Total cholesterol affects the outcome in anterior cerebral artery-occluded acute ischemic stroke patients treated with thrombolysis

doi:10.21203/rs.2.11048/v1

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Total cholesterol affects the outcome in anterior cerebral artery-occluded acute ischemic stroke patients treated with thrombolysis

https://doi.org/10.21203/rs.2.11048/v1

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Object

In this study, we investigated whether certain types of lipid profiles are major contributors to disease outcomes.

Methods

At two stroke medical centers, among 13,285 hospitalized patients treated with thrombolysis, thrombectomy, or conventional care, two hundred and seventy-six anterior cerebral artery-occluded acute ischemic stroke (AIS) patients were screened. We examined the plasma lipid profiles by using the cutoff values from a receiver operating characteristic (ROC) curve. A multivariate logistic regression or Fisher’s exact test was used to compare the outcome and risk events. The modified Rankin scale (mRS) score was used to assess the major clinical outcome of the patients 3 months after disease onset. Mortality and symptomatic intracranial hemorrhage (sICH) were both evaluated as risk factors. The disease outcome was examined by analyzing symptom improvement at discharge.

Results

In the anterior cerebral artery-occluded AIS (NIHSS ≥ 10) patients treated by intravenous (IV) thrombolysis, a total cholesterol (TC) level greater than 5.07 mmol/L predicted a poor outcome (OR 3.55, 95% CI 1.21,10.46, p = 0.021).

Conclusion

In anterior cerebral artery-occluded AIS patients, the TC level is a highly promising screening factor for predicting the outcome of IV thrombolysis.

Neurology

acute ischemic stroke

thrombolysis

total cholesterol

atherosclerosis

Atherosclerotic cardiovascular disease and its clinical manifestations, such as ischemic cerebrovascular disease and coronary artery disease, are the leading cause of morbidity and mortality worldwide¹ ²^,³. In most epidemiological cohort studies, the total cholesterol (TC) levels are well known to be associated with the cause of stroke. An increased risk of intracerebral hemorrhage (ICH) is closely associated with lower cholesterol levels ⁴. Patients with higher TC levels are susceptible to ischemic stroke^5-10. Therefore, determining whether certain types of plasma lipid profiles play critical roles in causing stroke is important. Lower HDL-C and TG levels have been used as two important parameters to independently predict a better survival rate after intravenous (IV) thrombolysis treatment in a retrospective analysis¹¹, and it has been well documented that patients can greatly benefit from this treatment. Lower low-density lipoprotein cholesterol (LDL-C) levels were found to be associated with ICH, while high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels do not differ between stroke patients with or without ICH¹². It is apparent that different types of biological lipoproteins are associated with certain disease types and their prognosis or consequences. Over the past decade, few studies have focused on the association between TC levels and prognosis in stroke patients. Thus, identifying the association between an individual’s plasma lipid profile and prognosis in AIS is critical.

In this study, we evaluated the association between the lipid profiles and prognosis in AIS patients. We analyzed the relationship between cholesterol levels and prognosis following thrombolysis. Subsequently, we compared the effect of cholesterol on three common AIS management strategies (thrombolysis, thrombectomy and conventional treatment). Importantly, we found that the lipid profiles presented in patients’ plasma can be used as indicators to predict the overall outcome of severe anterior cerebral artery-occluded AIS patients only among patients treated with IV thrombolysis.

Patients and methods

This retrospective study was approved by the Ethics Committee of Xinhua Hospital, Shanghai Jiao Tong University and the First People’s Hospital of Changzhou, Soochow University. The requirement for individual patient consent or consent from the patients’ relatives was waived, and the patients’ information was anonymized prior to analysis. In total, 13,285 AIS patients treated with thrombolysis, thrombectomy, or conventional care between December 2010 and May 2015 at Xinhua Hospital and The First People’s Hospital of Changzhou were recruited for this study. Among these patients, 396 patients received IV thrombolysis management, 98 patients received endovascular mechanical thrombectomy, and 12,791 patients were treated by conventional procedures not including thrombolysis or thrombectomy. Due to our specific patient selection requirements (National Institutes of Health Stroke Scale [NIHSS] score ≥ 10, anterior artery occlusion, and age < 80 years), the final results reported in the present study include a total of 276 patients. Among these patients, 78 patients were in the endovascular thrombectomy group, 95 patients were in the IV thrombolysis group, and 103 patients were in the conventional care group. The detailed screening processes are shown in Figure 1.

According to the baseline NIHSS score, which is a clinical measure of neurologic deficit with a range of 0 (no deficit) to 42 (maximum possible deficit), patients with a score of 10 or more, representing a greater than 80% likelihood of a major arterial occlusion¹³, were identified. A stroke neurologist clinically assessed all patients upon admission. Cranial computed tomography (CT) was obtained prior to IV recombinant tissue plasminogen activator (rt-PA) treatment to rule out intracranial hemorrhage.

