2025 Volume 32 Issue 2 Pages 141-162
Aim: We aimed to assess the association between non-high-density lipoprotein cholesterol (non-HDL-C) and symptomatic intracranial artery stenosis (sICAS), as well as the impact of non-HDL-C on recurrent vascular events in patients with mild ischemic stroke ( NIHSS score ≤ 5).
Methods: This prospective study was based on data from patients presenting within 72 hours of stroke occurrence. We included patients admitted to 8 Chinese hospitals between September 2019 and November 2021. The associations of non-HDL-C with sICAS and recurrent vascular risk were assessed using multivariate regression models and a restricted cubic spline analysis.
Results: Among the 2,544 patients analyzed at 12 months, 652 (25.6%) were diagnosed with sICAS. Elevated non-HDL-C was linked to a higher incidence of sICAS, and the adjusted odd ratios for quintile variables and continuous variables were 1.36 ([95% CI, 1.01–1.81]) and 1.14 ([95% CI, 1.04–1.24). In comparison to those in the first quintile, the adjusted hazard ratio of the fifth quintile of non-HDL-C was 1.19 ([95% CI 0.78–1.80]) for recurrent ischemic stroke and was 0.39 ([95% CI, 0.17–0.91]) for intracranialhemorrhage.
Conclusions: The non-HDL-C level may be a useful predictor of sICAS. Higher non-HDL-C levels may be associated with a lower risk of intracranial hemorrhage in mild, noncardiogenic stroke, but not a higher risk of recurrent ischemic stroke.
Xuemei Wu and Xiaoyuan Niu contributed equally to this work.
See editorial vol. 32: 122-124
Trial Registration Information
URL: https://www.chictr.org.cn/showproj.html?proj=41160
Unique Identifier: ChiCTR1900025214
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; LDL-C, Low-density lipoprotein cholesterol; non-HDL-C, non–high-density lipoprotein cholesterol; mRS, modified Rankin Scale; sICAS, symptomatic intracranial artery stenosis; ICH, intracranial hemorrhage.
Approximately half of acute ischemic stroke patients initially exhibit minor neurological impairments, with an NIHSS score of ≤ 5 1, 2), and they may subsequently experience disabling events. Besides antiplatelet agents, statin-based LDL-C-lowering therapy is a widely adopted strategy within 72 h of the onset of symptoms. However, in addition to LDL-C, numerous studies have focused on exploring new risk indicators that may be linked to the recurrence of vascular events after cardiovascular and cerebrovascular diseases. Non-high-density lipoprotein cholesterol (non-HDL-C) is often used to analyze the sum of proatherogenic lipoproteins, which include very low-density lipoprotein (VLDL), VLDL remnants, intermediate-density lipoprotein, LDL, and lipoprotein (a)3). It is easily obtainable and calculated by deducting HDL-C from total cholesterol (TC)3, 4).
Some published studies have confirmed that elevated non-HDL-C levels are positively associated with the incidence of cardiovascular events, both in healthy individuals and patients with basic cardiovascular diseases5-7). However, the association between non-HDL-C level and the risk of ischemic stroke remains debatable. High non-HDL-C levels have been linked to an increased risk of ischemic stroke in the majority of studies targeting healthy populations or the general population4, 8-11), but another study did not identify any connection7). In addition, there are a few conflicting reports on the connection between non-HDL-C and intracranial hemorrhage (ICH) following acute ischemic stroke. A large cohort study from China suggested that no significant relationship was observed between non-HDL-C levels and the risk of ICH12), while the Japan Public Health Center-based Prospective (JPHC) study found that among Japanese men, lower non-HDL-C levels were linked to a higher risk of ICH13).
There is no solid evidence regarding the impact of non-HDL-C on recurrent ischemic stroke and the occurrence of ICH following a minor stroke. To our knowledge, no previous research has investigated the possible link between symptomatic intracranial artery stenosis and non-HDL-C level.
This study aimed to evaluate the associations between non-HDL-C and sICAS, recurrent ischemic stroke, and intracranial hemorrhage within 12 months in patients who experienced a mild, noncardiogenic stroke within 72 hours after the onset of symptoms.
This study is a secondary report on “Safety and efficacy of aspirin-clopidogrel in acute non-cardiogenic minor ischemic stroke: a prospective and multicenter study based on real-world (SEACOAST)”, which has been registered at https://www.chictr.org.cn. The study was conducted in 8 hospitals in China from September 2019 to November 2021. We recruited participants who were admitted to hospitals within 72 h of stroke occurrence and who had an NIHSS score of ≤ 5. The protocol has been uploaded and the study was approved by the ethics committee of the First Hospital of Shanxi Medical University. Prior to enrollment, each patient or close relative provided their written informed consent. To avoid bias, patients included in this study received statin medication in addition to antiplatelet agents. Within hours of admission, statins were initiated and continued for 12 months or less.
Inclusion and Exclusion CriteriaThe study’s inclusion criteria were as follows: (1) acute mild ischemic stroke (NIHSS score ≤ 5); (2) within 72 hours from stroke occurrence to hospital arrival; (3) with signs of an acute ischemic stroke on brain computed tomography (CT) or diffusion-weighted imaging (DWI) associated with the symptoms; (4) intracranial vascular examination performed (magnetic resonance angiography [MRA], computed tomographic arteriography [CTA], or digital subtraction angiography [DSA]); (5) therapy using either clopidogrel or aspirin, or clopidogrel-aspirin; (6) medication with moderate- or high-intensity statins; (7) premorbid mRS score ≤ 1; (8) diagnosis of noncardiogenic stroke at discharge; and (9) assessment of TC and HDL-C levels. The following exclusion criteria were applied: (1) treatment with thrombolysis or surgical or endovascular therapy before the endpoint event occurred; (2) participation in clinical trials for other drugs within the past 3 months; (3) life expectancy of ＜3 months or pregnancy; and (4) early anticoagulant therapy. The mRS provides scores ranging from 0 (no symptoms) to 6 (death) to indicate the degree of disability or dependence in everyday activities. The NIHSS score ranges from 0 to 42, with higher scores indicating a more severe stroke.
Baseline Data CollectionThe baseline factors included age, sex, body mass index, mRS score before index stroke, NIHSS score on admission, medication history prior to stroke, blood pressure at admission, current smoking status, alcohol abuse, medical history (hypertension, diabetes mellitus, dyslipidemia, stroke, transient ischemic attack, myocardial infarction, coronary heart disease, and atrial fibrillation), lipid profile, image data, stroke classification, and in-hospital treatment. Stroke subtypes were categorized using the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria upon discharge from the hospital.
All patients had venous blood samples drawn from the anterior elbow vein for routine laboratory testing after fasting for at least eight hours in the previous evening. Blood samples were stored and processed according to the requirements of each sub-center laboratory.
Following this stroke, imaging data were acquired during the emergency care or hospital stay. T1-weighted imaging, T2-weighted imaging, DWI, and MRA sequences were used for cranial MRI. The location and degree of ICAS were assessed using CTA, MRA, or DSA. When an intracranial artery has ＞50% stenosis and is accompanied by matching DWI abnormalities and clinical symptoms, it is considered sICAS14).
Clinical Outcomes and Follow-UpRecurrent ischemic stroke and intracranial hemorrhage were considered as outcomes. A new focal neurological deficit of vascular origin lasting ＞24 h, an increase in the NIHSS score of ≥ 4, or imaging evidence on an MRI or CT scan (new infarction or enlargement of the existing infarction region) were all considered indicators of ischemic stroke recurrence. Intracranial hemorrhage was diagnosed by CT or MRI, including hemorrhagic transformation (according to the European Cooperative Acute Stroke Study radiological classification)15), intracerebral hemorrhage, and subarachnoid hemorrhage.
Follow-up examinations of all patients were performed on days 1, 10, 21, 90±7, and 365 after enrolment. Follow-up evaluations at 3 months and 12 months were conducted mainly by telephone interviews because of the coronavirus disease 2019 pandemic. The self-reported incidence of ischemic stroke was verified using the hospitalization records of patients who were readmitted to 8 hospitals. For those without readmission records, the chief and skilled investigators made a combined decision. A total of 84 (3%) and 253 (9%) patients were lost to follow-up after 3 and 12 months, respectively. We analyzed 2 sets of data.
Statistical MethodsPatients were divided into 5 categories based on non-HDL-C quintiles according to previous studies. Frequencies and percentages were used to represent categorical variables and means±standard deviations were used to represent continuous variables, as appropriate. The χ2 test was employed for categorical variables to compare baseline characteristics stratified by non-HDL-C quintiles, while the Kruskal-Wallis test was used for continuous variables to ascertain differences across the 5 groups.
First, we used non-HDL-C level as a continuous variable to analyze the linear association between non-HDL-C level and sICAS. Additionally, we divided non-HDL-C into 5 groups and used multivariate logistic regression models to examine the relationship between non-HDL-C and sICAS. Confounders were selected based on previous studies and univariate analyses. Subsequently, we explored the association between outcome events and quintiles of non-HDL-C levels using multivariate Cox regression models. Based on previous studies, the first quintile of non-HDL-C level was used as a reference for both ICH and recurrent ischemic stroke13, 16). These confounders were chosen based on their correlations with the relevant outcomes or because they caused an effect estimate change ＞10%.
Restricted cubic spline (RCS) plots were used to investigate the dose-response associations of non-HDL-C levels with sICAS, ischemic stroke recurrence, and ICH. We used a model with 4 knots at the 5th, 35th, 65th, and 95th percentiles and examined potential nonlinear associations. The hazard ratio was adjusted by accounting for all possible confounders at the baseline, excluding those with collinearity.
Using Cox models, subgroup analyses comparing patients with and without sICAS, as well as patients with different TOAST subtypes, were conducted to investigate the relationship between non-HDL-C quintiles and ischemic stroke. In addition, a sensitivity analysis of those included in the analysis versus those excluded and those with sICAS versus those without sICAS was conducted.
Given the adjusted HRs/ORs and their 95% confidence intervals, 2-tailed P values of ＜0.05 were considered to indicate statistical significance. All analyses were performed using the statistical software package R (http://www.R-project.org, The R Foundation) and Free Statistics software version 1.8.1.
A total of 3723 patients suspected of experiencing minor ischemic stroke within 72 h of onset were screened for study enrolment. Among them, 662 were deemed ineligible, and 264 individuals were excluded owing to TC or HDL-C deficiencies, absence of intracranial arterial imaging, and failure to receive any statin medication. Due to loss to follow-up, the 3-month and 12-month analyses included a total of 2,713 and 2,544 individuals with acute and noncardiogenic minor stroke, respectively. A comprehensive inclusion flow chart is shown in Fig.1. Based on the non-HDL-C quintiles, Table 1 presents the baseline characteristics of the patients at the 12-month follow-up examination. The mean age of the patients was 61.7±11.8 years and the study population included 1,861 (73.2%) male patients. The fifth quintile of non-HDL-C had a greater proportion of history of dyslipidemia, slightly higher body mass index, higher blood pressure, higher lipid levels, and in-hospital usage of high-intensity statins, antidiabetic drugs, and antihypertensive medications. Patients in the lowest percentile of non-HDL-C were more likely to be male, have a history of ischemic stroke or coronary heart disease, and to have taken statins and antiplatelet drugs more frequently before being admitted to the hospital. Supplemental Table 1 shows the baseline characteristics of the patients included and excluded from this investigation. With the exception of smoking status, history of coronary heart disease, and stroke classification, more patients in the included group received DAPT, high-intensity statins, and hypoglycemic treatment in hospitals. Supplemental Tables 2 and 3 show the baseline characteristics of patients enrolled in a 3-month analysis, as well as the characteristics of patients with and without sICAS. The presence of sICAS was associated with higher systolic blood pressure, higher LDL-C levels, higher NIHSS scores at admission, more history of TIA, and more large-artery atherosclerosis subtypes.
