Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 2004;35:2902-2909
Published online before print October 28, 2004, doi: 10.1161/01.STR.0000147965.52712.fa
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
35/12/2902    most recent
01.STR.0000147965.52712.fav1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Amarenco, P.
Right arrow Articles by Touboul, P.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Amarenco, P.
Right arrow Articles by Touboul, P.-J.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Carotid Artery Disease
*Stroke
Related Collections
Right arrow Lipids
Right arrow Primary prevention
Right arrow Secondary prevention
Right arrow Cerebrovascular disease/stroke
Right arrow Risk Factors
Right arrow Carotid Stenosis
Right arrow Risk Factors for Stroke

(Stroke. 2004;35:2902.)
© 2004 American Heart Association, Inc.

Progress Review

Statins in Stroke Prevention and Carotid Atherosclerosis

Systematic Review and Up-to-Date Meta-Analysis

Pierre Amarenco, MD; Julien Labreuche, Bst; Philippa Lavallée, MD Pierre-Jean Touboul, MD

From the Department of Neurology and Stroke Centre, Bichat, Claude Bernard University Hospital and Medical School, Denis Diderot University, Paris VII, Assistance Publique-Hôpitaux de Paris and "Formation de Recherche en Neurologie Vasculaire (Association Claude Bernard)," Paris, France.

Correspondence to Professor Pierre Amarenco, Department of Neurology and Stroke Centre, Bichat University Hospital and Medical School, Denis Diderot University –Paris VII, 46 rue Henri Huchard, 75018 Paris, France. E-mail amarenco{at}ccr.jussieu.fr


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose— Previously published meta-analyses exploring the effect of statins on stroke incidence included 20 000 patients and found a 2% to 30% risk reduction. It is not clear whether this is attributable to low-density lipoprotein–cholesterol (LDL-C) reduction. Statin trials have now included >90 000 patients. We have determined the effect of statins and LDL-C reduction on stroke prevention

Summary of Review— We performed a systematic review and meta-analysis of all randomized trials testing statin drugs published before August 2003. The trials were identified using a computerized PubMed search. We analyzed separately statin effect on incident strokes and on carotid intima-media thickness (IMT) according to LDL-C reduction. The relative risk reduction for stroke was 21% (odds ratio [OR], 0.79 [0.73 to 0.85]), with no heterogeneity between trials. Fatal strokes were reduced but not significantly: by 9% (OR, 0.91 [0.76 to 1.10]). There was no increase in hemorrhagic strokes (OR, 0.90 [0.65 to 1.22]). Statin size effect was closely associated with LDL-C reduction. Each 10% reduction in LDL-C was estimated to reduce the risk of all strokes by 15.6% (95% CI, 6.7 to 23.6) and carotid IMT by 0.73% per year (95% CI, 0.27 to 1.19).

Conclusions— Statins may reduce the incidence of all strokes without any increase in hemorrhagic strokes, and this effect is mainly driven by the extent of between-group LDL-C reduction. Carotid IMT progression also strongly correlated with LDL-C reduction.


Key Words: cardiovascular disease • carotid arteries • intima-media thickness • risk • stroke • stroke prevention


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
In the past decade, cholesterol lowering with 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) has proved to reduce vascular events significantly in primary and secondary prevention of coronary heart disease (CHD).1,2,6–14 The unexpected finding of a reduced incidence of stroke in the 2 first major statin trials conducted in patients with known CHD1,2 has aroused considerable interest and expectations for stroke prevention in the general population and in patients with previous stroke. Three meta-analyses pooled the data of these 2 trials and other smaller previously published trials involving a total of 20 000 patients.3–5 The consistent result among these meta-analyses was a stroke risk reduction of 2% to 30%. It is not clear whether this is attributable to a reduction in low-density lipoprotein–cholesterol (LDL-C) or to other pleiotropic effects of statins.

Since then, 9 major statin trials have been published.6–14 We have thus performed an up-to-date meta-analysis involving >90 000 patients, examining the effects of statins on stroke prevention and LDL-C reduction in this population.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Objectives
Our primary aim was to investigate the effect of statins on stroke incidence and stroke mortality. The second objective was to study the specific effect of statins on the incidence of hemorrhagic stroke. We also investigated the relationship between the magnitude of LDL-C reduction and the effect of statin treatment on stroke incidence. As an ancillary analysis, we also studied the relationship between LDL-C reduction and carotid artery intima-media thickness (IMT) change expressed as percentage increase or decrease per year in IMT studies.