IV rt-PA thrombolysis treatment was initiated within 4.5 hours of the onset of stroke symptoms, and mechanical thrombectomy treatment was initiated within 6 hours as we previously reported^14-16. The conventional care group consisted of patients who were subject to high risks during thrombolysis or thrombectomy or whose families did not consent to treatment. The time between onset and admission was less than 6 hours.

Patient treatment

The main inclusion criteria were as follows: 1. an NIHSS score ≥ 10 at admission; 2. imaging evidence revealing that the occlusion site was the anterior cerebral artery; and 3. analysis of the full lipid profile (including TG, TC, HDL-C and LDL-C) within 24 hours of stroke onset. The exclusion criteria included uncontrolled hypertension, severe sensitivity to radiographic contrast agents, and CT or magnetic resonance imaging (MRI) evidence of intracranial hemorrhage.

The patients in the thrombectomy group were treated as previously described^14-16. The technical details of the endovascular procedure have also been described in a previous study. Upon admission, a stroke neurologist examined all patients; cranial CT or multimodal MR angiography was performed on patients prior to each intervention to confirm the diagnosis of large-vessel occlusion and rule out intracranial hemorrhage. All interventional treatments were initiated within the first 6 hours of stroke onset. For the thrombolysis treatment, we followed the American Heart Association (AHA) guidelines¹⁷ as described in a previous study¹⁶. The patients in the conventional care group were treated with lipid-lowering drugs via oral administration. The CT scans were reviewed during hospitalization, and if intracranial hemorrhage occurred, anticoagulation therapy was ceased, and the treatment plan was adjusted. No thrombolysis or thrombectomy management was performed in the conventional care patient group.

The intracranial hemorrhagic transformations were divided into clinically silent or symptomatic and then further classified into different categories. Hemorrhage was scored using the Pessin criteria and formalized based on the European Cooperative Acute Stroke Study (ECASS) trials (hemorrhagic infarction types 1 and 2 and parenchymal hematoma types 1 and 2)^18-20. Symptomatic intracranial hemorrhage was defined as any parenchymal hematoma subarachnoid hemorrhage or intraventricular hemorrhage associated with a worsening of the NIHSS score by four or more points within 24 h²¹. CT and MR images are very useful tools for evaluating the infarct lesion in the brain. The Alberta Stroke Program Early CT Score (ASPECTS) was used as a grading system to standardize the quantification of the CT images²². As the ASPECTS criteria were not included in the treatment guidelines of our two centers, ASPECTS was not measured immediately before the rt-PA treatment and did not affect the choice of management strategy. ASPECTS was evaluated by two neurosurgeons at the initial stage of this retrospective study (CJ.G., Y.L., and Y.P. contributed to this work). The stroke mechanism was viewed according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. The subtypes of AIS were defined at the 3-month follow-up as follows: cardioembolic, large-vessel atherosclerosis, other (uncommon etiologies), or undetermined²³. When no etiology was found or two diagnoses were possible, the etiology was classified as undetermined. The outcome at 3 months was evaluated by the modified Rankin scale (mRS) score either at a face-to-face visit or by telephone. Favorable outcomes were defined as a score of 0 to 2, and unfavorable outcomes were defined as a score of 3 to 6.

First, the mRS score at 3 months (the major outcome variable) was evaluated in the patients in the thrombolysis group with TC ≤ 5.07 mmol/L or > 5.07 mmol/L. Then, the mRS score was compared with that in the thrombectomy group, the thrombolysis group, and the conventional care group. We also checked for symptom improvement after different management techniques. To evaluate the degree to which the symptoms improved after treatment, we compared the clinical improvement (discharge NIHSS score - admission NIHSS score ≥ 4) and the marked improvement (discharge NIHSS score - admission NIHSS score ≥ 10) rates of the patients among the treatment groups. Additionally, the difference in sICH and mortality risk between the thrombectomy (or thrombolysis) and conventional care groups was evaluated. The following data were also collected: age, gender, stroke reason, time between onset and needle, blood pressure at admission, plasma glucose and lipid profiles, medical history, documented occlusion site, and mRS score at 3 months.

Statistical analysis

The baselines and main outcomes are described as the means and standard deviations; the qualitative data are described as numbers and percentages. The lipid profiles were stratified using the cutoff values from the receiver operating characteristic (ROC) curve. For comparisons between different therapies, a Chi-square test or 2-sided Fisher’s exact test was used (significance was set as p < 0.05). The independent prognostic value of the lipid profiles, the associations among the different management options, and symptomatic improvement or some other risk events were analyzed by a bivariate logistic regression analysis. All statistical analyses were performed using SAS software (version 9.4, SAS Institute).

