The Complex Relationship Between Cholesterol and Brain Hemorrhage

Abstract

HomeCirculationVol. 119, No. 16The Complex Relationship Between Cholesterol and Brain Hemorrhage Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Complex Relationship Between Cholesterol and Brain Hemorrhage Larry B. Goldstein, MD Larry B. GoldsteinLarry B. Goldstein From the Department of Medicine (Neurology), Duke Stroke Center for Cerebrovascular Disease, and Center for Clinical Health Policy Research, Duke University Medical Center, and Durham VA Medical Center, Durham, NC. Search for more papers by this author Originally published28 Apr 2009https://doi.org/10.1161/CIRCULATIONAHA.109.856385Circulation. 2009;119:2131–2133In this issue of Circulation, Noda et al1 report an association between low levels of low-density lipoprotein cholesterol (LDL-C) and an increase in the risk of fatal intraparenchymal intracerebral hemorrhage in a Japanese population-based cohort. The relationship between lipid levels and stroke is complex. The Prospective Studies Collaboration conducted a meta-analysis evaluating the association between blood cholesterol and vascular mortality based on data from 61 prospective cohort studies including nearly 900 000 persons free of vascular disease at baseline (11.6 million person-years at risk).2 Lower levels of usual total cholesterol were strongly associated with lower risk of fatal ischemic heart disease; every 1 mmol/L lower cholesterol was associated with a 56% reduction (hazard ratio [HR], 0.44; 95% CI, 0.42 to 0.48) in those 40 to 49 years of age, a 34% reduction (HR, 0.66; 95% CI, 0.65 to 0.68) in those 50 to 69 years of age, and a 17% reduction (HR, 0.83; 95% CI, 0.81 to 0.85) in those 70 to 89 years of age. In contrast to death resulting from ischemic heart disease, there was only a weak relationship between usual total cholesterol and death caused by stroke in those 40 to 59 years of age (HR, 0.90; 95% CI, 0.84 to 0.97 for every 1 mmol/L lower cholesterol) and no relationship for older age groups after accounting for blood pressure. An analysis combing the data for the Prospective Studies Collaboration with data from the Multiple Risk Factors Intervention Trial (MRFIT) also found that lower usual total cholesterol was associated with a lower risk of fatal stroke in those 40 to 49 years of age (HR, 0.87; 95% CI, 0.76 to 1.00 per 1 mmol/L lower total cholesterol), with similar reductions in those 50 to 59 (HR, 0.91; 95% CI, 0.85 to 0.97) and 60 to 69 (HR =0.93; 95% CI 0.89 to 0.97) years of age but no reductions in those >70 years of age.2 There was no relationship between non–high-density lipoprotein cholesterol and stroke risk at any age. Data for analyses based on stroke subtype were limited because many of the studies did not verify whether a stroke was due to ischemia or hemorrhage with neuroimaging. The MRFIT included an analysis of the relationship between total cholesterol and fatal brain hemorrhage.3 Intracranial hemorrhage was 3 times more common (P=0.05) in men with serum cholesterol levels <160 mg/dL compared with those with higher levels, whereas higher levels were associated with an increased risk of ischemic stroke (P=0.007). Although there were too few deaths for meaningful analysis, there was no apparent relationship between non–high-density lipoprotein cholesterol and stroke subtype.Article p 2136The Prospective Studies Collaboration meta-analysis was based primarily on studies conducted in North America and Western Europe, and MRFIT was done in the United States. The study by Noda et al was carried out in Japan. The Asia-Pacific Cohort collaborators analyzed combined data from 29 regional studies.4 There was a 25% (95% CI, 13 to 40) increased risk of fatal ischemic stroke but a 20% (95% CI, 8 to 30) decreased risk of fatal hemorrhagic stroke for every 4.5-mg/dL increase in total cholesterol. Therefore, in both Western and Asian populations, the relationship between usual total cholesterol and overall stroke may be at least partially obscured by competing risks; higher levels of total cholesterol tend to be associated with an increased risk of ischemic stroke, with lower levels associated with an increased risk of hemorrhagic stroke.Consistent with the previously cited reports, after multivariable adjustment, the present study identified a lower risk of parenchymal brain hemorrhage associated with higher total cholesterol (HR, 0.55; 95% CI, 0.33 to 0.91; P=0.02 for total cholesterol >240 versus <160 mg/dL) but, in addition, found a somewhat stronger relationship with LDL-C (HR, 0.45; 95% CI, 0.30 to 0.69; P<0.001 for LDL-C >140 versus <80 mg/dL). The 95% CIs for the point estimates based on these 2 lipid indexes overlap and therefore do not differ significantly. The observation suggesting a relationship between LDL-C and brain hemorrhage supports the findings from a pooled cohort of the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS).5 Multivariable analysis found that older age, black ethnicity, hypertension, lower LDL-C, and lower triglycerides