dyslipidemiamanagement continuum 2011

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DyslipidemiaManagementPratik Bhattacharya, MD, MPH; Seemant Chaturvedi, MD, FAHA, FAAN

ABSTRACTPurpose of Review: Numerous studies have been conducted in the past decadeevaluating the use of statins and other lipid therapies for reducing vascular events.These studies have impacted the area of stroke prevention.Recent Findings: For patients with established coronary artery disease, statins reducethe rate of stroke. High-dose statin treatment has also been found to reduce the rate ofstroke in patients with recent cerebrovascular events and no evidence of heart disease.As a result, initiation of statin therapy for patients with stroke or TIA is now recom-mended in clinical guidelines. Whether agents that modulate high-density lipoproteincholesterol are effective in reducing stroke is still the subject of clinical study.

Summary: Most patients with stroke or TIA should be treated with statins. The era ofmultimodal medical therapy for stroke prevention is now well established.

Continuum Lifelong Learning Neurol 2011;17(6):12421254.

INTRODUCTIONThere have been several advances inthe understanding of dyslipidemia andits management in the last decade. Theresults of several epidemiologic studiesand clinical trials have been reported,resulting in landmark changes in treat-ment paradigms. Treatmentgoals for low-density lipoprotein cholesterol (LDL-C)levels have changed. A new category of patients with very high cardiovascular risk has been identified. The role of several emerging cardiovascular risk fac-tors, such as high-sensitivity C-reactiveprotein (hsCRP) and lipoprotein(a)[Lp(a)], has been elucidated, and studiesregarding treatment of these factors arenow available.

This article revisits the Adult Treat-ment Panel III (ATP III) guidelines es-tablished in the earlier part of thedecade. It outlines the results of studiesthat led to updated treatment goals for LDL-C and describes the results of twoimportant clinical trials, Justification for the Use of Statins in Prevention: an In-tervention Trial Evaluating Rosuvastatin(JUPITER) and Stroke Prevention by Ag-

gressive Reduction in Cholesterol Lev-els (SPARCL), which demonstrated therole of statins in primary and secondary stroke prevention, respectively. It de-scribes the current understanding of the pleiotropic effects of statins. Finally,

it addresses the role and treatments of secondary targets of dyslipidemia man-agement, such as low high-density lipo-protein cholesterol (HDL-C) and elevatedLp(a). The developments in the treat-ment of lipid disorders expand the ar-mamentarium of the neurologist aimingto reduce the burden of stroke.

LOW-DENSITY LIPOPROTEINCHOLESTEROL A large meta-analysis of randomized

trials using statins for primary or sec-ondary prevention demonstrated a sig-nificant correlation between the extentof LDL-C reduction and the degree of protection from stroke. The study esti-mated that each 10% reduction of LDL-Creduced the risk of stroke by about15.6%.1 Because of the strong epide-miologic evidence supporting thebenefit of LDL-C reduction, LDL-C

Address correspondence toDr Seemant Chaturvedi, Wayne State University, 4201Saint Antoine Street, 8CUniversity Health Center,Detroit, MI 48201, [email protected] Disclosure:Dr Bhattacharya reports nodisclosure. Dr Chaturvedihas received personalcompensation for speaking or consulting activities from Abbott Vascular, AstraZeneca,Boehringer Ingelheim, andBristol-Myers Squibb/SanofiPharmaceuticals Partnership;has received personalcompensation for expert witness testimony; and hasreceived research support

from Bayer HealthCarePharmaceuticals, Boehringer Ingelheim, andMerck/Schering-Plough.Unlabeled Use of Products/Investigational Use Disclosure:Drs Bhattacharya andChaturvedi report nodisclosure.Copyright * 2011, American Academy of Neurology. All rightsreserved.

1242 www.aan.com/continuum December 2011

Review Article

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


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remains the primary target for treat-ment of dyslipidemia.

Low-Density LipoproteinCholesterolTreatment GuidelinesThe ATP III National Cholesterol Edu-cation Program recommendations haveguided the management of dyslipide-mia in the United States. 2 Per theseguidelines, all adults age 20 years or

older should get a fasting lipid profileonce every 5 years. The 2001 guidelinesstratify patients into three coronary heartdisease (CHD) risk categories ( Table 3-1 ).Patients in the high risk category havea greater than 20% risk of develop-ing or having a recurrence of CHD in10 years. Patients in the moderate risk category have a 10% to 20% risk of aCHD event in 10 years, based on the

TABLE 3-1 Adult Treatment Panel III Risk Stratification to Guide Treatment Goals forLow-Density Lipoprotein Cholesterol

Risk CategoryLow-Density LipoproteinCholesterol Goal

Very high risk (Adult Treatment Panel [ATP] III update) Optional goal of G 70 mg/dL

Established cardiovascular disease plus:

Multiple major risk factors (especially diabetes)

Severe andpoorly controlled riskfactors (especially continuedcigarettesmoking)

Multiple risk factors of the metabolic syndrome (especially triglycerides Q200 mg/dL plus non Y high-density lipoprotein cholesterol [HDL-C] Q 130 mg/dLand HDL-C G 40 mg/dL)

Coronary artery syndromes

High risk (original ATP III guidelines) G 100 mg/dL

Established coronary heart disease (CHD)

CHD riskequivalents: Other forms of atherosclerosis, such as peripheral arterialdisease, abdominal aortic aneurysm, and symptomatic carotid disease

Moderate risk G 130 mg/dL

Two or more of the following risk factors that modify low-densitylipoprotein cholesterol goals:

Cigarette smoking

Hypertension (blood pressure Q 140/90 mm Hg or on antihypertensivemedication)

Low HDL-C (G 40 mg/dL)

Family history of premature CHD (CHD in male first-degree relative G 55 years;CHD in female first-degree relative G 65 years)

Age (men Q 45 years; women Q 55 years)

Low risk G 160 mg/dL

None or one of the risk factors outlined above

Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of theNational Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult TreatmentPanel III). JAMA 2001;285(19):2486 Y 2497. Copyright B 2001, American Medical Association. All rights reserved.

