Swiss Stroke Registry presenting with LS and treated with IVT were included. The study population was then divided into two groups based on patient sex, and a multivariable ordinal logistic regression analysis was performed to uncover sex differences in the modified Rankin Scale (mRS) score at 90 days after stroke.

 Results

A total of 413 patients with LS were treated with IVT: 177 (42.9%) women and 236 (57.1%) men. Women were older than men (median age 74 years, 25th–75th percentiles 67–84 years versus 70 years, 25th–75th percentiles 60–80 years, value of p 0.001) and, after adjustment for meaningful variables, showed more frequently increased odds of a higher mRS score at 90 days after stroke (adjusted odds ratio 1.49, 95% confidence interval 1.01–2.19, value of p 0.044).

 Conclusion

This study showed that female sex increased the odds of a worse functional response to IVT in patients with LS. Future studies should further elucidate the mechanisms underlying such sex differences.

 lacunar stroke intravenous thrombolysis sex differences functional outcome cohort study section-at-acceptance Stroke Introduction

Lacunar stroke (LS), which accounts for about a quarter of all acute ischaemic strokes (AIS) (1), is a sequela of cerebral small vessel disease (cSVD), a disorder of cerebral microvessels whose underlying pathogenesis remains not completely understood (2–4). Consequently, there are extensive debates on whether LS would benefit from acute reperfusion with intravenous thrombolysis (IVT) (5, 6), which is nowadays the approved treatment for AIS regardless of stroke subtype (7). It was shown that a better functional outcome was present in patients with LS treated with IVT as compared to patients with LS not treated with IVT (8) and that the functional outcome after IVT did not differ in patients with LS compared with other stroke subtypes (9).

LS prevalence is higher with age (10) and seems to be more frequent and severe in men than women (11, 12). Nevertheless, it has not yet been clarified whether there are sex differences in functional outcomes following IVT, specifically in patients with LS. Therefore, this study aimed to assess sex differences in the functional outcome of IVT as a distribution of the modified Rankin Scale (mRS) score at 90 days after stroke among patients with LS from the Swiss Stroke Registry (SSR).

 Methods Swiss stroke registry

This was a multicenter retrospective cohort study in the SSR, a national registry that collects standardized data from all consecutive patients admitted to certified stroke units and stroke centers across Switzerland. Data collected encompass patient demographics, medical history, medications used before admission, pre-stroke functional status, diagnostic procedures, in-hospital treatments, and outcomes (both during hospitalization and 90 days after stroke). The Clinical Trial Unit of the University Hospital of Basel, Switzerland, manages the database and provides irreversible anonymized data for study purposes. At the time of hospitalization, patients were informed about the collection and utilization of their personal data through informed consent. The registry and the present study were both approved by the responsible ethics committee (CE Req-2020-01042).

 Study population

Consecutive patients admitted from 1 January 2014 to 31 January 2020 to hospitals participating in the SSR presenting with LS and treated with IVT were included (Figure 1). In the SSR, the etiology of AIS refers to the TOAST classification (13). The diagnosis of LS was suspected in patients who presented with a recognized lacunar syndrome (e.g., pure motor hemiparesis, pure sensory stroke, ataxic hemiparesis, sensorimotor stroke, and dysarthria-clumsy hand syndrome) or other acute stroke symptoms without cortical involvement and was eventually confirmed upon finding a small subcortical infarct on CT or MRI. The study population was divided into two groups based on patient sex and thereafter compared in terms of patient demographics (age at the time of stroke onset and use of antiplatelets and/or anticoagulants before hospital admission), medical history (previous stroke, previous transient ischemic attack, previous intracranial hemorrhage, hypertension, diabetes, hyperlipidemia, smoking, and atrial fibrillation), pre-stroke functional status (i.e., disability as mRS score ranging from 0 = no symptoms to 6 = death), and stroke severity assessed as National Institutes of Health Stroke Scale (NIHSS) - score at admission (a measure of neurological deficits, ranging from 0 to 42, with higher scores indicating greater stroke severity), in-hospital treatments, and outcomes at 90 days after stroke.

CONSORT diagram showing the selection process of patients included in the study. SSR, Swiss Stroke Registry; IVT, intravenous thrombolysis; MT, mechanical thrombectomy; LVO, large vessel occlusion.

 Outcomes

The primary outcome was defined as the mRS score at 90 days after stroke and assessed in an ordinal logistic regression analysis (shift analysis). The safety outcome was in-hospital symptomatic intracerebral hemorrhage (sICH), defined as ICH with ≥4-point worsening of the NIHSS score occurring within 7 days of AIS onset.

