Introduction

About 610,000 people experience a first-time stroke annually, 87% of which are ischemic strokes (10% are intracerebral hemorrhages and 3% are subarachnoid hemorrhages). Stroke ranks number three among all causes of death, behind only heart disease and cancer. Incidence of stroke has decreased between 1950 and 2004 from 7.6% in men and 6.2% in women (1950–1977) to 5.3% in men and 5.1% in women (1990–2004). This can be attributed to heightened stroke research over the past 50 years and risk factor identification. Major modifiable risk factors for stroke include hypertension, atrial fibrillation, diabetes, and cigarette smoking [1••]. Dyslipidemia has long been recognized as a risk factor for coronary artery disease, but its role in stroke has become increasingly apparent over the past decade. This article analyzes the impact of hyperlipidemia on stroke and evaluates the benefit of risk factor identification and reduction.

Dyslipidemia is characterized as elevated low-density lipoprotein (LDL > 130 mg/dL) or triglycerides (>150 mg/dL) or decreased high-density lipoprotein (HDL < 40 mg/dL) [1••]. Total cholesterol, triglyceride, and LDL levels are known to increase from age 20 to age 60 years or 70 years, when they begin to decrease secondary to changes in body composition, malnutrition, and chronic disease states [2]. Between 2003 and 2006, the mean lipid values for American adults over age 20 years were as follows: LDL of 115 mg/dL, HDL of 54.3 mg/dL, triglycerides of 144.2 mg/dL. The prevalence of high LDL decreased from 26.6% between 1988 and 1994 to 25.3% between 1999 and 2004. During this same period, awareness about dyslipidemia increased from 39.2% to 63%, and use of lipid-lowering drugs (specifically statins) increased from 11.7% to 40.8% [1••].

Lipid Screening Guidelines

The United States Preventive Services Task Force (USPSTF) generated recommendations for lipid screening based on patient age and sex and the presence of pre-existing conditions that increase risk for a cardiovascular event, including personal history of cardiovascular event or atherosclerosis, diabetes, family history of cardiovascular event before age 50 years in male relatives or age 60 years in female relatives, tobacco use, hypertension, and obesity (body mass index > 30 kg/m2). These recommendations are summarized in Table 1 [3].

Table 1 United States preventive services task force lipid screening guidelines
Full size table

Treatment of Hyperlipidemia

Patients with elevated lipids should initially attempt to correct this abnormality via lifestyle modification. This includes adjustment in diet (decreased consumption of saturated fat and cholesterol) and increase in physical activity. If this is unsuccessful after 3 months, medical management should be considered [3].

Statins are the most commonly used medication for hyperlipidemia. They reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, thereby decreasing cholesterol production and increasing LDL receptor synthesis, leading to increased LDL clearance. They decrease LDL by 18% to 55%, increase HDL by 5% to 15%, and decrease triglycerides by 7% to 30%. Adverse effects include myopathy and transaminitis [4]. Experimental studies in animals and cell cultures demonstrate that statins also decrease risk of a vascular event via several pleiotropic effects. Statins play a role in neuroprotection via reduction of platelet aggregation and clot formation, facilitation of clot lysis, modulation of the inflammatory response, and reduction of excitotoxicity. They also impact neurorepair indirectly via promotion of angiogenesis to facilitate collateral blood flow, and via inhibition of nitric oxide metabolism and upregulation of endothelial nitric oxide synthase, leading to vasodilation. Statins impact neurorepair directly via promotion of neurogenesis and new synapse formation [5, 6].

There are six statins currently available in the United States (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin). Although they share a common mechanism of action, they differ in terms of their molecular structure, pharmacokinetics, and pharmacodynamics. The Comparative Dose Efficacy Study of Atorvastatin Versus Simvastatin, Pravastatin, Lovastatin, and Fluvastatin in Patients with Hypercholesterolemia (CURVES) by Jones et al. [7] compared atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin and found that atorvastatin produced a greater reduction in LDL than the other statins at milligram-equivalent doses (P ≤ 0.01). Crouse et al. [8] compared the effects of simvastatin and atorvastatin and found that although both medications decreased LDL by greater than 40%, simvastatin increased HDL more substantially than atorvastatin. Given the variety of pleiotropic effects of statins, the efficacy of a given medication at preventing strokes may be dependent on other features beyond lowering LDL and raising HDL. Foody et al. [9] compared atorvastatin with simvastatin use in patients without cardiovascular disease in an observational study and found that rate of stroke (per 100 patient-years) in patients taking atorvastatin was significantly less than that of patients taking simvastatin (0.162 vs 0.230; P < 0.001). Patients taking atorvastatin were also found to be more compliant than those taking simvastatin (median treatment duration of 158 vs 124 days; P < 0.001), but it is unclear why this was the case [9]. Further research is clearly warranted in head-to-head trials.