Prognostic factors of the clinical outcome in thrombolysis patients

Because blood lipids are reportedly inflammatory mediators and have been considered high risk factors of stroke, we examined the lipid profiles in plasma by using the cutoff values from the ROC curve. In this study, for the severe anterior cerebral artery-occluded AIS patients treated with thrombolysis, the cutoff values of TG, TC and LDL-C were 1.65 mmol/L (sensitivity 71.4%, specificity 87.5%), 5.07 mmol/L (sensitivity 83.3%, specificity 58.5%), and 3.01 mmol/L (sensitivity 63.5%, specificity 81.2%), respectively.

To determine whether the lipid profiles are predictors of the disease outcome, a univariate logistical regression was conducted. As shown in Table 1, a higher TC level (>5.07 mmol/L) can be clearly used as a predictor of a worse outcome (OR 3.55, 95% CI 1.21,10.46), while the TG and LDL-C levels are not suitable for predicting the disease outcome. Other parameters, such as the baseline ASPECTS (OR 0.54, 95% CI 0.39,0.76), admission NIHSS score (OR 1.14, 95% CI 1.00,1.29), plasma glucose level (OR 1.25, 95% CI 1.03,1.52), and systolic (OR 1.03, 95% CI 1.01,1.06) and diastolic (OR 1.04, 95% CI 1.01,1.08) pressure, were also considered associated with the disease outcome three months after disease onset. To determine the major contributors to the disease outcome three months after the disease onset, a multivariate logistic regression was conducted including the variables of systolic pressure, TC, admission ASPECTS and admission NIHSS score. By examining all clinical assessments and evaluations, it was found that the TC level (OR 6.64, 95% CI 1.84,23.96) is closely associated with the disease outcome of the patients (Table 1).

Population baseline

We also sought to determine whether the lipid profiles affect the prognosis of AIS patients who receive other types of treatment, such as mechanical thrombectomy and conventional treatment. In total, 13,285 hospitalized AIS patients were screened at Xinhua Hospital and The First People’s Hospital of Changzhou between December 2010 and May 2015. After the screening, 276 patients treated with 3 different management methods were chosen, as shown in Figure 1. Of these patients, 95 patients received IV rt-PA thrombolysis treatment (thrombolysis group), 78 patients underwent endovascular thrombectomy treatment (thrombectomy group), and the remaining 103 patients were managed by conventional care without IV rt-PA treatment or thrombectomy (control group). The mean ages of the patients in these 3 groups ranged from 60 to 70 years (the average age of the thrombolysis patients was 67.25 years, the average age of the thrombectomy patients was 61.41 years, and the average age of the conventional care patients was 65.14 years; Table 2). Nearly half of the patients’ symptoms were caused by large-artery atherosclerosis in the thrombectomy (46.15%) and thrombolysis (43.16%) groups, while 82.41% of the stroke cases resulted from large-artery atherosclerosis in the conventional care group. The detailed baseline characteristics of these three groups are listed in Table 2.

Clinical outcome

To determine whether TC affected the overall outcome, the mRS score of the patients in the different treatment groups at 3 months was analyzed based on the TC cutoff value. In addition to our previous analysis, a TC level > 5.07 mmol/L corresponded to a 3.55-fold greater possibility of an unfavorable outcome compared with that of a TC level ≤ 5.07 mmol/L (OR 3.55, 95% CI 1.21-10.46) in the thrombolysis group. The rate of unfavorable outcome was 65.00% (13 of 20) with a TC level > 5.07 in the thrombectomy group but 53.40% (31 of 58) in the patients with a TC level ≤ 5.07 in the thrombectomy group. The risk of unfavorable outcome among the patients with a TC level > 5.07 was 1.65 times (95% CI 0.49-5.61) greater than that among the patients with a TC level ≤ 5.07 in the control group, although this difference was not statistically significant. The distribution of mRS scores at 3 months within the different groups is shown in Figure 2. There was no significant prognostic improvement among the patients with a TC level ≤ 5.07 in the thrombectomy group (OR 0.62, 95% CI 0.22-1.77).

As shown in Table 4, the TC cutoff value among the different therapy groups was analyzed. The severe AIS patients with a TC level ≤ 5.07 significantly benefited from thrombectomy (OR 0.12, 95% CI 0.04-0.37) and thrombolysis (OR: 0.24, 95% CI 0.09-0.62) compared with the patients in the conventional care group. The outcome of the patients with a TC level > 5.07 did not significantly improve compared with that in the patients in the conventional care treatment group; and the thrombolysis treatment was associated with even worse outcomes (OR 1.41, 95% CI 0.25-7.84 Table 4). However, the mechanical thrombectomy treatment corresponded to a significant improvement in prognosis (OR 0.08, 95% CI 0.01-1.07, Table 4).

