Nikolai Anichkov first proposed a link between cholesterol and atherosclerosis in 1912.1 Decades later observational studies have incontrovertibly established hyperlipidemia as an independent risk factor for coronary artery disease, the nation's leading cause of death. The link between hyperlipidemia and the nation's third leading cause of death, stroke, was more difficult to establish.2 The difficulty arose in part because of the heterogeneous nature of stroke. To investigate a possible etiologic relationship between hyperlipidemia and stroke, it became essential to distinguish ischemic from hemorrhagic stroke. It now appears likely that hyperlipidemia is an independent risk factor for ischemic stroke.3
The enzyme involved in the rate limiting step in the synthesis of cholesterol is 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Drugs have recently been made available that inhibit HMG-CoA reductase. Atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mevacor®), pravastatin (Pravachol®), and simvastatin (Zocor®) are all HMG-CoA reductase inhibitors. They are often collectively referred to as the statins. Large randomized trials of statins for primary and secondary prevention of coronary artery disease prospectively included stroke among several study endpoints. Statins consistently have shown an ability to reduce the incidence of ischemic stroke. In a systematic overview of eight statin, trials the odds ratio for fatal and nonfatal stroke was 0.76 (95% CI, 0.62-0.92) in patients who were assigned to statin treatment.4 No significant stroke lowering effect was seen for dietary intervention (10 trials), fibrates (5 trials), resins (3 trials), or other interventions (5 trials) in the same overview. Other independently conducted overviews have confirmed the ability of statin drugs to reduce the risk of stroke.5,6 So why have the statins been able to lower the risk of ischemic stroke when so many other cholesterol lowering strategies have not? Greater efficacy in reducing total and LDL cholesterol is at least part of the answer. Statins can lower LDL cholesterol by about 30% compared to other pharmacologic and nonphar-macologic strategies which can lower LDL cholesterol by about 10%.
Lipids tend to temporarily fall after an acute stroke.7,8 This phenomenon is probably not strictly related to inadequate nutrition that might result from conservative early management of dysphagia because the same phenomenon has been seen in patients with many acute non-neurologic conditions. Aull and colleagues have recommended that a fasting lipid profile should be obtained on the first or second morning after stroke to avoid pseudonormalized values.7 Mendez and colleagues found in patients ages 60 to 69 that mean fasting LDL cholesterol levels changed from 136 ± 20 mg/dl on day 1 to 115 ± 17 mg/dl on day 7 and 160 ± 16 mg/dl at 3 months following an acute ischemic stroke.8 The investigators concluded that lipids should be checked at least three months after a stroke to avoid missing hyperlipidemia in some patients.
Recurrent carotid arterial stenosis to >50% occurs in about 25% of patients five years after carotid endarterectomy. Early restenosis (within 24 months after endarterectomy) is usually due to neointimal fibromuscular hyperplasia. Late restenosis is usually due to recurrent atherosclerosis. It is believed that late restenosis is more prone to cause stroke or transient ischemic attack than early restenosis. Medically preventing restenosis takes on added significance since there is an increased risk of stroke and cranial neuropathies with redo carotid endarterectomies. A small series of studies has demonstrated that lipid lowering agents can either slow the progression or cause regression of carotid intima-media thickness (IMT).9-12 Though the relative effect of statins and other lipid lowering agents may be large and statistically significant, the absolute effect is small. For example, in the Kuopio Atherosclerosis Prevention Study there was a 66% (95% CI, 30-95%) reduction in the rate of IMT progression in the common carotid artery with pravastatin.10 The magnitude of the effect was relatively small (pravastatin 0.010 mm/yr; placebo 0.029 mm/yr) at a baseline IMT of 1.35 mm. A significant favorable effect on IMT changes was noted in the one trial of colestipol and niacin.12 This same trial did not find significant differences in carotid luminal diameter changes. Most of the other studies of carotid IMT changes fail to comment on changes in luminal diameter, a well-established risk factor for stroke.
The second and most recent revision of the National Cholesterol Education Program (NCEPII) guidelines regarding the detection, evaluation and treatment of high blood cholesterol in adults was published in 1993.13 The guidelines recommend that men and postmenopausal women who are >35 years and have no cardiac risk factors or known coronary heart disease should be treated for hyperlipidemia if their LDL cholesterol is >190 mg/dl. When two or more cardiac risk factors are present, treatment of hyperlipidemia is recommended for LDL cholesterol >160 mg/dl. The cardiac risk factors cited in the NCEPII guidelines are: age >45 years for men and >55 years for women, family history of premature coronary disease, active tobacco smoking, hypertension, HDL cholesterol <35 mg/dl and diabetes mellitus. Certain groups of patients appear to benefit from lipid lowering with statins even if their LDL cholesterol is relatively normal. The AFCAPS/TexCAPS study of lovastatin in patients with average LDL-cholesterol levels (130-190 mg/dl) and no known coronary disease showed that lovastatin reduced risk of first acute major coronary event.14 Patients were relatively young in AFCAPS/TexCAPS study (mean 58 years), and they were required to have a below average HDL cholesterol (<45 mg/dl for men and <47 mg/dl for women). The CARE study compared pravastatin and placebo in patients with recent acute myocardial infarction and average cholesterol levels (LDL cholesterol of 115 to 174 mg/dl).15 Patients who took pravastatin had a significant reduction in the rate of coronary events and the need for revascularization. The rate of stroke was also reduced for those on pravastatin. Trials like AFCAPS/TexCAPS and CARE show that statins have an indication for use that is broader than implied by NCEPII Guidelines. More study is needed to clarify the indications for statin use.
Most of the evidence that statins can reduce the incidence of fatal and nonfatal stroke comes from trials designed to prevent first or recurrent coronary events. The average ages of the participants in many of the large completed coronary statin trials range from 55 to 62 years.4 This represents a much younger population than typically presents with acute ischemic stroke. It is not yet known whether statins are efficacious and cost effective in preventing recurrent strokes in the elderly. Future trials will be needed to clarify this issue, particularly in patients with borderline hyperlipidemia.
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