European Journal of Internal Medicine
Volume 19, Issue 1 , Pages 8-14, January 2008

Statins in stroke prevention: What an internist should know

Received 27 October 2006; received in revised form 14 April 2007; accepted 7 May 2007. published online 26 September 2007.

Article Outline

Abstract 

Historically, the etiological link between hypercholesterolemia and stroke has been less clear than for coronary heart disease. The lack of association between cholesterol levels and stroke in most epidemiological and observational studies has brought about this controversy. Many recent, long-term clinical studies have confirmed that statin therapy results in a reduced risk of strokes, even in so-called “normocholesterolemic” patients. The magnitude of the effect is great. A large-scale analysis of more than 90,000 individuals showed that every 10% reduction in the concentration of LDL-cholesterol reduces the risk of stroke by 15.6%. The positive effect of statins on stroke depends mainly on LDL cholesterol reduction, but other non-lipid mechanisms, so-called “pleiotropic” effects, have been shown to play a role. This review seeks to summarize the role of statins in stroke prevention. Despite the fact that our understanding of the benefits of statins in stroke prevention is still evolving, we find marked room for improvement in stroke risk factor management. Internists must face this challenge and integrate this new knowledge into their daily clinical practice.

Keywords: Statins, Lipids, Stroke prevention, Pleiotropic effects

 

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1. Introduction 

Statins – 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors – are the most commonly prescribed therapy for lowering cholesterol. The original compound was first isolated from fungi in 1976. It effectively blocked the conversion of HMG Co A to mevalonic acid and bore the name mevastatin [1]. Since then, numerous large, randomly controlled trials have been published on the effects of statins on low-density lipoprotein cholesterol (LDL-C), cardiovascular disease events, and mortality.

The benefits of statin treatment have also been shown for primary and secondary stroke prevention, and mounting evidence indicates that the aggressive lowering of lipids, particularly with statin therapy, will be of benefit to the majority of patients with an ischemic stroke [2]. However, several studies of stroke survivors suggest that an unacceptably high proportion of these individuals are neither on lipid-lowering therapy nor managed aggressively enough to achieve recommended target cholesterol levels [3], [4]. Therefore, it is crucial that internists know and follow guidelines for preventing strokes. This review seeks to summarize the role of statins in stroke prevention and to reinforce the need to analyze the use of statins in our current clinical practice.

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2. Statins in stroke prevention. Review of the evidence 

Historically, the etiological link between hypercholesterolemia and stroke has been less clear than for coronary heart disease (CHD). The lack of association between cholesterol levels and stroke in most epidemiological and observational studies has been a source of controversy. In fact, a meta-analysis of 45 prospective studies that included 450,000 subjects with 13,000 incident strokes among them found no association between total cholesterol level and stroke [5]. Nevertheless, several reasons need to be considered in the failure to establish this link. Few studies accounted for the differences in stroke subtype, given that a stroke is a heterogeneous disease, and most of these cohorts of patients were not representative of the entire population at risk for ischemic stroke.

2.1. Primary prevention trials 

The unexpected finding of a reduced incidence of stroke in the first major statin trials conducted in patients with known CHD raised new expectations (Table 1). In the Scandinavian Simvastatin Survival Study (4S) trial [6] of 4444 patients with CHD and high serum cholesterol levels, there was a significant reduction in strokes (30%) after 5 years in the simvastatin group as compared to the placebo group, although the number of deaths due to cerebrovascular disease was similar. The Cholesterol and Recurrent Events (CARE) and the Long-Term Intervention with pravastatin in Ischemic Disease (LIPID) [7] studies confirmed the efficacy of statins in reducing the incidence of strokes in patients with CHD and cholesterol levels within the normal range or moderately elevated levels. In the CARE trial, the pravastatin group had a 31% lower incidence of all strokes (p=0.03), although the incidence of fatal strokes, as in the 4S study, was about the same as in the control group. In the LIPID study, pravastatin significantly reduced the incidence of strokes by 19% (p=0.022).

Table 1. Summary of the major statin trials
TrialYearPatientsRRR-%
4-S19944,44429
CARE19964,15931
LIPID19989,01418
MIRACLE20013,08651
HPS200220,53625
PROSPER20025,804−3
ASCOT200310,30527
CARDS20042,83848
TNT200510,00125
SPARCLE20064,37116a

RRR—Relative risk reduction for stroke.

aStroke recurrence.