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Framingham Risk Score. Patients in thelow risk category have a less than 10%risk of having a CHD event in 10 years.The LDL-C treatment target for thehigh risk group is less than 100 mg/dL,for the moderate risk group is less than130 mg/dL, and for the low risk groupis less than 160 mg/dL. 2

Following the publication of the 2001guidelines and LDL-C goals, the resultsof several seminal clinical trials eval-uating statins in primary and secondary prevention were published, promptingan update to the ATP III guidelines in

2004.3

The updated guidelines de-fined a new risk class: very high risk ( Table 3-1 ). Results of contemporary clinical trials showed that an LDL-C of 100 mg/dL was not sufficient to prevent cardiovascular events for these very high risk patients, and more aggressivelowering of LDL-C resulted in additionalcardiovascular risk reduction. An op-tional LDL-C target of 70 mg/dL wasrecommended for patients at very highrisk. 3 These targets were also recom-mended by the secondary stroke prevention guidelines from the AmericanHeart Association (AHA) in 2006.

Low-Density LipoproteinCholesterol Targets for StrokeRisk ReductionThe Treating to New Targets (TNT) Trial was designed to evaluate the effect of LDL-C target levels below 100 mg/dL on vascular event risk reduction for patients with CHD.4 The study randomized pa-tients with CHD to receive either

atorvastatin 10 mg/d or atorvastatin 80mg/d. The mean LDL-C levels achieved were 77 mg/dL in the 80 mg/d groupand 101 mg/dL in the 10 mg/d group.This translated to a significant 25% risk reduction for fatal and nonfatal strokesin the high-dose group compared withthe low-dose group over the follow-upperiod of about 5 years. The study confirmed the accumulating body of

evidence that intensive statin therapy lowering LDL-C to levels below previ-ously established targets is an effectivestroke prevention strategy. 4 In 2011, in view of the benefit noted from aggres-sive lowering of LDL-C in the SPARCLtrial, the AHA presented recommenda-tions for LDL-C reduction greater than50%, with targets of less than 70 mg/dLfor all patients with strokes or TIAs,even those without CHD. 5

Therapeutic Lifestyle ChangesTherapeutic lifestyle changes are advo-

cated by the ATP III panel and mustaccompany any lipid-lowering regimen.Specifically, these include reduction of intake of saturated fats (less than 7% of total calories) and cholesterol (less than200 mg/d); therapeutic options for en-hancing LDL-C lowering, such as plantstanols/sterols (2 g/d) and increased vis-cous (soluble) fiber (10 g to 25 g/d); weight reduction; and at least moderatephysical activity. 2

Primary Prevention StudiesLow-density lipoprotein cholesterol inhigh-risk patients. Patients with hyper-tension, diabetes, or other vascular risk factors who have not experienced a ma-jor vascular event are at lower risk for stroke than patients who have already had a cardiac or cerebral ischemic event.Therefore, primary prevention studiesin these populations are usually not de-signed to prove a reduction in stroke, asstroke is typically a secondary end pointof interest. These studies have been re-

viewed elsewhere. To summarize, theprimary prevention studies were con-ducted in patients with elevated choles-terol or in those with multiple other risk factors. Figure 3-1 provides an over- view of the effects of LDL-C loweringon the risk of stroke. Although the ef-fects of statins on overall cardiovascular outcomes were robust, statin use didnot consistently reduce stroke risk.

KEY POINTSh Low-density lipoprotein

cholesterol is thekey treatment targetfor patients withatherosclerotic vasculardisease.

h In the past decade,more aggressivelow-density lipoproteincholesterol reductionhas been emphasizedby clinical guidelines.

h Some studies in theprimary preventionsetting have shown areduction in stroke withstatin use, but theresults have beensomewhat inconsistent.The evidence isstrongest for patientswith diabetes ormultiple risk factors.


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Primary prevention in patients withnormal low-density lipoprotein cho-

lesterol levels. About half of all myocar-dial infarctions and strokes occur amongpatients with levels of LDL-C below cur-rently recommended treatment thresh-olds. HsCRP is an inflammatory bio-marker established as an independentpredictor of vascularevents. TheJUPITER trial was designed to evaluate statin use asa primary prevention strategy among pa-tients with normal LDL-C but with elevated hsCRP. 6 Men 50 years and older and women 60 years and older were re-

cruited if they had an LDL-C less than130 mg/dL and an hsCRP greater thanor equal to 2 mg/dL. Participants wererandomized in a double-blind manner toreceive either rosuvastatin 20 mg/d or placebo. The study was terminated early after a median follow-up of 1.9 years be-cause of a strong effect size for the pri-mary and secondary outcomes overall, as well as within prespecified subgroups. 6

LDL-C level in the treatment arm wasreduced to a median of 55 mg/dL. Therelative risk reduction was a robust 44%for the primary end point of first major cardiovascular event (nonfatal myocar-dial infarction, nonfatal stroke, hospi-talization for unstable angina, arterialrevascularization, or death from cardiovascular causes). 6 A 47% relative risk re-duction resulted for the secondary endpoint of myocardial infarction, stroke, or death from cardiovascular causes. 6 Sim-ilar results were found for participants with elevated hsCRP and no other ATPIII risk factors. 6 Specifically, a 48% rela-

tive risk reduction for both fatal andnonfatal stroke 6 and a 51% reduction inthe risk of ischemic strokes occurredover the observation period. 7 The abso-lute risk reduction of both the primary outcome and the secondary outcome of stroke was greater in participants older than 70 years. 8

The study results were further ana-lyzed to determine the projected 5-year

number needed to treat (NNT). The 5- year NNT for the primary outcome was25; for myocardial infarction, stroke, or any death was 29 9; and for any stroke was 123.7 To put this in perspective, pre- viously reported NNTs for antihyperten-sive therapy in primary stroke preven-tion were between 80 and 160, and the5-year NNT for aspirin in primary prevention is more than 300. 9 One concernabout the JUPITER results was whether the cardiovascular benefit seen was truly due to hsCRP lowering and not simply aresult of aggressive LDL-C lowering. In a