 Statistical analyses

Quantitative data were presented as absolute numbers with percentages (if categorical) or as median with the 25th and 75th percentiles (if continuous). Comparisons of the different variables according to patient sex were performed with the Mann–Whitney test or chi-squared test, as appropriate. To investigate sex differences in the primary functional outcome of IVT among patients with LS, ordinal logistic regression was used. At first, the association between patient sex and other independent variables of clinical significance and the mRS score at 90 days after stroke was assessed in univariate models. Subsequently, patient sex and variables with a value of p ≤0.1 from univariate analyses were included in a multivariable ordinal logistic regression model to provide an overall point estimate as an odds ratio representing a shift in scores on the mRS at 90 days after stroke. All analyses were performed two-sided, and a value of p less than 0.05 was considered statistically significant. Analyses were performed using Statistical Analysis System Software (version 9.4; SA Institute, Cary, NC).

 Results

Out of 5,412 AIS patients treated with IVT, 413 suffered from LS. Supplementary Table S1 shows the distribution of hospitals participating in the SSR from which patients included in the present study were selected. There were 177 women (42.9%) and 236 men (57.1%) (Figure 1). Women were older than men (median age 74 years, 25th–75th percentiles 67–84 years, versus 70 years, 25th–75th percentiles 60–80 years, value of p = 0.001). No sex differences were observed in the use of antiplatelets before admission, medical history, pre-stroke disability, or NIHSS score at admission. Female patients showed more frequently worse functional outcomes (both primary and secondary) than male patients, among whom an event of in-hospital sICH occurred (Table 1). No events of sICH occurred among female patients.

Characteristics of the study population according to patient sex.

Characteristic Females(N = 177) Males(N = 236) Value of p
Age, years, No. (%)<6565–74≥75median [25th–75th percentiles] 31 (17.5)58 (32.8)88 (49.7)74 [67–84] 79 (33.5)68 (28.8)89 (37.7)70 [60–80] 0.001<0.0001
Antiplatelets before admission, No. (%)NoYes, single therapyAspirinClopidogrel 120 (67.8)57 (32.2)49 (27.7)8 (4.5) 160 (67.8)76 (32.2)59 (25.0)17 (7.2) 1.0000.5390.258
Medical history, No.(%)Previous strokePrevious transient ischemic attackPrevious intracranial hemorrhageHypertensionDiabetesHyperlipidemiaSmokingAtrial fibrillation 16 (9.0)12 (6.8)5 (2.8)145 (81.9)35 (19.8)128 (72.3)32 (18.1)4 (2.3) 29 (12.3)11 (4.7)2 (0.9)182 (77.1)59 (25.0)185 (78.4)83 (35.2)5 (2.1) 0.2940.3530.1440.2340.2100.1540.00011.000
Prestroke disability, No. (%)mRS score 0mRS score 1mRS score 2mRS score 3mRS score 4mRS score 5 107 (60.5)26 (14.7)6 (3.4)11 (6.2)1 (0.6)1 (0.6) 153 (64.8)23 (9.8)12 (5.1)7 (3.0)4 (1.7)- 0.164
Onset to treatment time (min)median [25th–75th percentiles] 122 (68.9)207 [131–242] 178 (75.4)200 [132–228] 0.497
Door to treatment time (min)median [25th–75th percentiles] 166 (93.8)38 [28–53] 220 (93.2)39 [29–55] 0.709
NIHSS at admission, No. (%)0–45–1011–1516–21≥22median [25th–75th percentiles] 69 (39.0)95 (53.7)12 (6.8)1 (0.6)0 (0.0)5 [3.5–7] 108 (45.8)111 (47.0)12 (5.1)4 (1.7)1 (0.4)5 [4–7] 0.3680.496
Functional outcomes at 90 days after stroke, No. (%)PrimarymRS score0123456SecondaryFunctional independence (mRS 0–2) 42 (23.7)45 (25.4)33 (18.6)29 (16.4)26 (14.7)0 (0)2 (1.1)120 (67.8) 82 (34.8)61 (25.9)48 (20.3)20 (8.5)18 (7.6)0 (0)7 (3.0)191 (80.9) 0.0070.002
Safety outcome at 90 days after stroke, No. (%)In-hospital sICH 0 (0) 1 (0.6) 0.430

mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; IVT, intravenous thrombolysis.

Univariate ordinal logistic regression analyses demonstrated that patient sex, use of antiplatelets before admission, previous stroke, medical history of hypertension and hyperlipidemia, as well as pre-stroke disability and NIHSS at admission, were associated with the mRS score at 90 days after stroke (Table 2). After adjustment, female sex was associated with increased odds of presenting a higher mRS score at 90 days after stroke than male sex (adjusted OR 1.49, 95% CI 1.01–2.19, value of p 0.044, Table 2).