Literature Search
We performed a systematic review of all randomized trials testing statin drugs and previous meta-analyses published before August 2003. The trials were identified using a computerized PubMed search. The keywords used for the search were pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, HMG-CoA reductase inhibitor, statin, and cholesterol-lowering drugs. In addition, a manual search was performed using the reference lists from the trials identified.

Trial Selection
We included trials in which the patients were randomly assigned to statin or a control group (placebo or usual care treatment) and in which stroke events (brain infarction and hemorrhage) were recorded and the data were reported in intention-to-treat. Trials relating to primary or secondary prevention of CHD and trials using unifactorial or multifactorial interventions were considered eligible studies. Because it is a rather "soft" end point, we did not consider transient ischemic attacks (TIAs) as an end point in the meta-analysis. If the occurrence of stroke, hemorrhagic stroke, or LDL-C reduction was incompletely reported or not reported in the original publication, the author was contacted by mail to provide this information. Trials with no data available on the stroke end point or in which no stroke event occurred, and trials evaluating the dose-response ratio were excluded. We also excluded the KLIS trial9 from the main analysis because the randomization was unsuccessful. Abbreviations of the trials are given in the footnote to Table 1.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Characteristics of the Selected Statin Trials

For the IMT analysis, we included all statin trials with common carotid artery wall thickness measurements as an end point. For 1 trial (Asymptomatic Carotid Artery Progression Study [ACAPS]), these data were lacking, and we used the combined end point, which included the mean maximum IMT thickness in the common carotid artery, internal carotid artery, and its bifurcation. For the purpose of this analysis, we used the data from the active and placebo or usual care control groups separately (the usual care control groups in the ASAP and ARBITER trials received "standard" statin treatment). Abbreviations of the trials are given in Table 2.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Characteristics of the Selected IMT Studies

Statistical Analysis
The summary effect of statin treatment on the incidence of all strokes and fatal strokes was subsequently assessed with the fixed-effect multiple outcomes model. Because the stroke rate in all the selected trials was low, the Mantel–Haenszel method was used to calculate the pooled odds ratios (ORs). Individual ORs were estimated as the cross-product of cell counts in the corresponding 2·2 table, with the variance of log-ORs equal to the sum of the reciprocal cell counts. Eight trials with zero stroke deaths in both treatment groups were excluded for analyses of fatal stroke end point. For trials with no events in 1 group, a pseudocount of 0.25 was added to each cell for these calculations. The between-trials homogeneity of the ORs was tested with the Breslow–Day method. Sensitivity analyses were conducted, first by excluding the trials for which stroke was not a prespecified secondary end point, and second by including the KLIS trial.

The specific effect of statin treatment on the incidence of hemorrhagic stroke was also studied by the same methods. We included in this analysis all trials for which the occurrence of hemorrhagic stroke was available. To test the influence of between-group LDL-C change on stroke incidence, we used an inverse-variance–weighted linear regression on the log-OR for stroke. The relationship between LDL-C change and carotid artery IMT change expressed as percentage increase or decrease per year was investigated with linear regression weighted by the size of each group.

We assessed the evidence of bias with a funnel plot. We measured the degree of funnel plot asymmetry by the intercept from an unweighted regression of standard normal deviate (log-OR for all stroke divided by its SE against precision [inverse of SE]).

Statistical testing was conducted at the 2-tailed {alpha}-level of 0.05, except tests for the homogeneity and bias in which an {alpha}-level of 0.10 was chosen. EasyMA software was used for the meta-analysis and SAS software (version 8.12) for the regression analysis.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
We identified 26 statin trials that met all our criteria and 1 large statin trial9 with unsuccessful randomization.1,2,6–34 The characteristics of these trials are presented in Table 1.

All Strokes, Stroke Mortality, and Hemorrhagic Strokes
All Strokes
When the 26 trials included in the main analysis (Figure 1) were combined, the summary effect of statins was significant (P<0.0001), with no evidence of heterogeneity between trials (P=0.35). The relative odds reduction was –21% (95% CI, –27% to –15%). Sensitivity analyses did not change this finding. After exclusion of trials for which stroke was not a prespecified end point,18–33 the pooled OR for stroke incidence was 0.80 (95% CI, 0.74 to 0.87), and after inclusion of the KLIS trial,9 the pooled OR was 0.79 (95% CI, 0.74 to 0.86).