These results were confirmed in other trials with atorvastatin. The MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) study showed that atorvastatin, initiated 24–96 h after an acute coronary syndrome, reduced recurrent ischemic events; remarkably and significantly, there were 50% fewer strokes in the atorvastatin group than in the placebo group (12 vs 24, p=0.045) [8]. Likewise, in the GRACE (GREak Atorvastatin and Coronary Heart Disease Evaluation) study, atorvastatin, in comparison to “usual” care, reduced the risk of stroke [relative risk reduction (RRR) 0.53; p=0.034)] [9].

Nevertheless, in a mixed primary–secondary prevention trial designed especially for the evaluation of the effects of pravastatin in the elderly (PROSPER: Pravastatin in Elderly Individuals at Risk), there was no effect on stroke incidence, with 4.5% strokes in the treatment group and 4.7% strokes in the placebo group. This was due to diverse factors, such as inadequate statistical data and a very short patient follow-up (3.2 years). However, the incidence of transient ischemic episodes did very nearly reach statistical significance (2.7% vs 3.5%; p=0.051) [10].

The reduction of strokes by statins was also confirmed in several meta-analyses. Later, a prospective meta-analysis of 14 randomized trials of statins in 90,056 patients (either asymptomatic or coronary patients) showed that every 10% LDL-C reduction was estimated to reduce the risk of all strokes by 15.6% [11].

2.2. Secondary prevention trials 

Evidence of the benefit of statin therapy in secondary stroke prevention in patients with previous cerebrovascular disease was first provided by the Heart Protection Study (HPS) [12]. A total of 20,536 patients with a high risk of vascular events were included in the HPS. Simvastatin treatment significantly reduced the risk of vascular events (RRR 24%, p<0.00001) and those events that cause strokes (RRR 27%, p<0.00001). This effect was also noticed in patients with relatively low levels of cholesterol (<193 mg/dL) and LDL-C (<116 mg/dL). The HPS included 3280 randomly chosen stroke patients [none with transient ischemic attack (TIAs)] and 1822 stroke patients without established CHD. In all stroke patients, there was a 19% RRR of major vascular events, and in the stroke patients without established CHD, the reduction in the risk of major vascular events was 23%. However, the HPS did not find a reduction in stroke risk among patients with recurrent cerebrovascular disease (10.4% of patients in the statin group had a recurrent stroke as compared with 10.5% of patients in the placebo group). This finding has been related to the late inclusion of patients at a mean of 4.3 years after their stroke or TIA, at a moment when patients were less likely to have a stroke event and more likely to have a coronary event [11]. Therefore, in patients with a prior stroke, statins likely reduced the incidence of coronary events, but there was no proof that statins reduced the incidence of recurrent strokes.

On the basis of these results, and despite the fact that evidence of the benefits of statins in the secondary prevention of stroke was lacking, the Food and Drug Administration approved simvastatin for stroke patients, independently of any measurement of LDL-C [13].

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial [14] was designed to address this question. The SPARCL trial randomly assigned, in a double-blinded manner, 80 mg/day of either placebo or atorvastatin to 4731 patients with a history of non-disabling stroke or TIA in the preceding 1–6 months and with no CHD or hypercholesterolemia. After 5 years, the rate of stroke was lowered by about 2% (RRR about 16%) in patients who were randomly assigned to received atorvastatin, and the rate of major cardiovascular events was lowered by 3.5% (RRR about 20%), despite a small increase in the incidence of hemorrhagic stroke.

Despite the benefits seen, several problems have been pointed out with the study [15], [16], [17]:

1.Patients with atrial fibrillation and other cardiac sources were excluded. This raises the issue of whether the SPARCL results apply to the roughly one in five ischemic strokes that are cardioembolic in origin.

2.It is not clear why hemorrhagic strokes were considered a qualifying event for inclusion, since only 93 such patients were enrolled in the trial.

3.One may not be able to generalize the results of the study to patients presenting within the first month of a TIA or stroke since the SPARCL trial included patients with a history of a non-disabling TIA or stroke in the preceding 1–6 months.

4.Translating this trial into clinical practice may be difficult as long as the overwhelming majority of strokes occur in subjects aged 70 years and older (the mean age of study participants was 63 years). In this population, side effects, long-term compliance, and polypharmacy are much more common problems.

The implication of the results of the SPARCL trial, when added to those of earlier trials, is that all patients with TIA or ischemic stroke due to presumed atherothromboembolism should be considered for long-term treatment with statins, irrespective of their initial blood cholesterol concentration or other characteristics at presentation [15].

Further studies are needed to definitively clarify the role of statin therapy in preventing recurrent strokes.

