Predictive Value of the Neutrophil-to-Lymphocyte Ratio for Prognosis in Patients with Acute Ischemic Stroke after Intravenous Thrombolysis: An Individual Patient Data Analysis Based on Three Randomized Controlled Trials

doi:10.3969/j.issn.1673-5765.2026.01.004

Abstract

Abstract: Objective To analyze the association between the neutrophil-to-lymphocyte ratio (NLR) before intravenous thrombolysis, at 24 hours and 7 days after intravenous thrombolysis and poor prognosis at 90 days in patients with acute ischemic stroke (AIS) within 4.5 hours of onset.
Methods This study integrated data of AIS patients who received intravenous thrombolysis within 4.5 hours of onset from three phase Ⅲ clinical trials (TRACE-Ⅱ, RAISE, PROST-2) conducted in China between March 2021 and March 2024. According to the mRS score at 90 days after intravenous thrombolysis, patients were divided into a favorable prognosis (mRS score 0-1) group and a poor prognosis (mRS score 2-6) group. Baseline characteristics including age, gender, and past medical history, as well as inflammatory indicators before intravenous thrombolysis, at 24 hours and 7 days after intravenous thrombolysis were collected for both groups. The inflammatory indicators included white blood cell count, lymphocyte count, neutrophil count, NLR, systemic immune inflammation index, platelet-to-lymphocyte ratio, and platelet-to-neutrophil ratio. The AUC was used to evaluate the predictive value of each inflammatory indicator for poor prognosis at 90 days in AIS patients after intravenous thrombolysis. Multivariate logistic regression analysis and restricted cubic spline model were applied to analyze the association between NLR and poor prognosis at 90 days in AIS patients after intravenous thrombolysis.
Results A total of 4273 AIS patients were enrolled. Among the seven inflammatory indicators measured at different time points, NLR at 24 hours after intravenous thrombolysis showed the best predictive efficacy for poor prognosis at 90 days (AUC 0.69). Multivariate logistic regression analysis indicated that elevated NLR was associated with an increased risk of poor prognosis at 90 days (OR 1.17, 95%CI 1.14-1.21, P<0.001). After adjusting for potential confounding factors, patients with NLR≥3.21 had a 1.55-fold higher risk of poor prognosis at 90 days compared to those with NLR<3.21 (OR 2.55, 95%CI 2.19-2.97, P<0.001). Restricted cubic spline analysis revealed a positive nonlinear relationship between NLR at 24 hours after intravenous thrombolysis and the risk of poor prognosis at 90 days in AIS patients (P<0.001).
Conclusions For AIS patients receiving intravenous thrombolysis within the standard time window, an NLR cutoff value of 3.21 can identify high risk populations with poor prognosis, providing a simple and objective reference for individualized clinical intervention.

Key words: Acute ischemic stroke; Inflammatory indicator; Intravenous thrombolysis; Individual patient data analysis; Neutrophil-to-lymphocyte ratio

摘要： 目的分析发病4.5 h内急性缺血性卒中（acute ischemic stroke，AIS）患者静脉溶栓前、静脉溶栓后24 h和静脉溶栓后7 d中性粒细胞与淋巴细胞比值（neutrophil-to-lymphocyte ratio，NLR）与90 d预后不良的关系。
方法本研究整合了2021年3月—2024年3月在中国开展的3项Ⅲ期临床研究（TRACE-Ⅱ、RAISE、PROST-2）中发病4.5 h内接受静脉溶栓治疗的AIS患者数据。根据静脉溶栓后90 d mRS评分，将患者分为预后良好（mRS评分为0～1分）组与预后不良（mRS评分为2～6分）组。收集两组患者的年龄、性别、既往病史等基线特征，以及静脉溶栓前、静脉溶栓后24 h和静脉溶栓后7 d的炎症指标（包括白细胞计数、淋巴细胞计数、中性粒细胞计数、NLR、系统性免疫炎症指数、血小板与淋巴细胞比值、血小板与中性粒细胞比值）。通过ROC曲线的AUC评估各项炎症指标对AIS患者静脉溶栓后90 d预后不良的预测价值。通过多因素logistic回归分析和限制性立方样条模型，分析NLR与AIS患者静脉溶栓后90 d预后不良之间的关联。
结果共纳入4273例AIS患者。在不同时间点检测的7项炎症指标中，静脉溶栓后24 h NLR对90 d预后不良的预测效能最佳（AUC 0.69）。多因素logistic回归分析显示，NLR升高与90 d预后不良风险增加相关（OR 1.17，95%CI 1.14～1.21，P<0.001）。在校正潜在混杂因素后，NLR≥3.21的患者较NLR<3.21的患者90 d预后不良风险增加1.55倍（OR 2.55，95%CI 2.19～2.97，P<0.001）。限制性立方样条分析显示，AIS患者静脉溶栓后24 h NLR与90 d预后不良风险之间存在正向非线性关联（P<0.001）。
结论在标准时间窗内接受静脉溶栓治疗的AIS患者中，以NLR＝3.21作为截断值可识别预后不良的高风险人群，为临床进行个体化干预提供了简便、客观的参考依据。

