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For which of the following conditions has cholesterol-lowering
been shown to possibly raise risk?
1. Myocardial infarction
2. Myocardial infarction in patients with moderate cholesterol levels
3. Ischemic stroke
4. Hemorrhagic stroke
Clinical Context
Elevated cholesterol levels can play an important role in cardiovascular
disease, and lowering these levels has been proven to reduce cardiovascular
morbidity and mortality, even among patients with moderate levels of
hypercholesterolemia. Although data regarding the relationship between
hypercholesterolemia and stroke are less robust, there is some suggestion
that reducing cholesterol can reduce ischemic stroke. However, the authors
of the current study note that this possible benefit must be weighed
against some evidence suggesting that lowering cholesterol levels may
increase the risk of hemorrhagic stroke, particularly among patients
with elevated blood pressure.
Evidence from studies examining atherosclerotic disease outcomes has
supported the use of statin drugs in the prevention of stroke. In a
prospective trial by White and colleagues of 9,014 patients with coronary
artery disease, pravastatin reduced the risk of ischemic stroke by 23%.
The study, published in the August 2000 issue of the New England Journal
of Medicine, also demonstrated that the risk of hemorrhagic stroke was
low overall and not altered with pravastatin treatment.
The authors of the current study used a large community-based population
sample to further elaborate the efficacy of statins in reducing the
risk of cerebrovascular disease.
Study Highlights
*** Patients were involved in the Heart Protection Study. All were between
40 and 80 years old and had cholesterol levels of at least 135 mg/dL.
They also had a history of cerebrovascular disease, coronary artery
disease, other arterial disease, diabetes, or hypertension. Patients
were excluded from participation if they had a history of vascular event
within 6 months of enrollment, chronic renal or liver disease, or severe
congestive heart failure.
*** Participants were randomized to receive either simvastatin 40 mg
daily or matching placebo. They were followed for 5 years at several
clinic visits during the first year, and then semi-annually.
*** The main study outcome was the combined outcome of nonfatal myocardial
infarction or coronary death, stroke, or any revascularization procedure.
The authors of the current study paid particular attention to stroke,
which was defined as a neurologic event lasting more than 24 hours.
Subjects were also followed for transient ischemic attack, carotid events,
cognitive function, and neuropathy.
*** 20,536 high-risk patients were recruited to participate in the study,
of whom 3,280 had a history of cerebrovascular disease. Of the subgroup
with cerebrovascular disease, 63% had a history of stroke, and 46% had
a history of transient ischemic attack.
*** Compliance with simvastatin treatment was 85%. 17% of the placebo
group started statin therapy during the intervention period.
*** Simvastatin produced a 24% relative reduction in the first occurrence
of nonfatal myocardial infarction or coronary death. The reduction of
cardiovascular events was similar between study subgroups of patients
with a history of cerebrovascular disease or other high-risk conditions
(20% and 25%, respectively).
*** The simvastatin group also had a 25% reduced overall rate of stroke
compared with the placebo group. This effect on stroke was statistically
significant by year 2 of the study. The positive effect of simvastatin
on stroke risk was limited to ischemic strokes; hemorrhagic strokes
were rare and occurred at similar frequencies in both treatment groups.
*** Of subjects with a previous history of stroke, simvastatin was not
protective in preventing another stroke compared with placebo.
*** A 39 mg/dL reduction in cholesterol level with simvastatin protected
14 of 1,000 subjects from stroke.
*** The reduction in stroke was similar among patients with various
atherosclerotic risk factors, including coronary disease and diabetes.
The results were also significant for subjects with cholesterol levels
as low as 100 mg/dL.
*** Rates of carotid endarterectomy or angioplasty were twice as high
in the placebo group compared with the simvastatin group. Simvastatin
was particularly protective regarding these outcomes in subjects with
a previous history of cerebrovascular disease.
*** Episodes of transient cerebral ischemia were reduced by 17% in the
simvastatin group compared with placebo.
*** There was no difference between the placebo and simvastatin groups
in cognitive function or neuropathy complications.
*** Given that compliance with the study protocol was not 100% in either
the simvastatin or placebo groups, the authors estimate that the relative
risk reduction for stroke with simvastatin may be underestimated in
the current study. They state that the relative risk reduction could
be up to one third in subjects with perfect compliance.
Pearls for Practice
*** Research has established cholesterol's effects in promoting cardiovascular
disease, but its role in cerebrovascular disease, especially whether
statins can improve cerebrovascular outcomes, is less clear.
*** Simvastatin seems effective in reducing cerebrovascular outcomes
in high-risk individuals. However, it may not be as effective in this
regard in patients with a prior history of stroke.
Lancet. 2004;363:757-67
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