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NEUROLOGY 2007;68:719720 Editorial

Low LDL cholesterol, statins, andbrain hemorrhage

Should we worry?Larry B. Goldstein, MD, FAAN, FAHA

In a retrospective observational study, Bang et al.report that low low-density lipoprotein (LDL) choles-terol levels are independently associated with an in-creased risk of hemorrhagic transformation afterrecanalization therapy for acute ischemic stroke. 1

What are the implications of this study for clinicalpractice?

As Bang et al. point out, it is important to recog-nize the limitations of their study design. Analyses of even large observational studies can be misleading.For example, epidemiologic studies of postmeno-pausal hormone therapy found their use was associ-ated with a reduction in cardiovascular events, 2 butrandomized trials found no effect or harm. 3-5 An ob-servational study can be useful for identifying poten-tial risk factors, especially when the finding issupported by other studies. Whether risk factor mod-ification alters outcomes can only be establishedthrough properly controlled, prospective studies.

Are there data from other studies to support arelationship between low LDL cholesterol and therisk of hemorrhagic infarction? Epidemiologic stud-ies generally find that lower cholesterol levels areassociated with an increased risk of brain hemor-rhage, even without recanalization therapy. For ex-ample, the Asia-Pacific Cohort study showed a 20%(95% CI: 8 to 30%) decreased risk of hemorrhagicstroke per 4.5 mg/dL increase in cholesterol levels. 6

Bang et al.s findings would be consistent with theepidemiologic observations if the bleeding in thesestudies was primarily due to hemorrhagic infarction(i.e., the pathophysiology of the hemorrhages wouldbe similar and related to reperfusion of ischemicbrain). It is not possible, however, to determinewhether the effect reported from epidemiologicstudies is related to an increase in hemorrhagic

transformation of ischemic infarctions, primaryhemorrhages, or both. Unless sequential brainscans are available, differentiating the two typesof parenchymal hemorrhages can be difficult. If the findings of Bang et al. are verified in otherstudies, understanding the mechanism by whichlow cholesterol (and low LDL cholesterol) increases

the risk of hemorrhagic infarction might lead totreatments to reduce this complication.

How much does low LDL cholesterol contribute tothe risk of symptomatic hemorrhagic transforma-tion? Bang et al. found the greatest risk of bleedingafter recanalization therapy was independently re-lated to current cigarette smoking followed by in-creasing stroke severity and lower LDL cholesterol.No threshold level below which risk increases wasreported with the impact of LDL cholesterol beingrelated to the magnitude of the reduction (a 3.2%decrease in risk was found for every 1 mg/dL in-crease in LDL cholesterol). The amount of variancein bleeding risk explained by the model is not given(i.e., the effect of the factors included in logisticalregression equation on total risk is not provided), sothe relative impact of unmeasured factors isuncertain.

An important question for current clinical practiceis whether lowering LDL cholesterol is associatedwith undue risk of brain hemorrhage. Meta-analysisof over 90,000 subjects, predominately with coronaryheart disease, enrolled in statin trials found a 19%proportional reduction (RR 0.81, 99% CI 0.74 to 0.89; p 0.0001) in ischemic strokes per mmol/L LDLcholesterol reduction with no difference in hemor-rhagic stroke (RR 1.05, 99% CI 0.78 to 1.41; p0.7). 7 Similarly, the Treating to New Targets (TNT)study found no increase in brain hemorrhages de-

See also page 737

From the Department of Medicine (Neurology), Center for Cerebrovascular Disease, Center for Clinical Health Policy Research, Duke University andDurham VA Medical Center, Durham, NC.Disclosure: Steering Committee for the Stroke Prevention with Aggressive Reduction in Cholesterol (SPARCL) study supported by Pfizer and a consult forPfizer. Address correspondence and reprint requests to Dr. Larry B. Goldstein, Box 3651, Duke University Medical Center, Durham, NC 27710; e-mail:golds004@mc.duke.edu

Copyright 2007 by AAN Enterprises, Inc. 719

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spite profound lowering of cholesterol levels in pa-tients with stable coronary heart disease. 8 Thebenefits of statin therapy outweigh the risks in thesepopulations.