FIGURE 3-1 Relationship between odds ratios for strokeevents and corresponding low-densitylipoprotein cholesterol reduction. The

regression line has been plotted and weighted for the inverseof the variance of odds ratios. *Size-weighted combinedestimates for the small trials. Post-CABG = Post CoronaryArtery Bypass Graft trial; GISSI = Gruppo Italiano per loStudio della Sopravvivenza nellInsufficienza Cardiaca trial;PROSPER = Prospective Study of Pravastatin in the Elderly atRisk trial; ALLHAT-LLT = Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial-Lipid Lowering Trial;WOSCOPS = West of Scotland Coronary Prevention Study;LIPID = Long-Term Intervention With Pravastatin in IschaemicDisease trial; AFCAPS/TexCAPS = Air Force/Texas CoronaryAtherosclerosis Prevention Study; HPS = Heart ProtectionStudy; ASCOT-LLA = Anglo-Scandinavian Cardiac OutcomesTrial-Lipid Lowering Arm trial; SSSS = ScandinavianSimvastatin Survival Study; CARE = Cholesterol and RecurrentEvents trial; GREACE = Greek Atorvastatin and CoronaryHeart Disease Evaluation study; MIRACL = MyocardialIschemia Reduction With Aggressive Cholesterol Loweringtrial; LDL = low-density lipoprotein.

Reprinted with permission from Amarenco P, Labreuche J, Lavalle e P, Touboul PJ.Statins in stroke prevention and carotic atherosclerosis: systematic review ofup-to-date meta-analysis. Stroke 2004;35(12):2902 Y 2909.




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subsequent analysis of the study results,the authors showed that hsCRP loweringdid provide an additional cardiovascular benefit (reduction in event rates) in par-ticipants who achieved LDL-C goals of less than 70 mg/dL. 10

Implications of the JUPITER study for primary prevention. An estimateusing National Health and Nutrition Ex-amination Survey data and JUPITER criteria suggests that an additional 6.5million US adults should be on statins. 11

Two studies have evaluated the cost-effectiveness of treating patients with

low LDL-C and elevated hsCRP withstatins for primary prevention. 12,13

Both analyses concluded this strategy to be cost-effective in the long run.

The 2009 Canadian guidelines for di-agnosis and treatment of dyslipidemiarecommend measurement of hsCRP inmen older than 50 years and womenolder than 60 years who are at moderaterisk for cardiovascular disease (basedon the Framingham score) and whoseLDL-C levels are less than 130 mg/dL. 14

Following the initiation of health be-havior interventions, the guidelines rec-ommend statins for the above patientsif their hsCRP is higher than 2 mg/dL. 14

The ATP III recognized hsCRP as anemerging risk factor. The panel did notrecommend modification of LDL-C goalsbased on the presence of an elevatedhsCRP but acknowledged its utility toguide the intensity of risk reductiontherapy. 2 The ATP IV panel guidelinesfor lipid management are expected inlate 2011. A greater influence of hsCRP

in risk stratification and treatment isanticipated.

Secondary Prevention StudiesLow-density lipoprotein cholesteroland stroke prevention in patients withcoronary heart disease. Most studiesevaluating the use of statins for sec-ondary prevention have been con-ducted in patients with established

CHD. The studies have evaluated dif-ferent agents in varying doses.

In the Scandinavian Simvastatin Sur- vival Study, which enrolled patients with established CHD, simvastatin 20 mgto 40 mg/d reduced LDL-C by about 35%throughout the study duration. The simvastatin group had a 30% relative risk reduction of fatal and nonfatal cerebrovascular events compared with placebo. 15

In the Cholesterol and RecurrentEvents (CARE) trial, patients with myo-cardial infarction and average levels of LDL-C(mean=139 mg/dL)were random-

ized to receive eitherpravastatin 40 mg/dor placebo. Pravastatin lowered LDL-Cby about 28% through the follow-upperiod and showed a 31% relative risk reduction (1.2% absolute risk reduc-tion) in all strokes. 16

The Greek Atorvastatin and Coronary heart disease Evaluation (GREACE)study randomized patients with estab-lished CHD to receive either atorvastatin(doses titrated from 10 mg to 80 mg/dto reach LDL-C less than 100 mg/dL) or usual medical care. Atorvastatin resultedin a 43% mean lowering of the LDL-Cand a 47% relative risk reduction in allstrokes. 17

In the Long-term Intervention withPravastatin in Ischaemic Disease (LIPID)study, patients with established CHDand a moderately high LDL-C (mean=150 mg/dL) were randomized to re-ceive either pravastatin 40 mg/d or placebo. Pravastatin resulted in a 25%mean decrease in LDL-C compared with placebo. A 19% relative risk reduc-

tion (0.8% absolute risk reduction) for any stroke was achieved with pravasta-tin. 18 In a subsequent analysis of theresults of this study, the relative strokerisk reduction was even more impres-sive among patients with diabetes andthose with impaired fasting glucose. 19

Patients with recent acute coronary events were randomized to receive either high-dose atorvastatin (80 mg/d) or

KEY POINTh A large study has shown

a reduced rate of strokein patients with averagelow-density lipoproteincholesterol levels butincreased C-reactiveprotein levels who aretreated with statins.


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placebo in the Myocardial Ischemia Re-duction with Aggressive CholesterolLowering (MIRACL) study.20 Over ashort duration of follow-up of 16 weeks,high-dose atorvastatin resulted in a 40%reduction in LDL-C and a significant 50%relative risk reduction in fatal and non-fatal strokes. The study established thatthe benefit of stroke risk reduction canbe achieved soon after a coronary eventby vigorous cholesterol lowering withatorvastatin. 20

In summary, patients with acute andchronic CHD appear to benefit in terms

of stroke risk reduction with the use of statin therapy.Low-density lipoprotein cholesterol

andstrokeprevention forpatients with-out coronary heart disease. Another question is whether patients with a pre- vious stroke but no definite coronary event benefit from cholesterol lowering.

