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Statins for the prevention of cerebrovascular disease: the rationale for robust intervention

K.M.A. Welch*

Rosalind Franklin University of Medicine and Science, 3333 GreenBay Road, North Chicago, IL, 60064 USA

* Correspondence: K.M. Welch, Rosalind Franklin University of Medicine and Science, Green Bay Road, North Chicago, IL 60064, USA. Tel.: +1-847-578-3238; fax: +1-847-578-3404
welch{at}finchcms.edu

Abstract

Cerebrovascular disease is one of the leading causes of morbidity and mortality worldwide, and places a huge burden on the healthcare system. The risk factors for cerebrovascular disease are, however, well established and largely modifiable. After blood pressure control, the reduction of serum cholesterol levels has the promise to provide the greatest benefit in reducing the risk of stroke. In particular, data from landmark trials have shown that lipid-lowering therapy with statins significantly reduces the risk of stroke in patients with existing coronary heart disease but no evidence of prior cerebrovascular disease. More recently, data have emerged suggesting that statin therapy is also beneficial in the secondary prevention of stroke, and ongoing trials, such as the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study, will clarify this further. Statins are likely to reduce the risk of stroke by the stabilization and/or regression of plaque, but they also exhibit pleiotropic effects (for example, anti-inflammatory and antioxidant properties), which further justify their use in the primary and secondary prevention and treatment of cerebrovascular disease.

Key Words: Cerebrovascular disease • Pleiotropic effects • Primary prevention • Secondary prevention • Statins • Stroke

Introduction

Cerebrovascular disease is a major global health problem. In 1990, stroke was the second leading cause of mortality worldwide after ischaemic heart disease, accounting for 4.4 million deaths.1,2 Statistics published by the American Heart Association attributed 167,366 deaths in the United States in 1999 to cerebrovascular accidents, implicating stroke as the third most important cause of mortality in America.3 In addition, it is estimated that, on average, someone in the United States suffers a stroke every 53 seconds and that a fatal stroke occurs every 3.1 minutes. Approximately 80% of these strokes are first attacks.3,4 Stroke also exacts an enormous financial burden: the total annual direct and indirect costs for stroke care in the United States in 2002 have been estimated at $50 billion.3

The aftermath of stroke

Strokes vary widely in their severity. At one end of the spectrum are patients who recover fully within hours to days; at the other are those who experience a fatal event.5 Somewhere between these two extremes are the stroke survivors with varying degrees of neurological deficit and functional impairment. Indeed, non-fatal strokes are a leading cause of serious, long-term disability in developed countries, with up to one-third of patients being disabled to the extent that they are permanently dependent upon others.3,4 Therefore, as well as representing a major drain on healthcare systems due to acute and long-term patient management, stroke also incurs societal costs in terms of lost work days by relatives and/or friends who are left to care for a severely disabled patient.

Among those patients who survive a stroke, the risk of further cardiovascular morbidity and mortality is very high. In the United States, it is estimated that 14% of individuals who survive a stroke or transient ischaemic attack (TIA) will experience a recurrence within the first year, 22% of men and 25% of women will die within a year of sustaining an initial stroke, and over half of all stroke victims will die within 8 years.3 Many of these deaths will be due to other manifestations of atherosclerotic vascular disease. For example, patients with documented ischaemic stroke have a 2–3-fold increased risk of myocardial infarction (MI) and a 9-fold increased risk of a second stroke compared with the general population.6,7

Pathophysiology of ischaemic stroke

The pathogenesis of stroke can be divided into two broad categories: ischaemic and haemorrhagic. The former category accounts for approximately 85% of presentations and the latter for just 15%.

Ischaemic strokes result from atherothrombotic occlusion or an embolism.4 Vessel occlusion usually arises from atherosclerosis, locations varying from the internal carotid artery just above the carotid bifurcation to small-vessel disease deep within the brain itself. Thrombus formation at the site of a ruptured atheroma may lead to further vessel occlusion and subsequent cerebral ischaemia and infarction. Ischaemia causes direct brain injury due to lack of flow, oxygen and metabolic substrate, and initiates a cascade of neurochemical events that lead to progressive damage over a number of hours.

For strokes with an embolic aetiology, the most common origins of the offending clot are the left atrium in a patient with atrial fibrillation or the left ventricle in a patient with MI or heart failure. Although the clots themselves sometimes lyse spontaneously, ischaemia may already have injured the brain.

Primary prevention of stroke

Stroke is a good candidate for preventive strategies. It has a high prevalence, high burden of illness, and there are several safe and effective interventions available, which can be targeted at high-risk or stroke-prone individuals (Table 1).