Clinical improvement

The clinical improvement rate in the thrombolysis group was 56.67% (17 of 30 patients) (OR 9.79, 95% CI 2.14-44.70) of that in the control group among patients with a TC level > 5.07 mmol/L. However, among the patients with a TC level ≤ 5.07 mmol/L, a clinical improvement rate of 75.38% (49 of 65 patients) was observed in the thrombolysis group (OR 14.71, 95% CI 5.52-39.21) as shown in Supplementary Table 1. Compared with the control group, in the thrombectomy group, 15 (75.00%) of 20 patients with a TC level > 5.07 mmol/L achieved clinical improvement (OR 23.69, 95% CI 3.57-157.39), and 47 (81.03%) of 58 patients with a TC level ≤ 5.07 mmol/L achieved clinical improvement (OR 21.50, 95% CI 6.81-67.87) (Supplementary Table 1).

Among the patients with a TC level > 5.07 mmol/L, the rate of marked improvement in the thrombolysis group was 20% (6 of 30 patients), which was significantly lower (OR 0.07, 95% CI 0.01-0.78) than that in the thrombectomy group. Among the patients with a TC level ≤ 5.07 mmol/L, the rate of marked improvement in the thrombolysis group increased to 38.64% (25 of 65 patients), which was not significantly different from that in the thrombectomy group (OR 0.50, 95% CI 0.21-1.21) as shown in Supplementary Table 2.

Mortality and sICH

The mortality rate of the patients with a TC level > 5.07 mmol/L was 13.30% (4 of 30 patients) in the thrombolysis group and did not show a significant advantage compared with that in the control group (OR 0.60, 95% CI 0.08-4.32). The mortality rate of the patients with a TC level ≤ 5.07 mmol/L increased to 20% (13 of 65 patients) in the thrombolysis group (OR 0.67, 95% CI 0.24-1.85 compared with the control group) as shown in Table 5. Four (20%) of 20 patients with a TC level > 5.07 mmol/L died in the thrombectomy group (OR 23.69, 95% CI 3.57-157.39, compared with the control group), and eleven (18.97%) of 58 patients with a TC level ≤ 5.07 mmol/L died in the thrombectomy group (OR 0.43, 95% CI 0.14-1.34, compared with the control group) (Table 5).

The symptoms of intracranial hemorrhage during therapy were considered risk factors for a disability outcome. In total, 6 (6.30%) and 9 (11.54%) patients suffered from sICH within 24 hours of treatment in the thrombolysis and thrombectomy groups, respectively, as shown in Supplementary Table 3. Two sICH (1.85%) occurred 24 hours after conventional care. Considering the TC cutoff value (5.07 mmol/L), there were no significant differences between the thrombolysis and thrombectomy groups as shown in Table 6.

The type of lipid profile and lipid accumulation at the location of cerebral large-artery occlusion have been reported to be critical factors of disease outcome. The efficacy of IV thrombolysis in large-artery occluded AIS patients is still controversial. Despite the extensive studies that have been conducted, the association between lipid profiles and AIS prognosis is highly controversial and remains unclear⁴^,⁸^,¹¹^,¹²^,^24-26. Thus, excluding patients with severe illnesses, we questioned whether other factors interfere with the efficiency of IV thrombolysis. As a result, our data demonstrated that the TC level was an independent prognostic factor for IV thrombolysis. Higher TC levels (> 5.07 mmol/L) independently predicted poor outcomes after thrombolysis treatment in severe anterior cerebral artery-occluded AIS patients.

Furthermore, our study aimed to identify the association between the patterns of plasma lipids and the outcome and prognosis of AIS and determine whether the best treatment strategy is either thrombolysis or mechanical thrombectomy. By performing a ROC curve analysis, we determined the relationships between the outcome of AIS and the plasma lipid profiles. More importantly, we provide a relatively definitive boundary that can help predict the outcome of disease based on plasma lipid levels. The threshold TC level of 5.07 mmol/L can be used as an indicator to predict disease outcome 3 months after disease onset among patients managed by IV thrombolysis.

A retrospective analysis of 1066 AIS patients reported that there was no association between lipid profiles and 3-month mRS scores or sICH²⁷. Additionally, other studies have shown that lower plasma TC, TG and HDL-C levels can each independently predict a poor 3-month outcome²⁶. In contrast, as described elsewhere, a higher HDL-C level has also been shown to be associated with a favorable outcome at 3 months¹¹. However, unexpectedly, higher HDL-C and TG levels were independently correlated with increased mortality in the same study¹¹. Our data clearly show that there is a close association between TC, but not TG and HDL-C, and the outcome of disease. In agreement with other studies, we did not observe an obvious association between the lipid profiles and sICH. Because the administration of statin can lower cholesterol levels, our data support the notion that lowering cholesterol levels does not affect the sICH risk in patients treated with IV thrombolysis.

The mechanism underlying the association between higher TC levels and poor 3-month outcome remains unclear. High plasma TC levels have been shown to be strongly associated with atherosclerosis stroke in large sample cohort studies performed by other researchers⁹^,¹⁰. The unfavorable outcome observed in AIS patients receiving IV thrombolysis might be caused by large-vessel atherosclerosis^28-30, which is closely associated with high levels of TC.