关键词: 急性缺血性卒中; 炎症指标; 静脉溶栓; 个体患者数据分析; 中性粒细胞与淋巴细胞比值

CLC Number:

HE Dandan, FENG Baoyu, LIU Gaifen, GU Hongqiu, LI Shuya. Predictive Value of the Neutrophil-to-Lymphocyte Ratio for Prognosis in Patients with Acute Ischemic Stroke after Intravenous Thrombolysis: An Individual Patient Data Analysis Based on Three Randomized Controlled Trials[J]. Chinese Journal of Stroke, 2026, 21(1): 38-47.

何丹丹, 冯宝玉, 刘改芬, 谷鸿秋, 李姝雅. 中性粒细胞与淋巴细胞比值对急性缺血性卒中静脉溶栓患者预后的预测价值：基于3项随机对照试验的个体患者数据分析[J]. 中国卒中杂志, 2026, 21(1): 38-47.

References

[1] WARDLAW J M，MURRAY V，BERGE E，et al. Thrombolysis for acute ischaemic stroke[J/OL]. Cochrane Database Syst Rev，2014（7）：CD000213[2025-12-23]. https://doi.org/10.1002/14651858.CD000213.pub3.
[2] EMBERSON J，LEES K R，LYDEN P，et al. Effect of treatment delay，age，and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke：a meta-analysis of individual patient data from randomised trials[J]. Lancet，2014，384（9958）：1929-1935.
[3] DRAXLER D F，LEE F，HO H，et al. t-PA suppresses the immune response and aggravates neurological deficit in a murine model of ischemic stroke[J/OL]. Front Immunol，2019，10：591[2025-12-23]. https://doi.org/10.3389/fimmu.2019.00591.
[4] IADECOLA C，BUCKWALTER M S，ANRATHER J. Immune responses to stroke：mechanisms，modulation，and therapeutic potential[J]. J Clin Invest，2020，130（6）：2777-2788.
[5] XIE J L，PANG C Y，YU H，et al. Leukocyte indicators and variations predict worse outcomes after intravenous thrombolysis in patients with acute ischemic stroke[J]. J Cereb Blood Flow Metab，2023，43（3）：393-403.
[6] LI L H，CHEN C T，CHANG Y C，et al. Prognostic role of neutrophil-to-lymphocyte ratio，platelet-to-lymphocyte ratio，and systemic immune inflammation index in acute ischemic stroke：a STROBE-compliant retrospective study[J/OL]. Medicine（Baltimore），2021，100（25）：e26354[2025-12-23]. https://doi.org/10.1097/MD.0000000000026354.
[7] LIU P A，JI L H，GAN J L，et al. Correlation between NLR to albumin ratio and 90-day prognosis after treatment for acute ischemic stroke[J]. J Cardiovasc Transl Res，2025，18（4）：970-982.
[8] CAO X F，ZHU Q，XIA X，et al. The correlation between novel peripheral blood cell ratios and 90-day mortality in patients with acute ischemic stroke[J/OL]. PLoS One，2020，15（8）：e0238312[2025-12-23]. https://doi.org/10.1371/journal.pone.0238312.
[9] WANG R H，WEN W X，JIANG Z P，et al. The clinical value of neutrophil-to-lymphocyte ratio（NLR），systemic immune-inflammation index（SII），platelet-to-lymphocyte ratio（PLR）and systemic inflammation response index（SIRI）for predicting the occurrence and severity of pneumonia in patients with intracerebral hemorrhage[J/OL]. Front Immunol，2023，14：1115031[2025-12-23]. https://doi.org/10.3389/fimmu.2023.1115031.
[10] LI Y Y，CHEN K Y，WANG L，et al. Values of lymphocyte-related ratios in predicting the clinical outcome of acute ischemic stroke patients receiving intravenous thrombolysis based on different etiologies[J/OL]. Front Neurol，2025，16：1542889[2025-12-23]. https://doi.org/10.3389/fneur.2025.1542889.
[11] LI S Y，CAMPBELL B C V，SCHWAMM L H，et al. Tenecteplase reperfusion therapy in acute ischaemic cerebrovascular events-Ⅱ（TRACE Ⅱ）：rationale and design[J]. Stroke Vasc Neurol，2022，7（1）：71-76.
[12] LI S Y，GU H Q，FENG B Y，et al. RhPro-UK in acute ischemic stroke within 4.5 h of stroke onset trial-2（the PROST-2 study）：rationale and design of a multicenter，prospective，randomized，open-label，blinded-endpoint，controlled phase 3 non-inferiority trial[J]. Int J Stroke，2024，19（10）：1182-1187.