View larger version (20K):
[in this window]
[in a new window]
  		Figure 1. ORs for all strokes in individual trials, small trials18–28,31–34 (data combined to simplify the presentation), and all trials. *Pooled OR for all strokes in small trials18–27,30–33 calculated with the Mantel–Haenszel method.

Stroke Death
Because separate information about fatal and nonfatal stroke was not available in the ASCOT-LLA,14 AFCAPS/TexCAPS,8 and Post-CABG reports,22 these trials could not be included in this part of the meta-analysis. Eight trials with zero stroke deaths were also not included in this analysis.18,23,25,26,28,29,32,33 The pooled analysis for the remaining 15 trials showed no significant reduction in fatal strokes with statins (P=0.37) and no heterogeneity between trials (P=0.71; Figure 2). This result was not modified in the sensitivity analysis with a pooled OR of 0.94 (95% CI, 0.78 to 1.13; P=0.52).



View larger version (20K):
[in this window]
[in a new window]
  		Figure 2. ORs for fatal strokes in individual trials, small trials18–27,30–33 (data combined to simplify the pres entation), and all trials. Fatal strokes were not available in the ASCOT-LLA, AFCAPS/TexCAPS, and Post-CABG reports. *Pooled OR for fatal strokes in small trials18–27,30–33 calculated with the Mantel–Haenszel method.

Hemorrhagic Stroke
Information on the incidence of hemorrhagic stroke was available in 12 trials, representing 49 843 randomized patients (KLIS included). Four trials with zero hemorrhagic strokes were not included in this analysis.18,19,25,33 Among the remaining 8 trials, a hemorrhagic stroke occurred in 78 patients in the statin group (0.32%) and 84 patients in the control group (0.36%). As shown in Figure 3, the specific effect of statins on the incidence of hemorrhagic stroke was not significant, with a pooled OR of 0.90 (95% CI, 0.65 to 1.22). We found the same results after excluding the KLIS trial (OR, 0.91; 95% CI, 0.65 to 1.26).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 3. ORs for all hemorrhagic strokes in individual trials and all trials.

Between-Group Difference in LDL-C Reduction
Stroke
No heterogeneity of the effect of statin was detected between trials. However, the duration of treatment and the statin regimen (dosage, compound, and use of statin in the control group) differed between trials (Table 1). This probably explains the variations observed between trials in between-group LDL-C reduction (from {approx}11% to 52%; Table 1). We then studied the relationship between the size effect of statin treatment on stroke incidence and LDL-C reduction in the 26 trials included in the main analysis. As shown in Figure 4, this relation was significant (r=0.58; P=0.002). Each 10% LDL-C reduction was estimated to reduce the risk of all strokes by 15.6% (95% CI, 6.7 to 23.6). Robustness analyses were performed first by excluding small trials and the PROSPER trial because of the absence of information on between-group LDL-C reduction either at the end of the trial or throughout the entire duration of the trial,12 and second by including the KLIS trial. The correlation between-group LDL-C reduction and effect size of statin treatment remained significant (r=0.89, P=0.0001; r=0.55, P=0.003, respectively), with the same estimated stroke reduction for each 10% reduction in LDL-C (15.0% [95% CI, 9.8 to 19.9]; 13.7% [95% CI, 5.3 to 21.2], respectively).



View larger version (15K):
[in this window]
[in a new window]
  		Figure 4. Relationship between ORs for stroke events and corresponding LDL-C reduction. The regression line has been plotted and weighted for the inverse of the variance of ORs. *Size-weighted combined estimates for the small trials.18–27,30–33

Carotid IMT
We identified 9 trials that met our criteria (Table 2).24,25,27,30–32,35–40 As shown in Figure 5, there was a strong correlation between LDL reduction and carotid IMT reduction (r=0.65; P=0.004). Each 10% reduction in LDL-C was estimated to reduce the carotid IMT by 0.73% per year (95% CI, 0.27 to 1.19).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 5. Relationship between LDL-C reduction and carotid IMT change. The regression line has been plotted and weighted for the size of groups.

Assessment of Presence of Biases
Funnel plotting of the log-ORs for all strokes versus precision showed an asymmetry (Figure 6) that was confirmed by the Egger’s analysis (intercept –0.48; 90% CI, –0.89 to –0.070; P=0.056). This result suggested the presence of some biases in our meta-analysis.



View larger version (7K):
[in this window]
[in a new window]
  		Figure 6. Funnel plots of all trials. The pooled estimate of log-OR for all strokes is shown with a dotted vertical line.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
This meta-analysis of >90 000 randomized patients shows that statins significantly reduced all strokes without increasing brain hemorrhage. However, stroke death was not significantly reduced.

