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CMDManagement™ Newsletters

DON’T FORGET
YOUR PATIENTS!
See page 5 for Considering Cholesterol, our patient-education tool. Photocopy and distribute this handy, plain-language summary of information. The more informed your patients are, the less challenging they are to treat.

This issue's article: Know Your Numbers!


REMEMBER–
LipidManagement™ is certified for CME credit–
see page 3.





Antonio M. Gotto, Jr, MD, DPhil
Joan and Sanford I. Weill Medical
   College of Cornell University

Elizabeth Barrett-Connor, MD
University of California, San Diego,
   School of Medicine

Peter Ganz, MD
Harvard Medical School
Brigham and Women's Hospital

Scott M. Grundy, MD, PhD
University of Texas Southwestern
   Medical Center at Dallas

Steven M. Haffner, MD
University of Texas Health Science Center

 Donald B. Hunninghake, MD
University of Minnesota Medical School

 Ronald M. Krauss, MD
Lawrence Berkeley National Laboratory
University of California, Berkeley

 John C. LaRosa, MD
SUNY Downstate Medical Center

 Peter Libby, MD
Harvard Medical School
Brigham and Women's Hospital

 Harry L. Metcalf, MD
SUNY/Buffalo School of Medicine and
   Biomedical Sciences

Copyright © 2002 Thomson Professional Postgraduate Services® (PPS), 150 Meadowlands Parkway, Secaucus, NJ 07094-2304 USA. All rights reserved.

This material may not be reproduced without the express written permission of PPS. LipidManagement™ is an educational initiative of the National Lipid Education Council™. NLEC, National Lipid Education Council and LipidManagement are trademarks used herein under license.



Supported by an unrestricted educational grant from Pfizer Inc


 
Related information on this website:
In the Slide Library section:
Effect of Cholesterol Lowering on Stroke Events: a Meta-analysis of Statin Trials

Effects of Statins on Stroke Events: A Meta-analysis of Primary- and Secondary-Prevention Trials

HPS: Effects of Simvastatin on First Major Vascular Event

HERS: Risk of Cerebrovascular Disease Events

MIRACL: Fatal or Nonfatal Stroke

In the Newsletter section:
Case Study: Patient With a Family History of Stroke

In the Current Literature section:
Effects of Atorvastatin on Stroke in Patients With Unstable Angina or Non–Q-Wave Myocardial Infarction: A Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Substudy.
Waters DD, Schwartz GG, Olsson AG, et al, for the MIRACL Study Investigators.
Circulation. 2002;106:1690-1695.

Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER): A Randomised Controlled Trial.
Shepherd J, Blauw GJ, Murphy MB, et al, on behalf of the PROSPER study group.
Lancet. 2002;360:1623-1630.
The Cholesterol/ Stroke Connection

More than a half million people in the United States experience a new or recurrent stroke every year,1 and about one fifth of them die.2 In fact, stroke is the third leading cause of death in this country, following heart disease and cancer, and it is the leading cause of serious long-term disability in adults.1,2 More than 80% of strokes are classified as ischemic.3

While hypercholesterolemia is an established risk factor for heart disease, evidence regarding a similar link between cholesterol and stroke is not consistent.4,5 The reasons for this apparent discrepancy may be biologic (eg, inherent differences in the cerebral vasculature) or methodologic. The term “stroke” represents a heterogeneous group of cerebrovascular disorders, yet epidemiologic studies often do not differentiate among stroke or cholesterol subtypes. Also, cerebral atherosclerosis occurs later in life than coronary atherosclerosis, yet data on stroke often come from studies involving middle-aged populations. Consequently, the small number of events may disguise the potential statistical significance of the relationship.4,6
    In the major trials of HMG-CoA reductase inhibitors (statins), stroke was not a primary end point. Still, these studies do show that lipid-lowering therapy can reduce the incidence of stroke in patients with coronary heart disease (CHD) or CHD risk equivalents (ie, prior stroke, other noncoronary atherosclerotic disease, or diabetes).6,7 Randomized double-blind clinical trials with stroke as a primary end point are needed to confirm these results and also to determine whether lipid lowering can reduce the incidence of stroke in individuals without established cardiovascular disease.
    Currently, pravastatin and simvastatin are approved for the prevention of stroke/transient ischemic attack (TIA) in patients with CHD.8,9