[13] LI S Y，GU H Q，DAI H G，et al. Reteplase versus alteplase for acute ischaemic stroke within 4.5 hours（RAISE）：rationale and design of a multicentre，prospective，randomised，open-label，blinded-endpoint，controlled phase 3 non-inferiority trial[J]. Stroke Vasc Neurol，2024，9（5）：568-573.
[14] HANLEY J A，MCNEIL B J. A method of comparing the areas under receiver operating characteristic curves derived from the same cases[J]. Radiology，1983，148（3）：839-843.
[15] DESQUILBET L，MARIOTTI F. Dose-response analyses using restricted cubic spline functions in public health research[J]. Stat Med，2010，29（9）：1037-1057.
[16] GILL D，VELTKAMP R. Dynamics of T cell responses after stroke[J/OL]. Curr Opin Pharmacol，2016，26：26-32[2025-12-23]. https://doi.org/10.1016/j.coph.2015.09.009.
[17] MEISEL C，SCHWAB J M，PRASS K，et al. Central nervous system injury-induced immune deficiency syndrome[J]. Nat Rev Neurosci，2005，6（10）：775-786.
[18] GILL D，SIVAKUMARAN P，ARAVIND A，et al. Temporal trends in the levels of peripherally circulating leukocyte subtypes in the hours after ischemic stroke[J]. J Stroke Cerebrovasc Dis，2018，27（1）：198-202.
[19] KIM J，SONG T J，PARK J H，et al. Different prognostic value of white blood cell subtypes in patients with acute cerebral infarction[J]. Atherosclerosis，2012，222（2）：464-467.
[20] ALY M，ABDALLA R N，BATRA A，et al. Follow-up neutrophil-lymphocyte ratio after stroke thrombectomy is an independent biomarker of clinical outcome[J]. J Neurointerv Surg，2021，13（7）：609-613.
[21] LI J J，MENG X，SHI F D，et al. Colchicine in patients with acute ischaemic stroke or transient ischaemic attack（CHANCE-3）：multicentre，double blind，randomised，placebo controlled trial[J/OL]. BMJ，2024，385：e079061[2025-12-23]. https://doi.org/10.1136/bmj-2023-079061.
[22] ELKIND M S V，VELTKAMP R，MONTANER J，et al. Natalizumab in acute ischemic stroke（ACTION Ⅱ）：a randomized，placebo-controlled trial[J/OL]. Neurology，2020，95（8）：e1091-e1104[2025-12-23]. https://doi.org/10.1212/WNL.0000000000010038.
[23] ELKINS J，VELTKAMP R，MONTANER J，et al. Safety and efficacy of natalizumab in patients with acute ischaemic stroke（ACTION）：a randomised，placebo-controlled，double-blind phase 2 trial[J]. Lancet Neurol，2017，16（3）：217-226.
[24] TIAN D C，SHI K B，ZHU Z L，et al. Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow[J]. Ann Neurol，2018，84（5）：717-728.
[25] FU Y，ZHANG N N N，REN L，et al. Impact of an immune modulator fingolimod on acute ischemic stroke[J]. Proc Natl Acad Sci U S A，2014，111（51）：18315-18320.
[26] ZHU Z L，FU Y，TIAN D C，et al. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke：a pilot trial[J]. Circulation，2015，132（12）：1104-1112.
[27] KELLY P，LEMMENS R，WEIMAR C，et al. Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke（CONVINCE）：a randomised controlled trial[J]. Lancet，2024，404（10448）：125-133.
[28] STRBIAN D，ENGELTER S，MICHEL P，et al. Symptomatic intracranial hemorrhage after stroke thrombolysis：the SEDAN score[J]. Ann Neurol，2012，71（5）：634-641.
[29] FLINT A C，RAO V A，CHAN S L，et al. Improved ischemic stroke outcome prediction using model estimation of outcome probability：the THRIVE-c calculation[J]. Int J Stroke，2015，10（6）：815-821.
[30] FLINT A C，CULLEN S P，FAIGELES B S，et al. Predicting long-term outcome after endovascular stroke treatment：the totaled health risks in vascular events score[J]. AJNR Am J Neuroradiol，2010，31（7）：1192-1196.
[31] SHEN B，YANG X，SUI R B，et al. The prognostic value of the THRIVE score，the iScore score and the ASTRAL score in Chinese patients with acute ischemic stroke[J]. J Stroke Cerebrovasc Dis，2018，27（10）：2877-2886.