Prestroke statins use reduces oxidized low density lipoprotein level and improves clinical outcomes in patients with atrial fibrillation related acute ischemic stroke

Abstract

Background

Ischemic stroke is the leading cause of death and disability among Chinese adults. 75% strokes are caused by atherothrombosis, and 20-25% strokes are caused by atrial fibrillation (AF). It is believed that prethrombotic forces, along with endothelial dysfunction and blood stasis of AF, are the basis of thrombus formation and growth, when large thrombi embolize to the cerebral circulation, leading to severe cerebral infarction. Strokes related to AF are associated with higher mortality and more severe neurologic disability [1-4].

Oxidized low density lipoprotein (Ox-LDL) has an important role in the pathogenesis of vascular atherosclerosis. It plays a pro-inflammatory and pro-atherogenic role by inducing endothelial dysfunction [5]. Atherosclerotic thrombosis and oxidative stress play key roles in acute ischemic stroke (AIS) [6,7]. Previous studies had shown that elevated plasma Ox-LDL level was associated with coronary heart disease [8,9]. High concentrations of plasma Ox-LDL were associated with an increased incidence of metabolic syndrome [10].

Increasing evidence suggests that statins had pleiotropic effects in addition to a lipid-lowering effect [11,12]. In clinical trials, statins had been shown to reduce cardiovascular events, including stroke, myocardial infarction and death [13-15]. Early statins administration enhances thrombolysis, augments antithrombotic responses, modulates endothelial nitric oxide synthase (eNOS), reduces nitric oxide production, decreases matrix metalloproteinase-9 (MMP-9) and ROS levels, increases cerebral blood flow [16-18]. On the other hand, statins could attenuate thrombus formation, thrombus growth, reduced infarct volume [14,15].

In a previous study, poststroke statins use was associated with improved 5-year survival in patients with AF-related stroke [19]. However, poststroke assessment of statins use was susceptible to some interference, such as survivor bias. A largest meta-analysis showed that statins use at the time of stroke onset was associated with improved clinical outcomes [20], but there was no AF subgroup analysis. There were limited studies about the potential use and effectiveness of pre-stroke statins in AIS. On the other hand, it was unclear whether prestroke statins use could reduce the plasma Ox-LDL and improve the outcome of AF-related stroke.

In this study, we assembled a cohort of patients with AF-related AIS from four centers. The purpose was to investigate whether prestroke statin use can reduce plasma Ox-LDL level and improve 3-month clinical outcomes in patients with AF related AIS.

Methods

Study Population

This study was a multicenter trial conducted in four medical centers: The Second People’s Hospital of Chengdu, Nuclear Industry 416 Hospital, Yongchuan Hospital and the First Affiliated Hospital, Chongqing Medical University. Patients with AIS were consecutively admitted to the stroke unit within 72 h of symptom onset from October 2015 to April 2018. Stroke was diagnosed according to clinical presentation, neurologic examination (sudden neurological deficit >24 h that has a presumable vascular etiology), and the results of brain computed tomography (CT) scan or diffusion-weighted imaging magnetic resonance imaging (MRI). Electrocardiogram evidence of AF was confirmed in all patients within the prior 6 months. Ischemic stroke was not explained by other etiologies, such as large artery atherosclerosis, intracerebral hemorrhage, tumor, infection, vasculitis, or procedural or surgical complication. AF-relate stroke was confirmed by an experienced neurologist who blinded to the study. The severity of stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS).

Inclusion criteria

Patients were included in the study only if they fulfilled all the following criteria: 1. Admission for first-ever AIS within 72h; 2. Evidence of acute ischemic lesion consistent with clinical manifestations; and 3. No patients received thrombolytic and mechanical thrombectomy therapy (because those patients undergo a different therapeutic strategy and a high percentage of hemorrhagic transformation); 4. Patients had to have electrocardiogram-confirmed AF within the prior 6 months. All patients received standard treatment after admission, which consisted of antiplatelet or anticoagulant therapy, lipid-lowering medications and so on.