Flow chart illustrating the inclusion of patients
| Variables | Total | Non-HDL-C quintiles | |||||
|---|---|---|---|---|---|---|---|
|
Quintile 1, ≤ 2.33 mmol/L |
Quintile 2, 2.34-2.81 mmol/L |
Quintile 3, 2.82-3.30 mmol/L |
Quintile 4, 3.31-3.92 mmol/L |
Quintile 5, ≥ 3.93 mmol/L |
P value | ||
| Patients, n | 2544 | 501 | 515 | 510 | 508 | 510 | |
| Age, Mean±SD | 61.7±11.8 | 62.8±12.3 | 61.8±11.9 | 61.7±11.4 | 60.8±11.9 | 61.4±11.7 | 0.11 |
| Male, n (%) | 1861 (73.2) | 411 (82) | 383 (74.4) | 393 (77.1) | 368 (72.4) | 306 (60) | ＜0.001 |
| BMI, Mean±SD | 24.9±3.5 | 24.0±3.3 | 24.8±3.5 | 25.1±3.5 | 25.2±3.5 | 25.2±3.7 | ＜0.001 |
| NIHSS on Admission, Mean±SD | 1.9±1.5 | 2.0±1.5 | 1.8±1.5 | 1.9±1.5 | 1.9±1.5 | 2.0±1.6 | 0.210 |
| LDL-C, mmol/L, Mean±SD | 2.6±0.8 | 1.6±0.5 | 2.2±0.3 | 2.5±0.3 | 3.0±0.3 | 3.7±0.7 | ＜0.001 |
| TG, mmol/L, Mean±SD | 1.7±1.2 | 1.1±0.7 | 1.4±0.7 | 1.6±1.0 | 1.8±1.0 | 2.5±1.7 | ＜0.001 |
| SBP, mmHg, Mean±SD | 153.1±21.9 | 149.0±22.3 | 150.3±20.8 | 153.9±21.9 | 156.3±21.1 | 155.8±22.4 | ＜0.001 |
| DBP, mmHg, Mean±SD | 88.5±13.8 | 86.6±13.6 | 87.0±13.6 | 89.1±13.6 | 90.2±14.2 | 89.7±13.6 | ＜0.001 |
| Toast, n (%) | 0.245 | ||||||
| Large-artery atherosclerosis | 779 (30.6) | 157 (31.3) | 149 (28.9) | 151 (29.6) | 150 (29.5) | 172 (33.7) | |
| Small-vessel occlusion | 1192 (46.9) | 212 (42.3) | 248 (48.2) | 253 (49.6) | 241 (47.4) | 238 (46.7) | |
| Other determined etiology | 47 (1.8) | 15 (3) | 10 (1.9) | 7 (1.4) | 7 (1.4) | 8 (1.6) | |
| Undetermined etiology | 526 (20.7) | 117 (23.4) | 108 (21) | 99 (19.4) | 110 (21.7) | 92 (18) | |
| sICAS, n (%) | 652 (25.6) | 116 (23.2) | 119 (23.1) | 129 (25.3) | 139 (27.4) | 149 (29.2) | 0.107 |
| Medical history | |||||||
| Hypertension, n (%) | 1545 (60.7) | 298 (59.5) | 301 (58.4) | 296 (58) | 326 (64.2) | 324 (63.5) | 0.126 |
| Diabetes mellitus, n (%) | 686 (27.0) | 127 (25.3) | 130 (25.2) | 135 (26.5) | 132 (26) | 162 (31.8) | 0.103 |
| Dyslipidemia, n (%) | 57 (2.2) | 7 (1.4) | 10 (1.9) | 7 (1.4) | 14 (2.8) | 19 (3.7) | 0.053 |
| Atrial fibrillation, n (%) | 15 (0.6) | 3 (0.6) | 3 (0.6) | 3 (0.6) | 2 (0.4) | 4 (0.8) | 0.97 |
| TIA, n (%) | 41 (1.6) | 11 (2.2) | 6 (1.2) | 7 (1.4) | 11 (2.2) | 6 (1.2) | 0.478 |
| Ischemic stroke, n (%) | 573 (22.5) | 179 (35.7) | 122 (23.7) | 98 (19.2) | 89 (17.5) | 85 (16.7) | ＜0.001 |
| Myocardial infarct, n (%) | 39 (1.5) | 5 (1) | 13 (2.5) | 7 (1.4) | 7 (1.4) | 7 (1.4) | 0.336 |
| Coronary heart disease, n (%) | 131 (5.1) | 41 (8.2) | 25 (4.9) | 23 (4.5) | 23 (4.5) | 19 (3.7) | 0.014 |
| Current smoker, n (%) | 1108 (43.6) | 222 (44.3) | 232 (45) | 235 (46.1) | 227 (44.7) | 192 (37.6) | 0.052 |
| Alcohol, n (%) | 896 (35.2) | 181 (36.1) | 179 (34.8) | 180 (35.3) | 188 (37) | 168 (33) | 0.729 |
| Previous treatment history, n (%) | |||||||
| Antiplatelet therapy | 293 (11.5) | 121 (24.2) | 58 (11.3) | 49 (9.6) | 27 (5.3) | 38 (7.5) | ＜0.001 |
| Statins | 192 (7.5) | 93 (18.6) | 41 (8) | 20 (3.9) | 19 (3.7) | 19 (3.7) | ＜0.001 |
| Antihypertensive therapy | 1048 (41.2) | 206 (41.1) | 224 (43.5) | 201 (39.4) | 215 (42.3) | 202 (39.6) | 0.671 |
| Antidiabetic therapy | 515 (20.2) | 98 (19.6) | 95 (18.4) | 101 (19.8) | 94 (18.5) | 127 (24.9) | 0.232 |
| In-hospital treatment, n (%) | |||||||
| Dual antiplatelet therapy | 1571 (61.8) | 289 (57.7) | 318 (61.7) | 323 (63.3) | 319 (62.8) | 322 (63.1) | 0.32 |
| High-intensity statins | 1479 (58.3) | 261 (52.2) | 295 (57.6) | 303 (59.9) | 311 (61.2) | 309 (60.6) | 0.025 |
| Antihypertensive therapy | 1295 (50.9) | 225 (44.9) | 249 (48.3) | 260 (51) | 280 (55.1) | 281 (55.1) | 0.02 |
| Antidiabetic therapy | 683 (26.8) | 125 (25) | 128 (24.9) | 125 (24.5) | 136 (26.8) | 169 (33.1) | ＜0.001 |
Abbreviations: HDL-C, high-density lipoprotein cholesterol; BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; SBP, systolic blood pressure; DBP, diastolic blood pressure; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; sICAS, symptomatic intracranial artery stenosis; TIA, transient ischemic attack.
| Variables | Total (n = 3061) | 0 (n = 348) | 1 (n = 2713) | p |
|---|---|---|---|---|
| Age, Mean±SD | 61.7±12.0 | 62.7±13.2 | 61.6±11.9 | 0.112 |
| Sex, n (%) | 0.688 | |||
| female | 817 (26.7) | 96 (27.6) | 721 (26.6) | |
| male | 2244 (73.3) | 252 (72.4) | 1992 (73.4) | |
| BMI, Mean±SD | 24.9±3.6 | 24.9±3.5 | 24.9±3.6 | 0.958 |
| Systolic pressure, Mean±SD | 153.0±21.9 | 154.1±22.4 | 152.8±21.8 | 0.29 |
| Diastolic pressure, Mean±SD | 88.5±13.7 | 88.8±13.7 | 88.4±13.7 | 0.599 |
| NIHSS on admission, n (%) | 0.793 | |||
| 0 | 659 (21.5) | 70 (20.1) | 589 (21.7) | |
| 1 | 667 (21.8) | 68 (19.5) | 599 (22.1) | |
| 2 | 670 (21.9) | 83 (23.9) | 587 (21.6) | |
| 3 | 482 (15.7) | 56 (16.1) | 426 (15.7) | |
| 4 | 357 (11.7) | 43 (12.4) | 314 (11.6) | |
| 5 | 226 (7.4) | 28 (8) | 198 (7.3) | |
| Toast, n (%) | ＜0.001 | |||
| LAA | 910 (29.7) | 84 (24.1) | 826 (30.4) | |
| SVO | 1425 (46.6) | 154 (44.3) | 1271 (46.8) | |
| OE | 51 (1.7) | 3 (0.9) | 48 (1.8) | |
| UD | 675 (22.1) | 107 (30.7) | 568 (20.9) | |
| LDL-C, Mean±SD | 2.6±0.8 | 2.6±0.9 | 2.6±0.8 | 0.478 |
| TG, Mean±SD | 1.7±1.2 | 1.6±0.9 | 1.7±1.2 | 0.189 |
| Current smoker | ＜0.001 | |||
| Yes | 1280 (41.8) | 97 (27.9) | 1183 (43.6) | |
| No | 1585 (51.8) | 133 (38.2) | 1452 (53.5) | |
| Unknown | 196 (6.4) | 118 (33.9) | 78 (2.9) | |
| Alcohol, n (%) | 0.184 | |||
| Yes | 1066 (35.1) | 105 (30.7) | 961 (35.6) | |
| No | 1909 (62.8) | 228 (66.7) | 1681 (62.3) | |
| Unknown | 66 (2.2) | 9 (2.6) | 57 (2.1) | |
| Antiplatelet therapy, n (%) | 0.023 | |||
| SAPT | 1192 (38.9) | 155 (44.5) | 1037 (38.2) | |
| DAPT | 1869 (61.1) | 193 (55.5) | 1676 (61.8) | |
| Lipid lowing therapy, n (%) | ＜0.001 | |||
| Moderate-intensity statins | 1233 (40.3) | 150 (43.1) | 1083 (39.9) | |
| High-intensity statins | 1802 (58.9) | 172 (49.4) | 1630 (60.1) | |
| No statins | 26 (0.8) | 26 (7.5) | 0 (0) | |
| Antihypertensive therapy, n (%) | 0.281 | |||
| No | 1278 (43.8) | 126 (48.3) | 1152 (43.3) | |
| Yes | 1500 (51.4) | 122 (46.7) | 1378 (51.8) | |
| Antidiabetic therapy, n (%) | ＜0.001 | |||
| No | 2141 (69.9) | 212 (60.9) | 1929 (71.1) | |
| Yes | 743 (24.3) | 49 (14.1) | 694 (25.6) | |
| Hypertension, n (%) | 0.47 | |||
| No | 1212 (39.6) | 144 (41.4) | 1068 (39.4) | |
| Yes | 1849 (60.4) | 204 (58.6) | 1645 (60.6) | |
| Diabetes mellitus, n (%) | 0.888 | |||
| No | 2251 (73.5) | 257 (73.9) | 1994 (73.5) | |
| Yes | 810 (26.5) | 91 (26.1) | 719 (26.5) | |
| Dyslipidemia, n (%) | 0.952 | |||
| No | 2992 (97.7) | 340 (97.7) | 2652 (97.8) | |
| Yes | 69 (2.3) | 8 (2.3) | 61 (2.2) | |
| Atrial fibrillation, n (%) | 0.449 | |||
| No | 3043 (99.4) | 345 (99.1) | 2698 (99.4) | |
| Yes | 18 (0.6) | 3 (0.9) | 15 (0.6) | |
| TIA, n (%) | 0.298 | |||
| No | 3011 (98.4) | 340 (97.7) | 2671 (98.5) | |
| Yes | 50 (1.6) | 8 (2.3) | 42 (1.5) | |
| Ischemic stroke, n (%) | 0.127 | |||
| No | 2364 (77.2) | 280 (80.5) | 2084 (76.8) | |
| Yes | 697 (22.8) | 68 (19.5) | 629 (23.2) | |
| Myocardial infarct, n (%) | 0.244 | |||
| No | 3013 (98.4) | 340 (97.7) | 2673 (98.5) | |
| Yes | 48 (1.6) | 8 (2.3) | 40 (1.5) | |
| Coronary heart disease, n (%) | 0.022 | |||
| No | 2895 (94.6) | 320 (92) | 2575 (94.9) | |
| Yes | 166 (5.4) | 28 (8) | 138 (5.1) | |
| Prior antiplatelet therapy, n (%) | 0.669 | |||
| No | 2704 (88.3) | 311 (89.4) | 2393 (88.2) | |
| Yes | 348 (11.4) | 37 (10.6) | 311 (11.5) | |
| Unknown | 9 (0.3) | 0 (0) | 9 (0.3) | |
| Prior statin therapy, n (%) | 0.767 | |||
| No | 2820 (92.1) | 322 (92.5) | 2498 (92.1) | |
| Yes | 234 (7.6) | 25 (7.2) | 209 (7.7) | |
| Unknown | 7 (0.2) | 1 (0.3) | 6 (0.2) | |
| Prior antihypertensive therapy, n (%) | 0.56 | |||
| No | 1724 (56.3) | 201 (57.8) | 1523 (56.1) | |
| Yes | 1260 (41.2) | 141 (40.5) | 1119 (41.2) | |
| Unknown | 77 (2.5) | 6 (1.7) | 71 (2.6) | |
| Prior hypoglycemic therapy, n (%) | 0.401 | |||
| No | 2437 (79.6) | 281 (80.7) | 2156 (79.5) | |
| Yes | 607 (19.8) | 67 (19.3) | 540 (19.9) | |
| Unknown | 17 (0.6) | 0 (0) | 17 (0.6) |
Abbreviations: BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; TIA, transient ischemic attack.