Statins have now been studied in 7 different populations: CHD,1,2,6,9–11 hypercholesterolemia,7,10 normocholesterolemia,8,10 the elderly,10,12 hypertensives,10,13,14 diabetics,17,41,42 and previous stroke.10,43 Stroke incidence was reduced in all of them except patients with previous stroke, for which we have very limited data, mostly from the HPS trial.10 In that trial, major vascular events (major coronary event, stroke, revascularization) were reduced by 19% in patients with previous stroke before randomization. This reduction of the composite primary end point was entirely attributable to the reduction of major coronary events and of revascularizations because there was no reduction in stroke recurrence (10.4% in each group);43 this surprising finding is possibly a result of 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 stroke events and more likely to have coronary events; thus, speculation about the lack of reduction of recurrent stroke with statins in patients treated within 4 years poststroke or TIA would be premature.

We found no increase in hemorrhagic stroke despite the fact that stroke reduction was also observed in patients with low baseline LDL-C, as shown in the HPS, LIPID, and ASCOT trials.10,14,17 Increased hemorrhagic stroke in these patients was a concern after observational cohorts showed that low cholesterol levels were associated with a greater risk of hemorrhagic stroke.44,45 A study using T2*-weighted gradient-echo brain MRI scans showed that LDL-C concentrations were significantly lower in patients with a severe degree of microbleeding.46 Low cholesterol levels are frequent in patients in poor condition such as weight loss, severe handicap, and severe and chronic illness,47 which may have constituted confounding factors for the relationship between the occurrence of a hemorrhagic stroke and low total cholesterol in observational studies.

One striking finding of the meta-analysis was that the greater the between-group difference in LDL-C reduction, the greater the reduction in stroke risk. This means that LDL-C reduction was probably the main mechanism whereby statins reduced stroke events. Indeed, in our meta-analysis, LDL-C reduction could explain between one third and 80% of the variance of stroke risk reduction, which also leaves room for possible additional pleiotropic effects. This was already apparent in the HPS trial, in which LDL-C reduction was the main explanation for stroke risk and coronary event reduction in the group receiving statin.10 The only trial in which stroke reduction did not parallel LDL-C reduction was the PROSPER trial, in which the between-group LDL-C reduction was 40 mg after 3 months.12 However, information on the between-group LDL-C difference throughout the trial or at the end of the trial has not yet been published.12 In ALLHAT and KLIS,9,13 in which the between-group LDL-C difference was 24 and 11 mg, respectively, stroke risk was not significantly reduced. All positive trials had a between-group LDL-C difference of at least 35 mg. Although statins may reduce stroke incidence by reducing blood cholesterol levels, cholesterol levels have never been clearly associated with stroke in epidemiological studies.48 However, in studies in which ischemic stroke subtypes were considered, the association was clear.44,49 In the Framingham Study, there was a positive association between carotid stenosis, hypercholesterolemia, and CHD.50 In the same epidemiological study, over a period of 34 years, moderate carotid stenosis exceeding 25% in men was associated with an increase of 20 mm Hg in systolic blood pressure (2.11 [1.51 to 2.97]), 10 mg/dL in total cholesterol level (1.10 [1.03 to 1.16]), and 5 pack years of smoking (1.08 [1.03 to 1.13]); the result was similar in women.51 These results clearly suggested that the cumulative effects of these important risk factors, including cholesterol levels, interfere with the development of carotid stenosis and further argued for a global cardiovascular risk approach on the basis of the Framingham or PROCAM score to prevent the development of atherothrombotic disease, even for carotid atherothrombosis.

However, by reducing LDL-C, statins first reduced the incidence of myocardial infarction (MI) and therefore reduced the incidence and thromboembolic complications of left ventricular (LV) mural thrombi.52 Statins may therefore simply reduce stroke incidence by reducing cardioembolic brain infarctions. In the MIRACL trial, statins were given immediately after an unstable angina or a non-Q-wave MI during a 4-month period.15 There was a significant reduction in MI and urgent rehospitalization for myocardial ischemia, as well as significant reduction in fatal and nonfatal strokes. Only 9 of the 36 strokes recorded were preceded by a nonfatal MI, with the stroke occurring between 2 and 86 days after the MI.16 This means that other mechanisms than the reduction in LV thrombus probably account for stroke prevention with statins.