Exclusion criteria

Exclusion criteria included 1.A history of acute myocardial infarction, rheumatic heart disease, and valvular atrial fibrillation; 2. Vasculitis, renal failure (estimated glomerular filtration rate <30 ml/min.1.73 m²), active malignancies, severe pulmonary disease, or procedural or surgical complications; and 3. A history of deep venous thrombosis or pulmonary embolism;4. Cerebral hemorrhage, fever (≥38℃), or hypoxia (arterial oxyhemoglobin saturation<90%) on admission.

Data collection

The previous medical history of all patients was collected to confirm whether statins were used before stroke. For patients with warfarin use, the International Normalized Ratio (INR) was measured after admission. All patients underwent a 72 h-Holter electrocardiogram monitoring on the next day after admission, which was evaluated by two investigators who were blinded for patients. The interobserver data differences were resolved by consensus, and 72 h-Holter electrocardiogram evidence of AF was confirmed in all patients. Cardiac ultrasonography examination was performed on admission to exclude rheumatic heart disease.

Blood samples were collected from all stroke patients on admission and 3 months. Plasma Ox-LDL concentration was measured using the enzyme-linked immunosorbent assay (ELISA) (E-EL-H0124c, Wuhan, China) according to manufacturer’s protocol. Each sample was assayed in duplicate. The intraassay variation among the duplicates for all samples was <10%. The Ox-LDL concentrations were expressed in U/L. Levels of serum Ox-LDL was considered abnormal if it was≥3.4u/l.

All patients were followed up for 3 months. The outcome was defined as death and major disability (scores 3–5 on the modified Rankin Scale [mRS]) at 3 months after stroke onset.

Statistical Analysis

First, patients were classified into prestroke statins use and no prestroke statins use groups according to statins use before stroke on admission. Demographic characteristics, vascular risk factors, current smoking, and so on were compared between the 2 subgroups by univariate analysis using Pearson χ2 test, Fisher exact 2-sided test, or Student’s t test; mean values (±standard deviation) were calculated for continuous variables. The Mann-Whitney U test was used to test differences between two groups. Second, we performed logistic regression analyses to determine the association between prestroke statins use and outcomes (death, major disability and death/major disability) in patients with AF, adjusting for all confounders (age, baseline NIHSS score, sex, BMI, hypertension, current smoking, current alcohol consumption, diabetes, hyperlipidemia, family history of stroke, and use of antihypertensive, and warfarin medications). The results were expressed as adjusted odds ratios (OR) with their corresponding 95% confidence intervals (CI). The data were analyzed using SPSS 22 software. P<0.05 was considered statistically significant.

Results

Characteristics of the patients

A total of 242 AIS patients with AF (118 men; 124 females) and 106 (43.80%) were assigned to the prestroke statins use group. The baseline characteristics of patients in the no prestroke statins use group (136) and prestroke statins use group (106) were compared (Table 1). At baseline, patients with prestroke statins use showed a significantly higher prevalence of hyperlipidemia than that in patients with no prestroke statins use (P<0.001). Patients with statins use showed significantly lower NIHSS score than patients with no statins use (P=0.041). 

Plasma Ox-LDL level in the prestroke statins use and no prestroke statins use groups

Plasma Ox-LDL level was significantly lower in the prestroke statins use group on admission (33.53±5.53 vs 27.61±5.14, P=0.000). Compared with the baseline, Ox-LDL of the 3-month treatment period decreased both in two groups, the prestroke statins use group had lower Ox-LDL level(24.44±7.58 vs 29.28±6.03,P=0.000). Ox-LDL decreased about 27.11% in the prestroke statins use group, 22.14% in the no prestroke statin use group. The data showed significantly different Ox-LDL levels in the two groups at different time points.

Association Between Plasma Ox-LDL level and Prognosis

We also analyzed whether the plasma Ox-LDL level had effect on outcomes. 70 patients had died, and 86 patients had major disability on 3 months. The result demonstrated that plasma Ox-LDL level was significantly different between the outcome groups. Compared with the surviving patients, the patients who died had higher Ox-LDL level (37.95±5.63vs 34.96±5.48, P=0.000) on admission, and on 3 months (28.77±4.67vs 26.50±7.34, P = 0.039). Patients with major disability had higher Ox-LDL level than patients with good prognosis on admission (36.36±5.95vs 33.60±4.62, P = 0.004), there was no significant difference between two groups on 3 months (27.59±6.42 vs 25.44±8.03, P = 0.099).