It is a general consensus that the poor artery recanalization of thrombolysis in stroke patients caused by atherosclerosis might lead to a poor prognosis³¹. The clinical outcome of severe AIS patients (NIHSSS ≥ 10) treated by thrombectomy does not significantly differ between patients divided by the TC threshold (> 5.07 mmol/L and ≤ 5.07 mmol/L) (Table 3). To further confirm whether the TC levels influence the clinical outcome after thrombectomy treatment in severe anterior cerebral artery-occluded AIS patients, we replotted the ROC curve based on another TC cutoff value obtained through the thrombectomy database. The subsequent multivariable logistic regression including the new TC cutoff value still did not reveal a significant difference as shown in Supplementary Table 3. Therefore, the efficacy of thrombectomy might not be linked to cholesterol levels given the excellent recanalization rate of the thrombectomy procedure. However, this result seems to contradict the lack of association between atherosclerosis and outcome in our logistic regression model. Thus, we speculate that the etiological classification is a subjective measurement that might represent some deviation. The artificial etiological classification might not truly reflect the real condition of AIS patients. Our data suggest that the TC level could be a much more informative parameter that accurately reflects the atherosclerosis status of patients. Thus, in severe anterior cerebral artery-occluded AIS patients, the TC level might be a useful screening parameter for IV thrombolysis.

Finally, as stated in the materials and methods section, the included patient samples might be insufficient and could limit the strength of our study. However, the data collected are significant according to the ROC curve analysis. Nonetheless, further work is needed for prospective clinical trial verification.

In anterior cerebral artery-occluded AIS (NIHSS ≥ 10) patients, a TC level greater than 5.07 mmol/L can be considered a threshold for predicting a poor outcome following IV thrombolysis treatment, and if the TC level of an AIS patient is above this threshold, it is recommended that the physician choose an appropriate therapeutic strategy, such as mechanical thrombectomy. The determination of the TC levels is a useful screening method for the prediction of the outcome of IV thrombolysis.

Acknowledgments

Conception and design: Shuming Pan, Lei Niu. Acquisition of the data: Ya Peng, Yi Li. Analysis and interpretation of the data: Shaowei Jiang, Lei Niu. Drafting the article: Shaowei Jiang, Yang Wang. Critically revising the article: Shaowei Jiang, Lei Niu. Reviewed submitted version of manuscript: Yang Wang, Connor. Approved the final version of the manuscript on behalf of all authors: Pan. Statistical analysis: Lei Niu, Jingchen Zhang. Administrative/technical/material support: Aihua Fei, Hai-rong Wang. Study supervision: Shuming Pan, Chengjin Gao. The authors would like to thank Dr. Hong-hua Mu and Connor Meaney from the University of Utah, Salt Lake City, United States of America for helping us thoroughly review the manuscript.

Sources of funding

This study was supported by a 2013–2014 National Clinical Key Specialty Construction Project, the National Natural Science Foundation of China (No. 81772111 [to Dr. Pan]), and the National Natural Science Foundation of China (No. 81601658 [to Dr. Zhang]).

Disclosures

The authors report that there are no conflicts of interest concerning the materials or methods used in this study or the findings reported in this paper.

Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the european atherosclerosis society consensus panel. Eur Heart J. 2017;38:2459-2472
Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD, Jr., DePalma SM, et al. 2016 acc expert consensus decision pathway on the role of non-statin therapies for ldl-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: A report of the american college of cardiology task force on clinical expert consensus documents. J Am Coll Cardiol. 2016;68:92-125
Rader DJ. New therapeutic approaches to the treatment of dyslipidemia. Cell Metab. 2016;23:405-412
Yaghi S, Elkind MS. Lipids and cerebrovascular disease: Research and practice. Stroke. 2015;46:3322-3328
Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP. Different risk factors for different stroke subtypes: Association of blood pressure, cholesterol, and antioxidants. Stroke. 1999;30:2535-2540
Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, et al. Cholesterol, coronary heart disease, and stroke in the asia pacific region. Int J Epidemiol. 2003;32:563-572
Kurth T, Everett BM, Buring JE, Kase CS, Ridker PM, Gaziano JM. Lipid levels and the risk of ischemic stroke in women. Neurology. 2007;68:556-562
Horenstein RB, Smith DE, Mosca L. Cholesterol predicts stroke mortality in the women's pooling project. Stroke. 2002;33:1863-1868
Cui R, Iso H, Yamagishi K, Saito I, Kokubo Y, Inoue M, et al. High serum total cholesterol levels is a risk factor of ischemic stroke for general japanese population: The jphc study. Atherosclerosis. 2012;221:565-569
Tirschwell DL, Smith NL, Heckbert SR, Lemaitre RN, Longstreth WT, Jr., Psaty BM. Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups. Neurology. 2004;63:1868-1875
Nardi K, Engelter S, Strbian D, Sarikaya H, Arnold M, Casoni F, et al. Lipid profiles and outcome in patients treated by intravenous thrombolysis for cerebral ischemia. Neurology. 2012;79:1101-1108
Nardi K, Leys D, Eusebi P, Cordonnier C, Gautier S, Henon H, et al. Influence of lipid profiles on the risk of hemorrhagic transformation after ischemic stroke: Systematic review. Cerebrovasc Dis Extra. 2011;1:130-141
Lewandowski CA, Frankel M, Tomsick TA, Broderick J, Frey J, Clark W, et al. Combined intravenous and intra-arterial r-tpa versus intra-arterial therapy of acute ischemic stroke: Emergency management of stroke (ems) bridging trial. Stroke. 1999;30:2598-2605
Jiang S, Fei A, Peng Y, Zhang J, Lu YR, Wang HR, et al. Predictors of outcome and hemorrhage in patients undergoing endovascular therapy with solitaire stent for acute ischemic stroke. PLoS One. 2015;10:e0144452
Jiang SW, Wang HR, Peng Y, Sun H, Chen M, Fei AH, et al. Mechanical thrombectomy by solitaire stent for treating acute ischemic stroke: A prospective cohort study. Int J Surg. 2016;28:2-7
Jiang S, Peng Y, Jing CH, Fei AH, Wang HR, Gao CJ, et al. Endovascular thrombectomy can be beneficial to acute ischemic stroke patients with large infarcts. J Neurosurg. 2018:1-8
Del Zoppo GJ, Saver JL, Jauch EC, Adams HP, Jr. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: A science advisory from the american heart association/american stroke association. Stroke. 2009;40:2945-2948
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The european cooperative acute stroke study (ecass). Jama. 1995;274:1017-1025
Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ecass ii). Second european-australasian acute stroke study investigators. Lancet. 1998;352:1245-1251
Pessin MS, Teal PA, Caplan LR. Hemorrhagic infarction: Guilt by association? AJNR Am J Neuroradiol. 1991;12:1123-1126
Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, et al. Solitaire flow restoration device versus the merci retriever in patients with acute ischaemic stroke (swift): A randomised, parallel-group, non-inferiority trial. Lancet. 2012;380:1241-1249
Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Aspects study group. Alberta stroke programme early ct score. Lancet. 2000;355:1670-1674
Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Toast. Trial of org 10172 in acute stroke treatment. Stroke. 1993;24:35-41
Perovic E, Mrdjen A, Harapin M, Simundic AM. Short term changes of serum lipids in acute ischemic stroke. Clin Lab. 2016;62:2107-2113
Li JJ, Gu HQ, Peng YJ, Zhao XQ, Wang YL, Meng X, et al. [the association of lipid profile and bleeding in patients with minor stroke or transient ischemic attack on antiplatelet therapy: Subgroup analysis of chance]. Zhonghua Nei Ke Za Zhi. 2018;57:723-730
Li W, Liu M, Wu B, Liu H, Wang LC, Tan S. Serum lipid levels and 3-month prognosis in chinese patients with acute stroke. Adv Ther. 2008;25:329-341
Rocco A, Sykora M, Ringleb P, Diedler J. Impact of statin use and lipid profile on symptomatic intracerebral haemorrhage, outcome and mortality after intravenous thrombolysis in acute stroke. Cerebrovasc Dis. 2012;33:362-368
Ducci RD, Lange MC, Zetola VHF. Predictors of in-hospital mortality and dependence at discharge in patients with mca stroke with intravenous thrombolysis. Intern Emerg Med. 2017;12:453-460
Ducci RD, Lange MC, Germiniani FMB, Zetola VHF. Predictors of dependence after mca ischemic stroke submitted to thrombolysis. Neurological research. 2017;40:97-101
Forlivesi S, Bovi P, Tomelleri G, Micheletti N, Carletti M, Moretto G, et al. Stroke etiologic subtype may influence the rate of hyperdense middle cerebral artery sign disappearance after intravenous thrombolysis. J Thromb Thrombolysis. 2017;43:86-90
Al Kasab S, Almadidy Z, Spiotta AM, Turk AS, Chaudry MI, Hungerford JP. Endovascular treatment for ais with underlying icad. 2017;9:948-951

Table 1. Comparison of patients with favorable and unfavorable outcomes at 3 months in the thrombolysis group

