Published online before print April 22, 2004, doi: 10.1161/01.STR.0000130460.09807.ec
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(Stroke. 2004;35:1523.)
© 2004 American Heart Association, Inc.
Controversies in Stroke |
Cholesterol as a Risk Factor for Stroke
The Fugitive?
omiej Piechowski-Jó
wiak, MDFrom the Department of Neurology, Centre Hospitalier Univ Vaudois, Lausanne, Switzerland.
Correspondence to Julien Bogousslavsky, MD, Cerebrovascular Diseases Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Email julien.bogousslavsky{at}chuv.hospvd.ch
Key Words: stroke • incidence • lipid-lowering therapy • statins
The burden of stroke is unquestionable in a myriad of aspects. Multiple stroke risk factors are known, and some of them are considered strong and primary while others are considered uncertain and secondary. Among the latter, there is hyperlipidemia. As the acute stroke treatment is costly, the saying that prevention is better than treatment bears a special meaning here. In this discussion, as prosecutors from our bar we stand to plead, "Cholesterol – guilty for stroke."
Several epidemiological studies demonstrated a correlation between increased blood total cholesterol levels and risk of myocardial infarction.1,2 The association between cholesterol levels and stroke occurrence is debated in the literature. In the Framingham cohort no connection was found between the levels of cholesterol and the incidence of stroke.1 Nonetheless, in young women, a positive correlation between total cholesterol levels and stroke-related mortality was observed, while in subjects in 6th and 7th decade of age, an inverse correlation between these parameters was found.3 The combined analysis of cohort trials showed no significant association between the increased level of serum cholesterol and stroke rate, except for patients younger than 45 years.4 However, this analysis did not stratify into stroke subgroups and thus a positive association with ischemic stroke might be offset by a negative association with hemorrhagic stroke. This was confirmed in a longitudinal study on men screened for multiple risk factors, as a positive correlation between total cholesterol levels and ischemic stroke risk, and a negative association between cholesterol level and occurrence of all hemorrhagic strokes was demonstrated. Serum cholesterol levels under 4.14 mmol/L increased the risk of fatal intracranial hemorrhage while the levels above 7.23 mmol/L increased the risk of death from ischemic stroke.5 An overview of Asian subjects showed a trend toward increased risk of hemorrhagic stroke and decreased risk of ischemic stroke in subjects with decreased cholesterol level.6 A positive correlation between very high total cholesterol levels >8 mmol/L, and the risk of nonhemorrhagic stroke was demonstrated in a prospective community based study.7 At this point we can state that there is indeed a convincing point for elevated cholesterol levels to be linked with increased risk of ischemic stroke. The reasons for not finding the clear-cut relationship between cholesterol level and stroke occurrence may be multiple. The longitudinal cohort studies were predestined to evaluate the role of cholesterol in coronary atherosclerosis, but not to investigate its role in stroke. Therefore, by selecting middle-aged subjects for cardiac studies, the older subjects, who were more susceptible to cerebral infarction, were undoubtedly lost. Moreover, analysis of the occurrence of stroke subtypes and differentiation between cholesterol components was not done. Additionally, the prophylactic treatment used might also influence the incidence of stroke.
While there may be some missing epidemiological evidence for the correlation between hypercholesterolemia and stroke occurrence, should we stop at this point and set our defendant free? With some circumstantial evidence we would like to prove its guilt.
The Heart Protection Study tested the effectiveness of simvastatin in patients with coronary disease, other occlusive disease, or diabetes in conjunction with LDL cholesterol levels at least 3.5 mmol/L.8 A 24% reduction in the rate of all-cause mortality and fatal or nonfatal vascular events between simvastatin and placebo groups was shown. There was a 25% reduction in the all-cause stroke incidence rate and a 30% reduction in the ischemic stroke incidence rate. Transient ischemic attacks were also significantly less frequent in the simvastatin versus placebo group (2% versus 2.4%). In this trial, there was a subgroup of patients with the history of cerebrovascular disease without coronary heart disease. However, there was no stratification for the past medical events, thus yielding the interpretation of the effects of simvastatin in subgroups untrustworthy. In this subgroup, a 21% relative risk reduction of major vascular events was demonstrated. However, no effect of simvastatin on stroke recurrence was observed.
A few meta-analyses on lipid-lowering therapy and coronary prevention were published in the past decade. The most recent one included all randomized trials, published between 1966 and 2001, testing statins, resins, fibrates, niacin, surgical interventions, and diet.9 There were 10 primary and 28 secondary prevention trials. This analysis showed a significant (17%) relative risk reduction of stroke incidence. There was no significant heterogeneity between trials either in intervention tested (primary versus secondary prevention) or type of lipid-lowering therapy examined. When analyzing subgroups, only statins yielded a significant (24%) relative risk reduction of stroke. When analyzing by type of intervention, the significant effect of statins on stroke incidence was present only in secondary prevention, with a 26% relative risk reduction of stroke. However, the incidence of fatal strokes was not influenced by lipid-lowering therapy. Lipid-lowering therapy did not change the incidence of hemorrhagic stroke. A strong evidence for the role of cholesterol in stroke comes with the documented correlation of stroke incidence and the degree of cholesterol reduction, baseline cholesterol level, and final cholesterol level. The final cholesterol level of 
6 mmol/L, achieved with lipid-lowering therapy, separated between absence and presence of stroke risk reduction and thus exposed an accused correlation between elevated serum cholesterol levels and reduction of stroke incidence.
Is elevated cholesterol a risk factor for stroke? While the evidence is mostly indirect for stroke, it is not disputable for coronary heart disease. This must be remembered when patient management is addressed, since prevention of atherothrombotic events should be a global effort.
Footnotes
Section Editors: Geoffrey A. Donnan, MD, FRACP, and Stephen M. Davis, MD, FRACP
Received February 24, 2004; accepted February 24, 2004.
References
1. Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and risk of coronary heart disease. The Framingham Study. Ann Epidemiol. 1992; 2: 23–28.[Medline] [Order article via Infotrieve]
2. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993; 16: 434–444.[Abstract]
3. Emond MJ, Zareba W. Prognostic value of cholesterol in women of different ages. J Women Health. 1997; 6: 295–307.[Medline] [Order article via Infotrieve]
4. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts. Lancet. 1995; 346: 1647–1653.[CrossRef][Medline] [Order article via Infotrieve]
5. Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350 977 men screened for the Multiple Risk Factors Interventional Trial. N Engl J Med. 1989; 320: 904–910.[Abstract]
6. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol, and stroke in eastern Asia. Lancet. 1998; 352: 1801–1807.[CrossRef][Medline] [Order article via Infotrieve]
7. Lindenstrom E, Boysen G, Nyobe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. BMJ. 1994; 309: 11–15.
8. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002; 360: 7–22.[CrossRef][Medline] [Order article via Infotrieve]
9. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, Lechat P. Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med. 2003; 163: 669–676.
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