Multivariable Models on the Association Between prestroke statins use and Death/Major disability

All patients with AF were followed up for 3 months. Seventy (70/242, 28.93%) patients had died, and they had a significantly higher NIHSS core on admission (13.43±6.42 vs 9.11±4.08, P<0.001) and were older (68.60±11.26 vs 65.73±9.74, P=0.022); a lower percentage had prestroke statins use [32.85% (23/70) vs 48.25% (83/172); OR, 0.53 (95% CI, 0.30-0.94); P=0.029].

    In the multivariable logistic regression model, after adjustment for age, baseline NIHSS score, sex, BMI, hypertension, current smoking, current alcohol consumption, diabetes, hyperlipidemia, insular stroke, family history of stroke, and use of antihypertensive and warfarin medication, the 3-month mortality in the prestroke statins use group was lower than in the no prestroke statins use group (adjusted odds ratio, 0.43; 95% CI, 0.20-0.93; P=0.031).

In addition to the 70 deaths, of the remaining 172 patients, 83 patients were in the prestroke statins use group; 32 (32/83, 38.55%) patients had a major disability, which was a lower percentage than that in patients with no prestroke statins use (54/89, 60.67%); patients with 3-month major disability had a significantly higher NIHSS at admission (10.25±4.18 vs 7.95±3.67, P<0.001) than that in patients with a good prognosis.

In the multivariable logistic regression model after adjustment for age, baseline NIHSS score, sex, BMI, hypertension, current smoking, current alcohol consumption, diabetes, hyperlipidemia, family history of stroke, and use of antihypertensive and warfarin medication, there was an association between prestroke statins use and major disability (adjusted odds ratio, 0.33; 95% confidence interval, 0.13–0.82; P=0.017) and composite outcome (adjusted odds ratio, 0.25; 95% confidence interval, 0.11-0.56; P=0.001) (Table 2).

Discussion

AF can increase platelet reactivity, lead to thrombin generation, and platelet aggregation, which underlie the formation of a thrombus, and the size of a thrombus can affect the infarct volume and severity of stroke [21]. According to previous study, AF increases the incidence of stroke fivefold, patients with cardioembolic strokes were at greater risk of death, severe disability and risk of hemorrhagic transformation [22]. Oral anticoagulants were the most effective treatment for preventing cardioembolic stroke. Statins had pleiotropic effects in addition to LDL-C lowering. Data had shown that statins had benefits on the endothelium, platelets, myocardium. Several studies had demonstrated that baseline statins could improve clinical outcome of patients with stroke [23,24]; only few studies had focused on AF-related stroke, and there was limited information about the effectiveness of pre-stroke statins in AF-related stroke. In this study, we found that prestroke statins use among AF -related stroke was associated with lower NIHSS score on admission, the result was independent of age, sex and other established risk factors. This study suggested that the prestroke statins use might reduce the severity of stroke.

Since AF-related stroke was associated with high mortality and morbidity, evaluating the effect of statins on prognosis was important. The recent study enrolled 1030 AF-related ischemic stroke patients, the authors aimed to observe the influence of prestroke statins use on functional outcome, all the patients were followed up for 30 days, the result showed that prestroke statins use was associated with a 32% reduction in frequency of severe stroke (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.50–0.92; P=0.011)[25]. There are biological mechanisms underlying the association between statins use and improved clinical outcomes after ischemic stroke. Prestroke statins use was associated with increased collateral blood flow, which might be beneficial in cardioembolic stroke and reduce infarct size [26, 27], and in the animal model, atorvastatin use could increase angiogenic responsiveness[28], and rosuvastatin could increase neovascularization via mechanisms independent of lipid lowering[24]. Statins could reduce platelet activation, inhibit subclinical inflammation, oxidative stress, improve endothelial dysfunction [30-34], and significantly reduce venous thromboembolism [34]. Statins had also been reported to decrease levels of C-reactive protein, interleukin-6, TNF-α, improve left ventricular function among individuals with heart failure [35].