Characteristics	Favorable		Unfavorable		Univariate Analysis OR (95% CI)		Multivariate Analysis OR (95% CI)*
Gender
Male		18 (56.25)		34 (53.97)		0.91 (0.39,2.15)
Female		14 (43.75)		29 (46.03)		1.00
Age (years)
≤60		11 (34.38)		13 (20.63)		1.00
60-70		7 (21.88)		20 (31.75)		2.42 (0.74,7.84)
>70		14 (43.75)		30 (47.62)		1.81 (0.65,5.05)
ASPECTS (mean ± SD) †		9.09 ± 1.03		7.10 ± 2.44		0.54 (0.39,0.76)	0.44 (0.29,0.67)
Occluded vessel‡
MCA_M1		11 (34.38)		43 (68.25)		1.00
MCA_M2		18 (56.25)		15 (23.81)		0.21 (0.08,0.55)
Other		3 (9.38)		5 (7.94)		0.36 (0.29,0.43)
Cause of stroke
Cardiogenic embolism		15 (46.88)		24 (38.10)		1.00
Large-artery atherosclerosis		9 (28.13)		32 (50.79)		2.22 (0.83,5.93)
Other		0 (0.00)		1 (1.59)		-
Undetermined		8 (25.00)		6 (9.52)		0.47 (0.14,1.62)
Time
Onset to arrival (mean ± SD)		71.88 ± 39.74		69.62 ± 40.12		1.00 (0.99,1.01)
Onset to treatment (mean ± SD)		175.47 ± 68.30		157.24 ± 45.10		0.99 (0.99,1.00)
NIHSS upon admission (mean ± SD)		13.28 ± 3.12		14.97 ± 3.99		1.14 (1.00,1.29)	1.19 (1.01,1.40)
Systolic (mean ± SD)		139.78 ± 16.56		151.94 ± 23.43		1.03 (1.01,1.06)	1.05 (1.01,1.09)
Diastolic (mean ± SD)		74.09 ± 9.88		80.97 ± 14.67		1.04 (1.01,1.08)
Plasma glucose (mean ± SD)		6.75 ± 2.40		8.20 ± 3.00		1.25 (1.03,1.52)
Total plasma cholesterol
≤5.07		27 (84.38)		38 (60.32)		1.00	1.00
>5.07		5 (15.63)		25 (39.68)		3.55 (1.21,10.46)	6.64 (1.84,23.96)
Plasma triglycerides
≤1.65		28 (87.50)		46 (73.02)		1.00
>1.65		4 (12.50)		17 (26.98)		2.59 (0.79,8.47)
Low-density lipoprotein cholesterol
≤3.01		30 (93.75)		59 (93.65)		1.00
>3.01		2 (6.25)		4 (6.35)		1.02 (0.18,5.87)
Atrial fibrillation
No		17 (53.13)		40 (63.49)		1.00
Yes		15 (46.88)		23 (36.51)		0.65 (0.27,1.54)
Diabetes
No		26 (81.25)		47 (74.60)		1.00
Yes		6 (18.75)		16 (25.40)		1.48 (0.51,4.23)
Hypertension No		11 (34.38)		20 (31.75)		1.00
Yes		21 (65.63)		43 (68.25)		1.13 (0.46,2.78)

* This analysis was performed by using a logistic regression.

† ASPECTS = Alberta Stroke Program Early CT Score.

‡ MCA_M1 = M1 segment of the middle cerebral artery; MCA_M2 = M2 segment of the middle cerebral artery.

Table 2. Baseline characteristics

Variable	Thrombolysis (n = 95)	Thrombectomy (n = 78)	Control (n = 103)	P-value*
Age (years; mean ± SD)	67.25 ± 8.96	61.41 ± 14.10	65.14 ± 10.87	0.0034
Gender (%)
Male	52 (54.74)	47 (60.26)	61 (56.48)	0.7606
Female	43 (45.26)	31 (39.74)	47 (43.52)
Baseline ASPECTS (Mean ± SD)*	7.77 ± 2.28	5.85 ± 2.91	7.03 ± 2.90	<0.0001
24 hour ASPECTS (Mean ± SD)	5.19 ± 3.03	3.28 ± 2.75	4.68 ± 2.65	<0.0001
Occluded vessel (%) †
MCA_M1	53 (55.79)	54 (69.23)	37 (34.26)	<0.0001
MCA_M2	34 (35.79)	8 (10.26)	58 (53.70)
ICA	3 (3.16)	3 (3.85)	9 (8.33)
ICA/MCA	4 (4.21)	13 (16.67)	4 (3.70)
Cause of stroke (%)
Cardiogenic embolism	39 (41.05)	34 (43.59)	13 (12.04)	<0.0001
Large-artery atherosclerosis	41 (43.16)	36 (46.15)	89 (82.41)
Other	1 (1.05)	5 (6.41)	0 (0.00)
Undetermined	14 (14.74)	3 (3.85)	6 (5.56)
NIHSS score upon admission (Mean ± SD)‡	14.41 ± 3.78	18.44 ± 3.81	16.16 ± 6.00	<0.0001
Systolic (Mean ± SD)	147.84 ± 22.05	142.54 ± 25.99	152.14 ± 25.17	0.0476
Diastolic (Mean ± SD)	78.65 ± 13.59	83.82 ± 13.72	81.71 ± 15.02	0.0148
Serum glucose (Mean ± SD)	7.71 ± 2.89	8.17 ± 3.98	9.91 ± 4.83	0.0003
Total cholesterol (Mean ± SD)	4.61 ± 0.97	4.49 ± 0.91	4.81 ± 1.10	0.1026
Triacylglycerol (Mean ± SD)	1.38 ± 0.88	1.74 ± 0.95	1.60 ± 1.06	0.0022
Low-density lipoprotein cholesterol (Mean ± SD)	2.66 ± 0.72	2.14 ± 0.64	2.89 ± 0.70	<0.0001
Atrial fibrillation (%)
No	57 (60.00)	42 (53.85)	92 (85.19)	<0.0001
Yes	38 (40.00)	36 (46.15)	16 (14.81)
Hypertension (%)
No	31 (32.63)	36 (46.15)	31 (28.70)	0.0410
Yes	64 (67.37)	42 (53.85)	77 (71.30)
Diabetes (%)
No	73 (76.84)	67 (85.90)	68 (62.96)	0.0015
Yes	22 (23.16)	11 (14.10)	40 (37.04)

