Abstract Background and aims Endovascular therapy (EVT) has revolutionized outcomes for large vessel occlusion (LVO) strokes, yet intravenous thrombolysis (IVT) remains the sole reperfusion therapy for lacunar strokes (LS). While LS microvascular mechanisms may limit IVT efficacy, studies have reported benefits of IVT in this population. However, IVT outcomes in LS have not been systematically compared with non-lacunar strokes of similar clinical severity in large, contemporary cohorts. Methods We analyzed prospectively collected data from the Swiss Stroke Registry (2014-2025). We included IVT-treated adult patients with supratentorial acute ischemic stroke: LS (mTOAST criteria) versus non-lacunar non-LVO strokes. Primary outcome was 90-day mRS shift analysis. Secondary outcomes included excellent outcome (mRS 0-1), functional independence (mRS 0-2), moderate-to-severe disability (mRS 3-5), overall mortality, and symptomatic ICH. Models were adjusted for major baseline clinical-demographic and treatment-related confounders. Results Among 3,941 included patients (603 LS; 3,338 non-lacunar non-LVO), baseline stroke severity was comparable between groups (median NIHSS 5, IQR 3-7 vs. 3-8). mRS shift analysis showed worse outcomes in LS (aOR 0.72 95% CI 0.62-0.85). LS patients had 31% lower odds of excellent outcome (aOR 0.69 0.56-0.83), 26% lower odds of functional independence (aOR 0.74 0.59-0.93), and 73% higher odds of moderate-to-severe disability (aOR 1.73 1.38-2.18). Conversely, LS demonstrated lower mortality (aOR 0.52 0.33-0.84) and symptomatic ICH (aOR 0.49 0.21-0.98). Conclusions Despite comparable severity and superior safety, IVT-treated lacunar stroke patients experienced worse functional recovery than non-LVO strokes. This observation challenges the common concept of LS as a benign entity and highlights a significant therapeutic gap in lacunar stroke care. Conflict of interest David J. Seiffge has served on advisory boards and received personal fees from Bayer, Alexion/AstraZeneca, and VarmX; he has also received research grants from the Swiss National Science Foundation, Swiss Heart Foundation, and Bangerter-Rhyner Foundation. Joanna Wardlaw reports serving as an advisor to IXICO. The remaining authors declare no relevant potential conflicts of interest. Figure 1 - belongs to Methods Figure 2 - belongs to Results
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