The mechanism of increased plasma Ox-LDL level after AIS was unclear, although it was speculated that AIS was associated with enhanced oxidative stress, which can further oxidize native LDL-cholesterol to Ox-LDL [36,37]. Another possible explanation might be the increase in lipolysis and lipid peroxidation after AIS [38,39]. In this study, we found that plasma Ox-LDL level increased on admission and decreased on 3 months after stroke. We also found that Ox-LDL level was significantly lower in the prestroke statins use group on admission, and elevated plasma Ox-LDL level was associated with poor prognosis. These findings suggest that plasma Ox-LDL may be a useful marker for monitoring the oxidative status of the brain after cerebral infarction, and prestroke statins use might inhibit Ox-LDL production, protect endothelial function.

In this study, we found that prestroke statins use among individuals presenting with AF was associated with a reduction in the risk of the stroke being severe or of death at 3 months. This association persisted after adjustment for age, baseline NIHSS score, sex, BMI, hypertension, current smoking, current alcohol consumption, diabetes, hyperlipidemia, family history of stroke, and use of antihypertensive and warfarin medications. During the 3-month follow-up period, 70 of 242 (28.93%) patients with AF died, 34.56% (47/136) of whom were in the no prestroke statins use group, a higher percentage than that in patients (21.70%, 23/106) with prestroke statins use (P=0.029). For the remaining 172 stroke survivors, the high percentage of patients with a mRS score of 0, 1 or 2 at 3 months in the statins group (61.44%, 51/83) compared to that in the no statins group [39.33%(35/89),P=0.004], showed that more patients from the statins group regained their walking independence and were able to carry out all the usual duties and activities. In fully adjusted models, there was an association between no prestroke statins use and death, major disability and composite outcome.

Some limitations of this study merit consideration. First, the limitations of our study are related to the small number of patients and the short duration of the study. Second, although we adjusted for NIHSS score, which has been shown to correlate with infarction volume, we lacked data on infarction volume. The strength of our study is that it was a multicenter clinical trial with robust results of high clinical relevance. Third, there are many different types of statins, and it is possible that each drug has different effects on the prognosis of stroke. This study did not separately list the effects of a given statin on the prognosis of stroke.

Conclusions

In conclusion, our findings indicated that AF-related stroke was associated with high mortality and major disability. Prestroke statins use could reduce plasma Ox-LDL level and improve clinical outcomes in patients with AF after acute ischemic stroke.

Abbreviations

CI: Confidence Interval; M: Mean; OR: Odds Ratio; SD: Standard Deviation; Ox-LDL: oxidized low density lipoprotein; AIS: acute ischemic stroke; AF: atrial fibrillation;

Declarations

Ethics approval and consent to participate

We obtained ethical approval for this study from the Medical and Health Research Ethics Committee in Second people’s Hospital of Chengdu, the Second Affiliated Hospital of Chengdu College, Nuclear Industry 416 Hospital of Chengdu, and Chongqing Medical University.The current study was carried out according to the Declaration of Helsinki. If the patient has consciousness disorder or aphasia, the decision cannot be made by themselves, the consent form can be signed by the patient's legal proxies. Prior to enrollment, all patients or their legal proxies will be given detailed information about the aims, scope and possible consequences of the trial by a physician. No diagnostic or interventional procedures required for the clinical trial. Written informed consent was obtained from all study participants or their legal proxies.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was funded by the Health and Family Planning Commission of Chengdu (2015009), which is not involved in the database management (collection, analysis, interpretation of data) and has no access to patient information. The funding body did not participate in designing the study or writing the manuscript. The study protocol has undergone peer-review process by the funding body.