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  		Table 1 Recommended interventions for the primary prevention of stroke10

 
Several conditions and lifestyle elements have been identified as risk factors for stroke.8–10 Non-modifiable risk factors include age, male gender, race (risk is elevated among blacks and some Hispanic Americans) and family history. Although these parameters cannot be altered, they help to identify individuals with a high stroke risk who might benefit from aggressive preventive strategies aimed at correcting modifiable risk factors. These include hypertension, diabetes mellitus, asymptomatic carotid stenosis, atrial fibrillation, elevated blood lipids, smoking and physical inactivity.9,10

Hypertension
The risk of stroke is strongly related to the usual level of both systolic blood pressure (SBP) and diastolic blood pressure (DBP).11–13 This relationship holds for primary and secondary stroke and for both ischaemic and haemorrhagic stroke. A systematic overview of 17 randomized trials of antihypertensive therapy, involving approximately 50,000 patients treated with diuretic- and/or ß-blocker-based regimens for 5 years, showed that reducing DBP by 5–6 mmHg or SBP by 10–12 mmHg decreased the probability of a first stroke by 35–40%.11 Furthermore, the Systolic Hypertension in the Elderly Program (SHEP) study showed that treating isolated hypertension in the elderly (>=60 years of age) decreases the incidence of stroke by 36%.14

Blood pressure goals of 140 mmHg for SBP and 90 mmHg for DBP are currently recommended,10,15 and lower targets are even more desirable. These targets may be achieved through lifestyle modification and/or antihypertensive drug treatment.

Diabetes mellitus
Compared with non-diabetic subjects, patients with insulin-dependent (type 1) diabetes mellitus are at increased risk of atherosclerosis and are more likely to have other atherogenic risk factors, such as hypertension, obesity and dyslipidaemia. The acceleration of atherosclerosis also means that diabetes is associated with an increased relative risk of ischaemic thromboembolic stroke, ranging from 1.8- to almost 6-fold.10

The incidence of stroke in diabetic patients can be substantially reduced by careful blood pressure control.16 Current guidelines recommend a target of 135 mmHg for SBP and 85 mmHg for DBP in patients with diabetes.15,17 Intensive glycaemic control appears to be less effective for stroke prevention than aggressive antihypertensive therapy, although it can reduce microvascular complications in patients with recent-onset type 1 diabetes.10

Asymptomatic carotid stenosis
Atherosclerotic carotid artery disease is another important stroke risk factor. The more severe the carotid stenosis, the higher the incidence of cerebral infarction ipsilateral to the stenosis. For example, with stenosis greater than 75%, the combined TIA and stroke rate has been reported as 10.5% per year, with 75% of events ipsilateral to the stenosed artery.18 Increasing the patency of the vessel by carotid endarterectomy can substantially reduce this risk.19 Owing to the risk of complications associated with the surgical procedure, however, carotid endarterectomy should only be considered in selected patients with high-grade carotid stenosis (60–100).10

Atrial fibrillation
Atrial fibrillation is the most common sustained cardiac arrhythmia encountered in clinical practice and an important risk factor for stroke. The relative stagnation of blood in the atria, the elevated plasma levels of some clotting factors and the increase in atrial natriuretic factor (which may cause an increase in haematocrit) that are observed during atrial fibrillation may contribute to thrombus formation in the atria. Fragments of this thrombus may become dislodged during atrial contraction and enter the systemic circulation where they can cause thromboembolism.

Thromboembolic stroke is the most important complication of atrial fibrillation. An analysis of data from the Framingham Heart Study has shown that there is a near 5-fold excess of stroke in the presence of atrial fibrillation.20 In addition, the proportion of strokes associated with atrial fibrillation increases with age, from 6.7% in subjects aged 50–59 years to 36.2% in those aged 80–89 years.21

Several placebo-controlled trials have assessed the efficacy of warfarin therapy in preventing primary thromboembolic stroke in patients with atrial fibrillation. Combined analysis of these trials has shown that anticoagulation with warfarin reduces the risk of embolic events by an average of 68%,22 although it causes a moderate risk of haemorrhagic complications (approximately 1% per year).

As a result, long-term anticoagulant therapy with warfarin or aspirin is indicated in patients with chronic atrial fibrillation, according to age and the presence of other risk factors. The International Normalized Ratio (INR) should be maintained between 2.0 and 3.0.10 Higher INR values increase the risk of bleeding complications, whereas lower values increase the risk of thrombosis.