It has also been suggested that statins can reduce blood pressure by 2 to 5 mm Hg,53 and it is known that a 2 mm Hg reduction in systolic blood pressure may account for a 15% reduction in stroke incidence.54 However, a careful post hoc analysis in the LIPID trial somewhat contradicted this hypothesis because the systolic and diastolic blood pressures were equal at entry and at the end of trial.17 Unlike the patients in whom statins have been shown to reduce blood pressure,53 the patients in the LIPID trial were not hypertensives at baseline. We therefore need more data on hypertensive patients, as in the ASCOT and HPS trials, to see whether statins helped to reduce high blood pressure or not. Overall, in ASCOT, there was no obvious between-group difference regarding blood pressure because it was an antihypertensive trial in which both arms were titrated to achieve blood pressure goal (<140/90 mm Hg).14 However, it is not yet known in ASCOT whether or not blood pressure decreased slightly more in patients on statins than in those on placebo.

Statins may also act on inflammation55,56 and on biological markers of plaque instability57 or the development of atherosclerosis.58–60 Statins reduced the carotid intima media thickness consistently with all statins.24,27,30,31,38–40 IMT is known to be a strong predictor of the development of carotid plaque and stenosis61 and is clearly associated with stroke and cholesterol levels. In the HPS trial, there was a significant 50% decrease in carotid endarterectomy in patients receiving simvastatin compared with those receiving the placebo (42 versus 79 patients).10 IMT regression has not yet been associated with a reduction in clinical events. In our meta-analysis, we also found a strong relationship between the magnitude of IMT reduction and the reduction in LDL-C from baseline (Figure 5). This again supports the view that the greater the LDL-C reduction, the greater the IMT and stroke risk reductions, and even if statins also have "pleiotropic" effects, their main action in stroke prevention seems to be through LDL reduction.

The strength of this meta-analysis is that it was based on >90 000 randomized patients. However, biases were probably present because there was a significant asymmetry of the funnel plot (Figure 6). Biases attributable to small trials were the most likely explanation of this asymmetry because stroke in these trials was not a primary or even a secondary end point. Despite these potential biases, sensitivity analyses confirmed our main results. The limitations of this meta-analysis are that: (1) it was not based on individual data but on available data from the literature and additional information provided by the authors; (2) some authors did not send us additional information on the incidence of hemorrhagic stroke or recurrent strokes in patients with previous stroke before randomization or stroke incidence in some other important subgroups, such as age (young versus elderly subjects), gender, and low or average LDL-C at baseline; and (3) unfortunately, very limited data on ischemic stroke subtyping precluded any meta-analysis by ischemic stroke subtype, particularly among atherothrombotic, lacunar, cryptogenetic, and cardioembolic strokes.

The remaining burning question is whether statins with an aggressive LDL-C reduction actually reduce stroke recurrence in patients with a recent previous stroke and in the different ischemic stroke subtypes. This will be addressed in future trials.62


*    Acknowledgments
 
Public, academic, and institutional funding sources were used to perform this meta-analysis (PHRC AOA98004, SOS-ATTAQUE CEREBRALE Association) and the Formation de Recherche en Neurologie Vasculaire (Association Claude Bernard).