Authors’ contributions

LYH was responsible for the concept and design of the study, data collection and analysis and the first draft of the paper and final manuscript. Ronghua Xu and JW was responsible for the concept and design of the study, the data analysis and interpretation. WWD was responsible for overseeing the concept and design of the study, the data analysis and interpretation, and writing the paper. LLZ YSD, LJZ and WZ were responsible for data collection. All authors read and approved the final manuscript for publication.

Acknowledgments

We thank all patients and their families for generously consenting to use of human tissues in this research.

References

1. Sposato LA, Riccio PM, Hachinski V. Poststroke atrial fibrillation: cause or consequence? Critical review of current views. Neurology.2004;82(13):1180-1186. https://doi. 10.1212/WNL.0000000000000265.
2. Dütsch M, Burger M, Dörfler C, Schwab S, Hilz MJ. Cardiovascular autonomic function in poststroke patients. Neurology.2007;69(24):2249-2255. https://doi.10.1212/01.wnl.0000286946.06639.a7.
3. Miglis MG, Muppidi S. Autonomic dysfunction predicts poor outcome in stroke: Updates on recent autonomic research. Clin Auton Res.2018;28(1):9-11. https://doi. 10.1007/s10286-017-0498-3.
4. Xiong L, Tian G, Leung H, Soo YOY, Chen X, Ip VHL, Mok VCT, Chu WCW, Wong KS, Leung TWH. Autonomic Dysfunction Predicts Clinical Outcomes After Acute Ischemic Stroke: A Prospective Observational Study. Stroke.2018;49(1):215-218. https://doi. 10.1161/STROKEAHA.117.019312
5. Mertens A, Holvoet P. Oxidized LDL and HDL: antagonists in atherothrombosis. FASEB J. 2001;15(12):2073–2084. https://doi. 1096/fj.01-0273rev.
6. Ruggeri ZM. Platelets in atherothrombosis. Nat Med. 2002;8(11):1227–1234. https://doi. 1096/fj.01-0273rev.
7. Cherubini A, Ruggiero C, Polidori MC, Mecocci P. Potential markers of oxidative stress in stroke. Free Radic Biol Med. 2005; 39(7):841–852. https://doi. 1096/fj.01-0273rev.
8. Ehara S, Ueda M, Naruko T, Haze K, Itoh A, Otsuka M, Komatsu R, Matsuo T, Itabe H, Takano T, Tsukamoto Y, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE: Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes.Circulation. 2001;103(15):1955–1960.[PMID:11306523]
9. Toshima S, Hasegawa A, Kurabayashi M, Itabe H, Takano T, Sugano J, Shimamura K, Kimura J, Michishita I, Suzuki T, Nagai R: Circulating oxidized low density lipoprotein levels. A biochemical risk marker for coronary heart disease. Arterioscler Thromb Vasc Biol 2000; 20(10):2243–2247. [PMID:11301210]
10. Holvoet P, Lee DH, Steffes M, Gross M, Jacobs DR Jr: Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome. JAMA.2008; 299(19):2287–2293. https://doi. 1001/jama.299.19.2287
11. Kwak BR, Mach F. Statins inhibit leukocyte recruitment: new evidence for their anti-inflammatory properties. Arterioscler Thromb Vasc Biol.2001;21(8):1256–1258.[ PMID:11498448]
12. Tailor A, Lefer DJ, Granger DN. HMG-CoA reductase inhibitor attenuates platelet adhesion in intestinal venules of hypercholesterolemic mice. Am J Physiol Heart Circ Physiol.2004;286:H1402–H1407. https://doi.10.1152/ajpheart.00993.2003
13. Tsivgoulis G, Safouris A, Kim DE, Alexandrov AV. Recent Advances in Primary and Secondary Prevention of Atherosclerotic Stroke. J Stroke.2018;20(2):145-166. https://doi. 5853/jos.2018.00773
14. Taguchi I, Iimuro S, Iwata H, Takashima H, Abe M, Amiya E,et al. High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial. Circulation.2018;137(19):1997-2009. https://doi. 10.1161/CIRCULATIONAHA.117.032615.