The HeartProtection Study (HPS)wasthe first study to present data on a sub-group of patients with prior stroke. Par-ticipants in the HPS were randomized toreceive either simvastatin 40 mg/d or pla-cebo. 21 The studyfounda marked benefitfrom simvastatin use in terms of a reduc-tion of major coronary events and re- vascularizations. However, there was noreductionin therisk ofstrokes among par-

ticipants who had had prior strokes. 21

There are two possible explanations for this negative result. First, on average, pa-tients in the HPS were recruited 4.3 yearsafter the initial event, and the risk of re-current stroke is highest in the first yearsafter stroke. Second, the study was notpowered to evaluate secondary strokeprevention as an end point.

The patient in Case 3-1 is illustrativeof prevention in a symptomatic patient.The SPARCL study was the first study to evaluate the efficacy of statins to re-duce the risk of recurrent stroke in pa-

tients who had had a recent TIA or stroke. 22 Patients with LDL-C between100 mg/dL and 190 mg/dL without CHD who had had a stroke or TIA within 6months of the study were randomizedto receive either atorvastatin 80 mg/dor placebo. On this regimen, the meanLDL-C achieved over the study durationin the atorvastatin group was73 mg/dL. 22

Results showed a 16% relative risk re-duction in the primary outcome of fatalor nonfatal stroke with high-dose atorvastatin. 22 The absolute risk difference at5 years was 2.2% (the 5-year NNT withatorvastatin 80 mg/d to prevent one fa-tal or nonfatal stroke was 46). If patients who discontinued treatments wereexcluded, the relative risk reduction

Case 3-1A 52-year-old African American man with a history of hypertension andsmoking presented with an episode of transient visual loss in the left eye. Thenext day, he had expressive aphasia for 30 minutes. He had no history ofcoronary artery disease. A cerebral angiogram revealed 80% stenosis in thecavernous segment of the internal carotid artery. His lipid profile was asfollows: total cholesterol 270 mg/dL, low-density lipoprotein cholesterol(LDL-C) 168 mg/dL, high-density lipoprotein cholesterol 52 mg/dL, andtriglycerides 220 mg/dL.

Comment. The patient in this case has documented atherosclerosis inthe internal carotid artery. On the basis of the results of the SPARCL study,the patient should be started on statin treatment. With a starting LDLof 168 mg/dL, the patient will require a potent agent to reduce the LDL-Cto less than 100 mg/dL. An LDL-C of less than 70 mg/dL would be desirable.Statin use in such patients reduces stroke risk by at least 16%.




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increased to 18%. There was also a 26%reduction in the risk of subsequent TIAs.Patients whose LDL-C decreased to lessthan 70 mg/dL had a 28% greater re-lative stroke risk reduction. Consistent with the HPS, a significant risk reduc-tion occurred for coronary events. 22 In asubgroup analysis of the SPARCL results,no significant difference in results wasobserved for patients younger than 65 years compared with older participants. 23

There was no difference in all-cause mor-tality between the two groups, but theatorvastatin group had a significant re-

duction in fatal strokes.22

When the outcomes were evaluatedby stroke subtypes, the atorvastatingroup had a 22% relative risk reductionin ischemic stroke when compared withplacebo. 22 In a further exploratory analysis,patientsonatorvastatinhadsig-nificantly milder recurrent strokes andTIAs (assessed as modified Rankin Scalescores 3 months after the outcome) thanthose on placebo. 24

StatinsRisk of hemorrhagic stroke with statinuse. Several epidemiologic studies havefound that lower cholesterol levels in-crease the risk of hemorrhagic stroke.For instance, in the Multiple Risk Factor Intervention Trial (MRFIT), patients withcholesterol less than 160 mg/dL had a

threefold greater risk of death from in-tracranial hemorrhage. 25 Similarly, in apooled cohort analysis of Atheroscle-rotic Risk In Communities (ARIC) andCardiovascular Health Study (CHS) data,low LDL-C was inversely associated withincident intracranial hemorrhage. 26

Should the results of these observatio-nal studies affect a clinicians decisionto treat with statins? An importantfinding in the SPARCL study was thatsubjects in the atorvastatin arm hada higher risk of hemorrhagic stroke(2.3% versus 1.4% in the placebo group).

However, the incidence of fatal hem-orrhages was not significantly differentin the two groups. 22 Further, the levelof LDL-C did not predict the occur-rence of a hemorrhagic stroke (ie, aggres-sive LDL-C lowering [mean 61 mg/dL within 1 month of initiating atorvasta-tin] did not result in increased hem-orrhages). A post hoc analysis of thestudy results determined that hemor-rhages tend to occur more in patients whose index events were hemorrhagicstrokes. Male sex, advanced age, hy-pertension (especially poorly con-trolled), and small vessel disease Y related strokes also conveyed higher risk for developing hemorrhages, asillustrated in Case 3-2 .27 Patients withhemorrhagic strokes are often at highrisk of ischemic strokes and coronary

KEY POINTh The SPARCL study

established the value ofstatin treatment inpatients with a recentTIA or stroke but nodefinite heart disease.

Case 3-2A 65-year-old woman with a history of hypertension and a myocardialinfarction 5 years ago presented with left hemiparesis. Her blood pressurewas inconsistently controlled, and she had left ventricular hypertrophy. Ahead CT revealed a 28-mL right putaminal hemorrhage. The patient waspreviously on a statin. The neurologist was called to advise regardingwhether the statin should be discontinued.

Comment. There is no definite proof that continued statin use willincrease the risk of a second hemorrhagic stroke. The patient has advancedhypertension, which is the major risk factor for cerebral hemorrhage. Thepatients coronary artery disease is a proven indication for statintreatment. The cerebral hemorrhage emphasizes the importance of bloodpressure control in the future.