Received June 18, 2004; revision received August 23, 2004; accepted August 31, 2004.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Scandinavian Simvastatin Survival Study (4S) Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet. 1994; 344: 1383–1389.[CrossRef][Medline] [Order article via Infotrieve]
  2. Sacks FM, Pfeffer MA, Moyé LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996; 336: 1001–1009.
  3. Blauw GJ, Lagaay AM, Smelt AHM, Westendorp RGJ. Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke. 1997; 28: 946–950.[Abstract/Free Full Text]
  4. Crouse JR III, Byington RP, Hoen HM, Furberg CD. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med. 1997; 157: 1305–1310.[Abstract]
  5. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol-lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. J Am Med Assoc. 1997; 278: 313–321.[Abstract]
  6. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339: 1349–1357.[Abstract/Free Full Text]
  7. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995; 333: 1301–1307.[Abstract/Free Full Text]
  8. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. J Am Med Assoc. 1998; 279: 1615–1622.[Abstract/Free Full Text]
  9. The Kyushu Lipid Intervention Study Group. Pravastatin use and risk of coronary events and cerebral infarction in Japanese men with moderate hypercholesterolemia. J Atheroscler Thromb. 2000; 7: 110–121.[Medline] [Order article via Infotrieve]
  10. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7–22.[CrossRef][Medline] [Order article via Infotrieve]
  11. Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, Demitriadis DS, Kontopoulos AG. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. Curr Med Res Opin. 2002; 18: 220–228.[CrossRef][Medline] [Order article via Infotrieve]
  12. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG; PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002; 360: 1623–1630.[CrossRef][Medline] [Order article via Infotrieve]
  13. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. J Am Med Assoc. 2002; 288: 2998–3007.[Abstract/Free Full Text]
  14. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003; 361: 1149–1158.[CrossRef][Medline] [Order article via Infotrieve]
  15. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL Study: a randomized controlled trial. J Am Med Assoc. 2001; 285: 1711–1718.[Abstract/Free Full Text]
  16. Waters DD, Schwartz GG, Olsson AG, Zeiher A, Oliver MF, Ganz P, Ezekowitz M, Chaitman BR, Leslie SJ, Stern T; MIRACL Study Investigators. Effects of atorvastatin on stroke in patients with unstable angina or non-Q-wave myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy. Circulation. 2002; 106: 1690–1695.[Abstract/Free Full Text]
  17. White HD, Simes RJ, Anderson NE, Hankey GJ, Watson JD, Hunt D, Colquhoun DM, Glasziou P, MacMahon S, Kirby AC, West MJ, Tonkin AM. Pravastatin therapy and the risk of stroke. N Engl J Med. 2000; 343: 317–326.[Abstract/Free Full Text]
  18. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001; 345: 1583–1592.[Abstract/Free Full Text]
  19. Herd JA, West MS, Ballantyne C, Farmer J, Gotto AM Jr. Baseline characteristics of subjects in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) with fluvastatin. Am J Cardiol. 1994; 73: 42D[CrossRef][Medline] [Order article via Infotrieve]
  20. Teo KK, Burton JR, Buller CE, Plante S, Catellier D, Tymchak W, Dzavik V, Taylor D, Yokoyama S, Montague TJ. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation. 2000; 102: 1748–1754.[Abstract/Free Full Text]
  21. GISSI Prevenzione Investigators. Results of low-dose (20 mg) pravastatin GISSI Prevenzione Trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico). Ital Heart J. 2000; 12: 810–820.
  22. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997; 336: 153–162.[Abstract/Free Full Text]
  23. Pitt B, Mancini GB, Ellis SG, Rosman HS, Park JS, McGovern ME. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC-I): reduction in atherosclerosis progression and clinical events. PLAC I investigation. J Am Coll Cardiol. 1995; 26: 1133–1139.[Abstract]
  24. Salonen R, Nyyssönen K, Porkkala E, Rummukainen J, Belder R, Park JS, Salonen JT. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary prevention trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation. 1995; 92: 1758–1764.[Abstract/Free Full Text]
  25. Jukema JW, Bruschke AVG, van Boven AJ, Reiber JH, Bal ET, Zwinderman AH, Jansen H, Boerma GJ, van Rappard FM, Lie KI. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation. 1995; 91: 2528–2540.[Abstract/Free Full Text]
  26. Waters D, Higginson L, Gladstone P, Boccuzzi SJ, Cook T, Lesperance J. Effects of cholesterol lowering on the progression of coronary atherosclerosis in women. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) substudy. Circulation. 1995; 92: 2404–2410.[Abstract/Free Full Text]
  27. Crouse JR III, Byington RP, Bond MG, Espeland MA, Craven TE, Sprinkle JW, McGovern ME, Furberg CD. Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol. 1995; 75: 455–459.[CrossRef][Medline] [Order article via Infotrieve]
  28. Weintraub WS, Boccuzzi SJ, Klein JL, Kosinski AS, King SB III, Ivanhoe R, Cedarholm JC, Stillabower ME, Talley JD, DeMaio SJ. Lack of effect of lovastatin on restenosis after coronary angioplasty. Lovastatin Restenosis Trial Study Group. N Engl J Med. 1994; 331: 1331–1337.[Abstract/Free Full Text]
  29. No author. Effect of simvastatin on coronary atheroma. Lancet. 1994; 344: 633–638.[CrossRef][Medline] [Order article via Infotrieve]
  30. Furberg CD, Adams HP, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation. 1994; 90: 1679–1688.[Abstract/Free Full Text]
  31. Adams HP, Byington RP, Hoen H, et al. Effect of cholesterol-lowering medications on progression of mild atherosclerotic lesions of the carotid arteries and on the risk of stroke. Cerebrovasc Dis. 1995; 5: 171–177.