15. Hosomi N, Kitagawa K, Nagai Y, Nakagawa Y, Aoki S, Nezu T,etal. Desirable Low-Density Lipoprotein Cholesterol Levels for Preventing Stroke Recurrence: A Post Hoc Analysis of the J-STARS Study (Japan Statin Treatment Against Recurrent Stroke). Stroke.2018;49(4):865-871. https://doi.10.1161/STROKEAHA.117.018870
16. Munshi A.Genetic variation in MDR1, LPL and eNOS genes and the response to atorvastatin treatment in ischemic stroke. Hum Genet.2012;131(11):1775-1781. https://doi. 1007/s00439-012-1202-2.
17. Endres, M,Laufs, U,Liao, J.K.Moskowitz, M.A. Targeting eNOS for stroke protection.Trends Neurosci.2004;27(5):283–289. https://doi. 1016/j.tins.2004.03.009
18. Zhao HD, Zhang YD.The effects of previous statin treatment on plasma matrix metalloproteinase-9 level in Chinese stroke patients undergoing thrombolysis. J Stroke Cerebrovasc Dis.2014; 23(10):2788-2793. https://doi.10.1016/j.jstrokecerebrovasdis
19. Hayden DT, Hannon N, Callaly E, Nii Chroiiniin D, Horgan G, Kyne L, et al. Rates and determinants of 5-year outcomes after atrial fibrillation-related stroke: a population study. Stroke.2015;46(12):3488–3493. https://doi.10.1161/STROKEAHA.115.011139
20. Ni Chroinin D, Asplund K, Asberg S, Callaly E, Cuadrado-Godia E, Diez-Tejedor E, et al. Statin therapy and outcome after ischemic stroke: systematic review and meta-analysis of observational studies and randomized trials. Stroke.2013;44(2):448–456. https://doi.10.1161/STROKEAHA.112.668277
21. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet.2009;373(9695):155–166. https://doi. 10.1016/S0140-6736(09)60040-4
22. Gebreyohannes EA, Bhagavathula AS, Tegegn HG. Poor outcomes associated with antithrombotic undertreatment in patients with atrial fibrillation attending Gondar University Hospital: a retrospective cohort study.Thromb J. 2018;16:22. https:// doi: 10.1186/s12959-018-0177-1. eCollection 2018.
23. Chaudagar KK, Mehta AA. Effect of atorvastatin on the angiogenic responsiveness of coronary endothelial cells in normal and streptozotocin (STZ) induced diabetic rats. Can J Physiol Pharmacol.2014;92(4):338–349. https://doi.10.1139/cjpp-2013-0391.
24. Zhou J, Cheng M, Liao YH, Hu Y, Wu M, Wang Q, et al. Rosuvastatin enhances angiogenesis via eNOS-dependent mobilization of endothelial progenitor cells. PLoS One.2013;8(5):e63126. https://doi.10.1371/journal.pone.0063126
25. Ko D, Thigpen JL, Otis JA, Forster K, Henault L, Quinn E, Tripodis Y, Berger PB, Limdi N, Hylek EM. Influence of statin therapy at time of stroke onset on functional outcome among patients with atrial fibrillation. Int J Cardiol. 2017;227:808-812. https://doi: 10.1016/j.ijcard.2016.10.055. Epub 2016 Oct 24.
26. Lee MJ, Bang OY, Kim SJ, Kim GM, Chung CS, Lee KH, et al. Role of statin in atrial fibrillation related stroke: an angiographic study for collateral flow. Cerebrovasc Dis.2014;37(2):77–84. https://doi.10.1159/000356114
27. Ovbiagele B, Saver JL, Starkman S, Kim D, Ali LK, Jahan R, et al. Statin enhancement of collateralization in acute stroke. Neurology.2007;68(24):2129–2131. https://doi.10.1212/01.wnl.0000264931.34941.f0
28. Chaudagar KK, Mehta AA. Effect of atorvastatin on the angiogenic responsiveness of coronary endothelial cells in normal and streptozotocin (STZ) induced diabetic rats. Can J Physiol Pharmacol. 2014; 92(4):338–49. https://doi.1139/cjpp-2013-0391
29. Undas A, Celinska-Lowenhoff M, Brummel-Ziedins KE, Brozek J, Szczeklik A, Mann KG. Simvastatin given for 3 days can inhibit thrombin generation and activation of factor V and enhance factor Va inactivation in hypercholesterolemic patients. Arterioscler Thromb Vasc Biol.2005;25(7):1524–1525. https://doi.10.1161/01.ATV.0000168913.25278.38
