Abstract: Background　Statins are the cornerstone of secondary prevention after ischemic stroke (IS) through low-density lipoprotein cholesterol (LDL-C) reduction, as endorsed by major clinical guidelines. Their effectiveness depends on both treatment intensity and long-term adherence. The cumulative defined daily dose (cDDD) integrates exposure intensity and adherence, yet its association with recurrent IS remains unclear. Objective　To investigate the impact of statin cDDD on recurrence risk in IS patients. Methods　The study enrolled patients aged ≥ 18 years with first-ever acute ischemic stroke (AIS) admitted to the North China University of Science and Technology Affiliated Hospital between January 2023 and March 2024. Baseline data were collected within 24 h of admission. Standardized secondary prevention education was provided at discharge, and patients were followed for 1 year. Participants were categorized into quartiles according to statin cDDD (Group1-Group4). Low-, medium-, and high-dose groups were defined by cumulative dose. Kaplan-Meier analysis assessed 1-year recurrence. Restricted cubic splines (RCS) and Cox proportional hazards models evaluated the association between cDDD and recurrence. Results　The study enrolled 728 patients (males: 455, 62.5%; females: 273, 37.5%). Patients were stratified into quartiles as follows: Group1 (cDDD ≤ 101, n=173), Group2 (101205, n=185). During follow-up, 100 recurrent strokes occurred (13.7%). Kaplan-Meier analysis demonstrated significant differences among cDDD quartiles (P<0.000 1). Cumulative recurrence rates decreased from Group 1 to Group 4: 29.5%, 16.2%, 6.7%, and 3.2%, respectively. Patients were categorized into low- (<2 400 mg, n=245), medium- (2 400-3 600 mg, n=251), and high-dose (>3 600 mg, n=232) groups based on cumulative statin exposure. Recurrence rates differed significantly among groups (χ2 =62.46, P<0.000 1), with the highest rate in the low-dose group (26.9%, 66/245), followed by the medium-dose (10.7%, 27/251), and high-dose groups (3.0%, 7/232). RCS analysis revealed a nonlinear inverse association between cDDD and recurrence (PNonlinear<0.001), with significantly reduced risk when cDDD exceeded 75. Multivariable Cox proportional hazards models consistently demonstrated a significantly lower recurrence risk in Group4 compared to Group1, Model 1 (HR=0.103, 95%CI=0.044-0.241), Model 2 (HR=0.107, 95%CI=0.046-0.251), and Model 3 (HR=0.123, 95%CI=0.052-0.289) (P<0.05). Conclusion　Statin cDDD shows a significant nonlinear inverse association with IS recurrence, with evidence of a dose-dependent threshold effect.

Key words: Ischemic stroke, Statins, Cumulative defined daily dose, Recurrence

摘要： 背景　在缺血性脑卒中（IS）的二级预防中，他汀类药物通过降低低密度脂蛋白胆固醇（LDL-C）被国内外指南列为核心药物。其临床疗效不仅取决于治疗强度，更与患者长期依从性密切相关。累积限定日剂量（cDDD）作为综合评估药物暴露强度与依从性的指标，可量化他汀类药物的累积暴露量。当前关于他汀类药物 cDDD 与 IS 患者复发风险的关系尚未明确。目的　探讨他汀类药物cDDD对IS复发风险的影响。方法　本研究纳入华北理工大学附属医院2023年1月—2024年3月收治的18岁以上首次急性缺血性脑卒中（AIS）患者，入院后 24 h 内采集基本信息，患者出院时均接受由神经内科医师提供的标准化二级预防健康教育，并对其随访 1 年。依据 1 年内他汀类药物 cDDD 四分位数进行分组（组 1~ 组 4），按 1 年内服药剂量进行低、中、高分组，采用 Kaplan-Meier 生存曲线评估患者 1 年内 IS 复发风险。通过限制性立方样条（RCS）及 Cox 比例风险回归模型探讨 cDDD 与复发风险的相关性。结果　本研究最终纳入 728 例患者，其中男 455 例（62.5%）、女 273 例（37.5%），组 1（cDDD ≤ 101）173 例、组2（101<cDDD ≤ 152）191 例、组 3（152<cDDD ≤ 205）179 例、组 4（cDDD>205）185 例。1 年随访期间卒中复发100 例（13.7%）。Kaplan-Meier 生存分析显示，不同 cDDD 四分位组 IS 复发率比较，差异有统计学意义（P<0.000 1），其中累积复发率由高到低依次为组 1 的 29.5%（51/173）、组 2 的 16.2%（31/191）、组 3 的 6.7%（12/179）、组 4 的3.2%（6/185）。低剂量组、中剂量组、高剂量组分别为累积剂量<2 400 mg、2 400~3 600 mg、>3 600 mg，例数分别为245 例、251 例、232 例；各组患者 IS 复发率比较，差异有统计学意义（χ2 =62.46，P<0.000 1），其中 IS 累积复发率由高到低依次为低剂量组的 26.9%（66/245）、中剂量组的 10.7%（27/251）、高剂量组的 3.0%（7/232）。RCS 结果显示 cDDD 与复发风险呈非线性负相关（PNonlinear<0.001），当 cDDD>75 时复发风险显著降低。多因素 Cox 比例风险回归模型结果显示，在调整不同协变量后，与组 1 比较，组 4 的复发风险在模型 1（HR=0.103，95%CI=0.044~0.241）、模型 2（HR=0.107，95%CI=0.046~0.251）及模型 3（HR=0.123，95%CI=0.052~0.289）的复发风险均降低（P<0.05）。结论　他汀类药物 cDDD 与卒中复发呈显著非线性负相关，且存在剂量依赖性阈值效应。

关键词: 缺血性脑卒中, 他汀类药物, 累积限定日剂量, 复发