Low-Density Lipoprotein Cholesterol and Risk of Hemorrhagic Stroke: a Systematic Review and Dose-Response Meta-analysis of Prospective Studies
Purpose of Review
To systematically examine the association between low-density lipoprotein cholesterol (LDL-C) and risk of hemorrhagic stroke.
A previous meta-analysis of prospective studies published in 2013 showed that higher concentrations of LDL-C were associated with lower risk of hemorrhagic stroke. Recently, seven large cohort studies were published examining LDL-C and risk of hemorrhagic stroke in different populations.
Twelve prospective studies with 476,173 participants and 7587 hemorrhagic stroke cases were included in the current meta-analysis. The results showed that a 10 mg/dL increase in LDL-C was associated with 3% lower risk of hemorrhagic stroke (pooled relative risk [RR] 0.97, 95% confidence interval [CI] 0.95–0.98). The association appeared to be more pronounced in Asians (pooled RR 0.95, 95% CI 0.92–0.98), relative to Caucasians (pooled RR 0.98, 95% CI 0.97–1.00), with a p heterogeneity of 0.05 between two ethnic groups. Further genetic studies and clinical trials with a stricter safety monitoring strategy are warranted to understand the underlying pathogenesis and determine the treatment target of LDL-C range with the lowest risk of hemorrhagic stroke in different population groups.
KeywordsLDL-C Hemorrhagic stroke Prospective studies Meta-analysis Dose-response
Compliance with Ethical Standards
Conflict of Interest
Chaoran Ma, Muzi Na, Samantha Neumann, and Xiang Gao declare they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 4.Ariesen MJ, Claus SP, Rinkel GJ, Algra A. Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke. 2003;34(8):2060–5. https://doi.org/10.1161/01.str.0000080678.09344.8d.CrossRefPubMedGoogle Scholar
- 6.Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel. Arch Intern Med. 1988;148(1):36-69.Google Scholar
- 7.Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-97.Google Scholar
- 8.Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32(14):1769–818. https://doi.org/10.1093/eurheartj/ehr158.CrossRefPubMedGoogle Scholar
- 9.Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–934. https://doi.org/10.1016/j.jacc.2013.11.002.CrossRefPubMedGoogle Scholar
- 11.Giugliano RP, Wiviott SD, Blazing MA, De Ferrari GM, Park JG, Murphy SA, et al. Long-term safety and efficacy of achieving very low levels of low-density lipoprotein cholesterol: a prespecified analysis of the IMPROVE-IT Trial. JAMA Cardiol. 2017;2(5):547–55. https://doi.org/10.1001/jamacardio.2017.0083.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.• Judge C, Ruttledge S, Costello M, Murphy R, Loughlin E, Alvarez-Iglesias A, et al. Lipid lowering therapy, low-density lipoprotein level and risk of intracerebral hemorrhage—a meta-analysis. J Stroke Cerebrovasc Dis. 2019;28(6):1703–9. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.02.018 This is the most recent meta-analysis of clinical trials showing lipid lowering was associated with an increased risk of intracerebral hemorrhage in secondary prevention trials only; no association was observed in primary prevention trials. CrossRefPubMedGoogle Scholar
- 16.Greenland S, Longnecker MP. Methods for trend estimation from summarized dose-response data, with applications to meta-analysis. Am J Epidemiol. 1992;135(11):1301–9. https://doi.org/10.1093/571oxfordjournals.aje.a116237.