Serum lipids
Recommendations for controlling serum lipid levels have recently been put forward, based on the results of landmark clinical trials with lipid-lowering therapy. In fact, after blood pressure control, reducing cholesterol levels appears to have the greatest benefit on stroke prevention (Fig. 1).8



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  		Fig. 1 Number of strokes preventable in the USA by control of individual risk factors. Permission granted by the American Medical Association.8

 
Patients with elevated cholesterol levels may be managed according to National Cholesterol Education Program Adult Treatment Panel III guideline principles.23 The use of lipid-lowering therapy for stroke prevention is discussed in greater detail below.

Lifestyle factors: smoking and physical inactivity
Cigarette smoking is a well-documented major risk factor for ischaemic stroke.10 In a meta-analysis of 32 studies, the overall relative risk of stroke for smokers was 1.5 (95% confidence interval, 1.4–1.6).24 Mechanisms involved include an impairment of blood vessel distensibility and compliance by increasing arterial wall stiffness.25 Smoking is also associated with increases in carotid artery plaque thickness, fibrinogen concentrations, platelet aggregation, haematocrit and blood pressure, and a reduction in high-density lipoprotein (HDL)-cholesterol levels.26 The simple recommendation for primary stroke prevention is to advise patients to stop smoking.

Regular exercise is known to reduce the risk of stroke as well as premature death and cardiovascular disease. The protective effect of physical activity on stroke appears to be through its impact on preventing hypertension, cardiovascular disease and diabetes, and its effect on reducing body weight.

Secondary prevention of stroke

Among those who survive a stroke or TIA, there is a very high risk of a further stroke,27,28 and the identification of safe and effective secondary treatment strategies is, therefore, of great importance. Such strategies include antihypertensive, antithrombotic and anticoagulant therapies, and surgery such as carotid endarterectomy.

Antihypertensive therapy
Although blood pressure is recognized as an important determinant of the risk of initial stroke (both in those with and without hypertension),29 there have been comparatively few randomized trials of antihypertensive treatments in patients with a history of cerebrovascular disease. The Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) was designed to address this issue.30 A total of 6105 hypertensive and non-hypertensive individuals, with a history of stroke or TIA, were randomized to receive either a flexible antihypertensive regimen consisting of 4 mg/day of the angiotensin-converting enzyme (ACE) inhibitor perindopril, with the addition of the diuretic indapamide (at the discretion of the patient's physician), or placebo. Over 4 years of follow-up, patients who received active treatment had a 28% relative risk reduction in the recurrence of stroke, compared with placebo (), and the risk reduction was similar for both hypertensive and non-hypertensive patients.30 In the active treatment group, combination therapy with perindopril and indapamide produced a reduction in blood pressure of 12/5 mmHg and a 43% reduction in the risk of stroke, whereas treatment with perindopril alone reduced blood pressure by 5/3 mmHg and resulted in no discernible reduction in the risk of stroke.30 It is clear therefore that aggressive blood pressure control is as effective in the secondary prevention of stroke as it is in primary prevention and that ACE inhibitors should be included in the antihypertensive regimens used.

Antithrombotic therapy
A systematic review of 11 trials of aspirin in patients with a history of stroke or TIA showed that, in doses above 75 mg/day, aspirin reduces the relative risk of stroke by approximately 13%.31 Thienopyridine derivatives, such as ticlopidine and clopidogrel, have been shown to provide a significantly () greater reduction in the recurrence of stroke than aspirin.32 Thienopyridine derivatives are associated with less gastrointestinal haemorrhage and other upper gastrointestinal upset than aspirin but are also linked to an excess of skin rash and diarrhoea.32 The combination of aspirin and modified-release dipyridamole appears to be more effective than aspirin alone.33 This is being investigated in the European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) in which patients with a TIA or minor ischaemic stroke (Rankin grade <=3) have been randomized to receive either oral anticoagulation (INR 2.0–3.0), the combination of dipyridamole (400 mg daily) plus aspirin (in any dose between 30 and 325 mg daily), or aspirin alone.34 The primary outcome measure is the composite event `death from all vascular causes, non-fatal stroke, non-fatal MI or major bleeding complication', whichever occurs first.34 The study is due to complete in 2003.

Anticoagulant therapy
In patients with atrial fibrillation who have had a prior TIA or stroke, long-term oral anticoagulant therapy reduces the annual risk of stroke from approximately 12.0% to 4.0%, and anticoagulant therapy is recommended for other TIA/ischaemic stroke patients at high risk of cardioembolism.28 For patients who have suffered a non-cardioembolic stroke, there is no scientific evidence supporting the use of anticoagulant therapy, although it may be useful in specific situations.