| Variables | Total | Non-HDL-C quintiles | |||||
|---|---|---|---|---|---|---|---|
|
Quintile 1, ≤ 2.33 mmol/L |
Quintile 2, 2.34-2.81 mmol/L |
Quintile 3, 2.82-3.31 mmol/L |
Quintile 4, 3.32-3.92 mmol/L |
Quintile 5, ≥ 3.93 mmol/L |
P value | ||
| Patients, n | 2713 | 536 | 544 | 544 | 542 | 547 | |
| Age, Mean±SD | 61.6±11.9 | 62.5±12.4 | 61.9±11.8 | 61.6±11.6 | 60.7±11.9 | 61.1±11.6 | 0.116 |
| Sex, n (%) | 1992 (73.4) | 440 (82.1) | 403 (74.1) | 417 (76.7) | 395 (72.9) | 337 (61.6) | ＜0.001 |
| BMI, Mean±SD | 24.9±3.6 | 24.1±3.4 | 24.9±3.8 | 25.1±3.5 | 25.2±3.5 | 25.2±3.7 | ＜0.001 |
| NIHSS on admission, n (%) | 0.705 | ||||||
| 0 | 589 (21.7) | 107 (20) | 127 (23.3) | 121 (22.2) | 116 (21.4) | 118 (21.6) | |
| 1 | 599 (22.1) | 118 (22) | 127 (23.3) | 116 (21.3) | 132 (24.4) | 106 (19.4) | |
| 2 | 587 (21.6) | 106 (19.8) | 118 (21.7) | 125 (23) | 115 (21.2) | 123 (22.5) | |
| 3 | 426 (15.7) | 99 (18.5) | 76 (14) | 86 (15.8) | 80 (14.8) | 85 (15.5) | |
| 4 | 314 (11.6) | 64 (11.9) | 63 (11.6) | 52 (9.6) | 63 (11.6) | 72 (13.2) | |
| 5 | 198 (7.3) | 42 (7.8) | 33 (6.1) | 44 (8.1) | 36 (6.6) | 43 (7.9) | |
| LDL-C, Mean±SD | 2.6±0.8 | 1.6±0.5 | 2.2±0.3 | 2.5±0.3 | 3.0±0.3 | 3.7±0.7 | ＜0.001 |
| TG, Mean±SD | 1.7±1.2 | 1.1±0.7 | 1.4±0.7 | 1.6±1.0 | 1.8±1.0 | 2.5±1.7 | ＜0.001 |
| Systolic pressure, mmHg, Mean±SD | 152.8±21.8 | 148.9±22.0 | 150.2±21.0 | 153.6±22.0 | 155.9±21.2 | 155.5±22.2 | ＜0.001 |
| Diastolic pressure, mmHg, Mean±SD | 88.4±13.7 | 86.6±13.4 | 86.8±13.5 | 89.0±13.5 | 90.0±14.4 | 89.5±13.5 | ＜0.001 |
| Toast, n (%) | 0.133 | ||||||
| Large-artery atherosclerosis | 826 (30.4) | 167 (31.2) | 159 (29.2) | 161 (29.6) | 156 (28.8) | 183 (33.5) | |
| Small-vessel occlusion | 1271 (46.8) | 224 (41.8) | 259 (47.6) | 270 (49.6) | 261 (48.2) | 257 (47) | |
| Other determined etiology | 48 (1.8) | 15 (2.8) | 11 (2) | 7 (1.3) | 7 (1.3) | 8 (1.5) | |
| Undetermined etiology | 568 (20.9) | 130 (24.3) | 115 (21.1) | 106 (19.5) | 118 (21.8) | 99 (18.1) | |
| sICAS, n (%) | 690 (25.4) | 123 (22.9) | 129 (23.7) | 137 (25.2) | 143 (26.4) | 158 (28.9) | 0.177 |
| Medical history | |||||||
| Hypertension, n (%) | 1645 (60.6) | 318 (59.3) | 319 (58.6) | 316 (58.1) | 346 (63.8) | 346 (63.3) | 0.154 |
| Diabetes mellitus, n (%) | 719 (26.5) | 135 (25.2) | 136 (25) | 143 (26.3) | 139 (25.6) | 166 (30.3) | 0.242 |
| Dyslipidemia, n (%) | 61 (2.2) | 8 (1.5) | 10 (1.8) | 8 (1.5) | 16 (3) | 19 (3.5) | 0.082 |
| Atrial fibrillation, n (%) | 15 (0.6) | 3 (0.6) | 3 (0.6) | 3 (0.6) | 2 (0.4) | 4 (0.7) | 0.975 |
| TIA, n (%) | 42 (1.5) | 11 (2.1) | 6 (1.1) | 8 (1.5) | 11 (2) | 6 (1.1) | 0.529 |
| Ischemic stroke, n (%) | 629 (23.2) | 193 (36) | 134 (24.6) | 108 (19.9) | 99 (18.3) | 95 (17.4) | ＜0.001 |
| Myocardial infarct, n (%) | 40 (1.5) | 5 (0.9) | 14 (2.6) | 7 (1.3) | 7 (1.3) | 7 (1.3) | 0.199 |
| Coronary heart disease, n (%) | 138 (5.1) | 42 (7.8) | 27 (5) | 24 (4.4) | 25 (4.6) | 20 (3.7) | 0.022 |
| Current smoker, n (%) | 1183 (43.6) | 239 (44.6) | 246 (45.2) | 247 (45.4) | 243 (44.8) | 208 (38) | 0.286 |
| Alcohol, n (%) | 961 (35.4) | 195 (36.4) | 188 (34.6) | 192 (35.3) | 201 (37.1) | 185 (33.8) | 0.82 |
| Previous treatment history | |||||||
| Prior antiplatelet therapy, n (%) | 311 (11.5) | 127 (23.7) | 63 (11.6) | 51 (9.4) | 32 (5.9) | 38 (6.9) | ＜0.001 |
| Prior statin therapy, n (%) | 209 (7.7) | 99 (18.5) | 47 (8.6) | 21 (3.9) | 23 (4.2) | 19 (3.5) | ＜0.001 |
| Prior antihypertensive therapy, n (%) | 1119 (41.2) | 223 (41.6) | 239 (43.9) | 213 (39.2) | 230 (42.4) | 214 (39.1) | 0.414 |
| Prior hypoglycemic therapy, n (%) | 539 (19.9) | 105 (19.6) | 101 (18.6) | 106 (19.5) | 97 (17.9) | 130 (23.8) | 0.364 |
| In-hospital treatment | |||||||
| Dual antiplatelet therapy | 1676 (61.8) | 310 (57.8) | 335 (61.6) | 343 (63.1) | 344 (63.5) | 344 (62.9) | 0.303 |
| High-intensity statins therapy | 1604 (59.1) | 288 (53.7) | 321 (59) | 324 (59.6) | 333 (61.4) | 338 (61.8) | 0.054 |
| Antihypertensive therapy, n (%) | 1378 (50.8) | 238 (44.4) | 262 (48.2) | 279 (51.3) | 297 (54.8) | 302 (55.2) | 0.006 |
| Antidiabetic therapy, n (%) | 717 (26.4) | 133 (24.8) | 135 (24.8) | 132 (24.3) | 144 (26.6) | 173 (31.6) | ＜0.001 |
Abbreviations: HDL-C, high-density lipoprotein cholesterol; BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; sICAS, symptomatic intracranial artery stenosis; TIA, transient ischemic attack.