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disease because of common risk fac-tors. Therefore, the benefits of initiat-ing statins to prevent ischemic strokein patients with intracerebral hemor-rhage should be carefully balanced withthe risks of recurrent hemorrhage.

The efficacy of different statins inlowering low-density lipoproteincholesterol. In the Statin Therapies for Elevated Lipid Levels compared Acrossdoses to Rosuvastatin (STELLAR) study, alarge group of patients was randomizedto receive different doses of rosuvastatin,atorvastatin, simvastatin, and pravasta-

tin.28

Over an average of 6 weeks, pa-tients taking rosuvastatin achieved an8.2% greater LDL-C reduction than thosetaking atorvastatin and a greater LDL-C re-duction and HDL-C elevation than thosetaking atorvastatin, simvastatin, and pravastatin. A significantly higher proportionof patients on rosuvastatin reached their target LDL-C. Most of the lipid-loweringbenefits of rosuvastatin were seen atthe lowest dose of 10 mg/d. 28 The ATPIII update recommended using a statindose that reduces plasma LDL-C by atleast 30% to 40%. Across several studiesoutlined in this review, the best results were obtained with that degree of LDL-Creduction. In the Antihypertensive andLipid-Lowering Treatment to PreventHeart Attack Trial-Lipid Lowering Trial(ALLHAT-LLT), only 18% LDL-C reduc-tion was noted, and no benefit was seen.The equivalent doses suggested toachieve 30% to 40% LDL-C reduction areatorvastatin 10 mg/d, pravastatin 40 mg/d,simvastatin 20 mg to 40 mg/d, fluvasta-

tin 40 mg to 80 mg/d, and rosuvasta-tin 5 mg to 10 mg/d. Recently, the USFood and Drug Administration issued a warning regarding an increased risk of muscle toxicity with the highest ap-proved dose of simvastatin (80 mg). Toreiterate, the recent secondary preven-tion of stroke guidelines recommend a50% LDL-C lowering among patients with a prior stroke or TIA. 5

Multimodal lipid therapies. While sta-tins are excellent agents to lower LDL-C,a large number of ischemic strokes oc-cur among patients with type 2 diabetesand metabolic syndrome. These patientshave a pattern of combined atherogenicdyslipidemia characterized by hyper-triglyceridemia, low HDL-C, a prepon-derance of small dense LDL-C particles,and an accumulation of cholesterol-richremnants (such as apolipoprotein B).Statins have modest efficacy in the treat-ment of increased triglycerides or low HDL-C. In such cases, combinationtherapies using niacin, fibrates, ezeti-mibe, and statins (based on their safety and effectiveness) may be reasonable.

Pleiotropic effects of statins. A meta-analysis of randomized trials for statinuse in stroke prevention estimatedthat LDL-C reduction explained about35% to 80% of stroke risk reduction. 1

This suggests that LDL-C reduction isthe most important effect of statin ther-apy, but other non Y lipid-lowering ef-fects of statins also contribute to strokerisk reduction. In vivo and in vitro stud-

ies have elucidated various nonlipidmechanisms of statin action 29 :& Statins improve endothelial function,

partly by LDL-C reduction and alsoby increase of endothelial nitricoxide. Statins increase nitric oxide by upregulation of nitricoxide synthase.

& Statins inhibit inflammatory responsesby reducing various markers of inflammation, including hsCRP,phospholipase A2, nuclear factor- 0 B, interleukins, and cytokines.

& Statins demonstrate antioxidantactivity by downregulating theproduction of reactive oxygenspecies while upregulating nitricoxide synthase.

& Statins modulate the immuneresponse by downregulating major histocompatibility complex IIexpression on blood immune cells.Major histocompatibility complex II




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is normally responsible for recognizing and processing antigensto initiate an immune response.

& Statins stabilize atheroscleroticplaque by causing plaque regressionin the long run. In the short term,statins decrease macrophageproliferation and matrix metalloproteinase production fromactivated macrophages within theplaque. Matrix metalloproteinases weaken fibrous plaque, makingit vulnerable to rupture.

& Statins modulate platelet function. The

precise mechanisms areunknown, butstatins probably modify cholesterolcontent in platelet walls, reduce theproduction of thromboxane A2,and decrease platelet activation by upregulating nitric oxide.

& Accumulating experimentalevidence indicates that statins may provide neuroprotection throughneurogenesis and synaptogenesisafter ischemic strokes.

LOW HIGH-DENSITY

LIPOPROTEIN CHOLESTEROLEpidemiologic data from the NorthernManhattan Study suggested that HDL-Cgreater than 35 mg/dL was protectiveagainst ischemic stroke. 30 The study also found a dose-response relation-ship; HDL-C greater than or equal to

50 mg/dL offered significantly greater protection against ischemic strokethan HDL-C 35 mg/dL to 49 mg/dL. 30This relationship held true across allraces/ethnicities. Later, a case-controlstudy showed that subjects in the higher quintilesof HDL-C valueshad betterpro-tection against ischemic stroke than thosein the lowest quintile. 31 In both studies,the benefit was the greatest againstlarge vessel atherosclerotic strokes. 30,31

The treatment of low HDL-C can bequite challenging. Therapeutic lifestylechanges, such as vigorous exercise, ad-

justment of alcohol intake, and weightloss, areknown to increase HDL-C.How-ever, these measures appear to be moreeffective in patients with preexistingnormal-high HDL-C and not as effec-tive in those with low HDL-C. 32 Targetgoals for HDL-C are not defined, butdrug treatment is recommended if HDL-C is less than 40 mg/dL, as illus-trated in Case 3-3 .

No studies have demonstrated a pro-tective role against stroke using either niacin or fibrates as monotherapy. Niacinhas primarily been studied in cardiovascular disease. When niacin combined with simvastatin was compared withplacebo in patients with CHD and low HDL-C, the combination treatment de-creased LDL-C by 42% and increasedHDL-C by 26%. The simvastatin-niacin

KEY POINTh Statins have a variety of

biologic effects inaddition to low-densitylipoprotein cholesterollowering.