Noting the Differences Between Types of Stroke
Strokes are either ischemic, occurring when blood flow in an artery supplying the brain is blocked, or hemorrhagic, occurring when a blood vessel in the brain leaks or ruptures.1,2
Ischemic: 83% of all strokes; 7.6% 30-day mortality3
Hemorrhagic: 17% of all strokes; 37.5% 30-day mortality3

Ischemic. Most of these strokes are classified as embolic or thrombotic. Embolic strokes occur when a blood clot or small piece of plaque or vegetation (ie, an embolus) travels through the bloodstream to the brain, where it lodges in one of the smaller cerebral arteries, blocking blood flow.1,2 Thrombotic strokes develop when a blood clot (ie, a thrombus) forms in an area of atherosclerosis in a carotid, vertebral, or cerebral artery and blocks blood flow to or within the brain.1,2 Thrombotic strokes are 2.5 times more common than embolic strokes.3

Hemorrhagic. These strokes may be caused by various disorders affecting the cerebral blood vessels, including chronic hypertension and aneurysms.1 Hemorrhagic strokes are either subarachnoid or intracerebral: In the former, an aneurysm bursts in a large artery on or near the meninges; in the latter, bleeding occurs from vessels within the brain itself.1 The most common cause of an intracerebral hemorrhagic stroke is uncontrolled hypertension.2

REFERENCES
1. www.stroke.org/pages/whats_typesof.cfm?category=all.
2. www.mayoclinic.com/findinformation/conditioncenters/
invoke.cfm?objectid=487C3.
3. American Heart Association. 2002 Heart and Stroke Statistical Update. 2002:14-15.

Risk Factors
Risk factors for stroke that cannot be controlled or modified include older age (two thirds of strokes occur in persons older than 65 years), male sex, black race, and a family history of stroke or TIA.10 Other stroke risk factors, some of which are potentially modifiable, include:
prior history of stroke/TIA2
hypertension and atrial fibrillation10
hypercholesterolemia10
congestive heart failure, prior myocardial infarction (MI), endocarditis, aortic valve disease2
diabetes10,11
sleep apnea10
elevated homocysteine level2,4,12
use of oral contraceptives2
smoking, heaving drinking, overweight/ obesity, use of illicit drugs2

Risk Markers
Certain plasma proteins and apolipoproteins (APOs) may serve as markers for stroke risk. The Physicians’ Health Study, which followed 1,086 apparently healthy men for 8 years, found that subjects with the highest levels of C-reactive protein (CRP), a marker for inflammation, were twice as likely as those with the lowest CRP levels to have a stroke.13 This increased risk was independent of other nonlipid and lipid risk factors. A prospective study of 137 patients scheduled for elective carotid endarterectomy revealed that CRP concentrations were significantly higher in the subgroup of 125 patients who had cerebrovascular symptoms than they were in the 12 patients who were asymptomatic (3.9 vs 2.1 mg/L).14 Finally, an investigation of a possible link between plasma APOs and stroke in 3,696 participants in the Third National Health and Nutrition Examination Survey (NHANES III) showed that an APO A-1 to APO B ratio greater than 1.59, relative to a ratio less than 1.04, was associated with a lesser likelihood of stroke and MI.15 The investigators concluded that a higher APO A-1 to APO B ratio may represent an important protective clinical marker for atherosclerosis.

