Supplementary Material for: Sex-Based Analysis of Treatment, Time Metrics and Outcomes in Acute Ischemic Stroke Patients Treated in the Netherlands.

Introduction
Sex disparities in stroke treatment have gained increasing interest, especially since women have worse post-stroke functional outcomes compared with men. Existing studies provide conflicting evidence, with some indicating women have longer delays and less often receive acute treatment, whereas others show no differences between men and women. We aimed to explore sex differences in acute treatment modalities and time metrics of patients with acute ischemic stroke (AIS) in a real-world setting. Secondly, we examined whether functional outcomes differed by sex and whether this was influenced by treatment timing.

Methods
We analyzed data from the Dutch Acute Stroke Audit, a prospective consecutive registry of AIS patients from 72 hospitals in the Netherlands, between 2017 and 2020. We captured data on type of treatment administered (intravenous thrombolysis [IVT] and endovascular thrombectomy [EVT]), time metrics (onset-to-door time [OTDT], door-to-needle and door-to-groin times), and functional outcomes at three months (modified Rankin scale [mRS]). The association between sex and poor outcome (mRS 3-6) was assessed with Cox proportional hazard models stratified by type of treatment and adjusted for age, additionally for National Institute of Health Stroke Scale (NIHSS) and OTDT.

Results
Of the 58,632 patients, 26,941 (46%) were women. Compared with men, women were, older (mean age 74.6 versus 71.0, p<.001) and presented with slightly higher NIHSS-scores (median 3 [IQR 2-7] versus 3 [IQR 1-6], p<.001). Treatment modalities distribution (no treatment, IVT, EVT) was similar between women and men (64%; 29%; 10% versus 63%; 30%; 9%, p=.16). Women had a slightly longer OTDT (median 145 versus 139 minutes, p<.01). Women had increased odds of poor outcomes (OR 1.49 [95%CI 1.34-1.56]). This was still statistically significant after adjusting for age and NIHSS-score (OR 1.22 [95%CI 1.16-1.28]). Neither treatment modality nor OTDT had an additional influence on this association.

Conclusion
In this large real-world registry, we observed no differences in distribution of treatment modalities between sexes. We did find a minor pre-hospital delay in women and worse functional outcomes in women. The minor delay in OTDT does not fully explain the observed worse outcomes in women. Our results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Dutch centers.

引言
卒中诊疗中的性别差异愈发受到学界关注，尤其是相较于男性患者，女性卒中后功能预后更差这一临床现象。现有研究结论存在分歧：部分研究显示女性的诊疗延误时间更长，且更少接受急性期治疗，而另有研究则认为男女之间并无此类差异。本研究旨在探究真实世界场景下急性缺血性卒中（acute ischemic stroke, AIS）患者的急性期诊疗方式与时间指标的性别差异；其次，本研究还探讨了功能预后是否存在性别差异，以及该差异是否受诊疗时机的影响。

方法
本研究分析了《荷兰急性卒中审计》（Dutch Acute Stroke Audit）的数据，该数据库为2017至2020年间荷兰72家医院收录的急性缺血性卒中患者前瞻性连续登记库。本研究收集了以下数据：给药治疗类型（包括静脉溶栓（intravenous thrombolysis, IVT）与血管内取栓（endovascular thrombectomy, EVT））、时间指标（发病到院时间（onset-to-door time, OTDT）、进门到给药时间及进门到股动脉穿刺时间），以及患者发病3个月时的功能预后情况（采用改良Rankin量表（modified Rankin scale, mRS）评估）。本研究采用按治疗类型分层的Cox比例风险模型，评估性别与不良预后（mRS评分3~6分）之间的关联，并校正了年龄、美国国立卫生研究院卒中量表（National Institute of Health Stroke Scale, NIHSS）评分及OTDT等混杂因素。

结果
本研究共纳入58632例患者，其中女性26941例，占比46%。与男性患者相比，女性患者年龄更大（平均年龄74.6岁 vs 71.0岁，P<0.001），美国国立卫生研究院卒中量表评分略高（中位数3分，四分位数间距2~7分 vs 中位数3分，四分位数间距1~6分，P<0.001）。男女患者的诊疗方式分布（未治疗、IVT、EVT）相似，分别为64%、29%、10%与63%、30%、9%（P=0.16）。女性患者的发病到院时间略长（中位数145分钟 vs 139分钟，P<0.01）。女性患者出现不良预后的优势比更高（优势比1.49，95%置信区间1.34~1.56）；在校正年龄与NIHSS评分后，该差异仍具有统计学意义（优势比1.22，95%置信区间1.16~1.28）。诊疗方式与发病到院时间均未对该关联产生额外影响。

结论
在这项大型真实世界登记研究中，本研究未观察到男女患者的诊疗方式分布存在差异。本研究发现女性患者存在轻微的院前延误，且功能预后更差。发病到院时间的轻微延迟无法完全解释女性患者更差的功能预后。本研究结果表明，荷兰所有参与本研究的医疗中心在急性卒中诊疗过程中均未出现明显的性别偏向，这一结论令人安心。