The impact of statins on intracranial vasculature and blood flow post-infarct has been demonstrated radiologically. A case study by Horimoto et al. [10] of two patients with hyperlipidemia (LDL > 130 mg/dL) and a history of ischemic infarct greater than 10 years prior showed increased regional cerebral blood flow as measured by single-photon emission computer tomography (SPECT) 6 months after initiating statin treatment. Tan et al. [11] evaluated 40 patients with hyperlipidemia, recent (<3 months) ischemic infarct/transient ischemic attack (TIA), and symptomatic stenosis of M1 or basilar artery and found improvement in degree of stenosis on magnetic resonance angiography (MRA) in 54% of stenotic vessels 6 months after starting 40 mg/d of atorvastatin [11].

The Relationship Between Lipids and Stroke Prevention and Outcome

Multiple studies have been conducted to evaluate the relationship between statins and stroke prevention and outcome. In the Scandinavian Simvastatin Survival Study (4S), one of the first large trials to evaluate the role of statins in stroke prevention, 4,444 patients with a history of stable coronary artery disease and hyperlipidemia (total cholesterol > 5.5 mmol/L) were randomized to simvastatin or placebo. Those who received simvastatin had a 28% relative risk reduction of stroke or TIA during a 5-year period [12]. A meta-analysis by Amarenco and Labreuche [13••] of 24 randomized trials comprised of 165,792 individuals showed that reduction of LDL by 39 mg/dL leads to reduction of relative risk of stroke by 21.1% (P = 0.009). They also demonstrated that incidence of all strokes was reduced by 18% while on a statin (P < 0.0001) [13••]. The Northern Manhattan Study (NOMAS) established the relationship between increased LDL and carotid plaques, which are often precursors to cerebrovascular disease [14]. The Monica Risk, Genetics, Archiving and Monograph (MORGAM) Project evaluated 93, 695 people without cardiovascular disease between the ages of 19 years and 77 years in 43 different cohorts from eight European nations over the course of 13.2 years and found that 1,851 strokes occurred. The study observed that increased HDL conferred a decreased risk of stroke, particularly in women [15]. The difference between the sexes in the benefit of increased HDL on risk of cardiovascular disease has been observed in other studies as well, but the etiology for this remains unclear [16].

Statins have also been shown to have a benefit during acute strokes. A retrospective chart review by Yu et al. [17] of 553 acute ischemic stroke patients who presented to Montreal General Hospital between 2002 and 2005 showed that use of statins prior to stroke was associated with better functional outcome based on modified Rankin scores (0: no symptoms, 1: no significant disability, 2: slight disability, 3: moderate disability, 4: moderate-severe disability, 5: severe disability, 6: dead) 10 days post-stroke. A review of the literature by Fuentes et al. [18] showed that use of statins is associated with lower stroke severity and better outcome in acute ischemic stroke patients (specifically patients with atherothrombotic and lacunar infarcts).

Not only do statins play a beneficial role during acute stroke, but discontinuation of statins immediately following a stroke may acutely impair vascular function secondary to downregulation of endothelial nitric oxide synthase expression and abrupt upregulation of platelet factor 4 and β-thromboglobulin, leading to vasoconstriction and reversing the protective effects of statins. These “rebound” effects are most prominent during the first 4 days after discontinuation of a statin. Patients whose statins are stopped in the immediate post-stroke period show worse outcomes (increased risk for death/dependency) than those whose statins are continued [19].

In addition to their impact on primary stroke prevention and acute stroke management, statins are also integral to secondary stroke prophylaxis. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial randomized 4,731 patients with recent stroke or TIA and LDL 100–190 mg/dL to 80 mg/d of atorvastatin or placebo and found that time to stroke was reduced by 16% in patients taking atorvastatin and that there was a significant increase in proportion of event-free patients in the treatment arm (P < 0.001) [20].

The Role for Statins in Stroke Prophylaxis in the Absence of Hyperlipidemia

Given the wide range of physiologic effects of statins, studies have also been done to look at the role of statin use for stroke prevention in patients who do not have hyperlipidemia. The Treating to New Targets (TNT) trial evaluated 10,001 patients with coronary artery disease in the absence of hyperlipidemia (LDL < 130 mg/dL) and compared risk of major cardiovascular event (including stroke) in patients assigned to 80 mg/d of atorvastatin versus 10 mg/d of atorvastatin. After a period of 4.9 years, there was an absolute reduction of 2.2% of major cardiovascular events in patients randomized to the 80-mg arm compared with the 10-mg arm [21]. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial compared the use of 20 mg/d of rosuvastatin versus placebo in 17, 802 healthy patients with elevated C-reactive protein but low LDL and found a 48% reduction in stroke (P = 0.002) in those taking rosuvastatin. This demonstrates the impact of statins on inflammation reduction as a means of primary stroke prevention, even in the absence of hyperlipidemia [22].