were independently associated with an increased risk of intracerebral hemorrhage. Although uncontrolled hypertension was the strongest risk factor for hemorrhage, the relative rate for the highest compared with the lowest quartile of LDL-C was 0.52 (95% CI, 0.31 to 0.88; P=0.008). The relationship between low, usual LDL-C and brain hemorrhage is further supported by a Korean study using T2*-weighted gradient-echo magnetic resonance imaging to detect “micobleeds,” areas of old extravasation of blood thought to be associated with an increased risk of intracerebral hemorrhage.6 Both total cholesterol and LDL-C levels were lower in those with compared with those without such magnetic resonance imaging findings.Although low, usual total cholesterol and LDL-C levels in persons free of cardiovascular disease or stroke appear to be associated with a higher risk of brain hemorrhage, this does not mean that treating patients with vascular disease with lipid-lowering medications increases risk. A meta-analysis of data from 90 056 participants in 14 randomized trials of statins found that treatment was associated with a 12% reduction in all-cause mortality per 1-mmol/L reduction in LDL-C (rate ratio [RR], 0.88; 95% CI, 0.84 to 0.91; P<0.0001) and reductions in myocardial infarction or coronary death (RR, 0.77; 95% CI, 0.74 to 0.80; P<0.0001) and in fatal or nonfatal stroke (RR, 0.83; 95% CI, 0.78 to 0.88; P<0.0001).7 There was no increase in brain hemorrhage with treatment (RR, 1.05; 95% CI, 0.78 to 1.41). This is consistent with another meta-analysis that found no relationship between statin therapy and the risk of hemorrhagic stroke (n=54 334; RR, 0.94; 95% CI, 0.68 to 1.30).8 The same lack of relationship between lipid lowering with statins and hemorrhagic stroke risk appears to be true in Japanese primary prevention populations.9 Even achieving very low levels of LDL-C (ie, <40 mg/ dL10 or <64 mg/dL11) with statins in patients with coronary heart disease is not associated with an increased risk of brain hemorrhage.The situation is somewhat more complicated in patients with a prior history of stroke. Secondary analysis of data from the subgroup of patients enrolled in the Heart Protection Study with prior cerebrovascular disease found a nonstatistically significant increase in hemorrhagic stroke in those treated with simvastatin 40 mg/d versus placebo (n=21 [1.3%] versus n=11 [0.7%]).12 There was, however, statistical heterogeneity between those with and without a prior stroke history for the risk of brain hemorrhage (P=0.03). The Stroke Prevention With Aggressive Reduction of Cholesterol Levels (SPARCL) trial cited by Noda et al in their discussion was a pure secondary cerebrovascular prevention trial.13 Subjects with a stroke or transient ischemic attack within the preceding 1 to 6 months, an LDL-C between 100 and 190 mg/dL, and no known coronary heart disease were randomized to atorvastatin 80 mg/d or placebo. The overall treatment-related benefit in reducing the risk of the primary end point (fatal or nonfatal stroke; adjusted HR, 0.84; 95% CI, 0.71 to 0.99; P=0.03; unadjusted P=0.05) was partially attenuated by a treatment-related increase in brain hemorrhage (HR, 1.66; 95% CI, 1.08 to 2.55). Thus, the relationship between statin therapy and the risk of brain hemorrhage may be different in patients with a history of cerebrovascular disease (who overall still benefit from statin treatment) compared with those without such a history.Noda et al1 write, “Although it is difficult to confirm the causality between low LDL cholesterol and increased risk of intraparenchymal hemorrhage through the present observational study only, the consistency of epidemiological and experimental evidence [referring to the SPARCL trial in which the average on-treatment LDL-C was 73 mg/dL] … supports a causal relationship” (p 2143).Although the epidemiological data based on usual total cholesterol and LDL-C levels suggest an association between low levels and increased risk of brain hemorrhage, as reviewed above, there is no evidence of a relationship between cholesterol levels and bleeding risk in patients with coronary heart disease whose lipid levels have been lowered medically. Furthermore, exploratory analyses of SPARCL trial data found that the risk of hemorrhage was independently related to treatment assignment, age, sex, a baseline hemorrhage, and uncontrolled hypertension.14 The risk of hemorrhage was unrelated to LDL-C levels in statin-treated subjects.14 Regardless of treatment assignment, there were no increase in hemorrhagic stroke in those who had the greatest reductions in LDL-C (HR, 1.04; 95% CI, 0.61 to 1.78; P=0.8864) and no LDL-C threshold below which the risk of brain hemorrhage was increased.15Establishing causality based on statistical associations from observational studies is always hazardous. In the general population, having low, usual total cholesterol and LDL-C appears to be associated with a higher risk of brain hemorrhage. In contrast, there is no evidence of a similar relationship in persons whose total cholesterol and LDL-C levels have been lowered therapeutically. This suggests no causal relationship between total cholesterol and LDL-C and bleeding risk.