| Variables | Total (n= 2713) | No (n= 2023) | Yes (n= 690) | p |
|---|---|---|---|---|
| Age, Mean±SD | 61.6±11.9 | 61.6±11.8 | 61.5±12.1 | 0.888 |
| Sex, n (%) | 0.079 | |||
| Female | 721 (26.6) | 520 (25.7) | 201 (29.1) | |
| Male | 1992 (73.4) | 1503 (74.3) | 489 (70.9) | |
| BMI, Mean±SD | 24.9±3.6 | 24.8±3.5 | 25.1±3.9 | 0.116 |
| Systolic pressure, mmHg, Mean±SD | 152.8±21.8 | 152.1±21.7 | 154.9±22.2 | 0.003 |
| Diastolic pressure, mmHg, Mean±SD | 88.4±13.7 | 88.3±14.0 | 88.7±13.0 | 0.573 |
| LDL-C, Mean±SD | 2.6±0.8 | 2.6±0.8 | 2.7±0.9 | 0.001 |
| TG, Mean±SD | 1.7±1.2 | 1.7±1.2 | 1.7±1.2 | 0.458 |
| Current smoker, n (%) | 1184 (44.9) | 893 (45.4) | 291 (43.4) | 0.35 |
| Alcohol, n (%) | 961 (36.4) | 713 (36.2) | 248 (36.7) | 0.889 |
| NIHSS on admission, n (%) | 0.027 | |||
| 0 | 589 (21.7) | 438 (21.7) | 151 (21.9) | |
| 1 | 599 (22.1) | 475 (23.5) | 124 (18) | |
| 2 | 587 (21.6) | 438 (21.7) | 149 (21.6) | |
| 3 | 426 (15.7) | 306 (15.1) | 120 (17.4) | |
| 4 | 314 (11.6) | 219 (10.8) | 95 (13.8) | |
| 5 | 198 (7.3) | 147 (7.3) | 51 (7.4) | |
| Toast, n (%) | ＜0.001 | |||
| Large-artery atherosclerosis | 826 (30.4) | 233 (11.5) | 593 (85.9) | |
| Small-vessel occlusion | 1271 (46.8) | 1226 (60.6) | 45 (6.5) | |
| Other determined etiology | 48 (1.8) | 32 (1.6) | 16 (2.3) | |
| Undetermined etiology | 568 (20.9) | 532 (26.3) | 36 (5.2) | |
| History of hypertension, n (%) | 0.219 | |||
| No | 1068 (39.4) | 810 (40) | 258 (37.4) | |
| Yes | 1645 (60.6) | 1213 (60) | 432 (62.6) | |
| History of diabetes mellitus, n (%) | 0.07 | |||
| No | 1994 (73.5) | 1505 (74.4) | 489 (70.9) | |
| Yes | 719 (26.5) | 518 (25.6) | 201 (29.1) | |
| History of dyslipidemia, n (%) | 0.653 | |||
| No | 2652 (97.8) | 1976 (97.7) | 676 (98) | |
| Yes | 61 (2.2) | 47 (2.3) | 14 (2) | |
| History of atrial fibrillation, n (%) | 1 | |||
| No | 2698 (99.4) | 2012 (99.5) | 686 (99.4) | |
| Yes | 15 (0.6) | 11 (0.5) | 4 (0.6) | |
| History of TIA, n (%) | 0.003 | |||
| No | 2671 (98.5) | 2000 (98.9) | 671 (97.2) | |
| Yes | 42 (1.5) | 23 (1.1) | 19 (2.8) | |
| History of ischemic stroke, n (%) | 0.529 | |||
| No | 2084 (76.8) | 1560 (77.1) | 524 (75.9) | |
| Yes | 629 (23.2) | 463 (22.9) | 166 (24.1) | |
| History of myocardial infarct, n (%) | 0.949 | |||
| No | 2673 (98.5) | 1993 (98.5) | 680 (98.6) | |
| Yes | 40 (1.5) | 30 (1.5) | 10 (1.4) | |
| History of coronary heart disease, n (%) | 0.411 | |||
| No | 2575 (94.9) | 1916 (94.7) | 659 (95.5) | |
| Yes | 138 (5.1) | 107 (5.3) | 31 (4.5) | |
| Prior antiplatelet therapy, n (%) | 0.093 | |||
| No | 2393 (88.5) | 1772 (87.9) | 621 (90.3) | |
| Yes | 311 (11.5) | 244 (12.1) | 67 (9.7) | |
| Prior statins use, n (%) | 0.064 | |||
| No | 2498 (92.3) | 1851 (91.7) | 647 (93.9) | |
| Yes | 209 (7.7) | 167 (8.3) | 42 (6.1) | |
| Prior antihypertensive therapy, n (%) | 0.038 | |||
| No | 1523 (57.6) | 1158 (58.8) | 365 (54.2) | |
| Yes | 1119 (42.4) | 811 (41.2) | 308 (45.8) | |
| Prior hypoglycemic therapy, n (%) | 0.115 | |||
| No | 2157 (80.0) | 1624 (80.7) | 533 (77.9) | |
| Yes | 539 (20.0) | 388 (19.3) | 151 (22.1) |
Abbreviations: sICAS, symptomatic intracranial artery stenosis; BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; LDL- C, low-density lipoprotein cholesterol; TG, triglyceride; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; TIA, transient ischemic attack.
This study is the first to investigate the relationship between non-HDL-C levels and the prevalence of sICAS. Among the 2,713 patients with minor ischemic stroke initially included in this study, 690 (25.4%) were diagnosed with sICAS (Supplemental Table 2). The findings of the univariate logistic regression analysis of the association between non-HDL-C and sICAS are shown in Supplemental Table 4. After adjusting for potential confounders in the multivariate logistic regression models, the risk of sICAS increased by 14% for each unit increase in non-HDL-C when considered as a continuous variable (OR, 1.14 [95% CI, 1.04–1.24]; P=0.005 at 12 months). As quintiles, the risk of sICAS increased by 36% in the fifth quintile of non-HDL-C in comparison to the first quintile (OR 1.36 [95% CI, 1.01-1.81]; P=0.040 at 12 months) (Table 2). The OR for 3-month analysis of sICAS incidence was 1.12 ([95% CI 1.03–1.22]; P=0.007) when non-HDL-C was considered as a continuous variable and was 1.33 ([95% CI 1.01–1.77]; P=0.044) in the fifth quintile in comparison to the first quintile of non-HDL-C (Table 2). Using a restricted cubic spline, a linear dose-response association between non-HDL-C and sICAS was discovered (Fig.2).
| Variable | 3 months | 12 months | ||
|---|---|---|---|---|
| OR_95CI | P value | OR_95CI | P value | |
| Age | 1 (0.99~1.01) | 0.888 | 1 (0.99~1.01) | 0.601 |
| Sex | 0.84 (0.69~1.02) | 0.079 | 0.84 (0.69~1.02) | 0.083 |
| BMI | 1.02 (1~1.04) | 0.116 | 1.02 (0.99~1.04) | 0.162 |
| Current smoker | 0.92 (0.77~1.1) | 0.357 | 0.9 (0.76~1.08) | 0.273 |
| Alcohol | 99708.93 (0~2.66780424188916e+281) | 0.972 | 1.02 (0.85~1.23) | 0.803 |
| LDL-C | 1.18 (1.07~1.31) | 0.001 | 1.2 (1.08~1.34) | 0.001 |
| TG | 1.03 (0.96~1.1) | 0.458 | 1.02 (0.95~1.1) | 0.591 |
| NIHSS on admission, =0 | 1(Ref) | 1(Ref) | ||
| NIHSS on admission, =1 | 0.76 (0.58~0.99) | 0.044 | 0.74 (0.56~0.98) | 0.038 |
| NIHSS on admission, =2 | 0.99 (0.76~1.28) | 0.921 | 1.03 (0.79~1.35) | 0.806 |
| NIHSS on admission, =3 | 1.14 (0.86~1.51) | 0.368 | 1.26 (0.95~1.68) | 0.109 |
| NIHSS on admission, =4 | 1.26 (0.93~1.7) | 0.138 | 1.34 (0.98~1.82) | 0.067 |
| NIHSS on admission, =5 | 1.01 (0.7~1.45) | 0.973 | 1 (0.68~1.47) | 0.982 |
| TOAST | ||||
| Large-artery atherosclerosis | 1(Ref) | 1(Ref) | ||
| Small-vessel occlusion | 0.01 (0.01~0.02) | ＜0.001 | 0.02 (0.01~0.02) | ＜0.001 |
| Other determined etiology | 0.2 (0.11~0.36) | ＜0.001 | 0.2 (0.11~0.38) | ＜0.001 |
| Undetermined etiology | 0.03 (0.02~0.04) | ＜0.001 | 0.03 (0.02~0.04) | ＜0.001 |
| Systolic pressure | 1.01 (1~1.01) | 0.003 | 1.01 (1~1.01) | 0.002 |
| Diastolic pressure | 1 (1~1.01) | 0.573 | 1 (1~1.01) | 0.6 |
| History of hypertension | 1.12 (0.94~1.34) | 0.219 | 1.15 (0.96~1.38) | 0.136 |
| History of diabetes mellitus | 1.19 (0.99~1.45) | 0.07 | 1.18 (0.97~1.44) | 0.098 |
| History of dyslipidemia | 0.87 (0.48~1.59) | 0.653 | 0.94 (0.51~1.74) | 0.852 |
| History of atrial fibrillation | 1.07 (0.34~3.36) | 0.912 | 1.06 (0.33~3.33) | 0.926 |
| History of TIA | 2.46 (1.33~4.55) | 0.004 | 2.55 (1.37~4.74) | 0.003 |
| History of ischemic stroke | 1.07 (0.87~1.31) | 0.529 | 1.13 (0.91~1.39) | 0.27 |
| History of myocardial infarct | 0.98 (0.48~2.01) | 0.949 | 1 (0.48~2.06) | 0.999 |
| History of coronary heart disease | 0.84 (0.56~1.27) | 0.411 | 0.89 (0.59~1.35) | 0.597 |
| Prior antiplatelet therapy | 0.78 (0.59~1.04) | 0.094 | 0.79 (0.59~1.06) | 0.114 |
| Prior antihypertensive therapy | 1.2 (1.01~1.44) | 0.038 | 1.21 (1.01~1.45) | 0.041 |
| Prior hypoglycemic therapy | 1.19 (0.96~1.47) | 0.115 | 1.18 (0.95~1.47) | 0.136 |
| Prior statins use | 0.72 (0.51~1.02) | 0.065 | 0.7 (0.48~1.01) | 0.055 |
Abbreviations: sICAS, symptomatic intracranial artery stenosis; BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; TIA, transient ischemic attack.
| Non-HDL-C Quintiles (mmol/L) | n. total | n. event % | Crude OR (95%CI) |
Crude P value |
Adjusted OR (95%CI) |
Adjusted P value |
|---|---|---|---|---|---|---|
| 3 months | ||||||
| Quintile 1, ≤ 2.33 | 536 | 123 (22.9) | Ref | Ref | ||
| Quintile 2, 2.34-2.81 | 544 | 129 (23.7) | 1.04 (0.79–1.38) | 0.766 | 1.04 (0.78–1.38) | 0.808 |
| Quintile 3, 2.82-3.30 | 544 | 137 (25.2) | 1.13 (0.85–1.49) | 0.39 | 1.11 (0.84–1.48) | 0.461 |
| Quintile 4, 3.31-3.92 | 542 | 143 (26.4) | 1.2 (0.91–1.59) | 0.191 | 1.18 (0.89–1.57) | 0.254 |
| Quintile 5, ≥ 3.93 | 547 | 158 (28.9) | 1.36 (1.04–1.79) | 0.026 | 1.33 (1.01–1.77) | 0.044 |
| P value for trend | 0.014 | 0.025 | ||||
| 12 months | ||||||
| Quintile 1, ≤ 2.33 | 501 | 116 (23.2) | Ref | Ref | ||
| Quintile 2, 2.34-2.81 | 515 | 119 (23.1) | 1 (0.75–1.34) | 0.986 | 1 (0.74–1.34) | 0.986 |
| Quintile 3, 2.82-3.30 | 510 | 129 (25.3) | 1.12 (0.84–1.5) | 0.427 | 1.12 (0.83–1.5) | 0.458 |
| Quintile 4, 3.31-3.92 | 508 | 139 (27.4) | 1.25 (0.94–1.66) | 0.124 | 1.24 (0.93–1.66) | 0.149 |
| Quintile 5, ≥ 3.93 | 510 | 149 (29.2) | 1.37 (1.03–1.82) | 0.029 | 1.36 (1.01–1.81) | 0.04 |
| P value for trend | 0.008 | 0.012 | ||||
| Non-HDL-C as continuous | ||||||
| at 3 months | 2713 | 690 (25.4) | 1.13 (1.04–1.23) | 0.003 | 1.12 (1.03–1.22) | 0.007 |
| at 12 months | 2544 | 652 (25.6) | 1.14 (1.05–1.25) | 0.002 | 1.14 (1.04–1.24) | 0.005 |
Adjusted for NIHSS on admission, medication history of statins and antihypertensive agents, history of TIA, and history of ischemic stroke. Abbreviations: HDL-C, high-density lipoprotein cholesterol; sICAS, symptomatic intracranial artery stenosis; OR, odds ratio; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack.
(A) Non-HDL-C and sICAS at 3 months. (B) Non-HDL-C and sICAS at 12 months. Solid lines indicate adjusted odd ratio, and the dashed lines indicate the 95% CI bands. A model with 4 knots located at the 5th, 35th, 65th and 95th percentiles was applied.