Surgery
The MRC European Carotid Surgery Trial (ECST) showed that, in patients who have suffered a recent carotid territory TIA or mild ischaemic stroke, who have severe carotid stenosis (>=80%), and who are fit and willing to undergo surgery, carotid endarterectomy reduces the 3-year risk of stroke from 26.5% to 14.9%.35 However, only a minority of TIA/ischaemic stroke patients meet these criteria. For patients contraindicated for carotid endarterectomy, or with stenoses at surgically inaccessible sites, carotid angioplasty is an alternative.36

Lipid-lowering therapy
The role of lipid-lowering therapy in the secondary prevention of stroke is currently being investigated and is discussed below.

Statin therapy and the prevention of stroke

Observational studies have shown a clear correlation between plasma cholesterol and the incidence of coronary heart disease (CHD).37,38 However, such studies have failed to show a clear correlation between cholesterol levels and the overall incidence of stroke. For example, in the Prospective Studies Collaboration, the association between blood cholesterol and subsequent stroke rate were investigated by reviewing 45 prospective observational cohorts involving 450,000 individuals with 5–30 years (mean 16 years) of follow-up, during which time 13,397 participants were recorded as having had a stroke.29 The majority of these were fatal strokes in studies that recorded only mortality and not incidence, but approximately 25% were from studies that recorded both fatal and non-fatal strokes. After adjustment for study, age, sex, DBP, CHD history and ethnicity, there was no significant correlation between serum cholesterol and stroke rates (Fig. 2).29 This could in part be due to the fact that all stroke subtypes were analyzed together and there may be a differential effect of lowering cholesterol levels on the incidence of ischaemic and haemorrhagic stroke.39 Analyses that include stroke subtypes have shown unequivocal correlations between serum lipoprotein levels and the risk of ischaemic stroke.40,41 For example, there was a positive association between serum cholesterol levels and death from non-haemorrhagic stroke () in a study of over 350,000 men screened for the Multiple Risk Factor Intervention Trial (MRFIT).40



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  		Fig. 2 Prospective Studies Collaboration: correlation between serum cholesterol and stroke rates. Reprinted from Ref.29, with permission from Elsevier.

 
Landmark trials have shown that statin therapy significantly reduces mortality and morbidity in patients with, or at risk of, CHD.42–46 In three of these trials, statins also produced a significant reduction in the risk of stroke in patients with existing CHD, but no evidence of prior cerebrovascular disease: in the Scandinavian Simvastatin Survival Study (4S), treatment with simvastatin resulted in a 28% reduction in the risk of stroke and TIA ();47 in the Cholesterol And Recurrent Events (CARE) trial, pravastatin treatment resulted in a 32% reduction in the risk of stroke ();48 and in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, pravastatin treatment resulted in a 23% reduction in the incidence of non-haemorrhagic stroke ().49

More recently, the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study has evaluated whether aggressive lipid lowering with atorvastatin 80 mg/day, versus placebo, initiated 24–96 h after an acute coronary syndrome, would reduce the incidence of death and non-fatal ischaemic events at 16 weeks follow-up.50 Even within this short timeframe, atorvastatin significantly reduced the incidence of fatal or non-fatal stroke (50% risk reduction; ; Fig. 3).50



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  		Fig. 3 MIRACL: effect of aggressive statin therapy on the incidence of stroke. Permission granted by the American Medical Association.50

 
The above data provide convincing evidence that the risk of stroke is reduced with the use of statins (Fig. 4). However, this might be as a result of statin-induced improvement in cardiac function and a reduction in MI, since these studies were carried out in patients who are not necessarily representative of the true stroke population. Generally, statin studies only represent approximately 15% of stroke patients. Compared to the patient populations in statin studies, stroke patients are older, have lower low-density lipoprotein (LDL)-cholesterol and may not have CHD.



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  		Fig. 4 Effect of statin therapy on the primary and secondary prevention of stroke.

 
Recently, the MRC/BHF Heart Protection Study has shown that, over a 5-year treatment period, simvastatin therapy resulted in a significant () 25% reduction in the incidence of stroke, compared with placebo, in patients with coronary disease, other occlusive arterial disease or diabetes.51 In a subgroup analysis of 1820 patients with a history of cerebrovascular disease, but not cardiovascular disease, there were a total of 384 vascular events (including stroke, CHD and revascularization procedures), 172 in the simvastatin group and 212 in the placebo group.51 However, the specific impact of statin therapy on the incidence of stroke in these patients was not analyzed. Moreover, these 1820 patients were not randomized as a group and there may, therefore, have been imbalances in stroke risk factors. Finally the study was insufficiently powered for definitive statistical analysis.