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3. Statins in stroke prevention. Cholesterol control and beyond 

The mechanism by which statins reduce stroke incidence and recurrence is still unclear. In a meta-analysis of 14 randomized trials of statins [11], the most important finding was that the greater the between-group differences in LDL-C reduction, the greater the reduction in stroke risk. This suggested that LDL-C reduction was probably the main mechanism whereby statins reduced stroke events. However, LDL-C reduction could only explain between 30% and 80% of the variance of stroke risk reduction, leaving room for other additional causes. These cholesterol-independent actions may provide additional cardiovascular benefits. Thus, an array of proposed “pleiotropic” effects has been suggested.

Statins may act as a mediator of endothelium dysfunction, a mediator of inflammatory and immune response, and may also develop antithrombotic and antiproliferative actions.

Statins have a direct effect on atherosclerotic plaques. This action exceeds their effect on plaque size by the mere reduction of lipid contents [18]. Statins have been shown to increase collagen content and to reduce metalloproteinase activity, thereby counteracting factors that lead to plaque destabilization and rupture. They also reduce inflammation in human atherosclerotic plaques, with significantly fewer macrophages and T cells, and they reduce the expression, production, and circulating levels of chemokines and such proinflammatory cytokines as tumor necrosis factor alpha and interleukin-6 (IL-6). Also, treatment with statins improves endothelial dysfunction by increasing the bioavailability of nitric oxide (NO), which is responsible for the paracrine anti-atheroscleroctic functions of the endothelium [18], [19], [20].

In addition, statins appear to have important effects on thrombogenesis, reducing the expression of tissue factor production and activity, increasing the production of tissue factor package inhibitors, decreasing platelet thrombus formation, and improving fibrinolysis [21].

Finally, statins have a number of important neuroprotective properties that likely attenuate the effects of ischemia on the brain vasculature and parenchyma. Statins augment cerebral blood flow, reducing cerebral infarction size mainly through over-control of endothelial nitric oxide synthase (NOS). Moreover, they increase the expression of neurotrophic factors such as vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), amplify endogenous brain plasticity, and reduce neurological deficits [22], [23].

As a consequence of all these effects, clinical benefits are produced by multiple mechanisms. Statins reduce the risk of myocardial infarction, which is related to low ejection fraction, ventricular clots, and atrial fibrillation. Thus, statins may reduce the number of cardioembolic strokes [24], [25]. Statins may also reduce atherothrombotic strokes due to effects on atherosclerosis plaques related to carotid stenosis, aortic arch atheroma and, most likely, intracranial stenosis. Statins reduce the carotid intima media thickness (IMT). Every 10% reduction in LDL-C is estimated to reduce carotid IMT by 0.73% per year [11]. IMT is known to be a predictor of the development of carotid plaques and stenosis, and is clearly associated with stroke [11], [24], [25]. The number of lacunar strokes secondary to either carotid stenosis or cardioembolism due to CHD (and probably associated with microatheromas as well) are reduced [25]. Statins may also reduce stroke incidence by reducing blood pressure. It is well known that a 2 mmHg reduction in systolic blood pressure may account for a 15% reduction in stroke incidence [26]. However, whether or not statins may reduce high blood pressure is still controversial [24].

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4. Current recommendations for statin therapy in the prevention of stroke 

In December of 2002, the National Cholesterol Education Program (NCEP) published its third expert panel report on the detection, evaluation, and treatment of high blood cholesterol in adults (Adults Treatment Panel III (ATP III)) [27]. Since then, several large, randomly controlled trials that have been published suggest that a more aggressive approach should be taken in cholesterol therapy. Based on these trials, in July 2004 the NCEP published recommended modifications to the ATP III guidelines [28]. In February 2006, the American Heart Association/American Stroke Association Stroke Council (AHA/ASA) published its guidelines for prevention of strokes in patients with an ischemic stroke or TIA [29]. Later, in June 2006, the AHA/ASA published their guidelines for primary prevention of stroke [30]. These guidelines provide an overview of the evidence on various potential and established risk factors and represent a complete revision on this topic. They recommend that cholesterol levels in patients with cerebrovascular disease should be managed according to the NCEP III guidelines, which include lifestyle modification, following dietary guidelines, and medication recommendations.

The proposed modifications to the ATP III guidelines were based on several recent studies that suggest that moderate to high-risk patients may benefit from more aggressive drug therapy than was recommended by ATP III [31]. The suggested revisions lower the LDL-C level at which to consider drug therapy in patients with CHD or CHD risk equivalent (high-risk category with 10-year risk >20%) to greater than or equal to 100 mg/dL, with an option for drug therapy for patients with LDL-C below 100 mg/dL. The moderately high-risk group (10-year risk of 10–20%) should still consider drug therapy at LDL-C levels greater than or equal to 130 mg/dL, with an option to use drug therapy for LDL-C levels at 100–129 mg/dL. Recommendations for lower risk individuals remain unchanged (Table 2) [31].