Cholesterol-Lowering and Stroke Risk
In an Israeli study, researchers followed 11,177 patients with documented CHD, but no history of stroke, for 6 to 8 years and identified 941 patients who developed nonhemorrhagic cerebrovascular disease (487 had a verified ischemic stroke/TIA).16 The researchers found a positive correlation between stroke/TIA risk and both TC and LDL-C, as well as an inverse correlation between stroke/TIA risk and HDL-C. The Women’s Pooling Project, a longitudinal prospective cohort study of 24,343 women with no previous cardiovascular disease, found that, among women younger than 55 years at baseline, those whose TC levels were in the highest quintile (relative to those whose levels were in the lowest quintile) were 2.13 times more likely to die of a nonhemorrhagic stroke.5 However, these studies do not include patients with prior stroke, and there is limited or no analysis of the relation between cholesterol levels and specific stroke subtypes.
    Several clinical trials have addressed issues raised by the use of lipid-lowering therapy to reduce the risk for stroke:
    Heart Protection Study. In this study, 20,536 patients aged 40 to 80 years with CHD or a CHD risk equivalent and a TC level of at least 135 mg/dL were randomized to receive simvastatin 40 mg daily or placebo for 5 years.17 At the end of the study, LDL-C levels were an average of 39 mg/dL lower in the simvastatin group than in the placebo group. There was also a 25% reduction in the incidence of first stroke, a secondary end point. This benefit was due mainly to a reduction in ischemic stroke; simvastatin treatment did not affect the rate of hemorrhagic stroke. Also, simvastatin use significantly reduced TIA risk by about 17%.17
    MIRACL. Statin therapy was linked to a significant 51% reduction in fatal/nonfatal stroke, although wide confidence intervals were noted, in a subanalysis of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering study. In MIRACL, 3,086 patients with unstable angina or non–Q-wave MI and a TC level of 270 mg/dL or lower18 were randomized to receive atorvastatin 80 mg daily or placebo. Treatment was begun 24 to 96 hours after hospital admission and continued for 16 weeks. In the atorvastatin group, LDL-C was reduced by 40% from baseline to a mean of 72 mg/dL. Most strokes were ischemic; the three strokes categorized as definitely hemorrhagic occurred in the placebo group.18 The absolute number of cerebrovascular events was small (12 in the atorvastatin group and 24 in the placebo group); as stated by the authors, study results must be confirmed in randomized, placebo-controlled trials.
    Other Trials. Data from three major secondary-prevention statin trials (Scandinavian Simvastatin Survival Study [4S], Cholesterol and Recurrent Events [CARE], Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID]) show a 19% to 29% reduction in the incidence of stroke, with no increase in risk for a hemorrhagic event.7 This is consistent with results of the Prospective Pravastatin Pooling (PPP) Project, in which the combined CARE and LIPID data show a significant 22% reduction in the incidence of total stroke and a 23% decrease in risk for nonhemorrhagic stroke with pravastatin therapy. A separate analysis of the primary-prevention West of Scotland Coronary Prevention Study (WOSCOPS), also included in the PPP, found no clear overall benefit associated with pravastatin.19

National Guidelines
Considering that hypertension is the most prevalent and modifiable risk factor for stroke, lowering blood pressure substantially decreases the incidence of a first ischemic or hemorrhagic event.20,21
    The National Stroke Association (NSA) and the Stroke Council of the American Heart Association have issued guidelines for the prevention of ischemic stroke. For primary prevention, both support regular screening for hypertension and comprehensive management as recommended by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.12,20 In patients with elevated cholesterol, the Stroke Council also recommends following the National Cholesterol Education Program (NCEP) guidelines, with consideration given to statin therapy when CHD is present. Hormone replacement therapy in postmenopausal women is not recommended for reducing cardiovascular risk. In the recent Women’s Health Initiative study, estrogen plus progestin increased the risk for fatal and nonfatal stroke by 41%, though the types of strokes were not differentiated.22
    To prevent a first stroke in patients with established coronary disease (including a prior MI), antihypertensive medication, an oral anticoagulant (ie, warfarin), and a statin are therapeutic options.12,20 For patients with a history of stroke or noncoronary atherosclerosis (ie, CHD risk equivalents) but without established CHD, the NSA recommends following the NCEP guidelines for dietary or drug treatment.20 According to the guidelines, patients with CHD or CHD risk equivalents should achieve an LDL-C goal <100 mg/dL, with the use of lipid-lowering therapy as needed.23
    Weight loss, limited alcohol intake, smoking cessation, and exercise are also important in decreasing the risk for stroke.12