Case 3-3A 58-year-old Asian woman with a history of diabetes and hypertensionexperienced the sudden onset of gait difficulty and right arm clumsiness. Abrain MRI revealed a right cerebellar infarct with right vertebral arteryocclusion. Her lipid profile was as follows: total cholesterol 180 mg/dL,low-density lipoprotein cholesterol (LDL-C) 98 mg/dL, high-density lipoproteincholesterol (HDL-C) 32 mg/dL, and triglycerides 160 mg/dL. After being startedon simvastatin 40 mg, her LDL-C improved to 74 mg/dL, but her HDL-C was30 mg/dL. She was started on niacin 1500 mg per day and her HDL-C improvedfrom 30 mg/dL to 46 mg/dL.

Comment . The patient has a low HDL-C level despite statin treatment.Therapy with niacin wouldbe reasonable. Clinical trials to assess whether niacinas an adjunct to statin treatment reduces cardiovascular events are in progress.


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group had a 90% reduction in clinicalevents, including stroke. 33 The secondand third Arterial Biology for theInvestigation of the Treatment Effectsof Reducing cholesterol (ARBITER-2 and ARBITER-3) studies randomized pa-tients taking statins at baseline (asmost stroke patients would) to receiveeither extended-release niacin or pla-cebo. At the end of 2 years, subjects tak-ing niacin had a 23% increase in HDL-Cand a significant atherosclerosis regres-sion of carotid intimal medial thickness. 34

A recent clinical trial studied the ef-

fect of adding extended-release niacinin patients with established vascular dis-ease who were already being treated with statins but had low HDL-C levels.Thetrial, theAtherothrombosisInterven-tion in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride andImpact on Global Health Outcomes(AIM-HIGH) study, was halted becauseof the lack of benefit seen with addingniacin to the lipid regimen. Further de-tails of the study have not been pub-lished at the time of this writing.

Fibrates are also effective in raisingHDL-C.However,in a head-to-headcom-parison study, niacin 2000 mg/d in-creased HDL-C more than gemfibrozil1200 mg/d, in addition to decreasingthe total cholesterol to HDL-C ratio andLp(a) levels. 35 A newer class of agents isbased on the cholesteryl ester transfer protein (CETP), which promotes thetransfer of cholesteryl esters fromHDL-C to other lipoproteins; the in-hibition of CETP raises HDL-C and de-

creases LDL-C. The first of the CETPinhibitors, torcetrapib, was tested in arandomized double-blind study of pa-tients at high cardiovascular risk. 36 At 12months, there was a 72.1% increase inHDL-C and a 24.9% decrease in LDL-Ccompared with baseline; however, thedrug also caused an increase in aldos-terone production, hypokalemia, signifi-cant blood pressure elevations, and a

25% increase in cardiovascular events. 36

Two other CETP inhibitors, anacetrapiband dalcetrapib, do not appear to havesuch toxicities and are currently under-going safety and efficacy trials.

LIPOPROTEIN(a)The ATP III regarded Lp(a) as an emerg-ing cardiovascular risk factor. A recentcollaborative evaluation of 24 cohortstudies has shown that Lp(a) is an in-dependent risk factor for ischemicstroke. 37 Structurally, Lp(a) comprisesan LDL-C moiety with two attached pro-

teins, apolipoprotein (a) and apolipo-protein B-100. 38 Lp(a), with its LDL-Cmoiety, is retained more avidly in the vessel wall than LDL-C, leading to itsproatherogenic tendency. Secondly, itinterferes with LDL-C Y clearing path- ways from the vessel wall. Third, apo-lipoprotein (a) is similar to plasminogen,and Lp(a) interferes with the physio-logic role of plasminogen, leading to aprothrombotic state. Finally, Lp(a) actsas a proinflammatory agent by bindingand accumulation of oxidized phospho-lipid molecules. 38

Target goals for Lp(a) have not beendefined. There appears to be a contin-uous increase in risk as levels of Lp(a)rise. 37 Levels higher than 30 mg/dLseem to correlate with poor prognosisin patients with established coronary artery disease, suggesting a role in prog-nostication for secondary preventioncases. 39 Lp(a) is believed to be geneti-cally determined and the influence of age, diet, or environment is uncertain.

Two therapies have been shown to beeffective in reducing Lp(a) levels: niacinand estrogen. The mechanism by whichniacin reduces Lp(a) levels is not under-stood, but it has been shown to reduceLp(a) levels by 36% to 38%. 40,41 Estro-gen is believed to upregulate LDL-Creceptor activity, leading to increasedLp(a) clearance. This is consistent withthe fact that postmenopausal women

KEY POINTh Studies are in progress

to determine whethermedications that raisehigh-density lipoproteincholesterol can reducemajor vascular events,including stroke.




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tend to have higher Lp(a) levels. Estro-gen therapy in these women tends toreduce Lp(a) levels. 42

EZETIMIBETrials evaluating ezetimibe therapy have not assessed hard clinical endpoints. A systematic reviewof 12 studiesusing ezetimibe as monotherapy founda modest 18.5% reduction in LDL-C, a3% elevation in HDL-C, and an 8% re-duction in triglyceride levels. Most stud-ies evaluated ezetimibe as combinationtherapy with other lipid-lowering agents. 43

In the Ezetimibe and Simvastatin inHypercholesterolemia Enhances Athero-sclerosis Regression (ENHANCE) study,the combination of simvastatin 80 mg/dand ezetimibe 10 mg/d was compared with simvastatin 80 mg/d. Combinationtherapy reduced LDL-C by 17% andhsCRP by 26%; however, carotid inti-mal medial thickness was the same inboth groups. 44 In the Simvastatin andEzetimibe in Aortic Stenosis (SEAS)trial, clinical end points were actually measured. The rates of ischemic car-diovascular events (a secondary endpoint) were lower in the combinationtherapygroup. 45 However,when partici-pants without coronary artery disease were analyzed, the modest 22% relativerisk reduction in ischemic events seen with the combination therapy was sim-ilar to the 24% risk reduction found inthe simvastatin monotherapy arm of the HPS. Until further data from large-scale randomized trials are available, itappears that adding ezetimibe does not

offer additional cardiovascular benefitover high-dose statin monotherapy. How-ever, ezetimibe alone or in combinationmay have a role in patients who are un-able to tolerate statins because of ad- verse effects.