Does lowering cholesterol levels with statins in-crease the risk of hemorrhagic infarction in personswith prior stroke? Bang et al. found that the effect of statin therapy was not significant after controllingfor the level of LDL cholesterol. This lack of effect of

statins in the multivariate model may have been dueto statistical colinearity (i.e., the use of statins wasstrongly related to lower LDL cholesterol levels). TheHeart Protection Study (HPS) comparing simvasta-tin 40 mg per day vs placebo in patients at high vascular risk included a subgroup of subjects withprior stroke. 9 An unplanned, post hoc analysis foundthe effect of statin treatment on bleeding risk dif-fered between those with and without a history of prior cerebrovascular disease. The small increase inhemorrhages in those treated with the statin (n21, 1.3% vs n 11, 0.7%) was not significant. Hem-orrhage subtype was not given. Although Bang et al.correctly indicate that the Stroke Prevention with Aggressive Reductions in Cholesterol Levels(SPARCL) trial found high dose statin therapy (ator- vastatin 80 mg per day) in patients with recentstroke or TIA and no known coronary heart diseasewas associated with an increase in brain hemor-rhage, this too was based on a post hoc analysis. 10

The pathophysiologic subtypes of brain hemorrhage(i.e., primary parenchymal hemorrhage vs hemor-rhagic infarction) were not reported. Therefore, thereremain no data showing that statin treatment in-creases the risk of hemorrhagic infarction.

Should clinicians worry about increasing the riskof hemorrhagic infarction or primary brain hemor-rhages by reducing LDL cholesterol with statins inpatients with prior stroke, and should recanalizationtherapy be withheld in those with low LDL choles-terol level? Although HPS found no reduction in re-current stroke with statin therapy, treatment was

associated with major reductions in other vascularevents in patients with prior cerebrovascular diseaseregardless of baseline cholesterol levels. In SPARCL,there was not only a significant 16% reduction in thecombined risk of nonfatal and fatal stroke with treat-ment, but also profound reductions in other major vascular events. Therefore, the available data sup-port the use of statins in patients with a history of cerebrovascular disease.

Whether low LDL cholesterol levels increase therisk of hemorrhagic infarction in patients undergo-ing recanalization therapy requires verification.Even if true, the increased chances of bleeding asso-ciated with this and other identified contributors torisk such as current cigarette smoking would need tobe balanced against the benefits of restoring circula-tion to ischemic brain.

References1. Bang OY, Saver JL, Liebeskind DS, et al. Cholesterol level and symp-

tomatic hemorrhagic transformation after ischemic stroke thromboly-sis. Neurology 2007;68:737742.

2. Mendelsohn ME, Karas RH. The protective effects of estrogen on the

cardiovascular system. N Engl J Med 1999;340:18011811.3. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. Aclinical trial of estrogen-replacement therapy after ischemic stroke. NEngl J Med 2001;345:12431249.

4. Simon JA, Hsia J, Cauley JA, et al. Postmenopausal hormone therapyand risk of stroke. The Heart and Estrogen-progestin ReplacementStudy (HERS). Circulation 2001;103:638642.

5. Writing Group for the Womens Health Initiative Investigators. Risksand benefits of estrogen plus progestin in healthy postmenopausalwomen: principal results From the Womens Health Initiative random-ized controlled trial. JAMA 2002;288:321333.

6. Zhang X, Patel A, Horibe H, et al. Cholesterol, coronary heart disease,and stroke in the Asia Pacific region. Int J Epidemiol 2003;32:563572.

7. Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy andsafety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet2005;366:12671278.

8. Waters DD, LaRosa JC, Barter P, et al. Effects of high-dose atorvasta-tin on cerebrovascular events in patients with stable coronary diseasein the TNT (Treating to New Targets) study. J Am Coll Cardiol 2006;48:17931799.

9. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in20 536 people with cerebrovascular disease or other high-risk condi-tions. Lancet 2004;363:757767.

10. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels(SPARCL) Investigators. High-dose atorvastatin after stroke or tran-sient ischemic attack. N Engl J Med 2006;355:549559.

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