A multivariate Cox regression model was used to examine clinical results. The relationships between each confounder and the relevant outcomes are shown in the Supplemental Materials (Supplemental Tables 5, 6, 7, 8).
| Term1 | coeff1 | Change. percentage1 | Term2 | coeff2 | Change. percentage2 | GVIF | DF | GVIF^(1/ (2*Df)) | colinearity | select | select. VIF |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Crude | 0.06 | Ref. | Full | -0.06 | Ref. | 5.955 | 1 | 2.44 | 1 | Ref. | Pending |
| Age | 0.06 | 1.6 | Age | -0.06 | 0 | 1.414 | 1 | 1.189 | 0 | No | No |
| Sex | 0.05 | -18.9 | Sex | -0.06 | -2.6 | 1.503 | 1 | 1.226 | 0 | Yes | Yes |
| BMI | 0.08 | 22.1 | BMI | -0.1 | 66.4 | 1.095 | 1 | 1.046 | 0 | Yes | Yes |
| NIHSS on admission | 0.06 | -3.4 | NIHSS on admission | -0.04 | -27.6 | 1.222 | 5 | 1.02 | 0 | Yes | Yes |
| LDL-C | -0.14 | -332.1 | LDL-C | 0.08 | -226.5 | 5.238 | 1 | 2.289 | 1 | Yes | Pending |
| TG | 0.13 | 103.3 | TG | -0.19 | 199.1 | 1.504 | 1 | 1.227 | 0 | Yes | Yes |
| SBP | 0.04 | -36.8 | SBP | -0.05 | -12.5 | 1.748 | 1 | 1.322 | 0 | Yes | Yes |
| DBP | 0.05 | -14.4 | DBP | -0.06 | 0.2 | 1.807 | 1 | 1.344 | 0 | Yes | Yes |
| Toast | 0.07 | 11 | Toast | -0.08 | 27 | 2.638 | 3 | 1.175 | 0 | Yes | Yes |
| sICAS | 0.05 | -26.5 | sICAS | -0.06 | -3.5 | 2.219 | 1 | 1.49 | 0 | Yes | Yes |
| Hypertension | 0.06 | -3.4 | Hypertension | -0.06 | -0.5 | 2.204 | 1 | 1.485 | 0 | No | No |
| Diabetes mellitus | 0.05 | -20.2 | Diabetes mellitus | -0.06 | -0.3 | 4.258 | 1 | 2.063 | 1 | Yes | Pending |
| Dyslipidemia | 0.05 | -17.5 | Dyslipidemia | -0.05 | -16.8 | 1.119 | 1 | 1.058 | 0 | Yes | Yes |
| Atrial fibrillation | 0.06 | -2.9 | Atrial fibrillation | -0.04 | -30.6 | 1.104 | 1 | 1.051 | 0 | Yes | Yes |
| TIA | 0.06 | 0 | TIA | -0.06 | -3.3 | 1.042 | 1 | 1.021 | 0 | No | No |
| Ischemic stroke | 0.08 | 22.9 | Ischemic stroke | -0.06 | -0.3 | 1.31 | 1 | 1.145 | 0 | Yes | Yes |
| Myocardial infarct | 0.06 | -0.8 | Myocardial infarct | -0.06 | 0.5 | 1.038 | 1 | 1.019 | 0 | No | No |
| Coronary heart disease | 0.06 | -0.2 | Coronary heart disease | -0.06 | -0.3 | 1.085 | 1 | 1.041 | 0 | No | No |
| Current smoker | 0.06 | -6.5 | Current smoker | -0.05 | -16.5 | 3.059 | 2 | 1.323 | 0 | Yes | Yes |
| Alcohol | 0.06 | -1.7 | Alcohol | -0.07 | 14.8 | 2.856 | 3 | 1.191 | 0 | Yes | Yes |
| Prior antiplatelet therapy | 0.07 | 7.9 | Prior antiplatelet therapy | -0.07 | 14.6 | 7.938 | 2 | 1.679 | 0 | Yes | Yes |
| Prior statins use | 0.05 | -17.5 | Prior statins use | -0.07 | 14.1 | 7.085 | 2 | 1.631 | 0 | Yes | Yes |
| Prior antihypertensive therapy | 0.06 | -2 | Prior antihypertensive therapy | -0.06 | -5.3 | 2.403 | 2 | 1.245 | 0 | No | No |
| Prior antidiabetic therapy | 0.05 | -21 | Prior antidiabetic therapy | -0.07 | 12.7 | 7.223 | 2 | 1.639 | 0 | Yes | Yes |
| Dual antiplatelet therapy | 0.06 | -1.1 | Dual antiplatelet therapy | -0.05 | -16.8 | 1.114 | 1 | 1.055 | 0 | Yes | Yes |
| High-intensity statins | 0.06 | -7.3 | High-intensity statins | -0.09 | 47.1 | 1.118 | 1 | 1.057 | 0 | Yes | Yes |
| Antihypertensive therapy | 0.06 | 2.6 | Antihypertensive therapy | -0.07 | 6.3 | 1.567 | 2 | 1.119 | 0 | No | No |
| Antidiabetic therapy | 0.05 | -24.6 | Antidiabetic therapy | -0.06 | 2.7 | 6.905 | 2 | 1.621 | 0 | Yes | Yes |
Abbreviations: BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; SBP, systolic blood pressure; DBP, diastolic blood pressure; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; sICAS, symptomatic intracranial artery stenosis; TIA, transient ischemic attack.
| Term1 | coeff1 | Change. percentage1 | Term2 | coeff2 | Change. percentage2 | GVIF | DF | GVIF^(1/ (2*Df)) | colinearity | select | select. VIF |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Crude | -0.04 | Ref. | Full | -0.21 | Ref. | 4.897 | 1 | 2.213 | 1 | Ref. | Pending |
| Age | -0.04 | -13 | Age | -0.2 | -1.5 | 1.454 | 1 | 1.206 | 0 | Yes | Yes |
| Sex | -0.06 | 38.8 | Sex | -0.2 | -1.8 | 1.453 | 1 | 1.205 | 0 | Yes | Yes |
| BMI | -0.03 | -14.2 | BMI | -0.23 | 13.9 | 1.118 | 1 | 1.057 | 0 | Yes | Yes |
| NIHSS on admission | -0.04 | -0.9 | NIHSS on admission | -0.2 | -3.9 | 1.035 | 1 | 1.017 | 0 | No | No |
| LDL-C | -0.22 | 442.4 | LDL-C | -0.03 | -85.7 | 4.315 | 1 | 2.077 | 1 | Yes | Pending |
| TG | 0 | -101.2 | TG | -0.25 | 20.4 | 1.457 | 1 | 1.207 | 0 | Yes | Yes |
| SBP | -0.06 | 37.1 | SBP | -0.2 | -3.9 | 1.74 | 1 | 1.319 | 0 | Yes | Yes |
| DBP | -0.05 | 12.1 | DBP | -0.21 | 1.7 | 1.809 | 1 | 1.345 | 0 | Yes | Yes |
| TOAST | -0.04 | -0.7 | TOAST | -0.21 | 4.3 | 2.108 | 3 | 1.132 | 0 | No | No |
| sICAS | -0.06 | 40.2 | sICAS | -0.2 | -4.3 | 1.93 | 1 | 1.389 | 0 | Yes | Yes |
| Hypertension | -0.04 | 9.2 | Hypertension | -0.2 | -0.4 | 2.011 | 1 | 1.418 | 0 | No | No |
| Diabetes mellitus | -0.05 | 22 | Diabetes.mellitus | -0.21 | 0.2 | 3.611 | 1 | 1.9 | 0 | Yes | Yes |
| Dyslipidemia | -0.05 | 25.9 | Dyslipidemia | -0.2 | -3.9 | 1.096 | 1 | 1.047 | 0 | Yes | Yes |
| Atrial fibrillation | -0.04 | 6.5 | Atrial fibrillation | -0.19 | -8.5 | 1.095 | 1 | 1.046 | 0 | No | No |
| TIA | -0.04 | -1.8 | TIA | -0.2 | -0.2 | 1.028 | 1 | 1.014 | 0 | No | No |
| Ischemic stroke | -0.01 | -65.6 | Ischemic stroke | -0.2 | -1.3 | 1.32 | 1 | 1.149 | 0 | Yes | Yes |
| Myocardial infarction | -0.04 | 2 | Myocardial infarction | -0.21 | 0.2 | 1.027 | 1 | 1.013 | 0 | No | No |
| Coronary heart disease | -0.04 | 1 | Coronary heart disease | -0.21 | 0.1 | 1.058 | 1 | 1.029 | 0 | No | No |
| Current smoker | -0.04 | 7.8 | Current smoker | -0.2 | -0.2 | 1.584 | 1 | 1.259 | 0 | No | No |
| Alcohol | -0.04 | -0.3 | Alcohol | -0.21 | 0.9 | 1.47 | 1 | 1.212 | 0 | No | No |
| Prior antiplatelet therapy | -0.03 | -29.8 | Prior antiplatelet therapy | -0.21 | 2.2 | 2.128 | 1 | 1.459 | 0 | Yes | Yes |
| Prior statins use | -0.03 | -19.6 | Prior statins use | -0.2 | -1.3 | 1.923 | 1 | 1.387 | 0 | Yes | Yes |
| Prior antihypertensive therapy | -0.03 | -18.8 | Prior antihypertensive therapy | -0.19 | -6.1 | 1.946 | 1 | 1.395 | 0 | Yes | Yes |
| Prior antidiabetic therapy | -0.04 | 10.1 | Prior antidiabetic therapy | -0.21 | 0.2 | 3.502 | 1 | 1.871 | 0 | Yes | Yes |
| Dual antiplatelet therapy | -0.04 | 1.2 | Dual antiplatelet therapy | -0.19 | -6.6 | 1.102 | 1 | 1.05 | 0 | No | No |
| High-intensity statins | -0.05 | 13.6 | High-intensity statins | -0.22 | 8.5 | 1.117 | 1 | 1.057 | 0 | Yes | Yes |
| Antihypertensive therapy | -0.04 | -7.5 | Antihypertensive therapy | -0.21 | 0 | 1.373 | 1 | 1.172 | 0 | No | No |
| Antidiabetic therapy | -0.05 | 12.4 | Antidiabetic therapy | -0.21 | 0.9 | 1.378 | 1 | 1.174 | 0 | Yes | Yes |
Abbreviations: BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; SBP, systolic blood pressure; DBP, diastolic blood pressure; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; sICAS, symptomatic intracranial artery stenosis; TIA, transient ischemic attack.