Role of Statins
In addition to lowering TC and LDL-C, statins appear to have anti-inflammatory, antithrombotic, and antioxidant properties24 that may improve outcomes in patients at high risk for ischemic stroke/TIA.
Inflammation, which contributes to the atherosclerotic process, may be a risk factor for stroke. Statins appear to reduce the level of CRP, an acute-phase reactant, although it is not clear whether CRP contributes to vascular disease or is a marker of vascular risk.2,12
Statins may also preserve or restore blood flow to the area of cerebral infarct. This neuroprotective effect may be mediated by inhibition of isoprenoid synthesis in the cholesterol biosynthesis pathway, which leads to upregulation of endothelial nitric oxide synthase, a vasodilator.24,25
By reducing the risk for coronary disease, statins may decrease the incidence of cardioembolic stroke.2
    An ongoing study, SPARCL (Stroke Prevention by Aggressive Reduction of Cholesterol Levels), is the first to test the effects of intensive lipid-lowering therapy (atorvastatin 80 mg daily) as secondary prevention in patients who have had a prior stroke/TIA but no history of CHD.26

Conclusion
A stroke occurs approximately every 53 seconds in the United States.26 Many cerebrovascular events may be preventable with lifestyle changes and pharmacologic intervention. Lipid-lowering therapy—along with antihypertensive, antithrombotic, and antiplatelet medications as indicated—may represent a unique approach toward that goal.

References*
1. www.americanheart.org/presenter.jhtml.
2. www.mayoclinic.com/findinformation/conditioncenters/
invoke.cfm?objectid=487C3.
3. American Heart Association. 2002 Heart and Stroke Statistical Update. 2002:14-15.
4. Gorelick PB. Stroke. 2002;33:862-875.
5. Horenstein RB, Smith DE, et al. Stroke. 2002;33:1863-1868.
6. Demchuk AM, Hess DC, et al. Arch Neurol. 1999;56:1518-1520.
7. Gotto AM Jr, Farmer JA. Circulation. 2002;106:1595-1598.
8. Pravachol® (pravastatin sodium) tablets [package insert]. Bristol-Myers Squibb Company. Revised May 2002.
9. Zocor® (simvastatin) tablets. Merck & Co., Inc. Issued May 2002.
10. www.stroke.org/stroke_risk.cfm.
11. Cucchiara BL, Kasner SE. Curr Treat Options Neurol. 2002;4:445-453.
12. Goldstein LB, Adams R, et al. Circulation. 2001;103:163-182.
13. Ridker PM, Cushman M, et al. N Engl J Med. 1997;336:973-979.
14. Rerkasem K, Shearman CP, et al. Eur J Vasc Endovasc Surg. 2002;23:505-509.
15. Qureshi A, Giles W, et al. Med Sci Monit. 2002;8:CR311-316.
16. Koren-Morag N, Tanne D, et al. Arch Intern Med. 2002;162:993-999.
17. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
18. Waters DD, Schwartz GG, et al. Circulation. 2002;106:1690-1695.
19. Byington RP, Davis BR, et al. Circulation. 2001;103:387-392.
20. Gorelick PB, Sacco RL, et al. JAMA. 1999;28:1112-1120.
21. Straus SE, Majumdar SR, et al. JAMA. 2002;288:1388-1395.
22. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.
23. 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;285:2486-2497.
24. Vaughan CJ, Delanty N, et al. CNS Drugs. 2001;15:589-596.
25. Liao JK. Atheroscler Suppl. 2002:3:21-25.
26. Callahan A. Am J Cardiol. 2001;88:33J-37J.

*For complete listing of references, please click here.

This article was reviewed for medical accuracy by Antonio M. Gotto, Jr, MD, DPhil, chairman of the National Lipid Education Council™. Dr Gotto has indicated a financial interest or affiliation as noted: consultant for AstraZeneca, Bayer Corporation, Bristol-Myers Squibb Company, Merck & Co., Inc., Pfizer Inc, and Reliant Pharmaceuticals.