REFERENCES1. Amarenco P, Labreuche J, Lavalle e P,

Touboul PJ. Statins in stroke prevention and

carotid atherosclerosis: systematic reviewand up-to-date meta-analysis. Stroke 2004;35(12):2902 Y 2909.

2. Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol inAdults. Executive summary of the thirdreport of the national cholesterol educationprogram (NCEP) Expert Panel on Detection,Evaluation, and Treatment of High BloodCholesterol in Adults (Adult TreatmentPanel III). JAMA 2001;285(19):2486 Y 2497.

3. Grundy SM, Cleeman JI, Merz CN, et al.Implications of recent clinical trials for theNational Cholesterol Education ProgramAdult Treatment Panel III Guidelines. J AmColl Cardiol 2004;44(3):720 Y 732.

4. LaRosa JC, Grundy SM, Waters DD, et al.

Intensive lipid lowering with atorvastatinin patients with stable coronary disease.N Engl J Med 2005;352(14):1425 Y 1435.

5. Furie KL, Kasner SE, Adams RJ, et al.Guidelines for the prevention of stroke inpatients with stroke or transient ischemicattack: a guideline for healthcareprofessionals from the American HeartAssociation/American Stroke Association.Stroke 2011;42(1):227 Y 276.

6. Ridker PM, Danielson E, Fonseca FA, et al.Rosuvastatin to prevent vascular events inmen and women with elevated C-reactiveprotein. N Engl J Med 2008;359(21):2195 Y 2207.

7. Everett BM, Glynn RJ, MacFadyen JG,Ridker PM. Rosuvastatin in the prevention ofstroke among men and women withelevated levels of C-reactive protein:Justification for the Use of Statins inPrevention: an Intervention Trial EvaluatingRosuvastatin (JUPITER). Circulation 2010;121(1):143 Y 150.

8. Glynn RJ, Koenig W, Nordestgaard BG, et al.Rosuvastatin for primary prevention inolder persons with elevated C-reactiveprotein and low to average low-densitylipoprotein cholesterol levels: exploratoryanalysis of a randomized trial. Ann InternMed 2010;152(8):488 Y 496, W174.

9. Ridker PM, MacFadyen JG, Fonseca FA, et al.Number needed to treat with rosuvastatinto prevent first cardiovascular events anddeath among men and women with lowlow-density lipoprotein cholesterol andelevated high-sensitivity C-reactive protein:Justification for the Use of Statins inPrevention: an Intervention Trial EvaluatingRosuvastatin (JUPITER). Circ CardiovascQual Outcomes 2009;2(6):616 Y 623.

10. Ridker PM, Danielson E, Fonseca FA, et al.Reduction in C-reactive protein and LDL


Dyslipidemia



12/13

cholesterol and cardiovascular event ratesafter initiation of rosuvastatin: a prospectivestudy of the JUPITER trial. Lancet 2009;373(9670):1175 Y 1182.

11. Michos ED, Blumenthal RS. Prevalence oflow low-density lipoprotein cholesterol withelevated high sensitivity C-reactive proteinin the U.S.: implications of the JUPITER(Justification for the Use of Statins inPrimary Prevention: An Intervention TrialEvaluating Rosuvastatin) study. J Am CollCardiol 2009;53(11):931 Y 935.

12. Slejko JF, Page RL 2nd, Sullivan PW.Cost-effectiveness of statin therapy forvascular event prevention in adults withelevated C-reactive protein: implications ofJUPITER. Curr Med Res Opin 2010;26(10):2485 Y 2497.

13. Ohsfeldt RL, Gandhi SK, Smolen LJ, et al.Cost effectiveness of rosuvastatin in patientsat risk of cardiovascular disease based onfindings from the JUPITER trial. J Med Econ2010;13(3):428 Y 437.

14. Genest J, McPherson R, Frohlich J, et al. 2009Canadian Cardiovascular Society/Canadianguidelines for the diagnosis and treatmentof dyslipidemia and prevention ofcardiovascular disease in the adult-2009recommendations. Can J Cardiol 2009;25(10):567 Y 579.

15. Scandinavian Simvastatin Survival StudyGroup. Randomised trial of cholesterollowering in 4444 patients with coronaryheart disease: the Scandinavian SimvastatinSurvival Study (4S). Lancet 1994;344(8934):1383 Y 1389.

16. Sacks FM, Pfeffer MA, Moye LA, et al. Theeffect of pravastatin on coronary eventsafter myocardial infarction in patients withaverage cholesterol levels. Cholesterol andRecurrent Events Trial investigators. N EnglJ Med 1996;335(14):1001 Y 1009.

17. Athyros VG, Papageorgiou AA, MercourisBR, et al. Treatment with atorvastatin to theNational Cholesterol Educational Programgoal versus usual care in secondarycoronary heart disease prevention. The GREekAtorvastatin and Coronary-heart-diseaseEvaluation (GREACE) study. Curr Med ResOpin 2002;18(4):220 Y 228.

18. The Long-Term Intervention withPravastatin in Ischaemic Disease (LIPID)Study Group. Prevention of cardiovascularevents and death with pravastatin inpatients with coronary heart disease and abroad range of initial cholesterol levels.N Engl J Med 1998;339(19):1349 Y 1357.

19. Keech A, Colquhoun D, Best J, et al.Secondary prevention of cardiovascular

events with long-term pravastatin inpatients with diabetes or impaired fastingglucose: results from the LIPID trial. DiabetesCare 2003;26(10):2713 Y 2721.