30. Biedermann JS, Kruip MJHA, van der Meer FJ, Rosendaal FR, Leebeek FWG, Cannegieter SC, et al. Rosuvastatin use improves measures of coagulation in patients with venous thrombosis. Eur Heart J.2018;39(19):1740-1747. https://doi.10.1093/eurheartj/ehy014.PMID:29394348
31. Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, et al. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation.2012,126(1):92–103. https://doi.10.1161/CIRCULATIONAHA.112.095554
32. Godino C, Pavon AG, Mangieri A, Salerno A, Cera M, Monello A,et al.Platelet reactivity in response to loading dose of atorvastatin or rosuvastatin in patients with stable coronary disease before percutaneous coronary intervention: The STATIPLAT randomized study. Clin Cardiol.2017;40(8):605-611. https://doi.10.1002/clc.22709.
33. Panes O, González C, Hidalgo P, Valderas JP, Acevedo M, Contreras S, et al. Platelet tissue factor activity and membrane cholesterol are increased in hypercholesterolemia and normalized by rosuvastatin, but not by atorvastatin. Atherosclerosis.2017;257:164-171. https://doi.10.1016/j.atherosclerosis
34. Zaccardi F, Kunutsor SK, Seidu S, Davies MJ, Khunti K.Is the lower risk of venous thromboembolism with statins related to low-density-lipoprotein reduction? A network meta-analysis and meta-regression of randomised controlled trials. Atherosclerosis.2018;271:223-231. https://doi.10.1016/j.atherosclerosis.2018.02.035.
35. Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol.2006;47(2):332–337. https://doi.10.1016/j.jacc.2005.06.088
36. Walder CE, Green SP, Darbonne WC, Mathias J, Rae J, Dinauer MC, Curnutte JT, Thomas GR: Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase. 1997;28(1):2252–2258.[ PMID:9368573]
37. Guldiken B, Guldiken S, Turgut B, Turgut N, Demir M, Celik Y, Arikan E, Tugrul A: The roles of oxidized low-density lipoprotein and interleukin-6 levels in acute atherothrombotic and lacunar ischemic stroke. 2008;59(2):224–229. https://doi: 10.1177/0003319707304134
38. Polidori MC, Frei B, Cherubini A, Nelles G, Rordorf G, Keaney JF Jr, Schwamm L, Mecocci P, Koroshetz WJ, Beal MF. Increased plasma levels of lipid hydroperoxides in patients with ischemic stroke. Free Radic Biol Med. 1998;25(4):561–[ PMID:9741593]
39. Nishi K, Itabe H, Uno M, Kitazato KT, Horiguchi H, Shinno K, Nagahiro S. Oxidized LDL in carotid plaques and plasma associates with plaque Arterioscler Thromb Vasc Biol. 2002;22(10):1649–1654.[PMID:12377744]

Tables

Table 1. Comparison of baseline characteristics between patients with no prestroke statins use prestroke statins use groups.

Bold indicates P-values less than 0.05.

*Comparison between no prestroke statins use and prestroke statins use groups. Continuous variables are expressed as the mean ± standard deviation. Categorical variables are expressed as frequency (percent) for P values. Pearson χ2 test, Fisher exact 2-sided test, and Student’s t test were used when appropriate. Mean values (±standard deviation) were calculated for continuous variables. The Mann-Whitney U test was used to test differences between two groups.

Table 2 Multivariable Models Showing Association Between prestroke Statins use and Prognosis

Bold indicates P-values less than 0.05.

*Multivariable adjusted for age, baseline NIHSS score, sex, BMI, hypertension, current smoking, current alcohol consumption, diabetes, hyperlipidemia, family history of stroke, and use of antihypertensive and warfarin medication.