The SPARCL study
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study is the first study primarily designed to evaluate prospectively the effect of statin treatment on secondary stroke prevention. It is an ongoing prospective, multi-centre, double-blind, randomized, placebo-controlled trial that will investigate the effects of atorvastatin 80 mg/day on specified cerebrovascular (primary) and cardiovascular (secondary) endpoints, in patients who have previously experienced a stroke or TIA, but who have no known CHD. Enrollment into the SPARCL study was completed in April 2001, and it is anticipated that it will complete early in 2004.

The mode of action of statins in stroke

Evidence suggests that the mechanisms by which statins produce beneficial reductions in the risk of both CHD and stroke include the stabilization and/or regression of atheromatous lesions, thereby reducing the tendency of plaque to undergo thrombotic disruption.52–54 In addition to lipid regulation, statins exhibit pleiotropic effects, which may also help to explain their ability to stabilize plaque.55–57 In animal models of atherosclerosis, statins have been shown to increase collagen formation and reduce the size of the plaque lipid core, and to have anti-inflammatory properties, by decreasing macrophage numbers and metalloproteinase production.58,59 By reducing LDL-cholesterol, statins increase tissue perfusion and improve the endothelial dysfunction that is associated with hypercholesterolaemia, and which plays a central role in atherogenesis.60,61 Endothelial dysfunction is associated with a reduction in nitric oxide (NO), which leads to impaired vasodilation, enhanced migration of monocytes into the vessel wall, proliferation of smooth muscle cells and reduced inhibition of platelet aggregation, all of which contribute to an increased risk of plaque rupture and thrombogenesis.

Different isoforms of NO synthase (NOS) have opposing roles in cerebral ischaemia. NO produced by endothelial NOS (eNOS) plays a physiologically protective role and controls the paracrine homeostatic functions of the endothelium, which include the inhibition of leukocyte and platelet adhesion, the control of vascular tone and the maintenance of a thromboresistant interface between the circulation and the vessel wall.62 In contrast, the inducible form of NOS (iNOS) is an important mediator of inflammatory responses during ischaemia and reperfusion.63 Astrocytes produce iNOS in response to proinflammatory mediators (for example, interleukin-6)64 and, in ischaemic stroke, infiltrating leukocytes have been shown to express iNOS.65 NO and its oxidative by-product peroxynitrate, produced as a result of astrocyte and macrophage iNOS expression, are thought to contribute to neuronal death during ischaemic stroke, due to the oxidation of structural neuronal proteins.62 This is supported by the finding that iNOS knockout mice have significantly reduced infarct volumes, compared with wild-type controls.62

Statins have been shown to up-regulate eNOS expression in vascular endothelial cells in vitro.66 In a normocholesterolaemic murine model, statin therapy was shown to increase cerebral blood flow, reduce infarct size by approximately 30% and improve neurological outcome, by directly up-regulating eNOS activity in the brain, independent of changes in cholesterol level.67 In addition, statin therapy has been shown to inhibit cytokine-mediated up-regulation of iNOS and the production of NO in rat astrocytes and macrophages.68

Statins may also confer neuroprotection via their antioxidant effects. Oxidative injury is a fundamental mechanism in cerebrovascular disease.69 The liberation of reactive oxygen species from leukocytes after acute stroke or during reperfusion may exacerbate tissue injury in the ischaemic penumbra. The generation of free radicals damages neurones and endothelial cells, due to lipid peroxidation, protein oxidation and direct damage to nucleic acids.62 Free radicals also induce endothelial cell apoptosis.70 During ischaemia and reperfusion, the protection of endogenous antioxidants, such as superoxide dismutase and catalase, may be overwhelmed.62 By inhibiting leukocyte adhesion and migration, statins reduce the oxidative injury caused by liberated reactive oxygen species. In addition, statins have been shown to reduce hyperoxia and the production of free radicals, by enhancing the activity of endogenous superoxide dismutase.71

The ischaemic penumbra provides a window of opportunity in terms of treatment, and the use of tissue plasminogen activator and clot-buster technology have provided the first acute treatment for stroke.72 In addition to being beneficial in the prevention of stroke, statins may also be able to extend this window of opportunity, thereby enhancing the acute treatment of stroke.

Conclusion

The prevention and treatment of cerebrovascular disease presents a major healthcare challenge, but there are therapeutic options available that can enable this challenge to be met. Among these, statin therapy has proven efficacy in the primary prevention of stroke in patients with existing CHD. In addition to their beneficial effects on lipid levels, statins exhibit pleiotropic effects that may directly or indirectly confer neuroprotection and/or enable them to positively impact the treatment and secondary prevention of cerebrovascular disease.

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