  32. Blankenhorn DH, Azen SP, Kramsch DM, Mack WJ, Cashin-Hemphill L, Hodis HN, DeBoer LW, Mahrer PR, Masteller MJ, Vailas LI. Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). The MARS Research Group. Ann Intern Med. 1993; 119: 969–976.[Abstract/Free Full Text]
  33. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dL) plus two additional atherosclerotic risk factors. Am J Cardiol. 1993; 72: 1031–1037.[CrossRef][Medline] [Order article via Infotrieve]
  34. Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J. Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation. 2001; 103: 387–392.[Abstract/Free Full Text]
  35. Crouse JR, Byington RP, Bond MG, Espeland MA, Sprinkle JW, McGovern M, Furberg CD. Pravastatin, lipids and atherosclerosis in the carotid arteries: design features of a clinical trial with carotid atherosclerosis outcome. Control Clin Trials. 1992; 13: 495–506.[CrossRef][Medline] [Order article via Infotrieve]
  36. de Groot E, Jukema JW, Montauban van Swijndregt AD, Zwinderman AH, Ackerstaff RG, van der Steen AF, Bom N, Lie KI, Bruschke AV. B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Am Coll Cardiol. 1998; 31: 1561–1567.[Abstract/Free Full Text]
  37. Mercuri M, Bond MG, Sirtori CR, Veglia F, Crepaldi G, Feruglio FS, Descovich G, Ricci G, Rubba P, Mancini M, Gallus G, Bianchi G, D’Alo G, Ventura A. Pravastatin reduces carotid intima-media thickness progression in an asymptomatic Mediterranean population: the Carotid Atherosclerosis Italian Ultrasound Study. Am J Med. 1996; 101: 627–634.[CrossRef][Medline] [Order article via Infotrieve]
  38. MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H. Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group. Circulation. 1998; 97: 1784–1790.[Abstract/Free Full Text]
  39. Smilde TJ, van Wissen S, Wollersheim H, Kastelein JJP, Stalenhoef AFH. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomised, double-blind trial. Lancet. 2001; 357: 577–581.[CrossRef][Medline] [Order article via Infotrieve]
  40. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation. 2002; 106: 2055–2060.[Abstract/Free Full Text]
  41. Goldberg RB, Mellies MJ, Sacks FM, Moye LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation. 1998; 98: 2513–2519.[Abstract/Free Full Text]
  42. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet. 2003; 361: 2005–2016.[CrossRef][Medline] [Order article via Infotrieve]
  43. Heart Protection Study Collaborative Group. Effect of cholesterol-lowering with simvastatin and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk condiditions. Lancet. 2004; 363: 757–767.[CrossRef][Medline] [Order article via Infotrieve]
  44. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350 977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med. 1989; 320: 904–910.[Abstract]
  45. Yano K, Reed DM, McLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke. 1989; 20: 1460–1465.[Abstract/Free Full Text]
  46. Lee SH, Bae HJ, Yoon BW, Kim H, Kim DE, Roh JK. Low concentration of serum total cholesterol is associated with multifocal signal loss lesions on gradient-echo magnetic resonance imaging: analysis of risk factors for multifocal signal loss lesions. Stroke. 2002; 33: 2845–2849.[Abstract/Free Full Text]
  47. Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. 2001; 358: 351–355.[CrossRef][Medline] [Order article via Infotrieve]
  48. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts. Lancet. 1995; 346: 1647–1653.[CrossRef][Medline] [Order article via Infotrieve]
  49. Lindenstrøm, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. BMJ. 1994; 309: 11–15.[Abstract/Free Full Text]
  50. Wolf PA, D’Agostino RB. Epidemiology of stroke. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM, eds. Stroke: Pathophysiology, Diagnosis, and Management. 3rd ed. New York, NY: Churchill Livingstone; 1998: 3–28.
  51. Wilson PW, Hoeg JM, D’Agostino RB, Silbershatz H, Belanger AM, Poehlmann H, O’Leary D, Wolf PA. Cumulative effects of high cholesterol levels, high blood pressure, and cigarette smoking on carotid stenosis. N Engl J Med. 1997; 337: 516–522.[Abstract/Free Full Text]
  52. Amarenco P. Hypercholesterolemia, lipid-lowering agents, and the risk for brain infarction. Neurology. 2001; 57 (suppl 2): S35–S44.[Abstract/Free Full Text]
  53. Glorioso N, Troffa C, Filigheddu F, Dettori F, Soro A, Parpaglia PP, Collatina S, Pahor M. Effect of the HMG-CoA reductase inhibitors on the blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension. 1999; 34: 1281–1286.[Abstract/Free Full Text]
  54. Cook NR, Cohen J, Hebert PR, Taylor JO, Hennekens CH. Implications of small reductions in diastolic blood pressure for primary prevention. Arch Intern Med. 1995; 155: 701–709.[Abstract]
  55. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998; 98: 839–844.[Abstract/Free Full Text]
  56. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr; Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001; 344: 1959–1965.[Abstract/Free Full Text]
  57. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001; 103: 926–933.[Abstract/Free Full Text]
  58. Levine GN, Keaney JF Jr, Vita JA. Cholesterol reduction in cardiovascular disease: clinical benefits and possible mechanisms. N Engl J Med. 1995; 332: 512–521.[Free Full Text]
  59. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. J Am Med Assoc. 1998; 279: 1643–1650.[Abstract/Free Full Text]
  60. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001; 21: 1712–1719.[Abstract/Free Full Text]
  61. Zureik M, Touboul PJ, Bonithon-Kopp C, Courbon D, Berr C, Leroux C, Ducimetiere P. Cross-sectional and 4-year longitudinal associations between brachial pulse pressure and common carotid intima-media thickness in a general population. The EVA study. Stroke. 1999; 30: 550–555.[Abstract/Free Full Text]
  62. The SPARCL Investigators. Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL). Cerebrovasc Dis. 2003; 16: 389–395.[CrossRef][Medline] [Order article via Infotrieve]