Table 2. Recommendations of the NCEP. Treatment according to LDL-C levels. Primary prevention
Risk categoryShould consider drug therapy mg/dLLDL Cholesterol goals mg/dL
High (CHD or CHD risk equivalent; 10-year risk >20%)≥0100 (<100a)<100 (<70a)
Moderately high (+//02 risk factors; 10-year risk 10–20%))≥0130 (100–129a)<130 (<100a)
Moderate (+//02 risk factors; 10-year risk <10%)≥0160<130
Low (0–1 risk factors)≥0190 (160–189a)<160

LDL, Low-density lipoprotein; CHD, coronary heart disease.

aOptional goal.

The administration of statins is indicated in secondary stroke prevention, according to the NCEP recommendations, in the prevention of TIA and atherothrombotic stroke due to atheromatous carotid disease and in asymptomatic carotid stenosis above 50%; in TIA and stroke associated with CHD, peripheral artery disease, or diabetes mellitus; and in hypertensive patients with three or more risk factors or a 10-year coronary risk above 20%. Drug therapy should be considered in patients with an LDL-C above 100 mg/dL (optionally <100 mg/dL) with a therapeutic target below 100 mg (optionally <70 mg/dl in patients with a very high risk). Very high-risk patients are those who have established cardiovascular disease plus multiple, major risk factors (especially diabetes), severe and poorly controlled risk factors (especially continued cigarette smoking), multiple risk factors of the metabolic syndrome (especially triglycerides ≥200 mg/dL with low HDL cholesterol <40 mg/dL), and patients with acute coronary syndromes [30], [31].

AHA/ASA recommendations for the prevention of strokes in patients with an ischemic stroke or TIA are summarized in Table 3. The AHA/ASA recommendations for the prevention of recurrent strokes state that it remains uncertain whether stroke patients without CHD will benefit from statin therapy to reduce the risk of recurrent stroke, according to the HPS findings. They also state that the results from the SPARCL trial should answer the question about the efficacy of statin therapy in preventing recurrent strokes. In August 2006, the results of the SPARCL trial were published [14]. They concluded that in patients with a recent stroke or TIA and without known CHD, high doses of atorvastatin reduce the overall incidence of strokes and of cardiovascular events.

Table 3. AHA/ASA recommendations for cholesterol management for the prevention of stroke in patients with ischemic stroke or TIA
Consider statins inLDL Cholesterol goals mg/dLClass/level of evidence
IS or TIA and<100Class I, Level A
Elevated cholesterol<70a
Co-morbid CHD
Evidence of an atherosclerotic origin
IS or TIA presumed to be of atherosclerotic origin but without pre-existing indications for statins (normal cholesterol, no co-morbid CHD, or no evidence of atherosclerosis)<100Class IIa, Level B
<70a

IS, ischemic stroke; TIA, transient ischemic accident; CHD, coronary heart disease.

aFor very high-risk persons with multiple risk factors.

Despite numerous caveats, the implications of the results of the SPARCL trial may support a change in our current clinical guidelines.

Finally, the results of statin trials like the HPS have provided support for treatment strategies based on global cardiovascular risk. Both stroke and CHD share common risk factors and pathophysiologies, and CHD is a significant cause of morbidity and mortality. Thus, among patients who have had a first stroke, the risk of myocardial infarction or of a fatal cardiovascular event is high, and the relative importance of mortality due to cardiac problems increases as one survives long after a stroke [32]. Therefore, the ability to rank stroke patients based on risk of future cardiovascular events should allow more effective, targeted, and cost-effective treatment [32], [33].

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5. Statins and stroke prevention. Final pending questions 

In view of the above, we can address some final pending questions:

When should we start treatment after TIA or ischemic stroke?

As previously noted, the SPARCL trial included patients with a history of a non-disabling TIA or stroke in the preceding 1–6 months; therefore, these results may not be able to be generalized to patients presenting within the first month [14], [15]. Nevertheless, for a stroke, statin therapy is believed to be effective even earlier in the acute phase of ischemic stroke. Currently, the roles that some statins may play in the acute phase of cerebral ischemia remain to be clarified. However, very recent evidence suggests that their administration could be beneficial as well.