Univariate and multivariable logistic regression analyses.

Independent variables Distribution of the mRS score at 90 days after stroke(shift analysis)
Univariate modelOR [95% CI] Value of p Multivariable modelAdjusted OR [95% CI] Value of p
Patient sex (female versus male) 0.59 [0.42–0.84] 0.003 1.49 [1.01–2.19] 0.044
Patient age (≥65 years versus < 65 years) 0.77 [0.52–1.14] 0.197 – –
Use of antiplatelets before admission (yes versus no) 0.48 [0.33–0.69] <0.0001 1.47 [0.94–2.29] 0.094
Previous stroke (yes versus no) 0.50 [0.29–0.87] 0.014 1.16 [0.59–2.30] 0.663
Previous transient ischemic attack (yes versus no) 1.01 [0.48–2.13] 0.9901 – –
Hypertension (yes versus no) 0.70 [0.46–1.08] 0.108 1.51 [0.91–4.50] 0.112
Diabetes (yes versus no) 0.90 [0.60–1.36] 0.6126 – –
Hyperlipidemia (yes versus no) 1.39 [0.93–2.08] 0.105 0.50 [0.32–0.80] 0.004
Smoking (yes versus no) 1.29 [0.88–1.89] 0.1990 – –
Prestroke disability (mRS 0 versus mRS 1–6) 0.23 [0.15–0.36] <0.0001 3.62 [2.27–5.76] <0.0001
NIHSS at admission (<5 versus ≥ 5) 0.55 [0.39–0.78] 0.001 1.75 [1.19–2.58] 0.005

OR, odds ratio; CI, confidence interval; mRS, modified Rankin Scale. In bold are variables with a value of p ≤ 0.1 that were included in the multivariable regression models.

 Discussion

This study showed that female sex is an independent predictor of a 90-day worse functional outcome in patients with LS treated with IVT. This result, not specifically addressed before, is novel and in line with a previous specific sex-oriented observation performed by our group on IVT efficacy in AIS patients across all stroke subtypes (14).

The reasons behind sex differences in IVT functional outcomes in LS patients are probably multifactorial. First, female patients in our study cohort were older than male patients. Although previous studies have shown that the worse functional outcome after IVT in female patients compared to male patients is not age-dependent (15), additional unmeasured sex- and age-related differences in vascular mechanisms might be involved (such as platelet reactivity or an increase in chronic low-grade systemic inflammation, which has been described to be higher in elderly female patients) (16). Second, the same vascular mechanisms could influence the safety of IVT in LS patients differently between female and male patients. Notably, in our study population, sICH, a feared side effect in patients with small vessel disease, was a rare event. Third, some environmental and social conditions, such as the pre- and post-hospital living situation, might have influenced the worse functional outcome of IVT among female patients with LS. However, despite correcting for the pre-stroke Rankin scale score and choosing a shift analysis as the primary outcome measure, the SSR does not collect detailed information about patient living and social conditions. A fourth factor potentially influencing sex differences in the functional outcome of IVT among LS patients may be related to disparities between male and female patients in acute stroke management, as reported in previous studies (17). However, we found no differences in the timing of treatment between the two sexes. Finally, the different locations of ischemic lesions between female and male patients could have contributed to the worse functional outcome observed in female patients (18). Nevertheless, based on the variables collected within the SSR, we cannot know the specific volumetric measurements of ischemic lesions as well as their location and other neuroimaging details.

Although the national coverage of the SSR may limit the generalizability of the results, the present study evaluates a numerically significant cohort of LS patients with IVT, leveraging the need for future studies aimed at defining the sex-specific mechanisms underlying a worse functional outcome of IVT in female patients with LS.

 Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, on request.

 Ethics statement

The study was approved by Comitato Etico Canton Ticino (CE Req-2020-01042). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

 Author contributions

PW: Data curation, Validation, Visualization, Writing – original draft. RN: Data curation, Formal analysis, Investigation, Software, Validation, Visualization, Writing – original draft. AP: Data curation, Formal analysis, Investigation, Methodology, Software, Writing – review & editing. GB: Resources, Writing – review & editing. DS: Resources, Writing – review & editing. PM: Resources, Writing – review & editing. KN: Resources, Writing – review & editing. LB: Resources, Writing – review & editing. GK: Resources, Writing – review & editing. JN: Resources, Writing – review & editing. TN: Resources, Writing – review & editing. AL: Resources, Writing – review & editing. SW: Resources, Writing – review & editing. LS: Resources, Writing – review & editing. FM: Resources, Writing – review & editing. BR: Resources, Writing – review & editing. NP: Resources, Writing – review & editing. SR: Resources, Writing – review & editing. MM: Resources, Writing – review & editing. EC: Resources, Writing – review & editing. UF: Resources, Writing – review & editing. GM: Resources, Writing – review & editing. CC: Conceptualization, Funding acquisition, Investigation, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing.

 Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

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 Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2024.1341423/full#supplementary-material

 References Sacco S Marini C Totaro R Russo T Cerone D Carolei A. A population-based study of the incidence and prognosis of lacunar stroke. Neurology. (2006) 66:1335–8. doi: 10.1212/01.wnl.0000210457.89798.0e, PMID: 16682663 Wardlaw JM Smith C Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. (2019) 18:684–96. doi: 10.1016/S1474-4422(19)30079-1 Markus HS de Leeuw FE. Cerebral small vessel disease: recent advances and future directions. Int J Stroke. (2023) 18:4–14. doi: 10.1177/17474930221144911, PMID: 36575578 Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. (2010) 9:689–701. doi: 10.1016/S1474-4422(10)70104-6, PMID: 20610345 Pantoni L Fierini F Poggesi A. Thrombolysis in acute stroke patients with cerebral small vessel disease. Cerebrovasc Dis. (2014) 37:5–13. doi: 10.1159/000356796 Caplan LR Mohr JP Kistler JP Koroshetz W. Should thrombolytic therapy be the first-line treatment for acute ischemic stroke? Thrombolysis--not a panacea for ischemic stroke. N Engl J Med. (1997) 337:1309–13. doi: 10.1056/NEJM199710303371812, PMID: 9345084 National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. (1995) 333:1581–8. doi: 10.1056/NEJM199512143332401 Matusevicius M Paciaroni M Caso V Bottai M Khurana D de Bastos M . Outcome after intravenous thrombolysis in patients with acute lacunar stroke: an observational study based on SITS international registry and a meta-analysis. Int J Stroke. (2019) 14:878–86. doi: 10.1177/1747493019840947, PMID: 30935349 Barow E Boutitie F Cheng B Cho TH Ebinger M Endres M . WAKE-UP investigators. Functional outcome of intravenous thrombolysis in patients with lacunar infarcts in the WAKE-UP trial. JAMA Neurol. (2019) 76:641–9. doi: 10.1001/jamaneurol.2019.0351, PMID: 30907934 Arboix A Massons J García-Eroles L Targa C Comes E Parra O . Nineteen-year trends in risk factors, clinical characteristics and prognosis in lacunar infarcts. Neuroepidemiology. (2010) 35:231–6. doi: 10.1159/000319460, PMID: 20861654 Jiménez-Sánchez L Hamilton OKL Clancy U Backhouse EV Stewart CR Stringer MS . Sex differences in cerebral small vessel disease: a systematic review and Meta-analysis. Front Neurol. (2021) 12:756887. doi: 10.3389/fneur.2021.756887, PMID: 34777227 Arboix A Cartanyà A Lowak M García-Eroles L Parra O Oliveres M . Gender differences and woman-specific trends in acute stroke: results from a hospital-based registry (1986-2009). Clin Neurol Neurosurg. (2014) 127:19–24. doi: 10.1016/j.clineuro.2014.09.024, PMID: 25459238 Adams HP Jr Bendixen BH Kappelle LJ Biller J Love BB Gordon DL . Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke. (1993) 24:35–41. doi: 10.1161/01.str.24.1.35, PMID: 7678184 Noseda R Rea F Pagnamenta A Agazzi P Bianco G Sihabdeen S . Sex differences in outcomes of intravenous thrombolysis in acute ischemic stroke patients with preadmission use of Antiplatelets. CNS Drugs. (2023) 37:351–61. doi: 10.1007/s40263-023-00997-7, PMID: 36976463 Spaander FH Zinkstok SM Baharoglu IM Gensicke H Polymeris A Traenka C . Sex differences and functional outcome after intravenous thrombolysis. Stroke. (2017) 48:699–703. doi: 10.1161/STROKEAHA.116.014739 Sabetta A Lombardi L Stefanini L. Sex differences at the platelet-vascular interface. Intern Emerg Med. (2022) 17:1267–76. doi: 10.1007/s11739-022-02994-y, PMID: 35576047 Gargano JW Wehner S Reeves MJ. Do presenting symptoms explain sex differences in emergency department delays among patients with acute stroke? Stroke. (2009) 40:1114–20. doi: 10.1161/STROKEAHA.108.543116, PMID: 19211483 Ryu WS Chung J Schellingerhout D Jeong SW Kim HR Park JE . Biological mechanism of sex difference in stroke manifestation and outcomes. Neurology. (2023) 100:e2490–503. doi: 10.1212/WNL.0000000000207346, PMID: 37094993