| Term1 | coeff1 | Change. percentage1 | Term2 | coeff2 | Change. percentage2 | GVIF | DF | GVIF^(1/ (2*Df)) | colinearity | select | select. VIF |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Crude | -0.44 | Ref. | Full | -0.69 | Ref. | 2.705 | 1 | 1.645 | 0 | Ref. | Ref. |
| Age | -0.44 | -0.1 | Age | -0.69 | -0.2 | 1.43 | 1 | 1.196 | 0 | No | No |
| Sex | -0.45 | 1.9 | Sex | -0.69 | -0.4 | 1.524 | 1 | 1.235 | 0 | No | No |
| BMI | -0.51 | 15.7 | BMI | -0.7 | 1.6 | 1.113 | 1 | 1.055 | 0 | Yes | Yes |
| SBP | -0.43 | -1.2 | SBP | -0.7 | 1.1 | 1.996 | 1 | 1.413 | 0 | No | No |
| DBP | -0.44 | -0.2 | DBP | -0.71 | 2.6 | 2.04 | 1 | 1.428 | 0 | No | No |
| LDL-C | -0.68 | 55.5 | LDL-C | -0.53 | -23.4 | 2.495 | 1 | 1.579 | 0 | Yes | Yes |
| TG | -0.35 | -21.1 | TG | -0.69 | -0.8 | 1.355 | 1 | 1.164 | 0 | Yes | Yes |
| Current smoker | -0.44 | 0 | Current smoker | -0.7 | 1.6 | 1.703 | 2 | 1.142 | 0 | No | No |
| Alcohol | -0.48 | 9.9 | Alcohol | -0.59 | -15.2 | 1.546 | 2 | 1.115 | 0 | Yes | Yes |
| NIHSS on admission | -0.44 | 1.5 | NIHSS on admission | -0.65 | -6.2 | 1.238 | 5 | 1.022 | 0 | No | No |
| Toast | -0.41 | -6.1 | Toast | -0.67 | -3.5 | 2.344 | 3 | 1.153 | 0 | No | No |
| sICAS | -0.46 | 5.5 | sICAS | -0.69 | -0.7 | 1.955 | 1 | 1.398 | 0 | No | No |
| History of hypertension | -0.44 | -0.6 | History of hypertension | -0.69 | -0.1 | 2.684 | 1 | 1.638 | 0 | No | No |
| History of diabetes mellitus | -0.44 | -0.1 | History of diabetes mellitus | -0.68 | -1.4 | 3.904 | 1 | 1.976 | 0 | No | No |
| History of dyslipidemia | -0.43 | -1.4 | History of dyslipidemia | -0.7 | 1.1 | 1 | 1 | 1 | 0 | No | No |
| History of atrial fibrillation | -0.44 | 0.2 | History of atrial fibrillation | -0.69 | 0.1 | 1 | 1 | 1 | 0 | No | No |
| History of TIA | -0.44 | 0 | History of TIA | -0.69 | -0.1 | 1.048 | 1 | 1.024 | 0 | No | No |
| History of ischemic stroke | -0.42 | -4.8 | History of ischemic stroke | -0.68 | -1.5 | 1.263 | 1 | 1.124 | 0 | No | No |
| History of myocardial infarct | -0.44 | -0.1 | History of myocardial infarct | -0.7 | 0.5 | 1 | 1 | 1 | 0 | No | No |
| History of coronary heart disease | -0.45 | 2.4 | History of coronary heart disease | -0.69 | -0.1 | 1.06 | 1 | 1.029 | 0 | No | No |
| Prior antiplatelet therapy | -0.49 | 11.3 | Prior antiplatelet therapy | -0.69 | -0.3 | 2.038 | 1 | 1.428 | 0 | Yes | Yes |
| Prior statins use | -0.48 | 9.3 | Prior statins use | -0.68 | -1.1 | 2.003 | 1 | 1.415 | 0 | No | No |
| Prior antihypertensive therapy | -0.4 | -7.9 | Prior antihypertensive therapy | -0.7 | 1.6 | 2.631 | 1 | 1.622 | 0 | No | No |
| Prior antidiabetic therapy | -0.43 | -1.8 | Prior antidiabetic therapy | -0.68 | -1.1 | 10.634 | 1 | 3.261 | 1 | No | Pending |
| Dual antiplatelet therapy | -0.42 | -3.1 | Dual antiplatelet therapy | -0.72 | 4 | 1.08 | 1 | 1.039 | 0 | No | No |
| High-intensity statins | -0.46 | 6 | High-intensity statins | -0.73 | 5 | 1.13 | 1 | 1.063 | 0 | No | No |
| Antihypertensive therapy | -0.41 | -6.2 | Antihypertensive therapy | -0.71 | 2.7 | 1.685 | 2 | 1.139 | 0 | No | No |
| Antidiabetic therapy | -0.45 | 2.2 | Antidiabetic therapy | -0.69 | -0.4 | 10.913 | 2 | 1.818 | 0 | No | No |
Abbreviations: BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; SBP, systolic blood pressure; DBP, diastolic blood pressure; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; sICAS, symptomatic intracranial artery stenosis; TIA, transient ischemic attack.
| Term1 | coeff1 | Change. percentage1 | Term2 | coeff2 | Change. percentage2 | GVIF | DF | GVIF^(1/ (2*Df)) | colinearity | select | select. VIF |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Crude | -0.4 | Ref. | Full | -0.55 | Ref. | 3.725 | 1 | 1.93 | 0 | Ref. | Ref. |
| Age | -0.39 | -0.8 | Age | -0.55 | 0 | 1.409 | 1 | 1.187 | 0 | No | No |
| Sex | -0.41 | 3 | Sex | -0.53 | -2.7 | 1.574 | 1 | 1.255 | 0 | No | No |
| BMI | -0.45 | 12.4 | BMI | -0.59 | 8.3 | 1.106 | 1 | 1.052 | 0 | Yes | Yes |
| NIHSS on admission | -0.4 | 1.6 | NIHSS on admission | -0.48 | -11.7 | 1.378 | 5 | 1.033 | 0 | Yes | Yes |
| LDL-C | -0.61 | 54.8 | LDL-C | -0.41 | -24.9 | 3.345 | 1 | 1.829 | 0 | Yes | Yes |
| TG | -0.33 | -16.3 | TG | -0.52 | -5.5 | 1.367 | 1 | 1.169 | 0 | Yes | Yes |
| SBP | -0.4 | 1.3 | SBP | -0.53 | -2.7 | 1.931 | 1 | 1.39 | 0 | No | No |
| DBP | -0.4 | -0.3 | DBP | -0.55 | 0.3 | 1.934 | 1 | 1.391 | 0 | No | No |
| Toast | -0.37 | -5.7 | Toast | -0.56 | 1.7 | 2.243 | 3 | 1.144 | 0 | No | No |
| sICAS | -0.42 | 5.4 | sICAS | -0.54 | -0.6 | 1.907 | 1 | 1.381 | 0 | No | No |
| Hypertension | -0.4 | 0 | Hypertension | -0.55 | 0 | 2.411 | 1 | 1.553 | 0 | No | No |
| Diabetes mellitus | -0.4 | 0.2 | Diabetes mellitus | -0.55 | -0.4 | 5.233 | 1 | 2.288 | 1 | No | Pending |
| Dyslipidemia | -0.39 | -1.8 | Dyslipidemia | -0.56 | 2.4 | 1 | 1 | 1 | 0 | No | No |
| Atrial fibrillation | -0.4 | 0.2 | Atrial fibrillation | -0.55 | 1 | 1 | 1 | 1 | 0 | No | No |
| TIA | -0.4 | 0 | TIA | -0.54 | -1.4 | 1.107 | 1 | 1.052 | 0 | No | No |
| Ischemic stroke | -0.35 | -10.9 | Ischemic stroke | -0.54 | -1.5 | 1.38 | 1 | 1.175 | 0 | Yes | Yes |
| Myocardial infarction | -0.4 | -0.1 | Myocardial infarction | -0.55 | -0.5 | 1 | 1 | 1 | 0 | No | No |
| Coronary heart disease | -0.41 | 3.1 | Coronary heart disease | -0.55 | 0 | 1.039 | 1 | 1.019 | 0 | No | No |
| Current smoker | -0.4 | 0 | Current smoker | -0.55 | 0.5 | 1.63 | 1 | 1.277 | 0 | No | No |
| Alcohol | -0.4 | -0.2 | Alcohol | -0.54 | -0.6 | 1.499 | 1 | 1.225 | 0 | No | No |
| Prior antiplatelet therapy | -0.4 | 1.6 | Prior antiplatelet therapy | -0.55 | 0.7 | 2.291 | 2 | 1.23 | 0 | No | No |
| Prior statins use | -0.4 | 1.7 | Prior statins use | -0.55 | -0.5 | 2.146 | 1 | 1.465 | 0 | No | No |
| Prior antihypertensive therapy | -0.4 | 0.1 | Prior antihypertensive therapy | -0.56 | 1.7 | 3.031 | 2 | 1.32 | 0 | No | No |
| Prior antidiabetic therapy | -0.4 | 0.9 | Prior antidiabetic therapy | -0.55 | 0.2 | 24.154 | 2 | 2.217 | 1 | No | Pending |
| Dual antiplatelet therapy | -0.38 | -4.1 | Dual antiplatelet therapy | -0.61 | 10.6 | 1.085 | 1 | 1.042 | 0 | Yes | Yes |
| High-intensity statins | -0.4 | 1.8 | High-intensity statins | -0.59 | 6.9 | 1.127 | 1 | 1.062 | 0 | No | No |
| Antihypertensive therapy | -0.37 | -6.1 | Antihypertensive therapy | -0.56 | 1.9 | 1.6 | 2 | 1.125 | 0 | No | No |
| Antidiabetic therapy | -0.4 | 1.9 | Antidiabetic therapy | -0.54 | -0.7 | 17.893 | 2 | 2.057 | 1 | No | Pending |
Abbreviations: BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; SBP, systolic blood pressure; DBP, diastolic blood pressure; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; sICAS, symptomatic intracranial artery stenosis; TIA, transient ischemic attack.
In the 12-month analysis, 13.3% of patients in the fifth quintile of non-HDL-C and 12.6% in the first quintile experienced recurrent ischemic stroke (adjusted hazard ratio 1.19 [95% CI, 0.78–1.80]; P=0.425) (Table 3). The restricted cubic spline between the levels of non-HDL-C and recurrent ischemic stroke is shown in Fig.3. No clear linear relationship was observed. In contrast to those in the first quintile, patients in the top quintile of non-HDL-C had a decreased risk of ICH (adjusted hazard ratio, 0.39 [95% CI, 0.17–0.91]; P=0.030, Table 3). A total of 68.1% of ICH cases were identified during hospitalization and 75.4% had hemorrhagic transformation (Supplemental Table 9). Using restricted cubic splines, we discovered a linear relationship between non-HDL-C level and the risk of ICH within 12 months. Comparable findings were also observed in the 3-month analysis (Table 3, Fig.3).
| Outcome | Non-HDL-C Quintiles (mmol/L) | |||||
|---|---|---|---|---|---|---|
|
Quintile 1, ≤ 2.33 |
Quintile 2, 2.34-2.81 |
Quintile 3, 2.82-3.30 |
Quintile 4, 3.31-3.92 |
Quintile 5, ≥ 3.93 |
P value for trend | |
| 3 months | ||||||
| Ischemic stroke | ||||||
| Events, n (%) | 38 (7.1) | 40 (7.4) | 41 (7.5) | 33 (6.1) | 52 (9.5) | |
| Unadjusted HR (95%CI), P value | Ref | 1.06 (0.68–1.66), 0.791 | 1.12 (0.72–1.76), 0.608 | 0.89 (0.56–1.43), 0.636 | 1.45 (0.95–2.22), 0.082 | 0.190 |
| Adjusted HR＊ (95%CI), P value | Ref | 1.20 (0.74–1.92), 0.459 | 1.28 (0.8–2.06), 0.307 | 0.99 (0.6–1.65), 0.976 | 1.58 (0.96–2.6), 0.070 | 0.191 |
| Intracerebral hemorrhage | ||||||
| Events, n (%) | 22 (4.1) | 10 (1.8) | 9 (1.7) | 7 (1.3) | 8 (1.5) | |
| Unadjusted HR (95%CI), P value | Ref | 0.44 (0.21–0.93), 0.032 | 0.4 (0.18–0.86), 0.020 | 0.31 (0.13–0.72), 0.007 | 0.35 (0.16–0.79), 0.011 | 0.003 |
| Adjusted HR† (95%CI), P value | Ref | 0.43 (0.2–0.93), 0.033 | 0.36 (0.15–0.83), 0.016 | 0.27 (0.1–0.69), 0.006 | 0.37 (0.14–0.95), 0.038 | 0.008 |
| 12 months | ||||||
| Ischemic stroke | ||||||
| Events, n (%) | 63 (12.6) | 62 (12) | 58 (11.4) | 45 (8.9) | 68 (13.3) | |
| Unadjusted HR (95%CI), P value | Ref | 0.95 (0.67–1.35), 0.767 | 0.89 (0.63–1.28), 0.535 | 0.69 (0.47–1.01), 0.055 | 1.08 (0.76–1.52), 0.676 | 0.759 |
| Adjusted HR‡ (95%CI), P value | Ref | 1.04 (0.71–1.52), 0.844 | 1.05 (0.71–1.54), 0.823 | 0.74 (0.48–1.14), 0.169 | 1.19 (0.78–1.80), 0.425 | 0.985 |
| Intracerebral hemorrhage | ||||||
| Events, n (%) | 27 (5.4) | 13 (2.5) | 11 (2.2) | 7 (1.4) | 10 (2) | |
| Unadjusted HR (95%CI), P value | Ref | 0.46 (0.24–0.89), 0.022 | 0.39 (0.20–0.79), 0.009 | 0.25 (0.11–0.58), 0.001 | 0.36 (0.17–0.74), 0.005 | 0.001 |
| Adjusted HR§ (95%CI), P value | Ref | 0.5 (0.25–0.99), 0.047 | 0.42 (0.2–0.89), 0.023 | 0.24 (0.1–0.61), 0.002 | 0.39 (0.17–0.91), 0.03 | 0.003 |
＊Adjusted for sex, BMI, NIHSS on admission, TG, SBP, DBP, Toast, sICAS, history of dyslipidemia, history of atrial fibrillation, history of ischemic stroke, current smoking, medication history of antiplatelet therapy, medication history of statins, medication history of antihypertensive agents, medication history of antidiabetic therapy, dual antiplatelet therapy, high-intensity statins, and antidiabetic therapy.