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Source of FundingThis work was supported in part by an American Stroke Association–Bugher Foundation Center for Stroke Prevention Research grant.DisclosuresDr Goldstein is a member of the SPARCL Trial Steering Committee (supported by Pfizer) and a consultant for Pfizer.FootnotesCorrespondence to Larry B. Goldstein, MD, FAAN, FAHA, Box 3651, Duke University Medical Center, Durham, NC 27710. E-mail [email protected] References 1 Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Doi M, Izumi Y, Ohta H. Low-density lipoprotein cholesterol concentrations and death due to intraparenchymal hemorrhage: The Ibaraki Prefectural Health study. Circulation. 2009; 119: 2136–2145.LinkGoogle Scholar2 Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007; 370: 1829–1839.CrossrefMedlineGoogle Scholar3 Iso H, Jacobs DRJ, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med. 1989; 320: 904–910.CrossrefMedlineGoogle Scholar4 Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, MacMahon S, Woodward M. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J Epidemiol. 2003; 32: 563–572.CrossrefMedlineGoogle Scholar5 Sturgeon JD, Folsom AR, Longstreth WT Jr, Shahar E, Rosamond WD, Cushman M. Risk factors for intracerebral hemorrhage in a pooled prospective study. Stroke. 2007; 38: 2718–2725.LinkGoogle Scholar6 Lee SH, Bae HJ, Yoon B-W, Kim H, Kim DE, Roh JK. Low concentration of serum total cholesterol is associated with multifocal signal loss lesions on gradient-echo magnetic resonance imaging: analysis of risk factors for multifocal signal loss lesions. Stroke. 2002; 33: 2845–2849.LinkGoogle Scholar7 Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet. 2005; 366: 1267–1278.CrossrefMedlineGoogle Scholar8 O'Regan C, Wu P, Arora P, Perri D, Mills EJ. Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients. Am J Med. 2008; 121: 24–33.CrossrefMedlineGoogle Scholar9 Mizuno K, Nakaya N, Ohashi Y, Tajima N, Kushiro T, Teramoto T, Uchiyama S, Nakamura H. Usefulness of pravastatin in primary prevention of cardiovascular events in women: analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA Study). Circulation. 2008; 117: 494–502.LinkGoogle Scholar10 Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005; 46: 1411–1416.CrossrefMedlineGoogle Scholar11 Waters DD, LaRosa JC, Barter P, Fruchart JC, Gotto AM Jr, Carter R, Breazna A, Kastelein JJ, Grundy SM. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (Treating to New Targets) study. J Am Coll Cardiol. 2006; 48: 1793–1799.CrossrefMedlineGoogle Scholar12 Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004; 363: 757–767.CrossrefMedlineGoogle Scholar13 Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006; 355: 549–559.CrossrefMedlineGoogle Scholar14 Goldstein LB, Amarenco P, Szarek M, Callahan A, Hennerici M, Sillesen H, Zivin J, Welch KMA. Secondary analysis of hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. Neurology. 2008; 70: 2364–2370.CrossrefMedlineGoogle Scholar15 Amarenco P, Goldstein LB, Szarek M, Sillesen H, Rudolph AE, Callahan A, Hennerici M, Simunovic L, Zivin JA, Welch KMA. Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke. 2007; 38: 3198–3204.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ali I, Abuissa M, Alawneh A, Subeh O, Abu Sneineh A, Mousa S, Deeb I and Rayyan H (2019) The Prevalence of Dyslipidemia and Hyperglycemia among Stroke Patients: Preliminary Findings, Stroke Research and Treatment, 10.1155/2019/8194960, 2019, (1-6), Online publication date: 30-Oct-2019. Rost N, Fitzpatrick K, Biffi A, Kanakis A, Devan W, Anderson C, Cortellini L, Furie K and Rosand J (2010) White Matter Hyperintensity Burden and Susceptibility to Cerebral Ischemia, Stroke, 41:12, (2807-2811), Online publication date: 1-Dec-2010. Noda H and Iso H (2009) Letter by Noda and Iso Regarding Article, “Low-Density Lipoprotein Cholesterol Concentrations and Death Due to Intraparenchymal Hemorrhage: The Ibaraki Prefectural Health Study”, Circulation, 10.1161/CIRCULATIONAHA.109.887927, 120:22, Online publication date: 1-Dec-2009. Goldstein L (2009) Response to Letter Regarding Article, “Low-Density Lipoprotein Cholesterol Concentrations and Death Due to Intraparenchymal Hemorrhage: The Ibaraki Prefectural Health Study”, Circulation, 10.1161/CIRCULATIONAHA.109.900399, 120:22, Online publication date: 1-Dec-2009. Melissano G and Chiesa R (2009) The “Other Revolution” in Stroke Prevention, European Journal of Vascular and Endovascular Surgery, 10.1016/j.ejvs.2009.04.016, 38:2, (141-142), Online publication date: 1-Aug-2009. April 28, 2009Vol 119, Issue 16 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.109.856385PMID: 19398675 Originally publishedApril 28, 2009 KeywordshemorrhagelipidsEditorialsstrokePDF download Advertisement SubjectsEpidemiologyIntracranial HemorrhageMetabolism