20. Schwartz GG, Olsson AG, Ezekowitz MD,et al. Effects of atorvastatin on earlyrecurrent ischemic events in acute coronarysyndromes: the MIRACL study: a randomizedcontrolled trial. JAMA 2001;285(13):1711 Y 1718.

21. Collins R, Armitage J, Parish S, et al. Effectsof cholesterol-lowering with simvastatin onstroke and other major vascular events in20536 people with cerebrovascular diseaseor other high-risk conditions. Lancet 2004;363(9411):757 Y 767.

22. Amarenco P, Bogousslavsky J, Callahan A 3rd,

et al. High-dose atorvastatin after stroke ortransient ischemic attack. N Engl J Med2006;355(6):549 Y 559.

23. Chaturvedi S, Zivin J, Breazna A, et al. Effectof atorvastatin in elderly patients with arecent stroke or transient ischemic attack.Neurology 2009;72(8):688 Y 694.

24. Goldstein LB, Amarenco P, Zivin J, et al.Statin treatment and stroke outcome in theStroke Prevention by Aggressive Reductionin Cholesterol Levels (SPARCL) trial. Stroke2009;40(11):3526 Y 3531.

25. Iso H, Jacobs DR Jr, Wentworth D, et al.Serum cholesterol levels and six-yearmortality from stroke in 350,977 men

screened for the multiple risk factorintervention trial. N Engl J Med 1989;320(14):904 Y 910.

26. Sturgeon JD, Folsom AR, Longstreth WT Jr,et al. Risk factors for intracerebral hemorrhagein a pooled prospective study. Stroke 2007;38(10):2718 Y 2725.

27. Goldstein LB, Amarenco P, Szarek M, et al.Hemorrhagic stroke in the Stroke Preventionby Aggressive Reduction in CholesterolLevels study. Neurology 2008;70(24 pt 2):2364 Y 2370.

28. Jones PH, Davidson MH, Stein EA, et al.Comparison of the efficacy and safety ofrosuvastatin versus atorvastatin, simvastatin,and pravastatin across doses (STELLAR*Trial). Am J Cardiol 2003;92(2):152 Y 160.

29. Pezzini A, Del Zotto E, Volonghi I, et al.New insights into the pleiotropic effects ofstatins for stroke prevention. Mini RevMed Chem 2009;9(7):794 Y 804.

30. Sacco RL, Benson RT, Kargman DE, et al.High-density lipoprotein cholesterol andischemic stroke in the elderly: the NorthernManhattan Stroke Study. JAMA 2001;285(21):2729 Y 2735.




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31. Tirschwell DL, Smith NL, Heckbert SR, et al.Association of cholesterol with stroke riskvaries in stroke subtypes and patientsubgroups. Neurology 2004;63(10):1868 Y 1875.

32. Williams PT. The relationships of vigorousexercise, alcohol, and adiposity to low andhigh high-density lipoprotein-cholesterollevels. Metabolism 2004;53(6):700 Y 709.

33. Brown BG, Zhao XQ, Chait A, et al.Simvastatin and niacin, antioxidant vitamins,or the combination for the prevention ofcoronary disease. N Engl J Med 2001;345(22):1583 Y 1592.

34. Taylor AJ, Lee HJ, Sullenberger LE. Theeffect of 24 months of combination statinand extended-release niacin on carotidintima-media thickness: ARBITER 3. Curr

Med Res Opin 2006;22(11):2243 Y

2250.35. Guyton JR, Blazing MA, Hagar J, et al.

Extended-release niacin vs gemfibrozil forthe treatment of low levels of high-densitylipoprotein cholesterol. Niaspan-GemfibrozilStudy Group. Arch Intern Med 2000;160(8):1177 Y 1184.

36. Barter PJ, Caulfield M, Eriksson M, et al.Effects of torcetrapib in patients at high riskfor coronary events. N Engl J Med 2007;357(21):2109 Y 2122.

37. Emerging Risk Factors Collaboration; ErqouS, Kaptoge S, Perry PL, et al. Lipoprotein(a)concentration and the risk of coronary heartdisease, stroke, and nonvascular mortality.

JAMA 2009;302(4):412 Y 423.38. Anuurad E, Enkhmaa B, Berglund L.

Enigmatic role of lipoprotein(a) in

cardiovascular disease. Clin Transl Sci 2010;3(6):327 Y 332.

39. Glader CA, Birgander LS, Stenlund H,Dahlen GH. Is lipoprotein(a) a predictor forsurvival in patients with establishedcoronary artery disease? Results from aprospective patient cohort study in northernSweden. J Intern Med 2002;252(1):27 Y 35.

40. Guyton JR, Goldberg AC, Kreisberg RA, et al.Effectiveness of once-nightly dosing ofextended-release niacin alone and incombination for hypercholesterolemia.Am J Cardiol 1998;82(6):737 Y 743.

41. Pan J, Van JT, Chan E, et al. Extended-releaseniacin treatment of the atherogenic lipidprofile and lipoprotein(a) in diabetes.Metabolism 2002;51(9):1120 Y 1127.

42. Shlipak MG, Simon JA, Vittinghoff E, et al.Estrogen and progestin, lipoprotein(a),and the risk of recurrent coronary heartdisease events after menopause. JAMA 2000;283(14):1845 Y 1852.

43. Pandor A, Ara RM, Tumur I, et al. Ezetimibemonotherapy for cholesterol lowering in2,722 people: systematic review andmeta-analysis of randomized controlledtrials. J Intern Med 2009;265(5):568 Y 580.

44. Kastelein JJ, Akdim F, Stroes ES, et al.Simvastatin with or without ezetimibe infamilial hypercholesterolemia. N Engl J Med2008;358(14):1431 Y 1443.

45. Rosseb AB, Pedersen TR, Boman K, et al.Intensive lipid lowering with simvastatin andezetimibe in aortic stenosis. N Engl J Med2008;359(13):1343 Y 1356.


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