Hyperlipidemia: A well-documented modifiable risk factor for stroke Content Points: Hyperlipidemia is a well-documented, modifiable risk factor for stroke, with clear supportive epidemiological evidence in addition to evidence of risk reduction with modification as demonstrated in clinical trials.35 An estimated 8% to 9% of adults less than 35 years of age have abnormal serum lipid levels. Abnormal lipid levels are found in 25% of 55-year-old men and 40% of 65-year-old women. Hyperlipidemia causes 25% of ischemic strokes in the population (the population attributable risk). Compared with a normal total cholesterol level, the relative risk for stroke is 1.8 with a total cholesterol level of 240-279 mg/dL; the relative risk increases to 2.6 in people with a total cholesterol level >280 mg/dL. There is an opportunity to lower the risk of stroke by 20% to 30% with statin therapy in patients with known CHD. Trials using these agents have demonstrated consistent benefits in reduction in stroke risk among these patients.

Elevated C-reactive protein concentrations predict risk of first ischemic stroke and TIA Content Points: The role of C-reactive protein (CRP) as a novel marker of atherothrombotic disease is currently under investigation. This data from the original cohort in the Framingham Study related plasma CRP levels to incidence of first ischemic stroke or transient ischemic attack (TIA). During 12 to 14 years of follow-up, 196 ischemic strokes and TIAs occurred.36 Independent of age, men in the highest CRP quartile had 2 times the risk of ischemic stroke/TIA (P = 0.028), and women had almost 3 times the risk (P = 0.0001) compared with those in the lowest quartile. After adjustment for smoking, total cholesterol, HDL-C, systolic blood pressure, and diabetes, the increase in risk across CRP quartiles remained statistically significant for both men and women. This indicates that independent of other cardiovascular risk factors, elevated plasma CRP levels significantly predict the risk of future ischemic stroke and TIA in the elderly.

Neuroprotective actions of statins in stroke and cerebral ischemia Content Points: A growing body of data suggests that statins possess important properties that may confer additional benefit beyond retardation of atherosclerosis. Among these neuroprotective effects, statins preserve endothelial function and have anti-inflammatory, antioxidant, and anti-thrombotic effects.37 In the endothelium, statins mediate effects of nitric oxide synthase (NOS) isoforms, which play important but opposing roles in cerebral ischemia. Statins may have a dual role in cerebral ischemia, whereby they may simultaneously upregulate eNOS (improving cerebral flow), and inhibit the iNOS (an important mediator of inflammatory responses) in a synergistically neuroprotective manner. Statins inhibit inflammatory processes that are important during cerebral ischemia and reperfusion. They exert beneficial effects on adhesion molecules and modulate central nervous system production of cytokines (interleukin-1β [IL-1β], IL-6, and tumor necrosis factor- α [TNF-α]). Although the precise role of the different cytokines is not fully known, they appear to modify adhesion molecule expression on cerebral endothelium and inflammatory cells, promote cell migration, enhance thrombogenesis through tissue factor expression, and augment platelet activating factor. Studies so far suggest that statins are a novel means of minimizing inflammatory neuronal loss during cerebral ischemia. Finally, statins may be neuroprotective through antioxidant effects. Oxidative injury is central to many neurological disorders, including cerebrovascular disease. Statins may reduce lipoprotein oxidation and free radical injury. Most studies have explored antioxidant properties of statins relative to LDL-C. However, statins may exert broader effects through preservation of superoxide dismutase.

Reduction in stroke risk with statin therapy Content Points: Recent evidence demonstrates treatment with statins substantially reduces the risk of stroke in patients with prior vascular disease. Baseline cholesterol levels in these studies have ranged from high to normal.38-40,17,18 The Cholesterol And Recurrent Events (CARE) reported a 32% reduction in stroke or transient ischemia with pravastatin in subjects with prior MI.38 All categories of stroke were reduced. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study found a 19% reduction in stroke risk in CHD patients with a wide range of cholesterol levels following treatment with pravastatin.39 In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, treatment with atorvastatin for 16 weeks following an acute coronary syndrome was associated with a 50% reduction in stroke risk compared with conventional treatment.18 A meta-analysis of 13 primary and secondary prevention lipid trials that included 20 303 participants found that treatment with various statins led to an overall risk reduction of 31%.40 The recent Heart Protection Study (HPS), which involved more than 20 000 patients, including patients with prior stroke, diabetes, and CHD, reported a 27% reduction in stroke with simvastatin in a broad range of high-risk patients with normal or low LDL-C levels.17 The benefit was seen in women, in the elderly, and in patients with diabetes.