John et al. [23] offer data to explain the efficacy of statins at stroke reduction in patients without hyperlipidemia. They evaluated the time frame of LDL reduction and endothelium-dependent vasodilation after starting a statin and demonstrated that although LDL was significantly reduced after only 3 days (LDL decreased by 11.9% after 3 days; P < 0.001), further reduction occurred after 14 days (LDL decreased by 29.6% after 14 days; P < 0.001), whereas endothelium-dependent vasodilation measured as forearm blood flow after administration of acetylcholine improved by 46.7% after only 3 days (P < 0.05) but showed no significant difference in vasodilation after 14 days compared with that at 3 days post-treatment (there was a significant difference after 14 days when compared with pretreatment vasodilation). No relationship was found between the improvement in endothelium-dependent vasodilation and the degree of reduction of LDL. This suggests that there is a lipid-independent effect of statins on endothelial function that may mediate the reduction of stroke in patients without hyperlipidemia as well as contributing to the reduction of stroke in patients with hyperlipidemia [23].

Hyperlipidemia: Screening, Treatment, and Compliance

In addition to scientific demonstration of the impact of hyperlipidemia on strokes and the benefit of statin use for stroke prophylaxis, primary prevention of strokes begins with screening, educating, and treating patients. The median percentage of adults in the United States who were screened for hyperlipidemia between 2002 and 2007 is 74.8%, but the median percentage of adults in the United States with documented high cholesterol during this period who were aware of their condition is only 37.6% [1••]. Of 558 patients admitted to four hospitals in Berlin, Germany with the diagnosis of stroke, 28% had hyperlipidemia and 73% reported knowing they had elevated cholesterol, but only 37% of those who knew they had high cholesterol were being treated pharmacologically [24]. A study of 9,497 individuals by the Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) group demonstrated that of 7,510 participants defined as high risk for cardiovascular event (self-reported heart disease, narrow or blocked coronary arteries or carotid artery disease, stroke, or type 2 diabetes), only 12.4% were taking statins (21.5% were taking any lipid-lowering medication). Of the individuals defined as moderate risk for cardiovascular event (two or more of the following traits: men > 45 years or woman > 55 years of age, diagnosis of low HDL, diagnosis of hypertension, current smoker, family history of heart disease or narrow/blocked vessels, stroke, or diabetes), 7.1% were taking statins (13% were taking any lipid-lowering medication). Of those defined as low risk (0 to 1 of the aforementioned risk factors), 1.7% were taking statins and 5.5% were taking any lipid-lowering medication [25].

Conclusions

Hyperlipidemia is one of the major modifiable risk factors for stroke. The American Heart Association states that treatment of hyperlipidemia reduces risk of stroke by 30%. Treatment for hyperlipidemia includes diet, exercise, and statins. There is Class IA evidence (ie, evidence and/or general agreement that treatment is useful and effective based on data from multiple randomized clinical trials) that patients with coronary artery disease or hypertension should be treated with lifestyle modification and a statin even if LDL level is normal for primary stroke prevention [26•]. Statins play a beneficial role in both primary and secondary stroke prophylaxis and in the acute phase of stroke [12, 13••, 14, 17, 18, 20] via a number of pleiotropic effects including reduction of platelet aggregation and clot formation, facilitation of clot lysis, modulation of inflammatory response, reduction of excitotoxicity, promotion of angiogenesis, inhibition of nitric oxide metabolism, upregulation of endothelial nitric oxide synthase, and promotion of neurogenesis [5, 6].

There are numerous barriers to maintaining adequate control of hyperlipidemia. Firstly, it is important for physicians to be aware of lipid guidelines and to appropriately screen patients for hyperlipidemia. These results must then be translated into a treatment plan inclusive of therapeutic lifestyle changes and/or medical management. Patients need to be educated about hyperlipidemia and its relationship to stroke. In order to improve patient compliance with medical management, the National Institute of Health recommends a multidisciplinary approach including collaborative care by pharmacists, nurses, and physicians [4]. This can be done in the setting of a regular clinic visit, but time constraints during a scheduled appointment with an internist may make it difficult to facilitate this process, suggesting that a lipid clinic or a specific stroke prevention clinic for patients who are at high risk for stroke (personal history of cardiovascular event or atherosclerosis, diabetes, family history of cardiovascular event before age 50 years in male relatives or age 60 years in female relatives, tobacco use, hypertension, or obesity [body mass index > 30 kg/m2]) may be beneficial.

It is important to note that primary prevention of stroke must begin early in life. Establishing good habits in the areas of nutrition and exercise at a young age decreases risk of atherosclerosis. Lipid screening is recommended by the American Academy of Pediatrics for patients with a family history of hyperlipidemia or premature cardiovascular disease, or for patients with hypertension, diabetes, or obesity [27].