Animal studies have demonstrated the effects of statins on enhanced functional outcome and induction of brain plasticity when administered after a stroke by induction of angiogenesis, neurogenesis, and synaptogenesis [22], [34]. There is little clinical data in humans on this issue. Some retrospective and clinical studies have shown that patients who were on treatment with statins before or during the acute phase of an ischemic stroke experienced a better medium-term clinical evolution than control subjects; conversely, the withdrawal of these drugs in the acute phase caused a greater extension of the area of infarction and poorer functional outcome [25], [35]. Furthermore, statin use on admission to the hospital for carotid endarterectomy was associated with a lower in-hospital mortality rate and a lower in-hospital ischemic stroke or death rate [36].

In addition, statin initiation during hospitalization for ischemic stroke is associated with higher rates of adherence to treatment, lower LDL-C levels, and higher rates of achieving national cholesterol guidelines [37].

Therefore, though the development of randomized, prospective studies will be necessary to clarify the exact timing of statin administration in an acute stroke, the initiation of statin therapy during hospitalization seems reasonable.

Does statin treatment increase the risk of hemorrhagic stroke?

One ongoing concern with lipid-lowering therapy is whether it may increase the risk of hemorrhagic stroke. In the Honolulu Heart Program, there was an inverse relation between serum cholesterol and risk of intracerebral hemorrhage, with a higher incidence rate only for men with a total cholesterol level in the lowest quintile [38]. Other epidemiological studies have also shown this association [15].

In contrast, this was not observed in al long-term clinical trials that focused on this secondary endpoint [24]. A prospective meta-analysis of 14 randomized trials of statins did not show an increase in the rate of hemorrhagic stroke among patients treated with statins [11]. Nevertheless, recently, SPARCL researchers found a small increase in the incidence of hemorrhagic stroke in patients treated with atorvastatin. There were 22 more hemorrhagic strokes in patients assigned atorvastatin (55 in the atorvastatin group vs. 33 in the placebo group), with a relative risk increase of 66% (8–155%) [14].

However, the increase in hemorrhagic stroke might be a chance finding. When data from the SPARCL trial are added to those from 14 earlier trials of statins, there is no significant increase in hemorrhagic stroke in patients assigned statins compared with controls (160/47419 vs. 132/47368; RR 1.21, 0.96–1.5) [15].

Recently, a cohort study of 787,442 Koreans showed that the increased risk of hemorrhagic stroke is confined to people with low cholesterol levels and markers of high alcohol consumption [39]. Therefore, this potential risk of statin therapy should mainly be considered in patients with markers of alcohol excess (e.g, raised gamma-glutamyl transferase) or other risk factors for hemorrhagic stroke [15].

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6. Conclusions 

Early epidemiological studies found little or no association between blood cholesterol levels and stroke but were likely confounded by the inclusion of hemorrhagic as well as ischemic stroke. Later, many long-term clinical studies confirmed that statin therapy is associated with a reduced risk of strokes, even in so-called “normocholesterolemic” patients. The magnitude of the effect is large. A prospective meta-analysis in more than 90,000 individuals showed that every 10% reduction in concentration of LDL-C reduces the risk of all strokes by 15.6%.

The positive effect of statins on stroke depends mainly on LDL-C reduction, but other non-lipid mechanisms, so-called “pleiotropic” effects, such as atherosclerortic plaque stabilization, regression, anti-inflammatory and antithrombotic effects, could be involved.

Statins reduce the incidence of stroke in high-risk populations, mainly hypertensives, diabetics, and CHD patients.

Controversy has surrounded the effect of statins on stroke recurrence. However, recently, the SPARCL trial has shown that a high dose of atorvastatin reduces stroke recurrence.

Finally, the message that needs to be spread is that there is enough evidence to support the use of statin therapy in stroke prevention. Current guidelines need to be translated into clinical practice.

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7. Learning points 


•Epidemiological studies have not shown a clear association between blood cholesterol levels and stroke. However, randomized trials have confirmed that statin therapy is associated with a reduced risk of stroke.

•The positive effect of statins on stroke depends mainly on LDL reduction, but other non-lipid mechanisms, so-called “pleiotropic” effects, have been shown to play a potential role as well.

•Statins reduce the incidence of stroke in high-risk populations, mainly hypertensives, diabetics, and CHD patients.

•The SPARCL trial has shown that in patients with a recent stroke or TIA and without known CHD, high doses of atorvastatin reduce the overall incidence of strokes and cardiovascular events.

•Whether statins are beneficial in the secondary prevention of all subtypes of stroke and in all patients regardless of their pre-morbid conditions remains to be answered.

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PII: S0953-6205(07)00245-2

doi:10.1016/j.ejim.2007.05.010

European Journal of Internal Medicine
Volume 19, Issue 1 , Pages 8-14, January 2008

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