†Adjusted for BMI, TG, and medication history of antiplatelet therapy.
‡Adjusted for age, sex, BMI, TG, SBP, DBP, sICAS, history of diabetes mellitus, history of dyslipidemia, history of ischemic stroke, medication history of antiplatelet therapy, medication history of statins, medication history of antihypertensive agents, history of antidiabetic therapy, high- intensity statins, and antidiabetic therapy.
§Adjusted for BMI, dual antiplatelet therapy, TG, NIHSS on admission, and history of ischemic stroke.
Abbreviations: HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; TG, triglyceride; SBP, systolic blood pressure; DBP, diastolic blood pressure; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; sICAS, symptomatic intracranial artery stenosis.
(A) Ischemic stroke within 3 months. (B) intracranial hemorrhage within 3 months. (C) ischemic stroke within 12 months. (D) intracranial hemorrhage within 12 months. Solid lines indicate adjusted odd ratios. Dashed lines indicate the 95% CI bands. Data were fitted with a Cox regression model of restricted cubic spline with 4 knots (at the 5th, 35th, 65th and 95th centiles) for levels of non-HDL-C, adjusting for potential covariates.
| Non-HDL-C quintiles, mmol/L | Occurrence time of ICH | Types of ICH | |||
|---|---|---|---|---|---|
| During hospitalization for mild stroke, n | After discharge from mild stroke, n | Hemorrhagic infarction, n | Intracerebral haemorrhage, n | Subarachnoid hemorrhage, n | |
| Quintile 1, ≤ 2.33 | 18 | 9 | 20 | 6 | 1 |
| Quintile 2, 2.34-2.81 | 8 | 5 | 9 | 4 | 0 |
| Quintile 3, 2.82-3.31 | 7 | 4 | 9 | 2 | 0 |
| Quintile 4, 3.32-3.92 | 7 | 0 | 7 | 0 | 0 |
| Quintile 5, ≥ 3.93 | 7 | 4 | 7 | 4 | 0 |
According to subgroup analysis of the 2 sets of data, patients with sICAS and the large-artery atherosclerosis subtype of the TOAST classification in the fifth quintile of non-HDL-C were found to have a proportionately increased risk of recurrence in comparison to those in the first quintile. When comparing the 12-month analysis to the 3-month analysis, this effect was less pronounced. Nevertheless, no interactions were found between the sICAS or TOAST categorization and the non-HDL-C quintile for the risk of recurrent ischemic stroke (Supplemental Tables 10 and 11).
| Subgroup | Non-HDL-C mmol/L | n. total | n. event_% | Crude HR (95%CI) |
Crude P value |
Adjusted HR (95%CI) |
Adjusted P value |
P for interaction |
|---|---|---|---|---|---|---|---|---|
| sICAS | 0.233 | |||||||
| Without sICAS | Quintile 1, ≤ 2.33 | 413 | 28 (6.8) | 1 (Ref) | 1 (Ref) | |||
| Quintile 2, 2.34-2.81 | 415 | 23 (5.5) | 0.76 (0.43~1.33) | 0.341 | 0.85 (0.48~1.5) | 0.564 | ||
| Quintile 3, 2.82-3.31 | 407 | 22 (5.4) | 0.79 (0.45~1.38) | 0.41 | 0.99 (0.55~1.76) | 0.966 | ||
| Quintile 4, 3.32-3.92 | 399 | 18 (4.5) | 0.64 (0.35~1.16) | 0.142 | 0.77 (0.42~1.45) | 0.423 | ||
| Quintile 5, ≥ 3.93 | 389 | 28 (7.2) | 1.07 (0.64~1.81) | 0.787 | 1.35 (0.74~2.45) | 0.331 | ||
| Trend.test | 1 (0.88~1.14) | 1 | 1.05 (0.91~1.22) | 0.488 | ||||
| With sICAS | Quintile 1, ≤ 2.33 | 123 | 10 (8.1) | 1 (Ref) | 1 (Ref) | |||
| Quintile 2, 2.34-2.81 | 129 | 17 (13.2) | 1.84 (0.82~4.12) | 0.14 | 2.04 (0.89~4.7) | 0.092 | ||
| Quintile 3, 2.82-3.31 | 137 | 19 (13.9) | 2.01 (0.91~4.46) | 0.086 | 2.4 (1.06~5.43) | 0.036 | ||
| Quintile 4, 3.32-3.92 | 143 | 15 (10.5) | 1.53 (0.67~3.51) | 0.315 | 1.87 (0.79~4.47) | 0.156 | ||
| Quintile 5, ≥ 3.93 | 158 | 24 (15.2) | 2.28 (1.06~4.93) | 0.036 | 2.96 (1.27~6.94) | 0.012 | ||
| Trend.test | 1.14 (0.98~1.33) | 0.1 | 1.2 (1.01~1.43) | 0.037 | ||||
| TOAST classification | 0.139 | |||||||
| LAA | Quintile 1, ≤ 2.33 | 167 | 16 (9.6) | 1 (Ref) | 1 (Ref) | |||
| Quintile 2, 2.34-2.81 | 159 | 13 (8.2) | 0.9 (0.43~1.89) | 0.784 | 0.94 (0.44~2) | 0.864 | ||
| Quintile 3, 2.82-3.31 | 161 | 17 (10.6) | 1.22 (0.6~2.44) | 0.584 | 1.4 (0.68~2.88) | 0.357 | ||
| Quintile 4, 3.32-3.92 | 156 | 14 (9) | 1.05 (0.5~2.17) | 0.906 | 1.16 (0.54~2.52) | 0.701 | ||
| Quintile 5, ≥ 3.93 | 183 | 26 (14.2) | 1.71 (0.9~3.24) | 0.099 | 2.09 (1.01~4.33) | 0.046 | ||
| Trend.test | 1.15 (0.99~1.33) | 0.077 | 1.2 (1.01~1.43) | 0.035 | ||||
| SVO | Quintile 1, ≤ 2.33 | 224 | 14 (6.2) | 1 (Ref) | 1 (Ref) | |||
| Quintile 2, 2.34-2.81 | 259 | 15 (5.8) | 0.94 (0.45~1.95) | 0.872 | 1.12 (0.53~2.37) | 0.757 | ||
| Quintile 3, 2.82-3.31 | 270 | 10 (3.7) | 0.59 (0.26~1.33) | 0.205 | 0.74 (0.32~1.71) | 0.483 | ||
| Quintile 4, 3.32-3.92 | 261 | 8 (3.1) | 0.43 (0.17~1.06) | 0.067 | 0.57 (0.22~1.45) | 0.238 | ||
| Quintile 5, ≥ 3.93 | 257 | 17 (6.6) | 1.08 (0.53~2.19) | 0.828 | 1.55 (0.69~3.47) | 0.292 | ||
| Trend.test | 1271 | 64 (5) | 0.96 (0.8~1.15) | 0.643 | 1.03 (0.84~1.26) | 0.773 | ||
| OE | Quintile 1, ≤ 2.33 | 15 | 0 (0) | 1 (Ref) | 1 (Ref) | |||
| Quintile 2, 2.34-2.81 | 11 | 4 (36.4) | 506069522.1 (0~Inf) | 0.998 |
13899158802665408512 (3502247344181315072~ 55160757204277534720) |
＜0.001 | ||
| Quintile 3, 2.82-3.31 | 7 | 2 (28.6) | 396510365.7 (0~Inf) | 0.998 |
239102282626023584 (28866679625108116~ 1980480689135051008) |
＜0.001 | ||
| Quintile 4, 3.32-3.92 | 7 | 3 (42.9) | 625451307.27 (0~Inf) | 0.998 |
2994958390344955392 (733446368244661120~ 12229627343257268224) |
＜0.001 | ||
| Quintile 5, ≥ 3.93 | 8 | 1 (12.5) | 164838647.06 (0~Inf) | 0.998 |
3217748708173934592 (386983568093668224~ 26755417032200425472) |
＜0.001 | ||
| Trend.test | 1.27 (0.85~1.9) | 0.252 | 1.38 (0.76~2.52) | 0.287 | ||||
| UE | Quintile 1, ≤ 2.33 | 130 | 8 (6.2) | 1 (Ref) | 1 (Ref) | |||
| Quintile 2, 2.34-2.81 | 115 | 8 (7) | 0.97 (0.35~2.68) | 0.953 | 0.87 (0.31~2.45) | 0.789 | ||
| Quintile 3, 2.82-3.31 | 106 | 12 (11.3) | 1.84 (0.75~4.5) | 0.182 | 1.65 (0.66~4.13) | 0.282 | ||
| Quintile 4, 3.32-3.92 | 118 | 8 (6.8) | 1.08 (0.41~2.88) | 0.876 | 0.97 (0.34~2.71) | 0.947 | ||
| Quintile 5, ≥ 3.93 | 99 | 8 (8.1) | 1.3 (0.49~3.47) | 0.596 | 1.11 (0.38~3.22) | 0.849 | ||
| Trend.test | 1.06 (0.86~1.31) | 0.567 | 1.04 (0.82~1.31) | 0.76 |
Adjusted for age, sex, NIHSS on admission, TG, Toast, history of dyslipidemia, history of atrial fibrillation, history of ischemic stroke, antidiabetic therapy.