This article has been cited by other articles:


Home page
 Therapeutic Advances in Cardiovascular DiseaseHome page
P. Talelli and R. J. Greenwood
Review: Recurrent stroke: where do we stand with the secondary prevention of noncardioembolic ischaemic strokes?
Therapeutic Advances in Cardiovascular Disease, October 1, 2008; 2(5): 387 - 405.
[Abstract] [PDF]

Home page
 NeurologyHome page
L. B. Goldstein, P. Amarenco, M. Szarek, A. Callahan III, M. Hennerici, H. Sillesen, J. A. Zivin, K.M.A. Welch, and On behalf of the SPARCL Investigators
Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study
Neurology, June 10, 2008; 70(24_Part_2): 2364 - 2370.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
M. J. Reeves, J. W. Gargano, Z. Luo, A. J. Mullard, B. S. Jacobs, A. Majid, and for the Paul Coverdell National Acute Stroke Regis
Effect of Pretreatment With Statins on Ischemic Stroke Outcomes
Stroke, June 1, 2008; 39(6): 1779 - 1785.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
J. J.P. Kastelein, F. Akdim, E. S.G. Stroes, A. H. Zwinderman, M. L. Bots, A. F.H. Stalenhoef, F. L.J. Visseren, E. J.G. Sijbrands, M. D. Trip, E. A. Stein, et al.
Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia
N. Engl. J. Med., April 3, 2008; 358(14): 1431 - 1443.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
E. I. Levy, J. Mocco, R. M. Samuelson, R. D. Ecker, B. S. Jahromi, and L. N. Hopkins
Optimal treatment of carotid artery disease.
J. Am. Coll. Cardiol., March 11, 2008; 51(10): 979 - 985.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
A. Nassief and J. D. Marsh
Statin Therapy for Stroke Prevention
Stroke, March 1, 2008; 39(3): 1042 - 1048.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
M. D.I. Vergouwen, R. J. de Haan, M. Vermeulen, and Y. B.W.E.M. Roos
Statin Treatment and the Occurrence of Hemorrhagic Stroke in Patients With a History of Cerebrovascular Disease
Stroke, February 1, 2008; 39(2): 497 - 502.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
J. I. Keddissi, W. G. Younis, E. A. Chbeir, N. N. Daher, T. A. Dernaika, and G. T. Kinasewitz
The Use of Statins and Lung Function in Current and Former Smokers
Chest, December 1, 2007; 132(6): 1764 - 1771.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
P. Amarenco, L. B. Goldstein, M. Szarek, H. Sillesen, A. E. Rudolph, A. Callahan III, M. Hennerici, L. Simunovic, J. A. Zivin, K. M. A. Welch, et al.
Effects of Intense Low-Density Lipoprotein Cholesterol Reduction in Patients With Stroke or Transient Ischemic Attack: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial
Stroke, December 1, 2007; 38(12): 3198 - 3204.
[Abstract] [Full Text] [PDF]