- 20.•• Ma C, Gurol ME, Huang Z, Lichtenstein AH, Wang X, Wang Y, et al. Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage. Neurology. 2019;93(5):e445. https://doi.org/10.1212/WNL.0000000000007853 This is a prospective study after the most recent meta-analysis of prospective studies published in 2013. CrossRefPubMedGoogle Scholar
- 21.•• Rist PM, Buring JE, Ridker PM, Kase CS, Kurth T, Rexrode KM. Lipid levels and the risk of hemorrhagic stroke among women. Neurology. 2019;92(19):e2286. https://doi.org/10.1212/WNL.0000000000007454 This is a prospective study after the most recent meta-analysis of prospective studies published in 2013. CrossRefPubMedGoogle Scholar
- 22.•• Zhang X, Liu J, Wang M, Qi Y, Sun J, Liu J, et al. Twenty-year epidemiologic study on LDL-C levels in relation to the risks of atherosclerotic event, hemorrhagic stroke, and cancer death among young and middle-aged population in China. J Clin Lipidol. 2018;12(5):1179–89.e4. https://doi.org/10.1016/j.jacl.2018.06.011 This is a prospective study after the most recent meta-analysis of prospective studies published in 2013. CrossRefPubMedGoogle Scholar
- 23.•• Stoekenbroek RM, Boekholdt SM, Luben R, Hovingh GK, Zwinderman AH, Wareham NJ, et al. Heterogeneous impact of classic atherosclerotic risk factors on different arterial territories: the EPIC-Norfolk prospective population study. Eur Heart J. 2016;37(11):880–9. https://doi.org/10.1093/eurheartj/ehv630 This is a prospective study after the most recent meta-analysis of prospective studies published in 2013. CrossRefPubMedGoogle Scholar
- 24.•• Glasser SP, Mosher A, Howard G, Banach M. What is the association of lipid levels and incident stroke? Int J Cardiol. 2016;220:890–4. https://doi.org/10.1016/j.ijcard.2016.06.091 This is a prospective study after the most recent meta-analysis of prospective studies published in 2013. CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Doi M, et al. Low-density lipoprotein cholesterol concentrations and death due to intraparenchymal hemorrhage: the Ibaraki Prefectural Health Study. Circulation. 2009;119(16):2136–45. https://doi.org/10.1161/circulationaha.108.795666.CrossRefPubMedGoogle Scholar
- 28.Holme I, Aastveit AH, Hammar N, Jungner I, Walldius G. Relationships between lipoprotein components and risk of ischaemic and haemorrhagic stroke in the Apolipoprotein MOrtality RISk study (AMORIS). J Intern Med. 2009;265(2):275–87. https://doi.org/10.1111/j.1365-2796.2008.02016.x.CrossRefPubMedGoogle Scholar
- 30.Psaty BM, Anderson M, Kronmal RA, Tracy RP, Orchard T, Fried LP, et al. The association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: the Cardiovascular Health Study. J Am Geriatr Soc. 2004;52(10):1639–47. https://doi.org/10.1111/j.1532-5415.2004.52455.x.CrossRefPubMedGoogle Scholar
- 31.•• Sun L, Clarke R, Bennett D, Guo Y, Walters RG, Hill M, et al. Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults. Nat Med. 2019;25(4):569–74. https://doi.org/10.1038/s41591-019-0366-x This is a prospective study after the most recent meta-analysis of prospective studies published in 2013. CrossRefPubMedPubMedCentralGoogle Scholar
- 32.•• Zheng J, Sun Z, Zhang X, Li Z, Guo X, Xie Y, et al. Non-traditional lipid profiles associated with ischemic stroke not hemorrhagic stroke in hypertensive patients: results from an 8.4 years follow-up study. Lipids Health Dis. 2019;18(1):9. https://doi.org/10.1186/s12944-019-0958-y This is a prospective study after the most recent meta-analysis of prospective studies published in 2013. CrossRefPubMedPubMedCentralGoogle Scholar
- 33.van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9(2):167–76. https://doi.org/10.1016/s1474-4422(09)70340-0.CrossRefPubMedGoogle Scholar
- 34.Karthikeyan G, Teo KK, Islam S, McQueen MJ, Pais P, Wang X, et al. Lipid profile, plasma apolipoproteins, and risk of a first myocardial infarction among Asians: an analysis from the INTERHEART Study. J Am Coll Cardiol. 2009;53(3):244–53. https://doi.org/10.1016/j.jacc.2008.09.041.CrossRefPubMedGoogle Scholar