* Determined using a Chi-square test or 2-sided Fisher’s exact test.

* ASPECTS = Alberta Stroke Program Early CT Score.

† MCA_M1 = M1 segment of the middle cerebral artery; MCA_M2 = M2 segment of the middle cerebral artery; ICA = internal carotid artery.

‡ NIHSS = National Institutes of Health Stroke Scale.

Table 3. Comparison of the major outcome variable (mRS score) among different therapies and usual management.

Group	mRS score* ≤2 (%)	mRS score >2 (%)	OR (95% CI) †	T value	P-value
Thrombolysis				5.30	0.02
TC > 5.07‡	5 (16.7%)	25 (83.3%)	3.55 (1.21 10.46)
TC ≤ 5.07	27 (41.5%)	38 (58.5%)	1
Thrombectomy				0.80	0.37
TC > 5.07	7 (35.0%)	13 (65.0%)	0.62 (0.22 1.77)
TC ≤ 5.07	27 (46.6%)	31 (53.4%)	1
Control				0.64	0.42
TC > 5.07	4 (16.7%)	33 (83.3%)	1.65 (0.49 5.61)
TC ≤ 5.07	11 (10.8%)	55 (89.2%)	1

* mRS score = modified Rankin scale score.

† This analysis was performed by using a logistic regression.

‡ TC = total cholesterol.

Table 4 Comparison of the major outcome variable (mRS score) among different therapies and usual management

Group	TC > 5.07*				TC ≤ 5.07
	mRS score† ≤ 2 (%)	mRS score > 2 (%)	OR (95% CI)	mRS score ≤ 2 (%)		mRS score > 2 (%)	OR (95% CI) ‡
Thrombolysis	5 (16.67)	25 (83.33)	1.41 (0.25,7.84)	27 (41.54)		38 (58.46)	0.24 (0.09,0.62)
Thrombectomy	7 (35.00)	13 (65.00)	0.08 (0.01,1.07)	27 (46.55)		31 (53.45)	0.12 (0.04,0.37)
Control	4 (10.81)	33 (89.19)	1.00	11 (16.67)		55 (83.33)	1.00

* TC = total cholesterol.

† mRS score = modified Rankin scale score.

‡ This analysis was performed by using a logistic regression.

Table 5. Comparison of death among different therapies and usual management

Group	TC > 5.07*			TC ≤ 5.07
	Alive (%)	Dead (%)	OR (95% CI)	Alive (%)	Dead (%)	OR (95% CI) †
Thrombolysis	26 (86.67)	4 (13.33)	0.60 (0.08,4.32)	52 (80.00)	13 (20.00)	0.67 (0.24,1.85)
Thrombectomy	16 (80.00)	4 (20.00)	0.08 (0.01,0.81)	47 (81.03)	11 (18.97)	0.43 (0.14,1.34)
Control	27 (72.97)	10 (27.03)	1.00	48 (72.73)	18 (27.27)	1.00

* TC = total cholesterol

†This analysis was performed by using a logistic regression.

Table 6 Comparison of sICH among different therapies and usual management

Group	TC > 5.07*			TC≤5.07
	No-sICH (%)†	sICH (%)	OR (95% CI)		No-sICH (%)	sICH (%)	OR (95% CI) ‡
Thrombolysis	27 (90.00)	3 (10.00)	0.94 (0.03,30.85)		62 (95.38)	3 (4.62)	0.79 (0.16,4.07)
Thrombectomy	18 (90.00)	2 (10.00)	1.00		51 (87.93)	7 (12.07)	1.00
Control	37 (100.00)	0 (0.00)	-		64 (96.97)	2 (3.03)	0.36 (0.04,3.11)

* TC = total cholesterol

† sICH = symptomatic intracranial hemorrhage

‡ This analysis was performed by using a logistic regression.

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Total cholesterol affects the outcome in anterior cerebral artery-occluded acute ischemic stroke patients treated with thrombolysis

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