MIRACL: Reduction in fatal and nonfatal stroke with atorvastatin in patients with ACS Content Points: The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study randomized 3086 patients with unstable angina or non-Q-wave MI to treatment with atorvastatin 80 mg/day or placebo beginning with 24 to 36 hours after hospital admission.18 Patients were followed-up for 16 weeks. Patients had a mean LDL-C level of 135 mg/dL in the placebo group and 72 mg/dL in the atorvastatin group. Overall, intensive cholesterol lowering with atorvastatin over 16 weeks reduced overall stroke by one half and did not cause hemorrhagic stroke.18,41 Patients receiving atorvastatin had a 50% reduction in fatal or nonfatal stroke. Of 36 fatal and nonfatal strokes, 24 occurred in the patients treated with placebo vs 12 in the group treated with atorvastatin (P = 0.04). Of 31 nonfatal strokes, 22 occurred in the placebo group vs 9 in the atorvastatin group, a 60% reduction (P = 0.02). There were 3 hemorrhagic strokes in the placebo group and none in the atorvastatin group. These findings will require confirmation, but they lend support to other statin trials showing that statins reduce the risk of stroke. The findings also suggest that cholesterol lowering does not increase the risk of hemorrhagic stroke, although the numbers are small.

Heart Protection Study: Effect of simvastatin on stroke by etiology Content Points: The Heart Protection Study found a 27% reduction in the risk of total stroke with statin treatment (2P < 0.00001).17 The benefit was particularly striking in the reduction in risk for ischemic stroke. (See earlier slides for discussion of the HPS study.) The results showed a trend toward a benefit in reductions in hemorrhagic stroke with statin therapy. Importantly, there is no evidence to support earlier concerns that cholesterol-lowering therapy might increase the risk of hemorrhagic stroke.42 The likely explanation for the relationship between cholesterol and ischemic stroke is the contribution of cholesterol toward the development of generalized atherosclerosis in the cerebral, coronary, and aortic vasculature.43

Ongoing statin trials for primary and secondary stroke prevention Content Points: Recently, several trials further examining the role of statin therapy in the primary and secondary prevention of stroke have begun, including Stroke Prevention with Aggressive Reduction of Cholesterol Lowering (SPARCL), which will examine the effects of low- and high-dose atorvastatin compared with placebo on subsequent rates of recurrent cerebrovascular events in patients with previous stroke or TIA but without known CHD.44 The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomized placebo-controlled trial investigating the effect of pravastatin 40 mg daily on the occurrence of stroke and coronary death and on functional status in an elderly population with a history of MI, stroke, diabetes, hypertension, or smoking.45 The Fluvastatin Assessment of Morbi-mortality in the Elderly (FAME) will evaluate the effect of fluvastatin therapy for primary prevention of non-fatal and fatal cardiovascular events, including stroke, in elderly men and women (aged 70-85 years) with diabetes or hypertension, but without cardiovascular disease.46

AHA recommendations: Managing hyperlipidemia for primary prevention of ischemic stroke Content Points: Recent studies have helped clarify the relationship between stroke and lipids, and have shown that the risk of stroke and amount of carotid atheroma can be reduced with cholesterol-lowering medications. To reduce the risk of ischemic stroke, patients with elevated cholesterol should be managed according to current NCEP guidelines. Patients with coronary disease and LDL-C levels ≥130 mg/dL should be considered for treatment with a statin.35 Statins should be initiated along with lifestyle modifications for patients with CHD and LDL-C of ≥130 mg/dL. For patients with LDL-C between 100 and 129 mg/dL, statin therapy is optional. The treatment goal is an LDL-C of <100 mg/dL. Although some of the stroke reduction with statin therapy may be due to lipoprotein alterations, statins may also act through mechanisms unrelated to their lipid-lowering effects, such as improved endothelial function, and antithrombotic, anti-inflammatory, and neuroprotective properties.