Abbreviations: sICAS, symptomatic intracranial artery stenosis; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; LAA, large-artery atherosclerosis; SVO, small-vessel occlusion; OE: other determined etiology; UE: undetermined etiology.
| Subgroup | Variable | n.total | n.event_% | crude.HR_95CI |
crude. P_value |
adj.HR_95CI |
adj. P_value |
P.for. interaction_1 |
|---|---|---|---|---|---|---|---|---|
| Without sICAS | 0.583 | |||||||
| Quintile 1, ≤ 2.33 mmol/L | 379 | 45 (11.9) | 1 (Ref) | 1 (Ref) | ||||
| Quintile 2, 2.34-2.81 mmol/L | 388 | 36 (9.3) | 0.76 (0.49~1.18) | 0.226 | 0.86 (0.53~1.38) | 0.526 | ||
| Quintile 3, 2.82-3.31 mmol/L | 378 | 35 (9.3) | 0.76 (0.49~1.18) | 0.217 | 0.95 (0.58~1.53) | 0.821 | ||
| Quintile 4, 3.32-3.92 mmol/L | 364 | 25 (6.9) | 0.56 (0.34~0.91) | 0.019 | 0.63 (0.36~1.1) | 0.102 | ||
| Quintile 5, ≥ 3.93 mmol/L | 353 | 38 (10.8) | 0.9 (0.58~1.39) | 0.635 | 1.14 (0.67~1.94) | 0.616 | ||
| Trend.test | 1862 | 179 (9.6) | 0.95 (0.85~1.05) | 0.315 | 1 (0.88~1.13) | 0.945 | ||
| With sICAS | ||||||||
| Quintile 1, ≤ 2.33 mmol/L | 122 | 18 (14.8) | 1 (Ref) | 1 (Ref) | ||||
| Quintile 2, 2.34-2.81 mmol/L | 127 | 26 (20.5) | 1.42 (0.78~2.6) | 0.25 | 1.56 (0.81~3.04) | 0.187 | ||
| Quintile 3, 2.82-3.31 mmol/L | 132 | 23 (17.4) | 1.21 (0.66~2.25) | 0.536 | 1.28 (0.65~2.52) | 0.478 | ||
| Quintile 4, 3.32-3.92 mmol/L | 144 | 20 (13.9) | 0.95 (0.5~1.8) | 0.879 | 1.04 (0.52~2.09) | 0.91 | ||
| Quintile 5, ≥ 3.93 mmol/L | 157 | 30 (19.1) | 1.37 (0.76~2.46) | 0.292 | 1.41 (0.7~2.86) | 0.338 | ||
| Trend.test | 682 | 117 (17.2) | 1.02 (0.9~1.16) | 0.726 | 1.02 (0.87~1.18) | 0.824 | ||
| TOAST classification | 0.581 | |||||||
| LAA | Quintile 1, ≤ 2.33 mmol/L | 157 | 26 (16.6) | 1 (Ref) | 1 (Ref) | |||
| Quintile 2, 2.34-2.81 mmol/L | 150 | 24 (16) | 0.95 (0.55~1.66) | 0.859 | 1 (0.54~1.87) | 0.993 | ||
| Quintile 3, 2.82-3.31 mmol/L | 152 | 22 (14.5) | 0.87 (0.49~1.53) | 0.629 | 1.08 (0.58~2.04) | 0.801 | ||
| Quintile 4, 3.32-3.92 mmol/L | 151 | 19 (12.6) | 0.75 (0.42~1.36) | 0.342 | 0.83 (0.42~1.63) | 0.585 | ||
| Quintile 5, ≥ 3.93 mmol/L | 171 | 32 (18.7) | 1.17 (0.7~1.97) | 0.544 | 1.31 (0.68~2.53) | 0.423 | ||
| Trend.test | 781 | 123 (15.7) | 1.02 (0.9~1.15) | 0.775 | 1.04 (0.89~1.21) | 0.606 | ||
| SVO | ||||||||
| Quintile 1, ≤ 2.33 mmol/L | 212 | 24 (11.3) | 1 (Ref) | 1 (Ref) | ||||
| Quintile 2, 2.34-2.81 mmol/L | 247 | 24 (9.7) | 0.86 (0.49~1.51) | 0.592 | 1.1 (0.6~2.04) | 0.755 | ||
| Quintile 3, 2.82-3.31 mmol/L | 250 | 19 (7.6) | 0.65 (0.36~1.19) | 0.166 | 0.91 (0.47~1.74) | 0.771 | ||
| Quintile 4, 3.32-3.92 mmol/L | 242 | 14 (5.8) | 0.49 (0.26~0.95) | 0.036 | 0.65 (0.31~1.36) | 0.255 | ||
| Quintile 5, ≥ 3.93 mmol/L | 236 | 23 (9.7) | 0.86 (0.49~1.53) | 0.611 | 1.29 (0.65~2.56) | 0.467 | ||
| Trend.test | 1187 | 104 (8.8) | 0.92 (0.8~1.06) | 0.246 | 1 (0.85~1.18) | 0.993 | ||
| OE | ||||||||
| Quintile 1, ≤ 2.33 mmol/L | 15 | 2 (13.3) | 1 (Ref) | 1 (Ref) | ||||
| Quintile 2, 2.34-2.81 mmol/L | 10 | 4 (40) | 3.34 (0.61~18.3) | 0.164 | 29.49 (0.75~1153.9) | 0.07 | ||
| Quintile 3, 2.82-3.31 mmol/L | 7 | 2 (28.6) | 2.28 (0.32~16.21) | 0.409 | 0.67 (0.03~16.55) | 0.809 | ||
| Quintile 4, 3.32-3.92 mmol/L | 7 | 3 (42.9) | 3.7 (0.62~22.22) | 0.153 | 1.94 (0.06~57.94) | 0.703 | ||
| Quintile 5, ≥ 3.93 mmol/L | 8 | 1 (12.5) | 0.92 (0.08~10.18) | 0.948 | 9.03 (0.29~277.22) | 0.208 | ||
| Trend.test | 47 | 12 (25.5) | 1.05 (0.73~1.53) | 0.78 | 0.79 (0.41~1.52) | 0.485 | ||
| UE | ||||||||
| Quintile 1, ≤ 2.33 mmol/L | 117 | 11 (9.4) | 1 (Ref) | 1 (Ref) | ||||
| Quintile 2, 2.34-2.81 mmol/L | 108 | 10 (9.3) | 0.96 (0.41~2.25) | 0.919 | 0.91 (0.34~2.4) | 0.844 | ||
| Quintile 3, 2.82-3.31 mmol/L | 101 | 15 (14.9) | 1.6 (0.73~3.47) | 0.239 | 1.43 (0.57~3.58) | 0.44 | ||
| Quintile 4, 3.32-3.92 mmol/L | 108 | 9 (8.3) | 0.87 (0.36~2.09) | 0.75 | 0.73 (0.26~2.05) | 0.552 | ||
| Quintile 5, ≥ 3.93 mmol/L | 95 | 12 (12.6) | 1.35 (0.59~3.05) | 0.475 | 1.05 (0.36~3.03) | 0.934 | ||
| Trend.test | 529 | 57 (10.8) | 1.05 (0.88~1.26) | 0.584 | 0.99 (0.78~1.25) | 0.906 | ||
Adjusted for age, sex, BMI, TG, SBP, DBP, sICAS, history of hypertension, history of dyslipidemia, history of atrial fibrillation, history of ischemic stroke, medication history of antiplatelet therapy, medication history of statins, medication history of antihypertensive agents, high-intensity statins, antidiabetic therapy.
Abbreviations: sICAS, symptomatic intracranial artery stenosis; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; LAA, large-artery atherosclerosis; SVO, small-vessel occlusion; OE: other determined etiology; UE: undetermined etiology.
Our study shows that in mild, noncardiogenic ischemic stroke individuals treated with antiplatelet medications and statin agents, elevated levels of non-HDL-C are not associated with recurrent ischemic stroke but can reduce the risk of intracranial hemorrhage. There was a positive correlation between non-HDL-C level and the incidence of sICAS.
Higher non-HDL-C levels have been associated with an increased risk of ischemic stroke in numerous studies focusing on healthy individuals or the general population. However, there is ongoing disagreement regarding the predictive value of non-HDL-C for recurrent stroke after acute ischemic stroke, which may be due to the diversity of the study population. Consistent with the results of the Vitamin Intervention for Stroke Prevention (VISP) trial, non-HDL-C was not significantly associated with the risk of recurrent stroke in patients who had experienced a non-disabling (mRs ≤ 3) and non-cardioembolic cerebral infarction within the previous 120 days16). However, non-HDL-C was positively correlated with the risk of recurrence in individuals with acute ischemic stroke, according to a cohort study involving Chinese patients who had a greater prevalence of stroke recurrence linked to a higher rate of large artery atherosclerotic disease12). It has been demonstrated that non-HDL-C levels can predict atherosclerotic diseases17). High non-HDL-C levels are linked to large-artery atherosclerotic stroke, and exhibit a great impact on large cerebral arteries18, 19). Similar to CHD, large artery occlusive infarction is an atherogenic disease. Thus, it is indicated that in the occurrence of ischemic stroke, non-HDL-C has a greater impact on intracranial large major arteries than on small arteries.
In the subgroup analysis, individuals with the large-artery atherosclerosis subtype and those with sICAS in the highest quintile of non-HDL-C showed a proportionately higher probability of recurrence in comparison to those in the first quintile. In the 12-month analysis, this effect was weakened in comparison to the 3-month analysis. The 30-year life history of the Framingham Offspring group demonstrated that non-HDL-C levels were generally steady20). Statins reduce non-HDL-C levels by having a moderate impact on triglyceride-rich lipoproteins (TRLs) and significantly lowering LDL-C levels. A meta-analysis showed that different types and doses of statins had varying non-HDL-C lowering effects in individuals with diabetes and a high risk of cardiovascular disease21). In our study, it is possible that the different types and intensities of statins had heterogeneous non-HDL-C lowering effects, as the number of days of statin therapy increased, thereby weakening the impact of non-HDL-C on the prevention of recurrent stroke. The findings of this study highlight the necessity of intracranial imaging examinations in patients with high non-HDL-C levels for the primary prevention of ischemic stroke. For patients with intracranial artery stenosis, in addition to focusing on LDL-C, non-HDL-C levels should also be controlled to achieve the target.
Our study found a negative correlation between non-HDL-C levels and the risk of intracranial hemorrhage within 1 year. The CNSR II study revealed that although there was no statistically significant correlation between non-HDL-C levels and ICH, those in the lowest quintile had a proportionately higher risk of ICH than those in the highest quintile12). In addition, a published study indicated that low non-HDL-C levels are independently associated with a higher risk of hemorrhagic transformation (HT)22). In our cohort, 75% of ICH events were hemorrhagic transformation. The mechanisms that explain the association between non-HDL-C levels and HT or ICH are uncertain. Several published studies suggest that higher cholesterol levels, which lead to increased non-HDL-C values, may help prevent ICH by maintaining the integrity of cerebral blood vessels, reducing erythrocyte membrane permeability, preventing vessel wall leakage and rupture, and promoting platelet aggregation, while also preventing arterionecrosis including arterial fragility, bleeding, and inadequate repair after minor hemorrhage23-26). Further research is needed to determine the relationship and mechanism between non-HDL-C levels and the risk of ICH after ischemic stroke.
The strength of our study was its prospective multicenter design targeting approximately 3,000 mild stroke participants from a real-world context. In addition, our study provides Class III evidence to support that non-HDL-C may be a useful predictor of sICAS, and that elevated levels of non-HDL-C may reduce the risk of ICH in patients with minor stroke (mainly hemorrhagic infarction). This suggests the potential of non-HDL-C as a therapeutic target, primarily for the prevention of stroke caused by intracranial large-artery stenosis. Otherwise, ICH caused by low non-HDL-C levels, especially hemorrhagic transformation after infarction, should be highly valued.
The present study was associated with several limitations. First, only Chinese patients with mild stroke were included in this study. This remains to be investigated in patients of other racial or ethnic backgrounds. Second, with the exception of baseline non-HDL-C levels, non-HDL-C values could not be collected during the follow-up. Furthermore, even though all patients received statin treatment, different types and intensities of statins may have heterogeneous non-HDL-C lowering effects. Nevertheless, statin intensity was adjusted as a covariate in this analysis. Third, owing to the Covid-19 epidemic, the majority of follow-up consultations were conducted over the phone, and the endpoint assessment could not be fully confirmed by hospital records, with the exception of patients who were readmitted at the 8 participating hospitals. More extensive studies on patients with mild stroke are required to confirm the applicability of our findings.
Taken together, in acute, patients with mild ischemic stroke of non-cardiogenic causes, elevated levels of non-HDL-C may reduce the risk of ICH but do not increase the risk of recurrent ischemic stroke. Non-HDL-C levels may be an appropriate predictor of sICAS.
None.
The authors would like to express their gratitude to all participating clinicians, study participants, and their relatives at the eight centers of the SEACOAST study.
The authors state that there is no conflict of interest to disclosure.
Data from this study are available and can be accessed upon reasonable request.
HF and XN conceived of and designed the study. XN and XW take responsibility for the integrity of the data and accuracy of the data analysis. HF drafted the manuscript and analyzed or interpreted the data. TL proposed and registered the research proposal. YW and KZ were responsible for the analysis and interpretation of the data. All authors were responsible for data collection and manuscript revision.
